WO1995013078A1 - Pharmaceutical composition and use thereof - Google Patents
Pharmaceutical composition and use thereof Download PDFInfo
- Publication number
- WO1995013078A1 WO1995013078A1 PCT/FI1994/000504 FI9400504W WO9513078A1 WO 1995013078 A1 WO1995013078 A1 WO 1995013078A1 FI 9400504 W FI9400504 W FI 9400504W WO 9513078 A1 WO9513078 A1 WO 9513078A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- salt
- active agent
- rectal
- administered
- clodronic acid
- Prior art date
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
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0031—Rectum, anus
Landscapes
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention concerns the use of clodronic acid or a salt thereof for making a pharmaceutical composition for the rectal treatment of abnormalities in the calcium and phosphate metabolism in a mammal.
Description
Pharmaceutical composition and use thereof
The present invention is directed on the use of clodronic acid for making a pharmaceutical composition, and the use of the composition.
Clodronic acid and its salts, especially its disodiu salt, is useful as the active agent in the treatment of abnormalities in the calcium and phosphate metabolism, especially for preventing, delaying and treating bone calcium loss, e.g. osteoporosis, in a mammal. Clodronate is traditionally administered orally, but due to the low absorption of orally administered clodronate, relatively high doses of clodronate have to be administered. In addition, the treatment has to be carried out for prolon¬ ged periods of time. In order to reduce the number of unit doses to be administered, as well as the size of the single doses, one aim has been to increase the concentra¬ tion of active agent per unit dose. Still the absorption and bioavailability of orally administered clodronate remains low, that is less than 5 %.
Intravenous administration, which would provide a good bioavailablity of clodronate, is not practical, already for the reason that such a form of administration re¬ quires the assistance of a medically trained person and thus difficult to carry out under home conditions.
It has now been found that the absorption of clodronate can be substantially improved by administering the same rectally.
According to the invention the clodronic acid or its salt is preferably formed into a suppository by mixing the same with at least one rectally acceptable carrier, and optionally further adjuvants. The carriers used as sup¬ pository bases are as such well known in the art. The suppository bases are typically based on natural or
synthetic fats or modified natural fats or their mixtu¬ res, such as mono-, di- and triglycerides, polyethylene glycols and cocoa butter. As suitable commercially avai¬ lable suppository bases the following product names may be mentioned: Suppocire (Gattefosse) , Novata (Henkel) , itepsol (Dynamit Nobel) , Massa Estarinum (Kay-Fries) . These commercial products are available in several types, which differ from each other regrading e.g. melting range, solidification point and hydroxyl value. Special grades may contain additives, such as polysorbates, ethoxylated fatty alcohols and ethoxylated partial fatty glycerides.
The active agent can also be administered rectally as a rectal solution or suspension (micro enema) or as a soft gelatin capsule or as a sustained release rectal dosage form. The clodronic acid or its salt is formed into a rectal solution or suspension by mixing the same with a suitable solvent or vehicle, e.g. water, ethanol, glyce- rol, propylene glycol, etc. Also suspending agents can be used, such as carboxymethylcellulose sodium, gelatin, povidone, carbomer, etc.
The pharmaceutical compositions may, in addition, contain further adjuvants, such as preservatives, antioxidants, pH-adjustment agents and stabilizing agents. Such agents are also well known in the art.
The amount of clodronate to be administered rectally naturally depends on the individual as well as the condi¬ tion to be treated, but generally a daily dose of the active agent (in anhydrous form) varies between 0.5 mg/kg to 50 g/kg, suitably 1-15 mg/kg body weight. A suitable amount to be incorporated into a single sup- pository can vary e.g. between 50 mg and 1000 mg, to be administered 1 - 3 times daily.
A suitable volume for rectal solution or suspension can vary between 1 and 20 ml and a suitable amount of active agent to be incorporated in a single dose can vary e.g. between 50 mg and 1000 mg.
Test report
The absorption of clodronate after rectal administration was tested in rats and compared to results obtained after intravenous administration.
As the test substance, clodronate (Bonefos ®) in the form of a 60 mg/ml infusion concentrate was used, diluted with 0.9 % NaCl to the suitable concentration. The test ani- mals were Sprague Dawley male rats, 250 - 350 g. The animals were fasted 24 h before and 3 h after administra¬ tion. Rectal administration was performed after anesthe¬ tization (carbon dioxide - oxygen mixture) with a syringe introduced 3 cm proximal to the anus. The volumes ad- ministered were 1 ml/kg body weight. As a control an intravenous injection was given.
The test animals were divided into five groups as fol¬ lows:
Group 1: clodronate 25 mg/kg i.v. in single dose. Per each time point, 3 animals were used. Group 2: clodronate 1 mg/kg p.r. in single dose. Per each time point, 3 animals were used. Group 3: clodronate 10 mg/kg p.r. in single dose. Per each time point, 3 animals were used. Group 4: clodronate 25 mg/kg p.r. in single dose. Per each time point, 3 animals were used. Group 5: clodronate 25 mg/kg p.r. in single dose. Per each time point 3 animals were used.
Blood samples were taken 5, 15, 30 min, 1, 2, 4, 7, 24 and 30 h after administration. Urine fractions 0-24 h, and 24h-30h were collected. The clodronate concentration at the specified time points were measured by gas chroma- tography-mass spectrometry.
The results are summarized as follows:
URINE
Urinary excrection Bioavailability
0-24 h, % of dose % mean
Group 1 58.1 Group 2 7.5 12.9 Group 3 4.8 8.3 Group 4 10.8 18.6
BLOOD
AUC o-∞ μg/ l x h mean
Group 1 28.85 Group 2 Group 3 1.15 10 Group 4 6.19 22 Group 5 5.29 18
The bioavailability is expressed as % compared to intra¬ venous administration. The results show remarkably better absorption after rectal administration as compared to oral, where a massive dose of 300 mg/kg gave a bioavaila¬ bility of only 7.7 %. Even this value is unusually high as generally the bioavailability of oral clodronate is less than 5 % and often even less than 2 %.
The following examples illustrate the invention.
Example 1
An anal suppository was made by combining the following substances:
itepsol -35 2.0 g
Disodium clodronate (anh.) 0.3 g
Witepsol W 35 was melted to appr. +45 °C. The disodium clodronate was added with vigorous mixing into the melted base when the temperature was +38 °C. The melt was pured into the molds, which can be the suppository wrapping material at the same time. The molds were cooled in a suitable manner.
Suppositories containing 50 - 500 mg of the active agent can be manufactured with the above method.
Example 2
An anal suppository was made by combining the following substances:
Disodium clodronate (anh.) 1.0 g
Novata E 2.0 g
Purified water 0.6 g
The disodium clodronate was suspended in water with a suitable mixer. Novata E was melted to appr. +45 °C. The active agent suspension was added with vigorous mixing into the melted base when the temperature was +38 °C. The melt was poured into suitable molds. The molds were cooled in a suitable manner.
Example 3
A rectal solution was made with the following composi¬ tion:
Disodium clodronate (anh.) 0.3 g
Sodium hydroxide to pH 5
Purified water to 5 ml
The disodium clodronate was dissolved in purified water and the pH of the solution was adjusted. The rectal solution was then filled into suitable single-unit con¬ tainers.
Claims
1. Use of clodronic acid or a salt thereof for the prepa- ration of pharmaceutical composition for rectal use for the treatment of abnormalities in the calcium and phos¬ phate metabolism, especially for preventing, delaying and treating bone calcium loss in a mammal.
2. Use according to claim 1, wherein the salt of the clodronic acid is a salt formed with an inorganic base, preferably a sodium salt.
3. Use according to claim 1, wherein the active agent is the disodium clodronate tetrahydrate.
4. Use according to any preceding claim for the preparation of a rectal suppository.
5. Use according to any one of claims 1 - 3 for the preparation of a rectal solution or suspension.
6. Use accoording to claim 4 or 5 for the preparation of a suppository or a unit dose comprising the active agent in an amount of 0.05 - 1 g.
7. Method for the treatment of abnormalities in the calcium and phosphate metabolism, especially for preven¬ ting, delaying and treatment of bone calcium loss in a mammal, comprising administering rectally thereto a pharmaceutically effective amount of clodronic acid or a salt thereof.
8. Method according to claim 7, wherein the salt of the clodronic acid is a salt formed with an inorganic base, preferably a sodium salt.
9. Method according to claim 8, wherein the active agent is the disodium clodronate tetrahydrate.
10. Method according to any preceding claim 7 to 9 wherein the active agent is administered in the form of a recta1 suppository.
11. Method according to any one of the claims 7 to 9 wherein the active agent is administered in the form of a rectal solution or suspension.
12. Method according to claim 10 or 11 wherein active agent is administered in an amount of 0.05 - 1 g per sup¬ pository or unit dose respectively.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU81083/94A AU8108394A (en) | 1993-11-12 | 1994-11-09 | Pharmaceutical composition and use thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9303740-6 | 1993-11-12 | ||
SE9303740A SE9303740L (en) | 1993-11-12 | 1993-11-12 | Pharmaceutical composition |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995013078A1 true WO1995013078A1 (en) | 1995-05-18 |
Family
ID=20391728
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FI1994/000504 WO1995013078A1 (en) | 1993-11-12 | 1994-11-09 | Pharmaceutical composition and use thereof |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU8108394A (en) |
SE (1) | SE9303740L (en) |
WO (1) | WO1995013078A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7862552B2 (en) | 2005-05-09 | 2011-01-04 | Boston Scientific Scimed, Inc. | Medical devices for treating urological and uterine conditions |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1254465A (en) * | 1967-12-11 | 1971-11-24 | Procter & Gamble | Composition for inhibiting anomalous deposition and mobilization of calcium phosphate in human tissue |
DE2813165C2 (en) * | 1977-03-28 | 1983-12-15 | The Procter & Gamble Co., 45202 Cincinnati, Ohio | Pharmaceutical composition based on an anti-inflammatory agent and dichloromethane diphosphonic acid |
-
1993
- 1993-11-12 SE SE9303740A patent/SE9303740L/en not_active Application Discontinuation
-
1994
- 1994-11-09 WO PCT/FI1994/000504 patent/WO1995013078A1/en active Application Filing
- 1994-11-09 AU AU81083/94A patent/AU8108394A/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1254465A (en) * | 1967-12-11 | 1971-11-24 | Procter & Gamble | Composition for inhibiting anomalous deposition and mobilization of calcium phosphate in human tissue |
DE2813165C2 (en) * | 1977-03-28 | 1983-12-15 | The Procter & Gamble Co., 45202 Cincinnati, Ohio | Pharmaceutical composition based on an anti-inflammatory agent and dichloromethane diphosphonic acid |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7862552B2 (en) | 2005-05-09 | 2011-01-04 | Boston Scientific Scimed, Inc. | Medical devices for treating urological and uterine conditions |
Also Published As
Publication number | Publication date |
---|---|
SE9303740D0 (en) | 1993-11-12 |
AU8108394A (en) | 1995-05-29 |
SE9303740L (en) | 1995-05-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0058418B1 (en) | Carbonate diester solutions of pge-type compounds | |
CA1203172A (en) | Propylene glycol diester solutions of pge-type compounds | |
AU622276B2 (en) | Medicament containing dihydrolipoic acid as active substance | |
PL106415B1 (en) | METHOD OF THE PRODUCTION OF NEW DERIVATIVES OF POLY / H- / SULFATE OF POLYGALACTOSIDOSUCROSE | |
IE51637B1 (en) | Pharmaceutical preparation | |
US4784855A (en) | Pharmaceutical compositions and suppository | |
FI88583B (en) | FREQUENCY REFRIGERATION FOR SUSPENSION, WITHOUT PROCEDURE I2 | |
Bowery et al. | t-Butyl bicyclo phosphate: a convulsant and GABA antagonist more potent than bicuculline [proceedings] | |
EP0470251B1 (en) | Liquid prostaglandin composition | |
WO1995013078A1 (en) | Pharmaceutical composition and use thereof | |
US4404212A (en) | Prostacyclin treatment of thrombosis | |
DE2720998A1 (en) | CYCLIC ETHERS, THE METHOD OF MANUFACTURING THEM AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM | |
DE3346526A1 (en) | PHARMACEUTICAL PREPARATION FOR THE THERAPEUTIC TREATMENT OF RHEUMATIC DISEASES | |
US5955456A (en) | Injectable pharmaceutical composition comprising ursodesoxycholic acid or tauroursodesoxycholic acid, a strong base and tromethamol | |
EP0003382B1 (en) | Solvent vehicle for therapeutics and pharmaceutical composition containing it | |
GB1600639A (en) | Medicament preparation having resorption properties and method of producing the same | |
CA2095499A1 (en) | Depot preparation | |
WO1997044053A1 (en) | Pharmaceutical compositions containing cyclosporine and a carrier comprising at least an ester of alpha-glycerophosphoric acid | |
US2541285A (en) | Aqueous solutions of vitamin a esters | |
RU2002110440A (en) | Conjugates of 4-benzylaminoquinolines with bile acid and their heteroanalogs, methods for their preparation, drugs containing these compounds and their use | |
US4612310A (en) | Antirheumatically active suppositories | |
IE903464A1 (en) | The use of alkylphosphoric acid compounds for combatting¹psoriasis disorders | |
JPS5731614A (en) | Lipid improver | |
DE2821737C2 (en) | ||
US3140233A (en) | Tasteless pharmaceutical composition and process |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU JP KE KG KP KR KZ LK LR LT LU LV MD MG MN MW NL NO NZ PL PT RO RU SD SE SI SK TJ TT UA US UZ VN |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): KE MW SD SZ AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
122 | Ep: pct application non-entry in european phase | ||
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
NENP | Non-entry into the national phase |
Ref country code: CA |