US20050245496A1 - 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 - Google Patents
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 Download PDFInfo
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- US20050245496A1 US20050245496A1 US11/176,842 US17684205A US2005245496A1 US 20050245496 A1 US20050245496 A1 US 20050245496A1 US 17684205 A US17684205 A US 17684205A US 2005245496 A1 US2005245496 A1 US 2005245496A1
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- tibolone
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- WZDGZWOAQTVYBX-SRXZLZDISA-N C#C[C@]1(O)CCC2C3C(CCC21C)C1=C(CC(=O)CC1)C[C@H]3C Chemical compound C#C[C@]1(O)CCC2C3C(CCC21C)C1=C(CC(=O)CC1)C[C@H]3C WZDGZWOAQTVYBX-SRXZLZDISA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
- C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
- C07J1/0096—Alkynyl derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
Definitions
- the invention relates to a high-purity composition
- a high-purity composition comprising (7 ⁇ , 17 ⁇ )-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.
- the compound (7 ⁇ , 17 ⁇ )-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one (Tibolone) having the structural formula 1: 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.
- 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®.
- 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
- a relatively dry atmosphere e.g., 45% relative humidity or below that.
- a problem in the preparation of pharmaceutical dosage units is that during their preparation, the relative amount of impurities may increase.
- the amount of one of the impurities which is already present in the bulk preparation i.e., (7 ⁇ , 17 ⁇ )-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.
- Org OM38 in compositions comprising Tibolone increase upon storage.
- 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.
- 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.
- 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.
- the Tibolone is left for at least 24 hours under wet conditions.
- 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.
- 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.
- the crystal formation procedure of the present invention can be combined perfectly well with the last step of the Tibolone synthesis wherein (7 ⁇ , 17 ⁇ )-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.
- 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.
- 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.
- 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
- 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%.
- 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.
- 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.
- a typical known formulation for Tibolone is a 100 mg dosage unit having 2.5 mg of Tibolone contained therein, a relatively small amount (e.g., approximately 1% by weight) of pharmaceutically acceptable auxiliaries, and a carrier making up the body of the tablet.
- the carrier typically is composed of 10% by weight of starch, for example, potato starch, and 90% by weight of lactose.
- the present invention now makes it also possible to provide for stable dosage units comprising Tibolone in an amount of less than 2.50 mg, preferably 1.25 mg or less, more preferably 0.625 mg or less. At a shelf life of 1.5 years, preferably two years, these dosage units still comprise less than 5% of OM38 (relative to the amount of Tibolone).
- the shelf life preferably is extended up to one year, preferably 1.5 years, more preferably, two years.
- shelf life means storage during a specified period under temperature conditions varying from 2° C. to 25° C.
- Dosage units can be packed, e.g., in push-through packs (PTP, blister) and are preferably stored in the dark (e.g., enclosed in cartons). Alternatively, they might also be stored in bottles, for example, high-density polyethylene bottles.
- PTP push-through packs
- bottles for example, high-density polyethylene bottles.
- the pharmaceutical dosage units of the present invention will generally take the form of tablets or capsules, but other solid or dry pharmaceutical preparations may also be utilized.
- Tablets and capsules are prepared of granulates using dry or wet granulation techniques as disclosed in The Theory and Practice of Industrial Pharmacy (3rd ed.), L. Lachman, H. A. Lieberman and J. L. Kanig (1986) p 1-99 and 293-345.
- the aim of granulation is to improve the flowability and compressibility of the powder mixture.
- Wet granulation forms the granules by binding the powders (a mixture of a diluent and disintegrant) together with an adhesive.
- the wet granulation technique employs a solution, suspension or slurry containing a binder, which is usually added to the powder mixture; however, the binder may be incorporated dry to the powder mix and the liquid may be added by itself.
- the wet granulation process is performed in mixers/kneaders or fluid bed systems.
- an amount of water is incorporated in the basic granulate ranging from 5.5% to 7%.
- the amount of water incorporated is at least 6%.
- the mass is dried to the desired water content using fluid bed dryers, tray dryers, vacuum dryers or other suitable dryers.
- the active is premixed with a part of the granulate, sieved using an oscillating sieve, a high-speed sieve or other suitable sieving equipment. Next this mixture is mixed with the remaining part of the granulate and a lubricant. This mixture is compressed to tablets, or filled into capsules.
- a basic granulate was prepared by granulation of a mixture of lactose (diluent), potato starch (disintegrant) and potato starch mucilage (binder) in a fluid bed granulator.
- the water content of the granulate varied within 5.5% to 6.5%.
- the basic granulate was passed through a conical high-speed sieve.
- Part of the granulate (10% w/w) was mixed with Tibolone and ascorbyl palmitate using a tumble blender and then passed through a conical high-speed sieve.
- the Tibolone premix and the remainder of the basic granulate were mixed in a ribbon blender. Magnesium stearate was added and mixed. The final granulate was compressed into round tablets.
- Tablets of 1.25 mg of Tibolone have been prepared as described in Example 4. The tablets were stored at 25° C. and 60% relative humidity and the decomposition product (Org OM38) was measured. TABLE 2 Content of decomposition product (Org OM38) in percentage of the declared amount of Tibolone per tablet. Stability of three development tablet batches (1.25 mg of Tibolone per 65 mg) was assessed (storage at 25° C. and 60% relative humidity). Batch No. 049514001 049515001 049516001 Amount of Org OM38 formed during Storage time storage (in percentage of the declared (months) amount of Tibolone) 0 0.7 1.0 1.3 6 2.3 2.6 2.9 12 3.5 3.7 3.8 18 4.3 4.2 4.3 24 5.1 4.9 4.9
- Tibolone as prepared in Example 2 was used as the active compound to prepare described in Example 4.
- TABLE 3 The stability of six tablet batches (1.25 mg of Tibolone per 65 mg) was assessed (storage at 25° C. and 60% relative humidity). The amount of water incorporated in the basic granulate was varied from 6.0% to 6.5%. Batch No.
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Abstract
The invention pertains to a process for the preparation of a high-purity composition of (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one. The process provides for a composition with less than 0.5% of (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one. This composition can be used as a source for the preparation of stable pharmaceutical dosage units.
Description
- 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.
- The invention relates to a high-purity composition comprising (7α, 17α)-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.
- The compound (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one (Tibolone) having the structural formula 1:
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. - 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®.
- 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).
- 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., (7α, 17α)-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.
- 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.
- 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.
- 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° C. for a period of 6 to 12 months. Such a lower stability is unacceptable in daily practice.
- 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.
- During the last step of the synthesis of Tibolone, a solution of (7α, 17α)-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° 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° C. to give (7α, 17α)-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).
- As this compound has a lower stability than the corresponding (7α, 17α)-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.
- 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.
- 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.
- 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.
- The crystal formation procedure of the present invention can be combined perfectly well with the last step of the Tibolone synthesis wherein (7α, 17α)-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. 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.
- 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%.
- 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.
- 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.
- A typical known formulation for Tibolone is a 100 mg dosage unit having 2.5 mg of Tibolone contained therein, a relatively small amount (e.g., approximately 1% by weight) of pharmaceutically acceptable auxiliaries, and a carrier making up the body of the tablet. The carrier typically is composed of 10% by weight of starch, for example, potato starch, and 90% by weight of lactose.
- Due to the excellent stability properties of dosage units with a lower amount of active substance than the present commercially available tablets of 2.5 mg active substance, the present invention now makes it also possible to provide for stable dosage units comprising Tibolone in an amount of less than 2.50 mg, preferably 1.25 mg or less, more preferably 0.625 mg or less. At a shelf life of 1.5 years, preferably two years, these dosage units still comprise less than 5% of OM38 (relative to the amount of Tibolone).
- It is another aspect of the present invention to provide dosage units comprising Tibolone in amounts of less than 2.50 mg, preferably 1.25 mg or less, more preferably 0.625 mg or less and comprising at a shelf life of six months, less than 3%, preferably 2% of OM38. The shelf life preferably is extended up to one year, preferably 1.5 years, more preferably, two years.
- As used herein, “shelf life” means storage during a specified period under temperature conditions varying from 2° C. to 25° C. Dosage units can be packed, e.g., in push-through packs (PTP, blister) and are preferably stored in the dark (e.g., enclosed in cartons). Alternatively, they might also be stored in bottles, for example, high-density polyethylene bottles.
- The pharmaceutical dosage units of the present invention will generally take the form of tablets or capsules, but other solid or dry pharmaceutical preparations may also be utilized.
- Methods for making such dosage units are well known. For example, in the standard English language text, Gennaro et al., Remington's Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, see especially, Part 8, “Pharmaceutical Preparations and Their Manufacture”), methods of making tablets, capsules and pills and their respective components are described.
- Tablets and capsules are prepared of granulates using dry or wet granulation techniques as disclosed in The Theory and Practice of Industrial Pharmacy (3rd ed.), L. Lachman, H. A. Lieberman and J. L. Kanig (1986) p 1-99 and 293-345.
- The aim of granulation is to improve the flowability and compressibility of the powder mixture. Wet granulation forms the granules by binding the powders (a mixture of a diluent and disintegrant) together with an adhesive. The wet granulation technique employs a solution, suspension or slurry containing a binder, which is usually added to the powder mixture; however, the binder may be incorporated dry to the powder mix and the liquid may be added by itself. The wet granulation process is performed in mixers/kneaders or fluid bed systems.
- Usually an amount of water is incorporated in the basic granulate ranging from 5.5% to 7%. Preferably, the amount of water incorporated is at least 6%.
- After granulation, the mass is dried to the desired water content using fluid bed dryers, tray dryers, vacuum dryers or other suitable dryers.
- To attain a good distribution of the active (Tibolone) over the total mass, the active is premixed with a part of the granulate, sieved using an oscillating sieve, a high-speed sieve or other suitable sieving equipment. Next this mixture is mixed with the remaining part of the granulate and a lubricant. This mixture is compressed to tablets, or filled into capsules.
- The following examples are illustrative for the invention and should in no way be interpreted as limiting the scope of the invention.
- A solution of (7α, 17α)-3,3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (15 kg) in a mixture of pyridine (630 ml) and ethanol (315 liters) was mixed with a solution of oxalic acid (750 gr) in water (90 liters). The mixture was stirred for two hours at approximately 30° C. The solution was poured out in a mixture of pyridine (1350 ml) and water (300 liters) and the resulting suspension was filtered. The crystals were washed with a mixture of water and pyridine and dried under vacuum at 40° C. to give (7α, 17α)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one containing 0.6% of the corresponding (7α, 17α)-17-hydroxy-7-methyl-19-norpregn-4-en-20-yn-3-one as indicated by HPLC analysis. A stress test was performed at 45° C. (duration one month) which indicated a 0.4% increase of the latter compound.
- A solution of (7α, 17α)-3,3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (15 kg) in a mixture of pyridine (630 ml) and ethanol (315 liters) was mixed with a solution of oxalic acid (375 gr) in water (90 liters). The mixture was stirred for three hours at approximately 30° C. The solution was poured out in a mixture of pyridine (1350 ml) and water (300 liters) and the resulting suspension was filtered. The crystals were washed with a mixture of water and pyridine and allowed to age for three to six days at room temperature. Subsequently, the crystals were dried under vacuum at 40° C. to give (7α, 17α)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one containing ≦0.1% of the corresponding (7α, 17α)-17-hydroxy-7-methyl-19-norpregn-4-en-20-yn-3-one as indicated by HPLC analysis. A stress test was performed at 45° C. (duration one week) which indicated a <0.1% increase of the latter compound.
- The preparation as described in Example 2 was repeated. (7α, 17α)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one was obtained which contained 0.2% of the corresponding (7α, 17α)-17-hydroxy-7-methyl-19-norpregn-4-en-20-yn-3-one as indicated by HPLC analysis. A stress test was performed at 45° C. (duration one week) which indicated a 0.1% increase of the latter compound.
- A basic granulate was prepared by granulation of a mixture of lactose (diluent), potato starch (disintegrant) and potato starch mucilage (binder) in a fluid bed granulator. The water content of the granulate varied within 5.5% to 6.5%. After granulation, the basic granulate was passed through a conical high-speed sieve. Part of the granulate (10% w/w) was mixed with Tibolone and ascorbyl palmitate using a tumble blender and then passed through a conical high-speed sieve.
- The Tibolone premix and the remainder of the basic granulate were mixed in a ribbon blender. Magnesium stearate was added and mixed. The final granulate was compressed into round tablets.
- The stability of the active compound (Tibolone) in tablets was determined.
TABLE 1 Content of decomposition product (Org OM38) in percentage of the declared amount of Tibolone per tablet, in tablets containing a various amount of Tibolone, after storage at 25° C. and 60% relative humidity. Concentration of Tibolone per tablet 0.46 0.96 1.92 2.5 Storage time Amount of Org OM38 formed during storage (months) (in percentage of the declared amount of Tibolone) 0 1.2 0.8 0.5 0.4 6 6.5 3.5 1.8 1.6 12 9.5 5.1 2.7 2.2 18 12.2 6.1 3.3 2.7 - Tablets of 1.25 mg of Tibolone have been prepared as described in Example 4. The tablets were stored at 25° C. and 60% relative humidity and the decomposition product (Org OM38) was measured.
TABLE 2 Content of decomposition product (Org OM38) in percentage of the declared amount of Tibolone per tablet. Stability of three development tablet batches (1.25 mg of Tibolone per 65 mg) was assessed (storage at 25° C. and 60% relative humidity). Batch No. 049514001 049515001 049516001 Amount of Org OM38 formed during Storage time storage (in percentage of the declared (months) amount of Tibolone) 0 0.7 1.0 1.3 6 2.3 2.6 2.9 12 3.5 3.7 3.8 18 4.3 4.2 4.3 24 5.1 4.9 4.9 - It can be concluded that the shelf life of tablets containing 1.25 mg of Tibolone per tablet of 65 mg is borderline
- Tibolone as prepared in Example 2 was used as the active compound to prepare described in Example 4. The amount of Org OM38 formed in several batches during as determined.
TABLE 3 The stability of six tablet batches (1.25 mg of Tibolone per 65 mg) was assessed (storage at 25° C. and 60% relative humidity). The amount of water incorporated in the basic granulate was varied from 6.0% to 6.5%. Batch No. Storage TD96.1128 TD96.1132 TD96.1133 162454001 162455001 162456001 time Amount of Org OM38 formed during storage (months) (in percentage of the declared amount of Tibolone) 0 0.7 0.5 0.5 0.9 0.8 0.9 6 1.3 1.1 1.1 1.8 1.7 1.8 12 1.8 1.5 1.6 18 2.0 1.5 1.7 Water 6.5 6.5 6.5 6.3 6.1 6.1 content of the basic granulate
Claims (16)
1-30. (canceled)
31. A dosage unit comprising a pharmaceutically suitable solid carrier and an amount of (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one (tibolone), wherein the dosage unit contains less than 2% by weight of (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one relative to the tibolone after storage, at a temperature of 25° C. and a relative humidity of 60%, for 1.5 years, wherein the water content of a granulate of the dosage unit is between 5.5% and 6.5%.
32. The dosage unit of claim 31 , wherein the (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one is present at less than 0.25% by weight relative to the tibolone.
33. The dosage unit of claim 31 , wherein the 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one is present at less than 0.1% by weight relative to the tibolone.
34. The dosage unit of claim 31 , wherein the dosage unit includes 2.50 mg of tibolone.
35. The dosage unit of claim 34 , wherein the dosage unit is a tablet.
36. The dosage unit of claim 34 , wherein the dosage unit is a capsule.
37. The dosage unit of claim 31 , wherein the dosage unit includes 1.25 mg of tibolone.
38. The dosage unit of claim 37 , wherein the dosage unit is a tablet.
39. The dosage unit of claim 37 , wherein the dosage unit is a capsule.
40. The dosage unit of claim 31 , wherein the dosage unit includes 0.625 mg of tibolone.
41. The dosage unit of claim 40 , wherein the dosage unit is a tablet.
42. The dosage unit of claim 40 , wherein the dosage unit is a capsule.
43. The dosage unit of claim 31 , wherein the dosage unit is formed from a granulation comprising a diluent, a disintegrant, and a binder mixed with the tibilone.
44. The dosage unit of claim 43 , wherein the tibilone is allowed to age for at least 24 hours in the presence of water.
45. The dosage unit of claim 31 , wherein the tibilone was aged for at least 24 hours in the presence of water.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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US11/176,842 US20050245496A1 (en) | 1998-10-16 | 2005-07-07 | 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 |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
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EP98203460 | 1998-10-16 | ||
EP98203460.5 | 1998-10-16 | ||
US09/787,215 US6969708B1 (en) | 1998-10-16 | 1999-10-11 | Process for the preparation of a high purity composition comprising (7α, 17α)- 17-hydroxy- 7-methyl- 19-nor-17-pregn-5(10)-en-20-yn-3-one |
PCT/EP1999/007768 WO2000023460A1 (en) | 1998-10-16 | 1999-10-11 | HIGH PURITY COMPOSITION COMPRISING (7α,17α)- 17-HYDROXY- 7-METHYL- 19-NOR-17-PREGN- 5(10)-EN-20-YN-3-ONE |
US10/887,397 US20040248870A1 (en) | 1998-10-16 | 2004-07-08 | High-purity composition comprising (7alpha, 17alpha)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one and a process for purifying (7alpha, 17alpha)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one |
US11/176,842 US20050245496A1 (en) | 1998-10-16 | 2005-07-07 | 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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US10/887,397 Continuation US20040248870A1 (en) | 1998-10-16 | 2004-07-08 | High-purity composition comprising (7alpha, 17alpha)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one and a process for purifying (7alpha, 17alpha)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one |
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US20050245496A1 true US20050245496A1 (en) | 2005-11-03 |
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US09/787,215 Expired - Fee Related US6969708B1 (en) | 1998-10-16 | 1999-10-11 | Process for the preparation of a high purity composition comprising (7α, 17α)- 17-hydroxy- 7-methyl- 19-nor-17-pregn-5(10)-en-20-yn-3-one |
US10/887,397 Abandoned US20040248870A1 (en) | 1998-10-16 | 2004-07-08 | High-purity composition comprising (7alpha, 17alpha)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one and a process for purifying (7alpha, 17alpha)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one |
US11/176,842 Abandoned US20050245496A1 (en) | 1998-10-16 | 2005-07-07 | 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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US09/787,215 Expired - Fee Related US6969708B1 (en) | 1998-10-16 | 1999-10-11 | Process for the preparation of a high purity composition comprising (7α, 17α)- 17-hydroxy- 7-methyl- 19-nor-17-pregn-5(10)-en-20-yn-3-one |
US10/887,397 Abandoned US20040248870A1 (en) | 1998-10-16 | 2004-07-08 | High-purity composition comprising (7alpha, 17alpha)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one and a process for purifying (7alpha, 17alpha)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one |
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US (3) | US6969708B1 (en) |
EP (2) | EP1275379A3 (en) |
JP (1) | JP2002527525A (en) |
KR (3) | KR20060071897A (en) |
CN (2) | CN100432093C (en) |
AR (1) | AR020832A1 (en) |
AT (1) | ATE239032T1 (en) |
AU (1) | AU763232B2 (en) |
BR (1) | BR9914441A (en) |
CA (1) | CA2344686C (en) |
CO (1) | CO5160271A1 (en) |
CZ (1) | CZ298703B6 (en) |
DE (1) | DE69907495T2 (en) |
DK (1) | DK1121375T3 (en) |
ES (1) | ES2197677T3 (en) |
HK (1) | HK1039620B (en) |
HU (1) | HUP0104206A3 (en) |
ID (1) | ID28463A (en) |
IL (1) | IL141850A (en) |
NO (1) | NO317427B1 (en) |
NZ (1) | NZ510501A (en) |
PE (1) | PE20001377A1 (en) |
PL (1) | PL197870B1 (en) |
PT (1) | PT1121375E (en) |
RU (1) | RU2220975C2 (en) |
SK (1) | SK284569B6 (en) |
TR (2) | TR200504091T2 (en) |
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Cited By (1)
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WO2020131917A1 (en) * | 2018-12-17 | 2020-06-25 | Aimmune Therapeutics, Inc. | Formulations for egg oral immunotherapy, methods of manufacture, and treatments for egg allergy |
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PL356465A1 (en) * | 2002-10-04 | 2004-04-05 | ANPHARM Przedsiębiorstwo Farmaceutyczne S.A. | METHOD OF MANUFACTURE OF 17beta-HYDROXY-7alpha-METHYL-19-NOR-17alpha-PREGN-5(10)-ENE-20-YNE-3-ONE |
TW200418525A (en) * | 2002-11-20 | 2004-10-01 | Akzo Nobel Nv | Coated pharmaceutical tablets containing Tibolone |
GB0304927D0 (en) | 2003-03-04 | 2003-04-09 | Resolution Chemicals Ltd | Process for the production of tibolone |
WO2005117899A1 (en) * | 2004-06-02 | 2005-12-15 | Cipla Limited | Pharmaceutical composition comprising tibolone and process for procuding the same |
KR100908529B1 (en) | 2005-02-01 | 2009-07-20 | 에프. 호프만-라 로슈 아게 | Ivandronate polymorph A |
EP2363401A1 (en) | 2005-02-01 | 2011-09-07 | F. Hoffmann-La Roche AG | Ibandronate polymorph B |
EP1883648A1 (en) * | 2005-05-23 | 2008-02-06 | Newchem S.p.A. | Process for the preparation of pure crystalline tibolone |
CZ300465B6 (en) * | 2007-07-25 | 2009-05-27 | Zentiva, A. S. | Process for preparing compressed pharmaceutical formulation containing tibolone |
ITMI20130120A1 (en) * | 2013-01-25 | 2014-07-26 | Ind Chimica Srl | PROCESS FOR PREPARATION IN THE CRYSTAL FORM OF TIBOLONE, (7ALFA, 17ALFA) -17-HYDROSSI-7-METHYL-19-NORPREGN-5 (10) -EN-20-IN-3-ONE |
CN114409717B (en) * | 2021-12-17 | 2023-03-17 | 湖南科益新生物医药有限公司 | Tibolone intermediate etherate and preparation method of tibolone |
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BE665514A (en) | 1964-06-16 | |||
CH488682A (en) | 1965-07-30 | 1970-04-15 | Ciba Geigy | Process for the preparation of 4,9,11-trienes of the 19-nor-androstane series |
NL146838B (en) | 1966-06-24 | 1975-08-15 | Organon Nv | PROCESS FOR PREPARING (DELTA) 5 (10) -3-KETO-19-NORSTEROIDS. |
US3515719A (en) | 1967-03-15 | 1970-06-02 | Upjohn Co | 7-methyl-6,19-epoxy steroids of the androstane series |
US4701450A (en) * | 1984-03-21 | 1987-10-20 | Akzo N.V. | Steroids for use as immunomodulators |
EP0406279A1 (en) | 1988-03-25 | 1991-01-09 | Akzo N.V. | Pharmaceutical preparation containing a fluoride salt |
IE63051B1 (en) * | 1989-03-18 | 1995-03-22 | Akzo Nv | Pharmaceutical composition which contains a pharmaceutically suitable carrier and the compound having the structure (7alpha, 17alpha)-17-Hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn- 3-one |
ES2134313T3 (en) * | 1993-03-05 | 1999-10-01 | Akzo Nobel Nv | USE OF PREGNANATE DERIVATIVES FOR THE TREATMENT OF TUMORS. |
IL115445A (en) * | 1994-10-17 | 1999-08-17 | Akzo Nobel Nv | Solid pharmaceutical compositions comprising low dosage active ingredient oil and excipient capable of binding water and their preparation |
TW448049B (en) | 1997-03-05 | 2001-08-01 | Akzo Nobel Nv | Use of a 7Α-methyl-17Α-ethynyl-estrane derivative for the treatment of atherosclerosis |
IL123984A (en) * | 1997-04-22 | 2004-09-27 | Akzo Nobel Nv | Pharmaceutical dosage units comprising tibolone and a pharmaceutically acceptable carrier |
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WO2020131917A1 (en) * | 2018-12-17 | 2020-06-25 | Aimmune Therapeutics, Inc. | Formulations for egg oral immunotherapy, methods of manufacture, and treatments for egg allergy |
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