WO2013168179A2

WO2013168179A2 - Controlled release pharmaceutical formulations of antiviral agents

Info

Publication number: WO2013168179A2
Application number: PCT/IN2013/000219
Authority: WO
Inventors: Pratibha Sudhir Pilgaonkar; Maharukh Tehmasp Rustomjee; Anilkumar Surendrakumar Gandhi
Original assignee: Rubicon Research Private Limited
Priority date: 2012-04-03
Filing date: 2013-04-03
Publication date: 2013-11-14
Also published as: WO2013168179A3

Abstract

The present invention relates to controlled release formulation of direct acting antiviral agents, and to processes for preparation of the same. The present invention provides controlled release formulation comprising direct acting antiviral agents, at least one release modifier and at least one pharmaceutically acceptable excipient.

Description

CONTROLLED RELEASE PHARMACEUTICAL FORMULATIONS OF

ANTIVIRAL AGENTS

Field of the Invention

The present invention relates to controlled release pharmaceutical formulations of direct acting antiviral agents and processes for preparation of the same. Particularly the present invention relates to controlled release formulation of Hepatitis C Virus (HCV) NS3/4A and/or NS5A/5B protease inhibitors. The invention relates to controlled release formulations comprising at least one direct acting antiviral agent, at least one release modifier and at least one pharmaceutically acceptable excipient.

Background of the Invention

Hepatitis is a medical condition defined by the inflammation of liver and characterized by the presence of inflammatory cells in the tissue of the organ. Hepatitis can be self- limiting or can progress to more severe disease states such as liver fibrosis (scarring) and cirrhosis. It may occur with limited or no symptoms, but often leads to jaundice, anorexia (poor appetite) and malaise. It is considered to be acute when it lasts less than six months and chronic when it persists longer. It may be a result of a liver injury caused by toxins such as alcohol, certain medications or environmental toxins, interruption of organ's normal blood supply, trauma to the abdomen in the area of the liver or attack by an autoimmune disorder. But generally viral infection by a group of viruses known as the hepatitis viruses is believed to be the most prominent cause of hepatitis. There are five viruses that are known to infect the liver and cause hepatitis; hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), the delta hepatitis virus (HDV) and hepatitis E virus (HEV) among which the most common types are hepatitis A, hepatitis B, and hepatitis C. Hepatitis C is a liver disease caused by the hepatitis C virus (HCV), which is found in the blood of people affected with the disease and spreads through direct contact with the infected blood. HCV infection is recognized as the most common cause of both acute and chronic hepatitis and is a leading cause of death worldwide. People with HCV infection may occasionally have symptoms such as jaundice, abdominal pain, fatigue and fever. Upon first exposure to HCV only about 20% of infected individuals develop acute clinical hepatitis while others may resolve the infection spontaneously. However, in almost 70% of instances, the virus establishes a chronic infection that persist for decades which further results into recurrent and progressively worsening liver inflammation that eventually leads to life threatening states like cirrhosis and hepatocellular carcinoma. Chronic infection with HCV is one of the most important causes of chronic liver disease.

HCV is a spherical, enveloped, single-stranded RNA virus belonging to the Flaviviridae family. The HCV genome encodes a polyprotein of 3010-3033 amino acids. Structural proteins (core, envelope proteins E1 and E2), which form the viral envelope, are located at the N-terminus, while non-structural proteins involved in viral replication occupy the rest of the polyprotein. Further a p7 protein of HCV lies at the junction between the structural and non-structural regions of the virus polyprotein. Two regions of the E2 protein, designated hypervariable regions 1 and 2, have an extremely high rate of mutation. The envelope protein E2 also contains the binding site for CD-81 which is a tetraspanin receptor expressed on hepatocytes and B lymphocytes, natural targets of HCV, that acts as a receptor or coreceptor for HCV and aids in their attachment and/or cell entry. The HCV nonstructural (NS) proteins are derived by proteolytic cleavage of the polyprotein and include NS2, NS3, NS4A, NS4B, NS5A, NS5B, whose proteins function as helicase-, protease-, and RNA-dependent RNA polymerase. The HCV nonstructural proteins are presumed to provide the essential catalytic machinery for viral replication. Upon infection, viremia persists and is accompanied by variable degrees of hepatic inflammation and fibrosis. RNA-dependent RNA polymerase, an enzyme critical in HCV replication, lacks proofreading properties and generates a large number of mutant viruses known as quasispecies. HCV quasispeeies pose a major challenge to immune-mediated control of HCV and may explain the variable clinical course and the difficulties in vaccine development. Six distinct but related HCV genotypes and multiple subtypes have been identified on the basis of molecular relatedness.

The HCV NS protein 3 (NS3) contains a serine protease activity. This HCV NS3 serine protease and its associated cofactor NS4 help process the majority of the viral enzymes, and is thus considered essential for viral replication and infectivity. This processing appears to be analogous to that followed by the human immunodeficiency virus aspartyl protease, which is also involved in viral enzyme processing. HIV protease inhibitors, which inhibit viral protein processing, are potent antiviral agents in man indicating that interrupting this stage of the viral life cycle results in therapeutically active agents. Consequently HCV NS3/4A serine protease is also an attractive target for drug discovery. Use of interferon for treatment of HCV has been only established therapy till recent time. However, interferons are associated with significant side effects and further reported to induce long term remission in only a fraction (~ 25%) of cases. Recent introductions of the pegylated forms of interferon and the standard combination therapy of pegylated interferon alfa with ribavirin have also resulted in only modest improvements in remission rates and only partial reduction of side effects. Therefore, there is a need for more effective anti-HCV therapies. The addition of direct acting HCV protease inhibitors to the combination of pegylated interferon alfa and ribavirin is becoming the new standard of care for hepatitis. Particularly direct acting HCV protease inhibitors such as HCV NS3/4A serine protease inhibitors are useful as HCV antiviral agents.

Telaprevir and boceprevir are direct acting antiviral agents (DAA) approved by USFDA to treat chronic hepatitis C (CHC) in adult patients with compensated liver disease, including cirrhosis, who are treatment -naive or who are previously treated with interferon-based treatment. These HCV NS3/4A protease inhibitors are indicated, in combination with pegylated interferon alfa and ribavirin, for the treatment of genotype 1 CHC. These direct acting antiviral agents act by inhibiting the HCV NS3/4A serine protease, necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of non structural proteins essential for viral replication.

US Patent 7,820,671 discloses telaprevir, while boceprevir is disclosed in US Patent 7,012,066. Telaprevir is currently made available under the brand name Incivek in the US andjncivo in the Europe by Vertex Pharmaceuticals as immediate release oral tablets of 375 mg strength. The recommended dose of Incivek/ Incivo is 750 mg (two 375 mg film-coated tablets) to be taken orally 3 times a day (7-9 hours apart) with food. Boceprevir is currently available under the brand name Victrelis in the US and Europe from Merck as immediate release tablets of 200mg strength. The recommended dose of Victrelis is 800mg (four 200mg capsules) 3 times daily (every 7-9 hours) with food. Telaprevir is poorly water soluble drug with an aqueous solubility of 0.0047 mg/mL. Telaprevir is absorbed in the small intestine, with no evidence for absorption in colon. Maximum plasma concentrations after a single dose of telaprevir are generally achieved after 4 to 5 hours. The systemic exposure to telaprevir was increased by 237% when telaprevir was administered with standard fat meal containing 533 kcal and 21 g fat compared to when telaprevir was administered under fasting conditions. The mean elimination half-life after single dose oral administration of telaprevir 750mg typically ranged from about 4.0 to 4.7 hours. Further, Boceprevir is slightly soluble in water. It is absorbed following oral administration with median Tmax of 2 hours. Food enhanced the exposure of boceprevir by up to 65% at 800mg three times daily dose, relative to the fasting state. The bioavailability of boceprevir was similar regardless of meal type. Further studies also indicate that the direct acting antiviral agents, telaprevir and boseprevir are substrates for P-glycoprotein. Since both telaprevir and boceprevir are poorly soluble in water, they are poorly absorbed and have low bioavailability. Telaprevir also has a short window of absorption. Further since they are substrates for P-glycoprotein, a decrease in their bioavailability is also attributed to these efflux pump proteins which actively eject absorbed substances or active agents from the cells. The presence of these efflux proteins in the gastrointestinal tract especially in distal parts of the small intestine and throughout colon contribute to the poor bioavailability of telaprevir and boceprevir. Additionally pharmaceutically active agents which exhibit low bioavailability unfortunately create a need for frequent dosing of a large amount of pharmaceuticals in order to provide and maintain therapeutic levels. The need for frequent dosing presents patient compliance problems and the need for large amount of active ingredient may result in increased peripheral drug load and toxicity.

Need thus exists for controlled release dosage form of direct acting antiviral agents such as telaprevir or boceprevir that would enable better patient compliance and offer advantages over conventional immediate release formulations employed for treatment of Hepatitis C. Controlled release formulation would also lessen or prevent potentially undesirable effects by reducing peak blood levels and increase drug efficacy by maintaining desired therapeutic plasma concentrations for longer period. Need also exists to address the bioavailability issue of direct acting antiviral agents and develop dosage forms thereof with desired, high or improved and reproducible bioavailability to successfully use them in the treatment of hepatitis C. Particularly, need exists for controlled release formulations of direct acting antiviral agents with improved solubility and bioavailability. Some attempts have been made to provide compositions of telaprevir, however these do not address the need to provide controlled release formulations thereof. WO2010093843A2 relates to combination therapies for the treatment of patients with bridging fibrosis infected with HCV and a therapeutic dosage regimen with telaprevir, an oral inhibitor of HCV protease, with pegylated interferon alfa-2a (peg-ERN or P) and/or ribavirin. In an embodiment, it further discloses two phase dispersion composition of telaprevir for oral administration comprising polymer or dispersant, surfactant and solvents. Further, attempts have not been made by researchers to provide controlled release formulations of direct acting antiviral agents with improved solubility.

The present inventors after rigorous experimentation provide controlled release formulations of direct acting antiviral agents that not only release the active agent continuously in a predetermined manner, reduce the frequency of dosing and side effects associated with immediate release tablets but also reduce peak blood levels and increase drug efficacy by maintaining desired therapeutic concentrations for longer periods at the site of action. The present inventors further provide controlled release formulations of direct acting antiviral agents with improved solubility and bioavailability. Further since direct acting antiviral agents such as HCVNS3/4A serine protease inhibitors - telaprevir and boceprevir have a short absorption window in the upper gastrointestinal tract, and since their absorption is affected by efflux pump P- glycoproteins and their site of action is liver and hepatic portal vein, the present inventors provide controlled release formulations of direct acting antiviral agents in the form of gastroretentive dosage form that continuously delivers the active in solubilized form at a predetermined rate near the window of absorption, minimizes exposure of the drug to efflux pump P-glycoprotein, releases the active near its site of action, reduces the peripheral drug load thereby improving bioavailability and efficacy.

The present inventors thus provide controlled release formulations comprising direct acting antiviral agents such as telaprevir or bociprevir, at least one release modifier and at least one pharmaceutically acceptable excipient.

Summary of the Invention

The present invention relates to controlled release formulations comprising at least one direct acting antiviral agents and at least one release modifier. Detailed Description of the Invention

A good oral bioavailability is necessary in most cases because the oral application of a drug is preferred to any other routes of administration. The drugs administered orally must overcome several barriers before reaching their targeted site. The first major hurdle is that the drug needs to dissolve in the gastrointestinal milieu and then cross the gastrointestinal epithelium near its absorption window. Further the drug must escape metabolism by the intestinal flora, be absorbed through the intestinal wall by passive and/ or active (via transporters) permeation, escape excretion in the intestinal lumen by efflux transporters (mainly p-glycoproteins), escape metabolism in the blood while being transported to the liver via the portal vein. All these factors limit the bioavailability of the drug. Direct acting antiviral agents, exhibit low oral bioavailability mainly due to low solubility, short absorption window and p-glycoproteins efflux mechanism. The advantages of controlled release formulations are well known in the pharmaceutical field. These include the ability of the given pharmaceutical preparation to maintain a desired therapeutic effect over a comparatively longer period of time, reduced side effects, etc. Moreover, for drugs having low bioavailability, improvement in bioavailability may be achieved by continuous delivery of the drug at a predetermined rate providing better therapeutic outcome with reduced dose and decreasing any adverse effects associated with the therapy.

Accordingly the present inventors after rigorous experimentation have developed controlled release pharmaceutical formulations of direct acting antiviral agents that comprise at least one direct acting antiviral agent, at least one release modifier and at least one pharmaceutically acceptable excipient.

The term "composition" or "formulation" or "dosage form" has been employed interchangeably for the purpose of the present invention and mean that it is a pharmaceutical composition which is suitable for administration to a patient or dubject in need thereof. The subject can be an animal, preferably a mammal, more preferably a human. For the purpose of the present invention term "controlled release" or "sustained release" or "extended release" or "prolonged release" have been used interchangeably and mean broadly that the direct acting antiviral agent is released at a predetermined rate that is slower than the immediate release. The sustained release gastroretentive dosage forms of the present invention can be administered once or twice daily.

The term "direct acting antiviral agent/s" as used herein refers to any pharmaceutical agent that inhibits the activity of HCV NS3/4A protease. One or more direct acting antiviral agent/s that may be employed in the compositions of the present invention include, but are not limited to, telaprevir, boceprevir and the like or any combinations thereof. In one embodiment, a pharmaceutically effective amount of direct acting antiviral agent/s in the form of, but not limited to, free base, free acid or pharmaceutically acceptable salts, prodrugs, precursors, active metabolites, derivatives, analogs, polymorphs, solvates, hydrates, amorphous forms, enantiomers, optical isomers, diastereomers, tautomers, diastereomeric mixtures, racemic mixtures and the like or any mixtures thereof. The dosage forms of the present invention can include crystalline or amorphous form of direct acting antiviral agent/s. In one embodiment direct acting- antiviral agent is present in the form of a complex with ion exchange resin. In a further embodiment the direct acting antiviral agent employed in the dosage form of the present invention is telaprevir. In another embodiment the direct acting antiviral agent employed in the dosage form of the present invention is bociprevir. The term "effective amount" refers to an amount effective to achieve desired therapeutic and/or beneficial effect.

In one embodiment, the direct acting antiviral agent is present in. the compositions of the present invention in an amount of about 1 % to about 95% by weight of the composition. In another embodiment the direct acting antiviral agent is present in the compositions of the present invention in an amount of about 2% to about 90% by weight of the composition. In a further embodiment the direct acting antiviral agent is present in the compositions of the present invention in an amount of about 5% to about 85% by weight of the composition. The direct acting antiviral agent in the form of, but not limited to, powder, granules, pellets, beads, minitablets or the like, or combinations thereof can be employed in the compositions of the present invention. In one embodiment the compositions of the present invention may administer a dose of about 5 mg to about 1000 mg of direct acting antiviral agent. In another embodiment the compositions of the present invention may administer a dose of about 10 mg to about 900 mg of direct acting antiviral agent. In one embodiment the compositions of the present invention may administer a dose of about 100mg to about 1000mg of boceprevir. In a further embodiment the compositions of the present invention may administer a dose of about 200mg of boceprevir. In one embodiment the compositions of the present invention may administer a dose of about 800mg of boceprevir. In one embodiment the compositions of the present invention may administer a dose of about 100mg to about 1000mg of telaprevir. In another embodiment, the compositions of the present invention may administer a dose of about 375mg of telaprevir. In one embodiment, the compositions of the present invention may administer a dose of about 750mg of telaprevir. In a further embodiment, the compositions of the present invention may reduce the dose otherwise required for direct acting antiviral agents.

The controlled release compositions of the present invention comprise along with at least one direct acting antiviral agent, at least one release modifier. The term "release modifier" as used herein means any excipient that can retard the release of active agent and includes, but is not limited to, non-polymeric release modifier and polymeric release modifier or combinations thereof.

Suitable polymeric release modifiers may be employed in the compositions of the present invention. According to the present invention, polymeric release modifier may be pH independent or pH dependent or any combination thereof. Polymeric release modifiers that are pH dependent exhibit pH dependent solubility, and hence their performance depends on the pH of the environment they encounter. Polymeric release modifiers that are pH independent exhibit solubility that is independent of pH and hence its performance does not depend on the pH of the environment they encounter. The polymeric release modifier employed in the compositions of the present invention may be swelling or non-swelling. In one embodiment, polymeric release modifiers that may be employed in the compositions of the present invention include, but are not limited to, cellulose derivatives, saccharides or polysaccharides, poly(oxyethylene)- poly(oxypropylene) block copolymers (poloxamers), vinyl derivatives or polymers or copolymers thereof, polyalkylene oxides and derivatives thereof, maleic copolymers, acrylic acid derivatives or the like or any combinations thereof. Cellulose derivatives include, but are not limited to, ethyl cellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, carboxymethylethyl cellulose, carboxy ethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethyl ethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate, cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, ethylhydroxy ethylcellulose phthalate, or combinations thereof. Saccharides or polysaccharides include, but are not limited to, guar gum,, xanthan gum, gum arabic, tragacanth or combinations thereof. Vinyl derivatives, polymers and copolymers thereof include, but are not limited to, polyvinylacetate aqueous dispersion (Kollicoat^® SR 30D), copolymers of vinyl pyrrolidone, copolymers of polyvinyl alcohol, mixture of polyvinyl acetate and polyvinylpyrrolidone (e.g. Kollidon^® SR), polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, polyvinylpyrrolidone (PVP), or combinations thereof. Polyalkylene oxides and derivatives thereof include, but are not limited to, polyethylene oxide and the like or any combinations thereof. Acrylic acid derivatives include, but are not limited to, methacrylic acids, polymethacrylic acids, polyacrylates, especially polymethacrylates like a) copolymer formed from monomers selected from methacrylic acid, methacrylic acid esters, acrylic acid and acrylic acid esters b) copolymer formed from monomers selected from butyl methacrylate, (2-dimethylaminoethyl)methacrylate and methyl methacrylate c) copolymer formed from monomers selected from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride or d) copolymers of acrylate and methacrylates with/without quarternary ammonium group in combination with sodium carboxymethylcellulose, e.g. those available from Rohm GmbH under the trademark Eudragit ^® like Eudragit EPO (dimethylaminoethyl methacrylate copolymer; basic butylated methacrylate copolymer), Eudragit RL and RS (trimethylammonioethyl methacrylate copolymer), Eudragit NE30D and Eudragit NE40D (ethylacrylate methymethacrylate copolymer), Eudragit® L 100 and Eudragit® S (methacrylic acid^'methyl methacrylate copolymer), Eudragit® L 100-55 (methacrylic acid^'ethyl acrylate copolymer), Eudragit RD 100 (ammoniomethacrylate copolymer with sodium carboxymethylcellulose); or the like or any combinations thereof. Maleic copolymer based polymeric release modifier includes, but is not limited to, vinylacetate maleic acid anhydride copolymer, styrenemaleic acid anhydride copolymer, styrene maleic acid monoester copolymer, vinylmethylether maleic acid anhydride copolymer, ethylene maleic acid anhydride copolymer, vinylbutylethermaleic acid anhydride copolymer, acrylonitrile methyl acrylate maleic acid anhydride copolymer, butyl acrylate styrene maleic acid anhydride copolymer and the like, or combinations thereof. In one embodiment, polymers with low viscosity are employed in the compositions of the present invention such as, but not limited to, Methocel K4M (hydroxypropyl methyl cellulose), and the like or combinations. The term "non-polymeric release modifier" as used herein refers to any excipient that can retard the release of an active agent and that does not comprise of repeating units of monomers. Suitable non-polymeric release modifiers employed in the present invention include, but are not limited to, fatty acids, long chain alcohols, fats and oils, waxes, phospholipids, eicosonoids, terpenes, steroids, resins and the like or combinations thereof. Non-polymeric release modifiers employed may be pH dependent or pH independent in nature. Fatty acids are carboxylic acids derived from or contained in an animal or vegetable fat or oil. Fatty acids are composed of a chain of alkyl groups containing from 4 to 22 carbon atoms and are characterized by a terminal carboxyl group. Fatty acids that may be employed in the present invention include, but are not limited to, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated cottonseed oil, and the like, and mixtures thereof. Other fatty acids include, but are not limited to, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, and the like, and mixtures thereof. In one embodiment the fatty acids employed include, but are not limited to, hydrogenated palm oil, hydrogenated castor oil, stearic acid, hydrogenated cottonseed oil, palmitic acid, and mixtures thereof. Suitable long chain monohydric alcohols include, but are not limited to, cetyl alcohol, stearyl alcohol or mixtures thereof. Waxes are esters of fatty acids with long chain monohydric alcohols. Natural waxes are often mixtures of such esters, and may also contain hydrocarbons. Waxes are low- melting organic mixtures or compounds having a high molecular weight and are solid at room temperature. Waxes may be hydrocarbons or esters of fatty acids and alcohols. Waxes that may be employed in the present invention include, but are not limited to, natural waxes, such as animal waxes, vegetable waxes, and petroleum waxes (i.e., paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic waxes. Specific examples include, but are not limited to, spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, or mixtures thereof. Mixtures of these waxes with the fatty acids may also be used. Waxes are also monoglyceryl esters, diglyceryl esters, or triglyceryl esters (glycerides) and derivatives thereof formed from a fatty acid having from about 10 to about 22 carbon atoms and glycerol, wherein one or more of the hydroxyl groups of glycerol is substituted by a fatty acid. Glycerides that may be employed in the present invention include, but are not limited to, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate, polyglyceryl diisostearate, lauroyl macrogolglycerides, oleyl macrogolglycerides, stearoyl macrogolglycerides, and the like, or mixtures thereof. Resins employed in the compositions of the present invention include, but are not limited to, shellac and the like or any combinations thereof. In one embodiment the non- polymeric release modifier employed includes, but is not limited to, Cutina^® (Hydrogenated castor oil), Hydrobase^® (Hydrogenated soybean oil), Castorwax^® (Hydrogenated castor oil, Croduret^® (Hydrogenated castor oil), Carbowax^®, Compritol^® (Glyceryl behenate), Sterotex^® (Hydrogenated cottonseed oil), Lubritab^® (Hydrogenated cottonseed oil), Apifil^® (Wax yellow), Akofine^® (Hydrogenated cottonseed oil), Softisan^® (Hydrogenated palm oil), Hydrocote^® (Hydrogenated soybean oil), Corona^® (Lanolin), Gelucire^® (Macrogolglycerides Lauriques), Precirol^® (Glyceryl Palmitostearate), Emulcire™ (Cetyl alcohol), Plurol^® diisostearique (Polyglyceryl Diisostearate), Geleol^® (Glyceryl Stearate), and mixtures thereof. In a further embodiment the non-polymeric release modifier employed includes, but is not limited to, Compritol^®, Sterotex^®, Lubritab^®, stearic acid, cetyl alcohol, or mixtures thereof.

The amount of release modifier used in the controlled release formulations of the present invention may vary depending upon the degree of controlled or sustained release desired. In an embodiment, release modifier is present in the composition in an amount from about 1 % to about 95% by weight of the dosage form. In another embodiment, release modifier is present in the formulation in an amount from about 2% to about 90% by weight of the dosage form. In a further embodiment, release modifier is present in the formulation in an amount from about 5% to about 85% by weight of the dosage form.

In one embodiment, the direct acting antiviral agent in the form of, but not limited to, powder, granules, pellets, beads, minitablets or the like is treated with at least one release modifier. The active ingredient may be treated by any of the techniques known in the art such as, but not limited to, melt granulation, hot melt extrusion, fluid bed coating, wet granulation, spray drying, extrusion-spheronization, dry granulation or roll compaction. Lipids or waxes can also be employed in the form of an aqueous dispersion stabilized by surfactants and suitable stabilizers. In another embodiment, the direct acting antiviral agent is blended or physically mixed with release modifier. In one embodiment, the direct acting antiviral agent when coated with a release modifier, coating may be carried out in the range from about 1 % to about 80% weight gain, preferably from about 2% to about 60%, more preferably from about 5 to about 50%. In a further embodiment treated direct acting antiviral agent is incorporated in the dosage forms of the present invention. In another embodiment, the direct acting antiviral agent is incorporated in the controlled release formulations of the present invention in the solubilized form. In another embodiment, the solubilized direct acting antiviral agent is treated or blended with at least one release modifier.

Controlled release of direct acting antiviral agent may be accomplished by any means known in the pharmaceutical art, such as, but not limited to, matrix controlled-release systems, coated controlled release systems, coated-matrix controlled release systems, osmotic controlled-release systems, multiparticulate controlled-release systems, non- gastroretentive controlled release systems and the like.

In one embodiment the controlled release formulation of the present invention is in the form of a gastroretentive dosage form. For the purpose of the present invention the term "gastroretentive" or "gastric retention" or "gastroretention" or "retained in upper gastrointestinal tract" when used with respect to the dosage form of the present invention, means that the dosage form or at least a portion thereof remains in the upper gastrointestinal tract including stomach, for about 30 minutes or more. In another embodiment, the gastroretentive dosage form of the present invention remains in the upper gastrointestinal tract including stomach, for about 30 minutes to about 12 hours. In a further embodiment gastroretentive dosage form is beneficial for a continual delivery of direct acting antiviral agent at the region of absorption. In another embodiment controlled release formulation of the present invention is in the form of a gastroretentive dosage form for improved bioavailability. In a further embodiment, gastroretentive dosage forms that are retained in the upper gastrointestinal tract for a prolonged period of time after oral administration and release the active ingredient continuously at a predetermined rate or in a sustained manner are employed for delivering direct acting antiviral agents that exhibit low oral bioavailability. Design of such gastroretentive dosage forms is a challenge for a formulator because of the complexities of physiological effects that have implications on drug release and absorption in vivo. The controlled release gastroretentive dosage forms of the present invention release the active at a predetermined rate and provide improved bioavailability when compared to conventional immediate release dosage forms.

The controlled release formulations of the present invention in the form of a gastroretentive dosage form comprise in addition to at least one direct acting antiviral agent and at least one release modifier as discussed above and at least one swelling agent. The swelling agents employed herein swell voluminously in the presence of gastric contents to increase the size of dosage form such that it precludes its passage through the pyloric sphincter thereby retaining the compositions of the present invention in the upper gastrointestinal tract. The controlled release gastroretentive formulations of the present invention comprise at least one directly acting antiviral agent, at least one release modifier, at least one swelling agent and at least one pharmaceutically acceptable excipient.

The swelling agent used in the present invention includes, but is not limited to, one or more swellable biocompatible hydrophilic polymers. In one embodiment, the swelling agents are employed in the dry state or in a form that has substantial capacity for water uptake. Hydrophilic polymers used as swelling agents that are useful in preparation of the dosage forms of the present invention are polymers that are nontoxic and swell in a dimensionally unrestricted manner upon imbibing gastric fluid. Suitable swelling agents employed in the dosage forms of the present invention include, but are not limited to, polyalkylene oxides; cellulosic polymers such as, but not limited to, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, methyl cellulose; acrylic acid and methacrylic acid polymers, and esters thereof, polyethylene oxide, maleic anhydride polymers; polymaleic acid; poly(acrylamides); poly(olefinic alcohol)s; poly(N-vinyl lactams); polyols; polyoxyethylated saccharides; polyoxazolines; polyvinylamines; polyvinylacetates; polyimines; starch and starch-based polymers; polyurethane hydrogels; chitosan; polysaccharide gums such as xanthan gum; alginates; zein; shellac-based polymers; polyacrylic acid, maltodextrin, pre-gelatinized starch and polyvinyl alcohol, or mixtures thereof. In one embodiment, swelling agents of different viscosity grades can be incorporated in the compositions of the present invention to achieve gastroretention. In another embodiment, swelling agents of high viscosity can be incorporated in the compositions of the present invention to achieve gastroretention such as, but not limited to, Methocel Κ10ΌΜ, Polyox WSR303, and the like or combinations thereof. In one embodiment, the swelling agent employed may function as a release modifier. In another embodiment, the swelling agent employed may be a swelling release modifier. The amount of swelling agent employed in the controlled release gastroretentive dosage forms of the present invention is- from about 5% to about 95 % by weight of the final dosage form. In one embodiment, the weight percent of the swelling agent in the final dosage form is about 10% to about 90%. In another embodiment, the weight percent of the swelling agent in the final dosage form is about 15% to about 85 %. The amount and type of swelling agents employed in the gastroretentive dosage forms of the present invention ensures that there is sufficient swelling for retention of the dosage form. In case wherein the controlled release dosage form is a multilayered tablet with drug layer and gastroretentive layer/s the swelling agents ensure that there is sufficient swelling for retention of the dosage form despite erosion of the drug layer. These swelling agents ensure that within 2 hours at least two dimensions of the dosage form namely length and width is more than 10 mm. In addition to the above discussed excipients, the controlled release compositions of the present invention comprise at least one pharmaceutically acceptable excipients, such as, but not limited to, solubility enhancing agents, p-glycoprotein inhibitors, swelling enhancers, permeation enhancers, binders, lubricants, diluents, disintegrants, glidants, stabilizers, pH modifiers, preservatives, colorants and the like. According to this invention, in one embodiment the increase in instantaneous solubility of direct acting antiviral agent is achieved by using at least one solubility enhancing agent. In another embodiment, the controlled release formulations of the present invention comprise solubilized direct acting antiviral agent comprising at least one direct acting antiviral agent, at least one solubility enhancing agent and optionally at least one pharmaceutically acceptable excipient, such as, but not limited to diluents and the like. The solubility enhancing agent or solubilizer that may be employed in the compositions of the present invention may include one or more surfactant, complexing agent, hydrotropic agent, ion pairing agent and the like or combinations thereof. The solubility enhancing agent as employed in the present invention includes, but is not limited to, hydrophilic surfactants, lipophilic surfactants and the like or mixtures thereof. The surfactants employed in the present invention may also include, but are not limited to, ionic surfactants comprising cationic or anionic surfactants, zwitterionic or amphiphilic surfactants or nonionic surfactants or the like or any .combinations thereof. The ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, Oligopeptides, or polypeptides; glyceride derivatives of amino acids; lecithins or hydrogenated lecithins; lysolecithins or hydrogenated lysolecithins; phospholipids or derivatives thereof; lysophospholipids or derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; sodium lauryl sulphate, fatty acid salts; sodium docusate; acyl lactylates; mono- or di-acetylated tartaric acid esters of mono- or di-glycerides; succinylated mono- or di-glycerides; citric acid esters of mono- or di-glycerides; or mixtures thereof. The amphiphilic surfactants include, but are not limited to, d-a-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS) and d-a- tocopherol acid salts such as succinate, acetate, etc. The non-ionic surfactants include, but are not limited to, fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols or sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- or di-glycerides; oil- soluble vitamins/vitamin derivatives; PEG fatty acid esters; polyglycerized fatty acid; polyoxyethylene-polyoxypropylene block copolymers; transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols wherein the commonly used oils are castor oil or hydrogenated castor oil, or an edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, almond oil and the commonly used polyols include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol and pentaerythritol; or mixtures thereof. The solubility enhancing agent that may be employed include, but are not limited to, PEG-20-glyceryl stearate (Capmul® by Abitec), PEG-40 hydrogenated castor oil (Cremophor RH 40® by BASF), PEG-35 castor oil, PEG 6 corn oil (Labrafil® by Gattefosse), lauryl macrogol - 32 glyceride (Gelucire 44/14® by Gattefosse), stearoyl macrogol glyceride (Gelucire 50/13® by Gattefosse), polyglyceryl - 10 mono dioleate (Caprol ® PEG 860 by Abitec), propylene glycol oleate (Lutrol OP® by BASF), propylene glycol dioctanoate (Captex® by Abitec), propylene glycol caprylate/caprate (Labrafac® by Gattefosse), glyceryl monooleate (Peceol® by Gattefosse), glycerol monolinoleate (Maisine ® by Gattefosse), glycerol monostearate (Capmul® by Abitec), PEG- 20 sorbitan monolaurate (Tween 20® by ICI), PEG - 4 lauryl ether (Brij 30® by ICI), sucrose distearate (Sucroester 7® by Gattefosse), sucrose monopalmitate (Sucroester 15® by Gattefosse), polyoxyethylene-polyoxypropylene block copolymer (Poloxamer or Lutrol® series BASF), polyethylene glycol 660 hydroxystearate, (Solutol® by BASF), sodium lauryl sulphate, sodium dodecyl sulphate, dioctyl suphosuccinate, L- hydroxypropyl cellulose, hydroxylethylcellulose, hydroxy propylcellulose, propylene glycol ^' alginate, sodium taurocholate, sodium glycocholate, sodium deoxycholate, betains , polyethylene glycol (Carbowax® by DOW), d-a-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS® by Eastman), or mixtures thereof. The complexing agent that may be employed include, but are not limited to, cyclodextrin class of molecules, such as cyclodextrins containing from six to twelve glucose units, especially, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, or their derivatives, such as hydroxypropyl beta cyclodextrins, or mixtures thereof. The complexing agents may also include cyclic amides, hydroxyl benzoic acid derivatives as well as gentistic acid. In this complexation process, a hydrophilic polymer may be additionally added to further enhance the solubility along with the complexing agent.

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In the composition of the present invention, the direct acting antiviral agent and one or more solubility enhancing agents may be employed in different ratios. The selected ratio depends upon the desired improvement in solubility and the type of solubility enhancing agents employed. It is contemplated within the scope of the invention that the ratio of direct acting antiviral agent to solubility enhancing agents may range from about 50:1 to about 1 :50. In one embodiment, the ratio of direct acting antiviral agent to solubility enhancing agent is from about 20:1 to about 1 :20. In another embodiment, the ratio of direct acting antiviral agent to solubility enhancing agent is from about 10:1 to about 1 :10. In one embodiment in the composition, the direct acting antiviral agent may be present in the form of physical blend, solid dispersion, solid solution or complex with the solubility enhancing agent. Different processes may be employed to prepare the composition of the direct acting antiviral agent with the solubility enhancing agents. It is contemplated within the scope of the invention that the processes for preparing solubilized direct acting antiviral agent may include, but not limited to, solubilization using melt granulation, solvent treatment, wet granulation, physical mixing or spray drying of the dissolved direct acting antiviral agent in a solvent with a solubility enhancing agent, melt extrusion, jet milling, shock cooling and the like or combinations thereof. In the case of melt granulation, the solubility enhancing agent is melted. The direct acting antiviral agent is then added and mixed with the molten mass, and allowed to solidify to form granules which are then separated from each other. In another embodiment the solubility enhancing agents are melted. The direct acting antiviral agent is then added and mixed with the molten mass. This blend is further mixed with diluents capable of converting this semisolid mass into dry powder. Non limiting examples of such drying agents include celluloses such as microcrystalline cellulose, silicon dioxide, silicates, magnesium aluminium silicate etc. In another illustrative embodiment of this system, the direct acting antiviral agent is granulated using a molten solubility enhancing agent. In some cases, the direct acting antiviral agent and the solubility enhancing agent both may be melted together and congealed to room temperature. In using a solvent treatment method, either the solubility enhancing agents or the direct acting antiviral agent, or both, are dissolved in a solvent which is then evaporated or spray dried. The resultant mass is a blend of direct acting antiviral agent and solubility enhancing agent, such that the solubility of the direct acting antiviral agent is increased. The solvent employed in this system may be aqueous or non-aqueous. In the case of physical mixing, the direct acting antiviral agent and the solubility enhancing agent are preferably intimately dry-mixed using a low shear granulator, a V-blender, or a high shear granulator. In the complexation method, complex of direct acting antiviral agent can be prepared using different techniques such as ball milling, solvent evaporation method which includes, but is not limited to, spray drying and lyophilization process, slurry method, and paste method. It is contemplated within the scope of the invention that a combination of aforementioned processes can be employed. For example, a combination of hot melt process, physical mixing, and solvent treatment method may be employed. In this case, the direct acting antiviral agent may be initially granulated with one or more molten solubility enhancing agents, which can be further treated with the same or different solubility enhancing agents in a solvent or with simple physical mixing or vice versa. It is also contemplated within the scope of the invention that any process known in the art suitable for making pharmaceutical compositions in general may be employed for the purpose of this invention.

In one embodiment suitable permeation enhancers that may be employed in the compositions of the present invention include, but are not limited to, surfactants, such as, but not limited to, ionic, non ionic, hydrophilic, amphiphilic, lipophilic surfactants; bile salts; polysaccharides; synthetic polymers; cyclodextrins; chelators and the like or any combinations thereof. Suitable ionic surfactants, include, but are not limited to, cetylpyridinium chloride, alkylammonium salts, sodium lauryl sulfate, sodium laureate, fusidic acid salts, fatty acid derivatives of amino acids, oligopeptides, polypeptides, glyceride derivatives of amino acids, lecithins or hydrogenated lecithins, lysolecithins or hydrogenated lysolecithins, phospholipids or derivatives thereof, lysophospholipids or derivatives thereof, carnitine fatty acid ester salts, salts of alkylsulfates, fatty acid salts, sodium docusate, acyl lactylates, mono- or di-acetylated tartaric acid esters of mono- or di-glycerides, succinylated mono- or di-glycerides, citric acid esters of mono- or di- glycerides, and the like or mixtures thereof. Suitable nonionic surfactants, include, but are not limited to, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol fatty acid monoesters, polyethylene glycol fatty acid diesters, hydrophilic trans-esterification products of alcohols or polyols with at least one member of the group consisting of natural and/or hydrogenated oils such as castor oil or hydrogenated castor oil, or an edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, almond oil; polysorbate-80, diethylene glycol octadecyl ether, and the like or mixtures thereof. Suitable bile salts include, but are not limited to, bile salts not limited to sodium glycodeoxycholate, sodium glycocholate, sodium taurodeoxycholate, sodium taurocholate and the like or mixtures thereof. Suitable polysaccharides include, but are not limited to, chitosan and the like or mixtures thereof; Suitable synthetic polymers include, but are not limited to carbopol, carbomer; fatty acids not limited to oleic acid, caprylic acid; thiolated polymers of polyacrylates not limited to thiolated sodium carboxy methyl cellulose and the like or mixtures thereof. Suitable chelators, include but are not limited to ethylenediaminetetraacetic acid, sodium citrate and the like or mixtures thereof.

In another embodiment the controlled release of the present invention with improved bioavailability optionally comprise P-glycoprotein inhibitors. The P-glycoprotein inhibitors that may be included in the compositions of the present invention include, but are not limited to, curcumin; phenyl cinnamate; coumarin; beta-amyrin cinnamate; apiole; bergamotin; caffeine; morin; nariturin; piperine; qurcetin; slavironin; silybin; theobromin; vanillin; vanillyl-N-nonlymine; surfactants such as, but not limited to, tocopherol polyethylene glycol succinic acid esters (TPGS) not limited to those that are commercially under the trade name Vitamin E TPGS; reaction products of a natural or hydrogenated castor oil and ethylene oxide not limited to those that are. available commercially under the trade name Cremophor^® EL, Cremophor^® RH40; polyoxyethylene-sorbitan-fatty acid esters not limited to those available commercially under the trade name Tween^® ; polyoxyethylene-polyoxypropylene co-polymers and block co-polymers or, poloxamers not limited to those available commercially under the trade name Pluronic^®; transesterified, polyoxyethylated caprylic-capric acid glycerides not limited to those available commercially under the trade name Labrasol^® , and the like or combinations thereof. Swelling enhancers help the swelling agents to swell rapidly to a large extent resulting in a dramatic increase in the size of the tablet. At lower concentrations, these excipients are used as superdisintegrants; however at concentration above 5 % w/w these agents function as swelling enhancers and help increase the size of the dosage form. According to the present invention, swelling enhancers that may be incorporated include, but are not limited to, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, cross-linked sodium or calcium carboxymethyl cellulose, cellulose fiber, cross-linked polyvinyl pyrrolidone, cross-linked polyacrylic acid, cross-linked amberlite resin, alginates, colloidal magnesium-aluminum silicate, corn starch granules, rice starch granules, potato starch granules, pregelatinised starch, sodium starch glycolate and sodium carboxymethyl starch. In one embodiment matrix osmogents, such as but not limited to, dextrose, mannitol, sodium chloride and the like or combinations thereof are employed as swelling enahncers. The amount of swelling enhancers used in the dosage forms of the present invention is about 5 to about 90 weight percent. In one embodiment, the amount of the swelling enhancer is about 10 to about 70 weight percent. In another embodiment, the amount of the swelling enhancer is about 15 to about 50 weight percent. In one embodiment, the dosage forms according to the present invention include at least one swelling agent and a swelling enhancer. When a combination of swelling agent and swelling enhancer is employed for gastric- retention, it allows a rapid and dramatic increase in the size of the tablets. Such a combination may be employed which allows rapid swelling and maintenance of integrity by polymeric network formed upon swelling of the polymer(s). Gas generating agents aid in the formation of highly porous, preferably honeycombed structure and enhance the buoyancy of the formulation. The gas generating agent employed in the present invention is selected from, but not limited to, alkali and alkaline-earth metal carbonates and bicarbonates such as sodium bicarbonate, sodium glycine carbonate, potassium bicarbonate, ammonium bicarbonate, sodium bisulfite, sodium metabisulfite, sodium carbonate, potassium carbonate and the like. In one embodiment, the gas generating agent is sodium bicarbonate. The pharmaceutical composition can further optionally comprise an acid source. The acid source may be, but is not limited to, citric acid, maleic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, phthalic acid, aspartic acid, glutamic acid, malic acid or tartaric acid. In a dry granulation process, the gas generating agent may be incorporated into the dosage form by blending it into the expanding composition before or after first compaction. In a wet granulation process, it may be provided as an extragranular constituent after wet granulation.

Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, polyvinyl prrolidone (PVP), copovidone, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts. Examples of suitable diluents include, but are not limited to, starch, dicalcium phosphate, microcrystalline cellulose, lactose monohydrate, dextrate hydrated and the like. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, and sodium stearyl fumarate. 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. Suitable disintegrants employed in the compositions of the present invention include croscarmellose sodium, crospovidone, sodium starch glycolate, starch or combinations thereof. Suitable pH modifiers that may optionally be incorporated include, but are not limited to malic acid, tartaric acid, fumaric acid, maleic acid, aspartic acid or citric acid. In a further embodiment the controlled release gastroretentive dosage forms of the present invention may be in the form of a monolithic system, an expanding biiayered or multilayered or in-lay system for oral administration which is adapted to deliver the drug at a predetermined rate. In one embodiment, the direct acting antiviral agent is incorporated in monolithic matrix type in the controlled release gastroretentive formulation. In another embodiment, the direct acting antiviral agent is incorporated in the form of a biiayered gastroretentive dosage form that consists of a drug layer and a gastroretentive expanding layer wherein the drug is released at a predetermined rate from the drug layer. In a further embodiment pharmaceutical controlled release gastroretentive composition in the form of an expanding biiayered system for oral administration is provided to deliver direct acting antiviral agent from a first layer immediately upon reaching the gastrointestinal tract, and to deliver same or different active, from a second layer, in a sustained manner over a specific time period. The second layer is also adapted to provide expanding nature for the dosage system, thereby making the dosage system have greater retention in the stomach. In yet another embodiment, the controlled release gastroretentive dosage form is in the form of a trilayered system consisting of a drug layer compressed between a first gastroretentive layer and a second gastroretentive layer wherein direct acting antiviral agent is released at a predetermined rate from the drug layer. In a further embodiment the controlled release gastroretentive dosage form of the present invention comprises direct acting antiviral agent treated with a release modifier. In a further embodiment the controlled release gastroretentive dosage form of the present invention comprises solubilized direct acting antiviral agent treated with a release modifier. The dosage forms of the present invention ensure desired gastroretention and controlled or sustained release of direct acting antiviral agent thereby improving the oral bioavailability. In yet another embodiment, the gastroretentive dosage form is in the form of a trilayered system consisting of a drug layer compressed between a gastroretentive layer and a barrier layer wherein DAA is released at a predetermined time from the drug layer. The barrier layer acts as a barrier modulating the release and is partially impermeable, for a predeterminable time, to the active ingredient contained in the adjacent drug layer. In one embodiment the excipients employed for the preparation of said barrier layer include but are not limited to, glyceryl monostearate and derivative thereof, semisynthetic glycerides, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, cetyl - alcohol, glycerin, cellulose derivatives, ethylcellulose, methylcellulose, sodium carboxymethylcellulose, polymethacrylates, polyvinylpyrrolidone, stearic acid, talc, sodium benzoate, boric acid, polyoxyethylene glycols, colloidal silica and the like. Further for the preparation of barrier layer, plasticizers may be employed such as but not limited to hydrogenated vegetable oils, fatty alcohols, fatty acids, glycerides and triglycerides and their substituted forms, polyoxyethylene glycols and derivatives thereof and the like. In one embodiment the barrier layer may also be characterized in that it can act as a barrier modulating the release and can rapidly swell, i.e. can rapidly increase in volume, and have bioadhesive properties allowing dosage form retention and adhesion to gastrointestinal mucosa. In a further embodiment controlled release gastroretentive dosage form of the present invention is in the form of an in-lay system comprising a drug containing tablet which is placed in another tablet comprising a blend of excipients that ensure gastric retention. In this system the drug containing tablet is small and is covered from all sides except at least one side with a blend of excipient that ensure the gastric retention.

In yet another illustrative embodiment according to the invention, the controlled release formulation with improved bioavailability may be optionally coated. Surface coatings may be employed for aesthetic purposes or for dimensionally stabilizing the dosage form. The coating may be carried out using any conventional technique employing conventional ingredient. 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, ethyl cellulose, polyvinyl alcohol, poly methacrylates or the like or combinations thereof. Tablets of the present invention may vary in shape including, but not limited to, oval, triangle, almond, peanut, parallelogram, pentagonal. It is contemplated within the scope of the invention that the dosage form can be encapsulated. Tablets in accordance with the present invention may be manufactured using conventional techniques of common tableting methods known in the art such as direct compression, dry granulation, wet granulation and extrusion/ melt granulation.

Further, in one embodiment, the present invention provides a process of preparing a controlled release formulation comprising: preparing solubilized direct acting antiviral agent by treatment with solubility enhancing agent; blending said solubilized direct acting antiviral agent with at least one release modifier, and at least one pharmaceutically acceptable excipient; lubricating the blend to form a lubricated blend; compressing the blend to form a monolithic tablet. In another embodiment, the present invention provides a process of preparing a controlled release gastroretentive formulation comprising: preparing solubilized direct acting antiviral agent by treatment with solubility enhancing agent; blending said solubilized direct acting antiviral agent with at least one release modifier, at least one swelling ^ agent and at least one pharmaceutically acceptable excipient; lubricating the blend to form a lubricated blend; compressing the blend to form a monolithic matrix tablet. Furthermore, the present invention also provides a process of preparing a controlled release gastroretentive dosage form of direct acting antiviral agent comprising: preparing solubilized direct acting antiviral agent by treatment with solubility enhancing agent; blending said solubilized direct acting antiviral agent with at least one release modifier and at least one pharmaceutically acceptable excipient, lubricating the blend to form drug layer blend; blending at least one swelling agent, at least one pharmaceutically acceptable excipient, lubricating the blend to form a gastroretentive layer blend; and compressing the drug layer and the gastroretentive layer to form a bilayer tablet.

The controlled release gastroretentive dosage form of the present invention that may be coated/ uncoated, single layer or multilayered composition, gradually swells upon contact with the gastric fluid. The time taken for swelling may vary from about 15 minutes to about 4 hours. In one embodiment, the time taken for swelling is within about 15 minutes to about 3 hours. In another embodiment, the time taken for swelling is within about 15 minutes to about 2 hours. Two dimensions of the dosage form namely length and width expand to more than about 8 mm after swelling within 2 hours in media simulating typical gastric environment (0.1 hydrochloric acid). In one embodiment, the length and width of the dosage form expand to more than about 10 mm after swelling within 2 hours in media simulating typical gastric environment (0.1 N hydrochloric acid). In another embodiment, the length and width of the dosage form expand to more than about 12 mm after swelling within 2 hours in media simulating typical gastric environment (0.1 N hydrochloric acid). The present invention provides controlled release formulations of direct acting antiviral agents that are more than about 1 to about 4 times more bioavailable than the conventional immediate release dosage forms. The controlled release formulations according to the present invention allow for controlled release of direct acting antiviral agent. In one embodiment the direct acting antiviral agent released over a period of more than about 4 hours. In another embodiment the direct acting antiviral agent released over a period of about 8 hours. In another embodiment the direct acting antiviral agent released over a period of about 12 hours. In another embodiment the direct acting antiviral agent released over a period of about 18 hours. In another embodiment the direct acting antiviral agent released over a period of about 24 hours. In a further embodiment, the formulation of the present invention is designed to release direct acting antiviral agent over an extended period of time from about 4 to about 24 hours. In another embodiment, the formulation of the present invention is designed to release direct acting antiviral agent over an extended period of time from about 6 to about 24 hours. In one embodiment, the formulation of the present invention is designed to release direct acting antiviral agent over an extended period of time from about 8 to about 24 hours. In another embodiment, the formulation of the present invention is designed to release direct acting antiviral agent over an extended period of time from about 12 to about 24 hours.

Further, within the purview of the present invention, are included formulations that comprise a combination of direct acting antiviral agents with other drugs or one or more active agents which may be delivered in an immediate release or modified release manner, including not limited to, ribavarin, interferon, and the like or combinations thereof. In a further embodiment is provided the use of controlled release formulations of direct acting antiviral agents of the present invention for the manufacture of a medicament for the treatment of hepatitis C infection. Further, the present invention provides a method of treating hepatitis C infection, comprising administering to the subject in need thereof controlled release formulations of the present invention.

While the present invention has been described in terms of its specific illustrative embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations. EXAMPLES

Example 1 : Controlled release gastroretentive tablet of telaprevir Preparation of controlled release gastroretentive tablet of telaprevir

Table 1 : Composition of gastroretentive tablet of telaprevir

Procedure: Telaprevir was mixed well with molten Vitamin E TPGS in jacketed rapid mixer granulator followed by addition of part of microcrystalline cellulose and sodium lauryl sulphate. The granulation mass was sized to get the granules which were further blended with the remaining excipients except lubricant. The blend was then lubricated and compressed to form gastroretentive tablet.

Example 2: Controlled release gastroretentive tablet of boceprevir

Preparation of gastroretentive tablet of boceprevir

Table 2: Composition of gastroretentive tablet of boceprevir

Ingredients mg/tablet

Boceprevir _. 200

Stearoyl macrogol glyceride, USP (Gelucire 50/13®) 150 Polyethylene oxide, USP 150

Hydroxy propyl methyl cellulose, USP (Methocel K100M) 60

Hydroxy ethyl cellulose, USP 100

Microcrystalline cellulose, USP 65

Povidone , USP 30

Crospovidone, USP 80

Sodium bicarbonate 40

Citric acid, USP 15

Magnesium stearate, USP 10

Total 900

Procedure: Stearoyl macrogol glyceride was melted and boceprevir, part of microcrystalline cellulose was added to the same. The mass was then sized and screened to obtain granules of boceprevir. These granules were then blended with other excipients except lubricant, and then lubricated and compressed to form gastroretentive tablet.

Example 3: Controlled release gastroretentive tablet of telaprevir A) Preparation of controlled release drug layer

Table 3: Composition of controlled release drug layer

Procedure: All the excipients except the lubricant were blended. This blend was then lubricated to form lubricated drug layer blend. B. Preparation of gastroretentive layer

Table 4: Composition of gastroretentive layer

Procedure: All ingredients except lubricant were dry mixed. The blend was then lubricated using magnesium stearate to form the gastroretentive layer blend.

A bilayer gastroretentive tablet of telaprevir was prepared by compressing the drug layer blend and the gastroretentive layer blend. Example 4: Controlled release gastroretentive tablet of telaprevir

A) Preparation of controlled release drug layer

Table 5: Composition of controlled release drug layer

Ingredients mg/tablet

Telaprevir 375

Poloxamer 407, USP 60

Stearoyl macrogol glyceride, USP (Gelucire 50/13) 40

Hydroxy propyl methyl cellulose, USP (Methocel K4M) 75

Microcrystalline cellulose, USP 80

Colloidal Silicon Dioxide, USP 40

Povidone, USP 20 Magnesium stearate, USP 10

Weight of drug layer 700

Procedure: Stearoyl macrogol glyceride was melted and telaprevir, poloxamer, collodal siicon dioxide and part of microcrystalline cellulose were added to the same to form a solid dispersion. The dispersion was mixed and cooled to achieve a homogeneous mass which was sized and screened. These granules of telaprevir obtained were then blended with other excipients except lubricant, and then lubricated to form the drug layer blend.

B. Preparation of gastroretentive layer

Table 6: Composition of gastroretentive layer

A bilayer gastroretentive tablet of telaprevir was prepared by compressing the drug layer blend and the gastroretentive layer blend.

Claims

claim:

1) A controlled release formulation comprising at least one direct acting antiviral agent, at least one release modifier and at least one pharmaceutically acceptable excipient.

2) The controlled release formulation of claim 1 , wherein the direct acting antiviral agent is telaprevir or boceprevir.

3) The controlled release formulation of claim 1 , wherein the direct acting antiviral agent is in the form of a free base, a free acid, a pharmaceutically acceptable salt, a prodrug, a precursor, an active metabolite, a derivative, an analog, a polymorph, a solvate, a hydrate, an amorphous form, an enantiomer, an optical isomer, a diastereomer, a tautomer, a diastereomeric mixtures, a racemic mixture or combinations thereof.

4) The controlled release formulation of claim 1 , wherein the release modifier is polymeric release modifier, non-polymeric release modifier or any combination thereof.

5) The controlled release formulation of claim 4, wherein the polymeric release modifier is a pH dependent polymeric release modifier, a pH independent polymeric release modifier or any combination thereof.

6) The controlled release formulation of claim 4, wherein the polymeric release modifier is cellulose derivative, saccharide or polysaccharide, poly(oxyethylene)-poly(oxypropylene) block copolymer, vinyl derivative or polymer or copolymer thereof, polyalkylene oxide or derivative thereof, maleic copolymer, acrylic acid derivative, or any combination thereof. 7) The controlled release formulation of claim 4, wherein the non-polymeric release modifier is a fatty acid, long chain alcohol, fat, oil, wax, phospholipid, eicosonoid, terpene, steroid, resin or any combination thereof.

8) The controlled release formulation of claim 1 , wherein the formulation further comprises at least one swelling agent.

9) The controlled release formulation of claim 8, wherein the swelling agent is at least one hydrophilic polymer.

10) The controlled release dosage from of claim 9, wherein the hydrophilic polymer is polyalkylene oxide, cellulosic polymer, acrylic acid and methacrylic acid polymer or ester thereof, polyethylene oxide, maleic anhydride polymer; polymaleic acid, poly(acrylamide); poly(olefinic alcohol), poly(N-vinyl lactam), polyol, polyoxyethylated saccharide, polyoxazoline, polyvinylamine, polyvinylacetate, polyimine, starch and starch-based polymer, polyurethane hydrogel, chitosan, polysaccharide gum, alginate, zein, shellac-based polymer, polyacrylic acid, maltodextrin, pre-gelatinized starch, polyvinyl alcohol, or any combination thereof.

1 1 ) The controlled release formulation of claim 1 , wherein the pharmaceutically acceptable excipient is a solubility enhancing agent, p-glycoprotein inhibitor, swelling enhancer, permeation enhancer, binder, lubricant, diluent, disintegrant, glidant, stabilizer, pH modifier, preservative, colorant or any combination thereof.

12) The controlled release formulation of claim 1 , wherein the formulation is in the form of a matrix controlled-release system, coated controlled release system, coated-matrix controlled release system, osmotic controlled-release system, multiparticulate controlled-release system, non-gastroretentive controlled release system.

13) The controlled release formulation of claim 1 , wherein the formulation is in the form of gastroretentive dosage form. 14) The controlled release formulation of claim 13, wherein the gastroretentive dosage form is in the form of a monolithic system, an expanding bilayered or multilayered or in-lay system.

15) The controlled release formulation of claim 14, wherein the bilayered gastroretentive dosage form comprises (a) a direct acting antiviral agent layer and (b) a gastroretentive layer.

16) The controlled release formulation of claim 15, wherein the direct acting antiviral agent layer comprises at least one direct acting antiviral agent, at least one release modifier, at least one pharmaceutically acceptable excipient, and optionally at least one swelling agent; and the gastroretentive layer comprises at least one swelling agent and at least one pharmaceutically acceptable excipient.

17) The controlled release formulation of claim 13, wherein the dosage form is retained in the upper gastrointestinal tract for a time period of about 30 min to about 12 hours.

18) The controlled release formulation of claim 1 , wherein the dosage form releases at least one direct acting antiviral agent over a period of up to about 24 hours.

19) The controlled release formulation of claim 1 , wherein the formulation further comprises one or more active agents.