WO2003064438A1 - Amorphous monosodium alendronate and preparation thereof - Google Patents
Amorphous monosodium alendronate and preparation thereof Download PDFInfo
- Publication number
- WO2003064438A1 WO2003064438A1 PCT/EP2002/007066 EP0207066W WO03064438A1 WO 2003064438 A1 WO2003064438 A1 WO 2003064438A1 EP 0207066 W EP0207066 W EP 0207066W WO 03064438 A1 WO03064438 A1 WO 03064438A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- monosodium alendronate
- amorphous
- amorphous monosodium
- alendronate
- preparation
- Prior art date
Links
- CAKRAHQRJGUPIG-UHFFFAOYSA-M sodium;[4-azaniumyl-1-hydroxy-1-[hydroxy(oxido)phosphoryl]butyl]-hydroxyphosphinate Chemical compound [Na+].NCCCC(O)(P(O)(O)=O)P(O)([O-])=O CAKRAHQRJGUPIG-UHFFFAOYSA-M 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 4
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229960004343 alendronic acid Drugs 0.000 claims abstract description 8
- 238000001694 spray drying Methods 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000007900 aqueous suspension Substances 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 239000007903 gelatin capsule Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 abstract description 2
- 238000004108 freeze drying Methods 0.000 abstract description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 150000004684 trihydrates Chemical class 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000008203 oral pharmaceutical composition Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 206010027452 Metastases to bone Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000003913 calcium metabolism Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- PAYGMRRPBHYIMA-UHFFFAOYSA-N sodium;trihydrate Chemical compound O.O.O.[Na] PAYGMRRPBHYIMA-UHFFFAOYSA-N 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
-
- 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
Definitions
- the present invention relates to the amorphous form of monosodium alendronate, a process for the preparation thereof and * oral pharmaceutical compositions containing amorphous monosodium alendronate.
- Alendronic acid i.e. 4-amino-l-hydroxy-butylidene diphosphonic acid (disclosed in EP 39 033) and the pharmaceutically acceptable salts thereof, particularly the sodium salts, have been used for some time in therapy for inhibiting hypercalcemia conditions in a number of disorders characterized by abnormal calcium metabolism.
- the therapeutical indications for this medicament mainly comprise osteoporosis, Paget' disease, bone metastases.
- alendronic acid is administered through the oral route in the form of the crystalline trihydrate monosodium salt, disclosed in EP 402 152.
- monosodium alendronate in the amorphous form ensures optimum absorption characteristics, providing better bioavailability than the crystalline forms used to date in therapy, in particular compared with the marketed trihydrate form.
- the present invention relates to oral pharmaceutical formulations containing as active ingredient amorphous monosodium alendronate in effective amounts, in admixture with suitable carriers or excipients.
- compositions of the invention will be preferably in the form of soft- or hard- gelatin capsules, tablets, suspensions, solutions, syrups, drops or other forms suitable for the oral administration. Capsules and tablets are most preferred.
- the therapeutical dosage will depend on a number of factors (weight, sex, age of the patient and type of disorder), but usually it will be similar to that already established for the trihydrate crystalline form. As a rule, the daily dosage will range from 0.01 to 1 mg/kg body weight.
- the amorphous form of the invention preferably contains more than 2% by weight of water.
- the monosodium alendronate amorphous form of the invention can be prepared by lyophilizing or spray drying the aqueous solution resulting from the addition of a stoichiometric amount of sodium hydroxide, sodium carbonate or sodium bicarbonate to an alendronic acid aqueous suspension.
- the resulting solution is filtered, then lyophilized by freezing it to temperatures below -30°C, typically about -45°C, under pressures below 100 mbars, with a lyophilization temperature gradient ranging from about 0 to about 50°C.
- the solution can be subjected to spray drying using conventional techniques and apparatuses.
- Example 1 illustrates the invention in greater detail.
- Example 3 The procedure as described in Example 1 is followed, but using sodium carbonate instead of sodium hydroxide for adjusting pH to 4.3 - 4.4. The same amorphous monosodium alendronate as in Example 1 is obtained.
- Example 3 The same amorphous monosodium alendronate as in Example 1 is obtained.
- Example 1 1 g of alendronic acid is suspended in 100 mL of water. The procedure as described in Example 1 is followed to obtain the same compound as in Example 1.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Physical Education & Sports Medicine (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Rheumatology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
Alendronic acid amorphous monosodium salt having improved absorption characteristics compared with the corresponding crystalline forms, it obtained by lyophilization or spray drying.
Description
AMORPHOUS MONOSODIUM ALENDRONATE AND PREPARATION THEREOF
The present invention relates to the amorphous form of monosodium alendronate, a process for the preparation thereof and * oral pharmaceutical compositions containing amorphous monosodium alendronate.
Alendronic acid, i.e. 4-amino-l-hydroxy-butylidene diphosphonic acid (disclosed in EP 39 033) and the pharmaceutically acceptable salts thereof, particularly the sodium salts, have been used for some time in therapy for inhibiting hypercalcemia conditions in a number of disorders characterized by abnormal calcium metabolism.
The therapeutical indications for this medicament mainly comprise osteoporosis, Paget' disease, bone metastases.
More particularly, alendronic acid is administered through the oral route in the form of the crystalline trihydrate monosodium salt, disclosed in EP 402 152.
Recently, an anhydrous crystalline form of monosodium alendronate has been described (WO 96/39149) which apparently induces fewer side effects at the gastro-intestinal level.
Studies and research in almost every field of the pharmaceutical industry have been focused on the effects of any polymorphisms on the pharmacokinetic, toxicological and technological aspects of drugs. In the case of monosodium alendronate, according to the known technical documents cited above, a crystalline form is preferred, either anhydrous or trihydrate.
It has now surprisingly been found that monosodium alendronate in the amorphous form ensures optimum absorption characteristics, providing better bioavailability than the crystalline forms used to date in therapy, in
particular compared with the marketed trihydrate form.
Therefore, the present invention relates to oral pharmaceutical formulations containing as active ingredient amorphous monosodium alendronate in effective amounts, in admixture with suitable carriers or excipients.
The compositions of the invention will be preferably in the form of soft- or hard- gelatin capsules, tablets, suspensions, solutions, syrups, drops or other forms suitable for the oral administration. Capsules and tablets are most preferred. The therapeutical dosage will depend on a number of factors (weight, sex, age of the patient and type of disorder), but usually it will be similar to that already established for the trihydrate crystalline form. As a rule, the daily dosage will range from 0.01 to 1 mg/kg body weight.
The amorphous form of the invention preferably contains more than 2% by weight of water.
The absence of crystallinity has been determined by X ray diffraction spectroscopy.
The monosodium alendronate amorphous form of the invention can be prepared by lyophilizing or spray drying the aqueous solution resulting from the addition of a stoichiometric amount of sodium hydroxide, sodium carbonate or sodium bicarbonate to an alendronic acid aqueous suspension.
The resulting solution is filtered, then lyophilized by freezing it to temperatures below -30°C, typically about -45°C, under pressures below 100 mbars, with a lyophilization temperature gradient ranging from about 0 to about 50°C.
Alternatively, as mentioned above, the solution can be subjected to spray drying using conventional techniques and apparatuses.
The following examples illustrate the invention in greater detail.
Example 1
10 g of alendronic acid are suspended in 200 mL of water. 1M NaOH is added to pH 4.3 - 4.4 to obtain a clear solution which is filtered through 0.22 micron filter, frozen at -45°C and lyophilized (< 100 mbar, 0-47°C) to give amorphous monosodium alendronate with water content >2%.
Example 2
The procedure as described in Example 1 is followed, but using sodium carbonate instead of sodium hydroxide for adjusting pH to 4.3 - 4.4. The same amorphous monosodium alendronate as in Example 1 is obtained. Example 3
1 g of alendronic acid is suspended in 100 mL of water. The procedure as described in Example 1 is followed to obtain the same compound as in Example 1.
Example 4 10 g of alendronic acid are suspended in 200 mL of water. 1M NaOH is added to pH 4.3 - 4.4, to obtain a clear solution which is filtered through 0.22 micron filter and subjected to spray drying under pressure (nozzle temperature = 180-200°C). The resulting amorphous monosodium alendronate is the same as in Example 1.
Claims
1. Amorphous monosodium alendronate.
2. Amorphous monosodium alendronate containing more than 2% by weight of water.
3. Pharmaceutical compositions containing as active ingredient amorphous monosodium alendronate of claim 1 or 2 in admixture with carriers or excipients.
4. Compositions as claimed in claim 3 in the form of soft- or hard- gelatin capsules or tablets.
5. A process for the preparation of amorphous monosodium alendronate which comprises lyophilizing or spray drying the aqueous solution resulting from the addition of a stoichiometric amount of sodium hydroxide, sodium carbonate or sodium bicarbonate to an alendronic acid aqueous suspension.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI2002A000146 | 2002-01-29 | ||
| IT2002MI000146A ITMI20020146A1 (en) | 2002-01-29 | 2002-01-29 | AMORPHOUS MONOSODIUM ALENDRONATE AND PROCESS FOR ITS PREPARATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2003064438A1 true WO2003064438A1 (en) | 2003-08-07 |
Family
ID=11449012
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2002/007066 WO2003064438A1 (en) | 2002-01-29 | 2002-06-26 | Amorphous monosodium alendronate and preparation thereof |
Country Status (2)
| Country | Link |
|---|---|
| IT (1) | ITMI20020146A1 (en) |
| WO (1) | WO2003064438A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ297262B6 (en) * | 2004-12-28 | 2006-10-11 | Zentiva, A. S. | Trisodium salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid |
| US7611722B2 (en) | 2001-12-24 | 2009-11-03 | Teva Pharmaceutical Industries Ltd. | Dosage form with a core tablet of active ingredient sheathed in a compressed annular body of powder or granular material, and process and tooling for producing it |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0402152A2 (en) * | 1989-06-09 | 1990-12-12 | Merck & Co. Inc. | Crystalline 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodium trihydrate, process therefor and compositions and use thereof |
| WO1996039149A1 (en) * | 1995-06-06 | 1996-12-12 | Merck & Co., Inc. | Anhydrous alendronate monosodium salt formulations |
| WO2000012517A1 (en) * | 1998-08-27 | 2000-03-09 | Teva Pharmaceutical Industries Ltd. | Novel hydrate forms of alendronate sodium, processes for manufacture thereof, and pharmaceutical compositions thereof |
| WO2000034293A1 (en) * | 1998-12-10 | 2000-06-15 | Aesgen, Inc. | Method for preparation of disodium pamidronate |
| WO2003033508A1 (en) * | 2001-10-18 | 2003-04-24 | Cipla Ltd. | Pharmaceutically acceptable alendronate salts in amorphous form |
-
2002
- 2002-01-29 IT IT2002MI000146A patent/ITMI20020146A1/en unknown
- 2002-06-26 WO PCT/EP2002/007066 patent/WO2003064438A1/en not_active Application Discontinuation
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0402152A2 (en) * | 1989-06-09 | 1990-12-12 | Merck & Co. Inc. | Crystalline 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodium trihydrate, process therefor and compositions and use thereof |
| WO1996039149A1 (en) * | 1995-06-06 | 1996-12-12 | Merck & Co., Inc. | Anhydrous alendronate monosodium salt formulations |
| WO2000012517A1 (en) * | 1998-08-27 | 2000-03-09 | Teva Pharmaceutical Industries Ltd. | Novel hydrate forms of alendronate sodium, processes for manufacture thereof, and pharmaceutical compositions thereof |
| WO2000034293A1 (en) * | 1998-12-10 | 2000-06-15 | Aesgen, Inc. | Method for preparation of disodium pamidronate |
| WO2003033508A1 (en) * | 2001-10-18 | 2003-04-24 | Cipla Ltd. | Pharmaceutically acceptable alendronate salts in amorphous form |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7611722B2 (en) | 2001-12-24 | 2009-11-03 | Teva Pharmaceutical Industries Ltd. | Dosage form with a core tablet of active ingredient sheathed in a compressed annular body of powder or granular material, and process and tooling for producing it |
| CZ297262B6 (en) * | 2004-12-28 | 2006-10-11 | Zentiva, A. S. | Trisodium salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| ITMI20020146A0 (en) | 2002-01-29 |
| ITMI20020146A1 (en) | 2003-07-29 |
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