WO2007031785A2 - Bisphosphonate formulation - Google Patents
Bisphosphonate formulation Download PDFInfo
- Publication number
- WO2007031785A2 WO2007031785A2 PCT/GB2006/003457 GB2006003457W WO2007031785A2 WO 2007031785 A2 WO2007031785 A2 WO 2007031785A2 GB 2006003457 W GB2006003457 W GB 2006003457W WO 2007031785 A2 WO2007031785 A2 WO 2007031785A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formulation
- antifoaming agent
- amount
- bisphosphonate
- calcium
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A61K9/2036—Silicones; Polysiloxanes
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Definitions
- the present invention relates to fo ⁇ nulations comprising bisphosphonates and their use in treatment of various conditions, especially such formulations for treatment of osteoporosis.
- Osteoporosis is a disease of bone in which the amount of bone is decreased and the strength of trabecular bone is reduced, cortical bone becomes thin and bones are susceptible to fracture.
- osteoporosis It is estimated that 10 million Americans have established osteoporosis and another 34 million have osteopenia, or low bone mass, which leads to osteoporosis. The disease is responsible for 1.5 millions fractures annually, mostly involving the lumbar vertebrae, hip, and wrist.
- Bisphosphonates are also commonly used in the prophylaxis and treatment of osteoporosis and corticosteroid-induced osteoporosis. Bisphosphonates are synthetic analogues of natural pyrophosphate that inhibit osteoclast activity and decrease bone turnover and resorption.
- the bisphosphonates alendronic acid and risedronate sodium are considered the drugs of choice for treatment of osteoporosis, but disodium etidronate may also be used. Treatment results in lower fracture rates and higher bone density in both male and female patients. Lifestyle changes are also generally prescribed for sufferers.
- Bisphosphonate treatment is so effective that it is very widely used. Patients have hitherto had to put up with the adverse symptoms associated with bisphosphonate use as there is no alternative treatment that gives such good results.
- WO 93/09785 and US 2003/0158154 disclose bisphosphonate formulations that contain very small amounts of surfactant, including in some instances simethicone, to facilitate tablet manufacture and give tablets a glossy appearance.
- An object of the invention is to ameliorate the above problems and disadvantages.
- An object of a specific embodiment of the invention is to provide a formulation of a bisphosphonate which provokes reduced gastric irritation and/or reduced reflux of stomach acid, leading preferably to increased patient compliance.
- the present invention provides a pharmaceutical formulation comprising a bisphosphonate and an antifoaming agent, and also provides for administration of a bisphosphonate in combination with an antifoaming agent.
- typical formulations of the invention comprise an amount of an antifoaming agent effective to reduce the formation of foam in the stomach.
- the antifoaming agent may comprise an agent to lower surface tension and/or to reduce the foaming tendency of stomach contents, and more than one agent may be advantageously used in concert to reduce foaming, and, in preferred embodiments also provide barrier protection.
- Formulations of the present invention may comprise an amount of an antifoaming agent in the range of 20 mg to 150 mg, preferably from 35mg to 125mg and specific embodiments set out in examples below have antifoaming agent present in the range of 50 mg to 100 mg - according to the United States Pharmacopeia, the minimum quantity of simethicone effective for reducing foam formation in the stomach is 20 mg.
- the invention also provides formulations that comprise at least 1%, preferably at least 2% antifoaming agent, and more generally an amount of an antifoaming agent in the range of 3% to 40% by weight, and preferably in the range of 5% to 30% by weight. Specific embodiments set out in the examples contain from about 7% to about 18% antifoaming agent by weight.
- Antifoaming agents are known to those of skill in the art. Whilst many different agents may be used in the formulations of the invention, presently there are only a limited number of approved antifoaming agents available for pharmaceutical formulations, and - A - these are particularly suitable. Siloxanes can be used. Some embodiments use one or more polydimethylsiloxanes as the antifoaming agent. Preferred embodiments of the formulation of the invention comprise dimethicone BP, simethicone BP (an activated form of dimethicone), or both.
- any bisphosphonate having the side-effect of promoting gastric irritation may suitably be used in the formulations of the invention.
- the invention applies generally to formulations of bisphosphonates, including for example alendronic acid, disodium etidronate, disodium pamidronate, ibandronic acid, risedronate sodium, sodium clodronate, strontium ranelate, tiludronic acid and zoledronic acid.
- the bisphosphonate may be selected from the group alendronic acid or alendronate, risedronate and etidronate.
- Particularly preferred formulations comprise alendronic acid or alendronate.
- the amount of bisphosphonate is from 5mg to 150mg of Alendronic acid (or a therapeutically equivalent amount of another bisphosphonate, or an equivalent amount of a bisphosphonate compound), preferably from about lOmg to about 70mg.
- Formulations of the invention comprise also a pharmaceutically acceptable carrier.
- Bisphosphonates can be co-administered with other agents helpful in treatment of osteoporosis, either directly or dealing e.g. with side effects of the treatment.
- Formulations of the invention may thus also include one or more of a vitamin D derivative and a calcium supplement.
- Vitamin D supplements suitable for inclusion in formulations of the invention include ergocalciferol (calciferol, vitamin D2), cholecalciferol (vitamin D3), dihydrotachysterol, alfacalcidol (l ⁇ - hydroxycholecalciferol), and calcitriol (1,25-dihydroxycholecalciferol).
- Some calcium supplements which may be used in the formulations of the invention are calcium salts, optionally selected from calcium gluconate, calcium chloride, calcium lactate, ADCAL®, CACIT®, CALCICHEW®, CALCIUM-500®, CALCIUM- SANDOZ® and SANDOCAL®. Treatments of the invention may also be carried out in combination with parenteral calcium supplements.
- Particularly preferred formulations of the invention comprise a bisphosphonate, antifoaming agent, a vitamin D derivative and a calcium supplement.
- Formulations of the invention include an amount of one or more agents effective for reducing the tendency of the stomach contents to foam, and which may also elicit barrier protection.
- Treatment according to the invention involves the administration of one or more such agents with bisphosphonates simultaneously, either together (in the same formulation) or separately (taken together at the same time), or separately (time delayed administration).
- the bisphosphonate and the antifoaming agent can be taken separately.
- the antifoaming agent is generally taken up to 1 hour before and not more than 10 minutes after the bisphosphonate.
- the antifoaming agent is taken not more than 10 minutes before and more preferably not more than 5 minutes before the bisphosphonate.
- kits including a bisphosphonate and an amount of an antifoaming agent effective for reducing the formation of foam in the stomach.
- kits include other actives such as vitamin D derivatives and/or calcium supplements.
- the invention provides for the use of an antifoaming agent in the manufacture of a medicament effective for the treatment or prophylaxis of osteoporosis in combination with a bisphosphonate.
- the invention also provides for the use of a bisphosphonate in the manufacture of a medicament for the treatment or prophylaxis of osteoporosis in combination with an antifoaming agent.
- the bisphosphonate is alendronate and the antifoaming agent is a siloxane.
- the medicament may advantageously contain other actives as outlined herein.
- treatment or prophylaxis of osteoporosis means any and all treatment or prophylaxis for Paget' s disease, osteopenia, osteoporosis and corticosteroid-induced osteoporosis.
- the invention also provides methods for the treatment of osteoporosis comprising administration to a patient of a bisphosphonate and an antifoaming agent.
- the formulations, methods, kits and uses discussed offer potential reduced mucosal irritation, gastric irritation and / or oesophageal irritation when compared to the art known bisphosphonate formulations.
- An anticipated advantage of the invention is hence that this irritation is reduced. Further anticipated advantages are that instructions to patients, which hitherto gave strict advice as to how to take the medicament, can be relaxed and lower irritation will naturally lead to greater patient compliance with the medication regime and greater overall effectiveness of treatment.
- the dry ingredients 1-5 dry ingredients 1-6 in examples 3, 10 and 17 where both simeticone and dimeticone are included
- Item 6 item 7 for examples 3, 10 and 17
- the wet granulate is then dried and milled to give a uniform granule.
- the dry milled granules are then mixed with excipients 7 & 8 and compressed to a suitable hardness.
- Tablets are prepared as above (example 22) but item 2 is omitted from the dry mix and then added to the solvent, ie item 6 (or 7), prior to it being added to the dry mix of ingredient. The remaining steps are the same as for example 22.
- Tablets are prepared as above for example 22 but item 6 (or 7), the solvent of granulation, is omitted and the product is manufactured by direct compression.
- a tablet is made in which simeticone granules are manufactured separately and then blended with the other ingredients.
- simeticone granules items 1-4 are dry mixed, water is added and then the mixture is wet mixed. The mixture is then dried and milled to give a uniform granule.
- simeticone granules in this particular case 259.0 mg are then mixed with ingredients A, C and D until a uniform mixture is obtained. The mixture is then compressed to a suitable hardness to give tablets.
- Tablets are prepared as for the method of Example 26 except that the amounts of items B-D are doubled to give a tablet containing lOOmg simeticone with a tablet compression weight of 633.36 mg.
- Tablets are prepared as for the method of Example 26 except initially using half amounts of ingredients C & D before dry granulation. The compacted granule is then milled and the remainder of items C & D added. The final mix is then blended and compressed to a suitable hardness to give tablets.
- Items 1 & 4 are dry mixed and then item 2 is slowly added until dispersed. A small quantity of water is then added followed by the etidronate disodium. The ingredients are mixed until well dispersed and additional water is added to form a wet granule suitable for compression. The wet granule is then dried and milled and the remaining items are added. The mixture is then compressed at a suitable hardness or encapsulate into a size 1 capsule.
- Tablets are prepared as for example 26 but alendronate is separately replaced with (a) 35mg of risedronic acid, (b) 400 mg of sodium clodronate, and (c) 200 mg of tiludronic acid.
- the invention thus provides formulations and uses thereof for treatment of osteoporosis with reduced gastric and other irritation.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002622322A CA2622322A1 (en) | 2005-09-16 | 2006-09-15 | Bisphosphonate formulation |
JP2008530623A JP2009508834A (en) | 2005-09-16 | 2006-09-15 | Bisphosphonate formulation |
BRPI0615770-0A BRPI0615770A2 (en) | 2005-09-16 | 2006-09-15 | bisphosphonate formulation |
EP06779468A EP1937362B1 (en) | 2005-09-16 | 2006-09-15 | Bisphosphonate formulation |
AU2006290519A AU2006290519B2 (en) | 2005-09-16 | 2006-09-15 | Bisphosphonate formulation |
NZ567200A NZ567200A (en) | 2005-09-16 | 2006-09-15 | Bisphosphonate formulation |
ZA2008/03086A ZA200803086B (en) | 2005-09-16 | 2008-04-08 | Bisphosphonate formulation |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0518952A GB2430156A (en) | 2005-09-16 | 2005-09-16 | Bisphosphonate formulation |
GB0518952.7 | 2005-09-16 | ||
GB0610311.3 | 2006-05-24 | ||
GB0610311A GB0610311D0 (en) | 2006-05-24 | 2006-05-24 | Bisphosphonate formulation |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2007031785A2 true WO2007031785A2 (en) | 2007-03-22 |
WO2007031785A3 WO2007031785A3 (en) | 2007-05-31 |
Family
ID=37865306
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2006/003457 WO2007031785A2 (en) | 2005-09-16 | 2006-09-15 | Bisphosphonate formulation |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP1937362B1 (en) |
JP (1) | JP2009508834A (en) |
AU (1) | AU2006290519B2 (en) |
BR (1) | BRPI0615770A2 (en) |
CA (1) | CA2622322A1 (en) |
NZ (1) | NZ567200A (en) |
WO (1) | WO2007031785A2 (en) |
ZA (1) | ZA200803086B (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1972341A1 (en) * | 2007-03-23 | 2008-09-24 | Novartis AG | Pharmaceutical compositions comprising a bisphosphonate and vitamin D |
EP2055297A1 (en) * | 2007-11-05 | 2009-05-06 | Merz Pharma GmbH & Co. KGaA | Therapy option for recoloration of hair via bisphosphonates by physiological repigmentation with age-related and/or premature "grayed" patients |
WO2010090614A1 (en) * | 2009-02-05 | 2010-08-12 | Bilgic Mahmut | Pharmaceutical formulation comprising risedronate, calcium carbonate and vitamin d3 combined in a single dosage form |
WO2010101537A1 (en) * | 2009-02-05 | 2010-09-10 | Bilgic Mahmut | Pharmaceutical composition of alendronate and a calcium salt combined in a single dosage form |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5914135A (en) | 1997-04-16 | 1999-06-22 | Mcneil-Ppc, Inc. | Liquid antacid compositions |
US20020022603A1 (en) | 2000-04-07 | 2002-02-21 | Lichtenberger Lenard M. | Unique compositions of zwitterionic phospholipids and bisphosphonates and use of the compositions as bisphosphate delivery systems with reduced GI toxicity |
US20040063670A1 (en) | 2000-11-29 | 2004-04-01 | Alyson Fox | Use of bisphosphonates for pain treatment |
WO2005115331A2 (en) | 2004-05-24 | 2005-12-08 | The Procter & Gamble Company | Enteric solid oral dosage form of bisphosphonate containing a chelating agent |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1238691A (en) * | 1996-10-04 | 1999-12-15 | 麦克公司 | Liquid alendronate preparation |
PL195272B1 (en) * | 1997-07-22 | 2007-08-31 | Merck & Co Inc | Method of inhibiting resorption of bone tissue |
US6015801A (en) * | 1997-07-22 | 2000-01-18 | Merck & Co., Inc. | Method for inhibiting bone resorption |
US20040062802A1 (en) * | 1998-04-02 | 2004-04-01 | Hermelin Victor M. | Maximizing effectiveness of substances used to improve health and well being |
JP2005516928A (en) * | 2001-12-13 | 2005-06-09 | メルク エンド カムパニー インコーポレーテッド | Bisphosphonate liquid formulation for bone abnormalities |
WO2003082236A1 (en) * | 2002-03-28 | 2003-10-09 | The Procter & Gamble Company | Hair bleach product |
WO2005051893A2 (en) * | 2003-11-20 | 2005-06-09 | Eli Lilly And Company | Vitamin d receptor modulators |
-
2006
- 2006-09-15 JP JP2008530623A patent/JP2009508834A/en active Pending
- 2006-09-15 WO PCT/GB2006/003457 patent/WO2007031785A2/en active Application Filing
- 2006-09-15 NZ NZ567200A patent/NZ567200A/en not_active IP Right Cessation
- 2006-09-15 EP EP06779468A patent/EP1937362B1/en not_active Not-in-force
- 2006-09-15 BR BRPI0615770-0A patent/BRPI0615770A2/en not_active IP Right Cessation
- 2006-09-15 AU AU2006290519A patent/AU2006290519B2/en not_active Ceased
- 2006-09-15 CA CA002622322A patent/CA2622322A1/en not_active Abandoned
-
2008
- 2008-04-08 ZA ZA2008/03086A patent/ZA200803086B/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5914135A (en) | 1997-04-16 | 1999-06-22 | Mcneil-Ppc, Inc. | Liquid antacid compositions |
US20020022603A1 (en) | 2000-04-07 | 2002-02-21 | Lichtenberger Lenard M. | Unique compositions of zwitterionic phospholipids and bisphosphonates and use of the compositions as bisphosphate delivery systems with reduced GI toxicity |
US20040063670A1 (en) | 2000-11-29 | 2004-04-01 | Alyson Fox | Use of bisphosphonates for pain treatment |
WO2005115331A2 (en) | 2004-05-24 | 2005-12-08 | The Procter & Gamble Company | Enteric solid oral dosage form of bisphosphonate containing a chelating agent |
Non-Patent Citations (1)
Title |
---|
SMART ET AL., JOURNAL OF THE ROYAL SOCIETY OF MEDICINE, vol. 83, 1990, pages 554 - 556 |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1972341A1 (en) * | 2007-03-23 | 2008-09-24 | Novartis AG | Pharmaceutical compositions comprising a bisphosphonate and vitamin D |
WO2008116809A1 (en) * | 2007-03-23 | 2008-10-02 | Novartis Ag | Pharmaceutical compositions comprising a bisphosphonate and vitamin d |
EP2055297A1 (en) * | 2007-11-05 | 2009-05-06 | Merz Pharma GmbH & Co. KGaA | Therapy option for recoloration of hair via bisphosphonates by physiological repigmentation with age-related and/or premature "grayed" patients |
WO2009059966A1 (en) * | 2007-11-05 | 2009-05-14 | Merz Pharma Gmbh & Co. Kgaa | Therapy option for recoloration of hair via bisphosphonates by physiological repigmentation with age-related and/or premature 'grayed' patients |
WO2010090614A1 (en) * | 2009-02-05 | 2010-08-12 | Bilgic Mahmut | Pharmaceutical formulation comprising risedronate, calcium carbonate and vitamin d3 combined in a single dosage form |
WO2010101537A1 (en) * | 2009-02-05 | 2010-09-10 | Bilgic Mahmut | Pharmaceutical composition of alendronate and a calcium salt combined in a single dosage form |
Also Published As
Publication number | Publication date |
---|---|
BRPI0615770A2 (en) | 2011-05-24 |
ZA200803086B (en) | 2009-12-30 |
WO2007031785A3 (en) | 2007-05-31 |
EP1937362B1 (en) | 2013-03-27 |
CA2622322A1 (en) | 2007-03-22 |
AU2006290519B2 (en) | 2012-10-18 |
JP2009508834A (en) | 2009-03-05 |
EP1937362A2 (en) | 2008-07-02 |
AU2006290519A1 (en) | 2007-03-22 |
NZ567200A (en) | 2010-08-27 |
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