CN113546044A - Lurasidone self-microemulsion composition and preparation method thereof - Google Patents

Lurasidone self-microemulsion composition and preparation method thereof Download PDF

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CN113546044A
CN113546044A CN202110867489.2A CN202110867489A CN113546044A CN 113546044 A CN113546044 A CN 113546044A CN 202110867489 A CN202110867489 A CN 202110867489A CN 113546044 A CN113546044 A CN 113546044A
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lurasidone
self
microemulsion composition
microemulsion
parts
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CN113546044B (en
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周群
黄建国
曹娟
罗熙
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Hunan Huize Bio Pharmaceutical Co ltd
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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
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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    • 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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

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Abstract

The invention belongs to the technical field of medicines, and particularly discloses a lurasidone self-microemulsion composition and a preparation method thereof, wherein the lurasidone self-microemulsion composition comprises, by weight, 0.1-20 parts of lurasidone, 5-70 parts of an oil phase, 10-70 parts of an emulsifier, and 0-50 parts of a co-emulsifier; the lurasidone self-microemulsion composition forms and releases a microemulsion when contacted with an aqueous medium. The lurasidone free alkali is used as a raw material medicine to prepare the lurasidone self-microemulsion composition, so that the solubility of fat-soluble auxiliary materials is improved, the drug loading rate of a self-microemulsion carrier is improved, and gastrointestinal irritation and other side effects are reduced.

Description

Lurasidone self-microemulsion composition and preparation method thereof
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a lurasidone self-microemulsion composition and a preparation method thereof.
Background
Lurasidone Hydrochloride (LH) belongs to atypical antipsychotic drugs, and is marketed as Lurasidone hydrochloride tablets approved by FDA of Sumitomo pharmaceutical company in U.S. 10 months 2010 under the trade name Latuda, with a recommended starting dose of 40mg/d and a maximum recommended dose of 80 mg/d; lurasidone should be taken with food at the same time, and is suitable for first-line treatment of schizophrenia patients. In clinical preparations, the lurasidone exists mainly in the form of hydrochloride, the lurasidone hydrochloride is a BCSII medicament, the solubility is poor, and the oral bioavailability of the lurasidone hydrochloride after the adult is fed after meals is only 9-19%. And the solubility of LH is also pH-dependent, with a maximum solubility at pH3.8, after which the solubility gradually decreases with increasing pH and is almost insoluble in the pH range of 6.0-7.8. The significant pH dependence and low solubility of lurasidone hydrochloride limit its applications.
Self-microemulsion drug delivery system (SMEDDS) is a homogeneous clear liquid formed by a drug, an oil phase, an emulsifier and a co-emulsifier, which spontaneously forms a microemulsion under gastrointestinal motility after oral administration. The SMEDDS can obviously improve the oral bioavailability of insoluble drugs by mechanisms of improving the solubility of the drugs, increasing the permeability of cells, triggering lymphatic transport and the like.
CN107875122A discloses a lurasidone hydrochloride self-microemulsion preparation and a preparation method thereof, wherein the lurasidone hydrochloride, an oil phase, an emulsifier and an auxiliary emulsifier form a liquid self-microemulsion preparation, or the obtained liquid self-microemulsion preparation is further prepared with an excipient into a solid self-microemulsion preparation.
CN112516315A discloses a self-microemulsion composition of a tyrosine kinase inhibitor (which relates to the self-microemulsion research of lurasidone hydrochloride), wherein an oil phase, a surfactant and a cosurfactant are subjected to ultrasonic mixing to form a transparent and uniform self-emulsifying solution, and lurasidone hydrochloride with a formula amount is added, stirred uniformly and fully dissolved and then filled in a soft capsule.
The above patents all use the hydrochloride form of lurasidone as a raw material drug, and compared with lurasidone free base, the lurasidone free base has low solubility in fat-soluble auxiliary materials, so that the drug loading rate is low.
Disclosure of Invention
In order to solve the problems of low oral bioavailability and the like caused by poor water solubility and low solubility of the lurasidone hydrochloride in the prior art, the lurasidone self-microemulsion composition is prepared by adopting lurasidone free alkali as a raw material medicine, so that the solubility of a fat-soluble auxiliary material is improved, the drug loading capacity of a self-microemulsion carrier is improved, and gastrointestinal irritation and other side effects are reduced.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
in one aspect, the invention provides a lurasidone self-microemulsion composition, which comprises lurasidone, an oil phase, an emulsifier and a co-emulsifier.
Furthermore, the lurasidone self-microemulsion composition comprises, by weight, 0.1% -20% of lurasidone, 5% -70% of an oil phase, 10% -70% of an emulsifier and 0% -50% of a co-emulsifier, wherein the sum of the weight percentages of the materials is 100%.
Further, the lurasidone self-microemulsion composition forms and releases a microemulsion when contacted with an aqueous medium.
Further, the lurasidone self-microemulsion composition forms and releases microemulsion when contacting an aqueous medium, and the particle size of the microemulsion is 2-500 nm. Further, the lurasidone self-microemulsion composition forms and releases a microemulsion when contacted with an aqueous medium, the microemulsion having a particle size of less than 500nm, 450nm, 400nm, 350nm, 300nm, 250nm, 200nm, 150nm, 100nm, 95nm, 90nm, 85nm, 80nm, 75nm, 70nm, 65nm, 60nm, 55nm, 50nm, 45nm, 40nm, 35nm, 30nm, 25nm, 20nm, 15nm, 10nm, or even less. Further, the lurasidone self-microemulsion composition forms and releases microemulsion when contacting an aqueous medium, and the particle size of the microemulsion is 50-400 nm or 10-150 nm or 10-100 nm or 10-60 nm or 10-100 nm or 10-35 nm.
Furthermore, in the lurasidone self-microemulsion composition, by weight, 0.1-20 parts of lurasidone, 5-70 parts of an oil phase, 10-70 parts of an emulsifier and 0-50 parts of a co-emulsifier are included. Further, in the composition, the lurasidone accounts for 1-5 parts by weight, and is selected from 0.1 part, 0.5 part, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 5 parts, 10 parts or 20 parts; 15-45 parts of oil phase selected from 5 parts, 10 parts, 15 parts, 19 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 60 parts or 70 parts; 35-60 parts of an emulsifier selected from 10 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts or 70 parts; the auxiliary emulsifier accounts for 10-25 parts and is selected from 1 part, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 40 parts, 45 parts or 50 parts.
Further, the oil phase is various pharmaceutically acceptable oil phases, and is selected from natural vegetable oil, vegetable oil after structural modification and hydrolysis, or medium chain length fatty acid glyceride with the chain length of C8-C10.
Further, the oil phase is selected from: corn oil, sunflower oil (e.g., refined sunflower oil), sesame oil, peanut oil, soybean oil, safflower oil, olive oil, palm oil, cottonseed oil, coix seed oil, castor oil, hydrogenated castor oil, bupleurum oil, cinnamon oil, vitex oil, calamus oil, turpentine oil, eucalyptus oil, clove oil, brucea javanica oil, garlic essential oil, anise oil, coconut oil C8/C10 monoglyceride or diester (CapmulMCM), coconut oil C8/C10 propylene glycol diester (Captex200), coconut oil C8/C10 triglyceride (Captex355), coconut oil aminopropyl betaine, purified acetylated monoglyceride (Miglyol812), purified sunflower oil monoglyceride, macrogol laurate, monooleate, monolinoleate, medium chain triglyceride, macrogol oleate, macrogol linoleate, macrogol caprylate, caprite, caprylate, Caprylic capric acid single and double glyceride, polyoxyethylene glyceryl oleate, polyoxyethylene glyceryl linoleate, camellia glyceride, glyceryl monocaprylate, almond oil oleic acid PEG-6 glyceride, corn oil linoleic acid PEG-6 glyceride, glyceryl oleate: propylene glycol (90:10 vol/vol), egg yolk lecithin, soybean lecithin, dioleoyl lecithin, dilauroyl lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, cephalin, creatinine, inositol phospholipid, lysophospholipid, phosphatidic acid, phosphatidylglycerol, stearoyl/palmitoyl/oleoyl phosphatidylcholine, stearoyl/palmitoyl/oleoyl phosphatidylethanolamine, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol, distearoyl phosphatidylethanolamine, oleoyl phosphatidylcholine, hexanoic acid, octanoic acid, oleic acid, vitamin E, stearic acid, isopropyl laurate, isopropyl palmitate, isopropyl myristate, propylene glycol monolaurate, propylene glycol monocaprylate, sorbitol oleate, sodium stearate, sodium myristate, sodium monolaurate, sodium oleate, sodium stearate, sodium oleate, sodium stearate, sodium oleate, sodium stearate, One or at least two of ethyl orthosilicate, ethyl myristate, ethyl oleate, ethyl linoleate, tocopherol, tricaprylin and oleoyl polyoxyethylene glyceride.
Further, the oil phase is one or at least two of star anise oil, soybean oil, oleic acid, caprylic capric acid mono-di-glyceride, mono-capric acid glyceride, mono-caprylic acid glyceride, ethyl oleate, caprylic capric acid polyethylene glycol glyceride, mono-oleic acid glyceride, mono-linoleic acid glyceride, tricaprylin and oleoyl polyoxyethylene glyceride.
Further, the emulsifier is a nonionic surfactant with the HLB value of 4-15.
Further, the emulsifier is selected from the group consisting of egg yolk lecithin, soybean lecithin, dioleoyl lecithin, dilauroyl lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, cephalin, creatinine, inositol phospholipid, lysophospholipid, phosphatidic acid, phosphatidylglycerol, stearoyl/palmitoyl/oleoyl phosphatidylcholine, palmitoyl lysophosphatidyl-L-serine, stearoyl/palmitoyl/oleoyl phosphatidylethanolamine, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol, distearoyl phosphatidylethanolamine, oleoyl phosphatidylcholine, dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, caprylic capric acid macrogolglyceride, distearoyl phosphatidylethanolamine, and mixtures thereof, Dimyristoylphosphatidylserine, acetylated monoglycerides, sorbitan fatty acid esters, macrogol glycerides amygdala, coconut oil C8/C10 macrogol glycerides, polyoxyethylene lauryl stearate, polyethylene glycol 100 vitamin E succinate, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene castor oil (Cremophor EL35), polyoxyethylene hydrogenated castor oil (Cremophor RH40), polyoxyethylene polyoxypropylene copolymer (e.g., poloxamer 188 and 407), polyoxyethylene sorbitan trioleate, polyoxyethylene glycerol trioleate, polyoxyethylene sorbitan fatty acid esters, sodium docusate, calcium docusate, potassium docusate, sodium lauryl sulfate, dipalmitoylphosphatidic acid, ethoxylated castor oil, mannitol oleate polyoxyethylene ethers, macrogol glycerides, polyoxyethylene sorbitan esters, polyoxyethylene sorbitan esters, polyoxyethylene, sodium succinate, ethoxylated castor oil, polyoxyethylene sorbitan oleate, polyoxyethylene sorbitan esters, and polyoxyethylene sorbitan esters, Oleoyl polyoxyethylene glycerides, polyethylene glycol fatty acid esters, polyethylene glycol-15 hydroxystearate (Solutol), polyethylene glycol-8-glyceryl caprylate/caprate, lauric acid polyethylene glycol-32 glycerides, lauroyl polyethylene glycol-32 glycerides, caprylic capric acid polyethylene glycol glycerides, sorbitan sesquioleate, polysorbates (such as polysorbate 20, polysorbate 80), DSS (sodium docusate, calcium docusate, potassium docusate), SDS (sodium dodecyl sulfate or sodium lauryl sulfate), span 80, tween-20, tween 80, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), caprylic acid, propylene glycol monocaprylate, sodium caprylate, bile acid and its salts, ursodeoxycholic acid, sodium cholate, sodium caprylate, and sodium caprylate, Sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-hexadecyl-N, N-dimethyl-3-ammine (amonio) -1-propanesulfonate, palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g., ethanolamine, choline, serine, or threonine 1-acyl-SN-glycero-3-phosphate), N-alkyl-N, N-dimethylamino-1-propanesulfonate, 3-cholamide-1-propyldimethylamino-1-propanesulfonate, choline dodecylphosphate, myristoyl lysophosphatidylcholine, egg lysolecithin, propylene glycol monolaurate, hexadecyl-trimethylammonium bromide, cetylpyridinium chloride, N-hexadecyl-3-propanesulfonate, N-acetyl lysophosphatidylcholine, N-acetyl-L-serine, N-acetyl-L-glycerophosphate, N-alkyl-N, N-dimethylamino-1-propanesulfonate, 3-cholamide-1-propyldimethylammonium-1-propanesulfonate, choline dodecylphosphate, myristoyl lysophosphatidylcholine, egg lysophosphatidylcholine, propylene glycol monolaurate, hexadecyl-trimethyl ammonium bromide, cetylpyridinium chloride, and N-acetyl-L-methyl-L-propanesulfonate, Polyethylene oxide/polypropylene oxide block copolymer (Pluronics/Tetronics, Triton X-100, dodecyl beta-D-glucopyranoside), sodium taurodihydrofusinate, oleic acid, acyl carnitine, lysine, arginine, histidine, lysine or at least two thereof.
Further, the emulsifier is one or at least two of propylene glycol monocaprylate, tween 80, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil and oleoyl polyoxyethylene glyceride.
Further, the co-emulsifier is selected from ethanol, propylene glycol, isopropanol, N-butanol, polyethylene glycol (molecular weight range of 100Da-10kDa, 300Da-2000Da, or 400Da-1000Da) such as polyethylene glycol 200-600 (such as PEG400, polyethylene glycol 600), polyethylene glycol vitamin E succinate, propylene carbonate, tetrahydrofurfuryl alcohol, ethylene glycol furfuryl alcohol, glycerol furfurol, dimethyl isosorbide, dimethyl acetamide, N-methyl pyrrolidone, one or at least two of diethylene glycol monoethyl ether (Transcutol or Transcutol P or Transcutol HP), ethylene glycol monoethyl ether, docosahexaenoic acid, cholesterol, azone, glycerol, ethyl acetate, polyoxyethylene, caprylic/capric polyethylene glycol glyceride, propylene carbonate, glyceryl monostearate, glyceryl distearate and polyglycerol-6-dioleate. The auxiliary emulsifier such as propylene glycol is beneficial to dissolving lurasidone and improving the dissolution rate and bioavailability of the medicine.
Further, the coemulsifier is one or more of diethylene glycol monoethyl ether, propylene glycol and polyethylene glycol 400.
On the other hand, the invention provides a preparation method of the self-microemulsion composition, which comprises the following steps:
evaluating the solubility of the carrier material oil phase, the emulsifier and the coemulsifier to lurasidone;
according to the order of the solubility, firstly dissolving the lurasidone in the carrier substance with high solubility, and then adding other carrier substances to be uniformly mixed, thus obtaining the self-microemulsion composition implemented by the invention.
Further, in the process of mixing uniformly, the latter substance is added after the former substance is completely dissolved, and mixing is carried out at 37 ℃ under the condition of keeping out of the light.
The invention carries out the mixing and dissolving of the materials according to the solubility condition, which is beneficial to improving the stability of the self-microemulsion composition and reducing the grain diameter of the nano-emulsion dispersed in the water medium.
The lurasidone self-microemulsion composition disclosed by the invention is emulsified into emulsion particles with the particle size of nanometer grade in digestive juice after being taken orally; or directly mixing with water, wrapping oil phase in nanocapsule to obtain microemulsion with low viscosity and low surface tension, avoiding demulsification during dilution of conventional emulsion, greatly increasing dispersity, reducing gastrointestinal reaction, improving drug absorption rate and transmucosal ability, and improving bioavailability.
Compared with the prior art, the invention has the following beneficial effects:
compared with a lurasidone hydrochloride self-microemulsion composition, the lurasidone is adopted as a raw material medicine, and the lurasidone self-microemulsion composition has high solubility and large drug-loading rate in a fat-soluble carrier auxiliary material; can effectively avoid gastrointestinal irritation and other side effects. In the self-microemulsion composition, the maximum daily use amount of the self-emulsifying carrier auxiliary material has a limit, and if the solubility of the lurasidone in the self-microemulsion composition can be increased, the drug loading amount of the lurasidone can be improved, the self-microemulsion composition has important significance for improving the bioavailability, reducing the inter-individual variability and improving the drug compliance of patients. The lurasidone self-microemulsion composition prepared by the application improves the apparent solubility of lurasidone and protects the drug from being degraded, so that the bioavailability of the drug is improved, and the inter-individual variability is reduced.
Compared with the limitation that the existing lurasidone hydrochloride tablets need to be taken with meals, the self-microemulsion composition preparation can eliminate the influence of food on the medicine. The self-microemulsion composition provided by the invention can effectively increase the drug loading rate in the self-microemulsion composition solution, and the prepared self-microemulsion composition has high solubility, stably exists at normal temperature, can form uniform and stable nano-emulsion with water in gastrointestinal tracts, and has short self-emulsifying time and simple preparation process in the preparation process.
Compared with the original medicine, the bioavailability of the lurasidone self-microemulsion composition provided by the invention is improved by multiple times. The lurasidone capsule prepared by the invention is stable, and the texture of the contents is uniform.
The lurasidone self-microemulsion composition provided by the invention is simple and feasible in preparation process and low in cost, and can realize industrial large-scale production.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention.
Examination of solubility:
adding lurasidone into the carrier material at room temperature, stirring to uniformly mix the lurasidone and the carrier material, and detecting the lurasidone content in the supernatant, wherein the specific solubility is as follows:
name of auxiliary Material Solubility (mg/g)
Oleum Anisi Stellati 100.2±0.03
Caprylic capric acid monoglyceride and diglyceride 31.5±0.07
Soybean oil 8.1±0.46
Oleic acid ethyl ester 20.2±0.07
Caprylic capric acid polyethylene glycol glyceride 10.1±0.22
Polyoxyethylene 35 castor oil 15.7±0.23
Tween 80 20.6±0.22
Diethylene glycol monoethyl ether 8.1±0.49
Propylene glycol 15.2±0.21
Example 1
Lurasidone 20mg
Caprylic capric acid monoglyceride 400mg
Tween 80400mg
Propylene glycol 200mg
The preparation process comprises the following steps:
adding lurasidone into caprylic capric acid mono-diglyceride, sequentially adding tween 80 and propylene glycol, stirring to uniformly mix and dissolve.
The particle size is as follows: about 500 nm.
Example 2
Lurasidone 20mg
Glycerol Monocaprylate 200mg
Polyoxyethylene 35 Castor oil 600mg
Diethylene glycol monoethyl ether 200mg
The preparation process comprises the following steps:
adding lurasidone into glyceryl monocaprylate, sequentially adding polyoxyethylene 35 castor oil and diethylene glycol monoethyl ether, and stirring to uniformly mix and dissolve.
The particle size is as follows: about 15 nm.
Example 3
Lurasidone 20mg
Glycerol monocaprylate 165mg
Oleic acid 165mg
Polyoxyethylene 35 Castor oil 440mg
Propylene glycol 230mg
The preparation process comprises the following steps:
adding lurasidone into a mixed oil phase of glyceryl monocaprylate and oleic acid, sequentially adding polyoxyethylene 35 castor oil and propylene glycol, stirring to uniformly mix and dissolve.
The particle size is as follows: approximately 250 nm.
Example 4
Lurasidone 20mg
Glycerol monocaprylate 150mg
Oleic acid 150mg
Polyoxyethylene 40 hydrogenated castor oil 467mg
Diethylene glycol monoethyl ether 233mg
The preparation process comprises the following steps:
adding lurasidone into a mixed oil phase of glyceryl monocaprylate and oleic acid, sequentially adding polyoxyethylene 40 hydrogenated castor oil and diethylene glycol monoethyl ether, and stirring to uniformly mix and dissolve.
The particle size is as follows: approximately 366 nm.
Example 5
Lurasidone 20mg
Glycerol monocaprylate 150mg
Oleic acid 150mg
Polyoxyethylene 40 hydrogenated Castor oil 233.5mg
Oleoylpolyoxyethylene glyceride 233.5mg
Propylene glycol 233mg
The preparation process comprises the following steps:
adding lurasidone into a mixed oil phase of glyceryl monocaprylate and oleic acid, sequentially adding polyoxyethylene 40 hydrogenated castor oil, oleoyl polyoxyethylene glyceride and propylene glycol, stirring to uniformly mix and dissolve.
The particle size is as follows: about 42 nm.
Example 6
Lurasidone 20mg
Glycerol monocaprylate 270mg
Oleic acid 130mg
Polyoxyethylene 40 hydrogenated Castor oil 250mg
Oleoyl polyoxyethylene glyceride 150mg
Propylene glycol 200mg
The preparation process comprises the following steps:
adding lurasidone into a mixed oil phase of glyceryl monocaprylate and oleic acid, sequentially adding polyoxyethylene 40 hydrogenated castor oil, oleoyl polyoxyethylene glyceride and propylene glycol, stirring to uniformly mix and dissolve.
The particle size is as follows: about 37 nm.
Example 7
Lurasidone 40mg
300mg of anise oil
Polyoxyethylene 40 hydrogenated castor oil 467mg
Propylene glycol 233mg
The preparation process comprises the following steps:
adding lurasidone into the aniseed oil, sequentially adding polyoxyethylene 40 hydrogenated castor oil and propylene glycol, stirring to uniformly mix and dissolve.
The particle size is as follows: approximately 320 nm.
Example 8
Lurasidone 40mg
300mg of anise oil
Polyoxyethylene 40 hydrogenated Castor oil 233.5mg
Oleoylpolyoxyethylene glyceride 233.5mg
Propylene glycol 233mg
The preparation process comprises the following steps:
adding lurasidone into anise oil, sequentially adding polyoxyethylene 40 hydrogenated castor oil, oleoyl polyoxyethylene glyceride and propylene glycol, stirring to uniformly mix and dissolve.
The particle size is as follows: approximately 130 nm.
Example 9
Lurasidone 40mg
Anise oil 350mg
Glycerol Monocaprylate 100mg
Polyoxyethylene 40 hydrogenated Castor oil 250mg
Oleoyl polyoxyethylene glyceride 150mg
Propylene glycol 150mg
The preparation process comprises the following steps:
adding lurasidone into a mixed oil phase of anise oil and glyceryl monocaprylate, sequentially adding polyoxyethylene 40 hydrogenated castor oil, oleoyl polyoxyethylene glyceride and propylene glycol, stirring to uniformly mix and dissolve.
The particle size is as follows: about 74 nm.
Example 10
Lurasidone 40mg
Illicium verum oil 370mg
Glycerol Monocaprylate 100mg
Polyoxyethylene 40 hydrogenated Castor oil 240mg
Oleoyl polyoxyethylene glyceride 140mg
Propylene glycol 150mg
The preparation process comprises the following steps:
adding lurasidone into a mixed oil phase of anise oil and glyceryl monocaprylate, sequentially adding polyoxyethylene 40 hydrogenated castor oil, oleoyl polyoxyethylene glyceride and propylene glycol, stirring to uniformly mix and dissolve.
The particle size is as follows: about 81 nm.
Test example 1 measurement of dispersibility and solubility
The lurasidone self-microemulsion composition provided by the embodiments 1-10 is dispersed in 250mL of aqueous medium to determine the dispersibility and solubility of the drug, and whether the drug is precipitated or not is observed.
The aqueous medium comprises water and a phosphate buffer (pH 6.8).
The research method comprises the following steps: usp method II (slurry method).
Dissolution apparatus: TDT-08L, aqueous medium: 250mL, 50rpm, 37 ℃.
The specific method comprises the following steps: 1g of the lurasidone self-microemulsion composition is placed in a dissolution cup for dispersion, 2mL of the lurasidone self-microemulsion composition is sampled at 10 min, 20min, 30 min and 60min respectively, and the sample is filtered by a 0.45 micron polypropylene filter and diluted for HPLC analysis.
The inventive example is respectively dispersed in water (pH7.0) or phosphate buffer (pH6.8), and is dissolved completely in 10-20 min; the lurasidone self-microemulsion composition disclosed by the invention is good in drug dispersibility and solubility, and no drug is separated out within 24 hours at 37 ℃, so that the oral bioavailability of lurasidone is improved, and individual difference is reduced.
Test example 2 stability test
This experimental example provides a stability test of the lurasidone self-microemulsion composition provided in the examples.
The prepared drug-loaded prescription is placed under the conditions of high temperature (40 ℃), illumination (45001x) and normal temperature (25 ℃, 60% RH) for 5, 10 and 30 days to achieve stability; the formulations were examined for stability under accelerated conditions (40 ℃, 75% RH) for 5, 10, 30 days.
Figure BDA0003186751900000091
Figure BDA0003186751900000101
The results show that: the sample prepared by the embodiment of the invention is placed for a long time in a high-temperature and high-humidity environment, which shows that the sample has good stability after being placed for 30 days, and the medicine is not separated out.
Test example 3 measurement of microemulsion size
The dynamic light scattering technology DLS is a technique in which a sample solution or suspension is irradiated with laser light, and a change with time of fluctuation of scattered light caused by brownian motion of sample particles is detected by a photodetector. The time correlation statistical calculation of the correlator can be used to obtain a correlation curve, and further obtain the Brownian motion velocity of the particles, namely the diffusion coefficient D. We relate the Brownian motion velocity of a particle and its particle size D by the Stokes-Einstein equationHIn connection with this:
Figure BDA0003186751900000102
wherein k isBIs the Boltzmann constant, T is the ambient temperature, η is the solvent viscosity, DHIs the hydrodynamic diameter of the particle.
In the research, a BT-90+ nanometer particle size analyzer is adopted to measure the particle size of the microemulsion formed by dispersing the lurasidone self-microemulsion composition in the aqueous medium and diluting the microemulsion composition by 100 times. The default test temperature control is 25 ℃ when the system is started up through a BT-90+ built-in temperature control system, and the temperature of the three samples is set to be 37 ℃ so as to simulate the temperature environment of a human body.
Each sample was tested at least three times after being placed in the cuvette to check the reproducibility of the results and to obtain the standard deviation of the results.
The self-microemulsion composition has the characteristics after emulsification: the solution is clear and has light blue luster, and is uniformly dispersed.
Particle size results are given in table 1 below:
Figure BDA0003186751900000103
Figure BDA0003186751900000111
in an aqueous medium, the coverage range of the microemulsion formed by dispersing the lurasidone self-microemulsion composition is narrow and uniform in distribution, the formed microemulsion is stable within 20h, and no drug is precipitated.
Test example 4 rat pharmacokinetic study experiment
This study investigated the single oral administration of the self-microemulsion composition (test formulation T) prepared according to the invention to rats under fasting conditions
Figure BDA0003186751900000113
(reference preparation R) pharmacokinetic profile.
SD rats weighing 180-220g were 12 in total and randomly divided into 2 groups of 6 rats.
The specific administration mode is as follows:
suspension of the ground reference formulation orally administered to group 1, 6 rats: (
Figure BDA0003186751900000114
Tablets) (reference formulation) at a dose of 4 mg/kg;
in group 2, 6 rats were orally administered the self-microemulsion composition (test preparation) prepared in example 10 at a dose of 4 mg/kg.
Fasting was overnight before dosing and 4 hours after dosing, and water was available ad libitum.
Sampling design: blood samples of 250. mu.L were collected from the saphenous vein of the forelimb at 0h before administration and at 0.08h, 0.16h, 0.33h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 10h, and 24h after administration, and plasma was centrifuged.
And (3) determining the concentration of lurasidone in the plasma by an LC-MS/MS method.
Mean pharmacokinetic parameters the results are shown in the following table:
Figure BDA0003186751900000112
Figure BDA0003186751900000121
wherein, T1/2For the half life of the drug, TmaxTo the peak time, CmaxTo maximum blood concentration, AUClastAUC is the duration from the start of dosing to the last point.
As can be seen from the results in the table, C is the amount of the self-microemulsion composition prepared in example 10 after administrationmaxSignificantly improved, self-microemulsion composition C prepared in example 10maxIs about
Figure BDA0003186751900000122
Tablet CmaxFour times of the total amount of the active components, the relative bioavailability is improved.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. The lurasidone self-microemulsion composition is characterized by comprising lurasidone, an oil phase, an emulsifier and a co-emulsifier.
2. The lurasidone self-microemulsion composition as recited in claim 1, wherein the lurasidone self-microemulsion composition comprises, by weight, 0.1 to 20 parts of lurasidone, 5 to 70 parts of an oil phase, 10 to 70 parts of an emulsifier, and 0 to 50 parts of a co-emulsifier.
3. The lurasidone self-microemulsion composition according to claim 1, wherein the lurasidone self-microemulsion composition forms and releases a microemulsion when contacting an aqueous medium, and the particle size of the microemulsion is 2-500 nm.
4. The lurasidone self-microemulsion composition according to claim 1, wherein the oil phase is various pharmaceutically acceptable oil phases selected from natural vegetable oils, structurally modified and hydrolyzed vegetable oils, or medium-chain-length fatty acid glycerides with chain lengths between C8-C10.
5. The lurasidone self-microemulsion composition according to claim 4, wherein the oil phase is one or at least two of anise oil, soybean oil, oleic acid, caprylic/capric acid mono-di-glyceride, mono-capric acid glyceride, mono-caprylic acid glyceride, ethyl oleate, caprylic/capric acid polyethylene glycol glyceride, mono-oleic acid glyceride, mono-linoleic acid glyceride, tri-caprylic acid glyceride, and oleoyl polyoxyethylene glyceride.
6. The lurasidone self-microemulsion composition according to claim 1, wherein the emulsifier is a nonionic surfactant having an HLB value of 4 to 15.
7. The lurasidone self-microemulsion composition according to claim 6, wherein the emulsifier is one or at least two of propylene glycol monocaprylate, tween 80, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, and oleoyl polyoxyethylene glyceride.
8. The lurasidone self-microemulsion composition according to claim 1, wherein the co-emulsifier is selected from one or at least two of ethanol, propylene glycol, isopropanol, N-butanol, polyethylene glycol vitamin E succinate, propylene carbonate, tetrahydrofurfuryl alcohol, ethylene glycol furfuryl alcohol, glycerol furfuryl aldehyde, dimethyl isosorbide, dimethylacetamide, N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol monoethyl ether, docosahexaenoic acid, cholesterol, azone, glycerol, ethyl acetate, polyethylene oxide, caprylic capric polyethylene glycol glyceride, propylene carbonate, glyceryl monostearate, glyceryl distearate, polyglycerol-6-dioleate.
9. A method for preparing the lurasidone self-microemulsion composition of claim 1, comprising the steps of:
evaluating the solubility of the carrier material oil phase, the emulsifier and the coemulsifier to lurasidone;
according to the order of the solubility, firstly dissolving the lurasidone in the carrier substance with high solubility, and then adding other carrier substances to be uniformly mixed, thus obtaining the self-microemulsion composition implemented by the invention.
10. The method for preparing the lurasidone self-microemulsion composition according to claim 9, wherein the latter substance is added after the former substance is completely dissolved during the uniform mixing process, and the mixing is performed at 37 ℃ in the dark.
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