Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE 2003
PROVISIONAL SPECIFICATION
[See section 10 and rule 131
1. TITLE OF THE INVENTION
"Stable pharmaceutical compositions of Acarbose and process of preparation
thereof
2. APPLICANT
(a) NAME: USV LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies ACT 1956
(c) ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Technical field of the invention:
The present invention relates to stable pharmaceutical compositions used for the treatment of type 2 diabetes mellitus comprising a therapeutically effective amount of Acarbose, a suitable amount of a water insoluble material and other suitable pharmaceutically acceptable excipients. The present invention further provides a process for preparation of the said stable compositions; the process comprising coating the particles of Acarbose by wet granulation method with a suitable amount of water insoluble material and further formulating the coated particles into a dosage form such as tablets using suitable pharmaceutically acceptable excipients.
Background and Prior art:
Diabetes mellitus type 2 also known as non insulin-dependent diabetes (NIDDM) is a metabolic disorder that is primarily characterized by insulin resistance, relative insulin deficiency, and hyperglycemia. Treatments of Diabetes mellitus type 2 include use of various oral antidiabetic agents. Oral sulfonylureas such as Glimepiride, Glyburide, Tolazamide; Biguanides such as Metformin; Alpha-glucosidase inhibitors such as Acarbose; Thiazolidinediones such as Rosiglitazone; Meglitinides such as Repaglinide and Nateglinide and so on.
Acarbose, an alpha-glucosidase inhibitor is used as an effective first-line therapy for patients with newly diagnosed type 2 diabetes. Acarbose acts as an antihyperglycemic by competitive reversible inhibition of the pancreatic alpha-amylase enzyme and alpha-glucosidase enzymes of the small intestine. This inhibition decreases and postpones the breakdown and digestion of ingested carbohydrates, thus decreasing the elevation of blood sugar levels after meals.
Acarbose is a polyglucose-based tetramer oligosaccharide obtained by fermentation of the microorganism Actinoplanes sp. (particularly A. utahensis). Acarbose is a complex oligosaccharide consisting of two glucoses, one
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deoxyglucose and one dideoxy glucose derivative. The first three monomelic units are bound by O-glycosidic links, while the fourth monomeric unit is bound by an N-glycosidic linkage. Chemically, Acarbose is 0-4,6-dideoxy-4-[[(lS,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cydohexen-l-yl]amino]-a-D-glucopyranosyl-(l->4)-0-a -D-glucopyranosyl-(l->4)-D-glucose. Acarbose is a white to off-white powder with a molecular weight of 645.6. Acarbose is soluble in water and has a pKaof 5.1. Acarbose is highly moisture sensitive.
There are various marketed preparations containing Acarbose alone or in combination with other anti-diabetic drugs. Acarbose is marketed in Europe by Bayer AG, under the brand name GLUCOBAY®, in Canada under the brand name PRANDASE® and in North America as PRECOSE®. PRECOSE® is available as 25 mg, 50 mg, and 100 mg tablets for oral use. The inactive ingredients of PRECOSE® are starch, microcrystalline cellulose, magnesium stearate, and colloidal silicon dioxide.
The purification process of Acarbose is covered by US Patents 4174439, 4666776, 4767850, 5989882, 6734300. US4904769 discloses purified Acarbose, which contains less than 10% by weight of sugar-like secondary components, which is obtained by column chromatograph of a solution of prepurified Acarbose with a pH 4 to 7.
US6849609 discloses a chemical composition used to stimulate weight loss in a patient, consisting essentially of: Acarbose; and a sustained release matrix, wherein Acarbose and sustained release matrix are combined to form a mixture.
EP0837069 discloses a method for preserving Acarbose or Acarbose-containing preparations, which is characterized by keeping Acarbose or Acarbose-containing preparations under low oxygen concentration conditions. The said method provides a package of Acarbose or an Acarbose-containing preparation, which
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comprises Acarbose or an Acarbose-containing preparation, a means for deoxidation and a substantially gas-impermeable, moisture proof container to accommodate them.
JP2006342126 discloses an Acarbose-containing tablet which shows less surface discoloration. The Acarbose-containing tablet is obtained by coating the Acarbose-containing naked tablet prepared under a dry condition with a film-coating composition containing a water-soluble polymer by using an organic solvent. The two or more film coating layers containing the water soluble polymer are applied to the Acarbose-containing naked tablet prepared under the dry condition and is characterized by performing the film-coating of the first layer of the naked tablet side by using an organic solvent.
JP2006131564 discloses a therapeutic and prophylactic agent effective for chronic heart failure. The therapeutic and/or prophylactic agent comprises an antihyperglycemic agent as an active ingredient. The antihyperglycemic agent is an [alpha]-glucosidase inhibitor such as Voglibose and Acarbose.
CN1626108 discloses an enteric-coated tablet of Acarbose, which is composed of the tablet core prepared from Acarbose and medicinal auxiliaries and the coated enteric layer. Its advantages are low dosage, high curative effect and low toxic by-effect.
Acarbose is highly moisture sensitive and this adversely affects the stability of the Acarbose containing compositions. On prolonged storage the compositions specially dosage forms such as tablets prepared by the method known in the art shows discoloration. The change in colour from white to brown is primarily due to the interaction with moisture in the air.
Prior patent publications teach that when water content of an Acarbose-containing
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tablet exceeds about 6 percent by weight, its Acarbose content decreases during storage at 60°C for 6 weeks thereby making the tablet discolored.
It is difficult to formulate Acarbose into dosage forms such as capsules since the shell of gelatin capsules contain a moisture content of about 12-15% which would affect the stability of Acarbose containing preparations. There have been attempts made to formulate Acarbose into film-coated tablets. However, it has been found that the film coated tablets comprising a film coat in accordance with the prior art still suffer from instability as they show discoloration on long term storage.
Another drawback associated with prior art is that due to moisture absorption the packed tablets stick to the inner surface of packing material such as foil. Further the tablets prepared by methods known in the art exhibits a rough surface.
It has been observed that even the use of several moisture protective packing materials do not render long-term stability to the Acarbose preparations. Other methods known in art for stabilization of Acarbose preparations are tedious and expensive.
Literature provides the dosage regimen recommended for Acarbose. Acarbose tablets should be taken orally three times daily at the start (with the first bite) of each main meal. Hence the hardness and disintegration time of the tablet plays an important role. Film coated tablets of Acarbose known in the prior art are quite hard having disintegration time of about 10 to 12 minutes. This is another disadvantage associated with prior art, which needs to be overcome.
While numerous pharmaceutical compositions containing Acarbose for oral administration are available, there still exists a need for commercially acceptable Acarbose compositions, which overcome the disadvantages of prior art and having good stability and patient compliance.
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Therefore, in view of the aforementioned drawbacks associated with prior art compositions used for the treatment of type 2 Diabetes mellitus it is apparent that there exists a need for stable Acarbose compositions, which do not discolour even on long-term storage.
Object of the Invention:
The main object of the invention is to provide stable pharmaceutical compositions for treatment of type 2 diabetes mellitus comprising a therapeutically effective amount of Acarbose, a suitable amount of water insoluble material and other pharmaceutically acceptable excipients.
Another object of the invention is to provide a process for preparation of stable compositions comprising coating the particles of Acarbose by wet granulation method with a suitable amount of water insoluble material and further formulating the coated particles into a dosage form such as tablets using suitable pharmaceutically acceptable excipients.
Yet another object of the invention is to overcome the problems associated with stability of the prior art compositions used in treatment of type 2 Diabetes mellitus.
Another object of the invention is to provide compositions of Acarbose, which provides good storage stability and patient compliance.
Summary of the invention:
The present invention discloses stable pharmaceutical compositions used for the treatment of type 2 diabetes mellitus comprising a therapeutically effective amount of Acarbose and a suitable amount of water insoluble material together with other suitable pharmaceutically acceptable excipients wherein the particles of
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Acarbose are coated with a suitable amount of water insoluble material to provide stability to the compositions. Particularly, the water insoluble materials used as per the present invention are ethyl cellulose and stearic acid. The process of preparation of the said stable composition involving wet granulation method is also disclosed herein.
Detailed Description:
The present invention describes stable pharmaceutical compositions used for the treatment of type 2 diabetes mellitus comprising a therapeutically effective amount of Acarbose, a suitable amount of water insoluble material and other suitable pharmaceutically acceptable excipients.
Further, the present invention describes a process for preparation of the said stable compositions; the process comprising coating the particles of Acarbose by wet granulation method with a suitable amount of water insoluble material and further formulating the coated particles into a dosage form such as tablets using suitable pharmaceutically acceptable excipients.
Acarbose is moisture sensitive and shows a tendency for browning on storage. Due to this moisture-absorbing tendency the preparations of Acarbose show discoloration on long-term storage.
The inventors of the present invention have developed a process to prepare stable Acarbose compositions. Acarbose compositions, more particularly the tablet dosage form so prepared is stable at accelerated conditions of temperature and humidity.
According to one aspect of the present invention, the active ingredient is coated with a suitable amount of water insoluble material, which forms a protective coat on Acarbose and reduces its moisture sensitivity and prevents discoloration of the
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dosage form even on long-term storage.
According to a preferred aspect water insoluble material such as ethyl cellulose and stearic acid are used to coat the active pharmaceutical ingredient in the tablet formulation. The Acarbose tablets prepared according to the present invention do not require film coating as the uncoated tablets show good shelf life stability.
As per the present invention, water insoluble materials such as ethyl cellulose and stearic acid serve the dual purpose of coating the Acarbose to reduce its moisture sensitivity and also act as a binding agent to produce compressible granules with good flow properties.
The solid dosage form contains alpha-glucosidase inhibitor and water insoluble material in the weight proportion of between 1:0.01 to 1:0.60, preferably between 1:0.015 to 1:0.50, more preferably between 1:0.02 to 1:0.40 especially between 1:0.02 to 1:0.30. Ethyl cellulose having viscosity in the range of 4 cps to 22 cps is used ; preferred viscosity being 5 to 15 cps.
Concentration of water insoluble materials such as ethyl cellulose and stearic acid in the solid dosage form can be in the range of 0.10% to 10.0%w/w; preferred being 0.75% to 2.0%w/w.
According to one aspect of the invention there is provided a process of making the stable pharmaceutical composition comprising the steps of,
i) sifting the active ingredient and diluents through 60# sieve on a vibratory
sifter, ii) mixing the sifted materials in step (i) in a suitable mixing equipment for
about 10 minutes, iii) preparing the binder by dissolving the water insoluble material in an organic solvent at 45±5°C,
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iv) granulating the dry mix of step (ii) in a suitable equipment with the binder
solution in step(iii), v) air drying the mixture obtained in step (iv) in a suitable equipment without
temperature till the smell of organic solvent is no longer evident, vi) drying the mixture of step(v) in a suitable equipment at 50±5°C for
sufficient time till loss on drying (LOD) is 3.0-4.0%, vii) sifting the dried mass through 30# sieve on a vibratory sifter, viii)lubricating the sifted granules with lubricants in a suitable equipment, ix) compressing the lubricated granules using suitable compression machine.
According to the present invention, the process of coating the particles of Acarbose by wet granulation method can be carried out using equipments known in the art such as rapid mixer granulator and fluid bed processor. The process of preparation of wet mass can be carried out in a conventional rapid mixer granulator and further dried using fluid bed drier. In a conventional fluid bed processor both the steps of granulation and drying can be carried out in the same equipment thereby simplifying the process and saving the processing time.
Suitable pharmaceutically acceptable excipients that can be mentioned include, but are not limited to, for example, diluents/fillers, binders, disintegrating agents, wetting agents, glidants, lubricants, antiadherants, water-insoluble polymers and the like.
Diluents which can be used as per the invention include, but are not limited to lactose anhydrous, maize starch, microcrystalline cellulose, dibasic calcium phosphate anhydrous or mixtures thereof in an amount from 10% to 60% by weight of the total composition.
Binders which can be used as per the invention include ethyl cellulose, stearic acid in an amount from 0.1% to 10% by weight of the total composition.
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Solvents which can be used as per the invention include, isopropyl alcohol, dichloromethane or mixtures thereof in an amount sufficient to dissolve the water insoluble polymer.
Disintegrants which can be used as per the invention include, but are not limited to maize Starch, croscarmellose sodium, sodium starch glycollate, crospovidone or mixtures thereof in an amount from 0.5% to 15% by weight of the total composition.
Glidants which can be used as per the invention include, but are not limited to colloidal silicon dioxide, talc and the like in an amount from 0.1% to 10% by weight of the total composition.
Lubricants which can be used as per the invention include, but are not limited to magnesium stearate, calcium stearate, sodium stearyl fumarate and the like in an amount from 0.25% to 10% by weight of the total composition.
According to one aspect of the invention, the therapeutically effective amount of Acarbose is in the range of 15% to 50% and preferably in the range of 30 to 40% by weight of the total composition. Tablets of strength 25mg, 50mg and lOOmg can be manufactured as per the present invention.
According to another aspect, tablets prepared according to the process described in the invention do not stick to the surface of packing material in the strip cavity since there is a considerable reduction in hygroscopic properties of the active ingredient as well as formulated dosage form due to the water insoluble material coating. As the tablets do not tend to absorb moisture the tablet surface remains smooth and do not exhibit any roughness.
As Acarbose tablets should be taken three times daily at the start (with the first
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bite) of each main meal, the hardness and disintegration time of the tablet becomes a critical factor in ensuring a quick bite and better patient compliance. The stable composition developed by the inventors of the present invention overcomes the disadvantages associated with prior art compositions. The present invention provides Acarbose tablets having low disintegration time of about 4 to 7 minutes. Use of water insoluble materials such as ethyl cellulose and stearic acid do not increase the disintegration time of the tablets.
Tablets are packed in Aluminium/Aluminium strip pack or Cold Forming Blister (CFB) pack. No special storage instructions are required as stated in innovator leaflet like: 'Do not store above 25°C (77°F). Protect from moisture. For bottles, keep container tightly closed'.
The present invention is further illustrated by reference to the following examples which does not limit the scope of the invention in any way. It will be apparent to those skilled in the art that many modifications, both to the materials and methods, can be practiced without departing from the purpose and scope of the disclosure.
Examples
Example 1
Acarbose 165.0 gm, co-sifted along with about 700 gm microcrystalline cellulose (Avicel PHI 12) through 60#. Ethyl Cellulose 10 cps 10.0 gm is dispersed in Isopropyl Alcohol 240.0 gm at 40 - 45°C by continuous stirring. Cool to room temperature. Mix the Acarbose and Avicel sifted portions in a suitable equipment like Rapid Mixer Granulator for 5 minutes till both the active and excipient are well mixed. Add the binder fluid and granulate the mixture to form suitably cohesive wet mass. Dry the wet mass in Glatt drier at inlet temperature 25°C for evaporation of the organic solvent. Further dry at temperature 50°C for sufficient time till loss on drying (LOD) is 3.0 to 4.0%. Co-sift sodium starch glycollate 9.0gm, colloidal Silicon dioxide (Aerosil 200, Degussa) 9.0 gm through 40#. Add
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these sifted materials to the dried granules. Mix in a suitable blender like a Cone blender or Conta blender. Sift lubricant magnesium stearate 4.5 gm through 60# and add to the mixture. Mix in a suitable blender like a Cone blender or Conta blender. Compress the lubricated blend on tooling 7.0 mm round standard concave plain upper and lower punches for Acarbose tablets 25 mg.
Example 2
Acarbose 165.0 gm, co-sifted along with microcrystalline cellulose (Avicel PHI 12) about 700 gm through 60#. Ethyl Cellulose 7 cps 20.0gm is dispersed in Isopropyl Alcohol 240.0gm at 40-45°C by continuous stirring. Cool to room temperature. Load the Acarbose and Avicel sifted into the Fluid bed processor (FBP). Spray the binder fluid using the top spray mechanism. After the total ethyl cellulose solution is sprayed the particulate dry mass obtained is checked for LOD 3.0 to 4.0%. Further drying is to be done in the FBP if the LOD is not within limits. Co-sift sodium starch glycollate 9.0 gm, colloidal silicon dioxide (Aerosil 200) 9.0 gm through 40#. Add these sifted materials to the dried granules. Mix in a suitable blender like a Cone blender or Conta blender. Sift lubricant magnesium stearate 4.5 gm through 60# and add to the mixture. Mix in a suitable blender like a Cone blender or Conta blender. Compress the lubricated blend on tooling 7.0mm round standard concave plain upper and lower punches.
Example 3
Acarbose 330.0 gm, co-sifted along with calcium phosphate about 530.0 gm through 60#. Ethyl cellulose 7 cps 18.0 gm is dispersed in Isopropyl Alcohol-Dichloromethane 3:1 mixture 250 gm at 40-45°C by continuous stirring. Cool to room temperature. Load the Acarbose and calcium phosphate sifted into the Fluid bed processor (FBP). Spray the binder fluid using the top spray mechanism. After the total ethyl cellulose solution is sprayed the particulate dry mass obtained is checked for LOD 3.0 to 4.0%. Further drying is to be done in the FBP if the LOD (3.0 to 4.0%) is not within limits.
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Co-sift sodium starch glycollate 9.0 gm, colloidal silicon dioxide (Aerosil 200) 9.0gm through 40#. Add these sifted materials to the dried granules. Mix in a suitable blender like a Cone blender or Conta blender. Sift lubricant magnesium stearate 4.5 gm through 60# and add to the mixture. Mix in a suitable blender like a Cone blender or Conta blender. Compress the lubricated blend on tooling 7.0mm round standard concave plain upper and lower punches.
Example 4
Acarbose 330.0 gm, co-sifted along with Avicel PH 112 about 450.0 gm through 60#. Ethyl Cellulose 7 cps 8.4 gm is dispersed in Isopropyl Alcohol 200.0 gm at 40-45°C by continuous stirring. Cool to room temperature. Load the Acarbose and Avicel PH 112 sifted into the Fluid bed processor (FBP). Spray the binder fluid using the top spray mechanism. After the total ethyl cellulose solution is sprayed the particulate dry mass obtained is checked for LOD (3.0 to 4.0%). Further drying is to be done in the FBP if the LOD is not within limits. Co-sift sodium starch glycollate 42.0 gm, colloidal silicon dioxide (Aerosil 200) 8.4 gm through 40#. Add these sifted materials to the dried granules. Mix in a suitable blender like a Cone blender or Conta blender. Sift lubricant magnesium stearate 4.2 gm through 60# and add to the mixture. Mix in a suitable blender like a Cone blender or Conta blender. Compress the lubricated blend on tooling 5.5 mm round standard concave plain upper and lower punches for Acarbose tablets 25 mg and 7.0 mm round standard concave plain upper and lower punches for Acarbose tablets 50 mg.
Example 5
Acarbose 55.0 gm, co-sifted along with Avicel PH 112 about 110.0 gm through 60#. Disperse the ethyl cellulose 4 cps 1.0 gm in Isopropyl Alcohol Dichloromethane 3:1 mixture 40.0 gm at 40- 45°C by continuous stirring. Cool to room temperature. Load the Acarbose and Avicel PH 112 sifted into the Kenwood mixer and mix. Add the binder fluid onto the dry mix till a wet mass is obtained.
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Sift the wet mass through 10# and dry in tray drier for sufficient time till LOD is 3.0 to 4.0%. Sift sodium starch glycollate 6.0 gm and add to the dried granules in a Kenwood mixer and mix. Co-sift colloidal silicon dioxide (Aerosil 200) 3.0 gm and Avicel PHI 12 about 15.0 gm through 40#. Add these sifted materials to the dried granules. Mix in Kenwood mixer. Sift lubricant magnesium stearate 0.5 gm through 60# and add to the mixture. Mix in a Kenwood mixer. Compress the blend on 6.35 mm FFBE round plain upper and lower punches and dies for 25mg strength tablets.
Example 6
Ethyl cellulose 4 cps (about 4.0 gm) is dispersed in hot Isopropyl Alcohol 60 gm and then Dichloromethane 20gm is added to this to prepare a clear solution. Acarbose 137.5 gm and 275.0 gm are mixed and granulated with ethyl cellulose solution. The wet mass is then sifted through 10#, dried till organic solvents evaporate and sifted through 30#. The dried granules are then mixed with appropriate amounts of croscarmellose sodium and magnesium stearate and taken for compression on 6.35 mm tooling for 25 mg strength tablets.
Example 7
Ethyl cellulose 4 cps (about 11.25gm) is dispersed in hot Isopropyl Alcohol 140 gm and then Dichloromethane 80gm is added to this to prepare a clear solution. Acarbose 412.5 gm and Avicel PHI 12 825.0 gm are mixed and granulated with ethyl cellulose solution. The wet mass is then sifted through 10#, dried till organic solvents evaporate and sifted through 30#. The dried granules are then mixed with appropriate amounts of croscarmellose sodium and magnesium stearate and taken for compression on 6.35 mm tooling for 25 mg strength tablets.
Example 8
Heat Isopropyl Alcohol 270 gm to 40 - 45°C. Dissolve stearic acid 30 gm in the
hot Isopropyl Alcohol. Cool the solution to room temperature. Mix presifted (60#)
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Acarbose 137.5 gm, lactose anhydrous Pharmatose DCL21 about 300 gm in a Kenwood Mixer. Granulate this mixture with the stearic acid solution. Dry the wet mass after evaporation of the organic solvent at about 50-55°C and size through 30#. Blend the dried mass with Pharmatose DCL21 100 gm, maize starch 25 gm and sodium starch glycollate 50 gm, colloidal silicon dioxide 5 gm, magnesium stearate 5 gm and compress on 7.0 mm round standard concave plain upper and lower punches for Acarbose tablets 50 mg.
Example 9
Heat Isopropyl Alcohol 432 gm to 40 - 45°C. Dissolve stearic acid 96 gm in the hot Isopropyl Alcohol. Cool the solution to room temperature. Mix presifted (60#) Acarbose 440 gm, calcium phosphate about 300 gm, Avicel PHI 12 about 660gm in a Kenwood Mixer. Granulate this mixture with the stearic acid solution. Sift the wet mass through 10# and dry in tray drier after evaporation of the organic solvent at about 50 -55°C and size through 30#. Blend the dried mass with Avicel PHI 12 about 270gm, colloidal silicon dioxide 9 gm and sodium starch glycollate 9 gm, magnesium stearate 9 gm and compress on 9.0 mm round standard concave plain upper and lower punches for Acarbose tablets 50 mg.
While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by the appended claims.
Dated this the 09th day of July 2007
DrKG Rajendran Head-Knowledge Cell USV Limited
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