WO2020119698A1 - 一种维拉佐酮固体分散体及其制备方法 - Google Patents

一种维拉佐酮固体分散体及其制备方法 Download PDF

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WO2020119698A1
WO2020119698A1 PCT/CN2019/124429 CN2019124429W WO2020119698A1 WO 2020119698 A1 WO2020119698 A1 WO 2020119698A1 CN 2019124429 W CN2019124429 W CN 2019124429W WO 2020119698 A1 WO2020119698 A1 WO 2020119698A1
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vilazodone
solid dispersion
carrier material
weight ratio
surfactant
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PCT/CN2019/124429
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English (en)
French (fr)
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方代龙
范露露
黄心
游劲松
黄芳芳
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广东东阳光药业有限公司
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Priority to US17/311,784 priority Critical patent/US20220071993A1/en
Priority to CN201980080366.5A priority patent/CN113164473B/zh
Publication of WO2020119698A1 publication Critical patent/WO2020119698A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the field of biomedicine, in particular to a solid dispersion of vilazodone and a preparation method and application thereof.
  • Verazodone is the first indole alkylamine antidepressant, which belongs to selective serotonin reuptake inhibitors and 5-HT1A receptor partial agonists.
  • the recommended dose of clinical medicine is 40mg/time/day, using a step-by-step incremental dosing regimen, the initial dose is 10mg/time/day, continuous administration for 7 days, then 20mg/time/day, continuous administration for 7 days, and finally maintained 40 mg/time/day administration dose.
  • the tablets After oral administration, the tablets are mainly absorbed in the small intestine, and the peak time (T max ) of the plasma drug concentration is 4 to 5 hours.
  • T max peak time
  • the solubility under the environmental conditions of gastric juice (pH 1.2) and intestinal juice (pH 4.5-6.8) is poor, and only has a certain solubility in an environment around pH 3.1, so Its fasting oral bioavailability is low, resulting in The bioavailability is extremely low when taken on an empty stomach, and it is difficult to meet the clinical treatment needs.
  • the instructions clearly indicate that the drug must be taken with food; under eating conditions, the pH value of the human gastric juice is about 3.1, and can delay the gastric emptying of the drug, which ultimately leads to The oral bioavailability under feeding conditions is about 72%, while under fasting conditions, the AUC (blood concentration) and C max (maximum peak concentration) decrease by 50% and 60%, respectively.
  • vilazodone hydrochloride In order to improve the solubility of vilazodone hydrochloride, the prior art discloses that it is prepared in an amorphous state, which can increase its solubility.
  • Patent CN104983711 discloses a solid dispersion prepared by vilazodone hydrochloride and povidone (PVP) or polyethylene glycol (PEG) in a weight ratio of 1:2.5, and the prepared solid dispersion is in a low specification (10mg)
  • PVP povidone
  • PEG polyethylene glycol
  • the dissolution rate under the conditions has been improved compared with ordinary preparations, but the degree of improvement is limited, and the highest dissolution platform is about 90%.
  • the dosage of carrier material in the prescription is too low (1:2.5), the stability of the later formulation may be problematic, which may eventually lead to lower oral bioavailability.
  • the present invention provides a solid dispersion of vilazodone with better stability and higher solubility, the solid dispersion containing vilazodone Ketone, carrier material and surfactant, the carrier material is a water-soluble polymer carrier material.
  • the vilazodone described in the present invention may be vilazodone free base, or a pharmaceutically acceptable salt or ester thereof, specifically referring to 5- ⁇ 4-[4-(5-cyano -3-indole)-butyl]-1-piperazinyl ⁇ -coumarone-2-carboxamide or a pharmaceutically acceptable salt or ester thereof.
  • a solid dispersion of vilazodone is proposed, the solid dispersion comprising vilazodone, a carrier material and a surfactant.
  • the carrier material is a water-soluble polymer carrier material, and the carrier material includes at least one selected from povidone, copovidone, and hydroxypropyl methyl cellulose.
  • povidone povidone
  • copovidone hydroxypropyl methylcellulose
  • a surfactant is added on the basis of the carrier material, and the surfactant has a greater influence on the improvement of the dissolution of the resulting solid dispersion and the improvement of its stability.
  • the carrier material is a water-soluble polymer carrier material
  • the ratio of vilazodone to water-soluble polymer carrier material it was found that When the weight ratio is less than or equal to 1:4, vilazodone exists in an amorphous form in the solid dispersion, and its dissolution rate in vitro is significantly higher than that of the commercially available preparation.
  • the weight ratio of vilazodone to carrier material in the solid dispersion of the present invention is 1:4 to 1:7.
  • the weight ratio of vilazodone to carrier material is 1:4 to 1:5; in some embodiments, the weight ratio of vilazodone to carrier material is 1:4 to 1:6; In some embodiments, the weight ratio of vilazodone to carrier material is 1:5 to 1:7; in some embodiments, the weight ratio of vilazodone to carrier material is 1:5 to 1:6; In some embodiments, the weight ratio of vilazodone to carrier material is 1:6 to 1:7.
  • the weight ratio of vilazodone to carrier material is 1:4; in some embodiments, the weight ratio of vilazodone to carrier material is 1:5; in some embodiments, vera ketone
  • the weight ratio of adjuvant to carrier material is 1:6; in some embodiments, the weight ratio of vilazodone to carrier material is 1:7.
  • the solid dispersion of vilazodone further includes a surfactant, which includes but is not limited to the following categories:
  • Polyoxyethylene alkyl ethers such as polyoxyethylene (3) lauryl ether, polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether, polyoxyethylene (5) stearyl ether; polyoxyethylene Vinyl alkyl aryl ethers, such as polyoxyethylene (2) nonylphenyl ether, polyoxyethylene (3) nonylphenyl ether, polyoxyethylene (4) nonylphenyl ether, polyoxyethylene (3 ) Octyl phenyl ether; polyethylene glycol glycerides, such as PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG -300 distearate, PEG-300 distearate: alkylene glycol fatty acid monoester, such as propylene glycol monolaurate; sucrose fatty acid esters, such as sucrose monostearate, sucrose distearate Esters, sucrose monolaurate,
  • the HLB (hydrophile-lipophile balance value) value of the surfactant is not less than 6; in some embodiments, the surfactant includes Tween, Span-20, polyoxyethylene castor oil, Polyoxyethylene 40 hydrogenated castor oil (RH40), caprylic capric acid polyethylene glycol glyceride (Labrasol), polyethylene glycol hydroxystearate, lauric acid polyethylene glycol glyceride, poloxamer, (D ) One or more of ⁇ -tocopherol polyethylene glycol succinate and sodium lauryl sulfate.
  • the weight ratio of the surfactant in the solid dispersion of vilazodone is not more than 20%, which is beneficial to the solubilization and/or stability performance of the obtained solid dispersion. In some embodiments, the weight ratio of the surfactant in the solid dispersion of vilazodone is not more than 10%, which is beneficial to the solubilization and/or stability performance of the resulting solid dispersion. In some embodiments, the weight ratio of the surfactant in the solid dispersion of vilazodone is 20%. In some embodiments, the weight ratio of the surfactant in the solid dispersion of vilazodone is 10%.
  • the solid dispersion of vilazodone comprises vilazodone, a carrier material and a surfactant, and the carrier material may be copovidone.
  • the solid dispersion of vilazodone prepared with copovidone as a carrier material has a greater dissolution rate in the simulated small intestine environment (pH 6.8 medium), which can significantly improve the oral bioavailability of vilazodone on an empty stomach.
  • the weight ratio of vilazodone to copovidone in the solid dispersion of vilazodone is 1:4 to 1:7. In some embodiments, the weight ratio of vilazodone to copovidone is 1:6.
  • the surfactant in the solid dispersion of vilazodone, may be poloxamer 188.
  • the vilazodone solid dispersion comprises vilazodone, copovidone, and poloxamer 188, and the poloxamer 188 is in the vilazodone solid dispersion
  • the weight ratio is not more than 20%. In some examples, the weight ratio of the poloxamer 188 in the solid dispersion of vilazodone is not more than 10%. In some examples, the weight ratio of the poloxamer 188 in the vilazodone solid dispersion is 20%; in some examples, the poloxamer 188 is in the vilazodone solid The weight ratio in the dispersion is 10%.
  • the solid dispersion of vilazodone comprises vilazodone, a carrier material and a surfactant, and the carrier material may be povidone.
  • the solid dispersion of vilazodone prepared with povidone as a carrier material has a greater dissolution rate in a simulated small intestine environment (pH 6.8 medium), which can significantly improve the oral bioavailability of vilazodone on an empty stomach.
  • the weight ratio of vilazodone to povidone in the solid dispersion of vilazodone is 1:4 to 1:7. In some embodiments, the weight ratio of vilazodone to povidone is 1:5; in some embodiments, the weight ratio of vilazodone to povidone is 1:6.
  • the solid dispersion of vilazodone comprises vilazodone, povidone, and poloxamer 188.
  • the solid dispersion of vilazodone comprises vilazodone, povidone, and Span-20.
  • the solid dispersion of vilazodone comprises vilazodone, povidone, poloxamer 188 and span-20.
  • the weight ratio of Span-20 in the solid dispersion of vilazodone is not more than 10%; in some embodiments, Span-20 is in the Vera The weight ratio of the adjuvant solid dispersion is not more than 5%.
  • the weight ratio of Span-20 in the solid dispersion of vilazodone is 10%; in some examples, Span-20 in the solid dispersion of vilazodone The weight ratio in is 5%.
  • the solid dispersion of vilazodone comprises vilazodone, a carrier material and a surfactant, and the carrier material may be hydroxypropyl methylcellulose.
  • the solid dispersion of vilazodone prepared with hydroxypropyl methylcellulose as the carrier material has a greater dissolution rate in the simulated small intestine environment (pH 6.8 medium), which can significantly improve the oral organisms of vilazodone on an empty stomach. Utilization.
  • the weight ratio of vilazodone to hydroxypropyl methylcellulose in the solid dispersion of vilazodone is 1:4 to 1:7. In some embodiments, the weight ratio of vilazodone to hydroxypropyl methyl cellulose is 1:6.
  • the solid dispersion of vilazodone comprises vilazodone, hydroxypropyl methyl cellulose and caprylic capric acid polyethylene glycol glyceride.
  • the vilazodone solid dispersion comprises vilazodone, hydroxypropyl methyl cellulose and polyoxyethylene 40 hydrogenated castor oil.
  • the vilazodone solid dispersion comprises vilazodone, hydroxypropyl methylcellulose, caprylic capric acid polyethylene glycol glyceride and polyoxyethylene 40 hydrogenated castor oil.
  • the weight ratio of the caprylic capric acid polyethylene glycol glyceride in the solid dispersion of vilazodone is not more than 10%. According to some embodiments of the present invention, the weight ratio of the polyoxyethylene 40 hydrogenated castor oil in the solid dispersion of vilazodone is not more than 10%. In some embodiments, the weight ratio of the caprylic capric acid polyethylene glycol glyceride in the vilazodone solid dispersion is 10%. In some embodiments, the weight ratio of the polyoxyethylene 40 hydrogenated castor oil in the solid dispersion of vilazodone is 10%.
  • the present invention investigates the addition of surfactants on the basis of a single carrier material.
  • the results show that for different carrier materials, the type of surfactant has a greater influence on the dissolution rate and stability.
  • poloxamer 188 was added to the copovidone material, the dissolution rate of the prepared solid dispersion of vilazodone was significantly improved and stable, while after adding other surfactants, the dissolution rate was improved but unstable, and appeared later Down.
  • the prepared vilazodone solid dispersion has a high and stable dissolution rate in vitro, which is significantly higher than that of commercially available preparations
  • the dissolution rate can significantly improve the oral bioavailability of vilazodone under fasting conditions.
  • specific surfactants on the basis of the carrier material can further increase the solubility and/or inhibit crystallization of vilazodone hydrochloride, reduce the decrease in dissolution rate, and help to improve the stability of the dispersion.
  • the solid dispersion of vilazodone comprises vilazodone and a water-soluble polymer carrier material
  • the water-soluble polymer carrier material is a mixed material
  • the mixed The material includes at least two of povidone, copovidone, and hydroxypropyl methyl cellulose.
  • the present invention found that when the dissolution rate is higher (greater than 70%), the dissolution rate of solid dispersions prepared with different ratios of a single material (without adding surfactant) has decreased to varying degrees, while The solid dispersions prepared by using mixed materials of different dosages and ratios have high and stable dissolution, can overcome the problem of dissolution reduction in single material prescriptions, and can significantly improve the oral bioavailability of vilazodone on an empty stomach.
  • the solid dispersion of vilazodone comprises vilazodone and a mixed material, the mixed material comprising copovidone and hypromellose.
  • the mixed material consists of copovidone and hypromellose.
  • the solid dispersion of vilazodone comprises vilazodone and the above mixed material, and the mixed material comprises povidone and hypromellose.
  • the mixed material consists of povidone and hypromellose.
  • the weight ratio of the vilazodone to the water-soluble polymer carrier material is 1:4 to 1:7. In some examples, the vilazodone to the water-soluble polymer carrier material The weight ratio is 1:5; in some examples, the weight ratio of vilazodone to water-soluble polymer carrier material is 1:6.
  • the solid dispersion of vilazodone comprises vilazodone, copovidone, and a surfactant.
  • the solid dispersion of vilazodone comprises vilazodone, povidone, and a surfactant.
  • the vilazodone solid dispersion comprises vilazodone, hydroxypropyl methylcellulose, and a surfactant.
  • a method for preparing the solid dispersion of vilazodone which can be prepared by various techniques, including but not limited to spray drying method and hot melt extrusion method , Freeze-drying method, solvent evaporation method, co-precipitation method, supercritical fluid method, etc.
  • the present invention uses a hot melt extrusion method to prepare a solid dispersion of vilazodone, which is easy to operate and easy to mass produce.
  • vilazodone exists in an amorphous form, and the dissolution rate of the solid dispersion in vitro is comparable to that of a commercially available preparation Significantly increased.
  • the present invention uses a spray drying method to prepare vilazodone solid dispersions.
  • the spray drying method includes the following steps: Weighing vilazodone and carrier material according to the ratio, adding to a solvent, stirring and dissolving, spray drying in a spray dryer, collecting powder, that is, a solid dispersion of vilazodone;
  • the solvent is an aqueous solution of acetone, and the volume concentration of acetone is greater than 60% and less than or equal to 70%.
  • the present invention optimizes and obtains a 60% to 70% acetone aqueous solution as a solvent through extensive screening.
  • a high-concentration and stable vilazodone solution can be prepared for spray drying, and at this concentration, the solubility of various carrier materials is also higher, which can greatly increase the solid content of the solution and significantly improve the efficiency of spray drying ,Reduce energy consumption.
  • a low-concentration vilazodone solution prepared with a lower-concentration acetone solution or a methanol or ethanol solution can also be used for spray drying.
  • the dissolution in order to make the prazodone drug substance and carrier material dissolve better and faster, the dissolution can be accelerated by heating or ultrasound.
  • the invention adopts a solid dispersion prepared by using 60% to 70% acetone aqueous solution as a solvent, vilazodone exists in an amorphous form, and the dissolution rate in vitro is significantly higher than that of a commercially available preparation
  • a solid dispersion of vilazodone and the use of the solid dispersion of vilazodone described above in the preparation of a vilazodone formulation.
  • the vilazodone formulation comprises vilazodone solid dispersion and pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients include but are not limited to the following: fillers, such as lactose, sucrose, fructose, low Sugars such as polyfructose, glucose, maltose, powdered sugar, sugar alcohols such as D-mannitol, erythritol, xylitol, starches such as corn starch, potato starch, rice starch, some alpha starch, microcrystalline fiber
  • Cellulose such as cellulose, inorganic salts such as calcium sulfate, calcium hydrogen phosphate, calcium carbonate
  • disintegrants such as starch, microcrystalline cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, cross-linked Povidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, etc.
  • lubricants such as magnesium stearate, calcium stearate, sodium fumarate stearate, stearic acid, talc, polyethylene Glycol, sucrose fatty
  • the vilazodone formulation provided by the present invention includes tablets, capsules, granules, powders or dry suspensions. According to the clinical treatment needs, the above-mentioned corresponding dosage forms can be selectively prepared, which is convenient for patients to take and improve patient compliance. In order to prevent the hygroscopicity and aging of the solid dispersion preparation of vilazodone, it can also be prepared as a coated tablet; in addition, in order to make vilazodone absorbed in the small intestine, it can also be prepared as an enteric coated tablet .
  • the present invention uses copovidone as a carrier material, poloxamer 188 as a surfactant, prepares a solid dispersion of vilazodone, and adds an appropriate amount of pharmaceutically acceptable auxiliary materials to prepare a tablet.
  • copovidone as a carrier material
  • poloxamer 188 as a surfactant
  • prepares a solid dispersion of vilazodone and adds an appropriate amount of pharmaceutically acceptable auxiliary materials to prepare a tablet.
  • its oral bioavailability in Beagle dogs is significantly higher than that of commercially available preparations
  • the solid dispersion formulation of vilazodone provided by the present invention is equivalent, eliminating food effects, suggesting that the solid dispersion of vilazodone provided by the present invention can be taken under both fasting and eating conditions. Can significantly improve the patient's convenience and compliance.
  • the present invention further investigates the stability of vilazodone solid dispersion. Under accelerated conditions (40°C, 75% RH), after 2 months of storage, vilazodone is still indefinite The form exists in the solid dispersion, and there is no significant change in the dissolution rate in vitro, which shows that the solid dispersion of vilazodone prepared by the present invention has good stability and meets the requirements of industrial production.
  • the solid dispersion of vilazodone provided by the present invention can significantly improve the solubility and dissolution of vilazodone in vitro, thereby improving its fasting bioavailability; further, the solid dispersion of vilazodone provided by the present invention also It can eliminate the influence of food, and its oral bioavailability is equivalent under fasting and eating conditions, suggesting that the solid dispersion preparation of vilazodone provided by the present invention can be taken under fasting or eating conditions, which significantly improves the convenience of patients taking medicine and Compliance can be used for the treatment of moderate to severe depression.
  • LC-MS-MS refers to liquid-mass spectrometry
  • XRD refers to X-ray diffraction
  • PVP povidone
  • VA64 copovidone
  • HPMC hydroxypropyl methylcellulose
  • Labrasol caprylic capric acid polyethylene glycol glyceride
  • Cremophor RH40 polyoxyethylene 40 hydrogenated castor oil
  • T-80 refers to vomiting Wen-80
  • F68 refers to Poloxamer 188
  • S-20 refers to Span-20
  • TPGS refers to (D) ⁇ -tocopherol polyethylene glycol 1000 succinate.
  • PEG polyethylene glycol
  • Soluplus refers to polyethylene glycol/vinyl caprolactam/vinyl acetate copolymer
  • HPMCAS hypromellose acetate succinate
  • HPC hydroxypropyl cellulose
  • AUC refers to the area under the blood drug concentration-time curve
  • C max refers to the peak blood drug concentration
  • M refers to moles
  • h refers to hours
  • g refers to grams
  • mm refers to millimeters
  • ⁇ m refers to micrometers
  • nm refers to nanometers
  • ⁇ l refers to microliters
  • min refers to minutes
  • °C refers to degrees Celsius
  • mg refers to milligrams
  • mL refers to milliliters
  • rpm refers to revolutions per minute .
  • Fig. 1 Example 3 (1) XRD pattern of a solid dispersion of vilazodone hydrochloride prepared with different amounts of VA64.
  • Fig. 4 XRD pattern of the solid dispersion of vilazodone hydrochloride prepared by different mixed carriers in Example 3 (4).
  • the reference preparation Verazodone hydrochloride tablets of 10mg and 40mg/tablet developed for the forest laboratory.
  • Hydroxypropyl methylcellulose succinate HPMCAS-LF and HPMCAS-MF
  • polyethylene glycol 4000 PEG-4000
  • Soluplus polyethylene glycol/vinyl caprolactam/vinyl acetate copolymer
  • Povidone PVP
  • Copovidone VA64
  • HPMC Hydroxypropyl methylcellulose
  • HPMC Hydroxypropyl methylcellulose
  • Tween-80 T-80
  • Poloxamer 188 F68
  • Span-20 S-20
  • polyoxyethylene 40 hydrogenated castor oil Cremophor RH40
  • caprylic capric acid polyethylene glycol glyceride Labrasol
  • TPGS ⁇ -tocopherol polyethylene glycol 1000 succinate
  • the method for determining the content of vilazodone is high performance liquid chromatography (HPLC), the specific conditions are: chromatographic conditions: the detection wavelength is 242nm, the chromatographic column uses kromasil 100-5C18 (4.6mm ⁇ 150mm, 5 ⁇ m), the mobile phase is pH 6. 0 0.02M dipotassium hydrogen phosphate and acetonitrile are 54:46 (V/V), the flow rate is 1.0ml/min, the injection volume is 10 ⁇ l, and the running time is 4.5min.
  • HPLC high performance liquid chromatography
  • Solvent concentration phenomenon Methylene chloride 10mg/ml Insoluble, a lot of precipitation Ethanol 10mg/ml Insoluble, a small amount of precipitation Methanol 10mg/ml Insoluble, a small amount of precipitation acetone 10mg/ml Insoluble, a small amount of precipitation Ethyl acetate 10mg/ml Insoluble, a lot of precipitation
  • vilazodone hydrochloride has relatively good solubility in ethanol, methanol or acetone, and can be used as a solvent for subsequent optimization.
  • Ethanol (ml) Water (ml) API phenomenon 0.1 0.9 10mg Insoluble, a lot of precipitation 0.2 0.8 10mg Insoluble, a lot of precipitation 0.3 0.7 10mg Insoluble, a lot of precipitation 0.4 0.6 10mg Dissolve and leave for 1 day to precipitate 0.5 0.5 10mg Dissolve, leave a little out 0.6 0.4 10mg Dissolve and leave for 1 day to precipitate 0.7 0.3 10mg Dissolve, leave a little out 0.8 0.2 10mg Insoluble, a lot of precipitation 0.9 0.1 10mg Insoluble, a lot of precipitation
  • Methanol (ml) Water (ml) API result 0.3 2.7 30mg Insoluble, a lot of precipitation 0.6 2.4 30mg Insoluble, a lot of precipitation 0.9 2.1 30mg Insoluble, a lot of precipitation 1.2 1.8 30mg Insoluble, a lot of precipitation 1.5 1.5 30mg Dissolve, continue to add a small amount of powder to 15mg/ml, insoluble 1.8 1.2 30mg Continue to add a small amount of powder to 15mg/ml, dissolve and leave to precipitate 2.1 0.9 30mg Continue to add a small amount of powder to 20mg/ml, insoluble 2.4 0.6 30mg Dissolve, continue to add a small amount of powder to 15mg/ml, insoluble 2.7 0.3 30mg Dissolve, continue to add a small amount of powder to 15mg/ml, insoluble
  • Acetone (ml) Water (ml) API phenomenon 0.1 0.9 10mg Insoluble, a lot of precipitation 0.2 0.8 10mg Insoluble, a lot of precipitation 0.3 0.7 10mg Insoluble, a lot of precipitation 0.4 0.6 10mg Completely dissolved, left to precipitate 0.5 0.5 10mg Completely dissolved, left to precipitate 0.6 0.4 10mg Completely dissolved, increase the concentration to 40mg/ml, no precipitation 0.7 0.3 10mg Completely dissolved, increase the concentration to 40mg/ml, no precipitation 0.8 0.2 10mg Completely dissolved, left to precipitate 0.9 0.1 10mg Insoluble, a lot of precipitation
  • the concentration of the acetone solution is 60% to 70% in order to satisfy both the dissolution of the drug and the carrier material and to obtain a suitable solution viscosity for spray drying.
  • the concentration range of acetone can be further expanded to 50% to 80%, or greater.
  • prescription 11 contains low melting point material PEG4000, the inlet air temperature is set to 95 °C, the outlet air temperature: 50 °C, speed: 20 rpm, the remaining prescription air inlet temperature is: 160 °C, the outlet air temperature : 85°C, speed: 20 rpm).
  • composition Prescription-8 Prescription-9 Prescription-10 Prescription 11
  • the solid dispersion of vilazodone hydrochloride prepared with mixed materials has a relatively high dissolution rate in simulated intestinal fluid (pH 6.8 medium) and is much larger than the reference preparation
  • the dissolution has a tendency to decrease.
  • the prepared solid dispersion of vilazodone hydrochloride (40mg specification) has the highest dissolution , Are both greater than 70%, and relatively stable (change range is less than 5%), no crystallization, dissolution rate reduction phenomenon, can significantly increase the oral bioavailability of vilazodone under fasting conditions.
  • composition Prescription-12 Prescription-13 Prescription-14 Prescription-15 Vilazodone hydrochloride 10g 10g 10g 10g
  • composition Prescription-16 Prescription-17 Prescription-18 Prescription-19 Vilazodone hydrochloride 10g 10g 10g 10g Povidone 40g 50g 60g 70g 60% acetone in water 1000ml 1000ml 1000ml 1000ml 1000ml
  • composition Prescription-20 Prescription-21 Prescription-22 Prescription-23 Vilazodone hydrochloride 10g 10g 10g Hydroxypropylmethylcellulose 40g 50g 60g 70g 60% acetone in water 1200ml 1200ml 1200ml 1200ml
  • Example 6 hot melt extrusion process to prepare vilazodone solid dispersion
  • composition Prescription-52 Prescription-53 Prescription-54 Vilazodone 10g 10g 10g HPMCAS-MF 60g 45g 30g Soluplus —— 15g 30g Poloxamer 188 7.78g 7.78g 5g
  • the spray-dried powder of prescription 33 is selected as the raw material, and the materials are weighed according to Table 27 and mixed evenly; the total mixed materials are passed through a 40-mesh sieve and directly compressed to obtain vilazodone hydrochloride tablets. According to the dissolution measurement method described in (1) of Example 2, the dissolution of the self-developed tablets in different media was tested.
  • vilazodone hydrochloride tablets (10 mg specification).
  • Six male, healthy adult Beagle dogs with a body weight ranging from 15 to 20 kg were randomly divided into two groups for a double crossover and two-cycle test to investigate self-developed vilazodone tablets (10 mg) on an empty stomach and fed (high fat , High-calorie food) pharmacokinetic properties.
  • the average Ratio is in the range of about 70% to about 143%, it can be determined that the dosage form has no food effect, and it is equivalent when taken with an empty stomach. That is to say, whether the dosage form is taken under eating or fasting conditions, Have basically the same bioavailability and efficacy. (Remarks: Fast means fasting, Fed means feeding; Test is self-developed vilazodone tablet, RLD is reference preparation )
  • Dissolution media 5min 10min 15min 20min 30min 45min PH3.1 41 ⁇ 9.02 78 ⁇ 12.74 92 ⁇ 2.52 95 ⁇ 1.53 96 ⁇ 2.08 98 ⁇ 2.52 PH6.8 41 ⁇ 3.06 85 ⁇ 4.58 90 ⁇ 1.53 92 ⁇ 1.15 94 ⁇ 1.53 94 ⁇ 1.00 0.1MHCl 65 ⁇ 20.00 81 ⁇ 18.52 87 ⁇ 9.61 89 ⁇ 7.55 91 ⁇ 6.03 92 ⁇ 4.16
  • the solid dispersion formulation of vilazodone provided by the present invention can significantly improve the bioavailability of vilazodone when taken on an empty stomach, eliminating the effects of food, and can be taken under both fasting and eating conditions, which significantly improves the patient's medication Convenience and improve patient compliance, which is of great clinical significance for patients with severe depression who require long-term medication and are often accompanied by loss of appetite and suicidal tendencies.

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Abstract

提供一种维拉佐酮固体分散体及其制备方法和用途，所述维拉佐酮固体分散体包含活性成分维拉佐酮、水溶性聚合物载体材料和表面活性剂。所述水溶性聚合物载体材料选自聚维酮、共聚维酮、羟丙基甲基纤维素中的至少一种。所述固体分散体中，维拉佐酮以非结晶态存在于固体分散体中，该固体分散稳定性好，显著提高维拉佐酮的溶解度和体外溶出度，从而显著增加其口服生物利用度。所述维拉佐酮固体分散体可用于制备维拉佐酮相关制剂。

Description

一种维拉佐酮固体分散体及其制备方法 技术领域
本发明涉及生物医药领域，具体涉及一种维拉佐酮固体分散体及其制备方法和应用。
背景技术
维拉佐酮是第一个吲哚烷基胺类抗抑郁药，属于选择性5-羟色胺再摄取抑制剂和5-HT1A受体部分激动剂。美国食品药品管理局(FDA)于2011年1月21日批准盐酸维拉佐酮片剂用于中重度抑郁症的治疗，其市售制剂的商品名为
Figure PCTCN2019124429-appb-000001
分别含有10mg、20mg、40mg规格。临床用药的推荐剂量为40mg/次/天，采用逐级递增给药方案，初始剂量为10mg/次/天，持续给药7天，接着20mg/次/天，连续给药7天，最后维持40mg/次/天的给药剂量。
Figure PCTCN2019124429-appb-000002
片剂口服给药后，主要在小肠部位吸收，其血浆药物浓度达峰时间(T max)为4～5h。然而，由于盐酸维拉佐酮溶解度低，在胃液(pH1.2)和肠液(pH4.5～6.8)环境条件下的溶解度均较差，只有在pH3.1左右的环境中有一定溶解度，故其空腹口服生物利用度较低，导致
Figure PCTCN2019124429-appb-000003
在空腹服用时生物利用极低，难以满足临床治疗需求。因此，
Figure PCTCN2019124429-appb-000004
说明书中明确指出该药物必须与食物同服；在进食条件下，人体胃液pH值约为3.1，且可延缓药物的胃排空，最终导致
Figure PCTCN2019124429-appb-000005
进食条件下的口服生物利用度约为72％，而在空腹条件下，其AUC(血药浓度)和C max(最大峰浓度)分别下降50％和60％。
为了提高盐酸维拉佐酮的溶解度，现有技术公开了将其制备成无定型态，可增加其溶解度。
IN 2012CH03815A专利公开了盐酸维拉佐酮与共聚维酮(S-630)或聚维酮(PVP-K30)制备的固体分散体，X-射线衍射(XRD)图谱显示盐酸维拉佐酮以无定形态存在于载体材料中，但文献中并未给出所制备的盐酸维拉佐酮固体分散体的溶解度或体外溶出度数据；US20140323498专利公开了盐酸维拉佐酮与聚维酮(PVP)或羟丙基甲基纤维素(HPMC)制备的无定型固体分散体；US20130324554专利公开了盐酸维拉佐酮与聚维酮(PVP)、羟丙甲纤维素(HPC)或邻苯二甲酸羟丙基甲基纤维素酯(HPMCP)制备的无定型固体分散体；US20150126525专利公开了盐酸维拉佐酮与聚维酮(PVP)或羟丙基甲基纤维素(HPMC)制备的无定型固体分散体；IN2013MU03458公开了盐酸维拉佐酮与共聚维酮或尤特奇材料制备的无定型固体分散体；CN106580895专利公开了盐酸维拉佐酮与聚维酮(PVP)或聚乙二醇(PEG)制备的固体分散体；CN106580914专利公开了盐酸维拉佐酮与聚乙二醇(PEG)或丙烯酸树脂制备的固体分散体。然而，上述现有技术文献均未公开所制备固体分散体的溶解度或体外溶出度数据，所制备的固体分散体是否能增加盐酸维拉佐酮的溶解度和空腹条件下的口服生物利用度并不清楚。
专利CN 104983711公开了盐酸维拉佐酮与聚维酮(PVP)或聚乙二醇(PEG)按重量比1:2.5比例制备的固体分散体，所制备的固体分散体在低规格(10mg)条件下的溶出度相比于普通制剂有所提高，但提高程 度有限，最高溶出平台大约90％左右。理论推测，在高规格(40mg)条件下，其溶出度更低，空腹条件下的口服生物利用度有限，无法满足临床用药需求。此外，由于处方中载体材料用量过低(1:2.5)，后期制剂的稳定性可能存在问题，可能最终导致口服生物利用度较低。
众所周知，通过固体分散体技术提高难溶性药物溶解度和口服生物利用度时，普遍存在两个重要问题：(1)高规格条件下，溶解的药物容易重新析出结晶，导致溶出度降低，最终引起生物利用度的降低；(2)储存过程中，固体分散体容易老化，出现析晶现象，导致溶出度降低，生物利用度减少。
因此，为满足临床用药需求，急需提供一种稳定性较好，溶解度较高的盐酸维拉佐酮固体分散体，应用于中重度抑郁症的治疗。
发明内容
为了解决维拉佐酮溶解度低导致的空腹生物利用度较低问题，本发明提供了一种稳定性较好且溶解度较高的维拉佐酮固体分散体，所述固体分散体包含维拉佐酮、载体材料和表面活性剂，所述载体材料为水溶性聚合物载体材料。除特别说明，本发明中所述的维拉佐酮可为维拉佐酮游离碱，或其药学上可接受的盐或酯，具体是指5-{4-[4-(5-氰基-3-吲哚)-丁基]-1-哌嗪基}-香豆酮-2-甲酰胺或其药学上可接受的盐或酯。
根据公知常识，在制备固体分散体时，采用不同种类及用量的载体材料对原料药(API)的增溶作用差异较大。因此，要获得增溶作用强且稳定性好的处方并不容易。本发明的发明人经过研究，提供了一种维拉佐酮固体分散体，其具有较好的增溶作用和较好的稳定性。
本发明的第一方面，提出了一种维拉佐酮固体分散体，所述固体分散体包含维拉佐酮、载体材料和表面活性剂。
根据本发明的实施例，所述载体材料为水溶性聚合物载体材料，所述载体材料包括选自聚维酮、共聚维酮、羟丙基甲基纤维素中的至少一种。通过对载体材料的研究，得到了以聚维酮、共聚维酮或羟丙基甲基纤维素等为载体材料制备的维拉佐酮固体分散体，所述维拉佐酮固体分散体在模拟小肠环境中(pH6.8介质)的溶出度均大于50％，显著高于市售制剂，可显著提高维拉佐酮空腹时的口服生物利用度。
根据本发明的实施例，在载体材料的基础上，加入表面活性剂，表面活性剂对所得固体分散体的溶出度的提高及其稳定性的提升有较大影响。
根据本发明的实施例，所述载体材料为水溶性聚合物载体材料，通过对维拉佐酮与水溶性聚合物载体材料的比例进行考察，发现维拉佐酮与水溶性聚合物载体材料的重量比小于等于1:4时，维拉佐酮在固体分散体中以非晶形态存在，且其体外溶出度显著高于市售制剂。此外，考虑到大量载体材料带来的毒性问题以及后期制剂制备的困难，本发明的固体分散体中维拉佐酮与载体材料的重量比为1:4～1:7。在一些实施例中，维拉佐酮与载体材料的重量比为1:4～1:5；在一些实施例中，维拉佐酮与载体材料的重量比为1:4～1:6；在一些实施例中，维拉佐酮与载体材料的重量比为1:5～1:7；在一些实施例中，维拉佐酮与载 体材料的重量比为1:5～1:6；在一些实施例中，维拉佐酮与载体材料的重量比为1:6～1:7。在一些实施例中，维拉佐酮与载体材料的重量比为1:4；在一些实施例中，维拉佐酮与载体材料的重量比为1:5；在一些实施例中，维拉佐酮与载体材料的重量比为1:6；在一些实施例中，维拉佐酮与载体材料的重量比为1:7。
根据本发明的实施例，所述维拉佐酮固体分散体还包括表面活性剂，所述表面活性剂包括但不限于以下几类：
聚氧乙烯烷基醚类，例如聚氧乙烯(3)月桂醚、聚氧乙烯(5)鲸蜡醚、聚氧乙烯(2)硬脂醚、聚氧乙烯(5)硬脂醚；聚氧乙烯烷基芳基醚类，例如聚氧乙烯(2)壬基苯基醚、聚氧乙烯(3)壬基苯基醚、聚氧乙烯(4)壬基苯基醚、聚氧乙烯(3)辛基苯基醚；聚乙二醇甘油酸酯类，例如PEG-200单月桂酸酯、PEG-200二月桂酸酯、PEG-300二月桂酸酯、PEG-400二月桂酸酯、PEG-300二硬脂酸酯、PEG-300二油酸酯：亚烷基二醇脂肪酸单酯，例如丙二醇单月桂酸酯；蔗糖脂肪酸酯类，例如蔗糖单硬脂酸酯、蔗糖二硬脂酸酯、蔗糖单月桂酸酯、蔗糖二月桂酸酯；脱水山梨醇脂肪酸单酯类，例如脱水山梨醇单月桂酸酯、脱水山梨醇单油酸酯、脱水山梨醇单棕榈酸酯、脱水山梨醇硼旨酸酯，或一种或多种上述的混合物。
其中，所述表面活性剂的HLB(亲水亲油平衡值)值不小于6；在一些实施方式中，所述表面活性剂包括选自吐温、司盘-20、聚氧乙烯蓖麻油、聚氧乙烯40氢化蓖麻油(RH40)、辛酸癸酸聚乙二醇甘油酯(Labrasol)、聚乙二醇羟基硬脂酸酯、月桂酸聚乙二醇甘油酯、泊洛沙姆、(D)α-生育酚聚乙二醇琥珀酸盐、十二烷基硫酸钠中的一种或多种。
根据本发明的实施例，所述表面活性剂在所述维拉佐酮固体分散体中的重量比例不大于20％，有利于所得固体分散体的增溶和/或稳定性能。在一些实施方式中，所述表面活性剂在所述维拉佐酮固体分散体中的重量比例不大于10％，有利于所得固体分散体的增溶和/或稳定性能。在一些实施例中，所述表面活性剂在所述维拉佐酮固体分散体中的重量比例为20％。在一些实施例中，所述表面活性剂在所述维拉佐酮固体分散体中的重量比例为10％。
根据本发明的实施例，所述维拉佐酮固体分散体包含维拉佐酮、载体材料和表面活性剂，所述载体材料可为共聚维酮。采用共聚维酮为载体材料制备的维拉佐酮固体分散体，在模拟小肠环境中(pH6.8介质)的溶出度较大，可显著提高维拉佐酮空腹时的口服生物利用度。根据本发明的实施例，维拉佐酮固体分散体中维拉佐酮与共聚维酮的重量比为1:4～1:7。在一些实施例中，维拉佐酮与共聚维酮的重量比为1:6。
根据本发明的实施例，所述维拉佐酮固体分散体中，所述表面活性剂可为泊洛沙姆188。根据本发明的一些实施例，所述维拉佐酮固体分散体包含维拉佐酮、共聚维酮和泊洛沙姆188，所述泊洛沙姆188在所述维拉佐酮固体分散体中的重量比例不大于20％。在一些示例中，所述泊洛沙姆188在所述维拉佐酮固体分散体中的重量比例不大于10％。在一些示例中，所述泊洛沙姆188在所述维拉佐酮固体分散体中的重量比例为20％；在一些示例中，所述泊洛沙姆188在所述维拉佐酮固体分散体中的重量比例为10％。
根据本发明的实施例，所述维拉佐酮固体分散体包含维拉佐酮、载体材料和表面活性剂，所述载体材 料可为聚维酮。采用聚维酮为载体材料制备的维拉佐酮固体分散体，在模拟小肠环境中(pH6.8介质)的溶出度较大，可显著提高维拉佐酮空腹时的口服生物利用度。
根据本发明的实施例，维拉佐酮固体分散体中维拉佐酮与聚维酮的重量比为1:4～1:7。在一些实施例中，维拉佐酮与聚维酮的重量比为1:5；在一些实施例中，维拉佐酮与聚维酮的重量比为1:6。
根据本发明的一些实施例，所述维拉佐酮固体分散体包含维拉佐酮、聚维酮和泊洛沙姆188。根据本发明的一些实施例，所述维拉佐酮固体分散体包含维拉佐酮、聚维酮和司盘-20。根据本发明的一些实施例，所述维拉佐酮固体分散体包含维拉佐酮、聚维酮、泊洛沙姆188和司盘-20。根据本发明的一些实施例，所述司盘-20在所述维拉佐酮固体分散体中的重量比例不大于10％；在一些实施方式中，所述司盘-20在所述维拉佐酮固体分散体中的重量比例不大于5％。在一些示例中，所述司盘-20在所述维拉佐酮固体分散体中的重量比例为10％；在一些示例中，所述司盘-20在所述维拉佐酮固体分散体中的重量比例为5％。
根据本发明的实施例，所述维拉佐酮固体分散体包含维拉佐酮、载体材料和表面活性剂，所述载体材料可为羟丙基甲基纤维素。采用羟丙基甲基纤维素为载体材料制备的维拉佐酮固体分散体，在模拟小肠环境中(pH6.8介质)的溶出度较大，可显著提高维拉佐酮空腹时的口服生物利用度。
根据本发明的实施例，维拉佐酮固体分散体中维拉佐酮与羟丙基甲基纤维素的重量比为1:4～1:7。在一些实施例中，维拉佐酮与羟丙基甲基纤维素的重量比为1:6。
根据本发明的一些实施例，所述维拉佐酮固体分散体包含维拉佐酮、羟丙基甲基纤维素和辛酸癸酸聚乙二醇甘油酯。根据本发明的一些实施例，所述维拉佐酮固体分散体包含维拉佐酮、羟丙基甲基纤维素和聚氧乙烯40氢化蓖麻油。根据本发明的一些实施例，所述维拉佐酮固体分散体包含维拉佐酮、羟丙基甲基纤维素、辛酸癸酸聚乙二醇甘油酯和聚氧乙烯40氢化蓖麻油。根据本发明的一些实施例，所述辛酸癸酸聚乙二醇甘油酯在所述维拉佐酮固体分散体中的重量比例不大于10％。根据本发明的一些实施例，所述聚氧乙烯40氢化蓖麻油在所述维拉佐酮固体分散体中的重量比例不大于10％。在一些实施例中，所述辛酸癸酸聚乙二醇甘油酯在所述维拉佐酮固体分散体中的重量比例为10％。在一些实施例中，所述聚氧乙烯40氢化蓖麻油在所述维拉佐酮固体分散体中的重量比例为10％。
本发明在单一载体材料的基础上，对加入表面活性剂进行了考察。结果显示，针对不同的载体材料，表面活性剂的种类对溶出度的提高及稳定性影响较大。当共聚维酮材料中加入泊洛沙姆188后，所制备的维拉佐酮固体分散体溶出度显著提高且稳定，而加入其它表面活性剂后，溶出度有所提高但不稳定，后期出现了下降。同样的，当聚维酮中加入泊洛沙姆188或司盘20时，或者羟丙基甲基纤维素材料中加入聚氧乙烯40氢化蓖麻油(RH40)或辛酸癸酸聚乙二醇甘油酯(Labrasol)时，所制备的维拉佐酮固体分散体体外溶出度高且稳定，显著高于市售制剂
Figure PCTCN2019124429-appb-000006
溶出度，可显著提高空腹条件下的维拉佐酮口服生物利用度。结果提示，在载体材料基础上，加入特定的表面活性剂后，可以进一步增加盐酸维拉佐酮的溶解度和/或抑制其析晶，减少溶出度的下降，有利于提升分散体的稳定性。
根据本发明的实施例，在一些实施方式中，所述维拉佐酮固体分散体包含维拉佐酮和水溶性聚合物载体材料，所述水溶性聚合物载体材料为混合材料，所述混合材料包含聚维酮、共聚维酮、羟丙基甲基纤维素中的至少两种。在一些实施例中，本发明发现，当溶出度较高(大于70％)时，采用不同比例单一材料制备的固体分散体(未加入表面活性剂)溶出度均出现了不同程度的下降，而采用不同用量及比例的混合材料制备的固体分散体溶出度高且稳定，可克服单一材料处方中的溶出度下降问题，能显著提高维拉佐酮空腹时的口服生物利用度。
根据本发明的实施例，所述维拉佐酮固体分散体包含维拉佐酮和混合材料，所述混合材料包含共聚维酮与羟丙甲纤维素。在一些实施例中，所述混合材料由共聚维酮与羟丙甲纤维素组成。
根据本发明的实施例，所述维拉佐酮固体分散体包含维拉佐酮和上述混合材料，所述混合材料包含聚维酮与羟丙甲纤维素。在一些实施例中，所述混合材料由聚维酮与羟丙甲纤维素组成。
根据本发明的实施例，所述维拉佐酮与所述水溶性聚合物载体材料的重量比为1:4～1:7，在一些示例中，维拉佐酮与水溶性聚合物载体材料的重量比为1:5；在一些示例中，维拉佐酮与水溶性聚合物载体材料的重量比为1:6。
在一些实施方式中，所述维拉佐酮固体分散体包含维拉佐酮、共聚维酮和表面活性剂。
在一些实施方式中，所述维拉佐酮固体分散体包含维拉佐酮、聚维酮和表面活性剂。
在一些实施方式中，所述维拉佐酮固体分散体包含维拉佐酮、羟丙基甲基纤维素和表面活性剂。
本发明的第二方面，提供了所述维拉佐酮固体分散体的制备方法，维拉佐酮固体分散体可通过多种技术制备得到，包括而不限于喷雾干燥法、热熔挤出法、冷冻干燥法、溶剂挥发法、共沉淀法、超临界流体法等。
在一些实施例中，本发明采用热熔挤出法制备了维拉佐酮固体分散体，该方法操作简便，易于大生产。在所制备的固体分散体中，维拉佐酮以非晶形态存在，且该固体分散体的体外溶出度相比于市售制剂
Figure PCTCN2019124429-appb-000007
显著提高。
在另一些实施例中，本发明采用了喷雾干燥法制备维拉佐酮固体分散体。所述喷雾干燥法包括以下步骤：按配比称量维拉佐酮和载体材料，加入至溶剂中，搅拌溶解，于喷雾干燥器中喷干，收集粉末，即得维拉佐酮固体分散体；所述溶剂为丙酮水溶液，丙酮的体积浓度为大于60％、小于等于70％。在喷雾干燥法制备固体分散体时，寻找一种既能溶解药物又能溶解材料、且比较安全的溶剂至关重要，只有药物和材料同时溶解的情况下，药物与材料才能充分地相互作用，得到更加稳定的固体分散体。本发明通过大量地筛选，优化得到了以60％～70％丙酮水溶液为溶剂。采用该溶剂可以配制高浓度且稳定的维拉佐酮溶液用于喷雾干燥，且在该浓度条件下，各种载体材料的溶解度也较高，这样可以大大提高溶液固含量，显著提高喷雾干燥效率，降低能耗。当然，在不考虑能耗的情况下，也可以采用较低浓度的丙酮溶液或甲醇、乙醇溶液等配制的低浓度维拉佐酮溶液用于喷雾干燥。此外，在配制维拉佐酮喷干溶液时，为了使维拉佐 酮原料药和载体材料更好和快速的溶解，可以通过加热或超声的方式加快溶解。本发明采用60％～70％丙酮水溶液为溶剂制备的固体分散体，维拉佐酮以非晶形态存在，且体外溶出度显著高于市售制剂
Figure PCTCN2019124429-appb-000008
本发明第三方面，提供了维拉佐酮固体分散体的用途，一种上述维拉佐酮固体分散体在制备维拉佐酮制剂中的用途。所述维拉佐酮制剂包含维拉佐酮固体分散体和药学上可接受的辅料，所述药学上可接受的辅料包括但不限于以下几种：填充剂，例如乳糖、蔗糖、果糖、低聚果糖、葡萄糖、麦芽糖、粉末糖等糖类，D-甘露醇、赤藓糖醇、木糖醇等糖醇类，玉米淀粉、马铃薯淀粉、米淀粉、部分α淀粉等淀粉类，微晶纤维素等纤维素类，硫酸钙、磷酸氢钙、碳酸钙等无机盐类；崩解剂，例如淀粉、微晶纤维素、羧甲基纤维素钙、交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素等；润滑剂，例如硬脂酸镁、硬脂酸钙、硬脂酸富马酸钠、硬脂酸、滑石粉、聚乙二醇、蔗糖脂肪酸酯、微粉硅胶。
本发明提供的维拉佐酮制剂包括片剂、胶囊、颗粒剂、散剂或干混悬剂。根据临床治疗需求，可选择性地制备成上述相应的剂型，方便患者服用，提高患者顺应性。为了防止维拉佐酮固体分散体制剂的吸潮和老化，也可将其制备成包衣片；此外，为了使维拉佐酮在小肠部位吸收，也可将其制备成肠溶包衣片。
在一些实施例中，本发明采用共聚维酮为载体材料，泊洛沙姆188为表面活性剂，制备维拉佐酮固体分散体，加入适量药学上可接受的辅料制备成片剂后，在空腹条件下，其在Beagle犬体内的口服生物利用度显著高于市售制剂
Figure PCTCN2019124429-appb-000009
且在空腹和进食状态下，本发明提供的维拉佐酮固体分散体制剂等效，消除了食物效应，提示本发明提供的维拉佐酮固体分散体在空腹和进食条件下均可服用，可显著提高患者服药方便性和依从性。
在一些实施例中，本发明进一步对维拉佐酮固体分散体的稳定性进行了考察，在加速条件(40℃，75％RH)，存储2个月后，维拉佐酮仍以无定形态存在于固体分散体中，且体外溶出度无显著变化，说明本发明制备的维拉佐酮固体分散体稳定性好，满足工业化生产要求。
本发明提供的维拉佐酮固体分散体，能显著提高维拉佐酮的溶解度和体外溶出度，进而提高其空腹生物利用度；更进一步地，本发明提供的维拉佐酮固体分散体还能消除食物的影响，在空腹和进食条件下，其口服生物利用度等效，提示本发明提供的维拉佐酮固体分散体制剂可在空腹或进食条件下服用，显著提高患者服药便利性和顺应性，可用于中重度抑郁症的治疗。
术语定义
本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
在本发明的上下文中，无论是否使用“大约”、“约”或“大概”等字眼，所有在此公开了的数字均为近似值。每一个数字的数值有可能会出现10％以下的差异或者本领域人员认为的合理的差异，如1％、2％、3％、4％或5％的差异。
LC-MS-MS指液质联用，XRD是指X射线衍射。
PVP指聚维酮，VA64指共聚维酮，HPMC指羟丙基甲基纤维素，Labrasol指辛酸癸酸聚乙二醇甘油酯，Cremophor RH40指聚氧乙烯40氢化蓖麻油，T-80指吐温-80，F68指泊洛沙姆188，S-20指司盘-20，TPGS指(D)α-生育酚聚乙二醇1000琥珀酸盐。
PEG指聚乙二醇，Soluplus指聚乙二醇/乙烯基己内酰胺/醋酸乙烯酯共聚物，HPMCAS是指醋酸羟丙甲纤维素琥珀酸酯，HPC指羟丙基纤维素。
AUC指血药浓度-时间曲线下面积，C max指达峰血药浓度。
M指摩尔，h指小时，g指克，mm指毫米，μm指微米，nm指纳米，μl指微升，min指分钟，℃指摄氏度，mg指毫克，mL指毫升，rpm指转/分钟。
附图说明
图1实施例3的(1)不同VA64用量制备的盐酸维拉佐酮固体分散体的XRD图谱。
图2实施例3的(2)不同PVP用量制备的盐酸维拉佐酮固体分散体的XRD图谱。
图3实施例3的(3)不同HPMC用量制备的盐酸维拉佐酮固体分散体的XRD图谱。
图4实施例3的(4)不同混合载体制备的盐酸维拉佐酮固体分散体的XRD图谱。
图5实施例7维拉佐酮固体分散体制剂Beagle犬体内药-时曲线图。
图6实施例8维拉佐酮固体分散体加速稳定性2个月后XRD图谱。
具体实施方式
为了更好的理解本发明的技术方案，下面结合具体实施例对本发明作进一步的阐述。除非特别说明，在下面实施例中没有明确描述具体技术或条件的，本领域技术人员可以按照本领域内的常用技术或条件或按照产品说明书进行。所用药品、试剂或仪器未注明生产厂商者，均为可市购的常规产品。
其中，参比制剂
Figure PCTCN2019124429-appb-000010
为森林实验室开发的规格为10mg和40mg/片的盐酸维拉佐酮片。
羟丙基甲基纤维素琥珀酸酯(HPMCAS-LF和HPMCAS-MF)、聚乙二醇4000(PEG-4000)购于美国Ashland公司；聚乙二醇/乙烯基己内酰胺/醋酸乙烯酯共聚物(Soluplus)、聚维酮(PVP)购于德国巴斯夫公司；共聚维酮(VA64)购于德国巴斯夫公司；羟丙基甲基纤维素(HPMC)购于Ashland公司；羟丙基纤维素(HPC)购于日本曹达公司。
吐温-80(T-80)、泊洛沙姆188(F68)、司盘-20(S-20)、聚氧乙烯40氢化蓖麻油(Cremophor RH40)、辛酸癸酸聚乙二醇甘油酯(Labrasol)、(D)α-生育酚聚乙二醇1000琥珀酸盐(TPGS)均为市售表面活性剂。
维拉佐酮含量测定方法为高效液相色谱法(HPLC)，具体条件为：色谱条件：检测波长为242nm，色谱柱采用kromasil 100-5C18(4.6mm×150mm，5μm)，流动相为pH6.0的0.02M磷酸氢二钾与乙腈为54:46(V/V)，流速为1.0ml/min，进样量为10μl，运行时间到4.5min。
实施例1溶剂的筛选
(1)单一溶剂的考察
分别称取10mg盐酸维拉佐酮固体粉末于4ml EP管中，每管中各加入1ml二氯甲烷、甲醇、乙醇、丙酮和乙酸乙酯，水浴超声30min，观察粉末溶解情况；样品在室温放置24h后，观察外观，注意是否有沉淀析出。具体结果见表1。
表1维拉佐酮在不同有机溶剂中的溶解情况
溶剂 浓度 现象
二氯甲烷 10mg/ml 不溶，大量沉淀
乙醇 10mg/ml 不溶，少量沉淀
甲醇 10mg/ml 不溶，少量沉淀
丙酮 10mg/ml 不溶，少量沉淀
乙酸乙酯 10mg/ml 不溶，大量沉淀
上述结果显示，采用单一有机溶剂均不能很好的配制10mg/ml的维拉佐酮溶液。相比较而言，盐酸维拉佐酮在乙醇、甲醇或丙酮中溶解度相对较好，可作为后续优化的溶剂。
(2)乙醇水溶液的考察
分别称取10mg盐酸维拉佐酮固体粉末于4ml EP管中，每管中各加入1ml不同浓度的乙醇水溶液，水浴超声30min，观察粉末溶解情况；样品在室温放置24h后，观察外观，注意是否有沉淀析出。具体结果见表2。
表2维拉佐酮在乙醇水溶液中的溶解情况
乙醇(ml) 水(ml) API 现象
0.1 0.9 10mg 不溶，大量沉淀
0.2 0.8 10mg 不溶，大量沉淀
0.3 0.7 10mg 不溶，大量沉淀
0.4 0.6 10mg 溶解，放置1天析出
0.5 0.5 10mg 溶解，放置略析出
0.6 0.4 10mg 溶解，放置1天析出
0.7 0.3 10mg 溶解，放置略析出
0.8 0.2 10mg 不溶，大量沉淀
0.9 0.1 10mg 不溶，大量沉淀
上述结果表明，采用不同浓度的乙醇水溶液配制10mg/ml的盐酸维拉佐酮溶液时，均不能得到高浓度的稳定溶液。
(3)甲醇水溶液的考察
分别称取30mg盐酸维拉佐酮固体粉末于10ml EP管中，每管中各加入3ml不同浓度的甲醇水溶液，水浴超声30min，观察粉末溶解情况；若粉末快速溶解，继续加入少量粉末，提高样品浓度，超声溶解；最后，溶液样品在室温放置24h，观察是否有沉淀析出。具体结果见表3。
表3维拉佐酮在甲醇水溶液中的溶解情况
甲醇(ml) 水(ml) API 结果
0.3 2.7 30mg 不溶，大量沉淀
0.6 2.4 30mg 不溶，大量沉淀
0.9 2.1 30mg 不溶，大量沉淀
1.2 1.8 30mg 不溶，大量沉淀
1.5 1.5 30mg 溶解，继续加入少量粉末至15mg/ml，不溶
1.8 1.2 30mg 继续加入少量粉末至15mg/ml，溶解，放置析出
2.1 0.9 30mg 继续加入少量粉末至20mg/ml，不溶
2.4 0.6 30mg 溶解，继续加入少量粉末至15mg/ml，不溶
2.7 0.3 30mg 溶解，继续加入少量粉末至15mg/ml，不溶
上述结果显示，采用50％以上浓度的甲醇水溶液可成功配置10mg/ml的盐酸维拉佐酮溶液，但继续增加药物浓度时，出现沉淀，不溶解，无法得到高浓度且稳定的维拉佐酮溶液，以满足实验要求。
(4)丙酮水溶液的考察
分别称取10mg盐酸维拉佐酮固体粉末于4ml EP管中，每管中各加入1ml不同浓度的丙酮水溶液，水浴超声30min，观察粉末溶解情况；若粉末快速溶解，继续加入少量粉末，提高样品浓度，超声溶解；最后，溶液样品在室温放置24h，观察是否有沉淀析出。具体结果见表4。
表4维拉佐酮在丙酮水溶液中的溶解情况
丙酮(ml) 水(ml) API 现象
0.1 0.9 10mg 不溶，大量沉淀
0.2 0.8 10mg 不溶，大量沉淀
0.3 0.7 10mg 不溶，大量沉淀
0.4 0.6 10mg 完全溶解，放置析出
0.5 0.5 10mg 完全溶解，放置析出
0.6 0.4 10mg 完全溶解，增加浓度至40mg/ml，未析出
0.7 0.3 10mg 完全溶解，增加浓度至40mg/ml，未析出
0.8 0.2 10mg 完全溶解，放置析出
0.9 0.1 10mg 不溶，大量沉淀
上述结果表明，采用60％～70％左右的丙酮水溶液可以成功配制稳定的高浓度盐酸维拉佐酮溶液，满足后续实验的要求。
(5)载体材料在丙酮溶液中的溶解性考察
分别取5ml丙酮溶液(50％、60％、70％、80％体积浓度)至50mL BD管中，加入约250mg载体材料，于磁力搅拌器中，搅拌溶解，若溶液变澄清，继续加入载体材料，搅拌溶解，直至溶液成浑浊状态，记录所加入的材料用量。具体结果见表5。
表5不同载体材料在丙酮水溶液中的溶解情况
Figure PCTCN2019124429-appb-000011
上述结果显示，为了同时满足药物和载体材料的溶解以及获得合适的溶液粘度用于喷雾干燥，丙酮溶 液的浓度为60％～70％。当然，若采用较低浓度的药物和材料，也可将丙酮浓度范围进一步扩大至50％～80％，或者更大。
实施例2不同载体材料的筛选
(1)市售制剂
Figure PCTCN2019124429-appb-000012
溶出度测定
取
Figure PCTCN2019124429-appb-000013
片剂(10mg/40mg)6片，按照美国药典Ⅱ法(USPⅡ)，以900mL介质，60rpm转速为条件，分别测定其在0.1M HCl、pH3.1和pH6.8介质中的溶出度。试验开始后，于5min、10min、15min、20min、30min和45min时间点取样10ml，立即补以10ml新鲜溶出介质，继续试验。将所取样品过0.45μm滤膜，取适量续滤液，用HPLC方法测定样品中药物含量，计算每个时间点的累积溶出率。具体结果见表6。
表6
Figure PCTCN2019124429-appb-000014
片剂体外溶出度测定结果
Figure PCTCN2019124429-appb-000015
(2)载体材料种类的考察
按表7中处方，称量各载体材料和盐酸维拉佐酮粉末于烧杯中，加入60％丙酮水溶液，40℃水浴加热条件下，搅拌溶解，将上述液体于Buchi喷雾干燥仪器中(进风温度：170℃，出风温度：95℃，转速：15rpm)，喷雾干燥，得到喷干粉末。将上述喷干粉末与微晶纤维素按1:3比例混合均匀，按照上述“市售制剂溶出度测定”项下方法，检测40mg规格样品在pH6.8介质中的溶出度，结果见表8。
表7不同载体材料处方
Figure PCTCN2019124429-appb-000016
Figure PCTCN2019124429-appb-000017
表8不同载体材料制备的固体分散体在pH6.8介质中的溶出度结果
Figure PCTCN2019124429-appb-000018
上述结果显示，采用共聚维酮(VA64)、聚维酮(PVP)或羟丙甲纤维素(HPMC)为材料制备的盐酸维拉佐酮固体分散体，在模拟肠液(pH6.8介质)中的溶出度相对较高，高规格(40mg)条件下，溶出平台均大于50％，且远远大于参比制剂
Figure PCTCN2019124429-appb-000019
的溶出度，可显著增加维拉佐酮在空腹条件下的口服生物利用度，作为后续处方优化的基础。然而，在高溶出度(70％)条件下，部分处方出现了溶出度下降的趋势。
(3)混合载体材料的考察
按表9中处方，称量各载体材料和盐酸维拉佐酮粉末于烧杯中，加入60％丙酮水溶液，50℃水浴加热条件下，搅拌溶解，将上述液体于Buchi喷雾干燥仪器中，喷雾干燥，得到喷干粉末；其中，处方11中含有低熔点材料PEG4000，进风温度设置为95℃，出风温度：50℃，转速：20rpm，其余处方的进风温度为：160℃，出风温度：85℃，转速：20rpm)。将上述喷干粉末与微晶纤维素按1:3比例混合均匀，按照上述“市售制剂溶出度测定”项下方法，检测40mg规格样品在pH6.8介质中的溶出度，结果见表10。
表9混合载体材料处方
组成 处方-8 处方-9 处方-10 处方11
盐酸维拉佐酮 10g 10g 10g 10g
VA64 20g 30g —— ——
PVP 40g —— 30g 24g
HPMC —— 30g 30g ——
PEG-4000 —— —— —— 26g
60％丙酮水溶液 1000ml 1000ml 1000ml 1000ml
表10混合载体材料制备的固体分散体在pH6.8介质中的溶出度结果
Figure PCTCN2019124429-appb-000020
上述结果显示，采用混合材料制备的盐酸维拉佐酮固体分散体，在模拟肠液(pH6.8介质)中的溶出度相对较高，且远远大于参比制剂
Figure PCTCN2019124429-appb-000021
的溶出度；而采用PVP+PEG4000为材料时，溶出度有下降的趋势，采用VA64+HPMC或PVP+HPMC混合材料时，所制备的盐酸维拉佐酮固体分散体(40mg规格)溶出度最高，均大于70％，且相对稳定(变化范围小于5％)，未出现析晶、溶出度下降现象，可显著增加维拉佐酮在空腹条件下的口服生物利用度。
实施例3载体材料用量的考察
(1)共聚维酮用量的考察
按表11中处方，称量不同用量共聚维酮(VA64)和盐酸维拉佐酮粉末于烧杯中，加入70％丙酮水溶液，搅拌溶解，将上述溶液于Buchi喷雾干燥仪器中(进风温度：170℃，出风温度：90℃，转速：20rpm)，喷雾干燥，得到喷干粉末。将上述喷干粉末与微晶纤维素按1:3比例混合均匀，按照实施例2中(1)所述溶出度测定方法，检测40mg规格样品在pH6.8介质中的溶出度，结果见表12。
此外，取适量上述处方的喷干粉末，于X射线衍射仪(XRD)中，测定维拉佐酮的X射线衍射峰，具体图谱见附图1。
表11不同共聚维酮用量处方
组成 处方-12 处方-13 处方-14 处方-15
盐酸维拉佐酮 10g 10g 10g 10g
共聚维酮 40g 50g 60g 70g
70％丙酮水溶液 1000ml 1000ml 1000ml 1000ml
表12不同用量共聚维酮制备的固体分散体在pH6.8介质中的体外溶出度结果
Figure PCTCN2019124429-appb-000022
上述结果显示，当盐酸维拉佐酮与共聚维酮(VA64)的重量比小于或等于1:4时，药物以非晶形态存在于固体分散体中，且其在模拟肠液(pH6.8介质)中的溶出度显著高于参比制剂
Figure PCTCN2019124429-appb-000023
(40mg规格)，且稳定，可显著增加维拉佐酮在空腹条件下的口服生物利用度。然而，随着材料量的增加，药物的溶出度并没有显著的增加。
(2)聚维酮用量的考察
按表13中处方，称量不同用量聚维酮(PVP)和盐酸维拉佐酮粉末于烧杯中，加入60％丙酮水溶液，搅拌溶解，将上述溶液于Buchi喷雾干燥仪器中(进风温度：170℃，出风温度：90℃，转速：20rpm)，喷雾干燥，得到喷干粉末。将上述喷干粉末与微晶纤维素按1:3比例混合均匀，按照实施例2中(1)所述溶出度测定方法，检测40mg规格样品在pH6.8介质中的溶出度，结果见表14。
此外，取适量上述处方的喷干粉末，于X射线衍射仪(XRD)中，检测维拉佐酮的X射线衍射峰，具体图谱见附图2。
表13不同聚维酮用量处方
组成 处方-16 处方-17 处方-18 处方-19
盐酸维拉佐酮 10g 10g 10g 10g
聚维酮 40g 50g 60g 70g
60％丙酮水溶液 1000ml 1000ml 1000ml 1000ml
表14不同用量聚维酮材料制备的固体分散体在pH6.8介质中的体外溶出度结果
Figure PCTCN2019124429-appb-000024
Figure PCTCN2019124429-appb-000025
上述结果显示，当盐酸维拉佐酮与聚维酮(PVP)的重量比小于或等于1:4时，药物以非晶形态存在于固体分散体中，且其在模拟肠液(pH6.8介质)中的溶出度显著高于参比制剂
Figure PCTCN2019124429-appb-000026
(40mg规格)，提示可显著增加维拉佐酮在空腹条件下的口服生物利用度。然而，不同比例聚维酮制备的固体分散体均出现了溶出下降的趋势，表现出不太稳定。
(3)羟丙基甲基纤维素用量的考察
按表15中处方，称量不同用量羟丙基甲基纤维素(HPMC)和盐酸维拉佐酮粉末于烧杯中，加入60％丙酮水溶液，搅拌溶解，将上述溶液于Buchi喷雾干燥仪器中(进风温度：170℃，出风温度：95℃，转速：20rpm)，喷雾干燥，得到喷干粉末。将上述喷干粉末与微晶纤维素按1:3比例混合均匀，按照实施例2中(1)所述溶出度测定方法，检测40mg规格样品在pH6.8介质中的溶出度，结果见表16。
此外，取适量上述处方的喷干粉末，于X射线衍射仪(XRD)中，检测维拉佐酮的X射线衍射峰，具体图谱见附图3。
表15不同羟丙基甲基纤维素用量处方
组成 处方-20 处方-21 处方-22 处方-23
盐酸维拉佐酮 10g 10g 10g 10g
羟丙基甲基纤维素 40g 50g 60g 70g
60％丙酮水溶液 1200ml 1200ml 1200ml 1200ml
表16不同用量HPMC材料制备的固体分散体在pH6.8介质中的体外溶出度结果
Figure PCTCN2019124429-appb-000027
上述结果显示，当盐酸维拉佐酮与羟丙基甲基纤维素(HPMC)的重量比小于或等于1:4时，药物以非晶形态存在于固体分散体中，且其在模拟肠液(pH6.8介质)中的溶出度显著高于参比制剂
Figure PCTCN2019124429-appb-000028
(40mg 规格)，可显著增加维拉佐酮在空腹条件下的口服生物利用度。然而，不同比例羟丙基甲基纤维素制备的固体分散体在溶出度测定后期均出现了下降现象。
(4)混合载体材料用量及比例的考察
按表17中处方，称量不同比例的载体材料和盐酸维拉佐酮粉末于烧杯中，加入60％丙酮水溶液，50℃水浴加热条件下，搅拌溶解，将上述液体于Buchi喷雾干燥仪器中(进风温度：150℃，出风温度：85℃，转速：20rpm)，喷雾干燥，得到喷干粉末。将上述喷干粉末与微晶纤维素按1:3比例混合均匀，按照上述“市售制剂溶出度测定”项下方法，检测40mg规格样品在pH6.8介质中的溶出度，结果见表18。
此外，取适量上述处方的喷干粉末，于X射线衍射仪(XRD)中，检测盐酸维拉佐酮的X射线衍射峰，具体图谱见附图4。
表17不同比例混合载体材料处方
Figure PCTCN2019124429-appb-000029
表18不同比例混合材料制备的固体分散体在pH6.8介质中的溶出度结果(Mean±SD)
Figure PCTCN2019124429-appb-000030
上述结果显示，采用不同比例的混合材料制备的盐酸维拉佐酮固体分散体，药物均以非晶形态存在于固体分散体中，其在模拟肠液(pH6.8介质)中的溶出度高且稳定(溶出度大于70％，溶出平台波动在5％以内)，且显著高于参比制剂
Figure PCTCN2019124429-appb-000031
(40mg规格)，可显著增加维拉佐酮在空腹条件下的口服生物利用度。
实施例4表面活性剂的考察
(1)共聚维酮+表面活性剂的考察
按表19中处方，称量各载体材料、表面活性剂和盐酸维拉佐酮粉末于烧杯中，加入60％丙酮水溶液，搅拌溶解，将上述溶液于Buchi小型喷雾干燥仪器中(进风温度：170℃，出风温度：90℃，转速：20rpm)，喷雾干燥，得到喷干粉末。将上述喷干粉末与微晶纤维素按1:3比例混合均匀，按照实施例2中(1)所述溶出度测定方法，检测40mg规格样品在pH6.8介质中的溶出度，结果见表20。
表19共聚维酮+不同表面活性剂处方
Figure PCTCN2019124429-appb-000032
表20共聚维酮+不同表面活性剂处方在pH6.8介质中的溶出度结果(Mean±SD)
Figure PCTCN2019124429-appb-000033
上述结果显示，在共聚维酮材料基础上，加入不同表面活性剂后，所制备的维拉佐酮固体分散体的溶出度均有较大提高，但大部分处方出现了不稳定现象，溶出度下降；而当加入泊洛沙姆188(F68)时，溶出度显著提高且稳定，显著高于参比制剂
Figure PCTCN2019124429-appb-000034
(40mg规格)溶出度，可显著增加维拉佐酮在空腹条件下的口服生物利用度。
(2)聚维酮或羟丙基甲基纤维素+表面活性剂的考察
按表21中处方，称量各载体材料、表面活性剂和盐酸维拉佐酮粉末于烧杯中，加入60％丙酮水溶液，搅拌溶解，将上述溶液于Buchi小型喷雾干燥仪器中(进风温度：170℃，出风温度：95℃，转速：15rpm)， 喷雾干燥，得到喷干粉末。将上述喷干粉末与微晶纤维素按1:3比例混合均匀，按照实施例2中(1)所述溶出度测定方法，检测40mg规格样品在pH6.8介质中的溶出度，结果见表22。
表21不同材料+表面活性剂处方
Figure PCTCN2019124429-appb-000035
表22不同材料+表面活性剂处方在pH6.8介质中的溶出度结果(Mean±SD)
Figure PCTCN2019124429-appb-000036
上述结果显示，在羟丙基甲基纤维素载体材料基础上，加入RH40或Labrasol表面活性剂时，固体分散体的溶出度高且稳定，而加入F68表面活性剂时，溶出度不稳定，出现下降；在聚维酮材料基础上，加入Span-20或F68表面活性剂时，固体分散体的溶出度高且稳定，而加入TPGS表面活性剂时，溶出度不稳定，出现下降。上述结果提示处方中加入特定表面活性剂后，可进一步增加维拉佐酮在空腹条件下的口服生物利用度。
实施例5表面活性剂用量的考察
按表23中处方，称量各载体材料、表面活性剂和盐酸维拉佐酮粉末于烧杯中，加入60％丙酮水溶液，搅拌溶解，将上述溶液于Buchi小型喷雾干燥仪器中(进风温度：170℃，出风温度：95℃，转速：20rpm)， 喷雾干燥，得到喷干粉末。将上述喷干粉末与微晶纤维素按1:3比例混合均匀，按照实施例2中(1)所述溶出度测定方法，检测40mg规格样品在pH6.8介质中的溶出度，结果见表24。
表23不同表面活性剂用量处方
Figure PCTCN2019124429-appb-000037
表24不同表面活性剂用量处方在pH6.8介质中的溶出度结果(Mean±SD)
Figure PCTCN2019124429-appb-000038
上述结果显示，加入表面活性剂后，固体分散体的溶出度显著提高，表面活性剂的用量在20％范围以内时，溶出度相对较稳定(下降变化在5％以内)，且显著高于参比制剂
Figure PCTCN2019124429-appb-000039
(40mg规格)的溶出度，可显著增加维拉佐酮在空腹条件下的口服生物利用度。
实施例6热熔挤出工艺制备维拉佐酮固体分散体
按表25中处方，称量各载体材料、表面活性剂和维拉佐酮游离碱粉末于塑料袋中，混合均匀，加入至Thermo双螺杆热熔挤出机中(挤出温度为180℃，螺杆转速为100转/分钟)，挤出混合物，冷却后粉碎，即得维拉佐酮固体分散体。将上述固体分散体粉末与微晶纤维素按1:3比例混合均匀，按照实施例2中(1)所述溶出度测定方法，检测10mg规格样品在pH6.8介质中的溶出度，结果见表26。
表25不同材料处方
组成 处方-52 处方-53 处方-54
维拉佐酮 10g 10g 10g
HPMCAS-MF 60g 45g 30g
Soluplus —— 15g 30g
泊洛沙姆188 7.78g 7.78g 5g
表26不同处方在pH6.8介质中的溶出度结果(Mean±SD)
Figure PCTCN2019124429-appb-000040
上述结果显示，采用热熔挤出工艺制备的维拉佐酮固体分散体在模拟肠液(pH6.8介质)中的溶出度显著高于参比制剂
Figure PCTCN2019124429-appb-000041
(10mg规格)，提示热熔挤出工艺制备的维拉佐酮固体分散体能显著增加维拉佐酮在空腹条件下的口服生物利用度。
实施例7 Beagle犬体内药物动力学性质考察
(1)维拉佐酮片剂的制备及溶出度测定
选用处方33的喷雾干燥粉末为原料，按表27称量各物料，混合均匀；总混物料过40目筛，直接压片，即得盐酸维拉佐酮片剂。按照实施例2中(1)所述溶出度测定方法，检测自研片剂在不同介质中的溶出度，结果见表28。
(2)Beagle犬体内药物动力学实验
采用上述盐酸维拉佐酮片剂(10mg规格)进行Beagel犬体内药动试验的考察。6只雄性、健康成年Beagle犬，体重范围为15～20kg，随机分为2组，进行双交叉、二周期试验，分别考察自研维拉佐酮片剂(10mg)在空腹、进食(高脂、高热量食物)条件下的药动学性质。动物口服给药后，分别于0.25、0.5、1、2、4、6、8、10、24h采取全血；将上述全血置于盛有K 2EDTA抗凝剂的离心管中，4℃条件下，3500转/分钟离心10min，收集上层血浆，-70℃条件下保存，待检测。
采用LC-MS-MS方法检测血浆中维拉佐酮的含量，血药浓度—时间曲线见附图6；应用WinNonlin 6.3软件非房室模型法计算药动学参数，食物效应评价标准按照Ratio值计算，Ratio＝Fed/Fast*100％，具体结果见表28(参比制剂
Figure PCTCN2019124429-appb-000042
的动物体内PK数据参考优先权专利WO2018082557A1)。对于给定的受 试动物群中的单只动物均按此公式计算Cmax和AUC的Ratio值，每只动物的Ratio值相加后，将总和除以受试动物只数，即得平均值。如果Ratio均值在大约70％到大约143％范围内，即可确定该剂型没有食物效应，进食和空腹服用时是等效的，也就是说，该剂型无论是在进食或空腹条件下服用，均具有基本相同的生物利用度和药效。(备注：Fast代表空腹给药，Fed代表进食给药；Test为自研维拉佐酮片剂，RLD为参比制剂
Figure PCTCN2019124429-appb-000043
)
表27维拉佐酮片剂处方
Figure PCTCN2019124429-appb-000044
表28自研片剂在不同溶出介质中的溶出度(Mean±SD)
溶出介质 5min 10min 15min 20min 30min 45min
PH3.1 41±9.02 78±12.74 92±2.52 95±1.53 96±2.08 98±2.52
PH6.8 41±3.06 85±4.58 90±1.53 92±1.15 94±1.53 94±1.00
0.1MHCl 65±20.00 81±18.52 87±9.61 89±7.55 91±6.03 92±4.16
表29空腹和进食状态下维拉佐酮片剂药动学数据(Mean±SD,n＝6)
Group T max(h) C max(ng/mL) AUC last(h*ng/mL)
Test-Fed 1.33±0.58 56±36 273±170
Test-Fast 0.83±0.29 62±27 240±120
Test-(Fed/Fast)％ —— 90.32 113.75
RLD-Fast 1.50±0.55 25±19 109±94
RLD-Fed 2.33±1.86 77±57 267±188
RLD-(Fed/Fast)％ —— 308.00 244.95
结果显示，自制维拉佐酮组合物片剂在空腹(Test-fast)和进食(Test–fed)状态下的Cmax和AUC接近，比值均在70％～143％范围内，认为无食物效应，说明本实施例的维拉佐酮固体分散体制备的制剂可显著提高空腹状态下的生物利用度，消除食物的影响，使空腹和进食状态下均可服用药物；而市售制剂
Figure PCTCN2019124429-appb-000045
(RLD,10mg)在空腹和进食状态下Cmax和AUC比值远远小于70％～143％范围，存在显著的食物效应。上述结果提示本发明提供的维拉佐酮固体分散体制剂可显著提高维拉佐酮空腹服用时的生物利用度，消除了食物的影响，空腹和进食条件下均可服用，显著改善患者服药的便利性，提高患者顺应性，这对于需要长期服药、且常伴有食欲不振和自杀倾向的重度抑郁症患者来说，具有重大的临床意义。
实施例8加速稳定性考察
按照处方28、处方33和处方41比例，喷雾干燥，得到喷干粉末，于双铝袋中密封包装，在40℃、75％RH(湿度)条件下，储存2个月；到达时间点后，取样，分别测定各个处方盐酸维拉佐酮的晶型以及体外pH6.8介质中的溶出度。各个处方喷干粉末样品储存2个月后的XRD粉末衍射图谱见附图6，溶出度结果见表29；结果显示，不同处方制备的盐酸维拉佐酮固体分散体在加速条件下储存2个月后，仍然于非晶形态存在，且体外溶出度稳定，提示本发明提供的维拉佐酮固体分散体稳定性良好。
表30不同处方喷干粉末在pH6.8介质中的溶出度结果
Figure PCTCN2019124429-appb-000046
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中各技术特征所有可能的组合进行描述；然而，只要这些技术特征的组合不存在矛盾，都应该被认为属于本发明说明书记载的范围。以上实施例仅表达了本发明的几种实施方式，其描述较为具体，但并不能理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。

Claims (30)

  1. 一种维拉佐酮固体分散体，其特征在于，包含维拉佐酮、载体材料和表面活性剂。
  2. 根据权利要求1所述的维拉佐酮固体分散体，其特征在于，所述载体材料为水溶性聚合物载体材料，所述载体材料包括选自聚维酮、共聚维酮、羟丙基甲基纤维素中的至少一种。
  3. 根据权利要求2所述的维拉佐酮固体分散体，其特征在于，所述维拉佐酮与所述水溶性聚合物载体材料的重量比为1:4～1:7。
  4. 根据权利要求1-3任一所述的维拉佐酮固体分散体，其特征在于，所述表面活性剂包括选自司盘-20、聚氧乙烯40氢化蓖麻油、辛酸癸酸聚乙二醇甘油酯和泊洛沙姆中的至少一种。
  5. 根据权利要求1所述的维拉佐酮固体分散体，其特征在于，所述表面活性剂在所述维拉佐酮固体分散体中的重量比例不大于20％。
  6. 根据权利要求1所述的维拉佐酮固体分散体，其特征在于，所述表面活性剂在所述维拉佐酮固体分散体中的重量比例不大于10％。
  7. 根据权利要求1所述的维拉佐酮固体分散体，其特征在于，所述载体材料为共聚维酮。
  8. 根据权利要求7所述的维拉佐酮固体分散体，其特征在于，所述维拉佐酮与所述共聚维酮的重量比为1:4～1:7。
  9. 根据权利要求8所述的维拉佐酮固体分散体，其特征在于，所述表面活性剂为泊洛沙姆188。
  10. 根据权利要求9所述的维拉佐酮固体分散体，其特征在于，所述泊洛沙姆188在所述维拉佐酮固体分散体中的重量比例不大于20％。
  11. 根据权利要求9所述的维拉佐酮固体分散体，其特征在于，所述泊洛沙姆188在所述维拉佐酮固体分散体中的重量比例不大于10％。
  12. 根据权利要求1所述的维拉佐酮固体分散体，其特征在于，所述载体材料为聚维酮。
  13. 根据权利要求12所述的维拉佐酮固体分散体，其特征在于，所述维拉佐酮与所述聚维酮的重量比为1:4～1:7。
  14. 根据权利要求13所述的维拉佐酮固体分散体，其特征在于，所述表面活性剂为包括选自司盘-20和泊洛沙姆188中的至少一种。
  15. 根据权利要求14所述的维拉佐酮固体分散体，其特征在于，所述表面活性剂为司盘-20。
  16. 根据权利要求15所述的维拉佐酮固体分散体，其特征在于，所述司盘-20在所述维拉佐酮固体分散体中的重量比例不大于10％。
  17. 根据权利要求15所述的维拉佐酮固体分散体，其特征在于，所述司盘-20在所述维拉佐酮固体分散体中的重量比例不大于5％。
  18. 根据权利要求1所述的维拉佐酮固体分散体，其特征在于，所述载体材料为羟丙基甲基纤维素。
  19. 根据权利要求18所述的维拉佐酮固体分散体，其特征在于，所述维拉佐酮与所述羟丙基甲基纤维素的重量比为1:4～1:7。
  20. 根据权利要求19所述的维拉佐酮固体分散体，其特征在于，所述表面活性剂包括选自辛酸癸酸聚乙二醇甘油酯、聚氧乙烯40氢化蓖麻油中的至少一种。
  21. 根据权利要求20所述的维拉佐酮固体分散体，其特征在于，所述表面活性剂在所述维拉佐酮固体分散体中的重量比例不大于10％。
  22. 一种维拉佐酮固体分散体，其特征在于，包含维拉佐酮和水溶性聚合物载体材料，所述水溶性聚合物载体材料为混合材料，所述混合材料包括选自聚维酮、共聚维酮、羟丙基甲基纤维素中的至少两种。
  23. 根据权利要求22所述的维拉佐酮固体分散体，其特征在于，所述混合材料包含共聚维酮与羟丙甲纤维素。
  24. 根据权利要求22所述的维拉佐酮固体分散体，其特征在于，所述混合材料包含聚维酮与羟丙甲纤维素。
  25. 根据权利要求22所述的维拉佐酮固体分散体，其特征在于，所述维拉佐酮与所述混合材料的重量比为1:4～1:7。
  26. 一种制备权利要求1-25任一项所述的维拉佐酮固体分散体的方法，其特征在于，包括以下步骤：按配比称量维拉佐酮和载体材料，加入至溶剂中，搅拌溶解，于喷雾干燥器中喷干，收集粉末，即得维拉佐酮固体分散体。
  27. 根据权利要求26所述的方法，其特征在于，所述溶剂为丙酮水溶液，丙酮的体积比例为大于60％、小于等于70％。
  28. 一种权利要求1-25任一项所述的维拉佐酮固体分散体在制备维拉佐酮制剂中的用途。
  29. 根据权利要求28所述的用途，其特征在于，所述维拉佐酮制剂的剂型包括颗粒剂、散剂、干混悬剂、片剂或胶囊剂。
  30. 根据权利要求29所述的用途，其特征在于，所述片剂为包衣片。
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CN106580895A (zh) * 2016-12-07 2017-04-26 万全万特制药（厦门）有限公司 含盐酸维拉佐酮固体分散体的口腔崩解片及其制备方法
CN106580914A (zh) * 2017-02-27 2017-04-26 佛山市弘泰药物研发有限公司 一种盐酸维拉佐酮软胶囊及其制备方法

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