FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
PROVISIONAL SPECIFICATION
(SECTION 10)
"NOVEL PHARMACEUTICAL COMBINATION COMPRISING MIGLITOL AND
METFORMIN"
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
Glenmark Pharmaceuticals Limited,Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala,
Andheri (East),
Mumbai - 400 099, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION
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"A NOVEL PHARMACEUTICAL COMBINATION COMPRISING MIGLITOL
AND METFORMIN"
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates generally to a novel pharmaceutical combination comprising Miglitol and Metformin. The Metformin portion of the tablet is sustained release in nature. The present invention also discloses the process for preparing the same.
2. Description of the Related Art
Miglitol, an oral alpha-glucosidase inhibitor for use in the management of non-insulin-dependent diabetes mellitus (NIDDM) and is chemically known as 3,4,5-piperidinetriol,l-(2-hydroxyethyl)-2-(hydroxymethyl)-, [2R-(2a,3b,4a,5b)]-. Miglitol is soluble in water and has a pK a of 5.9.
Structure:

Metformin Hydrochloride extended release tablet is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula of metformin hydrochloride (metformin HC1) is as shown:
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N-C-NH-C-NH2*HCI
/ II II
H3C NH NH
Type 2 diabetes mellitus (DM) is a large and growing health problem in many countries, and appears to be associated with urbanization, sedentary lifestyles and dietary changes including increased consumption of fat. The World Health Organization (WHO) has estimated that the global prevalence of type 2 diabetes will be more than double - from 135 million in 1995 to 300 million by 2025. India bears a sizeable burden of this epidemic of diabetes, and it is projected that one out of every 5 diabetics in the world will be an Indian by the year 2025.
Several large epidemiologic studies have identified risk factors for the development of type 2 DM. These risk factors include belonging to an ethnic minority population, having a first-degree relative who has diabetes, obesity, living a sedentary lifestyle, age greater than 45 years, and having features of the metabolic syndrome. The metabolic syndrome is associated with a significantly increased risk of developing diabetes and is characterized by the presence of three or more of the following risk factors: abdominal obesity (waist circumference > 102 cm in men and 88 cm in women); high serum triglycerides (> 150 mg/dL); low high-density lipoprotein cholesterol (< 40 mg/dL in men and < 50 mg/dL in women); high blood pressure (> 130/> 85 mm Hg); and impaired fasting glucose (> 110 mg/dL). The American Diabetes Association has subsequently revised normal fasting glucose as less than 100 mg/dL.
Type 2 DM is characterized by impaired insulin action (insulin resistance) and impaired pancreatic beta cell function. Insulin resistance occurs when there is reduced sensitivity in body tissues to the action of insulin. Over time higher concentrations of insulin are required to stimulate glucose disposal in peripheral tissues and suppress glucose production in the liver. Eventually, functional defects in the pancreatic beta cells prevent adequate insulin production in response to the high demands in the peripheral tissues resulting in overt type 2 DM. Insulin
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H3C
N-C-NH-C-NIVHCI
/ II II
H3C NH NH
Type 2 diabetes mellitus (DM) is a large and growing health problem in many countries, and appears to be associated with urbanization, sedentary lifestyles and dietary changes including increased consumption of fat. The World Health Organization (WHO) has estimated that the global prevalence of type 2 diabetes will be more than double - from 135 million in 1995 to 300 million by 2025. India bears a sizeable burden of this epidemic of diabetes, and it is projected that one out of every 5 diabetics in the world will be an Indian by the year 2025.
Several large epidemiologic studies have identified risk factors for the development of type 2 DM. These risk factors include belonging to an ethnic minority population, having a first-degree relative who has diabetes, obesity, living a sedentary lifestyle, age greater than 45 years, and having features of the metabolic syndrome. The metabolic syndrome is associated with a significantly increased risk of developing diabetes and is characterized by the presence of three or more of the following risk factors: abdominal obesity (waist circumference > 102 cm in men and 88 cm in women); high serum triglycerides (> 150 mg/dL); low high-density lipoprotein cholesterol (< 40 mg/dL in men and < 50 mg/dL in women); high blood pressure (> 130/> 85 mm Hg); and impaired fasting glucose (> 110 mg/dL). The American Diabetes Association has subsequently revised normal fasting glucose as less than 100 mg/dL.
Type 2 DM is characterized by impaired insulin action (insulin resistance) and impaired pancreatic beta cell function. Insulin resistance occurs when there is reduced sensitivity in body tissues to the action of insulin. Over time higher concentrations of insulin are required to stimulate glucose disposal in peripheral tissues and suppress glucose production in the liver. Eventually, functional defects in the pancreatic beta cells prevent adequate insulin production in response to the high demands in the peripheral tissues resulting in overt type 2 DM. Insulin
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mechanisms of action are different from those of sulfonylureas. Metformin SR decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity (increases peripheral glucose uptake and utilization). Unlike sulfonylureas, metformin does not produce hypoglycemia in either diabetic or nondiabetic subjects and does not cause hyperinsulinemia.
The magnitude of the decline in fasting blood glucose concentration following the institution of Metformin SR therapy is proportional to the level of fasting hyperglycemia. Type 2 DM with higher fasting glucose concentrations will experience greater declines in plasma glucose and glycosylated hemoglobin. Metformin SR possibly ameliorates the effect of glucotoxicity and/or lipotoxicity on insulin action and insulin secretion by pancreatic beta-cells.
Miglitol is a desoxynojirimycin derivative that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals, as a consequence of plasma glucose reduction, miglitol reduces levels of glycosylated hemoglobin in patients with type 2 dm. systemic nonenzymatic protein glycosylation , as reflected by levels of glycosylated hemoglobin (hbalc), is a function of average blood glucose concentration over time.
In contrast to sulfonylureas, miglitol does not enhance insulin secretion, the antihyperglycemic action of miglitol results from a reversible inhibition of membrane-bound intestinal a-glucoside hydrolase enzymes. Membrane-bound intestinal a-glucosidases hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in delayed glucose absorption and lowering of postprandial hyperglycemia.
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Absorption of miglitol is saturable at high doses; a dose of 25 mg is completely absorbed, whereas a dose of 100 mg is only 50-70% absorbed, for all doses, peak concentrations are reached in 2-3 hours. There is no evidence that systemic absorption of miglitol contributes to its therapeutic effect. The protein binding is negligible (<4.0%). Miglitol is not metabolized in man or in any animal species studied. No metabolites have been detected in plasma, urine, or feces, indicating a lack of either systemic or pre-systemic metabolism, miglitol is eliminated by renal excretion as unchanged drug. The elimination half-life from plasma is approximately 2 hours.
Adverse effects of miglitol include abdominal pain, diarrhea, and flatulence. The incidence of diarrhea and abdominal pain tended to diminish considerably with continued treatment. Skin rash was reported in 4.3% of patients treated with miglitol compared to 2.4% of placebo-treated patients. Rashes were generally transient.
Miglitol, indicated as an adjunct to diet to improve glycemic control in patients with type 2 dm whose hyperglycemia cannot be managed with diet alone. Miglitol may also be used in combination with sulphonylureas or biguanides when diet plus either miglitol or a biguanide alone do not result in adequate glycemic control. The effect of miglitol to enhance glycemic control is additive to that of biguanides when used in combination, presumably because its mechanism of action is different.
The recommended starting dose of miglitol is 25 mg, given orally 3 times daily at the start (with the first bite) of each main meal, however, some patients may benefit by starting at 25 mg once daily to minimize gastrointestinal adverse effects, and gradually increasing the frequency of administration to 3 times daily. The usual maintenance dose of miglitol is 50 mg three times daily.
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In summary, Metformin SR-treated patients show significant improvement in all parameters of glycemic control (FPG, PPG and HbAlc), stabilization or decrease in body weight, and a tendency to improvement in the lipid profile, particularly when baseline values are abnormally elevated.
The absolute bioavailability of a Metformin SR 500-mg tablet given under fasting conditions is approximately 50-60%. Food decreases the extent of and slightly delays the absorption of Metformin. Following a single oral dose of Metformin SR, Cmax is achieved with a median value of 7 hours and a range of 4 hours to 8 hours.
Although the extent of metformin absorption (as measured by AUC) from the Metformin SR tablet increased by approximately 50% when given with food, there was no effect of food on Cmax and Tmax of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of Metformin SR.
Miglitol acts at small intestine delays the digestion of ingested carbohydrates and metformin SR acts mainly at the liver to reduce hepatic glucose production by a mechanism that is not understood completely.
The pharmacokinetic profiles of miglitol and metformin sr are complimentary with thrice daily dosing schedule.
Both the drugs will be used in low doses in the fixed dose combination of miglitol and metformin SR. Hence, this will minimize the possibility of adverse events seen with high doses of individual drugs thus improving the tolerability. Generally the daily dose of Miglitol is approximately 25-50 mg when taken thrice a day in divided doses and for Metformin SR the daily divided dose is around 1.5 gm. It has been observed that when Miglitol is given in combination with Metformin the daily dose requirement can be reduced down to 1 mg of
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Metformin and upto 50 mg of Miglitol daily. Since the drugs are potent in nature, this reduction is concentration is found tobe beneficial and avoids the dose dumping.
Superior effects than either agent alone in controlling both FPG and PPG
Various combinations of antidiabetics are available in the market like Glimepiride and metformin tablet, Glimepiride and Pioglitazone etc.
SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention, is to make a novel pharmaceutical composition containing a combination of Miglitol and metformin.
Further aspect of the invention is Metformin portion of the tablet is Sustained released in nature.
Yet another aspect of the invention is that the drug has been manufactured in the form of a solid oral dosage form.
In accordance with another embodiment the manufacturing process of the said tablet involves making separate granulations for both the drugs. Miglitol is granulated using dry granulation technique, most preferably slugging and Metformin granules are prepared by wet granulation means using liquid solution as binder. Both the granules are lubricated separately and compressed in the form of bilayred tablet.
Further aspect represents that both the drugs in combination are exerting a synergestic effect.
The combination tablet of Miglitol and Metformin SR is forund to be stable physicochemically.
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Further aspect of the invention denotes that the tablet is manufactured in the form of a bilayred tablet.
Yet another aspect of the invention is to provide a process for making Miglitol and metformin combination tablet.
Further aspect indicates that the dose regime for the combination is Miglitol 25 mg + Metformin SR 500 mg one tablet 2-3 times a day and Miglitol 50 mg + Metformin SR 500 mg one tablet 2-3 times a day
Another aspect of the invention is the intelligent selection of the inactive excipients makes it a cost effective composion.
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.
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.
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The term "delivering" as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local, oral or by systemic administration of the active ingredient to the host.
"Diluents" is intended to mean substances that act as a filler in the formulation. Microcrystalline cellulose, lactose, sucrose, Mannitol, starch, Lactose monohydrate, dicalcium phosphate, starch etc. can be used as diluents in this composition, or combinations thereof and other material known to those of ordinary skill in the art.
The term lubricants used herein is used are selected from the group stearic acid, Colloidal silicon dioxide, polyethylene glycol, hydrogenated vegetable oil, sodium steryl fumarate , magnesium stearate, etc.
The term
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention discloses an orally administrable pharmaceutical composition of a bilayred tablet containing Miglitol and Metformin. Metformin portion of the tablet is sustained release in nature.
Example 1.
SRN O. INGREDIENTS Rationale in using Excipients
I Miglitol Active Drug
Microcrystalline Cellulose Diluent and Binder

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(Avicel PH 101)
Yellow oxide of iron Colorant
Lake Of Indigo Carmine Colorant
Magnesium Stearate Lubricant
II Magnesium Stearate Lubricant
I Metformin Active Drug
Luctoman P 5000 Release retarding agent
Starch 1500 Binder
II Purified water vehicle
Methyl paraben Preservatives
Propyl paraben Preservatives
III Methocel K l00M CR Release retarding agent
Starch 1500 Binder
Polyethylene Oxide (Polyox WSR 301) Release retarding agent
Magnesium Stearate Lubricant
Boricin Pharma Lubricant
Manufacturing Process:
I. PREPARATION OF MIGLITOL GRANULES;
STEP NO I: - DRY MIXING
Sifted through 60 # sieve Miglitol Sifted through 60 # sieve Avicel PH 101 Sifted through 100 # sieve Yellow Oxide of Iron Sifted through 100 # sieve Lake of indigo carmine Mixed the sifted material in polybag for 15
minutes.
STEP NO II: - SLUGGING
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Slugg the Dry mixed material through 16 mm Round FFBE Punches.
STEP NO III: -DIMINUTION
Passed the dried granules through a 18 # sieve.
STEP NO IV: -LUBRICATION
i. Sifted through 40 # sieve Magnesium Stearate.
ii. Mixed the above sifted lubricants with the fines from step III in polybag for 5 Minutes.
II. PREPARATION OF METFORMIN HYDROCHLORIDE GRANULES
STEP NO I; - DRY MIXING
Sift through 80 # sieve Metformin Hydrochloride.
Sift through 200 # sieve Luctoman 5000
Sift through 80 # sieve Starch 1500
Mixed the sifted material in polybag for 5 minutes.
STEP NO II: - BINDING SOLUTION
Purified Water Heat it and add, Methyl Paraben & Propyl Paraben
STEP NO III: - WET MIXING
Add above solution to the mixed material of Step I & kneaded properly. If needed, add extra quantity of Purified Water.
STEP NO IV: - WET SIFTING
Passed the mass formed in Step III through 10 # sieve.
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STEP NQ V: - DRYING
Equipment: FBD, Temperature: 60°C
Drying Time: 30 min
% Moisture Content of Dried Granules: - 1.5% to 2.0 %
Redrying(if reqd.)
STEP NO VI: - DIMINUTION
Passed the dried granules through a 20 # sieve. STEP NO VII: - LUBRICATION
i. Sifted through a 40 # sieve HPMC (Methocel K 100 MCR), Starch 1500,
Boricin Pharma and Magnesium Stearate.
ii. Mixed the above sifted lubricants with the fines obtained in step VI in polybag for 5 minutes.
STEP NO VIII: - EVALUATION OF LUBRICATED GRANULES
i. Weight of lubricated granules: (Note it at time of Mfg.) ii. % Moisture Content: 1.5% to 2.0 %
STEP NO IX: -COMPRESSION
i. Punch Specifications
Shape: Capsule shape, FFBE Plain on both sides.
Diameter (mm): 17.00 X 8.00 mm ii. Temperature of Cabin: 21 °C iii. % RH of Cabin: 35-40%
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and
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implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.

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