Fixed dose combination tablet formulation of acarbose and metformin and process for producing the same

Abstract

The present invention is related to a fixed dose combination tablet formulation comprising the glycosidase inhibitor acarbose (0-4,6-Didesoxy-4-{[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl] amino}-a-D-glucopyranosyl-(1,4)-0-a-D-glucopyranosyl-(1,4)-D-glucopyranose) and the glycerin-3-phosphate-Dehydrogenase inhibitor metformin (1,1-Dimethylbiguanid), particularly the hydrochloride salt of metformin. Also provided are processes for producing a fixed dose combination tablet formulation.

Claims

1-22. (canceled)

23. A fixed dose tablet formulation comprising metformin and acarbose at a weight ratio between 17 to 1 and 4 to 1, at least one type of a hydroxypropylcellulose as at least one dry binder, at least one disintegrant, at least one flow agent or lubricant, in which at least one type of a hydroxypropylcellulose has a viscosity of 2 to 3 mPas at a molecular weight of about 40,000 g/mol and a particle size D.sub.50 of about 20 m, D.sub.90 of 50 m respectively.

24. A fixed dose tablet formulation according to claim 23, wherein the formulation comprises another hydroxypropylcellulose as a dry binder that has a viscosity of 6 to 10 mPas at a molecular weight of about 140,000 g/mol and a particle size D.sub.50 of about 160 m, D.sub.90 of 335 m or 355 m respectively.

25. A fixed dose tablet formulation according to claim 24, wherein the moisture content of said formulation is 1.6% to 3.0%.

26. A fixed dose tablet formulation comprising metformin and acarbose at a weight ratio between 17 to 1 and 4 to 1, at least one type of a vinylpyrrolidone derivative as at least one dry binder, at least one disintegrant, at least one flow agent or lubricant, wherein the moisture content of said formulation is above 1.9%.

27. A fixed dose tablet formulation according to claim 26, wherein the vinylpyrrolidone derivative is a vinylpyrrolidone-vinyl acetate copolymer such as Kollidon VA64 or VA64F.

28. A fixed dose tablet formulation according to claim 25, wherein the ratio of the hydroxypropylcellulose with a viscosity of 2 to 3 mPas at a molecular weight of about 40,000 g/mol and a particle size D.sub.50 of about 20 m, D.sub.90 of 50 m respectively towards the hydroxypropylcellulose with a viscosity of 6 to 10 mPas at a molecular weight of about 140,000 g/mol and a particle size D.sub.50 of about 160 m, D.sub.90 of 335 m or 355 m respectively is between 4:1 and 1:1.

29. A fixed dose tablet formulation according to claim 23, wherein the dry binders are present in the formulation in an overall amount from about 5% to 15% by weight.

30. A fixed dose tablet formulation according to claim 23, wherein cross-linked polyvinylpyrrolidone is the disintegrant.

31. A fixed dose tablet formulation according to claim 27, wherein cross-linked polyvinylpyrrolidone is the disintegrant.

32. A fixed dose tablet formulation according to claim 23, wherein said formulation comprises magnesium stearate as a lubricant.

33. A fixed dose tablet formulation according to claim 27, wherein said formulation comprises magnesium stearate as a lubricant.

34. A fixed dose tablet formulation according to claim 23, further comprising microcrystalline cellulose as an excipient with disintegration promoting properties.

35. A fixed dose tablet formulation according to claim 23, wherein the formulation comprises: a) about 74% by weight of acarbose and metformin in a ratio of 1:10, b) about 10.5% by weight of dry binders, consisting of about 2.5% by weight of hydroxypropylcellulose with a viscosity of 6 to 10 mPas, a molecular weight of about 140,000 g/mol and a particle size D.sub.50 of about 160 m, and/or D.sub.90 of 335 m or 355 m respectively and about 8% by weight of hydroxypropylcellulose with a viscosity of 2 to 3 mPas, a molecular weight of about 40,000 g/mol and a particle size D.sub.50 of about 20 m, and/or D.sub.90 of 50 m respectively, c) about 9% by weight of microcrystalline cellulose as an excipient with disintegration promoting properties, d) about 4.5% by weight of a disintegrant being cross-linked polyvinylpyrrolidone with an average particle size of about 30 m, and e) about 0.5% by weight of both a lubricant and a flow agent, wherein the flow agent is highly-disperse silica and the lubricant is magnesium stearate.

36. A tablet comprising a fixed dose tablet formulation according to claim 23.

37. A tablet comprising a fixed dose tablet formulation according to claim 26.

38. A tablet according to claim 36, wherein said tablet has a length of about 18 mm, a width of about 8 mm and a thickness of about 6.3 to 7 mm.

39. A coated tablet comprising a core made up from a tablet according to claim 36, wherein such core is coated.

40. A coated tablet according to claim 39, wherein the coating is a mixture of about 60 wt. % hydroxypropylmethylcellulose, about 16 wt. % titanium dioxide, about 4 wt. % ferric oxide yellow, and about 20 wt. % polyethylene glycol.

41. A process for the production of a fixed dose tablet formulation according to claim 23, comprising the steps of: a) dry mixing metformin and acarbose together with at least one dry binder and at least one disintegrant, b) dry granulating the resulting mixture to obtain dry granules, c) optionally at least once blending said dry granules with a further excipient, and d) optionally arranging the fixed dose combination formulation in the form of a tablet.

42. A process according to claim 40, further comprising the steps of: a. determining the moisture content of the formulation or the dry granules, and b. adding water if the formulation moisture content as determined in step a) is below 1.6%.

Description

DESCRIPTION OF THE FIGURES

[0056] FIG. 1 shows the relationship between moisture content, compression force and breaking load for formulation 4*. Formulation 4* is the formulation 4 according to example 3 comprising 4 mg magnesium stearate/tablet instead of 3.5 mg magnesium stearate/tablet. A compression simulator was used for tableting and the profile of the rotary die press FE 55, with a speed of 100,000 tab/h was used. Optimal behavior is observed for a LoD of >1.6%.

EMBODIMENTS

[0057] Any tablet made from a formulation according to the present invention was surprisingly found to have a dramatically decreased tendency of capping when the formulation is arranged or pressed into the form of those tablets (see table 4).

[0058] According to a first aspect of the present invention this is achieved with a fixed dose tablet formulation comprising metformin and acarbose, at least one type of a hydroxypropylcellulose as at least one dry binder, at least one disintegrant, at least one flow agent and/or lubricant, characterized in that the at least one type of a hydroxypropylcellulose has a viscosity of 2 to 3 mPas at a molecular weight of about 40,000 g/mol and a particle size D.sub.50 of about 20 m, and/or D.sub.90 of 50 m respectively. In a preferred embodiment according to the first aspect the at least one type of a hydroxypropylcellulose is HPC-SSL-SFP. In the same or different preferred embodiments according to the first aspect the moisture content of said formulation is 1.6 to 3.0%, e.g. 1.7 to 2.0%, e.g. 1.8 to 1.9%, e.g. 1.7 or 1.8%.

[0059] According to a second aspect of the present invention a decreased tendency of capping is achieved by providing a fixed dose tablet formulation comprising metformin and acarbose, at least one type of a vinylpyrrolidone derivative as at least one dry binder, at least one disintegrant, at least one flow agent and/or lubricant, characterized in that the moisture content of said formulation is above 1.9%. In a preferred embodiment according to the second aspect the vinylpyrrolidone derivative is a vinylpyrrolidone-vinyl acetate copolymer such as Kollidon, such as Kollidon VA64 or VA64F.

[0060] According to a third aspect of the present invention there is provided a fixed dose tablet formulation comprising metformin and acarbose, at least one type of a hydroxypropylcellulose as at least one dry binder, at least one disintegrant, at least one flow agent and/or lubricant, characterized in that the moisture content of said formulation is 1.6 to 3.0%, e.g. 1.7 to 2.0%. In some preferred embodiments according to the third aspect the moisture content of said formulation is 1.8 to 1.9% and in a most preferred embodiment according to the third aspect the moisture content of said formulation is about 1.7 or 1.8%.

[0061] Where the moisture content of the formulation is tightly controlled as described for the current invention it was surprisingly found that the metformin/acarbose formulation showed beneficial behavior with regard to stability, capping and release of active ingredients, while degradation of active ingredients such as metformin and acarbose could be avoided (see tables 4, 5, 6 and FIG. 1).

[0062] Therefore according to one aspect of the present invention there is provided a fixed dose tablet formulation comprising metformin and acarbose, at least one dry binder, at least one disintegrant, at least one flow agent and/or lubricant, characterized in that the moisture content of said formulation is 1.6% to 3.0%.

[0063] In a preferred embodiment according to the first, second, third or any other aspect or mentioned embodiment of the current invention the formulation comprising metformin and acarbose is characterized in having an acarbose to metformin weight ratio of about 1 to 10 (e.g. 50 mg acarbose with 500 mg metformin), or about 1 to 8.5 (e.g. 100 mg acarbose with 850 mg metformin) or about 1 to 5 (e.g. 100 mg acarbose with 500 mg metformin). In other embodiments according to the first, second, third or any other aspect or mentioned embodiment of the current invention the formulation comprising metformin and acarbose is characterized in having an acarbose to metformin weight ratio of about 1 to 17 or 1 to 12.5.

[0064] In a preferred embodiment which is the same or different from the aforementioned embodiments, according to the first, second, third or any other aspect of the current invention the fixed dose tablet formulation is characterized in being arranged in the form of a tablet, e.g. in the form of a tablet that has 18 mm length, a width of about 8 mm and a thickness of about 6.3-7 mm. In a preferred embodiment which is the same or different from the aforementioned embodiments, according to the first, second, third or any other aspect of the current invention the fixed dose tablet formulation is characterized in being arranged in the form of a tablet, e.g. in the form of a tablet that has 18 mm length, a width of about 8 mm and a thickness of about 6.3-7 mm, wherein the resulting form of a tablet is furthermore coated.

[0065] Particularly preferred according to the current invention and in particular according to the first or second aspect and the aforementioned embodiments are formulations comprising the above referred to at least one hydroxypropylcellulose and another hydroxypropylcellulose as a dry binder that has a viscosity of 6 to 10 mPas at a molecular weight of about 140,000 g/mol and a particle size D.sub.50 of about 160 m, and/or D.sub.90 of 335 m or 355 m respectively.

[0066] Particularly preferred according to the current invention and in particular according to the first or second aspect and the aforementioned embodiments are formulations comprising the above referred to at least one hydroxypropylcellulose and another hydroxypropylcellulose as a dry binder that has a viscosity of 6 to 10 mPas at a molecular weight of about 140,000 g/mol and a particle size D.sub.50 of about 160 m, and/or D.sub.90 of 335 m or 355 m respectively, wherein the moisture content of said formulation is 1.6 to 3.0%, e.g. 1.7 to 2.0%, e.g. 1.8 to 1.9%, e.g. 1.7 or 1.8%.

[0067] In some of these aforementioned particularly preferred embodiments the another hydroxypropylcellulose is HPC-L.

[0068] It has surprisingly been found that the combination of both types of hydroxypropylcellulose has the above referred to advantageous properties of the tablet being pressed thereof showing no capping and additionally has an improved disintegration and release pattern (see tables 2, 3 and 4).

[0069] It has furthermore surprisingly been found that the beneficial impact of combining the two types of hydroxypropylcellulose could be increased by adjusting the moisture content as described above (see table 5 and 6).

[0070] Such combined advantage of faster disintegration/release and no capping synergizes to allowing to even further reduce the overall amount of excipients while resulting in a formulation that is good to be tableted and fast disintegrating/releasing, if the ratio of the hydroxypropylcellulose with a viscosity of 2 to 3 mPas at a molecular weight of about 40,000 g/mol and a particle size D.sub.50 of about 20 m, and/or D.sub.90 of 50 m respectively towards the hydroxypropylcellulose with a viscosity of 6 to 10 mPas at a molecular weight of about 140,000 g/mol and a particle size D.sub.50 of about 160 m, and/or D.sub.90 of 335 m or 355 m respectively is or is adjusted to a range between 4:1 and 1:1, particularly to about 3:1.

[0071] Particularly preferred according to the current invention and in particular according to the first or third aspect and the aforementioned embodiments are formulations comprising [0072] a) the above referred to at least one hydroxypropylcellulose characterized in having a viscosity of 2 to 3 mPas at a molecular weight of about 40,000 g/mol and a particle size D.sub.50 of about 20 m, and/or D.sub.90 of 50 m respectively, and [0073] b) another hydroxypropylcellulose as a dry binder characterized in having a viscosity of 6 to 10 mPas at a molecular weight of about 140,000 g/mol and a particle size D.sub.50 of about 160 m, and/or D.sub.90 of 335 m or 355 m respectively, [0074] c) wherein the ratio between said at least one hydroxypropylcellulose and said another hydroxypropylcellulose is between 4:1 and 1:1 (e.g. 3:1), and [0075] d) wherein the moisture content of said formulation is 1.6 to 3.0%, e.g. 1.7 to 2.0%, e.g. 1.8 to 1.9%, e.g. 1.7 or 1.8%.

[0076] According to some preferred embodiments of the present invention, the above referred to at least one hydroxypropylcellulose with a viscosity of 2 to 3 mPas at a molecular weight of about 40,000 g/mol and a particle size D.sub.50 of about 20 m, and/or D.sub.90 of 50 m respectively as a dry binder is present in the formulation in an amount from 2.5% to 10% by weight, preferably in an amount from 7% to 9%, more preferably in an amount of about 8% by weight. These embodiments are compatible and suggested to be combined with each embodiment comprising said at least one hydroxypropylcellulose.

[0077] According to further preferred embodiments of the present invention, the above referred to hydroxypropylcellulose with a viscosity of 6 to 10 mPas at a molecular weight of about 140,000 g/mol and a particle size D.sub.50 of about 160 m, and/or D.sub.90 of 335 m or 355 m respectively as a dry binder is present in the formulation in an amount from about 1.5% to 5% by weightpreferably in an amount from about 1.5% to 3.5% by weight, preferably in an amount from about 2% to 3%, more preferably in an amount of about 2.5 or 2.7% by weightor in an amount from about 2% to 4% by weight. These embodiments are compatible and suggested to be combined with each embodiment comprising said hydroxypropylcellulose with a viscosity of 6 to 10 mPas.

[0078] The dry binders are preferably present in the formulation in an overall amount from about 5% to 15% by weight, more preferably from about 7% to 12% by weight, even more preferably from about 8% to 11% by weight.

[0079] According to some preferred embodiments according to the first, the second, third or any other aspect according to the current invention the formulation further comprises microcrystalline cellulose, such as Avicel, e.g. as an excipient with disintegration promoting properties.

[0080] According to some different or same preferred embodiments of the present invention, microcrystalline cellulose as an excipient with disintegration promoting properties is present in the formulation in an amount from 5% to 15% by weight, preferably in an amount from 8% to 12%, more preferably in an amount of about 9% by weight.

[0081] Excipients with disintegration promoting properties such as microcrystalline cellulose may be omitted in the very preferred formulations of the present invention that have the above referred to hydroxypropylcellulose with a viscosity of 2 to 3 mPas at a molecular weight of about 40,000 g/mol and a particle size D.sub.50 of about 20 m, and/or D.sub.90 of 50 m respectively as well as the hydroxypropylcellulose with a viscosity of 6 to 10 mPas at a molecular weight of about 140,000 g/mol and a particle size D.sub.50 of about 160 m, and/or D.sub.90 of 335 m or 355 m, respectively at a range between 4:1 and 1:1, as those procure that the formulation maintains all relevant positive properties even in absence of such usually added excipients with disintegration promoting properties.

[0082] Addition of excipients with disintegration promoting properties such as microcrystalline cellulose, however further helps to improve the long time stability of the disintegration properties of tablets formed out of such formulations.

[0083] Formulations according to the present invention contain at least one disintegrant. Preferred disintegrants pursuant to the present invention are those selected from the list consisting of sodium starch glycolate (such as, for example, Explotab), cross-linked polyvinylpyrrolidone (such as Polyplasdone) and croscarmellose-sodium (such as, for example, AcDiSol). Very preferred disintegrants are cross-linked polyvinylpyrrolidones (such as Polyplasdone) and/or croscarmellose-sodium (such as AcDiSol). Particularly preferred disintegrants are cross-linked polyvinylpyrrolidones (such as Polyplasdone).

[0084] Those particularly preferred disintegrants being cross-linked polyvinylpyrrolidones are available at different grades, differentiated by particle size. If sold under the above referred to brand name Polyplasdone, three grades from coarse to fine can be discriminated. Those grades are Polyplasdone XL, Polyplasdone XL-10 and Polyplasdone INF-10 and correspondin the same orderto average particle sizes of about 100 m, about 30 m and about 11 m.

[0085] A particularly preferred formulation pursuant to the present invention comprises cross-linked polyvinylpyrrolidone with an average particle size of about 30 m as a disintegrant.

[0086] For particularly preferred embodiments pursuant to the present invention the at least one disintegrant is cross-linked polyvinylpyrrolidone with an average particle size of about 30 m, e.g. in an amount from 2.5% to 7.5% by weight, preferably in an amount from 3.5% to 5.5%, more preferably in an amount of about 4.5% by weight. According to the very preferred embodiments of the present invention, cross-linked polyvinylpyrrolidone or croscarmellose-sodium as a disintegrant are present in the formulation in an amount from 2.5% to 7.5% by weight, preferably in an amount from 3.5% to 5.5%, more preferably in an amount of about 4.5% by weight.

[0087] According to the particularly preferred embodiments of the present invention, cross-linked polyvinylpyrrolidone with an average particle size of about 30 m is used as a disintegrant in an amount from 2.5% to 7.5% by weight, preferably in an amount from 3.5% to 5.5%, more preferably in an amount of about 4.5% by weight.

[0088] Furthermore formulations according to the present invention contain at least one lubricant and/or flow agent.

[0089] Preferred lubricants according to the present invention are those selected from the list consisting of magnesium stearate, stearic acid and talc. A very preferred lubricant is magnesium stearate.

[0090] A preferred flow agent used in the formulation according to the present invention is highly-disperse silica (for example Aerosil).

[0091] If used in combination, a preferred combination of lubricant and flow agent is magnesium stearate and highly-disperse silica, such as Aerosil.

[0092] In a preferred embodiment of this invention the formulation comprises at least one flow agent and at least one lubricant.

[0093] In an equally preferred embodiment of this invention the formulation only comprises a lubricant, which preferably is magnesium stearate.

[0094] Preferred amounts of lubricants present in the formulation according to the present invention are amounts of from 0.1% to 3% by weight, more preferably amounts from 0.25% to 0.75%, even more preferably amounts of about 0.5% by weight.

[0095] If present, preferred amounts of flow agents are amounts of from 0.1% to 1% by weight, more preferably amounts from 0.25% to 0.75%, even more preferably amounts of about 0.5% by weight.

[0096] If flow agents and lubricants are both present in the formulation according to the present invention, the overall amount of flow agents and lubricants therefore is preferably from 0.2% to 4% by weight, preferably each in an amount from about 0.25% to 0.75%, more preferably each in an amount of about 0.5% by weight.

[0097] According to a likewise preferred embodiment of the present invention the flow agent is highly-disperse silica present in the formulation in an amount of from 0.1% to 1% by weight, preferably in an amount from 0.25% to 0.75%, more preferably in an amount of about 0.5% by weight, and the lubricant is magnesium stearate present in the formulation in an amount of from 0.1% to 3% by weight, preferably in an amount from 0.25% to 0.75%, more preferably in an amount of about 0.5% by weight.

[0098] Particularly preferred according to the current invention and in particular according to the first or third aspect and the aforementioned embodiments are formulations [0099] a) comprising the above referred to at least one hydroxypropylcellulose characterized in having a viscosity of 2 to 3 mPas at a molecular weight of about 40,000 g/mol and a particle size D.sub.50 of about 20 m, and/or D.sub.90 of 50 m respectively, and [0100] b) comprising another hydroxypropylcellulose as a dry binder characterized in having a viscosity of 6 to 10 mPas at a molecular weight of about 140,000 g/mol and a particle size D.sub.50 of about 160 m, and/or D.sub.90 of 335 m or 355 m respectively, [0101] c) wherein the ratio between said at least one hydroxypropylcellulose and said another hydroxypropylcellulose is between 4:1 and 1:1 (e.g. 3:1), and [0102] d) further comprising [0103] a. cross-linked polyvinylpyrrolidone (e.g. with 2.5% to 7.5% by weight), e.g. with an average particle size of about 30 m as a disintegrant and/or [0104] b. highly-disperse silica (e.g. with 0.1% to 1% by weight) and/or magnesium stearate (e.g. with 0.1% to 3% by weight) as the at least one flow agent and/or lubricant, [0105] e) wherein the moisture content of said formulation is 1.6 to 3.0%, e.g. 1.7 to 2.0%, e.g. 1.8 to 1.9%, e.g. 1.7 or 1.8%.

[0106] Particularly preferred according to the current invention and in particular according to the second, first or third aspect and the aforementioned embodiments are formulations [0107] a) comprising cross-linked polyvinylpyrrolidone (e.g. with 2.5% to 7.5% by weight), e.g. with an average particle size of about 30 m as a disintegrant and/or [0108] b) comprising highly-disperse silica (e.g. with 0.1% to 1% by weight) and/or magnesium stearate (e.g. with 0.1% to 3% by weight) as the at least one flow agent and/or lubricant.

[0109] The formulation according to the present invention is a fixed dose formulation of acarbose and metformin and thus the two actives are present in the formulation of the present invention in a pre-determined ratio.

[0110] The ratio of acarbose to metformin can befrom a formulation perspectiveany therapeutically effective ratio of the two actives. In a preferred embodiment of the present invention, the ratio of acarbose to metformin is 1:10 or 1:5.

[0111] In a very preferred embodiment of the present invention the formulation comprises an overall amount of at least 60% by weight of the actives in a ratio of 1:10 between acarbose and metformin.

[0112] In an even more preferred embodiment of the present invention the formulation comprises an overall amount of at least 70% by weight of the actives in a ratio of 1:10 between acarbose and metformin. Most preferably the formulation according to the present invention comprises acarbose and metformin in a ratio of 1:10 while the overall amount of these two actives is about 74% by weight.

[0113] Particularly preferred according to the current invention and in particular according to the first or second aspect and the aforementioned embodiments are formulations [0114] a) comprising acarbose and metformin at a weight ratio between 1 to 17 and 1 to 4 (e.g. of about 1 to 12.5, about 1 to 10, or about 1 to 8.5 or about 1 to 5), [0115] b) wherein optionally the overall amount of the actives is at least 60% (e.g. at least 70% or about 74%) by weight of said formulation, [0116] c) comprising the above referred to at least one hydroxypropylcellulose characterized in having a viscosity of 2 to 3 mPas at a molecular weight of about 40,000 g/mol and a particle size D.sub.50 of about 20 m, and/or D.sub.90 of 50 m respectively, and [0117] d) comprising another hydroxypropylcellulose as a dry binder characterized in having a viscosity of 6 to 10 mPas at a molecular weight of about 140,000 g/mol and a particle size D.sub.50 of about 160 m, and/or D.sub.90 of 335 m or 355 m respectively, [0118] e) wherein the ratio between said at least one hydroxypropylcellulose and said another hydroxypropylcellulose is between 4:1 and 1:1 (e.g. 3:1), and [0119] f) optionally further comprising [0120] a. cross-linked polyvinylpyrrolidone (e.g. with 2.5% to 7.5% by weight), e.g. with an average particle size of about 30 m as a disintegrant and/or [0121] b. highly-disperse silica (e.g. with 0.1% to 1% by weight) and/or magnesium stearate (e.g. with 0.1% to 3% by weight) as the at least one flow agent and/or lubricant, [0122] g) wherein the moisture content of said formulation is 1.6 to 3.0%, e.g. 1.7 to 2.0%, e.g. 1.8 to 1.9%, e.g. 1.7 or 1.8%.

[0123] Particularly preferred according to the current invention and in particular according to the second, first, third or any other aspect and the aforementioned embodiments are formulations [0124] a) comprising acarbose and metformin at a weight ratio between 1 to 17 and 1 to 4 (e.g. of about 1 to 12.5, about 1 to 10, or about 1 to 8.5 or about 1 to 5), [0125] b) wherein optionally the overall amount of the actives is at least 60% (e.g. at least 70% or about 74%) by weight of said formulation, [0126] c) further comprising cross-linked polyvinylpyrrolidone (e.g. with 2.5% to 7.5% by weight), e.g. with an average particle size of about 30 m as a disintegrant and/or [0127] d) highly-disperse silica (e.g. with 0.1% to 1% by weight) and/or magnesium stearate (e.g. with 0.1% to 3% by weight) as the at least one flow agent and/or lubricant.

[0128] As it can be seen from the most preferred embodiment of the present invention, the relative amount of excipients compared to the two actives is comparably low. This facilitates that the overall tablet size can be kept low as well.

[0129] In an outmost preferred embodiment of the present invention, the formulation comprises at least [0130] a) about 74% (e.g. between 67 and 77%) by weight of acarbose and metformin in a ratio of 1:10 or 1:5, about 10.5% (e.g. between 9.8 and 11.5%) by weight of dry binders, [0131] a. consisting of about 2.5% (e.g. 2.7%) by weight of hydroxypropylcellulose with a viscosity of 6 to 10 mPas, a molecular weight of about 140,000 g/mol and a particle size D.sub.50 of about 160 m, and/or D.sub.90 of 335 m or 355 m respectively and [0132] b. about 8% (e.g. between 8 and 12%) by weight of hydroxypropylcellulose with a viscosity of 2 to 3 mPas, a molecular weight of about 40,000 g/mol and a particle size D.sub.50 of about 20 m, and/or D.sub.90 of 50 m respectively [0133] b) about 9% (e.g. between 7 and 13%, e.g. 9.4%) by weight of microcrystalline cellulose as an excipient with disintegration promoting properties, [0134] c) about 4.5% by weight of a disintegrant (e.g. between 4.1 and 4.95%), preferably being cross-linked polyvinylpyrrolidone with an average particle size of about 30 m, and [0135] d) about 0.5% by weight of both a lubricant and a flow agent, wherein the flow agent is preferably highly-disperse silicas and the lubricant is preferably magnesium stearate.

[0136] As may be seen just above, the overall amount of ingredients of the outmost preferred formulation pursuant to the present invention do not sum up to 100% by weight, but only 98.5% by weight. This is because the above referred to amounts are specified to be about the values that are mentioned and because these values comprise rounding errors. Everyone of ordinary skill in the art should however be able to produce a formulation according to the present invention that intrinsically sums up to 100% by weight and satisfies the herein mentioned limitations while achieving the beneficial effects associated therewith without undue burden, when just referring to the embodiments disclosed just above.

[0137] For sake of clarification, a proportion or value characterized to be about a value, is always to be understood to also comprise any value lesser or higher than the actually stated value that allows the overall formulation to result in 100% by weight. Mostly the deviation around the explicitly stated values should not be more than 25% of the specified value to allow that.

[0138] As a matter of example, the above referred to rounding errors resulting in the ingredients of the outmost preferred embodiment of the present invention to sum up to only about 98.5% may be compensated by adding any of the above fillers or further excipients not specifically mentioned.

[0139] The tablets produced from a formulation pursuant to the preferred embodiments of the present invention combine all beneficial effects that have been referenced before.

[0140] According to a fourth aspect of the current invention there is provided a tablet comprising a formulation according to any of the aforementioned aspects. Those tablets formed from the formulation according to the present invention, form another aspect of the present invention.

[0141] Tablets pursuant to the present invention display no capping when produced even under high compaction forces and high tableting speed, show fast disintegration and thus rapid release of both actives, and are comparably small with regards to the overall amount of actives contained therein. With regard to disintegration, this is to be understood pursuant to the present invention to be a disintegration time measured pursuant to European Pharmacopoeia (2017) section 9.2. Obviously a shorter time is indicative for a faster disintegration and a longer time is indicative for inferior disintegration.

[0142] As particularly metformin is a substance that is to be used in the treatment of Type 2 Diabetes induced hyperglycemia, which may under sever conditions be live threatening per se, a comparably fast release of the Metformin to reduce the blood sugar level of the patient suffering from acute hyperglycemia back to a tolerable level is advantageous.

[0143] For a different reason, the same applies for the release of acarbose from the tablet. Acarbose is usually applied postprandial to mitigate the risk of hyperglycemia subsequent to uptake of food of a given Type 2 Diabetes patient by partial inhibition of a-glycosidases. To efficiently allow said effect, an immediate release of Acarbose administered via postprandial tablet intake is required.

[0144] The release of acarbose and/or metformin into the patient from a tablet made up from a formulation pursuant to the present invention is linked to above referred to disintegration time, but said link is not necessarily linear. In principle, however, a fast release is usually linked to an also fast disintegration, while fast disintegration does not necessarily result in an as fast as anticipated release.

[0145] Tablets according to the fourth aspect, e.g. made up from the formulation pursuant to the first, second or third aspect and the respective embodiments as described just above within this invention, share the positive effect of collectively having a disintegration time of less than 15 min. and display no capping.

[0146] Those tablets made of formulations pursuant to preferred embodiments of the invention have disintegration times of below 15 min and display no capping.

[0147] Resulting therefrom those tablets release more than 60% in preferred embodiments more than 80% of the labeled amount of both actives after 30 min. Tablets pursuant to the present invention may be in whatever kind of form that is deemed to be advantageous.

[0148] As outlined above, a fixed dose acarbose and metformin tablet that has 18 mm length, a width of about 8 mm and a thickness of about 6.3-7 mm is known to be well accepted on the Asian market as of being comparably easy to swallow while it comprises the necessary amount of active to result in sufficient Diabetes Type 2 efficacy.

[0149] The tablets according to the present invention may be coated or not. It is however preferred that the tablet according to the present invention is coated. According to the present invention tablet means the non-coated core.

[0150] In some preferred embodiments according to the fourth aspect, this invention therefore comprises a coated tablet comprising the above referred to tablet as a core that is made from any of the before described fixed dose tablet formulations according to the first, second or third aspect of the invention, characterized in that such tablet is coated.

[0151] The coating of the coated tablet pursuant to the third aspect of this invention may be any coating material that is pharmaceutically acceptable.

[0152] A mixture of the coating substances mentioned herein may also be used as a ready-to-use coating system such as commercially available under the trade name Opadry.

[0153] Opadry 14F220001 is a mixture of about 60 wt. % hydroxypropylmethylcellulose, about 16 wt. % titanium dioxide, about 4 wt. % ferric oxide yellow and about 20 wt. % polyethylene glycol.

[0154] Any coating according to the fourth aspect of the present invention can make up from 0.5% to 30% by weight of the coated tablet including the tablet according to the second aspect of the present invention made up from the formulation of the first aspect of the invention depending on the type of coating chosen. The higher percentage of weight ranges, usually apply to tablets coated with a sugar containing coating. One of ordinary skill in the art, would however than term the coated to be rather a dragee than a coated tablet. For the purpose of the present invention, the coated tablet can therefore be either a dragee or a coated tablet in a more narrow sense.

[0155] Preferably the coating is about 0.5% to 3% by weight of the coated tablet formulation, more preferably about 2% by weight of the coated tablet.

[0156] A very preferred coating is a coating made up from a mixture of about 60 wt. % hydroxypropylmethylcellulose, about 16 wt. % titanium dioxide, about 4 wt. % ferric oxide yellow and about 20 wt. % polyethylene glycol. If such mixture is used, the coating makes up from 0.5% to 3% by weight of the coated tablet including the tablet of the fourth aspect of the invention made up from the formulation according to the first, second or third aspect of the present invention. Preferably such coating is then about 1% to 2.5% by weight of the coated tablet, more preferably about 2% by weight of the coated tablet.

[0157] In a fifth aspect of the present invention, a process for the production of a tablet formulation or tablet according to the first, second, third or fourth aspect of the invention is provided, wherein said process comprises the steps of [0158] 1) dry mixing metformin and acarbose together with at least one dry binder and at least one disintegrant, [0159] 2) dry granulating the resulting mixture to obtain dry granules, [0160] 3) at least once blending said dry granules with at least one flow agent and/or lubricant to obtain the fixed dose combination formulation of acarbose and metformin, [0161] 4) tableting said fixed dose combination formulation of acarbose and metformin to become a tablet, e.g. with tableting forces of at least 7 kN using circumferential speeds of the punches of at least 0.15 m/s or producing at least 20,000 tablets/h, whichever is lower.

[0162] Said process according to the fifth aspect of the present invention, preferably comprises another step of [0163] 5) coating the tablet of step 4) e.g. to result in the coated tablet according to the fourth aspect of the present invention.

[0164] Within the process of the fifth aspect of the present invention, it is preferred that the dry granulation performed pursuant to step 2) of the process is done as a roller compaction, e.g. with a throughput of at least 20 kg/h. In a preferred embodiment, the process according to the fifth aspect is a dry granulation process. In a preferred embodiment, dry granulation of the material comprises use of a roller compaction process. According to some embodiments according to the current invention roller compaction is preferably done with a throughput of at least 20 kg/h.

[0165] It has surprisingly been found that the above referred to process allows to produce tablets of the fixed dose combination of acarbose and metformin formulation without having to add water. That is to say that true dry granulation instead of either elevated temperature (melt) granulation or wet granulation can be used, which is particularly advantageous, as such process addresses the (negative) hygroscopic properties of both actives as well as the poor thermal stability of acarbose.

[0166] Furthermore the above process is capable to produce tablets in high amounts in continuous manufacturing, which comes along with meeting the above referred to objective to provide tablets to a huge market at affordable prizes.

[0167] However, with regard to the formulations and the processes described herein it was found that a tight control of the water amount at different stages of the production process and in particular of the final formulation or tablet was beneficial to avoid capping of the tablets. These investigations showed that a certain amount of water within the formulation (Loss on Drying 1.6%) was beneficial to avoid capping of tablets comprising the fixed dose combination formulation and thus to obtain a more stable and reliable high-throughput production process.

[0168] According to a sixth aspect, there is provided a process for the production of a fixed dose tablet formulation according to the first, second or third or another aspect comprising the steps of [0169] 1) dry mixing metformin and acarbose, optionally together with the at least one dry binder and/or at least one disintegrant, [0170] 2) dry granulating the resulting mixture to obtain dry granules, [0171] 3) optionally at least once blending said dry granules with a further excipient, e.g. the at least one flow agent and/or lubricant to obtain the fixed dose tablet formulation of acarbose and metformin, [0172] 4) determining the moisture content of the formulation and/or the dry granules and [0173] 5) adding water if the formulation moisture content as determined is below 1.6% loss on drying (LoD), e.g. to reach a formulation target moisture of 1.6 to 3.0%, e.g. 1.7 to 2.0%, 1.8 to 1.9%, 1.7% or 1.8%, and [0174] 6) optionally arranging the fixed dose combination formulation in the form of a tablet (tableting), and [0175] 7) optionally coating the tablet obtained from step 5.

[0176] In a preferred embodiment, the order of steps according to the sixth aspect is step 1, step 4, step 2, step 5, step 3, step 6 and step 7. However the person skilled in the art easily recognizes that the order of steps can be changed and other sequences of the steps are possible according to the present invention.

[0177] According to a seventh aspect, there is provided a process wherein said process comprises the steps of [0178] 1) dry mixing metformin and acarbose together with at least one dry binder and at least one disintegrant, [0179] 2) dry granulating the resulting mixture to obtain dry granules, [0180] 3) at least once blending said dry granules with at least one flow agent and/or lubricant to obtain a fixed dose combination formulation of acarbose and metformin, [0181] 4) determining the moisture content of the formulation and/or the dry granules and [0182] 5) adding water if the formulation moisture content as determined is below 1.6% LoD, e.g. to reach a formulation target moisture of 1.6 to 3.0%, and optionally [0183] 6) tableting said fixed dose combination formulation of acarbose and metformin to become a tablet,

[0184] characterized in that said at least one dry binder is a hydroxypropylcellulose that has a viscosity of 2 to 3 mPas at a molecular weight of about 40,000 g/mol and a particle size D.sub.50 of about 20 m, and/or D.sub.90 of 50 m respectively.

[0185] In a preferred embodiment, the order of steps according to the seventh aspect is step 1, step 4, step 2, step 5, step 3 and step 6. However the person skilled in the art easily recognizes that the order of steps can be changed and other sequences of the steps are possible according to the present invention.

[0186] In a preferred embodiment according to the fifth, sixth and seventh aspect tableting occurs with tableting forces of at least 7 kN using circumferential speeds of the punches of at least 0.15 m/s or producing at least 20,000 tablets/h whichever is lower.

[0187] Monitoring/determining the moisture content of the formulation, e.g. the tight control of water content can be performed by analyzing the amount of water within the material as known in the art. For example, loss on drying (LOD) is a method to measure high level moisture (moisture content (MC)) in solid or semi-solid materials. As known in the art for this technique a sample of material or of the formulation is weighed, heated in an oven for an appropriate period, cooled in the dry atmosphere e.g. of a desiccator, and then reweighed. If the volatile content of the solid is primarily water, the LOD technique gives a good measure of moisture content. Where the moisture content or LoD is given as a percentage throughout this application the stated value refers to the specific value with an error of +/0.05%. Because the manual laboratory method is relatively slow, automated moisture analyzers have been developed that can reduce the time necessary for a test from a couple hours to just a few minutes. These analyzers incorporate an electronic balance with a sample tray and surrounding heating element. Under microprocessor control the sample can be heated rapidly and a result computed prior to the completion of the process, based on the moisture loss rate, known as a drying curve.

[0188] The amount of water depends on various factors and even where the process was highly standardized, the amount of water was found to vary between different production sites (e.g. different geographic regions or countries) and different production scales (e.g. lab scale and large scale for commercial production). While standardization of the environmental conditions and process conditions as described herein could improve the capping behavior of the tablets in general, in particular for production sites located in Asia the capping behavior could be furthermore improved by control of the water content of the formulation, mixture, granules, or tablets. While the critical lower limit for LoD was found to be 1.5% no sticking was observed up to a LoD of 3%. Capping could be largely avoided by adding water where the moisture content was found to be lower or equal to 1.6%.

[0189] Where the amount of water was found to be too low in the material, e.g. in the formulation, granules or the tablet, water can be added, e.g. to the granules, formulation, material or the tablet, to reach a specific amount of moisture content. The skilled person is well aware that the order of process steps may be varied and that for example adding water may occur at different time points. In some preferred embodiments e.g. according to the sixth or seventh aspect, adding water occurs by spraying. Preferably, for addition of the water, the water is sprayed onto the powdered material or the granules. For example, the spraying can be performed manually by using a commercially available pump spray, thereby adding water into the chamber. For example, the water is thereby sprayed on top of the material and the material is blended in between and afterwards manually or by using a blending machine.

[0190] Moreover, the spraying can for example be performed automatically, e.g. by using a spraying system consisting of a spray nozzle for nebulizing the water, a funnel, a pump and a reservoir for the water. The water is transported by the pump, e.g. out of the reservoir through the funnel into the spray nozzle and is subsequently sprayed out of the nozzle onto the material or granules. For example, water spraying can be performed either directly into a container comprising the material (e.g. powdered or as a batch of granules) or directly into a flow of granules.

[0191] Where spraying occurs directly into the container or drum, the water is preferably brought into a uniform distribution. To this end the container/drum may be rotated for blending. Where spraying occurs into a granule flow, the water is preferably brought into a uniform distribution, which can for example be reached by moving the material from a delivering unit (e.g. a drum, container, sieving machine, roller compactor) into a receiving unit (e.g. drum, container). For example this step may be carried out while the spraying process takes place or afterwards.

[0192] In a preferred embodiment according to the fifth, sixth or seventh aspect the process comprises determining the moisture content of the material and, optionally, where the moisture content is below 1.6%, adding water to the material e.g. powder, granules, mixture, formulation or tablet. Determining the moisture content can be performed as known in the art, preferably by LoD.

[0193] In a preferred embodiment according to the fifth, sixth or seventh aspect adding water occurs by spraying water. In a preferred embodiment according to the fifth or sixth aspect adding water occurs by adding water for a target moisture content for the material e.g. granules, formulation or tablet of 1.6 to 3.0%, e.g. 1.7 to 2.0%, 1.8 to 1.9% or 1.7 or 1.8%.

[0194] In a preferred embodiment according to the fifth, sixth or seventh aspect adding water occurs by spraying water, e.g. as described above, to reach a target moisture content for the material or tablet of 1.6 to 3.0%, e.g. 1.7 to 2.0%, 1.8 to 1.9% or 1.7% or 1.8%.

[0195] According to an eighth aspect, there is provided a fixed dose tablet formulation produced by a process according to the fifth, sixth or seventh aspect of the current invention.

[0196] The present invention further comprises the aspects defined in the following clauses.

[0197] According to clause 1 there is provided a fixed dose tablet formulation comprising metformin and acarbose, at least one type of a hydroxypropylcellulose as at least one dry binder, at least one disintegrant, at least one flow agent and/or lubricant, characterized in that the at least one type of a hydroxypropylcellulose has a viscosity of 2 to 3 mPas at a molecular weight of about 40,000 g/mol and a particle size D.sub.50 of about 20 m, D.sub.90 of 50 m respectively

[0198] According to clause 2 there is provided a fixed dose tablet formulation according to clause 1, wherein the formulation comprises another hydroxypropylcellulose as a dry binder that has a viscosity of 6-10 mPas at a molecular weight of about 140,000 g/mol and a particle size D.sub.50 of about 160 m, D.sub.90 of 335 m respectively.

[0199] According to clause 3 there is provided a fixed dose tablet formulation according to clause 2, wherein the ratio of the hydroxypropylcellulose with a viscosity of 2-3 mPas at a molecular weight of about 40,000 g/mol and a particle size D.sub.50 of about 20 m, D.sub.90 of 50 m respectively towards the hydroxypropylcellulose with a viscosity of 6-10 mPas at a molecular weight of about 140,000 g/mol and a particle size D.sub.50 of about 160 m, D.sub.90 of 335 m respectively is between 4:1 and 1:1, particularly to about 3:1.

[0200] According to clause 4 there is provided a fixed dose tablet formulation according to any one of the previous clauses, wherein the dry binders are present in the formulation in an overall amount from about 4% to 15.5% by weight, more preferably from about 9% to 13% by weight, even more preferably from about 8% to 11%.

[0201] According to clause 5 there is provided a fixed dose tablet formulation according to any one of the previous clauses, wherein cross-linked polyvinylpyrrolidone is the disintegrant.

[0202] According to clause 6 there is provided a fixed dose tablet formulation according to any one of the previous clauses, wherein said formulation magnesium stearate as a lubricant.

[0203] According to clause 7 there is provided a fixed dose tablet formulation according to any one of the previous clauses, further comprising microcrystalline cellulose as an excipient with disintegration promoting properties.

[0204] According to clause 8 there is provided a fixed dose tablet formulation according to any one of the previous clauses, wherein the formulation comprises about 74% by weight of acarbose and metformin in a ratio of 1:10, about 10.5% by weight of dry binders, consisting of about 2.5% by weight of hydroxypropylcellulose with a viscosity of 6-10 mPas, a molecular weight of about 140,000 g/mol and a particle size D50 of about 160 m, D90 of 335 m respectively and about 8% by weight of hydroxypropylcellulose with a viscosity of 2-3 mPas, a molecular weight of about 40,000 g/mol and a particle size D50 of about 20 m, D90 of 50 m respectively, about 9% by weight of microcrystalline cellulose as an excipient with disintegration promoting properties about 4.5% by weight of a disintegrant, preferably being cross-linked polyvinylpyrrolidone with an average particle size of about 30 m, and about 0.5% by weight of both a lubricant and a flow agent, wherein the flow agent is preferably highly-disperse silicas and the lubricant is preferably magnesium stearate.

[0205] According to clause 9 there is provided a tablet comprising a fixed dose tablet formulation of any one of the previous clauses.

[0206] According to clause 10 there is provided a tablet according to clause 9, wherein said tablet has a length of about 18 mm, a width of about 8 mm and a thickness of about 6.3-7 mm.

[0207] According to clause 11 there is provided a coated tablet comprising a core made up from a tablet according to any one of clauses 9 to 10 characterized in that such core is coated.

[0208] According to clause 12 there is provided a coated tablet according to clause 11, wherein the coating is a mixture of about 60 wt. % hydroxypropylmethylcellulose, about 16 wt. % titanium dioxide, about 4 wt. % ferric oxide yellow and about 20 wt. % polyethylene glycol.

[0209] According to clause 13 there is provided a process for the production of a tablet according to any one of the clauses 9 or 10, wherein said process comprises the steps of [0210] 1) dry mixing metformin and acarbose together with at least one dry binder and at least one disintegrant, [0211] 2) dry granulating the resulting mixture to obtain dry granules, [0212] 3) at least once blending said dry granules with at least one flow agent and/or lubricant to obtain the fixed dose combination formulation of acarbose and metformin, [0213] 4) tableting said fixed dose combination formulation of acarbose and metformin to become a tablet, [0214] characterized in that said at least one dry binder is a hydroxypropylcellulose that has a viscosity of 2-3 mPas at a molecular weight of about 40,000 g/mol and a particle size D.sub.50 of about 20 m, D.sub.90 of 50 m respectively.

[0215] According to clause 14 there is provided a process for the production of a coated tablet, wherein said process comprises the process according to claim 13 and further comprises another step of [0216] 5) coating the tablet [0217] after step 4) to result in the coated tablet according to any one of clauses 11 and 12.

EXAMPLES

Example 1

Process for Production of Fixed Dose Composition Tablet Formulation and Methods for Analysis

[0218] Excipients and active pharmaceutical ingredients (APIs) were blended. Afterwards these powder blends were compacted with an instrumented roller compactor and grinded. Subsequently the granules were blended with the flow agent and the lubricant. This ready-to-press blend was compressed on a rotary die press as well as on a compression simulator to obtain oval tablets of different sizes (188, 199 mm) and masses between 712.5 and 832.5 mg.

[0219] Tablets were visually inspected if lamination or capping occurred. To evaluate the capping tendency in more detail, the oval tablets were additionally crushed lengthwise using a standard hardness tester. Tablets offering a separation into layers (e.g. separation of the upper or lower cap) were declared as capped, tablets breaking just clearly into two halves were counted as non-capped.

[0220] Disintegration experiments were performed according to European Pharmacopoeia 9.2 (2017) section 2.9.1 Disintegration of tablets and capsules using a disk. The mean of the measurement times was calculated. The dissolution experiments were performed according to the USP 40 (chapter <711> Dissolution) using apparatus 2 (paddle method). Stirrer speed was between 50 or 75 rpm, release medium phosphate buffer pH 6.8 (1 L) and temperature 37 C. Capping tests were performed for n=10 tablets. For disintegration 3-6 tablets were used and for dissolution experiments 6 tablets were tested.

Example 2

Process for Production of Fixed Dose Composition Tablet Formulation and Methods for Analysis

[0221] Roll compaction/dry granulation was performed with an instrumented roller compactor (Minipactor 250/25, Gerteis Maschinen+Prozessengineering AG, Jona, Switzerland). A gap width of 3 mm, a roll speed of 2.5 rpm and a specific compaction force of 5 kN/cm was used. Ribbons were directly dry granulated through a 1 mm sieve with a star granulator, rotating 250 clockwise and 350 counterclockwise and the rotor speed set to 60 rpm clockwise and counterclockwise.

[0222] Granules were postblended and afterwards compressed to oval shaped tablets (188 mm and 199 mm) with a weight between 662.5 and 882.5 mg. Compression experiments where performed with an instrumented rotary die press (T 200, Kilian) and a compression simulator (Styl'One Evolution, Medelpharm). For the compression experiments different compression speeds (15, 40 and 72 rpm) as well as different compression pressures (between 15 and 45 kN) were used.

[0223] Tablets were characterized with respect to their weight, height, length, width and breaking load. To evaluate the capping tendency in more detail, the oval tablets were crushed lengthwise using a standard hardness tester. Tablets offering a separation into layers (e.g. separation of the upper or lower cap) were declared as capped, tablets breaking just clearly into two halves were counted as non capped.

[0224] Disintegration experiments were performed according to Ph. Eur. using a disk. All measurements beside the disintegration and dissolution were performed for n=10 tablets. For disintegration 3-6 tablets were used and for dissolution experiments 6 tablets were tested.

[0225] LoD, uniformity of mass, disintegration and friability can be and were determined as known in the art and as described in Ph. Eur. Thickness of uncoated or coated tablets can be determined as known in the art, e.g. by manual measurement with caliper or micrometer or automatic measurement with electronic gauge. The breaking load of the tablets is determined by a three-point bending test using a standard tablet hardness tester and a pair of breaking load measurement jaws. The measurement will be performed with tablets laying on the height. For the measurement the insert with the single, central, not adjustable spike will be placed on the movable jaw of the hardness tester. The insert with the two movable spikes will be placed on the unmovable jaw of the hardness tester. The distance (span) between the movable spikes has to be adjusted (screw, scale), in such a way, that of the length of the tablet is laying between the spikes and outside (two equal parts right and left).

TABLE-US-00001 TABLE 1 Tests and procedures for parameter characterization. Test Procedure Blend Loss of drying Ph. Eur. Uncoated tablets Uniformity of mass .sup.b Ph. Eur. Thickness manual measurement with caliper or micrometer or automatic measurement with electronic gauge Breaking load (mean value) instrumental determination of breaking load Disintegration (with disk) Ph. Eur. Friability Ph. Eur.

Example 3

Fixed Dose Formulations Pursuant to the Invention

[0226] Tablets made from a fixed dose combination formulation were prepared as described above but without adding water. All tablets comprised acarbose and metformin in a ratio of 1:10 at 50 mg acarbose and 500 mg metformin hydrochloride salt. All formulations comprised Aerosil as a flow agent at 4 mg/tablet and Magnesium stearate at 3.5 mg/Tablet. Avicel (CAS 9004-34-6) is a microcrystalline cellulose and HPC is an abbreviation of hydroxypropylcellulose, while the HPC L is a hydroxypropylcellulose of a viscosity of 6-10 mPas, a molecular weight of about 140,000 g/mol and a particle size D50 of about 160 m, D90 of 355 m respectively and HPC SSL SFP is an hydroxypropylcellulose of a viscosity of 2-3 mPas, a molecular weight of about 40,000 g/mol and a particle size D50 of about 20 m, D90 of 50 m respectively. Polyplasdones have been described above; these are cross-linked polyvinylpyrrolidones of different grades with regard to average particle size.

TABLE-US-00002 TABLE 2 Examples for the composition of different formulations Overall weight/tablet Avicel Dry Binder [mg] Disintegrant [mg] (w/o Formulation PH- 101 HPC-SSL- Polyplasdone Polyplasdone coating) # [mg] HPC-L SFP XL XL 10 [mg] 1 150 0 100 0 25 832.5 2 100 0 80 0 25 762.5 3 70 0 80 0 35 742.5 4 70 20 60 0 35 742.5 5 70 20 60 35 0 742.5

Example 4

Other Fixed Dose Formulations

[0227] Tablets made from a fixed dose combination formulation were prepared as described above but without adding water. All tablets comprised acarbose and metformin in a ratio of 1:10 at 50 mg acarbose and 500 mg metformin hydrochloride salt. All formulations comprised Aerosil as a flow agent at 4.0 mg/tablet and magnesium stearate at 3.5 mg/Tablet.

TABLE-US-00003 TABLE 3 Eight different formulations as comparative examples. HPC is an abbreviation of hydroxypropylcellulose while L-HPC NBD 21 is also a low- substituted hydroxypropylcellulose which is chemically identical to the current L-HPC grades. METHOCEL is the trade name of cellulose ethers while Methocel E3 Premium LV is characterized by a methoxyl substitution of 28-30% and a hydroxypropyl substitution of 7-12%. Overall Dry Binder [mg] weight/tablet Avicel MethocelTM Disintegrant [mg] (w/o Comparative PH- 101 Kollidon Kollidon E3 Premium L-HPC L-HPC Polyplasdone Polyplasdone coating) Example # [mg] HPC-L VA64 VA64F LV LH 11 NBD 21 XL XL 10 [mg] C1 150 0 0 0 100 0 0 0 25 832.5 C2 150 100 0 0 0 0 0 0 25 832.5 C3 150 0 0 0 0 100 0 0 25 832.5 C4 150 0 0 0 0 0 100 0 25 832.5 C5 50 0 70 0 0 0 0 35 712.5 C6 70 0 0 80 0 0 0 0 35 742.5 C7 50 100 0 0 0 0 0 25 0 737.5 C8 70 80 0 0 0 0 0 35 742.5

Example 5

Assessment of the Characteristics of the Tablets

[0228] Capping behavior, disintegration time and release of acarbose and metformin was determined for the formulations according to examples 3 and 4 as described above (table 3). The formulations according to table 3, which comprise a variety of alternative dry binders, collectively show capping. Favorable capping behaviour was observed for all formulations described in table 2 (see table 4). Relationship between moisture content (percentages) and capping for different compression forces for selected formulations are shown in table 5. Relationship between moisture content (MC) and capping for different breaking loads and two selected formulations are shown in table 6.

TABLE-US-00004 TABLE 4 Capping behavior, disintegration time and release of acarbose and metformin for the formulations according to table 2 and 3. Disinte- Release acarbose Release metformin gration [% of labeled [% of labeled time amount after amount after Example Capping [seconds] 30 min] 30 min] 1 NO 700 69.3 84.4 2 NO 533 na na 3 NO 628 87.03 96.7 4 NO 414 na na 5 NO 450 92.9 94.2 C1 YES 131 92 97.1 C2 YES 198 87.3 93.5 C3 YES na na na C4 YES na na na C5 YES 243 na na C6 YES 313 89.4 95.71 C7 YES 117 na na

TABLE-US-00005 TABLE 5 Relationship between moisture content (percentages) and capping for different compression forces for selected formulations. A compression simulator was used for tableting and the profile of the rotary die press FE 55, with a speed of 100.000 tab/h was used. Formulation 4* is the formulation 4 Formulation # C1 C2 C5 C8 4* Compression force 1.74% 1.72% 1.56% 1.39% 1.63% 25 kN 8/10 4/10 10/10 10/10 30 kN 9/10 5/10 10/10 10/10 35 kN 10/10 10/10 10/10 0/10 40 kN 0/10 45 kN 0/10 2.12% 2.05% 1.72% 1.77% 1.70% 25 kN 0/10 0/10 3/10 9/10 30 kN 4/10 4/10 8/10 10/10 35 kN 6/10 4/10 10/10 10/10 40 kN 45 kN 0/10 2.49% 2.51% 1.88% 1.88% 25 kN 0/10 8/10 30 kN 0/10 10/10 35 kN 0/10 0/10 0/10 10/10 40 kN 5/10 0/10 8/10 45 kN 0/10 0/10 6/10 1.91% 25 kN 30 kN 35 kN 0/10 40 kN 0/10 45 kN 0/10 1.95% 1.96% 25 kN 0/10 30 kN 0/10 0/10 35 kN 0/10 40 kN 0/10 0/10 45 kN 2/10 2.18% 2.07% 25 kN 0/10 0/10 30 kN 0/10 4/10 35 kN 0/10 8/10 40 kN 0/10 45 kN 0/10

[0229] according to example 3 comprising 4 mg magnesium stearate/tablet instead of 3.5 mg magnesium stearate/tablet. Favorable capping behaviour was observed for tight control of moisture content.

TABLE-US-00006 TABLE 6 Relationship between moisture content (MC) and capping for different breaking loads and two selected formulations. A compression simulator was used for tableting and the profile of the rotary die press FE 55, with a speed of 170100 tab/h used. Formulation 4* is the formulation 4 according to example 3 comprising 4 mg magnesium stearate/tablet instead of 3.5 mg magnesium stearate/tablet. C5 4* Compression force 1.63% MC 25 kN 30 kN 35 kN 0/10 40 kN 2/10 45 kN 1/10 1.70% MC 25 kN 30 kN 35 kN 0/10 40 kN 0/10 45 kN 2/10 1.95% MC 1.82% MC 25 kN 0/10 30 kN 2/10 35 kN 3/10 40 kN 45 kN 0/10