FORM-2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE Specification (Section 10, rule 13) A PROCESS FOR THE MANUFACTURE OF A SUSTAINED RELEASE FORMULATION ALKEM LABORATORIES LIMITED of 510 Shah Nahar Industrial Estates, Dr. E.Moses Road, Worli, Mumbai 400 018, Maharashtra, India, an Indian Company GRANTED THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE NATURE OF THIS INVENTION AND THE MANNER Original 22-6-2007 EST WHICH IT IS TO BE PERFORMED: The invention relates to a process for the manufacture or a sustained release formulation. The means by which a drug is introduced into the body is almost as important as the drug itself. It is imperative that the drug concentration in the blood be maintained at a level that provides maximum therapeutic benefit. Traditionally, delivery systems have not incorporated means of controlled release. The problem, however, is that with each dose on a non controlled release drug, the concentration of drug available to the body immediately peaks and then declines rapidly. At times, the drug concentration is very high, contributing to adverse effects. At other times, the concentration is too low to provide therapeutic benefit. It is desirable to release drugs at a constant rate i.e. zero order for prolonged period (upto 24hrs), thereby maintaining drug concentration within therapeutic range and eliminating the need for frequent dosages. To meet the above requirement Oral controlled-release drug delivery system were developed which provide continuous oral delivery of drugs at predictable and reproducible kinetics for a predetermined period throughout the course of the gastrointestinal transit. Also included in controlled release drug systems were systems that target the delivery of drugs to a specific region within the gastrointestinal tract for either a local or a systemic action. Oral controlled-release drug delivery systems involve the transport of the drug to a particular part of the body, which may be accomplished in a number of ways like osmotic pressure-controlled gastrointestinal delivery systems, membrane permeation controlled gastrointestinal delivery systems, Gel diffusion gastrointestinal delivery systems, pH controlled gastrointestinal delivery systems, and ion exchange controlled gastrointestinal delivery systems. In the prior art, oral controlled release drug delivery systems reported use polymers as excipients. These polymers may be hydrophilic in nature such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, and carboxymethyl cellulose etc. or hydrophobic polymers including Eudragits (methyl polyacrylic acid) and their derivatives. Oral controlled release delivery systems provide improved patient acceptance, convenience of administration, better drug utilization, more uniform blood concentration, reduced dosing frequency, a greater selectivity of pharmacological activity etc. A controlled /extended release formulation containing Theophylline is described in U.S. Pat. No. 5,164,193. Various oil components like hydrogenated castor oil, glycerin fatty acid ester compositions with stearic acid were employed according to the experimental description to make Theophylline formulations, which were then compressed into tablets. A sustained release or controlled release tablet formulation containing Niacin is described in U.S. Pat. No. 5,126,145. Various fatty acid materials like hydrogenated vegetable oil, glyceryl behenate compositions with Methocel K100M CR were employed according to the experimental description to make Niacin formulations. A sustained release pellets composition is described in U.S. Pat. No. 5,807,583. Various carriers like glyceryl monostearate, stearyl alcohol with beeswax were employed according to the experimental description to make Paracetamol pellets formulations. A sustained release formulation containing Cephalexin described in U.S. Pat. No. 4,797,286. Orally administrable pharmaceutical formulation was made employing wax like carrier to form a matrix. The composition was prepared by admixing a pharmaceutically active agent with molten waxy material and then filling capsules with the admixture. A sustained release formulation containing Captopril is described in U.S. Pat. No. 5,433,951. Various fatty acid compositions were employed according to the experimental description to make Captopril formulations, which were then used to fill hard gelatin capsules. A sustained release formulation containing theophylline with certain nucleation enhancers is described in U.s. Pat. No. 6,171,615. The pharmaceutical composition in this study, is in gelatin capsule by employing certain fatty excipients in combination with certain nucleation enhancers, are particularly stable with respect to dissolution upon aging. The above mentioned inventions using fats and additives, which claim to modify delivery of drugs usually, pertain to a single therapeutic agent. Also in some cases the fatty modifiers are mixed with actives and other excipients and compressed into tablets either directly or with the help of a solvent with the inherent problems. The processes using polymers are based on two principles of incorporating drugs, 1. Dissolving the polymer and the drug in a solvent with the disadvantage of the residual solvent retention and 2. Mixing the polymer, the drug and excipients and directly compressing the mixture with the possibility of segregation of individual components due to differences in density and size during processing. This causes non uniform distribution of drugs in unit doses and non uniform delivery of the drug to the body. Traditionally, there is no unique oral controlled release delivery system that delivers both acidic and basic drugs and also water soluble and insoluble drugs. Present invention to some extent solves the above mentioned problem for both acid and base type of drugs and also water soluble and insoluble drugs to deliver it at predictable and reproducible kinetics for a predetermined period throughout the course of the gastrointestinal transit. Present invention also describes the ease of making the present controlled release system without any special processes or equipments but modification of available equipment. Typically, the process in accordance with this invention, can use the active therapeutic agents that have range of solubility based on hydrophilic or lipophilic nature of the said active therapeutic agent. In addition to modifying the drug release profile kinetically, the process does not affect the stability of the incorporated drugs. This invention gives slow release in-vitro extending between 12-24 hrs. Matrix based and fatty materials and polymers have been employed with or without surfactants for controlled release of drugs. These include a mixture of waxes like bees wax (melting range 62°C to 65°C), carnuba wax (melting range 82°C to 85.5°C), glyceryl mono stearate (melting range 56°C to 58°C), stearic acid (melting range 69°C to 70°C), palmitic acid (melting range 63°C to 69°C), glyceryl mono palmitates, stearyl alcohol (melting range 59.4°C to 59.8°C) and cetyl alcohol. Other fats such as cocoa butter (melting range 31°C to 34°C), witepsol H15 (melting range 33.5°C to 35.5°C), witepsol W45 (melting range 29°C to 32°C) have been employed with or without surfactants, which solidify at room temperature. Another fat that has been used is sulfated castor oil with or without surfactants. Therapeutic agents which act on various physiological systems such as adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, the alimentary and excretory systems, the histamine system and the central nervous system may be selected from, for example, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, anti¬inflammatory corticosteroids, ocular drugs and synthetic analogs of these species are employed with the above mentioned polymers to achieve extended or modified release. These polymers have been used in several combinations with other polymers and other excipients to achieve desired drug release. The novel process of present invention involves melting and direct encapsulation and uses fatty materials either alone or in combination with other inert excipients to modify the drug release to a desired extent usually 12-24 hrs. In particular this invention envisages a process of incorporating / dispersing therapeutic agents in a mixture of inert low melting lipophilic excipients in a molten state between 40°C to 60°C and filling the said liquid in gelatin capsules. The novel process according to this invention uses a low melting lipophilic material with varying composition using different excipients and drug concentrations and overcomes the disadvantages of segregation due to rapid congealing of dispersed or soluble material. It also overcomes the disadvantage of residual solvent obviously because no solvent is employed. Thus, both the safety and efficacy are achieved which are the matter of concern even for regulatory authorities. In addition the release from the polymers normally is modified by several properties of the incorporated drugs including solubility, where as the novel matrix based process employed here is independent of the solubility of the incorporated drugs for the purposes of dissolution. The present invention also modifies the release of some water soluble and water insoluble therapeutic agents in a constant release manner for prolonged period of time usually 12-24 hrs. In the present invention however it was found that although the use of a lipophilic carrier alone did deliver a drug to a predictable and reproducible kinetics for a predetermined period throughout the course of the gastrointestinal transit, a combination with a release enhancers and water soluble surfactant having HLB value more than 8, in certain proportions gave far superior and the desired predictable and reproducible kinetics for a predetermined period of time usually upto 12-24 hrs. The present invention describes a matrix formulation of well mixed components comprising the drug from antidepressant category like Venlafaxin, cardiac drugs like Diltiazem, vasodilator like Pentoxifylline one or more lipophilic and/or hydrophilic polymer, water soluble surfactant having hydrophilic lipophilic balance more than 8 and release enhancers. The pharmaceutical composition is either compressed into tablets or filled in hard gelatin capsules or granulated and filled in capsules. A variety of pharmaceutically acceptable carrier matrices may be employed in the formulation of the invention. The quantity of the lipophilic carrier matrix present in a formulation of the invention will be in the range of about 10.0% to about 99.0% by weight. The lipophilic carrier matrices employed herein are selected from the group of vegetable oils, hydrogenated vegetable oils, partially hydrogenated vegetable oils, synthetic triglycerides, modified triglycerides, fractionated triglycerides, and mixtures. All available carriers are commercially available. Lipophilic carriers are available with varying physical properties such as melting point, HLB and solubility in various solvents. In accordance with a preferred embodiment of this invention, the formulation of the present invention also contain a release enhancer which assists in the delivery of the therapeutic agent in a predictable and reproducible kinetics for a predetermined period throughout the course of the gastrointestinal transit. The quantity of the release enhancer present in a formulation of the invention will be in the range of about 0.1% to about 20.0% by weight of the total formulation. The release enhancer employed herein is selected from the group consisting of triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-hydroxyethylpyrrolidone, hydroxypropyl cyclodextrins, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and mixtures thereof. The formulations of the present invention also contain a water soluble surfactant having HLB value more than 8, which has affinity for water and which tends to combine readily with water. Once this water soluble surfactant is incorporated in the present formulation, water is facilitated into the lipophilic carrier matrix so as to dissolve or emulsify or suspend the therapeutic agent and permits its release over a prolonged period of time in a controlled fashion. . The quantity of the water soluble surfactant present in a formulation of the invention will be in the range of about 1.0% to about 85.0% by weight of the total formulation. The water soluble surfactant is selected from the group consisting of polyethylene alkylethers, polyethylene glycols fatty acid esters, polyethylene glycol glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymer, polyglycerol fatty acid esters, polyethylene glycerides, vegetable oils, hydrogenated vegetable oils and sterols and mixtures. Any number of therapeutic agents may be employed in the formulations of the present invention. These active agents may exist as either solids or liquids at standard temperature and pressure. Exemplary pharmaceutical active agents suitable for use herein include, but are not limited to, the cholesterol reducing drugs such as simvastatin, lovastatin, pravastatin; the non-steriodal anti-inflammatory agents such as piroxicam, ibuprofen, nimesulide, fenoprofen; the antidepressant drugs such as fluoxetine, venlafaxin, vasodilator like pentoxifylline; the cardiac drugs such as diltiazem, losartan, nifedipine, the antibacterial drugs such as cefaclor, amoxicilln, ampicillin. Other agents capable of oral administration may also be used herein. The quantity of active agent present in a formulation of the invention will be from about 0.1% to about 70% by weight, more preferably from about 15.0% to about 50.0% by weight. The examples below are not limiting and are merely representative of various aspects and features of the present invention. The examples demonstrate methods of testing the release of the pharmaceutical agents from the formulations. In addition, the examples illustrate preparation procedures for the formulations of the invention. The concentrations described herein of the ingredients employed in a formulation of the invention are based only on the ingredients present in the semi-solid matrix. Therefore, the total concentration of the semi-solid matrix constitutes 100% of the total formulation, as the weight of the capsule and therapeutic agent are not considered when calculating the percentage provided hereinafter and the concentration of the therapeutic agent is mentioned percentage of the semi-solid matrix concentration. The preparation or process of making formulations is as follows: Typically, the lipophilic pharmaceutically acceptable carrier was melted in a thermally controlled vessel with a stirrer, whose temperature was maintained between 55°C to 75°C. The therapeutic agent was added in the molten mass in a three to four steps to ensure the homogeneous dispersion or solution. Next, the surfactant was added to the molten mass and it was ensured that homogeneous dispersion or solution was formed. After that the release enhancer and wetting agents and diluents were added in the molten mass respectively. The molten mass was filled in hard gelatin capsules with the help of syringe, with a facility of maintaining the temperature of molten mass between 50°C to 60°C. The filled capsules were allowed to cool to room temperature to provide a homogeneous solid mixture. In-Vitro Drug Release Evaluation: For evaluating the drug release behavior of the experimental formulations, a test-method was devised based upon the USP XXIV dissolution test for tablets and capsules. The dissolution apparatus (Make: Electrolab Tablet Dissolution Tester USP 24 Model: TDT-06P) as specified by the USP XXIV (apparatus 1) was used with Sorensens phosphate buffer, pH 7.8 equilibrated to 37.degree. C. The total volume of buffer added to each dissolution vessel was 1000 ml, with a basket rotation speed of 100 rpm. unless effect of agitation was studied. The test sample of Nimesulide was dropped into the basket, which was further immersed into the dissolution medium. After every hour, a 10 ml aliquot of the dissolution medium was removed and replaced with 10 ml of fresh buffer solution. Each 10 ml sample was initially filtered through 1.2 coarse filter. The absorbance for the filtered solution was then determined at 395 nm using a UV/VIS Spectrophotometer (Make: Jasco, Model: V-530) dissolution medium was calculated using a calibration curve for Nimesulide. For venlafaxin HC1 the dissolution medium used was water. The total volume of water added in to each vessel was 1000 ml. Remaining procedure was same as that for Nimesulide. The absorbance for the filtered solution was then determined at 226 nm and 273.5nm using a UV/VIS Spectrophotometer (Make: Jasco, Model: V-530). The drug released was calculated using a calibration curve for Venlafaxin. For Diltiazem HC1 the dissolution medium used was water. The total volume of water added in to each vessel was 1000 ml. Remaining procedure was same as that for Nimesulide. The absorbance for the filtered solution was then determined at 234 nm using a UV/VIS Spectrophotometer (Make: Jasco, Model: V-530). The amount released was calculated using a calibration curve for Diltiazem HC1. For Pentoxifylline the dissolution medium used was water. The total volume of water added in to each vessel was 1000 ml. Remaining procedure was same as that for Nimesulide. The absorbance for the filtered solution was then determined at 274 nm using a UV/VIS Spectrophotometer (Make: Jasco, Model: V-530). The amount released was calculated using a calibration curve for Pentoxifylline. The kinetics of the therapeutic agent release data were analyzed in terms of equation: Mt/Moo = ktn Where Mt, M k, and n are the amount of drug released at time t, the total amount of drug, a constant, and n is the exponent for the release kinetics used to characterize the release mechanism, respectively. According to the known criteria of release kinetics from systems zero-order, anomalous kinetics and Fickian release are represented by 0.89