WO2024113533A1 - 一种可注射的药物组合物及其制备方法与应用 - Google Patents

一种可注射的药物组合物及其制备方法与应用 Download PDF

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WO2024113533A1
WO2024113533A1 PCT/CN2023/081081 CN2023081081W WO2024113533A1 WO 2024113533 A1 WO2024113533 A1 WO 2024113533A1 CN 2023081081 W CN2023081081 W CN 2023081081W WO 2024113533 A1 WO2024113533 A1 WO 2024113533A1
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pharmaceutical composition
cabotegravir
preparation
pharmaceutically acceptable
pharmaceutical
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PCT/CN2023/081081
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English (en)
French (fr)
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沈毅
葛强
孙思平
蒋定强
叶聪
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浙江萃泽医药科技有限公司
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—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
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/10—Dispersions; Emulsions

Definitions

  • the present invention belongs to the field of pharmaceutical preparations, and in particular relates to an injectable pharmaceutical composition comprising cabotegravir, and a preparation method and application thereof.
  • HIV human immunodeficiency virus
  • CD4T lymphocytes the most important part of the human immune system, and destroys a large number of these cells, causing the body to lose its immune function.
  • Treatment compliance and stigma remain the main obstacles to combating the HIV-1 epidemic.
  • AIDS has entered a period of rapid growth, and the epidemic is developing in a severe trend. Therefore, seeking an effective treatment for AIDS has become a top priority and a hot topic of global concern.
  • Cabotegravir (Formula I) is a second-generation integrase strand transfer inhibitor (INSTI) produced by ViiV Health Care. Its special pharmaceutical properties make it suitable for long-acting sustained-release preparations.
  • INSTI integrase strand transfer inhibitor
  • Cabotegravir is highly effective, with an IC 50 of 0.22nmol/L against HIV. Cabotegravir can be taken orally at a dose of 5mg/d or 30mg/d. After a single treatment for 10 days, HIV RNA in plasma drops to 2.2-2.3 copies/mL. Cabotegravir can also be injected, which increases the half-life and the dosing interval during injection, thus avoiding the trouble of daily oral administration. Cabotegravir's metabolites are mainly excreted from the body through bile and urine, so its in vivo processes will not be affected by other drugs.
  • Cabenuva developed by ViiV Health care, is a two-bottle preparation containing one bottle of cabotegravir suspension and one bottle of rilpivirine suspension, which can be used
  • the controlled-release long-acting reservoir drug delivery system made of nanosuspension is administered by intramuscular injection. Intramuscular injection once a month or every two months can maintain the plasma concentration of the drug at more than 4 times the 90% inhibitory concentration (IC 90 ).
  • the production process is relatively complicated and has high requirements for production equipment in order to prepare a nanoparticle composition by co-grinding a drug composition containing cabotegravir, which also limits the expansion of production.
  • the storage conditions of the product need to be controlled at 2-8°C.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient and a pharmaceutically acceptable excipient
  • the active ingredient comprises cabotegravir or a pharmaceutically acceptable salt thereof, and the excipient comprises a surfactant and a suspending agent.
  • the pharmaceutical composition further comprises a lyophilization excipient.
  • the suspending agent is a cellulose suspending agent, for example, at least one selected from carboxymethyl cellulose and its sodium salt, hydroxypropyl cellulose and its sodium salt, hydroxypropyl methyl cellulose and its sodium salt, methyl cellulose and its sodium salt, hydroxyethyl cellulose and its sodium salt, sodium hyaluronate and polyvinyl pyrrolidone, for example, at least one selected from methyl cellulose, sodium carboxymethyl cellulose and hydroxypropyl cellulose.
  • a cellulose suspending agent for example, at least one selected from carboxymethyl cellulose and its sodium salt, hydroxypropyl cellulose and its sodium salt, hydroxypropyl cellulose.
  • the surfactant is selected from at least one of polysorbate or its derivatives, and polyethylene glycol stearate or its derivatives; for example, the polyethylene glycol stearate or its derivatives are selected from 15-hydroxy polyethylene glycol stearate, and the polysorbate or its derivatives are selected from polysorbate 80.
  • the surfactant is selected from at least one of 15-hydroxy polyethylene glycol stearate and polysorbate 80.
  • the lyophilization excipient is selected from at least one of mannitol, trehalose and glucose.
  • the auxiliary material may also contain an isotonic regulator.
  • the isotonic regulator may be selected from one or more of sodium chloride, mannitol, sorbitol, glucose, sucrose, fructose and lactose.
  • the isotonic regulator may be sodium chloride and mannitol.
  • the isotonic regulator may be sodium chloride.
  • the isotonic regulator may be mannitol.
  • the weight ratio of the surfactant to cabotegravir or a pharmaceutically acceptable salt thereof is selected from 1: (0.01-100), for example 1: (1-100), preferably 1: (10-70), and further preferably 1: (50-70).
  • the weight ratio of the surfactant to cabotegravir or a pharmaceutically acceptable salt thereof is 1: 6.67, 1: 10, 1: 20, 1: 40, 1: 42, 1: 60, 1: 66.67.
  • the weight ratio of the suspending agent to cabotegravir or a pharmaceutically acceptable salt thereof is selected from 1:(0.01-100), for example 1:(1-100), preferably 1:(2.5-50), and further preferably 1:(25-30).
  • the weight ratio of the suspending agent to cabotegravir or a pharmaceutically acceptable salt thereof is 1:2, 1:2.86, 1:2.5, 1:10, 1:25, or 1:26.
  • the weight ratio of the lyophilized excipient to cabotegravir or a pharmaceutically acceptable salt thereof is selected from 1: (0.01-100), for example 1: (0.1-50), preferably 1: (0.1-20).
  • the weight ratio of the lyophilized excipient to cabotegravir or a pharmaceutically acceptable salt thereof is 1: 0.5, 1: 1, 1: 5, 1: 5.9.
  • the pharmaceutical composition comprises 0.01-800 mg of cabotegravir or a pharmaceutically acceptable salt thereof, for example 10-500 mg, preferably 100-400 mg, and further preferably 200-400 mg, for example 40 mg, 100 mg, 200 mg, 300 mg, 400 mg, 423.7 mg, and 450 mg.
  • the active ingredient is cabotegravir or its sodium salt.
  • the pharmaceutical composition is a powder, preferably an injectable powder; as an example, the pharmaceutical composition is an injectable lyophilized powder.
  • the pharmaceutical composition comprises cabotegravir, polysorbate 80, sodium carboxymethyl cellulose and mannitol, and the weight ratio of cabotegravir, polysorbate 80, sodium carboxymethyl cellulose and mannitol is (5-70):1:(1-10):(5-30), for example, (6-68):1:(1.5-5):(10-25), and exemplarily is 10:1:3.5:20, 6.67:1:2.67:20, 66.67:1:3.5:20.
  • the pharmaceutical composition comprises cabotegravir or its sodium salt, 15-hydroxypolyethylene glycol stearate, sodium carboxymethyl cellulose and mannitol, and the weight ratio of cabotegravir or its sodium salt, 15-hydroxypolyethylene glycol stearate, sodium carboxymethyl cellulose and mannitol is (5-70):1:(1-10):(5-30), for example, (6-68):1:(1.5-5):(7-15), and exemplarily is 40:1:1.6:8.
  • the pharmaceutical composition may further comprise a second therapeutic agent, which is selected from HIV inhibitors.
  • a second therapeutic agent which is selected from HIV inhibitors.
  • the HIV inhibitor may be selected from one or more of nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and integrase inhibitors.
  • the present invention also provides a pharmaceutical preparation, which comprises the pharmaceutical composition.
  • the pharmaceutical preparation comprises the pharmaceutical composition and a dispersing solvent.
  • the pharmaceutical preparation is prepared by suspending the pharmaceutical composition in a dispersing solvent, preferably by suspending an injectable lyophilized powder in a dispersing solvent.
  • the dispersion solvent is water.
  • the concentration of cabotegravir or a pharmaceutically acceptable salt thereof is selected from 0.01 to 800 mg/mL, such as 10 to 400 mg/mL, preferably 20 to 400 mg/mL, and further preferably 150 to 200 mg/mL.
  • the particle size distribution of the particles of the pharmaceutical composition in the dispersion solvent is as follows: D10 is in the range of about 0.5 ⁇ m to about 10 ⁇ m, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ⁇ m; D50 In the range of about 2 ⁇ m to about 25 ⁇ m, for example 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 ⁇ m; D90 particle size is in the range of about 5 ⁇ m to about 50 ⁇ m, for example 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45 ⁇ m.
  • the D50 changes by less than about 2 ⁇ m, for example, the change range is 0.1, 0.3, 0.5, 0.7, 1.0, 1.2, 1.5, 1.8 ⁇ m; the D90 changes by less than about 5 ⁇ m, for example, the change range is 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 ⁇ m; in some embodiments, under normal temperature or high temperature (50-70°C, for example 60°C) accelerated experimental conditions, the D10, D50, and D90 change by less than 1 ⁇ m, for example, the change ranges are independently 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 ⁇ m.
  • the storage time may be 1 month, 2 months, 3 months or longer.
  • the D50 of the particles changes by less than about 2 ⁇ m, such as by 0.1, 0.3, 0.5, 0.7, 1.0, 1.2, 1.5, and 1.8 ⁇ m; the D90 changes by less than about 5 ⁇ m, such as by 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, and 4.5 ⁇ m.
  • the D50 particle size of the particles is less than 30 ⁇ m, preferably less than 20 ⁇ m, and more preferably less than 5 ⁇ m.
  • the D50 particle size is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 ⁇ m.
  • the pharmaceutical preparation is an injection, such as a suspension injection.
  • the unit dosage form of the pharmaceutical preparation contains 20-60 mg, for example, 30 mg, 40 mg, 50 mg of cabotegravir, and the content calculated as cabotegravir is a therapeutically effective amount.
  • the pharmaceutical preparation may be administered by subcutaneous injection or intramuscular injection.
  • the pharmaceutical preparation is used for preventing and/or treating diseases caused by human immunodeficiency virus (HIV) infection.
  • HIV human immunodeficiency virus
  • the present invention also provides a method for preparing the pharmaceutical composition, comprising the following steps: mixing an organic solution of cabotegravir or a pharmaceutically acceptable salt thereof with water, filtering, washing, mixing the obtained precipitate with an auxiliary material, and freeze-drying.
  • the organic solvent in the organic solution of cabotegravir or a pharmaceutically acceptable salt thereof is selected from at least one of DMF, DMA, DMSO and acetic acid.
  • the organic solution of cabotegravir or a pharmaceutically acceptable salt thereof is mixed with water by shearing or stirring at a rotation speed of 100-10000 rpm (eg, 600-8000 rpm, such as 3500-5000 rpm).
  • the preparation method comprises the following steps:
  • step (4) After step (4) is completed, freeze-drying is performed.
  • the water temperature is controlled at 0-100°C, preferably 0-60°C, such as 15°C, 25°C, 50°C.
  • the preparation method further comprises adjusting the particle size by homogenization and microfluidization before freeze-drying according to actual conditions.
  • the present invention also provides a method for preparing the above-mentioned pharmaceutical preparation, comprising suspending the above-mentioned pharmaceutical composition in a dispersing solvent to prepare the pharmaceutical preparation, preferably suspending the freeze-dried pharmaceutical composition prepared by the above-mentioned method in a dispersing solvent.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the subject compounds and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • Pharmaceutically acceptable salts include, among others, those described in Berge, J. Pharm. Sci., 1977, 66, 1-19, or in P H Stahl and C G Wermuth, eds., Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd ed., Stahl/Wermuth: Wiley-VCH/VHCA, 2011 (see http://www.wiley.com/WileyCDA/WileyTitle/productCd-3906390519.html).
  • Suitable pharmaceutically acceptable salts may include acid or base addition salts.
  • Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine (N, N'-diphenylmethylethylenediamine), bis(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1 -4-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole), cyclohexylamine, diphenylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (
  • stable related to particle size means: D10 is in the range of about 0.5 ⁇ m to about 10 ⁇ m, D50 is in the range of about 2 ⁇ m to about 25 ⁇ m, and D90 particle size is in the range of about 5 ⁇ m to about 50 ⁇ m; and the variation range of D50 is less than about 2 ⁇ m, and the variation range of D90 is less than about 5 ⁇ m.
  • D10 is in the range of about 0.5 ⁇ m to about 10 ⁇ m
  • D50 is in the range of about 2 ⁇ m to about 25 ⁇ m
  • D90 is in the range of about 5 ⁇ m to about 50 ⁇ m
  • the variation range of D10, D50, and D90 is less than 1 ⁇ m.
  • median particle size D50 refers to the particle size at which the cumulative distribution of particles is 50%, that is, the volume content of particles smaller than this particle size accounts for 50% of all particles.
  • D10 refers to the particle size at which the cumulative distribution of particles is 10%, that is, the volume content of particles smaller than this particle size accounts for 10% of all particles.
  • D90 refers to the particle size at which the cumulative distribution of particles is 90%, that is, the volume content of particles smaller than this particle size accounts for 90% of all particles.
  • the pharmaceutical composition provided by the present disclosure relates to the use of such pharmaceutical composition in the treatment and prevention of HIV infection, has good stability, and is suitable for industrial production.
  • the present invention provides an injectable pharmaceutical composition/lyophilized preparation of cabotegravir, which can be stored at room temperature and has a long storage period; after the lyophilized powder preparation is reconstituted, the particle size of the obtained cabotegravir suspension injection remains stable, even reaching Particularly stable.
  • the present invention also provides a method for preparing cabotegravir injection. Compared with the original dispersion and grinding preparation method, the production process is simpler, the prices of production raw materials and production equipment are relatively low, and it is easy to achieve production expansion.
  • the cabotegravir suspension injection also provided by the present invention can maintain a steady-state concentration for a longer period of time compared to the original nanosuspension injection, thereby reducing the frequency of administration.
  • FIG1 shows the particle size distribution of cabotegravir suspension injection (i.e., after reconstitution of lyophilized powder) of different prescriptions
  • FIG. 2 shows the plasma concentration-time curve of Example 10 by intramuscular injection.
  • Cabotegravir used in the examples was purchased from Shanghai Disano Co., Ltd., sodium carboxymethylcellulose was purchased from Ashland, polysorbate 80 was purchased from Nanjing Well Pharmaceutical Co., Ltd., mannitol was purchased from Roquette, France, NMP was purchased from Roan's Reagent, DMA (N, N-dimethylacetamide) was purchased from Finar Limited, DMSO was purchased from Merck KGaA, and acetic acid was purchased from Sinopharm Chemical Reagent Co., Ltd. Unless otherwise specified, the reaction temperature of each step is room temperature and the pressure is normal pressure.
  • the Synpatek laser particle size analyzer used to detect the particle size of the suspension in each example is HELOs, and the manufacturer is Synpatek Co., Ltd. of Germany.
  • the water temperature for crystallization of cabotegravir was room temperature.
  • Example 1 Cabotegravir suspension injection (lyophilized powder) I and its preparation
  • Preparation method Cabotegravir was dissolved in 15 times the weight of NMP at a dissolution temperature of 60-70°C. Under stirring conditions of 600rpm, the drug solution was uniformly added to water with a volume of 10 times that of NMP within 10 minutes to precipitate cabotegravir, filtered and washed with water, and then mixed evenly with the excipients in Table 1 and ultrapure water, and then freeze-dried to obtain cabotegravir suspension injection (lyophilized powder) I. After reconstitution with 2ml of water for injection, the particle size was detected, and the results were D10 2.00 ⁇ m, D50 8.25 ⁇ m, and D90 18.99 ⁇ m.
  • Example 2 Cabotegravir suspension injection (lyophilized powder) II and its preparation
  • Preparation method Cabotegravir was dissolved in 15 times the weight of DMSO at a dissolution temperature of 60-70°C. Under the shearing condition of 5000rpm, the drug solution was added to water (with an ice-water bath to control the crystallization water temperature below 15°C) with a volume of 10 times the volume of DMSO within 10 minutes to precipitate Cabotegravir, which was filtered and washed with water, and then mixed evenly with the excipients in Table 2 and ultrapure water, and then freeze-dried to obtain Cabotegravir suspension injection (lyophilized powder) II. After reconstitution with 2ml of water for injection, the particle size was detected, which was D10 1.43 ⁇ m, D50 5.33 ⁇ m, and D90 12.89 ⁇ m.
  • Example 3 Cabotegravir suspension injection (lyophilized powder) III and its preparation
  • Example 2 The specific operation steps are the same as those in Example 2. After freeze-drying, cabotegravir suspension injection (lyophilized powder) III is obtained. After reconstitution with 2 ml of water for injection, the particle size is detected, and the results are D10 1.23 ⁇ m, D50 4.13 ⁇ m, and D90 9.94 ⁇ m.
  • Example 4 Cabotegravir suspension injection (lyophilized powder) IV and its preparation
  • Preparation method Dissolve cabotegravir sodium with 10 times the weight of acetic acid at room temperature, add the drug solution to water with 4 times the volume of acetic acid under shearing conditions of 5000rpm within 10min to precipitate cabotegravir, filter and wash the precipitate with water, then mix it evenly with the excipients in Table 4 and ultrapure water, and obtain cabotegravir suspension injection (lyophilized powder) IV after freeze-drying. After re-dissolving with 2ml of water for injection, the particle size was detected, and the results were D10 7.97 ⁇ m, D50 22.32 ⁇ m, and D90 45.18 ⁇ m.
  • Example 5 Cabotegravir suspension injection (lyophilized powder) V and its preparation
  • Preparation method Cabotegravir was dissolved in 10 times the weight of acetic acid at room temperature, and the drug solution was added to water with 4 times the volume of acetic acid under the shear condition of 5000rpm within 10min to precipitate cabotegravir, filtered and washed with water, and then mixed with the excipients and ultrapure water in Table 5.
  • the drug solution was homogenized 3 times with a pressure of 1900bar by a homogenizer, and then freeze-dried to obtain cabotegravir suspension injection (lyophilized powder) V. After reconstitution with 2ml of water for injection, the particle size was detected, and the results were D10 1.20 ⁇ m, D50 3.54 ⁇ m, and D90 9.01 ⁇ m.
  • Cabotegravir sodium is dissolved in acetic acid to generate cabotegravir, which is prepared into cabotegravir suspension injection.
  • Cabotegravir can also be dissolved in acetic acid and prepared into cabotegravir suspension injection using the same process.
  • the particle size of the product can be further adjusted by homogenization and microfluidization before freeze-drying.
  • Example 2 The specific operation steps are the same as those in Example 2. After freeze-drying, cabotegravir suspension injection (lyophilized powder) VI is obtained. After reconstitution with 2 ml of water for injection, the particle size is detected, and the results are D10 2.00 ⁇ m, D50 8.47 ⁇ m, and D90 35.18 ⁇ m.
  • the freeze-dried powder of the suspension injection of each prescription was placed at room temperature or high temperature for a period of time and then re-dissolved, and the particle size was tested. The results are shown in Table 7.
  • the particle size results of the unfreeze-dried cabotegravir suspension after being placed at room temperature for 7 days are shown in Table 7.
  • Example 8 Cabotegravir suspension injection (lyophilized powder) VII and its preparation
  • the prescription is the same as that of Example 2, the temperature of the drug solution during crystallization in the process step is greater than 50°C, and the remaining steps are the same as those of Example 2. Finally, a sample with a particle size of D10 9.01 ⁇ m, D50 19.92 ⁇ m, and D90 43.16 ⁇ m after redissolution was obtained for animal experiments.
  • Example 9 Cabotegravir Nanosuspension Injection VIII and its preparation
  • the raw materials and excipients in the prescription amount are milled to prepare Cabotegravir Nanosuspension Injection VIII, and the milling equipment is RESEARCHLAB, ceramic accelerator, (TOSOH) ZrO2 microbeads were ground to obtain samples with a particle size distribution of D10 60.6nm, D50 139nm, and D90 489nm, which were used as control preparations for animal experiments.
  • FIG. 1 shows the average concentration-time curve of cabotegravir in plasma after intramuscular administration of different formulations in rats.
  • the cabotegravir concentration-time curve in plasma was relatively flat, and the peak concentration was lower than that of the control preparation (i.e., nanosuspension injection VIII). From 528 hours after administration, the maintained blood concentration was higher than that of the control preparation. Due to the limitation of the sampling time point, its concentration was still at a high level as of the last time point (720h).
  • the cabotegravir concentration in plasma increased and reached a level equivalent to that of the control preparation at around 250 hours, and then the cabotegravir concentration in plasma slowly decreased, maintaining a blood concentration higher than that of the control preparation. As of the last time point (720h), its concentration was still at a relatively high level.
  • the suspension injection VII (D50 about 20 ⁇ m) has a lower C max but can maintain a longer steady-state concentration, with a better sustained-release effect.
  • the suspension injection V (D50 about 3.5 ⁇ m) can be released quickly, reaching a C max equivalent to the control preparation, and the blood drug concentration decreases slowly after reaching the peak, with a strong sustained-release effect.
  • the original preparation needs to be injected once a month to maintain a steady-state concentration, and this product can reduce the frequency of administration and give medications at longer intervals. It can also maintain homeostasis.

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Abstract

本发明公开一种可注射的药物组合物及其制备方法与应用。所述药物组合物包含活性成分和药学上可接受的辅料；所述活性成分包含卡博特韦或其药学上可接受的盐，所述辅料包含表面活性剂、助悬剂。本发明提供的药物组合物及其制剂用于HIV感染的治疗和预防，稳定性好，适合工业化生产。

Description

一种可注射的药物组合物及其制备方法与应用
本申请要求申请人于2022年12月1日向中国国家知识产权局提交的专利申请号为202211538523.2，发明名称为“一种可注射的药物组合物及其制备方法与应用”的在先申请的优先权。所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于药物制剂领域，具体涉及一种包含卡博特韦的可注射的药物组合物及其制备方法与应用。
背景技术
艾滋病(AIDS)是由人类免疫缺陷病毒(HIV)引起的，HIV的可怕之处在于，它把人体免疫系统中最重要的CD4T淋巴细胞作为主要攻击目标，大量破坏该细胞，使人体丧失免疫功能。治疗依从性和病耻感仍然是抗击HIV-1流行的主要障碍。在中国，艾滋病已经进入快速增长期，流行发展趋势严峻。因此寻求有效治疗艾滋病的方法已成为当务之急和世界关注的热点。
卡博特韦(Cabotegravir，式I)是ViiV Health care公司生产的第2代整合酶链转移抑制剂(integrase strand transfer inhibitor，INSTI)，其特殊的药学特性使其适合制成长效缓释制剂。
卡博特韦药效很强，抗HIV的IC50为0.22nmol/L。卡博特韦可口服给药，剂量为5mg/d或30mg/d，单次治疗10d后血浆中HIV RNA下降至2.2～2.3copies/mL。卡博特韦也可注射给药，注射时半衰期增加，给药间隔延长，从而避免每日口服给药的麻烦。卡博特韦的代谢产物主要通过胆汁和尿液排出体外，因此其体内过程不会受到其他药物的影响。ViiV Health care公司研发的Cabenuva，为包含一瓶卡博特韦混悬剂和一瓶利匹韦林混悬剂的两瓶装制剂，即用 纳米悬浮液制成的控释长效储库给药系统，以肌内注射的方式给药，每月或每两个月肌内注射1次可使药物的血浆浓度维持在90％抑制浓度(IC90)的4倍以上。
根据ViiV Health care公司公布的WO2012/037320中所述生产工艺，为将含卡博特韦的药物组合物共研磨制备纳米颗粒组合物，生产工艺较为复杂，对生产设备的要求较高，也限制了产量的扩大。此外，为保障纳米混悬体系的稳定，该产品存储条件需控制在2～8℃。
因此，亟需开发一种稳定性好、便于存储和/或制备方法简单的卡博特韦的新型制剂。
发明内容
本发明提供了一种药物组合物，包含活性成分和药学上可接受的辅料；
所述活性成分包含卡博特韦或其药学上可接受的盐，所述辅料包含表面活性剂和助悬剂。
根据本发明的实施方案，所述药物组合物还进一步包括冻干赋形剂。
根据本发明的实施方案，所述助悬剂为纤维素类助悬剂，例如选自羧甲基纤维素及其钠盐、羟丙基纤维素及其钠盐、羟丙甲纤维素及其钠盐、甲基纤维素及其钠盐、羟乙基纤维素及其钠盐、透明质酸钠和聚乙烯吡咯烷酮中的至少一种，例如选自甲基纤维素、羧甲基纤维素钠和羟丙基纤维素中的至少一种。
根据本发明的实施方案，所述表面活性剂选自聚山梨酯或其衍生物、以及聚乙二醇硬脂酸酯或其衍生物中的至少一种；例如，所述聚乙二醇硬脂酸酯或其衍生物选自15-羟基聚乙二醇硬脂酸酯，所述聚山梨酯或其衍生物选自聚山梨酯80。优选地，所述表面活性剂选自15-羟基聚乙二醇硬脂酸酯以及聚山梨酯80中的至少一种。
根据本发明的实施方案，所述冻干赋形剂选自甘露醇、海藻糖和葡萄糖等中的至少一种。
根据本发明的实施方案，所述辅料还可以含有等渗调节剂。例如，所述等渗调节剂可以选自氯化钠、甘露醇、山梨醇、葡萄糖、蔗糖、果糖和乳糖中的一种或多种。在一种实施方式中，所述等渗调节剂可以是氯化钠和甘露醇。在另一种实施方式中，所述等渗调节剂可以是氯化钠。在另一种实施方式中，所述等渗调节剂可以是甘露醇。
根据本发明的实施方案，所述表面活性剂与卡博特韦或其药学上可接受的盐的重量比选自1:(0.01～100)，例如1:(1～100)，优选1:(10～70)，还优选1:(50～70)。作为示例，所述表面活性剂与卡博特韦或其药学上可接受的盐的重量比为1:6.67、1:10、1:20、1:40、1:42、1:60、1:66.67。
根据本发明的实施方案，所述助悬剂与卡博特韦或其药学上可接受的盐的重量比选自1:(0.01～100)，例如1:(1～100)，优选1:(2.5～50)，还优选1:(25～30)。作为示例，所 述助悬剂与卡博特韦或其药学上可接受的盐的重量比为1:2、1:2.86、1:2.5、1:10、1:25、1:26。
根据本发明的实施方案，所述冻干赋形剂与卡博特韦或其药学上可接受的盐的重量比选自1:(0.01～100)，例如1:(0.1～50)，优选1:(0.1～20)。作为示例，所述冻干赋形剂与卡博特韦或其药学上可接受的盐的重量比为1:0.5、1:1、1:5、1:5.9。
在一种实施方案中，所述的药物组合物包含卡博特韦或其药学上可接受的盐0.01～800mg，例如10～500mg，优选100～400mg，还优选200～400mg，作为示例为40mg、100mg、200mg、300mg、400mg、423.7mg、450mg。
在一种实施方案中，所述活性成分为卡博特韦或其钠盐。
根据本发明的一种实施方案，所述药物组合物为粉末，优选为可注射的粉末；作为示例，所述药物组合物为可注射的冻干粉末。
根据本发明示例性的实施方案，所述药物组合物包含卡博特韦、聚山梨酯80、羧甲基纤维素钠和甘露醇，所述卡博特韦、聚山梨酯80、羧甲基纤维素钠和甘露醇的重量比为(5-70):1:(1-10):(5-30)，例如为(6-68):1:(1.5-5):(10-25)，示例性为10:1:3.5:20、6.67:1:2.67:20、66.67:1:3.5:20。
根据本发明示例性的实施方案，所述药物组合物包含卡博特韦或其钠盐、15-羟基聚乙二醇硬脂酸酯、羧甲基纤维素钠和甘露醇，所述卡博特韦或其钠盐、15-羟基聚乙二醇硬脂酸酯、羧甲基纤维素钠和甘露醇的重量比为(5-70):1:(1-10):(5-30)，例如为(6-68):1:(1.5-5):(7-15)，示例性为40:1:1.6:8。
根据本发明的实施方案，所述药物组合物还可以包含第二种治疗剂，所述第二种治疗剂选自HIV抑制剂，例如所述HIV抑制剂可以选自核苷类逆转录酶抑制剂、非核苷逆转录酶抑制剂、蛋白酶抑制剂和整合酶抑制剂中的一种或几种。
本发明还提供一种药物制剂，所述药物制剂包括所述药物组合物。
在一些实施方案中，所述药物制剂包括所述药物组合物和分散溶剂。在一些实施方案中，所述药物制剂为将所述药物组合物混悬于分散溶剂中制备得到，优选为可注射的冻干粉末混悬于分散溶剂中制备得到。
根据本发明的实施方案，所述分散溶剂为水。
根据本发明的实施方案，所述卡博特韦或其药学上可接受的盐的浓度选自0.01～800mg/mL，例如10～400mg/mL，优选20～400mg/mL，还优选150～200mg/mL。
根据本发明的实施方案，所述药物制剂中，药物组合物在分散溶剂中的粒子的粒径分布如下：D10在约0.5μm至约10μm的范围内，例如为1，2，3，4，5，6，7，8，9，10μm；D50 在约2μm至约25μm的范围内，例如为2，3，4，5，6，7，8，9，10，11，12，13，14，15，16，17，18，19，20，21，22，23，24，25μm；D90粒径在约5μm至约50μm的范围内，例如6，7，8，9，10，11，12，13，14，15，16，17，18，19，20，25，30，35，40，45μm。
一些实施方案中，常温或高温(50～70℃，例如60℃)存储条件下，D50变化幅度小于约2μm，比如变化幅度为0.1、0.3、0.5、0.7、1.0、1.2、1.5、1.8μm；D90变化幅度小于约5μm，比如变化幅度为0.5、1.0、1.5、2.0、2.5、3.0、3.5、4.0、4.5μm；一些实施方案中，常温或高温(50～70℃，例如60℃)加速实验条件下，D10、D50、D90变化幅度均小于1μm，比如变化幅度独立地为0.1，0.2，0.3，0.4，0.5，0.6，0.7，0.8，0.9μm。
进一步地，存储的时间可以为1个月、2个月、3个月或者更长时间。
在一种实施方式中，常温下放置2个月期间，所述粒子的D50变化幅度小于约2μm，比如变化幅度为0.1、0.3、0.5、0.7、1.0、1.2、1.5、1.8μm；D90变化幅度小于约5μm，比如变化幅度为0.5、1.0、1.5、2.0、2.5、3.0、3.5、4.0、4.5μm。
根据本发明的实施方案，所述粒子的D50粒径小于30μm，优选小于20μm，还优选小于5μm。比如，D50粒径为1，2，3，4，5，6，7，8，9，10，11，12，13，14，15，16，17，18，19，20，21，22，23，24，25μm。
根据本发明的实施方案，所述药物制剂为注射剂，例如为混悬注射液。
根据本发明的实施方案，所述药物制剂的单位剂量形式包含20-60mg，例如30mg、40mg、50mg的卡博特韦，以卡博特韦计的含量为治疗有效量的。
根据本发明的实施方案，所述药物制剂的给药方式可以为皮下注射给药或肌肉注射给药。
根据本发明的实施方案，所述药物制剂用于预防和/或治疗由人类免疫缺陷病毒(HIV)感染引起的疾病。
本发明还提供了所述药物组合物的制备方法，包括如下步骤：卡博特韦或其药学上可接受的盐的有机溶液与水混合，过滤、洗涤，得到的沉淀物与辅料混合，冷冻干燥。
根据本发明的实施方案，所述卡博特韦或其药学上可接受的盐的有机溶液中的有机溶剂选自DMF、DMA、DMSO、乙酸中的至少一种。
根据本发明的实施方案，所述卡博特韦或其药学上可接受的盐的有机溶液与水混合的方式为：在100-10000rpm(例如600-8000rpm，比如3500-5000rpm)转速下进行剪切或搅拌混合。
根据本发明优选的实施方案，所述制备方法包括如下步骤：
(1)将卡博特韦或其药学上可接受的盐用有机溶剂溶解，得到第一混合物；
(2)在分散条件下，将第一混合物倒入水中，得到第二混合物；
(3)将第二混合物过滤，洗涤，得到卡博特韦；
(4)将步骤(3)得到的卡博特韦与上述药学上可接受的辅料混合均匀；
(5)步骤(4)完成后，冷冻干燥。
根据本发明的实施方案，步骤(2)中，所述水温控制在0～100℃，优选0～60℃，比如15℃、25℃、50℃。
任选地，所述制备方法还包括在冷冻干燥前，根据实际情况，通过均质和微射流等方法，进一步调整粒径。
本发明还提供上述药物制剂的制备方法，包括将上述药物组合物混悬于分散溶剂中制备得到，优选将前述方法制备得到的冷冻干燥的药物组合物混悬于分散溶剂中。
术语定义与解释
术语“药学上可接受的盐”是指保留本主题化合物的所需生物活性且展现极小非所需毒理效应的盐。这些药学上可接受的盐可在化合物最终分离和纯化期间原位制备，或通过使纯化的化合物以其游离酸或游离碱形式分别与合适的碱或酸分开反应来制备。
药学上可接受的盐包括尤其Berge，J.Pharm.Sci.，1977，66，1-19中所描述的盐，或P H Stahl和C G Wermuth编辑，Handbook of Pharmaceutical Salts：Properties，Selection and Use，第二版，Stahl/Wermuth：Wiley-VCH/VHCA，2011(参见http：//www.wiley.com/WileyCDA/WileyTitle/productCd-3906390519.html)中所描述的盐。
适合的药学上可接受的盐可包括酸或碱加成盐。代表性药学上可接受的碱加成盐包括但不限于铝、2-氨基-2-(羟甲基)-1，3-丙二醇(TRIS，氨丁三醇)、精氨酸、苯明青霉素(benethamine)(N-苯甲基苯乙基胺)、苄星青霉素(benzathine)(N，N′-二苯甲基乙二胺)、双(2-羟乙基)胺、铋、钙、氯普鲁卡因(chloroprocaine)、胆碱、克立咪唑(clemizole)(1-对氯苯甲基-2-吡咯烷-1’-基甲基苯并咪唑)、环己胺、二苯甲基乙二胺、二乙胺、二乙基三胺、二甲胺、二甲基乙醇胺、多巴胺、乙醇胺、乙二胺、L-组氨酸、铁、异喹啉、勒皮啶(lepidine)、锂、赖氨酸、镁、葡甲胺(N-甲基葡糖胺)、哌嗪、哌啶、钾、普鲁卡因(procaine)、奎宁(quinine)、喹啉(quinoline)、钠、锶、叔丁胺和锌。
除非另有说明，否则在本说明书和权利要求书中使用的表示含量、浓度、比例、重量、体积、转速、压力、粒径、百分比、技术效果等的所有数字在任何情况下均应理解为由术语“约”或“大致”修饰。“约”代表其所修饰的数值的±10％的范围。
因此，除非有相反的指示，否则以下说明书和所附权利要求书中列出的数字参数是近似值。除非另有说明，此处使用的术语对所属技术领域的技术人员具有通常的理解含义。对于本领域技术人员来说，其可以根据通过本发明寻求得到的期望性质和效果而变化，应根据有效数字位数和常规舍入方法或者本领域技术人员理解的方式来解释每个数值参数。
尽管阐述了本发明的广泛范围的数值范围和参数是近似值，但是尽可能精确地提供了在具体实施例中阐述的数值。然而，任何数值都会固有地包含某些误差，这些误差由于在其相应的测试测量中发现的标准偏差而必然地导致的。本说明书给出的每个数值范围将包括落入该较宽数值范围内的每个较窄数值范围，就如同这些较窄数值范围均在本文中明确写出一样。
与粒径相关的术语“稳定”是指：D10在约0.5μm至约10μm的范围内，D50在约2μm至约25μm的范围内，D90粒径在约5μm至约50μm的范围内；且D50变化幅度小于约2μm，D90变化幅度小于约5μm。当卡博特韦混悬注射液的粒径稳定时，既能够实现长时间缓释的效果，又使得血药浓度稳定，并且便于临床给药。
与粒径相关的术语“特别稳定”是指：D10在约0.5μm至约10μm的范围内，D50在约2μm至约25μm的范围内，D90在约5μm至约50μm的范围内；且D10、D50、D90变化幅度均小于1μm。当卡博特韦粉末制剂复溶后获得的混悬注射液的粒径特别稳定时，能够进一步实现长时间缓释、血药浓度稳定、便于临床给药。
术语“中值粒径D50”或“D50”是指颗粒累积分布为50％的粒径，即小于此粒径的颗粒体积含量占全部颗粒的50％。
术语“D10”是指颗粒累积分布为10％的粒径，即小于此粒径的颗粒体积含量占全部颗粒的10％。
术语“D90”是指颗粒累积分布为90％的粒径，即小于此粒径的颗粒体积含量占全部颗粒的90％。
术语“至少一种”指为两种、三种或更多种。
术语“几种”指两种、三种或更多种。
有益效果
本公开提供的药物组合物涉及此类药物组合物在HIV感染的治疗和预防中的用途，稳定性好，适合工业化生产。
本发明提供了一种可注射的卡博特韦的药物组合物/冻干制剂，常温即可存储且存储期长；将冻干粉末制剂复溶后，所得到的卡博特韦混悬注射液的粒径始终保持稳定，甚至达到 特别稳定的程度。
本发明还提供制备卡博特韦注射剂的方法，相较于原研分散碾磨制备方法，生产工艺更为简单，生产原料和生产设备的价格相对较低，易于实现产量的扩大。
本发明还提供的卡博特韦混悬注射剂，相较于原研纳米混悬注射液，可维持更长时间的稳态浓度，因此可以降低给药频率。
附图说明
图1示出了不同处方卡博特韦混悬注射液(即冻干粉复溶后)的粒径分布；
图2示出了实施例10的肌肉注射给药途径的血浆浓度-时间曲线。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实施例中使用的卡博特韦购自上海迪赛诺有限公司、羧甲基纤维素钠购自亚什兰公司、聚山梨酯80购自南京威尔药业股份有限公司、甘露醇购自法国罗盖特公司、NMP购自罗恩试剂、DMA(N,N-二甲基乙酰胺)购自Finar Limited公司、DMSO购自默克股份两合公司、乙酸购自国药集团化学试剂有限公司。除非另有说明，否则各个步骤的反应温度为室温，压力为常压。各实施例中检测混悬液粒径使用的新帕泰克激光粒度仪，型号为HELOs，厂家为德国新帕泰克有限公司。
下述实施例中，除另有说明外，卡博特韦析晶水温均为常温。
实施例1：卡博特韦混悬注射剂(冻干粉)I及其制备
表1：卡博特韦混悬注射剂(冻干粉)I
制备方法：将卡博特韦用15倍重量的NMP溶解，溶解温度为60～70℃。在600rpm的搅拌条件下，10min内将药液均速加入10倍NMP体积的水中沉淀得到卡博特韦，过滤并加水洗涤沉淀，再与表1中各辅料及超纯水混合均匀，经冷冻干燥处理后得到卡博特韦混悬注射剂(冻干粉)I。加2ml注射用水复溶后检测粒径，为D10 2.00μm，D50 8.25μm，D90 18.99μm。
实施例2：卡博特韦混悬注射剂(冻干粉)II及其制备
表2：卡博特韦混悬注射剂(冻干粉)II
制备方法：将卡博特韦用15倍重量的DMSO溶解，溶解温度为60～70℃。在5000rpm的剪切条件下，10min内将药液加入10倍DMSO体积的水(冰水浴使析晶水温控制在15℃以下)中沉淀得到卡博特韦，过滤并加水洗涤沉淀，再与表2中各辅料及超纯水混合均匀，经冷冻干燥处理后得到卡博特韦混悬注射剂(冻干粉)II。加2ml注射用水复溶后检测粒径，为D10 1.43μm，D50 5.33μm，D90 12.89μm。
实施例3：卡博特韦混悬注射剂(冻干粉)III及其制备
表3：卡博特韦混悬注射剂(冻干粉)III
具体操作步骤同实施例2，经冷冻干燥处理后得到卡博特韦混悬注射剂(冻干粉)III。加2ml注射用水复溶后检测粒径，为D10 1.23μm，D50 4.13μm，D90 9.94μm。
实施例4：卡博特韦混悬注射剂(冻干粉)IV及其制备
表4：卡博特韦混悬注射剂(冻干粉)IV

注：单剂量卡博特韦钠折合成卡博特韦为400mg
制备方法：将卡博特韦钠用10倍重量的乙酸常温溶解，在5000rpm的剪切条件下，10min内将药液加入4倍乙酸体积的水中沉淀得到卡博特韦，过滤并加水洗涤沉淀，再与表4中各辅料及超纯水混合均匀，经冷冻干燥处理后得到卡博特韦混悬注射剂(冻干粉)IV。加2ml注射用水复溶后检测粒径，为D10 7.97μm，D50 22.32μm，D90 45.18μm。
实施例5：卡博特韦混悬注射剂(冻干粉)V及其制备
表5：卡博特韦混悬注射剂(冻干粉)V
注：单剂量卡博特韦钠折合成卡博特韦为400mg
制备方法：将卡博特韦用10倍重量的乙酸常温溶解，在5000rpm的剪切条件下，10min内将药液加入4倍乙酸体积的水中沉淀得到卡博特韦，过滤并加水洗涤沉淀，再与表5中各辅料及超纯水混合均匀。药液用均质机，以1900bar压力均质3次后，经冷冻干燥处理后得到卡博特韦混悬注射剂(冻干粉)V。加2ml注射用水复溶后检测粒径，为D10 1.20μm，D50 3.54μm，D90 9.01μm。
卡博特韦钠用乙酸溶解后生成卡博特韦，制备成卡博特韦混悬注射液。卡博特韦也可以用乙酸溶解后，采用相同工艺制备成卡博特韦混悬注射液。
此外，在冷冻干燥前，可以通过均质和微射流等方法，进一步调整本品粒径。
实施例6：卡博特韦混悬注射剂(冻干粉)VI及其制备
表6：卡博特韦混悬注射剂(冻干粉)VI

具体操作步骤同实施例2，经冷冻干燥处理后得到卡博特韦混悬注射剂(冻干粉)VI。加2ml注射用水复溶后检测粒径，为D10 2.00μm，D50 8.47μm，D90 35.18μm。
图1粒径分布结果表明，除表面活性剂为泊洛沙姆188的卡博特韦混悬注射剂(冻干粉)VI复溶后有明显双峰，其余处方粒径分布为单峰，因此优选选用HS15(15-羟基聚乙二醇硬脂酸酯)、吐温80作为本品的表面活性剂。
实施例7：处方稳定性考察
将各处方的混悬注射剂的冻干粉常温或高温下放置一段时间后复溶，检测粒径，结果见表7。将未经冻干处理的卡博特韦混悬液，常温放置7天后的粒径结果见表7。
表7各处方粒径稳定性数据
从表7中的数据可以看出，卡博特韦混悬注射剂(冻干粉)I～V在上述条件下均较为稳定，粒度分布与起始相比无明显变化。实施例1将未冻干处理的混悬液常温放置7天后，D10、D50、D90较冻干粉复溶的粒径明显增长，说明冻干处理复溶得到的混悬注射剂的粒径稳定性 显著优于未冻干处理的混悬液。
实施例8：卡博特韦混悬注射剂(冻干粉)VII及其制备
处方同实施例2，工艺步骤中析晶时药液温度大于50℃，其余步骤同实施例2。最终得到复溶后粒径为D10 9.01μm，D50 19.92μm，D90 43.16μm的样品，用于动物实验。
实施例9：卡博特韦纳米混悬注射液VIII及其制备
表8：卡博特韦纳米混悬注射液VIII
根据ViiV Healthcare公司的原研制剂Cabenuva公开的FDA审评文件中的处方，以及原研专利WO2012/037320权利要求优选的粒径为≤200nm，将处方量原辅料采用碾磨工艺制备卡博特韦纳米混悬注射液VIII，碾磨设备为RESEARCHLAB，陶瓷加速器，(TOSOH)ZrO2微珠，碾磨得到粒径分布为D10 60.6nm，D50 139nm，D90 489nm的样品，作为动物实验的对照制剂。
实施例10：大鼠药代动力学研究
肌肉(IM)注射给予SD大鼠(4只/组，2雄2雌)：卡博特韦混悬注射液V、混悬注射液VII和纳米混悬注射液VIII，剂量均为20mg/kg，给予一次。给药之后，使大鼠保持720h非治疗时间。图2显示了大鼠肌肉给予不同制剂后血浆中卡博特韦的平均浓度-时间曲线。
大鼠肌注给予卡博特韦混悬注射液VII后，血浆中卡博特韦的药时曲线较为平缓，峰浓度比对照制剂(即纳米混悬注射液VIII)低，给药后528小时起，维持的血药浓度高于对照制剂，因受限于采样时间点，截止最后一个时间点(720h)，其浓度仍处于较高水平。
大鼠肌注给予卡博特韦混悬注射液V后，血浆中卡博特韦浓度升高并在250小时左右达到与对照制剂相当的水平，随后血浆中卡博特韦浓度缓慢下降，维持的血药浓度高于对照制剂，截止最后一个时间点(720h)，其浓度仍处于较高的水平。
根据表9的PK实验结果，混悬注射液VII(D50约20μm)相较对照制剂(D50约150nm)，Cmax较低但可维持更长时间的稳态浓度，具有较好的缓释效果。而混悬注射液V(D50约3.5μm)可快速释放，达到与对照制剂相当的Cmax，血药浓度达到峰值后下降缓慢，具有较强的缓释作用。原研制剂需每月注射一次维持稳态浓度，本品可以降低给药频率，间隔更长时间给药 也能维持稳态。
表9大鼠肌肉注射给予混悬注射液V、混悬注射液VII和纳米混悬注射液VIII后血浆中卡博特韦的药代动力学参数
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种药物组合物，其中所述药物组合物包含活性成分和药学上可接受的辅料；
    所述活性成分包含卡博特韦或其药学上可接受的盐，所述辅料包含表面活性剂、助悬剂。
  2. 根据权利要求1所述的药物组合物，其中，所述药物组合物还包括冻干赋形剂。
  3. 根据权利要求1或2所述的药物组合物，其中，所述助悬剂为纤维素类助悬剂，例如选自羧甲基纤维素及其钠盐、羟丙基纤维素及其钠盐、羟丙甲纤维素及其钠盐、甲基纤维素及其钠盐、羟乙基纤维素及其钠盐、透明质酸钠和聚乙烯吡咯烷酮中的至少一种；
    和/或，所述表面活性剂选自聚山梨酯或其衍生物、以及聚乙二醇硬脂酸酯或其衍生物中的至少一种；例如，所述聚乙二醇硬脂酸酯或其衍生物选自15-羟基聚乙二醇硬脂酸酯，所述聚山梨酯或其衍生物选自聚山梨酯80；
    和/或，所述冻干赋形剂选自甘露醇、海藻糖和葡萄糖中的至少一种；
    优选地，所述辅料还含有等渗调节剂。
  4. 根据权利要求1-3任一项所述的药物组合物，其中，所述表面活性剂与卡博特韦或其药学上可接受的盐的重量比选自1:(0.01～100)；
    和/或，所述助悬剂与卡博特韦或其药学上可接受的盐的重量比选自1:(0.01～100)；
    和/或，所述冻干赋形剂与卡博特韦或其药学上可接受的盐的重量比选自1:(0.01～100)。
  5. 根据权利要求1-4任一项所述的药物组合物，其中，所述药物组合物为粉末，优选为可注射的粉末，还优选为可注射的冻干粉末；
    优选地，所述药物组合物还包含第二种治疗剂，所述第二种治疗剂选自HIV抑制剂。
  6. 权利要求1-5任一项所述药物组合物的制备方法，其中，所述制备方法包括如下步骤：卡博特韦或其药学上可接受的盐的有机溶液与水混合，过滤、洗涤，得到的沉淀物与辅料混合，冷冻干燥。
  7. 一种药物制剂，其中，所述药物制剂包括权利要求1-5任一项所述药物组合物。
    优选地，所述药物制剂包括所述药物组合物和分散溶剂。
    优选地，所述药物制剂为将所述药物组合物混悬于分散溶剂中制备得到，优选为可注射的冻干粉末混悬于分散溶剂中制备得到。
    优选地，所述分散溶剂为水。
    优选地，所述卡博特韦或其药学上可接受的盐的浓度选自0.01～800mg/mL。
  8. 根据权利要求7所述的药物制剂，其中，所述药物制剂中药物组合物在分散溶剂中的粒 子的粒径分布如下：D10在约0.5μm至约10μm的范围内，D50在约2μm至约25μm的范围内，D90粒径在约5μm至约50μm的范围内。
  9. 根据权利要求8所述的药物制剂，其中，所述药物制剂为注射剂，例如为混悬注射液。
    优选地，所述药物制剂用于预防和/或治疗由人类免疫缺陷病毒感染引起的疾病。
  10. 权利要求7-9任一项所述药物制剂的制备方法，其中所述制备方法包括将权利要求1-5任一项所述药物组合物混悬于分散溶剂中制备得到。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103547266A (zh) * 2010-09-16 2014-01-29 Viiv保健公司 药物组合物
WO2016046786A1 (en) * 2014-09-26 2016-03-31 Glaxosmithkline Intellectual Property (No.2) Limited Long acting pharmaceutical compositions
WO2022079739A1 (en) * 2020-10-14 2022-04-21 Cipla Limited Fixed dose compositions of cabotegravir and rilpivirine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103547266A (zh) * 2010-09-16 2014-01-29 Viiv保健公司 药物组合物
WO2016046786A1 (en) * 2014-09-26 2016-03-31 Glaxosmithkline Intellectual Property (No.2) Limited Long acting pharmaceutical compositions
WO2022079739A1 (en) * 2020-10-14 2022-04-21 Cipla Limited Fixed dose compositions of cabotegravir and rilpivirine

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