Indian Patents. 260436:PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF DIABETES MELLITUS

Title of Invention	PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF DIABETES MELLITUS
Abstract	Disclosed herein do fixed dose pharmaceutical compositions comprise: a) Hydroxychloroquine b) an antidiabetic drug selected from the group consisting of Sulphonylureas, Biguanides or Thiazolidinediones and c) at least one pharmaceutical excipients/carrier, useful in the treatment of diabetes mellitus. 24 SEP ZQ06 18

Full Text	FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rulel3) 1. TITLE OF THE INVENTION: "Fixed dose combination of Hydroxychloroquine with antidiabetic drugs for the treatment of diabetes mellitus" 2. APPLICANT(S): (a) NAME: IPCA LABORATORIES LIMITED (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West), Mumbai-400 067, Maharashtra, India. 3. PREAMBLE To THE DESCRIPTION: The following specification describes the nature of this invention and the manner in which it is to be performed: TECHNICAL FIELD OF THE INVENTION: The present invention relates to a pharmaceutical formulation comprising fixed dose combination of hydroxychloroquine with antidiabetic drugs such as sulphonylureas, biguanides and thiazolidinediones. In particular, it relates to a method to treat diabetes mellitus using the said pharmaceutical formulation. BACKGROUND OF THE INVENTION: Diabetes mellitus is a common disorder associated with high morbidity and mortality. In developing countries its incidence is steadily increasing due to rapid changes in lifestyle. Type 2 diabetes affects up to 10% of all adults in the general population and up to 20% of people over age 65, and is a major risk factor for cardiovascular, eye, kidney, and nerve disease. (National Institutes of Health, NIH Publication No.95-1468, 1995, pp.47-68.) A wide range of antidiabetic agents with different mechanisms of action can be used to treat diabetes. Sulphonylureas and biguanides have been mainstay of therapy in diabetes mellitus. However, although oral monotherapy is often initially successful, it is associated with a high secondary failure rate, which contributes to the development of long term diabetes complications resulting from persistent hyperglycemia. (Am J Med. 2000 Apr 17; 108 Suppl6a:15S-22S.) Accumulating evidence suggests that combination therapy using oral antidiabetic agents with different mechanisms of action may be highly effective in achieving and maintaining target blood glucose levels. Such combination therapy offers the prospects of enhanced glycaemic control, fewer adverse effects and better outcomes. 2 The best studied combination is that of sulphonylurea plus metformin, a therapeutic approach that addresses both underlying defects in the disorder: insulin deficiency and insulin resistance. Sulphonylureas act by binding to sulphonylurea receptors on pancreatic p-cells, leading to increased secretion of insulin. Possible mechanism of actions of metformin includes inhibition of hepatic gluconeogenesis by decreasing hepatic insulin resistance, delay in the absorption of glucose from the gastrointestinal tract and an increase in insulin sensitivity and glucose uptake into cells. Often patients on combination therapy with sulphonylureas and metformin are not controlled and hence the option left is either addition of third drug or put patient on insulin therapy. Insulin therapy is costly as well as not preferred therapy by patient due to poor compliance. Newer antidiabetics such as thiazolidinediones are associated with adverse effects such as an excess risk of congestive heart failure, possibly acute myocardial infarction, increased rate of bone loss and liver toxicity. In the light of this, newer medications for diabetes are needed, which will have along with antihyperglycemic effect, a good tolerability profile. Diabetes is considered to be CHD risk equivalent. A drug reducing blood glucose levels along with having cardiovascular benefits is therefore preferred in diabetes. Hydroxychloroquine is a disease modifying antirheumatic drug (DMARD) and is being used in rheumatology for past four decades. The use of hydroxychloroquine is well established in rheumatoid arthritis and systemic lupus erythematosus. Hydroxychloroquine has shown antidiabetic effects in many studies. The mechanism by which hydroxychloroquine improves glucose control remains unclear. It appears to lower glucose levels without a large effect on insulin sensitivity or secretion. Data showing that the parent drug chloroquine slows insulin clearance, possibly by stabilizing intracellular lysosomes and slowing the breakdown of the internalized insulin-receptor complex 3 provides one possible explanation for the glucose lowering effect of hydroxychloroquine. This is supported by the fact that hydroxychloroquine inhibits cytosolic insulin metabolism. (Diabetes Res Clin Pract. 2002 Mar;55(3):209-19.) The glucose lowering efficacy of hydroxychloroquine has been studied in various clinical trials. A study conducted in 135 obese patients with diabetes mellitus, showed that hydroxychloroquine improved glycemic control in sulphonylurea-refractory patients with poorly controlled Type 2 diabetes. (Diabetes Res Clin Pract. 2002 Mar;55(3):209-19.) In another prospective, multicenter observational study of 4905 adults with rheumatoid arthritis, use of hydroxychloroquine is associated with a reduced risk of diabetes. (JAMA. 2007 Jul 11 ;298(2): 187-93). Hydroxychloroquine has shown efficacy in patients with resistant diabetes also. A study conducted in 38 patients with non insulin-dependent diabetes resistant to commonly used therapies (oral drugs, insulin, combination of insulin and oral drugs) showed statistically significant improvement in patients who received the insulin and Hydroxychloroquine. The daily insulin dose in patients treated with the combined insulin and hydroxychloroquine therapy had to be reduced by an average of 30%. The trial showed that combining antidiabetic therapy with hydroxychloroquine in decompensated, treatment-refractory patients with noninsul in-dependent diabetes may help to break the vicious circle of hyperglycemia and lead to better management of the disease . (Ann Intern Med 1990 May 1;112(9):678-81) Along with antihyperglycaemic effects, hydroxychloroquine is also associated with cardiovascular benefits, due to its lipid lowering effect and antiplatelet effect. Improvement of serum cholesterol in patients treated with hydroxychloroquine has been reported. These include a decrease in serum levels of cholesterol by approximately 10% and an increase in low-density lipoprotein receptors. Hydroxychloroquine also led to a rise in both HDL and %HDL. (Ann Rheum Dis. 1997 Jun;56(6):374-7.) 4 Hydroxychloroquine therapy had a high statistical association with low serum levels of cholesterol, triglycerides, and LDL, irrespective of concomitant steroid administration. The hydroxychloroquine-treated group had lower cholesterol and LDL levels than those receiving neither hydroxychloroquine nor steroids. Very-low-density lipoprotein cholesterol was reduced in the group receiving hydroxychloroquine, and this was associated with decreased plasma triglycerides in this group. (Br J Rheumatol. 1985 Aug; 24(3): 250-5.) In addition to its lipid lowering effect, hydroxychloroquine may be cardioprotective by reducing platelet aggregation. Hydroxychloroquine causes reduction in red blood cell aggregation without prolonging the bleeding time in humans and experimentally, reduces the size of the thrombus. There is a variably demonstrable reduction in platelet aggregation and blood viscosity in humans. (Am J Med. 1988 Oct 14;85(4A): 57-61) A more recent clinical study found a significant reduction jn plasma viscosity as well as whole blood viscosity in postoperative patients treated with hydroxychloroquine. WO/2001/032758 discloses Pharmaceutical composition comprising a combination of metformin with other anti diabetic drug, wherein the other antidiabetic agent is one or more of glyburide, glimepiride, glipyride, glipizide, chlorbropamide, gliclazide, acarbose, miglitol, troglitazone. rosiglitazone, pioglitazone, insulin and/or KRP-297. However, none of the prior art reveals compositions that comprising a fix dose combinations of Hydroxychloroquine with Sulphonyluers, Biguanides and Thiazolidinediones for the treatment of diabetes mellitus. Thus it is an object of the present invention to provide formulation comprising fixed dose combination of hydroxychloroquine with antidiabetic drugs such as sulphonyl ureas, 5 biguanides and thiazohdinediones for treatment of diabetes mellitus. Fixed dose combination of hydroxychloroquine with antidiabetic drugs such as sulphonylureas, bigUanides and thiazohdinediones will thus be an effective alternative for treatment of diabetes mellitus, because of its efficacy and safety. SUMMARY OF THE INVENTION The present invention provides a pharmaceutical formulation comprising of fixed dose combination of hydroxychloroquine with antidiabetic drugs such as sulphonylureas, biguanides and thiazohdinediones. More particularly, the fixed dose combinations of the invention comprises oral dosage forms such as tablets or capsules, is in immediate release or controlled release or modified release or in sustained release form. DETAILED DESCRIPTION OF THE INVENTION The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated The present invention comprises of fixed dose combination of hydroxychloroquine with antidiabetic drugs such as sulphonylureas, biguanides and thiazohdinediones; wherein the hydroxychloroquine and the antidiabetic drug may be present as separate entities in the fixed dose pharmaceutical composition. The fixed dose composition of the present invention can be prepared as For example a multilayer tablet, a two-layer tablet, or capsules or sachets containing the active ingredients in separate granulates or beads, either granulate or bead optionally being coated with a protective coating or an enteric-coating. Accordingly, the fixed dose combination of the present invention comprises therapeutically effective amount of hydroxychloroquine and antidiabetic drugs such as sulphonylureas, biguanides and thiazohdinediones for treatment of diabetes mellitus. The term "therapeutically effective amount" means the amount which provides the desired therapeutic effect on administration of the same. 6 The advantages associated with fixed dose combination of hydroxychloroquine with antidiabetic drugs such as sulphonyl ureas, biguanides and thiazolidinediones are synergistic glucose lowering efficacy, significant improvement in glycaemic control in drug resistant diabetes mellitus, dosage reduction of oral hypoglycaemic agents as well as insulin, cardiovascular benefits such as lipid lowering effect, reduction of platelet aggregation and blood viscosity and low toxicity profile. Fixed dose combination of hydroxychloroquine with antidiabetic drugs such as sulphonylureas, biguanides and thiazolidinediones will therefore provide an useful treatment option for patients with diabetes mellitus. The fixed dose formulation of the present invention is preferably in the form of tablets or capsules, wherein tablets/capsules can be prepared in immediate release, modified/controlled release, extended or in sustain release form. The combination of Hydroxychloroquine with antidiabetic drugs according to the present invention will offer following advantages: 1. Synergistic glucose lowering efficacy 2. Significant improvement in glycaemic control in patients with diabetes resistant to oral hypoglycaemic agents (such as sulphonylureas, biguanides and thiazolidinediones), insulin or combination of insulin and oral drugs 3. Reduces dosage of oral hypoglycaemic agents as well as insulin 4. Cardiovascular benefits such as lipid lowering effect, reduction of platelet aggregation and blood viscosity 5. Low toxicity profile Keeping in view of a better combination therapy with greater pharmacological aspects, the inventor has conducted a comparative, open label pre-clinical (animal) study to 7 evaluate the efficacy in terms of potency of hydroxychloroquine in combination with antidiabetic drugs such as sulphonylureas, biguanides and thiazolidinediones. The therapeutically effective amount of hydroxychloroquine is generally in the range of 100 mg to 400mg, when it is administered in association with other anti diabetics such as sulphonylureas, biguanides and thiazolidinediones. The present invention can safely be carried out. According to a preferred embodiment, the invention discloses a fixed dose pharmaceutical composition which comprises hydroxychloroquine in combination with sulfonylureas. For example, Glimepiride can be used in the range of 1 mg to 8mg that can be administered as fixed dosage form in combination with hydroxychloroquine for an average adult. Similarly, the fixed dose composition of the present invention comprises hydroxychloroquine and gliclazide. The normal dose of gliclazide ranges in an amount of 30 mg to 320mg. Further, the present invention describes fixed dose pharmaceutical composition that comprises hydroxychloroquine with glibenclamide. Glibenclamide normally ranges in an amount of 1 mg to 20mg. The present invention further discloses a pharmaceutical composition which comprises hydroxychloroquine in combination with glipizide as fixed dose composition. Glipizide is typically present in an amount of 1 mg to 40 mg in the composition. According to another preferred embodiment, the invention discloses a fixed dose pharmaceutical composition which comprises hydroxychloroquine in combination with biguanides. The fixed dose composition of hydroxychloroquine and biguanide comprises; for example, hydroxychloroquine in amount of lOOmg to 400mg in combination with metformin in an amount of 250mg to 2500mg. According to another preferred embodiment, the invention discloses a fixed dose pharmaceutical composition which comprises hydroxychloroquine in combination with thiazolidinediones. The fixed dose composition of hydroxychloroquine and 8 thiazolidinediones comprises; for example, hydroxychloroquine in amount of lOOmg to 400 mg in combination with rosiglitazone 2mg to 8mg. Similarly, hydroxychloroquine in amount of lOOmg to 400mg in combination with pioglitazone lOmg to 45mg. Thus, the quantity of the compound/compounds used in fixed dose pharmaceutical compositions of the present invention will vary depending upon the body weight of the patient and the mode of administration and can be of any effective amount to achieve the desired therapeutic effect. The fixed dose composition of hydroxychloroquine with other antidiabetic drugs such as sulphonylureas, biguanides and thiazolidinediones can be administered orally in combination with at least one pharmaceutical carrier/excipient. As used herein the term 'at least one pharmaceutical carrier/excipient' refers to any conventional pharmaceutical carrier/excipient routinely used in preparation of desired dosage forms like solid; liquid and injectable dosage forms. For oral use, suitable pharmaceutical carriers include inert diluents or fillers thereby forming oral dosage forms such as tablets, powders, pellets, capsules, syrups or suspensions and the like. For example, tablets containing variety of excipients such as disintegrants such as starch, complex silicates together with binding agents such as poly vinyl pyrrolidone, sucrose, gelatin and acacia. Lubricants such as magnesium silicate, sodium lauryl sulfate and talc are often used in tabletting purposes. Solid compositions of the present invention can also be filled into soft and hard gelatin capsules. For soft gelatin capsule, the composition may be solubilized in suitable vegetable or edible oil such as sunflower oil, corn oil, peanut oil or any other suitable oil. According to another embodiment, the invention provides method for treating diabetes, wherein said method comprises administering therapeutically effective amounts of fixed dose combination of the present invention or pharmaceutical composition comprising the same. 9 The safety, efficacy and synergy of the fixed dose combinations of hydroxychloroquine with other antidiabetic drugs selected drugs such as sulphonylureas, biguanides and thiazolidinediones is clinically established by the following experiments. The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. Examples: Example 1 Experimental study on fixed dose combination of Hydroxychloroquine with Glimepiride Thirty Wistar rats weighing 150 - 200 g of either sex were divided into six groups consisting of five rats each. Experimental diabetes was induced in rats by injecting alloxan monohydrate intraperitonially at a dose of 90 mg/kg body weight. Rats with blood sugar level of 250- 350 mg/dl, were considered as diabetic and employed in the study. Group 1 (normal control) consisted of normal rats that neither received alloxan monohydrate nor any drug. Group 2 served as diabetic control which received vehicle orally. Group 3 was diabetic and treated with hydroxychloroquine (HCQ) at the dose of 160 mg/kg; p.o. Group 4 was diabetic and treated with glimepiride (GLM) at the dose of 8 mg/kg; p.o. Group 5 was diabetic and treated with low dose combination of GLM (4mg/kg) and HCQ (80 mg/kg), whereas Group 6 was diabetic and treated with high dose combination of GLM (8mg/kg) and HCQ (160 mg/kg). The study drugs were administered for nine days. There was a significant difference between the treated groups with respect to fall in blood glucose levels. Both ( low dose and high dose) combination treatment showed 10 significantly more fall in blood glucose levels as compared to individual treatment groups (p The present study demonstrates that GLM and HCQ in high dose combination is superior than their individual components in terms of glucose lowering activity in alloxan-induced diabetic rats. Example 2 Experimental study on fixed dose combination of Hydroxychloroquine with Metformin Thirty Wistar rats weighing 150 - 200 g of either sex were divided into six groups consisting of five rats each. Experimental diabetes was induced in rats by injecting alloxan monohydrate intraperitonially at a dose of 90 mg/kg body weight. Rats with blood sugar level of 250- 350 mg/dl, were considered as diabetic and employed in the study. Group 1 (normal control) consisted of normal rats that neither received alloxan monohydrate nor any drug. Group 2 served as diabetic control which received vehicle orally. Group 3 was diabetic and treated with hydroxychloroquine (HCQ) at the dose of 160 mg/kg; p.o. Group 4 was diabetic and treated with metformin (MET) at the dose of 500 mg/kg; p.o. Group 5 was diabetic and treated with low dose combination of MET (250mg/kg) and HCQ (80 mg/kg), whereas Group 6 was diabetic and treated with high dose combination of MET (500 mg/kg) and HCQ (160 mg/kg). The study drugs were administered for.nine days. 11 There was a significant difference between the treated groups with respect to fall in blood glucose levels. Both ( low dose and high dose) combination treatment showed significantly more fall in blood glucose levels as compared individual treatment groups. (p=0.04; p=0.001 for low dose and high dose respectively). Moreover the fall in blood glucose of high dose combination group was significantly more than low dose combination treated group (p=0.015). Reduction in body weight of animals treated with high and low dose combination of HCQ and MET was significantly lower (P Results of the present study show that the combination of HCQ and MET is superior in terms of glucose lowering activity. Example 3 Experimental study on fixed dose combination of Hydroxychloroquine with Pioglitazone Thirty Wistar rats weighing 150 - 200 g of either sex were divided into six groups consisting of five rats each. Experimental diabetes was induced in rats by injecting alloxan monohydrate intraperitonially at a dose of 90 mg/kg body weight. Rats with blood sugar level of 250- 350 mg/dl, were considered as diabetic and employed in the study. Group 1 (normal control) consisted of normal rats that neither received alloxan monohydrate nor any drug. Group 2 served as diabetic control which received vehicle orally. Group 3 was diabetic and treated with Hydroxychloroquine (HCQ) at the dose of 160 mg/kg; p.o. Group 4 was diabetic and treated with pioglitazone (PIO) at the dose of 10 mg/kg; p.o. Group 5 was diabetic and treated with low dose combination of PIO (6mg/kg) and HCQ (80 mg/kg), whereas Group 6 was diabetic and treated with high dose combination of PIO (10 mg/kg) and HCQ (160 mg/kg). The study drugs were administered for nine days. 12 Administration of high dose combination of HCQ and PIO resulted in significant (P<.001 reduction in blood glucose levels as compared to their individual components alloxan induced diabetic rats. however case of low dose combination treated group the level was not significantly different from components. fall high more than body weight animals with and hcq pio lower control group. moreover both reduced total cholesterol triglyceride increased hdl hemoglobin protein albumin> The results suggested that the combination of HCQ and PIO exhibit significant glucose lowering activity on alloxan induced diabetic rats as compared to their individual components. The invention is further illustrated by following non-limiting example. Example 4 Fixed dose combination of hydroxychloroquine with sulphonylureas i. Each tablet/capsule contains: Hydroxychloroquine .. ..lOOmg to 400mg Glimepiride lmg to 8mg ii. Each tablet/capsule contains: Hydroxychloroquine .... 1 OOmg to 400mg Gliclazide (including Gliclazide modified/controlled release 30mg to 320mg iii. Each tablet/capsule contains: Hydroxychloroquine .... 1 OOmg to 400mg 13 Glibenclamide (Glyburide) 1 mg to 20mg iv. Each tablet/capsule contains: Hydroxychloroquine .... 1 OOmg to 400mg Glipizide Imgto40mg Example 5 Fixed dose combination of Hydroxychloroquine with biguanides i. Each tablet/capsule contains: Hydroxychloroquine ....lOOmg to 400mg Metformin (including metformin extended/controlled release)...250mg to 2500mg Example 6 Fixed dose combination of Hydroxychloroquine with thiazolidinediones i. Each tablet/capsule contains: Hydroxychloroquine .... 1 OOmg to 400mg Pioglitazone .... 1 Omg to 45mg ii. Each tablet/capsule contains: Hydroxychloroquine .... 1 OOmg to 400mg Rosiglitazone ....2mg to 8mg Process for preparation: The pharmaceutical composition as described above can be formulated into different dosage forms using suitable conventional pharmaceutical excipients/carrier that can be selected from but not limited to pharmaceutical acceptable polymers, fillers, diluents, glidants, disintegrant, lubricants and the like, using conventional preparative techniques. 14 The fixed dose formulation of the present invention is preferably in the form of tablets or capsules, wherein tablets/capsules can be prepared in immediate release, modified/controlled release, extended or in sustain release form. 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 alematives, modifications and equivalents included within scope, as defined by appended claims. 15 We claim, 1. A fixed dose pharmaceutical composition comprising: a) Hydroxychloroquine b) an antidiabetic drug selected from the group consisting of Sulphonylureas, Biguanides or Thiazolidinediones and c) at least one pharmaceutical excipients/carrier, useful in the treatment of diabetes mellitus. 2. The pharmaceutical composition as claimed in claim 1 wherein Hydroxy¬chloroquine is present in the range of 100 mg to 400 mg. 3. The pharmaceutical composition as claimed in claim 1 wherein Sulphonylurea is selected from Glimepiride, Gliclazide, Glibenclamide, or Glipizide. 4. The pharmaceutical composition as claimed in claim 1 wherein Glimepiride is present in the range of 1 mg to 8 mg. 5. The pharmaceutical composition as claimed in claim 1 wherein Gliclazide is present in an amount of 30mg to 320mg. 6. The pharmaceutical composition as claimed in claim 1 wherein Glibenclamide is present in an amount of lmg to 20mg. 7. The pharmaceutical composition as claimed in claim 1 wherein Glipizide is present in an amount of lmg to 40mg. 8. The pharmaceutical composition as claimed in claim 1 wherein Biguanides is Metformin present in an amount of 250 mg to 2500 mg. 9. The pharmaceutical composition as claimed in claim 1 wherein Thiazolidinediones is selected from Rosiglitazone or Pioglitazone. 16 10. The pharmaceutical composition as claimed in claim 1 wherein pioglitazone is present in an amount of l0mg to 45mg. 11. The pharmaceutical composition as claimed in claim 1 wherein rosiglitazone is present in an amount of 2 mg to 8mg. 12. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical excipients/carrier is selected from but not limited to pharmaceutical acceptable polymers, fillers, diluents, glidants, disintegrant, lubricants and the like. 13. The pharmaceutical composition as claimed in any of the preceding claims, wherein said formulation is in the solid dosage form preferably in the form of tablets or capsules, wherein tablets/capsules are in immediate release, modified/controlled release, extended or in sustain release form. 14. The pharmaceutical composition as claimed in claim 1, wherein Hydroxychloroquine and Glimepiride is in the range of 100 mg to 400 mg and in range of 1 mg to 8 mg respectively. 15. The pharmaceutical composition as claimed in claim 1, wherein Hydroxychloroquine and Metformin is in the range of 100 mg to 400 mg and in the range of 250 mg to 2500mg respectively. 16. The pharmaceutical composition as claimed in claim, 1 wherein Hydroxychloroquine and Pioglitazone is in the range of 100 mg to 400 mg and in the range of 10 mg to 45 mg respectively. Dated this 24th Day of September, 2008 Dr. P. Aruna Sree Agent for the Applicant 17

Full Text

FORM 2 THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"Fixed dose combination of Hydroxychloroquine with antidiabetic drugs for the
treatment of diabetes mellitus"

2. APPLICANT(S):
(a) NAME: IPCA LABORATORIES LIMITED
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West), Mumbai-400 067, Maharashtra, India.
3. PREAMBLE To THE DESCRIPTION:
The following specification describes the nature of this invention and the manner in which it is to be performed:

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to a pharmaceutical formulation comprising fixed dose combination of hydroxychloroquine with antidiabetic drugs such as sulphonylureas, biguanides and thiazolidinediones. In particular, it relates to a method to treat diabetes mellitus using the said pharmaceutical formulation.
BACKGROUND OF THE INVENTION:
Diabetes mellitus is a common disorder associated with high morbidity and mortality. In developing countries its incidence is steadily increasing due to rapid changes in lifestyle. Type 2 diabetes affects up to 10% of all adults in the general population and up to 20% of people over age 65, and is a major risk factor for cardiovascular, eye, kidney, and nerve disease. (National Institutes of Health, NIH Publication No.95-1468, 1995, pp.47-68.)
A wide range of antidiabetic agents with different mechanisms of action can be used to treat diabetes. Sulphonylureas and biguanides have been mainstay of therapy in diabetes mellitus.
However, although oral monotherapy is often initially successful, it is associated with a high secondary failure rate, which contributes to the development of long term diabetes complications resulting from persistent hyperglycemia. (Am J Med. 2000 Apr 17; 108 Suppl6a:15S-22S.)
Accumulating evidence suggests that combination therapy using oral antidiabetic agents with different mechanisms of action may be highly effective in achieving and maintaining target blood glucose levels. Such combination therapy offers the prospects of enhanced glycaemic control, fewer adverse effects and better outcomes.
2

The best studied combination is that of sulphonylurea plus metformin, a therapeutic approach that addresses both underlying defects in the disorder: insulin deficiency and insulin resistance.
Sulphonylureas act by binding to sulphonylurea receptors on pancreatic p-cells, leading to increased secretion of insulin. Possible mechanism of actions of metformin includes inhibition of hepatic gluconeogenesis by decreasing hepatic insulin resistance, delay in the absorption of glucose from the gastrointestinal tract and an increase in insulin sensitivity and glucose uptake into cells.
Often patients on combination therapy with sulphonylureas and metformin are not controlled and hence the option left is either addition of third drug or put patient on insulin therapy. Insulin therapy is costly as well as not preferred therapy by patient due to poor compliance. Newer antidiabetics such as thiazolidinediones are associated with adverse effects such as an excess risk of congestive heart failure, possibly acute myocardial infarction, increased rate of bone loss and liver toxicity.
In the light of this, newer medications for diabetes are needed, which will have along with antihyperglycemic effect, a good tolerability profile.
Diabetes is considered to be CHD risk equivalent. A drug reducing blood glucose levels along with having cardiovascular benefits is therefore preferred in diabetes.
Hydroxychloroquine is a disease modifying antirheumatic drug (DMARD) and is being used in rheumatology for past four decades. The use of hydroxychloroquine is well established in rheumatoid arthritis and systemic lupus erythematosus. Hydroxychloroquine has shown antidiabetic effects in many studies. The mechanism by which hydroxychloroquine improves glucose control remains unclear. It appears to lower glucose levels without a large effect on insulin sensitivity or secretion. Data showing that the parent drug chloroquine slows insulin clearance, possibly by stabilizing intracellular lysosomes and slowing the breakdown of the internalized insulin-receptor complex
3

provides one possible explanation for the glucose lowering effect of hydroxychloroquine. This is supported by the fact that hydroxychloroquine inhibits cytosolic insulin metabolism. (Diabetes Res Clin Pract. 2002 Mar;55(3):209-19.)
The glucose lowering efficacy of hydroxychloroquine has been studied in various clinical trials. A study conducted in 135 obese patients with diabetes mellitus, showed that hydroxychloroquine improved glycemic control in sulphonylurea-refractory patients with poorly controlled Type 2 diabetes. (Diabetes Res Clin Pract. 2002 Mar;55(3):209-19.)
In another prospective, multicenter observational study of 4905 adults with rheumatoid arthritis, use of hydroxychloroquine is associated with a reduced risk of diabetes. (JAMA. 2007 Jul 11 ;298(2): 187-93).
Hydroxychloroquine has shown efficacy in patients with resistant diabetes also. A study conducted in 38 patients with non insulin-dependent diabetes resistant to commonly used therapies (oral drugs, insulin, combination of insulin and oral drugs) showed statistically significant improvement in patients who received the insulin and Hydroxychloroquine. The daily insulin dose in patients treated with the combined insulin and hydroxychloroquine therapy had to be reduced by an average of 30%. The trial showed that combining antidiabetic therapy with hydroxychloroquine in decompensated, treatment-refractory patients with noninsul in-dependent diabetes may help to break the vicious circle of hyperglycemia and lead to better management of the disease . (Ann Intern Med 1990 May 1;112(9):678-81)
Along with antihyperglycaemic effects, hydroxychloroquine is also associated with cardiovascular benefits, due to its lipid lowering effect and antiplatelet effect.
Improvement of serum cholesterol in patients treated with hydroxychloroquine has been reported. These include a decrease in serum levels of cholesterol by approximately 10% and an increase in low-density lipoprotein receptors. Hydroxychloroquine also led to a rise in both HDL and %HDL. (Ann Rheum Dis. 1997 Jun;56(6):374-7.)
4

Hydroxychloroquine therapy had a high statistical association with low serum levels of cholesterol, triglycerides, and LDL, irrespective of concomitant steroid administration. The hydroxychloroquine-treated group had lower cholesterol and LDL levels than those receiving neither hydroxychloroquine nor steroids. Very-low-density lipoprotein cholesterol was reduced in the group receiving hydroxychloroquine, and this was associated with decreased plasma triglycerides in this group. (Br J Rheumatol. 1985 Aug; 24(3): 250-5.)
In addition to its lipid lowering effect, hydroxychloroquine may be cardioprotective by reducing platelet aggregation.
Hydroxychloroquine causes reduction in red blood cell aggregation without prolonging the bleeding time in humans and experimentally, reduces the size of the thrombus. There
is a variably demonstrable reduction in platelet aggregation and blood viscosity in
humans. (Am J Med. 1988 Oct 14;85(4A): 57-61)
A more recent clinical study found a significant reduction jn plasma viscosity as well as whole blood viscosity in postoperative patients treated with hydroxychloroquine.
WO/2001/032758 discloses Pharmaceutical composition comprising a combination of metformin with other anti diabetic drug, wherein the other antidiabetic agent is one or more of glyburide, glimepiride, glipyride, glipizide, chlorbropamide, gliclazide, acarbose, miglitol, troglitazone. rosiglitazone, pioglitazone, insulin and/or KRP-297.
However, none of the prior art reveals compositions that comprising a fix dose combinations of Hydroxychloroquine with Sulphonyluers, Biguanides and Thiazolidinediones for the treatment of diabetes mellitus.
Thus it is an object of the present invention to provide formulation comprising fixed dose combination of hydroxychloroquine with antidiabetic drugs such as sulphonyl ureas,
5

biguanides and thiazohdinediones for treatment of diabetes mellitus. Fixed dose combination of hydroxychloroquine with antidiabetic drugs such as sulphonylureas, bigUanides and thiazohdinediones will thus be an effective alternative for treatment of diabetes mellitus, because of its efficacy and safety.
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical formulation comprising of fixed dose combination of hydroxychloroquine with antidiabetic drugs such as sulphonylureas, biguanides and thiazohdinediones. More particularly, the fixed dose combinations of the invention comprises oral dosage forms such as tablets or capsules, is in immediate release or controlled release or modified release or in sustained release form.
DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in detail in connection with certain preferred and
optional embodiments, so that various aspects thereof may be more fully understood and
appreciated
The present invention comprises of fixed dose combination of hydroxychloroquine with
antidiabetic drugs such as sulphonylureas, biguanides and thiazohdinediones; wherein the
hydroxychloroquine and the antidiabetic drug may be present as separate entities in the
fixed dose pharmaceutical composition.
The fixed dose composition of the present invention can be prepared as For example a
multilayer tablet, a two-layer tablet, or capsules or sachets containing the active
ingredients in separate granulates or beads, either granulate or bead optionally being
coated with a protective coating or an enteric-coating.
Accordingly, the fixed dose combination of the present invention comprises therapeutically effective amount of hydroxychloroquine and antidiabetic drugs such as sulphonylureas, biguanides and thiazohdinediones for treatment of diabetes mellitus.
The term "therapeutically effective amount" means the amount which provides the desired therapeutic effect on administration of the same.
6

The advantages associated with fixed dose combination of hydroxychloroquine with antidiabetic drugs such as sulphonyl ureas, biguanides and thiazolidinediones are synergistic glucose lowering efficacy, significant improvement in glycaemic control in drug resistant diabetes mellitus, dosage reduction of oral hypoglycaemic agents as well as insulin, cardiovascular benefits such as lipid lowering effect, reduction of platelet aggregation and blood viscosity and low toxicity profile.
Fixed dose combination of hydroxychloroquine with antidiabetic drugs such as sulphonylureas, biguanides and thiazolidinediones will therefore provide an useful treatment option for patients with diabetes mellitus.
The fixed dose formulation of the present invention is preferably in the form of tablets or capsules, wherein tablets/capsules can be prepared in immediate release, modified/controlled release, extended or in sustain release form.
The combination of Hydroxychloroquine with antidiabetic drugs according to the present invention will offer following advantages:
1. Synergistic glucose lowering efficacy
2. Significant improvement in glycaemic control in patients with diabetes resistant to oral hypoglycaemic agents (such as sulphonylureas, biguanides and thiazolidinediones), insulin or combination of insulin and oral drugs
3. Reduces dosage of oral hypoglycaemic agents as well as insulin
4. Cardiovascular benefits such as lipid lowering effect, reduction of platelet aggregation and blood viscosity
5. Low toxicity profile
Keeping in view of a better combination therapy with greater pharmacological aspects, the inventor has conducted a comparative, open label pre-clinical (animal) study to
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evaluate the efficacy in terms of potency of hydroxychloroquine in combination with antidiabetic drugs such as sulphonylureas, biguanides and thiazolidinediones.
The therapeutically effective amount of hydroxychloroquine is generally in the range of 100 mg to 400mg, when it is administered in association with other anti diabetics such as sulphonylureas, biguanides and thiazolidinediones.
The present invention can safely be carried out. According to a preferred embodiment, the invention discloses a fixed dose pharmaceutical composition which comprises hydroxychloroquine in combination with sulfonylureas. For example, Glimepiride can be used in the range of 1 mg to 8mg that can be administered as fixed dosage form in combination with hydroxychloroquine for an average adult.
Similarly, the fixed dose composition of the present invention comprises hydroxychloroquine and gliclazide. The normal dose of gliclazide ranges in an amount of 30 mg to 320mg. Further, the present invention describes fixed dose pharmaceutical composition that comprises hydroxychloroquine with glibenclamide. Glibenclamide normally ranges in an amount of 1 mg to 20mg. The present invention further discloses a pharmaceutical composition which comprises hydroxychloroquine in combination with glipizide as fixed dose composition. Glipizide is typically present in an amount of 1 mg to 40 mg in the composition.
According to another preferred embodiment, the invention discloses a fixed dose pharmaceutical composition which comprises hydroxychloroquine in combination with biguanides. The fixed dose composition of hydroxychloroquine and biguanide comprises; for example, hydroxychloroquine in amount of lOOmg to 400mg in combination with metformin in an amount of 250mg to 2500mg.
According to another preferred embodiment, the invention discloses a fixed dose pharmaceutical composition which comprises hydroxychloroquine in combination with thiazolidinediones. The fixed dose composition of hydroxychloroquine and
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thiazolidinediones comprises; for example, hydroxychloroquine in amount of lOOmg to 400 mg in combination with rosiglitazone 2mg to 8mg. Similarly, hydroxychloroquine in amount of lOOmg to 400mg in combination with pioglitazone lOmg to 45mg.
Thus, the quantity of the compound/compounds used in fixed dose pharmaceutical compositions of the present invention will vary depending upon the body weight of the patient and the mode of administration and can be of any effective amount to achieve the desired therapeutic effect.
The fixed dose composition of hydroxychloroquine with other antidiabetic drugs such as sulphonylureas, biguanides and thiazolidinediones can be administered orally in combination with at least one pharmaceutical carrier/excipient.
As used herein the term 'at least one pharmaceutical carrier/excipient' refers to any conventional pharmaceutical carrier/excipient routinely used in preparation of desired dosage forms like solid; liquid and injectable dosage forms. For oral use, suitable pharmaceutical carriers include inert diluents or fillers thereby forming oral dosage forms such as tablets, powders, pellets, capsules, syrups or suspensions and the like.
For example, tablets containing variety of excipients such as disintegrants such as starch, complex silicates together with binding agents such as poly vinyl pyrrolidone, sucrose, gelatin and acacia. Lubricants such as magnesium silicate, sodium lauryl sulfate and talc are often used in tabletting purposes. Solid compositions of the present invention can also be filled into soft and hard gelatin capsules.
For soft gelatin capsule, the composition may be solubilized in suitable vegetable or edible oil such as sunflower oil, corn oil, peanut oil or any other suitable oil. According to another embodiment, the invention provides method for treating diabetes, wherein said method comprises administering therapeutically effective amounts of fixed dose combination of the present invention or pharmaceutical composition comprising the same.
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The safety, efficacy and synergy of the fixed dose combinations of hydroxychloroquine with other antidiabetic drugs selected drugs such as sulphonylureas, biguanides and thiazolidinediones is clinically established by the following experiments.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples:
Example 1
Experimental study on fixed dose combination of Hydroxychloroquine with
Glimepiride
Thirty Wistar rats weighing 150 - 200 g of either sex were divided into six groups consisting of five rats each. Experimental diabetes was induced in rats by injecting alloxan monohydrate intraperitonially at a dose of 90 mg/kg body weight. Rats with blood sugar level of 250- 350 mg/dl, were considered as diabetic and employed in the study.
Group 1 (normal control) consisted of normal rats that neither received alloxan monohydrate nor any drug. Group 2 served as diabetic control which received vehicle orally. Group 3 was diabetic and treated with hydroxychloroquine (HCQ) at the dose of 160 mg/kg; p.o. Group 4 was diabetic and treated with glimepiride (GLM) at the dose of 8 mg/kg; p.o. Group 5 was diabetic and treated with low dose combination of GLM (4mg/kg) and HCQ (80 mg/kg), whereas Group 6 was diabetic and treated with high dose combination of GLM (8mg/kg) and HCQ (160 mg/kg). The study drugs were administered for nine days.
There was a significant difference between the treated groups with respect to fall in blood glucose levels. Both ( low dose and high dose) combination treatment showed
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significantly more fall in blood glucose levels as compared to individual treatment groups (p The present study demonstrates that GLM and HCQ in high dose combination is superior than their individual components in terms of glucose lowering activity in alloxan-induced diabetic rats.
Example 2
Experimental study on fixed dose combination of Hydroxychloroquine with
Metformin
Thirty Wistar rats weighing 150 - 200 g of either sex were divided into six groups consisting of five rats each. Experimental diabetes was induced in rats by injecting alloxan monohydrate intraperitonially at a dose of 90 mg/kg body weight. Rats with blood sugar level of 250- 350 mg/dl, were considered as diabetic and employed in the study. Group 1 (normal control) consisted of normal rats that neither received alloxan monohydrate nor any drug. Group 2 served as diabetic control which received vehicle orally. Group 3 was diabetic and treated with hydroxychloroquine (HCQ) at the dose of 160 mg/kg; p.o. Group 4 was diabetic and treated with metformin (MET) at the dose of 500 mg/kg; p.o. Group 5 was diabetic and treated with low dose combination of MET (250mg/kg) and HCQ (80 mg/kg), whereas Group 6 was diabetic and treated with high dose combination of MET (500 mg/kg) and HCQ (160 mg/kg). The study drugs were administered for.nine days.
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There was a significant difference between the treated groups with respect to fall in blood glucose levels. Both ( low dose and high dose) combination treatment showed significantly more fall in blood glucose levels as compared individual treatment groups. (p=0.04; p=0.001 for low dose and high dose respectively). Moreover the fall in blood glucose of high dose combination group was significantly more than low dose combination treated group (p=0.015). Reduction in body weight of animals treated with high and low dose combination of HCQ and MET was significantly lower (P Results of the present study show that the combination of HCQ and MET is superior in terms of glucose lowering activity.
Example 3
Experimental study on fixed dose combination of Hydroxychloroquine with
Pioglitazone
Thirty Wistar rats weighing 150 - 200 g of either sex were divided into six groups consisting of five rats each. Experimental diabetes was induced in rats by injecting alloxan monohydrate intraperitonially at a dose of 90 mg/kg body weight. Rats with blood sugar level of 250- 350 mg/dl, were considered as diabetic and employed in the study. Group 1 (normal control) consisted of normal rats that neither received alloxan monohydrate nor any drug. Group 2 served as diabetic control which received vehicle orally. Group 3 was diabetic and treated with Hydroxychloroquine (HCQ) at the dose of 160 mg/kg; p.o. Group 4 was diabetic and treated with pioglitazone (PIO) at the dose of 10 mg/kg; p.o. Group 5 was diabetic and treated with low dose combination of PIO (6mg/kg) and HCQ (80 mg/kg), whereas Group 6 was diabetic and treated with high dose combination of PIO (10 mg/kg) and HCQ (160 mg/kg). The study drugs were administered for nine days.
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Administration of high dose combination of HCQ and PIO resulted in significant (P<.001 reduction in blood glucose levels as compared to their individual components alloxan induced diabetic rats. however case of low dose combination treated group the level was not significantly different from components. fall high more than body weight animals with and hcq pio lower control group. moreover both reduced total cholesterol triglyceride increased hdl hemoglobin protein albumin> The results suggested that the combination of HCQ and PIO exhibit significant glucose lowering activity on alloxan induced diabetic rats as compared to their individual components.
The invention is further illustrated by following non-limiting example.
Example 4
Fixed dose combination of hydroxychloroquine with sulphonylureas
i. Each tablet/capsule contains:
Hydroxychloroquine .. ..lOOmg to 400mg
Glimepiride lmg to 8mg
ii. Each tablet/capsule contains:
Hydroxychloroquine .... 1 OOmg to 400mg
Gliclazide (including Gliclazide modified/controlled release 30mg to 320mg
iii. Each tablet/capsule contains:
Hydroxychloroquine .... 1 OOmg to 400mg
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Glibenclamide (Glyburide) 1 mg to 20mg
iv. Each tablet/capsule contains:
Hydroxychloroquine .... 1 OOmg to 400mg
Glipizide Imgto40mg
Example 5
Fixed dose combination of Hydroxychloroquine with biguanides
i. Each tablet/capsule contains:
Hydroxychloroquine ....lOOmg to 400mg
Metformin (including metformin extended/controlled release)...250mg to 2500mg
Example 6
Fixed dose combination of Hydroxychloroquine with thiazolidinediones
i. Each tablet/capsule contains:
Hydroxychloroquine .... 1 OOmg to 400mg Pioglitazone .... 1 Omg to 45mg
ii. Each tablet/capsule contains:
Hydroxychloroquine .... 1 OOmg to 400mg Rosiglitazone ....2mg to 8mg
Process for preparation:
The pharmaceutical composition as described above can be formulated into different dosage forms using suitable conventional pharmaceutical excipients/carrier that can be selected from but not limited to pharmaceutical acceptable polymers, fillers, diluents, glidants, disintegrant, lubricants and the like, using conventional preparative techniques.
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The fixed dose formulation of the present invention is preferably in the form of tablets or capsules, wherein tablets/capsules can be prepared in immediate release, modified/controlled release, extended or in sustain release form.
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 alematives, modifications and equivalents included within scope, as defined by appended claims.
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We claim,
1. A fixed dose pharmaceutical composition comprising: a) Hydroxychloroquine b) an antidiabetic drug selected from the group consisting of Sulphonylureas, Biguanides or Thiazolidinediones and c) at least one pharmaceutical excipients/carrier, useful in the treatment of diabetes mellitus.
2. The pharmaceutical composition as claimed in claim 1 wherein Hydroxy¬chloroquine is present in the range of 100 mg to 400 mg.
3. The pharmaceutical composition as claimed in claim 1 wherein Sulphonylurea is selected from Glimepiride, Gliclazide, Glibenclamide, or Glipizide.
4. The pharmaceutical composition as claimed in claim 1 wherein Glimepiride is present in the range of 1 mg to 8 mg.
5. The pharmaceutical composition as claimed in claim 1 wherein Gliclazide is present in an amount of 30mg to 320mg.
6. The pharmaceutical composition as claimed in claim 1 wherein Glibenclamide is present in an amount of lmg to 20mg.
7. The pharmaceutical composition as claimed in claim 1 wherein Glipizide is present in an amount of lmg to 40mg.
8. The pharmaceutical composition as claimed in claim 1 wherein Biguanides is Metformin present in an amount of 250 mg to 2500 mg.
9. The pharmaceutical composition as claimed in claim 1 wherein Thiazolidinediones is selected from Rosiglitazone or Pioglitazone.
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10. The pharmaceutical composition as claimed in claim 1 wherein pioglitazone is present in an amount of l0mg to 45mg.
11. The pharmaceutical composition as claimed in claim 1 wherein rosiglitazone is present in an amount of 2 mg to 8mg.
12. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical excipients/carrier is selected from but not limited to pharmaceutical acceptable polymers, fillers, diluents, glidants, disintegrant, lubricants and the like.
13. The pharmaceutical composition as claimed in any of the preceding claims, wherein said formulation is in the solid dosage form preferably in the form of tablets or capsules, wherein tablets/capsules are in immediate release, modified/controlled release, extended or in sustain release form.
14. The pharmaceutical composition as claimed in claim 1, wherein Hydroxychloroquine and Glimepiride is in the range of 100 mg to 400 mg and in range of 1 mg to 8 mg respectively.
15. The pharmaceutical composition as claimed in claim 1, wherein Hydroxychloroquine and Metformin is in the range of 100 mg to 400 mg and in the range of 250 mg to 2500mg respectively.
16. The pharmaceutical composition as claimed in claim, 1 wherein Hydroxychloroquine and Pioglitazone is in the range of 100 mg to 400 mg and in the range of 10 mg to 45 mg respectively.
Dated this 24th Day of September, 2008
Dr. P. Aruna Sree Agent for the Applicant
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PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF DIABETES MELLITUS

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