Note: Descriptions are shown in the official language in which they were submitted.
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PHARMACEUTICAL FORMULATIONS
THIS INVENTION relates to pharmaceutical formulations, to methods of making
them' and to their use in the treatment and prophylaxis of diseases in
mammals,
particularly humans.
Desmopressin (1-desamino-8-D-arginine vasopressin, DDAVP) is an analogue of
vasopressin having high antidiuretic activity. It is commercially available as
the acetate
salt both in tablet form and as a nasal spray, and is commonly prescribed for
voiding
postponement, incontinence, primary nocturnal enuresis (PNE) and nocturia,
among
other indications, including central diabetes insipidus.
While existing formulations of desmopressin have met the needs of patients,
there is still
a need for improvement. Tablets are often preferred by patients because of
their ease of
use, discretion and the lack of uncertainty of correct administration.
However, tablets
generally need to be taken with a glass of water or other drink, which is a
problem as
fluid intake need to be restricted in connection with desmopressin treatment,
and the
message to the patient is much clearer when there is no water intake at all.
Furthermore
the bioavailability of desmopressin when taken by tablet is about 0.1% when
compared
to intravenous injection, a figure which clearly leaves room for improvement.
Intranasal administration leads to higher bioavailability, but is less
preferred by patients.
Further, intranasal administration may adversely affect the cilia, such that
viruses and
bacteria may more readily pass into the mucosa.
Sublingual formulations of desmopressin have previously been proposed.
Grossman et
al., Br. Med. J. 1215 (17 May 1980) reported administration of desmopressin in
a
sublingual lozenge of unspecified composition. In the same year, Laczi et al.,
Int. J.
Clin. Pharm. Ther. Tox. 18 (12) 63-68 (1980) reported administration of 30pg
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desmopressin in 200mg sublingual tablets containing sucrose, potato starch,
stearin,
ethanol (as rectified spirit), white gelatin, distilled water and powdered
cocoa. However,
in WO-A-8502119 it is stated:
The so-called sublingual tablet is also objectionable since it requires a
relatively long dissolving time and is dependent on a patient's saliva
secretion. [WO-A-8502119, page 2, lines 4-6]
Fjellestad-Paulsen et al., Clin. Endocrinol. 3$ 177-82 (1993) administered a
liquid nasal
spray formulation of desmopressin sublingually, which avoided the problems
noted
above for the sublingual tablet. However, the authors reported that, following
sublingual
administration of the liquid, no detectable desmopressin was found in the
blood.
It has now been discovered that desmopressin can be administered as a solid
orodispersible dosage form which provides improved bioavailability compared to
pharmaceutical dosage form of desmopressin. Preferably the dosage form is of
desmo-
pressin acetate and which disintegrates in the mouth within 10 seconds.
According to a first aspect of the invention, there is provided an
orodispersible
pharmaceutical dosage form of desmopressin.
The desmopressin may be in the form of the free base or a pharmaceutically or,
where
appropriate veterinarily, acceptable salt, or in any other pharmaceutically or
veterinarily
acceptable form. The acetate salt is particularly preferred.
The formulation will typically be solid. It may disperse rapidly in the mouth,
for
example within 10, 5, 2 seconds, or even within 1 second, in increasing order
of
preference. Such formulations are termed 'orodispersible'. The formulation
will
typically comprise a suitable carrier for this purpose, which will be
pharmaceutically
acceptable (or veterinarily acceptable in the case of administration to non-
human
animals).
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The daily dosage of desmopressin, measured as the free base, will generally be
from 0.5
or 1 pg to 1 mg per dosage form. In one preferred dosage range, the dosage
will
typically range from 2 ~,g to 800 pg per dosage form and preferably from 10
p,g to 600
~,g. Relative low doses are also specifically contemplated, for example from
0.5 pg to
75 wg, preferably 0.5 or 1 ~,g to 50 fig. When one dosage form per day is
administered,
as is usual for PNE and nocturia, this will typically be the dose per dosage
form. When
the daily dose is administered in two or more dosages, as will typically be
the case for
central diabetes insipidus, the amount of active compound per dosage form will
be
reduced accordingly.
Other active ingredients, whether or not peptides, may also be present.
Pharmaceutical dosage forms of the present invention are adapted to supply the
active
ingredient to the oral cavity. The active may be absorbed across the
sublingual mucosa,
and/or otherwise from the oral cavity (e.g. across the buccal and/or gingival
mucosa)
and/or from the gastrointestinal tract for systemic distribution.
A variety of formulations are known which are suitable for delivering other
active
ingredients for absorption from the oral cavity. Such formulations may be
useful in the
present invention. Among them are intrabuccally disintegrating solid
formulations or
preparations which comprise the active ingredient, a sugar comprising lactose
and/or
mannitol and 0.12 to 1.2 w/w%, based on the solid components, of agar and
which has a
density of 400 mg/ml to 1,000 mg/ml and have a sufficient strength for
handling, which
in practice may mean sufficient strength to withstand removal from a blister
packaging
without disintegrating. Such formulations, and how to make them, are disclosed
in US-
A-5466464, to which reference is made for further details.
In this embodiment of the invention, the sugar may be used in the formulation
in an
amount of at least 50 w/w%, preferably 80 w/w% or more, more preferably 90
w/w% or
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more, based on the total solid components, although it may vary depending on
the
quality and quantity of the active ingredient to be used.
Though types of agar are not particularly limited, those listed in the
Japanese
Pharmacopoeia may be used preferably. Examples of the listed agar include agar
powders PS-7 and PS-8 (manufactured by Ina Shokuhin).
Agar may be used in an amount of from 0.12 to 1.2 w/w%, preferably from 0.2 to
0.4
w/w%, based on the solid components.
In order to produce a formulation in accordance with this embodiment of the
present
invention, a sugar comprising lactose and/or mannitol is suspended in an
aqueous agar
solution, filled in a mould, solidified into a jelly-like form and then dried.
The aqueous
agar solution may have a concentration of from 0.3 to 2.0%, preferably from
0.3 to
0.8%. The aqueous agar solution may be used in such an amount that the
blending ratio
of agar based on the solid components becomes 0.12 to 1.2 w/w%, but preferably
40 to
60 w/w% of agar solution based on the solid components.
Other formulations known for delivering active ingredients for absorption from
the oral
cavity are the dosage forms disclosed in US-A-6024981 and US-A-6221392. They
are
hard, compressed, rapidly dissolvable dosage forms adapted for direct oral
dosing
comprising: an active ingredient and a matrix including a non-direct
compression filter
and a lubricant, said dosage form being adapted to rapidly dissolve in the
mouth of a
patient and thereby liberate said active ingredient, and having a friability
of about 2% or
less when tested according to the U.S.P., said dosage form optionally having a
hardness
of at least about 15 Newtons (N), preferably from 15-50 N. US-A-6024981 and US-
A-
6221392 disclose further details and characteristics of these dosage forms and
how to
make them.
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Preferably, dosage forms in accordance with this embodiment of the invention
dissolve
in about 90 seconds or less (preferably 60 seconds or less and most preferably
45
seconds or less) in the patient's mouth. It is also often desirable that the
dosage form
include at least one particle. The particle would be the active ingredient and
a protective
material. These particles can include rapid release particles and or sustained
release
particles.
In a particularly preferred formulation in accordance with this embodiment of
the
present invention there is provided a hard, compressed, rapidly dissolving
tablet adapted
for direct oral dosing. The tablet includes particles made of an active
ingredient and a
protective material. These particles are provided in an amount of between
about 0.01 and
about 75% by weight based on the weight of the tablet. The tablet also
includes a matrix
made from a non-direct compression filler, a wicking agent, and a hydrophobic
lubricant. The tablet matrix comprises at least about 60% rapidly water
soluble
ingredients based on the total weight of the matrix material. The tablet has a
hardness of
between about 15 and about 50 Newtons, a friability of less than 2% when
measured by
U.S.P. and is adapted to dissolve spontaneously in the mouth of a patient in
less than
about 60 seconds and thereby liberate said particles and be capable of being
stored in
bulk.
A very fine grained or powdered sugar known as a non-direct compression sugar
may be
used as a filler in the matrix of this embodiment the present invention. This
material, in
part because of its chemical composition and in part because of its fine
particle size, will
dissolve readily in the mouth in a mater of seconds once it is wetted by
saliva. Not only
does this mean that it can contribute to the speed at which the dosage form
will dissolve,
it also means that while the patient is holding the dissolving dosage form in
his or her
mouth, the filler will not contribute a "gritty" or "sandy" texture thus
adversely affecting
the organoleptic sensation of taking the dosage form. In contrast, direct
compression
versions of the same sugar are usually granulated and treated to make them
larger and
better for compaction. While these sugars are water soluble, they may not be
solubilised
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quickly enough. As a result, they can contribute to the gritty or sandy
texture of the
dosage form as it dissolves. Dissolution time in the mouth can be measured by
observing
the dissolution time of the tablet in water at about 37°C. The tablet
is immersed in the
water without forcible agitation or with minimal agitation. The dissolution
time is the
time from immersion to substantially complete dissolution of the rapidly water
soluble
ingredients of the tablet as determined by visual observation.
Particularly preferred fillers, in accordance with the present invention are
non-direct
compression sugars and sugar alcohols which meet the specifications discussed
above.
Such sugars and sugar alcohols include, without limitation, dextrose,
mannitol, sorbitol,
lactose and sucrose. Of course, dextrose, for example, can exist as either a
direct
compression sugar, i.e., a sugar which has been modified to increase its
compressibility,
or a non-direct compression sugar.
Generally, the balance of the formulation can be matrix. Thus the percentage
of filler
can approach 100%. However, generally, the amount of non-direct compression
filler
useful in accordance with the present invention ranges from about 25 to about
95%,
preferably between about 50 and about 95% and more preferably from about 60 to
about
95%.
The amount of lubricant used can generally range from between about 1 to about
2.5%
by weight, and more preferably between about 1.5 to about 2% by weight.
Hydrophobic lubricants useful in accordance with the present invention include
alkaline
stearates, stearic acid, mineral and vegetable oils, glyceryl behenate and
sodium stearyl
fumarate. Hydrophilic lubricants can also be used.
Protective materials useful in accordance with this embodiment of the present
invention
may include any of the polymers conventionally utilized in the formation of
microparticles, matrix-type microparticles and microcapsules. Among these are
cellulosic materials such as naturally occurring cellulose and synthetic
cellulose
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derivatives; acrylic polymers and vinyl polymers. Other simple polymers
include
proteinaceous materials such as gelatin, polypeptides and natural and
synthetic shellacs
and waxes. Protective polymers may also include ethylcellulose,
methylcellulose,
carboxymethyl cellulose and acrylic resin material sold under the registered
trade mark
S EUDRAGIT by Rhone Pharma GmbH of Weiterstadt, Germany.
In addition to the ingredients previously discussed, the matrix may also
include wicking
agents, non-effervescent disintegrants and effervescent disintegrants. Wicking
agents are
compositions which are capable of drawing water up into the dosage form. They
help
transport moisture into the interior of the dosage form. In that way the
dosage form can
dissolve from the inside, as well as from the outside.
Any chemical which can function to transport moisture as discussed above can
be
considered a wicking agent. Wicking agents include a number of traditional non-
15. effervescent disintegration agents. These include, for example,
microcrystalline cellulose
TAI TAI TAI TI11
(AVICEL PH 200, AVICEL PH 101), Ac-Di-Sol (Croscarmelose Sodium) and PVP-XL
(a crosslinked polyvinylpyrrolidone); starches and modified starches,
polymers, and gum
such as arabic and xanthan. Hydroxyalkyl cellulose such as
hydroxymethylcellulose,
hydroxypropylcellulose and hydroxyopropylmethylcellulose, as well as compounds
such
as carbopol may be used as well.
The conventional range of non-effervescent disintegrant agents used in
conventional
tablets can be as high as 20%. However, generally, the amount of
disintegration agent
used ranges from between about 2 and about 5%, according to the Handbook of
Pharmaceutical Excipients.
In accordance with this embodiment of the present invention, the amount of
wicking
agents used may range from between 2 to about 12% and preferably from between
2 to
about 5%.
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_g_
It is also possible, of course, to include non-effervescent disintegrants
which may not act
to wick moisture, if desirable. In either event, it is preferable to use
either rapidly water
soluble, non-effervescent disintegrants or wicking agents and/or to minimize
the use of
generally non-water soluble wicking agents or non-effervescent disintegrants.
Non-
rapidly dissolvable, non-rapidly water soluble elements if used in sufficient
quantity, can
adversely affect the organoleptic properties of the tablets as they dissolve
within the
mouth and therefore should be minimized. Of course, wicking agents or non-
effervescent disintegrants which are rapidly water soluble as discussed herein
can be
used in greater quantity and they will not add to the grittiness of the
formulation during
dissolution. Preferred wicking agents in accordance with the present invention
include
crosslinked PVP, although, the amounts of these must be controlled as they are
not
rapidly water soluble.
In addition, it may be desirable to use an effervescent couple, in combination
with the
other recited ingredients to improve the disintegration profile, the
organoleptic
properties of the material and the like. Preferably, the effervescent couple
is provided in
an amount of between about 0.5 and about 50%, and more preferably, between
about 3
and about 15% by weight, based on the weight of the finished tablet. It is
particularly
preferred that sufficient effervescent material be provided such that the
evolved gas is
less than about 30 cm, upon exposure to an aqueous environment.
The term "effervescent couple" includes compounds which evolve gas. The
preferred
effervescent couple evolve gas by means of a chemical reaction which takes
place upon
exposure of the effervescent disintegration couple to water and/or to saliva
in the mouth.
This reaction is most often the result of the reaction of a soluble acid
source and an
alkali monohydrogencarbonate or other carbonate source. The reaction of these
two
general compounds produces carbon dioxide gas upon contact with water or
saliva. Such
water-activated materials must be kept in a generally anhydrous state and with
little or
no absorbed moisture or in a stable hydrated form, since exposure to water
will
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prematurely disintegrate the tablet. The acid sources may be any which are
safe for
human consumption and may generally include food acids, acid and hydrite
antacids
such as, for example: citric, tartaric, malic, fiunaric, adipic, and
succinics. Carbonate
sources include dry solid carbonate and bicarbonate salt such as, preferably,
sodium
S bicarbonate, sodium carbonate, potassium bicarbonate and potassium
carbonate,
magnesium carbonate and the like. Reactants which evolve oxygen or other
gasses and
which are safe for human consumption are also included.
In the case of the orally dissolvable tablets in accordance with the present
invention, it is
preferred that both the amount and the type of disintegration agent, either
effervescent or
non-effervescent, or the combination thereof be provided sufficient in a
controlled
amount such that the tablet provides a pleasant organoleptic sensation in the
mouth of
the patient. In some instances, the patient should be able to perceive a
distinct sensation
of fizzing or bubbling as the tablet disintegrates in the mouth. In general,
the total
amount of wicking agents, non-effervescent disintegrants and effervescent
disintegrants
should range from 0-50%. However, it should be emphasized that the
formulations of
the present invention will dissolve rapidly and therefore, the need for
disintegrating
agents is minimal. As illustrated in the examples, appropriate hardness,
friability and
dissolution times can be obtained even without effervescent disintegrants or
high
quantities of wicking agents.
The use of a non-direct compression filler eliminates the need for many
conventional
processing steps such as granulation and/or the need to purchase more
expensive pre-
granulated, compressible fillers. At the same time, the resulting dosage form
is a balance
of performance and stability. It is robust enough to be conventionally
produced using
direct compression. It is robust enough to be stored or packaged in bulk. Yet,
it rapidly
dissolves in the mouth while minimizing the unpleasant feel of conventional
disintegrating tablets to the extent possible.
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Formulations in accordance with this embodiment of the invention may be made
by a
method including the steps of:
(a) forming a mixture including an active ingredient and a matrix including a
non-direct
compression filler and a lubricant;
(b) compressing the mixture to form a plurality of hard, compressed, rapidly
disintegrable dosage forms including the active ingredient distributed in the
orally
dissolvable matrix; and optionally
(c) storing the dosage forms in bulk prior to packaging. In a preferred
embodiment, the
dosage forms are then packaged in a lumen of a package such that there is at
least one
per package. In a preferred particularly preferred embodiment, the dosage
forms are then
packaged in a lumen of a package such that there more than one per package.
Direct
compression is the preferred method of forming the dosage forms.
Other formulations known for delivering active ingredients for absorption from
the oral
cavity are the dosage forms disclosed in US-A-6200604, which comprise an
orally
administrable medicament in combination with an effervescent agent used as
penetration
enhancer to influence the permeability of the medicament across the buccal,
sublingual,
and gingival mucosa. In the context of the present invention, the medicament
is
desmopressin, which is administered in some embodiments across the sublingual
mucosa. In the formulations of this embodiment of the invention, effervescent
agents
can be used alone or in combination with other penetration enhancers, which
leads to an
increase in the rate and extent of oral absorption of an active drug.
Formulations or dosage forms in accordance with this embodiment of the
invention
should include an amount of an effervescent agent effective to aid in
penetration of the
drug across the oral mucosa. Preferably, the effervescent is provided in an
amount of
between about S% and about 95% by weight, based on the weight of the finished
tablet,
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and more preferably in an amount of between about 30% and about 80% by weight.
It is
particularly preferred that sufficient effervescent material be provided such
that the
evolved gas is more than about 5 cm3 but less than about 30 cm3, upon exposure
of the
tablet to an aqueous environment.
The term "effervescent agent" includes compounds which evolve gas. The
preferred
effervescent agents evolve gas by means of a chemical reaction which takes
place upon
exposure of the effervescent agent (an effervescent couple) to water and/or to
saliva in
the mouth. This reaction is most often the result of the reaction of a soluble
acid source
and a source of carbon dioxide such as an alkaline carbonate or bicarbonate.
The
reaction of these two general compounds produces carbon dioxide gas upon
contact with
water or saliva. Such water-activated materials must be kept in a generally
anhydrous
state and with little or no absorbed moisture or in a stable hydrated form,
since exposure
to water will prematurely disintegrate the tablet. The acid sources may be any
which are
safe for human consumption and may generally include food acids, acid and
hydrite
antacids such as, for example: citric, tartaric, amalic, fumeric, adipic, and
succinics.
Carbonate sources include dry solid carbonate and bicarbonate salt such as,
preferably,
sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium
carbonate,
magnesium carbonate and the like. Reactants which evolve oxygen or other
gasses and
which are safe for human consumption are also included.
The effervescent agents) useful in this embodiment of the present invention is
not
always based upon a reaction which forms carbon dioxide. Reactants which
evolve
oxygen or other gasses which are safe for human consumption are also
considered
within the scope. Where the effervescent agent includes two mutually reactive
components, such as an acid source and a carbonate source, it is preferred
that both
components react completely. Therefore, an equivalent ratio of components
which
provides for equal equivalents is preferred. For example, if the acid used is
diprotic, then
either twice the amount of a mono-reactive carbonate base, or an equal amount
of a di-
reactive base should be used for complete neutralization to be realised.
However, in
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other embodiments of the present invention, the amount of either acid or
carbonate
source may exceed the amount of the other component. This may be useful to
enhance
taste and/or performance of a tablet containing an overage of either
component. In this
case, it is acceptable that the additional amount of either component may
remain
S unreacted.
Such dosage forms may also include in amounts additional to that required for
effervescence a pH adjusting substance. For drugs that are weakly acidic or
weakly
basic, the pH of the aqueous environment can influence the relative
concentrations of the
ionised and unionised forms of the drug present in solution according to the
Henderson-
Hasselbach equation. The pH solutions in which an effervescent couple has
dissolved is
slightly acidic due to the evolution of carbon dioxide. The pH of the local
environment,
e.g. saliva in immediate contact with the tablet and any drug that may have
dissolved
from it, may be adjusted by incorporating in the tablet a pH adjusting
substances which
1 S permit the relative portions of the ionised and unionised forms of the
drug to be
controlled. In this way, the present dosage forms can be optimised for each
specific
drug. If the unionised drug is known or suspected to be absorbed through the
cell
membrane (transcellular absorption) it would be preferable to alter the pH of
the local
environment (within the limits tolerable to the subject) to a level that
favours the
unionised form of the drug. Conversely, if the ionised form is more readily
dissolved the
local environment should favour ionisation.
The aqueous solubility of the drug should preferably not be compromised by the
effervescent and pH adjusting substance, such that the dosage forms permit a
sufficient
concentration of the drug to be present in the unionised form. The percentage
of the pH
adjusting substance and/or effervescent should therefore be adjusted depending
on the
drug.
Suitable pH adjusting substance for use in the present invention include any
weak acid
or weak base in amounts additional to that required for the effervescence or,
preferably,
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any buffer system that is not harmful to the oral mucosa. Suitable pH
adjusting
substance for use in the present invention include, but are not limited to,
any of the acids
or bases previously mentioned as effervescent compounds, disodium hydrogen
phosphate, sodium dihydrogen phosphate and the equivalent potassium salt.
The dosage form of this embodiment of the invention preferably includes one or
more
other ingredients to enhance the absorption of the pharmaceutical ingredient
across the
oral mucosa and to improve the disintegration profile and the organoleptic
properties of
the dosage form. For example, the area of contact between the dosage form and
the oral
mucosa, and the residence time of the dosage form in the oral cavity can be
improved by
including a bioadhesive polymer in this drug delivery system. See, for
example,
Mechanistic Studies on Effervescent-Induced Permeability Enhancement by
Jonathan
Eichman (1997). Effervescence, due to its
mucus stripping properties, would also enhance the residence time of the
bioadhesive,
thereby increasing the residence time for the drug absorption. Non-limiting
examples of
TM
bioadhesives used in the present invention include, for example, Carbopol 934
P, Na
TM
CMC, Methocel, Polycarbophil (Noveon A.A-1), HPMC, Na alginate, Na Hyaluronate
and other natural or synthetic bioadhesives.
In addition to the effervescence-producing agents, a dosage form according to
this
embodiment of the present invention may also include suitable non-effervescent
disintegration agents. Non-limiting examples of non-effervescent
disintegration agents
include: microcrystalline, cellulose, croscarmelose sodium, crospovidone,
starches, corn
starch, potato starch and modified starches thereof, sweeteners, clays, such
as bentonite,
alginates, gums such as agar, guar, locust bean, karaya, pectin and
tragacanth.
Disintegrants rnay comprise up to about 20 weight percent and preferably
between about
2 and about 10% of the total weight of the composition.
In addition to the particles in accordance with this embodiment of the present
invention,
the dosage forms may also include glidants, lubricants, binders, sweeteners,
flavouring
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and colouring components. Any conventional sweetener or flavouring component
may
be used. Combinations of sweeteners, flavouring components, or sweeteners and
flavouring components may likewise be used.
S Examples of binders which can be used include acacia, tragacanth, gelatin,
starch,
cellulose materials such as methyl cellulose and sodium carboxy methyl
cellulose,
alginic acids and salts thereof, magnesium aluminium silicate, polyethylene
glycol, guar
gum, polysaccharide acids, bentonites, sugars, invert sugars and the like.
Binders may be
used in an amount of up to 60 weight percent and preferably about 10 to about
40 weight
percent of the total composition.
Colouring agents may include titanium dioxide, and dyes suitable for food such
as those
known as F.D.& C. dyes and natural coloring agents such as grape skin extract,
beet red
powder, beta-carotene, annato, carmine, turmeric, paprika, etc. The amount of
colouring
used may range from about 0.1 to about 3.5 weight percent of the total
composition.
Flavours incorporated in the composition may be chosen from synthetic flavours
oils
and flavouring aromatics and/or natural oils, extracts from plants, leaves,
flowers, fruits
and so forth and combinations thereof. These may include cinnamon oil, oil of
wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme
oil, cedar
leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.
Also useful as
flavours are vanilla, citrus oil, including lemon, orange, grape, lime and
grapefruit, and
fruit essences, including apple, pear, peach, strawberry, raspberry, cherry,
plum,
pineapple, apricot and so forth. Flavours which have been found to be
particularly useful
include commercially available orange, grape, cherry and bubble gum flavours
and
mixtures thereof. The amount of flavouring may depend on a number of factors,
including the organoleptic effect desired. Flavours may be present in an
amount ranging
from about 0.05 to about 3 percent by weight based upon the weight of the
composition.
Particularly preferred flavours are the grape and cherry flavours and citrus
flavours such
as orange.
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One aspect of the invention provides a solid, oral tablet dosage form suitable
for
sublingual administration. Excipient fillers can be used to facilitate
tableting. The filler
desirably will also assist in the rapid dissolution of the dosage form in the
mouth. Non-
limiting examples of suitable fillers include: mannitol, dextrose, lactose,
sucrose, and
calcium carbonate.
As described in US-A-6200604, tablets can either be manufactured by direct
compression, wet granulation or any other tablet manufacturing technique. The
dosage
form may be administered to a human or other mammalian subject by placing the
dosage
form in the subject's mouth and holding it in the mouth, beneath the tongue
(for
sublingual administration). The dosage form spontaneously begins to
disintegrate due to
the moisture in the mouth. The disintegration, and particularly the
effervescence,
stimulates additional salivation which further enhances disintegration.
Although the above described formulations are within the scope of the present
invention,
the most preferred orodispersible solid pharmaceutical dosage forms according
to the
invention comprise desmopressin and an open matrix network carrying the
desmopressin, the open matrix network being comprised of a water-soluble or
water-
dispersible carrier material that is inert towards desmopressin.
Pharmaceutical dosage forms comprising open matrix networks are known from GB-
A-
1548022, to which reference is made for further details. Pharmaceutical dosage
forms of
the invention can be rapidly disintegrated by water. By "rapidly
disintegrated" is meant
that the shaped articles are disintegrated in water within 10 seconds.
Preferably the
shaped article disintegrates (dissolves or disperses) within 5 seconds or even
two
seconds or one second or less. The disintegration time is measured by a
procedure
analogous to the Disintegration Test for Tablets, B.P. 1973. The procedure is
described
in GB-A-1548022 and outlined below.
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Apparatus
A glass or suitable plastic tube 80 to 100 mm long, with an internal diameter
of
about 28 mm and an external diameter of 30 to 31 mm, and fitted at the lower
end,
so as to form a basket, with a disc of rustproof wire gauze complying with the
requirements for a No. 1.70 sieve.
A glass cylinder with a flat base and an internal diameter of about 45 mm
containing water not less than 15 cm deep at a temperature between 36°
and 38°C.
The basket is suspended centrally in the cylinder in such a way that it can be
raised
and lowered repeatedly in a uniform manner so that at the highest position the
gauze just breaks the surface of the water and at the lowest position the
upper rim
of the basket just remains clear of the water.
Method
Place one shaped article in the basket and raise and lower it in such a manner
that
the complete up and down movement is repeated at a rate equivalent to thirty
times
a minute. The shaped articles are disintegrated when no particle remains above
the
gauze which would not readily pass through it. No such particle should remain
after 10 seconds.
By the term "open matrix network" there is meant a network of water-soluble or
water-
dispersible carrier material having interstices dispersed throughout. The open
matrix
network of carrier material is of generally low density. For example the
density may be
within the range 10 to 200 mg/cc e.g. 10 to 100 mg/cc, preferably 30 to 60
mg/cc. The
density of the shaped article may be affected by the amount of active
ingredient, or any
other ingredients, incorporated into the article and may be outside the above
mentioned
preferred limits for the density of the matrix network. The open matrix
network which is
similar in structure to a solid foam enables a liquid to enter the product
through the
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interstices and permeate through the interior. Permeation by aqueous media
exposes the
carrier material of both the interior and exterior of the product to the
action of the
aqueous media whereby the network of carrier material is rapidly
disintegrated. The
open matrix structure is of a porous nature and enhances disintegration of the
product as
compared with ordinary solid shaped pharmaceutical dosage forms such as
tablets, pills,
capsules, suppositories and pessaries. Rapid disintegration results in rapid
release of the
active ingredient carried by the matrix.
The carrier material used in the product of the invention may be any water-
soluble or
water-dispersible material that is pharmacologically acceptable or inert to
the chemical
and which is capable of forming a rapidly disintegratable open matrix network.
It is
preferred to use water-soluble material as the carrier since this results in
the most rapid
disintegration of the matrix when the product is placed in an aqueous medium.
A
particularly advantageous carrier may be formed from polypeptides such as
gelatin,
particularly gelatin which is particularly hydrolysed, e.g. by heating in
water. For
example, the gelatin may be partially hydrolysed by heating a solution of the
gelatin in
water, e.g. in an autoclave at about 120°C. for up to 2 hours, e.g.
from about 5 minutes
to about 1 hour, preferably from about 30 minutes to about 1 hour. The
hydrolysed
gelatin is preferably used at concentrations of about 1 to 6% or 8%
weight/vol., most
preferably at 2 to 4% e.g. about 3%, or at 4 to 6% e.g. about 5%. As is
apparent from
the Examples herein, these concentrations refer to the total formulation prior
to removal
of the water for example by freeze drying.
Although mammalian derived gelatin may be used, it has an unpleasant taste and
thus
necessitates the use of sweeteners and flavours to mask the taste of the
gelatin in
addition to any sweeteners and flavours which may be required to mask the
taste of the
active ingredient. Moreover, the heating step necessary with the use of
mammalian
gelatin increases processing times and incurs heating costs thereby increasing
the overall
costs of the process. Therefore, the use of fish gelatin, especially non-
gelling fish
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gelatin, is preferred, especially for desmopressin. Reference is made to WO-A-
0061117
for further details.
Other carrier materials may be used in place of partially hydrolysed gelatin
or fish
gelatin, for example polysaccharides such as hydrolysed dextran, dextrin and
alginates
(e.g. sodium alginate) or mixtures of above mentioned carriers with each other
or with
other carrier materials such as polyvinyl alcohol, polyvinylpyrrolidine or
acacia.
Modified starch may also be used in place of gelatin, as described in WO-A-
0044351, to
which reference is made for further details.
Other carrier materials which may be present in addition to, or in some cases
in place of,
the above carriers include: gums such as tragacanth, xanthan, carageenan, and
guar;
mucilages including linseed mucilage and agar; polysaccharides and other
carbohydrates
such as pectin and starch and its derivatives, particularly soluble starch and
dextrates;
water soluble cellulose derivatives, such as hydroxyethylmethyl cellulose,
hydroxypropylmethyl cellulose and hydroxypropyl cellulose; and carbomer.
A filler may also be present. The filler desirably will also assist in the
rapid dissolution
or dispersion of the dosage form in the mouth. Non-limiting examples of
suitable fillers
include sugars such as mannitol, dextrose, lactose, sucrose and sorbitol. The
filler is
preferably used at concentrations of about 0 to 6% or 8% weight/vol., most
preferably at
2 to 4% e.g. about 3%, or at 4 to 6% e.g. about 5%. Again, these
concentrations refer to
the total formulation prior to removal of the water for example by freeze
drying.
Pharmaceutical dosage forms of the invention may be in the form of shaped
articles.
They may incorporate ingredients in addition to the active ingredient(s). For
example the
pharmaceutical dosage form of the present invention may incorporate
pharmaceutically
acceptable adjuvants. Such adjuvants include, for example, colouring agents,
flavouring
agents, preservatives (e.g. bacteriostatic agents), and the like. US-A-5188825
teaches
that water soluble active agents should be bonded to an ion exchange resin to
form a
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substantially water insoluble active agent/resin complex; although that
teaching may be
practised here (for which reference to US-A-5188825 is made for further
details), it has
been found in the development of the present invention that water soluble
peptides such
as desmopressin may be formulated in solid dosage forms of the invention
without the
need for bonding to an ion exchange resin. Such dosage forms may therefore be
free of
an ion exchange resin. For hydrophobic peptides, which desmopressin is not, a
surfactant may be present, as taught in US-A-5827541, to which reference is
made for
further details. For peptides with an unpleasant taste (which desmopressin
does not
have), a lipid such as a lecithin may be present to improve patient
acceptability, as
taught in US-A-6156339, to which reference is made for further details. Other
strategies
for taste masking include conversion of a soluble salt to a less soluble salt
or to the free
base, as taught by US-A-5738875 and US-A-5837287, and the use of a process
disclosed
in US-A-5976577 wherein, prior to freeze drying, a suspension of uncoated or
coated
coarse particles of the pharmaceutically active substances) in a carrier
material is
cooled to reduce the viscosity and minimize release of the active substance
during
processing, as well as beyond the point of disintegration of the form in the
mouth, to
minimise bad taste from the peptide; reference is made to the cited patents
for further
details.
For insoluble or poorly soluble peptides having a large particle size, xanthan
gum may
be present, particularly when the carrier is formed from gelatin, as the
xanthan gum may
act as a gelatin flocculating agent, as disclosed in US-A-5631023, to which
reference is
made for further details.
As taught by WO-A-9323017 one or more amino acids having from about 2 to 12
carbon atoms may be present, when the matrix is selected from the group
consisting of
gelatin, pectin, soy fibre protein and mixtures thereof. In this formulation
the preferred
amino acid is glycine, while the preferred matrix forming agent is gelatin
and/or pectin;
in a particularly preferred embodiment, the dosage form additionally comprises
mannitol.
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All excipients will be chosen to be pharmaceutically acceptable.
Pharmaceutical dosage forms of the present invention may be prepared by a
process as
described in GB-A-1548022, which comprises subliming solvent from a
composition
comprising the pharmaceutical substance and a solution of the carrier material
in a
solvent, the composition being in the solid state in a mould.
The sublimation is preferably carried out by freeze drying a composition
comprising the
active ingredient and a solution of the carrier material in a solvent. The
composition may
include additional ingredients, such as those mentioned above. The solvent is
preferably
water but it may contain a co-solvent (such as an alcohol e.g. tert-butyl
alcohol) to
improve the solubility of the chemical. The composition may also contain a
surfactant
e.g. Tweeri'80 (polyoxyethylene (20) sorbitan mono-oleate). The surfactant may
help to
prevent the freeze dried product sticking to the surface of the mould. It may
also aid in
the dispersion of the active ingredient.
The composition may contain a pH adjusting agent to adjust the pH of a
solution from
which the dosage form is prepared within the range of from 3 to 6, preferably
from 3.5
to 5.5, and most preferably from 4 to 5, for example 4.5 or 4.8. Citric acid
is a preferred
pH adjusting agent, but others including hydrochloric acid, malic acid can be
used. Such
non-volatile pH adjusting agents will not be removed by the freeze drying or
other
sublimation process and so may be present in the final product.
The mould may comprise a series of cylindrical or other shape depressions in
it, each of
a size corresponding to the desired size of the shaped article. Alternatively,
the size of
the depression in the mould may be larger than the desired size of the article
and after
the contents have been freeze dried the product can be cut into the desired
size (for
example thin wafers).
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However, as described in GB-A-2111423, the mould is preferably a depression in
a
sheet of filmic material. The filmic material may contain more than one
depression.
The filmic material may be similar to that employed in conventional blister
packs which
are used for packaging oral contraceptive tablets and like medicament forms.
For
example the filmic material may be made of thermoplastic material with the
depressions
formed by thermoforming. The preferred filmic material is a polyvinyl chloride
film.
Laminates of filmic material may also be used.
In one embodiment the mould comprises a metal plate (e.g. an aluminium plate)
containing one or more depressions. In a preferred process using such a mould,
the
mould is cooled with a cooling medium (e.g. liquid nitrogen or solid carbon
dioxide).
When the mould is cooled a predetermined amount of water containing the
carrier
material, the active ingredient and any other desired ingredient is fed into
the
depression(s). When the contents of the depressions) are frozen the mould is
subjected
to reduced pressure and, if desired, controlled application of heat to aid the
sublimation.
The pressure can be below about 4 mm. Hg; GB-A-1548022 teaches that employment
of pressures of below 0.3 mm Hg, for example 0.1 to 0.2 mm is preferred. The
freeze
dried products may then be removed from the depressions in the mould and
stored for
future use, e.g. in airtight jars or other suitable storage containers.
Alternatively, the
freeze dried product may be enclosed by filmic material as described in GB-A-
2111423
A later developed process useful for making pharmaceutical dosage forms in
accordance
with the invention is described in GB-A-2111423, to which reference is made
for further
details. The process comprises filling a composition comprising a
predetermined
amount of active ingredient and a solution of partially hydrolysed gelatin
into a mould,
freezing the composition in the mould by passing gaseous cooling medium over
the
mould and then subliming solvent from the frozen composition so as to produce
a
network of partially hydrolysed gelatin carrying the active ingredient.
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In order to help ensure an even thickness of product, the side wall or walls
of the mould
may diverging outwards from the base and making an angle with the vertical of
at least
5° at the surface of the composition, as described in GB-A-2119246 to
which reference
is made for further details.
Alternatively or in addition, pharmaceutical dosage forms of the present
invention may
be prepared by a process as described in GB-A-2114440 which comprises freezing
a
composition comprising a solution in a first solvent of a water-soluble or
water-
dispersible carrier material that is inert towards the active ingredient,
subliming the first
solvent from the frozen composition so as to produce a product having a
network of
carrier material, adding to said product a solution or suspension of a second
non-aqueous
solvent containing a predetermined amount of the active ingredient and
allowing or
causing the second solvent to evaporate. Reference is made to GB-A-2114440 for
further details.
Alternatively or in addition, pharmaceutical dosage forms of the present
invention may
be prepared by a process as described in GB-A-2111184, which comprises
introducing
the liquid medium in the form of droplets beneath the surface of a cooling
liquid which
is maintained at a temperature lower than the freezing point of the liquid
medium, the
cooling liquid being immiscible with, and inert with respect to, the liquid
medium and
having a density greater than that of both the liquid medium and the resulting
frozen
particles such that as the liquid droplets float upwards in the cooling liquid
towards the
surface thereof, they are frozen to form spherical particles. The frozen
spherical particles
can be collected at or near the upper surface of the cooling liquid. Reference
is made to
GB-A-2111184 for further details.
Dosage forms in accordance with the invention have improved bioavailability.
They are
intended to be taken orally, and are highly suitable for that purpose. They
disperse
rapidly in the mouth, and may for example be placed under the tongue (sub-
lingually),
or they may be placed on the tongue or against the cheek or gingiva.
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According to a second aspect of the invention, there is provided a dosage form
as
described above for use in medicine, particularly, for voiding postponement,
incontinence, primary nocturnal enuresis (PNE), nocturia and central diabetes
insipidus.
The invention provides a method of postponing voiding, treating or preventing
incontinence, primary nocturnal enuresis (PNE), nocturia and/or central
diabetes
insipidus, the method comprising administering an effective and generally non-
toxic
amount of desmopressin to a subject in an orodispersible pharmaceutical dosage
form,
for example in a dosage form as described above. Any other disease or
condition
treatable or preventable by desmopressin may similarly be addressed by means
of the
invention. The invention therefore extends to the use of desmopressin in the
manufacture of an orodispersible pharmaceutical formulation. The invention
also
extends to a pack comprising an orodispersible pharmaceutical dosage form of
desmopressin together with instructions to place the dosage form in a
patient's mouth.
Encompassed within the invention is also a method for preparing a packaged
dosage
form of desmopressin, the method comprising bringing into association an
orodispersible pharmaceutical dosage form of desmopressin and instructions to
place the
dosage form in a patient's mouth. The instructions may for example be printed
on
packaging encompassing the dosage form when sold or dispensed, or may be on a
product information leaflet or insert within the packaging.
Other peptides apart from desmopressin are formulatable in the formulations
described
above. The invention therefore extends to a orodispersible pharmaceutical
dosage form
of a pharmaceutically active peptide.
According to a further aspect of the invention, there is provided a solid
pharmaceutical
dosage form, for example for oral administration, the dosage form comprising a
pharmaceutically active peptide and an open matrix network carrying the
peptide, the
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open matrix network being comprised of a water-soluble or water-dispersible
carrier
material that is inert towards the peptide.
Although oral vaccines made from fast dissolving dosage forms are known from
WO-A-
S 9921579, there is no disclosure of pharmaceutically active peptides
retaining their
activity after administration. The experimental work in WO-A-9921579 merely
shows
the presence in saliva of IgA antibodies to tetanus toxoid following the
administration of
tetanus toxoid by means of an adjuvanted fast dissolving dosage vaccine
formulation.
Formulations of the present invention are not vaccines and do not include
adjuvants.
Pharmaceutical dosage forms of this aspect of the invention contain a
pharmaceutically
active peptide. Such peptides may be directly active per se or they may have
one or
more active metabolites, i. e. they may be prodrugs for the primary or true
active
principle. The peptides may have for example from 2 to 20, preferably from 5
to 15,
amino acid residues (at least some of which may be o-isomers, although L-
isomers will
generally be predominant). The peptides may be linear, branched or cyclic, and
may
include natural residues or substituents or residues or substituents not found
in natural
peptides or proteins either commonly or at all. Pharmaceutically acceptable
salts, simple
adducts and tautomers are included where appropriate.
Examples of peptides usefully formulated by means of the invention include
somatostatin and its analogues including Cyclo(MeAla-Tyr-D-Trp-Lys-Val-Phe)
and
Cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-GABA), enkephalins including MetS-
enkephalin and Leus-enkephalin, oxytocin analogues such as atosiban (1-deamino-
2-D-
Tyr-(OEt)-4-Thr-8-Orn-oxytocin), GnRH analogues such as triptorelin (6-D-Trp-
GnRH),
leuprolide ([D-Leu6, ProB-NHEt]-GnRH), degarelix (Ac-D-2Na1-D-4Cpa-D-3Pa1-Ser-
4Aph(t..-Hydroorotyl)-D-4Aph(Cbm)-Leu-Ilys-Pro-~-Ala-NH2, where 2Nal is 2-
naphthylalanine, 4Cpa is 4-chlorophenylalanine, 3Pa1 is 3-pyridylalanine, ILys
is N(E)-
isopropyllysine, 4Aph is 4-aminophenylalanine and Cbm is the carbamoyl group)
and
other GnRH antagonists disclosed in US-A-5925730 and US-A-4072668, and
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vasopressin analogues such as desmopressin. It is particularly preferred to
formulate by
means of the invention agonists of naturally active peptides, such as those
described
above, since agonists may be active at lower doses than antagonists.
Dosage will be as determined by the physician or clinician, depending on the
nature of
the peptide, the nature of the disease or condition being treated or
prevented, and other
factors.
The invention extends to the use of a peptide in the manufacture of a dosage
form as
described above for treating or preventing a disease or condition which is
treatable or
preventable by a peptide.
The invention also provides a method of treating or preventing a disease or
condition
which is treatable or preventable by a peptide, the method comprising
administering an
effective and generally non-toxic amount of the peptide to a subject in a
dosage form as
described above.
The contents of each of the documents referred to in this specification are
incorporated
herein by reference to the fullest extent allowed by law.
Preferred features of each aspect of the invention, and where feasible and
appropriate
each embodiment of each aspect of the invention, are as for each other aspect
or
embodiment, mutatis mutandis. In particular, it is contemplated that aspects,
features
and embodiments of the invention described above specifically in relation to
desmopressin are applicable also to other peptides.
The invention will now be illustrated by the following examples.
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EXAMPLE 1 200pg Desmopressin Orodispersible Dosage Form
Spray-dried fish gelatin (4g) and mannitol (3g) are added to a glass beaker.
Purified
water (93 g) is then added and solution effected by stirring using a magnetic
follower.
The pH is checked and adjusted to 4.8 with citric acid as necessary.
A Gilson pipette can then be used to deliver 500 mg of this solution into each
one of a
series of pre-formed blister pockets having a pocket diameter of about 16 mm.
The
blister laminate may comprise PVC coated with PVdC. The dosed units are then
frozen
at a temperature of -110°C in a freeze tunnel with a residence time of
3.2 minutes and
the frozen units are then held in an upright freezer for a time greater than
1.5 hours at a
temperature of -25°C (t5°C). The units are then freeze-dried
overnight with an initial
shelf temperature of 10°C rising to +20°C at a pressure of 0.5
mbar. The units can be
checked for moisture prior to unloading by the drying trace and by the
pressurised
moisture check.
In this way, following the general procedure given in Example 1 of WO-A-
0061117, a
desmopressin orodispersible dosage form is prepared using the following
ingredients per
unit dosage form:
Desmopressin (PolyPeptide Laboratories, Sweden) 200 ~,g
Mannitol EP/L1SP (Roquette, Mannitol 35) 15 mg
Fish gelatin USNF/EP 20 mg
Citric acid (if necessary) [pH adjusting agent] q.s. to pH 4.8
Purified water [Removed during processing]
EXAMPLE 2 400pg Desmopressin Orodispersible Dosage Form
The procedure of Example 1 herein is followed, except that the amount of
desmopressin
per unit dosage form was 400 fig.
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EXAMPLE 3 800pg Desmopressin Orodispersible Dosage Form
The procedure of Example 1 herein is followed, except that the amount of
desmopressin
per unit dosage form was 800 fig.
EXAMPLE 4 200~g Desmopressin Orodispersible Dosage Form
Following the general procedure given in Example 1 of WO-A-0061117, a
desmopressin
dosage form orodispersible dosage form was prepared using the following
ingredients
per unit dosage form:
Desmopressin (PolyPeptide Laboratories, Sweden) 200 ~g
Mannitol EP/USP (Roquette, Mannitol 35) 6 mg
Fish gelatin USNF/EP 10 mg
Citric acid (if necessary) [pH adjusting agent] q. s. to pH 4.8
Purified water [Removed during processing]
EXAMPLE 5 400~g Desmopressin Orodispersible Dosage Form
The procedure of Example 4 herein was followed, except that the amount of
desmopressin per unit dosage form was 400 p,g.
EXAMPLE 6 800pg Desmopressin Orodispersible Dosage Form
The procedure of Example 4 herein was followed, except that the amount of
desmopressin per unit dosage form was 800 p,g.
COMPARATIVE EXAMPLE 1 Desmopressin i.v. Solution
An injectable preparation of desmopressin was conventionally prepared using
the
following ingredients:
Desmopressin (PolyPeptide Laboratories, Sweden) 4 mg
Sodium chloride 9mg
(National Corporation of Swedish Pharmacies, Sweden)
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Hydrochloric acid (1N) (Merck, Germany) q.s. to pH 4
Water for injection q.s. to 1 ml
COMPARATIVE EXAMPLE 2 200pg Desmopressin Conventional Tablet
Using a conventional wet granulation process, tablets containing the following
ingredients were prepared:
Desmopressin (PolyPeptide Laboratories,200 ~g
Sweden)
Lactose (Pharmatose'1 SOM, DMV, The 120 mg
Netherlands)
Potato starch (Lyckeby AB, Sweden) 77mg
PVP (Kollidoii 25, BASF, Germany) l.8mg
Magnesium stearate (Peter Greven, Germany)1 mg
Granulation Liquid (water, ethanol)
[Removed during processing)
COMPARATIVE EXAMPLE 3 1001tg Desmopressin Conventional Tablet
The procedure of Comparative Example 2 was followed, except that the amount of
desmopressin was 100 ~g per tablet.
EXAMPLE 7 Bioavailability of Desmopressin Administered in Accordance with
Examples 4 to 6
Study Design
Twenty-four healthy non-smoking male volunteers were enrolled in the present
study.
The study was designed as a one-centre, open-labelled, randomised, balanced, 4-
way
cross-over phase I study. Each subject was, in a randomised order,
administered
sublingually desmopressin as a 200 p,g, 400 ~,g and 800 ~.g orodispersible
dosage form
(Examples 4, 5 and 6, respectively) and 2 pg as an i.v. bolus dose
(Comparative
Example 1). Between the doses there was a washout period of 72 hours. In order
to
standardise the buccal mucosa before administration of the orodispersible
tablet, the
subjects were asked to avoid foods, chewing gum etc. Subjects were allowed to
brush
their teeth in the morning before dosing, but without toothpaste.
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Blood Samples
Blood samples for plasma concentration of desmopressin were collected
according to the
following schedule: pre-dose and 15, 30 and 45 min and at 1, 1.5, 2, 3, 4, 6 ,
8, 10, 12
and 24 hours post-dosing. After intravenous administration additional blood
samples
were collected 5 and 10 minutes post-dosing.
Assay
The concentration of desmopressin in plasma was determined by a validated RIA
method.
Pharmacokinetic Analysis
The concentration of desmopressin in plasma was analysed for the individual
volunteer
in each administration group, by use of non-compartmental methods using the
1 S commercially available software WinNonlinTM Pro, ver. 3.2 (Pharsight
Corporation,
US). A plasma concentration value below limit of quantitation (LOQ) followed
by
values above LOQ was set at 'LOQ/2' for the NCA analysis and for the
descriptive
statistics on concentrations. Values below LOQ not followed by values above
the LOQ
are excluded from the NCA analysis, and set to zero in the descriptive
statistics on
concentrations.
Results of Pharmacokinetic Analysis
After i.v. administration the mean volume of distribution at steady state
(Vss) was 29.7
dm3. The mean clearance was calculated to be 8.5 dm3/hr and the mean
elimination half
life was determined to be 2.8 hours. After oral administration of desmopressin
maximum plasma concentrations were observed at 0.5-2.0 hours after dosing. The
maximum plasma concentration was 14.25, 30.21 and 65.25 pg/ml after an oral
dose of
200, 400 and 800 fig, respectively. After reaching the maximum value
desmopressin was
eliminated with a mean elimination half life in the range of 2.8-3.0 hours.
The
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bioavailability was determined to be 0.30% with at 95% confidence interval of
0.23-
0.38%.
The pharmacokinetics of desmopressin is linear, when administered as the
orodispersible
dosage form of Example 4, 5 or 6.
COMPARATIVE EXAMPLE 4 Bioavailability of Desmopressin Administered in
Accordance with Comparative Examples 2 and 3
Thirty six healthy male volunteers (Caucasian, Black and Hispanic) were
enrolled in this
study, which was designed as an open label, single dose, 3-way crossover
study. Each
subject was, in a randomised order, administered 200 ~g desmopressin as a
single 200
p,g tablet (Comparative Example 2), 200 ~,g desmopressin as two 100 ~,g
tablets
(Comparative Example 3) and 2 ~g as an i.v. bolus dose (Comparative Example
1).
After i.v. administration the mean elimination half life was determined to be
2.24 hours.
After oral administration of desmopressin maximum plasma concentrations were
observed at 1.06 hours (2 x 100 pg) or 1.05 hours (1 x 200 wg) after dosing.
The
maximum plasma concentration was 13.2 and 15.0 pg/ml after an oral dose of 2 x
100
~,g and 1 x 200 ~,g, respectively. The bioavailability was determined to be
0.13% (2 x
100 wg) or 0.16% (1 x 200 ~,g).
