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WO2006018033A1 - Formulations of bisphosphonates - Google Patents

Formulations of bisphosphonates Download PDF

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Publication number
WO2006018033A1
WO2006018033A1 PCT/EP2004/009347 EP2004009347W WO2006018033A1 WO 2006018033 A1 WO2006018033 A1 WO 2006018033A1 EP 2004009347 W EP2004009347 W EP 2004009347W WO 2006018033 A1 WO2006018033 A1 WO 2006018033A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
tablet
weight
excipients
composition according
Prior art date
Application number
PCT/EP2004/009347
Other languages
French (fr)
Inventor
Max Werner Scheiwe
Charu Kochhar
Timo Schmidt
Original Assignee
Mepha Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mepha Ag filed Critical Mepha Ag
Priority to EP04764331A priority Critical patent/EP1781258A1/en
Priority to PCT/EP2004/009347 priority patent/WO2006018033A1/en
Publication of WO2006018033A1 publication Critical patent/WO2006018033A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present invention relates to a pharmaceutical composition, in particular tablets comprising such composition and to a process for the preparation of such a composition.
  • lactose as an inert diluent
  • allergic reactions of patients taking such tablets are widespread. Therefore, there is a need for tablets without lactose in the composition.
  • the tablets are needed to be easily swallowable to improve the patient compliance (due to small size of the tablet, owing to the high concentration of the active ingredient). Furthermore, there is a need that the tablets do not harm the oesophagus.
  • the present invention offers a solution to the mentioned needs and provides a pharmaceutical composition
  • a pharmaceutical composition comprising from 40 to 70 % by weight of bisphosphonic acid or a pharmaceutically acceptable salt thereof and from 30 to 60 % by weight of excipients, said excipients comprising a diluent selected from the group consisting of cellulose derivatives, starch and inorganic phosphates.
  • compositions Due to the absence of lactose, such pharmaceutical compositions can also be administered to persons who are allergic to lactose. Their manufacture is also easier as no anhydrous lactose is required. Such compositions can be handled easier and have a better storage stability. Owing to high concentration of active ingredient, these compositions are well suited for the production of smaller tablets with the advantage mentioned above.
  • the tablets prepared with such compositions can be film coated in order to render them less irritating to the oesophagus. By the use of direct tabletting, compaction, or slugging techniques for the preparation of tablets on the basis of such pharmaceutical compositions, the optimal distribution of active ingredient is ensured.
  • the inert diluent used as the main excipient in the pharmaceutical compositions according to the invention can be a cellulose derivative, such as cellullose, powdered cellulose, or microcrystalline cellulose; or starch, such as maize starch, potato starch, or pregelatinised starch; or an inorganic phosphate, such as calcium hydrogenphosphate or dibasic calcium phosphate.
  • Preferred materials are microcrystalline cellulose, pregelatinised starch or calcium hydrogenphosphate. These materials are used in a concentration from 25 to 45 % by weight, based on the total composition.
  • the pharmaceutical compositions according to the invention may contain the usual excipients for the formulation of tablets like a dry binder, a disintegrant, a lubricant and a flow regulating agent.
  • cellulose derivatives starch, or inorganic phosphates can be used.
  • Preferred materials are microcrystalline cellulose, powdered cellulose, pregelatinised starch, maize starch, calcium phosphate and calcium hydrogenphosphate.
  • cellulose derivatives such as cross-linked carboxymethyicellulose sodium, (croscarmellose sodium), hydroxypropylcellulose; starch derivatives such as sodium starch glycolate, pregelatinised starch or crosslinked polyvinylpyrollidone derivatives such as crospovidone can be used.
  • the preferred material is cross-linked carboxymethyicellulose sodium.
  • all fumarat ⁇ s e. g. sodium fumarate, sodium stearyl fumarate
  • all stearates e. g. calcium stearate, magnesium stearate, stearic acid
  • talcum e.g. calcium stearate, magnesium stearate, stearic acid
  • the preferred material is magnesium stearate.
  • talcum or silicates can be used as a flow regulating agent.
  • the bisphosponic acids employed as the active ingredient in the present invention are as described for example in US Patent 5,583,122, US Patent 4,922,007 and US Patent 5,019,651 which are incorporated herein by reference.They can be for example alendronic acid, pamidronic acid or risedronic acid, preferably alendronic acid.
  • the term "risedronate” denotes the bisphosphonate compound 3-pyridyl-1-hydroxyethylidene-1 ,1- bisphosphonic acid. It is described in US Patent 5,583,122.
  • the term “alendronate” denotes the bisphosphonate compound 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid as described in US Patents 4,922,007 and 5,019,651.
  • the term "alendronate active ingredient” includes alendronate, alendronate salts and alendronate esters, or any mixture thereof. Any pharmaceutically acceptable, non-toxic salt or ester of alendronate may be used as the alendronate active ingredient in the present invention.
  • the salts of alendronate may be acid addition salts, in particular the hydrochloride, but any pharmaceutically acceptable, non-toxic organic or inorganic salt may be used.
  • salts formed with the phosphonic acid group may be used, including, but not limited to alkali metal salts (K, Na) and alkaline earth metal salts (Ca, Mg), the Ca and Na salts being preferred.
  • esters which are suitable for use as the alendronate active ingredient are straight chain or branched chain CrC 18 alkyl esters like methyl, ethyl, propyl, isopropyl, butyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl and stearyl esters, straight chain or branched C 2 -C 18 alkenyl esters like vinyl, undecenyl and linolenyl esters, C 3 -C 8 cycloalkyl esters like cyclopropyl, cyclobutyl, cyclopenlyl, cyclohexyl, cycloheptyl and cyclooclyl esters, aryl esters like phenyl, toluyl, xylyl and naphthyl esters, alicyclic esters like menthyl esters and
  • the preferred alendronate active ingredient is a pharmaceutically acceptable salt, and especially preferred its monosodium salt trihydrate.
  • An important feature of the present invention is the high concentration of active ingredient in the pharmaceutical composition used for the formulation of tablets. This concentration is from 40 to 70 % by weight of the total composition and preferably is from 40 to 55 % by weight.
  • tablette is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes, whether coated or uncoated.
  • Substances which may be used as coating agents include hydroxypropylmethylcellulose, hydroxypropylethylcellulose, methylcellulose, ethylcellulose; opacifiers such as titanium dioxide, glidants such as talcum, artificial sweeteners such as cyclamate and colorants.
  • the said film coating is preferably applied to a compressed tablet which contains particles or granules of active ingredient; however, in the event the particles or granules are themselves film coated before being compressed into a tablet, then the film coating of the compressed tablet itself is optional.
  • these tablets will avoid the undesirable delivery of the active ingredient to the mucosal and epithelial tissues of the upper gastrointestinal tract, especially the mouth, pharynx and esophagus.
  • Said coating also achieves the delivery of the active ingredient to the stomach which can be regulated by choosing the nature of the coating polymers, its type and/or its thickness.
  • Preferred polymers for film coating are soluble at about pH 1.2 - 5.
  • Particularly preferred polymers are selected from the group consisting of hydroxypropylmethylcellulose (HPMC) alone and/or in combination, carboxymethylcellulose, methylcellulose, ethylcellulose, acrylic resins, polyvinyl- pyrrolidone, polyvinyl alcohol and gelatin or other commercially available film coating preparations such as Dri-Klear, manufactured by Grompton & Knowles Corp., or Opadry, manufactured by Colorcon.
  • HP(ViC and polyvinyl alcohol are particularly preferred.
  • the lower viscosity grades of HPlViC, E-5 and E-15 are the preferred ones and the most preferred is the E-5 grade.
  • the amount of coating deposited on the tablet is usually in the range of from about 2% to about 5% weight gain with a preferred weight gain of about 3%.
  • the coating can, and usually will, contain a plasticizer.
  • the preferred plastici ⁇ ers are polyethylene glycol and polypropylene glycol, the former being the most preferred.
  • the amount of plasticizer required depends upon the nature and type of the polymer used for coating.
  • the preferred amount of plasticizer is from about 5% to about 40% with respect to the film-forming polymer, with the most preferred level of about 20%.
  • Dyes or pigments may also be added to provide the required opacity and color to the film coating.
  • the preferred level of the pigment is from about 10% to about 40% with respect to the film-forming polymer, with the most preferred level of from about 20% to about 30%.
  • Other additives may be added to minimize foam or to facilitate spraying of the solution on the tablets, preferably with hydroxypropylmethylcellulose or polyvinylalcohol.
  • the active ingredient, the diluent or the dry binder, the flow regulating agent and the disintegrant are mixed, the lubricant is added and, after mixing again, the mixture is compacted. After adding further disintegrant and lubricant (Pos. 5 and 6), and further mixing, the whole mass is compressed to tablets.
  • the polymer and the plasticizer are dissolved in a part of the water, the talcum and titanium dioxide added to the rest of water and homogenised. This mixture is added to the solution of polymer and plasticizer and stirred. Finally, the tablets are coated with this coating formulation.
  • the following examples 2 to / are made by direct tabletting of the complete mixture for the tablet core as described in example 1.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to a pharmaceutical composition comprising from 40 to 70 % by weight of bisphosphonic acid or a pharmaceutically acceptable salt thereof and from 30 to 60 % by weight of excipients, said excipients comprising a diluent selected from the group consisting of cellulose derivatives, starch and inorganic phosphates as well as to a tablet formed with such composition and a process for the formulation of such tablet.

Description

FORMULATIONS OF BISPHOSPHONATES
The present invention relates to a pharmaceutical composition, in particular tablets comprising such composition and to a process for the preparation of such a composition.
The pharmaceutical industry employs various methods for manufacturing pharmaceutical agents in tablet formulations. A variety of bisphosphonic acids have been disclosed as being useful in the treatment and prevention of diseases involving bone resorption. Standard methods for tablet formulation of bisphosphonic acids, however, suffer serious difficulties and many proposals have been made to meet such difficulties. In EP 690719 e.g. it has been proposed to prepare pharmaceutical compositions of bisphosphonic acids using anhydrous lactose as the diluent excipient by direct compression (dry mix) tablet formulation in order to avoid interaction between the bisphosphonic acids and the moisture present in lactose.
Although the use of lactose as an inert diluent is generally desirable for tablet formulations, allergic reactions of patients taking such tablets are widespread. Therefore, there is a need for tablets without lactose in the composition. The tablets are needed to be easily swallowable to improve the patient compliance (due to small size of the tablet, owing to the high concentration of the active ingredient). Furthermore, there is a need that the tablets do not harm the oesophagus.
The present invention offers a solution to the mentioned needs and provides a pharmaceutical composition comprising from 40 to 70 % by weight of bisphosphonic acid or a pharmaceutically acceptable salt thereof and from 30 to 60 % by weight of excipients, said excipients comprising a diluent selected from the group consisting of cellulose derivatives, starch and inorganic phosphates.
Due to the absence of lactose, such pharmaceutical compositions can also be administered to persons who are allergic to lactose. Their manufacture is also easier as no anhydrous lactose is required. Such compositions can be handled easier and have a better storage stability. Owing to high concentration of active ingredient, these compositions are well suited for the production of smaller tablets with the advantage mentioned above. The tablets prepared with such compositions can be film coated in order to render them less irritating to the oesophagus. By the use of direct tabletting, compaction, or slugging techniques for the preparation of tablets on the basis of such pharmaceutical compositions, the optimal distribution of active ingredient is ensured.
As indicated above, the inert diluent used as the main excipient in the pharmaceutical compositions according to the invention can be a cellulose derivative, such as cellullose, powdered cellulose, or microcrystalline cellulose; or starch, such as maize starch, potato starch, or pregelatinised starch; or an inorganic phosphate, such as calcium hydrogenphosphate or dibasic calcium phosphate. Preferred materials are microcrystalline cellulose, pregelatinised starch or calcium hydrogenphosphate. These materials are used in a concentration from 25 to 45 % by weight, based on the total composition.
Besides the mentioned inert diluent, the pharmaceutical compositions according to the invention may contain the usual excipients for the formulation of tablets like a dry binder, a disintegrant, a lubricant and a flow regulating agent.
As dry binder all cellulose derivatives, starch, or inorganic phosphates can be used. Preferred materials are microcrystalline cellulose, powdered cellulose, pregelatinised starch, maize starch, calcium phosphate and calcium hydrogenphosphate.
As a disintegrant, cellulose derivatives, such as cross-linked carboxymethyicellulose sodium, (croscarmellose sodium), hydroxypropylcellulose; starch derivatives such as sodium starch glycolate, pregelatinised starch or crosslinked polyvinylpyrollidone derivatives such as crospovidone can be used. The preferred material is cross-linked carboxymethyicellulose sodium.
As a lubricant, all fumaratβs (e. g. sodium fumarate, sodium stearyl fumarate), all stearates (e. g. calcium stearate, magnesium stearate, stearic acid), or talcum can be used. The preferred material is magnesium stearate.
As a flow regulating agent, talcum or silicates can be used. Preferred are silicium dioxide compounds.
The bisphosponic acids employed as the active ingredient in the present invention are as described for example in US Patent 5,583,122, US Patent 4,922,007 and US Patent 5,019,651 which are incorporated herein by reference.They can be for example alendronic acid, pamidronic acid or risedronic acid, preferably alendronic acid.
The term "risedronate" denotes the bisphosphonate compound 3-pyridyl-1-hydroxyethylidene-1 ,1- bisphosphonic acid. It is described in US Patent 5,583,122. The term "alendronate" denotes the bisphosphonate compound 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid as described in US Patents 4,922,007 and 5,019,651. The term "alendronate active ingredient" includes alendronate, alendronate salts and alendronate esters, or any mixture thereof. Any pharmaceutically acceptable, non-toxic salt or ester of alendronate may be used as the alendronate active ingredient in the present invention. The salts of alendronate may be acid addition salts, in particular the hydrochloride, but any pharmaceutically acceptable, non-toxic organic or inorganic salt may be used. In addition, salts formed with the phosphonic acid group may be used, including, but not limited to alkali metal salts (K, Na) and alkaline earth metal salts (Ca, Mg), the Ca and Na salts being preferred. Among the esters which are suitable for use as the alendronate active ingredient are straight chain or branched chain CrC18 alkyl esters like methyl, ethyl, propyl, isopropyl, butyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl and stearyl esters, straight chain or branched C2-C18 alkenyl esters like vinyl, undecenyl and linolenyl esters, C3-C8 cycloalkyl esters like cyclopropyl, cyclobutyl, cyclopenlyl, cyclohexyl, cycloheptyl and cyclooclyl esters, aryl esters like phenyl, toluyl, xylyl and naphthyl esters, alicyclic esters like menthyl esters and aralkyl esters like benzyl and phenethyl esters.
The preferred alendronate active ingredient is a pharmaceutically acceptable salt, and especially preferred its monosodium salt trihydrate.
An important feature of the present invention is the high concentration of active ingredient in the pharmaceutical composition used for the formulation of tablets. This concentration is from 40 to 70 % by weight of the total composition and preferably is from 40 to 55 % by weight.
The term "tablet" is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes, whether coated or uncoated. Substances which may be used as coating agents include hydroxypropylmethylcellulose, hydroxypropylethylcellulose, methylcellulose, ethylcellulose; opacifiers such as titanium dioxide, glidants such as talcum, artificial sweeteners such as cyclamate and colorants.
For the preparation of tablets on the basis of the pharmaceutical compositions according to the invention, different methods can be used like direct tabletting, or compaction (dry granulation), or slugging. In general, the active ingredient is mixed with a part of the excipients, this mixture is compacted and the obtained dry granulate is sieved. This granulate is mixed with the other excipients and compressed to a tablet. Optionally, such a tablet is then filmcoated with the known coating agents of the prior art.
The said film coating is preferably applied to a compressed tablet which contains particles or granules of active ingredient; however, in the event the particles or granules are themselves film coated before being compressed into a tablet, then the film coating of the compressed tablet itself is optional.
Because of their fim coating, these tablets will avoid the undesirable delivery of the active ingredient to the mucosal and epithelial tissues of the upper gastrointestinal tract, especially the mouth, pharynx and esophagus. Said coating also achieves the delivery of the active ingredient to the stomach which can be regulated by choosing the nature of the coating polymers, its type and/or its thickness.
Preferred polymers for film coating are soluble at about pH 1.2 - 5. Particularly preferred polymers are selected from the group consisting of hydroxypropylmethylcellulose (HPMC) alone and/or in combination, carboxymethylcellulose, methylcellulose, ethylcellulose, acrylic resins, polyvinyl- pyrrolidone, polyvinyl alcohol and gelatin or other commercially available film coating preparations such as Dri-Klear, manufactured by Grompton & Knowles Corp., or Opadry, manufactured by Colorcon. Particularly preferred are HP(ViC and polyvinyl alcohol. The lower viscosity grades of HPlViC, E-5 and E-15 are the preferred ones and the most preferred is the E-5 grade.
The amount of coating deposited on the tablet is usually in the range of from about 2% to about 5% weight gain with a preferred weight gain of about 3%. The coating can, and usually will, contain a plasticizer. The preferred plastici∑ers are polyethylene glycol and polypropylene glycol, the former being the most preferred. The amount of plasticizer required depends upon the nature and type of the polymer used for coating. The preferred amount of plasticizer is from about 5% to about 40% with respect to the film-forming polymer, with the most preferred level of about 20%. Dyes or pigments may also be added to provide the required opacity and color to the film coating. The preferred level of the pigment is from about 10% to about 40% with respect to the film-forming polymer, with the most preferred level of from about 20% to about 30%. Other additives may be added to minimize foam or to facilitate spraying of the solution on the tablets, preferably with hydroxypropylmethylcellulose or polyvinylalcohol.
The invention can be illustrated by but is not limited to the following examples.
Example i
Figure imgf000006_0001
**: volatile portion
The preparation of these tablets is performed as follows:
The active ingredient, the diluent or the dry binder, the flow regulating agent and the disintegrant are mixed, the lubricant is added and, after mixing again, the mixture is compacted. After adding further disintegrant and lubricant (Pos. 5 and 6), and further mixing, the whole mass is compressed to tablets. The polymer and the plasticizer are dissolved in a part of the water, the talcum and titanium dioxide added to the rest of water and homogenised. This mixture is added to the solution of polymer and plasticizer and stirred. Finally, the tablets are coated with this coating formulation. The following examples 2 to / are made by direct tabletting of the complete mixture for the tablet core as described in example 1.
Example 2
Figure imgf000007_0001
Example 3
Figure imgf000008_0001
E∑iarnple 4
Figure imgf000009_0001
**Volatile portion
Example S
Figure imgf000010_0001
Example 6
Figure imgf000011_0001
*: volatile portion Example '
Figure imgf000012_0001

Claims

- ι_ -Claims
1. A pharmaceutical composition comprising from 40 to 70 % by weight of bisphosphonic acid or a pharmaceutically acceptable salt thereof and from 30 to 60 % by weight of excipients, said excipients comprising a diluent selected from the group consisting of cellulose derivatives, starch and inorganic phosphates.
2. A pharmaceutical composition according to claim 1 comprising a dry binder, a disinlegrant, a lubricant and a flow regulating agent as further excipients.
3. A pharmaceutical composition according to claim 1 comprising a cellulose derivative, croscarmellose sodium, magnesium stearate and a silicate as excipients.
4. A pharmaceutical composition according to claim 1 comprising from 25 to 45 % by weight of diluent.
5. A pharmaceutical composition according to claim 1 comprising from 40 to 55 % by weight of active ingredient.
6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the active ingredient is the monosodium salt trihydrate of bisphosphonic acid, preferably monosodium salt trihydrate of alendronic acid.
7. A tablet prepared from the pharmaceutical composition of any one of claims 1 to 6.
8. A process for the preparation of a tablet according to claim 7, which process comprises direct compression, compaction or slugging.
9. A tablet according to claim 7 which is fimcoated.
10. A process according to claim 8 comprising coating of the obtained tablet by a film of hydroxypropylmethylcellulose (HPMC) or polyvinyl alcohol.
PCT/EP2004/009347 2004-08-20 2004-08-20 Formulations of bisphosphonates WO2006018033A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP04764331A EP1781258A1 (en) 2004-08-20 2004-08-20 Formulations of bisphosphonates
PCT/EP2004/009347 WO2006018033A1 (en) 2004-08-20 2004-08-20 Formulations of bisphosphonates

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
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Publications (1)

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WO2006018033A1 true WO2006018033A1 (en) 2006-02-23

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008023184A3 (en) * 2006-08-24 2008-04-24 Arrow Int Ltd Solid dosage form
WO2009018834A1 (en) * 2007-08-06 2009-02-12 Pharmathen S.A. Pharmaceutical composition containing bisphosphonate and method for the preparation thereof
US8399023B2 (en) 2009-07-31 2013-03-19 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9169279B2 (en) 2009-07-31 2015-10-27 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9340565B2 (en) 2010-11-24 2016-05-17 Thar Pharmaceuticals, Inc. Crystalline forms
US10093691B2 (en) 2009-07-31 2018-10-09 Grunenthal Gmbh Crystallization method and bioavailability
US10195218B2 (en) 2016-05-31 2019-02-05 Grunenthal Gmbh Crystallization method and bioavailability

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5096717A (en) * 1989-09-07 1992-03-17 Ciba-Geigy Corporation Double-coated granules of disodium pamidronate
US5488041A (en) * 1993-04-05 1996-01-30 Sanofi Method of promoting bone repair using tiludronic disodium salt
WO2002003963A1 (en) * 2000-07-11 2002-01-17 Léciva A.S. Tablet obtained by direct compression comprising 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid as active ingredient
WO2004075828A2 (en) * 2003-02-27 2004-09-10 Lek Pharmaceuticals D. D. Pharmaceutical composition of alendronic acid, salts or esters thereof, and a process for its preparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5096717A (en) * 1989-09-07 1992-03-17 Ciba-Geigy Corporation Double-coated granules of disodium pamidronate
US5488041A (en) * 1993-04-05 1996-01-30 Sanofi Method of promoting bone repair using tiludronic disodium salt
WO2002003963A1 (en) * 2000-07-11 2002-01-17 Léciva A.S. Tablet obtained by direct compression comprising 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid as active ingredient
WO2004075828A2 (en) * 2003-02-27 2004-09-10 Lek Pharmaceuticals D. D. Pharmaceutical composition of alendronic acid, salts or esters thereof, and a process for its preparation

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008023184A3 (en) * 2006-08-24 2008-04-24 Arrow Int Ltd Solid dosage form
US10420725B2 (en) 2006-08-24 2019-09-24 Allergan Pharmaceuticals International Limited Solid dosage form of coated bisphosphonate particles
US8697124B2 (en) 2006-08-24 2014-04-15 Arrow International Limited Solid dosage form of coated bisphosphonate particles
WO2009018834A1 (en) * 2007-08-06 2009-02-12 Pharmathen S.A. Pharmaceutical composition containing bisphosphonate and method for the preparation thereof
US9334296B2 (en) 2009-07-31 2016-05-10 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9169279B2 (en) 2009-07-31 2015-10-27 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US8933057B2 (en) 2009-07-31 2015-01-13 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US10093691B2 (en) 2009-07-31 2018-10-09 Grunenthal Gmbh Crystallization method and bioavailability
US10323052B2 (en) 2009-07-31 2019-06-18 Grunenthal Gmbh Crystallization method and bioavailability
US8399023B2 (en) 2009-07-31 2013-03-19 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9340565B2 (en) 2010-11-24 2016-05-17 Thar Pharmaceuticals, Inc. Crystalline forms
US10519176B2 (en) 2010-11-24 2019-12-31 Thar Pharma, Llc Crystalline forms
US10195218B2 (en) 2016-05-31 2019-02-05 Grunenthal Gmbh Crystallization method and bioavailability

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