WO2020103952A1 - Nouvelle préparation de stéroïde neuroactif - Google Patents

Nouvelle préparation de stéroïde neuroactif

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Publication number
WO2020103952A1
WO2020103952A1 PCT/CN2019/120390 CN2019120390W WO2020103952A1 WO 2020103952 A1 WO2020103952 A1 WO 2020103952A1 CN 2019120390 W CN2019120390 W CN 2019120390W WO 2020103952 A1 WO2020103952 A1 WO 2020103952A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
neuroactive steroid
content
preferred
Prior art date
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PCT/CN2019/120390
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English (en)
Chinese (zh)
Inventor
刘飞
吴刚
张翠霞
林成刚
姜伟化
刘迪
尹德燕
王露露
Original Assignee
南京诺瑞特医药科技有限公司
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Publication of WO2020103952A1 publication Critical patent/WO2020103952A1/fr

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    • 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
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the invention relates to the field of pharmaceutical preparations, in particular to oily preparations of neuroactive steroids, methods for preparing the above preparations, and uses of the preparations for preparing medicines for treating central nervous system diseases.
  • Neuroactive steroids are active steroids in nerve tissues.
  • Neurosteroids which play an important regulatory role in the human body, mainly include progesterone, pregnenolone, and allogestrelone. Progesterone, pregnenolone, and alloprenol are all metabolized by cholesterol through different pathways.
  • Cholesterol is transferred from the outer mitochondrial membrane to the inner membrane under the mediation of 18kDa translocator protein, and then passes through the cytochrome P450 cholesterol side chain lyase It is metabolized to produce pregnenolone, which is then metabolized to progesterone by 3 ⁇ -hydroxysteroid dehydrogenase, and then is continuously metabolized by 5 ⁇ -reductase and 3 ⁇ -hydroxysteroid dehydrogenase to produce allogestrel ketone.
  • Neuroactive steroids can be used as anesthetics, sedatives, sleeping pills, anxiolytics, antidepressants and anticonvulsants.
  • Allogestrelone has been a research hotspot in recent years. As early as 1986, it has been pointed out that allogestrelone is a positive regulator of GABA A receptors. However, it was not until 2006 that it was discovered that alloprenolone may mainly bind to the ⁇ and ⁇ subunits of the GABA A receptor, increase the frequency of opening of the chloride channel on the receptor, reduce nerve excitability, and thus produce calming and anti-inflammatory Anxiety effect.
  • progesterone and its metabolites are different in different stages of the menstrual cycle.
  • PMS premenstrual syndrome
  • the concentration of allogestrolone in the plasma of healthy pregnant women increases, and the concentration of allogestrolone will drop sharply after delivery.
  • allogestrolone has low water solubility and poor oral availability.
  • the plasma half-life of human body is about 45 minutes and can be rapidly metabolized.
  • Brexanolone in clinical stage is a water-soluble ⁇ -cyclodextrin-based preparation of allogestrolone, which produces a stable physiological concentration of allogestrolone by intravenous injection.
  • Brexanolone requires intravenous infusion for up to 60 hours, and the patient's compliance is poor.
  • a single administration of oily formulations can continuously release the active ingredients, and the development of oily formulations can solve the problem of Brexanolone requiring long-term injection administration.
  • Aveed is a long-acting intramuscular testosterone preparation, in which testosterone undecanoate is dissolved in castor oil, the first injection interval is 4 weeks, and the subsequent injection interval is extended to 10 weeks.
  • Delestrogen is a long-acting intramuscular injection of estradiol valerate, in which estradiol valerate is dissolved in sesame oil at an interval of 2 weeks.
  • oily carriers such as castor oil and sesame oil have a slow-release effect, and the preparations made from them cannot quickly reach the effective blood drug concentration after administration and exert their effects.
  • the object of the present invention is to provide a new preparation containing a neuroactive steroid; the object of the present invention is also to provide the application of the above new preparation in the preparation of a medicament for treating diseases caused by abnormalities of the central nervous system.
  • a pharmaceutical composition in one aspect, includes a neuroactive steroid, castor oil, and at least one non-aqueous ester solvent.
  • the non-aqueous ester solvent in the pharmaceutical composition is selected from benzyl benzoate, ethyl oleate, sorbitan monolaurate (Span 20), glyceryl monooleate, isopropyl myristate One or more of ester, isopropyl myristate or isopropyl palmitate.
  • the non-aqueous ester solvent in the pharmaceutical composition is selected from benzyl benzoate.
  • the content of the non-aqueous ester solvent in the pharmaceutical composition is 10-50% W / W.
  • the content of the non-aqueous ester solvent in the pharmaceutical composition is 15-45% W / W.
  • the content of the non-aqueous ester solvent in the pharmaceutical composition is 20-40% W / W.
  • the content of the non-aqueous ester solvent in the pharmaceutical composition is 25-35% W / W.
  • the content of the non-aqueous ester solvent in the pharmaceutical composition is 10-50% W / W, or 11-49% W / W, or 12-48% W / W, or 13-47% W / W, or 14-46% W / W, or 15-45% W / W, or 16-44% W / W, or 17-43% W / W, or 18-42% W / W, or 19 -41% W / W, or 20-40% W / W, or 21-39% W / W, or 22-38% W / W, or 23-37% W / W, or 24-36% W / W, or 25-35% W / W, or 26-34% W / W, or 27-33% W / W, or 28-32% W / W, or 29-31% W / W.
  • the content of the non-aqueous ester solvent in the pharmaceutical composition is 11% W / W, or 12% W / W, or 13% W / W, or 14% W / W, or 15% W / W, or 16% W / W, or 17% W / W, or 18% W / W, or 19% W / W, or 20% W / W, or 21% W / W, or 22% W / W , Or 23% W / W, or 24% W / W, or 25% W / W, or 26% W / W, or 27% W / W, or 28% W / W, or 29% W / W, Or 30% W / W, or 31% W / W, or 32% W / W, or 33% W / W, or 34% W / W, or 35% W / W, or 36% W / W, or 37% W / W, or 38% W / W, or 39% W / W, or 40% W / W / W
  • the content of castor oil in the pharmaceutical composition is 20-90% W / W.
  • the content of castor oil in the pharmaceutical composition is 30-80% W / W.
  • the content of castor oil in the pharmaceutical composition is 40-70% W / W.
  • the content of castor oil in the pharmaceutical composition is 20-90% W / W, 21-89% W / W, or 22-88% W / W, or 23-87% W / W, or 24-86% W / W, or 25-85% W / W, or 26-84% W / W, or 27-83% W / W, or 28-82% W / W, or 29-81% W / W, or 30-80% W / W, or 31-79% W / W, or 32-78% W / W, or 33-77% W / W, or 34-76% W / W, or 35 -75% W / W, or 36-74% W / W, or 37-73% W / W, or 38-72% W / W, or 39-71% W / W, or 40-70% W / W, or 41-69% W / W, or 42-68% W / W, or 43-67% W / W, or 44-66% W / W, or 45-60% W / W, or 39- 41% W / W, or
  • the content of castor oil in the pharmaceutical composition is 20% W / W, or 21% W / W, or 22% W / W, or 23% W / W, or 24% W / W, or 25% W / W, or 26% W / W, or 27% W / W, or 28% W / W, or 29% W / W, or 30% W / W, or 31% W / W, or 32 % W / W, or 33% W / W, or 34% W / W, or 35% W / W, or 36% W / W, or 37% W / W, or 38% W / W, or 39% W / W, or 40% W / W, or 41% W / W, or 42% W / W, or 43% W / W, or 44% W / W, or 45% W / W, or 46% W / W, or 47% W / W, or 48% W / W, or 49% W / W, or 50% W / W,
  • the neuroactive steroid in the pharmaceutical composition is progesterone, pregnenolone, alloprenolone, afadorolone, ganaxolone, alfasharon, or other progesterone analogs.
  • the content of the neuroactive steroid in the pharmaceutical composition is 2-30% W / W.
  • the content of the neuroactive steroid in the pharmaceutical composition is 3-20% W / W.
  • the content of the neuroactive steroid in the pharmaceutical composition is 5-10% W / W.
  • the content of the neuroactive steroid in the pharmaceutical composition is 2-30% W / W, or 3-29% W / W, or 4-28% W / W, or 5-27% W / W , Or 6-26% W / W, or 7-25% W / W, or 8-24% W / W, or 9-24% W / W, or 10-23% W / W, or 5-22 % W / W, or 5-21% W / W, or 5-20% W / W, or 5-19% W / W, or 5-18% W / W, or 5-17% W / W, Or 5-16% W / W, or 5-15% W / W, or 5-14% W / W, or 5-13% W / W, or 5-12% W / W, or 5-11% W / W, or 5-10% W / W, or 5-9% W / W.
  • the neuroactive steroid is allogestrelone.
  • the content of the neuroactive steroid in the pharmaceutical composition is selected from 2% W / W, 2.5% W / W, 5% W / W, 3% W / W, 3.5% W / W, 4% W / W, 4.5% W / W, 5.5% W / W, 6% W / W, 6.5% W / W, 7% W / W, 7.5% W / W, 8% W / W, 8.5% W / W , 9% W / W, 9.5% W / W, 10% W / W, 10.5% W / W, 11% W / W, 11.5% W / W, 12% W / W, 12.5% W / W, 13 % W / W, 13.5W / W%, 14W / W%, 14.5W / W%, 15W / W%, 15.5W / W%, 16W / W%, 16.5W / W%, 17W / W%, 17.5 W / W%, 18W / W / W
  • the pharmaceutical composition further comprises a mixture of one or more alcohol excipients.
  • the alcohol excipient in the pharmaceutical composition is one or more of ethanol, propylene glycol, polyethylene glycol or benzyl alcohol.
  • the alcohol excipient in the pharmaceutical composition is ethanol, or ethanol and benzyl alcohol, or ethanol and propylene glycol, or a mixture of ethanol and polyethylene glycol.
  • the pharmaceutical composition contains 30% or less alcohol excipient.
  • the pharmaceutical composition contains 29% or less alcohol excipient.
  • the pharmaceutical composition contains 28% or less alcohol excipient.
  • the pharmaceutical composition contains 27% or less alcohol excipient.
  • the pharmaceutical composition contains 26% or less alcohol excipient.
  • the pharmaceutical composition contains 25% or less of an alcohol excipient.
  • the content of the alcohol excipient in the pharmaceutical composition is selected from 5-30% W / W, or 6-29% W / W, or 7-28% W / W, or 8- 27% W / W, or 9-26% W / W, or 10-25% W / W, or 11-20% W / W, or 12-23% W / W, or 13-22% W / W , Or 14-21% W / W, or 15-20% W / W.
  • the content of the alcohol excipient in the pharmaceutical composition is selected from 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.
  • the pharmaceutical composition includes a neuroactive steroid, castor oil, a non-aqueous ester solvent, and an alcohol excipient.
  • the non-aqueous ester solvent is benzyl benzoate.
  • the alcohol excipient is ethanol, or a mixture of ethanol and benzyl alcohol, or ethanol and propylene glycol, or ethanol and polyethylene glycol.
  • the neuroactive steroid in the pharmaceutical composition is progesterone, pregnenolone, allogestrelone, afadrolone, ganaxolone, alfasharon, or other progesterone analogs.
  • the content of the non-aqueous ester solvent in the pharmaceutical composition is 10-50% W / W, or 15-45% W / W, or 20-40% W / W, or 25-35% W / W.
  • the non-aqueous ester solvent is benzyl benzoate.
  • the content of the non-aqueous ester solvent in the pharmaceutical composition is 10-50% W / W, or 11-49% W / W, or 12-48% W / W, or 13-47% W / W, or 14-46% W / W, or 15-45% W / W, or 16-44% W / W, or 17-43% W / W, or 18-42% W / W, or 19-41% W / W, or 20-40% W / W, or 21-39% W / W, or 22-38% W / W, or 23-37% W / W, or 24-36% W / W, or 25-35% W / W, or 26-34% W / W, or 27-33% W / W, or 28-32% W / W, or 29-31% W / W.
  • the non-aqueous ester solvent is benzyl benzoate.
  • the content of the non-aqueous ester solvent in the pharmaceutical composition is 11% W / W, or 12% W / W, or 13% W / W, or 14% W / W, or 15% W / W, or 16% W / W, or 17% W / W, or 18% W / W, or 19% W / W, or 20% W / W, or 21% W / W, or 22% W / W, or 23% W / W, or 24% W / W, or 25% W / W, or 26% W / W, or 27% W / W, or 28% W / W, or 29% W / W , Or 30% W / W, or 31% W / W, or 32% W / W, or 33% W / W, or 34% W / W, or 35% W / W, or 36% W / W, Or 37% W / W, or 38% W / W, or 39% W / W, or 40% W / W, or 2
  • the content of castor oil in the pharmaceutical composition is 20-90% W / W, or 30-80% W / W, or 40-70% W / W.
  • the content of castor oil in the pharmaceutical composition is 20-90% W / W, 21-89% W / W, or 22-88% W / W, or 23-87% W / W, Or 24-86% W / W, or 25-85% W / W, or 26-84% W / W, or 27-83% W / W, or 28-82% W / W, or 29-81% W / W, or 30-80% W / W, or 31-79% W / W, or 32-78% W / W, or 33-77% W / W, or 34-76% W / W, or 35-75% W / W, or 36-74% W / W, or 37-73% W / W, or 38-72% W / W, or 39-71% W / W, or 40-70% W / W, or 41-69% W / W, or 42-68% W / W, or 43-67% W / W, or 44-66% W / W, or 45-65% W / W, or 39 -41% W / W, or 39
  • the content of castor oil in the pharmaceutical composition is 20% W / W, or 21% W / W, or 22% W / W, or 23% W / W, or 24% W / W, Or 25% W / W, or 26% W / W, or 27% W / W, or 28% W / W, or 29% W / W, or 30% W / W, or 31% W / W, or 32% W / W, or 33% W / W, or 34% W / W, or 35% W / W, or 36% W / W, or 37% W / W, or 38% W / W, or 39 % W / W, or 40% W / W, or 41% W / W, or 42% W / W, or 43% W / W, or 44% W / W, or 45% W / W, or 46% W / W, or 47% W / W, or 48% W / W, or 49% W / W, or 50%
  • the content of the neuroactive steroid in the pharmaceutical composition is 2-30% W / W, or 3-20% W / W, or 5-10% W / W.
  • the neuroactive steroid is allogestrolone.
  • the content of the neuroactive steroid in the pharmaceutical composition is 2-30% W / W, or 3-29% W / W, or 4-28% W / W, or 5-27% W / W, or 5-26% W / W, or 5-25% W / W, or 5-24% W / W, or 6-24% W / W, or 5-23% W / W, or 5- 22% W / W, or 5-21% W / W, or 5-20% W / W, or 5-19% W / W, or 5-18% W / W, or 5-17% W / W , Or 5-16% W / W, or 5-15% W / W, or 5-14% W / W, or 5-13% W / W, or 5-12% W / W, or 5-11 % W / W, or 5-10% W / W, or 5-9% W / W.
  • the neuroactive steroid is allogestrolone.
  • the content of the neuroactive steroid in the pharmaceutical composition is selected from 2% W / W, 2.5% W / W, 5% W / W, 3% W / W, 3.5% W / W, 4% W / W, 4.5% W / W, 5.5% W / W, 6% W / W, 6.5% W / W, 7% W / W, 7.5% W / W, 8% W / W, 8.5% W / W, 9% W / W, 9.5% W / W, 10% W / W, 10.5% W / W, 11% W / W, 11.5% W / W, 12% W / W, 12.5% W / W, 13% W / W, 13.5W / W%, 14W / W%, 14.5W / W%, 15W / W%, 15.5W / W%, 16W / W%, 16.5W / W%, 17W / W%, 17.5W / W%, 18W / W
  • the content of the alcohol excipient in the pharmaceutical composition is 5-30% W / W, or 6-29% W / W, or 7-28% W / W, or 8-27% W / W, or 9-26% W / W, or 10-25% W / W, or 11-20% W / W, or 12-23% W / W, or 13-22% W / W, or 14-21% W / W, or 15-20% W / W.
  • the alcohol excipient is ethanol, or a mixture of ethanol and benzyl alcohol, or ethanol and propylene glycol, or ethanol and polyethylene glycol.
  • the content of the alcohol excipient in the pharmaceutical composition is selected from 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.
  • the alcohol excipient is ethanol, or a mixture of ethanol and benzyl alcohol, or ethanol and propylene glycol, or ethanol and polyethylene glycol.
  • the pharmaceutical composition contains neuroactive steroids, castor oil, benzyl benzoate and ethanol.
  • the content of the neuroactive steroid in the pharmaceutical composition is 2-30% W / W, or 3-20% W / W, or 5-10% W / W.
  • the neuroactive steroid is allogestrolone.
  • the content of the neuroactive steroid in the pharmaceutical composition is 2-30% W / W, or 3-29% W / W, or 4-28% W / W, or 5-27% W / W , Or 6-26% W / W, or 5-25% W / W, or 6-24% W / W, or 5-24% W / W, or 5-23% W / W, or 5-22 % W / W, or 5-21% W / W, or 5-20% W / W, or 5-19% W / W, or 5-18% W / W, or 5-17% W / W, Or 5-16% W / W, or 5-15% W / W, or 5-14% W / W, or 5-13% W / W, or 5-12% W / W, or 5-11% W / W, or 5-10% W / W, or 5-9% W / W.
  • the neuroactive steroid is allogestrolone.
  • the content of the neuroactive steroid in the pharmaceutical composition is selected from 2% W / W, 2.5% W / W, 5% W / W, 3% W / W, 3.5% W / W, 4% W / W, 4.5% W / W, 5.5% W / W, 6% W / W, 6.5% W / W, 7% W / W, 7.5% W / W, 8% W / W, 8.5% W / W, 9% W / W, 9.5% W / W, 10% W / W, 10.5% W / W, 11% W / W, 11.5% W / W, 12% W / W, 12.5% W / W, 13% W / W, 13.5W / W%, 14W / W%, 14.5W / W%, 15W / W%, 15.5W / W%, 16W / W%, 16.5 W / W%, 17W / W%, 17.5W / W%, 18W / W
  • the content of castor oil in the pharmaceutical composition is 20-90% W / W, or 30-80% W / W, or 40-70% W / W.
  • the content of castor oil in the pharmaceutical composition is 20-90% W / W, 21-89% W / W, or 22-88% W / W, or 23-87% W / W, Or 24-86% W / W, or 25-85% W / W, or 26-84% W / W, or 27-83% W / W, or 28-82% W / W, or 29-81% W / W, or 30-80% W / W, or 31-79% W / W, or 32-78% W / W, or 33-77% W / W, or 34-76% W / W, or 35-75% W / W, or 36-74% W / W, or 37-73% W / W, or 38-72% W / W, or 39-71% W / W, or 40-70% W / W, or 41-69% W / W, or 42-68% W / W, or 43-67% W / W, or 44-66% W / W, or 45-65% W / W, or 39 -41% W / W, or 39
  • the content of castor oil in the pharmaceutical composition is 20% W / W, or 21% W / W, or 22% W / W, or 23% W / W, or 24% W / W, Or 25% W / W, or 26% W / W, or 27% W / W, or 28% W / W, or 29% W / W, or 30% W / W, or 31% W / W, or 32% W / W, or 33% W / W, or 34% W / W, or 35% W / W, or 36% W / W, or 37% W / W, or 38% W / W, or 39 % W / W, or 40% W / W, or 41% W / W, or 42% W / W, or 43% W / W, or 44% W / W, or 45% W / W, or 46% W / W, or 47% W / W, or 48% W / W, or 49% W / W, or 50%
  • the content of benzyl benzoate in the pharmaceutical composition is 10-50% W / W, or 15-45% W / W, or 20-40% W / W, or 25-35% W / W.
  • the content of benzyl benzoate in the pharmaceutical composition is 10-50% W / W, or 11-49% W / W, or 12-48% W / W, or 13-47% W / W, or 14-46% W / W, or 15-45% W / W, or 16-44% W / W, or 17-43% W / W, or 18-42% W / W, or 19-41% W / W, or 20-40% W / W, or 21-39% W / W, or 22-38% W / W, or 23-37% W / W, or 24-36% W / W, or 25-35% W / W, or 26-34% W / W, or 27-33% W / W, or 28-32% W / W, or 29-31% W / W.
  • the content of benzyl benzoate in the pharmaceutical composition is 11% W / W, or 12% W / W, or 13% W / W, or 14% W / W, or 15% W / W, or 16% W / W, or 17% W / W, or 18% W / W, or 19% W / W, or 20% W / W, or 21% W / W, or 22% W / W, or 23% W / W, or 24% W / W, or 25% W / W, or 26% W / W, or 27% W / W, or 28% W / W, or 29% W / W , Or 30% W / W, or 31% W / W, or 32% W / W, or 33% W / W, or 34% W / W, or 35% W / W, or 36% W / W, Or 37% W / W, or 38% W / W, or 39% W / W, or 40% W / W / W, or
  • the content of ethanol in the pharmaceutical composition is 5-30% W / W, or 6-29% W / W, or 7-28% W / W, or 8-27% W / W , Or 9-26% W / W, or 10-25% W / W, or 11-20% W / W, or 12-23% W / W, or 13-22% W / W, or 14-21 % W / W, or 15-20% W / W.
  • the ethanol content in the pharmaceutical composition is 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16 %, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.
  • the pharmaceutical composition further comprises benzyl alcohol.
  • the content of benzyl alcohol is 5-30% W / W, or 6-29% W / W, or 7-28% W / W, or 8-27% W / W, or 9-26% W / W, or 10-25% W / W, or 11-20% W / W, or 12-23% W / W, or 13-22% W / W, or 14-21% W / W, or 15-20% W / W.
  • the content of benzyl alcohol is 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.
  • the pharmaceutical composition comprises 4-20% W / W neuroactive steroid, 30-60% W / W castor oil, 25-40% W / W benzyl benzoate, 5-20% W / W ethanol.
  • the content of the neuroactive steroid in the pharmaceutical composition is 4-9% W / W, or 4-8% W / W, 4-7% W / W, or 5-10% W / W , Or 5-9% W / W, or 5-8% W / W, or 6-8% W / W, or 6-9% W / W, or 6-10% W / W.
  • the neuroactive steroid is progesterone, pregnenolone, allogestrelone, afadrolone, ganaxolone, alfasharon, or other progesterone analogs.
  • the neuroactive steroid is allogestrolone.
  • the castor oil content in the pharmaceutical composition is 35-50% W / W, or 40-55% W / W, or 40-50% W / W.
  • the content of benzyl benzoate in the pharmaceutical composition is 30-40% W / W.
  • the content of ethanol in the pharmaceutical composition is 6-17% W / W, or 8-15% W / W, or 10% W / W.
  • the pharmaceutical composition further comprises 5-20% W / W benzyl alcohol.
  • the content of benzyl alcohol is 5% W / W, or 6% W / W, or 7% W / W, or 8% W / W, or 9% W / W, or 10% W / W, or 11% W / W, or 12% W / W, or 13% W / W, or 14% W / W, or 15% W / W, or 16% W / W, or 17% W / W, or 18% W / W, or 19% W / W, or 20% W / W.
  • the benzyl alcohol content is 6-19% W / W, or 7-18% W / W, or 8-17% W / W, or 9-16% W / W, or 10 -15% W / W.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising 5-10% W / W of neuroactive steroids, 40-50% W / W of castor oil, 25-35% W / W benzyl benzoate, 5-15% W / W ethanol and 5-15% W / W benzyl alcohol.
  • the pharmaceutical composition of the present invention is administered by injection.
  • the injection method is subcutaneous injection, or intramuscular injection.
  • the neuroactive steroid is progesterone, pregnenolone, allogestrelone, afadorolone, ganaxolone, alfasharon or other progesterone analogs.
  • the neuroactive steroid is allogestrelone.
  • the unit volume of the pharmaceutical composition of the present invention is 6 mL or less, and the concentration of the neuroactive steroid is 5-10% W / W.
  • the neuroactive steroid is progesterone, pregnenolone, allogestrelone, afadorolone, ganaxolone, alfasharon or other progesterone analogs.
  • the neuroactive steroid is allogestrelone.
  • the pharmaceutical composition of the present invention can sufficiently dissolve the neuroactive steroid as an active ingredient therein, so that it can be administered by injection while maintaining a sufficient content of the active ingredient.
  • the pharmaceutical composition of the present invention can not only reduce the administration time by injection, but also can quickly take effect and maintain a stable physiological concentration of neuroactive steroids in the body, such as allogestrolone, for a long time.
  • the pharmaceutical composition of the present invention reaches 70-85% of the peak plasma concentration about 2 hours after injection administration; preferably 80-85%.
  • the pharmaceutical composition of the present invention reaches a peak plasma concentration about 4 hours after administration.
  • the use of the pharmaceutical composition in the preparation of a medicament for the treatment of disorders of the central nervous system is provided.
  • the central nervous system disease of the present invention is selected from the group consisting of idiopathic tremor, epilepsy, clinical depression, postpartum or postpartum depression, atypical depression, psychotic major depression, stress depression, seasonal mood Disorders, poor mood, double depression, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar disorder or manic depressive disorder, post-traumatic stress disorder, depression due to chronic medical conditions, tolerance Therapeutic depression, refractory depression, suicidal tendency, suicidal ideation or suicidal behavior.
  • the neuroactive steroids are progesterone, pregnanolone (Eltanolone), allopregnanolone (Allopregnanolone), Alfadolone (Alfadolone), Ganaxolone (Ganaxolone), Alfa Salon (alfaxalone) or other progesterone analogs.
  • the neuroactive steroid is allogestrolone or a derivative thereof.
  • the neuroactive steroid is allogestrelone.
  • the invention provides a pharmaceutical composition for the preparation of a medicament for the treatment of disorders of the central nervous system.
  • the present invention provides a medicament for treating central nervous system disorders containing the pharmaceutical composition of the present invention.
  • the present invention provides a method for treating disorders of the central nervous system, the method comprising the step of administering the pharmaceutical composition of the present invention to a subject in need of treatment for disorders of the central nervous system.
  • the castor oil in the present invention refers to an oily non-aqueous solvent commonly used in pharmacy.
  • the castor oil may also contain components such as ricinoleic acid and ricinoleic acid glyceride.
  • Neuroactive steroids are natural, synthetic or semi-synthetic steroids that rapidly change the excitability of neurons by interacting with neurotransmitter-gated ion channels.
  • the role of neuroactive steroids is to bind to membrane-bound receptors such as those used for inhibitory and / or excitatory neurotransmitters, including GABA A , NMDA and sigma receptors.
  • Neurosteroids can be divided into estrogen, progesterone and androgen based on chemical structure and physiological activity.
  • the neurosteroids in the present invention are mainly selected from progestins (ie progesterone) and their derivatives (including synthetic and natural products), as well as progesterone metabolites such as progesterone.
  • progesterone as used in the present invention means a member of the progesterone family, and progesterone is also called D4-pregnene-3,20-dione; ⁇ 4-pregnene-3,20-dione; or progestin-4 -Ene-3,20-dione.
  • synthetic progesterone used in the present invention is a molecule whose structure is related to the structure of progesterone, which is obtained by synthetic means, and retains the biological activity of progesterone.
  • Representative synthetic progestins include, but are not limited to, substitution at the 17-position of the progesterone ring to introduce hydroxyl, acetyl, hydroxyacetyl, aliphatic, nitro, or heterocyclic groups to produce 17 ⁇ -OH esters (ie 17 ⁇ -hydroxyprogesterone caproate), and the introduction of 6-methyl, 6-ene and 6-chloro substituents on the progesterone (ie medroxyprogesterone acetate, megestrol acetate and chlorgesterone acetate) .
  • the progesterone derivatives in the present invention include 5-dehydroprogesterone, 6-dehydro-retroprogesterone, allogestrolone, diacetinol, hydroxyprogesterone caproate (pregnant- 4-ene-3,20-dione, 17- (1-oxohexyl) oxy), levonorgestrel (levonorgestrel), norethindrone, norethindrone acetate (17 ⁇ -hydroxy-9 -Nor-17 ⁇ -pregnant-4-en-20-yn-3-one-17-acetate), norethindrone, norgestrel, pregnenolone, ganaxolone (also Called CCD-1042 or INN) and megestrol acetate.
  • Progestogens can also include alloprogesterone-3 ⁇ or 3 ⁇ , 20 ⁇ or 20 ⁇ -diol (see Merck Index 258-261), allopregnane-3 ⁇ , 21-diol-11, 20-dione, allogestane- 3 ⁇ , 17 ⁇ -diol-20-ketone, 3,20-Allopregnane dione, Allopregnane-3 ⁇ , 11 ⁇ , 17 ⁇ , 20 ⁇ , 21-Pentaol, Allopregnane-3 ⁇ , 17 ⁇ , 20 ⁇ , 21- Tetral, Allopregnane-3 ⁇ or 3 ⁇ , 11 ⁇ , 17 ⁇ , 21-Tetral-20-one, Allopregnane-3 ⁇ , 17 ⁇ , 21-Triol-11, 20-Dione, Allopregnane-3 ⁇ , 11 ⁇ , 21-triol-20-one, allogestane-3 ⁇ , 17 ⁇ , 21-triol-20-one, allogestin-3 ⁇ or 3 ⁇ -ol-20-one, pregnanedi
  • neuroactive steroids include WIPO Publication Nos. WO2013 / 188792, WO2013 / 056181, WO2015 / 010054, WO2014 / 169832, WO2014 / 169836, WO2014 / 169833, WO2014 / 169831, WO2015 / 027227, WO2014 / 100228, U.S.
  • the neuroactive steroids described in Patent Nos. 5,232,917, US 8,575,375 and US 8,759,330 are disclosed.
  • Allogestrelone in the present invention includes the individual enantiomers (dextrorotatory and levorotatory enantiomers) as well as pharmaceutically acceptable salts, mixtures of enantiomers and their pharmaceutically acceptable salts.
  • the pharmaceutically acceptable salt in the present invention refers to a derivative of the disclosed compound in which the parent compound is modified by preparing its acid addition or base addition salt.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic acids or organic acid salts of basic residues such as amines; and alkali metal salts or organic salts of acidic residues such as carboxylic acids.
  • Pharmaceutically acceptable salts include conventional non-toxic salts or, for example, quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids.
  • Such conventional non-toxic salts include: those obtained from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, hard acid Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetyl Oxybenzoic acid, fumaric acid, toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and isethionate salts.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfa
  • % W / W in the present invention refers to the mass percentage, for example as follows, "the content of a certain component is 5% W / W” refers to the total mass of the pharmaceutical composition is 1g, the mass of the component in the pharmaceutical composition 50mg.
  • Effective treatment means that it achieves relief of one or more symptoms of injury such as improved morphological recovery (ie, enhanced tissue activity) and / or behavioral recovery. This improvement can be characterized as an increase in the rate and / or degree of behavioral recovery and / or anatomical recovery after traumatic central nervous system injury.
  • Effective therapeutic concentration refers to the blood drug concentration when effective therapeutic purposes are achieved.
  • the composition described in the present invention contains a sufficient amount of volume so that an assistant doctor or a caregiver can administer a sufficient dose to the patient.
  • the pharmaceutical composition should contain a maximum amount of 0.25 mL, preferably a maximum of 0.15 mL.
  • the pharmaceutical composition is a vial or a prefilled syringe as a container, and the container is filled with a unit dose of the pharmaceutical composition, and these constitute further features of the present invention.
  • the pharmaceutical composition provided by the present invention can maintain physical and chemical stability during storage.
  • the active ingredient in the pharmaceutical composition has The higher content can reduce the volume required for administration and reduce the adverse effects of large amounts of administration on patients.
  • the administration time of the pharmaceutical composition of the present invention is reduced, thereby improving the patient's medication comfort.
  • the pharmaceutical composition of the present invention can also take effect quickly and maintain the blood drug concentration at a therapeutically effective concentration for a long time.
  • the AUClast and Cmax values of the pharmaceutical composition of the present invention are significantly improved, and have a longer half-life in vivo.
  • Figure 1 shows the relationship between plasma drug concentration and time after administration of beagle dogs.
  • Test method Disperse excess alloprenolone in different solvents, shake at room temperature for 24 hours, filter and determine the content by HPLC.
  • Test method Weigh allogestrelone, benzyl benzoate, ethanol or benzyl alcohol in a vial according to the prescription in Table-2, heat and stir for 10 to 30 minutes, then add a prescribed amount of castor oil and stir at 60 ° C to observe the drug Whether it is completely dissolved.
  • ethanol has an unexpected contribution to the stability of allogestrel ketone prescriptions.
  • Table-1 the solubility of benzyl alcohol is significantly higher than that of ethanol, which is more than twice the solubility in ethanol.
  • the prescription of adding ethanol should be less soluble and less stable than the prescription of adding benzyl alcohol.
  • the prescription of adding ethanol in the present invention has a significantly better effect than benzyl alcohol.
  • the male beagle dog (ordinary grade) used in this example is 6-15 kg in weight and was purchased from Beijing Mas Biotechnology Co., Ltd.
  • test animals were administered by intramuscular injection (i.m.).
  • the samples in the oil solution were dissolved in an oily solvent containing castor oil and benzyl benzoate at a dosage of 20 mg / kg.
  • the experimental animals were in an anesthetized state. Before administration (0) and after administration 2h, 4h, 8h, 12h, 24h, 32h, 48h, 72h, 96h, 120h, 144h, 168h, 192h, 216h, about 0.6mL of blood samples collected by peripheral vein were transferred to contain -1.15mg K 2 EDTA anticoagulant commercial centrifuge tube (Jiangsu Kangjian Medical Supplies Co., Ltd.). Plasma was centrifuged within 60 minutes after blood collection (at about 4 ° C, centrifuged at 3000g for 10 minutes) and then analyzed.
  • the plasma concentration of EDTA (4mM) anticoagulated SD rat plasma was determined by LC / MS / MS method, and the plasma concentration-time data was analyzed using WinNonlin 6.3 software.
  • the relevant pharmacokinetic parameters of the concentration at each time point were detailed See Table 4 and the concentration time curve is shown in the figure.
  • C max and T max are both expressed by measured values, and “ND” indicates that it is not detected.
  • t 1/2 0.693 / ⁇ z
  • ⁇ z the end elimination rate constant obtained by the linear part of the log concentration-time curve at the end, and can be obtained by the slope of the linear part of the log concentration-time curve at the end .
  • the content of allogestrelone in the samples of the administration group was 70 mg / g, benzyl benzoate 50% W / W, ethanol 10% W / W, benzyl alcohol 10% W / W, and was prepared with castor oil to the rated amount.
  • the present inventors further studied the effects of mixing benzyl alcohol, ethanol, benzyl benzoate, and castor oil with allogestrel in different proportions.
  • the present inventors determined the pharmaceutical preparation consisting of benzyl alcohol, ethanol, benzyl benzoate, castor oil and allogestrol.
  • the preparation can dissolve allogestrelone and is suitable for injection administration.

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Abstract

La présente invention concerne le domaine des préparations pharmaceutiques, et concerne spécifiquement une nouvelle préparation de stéroïde neuroactif, une méthode de préparation de la préparation mentionnée ci-dessus et l'utilisation de la préparation mentionnée ci-dessus dans la préparation d'un médicament pour le traitement d'une maladie du système nerveux central.
PCT/CN2019/120390 2018-11-22 2019-11-22 Nouvelle préparation de stéroïde neuroactif WO2020103952A1 (fr)

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CN102415995A (zh) * 2011-12-09 2012-04-18 广东众生药业股份有限公司 一种黄体酮过饱和自微乳组合物及其制备方法
CN107106574A (zh) * 2014-09-08 2017-08-29 萨奇治疗股份有限公司 神经活性类固醇、组合物及其用途
CN108367046A (zh) * 2015-12-18 2018-08-03 普罗因韦特创新股份公司 用于控制生殖周期和排卵的制剂和方法

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SE9302295D0 (sv) * 1993-07-02 1993-07-02 Kabi Pharmacia Ab New pharmaceutical composition

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102415995A (zh) * 2011-12-09 2012-04-18 广东众生药业股份有限公司 一种黄体酮过饱和自微乳组合物及其制备方法
CN107106574A (zh) * 2014-09-08 2017-08-29 萨奇治疗股份有限公司 神经活性类固醇、组合物及其用途
CN108367046A (zh) * 2015-12-18 2018-08-03 普罗因韦特创新股份公司 用于控制生殖周期和排卵的制剂和方法

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