Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus acids or salts thereof
Reexamination Certificate
2000-08-15
2001-07-31
Vollano, Jean F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus acids or salts thereof
Reexamination Certificate
active
06268524
ABSTRACT:
BACKGROUND OF THE INVENTION
Disodium 3-amino-1-hydroxypropane-1,1-diphosphoniate or “disodium pamidronate” has the formula:
It is commercially available as the lyophilized pentahydrate, under the name AREDIA® from Novartis Pharmaceuticals Corp., and is used to inhibit bone resorption, i.e., to treat moderate or severe hypercalcemia associated with malignancy, with or without bone metastases. The preparation of the crystalline pentahydrate from pamidronic acid is disclosed by Stahl et al. in U.S. Pat. Nos. 4,711,880 and 4,639,338. This material is prepared by partially neutralizing a heated slurry of pamidronic acid with aqueous sodium hydroxide (NaOH) to pH 7-7.5 and then initiating crystallization at ≧50° C. The mixture is slowly cooled to 0-5° C. and the disodium pamidronate is collected by filtration. This product is described as having “excellent crystallinity” and as being “completely stable to storage under approximately normal ambient conditions.” It comprises about 24.1-25% water.
The crystalline product (“Modification E”) is contrasted with an amorphous product disclosed to be prepared by the general process of Jary et al. (U.S. Pat. No. 4,304,734). In Comparison Example 1 of the '338 patent, pamidronic acid is neutralized to pH 7.4 with aqueous NaOH and the reaction mixture is concentrated to dryness under reduced pressure at 60-70° C. and then dried at 20 mbar to constant weight. However, the amorphous product that is obtained is described as deliquescent in air, contains 12.9% of retained water and, as taught in the '338 patent, will convert to the pentahydrate. Stahl et al. also teach the interconversion of other crystalline forms of disodilum pamidroniate depending upon humidity and amount of water present, which demonstrates the difficulty in utilizing preformed disodium salts of pamidronic acid for further processing into sterile pharmaceutical dosage forms.
Thus, a need exists for a simple method to prepare disodium pamidronate that is stable to storage and suitable for reconstitution and intravenous infusion/injection.
SUMMARY OF THE INVENTION
The present invention provides a method for the preparation of amorphous, essentially anhydrous (≦1-2 wt-% water) disodium pamidronate (the “product”). The product of the invention can be stored under nitrogen at otherwise ambient conditions, and readily reconstituted with sterile water or physiological salt solutions for injection or infusion into a patient in need of treatment therewith.
The method comprises addition of aqueous sodium hydroxide to a stirred slurry of pamidronic acid in an about 2:1 molar ratio of NaOH to acid, optionally comprising excess mannitol, to yield a clear solution of pH 6.5±0.1. Aqueous phosphoric acid is added as needed if the pH following NaOH addition is too high. A small amount of aqueous NaOH can be added if the pH is too low. Preferably, 1 N aqueous NaOH is used.
The solution is frozen and lyophilized under reduced pressure to yield amorphous, essentially anhydrous disodium pamidronate. The product is stable when stored under dry nitrogen at otherwise ambient conditions.
Preferably, the about pH 6.5 solution is filtered and aliquots are introduced into suitable container(s), then frozen (−25 to −40° C.), lyophilized (10-25 mbar, 20-40° C.) in situ, and the containers sealed under positive nitrogen pressure to yield a plurality of unit dosage forms of disodium pamidronate, optionally in admixture with mannitol.
For example, vials containing 30 mg, 60 mg and 90 mg of sterile lyophilized disodium pamidronate, each optionally containing 470 mg, 400 mg, and 375 mg of mannitol can readily be prepared and utilized as disclosed in
Physician's Desk Reference
(52d ed., 1988) at pages 1824-1828.
As used herein, the term “about” incorporates inherent variability of the parameter referenced, due to measurement techniques known to the art, i.e., pH, or water content (loss on drying).
REFERENCES:
patent: 3962432 (1976-06-01), Schmidt-Dunker
patent: 4142916 (1979-03-01), Ogasa et al.
patent: 4304734 (1981-12-01), Jary et al.
patent: 4327039 (1982-04-01), Blum et al.
patent: 4439194 (1984-03-01), Harwood et al.
patent: 4513891 (1985-04-01), Hain et al.
patent: 4639338 (1987-01-01), Stahl et al.
patent: 4711880 (1987-12-01), Stahl et al.
patent: 4797388 (1989-01-01), Francis
patent: 4814326 (1989-03-01), Rosini et al.
patent: 4816259 (1989-03-01), Matthews et al.
patent: 4922007 (1990-05-01), Kieczykowski et al.
patent: 5096717 (1992-03-01), Wirth et al.
patent: 5139786 (1992-08-01), Ferrini et al.
patent: 5159108 (1992-10-01), Kieczykowski
patent: 5296475 (1994-03-01), Flesch et al.
patent: 5344825 (1994-09-01), Khanna et al.
patent: 5366965 (1994-11-01), Strein
patent: 5403829 (1995-04-01), Lehtinen et al.
patent: 5431920 (1995-07-01), Bechard
patent: 5449819 (1995-09-01), Venkataramani et al.
patent: 5650165 (1997-07-01), Akemi et al.
patent: 5780055 (1998-07-01), Habib et al.
patent: 5785985 (1998-07-01), Czech et al.
patent: 5888550 (1999-03-01), Cook et al.
patent: 5932240 (1999-08-01), D'Angelo et al.
patent: 19820974 (1999-11-01), None
patent: 0177443 (1984-08-01), None
patent: 88/00829 (1988-02-01), None
Bentley's “Textbook of Phamaceuticals” Eighth Edition edited by Rawlins pp 186-194, 1977.*
English translation of “Angewandte Biopharmazie” ed by Ritschel p.12 (submitted p 1 +12), 1973.*
CA:75:91517 abs of Pharmazie by Huettehrauch et al 26(7), pp 438 1971.*
“Aredia (R)—Pamidronate Disodium for Injection”,Physicians' Desk Reference, 52nd Edition, Arky, R., (ed.), Medical Economics Company, Inc., Montvale, N.J., p. 1824-1828, (1998).
“CA:111:28530 abs if WO8800829”, (Feb. 1998).
Cooper, J., “Quality Control of Plastic Pharmaceutical Containers”,Cron. Farm., 14(1), Abstract, CAPLUS Document No. 75:40273, pp. 19-27, (1971).
Nicklin, P.L., et al., “Development of a Minimum-Calcuium Caco-2 Monolayer Model: Calcium and Magnesium Ions Retard the Transport of Pamidronate”,Int. J. Pharm., 123(2), Abstract, CAPLUS Document No. 123:1319687, pp. 187-197, (1995).
Su, G., et al., “Preparation of amino-diphosphinic acid and its sodium salts as bone absorption inhibitors”,Chemical Abstracts, 128(10), Abstract No. 115081, 1 p., (Mar. 9, 1998).
Aesgen, Inc.
Schwegman Lundberg Woessner & Kluth P.A.
Vollano Jean F.
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