PHARMACEUTICAL COMPOSITIONS

Abstract

The present invention relates to solid oral fixed dose compositions of metformin, atorvastatin, and valsartan, or their pharmaceutically acceptable salts, processes for the preparation thereof, and the use of the composition to treat certain diseases.

Claims

1. A solid oral fixed dose tablet composition comprising a bilayer part comprising a. an extended release layer comprising metformin or a pharmaceutically acceptable salt thereof, and one or more excipients; and b. an immediate release layer comprising valsartan or a pharmaceutically acceptable salt thereof, and one or more excipients; and further comprising an immediate release coating layer comprising atorvastatin, or a pharmaceutically acceptable salt thereof, and one or more excipients, wherein the immediate release coating layer is coated over the bilayer part.

2. The composition according to claim 1 wherein the metformin or pharmaceutically acceptable salt thereof is metformin hydrochloride.

3. The composition according to claim 2 wherein the metformin hydrochloride is present in the form of granules which additionally comprise povidone and magnesium stearate.

4. The composition according to claim 3 wherein the extended release layer further comprises sodium stearyl fumarate, or magnesium stearate; colloidal silicon dioxide; and microcrystalline cellulose.

5. The composition according to claim 4 wherein the metformin hydrochloride is present in a unit dose strength selected from the group consisting of about 250, about 500, and about 750 mg.

6. The composition according to claim 5 wherein the metformin hydrochloride is present in a unit dose strength of about 500 mg.

7. The composition according to claim 1 wherein the valsartan, or pharmaceutically acceptable salt thereof, is valsartan.

8. The composition according to claim 7 wherein the valsartan is present in a unit dose strength selected from the group consisting of about 40, about 50, about 60, about 70, and about 80 mg.

9. The composition according to claim 8 wherein the valsartan is present in a unit dose strength of about 80 mg.

10. The composition according to claim 1 wherein the atorvastatin, or pharmaceutically acceptable salt thereof, is atorvastatin calcium trihydrate.

11. The composition according to claim 10 wherein the atorvastatin calcium trihydrate is present in a unit dose strength selected from the group consisting of about 5, about 10, about 15, and about 20 mg.

12. The composition according to claim 11 wherein the atorvastatin calcium trihydrate is present in a unit dose strength of about 10 mg.

13. (canceled)

14. The composition according to claim 1 wherein the tablet is of a pharmaceutically acceptable size to be swallowed intact by an adult.

15. (canceled)

16. A process for preparing a solid oral fixed dose tablet composition according to claim 1 comprising forming a compressed bilayer part comprising: a. an extended release layer comprising metformin, or a pharmaceutically acceptable salt thereof, and one or more excipients; and b. an immediate release layer comprising valsartan, or a pharmaceutically acceptable salt thereof, and one or more excipients; and coating with an immediate release coating layer comprising atorvastatin, or a pharmaceutically acceptable salt thereof, and one or more excipients.

17. The process according to claim 16 wherein the pH for the immediate release coating layer comprising atorvastatin, or a pharmaceutically acceptable salt thereof, is maintained at or above pH 6.

Description

EXAMPLE 1

[0117] A Fixed Dose Combination Tablet Comprising 500 mg Metformin HCl, 80 mg Valsartan, 10 mg Atorvastatin Calcium Trihydrate

[0118] The composition is prepared using the components set forth in Table A, below. Hypromellose, colloidal silicon dioxide, metformin HCl granules (95% granulation potency), and microcrystalline cellulose are pre-blended in a bag for 1 to 2 minutes, de-lumped and blended again in a V-blender for 10 minutes. After sieving, magnesium stearate is charged to the same V-blender and the mixture is blended for 3 minutes.

[0119] For layer 2, valsartan, microcrystalline cellulose, colloidal silicon dioxide, iron oxide red, and croscarmellose sodium are pre-blended in a bag for 1-2 minutes, de-lumped, and blended in a V-blender for 10 minutes. After sieving, the magnesium stearate is charged to the same V-blender and the mixture is blended for 3 minutes.

[0120] The blends are loaded into separate hoppers in a bilayer tablet press. Using modified oval tooling (0.3605×0.7435 inch), bilayer tablets are prepared targeting a 900 mg metformin layer weight and a 170 mg valsartan layer weight.

[0121] The coating suspensions are prepared using commercially available coating system (for example, Opadry, 03K19229 Clear from Colorcon, West Point, Pa., USA). The intermediate coat and top coat suspension are prepared by dispersing/dissolving the coating system in deionized water to 5% total solids content and mixing for not less than 30 minutes. The suspension is prepared to a batch size of 1.28 kg, which includes an excess. The pH of the coating suspension is measured as 6.44. The active coat is prepared in a substantially the same as the intermediate coat and top coat; however, the total solids content is comprised of 1.08% atorvastatin calcium trihydrate and 3.92% coating system giving a total solids content of 5%. The coating system is first dispersed/dissolved in deionized water and mixed for not less than 30 minutes. The atorvastatin calcium trihydrate is added to the coating mixture and mixed for not less than 30 minutes to fully disperse the atorvastatin. The pH of the coating suspension is measured as 6.69.

[0122] Core bilayer tablets are loaded into a pan coater with an 11 inch coating pan and a Spraying System Spray Nozzle Setup. Tablets are pre-warmed to 40° C. in the pan coater. The average weight of 30 pre-warmed tablets is measured. For the optional intermediate coat application, the tablets are coated to a theoretical weight gain of 1%, assuming a core tablet weight of 1070 mg. The coating conditions, spray rate, inlet temperature, and flow volume, are adjusted to maintain a temperature of 40° C. during coating. Once the intermediate coat weight gain is achieved, the active coat is then applied in a substantially the same manner, targeting a theoretical weight gain of 4.6729%, assuming a core tablet weight of 1070 mg. The coating conditions are adjusted to maintain a temperature of 40° C. during coating. Once the active-coat weight gain is achieved, the optional top coat is applied in substantially the same way as the intermediate coat, targeting a theoretical weight gain of 1%, assuming a core tablet weight of 1070 mg. The coating conditions are adjusted to maintain a temperature of 40° C. during coating. Tablets are then dried in the pan coater for 4-6 minutes at 60° C. and then discharged into a bag.

TABLE-US-00001 TABLE A Component Amount (mg) Metformin - Layer-1 Metformin HCl granules 526.32 Metformin HCl 500 Povidone 23.68 Magnesium stearate 2.64 Hypromellose 2208, 100,000 mPa .Math. s viscosity 315.00 Microcrystalline cellulose, silicified 45.18 Magnesium stearate 9.00 Colloidal silicon dioxide 4.5 Total layer 1 900 Valsartan -Layer-2 Valsartan 80.00 Microcrystalline cellulose, silicified 78.66 Croscarmellose sodium 7.00 Iron oxide red 0.14 Magnesium stearate 2.5 Colloidal silicon dioxide 1.70 Total layer 2 170 Intermediate coat Hypromellose 2910, 6,000 mPa .Math. s viscosity 9.00 Triacetin 0.90 Talc 0.80 Total intermediate coat 10.70 Active coat Atorvastatin calcium 10.85 Hypromellose 2910, 6,000 mPa .Math. s viscosity 32.92 Triacetin 3.29 Talc 2.94 Total active coat 50.00 Top coat Hypromellose 2910, 6,000 mPa .Math. s viscosity 9.00 Triacetin 0.90 Talc 0.80 Total top coat 10.70 Total coated tablet weight 1141.4

[0123] The final fixed dose combination tablet is oval in shape and measures 9.2 mm×18.9 mm.

[0124] The tablet size and weight are acceptable to the patient for oral consumption without fracturing the tablet. The formulation comprising fixed dose combination of Example 1 is consistent with pharmaceutically elegant formulations that may be swallowed without fracture of the tablet.

EXAMPLE 2

[0125] The fixed dose composition is prepared substantially as described for Example 1, except that PEG400 is used instead of triacetin at each occurrence.

[0126] Alternate Preparation 1

[0127] Wet Granulation

[0128] For comparison, a bilayer tablet is prepared using a wet granulation formulation.

[0129] 1) Atorvastatin calcium trihydrate is wet granulated with calcium carbonate and the granulating excipients: hydroxypropyl cellulose, polysorbate 80, microcrystalline cellulose, lactose, and croscarmellose sodium, using water as the granulating liquid.

[0130] 2) The resulting wet granules are thoroughly dried and sized using, appropriate pharmaceutical equipment.

[0131] 3) Valsartan and the appropriate tableting excipients are pre-blended together using suitable pharmaceutical blending equipment.

[0132] 4) The dried and sized atorvastatin granules are then combined with the valsartan pre-blend and blended together using suitable pharmaceutical blending equipment. This blend is then lubricated with an appropriate excipient using suitable pharmaceutical blending equipment.

[0133] 5) Metformin, hypromellose and other appropriate tableting excipients are blended together using suitable pharmaceutical blending equipment.

[0134] 6) The two blends are then combined at the desired ratios, using suitable pharmaceutical tablet compression equipment, to produce a bilayer tablet of equivalent dose as the fixed dose combination of Example 1.

[0135] Alternate Preparation 2

[0136] Dry Mix

[0137] A bilayer tablet is prepared using a simple dry mix. [0138] a. Atorvastatin calcium trihydrate is pre-blended (dry) with a stabilizing excipient, calcium carbonate, using suitable pharmaceutical blending equipment. [0139] b. The atorvastatin pre-blend, valsartan, and appropriate tableting excipients are blended together using suitable pharmaceutical blending equipment. This blend is lubricated with an appropriate excipient using suitable pharmaceutical blending equipment [0140] c. Metformin hydrochloride, hypromellose, and other appropriate tableting excipients are blended together using suitable pharmaceutical blending equipment. [0141] d. The two blends are then combined at the desired ratios, using suitable pharmaceutical tablet compression equipment, to produce a bilayer tablet of equivalent dose as the composition of Example 1.

[0142] Tablets are placed on an accelerated stability study and the primary degradant, the atorvastatin lactone, is monitored to gauge the effectiveness of the stabilization of atorvastatin in the dosage form. Samples are stored in an open dish at elevated controlled temperature and humidity. Samples are tested for the atorvastatin lactone impurity using HPLC with UV detection. The data provided in Table B and Table C, demonstrate the stability of the Example 1 and Example 2 compositions. The data provided in Table D and Table E suggest that the compositions of Example 1 and Example 2 provide dissolution profiles that are comparable to the respective regulatory agency approved mono-product.

[0143] Atorvastatin Stability

[0144] Unexpectedly, the composition of Example 2 resulted in more atorvastatin lactone formation than expected.

TABLE-US-00002 TABLE B % atorvastatin lactone measured on stability: 40° C./50% RH Presentation Initial 1 week 2 weeks 4 weeks Alternate Preparation 2 0.36 0.40 0.45 0.44 Alternate Preparation 1 0.38 0.62 0.79 0.93 Example 2 0.46 0.76 0.99 1.25

[0145] Also surprisingly, the pH of the coating suspension of atorvastatin in Example 2 is measured as a pH=4.53 despite all excipients in the coating having no acidic functionality, and being neutral in nature.

[0146] The composition of Example 1 is compared to the Alternate Preparation 2 in an open dish stressed stability study. Example 1 is found to have superior stability, with no measureable increase of the lactone impurity found in Example 1. This demonstrates that separating the atorvastatin from the valsartan and adding it to a coating layer has a favourable effect on stability.

TABLE-US-00003 TABLE C % atorvastatin lactone measured on stability: 50° C./55% RH 55° C./45% RH Presentation Initial 1 day 2 day 1 day 2 day Example 1 0.28 0.26 0.27 0.26 0.26 Alternate Preparation 2 0.28 0.62 0.99 0.62 0.90

[0147] Dissolution

[0148] Dissolution of the two immediate release actives are measured using a USP apparatus II and HPLC with UV detection and 50 mM pH 6.8 phosphate buffer at 37° C. as the media. The film coated prototypes compare favorably to the regulatory approved mono products in dissolution testing. The regulatory approved atorvastatin product is Lipitor® and the regulatory approved valsartan product is Diovan®.

TABLE-US-00004 TABLE D Average (n = 6) % release at 30 minutes Presentation Atorvastatin Valsartan Regulatory approved 98 100 mono product Example 1 90 104 Example 2 92 104

[0149] Dissolution of metformin is measured in 50 mM pH 6.8 phosphate buffer at 37° C. using a USP apparatus II with HPLC and UV detection. The percent release of metformin in the film coated prototypes compare favorably to the regulatory approved mono product (Glucophage® XR) over 10 hours.

TABLE-US-00005 TABLE E Average (n = 6) % release metformin HCl Regulatory approved Time (hr) Example 2 mono product 1 24 26 3 47 48 6 70 68 10 90 85 Average (n = 6) % release metformin HCl Regulatory approved Time (hr) Example 1 mono product 1 24 26 3 48 48 6 73 68 10 91 85

[0150] Size of Metformin Layer and Dissolution Rate

[0151] The dissolution rate of metformin hydrochloride in two metformin-valsartan bilayer tablets in which the total weight of metformin layer was reduced relative to the commercially available metformin product Glucophage®XR was measured and compared to the dissolution rate in Glucophage®XR.

[0152] The bilayer tablets are prepared substantially as described in Example 1. The composition of the bilayer tablet is set out below in Table F.

TABLE-US-00006 TABLE F Component Amount mg % wt of layer Metformin HCl granules (95%)* 526 56.9 HPMC 343 37.1 Microcrystalline Cellulose 47 5.1 Sodium stearyl fumarate 9 1.0 TOTAL layer 925 100.0 Valsartan 80 38.1 Microcrystalline cellulose 92 43.8 Croscarmellose sodium 31.5 15.0 Silicon dioxide 2.1 1.0 Iron oxide red 0.2 0.1 Sodium stearyl fumarate 4.2 2.0 TOTAL layer 210 100.0 Metformin HCl granules (95%)* 526 53.9 HPMC 363.2 37.2 Microcrystalline cellulose 76.1 7.8 Sodium stearyl fumarate 9.8 1.0 TOTAL layer 975.1 100.0 Valsartan 80 27.2 Microcrystalline cellulose 154.9 52.7 Croscarmellose sodium 44.1 15.0 Silicon dioxide 7.4 2.5 Iron oxide red 0.3 0.1 Sodium stearyl fumarate 7.4 2.5 TOTAL layer 294.1 100.0 *Granules composed of: 95% wt metformin HCl, 0.5% wt magnesium stearate and 4.5% wt povidone.

[0153] Dissolution of metformin hydrochloride is measured in 50 mM pH 6.8 phosphate buffer at 37° C. using a USP apparatus I. The results are set out below in Table G.

TABLE-US-00007 TABLE G % metformin HCl released 60 120 180 360 600 720 min min min min min min Glucophage ®XR 1025 31.2 45.4 56.1 77.6 95.5 100 mg tablet Bilayer tablet with 31.9 46.8 58.7 80.3 96.7 100 925 mg metformin layer total wt Bilayer tablet with 30.2 45.3 56.7 78.6 96.3 100 975 mg metformin layer total wt

[0154] It is well known that the surface area to volume ratio (SA/Vol) of a matrix XR tablet impacts the release rate of the drug, with a higher SA/Vol resulting in a faster release. As the Glucophage® XR tablet is oval (unit dose of metformin HCl is 500 mg) in shape and weighs about 1025 mg, it would be expected that a tablet of similar composition and shape, only smaller in mass, should have a faster dissolution rate. However, these data surprisingly show that the size of the metformin layer can be reduced without resulting in a measurable difference in dissolution rate.