Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
Pharmaceutical compositions comprising desglymidodrine as an active drug
substance
Introduction
The present invention relates to novel pharmaceutical compositions comprising
desglymidodrine or a pharmaceutically acceptable salt thereof as an active
drug
substance. Desglymidodrine is the active metabolite of the prodrug midodrine.
The
pharmaceutical composition may be presented in a suitable dosage form for
oral,
parenteral, mucosal, nasal, sublingual, buccal, topical, vaginal, rectalor
ocular etc.
administration. A pharmaceutical composition of the invention may be in the
form of an
immediate and/or modified release composition or it may be designed to release
the
active drug substance, desglymidodrine, in a relatively fast manner in order
to enable a
relatively fast onset of the therapeutic effect.
A pharmaceutical composition according to the invention has a suitable shelf-
life, i.e. the
desglymidodrine contained in the composition is not subject to a significant
degradation
under storage conditions normally acceptable for pharmaceuticals.
The invention also relates to a method for treating animals such as, e.g.
mammals and
humans with a novel pharmaceutical composition comprising desglymidodrine.
Furthermore, the invention relates to a novel use of desglymidodrine in the
treatment of
septic shock and to a method for treating mammals (e.g. humans) suffering from
septic
shock with a sufficient amount of desglymidodrine.
Desglymidodrine is the active metabolite of midodrine, i.e upon administration
of
midodrine to a patient, midodrine is (enzymatically) metabolised to
desglymidodrine. The
indications of desglymidodrine are therefore similar to the indications of
midodrine, but as
will be explained below desglymidodrine may also be used for novel
indications.
The indications of desglymidodrine include symptomatic orthostatic
hypotension, syncope,
orthostatic intolerance, symptomatic hypotension (e.g. hypotension associated
with
infections, the convalescent period, surgical operations, delivery, changes in
the weather
as well as what is called "difficulties in getting started in the mornings"),
as well as in the
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
2
control of hypotensive side effects of hypnotics and psychotropics.
Furthermore,
desglymidodrine is expected to be effective in the treatment of urinary
incontinence. Many
of these indications call for a very individual treatment regimen where a
basic "all day"
treatment supplied with one or more fast onset formulations are very
beneficial.
In another aspect, the invention relates to a method for treating hypotension
and/or
urinary incontinence, the method comprising administration to a patient in
need thereof of
an effective amount of desglymidodrine in a pharmaceutical composition
according to the
invention. An interesting pharmaceutical composition according to the
invention for this
use is a controlled release composition, optionally together with one or more
fast onset
compositions comprising an effective amount of desglymidodrine.
Background of the invention
Desglymidodrine is the active form of the prodrug midodrine. Desglymidodrine
is a potent
adrenergic agonist at the alpha-1 receptors that are mainly localised in
resistance and
capacitance vessels and in the bladder neck. The effect when given to patients
suffering
from orthostatic hypotension is an increase in blood pressure and when given
to patients
suffering from stress incontinence and improvement of continence. Clinical
trials of the
latter effect have up till now yielded conflicting results.
During development of the compound in the sixties and seventies focus was put
on
midodrine probably in order to secure a relative long lasting effect when
administered
orally. New formulation techniques and the search for new indications have
turned the
inventor's focus to desglymidodrine again.
Disclosure of the invention
As the active metabolite of midodrine, desglymidodrine is a potent drug
substance.
However, in the past decades focus has been directed to the development of
suitable
midodrine compositions most likely due to the detailed knowledge of the
behaviour of
midodrine in clinical studies. However, the need for optimising the treatment
of conditions
responsive to midodrine has turned the inventors' focus on desglymidodrine. By
administering pharmaceutical compositions comprising desglymidodrine, the
conversion
step in vivo from the inactive form, midodrine, to the active form,
desglymidodrine, is
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
3
omitted and, thus, it is anticipated that treatment with desglymidodrine can
lead to a fast
onset of the therapeutic effect. Furthermore, individual variations with
respect to the
enzymatic conversion of midodrine to desglymidodrine are of no importance when
the
treatment is performed with desglymidodrine. Thus, there is a need for the
development of
suitable pharmaceutical compositions of desglymidodrine for use in the
treatment of
conditions for which midodrine is indicated. Such compositions provide
attractive
alternatives or supplements to the treatment of diseases or conditions with a
drug
substance that acts by stimulating a~ receptors.
Midodrine is a prodrug, which is activated within the human body by an
enzymatic
hydrolysis to release the therapeutically active metabolite desglymidodrine.
Only very little
information is available from the literature concerning desglymidodrine.
The following is a review of the pharmacokinetics of desglymidodrine as parent
compound.
Clinical studies
The pharmacokinetics of midodrine and desglymidodrine after administration of
midodrine
have been described by Grobecker (Grobecker HF, ICees F. Pharmacokinetic
parameters
and haemodynamic actions of midodrine in young volunteers. Int Angiol 1993;
12(2):119-
124).
In a Japanese study (Tsutsui S, et al. Pharmacokinetics of midodrine -
Bioavailability of
midodrine. The clinical report 1987; 21, No.4:1759-1807) the pharmacokinetics
of
midodrine and desglymidodrine given as prodrug and as parent compound,
respectively,
was investigated in five healthy volunteers. It was found that the
bioavailabily of
desglymidodrine was slightly lower when given as parent compound as compared
to
when given as prodrug. Tmax (time to maximum plasma concentration) for
midodrine,
desglymidodrine as prodrug and as parent compound, respectively, are given in
Table 1
with the results of Grobecker as comparison:
Table 1
study administered Tmax (h.)
drug
midodrine desglymidodrine
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
4
Tsutsui midodrine ~ 1.4 0.2 2.0 0.0
Tsutsui desglymidodrine 1.2 0.2
Grobecker midodrine 0.5 0.2 1.1 0.5
Pharmacokinetic data (Tmax) of midodrine and desglymidodrine in two studies
Tsutsui (n=5) and
Grobecker (n=12).
In a pharmacodynamic study (Pittner H. Double-blind trial to compare the
effect of
midodrine and ST 1059 after oral aministration to volunteers. internal report:
DFP 1979) of
midodrine, desglymidodrine as parent compound and placebo in seven healthy
volunteers, the action of desglymidodrine measured as time to occurrence of
pilomotor
reaction was shorter; 34~25 min for the parent compound as compared to the
prodrug
74~29 min. There was a tendency to a surprisingly longer lasting effect of the
parent
compound, 160 (135-185) min versus 150 (30-240) min for midodrine.
Engel (Engel K, Havelec L, Klausgraber F, Pramer I. Comparative studies and
evaluation
of the therapeutic usability of midodrine (Gutron) in the hypotension
syndrome. IlViener
medizinische IlVochenschrift 1974; 124:501-507) has summarised different
studies. One
of them is a study where it was shown that intravenous injection of 5 mg of
desglymidodrine is as potent as 20-25 mg midodrine intravenously with respect
to
increase of blood pressure. However, the effect of desglymidodrine lasted only
3-4 min.
Only very preliminary conclusions, if any, can be drawn from the above-
mentioned
studies regarding desglymidodrine. The bioavailability is lower when it is
given as parent
compound probably due to intraluminal degradation. The time to effect is
shorter and the
effect is lasting shorter with respect to blood pressure effect, but no
difference with
respect to pilomotor reaction has been observed. Further studies are needed to
characterise the pharmacokinetic of desglymidodrine given as parent compound.
Clinical indications
The short period of the effect makes desglymidodrine attractive as a quick
acting
medication in patients with autonomic dysregulation including orthostatic
hypotension. A
combination with desglymidodrine (or midodrine) in a controlled release
formulation would
yield an opportunity to create a medication with fast and long lasting effect.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
Desglymidodrine acts by a stimulation of a~ receptors. The prodrug of
desglymidodrine,
midodrine is used in the treatment of symptomatic orthostatic hypotension.
Disorders
causing orthostatic hypotension are e.g.,
5 Generalized primary autonomic failure
Pure autonomic failure or idiopathic orthostatic hypotension (Bradbury-
Eggleston
syndrome)
Pure autonomic failure with multiple-system atrophy or Shy-Drager syndrome
Acute pandysautonomia (panautonomic neuropathy)
~ Familial dysautonomia (Riley-Day syndrome)
Partial primary autonomic failure
Dopamine ~i-hydroxylase deficiency
Postural orthostatic tachycardia syndrome (length-dependent autonomic
neuropathy)
Monoamine oxidase deficiency
Pure vasomotor failure
Disorders
of
idiopathic
orthostatic
intolerance
~ Postural orthostatic tachycardia
syndrome
Mitral valve prolapse
Due to prolonged bed rest
or space flight
Due to asthenic habitus
Disorders
of
the
central
nervous
system
Tumors (hypothalamic, parasellar,
posterior fossa)
Multiple cerebral infarcts
Wernicke's encephalopathy
Tabes dorsalis
Traumatic and inflammatory myelopathies
~
Parkinson's disease
Hereditary system degenerations
Syringomyelia
Dysautonomia of advanced age
Multiple sclerosis
~
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
6
Systemic
diseases
with
autonomic
neuropathy
Botulism
Diabetic neuropathy
~ Primary systemic amyloidosis
Guillain-Barre syndrome
Porphyria
Lambert-Eaton myasthenic syndrome
Paraneoplastic autonomic neuropathy
~ Uremic neuropathy
i; Connective tissue disease
Tangier and Fabry's diseases
Vincristine and heavy metal
neuropathies
Leprosy
~ B~z deficiency
Chronic Chagas' disease
Propafenone neuropathy
Endorcine-metabolic disorders
~ Primary and secondary adrenocortical insufficiency
Pheochromocytoma
Marked potassium depletion
Severe hypoaldosteronism
latrogenic causes
Antihypertensive drugs (a-methyldopa, guanethidine, prazosin, ~i-blockers)
Psychotropic drugs (phenothiazines, butyrophenones)
Antiparkinsonian drugs (Sinemet, Parlodel)
Vasodilator drugs (nitrates)
~ Certain illicit drugs (marijuana)
Thoracolumbar sympathectomy
Disorders with diminished cardiac output
Reduced intravascular volume
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
7
Acute and chronic blood loss
i; Fluid loss due to vomiting,
diarrhea, diuretics
Gastrectomy with the dumping
syndrome
i; Salt-losing nephropathy
~ Altered capillary permeability
Impaired venous return
Severe varicose veins
Venous obstruction (late pregnancy)
Reflex and pharmacologic vasodilatation
~ Muscle wasting and prolonged
recumbency
Intrinsic cardiac disease
Myocardial infarct
Arrhythmias
Restrictive pericardial/myocardial
diseases
Miscellaneous
causes
Hyperbradykinnism
Chronic renal hemodialysis
Anorexia nervosa
~ Reduced aortic compliance
Mastocytosis
Baroreflex failure
Furthermore, midodrine may be used in disorders retrograde ejaculation;
disorder of
semen ejaculation, or to attenuate symptoms of chronic orthostatic hypotension
due to
autonomic failure in patients with Bradbury-Eggleston, Shy-Drager syndromes,
diabetes
mellitus disease and Parkinson's disease.
The prodrug of desglymidodrine, midodrine, is approved in a variety of
European and
overseas countries including the U.S.A. mainly for the treatment of
symptomatic
orthostatic hypotension.
FDA has recommended a dosing of midodrine of up to 10 mg 3 times daily for the
treatment of hypotension. According to FDA, the latest dose must not be given
later than
6 pm for safety reasons in order to avoid or reduce the risk of supine
hypertension. Other
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
8
countries recommend that the latest dose must not be given later than 4 hours
before
bedtime.
Midodrine for use in stress urinary incontinence is a very promising use with
a
tremendous market potential also due to the ageing population. Current
conservative
therapeutic approaches are a-sympathomimetics, pelvic floor exercises and
estrogens, or
surgery, which are rather complementary than competitive.
It is contemplated that desglymidodrine is effective as a drug substance in
the treatment
of the above-metioned conditions. Furthermore, a completely novel indication
for
desglymidodrine is described in the following.
Novel therapeutic indication
Septic shock is a condition in which bacteremia produces changes in the
circulation
resulting in critically reduced tissue perfusion. Acute circulatory failure,
hypotension and
multiorgan failure are characteristic. The pathogenesis is not fully
understood but bacterial
infection with release of toxins initiate a vicious circle of reactions
resulting in
vasodilatation and organ hypoperfusion. The cornerstone of the treatment is
antibiotics
and circulatory support is mandatory to secure organ perfusion. Typically the
circulatory
disorders are treated with vasopressors initially dopamine followed by
addition of
norephinephrine and eventually epinephrine.
Norephinephrine has alfa adrenergic and slight beta adrenergic action whereas
desglymidodrine only has alpha adrenergic action. Furthermore desglymidodrine
does not
cross the blood brain barrier in contrast to norepinephrine.
The lack of beta adrenergic action meaning that desglymidodrine has no effect
on the
heart and the lack of central nervous system stimulation makes desglymidodrine
an
attractive substitute for norepinephrine in the treatment of septic shock as
these actions
are unwanted.
Active drug substances
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
9
A pharmaceutical composition according to the invention contains
desglymidodrine or a
pharmaceutically acceptable salt thereof. From a clinical point of view it may
in some
cases be advantageous to include midodrine or a pharmaceutically acceptable
salt
thereof in the composition in order to take advantage of the different
pharmacokinetic of
the two different substances. As mentioned in the following, the invention
also relates to a
kit comprising two different compositions, one of the compositions being a
composition as
described above.
Although the present invention is focused on the use of desglymidodrine, there
are cases
- as mentioned above - where the concomittant use of midodrine or a midodrine
containing composition is relevant. Therefore, in the following is given a
description of
desglymidodrine as well as midodrine.
With respect to treatment of orthostatic hypotension and the other conditions
mentioned
above, desglymidodrine or its prodrug midodrine are drugs of choice.
Desglymidodrine as well as midodrine exist in racemic form and in the form of
the two
enantiomeric species.
Desglymidodrine is also known as ST 1059, alpha-(aminomethyl)-2,5-dimethoxy-
benzenemethanol. It may be present in racemic form, i.e. as (~)-
desglymidodrine, (~)-
ST1059 or (~)-alpha-(aminomethyl)-2,5-dimethoxy-benzenemethanol, or in its
enantiomeric form as (-)-desglymidodrine, (R)-desglymidodrine, (-)-ST1059, (R)-
ST1059,
(-)-alpha-(aminomethyl)-2,5-dimethoxy-benzenemethanol or (R)-alpha-
(aminomethyl)-2,5-
dimethoxy-benzenemethanol, or in its other enatiomeric form (+)-
desglymidodrine, (S)-
desglymidodrine, (+)-ST1059, (S)-ST1059, (+)-alpha-(aminomethyl)-2,5-dimethoxy-
benzenemethanol or (S)-alpha-(aminomethyl)-2,5-dimethoxy-benzenemethanol.
A composition according to the invention may therefore include desglymidodrine
in the
racemic form (RS), in the enantiomeric form (R), in the enantiomeric form (S)
or in
mixtures thereof.
In an embodiment according to the invention, a composition contains the active
metabolite desglymidodrine (ST 1059), and desglymidodrine is present in the
form of (~)-
a-(aminomethyl)-2,5-dimethoxy-benzenemethanol (~ ST 1059), (+)-a-(aminomethyl)-
2,5-
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
dimethoxy-benzenemethanol (+ ST 1059), (-)-a-(aminomethyl)-2,5-dimethoxy-
benzenemethanol (- ST 1059) or mixtures thereof.
In another embodiment a composition according to the invention contains
5 desglymidodrine in the racemic form (RS), in the enantiomeric form (R), in
the
enantiomeric form (S) or in mixtures thereof, or it contains at least 90% wlw
such as, e.g.,
at least 95% w/w, at least 97% w/w, at least 98% w/w, at least 99% w/w of
desglymidodrine is present in the therapeutically active enantiomeric form.
The
therapeutically active enantiomeric form of desglymidodrine is contemplated to
be (-)-a-
10 (aminomethyl)-2,5-dimethoxy-benzenemethanol (- ST 1059) or the (R) form of
desglymidodrine ((R) ST 1059).
Midodrine is also known as ST 1085, or 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-
hydroxyethyl]-acetamide. It may be in present in racemic form, i.e. as (~)-
midodrine, (~)-
ST 1085, or (~)-2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-acetamide,
(~)-2-
amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-acetamide, or in its
enatiomeric form
as (-)-midodrine, (R)-midodrine, (-)-ST 1085, (R)-ST 1085, (-)- 2-amino-N-[2-
(2,5-
dimethoxyphenyl)-2-hydroxyethyl]-acetamide or (R)- 2-amino-N-[2-(2,5-
dimethoxyphenyl)-
2-hydroxyethyl]-acetamide, or in its other enantiomeric form (+)-midodrine or
(S)-
midodrine, (+)-ST 1085, or (S)-ST 1085, (+)- 2-amino-N-[2-(2,5-
dimethoxyphenyl)-2-
hydroxyethyl]-acetamide or (S)- 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-
hydroxyethyl]-
acetamide.
In an embodiment, the invention relates to a pharmaceutical kit comprising two
different
pharmaceutical compositions and one of the compositions is a controlled
release
composition. In such a kit, one of the compositions may contain midodrine as
the active
substance and the other may contain desglymidodrine.
In a composition according to the invention desglymidodrine (and whenever
relevant
midodrine) is present in the form of a pharmaceutically acceptable salt such
as a salt
formed between desglymidodrine (and whenever relevant midodrine) and an
inorganic
acid such as e.g., a hydrochloride, a hydrobromide, a hydroiodide, a nitrate,
a nitrite, a
H3P03 salt, a H3P04 salt, a HZS03 salt, a sulfate, a H2S05 salt, or a salt
formed between
desglymidodrine (and whenever relevant midodrine) and an organic acid such as
organic
acids like e.g. H2C03, acetic acid, CZHSCOOH, C3H~COOH, C4H9COOH, (COOH)2,
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
11
CH~(COOH)2, C2H5(COOH)2, C3H6(COOH)2, C4H$(COOH)2, CSH~o(COOH)~, fumaric acid,
malefic acid, lactic acid, tartaric acid, citric acid, ascorbic acid, benzoic
acid, salicylic acid
and phthalic acid.
A composition according to the invention may comprise a further active drug
substance,
i.e. the composition may be in the form of a so-called combination composition
comprising
at least two different active drug substances. The further active drug
substance may be
any active drug substance, which beneficially is used in combination with
desglymidodrine. Interesting examples of further active drug substances are
midodrine,
steroids like e.g. hydrocortisone or fludrocortisone or somatostin analogoues
like e.g.
octreotide.
Dosage
In general, the dosage of the active drug substance present in a composition
according to
the invention depends inter alia on the specific drug substance, the age and
condition of
the patient and of the disease to be treated.
In general, a composition according to the invention is designed for
administration 1-6
times daily. The dosage frequency depends on the specific condition to be
treated and on
the specific composition used. For example, a nasal composition may be
administered
only once daily e.g. in order to achieve a relatively fast onset of the
therapeutic effect or it
may be administered more often in order to treat break-through symptoms. The
same
applies to e.g. a plain tablet composition, a buccal composition, a rectal
composition etc.
A controlled release composition according to the present invention aims at a
dosage
once, twice or three times daily, preferably once or twice daily. In the
present context the
term "once daily"/"once-a-day" is intended to mean that it is only necessary
to administer
the pharmaceutical composition once a day in order to obtain a suitable
therapeutic
and/or prophylactic response; however, any administration may comprise co-
administration of more than one dosage unit, such as, e.g. 2-4 dosage units.
In agreement with the above-mentioned definition of "once daily"/"once-a-day",
"twice
daily"/"twice-a-day" is supposed to mean that it is only necessary to
administer the
controlled release composition at the most twice a day in order to obtain a
suitable
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
12
therapeutic and/or prophylactic response in the patient which can form a basis
for an
individual supply with the relatively fast onset composition.
irrespective of the above-mentioned definitiones of "once" and "twice" daily,
a dosage
unit, which is constructed to deliver the active ingredient after only one
daily
administration is often preferred by the patient. However, due to individual
circumstances
some patients may need a new dosage after e.g. 7-18 hours such as, e.g. about
7-8
hours or about 12 or about 18 hours if the patient e.g. has abnormal
absorption or bowel
transit time. If the individual has a relatively fast bowel transit time, some
of the active
drug substance may be excreted before the full dosage is released.
Controlled release compositions designed for topical (e.g. transdermal
delivery systems),
ocular (e.g. ocular delivery systems) or parenteral (e.g. parenteral delivery
systems like
implants) delivery of desglymidodrine generally aim at less frequent dosage.
Thus, a
dosage frequency corresponding to 1-2 times a week or 1-2 times a month is
often
considered appropriate for such delivery systems.
With respect to desglymidodrine, the normal daily dose is from 2.5 to 10 mg
three or up to
four times daily (calculated as desglymidodrine hydrochloride), i.e. a daily
dose of from
about 7.5 mg to about 40 mg in the treatment of orthostatic hypertension.
However, the
daily dose in the treatment of urinary incontinence may be different and,
accordingly, a
composition according to the present invention typically contains from about
2.5mg to
about 50 mg desglymidodrine such as, e.g. 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5
mg, 15
mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg. The same
applies in
general in connection with the treatment of septic shock, where it is
anticipated that the
dosis range of desglymidodrine is 25-250 pg/kg body weight/min when given as a
continuous infusion. The treatment of septic shock is adjusted according to
individual
susceptibility to desglymidodrine with respect to blood pressure.
In cases, where desglymidodrine is employed in another form, e.g. in another
salt form
than desglymidodrine hydrochloride, the above-mentioned dosage ranges are of
course
to be recalculated so that the same dosage is employed on a molar basis.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
13
The total daily doses of desglymidodrine will depend on the indication for the
treatment
and the individually tolerated doses. The composition or the kit of the
present invention
provides a possibility of a treatment regimen adapted for the specific
patient.
The individual fast onset doses of a composition of the invention may be from
0.2 mg to
mg, preferreably from 0.5 mg to 7.5 mg such as of 0.75 mg, 1 mg, 1.25 mg, 1.5
mg, 2
mg, 2.5 mg, 3 mg, 4 mg, or 5 mg.
As discussed above, desglymidodrine may be present as the racemic form or in
one of its
10 enantiomeric forms, preferably the therapeutically active enantiomeric
form. In those
cases where desglymidodrine is present in its therapeutically active
enantiomeric form a
reduction in the above-mentioned dosage ranges may be relevant.
With respect to the dosage in those cases where midodrine also is employed it
is
envisaged that the same dosages as mentioned above are relevant. Thus when
both
midodrine and desglymidodrine are employed either in combination or in a kit
according to
the invention, then the total dose of desglymidodrine and midodrine is
contemplated to be
in the above-mentioned dosage ranges on a molecular basis.
Pharmaceutical compositions
A pharmaceutical composition of the invention comprises desglymidodrine or a
pharmaceutically acceptable salt thereof together with one or more
pharmaceutically
acceptable excipients.
A composition according to the invention may be in the form of a solid, semi-
solid or fluid
composition. Examples of solid compositions are e.g. tablets such as, e.g,
conventional
tablets, effervescent tablets, melt tablets, coated tablets (e.g. film coated,
enteric coated,
controlled release coated), sublingual tablets, buccal tablets, capsules,
sachets, powders,
granules, pellets, microcapsules, microspheres, nanoparticles etc. Examples of
semi-solid
compositions are e.g. ointments, creams, liniments, chewing gums, hydrogels,
pastes,
suppositories, enemas, etc. Examples of fluid and/or liquid compositions are
e.g. drops,
dispersions, solutions, emulsions, suspensions, liposomes, sprays, mixtures,
syrups, gels,
hydrogels, aerosols. A composition according to the invention may be suitable
for
administration via the oral, peroral, buccal, sublingual, rectal, vaginal,
nasal, ocular,
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
14
topical and parenteral route. Examples on suitable compositions are also e.g.
nasal
compositions such as, e.g. nasal spray or nasal powder compositions,
compositions for
pulmonary administration such as, e.g. inhalators, chewing compositions such
as, e.g.,
chewing gum, etc. Especially suited compositions for a fast onset are
compositions in fluid
form and in the form of nasal compositions as well as quick release tablets.
Especially
suited compositions for controlled or modified release of desglymidodrine are
controlled
release pellets, controlled release tablets, controlled release granules,
controlled release
capsules, transdermal delivery systems (e.g. patches, plasters), ocular
delivery systems
(e.g. lenses), parenteral delivery systems (e.g. implants, oil-based
compositions) and
bioadhesive delivery systems (e.g. for oral, buccal or topical use). The
controlled release
of desglymidodrine may be obtained by employment of various controlled release
techniques such as, e.g. matrix tablets, application of controlled release
coatings) etc.
In an embodiment of the invention, the composition is in the form of tablets
having a
disintegration time of of the most about 2.5 min such as, e.g at the most
about 30 sec, at
the most about 45 sec, at the most about 1 min, at the most about 1.5 min or
at the most
about 2 min.
Generally, a composition of the invention has a shelf-life at room temperature
of at least 6
months such as, e.g. at least 1 year, at least 1.5 years, at least 2 years, at
least 2, 5
years, 3 years, 4 years or 5 years. Shelf life is defined as the time period
in which a
change in the content of desglymidodrine in the composition is at the most
~10% w/w
such as, e.g., at the most ~7.5% w/w or ~5% w/w; in the present context the
shelf-life is
determined under conditions of room temperature, 25 °C and a relative
humidity of 60%.
The compositions of the invention are thus stable, i.e. no significant
degradation of
desglymidodrine is observed during normal storage conditions.
Plain compositions
In the embodiments of the invention in which the composition is not
specifically designed
to release desglymidodrine in a controlled manner, the release kinetics of
desglymidodrine from the composition corresponds to that of a plain release
tablet. The
release kinetic of desglymidodrine from such compositions corresponding to a
zero or a
first order release, a mixture of zero and first order release, or any other
order of release
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
such as, e.g. 1 ~h, second, third or fourth order release (the same applies
also to controlled
release compositions of the invention).
The invention also relates to a pharmaceutical composition comprising
desglymidodrine
5 (ST 1059) or a pharmaceutically acceptable salt thereof, the composition
being adapted
to provide desglymidodrine in such a manner that a relatively fast
therapeutically effective
concentration of desglymidodrine is obtained after administration of the
composition.
Accordingly, a composition of the invention may be adapted to release
desglymidodrine in
10 such a manner that a relatively fast therapeutic effective concentration of
desglymidodrine
is obtained after administration of the composition e.g. to obtain an onset of
action at the
most 15 min after administration such as, e.g. at the most about 1 min, at the
most about
2 min, at the most about 3 min, at the most about 4 min, at the most about 5
min, at the
most about 7.5 min, at the most about 10 min or at the most about 12.5 min
after
15 administration.
Alternatively, a composition of the invention may be designed in such a manner
that a
therapeutically effective concentration is obtained within 90 min such as,
e.g. within 60
min, within 45 min, within 30 min, within 20 min, within 15 min, within 10
min, within 5 min
from administration of the composition.
For such compositions (i.e. not controlled release compositions) a relatively
fast peale
plasma concentration of desglymidodrine is obtained about 1 min - 6 hours such
as, e.g.
about 5 min - 6 hours, about 10 min - 5 hours, about 15 min - 5 hours, about
0.5-6
hours, about 1-6 hours, about 2-5.5 hours, or about 2.5-5.2 hours after
administration.
Controlled release compositions
In a further aspect, the invention relates to a controlled release
pharmaceutical
composition comprising desglymidodrine. The controlled composition may be
designed for
administration via the oral, parenteral, topical, buccal, vaginal, ocular etc.
route.
A controlled release pharmaceutical composition of desglymidodrine according
to the
invention may also be designed for administration once, twice or three times
daily,
preferably once or twice daily, i.e. a therapeutically effective concentration
of
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
16
desglymidodrine is maintained for a period of at least 6 hours such as, e.g.
at least 7
hours, at least 8 hours, at least 9 hours or at least about 10-16 hours
followed by a wash
out period of about 8-12 hours in order to avoid side effect with respect to
supine
hypertension. Such side effects are well known after administration of
midodrine.
A controlled release composition provides a base line plasma concentration,
which during
most of the day is therapeutically effective. When a higher concentration is
needed, only a
minor supply of active drug substance is necessary to obtain a very fast
relief from
symptoms. If the base line plasma concentration is absent, it would be
necessary to use a
relative higher fast onset dose to reach the high therapeutically effective
level. The high
therapeutically effective level may be due to individual circumstances in the
patient or may
be a consequence of physical routines and/or the nature of the underlying
disease. The
situations and symptoms are often well recognized and experienced by the
patient
himself. The composition according to the present invention is a superior tool
for obtaining
an optimal treatment with a minimum of active drug substance.
In the present context a therapeutically effective concentration of
desglymidodrine is
defined as a plasma concentration of desglymidodrine of at least about 3 ng/ml
such as,
e.g. at least about 3.2 ng/ml, at least about 3.5 ng/ml, at least about 3.7
ng/ml, at least
about 4.0 ng/ml, at least about 4.2 ng/ml, at least about 4.5 ng/ml, at least
about 4.7 ng/ml
or at least about 5 ng/ml.
The controlled release pharmaceutical composition may be designed to release
desglymidodrine in such a manner that a relatively fast peak plasma
concentration of
desglymidodrine is obtained followed by a prolonged and relatively constant
plasma
concentration of desglymidodrine. However, the patient may due to individual
needs or
because of activities during the day experience situations where an increase
in the
plasma concentration is needed for an optimal treatment regimen. Therefore,
the patient
may on an individual basis supply the controlled release composition with one
or more
administrations of a quick release composition or another composition
providing a
relatively fast onset.
A composition according to the invention may comprise one or more further
active drug
substances.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
17
Pharmaceutical kit
In a further aspect, the invention relates to a pharmaceutical kit comprising
a plain
composition and a controlled release composition.
Accordingly, a pharmaceutical kit of the invention comprises
i) a relatively fast onset pharmaceutical composition, wherein the composition
is
adapted to provide desglymidodrine in such a manner that a relatively fast
therapeutically effective concentration of desglymidodrine is obtained after
administration, and
ii) a controlled release pharmaceutical composition, wherein the composition
is
adapted to release desglymidodrine in such a manner that a therapeutically
effective plasma concentration of desglymidodrine is maintained for at least
about 2 hours, such as, e.g. at least about 3 hours, at least about 4 hours,
at
least about 5 hours, at least about 6 hours, at least about 7 hours, at least
about 8 hours or at least about 9 hours.
In alternative embodiments, the invention relates to a pharmaceutical kit
comprising
i) a relatively fast onset pharmaceutical composition comprising midodrine,
wherein the composition is adapted to provide midodrine in such a manner that
a relatively fast therapeutically effective concentration of midodrine is
obtained
after administration, and
ii) a controlled release pharmaceutical composition of desglymidodrine,
wherein
the composition is adapted to release desglymidodrine in such a manner that a
therapeutically effective plasma concentration of desglymidodrine is
maintained for at least about 2 hours, such as, e.g. at least about 3 hours,
at
least about 4 hours, at least about 5 hours, at least about 6 hours, at least
about 7 hours, at least about 8 hours or at least about 9 hours.
A pharmaceutical kit comprising
i) a relatively fast onset pharmaceutical composition of desglymidodrine,
wherein
the composition is adapted to provide desglymidodrine in such a manner that a
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
18
relatively fast therapeutically effective concentration of desglymidodrine is
obtained after administration, and
ii) a controlled release pharmaceutical composition comprising midodrine,
wherein the composition is adapted to release midodrine in such a manner that
a therapeutically effective plasma concentration of midodrine is maintained
for
at least about 2 hours, such as, e.g. at least about 3 hours, at least about 4
hours, at least about 5 hours, at least about 6 hours, at least about 7 hours,
at
least about 8 hours or at least about 9 hours.
International patent application No. PCT/DK01/00213 being in possession of the
same
assignee as the present application discloses specific controlled release
compositions for
oral use comprising midodrine and/or desglymidodrine. Therefore, for states in
which the
present application is co-pending with a national phase of the above-mentioned
patent
application, such specific compositions may conveniently be outside the scope
of the
present invention.
The various compostions may be prepared by a person skilled in the art
optionally with
guidance from Remington's Pharmaceutical Sciences and with guidance from the
disclosure and examples of international patent application No. PCT/DK01/00213
and
PCT/DK01/00214.
Formulation technipues
Any relevant formulation technique for preparing pharmaceutical compositions
may be
applied when formulating a composition according to the invention. A person
skilled in the
art of pharmaceutical formulation techniques can find guidance in the handbook
Remington's Pharmaceutical Sciences and in the non-limiting Examples herein.
In principle any relevant non-controlled or controlled formulation technique
for preparing
an oral non-controlled or controlled release composition may be applied. Thus,
the
dosage form may be in the form of a liquid having e.g. particles dispersed in
a dispersion
medium or it may be in the form of a single or a multiple unit dosage form
intended for use
as such as for dispersing in a dispersion medium before use.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
19
In the following is given a brief non-limiting description of controlled
release formulation
techniques. Examples of different controlled release technologies especially
for the
preparation of compositions for oral use are:
1. Single units
1.1 Coated matrix
1.2 Double or triple compression
1.3 Multilayer coating
1.4 Coated single units (e.g. enteric coating and employment of amylose e.g.
as a
colon degradable excipient).
2. Multiple units
2.1 Units having a controlled release coating
2.2 Units having a controlled release matrix
2.3 Units having a controlled release compression coating
2.4 Units with a multilayer coating.
Ofiher relevant controlled release compositions are e.g. patches, plasters
(for e.g.
transdermal use), emulsions, imlants, dispersions (for e.g. parenteral,
topical, vaginal or
ocular use), or incorporation of desgiymidodrine info a suitable delivery
system (for e.g.
vaginal, parenteral, ocular, buccal use).
Multiple unit systems
The units comprise pellets, granules, crystals, mini tablets or mixtures
thereof. A relatively
fast relase can be obtained by use of an uncoated unit. A controlled release
can be
obtained by the application of a controlled release coating or by formulating
the unit as a
matrix or a coated matrix. A delayed release can be obtained by the use of an
enteric
polymer or amylose, or by having units compressed as described in the triple
compression
technology, cf. the examples herein.
In specific embodiments, a composition according to the invention is in the
form of a solid
dosage form.such as, e.g., tablets, capsules, sachets, solid dispersion,
crystals, granules
and the like.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
A controlled release composition according to the invention can also comprise
at least two
parts such as at least a first and a second part, each part contains
desglymidodrine, and
the first part being adapted to release desglymidodrine in a controlled manner
during the
first 0-14 such as, e.g. 0-11 hours, 0-10 hours, 0-9 hours, 1-8 hours, 1-7
hours, 1-6 hours,
5 2-5 hours, 2-4 hours or 2-3 hours after oral intake and the second part
being adapted to
release desmidodrine starting at least 2 hours such as, e.g. at least 3 hours,
at least 4
hours, at least 5 hours or at least 6 hours after oral intake.
In such a composition at least one of the at least two parts is present in the
composition in
10 the form of a multiplicity of individual units such as, e.g. pellets or
minitablets. The
individual pellets or minitablets may be the same or different, i.e. they may
have the same
or different dissolution characteristics.
A composition according to the invention may also as individual units contain
minitablets,
15 i.e. be in the form of a multiple unit dosage form comprising at least two
different types of
minitablets, the first type of minitablets corresponding to the first part and
the second type
of minitablets corresponding to the second part. In the present context a
minitablet is a
tablet having a size in a range corresponding to from about 0.7 mm to about 7
mm in
diameter such as, e.g., in a range corresponding to from about 1 to about 7
mm, from
20 about 1.5 to about 6 mm, from about 2 mm to about 5 mm, from about 2 mm to
about 4
mm such as in a range corresponding to from about 2 to about 3 mm in diameter.
A controlled release composition according to the invention may also as
individual units
contain relatively large crystals of the active drug substance. In such cases,
the size of the
unit is at the most about 1 mm such as, e.g., in a range corresponding to from
about 0.1
to about 1 mm, from about 0.2 mm to about 0.8 mm, from about 0.2 mm to about
0.7 mm
or from about 0.3 mm to about 0.7 mm.
A composition or a controlled release composition according to the invention
may be in
the form of a multiple unit dosage form, wherein the first or the second part
is in the form
of minitablets, in the form of pellets or in the form of large crystals of the
active drug
substance.
Moreover, at least two fractions may be present in a tablet such as, e.g. a
multilayer tablet
and the at least first and the second part are each comprised in a layer in
the tablet.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
21
Furthermore, a composition according to the invention may comprise a third
part adapted
to release desglymidodrine relatively fast from the composition and/or a
fourth part
adapted to release desglymidodrine from the composiiton 6-10 hours after oral
intake.
In one embodiment the third and/or, if present, the fourth part comprise
pellets or
minitablets or are a layer in a tablet.
With respect to release kinetics, a composition according to the invention may
have a first
part, a second part, a third part and/or a fourth part which have a release
kinetic
corresponding to a zero or a first order release or a mixture of zero and
first order release.
Other orders of release may be 1.5, 2, 3 or 4.
All the above-mentioned combinations of different types of compositions or
formulation
techniques apply, whenever relevant, mutatis mutandi to a composition of the
invention.
The same applies to the combination of the controlled release part or
composition and the
fast release part or composition of a kit of the invention
Pharmaceutically acceptable excipients
Apart from the active drug substance in the composition, a pharmaceutical
composition
according to the invention may further comprise pharmaceutically acceptable
excipients.
In the present context, the term "pharmaceutically acceptable excipient" is
intended to
denote any material, which is inert in the sense that it substantially does
not have any
therapeutic and/or prophylactic effect per se. A pharmaceutically acceptable
excipient
may be added to the active drug substance with the purpose of making it
possible to
obtain a pharmaceutical composition, which has acceptable technical
properties.
The choice of pharmaceutically acceptable excipients depends inter alia on the
specific
composition and the intended administration route.
Water is very often an acceptable excipient and this is also the case in the
present
context. However, it is contemplated that there may have been described
solutions or
other kind of compositions containing desglymidodrine and water e.g. in
connection with
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
22
testing of the in vivo behaviour of desglymidodrine. An example is e.g.
employment of 3H-
desglymidodrine in a study by Kolassa et al. (Archives internationals de
Pharmacodynamie et Therapie, 1979, vol. 238, 96-104). In this paper it is not
explicity
stated that e.g. water is employed as solvent, but if necessary and for
jurisdictions where
it may be relevant, it may be necessary to disclaim compositions containing a
specific
desglymidodrine and a specific solvent (e.g. the labelled desglymidodrine in
the specific
concentration used and in the specific solvent used (which in this case may be
water).
Fillers/diluents/binders may be incorporated such as sucrose, sorbitol,
mannitol, lactose
(e.g., spray-dried lactose, a-lactose, (3-lactose, Tabletose~, various grades
of Pharma-
tose~, Microtose or Fast-Floc~), microcrystalline cellulose (e.g., various
grades of
Avicel~, such as Avicel~ PH101, Avicel~ PH102 orAvicel~ PH105, Elcema~ P100,
Emcocel~, Vivacel~, Ming Tai~ and Solka-Floc~), hydroxypropylcellulose, L-
hydroxypropylcellulose (low-substituted) (e.g. L-HPC-CH31, L-HPC-LH11, LH 22,
LH 21,
LH 20, LH 32, LH 31, LH30), dextrins, maltodextrins (e.g. Lodex~ 5 and Lodex~
10),
starches or modified starches (including potato starch, maize starch and rice
starch),
sodium chloride, sodium phosphate, calcium phosphate (e.g. basic calcium
phosphate,
calcium hydrogen phosphate), calcium sulfate, calcium carbonate, gelatine,
polyvinylpyrrolidone (30, 90, Kollidon VA 64), and sodium
carboxymethylcellulose.
Disintegrants may be used such as cellulose derivatives, including
microcrystalline cellu-
lose, low-substituted hydroxypropyl cellulose (e.g. LH 11, LH 22, LH 21, LH
20, LH 32, LH
31, LH30); starches, including potato starch; croscarmellose sodium (i.e.
cross-linked
carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol~); alginic acid or
alginates; insoluble
polyvinylpyrrolidone (e.g. Polyvidon~ CL, Polyvidon~ CL-M, Kollidon~ CL,
Polyplasdone~ XL, Polyplasdone~ XL-10); sodium carboxymethyl starch (e.g.
Primogel~
and Explotab~).
Glidants and lubricants may be incorporated such as stearic acid, metallic
stearates, talc,
waxes and glycerides with high melting temperatures, colloidal silica, sodium
stearyl
fumarate, polyethylenglycols and alkyl sulphates.
Surfactants may be employed such as non-ionic (e.g., polysorbate 20,
polysorbate 21,
polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate
80,
polysorbate 81, polysorbate 85, polysorbate 120, sorbitane monoisostearate,
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
23
sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan
monooleate, sorbitan sesquioleate, sorbitan trioleate, glyceryl monooleate and
polyvinylalkohol), anionic (e.g., docusate sodium and sodium lauryl sulphate)
and cationic
(e.g., benzalkonium chloride, benzethonium chloride and cetrimide) or mixtures
thereof.
Examples of amphoteric surfactants are 1,2-diacyl-L-phosphatidylcholine, N-
lauryl-N,N-
dimethylglycine, alkylaminopropionic acid, alkyliminodipropionic acid, and
dimethyl-(3-
palmitamidopropyl)-aminoacetate.
Other appropriate pharmaceutically acceptable excipients may include
colorants,
organoleptic improving agents, taste-improving agents, flavouring agents,
antioxidants,
vitamins, pH adjusting agents, solubilizing agents, wetting agents and
buffering agents.
For application to the rectal or vaginal mucosa suitable compositions
according to the
invention include suppositories (emulsion or suspension type), solutions,
enemas and
rectal gelatin capsules (solutions or suspensions) as well as the compositions
mentioned
in the Examples herein. Appropriate suppository bases include cocoa butter,
esterified
fatty acids, glycerinated gelatin, and various wafer-soluble or dispersible
bases like
polyethylene glycols and polyoxyethylene sorbitan fatty acid esters. Various
additives like
e.g. enhancers may be added.
For application to the nasal mucosa, nasal sprays and aerosols for inhalation
are suitable
compositions according to the invention. In a typically nasal composition, the
active drug
substance is dissolved or dispersed in a suitable vehicle. The
pharmaceutically
acceptable vehicles and excipients present in the composition are all selected
in
accordance with conventional pharmaceutical practice in a manner understood by
a
person skilled in the art of formulating pharmaceutics (for specific examples,
see the
examples herein).
For application to the oral cavity or skin, the compositions according to the
invention may
contain conventionally non-toxic pharmaceutically acceptable carriers and
excipients
including microspheres and liposomes. The compositions include creams,
ointments,
lotions, liniments, gels, hydrogels, solutions, suspensions, sticks, sprays,
pastes,
dressings, bandages, plasters, and the like. The pharmaceutical acceptable
carriers or
excipients may include emulsifying agents, antioxidants, bufFering agents,
preservatives,
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
24
humectants, penetration enhancers, chelating agents, gelforming agents,
ointment bases,
perfumes and skin protective agents.
Examples of emulsifying agents are naturally occurring gums, e.g. gum acacia
or gum
tragacanth, naturally occurring phosphatide, e.g soybean lecithin and sorbitan
monooleate derivatives.
Examples of enhancers are alcohols (such as, e.g., ethanol, lauryl alcohol),
esters (e.g.
glycerol monolaurate), salicylic acid, anionic surfactant, (e.g. sodium
dodecyl sulfate),
cationic surfactant (e.g. cetyltrimethyl ammonium bromide), non-ionic
surfactants (e.g.
polysorbates), phosporlipids (e.g. phosphtidyl choline), urea, propylene
glycol, DMSO,
triethanolamine, N.Ndimethylacetamide, N,N-dimethylformamide, 2-pyrrolidone
and
derivatives thereof, tetragydrofuryl alcohol, Azone.
Modified release coating
A unit comprised in a composition according to the invention or the
composition itself may
be coated with a modified release coating.
The modified release coating is a substantially water-insoluble but water-
diffusible
coating.
The modified release coating may be applied on the multiple units or on the
single units
from a solution and/or suspension preferably in an aqueous solvent, but an
organic
coating composition may also be applied. The modified release coating may also
be
applied as a compression coating comprising a dry mixture of polymers) and the
e.g. the
active drug substance.
Examples of matrix-forming agents are hydroxypropylmethylcellulose such as,
e.g., 1828,
2208, 2906 or 2910 according to USP, hydroxypropylcellulose, micronised
ethylcellulose,
low-substituted hydroxypropylcellulose (LH 20, 21, 31).
Examples of film-forming agents which are suitable for use in accordance with
the present
invention are agents selected from the group consisting of cellulose
derivatives such as,
e.g., ethylcellulose, cellulose acetate, cellulose propionate, cellulose
butyrate, cellulose
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
valerate, cellulose acetate propionate; acrylic polymers such as, e.g.,
polymethyl
methacrylate; vinyl polymers such as, e.g., polyvinyl acetate, polyvinyl
formal, polyvinyl
butyryl, vinyl chloride-vinyl acetate copolymer, ethylene-vinyl acetate
copolymer, vinyl
chloride-propylene-vinyl acetate copolymer; silicon polymers such as, e.g.,
ladder polymer
5 of sesquiphenyl siloxane, and colloidal silica; polycarbonate; polystyrene;
polyester;
coumarone-indene polymer; polybutadiene; and other high molecular synthetic
polymers.
In certain preferred embodiments, the acrylic polymer is comprised of one or
more
ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well
known in
10 the art, and are described in NF XVII as fully polymerized copolymers of
acrylic and
methacrylic acid esters with a low content of quaternary ammonium groups.
In one preferred embodiment, the acrylic coating is an acrylic resin lacquer
used in the
form of an aqueous dispersion, such as that which is commercially available
from Rohm
15 Pharma under the tradename Eudragit~. In further preferred embodiments, the
acrylic
coating comprises a mixture of two acrylic resin lacquers commercially
available from
Rohm Pharma under the tradenames Eudragit~ RL 30 D and Eudragit~ RS 30 D, re-
spectively. Eudragit~ RL 30 D and Eudragit~ RS 30 D are copolymers of acrylic
and
methacrylic esters with a low content of quaternary ammonium groups, the molar
ratio of
20 ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in
Eudragit~
RL 30 D and 1:40 in Eudragit~ RS 30 D. Eudragit~ RL/RS mixtures are insoluble
in water
and in digestive fluids. However, coatings formed from the same are swellable
and
permeable in aqueous solutions and digestive fluids. The Eudragit~ RL/RS
dispersions
may be mixed together in any desired ratio in order to ultimately obtain a
modified release
25 formulation having a desirable dissolution profile. The most desirable
modified release
formulations may be obtained from a retardant coating based on Eudragit~ NE
30D,
which is a neutral resin having a molecular weight of 800,000.
Examples of enteric polymers are cellulose acetate phthalate, cellulose
acetate
trimellitate, hydroxy propyl methyl cellulose acetate phthalate, hydroxy
propyl methyl
cellulose acetate succinate, carboxy methyl ethyl cellulose, polyvinyl acetate
phthalate,
copolymer of vinyl acetate and crotonic acid and poly(methacrylic acid,
ethacrylate), and
Eudragit~ S 12.5, Eudragit~ S 100, Eudragit~ FS 30D (all from Rohm),
Sureteric~ (from
Colorcom), Aquateric~ (from FMC) or HPMCP (from Shin-Etsu).
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
26
The amount of coating applied is adapted so as to obtain a predetermined
dissolution
characteristic of the composition.
However, the amount of coating applied should also be adapted so that there
will be no
rupturing problems.
The coating may be admixed with various excipients such as plasticizers, anti-
adhesives
such as, e.g., colloidal silicium dioxide, inert fillers, lipophilic agents
such as, e.g, stearic
acid, capric acid or hydrogenated castor oil, colon targeting excipients such
as, e.g.
amylose, ethylcellulose, Eudragit S 12.5 etc., and pigments in a manner known
per se.
Tackiness of the water-dispersible film-forming substances may be overcome by
simply
incorporating an anti-adhesive in the coating. The anti-adhesive is preferably
a finely
divided, substantially insoluble, pharmaceutically acceptable non-wetting
powder having
anti-adhesive properties in the coating. Examples of anti-adhesives are
metallic stearates
such as magnesium stearate or calcium stearate, microcrystalline cellulose, or
mineral
substances such as calcite, substantially water-insoluble calcium phosphates
or substan-
tially water-insoluble calcium sulphates, colloidal silica, titanium dioxide,
barium sulphates,
hydrogenated aluminium silicates, hydrous aluminium potassium silicates and
talc. The
preferred anti-adhesive is talc. The anti-adhesive or mixture of anti-
adhesives is
preferably incorporated in the coating in an amount of about 0.1-70% by
weight, in
particular about 1-60% by weight, and preferably about 8-50% by weight of the
film layer.
By selecting a small particle size of the talc, a larger surface area is
obtained; the
consequent higher anti-adhesive effect makes it possible to incorporate
smaller amounts
of specific anti-adhesives.
The units or the composition may further comprise an outer film layer.
In one aspect, the outer second layer comprises a water-based film-forming
agent which
prevents adhesion between the units at elevated temperatures and imparts
flowability to
the units, the water-based film-forming agent being anti-adhesive at
temperatures above
about 40 °C, especially temperatures above about 50 °C, such as
a temperature between
about 60 °C and about 120 °C, and being selected from diffusion
coating materials such
as ethylcellulose or enteric coating materials such as anionic
poly(meth)acrylic acid
esters, hydroxypropylmethylcellulosephthalate, celluloseacetatephthalate,
polyvinyl-
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
27
acetatephthalate, polyvinylacetatephthalate-crotonic acid copolymerisates, or
mixtures
thereof, or water-soluble coating materials such as water-soluble cellulose
derivatives,
e.g. hydroxypropylcellulose, carboxymethylcellulose, methylcellulose,
propylcellulose,
hydroxyethylcellulose, carboxyethylcellulose,
carboxymethylhydroxyethylcellulose,
hydroxymethylcellulose, carboxymethylethylcellulose,
methylhydroxypropylcellulose or
hydroxypropylmethylcellulose.
Examples of plasticizers for use in accordance with the present invention
include triacetin,
acetylated monoglyceride, rape oil, olive oil, sesame oil, acetyl tributyl
citrate, acetyl
triethyl citrate, glycerin, sorbitol, diethyloxalate, diethylmalate,
diethylmaleate,
diethylfumarate, diethylsuccinate, diethylmalonate, dioctylphthalate,
dibutylsebacetate,
triethylcitrate, tributylcitrate, glyceroltributyrate, polyethyleneglycol,
propyleneglycol, 1,2-
propyleneglycol, dibutylsebacate, diethylsebacate and mixtures thereof. The
plasticizer is
normally incorporated in an amount of less than 20% by weight, calculated on
the dry
matter content of the coating composition.
A relatively fast onset composition according to the invention may be any
composition well
lenown in the art to provide a relative fast release.
With respect to nasal vehicles, polyethyleneglycols is especially preferred
such as more
n-ethylene glycols represented by the following formula
H(OCHzCH2)POH
wherein p is an integer in the range of 1 to 14. Examples of n-ethylene
glycols are
monoethylene glycol (1 EG), di ethylene glycol (2EG), triethylene glycol
(3EG),
tetraethylene glycol (4EG), penta ethylene glycol (5EG), hexaethylene glycol
(6EG),
heptaethylene glycol (7EG), octaethylene glycol (8EG), nonaethylene glycol
(9EG),
decaethylene glycol (10EG), undecaethylene glycol (11 EG), dodecaethylene
glycol
(12EG), tridecaethylene glycol (13EG), and tetradecaethylene glycol (14EG).
The
ethylene glycols may be used in the form of the single compounds or as a
mixture of two
or more n-ethylene glycols, e.g. commercial products such as polyethylene
glycol 200
(PEG 200), polyethylene glycol 300 (PEG 300) or polyethylene glycol 400 (PEG
400). The
polyethyleneglycols may be used in combination with glycofurols (a-
[(tetrahydro-2-
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
28
furany)methyl]-w-hydroxy-poly(oxy-1,2-ethanediyl)). The latter may also be
used
separately.
The volume of a nasal dosage is preferably within 500 p1 such as within 300 p1
such as in
a range of 10-250 p1.
Composition characteristics
Due to the rather short half-life of approximately 3 hours desglymidodrine
normally must
be administered 2-4 times daily. Considering the chronic nature of the
diseases in
question, which requires a long-term treatment as well as the correlation
between plasma
levels and the incidence and severity of adverse events, the development of a
controlled
release form is highly desired. As discussed earlier, the development of a non-
controlled
release form is also important from a clinical point of view and the same
applies to the
development of a composition intended for a relatively fast onset.
With respect to midodrine, the prodrug of desglymidodrine, it has now been
found that
absorption takes place through the whole gastrointestinal tract. Thus, it has
been found
that when midodrine reaches the colon (about 8 hours after intake of a single
unit capsule
containing midodrine) the prodrug midodrine is not measured in plasma at least
not at a
therapeutic level while the extent of absorption of the active metabolite is
identical to that
of a solution. In other words, with respect to absorption from the colon it
has been found
that it is not midodrine, which is measured after oral intake of midodrine but
instead it is
the active metabolite desglymidodrine itself.
After colon absorption a maximum plasma concentration of desglymidodrine is
found to
take place at approximately 3 hours after application, i.e. TmaX corresponds
to approx. 3
hours. In contrast thereto, a tmaX of about 1-2 hour for desglymidodrine is
observed after
oral intake of midodrine and the corresponding value for midodrine itself is a
Tmax of about
30 min.
The finding that midodrine is converted to the active metabolite before or
during
absorption from the colon is of importance with respect to the dissolution
requirements of
a composition of the present invention. A further important issue is the fact
that FDA has
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
29
recommended that the latest dose of midodrine is taken not later than 6 pm for
safety
reasons, thus a wash out period through the night is desirable.
Based on the above findings and the therapeutic needs, the present inventors
have
developed a composition containing desglymidodrine. A composition of the
invention may
be suitable for use as the sole medicament or it may be suitable for use in
combination
with another drug substance such as, e.g., midodrine. For use in the latter
case, the
invention provides a kit containing at least two different parts at least one
of which
contains desglymidodrine.
Basically two different compositions are of specific interest, i.e. a
composition for normal
or relatively quick release of desglymidodrine and a composition for
controlled release of
desglymidodrine. Besides those two kind of compositions, the invention relates
to a kit
comprising two compositions, the one being a normal or relatively quick
release
composition and the other being a controlled release composition. The
compositions of
the kit generally contains desglymidodrine, but there may be situations where
it is
advantategous to have the normal/quick release composition having a content of
midodrine or, alternatively, to have the controlled release composition being
a midodrine
controlled release compositor.
In the present context the term kit is intended to include
i) a package comprising at least a first and a second pharmaceutical
composition, wherein
the first composition is designed to release the desglymidodrine relatively
fast in order to
obtain a relatively fast onset of the therapeutic effect and the second
composition is in the
form of a controlled release composition (cf. a co-pending patent application
by the same
Applicant) which is designed to give a release pattern as described below in
order to
utilize the possibility of having the active drug substance absorbed not only
in the upper
part of the gastrointestinal tract but also during its passage through colon,
the first and the
second composition may be of the same kind, e.g. in the form of tablets or
capsules or
they may be in the form of two different types of pharmaceutical compositions
e.g. the first
composition may be in the form of plain tablets or a nasal spray and the
second
composition may be in the form of controlled release tablets or capsules, and
ii) a pharmaceutical composition which include a first and a second part,
wherein the first
part is designed to release desglymidodrine relatively fast in order to obtain
a relatively
fast onset of the therapeutic effect and the second part is a controlled
release part (cf. a
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
co-pending patent application by the same Applicant) which is designed to give
a release
pattern as described below in order to utilize the possibility of having the
active drug
substance absorbed not only in the upper part of the gastrointestinal tract
but also during
its passage through colon, and the first and the second part are presented in
the form of a
5 single composition such as, e.g. in the form of a tablet, a capsule (e.g.
containing pellets
which may be the same or different), sachets, powders etc
In a kit according to the invention, the composition (or part) intended for
relatively fast
release contains desglymidodrine as the active substance and the composition
(or part)
10 intended for controlled release contains desglymidodrine or midodrine or a
combination
thereof.
Interesting compositions of the invention are those, which are designed to
release
desglymidodrine relatively fast in order to obtain a relatively fast onset of
action, i.e an
15 action within 1-2 min after administration such as, e.g. within about 3
min. within about 4
min, within about 5 min, within about 7.5 min, within about 10 min within
about 12.5 min or
within about 15 min after administration.
With respect to the release of desglymidodrine from a relatively fast onset
composition,
20 the following applies:
Tablets (plain): disintegration time less than 15 min and often less than 5
min such as,
e.g. 1-3 min.
25 Sublingual, buccal and melt tablets: by mould technique: disintegration
time less than
about 30 sec such as, e.g. about 2-10 sec; by compression or compacting:
disintegration
time less than about 4 min such as, e.g.. about 2-3 min.
Other compositions normally contain desglymidodrine in dissolved form. Thus,
no
30 retardation of the release of the active drug substance from such
compositions is
expected.
In the following details on the controlled release compositions are given.
Reference is
also given to the co-pending PCT application PCT/DK01/00213 for further detail
and
which is incorporated herein by reference. For the sake of clarity please note
that
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
31
according to the discussion above, the active substance generally is
desglymidodrine, but
in the case of a kit midodrine may be included as well. Thus, even if e.g.
only
desglymidodrine is specifically mentioned, all details apply mutatis mutandi
for midodrine
and for a combination of desglymidodrine and midodrine. Moreover, whenever
relevant,
the initial relase described for the controlled release composition also
applies for the
desglymidodrine composition intended for a relatively fast release of the
active substance.
In an embodiment of the invention, the present inventors have developed a
pharmaceutical controlled release composition for oral use containing
midrodrine and/or
desglymidodrine and the composition is designed to the release of
desglymidodrine in at
least the following consecutive steps:
Step 1 an initial relatively fast release of desglymidodrine (in order to
obtain a
relatively fast onset of action),
Step 2 a steady release or a slower release than in step 1 of desglymidodrine
(in
order to maintain a plasma concentration of desglymidodrine which is
prolonged and relatively constant),
Step 3 a second rise in release of desglymidodrine (in order to take advantage
of
absorption from the colon, i.e. such a second rise release is designed to
take place when the composition (or the disintegrated parts of the
composition) reaches the colon; normally this is regarded to take about 3
hours after oral intake, and
Step 4 a decline in release rate corresponding to that essentially all
desglymidodrine have been released from the composition.
The first part or first composition of the kit according to the invention
(i.e. the part or
composition giving rise to a relatively fast onset of desglymidodrine)
releases the active
drug substance as described in step 1 above. Whenever relevant, details
relating to such
a first step including the relevant formulation techniques as well as the
relevant
pharmacokinetic parameters (absorption, metabolism and elimination) also apply
to the
non-controlled desglymidodrine composition of the invention.
The above release pattern is contemplated in order to obtain the desired
plasma
concentration of desglymidodrine during day and night after administration
orally once or
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
32
twice daily. Thus, the release pattern above is based on the following
requirements with
respect to the plasma concentration of desglymidodrine:
1. an initial rise in plasma concentration until a peak concentration is
reached (in the
present context "a peak concentration" is intended to mean a peak value, a
shoulder
value or a plateau value in the concentration),
2. a relatively constant plasma concentration of desglymidodrine for
approximately about
4.5-14 hours such as, e.g., about 5-14 hours, about 6-14 hours, about 7-14
hours,
about 8-13 hours, about 9-13 hours, about 10-14 hours, about 10-13 hours, or
such
as, e.g. for at least about 4.5 hours, at least about 5 hours, at least about
6 hours, at
least about 7 hours, at least about 8 hours, at least about 9 hours, at least
about 10
hours, or at least about 11 hours. In some case, the constant plasma
concentration of
desglymidodrine may last for at least about 12 hours, at least about 13 hours
or at
least about 14 hours,
3. a decline in plasma concentration with a half-life of e.g. about 3-4 hours
to avoid
supine hypertension but other half-lives may also be acceptable e.g.
reflecting a
continous release of midodrine and/or desglymidodrine from the composition.
Compositions according to the invention are therefore designed based on the
following
principle; the term "part" is intended to include a separate part within the
composition (the
composition may contain pellets of e.g. two different types, or an integrated
element of the
composition, e.g. a multilayer tablet):
1. The composition contains a part intended for relatively fast release of
desglymidodrine
2. The composition contains a part intended for prolonged release of
desglymidodrine (or
wherever relevant midodrine), and the prolonged release is intended to last
for at least
about 7-8 hours.
3. The composition contains a part intended to release desglymidodrine (or
wherever
relevant midodrine) relatively fast when the composition (or the disintegrated
parts of
the composition) reaches the colon, i.e. about 6-10 hours such as, e.g., about
8 hours
after oral administration.
4. The release of desglymidodrine (or wherever relevant midodrine) from a
composition
according to the invention is terminated at the most about 12-16 hours after
administration in order to obtain a wash out period during night.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
33
In one aspect the kit according to the invention comprises a controlled
release
pharmaceutical composition for oral use comprising midodrine (ST 1085) or a
pharmaceutically acceptable salt thereof and/or its active metabolite
desglymidodrine (ST
1059) or a pharmaceutically acceptable salt thereof, the composition being
adapted to
release desglymidodrine in such a manner that a relatively fast peak plasma
concentration of desglymidodrine is obtained and that a therapeutically
effective plasma
concentration of desglymidodrine is maintained for at least about 9 hours such
as, e.g. at
least about 10 hours, at least about 11 hours, at least about 12 hours, at
least about 13
hours, or at least about 14 hours.
More specifically, a relatively fast peak (or shoulder or plateau) plasma
concentration of
desglymidodrine is obtained about 15 min - 6 hours such as, e.g. about 0.5-6
hours, about
1-6 hours, about 2-5.5 hours, or about 2.5-5.2 hours after oral administration
of a
composition according to the invention.
As mentioned above, it is important to keep the plasma concentration at a
relatively
constant level and, therefore, the plasma concentration of desglymidodrine
after
administration of midodrine and/or desglymidodrine is preferably maintained at
a
therapeutically active level for about 5-16 hours, such as, e.g., about 6-16
hours, about 7-
16, about 8-15, about 9-15, about 10-15, about 11-14, about 12-14 or about 13,
or for at
least about 5 hours, at least about 6 hours, at least about 7 hours, at least
about 8 hours,
at least about 9 hours, at least about 10 hours, at feast about 11 hours, at
least about 12
hours, at least about 13 hours, at least about 14 hours, at least about 15
hours or at least
about 16 hours.
In the present context, the term "relatively constant level" means that n is n
~ 60%, such
as, e.g., n ~ 50% or n ~ 40% and wherein n is the plasma concentration in
ng/ml and
monifiored in a healthy person. The determination of the "relatively constant
level" is
perfomed as described in Example 28 herein.
It should be noted that the initial fast release from the controlled release
composition may
be supplemented with or replaced by a separate fast onset composition (e.g.
another
composition or another part or composition of the kit) resulting in a peak
plasma
concentration within the period stated for the initial rise in plasma
concentration. A
separate fast onset composition gives a flexibility with respect to the dose
administered,
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
34
i.e. if needed a relatively low or a relatively high dose of the active drug
substance may be
administered dependent on the patient's needs. Thus, in other aspects the
invention
relates to such relatively fast onset compositions.
In principle, relevant active drug substances for use in a composition
according to the
invention are any drug substance for which a dissolution pattern as described
below is of
relevance. The most interesting drug substances in this respect and with
respect to
treatment of orthostatic hypotension and urinary incontinence are the prodrug
midodrine
and its active metabolite desglymidodrine. In a preferred aspect, a
composition according
to the invention includes desglymidodrine, or a combination of midodrine and
desglymidodrine. Of course such compositions may also contain other active
drug
substances, if relevant.
Generally, after oral administration of a composition according to the
invention containing
desglymidodrine, a peak plasma concentration of desglymidodrine is obtained
abot 1-2
min after administration such as, eg. about 2-5 min, about 5-10 min or about
15-30 min
after administration or 15-90 min after oral administration. Moreover, the
plasma
concentration of desglymidodrine after oral administration is maintained at a
relatively
constant level for about 0.7-4 hours such as, e.g. at least about 0.7 hours,
at least about 1
hour, at least about 2 hours, at least about 3 hours, or at least about 4
hours.
To this end, the term "relatively constant" is intended to mean m is m ~ 60%,
such as,
e.g., m ~ 50% or m ~ 40% and wherein m is the plasma concentration in ng/ml
and
monitored in a healthy person. The determination of the "relatively constant
level" is
perfomed as described in Example 28 herein.
In the following further details on a controlled release composition according
to the
invention and, accordingly, also on a controlled release composition of a kit
according to
the invention is given.
Examples on compositions (inter alia relatively fast onset compositions and
controlled
release compositions, respectively) are illustrated in the Examples.
Dissolution requirements
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
As described in the following, a target plasma profile and release profile can
be designed
for the controlled release composition or the controlled release part of the
kit comprising
desglymidodrine.
5 i) Based on the desired effect of desglymidodrine and plasma profiles of
desglymidodrine after administration of midodrine a target in vivo profile has
been
estimated (Fig. 1) (see also PCT application No. PCT/DK01/00213 or
PCT/DK01/00214 for further details).
10 Target release in vitro profile for a controlled release composition
estimated as described
above:
Time (hours) % w/w released desglymidodrine
0.5 25
15 1 35
2 39
3 47
4 53
5 60
20 6 66
7 73
8 80
9 87
10 93
25 12 100
In order to reflect the second rise in release of desglymidodrine
corresponding to the time
when the composition reaches the colon, the following target profile is also
relevant:
30 Time (hours) % w/w released desglymidodrine
0.5 25
1 35
2 39
3 47
35 4 53
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
36
60
6 66
7 75
8 90
5 9 95
97
11 99
12 100
10 As apparent from the above, an initial relatively fast release of
desglymidodrine is suitable
and after about 6-8 hours a second rise in release should be observed.
Accordingly, a
target release rate profile is as follow (the release rate is given in %
dissolved/hour):
about 35 %/hour about 30 min after start of the dissolution test,
about 12 %/hour about 1 hour after start of the dissolution test,
about 6 %/hour about 2 hours after start of the dissolution test,
about 7 %/hour about 3 hours after start of the dissolution test,
about 6.5 %/hour about 4 hours after start of the dissolution test,
about 6.5 %/hour about 5 hours after start of the dissolution test,
about 7.5 %/hour about 6 hours after start of the dissolution test,
about 12 %/hour about 7 hours after start of the dissolution test,
about 10 %/hour about 8 hours after start of the dissolution test,
about 3.5 %/hour about 9 hours after start of fihe dissolution test
about 2 %/hour about 10 hours after start of the dissolution test,
about 1 %/hour about 12 hours after start of the dissolution test.
In Fig. 2 is given a target dissolution profile and a target release rate
curve. Suitable
dissolution methods are found in the Examples herein.
Specific embodiments of interest are as follows (wherein the release pattern
of
desglymidodrine (or whenever relevant midodrine) from the controlled release
composition - when tested in vitro using a Dissolution Method described in the
Experimental part herein - is):
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
37
00 0 o o0 s
s o o
00 0 o nu~
m o
NN N N 'V'I'
N O r
OO O O OO O
~ O
00tn r O00 ~ O
In u7 O
NM d' 1~1~
~iWf7 O
3
3
a
o
'D
_~ 00 0 0 00 0
~ \0 \0 \ o
- \ \ \ \
\ \
N ~~ ~ I~ COin O
p M O ~
'
NM M d COf~ r
~ OD
N
3
u~
- oa o o ~0 0 0
a 0
a ~ mo o m ttm o r
o ~, v cn
>
N r ~O ~ O OO O O
O o O
rN N M tl~(O
~ t~
O
D
-
\
' o~ o o o0 \ o
j 0
d ~ ~ o 0
t o ~N ~n
~ r ~ ~
~ ..
cn o
o
i r, oa o o o~n ~ o
o ~ ~ci
rr N N MM O O o
~ ~
O
1
N
o
O
3
L o
o ~n
( N~ 0 +1
0 0O 0 0
> 0 0 0
NM M ~ r
M COO O ~ +1 3
~ o~ v a
o r f
_ +1 +~
,.
0 3
0
O \ on o~ \ o N
3 o \ o
t ~t ~~ O O_ +1 O
~ O O ~d
N
Md' L(7 1~v r r o r
l(]
~
'-2r OIn O OO tnIn ~ +1
~ O o
rr N N Mtn ~O~ N
Ln
L
+I
D N d' ~
=
~
o O
Vi N
3 o WW W W WW o 0 0
~
C ~ tf~O O in d'~ O O U
~ ~ ~ f~a0 O '-
. ,
"-' .
~ v
O r M~ 11 r r
\ 1~ ~
1 1
r ~r N N M~
\
= t
n
vi t~ O O
tit ~ M M
~
D N +1 +1
.
C C .Ct
L t L L.C
.C L
r N M (D!' ~ N 1 '
d' OD
O O
M M
I-'V
I
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
38
In those cases where the controlled release composition of a kit according to
the invention
contains midodrine or a pharmaceutically acceptable salt thereof then the
release pattern
of midodrine generally follows the patterns given above for desglymidodrine.
If the controlled release composition of a kit according to the invention
contains midodrine
or a pharmaceutically acceptable salt thereof and desglymidodrine or a
pharmaceutically
acceptable salt thereof, then the release pattern of the sum of midodrine and
desglymidodrine is calculated on a molar basis follows the patterns given
above for
midodrine.
As discussed earlier the release rate of desglymidodrine is important in order
to achieve a
suitable release pattern. Thus, a controlled release composition according to
the present
invention normally has a release rate of desglymidodrine (or whenever relevant
midodrine) - when tested in vitro employing any of Dissolution Method I, II,
III or IV - that
corresponds to a curve that has a shape corresponding to
i) a relatively fast first initial release followed by
ii) a steady release or a slower release than in step i) above, which is
followed by
iii) a second rise in release rate and, finally,
iv) a decline in release rate.
In general, the second rise in release rate takes place 5-10 hours such as,
e.g., about 5-9
hours, about 6-8 hours after start of the dissolution test, or 6.5-9 hours
after start of the
dissolution test simulating the time it takes to reach the colon after oral
administration.
With respect to the steady release period, it normally starts about 1-3 hours
after the start
of the dissolution test, and the steady release is maintained for at least 2
hours such as,
e.g. at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours,
at least 7 hours, at
least 8 hours such as about 6-8 hours.
More specifically, the release rate of desglymidodrine (or midodrine or the
sum of
midodrine and desglymidodrine on a molar basis) from a controlled release
composition of
a kit according to the invention - when tested in vitro employing dissolution
apparatus 2
(paddle) according to USP and Ph. Eur, 100 rpm, 0.1 N hydrochloric acid as
dissolution
medium or any of Dissolution Method I, II, III or IV as described herein and a
temperature
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
39
of 37 °C - in %/hour is as follows (~10-40%such as, e.g. ~10-30% or ~
10%, ~ 15% or ~
20% of the values stated below):
about 35 %/hour about 30 min after start of the test (range e.g. 15-40
%/hour),
about 12 %lhour about 1 hour after start of the test (range e.g 4-15 %/hour),
about 6 %/hour about 2 hours after start of the test (range e.g. 2-10 %/hour),
about 7 %/hour about 3 hours after start of the test (range e.g. 2-10 %/hour),
about 6.5 %/hour about 4 hours after start of the test (range e.g. 2-15
%/hour),
about 7.5 %/hour about 6 hours after start of the test (range e.g. 2-30% such
as, e.g., 2-
10 %/hour),
about 10 %/hour about 8 hours after start of the test (range e.g. 2-15
%/hour),
about 2 %/hour about 10 hours after start of the test (range e.g. 0-10
%/hour),
about 1 %/hour about 12 hours after start of the test (range e.g. 0-10
%/hour).
A controlled release composition according to the invention is normally
suitable for
administration once or twice daily, and it differs from a plain tablet
composition, e.g.
Gutron~ tablets, in many ways. In the following is given pharmacolcinetic
values of
importance for achievement of a prolonged therapeutic effect of a composition
according
to the invention. Further details concerning the definition of the parameters
and the
method of obtaining relevant values are given in Example 28 herein.
When tested as described in Example 28 herein, W5o of desglymidodrine (defined
as
corresponding to the time the plasma concentration curve is or is above 50% of
the CmaX
value) is from about 5 to about 12 hours such as, e.g. from about 6 to about
11 hours
such as, e.g. at least about 7 hours.
Furthermore, TmaX is increased with a factor of at least 2 when compared with
a plain
GutronO tablet administered in the same dose. Tmax is determined from a plasma
concentration versus time curve and the plasma concentration reflects the sum
concentration in nmol/I of midodrine and desglymidodrine.
MRT (mean residence time) is increased with a factor of at least 1.5 such as,
e.g., at least
2, at least 2.5 or at least 3 when compared with a plain Gutron~ tablet
administered in the
same dose. MRT is determined from a plasma concentration versus time curve and
the
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
plasma concentration reflects the sum concentration in nmol/I of midodrine and
desglymidodrine.
MRT for midodrine is at least about 1.5 hours such as, e.g., at least about 2
hours, at
5 least about 2.5 hours or at least about 3 hours, and/or MRT for
desglymidodrine is at least
about 6 hours such as, e.g., at least about 7 hours, at least about 7.5 hours,
at least about
8 hours, at least about 8.5 hours, at least about 9 hours, or at least about
9.5 hours.
The invention is further illustrated in the drawing, wherein
fig. 1 shows the estimated plasma concentration of desglymidodrine,
fig. 2 shows the estimated in vitro target for dissolution of desglymidodrine
and the
estimated release rate,and
figs. 3-4 illustrate the results of Example 28.
The following examples are intended to illustrate specific embodiments of the
present
invention but are not intended in any way to limit the invention. Some of the
examples are
included in order to illustrate that the release rate and dissolution
characteristics of a
composition can be changed by varying a number of formulation parameters.
METHODS
DISSOLUTION METHOD I
Apparatus Ph.Eur /USP dissolution apparatus + Perkin
Elmer fully automatic dissolution system +
Disslab PC-programme
Glass fibre filter 0.7 pm
Dissolution medium 600 ml 0.1 N HCI
Rotation speed 100 rpm
Stirrer Basket
Sampling times As appear from tables
Detection wavelength 290 nm
Measuring equipment UV-spectrophotometer, 10 mm quartz cuvette
Temperature of dissolution medium 37°C ~ 0.5°C
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
41
Reagents:
0.1 N HCI is prepared by dilution of concentrated HCI (37%) with purified
water.
Standards:
Two solutions are prepared with a concentration of 10 pg/ml midodrine
hydrochloride in
0.1 N HCI. 0.1 N HCI is used as blind. The absorbances of the solutions are
measured on
the spectrophotometer.
E~a~oi~m is calculated.
E~oa,~m = A x 1000, where 1000 is due to the fact, that the solution is only
0.001 %.
The mean value of the to measurements is inserted in the software programme in
accordance with the manual for the automated dissolution system.
Performance:
600 ml 0.1 N HCI is filled in each of the six vessels in the dissolution
equipment. The
media is heated to a temperature of 37°C ~ 0.5°C. One weighed
tablet is placed in each
of the six baskets. The stirring is started as soon as the baskets are lowered
into the
vessels. The sample is filtered through a 0.7 ~tm filter. The absorbances of
the filtered
samples are measured directly at 290 nm.
DISSOLUTION METHOD II. HPLC-detection.
The dissolution parameters are described in Method I. The measurement is
performed by
HPLC.
Column Spherisorb ODS-1; 5 Nm; 25 cm; ID 4.6
pm
Injection volume 20 p1
Flowrate 1.0 ml/min
Mobile phase Phosphate buffer pH 3: methanol 77:23
(v/v)
Detection 290 nm
Runtime 30 min
Reagents for dissolution are described in Method I.
Buffer solution pH 3 is prepared by dissolving 23.6 g potassium dihydrogen
phosphate in
900 ml purified water. o-Phosphoric acid 85% is used to adjust pH. The flask
is filled to 1 I.
Standards:
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
42
Two stock solutions with a concentration of midodrine hydrochloride 120 pg/ml
in 0.01 N
HCI are prepared. The solutions are stored in refrigerator.
Prepare from each stock solution two standard solutions with a concentration
of midodrine
hydrochloride approximately 1.5 pg/ml and 15 pg/ml respectively, diluted with
0.01 N HCI.
Desglymidodrine hydrochloride is quantified against the standard curve of
midodrine
hydrochloride. The relative response factor is 1.25 for Desglymidodrine
hydrochloride to
midodrine hydrochloride.
Performance:
The dissolution is performed as described in Method I. The sample is withdrawn
with a
pipette and transferred to a syringe. The sample is filtered through a 0.7 pm
filter. The first
ml is returned to the vessel in order to reduce deviation from the desired
volume. A
sample of approximately 1.5 - 2 ml is transferred to the vial, the rest is
returned to the
vessel. The absorbances of the filtered samples are measured as described.
Calculations:
A standard curve is calculated by linear regression, using the standard
solutions. The
peak area of the sample is the sum of the peak area of Midodrine Hydrochloride
and the
peak area of Desglymidodrine hydrochloride, where the latter is divided by the
relative
response factor 1.25.
The results are calculated as % released at any time and presented as a mean
value of
the six samples together with min and max.
dissolved A yol 100
b x
Where
A sum of peak area of midodrine hydrochloride and Desglymidodrine
hydrochloride
(corn)
Vol 600 ml for tablets (MITAB)
100
b slope of the calibration curve (A/mg/ml)
x declared amount (mg)
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
43
DISSOLUTION METHOD III
Apparatus Ph.Eur/USP dissolution apparatus + Perkin Eimer
fully automatic dissolution system + Disslab PC-
programme
Glass fibre filter 0.7 pm
Dissolution medium at the 600 ml 0.1 N HCI
beginning
Dissolution media at changeAddition of 130 ml 0.23 M Na3P04solution
to pH 6.0
Dissolution media at changeAddition of further 70 ml 0.23
to pH 7.5 M Na3P04 solution
Time for change to pH 6.0 2 hours (120 min)
Time for change to pH 7.5 7.5 hours (450 min)
Rotation speed 100 rpm
Stirrer Basket
Sampling times As appear from tables
Detection wavelength 290 nm
Measuring equipment UV-spectrophotometer, 10 mm
quartz cuvette
Temperature of dissolution37C 0.5C
medium
Reference (vessel no 7) An empty capsule dissolved
in 600 ml 0.1 N HCI
Vessel no 7 is added Na3P04
solution in
parallel with the six sample
vessels
Reagents:
0.1 N HCI is prepared by dilution of concentrated HCI (37%) with purified
water.
0.23 M Na3P04 solution: Dissolve an amount of Na3P04~12H~0 in a bit of 1 M HCI-
R and
add water to a concentration of 0.23 M. (Strong alkaline).
Buffer solution pH 6.0: 600 ml 0.1 N HCI is added 130 ml 0.23 M Na3PO
solution.
Buffer solution pH 7.5: Buffer solution pH 6.0 is added further 70 ml 0.23 M
Na3P0
solution.
Standards:
Two solutions are prepared with a concentration of 10 pg/ml midodrine
hydrochloride in
0.1 N HCI. 0.1 N HCI is used as blind. The absorbances of the solutions are
measured on
the spectrophotometer.
E~o~o~cm is calculated. It has previously been determined, that the E~o~o,cm
is the same for the
three media, so it is only necessary to perform the test in 0.1 N HCI.
E~o~o~cm= A x 1000, where 1000 is due to the fact, that the solution is only
0.001 %.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
44
The mean value of the to measurements is inserted in the software programme in
accordance with the manual for the automated dissolution system.
Performance:
600 ml 0.1 N HCI is filled in each of the seven vessels in the dissolution
equipment. The
media is heated to a temperature of 37°C ~ 0.5°C. One weighed
capsule is placed in each
of the six baskets. In the seventh basket an empty capsule is placed. This is
measured as
a blank reference. The stirring is started as soon as the baskets are lowered
into the
vessels. The measured amounts of buffer solution, needed for the changes of pH
in the
vessels, are preheated to 37°C, before addition to the vessels. When
the buffer is to be
added, the baskets are elevated from the vessels, the buffer is added, the
solution in the
vessel is stirred to homogenise the solution and the baskets are lowered into
the vessels
again. The sample is filtered through a 0.7 pm filter. The absorbances of the
filtered
samples are measured directly at 290 nm.
DISSOLUTION METHOD IV, HPLC-detection.
The dissolution parameters are described in Method III. The measurement is
performed
by HPLC.
Column Spherisorb ODS-1; 5 Vim; 25 cm; ID 4.6 ~m
Injection volume 20 ~I
Flowrate 1.0 ml/min
Mobile phase Phosphate buffer pH 3: methanol 77:23 (v/v)
Detection 290 nm
Runtime 30 min
Reagents for dissolution are described in Method III.
Buffer solution pH 3 is prepared by dissolving 23.6 g potassium dihydrogen
phosphate in
900 ml purified water. o-Phosphoric acid 85% is used to adjust pH. The flask
is filled to 1 I.
Standards:
Two stock solutions with a concentration of midodrine hydrochloride 120 pg/ml
in 0.01 N
HCI are prepared. The solutions should be stored in refrigerator.
Prepare from each stock solution two standard solutions with a concentration
of midodrine
hydrochloride approximately 1.5 pg/ml and 15 Ng/ml respectively, diluted with
0.01 N HCI.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
Desglymidodrine hydrochloride is quantified against the standard curve of
midodrine
hydrochloride. The relative response factor is 1.25 for desglymidodrine
hydrochloride to
midodrine hydrochloride.
5 Performance:
The dissolution is performed as described in Method III. The sample is
withdrawn with a
pipette, transferred to a syringe. The sample is filtered through a 0.7 qm
filter. The first ml
is returned to the vessel in order to reduce deviation from the desired
volume. A sample of
approximately 1.5 - 2 ml is transferred to the vial, the rest is returned to
the vessel. The
10 absorbances of the filtered samples are measured as described.
Calculations:
A standard curve is calculated by linear regression, using the standard
solutions. The
peak area of the sample is the sum of the peak area of midodrine hydrochloride
and the
15 peak area of desglymidodrine hydrochloride, where the latter is divided by
the relative
response factor 1.25.
The results are calculated as % released at any time and presented as a mean
value of
the six samples together with min and max.
dissolved A vol 100
b x
Where
A sum of peak area of midodrine hydrochloride and desglymidodrine
hydrochloride
(corn)
Vol 600 ml for up to 2 hours 730 ml for up to 7.5 hours and 800 ml for up to
12 hours
for capsules (MICAP)
100
b slope of the calibration curve (A/mg/ml)
x declared amount (mg)
DISSOLUTION METHOD V (Melt Tablets)
Dissolution apparatus 2 according to USP and Ph. Eur.
Paddle method
Rotations: 50 rpm
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
46
Temperature: 37°C
Dissolution medium: isotonic buffer pH 6.8 or purified water
Volumen: 600 ml
Sample time: 5 min
RP-HPLC: Phosphate buffer pH 3 : methanol 77:23 (v/v)
Detection at 290 nm.
DISSOLUTION METOD VI CSublinaual Tablets)
Dissolution apparatus 2 according to USP and Ph. Eur.
Paddle method
Rotations: 50 rpm
Temperature: 37°C
Dissolution medium: isotonic buffer pH 6.8 or purified water
Volume: 600 ml
Sampling time: 5 min
RP-HPLC: Phosphate buffer pH 3 : methanol 77:23 (v/v)
Detection at 290 nm.
EXAMPLES
In the following examples desglymidodrine refers to desglymidodrine-HCI, if
nothing else
is mentioned.
Example 1
Preparation of a desglymidodrine composition by employment of triple
compression
The following example illustrates a composition made by employment of triple
compression
Composition:
Core:
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
47
Desglymidodrine 4.0 mg
Klucel MF 2.0 mg
Methocel E 50 94.0 mg
1St compression layer:
Desglymidodrine - 1.2 mg
Klucel MF 6.6 mg
Methocel E 15 157.2 mg
2"d compression layer:
Desglymidodrine 2.3 mg
Methocel E 50 247.7 mg
Using the core composition a core weighing 100 mg is compressed using a punch
6 mm
in diameter. The core is compression coated using 165 mg of the 1St
compression layer
composition and a punch of 9 mm in diameter. The thus compression coated core
is
compression coated again using 250 mg of the 2"d compression layer composition
and a
punch of 11 mm in diameter.
A composition comprising desglymidodrine 0.96 mg, Methocel E5 9.7 mg and talc
8.7 mg
is applied to the tablet by spray coating.
Example 2
Preparation of a desglymidodrine composition by employment of triple
compression
The following example illustrates a composition made by employment of triple
compression
Composition:
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
48
Core: Desglymidodrine 1.33 mg
Hydroxypropylmethyl cellulose E 50 48.67 mg
Croscarmellose sodium 10.00 mg
60.00 mg
1St compression layer Desglymidodrine 0.50 mg
Hydroxypropylmethyl cellulose E 15 126.50 mg
Hydroxypropylmethyl cellulose K 100 LV 8.00 mg
135.00 mg
2"d compression layer Desglymidodrine 1.60 mg
Hydroxypropylmethyl cellulose E 50 143.40 mg
145.00 mg
Using the core composition a core weighing 60 mg is compressed using a punch
of 6 mm
in diameter. The core is compression coated using 135 mg of the 1St
compression layer
composition and a punch of 9 mm in diameter. The thus compression coated core
is
compression coated again using 145 mg of the 2"d compression layer composition
and a
punch of 11 mm in diameter.
A composition comprising desglymidodrine 0.59 mg, hydroxypropylmethyl
cellulose E 5
3.58 mg, talc 2.65 mg and propylene glycol 0.71 mg is applied to the tablet by
spray
coating.
Finally a top coat comprising hydroxypropylmethyl cellulose E 5 1.79 mg, talc
1.25 mg
and propylene glycol 0.36 mg is applied to the tablet by spray coating.
Example 3
Desglymidodrine composition made as a coated matrix
The following compositions are prepared:
Composition 1: Core:
Desglymidodrine 8.0 mg
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
49
Klucel LF 342.0 mg
Insoluble inner coat
Methocel E 5 0.2 mg
Magnesium stearate 0.1 mg
Talc Ponderax 0.4 mg
Anti foam 4.8 pg
Eudragit NE 30 D 4.5 mg
Soluble outer coat
Methocel E 5 1.8 mg
Talc Ponderax 1.8 mg
Composition 2: Core:
Desglymidodrine 8.0 mg
Klucel MF 342.0 mg
Insoluble inner coat
Methocel E 5 0.2 mg
Magnesium stearate 0.1 mg
Talc Ponderax 0.4 mg
Anti foam 4.8 pg
Eudragit NE 30 D 4.5 mg
Soluble outer coat
Methocel E 5 1.8 mg
Talc ponderax 1.8 mg
Cores of both composition 1 and composition 2 are compressed using a punch 10
mm in
diameter. Core weighing 350 mg.
Both types of cores are coated with an insoluble inner coat and a soluble
outercoat. The
release profile can be shifted up or down by changing the amount of weight
increase of
cores when applying the inner coat.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
If suitable, the release profile can be changed by coating with other acrylic
resins such as
Eudragit RL 30 D, Eudragit RS 30 D or combinations thereof, or using other
types of film
forming agents such as ethylcellulose or silicone polymers. Furthermore, the
release
profile can be changed by using other types of matrix former such as acrylic
resins, other
5 types of cellulose ethers such as L-HPC (low-substituted
hydroxypropylcellulose), HPC
(hydroxypropylcellulose), HPMC (hydroxypropylmethylcellulose), HEC
(hydroxyethylcellulose), MC (methylcellulose), HEMC
(hydroxyethylmethylcellulose), EC
(ethylcellulose) or other viscosity grades of HPC (hydroxypropylcellulose).
10 Example 4
Multilayer coating compositions
Composition:
Composition 1: Core (Non pareil) 200 mg
1. coat
Desglymidodrine 3.2 mg
Methocel E 5 M 0.3 mg
Magnesium Stearate 60.0 pg
Talc ponderax 0.5 mg
Anti foam 4.0 pg
Eudragit NE 30 D 5.2 mg
2. coat
Desglymidodrine 2.4 mg
Methocel E 5 M 0.3 mg
Magnesium Stearate 60.0 pg
Talc ponderax 0.5 mg
Anti foam 4.0 pg
Eudragit NE 30 D 6.1 mg
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
51
3. coat
Desglymidodrine 1.6 mg
Methocel E 5 M 0.3 mg
Magnesium Stearate 80.0 pg
Talc ponderax 0.6 mg
Anti foam 6.0 pg
Eudragit NE 30 D 7.1 mg
4. coat
Desglymidodrine 0.8 mg
Methocel E 5 M 0.4 mg
Magnesium Stearate 80.0 pg
Talc ponderax 0.7 mg
Anti foam 6.0 pg
Eudragit NE 30 D 7.8 mg
Outer coat
Methocel E 5 1.0 mg
Talc ponderax 1.0 mg
Non-pareil beads are coated in four steps with four different films in a fluid
bed coater.
1. film comprising 1. coat
2. film comprising 2. coat
3. film comprising 3. coat
4. film comprising 4. coat.
A final layer of coating comprising the outer coat is applied and the films
are cured at
70°C
Composition 2: Core (Non pareil) 200 mg
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
52
Non-pareil beads are coated in seven steps with four different films
alternating with a
blank film in a fluid bed coater.
The four different film formulations are similar to the four different film
formulations in
composition 1, the alternating coats are as follows:
Alternating coat
Methocel E 5 M 0.2 mg
Magnesium stearate 40.0 pg
Talc ponderax 0.3 mg
Anti foam 2.0 pg
Eudragit NE 30 D 3.5 mg
1. film comprising 1. coat
2, film comprising Alternating coat
3. film comprising 2. coat
4. film comprising Alternating coat
5. film comprising 3. coat
6. film comprising Alternating coat
7. film comprising 4. coat
A final layer of coating comprising outer coat in composition 1 is applied and
the films
are cured at 70°C.
Composition 3: Core (Non pareil) 200 mg
1. coat
Desglymidodrine 3.2 mg
Paraffin, solid 0.3 mg
Acetyltributyl citrate 0.1 mg
Ethylcellulose 1.9 mg
Aerosi1200 28.0 pg
2. coat
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
53
Desglymidodrine 2.4 mg
Paraffin, solid 0,3 mg
Acetyltributyl citrate 0.1 mg
Ethylcellulose 2.2 mg
Aerosi1200 32.0 pg
3. coat
Desglymidodrine 1.6 mg
Paraffin, solid 0.4 mg
Acetyltributyl citrate 0.1 mg
Ethylcellulose 2.5 mg
Aerosi1200 40.0 pg
4. coat
Desglymidodrine 0.8 mg
Paraffin, solid 0.4 mg
Acetyltributyl citrate 0.2 mg
Ethylcellulose 2.8 mg
Aerosi1200 40.0 pg
Outer coat
Paraffin, solid 0.5 mg
Acetyltributyl citrate 0.2 mg
Ethylcellulose 3.3 mg
Aerosi1200 50.0 pg
Non-pareil beads are coated in four steps with four different films in a fluid
bed coater:
1. film comprising 1. coat
2. film comprising 2. coat
3. film comprising 3. coat
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
54
4. film comprising 4. coat.
A final layer of coating comprising outer coat is applied.
If suitable, the release profile can be changed by coating with other acrylic
resins such as
Eudragit RL 30 D, Eudragit RS 30 D or combinations thereof, or using other
types of film
forming agents such as ethylcellulose or silicone polymers, or incorporating
lipophilic
compounds such as, e.g., stearic acid, capric acid or hydrogenated castor oil
in the film.
Example 5
Preparation of a controlled release composition using commercially available
filmforming agents
The present example illustrates the preparation of a coated pellet
composition. The aim is
to prepare pellets having a release kinetic different from zero order release.
Pellets are prepared from the following ingredients:
I Desglymidodrine 482.3 g
I I Microcrystalline cellulose (Type PH 101 ) 778.0 g
III Lactose monohydrate 2700.0 g
IV Sodium carboxymethylcellulose 40.0 g
V Purified water 1120.0 g
I + II + III + IV are admixed in a Fielder intensive mixer at an appropriate
time and mixing
intensity.
V is applied to the mixture (I-IV) while mixing. When V is applied the mixing
is continued
at an appropriate time with an appropriate mixing intensity.
The wetted mass is extruded through a screen with apertures between 0.4 -1.0
mm.
The extrudate is spheronised until the surface of the resulting pellets is
smooth.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
An inner and an outer coating are applied:
Inner coat
5 The weight of the pellets is increased with 8.5% w/w.
I Hydroxypropylmethylcellulose 13.5 g
II Magnesium stearate 2.9 g
II Talc 25.2 g
10 IV Eudragit NE 30 D 895.1 g
V Purified water 1135.4 g
The pellets are coated in a fluid bed with appropriate process parameters.
15 Immediately after the inner coat has been applied an outer coat is applied.
Outer coat
The weight of the pellets is increased with 1 % w/w.
I Hydroxypropylmethylcellulose 20.0 g
II Talc 20.0 g
III Purified water 460.0 g
The pellets are coated in a fluid bed with appropriate process parameters.
The weight of 1 unit dose containing 30 mg desglymidodrine is 272.7 mg.
The release profile can be shifted up or down by changing the amount of weight
increase
of pellets when applying the inner coat.
The release profile may be changed using different mixtures of pellet
fractions having
different amounts of inner coating applied. The release profile may also be
changed by
coating with other acrylic resins such as Eudragit RL 30 D, Eudragit RS 30 D
or
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
56
combinations thereof, or using other types of film forming agents such as
ethylcellulose or
silicone polymers.
Furthermore, the release profile can be changed by applying a fraction of non-
coated
pellets or by applying an enteric coating to a fraction of pellets.
Example 6
Preparation of a controlled release composition using a film containing
paraffin
The present example illustrates the preparation of a coated pellet
composition. The aim is
to prepare pellets having a release kinetic different from zero order release.
Coated pellets are prepared from the following ingredients:
The composition and manufacturing process of pellets are similar to Example 5.
A paraffin-containing coating are applied; the weight of the pellets is
increased with 6%
w/w.
I Paraffin, solid 29.89 g
II Acetyltributyl citrate 10.53 g
III Ethyl cellulose 196.61 g
IV Silicium dioxide (Aerosil 200) 2.95 g
V Isopropyl alcohol 3970.03 g
The pellets are coated in a fluid bed with appropriate process parameters.
The weight of 1 unit dose containing 30 mg desglymidodrine is 263.7 mg.
Example 7
Preparation of a controlled release composition having a zero order release
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
57
The present example illustrates the preparation of a coated bead composition.
The aim is
to prepare beads having a zero order release kinetic.
Coated beads are prepared as follows:
Non dissolvable non-pareil beads of equal size are coated with a suspension of
desglymidodrine. A diffusion barrier is coated on top of the desglymidodrine
layer, and
thereby controlling the release of desglymidodrine.
4000 g non-pareil beads having a uniform particle size in a range between 0.4
mm and
1.0 mm are transferred to a fluid bed coater.
The beads are coated with coating suspension 1 (containing desglymidodrine)
I Hydroxypropylmethylcellulose 8.8 g
II Magnesium stearate 1.9 g
III Talc 16.5 g
IV Eudragit NE 30 D 585.1 g
V Purified water 742.1 g
VI Desglymidodrine 160.7 g
The weight of the beads is increased with 9% w/w.
The beads are coated employing appropriate process parameters.
Immediately after coating with suspension 1 a second coating suspension is
applied.
The beads are coated with coating suspension 2:
I Hydroxypropylmethylcellulose 11.7 g
II Magnesium stearate 2.5 g
III Talc 21.7 g
IV Eudragit NE 30 D 772.3 g
V Purified water 979.6 g
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
58
The weight of the coated beads is increased with 6% w/w.
The pellets are coated employing appropriate process parameters.
Immediately after coating with suspension 2 a third coating suspension is
applied.
The beads are coated with coating suspension 3:
I Hydroxypropylmethylcellulose 23.3 g
II Talc 23.3 g
III Purified water 536.8 g
The weight of the coated beads is increased with1% w/w.
The beads are coated in a fluid bed employing appropriate process parameters.
The weight of 1 unit dose containing 20 mg desglymidodrine is 587.5 mg.
By changing the weight gain of the beads when applying the second coating
suspension,
the release profile can be shifted up or down.
The release profile may be changed using different mixtures of bead fractions
having
different amounts of second coating suspension applied. The release profile
may also be
changed by coating with other acrylic resins such as Eudragit RL 30 D,
Eudragit RS 30 D
or combinations thereof, or using other types of film forming agents such as
ethylcellulose
or silicone polymers.
The above-mentioned filmforming agents can also be combined with pore forming
agents
such as cellulose ethers, polyoles, PEG's.
Furthermore, the release profile can be changed by applying an enteric coating
to a
fraction of the coated beads.
Example 8
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
59
Preparation of a zero order controlled release composition
The present example illustrates the preparation of a coated minitablet
composition. The
aim is to prepare coated minitablets of equal size in order to obtain a zero
order release
kinetic.
Formulation of minitablets:
I Desglymidodrine 800.0 g
Ii Dicalcium phosphate 2960.0 g
III Talc 100.0 g
IV Magnesium stearate 40.0 g
V Polyvinylpyrrolidone 90 100.0 g
VI Purified water 800.0 g
V is dissolved in VI.
I + II are transferred to a Fielder intensive mixer and admixed at an
appropriate time and
mixing intensity.
The mixture is wetted with the solution V + VI.
Granulation is performed at an appropriate time and mixing intensity.
The drying of the wet granulate is carried out in an Aeromatic fluid bed.
The dried granulate is passed through a suitable sieve. IV + V are sieved
through a 0.3
mm sieve and admixed to the sieved particulate mixture in a cube mixer for 10
min.
The thus obtained particulate mixture is compressed into tablets weighing 15
mg.
A dose of 30 mg desglymidodrine corresponds to 10 minitablets.
Coating of the minitablets:
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
The minitablets are coated with inner and outer coatings corresponding to the
description
of coating suspension 2 and 3 in Example 7.
By changing the weight gain of the minitablets when applying the inner coat,
the release
5 profile can be shifted up or down
The release profile may be changed using mixtures of mintablet fractions
having different
amounts of inner coating applied. The release profile may also be changed by
coating
with other acrylic resin such as Eudragit RL 30 D, Eudragit RS 30 D or
combinations
10 thereof, or using other types of film forming agents such as ethylcellulose
or silicone
polymers.
The above mentioned filmforming agents can also be combined with pore forming
agents
such as, e.g., cellulose ethers, polyoles, PEG's, etc.
Furthermore, the release profile may be changed applying an enteric coating to
a fraction
of coated minitablets.
Example 9
Preparation of a controlled release composition having a release kinetic
different
from that of zero order
Matrix minitablets:
I Desglymidodrine 800.0 g
II Ethyl cellulose (10 pm) 2960.0 g
III Talc 200.0 g
IV Magnesium stearate 40.0 g
V Purified water 800.0 g
I + II are admixed in a Fielder intensive mixer at an appropriate time and
mixing intensity.
The mixture is wetted with V while mixing at an appropriate mixing intensity.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
61
The wetted mixture is granulated at an appropriate time and mixing intensity.
The drying of the wet granulate is carried out in an Aeromatic fluid bed.
The dried granulate is passed through a suitable sieve. III + IV are sieved
through a 0.3
mm sieve and admixed to the sieved particulate mixture in a cube mixer for 10
min.
The thus obtained particulate mixture is compressed into tablets weighing 15
mg.
A dose of 30 mg desglymidodrine is contained in 10 minitablets.
If suitable, the release profile can be changed by using other cellulose
ethers such as
HPC, L-HPC, HPMC or combinations of thereof.
The principle of a matrix composition may also be used for a single unit
tablet containing
the total amount of desglymidodrine in one unit.
In order to further increase the retardation of the dissolution of
desglymidodrine the
minitablets may be coated with inner and outer coatings corresponding to the
description
of coating suspension 2 and 3 in Example 7. The amount of coating applied may
be
varied to shift the dissolution profile up or down.
Example 10
Preparation of a controlled release composition having release kinetic
different
form zero order
Matrix minitablets:
I Desglymidodrine 800.0 g
II Ethyl cellulose (10 pm) 2960.0 g
III Talc 200.0 g
IV Magnesium stearate 40.0 g
V Isopropyl alcohol 800.0 g
I + II are admixed in a Fielder intensive mixer at an appropriate time and
mixing intensity.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
62
The mixture is wetted with V while mixing at an appropriate mixing intensity.
The wetted mixture is granulated for an appropriate time and mixing intensity.
The drying of the wet granulate is carried out in an Aeromatic fluid bed.
The dried granulate is passed through a suitable sieve. III + IV are sieved
through a 0.3
mm sieve and admixed to the sieved particulate mixture in a cube mixer for 10
min.
The thus obtained particulate mixture is compressed into tablets weighing 15
mg.
A dose of 30 mg of desglymidodrine is contained in 10 minitablets.
In order to further increase the retardation of the dissolution of
desglymidodrine the
minitablets may be coated according to Example 7. The amount of coating
applied may
be varied to shift the dissolution profile up or down.
Example 11
Composition made by employment of double compression
A tablet was prepared from the following ingredients:
1St compression layer Desglymidodrine 1.93 g
Starch 1500 89.93
g
Lactose monohydrate 180.00
g
Eudragite RS 30 D 75.0 g
Acetyl tributylcitrate 5.64 g
2"d compression layer Desglymidodrine 0.4 g
Hydroxypropylmethyl- 49.6 g
cellulose E 50
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
63
The granulate for 1St compression layer is prepared in the following way:
Desglymidodrine and Starch 1500 was mixed by hand. This mixture and lactose
monohydrate is mixed in a Moulinex food processor for 30 sec.
The granulating fluid comprising Eudragit RS 30 D and acetyl tributylcitrate
is mixed by
stirring for 5 min.
The granulating fluid was applied to the powder mixture while mixing in the
Moulinex food
processor. The time for applying the granulating fluid is 45 sec.
Wet massing time for the moist powder mixture is 30 sec.
The moist granulate is tray dried and the dried granulate is passed through a
1000 pm
screen.
The granulate for 2"d compression layer is prepared in the following way:
Desglymidodrine and hydroxypropylmethyl cellulose E 50 are mixed by hand and
passed
through a 500 pm screen.
A double compression tablet is prepared in the following way:
A shallow concave round punch of 11 mm in diameter is used to compress the
tablet.
250 mg granulate for 1St compression layer is weighed into the die and
compressed gently
to a loose compact. 200 mg granulate for 2"d compression layer is weighed on
top the
loose compact. The loose compact and the granulate for 2"d compression layer
is
compressed with a force of approx. 17 kN to form a coherent tablet.
After compression a release controlling film, a film containing
desglymidodrine and a
blank film is applied to the tablets.
The following films are applied to each tablet:
Release controlling film: Purified water 42.23 mg
Hydroxypropylmethyl cellulose E 5 0.51 mg
Talc. pond. + Magnesium stearate 1.04 mg
(9+1)
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
64
Eudragite NE 30 D 33.30 mg
Film containing desglymidodrine: Purified water 72.61 mg
Hydroxypropylmethyl cellulose E 5 4.06 mg
Desglymidodrine 0.81 mg
Propylene glycol 0.81 mg
Blank film: Purified water 32.67
mg
Hydroxypropylmethyl cellulose E 5 1.80 mg
Talc. pond 1.27 mg
Propylene glycol 0.36 mg
Example 12
Preparation of a controlled release composition made in the form of capsules
containing multiple units
A desglymidodrine controlled release product is prepared by manufacturing one
type of
pellet, which afterwards is coated with different types of film coatings. The
capsule ends
up with 3 different types of pellets (one non-coated pellet, one controlled
release (CR)-
coated pellet and one enteric coated (EC)-pellet).
Pellet preparation
The pellet is prepared by the use of an extrusion/spheronization technique.
The
ingredients are listed in Scheme 12-1.
Scheme 12-1:
Ingredients Amount (g) pr. Batchsize
Microcrystalline 2146.0
cellulose
Lactose monohydrate1213.7
Carmellose sodium70.0
Desglymidodrine 70.3
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
Purified water 2000.
The ingredients are mixed and wetted in a Fielder high shear mixer in which
the water is
applied by a nozzle.
5 The wetted mass is extruded in a Nica E 140 extruder with a screen size of
600 pm (those
pellets which are being used for non coated pellets and for CR-coating) or 800
pm (those
pellets used for EC-coating). The extrudate is spheronized in a laboratory
unit for 5 min.
The pellets are dried in a laboratory scale fluid bed for approx. 75 min at
50°C.
10 The dried pellets used for non coated pellets and for CR-coating are passed
through a
screen of 700 pm and the dried pellets used for EC-coating are fractionated
with a lower
screen of 500 pm and a upper screen of 1000 pm.
Step 1 pellets (non coated pellets)
One batch of these pellets is not coated, as it is used as an immediate
release unit. The
pellets are a part of the content in the capsule.
Step 2 pellets (CR-coated pellets)
One batch of these pellets is coated with an inner coat and an outer coat in a
fluid bed
(GPCG3) with a 0.8 mm spray nozzle and a spray pressure of 2.5 bar. The
composition
for the coating is shown in Scheme 12-2.
Scheme 12-2:
Ingredients Amount (g) pr.
batchsize
Inner coat (batchsize
2000 )
Hypromellose (viscosity13.1
5cps)
Purified water 1094.0
Magnesium stearate 2.7
Talc 26.2
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
66
Polyacrylate dispersion 864.0
30%
(Eudragit NE30D)
Outer coat (batchsize
1000 )
Hypromellose (viscosity 40.0
5cps)
Purified water 920.0
I
Talc 40.0
In the coating process the following amount of inner and outer coats are
applied. The
amount of dry matter applied calculated in percentage of the core weight also
appears
from below.
Inner coat: 1788.1 g per 3000.0 g pellets (dry matter: 9% of the core weight)
Outer coat: 375.0 g per 3000.0 g pellets (dry matter: 1 % of the core weight)
Throughout the coating process the bed temperature is maintained substantially
in the
interval from 20-25°C by adjustment of the liquid flow rate or the
inlet temperature. The
inlet air temperature is kept at approximately 32°C. After application
of the coatings the
coated pellets are cured at a bed temperature of approximately 70°C for
30 min. Then the
pellets are passed through a screen 1.0 mm. Oversized material is discarded.
Step 3 pellets (EC pellets)
One batch of these pellets is coated with an EC-coat in a fluid bed (Wurster
technique)
with a 0.8 mm spray nozzle and a spray pressure of 2.5 bar. The composition
for the
coating is shown in Scheme 12-3.
Scheme 12-3:
Ingredients Amount (g) pr. batchsize
Isopropyl alcohol 3852.0
Talc 100.0
Acetyltributyl citrate 99.2
Methacrylic acid - methyl methacrylate
copolymer
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
67
(1:2) 3948.8
(Eudragit S12.5)
In the coating process the following amount of the coat is applied. The amount
of dry
matter applied calculated in percentage of the core weight also appears from
below.
15,517.2 g per 3000.0 g pellets (dry matter: 45% of the core weight)
Throughout the coating process the bed temperature is maintained substantially
in the
interval from 30-38°C by adjustment of the liquid flow rate or the
inlet temperature. The
inlet air temperature is kept at approximately 49°C. After the
application of the coating the
pellets are passed through a screen 1.3 mm. Oversized material is discarded.
Capsule filling
The 3 different pellets (steps 1, 2 and 3) are filled into capsules by hand.
The amount of
pellets per capsule is shown in Scheme 12-4.
Scheme 72-4:
Unit Amount (mg) per capsule
Capsule approx. 76.3
Pellets step 1 Approx. 50.4 corresp. to 1.00 mg desglymidodrine
Pellets step 2 Approx. 110.6 corresp. to 2.0 mg desglymidodrine
Pellets step 3 Approx. 72.7 corresp. to 1.0 mg desglymidodrine
Total weight of Approx. 310 corresp. to 4.0 mg desglymidodrine
capsule
Example 13
Composition made by employment of mixing a matrix granulate and a slow release
granulate
The composition of the granulates are equal to the granulates described in
Example 11.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
68
250 mg of granulate called 1St compression layer (slow release granulate) is
mixed with
200 mg of granulate called 2"d compression layer (matrix granulate).
A shallow concave round punch 11 mm in diameter is used to compress the
tablet.
The granulate mixture is placed in the die and the granulate is compressed
with a
compression force of approx. 17 kN to form a coherent tablet.
After compression a release controlling film, a film containing
desglymidodrine and a
blank film were applied to the tablets.
The film compositions and the applied amounts are equal to the compositions
and
amounts applied in Example 11.
Example 14
Preparation of desglymidodrine plain tablets
The present example illustrates the preparation of plain tablets containing
desglymidodrine as the active drug substance.
Composition:
I Colloidal anhydrous silica 1.6 g
II Desglymidodrine hydrochloride 1.6 g
III Microcrystalline cellulose 14.3 g
IV Maize starch 28.84 g
V Granulation liquid 27.5 g
VI Talc 2.3
VII Magnesium stearate 1.6
V Granulation liquid:
Maize starch 18.3 g
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
69
Purified water 122 g
II, III and IV were sieved through a 0.3 mm sieve. II was mixed by hand with
equal parts of
III, I + IV were mixed in the same way.
Hereafter I, II, III and IV were mixed in 5 minutes in a cube mixer. The
mixture was wetted
with V while mixing at an appropriate mixing intensity.
The moist granulate was passed through a 1000 pm sieve and tray dried at 52
°C for 3
hours.
The dried granulate was passed through a 1000 pm sieve. VI + VII was passed
through a
300 pm sieve and mixed by hand with equal parts of the granulate. This mixture
was
admixed in a cube mixer for 5 min.
The obtained particulate mixture was compressed into tablets weighting 130 mg
using a
punch of 6 mm in diameter.
The tablets were subject to stability testning. For comparison purposes
figures for stability
testing of a desglymidodrine solution are included. The following initial
results were
obtained:
Stability of desglymidodrinein solution
Based on comparison of peak areas
Media O days (peak area) 7 days (peak area)
Water 1582140 1601999
0.1 N HCI 1548689 1516212
Buffer pH 7.4 1341613 1289393
Media 0 days (peak area) Autoclave 120 C
Water 100 100
0.1 N HCI 99 101
Buffer pH 7.4 102 102
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
Stability of desglymidodrine
Based on a calibration curve of desglymidodrine
Condition Glass
0 days 14 days 21 days
25C/60%RH 100 103 100
25C/60%RH 1.2mioluxh- 103 -
40C175%RH - 102 100
Condition Open petri
dish
0 days 14 days 21 days
25C/60%RH 100 102 100
40C/75%RH - 102 97
5 Stability of desglymidodrine plain tablets 4 mg
Based on calculated curved of desglymidodrine
Condition Glass
0 days 14 days 21 days
25C/60%RH 4.0 4.0 4.0
25CI60%RH 1.2mioluxh- 4.0
40C175%RH - 4.0 3.9
Based on calculated curved of desglymidodrine
Condition Open petridish
0 days 14 days 21 days
25C/60%RH 4.0 4.1 4.0
40C/75%RH - 4.0 3.9
The results shown above clearly indicates that desglymidodrine in the specific
tablet
composition is stable for at least 21 days. The experiments have also be
conducted under
stressed temperature conditions (40 °C), and it is contemplated that
the shelf-live of a
composition according to the invention, i.e. the time period from the
manufacture of the
composition and until the content of desglymidodrine in the composition has
changed
more than ~10% w/w, at room temperature is at least 6 months such as, e.g. at
least 1
year, at least 1.5 years, at least 2 years, at least 2, 5 years, 3 years, 4
years or 5 years.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
71
Example 15
Powder preparation e.g for use in a needle-free device
Composition:
I Desglymidodrine 1000.0 g
The particle size distributions for the ingredients should be appropriate for
deposition of
the composition in an appropriate layer of the skin e.g. 0.5 pm to 10 pm.
The powder is filled into a drug casette, each containing 4 mg
desglymidodrine.
Suspending agents such as glucose, lactose, celluloses, starches (maize-, rice-
,
potato-), calcium phosphate or mixtures of these may be used.
Example 16
Liquid composition for use in a needle-free device
Composition:
I Desglymidodrine 40.0 g
II Sodium edetate 0.5 g
Disodium hydrogen phosphate dehydrate2.0 g
Sodium dihydrogen phosphate dehydrate2.0 g
III Water for injection 900.0 g
IV Water for injection ad 1000.0
g
I is dissolved in III upon continuous stirring. The remaining solid
ingredients (II) are added
to the solution one by one during continuous stirring. Following complete
dissolution of the
solids, purified water is added to a total weight of 1000.0 g.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
72
The formulation is filtrated (0,22 pm) and is filled into glass devices with a
piston (e.g.
teflon) and a stopper (e.g. rubber (natural or synthetic substances)).
Tonicity agents may be dextrose, glycerol, sorbitol, mannitol, potassium
nitrate and
sodium sulphate decahydrate or mixtures thereof.
pH may be adjusted to the appropriate value by use of additional buffer salts
such as citric
acid, sodium citrate, and potassium dihydrogen phosphate or mixtures of these.
Example 17
Liquid compositions for pulmonal delivery
Example 17.1
Pressurised metered-dose preparation for inhalation
Composition:
I Desglymidodrine 40.0 g
II Norflurane ad 1000.0 ml
I is dissolved or suspended in liquid II at low temperature during continuous
agitation.
For suspensions, the particle size distribution should be appropriate for
deposition of the
composition in the lung, e.g. 0.5 pm to 10 pm.
The product is filled into suitable pressurised multi-dose containers
delivering e.g.100 p1
pr. dose.
Other propellants such as dichlorodifluoromethane, dichlorotetrafluoroethane
and
trichlorofluoromethane or mixtures of these may be used.
Glidants such as oleic acid and derivatives and isopropyl myristate or
mixtures of these
may be used to reduce friction during administration.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
73
Example 17.2
Liquid for nebulisation
Composition:
I Desglymidodrine 2.0 g
II Sodium edetate 0.5 g
Disodium hydrogen phosphate dehydrate 2.0 g
Sodium dihydrogen phosphate dehydrate 2.0 g
11! Purified water 900.0 g
IV Purified water ad 1000.0 g
I is dissolved in III upon continuous stirring. The remaining solid
ingredients (II) are
added to the solution one by one during continuous stirring. Following
complete
dissolution of the solids, purified water is added to a total weight of 1000.0
g.
The composition is filled into 2 ml ampoules or other suitable unit-dose
containers.
Other excipients may also be added such as polyethylene glycol, alcohol,
glycofurol,
phospholipids, poloxamer, polyoxyethylene castor oil derivatives,
polysorbates, propylene
glycol and cyclodextrins or combinations of these.
Tonicity agents may be e.g dextrose, glycerol, sorbitol, mannitol, sodium
chloride,
potassium nitrate and sodium sulphate decahydrate or mixtures thereof.
pH may be adjusted to the appropriate value by use of additional buffer salts
such as citric
acid, sodium citrate, and potassium dihydrogen phosphate or mixtures of these.
Sufficient microbiological preservation may be achieved by addition of
benzalconium
chloride or parabenes. Suitable flavours can be added to the composition and
use of
sweeteners such as saccharin, acesulfame, aspartame, cyclamate salts or
mixtures of
these can further adjust the taste.
Example 18
Powder composition for pulmonal delivery
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
74
Composition:
I Desglymidodrine 400.0 g
II Glucose 500.0 g
The particle size distributions for the ingredients should be appropriate for
deposition of
the composition in the lung, e.g. 0.5 pm to 10 pm. I and II are carefully
mixed and sieved.
The powder is filled into capsules or other suitable unit-dose containers,
each containing
mg of the composition.
Other suspending agents such as lactose, celluloses, starches (maize-, rice-,
potato-)
calcium phosphate or mixtures of these may be used.
Example 19
Nasal compositions
General description of a nasal composition
A nasal composition of desglymidodrine is buffered, and tonicity adjusted and
it can be
delivered from a device, which may or may not require the presence of
antimicrobial
agents in the composition. The amount of desglymidodrine reaching the systemic
circulation may be increased by addition of absorption enhancer(s) to the
composition.
The variability of a nasal composition
The total amount of absorption enhancers included in the composition will,
typically, vary
between 0.01 % and 10%. However, some absorption enhancers may also serve as
vehicles and thereby totally replace the content of water in the composition.
One can
include one, two or several absorption enhancing agents in the composition.
The final
nasal composition may be a homogenous liquid, a suspension, an emulsion, a gel
or a
powder. The dose administered intranasally may be adjusted by choice of the
volume of
the formulation, ranging from 10 p1 to 250 p1 per nostril or of the mass of
the composition,
ranging from 5 mg to 50 mg.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
Specific examples of nasal compositions
Example 19.1
5 Nasal composition without absorption enhancer
Composition: Function of
ingr.
I Desglymidodrine 40.0 g Active ingr.
II Sodium edetate 0.5 g Stabiliser
10 Disodium hydrogen phosphate dehydrate2.0 g Buffer component
Sodium dihydrogen phosphate dehydrate2.0 g Buffer component
III Purified water 900.0 Solvent
g
IV Purified water ad to 1000.0 Solvent
g
15 I is dissolved in III upon continuos stirring. The remaining solid
ingredients (II) are added
to the solution one by one during continuos stirring. Following complete
dissolution of the
solids, purified water is added to a total weight of 1000.0 g.
The composition is filled into appropriate nasal spray devices delivering e.g.
100 p1
20 pr.dose.
pH may be adjusted to the appropriate value by use of additional buffer salts
such as citric
acid, sodium citrate and potassium dihydrogen phosphate or mixtures of these.
Sufficient
microbiological preservation may be achieved by addition of benzalconium
chloride,
25 sorbic acid or parabenes such as methylparaben, ethylparaben, propylparaben
and
butylparaben or mixtures of these.
Example 19.2
30 Nasal composition with absorption enhancer
Composition: Function of ingr.
I Desglymidodrine 40.0 g Active ingr.
II Sodium glycocholate 5.0 g Abs. enhancer
35 III Sodium edetate 0.5 g Stabiliser
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
76
Disodium hydrogen phosphate dihydrate 2.0 g Buffer component
Sodium dihydrogen phosphate dihydrate 2.0 g Buffer component
IV Purified water 900.0 g Solvent
V Purified water to 1000.0 g Solvent
II is dissolved in IV, and I is added upon continuous stirring. The remaining
solid
ingredients (III) are added to the solution one by one during continuos
stirring. Following
complete dissolution of the solids, purified water is added to a total weight
of 1000.0 g.
The composition is filled into appropriate nasal spray devices delivering e.g.
100 p1
pr.dose.
One, two or several of the absorption enhancers sodium cholate, sodium
deoxycholate,
sodium taurocholate, sodium taurodeoxycholate, sodium glycodeoxycholate, a-
cyclodextrin, (3-cyclodextrin, y-cyclodextrin, methyl cyclodextrin,
hydroxypropyl-j3-
cyclodextrin, dimethyl-(3-cyclodextrin, sodium taurodihydrofusidate,
phosphatidylcholines,
chitin, chitosan, hyaluronic acid, polyetylene glycols, starch microspheres
and dextran
microspheres may be included in the composition.
pH may be adjusted to the appropriate value by use of additional buffer salts
such as citric
acid, sodium citrate and potassium dihydrogen phosphate or mixtures of these.
Sufficient
microbiological preservation may be achieved by addition of benzalconium
chloride,
sorbic acid or parabenes such as methylparaben, ethylparaben, propylparaben
and
butylparaben or mixtures of these.
General description of a composition containing liposomes
Liposomes, or lipid vesicles, are spherical self-closed structures composed of
concentric
bilayers that entrap part of the solvent or active drug substance in the
central core or in
the bilayer depending on the hydrophilicity of the active drug substance.
Liposomes are
predominantly made of natural amphiphilic lipids, e.g. phospolipids. Liposomes
are likely
to enhance the penetration of the active ingredient into the mucosa such as,
e.g. the
nasal, buccal, oral, rectal or vaginal mucosa.
Description of the variability of a liposomal composition
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
77
The liposomes can be based on liposome forming lipids and liposome stabilising
or
destabilising lipids. The total amount of lipids in the composition can vary
between 20-
80% w/w. The ratio between liposome forming lipids and
stabilising/destabilising lipids can
be between 1:1 to 40:1 (on a molar basis) or the composition can contain
liposome
forming lipids alone. One can include one, two or several liposome forming
lipids in the
composition.
Example 19.3
Nasal composition with liposomes
Composition: Function of
ingr.
I Desglymidodrine 40.0 g Active ingr.
Disodium hydrogen phosphate dehydrate2.0 g Buffer component
Sodium dihydrogen phosphate dehydrate2.0 g Buffer component
II Purified water 900.0 g Solvent
III Purified water to 1000.0 Solvent
g
IV DSPC 300.0 g Liposome forming
CH 84.0 g Liposome
stabiliser/
destabiliser
I is dissolved in II upon continuos stirring. Following complete dissolution
of the solids,
purified water is added to a total weight of 1000.0 g.
The dry mix of DSPC:CH (7 mol DSPC :2 mol CH) (IV) is dispersed in water, and
dehydrated.The liquid composition containing desglymidodrine is poured into
the
dehydrated DSPC:CH during vigorous stirring to rehydrate the mixture of
DSPC:CH.
pH may be adjusted to the appropriate value by use of additional buffer salts
such as citric
acid, sodium citrate and potassium dihydrogen phosphate or mixtures of these.
Sodium
edetate may be added to the composition as stabiliser. Sufficient
microbiological
preservation may be achieved by addition of sorbic acid or parabenes such as
methylparaben, ethylparaben, propylparaben and butylparaben. Propylene glycol
(10%)
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
78
can be added to potentiate the antimicrobial activty of the parabens in the
presence of
some amphiphilics.
The composition is filled into appropriate nasal spray devices delivering the
desired dose.
The volume of the dose can be between 10-250 p1, preferably 100 p1. The dose
can also
be administrered by application of two puffs, one in each nostril.
Other vesicle forming lipids can also be used instead of DSPC in the lipid
bilayer. These
amphiphilic lipids may be cationic, anionic or neutral, such as DPPC, DLPC,
DOPC,
DSEPC, dialkyl (C$-C2o) sulfosuccinate or fatty alcohol ethoxylate (with alkyl
chain length
of C$-Czo and 4 to 6 ethoxy groups). The molecular amount of lipids compared
to active
compound can be optimised with different liposome building lipids.
CH can be replaced by cholesterol derivatives or any other
stabiliser/destabiliser such as
alkyl (Cs-C2o) phosphate, alkyl (C$-C2o) sulfate, alkyl (C$-Czo) ethersulfate,
alkyl (Ca-Cao)
ether carboxylate. Further stabilisers/destabilisers can be employed such as
stearoyl
lysophosphatidyl choline, lysophosphatidylcholine, palmitoyl lysophosphatidyl
choline and
didecanoyl phosphatidyl choline.
Example 20
Buccal compositions
General description of a buccal composition
A buccal composition of desglymidodrine is buffered and tonicity adjusted. It
can be
delivered from a device, which may or may not require the presence of
antimicrobial
agents in the formulation. The amount of desglymidodrine reaching the systemic
circulation may be increased by addition of absorption enhancer(s) to the
composition.
The variability of the buccal composition
The total amount of absorption enhancers included in the composition will,
typically, vary
between 0.01 % and 10%. However, some absorption enhancers may also serve as
vehicles and thereby totally replace the content of water in the formulation.
One can
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
79
include one, two or several absorption enhancing agents in the formulation.
The final
buccal formulation may be a homogenous liquid, a suspension, an emulsion, a
gel or a
powder. The dose administered buccally may be adjusted by choice of the volume
of the
formulation, ranging from 10 p1 to 500 p1 or the mass of the composition,
ranging from 5
mg to 100 mg.
Example 20.1
Buccal composition with liposomes
Composition: Function of ingr.
I Desglymidodrine 40.0 g Active ingr.
Disodium hydrogen phosphate dihydrate2.0 g Buffer component
Sodium dihydrogen phosphate dihydrate2.0 g Buffer component
II Purified water 900.0 Solvent
g
III Purified water to 1000.0 Solvent
g
IV DSPC 300.0 Liposome forming
g
CH 84.0 g Liposome stabiliser/
destabiliser
I is dissolved in II upon continuos stirring. Following complete dissolution
of the solids,
purified water is added to a total weight of 1000.0 g.
The dry mix of DSPC:CH (7 mol DSPC:2 mol CH) (IV) is dispersed in water, and
dehydrated. The liquid composition containing desglymidodrine is poured into
the
dehydrated DSPC:CH during vigorous stirring to rehydrate the mixture of
DSPC:CH.
pH may be adjusted to the appropriate value by use of additional buffer salts
such as citric
acid, sodium citrate and potassium dihydrogen phosphate or mixtures of these.
Sodium
edetate may be added to the composition as stabiliser. Sufficient
microbiological
preservation may be achieved by addition of sorbic acid or parabenes such as
methylparaben, ethylparaben, propylparaben and butylparaben. Propylene glycol
(10%)
can be added to potentiate the antimicrobial activty of the parabens in the
presence of
some amphiphilics.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
The composition is fiilled into appropriate buccal spray devices delivering
the desired
dose. The volume ofi the dose can be between 10-500 p1 or the dose can be
administrered by application of multiple puffs.
5 Other vesicle forming lipids can also be used instead ofi DSPC in the lipid
bilayer. These
amphiphilic lipids may be cationic, anionic or neutral, such as DPPC, DLPC,
DOPC,
DSEPC, dialkyl (C8-C2o) sulfosuccinate or fatty alcohol ethoxylate (with alkyl
chain length
of C$-C2o and 4 to 6 ethoxy groups). The molecular amount of lipids compared
to active
compound can be optimised with different liposome building lipids.
CH can be replaced by cholesterol derivatives or another
stabiliserldestabiliser such as
alkyl (C$-Cao) phosphate, alkyl (C$-Coo) sulfate, alkyl (C$-C2o) ethersulfate,
alkyl (C$-C2o)
ether carboxylate.
LIST OF ABBREVIATIONS
CH cholesterol
DSPC distearoyl glycero phosphatidyl
choline
DSEPC distearoyl glysero ethyl phosphatidyl
choline
DPPC dipalmitoyl phosphatidyl choline
DLPC dilauroyl phosphatidyl choline
DOPC dioleoyl phosphatidyl choline
PC phosphatidyl choline
Example 20.2
Buccal composition without absorption enhancer
Composition: Function of
ingr.
I Desglymidodrine 40.0 g Active ingr.
II Sodium edetate 0.5 g Stabiliser
Disodium hydrogen phosphate dihydrate2.0 g Buffer component
Sodium dihydrogen phosphate dihydrate2.0 g Buffer component
III Purified water 900.0 g Solvent
IV Purified water to 1000.0 Solvent
g
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
81
I is dissolved in III upon continuos stirring. The remaining solid ingredients
(II) are added
to the solution one by one during continuos stirring. Following complete
dissolution of the
solids, purified water is added to a total weight of 1000.0 g.
The composition is filled into appropriate buccal spray devices delivering
e.g. 100 p1
pr.dose.
pH may be adjusted to the appropriate value by use of additional buffer salts
such as citric
acid, sodium citrate and potassium dihydrogen phosphate or mixtures of these.
Sufficient
microbiological preservation may be achieved by addition of benzalconium
chloride,
sorbic acid or parabenes such as methylparaben, ethylparaben, propylparaben
and
butylparaben or mixtures of these.
Example 20.3
Buccal composition with absorption enhancer
Composition: Function of
ingr.
I Desglymidodrine 40.0 g Active ingr.
II Sodium glycocholate 5.0 g Abs. enhancer
III Sodium edetate 0.5 g Stabiliser
Disodium hydrogen phosphate dihydrate2.0 g Buffer component
Sodium dihydrogen phosphate dihydrate2.0 g Buffer component
IV Purified water 900.0 g Solvent
V Purified water to 1000.0 Solvent
g
II is dissolved in IV, and I is added upon continuous stirring. The remaining
solid
ingredients (III) are added to the solution one by one during continuos
stirring. Following
complete dissolution of the solids, purified water is added to a total weight
of 1000.0 g.
The composition is filled into appropriate buccal spray devices delivering
e.g. 100 p1
pr.dose.
One, two or several of the absorption enhancers sodium cholate, sodium
deoxycholate,
sodium taurocholate, sodium taurodeoxycholate, sodium glycodeoxycholate, a-
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
82
cyclodextrin, ~3-cyclodextrin, y-cyclodextrin, methyl cyclodextrin,
hydroxypropyl-~3-
cyclodextrin, dimethyl-~3-cyclodextrin, sodium taurodihydrofusidate,
phosphatidylcholines,
chitin, chitosan, hyaluronic acid, polyetylene glycols, starch microspheres
and dextran
microspheres may be included in the composition.
pH may be adjusted to the appropriate value by use of additional buffer salts
such as citric
acid, sodium citrate and potassium dihydrogen phosphate or mixtures of these.
Sufficient
microbiological preservation may be achieved by addition of benzalconium
chloride,
sorbic acid or parabenes such as methylparaben, ethylparaben, propylparaben
and
butylparaben or mixtures of these.
Example 21
Desglymidodrine sublingual tablets
General description
Sublingual tablets are designed to give a fast disintegration in the mouth by
the amount of
salvia normally available in that region. The disintegration time is therefore
very short or
short and there may be additives, which promote salvia secreting in the
composition.
A fast disintegration together with a high solubility of the drug substance
give the
possibility of a fast absorption through the mucous membrane of the mouth,
especially
under the tongue where the blood vessels run close to the surface.
Sublingual absorbed drugs avoid more or less the first pass liver metabolism.
Description of variability in sublingual compositions
Sublingual tablets may be prepared by mould technique, by direct compression
or by
conventional wet granulation or dry granulation (e.g. roller compaction) of
the ingredients.
As mentioned, taste improving substances may be added to promote salvia
secretion.
This may include artificial sweeteners (cyclamate, saccharin sodium,
aspartame, etc.),
natural sweeteners (saccharose, sorbitol, xylitol, etc.), week organic acids
(citric-, acetic-,
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
83
ascorbic acid, etc.) natural or artificial flavours (strawberry, black
currant, pineapple,
apple, orange, lemon, etc.) in the below mentioned compositions.
Example 21.1
Composition: Function
I Desglymidodrine 2.0 g 4.0 Active
g ingr.
II Purified water Solvent
Ethanol 96% equal parts q.s. q.s. Moist.
agent
III Lactose 53 g 51 g Filler
Mannitol 45 g 45 g Filler
The amounts of lactose and mannitol may be varied from 25 to about 100 g. Dose
100 mg
(50-200 mg) corresponds to 2.0 or 4.0 mg desglymidodrine of the two
compositions,
respectively.
Disintegration time is extremely short (2-5 sec).
II is prepared, and I is dissolved in II. The solution is incorporated in III
to a homogeneous
mixture is achieved. More II may be added.
The moistured mass is spread on a suitable plate equipped with wholes into
which the
mass is pressed and which have a depth that gives the wanted dose of drug
substance.
The wet mass is pressed out of the wholes and allowed to dry before further
handling.
(Sublingual tablet preparation by mould-technique).
II may be replaced by mixtures of different volatile organic solvents and may
have a water
content of 0 - 90%. III may be replaced by different mixtures of soluble
pharmaceutically
acceptable excipients as sorbitol, mannitol, xylitol, maltodextrin, lycasin,
lactitol etc.
Example 21.2
Composition: Function
I Desglymidodrine 2.0 g 4.0 g active ingr.
II Tablettose 55.0 g 55.0 g filler
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
84
III Cellulose, microcryst.10.0 g 10.0 g filler/binder
Type 102
IV Agar sieve 180 5.0 g 5.0 g disintegrant
V Magnesium stearate 0.5 g 0.5 g glidant/lubricant
Talc 4.5 g 4.5 g glidant/lubricant
I is mixed with I I and further with III, IV and V and compressed into
tablets.
The amount of the filler, tablettose, may vary from 25 to 75 g, the
filler/binder (cellulose)
may vary from 5 to 25 g, the disintegrant from 1 to 15 g, magnesium stearate
from 0.1 to
2.5 g and talc from 1.0 to 10 g.
Mass weight of 77 mg corresponds to a dose of 2.0 mg or mass weight of 79 mg
corresponds to a dose of 4.0 mg desglymidodrine in the two compositions,
respectively.
Disintegration time is short (30 sec - 4 min).
Tablettose may be replaced by other qualities of lactose with good
flowability.
Agar may be replaced by other disintergrants as croscarmellose sodium/calcium
or the
like, crosspovidone, starch glycolate, alginates or other disintegrants.
Magnesium stearate
may be replaced by other glidants as different types of silica colloidal
hydrous or
anhydrous, Ca-stearate, stearic acid, sodium stearylfumarate, cotton-seed oil,
hydrogenated vegetable oils or other suitable lipid substances as e.g.
Myvatex.
Example 21.3
Composition: Function
I Desglymidodrine 2.0 g 4.0 g active ingr.
II Maize starch 9.5 g 7.0 g filler
Lactose 66 g 66 g filler
III Povidone 30 2.5 g 2.5 g binder
IV Purified water q.s. q.s. solvent
V Mannitol 36 g 36 g filler/taste
VI Magnesum stearate 1.5 g 1.5 g lubricant
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
I is mixed with II and granulated with III dissolved in IV. More IV may be
added. After
drying, V and VI are added and tablets are compressed.
The amount of maize starch may vary from 5 to 15 g, lactose from 30 to 100 g,
mannitol
5 from 10 to 80 g, and magnesium stearate from 0.5 to 5 g.
Disintegration time is about 5 min.
Maize starch may be replaced by other suitable starches such as rice- or
potato starch.
10 Lactose may be replaced by maltodextrine, dextrin etc.
Povidone 30 may be replaced by povidone VA 64 or 90 or gelatine or
pregelatinized
starch or different types of cellulose (methylcellulose, hydroxypropyl
cellulose etc.).
Mannitol may be replaced by sorbitol, xylitol, maltitol, maltodextrin,
lactitol, etc.
Magnesum stearate may be replaced by other glidants as different types of
colloidal silica
15 hydrous or anhydrous, Ca-stearate, stearic acid, sodium stearylfumarate,
cotton-seed oil,
hydrogenated vegetable oils or other suitable lipid substances as e.g.
Myvatex.
Example 22
20 Desglymidodrine melt tablets
General description of melt tablets
Melt-tablets are also referred to as fast/rapidly- disintegrating tablets,
dispersing tablets
25 and dissolving tablets. In this example, the term "melt-tablet" is applied.
Melt-tablets are a tablet dosage form for oral administration, one that
disintegrates
instantaneously and releasing the drug, which dissolves or disperse rapidly in
saliva and
afterwards swallowed without the need for water. The drug substance is
absorbed via the
30 gastrointestinal tract.
Less frequently melt-tablets are designed in a way so the drug substance are
to be
absorbed through the buccal mucosa. In that case the bioavailability of the
drug from the
melt-tablet may be even greater than observed for standard dosage forms.
Further more
35 side-efFects may be reduced if they are caused by first-pass metabolites.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
86
A description of the variability of the melt-tablets
Techniques currently applied for formulate melt-tablets are namely freeze-
drying
(lyophilisation), spray drying, tablet moulding and direct compression. In
this example only
melt-tablets prepared by lyophilisation are described.
To ensure melt-tablets fast- disintegrating and dissolving attribute water
must quickly
progress into the tablet matrix to cause rapid disintegration and
instantaneous dissolution
of the tablet. Maximising the porous structure of the tablet matrix and
incorporating
appropriate disintegrating agent and/or highly water-soluble excipients in the
tablet
formulation are the basic approaches applied in the current melt-tablet
technologies.
In the formulation the total amount of disintegrating agents and/or highly
water-soluble
excipients can vary between 5-80% (w/v) and the total amount of binding agents
can vary
between 0.05-5% (w/v). Water is used to ensure the porous structure.
Sufficient
microbiological preservatives (benzoic acid, methylparaben etc.) may be added
to prevent
microbiological growth of the aqueous solution during production. When the
product has
been dried, the preservative has no further function.
Taste improving agents may be added to promote salvia secretion. This may
include
artificial sweeteners (aspartame, cyclamate, saccharin etc.), natural
sweeteners (sucrose,
sorbitol, xylitol etc.) week organic acids (citric-, ascorbic acid etc.),
natural or artificial
flavours (strawberry, black currant, pineapple, apple, orange, lemon etc.).
Colouring
agents may also be added to give the melt-tablets elegance and identity.
Permeation enhancers (sodium lauryl sulphate etc.) may be added to optimise
the
transmucosal absorption and pH-adjusting excipients (hydrochloride, sodium
hydroxide
etc.) may be used to optimise the chemical stability of the drug. Collapse
protecting
agents (glycine etc.) to prevent the shrinkage of the tablet during
lyophilisation process or
during long-term storage.
Melt-tablet prepared by lyophilisation
Composition: Function of ingredient
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
87
I Desglymidodrine 4.0 g Active
II Maltodextrin 200 g Water-soluble
III Xanthan gum 20 g Binding agent
IV Purified water 776 g Solvent
II and III are dissolved in IV upon continuos stirring and I is added to the
solution during
stirring. Purified water is added to a total weight of 1000.0 gram.
The solution is filled in PVC blister with a diameter of 15 mm and a depth of
6 mm, so the
resulting dose of Desglymidodrine is 4.0 mg pr. tablet.
The blisters are placed on the shelves of the freeze-dryer. Samples are frozen
to -45°C at
a rate of 0.5°C/min and kept at this temperature for 1.5 hour.
Primarily, drying is
performed by keeping the blisters for 8 hour at a pressure of 1 mbar, a shelf
temperature
of -10°C, and a condensor temperature of -60°C.
Reducing the pressure to 0.1 mbar, carrying out secondary drying and
increasing the
shelf temperature to 25°C. Secondary drying time is 6 hour.
Lyophilisation is terminated
by venting the drying chamber with air.
II may be replaced by lactose, mannitol, dextrose, xylitol, fructose, sucrose,
maltose,
sorbitol etc. or mixtures of these. As disintegrating agent croscarmellose,
crospovidone
etc. may be added. Other excipients may also be used instead of III. These
excipients
may be gelatine, tragacanth gum, agar, acacia, alginate, dextran, povidone,
hydroxyethylcellulose etc. or mixtures of these.
Example 23
Desglymidodrine rectal compositions
General description
Rectal solution is a way of drug administration, which can be used
independently of the
condition of the patient. Furthermore a quite quick onset of effect is seen
for some
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
88
compositions. A major part of the absorbed drug dose does not undergo first
pass
metabolism, which in some cases may be an advantage.
Description of variability in composition
The amount of rectal solution to give one dose is kept on the small amount of
1-4 ml such
as, e.g., 2.0 ml. This is to avoid any emptying reflex from the rectum mucosa
after
applying the solution in the rectum. The solution will be dispensed in a
suitable container
as a single-dose syringe or sealed plastic tube. Both equipped with a suitable
tip.
The following examples have been chosen to illustrate formulation of a rectal
solution.
24.1: A solution with high content of pharmaceutical acceptable organic
solvent to
promote absorption, 24.2: A simple aqueous isotonic solution, 24.3: A simple
slightly
viscous aqueous isotonic, and finally 24.4: An aqueous pH-adjusted isotonic
solution.
Example 23.1
Composition: Function of ingredient
Desglymidodrine 1.00 g 2.00 g Active ingr.
Glycerol 85% 500 g 500 g Solvent/abs. Enhancer
Purifed water 1000 ml 1000 ml Solvent
One dose of 2.0 ml = 2.0 mg desglymidodrine or 2.0 ml = 4.0 mg
desglymidodrine.
Glycerol may be exchanged with glycofurol, polythylene glycols 200 to 600,
propylene
glycol or similar non-irritant suitable solvent. The amount of glycerol may
vary from about
200 to 800 g.
Example 23.2
Composition: Function of ingredient
Desglymidodrine 1.00 g 2.00 g Active ingr.
Sodium chloride 9.0 g 9.0 g Isotonic agent
Propylis paraoxibenzoate0.2 g 0.2 g Preservative
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
89
Methylis paraoxibenzoate 0.8 g 0.8 g Preservative
Purifed water up to 1000 ml 1000 ml Solvent
The mixture of paraoxibenzoates may be exchanged with other suitable
preservatives.
Dose 2.0 ml = 2.0 mg desglymidodrine or 2.0 ml = 4.0 mg desglymidodrine
Example 23.3
Composition: Function of
ingredient
Desglymidodrine 1.00 g 2.00 Active ingr.
g
Sodium carboxymethylcellulose6.0 g 6.0 Viscosity incr.
g agent
Propylis paraoxibenzoate0.2 g 0.2 Preservative
g
Methylis paraoxibenzoate0.8 g 0.8 Preservative
g
Purifed water up to 1000 ml 1000 Solvent
ml
The mixture of paraoxibenzoates may be exchanged with other suitable
preservatives.
Dose 2.0 ml = 2.0 mg desglymidodrine or 2.0 ml = 4.0 mg desglymidodrine. The
amount
of viscosity increasing agent may vary from about 2 to about 8 g.
Example 23.4
Composition: Function of
ingredient
Desglymidodrine 1.00 g 2.00 Active ingr.
g
Sodium acetate 1.0 g 1.0 Buffer agent
g
Sodium chloride 8.5 g 8.5 Isotonic agent
g
Propylis paraoxibenzoate0.2 g 0.2 Preservative
g
Methylis paraoxibenzoate0.8 g 0.8 Preservative
g
Purifed water up to 1000 ml 1000 Solvent
ml
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
The mixture of parabenzoates may be exchanged by other suitable preservative.
Sodium acetate may be exchanged by other suitable pH regulating substance or a
buffer
mixture with pH in the interval of 7.0 - 8Ø The amount of buffer agent may
vary from
about 0.5 to about 3.0 g.
5
Dose 2.0 ml = 2.5 mg desglymidodrine or 2.0 ml = 4.0 mg desglymidodrine.
Example 24
10 Desglymidodrine oral drops
General description of oral drops
Oral drops are a dosage form for peroral administration. The formulation
allows the
15 patient to use a dose of 5 -15 drops of the product and, optinally, dilute
this dose in water
or other better tasting liquids (e.g. orange juice) before ingestion.
Description of variability in composition
20 The amount of oral drops containing one drug dose is kept at the small
amount of 5 -15
drops. The standard volume of drops is normally 10 - 25 ml in a bottle
equipped with a
suitable tip. This tip is constructed to deliver the drops with a speed
suitable for counting
the drops as they leave the tip, when the bottle is turned around with the
button up.
This aggregate has to confirm with Ph. Eur demands.
Example 24.1
Composition: Function of ingredient
Desglymidodrine 10.0 g Active ingr.
Ethanol 96% 120 g Solvenfi/preservative
Purified water up to 1000 ml Solvent
One dose of 2.0 mg is equivalent to approximately 6 drops (have to be measured
exactly), normally ingested in 20 - 200 ml water or other drinkable fluid.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
91
Example 24.2
Composition: Function of
ingredient
Desglymidodrine 10.0 g Active ingr.
Propyl paraoxibenzoate 0.2 g Preservative
Methyl paraoxibenzoate 0.8 g Preservative
Purified water up to 1000 ml Solvent
The mixture of paraoxibenzoates may be exchanged with other suitable
preservatives.
One dose of 2.0 mg is equivalent to approximately 4 drops (have to be measured
exactly), this does is normally ingested in 20 - 200 ml water or other
drinkable fluid.
Example 25
Desglymidodrine oral solution
General description of oral solution
Oral solution is for peroral administration. The oral solution is in the form
of a solution of
the drug substance in a suitable and well tasting vehicle.
Description of variability in composition
Oral solution is normally given in a volume of 2.0 -15 ml measured with a
suitable device,
which is able to give the desired volume with the specified (Ph.Eur.)
precision. Oral
solution may be taste masked and may be formulated with or without sugar,
furthermore
viscosity-increasing substance may be added to make to make the handling and
administration of the solution easier.
Example 25.1
Composition: Function of ingredient
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
92
Desglymidodrine 0,400 g 0.800 g Active ingr.
Sucrose 760 g 760 g Sweetener
Purified water up to 1000 ml 1000 ml Solvent
5.0 ml equivalent to 2.0 mg or 4.0 mg
Preservative may be added.
0.1 N HCI may be added to adjust pH in the interval 2.5 - 3.5.
Example 25.2
Composition: Function of
ingredient
Desglymidodrine 0.800 g Active ingr.
Black currant juice 240 g Taste masking
Sorbitiol 400 g Sweetener
Potassium sorbate 0.14 g Preservative
Levomenthol 0.044 g Taste masking
Ethanol96% ~ 0.176 Solvent
Purified water up to 1000 ml Solvent
0.1 N HCI may be added to adjust pH in the interval 2.5 - 3.5.
The concentration of the active ingredient may be changed in the interval of
0.1 to 10 g if
needed.
Potassium sorbate may be exchanged with other suitable preservatives.
Black currant juice may be exchanged with other fruit juices or mixtures of
these.
Sorbitol may be exchanged with other sweetener as mannitol, xylitol,
maltodextrin,
lycasin, lactitol etc. or mixtures of these.
Levomenthol may be exchanged with other taste masking ingredients: natural or
artificial
flavours (strawberry, black currant, pineapple, apple, orange, lemon etc. or
mixtures of
these).
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
93
Artificial sweeteners (aspartame, cyclamate, saccharin etc) and/or week
organic acids
(citric-, ascorbic acid etc.) may also be added.
Colours may also be added to improve the organoleptic properties.
Example 25.3
Composition: Function of
ingredient
Desglymidodrine 0.800 g Active ingr.
Poloxamer 8000 6.00 g Solubilizer
Methyl parahydroxybenzoate1.10 g Preservative
Anis oil 0.13 g Taste masking
Eucalyptol 0.17 g Taste masking
Ethanol96% 0.176 Solvent
Hydrogenated glucose syrup385 g Sweetener
Purified water up to 1000 ml Solvent
0.1 N HCI may be added to adjust pH in the interval 2.5 - 3.5.
Poloxamer 8000 may be exchanged with other GRAS accepted surFactants.
The composition of this example has a high content of taste masking
ingredients, which
explains the need for a surfactant.
Dose 5.0 ml equivalents 4.0 mg desglymidodrine.
Example 26
Desglymidodrine solution for infusion or injection
General description of solutions for infusion or injection
Solution for infusion is a ready for use solution aimed for infusion in one of
the major
veins. Solutions for injection may be injected i.v., s.c., i.m. or by any
other suitable route.
The solution is formulated as simple as possible. For stability reasons the pH
may be
adjusted in acidic direction and this cause the infusion time have to run over
a couple of
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
94
minutes. In some cases this is done by injection of a desglymidodrine solution
for infusion
into an already established infusion of glucose or sodium chloride.
Example 26.1
Composition: Function of ingredient
Desglymidodrine 0.400 g 0.800 g Active ingr.
Sodium chloride 9.0 g 9.0 g Isotonic agent
Purified water up 1000 ml 1000 ml Solvent
to
0.1 N HCI at pH 2.5 - 3.5 may be added.
Dose: 2.0 mg in 5 ml or 4.0 mg in 5 ml.
The solution may also be presented in vials or the form of a unit dose e.g. in
ampoules.
Example 27
General description of transdermal drug delivery systems
Transdermal drug delivery systems are designed to deliver a drug substance
through the
skin for systemic circulation and effect. A transdermal drug delivery system
can be
designed to deliver a drug substancento the skin at a given rate.
Drugs reaching the systemic circulation through the skin more or less surpass
the first-
pass metabolism in the liver.
Description of variability in the transdermal drug delivery system
Transdermal drug delivery systems can be prepared in different ways; Drug
substance in
an adhesive type of delivery system, a drug substance in a matrix type of
delivery system
or in a reservoir type of delivery system, or by a combining the different
types of
preparation techniques. The three types of delivery systems offer different
ways in
controlling the release of drug from the delivery system into the skin.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
The formulation principle of the three different systems are described in the
following:
Drug substance in an adhesive type of delivery system
5 Backing: The backing is a filmforming polymer e.g. containing
ethylcellulose,
plastic and/or alufoil or other impermeable material.
Adhesive layer: The adhesive layer may contain an adhesive, pressure sensitive
polymer layer, e.g. polyacrylate, ethylcellulose or silicone.
10 An enhancer like; e.g. lauric acid, dioctylcyclohexane, glycerin, n-
dodecanol, Eutanol G, isopropylmyristat, PEG 400, propandiol and/or
Tween 80 may be added.
Drug: The drug substance can be dissolved or dispersed in the adhesive layer
15 e.g. by a solvent casting or hot melt process. The drug substance can
be incorporated in the adhesive layer as microreservoirs.
Liner: A protective liner, to be removed before use, is attached to the
adhesive
side.
Drug substance in a matrix type delivery system
Backing: The backing is a filmforming polymer e.g. containing ethylcellulose,
plastic and/or alufoil or other impermeable material.
Matrix: The matrix may contain a hydrophilic or lipophilic polymer matrix
comprising e.g. polyisobutylene.
An enhancer like; lauric acid, dioctylcyclohexane, glycerin, n-dodecanol,
Eutanol G, isopropylmeristat, PEG 400, propandiol or Tween 80 may be
added.
Drug: The drug substance is dispersed in the matrix layer or it may be
incorporated in the matrix by a moulding process or be incorporated in
the layer as microreservoirs.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
96
Membrane: A rate controlling membrane e.g. of polymeric material might be used
to
control the diffusion of the drug into the skin. An adhesive layer might be
applied on the membrane. The membrane might be omitted.
Adhesive layer: The adhesive layer may contain an adhesive, pressure sensitive
polymer layer, e.g. polyacrylate, ethylcellulose or silicone. The adhesive
is applied on the rim of the patch, surrounding the matrix-containing
drug.
Liner: A protective liner, to be removed before use, is attached to the
adhesive
side.
Reservoir type delivery system
Backing: The backing is a filmforming polymer e.g. containing ethylcellulose,
plastic andlor alufoil or other impermeable material.
Reservoir: The reservoir may contain e.g. an unleachable, viscous liquid
medium
(e.g. silicone fluid) or a releasable solvent (e.g. alkyl alcohol or glycerol)
An enhancer like; lauric acid, dioctylcyclohexane, glycerin, n-dodecanol,
Eutanol G, isopropylmeristat, PEG 400, propandiol or Tween 80 may be
added.
Membrane: A rate controlling membrane e.g. of polymeric material is used to
control
the diffusion of the drug into the skin. The membrane can be either a
microporous or a nonporous membrane e.g. ethylene-vinyl acetate
copolymer, with a specific drug permeability. On the external surFace of
the polymeric membrane a thin layer of drug compatible, pressure-
sensitive adhesive copolymer, e.g. silicone adhesive may be applied to
ensure the contact to the skin.
Adhesive layer: The adhesive layer may comprise an adhesive, pressure
sensitive
polymer layer, e.g. polyacrylate, ethylcellulose or silicone . The adhesive
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
97
is applied on the rim of the patch, surrounding the reservoir-containing
drug.
Drug: The drug substance can be dissolved or dispersed in the reservoir layer.
Liner: A protective liner, to be removed before use, is attached to the
adhesive
side.
Example 27.1
The following example illustrates a composition of a drug substance
(desglymidodrine) in
an adhesive transdermal delivery system. A direct contact between the hydrogel
and the
skin is expected to be essential, to ensure a sufficient flux through stratum
corneum.
Backing: The backing is a filmforming polymer e.g. constaining ethylcellulose,
plastic and/or alufoil or other impermeable material.
Adhesive layer: The adhesive layer consists of an adhesive, pressure sensitive
polyacrylate. The size of the adhesive layer is about 16-20 cm2, forming
a rim around the active layer. The layer contains 0.3-1.0 % of
desglymidodrine base, to prevent a flux of desglymidodrine base from
the active layer to the adhesive layer.
Active layer: The drug substance, desglymidodrine, is dispersed in a hydrogel
comprising polyvinylpyrrolidone or partly hydrolised polyvinylic alcohol
with a resulting concentration of 15-25% w/w desglymidodrine base. The
size of the layer is about 10 cm2.
A stabiliser like ~i-cyclodextrin might be added.
Liner: A protective liner, to be removed before use, is attached to the
adhesive
side.
After removal of the liner the drug delivery system is placed on the skin and
the
desglymidodrine is delivered for systemic circulation through the skin.
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
98
Example 28
Pilot bioavailability study of two prototypes of midodrine controlled release
formulations compared to standard formulation (tablet) in healthy volunteers
Introduction
Systolic blood pressure is transiently and minimally decreased in normal
individuals when
rising to upright position. Normal physiologic feedback mechanisms work
through neurally
mediated pathways to maintain the standing blood pressure and thus support
adequate
cerebral perfusion. These compensatory mechanisms that regulate blood pressure
when
standing are deficient in patients with orthostatic hypotension, a condition
that may lead to
inadequate cerebral perfusion with accompanying symptoms of syncope,
dizziness/light-
headedness and blurred vision, among others.
Midodrine is a prodrug labeled for treatment of orthostatic hypotension. After
absorption it
is readily metabolized to desglymidodrine that acts as an agonist at the
peripheral a-1
receptors in the smooth muscles of arteries and veins, but has no direct
central nervous
or cardiac effects. Its main effect is to increase the vascular tone thus
increasing the total
peripheral resistance and rising blood pressure. The pressor effect of
midodrine is
manifest within 20 to 90 minutes after oral administration of a single dose.
This pressor
effect usually persists for 3 to 6 hours. Doses used in clinical practise (10
mg t.i.d.)
significantly increase standing blood pressure, thus alleviating symptoms of
orthostatic
hypotension.
Controlled release formulation
The rationale of the development of a controlled release formulation is to
reduce the
number of dosings during the day and to avoid major changes in plasma
concentration of
desglymidodrine. This will increase compliance and reduces changes in severity
of
symptoms of orthostatic hypotension and thus possibly increase quality of
life.
Two prototypes have been developed according to the present invention. One
prototype
"Micap" is a multiple unit formulation (see Example 12 of PCT application No.
PCT/DK01/00214), each unit releasing its amount of midodrine dependent on the
acidity
of the environment. As the acidity is different in different parts of the gut
the result is a
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
99
continuous release during the passage. The other prototype "Mitab" is composed
of three
layers releasing midodrine differently creating a time-dependent release (see
Example 2
of PCT application No. PCT/DK01/00214). The strength of the controlled release
formulations has been chosen to 5 mg to allow for individual titration of the
total daily
dose. The study is a pilot trial of the bioavailability of the two prototypes
compared to a
standard tablet.
Objective
To determine the bioavailability of two novel prototypes of controlled release
formulations
of midodrine hydrochloride compared to standard tablets.
Trial design
Open-labeled randomized 3 way cross-over trial. All subjects were administered
10 mg
midodrine hydrochloride either as a standard tablet or as one of two novel
controlled
release formulations at three occasions distributed 3 days apart.
Trial population
Eight healty volunteers, both genders, 18-55 years of age, normal weight,
informed
consent, not pregnant or lactating, not trying to become pregnant, no liver,
renal or
gastrointestinal disease that may influence pharmacokinetics or the health of
the
volunteers, no history of alcohol and drug abuse, non-smokers.
Assessments
AUCt (area under the plasma concentration curve to time t), Cmax(peak (or
shoulder or
plateau) plasma concentration), tmaX (time to peak (or shoulder or plateau)
plasma
concentration), MRT (mean residence time), t>~5~,o cm~ (W~5 - duration of
plasma
concentration above 75% Of CmaX), HVD (W5o - half value duration) and time to
a possible
second peak (or shoulder or plateau) were calculated for midodrine and its
biologically
active metabolite, desglymidodrine. AUC;~fni~ (area under the plasma
concentration curve
extrapolated to infinity) and t,,2 (plasma concentration half life) are
calculated, whenever
relevant.
Whenever, the concentration went under the detection limit, the values were
set to'/ x
detection limit, i.e. for midodrine'h x 1 ng/ml and for desglymidodrine'h x
0.5 ng/ml.
Because of such a contribution to the AUC, AUC24 was often larger than
AUC~nfinity~
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
100
Trial products
Midodrine tablets 5 mg, Gutron from Nycomed, Denmark, midodrine controlled
release
formulation (pH dependent release) prepared as described in Example 12 of PCT
application No. PCT/DK01/00214, 5 mg, and midodrine controlled release
formulation
(time dependent release) prepared as described in Example 2 of PCT application
No.
PCT/DK01 /00214, 5 mg.
Food and liquid
The subjects were fasting from 8 hours before dosing until 3 hours post
dosing. Water
was allowed until 1 hour before dosing. No alcoholic beverages or beverages
containing
caffeine (coffee, tea or cola) are allowed from 8 hours before dosing until
last blood
sample has been drawn (24 hours).
Study drug was administered to the subjects with 150 ml of water. Additional
150 ml of
water was administered to the subjects 1 and 2 hours after dosing.
Meals were standardized throughout all 3 study visits and served according to
the
following schedule:
4 hours after dosing: lunch
7 hours after dosing: snack
10 hours after dosing: dinner
14 hours after dosing: snack
Study drug
Two tablets or capsules of study drug (midodrine tablets, Mitab or Micap)
(total dose 10
mg) were administered between 7.30 and 8.30 am. Administration of study drug
is
followed by at least three days washout.
Blood samples
Seven ml of venous blood were withdrawn immediately before dosing, and at 15
and 30
minutes, 1, 1.5, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 20 and 24 hours
after dosing. The
blood samples were placed on ice immediately after drawing and centrifuged and
frozen
within 20 minutes. Analysis for midodrine and desglymidodrine was performed by
HPLC
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
101
with fluorescence detection. The analyses were performed by Quintiles AB,
Uppsala,
Sweden.
Results
The mean plasma concentration curves for midodrine and desglymidodrine,
respectively,
are shown in Figs. 3 and 4. The measured and calculated parameters for each
composition (n= 7 for Micap and Mitab, n= 8 for standard tablets) are given in
the
following.
AUC and MRT have been calculated using the trapezoidal rule and the AUMC
method
(Yamaoka K., Nakagawa T., Uno T.: Statistical moments in pharmacokinetics, J.
Pharmacokin. Biopharm. 1978:6:547-58).
For extrapolation to infinity (the tail) the following formulas have been
used:
Cp/ke (for AUC) and nC~/(ke~ ) (for AUMC)
Where Cp = the last measured plasma concentration
ke = the elimination rate constant
N = the time for last data point with measurable concentrations.
Midodrine ng/ml,
mean values
(standard
deviation):
Micap Mitab Standard tablets
AUC24 32.8 (6.7) 32.7 (12.1) 51.7 (13.5)
Cmax 10.0 (2.6) 12.8 (6.5) 41.4 (12.6)
tmax 0.7 (0.4) 0.9 (0.5) 0.5 (0.2)
MRT 3.0 (0.4) 2.3 (0.3) 1.0 (0.2)
HVD 2.6 (1.1 ) 1.5 (0.8) 0.9 (0.3)
t>~s~~o cmax 1.0 (1.0) 0.8 (0.6) 0.5 (0.1 )
AUC;nfnity 24.1 (6.7) 21.8 (13.1) 41.3 (14.0)
Desglymidodrine ng/ml, mean
values (standard
deviation):
Micap Mitab Standard tablets
AUCz4 106.0 (29.1 ) 92.7 (36.4) 114.4 (31.9)
Cmax 11.4 (3.2) 8.7 (5.0) 21.7 (5.1 )
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
102
tmax 5.0 (0.0) 2.9 (1.1) 1.4 (0.4)
M RT 9.5 (1.0) 11.8 (4.1) 4.7 (0.5)
HVD 7.7 (0.4) 9.9 (4.1) 4.1 (0.4)
t>~s~~o cmax3.4 (0.3) 4.4 (0.5) 2.1 (0.4)
AUC;nfnity111.5 (33.9) 104.1 (36.9) 112.9 (32.5)
Sum of midodrine and desglymidodrine nmol/I, mean values (standard deviation):
Micap Mitab Standard tablets
AUC24 566.1 (145.6) 509.1 (195.2) 667.3 (176.4)
Cmax 60.5 (14.5) 66.0 (29.7) 195.1 (51.9)
tmax 3.0 (1.7) 1.3 (0.9) 0.6 (0.2)
M RT 9.7 (1.0) 1 2.4 (4.5) 4.6 (0.6)
HVD 7.7 (0.8) 5.0 (2.5) 1.9 (0.8)
t>75o~o 4.4 (1.2) 1.$ (1.3) 0.9 (0.4)
cmax
AUCintinity 608.7 (172.8) 588.2 (190.1) 661.1 (183.3)
Midodrine nmol/I, mean values (standard deviation)
Micap Mitab Standard tablets
AUC24 112.7 (23.2) 112.5 (41.6) 178.0 (46.4)
Cmax 34.3 (9.1 ) 43.9 (22.4) 142.3 (43.5)
tmax 0.7 (0.4) 0.9 (0.5) 0.5 (0.2)
MRT 3.0 (0.4) 2.3 (0.3) 1.0 (0.2)
HVD 2.6 (1.1) 1.5 (0.8) 0.9 (0.3)
t>~s~~ocmax 1.0 (1.0) 0.8 (0.6) 0.5 (0.1)
AUC;ntinity 83.0 (23.1 ) 74.9 (45.0) 142.1 (48.2)
Desglymidodrine
nmol/I, mean
values (standard
deviation):
Micap Mitab Standard tablets
AUC24 453.4 (124.7) 396.6 (156.0) 489.4 (136.5)
Cmax 48.6 (13.5) 37.4 (21.5) 92.9 (22.0)
tmax 5.0 (0.0) 2.9 (1.1) 1.4 (0.4)
M RT 9.5 (1.0) 11.8 (4.1) 4.7 (0.5)
HVD 7.7 (0.4) 9.9 (4.1) 4.1 (0.4)
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
103
t»s~~o cmax 3.4 (0.3) 4.4 (0.5) 2.1 (0.4)
AUC;nfnity 477.2 (144.9) 445.4 (157.7) 483.3 (138.9)
Furthermore, the time interval in which the concentration of midodrine,
desglymidodrine or
the sum of midodrine and desglymidodrine is at a constant value ~ 40% has been
determined. The time interval is found by looking at all possible time
intervals (using the
time points from the blood sampling) of all possible lengths. For each time
interval the
mean is calculated and it is checked whether all plasma concentration points
in that time
interval is lying within ~ 40% of the mean value. The time interval in
question is the
longest time interval for which all concentration points in the interval lie
within the mean of
the time interval ~ 40%. In order to get a relevant interval the constant
value minus 40%
has to be higher than the detection limit. The interval is calculated for each
patient and the
mean value of the length of time interval is given.
For example, for patient 1 the MICAP capsules gave a mean plasma concentration
of
desglymidodrine at 8.5 ng/ml in the time interval from 2 hours to 9 hours
(i.e. a 7 hours
interval). In this period the maximum plasma concentration of desglymidodrine
was
measured as 11.8 ng/ml and the minimum plasma concentration as 5.5 ng/mi.
Since 8.5
ng/ml + 40% is 11.9 ng/ml and 8.5 ng/ml - 40% is 5.1 ng/ml all measured plasma
concentration points in that particular interval lie within the mean value ~
40%. Since this
was the longest time interval where all concentration points lie within the
mean ~ 40% the
resulting time interval for the MICAP capsules for patient 1 was 7 hours.
The following results were obtained:
Time interval (hours) where the concentration of midodrine lies at a constant
value ~ 40%:
Micap (n=7) 1.7
Mitab (n=7) 1.4
Standard tablets (n=8) 0.63
Time interval (hours) where the concentration of desglymidodrine lies at a
constant value
~ 40%:
Micap (n=7) 6.3
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
104
Mitab (n=7) 11,5
Standard tablets (n=8) 3.7
Time interval (hours) where the sum of the concentration of midodrine and
desglymidodrine lies at a constant value ~ 40%:
Micap (n=7) 7.5
Mitab (n=7) 11.9
Standard tablets (n=8) 3.5
The aim of the pilot study was to test the bioavailability of the two novel
compositions and
a standard Gutron tablet and to estimate whether the compositions are
bioequivalent.
Furthermore, the controlled release properties of the novel compositions as
compared to
the standard composition (Gutron tablet) can be depicted from the data
generated.
The values of Cma~ and AUCo_2a IAUC~nfn~tY of the standard tablet are greater
than the same
values of each of the two prototypes considering the plasma values of
midodrine,
desglymidodrine and the sum of the two. It is expected that CmaX is lower in
controlled
release compositions than in plain release compositions as this reflects a
lesser degree of
fluctuation of plasma values. This is one of the purposes of a controlled
release
composition. It is further supported by the prolongation of the time interval
in which the
plasma values of midodrine, desglymidodrine and the sum of the concentrations
of the
two lie at a constant value.
The sum of the plasma concentrations of midodrine and the active metabolite
desglymidodrine reflects the total amount of drug absorbed into the blood
stream. The
values of TmaX, Wso and T>~5ao cmax (W~s~io) and MRT for this sum
concentration are more
than 2 times greater of the novel controlled release compositions than the
values of the
standard tablet. The prolongation of the above mentioned values means that the
active
drug substance resides in the plasma for a longer time period reducing the
numbers of
daily dosing needed. Thus, another purpose of a controlled release composition
is
fulfilled.
Conclusion
CA 02409950 2002-11-22
WO 01/89473 PCT/DKO1/00362
105
Based on the AUC values, the bioavailabilities of the novel controlled release
compositions are lesser than the bioavailability of the standard tablet
indicating that the
content of active drug substance in the controlled release compositions should
be
increased to establish bioequivalence.
The novel compositions possess controlled release properties as compared to
the
standard tablet for reasons discussed above.
