CN111346065A - Solid pharmaceutical composition for oral cavity of benzodiazepine compound and preparation method thereof - Google Patents

Solid pharmaceutical composition for oral cavity of benzodiazepine compound and preparation method thereof Download PDF

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CN111346065A
CN111346065A CN201811570573.2A CN201811570573A CN111346065A CN 111346065 A CN111346065 A CN 111346065A CN 201811570573 A CN201811570573 A CN 201811570573A CN 111346065 A CN111346065 A CN 111346065A
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compound
pharmaceutical composition
pharmaceutically acceptable
benzodiazepine
formula
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CN111346065B (en
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李莉娥
符义刚
廖娇
何姿姿
鲁明骞
金芬
郭建锋
杨玉萍
汪淼
吕金良
田峦鸢
曲龙妹
李仕群
李�杰
杜文涛
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Yichang Humanwell 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2813—Inorganic 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61P25/20—Hypnotics; Sedatives

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Abstract

The invention discloses benzodiazepine
Figure DDA0001915400080000012
A solid pharmaceutical composition for oral cavity of class compound, wherein R is pyridineThe details are shown in the specification; the solid pharmaceutical composition for oral use comprises benzodiazepine
Figure DDA0001915400080000013
Microparticles of a compound or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient layer, and a coating layer; the dinitrogen benzene
Figure DDA0001915400080000014
The microparticles of class of compounds or their pharmaceutically acceptable salts are made of benzodiazepine
Figure DDA0001915400080000015
The compound (shown in formula (I)) or pharmaceutically acceptable salt thereof, a high molecular dispersion carrier material and a hot-melt protective agent are subjected to micronization and crushing, optionally added with a fluxing agent, uniformly mixed to prepare a physical mixture, and then subjected to hot-melt extrusion and micronization to obtain the compound. Also discloses a preparation method of the solid pharmaceutical composition for oral cavity. The oral solid pharmaceutical composition has the advantages of simple preparation process, short production period, low manufacturing cost, quick effect taking after the patient takes the oral solid pharmaceutical composition, no first pass effect of liver, bioavailability equivalent to that of freeze-dried powder injection, and more stable active ingredients.
Figure DDA0001915400080000011

Description

Solid pharmaceutical composition for oral cavity of benzodiazepine compound and preparation method thereof
Technical Field
The invention relates to a pharmaceutical preparation technology, in particular to benzodiazepine
Figure BDA0001915400060000013
Solid pharmaceutical composition for oral cavity containing the compound and its preparation method are provided.
Background
The compound shown in the formula (I) (wherein R is hydrogen or C1-4 alkyl) is a novel benzodiazepine
Figure BDA0001915400060000014
The compound belongs to a short-acting sedative. The medicine can be clinically used for program sedation, general anesthesia induction and maintenance, ICU patient tranquilization and the like. Short-acting sedatives can rapidly restore consciousness and allow patients to be discharged as quickly as possible. The demand of the medicines is particularly urgent in the face of the current situation that the short-term hospitalization cases are gradually increased. Chinese patent CN103202815B reports a freeze-dried preparation of salt of a compound (R is methyl) shown in formula (I), the freeze-drying process has long preparation period, about 5 days is one production period, the use amount of auxiliary materials is large, the industrial production cost is high, and the preparation is inconvenient for professional medical workers to use by injection. It is reported in Chinese patent CN101501019B that the compound of formula (I) (R is methyl) is stable when stored at 5 ℃, but 30 ℃/75% relative humidity (open)) The lower stored samples deliquesced, turned yellow to orange in color, and showed a significant level reduction relative to the initial level. Therefore, the compound is extremely unstable at room temperature.
Figure BDA0001915400060000011
At present, most of the reports of documents are that the compound shown in the formula (I) is prepared into a freeze-dried powder injection preparation and then is used clinically, and the preparation process of the preparation has long production period and high production cost; the injection is prepared into solution temporarily to be used under the guidance of a professional doctor, and the injection is often accompanied with injection pain, so that the patient is inconvenient to take the injection and has poor compliance.
Therefore, there is a need to develop a formulation which can allow the compound represented by formula (I) to be stably stored at room temperature, and can reduce the production period and production cost of the formulation, making it convenient for patients to take.
Disclosure of Invention
In order to overcome the problem of benzodiazepine represented by the formula (I) in the prior art
Figure BDA0001915400060000022
The invention relates to a method for preparing and using benzodiazepine shown in formula (I)
Figure BDA0001915400060000023
Solid pharmaceutical composition for oral cavity of the compound. The invention also aims to provide a preparation method of the solid pharmaceutical composition for oral cavity.
In an embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000024
A solid pharmaceutical composition for oral cavity containing benzodiazepine represented by formula (I)
Figure BDA0001915400060000025
Microparticles of a compound or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient layer, and a coating layer;
Figure BDA0001915400060000021
wherein R in the formula (I) is hydrogen, methyl, ethyl or isopropyl;
the dinitrogen benzene
Figure BDA0001915400060000026
The microparticles of class of compounds or their pharmaceutically acceptable salts are made of benzodiazepine
Figure BDA0001915400060000027
Micronizing and crushing the compound or pharmaceutically acceptable salt thereof, the high-molecular dispersion carrier material and the hot-melt protective agent, optionally adding a fluxing agent, uniformly mixing to obtain a physical mixture, and carrying out hot-melt extrusion and micronization to obtain the compound;
the medicinal excipient layer is coated on the benzodiazepine
Figure BDA0001915400060000028
The micro-particles of the compound or the pharmaceutically acceptable salt thereof, and the coating layer is coated on the medicinal excipient layer.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000029
Solid pharmaceutical composition for oral use of a compound, wherein the benzodiazepine
Figure BDA00019154000600000210
The compound can be isomer, racemate, enantiomer or enantiomer mixture thereof, or pharmaceutically acceptable salt thereof, or isomer, racemate, enantiomer or enantiomer mixture thereof.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000031
Solid pharmaceutical composition for oral use of a compound, wherein the benzodiazepine
Figure BDA0001915400060000032
The pharmaceutically acceptable salt of the compound is selected from one or more of benzene sulfonate, toluene sulfonate, methane sulfonate, tartrate, malate, maleate, fumarate, hydrochloride, hydrobromide, sulfate and ethane sulfonate; preferably, it is one of benzene sulfonate, toluene sulfonate, and ethane sulfonate.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000033
The solid medicine composition for the oral cavity of the compound is characterized in that the macromolecular dispersion carrier material is selected from one or more of povidone (PVP-VA64, povidone-S630 or K30) and Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer).
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000034
The solid pharmaceutical composition for oral cavity of the compound is prepared from magnesium stearate or talcum powder
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000035
The solid medicine composition for oral cavity of the compound, wherein the fusing agent is selected from polyethylene glycol, preferably the molecular weight of the polyethylene glycol is 2000-6000.
In a preferred embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000036
Solid pharmaceutical composition for oral use of a compound, wherein the benzodiazepine is present in the oral cavity
Figure BDA0001915400060000037
In the fine particles of the compound, benzodiazepine shown in formula (I)
Figure BDA0001915400060000038
0.3-50% of a compound or a pharmaceutically acceptable salt thereof, 20-60% of a macromolecular dispersion carrier material, 1-3.5% of a hot-melt protective agent and 20-50% of a fluxing agent.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000039
The solid pharmaceutical composition for the oral cavity of the compound is prepared by hot-melt extrusion at a temperature of 100-180 ℃.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA00019154000600000310
Solid pharmaceutical composition for oral use of a compound, wherein the benzodiazepine
Figure BDA00019154000600000311
The particle size of the compound or the pharmaceutically acceptable salt thereof and the macromolecular dispersion carrier material after micronization and crushing is less than 10 μm, preferably less than 5 μm.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA00019154000600000312
Solid pharmaceutical composition for oral use of a compound, wherein the benzodiazepine
Figure BDA00019154000600000313
The particle size of the fine particles of the compound or the pharmaceutically acceptable salt thereof is 50 to 800 μm, preferably 60 to 600 μm, and more preferably 80 to 150 μm.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000041
Solid pharmaceutical composition for oral use of a compound, wherein the benzodiazepine
Figure BDA0001915400060000042
Benzodiazepine in solid pharmaceutical composition for oral cavity of compound
Figure BDA0001915400060000043
The content of the compound or the pharmaceutically acceptable salt thereof is 0.01-30 mg/tablet, preferably 0.5-10 mg/tablet.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000044
The solid medicine composition for the oral cavity of the compound, wherein the medicinal excipient layer comprises one or more of a binding agent, a filling agent, a surface active agent and a lubricating agent.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000045
The solid medicine composition for the oral cavity of the compound is characterized in that the adhesive accounts for 20 to 35 percent of the total weight of the medicinal excipient layer; the adhesive is selected from one or more of polyvinylpyrrolidone, cellulose polymers, acrylic acid polymers and polyethylene glycol; the cellulose polymer is hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose acetyl succinate.
In one embodiment of the invention, the inventionThe invention provides benzodiazepine shown in formula (I)
Figure BDA0001915400060000046
The solid pharmaceutical composition for oral cavity of the compound is characterized in that the filler accounts for 30-80% of the total weight of the medicinal excipient layer; the filler is one or more selected from sucrose, lactose, glucose, mannitol, sorbitol and lactitol.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000047
The solid pharmaceutical composition for the oral cavity of the compound comprises a surfactant, wherein the surfactant accounts for 0.1-30% of the total weight of a medicinal excipient layer; the surfactant is selected from one or more of cationic, anionic, nonionic and amphoteric surfactants; preferably, the surfactant is one or more selected from stearic acid, sodium dodecyl benzene sulfonate, quaternary ammonium compound, lecithin, amino acid type, betaine type, fatty glyceride, sorbitan fatty acid (span) and polysorbate (tween).
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000048
The solid pharmaceutical composition for the oral cavity of the compound is characterized in that the lubricant is one or more selected from magnesium stearate, talcum powder and silicon dioxide.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000049
The solid medicine composition for oral cavity of the compound is characterized in that the coating layer comprises one or more of antistatic agent, effervescent agent, sweetening agent and flavoring agent.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000051
The solid medicine composition for oral cavity of the compound, wherein, the antistatic agent in the coating layer is selected from one or more of colloidal silicon dioxide, precipitated silicon dioxide and talcum powder, preferably precipitated silicon dioxide; optionally, 60% by weight of the total coating layer.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000052
The solid oral pharmaceutical composition comprises a compound, wherein an effervescent agent in the coating layer is selected from one or two of an acidic substance and a basic substance, the acidic substance is selected from one or more of tartaric acid, citric acid, maleic acid, fumaric acid, malic acid, adipic acid, succinic acid, lactic acid, glycolic acid, α -hydroxy acid, ascorbic acid, amino acids, and salts and derivatives thereof, and the basic substance is selected from one or more of potassium carbonate, lithium carbonate, sodium carbonate, calcium carbonate, ammonium carbonate, L-lysine carbonate, arginine carbonate, sodium glycinate carbonate, sodium amino acid carbonate salt, anhydrous sodium perborate, effervescent sodium perborate, sodium perborate monohydrate, sodium percarbonate, sodium dichloroisocyanurate, sodium hypochlorite and calcium hypochlorite.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000053
The solid medicine composition for oral cavity of the compound is characterized in that the sweetening agent in the coating layer is one or more selected from acesulfame potassium, aspartame, acesulfame potassium, saccharin sodium, neohesperidin aryl acryloyl aryl galloyl, sucralose and monoammonium glycyrrhizinate.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000054
Solid medicine for oral cavity of compoundThe composition comprises a coating layer and a flavoring agent, wherein the flavoring agent in the coating layer is selected from one or more of aspartame, sucrose, menthol, peppermint oil, orange peel tincture, cassia oil, fennel oil and essences with various flavors.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000055
The solid pharmaceutical composition for the oral cavity of the compound is a tablet, wherein the diameter of the tablet is 2-14 mm; optionally circular, oval, oblong or other shape, optionally with a flat, convex or other shape of its surface.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000056
A solid pharmaceutical composition for oral use of a compound, wherein the solid pharmaceutical composition is a sublingual tablet, optionally a film-coated tablet.
In one embodiment of the present invention, there is provided a benzodiazepine of formula (I)
Figure BDA0001915400060000061
The solid pharmaceutical composition for the oral cavity of the compound is a tablet, and the disintegration time of the solid pharmaceutical composition is 1-10 min, preferably 3-10 min.
In another aspect, the present invention provides a benzodiazepine of formula (I) above
Figure BDA0001915400060000062
A method for preparing an oral solid pharmaceutical composition of a compound, comprising the steps of:
(1) dinitrogen benzene
Figure BDA0001915400060000063
Micro-powder of the compound or the pharmaceutically acceptable salt thereof, the macromolecular dispersion carrier material and the hot-melt protective agentPulverizing, optionally adding fluxing agent, and mixing to obtain physical mixture;
(2) carrying out hot melt extrusion on the physical mixture obtained in the step (1), and micronizing to obtain the benzodiazepine
Figure BDA0001915400060000064
Microparticles of a compound of class i or a pharmaceutically acceptable salt thereof;
(3) spraying a part of medicinal excipient on the surface of the particles obtained in the step (2) to obtain particles;
(4) adding the rest part of medicinal excipient into the granules obtained in the step (3), and uniformly mixing;
(5) coating the product obtained in the step (4).
In one embodiment of the present invention, there is provided the benzodiazepine of the above formula (I)
Figure BDA0001915400060000065
The preparation method of the oral solid pharmaceutical composition of the compound comprises the following steps:
(1) dinitrogen benzene
Figure BDA0001915400060000066
Micronizing and crushing the compound or pharmaceutically acceptable salt thereof, the high-molecular dispersion carrier material and the hot-melt protective agent, optionally adding a fluxing agent, and uniformly mixing to obtain a physical mixture;
(2) carrying out hot melt extrusion on the physical mixture obtained in the step (1), and micronizing to obtain the benzodiazepine
Figure BDA0001915400060000067
Microparticles of a compound of class i or a pharmaceutically acceptable salt thereof;
(3) spraying medicinal excipients except a lubricant on the surfaces of the particles obtained in the step (2) to obtain particles;
(4) adding a lubricant into the granules obtained in the step (3), uniformly mixing, and tabletting to obtain tablets;
(5) coating the tablets obtained in the step (4).
In one embodiment of the present invention, there is provided the benzodiazepine of the above formula (I)
Figure BDA0001915400060000068
A preparation method of the oral solid pharmaceutical composition of the compound, wherein the step (1) comprises the following steps: in the step, a small amount of hot melt protective agent is added, the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof, a high molecular carrier material and a hot melt protective agent are mixed and then micronized, and then the mixture is uniformly mixed with a melting agent, so that the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof can be fully and uniformly mixed during micronization, the powder properties and the flowability of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof can be improved, the stability of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof can be protected, the phenomenon that the compound is decomposed and generates impurities due to high temperature of hot melt extrusion can be avoided, the phenomenon that mixed crystals are formed when the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof is formed into an amorphous form can be avoided, and the release of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof (uniform release, Sufficient).
In one embodiment of the present invention, there is provided the benzodiazepine of the above formula (I)
Figure BDA0001915400060000071
A preparation method of the oral solid pharmaceutical composition of the compound, wherein the step (2) comprises the following steps: setting the extrusion temperature of a double-screw extruder to be 100-180 ℃, starting the screw after the temperature is raised to the set temperature, adding the product obtained in the step (1) into the extruder, and extruding the product in spherical particles after hot melting and extrusion; cooling, crushing and sieving with a 100-180 mesh sieve to obtain the dinitrogen benzene
Figure BDA0001915400060000072
Microparticles of the compound or a pharmaceutically acceptable salt thereof.
In one embodiment of the present invention, there is provided the benzodiazepine of the above formula (I)
Figure BDA0001915400060000073
The preparation method of the solid pharmaceutical composition for oral cavity of the compound, wherein the spraying of the step (3) can be carried out by a porous rotary drum (drum) or a fluidized bed coating machine.
In one embodiment of the present invention, there is provided the benzodiazepine of the above formula (I)
Figure BDA0001915400060000074
The preparation method of the oral solid pharmaceutical composition of the compound comprises the step (4) of tabletting, wherein the stress area is 1cm2The pressure is 5-50 KN (i.e. 50-500 MPa), preferably 10-30 KN, and the pressure can be adjusted to make the hardness of the obtained tablet 10-180 KN, more preferably 15-100N.
In one embodiment of the present invention, there is provided the benzodiazepine of the above formula (I)
Figure BDA0001915400060000075
The preparation method of the oral solid pharmaceutical composition of the compound, wherein the step (5) of coating is to combine the components of the coating layer in water, spray the mixture in the form of solution, suspension or colloidal dispersion or the mixture of the above, and then dry the mixture.
The benzodiazepine obtained by the invention
Figure BDA0001915400060000076
The compound or the pharmaceutically acceptable salt particles thereof are in an amorphous state, the melting point of the compound or the pharmaceutically acceptable salt particles thereof is reduced, the compound or the pharmaceutically acceptable salt particles thereof is more beneficial to the release of active ingredients in the preparation compared with a common tablet, the onset time is shortened, the compound or the pharmaceutically acceptable salt particles thereof is particularly suitable for patients needing acute medication, the bioavailability of the compound or the pharmaceutically acceptable salt particles thereof is improved, and the active ingredients are more stable.
The invention avoids, in terms of safety, the handling of the active ingredient in the form of a powder mixture, as in the conventional granulation and/or tabletting steps, but instead sprays the active ingredient in the form of a solution or suspension to give the product.
Benzodiazepines of the present invention
Figure BDA0001915400060000082
The solid pharmaceutical composition for oral cavity has the following characteristics: the integral fineness is far less than 5%, the fineness of a plurality of 300-500 mg-grade tablets is 1%, the friability is less than 1%, the dissolution time at 37 ℃ is less than 10min, and the hardness is 0-200N. These parameters can be adjusted by the interplay of tablet parameters.
The sublingual tablet containing the compound shown in the formula (I) solves the problems that the compound shown in the formula (I) in the literature is required to be injected and administered by medical personnel, the administration mode is single, the production period is long, the production cost is high, the use is inconvenient, and the compliance of patients is poor. In addition, the invention adopts the direct compression process to prepare the sublingual tablet, has simple process, short production period and low manufacturing cost, and has quick effect after the patient takes the medicine, no first pass effect of liver, equivalent bioavailability to that of a freeze-dried powder injection preparation and more stable active ingredients.
The compound shown in the formula (I) is easy to generate the following 4 impurities in the preparation and storage processes:
Figure BDA0001915400060000081
the sublingual tablet according to the invention was subjected to a stability study, taking as an example the compound of formula (I), wherein R is methyl, and the results are as follows:
the HPLC detection conditions were as follows:
the instrument comprises the following steps: waters2695 model high performance liquid chromatograph
Column: YMC ODS-AQ,250X 4.6mm, 3 μm particle size;
mobile phase: a: 0.01% aqueous trifluoroacetic acid, B: 0.01% trifluoroacetic acid in acetonitrile;
flow rate: 1.0 ml/min;
column temperature: 40 ℃;
detection wavelength: UV at 230 nm;
injection volume: 10 μ l
Gradient:
time (min) A％ B％
0 75 25
20.0 60 40
30.0 20 80
32.5 75 25
40 75 25
Dissolution instrument: RC-806 medicine dissolving-out instrument
The placing conditions are as follows: 25 +/-2 ℃; RH 60% +/-5%
Figure BDA0001915400060000091
Therefore, the quality of the medicinal preparation obtained by the invention still meets the quality standard and is very stable when the medicinal preparation is placed at room temperature for up to three years, and similar results are obtained when R is hydrogen, ethyl or isopropyl.
Drawings
FIG. 1 shows a DSC of a benzenesulfonate salt of a compound represented by the formula (I) (R is a methyl group).
FIG. 2 shows a DSC of the fine particles of the compound of formula (I) (R is methyl) benzenesulfonate and Soluplus.
FIG. 3 shows an X-ray powder diffraction pattern of a benzenesulfonate salt of a compound represented by the formula (I) (R is methyl).
FIG. 4 shows the X-powder diffraction pattern of the compound (R is methyl) benzene sulfonate shown in the formula (I) and Soluplus in a physical mixing state.
FIG. 5 shows the X-ray powder diffraction pattern of the compound of formula (I) (R is methyl) benzene sulfonate and Soluplus forming particles.
FIG. 6 shows the mean concentration-time curves of the principal drug in the plasma of animals after administration of the lyophilized formulation group and the group of example 1 of the present invention.
FIG. 7 shows the mean concentration-time profile of the principal drug in the plasma of animals following administration of different samples of the sublingual formulation of a compound of formula (I).
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention. The invention is further described below with reference to examples:
the instrument comprises the following steps:
a hot-melting extruder: drug hot melt extruder hartek HTGD-16
A tablet press: german Feite P2020 type tablet press
A coating machine: LDP-B fluidized bed coating machine
XTRA/3KW X-ray diffractometer (ARL, Switzerland).
EXAMPLE 1 Process for the preparation of Sublingual tablets of a Compound of formula (I) (R is methyl) Benzenesulfonate
Prescription:
Figure BDA0001915400060000101
Figure BDA0001915400060000111
the preparation process comprises the following steps:
(1) taking the compound (R is methyl) benzene sulfonate shown in the formula (I) as an API (active ingredient, or called bulk drug), micronizing and crushing Soluplus and magnesium stearate (the particle diameter is less than 5 mu m), adding polyethylene glycol 4000 with the formula amount, and uniformly mixing to prepare a physical mixture.
(2) Setting the extrusion temperature of a double-screw extruder to be 150 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, and carrying out hot melting, extrusion and extrusion in the form of spherical particles.
(3) Cooling, pulverizing, and sieving with 120 mesh sieve to obtain compound (R is methyl) fine particles shown in formula (I).
(4) Preparing a medicinal excipient layer: weighing polyvinylpyrrolidone, lactose and sodium dodecyl sulfate according to the formula proportion, adding about 10ml of water to prepare a solution, and uniformly stirring; uniformly spraying the prepared solution on the particles obtained in the step (3) by adopting a fluidized bed coating process; drying to obtain particles; adding magnesium stearate into the prepared granules in proportion, mixing uniformly, and tabletting. Control tablet weight about 400mg, hardness: 40-90N.
(5) Coating: preparing pulvis Talci, tartaric acid, acesulfame potassium, fructus Citri Limoniae powder essence and fructus Citri Junoris powder essence into coating solution, sieving with 80 mesh sieve, and coating.
EXAMPLE 2 Process for the preparation of Sublingual tablets of the Compound of formula (I) (R is methyl, tosylate)
Prescription:
Figure BDA0001915400060000112
Figure BDA0001915400060000121
(1) micronizing and crushing a compound (R is methyl and tosylate) shown as a formula (I), Soluplus and talcum powder (the particle diameter is less than 10 mu m), adding polyethylene glycol 2000 with a formula amount, and uniformly mixing to prepare a physical mixture.
(2) Setting the extrusion temperature of a double-screw extruder to 130 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, and carrying out hot melting, extrusion and extrusion in the form of spherical particles.
(3) Cooling, pulverizing, and sieving with 180 mesh sieve to obtain fine particles.
(4) Preparing a medicinal excipient layer: weighing hydroxypropyl methylcellulose, glucose and sodium dodecyl benzene sulfonate according to the proportion of a prescription, adding about 10ml of water to prepare a solution, and uniformly stirring; uniformly spraying the prepared solution on the particles obtained in the step (3) by adopting a fluidized bed coating process; drying to obtain particles;
adding pulvis Talci into the obtained granule, mixing, and tabletting. Control tablet weight about 440mg, hardness: 30-60N.
(5) Coating: refining silicon dioxide, malic acid, aspartame, cassia oil and sucrose into coating solution, sieving with 80 mesh sieve, and coating.
EXAMPLE 3 preparation of sublingual tablet of the Compound of formula (I) (R is ethyl, maleate)
Prescription:
Figure BDA0001915400060000131
(1) micronizing and crushing the compound (R is ethyl and maleate) shown in the formula (I), povidone PVP-VA64 and magnesium stearate (the particle diameter is less than 10 mu m), adding the polyethylene glycol 5000 according to the prescription amount, and uniformly mixing to obtain a physical mixture.
(2) Setting the extrusion temperature of a double-screw extruder to 170 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, and carrying out hot melting, extrusion and extrusion in the form of spherical particles.
(3) Cooling, pulverizing, and sieving with 160 mesh sieve to obtain fine particles.
(4) Preparing a medicinal excipient layer: weighing hydroxypropyl vitamin, lactose, mannitol and span according to the prescription proportion, adding about 10ml of water to prepare a solution, and uniformly stirring; uniformly spraying the prepared solution on the particles obtained in the step (3) by adopting a fluidized bed coating process; drying to obtain particles;
adding silicon dioxide into the prepared granules in proportion, mixing uniformly, and tabletting. Control tablet weight of about 224mg, hardness: 20 to 70N.
(5) Coating: preparing pulvis Talci, citric acid, sucralose and menthol into coating solution, sieving with 80 mesh sieve, and coating.
EXAMPLE 4 preparation of sublingual tablet of the compound of formula (I) (R is ethyl)
Prescription:
Figure BDA0001915400060000141
(1) micronizing and crushing the compound (R is ethyl) shown in the formula (I), povidone PVP-VA64 and talcum powder (the particle diameter is less than 3 mu m), adding polyethylene glycol 4000 with the formula amount, and uniformly mixing to obtain a physical mixture.
(2) Setting the extrusion temperature of a double-screw extruder to be 180 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, and carrying out hot melting, extrusion and extrusion in the form of spherical particles.
(3) Cooling, pulverizing, and sieving with 140 mesh sieve to obtain fine particles.
(4) Preparing a medicinal excipient layer: weighing povidone K90, sorbitol and tween according to the formula proportion, adding about 10ml of water to prepare a solution, and uniformly stirring; uniformly spraying the prepared solution on the particles obtained in the step (3) by adopting a fluidized bed coating process; drying to obtain particles;
adding magnesium stearate into the prepared granules in proportion, mixing uniformly, and tabletting. Control tablet weight 100mg, hardness: 20 to 60N.
(5) Coating: preparing the precipitated silicon dioxide, sodium hypochlorite, saccharin sodium, aspartame and orange peel tincture into a coating solution, sieving with a 80-mesh sieve, and coating.
EXAMPLE 5 sublingual tablet preparation of a Compound of formula (I) (R is isopropyl)
Prescription:
Figure BDA0001915400060000151
the preparation process comprises the following steps:
(1) micronizing compound (R is isopropyl), polyvidone PVP-VA64, and pulvis Talci, adding polyethylene glycol 3000, and mixing to obtain physical mixture;
(2) setting the extrusion temperature of a double-screw extruder to be 120 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, and carrying out hot melting, extrusion and extrusion in the form of spherical particles;
(3) cooling, pulverizing, and sieving with 100 mesh sieve to obtain fine particles.
(4) Preparing a medicinal excipient layer: weighing polyvinylpyrrolidone, lactitol and stearic acid according to the formula proportion, adding about 10ml of water to prepare a solution, and uniformly stirring; uniformly spraying the prepared solution on the particles obtained in the step (3) by adopting a fluidized bed coating process; drying to obtain particles;
adding magnesium stearate into the prepared granules in proportion, mixing uniformly, and tabletting. Control tablet weight 260mg, hardness: 40 to 100N.
(5) Coating: making hydroxypropyl cellulose, pulvis Talci, sodium carbonate, aspartame, menthol, and orange essence into coating solution, sieving with 100 mesh sieve, and coating.
EXAMPLE 6 preparation of sublingual tablet of the compound of formula (I) (R is isopropyl)
Prescription:
Figure BDA0001915400060000161
the preparation process comprises the following steps:
(1) micronizing compound (R is isopropyl), polyvidone-S630 and magnesium stearate, pulverizing (particle diameter is less than 7 μm), adding polyethylene glycol 4000, and mixing to obtain physical mixture;
(2) setting the extrusion temperature of a double-screw extruder to be 120 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, and carrying out hot melting, extrusion and extrusion in the form of spherical particles;
(3) cooling, pulverizing, and sieving with 160 mesh sieve to obtain fine particles.
(4) Preparing a medicinal excipient layer: weighing polyvinylpyrrolidone, sucrose and quaternary ammonium compound according to the proportion of the formula, adding about 10ml of water to prepare a solution, and uniformly stirring; uniformly spraying the prepared solution on the particles obtained in the step (3) by adopting a fluidized bed coating process; drying to obtain particles;
adding magnesium stearate into the prepared granules in proportion, mixing uniformly, and tabletting. Control tablet weight 310mg, hardness: 40-80N.
(5) Coating: preparing hydroxypropyl cellulose, silicon dioxide, lactic acid, monoammonium glycyrrhizinate, anise oil and orange essence into a coating solution, sieving with a 80-mesh sieve, and coating.
EXAMPLE 7 preparation of sublingual tablet of the compound of formula (I) (R is hydrogen)
Prescription:
Figure BDA0001915400060000171
the preparation process comprises the following steps:
(1) micronizing compound (R is hydrogen) shown in formula (I), Soluplus, and magnesium stearate, pulverizing (particle diameter is less than 10 μm), adding polyethylene glycol 6000, and mixing to obtain physical mixture;
(2) setting the extrusion temperature of a double-screw extruder to be 100 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, and carrying out hot melting, extrusion and extrusion in the form of spherical particles;
(3) cooling, pulverizing, and sieving with 30 mesh sieve to obtain fine particles.
(4) Preparing a medicinal excipient layer: weighing polyvinylpyrrolidone, sucrose and fatty glyceride according to the formula proportion, adding about 10ml of water to prepare a solution, and uniformly stirring; uniformly spraying the prepared solution on the particles obtained in the step (3) by adopting a fluidized bed coating process; drying to obtain particles;
adding magnesium stearate into the prepared granules in proportion, mixing uniformly, and tabletting. Control tablet weight 200mg, hardness: 150-200N.
(5) Coating: preparing hydroxypropyl cellulose, talcum powder, sodium perborate monohydrate, aspartame and orange essence into a coating solution, sieving with a 80-mesh sieve, and coating.
EXAMPLE 8 sublingual tablet preparation of a Compound of formula (I) (R is hydrogen)
Prescription:
Figure BDA0001915400060000181
the preparation process comprises the following steps:
(1) micronizing and pulverizing compound (R is hydrogen) shown in formula (I), polyvidone PVP-VA64 and pulvis Talci (particle diameter is less than 4 μm), adding polyethylene glycol 4000, and mixing to obtain physical mixture;
(2) setting the extrusion temperature of a double-screw extruder to 110 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, and carrying out hot melting and extrusion to obtain spherical particles;
(3) cooling, pulverizing, and sieving with 100 mesh sieve to obtain fine particles.
(4) Preparing a medicinal excipient layer: weighing polyvinylpyrrolidone, sucrose and quaternary ammonium compound according to the formula proportion, adding a proper amount of water (about 10ml) to prepare a solution, and uniformly stirring; uniformly spraying the prepared solution on the particles obtained in the step (3) by adopting a fluidized bed coating process; drying to obtain particles;
adding magnesium stearate into the prepared granules in proportion, mixing uniformly, and tabletting. Control tablet weight 300mg, hardness: 120 to 150N.
(5) Coating: preparing hydroxypropyl cellulose, silicon dioxide, amino acid, aspartame and lemon essence into a coating solution, sieving with a 100-mesh sieve, and coating.
EXAMPLE 9 sublingual tablet preparation of a Compound of formula (I) (R is hydrogen)
Prescription:
Figure BDA0001915400060000191
the preparation process comprises the following steps:
(1) micronizing and pulverizing compound (R is hydrogen) shown in formula (I), polyvidone PVP-VA64, and magnesium stearate (particle diameter less than 2 μm), adding polyethylene glycol 4000, mixing well, and making into physical mixture;
(2) setting the extrusion temperature of a double-screw extruder to be 160 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, and carrying out hot melting, extrusion and extrusion in the form of spherical particles;
(3) cooling, pulverizing, and sieving with 170 mesh sieve to obtain fine particles.
(4) Preparing a medicinal excipient layer: weighing polyvinylpyrrolidone, sucrose and lecithin according to the proportion of the prescription, adding about 10ml of water to prepare a solution, and uniformly stirring; uniformly spraying the prepared solution on the particles obtained in the step (3) by adopting a fluidized bed coating process; drying to obtain particles;
adding magnesium stearate into the prepared granules in proportion, mixing uniformly, and tabletting. Control tablet weight 300mg, hardness: 70-120N.
(5) Coating: preparing hydroxypropyl cellulose, silicon dioxide, amino acid, aspartame and lemon essence into a coating solution, sieving with a 100-mesh sieve, and coating.
EXAMPLE 10 preparation of Orodial Ormossy film of Compound (I) (R is methyl)
Prescription:
Figure BDA0001915400060000201
(1) preparing particles: micronizing and crushing the compound (R is methyl) shown in the formula (I), PVP-VA64 and talcum powder (the particle diameter is less than 1 μm), adding polyethylene glycol 4000 with the formula amount, and uniformly mixing to obtain a physical mixture.
(2) Setting the extrusion temperature of a double-screw extruder to be 180 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, and carrying out hot melting, extrusion and extrusion in the form of spherical particles.
(3) Cooling, pulverizing, and sieving with 170 mesh sieve to obtain fine particles.
(4) Preparing a medicinal excipient layer: weighing povidone K90, sorbitol and tween according to the formula proportion, adding about 10ml of water to prepare a solution, and uniformly stirring; uniformly spraying the prepared solution on the particles obtained in the step (3) by adopting a fluidized bed coating process; drying to obtain particles;
adding magnesium stearate into the prepared granules in proportion, mixing uniformly, and tabletting. Control tablet weight 100mg, hardness: 10 to 40N.
(5) Coating: preparing the precipitated silicon dioxide, sodium hypochlorite, saccharin sodium, aspartame and orange peel tincture into a coating solution, sieving with a 80-mesh sieve, and coating.
EXAMPLE 11 preparation of Orodia Ormosia film of Compound (I) (R is methyl)
Prescription:
Figure BDA0001915400060000211
(1) micronizing the compound (R is methyl) shown in formula (I), PVP-VA64 and magnesium stearate, pulverizing (particle diameter is less than 7 μm), adding polyethylene glycol 3000 according to formula amount, and mixing to obtain physical mixture.
(2) Setting the extrusion temperature of a double-screw extruder to be 180 ℃, starting the screw after the temperature is raised to the set temperature, adding the physical mixture obtained in the step (1) into the extruder, and carrying out hot melting, extrusion and extrusion in the form of spherical particles.
(3) Cooling, pulverizing, and sieving with 150 mesh sieve to obtain fine particles.
(4) Weighing povidone K90, sorbitol and tween according to the formula proportion, adding about 10ml of water to prepare a solution, and uniformly stirring; uniformly spraying the prepared solution on the particles obtained in the step (3) by adopting a fluidized bed coating process; drying to obtain particles;
adding magnesium stearate into the prepared granules in proportion, mixing uniformly, and tabletting. Control tablet weight 100mg, hardness: 20 to 60N.
(5) Coating: preparing the precipitated silicon dioxide, sodium hypochlorite, saccharin sodium, aspartame and orange peel tincture into a coating solution, sieving with a 80-mesh sieve, and coating.
EXAMPLE 12 comparison of bioavailability of samples prepared according to the present invention (example 1) with that of lyophilized powder formulations
In this experiment, the bioavailability of the sample prepared in the present invention (example 1) and the lyophilized powder injection preparation (prepared in example 1 of patent CN 201410767723.4) were compared by separately administering the sample prepared in the present invention (example 1) and the lyophilized powder injection preparation to compare the pharmacokinetic characteristics of the two dosage forms.
12 monkeys, each half of male and female, were selected for testing, and were randomly divided into two groups, i.e., a group (group a) of example 1 and a lyophilized powder injection group (example 1 of patent CN105726495A, see group B), of the present invention, and 6 monkeys were tested. Animals in group A took 1 tablet (equivalent to 10mg of main drug, namely 2.5mg/kg) of the preparation of the invention in the embodiment 1 sublingually; the animals in group B were administered the lyophilized powder injection (dissolved in physiological saline at a concentration of 0.75mg/ml) by intravenous infusion at a rate of 30mg/kg/h for 5 min. After completion of the administration, about 0.4ml of whole blood was collected intravenously from the anterior/posterior limb (non-administration limb at the time of administration) at 0min, 3min, 5min, 15min, 30min, 1h, 1.5h, 2h, 3h, 4h, 6h, and 10 h. After blood collection, the blood sample was placed in an anticoagulation tube (1000IU/ml, about 10. mu.l) containing heparin sodium, centrifuged at 4000rpm for 5min at 4 ℃, and plasma was separated and the concentration of the principal drug in the plasma was measured by LC-MS/MS. Calculation of the Primary Metabolic kinetic parameter t Using WinNonlin (V6.2)1/2，Tmax，Cmax，AUC。
The experimental results (see fig. 6) are as follows:
TABLE 1 Metabolic kinetic parameters required in animals of the lyophilized formulation group and the group of example 1 of the present invention
Figure BDA0001915400060000231
Comparative lyophilized formulation group and inventive example 1Pharmacokinetic parameters t in cynomolgus monkeys1/2、Tmax、CmaxAfter AUC, the concentration change trends of the main drugs in the animal blood plasma of the freeze-dried preparation group and the animal blood plasma of the freeze-dried preparation group are basically consistent without obvious difference, and the bioequivalence research preliminarily considers the bioequivalence of the freeze-dried preparation group and the freeze-dried preparation group of the invention.
Comparative example 1 preparation of Sublingual tablets of a Compound of formula (I) wherein R is methyl, besylate and powder diffraction Pattern is shown in figure 3
Prescription:
Figure BDA0001915400060000232
the preparation process comprises the following steps:
(1) preparing a medicinal excipient layer: weighing polyvinylpyrrolidone, lactose and sodium dodecyl sulfate according to the formula proportion, adding about 10ml of water to prepare a solution, and uniformly stirring; uniformly spraying the prepared solution on API by adopting a fluidized bed coating procedure; drying to obtain the granules.
(2) Tabletting: adding magnesium stearate into the prepared granules in proportion, mixing uniformly, and tabletting. Control tablet weight 290mg, hardness: 40-90N.
(3) Coating, preparing talcum powder, tartaric acid, acesulfame potassium, lemon powder essence and orange powder essence into a coating solution, sieving with a 80-mesh sieve, and coating.
The preparation method of the crystal form in figure 3 comprises the following steps:
13.6g of the compound (R is methyl and benzene sulfonate) shown as the formula (I) is heated and dissolved in 10ml of methanol and 10ml of ethanol, cooled and crystallized (0-5 ℃), filtered, dried under reduced pressure at 40-50 ℃ to obtain 10.2g, and subjected to X-powder diffraction detection to obtain the crystal form shown as the figure 3. The compound shown in the formula (I) (R is methyl and benzene sulfonate) in the crystal form is used as API in the application.
Comparative example 2 preparation of Sublingual tablets of the Compound of formula (I) (R is methyl, besylate)
Sublingual tablets were prepared with reference to the patent cn201710272877.x preparation method of example 1:
1. pretreatment: taking 8mg of a compound (R is methyl) benzene sulfonate shown in a formula (I), 130mg of lactose, 39mg of mannitol, 5mg of sodium carboxymethyl starch, 5mg of cross-linked sodium carboxymethyl cellulose and 3mg of stevioside, respectively placing the compound in a universal pulverizer, pulverizing and sieving with a 100-mesh sieve for later use; dissolving povidone K30 with the prescription amount into ethanol solution with the volume fraction of 50% with the prescription amount to obtain povidone K3010 mg ethanol solution for later use;
2. mixing: placing the pretreated compound (R is methyl) benzene sulfonate, lactose, mannitol, sodium carboxymethyl starch, croscarmellose sodium and stevioside in a three-dimensional motion mixer, and mixing uniformly to obtain mixed powder for later use;
3. granulating and drying: placing the mixed powder obtained in the step 2 in a boiling drying granulator, spraying the povidone K30 ethanol solution obtained in the step 1 for boiling granulation and drying, setting the atomizing pressure to be 0.4-0.6 MPa, the atomizing speed to be 80-100 ml/min, continuing to boil for 10-20 minutes after the povidone K30 ethanol solution is completely sprayed, and taking out the mixed powder for later use, wherein the water content of the granules is lower than 3%;
4. sieving and total mixing: sieving the granules subjected to boiling drying in the step 3 by a 20-mesh sieve for finishing, placing the granules into a square cone mixer after the sieving and finishing, adding magnesium stearate in a prescription amount for mixing, setting the mixing rotation speed to be 8-12 r/min, mixing for 20-30 minutes, and taking out for later use after the mixing is finished;
5. tabletting: pressing the granules prepared in the step 4 into sublingual tablets with tablet weight of 0.2 g;
6. aluminum-plastic inner wrapping: packaging the sublingual tablets prepared in the step 5 by using a full-automatic blister packaging machine, and setting the temperature of an upper heating plate to be 105-115 ℃, the temperature of a lower heating plate to be 105-115 ℃ and the heat sealing temperature to be 135-145 ℃;
7. outsourcing: and (5) outsourcing, full inspection and warehousing to obtain the product.
EXAMPLE 13 comparison of pharmacokinetics of the sample of example 1 in which the compound of formula (I) (R is methyl) benzenesulfonate with those of comparative examples 1 and 2
The test uses 18 cynomolgus monkeys, half male and half female, randomly divided into three groups, which are the sample of the invention of example 1 (group A), the benzenesulfonate salt of the compound of formula (I)Example 1 sample group (group B) and prior art besylate salt of compound of formula (I) comparative example 2 sample group (group C), 6 of each group were tested. A. B, C three groups of animals are sublingually administered 1 tablet (equivalent to 10mg of main drug, i.e. 2.5mg/kg) of compound preparation with different crystal forms and different techniques shown in formula (I). After completion of the administration, about 0.4ml of whole blood was collected intravenously from the anterior/posterior limb (non-administration limb at the time of administration) at 0min, 3min, 5min, 15min, 30min, 1h, 1.5h, 2h, 3h, 4h, 6h, and 10 h. After blood collection, the blood sample was placed in an anticoagulation tube (1000IU/ml, about 10. mu.l) containing heparin sodium, centrifuged at 4000rpm for 5min at 4 ℃, and plasma was separated and the concentration of the principal drug in the plasma was measured by LC-MS/MS. Calculation of the Primary Metabolic kinetic parameter t Using WinNonlin (V6.2)1/2，Cmax，AUC，TmaxAnd the like.
The experimental results (see fig. 7) are as follows:
TABLE 2 pharmacokinetic parameters in animals following sublingual formulation administration of different samples of the compound of formula (I)
Figure BDA0001915400060000251
Comparison of the pharmacokinetic parameters t in cynomolgus monkeys of the different sample groups of sublingual formulation A, B, C of the compound of formula (I)1/2、Tmax、CmaxAfter AUC, the absorption rate of the compound of formula (I) in group a was found to be faster in cynomolgus monkeys than in group B, C, and the bioavailability was higher than in group B, C.
Example 14 DSC and X-ray powder diffraction detection of Compound represented by formula (I) wherein R is methyl
The results of DSC and X-powder diffraction detection of the compound (R is methyl) benzene sulfonate shown in the formula (I), the compound (R is methyl) benzene sulfonate shown in the formula (I) and Soluplus formed particles and the physical mixture of the compound (R is methyl) benzene sulfonate shown in the formula (I) and Soluplus are shown in figures 1-5, and it can be seen from the figures that after hot melt extrusion, the compound (R is methyl) shown in the formula (I) is converted from a polycrystalline state to an amorphous state, which is more beneficial to absorption of drugs, and the amorphous state is also proved to be stable in preparation research.
Detection conditions are as follows:
powder X-ray diffraction (PXRD)
The instrument comprises the following steps: XTRA/3KW X-ray diffractometer (Swiss ARL company)
Target Cu-K α radiation
Wavelength: 1.5406A
Pipe pressure: 40KV
Pipe flow: 40mA
Step length: 0.02 degree
Scanning speed: 10 °/min
Differential Scanning Calorimetry (DSC)
The instrument comprises the following steps: pyris 1 thermal analyzer (PerkinElmer, USA)
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.

Claims (12)

1. A solid pharmaceutical composition for oral cavity comprising benzodiazepine represented by formula (I)
Figure FDA0001915400050000012
Microparticles of a compound or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient layer, and a coating layer;
Figure FDA0001915400050000011
wherein R in the formula (I) is hydrogen, methyl, ethyl or isopropyl;
the dinitrogen benzene
Figure FDA0001915400050000013
The microparticles of class of compounds or their pharmaceutically acceptable salts are made of benzodiazepine
Figure FDA0001915400050000014
A compound or a pharmaceutically acceptable salt thereof,Carrying out micronization and crushing on a high-molecular dispersion carrier material and a hot-melt protective agent, optionally adding a fluxing agent, uniformly mixing to prepare a physical mixture, and carrying out hot-melt extrusion and micronization to obtain the high-molecular dispersion carrier material;
the medicinal excipient layer is coated on the benzodiazepine
Figure FDA0001915400050000015
The micro-particles of the compound or the pharmaceutically acceptable salt thereof, and the coating layer is coated on the medicinal excipient layer.
2. The pharmaceutical composition of claim 1, wherein the polymeric dispersing carrier material is povidone, or a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;
the hot-melt protective agent is magnesium stearate or talcum powder.
3. The pharmaceutical composition according to claim 1, wherein the temperature of the hot-melt extrusion is 100 to 180 ℃.
4. The pharmaceutical composition of claim 1, wherein the benzodiazepine
Figure FDA0001915400050000016
The particle size of the compound or the pharmaceutically acceptable salt thereof, the macromolecular dispersion carrier material and the hot-melt protective agent after micronization and pulverization is less than 10 μm, preferably less than 5 μm.
5. The pharmaceutical composition according to claim 1, wherein the fusing agent is selected from polyethylene glycol, preferably polyethylene glycol having a molecular weight of 2000-6000.
6. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipient layer comprises one or more of a binder, a filler, a surfactant, and a lubricant.
7. The pharmaceutical composition of claim 1, wherein the benzodiazepine
Figure FDA0001915400050000021
The particle size of the fine particles of the compound or the pharmaceutically acceptable salt thereof is 50 to 800 μm, preferably 60 to 600 μm, and more preferably 80 to 150 μm.
8. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a tablet, and the disintegration time is 1-10 min, preferably 3-10 min.
9. Pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is a sublingual tablet, optionally a film coated tablet.
10. The pharmaceutical composition according to any one of claims 1 to 9, wherein in the benzodiazepine
Figure FDA0001915400050000022
In the microparticles of the compound or the pharmaceutically acceptable salt thereof, the benzodiazepine shown in the formula (I)
Figure FDA0001915400050000023
0.3-50% of a compound or a pharmaceutically acceptable salt thereof, 20-60% of a macromolecular dispersion carrier material, 1-3.5% of a hot-melt protective agent and 20-50% of a fluxing agent.
11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition comprises benzodiazepine
Figure FDA0001915400050000024
The content of the compound or the pharmaceutically acceptable salt thereof is 0.01-30 mg/tablet, preferably 0.5-10 mg/tablet.
12. A process for the preparation of a pharmaceutical composition according to any one of claims 1-11, comprising the steps of:
(1) dinitrogen benzene
Figure FDA0001915400050000025
Micronizing and crushing the compound or pharmaceutically acceptable salt thereof, the high-molecular dispersion carrier material and the hot-melt protective agent, optionally adding a fluxing agent, and uniformly mixing to obtain a physical mixture;
(2) carrying out hot melt extrusion on the physical mixture obtained in the step (1), and micronizing to obtain the benzodiazepine
Figure FDA0001915400050000026
Microparticles of a compound of class i or a pharmaceutically acceptable salt thereof;
(3) spraying a part of medicinal excipient on the surface of the particles obtained in the step (2) to obtain particles;
(4) adding the rest part of medicinal excipient into the granules obtained in the step (3), and uniformly mixing;
(5) and (4) coating.
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