WO2022048592A1 - 优替德隆的固体口服制剂 - Google Patents

优替德隆的固体口服制剂 Download PDF

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WO2022048592A1
WO2022048592A1 PCT/CN2021/116194 CN2021116194W WO2022048592A1 WO 2022048592 A1 WO2022048592 A1 WO 2022048592A1 CN 2021116194 W CN2021116194 W CN 2021116194W WO 2022048592 A1 WO2022048592 A1 WO 2022048592A1
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solid oral
hypromellose
eutedron
oral preparation
pharmaceutical excipients
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PCT/CN2021/116194
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English (en)
French (fr)
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唐莉
张川
邱荣国
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北京华昊中天生物医药股份有限公司
成都华昊中天药业有限公司
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Priority to CA3184960A priority Critical patent/CA3184960A1/en
Priority to EP21863656.1A priority patent/EP4062913B1/en
Priority to AU2021337086A priority patent/AU2021337086B2/en
Priority to CN202180006314.0A priority patent/CN114727995B/zh
Priority to US17/758,110 priority patent/US20230048901A1/en
Priority to KR1020237001452A priority patent/KR20230024389A/ko
Priority to BR112023003572A priority patent/BR112023003572A2/pt
Priority to JP2022539043A priority patent/JP2023508090A/ja
Publication of WO2022048592A1 publication Critical patent/WO2022048592A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K9/2013—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
    • A61K9/2022—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals

Definitions

  • the present application belongs to the field of medicine, and specifically relates to a solid oral preparation of Utilidron and its preparation method and use.
  • Eutedron a class of epothilone derivatives, is a macrolide compound, a secondary metabolite produced by the genetically modified Myxobacteria cellulosic fungus. Studies have shown that epothilone antibiotics have the same pharmacological mechanism of action as paclitaxel, which exerts anti-tumor effect by inhibiting the depolymerization of tubulin.
  • the chemical name of Eutedron is: 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-thiazole-4- base)-vinyl]-hexadecoxetane-13-en-2,6-one lactone, its chemical structure is shown below;
  • Utilidron injection (trade name: Utilid TM ), specification 5ml: 50mg, intravenous drip for about 1.5 hours, dose 30-40mg/ m2 /day, administered once a day for 5 consecutive days, 21 days is a treatment cycle. Until disease progression or intolerable toxicity. Utilidron injection needs to be diluted with normal saline for injection (the final concentration of Utilidone is 0.2mg/ml to 0.5mg/ml) before use. It is used for the treatment of patients with advanced breast cancer, lung cancer, gastric cancer, liver cancer and other solid tumors.
  • Eutedron is easily soluble in ethanol, methanol, ethyl acetate, and chloroform, but insoluble in water, and its saturated solubility in water is less than 1ug/ml, making it difficult to develop into an oral preparation with suitable bioavailability.
  • the currently marketed epothilone antitumor drugs such as Eutedron injection and Ixabepilone injection all use non-aqueous solvents such as ethanol and polyoxyethylene castor oil as solvents, which are chlorinated before clinical use. After the sodium injection is diluted, it is administered by intravenous drip. Because polyoxyethylene castor oil is a strong allergenic substance, antiallergic treatment must be given before intravenous administration, which reduces the compliance of this type of drug in clinical use, increases the adverse reactions of patients, and limits its clinical application.
  • Solid oral preparations of epothilone compounds are relatively rare, and the combination of pharmaceutical preparations for intravenous administration is often used for oral administration, such as patent CN 101112373. Because epothilone compounds are prone to ring-opening degradation in solution state, and crystallize out due to poor solubility in the body, so the epothilone compound pharmaceutical preparations in solution-type oral preparations usually have poor stability and are stimulated by oral administration. Due to the defects of high bioavailability and low bioavailability, it is basically not pharmaceutically feasible. Therefore, it is an industry consensus to develop an oral preparation with high bioavailability and high drug stability.
  • the present application provides an oral preparation using Eurideron as an active ingredient and a preparation method thereof.
  • the oral preparation of the present application has high bioavailability and good physical and chemical stability, which makes it possible to administer the active ingredients orally, improves medication compliance, and eliminates the problems caused by injection administration. Strong allergic reaction to polyoxyethylene castor oil.
  • the oral preparation of the present application not only effectively improves the solubility of Utilidone, but also solves the in vivo and in vitro stability of Utilidone, significantly improves the bioavailability of the pharmaceutical preparation, and creates a drug suitable for industrialized large-scale production. Preparation process.
  • the oral preparation of Eutedron of the present application can be prepared into solid preparations such as capsules, tablets or granules, for example, pellet capsules.
  • solid preparations such as capsules, tablets or granules, for example, pellet capsules.
  • the dissolution and bioavailability of the solid oral dosage form of the present application has been shown to have good bioavailability by the data.
  • the present application provides a solid oral dosage form suitable for oral administration containing an active ingredient of epothilone, such as utidron.
  • poorly soluble drugs can improve the solubility of drugs by reducing the particle size of API, preparing solid dispersions with hydrophilic carrier materials, and adding surfactants, thereby improving the bioavailability of drugs.
  • Due to the particularly poor water solubility of Utilidron it is difficult to obtain an ideal drug dissolution effect by reducing the particle size of the drug and adding a surfactant within the acceptable range of pharmacy. Therefore, it is very challenging and creative to obtain oral formulations with physical and chemical stability and enhanced solubility and oral bioavailability of Eutedron.
  • the oral solid preparation containing Utilidron of the present application comprises an active ingredient (ie, active ingredient: Utilidron or a pharmaceutically acceptable salt, solvate or ester thereof) and pharmaceutical excipients.
  • the oral preparation comprises: 1) Eutedron or a pharmaceutically acceptable salt, solvate or ester thereof; 2) at least one hydrophilic pharmaceutical excipient; 3) at least one sustained-release pharmaceutical excipient; 4 ) optional at least one surfactant ingredient.
  • the present application is not only applicable to Eutedron, but also to other epothilone derivatives of the same class of Eutedron.
  • the solid oral preparation of the present application such as a pellet capsule, comprises: 1) Eutedron or a pharmaceutically acceptable salt, solvate or ester thereof; 2) at least one hydrophilic drug 3) at least one sustained-release pharmaceutical excipient; and 4) at least one surfactant ingredient excipient.
  • the ratio of utidron to pharmaceutical excipients is in the range of 1:1 to 1:30, preferably 1:5 to 1:20.
  • the pellets in the pellet capsule of the present application include a pellet core and a drug composition coating layer or/and a drug coating layer wrapped on the pellet core.
  • the described pill core for example, can be a circular or oval pharmaceutical excipient with a particle size of 100-1000um, and the scaffold material used for the tablet and the pill core is generally referred to as a pill core material, such as sucrose, starch, lactose, microparticles, etc. Crystalline cellulose, mannitol and biodegradable polymers, etc.
  • the micropellet capsule or tablet comprises about 2%-10% (w/w) of Eutedron; and about 30%-70% (w/w) of pharmaceutical excipients and about 20%-60% ( w/w) pellet core material, the above weight percentages are calculated based on the total weight of pellets or tablets.
  • the fillable pellets in each capsule contain 5-30 mg of eutedron, and each tablet may contain about 5-20 mg of eutedron.
  • the pellet cores used in the preparation of pellets for the oral formulation of the present application are selected from sucrose, starch, microcrystalline cellulose pellet cores or other pharmaceutically acceptable pellet cores, preferably sucrose pellet cores.
  • the diameter of the pellet core is 0.2 mm to 1.5 mm, preferably 0.4 mm to 1.0 mm.
  • the particle size of the drug-coated pellets is 0.5-1.5 mm.
  • the hydrophilic pharmaceutical adjuvant in the oral preparation (such as pellet capsule) of the present application is selected from one of povidone, hypromellose, mannitol, lactose, sucrose, poloxamer, polyvinyl alcohol, etc.
  • the sustained-release pharmaceutical excipients in the oral preparations (such as pellet capsules) of the present application are selected from povidone, hypromellose, polyethylene glycol, ethyl cellulose, polyvinyl acetal diethylamine acetic acid ester, hypromellose acetate succinate, acetate methacrylate copolymer, cellulose acetate, methyl cellulose, polyacrylic resin, polyvinyl phthalate, cellulose phthalate, One or more mixtures of hypromellose phthalate, such as high-viscosity hypromellose, high-viscosity polyethylene glycol, ethyl cellulose, and cellulose acetate.
  • the surfactant adjuvant in the oral preparation of the present application is selected from polysorbate, polyoxyethylene castor oil, sodium lauryl sulfate, cholate, fatty acid glyceride, sorbitan, polyoxyethylene One or more mixtures of fatty acid ester, polyoxyethylene fatty alcohol ether, poloxamer, etc., preferably polyoxyethylene castor oil, secondly polysorbate and poloxamer.
  • the present application provides a solid oral preparation, such as micro-pellet capsule, which uses Eutedron as the active ingredient, and uses polyoxyethylene (40) hydrogenated castor oil, low-viscosity hypromellose (such as E50), high-viscosity hypromellose (such as K100) are medicinal excipients, and the pellet core is sucrose.
  • a solid oral preparation such as micro-pellet capsule, which uses Eutedron as the active ingredient, and uses polyoxyethylene (40) hydrogenated castor oil, low-viscosity hypromellose (such as E50), high-viscosity hypromellose (such as K100) are medicinal excipients, and the pellet core is sucrose.
  • the present application provides a method of preparing an oral formulation.
  • the preparation method of micropellet capsules containing eutedron is as follows: after dissolving eutedron and corresponding excipients in a solvent, using a coating process to wrap eutedron in a pellet core to prepare micropellets, and finally encapsulated in a Capsules are prepared into capsules or compressed into tablets.
  • the preparation method solves the problem of poor drug bioavailability caused by defects such as in vitro and in vivo recrystallization of the pharmaceutical preparations prepared by solid dispersion technology, which are difficult to dissolve due to poor water solubility.
  • the oral preparation of the present application does not need to strictly control the particle size and crystal form of the raw material drug to ensure the stability of the preparation process; the dust generation during the production process is low, and the preparation can be fully enclosed to reduce occupational hazards.
  • Utilidron exists in the form of amorphous or molecular form in the oral solid preparation of Tidenon.
  • At least one hydrophilic pharmaceutical excipient component is included in the oral preparation to improve the solubility of the drug.
  • Oral preparations can contain pharmaceutical excipients with sustained release function to inhibit the release rate of the drug in the solid dispersion prepared with hydrophilic pharmaceutical excipients, thereby reducing the supersaturated concentration of the drug in the body and inhibiting the drug in the body. Recrystallization process.
  • Oral preparations can contain one or more surface active ingredients to further inhibit the recrystallization process of the drug in vitro and in vivo, and at the same time play a certain plasticizing role in the preparation process of pellets, increasing the toughness of the finished pellets.
  • Eutedron needs to be first dissolved in an organic solvent or a mixture of organic solvents or a mixture of organic solvent and water.
  • Eutedron dissolved in an organic solvent or an organic solvent mixture or a mixture of an organic solvent and water needs to be mixed with hydrophilic pharmaceutical excipients and/or sustained-release pharmaceutical excipients and/or surfactants. and other pharmaceutical excipients for co-drying to prepare a solid dispersion with higher solubility or a pellet with both higher solubility and sustained release properties.
  • organic solvent is selected from pharmaceutically acceptable organic solvents such as ethanol, methanol, ethyl acetate, acetone, dichloromethane, chloroform, for example ethanol, methanol, ethyl acetate or acetone or the above-mentioned two mixed in any proportion. or a mixture of two or more solvents.
  • pharmaceutically acceptable organic solvents such as ethanol, methanol, ethyl acetate, acetone, dichloromethane, chloroform, for example ethanol, methanol, ethyl acetate or acetone or the above-mentioned two mixed in any proportion. or a mixture of two or more solvents.
  • the above-mentioned co-drying preparation processes are mainly fluidized bed coating process, spray drying process, reduced pressure vacuum drying process, heating drying, freeze drying and other drying processes.
  • the oral preparation of the present application which is suitable for human patients (or animals), includes solid preparations such as soft and hard capsules, tablets, granules, multi-particulates or micro-pills such as micro-pellet capsules.
  • the daily dosage and frequency of administration can be based on commercially available unit dosage forms, and the daily dosage of the oral formulations of the present application can be obtained by administering half-unit, single unit, or more unit dosage forms.
  • cancer refers to various forms of cancer, wherein said tumors are solid tumors, especially breast cancer, lung tumors, gastrointestinal tumors, lymphoma tumors, prostate cancer, brain cancer, gynecological tumors, liver cancer, Head and neck tumors, such as breast cancer, lung cancer, liver cancer, ovarian cancer, colon cancer and stomach cancer;
  • compositions refer to the excipients and additives used in the production of drugs and the formulation of prescriptions. Except for the active ingredients, the safety has been reasonably evaluated and included in the pharmaceutical preparations.
  • Pills are the master batches necessary for the production of skeleton-type pellets.
  • Hydrophilic pharmaceutical excipients refers to pharmaceutical excipients that have a large affinity for water, can attract water molecules, or are easily soluble in water.
  • Sustained-release pharmaceutical excipients materials that can release the drug slowly to prolong the action time of the drug, such as microcapsules that can carry the drug and release it slowly.
  • Low-viscosity hypromellose refers to hypromellose with a viscosity of ⁇ 80 mPa.S. Such as E5, E3, E15, E50, K3 and other types of hypromellose.
  • High-viscosity hypromellose refers to hypromellose with a viscosity of ⁇ 80mPa.S. Such as K100LV, K100M, K100LVP, K4M, E4M, E4MP, K100MP and other types of hypromellose.
  • High-viscosity polyethylene glycol refers to polyethylene glycol with molecular weight > 1000, such as PEG1000, PEG2000, PEG4000, PEG8000 and other types of polyethylene glycol.
  • the present application has the following advantages
  • the bioavailability of the oral preparation of the present application is high, even up to more than 55%.
  • the preparation process of the present application does not need to strictly control the particle size and crystal form of the raw drug as in the conventional oral solid preparation preparation process. After dissolving the active ingredient in a soluble organic solvent, it is sprayed onto the medicinal blank pellet core through a coating process, and the Eutedron in the pellet obtained after drying exists in the pellet in the form of amorphous and molecular states. Or powder, and has a certain stability.
  • the preparation process of the oral preparation of the present application can adopt an integrated molding process.
  • a closed operation is basically adopted, which can effectively avoid occupational exposure hazards caused by cytotoxic compounds.
  • the total yield of the oral preparation of the present application in preparation reaches more than 90%, which is far higher than the total yield of materials of conventional oral solid preparations.
  • the active ingredient Eutedron in the solid oral preparation of the present application exists in an amorphous or molecular form, rather than in a non-crystalline form.
  • Figure 1 Dissolution profile of the oral formulation of Example 1;
  • Figure 2 Dissolution profile of the oral formulation of Example 2
  • Figure 3 Dissolution profile of the oral formulation of Example 3;
  • Figure 4 Dissolution profile of the oral formulation of Example 4.
  • Figure 5A Dissolution profile of the oral formulation of Example 5-A
  • Figure 5B Dissolution profile of the oral formulation of Example 5-B
  • Figure 6 Area under the plasma concentration-time curve of Eutedron injection
  • Figure 7 Area under the plasma concentration-time curve of Eutedron capsules of Example 1;
  • Figure 8 Area under the plasma concentration-time curve of Eutedron injection
  • Fig. 9 the area under the plasma concentration-time curve of Eutedron Capsule of Example 5-A;
  • Figure 10 X-ray diffraction pattern of the crystal form of Eutedron
  • Figure 11 X-ray diffraction pattern of the amorphous form of Eutedron
  • Figure 12 X-ray diffraction pattern of the pharmaceutical excipients (inactive ingredients) used in the Eutedron capsules prepared in Example 5-A;
  • Figure 13A the X-ray diffraction pattern of the contents in the Eutedron capsules (stored at room temperature) prepared in Example 5-A;
  • Figure 13B HPLC chromatogram of the contents of the Utilidron capsules (stored at room temperature) prepared in Example 5-A.
  • Utilide used in the formulations of the following examples is manufactured by Chengdu Huahao Zhongtian Pharmaceutical Co., Ltd., and the implementation standards of all excipients are the national approval or the 2020 edition of the Chinese Pharmacopoeia, wherein, polyoxyethylene (40) hydrogenated castor oil Manufactured by BASF China Co., Ltd., Hypromellose E50 is manufactured by Rohm and Haas, Hypromellose K100 is manufactured by Rohm and Haas, Pellets (sucrose) are manufactured by Shanghai Colorcon Coating, Hypromellose Cellulose hollow capsules are manufactured by Suzhou Capsule Co., Ltd.
  • the excipients used in the oral solid preparations of the following examples are not limited by the manufacturer.
  • test sample was a capsule containing 20 mg of ustedron.
  • “Chinese Pharmacopoeia” 2020 Edition Appendix 0931 Dissolution and Release Determination Method 1 test capsules were added to the rotating basket, the rotation speed was 100 rpm, and the dissolution medium was 900ml pH 6.8 phosphate buffer.
  • the dissolution profile is shown in Figure 1.
  • the hydrophilic carrier material is used as the solid dispersion carrier and Eutedron is prepared into a solid dispersion, although the solubility of the drug is significantly improved, the dissolved drug is prone to recrystallization in the body, thereby reducing the bioavailability of the drug. Spend.
  • the bioavailability in the beagle of this example was 29%.
  • the test sample is a capsule containing 20 mg of ustedron.
  • “Chinese Pharmacopoeia” 2020 Edition Appendix 0931 Dissolution and Release Determination Method 1 add test capsules to the rotating basket, the rotation speed is 100 rpm, and the dissolution medium is 900ml pH 6.8 phosphate buffer.
  • the dissolution profile is shown in Figure 2.
  • the test sample is a capsule containing 20 mg of ustedron.
  • “Chinese Pharmacopoeia” 2020 Edition Appendix 0931 Dissolution and Release Determination Method 1 add test capsules to the rotating basket, the rotation speed is 100 rpm, and the dissolution medium is 900ml pH 6.8 phosphate buffer.
  • the dissolution profile is shown in Figure 3:
  • the test sample was a capsule containing 20 mg of ustedron.
  • “Chinese Pharmacopoeia” 2020 Edition Appendix 0931 Dissolution and Release Determination Method 1 add test capsules to the rotating basket, the rotation speed is 100 rpm, and the dissolution medium is 900ml pH 6.8 phosphate buffer.
  • the dissolution profile is shown in Figure 4:
  • the test sample was a capsule containing 20 mg of ustedron.
  • “Chinese Pharmacopoeia” 2020 Edition Appendix 0931 Dissolution and Release Determination Method 1 test capsules were added to the blue, the speed was 100 rpm, and the dissolution medium was 900ml pH 6.8 phosphate buffer, 0.1mol /L hydrochloric acid, purified water and pH 4.5 acetate buffer.
  • the dissolution profile is shown in Figure 5A.
  • the in vitro dissolution characteristics of the prepared samples meet the expected target. Under different conditions, they dissolve about 57% at 30 minutes and about 99% at 60 minutes, and there is no burst release or incomplete release phenomenon.
  • the preparation method and the dissolution testing method of the micropellet capsules in this example are the same as those in Example 5-A.
  • Hypromellose E50 60g Hypromellose K100 45g Ball core (sucrose) 75g Povidone K30 50g lactose 125g talcum powder 5g anhydrous ethanol 3000g purified water 1400g
  • polyethylene glycol 6000 155g Polyoxyethylene (40) Hydrogenated Castor Oil 30g Povidone K90 15g lactose 100g silica 155g anhydrous ethanol 1000g
  • Utilide solid dispersion and lactose, silicon dioxide, and povidone K90 in prescription quantities are taken and granulated by a dry granulator, and compressed into tablets to obtain Utilidron tablets.
  • Utilide solid dispersion and formulation amount of lactose, silicon dioxide, glyceryl behenate and polyvinylpyrrolidone are obtained after dry granulation by a dry granulator, and tableting is performed to obtain Utilidron tablets.
  • the average relative bioavailability of the oral preparation of Example 1 can reach about 29%.
  • the 6 Beagle dogs were divided into 2 groups, with 3 dogs in each group.
  • each dog in the first group was orally administered with 1.5 mg/kg of Eutedron capsule of Example 5-A;
  • each dog received an intravenous infusion of 1 mg/kg of Utilidron.
  • Intravenous blood was collected before administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h and other time periods after administration. After the samples were centrifuged to separate the plasma, the concentration of utidron in the plasma was determined by LC-MS/MS. The results of the injection test are shown in Figure 8. The experimental results of the capsules are shown in FIG. 9 .
  • Table 3 Mean values of pharmacokinetic parameters after single intravenous administration of Utilidron injection and oral administration of Utilidron capsules in beagle dogs
  • the relative bioavailability of Utilidron capsules after a single oral administration was between 53.1% and 103.8%, and the average relative bioavailability was 78.5%.
  • Example 5-A With the test method of Example 5-A, it was found that the average relative bioavailability of the Utilidron tablets prepared in Example 6 could reach more than 55%.
  • Utilide capsules (Examples 1, 5) were stored for 1 month under the accelerated test conditions of 40°C and 75% RH. The X-ray diffraction test showed that the Utilide in Long exists in amorphous or molecular form.
  • Method 3 Dissolve 1 g of Utilide in 10 ml of methanol or ethanol solvent, and evaporate to dryness under reduced pressure with a rotary evaporator.
  • the X-ray diffraction pattern of Eutedron amorphous is shown in FIG. 11 .
  • Eutedron in the capsules obtained by the process technology of the embodiment of the present patent exists in an amorphous or molecular form.

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Abstract

一种适用于口服给药的4,8-二羟基-5,5,7,9,13-五甲基-16-[1-甲基-2-(2-甲基-噻唑-4-基)-乙烯基]-十六烷氧杂环-13-烯-2,6-酮内酯(优替德隆)为活性成分的口服药物制剂。所述药物制剂为片剂、胶囊剂等固体制剂，所述药物剂型具有良好的稳定性，体外溶出行为及生物利用度。

Description

优替德隆的固体口服制剂 技术领域
本申请为医药领域，具体涉及优替德隆的固体口服制剂及其制备方法与用途。
背景技术
优替德隆是一类埃博霉素类衍生物，为大环内脂类化合物，由经基因修饰后的黏细菌纤维堆囊菌产生的次级代谢物。经研究表明埃博霉素类抗生素具有与紫杉醇相同的药理作用机制，其通过抑制微管蛋白的解聚而发挥抗肿瘤作用。优替德隆的化学名称为：4,8-二羟基-5,5,7,9,13-五甲基-16-[1-甲基-2-(2-甲基-噻唑-4-基)-乙烯基]-十六烷氧杂环-13-烯-2,6-酮内酯，其化学结构式如下所示；
Figure PCTCN2021116194-appb-000001
优替德隆注射液(商标名为：优替帝 TM)，规格5ml:50mg，静脉滴注1.5小时左右，剂量30-40mg/m 2/天，每天给药一次，连续给药5天，21天为一个治疗周期。直至患者疾病进展或毒性不可耐受。优替德隆注射液需用注射用生理盐水稀释(优替德隆最终浓度0.2mg/ml至0.5mg/ml)后使用，用于治疗晚期乳腺癌、肺癌、胃癌、肝癌等实体肿瘤患者。
优替德隆易溶于乙醇、甲醇、乙酸乙酯、三氯甲烷，难溶于水，在水中的饱和溶解度低于1ug/ml，难以开发成具有合适生物利用度的口服制剂。目前已上市的埃博霉素类抗肿瘤药物如优替德隆注射液、伊沙匹隆注射液等均采用乙醇、聚氧乙烯蓖麻油等非水溶剂作为溶剂，在临床使用前经氯化钠注射液稀释后，静脉滴注给药。由于聚氧乙烯蓖麻油为强致敏性物质，静脉给药前，必须先给予抗过敏治疗，降低了该类药物临床使用的顺应性，增加了患者的不良反应，限制了其临床适用范围。
埃博霉素类化合物的固体口服制剂较罕见，多采用将静脉注射给药的药物制剂组 合用于口服给药，比如专利CN 101112373。由于埃博霉素类化合物在溶液状态下，易发生开环降解，在体内由于溶解度差而结晶析出，因此溶液型口服制剂的埃博霉素类化合物药物制剂通常存在稳定性差，口服给药刺激性高，生物利用度低等缺陷，基本不具有药学上的可行性，因此开发一种具有高生物利用度、高药物稳定性的口服制剂为业内共识。
发明内容
为解决上述问题，本申请提供了一种以优替德隆为活性成分的口服制剂及其制备方法。本申请的口服制剂在具有较高的生物利用度的同时具有良好的物理、化学稳定性，使该类活性成分经口给药成为可能，并提高了用药顺应性、消除了由于注射给药由聚氧乙烯蓖麻油引起的强过敏反应。
本申请的口服制剂在有效提升优替德隆溶解度的同时，解决了优替德隆体内、体外的稳定性，显著提升了药物制剂的生物利用度，创造出一种适用于工业化大生产的药物制剂制备工艺。
本申请的优替德隆口服制剂可制备成胶囊剂、片剂或颗粒剂等固体制剂，例如微丸胶囊剂。本申请的固体口服制剂的溶出度和生物利用度经数据表明具有良好的生物利用度。
根据一个方面，本申请提供了一种适宜口服给药的含埃坡霉素类活性成分例如优替德隆的固体口服制剂。
通常情况下难溶性药物可通过减小API粒径、以亲水性载体材料制备成固体分散体、添加表面活性剂等制剂手段提高药物的溶解度，从而提升药物的生物利用度。由于优替德隆的水溶性特别差，难以通过减小药物粒径、添加药学允许范围内的表面活性剂等单一手段获得理想的药物溶出效果。因此获得具有物理、化学稳定性并增强优替德隆溶解度和口服生物利用度的口服制剂非常具有挑战性和创造性。
本申请的包含优替德隆的口服固体制剂包含原料药(即活性成分：优替德隆或其药学上可接受的盐、溶剂化物或酯)和药用辅料。该口服制剂包括：1)优替德隆或其药学上可接受的盐、溶剂化物或酯；2)至少一种亲水性药用辅料；3)至少一种缓释性药用辅料；4)任选的至少一种表面活性剂成分。
本申请不仅适用于优替德隆，也应适用于优替德隆同类的其他埃坡霉素衍生物。
根据一些实施方式，本申请的固体口服制剂，例如为微丸胶囊，其包括：1)优替 德隆或其药学上可接受的盐、溶剂化物或酯；2)至少一种亲水性药用辅料；3)至少一种缓释性药用辅料；和4)至少一种表面活性剂成分辅料。
本申请的口服制剂中，优替德隆与药用辅料的比例为1:1至1:30的范围，优选1:5～1:20。
本申请的微丸胶囊中的微丸包括丸芯和包裹于丸芯上的药物组合物包衣层或/和药物包衣层。所述的丸芯，例如可以是粒径为100-1000um的圆形或椭圆形药用辅料，片剂和丸芯所用的支架材料通称为丸芯材料，例如可以是蔗糖、淀粉、乳糖、微晶纤维素、甘露醇和可生物降解的聚合物等。
所述的微丸胶囊或片剂包含约2％-10％(w/w)的优替德隆；和约30％-70％(w/w)的药用辅料及约20％～60％(w/w)的丸芯材料，上述重量百分比是基于微丸或片剂总重量而计算得到。优选每粒胶囊中可填充微丸含5-30mg优替德隆，每片中可含约5-20mg优替德隆。
本申请的口服制剂在制备微丸时所采用的丸芯选自蔗糖、淀粉、微晶纤维素丸芯或其他药学上可接受的丸芯，优选蔗糖丸芯。丸芯的直径为0.2mm～1.5mm，优选0.4mm～1.0mm。含药物包衣的微丸的粒径为0.5-1.5mm。
本申请的口服制剂(如微丸胶囊)中的亲水性药用辅料选自聚维酮、羟丙甲纤维素、甘露醇、乳糖、蔗糖、泊洛沙姆、聚乙烯醇等中的一种或几种的混合物，例如低粘度羟丙甲纤维素、聚维酮、泊洛沙姆。
本申请的口服制剂(如微丸胶囊)中的缓释性药用辅料选自聚维酮、羟丙甲纤维素、聚乙二醇、乙基纤维素、聚乙烯缩乙醛二乙胺醋酸酯、醋酸羟丙甲纤维素琥珀酸脂、甲基丙烯酸醋酸酯共聚物、醋酸纤维素、甲基纤维素、聚丙烯酸树脂、邻苯二甲酸聚乙烯醇脂、邻苯二甲酸纤维素脂、羟丙甲纤维素酞酸酯等中的一种或几种的混合物，例如高粘度羟丙甲纤维素、高粘度聚乙二醇、乙基纤维素、醋酸纤维素。
本申请的口服制剂(如微丸胶囊)中的表面活性剂辅料选自聚山梨酯、聚氧乙烯蓖麻油、十二烷基硫酸钠、胆酸盐、脂肪酸甘油酯、山梨坦、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、泊洛沙姆等中的一种或几种的混合物，优选聚氧乙烯蓖麻油，次选聚山梨酯、泊洛沙姆。
根据一个实施方式，本申请提供的一种固体口服制剂，例如微丸胶囊，其以优替德隆为活性成分，以聚氧乙烯(40)氢化蓖麻油、低粘度羟丙甲纤维素(如E50)、高粘度羟丙甲纤维素(如K100)为药用辅料，丸芯为蔗糖。
根据另一方面，本申请提供了一种制备口服制剂的方法。例如，含优替德隆的微丸胶囊的制备方法为；将优替德隆与相应辅料用溶剂溶解后，利用包衣工艺将优替德隆包裹于丸芯制备成微丸，最后封装于胶囊中制备成胶囊或压制成片剂。该制备方法解决了优替德隆药物由于水溶性差而难以溶出，而通过固体分散体技术制备的药物制剂易发生体外、体内重结晶等缺陷导致的药物生物利用度差的问题。同时本申请的口服制剂无需要严格控制原料药粒径、晶型以保证制剂工艺稳定性；在生产过程中产尘较低，可做到全封闭制备从而降低职业危害等优势；所制得的优替德隆口服固体制剂中优替德隆以无定型或分子形态的形式存在。
上述优替德隆口服制剂及其制备工艺的特征至少有；
1)口服制剂中至少包含一种亲水性药用辅料成分以提升药物的溶解度。
2)口服制剂中可包含具有缓释功能的药用辅料以抑制以亲水性药用辅料制备的固体分散体中药物的释放速度，从而降低药物在体内的过饱和浓度，抑制药物在体内的重结晶进程。
3)口服制剂中可含有一种或以上的表面活性成分以进一步抑制药物在体内外的重结晶进程，同时在微丸制备工艺中起到一定的增塑作用，增加成品微丸的韧性。
4)制备工艺过程中，需首先将优替德隆溶解于有机溶剂或有机溶剂的混合物或有机溶剂与水的混合物。
5)制备工艺过程中，溶解于有机溶剂或有机溶剂混合物或有机溶剂与水的混合物的优替德隆需与亲水性药用辅料和/或缓释性药用辅料和/或表面活性剂等药用辅料进行共干燥，制备成一种具有较高溶解度的固体分散体或制备成一种同时具有较高溶解度及缓释特性的微丸。
上述有机溶剂选自乙醇、甲醇、乙酸乙酯、丙酮、二氯甲烷、三氯甲烷等药学上可接受的有机溶剂，例如乙醇、甲醇、乙酸乙酯或丙酮或以任意比例混合的上述两种或两种以上的溶剂的混合物。
上述共干燥制备工艺主要为流化床包衣工艺、喷雾干燥工艺、减压真空干燥工艺和加热烘干、冷冻干燥等干燥工艺。
本申请的口服制剂，其适用于人类患者(或动物)，包括软硬胶囊、片剂、颗粒剂、多颗粒剂或微丸剂如微丸胶囊等固体制剂。
根据市售的单位剂型，可以施用日剂量和频率，可通过施用半单位、单个单位或更多种单位剂型来获得本申请口服制剂的日剂量。
根据另一个方面，本申请用于人或动物癌症的治疗。如本文所述，癌症是指各种形式的癌症，其中所说的肿瘤是实体瘤,尤其是乳腺癌，肺部肿瘤、消化道肿瘤、淋巴肿瘤、前列腺癌，脑癌，妇科肿瘤，肝癌，头颈肿瘤等，例如乳腺癌、肺癌，肝癌、卵巢癌、结肠癌和胃癌；
术语定义
药用辅料：药用辅料指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，在安全性方面已进行了合理的评估，且包含在药物制剂中的物质。
丸芯：丸芯是制备生产骨架型微丸必需的起模母粒。
亲水性药用辅料：指对水有较大的亲和能力，可以吸引水分子，或易溶解于水的药用辅料。
缓释性药用辅料：可使药物缓慢释放以延长药物作用时间的材料，如制成可承载药物并使其缓慢释放的微胶囊。
低粘度羟丙甲纤维素：指粘度＜80mPa.S的羟丙甲纤维素。如E5、E3、E15、E50、K3等型号的羟丙甲纤维素。
高粘度羟丙甲纤维素：指粘度≥80mPa.S的羟丙甲纤维素。如K100LV、K100M、K100LVP、K4M、E4M、E4MP、K100MP等型号的羟丙甲纤维素。
高粘度聚乙二醇：指分子量＞1000的聚乙二醇，如PEG1000、PEG2000、PEG4000、PEG8000等型号的聚乙二醇。
本申请具有如下优点；
1.本申请的口服制剂的生物利用度高，甚至可达55％以上。
2.本申请的制备工艺无需同常规口服固体制剂制备工艺那样对原料药的粒径晶型进行严格控制。将活性成分溶解至易溶的有机溶剂中后，经包衣工艺喷涂至药用空白微丸丸芯，干燥后得到的微丸中的优替德隆以无定型和分子态的形式存在于微丸或粉末中，且具有一定稳定性。
3.本申请的口服制剂的制备工艺可采用一体化成型工艺，在工艺制备过程中，基本采用密闭操作，可有效避免由于细胞毒类化合物带来的职业暴露危害。
4.本申请的口服制剂在制备中产品的总收率达到90％以上，远远高于常规口服 固体制剂的物料总收率。
5.本申请的固体口服制剂中的活性成分优替德隆以无定形或分子形态存在，而非晶型形态。
附图说明
图1：实施例1的口服制剂的溶出曲线；
图2：实施例2的口服制剂的溶出曲线；
图3：实施例3的口服制剂的溶出曲线；
图4：实施例4的口服制剂的溶出曲线；
图5A：实施例5-A的口服制剂的溶出曲线；
图5B：实施例5-B的口服制剂的溶出曲线；
图6：优替德隆注射液的血药浓度-时间曲线下面积；
图7：实施例1的优替德隆胶囊的血药浓度-时间曲线下面积；
图8：优替德隆注射液的血药浓度-时间曲线下面积；
图9：实施例5-A的优替德隆胶囊的血药浓度-时间曲线下面积；
图10：优替德隆晶体形式的X-射线衍射图谱；
图11：优替德隆无定形形式的X-射线衍射图谱；
图12：实施例5-A制备的优替德隆胶囊所使用的药用辅料(无活性成分)的X-射线衍射图谱；
图13A：实施例5-A制备的优替德隆胶囊(室温保存)中内容物的X-射线衍射图谱图；
图13B：实施例5-A制备的优替德隆胶囊(室温保存)中内容物的HPLC图谱图。
具体实施方式
下面结合具体实施例进一步阐述说明本申请，但本申请并不局限于下述实施例，对于本技术领域的工作人员来说，在不脱离本申请原理的前提下，还可进行适当优化与修缮，这些改进与修饰也被视为本申请的保护范围。
材料：
以下实施例的制剂处方中使用的优替德隆由成都华昊中天药业有限公司制造，所 有辅料的执行标准为国家批准或中国药典2020版，其中，聚氧乙烯(40)氢化蓖麻油由巴斯夫中国有限公司制造，羟丙甲纤维素E50由罗门哈斯制造，羟丙甲纤维素K100由罗门哈斯制造，丸芯(蔗糖)由上海卡乐康包衣制造，羟丙甲纤维素空心胶囊由苏州胶囊有限公司制造。但以下实施例的口服固体制剂所使用的辅料并不受限于制造商。
实施例1：优替德隆口服固体制剂处方
Figure PCTCN2021116194-appb-000002
取处方量的优替德隆、聚氧乙烯(40)氢化蓖麻油、聚维酮K30置烧杯中用处方量无水乙醇使溶解。加入处方量纯化水，混匀；或取处方量羟丙甲纤维素E5加入处方量纯化水中边加边搅拌使溶解，将羟丙甲纤维素E5水溶液缓慢加入无水乙醇溶液中，持续搅拌约1小时使充分混匀。在多功能制粒包衣机中加入处方量的丸芯，上药包衣，包衣完成后充分干燥，出料，将所得微丸充填于胶囊中。每粒胶囊中可填充10-30mg优替德隆。
溶出度试验：
测定样品为含20mg优替德隆的胶囊。根据《中国药典》2020版附录0931溶出度与释放度测定法第一法测定，在转篮中加入测试胶囊，转速为100转/分钟，溶出介质为900ml pH 6.8磷酸盐缓冲液。利用高效液相色谱法测定释放度，色谱柱为C18色谱柱，流动相为乙腈-水＝(65:35)，柱温为30℃，检测波长为250nm。溶出曲线如图1所示。
以亲水性载体材料作为固体分散体载体与优替德隆制备成固体分散体后，药物的溶解性虽然有显著提高但溶解后的药物在体内易发生重结晶现象，从而降低药物的生物利用度。本实施例的比格犬内的生物利用度为29％。
实施例2
优替德隆口服固体制剂处方
名称 处方量
优替德隆 15g
聚氧乙烯(40)氢化蓖麻油 30g
羟丙甲纤维素E5 155g
丸芯(蔗糖) 100g
乙基纤维素 11g
聚乙二醇400 1.5g
无水乙醇 2800g
纯化水 1200g
取处方量的优替德隆、聚氧乙烯(40)氢化蓖麻油置烧杯中，用处方量无水乙醇使溶解；取处方量羟丙甲纤维素E5加入处方量纯化水中边加边搅拌使溶解；将羟丙甲纤维素E5水溶液缓慢加入无水乙醇溶液中，持续搅拌约1小时使充分混匀。在多功能制粒包衣机中加入处方量丸芯，上药包衣，包衣完成后充分干燥，出料得含药微丸。
取乙基纤维素11g、聚乙二醇400 1.5g至烧杯中用无水乙醇175ml使溶解后，加水稀释至250ml，得控释包衣液。将含药微丸置流化床中，上控释包衣液，包衣增重约4％，包衣完成后，40℃老化2小时以上得优替德隆缓释微丸，将优替德隆缓释微丸充填于胶囊中。
溶出度试验：
测定样品为含20mg优替德隆的胶囊。根据《中国药典》2020版附录0931溶出度与释放度测定法第一法测定，在转篮中加入测试胶囊，转速为100转/分钟，溶出介质为900ml pH 6.8磷酸盐缓冲液。利用高效液相色谱法测定释放度，色谱柱为C18色谱柱，流动相为乙腈-水＝(65:35)，柱温为30℃，检测波长为250nm。溶出曲线如图2所示。
实施例3
优替德隆口服固体制剂处方
名称 处方量
优替德隆 15g
聚氧乙烯(40)氢化蓖麻油 30g
羟丙甲纤维素E50 80g
羟丙甲纤维素K100 25g
丸芯(蔗糖) 100g
无水乙醇 3000g
纯化水 1400g
取处方量的优替德隆、聚氧乙烯(40)氢化蓖麻油置烧杯中用处方量无水乙醇使溶解；取处方量羟丙甲纤维素E50、K100加入处方量纯化水中边加边搅拌使溶解；将羟丙甲纤维素水溶液缓慢加入无水乙醇溶液中，持续搅拌约1小时使充分混匀。在多功能制粒包衣机中加入处方量丸芯，上药包衣，包衣完成后充分干燥，出料，将所得微丸充填于胶囊中。
溶出度试验：
测定样品为含20mg优替德隆的胶囊。根据《中国药典》2020版附录0931溶出度与释放度测定法第一法测定，在转篮中加入测试胶囊，转速为100转/分钟，溶出介质为900ml pH 6.8磷酸盐缓冲液。利用高效液相色谱法测定释放度，色谱柱为C18色谱柱，流动相为乙腈-水＝(65:35)，柱温为30℃，检测波长为250nm。溶出曲线如图3所示：
实施例4
优替德隆口服固体制剂处方
名称 处方量
优替德隆 15g
聚氧乙烯(40)氢化蓖麻油 30g
羟丙甲纤维素E50 95g
乙基纤维素 10g
丸芯(蔗糖) 100g
无水乙醇 2800g
纯化水 1200g
取处方量的优替德隆、聚氧乙烯(40)氢化蓖麻油、乙基纤维素置烧杯中用处方量无水乙醇使溶解；取处方量羟丙甲纤维素E50加入处方量纯化水中边加边搅拌使溶解；将羟丙甲纤维素溶液缓慢加入无水乙醇溶液中，持续搅拌约1小时使充分混匀。在多功能制粒包衣机中加入丸芯，上药包衣，包衣完成后充分干燥，出料，将所得微丸充填于胶囊中。
溶出度试验：
测定样品为含20mg优替德隆的胶囊。根据《中国药典》2020版附录0931溶出度与释放度测定法第一法测定，在转篮中加入测试胶囊，转速为100转/分钟，溶出介质为900ml pH 6.8磷酸盐缓冲液。利用高效液相色谱法测定释放度，色谱柱为C18色谱柱，流动相为乙腈-水＝(65:35)，柱温为30℃，检测波长为250nm。溶出曲线如图4所示：
实施例5-A
优替德隆口服固体制剂处方
名称 处方量
优替德隆 15g
聚氧乙烯(40)氢化蓖麻油 30g
羟丙甲纤维素E50 60g
羟丙甲纤维素K100 45g
丸芯(蔗糖) 100g
无水乙醇* 3000g
纯化水* 1400g
羟丙甲纤维素空心胶囊 按需
*：为工艺中使用并最终去除的溶剂。
取处方量的优替德隆、聚氧乙烯(40)氢化蓖麻油置烧杯中用处方量无水乙醇使溶解；取处方量羟丙甲纤维素E50、K100加入处方量纯化水中边加边搅拌使溶解；将羟丙甲纤维素水溶液缓慢加入无水乙醇溶液中，持续搅拌约1小时使充分混匀。在多功能制粒包衣机中加入处方量丸芯，上药包衣，包衣完成后充分干燥，出料，将所得 微丸充填于胶囊中得优替德隆胶囊。
溶出度试验：
测定样品为含20mg优替德隆的胶囊。根据《中国药典》2020版附录0931溶出度与释放度测定法第一法测定，在转蓝中加入测试胶囊，转速为100转/分钟，溶出介质分别为900ml pH 6.8磷酸盐缓冲液、0.1mol/L盐酸、纯化水和pH4.5醋酸盐缓冲液。利用高效液相色谱法测定释放度，色谱柱为C18色谱柱，流动相为乙腈-水＝(65:35)，柱温为30℃，检测波长为250nm。溶出曲线如图5A所示。通过所制样品的体外溶出特征符合预期目标，在不同条件下，其在30分钟时溶出约57％、60分钟时溶出约99％，无突释、释放不完整现象。
实施例5-B
本实施例的微丸胶囊的制备方法以及溶出度检测方法与实施例5-A相同。
名称 处方量
优替德隆 15g
聚氧乙烯(40)氢化蓖麻油 30g
羟丙甲纤维素E50 80g
羟丙甲纤维素K100 30g
丸芯(蔗糖) 100g
无水乙醇* 2500g
纯化水* 2000g
羟丙甲纤维素空心胶囊 按需
溶出曲线示于图5B中，显示多批次制备的胶囊的各批释放均匀性良好(如图5B所示)。
实施例6
优替德隆口服固体制剂处方；
名称 处方量
优替德隆 15g
聚氧乙烯(40)氢化蓖麻油 30g
名称 处方量
羟丙甲纤维素E50 60g
羟丙甲纤维素K100 45g
丸芯(蔗糖) 75g
聚维酮K30 50g
乳糖 125g
滑石粉 5g
无水乙醇 3000g
纯化水 1400g
取处方量的优替德隆、聚氧乙烯(40)氢化蓖麻油置烧杯中用处方量无水乙醇使溶解；取处方量羟丙甲纤维素E50、K100加入处方量纯化水中边加边搅拌使溶解；将羟丙甲纤维素水溶液缓慢加入无水乙醇中，持续搅拌约1小时使充分混匀。在多功能制粒包衣机中加入处方量丸芯，上药包衣，包衣完成后充分干燥，出料，得含药微丸。将含药微丸与处方量聚维酮K30、乳糖、滑石粉混合均匀，压片，得优替德隆片。
实施例7
优替德隆口服固体制剂处方
名称 处方量
优替德隆 15g
聚氧乙烯(40)氢化蓖麻油 10g
聚维酮K30 120g
乳糖 100g
羟丙甲纤维素K100M 150g
滑石粉 5g
无水乙醇 600g
取处方量的优替德隆、聚氧乙烯(40)氢化蓖麻油、聚维酮K30置烧杯中用处方量无水乙醇使溶解，混匀，得药液。将该药液用多功能制粒包衣机进行喷雾干燥后得优替德隆固体分散体。将该优替德隆固体分散体与处方量的乳糖、羟丙甲纤维素K100M及滑石粉经干法制粒后，压片，得优替德隆片。
实施例8
优替德隆口服固体制剂处方
名称 处方量
优替德隆 15g
聚乙二醇6000 155g
吐温80 30g
丸芯(蔗糖) 100g
无水乙醇 1500g
纯化水 500g
取处方量的优替德隆、聚氧乙烯(40)氢化蓖麻油、吐温80、聚乙二醇6000置烧杯中用处方量无水乙醇使溶解，再加入处方量纯化水，混匀，在多功能制粒包衣机中加入处方量的丸芯，上药包衣，包衣完成后充分干燥，出料，将所得微丸充填于胶囊中。
实施例9
优替德隆口服固体制剂处方
名称 处方量
优替德隆 15g
泊洛沙姆407 65g
聚乙二醇8000 85g
丸芯(蔗糖) 100g
无水乙醇 1500g
纯化水 500g
取处方量的优替德隆、泊洛沙姆407、聚乙二醇8000置烧杯中用处方量无水乙醇使溶解，再加入处方量纯化水，混匀，在多功能制粒包衣机中加入处方量的丸芯上药包衣，包衣完成后充分干燥，出料，将所得微丸充填于胶囊中。
实施例10
优替德隆口服固体制剂处方
名称 处方量
优替德隆 15g
聚乙二醇6000 155g
聚氧乙烯(40)氢化蓖麻油 30g
聚维酮K90 15g
乳糖 100g
二氧化硅 155g
无水乙醇 1000g
取处方量的优替德隆、聚氧乙烯(40)氢化蓖麻油、聚乙二醇6000置烧杯中用处方量无水乙醇使溶解，混匀，用多功能制粒包衣机中喷雾干燥，得优替德隆固体分散体。
取优替德隆固体分散体及处方量的乳糖、二氧化硅、聚维酮K90经干法制粒机制粒后，压片，得优替德隆片。
实施例11
优替德隆口服固体制剂处方
名称 处方量
优替德隆 15g
聚乙二醇4000 150g
泊洛沙姆407 30g
山嵛酸甘油酯 30g
聚乙烯吡咯烷酮 5g
蔗糖 100g
微粉硅胶 100g
无水乙醇 1500g
取处方量的优替德隆、泊洛沙姆407、聚乙二醇4000置烧杯中用处方量无水乙醇使溶解后，混匀，用多功能制粒包衣机中喷雾干燥，得优替德隆固体分散体。
取优替德隆固体分散体及处方量的乳糖、二氧化硅、山嵛酸甘油酯、聚乙烯吡咯烷酮用经干法制粒机干法制粒后，压片，得优替德隆片。
实施例12
优替德隆口服固体制剂处方
名称 处方量
优替德隆 15g
聚山梨酯80 30g
蔗糖 110g
醋酸纤维素 45g
丸芯 100g
无水乙醇 3000g
纯化水 1400g
取处方量的优替德隆、聚山梨酯、醋酸纤维素置烧杯中用处方量无水乙醇使溶解；取处方量乳糖加入处方量纯化水中边加边搅拌使溶解；将纯化水溶液缓慢加入无水乙醇溶液中，持续搅拌约1小时使充分混匀。在多功能制粒包衣机中加入处方量丸芯，上药包衣，包衣完成后充分干燥，出料，将所得微丸充填于胶囊中得优替德隆胶囊。
实施例13:生物利用度试验
1、采用实施例1制备的优替德隆胶囊的生物利用度
试验方法：
将4只Beagle犬分为2组，其中一组在第1次试验时，每只犬口服给予优替德隆微丸1mg/kg；另外一组在第1次试验时，每只犬静脉滴注优替德隆注射液1mg/kg。在给药前及给药后的0.5h、1h、1.5h、2h、2.5h、3h、4h、6h、8h、12h及24h等时间段内静脉取血。样品经离心分离出血浆后，用LC-MS/MS法测定血浆中优替德隆的浓度。试验结果如图6所示。
优替德隆注射液及优替德隆胶囊(实施例1)的药代动力学数据如下表所示；
表1：优替德隆注射液P K/P D数据
Figure PCTCN2021116194-appb-000003
表2：优替德隆胶囊(实施例1)P K/P D数据
Figure PCTCN2021116194-appb-000004
实施例1的口服制剂的平均相对生物利用度可达29％左右。
采用相同测试实验方法，测得实施例2，3，4制备的优替德隆制剂的平均相对生物利用度在30-50％之间。
2、采用实施例5和6制备的优替德隆制剂的生物利用度试验
试验方法；
将6只Beagle犬分为2组，每组3只犬，第一组每只犬口服给予实施例5-A的优替德隆胶囊1.5mg/kg；另外一组以优替德隆注射液为参比，每只犬静脉滴注优替德隆1mg/kg。在给药前及给药后的0.5h、1h、1.5h、2h、2.5h、3h、4h、6h、8h、12h、24h等时间段内静脉取血。样品经离心分离出血浆后，用LC-MS/MS法测定血浆中优替德隆的浓度。注射液试验结果如图8所示。胶囊的实验结果示于图9中。
优替德隆注射液及优替德隆胶囊(实施例5-A)的药代动力学数据如下表3所示。
表3：比格犬单次静脉给予优替德隆注射液及口服给予优替德隆胶囊后各药代参数均值
Figure PCTCN2021116194-appb-000005
Figure PCTCN2021116194-appb-000006
单次口服给予优替德隆胶囊的相对生物利用度在53.1％～103.8％之间，平均相对生物利用度为78.5％。
同实施例5-A的测试实验方法，测得采用实施例6制备的优替德隆片剂的平均相对生物利用度可达55％以上。
实施例14:稳定性
优替德隆胶囊(实施例1、5)在40℃、75％RH的加速试验条件下，储存1个月后的有关物质检测结果表明，产品中的降解杂质在ICH Q3规定的范围内，表明本发明的优替德隆口服制剂具有良好的稳定性。
优替德隆胶囊(实施例1、5)在40℃、75％RH的加速试验条件下，储存1个月后制剂产品经X-射线衍射检测表明，优替德隆胶囊中的优替德隆以无定形或分子形态存在。
实施例15:优替德隆无定形物的制备
方法一：
取优替德隆1g溶解于5ml二氯甲烷或三氯甲烷或二氯甲烷、三氯甲烷、乙酸乙酯中任意2种或三种的混合溶剂中，30℃～80℃，-0.05Mpa减压挥干，即得。
方法二：
取优替德隆1g溶解于5ml二氯甲烷或三氯甲烷或二氯甲烷、三氯甲烷、乙酸乙酯中任意2种或三种的混合溶剂中，用流化床进行喷雾干燥，物料与进风温度≥30℃，即得。
方法三：取优替德隆1g溶解于10ml甲醇或乙醇溶剂中，用旋转蒸发仪减压蒸干，即得。
优替德隆无定形物的X-射线衍射图谱示于图11。
通过本专利实施例工艺技术获得的胶囊中的优替德隆以无定形或分子形态存在。

Claims (13)

  1. 一种固体口服药物制剂，其特征在于，所述口服制剂包含优替德隆、其药学上可接受的盐、溶剂化物或酯为活性成分，还包含药用辅料。
  2. 根据权利要求1所述的固体口服制剂，其特征在于，所述药用辅料包含亲水性药用辅料、缓释性药用辅料和任选的表面活性剂。
  3. 根据权利要求1或2所述的固体口服制剂，其特征在于，所述活性成分与药用辅料的重量百分比为1:1至1:30。
  4. 根据权利要求3所述的固体口服制剂，其特征在于，所述活性成分与药用辅料的重量百分比为1:5～1:20。
  5. 根据权利要求1-4中任一项所述的固体口服制剂，其特征在于，所述亲水性药用辅料选自聚维酮、羟丙甲纤维素、甘露醇、乳糖、蔗糖、泊洛沙姆和聚乙烯醇中的至少一种；所述缓释性药用辅料选自聚维酮、羟丙甲纤维素、聚乙二醇、乙基纤维素、聚乙烯缩乙醛二乙胺醋酸酯、醋酸羟丙甲纤维素琥珀酸脂、甲基丙烯酸醋酸酯共聚物、醋酸纤维素、甲基纤维素、聚丙烯酸树脂、邻苯二甲酸聚乙烯醇脂、邻苯二甲酸纤维素脂和羟丙甲纤维素酞酸酯中的至少一种；所述表面活性剂选自聚山梨酯、聚氧乙烯蓖麻油、十二烷基硫酸钠、胆酸盐、脂肪酸甘油酯、山梨坦、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚和泊洛沙姆中的至少一种。
  6. 根据权利要求5所述的固体口服制剂，其特征在于，所述亲水性药用辅料选自低粘度羟丙甲纤维素、聚维酮和泊洛沙姆中的至少一种；所述缓释性药用辅料选自高粘度羟丙甲纤维素、高粘度聚乙二醇、乙基纤维素和醋酸纤维素中的至少一种；所述表面活性剂选自聚氧乙烯蓖麻油、聚山梨酯和泊洛沙姆中的至少一种。
  7. 根据权利要求1-6中任一项所述的固体口服制剂，其特征在于，所述口服制剂为微丸胶囊或片剂。
  8. 根据权利要求7所述的固体口服制剂，其特征在于，所述微丸胶囊或片剂包含基于微丸重量或片剂重量的2％-10％(w/w)的活性成分。
  9. 根据权利要求8所述的固体口服制剂，其特征在于，所述每个微丸胶囊中的微丸含5-30mg优替德隆，每片含5-20mg优替德隆。
  10. 根据权利要求8或9所述的固体口服制剂，其特征在于，所述微丸胶囊或片剂还包含基于微丸重量或片剂重量的30％-70％(w/w)的药用辅料和20％～60％(w/w)的丸芯。
  11. 根据权利要求1-10中任一项所述的固体口服制剂，其为微丸胶囊，以优替德隆为 活性成分，以聚氧乙烯(40)氢化蓖麻油、低粘度羟丙甲纤维素和高粘度羟丙甲纤维素为药用辅料。
  12. 根据权利要求11所述的固体口服制剂，其中，所述微丸胶囊以蔗糖为丸芯。
  13. 根据权利要求1-12中任一项所述的固体口服制剂，其中，活性成分优替德隆以无定形或分子形态存在。
PCT/CN2021/116194 2020-09-02 2021-09-02 优替德隆的固体口服制剂 WO2022048592A1 (zh)

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CA3184960A CA3184960A1 (en) 2020-09-02 2021-09-02 Solid oral formulation of utidelone
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AU2021337086A AU2021337086B2 (en) 2020-09-02 2021-09-02 Solid oral formulation of utidelone
CN202180006314.0A CN114727995B (zh) 2020-09-02 2021-09-02 优替德隆的固体口服制剂
US17/758,110 US20230048901A1 (en) 2020-09-02 2021-09-02 Solid oral formulation of utidelone
KR1020237001452A KR20230024389A (ko) 2020-09-02 2021-09-02 우티델론의 고체 경구용 제제
BR112023003572A BR112023003572A2 (pt) 2020-09-02 2021-09-02 Formulação oral sólida de utidelona
JP2022539043A JP2023508090A (ja) 2020-09-02 2021-09-02 ウチデロンの経口固形製剤

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