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WO2000050041A1 - Compositions pharmaceutiques contenant une forme cristalline du progestagene (17alpha)-17-hydroxy-11-methylene-19-nor-pregna-4,15-diene-20-yn-3-one (org 30659) et du lactose - Google Patents

Compositions pharmaceutiques contenant une forme cristalline du progestagene (17alpha)-17-hydroxy-11-methylene-19-nor-pregna-4,15-diene-20-yn-3-one (org 30659) et du lactose Download PDF

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Publication number
WO2000050041A1
WO2000050041A1 PCT/EP2000/000886 EP0000886W WO0050041A1 WO 2000050041 A1 WO2000050041 A1 WO 2000050041A1 EP 0000886 W EP0000886 W EP 0000886W WO 0050041 A1 WO0050041 A1 WO 0050041A1
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WO
WIPO (PCT)
Prior art keywords
org
formulation
crystalline
pharmaceutical
lactose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2000/000886
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English (en)
Inventor
Franciscus Theodorus Leonardus Brands
Hendrika Gerardina Maria Poels-Janssen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Akzo Nobel NV
Original Assignee
Akzo Nobel NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Akzo Nobel NV filed Critical Akzo Nobel NV
Priority to AU26697/00A priority Critical patent/AU2669700A/en
Publication of WO2000050041A1 publication Critical patent/WO2000050041A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • the invention pertains to the use of crystalline (17 ⁇ )-17-hydroxy-11-methylene- 19-norpregna-4,15-diene-20-yn-3-one, hereinafter referred to as Org 30659, for the preparation of a pharmaceutical formulation.
  • Org 30659 is a progestational steroid with high progestagenic activity and with low estrogenic and low androgenic activity.
  • Org 30659 is suitable for being utilised in hormone replacement therapy (HRT) and in contraception.
  • HRT hormone replacement therapy
  • Org 30659 as a chemical compound in the form of a powder is known from EP 210 678 and WO 96/09056.
  • the chemical synthesis is described in the first document and an improved process of making pharmaceutical formulations is described in the latter document.
  • WO 96/09056 refers to Org 30659 as a known compound without specifically teaching its crystallinity or the selection of a particular preparation method.
  • EP 0897927 an invention is described, which makes pure Org 30659 available in different well-defined and well-obtainable crystalline forms. Some of those crystalline forms were named form A, form B, form C and form X.
  • Org 30659 in crystalline form C having a melting point of 158.7°C, an enthalpy of 71.9 mJ/mg and the solid state 13 C nuclear magnetic resonance (NMR) spectral characteristics as shown in figure 1 , exhibits a higher stability in a pharmaceutical formulation during prolonged storage under unfavourable conditions than Org 30659 in other crystalline forms.
  • NMR nuclear magnetic resonance
  • this invention makes a pharmaceutical formulation available comprising a pharmaceutically acceptable carrier and crystalline Org 30659, whereby the crystalline Org 30659 is in a crystal form C, having a melting point of 158.7°C, an enthalpy ⁇ H of 71.9 mJ/mg and the solid state 13 C nuclear magnetic resonance (NMR) spectral characteristics as shown in figure 1.
  • a pharmaceutical formulation containing Org 30659 in crystalline form C is made 5 available, which pharmaceutical formulation retains a content of Org 30659 of more than 90% of the starting content of the pharmaceutical formulation after storage for 8 months under conditions of 40°C and relative environmental humidity between 10 and 20 %.
  • the crystal form C is further characterised by the X-ray power diffraction (XRPD) spectrum of figure 2, as will be explained in more 10 detail hereinafter.
  • Org 30659 in crystalline form C it can be used to obtain a more stable pharmaceutical formulation with a longer shelf-life than the shelf-life of other pharmaceutical products prepared according to the disclosure EP 210 678 5 or WO 96/09056. This improvement is of most significance under dry and dark storage conditions. Therefore, it is a further aspect of this invention to provide for a pharmaceutical formulation comprising Org 30659 in the crystalline form C, provided that auxiliaries are selected such that the formulation retains a content of Org 30659 of more than 90% of the starting content of the pharmaceutical 0 formulation after storage for 8 months under conditions of 40°C and relative environmental humidity between 10 and 20 %.
  • the preferred pharmaceutical formulation with these characteristics is a solid dosage form in which Org 30659 is in contact with dry and solid pharmaceutical excipients.
  • Those formulations in which poiy-alcohol or carbohydrate excipients, such as cellulose, 5 hydroxypropylcellulose, amylopectin, sugars, starches, dextrin, and maltodextrin are used as carrier or binder are suitable embodiments (Handbook of Pharmaceutical Excipients; Published by the Academy of Pharmaceutical Sciences / Pharmaceutical Society of Great Britain). More preferred are pharmaceutical formulations comprising spray-dried polyalcohols and granulated 0 ⁇ -lactose monohydrate and mixtures thereof as carrier and particularly preferred is spray-dried lactose for direct compression e.g. Pharmatose® DCL-11 (DMV Campina bv, Veghel, NL).
  • the pharmaceutical formulations of the invention may further comprise other acceptable auxiliaries.
  • Org 30659 can be present as the only pharmaceutically active ingredient, or combined with other pharmaceutically active compounds, e.g. an estrogenic compound such as ethinyl estradiol, estradiol, or esters thereof. Org 30659 itself is used in the pure crystalline form of this invention. In the art of making pharmaceutical formulations of compounds exhibiting poiymorphicity, the presence of 90% or more of a single crystalline form is considered to be an acceptable crystalline purity. It should be noted that such a pure crystalline form is not obtained by applying the teaching in EP 210 678.
  • solvate crystals can be obtained.
  • the crystal form of this invention may be prepared by heating the toluene solvate crystals during 2 hours at 60- 65°C in vacuo, followed by heating at 140°C during 90 minutes in vacuo.
  • Org 30659 Other crystal forms of Org 30659 were obtained when e.g. the crude product obtained in accordance with EP 210 678 is crystallised from e.g. a mixture of ethyl acetate and n-heptane.
  • a crystal form may result to which is referred here as form A.
  • This form has a ⁇ H of 82 mJ/mg and a melting point of 163.5 °C (both as determined by Differential Scanning Calorimetry (DSC)).
  • form B By heating the crystals of form A to approximately 162°C conversion to another crystalline form hereinafter referred to as form B can be prepared.
  • This form B can also be obtained using so-called anti-solvent crystallisation conditions. This is a principle known in the art, which can be applied by the person of ordinary skill in the art without undue experimentation.
  • Yet another crystalline form of Org 30659 can form when the crude product obtained in accordance with EP 210 678 is crystallised from toluene and the product is heated for two hours at 60-65°C in vacuo.
  • This form is referred to as form X. It has a ⁇ H of 52.8 mJ/mg and a melting point 158.2°C.
  • This crystal form X can be used as intermediary crystal form for the preparation of the crystal form C of this invention.
  • Form C may be obtained by heating form X at 140°C during 90 minutes in vacuo.
  • a pharmaceutical formulation according to the invention will generally take the form of a dosage unit such as a tablet or a capsule, but other solid or dry pharmaceutical preparations are included.
  • Methods for making such pharmaceutical preparations are well known and usually start with mixing the crystalline compound according to this invention with acceptable auxiliary substances.
  • Methods of making tablets, capsules and pills and their respective components are described.
  • Daily doses of Org 30659 typically are in a range of from a few micrograms (as few as possible, but by general preference at least 7,5 ⁇ g) to 240 ⁇ g.
  • Org 30659 being in a crystalline form selected in accordance with the present invention, can be processed in accordance with the disclosure of WO 96/09056, or any other suitable dry or wet processing method available in the art.
  • a preferred method for preparation of the formulation containing the crystal form C of Org 30659 is with dry-mixing of the excipient with Org 30659, for example according to EP 0 503 521 .
  • the invention furthermore pertains to the use of crystalline Org 30659 having a crystalline form C, for the preparation of an oral contraceptive as well as for the preparation of a medicament for HRT.
  • crystalline Org 30659 having a crystalline form C for the preparation of an oral contraceptive as well as for the preparation of a medicament for HRT.
  • the advantage of using a crystalline form according to the invention in preparing such medicinal agents resides, int.al., in the consistency of the physical state of the pharmaceutical formulation.
  • DSC Differential Scanning Calorimetry
  • the XRPD patterns were recorded using a Philips PW1050 refiection- diffractometer with Cu-K ⁇ radiation, the generator settings being 40 kV, 40 mA. Splits: 0.5°, 0.2 mm, 0.5°.
  • Org 30659 100 grams of Org 30659 are dissolved in 300 ml ethyl acetate at reflux temperature. At this temperature 300 ml of heptane are added in 15 minutes. The solution is cooled to 70 °C and at this temperature the mixture is seeded with 0.2 gram crystalline form A to initiate crystallisation. The temperature is raised again to reflux temperature and 1200 mi of heptane are introduced during 30 minutes. Stirring at reflux temperature is continued for 2 hours. After that the suspension is allowed to cool to room temperature and subsequently stirred at -15 °C for two hours. The crystals are filtered off, washed with cold heptane and dried in vacuo at 50 °C. Obtained are 91.4 g of Org 30659 in the crystalline form denoted A.
  • Org 30659 100 grams are dissolved in 300 ml ethyl acetate at reflux temperature. This warm solution is added over a period of 45 minutes to a suspension of 1500 ml of heptane and 0.2 gram of crystalline form B at room temperature. The suspension is stirred for an additional 1 hour at room temperature and 2 hours at - 15 °C. The crystals are filtered off, washed with cold heptane and dried in vacuo at 50 °C . Obtained are 88.7 g of Org 30659 in the crystalline form denoted B.
  • the polymorphous forms studied were: Form C, Form X, Form A and Form B.
  • Forms C. A and B were finely ground with a mortar. Tablets of a total weight of 65 mg were made.
  • the amount of Org 30659 in the dry mix was calculated to be 60 ⁇ g Org 30659 per tablet. However, due to adhesion to the sieve the tablet content was below 60 ⁇ g Org 30659.
  • the actual average content in the tablets is given in the table of results.
  • 500 G of a mixture for tabletting containing 0.462 g Org 30659, 477.0 g lactose DCL-11 , 200.0 g Primojel® and 2.5 g magnesiumstearate was prepared according to the following instructions:
  • Lactose DCL-11 is sieved with a 150 ⁇ m Retsch vibrating sieve (amplitude 3 mm) for 10 minutes to obtain 100 g of sieved lactose DCL-11.
  • 50 G of sieved lactose DCL-11 is weighed into a securitainer (62*113 mm) and 0.462 g Org 30659 of selected crystal form is added. This mass is thoroughly mixed for 10 min at 20 rpm (rotation per minute) in a Turbula mixer. The resulting mixture is transferred to a securitainer (75*130 mm) and the amount is completed to a total amount of 100.462 g with sieved lactose DCL-11.
  • the mass is again mixed in a Turbula for 10 min at 20 rpm and the mass is sieved again in a 150 ⁇ m Retsch vibration sieve (amplitude: 3 mm, 10 min.).
  • the sieved mixture is brought to a total mass of 377 g by addition of unsieved lactose DCL-11 and mixed again in a glass Turbula pot for 10 min at 20 rpm.
  • Primojel (20 g) is added and mixed in the Turbula at 20 rpm for 10 min.
  • the mixture is finished with magnesium stearate (2.50 g ⁇ 300 ⁇ m) in the Turbola at 20 rpm for 5 min and the tablets are pressed. Tablets were analysed after 3 and 8 months storage in open containers.
  • the horizontal axis conventionally represents the chemical shift (in ppm) relative to adamantane as a standard (38.56 ppm),
  • the vertical axis indicates the peak-intensity.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biophysics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Cette invention concerne l'utilisation de (17α)-17-hydroxy-11-méthylène-19-norpregna-4,15-diène-20-yn-3-one cristalline (Org 30659) pour la préparation d'une formulation pharmaceutique dans laquelle ce composé Org 30659 se trouve sous une forme cristalline C, présente un point de fusion de 158,7 °C et une enthalpie ΔH de 71,9 mJ/mg. Cette formulation pharmaceutique retient une quantité d'Org 30659 supérieure à 90 % de la quantité de départ de formulation pharmaceutique après un stockage pendant 8 mois à 40 °C avec une humidité ambiante relative de 75 %.
PCT/EP2000/000886 1999-02-24 2000-02-04 Compositions pharmaceutiques contenant une forme cristalline du progestagene (17alpha)-17-hydroxy-11-methylene-19-nor-pregna-4,15-diene-20-yn-3-one (org 30659) et du lactose Ceased WO2000050041A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU26697/00A AU2669700A (en) 1999-02-24 2000-02-04 Pharmaceutical compositions containing a crystalline form of the progestagen-(17alpha)-17-hydroxy-11-methylene-19-nor-pregna- 4,15-dien-20-yn-3-one (org 30659) and lactose

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP99200515 1999-02-24
EP99200515.7 1999-02-24

Publications (1)

Publication Number Publication Date
WO2000050041A1 true WO2000050041A1 (fr) 2000-08-31

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Application Number Title Priority Date Filing Date
PCT/EP2000/000886 Ceased WO2000050041A1 (fr) 1999-02-24 2000-02-04 Compositions pharmaceutiques contenant une forme cristalline du progestagene (17alpha)-17-hydroxy-11-methylene-19-nor-pregna-4,15-diene-20-yn-3-one (org 30659) et du lactose

Country Status (2)

Country Link
AU (1) AU2669700A (fr)
WO (1) WO2000050041A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4632828A (en) * 1984-02-08 1986-12-30 Farmitalia Carlo Erba S.P.A. Pharmaceutical composition
EP0503521A1 (fr) * 1991-03-12 1992-09-16 Akzo Nobel N.V. Préparations pharmaceutiques séches à faible dose
WO1996009056A1 (fr) * 1994-09-22 1996-03-28 Akzo Nobel N.V. Procede de fabrication d'unites posologiques au moyen d'une granulation par voie humide
NZ331197A (en) * 1997-08-11 1998-11-25 Akzo Nobel Nv Crystalline (17alpha)-17 hydroxy-11-methylene-19-norpregna-4,15-diene-20-yn-3-one (org 30659) and the process and use of making this compound for oral contraceptives and hormone replacement therapy

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4632828A (en) * 1984-02-08 1986-12-30 Farmitalia Carlo Erba S.P.A. Pharmaceutical composition
EP0503521A1 (fr) * 1991-03-12 1992-09-16 Akzo Nobel N.V. Préparations pharmaceutiques séches à faible dose
WO1996009056A1 (fr) * 1994-09-22 1996-03-28 Akzo Nobel N.V. Procede de fabrication d'unites posologiques au moyen d'une granulation par voie humide
NZ331197A (en) * 1997-08-11 1998-11-25 Akzo Nobel Nv Crystalline (17alpha)-17 hydroxy-11-methylene-19-norpregna-4,15-diene-20-yn-3-one (org 30659) and the process and use of making this compound for oral contraceptives and hormone replacement therapy

Also Published As

Publication number Publication date
AU2669700A (en) 2000-09-14

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