Note: Descriptions are shown in the official language in which they were submitted.
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ANTIUIRAL COMBINATIONS CONTAINING THE CARBOCYCLIC NUCLEOSIDE 1592U89
The present invention relates to therapeutic combinations of (-)-(1S, 4R) -4-
[2-amino-6-
(cyclopropyiamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (1592U89) and non-
nucleoside reverse transcriptase inhibitors (NNRTIs), which have anti-HIV
activity. The
present invention is also concerned with pharmaceutical compositions
containing said
combinations and their use in the treatment of HIV infections including
infections with
HIV mutants bearing resistance to nucleoside and/or non-nucleoside inhibitors.
The therapeutic agent 1592U89 (European Specification EP0434450) is a
promising anti-
HIV chemotherapeutic candidate (International Conference on Antiviral
Research, April
23, 1995) showing potent activity against Human immunodeficiency Virus (HIV),
the
causative agent of Acquired immune Deficiency Syndrome (AIDS), low
cytotoxicity and
excellent penetration into the brain which is important for the treatment of
AIDS and
HIV linked central nervous system conditions such as AIDS dementia complex.
An attractive target for the inhibition of HIV is the virally-encoded enzyme,
reverse
transcriptase (RT), which acts at the beginning of the viral replication
cycle. The reverse
transcriptase comprises polymerase and ribonuclease components which together
are
responsible for the transcription of viral RNA into double-stranded DNA prior
to
integration in the host cell genome. Reverse transcriptase inhibitors, such as
zidovudine
didanosine, zalcitabine, and 1592U89 are all nucleosides which rely on
cellular kinases to
convert them into their triphosphates, which are competitive inhibitors of the
natural
substrate for RT. An attractive alternative strategy is the use of suitable
non-nucleoside
reverse transcriptase inhibitors.
Non-nucleoside reverse transcriptase inhibitors which have been synthesized to
date
include HEPT, TIBO derivatives, atevirdine, L-ofloxacin, L-697,639, L-697-661,
nevi rapine
(BI-RG-587), loviride ( oc-APA), delavuridine (BHAP), phosphonoformic acid,
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benzodiazepinones, dipyridodiazepinones, 2-pyridones,
bis(heteroaryl)piperazines, 6-
substituted pyrimidines, imidazopyridazines, 1,4-dihydro-2H-3,1-benzoxazin-2-
ones,
such as (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-
benzoxazin-2-one (L-743,726 or DMP-266), and quinoxalines, such as isopropyl
(2S)-7-
fluoro-3,4-dihydro-2-ethyl-3-oxo-1- (2H)-quinoxalinecarboxylate (HBY 1293),
HBY 097,
or MKC 442.
It has now been found that by combining 1592U89 and non-nucleoside reverse
transcriptase inhibitors, a synergistic anti-HIV effect is achieved. It is a
feature of this
invention that the use of such a drug combination will provide one or more of
the
following effects : synergistic antiviral effects, more complete viral
suppression, viral
suppression over a longer period, limit the emergence of drug resistant HIV
mutants,
and/or allow better management of drug-related toxicities.
According to one aspect of the invention there is provided a combination
comprising
1592U89, or a physiologically functional derivative thereof, and a non-
nucleoside reverse
transcriptase inhibitor or a physiologically functional derivative thereof.
A further feature of the present invention is a combination comprising
1592U89, a
NNRTI, and a second reverse transcriptase inhibitor, for example lamivudine.
The ratios of
the components of such combinations will conveniently be the same as the
ratios of the
relevant compounds in the double combinations of the invention.
In a further aspect of the present invention there is presented a combination
comprising
1592U89, a NNRTI, and a HIV protease inhibitor. The ratios of the components
of such
combinations will conveniently be the same as the ratios of the relevant
compounds in
the double combinations of the invention.
Examples of protease inhibitor compounds include those disclosed in WO
94/05639, WO
95/24385, WO 94/13629, WO 92/16501, WO 95/16688, WO/US94/13085,
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W0/US94/12562, US 93/59038, EP 541168, WO 94/14436, WO 95/09843, WO 95/32185,
WO 94/15906, WO 94/15608, WO 94/04492, WO 92/08701, WO 95/32185, and U.S.
Patent No. 5,256,783, in particular (S)-N- ((.alpha.S)-((1 R)-2-((3S,
4ocS,8aS)-3-(tert-
Butylcarbamoyl)octahydro-2-(1 H)-isoquinolyl)-1-hydroxyethyl)phenethyl)-Z-
quinaldaminosuccinamide monomethanesulfonate (saquinavir), N-(2(R)-Hydroxy-
1 (S)indanyl)-2(R)-(phenylmethyl)-4(S)-hydroxy-5-[1-[4-(3-pyridylmethyl)-2(S)-
(N-tert-
butylcarbamoyl)piperazinyl]]pentaneamide (indinavir), 10-hydroxy-2-methyl-5-(1-
methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-
bis(phenylmethyl)-
2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester (ritonavir), (
N-(1,1-
dimethyl)decahydro-2-[2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-
(phenylthio)butyl]- 3-isoquinolinecarboxamide monomethanesulfonate
(nelfinavir), and
related compounds.
Another aspect of the present invention is a combination comprising 1592U89, a
second
reverse transcriptase inhibitor, for example, lamivudine, a NNRTI, and a HIV
protease
inhibitor. The ratios of the components of such combinations will conveniently
be the
same as the ratios of the relevant compounds in the double or triple
combinations of the
invention.
As used herein, the term "physiologically functional derivative" includes any
physiologically acceptable solvate, salt, ether, ester, salt of such ester, or
solvates of any
such salt, ether or ester, of 1592U89 or PJNRTI(s); or any other compound
which upon
administration to the recipient, is capable of providing (directly or
indirectly) such a
compound or an antivirally active metabolite or residue thereof.
Preferred esters in accordance with the invention are independently selected
from the
following group: (1) carboxylic acid esters in which the non-carbonyl moiety
of the
carboxylic acid portion of the ester grouping is selected from straight or
branched chain
alkyl (for example, methyl, n-propyl, t-butyl, or n-butyl), cycloalkyl,
alkoxyalkyl (for
example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for
example,
phenoxymethyl), aryl (for example, phenyl optionally substituted by, for
example,
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halogen, C,_4 alkyl, or C,_, aikoxy), or amino; (2) sulphonate esters, such as
alkyl- or
aralkylsulphonyl (for example, methanesulphonyl); (3) amino acid esters (for
example, L-
valyl or L-isoleucyl); and (4) phosphonate esters. In such esters, unless
otherwise
specified, any alkyl moiety present advantageously contains from 1 to 18
carbon atoms,
particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon
atoms. Any
cycloalkyl moiety present in such esters advantageously contains from 3 to 6
carbon
atoms. Any aryl moiety present in such esters advantageously comprises a
phenyl group.
Any reference to any of the above compounds also includes a reference to a
physiologically acceptable salt thereof.
Preferred derivatives of 1592089 are the mono-, di-, and tri-phosphate esters
of
(1R, 4S)-9-[4-(hydroxymethyl)-2-cyclopenten-1-yl]guanine (carbovir).
Examples of physiologically acceptable salts of 1592089 or NNRTI(s) and their
physiologically acceptable derivatives include salts derived from an
appropriate base,
such as an alkali metal (for example, sodium), an alkaline earth (for example,
magnesium),
ammonium and NX4' (wherein X is C,_4 alkyl). Physiologically acceptable salts
of an
hydrogen atom or an amino group include salts of organic carboxylic acids such
as acetic,
lactic, tartaric, malic, isethionic, lactobionic, and succinic acids, organic
sulphonic acids,
such as methanesulphonic, ethanesulphonic, benzenesulphonic and p-
toluenesulphonic
acids and inorgainic acids, such as hydrochloric, sulphuric, phosphoric and
sulphamic
acids. Physiologically acceptable salts of a compound of an hydroxy group
include the
anion of said compound in combination with a suitable cation such as Na+, NH4+
and NXQ+
(wherein X is a C,~ alkyl group).
For therapeutic use, salts of 1592089 or NNRTI(s) will be physiologically
acceptable, i.e.
they will be salts derived from a physiologically acceptable acid or base.
However, salts
of acids or bases which are not physiologically acceptable may also find use,
for example,
in the preparation or purification of a physiologically acceptable compound.
All salts,
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whether or not derived from- a physiologically acceptable acid or base, are
within the
scope of the present invention.
Preferred salts of 1592U89 are the succinate salt and the hemisulphate salt.
5
Combinations of 1592U89, or a physiologically functional derivative thereof,
and
NNRTI(s) or a physiologically functional derivative thereof, including
combinations
containing one or more reverse transcriptase inhibitor(s), or physiologically
functional
derivatives thereof, and one or more HIV protease inhibitor(s), or
physiologically
functional derivatives thereof, may hereinafter be referred to as combinations
according
to the invention.
The present invention further provides combinations according to the invention
for use
in the treatment of an HIV infection including infections with HIV mutants
bearing
resistance to nucleoside inhibitors, particularly zidovudine, lamivudine, ddl,
ddC or d4T or
combinations thereof and HIV protease inhibitors. Furthermore, the
combinations
according to the invention are especially useful for the treatment of AIDS and
related
clinical conditions such as AIDS related complex (ARC), progressive
generalized
lymphadenopathy (PGL), Kaposi's sarcoma, thrombocytopenic purpura, AIDS-
related
neurological conditions such as AIDS dementia complex, multiple sclerosis or
tropical
paraperesis, and also anti-HIV antibody-positive and HIV-positive conditions,
including
such conditions in asymptomatic patients.
According to another aspect, the present invention provides a method for the
treatment
of an HIV infection in an infected animal, for example, a mammal including a
human,
which comprises treating said animal with a therapeutically effective amount
of a
combination of 1592U89, or a physiologically functional derivative thereof,
and at least
one NNRTI or a physiologically functional derivative thereof, or other
combinations
according to the invention.
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Reference herein to treatment extends to prophylaxis as well as the treatment
of
established infections or symptoms.
It will be appreciated that the compounds of the combination may be
administered
simultaneously, either in the same or different pharmaceutical formulations or
sequentially. If there is sequential administration, the delay in
administering the second
and any subsequent active ingredient should not be such as to lose the benefit
of a
synergistic therapeutic effect of the combination of the active ingredients.
It will also be
understood that the compounds of the combination or the physiologically
functional
derivatives of any thereof, whether presented simultaneously or sequentially,
may be
administered individually or in multiples or in any combination thereof.
1592089 and
NNRTI(s) are preferably administered simultaneously or sequentially in
separate
pharmaceutical formulations, most preferably simultaneously.
The present invention also provides the use of 1592089 in the manufacture of a
medicament for administration simultaneously or sequentially with at least one
NNRTI
for the treatment and/or prophylaxis of HIV infections and associated clinical
conditions
hereinbefore described. It will be appreciated that 1592089 and at least one
NNRTI may
be used in the manufacture of the above medicament.
The synergistic effects of the combination of 1592089 and a NNRTI or a
physiologically
functional derivative of any thereof may be seen over a ratio, for example, of
1 to 10: 1
to 20 (by weight), preferably 1 to 5: 1 to 10 (by weight), particularly 1 to
2: 1 to 3 (by
weight). Convenient ratios of 1592089 to a NNRTI include 1:1, 1:1.5, 1:2, 1:3,
and 1:4.
The synergistic effects of the combination of 1592089, a NNRTI and a HIV
protease
inhibitor or a physiologically functional derivative of any thereof may be
seen over a
ratio, for example, of 1 to 10: 1 to 20: 1 to 20 (by weight), preferably 1 to
5: 1 to 10:1 to
10 (by weight), particularly 1 to 2:1 to 3:1 to 3 (by weight). Convenient
ratios of
1592089: NNRTI: HIV protease inhibitor include 1:1:1.5, 1:1.5:2, 1:2:3 and
1:3:4.
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Conveniently each compound may be employed in the combination in an amount at
which it exhibits antiviral activity when used alone.
The amount of a combination of 1592089 and one or more NNRTis required to be
effective as an anti-HIV agent may, of course, vary and is ultimately at the
discretion. of
the medical practitioner. The factors to be considered include the route of
administration and nature of the formulation, the animal's body weight, age
and general
condition and the nature and severity of the disease to be treated.
In general a suitable dose of 1592089 for administration to a human for
treatment of an
HIV injection may be in the range of 0.1 to 120 mg per kilogram body weight of
the
recipient per day, preferably in the range of 3 to 90 mg per kilogram body
weight per day
and most preferably in the range 5 to 60 mg per kilogram body weight per day.
In general, a suitable dose of a NNRTI for administration to a human may be in
the range
of 1 to 100 mg per kilogram body weight per day, advantageously in the range
of 3 to 70
mg per kilogram body weight per day, preferably in the range of 5 to 60 mg per
kilogram
body weight per day.
In general, a suitable dose of a protease inhibitor for administration to a
human may be
in the range of 5 to 100 mg per kilogram body weight per day, advantageously
in the
range of 8 to 70 mg per kilogram body weight per day, preferably in the range
of 8 to 50
mg per kilogram body weight per day.
Unless otherwise indicated all weights of active ingredients are calculated in
terms of the
drug ep r se. In the case of a physiologically functional derivative of
1592089 or an
NNRTI, or a solvate of any thereof the figures would be increased
proportionately. The
desired dose may preferably be presented as one, two, three, four, five, six
or more sub-
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doses administered at appropriate intervals throughout the day. These sub-
doses may be
administered in unit dosage forms, for example, containing from 1 to 1500 mg,
preferably from 5 to 1000 mg, most preferably from 10 to 700 mg of active
ingredient
per unit dosage form. Alternatively, if the condition of the recipient so
requires, the dose
may be administered as a continuous infusion.
The components of the combination which may be referred to as active
ingredients may
be administered for therapy to an animal e.g. a mammal including a human in a
conventional manner.
White it possible for the active ingredients of the combination to be
administered as the
raw chemical it is preferable to present them as a pharmaceutical formulation.
Pharmaceutical formulations according to the present invention comprise a
combination
according to the invention together with one or more pharmaceutically
acceptable
carriers or excipients and optionally other therapeutic agents. The carriers)
must be
acceptable in the sense of being compatible with the other ingredients of the
formula
and not deleterious to the recipient thereof. When the individual components
of the
combination are administered separately they are generally each presented as a
pharmaceutical formulation. The references hereinafter to formulations refer
unless
otherwise stated to formulations containing either the combination or a
component
thereof.
A combination of 1592089 and one or more NNRTIs, or a physiologically
functional
derivative of any thereof may conveniently be presented as a pharmaceutical
formulation
in a unitary dosage form. A convenient unitary dosage formulation contains the
active
ingredients in amounts of from 50 mg to 3 g each, for example, 100 mg to 2 g.
It is also possible to combine any two of the active ingredients in a unitary
dosage form
for simultaneous or sequential administration with the third active
ingredient, for
example, a typical unitary dosage may contain 50 mg to 3 g each of 1592089 and
and
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one or more NNRTIs, advantageously 100 mg to 2 g each of 1592U89 and one or
more
NNRTIs.
As a further feature of the present invention presented is a unitary dosage
form
comprising at least two active ingredients selected from i 592089 and one or
more
NNRTIs or physiologically functional derivatives of any thereof and a
pharmaceutically
acceptable carrier therefor.
Pharmaceutical formulations are often prescribed to the patient in "patient
packs"
containing the whole course of treatment in a single package, usually a
blister pack.
Patient packs have an advantage over traditional prescriptions, where a
pharmacist
divides a patient's supply of a pharmaceutical from a bulk supply, in that the
patient
always has access to the package insert contained in the patient pack,
normally missing
in traditional prescriptions. The inclusion of a package insert has been shown
to improve
patient compliance with the physician's instructions and, therefore, lead
generally to
more successful treatment.
it will be understood that the administration of the combination of the
invention by
means of a single patient pack, or patient packs of each formulation,
containing within a
package insert instructing the patient to the correct use of the invention is
a desirable
additional feature of this invention.
According to a further aspect of the invention provided is a multiple, for
example, double
or triple, pack comprising at least one active ingredient 1592089 and one or
more
NNRTI(s) of the combination of the invention and an information insert
containing
directions on the use of the combination of the invention.
According to another aspect the invention provides a patient pack comprising
in
association for separate administration 1592089 or a physiologically
functional
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derivative thereof together with at least one NNRTI or a physiologically
functional
derivative thereof.
Formulations include those suitable for oral, rectal, nasal, topical
(including transdermal,
5 buccal and sublingual), vaginal or parenteral (including subcutaneous,
intramuscular,
intravenous and intradermal) administration. The formulations may conveniently
.be
presented in unit dosage form and may be prepared by any methods well known in
the
art of pharmacy. Such methods represent a further feature of the present
invention and
include the step of bringing into association the active ingredients with the
carrier which
10 constitutes one or more accessory ingredients. In general, the formulations
are prepared
by uniformly and intimately bringing into association the active ingredients
with liquid
carriers or finely divided solid carriers or both, and then if necessary
shaping the product.
Formulations of the present invention suitable for oral administration may be
presented
as discrete units such as capsules, caplets, cachets or tablets each
containing a
predetermined amount of the active ingredients; as a powder or granules; as a
solution
or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water
liquid
emulsion or a water-in-oil liquid emulsion. The active ingredient may also be
presented
as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more
accessory
ingredients. Compressed tablets may be prepared by compressing in a suitable
machine
the active ingredients in a free-flowing form such as a powder or granules,
optionally
mixed with a binder (e.g. povidone, gelatin, hydroxypropyimethyf cellulose),
lubricant,
inert diluent, preservative, disintegrant (e.g. sodium starch glycoilate,
cross-linked
povidone, cross-linked sodium carboxymethyl cellulose) surface-active or
dispersing
agent. Molded tablets may be made by molding a mixture of the powdered
compound
moistened with an inert liquid diluent in a suitable machine. The tablets may
optionally
be coated or scored any may be formulated so as to provide slow or controlled
release of
the active ingredients therein using, for example, hydroxypropylmethyl
cellulose in
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varying proportions to provide the desired release profile. Tablets may
optionally be
provided with an enteric coating, to provide release in parts of the gut other
than the
stomach.
Formulations suitable for topical administration in the mouth include lozenges
comprising the active ingredients in a flavored base, usually sucrose and
acacia or
tragacanth; pastilles comprising the active ingredient in an inert basis such
as gelatin and
glycerin, or sucrose and acacia; and mouthwashes comprising the active
ingredient in a
suitable liquid carrier. Formulations for rectal administration may be
presented as a
suppository with a suitable base comprising, for example, cocoa butter or a
saficylate.
Topical administration may also be by means of a transdermal iontophoretic
device.
Formulations suitable for vaginal administration may be presented as
pessaries, tampons,
creams, gels, pastes, foams or spray formulations containing in addition to
the active
ingredient such carriers as are known in the art to be appropriate.
Pharmaceutical formulations suitable for recta! administration wherein the
carrier is a
solid are most preferably presented as unit dose suppositories. Suitable
carriers include
cocoa butter and other materials commonly used in the art. The suppositories
may be
conveniently formed by admixture of the active combination with the softened
or melted
carriers) followed by chilling and shaping in molds.
Formulations suitable for parenteral administration include aqueous and
nonaqueous
isotonic sterile injection solutions which may contain anti-oxidants, buffers,
bacteriostats
and solutes which render the formulation isotonic with the blood of the
intended
recipient; and aqueous and non-aqueous sterile suspensions which may include
suspending agents and thickening agents; and liposomes or other
microparticulate
systems which are designed to target the compound to blood components or one
or more
organs. The formulations may be presented in unit-dose or multi-dose sealed
containers,
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for example, ampoules and vials, and may be stored in a freeze-dried
(lyophilized)
condition requiring only the addition of the sterile liquid carrier, for
example water for
injection, immediately prior to use. Extemporaneous injection solutions and
suspensions
may be prepared from sterile powders, granules and tablets of the kind
previously
described.
Preferred unit dosage formulations are those containing a daily dose or daily
subdose of
the active ingredients, as hereinbefore recited, or an appropriate fraction
thereof.
It should be understood that in addition to the ingredients particularly
mentioned above
the formulations of this invention may include other agents conventional in
the art
having regard to the type of formulation in question, for example, those
suitable for oral
administration may include such further agents as sweeteners, thickeners and
flavoring
agents.
The compounds of the combination of the present invention may be obtained in a
conventional manner.
1592U89 may be prepared by the method described in European Specification
EP0434450, PCT application PCT/GB/4500225, PCT/GB95/02014, U.S. Patent No.
5,034,394, or GB9709945.1 which are incorporated herein by reference hereto.
NNRTIs may be prepared by any method known to persons skilled in the art, for
example
those methods disclosed in EPA 0509398, EP429987, U.S. 5,366,972, EP482481,
EP667348, U.S. 5,571,912, U.S. 5,532,358, WO 94/02155, EP582455, WO 95/20389,
WO
91/09849, EP507861, US 5,563,142, WO 95/28398, WO 92/00952, EP538301, U.S.
5,556,886, which are incorporated herein by reference hereto.
HIV protease inhibitors may be prepared by any method known to persons skilled
in the
art, for example those methods disclosed in WO 94/05639, WO 95/24385, WO
94/13629,
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WO 92/16501, WO 95/16688, WO/US94/13085, WO/US94/12562, US 93/59038, EP
541168, WO 94/14436, WO 95/09843, WO 95/32185, WO 94/15906, WO 94/15608, WO
94/04492, WO 92/08701, WO 95/32185, and U.S. 5,256,783, incorporated herein by
reference hereto.
The following examples are intended for illustration only and are not intended
to limEt
the scope of the invention in any way. "Active ingredient" denotes 1592089,
NNRTI(s),
HIV protease inhibitor(s), or multiples thereof or a physiologically
functional derivative of
any of the aforementioned compounds.
'I 0
Example 1: Tablet Formulation
The following formulations A, B and C are prepared by wet granulation of the
ingredients
with a solution of povidone, followed by addition of magnesium stearate and
compression.
C.~.....,..L.+:.,... A
m /tablet
Active Ingredient 250
Lactose B.P. 210
Povidone B.P. 15
Sodium Starch Glycollate 20
Magnesium Stearate 5
500
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r_______~_~:_~ n
mg/tablet
Active Ingredient 250
Lactose B.P. 150
Avicel PH 101 60
Povidone B.P. 15
Sodium Starch Glycollate 20
Magnesium Stearate 5
500
Formulation C
mgJtablet
Active ingredient 250
Lactose B.P. 200
Starch 50
Povidone 5
Magnesium Stearate 4
359
The following formulations, D and E, are prepared by direct compression of the
admixed
ingredients. The lactose in formulation E is of the direct compression type
(Dairy Crest
"Zeparox").
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Formulation D
mgJtablet
Active Ingredient 250
5 Pregelatinized Starch NF15 750
400
Formulation E
mg/tablet
Active Ingredient 250
Lactose B.P. 150
Avicel 100
500
Formulation F (Controlled Release Formulation)
The formulation is prepared by wet granulation of the ingredients with a
solution of
povidone followed by the addition of magnesium stearate and compression.
mg/tablet
Active Ingredient 500
Hydroxypropylmethylcellulose 112
(Methocel K4M Premium)
Lactose B.P. 53
Povidone B.P. 28
Magnesium Stearate 7
700
i
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Drug release takes place over a period of about 6-8 hours and is complete
after 12 hours.
Example 2: Capsule Formulations
A capsule formulation is prepared by admixing the ingredients of formulation D
in
Example 1 above and filling into a two-part hard gelatin capsule. Formulation
B (infra) is
prepared in a similar manner.
Formulation B
mgJcapsule
Active Ingredient 250
Lactose B.P. 143
Sodium Starch Glycoilate 25
Magnesium Stearate 2
TGV
Formulation C
mg/capsule
Active Ingredient 250
Macrogel 4000 B.P. 350
600
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Capsules of formulation C are prepared by melting the Macrogel 4000 B.P.,
dispersing the
active ingredient in the melt and filling the melt into a two-part hard
gelatin capsule.
r~...r..i..4:..~ n
mg/capsule
Active Ingredient 250
Lecithin 100
Arachis Oil 100
450
Capsules of formulation D are prepared by dispersing the active ingredient in
the lecithin
and arachis oil and filling the dispersion into soft, elastic gelatin
capsules.
C.....,.,. . . L. a: ...... C
mg/capsule
Active Ingredient 150.0
Vitamin E TPGS 400.0
Polyethylene Glycol 400 NF 200.5
Propylene Glycol USP 39.5
Four (4) kilograms (kg) of Vitamin E TPGS (obtained from Eastman Chemical Co.)
was
heated at 50 C until liquefied. To the liquified Vitamin E TPGS, 2.005 kg of
polyethylene
glycol 400 (PEG400) (low aldehyde, <10 ppm, obtained from Union Carbide or Dow
Chemical Co.) heated to 50 C was added and mixed until a homogeneous solution
was
formed. The resultant solution was heated to 65~C. 1.5 kg of active ingredient
was
dissolved in the liquefied solution of Vitamin E TPGS and PEG 400. 0.395 kg of
propylene
glycol at room temperature was added and mixed until a homogenous solution,
was
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18
formed. The solution was cooled to 28-35~C. The solution was then de-gassed.
The
mixture was preferably encapsulated at 28-35~C at a fill weight equivalent to
150 mg of
volatiles-free compound, into Size 12 oblong, white opaque soft gelatin
capsules using a
capsule filling machine. The capsule shells were dried to a constant fill
moisture of 3-60/0
water and a shell hardness of 7-10 newtons, and placed in a suitable
container.
Formulation F (Controlled Release Capsule)
The following controlled release capsule formulation is prepared by extruding
ingredients
a,b, and c using an extruder, followed by spheronization of the extrudate and
drying. The
dried pellets are then coated with release-controlling membrane (d) and filled
into a
two-piece, hard gelatin capsule.
mg/capsule
(a) Active Ingredient 250
(b) Microcrystalline Cellulose 125
(c) Lactose B.P. 125
(d) Ethyl Cellulose 13
513
Example 3: Injectable Formulation
Formulation A
Active Ingredient 200
Hydro chloric Acid Solution 0.1 M or
Sodium Hydroxide Solution 0.1M q.s. to pH 4.0 to 7.0
Sterile water q.s. to 10 ml
The active ingredient is dissolved in most of the water (35 - 40 C) and the pH
adjusted
to between 4.0 and 7.0 with the hydrochloric acid or the sodium hydroxide as
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appropriate. The batch is then made up to volume with water and filtered
through a
sterile micropore filter into a sterile 10 m( amber glass vial (type 1) and
sealed with sterile
closures and overseals.
Formulation B
Active Ingredient 125 mg
Sterile, Pyrogen-free, pH 7 Phosphate
Buffer, q.s. to 25 ml
Example 4: Intramuscular Injection
Active Ingredient 200 mg
Benzyl Alcohol 0.10 g
Giycofurol 75 1.45 g
Water for injection q.s. to 3.00 ml
The active ingredient is dissolved in the glycofurol. The benzyl alcohol is
then added and
dissolved, and water added to 3 ml. The mixture is then filtered through a
sterile
micropore filter and sealed in sterile 3 ml amber glass vials (type 1).
Example 5: Syrup
Active ingredient 250 mg
Sorbitol Solution 1.50 g
Glycerol 2.00 g
Sodium Benzoate 0.005 g
Flavor, Peach 17.42.3169 0.0125 ml
Purified Water q.s. to 5.00 ml
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WO 98/52570 PCT/EP98/02836
The active ingredient is dissolved in a mixture of the glycerol and most of
the purified
water. An aqueous solution of the sodium benzoate is then added to the
solution,
followed by addition of the sorbital solution and finally the flavor. The
volume is made
up with purified water and mixed well.
5
Example 6: Suppository
mg/capsule suppository
Active Ingredient 250
10 Hard Fat, B.P. (Witepsol H15-Dynamit Nobel) 1770
2020
One-fifth of the Witepsol H15 is melted in a steam-jacketed pan at 45~C
maximum. The
15 active ingredient is sifted through a 200pm sieve and added to the molten
base with
mixing, using a Silverson fitted with a cutting head, until a smooth
dispersion is achieved.
Maintaining the mixture at 45~ C, the remaining Witepsol Hi5 is added to the
suspension
and stirred to ensure a homogenous mix. The entire suspension is passed
through a
250pm stainless steel screen and, with continuous stirring, is allowed to cool
to 45~ C. At
20 a temperature of 38~ C to 40 C, 2.02 g of the mixture is filled into
suitable, 2 ml plastic
molds. The suppositories are allowed to cool to room temperature.
Example 7: Pessaries
mg/pessary
Active Ingredient 250
Anhydrate Dextrose 380
Potato Starch 363
Magnesium Stearate 7
X000 w
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The above ingredients are mixed directly and pessaries prepared by direct
compression of
the resulting mixture.
The application of which this description Gnd claims form part may be used as
a basis for
priority in respect of any subsequent application. The claims of such
subsequent
application may be directed to any feature or combination of features
described herein.
They may take the form of product, composition, process or use claims and may
include,
by way of example and without limitation, one or more of the following claims.
