JP2002504138A - Treatment of diabetes with rosiglitazone and insulin - Google Patents

Abstract

  (57) [Summary] A method for treating diabetes and diabetes-related conditions in a mammal, comprising administering to a mammal in need thereof an effective, non-toxic and pharmaceutically acceptable amount of compound (I) and insulin.

Description

DETAILED DESCRIPTION OF THE INVENTION            Treatment of diabetes with rosiglitazone and insulin   The present invention relates to a method of treatment, in particular a method of treating diabetes, in particular insulin-independent For treating diabetes mellitus (NIDDM) or type II diabetes and diabetes-related symptoms Related.   Insulin is at the forefront of treatment for type I diabetes (or insulin-dependent diabetes) You. Insulin has also been used as an antihyperglycemic agent in NIDDM.   EP-A-0306228 has antihyperglycemic and antihyperlipidemic activity. Certain thiazolidinedione derivatives disclosed as You. One special thiazolidine disclosed in EP-A-0 306 228 Dione is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy]. [S] benzyl] thiazolidine-2,4-dione (hereinafter referred to as “compound (I)” ). WO 94/05659 contains the maleate salt of Example 1 thereof. Thus, certain salts of compound (I) are disclosed.   International Patent Application Publication No. WO 97/05875 describes a therapeutically effective amount of thiazolidi NIDDM by administering a dianion derivative and / or related compound. Methods for reducing the amount of exogenous insulin administered to a patient having the same have been disclosed.   This time, surprisingly, compound (I) combined with insulin is Has a particularly beneficial effect on Therefore, such a combination Skin is particularly useful in the treatment of diabetes, especially type II diabetes and diabetes-related conditions.   Thus, the present invention relates to diabetes, particularly type II sugars, in mammals such as humans. Provided is a method for treating urine and diabetes related conditions, said method being effective, non-toxic and pharmaceutical An acceptable amount of compound (I) and insulin is administered to the mammal in need of treatment. Including giving.   Preferably, especially the daily dose of compound (I) is up to 12 mg.   The method comprises the simultaneous administration of compound (I) and insulin or their sequential administration including.   Simultaneous administration may involve administration of both an insulin sensitizer such as compound (I) and insulin. Or, more suitably, essentially the same as a separate formulation for each drug. Time administration.   In one particular embodiment, the method comprises, in particular, 2 to 12 mg per day. And the administration of compound (I).   In particular, the method comprises 2 to 4, 4 to 8, or 8 to 1 per day. Includes administration of 2 mg of compound (I).   In particular, the method comprises the administration of 2 to 4 mg of compound (I) per day. No.   In particular, the method comprises 4 to 8 mg per day (eg more than 4 mg). For example, 4.1 mg) of compound (I).   In particular, the method comprises administering 8 to 12 mg of compound (I) per day. Including.   Preferably, the method comprises the administration of 2 mg of compound (I) per day.   Preferably, the method comprises administering 4 mg of compound (I) per day.   Preferably, the method comprises administering 8 mg of compound (I) per day.   Compound (I) and insulin are each in a pharmaceutically acceptable form (the relevant pharmacology). Pharmaceutically acceptable salts, esters and solvates depending on the active ingredient (Including pharmaceutically acceptable derivatives).   Suitable salt forms of compound (I) are described in EP 0 306 228 and WO 94/05 659. A preferred pharmaceutically acceptable salt is maleic acid Salt.   Suitable pharmaceutically acceptable solvate forms of compound (I) are described in EP030622. 8 and those described in WO 94/05659, especially hydrates .   Suitable pharmaceutically acceptable forms of insulin are described in British Pharmacopoeia, U.S.P. ngton's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example, 31st edition) (See page 341 and the pages cited therein)) in standard textbooks. Or has been mentioned.   Compound (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof Solvates can be prepared by known methods, for example as described in EP 0 306 228 and WO 94/05 It may be manufactured using the method disclosed in US Pat. EP 0306228 and w The disclosure of 094/05659 is considered to be as set forth herein by reference. .   Compound (I) exists as one of several tautomers and all tautomers The sex, whether an individual tautomer or a mixture thereof, Product (I) ". Compound (I) contains a chiral carbon atom and is therefore 2 Up to species stereoisomers can exist and the term "compound (I)" All of these, whether isomers or their mixtures, including racemates, Of isomers.   Insulin is manufactured by a known method, which is Pharmacopoeia, United States Pharmacopeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Pres s) (see, for example, page 341 of the 31st edition and the pages cited therein) Found or referred to in classic textbooks.   As used herein, the term "diabetes-related condition" refers to a condition related to diabetes itself and diabetes. Includes complications associated with the disease.   “Symptoms related to diabetes itself” include hyperglycemia, insulin resistance, and acquired Insulin resistance and obesity. Additional symptoms related to diabetes itself , High blood pressure, cardiovascular diseases, especially atherosclerosis, certain eating disorders , In particular, diseases that require regulation of appetite and food intake, for example, Diseases such as anorexia nervosa, and diseases associated with overeating, such as fertilization And phagocytosis. Additional symptoms related to diabetes itself are many Cystic ovary syndrome and steroid-induced insulin resistance and pregnancy Sexual diabetes.   “Diabetes-related complications” refers to kidney diseases, particularly those associated with type II diabetes. Encompasses diseases, including neuropathy and retinopathy.   Kidney diseases associated with type II diabetes include nephropathy, glomerulonephritis, glomerulosclerosis , Nephrotic syndrome, hypertensive renal sclerosis and the final stages of kidney disease.   As used herein, the term "pharmaceutically acceptable" is used for both humans and domestic animals For example, the term “pharmaceutically acceptable” means veterinarily acceptable Compounds.   For the avoidance of doubt, scalar amounts herein are pharmaceutically acceptable. The amount of compound (I) in the form of mg and% by weight includes It shall be called. For example, 2 mg of the maleate salt of compound (I) It is the amount of maleate salt containing mg of compound (I).   Preferably, the diabetes is type II.   A particularly beneficial effect on glycemic control provided by the treatment of the present invention is Demonstrated to be synergistic to the expected control effect with respect to the sum of the component effects Is done.   Conventional methods, such as fasting plasma glucose or glycosylated hemoglobin ( Glycemic control is characterized by a glycemic control index typically used, such as Hb Alc). You may ask. Standard methods, for example, Tuescher A, Richterich, P., Schweitz. me d. Wschr. 101 (1971), 345 and 390, and Frank P., 'Monitoring the Diabe tic Patent with Glycosylated Hemoglobin Measurements', Clinical Products  The index is determined using the method described in 1988.   In a preferred embodiment, the dose level of each active agent used according to the treatment of the invention is Will be lower than the dose required for a purely additive effect on glycemic control.   In the method of the present invention, the active drug is preferably administered in the form of a pharmaceutical composition. You. As noted above, such compositions include both drugs or only one drug.   In the treatment of the present invention, injection or other known methods, such as Insulin is administered by the method described in the textbook mentioned in the detailed description. Therefore, Comments may include compositions, formulations and administrations, where appropriate, of compounds (I). And administration.   Usually, the composition is for oral administration. However, they can be administered in other ways. For example, it may be for parenteral administration, sublingual administration or transdermal administration.   Administerable compositions include tablets, capsules, powders, granules, sweetened tablets, suppositories, and reconstitutable Liquid powder such as active powder or oral or sterile parenteral solution or suspension. It may be in the form of a combined product.   To achieve consistent administration, the compositions of the present invention are preferably in unit dosage form. New   Oral unit dosage forms can be tablets or capsules, and binders such as Molasses, gum arabic, gelatin, sorbitol, tragacanth, or polyvinyl alcohol Lupyrrolidone; fillers such as lactose, sugar, corn starch, liquor Calcium phosphate, sorbitol or glycine; tableting lubricants such as stear Magnesium phosphate; disintegrants such as starch, polyvinylpyrrolidone, starch Sodium glycolate or microcrystalline cellulose; or sodium lauryl sulfate It may contain a pharmaceutically acceptable wetting agent such as thorium.   Solid oral compositions are prepared by conventional methods, such as mixing, filling or tableting. You may. Apply the active ingredient to the whole composition using a repetitive mixing operation using a large amount of filler. It may be dispersed in the body. Of course, such operations are conventional in the art . Well-known methods in normal pharmaceutical practice, especially tablets with enteric coating An agent may be coated.   The oral liquid formulation is in the form of an emulsion, syrup, or elixir Or a dry product form that is reconstituted with water or a suitable carrier before use It may be in a state. Such liquid preparations may contain suspending agents such as sorbitol, molasses , Methylcellulose, gelatin, hydroxyethylcellulose, carboxymethyl Cellulose, aluminum stearate gel, hydrogenated edible oil; emulsifier Eg, lecithin, sorbitan monooleate, or gum arabic; non-aqueous Carriers, which may include edible oils such as almond oil, fractionated coconut oil, glycerin Oily ester of propylene glycol or ethyl alcohol ester Le; Preservatives, for example methyl or propyl p-hydroxybenzoate or sorby Acid; and, if desired, customary perfumes or colorings.   For parenteral administration, liquid unit dosage forms are prepared using the compound and a sterile carrier. . The compound can be suspended or dissolved depending on the concentration used. When producing solutions And dissolve the compound in water for injection, filter sterilize and then place in an appropriate vial. Alternatively, an ampoule may be filled and sealed. Advantageously, local anesthetics, preservatives and Buffering agents can be dissolved in the carrier. To improve stability, After filling into the vial, the water can be frozen to remove water under reduced pressure. Compound (I) Suspend instead of dissolving in the carrier, except that sterilization is not performed by filtration. A parenteral suspension is prepared in a qualitatively identical manner. By exposure to ethylene oxide The compound can be sterilized and then suspended in a sterile carrier. Advantageously, the interface Includes activator or wetting agent in composition to facilitate uniform distribution of compound .   Depending on the method of administration, unless otherwise specified, the composition of the present invention may comprise from 0.1% by weight to It may contain 99% by weight, preferably 10-60% by weight of active ingredient.   If desired, the composition can be in the form of a pack with written or printed instructions for use. It may be in a state.   Standard literature, for example, British Pharmacopoeia and United States Pharmacopeia, Remington's Pharmaceut ical Sciences (Mark Publishing Co.), Martindale The Extra Pharmacopoeia (L ondon, The Pharmaceutical Press) (e.g., page 341 of the 31st edition and there) Cited pages) and Harry's Cosmeticology (Leonard Hill Books) The compositions of the present invention may be prepared and formulated according to conventional methods as described.   Preferably, the compositions are in unit dosage form in an amount suitable for a daily dose.   Suitable as a unit dose of compound (I) are 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11 or 12 mg.   In treatment, the medicament may be administered one to six times a day, but most preferably Once or twice a day.   Appropriate unit doses of insulin include United Kingdom Pharmacopeia, United States Pharmacopeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example, 31st edition) Page 341 and the pages cited therein). Or known doses, including unit doses of those compounds mentioned.   The range of 2 to 4 mg refers to 2.1 to 4, 2.2 to 4, 2.3 to 4 Not 2.4 to 4, 2.5 to 4, 2.6 to 4, 2.7 to 4, 2.8 4, 2.9 to 4 or 3 to 4 mg.   The range of 4 to 8 mg refers to 4.1 to 8, 4.2 to 8, 4.3 to 8 Not 4.4 to 8, 4.5 to 8, 4.6 to 8, 4.7 to 8, 4.8 8, 4.9-8, 5-8, 6-8 or 7-8 mg Include.   The range of 8 to 12 mg is 8.1 to 12, 8.2 to 12, 8.3. Chair 12, 8.4 to 12, 8.5 to 12, 8.6 to 12, 8.7 to 12, 8.8 to 12, 8.9 to 12, 9 to 12, 10 to 12, or Includes a range of 11 to 12 mg.   Adverse toxicological effects of the compositions or methods of the invention in the above dosage ranges Was not confirmed.   The following examples illustrate the invention but do not limit it in any way. No. Composition of compound (I) A Concentrated preparation   Approximately two-thirds of lactose-hydrate is sieved through a suitable sieve and the ground compound (I ). Sodium starch glycolate, hydroxyp Remove propyl methylcellulose, microcrystalline cellulose and the remaining lactose Sift and add to the above mixture. Thereafter, mixing is continued. Then get The resulting mixture is wet-granulated with purified water. Then sift the wet granules , Dried on a fluid bed dryer, sieved the dried granules further and finally homogenized Nize.                   Ingredient% value of granular concentrate Ingredient Amount (%) Ground compound (I) maleate 13.25                                                 (Pure maleate) Sodium starch glycolate 5.00 Hydroxypropyl methylcellulose 2910 5.00 Microcrystalline cellulose 20.00 Lactose-hydrate (regular grade) Add to 100 purified water * * Remove during processing B: Formulation of concentrate into tablets   The granules obtained in Example 1 are placed in a tumble blender. About 2/3 lactose And add to the blender. Microcrystalline cellulose, starch glycol Sift sodium luate, magnesium stearate and remaining lactose Add to the blender and mix the mixture. The resulting mixture is then Tableted with a Lee tablet press and weighs 150 mg for 1, 2 and 4 mg tablets. The weight of a tablet of 8 mg is 300 mg.   The tablet core is then transferred to a tablet coating machine and pre-warmed with warm air (about 65 ° C) and then film coating until the tablet weight is increased by 2.0 to 3.5%. To                                     Amount (mg per tablet) Tablet strength 1.0mg 2.0mg 4.0mg 8.0mg Active ingredient: Maleic acid salt of compound (I) 10.00 20.00 40.00 80.00 Concentrated granules Other ingredients: Starch glycolic acid 6.96 6.46 5.46 10.92 sodium Microcrystalline cellulose 27.85 25.85 5.46 10.92 Lactose-hydrate 104.44 96.94 81.94 163.8 Magnesium stearate 0.75 0.75 0.75 1.50 Total weight of tablet cores 150.0 150.0 150.0 300.0 Aqueous film coating material 4.5 4.5 4.5 9.0 154.5 154.5 154.5 309.0 with film coating Total tablet weight

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, L S, MW, SD, SZ, UG, ZW), EA (AM, AZ , BY, KG, KZ, MD, RU, TJ, TM), AL , AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, E E, ES, FI, GB, GE, GH, GM, GW, HU , ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, M D, MG, MK, MN, MW, MX, NO, NZ, PL , PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, U Z, VN, YU, ZW

Claims (1)

[Claims]   1. A method of treating diabetes and diabetes-related symptoms in a mammal, comprising the steps of: Need non-toxic and pharmaceutically acceptable amounts of compound (I) and insulin And administering to a mammal.   2. The method according to claim 1, comprising administering 2.2 to 12 mg of the compound (I). Method.   3. The method according to claim 1, comprising administering 3.2 to 12 mg of the compound (I). The method described in.   4.2 administration of 2 to 4, 4 to 8, or 8 to 12 mg of compound (I) The method according to any one of claims 1 to 3, comprising:   4. The method according to claim 1, which comprises administering 5.2 to 4 mg of the compound (I). The method described in.   4. The method according to claim 1, which comprises administering 6.4 to 8 mg of the compound (I). The method described in.   4. The method according to claim 1, comprising administering 7.8 to 12 mg of the compound (I). The method described in Crab.   4. The method according to claim 1, which comprises administering 8.2 mg of the compound (I). Method.   4. The method according to claim 1, which comprises administering 9.4 mg of the compound (I). Method.   4. The method according to claim 1, which comprises administering 10.8 mg of the compound (I). the method of.   11. Pharmaceutical composition comprising compound (I), insulin and a pharmaceutically acceptable carrier object.   12. The composition according to claim 11, wherein the insulin sensitizer is compound (I).   13. The composition according to claim 1, comprising up to 13.12 mg or 2 to 12 mg of compound (I). 13. A compound according to claim 1 or claim 12.   14． An active drug comprising compound (I), insulin and a pharmaceutically acceptable carrier. Pharmaceutical compositions used as therapeutics.   15. A compound comprising compound (I), insulin and a pharmaceutically acceptable carrier; And a pharmaceutical composition used for treating diabetes-related symptoms.