FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule!3)
1. TITLE OF THE INVENTION:
"A NOVEL ORAL CONTROLLED RELEASE DOSAGE FORMS FOR
WATER SOLUBLE DRUGS"

2. APPLICANT (S):
(a) NAME: FDC Limited
(b)NATIONALITY: Indian company incorporated under the Companies
Act 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (W), Mumbai - 400 102, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.


Technical field:
The present invention relates to novel oral controlled release drug delivery system for water soluble drugs and their pharmaceutical acceptable salts thereof selected from therapeutic categories like cardiovascular drugs, neurotherapeutics agents, anti-infective, analgesics and drugs acting on endocrine and respiratory systems and a process of manufacturing the same.
Background and prior art:
Developing oral controlled release matrix system for water-soluble drugs with constant release rate has always been a challenge to the pharmaceutical technologist. Most of water-soluble drugs; if not formulated properly, may readily release the drug at a faster rate, and are likely to produce high blood concentrations leading to toxic effects after oral administration. The release of drug from controlled release dosage form not only determines the duration of therapeutic efficacy but also the. toxicity. Design of reliable and reproducible dosage form, which releases the drug in pre-programmed manner without the possibilities of dose dumping, is a challenging task and hence the development of such an ideal dosage form is essential to meet never ending medical demands.
Soluble drugs are difficult to formulate into a controlled release dosage forms. Solubility is a driving force for a drug substance to dissolve in water; the greater the solubility the greater the rate of dissolution, when all other factors are kept constant.
Large numbers of controlled release drug delivery systems have been reported in literatures. These systems are based on different drug release mechanisms such as diffusion controlled, disintegration controlled, osmotically controlled and pH triggered systems. However, many systems fail to produce desirable drug release in in-vivo environment. The ideal system should provide consistent release profile in both in-vitro and in-vivo condition and the drug release should be independent of physiological variability such as pH, gastrointestinal fluid and gastrointestinal transit time. Designing and development of controlled release or sustained release drug delivery system for the drugs having high aqueous solubility along with high dose is a challenging task for pharmaceutical scientist. Drugs having high solubility along with high dose easily leach

from the matrix system and hence it is very difficult to control the release profile of the drug. Diffusion controlled release system using polymeric system have been used to deliver the soluble drug.
US 6475521, discloses a dosage form for Metformin a water soluble drug. Metformin, an oral hypoglycemic agent, has very high aqueous solubility (>300mg/ml at 25°C) and hence it is extremely difficult to formulate controlled release preparation. However patent relates to the formulation of gastro retentive drug delivery system for sustained delivery of Metformin. Metformin has been reported to have a better absorption of drug in proximal part of gastrointestinal tract.
US6682759 also discloses a two-phase controlled release technique of water soluble drug like Metformin. Technique herein relates to an immediate release coat with a sustained release core. The sustained-release core can be prepared with uniform quality without difficulty, but immediate release coat is prepared by wet coating hence it is difficult to form uniform coating.
WO 2008/061226 demonstrated the composition and preparation method for sustained release formulation of Topiramate. The proposed formulation comprises a sustained release compartment and an optional immediate release compartment. Sustained release formulation disclosed in this publication may not be considered as an ideal formulation because of higher chances of dose dumping.
US Patent application No: 20070224281, teaches composition and method for producing sustained release preparation of Topiramate. The sustained release Topiramate was produced by using double granulation method. Solid dispersion method involved the utilization of high thermal energy for processing and/or removal of solvents. High operational temperature may be the hurdle for drug stability, excipients stability, compatibility and so on. Therefore, thermal .free process at ambient temperature, if at all invented, can be applied effectively for preparation of Topiramate sustained release formulations.

WO 2004/010970 describes the formulations and dosage form for controlled delivery of Topiramate. The invention, uses surfactants for solubility enhancement of Topiramate. Usage of surfactant in oral formulation for chronic therapies such as epilepsy is not advisable and some time this may leads to lethal effects. The system, which was developed in this publication, is based on osmotic controlled release drug delivery. The orifice diameter, matrix integrity and other parameter, which not only affect drug release but also therapeutic efficacy of dosage form.
US Publication No: 0121112 describes once daily controlled release pharmaceutical formulation, which contains therapeutic amount of Topiramate, capable of being administered to specific region along gastrointestinal tract. The combination of delayed, immediate and sustained release system was developed to improve the therapeutic efficacy of Topiramate and reduce the dose-associated side effects. Delayed release system is based on the gastrointestinal physiological environments such as pH, ionic composition, bacteria etc. Concomitant administration of food, antibiotics, antacids and other drugs may have an influence of gastrointestinal physiology and hence alter the drug release from dosage form.
With the moisture sensitive drugs, usage of water in wet granulation may interfere its stability in dosage forms. Moreover, other solvents as wet granulation fluid needs drying, monitoring of residual solvents, monitoring of toxicity of solvent and other environmental factors. The above constraints have been overcome by the present invention.
The present invention offers a technology which provides controlled mode of drug release of water soluble drugs in about 6 to 21 hours. Moreover, the dosage form is based on diffusion and disintegration controlled release mechanism, predominantly, drug release is controlled by diffusion. Such release pattern offers uniform and desirable amount of plasma drug concentration. Another commonly associated problem with water soluble drug is 'burst release' of drug from dosage form and hence leading to poor matrix mechanical stability and dose dumping. Dose dumping not only offers toxic plasma drug concentration but also leads to therapeutic failure. The present technology relates to unique combination of high molecular weight polymers and acid insoluble polymers that leads to better matrix integrity and minimum possibilities of dose dumping. The unique

system also offers programmable controlled release profile drug in biological fluids with better therapeutic efficacy.
Object of the invention:
The primary objective of the present invention is to provide a controlled release oral pharmaceutical composition of water-soluble drugs or pharmaceutically acceptable salts thereof in a hydrophilic matrix system.
Another objective of the invention is to provide a process for preparing an oral controlled release pharmaceutical composition of water-soluble drugs or pharmaceutically acceptable salts thereof.
Further objective of the invention is to provide an alternative strategy, which can deliver the drug with desirable release kinetics and least possibility for dose dumping.
It is further object of the present invention to provide cost effective technology for once daily oral dosage formulation by simple processes such as direct compression or granulation.
Summary of the invention:
In accordance with the above objectives, the present invention provides a novel controlled release oral pharmaceutical composition of water-soluble drugs and pharmaceutically acceptable salts thereof selected from therapeutic categories like cardiovascular drugs, neurotherapeutics agents, chemotherapeutic agents and drugs acting on endocrine system and a process of manufacturing the same in a hydrophilic matrix system, wherein the matrix comprises of pH independent polymers in combination with acid insoluble polymers, a diluent, a lubricant and a glidant.
Detailed description of the invention:
Accordingly, the present invention provides an oral controlled release pharmaceutical formulation comprising water-soluble drugs and pharmaceutically accepted salts thereof in a hydrophilic matrix system by direct compression or granulation.

The active ingredient in the formulation of the invention is selected from therapeutic categories like cardiovascular drugs such as Antilipedemics, (3-blockers, ACE inhibitors, diauretics, a-receptor agonist, calcium channel blockers, anti coagulants, anti anginal and anti arrhythmic agents , neurotherapeutics agents such as anti epileptics, anti depressants, tranquillizers, psychotherapeutic agents, sedatives and hypnotics, anti migraine, anti pyretic agents, anti emetics, anti spasmodic agents, anti infective agents such as 3 lactam antibiotics, macrolide antibiotics, anti-fungal, anti viral, antifungal, and cytotoxic chemotherapeutic agents, drugs acting on endocrine system such as oral hypoglycemic agents, thyroid and anti thyroid drugs, synthetic and semi synthetic hormones and drugs acting on respiratory system such as antitussives, decongestants and anti asthmatics, prepared through a synthetic process.
According to the present invention wherein the said matrix comprises of pH independent polymers in combination with acid insoluble polymer and/or a diluent, a lubricant and/or a glidant.
Primarily, pH independent polymers are incorporated in the formulation to provide pH independent release of drug from the formulation of water soluble drugs. In addition, pH independent polymers provide controlled release of drug in stomach, whereas the controlled mode of drug release will be achieved in distal part of gastrointestinal tract due to high viscosity of diffusion layer of pH independent matrix system, erosion of pH dependent polymer and high solubility of such drugs in alkaline pH.
In the preferred embodiment pH independent polymers are selected from the group consisting of cellulose derivatives, chitosen derivatives, natural gums and polymethacrylates. Cellulose derivatives are selected from the group consisting of hydroxy propyl cellulose, hydroxy propyl ethyl cellulose, hydroxy ethyl cellulose, hydroxy propyl methyl cellulose, hydroxy methyl cellulose preferably hydroxy ethyl cellulose, hydroxy propyl methyl cellulose.
In the present invention pH independent polymer is ranging from 10 -90 %.

Acid insoluble polymers are used to retard the release in stomach and provide matrix integrity to the tablet and hence it prevents dose dumping.
Further in the preferred embodiment acid insoluble polymers are selected from group of alginate acid derivatives, acrylic acid derivatives and phthalates, acetates, succinates, acetate succinate of cellulose esters preferably are acrylic acid derivatives, ranging from 5 -70%.
A diluent is selected from the group consisting of cellulose derivatives, sugars, inorganic phosphates preferably microcrystalline cellulose, lactose, mannitol and dibasic calcium phosphate, ranging from 5 -95 %.
A lubricant is selected from the group consisting of magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, stearic acid, talc, zinc stearate, magnesium lauryl sulfate and colloidal silicon dioxide.
Glidants are added to improve the flow properties of the formulation and to improve the accuracy of dosing. Glidant is selected from the group consisting of silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
According to the invention, an oral controlled release delivery system for water soluble drugs and their pharmaceutical acceptable salt thereof are prepared by, direct compression or granulation method in a hydrophilic pH independent matrix system using pH independent polymer in combination with acid insoluble polymer. For moisture sensitive drugs the usage of water in wet granulation may interfere its stability in dosage form. Moreover, other solvents as wet granulation fluid need drying, presence of residual solvents, toxicity of solvents and other environmental issues. Direct compression is not only the convenient process for make a stable formulation but also provide cost effective formulations.
The inventive composition according to the present invention essentially comprises of following excipients:
• active
• Acid insoluble polymer (20-70% w/w)

• Matrix forming agent (10-90% w/w)
• Diluents (5-95% w/w)
• Lubricants (qs)
• Glidants (qs)
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples Example 1
Accurately weighted quantities of Topiramate, Hydroxylpropyl methylcellulose, Eudragit, Microcrystalline cellulose and Aerosol are sieved individually and are blended thoroughly. The blend was lubricated with magnesium stearate and directly compressed using 9.5mm S.C punches. The ingredients are added in following proportions

Topiramate 200mg
Hydroxylpropyl methylcellulose 50mg
Eudragit 50mg
Microcrystalline cellulose lOOmg
Magnesium stearate 3mg
Colloidal silicondioxide 3mg
Example 2
Accurately weighted quantities of Topiramate, Hydroxylpropyl methylcellulose, Sodium alginate, Microcrystalline cellulose and Aerosol are sieved individually and are blended thoroughly. The blend was lubricated with magnesium stearate and directly compressed using 9.5mm S.C punches. The ingredients are added in following proportions

Topiramate 200mg
Hydroxylpropyl methylcellulose 50mg
Sodium alginate 50mg
Microcrystalline cellulose lOOmg
Magnesium stearate 3mg
Colloidal silicondioxide 3mg
Example 3

Accurately weighted quantities of Sodium Feredetate, Hydroxylpropyl methylcellulose, Polycarbophil, Dibasic calcium phosphate and Aerosol are sieved individually and are blended thoroughly. The blend was lubricated with magnesium stearate and directly compressed using 9.5mm S.C punches. The ingredients are added in following proportions

Sodium Feredetate 257mg
Hydroxylpropyl methylcellulose 50mg
Polycarbophil 50mg
Dibasic calcium phosphate lOOmg
Magnesium stearate 3mg
Colloidal silicondioxide 3mg