Patent Application
20070092568
The present invention relates to controlled release compositions of galantamine, processes to prepare the compositions, their in vitro release profiles and methods of use and methods of treatment using the said compositions.
Galantamine is chemically known as (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol and is structurally represented as Formula I. It is a reversible inhibitor of acetylcholinesterase that binds specifically to the nicotinic receptors. Galantamine hydrobromide is a white to almost white powder and is sparingly soluble in water.
Galantamine hydrobromide been approved in the United States for treating Alzheimer's disease. It is marketed by Janssen under the brand name of RAZADYNE™ tablets containing galantamine hydrobromide and having strengths of 4, 8, and 12 mg; RAZADYNE™ oral solution of strength 4 mg/ml; and RAZADYNE™ ER extended release capsules of strengths 8, 16, and 24 mg. These strengths are expressed as contained galantamine base. RAZADYNE™ is indicated for the treatment of mild to moderate dementia of the Alzheimer's type.
International Application Publication Nos. WO 00/38686 and WO 2005/048979 disclose modified release formulations containing galantamine.
International Application Publication No. WO 2005/065661 discloses a fast dissolving formulation and a sustained release formulation comprising galantamine.
U.S. Patent Application Publication No. 2004/0097484 discloses a once-daily pharmaceutical composition comprising galantamine.
The extended release pharmaceutical composition of the present invention exhibits a desired in vitro dissolution profile and can serve as an economical alternative to the marketed product, RAZADYNE™ ER extended release capsules, with a decrease in the frequency of administration and thus, better patient compliance.
This and other needs are addressed by the present invention.
An aspect of present invention provides for a pharmaceutical composition comprising galantamine or a salt thereof, a portion of the contained galantamine being present in an immediate release form and another portion being present in an extended release form.
Another aspect of present invention provides for a pharmaceutical composition comprising galantamine or a salt thereof in combination with a rate controlling substance, having an exterior coating of the same or a different rate controlling substance.
In one aspect, a pharmaceutical composition comprises a capsule containing tablets comprising galantamine or a salt thereof, the tablets being coated with a rate controlling substance.
In another aspect, a pharmaceutical composition comprises a capsule containing pharmacologically inert particles having a coating comprising galantamine or a salt thereof and a rate controlling substance, and having an exterior coating comprising a rate controlling substance.
In an embodiment of the invention, a pharmaceutical composition comprises a portion of the contained galantamine, which is present in more than one extended release form.
In another embodiment of the invention, an immediate release form of pharmaceutical composition comprises pharmacologically inert particles that are coated with galantamine or a salt thereof.
In further embodiment of the invention an extended release form of pharmaceutical composition comprises pharmacologically inert particles that are coated with galantamine or a salt thereof, and having an outer coating comprising a rate controlling substance.
In an embodiment of the invention, controlled release compositions of galantamine provides a release of at least about 30 to about 70 percent of contained galantamine in about 1 hour and more than about 70 percent of the galantamine in about 10 hours, as measured in a buffer pH 6.8 at 37° C., using USP dissolution apparatus 2 at 50 rpm.
An embodiment of the invention includes a pharmaceutical composition comprising galantamine or a salt thereof, a portion of the contained galantamine being present in an immediate release form and another portion being present in an extended release form.
Another embodiment of the invention includes a pharmaceutical composition comprising galantamine or a salt thereof in combination with a rate controlling substance, having an exterior coating of the same or a different rate controlling substance.
A further embodiment of the invention includes a pharmaceutical composition comprising a capsule containing particles comprising galantamine or a salt thereof, the particles being coated with a rate controlling substance.
The term “active ingredient” herein refers to a pharmaceutically active molecule as well as its pharmaceutically acceptable and therapeutically active salts, esters, amides, prodrugs, metabolites, enantiomers, polymorphs, analogs, etc. that induce a desired pharmacological or physiological effect. Terms like “active”, “active agent”, “active substance”, “active pharmaceutical substance”, “pharmacologically active agent”, “drug” and “drug substance” may be used synonymously for “active ingredient”.
The present invention relates to controlled release compositions of galantamine, processes to prepare the compositions, their in vitro release profiles and methods of use and methods of treatment using the compositions.
Different aspects of the invention include, without limitation thereto:
capsule compositions comprising mini-formulations in the form of pellets;
capsule compositions comprising mini-formulations in the form of compressed tablets;
capsule compositions comprising mini-formulations in the form of pellets and compressed tablets;
mini-formulations having cores comprising an active ingredient and water-soluble or water-insoluble components, coated with combinations of at least a water-soluble and at least a water-insoluble component;
mini-formulations having cores comprising an active ingredient and coated with a combination of at least a water-soluble and at least a water-insoluble component;
mini-formulations having a core coated with a mixture of active ingredient and a water-soluble or water-insoluble component and further coated with combination of at least a water-soluble and at least a water-insoluble component; and
mini-formulations having a core coated with active ingredient and further coated with a combination of at least a water-soluble and at least a water-insoluble component.
In an embodiment, the present invention includes controlled release compositions of galantamine, wherein compositions comprise two separate portions wherein one portion releases galantamine in an immediate release (“IR”) manner and other portion releases galantamine in an extended release (“ER”) manner.
In another embodiment of the invention, controlled release compositions of galantamine comprise galantamine and at least one rate controlling substance in a single layer with or without other pharmaceutically acceptable excipients.
In an embodiment of the invention, controlled release compositions of galantamine provides a release of at least about 30% to about 70% of galantamine in about 1 hour and more than about 70% of galantamine in about 10 hours, as measured in a buffer pH 6.8 at 37° C., using USP dissolution apparatus 2 at 50 rpm.
Galantamine used in the present invention can be in the form of the base or a pharmaceutically acceptable salt, or combinations of base and one or more salts, or combinations of one or more salts. Pharmaceutically acceptable salts of galantamine include but are not limited to the hydrochloride, hydrobromide and the like.
In an embodiment of the invention, galantamine hydrobromide is a useful active ingredient in the range of about 2 mg to 60 mg, or about 4 mg to 40 mg, per dosing unit.
In an aspect of the invention, compositions comprising two separate portions may be presented in the form of particulate compositions comprising immediate release galantamine particles and extended release galantamine particles in a defined ratio either filled into a capsule shell or compressed as a tablet formulation or filled into sachets.
In an embodiment of the invention, the ratio of the two portions IR to ER may range from 10:90 to 50:50, or 20:80 to 30:70, w/w equivalent to total galantamine present in the dosage form.
Immediate release particles of the invention may be prepared as powders, granules, pellets, beads and the like using manufacturing processes such as direct blending, dry granulation, wet granulation, pelletization techniques such as but not limited to extrusion-spheronization, dry powder or solution or dispersion layering of galantamine onto inert beads or pellets or particles using conventional coating techniques or fluid bed coating techniques.
Extended release particles of the invention may be prepared as powders, granules, pellets, beads and the like using manufacturing processes such as direct blending, dry granulation, wet granulation, pelletization techniques such as but not limited to extrusion-spheronization, dry powder or solution or dispersion layering of galantamine onto inert beads or pellets or particles using conventional coating techniques or fluid bed coating techniques. Extended release particles may comprise galantamine and rate controlling substance together in one layer, or galantamine and a portion of rate controlling substance together in one layer and a remaining portion of rate controlling substance in a different layer, or galantamine and rate controlling substances together in different layers. In a specific embodiment of the invention wherein galantamine and rate controlling substances are together in different layers, then a galantamine layer comprises a water insoluble component.
In an embodiment of the invention, two portions of the composition comprise:
1) IR portion comprising
2) ER portion comprising
In another embodiment of the invention, wherein galantamine and at least one rate controlling substance are present in a single layer include but not limited to compositions:
Useful water-soluble components include, but are not limited to: cellulosic polymers such as carboxymethyl cellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose; polyethylene oxide; polyvinyl alcohol; carbomer; carageenan; sugars such as mannitol and lactose; and mixtures thereof.
Useful water-insoluble components include, but are not limited to: acrylic acid derivatives; cellulose polymers including alkyl derivatives of cellulose like ethylcellulose, cellulose esters such as cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, and cellulose triacetate; waxes such as beeswax, carnauba wax, and microcrystalline wax; fatty alcohols such as cetostearyl alcohol, stearyl alcohol, cetyl alcohol, and myristyl alcohol; and fatty acid esters like glyceryl monostearate, glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, and glyceryl palmitostearate, glyceryl behenate; and hydrogenated castor oil.
In an embodiment of the invention, ethylcellulose and various grades of Eudragit™ products such as Eudragit NE30D were found to be useful as a water-insoluble component. Eudragit NE30D is a 30% aqueous dispersion of poly(ethylacrylate-methylmethactylate).
Ethylcellulose is commercially available as Ethocel®. Ethocel® Premium is available in different viscosities like 7 cps, 10 cps, 20 cps, 45 cps and 100 cps, with an average particle size more than 250 μm. It is used by dissolving in an organic solvent for the preparation of dosage form while Ethocel® standard FP premium which is available in viscosities 7 cps, 10 cps and 100 cps is very finely milled and can be used for direct compression in matrix compositions. Ethylcellulose is also available as an aqueous dispersion under the trade name of Aquacoat® ECD, Aqualon® and Surelease®.
Surelease® is a plasticized aqueous dispersion of ethylcellulose used for extended release coatings and taste masking applications, available in 25% by weight solid content and manufactured by Colorcon Ltd. of Dartford Kent, United Kingdom.
In another aspect of the invention, the water-soluble component is used as a pore-forming agent. The term “pore-forming agent” refers to a pharmaceutically acceptable agent that dissolves in its surrounding medium and results in formation of pores in the membrane to facilitate the diffusion of active ingredient through the membrane.
In one aspect of the invention, hydroxypropyl methylcellulose was found to be useful as a water-soluble component.
Compositions of present invention may comprise pharmaceutical excipients such as, but not limited to, diluents, binders, disintegrants, colourants, anti-oxidants, sweeteners, and film-forming agents.
Common diluents useful in the present invention include, but are not limited to, microcrystalline cellulose, silicified microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, mannitol, sorbitol, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, polymethacrylates, and mixtures thereof.
Binders useful in the present invention include, but are not limited to, starches, microcrystalline cellulose, methylcellulose, cellulose ethers, sodium carboxymethylcellulose, ethylcellulose, dextrose, lactose, sucrose, sorbitol, mannitol, polyethylene glycol, polyvinylpyrrolidone, pectins, gelatin, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, and mixtures thereof.
Inert beads or pellets useful in the present invention include, but are not limited to microcrystalline cellulose spheres, silicon dioxide or glass beads, dicalcium phosphate particles, plastic (polypropylene or polyethylene) resin particles, and the like.
In an embodiment of the invention, Celphere™ microcrystalline cellulose spheres manufactured by Asahi Kasei Chemicals Corporation, Tokyo, Japan are useful.
Rate controlling substances useful in the present invention include but are not limited to water soluble or water insoluble substances. Water soluble rate controlling substances include but are not limited to cellulose derivatives such as methylcellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked hydroxypropyl cellulose; carboxymethylamide; potassium methacrylate/divinylbenzene copolymers; polymethylmethacrylate; polyhydroxyalkyl methacrylate; cross-1 inked polyvinylpyrrolidone; high-molecular weight polyvinylalcohols; gums such as natural gum, agar, agrose, sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, hypnea, eucheums, gum arabic, gum ghatti, gum karaya, gum tragacanth and locust bean gum; hydrophilic colloids such as alginates, carbopol and polyacrylamides; other substances such as arbinoglactan, pectin, amylopectin, gelatin, N-vinyl lactams, polysaccharides; and the like. Combinations of any two or more of these polymers, and other polymers having the required properties are within the scope of the invention.
Water insoluble substances include but not limited to celluloses such as methyl cellulose, ethyl cellulose, low-substituted hydroxypropylcellulose (L-HPC), cellulose acetates and their derivatives, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tri-cellulose alkanylates, mono-, di-, and tri-cellulose arylates, and mono-, di- and tri-cellulose alkenylates, crosslinked vinylpyrrolidone polymers (also called “crospovidone”), glyceryl behenate, polymethacrylic acid based polymers and copolymers sold under the trade name of EUDRAGIT™ (including Eudragit RL and RS, NE-30D), zein, and aliphatic polyesters. Other classes of polymers, copolymers of these polymers or their mixtures in various ratios and proportions as required are within the scope of this invention without limitation.
The composition disclosed in the present invention is useful in clinical conditions requiring administration of galantamine and pharmaceutically acceptable salts. Such conditions include treatment of Alzheimer's dementia and related dementias, facial neuralgia, alcoholism, nicotine dependence, nerve gas poisoning, mania, chronic fatigue syndrome, schizophrenia, and negative effects of benzodiazepine treatment.
The following examples further illustrate certain specific aspects and embodiments of the invention in greater detail and are not intended to limit the scope of the invention.
*Celphere ™ CP507 (microcrystalline cellulose spheres, particle size range 500-710 μm) is manufactured by Asahi Kasei Chemicals Corporation, Tokyo, Japan.
**Eudragit NE30D and Eudragit EPO are manufactured by Rohm and Haas.
Manufacturing Process:
Immediate Release Pellets:
In vitro Release Profile with the Following Parameters:
Apparatus 2 (Paddle) from Test 711-Dissolution in United States Pharmacopeia 24, United States Pharmacopeial Convention, Inc., Rockville, Md. (1999).
Manufacturing Process:
A. Drug Loading:
In Vitro Release Profile with the Following Parameters:
Apparatus: USP apparatus 2 (Paddle) from Test 711-Dissolution in United States Pharmacopeia 24, United States Pharmacopeial Convention, Inc., Rockville, Md. (1999).
Manufacturing Process:
Manufacturing Process:
A. Core Pellets
Manufacturing Process:
A. Core Pellets
Manufacturing Process:
A. Core Pellets
Manufacturing Process:
A. Preparation of Mini-Formulations:
Manufacturing Process:
Dissolution conditions (Test 711-Dissolution from United States Pharmacopeia 24, United States Pharmacopoeial Convention, Inc., Rockville, Md., 1999).
Stirring speed 100 rpm
| Number | Date | Country | Kind |
|---|---|---|---|
| 1447/CHE/2005 | Oct 2005 | IN | national |
| Number | Date | Country | |
|---|---|---|---|
| 60745243 | Apr 2006 | US |
