Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-08-30
2002-09-17
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S465000, C424S468000, C424S474000, C424S475000, C424S470000
Reexamination Certificate
active
06451343
ABSTRACT:
The present invention relates to novel formulations, and to their use in the treatment and/or prophylaxis of certain disorders.
[R-(Z)]-&agr;-(methoxyimino)-&agr;-(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.
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.
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.
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.
Accordingly, in a first aspect the present invention provides a controlled release oral dosage form containing 0.04% w/w pfb compound X and 98.5-99.5% w/w total mono, di and triglycerides and polyethylene glycol mono and diesters consisting of Gelucire 50/13 (EP) and Gelucire 50/02 (Fr Ph) in a ratio of >0.02 Gelucire 50/13 (EP) to Gelucire 50/02 (Fr Ph), in a hard gelatin capsule containing 0.10 mg/capsule compound X pfb, such that the release profile of the capsule in 1 mM HCl is 20-60% after 8 hr.
Preferably the release profile after 8 hr is 20-40% or 30-60%.
Gelucire 50/13 (EP) is a mixture of mono, di and triglycerides and polyethylene glycol mono and diesters specified in the European Pharmacopeia “Stearoyl Macroglycerides” (Supplement 1998) as:
specific mixtures of monoesters, diesters and triesters of glycerol and monoesters and diesters of macrogols with a mean relative molecular mass between 300 and 4000 comprising:
free glycerol content: <3%
lauric acid (C12): <5%
myristic acid (C14): <5%
different nominal amounts of stearic acid (C18) and of palmitic acid (C16). The sum of stearic acid and of palmitic acid is not less than 90%.
Gelucire 50/02 (Fr Ph) is a mixture of mono, di and triglycerides and polyethylene glycol mono and diesters specified in the French Pharmacopoeia “Glycerides Polyglycolyses Satures” (1990) as:
specific mixtures of mono, di and triglycerides and polyethylene glycol mono and diesters, obtained either by partial alcoholysis of hydrogenated vegetable oils using polyethylene glycol of relative molecular weight ranging 200-2000, or by esterification of saturated fatty acids using polyethylene glycol of relative molecular weight ranging 200-2000, comprising:
free glycerol content: <3%
caprylic acid (C8): <15%
capric acid (C10): <15%
lauric acid (C12): <50%
myristic acid (C14): <25%
palmitic acid (C16): <55%
stearic acid (C18): <97%
The mono, di and triglycerides and polyethylene glycol mono and diesters preferably make up 99.41% of the dosage form. The ratio of Gelucire 50/13 (EP) to Gelucire 50/02 (Fr Ph) is preferably <0.055, more preferably ≦0.053.
In a preferred aspect the mixture of mono, di and triglycerides and polyethylene glycol mono and diesters consists of Gelucire 50/13 (Gattefosse) and Gelucire 50/02 (Gattefosse). Most preferably the composition comprises 97.41% Gelucire 50/13 (Gattefosse) and 2.00% Gelucire 50/02 (Gattefosse) or 94.41% Gelucire 50/13 (Gattefosse) and 5.00% Gelucire 50/02 (Gattefosse).
The composition preferably additionally comprises propylene glycol, preferably at 0.45% w/w (1.13 mg/capsule).
The composition preferably additionally comprises 3,4,5-trihydroxybenzoic acid propyl ester, preferably at 0.10% w/w (0.25 mg/capsule).
In a preferred embodiment of the first aspect the composition is selected from:
Component
% w/w
mg/capsule
Compound X
0.04 pfb
0.10 pfb
Gelucire 50/02 (EP)
94.41
236.00
Gelucire 50/13 (Fr Ph)
5.00
12.50
propylene glycol
0.45
1.13
3,4,5-trihydroxybenzoic
0.10
0.25
acid propyl ester
and
Compound X
0.04 pfb
0.10 pfb
Gelucire 50/02 (EP)
97.41
243.52
Gelucire 50/13 (Fr Ph)
2.00
5.00
propylene glycol
0.45
1.13
3,4,5-trihydroxybenzoic
0.10
0.25
acid propyl ester
in a hard gelatin capsule.
In a second aspect, the present invention provides a controlled release oral dosage form containing compound X of the following composition:
Ingredient
mg/tablet
%/tablet
Compound X
0.005-0.1 pfb
hydroxpropyl methylcellulose
37.5-45
25-30
dibasic calcium phosphate dihydrate
45-52.5
30-35
microcrystalline cellulose
19.5
13.0
(nominal mean particle size 50 microns)
microcrystalline cellulose
37.76
25.2
(nominal mean particle size 100 microns)
granulated, compressed into tablets and coated to a 3% weight gain with a seal coat consisting of a solution of hydroxypropyl methylcellulose aqueous dispersion with plasticizer in purified water at 10% solids followed by a coat consisting of ethylcellulose aqueous dispersion with oleic acid, ammonium hydroxide and plasticizer or a mixture of ethylcellulose aqueous dispersion with oleic acid, ammonium hydroxide and plasticizer and hydroxypropylmethylcellulose aqueous dispersion with polytheylene glycol plasticizer, such that 40-65% of the drug is released within 8 hours in water.
The composition preferably additionally comprises: sodium dihydrogen citrate, preferably at a level of 1.50 mg/tablet (1.0%) and/or magnesium stearate, preferably at a level of 1.125 mg/tablet (0.75%).
In preferred embodiments of the second aspect:
hydroxpropyl methylcellulose is Methocel E4M CR;
microcrystalline cellulose (nominal mean particle size 50 microns) is Avicel PH101;
microcrystalline cellulose (nominal mean particle size 100 microns) is Avicel PH102;
hydroxypropyl methylcellulose aqueous dispersion has polyethylene glycol plasticizer and is preferably Opadry White or Opadry Clear (YS-1-9025A); and/or ethylcellulose aqueous dispersion has fractionated coconut oil plasticizer and is preferably Surelease Clear (E-7-19010).
In a third aspect, the present invention provides a controlled release oral dosage form containing compound X of the following composition:
Ingredient
mg/tablet
%/tablet
Compound X
0.005-0.1 pfb
ethylcellulose
22.5-37.5
15-25
dibasic calcium phosphate dihydrate
63.3-78.3
42.2-52.2
microcrystalline cellulose
30.0-40.0
19.8-26.7
compressed into tablets and coated to a 3% weight gain with a seal coating solution consisting of hydroxymethylcellulose aqueous dispersion with plasticizer in purified water at 10% solids concentration followed by a coat consisting of ethylcellulose aqueous dispersion with oleic acid, ammonium hydroxide and plasticizer or a mixture of ethylcellulose aqueous dispersion with oleic acid, ammonium hydroxide and and hydroxypropylmethylcellulose aqueous dispersion with plasticizer.
In one preferred embodiment of the third aspect the composition additionally comprises sodium dihydrogen citrate, preferably at a level of 3.00 mg/tablet (2.0%) and/or colloidal silicon dioxide, preferably at a level of 0.75 mg/tablet (0.50%) and/or magnesium stearate, preferably at a level of 1.125 mg/tablet (0.75%) and/or the microcrystalline cellulose has a mean particle size of 100 microns, preferably at a level of 32.5 mg/tablet (21.7%); and coated to a 3% weight gain with a seal coating solution consisting of hydroxymethylcellulose aqueous dispersion with plasticizer in purified water at 10% solids concentration followed by a coat consisting of ethylcellulose aqueous dispersion with oleic acid, ammonium hydroxide and plasticizer or a mixture of ethylcellulose aqueous dispersion with oleic acid, ammon
Glinecke Robert
Milosovich Susan Marie
Muldoon William
Rousseau Laurence
Sauer Joseph
Bennett Rachel M.
Hall Linda E.
Kinzig Charles M.
Page Thurman K.
SmithKline Beecham Corporation
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