Patent Application
20080003286
The present invention provides a pharmaceutical formulation for alfuzosin or pharmaceutically acceptable salts, solvates, enantiomers or mixtures thereof with an improved and predictable controlled release dissolution profile.
The said formulation comprises multiple reservoirs embedded in a matrix composition, wherein both reservoir and matrix compositions control the release of alfuzosin. Such a formulation that uses a dual retard technique leads to significantly improved pharmaceutical compositions overcoming shortcomings such as risk of dose dumping and burst release.
The present invention provides alfuzosin in multiple reservoir systems of defined size that are coated with a coating material to a defined coating built up, and the multiple reservoirs are embedded in a matrix composition with or without use of other pharmaceutically accepted excipients.
“Reservoir systems” as used herein are defined as any of:
Multiple reservoir systems may be produced by any technique known in the art including but not limited to extrusion, spheronisation, fluid bed coating, conventional coating, solution spraying, drenching, powder spraying, including top, bottom or tangential coating techniques and the like.
The reservoir systems herein can have a size in the range of 10 μm to 1 mm, or 150 μm to 400 μm.
Reservoir systems of the present invention are prepared from pharmaceutically inert particulate components such as but not limited to microcrystalline cellulose (MCC), dicalcium phosphate, tricalcium phosphate, sugar crystals, sugar globules, mannitol, microcrystalline cellulose spheres (e.g. CELPHERE™, a product of Asahi Kasei Chemicals Corporation, Tokyo, Japan), silicon dioxide particles and the like.
Alfuzosin is applied as a coating on the inert particles, such as in a liquid composition comprising the drug, and a water-soluble or water-dispersible polymer. The alfuzosin coating can be an intermediate coating or the only coating on the particles.
The pharmaceutical compositions of the present invention may contain one or more hydrophobic outer coating materials on the reservoir particles used for retarding the release of drug from reservoirs, such as but not limited to waxes such as carnauba wax and white wax, fatty alcohols, fatty acid esters, glycerol monooleate, acetylated monoglycerides, glyceryl behanate, glyceryl monostearate, hydrogenated vegetable oils, paraffin, cellulose polymers such as ethylcellulose, and the like.
The pharmaceutical compositions of the present invention may contain one or more hydrophilic outer coating materials on the reservoir particles useful for retarding release of the drug from reservoirs such as but not limited to various grades of poly(N-vinylpyrrolidone), polyacrylamide, polyethylene oxide, acrylic acid, acrylic acid derivatives, acrylic acid esters, polyacrylic acid, cellulose polymers such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxylethylcellulose, hydroxypropyl methylcellulose, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol and the like.
The amount of hydrophilic or hydrophobic outer coating build up in reservoir systems can generally range from 1% to 50%, or from 5% to 25%, or from 10% to 20%, by weight of the reservoir composition.
Matrix compositions used in the present invention are intended to contribute to the release profile of alfuzosin from the composition and also help in prolonging the residence time in the gastrointestinal tract.
External matrix compositions may be prepared by simple dry mixing of a hydrophilic polymer and other pharmaceutically acceptable excipients, dry granulation or wet granulation using aqueous, hydro alcoholic or solvent based granulation using conventional granulation techniques such as rapid mixer granulation, planetary mixing, mass mixing, fluid bed granulation and the like.
Hydrophilic polymers or combinations thereof used in various ratios are exemplified by but are not limited to cellulose polymers such as various grades of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC); homo- or co-polymers of N-vinyl pyrrolidones such as polyvinyl pyrrolidone; polyacrylic acid and its derivatives; copolymers of polyethylene glycols, polyorthoesters, polyurethanes and the like.
In the external matrix composition, polysaccharide materials such as but not limited to lactose, mannitol, sorbitol, maltitol, microcrystalline cellulose and powdered cellulose can be used to modulate the rate of release of alfuzosin, and the amount of such material with respect to the matrix composition can range from 5% to 60%, or from 10% to 50% by weight.
The multiple reservoirs and external matrix composition along with other pharmaceutically acceptable excipients can be formulated into a suitable solid oral dosage form such as tablets and the like by procedures known to a person skilled in the art of preparation of pharmaceutical formulations. Such compositions can include other excipients as are required for the preparation of the compositions including but not limited to diluents, granulating agents, solvents, lubricants, wetting agents, disintegrating agents and the like, and any combinations thereof.
The pharmaceutical compositions of the present invention may contain one or more diluents added to increase mass and, hence, provide easier handling for the patient and caregiver. Common diluents are microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, potassium chloride, powdered cellulose, sodium chloride, sorbitol, talc and the like.
Binders also can be included in the pharmaceutical compositions of the present invention. Some typical binders are acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methylcellulose (HPMC) (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, polyvinylpyrrolidone (PVP or povidone, e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, starch and the like.
Pharmaceutical compositions for tableting and film formation may include without limitation, any one or more of pharmaceutically acceptable glidants, lubricants, flavoring agents, plasticizers, opacifiers, colorants and other commonly used excipients.
In an embodiment, the present invention provides a unit dose of alfuzosin of about 0.1 to about 20 milligrams per dosage form.
The following examples will further describe certain specific aspects and embodiments of the invention in greater detail and are not intended to limit the scope of the invention.
The in-vitro release of alfuzosin hydrochloride from the composition of Example 1 was studied at pH 6.8 using Apparatus 2 of Procedure 711 (Dissolution) of The United States Pharmacopoeia 24, United States Pharmacopoeial Convention, Rockville, Md. U.S.A. 2000.
a) Composition of the Drug Reservoirs:
b) Polymer Coating:
c) Composition of the Matrix System:
d) Preparation of the Final Dosage Form:
In-vitro dissolution of the composition of Example 3 was compared with that of commercial UROXATRAL® 10 mg capsules (Batch No. TH35). The study was performed using a USP type II (paddle) dissolution apparatus and 900 ml of pH 6.8 phosphate buffer at 37° C.±0.5° C. as the dissolution medium.
A randomized, open-label, balanced, two-treatment, two-period, two-sequence, single dose, crossover bioequivalence study of compositions of Example 3 (“Test”) with UROXATRAL® (“Reference”) 10 mg alfuzosin extended release tablets from Sanofi-Synthelabo, Inc. in twenty-four healthy, adult male, human subjects under fasting conditions. The washout period between treatments was seven days.
The composition is prepared in a similar manner to that of Example 3 except that Surelease® is used for coating of drug loaded Celpheres of step 5. Further, steps 10 through 16 are followed as in Example 3.
The compositions are prepared in a similar manner to that of Example 3 except that the drug loaded Celpheres of step 5 are coated with coating mixture prepared by dissolving ethylcellulose and HPMC in a solvent mixture of isopropyl alcohol and methylene chloride and further addition of TEC to this mixture. Further, steps 10 through 16 are followed as in Example 3.
