FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
'HE PATENTS RULES, 2003
Provisional Specification
See Sections 10 and rule 13 ]
Title: Modified Release Oral Dosage Form Using Co-Polymer of Polyvinyl Acetate
Applicant: (a) Astron Research Limited
(b) Nationality: Indian
(c) 10th Floor, Premier House Bodakdev, Opp. Gurudwara Sarkhej -Gandhinagar Highway Ahmedabad 380054
The Following specification describes the invention:


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Field of the invention
The present invention relates to the use of co-polymer of polyvinyl acetate or Eudragit NE 30 D or Eudragit L30D55 as the release-controlling agent for a modified release pharmaceutical oral dosage. This dosage form may be pellets, capsule or tablet of pharmaceutical active ingredient.
Background
r
Immediate release dosage forms of pharmaceutically active ingredient results rapid dissolution and rapid rise in plasma concentration within a short period of dosage administration. Subsequently, due to metabolism and elimination, the plasma concentrations fall below the therapeutic level within period of 8-12 hours, thus requiring additional dosing, which may cause unpleasant side effects.
In order to avoid such high fluctuations in plasma concentration, the release of pharmaceutically active ingredient can be controlled in the gastrointestinal tract, so as to have a prolonged effect of drug even after a dose of once or twice a day, more preferably once a day.
Immediate release dosage forms of pharmaceutically active ingredients such as Venlafaxine hydrochloride, Bupropion hydrochloride, Pravastatin, etc results in a high plasma concentration, which causes unpleasant side effects, such as nausea or vomiting in a considerable part of thepatients. In order to avoid such high plasma concentration the release of Venlafaxine should be controlled throughout«the gastrointestinal tract
Objects of the invention
First object of the invention is to provide oral controlled release pharmaceutical dosage form of pharmaceutically active ingredients.
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Another object of the invention is to prepare an oral dosage form preferably capsule or tablet of a pharmaceutically active ingredients using co-polymer of polyvinyl acetate as the release controlling excipient.
Still another object of invention is to provide orally administrable modified release pharmaceutical dosage form of different actives such as Venlafaxine hydrochloride, Bupropion hydrochloride, Pravastatin, Lansoprazole, etc.
Still another object of invention is to provide once or twice a day more preferably once a day oral modified release pharmaceutical dosage form of pharmaceutically active ingredients.
One more object of the invention is to provide a process for the preparation of oral modified release pharmaceutical oral dosage form of pharmaceutically active ingredient and pharmaceutically acceptable salts thereof.
This present invention further aims to develop the pharmaceutical formulations for oral use provides release of an active ingredient through out the gastro intestinal tract or can be modified to target a segment of the gastrointestinal tract

Summary of the Invention
The present invention relates to the use of co-polymer of polyvinyl acetate or Eudragit NE 30 D or Eudragit L30D55 for the preparation of modified release pharmaceutical oral dosage form of pharmaceutically active ingredient. This dosage form is in the form of pellets, granules, capsule or tablet. The controlled release of pharmaceutically active ingredient through out the gastrointestinal tract is achieved by the process of coating the co-polymer of polyvinyl acetate onto the core of drug like drug loaded non-peril seeds or drug containing pellets or alternatively by including it in the core tablets to form a matrix which controls the drug release.
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Detailed Description of the Invention
The present invention is to provide oral controlled release pharmaceutical dosage form of pharmaceutically active ingredients using co-polymer of polyvinyl acetate as the release controlling excipient.
The dosage form can be in the form of pellets in capsule or tablet or
alternatively matrix tablets used once or twice a day, more preferably once a
day.
The oral formulations use provides release of an active ingredient through out the gastro intestinal tract or can be modified to target a segment of the gastrointestinal tract.
To have controlled release of drugs such as Venlafaxine hydrochloride. Bupropion, Lansoprazole, etc. the dosage form is prepared using co-polymer of polyvinyl acetate. The polymer may be present in the core tablets to form a matrix dosage form, which will control the release of the drug from it. Alternatively, it may also be used in the coating solution to provide a barrier coat from which the drug will be released gradually. In addition, the polymer may also be coated onto drug loaded non-peril seeds or drug containing pellets to provide a controlled release barrier film.
The present invention provides a modified release pharmaceutical oral dosage form of a pharmaceutically active ingredient. This dosage form comprises diluents 15 - 25%, active ingredient 25 - 45%, polymer 5 - 50%, glidant 0.1 -10%, opacifier/color 0.1 - 10%, retardant 5 - 40%, plasticizer 0.5 - 10% and solvent as per the requirement. These ingredients can be used in the amount as per the requirement in different stage of the process for preparation of the dosage form.
Modified release in the present invention means release of active ingredient from, the dosage form through out the gastrointestinal tract. The dissolution of
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the active ingredient in 2hr - not more than 50 %, in 6 hr- 40 -70 %, in 12 hr -
50 - 90 % and in 24 hr - not less than 80 %
The diluents used may be those commonly used in tablets dosage form such as lactose, starch, microcrystalline cellulose, dicalcium phosphate, or combinations thereof.
Alternatively non-peril seeds can be cellulose base or sugar base.
The pharmaceutically active ingredient can be selected from the group comprising of but not limited to class of phenethyl amines such as Bupropion & its salts and analogues, (±)-l-[2-(Dimethylamino)-l-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride and its analogues. Benzimidazole class of proton pump inhibitors such as lansoprazole and its salts and analogues, HMG-CoA reductase inhibitors such as Pravastatin and its salts and analogues, etc.
v
Polymers or retardants can be polymers or waxes selected from the group
comprising of but not limited to cellulose and cellulose derivatives such as
hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl
cellulose, microcrystalline cellulose, carboxymethylcellulose, sodium
carboxymethylcellulose, calcium carboxymethylcellulose, methylcellulose and
ethylcellulose; alginates such as sodium alginate, polyvinylpyrrolidones,
polyethylenoxides and polyacrylic/methacrylic acids including their
copolymers and crosslinked polymers thereof, i.e. carbopol, Eudragit,
polycarbophil and chitosan polymers, waxes include white beeswax,
microcrystalline wax, carnauba wax, hydrogenated castor oil, glyceryl
behenate, glycerylpalmito stearate, saturated polyglycolyzed glycerate and the
like.
Glidants or anti-sticking agents can be selected from the group comprising of but not limited to talc, colloidal silicon dioxide, stearic acid and stearates such as magnesium stearate, calcium stearate, glycerly monostearate and the like.
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Opacifier can be titanium dioxide and the like
Plasticizers can be selected from the group comprising of but not limited to acetyltributyl citrate, triacetin, acetyltriethyl citrate, dioctylphthalate, dibutylphthalate, triethyl citrate, tributylcitrate, polyethylene glycol, propylene glycol and the like.
Solvents can be water, isopropanol, acetone, ethanol and the like.
One of the methods for preparing the formulation of the present invention could be by fluidized bed coating technology, which comprises following steps:
1) Load the drug on non-peril seeds (NPS) in the form of a solution containing the pharmaceutically active ingredient along with suitable excipients such as polymer, glidant, opacifier, colorant, etc by fluid bed coating technique OR alternatively drug containing pellets may be prepared by the process of extrusion/ spheronization wherein the active ingredient is mixed with suitable excipients such as but not limited to starch, microcrystalline cellulose, dicalcium phosphates, glucose, lactose, Mannitol, etc,
2) Seal coating the drug loaded pellets using solution containing excipients
such as polymer, glidant, opacifier, colorant, etc. by fluid bed coating <
technique
3) Functional coat the seal coated pellets using solution containing excipients
such as retardant, plasticizer, colorant, opacifier, glidant, etc. by fluid bed
coating technique.

The pellets thus prepared can be filled in capsules or compressed into tablets after mixing with other suitable excipients. For capsules, the shell used can be of gelatin, hydroxy propyl methylcellulose and the like.
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Alternatively the controlled release dosage form can also be prepared by the process of granulation, wherein the release controlling excipient may be incorporated with the active pharmaceutical ingredient and other suitable commonly used exciptents so as to obtain granules, which may be then compressed into tablets for filled into capsules.
An alternate process would be to prepare the pellets as stated earlier, mix them with suitable excipients and compress them into tablets
Throughout this specification and the appended claims it is to be understood that the words "comprise" and include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
Example 1
The present invention has been described by way of example only, and it is to be recognized that modifications thereto which fall within the scope and spirit of the appended claims, and which would be obvious to a skilled person based upon the disclosure herein, are also considered to be included within the invention.
The above said invention can be illustrated by but not limited to following examples.
37.5,mg Venlafaxine capsule comprises non peril seeds 21.30%, Venlafaxine HC1 41.90%, sodium alginate 16.97%, talc 5.35%, titanium dioxide 1.63%, Kollicoat SR30D 11.68%, propylene glycol 1.17% and purified water in required quantity. These ingredients are used in different stage and in different proportion in the process of preparation of the said capsule.
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Formulation of Venlafaxine HCI (37.5 mg Venlafexine) Capsules

Sr.No. Ingredients mg / cap %w/w
;• 1 Non Peril Seeds 32.00 26.67
Drug Coating ;
2 Venlafaxine HC1 42.4 35.33
3 Sodium Alginate 10.60 8.83
4 Talc 2.0 1.66
' 5 Titanium Dioxide 2.0 1.66
6. Purified Water Q.S.* -
Sub Total 89.00 -
Seal Coating
7. Sodium Alginate 6.0 5.0
8. Talc :I 1.0 0.83
9. Titanium Dioxide 1.0 0.83
10. Purified Water Q.S.* -
Sub Total 97.00 -
Functional Coating
11.r Kollicoat SR30D 17.80 14.83
12. Propylene Glycol 1.8 1.50
13. Talc 3.40 2.83
* Does not remain in formulation.
Process:
1) Load the drug on NPS using solution containing Venlafaxine HCI. Sodium alginate, Talc & titanium dioxide by fluid bed coating technique.
2) Seal coating the drug coated pellets using solution containing Sodium alginate, Talc & titanium dioxide by fluid bed coating technique
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14. Purified Water Q.S.* -
Total 120.00 100

3) Functional coat the seal coated pellets using solution containing Kollicoat SR30D, Propylene glycol & Talc by fluid bed coating technique
Example 2
Another example using methacrylates such as Eudragit NE30D as the polymer
in example 1 can be as stated below:-
Formulation of Venlafaxine HCI (37.5 me Venlafexine) Capsules

Sr.No. Ingredients mg / cap %w/w
1 Non Peril Seeds 42.00 35.00
Drug Coating
2 Venlafaxine HC1 42.4 35.33
3 Sodium Alginate 10.60 8.83
- 4 Talc ' 2.0 1.66
5 Titanium Dioxide 2.0 1.66
6. Purified Water Q.S.* -
Sub Total 99.00 -
Seal Coating
7. Sodium Alginatei 6.0 5.0
8. Talc L 1.0 0.83
9. Titanium Dioxide 1.0 0.83
10. Purified Water Q.S.* -
Sub Total 107.00 -
Functional Coating
11. Eudragit NE30D 9.90 8.25
13. Talc 3.10 2.58
14. Purified Water Q.S.* -
Total 120.00 100
* Does not remain in formulation.
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Example 3
A further example using methacrylate such as Eudragit RS30D as the polymer in example 1 can be as stated below:-
Formulation of Venlafaxine HC1 (37.5 mg Venlafexine) Capsules

Sr.No. Ingredients mg / cap %w/w
1 Non Peril Seeds 27 22.5
Drug Coating
2 Venlafaxine HC1 42.4 35.33
'' 3 Sodium Alginate 10.60 8.83
4 Talc 2.0 1.66
5 Titanium Dioxide 2.0 1.66
6. Purified Water Q.S.* -
Sub Total 84.00 -
Seal Coating
7. Sodium Alginate 6.0 5.0
8. Talc 1.0 0.83
9. Titanium Dioxide 1.0 0.83
10. Purified Water Q.S.* -
Sub Total 92.00 -
Functional Coating
11. Eudragit RS30D 21.0 17.50
12. Tri Ethyl Citrate 4.0 3.33
13. Talc 3.0 2.50
t, 14. Purified Water Q.S.* -
Total 120.00 100
-;.* Does not remain in formulation.
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Example 4
Formulation of Bupropion hydrochloride tablets 150 mg

Sr.No. Ingredients mg / tablet %w/w
1. Bupropion Hydrochloride 150 36.06
2. Microcrystalline cellulose 40 9.62
3. Maize starch 29.5 7.09
4. Co-polymer of polyvinyl acetate 60.0 14.42
5. Ethyl cellulose 120.0 28.85
6. Hydrochloric Acid 2.5 0.6
7. Purified* Water QS Qs
8. Mg. Stearate 4.0 0.96
9. Opadry 10.0 2.40
Process: Granulate Bupropion hydrochloride, microcrystalline cellulose, maize starch, co-polymer of polyvinyl acetate, and ethyl cellulose using water containing hydrochloric acid, dry the granules and lubricate suitably.
These granules can then be compressed into tablets using suitable punches and coated using Opadry.
Example 5
Formulation of Pravastatin tablets 10 mg

Sr.No. Ingredients mg / tablet %w/w
1 Non Peril Seeds 10.3 10.3
'« 2- Pravastatin sodium 10.3 10.3
3 HPMC 1.3 1.3
4 Talc 5.7 5.7
5. Purified Water QS QS
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Functional Coating
6. Kollicoat SR30D 8.9 8.9
, 7. Propylene Glycol 0.5 0.5
8. HPMC 4 5.0 5.0
9. Talc 0.3 0.3
10. Purified Water QS QS
Lubrication
r 11. Microerystalline cellulose 46.45 46.45
12. Crosscarmellose sodium 10.0 10.0
13. Magnesium Stearate 1.25 1.25
Total 100.00 100.00
Dated this 17th day of January 2006.

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