WO2016050193A1 - 一种A-失碳-5α雄甾烷化合物的口服制剂 - Google Patents

一种A-失碳-5α雄甾烷化合物的口服制剂 Download PDF

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WO2016050193A1
WO2016050193A1 PCT/CN2015/090951 CN2015090951W WO2016050193A1 WO 2016050193 A1 WO2016050193 A1 WO 2016050193A1 CN 2015090951 W CN2015090951 W CN 2015090951W WO 2016050193 A1 WO2016050193 A1 WO 2016050193A1
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carbon
androstane
compound
preparation
reducing
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PCT/CN2015/090951
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English (en)
French (fr)
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陈雅君
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陈雅君
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Priority to CA2963006A priority Critical patent/CA2963006C/en
Priority to JP2017518151A priority patent/JP6626891B2/ja
Priority to EP15847156.5A priority patent/EP3202404B1/en
Priority to AU2015327509A priority patent/AU2015327509B2/en
Priority to US15/515,555 priority patent/US10537583B2/en
Publication of WO2016050193A1 publication Critical patent/WO2016050193A1/zh

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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
    • A61K31/565—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
    • 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
    • A61K47/26—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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of medicine, and particularly relates to an oral preparation of an A-carbon-inferior-5 ⁇ -androstane compound having anti-tumor effect and anti-prostatic hyperplasia effect.
  • the active component A-carbon-deficient-5 ⁇ -androstane compound is a new compound independently developed by Li Ruilin et al. in 2000.
  • the animal efficacy test shows that it has a better therapeutic effect on prostate hyperplasia and has its own invention patent (patent number: ZL00116781.2).
  • the new anti-tumor drug A-carbon-lowering-5 ⁇ -androstane compound is a novel tumor angiogenesis inhibitor (TAI).
  • TAI tumor angiogenesis inhibitor
  • TAI "starved" tumors by inhibiting or destroying tumor angiogenesis and cutting off the source of tumor nutrition.
  • TAI drugs have high selectivity and are less toxic to normal cells while killing local cancer cells and killing systemic metastatic lesions.
  • the pharmacodynamic test proves that the A-carbon-lowering-5 ⁇ -androstane compound has a more obvious effect of inhibiting tumor growth, inhibiting tumor proliferation and having the advantage of improving body weight loss. It can prevent the division of tumor cells and inhibit the spread of tumor cells without affecting normal cells. It is a new anti-tumor drug with low toxicity and good therapeutic effect.
  • the object of the present invention is to provide a novel oral preparation, which has the A-carbon-free-5 ⁇ -androstane compound as an active component, has stable and controllable quality, and has good drug absorption, which is beneficial to the main drug to exert therapeutic effects.
  • an oral preparation comprising as an active ingredient an A-carbon-reduced-5 alpha androstane compound having one or more characteristics selected from the group consisting of:
  • the dissolution rate of the A-carbon-reducing-5 ⁇ -androstane compound in the preparation is 30 ⁇ 80%, preferably, Y 30 ⁇ 85%, more preferably within 30 min at pH 5.0-8.0. Ground ⁇ 90%;
  • the dissolution rate of the A-carbon-deficient-5 ⁇ -androstane compound in the preparation is 60 % ⁇ 80%, preferably Y 60 ⁇ 85%, more preferably Ground ⁇ 90%;
  • the dissolution rate of the A-carbon-reduced-5 ⁇ -androstane compound in the formulation is ⁇ 90% within 30 min of PBS conditions of pH 6.0.
  • the oral preparation is placed at a high temperature of 60 degrees, a high humidity of 92.5%, an illumination intensity of 45001x for 10 days, and at a pH of 6.0 PBS for 30 minutes, the A-carbon-free-5 ⁇ in the preparation.
  • the dissolution rate of the androstane compound is ⁇ 85%, preferably ⁇ 90%.
  • the dissolution of the A-carbon-reducing-5 ⁇ -androstane compound in the preparation is carried out within 30 minutes of pH 6.0 PBS.
  • the degree is ⁇ 85%, preferably, the dissolution is ⁇ 90%.
  • the formulation comprises components having the following parts by weight:
  • the active component is an A-carbon-reducing-5 alpha androstane compound.
  • the other components are mainly water-soluble adjuvants, except for the active component, wherein the sum of the weights of the water-insoluble adjuvants is from 0 to 20% by weight of the oral preparation excipients, preferably 0- 10%, optimally 0-5%.
  • the sum of the weights of the above components is 70-100%, preferably 80-100%, more preferably 90-100%, most preferably 95-100 by weight of the total weight of the oral preparation. %.
  • the content of the microcrystalline cellulose in the oral preparation is ⁇ 10% by weight, preferably ⁇ 5% by weight, more preferably ⁇ 1% by weight, optimally, the microcrystalline cellulose in the oral preparation
  • the content is 0% by weight.
  • the filler is selected from one or more of the group consisting of lactose, sucrose, sorbitol, mannitol, polyethylene glycol, starch, and inorganic salts; and/or
  • the disintegrant is selected from the group consisting of crospovidone (PVPP), croscarmellose sodium (CC Na), sodium carboxymethyl starch (CMS-Na), and low-substituted hydroxypropyl cellulose (L- One or more of HPC); and/or
  • the lubricant is selected from one or more of stearic acid, sodium stearate, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oil; and/or
  • the binder is selected from one or more of starch syrup, hydroxypropyl methylcellulose (HPMC), povidone (PVP) or copolyvidone (Kollidon); and/or
  • the glidant is selected from one or both of micronized silica gel and talc.
  • the formulation is a tablet, granule, or capsule.
  • an oral formulation comprising a component having the following parts by weight:
  • the active component is an A-carbon-reducing-5 alpha androstane compound.
  • the formulation contains primarily water soluble adjuvants in addition to the active component.
  • the sum of the weights of the water-insoluble adjuvants is from 0 to 20%, preferably from 0 to 10%, most preferably from 0 to 5% by weight of the oral preparation excipient.
  • the sum of the weights of the above components is 70-100%, preferably 80-100%, more preferably 90-100%, most preferably 95-100 by weight of the total weight of the oral preparation. %.
  • the content of the microcrystalline cellulose in the oral preparation is ⁇ 10% by weight, preferably ⁇ 5% by weight, more preferably ⁇ 1% by weight, optimally, the microcrystalline cellulose in the oral preparation
  • the content is 0% by weight.
  • the filler is selected from one or more of the group consisting of lactose, sucrose, sorbitol, mannitol, and inorganic salts; and/or
  • the disintegrant is selected from the group consisting of crospovidone (PVPP), croscarmellose sodium (CC Na), sodium carboxymethyl starch (CMS-Na), and low-substituted hydroxypropyl cellulose (L- One or more of HPC); and/or
  • the lubricant is selected from one or more of stearic acid, sodium stearate, magnesium stearate, and polyethylene glycol; and/or
  • the binder is selected from one or more of starch syrup, hydroxypropyl methylcellulose (HPMC), polyethylene glycol, povidone (PVP) or copolyvidone (Kollidon); and / or
  • the glidant is selected from one or both of micronized silica gel and talc.
  • the formulation is a tablet, granule, or capsule.
  • the tablet has a weight of 110-130 mg or 230-250 mg.
  • the A-carbon-reducing-5 ⁇ -androstane compound is contained in the tablet in an amount of from 1 to 100 mg per tablet, preferably from 1 to 50 mg per tablet.
  • the dissolution properties of the oral formulation are as described in the first aspect.
  • the method for the preparation of the oral preparation of the first aspect or the second aspect comprising the steps of:
  • the active component is an A-carbon-reducing-5 ⁇ -androstane compound
  • the step (2) comprises preparing an oral preparation by a powder direct compression method, a wet granulation method or a dry granulation method.
  • the preparation is prepared by direct compression, and the preparation method comprises the following steps:
  • a lubricant and a glidant are added to the mixture obtained in the step a1), and after mixing, tableting is carried out to obtain the preparation.
  • the preparation is prepared by a wet granulation method, and the preparation method comprises the following steps:
  • step a2) adding a binder to the mixture obtained in step a2) to obtain a soft material
  • the soft material obtained in the step b2) is granulated, sized, and then added, as needed, a disintegrant, a lubricant, and a glidant are added, and after mixing, the tablet is obtained by tableting.
  • the formulation is prepared by a dry granulation process comprising the steps of:
  • the mixture obtained in the step a3) is dry granulated, granulated, and then a lubricant and a disintegrating agent are added, and after mixing, the tablet is obtained by tableting.
  • R 1 and R 2 are independently selected from H, a substituted or unsubstituted -C 1-10 alkyl group, a substituted or unsubstituted -C 3-8 cycloalkyl group, a substituted or unsubstituted benzene ring, Substituted or unsubstituted benzoyl, substituted or unsubstituted -COC n H 2n+1 , substituted or unsubstituted -COC r H 2r COOC m H 2m++1 , or -COC p H 2p COO - W; Wherein n, p, r, and m are each independently an integer of 0 to 18, and W is H + , Na + , K + , NH 4 + , 1/2Ca 2+ , 1/2Mg 2+ , 1/2 ( AlOH) 2+ , or 1/2Zn 2+ ,
  • substitution means having one or more (e.g., 1-3) substituent groups: a hydroxyl group, a halogen, a nitro group, an amino group, an amine group, and a carboxyl group.
  • the A-carbon-deficient-5 alpha androstane compound is:
  • a fourth aspect of the invention provides the use of the oral preparation of the first aspect or the second aspect, (i) for preparing an antitumor drug; or (ii) for preparing a medicament for treating benign prostatic hyperplasia.
  • the formulation is for the treatment of tumor or prostatic hyperplasia at a dose of 2.5-20 mg/time per day, which is administered 1-4 times a day.
  • the tumor is prostate cancer, liver cancer, pancreatic cancer, gastric cancer, intestinal cancer, lung cancer.
  • the oral preparation of the invention has the effects of significantly inhibiting the growth of malignant tumor cells, and is a novel anti-malignant drug with low toxicity, good therapeutic effect and targetedness, and the compounds only act specifically. In tumor cells without affecting normal cells.
  • the active ingredient also has an anti-prostatic hyperplasia effect.
  • the oral preparation of the invention has good compatibility between the active ingredient and each auxiliary agent, and the oral preparation has high stability, convenient administration and better dissolution performance, for example, at a temperature of 40 ° C ⁇ 2 ° C, relative After storage for 30-365 days under the conditions of humidity of 75% ⁇ 5%, temperature of 25°C ⁇ 2°C, relative humidity of 60% ⁇ 10%, etc., the ratio of dissolution of oral preparations is ⁇ 85% or even ⁇ 90% compared with before storage. Or ⁇ 95%, the quality is stable and controllable, the use is safe and reliable, and has great social and economic benefits.
  • Figure 1 is a dissolution profile of the tablets prepared in Example 2 under various conditions.
  • Figure 2 is a dissolution profile of the tablets prepared in Example 5 under various conditions.
  • Figure 3 is a dissolution profile of the tablets prepared in Example 7 under various conditions.
  • Figure 4 is a dissolution profile of the tablets prepared in Example 9 under various conditions.
  • Figure 5 is a dissolution profile of a microcrystalline cellulose-containing tablet under various conditions.
  • Figure 6 is a dissolution profile of a microcrystalline cellulose-containing tablet under various conditions.
  • the inventors of the present application accidentally developed an oral preparation with an A-carbon-reducing-5 ⁇ -androstane compound as an active component, and various adjuvants, wherein the water-insoluble adjuvant accounts for
  • the sum of the weights of the oral preparation adjuvants should be less than 20%, the content of the microcrystalline cellulose is ⁇ 10% by weight, preferably ⁇ 5% by weight, more preferably ⁇ 1% by weight, optimally, the microcrystalline cellulose in the oral preparation The content is 0.
  • the dissolution rate of the A-carbon-deficient-5 ⁇ -androstane compound in the preparation was ⁇ 80%, more preferably ⁇ 90%, after 30 days, 60 days, 120 days, 365 days, within 30 min of pH 6.0 PBS.
  • Oral preparation in the condition of pH 5.0-8.0, 30 min or 60 min, the dissolution rate of the A-carbon-deficient-5 ⁇ -androstane compound in the preparation is ⁇ 85% compared with before the placement, preferably, the ratio is ⁇ 90% Even the ratio is ⁇ 95%.
  • the oral preparation of the invention has stable and controllable quality, good dissolution and absorption in the digestive tract, and facilitates the therapeutic effect of the active ingredient. On the basis of this, the present invention has been completed.
  • active component means an A-carbon-reducing-5 ⁇ -androstane compound having the following structure:
  • R 1 and R 2 are independently selected from the group consisting of: H, a substituted or unsubstituted -C 1-10 alkyl group, a substituted or unsubstituted -C 3-8 cycloalkyl group, a substituted or unsubstituted benzene ring, Substituted or unsubstituted benzoyl, substituted or unsubstituted -COC n H 2n+1 , substituted or unsubstituted -COC r H 2r COOC m H 2m++1 , or -COC p H 2p COO - W; Wherein n, p, r, and m are each independently an integer of 0 to 18, and W is H + , Na + , K + , NH 4 + , 1/2Ca 2+ , 1/2Mg 2+ , 1/2 ( AlOH) 2+ , or 1/2Zn 2+ ,
  • substitution means having one or more (e.g., 1-3) substituent groups: a hydroxyl group, a halogen, a nitro group, an amino group, an amine group, and a carboxyl group.
  • the A-carbon-reduced-5 alpha androstane compound is:
  • the present invention relates to an oral preparation of an A-carbon-reducing-5 ⁇ -androstane compound, which provides a basis for the study of pharmaceutical preparations by pre-prescription studies.
  • the water-insoluble drug A-carbon-free-5 ⁇ -androstane compound (solubility in water was 6.5 ⁇ g per ml, defined as insoluble in the pharmacopoeia.) Good dissolution and absorption in intestinal fluid, its in vivo Transport, uptake, and absorption mechanisms are all passively diffused, and intake is time and dose dependent.
  • the A-carbon deficient-5 alpha androstenane compound can be administered by the oral route.
  • oral administration is convenient, and the compliance of the patient can be improved. Therefore, the present invention is designed as an oral preparation, such as a common oral tablet. Oral capsules and other controlled release preparations.
  • the oral preparation of the present invention is as follows:
  • the active component is an A-carbon-reducing-5 ⁇ -androstane compound
  • the filler added may be one or several ingredients that increase the weight and volume of the tablet.
  • the filler is selected from one or more of lactose, sucrose, sorbitol, mannitol, polyethylene glycol, starch, and inorganic salts.
  • the filler is used in an amount of 20 to 95% by mass based on the total amount of the preparation, preferably 60 to 95%, more preferably 70 to 95%, most preferably 80 to 95%.
  • lactose is used as a filler, the amount of lactose is 20-95% of the total amount of the preparation.
  • sucrose When sucrose is used as a filler, the amount of sucrose is 10-30% of the total amount of the preparation, and when sorbitol is used as a filler, the amount of sorbitol is used. 20-95% of the total preparation, when mannitol is used as a filler, the amount of mannitol is 20-95% of the total amount of the preparation.
  • the inorganic salt When the inorganic salt is used as a filler, the amount of the inorganic salt is 5-20 of the total amount of the preparation. %.
  • the filler is lactose, mannitol, sorbitol or a mixture thereof; preferably, the filler is a mixture of lactose and mannitol.
  • the disintegrant is selected from the group consisting of crospovidone (PVPP), croscarmellose sodium (CC Na), sodium carboxymethyl starch (CMS-Na), and low-substituted hydroxypropyl cellulose (L).
  • PVPP crospovidone
  • CMS-Na sodium carboxymethyl starch
  • L low-substituted hydroxypropyl cellulose
  • PVPP crospovidone
  • CC Na croscarmellose sodium
  • CMS-Na sodium carboxymethyl starch
  • L low-substituted hydroxypropyl cellulose
  • One or more of -HPC of which PVPP and CC Na are preferred, and most preferred is CC Na.
  • the disintegrant is used in an amount ranging from 0 to 20%, usually from 1 to 10%, most preferably from 3 to 5%.
  • the lubricant is selected from the group consisting of stearic acid, sodium stearate, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oil, or two or more thereof, wherein magnesium stearate is most suitable. .
  • the lubricant is used in an amount ranging from 0.1 to 5%, usually from 0.2 to 4%, most preferably from 0.3 to 3%.
  • the binder used may be one or several ingredients which are advantageous for granulation.
  • the binder is selected from one or more of starch syrup, hydroxypropylmethylcellulose (HPMC), polyethylene glycol, povidone (PVP) or copolyvidone (Kollidon). PVP is preferred.
  • HPMC hydroxypropylmethylcellulose
  • PVP polyethylene glycol
  • PVP copolyvidone
  • Kollidon copolyvidone
  • the glidant is selected from one or two of micronized silica gel and talc, more preferably micronized silica gel.
  • the inorganic salt is selected from the group consisting of calcium sulfate (crystal water containing two molecules); calcium hydrogen phosphate; medicinal calcium carbonate and the like.
  • the tablets of the present invention may also contain other conceivable excipients well known to those skilled in the art.
  • the preparation of the tablets of the present invention may employ preparative techniques well known in the art. For example, in the preparation of a tablet, a direct compression method, a wet granulation tableting method, or a dry granulation tableting method can be employed.
  • the present invention provides a common tablet of A-carbon-reducing-5 ⁇ -androstane compound, which is determined according to the pharmacodynamic study and determines the A-carbon-free 5 ⁇ -androstane compound to meet the clinical treatment needs.
  • the tablet specification is 1-100 mg/tablet, preferably 1-50 mg/tablet, such as 2.5 mg/tablet, 5 mg/tablet, 10 mg/tablet, 25 mg/tablet, and the like.
  • the oral dosage form of the present invention has a simple and reasonable prescription composition, mainly adopts a water-soluble filler, and does not use a conventional water-insoluble filler microcrystalline cellulose, and the quality of the oral dosage form is stable and controllable, which is advantageous for the active component to exert a therapeutic effect.
  • the oral preparation of the invention has beautiful appearance, convenient administration, safe and reliable use, easy acceptance by patients, and high social and economic value.
  • the dissolution test was carried out according to the second edition of the Chinese Pharmacopoeia Appendix XC "Dissolution Determination Method".
  • the instrument device was debugged so that the bottom of the blade was 25 mm ⁇ 2 mm from the inner bottom of the dissolution cup, and the rotation speed was set to 50 rpm.
  • the degassed dissolution medium such as pH 6.0 phosphate buffer solution 900 mL was separately weighed and placed in each dissolution cup. After the temperature of the dissolution medium is constant at 37 °C ⁇ 0.5 °C, take 6 samples of the test sample and put them into 6 dissolution cups respectively.
  • the formulation study of the A-carbon-reducing-5 ⁇ -androstane compound first determines the route of administration.
  • This example will study the pre-prescription work of solubility, oil-water partition coefficient, cell transport, cell uptake and gastrointestinal absorption of A-carbon-deficient-5 ⁇ -androstane compound, thereby providing a basis for determining the route of administration.
  • the solubility of the A-carbon-deficient-5 ⁇ -androstane compound was pH-dependent and increased as the pH of the PBS solution increased. Since the dissolution of the drug has a certain relationship with the solubility, the solubility of the A-carbon-free-5 ⁇ -androstane compound under acidic conditions is very low, and the dissolution of the drug may become a rate-limiting step of absorption. Under the conditions of jejunum and ileum pH (pH 6.5 in the jejunum, pH 7 in the proximal end of the small intestine, and pH 7.5 in the distal ileum), the solubility of the A-carbon-reducing 5- ⁇ -androstane compound is large. , dissolution may not be a key factor affecting the absorption of A-carbon-free-5 ⁇ androstenane compounds.
  • the PBS of different pH was prepared, and the A-carbon-free-5 ⁇ -androstane compound (Ia) was determined by a shake flask method in a buffer solution of different pH such as PBS (pH 2.0, 4.5, 5.0, 6.0, 6.8, 7.4, respectively). Oil-water partition coefficient. Prepare a stock solution of A-carbon-free-5 ⁇ -androstane compound with a concentration of about 10 mg/mL with n-octanol saturated with water, and take 5 ml of various PBS and aqueous solution saturated with n-octanol in a stoppered glass test tube.
  • the LogP of the drug is too high (>3), indicating that the drug is too fat-soluble and not easily released from the biofilm; while the LogP is too low ( ⁇ -2), indicating that the drug is too water-soluble and difficult to penetrate the organism.
  • the membrane is absorbed; the optimal LogP value of the drug is -1 ⁇ LogP ⁇ 2.
  • the pH values of different parts of the gastrointestinal tract are: stomach 1.5-2.5, duodenum 5.5-6.1, jejunum 6.5, ileum 7, colon 7.5, therefore, A-carbon-free-5 ⁇ -androstane compound may be in the intestine Have a good absorption.
  • Caco-2 cells were spotted on a six-well plate.
  • the cells were grown to a seeding density of 8 ⁇ 10 4 /mL, the cells were cultured in a drug-containing medium to examine the uptake and uptake time of the cells, and A-carbon-free The relationship between the concentration of the decane compound (Ia), the cells were scraped off after the end of the experiment, and the cells were disrupted by repeated freezing and thawing.
  • the cell samples were precipitated with acetonitrile and analyzed by HPLC.
  • a suitable concentration of A-carbonza-5 ⁇ -androstane compound (Ia) intestinal circulation solution was prepared using PBS containing phenol red at pH 5.5 and pH 6.8, respectively. Rats who were fasted for more than 12 hours before the experiment were anesthetized by intraperitoneal injection of urethane solution (dose 4 mL/Kg) at a concentration of 0.3 g/ml, fixed, and cut about 3 cm along the midline of the abdomen, respectively, in the duodenum (from the pylorus Starting at 1 cm, A-carbon-free-5 ⁇ -androstane compound circulating solution at pH 5.5), jejunum (A-carbon-free-5 ⁇ -androstane compound circulating solution at pH 6.8 from 20 cm below the pylorus), ileum (After 30 cm from the cecum, A-carbon-free-5 ⁇ -androstane compound circulating solution at pH 6.8) was cannulated, ligated, and the contents of the intestine were washed with physiological saline preheated
  • Discharge the physiological saline cover the wound with gauze, irradiate the infrared lamp with heat (37 ° C), connect the reflux device, and equilibrate the 50 ml drug-containing circulating solution at 37 ° C for 5 min at 3 mL/min, then adjust the flow rate to 1 mL / Min began to count, sampling 1 mL at 0, 15, 30, 45, 60, 90, 120 min, and adding 1 mL of blank circulating solution, and the sample was subjected to HPLC analysis after appropriate treatment.
  • the volume of the circulating fluid was corrected, and the residual drug amount X in the circulating fluid was calculated from the concentration of A-carbon-reducing-5 ⁇ -androstane compound and the circulating fluid volume, and the linear regression was performed by lnX on t.
  • the product has good absorption in the animal body, and the absolute bioavailability of the original drug A-carbon-free 5 ⁇ -androstane compound (Ia) AUC 0-t , Beagle dog after oral administration of 1.0 mg/kg dose is 56.8. %; based on the AUC 0-t of the major metabolites in the population, the absolute bioavailability was 93.0%.
  • the main metabolites in the population are the main metabolites and the unmetabolized proto-drug A-carbon--5 ⁇ -androstane compounds and hydrolysates.
  • A-carbon-free-5 ⁇ -androstane compounds have better dissolution and absorption in intestinal fluid. It can be administered by the oral route, and the treatment of cancer requires long-term administration, and oral administration is convenient, and the compliance of the patient can be improved. Therefore, the present invention can be designed into oral dosage forms such as ordinary oral tablets, oral capsules, and other sustained-release preparations.
  • the A-carbon-reducing-5 ⁇ -androstane compound (Ia) is uniformly mixed with xylitol, mannitol and lactose.
  • the granules were granulated with a 12% (wt/v) aqueous solution of hypromellose, dried at 40 degrees, and sized with a 20 mesh sieve.
  • the crospovidone, magnesium stearate and fine powder silica gel are added to the dry granules, uniformly mixed, and tableted.
  • Fig. 1 The results show that the A-carbon-free-5 ⁇ -androstane compound tablet can be completely dissolved in the dissolution condition for 30 minutes (dissolution degree is greater than or equal to 95). %).
  • the ratio of A-carbon-lowering-5 ⁇ -androstane compound and each auxiliary material is basically the same as before placing. It shows that the A-carbon-reducing-5 ⁇ -androstane compound has good compatibility with each excipient.
  • the A-carbon-deficient-5 ⁇ -androstane compound (Ib) was uniformly mixed with lactose and a half of the cross-linked povidone.
  • the granules were granulated with a 4% (wt/v) aqueous povidone K30 solution, dried at 40 degrees, and sized with a 20 mesh sieve.
  • Magnesium stearate, talc and the remaining prescription amount of crospovidone are added to the dry granules, mixed uniformly, and tableted.
  • the A-carbon-deficient-5 ⁇ -androstane compound (Id) was uniformly mixed with lactose and mannitol.
  • the granules were granulated with an aqueous solution of 20% (wt/v) povidone K30 in ethanol (the ratio of ethanol to water was 3:7), dried at 40 ° C to semi-dry, and sieved to a 20-mesh sieve, followed by drying.
  • Magnesium stearate and micronized silica gel are added to the dry granules, mixed uniformly, and tableted.
  • the dissolution rate of 30min is greater than or equal to 95%.
  • the A-carbon-reducing-5 ⁇ -androstane compound (Ic) is uniformly mixed with mannitol, lactose, and croscarmellose.
  • the granules were granulated with 25% (w/v) starch syrup, dried at 40 ° C to semi-dry, and sieved to a 20-mesh sieve, followed by drying.
  • Magnesium stearate and talc powder are added to the dry granules, mixed well, and tableted.
  • the ratio of A-carbon-free-5 ⁇ -androstane compound and each auxiliary material is basically the same as before, indicating The A-carbon-deficient-5 ⁇ -androstane compound has good compatibility with each excipient.
  • the A-carbon-deficient-5 ⁇ -androstane compound (Ie) was uniformly mixed with sorbitol, pregelatinized starch, calcium sulfate and copolyvidone VA64, dried and crushed, and sieved by 20 mesh.
  • Sodium carboxymethyl starch, polyethylene glycol and talc are added to the dry granules, mixed uniformly, and tableted.
  • the 0-day sample and the 10-day sample under the experimental conditions of each influencing factor were dissolved under the conditions of 30 minutes, and the dissolution rate was greater than or equal to 95%.
  • the A-carbon-deficient-5 ⁇ -androstane compound (If) was uniformly mixed with hypromellose, mannitol and lactose in equal amounts. The mixture was granulated using a dry granulation mechanism. The croscarmellose sodium, the microsilica gel and the magnesium stearate are added to the prepared granules and mixed, and compressed.
  • A-carbon-free-5 ⁇ -androstane compound (Ig) is treated with L-HPC, mannitol and pregelatinized starch and copolyvidone VA64, low-substituted hydroxypropylcellulose, micronized silica gel and magnesium stearate. Add and mix evenly. The obtained powder was directly compressed into tablets.
  • the 0-day sample and the 10-day sample under the experimental conditions of each influencing factor were dissolved under the conditions of 30 minutes, and the dissolution rate was greater than or equal to 95%.
  • the A-carbon-reducing-5 ⁇ -androstane compound (Ih) was uniformly mixed with the copolyvidone VA64, mannitol, lactose and sodium carboxymethylcellulose in equal amounts. Magnesium stearate and talc are added in equal amounts to the previous mixture. The obtained powder was directly compressed into tablets.
  • Example 5 The procedure was essentially the same as in Example 5 except that the components of the tablets were as shown in the above table.
  • the 0-day sample and the 10-day sample under the experimental conditions of each influencing factor were dissolved under the conditions of 30 minutes, and the dissolution rate was greater than or equal to 95%.
  • Table 6, Table 7, and Table 8 show the dissolution data of the samples prepared in Example 2 for 6 months and 6 months and 2 years, respectively.
  • Example 2 The results show that the sample prepared in Example 2 can still reach 91%-95% in 30min after accelerated 6-month experiment, and 90% in 30min after long-term 6-month experiment. 95%, even after a long-term 2-year experiment, the dissolution rate in 30min can reach 82%-88%, with good dissolution properties.
  • the A-carbon-reducing 5- ⁇ -androstane compound is uniformly mixed with crospovidone, lactose and microcrystalline cellulose 101, granulated with an aqueous solution of 20% (wt/v) povidone K30, and baked at 40 ° C to half. Dry, 20 mesh sieve, and then dry. Magnesium stearate and micronized silica gel are added to the dry granules, mixed uniformly, and tableted.
  • the dissolution profile of the 0-day sample and the experimental conditions of the influencing factors at 60 ° C, RH 92.5% and light for 10 days is shown in Fig. 5.
  • the dissolution rate of the 0-day sample at 30 min is less than 75%, and the influencing factors are 60 ° C, RH 92.5. % and light were placed for 10 days.
  • the dissolution curve of the sample was less than 60% at 30 min. The results showed that the dissolution was slow and the dissolution was limited after being placed under various influencing factors.
  • the A-carbon-deficient-5 ⁇ -androstane compound was uniformly mixed with the sodium carboxymethyl starch, the copolyvidone VA64, and the microcrystalline cellulose 102 in equal amounts.
  • the micronized silica gel was uniformly mixed with the previous mixture by an equal amount of addition.
  • the obtained powder was directly compressed into tablets.
  • the dissolution profile of the 0-day sample and the experimental conditions of the influencing factors at 60 ° C, RH 92.5% and light for 10 days is shown in Figure 6.
  • the dissolution of the sample at 30 min for the 0-day sample is about 80%, in the influencing factors, the experimental conditions are 60 ° C, RH 92.5. % and light were placed for 10 days.
  • the dissolution profile of the sample was about 60% for 30 min. The results showed that the dissolution was slow and the dissolution was limited after being placed under various influencing factors.
  • the A-carbon-reduced-5 ⁇ -androstane compound (Ic) is uniformly mixed with xylitol, mannitol, lactose and microcrystalline cellulose 101.
  • the granules were granulated with a 12% (wt/v) aqueous solution of hypromellose, dried at 40 degrees, and sized with a 20 mesh sieve.
  • the crospovidone, magnesium stearate and fine powder silica gel are added to the dry granules, uniformly mixed, and tableted.
  • the samples containing the insoluble auxiliary microcrystalline cellulose were tested for dissolution under different conditions. The results are shown in Table 9.
  • the dissolution of the insoluble adjuvant microcrystalline cellulose at the 0 day of the sample was about 80% at 40 minutes, 40 degrees. After 10 days, the dissolution decreased to about 60%, and the dissolution decreased to about 59% after being placed at 60 degrees for 10 days. Under the conditions of various influencing factors, the dissolution decreased with the extension of the standing time.
  • the experimental results show that the auxiliary microcrystalline cellulose has a great influence on the stability and dissolution of the preparation.
  • the content of the microcrystalline cellulose is preferably as small as possible (e.g., ⁇ 5 wt%, more preferably ⁇ 1 wt%), even without microcrystalline cellulose.

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Abstract

一种口服制剂及其制备方法和用途。所述口服制剂包含1-50重量的A-失碳-5α-雄甾烷化合物、20-95重量份的填充剂、0-20重量份的崩解剂、0.1-30重量份的粘合剂、0.1-5重量份的润滑剂、0.1-5重量份的助流剂。该口服制剂稳定性高、溶出性能好。

Description

一种A-失碳-5α雄甾烷化合物的口服制剂 技术领域
本发明属于医药领域，具体涉及一种具有抗肿瘤作用和抗前列腺增生作用的A-失碳-5α雄甾烷化合物的口服制剂。
背景技术
活性组分A-失碳-5α雄甾烷化合物是2000年李瑞麟等人自主研发合成的全新化合物，动物药效试验表明有较好的治疗前列腺增生作用，拥有自己的发明专利(专利号为：ZL00116781.2)。
之后，发明人在长期的进一步研究中，发现本品具有显著的体内和体外抗恶性肿瘤活性，可以设计制备抗恶性肿瘤药物(申请号为：201110088946.4)。抗肿瘤新药A-失碳-5α雄甾烷化合物是一种新型的肿瘤血管生成抑制剂(tumor angiogenesis inhibitors，TAI)。TAI不同于传统的化疗药物，其通过抑制或破坏肿瘤血管生成，切断肿瘤营养来源而“饿死”肿瘤。TAI药物具有较高的选择性，在杀死局部癌细胞和杀伤全身转移病灶的同时，对正常细胞的毒性较小。药效试验证明，A-失碳-5α雄甾烷化合物具有较明显的抑制肿瘤生长作用，抑制肿瘤增殖的同时具有改善动物体重降低的优势。在不影响正常细胞的前提下选择性阻止肿瘤细胞的分裂，从而抑制肿瘤细胞的扩散，是一种药物毒性小，治疗效果好的抗肿瘤的新型药物。
目前尚无A-失碳-5α雄甾烷化合物的制剂上市，亦无研究报道，因此，本领域需要提供一种有效的质量稳定可控的剂型，利于其发挥治疗作用。
发明内容
本发明的目的在于提供一种新型的口服制剂，以A-失碳-5α雄甾烷化合物为活性组分，质量稳定可控，药物吸收良好，利于主药发挥治疗作用。
本发明的第一方面，提供一种口服制剂，含有作为活性组分的A-失碳-5α雄甾烷化合物，具有选自下组的一个或多个特征：
(i)在pH5.0-8.0条件下，30min内，所述制剂中A-失碳-5α雄甾烷化合物的溶出度Y30≥80％，较佳地，Y30≥85％，更佳地≥90％；
(ii)在pH5.0-8.0条件下，60min内，所述制剂中A-失碳-5α雄甾烷化合物的溶出度Y60≥80％，较佳地，Y60≥85％，更佳地≥90％；
并且所述口服制剂还具有选自下组的一个或多个特征：
(a)X1≥85％，其中X1＝Y1/Y30；Y1为所述口服制剂在温度40℃±2℃、相对湿度75％±5％的条件下存储30天后在pH5.0-8.0条件下，30min内，制剂中A-失碳-5α雄甾烷化合物的溶出度；较佳地，X1≥90％，甚至X1≥95％；
(b)X2≥85％，其中X2＝Y2/Y30；Y2为所述口服制剂在温度40℃±2℃、相对湿 度75％±5％的条件下存储60天后在pH5.0-8.0条件下，30min内，制剂中A-失碳-5α雄甾烷化合物的溶出度；较佳地，X2≥90％，甚至X2≥95％；
(c)X3≥85％，其中X3＝Y3/Y30；Y3为所述口服制剂在温度40℃±2℃、相对湿度75％±5％的条件下存储180天后在pH5.0-8.0条件下，30min内，制剂中A-失碳-5α雄甾烷化合物的溶出度；较佳地，X3≥90％；
(d)X4≥85％，其中X4＝Y4/Y30；Y4为所述口服制剂在温度25℃±2℃、相对湿度60％±10％的条件下存储365天后在pH5.0-8.0条件下，30min内，制剂中A-失碳-5α雄甾烷化合物的溶出度；较佳地，X4≥90％；
(e)X5≥85％，其中X5＝Y5/Y60；Y5为所述口服制剂在温度40℃±2℃、相对湿度75％±5％的条件下存储30天后在pH5.0-8.0条件下，60min内，制剂中A-失碳-5α雄甾烷化合物的溶出度；较佳地，X5≥90％；
(f)X6≥85％，其中X6＝Y6/Y60；Y6为所述口服制剂在温度40℃±2℃、相对湿度75％±5％的条件下存储60天后在pH5.0-8.0条件下，60min内，制剂中A-失碳-5α雄甾烷化合物的溶出度；较佳地，X6≥90％；
(g)X7≥85％，其中X7＝Y7/Y60；Y7为所述口服制剂在温度40℃±2℃、相对湿度75％±5％的条件下存储180天后在pH5.0-8.0条件下，60min内，制剂中A-失碳-5α雄甾烷化合物的溶出度；较佳地，X7≥90％；
(h)X8≥85％，其中X8＝Y8/Y60；Y8为所述口服制剂在温度25℃±2℃、相对湿度60％±10％的条件下存储365天后在pH5.0-8.0条件下，60min内，制剂中A-失碳-5α雄甾烷化合物的溶出度；较佳地，X8≥90％。
在另一优选例中，在pH6.0的PBS条件下，30min内，所述制剂中A-失碳-5α雄甾烷化合物的溶出度达≥90％。
在另一优选例中，所述口服制剂在高温60度，高湿92.5％，光照强度4500lx条件下放置10天后，在pH6.0PBS条件下，30min内，所述制剂中A-失碳-5α雄甾烷化合物的溶出度达≥85％，较佳地，≥90％。
在另一优选例中，所述口服制剂放置3个月、6个月甚至1年后，在pH6.0PBS条件下，30min内，所述制剂中A-失碳-5α雄甾烷化合物的溶出度达≥85％，较佳地，溶出度≥90％。
在另一优选例中，所述制剂包含具有以下重量份的组分：
  重量份 优选重量份
活性组分 1-50重量份 1-25重量份
填充剂 20-95重量份 30-90重量份
崩解剂 0-20重量份 1-10重量份
粘合剂 0.1-30重量份 0.5-10重量份
润滑剂 0.1-5重量份 0.2-2.5重量份
助流剂 0.1-5重量份 0.2-2.5重量份
其中，所述活性组分为A-失碳-5α雄甾烷化合物。
在另一优选例中，除活性组分外，其他组分主要为水溶性辅剂，其中水不溶性辅剂的重量之和占所述口服制剂辅料重量的0-20％，较佳地0-10％，最佳地0-5％。
在另一优选例中，上述组分的重量之和占所述口服制剂的总重量的70-100％，较佳地80-100％，更佳地90-100％，最佳地95-100％。
在另一优选例中，所述口服制剂中微晶纤维素的含量≤10wt％，较佳地≤5wt％，更佳地≤1wt％，最佳地，所述口服制剂中微晶纤维素的含量为0wt％。
在另一优选例中，所述填充剂选自乳糖、蔗糖、山梨醇、甘露醇、聚乙二醇，淀粉以及无机盐中的一种或者两种以上；和/或
所述崩解剂选自交联聚维酮(PVPP)、交联羧甲基纤维素钠(CC Na)、羧甲基淀粉钠(CMS-Na)、低取代羟丙基纤维素(L-HPC)中的一种或者两种以上；和/或
所述润滑剂选自硬脂酸、硬脂酸钠、硬脂酸镁、硬脂酸钙、聚乙二醇、氢化植物油中的一种或者两种以上；和/或
所述粘合剂选自淀粉浆、羟丙基甲基纤维素(HPMC)、聚维酮(PVP)或共聚维酮(Kollidon)中的一种或者两种以上；和/或
所述助流剂选自微粉硅胶和滑石粉中的一种或者两种。
在另一优选例中，所述制剂为片剂、颗粒剂、或胶囊。
本发明的第二方面，提供一种口服制剂，包含具有以下重量份的组分：
  重量份 优选重量份
活性组分 1-50重量份 1-25重量份
填充剂 20-95重量份 30-90重量份
崩解剂 0-20重量份 1-10重量份
粘合剂 0.1-30重量份 0.5-10重量份
润滑剂 0.1-5重量份 0.2-2.5重量份
助流剂 0.1-5重量份 0.2-2.5重量份
其中，所述活性组分为A-失碳-5α雄甾烷化合物。
在另一优选例中，除活性组分外，制剂中主要包含水溶性辅剂。
在另一优选例中，水不溶性辅剂的重量之和占所述口服制剂辅料重量的0-20％，较佳地0-10％，最佳地0-5％。
在另一优选例中，上述组分的重量之和占所述口服制剂的总重量的70-100％，较佳地80-100％，更佳地90-100％，最佳地95-100％。
在另一优选例中，所述口服制剂中微晶纤维素的含量≤10wt％，较佳地≤5wt％，更佳地≤1wt％，最佳地，所述口服制剂中微晶纤维素的含量为0wt％。
在另一优选例中，所述填充剂选自乳糖、蔗糖、山梨醇、甘露醇、以及无机盐中的一种或者两种以上；和/或
所述崩解剂选自交联聚维酮(PVPP)、交联羧甲基纤维素钠(CC Na)、羧甲基淀粉钠(CMS-Na)、低取代羟丙基纤维素(L-HPC)中的一种或者两种以上；和/或
所述润滑剂选自硬脂酸、硬脂酸钠、硬脂酸镁、聚乙二醇中的一种或者两种以上；和/或
所述粘合剂选自淀粉浆、羟丙基甲基纤维素(HPMC)、聚乙二醇、聚维酮(PVP)或共聚维酮(Kollidon)中的一种或者两种以上；和/或
所述助流剂选自微粉硅胶、滑石粉中的一种或者两种。
在另一优选例中，所述制剂为片剂、颗粒剂、或胶囊。
在另一优选例中，所述片剂的重量为110-130mg或230-250mg。
在另一优选例中，所述片剂中A-失碳-5α雄甾烷化合物的含量为1-100mg/片，较佳地，为1-50mg/片。
在另一优选例中，所述口服制剂的溶出性能如第一方面所述。
本发明的第三方面，提供第一方面或第二方面所述的口服制剂的制法，包括步骤：
(1)提供以下材料作为原料；
  重量份 优选重量份
活性组分 1-50重量份 1-25重量份
填充剂 20-95重量份 30-90重量份
崩解剂 0-20重量份 1-10重量份
粘合剂 0.1-30重量份 0.5-10重量份
润滑剂 0.1-5重量份 0.2-2.5重量份
助流剂 0.1-5重量份 0.2-2.5重量份
其中，所述活性组分为A-失碳-5α雄甾烷化合物，
(2)将上述材料制成口服制剂。
在另一优选例中，步骤(2)中包括用粉末直接压片法、湿法制粒法或干法制粒法制备口服制剂。
在另一优选例中，采用直接压片法制备所述制剂，制备方法包括以下步骤：
a1)采用等量递加法将活性组分、填充剂、崩解剂、粘合剂混合均匀；
b1)在步骤a1)得到的混合物中加入润滑剂和助流剂，混匀后压片得到所述制剂。
在另一优选例中，采用湿法制粒法制备所述制剂，制备方法包括以下步骤：
a2)采用等量递加法将活性组分、填充剂、崩解剂混合均匀；
b2)在步骤a2)得到的混合物中加入粘合剂制得软材；
c2)将步骤b2)得到的软材经制粒、整粒后加入根据需要，加入崩解剂、润滑剂和助流剂，混匀后压片得到所述制剂。
在另一优选例中，采用干法制粒法制备所述制剂，制备方法包括以下步骤：
a3)采用等量递加法将活性组分、填充剂、崩解剂、粘合剂、助流剂混合均匀；
b3)将步骤a3)得到的混合物干法制粒、整粒后加入润滑剂和崩解剂，混匀后压片得到所述制剂。
本发明中，所述A-失碳-5α雄甾烷化合物的结构如式I所示：
Figure PCTCN2015090951-appb-000001
式中，R1、R2独立地选自自H、取代或未取代的-C1-10烷基、取代或未取代的-C3-8环烷基、取代或未取代的苯环、取代或未取代的苯甲酰基、取代或未取代的-COCnH2n+1、取代或未取代的-COCrH2rCOOCmH2m++1、或-COCpH2pCOO-W；其中，n、p、r、m各自独立地为0～18的整数，W为H+、Na+、K+、NH4 +、1/2Ca2+、1/2Mg2+、1/2(AlOH)2+、或1/2Zn2+，
所述取代是指具有一个或多个(如1-3个)以下取代基团：羟基、卤素、硝基、氨基、胺基、羧基。
较佳地，所述A-失碳-5α雄甾烷化合物为：
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双乙酸酯化合物；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双丙酸酯化合物；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基-2β-单琥珀酸酯化合物(Id)；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双琥珀酸酯化合物；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双丁酸酯化合物；
2α，17α-双羟丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物；
2α，17α-双氰基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双三氯乙酸酯化合物；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基-2β-丙酸酯-17β琥珀酸酯化合物；
2α，17α-双丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物；或
2α，17α-双丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双丙酸酯化合物。
本发明的第四方面，提供第一方面或第二方面所述的口服制剂的用途，(i)用于制备抗肿瘤药物；或(ii)用于制备治疗前列腺增生的药物。
在另一优选例中，所述制剂用于治疗肿瘤或前列腺增生，剂量是每天2.5-20mg/次，该剂量以每日1-4次服用。
在另一优选例中，所述肿瘤为前列腺癌、肝癌、胰腺癌、胃癌、肠癌、肺癌。
本发明的口服制剂，活性组分具有显著的抑制恶性肿瘤细胞生长的作用，是一类药物毒性小、治疗效果好，具靶向性的新型抗恶性肿瘤药物，并且此类化合物只特异地作用于肿瘤细胞，而不影响正常细胞。该活性组分还具有抗前列腺增生的作用。本发明的口服制剂，活性组分和各辅剂之间具有良好的相容性，且口服制剂稳定性高、给药方便且具有较佳的溶出性能，如在温度40℃±2℃、相对湿度75％±5％；温度25℃±2℃、相对湿度60％±10％等条件下储存30-365天之后，口服制剂的溶出度与放置前相比比值≥85％，甚至≥90％或≥95％，质量稳定可控、使用安全可靠，具有巨大的社会和经济效益。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为实施例2制备的片剂在各种条件下的溶出曲线。
图2为实施例5制备的片剂在各种条件下的溶出曲线。
图3为实施例7制备的片剂在各种条件下的溶出曲线。
图4为实施例9制备的片剂在各种条件下的溶出曲线。
图5为含微晶纤维素片剂在各种条件下的溶出曲线。
图6为含微晶纤维素片剂在各种条件下的溶出曲线。
具体实施方式
本申请的发明人经过广泛而深入的研究，意外研发出一种口服制剂，以A-失碳-5α雄甾烷化合物为活性组分，配以各种辅剂，其中水不溶性辅剂占所述口服制剂辅剂重量之和应小于20％，微晶纤维素的含量≤10wt％，较佳地≤5wt％，更佳地≤1wt％，最佳地，所述口服制剂中微晶纤维素的含量为0。在pH6.0PBS条件下，30min内，所述制剂中A-失碳-5α雄甾烷化合物的溶出度≥80％，更佳地≥90％，放置30天、60天、120天、365天后，口服制剂在pH5.0-8.0条件下，30min或60min内，制剂中A-失碳-5α雄甾烷化合物的溶出度与放置前相比比值≥85％，较佳地，比值≥90％，甚至比值≥95％。本发明的口服制剂，质量稳定可控、在消化道内具有良好的溶出和吸收，利于活性组分发挥治疗作用。在此基础上，完成了本发明。
活性组分
本发明中，术语“活性组分”是指A-失碳-5α雄甾烷化合物，具有如下结构：
Figure PCTCN2015090951-appb-000002
式中，R1、R2独立地选自：H、取代或未取代的-C1-10烷基、取代或未取代的-C3-8环烷基、取代或未取代的苯环、取代或未取代的苯甲酰基、取代或未取代的-COCnH2n+1、取代或未取代的-COCrH2rCOOCmH2m++1、或-COCpH2pCOO-W；其中，n、p、r、m各自独立地为0～18的整数，W为H+、Na+、K+、NH4 +、1/2Ca2+、1/2Mg2+、1/2(AlOH)2+、或1/2Zn2+，
所述取代是指具有一个或多个(如1-3个)以下取代基团：羟基、卤素、硝基、氨基、胺基、羧基。
较佳地，A-失碳-5α雄甾烷化合物为：
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物(Ia)；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双乙酸酯化合物(Ib)；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双丙酸酯化合物(Ic)；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基-2β-单琥珀酸酯化合物(Id)；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双琥珀酸酯化合物(Ie)；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双丁酸酯化合物(If)；
2α，17α-双羟丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物(Ig)；
2α，17α-双氰基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物(Ih)；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双三氯乙酸酯化合物(Ii)；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基-2β-丙酸酯-17β琥珀酸酯化合物(Ij)；
2α，17α-双丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物(Ik)；或
2α，17α-双丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双丙酸酯化合物(Il)。
口服制剂
本发明涉及一种活性组分为A-失碳-5α雄甾烷化合物的口服制剂，通过处方前研究为药物制剂的研究提供依据。
处方前研究结果表明：水不溶性药物A-失碳-5α雄甾烷化合物(水中溶解度为6.5微克每毫升，按药典定义为不溶。)在肠液中有较好的溶出和吸收，其在体内的转运、摄取和吸收机制均为被动扩散，且摄取量呈现时间和剂量依赖性。A-失碳-5α雄甾烷化合物可以通过口服途径给药。且由于癌症的治疗需要长期服药，口服给药方便，可以提高患者的顺应性，因此本发明将其设计为口服制剂，如普通口服片剂、 口服胶囊以及其他缓控释制剂。
本发明的口服制剂，其组份和各组分的重量份如下：
Figure PCTCN2015090951-appb-000003
所述的活性组分为A-失碳-5α雄甾烷化合物；
所添加的填充剂可以是一种或者几种增加片剂重量和体积的成分。本发明中，所述填充剂选自乳糖、蔗糖、山梨醇、甘露醇、聚乙二醇、淀粉以及无机盐中的一种或者两种以上。所述填充剂的用量占制剂总量的20-95％，较佳为60-95％，更佳为70-95％，最佳为80-95％。当乳糖作为填充剂时，乳糖的用量占制剂总量的20-95％，蔗糖作为填充剂时，蔗糖的用量占制剂总量的10-30％，山梨醇作为填充剂时，山梨醇的用量占制剂总量的20-95％，甘露醇作为填充剂时，甘露醇的用量占制剂总量的20-95％，无机盐作为填充剂时，无机盐的用量占制剂总量的5-20％。在另一优选例中，所述填充剂为乳糖、甘露醇、山梨醇或它们的混合物；较佳地，所述填充剂为乳糖和甘露醇的混合物。
所述的崩解剂选自交联聚维酮(PVPP)、交联羧甲基纤维素钠(CC Na)、羧甲基淀粉钠(CMS-Na)、低取代羟丙基纤维素(L-HPC)中的一种或者两种以上，其中以PVPP和CC Na为佳，最佳为CC Na。崩解剂的用量范围(与总重比)为0–20％，一般用量为1–10％，最佳为3–5％。
所述的润滑剂选自硬脂酸、硬脂酸钠、硬脂酸镁、硬脂酸钙、聚乙二醇、氢化植物油中的一种或者两种以上，其中以硬脂酸镁最为适宜。润滑剂的用量范围(与总重比)为0.1–5％，一般用量为0.2–4％，最佳为0.3–3％。
所采用的粘合剂可以是一种或几种有利于制粒的成分。所述的粘合剂选自淀粉浆、羟丙基甲基纤维素(HPMC)、聚乙二醇、聚维酮(PVP)或共聚维酮(Kollidon)中的一种或者两种以上。优选PVP。当淀粉浆作为粘合剂时，淀粉浆的用量占制剂总量的10-30％，当HPMC作为粘合剂时，HPMC的用量占制剂总量的2-5％，当PVP作为粘合剂时，PVP的用量占制剂总量的2-20％，当聚维酮作为粘合剂时，共聚维酮的用量占制剂总量的0.1-10％。
所述的助流剂，选自微粉硅胶和滑石粉中的一种或者两种，更优选为微粉硅胶。
在另一优选例中，所述无机盐选自：硫酸钙(含两个分子的结晶水)；磷酸氢钙；药用碳酸钙等。
通常而言，本发明片剂还可以含有本领域技术人员熟知的其他易想到的辅料， 本发明片剂的制备可以采用本领域公知的制备技术。如在制备片剂时，可以采用直接压片法、湿法制粒压片法、干法制粒压片法。
本发明提供一种A-失碳-5α雄甾烷化合物的普通片剂，根据药效学研究确定的其临床给药剂量，为满足临床治疗需要，确定A-失碳-5α雄甾烷化合物片剂规格为1-100mg/片，较佳地，为1-50mg/片，如2.5mg/片、5mg/片、10mg/片、25mg/片等。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
本发明的有益之处在于：
(1)提供一种新型的以A-失碳-5α雄甾烷化合物为活性组分的口服剂型，在肠道内具有良好的溶出和吸收，填补了A-失碳-5α雄甾烷化合物剂型上的空白。
(2)本发明的口服剂型处方组成简单合理，主要采用水溶性填充剂，未使用常规的非水溶性填充剂微晶纤维素，口服剂型质量稳定可控，利于活性组分发挥治疗作用。
(3)本发明的口服剂型制备工艺简单易行，且便于工业化生产衔接。
(3)本发明的口服制剂外形美观，给药方便，使用安全可靠，患者易接受，具有较高的社会和经济价值。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
通用方法
溶出度
根据2010版中国药典附录XC《溶出度测定法》第二法浆法进行溶出度试验。实验前调试仪器装置，使桨叶底部距溶出杯的内底部25mm±2mm，转速设定50rpm。分别量取经脱气处理的溶出介质如pH6.0磷酸盐缓冲液900mL，置各溶出杯内。待溶出介质温度恒定在37℃±0.5℃后，取供试品6片，分别投入6个溶出杯内，注意供试品表面上不要有气泡，启动仪器，计时；至规定的取样时间(5、10、15、30、 45、60min)，吸取溶出液10mL立即用微孔滤膜滤过，自取样至滤过应在30秒钟内完成。取澄清滤液进行HPLC测定，计算每片的溶出量。
另根据2010版中国药典附录XIXC《原料药与药物制剂稳定性试验指导原则》进行A-失碳-5α雄甾烷化合物片剂的高温(60℃)、高湿(25℃，相对湿度92.5％)、强光照射(4500lx)加速试验和长期试验，测定供试品的溶出度，并与0天样品相比较。
实施例1
给药途径的确定
作为一类新药，A-失碳-5α雄甾烷化合物的制剂研究首先要确定给药途径。本实施例将对A-失碳-5α雄甾烷化合物的溶解度、油水分配系数、细胞转运、细胞摄取及胃肠吸收等处方前工作进行研究，从而为给药途径的确定提供依据。
1.1平衡溶解度测定
配制不同pH的磷酸盐缓冲液(PBS)(pH分别为1.0、5.0、5.5、5.8、6.0、6.8、7.4)，采用平衡法测定A-失碳-5α雄甾烷化合物(Ia)在不同pH的PBS中的平衡溶解度。方法：移取5mL各介质于具塞试管中，分别加入约30mg A-失碳-5α雄甾烷化合物原料药，放入37℃恒温振荡器中，100rpm振摇，72h后取样，样品进行HPLC分析，结果见表1。
表1 A-失碳-5α雄甾烷化合物(Ia)在不同介质中的平衡溶解度(n＝3)
Figure PCTCN2015090951-appb-000004
由结果可知，A-失碳-5α雄甾烷化合物的溶解度具有pH依赖性，随PBS溶液的pH的升高而增大。由于药物的溶出与溶解度有一定关系，A-失碳-5α雄甾烷化合物在酸性条件下的溶解度很低，此时药物的溶出可能成为吸收的限速步骤。而在空肠和回肠pH条件下(空肠中的pH值为6.5，小肠近端的pH值为7，远端回肠中的pH值为7.5)，A-失碳-5α雄甾烷化合物的溶解度大，溶出可能不会成为影响A-失碳-5α雄甾烷化合物吸收的关键因素。
1.2油水分配系数
配制不同pH的PBS，采用摇瓶法测定A-失碳-5α雄甾烷化合物(Ia)在不同pH的缓冲溶液如PBS(pH分别为2.0、4.5、5.0、6.0、6.8、7.4)中的油水分配系数。用水饱和过的正辛醇配制浓度约为10mg/mL的A-失碳-5α雄甾烷化合物储备液，取各种被正辛醇饱和过的PBS及水溶液5ml于具塞玻璃试管中，分别加入0.5mL A-失碳-5α雄甾烷化合物储备液，密封完全，放入37℃恒温振荡器中，振摇24h后取样，取水相和油相样品分别进行HPLC分析，分别计算药物在水相和油相的浓度，按照LogP＝-Log(C油/C水)计算油水分配系数(LogP)，结果见表2。
表2 A-失碳-5α雄甾烷化合物(Ia)在不同pH缓冲溶液中油水分配系数测定(n＝3)
pH 2.0 4.5 5.0 6.0 6.8 7.4
LogP ∞ 4.19±0.084 3.80±0.049 2.52±0.006 0.98±0.003 0.11±0.0004
通常，药物的LogP过高(>3)，说明药物的脂溶性太高，不易从生物膜内释放出来；而LogP过低(<-2)，说明药物的水溶性太好，不易穿透生物膜而被吸收；药物的最佳LogP值为：-1<LogP<2。
结果显示，A-失碳-5α雄甾烷化合物在近中性条件下可能有较好的吸收。而胃肠道不同部位的pH值分别为：胃1.5-2.5，十二指肠5.5-6.1，空肠6.5，回肠7，结肠7.5，因此，A-失碳-5α雄甾烷化合物在肠道中可能有较好的吸收。
1.3体外细胞试验
细胞转运
取符合转运试验要求的Transwell板，用Hank’s平衡盐溶液(HBSS)配制含药培养液，考察不同浓度A-失碳-5α雄甾烷化合物(Ia)在Caco-2细胞的双向转运，结果见表3。
表3 A-失碳-5α雄甾烷化合物(Ia)细胞转运试验结果
Figure PCTCN2015090951-appb-000005
由结果可知，A-失碳-5α雄甾烷化合物在Caco-2细胞的表观渗透系数(Papp)随浓度的增加而变大，但外排率(ER)变化不大，推测A-失碳-5α雄甾烷化合物的转运机制主要为被动扩散。各种条件下的Papp均>1×10-6cm/s，提示A-失碳-5α雄甾烷化合物在消化道中有较好的吸收。
细胞摄取
将Caco-2细胞点样于六孔板，当细胞生长到8×104个/mL的接种密度后，用含药培养基培养细胞，考察细胞摄取与摄取时间、A-失碳-5α雄甾烷化合物(Ia)浓度的关系，实验结束后将细胞刮下，反复冻融使细胞破碎，细胞样品用乙腈沉淀后HPLC分析。
由摄取试验结果可知，摄取量与摄取时间呈线性(y＝0.204x+6.107，r＝0.9952)，摄取量随摄取时间的增加而增加；摄取量与A-失碳-5α雄甾烷化合物(Ia)的浓度呈线性(y＝40.59x-10.47，r＝0.9994)，摄取量随A-失碳-5α雄甾烷化合物浓度的增加而增加，提示A-失碳-5α雄甾烷化合物的摄取机制是被动扩散。
1.4大鼠在体试验
在体肠吸收
分别采用含酚红的pH5.5和pH6.8的PBS配制适宜浓度的A-失碳-5α雄甾烷化合物(Ia)肠循环液。选实验前禁食12h以上的大鼠，腹腔注射浓度为0.3g/ml乌拉坦 溶液(剂量4mL/Kg)麻醉，固定，沿腹中线剪开约3cm，分别于十二指肠(从幽门下1cm处开始，pH5.5的A-失碳-5α雄甾烷化合物循环液)、空肠(从幽门下20cm处开始，pH6.8的A-失碳-5α雄甾烷化合物循环液)、回肠(从盲肠上行30cm处开始，pH6.8的A-失碳-5α雄甾烷化合物循环液)插管，结扎，用预热至37℃的生理盐水将肠内容物洗净，再通入空气将生理盐水排净，用纱布盖上创口，红外灯照射保温(37℃)，连接好回流装置，将恒温37℃的50ml含药循环液以3mL/min平衡5min后，将流速调至1mL/min开始计时，分别于0、15、30、45、60、90、120min取样1mL，同时补加空白循环液1mL，样品经适当处理后进行HPLC分析。根据酚红的浓度校正循环液的体积，再由A-失碳-5α雄甾烷化合物浓度与循环液体积计算循环液中的剩余药量X，以lnX对t进行线性回归分析，直线斜率为药物的吸收速率常数(Ka)；由2h药物的吸收量(Q)比吸收前初始药量(X0)求出药物的累积吸收百分率(P)，结果如表4及表5所示。
表4 不同肠段A-失碳-5α雄甾烷化合物(Ia)的吸收(n＝3)
Figure PCTCN2015090951-appb-000006
表5 不同浓度A-失碳-5α雄甾烷化合物(Ia)在空肠的吸收(n＝3)
Figure PCTCN2015090951-appb-000007
结果表明，A-失碳-5α雄甾烷化合物在空、回肠的吸收较好，吸收百分率均>50％；以lnX对t进行线性回归分析，各回归直线的r值均>0.9，表明在空、回肠部位，药物浓度的下降与循环时间呈线性关系，提示A-失碳-5α雄甾烷化合物的吸收动力学为一级吸收；A-失碳-5α雄甾烷化合物吸收量与浓度有较好的线性关系(y＝20.34x+649.7,r＝0.9869)，表明A-失碳-5α雄甾烷化合物的吸收机制可能是被动扩散。肠吸收结果表明A-失碳-5α雄甾烷化合物在小肠中有较好的吸收。
1.5药代动力学研究的生物利用度
本品在动物体内有良好的吸收，以原形药物A-失碳-5α雄甾烷化合物(Ia)AUC0-t计，Beagle犬灌胃给予1.0mg/kg剂量后的绝对生物利用度为56.8％；以总体内的主要代谢产物的AUC0-t计，绝对生物利用度为93.0％。
注：总体内的主要代谢产物为主要代谢产物和未被代谢的原形药物A-失碳-5α雄甾烷化合物及水解产物。
以上处方前研究表明，A-失碳-5α雄甾烷化合物在肠液中有较好的溶解吸收， 可以通过口服途径给药，且癌症的治疗需要长期服药，口服给药方便，可以提高患者的顺应性，因此本发明可以设计为普通口服片剂、口服胶囊以及其他缓控释制剂等口服剂型。
以下以片剂为例，对本发明的口服制剂的组分及配制进行说明。
实施例2
片剂及其制备
Figure PCTCN2015090951-appb-000008
将A-失碳-5α雄甾烷化合物(Ia)与木糖醇、甘露醇和乳糖混合均匀。用12％(wt/v)的羟丙甲纤维素水溶液制粒，40度烘干，用20目筛整粒。将交联聚维酮、硬脂酸镁和微粉硅胶加入到干颗粒中，混合均匀，压片，即得。
0天样品及在各影响因素实验条件放置10天样品溶出曲线见图1，结果表明A-失碳-5α雄甾烷化合物片剂在该溶出条件下，30min可完全溶出(溶出度大于等于95％)。
此外，经检测，在相对湿度92.5％、25℃条件下；光照强度4500lx条件下和高温60℃条件下放置10天后，A-失碳-5α雄甾烷化合物与各辅料比例与放置前基本相同，表明，A-失碳-5α雄甾烷化合物与各辅料相容性良好。
实施例3
片剂及其制备
Figure PCTCN2015090951-appb-000009
将A-失碳-5α雄甾烷化合物(Ib)与乳糖和处方量一半的交联聚维酮混合均匀。 用4％(wt/v)的聚维酮K30水溶液制粒，40度烘干，用20目筛整粒。将硬脂酸镁、滑石粉和剩余处方量的交联聚维酮加入到干颗粒中，混合均匀，压片，即得。
经检测，0天样品及在高温60度、光照强度4500lx，高湿92.5％条件下放置10天样品在溶出条件下，30min的溶出度均大于等于95％。
实施例4
片剂及其制备
Figure PCTCN2015090951-appb-000010
将A-失碳-5α雄甾烷化合物(Id)与乳糖、甘露醇混合均匀。用20％(wt/v)聚维酮K30的乙醇水溶液(乙醇与水的体积比为3:7)制粒，40℃烘至半干，20目筛整粒，之后烘干。将硬脂酸镁和微粉硅胶加入到干颗粒中，混合均匀，压片，即得。
经检测，0天样品及在高温60度、光照强度4500lx，高湿92.5％条件放置10天样品在溶出条件下，30min的溶出度均大于等于95％。
实施例5
片剂及其制备
Figure PCTCN2015090951-appb-000011
将A-失碳-5α雄甾烷化合物(Ic)与甘露醇、乳糖、交联羧甲基纤维素纳混合均匀。用25％(w/v)淀粉浆制粒，40℃烘至半干，20目筛整粒，之后烘干。将硬脂酸镁和滑石粉加入到干颗粒中，混合均匀，压片，即得。
0天样品及在各影响因素实验条件60℃、RH92.5％和光照放置10天样品溶出曲线见图2，结果表明A-失碳-5α雄甾烷化合物片剂在该溶出条件下，30min的溶 出度均大于等于95％，溶出完全。
经检测，在相对湿度92.5％、25℃条件下；光照强度4500lx条件下和高温60℃条件下放置10天后，A-失碳-5α雄甾烷化合物与各辅料比例与放置前基本相同，表明，A-失碳-5α雄甾烷化合物与各辅料相容性良好。
实施例6
片剂及其制备
Figure PCTCN2015090951-appb-000012
将A-失碳-5α雄甾烷化合物(Ie)与山梨醇、预胶化淀粉、硫酸钙与共聚维酮VA64混合均匀，干压后粉碎，20目筛整粒。将羧甲基淀粉钠、聚乙二醇和滑石粉加入到干颗粒中，混合均匀，压片，即得。
经检测，0天样品及在各影响因素实验条件放置10天样品在溶出条件下，30min的溶出度均大于等于95％。
实施例7
片剂及其制备
Figure PCTCN2015090951-appb-000013
将A-失碳-5α雄甾烷化合物(If)与羟丙甲纤维素、甘露醇和乳糖采用等量递加混合均匀。将混合物用干法制粒机制粒。将交联羧甲基纤维素纳、微粉硅胶和硬脂酸镁加入制好的颗粒中混匀，压片。
0天样品及在影响因素实验条件60℃、RH92.5％和光照放置10天样品溶出曲线见图3，结果表明A-失碳-5α雄甾烷化合物片剂在该溶出条件下，30min的溶出度均大于等于95％，溶出完全。
实施例8
片剂及其制备
Figure PCTCN2015090951-appb-000014
将A-失碳-5α雄甾烷化合物(Ig)与L-HPC、甘露醇和预胶化淀粉和共聚维酮VA64、低取代羟丙基纤维素、微粉硅胶和硬脂酸镁采用等量递加混合均匀。将所得粉末，直接压片，即得。
经检测，0天样品及在各影响因素实验条件放置10天样品在溶出条件下，30min的溶出度均大于等于95％。
实施例9
片剂及其制备
Figure PCTCN2015090951-appb-000015
将A-失碳-5α雄甾烷化合物(Ih)与共聚维酮VA64、甘露醇、乳糖和羧甲基纤维素钠采用等量递加混合均匀。将硬脂酸镁和滑石粉采用等量递加与之前的混合物混合均匀。将所得粉末，直接压片，即得。
所述0天样品及在影响因素实验条件60℃、RH92.5％和光照放置10天样品溶出曲线见图4。结果表明A-失碳-5α雄甾烷化合物片剂在该溶出条件下，30min的 溶出度均大于等于95％，溶出完全。
实施例10
片剂及其制备
Figure PCTCN2015090951-appb-000016
工艺与实施例5基本相同，不同之处仅在于片剂的组分，如上表所示。
经检测，0天样品及在各影响因素实验条件放置10天样品在溶出条件下，30min的溶出度均大于等于95％。
实施例11
片剂及其制备
Figure PCTCN2015090951-appb-000017
工艺与实施例5基本相同，不同之处仅在于片剂的组分，如上表所示，且分别采用2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基-2β-丙酸酯-17β琥珀酸酯化合物(Ij)、2α，17α-双丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物(Ik)、2α，17α-双丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双丙酸酯化合物(Il)作为片剂的活性组分。
经检测，0天各样品及在各影响因素实验条件放置10天的各样品在溶出条件下，30min的溶出度均大于等于95％。
实施例12
加速及长期实验
根据2010版中国药典附录XIXC《原料药与药物制剂稳定性试验指导原则》，对实施例2-实施例11制备的样品进行加速和长期实验。
表6、表7和表8分别示出实施例2制备的样品加速6个月和长期6个月及2年的溶出度数据。
表6 加速6个月的溶出度数据
批次 1 2 3
30min溶出度％(10mg规格) 94.13 95.00 94.64
30min溶出度％(5mg规格) 91.67 95.55 94.51
表7 长期6个月的溶出度数据
批次 1 2 3
30min溶出度％(10mg规格) 92.74 93.77 94.53
30min溶出度％(5mg规格) 90.62 94.82 93.52
表8 长期2年的溶出度数据
批次 1 2 3
30min溶出度％(10mg规格) 82.4 82.5 87.24
30min溶出度％(5mg规格) 85.68 85.16 87.71
结果表明，实施例2制备的样品经历加速6个月实验后在30min中的溶出度仍可达到91％-95％，经历长期6个月实验后在30min中的溶出度也可达到90％-95％，甚至在经历长期2年实验后在30min中的溶出度也可达到82％-88％，具有良好的溶出性能。
对实施例3到实施例11制备的样品进行加速和长期实验的结果表明，实施例3到实施例11制备的各样品经历加速6个月实验后在30min中的溶出度可达到90％-95％，经历长期6个月实验后在30min中的溶出度也可达到90％-95％，在经历长期2年实验后在30min中的溶出度也可达到80％-90％，均具有良好的溶出性能
对比例1
含微晶纤维素的A-失碳-5α雄甾烷化合物片剂
Figure PCTCN2015090951-appb-000018
Figure PCTCN2015090951-appb-000019
将A-失碳-5α雄甾烷化合物与交联聚维酮、乳糖和微晶纤维素101混合均匀，用20％(wt/v)聚维酮K30的水溶液制粒，40℃烘至半干，20目筛整粒，之后烘干。将硬脂酸镁和微粉硅胶加入到干颗粒中，混合均匀，压片，即得。
0天样品及在影响因素实验条件60℃、RH92.5％和光照放置10天样品溶出曲线见图5。0天样品30min的溶出度小于75％，在影响因素实验条件60℃、RH92.5％和光照放置10天样品溶出曲线30min的溶出度小于60％。结果表明，在各影响因素条件下放置后均有溶出变慢、溶出受限的现象。
对比例2
含微晶纤维素的A-失碳-5α雄甾烷化合物片剂
Figure PCTCN2015090951-appb-000020
将A-失碳-5α雄甾烷化合物与羧甲基淀粉钠、共聚维酮VA64和微晶纤维素102采用等量递加混合均匀。将微粉硅胶采用等量递加法与之前的混合物混合均匀。将所得粉末，直接压片，即得。
0天样品及在影响因素实验条件60℃、RH92.5％和光照放置10天样品溶出曲线见图6。0天样品30min的溶出度约80％，在影响因素实验条件60℃、RH92.5％和光照放置10天样品溶出曲线30min的溶出度约60％。结果表明，在各影响因素条件下放置后均有溶出变慢、溶出受限的现象。
对比例3
含微晶纤维素的A-失碳-5α雄甾烷化合物片剂
Figure PCTCN2015090951-appb-000021
Figure PCTCN2015090951-appb-000022
将A-失碳-5α雄甾烷化合物(Ic)与木糖醇、甘露醇、乳糖和微晶纤维素101混合均匀。用12％(wt/v)的羟丙甲纤维素水溶液制粒，40度烘干，用20目筛整粒。将交联聚维酮、硬脂酸镁和微粉硅胶加入到干颗粒中，混合均匀，压片，即得。
表9 含不溶性辅料微晶纤维素制剂的溶出性能
Figure PCTCN2015090951-appb-000023
将含不溶性辅料微晶纤维素的样品在不同条件下放置后测试溶出度，结果如表9所示，含不溶性辅料微晶纤维素处方0天时样品30min的溶出度约为80％，40度放置10天后溶出度降为约60％，60度放置10天后溶出度降为约59％，且在各影响因素条件下，随着放置时间的延长溶出度减小。
综上实验结果可知，辅料微晶纤维素对制剂的稳定性和溶出度具有极大影响。在本发明制剂中，微晶纤维素的含量宜越少越好(如≤5wt％，更佳地≤1wt％)，甚至不含微晶纤维素。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种口服制剂，其特征在于，所述口服制剂含有作为活性组分的A-失碳-5α雄甾烷化合物，具有选自下组的一个或多个特征：
    (i)在pH5.0-8.0条件下，30min内，所述制剂中A-失碳-5α雄甾烷化合物的溶出度Y30≥80％，较佳地，Y30≥85％，更佳地≥90％；
    (ii)在pH5.0-8.0条件下，60min内，所述制剂中A-失碳-5α雄甾烷化合物的溶出度Y60≥80％，较佳地，Y60≥85％，更佳地≥90％；
    并且所述口服制剂还具有选自下组的一个或多个特征：
    (a)X1≥85％，其中X1＝Y1/Y30；Y1为所述口服制剂在温度40℃±2℃、相对湿度75％±5％的条件下存储30天后在pH5.0-8.0条件下，30min内，制剂中A-失碳-5α雄甾烷化合物的溶出度；较佳地，X1≥90％，甚至X1≥95％；
    (b)X2≥85％，其中X2＝Y2/Y30；Y2为所述口服制剂在温度40℃±2℃、相对湿度75％±5％的条件下存储60天后在pH5.0-8.0条件下，30min内，制剂中A-失碳-5α雄甾烷化合物的溶出度；较佳地，X2≥90％，甚至X2≥95％；
    (c)X3≥85％，其中X3＝Y3/Y30；Y3为所述口服制剂在温度40℃±2℃、相对湿度75％±5％的条件下存储180天后在pH5.0-8.0条件下，30min内，制剂中A-失碳-5α雄甾烷化合物的溶出度；较佳地，X3≥90％；
    (d)X4≥85％，其中X4＝Y4/Y30；Y4为所述口服制剂在温度25℃±2℃、相对湿度60％±10％的条件下存储365天后在pH5.0-8.0条件下，30min内，制剂中A-失碳-5α雄甾烷化合物的溶出度；较佳地，X4≥90％；
    (e)X5≥85％，其中X5＝Y5/Y60；Y5为所述口服制剂在温度40℃±2℃、相对湿度75％±5％的条件下存储30天后在pH5.0-8.0条件下，60min内，制剂中A-失碳-5α雄甾烷化合物的溶出度；较佳地，X5≥90％；
    (f)X6≥85％，其中X6＝Y6/Y60；Y6为所述口服制剂在温度40℃±2℃、相对湿度75％±5％的条件下存储60天后在pH5.0-8.0条件下，60min内，制剂中A-失碳-5α雄甾烷化合物的溶出度；较佳地，X6≥90％；
    (g)X7≥85％，其中X7＝Y7/Y60；Y7为所述口服制剂在温度40℃±2℃、相对湿度75％±5％的条件下存储180天后在pH5.0-8.0条件下，60min内，制剂中A-失碳-5α雄甾烷化合物的溶出度；较佳地，X7≥90％；
    (h)X8≥85％，其中X8＝Y8/Y60；Y8为所述口服制剂在温度25℃±2℃、相对湿度60％±10％的条件下存储365天后在pH5.0-8.0条件下，60min内，制剂中A-失碳-5α雄甾烷化合物的溶出度；较佳地，X8≥90％。
  2. 如权利要求1所述的制剂，其特征在于，所述制剂包含具有以下重量份的组分：
    Figure PCTCN2015090951-appb-100001
    Figure PCTCN2015090951-appb-100002
    其中，所述活性组分为A-失碳-5α雄甾烷化合物。
  3. 如权利要求2所述的制剂，其特征在于，所述填充剂选自乳糖、蔗糖、山梨醇、甘露醇、聚乙二醇，淀粉以及无机盐中的一种或者两种以上；和/或
    所述崩解剂选自交联聚维酮(PVPP)、交联羧甲基纤维素钠(CC Na)、羧甲基淀粉钠(CMS-Na)、低取代羟丙基纤维素(L-HPC)中的一种或者两种以上；和/或
    所述润滑剂选自硬脂酸、硬脂酸钠、硬脂酸镁、硬脂酸钙、聚乙二醇、氢化植物油中的一种或者两种以上；和/或
    所述粘合剂选自淀粉浆、羟丙基甲基纤维素(HPMC)、聚维酮(PVP)或共聚维酮(Kollidon)中的一种或者两种以上；和/或
    所述助流剂选自微粉硅胶和滑石粉中的一种或者两种。
  4. 如权利要求1-3任一项所述的制剂，其特征在于，所述制剂为片剂、颗粒剂、或胶囊。
  5. 一种口服制剂，其特征在于，所述制剂包含具有以下重量份的组分：
    Figure PCTCN2015090951-appb-100003
    其中，所述活性组分为A-失碳-5α雄甾烷化合物。
  6. 如权利要求5所述的制剂，其特征在于，所述填充剂选自乳糖、蔗糖、山梨醇、甘露醇、以及无机盐中的一种或者两种以上；和/或
    所述崩解剂选自交联聚维酮(PVPP)、交联羧甲基纤维素钠(CC Na)、羧甲基淀粉钠(CMS-Na)、低取代羟丙基纤维素(L-HPC)中的一种或者两种以上；和/或
    所述润滑剂选自硬脂酸、硬脂酸钠、硬脂酸镁、聚乙二醇中的一种或者两种以上；和/或
    所述粘合剂选自淀粉浆、羟丙基甲基纤维素(HPMC)、聚乙二醇、聚维酮(PVP)或共聚维酮(Kollidon)中的一种或者两种以上；和/或
    所述助流剂选自微粉硅胶、滑石粉中的一种或者两种。
  7. 如权利要求5或6所述的制剂，其特征在于，所述制剂为片剂、颗粒剂、或胶囊。
  8. 一种口服制剂的制法，其特征在于，包括步骤：
    (1)提供以下材料作为原料；
    Figure PCTCN2015090951-appb-100004
    其中，所述活性组分为A-失碳-5α雄甾烷化合物，
    (2)将上述材料制成口服制剂。
  9. 如权利要求1-8任一项所述的口服制剂，其特征在于，所述A-失碳-5α雄甾烷化合物的结构如式I所示：
    Figure PCTCN2015090951-appb-100005
    式中，R1、R2独立地选自：H、取代或未取代的-C1-10烷基、取代或未取代的-C3-8环烷基、取代或未取代的苯环、取代或未取代的苯甲酰基、取代或未取代的-COCnH2n+1、取代或未取代的-COCrH2rCOOCmH2m++1、或-COCpH2pCOO-W；其中，n、p、r、m各自独立地为0～18的整数，W为H+、Na+、K+、NH4 +、1/2Ca2+、1/2Mg2+、1/2(AlOH)2+、或1/2Zn2+，
    所述取代是指具有一个或多个(如1-3个)以下取代基团：羟基、卤素、硝基、氨基、胺基、羧基。
    较佳地，所述A-失碳-5α雄甾烷化合物为：
    2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物；
    2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双乙酸酯化合物；
    2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双丙酸酯化合物；
    2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基-2β-单琥珀酸酯化合物(Id)；
    2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双琥珀酸酯化合物；
    2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双丁酸酯化合物；
    2α，17α-双羟丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物；
    2α，17α-双氰基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物；
    2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双三氯乙酸酯化合物；
    2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基-2β-丙酸酯-17β琥珀酸酯化合物；
    2α，17α-双丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物；或
    2α，17α-双丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双丙酸酯化合物。
  10. 如权利要求1-9任一项所述的口服制剂的用途，其特征在于，
    (i)用于制备抗肿瘤药物；或
    (ii)用于制备治疗前列腺增生的药物。
PCT/CN2015/090951 2014-09-29 2015-09-28 一种A-失碳-5α雄甾烷化合物的口服制剂 WO2016050193A1 (zh)

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