| High-purity composition comprising (7a,17a)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one and a process for purifying (7a,17a)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one -> Monitor Keywords |
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High-purity composition comprising (7a,17a)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one and a process for purifying (7a,17a)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-oneRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Cyclopentanohydrophenanthrene Ring System Doai, Oxygen Double Bonded To A Ring Carbon Of The Cyclopentanohydrophenanthrene Ring System, Oxygen Single Bonded To A Ring Carbon Of The Cyclopentanohydrophenanthrene Ring SystemHigh-purity composition comprising (7a,17a)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one and a process for purifying (7a,17a)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20050245496, High-purity composition comprising (7a,17a)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one and a process for purifying (7a,17a)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of application Ser. No. 10/887,397, filed Jul. 8, 2004, pending, which is a continuation of U.S. Ser. No. 09/787,215, filed May 17, 2001, pending, which is the national phase of PCT International Application No. PCT/EP99/07768, filed Oct. 11, 1999, now International Publication No. WO 00/23460, with a publication date of Apr. 27, 2000, the contents of both of which is incorporated by this reference. TECHNICAL FIELD [0002] The invention relates to a high-purity composition comprising (7.alpha., 17.alpha.)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-- 3-one, a method for the preparation of this compound for use in the pharmaceutical composition, as well as a pharmaceutical composition prepared by admixing a pharmaceutically suitable carrier and the high-purity composition. BACKGROUND [0003] The compound (7.alpha., 17.alpha.)-17-hydroxy-7-methyl-19-nor-17-pr- egn-5(10)-en-20-yn-3-one (Tibolone) having the structural formula 1: 1 [0004] is known, for example from U.S. Pat. Nos. 3,340,279 and 4,701,450. The method described in these patents leads to a compound having combined oestrogenic, progestagenic and androgenic characteristics. This compound is used in medicaments having gonadomimetic, ovulation-inhibiting or immuno-modulating action. [0005] Compositions comprising Tibolone and a pharmaceutically acceptable solid carrier have been described in European Patent application 389,035, which disclosure is incorporated herein by reference. Tablets are available on the European market under the name of Livial.RTM.. [0006] The known tablets can be stably stored very well for, typically, two years at ambient temperature. A sufficiently humid atmosphere (e.g., 50-70% relative humidity) makes for a better storage stability than a relatively dry atmosphere (e.g., 45% relative humidity or below that). [0007] A problem in the preparation of pharmaceutical dosage units is that during their preparation, the relative amount of impurities may increase. In particular, the amount of one of the impurities which is already present in the bulk preparation, i.e., (7.alpha., 17.alpha.)-17-hydroxy-7- -methyl-19-nor-17-pregn-4-en-20-yn-3-one (Org OM38) tends to increase during the process of making pharmaceutical dosage units. It is furthermore known that the amounts of Org OM38 in compositions comprising Tibolone increase upon storage. [0008] The end of shelf life specification with respect to the amount of Org OM38 formed during storage is 5%. A minimum acceptable shelf life period for these dosage units is one year. [0009] The customary amount of Tibolone in the known dosage unit is 2.5 mg in tablets or capsules of 100 mg total weight, i.e., 2.5%. For the sake of providing therapies better tailored to an individual woman's needs, it is desired to provide dosage units having a lower amount. [0010] However, adaptation of a known formulation by simply including a lower amount of Tibolone further decreases the stability of the dosage unit substantially. For example, if a 2.5 mg Tibolone dosage unit has a shelf life of, for example, two to three years at room temperature, the same unit upon lowering the amount of Tibolone to, for example, 0.3 mg can only be kept at 4.degree. C. for a period of 6 to 12 months. Such a lower stability is unacceptable in daily practice. [0011] One of the possibilities to also keep the amount of Org OM-38 below a desired level after a prolonged storage time is to limit the amount initially present in the bulk preparation. Thus, a need exists to synthesize high-purity Tibolone batches with a low contamination content of Org OM-38. [0012] During the last step of the synthesis of Tibolone, a solution of (7.alpha., 17.alpha.)-3,3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5 (10)-en-20-yn-3-one in a mixture of pyridine and ethanol is mixed with a solution of oxalic acid in water and the mixture is stirred for three hours at approximately 30.degree. C. The solution is then poured out in a mixture of pyridine and water and the resulting suspension is filtered. The crystals are washed with a mixture of water and pyridine and subsequently, the crystals are dried under vacuum at 40.degree. C. to give (7.alpha., 17.alpha.)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn- -3-one (see also van Vliet et al (1986), Recl. Trav. Chim. Pays-Bas 105, 111-115). [0013] As this compound has a lower stability than the corresponding (7.alpha., 17.alpha.)-17-hydroxy-7-methyl-19-nor-pregn-4-en-20-yn-3-one, there is always formed a small percentage of the latter compound via acid catalyzed isomerization. Furthermore, this isomerization takes place at higher temperatures and upon long-term storage of the crystals. SUMMARY OF THE INVENTION [0014] Unexpectedly, it has been found that the rate of formation of Org OM38 during drying and storage in a specific batch can be decreased if crystals of Tibolone are washed with water and are allowed to age for at least 24 hours in the presence of water. Thus, the Tibolone is left for at least 24 hours under wet conditions. Preferentially, the crystals are left under these conditions for a period of at least three days. There is no limit to a maximum period but a period of three to six days is best suited. The aging temperature is preferably room temperature. [0015] Thus, according to the procedure of the present invention, highly pure Tibolone with a low Org OM38 impurity is obtained by including a delay of several days before drying. The procedure reliably results in batches of Tibolone having a low Org OM38 content. A further advantage is that these batches have an excellent stability. Furthermore, these batches do not form additional amounts of the latter compound upon heating or long-term storage. [0016] The invention provides dosage forms having a lower content of Tibolone (which are more prone to stability problems than regular dosage forms) that can be suitably kept for a prolonged period of time. The present invention further provides for high-purity batches of Tibolone. The invention also improves upon the storage stability, i.e., enhances the shelf life of the dosage units. [0017] The crystal formation procedure of the present invention can be combined perfectly well with the last step of the Tibolone synthesis wherein (7.alpha., 17.alpha.)-3,3-dimethoxy-17-hydroxy-7-methyl-19-norpre- gn-5 (10)-en-20-yn-3-one in a mixture of pyridine and ethanol is mixed with a solution of oxalic acid in water. In general, this reaction proceeds under mild acidic conditions in the presence of an organic solvent and water within a pH range of 3 to 5, preferentially 3.5 to 4.5. The acid preferentially is a weak organic acid having a pKa value in the range of 1 to 5, such as, citric acid, malonic acid, oxalic acid, dichloroacetic acid and acetic acid, optionally buffered with a base such as pyridine. As the organic solvent, for example, ethanol, methanol, acetone, 2-propanol or tetrahydrofuran, can be used. The solution is then poured out in water, which is made slightly alkaline by addition, for example, of a low amount of pyridine. After filtering the suspension, the crystals are washed with a mixture of water made slightly alkaline by, for example, pyridine. Before drying, the crystals are left wet for at least 24 hours. [0018] Inclusion of the crystal aging step according to the invention results in bulk Tibolone batches with a low Org OM38 content. Routinely, batches are obtained with an Org OM38 content of less than 0.5%. Often, even batches with less than 0.25% or even 0.1% of Org OM38 are obtained. Thus, high-purity compositions with Tibolone having less than 0.5% of Org OM38, preferably 0.25%, more preferably 0.10% of Org OM38 form part of the present invention. The amount of Org OM38 is calculated as the percentage (w/w) of the total amount of the bulk substance including some minor impurities. The amount of Tibolone usually is more than 98%. [0019] The batches of these high-purity Tibolone compositions with their low initial Org OM38 content are perfectly well suited to be used as a source for the preparations of pharmaceutical formulations. This guarantees a formulation with a low initial Org OM38 content and, therefore, improves its storage properties. Pharmaceutical preparations prepared with high-purity Tibolone usually result in preparations with less than 1% of Org OM38, often even less than 0.7% of Org OM38, and these preparations are less prone to increase in Org OM38 content during storage. [0020] As indicated herein, the amount of Org OM38 in a dosage form also depends upon the concentration of the active substance, the amount of impurity increasing as the amount of Tibolone in the dosage unit decreases. Therefore, by using the high-purity Tibolone as the active substance, dosage units can now be prepared with a lower amount of Tibolone and still have an acceptable shelf life. Thus, the invention also relates to pharmaceutical dosage units, which can be prepared by admixture of a pharmaceutically suitable solid carrier and the high-purity composition of the present invention. Continue reading about High-purity composition comprising (7a,17a)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one and a process for purifying (7a,17a)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one... 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