Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-09-19
2002-10-22
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S464000, C424S468000, C424S489000, C424S490000, C424S472000, C424S463000
Reexamination Certificate
active
06468560
ABSTRACT:
The present invention relates to a novel formulation, and to its 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, the present invention provides a controlled release oral dosage form containing compound X. its parent free base or any other pharmaceutically acceptable salt thereof.
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.
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.
Examples of controlled release formulations which are suitable for incorporating compound X are described in:
Sustained Release Medications, Chemical Technology Review No. 177. Ed. J. C. Johnson. Noyes Data Corporation 1980.
Controlled Drug Delivery, Fundamentals and Applications. 2nd Edition. Eds. J. R. Robinson, V. H. L Lee. Marcel Dekker Inc. New York 1987.
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.
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.
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 trimesters 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 carnuba wax.
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, polymethyimethacrylate, 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 polyvinylalcohols, 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.
Release controlling polymers include hydrogel polymers such as those listed above, hydrophobic polymers and enteric, or pH dependent, polymers.
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).
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).
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)).
The formulation may also include plasticisers such as triethyl citrate, dibutyl sebacate or medium chain triglycerides in the release controlling polymer layer.
Pellet-forming materials include suitable grades of microcrystalline cellulose such as Avicel PH101 (FMC).
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 search.
Beads may be formed by layering or spraying on non-pareil seeds.
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.
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.
Wetting agents such as sodium lauryl sulphate, lubricants such as magnesium stearate and glidants such as colloidal silica may also be included.
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® 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, hydroxyal
Milosovich Susan Marie
Muldoon William Thomas
Napper James Albert
Rousseau Laurence
Sauer Joseph Peter
Hall Linda E.
Kinzig Charles M.
Page Thurman K.
Pulliam Amy E
SmithKline Beecham p.l.c.
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