Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1998-06-17
2001-02-13
Moezie, F. T. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S559000
Reexamination Certificate
active
06187818
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the manufacture of an improved formulation for prostaglandins such as dinoprost tromethamine, a compound marketed under the trademark Lutalyse®.
BACKGROUND OF THE INVENTION
Dinoprost tromethamine, a compound marketed under the trademark Lutalyse®, is described and claimed in U.S. Pat. No. 3,917,864 (incorporated herein by reference). When properly administered this compound is able to induce regression of the corpora lutea of many mammals, especially farm animals such as horses, cows and pigs. The active ingredient is frequently formulated as a solution intended for administration by injection. Here we present a surprising and new formulation of dinoprost tromethamine solution for injection that provides advantages over currently available formulations. This new method of formulation appears suitable for dinoprost tromethamine and other prostaglandin drugs.
SUMMARY OF THE INVENTION
This invention comprises new formulations, both as compositions per se and as products by process as well as new procedures for making those formulations. The formulations include, a solution comprising a prostaglandin such as dinoprost tromethamine and benzyl alcohol, the benzyl alcohol may be between about 1.2 to 2.0%, the entire solution is adjusted to a pH of between about 5.5-7.5, or more preferred to a pH of between about 6-7 and most preferred is between about 6.4-6.6, or about 6.5. The concentration of dinoprost tromethamine may be 1-10 mg/ml, preferably it is 3-7 mg/ml and more preferably it is 5 mg/ml. The concentration of benzyl alcohol may be between about 12-20 mg/ml and the concentration of dinoprost tromethamine may be between about 4-6 mg/ml. Preferably the concentration of dinoprost tromethamine is about 5 mg/ml and the concentration of benzyl alcohol is about 16.5 mg/ml in the final solution. The solution may be adjusted to a pH of about 6.5 or 6.6.
Also disclosed is a product made by a particular process. A solution of prostaglandin and benzyl alcohol adjusted to a pH of between about 5.5-7.5, more preferred is between about 6-7 and most preferred is between about 6.4-6.7, or about 6.5, where the concentration of benzyl alcohol is between about 1.2 to 2%, more preferred is 1.4 to 1.8%, with the most preferred being 1.65% and where the concentration of dinoprost tromethamine is 1-10 mg/ml., made by the process of either a) dissolving dinoprost tromethamine in water and then adding diluted benzyl alcohol or diluting benzyl alcohol and adding the dinoprost to the benzyl alcohol water solution (where diluted benzyl alcohol may be a solution of between about 4 and 1.2% benzyl alcohol, more preferred is 1.2-3.3%, even more preferred is 1.8 to 2.6% and most preferred is a 2.0% solution of benzyl alcohol, or b) by dissolving dinoprost in one vessel and dissolving benzyl alcohol in water in another vessel, using a solution of benzyl alcohol between about 4.0%-1.2%, more preferred is 1.2-3.3%, even more preferred is 1.8 to 2.6% and most preferred is a 2.0% solution of benzyl alcohol, followed by mixing the contents of the two vessels. This is followed by adjusting the pH to between about 5.5 and 7.5 or more preferably between about 6 and 7 with a weak acid or base, and if needed with a final pH adjustment of between 5.5-7.5, or better between about 6-7 or even better right at about 6.5. The prostaglandin formulated by this process may be dinoprost tromethamine. In this process the pH of the benzyl alcohol water solution may be adjusted to between 5.5-7.5 before or after it is mixed with the dinoprost tromethamine in water solution. The pH may be adjusted with an acid or base such as HCl or NaOH. The final concentration of benzyl alcohol can be between about 1.2 and 2.0% or more preferred is between about 1.4 and 1.8%, even more preferred is between about 1.6-1.7% or about 1.65% which is also about 16.5 mg/ml of benzyl alcohol in water in the final solution.
Also disclosed is a process for preparing a pharmaceutical formulation of a prostaglandin comprising: either I) dissolving the prostaglandin in water first and then adding benzyl alcohol or II) diluting benzyl alcohol in water to a solution of about 4% or less and then adding the prostaglandin. If the former procedure is used, it may be done by a) dissolving dinoprost tromethamine in water and adding diluted (solution of 4% to 1.2% benzyl alcohol) and adjusting the pH to between about 5.5.-7.5, or 6-7 or about 6.5 or b) dissolving dinoprost tromethamine in water in one vessel and dissolving benzyl alcohol in water in another vessel, followed by mixing the contents of the two vessels together and adjusting the pH to between about 5.5.-7.5, or about 6.0-7.0 or about 6.5 with a weak acid or base. The prostagladin can be dinoprost tromethamine. The concentration of benzyl alcohol in this process can be between about 1.2 to 2.0%, or 1.4-1.8%, 1.5-1.7%, 1.6-1.7%, preferably it is 1.65% or 16.5 mg/ml.
A different but related procedure may be used where the dinoprost is added to water and then the pH is raised to pH 8.0 or above, then benzyl alcohol is added (either pure or diluted benzyl alcohol) and then the pH is lowered to between about 5.5.-7.5, or 6-7 or about 6.5 with a weak acid or base
The concentration of dinoprost tromethamine is 1-10 mg/ml in the process, preferably 3-7 mg/ml, more preferably it is 4-6 mg/ml and even more preferably 5 mg/ml. In this process the pH may be adjusted in the benzyl alcohol water solution both after the benzyl alcohol is mixed with the water but before the dinoprost tromethamine water solution is added to the benzyl alcohol water solution and/or after the the benzyl alcohol water solution is added to the dinoprost tromethamine water solution or the pH may be adjusted either before or after the benzyl alcohol in water solution is made and before or after the dinoprost is added to the diluted alcohol water solution if that procedure is used and with either of these procedures, the final pH may be adjusted to between about pH 5.5-7.5 or more preferably 6.0 or 7.0, or more preferred between about 6.4-6.6 or about 6.5 for either or both pH adjustments. The concentration of benzyl alcohol in this process can be between about 1.2 to 2.0%, or 1.4-1.8%, 1.5-1.7%, 1.6-1.7%, preferably it is about 1.65% or 16.5 mg/ml.
ADDITIONAL DESCRIPTION OF THE INVENTION
Dinoprost tromethamine is a type of prostaglandin, see U.S. Pat. No. 3,917,864, incorporated by reference. Prior to this invention it was widely believed that most prostaglandins, and dinoprost tromethamine in particular, needed to be formulated into an alkaline solution in order to produce chemically and physically stable solutions of the drug. For example see, Mats Hamberg, Lian-Ying Zhang, Sune Bergstroem, “On the pH-dependent degradation of 15(S)-15 methyl-prostaglandin F2 alpha (Carboprost)”
Eur. J. Pharm. Sci.,
3(1), 27-38 (English) 1995. This study found a gradual increase in stability of a tromethamine salt of a prostaglandin when the pH values of the buffers used were increased from 9.1 to higher and concluded that the drug could be stored for at least a year with only 3-4% degradation when maintained at 37 degree provided the buffer was maintained at pH 9.55. The study is typical of what was believed about prostaglandins, that they were more stable when maintained at a higher pH. The inventors here have discovered a new method of making a new formulation of dinoprost tromethamine that no longer requires an alkaline formulation. The elimination of the alkaline normally used to keep dinoprost tromethamine and other prostaglandins chemically stable and in solution may even allow for an injectable formulation with fewer injection site complications than a high pH solution.
In addition to these important pH related improvements to this new formulation and method of manufacture of prostaglandins the inventors have discovered a novel method of producing an injectable solution that is superior at decreasing microbial contamination of the solution. The inventors here have created a novel method of producing a st
Moezie F. T.
Pharmacia & Upjohn Company
Solomon Andrew M.
Wootton Thomas A.
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