FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION COMPRISING THEOPHYLLINE"
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GlenmarkPhanMcMticals Limited
an Indian Company, registered brider1 the Indian company's Act 1957
and having its registered office at
Glenmark House, HDO - Corporate Bldg,
Wing -A, B.D. Sawant Marg,
Cfiakkl^kiSMi(fiist),
Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION
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Technical Field
The present invention relates to the extended release pharmaceutical composition comprising theophylline or its pharmaceutically acceptable salts, and water less than 4% by weight of the composition and to the process of prepg^ionitfteltfeft
Description of the Related Art
Theophylline is a methylxanthine drug used in treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) or asthma under a variety of brand names. Theophylline being a member of the xanthine family bears structural and pharmacological similarity to caffeine.
Theophylline is very old product and it is available in various dosage forms like tablet, capsule, elixir, solution and injection. The extended release tablets currently sold in United States are Uniphyl®, Theochron, Quibron-T/SR. Uniphyl® is sold by Purdue Frederick as 400mg and 600mg strengths. Majority of theophylline compositions have discontinued from market due to various reasons. Majority of manufacturers, tfa.ced- a common problem in extended release theophylline composition was the non-uniform release profile. In the past extended release compositions of theophylline were developed by using the techniques limited to matrix tablets and multiparticulate compositions (pellets beads enclosed in hard gelatin capsule). Few matrix based compositions in prior art were based on wax or fatty acids.
U.S. Patent No. 4828836 ("the '836 patent") assigned to Euroceltique describes a controlled release pharmaceutical composition comprising a solid active ingredient incorporated in a controlled release matrix that comprises a vvater soluble polydextrose and the composition contains between about 48% and 90% fey weight of the active ingredient.
U.S. Patent No. 5091189 ("the '189 patent") assigned to Euroceltique deals with the controlled release tablet composition of theophylline, based on a matrix consisting of hydrophilic or hydrophobic polymer, wax having a melting point between 20°and 90°C, and between 3% and 10% by weight water.
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The '189 patent describes very critical aspect pf the theophylline controlled release tablets i.e the appropriate percent of water/moisture content in the composition. The percent of water/moisture content affects the in-vitro release profile of the drug. Below 3% water content the composition showed the slow release rate and above 10% water content the composition has fast release rate, only the dosage forms having water content, bettween 3% and 10% (by wt) were found to be more stable over a 1-2 year period, with. regard to rate of release of the active ingredient. Author of '189 patent set a very complex limitation of water content to achieve the stable and pH independent dissolution profile of extended release compositions of Theophylline.
The inventors of present invention overcome the critical limitation of water content identified in '189 patent. The present inventions provides the theophylline controlled release composition with low water content having stable and pH independent dissolution profile.
The objective of Invention:
The objective of present invention is to provide an extended release pharmaceutical composition comprising Theophylline or its pharmaceutically acceptable salts, wherein the moisture content of said composition is less than 4% of the weight of composition.
The objective of present invention is to provide an extended release pharmaceutical composition comprising Theophylline or its pharmaceutically acceptable salts, wherein the moisture content of said composition is less than 4%, more preferably less than 3% of the weight of composition.
Another objective of present inventiorfis toprovidean extended release tablet of Theophylline or its pharmaceutically acceptable salts, prepared by non-aqueous granulation, wherein the moisture content of said composition is less than 4%, more preferably less than 3% of the weight of composition.
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Summary of the Invention:
The present invention provides an extended release pharmaceutical composition comprising Theophylline or its pharmaceutically acceptable salts wherein the moisture content of said composition is less than 4% of the weight of composition. The said controlled release composition for oral administration is prepared by non-aqueous granulation.
Detailed description of the preferred embodiments:
The term "controlled release pharmaceutical composition" for the purpose of said invention represents a dosage form that delivers a drug over an extended period of time and extends the duration of drug action over that achieved by conventional delivery. The term "low moisture content" or "low water content" used herein means moisture/water content less than 4% more preferably less than 3% of the weight of composition.
Theophylline for the purpose of preseftt invention may fee used in its anhydrous form or hydrate
form, but anhydrous form is most preffered form. The preferred dose of theophylline in the
extended release dosage form, according to the present invention ranges from 50 to 600mg.
The extended release dosage form of theophylline of present invention preferably contains theophylline more than the 50% (by wt) of the composition, preferably more than 70% (by wt). The release retarding material in the present composition may be hydrophilic or hydrophobic in nature, and it can be selected from the group comprising but not limited to gums, cellulose ethers, acrylic resins and protein derived materials. Of these polymers, the cellulose ethers, especially hydroxyalkylcelluloses and carboxyalkylcelluloses, are preferred. The oral dosage form may contain between 1% and 20%, especially between 2% and 12% (by weight) of the atleast one hydrophilic or hydrophobic polymer.
The extended release dosage form of theophylline of the present invention, in addition to the
polymer, consists of one or more waxes. The at least one wax may be, for example, a
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polyalkylene glycol, a fatty (aliphatic) acid, a fatty (aliphatic) ester or, which is preferred, a fatty (aliphatic) alcohol, particularly a C12 -C36 fatty alcohol, especially a C14 -C22 fatty alcohol such as myristyl alcohol, cetyl alcohol, stearyl alcohol or cetostearyl alcohol.
In addition to the above ingredients, a controlled release pharmaceutical composition according to this invention may also contain suitable quantities of other materials, e.g. diluents, lubricants, binders, granulating aids, colorants, "flavourants and glidants that are conventional in the pharmaceutical art.
Another embodiment of the present invention consists of a process of preparing extended release compositions of theophylline, prepared by avoiding the use of water. The process of preparing extended release compositions of theophylline comprises, uniform mixing of at least one hydrophilic or hydrophobic polymer and theophylline, further granulating the above blend by using a solvent other than water. The preferred solvent for the purpose of this granulation is Isopropyl alcohol. Drying the granules consisting of hydrophilic or hydrophobic polymer and theophylline. The dried granules were further mixed with at least one melted wax having melting point between 25° to 90 ° C. Preferably the melted wax is added to a suitable Non-aqueous solvent before adding to the dried granules. The granules consisting wax and hydrophilic or hydrophobic polymer further dried and lubricated The lubricated granules are then compressed into tablet or filled in the hard gelatin capsule. The final composition thus obtained was subjected to the test of determination of water content using Karl Fischer Method. The extended release composition of present invention consists of water less than 3%, preferably less than 2%, more preferable less than 1%.
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Example: Extended release composition, of Theophylline consisting water less than 4%, prepared by using Isopropyl alcohol as granulation liquid.

Sr. No. Ingredients Quantity per tablet ( mg)
400 mg 600 mg
1. Theophylline anhydrous 400 600
2. Cetostearyl alcohol 16 24
3. Polyvinyl pyrrolidone (PVPK-30) 8 12
4. Magnesium stearate 5 7.5
5. Hydroxyethyl cellulose (HHX 250 ) 10 15
6. Talc 5 7.5
7. Polyethylene glycol 6000(PE$ 6000) ... ,, 20 30
8. Isopropyl alcohol QS QS
1. Theophylline & Hydroxyl ethyl cellulose were passed through ASTM 40 # & mixed in rapid mixer granulator (RMG)
2. PVP K- 30 was dissolved in isopropyl alcohol and the blend in step 1 was granulated in rapid mixer granulator
3. The granules were dried initially using air and then at 60°C for 20-30 minute till LOD was not more than 2.0 %
4. The granules were passed through ASTM 30 # using oscillating granulator
5. PEG 6000 and Cetostearyl alcohol were melted and isopropyl alcohol was added to form clear solution and the blend in step 4 was granulated in RMG.
6. The granules were dried at 30-35 °C till LOT) at 105°C-NMT 2.00 %
7. The granules were dry passed through ASTM 20 # mesh using oscillating granulator.
8. Magnesium stearate and Talc was added after passing though ASTM 60 #.
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However the Extended release Theophylline tablets having water content below 3%, exhibit a stable dissolution profile in the accelerated conditions 40° C /75 % RH after the end of two months.
Moreover the release of theophylline from the extended release theophylline tablets of present invention was found to be substantially same when dissolution study was performed at pH 1.2 and pH 4.5 in USP apparatus I, 900 ml of dissolution medium, at 100RPM presented in table I and figure 1.
Table II

% release of theophylline against time in hours
pHanddissolutionmedium 1 2 3 4 5. 6 8 10 12 16 20 24
pH4.5 Acetate buffer 12 18.7 23.8 27.8 31.7 35.3 41.2 45.8 50.9 58.1 64 68.5
pH1.2 O.lNHCl 11.6 18.5 24 28.8 32.5 36.3 42.6 48.1 52.9 61 68 73.7
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