JP2003514011A - Pharmaceutical composition comprising thiazolidinedione-metformin hydrochloride - Google Patents

Abstract

  (57) [Summary] A pharmaceutical composition comprising thiazolidinedione, metformin hydrochloride and a pharmaceutically acceptable carrier, wherein the thiazolidinedione is formulated on the surface of metformin hydrochloride, and use of such a composition in medicine.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to novel compositions, in particular compositions comprising one or more active ingredients and their use in medicine, in particular diabetes mellitus, preferably type II diabetes, and the treatment of conditions associated with diabetes. For use in.

BACKGROUND ART Biguanide hypoglycemic drugs are non-insulin dependent diabetes mellitus (NI).
DDM, or type II diabetes) is commonly used. 1,1
-Dimethyl biguanidine (metformin) is one example of a biguanide hypoglycemic drug. EP-A-0306228 relates to certain thiazolidinedione derivatives disclosed as having hypoglycemic and hypolipidemic activity. Certain thiazolidinediones disclosed in EP 0306228 are 5
It is-[4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione (hereinafter referred to as "compound (I)").
EP 0658161 discloses in its Example 1 certain salts of compound (I) containing the maleate salt. Compound (I) is an example of a type of hypoglycemic drug known as "insulin sensitizer". In particular, compound (I) is a thiazolidinedione type insulin sensitizer. The publications mentioned above are incorporated herein by reference. The most important consideration in preparing a formulation containing a combination of active agents is the stability of a given active agent, such that the interaction of the active agent itself or the interaction of the active agent with the excipient can destabilize the agent. In nature. Metformin is most commonly administered in the form of its hydrochloride salt (metformin hydrochloride). In certain formulations, compound (I) has been shown to be susceptible to degradation during preparation and storage due to the presence of metformin hydrochloride. On this occasion,
The present inventors have made compound (I) in which the instability of compound (I) is inhibited or prevented.
And a pharmaceutical composition containing metformin hydrochloride.

DISCLOSURE OF THE INVENTION Accordingly, the present invention is a pharmaceutical composition comprising a thiazolidinedione, such as compound (I), metformin hydrochloride and a pharmaceutically acceptable carrier, wherein the thiazolidinedione is formulated on the surface of metformin hydrochloride. Pharmaceutical compositions are provided. Suitably, the thiazolidinedione is formulated as a thin layer on the surface of metformin hydrochloride. In a preferred embodiment, metformin hydrochloride is in compressed form, eg in tablet form. Preferably, the composition also includes an inert barrier layer between the layer containing the thiazolidinedione and metformin hydrochloride. The composition thus produced is a multi-layer composition, generally a two-layer composition, in which one active ingredient, generally in liquid form, is applied directly to the surface of another active ingredient, usually in solid form. The article consists of a three-layer or four-layer composition (or actually more multilayers) in which each active ingredient layer is repeatedly formed, preferably separated by an inert barrier layer. May be.

Suitable doses, preferably unit doses of thiazolidinediones such as compound (I) and metformin hydrochloride are the United Kingdom and US Pharmacopoeia, Remington's Pharmaceutical
Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (Lo
ndon, The Pharmaceutical Press) (see, eg, 31st Edition, page 341 and the pages cited therein) or any reference to such compounds as described or referenced in reference books such as the publications mentioned above. Including allowance. The dosage of each particular active agent in a given composition can, if necessary, be varied within the range of known dosages required in the accepted modes of administration for the compound.

In certain embodiments, the composition comprises 2 to 12 mg of Compound (I). Suitably, the composition is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 1.
It contains 2 mg of compound (I). In particular, the compound comprises 2 to 4, 4 to 8 or 8 to 12 mg of compound (I). In particular, the composition comprises 2 to 4 mg of compound (I). In particular, the composition comprises 4 to 8 mg of compound (I). In particular, the composition comprises 8 to 12 mg of compound (I). Preferably, the composition comprises 2 mg of compound (I). Preferably, the composition comprises 4 mg of compound (I). Preferably, the composition comprises 8 mg of compound (I). As noted above, unit doses of metformin include the doses found in the references cited herein, including the doses detailed below. A suitable amount of metformin hydrochloride is 100 to 3000 mg, for example 250
, 500 mg, 850 mg, or 1000 mg.

A particular composition of the invention is compound (I) in the range 2-12 mg and a dose of metformin hydrochloride in the range 100 to 3000 mg, eg 4 mg of compound (I).
And 500 mg metformin hydrochloride. Other formulations are 2 mg compound (I) and 500 mg or 850 mg metformin hydrochloride or 4 mg compound (I).
And 850 mg metformin hydrochloride. Other thiazolidinediones are (+)-5-[[4-[(3,4-dihydro-6-
Hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione (troglitazone), 5- [4-[(1 -Methylcyclohexyl) methoxy]
Benzyl] thiazolidine-2,4-dione (ciglitazone),
5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidine-2,4-dione (pioglitazone) or 5-[(
2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl] thiazolidine-2,4-dione (englitazone).

The compounds herein, especially the thiazolidinediones, such as compound (I), exist as one of several tautomers, all of which may be present as individual tautomers or mixtures thereof. include. The compounds described herein contain one or more chiral carbon atoms and therefore exist as two or more stereoisomers, all of which are individual isomers or isomers, including racemates. It is included in the present invention as a mixture.

The thiazolidinediones and metformin, such as compound (I), include pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and solvates thereof, as appropriate for the relevant pharmaceutically active substance of choice. , It will be seen that it is a pharmaceutically acceptable form. The names used as antidiabetic agents herein in certain cases relate to the particular pharmaceutical form of the active substance concerned. It will be appreciated that all pharmaceutically acceptable forms of the active substance itself are included in the present invention.

Suitable pharmaceutically acceptable forms of thiazolidinediones such as compound (I) and metformin include known pharmaceutically acceptable forms. Such derivatives are described in Remington's Pharmaceutical Sciences (Mack Publishing Co.
), The Extra Pharmacopoeia (London, The Pharmaceutical Press) (see, eg, 31st Edition, page 341 and the pages cited therein) and standard reference texts such as the publications mentioned above. There is. For example, a particular form of metformin is metformin hydrochloride. Suitable pharmaceutically acceptable forms of compound (I) are described in EP 0306228 and WO
94/05659, especially in the form of pharmaceutically acceptable salts or solvates. A preferred pharmaceutically acceptable salt form of Compound (I) is the maleate salt. A preferred pharmaceutically acceptable solvate form of Compound (I) is a hydrate. A preferred form of pioglitazone is its hydrochloride salt.

Metformin is prepared according to known methods, such methods being described in the British and US Pharmacopoeia, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Ma.
rtindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (see, eg, 31st Edition page 341 and pages cited therein) or standard reference texts such as those mentioned in the publications above. Has been done. Compound (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is prepared using known methods, such as those disclosed in EP0306228 and WO94 / 05659. EP0306228 and WO94 / 0
The disclosure of 5659 is incorporated herein by reference in its entirety.

The term “diabetes associated conditions” as used herein includes conditions associated with a pre-diabetic condition, diabetes associated with diabetes mellitus itself, and complications associated with diabetes mellitus. The term "conditions associated with a pre-diabetic state" as used herein includes conditions such as insulin resistance, impaired glucose tolerance, impaired fasting glucose and hyperinsulinemia. “Symptoms associated with diabetes mellitus itself” include hyperglycemia, insulin resistance and obesity. In addition, diabetes mellitus has associated symptoms such as hypertension and cardiovascular disease,
In particular, the conditions associated with atherosclerosis and insulin resistance are included. Symptoms associated with insulin resistance include polycystic ovary syndrome, steroid-induced insulin resistance and gestational diabetes. "Complications associated with diabetes mellitus" include kidney disease, particularly kidney disease associated with type II diabetes, neuropathy and retinopathy. Kidney diseases associated with type II diabetes include nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease.

The term “pharmaceutically acceptable” as used herein includes both human and veterinary use. For example, the term "pharmaceutically acceptable" includes veterinary acceptable compounds. The term "liquid form" as used herein includes solutions and suspensions. For the avoidance of doubt, unless otherwise stated, when referring to a scalar amount, including the amount of mg, of an active compound such as a pharmaceutically acceptable form of compound (I) herein, the referred scalar amount is The amounts referred to the active compound itself. For example, 2 mg of compound (I) in the maleic acid form is the amount of maleate salt that provides 2 mg of compound (I). Diabetes mellitus is preferably type II diabetes. Glycemic control can be characterized using conventional methods by measuring typically used indicators of glycemic control such as fasting plasma glucose or glycosylated hemoglobin (HbA1c). Such indicators are standard methods, eg Tuescher A, Richterich P., Schweiz.med. Wschr. 101 (19).
71), 345 and 390, and Frank P., "Monitoring the Diabetic Pa.
“Tent with Glycosolated Hemoglobin Measurements”, Clinical Products 19
It is determined using the method described in 88.

The composition may be in the form of tablets, lozenges, suppositories or capsules. Normal,
The composition is adapted for oral administration. However, they may be applied to other modes of administration, such as sublingual or transdermal administration. In a further aspect, the invention provides a process for the preparation of a pharmaceutical composition comprising a thiazolidinedione such as compound (I), metformin hydrochloride and a pharmaceutically acceptable carrier, wherein the thiazolidinedione is formulated on the surface of metformin hydrochloride. (I) formulating the required metformin hydrochloride, preferably in compressed form;
(Ii) providing a method comprising formulating a thiazolidinedione onto the surface of its metformin hydrochloride.

Suitable carriers for metformin hydrochloride include binders, preferably one or more components selected from PVP, fillers, lubricants, lubricants, disintegrants and wetting agents. A suitable carrier for metformin hydrochloride, as indicated, is PVP, although
If desired, at least one further binder may also be used, for example hydroxypropylmethylcellulose (HPMC). In a particularly preferred embodiment, if additional binder (s) are used, the amount of PVP is the minimum amount required to provide the required compressibility for metformin. Generally, the thiazolidinedione is dissolved or dispersed in a liquid and it is applied to the surface of metformin hydrochloride. The liquid can be water or a suitable organic solvent such as ethanol. Suitably, a film forming agent such as Opadry is mixed with the thiazolidinedione solution or dispersion and applied to the surface of metformin hydrochloride. Alternatively, the thiazolidinedione solution or dispersion may be applied to metformin hydrochloride followed by the film coating solution or dispersion.

Preferably the composition is in unit dosage form. Unit dose dosage forms for oral administration may optionally contain conventional excipients such as binding agents, fillers, lubricants, lubricants, disintegrants and wetting agents. As the binder, for example, acacia, alginic acid, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, dextrate, dextrin, dextrose, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminum silicate, malt. Examples include dextrin, methyl cellulose, polymethacrylate, polyvinylpyrrolidone, pregelled starch, sodium alginate, sorbitol, starch, syrup and tragacanth gum.

As the filler, for example, calcium carbonate, calcium phosphate, calcium sulfate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, compressed sugar, dragee, dextrate, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic Calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil type 1, kaolin, lactose, corn starch, magnesium carbonate, magnesium oxide, malt dextrin, mannitol, microcrystalline cellulose, polymethacrylate, potassium chloride,
Mention may be made of powdered cellulose, polygelated starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate and xylitol. Examples of the lubricant include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulfate, stearic acid, sodium stearyl fumarate, talc and Examples include zinc stearate.

Lubricants include, for example, colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide and talc. As a disintegrant, for example, alginic acid, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone, polacrilin potassium (polacrilin potassium). ), Pregelled starch, sodium alginate, sodium lauryl sulphate and sodium starch glycolate. An example of a pharmaceutically acceptable wetting agent is sodium lauryl sulfate.

If desired, the composition may be prepared by conventional methods of blending, tabletting or encapsulation. Repeated mixing operations can be used to distribute the active agent throughout the composition using large amounts of filler. Such operations are known to those skilled in the art. The tablets may be coated according to methods well known in standard pharmaceutical practice. As noted above, the compositions may be formulated in conventional manner, eg, in standard textbooks such as the British and US Pharmacopoeia, Remington's Pharmaceutical Sciences (Mack Publis.
hing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutic
al Press) (see, eg, 341st Edition, page 341 and the pages cited therein) and Harry's Cosmeticology (Leonard Hill Books).

The invention also provides a composition according to the invention for use in a method of treating diabetes mellitus, preferably type II diabetes and conditions associated with diabetes mellitus. If desired, the composition can be in the form of a pack with handwritten or printed instructions for use. No adverse toxicological effects are expected when the compositions of the invention are used in the dosage ranges indicated above. The following examples illustrate the invention but do not limit it in any way.

EXAMPLES Example 1 Aqueous and Non-Aqueous Film Coating Compound (I) is added to an Opadry coating suspension and applied to the surface of preformed metformin tablets. Opadry I barrier and sealing coat have the same formulation, 15% w / w
Prepare as lake tie suspension. A suspension of Opadry I and Compound (I) is prepared as a 15% w / w solid suspension in which Opadry was compounded with Compound (I) in a ratio of 2: 1.

[0021]   Metformin hydrochloride tablets (equivalent to 500 mg metformin hydrochloride)   Formed by compressing granules of metformin hydrochloride. Metformin hydrochloride granules mg   Metformin hydrochloride 500   Polyvinylpyrrolidone 15   Magnesium stearate 5 Or Metformin hydrochloride granules   Metformin hydrochloride 500   Polyvinylpyrrolidone 15   HPMC 20   Magnesium stearate 2.5

[0022] Oppa dry rear coat% w / w Opadry Solid 15 Water 85

[0023] Opadry + Compound (I)% w / w Opadry Solid 10 Compound (I) 5 Water 85

[0024] Opadry ceiling coat   Same as Opadry I Barrier Court

[0025] Prescription mg / tablet Metformin hydrochloride tablets 520 (Equivalent to 500 mg of metformin hydrochloride) Opa dry rear coat (1% of tablet core) 5.20 Opadry + Compound (I) 15.90 (Corresponding to 4 mg of compound (I)) Opadry I Shearing Coat 10.80 (2% of tablet core)

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 3/10 A61P 3/10 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, G M, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ) , MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, C , CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG , SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Karen Lewis UK, 19.5 A.D. Essex, Harlow, Third Avenue, New Frontiers Science Park South, Smithclin Beecham Pharmaceuticals (72) Inventor Nikola Jane Lilot, CM 19 UK・ 5 ADA, Essex, Harlow, Third Avenue, New Frontiers Science Park South, Smith Crane Beecham Pharmaceuticals (72) Inventor Donald Colin McKenzie Cm 19 UK・ 5A Blue, Essex, Harlow, Third Avenue, New Frontiers Science Park South, Smith Crane Beecham Pharmaceuticals F-Term (reference) 4C076 AA40 CC21 DD41 EE16A EE32 EE56H FF04 FF05 FF06 FF09 FF36 FF57 4C086 AA01 AA02 BC82 GA02 GA08 GA10 MA03 MA05 MA35 NA03 ZC35 4C206 AA01 AA02 HA31 KA14 MA03 MA05 MA14 MA55 NA03 ZC35

Claims (14)

[Claims] 1. A pharmaceutical composition comprising thiazolidinedione, metformin hydrochloride and a pharmaceutically acceptable carrier, wherein the thiazolidinedione is formulated on the surface of metformin hydrochloride. 2. A composition according to claim 1, wherein metformin hydrochloride is in a compressed form. 3. The composition according to claim 1, wherein the thiazolidinedione is formulated as a thin layer on the surface of metformin hydrochloride. 4. The composition according to claim 1, further comprising an inert barrier layer between the layer containing thiazolidinedione and metformin hydrochloride. 5. A composition according to claim 1, wherein the composition is in the form of a multi-layer composition. 6. The composition according to any one of claims 1 to 5, wherein the composition is in the form of a tablet. 7. A suitable carrier for metformin hydrochloride comprises one or more components selected from binders which are PVP, fillers, lubricants, lubricants, disintegrants and wetting agents. 7. The composition according to any one of 1 to 6. 8. A composition according to claim 7, wherein the suitable carrier for metformin hydrochloride comprises at least one further binder. 9. The composition of claim 7, wherein the amount of PVP is the minimum amount that provides the required compressibility for metformin hydrochloride. 10. A thiazolidinedione is a compound (I) or (+)-5.
[[4-[(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2,
4-thiazolidinedione (troglitazone), 5- [4-[(1-methylcyclohexyl) methoxy] benzyl] thiazolidine-2,4-dione (ciglitazone), 5- [4- [2- (5-ethylpyridine-2) -Yl) ethoxy] benzyl]
Thiazolidine-2,4-dione (pioglitazone) or 5-[(2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl] thiazolidine-2,4-
Diones (englitazone), especially 5- [4- [2- (5-ethylpyridine-2-
Iyl) ethoxy] benzyl] thiazolidine-2,4-dione (pioglitazone)
10. A composition according to any one of claims 1 to 9 selected from the group comprising: 11. The composition according to claim 1, wherein the composition comprises 2 to 12 mg of compound (I). 12. A composition according to any one of claims 1 to 10, wherein the composition comprises 100 to 3000 mg metformin hydrochloride. 13. A process for preparing a pharmaceutical composition comprising thiazolidinedione, metformin hydrochloride and a pharmaceutically acceptable carrier, wherein thiazolidinedione is formulated on the surface of metformin hydrochloride, comprising: (i) the required metformin hydrochloride. (Ii) formulating a thiazolidinedione on the surface of its metformin hydrochloride. 14. A composition according to any one of claims 1 to 12 for use in a method of treating diabetes mellitus and conditions associated with diabetes mellitus.