WO2006054152A1

WO2006054152A1 - Monocompartment osmotic-controlled delivery system of doxazosin

Info

Publication number: WO2006054152A1
Application number: PCT/IB2005/003432
Authority: WO
Inventors: Rajan Kumar Verma; Narayanan Badri Viswanathan; Rajeev Singh Raghuvanshi; Ashok Rampal
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2004-11-22
Filing date: 2005-11-16
Publication date: 2006-05-26
Also published as: EP1824491A1

Abstract

Monocompartment osmotic-controlled delivery system of doxazosin is disclosed. The delivery system comprises a core comprising co-processed doxazosin and at least one alginic acid derivative; a semipermeable membrane enclosing the core; and at least one passageway through the semipermeable membrane. A process for the preparation of monocompartment osmotic-controlled drug delivery system is also disclosed.

Description

MONOCOMPARTMENT OSMOTIC-CONTROLLED DELIVERY SYSTEM OF

DOXAZOSIN

Field of the Invention

The present invention relates to a monocompartment osmotic-controlled delivery system of doxazosin comprising co-processed doxazosin and at least one alginic acid derivative.

Background of the Invention

Advantages of controlled release drug delivery systems are well documented. Numerous technologies have been exploited to achieve desired drug release profiles, as required to satisfy therapeutic needs and patient compliance. One such widely used controlled release technology is based on osmotic pressure controlled drug delivery, introduced by Theewas in J. Pharm. ScL, 64, 12, 1987-91 (1975). The elementary oral osmotic system (OROS^®, Alza Corp.) in its simplest version takes the form of a conventional coated tablet. It comprises a homogenous core tablet of drug coated with a semi-permeable wall/layer and an aperture created through the wall for the release of contents from the core. When placed in dissolution media/gastrointestinal fluid, water permeates into the core through the semipermeable wall and dissolves the drug. The osmotic pressure thus built, exerts pressure against the wall and thereby releases out the solution of drug, through the aperture in the wall. Osmotic-controlled drug delivery systems show better in vitro-in vivo correlation as their performance is reported to be independent of pH and contents of the gastrointestinal tract. Moreover, they are highly resistant to mechanical stress encountered within the gut. Hence, properly designed osmotic systems may prove to be of paramount importance. Practically, use of simple osmotic system designed by Theewas is confined to that limited number of drugs which are soluble enough to produce a sufficiently high osmotic pressure. Sparingly soluble drugs fail to be delivered from this system in the desired manner.

U.S. Patent No. 4,111,202 assigned to Alza Corp. addresses this problem by the fabrication of "push-pull" (double compartment core) osmotic system wherein the core of the OROS^® system is replaced by a pull compartment containing a sparingly soluble drug composition and a push compartment containing water soluble osmotically active agents. Though advantageous over the OROS^® system, manufacturing of "push-pull" systems is technically complicated and costly, requiring proper placement of elastic diaphragm between the two compartments. Further, for sparingly soluble drugs having large therapeutic doses, unacceptably large sized "push-pull" systems are needed.

The concept of "push-pull" systems is also presented simplified in European Patent Application No. 52917, by developing osmotic systems without an elastic diaphragm. The osmotic system disclosed in this patent application has the two compartments of the push pull system replaced by two different composition layers, viz., drug layer containing drug and osmotic agents, and an expandable driving member layer formed of a water swellable hydrogel. Manufacturing of the above system is still problematic, requiring multiple compression steps and high level of uniformity in the grain size of granulate during compression. Identification of drug layer surface for drilling of aperture through the semipermeable wall is also cumbersome.

The above problems are overcome by a homogeneous monocompartment osmotic system disclosed in U.S. Patent No. 4,857,336 reissued as U.S. RE 34990 and U.S. Patent No. 4,992,278. U.S. Patent No. 4,992,278 discloses a monocompartment therapeutic system comprising (a) a casing made of a material that is permeable to water and is impermeable to the components of the core containing the active ingredient, (b) a core containing an active ingredient that is sparingly soluble in water or a mixture of such active ingredients, a hydrophilic polymeric swelling agent consisting of a mixture of a vinylpyrrolidone / vinyl acetate copolymer with an ethylene oxide homopolymer, optionally water soluble substance for inducing osmosis and optionally further pharmaceutically acceptable adjuncts and (c) passage through the casing (a) for the transport of the constituents contained in the core into the surrounding aqueous body fluid. Further, this patent teaches that the use of conventional swelling agents of two- compartment system such as polyvinylpyrrolidone, polyethylene oxide, polymethacrylate and the like, in single compartment system does not work. This is because the swelling pressure of these polymers is so great that in contact with water the semipermeable membrane bursts and the whole system disintegrates in the stomach after a short period of time.

Summary of the Invention

The present inventors have provided suitable swelling agents which enable easy fabrication of monocompartment systems as well as providing controlled swelling without rupture of a semipermeable membrane. On the other hand, the swelling pressure should be sufficient enough to force the contents out of the system and achieve desired controlled drug release profiles.

The present inventors have discovered that use of at least one alginic acid derivative as swelling agent in monocompartment osmotic-controlled drug delivery system overcomes the above problems and helps in achieving desired controlled drug release profiles for a poorly soluble drag.

Hence, in one general aspect, there is provided a monocompartment osmotic- controlled drug delivery system comprising a poorly soluble drag and at least one alginic acid derivative.

In another general aspect, there is provided a monocompartment osmotic- controlled drag delivery system comprising

(a) a core comprising

(i) a poorly soluble drug, (ii) at least one alginic acid derivative, and

(iii) at least one pharmaceutically acceptable inert excipient;

(b) a semipermeable membrane enclosing the core; and

(c) at least one passageway in the semipermeable membrane, for delivering the contents of the core into the surrounding media. In another general aspect, there is provided a monocompartment osmotic- controlled drag delivery system comprising:

(a) a core comprising

(i) a poorly soluble drag, (ii) at least one alginic acid derivative, (iii) an osmotic agent, and

(iv) at least one pharmaceutically acceptable inert excipient; (b) a semipermeable membrane enclosing the core, and (c) at least one passageway in the semipermeable membrane, for delivering the content of the core into the surrounding media.

In another general aspect, there is provided a monocompartment osmotic- controlled delivery system of doxazosin comprising

(a) a core comprising (i) co-processed doxazosin,

(ii) at least one alginic acid derivative, and

(iii) at least one pharmaceutically acceptable inert excipient;

(b) a semipermeable membrane enclosing core; and

(c) at least one passageway in the semipermeable membrane, for delivering the contents of the core into the surrounding media.

In another general aspect, there is provided a process for the preparation of a monocompartment osmotic-controlled drug delivery system comprising steps of:

(a) blending a poorly soluble drug, at least one alginic acid derivative and at least one pharmaceutically acceptable inert excipient; optionally granulating the blend with a binder; and compressing the blend /granules into a compact core;

(b) enclosing the core with a solution/dispersion of the enclosing composition comprising semipermeable membrane forming polymer and other coating additives; and

(c) creating at least one passageway in the semipermeable membrane. In another general aspect, there is provided a process for the preparation of a monocompartment osmotic-controlled delivery device of doxazosin comprising steps of: (a) blending co-processed doxazosin, at least one alginic acid derivative, and at least one pharmaceutically acceptable inert excipient; optionally granulating the blend with a binder; and compressing the blend /granules into a compact core; (b) enclosing the core with a solution/dispersion of the enclosing composition comprising semipermeable membrane forming polymer and other coating additives; and

(c) creating at least one passageway in the semipermeable membrane.

In another general aspect, there is provided a process for the preparation of a monoconipartment osmotic-controlled drug delivery system comprising steps of:

(a) blending a poorly soluble drug, at least one alginic acid derivative, an osmotic agent and at least one pharmaceutically acceptable inert excipient; optionally granulating the blend with a binder; and compressing the blend /granules into a compact core; (b) enclosing the core with a solution/dispersion of the enclosing composition comprising semipermeable membrane forming polymer and other coating additives; and

(c) creating at least one passageway in the semipermeable membrane.

In another general aspect, there is provided a method of achieving controlled delivery of a poorly soluble drug over a period of at least 4 hours, from a monocompartment osmotic-controlled drug delivery system comprising a poorly soluble drug and at least one alginic acid derivative.

In another general aspect there is provided a method of treating benign prostatic hyperplasia in a mammal by administering to the said mammal a monocompartment osmotic-controlled delivery system of doxazosin comprising

(a) a core comprising

(i) co-processed doxazosin,

(ii) at least one alginic acid derivative, and

(iii) at least one pharmaceutically acceptable inert excipient; (b) a semipermeable membrane enclosing core; and

These as well as other aspects of the present invention will become apparent from the appended specification.

Brief Description of the Drawings

Figure 1 is a graph which compares the in vitro release of drug (glipizide) from monocompartment osmotic-controlled drug delivery systems as per composition of Examples Ia, Ib and Ic. Figure 2 is a graph which compares the in vitro release of drug (glipizide) from monocompartment osmotic-controlled drug delivery systems as per composition of Examples 2a, 2b and 2c.

Figure 3 is a graph which compares the in vitro release of drug (glipizide) from five different sets of monocompartment osmotic-controlled drug delivery systems as per composition of Example 3 with semipermeable membrane thickness equivalent to weight gains of 11, 13, 15, 18 and 20% of core weight respectively.

Figure 4 is a graph which compares the in vitro release of drug (doxazosin mesylate) from monocompartment osmotic-controlled drug delivery systems as per composition of Examples 4a, 4b, 4c and 4d. Figure 5 is a graph which compares the in vitro release of drug (cilostazol) from monocompartment osmotic-controlled drug delivery systems as per composition of Examples 5, with semipermeable membrane thickness equivalent to weight gains of 7.6 and 10.8% of core weight respectively.

Figure 6 is a graph that compares the in vitro release of drug (doxazosin mesylate) from monocompartment osmotic-controlled drug delivery systems as per composition of Examples 7a, 7b, 7c, 7d, 7g, and 7h.

Figure 7 is a graph that compares the in vitro release of drug (doxazosin mesylate) from monocompartment osmotic-controlled drug delivery systems as per composition of Examples 8a, 8b, 9a, 9b, and 9c. Detailed Description of the Invention

Alginic acid derivatives used as swelling agents in the monocompartment osmotic- controlled drug delivery system are now discovered to possess the required swelling property to form a dispersion of the poorly soluble drug of a consistency, which is easily flowable through the passageway without damaging the semipermeable membrane. The amount of alginic acid derivative used in the core may be varied over a wide range. With proper choice and use of varying amount of osmotic agents and other pharmaceutically acceptable inert excipients, the drug delivery system may be designed to achieve drug release profiles of varied nature. The rate of drug release may also be manipulated by controlling the thickness and nature of semipermeable membrane, e.g. , with proper choice of other coating additives.

When the monocompartment osmotic-controlled drug delivery system of the present invention is placed in dissolution media/gastrointestinal fluid, water permeates into the core, through the semipermeable membrane. Absorption of water causes swelling of the alginic acid derivative in the core, which thereby exerts pressure against the semipermeable membrane and forces the dispersion of poorly soluble drug through the passageway, into the surrounding media. On coming out of the system, the drug in the dispersion gets dissolved in the surrounding media.

The term "swelling" as used herein refers to increase in the volume on coming in contact to water. In some cases swelling may even lead to a formation of gel like consistency into which the poorly soluble drug is embedded in the form of dispersion. Hence, the terms "swelling" and "gelling" are used interchangeably herein.

The term "core" as used herein covers any compact composition having a defined shape such as tablet, mold, capsule and the like. The term "poorly soluble drug" as used herein includes drugs having solubility of about 1 part in 25 or more parts of water. It also includes those drugs wherein 1 part of drug dissolves in less than 25 parts of water, but under acidic or alkaline conditions, or under the influence of other excipients the solubility is decreased up to 1 in 25 parts of water. Suitable examples of the therapeutic classes, for the purpose of present invention include antidiabetics, antineoplastic agents, antihypertensives, psychopharmacological agents, cardiovascular agents, platelet aggregation inhibitors, analgesics, antimicrobials, diuretics, spasmolytics and the like. Specific examples of poorly soluble drugs include glipizide, doxazosin, verapamil, prazosin, isradipine, cilostazol, nifedipine, nisoldipine, bendrofiumethazide, chlorpropamide, hydrocortisone, ibuprofen, diclofenac, and the like, and combinations thereof. The term "drug" as used herein include free drug well as any pharmaceutically acceptable salt thereof. The poorly soluble drug as used herein may be in a commercially available form as such; or in a processed form using techniques of comminution, micro emulsification, co-melting, solid dispersion, spray drying, co¬ processing with pharmaceutically acceptable inert excipients, drug-inclusion complexation and the like. The term "co-processed doxazosin" as used herein refers to a solid mixture of doxazosin or any of its pharmaceutically acceptable salts, sovates, esters, or enantiomers with wetting agent. The wetting agent aids in improving the wetting of doxazosin with dissolution media/gastro-intestinal fluids increasing the dissolution rate and consequently the bioavailability. Co-processed doxazosin may be prepared by co-processing doxazosin and wetting agent with or without pharmaceutically acceptable inert excipients using conventional methods, including spray drying, milling, sieving, and melting. In particular melting processes may be used.

Examples of wetting agents include cellulose derivatives such as hydroxypropylcellulose, and hydroxypropyl methylcellulose; starches such as maize, rice, corn and potato starch; super disintegrants such as croscarmellose sodium, sodium starch glycolate, and crospovidone; polyvinyl alcohol; polyvinyl pyrrolidone; solid grades of polyethylene glycols; and methacrylic acid polymers and copolymers, and the like.

"Alginic acid derivative" as used herein includes alginic acid as well as any of its pharmaceutically acceptable derivatives such as salts, esters, and the like, and mixtures thereof. Specific examples of alginic acid salts include salts of alginic acid with sodium, potassium, magnesium, calcium or ammonia. Specific alginic acid esters include propylene glycol alginate.

Alginic acid is a naturally occurring hydrophilic colloidal polysaccharide consisting mainly of residues of β- 1 ,4-linked D-mannuronic acid and α- 1 ,4-linked L- glucuronic acid. Depending on the species of kelp used in manufacturing, ratios of niannuronic acid to glucuronic acid content typically range from about 0.4 to about 0.9. Alginic acid has an average molecular weight varying from about 10,000-600,000 and is widely used in the pharmaceutical field as a stabilizer, thickener, gelling agent and emulsifier. It is insoluble in water but its salts form thermally irreversible gels with water, the viscosity of which decreases at higher pH values. Alginic acid derivatives are marketed, for example, by ISP alginates as white to yellowish brown filamentous, grainy, granular or powdered form under the trade names - KELACID®, ALGINIC ACID HF/D, ALGINIC ACID DC, KELTONE® LVCR, KELTONE® HVCR, MANUCOL® LKX, MANUCOL LB, MANUCOL DMF, KELCOSOL®, MANUGEL® DMB, KELCOLOID® LVF, MANUCOL ESTER ERK, Improved KELMAR®, KELTOSE ®, and many others. Based on the grade used and desired drug release profile, the amount of alginic acid derivative may vary from about 5% to about 98% by weight of the total weight of core, from about 19% to about 86%, or from about 30% to about 55%, or from about 40% to about 50%. One of the important factors in achieving effective hydration and thereby controlled swelling of the alginic acid derivative is proper dispersion of individual particles into the core. Poor dispersion may lead to the formation of large lumps of unhydrated alginic acid derivative and significantly extend the hydration and swelling time, producing erratic drug release profiles. One way of achieving proper dispersion of alginic acid derivative particles is blending with an osmotic agent, which diminishes its tendency to form lumps. Further, the osmotic agent may be used to manipulate the viscosity of the dispersion of poorly soluble drug formed in the core, and also to manipulate drug release profile.

The term "osmotic agent" as used herein includes all pharmaceutically acceptable inert water soluble compounds suitable for inducing osmosis, referred to in the Pharmacoepias, or in "Hager" as well as in Remington's Pharmaceutical sciences. Examples of compounds suitable as osmotic agents include water soluble salts of inorganic acids such as magnesium chloride or magnesium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate; water soluble salts of organic acids such as sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, sodium ascorbate; non ionic organic compounds with high water solubility e.g. carbohydrates such as mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, raffinose; water-soluble amino acids such as glycine, leucine, alanine, or methionine; urea and urea derivatives; and the like and mixtures thereof. The amount of osmotic agent used in the core may be up to about 60% by weight of the total weight of core.

"Semipermeable membrane" as used herein is a membrane or coating, which allows movement of water molecules through it, but does not allow contents of the core to pass through. Semipermeable membrane of the comprises membrane forming polymer and other pharmaceutically acceptable coating additives. Membrane forming polymers are those, which are not metabolized in the gastrointestinal tract, i.e. are ejected unchanged from the body in feces. Membrane forming polymers include those known in the art for fabrication of semipermeable membrane and described in the literature, e.g. in U.S. Patent Nos. 3,916, 899 and 3,977,404. Examples of semipermeable membrane forming polymers include cellulose derivatives such as cellulose acetate, cellulose triacetate, agar acetate, amylose acetate, cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate ethyl carbonate, cellulose acetate chloroacetate, cellulose acetate ethyl oxalate, cellulose acetate methyl sulphonate, cellulose acetate butyl sulphonate, cellulose acetate propionate, cellulose acetate diethylamino-acetate, cellulose acetate octate, cellulose acetate laurate, cellulose acetate p-toluenesulphonate, cellulose acetate butyrate; polymeric epoxides; copolymers of alkylene oxides and alkyl glycidyl ethers; polyglycols or polylactic acid derivatives; copolymer of acrylic acid ethyl ester and methacrylic acid methyl ester; and the like; and mixtures thereof. Alternatively a combination of cellulose acetates with different degrees of acetylation may be used as membrane forming polymer. As the degree of acetylation of cellulose acetate increases, permeability of the membrane decreases. In particular, a combination of cellulose acetates having acetyl content in the range of about 8% to about 50% may be used. Further, other coating additives may be combined with the membrane forming polymers to adjust the permeability to our choice. Controlling membrane thickness also helps to manipulate the permeability of the membrane, which may vary from about 3% to about 40% weight build up over the weight of core.

The term "passageway" as used herein covers any suitable means for releasing the contents of the core into the surrounding media. The term includes passages, apertures, bores, holes, openings and the like, created through the semipermeable membrane and forming a connection between the core and the surrounding media. The passageway may be created by mechanical drilling or laser drilling, or formed in response to the osmotic pressure acting on the drug delivery system. Based on the nature of desired drug release profile, the number and diameter of the passageway may be adjusted. However, the diameter of the passageway should not be large enough to allow body fluids to enter the drug delivery system by the process of convection.

The term "pharmaceutically acceptable inert excipients" as used herein includes all excipients used in the art of manufacturing osmotic-controlled dosage forms and described in the literature. Examples include binders, diluents, surfactants, pH modifiers, lubricants/glidants, stabilizers, plasticizers, coloring agents, and the like, and mixtures thereof.

Specific examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like, and mixtures thereof.

Specific examples of diluents include calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like, and mixtures thereof.

Surfactants may be used to promote wetting of poorly soluble drug as well as promote hydration of alginic acid derivative and include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical compositions. These include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides for example glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and the like; and mixtures thereof.

The pH modifiers are substances which help in maintaining the pH of the local environment surrounding the drug at a value favorable for suitably modifying the solubility behavior of drug and/or gelling behavior of alginic acid derivative. Specific examples of pH modifiers include dibasic sodium phosphate, sodium ascorbate, meglumine, sodium citrate, trimethanolamine, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium oxide, magnesium hydroxide, ammonia, tertiary sodium phosphate, diethanolamine, ethylenediamine, L-lysine and the like, and mixtures thereof

Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like, and mixtures thereof.

Specific examples of plasticizers include acetylated triacetin, triethylcitrate, tributylcitrate, glyceroltributyrate, monoglyceride, rape oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethyl phthalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, and the like, and mixtures thereof.

Stabilizers include antioxidants, buffers, acids, and the like, and mixtures thereof.

Coloring agents include any FDA approved colors for oral use, and mixtures thereof. The term "coating additives" as used herein includes all conventional coating additives used in the art of coating technology and described in the literature. Examples include flux enhancers as well as those described above under pharmaceutically acceptable inert excipients. Flux enhancers are water soluble substances, which aid in drawing water from the surrounding media and are thereby helpful in manipulating the semipermeable membrane's permeability. Specific examples include hydroxymethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, hydroxypropylcellulose, propylene glycol, polyvinylpyrrolidone, and the like, and mixtures thereof. In one of the embodiments, the monocompartment osmotic-controlled drug delivery system may be prepared by processes known in the prior art, e.g. by comminuting, mixing, granulation, sizing, filling, molding, spraying, immersing, coating etc. The core may be prepared by blending a poorly soluble drug, at least one alginic acid derivative, optionally an osmotic agent and other pharmaceutically inert excipients; optionally granulating the blend; and compressing the blend/granules in to a compact core. The core may be enclosed within a semipermeable membrane by applying the enclosing composition in the form of a solution/dispersion comprising semipermeable membrane forming polymer and coating additives. Finally a passageway may be created through the semipermeable membrane using a suitable technique. In another embodiment, the monocompartment osmotic-controlled delivery system of doxazosin may be prepared by the following process: the core may be prepared by blending co-processed doxazosin, at least one alginic acid derivative, optionally an osmotic agent and other pharmaceutically inert excipients; optionally granulating the blend; and compressing the blend/granules in to a compact core. The core may be enclosed within a semipermeable membrane by applying the enclosing composition in the form of a solution/dispersion comprising semipermeable membrane forming polymer and coating additives. Finally a passageway may be created through the semipermeable membrane using a suitable technique.

Examples of solvents used for the purpose of granulation or for preparing solution/dispersion of the coating composition include dichloromethane, isopropyl alcohol, acetone, methanol, ethanol, water, and the like, and mixtures thereof. Alternatively, additional coating layers may be applied over the cores either below or/and over the semipermeable membrane. The additional layers comprise coating additives and provide smooth surfaces; over which semipermeable membrane may be uniformly applied or identification marks may be printed. In addition it promotes aesthetic appeal.

In case, an immediate action is desired, the monocompartment osmotic-controlled delivery system may be coated with an immediate release layer comprising the same drug as in the core or a different drag, over the semipermeable membrane.

Further, a combination of more than one drug may also be used in the core and/or in the immediate release layer.

The invention is further illustrated by the following examples, which illustrate particular aspects and do not limit the scope of the invention in any way.

Example Ia-Ic

I. Core composition

II. Semipermeable membrane composition

Procedure: 1. The core ingredients were sieved to the desired size level and required amounts weighed out.

2. Glipizide, sodium alginate, sorbitol and polyvinylpyrrolidone were mixed together to form a homogenous blend. 3. The blend of step 2 was granulated using a mixture of isopropyl alcohol and methanol (50:50 v/v).

4. The wet granules were dried in a fluidized bed drier and sized through suitable sieves.

5. The dried granules were lubricated by blending with magnesium stearate and compressed into round concave-shaped cores using suitable tooling.

6. Cellulose acetate, hydroxypropyl methylcellulose and polyethylene glycol were dissolved in a mixture of dichloromethane and methanol (80:20 w/w) to prepare a 4% w/w solution.

7. Cores of step 5 were coated with the solution of step 6 in a coating pan up to a weight gain of 10% (Example Ia and Ib) or 16% (Example Ic) of core weight.

8. The coated cores were dried in hot air oven and finally an orifice is drilled through the semipermeable membrane using a 1 mm mechanical drill to obtain monocompartment osmotic-controlled drug delivery systems.

The in vitro release of drug (glipizide) from monocompartment osmotic-controlled drug delivery systems as per Examples Ia, Ib and Ic was studied in 900 ml phosphate buffer (pH 7.5) using USP II dissolution apparatus, at a paddle speed of 50 rpm. The results of the study are incorporated herein for reference in Figure 1.

Figure 1 reveals that both the rate and the amount of drug released from Example Ia (having no alginic acid derivative) are drastically low as compared to Example Ib and Ic. Hence, alginic acid derivatives play a major role in achieving acceptable release profiles for poorly soluble drugs from monocompartment osmotic-controlled drug delivery systems. Further, though the drug release profiles from Example Ib and Ic are similar, Example Ic (having an osmotic agent) has a lower lag time compared to Example Ib. Thus, use of an osmotic agent in combination to an alginic acid derivative may prove to be a useful approach in manipulating drag release profiles.

Example 2a-2c

I. Core composition

II. Semipermeable membrane composition

Procedure:

1. The core ingredients were sieved to the desired size level and required amounts weighed out.

2. Glipizide, sodium alginate, sorbitol, lactose and polyvinylpyrrolidone were mixed together to form a homogenous blend.

3. The blend of step 2 was granulated using isopropyl alcohol.

5. The dried granules were lubricated by blending with magnesium stearate and compressed into round concave-shaped cores using suitable tooling. 6. Cellulose acetate, hydroxypropyl methylcellulose and polyethylene glycol were dissolved in a mixture of dichloromethane and methanol (80:20 w/w) to prepare a 3.5% w/w solution.

7. Cores of step 5 were coated with the solution of step 6 in a coating pan up to a weight gain of 17% of core weight.

The in vitro release of drug (glipizide) from monocompartment osmotic-controlled drug delivery systems as per Examples 2a, 2b, and 2c was studied in 900 ml phosphate buffer (pH 7.5) using USP II dissolution apparatus, at a paddle speed of 50 rpm. The results of the study are incorporated herein for reference in Figure 2.

Figure 2 reveals that though the drug release profiles from Examples 2a, 2b, and 2c are almost similar, the lag time for Examples 2a (using sorbitol as osmotic agent) is lower than as compared to that obtained for Examples 2b (using sorbitol and lactose in equal weights as osmotic agents), which is again lower than that for Examples 2c (using lactose as osmotic agent). As the solubility of lactose is much less than sorbitol, it is inferred that with the increase in solubility of osmotic agent, lag time decreases. Hence, delivery systems with the desired lag time may be achieved by proper selection of osmotic agents.

Example 3

I. Core composition

II. Precoating composition

Procedure:

2. Glipizide, sodium alginate and sorbitol were mixed together to form a homogenous blend.

3. The blend of step 2 was granulated using a solution of polyvinylpyrrolidone in isopropyl alcohol. 4. The wet granules were dried in a fluidized bed drier and sized through suitable sieves.

6. Hydroxypropyl methylcellulose and polyethylene glycol were dissolved in a mixture of isopropyl alcohol and dichloromethane (60:40 w/w) to prepare a 5% w/w solution.

7. Cores of step 5 were coated with the solution of step 6 in a coating pan to form a precoated core, up to a weight gain of 1% of core weight. 8. Cellulose acetate, hydroxypropyl methylcellulose and polyethylene glycol were dissolved in a mixture of dichloromethane and methanol (80:20 w/w) to prepare a 3.5% w/w solution.

9. Precoated cores of step 7 were coated with the solution of step 8 in a coating pan to prepare five different sets of coated cores having weight gain of 11, 13, 15, 18 and 20% of core weight, respectively.

10. The coated cores of step 10 were dried in hot air oven and finally an orifice was drilled through the semipermeable membrane using a 0.6 mm mechanical drill to obtain monocompartment osmotic-controlled drug delivery systems.

The in vitro release of drug (glipizide) from five different sets of monocompartment osmotic-controlled drug delivery systems as per composition of Example 3 and with semipermeable membrane thickness equivalent to weight gain of 11, 13, 15, 18 and 20% of core weight respectively, was studied in 900 ml phosphate buffer (pH 7.5) using USP II dissolution apparatus, at a paddle speed of 50 rpm. The results of the study are incorporated herein for reference in Figure 3.

The drug release profiles in Figure 3 clearly indicate a decrease in drug release rate with an increase in the semipermeable membrane thickness equivalent to above 18% weight gain of core weight. Hence, controlling the thickness of the semipermeable membrane may be useful in manipulating drug release profiles.

Example 4a-4d

I. Core composition

Magnesium stearate 3.0 3.0 3.0 4.6

II Semipermeable membrane composition

2. Doxazosin mesylate, sodium alginate, sorbitol, polyvinylpyrrolidone, colloidal silicon dioxide, magnesium oxide (only Example 4b), meglumine (only Example 4c) and polaxamer (only example 4d) were mixed together to form homogenous blends.

3. Blends of step 2 were lubricated by blending with magnesium stearate and compressed into round concave-shaped cores using suitable tooling.

4. Cellulose acetate and polyethylene glycol were dissolved in a mixture of acetone and water (90: 10 w/w) to prepare a 4% w/w solution (Example 4a-4c), whereas for Example 4d cellulose acetate, polyethylene glycol and hydroxypropyl methylcellulose were dissolved in a mixture of dichloromethane and methanol (80:20 w/w) to prepare a 3.5% w/w solution.

5. Cores of step 5 were coated with the corresponding coating solutions of step 6 in a coating pan up to a weight gain of 11% (Example 4a), 12% (Example 4b, 4c and 4d) of core weight. 6. The coated cores were dried in hot air oven and finally an orifice was drilled through the semipermeable membrane using a 0.6 mm mechanical drill to obtain monocompartment osmotic-controlled drug delivery systems.

The in vitro release of drag (doxazosin mesylate) from monocompartment osmotic-controlled drug delivery systems as per Example 4a-4d was studied in 900 ml phosphate buffer (pH 6.8) with 0.5% sodium lauryl sulphate using USP II dissolution apparatus, at a paddle speed of 50 rpm. The results of the study are shown in Figure 4.

Example 5

I. Core composition

II. Semipermeable membrane

Procedure:

2. Cilostazol, sodium alginate, sorbitol, lactose, sodium lauryl sulphate and polyvinylpyrrolidone were mixed together to form a homogenous blend.

3. The blend of step 2 was granulated using isopropyl alcohol.

4. The wet granules of step 3 were dried and sieved through suitable sieves. 5. The dried granules were lubricated by blending with magnesium stearate and compressed into round concave-shaped cores using suitable tooling.

6. Cellulose acetate and polyethylene glycol were dissolved in a mixture of acetone and water (90: 10 w/w) to prepare a 4% w/w solution.

7. Cores of step 5 were coated with the solution of step 6 in a coating pan to prepare two different sets of coated cores having weight gains of 7.6% and 10.8% of core weight respectively.

8. The coated cores of step 7 were dried in hot air oven and finally an orifice was drilled through the semipermeable membrane using a 0.6 mm mechanical drill to obtain monocompartment osmotic-controlled drug delivery systems.

The in vitro release of drug (Cilostazol) from two different sets of monocompartment osmotic-controlled drug delivery systems as per composition of Example 5 and with semipermeable membrane thickness equivalent to weight gain of 7.6% and 10.8% of core weight respectively, was studied in 900 ml phosphate buffer (pH 6.8) with 0.25% sodium lauryl sulphate using USP II dissolution apparatus, at a paddle speed of 50 rpm. The results of the study are incorporated herein for reference in Figure 5.

Example 6

Compositions of Co-processed doxazosin

* The weight of doxazosin mesylate is expressed as weight of doxazosin base (Assay: 99.9%; Water by KF: 1%).

Procedure: 1. Polyethylene glycol (PEG 6000) was melted and doxazosin mesylate was added into it with constant stirring.

2. The melt of step 1 was cooled to solidify followed by crushing and sieving through #44 BSS sieve to form co-processed doxazosin mesylate granules.

RLL-622WO

24

Example 7a-7i

I. Core composition

5 II. Semipermeable membrane

Procedure:

1. The core ingredients were sieved to the desired size level and the required amounts weighed out.

2. Co-processed doxazosin was blended with colloidal silicon dioxide, followed by blending with sodium alginate, sorbitol, and polyvinyl pyrrolidone.

3. The blend of step 2 was lubricated with magnesium stearate and compressed into round concave-shaped cores using suitable tooling.

4. Cellulose acetate and polyethylene glycol were dissolved in a mixture of acetone and water (90: 10 w/w) to prepare a 4% w/w solution. 5. The cores of step 3 were coated with the coating solution of step 4 in a coating pan until they attained a weight gain of 9-10% of core weight.

6. The coated cores were dried in a hot air oven and then an orifice was drilled through the semipermeable membrane using a 0.6 mm mechanical drill to obtain monocompartment osmotic-controlled drug delivery systems. The in vitro release of drug (doxazosin mesylate) from monocompartment osmotic-controlled drug delivery systems as per Examples 7a-7d, 7g and 7h was studied in 900 ml phosphate buffer (pH 6.8) with 0.5% (Example 7a, 7b) or 1% (Example 7c, 7d, 7g, 7h) sodium lauryl sulphate using USP II dissolution apparatus, at a paddle speed of 50 rpm. The results of the study are illustrated in Figure 6.

Example 8 (a-b) - 9 (a-c)

I. Core composition

II. Precoating composition

III. Semipermeable membrane composition

Procedure:

2. Co-processed doxazosin, colloidal silicon dioxide and a part of polyvinylpyrrolidone were mixed together to form a homogenous blend.

3. The blend of step 2 was blended with sodium alginate and sorbitol. 4. The blend of step 3 was granulated using a solution of the remaining part of polyvinylpyrrolidone in isopropyl alcohol.

5. The wet granules were dried in a fluidized bed drier and sized through suitable sieves. 6. The dried granules were lubricated by blending with magnesium stearate and compressed into round concave-shaped cores using suitable tooling.

7. Hydroxypropyl methylcellulose and polyethylene glycol were dissolved in a mixture of isopropyl alcohol and dichloromethane (60:40 w/w) to prepare a 5% w/w solution. 8. The cores of step 6 were coated with the solution of step 7 in a coating pan to form a precoated core until they attained a weight gain of 0.5% (Example 8) and 1.8% (Example 9) of core weight.

9. Cellulose acetate and polyethylene glycol were dissolved in a mixture of acetone and water (80:20 w/w) to prepare a 4% w/w solution. 10. The precoated cores of step 8 were coated with the solution of step 9 in a coating pan to prepare 2 different sets of coated cores of Example 8 (8a and 8b) having weight gain of 11 and 12% of core weight, and 3 different sets of coated cores of Example 9 (9a, 9b and 9c) having weight gain of 17, 18 and 21% of core weight respectively. 11. The coated cores of Example 8 of step 10 were coated with 10% (w/w) solution of

Opadry® white in water up to a weight gain of 2% of coated core weight.

12. The coated cores of step 10 and 11 were dried in a hot air oven and then an orifice was drilled through the semipermeable membrane using a 0.6 mm mechanical drill to obtain monocompartment osmotic-controlled drug delivery systems.

The in vitro release of drug (doxazosin mesylate) from 2 different sets of monocompartment osmotic-controlled drug delivery systems as per composition of Example 8, 3 different sets of monocompartment osmotic-controlled drug delivery systems as per composition of Example 9 was studied in 900 ml phosphate buffer (pH 6.8) with 0.5% sodium lauryl sulphate using USP II dissolution apparatus, at a paddle speed of 50 rpm. The results of the study are illustrated in Figure 7.

While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text and claims can be made without departing from the spirit and scope of the invention. Moreover, it is contemplated that any single feature or any combination of optional features of the inventive variations described herein may be specifically excluded from the claimed invention and be so described as a negative invention. Accordingly, the invention is not limited, except as by the appended claims.

Claims

We claim: L A monocompartment osmotic-controlled delivery system of doxazosin comprising (a) a core comprising (i) co-processed doxazosin, (ii) at least one alginic acid derivative, and (iii) at least one pharmaceutically acceptable inert excipient; (b) a semipermeable membrane enclosing the core; and (c) at least one passageway in the semipermeable membrane, for delivering the contents of the core into the surrounding media.

2. The monocompartment osmotic-controlled delivery system of claim 1 wherein co- processed doxazosin comprises doxazosin and wetting agent.

3. The monocompartment osmotic-controlled delivery system of claim 2 wherein doxazosin is selected from free doxazosion base, and pharmaceutically acceptable salts, solvates, esters, or enantiomers thereof.

4. The monocompartment osmotic-controlled delivery system of claim 2 wherein wetting agent is selected from cellulose derivatives such as hydroxypropylcellulose, hydroxypropyl methylcellulose; starches such as maize, rice, corn and potato starch; super disintegrants such as croscarmellose sodium, sodium starch glycolate, and crospovidone; polyvinyl alcohol; polyvinyl pyrrolidone; solid grades of polyethylene glycols; and methacrylic acid polymers, and copolymers.

5. The monocompartment osmotic-controlled delivery system of claim 1 wherein co- processed doxazosin is prepared by spray drying, milling, sieving or melting.

6. The monocompartment osmotic-controlled delivery system of claim 1 wherein core further comprises an osmotic agent.

7. The monocompartment osmotic-controlled delivery system of claim 1 wherein core is coated with additional layers below and/or over the semipermeable membrane.

8. The monocompartment osmotic-controlled drug delivery system of claim 1 wherein core is selected from any compact composition having a defined shape such as tablet, mold, or capsule.

9. The monocompartment osmotic-controlled drug delivery system of claims 1 wherein alginic acid derivative is selected from alginic acid and its pharmaceutically acceptable derivative such as salts, and esters.

10. The monocompartment osmotic-controlled drug delivery system of claim 10 wherein alginic acid salt is selected from salts of alginic acid with sodium, potassium, magnesium, calcium or ammonium.

11. The monocompartment osmotic-controlled drug delivery system of claim 1 wherein pharmaceutically acceptable inert excipient is selected from binders, diluents, surfactants, pH modifiers, lubricants/glidants, stabilizers, plasticizers, and coloring agents.

12. The monocompartment osmotic-controlled drug delivery system of claim 1 wherein semipermeable membrane comprises semipermeable membrane forming polymer and coating additives.

13. The monocompartment osmotic-controlled drug delivery system of claim 13 wherein semipermeable membrane forming polymer is selected from cellulose derivatives, polymeric epoxides, copolymers of alkylene oxides and alkyl glycidyl ethers, polyglycols or polylactic acid derivatives, and copolymers of acrylic acid ethyl ester and methacrylic acid methyl ester.

14. The monocompartment osmotic-controlled drug delivery system of claim 13 wherein coating additives selected from flux enhancers and pharmaceutically acceptable inert excipients.

15. The monocompartment osmotic-controlled drug delivery system of claim 7 wherein the osmotic agent is selected from water soluble salts of inorganic acids, water soluble salts of organic acids, non ionic organic compounds with high water solubility, water-soluble amino acids, and urea and urea derivatives.

16. A process for the preparation of a monocompartment osmotic-controlled delivery device of doxazosin comprising the steps of: (a) blending co-processed doxazosin, at least one alginic acid derivative, and at least one pharmaceutically acceptable inert excipient; optionally granulating the blend with a binder; and compressing the blend /granules into a compact core; (b) enclosing the core with a solution/dispersion of the enclosing composition comprising semipermeable membrane forming polymer and other coating additives; and (c) creating at least one passageway in the semipermeable membrane.

17. The process of claim 17 wherein granulation or solution/dispersion of the enclosing composition is made in a solvent selected from dichloromethane, isopropyl alcohol, acetone, methanol, ethanol, and water.

18. A method of achieving controlled delivery of doxazosin over a period of at least 4 hours, the method comprising providing a monocompartment osmotic-controlled delivery system of doxazosin comprising co-processed doxazosin and at least one alginic acid derivative.

19. A method of treating benign prostatic hyperplasia in a mammal by administering to the mammal a monocompartment osmotic-controlled delivery system of doxazosin according claim 1.