FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
PROVISIONAL SPECIFICATION
(Section 10)
A PROCESS OF PREPARING OSMO MICROSEALED DRUG DELIVERY SYSTEM
FOR ERYTHROMYCIN ESTOLATE
M/S. ALEMBIC LIMITED, ALEMBIC ROAD, VADODARA - 390 003, GUJARAT, an Indian Company incorporated under the Companies Act, 1956.
The following manufacturing process particularly describes the nature of this invention.
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Title of the Invention :
A Process of Preparing Osmo Microsealed Drug delivery System for Erythromycin Estolate.
Background of the Invention :
Erythromycin Estolate is the first macrolide to be available, and has predominant activity against Gram positive pathogens (Streptococci & Staphylococci), as well as a typical pathogens (Myco pneumoniae Lpneumophila & Chlamydia pneumoniae). Unlike Erythromycin base and Erythromycin Stearate, Erythromycin Estolate is acid stable and absorbed from the gastrointestinal tract more completely. Erythromycin Estolate is apparently absorbed mainly as the ester. Erythromycin Estolate is available in conventional dosage forms.
The present invention relates to an Osmo Microsealed Erythromycin Estolate particles in hydrophilic matrix, it pertains to Osmo-Microsealed Erythromycin Estolate in sustain release dosage form, which provides better control of blood plasma levels than conventional tablet formulations which must be administered two or more times a day and further provides a lower incidence of nausea and vomiting than the conventional tablets.
Detailed description of the invention
The novel pharmaceutical composition of this invention comprises an Erythromycin Estolate as an active ingredient and optionally a pharmaceutically acceptable carrier
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suitable for oral or parental administration the formulation may be in solid form, as for
example tablets and capsules, or in liquid form, as for example, syrup, elixirs, emulsions
and injectables. In the formulation of pharmaceuticals dosage forms there generally is
utilized excipients such as microcrystalline cellulose starch lactose hydroxyl propyl
methyl cellulose, magnesium stearate, sodium chloride, sodium citrate and talc. A
preferred formulation is folly described in the composition of the present invention.
In this novel invention, the Erythromycin Estolate is designed as Sustain Release Osmo
Microsealed Erythromycin Estolate tablet. There will be immediate release of the half of
the dose, which will ensure prompt achievement of effective antibacterial concentration.
The remaining half of the dose is proposed to be released gradually over the next few
hours. This will ensure that adequate concentrations persist till the next dose is taken.
Erythromycin Estolate being water insoluble drug, conventional hydrophilic matrix
systems necessitate a very high polymer level. Therefore the coating of Erythromycin
Estolate provided in the present invention provides for an efficient modulation of the
system for desired drug release.
A combination of water insoluble and water swellable polymer helps to achieve the drug
levels in plasma
The presence of osmotic agent in the micro sealed systems enables a driving force for
water to penetrate into the system and thereby ensures complete drug release from water
insoluble polymer coated micro particle.
By altering the level of osmogen the desired release profile from the micro osmotic
system can be achieved.
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The external hydrophilic matrix base enables the regulated loading of individual micro
osmotic particles of Erythromycin Estolate in the GIT (Gastro Intestinal Tract)
Water insoluble polymer surrounding the drug osmogen mixture prevents dose dumping
at any instance.
The osmo microsealed device enables a higher gastric residence time.
Composition of the present Invention
EXAMPLE I: Erythromycin Estolate 500 mg Sustain releasetablets

S.No. Ingredients % w/w
1. Erythromycin Estolate 70.51
2. Ethylcellulose 10.06
3. Sodium Citrate 2.26
4. Hydroxypropylmethyl cellulose (K100LV) 13.22
5. Purified Talc 1.03
6. Magnesium Sterate 1.03
7. Microcrystalline cellulose 1089
Manufacturing Procedure of the present Invention :
EXAMPLE 1: Erythromycin Estolate 500 mg Sustain Release tablets
1. Pass Osmotic agent and Erythromycin Estolate through # 60.
2. Granulate the Erythromycin Estolate and Osmotic agent mixture with ethyl cellulose and or other water water insoluble polymer.
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3. Dry the granules in oven at 55-600C until moisture content comes down to 2.0-2.2% w/w.
4. Pass the dried granules through #20.
5. Lubricate the dried granules with magnesium Stearate, Hydroxypopyl methylcellulose and purified talc.
6. Compress the tablets with 10 x 20 mm oval punch.
Dated this 29th day of October, 2002

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FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION (See Section 10)
A PROCESS OF PREPARING CONTROLLED RELEASE FORMULATION OF
ERYTHROMYCIN ESTOLATE
M/S. ALEMBIC LIMITED, ALEMBIC ROAD, VADODARA- 390 003, GUJARAT, an Indian Company incorporated under the Companies Act, 1956.
The following specification particularly describes the nature of this invention, and the
manner in which it is to be performed.
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This invention relates to a process of preparing Controlled release formulation of Erythromycin estolate.
The formulation prepared by the process of the invention is a controlled release pharmaceutical formulation of erythromycin estolate and a pharmaceutically acceptable polymer, which have an effective way to reduce the fluctuation of plasma blood levels so as to deliver the drug in a dosage form which results in zero order absorption kinetics and reduced gastrointestinal side effect as compared to those for the immediate release composition.
Erythromycin Estolate is the first macrolide to be available, and has predominant activity against Gram positive pathogens (Streptococci & Staphylococci), as well as a typical pathogens (My co pneumoniae, L pneumophila & Chlamydia pneumoniae).
The present invention relates to a process of preparing an osmo-microsealed erythromycin estolate particles in hydrophilic matrix, it pertains to osmo-microsealed erythromycin estolate in controlled release dosage form, which provides better control of blood plasma levels than conventional tablet formulations and further provides a lower incidence of nausea and vomiting than the conventional tablets.
The novel pharmaceutical composition prepared by the process of this invention comprises a erythromycin estolate as an active ingredient and optionally a pharmaceutically acceptable carrier suitable for oral or parental administration the formulation may be in solid form, as for example tablets and capsules, or in liquid form,
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as for example, syrup, elixirs, emulsions and injectables. In the formulation of pharmaceutical dosage forms there are generally utilized excipients such as microcrystalline cellulose, starch, lactose, hydroxyl propyl methylcellulose, magnesium stearate, sodium chloride, sodium citrate and talc. A preferred formulation is fully described in the composition of the present invention.
In this novel invention, the formulation is designed as controlled release osmo microsealed erythromycin estolate tablet. There will be immediate release of the half of the dose, which will ensure prompt achievement of effective antibacterial concentration. The remaining half of the dose is proposed to be released gradually over the next few hours. This will ensure that adequate concentration persist till the next dose is taken.
Erythromycin Estolate being water insoluble drug, conventional hydrophilic matrix systems, is necessary at a very high polymer level. Therefore, the coating of Erythromycin Estolate provided in the present invention provides for an efficient modulation of the system for desired drug release.
A combination of water insoluble and water swellable polymer helps to achieve the desired drug levels in plasma.
The presence of osmotic agent in the micro sealed systems enables a driving force for water to penetrate in to the system and thereby ensures complete drug release from water insoluble polymer coated micro particle.
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By altering the level of osmogen, the desired release profile from the micro osmotic system can be achieved.
The external hydrophilic matrix base enables the regulated loading of individual micro osmotic particles of erythromycin estolate in the gastrointestraal tract (GIT).
Water insoluble polymer surrounding the drug osmogen mixture prevents dose dumping at any instance.
The osmo microsealed device enables a higher gastric residence time.
A controlled release pharmaceutical formulation wherein the macrolide may be erythromycin, clarithromycin or roxithromycin.
A controlled release pharmaceutical formulation wherein the filler is selected from the group consisting of lactose, starches, glucose, sucrose, mannitol and celluloses.
A controlled release pharmaceutical formulation wherein said at least one hydrophilic polymer comprises at least one of ethylcellulose dispersion, hydroxypropyl cellulose, Hydroxypropyl methyl cellulose and methacrylic acid copolymer.
A controlled release pharmaceutical formulation wherein said one or more grades of Hydroxypropyl methyl; cellulose and wherein said one or more of grades of Hydroxypropyl methylcellulose have a viscosity from 50 to 21,000 centipoise.
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A controlled release pharmaceutical formulation wherein said hydrophilic polymers are Methocel K 100 LV and ethycellulose, said binder is polyvinyl pyrrolidone, said filler is microcrystallme cellulose, said lubricants are talc and magnesium stearate and said macrolide is erythromycin estolate.
A controlled release pharmaceutical formulation comprising 55-85% by weight macrolide, 3-15% by weight hydrophilic polymer, 0-10 % by weight hydrophobic polymer, 0-10% by weight fillers and 0.2-10% by weight lubricants.
A controlled release pharmaceutical formulation wherein the formulation is a solid oral dosage form, for example a tablet, capsule, pill, granule or dry syrup.
A controlled release pharmaceutical formulation wherein said formulation comprises a potency equivalent to 500 mg erythromycin IP.
A process of preparing Controlled release formulation of erythromycin derivatives comprising of an osmo micro particle consisting of therapeutically effective amount of Erythromycin Estolate or salt thereof and at least one osmotic agent or osmo polymer; a polymer membrane surrounding the core and having a porous membrane for pass away through; and an external matrix constituting of water soluble and / or swellable polymer; and wherein the coated core and the surrounding matrix provides for the controlled release of erythromycin estolate.
The osmo micro particle, wherein the particles coat is applied by spraying a composition on to the drug osmogen mixture.
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The osmo micro particle, wherein the particles coat is compressed on to the drug osmogen mixture.
The osmo micro particle, wherein the particle coat is obtained by co granulation of the coating polymer along with drug osmogen mixture forming a matrix of drug osmogen and the polymer.
The osmo microsealed device, wherein the surrounding polymer loads the osmo particles in the GIT through the mechanism of diffusion across the swollen polymer membrane.
The osmo microsealed device, wherein the surrounding polymer loads the osmo particles in the GIT through the mechanism of erosion of the polymer membrane.
The osmo microsealed device, wherein the surrounding matrix polymer loads the osmo particles in the GIT through the combined mechanism of both diffusion across the swollen polymer membrane and erosion of the polymer membrane.
The osmo microsealed device, wherein the surrounding matrix polymer constitutes of either a swellable polymer or a soluble polymer or a combination of both.
The osmo microsealed device, wherein the surrounding matrix may constitute of a hydrophobic or waxy or oily material.
The osmo microsealed device, wherein the osmotic agent may constitute of a salts, polyols, sugars or carbohydrates or an agent capable of generating osmosis or a combination thereof.
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The osmo microsealed device, wherein the micro particle coat may constitute of cellulose acetate, ethyl cellulose, methacrylic acid copolymers or any water insoluble polymer or a combination of polymers capable of providing semi permeable membrane.
This invention provides a process of preparing a controlled release formulation erythromycin estolate comprising of following steps:
passing osmotic agent and erythromycin estolate through # 60;
granulating the erythromycin estolate and osmotic agent mixture with ethyl cellulose and/or other water insoluble polymer;
drying the granules in an oven at 55 - 60°C until moisture content comes down to 2.0 -
2.2% w/w;
passing the dried granules through # 20;
lubricating the dried granules with magnesium stearate, hydroxypropyl methylcellulose and purified talc;
compressing the tablets with 10x20 mm oval punch.
Composition prepared by the process of the present Invention
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Example 1: Erythromycin Estolate 500 mg controlled release tablets

S.No. Ingredients %w/w
1. Erythromycin Estolate 80.00
2. Polyvinyl pyrrolidone K-30 4.00
3. Ethycellulose 1.50
4. Sodium Citrate 2.00
5. Hydroxypropylmethyl cellulose (K100LV) 6.50
6. Purified Talc 1.50
7. Magnesium Sterate 1.50
8. Microcrystalline cellulose 3.00
The process of preparing controlled release formulation of Erythromycin Estolate 500 mg tablets:
i) passing osmotic agent and erythromycin estolate through # 60;
ii) granulating the erythromycin estolate and osmotic agent mixture with ethyl cellulose and / or other water insoluble polymer;
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iii) drying the granules in an oven at 55-60°C until moisture content comes down to 2.0 - 2.2% w/w;
iv) passing the dried granules through #20;
v) lubricating the dried granules with magnesium stearate, hydroxypropyl methycellulose and purified talc;
vi) compressing the tablets with 10x20 mm oval punch.
Example 2: Erythromycin Estolate 500 mg controlled release tablets

S. No. Ingredients %w/xv
1. Erythromycin Estolate 80.00
2. 1 Glyceryl behenate (Compritol 888) 6.06
3- Sodium Citrate 2.26
4. Hydroxypropylmethyl cellulose (E 50 LV) 4.73
5. Polyvinyl pyrrolidone K 30 3.00
6. Purified Talc 1.03
7. Magnesium Stearate 1.03
8. Microcrystalline cellulose 1.89
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The process of preparing controlled release formulation Erythromycin Estolate 500 mg tablets:
i) passing osmotic agent and erythromycin estolate through # 60;
ii) granulating the erythromycin estolate and osmotic agent mixture with Hydroxypropyl methylcellulose, microcrystalline cellulose and polyvinyl pyrridone;
iii) drying the granules in an oven at 55 - 60°C until moisture content comes down to 2.0 - 2.2% w/w;
iv) melting glyceryl behenate in a suitable container and add it to the granules of step ii in RMG;
v) cooling the granules at 20-25°C;
vi) passing the dried granules through #20;
vii) lubricating the dried granules with magnesium stearate, hydroxypropyl methylcellulose and purified talc;
viii) compressing the tablets with 10x20 mm oval punch.
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Example 3: Erythromycin Estolate 500 mg controlled release tablets

S.No. Ingredients %w/w
1. Erythromycin Estolate 75.50
2. Hydroxypropylmethyl cellulose (K 15 MCR) 6.06
3. Sodium Citrate 2.26
4. Hydroxypropylmethyl cellulose (K 4 MCR) 13.22
5. Polyvinyl pyrrolidone K 30 4.00
6. Purified Talc 1.03
7. Magnesium Stearate 1.03
8. Microcrystalline cellulose 1.89
The process of preparing controlled release formulation Erythromycin Estolate 500 mg tablets:
i) passing osmotic agent and erythromycin estolate through # 60;
ii) granulating the erythromycin estolate and osmotic agent mixture with hydroxypropyl methylcellulose (K 4MCR), microcrystalline cellulose and polyvinylpyrridone ;
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iii) drying the granules in an oven at 55 - 60°C until moisture content comes down to 2.0-2.2% w/w;
iv) passing the dried granules through #20;
v) lubricating the dried granules with magnesium stearate, hydroxypropyl methylcellulose (K 15 MCR) and purified talc;
vi) compressing the tablets with 10x20 mm oval punch.
The above description and examples are given to understand the invention rather than limit its scope.
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We claim,
1) A process for preparing a controlled release formulation of macrolide such as erytlttomycin estolate comprising 50-85%, by wL said .macxolide, 3 to 15%. by wL polymers and pharmaceutically acceptable carriers such as osmotic agent, filler, lubricant and binder, said process comprises the following steps:
a) passing osmotic agent, filler, binder and erythromycin estolate through # 60 to obtain their mixture;
b) granulating the mixture of erythromycin Estolate, osmotic agent, filler and binder with ethyl cellulose and/or other water insoluble polymers;
c) drying the resultant granules- in oven at 55 — 60°C until moisture content comes down to 2..Q - 2.2%, w/w;
4} cooling the granules of step (c) at 20— 25°C temperature;
e) passing the dried and cooled granules through #2Q to obtain granules of same
f) lubricating the granules of step (e) with lubricants such as magnesium stearate and purified talc; and
g) compressing the lubricated granules into tablet with 10 X 20 mm oval punch.
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2.) A process for preparing controlled release formulation as claimed in claim! T wherein, the. osmotic, agent is, constituted of a salts,, palyok,, sugars,, carbohydrates or an agent capable of generating osmosis or a combination thereof.
3) A. process for preparing controlled release formulation, as claimed in. claim 1, wherein the water insoluble polymer is at. least one hydrophilic polymer selected from, hydroxypropyl methyl cellulose,, bydroxypropyl cellulose and methacrylic acid co-polymer.
4) A process, for preparing controlled release formulation as claimed in claim 1, wherein the hydroxypropyl methyl cellulose have a viscosity from 50 to 21, 00Q centipoise is used as polymer.
5) A process for preparing controlled release pharmaceutical formulation as claimed in claim 1, wherein the filler is selected from the group of lactose, starches, glucose,, sucrose mannitol and celluloses.
6) A process for preparing controlled release formulation as claimed in claim 5, wherein the microcrystalline cellulose is used as filler.
7) A process for preparing controlled release formulation as claimed in claim 1, wherein polyvinyl pyrrolidone is used as binder.
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A process for preparing controlled release formulation as claimed in claim 1 wherein, said formulation comprises a potency equivalent, to 5Q0 mg erythromycin IP.
Dated- this-14 day of November, 2003-.



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ABSTRACT OF THE INVENTION
A process. For preparing a. controlled. release formulation, of macrolide such as erythromycin estolate comprising 50-85% by wt said macrolide 3 to 15% by wt polymers and pharmaceutically acceptable carriers such. as. osmotic agent, filler, lubricant and binder,, said process comprises the following steps:
a) passing osmotic agent, -filler, binder and erythromycin estolate through # 60 to obtain their mixture;
b) granulating the mixture of erythromycin Estolate^ osmotic agent,, filler and binder with ethyl cellulose and/or other water insoluble polymers;
c) drying the resultant granules in oven at 55 — 60°C until moisture content comes down to 2,0 - 2.2%. w/w;
d) cooling the granules of step (c) at 20— 25 C temperature;
e) passing the dried and cooled granules through .#20 to obtain granules of same size;
f) lubricating the granules of step (e) with lubricants such as magnesium stearate and purified talc; and
g) compressing the lubricated granules into tablet with 10x20 mm oval punch. Dated this 14th day of November, 2003.