Title of Invention

A PHARMACEUTICAL COMPOSITION COMPRISING IBANDRONATE FORMULATION AND PROCESS FOR PREPARING THE SAME

Abstract

The invention relates to a pharmaceutical composition for oral application consisting of up to 250 mg of ibandronic acid or sodium salts thereof for oral application, wherein the tablet kernel consists of 30.0 to 36.0 % of active substance 4.0 to 6.0% by weight of binder; 39.6 to 59.4 % by weight of filler; 4.5 to 5.5% by weight of disintegrant; 1.8 to 2.2% by weight of lubricant; and 0.9 to 1.1% by weight of flow regulator and to process for the preparation of such compositions. ABSTRACT 2474/CHENP/2004 A PHARMACEUTICAL COMPOSITION COMPRISING IBANDRONATE FORMULATION The invention relates to a pharmaceutical composition for oral application consisting of up to 250 mg of ibandronic acid or sodium salts thereof for oral application, wherein the tablet kernel consists of 30.0 to 36.0 % of active substance 4.0 to 6.0% by weight of binder; 39.6 to 59.4 % by weight of filler; 4.5 to 5.5% by weight of disintegrant; 1.8 to 2.2% by weight of lubricant; and 0.9 to 1.1% by weight of flow regulator and to process for the preparation of such compositions.

Full Text

This invention relates to a pharmaceutical composition comprising ibandronate formulation. The invention further relates to a pharmaceutical composition for oral application consisting of a high dose of bisphosphonates or physiologically safe salts (hereof as active substance and to a process for the preparation of such compositions. Aminoalkyl-1,1 -diphosphonic acid derivatives (hereinafter called by the general term 5 bisposphonates) are important pharmaceutical agents in the treatment of bone diseases and some disturbances of calcium metabolism such as hypercalcaemia, osteoporosis, tumour osteolysis, Paget's disease, etc. Bisposphonates as pharmaceutical agents are described for example in EP-A-170,228, EP A-197,478, EP-A-22,751: EP-A 252,504, EP-A- 252,505, EP-A-258,618. EP-A-350,002, EP-A-273,190, WO-A-90y00798 each of which are incorporated herein by reference. Pharmaceutical forms of currently marketed bisphosphonates are oral formulations (tablets or capsules) or solutions for intravenous injection or infusion. They are systemically well tolerated when administered at therapeutic doses. However, bisphsphonates as a class are irritant to skin and mucous membranes and when given orally on a continuous basis may result in digestive tract side effects, e.g. esophageal adverse events or gastrointestinal disturbances. In consequence, and due to their low oral bioavailability, the oral route of administration has, to date, to follow inconvenient recommendations of use for the patient. As described, bisphosphonates are accepted as providing strong efficacy in the management of osteoporosis. However, given the administration restrictions related to low oral bioavailability and potential for gastro-metical side effects, there is a clear opportunity for regimens which offer improved convenience and flexibility, leading to a higher level of compliance and superior patient management / satisfaction. The said substances and their preparation are known and despaired, for example, in the following references: US Patent No. 4,705^51 (Alendronate), US f^tent No. 4,927,814 (Ibandronate), US Patents No8.3,468,955,3,400,147,3,475,486 (Etidronate), O.T. Quimby et al, J. Org. Chem. 22.4111 (1967) (Qodronate) and US Patent No. 4,505,321 (Risedronate) and US Patents Nos. 4,134,969 and 3,962,432 (Pamidronate), US Patent No. 5,130304 (EB--1053), US Patent No. 4,970,335 (Incadronate), Bdgian Patent Na 885139 (Neridronate), US Patent No. 4,054.598 (Olpadronate), US Patents Nos. 4,746,654,4,876,248 and 4,980,171 (Tdudronate), US Patent No. 4,990,503 (YH 529) and US Patent No. 4,939,130 (Zoledronate). Preferred are composition* comprising the equivalent of 150 mg bisphosphonates or physiological safe salts thereof and compositioiis comprising the equivalent of 100 mg bisphosphonates or physiological safe salts as active substances, respectively. Ibandronate or a physiological saft salt thereof is a particularly preferred active substance, particularly in the form of Na-Ibandronate monohydrate. The composition farther comprises adjuvant such as binders for example polyvinypyrrodone (eg. Poisoned®) or hydroxypropylmetliyl cdlulose (e.g. Phannacoat®), fillers for example lactose in hydrate or anhydrite form, cellulose in microcrystalline or fibrous form (e.g. Avicel®), or starch, disintegrates for example cross-linfced polyvinyl) pyrrolidone (e.g, Crospovidone® USPNP) or cross cannelose, lubricates for example stearic add or magnesium steerage, and flow-regulators for example colloidal silicon dioxide. The preferred form of the composition are tablets preferably coated by a film coating mixture and a plasticizer. Such film coating mixtures and plastizisers are known to the person sallied in the art. According to die invention the tweet kernd consists of 30.O to 36.0, preferably of .33,3.% of active substance; of 4.0 to 6.0, preferably of 4.8 to 5.2 % by Wight of binder; of 39.6 to 59.4, preferably of 47.0 to 52.0 % by freight of filler; of 4.5 to 5.5, preferably of 4.8 to 5.2 % by went of disintegrate; of 1.8 to 2.2, preferably of 1.9 to 2.1 % by weight of lubricant; and of 0.9 to 1.1, preferably of 0.95 to 1.05 % by weight of flow regulator. Preferably the active substance is ibandronate or a physiological safe salt thereof; preferably the binder is polyvinyipyrrolidonej preferred fillers are lactose in hydrate or abdicate form, or cellulose in microcrystalline or fibrous form; and a preferred disintegrate is cross-Holed polyvinyl pyrrolidone. Preferred are compositions wherein the disintegrate is added We claim; 1. A pharmaceutical composition containing as active substance up to 250 mg of ibandronic acid or sodium salts thereof for oral application, wherein the tablet kernel consists of 30.0 to 36.0 % of active substance 4.0 to 6.0% by weight of binder; 39.6 to 59.4 % by weight of filler; 4.5 to 5.5% by weight of disintegrant; 1.8 to 2.2% by weight of lubricant; and 0.9 to 1.1% by weight of flow regulator. 2. The pharmaceutical composition as claimed in claim 1, wherein the tablet kernel consists of 33.3.% of active substance; 4.8 to 5.2 % by weight of binder; 47.0 to 52.0 % by weight of filler; 4.8 to 5.2 % by weight of disintegrant; 1.8 to 2.1 % by weight of lubricant; and 0.95 to 1.05 % by weight of flow regulator. 3. The pharmaceutical composition as claimed in claim 1 or 2 comprising the equivalent of 150 mg ibandronic acid or its sodium salts as active substance. 4. The pharmaceutical composition as claimed in claim 1 or 2 comprising the equivalent of 100 mg ibandronic acjd or its sodium salts as active substance. 5. A pharmaceutical composition comprising Ibandronic acid 100.0 mg - as mono-sodium salt (IH2O) of Ibandronic acid 112.50 mg Povidone K25® 15.0 mg Lactose, monohydrate 108.50 mg Cellulose, microcrystalHne 40.0 mg Crospovidone 15.0 mg Stearic acid 95 6.0 mg Silica, anhydrous colloidal 3.0 mg Film-coat Film-coating mixture * 10.20 mg Macrogol 6000® 1.80 mg 6. A pharmaceutical composition comprising Ibandronic acid 150.0 mg - as mono-sodium salt (IHaO) of Ibandronic acid 168.75 mg Povidone (K25) 22.5 mg Lactose, monohydrate 162.75 mg Cellulose, macrocrystalline 60.0 mg Crospovidone 22.5 mg Stearic acid 95 9.0 mg Silica, anhydrous colloidal 4.5 mg Film-coat Film-coating mixture 12.75 mg Macrogol 6000 2.25 mg 7. The phannaceutical composition as claimed in claims 1 to 6, wherein the disintegrant is added in the granulate together with the active substance and with a part of the filler material. 8. A process for the preparation of a pharmaceutical composition as claimed in claims 1 to 7, said process comprising a) dissolving the Povidone in purified water; b) charging a drier, preferably a fluid-bed drier with ibandronic acid mono-sodium salt (1 H2O), a part of the lactose monohydrate and up to 60 % by weight of the total amount of mlcrocrystalline cellulose, and Crospovidone; c) spray-granulating the raw materials of step b) at a temperature of 60 to 80 °C, preferably at about 70°C with the granulation fluid of step a), e) drying the spray granulated material of step c) at a temperature of 60 to 80 °C, preferably at about 70'C (setpoint of inlet-air temperature) and subsequently screening the dried intermediate through a fine sieve; f) mixing the granulate of step e) with the remaining amount of microcrystalline cellulose, the stearic acid and the anhydrous colloidal silica which were previously passed through a fine sieve (e.g. 1mm); g) compressing the final blend of step 1) into tablet kernels; and coating the tablet with a coating suspension using purified water and a film-coating mixture comprising hypromellose, titanium dioxide and talc and Macrogol 6000®, 9. The process as claimed in claim 7 or 8, wherein the bisphosphonate is mono sodium salt (lH20)of Ibandronic acid. 10. The process as claimed in anyone of claims 7 to 9, wherein the disintegrant is crospovidone.

Documents:

2474-chenp-2004 abstract-duplicate.pdf

2474-chenp-2004 abstract.pdf

2474-chenp-2004 claims duplicate.pdf

2474-chenp-2004 claims.pdf

2474-chenp-2004 correspondence-others.pdf

2474-chenp-2004 correspondence-po.pdf

2474-chenp-2004 description (complete).pdf

2474-chenp-2004 description(completed) duplicate.pdf

2474-chenp-2004 form-1.pdf

2474-chenp-2004 form-18.pdf

2474-chenp-2004 form-26.pdf

2474-chenp-2004 form-3.pdf

2474-chenp-2004 form-5.pdf

2474-chenp-2004 pct search report.pdf

2474-chenp-2004 pct.pdf

2474-chenp-2004 petition.pdf