FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
(SECTION 10)
"NOVEL PHARMACEUTICAL COMPOSITION FOR
DESMOPRESSIN"
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
B/2, Mahalaxmi Chambers, 22, Bhulabhai Desai Road
Post Box No. 26511
Mumbai - 400 026, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION
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NOVEL PHARMACEUTICAL COMPOSITION FOR DESMOPRESSIN
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates to a novel pharmaceutical composition as a solid dosage form comprising desmopressin acetate as a therapeutically active ingredient, and method for manufacturing the same.
2. Description of the Related Art
Desmopressin is a psychotropic agent that belongs to the category of anti diuretics. The chemical designation l-(3-Mercaptopropanoic acid)-8-D-arginine vasopressin; 8-D-arginine-l-(3-mercaptopropanoic acid) vasopressin; and having structure :

A synthetic drug that mimics the action of antidiuretic hormone, also known as arginine vasopressin. Desmopressin (l-desamino-8-d-arginine vasopressin) is a modified form of the normal human hormone arginine vasopressin, an octapeptide (a chain of eight amino acids).
Desmopressin binds to V2 receptors in renal collecting ducts, increasing water resorption. It also stimulates release of factor VIII from endothelial cells due to stimulation of the Via receptor.
Desmopressin is degraded more slowly than recombinant vasopressin, and requires less frequent administration. In addition, it has little effect on blood pressure, while vasopressin may cause arterial hypertension.
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Desmopressin is used to reduce urine production in central diabetes insipidus patients and to promote the release of von Willebrand factor and factor VIII in patients with coagulation disorders such as type I von Willebrand disease, mild hemophilia A, and thrombocytopenia. Desmopressin is not effective in the treatment of hemophilia B or severe hemophilia A.
It may also be prescribed to reduce frequent bedwetting episodes in children by decreasing noctural urine production.
Compared to vasopressin, desmopressin's first amino acid has been deaminated, and the arginine at the eighth position is in the levo rather than the dextro form
The DDAVP.RTM. tablet that is currently marketed, and thus produced in industrial scale, consists of the therapeutically active ingredient desmopressin together with potato starch and lactose as excipients, and a suitable amount of binder and lubricant, respectively.
US 5047398 patent assigned to Ferring B.V., claims an invention of anti diuretic composition for humans comprising a gastrointestinally absorbable, antidiuretically effective amount of desmopressin with acceptable carrier in solid dosage form for absorption in the gastrointestinal tract of said humans .This patent also discloses desmopressin tablet composition and use of talc and magnesium stearate as lubricants.This patent does not discloses any process for preparing the said tablet or capsule dosage form.
US 7022340 patent assigned to Ferring claims a tablet comprising desmopressin with the therapeutically effective amount of lubricant from 0.05 to 0.4 percent by weight of said pharmaceutical composition.The marketed formulation of the innovator is using 0.5 % of lubricant (magnesium stearate) by weight of the tablet According to the '340' patent lubricants in the innovator composition in the range of 0.05 % -0.4 % range is an essential element to provide desired hardness. Inventor of the present application surprisingly found that Desmopressin tablets can also be manufactured using the lubricants in the range above 0.5% % w/w and maintaining the optimized speed of the compression machine, still the resultant tablet gives the satisfactory results for disintegration and dissolution without
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causing any wear and tear to the compression machine as that of the innovator's tablets (DDAVP) in the market. The blend so prepared can also be used for filling the capsules .
US 7018653 is an improvement patent over the previously mentioned patents of the innovator, Ferring. This patent specifically claims method for the preparation of solid dosage form of desmopressin acetate using a fluid bed granulation technique wherein preparation of said granulate comprises fluid bed granulation processing within an apparatus adapted therefor. More specifically, said processing comprises providing conditions to provide mixing and shearing action. Said conditions typically comprise adjusting fluidising air flow and processing temperature and time. This patent in its example discloses use of Planetary mixer for granulation in example 1 and use fluid bed granulator in example 2.Use of planetary mixer may result in desmopressin coming in contact with the solvent for longer duration of time and may result in degradation of the product, also the heat and moisture combined with the circulating air and particles in a fluid bed granulation results in decreasing the stability of the product. Thus planetary mixer may not be the choice of equipment for the same. The inventors of this application surprisingly found that using the traditional method of rapid mixer granulation technique also gives much satisfactory result as it is working on the principle of (a) Spinning close to the bottom of the mixing bowl (b) The impeller sets the entire mixture in a whirling-rising tumbling motion ensuring a quick and even distribution of all dry components which leads to an even distribution of all dry components which leads to an even wetting of every granule. Due to rapid action of the blade and chopper and rapid speed of granulation, the drug remains in contact with the granulation fluid for a very short period of time, as a result the process helps in improving the stability of the product. The tablet with good physicochemical properties can be achieved. Desmopressin is a highly moisture sensitive drug. In the presence of solvents like alcohol and water it degradates and the effective therapeutic dose of drug is not available for desired effect. The inventors also found that the blend so prepared for tablets can also filled in the capsules. The resultant capsules are bioequivalent to that of the innovator's tablets in the market.
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US 7,094,545 ('545' patent) assigned to Ferring BV (Hoofddorp, NL) claims an improved pharmaceutical composition as a solid dosage form comprising desmopressin acetate, as a therapeutically active ingredient and mixing desmopressin acetate and an excipient, diluent or carrier, or mixture thereof, optionally in the presence of a wetting agent, wherein at least one of said excipient, diluent and carrier is a disaccharide, wherein said disaccharide has an average particle size in the range of from 70 to 500 .mu.m., wherein said solid dosage form is a tablet. In the marketed tablet is using the lactose (as disaccharide) particles (Pharmatose 150M provided by DMV, the Netherlands) have an average size of about 50 mu.m, as determined by an air jet sieve (provided by Alpine GmbH, DE). That particle size does not provide a granulate that allows a compressing speed exceeding about 170 000 tablets per hour (hr). Also the process disclosed in US'545 patent allows a compressing speed of up to about 250 000 tablets/h with the desired tablet quality and retained low level of wear on the tabletting machinery.Inventors of this patent specification are using disaccharide with the average particle size less than 60 micron and surprisingly found that the tablets can still be compressed with the satisfactory compression parameters , with satisfactory speed of tableting and low level of wear on the tabletting machinery. The blend so prepared can also filled in the capsules , and the resultant capsules is bioequivalent to the innovator's product in the market (DDAVP).
So the inventors of the present invention have come up with an invention so that have been able to overcome the difficulties that are criticized in the prior art. Thus the inventors of the present invention found that with the use of high concentration of lubricants (i.e. lubricants used at a concentration more than 0.5% w/w), and using the lower particle size of saccharides, and by maintaining the optimized speed of compression machine , the inventors are able to achieve stable desmopressin tablets with the desired disintegration and dissolution properties to that of the innovator's composition, without causing any wear and tear to the compression machine. Also the inventors of this present invention have found that a stable capsule dosage form can also be prepared using the same blend prepared for tablets and the so prepared capsules are found bioequivalent to that of the inovator's tablet composition of DDAVP.
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SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention is to make a physico-chemically stable composition of desmopressin acetate tablets and capsules.
Yet another aspect of the invention is to use the process of direct compression, wet granulation or slugging to prepare stable desmopressin acetate tablets that matches the dissolution profile of marketed formulation by the innovator.
Further aspect of the invention is to make desmopressin acetate tablets that can also be manufactured using the lubricants in the range of 0.5%-10% of tablet weight and still achieve the tablets that are having desired hardness and gives the satisfactory results for dissolution as that of the innovator's tablets (DDAVP) in the market.
Yet another aspect of the invention is to prepare tablets of desmopressin using rapid mixer and granulator during is wet granulation process.
Further aspect of the invention is to prepare tablets using saccharides with the average particle size less than 60 micron.
Further aspect of the invention is the use of saccharides such as monosaccharide, disaccharides, polysaccharides or combination thereof with the average particle size less than 60 micron.
Yet another aspect of the invention is using dibasic calcium phosphate as one of the essential ingredient in manufacturing desmopressin acetate tablet and capsules.
Yet another aspect of the invention is to prepare Desmopressin acetate tablet using slugging, direct compression or wet granulation method.
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Further aspect of the invention is to process of preparing Desmopressin acetate tablets that are matching the dissolution profile to that of the innovator product (DDAVP) in the market.
Another aspect of the invention is that the resultant Desmopressin acetate tablets are physicochemically stable in nature.
Further one more aspect of the invention is to make desmopressin acetate tablet having friability within the range of not more than (NMT)1% w/w as per USP method.
Yet another aspect of the invention is the granules or the blend so prepared for tablets, the same blend can be used to fill the capsules by selecting the appropriate capsule size to fill the desired therapeutically equivalent dose of desmopressin acetate in the capsule.
Another aspect of the invention is to pack the tablets in such a container that the finished product is protected by the moisture to retain its physicochemical stability for the desired period of time.
DEFINITIONS
The term "treating" or "treatment" of a state, disorder or condition as used herein means: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
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The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
By "pharmaceutically acceptable" is meant those salts and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. The term "subject" or "a patient" or "a host" as used herein refers to mammalian animals, preferably human.
The term "binders" is intended to mean substances used to cause adhesion of powder particles in tablet granulations. Such compounds include, by way of example and without limitation, acacia alginic acid, tragacanth, carboxymethylcellulose sodium, poly (vinylpyrrolidone), compressible sugar (e.g., NuTab), hydroxypropyl cellulose, hydroxypropyl methyl cellulose,ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch, polyvinyl pyrrolidone, combinations thereof and other material known to those of ordinary skill in the art.
When needed, other binders may also be included in the present invention. Exemplary binders include starch, poly (ethylene glycol), guar gum, polysaccharide, bentonites, sugars, invert sugars, collagen, albumin, celluloses in nonaqueous solvents, combinations thereof and the like. Other binders include, for example, poly (propylene glycol), polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, poly (ethylene oxide), microcrystalline cellulose, dibasic calcium phosphate, , combinations thereof and other such materials known to those of ordinary skill in the art.
The term "diluent" or "filler" as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the
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preparation of tablets and capsules. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, lactose, sucrose, mannitol, microcrystalline cellulose, corn starch, mannitol, pregelatinized starch, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, lactose, mono or di or oligo or polysaccharide or combinations thereof and other such materials known to those of ordinary skill in the art.
The saccharides used basically are chosen from the category , but are not limited to mannitol, lactose, starch, starch 1500, microcrystalline cellulose and combinations thereof.
The term "glidant" as used herein is intended to mean agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
The term "lubricant" as used herein is intended to mean substances used in tablet formulations to reduce friction during tablet compression. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate,talc, combinations thereof and other such materials known to those of ordinary person skilled in the art.
The term "disintegrant" is intended to mean a compound used in solid dosage forms to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, crospovidone, croscarmellose sodium, pre-gelatinized and modified starched thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g. Avicel™), carsium (e.g. Amberlite™), alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.

Most of these excipients are described in detail in Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20th Ed. 2000); and A. Kibbe, Handbook of Pharmaceutical Excipients, (3rd Ed. 2000), which are incorporated by reference herein.
The stable pharmaceutical compositions of the present invention can advantageously be prepared in a solid dosage form, e.g., a tablet, utilizing directly compressible ingredients, ingredients suitable for slugging, or direct compression or using granulation.
The stable pharmaceutical compositions of the present invention can also be prepared in the form of capsules. The blend prepared for tablets using all the examples disclosed harein in this specification; the same blend can also used to fill the capsules , using fill weigh such that the desired therapeutic dose of the drug can be administered. The capsules so prepared are bioequivalent to that of the inovator's tablet DDAVP in the market.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention discloses an oral pharmaceutical composition in the form of tablets and capsules having containing therapeutically effective component of Desmopressin acetate. This invention is not limited to the inactive excipients disclosed herein, but all those excipients known to the person skilled in the art can be used to make the said Desmopressin acetate tablet and capsules.
The following example is provided to enable one skilled in the art to practice the invention and is merely illustrative of the invention. The examples should not be read as limiting the scope of this invention.
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Tablets formulations Formula 1: (Wet granulation):

S.No. Ingredients % by wt in the unit tablet
01 Desmopressin acetate 0.1/0.2 mg/tab.
02 Lactose 1 to 95%
03 Corn starch 1 to 95%
04 PVP 0.5 to 5%
05 Water qs
06 Solvent(Isopropyl Alcohol(IPA)/Ethanol/Ac etone/Methylene chloride) qs
07 Crospovidone/Cros-carmellose sodium 0.5 to 5%
08 Colloidal silicon dioxide 0.1 to 0.5%
09 Talc 4 % to 5%
10 Magnesium Stearate 1% to 2%
Manufacturing Processes:
A) Addition of drug into the binder solution
a) Mix PVP in Solvent (IPA) and dissolve.
b) In another vessel, add drug in water/solvent mixture and dissolve.
c) Mix step (a) with step (b).
d) In RMG (Rapid mixer granulator), add Lactose & corn starch. Pour the mixture of step (c) to granulate the blend.
e) Dry the granules of step (d) in the tray drier or fluid bed drier, post to the granulation in the RMG.
f) Size the granules after drying using mechanical sifter.
g) Add Colloidal silicon dioxide, Crospovidone or Croscarmellose sodium with the dried & sized granules of step (f) and blend in a suitable blender.
h) Lubricate the blend of step (g) with Talc &magnesium stearate. i) Compress the blend of step (h) using a suitable compression machine for making tablets.
B) Addition of drug with the diluent
a) Mix PVP in Solvent (IPA) and dissolve.
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b) In RMG (Rapid mixer granulator), add drug , Lactose & corn starch. Pour the mixture of step (a) to granulate the blend.
c) Dry the granules of step (b) in the tray drier or fluid bed drier, post to the granulation in the RMG.
d) Size the granules after drying using mechanical sifter.
e) Add Colloidal silicon dioxide, Crospovidone or Croscarmellose sodium with the dried & sized granules of step (d) and blend in a suitable blender.
f) Lubricate the blend of step (e) with Talc &magnesium stearate.
g) Compress the blend of step (f) using a suitable compression machine for making tablets.
Formula 2: (Dry granulation)

S.No. Ingredients % by wt in the unit tablet
01 Desmopressin acetate 0.1/0.2 mg/tab.
02 Lactose 1 to 94%
03 Mannitol 1 to 94%
04 Microcrystalline cellulose(MCC) 1 to 94%
08 Croscarmellose sodium 0.5 to 5%
09 Talc 4% to 5%
10 Magnesium Stearate l%to2%
Manufacturing Process:
a) Blend API, lactose, Mannitol & MCC in a suitable blender geometrically and prepare slug with the help of a slugging machine. Optionally adding some portion of Croscarmellose sodium in to the blend of above prior slugging process.
b) Size the slug of step (a) with the help of a sizing machine like oscillatory granulator or multi-mill.
c) Mix the sized blend of step (b) with Croscarmellose sodium in a suitable blender.
d) Lubricate the blend of step (c) with magnesium stearate & Talc.
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e) Compress the blend of step (d) using a suitable compression machine for making tablets.
Formula 3(Dry granulation):

S.No Ingredients % by wt in the unit tablet
01 Desmopressin acetate 0.1/0.2 mg/tab.
02 Lactose 1 to 93%
03 Starch, Pregelatinized 1 to 93%
04 Hydroxypropyl cellulose(HPC) 2 to 6 %
05 Croscarmellose sodium 0.5 to 5%
06 Talc 4% to 5%
07 Magnesium Stearate l%to2%
Manufacturing Process:
a) Blend API, lactose, HPC & starch, pregelatinized in a suitable blender geometrically and prepare slug with the help of a slugging machine. Optionally adding some portion of Croscarmellose sodium in to the blend of above prior slugging process.
b) Size the slug of step (a) with the help of a sizing machine like oscillatory granulator or multi-mill.
c) Mix the sized blend of step (b) Croscarmellose sodium in a suitable blender.
d) Lubricate the blend of step (c) with magnesium stearate & Talc.
e) Compress the blend of step (d) using a suitable compression machine for making tablets.
Formula 4 (Direct compression):

S.No. Ingredients % by wt in the unit tablet
01 Desmopressin acetate 0.1/0.2 mg/tab.
02 Lactose 1 to 99%
03 MCC 1 to 99%
04 Cal. Phos, dibasic 1 to 99%
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anhydrous (DCP)
05 Crospovidone/Cros-carmellose sodium 0.5 to 5%
06 Colloidal silicon dioxide 0.1 to 0.5%
07 Talc 4% to 5%
08 Magnesium Stearate/Stearic acid l%to2%
Manufacturing Process:
a) Blend API, lactose, MCC, colloidal silicon dioxide & DCP anhydrous in a suitable blender geometrically.
b) Mix Crospovidone or Croscarmellose sodium with the blend of step (b).
c) Lubricate the blend of step (b) with magnesium stearate & Talc.
d) Compress the blend of step (c) using a suitable compression machine for making tablets.
Formula 6(Direct compression):

S.No. Ingredients % by wt in the unit tablet
01 Desmopressin acetate 0.1/0.2 mg/tab.
02 Mannitol 1 to 94%
03 Pregelatinized starch 1 to 94%
04 Croscarmellose sodium 0.5 to 5%
05 Colloidal silicon dioxide 0.1% to 0.5%
06 Talc 4% to 5%
07 Magnesium Stearate l%to2%
Manufacturing Process:
a) Blend API, Mannitol, Colloidal silicon dioxide & Pregelatinized starch in a suitable blender geometrically.
a) Mix Croscarmellose sodium with the blend of step (b).
b) Lubricate the blend of step (b) with magnesium stearate & Talc.
b) Compress the blend of step (c) using a suitable compression machine for making tablets.
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Formula 6 (Direct compression):

S.No. Ingredients % by wt in the unit tablet
01 Desmopressin acetate 0.1/0.2 mg/tab.
02 Partially Pregelatinized starch or Mono or Oligo or Polysaccharide 1 to 96%
03 Talc 4% to 5%
04 Magnesium Stearate l%to2%
Manufacturing Process:
a) Blend drug & Partially Pregelatinized starch or Mono or Oligo or Polysaccharide in a suitable blender geometrically.
b) Lubricate the blend of step (b) with magnesium stearate & Talc.
c) Compress the blend of step (c) using a suitable compression machine for making tablets.
Capsule formulation
Formula 1: (Wet granulation & Capsule filling):

S.No. Ingredients % by wt in the unit capsule
01 Desmopressin acetate 0.1/0.2 mg/tab.
02 Lactose 1 to 99%
03 Potato starch 1 to 99%
04 PVP 0.5 to 5%
05 Water qs
06 Solvent(Isopropyl Alcohol(IPA)/Ethanol/ Acetone/Methylene chloride) qs
07 Magnesium Stearate 0.05% & above
08 Empty hard gelatin capsule one
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Manufacturing Processes:
A) Addition of drug into the binder solution (Granulation in either RMG or FBP)
a) Mix PVP in Solvent (IPA/Ethanol) and dissolve.
b) In another vessel, add drug in water/solvent mixture and dissolve.
c) Mix step (a) with step (b).
d) In RMG (Rapid mixer granulator) or FBP (Fluid bed processor), add Lactose & potato starch. Pour or spray the mixture of step (c) to granulate the blend.
e) Dry the granules of step (d) in the tray drier/FBD in case of RMG granulation or in fluid bed processor in case of FBP granulation.
f) Size the granules after drying using mechanical sifter.
g) Lubricate the blend of step (f) with magnesium stearate.
h) Fill the blend of step (g) in HGC using manual or automated capsule filling machine. B) Addition of drug with the diluent
a) Mix PVP in Solvent (IPA/Ethanol) and dissolve.
b) In RMG (Rapid mixer granulator), add API, Lactose & potato starch. Pour the mixture of step (a) to granulate the blend.
c) Dry the granules of step (b) in the tray drier or fluid bed drier, post to the granulation in the RMG.
d) Size the granules after drying using mechanical sifter.
e) Lubricate the blend of step (e) with magnesium stearate.
f) Fill the blend of step (e) in HGC using manual or automated capsule filling machine.
Formula 2 (Blending & Capsule filling):

S.No. Ingredients % by wt in the unit capsule
01 Desmopressin acetate 0.1/0.2 mg/tab.
02 Diluent/s 1 to 99%
03 Lubricant/s MT 0.05%
04 Empty hard capsule gelatin one
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Manufacturing Process:
a) Blend drug & diluent/s in a suitable blender geometrically.
b) Lubricate the blend of step (a) with lubricant/s.
c) Fill the blend of step (b) in HGC using manual or automated capsule filling machine.
Proposal for the rest capsule dosage form formulas & processes:
Inventors of this specification have have used the same blend as that of the tablet compositions mentioned in formula-1 to formula- 6 under tablet dosage form. In stead of compressing the blend to make tablets, inventors have filled the same blend into hard gelatin capsules using the fill weight such that therapeutically effective dose of drug can be delivered.The resultant capsules are bioequivalent to that of the innovator's composition of DDV AP in the market.
Dated this Eighteenth (18th) day of September, 2006

Taranpreet Lamba. (Sr. Manager-IPM )
Glenmark Pharmaceuticals Limited
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