WO2013168177A2

WO2013168177A2 - Osmotically controlled drug delivery systems

Info

Publication number: WO2013168177A2
Application number: PCT/IN2013/000196
Authority: WO
Inventors: Pratibha Sudhir Pilgaonkar; Maharukh Tehmasp Rustomjee; Anilkumar Surendrakumar Gandhi
Original assignee: Rubicon Research Private Limited
Priority date: 2012-03-26
Filing date: 2013-03-26
Publication date: 2013-11-14
Also published as: WO2013168177A3

Abstract

The present invention relates to osmotically controlled drug delivery systems comprising fenugreek osmopolymer. The present invention also provides processes for preparing such compositions.

Description

OSMOTICALLY CONTROLLED DRUG DELIVERY SYSTEMS

Field of the Invention

The present invention relates to osmotically controlled drug delivery systems comprising fenugreek osmopolymer. The present invention also provides processes for preparing such compositions and methods of using such compositions.

Background of the Invention

Many controlled release drug dosage forms have been designed to modulate the release of the drug over an extended period of time. Controlled drug delivery involves delivering the drug at a predetermined rate either locally or systemically for a specified period of time. Controlled release drug delivery systems allow maintenance of plasma concentrations of the active within the therapeutic range while reducing the dosing frequency. These controlled release formulations provide significant benefits over immediate release formulations, including greater effectiveness in the treatment of disease conditions, reduced side effects and greater patient convenience due to a simplified dosing schedule. A majority of the controlled release systems rely on dissolution, diffusion or dissolution and diffusion mechanisms to deliver the drug at a predetermined rate. However, generally rate and extent of drug release and absorption from such conventional controlled release systems may vary greatly depending on the route of administration on factors such as pH of the gastrointestinal tract, presence or absence of food and other physiological factors.

Active agents can be delivered in a controlled pattern over desired period of time by the process of osmosis. Osmosis refers to the process of movement of solvent molecules from lower to higher solute concentration across a semi permeable membrane. The pressure applied to the higher solute concentration side to inhibit solvent flow is the osmotic pressure. It is a colligative property that depends on the concentration of solute (neutral molecule or ionic species). Solutions of different concentrations having the same solute and solvent system exhibit an osmotic pressure proportional to their concentrations. Osmotic drug delivery systems utilize osmotic pressure or osmotic gradient as driving force for controlled delivery of drugs. Osmotic imbibition of water results in the formation of saturated solute and/or drug solution that is delivered at a controlled rate from the delivery orifice in the semipermeable membrane. The rate of imbibition of water is determined by the fluid permeability of the semipermeable membrane and the osmotic pressure of the solute and/or drug molecules. A constant osmotic pressure and thereby a constant influx or imbibition of water across the semi permeable membrane, can be achieved by an osmotic drug delivery system resulting in a constant release rate of drug. The rate of delivery generally follows the zero order kinetics and declines after the solution concentration falls below saturation.

Drug delivery from such osmotically controlled systems is independent of physiological factors such as gastrointestinal pH and hydrodynamic conditions of the body such as presence of food. Zero-order delivery rate achievable with these osmotic systems provides better control over in-vivo performance of the delivery system. The release rate of the active from osmotic systems is predictable and can be programmed as desired by modulating the release control parameters. Further a high degree of in vivo-in vitro correlation is obtained in osmotically controlled drug delivery systems since the factors that are responsible for causing differences in release profile in vitro and in vivo such as variable pH affect these systems to a much lesser extent.

However, to achieve a zero-order release rate from osmotically controlled drug delivery systems it is necessary to keep constant osmotic pressure by maintaining a saturated solute solution. Many times, the osmotic pressure generated by the saturated drug solution may not be sufficient to achieve the required driving force for imbibition of water within the drug delivery system. Therefore additional osmotic agents are added to enhance osmotic pressure. Osmotic agents also called as osmogens, osmogents or osmotic driving agents imbibe water from use environment and their osmotic pressure exceeds that of the use environment thereby providing osmotic pressure driving force for permeation of water into the osmotic drug delivery system. Osmotic agents thus maintain a concentration gradient across the selectively permeable membrane or semipermeable membrane used in osmotically controlled drug delivery systems. They generate a driving force for the uptake of water and assist in maintaining drug uniformity in the hydrated formulation. Osmogens can be of different types such as water soluble inorganic salts, water soluble salts of organic acids, sugars or carbohydrates, water soluble amino acids or organic polymeric osmogents. Hydrophilic organic polymers are commonly used as organic polymeric osmogents. These materials maintain a concentration gradient across the semipermeable membrane. They also generate a driving force for uptake of water and assist in maintaining drug uniformity in the hydrated formulation. Some of the hydrophilic organic polymers have the ability to swell in water or biological fluids, while retaining a significant portion of fluid within their structure. Such hydrophilic organic polymers are called osmopolymers and are used in osmotic delivery systems as an expandable means that interacts with water, or aqueous biological fluids so as to expand to an equilibrium state and cause delivery of active agent. Some hydrophilic polymers serve as both osmogent and osmopolymer.

Many osmotically controlled drug delivery systems developed have particularly employed polyethylene oxide as the organic polymeric osmogent or osmopolymeric agent. European Patent 1600154B1 discloses an osmotic extended release dosage form comprising a drug layer, an interior wall in contact with the drug layer comprising a blend of ethylcellulose and hydroxyalkylcellulose, an exterior wall in contact with the interior wall comprising cellulose' acetate and at least one exit that connects the exterior environment with the drug layer; wherein said drug layer comprises a member selected from the group consisting of hydromorphone and its pharmaceutically acceptable salts, acetaminophen, and a pharmaceutically acceptable polyethylene oxide , carrier. PCT Publication 2007057762A2 discloses an osmotic bi-layer tablet for the controlled release of a low-solubility drug comprises an inner core containing a drug-containing layer and a water-swellable layer, and a water-permeable outer coating including at least one delivery port, wherein the drug- containing layer comprises a drug substance, polyethylene oxide polymer having an average molecular weight from about 200,000 to 600,000Da, and another osmogen, and the water-swellable layer also comprises polyethylene oxide polymer having a weight average molecular weight of from about 4,000,000 to about 7,000,000Da and a sweller layer strengthening agent. PCT Publication 2007057762A2 discloses a dual compartment osmotic delivery device comprising: a) a core comprising: 1) a drug layer comprising one or more active ingredients, one or more gelling agents and, optionally, one or more pharmaceutically acceptable excipients; 2) a push layer comprising polyethylene oxide having a molecular weight of about 4,000,000 or lower and, optionally, one or more pharmaceutically acceptable excipients; b) a semipermeable membrane surrounding the core; and c) at least one passageway through the semipermeable membrane into the drug layer.

However use of polyethylene oxide has some inherent disadvantages. Firstly polyethylene oxide can cause a rather extensive time lag in delivering the drug because of its slow speed of water absorption and hydration. Secondly poly (ethylene oxide) tends to undergo oxidation with concomitant drop in its hydration properties which alters its performance. Thirdly poly(ethylene oxide) is a very sticky material requiring special handling precautions and cleaning methodologies. Furthermore polyethylene oxide is also an expensive polymer. Additionally polyethylene oxide is susceptible to cross-linking with other excipients in the formulations and may also tend to form stronger associations with polar compounds. This may therefore affect the release of the active as well the system performance.

A need therefore exists to identify excipients for development of osmotically controlled drug delivery systems which are stable, easy to handle and cost effective. The present inventors after thorough research surprisingly found that an excipient from fenugreek seeds comprising fenugreek fibers when incorporated in a controlled release dosage form with a selectively water permeable membrane provides an osmotically controlled drug delivery system for delivery of an active agent that is comparable or better in performance than an osmotically controlled drug delivery system comprising polyethylene oxide as^a primary osmogent/osmopolymer.

Such a fenugreek osmopolymer due to its swelling nature and/or hydrogel forming ability serves as an expandable means that retains a significant portion of imbibed water within its structure and aids delivery of the active agent. The fenugreek osmopolymer may also function as an osmogent that maintains an osmotic gradient across a selectively permeable membrane in an osmotic dosage form. The use of dietary fibers from Fenugreek is cost-effective. The fenugreek osmopolymer comprising fenugreek fibers shows hydration and swelling that is comparable to polyethylene oxide and other osmopolymers commonly used in osmotically controlled drug delivery systems such as hydroxypropyl methylcellulose, sodium carboxymethylcellulose and the like. The fenugreek osmopolymer imbibes water from use environment across the selectively permeable membrane used in osmotically controlled drug delivery systems and may also generate osmotic pressure driving force for permeation of water into the osmotic drug delivery system. Fenugreek osmopolymer on imbibition of water hydrate and swell, thereby pushing or delivering the active out of delivery system through manually drilled orifice/s in the selectively permeable membrane or orifices generated in-situ in the selectively permeable membrane. Further fenugreek osmopolymer is stable and does not undergo any oxidation thereby maintaining their performance over a period of time. Fenugreek osmopolymer comprising fenugreek dietary fibers, soluble dietary fibers, insoluble dietary fibers or combinations thereof can be employed in osmotically controlled drug delivery systems in accordance with the present invention. Fenugreek osmopolmyer comprising fenugreek fibers with soluble and insoluble dietary fibers and processes for preparation thereof have been described in European Patent 1697050B1 and PCT Publication WO2011/124973A1 , entire contents of which have been incorporated herein by reference. Summary of the Invention

The present invention relates to osmotically controlled drug delivery systems comprising fenugreek osmopolymer. The present invention also provides processes for preparing such compositions. Detailed Description of the Invention

The present invention provides an osmotically controlled drug delivery system comprising:

• one or more active agents;

• fenugreek osmopolymer; and

· at least one selectively permeable membrane

The osmotically controlled drug delivery systems of the present invention can be employed to deliver one or more active agents such as, but not limited to, anti-cancer agents, antitussives, antihistamine agents, decongestants, alkaloids, laxatives, vitamins, antacids, anti-cholesterplemic agens, anti-lipid agents, antiarrhythmics, antipyretics, analgesics, appetite suppressants, expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatory substances, anti-infectives, stimulants, gastrointestinal agents, sedatives, antidiarrheal preparations or agents, anti-anginal drugs, vasodialators, antihypertensive drugs, vasoconstrictors, anti-cholinergic agents, migraine treatment agents, antibiotics, tranquilizers, anti-psychotics, antitumor drugs, anticoagulants, antithrombotic drugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hypoglycemic agents, thyroid and antithyroid preparation, diuretics, antispasmodics, uterine relaxants, mineral and nutritional additives, antiobesity drugs, anabolic drugs, erythropoietic drugs, antiasthmatics, cough suppressants, mucolytics, anti-uricemic drugs, anti-viral drugs, minerals, nutraceuticals, oral care agents and the like or combinations thereof.

The osmotically controlled drug delivery systems of the present invention can be employed to deliver a variety of active agents such as, but not limited to, nifedipine, verapamil, oxybutynin, pseudoephedrine, brompheniramine, glipizide, prazosin, enalapril, diltiazem, albuterol, famotidine, omeprazole, lansoprazole; sucralfate, misoprostol; prucalopride, clarithromycin, amoxicillin, tetracycline, metronidazole; diphenoxylate, loperamide; glycopyrrolate, ondansetron, ibuprofen, naproxen, ketoprofen. indomethacin, diclofenac, sulindac, tolmetin, mefenamic acid, diflunisal, piroxicam, meloxicam, pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, astemizole, terfenadine, fexofenadine, loratadine, desloratadine, cetirizine, carbamazepine, oxcarbazepine, phenytoin, phensuximide, perphenazine, erythromycin, acyclovir, azithromycin, doxycycline, acetaminophen, atovaquone.tamsulosin, oxytetracycline, paroxetine, pentoxifylline, prednisolone, rofecoxib, sulfamethoxazole, sulfisoxazole, tacrolimus, chlorothiazide, ciprofloxacin, clavulanate, fluconazole, griseofulvin, nevirapine, ziprasidone, ceclor, cefdinir, cefodoxime proxetil, cefprozil, cefibuten, colistin sulfate, megestrol acetate, mesalamine, trovafloxacin mesylate, mycophenolate mofetil and the like or combinations thereof in the form of free acid or free base or pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable salts of prodrugs, active metabolites, polymorphs, solvates, hydrates, enantiomers, Optical isomers, tautomers or racemic mixtures thereof. In one embodiment one or more active agents within any dose range can be delivered with the osmotically controlled drug delivery system of the present invention comprising fenugreek osmopolymer. In a further embodiment one or more active agents within any water solubility range can be delivered with the osmotically controlled drug delivery system of the present invention comprising fenugreek osmopolymer. The osmotically controlled drug delivery systems of the present invention can be employed for systemic, local or targeted delivery of a variety of active agents.

Fenugreek osmopolymer isolated from seeds of Fenugreek or Trigonella foenum- graceum is employed in osmotically controlled compositions of the present invention. Fenugreek or Trigonella foenum-graceum is an herbaceous plant of the leguminous family and is one of the oldest cultivated plants and through the ages has found wide applications as a food, a food additive and as a traditional medicine in every region where it has been cultivated.

The term "fenugreek osmopolymer" as used in the present invention refers to an excipient obtained from fenugreek or Trigonella foenum-graceum seeds comprising fenugreek dietary fibers such as soluble fenugreek dietary fibers, insoluble fenugreek dietary fibers or any combinations thereof. In one embodiment, fenugreek osmopolymer comprises fenugreek fibers. The soluble fenugreek dietary fiber that may be present in the fenugreek osmopolymer includes, but is not limited to, fenugreek galactomannans. The insoluble fenugreek dietary fiber that may be present in the fenugreek osmopolymer includes, but is not limited to, cellulose, hemicellulose, lignin and the like or any combinations thereof. In one embodiment, fenugreek osmopolymer comprises at least about 30% by weight of fenugreek dietary fibers such as soluble fenugreek dietary fibers, insoluble fenugreek dietary fibers or any combinations thereof. In another embodiment, fenugreek osmopolymer comprises at least about 50% by weight of fenugreek dietary fibers such as soluble fenugreek dietary fibers, insoluble fenugreek dietary fibers or any combinations thereof. In a further embodiment, fenugreek osmopolymer comprises at least about 75% by weight of fenugreek dietary fibers such as soluble fenugreek dietary fibers, insoluble fenugreek dietary fibers or any combinations thereof. In one embodiment, fenugreek osmopolymer comprises at least about 85% by weight of fenugreek dietary fibers such as soluble fenugreek dietary fibers, insoluble fenugreek dietary fibers or any combinations thereof. In yet another embodiment, fenugreek osmopolymer comprises at least about 90% by weight of fenugreek dietary fibers such as soluble fenugreek dietary fibers, insoluble fenugreek dietary fibers or any combinations thereof. In another embodiment, fenugreek osmopolymer comprises at least about 95% by weight of fenugreek dietary fibers such as soluble fenugreek dietary fibers, insoluble fenugreek dietary fibers or any combinations thereof.

In one embodiment the fenugreek osmopolymer employed in the composition of the present invention has a viscosity of at least 10,000 cps at 2%w/v at 25°C. In a further embodiment the fenugreek osmopolymer employed in the composition of the present invention has a viscosity of at least 50,000 cps at 2%w/v at 25°C. In another embodiment the fenugreek bsmopolymer employed in the composition of the present invention has a protein content of not more than about 10% by weight of the osmopoiymer. In a further embodiment the fenugreek osmopoiymer employed in the composition of the present invention is substantially free of 4-hydroxyisoleucine, saponins and alkaloids. The term "substantially free" as used herein means the fenugreek osmopoiymer employed in the compositions of the present invention contain not more than 1 % by weight, preferably not more than 0.4% by weight of 4-hydroxyisoleucine, not more than 5% by weight, preferably not more than 1 % by weight, more preferably not more than 0.5% by weight of alkaloids such as trigonelline and not more than 5% by weight, preferably not more than 1 % by weight, more preferably not more than 0.5% by weight of saponins such as diosgenin.

The fenugreek osmopoiymer may be present in the compositions of the present invention in an amount of about 5% to about 95% by weight of the osmotically controlled drug delivery system.

In one embodiment, the fenugreek osmopoiymer employed in the osmotically controlled drug delivery system of the present invention comprises soluble dietary fibers and insoluble dietary fibers. In a further embodiment, the fenugreek osmopoiymer employed in the osmotically controlled drug delivery system of the present invention comprises soluble dietary fibers and insoluble dietary fibers wherein the total dietary fibers including soluble and insoluble dietary fibers are present in an amount of at least about 30% by weight of the fenugreek osmopoiymer. In one embodiment, the fenugreek osmopoiymer employed in the osmotically controlled drug delivery system of the present invention comprises soluble dietary fibers and insoluble dietary fibers wherein the total dietary fibers are present in an amount of at least about 50% by weight of the fenugreek - osmopoiymer. In another embodiment, the fenugreek osmopoiymer employed in the osmotically controlled drug delivery system of the present invention comprises soluble dietary fibers and insoluble dietary fibers wherein the total dietary fibers are present in an amount of at least about 75% by weight of the fenugreek osmopoiymer. In another embodiment, the fenugreek osmopoiymer employed in the osmotically controlled drug delivery system of the present invention comprises soluble dietary fibers and insoluble dietary fibers wherein the total dietary fibers are present in an amount of at least about 85% by weight of the fenugreek osmopoiymer. In another embodiment, the fenugreek osmopolymer employed in the osmotically controlled drug delivery system of the present invention comprises soluble dietary fibers and insoluble dietary fibers wherein the total dietary fibers are present in an amount of at least about 90% by weight of the fenugreek osmopolymer. In another embodiment, the fenugreek osmopolymer employed in the osmotically controlled drug delivery system of the present invention comprises soluble dietary fibers and insoluble dietary fibers wherein' the total dietary fibers are present in an amount of at least about 95% by weight of the fenugreek osmopolymer.

In one embodiment of the present invention, the fenugreek osmopolymer when comprising soluble and insoluble dietary fibers, the ratio of insoluble dietary fiber to soluble dietary fiber in the fenugreek osmopolymer is about 0.05 to about 5. In another embodiment of the present invention, this ratio of insoluble dietary fiber to soluble dietary fiber is about 0.1 to about 4. In further embodiment of the present invention; this ratio of insoluble dietary fiber to soluble dietary fiber is about 0.5 to about 4. In another embodiment of the present invention, this ratio of insoluble dietary fiber to soluble dietary fiber is about 0.8 to 3. In yet another embodiment, this ratio of insoluble dietary fiber to soluble dietary fibers is about 1 to about 3. In a further embodiment, this ratio of insoluble dietary fiber to soluble dietary fibers is about 0.05 to about 1. In another embodiment, this ratio of insoluble dietary fiber to soluble dietary fibers is about 0.075 to about 0.8. In a further embodiment, this ratio of insoluble dietary fiber to soluble dietary fibers is about 0.1 to about 0.6. In a further embodiment, fenugreek fibers can be incorporated in the compositions of the present invention in any suitable form not restricted to powder and granules. Without being bound to any theory, it is believed that the fenugreek osmopolymer employed in the present osmotically controlled drug delivery systems hydrates and swells and exerts force or push required for the delivery of the active present in the same or adjacent components of the delivery system depending of the design of the osmotically controlled drug delivery system, thereby resulting in controlled release delivery of the active. In addition to swelling and hydrating, fenugreek osmopolymer may also cause imbibition of water thereby providing an osmotic pressure based driving force for influx of water in the drug delivery system. The fenugreek osmopolymer may maintain a concentration gradient across the selectively permeable membrane. However, without being bound to any theory it is believed that the fenugreek osmopolymer employed in the present delivery systems at least hydrates and/or swells and exerts force or push required for the delivery of the active while optionally functioning as an osmogent or osmotic pressure driving excipient. The fenugreek osmopolymer also assists in maintaining active agent uniformity in the hydrated formulation within the selectively permeable membrane.

The fenugreek osmopolymer may be useful for the osmotically controlled delivery of actives within all water solubility ranges and within all dose ranges. The osmotically controlled drug delivery system of the present invention comprises in addition to one or more active agents, fenugreek osmopolymer, at least one selectively permeable membrane. The selectively permeable membrane is selective to the passage of water (solvent) and not to solutes/active agents. In one embodiment, the selectively permeable membrane is applied in the form of a coat.

In one embodiment, the selectively permeable membrane depending on the design of the delivery system can be a single-layered membrane or wall. In another embodiment, the selectively permeable membrane depending on the design of the delivery system can be in the form of a composite wall. In a further embodiment, the selectively permeable membrane can be in the form of multilayered composite. In another embodiment, the selectively permeable membrane can be in the form of a laminate. In a further embodiment, the selectively permeable membrane can be in the form of an asymmetric structure/membrane. Numerous polymers can be employed to form semipermeable membranes such as but not limited to, cellulose ethers, cellulose esters, cellulose ester-ethers, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, and mono-, di-,and tricellulose alkanylates, ethyl cellulose, ethyl cellulose and hydroxypropyl cellulose, acetaldehyde dimethyl cellulose acetate, cellulose acetate ethyl carbamate, cellulose dimethylamino acetate, polyamides, polyurethanes, sulfonated polystyrenes, cellulose acetate butyrate, agar acetate, amylose triacetate, beta glucan acetate, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminacetate, cellulose acetate chloracetate, cellulose dipalmatate, cellulose dioptanoate, cellulose dicaprylate, cellulose pentanalate, cellulose acetate valerate, cellulose propionate succinate, cellulose acetate p-toluene sulfonate, selectively permeable polymers formed by co-precipitation, polystyrene derivatives, poly(sodium styrene sulfonate), poly(vinylbenzyltri methyl ammonium chloride), acrylate latexes and the like or combinations thereof.

In one embodiment, the polymers employed to form semipermeable membrane are cellulose acetate, cellulose acetate butyrate, and the like or combinations thereof.

In one embodiment, the selectively permeable membrane forms a coat on the core comprising one or more active agents and fenugreek osmopolymer. In another embodiment, the selectively permeable membrane polymers can be employed for coating along with additional pharmaceutically acceptable excipients such as, but not limited to, plasticizers, pigments, flux regulators, surfactants and the like or mixtures thereof. Suitable plasticizers that may be employed include, but are not limited to, triethyl citrate, triacetin, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diethyl sebacate, straight chain phthalates of six to eleven carbons, diisononyl phthalate, diisodecyl phthalate, citric acid esters, dioctyl azelate, epoxidized tallate, triisoctyl trimellitate, triisononyl trimellitate, sucrose acetate isobutyrate, epoxidized soybean oil, and the like or mixtures thereof. Solvents suitable for applying semipermeable membrane include, but are not limited to, acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1 ,4-dioxane, tetrahydrofuran, diglyme, water, and mixtures thereof such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene dichloride and methanol and the like, or combinations thereof. Suitable flux regulators that may be employed include, but are not limited to, polyhydric alcohols, polyalkylene glycols, polyalkylenediols, polyesters of alkylene glycols, polyethylene glycol, poly(ethylene glycol-co-propylene glycol), polypropylene glycol, polybutylene glycol, polyamylene glycol, poly(1 ,3-propanediol), poly(1 ,4-butanediol), poly(1 ,6-hexanediol), 1 ,3-butylene glycol, 1 ,4-pentamethylene glycol, 1 ,4-hexamethylene glycol, glycerine, 1 ,2,3-butanetriol, 1 ,2,4-hexanetriol, 1 ,3,6- hexanetriol, ethylene glycol dipropionate, ethylene glycol butyrate, butylene glucol dipropionate, glycerol acetate esters, and the like, or any combinations thereof. Suitable surfactants include, but are not limited to, cationic, anionic, amphoteric or zwitterionic surfactants. Non-limiting examples of surfactants include, but are not limited to, sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, sorbic acid, sorbitan fatty acid ester, and mixtures thereof.

In a further embodiment, the semi-permeable membrane of the osmotically controlled drug delivery system is applied by molding, forming, spraying, dipping methods.

In another embodiment, the selective water permeable membrane optionally comprises at least one orifice, aperture, pore, bore, hole or passageway suitable for releasing the drug or active agent into the use environment. In one embodiment, at least one orifice is manually or mechanically made or drilled by methods, such as, but not limited to, mechanical drilling, laser drilling, use of modified punches and the like. In a further embodiment, one or more orifices are generated in-situ. In one embodiment the size of the orifice may vary depending on the release profile desired. In one embodiment, an erodible element such as, but not limited to, a gelatin plug erodes to yield the orifice in the environment of use. In an embodiment, the osmotic passageway in the osmotic delivery system is formed in the environment of use in response to the hydrostatic pressure generated in the delivery system. In a further embodiment, controlled porosity pores are formed in-situ in the selectively permeable membrane to release the active agent or drug into the environment of use wherein such pores are formed with the incorporation of water-soluble additives such as, but not limited to, pore formers in the semipermeable membrane wall. Suitable pore formers include, but are not limited to, mannitol, sorbitol, pentaerythritol, organic aliphatic and aromatic acids, saccharides and the like or combinations thereof. In one embodiment, the pores may be formed in the selectively permeable membrane due to gas generation or volatilization mechanisms.

In one embodiment the osmotically controlled drug delivery systems of the present invention may further optionally comprise additional osmogents such as, but not limited to, organic compounds, inorganic salts, sugars and carbohydrates, amino acids, organic hydrophilic polymers and the like or combinations thereof. Non limiting examples of inorganic salts include magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium chloride, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, potassium phosphate, sodium phosphate, sodium sulfate, potassium sulfate and the like or combinations thereof. Non limiting examples of sugars and carbohydrates include mannitol, sorbitol, xylitol, inositol, raffinose, sucrose, glucose, fructose, lactose, and the like or combinations thereof. Non limiting examples of amino acids include, but are not limited to, glycine, leucine, alanine, methionine, and the like or combinations thereof. Non limiting examples of organic compounds include urea, organic acids and salts thereof, organic hydrophilic polymers and the like or combinations thereof. Organic acids and salts thereof include, but are not limited to, tartaric acid, fumaric acid, citric acid, adipic acid, calcium lactate, sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, sodium ascorbate, and the like or combinations thereof. Organic hydrophilic polymers that may ^' be optionally employed as osmogent include, but are not limited to, sodium carboxy ^? methylcellulose, hydroxypropyl methylcellulose, hydroxyl ethyl cellulose, hydroxyethyl methylcellulose, cross-linked polyvinyl pyrrolidone, polyethylene oxide, carbopol, polyacrylamide, and the like or combinations thereof. Organic hydrophilic polymers of different viscosities may be employed. The composition of the present invention may further include at least one pharmaceutically acceptable excipient to ease the manufacturing process as well as to improve the performance of the delivery system. Common pharmaceutically acceptable excipients that may be employed include,, but are not limited to, diluents, lubricants, binders, colorants, flavorants, surfactants, pH adjusters, anti-adherents, gildants, disintegrants, solubilizers, stabilizers, wicking agents and the like.

The present invention may include one or more diluents including, but not limited to, lactose, lactose monohydrate, sugar, dextrate, dextrate hydrated, dextrins, fructose, lactitol, corn starch, modified corn starch, inorganic salts such as calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate and/or cellulose derivatives such as wood cellulose and microcrystalline cellulose, and the like, or mixtures thereof. Binders employed in the dosage form include, but are not limited to, starch, microcrystalline cellulose, highly dispersed silica, lactose, polyethylene glycol, polyvinylpyrrolidone, vinyl copolymers, copovidone, cross-linked carboxymethylcellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, natural or synthetic gums and the like or mixtures thereof. Lubricants employed in the dosage form include, but are not limited to, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, polyethylene glycol, colloidal silicon dioxide, sodium stearyl fumarate, carnauba wax and the like and mixtures thereof. Compositions of the present invention may optionally also include a glidant such as, but not limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof. Compositions of the present invention may optionally also include anti-adherents such as, but are not limited to, talc, magnesium stearate or finely divided silica, or combinations thereof. Disintegrants that may be employed include, but are not limited to natural, modified or pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose and calcium silicate. Suitable surfactants include, but are not limited to, cationic, anionic amphoteric or zwitterionic surfactants. Non-limiting examples of surfactants include, but are not limited to, sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, sorbic acid, sorbitan fatty acid ester, and mixtures thereof. pH adjusters include, but are not limited to, sodium citrate, magnesium oxide, citric acid or combinations thereof. One or more flavorants - employed, include but are not limited to, mint flavor, orange flavor, lemon flavors, · strawberry aroma, vanilla flavor, raspberry aroma, cherry flavor, tutty frutty flavor, magnasweet 135, key lime flavor, grape flavor, trusil art 511815, and fruit extracts. One or more colorants employed, include, but are not limited to, titanium dioxide, dyes, lake pigments or natural colors. Depending on the solubility of the active agent to be delivered, solubility enhancing agents, such as, but not limited to, surfactants, pH modifiers, complexing agents and the like or combinations thereof may be employed. Complexing agents such as, but not limited^ to, cyclodextrins, cyclic amides, hydroxy

i

benzoic acid derivatives, and the like may be employed. Non-limiting examples of cyclodextrins include, but are not limited to, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, or their derivatives, such as, but not limited to, hydroxypropyl beta cyclodextrins, and the like or mixtures thereof. Suitable wicking agents that may be employed include, but are not limited to, colloidal silicon dioxide, kaolin, titanium dioxide, alumina, low molecular weight poiy(vinylpyrrolidone), bentonite and the like or combinations thereof. In one embodiment, the osmotically controlled drug delivery system may be for delivery by any route of administration, such as, but not limited to, oral, buccal, sublingual, parentral, transdermal, and the like. In a further embodiment, the osmotically controlled drug delivery system is for controlled administration of the drug by implantation. In a further embodiment, the osmotically controlled drug delivery system may be in the form of tablets, capsules, pellets, minitablets, and the like. In another embodiment, the osmotically controlled delivery system of the present invention may be a monolithic, bilayered, multilayered or multiparticulate system, wherein the active agent is delivered in an osmotically controlled 'manner. In a further embodiment, the osmotically controlled delivery systems of the present invention comprising fenugreek osmopolymer may be in the form of solid, liquid or semisolid dosage form, wherein the release of the active agent is osmotically controlled.

In one embodiment, the osmotically controlled drug delivery system of the present invention is in the form of an elementary osmotic pump. In another embodiment, the osmotically controlled drug delivery system in the form of elementary osmotic pump comprises an osmotic core coated with a semipermeable membrane; wherein the osmotic core comprises one or active agents, fenugreek osmopolymer and optionally at least one pharmaceutically acceptable excipient and the delivery of the active agent occurs from the delivery orifice in the membrane. ,

In another embodiment, the osmotically controlled drug delivery system of the present invention is in the form of a push-pull osmotic pump. In one embodiment, the push-pull type osmotically controlled drug delivery system comprises a bilayered tablet core coated with a semipermeable membrane. One layer of such a bilayered tablet core comprises one or more active agents, optionally fenugreek osmopolymer or other osmogents and at least one pharmaceutically acceptable excipient and the other push layer of the bilayered tablet comprises fenugreek osmopolymer, optionally additional osmogents and at least one pharmaceutically acceptable excipient. The drug layer delivers the active to the outside use environment by a delivery orifice in the semipermeable membrane. In one embodiment, the push-pull type osmotically controlled drug delivery system comprises a multilayered tablet core coated with a semipermeable membrane. In one embodiment, the push-pull type osmotically controlled drug delivery system is in the form of delayed release system. In another embodiment, the push-pull type delayed release osmotically controlled drug delivery system comprises an enteric polymer coating over the semipermeable membrane covering the biiayered or multilayered tablet core. In a further embodiment, the osmotically controlled drug delivery system of the present invention is in the form of a sandwiched osmotic tablet. In another embodiment, the sandwiched osmotically controlled drug delivery system of the present invention comprises a push layer sandwiched between two active layers and coated with a semipermeable membrane; wherein the push layer comprises fenugreek osmopolymer, optionally additional osmogents and at least one pharmaceutically acceptable excipient and the active layers comprise same or different active agents, optionally fenugreek osmopolymer or other osmogents and at least one pharmaceutically acceptable excipient. The two active layers deliver same or different active agents to the outside use environment by two delivery orifices on either side in the semipermeable membrane.

In another embodiment, the osmotically controlled drug delivery system of the present invention is in the form of a controlled porosity osmotic pump. In one embodiment, the controlled porosity osmotic pump comprises pore-formers or water soluble additives in the semi-permeable membrane which dissolve after coming in contact with aqueous fluid of the use environment resulting in an in-situ formation of a microporous membrane through which drug release then takes place.

In a further embodiment, the osmotically controlled drug delivery system of the present invention is in the form of osmotic bursting osmotic pump. In another embodiment, the osmotic bursting osmotic pump has a structure similar to that of elementary osmotic pump described above except that the delivery orifice is absent. When placed in an aqueous use environment, such a osmotic bursting pump imbibes water and hydraulic pressure is built up in the core that ruptures the wall and releases the active in the use environment. Varying thickness and area of the semipermeable membrane controls the release of the active.

In one embodiment, the osmotically controlled drug delivery system of the present invention can be used for targeting drug delivery to a specific area in the gastrointestinal tract, such as but not limited to, targeting to the colon, or the like. In another embodiment, the osmotically controlled delivery system for colon targeting system in the form of capsule comprises a single osmotic unit or multiple osmotic units filled therein, wherein an osmotic unit comprises a drug core comprising one or more actives, fenugreek osmopolymer, optionally additional osmogents and at least one pharmaceutically acceptable excipient. Such an osmotically controlled delivery system for colon targeting system is further enterieally coated.

Enteric polymers that may optionally be employed in the osmotically controlled delivery systems of the present invention inciude, but are not limited to, includes, but is not limited to, polyacrylic acid, polymethacrylic acid polymer, cellulose polymer, maleic acid copolymer, polyvinyl polymer, or derivative or a combination thereof. Suitable enteric polymers include, but are not limited to, cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, ethylhydroxycellulose phthalate, carboxymethyl ethyl cellulose, ^■·^■ hydroxymethylethylcellulose phthalate, cellulose acetate maleate, cellulose benzoate · phthalate, cellulose propionate phthalate, polyvinyl alcohol phthalate, polyvinylacetal ^* phthalate, poly vinylbuty rate acetate, polyvinylacetate phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, methyl acrylate acrylic acid copolymer, methyl " acrylate methacrylic acid copolymer, methacrylic acid methyl methacrylate copolymer, methacrylic acid ethyl acrylate copolymer, methyl acrylate methacrylic acid octyl acrylate copolymer, and the like or a combination thereof.

In one embodiment, the osmotically controlled drug delivery system of the present invention can be in a form that delivers drugs as liquid formulations. In a further embodiment, the osmotically controlled drug delivery system of the present invention comprises a liquid drug formulation or formulation with drug in a dissolved state in a soft gelatin or hard gelatin capsule, further covered with a barrier layer, an osmotic layer arid a semi-permeable membrane coating The osmotic layer in such a delivery system comprises fenugreek osmopolymers. The drug dispersion or liquid drug formulation may also optionally comprise fenugreek osmopolymer.

In another embodiment barrier layer if employed in the osmotically controlled drug delivery systems of the present invention, it may be employed in order to restrict entry of water into certain parts of the delivery; system or to separate the active agent layer from the osmotic layer. Suitable barrier layer formers that may be employed in the composition of the present include, but are not limited to, high-density polyethylene, waxes, rubber and the like or combinations thereof.

In a further embodiment, the osmotically controlled drug delivery system of the present invention is in the form of multi-particulate delayed release system. In another embodiment, the multiparticulate delayed release osmotic dosage form comprises pellets of one or more active agents coated with semipermeable membrane, wherein the pellets comprise one or more active agents, fenugreek osmopolymer, optionally additional osmogents and at least one pharmaceutically acceptable excipient. Such pellets after coming in contact with the aqueous use environment, imbibe water osmotically resulting in rapid expansion of the membrane and leading to the formation of pores, through which the delivery of the drug in a controlled manner occurs. In one embodiment, the osmotically controlled drug delivery system of the present invention is in the form of a telescopic capsule for delayed release. Such an osmotic dosage form comprises two chambers, the first comprises one or more active agents, optionally fenugreek fibers, at least one pharmaceutically acceptable excipient and an orifice and the second chamber comprises fenugreek osmopolymer and optionally additional osmogens and at least one pharmaceutically acceptable excipient; wherein a barrier layer of hydrophobic excipient as listed above separates the two sections.

In one embodiment, the osmotically controlled drug delivery system is in the form of a single chamber osmotic delivery system. In a further embodiment, the single chamber osmotic delivery system is in the form of, but not limited to, an elementary osmotic pump, and the like: In another embodiment, the osmotically controlled drug delivery system of the present invention is in the form of a multi-chamber osmotic delivery system. In a further embodiment, the multi-chamber chamber osmotic delivery system is in the form of, but not limited to, push-pull type osmotic delivery system, sandwiched osmotic delivery system, and the like.

In yet another embodiment of the present invention, the dosage form may be optionally coated. Surface coatings may be employed for aesthetic purposes or for dimensionally stabilizing the compressed dosage form or for retarding the drug release. The surface coating may be any conventional coating which is suitable for enteral use. The coating may be carried out using any conventional technique employing conventional ingredients. A surface coating can for example be obtained using a quick-dissolving film using conventional polymers such as, but not limited to, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, poly methacrylates or the like.

In one embodiment, the compositions of the present invention release the active agent in a controlled manner over a period of up to about 24 hours. In another embodiment, the compositions of the present invention release the active agent in a controlled manner over a period of up to about 4 to about 24 hours.

In another embodiment, the compositions of the present invention are prepared by methods, such as but not limited to, direct compression, wet granulation, dry granulation, ^'» extrusion melt granulation and the like or any combinations thereof.

In a further embodiment, the present invention provides a process for preparing an osmotically controlled delivery system of the present invention comprising fenugreek osmopolymer. In one embodiment, the present invention provides a process comprising blending one or more active agents, fenugreek osmopolymer, optionally one or more osmogent and at least one pharmaceutically acceptable excipient, lubricating and compressing the blend to form a tablet core, followed by coating with a selectively permeable membrane and optionally mechanically drilling an orifice in the membrane. In another embodiment, the present invention provides a process comprising a) blending one or more active agents, optionally fenugreek osmopolymer, optionally one or more osmogent and at least one pharmaceutically acceptable excipient to form the drug layer blend; b) blending fenugreek osmopolymer, optionally one or more osmogent and at least one pharmaceutically acceptable excipient to form the swelling or push layer blend; c) compressing the drug layer and push layer blend to form a bilayered core tablet; d) coating the tablet core with a selectively permeable membrane and optionally mechanically drilling an orifice in the membrane.

In one embodiment, the compositions of the present invention may be employed to deliver one or more active agents. The compositions of the present invention are useful for the treatment of humans or animals. In yet another embodiment, the present invention discloses use of fenugreek osmopolymer for the manufacture of a medicament that delivers one or more active agent in an osmotically controlled manner. Still another embodiment of the present invention discloses a method of using compositions of the present invention employing, fenugreek osmopolymer comprising administering to a subject in need thereof an effective amount of the composition depending on the active agent used. In one embodiment the present invention discloses a method of preparing osmotically controlled compositions incorporating fenugreek osmopolymer in the compositions along with one or more active agents, at least one pharmaceutically acceptable excipient and at least one selectively permeable membrane. According to a further aspect of the invention there is provided a method of treatment or prophylaxis of a disease which comprises administration of osmotically controlled delivery system of the invention comprising fenugreek osmopolymer, at least one selectively permeable membrane and one or more active agent which is effective against said disease to a patient in need of such treatment.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in₀the art and are intended to be included within the scope of the present invention. The invention is further illustrated by the following examples, which are for illustrative purposes and should not be construed as limiting the scope of the invention in any way.

EXAMPLES Example 1 : Oral osmotic delivery system of verapamil

A) Formulation of drug core

Table 1 : Composition of drug core

Ingredients mg/tablet

Verapamil hydrochloride 120

Fenugreek osmopolymer 60

Mannitol, USP 52

Polyvinylpyrrolidone K30, USP 15

Magnesium stearate, USP 3

Total 250 Procedure: Weighed quantities of the active ingredient, mannitol, fenugreek osmopolymer were screened and blended to form a homogenous blend. Solution of polyvinylpyrrolidone in isopropyl alcohol was used to wet granulate the above blend formed. The granules were dried and sized and lubricated with magnesium stearate and compressed into tablet core.

B) Formulation of the osmotic delivery system

Table 2: Composition of selectively permeable membrane coat

Procedure: Cellulose acetate, and polyethylene glycol in proportions as shown in Table 2 above were dissolved in a mixture of acetone and methanol (80:20 w/w) to prepare 3.5% w/w selectively permeable membrane coating composition. The tablet core formed in previous step was spray coated with this selectively permeable membrane coating composition to 10 % weight gain. The coated dosage form was dried An orifice of about 0.6 mm was drilled through the selectively permeable membrane wall to connect the" drug core with the exterior of the dosage form.

Example 2: Oral osmotic delivery system of pseudoephedrine

A) Formulation of drug core

Table 3: Composition of drug core

Ingredients mg/tablet

Pseudoephedrine hydrochloride 120

Fenugreek osmopolymer 50

Sodium chloride, USP 15

Polyvinylpyrrolidone K30, USP 12

Magnesium stearate, USP 3

Total 200 Procedure: Weighed quantities of the active ingredient, fenugreek osmopolymer, sodium chloride were screened and blended to form a homogenous blend. Solution of polyvinylpyrrolidone in isopropyl alcohol was used to wet granulate the above blend formed. The granules were dried and sized and lubricated with magnesium stearate and compressed into tablet core.

B) Formulation of the osmotic delivery system

Table 4: Composition of selectively permeable membrane coat

Procedure: Cellulose acetate, polyethylene glycol and triethyl citrate in proportions as shown in Table 4 above were dissolved in acetone to prepare a 3.5% w/w selectively permeable membrane coating composition. The tablet core formed in previous step was spray coated with this selectively permeable membrane coating composition to 12 % weight gain. The coated dosage form was dried to form ora!_^osmotic delivery system of pseudoephedrine.

Example 3: Oral osmotic delivery system of Nifedipine

A) Formulation of bilayered tablet core

a) Formulation of drug layer

Table 5: Composition of drug layer containing nifedipine

Procedure: Weighed quantities of active ingredient, fenugreek osmopolymer, sodium lauryl sulphate and sodium chloride were screened and blended to form a homogenous blend. Solution of polyvinylpyrrolidone in isopropyl alcohol was used to wet granulate the above blend formed. The granules were dried and sized. The granules were lubricated with magnesium stearate. b) Formulation of push or swelling layer

Table 6: Composition of push or swelling layer

Procedure: Fenugreek osmopolymer and copovidone were blended and then lubricated with magnesium stearate. c) Formulation of bilayered tablet cores

The lubricated drug layer blend and push layer blend were compressed to form a tablet core.

B) Formulation of the osmotic delivery system

Table 7: Composition of selectively permeable membrane coat

Procedure: Cellulose acetate and polyethylene glycol in proportions as shown in Table 7 above were dissolved in acetone to prepare a 4%w/w selectively permeable membrane coating composition. The bilayered tablet core formed in previous step was spray coated with this selectively permeable membrane coating composition to a 12% weight gain. The coated dosage form was dried. An orifice of about 0.6 mm was drilled through the selectively permeable membrane wall on the drug layer side of the tablet core to form an oral osmotic delivery system of Nifedipine. Example 4: Oral osmotic delivery system of Oxybutynin Chloride

A) Formulation of bilayered tablet core

a) Formulation of drug layer

Table 8: Composition of drug layer containing oxybutynin chloride

Procedure: Polyethylene oxide, hypromellose, sodium chloride were sifted and blended. This blend was then granulated with solution of oxybuytnin chloride in ethanol. The granulated mass was sieved, dried and the granules were then lubricated with magnesium stearate. b) Formulation of push or swelling layer

Table 9: Composition of push or swelling layer

Procedure: Fenugreek osmopoiymer and sodium chloride were sifted. Ferric oxide was co-sifted with hypromellose. All the sifted ingredients were blended and granulated with ethanol. The granulated mass was sieved, dried and the granules were then lubricated with magnesium stearate. c) Formulation of bilayered tablet cores

The lubricated drug layer blend and push layer blend were compressed to form a tablet core. B) Formulation of the osmotic delivery system

Table 10: Composition of selectively permeable membrane coat

Procedure: Cellulose acetate and polyethylene glycol in proportions as shown in Table 10 above were dissolved in acetone to prepare a 4%w/w selectively permeable membrane coating composition. The bilayered tablet core formed in previous step was spray coated with this selectively permeable membrane coating composition to a 16% weight gain. The coated dosage form was dried. An orifice of about 0.6 mm was drilled through the selectively permeable membrane wall on the drug layer side of the tablet core to form an oral osmotic delivery system of oxybutynin chloride.

Dissolution study of these oxybutynin chloride tablets was carried out in 50ml simulated gastric fluid without enzyme in USP apparatus 7 at rpm of 30 cycles per minute of 2-3 cm amplitude at 37.0 ° C. The in-vitro release profile as shown beneath was observed.

This indicates that the fenugreek osmopolymer employed in the present osmotically controlled drug delivery system hydrates and swells and exerts force or push required for the delivery of the active agent present in the adjacent drug layer component of the delivery system through the selectively permeable membrane, thereby resulting in controlled release delivery of the active.

Claims

We claim: 1) An osmotically controlled drug delivery system comprising:

one or more active agents;

fenugreek osmopolymer; and

at least one selectively permeable membrane. 2) The delivery system of claim 1 wherein said active agent is an anti-cancer agent, an antitussive, antihistamine agent, decongestant, alkaloid, laxative, vitamin, antacid, anti-cholesterolemic agent, anti-lipid agent, antiarrhythmic, antipyretic, analgesic, appetite suppressant, expectorant, anti-anxiety agent, anti-ulcer agent, antiinflammatory substance, anti-infective, stimulant, gastrointestinal agent, sedative, antidiarrheal agent, anti-anginal drug, vasodialator, anti-hypertensive drug, vasoconstrictor, anti-cholinergic agent, migraine treatment agent, antibiotic, tranquilizer, anti-psychotic, antitumor drug, anticoagulant, antithrombotic drug, hypnotic, anti-emetic, anti-nauseant, anti-convulsant, neuromuscular drug, hypoglycemic agent, thyroid and antithyroid preparation, diuretic, antispasmodic, uterine relaxant, mineral and nutritional additive, antiobesity drug, anabolic drug, erythropoietic drug, antiasthmatic agent, cough suppressant, mucolytic, anti-uricemic drug, anti-viral drug, mineral, nutraceutical, oral care agent or combinations thereof.

3) The delivery system of claim 1 wherein said active agent is nifedipine, verapamil, oxybutynin, pseudoephedrine, brompheniramine, glipizide, prazosin, enalapril, diltiazem, albuterol, famotidine, omeprazole, lansoprazole; sucralfate, misoprostol; prucalopride, clarithromycin, amoxicillin, tetracycline, metronidazole; diphenoxylate, loperamide; glycopyrrolate, ondansetron, ibuprofen, naproxen, ketoprofen. indomethacin, diclofenac, sulindac, tolmetin, mefenamic acid, diflunisal, piroxicam, meloxicam, pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, astemizole, terfenadine, fexofenadine, loratadine, desloratadine, cetirizine, carbamazepine, oxcarbazepine, phenytoin, phensuximide, perphenazine, erythromycin, acyclovir, azithromycin, doxycycline, acetaminophen, atovaquone, tamsulosin, oxytetracycline, paroxetine, pentoxifylline, prednisolone, rofecoxib, sulfamethoxazole, sulfisoxazole, tacrolimus, chlorothiazide, ciprofloxacin, clavulanate, fluconazole, griseofulvin, nevirapine, ziprasidone, ceclor, cefdinir, cefodoxime proxetil, cefprozil, cefibuten, colistin sulfate, megestrol acetate, mesalamine, trovafloxacin mesylate, mycophenolate mofetil or combinations thereof.

4) The delivery system of claim 1 wherein the active agent is in the form of free acid or free base or pharmaceutically acceptable prodrug, pharmaceutically acceptable salt, pharmaceutically acceptable salt of prodrug, active metabolite, polymorph, solvate, hydrate, enantiomer, optical isomer, tautomer, racemic mixture thereof or combination thereof.

5) The delivery system of claim 1 wherein the fenugreek osmopolymer comprises fenugreek fibers. 6) The delivery system of claim 5 wherein the fenugreek fibers comprise soluble- fenugreek fibers, insoluble fenugreek fibers or combinations thereof.

7) The delivery system of claim 6 wherein the fenugreek fibers comprise insoluble fibers and soluble fibers in a ratio of insoluble fibers to soluble fibers of about 0.05 to about 5.

8) The delivery system of claim 1 wherein the fenugreek osmopolymer comprises not more than about 10% by weight of proteins. 9) The delivery system of claim 1 wherein the fenugreek osmopolymer is substantially free of 4-hydroxyisoleucine, saponins and alkaloids.

10) The delivery system of claim 1 wherein the selectively permeable membrane is of cellulose ether, cellulose ester, cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, monocellulose alkanylate, dicellulose alkanylate, tricellulose alkanylate, ethyl cellulose, hydroxypropyl cellulose, acetaldehyde dimethyl cellulose acetate, cellulose acetate ethyl carbamate, cellulose dimethylamino acetate, polyamide, polyurethane, sulfonated polystyrene, cellulose acetate butyrate, agar acetate, amylose triacetate, beta glucan acetate, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminacetate, cellulose acetate chloracetate, cellulose dipalmatate, cellulose dioctanoate, cellulose dicaprylate, cellulose pentanalate, cellulose acetate valerate, cellulose propionate succinate, cellulose acetate p-toluene sulfonate, polystyrene derivative, poly(sodium styrene sulfonate), poly(vinylbenzyltrimethyl ammonium chloride), acrylate latex or combinations thereof.

11 ) The delivery system of claim 10 wherein the selectively permeable membrane is of cellulose acetate, cellulose butyrate or combinations thereof.

12) The delivery system of claim 1 wherein the selectively permeable membrane is present in the form of a coat. 13) The delivery system of claim 1 wherein the selectively permeable membrane further comprises at least one orifice for releasing the active agent into the use environment.

14) The delivery system of claim 13 wherein the one or more orifices in the selectively permeable membrane are mechanically drilled or are generated in-situ.

15) The delivery system of claim 1 wherein the delivery system further comprises additional osmogents selected from organic compounds, inorganic salts, sugars and carbohydrates, amino acids, organic hydrophilic polymers or combinations thereof. 16)The delivery system of claim 1 wherein the delivery system further comprises at least one pharmaceutically acceptable excipient.

17) The delivery system of claim 16 wherein the pharmaceutically acceptable excipient is a diluent, lubricant, binder, colorant, flavorant, surfactant, pH adjuster, anti-adherent, gildant, disintegrant, solubilizer, stabilizer, or wicking agent.

18) The delivery system of claim 1 wherein the delivery system is in the form of a monolithic, bilayered, multilayered or multiparticulate system for delivery of the active agent in an osmotically controlled manner. 19) The delivery system of claim 1 wherein the delivery system is in the form of an elementary osmotic pump, push-pull type system or osmotic bursting osmotic pump.

20) The delivery system of claim 1 wherein delivery system releases the active agent in a controlled manner over a period of up to about 4 hours to about 24 hours.

21 ) Use of fenugreek osmopolymer for the manufacture of the delivery system of claim 1 for the delivery of one or more active agents in an osmotically controlled manner.