WO2009120844A2

WO2009120844A2 - Pharmaceutical compositions comprising insulin sensitizer and insulin secretagogue

Info

Publication number: WO2009120844A2
Application number: PCT/US2009/038365
Authority: WO
Inventors: Itamar Kanari; Minutza Liebovici; Michael Fox
Original assignee: Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals Usa, Inc.
Priority date: 2008-03-26
Filing date: 2009-03-26
Publication date: 2009-10-01
Also published as: EP2190417A2; WO2009120844A3

Abstract

Dosage forms containing an insulin sensitizer, such as pioglitazone, and an insulin secretogogue, such as glimepiride, are described. Including a cellulose derivative in the dosage form increased the dissolution rate of the insulin sensitizer and/or the insulin secretagogue.

Description

Pharmaceutical Compositions Comprising Insulin Sensitizer and Insulin Secretagogue

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Application Serial No.

61/039,691, filed March 26, 2008, the contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] Pioglitazone hydrochloride (±)-5-[[4-[2-(5-ethyl-2- pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione monohydrochloride is reported to be an oral antihyperglycemic agent that acts primarily by decreasing insulin resistance. Reportedly, Pioglitazone hydrochloride, a member of the thiazolidinedione class is used in the management of type 2 diabetes. [0003] Glimepiride l-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-l- carboxamido)ethyl]phenyl]sulfonyl]-3-(frα«5-4-methylcyclohexyl)-urea is an oral blood glucose-lowering drug of the sulfonylurea class and is normally used in the management of type 2 diabetes.

[0004] Thiazolidinediones are apparently insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas sulfonylureas are insulin secretogogues that act primarily by stimulating release of insulin from functioning pancreatic beta cells.

[0005] Duetact® is available as a tablet for oral administration containing 30 mg pioglitazone hydrochloride (as the base) with 2 mg glimepiride (30 mg/2 mg) or 30 mg pioglitazone hydrochloride (as the base) with 4 mg glimepiride (30 mg/4 mg) formulated with the following excipients: croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF, hydroxypropyl cellulose NF, polysorbate 80 NF, and microcrystalline cellulose NF.

[0006] US Patent Application Publication No. 2004/0147564 discloses tablets containing glimepiride and a thiazolidinedione, wherein all of the examples have a coating containing polyethylene glycol.

[0007] According to US Patent Application Publication No. 2006/0223870, a solid preparation comprising an insulin sensitizer and an insulin secretagogue had the undesirable dissolution property of the insulin secretagogue. That is, the dissolution rate of an insulin secretagogue in the solid preparation was slower as compared with that of "a solid preparation containing an insulin secretagogue as a single active ingredient". Doken et al published that the dissolution property of an insulin secretagogue could be improved by incorporating a polyoxyethylene sorbitan fatty acid ester in the solid preparation.

[0008] It is known that a potential disadvantage of using surfactants, including polysorbates such as TWEEN, is that the addition of surfactants has effect on tabletting process, e.g., it apparently decrease tablet hardness and increases friability. Therefore, there is a need for solid preparations of insulin sensitizers and insulin secretogogues having excellent dissolution properties, notwithstanding the low aqueous solubility of insulin secretogogue compounds, without using a surfactant such as TWEEN.

SUMMARY OF THE INVENTION

[0009] In one embodiment, the invention provides a solid preparation comprising an insulin sensitizer, an insulin secretagogue, and at least one cellulose derivative, wherein the w/w ratio of cellulose derivative : insulin secretagogue is about 20: 1 to about 100:1, wherein the solid preparation is substantially free of polyoxyethylene sorbitan fatty acid ester, and wherein about 60%, or more, of the insulin secretagogue in the solid preparation dissolves within 45 minutes when measured in 900 mL of an aqueous solution of 0.5% sodium lauryl sulphate and

0.01N HCl using USP paddle apparatus II at 75 rpm at 37 ⁰C.

[0010] Alternatively, the amount of cellulose derivative may be present in an amount such that the ratio (w/w) of cellulose derivative : insulin secretagogue is at least about 10:1, at least about 15:1, or at least about 30: 1.

[0011] In some embodiments the solid preparation is substantially free of surfactant and/or substantially free of polyethylene glycol.

[0012] In some embodiments the insulin sensitizer is pioglitazone and/or the insulin secretagogue is glimepiride.

[0013] In some embodiments, the solid preparation is uncoated.

[0014] A preferred method for preparing solid preparations of the invention is by wet granulating an insulin sensitizer, an insulin secretagogue, and a cellulose derivative in amounts described herein. DETAILED DESCRIPTION OF THE INVENTION

[0015] As used herein "substantially free" means a functionally insignificant amount. In the case of "substantially free of polyethylene glycol", this typically means about 0.1%, or less, by weight of the composition. "Substantially free of surfactant" typically means about 0.07%, or less, by weight of the composition. [0016] Although other excipients, such as microcrystalline cellulose, can sometimes function as a filler (as this term is often used in the art), the term "filler" is used herein to refer only to sugars and sugar alcohols.

[0017] Solid preparations of the invention can be prepared by combining at least one insulin sensitizer, at least one insulin secretagogue, and at least one dissolution enhancer. The solid preparations can be formed by methods known in the art, such as direct compression, wet granulation or dry granulation. [0018] Examples of insulin sensitizers include pioglitazone, rosiglitazone, and salts, hydrates and solvates thereof. Preferably, the insulin sensitizer is pioglitazone hydrochloride or rosiglitazone maleate.

[0019] Examples of insulin secretagogues include sulfonylurea agents, such as glimepiride, glipizide, glibenclamide and tolbutamide.

[0020] The preferred particle size of the active agents is a d(0.5) of less than

10 microns, e.g., 1-4 microns.

[0021] Preferred dissolution enhancers are cellulose derivatives, such as microcrystalline cellulose and low-substituted hydroxypropyl cellulose. Examples of cellulose derivatives include microcrystalline cellulose, ethyl cellulose, cellulose acetate, cellulose phthalate, etc.

[0022] The amount of cellulose derivative is preferably about 20% to about

85%, about 30% to about 60%, or about 50% to about 60%, by weight of the total composition.

[0023] Alternatively or additionally, the amount of cellulose derivative is preferably present in an amount such that the ratio (w/w) of cellulose derivative : insulin secretagogue exceeds about 10:1, about 15:1, or equals or exceeds about 30:1. For example, the ratio can be about 20:1 to about 100:1, about 20:1 to about 70: 1, about 30: 1 to about 100: 1, about 30:1 to about 70: 1, about 30:1 to about 60:1, about 30: 1 to about 50: 1, about 40: 1 to about 60: 1 , or about 46: 1 to about 60: 1. Alternatively, other ranges using these ratios or other preferred ratios, such as those set forth in the examples, in any combination, may be used. [0024] In some embodiments of the invention, the solid preparations contain a filler, such as lactose and/or one or more polyols, such as mannitol or sorbitol. In some embodiments the dissolution enhancer : filler w/w ratio is at least 2:1. In some embodiments the dissolution enhancer : filler w/w ratio is about 3: 1 to about 4: 1. [0025] In various embodiments the filler or lactose content is about 50%, or less, 0% to about 40%, about 14% to about 20%, about 18% to about 20%, or about 14.5% to about 18% by weight of the composition.

[0026] Some embodiments of the invention also include excipients commonly found in the art, such as binders, disintegrants, lubricants, colors, flavors, and glidants. Suitable lubricants include, but are not limited to, stearic acid, talc, hydrogenated castor oil, glyceryl behenate, sodium lauryl sulfate, and calcium stearate or combinations thereof. Suitable disintegrants include, but are not limited to, croscarmellose sodium, carboxymethyl cellulose calcium, microcrystalline cellulose, pregelatinized starch, sodium alginate, crospovidone, low-substituted hydroxy propyl cellulose, and colloidal silicon dioxide or combinations thereof. Suitable binders include, but are not limited to, povidone, copovidone, hypromellose, HPC, pregelatinized starch or combinations thereof.

[0027] In some embodiments of the invention, the solid preparations are substantially free of surfactants and/or wetting agents, such as sodium lauryl sulphate, Polyoxyethylene Sorbitan Fatty Acid Esters, Sorbitan Fatty Acid Esters, Poloxamers, Carbomers, Acacia gum, Docusate sodium, Polyoxyethylene Alkyl Ethers, Glyceryl monostearate, Polysorbates 20, 40, 60, and 80, and/or Hydrogenated polyoxyl castor oil.

[0028] Optionally, the solid preparation of the present invention, e.g., tablets, can be further coated using standard coating material, preferably one not comprising polyethylene glycol or surfactants, e.g., SEPIFILM LP 007 or Kollicoat IR. Said coated preparations are preferably substantially free of polyethylene glycol or surfactants. Coating can be achieved, for example, by preparing a coating dispersion then film coating the tablet. The coating can be applied using typical coaters, e.g., horizontal drum coaters, fluidised bed coaters, immersion sword coaters, and coating pans under the usual conditions for aqueous solutions.

[0029] Preferably, the solid preparations of the present invention have high stability and industrially acceptable degradation rates. [0030] In one embodiment, the invention provides a solid preparation comprising an insulin sensitizer, an insulin secretagogue and at least one cellulose derivative, wherein the w/w ratio of cellulose derivative : insulin secretagogue is about 20: 1 to about 100:1, wherein the solid preparation is substantially free of polyoxyethylene sorbitan fatty acid ester, and wherein about 60%, or more, of the insulin secretagogue in the solid preparation dissolves within 45 minutes when measured in 900 mL of an aqueous solution of 0.5% sodium lauryl sulphate and 0.01N HCl using USP paddle apparatus II at 75 rpm at 37 ⁰C. [0031 ] In one embodiment, the invention provides a solid preparation comprising an insulin sensitizer, an insulin secretagogue, and at least one cellulose derivative, wherein at least about 80%, more preferably at least about 85%, of said insulin sensitizer and/or at least about 60%, preferably at least about 65%, of said insulin secretagogue is dissolved within 45 minutes, preferably within 30 minutes, more preferably within 5 minutes, when measured in 900 mL of an aqueous solution of 0.5% sodium lauryl sulphate ("SLS") and 0.01N HCl using a paddle apparatus (USP Apparatus II) at 75 rpm, 37°C.

[0032] The improvement in dissolution rate achieved by preferred embodiments of the invention may occur by various mechanisms. While not intending to be bound by any particular theory as to how the relatively high concentration of dissolution enhancer, exemplified by microcrystalline cellulose, increases the rate of dissolution of a poorly soluble drug, it was observed in the context of the Examples that solubility was independent of the rate of disintegration.

[0033] In a preferred embodiment, the invention provides a solid preparation comprising between about 30 mg and about 45 pioglitazone hydrochloride, between about 2 mg and about 4 mg glimepiride, and between about 120 and about 180 mg dissolution enhancer. For example, a preferred embodiment contains about 5% to about 23% pioglitazone and/or about 0.3% to about 2% gilperimide and/or about 20% to about 90% dissolution enhancer, w/w of the total composition. [0034] In another preferred embodiment, the invention provides a solid preparation comprising between about 2 mg and about 8 mg rosiglitazone maleate, between about 1 mg and about 4 mg glimepiride, and between about 120 and about 180 mg dissolution enhancer. For example, a preferred embodiment contains about 0.3% to about 5.3% rosiglitazone and/or about 0.3% to about 2.6% gilperimide and/or about 20% to about 80% dissolution enhancer, w/w of the total composition. [0035] Solid preparations of the present invention can be in the form of tablets, capsules, granules, troches, etc. Preferably, the solid preparation is tablets. [0036] An exemplary method for making a solid preparation embodiment by wet granulation includes the steps of: (1) admixing insulin sensitizer, insulin secretagogue, and an intra-granular excipient to form a mixture; (2) preparing a granulation solution; (3) granulating said mixture with said solution to form granules;

(4) optionally admixing said granules with at least one extra-granular excipient; and

(5) compressing to a tablet. Preferably, the mixing time in step (3) is less than about 150 seconds, such as 10-90 seconds or 30-60 seconds, using a Diosna high shear mixer, or an equivalent thereto. The preferred mixing time may vary upon using different mixers. One of ordinary skill in the art can easily determine a preferred mixing time using two criteria. First, the mixture to be mixed to the extent that a good end point is achieved, which one skilled in the art can determine through observation. For example, generally the granulate should not be a dry powder or should not be overly wet and/or clumpy. Second, the preparation resulting from the granulate should be tested for dissolution, hi some cases, for example, overmixing may provide a satisfactory-looking granulate but has a diminished dissolution profile. [0037] In some embodiments the granulation solution of step (2) comprises at least one of insulin sensitizer and at least one insulin secretagogue.

[0038] The intra-granular excipient in step (3) and/or the extra-granular excipient in step (4) may include a dissolution enhancer.

[0039] The following Examples illustrate certain preferred embodiments of the invention for the purpose of illustrating the process disclosed herein and do not, in anyway, limit the scope of the invention. Unless stated otherwise, all percentages are by weight and all ratios are weight/weight (w/w). As used herein, the phrase "at least about . . ." is equivalent to the phrase "about . . . or more".

EXAMPLES Example 1: Preparations 1-9

[0040] The following Preparations were prepared according to the general method described in Example 2. Table I

30 Min 36 98 36 98 19 91 19 74 76 102 66 101 59 88 84 96 94 95

45 Min 50 98 50 98 27 93 24 78 85 102 77 101 67 88 92 96 97 97

60 Min 61 98 61 98 35 94 29 82 91 102 84 102 71 88 96 96 97 97

All units are in mg/tablet unless otherwise specified. (*) Preparation 9 is Duetact®. (+) symbolizes the presence of an ingredient although the amount is unknown.

[0041] The Preparations in Table I comprise pioglitazone hydrochloride as the insulin sensitizer and glimepiride as the insulin secretagogue.

[0042] Preparations 1-3 contain no dissolution enhancer. The dissolution rate of glimepiride is less than 20% in 15 min and up to 50% in 45 min.

[0043] Preparation 4 does contain a microcrystalline cellulose, but at a relatively low content, namely about 17% by weight of the total preparation. The cellulose derivative/pioglitazone hydrochloride and cellulose derivative/glimepiride w/w ratios are about 1.1 : 1 and about 17:1, respectively. The dissolution rates do not show a significant improvement.

[0044] Preparations 5-8 in the table comprise dissolution enhancer at significantly higher contents. For example, the microcrystalline cellulose is about

61%, 34%, 50%, and 54% by weight of the total preparation, respectively. The dissolution enhancer/pioglitazone hydrochloride and dissolution enhancer/glimepiride w/w ratios are also high.

[0045] In Preparation 5, part of the dissolution enhancer is incorporated extra- granularly. In Preparations 6 and 7, the glimepiride is introduced in the granulation solution.

[0046] In Preparations 5-8, the dissolution rates are drastically increased. For example, after 15 min, the glimepiride dissolution rates are 57%, 46%, 46%, and

66%, respectively, and after 45 min, 86%, 77%, 67%, and 92%, respectively. These results demonstrate the finding of the inventors that high dissolution rates, including those of glimepiride, are attainable using relatively high amounts of a dissolution enhancer, without the need of polyoxyethylene sorbitan fatty acid ester or any other surfactant.

[0047] The dissolution of Duetact®, which contains surfactants, is shown in the last column of Table I. Example 2. Glimepiride and pioglitazone HCl tablet

Part i:

1) load all components of Part I (excluding the granulation solution) into a high shear mixer (DIOSNA) and mix;

Granulation solution:

2) dissolve the PVP K-30 in purified water by mixing with stirrer to obtain a clear solution;

3) add the solution from step 2) to the mixture from step 1) in the high shear mixer and mix until a good end point for the wet granulate is obtained;

4) dry the wet granulate from step 3) in a fluidized bed dryer;

5) mill the dry granulate from step 4) through a mill (QUADRO COMIL);

6) transfer the milled granulate from step 5) to an Y-cone or Flow-bin; Part II:

7) add the components of part II to the mixture from step 6) in the Y-cone or Flow-bin and mix;

Part III:

8) screen the magnesium stearate NF through #50 mesh sieve; 9) add the magnesium stearate NF from step 8) to the mixture from step 7) in the Y- cone or Flow-bin and mix;

10) compress the final blend from step 9) into tablets.

Example 3. Glimepiride & Pio2litazone HCL tablets (Low-HPC)

[0048] The process of Example 2 was repeated using the following ingredients:

* 33.07 mg of Pioglitazone HCL is Equivalent to 30 mg of Pioglitazone base

Dissolution (%) for Glimepiride

Example 4: Glimepiride / Pioglitazone - Mixing Time

** Process solvent only

[0049] The formulation of Example 4 was prepared twice according to the method of Example 2, except the mixing time in step (3) was either 45 or 60 seconds.

Example 5: Predicted Dissolution Times Based on Mixing Times

Based on experiments conducted (actual data not available), the following dissolution profiles were obtained (estimated):

Ingredients Example 5 (mg)

Part i

Glimepiride USP 4.0

Pioglitazone HCL *33.07

Avicel PH lOl 100.0

Lactose Monohydrate 95.0 (mesh 200)

Primellose 15.0

Granulate Solution

PVP K-30 7.5

TOTAL WEIGHT 300.0

* 33.07 mg of Pioglitazone HCl is Eq. to 30 mg of Pioglitazone base ** Process solvent only

Dissolution (wt %):

90 sec mixing time 240 sec mixing time

5 min 6 0

15 min 15- 25 nmt* 10

30 min 50-60 rant 20

45 min 55-65 20-30

60 min 70 40

(*nmt = not more than) [0050] Comparative Examples 6 and 7:

* 33.07mg of Pioglitazone HCL is Eq. to 30mg of Pioglitazone base ** Process solvent only

[0051] It is to be understood that the invention is not to be limited to the exact configuration as illustrated and described herein. Accordingly, all expedient modifications readily attainable by one of ordinary skill in the art from the disclosure set forth herein, or by routine experimentation therefrom, are deemed to be within the spirit and scope of the invention as defined by the appended claims.

Claims

What is claimed is:

1. A solid preparation comprising an insulin sensitizer, an insulin secretagogue, and at least one cellulose derivative, wherein the w/w ratio of cellulose derivative : insulin secretagogue is about 20:1 to about 100:1, wherein the solid preparation is substantially free of polyoxyethylene sorbitan fatty acid ester, and wherein about 60%, or more, of the insulin secretagogue in the solid preparation dissolves within 45 minutes when measured in 900 mL of an aqueous solution of 0.5% sodium lauryl sulphate and 0.0 IN HCl using USP paddle apparatus II at 75 rpm at 37 ⁰C.

2. The solid preparation of claim 1, wherein the cellulose derivative is selected from the group consisting of microcrystalline cellulose, low substituted hydroxypropyl cellulose and combinations thereof.

3. The solid preparation of any of claims 1 -2, wherein about 65%, or more, of the insulin secretagogue in the solid preparation is dissolved within 30 minutes when measured in 900 mL of an aqueous solution of 0.5% sodium lauryl sulphate and

0.0 IN HCl using USP paddle apparatus II at 75 rpm at 37 ⁰C.

4. The solid preparation of any of claim 1 -4, wherein the preparation contains less than 50% filler by weight of the total preparation.

5. The solid preparation of claim 4, wherein the filler comprises lactose, at least one polyol, or a combination thereof.

6. The solid preparation of any of claim 1 -5, wherein the solid preparation is substantially free of surfactant.

7. The solid preparation of any of claim 1-6, wherein the solid preparation is substantially free of polyethylene glycol.

8. The solid preparation of any of claim 1-7, wherein the cellulose derivative is about 20 % to about 90 % of the total composition.

9. The solid preparation of any of claim 1-8, wherein the insulin sensitizer is pioglitazone and the insulin secretagogue is glimepiride.

10. The solid preparation of any of claim 1 -9, wherein the preparation is uncoated.

11. The solid preparation of any of claim 1-10, wherein about 80%, or more, of the insulin sensitizer in the solid preparation dissolves within 45 minutes when measured in 900 mL of an aqueous solution of 0.5% sodium lauryl sulphate and 0.01N HCl using USP paddle apparatus II at 75 rpm at 37 ⁰C.

12. The solid preparation of any of claim 1-11, wherein the w/w ratio of cellulose derivative : insulin secretagogue is about 30: 1 to about 100:1.

13. The solid preparation of any of claim 1-12, wherein the w/w ratio of cellulose derivative : insulin secretagogue is about 30:1 to about 60: 1.

14. The solid preparation of any of claim 1-13, wherein the w/w ratio of cellulose derivative : insulin secretagogue is about 30: 1 or greater.

15. A method of preparing a solid preparation, comprising wet granulating an insulin sensitizer, an insulin secretagogue, and a cellulose derivative, wherein the w/w ratio of cellulose derivative : insulin secretagogue is about 20: 1 to about 100: 1.

16. The method of claim 15, wherein the wet granulating step includes a step of forming a wet granulate by mixing the components of the wet granulate in mixing conditions selected from the group consisting of mixing in a high shear mixer for less than 150 seconds, and mixing in a non-high shear mixer for a time equivalent to mixing in a high shear mixer for less than 150 seconds.

17. The method of any of claims 15-16, wherein about 60%, or more, of the insulin secretagogue in the solid preparation dissolves within 45 minutes when measured in 900 mL of an aqueous solution of 0.5% sodium lauryl sulphate and 0.01N HCl using USP paddle apparatus II at 75 rpm at 37 ⁰C.