AU724989B2 - A method of reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus - Google Patents

Description

WO 97/05875 PCT/US96/12430 -1- A METHOD OF REDUCING THE AMOUNT OF EXOGENOUS INSULIN ADMINISTERED TO A PATIENT HAVING NONINSULIN-DEPENDENT DIABETES MELLITUS FIELD OF THE INVENTION The present invention provides a method of reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus.

BACKGROUND OF THE INVENTION Diabetes is one of the most prevalent chronic disorders worldwide with significant personal and financial costs for patients and their families, as well as for society. Different types of diabetes exist with distinct etiologies and pathogeneses. For example, diabetes mellitus is a disorder of carbohydrate metabolism, characterized by hyperglycemia and glycosuria and resulting from inadequate production or utilization of insulin.

Noninsulin-dependent diabetes mellitus (NIDDM), or Type II diabetes, is a form of diabetes mellitus that occurs predominantly in adults in whom adequate production of insulin is available for use, yet a defect exists in insulin-mediated utilization and metabolism of glucose in peripheral tissues.

Overt NIDDM is characterized by three major metabolic abnormalities: resistance to insulinmediated glucose disposal; impairment of nutrientstimulated insulin secretion; and overproduction of glucose by the liver.

WO 97/05875 PCT/US96/12430 -2- Failure to treat NIDDM control blood glucose levels) can result in mortality due to cardiovascular disease and in other diabetic complications including retinopathy, nephropathy, and peripheral neuropathy.

The treatment of NIDDM to control blood glucose levels in patients having NIDDM has included diet and exercise, as well as the use of sulfonylurea and biguanide therapeutic compounds. In addition, the compounds metformin and acarbose have recently been used to treat patients having NIDDM. However, in some patients, hyperglycemia cannot be adequately controlled by diet and exercise and/or the use of such therapeutic compounds. In such cases, exogenous insulin must be administered to the patient. The administration of insulin by injection to a patient, in addition to being expensive and painful, can result in various conditions or complications that are detrimental to the patient.

For example, an insulin reaction (hypoglycemia) can occur because of an error in insulin dosage, a missed meal, unplanned exercise or without apparent cause. In addition, local and/or generalized allergic reactions and immunological resistance to insulin can occur.

Thus, the present invention is a method of reducing the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus. A partial or total reduction of the amount of exogenous insulin administered to a patient having noninsulin-dependent diabetes mellitus can also be called "insulin rescue" as the patient is rescued from the need to use exogenous insulin to control serum glucose levels. As described below, in ongoing clinical trials 7 out of 17 human patients given a compound of the present method were completely removed or rescued from the need for exogenous insulin, a very exciting and unexpected discovery, as it was thought by -3those skilled in the art that a patient having NIDDM and requiring insulin suffered from insulin resistance and B-cell failure. B-cells are the cells in the pancreas that make endogenous insulin.

See, for example, Saad in The American Journal of Medicine, 1991;90:229-235, which discusses the role of pancreatic B-cell burnout in the progression of insulin resistance to

NIDDM.

SUMMARY OF THE INVENTION According to a first aspect, the invention provides a method for eliminating the need for exogenous insulin in a patient having non-insulin dependent diabetes mellitus and requiring S. exogenous insulin, the method comprising administering an exogenous insulin eliminating amount of rosiglitazone.

According to a second aspect, the invention provides a method for eliminating the need for exogenous insulin in a patient having non-insulin dependent diabetes mellitus and requiring exogenous insulin, the method comprising administering an exogenous insulin eliminating ooo* amount of pioglitazone.

According to a third aspect, the invention provides the use of rosiglitazone for the manufacture of a medicament for the elimination of the need for exogenous insulin in a patient having non-insulin dependent diabetes mellitus and requiring exogenous insulin.

According to a fourth aspect, the invention provides the use of pioglitazone for the manufacture of a medicament for the elimination of the need for exogenous insulin in a patient having non-insulin dependent diabetes mellitus and requiring exogenous insulin.

BRIEF DESCRIPTION OF THE DRAWING Figure 1 shows a chart representing patients' mean blood glucose levels and mean total daily exogenous insulin over time with the administration of a compound analogous to those of th D n sent method.

-4- DETAILED DESCRIPTION OF THE INVENTION The two compounds used in the present invention are: Pioglitazone is also known as 5-[p-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl]-2,4thiazolidinedione.

Rosiglitazone also known as 5-[(4-[2-Methyl-2-pyrindinylamino)ethoxy]phenyl)methyl]- 2,4-thiazolidinedione-(Z)-2-butenedioate The term "patient" includes humans and other animals. The term "exogenous insulin" means insulin which is administered to a patient from an external a EDITORIAL NOTE No. 66411/96 This specification does not contain pages numbered 5 to WO 97/05875 PCT/US96/12430 -21source as compared to endogenous insulin, which is insulin that is secreted by the pancreas of the patient.

The phrase "reducing the amount of exogenous insulin administered to a patient having noninsulindependent diabetes mellitus" means that in a patient requiring the control of blood sugar levels using exogenous insulin, the amount of insulin required to achieve the desired control of blood sugar levels in the absence of a compound of the present invention is more than the amount of insulin required when a compound of the present invention is administered to the patient. It is also intended that the term "reduction" include complete cessation of the administration of exogenous insulin to a patient.

It is surprising and unexpected that patients requiring exogenous insulin because their blood glucose levels could not be adequately controlled by diet and exercise and/or any of the commonly used therapeutic substances could be completely removed from insulin and that adequate control of blood glucose could be achieved by the administration of a compound of the present method. Thus, the present method provides a way of treating the most severe cases of noninsulindependent diabetes mellitus-those requiring exogenous insulin. Moreover, the present method provides for the complete cessation of exogenous insulin administration in those patients where insulin had heretobefore been required.

In general, it is desired to control the fasting blood glucose levels of patients having NIDDM in the range of about 80 mg/dL to about 140 mg/dL, which is the normal range as defined by the American Diabetes Association. The range of about 150 mg/dL to about 200 mg/dL has been considered as providing adequate control. Generally, a person having diabetes mellitus -22has been defined as a person having a fasting glucose of 140 mg/dL or higher.

The patients of the present method typically show a C-peptide level (fasting) that is 1.5 ng/mL or higher.

The compounds of the invention are capable of further forming both pharmaceutically acceptable acid addition and/or base salts. All of these forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds of Formulas I through X include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, 25 succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.

Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate, n-methyl glucamine (see, for example, Berge S.M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977;66:1-19).

The acid addition salts of said basic compounds are prepared by contacting the free base form with a WO 97/05875 PCT/US96/12430 -23sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner or as above. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.

Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977;66:1-19).

The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner or as above. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.

Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the -24solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in different configurations. The compounds can, therefore, form stereoisomers. Although these are all represented herein by a limited number of molecular formulas, the present invention includes the use of both the individual, isolated isomers and mixtures, including racemates, thereof. Where stereospecific synthesis techniques are employed or optically active compounds are employed as starting materials in the preparation of the compounds, individual isomers may be prepared directly; on the other hand, if a mixture of *isomers is prepared, the individual isomers may be obtained by conventional resolution techniques, or the mixture may be used as it is, without resolution.

Furthermore, the thiazolidine part of 20 the compounds can exist in the form of tautomeric isomers. All of the tautomers are intended to be a part of the present invention.

For preparing pharmaceutical compositions from the 25 compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid.

Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.

WO 97/05875 PCT/US96/12430 In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.

WO 97/05875 PCT/US96/12430 -26- Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsules, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 600 mg preferably 0.5 mg to 400 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a -27particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

The compounds of the present invention, and methods of making these compounds, are known and disclosed in U.S. Patents 5,223,522 issued June 29, 1993; 5,132,317 issued July 12, 1992; 5,120,754 issued June 9, 1992; 5,061,717 issued October 29, 1991; 4,897,405 issued January 30, 1990; 4,873,255 issued October 10, 1989; 4,687,777 issued August 18, 1987; 10 4,572,912, issued February 25, 1986; and 4,287,200, issued September 1, 1981. These issued patents are incorporated herein by reference.

The example presented below is intended to illustrate particular embodiments of the invention, and are not intended to limit the specification, including the claims, in any manner.

The compound used in this Example is also known as troglitazone which is analogous to the two 15 compounds of the invention. This Example illustrates the methodology of treating patients with the compounds of this invention.

EXAMPLE

Clinical Study Study of 5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2vl)methoxylphenylmethyl]-2,4-thiazolidinedione in NIDDM Patients Requiring Insulin Study Protocol After meeting the patient selection criteria set forth below, all patients participating in the study took 400 mg of 5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- -benzopyran-2initially maintaining WO 97/05875 PCT/US96/12430 -28their current insulin therapy. Every two weeks, fasting serum glucose (FSG) hemoglobin Alc (HbA 1 c), C-peptide, and total insulin measurements were made.

Home diaries were used to monitor blood glucose levels between visits to the clinic and to make clinical judgments for insulin dosage adjustments at clinic visits. Based on home diary information of the prior two weeks, the insulin dose was adjusted accordingly.

At the first visit that glycemic control was achieved, the insulin dose was decreased to half the value at baseline. At subsequent visits to the clinic, if glycemic control was still evident, the current insulin dose was halved. This reduction continued until the patient no longer required exogenous insulin.

Patient Selection Patients were to: 1) have NIDDM as defined by the criteria of the National Diabetes Data Group; 2) have evidence of failure of blood sugar control on sulfonylureas; 3) have evidence of poor control as documented by a glycosylated hemoglobin above the normal range HbA1, greater than the upper limit of normal); 4) have a C-peptide greater than 1.5 ng/mL; be over 18 years of age; and 6) have concomitant therapy with insulin for 6 months or less.

The study enrolled 17 patients over a 2-week period at a single center. All patients had a 2-week baseline period in which they maintained their dose of insulin at a constant level and performed home glucose monitoring 2-3 times/day. This frequency of home glucose monitoring was maintained during the study and values were recorded on diary cards. These were examined during the course of the study at 2-week intervals. The investigators was instructed to decrease a patient's dose of insulin at these visits if WO 97/05875 PCTIUS96/12430 -29the glycemic control appeared to be improved or stable based on the glucose monitoring levels or at any time during the study if a reduction were required for safety reasons. Similarly, the investigator could increase insulin doses if glycemic control appeared to worsen. The data represents 8 weeks of data from a 12-week study, the last 4 weeks of which are still in progress.

Patient Characteristics 17 Patients (10 males, 7 females) Mean Age (Range): 57 years (35-72) Mean Weight 104 kg (76-126) Mean HbAlc: 11.8% (8.6-15.4) Mean C-peptide 2.8 ng/mL (1.5-4.2) Mean Blood Glucose 205 mg/dL (101-363) Mean Duration Diabetes 11 years (2-31) Mean Duration Insulin Use 4 years (6 monthsyears) Mean Insulin Dose 58 units/day (20-21) Results As stated above, this summary represents 8-week interim data from a 12-week study. Based upon a favorable decrease in blood glucose levels, all 17 patients have had their dose of insulin reduced or discontinued. The mean decrease in insulin dose is with a range of 30% to 100%. The glucose levels have decreased by 10% (20 mg/dL) in the total group with a range of 0 to 133 mg/dL). (See Figure 1.) A total of 7 patients have had their insulin discontinued at this time (8 weeks). These patients have not had an overall decrease in their mean blood WO 97/05875 PCT/US96/12430 glucose as a group but have maintained their mean level of 160 mg/dL with a decrease from 42 units/day of insulin to 0. Three of these patients have decreased their fasting blood glucose to a level below 140 mg/dL.

Four of the 7 patients have been off insulin for over a month with maintenance of their glucose control. All seven are currently being maintained on dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran- 2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione.

The 10 patients that are still on insulin have had a mean decrease of 45% (39 units) in their daily dose of insulin and appear to be continuing to reduce their insulin requirements. At the same time, their glycemic control is improving with a mean decrease of (36 mg/dL) in blood glucose.

This group of subjects have had a significant decrease in their total exogenous insulin requirements with an improvement in their glycemic control. Prior to this study, these patients were being treated in a tertiary care setting with appropriate patient education and aggressive glucose-control management.

However, even with this type of management, glucose control was poor as evidenced by a mean HbAlc of 11.8.

This value underscores the fact that patients treated with insulin are in general, not well controlled in spite of the burden of insulin treatment.

All patients have had a decrease in their insulin doses with 7 patients being able to discontinue insulin completely. Of this latter group, 3/7 have fasting glucose levels within the desired range for diabetic control. Given the potential risk of increased atherosclerotic disease due to injecting large doses of exogenous insulin, the ability to decrease insulin use and improve glycemic control is important.

Claims (4)

1. A method for eliminating the need for exogenous insulin in a patient having non-insulin dependent diabetes mellitus and requiring exogenous insulin, the method comprising administering an exogenous insulin eliminating amount of rosiglitazone.

2. A method for eliminating the need for exogenous insulin in a patient having non-insulin dependent diabetes mellitus and requiring exogenous insulin, the method comprising administering an exogenous insulin eliminating amount of pioglitazone.

3. The use of rosiglitazone for the manufacture of a medicament for the elimination of the o need for exogenous insulin in a patient having non-insulin dependent diabetes mellitus and 4 10 requiring exogenous insulin.

4. The use of pioglitazone for the manufacture of a medicament for the elimination of the *6 need for exogenous insulin in a patient having non-insulin dependent diabetes mellitus and S requiring exogenous insulin. DATED this 4th Day of August 2000 15 WARNER-LAMBERT COMPANY Attorney: DENIS E. TUFFERY Registered Patent Attorney of BALDWIN SHELSTON WATERS