Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1996-03-28
1998-04-21
Kishore, Gollamudi S.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424400, 514559, 514573, A61K 31557, A61K 914
Patent
active
057415234
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Prostaglandin E.sub.1 (PGE-1) is an inherently unstable compound. PGE-1 is chemically (11.alpha., 13E, 15S )-11,15-dihydroxy-9-oxoprost-13-en-1-oic acid; or 3-hydroxy-2-(3-hydroxy-1l-octenyl)-5-oxo-cyclopentaneheptanoic acid; and is commonly referred to as alprostadil or PGE.sub.1. PGE-1 is a primary prostaglandin which is easily crystallized from purified biological extracts. A goal of this invention was the development of a room temperature stable formulation of PGE-1. More preferred would be a method to stabilize a low dose (5-20 .mu.g) formulation of PGE-1 suitable for use in the treatment of erectile dysfunction.
Various attempts to freeze-dry PGE-1 have been described in U.S. Pat. Nos. 3,952,004 and 3,927,197. The first patent "004 describes the stabilization of PGE-1 in tertiary butyl alcohol and sodium chloride and that lactose or other "simple sugars" destabilize PGE-1. The second patent '197 describes PGE-1 stabilized with tertiary butyl alcohol.
Despite various attempts to stabilize PGE-1, better and more effective methods are in demand to increase shelf life and maintain efficacy. PGE-1 formulations in lactose appears to degrade through an apparent second order mechanism with respect to PGE.sub.1 concentration in the solid state. Maximum stability can be achieved by either minimizing the PGE-1 concentration in a suitable lactose diluent or by optimizing other parameters which may impact the second order rate constant. The second order rate constant is affected by the solid state pH, the buffer content, the moisture content, the use of tertiary butyl alcohol during processing, the freezing rate, and the drying rate. All of these parameters have been optimized to minimize the value of the second order rate constant.
SUMMARY OF THE INVENTION
In one aspect the subject invention is a lyophilized formulation of PGE-1 made by the process comprising:
a) dissolving PGE-1 in a solution of lactose and tertiary butyl alcohol wherein the tertiary butyl alcohol is present in an amount of from about 15% to 33% volume/volume and the ratio of lactose to PGE-1 is from about 40,000 to 1 to about 10,000 to 1 weight/weight (25 to 100 ppm in lactose) whereby a formulation of PGE-1dispersed in lactose is formed;
b) adjusting and maintaining the pH of the formulation from about 3.5 to about 6 with an organic acid buffer (preferably sodium citrate);
c) freezing the formulation to about -50.degree. C.; and
d) drying the formulation to obtain a moisture content of less than 1% by dry weight and a tertiary butyl alcohol content of less than 3% by dry weight. ppm lactose and the pH is adjusted and maintained at 4 to 5 by the presence of a buffer. Preferably, the freezing step (c) includes an annealing process by freezing the formulation to about -50.degree. C., warming to about -25.degree. C. for about 2 hours then refreezing to about -50.degree. C.
In another aspect, the subject invention is a method for preparing a stabilized, lyophilized formulation of PGE-1 comprising the steps set forth above.
In yet another aspect, the present invention is a freeze-dried formulation of PGE-1 for use in the treatment of erectile dysfunction. Typical dosages of the formulation are (5-20 .mu.g) formulations of PGE-1. These formulations correspond to a ratio of lactose to PGE-1 of from about 40,000 to 1 to about 10,000 to 1 weight/weight (25 to 100 ppm in lactose). That is, 5 .mu.g corresponds to 40,000 to 1; 10 .mu.g corresponds to 20,000 to 1 and 20 .mu.g corresponds to 10,000 to 1.
DETAILED DESCRIPTION OF THE INVENTION
The subject invention is a lyophilized PGE-1 composition made from a bulk sterile filtered solution which contains 20% v/v tertiary butyl alcohol (TBA) and has an apparent pH of approximately 4. Both the water and TBA are removed during the freeze-drying process. Residual water and TBA remaining after lyophilization are <0.5% and 0.5-2% respectively of the dried cake mass. In one formulation, a vial dosage contains after completion of lyophilization: 23 .mu.g of PGE-1 (alprostadil),
REFERENCES:
patent: 3927197 (1975-12-01), Moonkhouse
patent: 3952004 (1976-04-01), Moonkhouse
patent: 4113882 (1978-09-01), Okazaki
patent: 5082664 (1992-01-01), Lenk
Congres International de Technologie Pharmaceutique, P.P. Deluca et al., "Acceleration of Freeze-Drying Cycles of Aqueous Solutions of Lactose and Sucrose With Tertiary Butyl Alcohol", 574, vol. 1, pp. 439-447 (1989).
Gold Paul M.
Petre William J.
Teagarden Dirk L.
Corneglio Donald L.
Kishore Gollamudi S.
Pharmacia & Upjohn Company
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