WO2021109823A1 - 一种大麻素纳米胶束制剂及其制备方法 - Google Patents

一种大麻素纳米胶束制剂及其制备方法 Download PDF

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Publication number
WO2021109823A1
WO2021109823A1 PCT/CN2020/128307 CN2020128307W WO2021109823A1 WO 2021109823 A1 WO2021109823 A1 WO 2021109823A1 CN 2020128307 W CN2020128307 W CN 2020128307W WO 2021109823 A1 WO2021109823 A1 WO 2021109823A1
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Prior art keywords
cannabinoid
nanomicelle
preparation
polyethylene glycol
drying
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PCT/CN2020/128307
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English (en)
French (fr)
Inventor
谭昕
王曙宾
范德凯
孙武兴
邢俊波
张旭然
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汉义生物科技（北京）有限公司
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Application filed by 汉义生物科技（北京）有限公司 filed Critical 汉义生物科技（北京）有限公司
Priority to EP20896688.7A priority Critical patent/EP4056177B1/en
Priority to MX2022006524A priority patent/MX2022006524A/es
Priority to JP2022530142A priority patent/JP7421027B2/ja
Priority to US17/781,529 priority patent/US20230000770A1/en
Priority to CA3160732A priority patent/CA3160732A1/en
Priority to AU2020394709A priority patent/AU2020394709A1/en
Publication of WO2021109823A1 publication Critical patent/WO2021109823A1/zh
Priority to ZA2022/05648A priority patent/ZA202205648B/en

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    • 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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
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Definitions

  • the invention relates to the technical field of pharmaceutical preparations, in particular to a cannabinoid nano-micelle preparation and a preparation method thereof, in particular to a cannabinoid nano-micelle solid preparation and a preparation method thereof.
  • Polymer micelles are core-shell nanoparticles formed by self-assembly of block copolymers in aqueous solutions.
  • Hydrophobic drugs can be embedded in the hydrophobic core, and the shell composed of hydrophilic segments forms a hydration layer barrier to provide micelle stability. Its amphiphilicity is achieved by the hydrophilic block and the hydrophobic block.
  • the hydrophilic block includes polyethylene glycol (PEG), polyoxyethylene (PEO), and polyvinylpyrrolidone (PVP); the hydrophobic block includes polypropylene, polyamino acid, and polylactic acid.
  • Polymer micelles are divided into amphiphilic block copolymers, triblock copolymers, crosslinked copolymers and graft copolymers.
  • Polymer micelle solutions are mostly transparent solutions of 10-100 nanometers, and solutions larger than 100 nanometers are opaque and are milky or suspended.
  • drug-loaded particles or drug nanocrystals with a size of 1-1000 nm are called nano-drugs.
  • Polymer nanomicelles have several unique advantages: 1. High drug loading, which greatly improves the solubility of insoluble raw materials in water; 2. The chemical structure of the raw materials can be solubilized without modification; 3. It can realize drug slowing down. Release and controlled release to ensure stable blood drug concentration in the body for a long time; 4. Promote oral absorption of the drug; 5. Targeting effect, smaller particle size is conducive to penetration into tumors with poor permeability; 6. Lower CMC (Critical Micelle Concentration) can help maintain the micellar structure when diluted by blood.
  • CMC Chronic Micelle Concentration
  • Nanomicelle preparations are generally liquid oral preparations, especially in the field of cannabinoid and monomer preparations, there is almost no solid form preparation.
  • patent WO2019008178A1 describes a cannabinoid micellar liquid preparation.
  • Cannabinoids are fat-soluble substances and are almost insoluble in water, which greatly restricts their development in the field of preparations. Cannabis preparations are mostly oil solutions, which are inconvenient to take, have poor stability, and have low absorption bioavailability.
  • the aqueous solution of cannabinoids contains nanoemulsions, nanocapsules, nanospheres, cyclodextrin inclusions, etc., and the drug loading is generally low, about 0-3%, the stability of the aqueous solution is poor, and the stability of the gastric juice is poor.
  • the present invention provides a cannabinoid nanomicelle preparation and a preparation method thereof.
  • the above-mentioned cannabinoid nanomicelle preparation comprises: cannabinoids, amphiphilic polymers, and optionally, a pharmaceutically acceptable freeze-dried protective agent and pH adjuster, which are prepared by a method including the following steps:
  • step (3) The cannabinoid nanomicelle powder obtained in step (2) is prepared into a cannabinoid nanomicelle preparation.
  • the weight percentage content of cannabinoids is 1-40% (specifically, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%). , 40%).
  • the content of amphiphilic polymer is 1-99% (specifically, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35 %, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%).
  • the above-mentioned cannabinoids are selected from one or a combination of two or more of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND pure products, which may be plant extracts Cannabinoids or synthetic cannabinoids, preferably plant-derived cannabinoids.
  • the above-mentioned cannabinoid is a cannabis extract, which comprises one or a combination of two or more of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND.
  • the above-mentioned cannabinoid is CBD.
  • the above-mentioned amphiphilic polymer is vitamin E succinate polyethylene glycol ester (TPGS).
  • the aforementioned TPGS is selected from one or more of TPGS200, 238, 400, 600, 1000, 2000, 3400, 3500, 4000, 6000; in an embodiment of the present invention, the aforementioned TPGS is TPGS1000.
  • the above-mentioned amphiphilic polymer is amphiphilic polyurethane.
  • the above-mentioned amphiphilic polyurethane is an alternating copolymer, which is obtained by alternating copolymerization of hydrophilic segments with diisocyanates, etc., wherein the hydrophilic segments can be polyethylene glycol, polyoxyethylene, etc., and the diisocyanate is Aliphatic or cycloaliphatic diisocyanates, such as hexamethylene diisocyanate, trimethyl-1,6-hexamethylene diisocyanate, isophorone diisocyanate, cyclohexane dimethylene diisocyanate, 4,4-Dicyclohexylmethane diisocyanate, 1,4-cyclohexane diisocyanate, etc.
  • the hydrophilic segments can be polyethylene glycol, polyoxyethylene, etc.
  • the diisocyanate is Aliphatic or cycloaliphatic diisocyanates, such as hexamethylene diisocyanate, trimethyl-1,6-hexamethylene
  • the number average molecular weight of the above-mentioned amphiphilic polyurethane is 1000-50000 (specifically, 1000, 2000, 3000, 4000, 5000, 6000, 8000, 10000, 12000, 14000, 16000, 18000, 20000, 22000, 24000, 26000, 28000, 30000, 32000, 34000, 36000, 38000, 40000, 42000, 44000, 46000, 48000, 50000).
  • the hydrophilic segment in the above-mentioned amphiphilic polyurethane is polyethylene glycol
  • the number average molecular weight of the polyethylene glycol segment may be 200-12000 (specifically, 200, 200, 200). 400, 500, 600, 750, 1000, 2000, 4000, 5000, 6000, 8000, 10000, 12000), in one embodiment of the present invention, the number average molecular weight of the polyethylene glycol segment may be 600-6000, In an embodiment of the present invention, the number average molecular weight of the polyethylene glycol segment is 1,000 or 1,500.
  • the above-mentioned amphiphilic polymer is an amphiphilic polymer block copolymer, which is a block polymer composed of two or more polymers, and its hydrophilic part may be polyethylene glycol.
  • amphiphilic polymer block copolymer which is a block polymer composed of two or more polymers, and its hydrophilic part may be polyethylene glycol.
  • the above-mentioned poloxamer is selected from: one or a combination of two or more of poloxamers 188, 338, 407, 124, 215, 237, etc.; in an embodiment of the present invention, the above-mentioned poloxamer Sham is poloxamer 188 or poloxamer 338.
  • the number average molecular weight of the polyethylene glycol part may be 200-12000 (specifically, 200, 400, 500, 600, 750, 1000). , 2000, 4000, 5000, 6000, 8000, 10000, 12000). In one embodiment of the present invention, the number average molecular weight of the polyethylene glycol part may be 1000-6000.
  • the number average molecular weight of polycaprolactone block copolymer, polyethylene glycol-polylactic acid block copolymer, and polyethylene glycol-polystyrene block copolymer is 500-50000 (specifically, 500, 1000, 2000 , 3000, 4000, 5000, 6000, 8000, 10000, 12000, 14000, 16000, 18000, 20000, 22000, 24000, 26000, 28000, 30000, 32000, 34000, 36000, 38000, 40000, 42000, 44000, 46000, 48000 , 50000); wherein the polyethylene glycol is polyethylene glycol monomethyl ether, and the number average molecular weight of the polyethylene glycol part can be 200-12000 (specifically, 200
  • the above-mentioned cannabinoid nanomicelle preparation further comprises a pharmaceutically acceptable freeze-dried protective agent.
  • the content of the freeze-dried protective agent is 1-10% (specifically, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%).
  • freeze-dried protective agent is selected from one of lactose, mannitol, sorbitol, cyclodextrin, hydroxypropyl ⁇ cyclodextrin, EDTA-2Na, trehalose, glucose, xylitol, and maltose or Multiple
  • the above-mentioned cannabinoid nanomicelle preparation further comprises a pH adjusting agent.
  • the content of the pH adjusting agent is 0.01-10% (specifically, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%). %, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%).
  • the aforementioned pH adjusting agent is selected from: one of citric acid, sodium citrate, tartaric acid, sodium tartrate, acetic acid, sodium acetate, sodium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid, lactic acid, and sodium hydroxide Or multiple.
  • the above step (1) includes the following steps:
  • step (1-1) Cut the mixture obtained in step (1-1) with a high-speed shearing dispersing emulsifier to obtain an emulsion;
  • step (1-3) Stir the emulsion obtained in step (1-2) to obtain a clear and transparent nanomicelle solution.
  • the solvent in step (1-1) is water, such as water for injection.
  • the amount of solvent in step (1-1) is 2-10 times (mass ratio, specifically, 2, 3, 4, 5, 6, 7, 8, 9, 10 times) of the raw material components.
  • the swelling time in step (1-1) is 0.1-2 hours (specifically, 0.1, 0.5, 1, 1.5, 2 hours).
  • the shearing time in step (1-2) is 1-30 minutes (specifically, 1, 5, 10, 15, 20, 25, 30 minutes).
  • the stirring temperature is 15-35°C (specifically, 15, 20, 25, 30, 35°C), and the stirring time is 1-48 hours (specifically, such as 1, 6, 12, 24, 36, 48 hours).
  • the particle size of the cannabinoid nanomicelle solution is 1-500 nm (specifically, 1, 10, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500 nm).
  • the solvent used for the dilution in step (2) is water, especially water for injection.
  • the dilution factor in step (2) is 2-100 times (specifically, 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 times).
  • the drying in step (2) is atomized freeze drying or freeze drying.
  • the above atomized freeze-drying includes: atomization, freezing and drying steps; wherein the atomization method is selected from: one or more of pneumatic atomization, pressure atomization, centrifugal atomization, and ultrasonic atomization
  • the freezing temperature is -10 ⁇ -50°C (specifically, -10, -15, -20, -25, -30, -35, -40, -45, -50°C); the degree of vacuum in the drying step It is 40 Pa or less (specifically 40, 30, 20, 10 Pa), and the drying temperature is 10-35°C (specifically, 10, 15, 20, 25, 30, 35°C).
  • the above freeze-drying includes: pre-freezing, sublimation drying and analytical drying steps; wherein the pre-freezing temperature is -30 to -50°C (specifically, -30, -35, -40, -45, -50°C),
  • the pre-freezing time is 0.5-3h (for example, 0.5, 1, 2, 3h), and the vacuum degree in the pre-freezing step is controlled to 1-100Pa (1, 10, 20, 30, 40, 50, 60, 80, 100Pa);
  • Sublimation drying temperature is -20 ⁇ 10°C (specifically -20, -10, -5, 0, 5, 10°C)
  • sublimation drying time is 1-36h (specifically 1, 6, 12, 18, 24, 30 , 36h);
  • the analytical drying temperature is 10°C-30°C (specifically 10, 15, 20, 25, 30°C), and the analytical drying time is 1-24h (specifically 1, 6, 12, 18, 24h).
  • the cannabinoid nanomicelle preparation is a solid preparation or a semi-solid preparation.
  • the above-mentioned cannabinoid nanomicelle preparations are oral preparations, such as effervescent tablets, sustained-release tablets, fast-disintegrating tablets, dripping pills and the like.
  • the above-mentioned cannabinoid nanomicelle preparations are mucosal administration preparations, such as suppositories.
  • the cannabinoid nanomicelle preparation is an inhalation preparation, such as a dry powder inhalation.
  • the above-mentioned cannabinoid nanomicelle preparation is a transdermal administration preparation, such as a gel patch and the like.
  • the above-mentioned cannabinoid nanomicelle preparation is an inhalant with a particle size of 1-5 ⁇ m (specifically, 1, 2, 3, 4, 5 ⁇ m), wherein the drying in the above step (2) Freeze drying for atomization.
  • the above-mentioned cannabinoid nanomicelle preparation is an effervescent tablet, a sustained-release tablet, a quick-disintegrating tablet, a dripping pill, a suppository or a gel patch, wherein the drying in the above step (2) is Freeze dry.
  • the preparation method of the cannabinoid nanomicelle preparation provided by the present invention includes the following steps:
  • step (3) The cannabinoid nanomicelle powder obtained in step (2) is prepared into a cannabinoid nanomicelle preparation.
  • the above step (1) includes the following steps:
  • step (1-1) Cut the mixture obtained in step (1-1) with a high-speed shearing dispersing emulsifier to obtain an emulsion;
  • step (1-3) Stir the emulsion obtained in step (1-2) to obtain a clear and transparent nanomicelle solution.
  • the solvent in step (1-1) is water, such as water for injection.
  • the amount of solvent in step (1-1) is 2-10 times (mass ratio, specifically, 2, 3, 4, 5, 6, 7, 8, 9, 10 times) of the raw material components.
  • the swelling time in step (1-1) is 0.1-2 hours (specifically, 0.1, 0.5, 1, 1.5, 2 hours).
  • the shearing time in step (1-2) is 1-30 minutes (specifically, 1, 5, 10, 15, 20, 25, 30 minutes).
  • the stirring temperature is 15-35°C (specifically, 15, 20, 25, 30, 35°C), and the stirring time is 1-48 hours (specifically, such as 1, 6, 12, 24, 36, 48 hours).
  • the particle size of the cannabinoid nanomicelle solution is 1-500 nm (specifically, 1, 10, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500 nm).
  • the solvent used for the dilution in step (2) is water, especially water for injection.
  • the dilution factor in step (2) is 2-100 times (specifically, 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 times).
  • the drying in step (2) is atomized freeze drying or freeze drying.
  • the above atomized freeze-drying includes: atomization, freezing and drying steps; wherein the atomization method is selected from: one or more of pneumatic atomization, pressure atomization, centrifugal atomization, and ultrasonic atomization
  • the freezing temperature is -10 ⁇ -50°C (specifically, -10, -15, -20, -25, -30, -35, -40, -45, -50°C); the degree of vacuum in the drying step It is 40 Pa or less (specifically 40, 30, 20, 10 Pa), and the drying temperature is 10-35°C (specifically, 10, 15, 20, 25, 30, 35°C).
  • the above freeze-drying includes: pre-freezing, sublimation drying and analytical drying steps; wherein the pre-freezing temperature is -30 to -50°C (specifically, -30, -35, -40, -45, -50°C),
  • the pre-freezing time is 0.5-3h (for example, 0.5, 1, 2, 3h), and the vacuum degree in the pre-freezing step is controlled to 1-100Pa (1, 10, 20, 30, 40, 50, 60, 80, 100Pa);
  • Sublimation drying temperature is -20 ⁇ 10°C (specifically -20, -10, -5, 0, 5, 10°C), sublimation drying time is 1-36h (specifically 1, 6, 12, 18, 24, 30 , 36h);
  • the analytical drying temperature is 10°C-30°C (specifically 10, 15, 20, 25, 30°C), and the analytical drying time is 1-24h (specifically 1, 6, 12, 18, 24h).
  • the present invention also provides a method for preventing and/or treating diseases, which includes the step of administering an effective amount of the cannabinoid nanomicelle preparation of the present invention to a subject in need thereof.
  • the cannabinoid nanomicelle preparation has the above definition of the present invention.
  • the disease is the indication of the corresponding cannabinoid in the cannabinoid nanomicelle preparation, such as pain (such as chronic pain), inflammation (such as dermatitis), tumor (such as glioma, leukemia, Prostate cancer, etc.), liver damage (such as ischemic liver damage, liver damage caused by chronic alcoholism), neurological diseases (such as epilepsy, multiple sclerosis, Parkinson's disease, Alzheimer's disease, etc.), etc. ( See, for example, "Guo Rong, Chen Xuan, Guo Hongyan. Advances in pharmacological research of THC and Cannabidiol. Research and Development of Natural Products, 2017, 29: 449-1453.”).
  • pain such as chronic pain
  • inflammation such as dermatitis
  • tumor such as glioma, leukemia, Prostate cancer, etc.
  • liver damage such as ischemic liver damage, liver damage caused by chronic alcoholism
  • neurological diseases such as epilepsy, multiple sclerosis, Parkinson's disease, Alzheimer's disease
  • the above-mentioned subject is a mammal, especially a human.
  • the effective amount of the above-mentioned cannabinoid nanomicelle preparation depends on many factors, including the patient’s age, weight, gender, natural health status, nutritional status, time of administration, metabolic rate, severity of the disease, and the subjective judgment of the physician ,Wait.
  • the present invention also provides a health product comprising the cannabinoid nanomicelle preparation of the present invention.
  • the present invention also provides a method for improving immunity and anti-oxidation, which includes the step of administering an effective amount of the above-mentioned health products to subjects in need thereof.
  • the cannabinoid nanomicelle preparation provided by the present invention has high active ingredient encapsulation rate and transfer rate, high drug loading capacity, and strong stability.
  • the new normal temperature self-assembly technology is adopted to prevent the active ingredient cannabinoid from degrading and discoloring at high temperature;
  • the ingredients have high bioavailability and can reduce the single dose.
  • dry powder inhalants with high drug loading (above 10%), strong stability (shelf life: 2-3 years), and high deposition rate in vitro (emptying rate up to 95%, effective deposition rate up to 45%), Inhalation takes effect quickly and can provide continuous and stable blood concentration.
  • CBDV Sub-Cannabidiol
  • CBDB 4-butyl-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-(1,1′-biphenyl)-2, 6-diol, Cannabidibutol
  • cannabinoid refers to a class of secondary metabolites that contain alkyl and monoterpene group molecular structures unique to cannabis plants, for example, CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL, CBND, etc. (as described in “Chen Xuan, Yang Ming, Guo Hongyan. Research progress in cannabinoids in cannabis plants, Acta Phytoplasma Sinica, 2011, 46(2):197-205").
  • the pure products of CBD, CBDV, CBG, CBC, CBN, CBDB, CBE, CBL and CBND refer to the pure products of the above-mentioned compounds, especially the corresponding commercial products, wherein the purity of the compound is at least 99.5% or more , Especially 99.9% or more (the rest are impurities).
  • the cannabinoid micellar solution was prepared by feeding the materials according to the formula 1-6, as follows:
  • Emulsification Use a high-speed shearing dispersing emulsifier 50HZ for the mixture obtained after swelling, shearing for 30min;
  • the cannabinoid micellar solution was prepared by feeding the materials according to the formula 1-6, as follows:
  • Dissolution According to the formula 1-6 in Table 1, add mannitol, sorbitol, citric acid, tartaric acid, cyclodextrin, hydroxypropyl ⁇ cyclodextrin, EDTA-2Na, trehalose, leucine, Lactose is dissolved in 8 times water to make liquid 2;
  • the cannabinoid nanomicelles prepared by the first group of processes have a higher transfer rate than the cannabinoid nanomicelles prepared by the second group of processes, which may be due to the second group of processes.
  • a melting step is used to degrade the cannabinoids.
  • micellar powder The drying methods for preparing micellar powder include vacuum drying, atomized freeze drying, nano spray drying, supercritical fluid technology, and freeze drying.
  • the formula 1 prepared by the first set of processes in Example 1 is prepared by the above-mentioned drying techniques. Cannabinoid nanomicelle powder and quality comparison research, the specific drying method comparison is shown in Table 4.
  • Atomized freeze-drying Spray the cannabinoid nanomicelle solution into the atomized freeze dryer to produce cannabinoid micelle powder.
  • the specific process is as follows:
  • the nanomicelle solution prepared by "Process 1" in Example 1 was diluted to 100 times with purified water, and then atomized and freeze-dried with an atomization freeze dryer, and the atomization device was ultrasonic atomization.
  • Solid content 40% for pneumatic atomization, pressure test atomization, centrifugal atomization, and 10% for ultrasonic atomization;
  • Feed flow rate 10ml/min
  • Freezing temperature -45°C
  • Freeze-drying process put the cannabinoid nanomicelle solution into a freeze-drying box, freeze at -40°C for 3h, control the vacuum to be less than 10Pa, dry at -10°C for the first time, dry for 24h; dry at 25°C for the second time, dry for 12h; After drying, the material is sized through No. 1-5 sieve.
  • Example 2 the particle size of the powder obtained by atomization and freeze-drying is 1-5 ⁇ m, the surface morphology is spherical, the fluidity is better, the emptying rate is 95%, and the deposition rate is 45%. It is suitable for inhalation powder. Packed into No. 2 to No. 00 capsules, vesicles, storage, or can be directly inhaled with powder for administration.
  • cannabinoid micelle powder (the powder obtained by freeze-drying process in Example 2), DL tartaric acid, citric acid, sodium bicarbonate, mannitol, lactose, aspartame, xylitol, polyethylene Glycol.
  • the specific formula table is shown in the following table.
  • the weight of the film is 2g.
  • the cannabinoid micelle powder, DL tartaric acid, citric acid, mannitol, and polyethylene glycol are granulated into granules 1 by fluidized bed or wet granulation; sodium bicarbonate, aspartame, lactose , Xylitol, polyethylene glycol fluidized bed or wet granulation to make granules 2; mix granules 1, granules 2, and cannabinoid micelle powders and press them into effervescent tablets, the tablet weight is controlled at 2g.
  • Disintegration time/min Dispersion uniformity Solution state after effervescence Content stability 1 2 qualified Clear and transparent Tablet accelerated for 6 months and stable content 2 3 qualified Clear and transparent Tablet accelerated for 6 months and stable content 3 5 qualified Clear and transparent Tablet accelerated for 6 months and stable content
  • the above-mentioned effervescent tablets meet the quality standards of effervescent tablets, dissolve water quickly, are convenient to use and carry, and can increase the dissolution rate of cannabinoid powder.
  • the effervescent solution is a cannabinoid nanomicelle solution. Can be taken directly.
  • cannabinoid micelle powder (powder obtained by freeze-drying process in Example 2), hypromellose, polyvinylpyrrolidone, ethyl cellulose, lactose, micronized silica gel, and magnesium stearate.
  • the specific formula table is shown in the following table.
  • the properties, weight difference, hardness, in vitro dissolution, and stability of the sustained-release tablets of the above formula meet the requirements, and can slowly release cannabinoids in the intestine. After entering the blood, the cannabinoid nanomicelles will also slowly release cannabinoids.
  • the effect of double sustained release enables cannabinoids to maintain a stable blood concentration in the body for a long time, and has a lasting effect on chronic pain.
  • cannabinoid micelle powder powder obtained through the freeze-drying process in Example 2
  • L-HPC lactose
  • microcrystalline cellulose pre-crossed starch
  • micronized silica gel micronized silica gel
  • magnesium stearate magnesium stearate
  • the above materials are made into granules by wet method or one-step granulation, and compressed into 0.5g fast disintegrating tablets.
  • the properties, difference in tablet weight, disintegration time limit, difference in tablet weight, and stability of the three formulations meet the requirements. After oral administration, they can quickly disintegrate in the mouth and absorb into the blood under the tongue to avoid first-pass effects and facilitate It is taken by patients who have difficulty swallowing.
  • cannabinoid micelle powder (powder obtained by freeze-drying process in Example 2), carbomer, glycerin, propylene glycol, triethanolamine, EDTA-2Na, and ethyl paraben.
  • carbomer obtained by freeze-drying process in Example 2
  • glycerin glycerin
  • propylene glycol propylene glycol
  • triethanolamine EDTA-2Na
  • ethyl paraben ethyl paraben
  • the gel properties, uniformity, and stability of the three formulas meet the requirements.
  • Direct application to the affected area can treat dermatitis, chronic joint pain, and remove acne and spots.
  • cannabinoid micelle powder (powder obtained by freeze-drying process in Example 2), polyethylene glycol 4000, polyethylene glycol 6000. The specific formula is shown in the table below.
  • Preparation process According to the formula in Table 14, the cannabinoid micelle powder, polyethylene glycol 4000, polyethylene glycol 6000, and purified water are heated and melted at 70°C to prepare slurry 1, and the paraffin oil condensation temperature is controlled to 10 °C, put the slurry 1 into the dropping pill machine, drop it into a drop of 50mg/pill, and remove the paraffin oil from the surface of the drop pill with oil-absorbing cotton.
  • the properties, differences in pill weight, disintegration time limit, and stability of the three formulations of dripping pills meet the requirements. They can be taken orally or sublingually, with quick onset and long-lasting blood concentration.
  • cannabinoid micelle powder (the powder obtained by freeze-drying process in Example 2), cocoa butter, mixed fatty acid glycerides, and polyethylene glycol ethyl paraben.
  • the specific formula is shown in the table below.
  • the properties, weight difference, melting time limit, and stability of the three formula suppositories all meet the requirements. They can directly reach the lesion to play an anti-inflammatory effect, or be used for systemic administration to treat chronic pain, which expands the application range of cannabinoids.

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Abstract

本发明公开了一种大麻素纳米胶束制剂及其制备方法。该大麻素纳米胶束制剂包含：大麻素、两亲性高分子；其中大麻素的重量百分比含量为1-40％，两亲性高分子的含量为1-99％，制备方法包括：(1)将大麻素和两亲性高分子制备大麻素纳米胶束溶液；(2)将步骤(1)所得胶束溶液干燥得到大麻素纳米胶束粉末；(3)将步骤(2)所得大麻素纳米胶束粉末制备成大麻素纳米胶束制剂。该大麻素纳米胶束制剂，有效成分包裹率和转移率高，载药量高，稳定性强，采用新的常温自组装技术，避免活性成分大麻素在高温下降解变色；活性成分的生物利用度高，可降低单次服用量。特别是干粉吸入剂，体外沉积率高，吸入起效快，可提供持续稳定的血药浓度。

Description

一种大麻素纳米胶束制剂及其制备方法 技术领域
本发明涉及药物制剂技术领域，具体涉及一种大麻素纳米胶束制剂及其制备方法，特别是一种大麻素纳米胶束固体制剂及其制备方法。
背景技术
聚合物胶束是一种嵌段共聚物在水溶液中自组装形成的核壳类型的纳米颗粒。疏水性药物可以被包埋在疏水核心，亲水性链段组成的外壳形成水化层屏障来提供胶束稳定性。其两亲性是由亲水性嵌段和疏水性嵌段实现的。亲水性嵌段包括聚乙二醇(PEG)、聚氧乙烯(PEO)以及聚乙烯吡咯烷酮(PVP)；疏水嵌段包括聚丙烯、聚氨基酸以及聚乳酸等。聚合物胶束分为两亲性嵌段共聚物，三嵌段共聚物，交联共聚物以及接枝共聚物。聚合物胶束溶液大多为10-100纳米的透明溶液，大于100纳米溶液不透明，为乳状或混悬状。在药剂学领域，将尺寸在1-1000nm的载药粒子或药物纳米晶体称为纳米药物。
聚合物纳米胶束载药拥有几个独特优势：1、载药量高，大幅提高难溶性原料在水中溶解度；2、原料的化学结构不需要进行改动即可增溶；3、能实现药物缓释、控释，体内长时间保证稳定血药浓度；4、促进药物的口服吸收；5、靶向作用，较小的粒径有利于渗透进入可渗透性较差的肿瘤；6、较低的CMC(临界胶束浓度)可以有利于在被血液稀释的情况下保持胶束结构。
纳米胶束制剂一般为液体口服制剂，尤其在大麻素及单体制剂领域几乎无固态形式制剂，如专利WO2019008178A1，描述了一种大麻素胶束液体制剂。
大麻素为脂溶性物质，几乎不溶于水，极大制约了其在制剂领域的发展。大麻制剂多为油溶液，服用不方便，稳定性差，吸收生物利用度低。大麻素的水溶液制剂含纳米乳、纳米囊、纳米微球、环糊精包合等，载药量普遍偏低，约为0-3％左右，水液的稳定性差，胃液稳定性差。
发明内容
为克服现有技术的不足，本发明提供一种大麻素纳米胶束制剂及其制备方法。
具体地，上述大麻素纳米胶束制剂包含：大麻素、两亲性高分子，以及任选地，药学上可接受的冻干保护剂、pH调节剂，其通过包括如下步骤的方法制备：
(1)将大麻素和两亲性高分子制备大麻素纳米胶束溶液；
(2)将步骤(1)所得胶束溶液稀释、干燥得到大麻素纳米胶束粉末；
(3)将步骤(2)所得大麻素纳米胶束粉末制备成大麻素纳米胶束制剂。
具体地，上述大麻素纳米胶束制剂中，大麻素的重量百分比含量为1-40％(具体如，1％、5％、10％、15％、20％、25％、30％、35％、40％)。
具体地，上述大麻素纳米胶束制剂中，两亲性高分子的含量为1-99％(具体如，1％、5％、10％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％、80％、85％、90％、95％、99％)。
在本发明的一个实施方式中，上述大麻素选自：CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL和CBND纯品中的一种或两种以上的组合，其可为植物提取类大麻素或合成类大麻素，优选为植物提取类大麻素。
在本发明的另一个实施方式中，上述大麻素为大麻提取物，其包含CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL和CBND中的一种或两种以上的组合。
在本发明的一个实施例中，上述大麻素为CBD。
在本发明的一个实施方式中，上述两亲性高分子为维生素E琥珀酸聚乙二醇酯(TPGS)。
具体地，上述TPGS选自：TPGS200、238、400、600、1000、2000、3400、3500、4000、6000中的一种或多种；在本发明的一个实施例中，上述TPGS为TPGS1000。
在本发明的一个实施方式中，上述两亲性高分子为两亲性聚氨酯。
具体地，上述两亲性聚氨酯为交替共聚物，其由亲水性链段与二异氰酸酯等交替共聚得到，其中，亲水性链段可为聚乙二醇、聚氧乙烯等，二异氰酸酯为脂肪族或脂环族二异氰酸酯，具体如六亚甲基二异氰酸酯、三甲基-1,6-六亚甲基二异氰酸酯、异佛尔酮二异氰酸酯、环己烷二亚甲基二异氰酸酯、4,4-二环己基甲烷二异氰酸酯、1,4-环己烷二异氰酸酯等。
具体地，上述两亲性聚氨酯的数均分子量为1000-50000(具体如，1000、2000、3000、4000、5000、6000、8000、10000、12000、14000、16000、18000、20000、22000、24000、26000、28000、30000、32000、34000、36000、38000、40000、42000、44000、46000、48000、50000)。
在本发明的一个实施例中，上述两亲性聚氨酯中的亲水性链段为聚乙二醇，且其中聚乙二醇链段的数均分子量可为200-12000(具体如，200、400、500、600、750、1000、2000、4000、5000、6000、8000、10000、12000)，在本发明的一个实施方式中，聚乙二醇链段的数均分子量可为600-6000，在本发明的一个实施例中，聚乙二醇链段的数均分子量为1000或1500。
在本发明的一个实施方式中，上述两亲性高分子为两亲性高分子嵌段共聚物，其为两种以上聚合物组成的嵌段聚合物，其亲水部分可为聚乙二醇、聚氧乙烯、聚维酮等，其疏水部分可为聚氧丙烯、聚乳酸、聚苯乙烯、聚己内酯、聚氨基酸、聚乳酸羟基乙酸、聚丙烯酸等，例如，泊洛沙姆(PEO-PPO-PEO，Poloxamer)、聚乳酸-聚乙二醇-聚乳酸三嵌段共聚物(PLA-PEG-PLA)、聚乙二醇-聚丙烯酸嵌段共聚物(PEG-PAA)、聚乙二醇-聚天冬氨酸嵌段共聚物(PEG-PASP)、聚乙二醇-聚乳酸羟基乙酸嵌段共聚物(PEG-PLAG)、聚乙二醇-聚己内酯嵌段共聚物(PEG-PCL)、 聚乙二醇-聚乳酸嵌段共聚物(PEG-PLA/PTX)、聚乙二醇-聚苯乙烯嵌段共聚物(PEG-b-PS)等中的一种或两种以上的组合。
具体地，上述泊洛沙姆选自：泊洛沙姆188、338、407、124、215、237等中的一种或两种以上的组合；在本发明的一个实施例中，上述泊洛沙姆为泊洛沙姆188或泊洛沙姆338。
具体地，上述聚乳酸-聚乙二醇-聚乳酸三嵌段共聚物中，聚乙二醇部分的数均分子量可为200-12000(具体如，200、400、500、600、750、1000、2000、4000、5000、6000、8000、10000、12000)，在本发明的一个实施方式中，聚乙二醇部分的数均分子量可为1000-6000，在本发明的一个实施例中，聚乙二醇部分的数均分子量为1000或2000；其中嵌段比PEG:LA＝1:5-50(摩尔比)(具体如1:5、1:10、1:12、1:15、1:20、1:25、1:30、1:40、1:50)；在本发明的一个实施例中，嵌段比PEG:LA＝1:10或1:20。
具体地，上述聚乙二醇-聚丙烯酸嵌段共聚物、聚乙二醇-聚天冬氨酸嵌段共聚物、聚乙二醇-聚乳酸羟基乙酸嵌段共聚物、聚乙二醇-聚己内酯嵌段共聚物、聚乙二醇-聚乳酸嵌段共聚物、聚乙二醇-聚苯乙烯嵌段共聚物的数均分子量为500-50000(具体如，500、1000、2000、3000、4000、5000、6000、8000、10000、12000、14000、16000、18000、20000、22000、24000、26000、28000、30000、32000、34000、36000、38000、40000、42000、44000、46000、48000、50000)；其中，聚乙二醇为聚乙二醇单甲醚，聚乙二醇部分的数均分子量可为200-12000(具体如，200、400、500、600、750、1000、2000、4000、5000、6000、8000、10000、12000)，在本发明的一个实施方式中，聚乙二醇部分的数均分子量可为1000-6000，在本发明的一个实施例中，聚乙二醇部分的数均分子量为1000、2000或5000。
在本发明的一个实施方式中，上述大麻素纳米胶束制剂还包含药学上可接受的冻干保护剂。
具体地，上述大麻素纳米胶束制剂中，冻干保护剂的含量为1-10％(具体如1％、2％、3％、4％、5％、6％、7％、8％、9％、10％)。
具体地，上述冻干保护剂选自：乳糖、甘露醇、山梨醇、环糊精、羟丙基β环糊精、EDTA-2Na、海藻糖、葡萄糖、木糖醇、麦芽糖中的一种或多种；
在本发明的一个实施方式中，上述大麻素纳米胶束制剂还包含pH调节剂。
具体地，上述大麻素纳米胶束制剂中，pH调节剂的含量为0.01-10％(具体如0.01％、0.05％、0.1％、0.2％、0.3％、0.4％、0.5％、1％、2％、3％、4％、5％、6％、7％、8％、9％、10％)。
具体地，上述pH调节剂选自：枸橼酸、枸橼酸钠、酒石酸、酒石酸钠、醋酸、醋酸钠、磷酸二氢钠、磷酸氢二钠、盐酸、乳酸、氢氧化钠中的一种或多种。
在本发明的一个实施方式中，上述步骤(1)包括如下步骤：
(1-1)将上述大麻素纳米胶束制剂的原料组分加入溶剂中溶胀；
(1-2)将步骤(1-1)所得混合物用高速剪切分散乳化机剪切，得到乳液；
(1-3)将步骤(1-2)所得乳液搅拌，得到澄清透明纳米胶束溶液。
在本发明的一个实施例中，步骤(1-1)中的溶剂为水，如注射用水。
具体地，步骤(1-1)中溶剂用量为原料组分的2-10倍(质量比，具体如，2、3、4、5、6、7、8、9、10倍)。
具体地，步骤(1-1)中溶胀时间为0.1-2小时(具体如，0.1、0.5、1、1.5、2小时)。
具体地，步骤(1-2)中剪切时间为1-30分钟(具体如，1、5、10、15、20、25、30分钟)。
具体地，步骤(1-3)中，搅拌温度为15-35℃(具体如，15、20、25、30、35℃)，搅拌时间为1-48小时(具体如1、6、12、24、36、48小时)。
具体地，上述大麻素纳米胶束溶液粒径为1-500nm(具体如，1、10、50、100、150、200、250、300、350、400、450、500nm)。
具体地，步骤(2)中稀释所用溶剂为水，特别是注射用水。
具体地，步骤(2)中稀释倍数为2-100倍(具体如2、5、10、20、30、40、50、60、70、80、90、100倍)。
具体地，步骤(2)中的干燥为雾化冷冻干燥或冷冻干燥。
具体地，上述雾化冷冻干燥包括：雾化、冻结和干燥步骤；其中，雾化方式选自：气动雾化、压力式雾化、离心雾化、超声雾化中的一种或两种以上的组合；冻结温度为-10～-50℃(具体如，-10、-15、-20、-25、-30、-35、-40、-45、-50℃)；干燥步骤中真空度为40Pa以下(具体如40、30、20、10Pa)，干燥温度为10-35℃(具体如10、15、20、25、30、35℃)。
具体地，上述冷冻干燥包括：预冻、升华干燥和解析干燥步骤；其中，预冻温度为-30～-50℃(具体如-30、-35、-40、-45、-50℃)，预冻时间为0.5-3h(具体如0.5、1、2、3h)，预冻步骤中真空度控制为1-100Pa(1、10、20、30、40、50、60、80、100Pa)；升华干燥温度为-20～10℃(具体如-20、-10、-5、0、5、10℃)，升华干燥时间为1-36h(具体如1、6、12、18、24、30、36h)；解析干燥温度为10℃-30℃(具体如10、15、20、25、30℃)，解析干燥时间为1-24h(具体如1、6、12、18、24h)。
具体地，上述大麻素纳米胶束制剂为固体制剂或半固体制剂。
在本发明的一个实施方式中，上述大麻素纳米胶束制剂为口服制剂，如泡腾片、缓释片、速崩片、滴丸等。
在本发明另一个实施方式中，上述大麻素纳米胶束制剂为粘膜给药制剂，如栓剂等。
在本发明另一个实施方式中，上述大麻素纳米胶束制剂为吸入制剂，如干粉吸入剂等。
在本发明另一个实施方式中，上述大麻素纳米胶束制剂为经皮给药制剂，如凝胶贴剂等。
在本发明的一个实施例中，上述大麻素纳米胶束制剂为吸入剂，其粒径为1-5μm(具体如1、2、3、4、5μm)，其中上述步骤(2)中的干燥为雾化冷冻干燥。
在本发明的另一个实施例中，上述大麻素纳米胶束制剂为泡腾片、缓释片、速崩片、滴丸、栓剂或凝胶贴剂，其中上述步骤(2)中的干燥为冷冻干燥。
本发明提供的大麻素纳米胶束制剂的制备方法包括如下步骤：
(1)将大麻素和两亲性高分子制备大麻素纳米胶束溶液；
(2)将步骤(1)所得胶束溶液稀释、干燥得到大麻素纳米胶束粉末；
(3)将步骤(2)所得大麻素纳米胶束粉末制备成大麻素纳米胶束制剂。
在本发明的一个实施方式中，上述步骤(1)包括如下步骤：
(1-1)将上述大麻素纳米胶束制剂的原料组分加入溶剂中溶胀；
(1-2)将步骤(1-1)所得混合物用高速剪切分散乳化机剪切，得到乳液；
(1-3)将步骤(1-2)所得乳液搅拌，得到澄清透明纳米胶束溶液。
在本发明的一个实施例中，步骤(1-1)中的溶剂为水，如注射用水。
具体地，步骤(1-1)中溶剂用量为原料组分的2-10倍(质量比，具体如，2、3、4、5、6、7、8、9、10倍)。
具体地，步骤(1-1)中溶胀时间为0.1-2小时(具体如，0.1、0.5、1、1.5、2小时)。
具体地，步骤(1-2)中剪切时间为1-30分钟(具体如，1、5、10、15、20、25、30分钟)。
具体地，步骤(1-3)中，搅拌温度为15-35℃(具体如，15、20、25、30、35℃)，搅拌时间为1-48小时(具体如1、6、12、24、36、48小时)。
具体地，上述大麻素纳米胶束溶液粒径为1-500nm(具体如，1、10、50、100、150、200、250、300、350、400、450、500nm)。
具体地，步骤(2)中稀释所用溶剂为水，特别是注射用水。
具体地，步骤(2)中稀释倍数为2-100倍(具体如2、5、10、20、30、40、50、60、70、80、90、100倍)。
具体地，步骤(2)中的干燥为雾化冷冻干燥或冷冻干燥。
具体地，上述雾化冷冻干燥包括：雾化、冻结和干燥步骤；其中，雾化方式选自：气动雾化、压力式雾化、离心雾化、超声雾化中的一种或两种以上的组合；冻结温度为-10～-50℃(具体如，-10、-15、-20、-25、-30、-35、-40、-45、-50℃)；干燥步骤中真空度为40Pa以下(具体如40、30、20、10Pa)，干燥温度为10-35℃(具体如10、15、20、25、30、35℃)。
具体地，上述冷冻干燥包括：预冻、升华干燥和解析干燥步骤；其中，预冻温度为-30～-50℃(具体如-30、-35、-40、-45、-50℃)，预冻时间为0.5-3h(具体如0.5、1、2、3h)，预冻步骤中真空度控制为1-100Pa(1、10、20、30、40、50、60、80、100Pa)；升华干燥温度为-20～10℃(具体如-20、-10、-5、0、5、10℃)，升华干燥时间为1-36h(具体如1、6、12、18、24、30、36h)；解析干燥温度为10℃-30℃(具体如10、15、20、25、30℃)，解析干燥时间为1-24h (具体如1、6、12、18、24h)。
本发明还提供一种预防和/或治疗疾病的方法，其包括向由此需要的受试者给与有效量的本发明上述大麻素纳米胶束制剂的步骤。
具体地，上述方法中，大麻素纳米胶束制剂具有本发明上述定义。
具体地，上述方法中，所述疾病为上述大麻素纳米胶束制剂中相应大麻素的适应症，如疼痛(如慢性疼痛)、炎症(如皮炎)、肿瘤(如神经胶质瘤、白血病、前列腺癌等)、肝损伤(如缺血型肝损伤、慢性酒精中毒引起的肝损伤)、神经系统疾病(如癫痫、多发性硬化症、帕金森氏病、阿尔茨海默症等)等(参见例如，“郭蓉，陈璇，郭鸿彦.四氢大麻酚和大麻二酚的药理研究进展.天然产物研究与开发，2017，29：449-1453.”)。
在本发明的一个实施方式中，上述受试者为哺乳动物，特别是人。
具体地，上述大麻素纳米胶束制剂的有效量取决于诸多因素，包括患者的年龄、体重、性别、自然健康状况、营养状况、服用时间、代谢速率、病症的严重程度以及诊治医师的主观判断，等。
本发明还提供一种保健品，其包含本发明上述大麻素纳米胶束制剂。
本发明还提供一种提高免疫力、抗氧化的方法，其包括向由此需要的受试者给与有效量的上述保健品的步骤。
本发明所提供的大麻素纳米胶束制剂，有效成分包裹率和转移率高，载药量高，稳定性强，采用新的常温自组装技术，避免活性成分大麻素在高温下降解变色；活性成分的生物利用度高，可降低单次服用量。特别是干粉吸入剂，载药量高(10％以上)，稳定性强(保质期：2-3年)，体外沉积率高(排空率可达95％，有效沉积率可达45％)，吸入起效快，可提供持续稳定的血药浓度。
具体实施方式
除非另有定义，本发明中所使用的所有科学和技术术语具有与本发明涉及技术领域的技术人员通常理解的相同的含义，如在本发明中出现的以下缩写及其对应的物质为：
CBDV     次大麻二酚
CBD      大麻二酚
CBG      大麻萜酚
CBN      大麻酚
CBC      大麻色原烯
CBDB     4-butyl-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-(1,1′-biphenyl)-2,6-diol,Cannabidibutol
CBE      大麻艾尔松(cannabieLsoin)
CBL         大麻环酚
CBND        脱氢大麻二酚
TPGS        维生素E琥珀酸聚乙二醇酯
Poloxamer   泊洛沙姆
PEG-PAA     聚乙二醇-聚丙烯酸嵌段共聚物
PEG-PASP    聚乙二醇-聚天冬氨酸嵌段共聚物
PEG-PLAG    聚乙二醇-聚乳酸羟基乙酸嵌段共聚物
PEG-PCL     聚乙二醇-聚己内酯嵌段共聚物
PEG-PLA/PTX 聚乙二醇-聚乳酸嵌段共聚物
PEG-b-PS    聚乙二醇-聚苯乙烯嵌段共聚物
SFD         喷雾冷冻干燥
在本发明中，术语“大麻素”指大麻植物中特有的含有烷基和单萜基团分子结构的一类次生代谢产物，例如，CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL、CBND等(如“陈璇，杨明，郭鸿彦.大麻植物中大麻素成分研究进展，植物学报，2011，46(2)：197-205”所描述)。
在本发明中，CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL以及CBND的纯品是指上述化合物的纯净物产品，特别是相应的市售产品，其中化合物纯度至少为99.5％以上，特别是99.9％以上(其余为杂质)。
下面将结合本发明实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1：大麻素纳米胶束溶液制备
1、大麻素纳米胶束溶液的具体配方如下表所示。
表1大麻素纳米胶束溶液配方表
Figure PCTCN2020128307-appb-000001
Figure PCTCN2020128307-appb-000002
2、制备工艺
(1)第一组制备工艺(工艺1)
按配方1-6的配比投料进行大麻素胶束溶液制备，具体如下：
a、溶胀：按表1配方取原料100g，加入800g水中溶胀2h；
b、乳化：将溶胀后所得混合物用高速剪切分散乳化机50HZ，剪切30min；
c、搅拌：将乳化体系温度控制在30℃，搅拌48h，搅拌后溶液为澄清透明纳米胶束溶液，溶液粒径小于500nm。
上述制备工艺所得大麻素纳米胶束溶液质量对比如下表所示。
表2大麻素纳米胶束溶液质量对比
Figure PCTCN2020128307-appb-000003
(2)第二组制备工艺(工艺2)
按配方1-6的配比投料进行大麻素胶束溶液制备，具体如下：
a、熔融：根据表1中的配方1-6，将TPGS1000、Poloxamer188、聚氨酯4000、PEG2000-PAA2000、PEG2000-PASP1000、PEG1000-PLAG3000、PEG1000-PCL2000、PEG3400-PLA/PTX4000、PEG5000-b-PS5000按处方量加入，70℃熔融，熔融后加大麻素及其单体，分散均匀，制成液体1；
b、溶解：根据表1中的配方1-6，将甘露醇、山梨醇、枸橼酸、酒石酸、环糊精、羟丙基β环糊精、EDTA-2Na、海藻糖、亮氨酸、乳糖用8倍水溶解，制成液体2；
c、混合溶解：将液体“1”、“2”在40℃下混合溶解，慢速搅拌12h，溶液粒径小于500nm。
上述制备工艺所得大麻素纳米胶束溶液质量对比如下表所示。
表3大麻素纳米胶束溶液质量对比
Figure PCTCN2020128307-appb-000004
由表2和表3结果可知，在相同配方下，第一组工艺制备的大麻素纳米胶束比第二组工艺制备的大麻素纳米胶束转移率要高，可能是由于第二组工艺中采用了熔融步骤，使大麻素发生了降解。
实施例2：大麻素纳米胶束粉末的制备
制备胶束粉末的干燥方式包括真空干燥、雾化冷冻干燥、纳米喷雾干燥、超临界流体技术、冷冻干燥，将实施例1中第一组工艺制备的配方1分别用上述几种干燥技术制备的大麻素纳米胶束粉末并进行质量对比研究，具体干燥方式对比见表4。
雾化冷冻干燥：将大麻素纳米胶束溶液喷入雾化冷冻干燥机中生产大麻素胶束微粉，具体流程如下：
a、雾化：
将实施例1中“工艺1”制备的纳米胶束溶液，用纯化水稀释至100倍，用雾化冷冻干燥机进行雾化冷冻干燥，雾化装置采用超声雾化。
b、冻结：
固含量：气动雾化、压力试雾化、离心雾化为40％，超声雾化为10％；
进料流量：10ml/min；
冻结温度：-45℃；
c、干燥：
真空度：40Pa以下；
干燥温度：30℃。
冷冻干燥工艺：将大麻素纳米胶束溶液放入冷冻干燥箱内，-40℃冷冻3h，真空度控制小于10Pa，一次干燥温度-10℃，干燥24h；二次干燥温度25℃，干燥12h；干燥后物料过1-5号筛整粒。
上述几种干燥工艺制备的粉末质量对比如下表所示。
表4不同干燥工艺所得粉末质量对比
Figure PCTCN2020128307-appb-000005
结果分析：通过几种干燥方式从工艺可控度、粉末吸湿性、溶解性、表面形态、粒径分布、体外沉积率测定等指标等几方面进行对比分析，确定雾化冷冻干燥在吸入制剂方面比其他粉末更有优势，冷冻干燥的粉末更适合制备其他固体制剂。
实施例3：大麻素纳米胶束吸入制剂
实施例2中通过雾化冷冻干燥所得粉末粒径在1-5μm，表面形态为球状，流动性较佳，排空率为95％，沉积率为45％，适宜用作吸入粉末，将其灌装至2号至00号胶囊、泡囊中、储库或可直接用粉末吸入给药。
上述大麻素纳米胶束吸入粉末与根据专利申请WO2019008178A1实施例所描述的方法制备的胶束溶液的生物利用度对比如下表所示。
表5生物利用度对比
项目 生物利用度AUC
本方案制备的吸入粉末 60％
按专利WO2019008178A1制备的胶束溶液 18％
实施例4：大麻素纳米胶束泡腾片制备
1、配方：含大麻素胶束粉末(实施例2中通过冷冻干燥工艺所得粉末)、DL酒石酸、枸橼酸、碳酸氢钠、甘露醇、乳糖、阿斯帕坦、木糖醇、聚乙二醇。具体配方表如下表所示。
表6大麻素纳米胶束泡腾片配方表
Figure PCTCN2020128307-appb-000006
规格：片重2g。
2、制备工艺
根据表6配方，将大麻素胶束粉末、DL酒石酸、枸橼酸、甘露醇、聚乙二醇用流化床或湿法制粒制成颗粒1；将碳酸氢钠、阿斯帕坦、乳糖、木糖醇、聚乙二醇流化床或湿法制粒制成颗粒2；将颗粒1、颗粒2、大麻素胶束粉末混匀后压制成泡腾片，片重控制在2g。
不同配方的泡腾片质量对比如下表所示。
表7大麻素纳米胶束泡腾片质量对比
配方 崩解时间/min 分散均匀性 泡腾后溶液状态 含量稳定性
1 2 合格 澄清透明 片剂加速6个月含量稳定
2 3 合格 澄清透明 片剂加速6个月含量稳定
3 5 合格 澄清透明 片剂加速6个月含量稳定
结果分析：上述几种泡腾片均符合泡腾片质量标准要求，溶水迅速，使用、携带方便，可增加大麻素粉末的溶解速度，泡腾后的溶液为大麻素纳米胶束溶液，其可直接被服用。
实施例5：大麻素纳米胶束缓释片制备
1、配方：大麻素胶束粉末(实施例2中通过冷冻干燥工艺所得粉末)、羟丙甲纤维素、聚乙 烯吡咯烷酮、乙基纤维素、乳糖、微粉硅胶、硬脂酸镁。具体配方表如下表所示。
表8大麻素纳米胶束缓释片配方表
Figure PCTCN2020128307-appb-000007
2、制备工艺：根据表8配方，投入羟丙甲纤维素、聚乙烯吡咯烷酮、乙基纤维素、乳糖、酒石酸用一定量的无水乙醇制粒，加入大麻素胶束粉末、微粉硅胶、硬脂酸镁，混匀，压制成1g的缓释片。
不同配方的缓释片质量对比如下表所示。
表9大麻素纳米胶束缓释片质量对比
Figure PCTCN2020128307-appb-000008
上述配方的缓释片性状、片重差异、硬度、体外溶出度、稳定性均符合要求，可使大麻素在肠道内缓慢释放，入血后大麻素纳米胶束也会缓慢释放大麻素，起到双重缓释的作用，使大麻素在体内持久维持平稳的血药浓度，对慢性疼痛持久起效。
实施例6：大麻素纳米胶束口崩片制备
1、配方：大麻素胶束粉末(实施例2中通过冷冻干燥工艺所得粉末)、L-HPC、乳糖、微晶纤维素、预交化淀粉、微粉硅胶、硬脂酸镁。具体配方如下表所示。
表10大麻素纳米胶束口崩片配方表
Figure PCTCN2020128307-appb-000009
Figure PCTCN2020128307-appb-000010
2、制备工艺
将上述物料用湿法或一步制粒制成颗粒，压制成0.5g速崩片。
不同配方的速释片质量对比如下表所示。
表11大麻素纳米胶束速释片质量对比
配方 性状 崩解时限S 片重差异 稳定性
1 白色至棕色片 40S ±2.5％ 加速6个月稳定
2 白色至棕色片 45S ±2.3％ 加速6个月稳定
3 白色至棕色片 48S ±2.2％ 加速6个月稳定
三个配方的口崩片性状、片重差异、崩解时限、片重差异、稳定性均符合要求，口含服后可在口中快速崩解，舌下吸收入血，避免首过效应，便于吞咽困难的病人服用。
实施例7：大麻素纳米胶束凝胶制备
1、配方：大麻素胶束粉末(实施例2中通过冷冻干燥工艺所得粉末)、卡波姆、甘油、丙二醇、三乙醇胺、EDTA-2Na、羟苯乙酯。具体配方如下表所示。
表12大麻素纳米胶束凝胶配方表
Figure PCTCN2020128307-appb-000011
2、制备工艺：根据表12配方，将卡波姆加100倍水溶胀，加三乙醇胺，形成凝胶基质，再加入大麻素胶束粉末、甘油、丙二醇、EDTA-2Na、羟苯乙酯，搅匀即得。
不同配方的凝胶质量对比如下表所示。
表13大麻素纳米胶束凝胶质量对比
配方 性状 均匀性 稳定性
1 无色至棕色膏状固体 分散均匀、细腻 加速6个月稳定
2 无色至棕色膏状固体 分散均匀、细腻 加速6个月稳定
3 无色至棕色膏状固体 分散均匀、细腻 加速6个月稳定
三个配方凝胶性状、均匀性、稳定性均符合要求，直接涂抹置患处可起到治疗皮炎、关节慢性疼痛、祛痘除斑等作用。
实施例8：大麻素纳米胶束滴丸制备
1、配方：大麻素胶束粉末(实施例2中通过冷冻干燥工艺所得粉末)、聚乙二醇4000、聚乙二醇6000。具体配方如下表所示。
表14大麻素纳米胶束滴丸配方表
Figure PCTCN2020128307-appb-000012
2、制备工艺：根据表14配方，将大麻素胶束粉末、聚乙二醇4000、聚乙二醇6000、纯化水在70℃加热熔融制成浆料1，将石蜡油冷凝温度控制到10℃，将浆料1投入滴丸机中，滴制成50mg/丸的滴丸，将滴制好的滴丸用吸油棉除去表面石蜡油即得。
不同配方的滴丸质量对比如下表所示。
表15大麻素纳米胶束滴丸质量对比
配方 性状 丸重差异 崩解时限/min 稳定性
1 白色至黄棕色丸 ±8％ 10min 加速6个月稳定
2 白色至黄棕色丸 ±7％ 9min 加速6个月稳定
3 白色至黄棕色丸 ±8％ 11min 加速6个月稳定
三个配方滴丸性状、丸重差异、崩解时限、稳定性均符合要求，可口服也可舌下含服，起效快，且血药浓度持久。
实施例9：大麻素纳米胶束栓剂制备
1、配方：大麻素胶束粉末(实施例2中通过冷冻干燥工艺所得粉末)、可可脂、混合脂肪酸甘油酯、聚乙二醇羟苯乙酯。具体配方如下表所示。
表16大麻素纳米胶束栓剂配方表
Figure PCTCN2020128307-appb-000013
Figure PCTCN2020128307-appb-000014
2、制备工艺：根据上表配方，将大麻素胶束粉末、可可脂、混合脂肪酸甘油酯、聚乙二醇、羟苯乙酯，在40-60℃熔融，至栓剂制备机中，制备成球形栓、子弹型、胶囊型等栓剂。
不同配方的栓剂质量对比如下表所示。
表17大麻素纳米胶束栓剂质量对比
配方 性状 重量差异％ 融变时限/min 稳定性
1 白色至棕色栓 4.1％ 25min 加速6个月稳定
2 白色至棕色栓 4.0％ 26min 加速6个月稳定
3 白色至棕色栓 4.5％ 27min 加速6个月稳定
三个配方栓剂的性状、重量差异、融变时限、稳定性均符合要求，可直达病灶起到消炎作用，或用于全身给药治疗慢性疼痛，拓展了大麻素的应用范围。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换等，均应包含在本发明的保护范围之内。

Claims (20)

  1. 一种大麻素纳米胶束制剂，其包含：大麻素、两亲性高分子；其中，所述大麻素的重量百分比含量为1-40％，所述两亲性高分子的含量为1-99％，所述的制剂的制备方法包括：
    (1)将大麻素和两亲性高分子制备大麻素纳米胶束溶液；
    (2)将步骤(1)所得胶束溶液稀释、干燥得到大麻素纳米胶束粉末；
    (3)将步骤(2)所得大麻素纳米胶束粉末制备成大麻素纳米胶束制剂。
  2. 如权利要求1所述的大麻素纳米胶束制剂，其特征在于，所述大麻素选自：CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL和CBND纯品中的一种或两种以上的组合；或，
    所述大麻素为大麻提取物，其包含CBD、CBDV、CBG、CBC、CBN、CBDB、CBE、CBL和CBND中的一种或两种以上的组合。
  3. 如权利要求1所述的大麻素纳米胶束制剂，其特征在于，所述两亲性高分子为维生素E琥珀酸聚乙二醇酯；
    优选地，所述维生素E琥珀酸聚乙二醇酯选自：TPGS200、238、400、600、1000、2000、3400、3500、4000、6000中的一种或多种。
  4. 如权利要求1所述的大麻素纳米胶束制剂，其特征在于，所述两亲性高分子为两亲性聚氨酯；
    优选地，所述两亲性聚氨酯通过聚乙二醇链段与包括二异氰酸酯的原料交替共聚得到；其中，所述两亲性聚氨酯的数均分子量为1000-50000，所述聚乙二醇链段的数均分子量为200-12000；所述二异氰酸酯选自：六亚甲基二异氰酸酯、三甲基-1,6-六亚甲基二异氰酸酯、异佛尔酮二异氰酸酯、环己烷二亚甲基二异氰酸酯、4,4-二环己基甲烷二异氰酸酯、1,4-环己烷二异氰酸酯。
  5. 如权利要求1所述的大麻素纳米胶束制剂，其特征在于，所述两亲性高分子选自：泊洛沙姆、聚乳酸-聚乙二醇-聚乳酸三嵌段共聚物、聚乙二醇-聚丙烯酸嵌段共聚物、聚乙二醇-聚天冬氨酸嵌段共聚物、聚乙二醇-聚乳酸羟基乙酸嵌段共聚物、聚乙二醇-聚己内酯嵌段共聚物、聚乙二醇-聚乳酸嵌段共聚物和聚乙二醇-聚苯乙烯嵌段共聚物中的一种或两种以上的组合；
    优选地，所述泊洛沙姆选自：泊洛沙姆188、338、407、124、215和237中的一种或两种以上的组合；
    所述聚乳酸-聚乙二醇-聚乳酸三嵌段共聚物中，聚乙二醇部分的数均分子量为200-12000，其中嵌段比PEG:LA＝1:5-50；
    所述聚乙二醇-聚丙烯酸嵌段共聚物、聚乙二醇-聚天冬氨酸嵌段共聚物、聚乙二醇-聚乳酸羟基乙酸嵌段共聚物、聚乙二醇-聚己内酯嵌段共聚物、聚乙二醇-聚乳酸嵌段共聚物、聚乙二醇-聚苯乙烯嵌段共聚物的数均分子量为500-50000，其中，聚乙二醇为聚乙二醇单甲醚，聚乙二醇部分的数均分子量为200-12000。
  6. 如权利要求1所述的大麻素纳米胶束制剂，其特征在于，所述大麻素纳米胶束制剂还包含药学上可接受的冻干保护剂，其中，所述冻干保护剂的含量为1-10％，所述冻干保护剂选自：乳糖、甘露醇、山梨醇、环糊精、羟丙基β环糊精、EDTA-2Na、海藻糖、葡萄糖、木糖醇和麦芽糖中的一种或多种。
  7. 如权利要求6所述的大麻素纳米胶束制剂，其特征在于，所述大麻素纳米胶束制剂还包含pH调节剂，其中，所述pH调节剂的含量为0.01-10％，所述pH调节剂选自：枸橼酸、枸橼酸钠、酒石酸、酒石酸钠、醋酸、醋酸钠、磷酸二氢钠、磷酸氢二钠、盐酸、乳酸和氢氧化钠中的一种或多种。
  8. 如权利要求1-7任一项所述的大麻素纳米胶束制剂，其特征在于，所述步骤(1)包括如下步骤：
    (1-1)将所述大麻素纳米胶束制剂的原料组分加入溶剂中溶胀；
    (1-2)将步骤(1-1)所得混合物用高速剪切分散乳化机剪切，得到乳液；
    (1-3)将步骤(1-2)所得乳液搅拌，得到澄清透明纳米胶束溶液。
  9. 如权利要求8所述的大麻素纳米胶束制剂，其特征在于，步骤(1-1)中所述溶剂与原料组分的质量比为2-10：1；
    步骤(1-1)中所述溶胀时间为0.1-2小时；
    步骤(1-2)中所述剪切时间为1-30分钟；
    步骤(1-3)中所述搅拌温度为15-35℃。
  10. 如权利要求8所述的大麻素纳米胶束制剂，其特征在于，所述大麻素纳米胶束溶液粒径为1-500nm。
  11. 如权利要求1-7任一项所述的大麻素纳米胶束制剂，其特征在于，步骤(2)中所述稀释倍数为2-100倍。
  12. 如权利要求1-7任一项所述的大麻素纳米胶束制剂，其特征在于，步骤(2)中所述的干燥为雾化冷冻干燥或冷冻干燥，优选地，步骤(2)中所述的干燥为雾化冷冻干燥，其中雾化方式选自：气动雾化、压力式雾化、离心雾化、超声雾化中的一种或 两种以上的组合。
  13. 如权利要求1所述的大麻素纳米胶束制剂，其特征在于，所述的制剂为固体制剂或半固体制剂。
  14. 如权利要求1所述的大麻素纳米胶束制剂，其特征在于，所述的制剂为口服制剂、粘膜给药制剂或经皮给药制剂；
    优选地，所述制剂为口服制剂，优选自：泡腾片、缓释片、速崩片、滴丸；或，
    所述制剂为粘膜给药制剂，优选为栓剂；或，
    所述制剂为吸入制剂，优选为干粉吸入剂；或，
    所述制剂为经皮给药制剂，优选为凝胶贴剂。
  15. 一种权利要求1-14任一项所述的大麻素纳米胶束制剂的制备方法，其包括如下步骤：
    (1)将大麻素和两亲性高分子制备大麻素纳米胶束溶液；
    (2)将步骤(1)所得胶束溶液稀释、干燥得到大麻素纳米胶束粉末；
    (3)将步骤(2)所得大麻素纳米胶束粉末制备成大麻素纳米胶束制剂；
    优选地，所述步骤(1)包括如下步骤：
    (1-1)将权利要求1-9任一项所述的大麻素纳米胶束制剂的原料组分加入溶剂中溶胀；
    (1-2)将步骤(1-1)所得混合物用高速剪切分散乳化机剪切，得到乳液；
    (1-3)将步骤(1-2)所得乳液搅拌，得到澄清透明纳米胶束溶液。
  16. 如权利要求15所述的制备方法，其特征在于，步骤(1-1)中所述溶剂与原料组分的质量比为2-10：1；
    步骤(1-1)中所述溶胀时间为0.1-2小时；
    步骤(1-2)中所述剪切时间为1-30分钟；
    步骤(1-3)中所述搅拌温度为15-35℃。
  17. 如权利要求15所述的制备方法，其特征在于，步骤(2)中稀释倍数为2-100倍。
  18. 如权利要求15所述的制备方法，其特征在于，步骤(2)中所述的干燥为雾化冷冻干燥或冷冻干燥。
  19. 如权利要求18所述的制备方法，其特征在于，所述雾化冷冻干燥包括：雾化、冻结和干燥步骤，
    其中，所述雾化方式选自：气动雾化、压力式雾化、离心雾化、超声雾化中的一种 或两种以上的组合；
    所述冻结温度为-10～-50℃；
    所述干燥步骤中真空度为40Pa以下，干燥温度为10-35℃。
  20. 如权利要求18所述的制备方法，其特征在于，所述冷冻干燥包括：预冻、升华干燥和解析干燥步骤；
    其中，所述预冻步骤中，预冻温度为-30～-50℃，预冻时间为0.5-3h，真空度控制为1-100Pa；
    所述升华干燥温度为-20～10℃，升华干燥时间为1-36h；
    所述解析干燥温度为10℃-30℃，解析干燥时间为1-24h。
PCT/CN2020/128307 2019-12-06 2020-11-12 一种大麻素纳米胶束制剂及其制备方法 WO2021109823A1 (zh)

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