Indian Patents. 257806:A TABLET CONTAINING BIPHOSPHONATES AS ACTIVE SUBSTANCE AND A PROCESS FOR THE PREPARATION OF A COMPOSITION COMPRISING THE SAME

Title of Invention	A TABLET CONTAINING BIPHOSPHONATES AS ACTIVE SUBSTANCE AND A PROCESS FOR THE PREPARATION OF A COMPOSITION COMPRISING THE SAME
Abstract	This invention relates to a high dose oral formulation of hisphosphonates and to a process for the preparation of such formulations.

Full Text	This invention relates to a pharmaceutical composition (tablet) containing biphosphonate as an active substance and process to prepare the composition. The invention further relates to a pharmaceutical composition for oral application consisting of a high dose of bisphosphonates or physiologically safe salts thereof 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, turnour 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-90/00798 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-intestinal 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. Furthermore it has been found in the Ibandronate clinical development program, that Ibandronate showed fracture reduction efficacy with a drug-free interval beyond daily administration. It was quite unexpected that fracture reduction benefit could be derived from a weekly or monthly administration of an oral bisphosphonate with a single or multiple tablet administration scheme. For this purpose a new composition comprising a high dose, namely up to 250 mg, preferably comprising 150 mg or 100 mg of a bisphosphonate derivative, especially of ibandronate or physiological safe salts thereof had to be prepared, which on the one hand has an increased ratio of active substances vs excipients and on the other hand which fulfills the requirements of stability. It has been found that the stability of such high dose formulations is substantially increased by adding the disintegrant already in the granulation step together with the active substance and with a part of the filler material. Such compositions are easily dissolvable and have an increased stability on storage both with regard to temperature and humidity. The pharmaceutical composition according to the invention comprises up to 250 mg, preferably up to 200 mg, especially comprising 150 mg or 100 mg of a bisphosphonate, especially of ibandronate or a physiological safe salt thereof as an active substance. The following bisphosphonates are active substances which can be used in the pharmaceutical compositions according to the invention in the form of free acids or physiological safe salts or hydrates, particularly sodium salts: (4-amino-l-hydroxybutylidene)bis-phosphonate (alendronate), (dichloromethylene)bis-phosphonate(clodronate), [ l-hydroxy-3-( l-pyrrolidinyl)-propylidene]bis-phosphonate (EB-1053), (l-hydroxyethylidene)bis-phosphonate (etidronate), [l-hydroxy-3-(methyl pentyl amino)propylidene]bis-phosphonate (ibandronate), [Cycloheptylamino)-methylene]bis-phosphonate(incadronate), (6-amino-l -hydroxyhexylidene)bis-phosphonate (neridronate), [3-(dimethylamino)-l-hydroxypropylidene]bis-phosphonate(olpadronate), (3-amino-l-hydroxypropylidene)bis-phosphonate (pamidronate), [l-hydroxy-2-(3-pyridinyl)ethylene]bis-phosphonate(risedronate), [[(4-chlorophenyl)thiol]-methylene]bis-phosphonate(tiludronate), [l-hydroxy-2-imidazo-(l,2-a)pyridin-3-yl ethylidene]bis-phosphona.te (YH 529), [l-hydroxy-2-(lH-imidazol-l-yl)ethylidene]bis-phosphonate (zoledronate); especially [1- hydroxy-3-(methyl pentyl amino)propylidene]bis-phosphonate (ibandronate) The said substances and their preparation arc known and described, for example, in the following references: US Patent No, 4,705,651 (Alendronate), US Patent No. 4,927,814 (Ibandronate), US Patents Nos. 3,468,935,3,400,147,3,475,486 (Etidronate), O.T. Quimby et al, J. Org. Chem, 32,4111 (1967) (Clodronate) and US Patent No. 4,505321 (Rxsedronate) and US PatentsNos. 4,134,969 and 3,962,432 (Pamidronate), US Patent No. 5,130304 (EB-1053), US Patent No. 4,970,335 (Incadronate), Belgian Patent No. 885139 (Neridronate), US Patent No. 4,054,598 (Olpadronate), US Patents Nos. 4,746,654,4,876,248 and 4,980,171 (Tiludronate), US Patent No. 4,990,503 (YH 529) and US Patent No. 4,939,130 (Zoledronate). Preferred are compositions comprising the equivalent of 150 mg bisphosphonates or physiological safe salts thereof and compositions comprising the equivalent of 100 mg bisphosphonates or physiological safe salts as active substances, respectively. Ibandxonate or a physiological safe salt thereof is a particularly preferred active substance, particularly in the form of Na-Ibandronate monohydrate. The composition further comprises adjuvants such as binders for example polyvinylpyrrolidone (e.g. Povidone®) or hydroxypropylmethyl cellulose (e.g. Pharmacoat®), tillers for example lactose in hydrate or anhydrate form, cellulose in microcrystalline or fibrous form (e.g. Avicel®), or starch, disintegrants for example cross-linked polyvinyl pyrrolidone (e.g, Crospovidone® USPNF) or cross carmelose, lubricants for example stearic acid or magnesium stearate, 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 plastiziser. Such film coating mixtures and plastizisers are known to the person skilled in the art. According to the inventions the tablet kernel consists of 30.0 to 36.0, preferably of .33,3.% of active substance', of 4.0 to 6.0, preferably of 4.8 to 5.2 % by weight of binder; of 39.6 to 59.4, preferably of 47.0 to 52.0 % by weight of filler; of 4.5 to 5.5, preferably of 4.8 to 5.2 % by weight of disintegrant; 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 %byweight of flow regulator. Preferably the active substance is ibandronate or a physiological safe salt thereof; preferably the binder is polyvinylpyrrolidone; preferred fillers are lactose in hydrate or anhydrate form, or cellulose in microcrystalline or fibrous form; and a preferred disintegrant is cross-linked polyvinyl pyrrolidone. Preferred are compositions wherein the disintegrant is added already in the granulate together with the active substance and with a part of the filler material. Furthermore, the invention relates to a process for the preparation of pharmaceutical compositions for the oral application comprising a high dose of bisphosphonates, especially of ibandronate or a physiological safe salt thereof. According to the invention the pharmaceutical composition is prepared - by wet granulation of the bisphosphonate or pharmaceutically acceptable salt thereof in the presence of adjuvants such as the binder and a part of fillers mentioned above, characterized in that the disintergrant is added into the granulation mixture; - fluidising the granulation mixture in a manner known per se; - subsequently drying the wet granulate and screening the dried granulate through a screen having a suitable mesh width; - adding the remaining adjuvants such as the fillers, lubricant and flow regulators mentioned above and blending the mixture before processing it by techniques known per se to form pharmaceutical compositions. In a preferred form of the invention the active substance, a part of the filler, and the disintegrant in dry powder form are granulated by spraying an aqueous binder solution into the powder mixture. The process is preferably carried out at a temperature of 60 to 80 °C, preferably at about 70°C. The spray granulated material is then dried preferably at a temperature of 60 to 80 °C, preferably at about 70°C and subsequently screened through a fine sieve; the dried granulate is mixed with the remaining amount of the filler, the lubricant, and the flow regulator which were previously passed through a fine sieve. The final blend is then pressed into tablet kernels which are coated with a coating suspension using purified water and a film-coating mixture. The process according to the invention is carried out as follows: a) dissolving the binder, preferably Povidone K25® in purified water; b) charging a drier, preferably a fluid-bed drier with the bisphosphonate, preferably with the mono-sodium salt (IH2O) of Ibandronic acid, a part of the filler preferably with lactose monohydrate and up to 60 % by weight of the total amount of microcrystalline cellulose, and the disintegrant; c) spray-granulating the raw materials of step b) at a temperature of (50 to 80 °C, preferably at about 70°C with the granulation fluid of step a), d) 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; e) mixing the granulate of step e) with the remaining amount of the filler e.g. micro-crystalline cellulose, the lubricant, preferably stearic acid and the flow regulator, for example anhydrous colloidal silica which were previously passed through a fine sieve (e.g. lmm); f) compressing the final blend off) into tablet kernels; and coating the tablet with a coating suspension using purified water and a film-coating mixture comprising for example hypromellose, titanium dioxide and talc (the mixture is purchased from the market e.g. Opadry® 00A28646) and Macrogol 6000®. The adjuvants are known in the art and are commercially available. The invention will now be explained in further detail with reference to examples, without being limited thereto. Example 1: the preparation of a film coated tablet containing 150 mg active substance is carried out as follows: 1. Dissolve Povidone K25® in purified water. 2. Charge a fluid-bed drier with mono-sodium salt (IH2O) of Ibandronic acid, lactose monohydrate, crospovidone and microcrystalline cellulose. Crospovidone and the microcrystalline cellulose were passed through a fine sieve (e.g. lmm) before mixing. 3. Spray-granulate the raw materials of step 2 at 70°C (set point of inlet-air temperature) with the granulation fluid of step 1. 4. Perform a final drying of the spray granulated material of step 3 at 70°C (setpoint of inlet-air temperature). 5. Screen the dried intermediate granulate through a fine sieve (e.g. 2mm perforations) and 6. where required, repeat steps 1-5 to obtain the required final batch size. 7. Mix the granulate of step 6 in a container mixer with microcrystalline cellulose, stearic acid and anhydrous colloidal silica. The microcrystalline cellulose, the stearic acid and the anhydrous colloidal silica were passed through a fine sieve (e.g. lmm) before mixing. 8. Compress the final blend of step 7 into tablet kernels using a rotary tablet press. 9. Prepare the coating suspension using purified water, film-coating mixture comprising hypromellose (60.5%), titanium dioxide (29%) and talc (10.5%);; the mixture is purchased from the market (e.g. Opadry® 00A28646) and Macrogol 6000®. 10. Spray the coating suspension of step 9 onto the tablet kernels using a coating unit. The tablet composition is as follows: Tablet kernel Ibandronic acid 150.0 mg - as mono-sodium salt (IH2O) of Ibandronic acid 168.75 mg Povidone K25® 22.5 mg Lactose, monohydrate 162.75 mg Cellulose, micro crystalline 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 this film-coating mixture contains: hypromellose (60.5%), titanium dioxide (29%) and talc (10.5%); the mixture is purchased from the market (e.g. Opadry® 00A28646) The kernel weight is 450 mg and the total tablet weight is 465 mg, the amount of active substance per tablet is equivalent to 150mg of free Ibandronic acid. Example la: for a batch of 110 000 tablets 1. A suitable vessel was charged with 14.850 kg demineralised water and 2.475 kg of Povidone K25® was added under constant stirring. The time of addition was about 15 minutes. 2. A fluid-bed dryer was charged with 18.563 kg ibandronic acid mono sodium salt, 17.903 kg of lactose monohydrate 100,4.125 kg Avicel FH-102® and 2.475 kg Crospovidone CL®. 3. The components were mixed and spray granulated at a temperature of 70°C with the aqueous solution of Povidone K25® prepared above which was added at 300 g/min with a pressure of 2.5 bar. 4. The granulate was then dried in a fluid-bed dryer at 70°C; and 5. subsequently screened (2.0 mm meshes) to yield 44.540 kg of dried granulated material. 6. 2.426 kg AVICEL PH-102®, 0.970 kg stearic acid and 0.4850 kg silicic acid AEROSIL 200® were screened and added to the dried granulated material (44.650 kg), the components were mixed; and 7. the final blend was compressed into tablets kernels, yield 103 244 kernels. 8. A coating suspension was prepared by dissolving 0.290 kg PEG 6000® (MACROGOL 6000) in 7.743 kg demineralised water and subsequently disperging 1.645 kg OPADRY 00A28646® into this solution. 9. The kernels were coated with the coating suspension under standard conditions. The tablets have the composition and the weight given in example L1 Example 2: the preparation of a film coated tablet containing 100 mg active substance was carried out as described in example 1: Tablet kernel 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, microcrystalline 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 Macrogol6000 1.80 mg *composition as mentioned example 1 The kernel weight is 300 mg and the total tablet weight is 312 mg, the amount of active substance per tablet is equivalent to lOOmg of free Ibandronic acid. WE CLAIM: 1. A tablet containing as active substance up to 250 mg of bisphosphonates or physiologically safe salts or hydrates 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 6.0 % 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 tablet 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 tablet as claimed in any one of claims 1 or 2, wherein the bisphosphonates or physiologically safe salts or hydrates used is alendronate, clodronate, EB- 1053, etidronate, ibandronate, incadronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529 or zoledronate in the form of the free acid or a pharmaceutically compatible salt or hydrate, particularly the sodium salt. 4. The tablet as claimed in claim 3, comprising the equivalent of 150 mg bisphosphonates or physiologically safe salts or hydrates as active substance. 5. The tablet as claimed in claim 3, comprising the equivalent of 100 mg bisphosphonates or physiologically safe salts or hydrates as active substance. 6. The tablet as claimed in claims 1 to 5, wherein the disintegrant is added in the granulate together with the active substance and with a part of the filler material. 7. A process for the preparation of a composition as claimed in any one of claims 1 to 6, said process comprising a) spray-granulating the bisphosphonate, a part of the filler and the disintegrant with a solution of the binder in purified water at a temperature of about 70°C; b) drying the spray granulated material at a temperature of about 70°C and subsequently screening the dried intermediate through a fine sieve; c) mixing the granulate with the remaining amount of the filler, the lubricant, and the flow regulator which were previously passed through a fine sieve; d) compressing the final blend into tablet kernels; and coating the tablet with a coating suspension using purified water and a film-coating mixture. 8. The process as claimed in claim 7, said process comprising a) dissolving the binder in purified water; b) charging a drier with the bisphosphonate, a part of the filler, and the disintegrant; c) spray-granulating the raw materials of step b) at a temperature of about 70°C with the granulation fluid of step a); e) drying the spray granulated material of step c) at a temperature of about 70°C and subsequently screening the dried intermediate through a fine sieve; f) mixing the granulate of step e) in a mixer with remaining amount of the filler, the lubricant, and the flow regulator which were previously passed through a fine sieve; g) compressing the final blend of f) into tablet kernels; and coating the tablet with a coating suspension using purified water and a film-coating mixture. 9. The process as claimed in claim 7 or 8, wherein the bisphosphonate is mono- sodium salt (1H20) of Ibandronic acid. 10. The process as claimed in any one of claims 7 to 9, wherein the disintegrant is crospovidone. 11. A tablet obtainable by the process as claimed in any one of claims 7 to 10.

Full Text

This invention relates to a pharmaceutical composition (tablet) containing biphosphonate as an active substance and process to prepare the composition.
The invention further relates to a pharmaceutical composition for oral application consisting of a high dose of bisphosphonates or physiologically safe salts thereof 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, turnour 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-90/00798 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-intestinal 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.

Furthermore it has been found in the Ibandronate clinical development program, that Ibandronate showed fracture reduction efficacy with a drug-free interval beyond daily administration. It was quite unexpected that fracture reduction benefit could be derived from a weekly or monthly administration of an oral bisphosphonate with a single or multiple tablet administration scheme.
For this purpose a new composition comprising a high dose, namely up to 250 mg, preferably comprising 150 mg or 100 mg of a bisphosphonate derivative, especially of ibandronate or physiological safe salts thereof had to be prepared, which on the one hand has an increased ratio of active substances vs excipients and on the other hand which fulfills the requirements of stability.
It has been found that the stability of such high dose formulations is substantially increased by adding the disintegrant already in the granulation step together with the active substance and with a part of the filler material. Such compositions are easily dissolvable and have an increased stability on storage both with regard to temperature and humidity.
The pharmaceutical composition according to the invention comprises up to 250 mg, preferably up to 200 mg, especially comprising 150 mg or 100 mg of a bisphosphonate, especially of ibandronate or a physiological safe salt thereof as an active substance.
The following bisphosphonates are active substances which can be used in the
pharmaceutical compositions according to the invention in the form of free acids or
physiological safe salts or hydrates, particularly sodium salts:
(4-amino-l-hydroxybutylidene)bis-phosphonate (alendronate),
(dichloromethylene)bis-phosphonate(clodronate),
[ l-hydroxy-3-( l-pyrrolidinyl)-propylidene]bis-phosphonate (EB-1053),
(l-hydroxyethylidene)bis-phosphonate (etidronate),
[l-hydroxy-3-(methyl pentyl amino)propylidene]bis-phosphonate (ibandronate),
[Cycloheptylamino)-methylene]bis-phosphonate(incadronate),
(6-amino-l -hydroxyhexylidene)bis-phosphonate (neridronate),
[3-(dimethylamino)-l-hydroxypropylidene]bis-phosphonate(olpadronate),
(3-amino-l-hydroxypropylidene)bis-phosphonate (pamidronate),
[l-hydroxy-2-(3-pyridinyl)ethylene]bis-phosphonate(risedronate),
[[(4-chlorophenyl)thiol]-methylene]bis-phosphonate(tiludronate),
[l-hydroxy-2-imidazo-(l,2-a)pyridin-3-yl ethylidene]bis-phosphona.te (YH 529),
[l-hydroxy-2-(lH-imidazol-l-yl)ethylidene]bis-phosphonate (zoledronate); especially [1-
hydroxy-3-(methyl pentyl amino)propylidene]bis-phosphonate (ibandronate)

The said substances and their preparation arc known and described, for example, in the following references:
US Patent No, 4,705,651 (Alendronate), US Patent No. 4,927,814 (Ibandronate), US Patents Nos. 3,468,935,3,400,147,3,475,486 (Etidronate), O.T. Quimby et al, J. Org. Chem, 32,4111 (1967) (Clodronate) and US Patent No. 4,505321 (Rxsedronate) and US PatentsNos. 4,134,969 and 3,962,432 (Pamidronate), US Patent No. 5,130304 (EB-1053), US Patent No. 4,970,335 (Incadronate), Belgian Patent No. 885139 (Neridronate), US Patent No. 4,054,598 (Olpadronate), US Patents Nos. 4,746,654,4,876,248 and 4,980,171 (Tiludronate), US Patent No. 4,990,503 (YH 529) and US Patent No. 4,939,130 (Zoledronate).
Preferred are compositions comprising the equivalent of 150 mg bisphosphonates or physiological safe salts thereof and compositions comprising the equivalent of 100 mg bisphosphonates or physiological safe salts as active substances, respectively. Ibandxonate or a physiological safe salt thereof is a particularly preferred active substance, particularly in the form of Na-Ibandronate monohydrate.
The composition further comprises adjuvants such as binders for example polyvinylpyrrolidone (e.g. Povidone®) or hydroxypropylmethyl cellulose (e.g. Pharmacoat®), tillers for example lactose in hydrate or anhydrate form, cellulose in microcrystalline or fibrous form (e.g. Avicel®), or starch, disintegrants for example cross-linked polyvinyl pyrrolidone (e.g, Crospovidone® USPNF) or cross carmelose, lubricants for example stearic acid or magnesium stearate, 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 plastiziser. Such film coating mixtures and plastizisers are known to the person skilled in the art.
According to the inventions the tablet kernel consists of 30.0 to 36.0, preferably of .33,3.% of active substance', of 4.0 to 6.0, preferably of 4.8 to 5.2 % by weight of binder; of 39.6 to 59.4, preferably of 47.0 to 52.0 % by weight of filler; of 4.5 to 5.5, preferably of 4.8 to 5.2 % by weight of disintegrant; 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 %byweight of flow regulator.
Preferably the active substance is ibandronate or a physiological safe salt thereof; preferably the binder is polyvinylpyrrolidone; preferred fillers are lactose in hydrate or anhydrate form, or cellulose in microcrystalline or fibrous form; and a preferred disintegrant is cross-linked polyvinyl pyrrolidone. Preferred are compositions wherein the disintegrant is added

already in the granulate together with the active substance and with a part of the filler material.
Furthermore, the invention relates to a process for the preparation of pharmaceutical compositions for the oral application comprising a high dose of bisphosphonates, especially of ibandronate or a physiological safe salt thereof. According to the invention the pharmaceutical composition is prepared
- by wet granulation of the bisphosphonate or pharmaceutically acceptable salt thereof in the presence of adjuvants such as the binder and a part of fillers mentioned above, characterized in that the disintergrant is added into the granulation mixture;
- fluidising the granulation mixture in a manner known per se;
- subsequently drying the wet granulate and screening the dried granulate through a screen having a suitable mesh width;
- adding the remaining adjuvants such as the fillers, lubricant and flow regulators mentioned above and blending the mixture before processing it by techniques known per se to form pharmaceutical compositions.
In a preferred form of the invention the active substance, a part of the filler, and the disintegrant in dry powder form are granulated by spraying an aqueous binder solution into the powder mixture. The process is preferably carried out at a temperature of 60 to 80 °C, preferably at about 70°C.
The spray granulated material is then dried preferably at a temperature of 60 to 80 °C, preferably at about 70°C and subsequently screened through a fine sieve; the dried granulate is mixed with the remaining amount of the filler, the lubricant, and the flow regulator which were previously passed through a fine sieve. The final blend is then pressed into tablet kernels which are coated with a coating suspension using purified water and a film-coating mixture.
The process according to the invention is carried out as follows:
a) dissolving the binder, preferably Povidone K25® in purified water;
b) charging a drier, preferably a fluid-bed drier with the bisphosphonate, preferably with the mono-sodium salt (IH2O) of Ibandronic acid, a part of the filler preferably with lactose monohydrate and up to 60 % by weight of the total amount of microcrystalline cellulose, and the disintegrant;
c) spray-granulating the raw materials of step b) at a temperature of (50 to 80 °C, preferably at about 70°C with the granulation fluid of step a),

d) 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;
e) mixing the granulate of step e) with the remaining amount of the filler e.g. micro-crystalline cellulose, the lubricant, preferably stearic acid and the flow regulator, for example anhydrous colloidal silica which were previously passed through a fine sieve (e.g. lmm);
f) compressing the final blend off) into tablet kernels; and coating the tablet with a coating suspension using purified water and a film-coating mixture comprising for example hypromellose, titanium dioxide and talc (the mixture is purchased from the
market e.g. Opadry® 00A28646) and Macrogol 6000®.
The adjuvants are known in the art and are commercially available.
The invention will now be explained in further detail with reference to examples, without being limited thereto.
Example 1:
the preparation of a film coated tablet containing 150 mg active substance is carried out as
follows:
1. Dissolve Povidone K25® in purified water.
2. Charge a fluid-bed drier with mono-sodium salt (IH2O) of Ibandronic acid, lactose monohydrate, crospovidone and microcrystalline cellulose. Crospovidone and the microcrystalline cellulose were passed through a fine sieve (e.g. lmm) before mixing.
3. Spray-granulate the raw materials of step 2 at 70°C (set point of inlet-air temperature) with the granulation fluid of step 1.
4. Perform a final drying of the spray granulated material of step 3 at 70°C (setpoint of inlet-air temperature).
5. Screen the dried intermediate granulate through a fine sieve (e.g. 2mm perforations) and
6. where required, repeat steps 1-5 to obtain the required final batch size.
7. Mix the granulate of step 6 in a container mixer with microcrystalline cellulose, stearic acid and anhydrous colloidal silica. The microcrystalline cellulose, the stearic acid and the anhydrous colloidal silica were passed through a fine sieve (e.g. lmm) before mixing.

8. Compress the final blend of step 7 into tablet kernels using a rotary tablet press.
9. Prepare the coating suspension using purified water, film-coating mixture comprising hypromellose (60.5%), titanium dioxide (29%) and talc (10.5%);; the mixture is purchased from the market (e.g. Opadry® 00A28646) and Macrogol 6000®.
10. Spray the coating suspension of step 9 onto the tablet kernels using a coating unit.
The tablet composition is as follows:
Tablet kernel
Ibandronic acid 150.0 mg
- as mono-sodium salt (IH2O) of Ibandronic acid 168.75 mg
Povidone K25® 22.5 mg
Lactose, monohydrate 162.75 mg
Cellulose, micro crystalline 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
*this film-coating mixture contains: hypromellose (60.5%), titanium dioxide (29%) and talc (10.5%); the mixture is purchased from the market (e.g. Opadry® 00A28646)
The kernel weight is 450 mg and the total tablet weight is 465 mg, the amount of active substance per tablet is equivalent to 150mg of free Ibandronic acid.
Example la: for a batch of 110 000 tablets
1. A suitable vessel was charged with 14.850 kg demineralised water and 2.475 kg of Povidone K25® was added under constant stirring. The time of addition was about 15 minutes.
2. A fluid-bed dryer was charged with 18.563 kg ibandronic acid mono sodium salt, 17.903 kg of lactose monohydrate 100,4.125 kg Avicel FH-102® and 2.475 kg Crospovidone CL®.
3. The components were mixed and spray granulated at a temperature of 70°C with the aqueous solution of Povidone K25® prepared above which was added at 300 g/min with a pressure of 2.5 bar.

4. The granulate was then dried in a fluid-bed dryer at 70°C; and
5. subsequently screened (2.0 mm meshes) to yield 44.540 kg of dried granulated material.
6. 2.426 kg AVICEL PH-102®, 0.970 kg stearic acid and 0.4850 kg silicic acid AEROSIL 200® were screened and added to the dried granulated material (44.650 kg), the components were mixed; and
7. the final blend was compressed into tablets kernels, yield 103 244 kernels.
8. A coating suspension was prepared by dissolving 0.290 kg PEG 6000® (MACROGOL 6000) in 7.743 kg demineralised water and subsequently disperging 1.645 kg OPADRY 00A28646® into this solution.
9. The kernels were coated with the coating suspension under standard conditions. The tablets have the composition and the weight given in example L1
Example 2:
the preparation of a film coated tablet containing 100 mg active substance was carried out
as described in example 1:
Tablet kernel
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, microcrystalline 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
Macrogol6000 1.80 mg
*composition as mentioned example 1
The kernel weight is 300 mg and the total tablet weight is 312 mg, the amount of active substance per tablet is equivalent to lOOmg of free Ibandronic acid.

WE CLAIM:
1. A tablet containing as active substance up to 250 mg of bisphosphonates or
physiologically safe salts or hydrates 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 6.0 % 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 tablet 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 tablet as claimed in any one of claims 1 or 2, wherein the bisphosphonates
or physiologically safe salts or hydrates used is alendronate, clodronate, EB-
1053, etidronate, ibandronate, incadronate, neridronate, olpadronate,
pamidronate, risedronate, tiludronate, YH 529 or zoledronate in the form of the
free acid or a pharmaceutically compatible salt or hydrate, particularly the
sodium salt.

4. The tablet as claimed in claim 3, comprising the equivalent of 150 mg bisphosphonates or physiologically safe salts or hydrates as active substance.
5. The tablet as claimed in claim 3, comprising the equivalent of 100 mg bisphosphonates or physiologically safe salts or hydrates as active substance.
6. The tablet as claimed in claims 1 to 5, wherein the disintegrant is added in the granulate together with the active substance and with a part of the filler material.
7. A process for the preparation of a composition as claimed in any one of claims 1 to 6, said process comprising

a) spray-granulating the bisphosphonate, a part of the filler and the disintegrant with a solution of the binder in purified water at a temperature of about 70°C;
b) drying the spray granulated material at a temperature of about 70°C and subsequently screening the dried intermediate through a fine sieve;
c) mixing the granulate with the remaining amount of the filler, the lubricant, and the flow regulator which were previously passed through a fine sieve;
d) compressing the final blend into tablet kernels; and coating the tablet with a coating suspension using purified water and a film-coating mixture.
8. The process as claimed in claim 7, said process comprising
a) dissolving the binder in purified water;

b) charging a drier with the bisphosphonate, a part of the filler, and the
disintegrant;
c) spray-granulating the raw materials of step b) at a temperature of about
70°C with the granulation fluid of step a);
e) drying the spray granulated material of step c) at a temperature of about
70°C and subsequently screening the dried intermediate through a fine
sieve;
f) mixing the granulate of step e) in a mixer with remaining amount of the
filler, the lubricant, and the flow regulator which were previously passed
through a fine sieve;
g) compressing the final blend of f) into tablet kernels; and coating the
tablet with a coating suspension using purified water and a film-coating
mixture.
9. The process as claimed in claim 7 or 8, wherein the bisphosphonate is mono-
sodium salt (1H20) of Ibandronic acid.
10. The process as claimed in any one of claims 7 to 9, wherein the disintegrant is
crospovidone.
11. A tablet obtainable by the process as claimed in any one of claims 7 to 10.

Documents:

2895-CHENP-2007 AMENDED CLAIMS 28-10-2013.pdf

2895-CHENP-2007 CORRESPONDENCE .OTHERS 05-09-2013.pdf

2895-CHENP-2007 CORRESPONDENCE OTHERS 28-10-2013.pdf

2895-CHENP-2007 CORRESPONDENCE OTHERS 05-09-2013.pdf

2895-CHENP-2007 CORRESPONDENCE OTHERS 19-09-2013.pdf

2895-CHENP-2007 CORRESPONDENCE OTHERS 16-08-2013.pdf

2895-chenp-2007-abstract.pdf

2895-chenp-2007-claims.pdf

2895-chenp-2007-correspondnece-others.pdf

2895-chenp-2007-description(complete).pdf

2895-chenp-2007-form 1.pdf

2895-chenp-2007-form 26.pdf

2895-chenp-2007-form 3.pdf

2895-chenp-2007-form 5.pdf

2895-chenp-2007-pct.pdf

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Patent Number

257806

Indian Patent Application Number

2895/CHENP/2007

PG Journal Number

45/2013

Publication Date

08-Nov-2013

Grant Date

06-Nov-2013

Date of Filing

29-Jun-2007

Name of Patentee

F. HOFFMANN-LA ROCHE AG

Applicant Address

124 GRENZACHERSTRASSE CH-4070 BASEL

Inventors:

#	Inventor's Name	Inventor's Address
1	KAESTLE, HANS, G	IM GRUEN 6 D-79426 BUGGINGEN
2	MEYER, BERNARD	11 RUE DU JURA F-68440 DIETWILLER

PCT International Classification Number

A61K31/663

PCT International Application Number

PCT/EP03/08732

PCT International Filing date

2003-08-07

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	02028745.4	2002-12-20	EUROPEAN UNION