U.S. patent application number 10/229645 was filed with the patent office on 2003-08-21 for controlled release dosage form of [r-(z)]-alpha-(methoxyimino)-alpha-(1-az- abicyclo[2.2.2]oct-3-yl)acetonitrile monohydrochloride.
This patent application is currently assigned to SmithKline Beecham Corporation and SmithKline Beecham p.l.c.. Invention is credited to Milosovich, Susan Marie, Muldoon, William Thomas, Napper, James Albert, Rousseau, Laurence, Sauer, Joseph Peter.
Application Number | 20030157169 10/229645 |
Document ID | / |
Family ID | 26310028 |
Filed Date | 2003-08-21 |
United States Patent
Application |
20030157169 |
Kind Code |
A1 |
Sauer, Joseph Peter ; et
al. |
August 21, 2003 |
Controlled release dosage form of
[R-(Z)]-alpha-(methoxyimino)-alpha-(1-az-
abicyclo[2.2.2]oct-3-yl)acetonitrile monohydrochloride
Abstract
A controlled release formulation of an acetonitrile compound and
its use in the treatment and/or prophylaxis of certain
disorders.
Inventors: |
Sauer, Joseph Peter;
(Sarasota, FL) ; Milosovich, Susan Marie;
(Phoenixville, PA) ; Muldoon, William Thomas;
(Philadelphia, PA) ; Napper, James Albert; (Pound
Hill, GB) ; Rousseau, Laurence; (Broxbourne,
GB) |
Correspondence
Address: |
GLAXOSMITHKLINE
Corporate Intellectual Property - UW2220
P. O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham Corporation and
SmithKline Beecham p.l.c.
|
Family ID: |
26310028 |
Appl. No.: |
10/229645 |
Filed: |
August 28, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10229645 |
Aug 28, 2002 |
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09956617 |
Sep 19, 2001 |
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6468560 |
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09956617 |
Sep 19, 2001 |
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09759576 |
Jan 12, 2001 |
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09759576 |
Jan 12, 2001 |
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09254621 |
Mar 11, 1999 |
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09254621 |
Mar 11, 1999 |
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PCT/GB97/02418 |
Sep 8, 1997 |
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Current U.S.
Class: |
424/468 ;
514/304 |
Current CPC
Class: |
A61K 9/1617 20130101;
A61K 9/2086 20130101; A61K 9/2054 20130101; A61K 9/5078 20130101;
A61K 31/439 20130101; A61K 9/2059 20130101 |
Class at
Publication: |
424/468 ;
514/304 |
International
Class: |
A61K 009/22 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 12, 1996 |
GB |
9619074.9 |
Claims
1. A controlled release oral dosage form containing
[R-(Z)]-.alpha.-(methoxyimino)-.alpha.-(1-azabicyclo
[2.2.2]oct-3-yl)acetonitrile monohydrochloride (compound X), its
parent free base or any other pharmaceutically acceptable salt
thereof.
2. A dosage form according to claim 1 which provides an in vitro
release profile selected to provide an area under the in vivo
plasma profile curve that is similar to that obtained following
conventional oral administration of a fast release tablet 5 to 75
.mu.g (calculated as free base) compound X twice a day.
3 A dosage form according to claim 1 or 2 which provides an in
vitro release profile of 25-70% over 4 hours and 70-100% over 8
hours.
4. A dosage form according to any of claims 1 to 3 selected from
wax matrices, swellable and/or gellable matrices, tablets coated
with release controlling polymers or waxes, and pellets, granules
or beads comprising matrices or coated with release controlling
polymers or waxes and then formulated as capsules, compressed
tablets or suspensions.
5. A dosage form according to any preceding claim comprising a
swellable and/or gellable matrix selected from alkyl celluloses,
hydroxyalkylcelluloses, polyvinyl alcohol, polymethacrylates,
polymethylmethacrylates, methacrylate/divinylbenzene copolymers,
carboxymethylamide, polyoxyalkylene glycols, polyvinyl pyrrolidone
and carboxymethyl cellulose.
6. A dosage form according to claim 5 wherein the matrix is
selected from alkyl celluloses, hydroxyalkylcelluloses, polyvinyl
alcohol, polymethacrylates, cross-linked polyvinylpyrrolidone and
sodium carboxymethyl cellulose.
7. A dosage form according to claim 5 or 6 comprising a hydrogel
matrix tablet coated with a hydrophobic release controlling polymer
coating selected from alkyl celluloses and methacrylic acid
derivatives.
8. A dosage form according to claim 7 wherein the polymer matrix
comprises 10-50% and the hydrophobic release controlling polymer
comprises 4-10% by weight of the tablet.
9. A dosage form according to claim 7 or 8 comprising a tablet of
the following composition (mg/tablet):
32 Compound X 0.005-0.1 pfb Hydroxpropyl Methcellulose E4M CR 75.0
Sodium Dihydrogen Citrate 0-3.00 Lactose, Fast Flo 70.38-73.38
Magnesium Stearate 1.50 Opadry .RTM. White 2.25
seal coated with a solution of Opadry.RTM. Clear (YS-1-7006) in
purified water at 10% solids concentrations and polymer coated with
a 60% w/w (25% as solids) dispersion containing Ethylcellulose
(Surelease.RTM.) at 10% weight gain, formed into core tablets,
coated with the Opadry.RTM. Clear seal coating solution and polymer
coated to 4% weight gain using 60% w/w (25% as solids) dispersion
containing Ethylcellulose (Surelease.RTM.). -
10. A dosage form according to any of claims 1 to 4 which comprises
drug-layered beads coated with a release controlling polymer either
alone or in combination with drug-layered beads not coated with a
release controlling polymer (immediate release beads) and
optionally, inert excipients and/or retardants and/or one or more
binders.
11. A dosage form according to claim 10 wherein the layered beads
are seal coated with a film-forming polymer.
12. A dosage form according to claim 10 or 11 wherein the release
controlling polymer coating is selected from from alkyl celluloses,
hydroxyalkylcelluloses, sodium carboxymethyl cellulose and
methacrylic acid derivatives.
13. A dosage form according to any of claims 10 to 12 wherein the
polymer(s) make up 10 to 30% by weight of the total dosage
form.
14. A dosage form according to claim 10 in capsule form comprising
non-pareil sugar beads of 16-20, 20-25 or 25-30 mesh size, coated
to a drug loading of 100 microgrammes (calculated as free base) per
200 mg beads, with a medicated aqueous layer solution of the
following composition (%w/w):
33 Compound X 0.003-0.06 pfb Opadry .RTM. Clear 3 Sodium dihydride
citrate 0-1.5
seal coated with a solution of Opadry.RTM. Clear (YS-1-7006) in
purified water at 10% solids concentrations to a weight gain of 3%,
and a portion of the beads further polymer coated to a weight gain
of 10-25% with a 60%w/w (25% as solids) dispersion containing
ethylcellulose (Surelease.RTM.) and then seal coated to a weight
gain of 2% with the above seal coat.
15. A method of treatment and/or prophylaxis of dementia, including
Alzheimer's disease, in mammals by administering an effective
amount of a controlled release oral dosage form according to claim
1, to a sufferer in need thereof.
16. A method for enhancing amyloid precursor protein processing
along a non-amyloidogenic pathway in patients suffering from, or at
risk of developing, Alzheimer's disease by administering an
effective amount of a controlled release oral dosage form according
to claim 1, to a sufferer in need thereof.
17. The use of a controlled release oral dosage form according to
claim 1 in the manufacture of a medicament for treatment and/or
prophylaxis of dementia, including Alzheimer's disease, in
mammals.
18. The use of a controlled release oral dosage form according to
claim 1, in the manufacture of a medicament for enhancing amyloid
precursor protein processing along a non-amyloidogenic pathway in
patients suffering from, or at risk of developing, Alzheimer's
disease.
19. A pharmaceutical composition for treatment and/or prophylaxis
of dementia, including Alzheimer's disease, in mammals which
comprises a controlled release oral dosage form according to claim
1.
20. A pharmaceutical composition for enhancing amyloid precursor
protein processing along a non-amyloidogenic pathway in patients
suffering from, or at risk of developing, Alzheimer's disease which
comprises a controlled release oral dosage form according to claim
1.
21. A dosage form, method, use or composition according to any
preceding claim in which release in the gastro-intestinal tract
takes place predominantly over the first-eight to twelve hours
following ingestion.
22. A dosage form, method, use or composition according to any
preceding claim containing
[R-(Z)]-.alpha.-(methoxyimino)-.alpha.-(1-azabicyclo
[2.2.2]oct-3-yl)acetonitrile monohydrochloride.
23. A dosage form, method, use or composition according to any of
claims 1 to 22 containing 5 .mu.g compound X (calculated as free
base).
24. A dosage form, method, use or composition according to any of
claims 1 to 22 containing 12.5 .mu.g compound X (calculated as free
base).
25. A dosage form, method, use or composition according to any of
claims 1 to 22 containing 25 .mu.g compound X (calculated as free
base).
26. A dosage form, method, use or composition according to any of
claims 1 to 22 containing 50 .mu.g compound X (calculated as free
base).
27. A dosage form, method, use or composition according to any of
claims 1 to 22 containing 75 .mu.g compound X (calculated as free
base).
28. A dosage form, method, use or composition according to any of
claims 1 to 22 containing 100 .mu.g compound X (calculated as free
base).
Description
[0001] The present invention relates to a novel formulation, and to
its use in the treatment and/or prophylaxis of certain
disorders.
[0002] [R-(Z)]-.alpha.-(methoxyimino)-.alpha.-(1-azabicyclo
[2.2.2]oct-3-yl)acetonitrile monohydrochloride (compound X) and
methods for its preparation are disclosed in EP-A-0392803,
WO95/31456 and WO93/17018. The compound enhances acetylcholine
function via an action at muscarinic receptors within the central
nervous system and is therefore of potential use in the treatment
and/or prophylaxis of dementia in mammals.
[0003] WO96/12486 discloses the use of compound X in the
manufacture of a medicament for enhancing amyloid precursor protein
processing along a non-amyloidogenic pathway in patients suffering
from, or at risk of developing, Alzheimer's disease.
[0004] Fast-release swallow tablet and oral solution formulations
of compound X both result in rapid absorption of the compound into
the circulation, and require twice a day dosing for optimal
efficacy.
[0005] It has now been surprisingly found that it is possible to
formulate compound X, which has very high water solubility and is
active at extremely low doses, in such a way that release is
controlled to take place over a period of hours. Such a formulation
would require dosing only once a day: this is likely to improve
compliance in a patient population characterised by poor memory; it
may also reduce side-effects in case of accidental overdosing.
[0006] Accordingly, the present invention provides a controlled
release oral dosage form containing compound X, its parent free
base or any other pharmaceutically acceptable salt thereof.
[0007] By controlled release is meant any formulation technique
wherein release of the active substance from the dosage form is
modified to occur at a slower rate than that from an immediate
release product, such as a conventional swallow tablet or
capsule.
[0008] Controlled release includes delayed release wherein release
of the active substance from the dosage form is modified to occur
at a later time than that from a conventional immediate release
product. The subsequent release of active substance from a delayed
release formulation may also be controlled to occur at a slower
rate.
[0009] Examples of controlled release formulations which are
suitable for incorporating compound X are described in:
[0010] Sustained Release Medications, Chemical Technology Review
No. 177. Ed. J. C. Johnson. Noyes Data Corporation 1980.
[0011] Controlled Drug Delivery, Fundamentals and Applications, 2nd
Edition. Eds. J. R. Robinson, V. H. L. Lee. Marcel Dekker Inc. New
York 1987.
[0012] Such controlled release formulations are preferably
formulated in a manner such that release of compound X is effected
throughout the gastro-intestinal tract. and takes place
predominantly over the first eight to twelve hours following
ingestion.
[0013] Preferred formulations include wax matrices, swellable
and/or gellable polymer or hydrogel matrices, tablets coated with
release controlling polymers or waxes and pellets, granules or
beads comprising matrices or coated with release controlling
polymers or waxes and then formulated as capsules, compressed
tablets or suspensions.
[0014] Suitable waxes for matrix formation or release controlling
coating include non-ionic beeswax derivatives such as Gelucire
62/05, 50/02 or 50/13 (Gattefosse), glyceryl behenate, other fatty
acid mono-, di- or tri-esters of glycerol such as Precirol ATO5
(Gattefosse), microcrystalline wax, hydrogenated castor oil or
hydrogenated vegetable oil, long-chain aliphatic alcohols such as
stearyl alcohol and camuba wax.
[0015] Suitable materials for the formation of hydrogel matrices or
swellable and/or gellable polymer matrices may be selected from
alkyl celluloses, hydroxyalkylcelluloses, polyvinyl alcohol,
polymethacrylates, polymethylmethacrylates,
methacrylate/divinylbenzene copolymers, carboxymethylamide,
polyoxyalkylene glycols, polyvinyl pyrrolidone and carboxymethyl
cellulose. The swellable polymeric material in particular may be
selected from crosslinked sodium carboxymethylcellulose,
crosslinked hydroxypropylcellulose, high molecular weight
polyhydroxypropylmethylcellulose, carboxymethylamide, potassium
methacrylate/divinylbenzene copolymer, polymethylmethacrylate,
crosslinked polyvinylpyrrolidone and high molecular weight
polyvinyl alcohol. The gellable polymeric material in particular
may be selected from methylcellulose, carboxymethylcellulose,
low-molecular weight hydroxypropylmethylcellulose, low-molecular
weight polyvinvlalcohols, polyoxyethyleneglycols and
non-cross-linked polyvinylpyrrolidone. The swellable and gellable
polymeric material in particular may be selected from
medium-viscosity hydroxypropylmethylcellulose and medium-viscosity
polyvinylalcohols.
[0016] Release controlling polymers include hydrogel polymers such
as those listed above, hydrophobic polymers and enteric, or pH
dependent, polymers.
[0017] Suitable materials for the formation of hydrophobic release
controlling polymer coatings include alkyl celluloses, which may be
used in the form of latex suspensions such as Surelease (Colorcon)
or Aquacoat (FMC), and methacrylic acid derivatives, which may be
used in the form of latex suspensions such as Eudragit RS, RL and
NE (Rohm).
[0018] Suitable materials for the formation of enteric or pH
dependent polymer coatings include methacrylic acid derivatives,
which may be used in the form of latex suspensions such as Eudragit
L and S (Rohm).
[0019] Seal coats, film layers used to separate the various
functional layers of the formulation or to provide a final layer to
the outside of the formulation. contain suitable materials for film
forming such as alkylcelluloses, which may be used in the form of
latex suspensions such as Surelease (Colorcon) or Aquacoat (FMC),
and hydroxyalkycelluloses such as hydroxypropylmethylcellulose (for
example Opadry (Colorcon)).
[0020] The formulation may also include plasticisers such as
triethyl citrate, dibutyl sebacate or medium chain triglycerides in
the release controlling polymer layer.
[0021] Pellet-forming materials include suitable grades of
microcrystalline cellulose such as Avicel PH101 (FMC).
[0022] Granules may be formed from any of the commonly used
pharmaceutical fillers or diluents such as lactose, lactose
monohydrate, mannitol, microcrystalline cellulose, dicalcium
phosphate or starch.
[0023] Beads may be formed by layering or spraying on non-pareil
seeds.
[0024] Other suitable ingredients in controlled-release dosage
forms include polyethylene glycol and propylene glycol and these,
as well as the pharmaceutical fillers, may be used to modify the
release rate by inclusion in matrices, pellets, granules or
beads.
[0025] The formulation may also include hydrophobic excipients that
retard the release from the formulation such as ethylcellulose,
talc, colloidal silicon dioxide or glyceryl monostearate and/or one
or more binders such as hydroxypropylmethylcellulose,
microcrystalline cellulose or polyvinylpyrrolidone.
[0026] Wetting agents such as sodium lauryl sulphate, lubricants
such as magnesium stearate and glidants such as colloidal silica
may also be included.
[0027] A particularly preferred formulation comprises drug-layered
beads coated with a release controlling polymer either alone or in
combination with drug-layered beads not coated with a release
controlling polymer (immediate release beads). In the drug layering
process onto non-pareil beads, appropriate size non-pareil sugar
beads may be layered with a solution or dispersion containing the
active substance, inert excipients, and/or retardants such as
ethylcellulose, talc, colloidal silicon dioxide or glyceryl
monostearate and/or one or more binders such as
hydroxypropylmethylcellulose or polyvinylpyrrolidone. The layering
of the active substance may be accomplished at a predetermined rate
and temperature using either a coating pan or a fluid bed drier.
The layered beads may be seal coated with a suitable film forming
polymer such as hydroxypropylmethylcellulose (e.g. Opadry) or
Eudragit.RTM. L30D-55 (a methacrylic acid copolymer) and then may
be coated with one or more suitable release controlling polymers
preferably selected from from alkyl celluloses,
hydroxyalkylcelluloses, sodium carboxymethyl cellulose and
methacrylic acid derivatives, such as ethylcellulose, Eudragit.RTM.
RS, Eudragit.RTM. RL dr Methocel E4M, to produce beads that release
compound X over an eight to twelve hour period and/or release
compound X in one or more pulses. Seal coated beads may be used for
an immediate release dose. The controlled release or a mixture of
controlled release and immediate release beads may then be filled
into an appropriate size capsule or compressed with inert
excipients into tablets of appropriate physical parameters such as
shape, size, hardness and disintegration. The polymer(s), release
controlling plus any seal coat polymer(s), preferably make up 10 to
30% by weight of the total dosage form. Plasticizer is normally
present and may make up at least 2% by weight. Binder(s) and
retardant(s) typically make up to 3-10% by weight.
[0028] Another particularly preferred formulation comprises a
swellable and/or gellable polymer matrix tablet. The polymer matrix
is preferably a hydrogel polymer selected from alkyl celluloses
such as methylcellulose, hydroxyalkylcelluloses such as
hydroxypropylcellulose and hydroxypropylmethylcellulose, polyvinyl
alcohol, polymethacrylates, cross-linked polyvinylpyrrolidone and
sodium carboxymethyl cellulose. The polymers typically make up 10
to 50% by weight of the tablet. The matrix tablet can be sealed
with a hydrophobic release controlling polymer coating such as
ethylcellulose (Surelease (Colorcon)) to retard the hydration of
the hydrogel matrix in the tablet. The hydrophobic coating polymer
typically make up 4 to 10% by weight of the tablet.
[0029] Such matrix tablet formulations can be prepared by either
direct compression or wet granulation processes. Coating may be
accomplished using a coating pan.
[0030] Other preferred formulations are described in U.S. Pat. No.
5,422,123.
[0031] Thus, a particular aspect of the invention provides a system
for the controlled release of an active substance which is compound
X, its parent free base or any other pharmaceutically acceptable
salt thereof, comprising (a) a deposit-core comprising an effective
amount of the active substance and having defined geometric form,
and (b) a support-platform applied to said deposit-core, wherein
said deposit-core contains at least the active substance, and at
least one member selected from the group consisting of (1) a
polymeric material which swells on contact with water or aqueous
liquids and a gellable polymeric material wherein the ratio of the
said swellable polymeric material to said gellable polymeric
material is in the range 1:9 to 9:1, and (2) a single polymeric
material having both swelling and gelling properties, and wherein
the support-platformn is an elastic support, applied to said
deposit-core so that it partially covers the surface of the
deposit-core and follows changes due to hydration of the
deposit-core and is slowly soluble and/or slowly gellable in
aqueous fluids.
[0032] The swellable polymeric material in (1) may be selected from
crosslinked sodium carboxymethylcellulose, crosslinked
hydroxypropylcellulose, high molecular weight
polyhydroxypropyl-methylcel- lulose, carboxy-methyl starch,
potassium methacrylate/divinylbenzene copolymer, crosslinked
polyvinylpyrrolidone and polyvinyl alcohol. The gellable polymeric
material in (1) may be selected from methylcellulose and
non-cross-linked polyvinylpyrrolidone.
[0033] The support-platform may comprise; polymers such as
polyhydroxypropylmethylcellulose, polyvinyl alcohol, polyacrylate,
polymethacrylate, polyhydroxpropyl cellulose and polysodium
carboxymethylcellulose; plasticizers such as polyoxyethylene
glycols, castor oil, hydrogenated cator oil, ethyl phthalate, butyl
phthalate, natural glycerides, synthetic glycerides and
semisynthetic glycerides; binders such as polyvinylpyrrolidone,
methylcellulose, ethyl cellulose gum arabic and alginic acid;
hydrophilic agents such as mannitol, lactose, starch and colloidal
silica; and/or hydrophobic agents such as hydrogenated castor oil,
magnesium stearate, a fatty substance, wax, natural glycerides and
synthetic glycerides. The polymer(s) typically make up 30 to 90% by
weight of the support-platform, for example about 35 to 40%.
Plasticizer may make up at least 2% by weight of the
support-platform, for example about 15 to 20%. Binder(s),
hydrophilic agent(s) and hydrophobic agent(s) typically total up to
about 50% by weight of the support-platform, for example about
40-to 50%.
[0034] Such formulation may be prepared as generally described in
U.S. Pat. No. 5,422,123.
[0035] U.S. Pat. No. 4,839,177 discloses a further alternative
controlled release formulations suitable for use in the present
invention.
[0036] Thus a further aspect of the invention provides a system for
the controlled-rate release of compound X, consisting of:
[0037] a) a deposit-core comprising effective amounts of compound X
and having defined geometric form,
[0038] b) a support-platform applied to said deposit-core wherein
said deposit-core contains, mixed with the active substance, at
least one member selected from the group consisting of a (a) 5-80%
by weight of the total weight of deposit-core of a polymeric
material having a high degree of swelling on contact with water or
aqueous liquids and 90-10% by weight of the total weight of the
deposit core of a gellable polymeric material, and (b) a single
polymeric material having both swelling and gelling properties, and
other adjuvants able to provide the mixture with suitable
characteristics for compression and for intake of water, and
wherein said support-platform consists of a polymeric material
insoluble in aqueous liquids and partially coating said deposit
core.
[0039] The swellable polymeric material in (a) may be selected from
crosslinked sodium carboxymethylcellulose, crosslinked
hydroxypropylcellulose, high molecular weight
polyhydroxypropyl-methylcel- lulose, carboxy-methylamide, potassium
methacrylate/divinylbenzene copolymer, polymethylmethacrylate,
crosslinked polyvinylpyrrolidone and high molecular weight
polyvinyl alcohol. The gellable polymeric material in (a) may be
selected from methylcellulose, carboxymethylcellulose,
low-molecular weight hydroxypropylmethylcellulose, low-molecular
weight polyvinylalcohols, polyoxyethyleneglycols and
non-cross-linked polyvinylpyrrolidone. The swellable and gellable
polymeric material in (b) may be selected from medium-viscosity
hydroxypropylmethylcellulose and medium-viscosity
polyvinylalcohols. The support platform may comprise insoluble
polymeric material selected from acrylates, cellulose,
ethylcellulose, cellulose acetate-propionate, polyethylene,
methacrylates, acrylic acid copolymers and high-molecular weight
polyvinylalcohols.
[0040] Such formnulation may be prepared as generally described in
U.S. Pat. No. 4,839,177.
[0041] WO 94/06416 discloses a yet further alternative controlled
release formulations suitable for use in the present invention.
[0042] Thus a yet further aspect of the invention provides a system
for the controlled-rate release of compound X, consisting of a
pharmaceutical compressed tablet capable of releasing compound X at
different rates, consisting of three layers, wherein
[0043] a first layer contains compound X with immediate or
controlled release formulation, composed of rapidly swelling and/or
soluble and/or erodible polymeric substances by contact with
aqueous fluids, and adjuvants;
[0044] a second layer contains compound X, either equal to or
different from those of the first layer, with slow release
formulation, composed of swelling and/or gellable and/or erodible
polymeric substances by contact with aqueous fluids, and
adjuvants;
[0045] a low-permeability barrier-type layer coating said second
layer or, alternatively, placed between the first and second layer,
consisting of polymeric substances, adjuvants, plasticizing agents
and, if necessary, compound X.
[0046] The polymeric substances of the first layer may be selected
from cross-linked polyvinylpyrrolidone, low- and
medium-molecular-weight hydroxypropyl cellulose and hydroxypropyl
methylcellulose, cross-linked sodium carboxymethylcellulose,
carboxymethyl starch, potassium methacrylate-divinylbenzene
copolymer, polyvinyl alcohols, starches, starch derivatives,
microcrystalline cellulose and cellulose derivatives,
.beta.-cyclodextrin and dextrin derivatives.
[0047] The polymeric substances of the second layer may be selected
from the group consisting of hydroxypropyl methylcellulose having
molecular weight from 1,000 to 4,000,000, hydroxypropyl cellulose
having molecular weight from 2,000 to 2,000,000, carboxyvinyl
polymers, polyvinyl alcohols, glucans, scleroglucans, mannans,
xanthans, alginic acid and derivatives thereof,
carboxymethylcellulose and derivatives thereof, poly(methyl vinyl
ethers/maleic anhydride), ethylcellulose, methylcellulose, and
cellulose derivatives.
[0048] The adjuvants of the first and second layers may be selected
from the group consisting of starch, pregelled starch, calcium
phosphate. mannitol, lactose, saccharose, glucose, sorbitol,
microcrystalline cellulose, gelatin, polyvinylpyrrolidone,
methylcellulose, starch solution, ethylcellulose, arabic gum,
tragacanth gum, magnesium stearate, stearic acid, colloidal silica,
glyceryl monostearate, hydrogenated castor oil, waxes, and mono-,
bi-, and trisubstituted glycerides.
[0049] The polymeric substances of the barrier type layer may be
selected from the group consisting of hydroxypropyl methylcellulose
having molecular weight from 1,000 to 4,000,000, hydroxypropyl
cellulose having molecular weight from 2,000 to 2,000.000,
carboxyvinyl polymers, polyvinyl alcohols, glucans, scleroglucans,
mannans, xanthans, carboxymethylcellulose, ethylcellulose, and
methylcellulose.
[0050] The adjuvants of the barrier-type layer may be selected from
the group consisting of glyceryl monostearate, semisynthetic
glycerides, glyceryl palmitostearate, glyceryl behenate,
polyvinylpyrrolidone, gelatine, ethylcellulose, methylcellulose,
sodium carboxymethylcellulose, magnesium stearate, stearic acid,
sodium stearate, talc, sodium benzoate, boric acid, and colloidal
silica.
[0051] The plasticizing agents of the barrier-type layer may be
selected from the group consisting of hydrogenated castor oil,
fatty acids, substituted triglycerides and glycerides,
polyoxyethylene glycols and derivatives thereof having molecular
weight from 400 to 60,000.
[0052] Such formulation may be prepared as generally described in
WO 94/06416.
[0053] The dosage form preferably contains compound X itself.
[0054] Compound X has active doses around 5-125 microgramme (.mu.g)
(calculated as free base). It has been found through administration
to human patients that efficacy as a cognition enhancer may be
obtained at daily doses below 0.01 mg/kg more particularly 0.003
mg/kg and below, for example 0.0001-0.003 mg/kg, such as
0.00035-0.003 mg/kg, 0.0007-0.003 mg/kg, 0.0001-0.0007 mg/kg or
0.00035-0.002 mg/kg.
[0055] Suitable unit doses to achieve such daily doses are 5, 12.5,
25, 50 or 75 .mu.g, administered twice daily or 50 .mu.g or 100
.mu.g, once daily. Such unit doses are calculated on the basis of
50-70 .mu.g individuals and as free base.
[0056] Suitably, the in vitro release profile of the dosage form
i.e. the amount of compound X released over time will be selected
so that it will provide an area under the in vivo plasma profile
curve that is similar to that obtained following conventional oral
administration of a fast release tablet, 5 to 75 .mu.g (calculated
as free base) compound X twice a day. Preferably 25-70% is released
over 4hours and 70-100% is released over 8 hours.
[0057] The dosage form of the invention may be used in the
treatment and/or prophylaxis of dementia, including Alzheimer's
disease, in mammals, and for enhancing amyloid precursor protein
processing along a non-amyloidogenic pathway in patients suffering
from, or at risk of developing, Alzheimer's disease. These
disorders are herein after referred to as "the Disorders".
[0058] The present invention provides a method of treating "the
Disorders" by administering an effective amount of a controlled
release oral dosage form containing compound X, its parent free
base or any other pharmaceutically acceptable salt thereof, to a
sufferer in need thereof.
[0059] The present invention further provides the use of a
controlled release oral dosage form containing compound X, its
parent free base or any other pharmaceutically acceptable salt
thereof, in the manufacture of a medicament for treating "the
Disorders".
[0060] The present invention also provides a pharmaceutical
composition for use in the treatment of "the disorders" which
comprises a controlled release oral dosage form containing compound
X, its parent free base or any other pharmaceutically acceptable
salt thereof.
[0061] The following examples illustrate the present invention.
EXAMPLES
[0062] In the following examples, the weight shown is the weight of
free base; compound X is the hydrochloride salt. (pfb=pure free
base). Mesh sizes are US standard.
Example 1 (Wax matrix)
[0063]
1 Compound X 0.005-0.1 mg pfb Gelucire 62/05 (Gattefosse) 190 mg
Propylene glycol 10 mg
Example 2
Film Coated Pellets
[0064]
2 Component mg/capsule (500 mg) Function Compound X 0.005-0.1 mg
pfb Active Lactose 300 Hydrophilic diluent Avicel PH 101 (FMC) 200
Inert pellet matrix Film coat: w/w of pellet cores Surelease
(Colorcon) 2-10% Release controlling polymer coat Silicone antifoam
Antifoaming agent
Example 3
Film Coated Pellets
[0065]
3 Component mg/capsule (500 mg) Function Compound X 0.005-0.1 mg
pfb Active Lactose 400 Hydrophilic diluent Avicel PH 101 100 Inert
pellet matrix Film coat: w/w of pellet cores Aquacoat (FMC) 2-10%
Release controlling polymer coat Silicone antifoam Antifoaming
agent Di-butylsebacate 20-30% (of polymer Plasticizer weight)
[0066] In Examples 2 and 3, pellets are produced by
extrusion/spheronization, using water as a granulation liquid and
an appropriate size fraction is obtained by screening. Pellets are
then coated in a fluid bed coater (bottom spray) with 2-10% (w/w)
of an aqueous Surelease dispersion (15% solids in dispersion).
[0067] Desired release profiles are obtained by mixing uncoated
(=immediate release pellets) and coated pellets of suitable coating
levels (=sustained release pellets), that are then filled into hard
gelatine capsules.
Example 4
Matrix Pellets
[0068]
4 Component mg/capsule (500 mg) Function Compound X 0.005-0.1 mg
pfb Active Glyceryl behenate 200 Hydrophobic matrix Avicel PH 101
300 Inert pellet matrix Sodium lauryl sulphate 0.1 Wetting
agent
[0069] Pellets are produced by extrusion/spheronization using water
and sodium laurylsulphate as a granulation liquid, and an
appropriate size fraction is obtained by screening. Pellets may
additionally be coated in a fluid bed coater (bottom spray) with
aqueous polymer dispersions to further reduce release rates and
obtain the desired release profiles.
Example 5
Hydrogel Matrix
[0070]
5 Excipient % w/w mg/tablet mg/tablet Compound X 0.003-0.07 pfb
0.005 pfb 0.1 pfb Hydroxypropylcellulose 25 37.5 37.5 Purified
water -- -- -- Starch to 100 109.5 108.5 Magnesium stearate 2 3.0
3.0 Total 100 150 150
[0071] Tablets may be prepared by the following procedure:
[0072] 1. Blend the starch and HPC in a high shear mixer
[0073] 2. Dissolve the drug into a small quantity of water and
spray into blend while mixing
[0074] 3. Wash spray mechanism with small volume of water into
blend while mixing
[0075] 4. Granulate mix with sufficient water to achieve a medium
to heavy granule
[0076] 5. Partially dry granule
[0077] 6. Screen through a suitable mill
[0078] 7. Complete drying of milled granule
[0079] 8. Lubricate with Mg stearate
[0080] 9. Compress into tablets with a target weight of 150 mg
Example 6
Wax Matrix
[0081]
6 Excipient % w/w mg/tablet mg/tablet Compound X 0.003 to 0.07 pfb
0.005 pfb 0.1 pfb Lactose Anhydrous to 100 to 150 to 150 Gelucire
62/05 18 27.0 27.0 Magnesium stearate 2 3.0 3.0 Total 100 150
150
[0082] Tablets may be prepared by the following procedure:
[0083] 1. Preblend the drug with a small quantity of lactose
[0084] 2. Sandwich the drug preblend with the remaining lactose and
the required % of Gelucire 62/05 in a preheated pelletiser.
[0085] 3. Pelletise until the required pellet size has been
achieved
[0086] 4. Remove the pellets and allow them to cool
[0087] 5. Screen pellets as necessary
[0088] 6. Lubricate pellets
[0089] 7. Compress or encapsulate pellets
Example 7
Controlled Release Bilayer Tablet
[0090]
7 mg/tablet Function Active Layer Component Compound X 0.005-0.1 mg
pfb Active Hydroxypropylmethylcellulose 68.5 Hydrogel matrix former
Mannitol 20 Soluble filler Ethyl cellulose (applied in 7.5 Binder
ethanolic solution) Magnesium stearate 2 Lubricant Colloidol silica
2 Glidant Support platform Component Hydroxypropylmethylcellulose
39.75 Hydrogel matrix former Hydrogenated castor oil 6.5 Insoluble
filler Ethylcellulose (applied in 2.5 Binder ethanolic solution)
Yellow iron oxide pigment 0.5 Pigment Magnesium stearate 0.5
Lubricant Colloidal silica 0.25 Glidant Tablets may be prepared as
described in U.S. Pat. No. 5433123.
Example 8
Wax Matrix
[0091]
8 Component % w/w Function Compound X 0.02 pfb Active Gelucire
50/02 91.5 Wax matrix Gelucire 50/13 5 Wax matrix Propylene glycol
1.98 Solvent Colloidal silica 1.5 Hydrophobic excipient Sodium
dihydrogen citrate 0-1.5 Stabilizer
[0092] Process
[0093] The Gelucire waxes were melted together at around 60 degrees
C. Compound X was dissolved in propylene glycol, and blended into
the waxes. The colloidal silica was then also blended in, and the
mixture filled into size 3 hard gelatin capsule shells.
9TABLE 1 Release Profile of wax-filled capsules of Compound X in
water (0% citrate) Time (hr) % Released 1 13 3 29 5 53 8 73
Example 9
Ethylcellulose Coated Beads
[0094] 200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30
mesh size may be used. A medicated layer solution of the following
composition was used:
10 Component % w/w Function Compound X 0.003-0.05 pfb Active Opadry
.RTM. Clear 3 Binder Sodium dihydrogen citrate 1.5 Stabilizer
Purified water q.s. Total 100
[0095] Seal coating solution: A solution of Opadry.RTM. Clear
(YS-1-9025A) in purified water at 10% solids concentrations was
made by dissolving 100 grams of Opadry.RTM. Clear into 900 grams of
purified water.
[0096] Polymer Coating: A polymer coating dispersion containing
ethylcellulose (Surelease.RTM.) of the following composition was
made and used for polymer coating the seal coated beads at an 10%
to 25% weight gain, in particular 10, 12, 15, 17, 22 and 25%.
11 Component % w/w Function Surelease .RTM. 60 (25% as solids)
Release controlling polymer coat with plasticiser Purified water
q.s. Total 100
[0097] Drug layered beads were produced by layering the drug
solution onto 25-30 mesh non-pareil beads using a Niro STREA-1
fluid bed dryer so as to layer 100 micrograms of the drug as the
free base onto 200 mg of the non-pareil beads. The drug layered
beads were seal coated with Opadry.RTM. Clear seal coating solution
to a weight gain of 3% to produce the immediate release beads. A
portion of the immediate release beads were polymer coated to a
weight gain of 10% to 25% with the Surelease.RTM. coating
dispersion. The final polymer coated beads were produced by seal
coating the polymer coated beads to a weight gain of 2% with the
Opadry.RTM. Clear seal coating solution.
12TABLE 2 Release Profile Range of Ethylcellulose coated beads,
10-25% by weight of Compound X in Water Time (hr) % Released 1
0.8-36 2 5-57 4 13-75 8 18-91
Example 10
Ethylcellulose Coated Beads
[0098] 200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30
mesh size may be used. A medicated layer solution of the following
composition was used:
13 Component % w/w Function Compound X 0.003-0.05pfb Active Opadry
.RTM. Clear 3 Binder Sodium dihydrogen citrate 1.5 Stabilizer
Purified water q.s. Total 100
[0099] Seal coating: A seal coating dispersion containing
Eudragit.RTM. L30D-55 of the following composition was made and
used for seal coating the drug layered beads at an 4% weight
gain.
14 Component % w/w Function Eudragit .RTM. L30D-55 45 (30% as
solids) Polymeric seal coat Triethyl citrate 2.02 Plasticizer Talc
3.10 Anti-tack Purified water q.s. Total 100
[0100] Polymer Coating: A polymer coating dispersion containing
ethylcellulose (Surelease.RTM.) of the following composition was
made and used for polymer coating the seal coated beads at an 10%
to 25% weight gain.
15 Component % w/w Function Surelease .RTM. 60 (25% as solids)
Release controlling polymer coat with plasticiser Purified water
q.s. Total 100
[0101] Drug layered beads were produced by layering the drug
solution onto 25-30 mesh non-pareil beads using a Niro STREA-1
fluid bed dryer so as to layer 100 micrograms of the drug as the
free base onto 200 mg of the non-pareil beads. The drug layered
beads were seal coated with Eudragit.RTM. L30D-55 seal coating
dispersion to a weight gain of 4% to produce the immediate release
beads. A portion of the immediate release beads were polymer coated
to a weight gain of 10% tp 25% with the Surelease.RTM. coating
dispersion. The final polymer coated beads were produced by seal
coating the polymer coated beads to a weight gain of 2% with the
Opadry.RTM. Clear seal coating solution.
16TABLE 3 Release Profile of Eudragit .RTM. L30D Seal
Coated/Ethylcellulose Coated Beads of Compound X in Water Time (hr)
% Released, 10% Surelease 0.5 1.5 1 5 2 20 4 39 6 49 8 56
Example 11
Ethylcellulose Coated Beads
[0102] 200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30
mesh size may be used. A medicated layer solution of the following
composition was used:
17 Component % w/w Function Compound X 0.003-0.05pfb Active Opadry
.RTM. Clear 3 Binder Sodium dihydrogen citrate 1.5 Stabilizer
Purified water q.s. Total 100
[0103] Seal coating solution: A solution of Opadry.RTM. Clear
(YS-1-9025A) in purified water at 10% solids concentrations was
made by dissolving 100 grams of Opadry.RTM. Clear into 900 grams of
purified water.
[0104] Polymer Coating: A polymer coating dispersion containing
Ethylcellulose (Aquacoat.RTM.) of the following composition was
made and used for polymer coating the seal coated beads at a 10%
weight gain.
18 Component % w/w Function Aquacoat .RTM. 50 (30% as solids)
Release controlling polymer coat Triethyl Citrate 2.02 Plasticizer
Purified water q.s. Total 100
[0105] Drug layered beads were produced by layering the drug
solution onto 25-30 mesh non-pareil beads using a Niro STREA-1
fluid bed dryer so as to layer 100 micrograms of the drug as the
free base onto 200 mg of the non-pareil beads. The drug layered
beads were seal coated with Opadry.RTM. Clear seal coating solution
to a weight gain of 3% to produce the immediate release beads. A
portion of the immediate release beads were polymer coated to a
weight gain of 10% with the Aquacoat.RTM. coating dispersion. The
final polymer coated beads were produced by seal coating the
polymer coated beads to a weight gain of 2% with thie Opadry.RTM.
Clear seal coating solution.
Example 12
Eudragit Coated Beads
[0106] 200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30
mesh size may be used. A medicated layer solution of the following
composition was used:
19 Component % w/w Function Compound X 0.003-0.05pfb Active Opadry
.RTM. Clear 3 Binder Sodium dihydrogen citrate 1.5 Stabilizer
Purified water q.s. Total 100
[0107] Seal coating solution: A solution of Opadry.RTM. Clear
(YS-1-9025A) in purified water at 10% solids concentrations was
made by dissolving 100 grams of Opadry.RTM. Clear into 900 grams of
purified water.
[0108] Polymer Coating: A polymer coating dispersion containing
gudragit.RTM. RS or RS/RL of the following composition was made and
used for polymer coating the seal coated beads at an 10% weight
gain.
20 Component % w/w Function Eudragit .RTM. RS 30D 45 (30% as
solids) Release controlling polymer coat Triethyl citrate 2.02
Plasticizer Talc 3.10 Anti-tack Purified water q.s. Total 100 or
Eudragit .RTM. RS 30D 36 (30% as solids) Release controlling
polymer coat Eudragit .RTM. RL 30D 9 (30% as solids) Release
controlling polymer coat Triethyl citrate 2.02 Plasticizer Talc
3.10 Anti-tack Purified water q.s. Total 100
[0109] Drug layered beads were produced by layering the drug
solution onto 25-30 mesh non-pareil beads using a Niro STREA-1
fluid bed dryer so as to layer 100 micrograms of the drug as the
free base onto 200 mg of the non-pareil beads. The drug layered
beads were seal coated with Opadry.RTM. Clear seal coating solution
to a weight gain of 3% to produce the immediate release beads. A
portion of the immediate release beads were polymer coated to a
weight gain of 10% with the Eudragit.RTM. RS or RS/RL coating
dispersion. The final polymer coated beads can be produced by seal
coating the polymer coated beads to a weight gain of 2% with the
Opadry.RTM. Clear seal coating solution.
21TABLE 4 Release Profile of Eudragit .RTM. RS/RL coated beads of
Compound X in water Time (hr) % Released 0.5 0.2 1 0.3 2 0.4 4 1.9
6 13 8 20
Example 13
Methocel Coated Beads
[0110] 200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30
mesh size may be used. A medicated layer solution of the following
composition was used:
22 Component % w/w Function Compound X 0.003-0.05pfb Active
Methocel E4M 15 Release controlling polymer coat Sodium dihydrogen
citrate 1.5 Stabilizer Purified water q.s. Total 100
[0111] Seal coating solution: A solution of Opadry.RTM. Clear
(YS-1-7006) in purified water at 10% solids concentrations was made
by dissolving 100 grams of Opadry.RTM. Clear into 900 grams of
purified water.
Example 14
Ethylcellulose Coated Beads with a Retardant
[0112] 200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30
mesh size may be used. A medicated layer solution of the following
composition was used:
23 Component % w/w Function Compound X 0.003-0.05pfb Active Opadry
.RTM. Clear 1.5 Binder Surelease .RTM. 1.5 Retardant Sodium
dihydrogen citrate 1.5 Stabilizer Purified water q.s. Total 100
[0113] Seal coating solution: A solution of Opadry.RTM. Clear
(YS-1-9025A) in purified water at 10% solids concentrations was
made by dissolving 100 grams of Opadry.RTM. Clear into 900 grams of
purified water.
[0114] Polymer Coating: A polymer coating dispersion containing
Ethylcellulose (Surelease.RTM.) of the following composition was
made and used for polymer coating the seal coated beads at 10%
weight gain.
24 Component % w/w Function Surelease .RTM. 60 (25% as solids)
Release controlling polymer coat with plasticiser Purified water
q.s. Total 100
[0115] Drug layered beads were produced by layering the drug
solution onto 25-30 mesh non-pareil beads using a Niro STREA-1
fluid bed dryer so as to layer 100 micrograms of the drug as the
free base ontc 200 mg of the non-pareil beads. The drug layered
beads were seal coated with Opadry.RTM. Clear seal coating solution
to a weight gain of 3% to produce the immediate release beads. A
portion of the immediate release beads were polymer coated to a
weight gain of 10% with the Surelease.RTM. coating dispersion. The
final polymer coated beads can be produced by seal coating the
polymer coated beads to a weight gain of 2% with the Opadry.RTM.
Clear seal coating solution.
25TABLE 5 Release Profile of Ethylcellulose Coated Beads, with
Retardant, of Compound X in Water % Released Time (hr) Without
Retardant With Retardant 0.5 12 8 1 37 22 2 57 35 4 73 48 6 85 53 8
58
Example 15
Enteric Coated Beads)
[0116] 200 mg of non-pareil sugar beads of 16-20,20-25 or 25-30
mesh size may be used. A medicated layer solution of the following
composition was used:
26 Component % w/w Function Compound X 0.003-0.05pfb Active Opadry
.RTM. Clear 3 Binder Sodium dihydrogen citrate 1.5 Stabilizer
Purified water q.s. Total 100
[0117] Seal coating solution: A solution of Opadry.RTM. Clear
(YS-1-9025A) in purified water at 10% solids concentrations was
made by dissolving 100 grams of Opadry.RTM. Clear into 900 grams of
purified water.
[0118] Polymer Coating: A nolymer coating dispersion containing
Eudragit.RTM. L30D-55 of the following composition was made and
used for polymer coating the seal coated beads at an 20% weight
gain.
27 Component % w/w Function Eudragit L30D-55 45.00 (30% as solids)
Enteric (pH dependent) polymer Triethyl citrate 2.02 Plasticizer
Talc 3.10 Anti-tack Purified water q.s. Total 100
[0119] Drug layered beads were produced by layering the drug
solution onto 25-30 mesh non-pareil beads using a Niro STREA-1
fluid bed dryer so as to layer 100 micrograms of the drug as the
free base onto 200 mg of the non-pareil beads. The drug layered
beads were seal coated with Opadry.RTM. Clear seal coating solution
to a weight gain of 3% to produce the immediate release beads. A
portion of the immediate release beads were enteric coated to a
weight gain of 20% with the Eudragit.RTM. enteric coating
dispersion. The final enteric coated beads were produced by seal
coating the enteric coated beads to a weight gain of 2% with the
Opadry Clear seal coating solution.
Example 16
Matrix Tablet
[0120]
28 Ingredient mg/tablet Function Compound X 0.005-0.1 pfb Active
Hydroxpropyl Methcellulose 75.0 Hydrogel matrix E4M CR Sodium
Dihydrogen Citrate 3.00 Stabilizer Lactose, Fast Flo 70.38
Hydrophilic diluent Magnesium Stearate 1.50 Lubicant Opadry .RTM.
White 2.25 Seal coat polymer
[0121] Seal coating solution: A solution of Opadry.RTM. Clear
(YS-1-9025A) in purified water at 10% solids concentrations was
made by dissolving 100 grams of Opadry.RTM. Clear into 900 grams of
purified water.
[0122] Polymer Coating: A polymer coating dispersion containing
Ethylcellulose (Surelease.RTM.) of the following composition was
made and used for polymer coating the seal coated beads at 10%
weight gain.
29 Component % w/w Function Surelease .RTM. 60 (25% as solids)
Release controlling polymer coat with plasticiser Purified water
q.s. Total 100
[0123] 700 grams of core tablets were coated using a Vector LDCS
pan to a 3% weight gain with the Opadry.RTM. Clear seal coating
solution. The seal coated tablets were then polymer coated to 4%
weight gain using the Surelease.RTM. coating dispersion.
30TABLE 6 Release Profile for a Matrix Tablet of Compound X in
water Time (hr) % Dissolved 1 8 2 30 4 58 8 96
Example 17
Controlled Release Bilayer Tablet
[0124]
31 mg/tablet Function Active Layer Component Compound X 0.005-0.1
mg pfb Active Methocel K4M 15.00 Hydrogel polymer Lactose
monohydrate 62.0 Hydrophilic filler Polyvinylpyrrolidone 3.0 Binder
Magnesium stearate 1.0 Hydrophobic lubricant Syloid 244 1.0
Hydrophilic glidant Support platform Component Compritol 888 15.0
Plasticizer Lactose monohydrate 29.0 Hydrophilic filler
Polyvinylpyrrolidone 4.0 Binder Magnesium stearate 1.5 Hydrophobic
lubricant Methocel E5 29.4 Hydrogel polymer Iron oxide 0.1
Colourant
* * * * *