GB2331459A - Use of bisphosphonates in pharmaceutical preparations intended for intramuscular use - Google Patents
Use of bisphosphonates in pharmaceutical preparations intended for intramuscular use Download PDFInfo
- Publication number
- GB2331459A GB2331459A GB9825409A GB9825409A GB2331459A GB 2331459 A GB2331459 A GB 2331459A GB 9825409 A GB9825409 A GB 9825409A GB 9825409 A GB9825409 A GB 9825409A GB 2331459 A GB2331459 A GB 2331459A
- Authority
- GB
- United Kingdom
- Prior art keywords
- acid
- bisphosphonate
- benzyl alcohol
- pharmaceutical composition
- composition according
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Pharmaceutical preparations containing a bisphosphonate and benzyl alcohol have been found to overcome the pain and discomfort associated with preparations containing bisphosphonates only when administered by intramuscular injection. The bisphosphonates may comprise alendronic acid, clodronic acid, etiodronic acid, medronic acid or pamidronic acid, or pharmaceutically acceptable salts thereof. These preparations may be used for the treatment of skeletal and bone disorders such as pagets disease and osteoporosis. Tests were performed on rabbits.
Description
1 2331459 UTILIZATION OF THE 1RISPHOSPHOITATES IN T11E PREPARATION OF
PHARMACEUTIC, &L FORMS INTENDET) FOR THE TNTRKMUSCULAR USE.
This invention relates to intramuscular pharmaceutical compositions containing a pharmacologically active bisphosphonate and benzyl alcohol, useful in the therapeutic treatment of skeletal pathologies.
The bisphosphonates are more and more used in several affections of the skeletal system, such as osteoporosis, Paget's disease (osteitis deformans), hyperthyroidism, hypercalcemia (in particular when associated with malignant tumour forms), ectopic ossification, treatment of bone metastases. These pathologies are becoming more and more frequent owing o the ever increasing mean age of the population, and their social impact is widening, in view also of the seriously invalidating characteristics of these affections and the potentially fatal outcome of some of them.
The pharmacological action of the bisphosphonates takes place at the level of the skeletal system by inhibiting growth and dissolution of the hydroxy-apatite crystals in bones and by hindering osteoclastic activity; bone absorption and relative turnover is reduced.
The bisphosphonates are usually administered by oral or intravenous route.
In clinic the oral route is the most used as it proves the simplest and easiest for the patient. From a 2 theoretical point of view however, the oral route is not optimal since bioavailability of the bisphosphonates if generally very low, that is, 1-2% for clodronate disodium, 1-6% for etidronate disodium and 1-3% for pamidronate disodium (J.E.F. Reynolds et al.., Martindale - The Extra Pharmacopeia, XXXI - The Pharmaceutical Press, London 1996, 779-781). In these cases low bioavailability can be counteracted by administration of much larger doses. This means that 94 to 99% of the drug is wasted from the pharmacologic efficacy point of view while, at the same time, side effects are increased specially at gastroenteric level (nausea and diarrhoea).
The intravenous route, presenting no problem in hospital, is scarcely usable at home, as is the case in most osteoporotic patients.
The intramuscular route should be the route of choice, presenting no bioavailability problems and being easily applicable even in home patients, however it ' has been found that in practice it is not substantially usable since intramuscular injection of these products is generally painful and elicits scarce compliance of the patient.
We have now surprisingly found that the addition of benzyl alcohol to prevalently aqueous solutions of bisphosphonates allows administration by intramuscular route, without onset of painful phenomena hindering at present the use of these products in the preparation of formulations intended for the intramuscular use.
3 According to a first aspect, the present invention provides a pharmaceutical composition comprising a pharmacologically active bisphosphonate and benzyl alcohol. The bisphosphonate may comprise alendronic acid, clodronic acid, etidronic acid, medronic acid, pamidronic acid and/or an acceptable salt thereof, preferably a pharmaceutically acceptable salt. The salt may be an alkaline salt. In a preferred embodiment, the bisphosphonate may be clodronic acid or one of its salts, preferably clodronate disodium. The concentration of the bisphosphonate may vary from 1 mg/ml to 200 mg/ml, preferably from 3 mg/ml to 60 mg/ml. The concentration of benzyl alcohol in solution may vary from 1 mg/ml to 200 mg/ml, more preferably from 10 mg/ml to 100 mg/ml. The composition may also comprise any pharmaceutically acceptable excipients and/or diluents known in the art.
In a second aspect, the present invention provides the use of a pharmaceutical composition according to the first aspect of the present invention in medicine. Preferably, the bisphosphonate in the composition comprises alendronic acid, clodronic acid, etidronic acid, medronic acid, pamidronic acid and/or an acceptable salt thereof, preferably a pharmaceutically acceptable salt.
clodronic acid or one of its salts. The composition may also comprise any pharmaceutically acceptable excipients and/or diluents known in the art.
In a third aspect, the present invention provides the use of a pharmacologically active bisphosphonate and benzyl alcohol in the preparation of a medicament for the treatment of skeletal pathologies. The medicament may be administered by intramuscular route.
The preferred features of the second and subsequent aspects of the present invention are all as for the first aspect mutatis mutandis.
Benzyl alcohol. is a substance having very low systemic toxicity, presenting LD50 by i.v. route in The bisphosphonate may be 4 mice of 480 mg/kg and LDO by i.v. route in cats and dogs of 60 and 50 mg/kg respectively' (N.I. Sax et al.., Dangerous Properties of Industrial Materials, Vi Ed., Van Nostrand Reinhold Company, New York, 1984, page 399). It is widely used in the formulation of injectable products both as a solvent (K.E. Avis et al.., Pharmaceutical Dosage Forms: Parenteral Medications, II Ed., Marcel Dekker, New York, 1992, V01. 1, page 178) and as a preservative (Sandeep Nema et al.., PDA J.
Pharm. Sci. and Technol., 51 (4), 166, 1997).
This invention relates therefore to intramuscular pharmaceutical compositions containing pharmacologically active bisphosphonates and benzyl alcohol, whose use forestalls the onset of marked pain connected with intramuscular injection. of the bisphosphonates. This obviates admission to hospital of the patient, as is the case with intravenous administration, and prevents overdosage connected with oral administration. In any case therefore the decrease in side effects connected with. oral administration combines with a sensible reduction of the treatment cost.
The active substance (e.g., alendronate monosodium, clodronate disodium, etidronate disodium, medronate disodium, pamidronate disodium) is used in a prevalently aqueous solution at a concentration varying from 1 mg/ml to 200 mg/ml (preferably 3-60 mg/ml). In addition to the ordinary excipients useful for the pharmaceutical formulation, the active ingredient solution also contains benzyl alcohol at a concentration varying from 1 to 200 mg/ml (preferably 10-100 mg/ml).
Reduction of the painful action of the bisphosphonates was found to be, within certain limits, proportional to the percent contents of benzyl alcohol (see example 4).
Administration by. intramuscular use can be carried out, depending on the type of bisphosphonate, on the gravity of the pathology etc., both with a daily frequency and -with intermittent rhythm (from alternate days up to two weekly intervals).
The following examples are given with the sole purpose of better illustrating the invention, as in no way should they be taken as limiting the scopes of the invention itself.
Exampl-e- -1 Formulation of an ampoule for intramuscular administration of clodronate disodium:
clodronate disodium 100 mg benzyl alcohol 100 mg sodium bicarbonate 1.65 mg water for injectable preparations q.s. ad 3.3 "ml To prepare, dissolve in water the following in this order: benzyl alcohol, clodronate disodium and sodium bicarbonate; dilute to the final volume with water and filter the solution under sterile conditions through a 0. 22 p membrane; under st4rile conditions distribute into neutral glass vials having a low calcium content.
6 Vxampl-e- 2 Formulation of an ampoule for administration of alendronate monosodium: alendronate monosodium benzyl alcohol sodium chloride intramuscular mg 10 mg 3 mg sodium hydroxide q.s. ad pH 4 water for injectable preparations 6 ml To prepare, dissolve in water the following in this order: benzyl alcohol, alendronate monosodium, sodium chloride. Adjust to pH 4. 5 with 1N sodium hydroxide; dilute to. the final volume with water; filter the solution under sterile conditions through a 0.22 p membrane; under sterile conditions distribute into neutral glass vials.
ExamDle 3 Formulation of an ampoule for administration of etidronate disodium etidronate disodium 300 mg benzyl alcohol 200 mg sodium hydroxide q.s. ad pH 4.5 water for injectable preparations q.s. ad 6 ml To prepare, dissolve in water the following in this order: benzyl alcohol and etidronate disodium. Adjust to pH 4.5 with 1N sodium hydroxide; dilute to the final volume with water; filter the solution under sterile conditions through a 0.22 p membrane; under sterile conditions distribute into neutral glass vials.
Example 4
The efficacy of increasing quantities of benzyl alcohol in reducing the painful effect of clodronate intramuscular 7 disodium was tested 'in the rabbit by the licking test.
The test was carried out in New Zealand male albino rabbits weighing 2.5 to 4.0 kg. Before testing all animals had their dorsal area shaven.
Treatment was carried out by intradermic injection of 200 pl of the test compound into the back of the animal. Each animal was kept under observation for 30 minutes. Tolerance to the pain caused by the test compound is inversely proportional to the number of responses of the animal, reacting to the discomfort or to the pain caused by treatment by licking the affected portion of skin.
i i h-g:y (D m 0 -A r_ rt -4.
0 0 U) Solution A Solution B Solution C Solution D Solution E rt (D Clodronate 30 mg/ml 30 mglml 30 mg/ml 30 mgIml_ m rt disodium (D 01 Benzyl Alcohol 10 mg/M1 15 mg/M1 20 mg/ml JC (D 0. 5 mglml 0. 5 m91m1 0. 5 m91M1 0.5. mg/M1 m CO Sodium 0. 5 mg/M1 (D bicarbonate Water q.s. ad 1 M1 1 M1 1 M1 1 M1 0 F-A 1-A 0 IC T Response to painful stimulation by the licking test in rabbits Treatment no. of total no. of mean, std. deviat.
animal responses (no. of resp./ animal) Solution A Solution B Solution C Solution D Solution E 39 23 9 11 7.8 4.6 4.0 1.8 2.2 2.05 1.52 1.87 0.84 c.
2.05 significance in respt.to A P<O. 01 M.05 M.001 P0. 01 $-a r 0 m (D m r_ F j-)' m M (D 0 m Cr (D 0 0 0 kD As can be seen the tolerance of solutions B, C and D, containing benzyl alcohol, is significantly better (Student's t test) than the tolerance of solution A, free from benzyl alcohol. Moreover, the efficacy of benZY1 alcohol is proportional to the quantity contained. The figure enclosed -herewith shows the optimum line resulting from the experimental data by the least squares method, with a correlation coefficient of 0.988 (P< 0.05).
Example 5
The efficacy of benzyl alcohol in reducing the painful effect of etidronate disodium was tested in the rabbit by the licking test.
The method employed was that described in the preceding example 4.
The following were the solutions tested Solution A Solution B Etidronate disodium 7.5 mglml 7.5 mglml Benzyl alcohol 20 mg/ml Water q. s. ad 1 1 M1 Response to painful stimulation by the licking test. in rabbits std. deviat.
Treatment Solution A 6 Solution B 6 no. of total no. of animal responses 58 31 mean, (no. of resp./ animal) 9.7 5.2 1.5 0.75 significance in respt.to A P<O. 01 -3 bcr (D M (D m r_ 1.. 1 rt m Pi m (D m (D 0 h rt (D Ch I:i 9) te #-A (D bi "h 0 -i t-i 0 z h, 0 %Q 12 As can be seen the tolerance of solutions B, containing benzyl alcohol, is significantly better (Student's t test) than the tolerance of solution A, free from benzyl alcohol.
Example 6
The efficacy of benzyl alcohol in reducing the painful effect of alendronate monosodium was tested in the rabbit by the licking test.
The method employed was that described ' in the preceding example 4.
The following were the solutions tested Solution A Solution B Alendronate monosodium 8 mg/M1 8 mglml Benzyl alcohol 20 mglml is Lactose 45 mglml 45 mglml Water q.s. ad 1 M1 1 M1 Response to painful stimulation by the licking test in rabbits std. deviat.
Treatment no. of total no. of animal responses mean (no. of resp./ animal) significance in respt.to A j r (D m M m r_ rt m 0 (D m (D 10 0 rlf, (D P4 i.
3 Solution A 6 62 10.3 2.25 Solution B 6 34 5.7 l.,21 P<0.01 (D W #-h 0 bA h 0 IC -6 0 0 14
Claims (17)
1 1
2. A composition according to claim 1 wherein the bisphosphonate comprises alendronic acid, clodronic acid, etidronic acid, medronic acid, pamidronic acid and/or a pharmaceutically acceptable salt thereof.
3. A composition according to claim 2 wherein the salt of the bisphosphonate is an alkaline salt.
4. A pharmaceutical composition according to claim 1 wherein the bisphosphonate is clodronic acid or one of its salts.
5. A pharmaceutical composition according to claim 4 wherein the bisphosphonate is clodronate disodium.
6. A pharmaceutical composition according to any of claims 1 to 5 wherein the concentration of the bisphosphonate in solution varies from 1 mg/ml to 200 mg/ml.
7. A pharmaceutical composition according to claim 6 wherein the concentration of the bisphosphonate varies from 3 mg/ml to 60 mg/ml.
8. A pharmaceutical composition according to any of claims 1 to 7 wherein the concentration of benzyl alcohol in solution varies from 1 mg/ml to 200 mg/ml.
9. A pharmaceutical composition according to claim 8 wherein the benzyl alcohol concentration varies from 10 mg/M1 to 100 mg/M1.
10. The use of a pharmaceutical composition as defined in any of claims 1 to 9 in medicine.
11. The use according to claim 10 wherein the bisphosphonate in the composition comprises alendronic acid, clodronic acid, etidronic acid, medronic acid, pamidronic acid and/or a pharmaceutically acceptable salt thereof.
12. The use according to claim 11 wherein the bisphosphonate is clodronic acid or one of its salts.
13. The use of a pharmacologically active bisphosphonate and benzyl alcohol in the preparation of a medicament for the treatment of skeletal pathologies.
14. The use as claimed in claim 13 wherein the medicament is administered by intramuscular route.
15. The use according to claim 13 or 14 wherein the bisphosphonate comprises alendronic acid, clodronic acid, etidronic acid, medronic acid, pamidronic acid and/or a pharmaceutically acceptable salt thereof.
16. The use according to claim 15 wherein the bisphosphonate is clodronic acid or one of its salts.
17. A pharmaceutical composition substantially as hereinbefore described in any one of Examples 1 to 6.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT002603 IT1296495B1 (en) | 1997-11-21 | 1997-11-21 | USE OF BISPHOSPHONATES IN THE PREPARATION OF PHARMACEUTICAL FORMS FOR INTRAMUSCULAR ADMINISTRATION |
Publications (3)
Publication Number | Publication Date |
---|---|
GB9825409D0 GB9825409D0 (en) | 1999-01-13 |
GB2331459A true GB2331459A (en) | 1999-05-26 |
GB2331459A8 GB2331459A8 (en) | 1999-07-15 |
Family
ID=11378254
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB9825409A Withdrawn GB2331459A (en) | 1997-11-21 | 1998-11-19 | Use of bisphosphonates in pharmaceutical preparations intended for intramuscular use |
Country Status (6)
Country | Link |
---|---|
BE (1) | BE1012137A3 (en) |
DE (1) | DE19853483A1 (en) |
ES (1) | ES2152865B1 (en) |
FR (1) | FR2771638B1 (en) |
GB (1) | GB2331459A (en) |
IT (1) | IT1296495B1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6548042B2 (en) | 2000-08-07 | 2003-04-15 | Arstad Erik | Bis-phosphonate compounds |
EP1605900A2 (en) * | 2003-03-26 | 2005-12-21 | Becton, Dickinson and Company | Use of benzyl alcohol, and other phenolic preservatives to reduce pain during intradermal injection |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1136069A1 (en) * | 2000-03-21 | 2001-09-26 | SPA SOCIETA' PRODOTTI ANTIBIOTICI S.p.A. | Pharmaceutical compositions containing clodronates for high local tolerance intramuscular administration |
SI1296689T1 (en) * | 2000-06-20 | 2006-08-31 | Novartis Ag | Method of administering bisphosphonates |
AU7410901A (en) | 2000-06-20 | 2002-01-02 | Novartis Ag | Method of administering bisphosphonates |
ITTO20020406A1 (en) * | 2002-05-13 | 2003-11-13 | Chiesi Farma Spa | FORMULATIONS OF BISPHOSPHONATES FOR INJECTABLE USE. |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0051163A2 (en) * | 1980-11-03 | 1982-05-12 | Dr. Franz Köhler Chemie KG | A 4-dimethylaminophenol-hydrochloride solution for painless intramuscular administration, and process for its preparation |
EP0077172A2 (en) * | 1981-10-08 | 1983-04-20 | Konica Corporation | A method for forming a direct positive color image |
JPH03190823A (en) * | 1989-12-21 | 1991-08-20 | Snow Brand Milk Prod Co Ltd | Erythropoietin hypodermic or intramuscular administration agent |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2035179C (en) * | 1990-01-31 | 2001-08-14 | Gerald S. Brenner | Pharmaceutical compositions containing insoluble salts of bisphosphonic acids |
BR9407869A (en) * | 1993-10-19 | 1996-10-29 | Merck & Co Inc | Combination of pharmaceutical composition and process for the treatment of osteoporosis |
US5646134A (en) * | 1994-04-21 | 1997-07-08 | Merck & Co., Inc. | Alendronate therapy to prevent loosening of, or pain associated with, orthopedic implant devices |
-
1997
- 1997-11-21 IT IT002603 patent/IT1296495B1/en active IP Right Grant
-
1998
- 1998-11-17 ES ES9802412A patent/ES2152865B1/en not_active Expired - Fee Related
- 1998-11-19 DE DE1998153483 patent/DE19853483A1/en not_active Ceased
- 1998-11-19 GB GB9825409A patent/GB2331459A/en not_active Withdrawn
- 1998-11-19 FR FR9814554A patent/FR2771638B1/en not_active Expired - Fee Related
- 1998-11-20 BE BE9800841A patent/BE1012137A3/en not_active IP Right Cessation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0051163A2 (en) * | 1980-11-03 | 1982-05-12 | Dr. Franz Köhler Chemie KG | A 4-dimethylaminophenol-hydrochloride solution for painless intramuscular administration, and process for its preparation |
EP0077172A2 (en) * | 1981-10-08 | 1983-04-20 | Konica Corporation | A method for forming a direct positive color image |
JPH03190823A (en) * | 1989-12-21 | 1991-08-20 | Snow Brand Milk Prod Co Ltd | Erythropoietin hypodermic or intramuscular administration agent |
Non-Patent Citations (4)
Title |
---|
JEF Reynolds, 'Martindale. The Extra Pharmacopoeia', 1996, Royal Pharm. Soc., pages 1119-1120 * |
Nucklearmedezin, 1982, vol 19; F. Lore et al., (Stuggart), pages 911-915 * |
Therapie, vol 37, no 3, 1982; A Gouyette et al., pages 269-274 * |
WPI Abstract Accesion No. 91-286074/39 & JP 03190823 A * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6548042B2 (en) | 2000-08-07 | 2003-04-15 | Arstad Erik | Bis-phosphonate compounds |
EP1605900A2 (en) * | 2003-03-26 | 2005-12-21 | Becton, Dickinson and Company | Use of benzyl alcohol, and other phenolic preservatives to reduce pain during intradermal injection |
EP1605900A4 (en) * | 2003-03-26 | 2007-10-17 | Becton Dickinson Co | Use of benzyl alcohol, and other phenolic preservatives to reduce pain during intradermal injection |
Also Published As
Publication number | Publication date |
---|---|
FR2771638A1 (en) | 1999-06-04 |
ES2152865A1 (en) | 2001-02-01 |
GB9825409D0 (en) | 1999-01-13 |
DE19853483A1 (en) | 1999-05-27 |
ITMI972603A1 (en) | 1999-05-21 |
IT1296495B1 (en) | 1999-06-25 |
BE1012137A3 (en) | 2000-05-02 |
ES2152865B1 (en) | 2001-08-16 |
FR2771638B1 (en) | 2000-09-08 |
GB2331459A8 (en) | 1999-07-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2238736C2 (en) | Bisphosphonate-containing pharmaceutical parenteral composition | |
Martin et al. | Bisphosphonates-mechanisms of action | |
TWI275393B (en) | Use of bisphosphonates for pain treatment | |
KR100642961B1 (en) | Bisphosphonic acid for the treatment and prevention of osteoporosis | |
JP3062001B2 (en) | Use of bisphosphonic acid derivatives for the preparation of a pharmaceutical composition intended to promote bone repair and the corresponding pharmaceutical composition | |
US20140349974A1 (en) | Zoledronic acid dosage forms for the treatment of pain | |
EP0998292B1 (en) | Method for inhibiting bone resorption | |
EP0600834A1 (en) | Use of methanebisphosphonic acid derivatives for the manufacture of a medicament for fracture healing | |
GB2331459A (en) | Use of bisphosphonates in pharmaceutical preparations intended for intramuscular use | |
CA2409930A1 (en) | Use of zoledronate for the manufacture of a medicament for the treatment of bone metabolism diseases | |
US20030064966A1 (en) | Inhalation administration of biophosphonates | |
US6255288B1 (en) | Certain methanebisphosphonic acid derivatives in fracture healing | |
Ghinoi et al. | Clodronate: mechanisms of action on bone remodelling and clinical use in osteometabolic disorders | |
ES2215856T3 (en) | SOLUTION OF MONOSODIC SALT TETRAHYDRATE OF N- (O- (P-PIVALOYLOXIBENCENO-SULFONYLAMINE) BENZOIL) GLYCINE AND MEDICINAL PRODUCT CONTAINING THIS SOLUTION. | |
GB2336311A (en) | Bisphosphonate Dosing Regimen | |
EP1136069A1 (en) | Pharmaceutical compositions containing clodronates for high local tolerance intramuscular administration | |
WO2005044280A1 (en) | Biphosphonate pharmaceutical formulations (water emulsion of lipids/phospholipids) and use thereof | |
ITMI20001174A1 (en) | PREPARATIONS FOR THE INTRAMUSCULAR USE OF BISPHOSPHONATES | |
ITMI20000584A1 (en) | LYOPHILIZED PHARMACEUTICAL FORMS CONTAINING CLODRONATED FOR INTRAMUSCULAR ADMINISTRATION WITH HIGH LOCAL TOLERABILITY | |
ITMI992356A1 (en) | PHARMACEUTICAL FORMS CONTAINING CLODRONATED FOR INTRAMUSCULAR ADMINISTRATION WITH HIGH LOCAL TOLERABILITY | |
ITMI20001694A1 (en) | PHARMACEUTICAL FORMS CONTAINING CLODRONATED FOR INTRAMUSCULAR ADMINISTRATION WITH HIGH LOCAL TOLERABILITY. | |
JPH08277223A (en) | Medicine for treating hypercalcemia | |
ITMI972470A1 (en) | USE OF BISPHOSPHONATES FOR THE PREPARATION OF ADMINISTRABLE MEDICATIONS BY IONTOPHORESIS |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |