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CN107028903B - Blonanserin tablet pharmaceutical composition and preparation method thereof - Google Patents

Blonanserin tablet pharmaceutical composition and preparation method thereof Download PDF

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CN107028903B
CN107028903B CN201710305669.5A CN201710305669A CN107028903B CN 107028903 B CN107028903 B CN 107028903B CN 201710305669 A CN201710305669 A CN 201710305669A CN 107028903 B CN107028903 B CN 107028903B
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blonanserin
tablet
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pharmaceutical composition
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CN107028903A (en
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刘晓燕
胡克余
马俊
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Shenzhen Wanhe Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

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Abstract

The invention relates to a blonanserin tablet pharmaceutical composition and a preparation method thereof. Specifically, the blonanserin tablet pharmaceutical composition comprises 4 parts by weight of blonanserin, 60-200 parts by weight of diluent, 5-20 parts by weight of disintegrant, 1-5 parts by weight of binder, 0.1-2 parts by weight of glidant and 0.1-1 part by weight of lubricant. The blonanserin tablets of the invention have excellent properties as described in the description of the invention, for example have excellent tablet dissolution properties.

Description

Blonanserin tablet pharmaceutical composition and preparation method thereof
Technical Field
The invention belongs to the technical field of medicines, relates to an antipsychotic drug and a preparation method thereof, and particularly relates to a blonanserin-containing tablet drug composition and a preparation method thereof.
Background
Schizophrenia is a disease characterized by deep cognitive and emotional divisions that manifest as the most basic human behavior, such as language, thought, perception, and self-perception. The symptoms of the disease include a wide range of disorders, most commonly mental disorders such as hallucinations, delusions, and delusions.
Statistically, the global prevalence of schizophrenia is between 0.5% and 1.5%, while only 5% of all treated patients eventually recover completely. In addition, since schizophrenia often causes complications such as anxiety disorder, depression, or psychotropic substance abuse, a research study by Datamonitor has shown that schizophrenia patients exceeding 1/3 (38%) suffer from at least one or more concurrent mental or cognitive disorders. Therefore, TBUstun listed schizophrenia as the third most global disability disease in 1999 in a survey conducted on the global burden of mental disorders, ranked first even beyond hemiplegia and blindness, and thus became a disconcerting disease.
Drugs for treating schizophrenia since the discovery of the antipsychotic effect of chlorpromazine in the early 50 s of the 20 th century, schizophrenia has been mainly treated with drugs. Currently used antipsychotic drugs are classified into two general categories, typical and atypical, according to receptor blockade: typical antipsychotics are represented by chlorpromazine and haloperidol, have main action mechanism of blocking dopamine receptors, have good curative effect on positive symptoms (hallucinations, delusions, agitation, impulsive behaviors and the like) of schizophrenia, are common in extrapyramidal system reaction (EPS), and have poor curative effect on negative symptoms (apathy, poor thinking, hypovolemia and the like); the atypical anti-sperm split drug has wider treatment spectrum, obviously better negative symptom effect than the traditional drugs, high safety, slight side effect and smaller dosage, also presents a plurality of more advanced dosage forms, greatly improves the compliance of patients, and represents drugs such as clozapine, risperidone, olanzapine, perospirone and the like.
In the last decade, the incidence of schizophrenia has shown an increasing trend. For example, the incidence of schizophrenia has increased from 5.69% in 1982 to 6.55% in recent years. According to the report of the Ministry of health in 2002, about 800 million patients exist in schizophrenic patients in China, 15 million patients are newly added every year, and 860 million patients are increased by 2006.
Blonanserin is an atypical antipsychotic drug marketed in japan in 4 months 2008, developed by sumitomo pharmaceutical corporation. It belongs to 5-hydroxytryptamine and dopamine antagonists and has the effect of blocking dopamine D2 receptor and 5-HT2A receptor. Compared with other anti-psychosis medicines on the market, the medicine has fewer side effect reactions of extrapyramidal systems.
Blonanserin, 2- (4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydrocycloocta [ b ] pyridine, is a new generation of atypical anti-schizophrenia drug, was first disclosed in european patent EP0385237, which is an excellent medical public, and is disclosed for use in the treatment of schizophrenia. At present, the product is not imported at home, and the preparation is not produced. Spain and the United states are in phase II clinical trials. 2- (4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydro-cycloocta [ b ] pyridine is known under the general name Blonanserin (Blonanserin) and has the formula: C23H30FN3, molecular weight: 367.5, the structural formula is as follows:
Figure BDA0001285581300000021
it belongs to a drug that specifically acts on the 5-HT2 receptor and the D2 receptor, and is the closest to the selective action drug in the current atypical antipsychotic market. Obviously improves the positive symptoms (such as hallucinations, illusions and the like) and negative symptoms (such as emotional depression, hypokinesia and the like) of schizophrenia, reduces the incidence rate of extrapyramidal side reactions (Parkinson's syndrome, acute dystonia, akathisia and the like) and other adverse reactions, and has obviously better safety tolerance than the traditional antipsychotic drugs. It can be said that its appearance is a great progress in the history of drug treatment for schizophrenia. As a first-line medicine for treating schizophrenia, the compound has broad application prospect in China.
Blonanserin is soluble in acetic acid, insoluble in ethanol and insoluble in water. At present, blonanserin is marketed in Japan as tablets and powder, the prescription comprises lactose, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, aerosil and magnesium stearate, the auxiliary components in the prescription are common auxiliary materials, researchers adopt the same auxiliary materials as the original preparation to carry out prescription screening, and the dissolution rate of the blonanserin is found to be hardly over 75 percent. It is understood that the search for ways to increase the solubility of blonanserin becomes a key to the formulation.
Chinese patent CN101766626A discloses an oral preparation containing blonanserin for treating schizophrenia, which takes 2- (4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydro-cycloocta [ b ] pyridine as a raw material and comprises one or more medicinal excipients, the preparation method comprises mixing 2- (4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydro-cycloocta [ b ] pyridine, optional diluent, binder, disintegrant, anti-adhesion agent and lubricant, adding appropriate amount of wetting agent to obtain soft material, sieving to obtain wet granule, drying wet granule, sieving to obtain granule, and making into oral preparation, wherein blonanserin accounts for 0.1-30 wt% of the preparation.
Chinese patent CN101530412 discloses a composition comprising [2- (4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9, 10-hexahydro-cycloocta [ b ] pyridine ] or a pharmaceutically acceptable salt thereof, which contains not less than 10% by weight of a basic substance as a stabilizer, and a method for preparing the same. The composition of the invention is believed to have good stability, can block 5-hydroxytryptamine-2 receptors and dopamine-2 receptors, and can be used for treating schizophrenia.
CN 102078321 a (201010618820.9) discloses a pharmaceutical composition containing blonanserin, which comprises the following components by weight percent: 3.3-20% of blonanserin, 60-85% of a filler, 5-25% of a disintegrating agent, 2-6% of an adhesive, 0.25-5% of a lubricant and 0.5-2% of a glidant. The dissolution rate of the pharmaceutical composition in a dissolving medium with the pH value of 4.0-6.0 can reach more than 75%, and the problem of the dissolution rate of blonanserin is effectively solved.
CN 102240270B (201010170835.3) discloses a blonanserin tablet and a preparation method thereof, wherein the tablet comprises blonanserin, lactose and microcrystalline cellulose. Compared with the existing product and the preparation process thereof, the blonanserin tablet has higher active ingredient content and improved hardness due to small active ingredient loss in the preparation process of direct tabletting, and meets the requirements of commercial production and clinical medication.
CN 102038687 a discloses a blonanserin pharmaceutical composition with improved oral absorbability, which is characterized in that: the components and the proportion are as follows: 4g of blonanserin, 25g of beta-cyclodextrin, 20g of crospovidone, 50g of microcrystalline cellulose, 60g of lactose, 20g of pregelatinized starch, 1g of talcum powder, 1g of magnesium stearate and 5% of povidone absolute ethanol solution. The preparation method comprises placing blonanserin and BETA-cyclodextrin in a mortar, adding small amount of water, grinding into paste, drying below 50 deg.C, pulverizing into 80-100 mesh fine powder, mixing with sieved microcrystalline cellulose, lactose, croscarmellose sodium, pregelatinized starch, pulvis Talci, and magnesium stearate, mixing with 5% polyvinylpyrrolidone anhydrous ethanol solution, mixing, making into 30-40 mesh granule, drying below 50 deg.C, grading, adding lubricant, mixing, and tabletting; the preparation can greatly improve in vitro release rate, thereby improving bioavailability.
CN 105560242A (201410524686.4) discloses a blonanserin pharmaceutical composition and a preparation method thereof, wherein auxiliary materials of pregelatinized starch and mannitol in a specific ratio are selected, the in vitro release degree can be greatly improved, so that the bioavailability is improved, and a preparation with good stability is provided.
CN 103211776A (201310107637.6) discloses a pharmaceutical composition containing blonanserin orally disintegrating tablets and a preparation method thereof, the dosage form can be rapidly disintegrated in oral cavity so as to improve the medicine taking compliance of the medicine, and the dissolution rate and the bioavailability of the slightly soluble medicine prepared by the method can be improved.
CN 105476967A (201410524687.9) discloses a blonanserin pharmaceutical composition, wherein mannitol and microcrystalline cellulose are used as fillers in the prescription, and the dosage of the mannitol and the microcrystalline cellulose is 40-55% and 20-30% in percentage by weight. The blonanserin pharmaceutical composition has good stability, has more obvious advantages for improving the product yield, reducing the cost, realizing industrialization, being better applied to clinic, and can effectively improve the dissolution rate and the bioavailability.
As described above, although the prior art discloses a number of formulations and methods for preparing blonanserin tablets, given that blonanserin is a very potent pharmaceutical agent and its solubility in some cases is very poor, it is extremely important that its formulation performance, in particular its in vitro dissolution behavior, e.g. as characterized by the dissolution profile, is consistent with the original formulation. The former manufacturer of blonanserin tablets is large Japanese Sumitomo pharmaceutical Co., Ltd, and its trade name is
Figure BDA0001285581300000041
(ロナセン)。
However, the existing blonanserin has a specification of 4mg, which belongs to a small dosage specification, and the preparation of blonanserin tablets in the prior art generally adopts a wet granulation process, and the process and the prepared blonanserin tablets have the following defects: 1) the loss of active ingredients is large in the preparation process, and is about 10-20%; 2) the viscosity of the binder used for granulation is not sufficient, and the resulting granules are relatively fine, so that it is difficult to pressurize upon tableting, resulting in a tablet having a low hardness. Therefore, there is a need for improvement in the prescription of blonanserin tablets or the process for preparing the same, so as to develop a tablet that is comparable to ground drug in terms of dissolution behavior of the preparation.
Disclosure of Invention
The purpose of the present invention is to provide a blonanserin tablet pharmaceutical composition which is expected to have excellent pharmaceutical properties, particularly, for example, to be comparable to a ground drug in terms of the dissolution behavior of the preparation. The present inventors have surprisingly found that blonanserin tablet pharmaceutical compositions prepared using the formulations and methods of the present invention have superior properties exhibiting one or more aspects as described herein. The present invention has been completed accordingly.
To this end, the invention provides a blonanserin tablet pharmaceutical composition, which comprises blonanserin, a diluent, a disintegrant, a binder, a glidant and a lubricant.
The blonanserin tablet pharmaceutical composition according to any one of the embodiments of the first aspect of the invention comprises 4 parts by weight of blonanserin, 60-200 parts by weight of diluent, 5-20 parts by weight of disintegrant, 1-5 parts by weight of binder, 0.1-2 parts by weight of glidant and 0.1-1 part by weight of lubricant.
The blonanserin tablet pharmaceutical composition according to any one of the embodiments of the first aspect of the invention comprises 4 parts by weight of blonanserin, 80-150 parts by weight of diluent, 5-15 parts by weight of disintegrant, 1-3 parts by weight of binder, 0.2-1 part by weight of glidant and 0.2-0.5 part by weight of lubricant.
The blonanserin tablet pharmaceutical composition according to any embodiment of the first aspect of the invention, wherein the diluent is selected from the group consisting of: sucrose, lactose, microcrystalline cellulose, starch, modified starch, pregelatinized starch, mannitol, sorbitol, xylitol, or a combination thereof.
The blonanserin tablet pharmaceutical composition according to any embodiment of the first aspect of the invention, wherein the diluent is a combination of both lactose and microcrystalline cellulose. In one embodiment, the weight ratio of lactose to microcrystalline cellulose is 1: 0.5 to 2.
The blonanserin tablet pharmaceutical composition according to any embodiment of the first aspect of the invention, wherein the disintegrant is selected from the group consisting of: croscarmellose sodium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, crospovidone, or combinations thereof. The blonanserin tablet pharmaceutical composition according to any embodiment of the first aspect of the invention, wherein the disintegrant is low substituted hydroxypropyl cellulose.
The blonanserin tablet pharmaceutical composition according to any embodiment of the first aspect of the invention, wherein the binder is selected from the group consisting of: hydroxypropyl cellulose, povidone, starch, hydroxypropyl methylcellulose, polyethylene glycol.
The blonanserin tablet pharmaceutical composition according to any embodiment of the first aspect of the invention, wherein the glidant is selected from the group consisting of: talc, silica, aerosil or a combination thereof. The blonanserin tablet pharmaceutical composition according to any embodiment of the first aspect of the invention, wherein the glidant is silicon dioxide or aerosil.
The blonanserin tablet pharmaceutical composition according to any embodiment of the first aspect of the invention, wherein the lubricant is selected from the group consisting of: magnesium stearate, stearic acid, polyethylene glycol 6000, calcium stearate, zinc stearate or combinations thereof. The blonanserin tablet pharmaceutical composition according to any embodiment of the first aspect of the invention, wherein the lubricant is magnesium stearate.
The blonanserin tablet pharmaceutical composition according to any embodiment of the first aspect of the invention is prepared according to a method comprising the steps of:
(i) pre-grinding the raw materials and the auxiliary materials into fine powder of 120 meshes;
(ii) carrying out micronization treatment on blonanserin and microcrystalline cellulose which is 1-2 times of blonanserin in weight until the particle size is less than 10 micrometers (for example, more than 90% of the particle diameter is within the range of 3-10 micrometers), then adding half of the amount of disintegrant in the prescription, mixing, and continuously crushing until the particle size of all particles is less than 25 micrometers to obtain micronized powder;
(iii) (iii) uniformly mixing the micronized powder obtained in the step (ii) with the balance of diluent, the balance of disintegrant and half of the flow aid in the formula, placing the mixture in a fluidized bed granulator, preparing the adhesive into an adhesive solution with the concentration of 2-3% by using water, performing fluidized bed granulation on the mixed solid material by using the adhesive solution, and drying until the water content is less than 5%;
(iv) and uniformly mixing the granules prepared by the fluidized bed with the lubricant and the balance of the glidant to obtain a final mixed material, and pressing the final mixed material into tablets to obtain the tablet.
It has been surprisingly found that the tablets prepared by the above process of the present invention have substantially the same drug dissolution behavior as the original tablets, and have more advantages in chemical stability than the original tablets.
The blonanserin tablet pharmaceutical composition according to any embodiment of the first aspect of the invention, said tablet comprising 2-8 mg, such as 2-6 mg, such as 2mg or 4mg of blonanserin per tablet.
Further, the second aspect of the present invention relates to a method for preparing a blonanserin tablet pharmaceutical composition comprising blonanserin, a diluent, a disintegrant, a binder, a glidant, a lubricant; the method comprises the following steps:
(i) pre-grinding the raw materials and the auxiliary materials into fine powder of 120 meshes;
(ii) carrying out micronization treatment on blonanserin and microcrystalline cellulose which is 1-2 times of blonanserin in weight until the particle size is less than 10 micrometers (for example, more than 90% of the particle diameter is within the range of 3-10 micrometers), then adding half of the amount of disintegrant in the prescription, mixing, and continuously crushing until the particle size of all particles is less than 25 micrometers to obtain micronized powder;
(iii) (iii) uniformly mixing the micronized powder obtained in the step (ii) with the balance of diluent, the balance of disintegrant and half of the flow aid in the formula, placing the mixture in a fluidized bed granulator, preparing the adhesive into an adhesive solution with the concentration of 2-3% by using water, performing fluidized bed granulation on the mixed solid material by using the adhesive solution, and drying until the water content is less than 5%;
(iv) and uniformly mixing the granules prepared by the fluidized bed with the lubricant and the balance of the glidant to obtain a final mixed material, and pressing the final mixed material into tablets to obtain the tablet.
The method according to any embodiment of the second aspect of the invention, wherein the blonanserin tablet pharmaceutical composition comprises 4 parts by weight of blonanserin, 60-200 parts by weight of diluent, 5-20 parts by weight of disintegrant, 1-5 parts by weight of binder, 0.1-2 parts by weight of glidant and 0.1-1 part by weight of lubricant.
The method according to any embodiment of the second aspect of the invention, wherein the blonanserin tablet pharmaceutical composition comprises 4 parts by weight of blonanserin, 80-150 parts by weight of diluent, 5-15 parts by weight of disintegrant, 1-3 parts by weight of binder, 0.2-1 part by weight of glidant and 0.2-0.5 part by weight of lubricant.
The method according to any embodiment of the second aspect of the present invention, wherein the diluent is selected from the group consisting of: sucrose, lactose, microcrystalline cellulose, starch, modified starch, pregelatinized starch, mannitol, sorbitol, xylitol, or a combination thereof.
The process according to any embodiment of the second aspect of the invention, wherein the diluent is a combination of both lactose and microcrystalline cellulose. In one embodiment, the weight ratio of lactose to microcrystalline cellulose is 1: 0.5 to 2.
The method according to any embodiment of the second aspect of the invention, wherein the disintegrant is selected from the group consisting of: croscarmellose sodium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, crospovidone, or combinations thereof. The method according to any one of the embodiments of the second aspect of the present invention, wherein the disintegrant is low-substituted hydroxypropylcellulose.
The method according to any embodiment of the second aspect of the present invention, wherein the binder is selected from the group consisting of: hydroxypropyl cellulose, povidone, starch, hydroxypropyl methylcellulose, polyethylene glycol.
The method according to any embodiment of the second aspect of the invention, wherein the glidant is selected from the group consisting of: talc, silica, aerosil or a combination thereof. The method according to any embodiment of the second aspect of the invention, wherein the glidant is silicon dioxide or aerosil.
The method according to any one of the embodiments of the second aspect of the present invention, wherein the lubricant is selected from the group consisting of: magnesium stearate, stearic acid, polyethylene glycol 6000, calcium stearate, zinc stearate or combinations thereof. The method according to any embodiment of the second aspect of the invention, wherein the lubricant is magnesium stearate.
The method according to any embodiment of the second aspect of the invention, wherein the blonanserin tablet pharmaceutical composition comprises 2-8 mg, such as 2-6 mg, such as 2mg or 4mg of blonanserin per tablet.
A further third aspect of the invention provides the use of a blonanserin tablet pharmaceutical composition comprising blonanserin, a diluent, a disintegrant, a binder, a glidant, a lubricant for the manufacture of a medicament for the treatment of a psychotic disorder, e.g. schizophrenia.
The use according to any embodiment of the third aspect of the invention, wherein the blonanserin tablet pharmaceutical composition comprises 4 parts by weight of blonanserin, 60-200 parts by weight of diluent, 5-20 parts by weight of disintegrant, 1-5 parts by weight of binder, 0.1-2 parts by weight of glidant and 0.1-1 part by weight of lubricant.
The use according to any embodiment of the third aspect of the invention, wherein the blonanserin tablet pharmaceutical composition comprises 4 parts by weight of blonanserin, 80-150 parts by weight of diluent, 5-15 parts by weight of disintegrant, 1-3 parts by weight of binder, 0.2-1 part by weight of glidant and 0.2-0.5 part by weight of lubricant.
The use according to any embodiment of the third aspect of the present invention, wherein the diluent is selected from the group consisting of: sucrose, lactose, microcrystalline cellulose, starch, modified starch, pregelatinized starch, mannitol, sorbitol, xylitol, or a combination thereof.
The use according to any embodiment of the third aspect of the present invention, wherein the diluent is a combination of both lactose and microcrystalline cellulose. In one embodiment, the weight ratio of lactose to microcrystalline cellulose is 1: 0.5 to 2.
The use according to any of the embodiments of the third aspect of the present invention, wherein the disintegrant is selected from the group consisting of: croscarmellose sodium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, crospovidone, or combinations thereof. The use according to any of the embodiments of the third aspect of the present invention, wherein the disintegrant is low-substituted hydroxypropylcellulose.
The use according to any embodiment of the third aspect of the present invention, wherein the binder is selected from the group consisting of: hydroxypropyl cellulose, povidone, starch, hydroxypropyl methylcellulose, polyethylene glycol.
The use according to any embodiment of the third aspect of the invention, wherein the glidant is selected from the group consisting of: talc, silica, aerosil or a combination thereof. The use according to any embodiment of the third aspect of the invention, wherein the glidant is silicon dioxide or aerosil.
The use according to any embodiment of the third aspect of the present invention, wherein the lubricant is selected from the group consisting of: magnesium stearate, stearic acid, polyethylene glycol 6000, calcium stearate, zinc stearate or combinations thereof. The use according to any embodiment of the third aspect of the invention, wherein the lubricant is magnesium stearate.
The use according to any of the embodiments of the third aspect of the present invention, wherein the blonanserin tablet pharmaceutical composition is prepared according to a process comprising the steps of:
(i) pre-grinding the raw materials and the auxiliary materials into fine powder of 120 meshes;
(ii) carrying out micronization treatment on blonanserin and microcrystalline cellulose which is 1-2 times of blonanserin in weight until the particle size is less than 10 micrometers (for example, more than 90% of the particle diameter is within the range of 3-10 micrometers), then adding half of the amount of disintegrant in the prescription, mixing, and continuously crushing until the particle size of all particles is less than 25 micrometers to obtain micronized powder;
(iii) (iii) uniformly mixing the micronized powder obtained in the step (ii) with the balance of diluent, the balance of disintegrant and half of the flow aid in the formula, placing the mixture in a fluidized bed granulator, preparing the adhesive into an adhesive solution with the concentration of 2-3% by using water, performing fluidized bed granulation on the mixed solid material by using the adhesive solution, and drying until the water content is less than 5%;
(iv) and uniformly mixing the granules prepared by the fluidized bed with the lubricant and the balance of the glidant to obtain a final mixed material, and pressing the final mixed material into tablets to obtain the tablet.
The use according to any embodiment of the third aspect of the invention, wherein the blonanserin tablet pharmaceutical composition comprises 2-8 mg, such as 2-6 mg, such as 2mg or 4mg, of blonanserin per tablet.
According to any one of the embodiments of the first aspect of the present invention, wherein the blonanserin tablet pharmaceutical composition has the formulation ratio as described in any one of the examples of the specification or is optionally prepared by a preparation method thereof.
In the above-described steps of the preparation method of the present invention, although the specific steps described therein are distinguished in some detail or in language description from the steps described in the preparation examples of the detailed embodiments below, those skilled in the art can fully summarize the above-described method steps in light of the detailed disclosure throughout the present disclosure.
Any embodiment of any aspect of the invention may be combined with any other embodiment of the invention, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in any other embodiment of the invention, provided that they do not contradict.
The invention is further described below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
The preparation method of the tablet pharmaceutical composition of the invention is a method used in the field, for example, micronization treatment of the raw material drug can be carried out by using equipment such as a jet mill of a QYF400 jet mill, for example, a fluidized bed granulator can use WBF-2G type multifunctional fluidized bed of Chongqing Ying Ge coating granulation technology, Inc., a material mixer can use SBH-25 type three-dimensional oscillating mixer of Tanshan Pohua pharmaceutical machinery factory in Jiangyin city, and a tablet press can use YP-5 type tablet press of Canuo medicine, Inc. in Guangzhou province. The operating parameters of these devices and their corresponding processes are well known to those skilled in the art.
Drawings
FIG. 1: blonanserin tablets (131101 lots) and
Figure BDA0001285581300000081
comparison of the dissolution curves in water,
FIG. 2: blonanserin tablets (131101 lots) and
Figure BDA0001285581300000082
comparison of dissolution curves in hydrochloric acid solution at pH1.2,
FIG. 3: blonanserin tablets (131101 lots) and
Figure BDA0001285581300000083
comparison of dissolution profiles in acetate solution at pH4.0,
FIG. 4: blonanserin tablets (131101 lots) and
Figure BDA0001285581300000084
comparison of dissolution profiles in phosphate solution at pH6.0,
FIG. 5: blonanserin tablets (131101 lots) and
Figure BDA0001285581300000085
comparison of dissolution profiles in phosphate solution at pH 6.8.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. The following examples further illustrate the invention without limiting it. In the following description of the preparation of tablets, taking the case of compressing tablets with a 4mg blonanserin standard per tablet, the fact that the dosage of the tablet has no effect on achieving the objects of the present invention is merely to scale up or down the materials in the formulation. In addition, when tablets are prepared below, the dosage amount per batch is dosed at a size of at least 2 ten thousand tablets.
First, example of tablet preparation
Example 1: blonanserin tablet
Prescription:
blonanserin (principal drug) 4.0 parts by weight of,
Lactose (Diluent) 60 parts by weight,
Microcrystalline cellulose (Diluent) 45 parts by weight of,
Hydroxypropyl cellulose (adhesive) 2 parts by weight,
Low-substituted hydroxypropyl cellulose (disintegrant) 8 parts by weight of,
Silicon dioxide (glidant) 0.6 part by weight,
Magnesium stearate (Lubricant) 0.3 part by weight,
Purified water (binding solvent) Appropriate amount (solvent used in the process and eventually removed).
The preparation method comprises the following steps:
(i) pre-grinding the raw materials and the auxiliary materials into fine powder of 120 meshes;
(ii) carrying out micronization treatment on blonanserin and microcrystalline cellulose which is 1.5 times of blonanserin in weight until the particle size is less than 10 micrometers (more than 90 percent of particles have the diameter within the range of 3-10 micrometers), then adding half of the amount of disintegrant in the prescription, mixing, and continuously crushing until the particle size of all particles is less than 25 micrometers to obtain micronized powder;
(iii) (iii) mixing the micronized powder obtained in step (ii) with the balance of diluent, the balance of disintegrant and half of the amount of glidant in the prescription, placing the mixture in a fluidized bed granulator, preparing the binder into a binder solution with the concentration of 2.5% by using water, performing fluidized bed granulation on the mixed solid material by using the binder solution, and drying the mixed solid material until the water content is less than 5%;
(iv) and uniformly mixing the granules prepared by the fluidized bed with the lubricant and the balance of the glidant to obtain a final mixed material, and pressing the final mixed material into tablets to obtain the tablet.
Example 2: blonanserin tablet
Prescription:
Figure BDA0001285581300000091
Figure BDA0001285581300000101
the preparation method comprises the following steps:
(i) pre-grinding the raw materials and the auxiliary materials into fine powder of 120 meshes;
(ii) carrying out micronization treatment on blonanserin and microcrystalline cellulose with the weight of 1 time of the blonanserin until the particle size is less than 10 micrometers (more than 90 percent of the particle diameter is within the range of 3-10 micrometers), then adding half of the amount of disintegrant in the prescription, mixing, and continuously crushing until the particle size of all particles is less than 25 micrometers to obtain micronized powder;
(iii) (iii) mixing the micronized powder obtained in step (ii) with the balance of diluent, the balance of disintegrant and half of the amount of glidant in the prescription, placing the mixture in a fluidized bed granulator, preparing the binder into a binder solution with the concentration of 3% by using water, performing fluidized bed granulation on the mixed solid material by using the binder solution, and drying the mixed solid material until the water content is less than 5%;
(iv) and uniformly mixing the granules prepared by the fluidized bed with the lubricant and the balance of the glidant to obtain a final mixed material, and pressing the final mixed material into tablets to obtain the tablet.
Example 3: blonanserin tablet
Prescription:
blonanserin (principal drug) 4.0 parts by weight of,
Lactose (Diluent) 67 parts by weight,
Microcrystalline cellulose (Diluent) 133 parts by weight,
Hydroxypropyl cellulose (adhesive) 5 parts by weight,
Low-substituted hydroxypropyl cellulose (disintegrant) 20 parts by weight of,
Silicon dioxide (glidant)) 2 parts by weight,
Magnesium stearate (Lubricant) 0.1 part by weight,
Purified water (binding solvent) Appropriate amount (solvent used in the process and eventually removed).
The preparation method comprises the following steps:
(i) pre-grinding the raw materials and the auxiliary materials into fine powder of 120 meshes;
(ii) carrying out micronization treatment on blonanserin and microcrystalline cellulose 2 times of the blonanserin until the particle size is less than 10 micrometers (more than 90 percent of the particle diameter is within the range of 3-10 micrometers), then adding half of the disintegrating agent in the prescription, mixing, and continuously crushing until the particle size of all particles is less than 25 micrometers to obtain micronized powder;
(iii) (iii) mixing the micronized powder obtained in step (ii) with the balance of diluent, the balance of disintegrant and half of the amount of glidant in the prescription, placing the mixture in a fluidized bed granulator, preparing the binder into a 2% binder solution with water, performing fluidized bed granulation on the mixed solid material by using the binder solution, and drying the mixed solid material until the water content is less than 5%;
(iv) and uniformly mixing the granules prepared by the fluidized bed with the lubricant and the balance of the glidant to obtain a final mixed material, and pressing the final mixed material into tablets to obtain the tablet.
Example 4: blonanserin tablet
Prescription:
blonanserin (principal drug) 4.0 parts by weight of,
Lactose (Diluent) 80 parts by weight of,
Microcrystalline cellulose (Diluent) 70 parts by weight,
Hydroxypropyl cellulose (adhesive) 3 parts by weight of,
Low-substituted hydroxypropyl cellulose (disintegrant) 5 parts by weight,
Silicon dioxide (glidant) 1 part by weight,
Magnesium stearate (Lubricant) 0.2 part by weight,
Purified water (binding solvent) Appropriate amount (solvent used in the process and eventually removed).
The preparation method comprises the following steps:
(i) pre-grinding the raw materials and the auxiliary materials into fine powder of 120 meshes;
(ii) carrying out micronization treatment on blonanserin and microcrystalline cellulose 2 times of the blonanserin until the particle size is less than 10 micrometers (more than 90 percent of the particle diameter is within the range of 3-10 micrometers), then adding half of the disintegrating agent in the prescription, mixing, and continuously crushing until the particle size of all particles is less than 25 micrometers to obtain micronized powder;
(iii) (iii) mixing the micronized powder obtained in step (ii) with the balance of diluent, the balance of disintegrant and half of the amount of glidant in the prescription, placing the mixture in a fluidized bed granulator, preparing the binder into a 2% binder solution with water, performing fluidized bed granulation on the mixed solid material by using the binder solution, and drying the mixed solid material until the water content is less than 5%;
(iv) and uniformly mixing the granules prepared by the fluidized bed with the lubricant and the balance of the glidant to obtain a final mixed material, and pressing the final mixed material into tablets to obtain the tablet.
Example 5: blonanserin tablet
Prescription:
blonanserin (principal drug) 4.0 parts by weight of,
Lactose (Diluent) 30 parts by weight of,
Microcrystalline cellulose (Diluent) 50 parts by weight of,
Hydroxypropyl cellulose (adhesive) 1 part by weight,
Low-substituted hydroxypropyl cellulose (disintegrant) 15 parts by weight,
Silicon dioxide (glidant) 0.2 part by weight,
Magnesium stearate (Lubricant) 0.5 part by weight,
Purified water (binding solvent) Appropriate amount (solvent used in the process and eventually removed).
The preparation method comprises the following steps:
(i) pre-grinding the raw materials and the auxiliary materials into fine powder of 120 meshes;
(ii) carrying out micronization treatment on blonanserin and microcrystalline cellulose with the weight of 1 time of the blonanserin until the particle size is less than 10 micrometers (more than 90 percent of the particle diameter is within the range of 3-10 micrometers), then adding half of the amount of disintegrant in the prescription, mixing, and continuously crushing until the particle size of all particles is less than 25 micrometers to obtain micronized powder;
(iii) (iii) mixing the micronized powder obtained in step (ii) with the balance of diluent, the balance of disintegrant and half of the amount of glidant in the prescription, placing the mixture in a fluidized bed granulator, preparing the binder into a binder solution with the concentration of 3% by using water, performing fluidized bed granulation on the mixed solid material by using the binder solution, and drying the mixed solid material until the water content is less than 5%;
(iv) and uniformly mixing the granules prepared by the fluidized bed with the lubricant and the balance of the glidant to obtain a final mixed material, and pressing the final mixed material into tablets to obtain the tablet.
Example 6: blonanserin tablet
The formulation and preparation are as described in examples 1 to 5, respectively, except that in step (ii) blonanserin is micronized to a particle size of 90% or more of particles with a diameter in the range of 3 to 10 μm, as follows:
(i) pre-grinding the raw materials and the auxiliary materials into fine powder of 120 meshes;
(ii) micronizing blonanserin until the particle size is less than 10 micrometers (more than 90% of particles have the diameter within the range of 3-10 micrometers), so as to obtain micronized powder;
(iii) (iii) mixing the micronized powder from step (ii) with diluent, disintegrant and half of the amount of flow aid, placing in a fluid bed granulator, performing fluid bed granulation on the mixed solid material with binder solution and drying until the water content is less than 5%;
(iv) and uniformly mixing the granules prepared by the fluidized bed with the lubricant and the balance of the glidant to obtain a final mixed material, and pressing the final mixed material into tablets to obtain the tablet. The 5 batches of tablets thus obtained with reference to the recipe preparation of examples 1-5, respectively, can be labeled as samples of examples 61-65, respectively.
Example 7: blonanserin tablet
The formulation and preparation are as described in examples 1 to 5, respectively, except that no disintegrant is added during micronization in step (ii), as follows:
(i) pre-grinding the raw materials and the auxiliary materials into fine powder of 120 meshes;
(ii) carrying out micronization treatment on blonanserin and microcrystalline cellulose together until the particle size is less than 10 micrometers (more than 90% of particles have the diameter within the range of 3-10 micrometers), so as to obtain micronized powder;
(iii) (iii) uniformly mixing the micronized powder obtained in step (ii) with the balance of diluent, disintegrant and half of the amount of flow aid in the prescription, placing the mixture in a fluidized bed granulator, performing fluidized bed granulation on the mixed solid material by using a binder solution, and drying until the moisture content is less than 5%;
(iv) and uniformly mixing the granules prepared by the fluidized bed with the lubricant and the balance of the glidant to obtain a final mixed material, and pressing the final mixed material into tablets to obtain the tablet. The 5 batches of tablets thus obtained with reference to the recipe preparation of examples 1-5, respectively, can be labeled as samples from examples 71-75, respectively.
Example 8: blonanserin tablet
The formulation and preparation were as described in examples 1 to 5, respectively, except that no microcrystalline cellulose was added during micronization in step (ii), as follows:
(i) pre-grinding the raw materials and the auxiliary materials into fine powder of 120 meshes;
(ii) carrying out micronization on blonanserin and an equivalent disintegrant until the particle size is less than 10 micrometers (more than 90 percent of particles have the diameter within the range of 3-10 micrometers), so as to obtain micronized powder;
(iii) (iii) mixing the micronized powder obtained in step (ii) with diluent, rest disintegrant and half of glidant in the prescription, placing in a fluidized bed granulator, preparing adhesive solution with concentration of 3% by using water, performing fluidized bed granulation on the mixed solid material by using the adhesive solution, and drying until the water content is less than 5%;
(iv) and uniformly mixing the granules prepared by the fluidized bed with the lubricant and the balance of the glidant to obtain a final mixed material, and pressing the final mixed material into tablets to obtain the tablet. The 5 batches of tablets thus obtained with reference to the recipe preparation of examples 1-5, respectively, can be labeled as samples from examples 81-85, respectively.
Example 9: blonanserin tablet
The formulation and preparation were as described in examples 1 to 5, respectively, except that the microcrystalline cellulose was changed to lactose during micronization in step (ii), as follows:
(i) pre-grinding the raw materials and the auxiliary materials into fine powder of 120 meshes;
(ii) carrying out micronization treatment on blonanserin and lactose together until the particle size is less than 10 micrometers (more than 90% of particles have the diameter within the range of 3-10 micrometers), then adding half of the disintegrating agent in the prescription, mixing, and continuously crushing until the particle size of all particles is less than 25 micrometers to obtain micronized powder;
(iii) (iii) mixing the micronized powder obtained in step (ii) with the balance of diluent, the balance of disintegrant and half of the amount of glidant in the prescription, placing the mixture in a fluidized bed granulator, preparing the binder into a binder solution with the concentration of 3% by using water, performing fluidized bed granulation on the mixed solid material by using the binder solution, and drying the mixed solid material until the water content is less than 5%;
(iv) and uniformly mixing the granules prepared by the fluidized bed with the lubricant and the balance of the glidant to obtain a final mixed material, and pressing the final mixed material into tablets to obtain the tablet.
Example 10: blonanserin sheet (#321E1)
The material dosage (g) of each 1000 tablets:
color of clothForest (3 to 5 μm) 2g、
Lactose 39.1g、
Hydroxypropyl cellulose (2%) 0.5g、
Low-substituted hydroxypropyl cellulose 9g、
Microcrystalline cellulose PH101 8.5g、
Magnesium stearate 0.6g、
Silica gel micropowder 0.3g、
The preparation method comprises the following steps: controlling the particle size of blonanserin to be 3-5 mu m by an air jet mill, uniformly mixing with lactose, internally added 3g of low-substituted hydroxypropyl cellulose and microcrystalline cellulose PH101, adding 25g of hydroxypropyl cellulose solution (2%) as a binding agent, granulating by a wet method, drying the granules in a constant-temperature drying oven at 50 ℃ until the moisture content is less than 5%, externally added 6g of low-substituted hydroxypropyl cellulose, added with magnesium stearate and aerosil, uniformly mixing, and tabletting.
Example 11: blonanserin sheet (#321E5)
The dosage (g) of each 1000 tablets
Blonanserin (3 to 5 mu m) 4g、
Lactose 66.96g、
Hydroxypropyl cellulose (2%) 0.48g、
Low-substituted hydroxypropyl cellulose 18g、
Microcrystalline cellulose PH101 27g、
Magnesium stearate 1.2g、
Silica gel micropowder 2.4g、
The preparation method comprises the following steps: sieving the raw materials which are not micronized through a 200-mesh sieve, mixing the raw materials with lactose, sieving the mixture through a 80-mesh sieve, micronizing the mixture (the particle diameter of more than 90 percent is within the range of 3-10 mu m), mixing the mixture with microcrystalline cellulose 101, sieving the mixture through the 80-mesh sieve, adding 6g of low-substituted hydroxypropyl cellulose, adding 24g of hydroxypropyl cellulose solution (2 percent) serving as an adhesive, granulating the mixture through a wet method, drying the granules in a constant-temperature drying oven at 50 ℃ until the moisture content is less than 5 percent, adding 12g of low-substituted hydroxypropyl cellulose, adding magnesium stearate and aerosil, uniformly mixing, and tabletting.
Test example 1: in vitro dissolution characteristics testing of tablets
As blonanserin is a medicine with poor solubility, blonanserin tablets are common oral solid preparations, the dissolution rate is the key performance of the oral solid preparations when the medicines are taken orally, and compared with the dissolution rate property of the original medicines in the market, the blonanserin tablets are an important evaluation index in the pharmaceutical field and an important test model for predicting the absorption behavior of the medicines in vivo. The dissolution properties of the tablets were tested as follows.
Test drugs: blonanserin tablets prepared in example 1 above, having lot number 131101, specification: 4 mg/tablet, and packaging by aluminum plastic;
control drug:
Figure BDA0001285581300000151
(ロナセン), 4 mg/tablet, manufactured by Sumitomo pharmaceutical Co., Ltd.; lot No. 2054F, pot life to 201601, aluminum plastic packaging.
Investigation of blonanserin tablets of the invention and
Figure BDA0001285581300000152
(ロナセン) cumulative dissolution profiles in five different dissolution media were compared.
Dissolution conditions:
dissolution medium: 900ml of each of water, a hydrochloric acid solution of pH1.2, an acetate buffer solution of pH4.0, a phosphate buffer solution of pH6.0 and a phosphate buffer solution of pH6.8 was used as an elution medium.
The method comprises the following steps: XC second method and paddle method as appendix of 2010 edition second part of Chinese pharmacopoeia
Rotating speed: 50 revolutions per minute
Sampling points are as follows: the dissolution curves of water, hydrochloric acid solution with pH1.2, acetate buffer solution with pH4.0, phosphate buffer solution with pH6.0, and phosphate buffer solution with pH6.8 are respectively 5, 10, 15, 30, 60, and 120 min; 10ml of the solution is respectively taken and filtered by a filter membrane of 0.45 mu m, and a subsequent filtrate is taken and simultaneously added with the same amount of the same-temperature digestion solution.
The determination method comprises the following steps: taking a proper amount of the solution, filtering, and taking a proper amount of a subsequent filtrate as a test solution; and dissolving a proper amount of blonanserin reference substance into a solution containing about 4 mu g of blonanserin in every 1ml by adding a corresponding solvent to serve as a reference substance solution. The sample solution and the reference solution are respectively taken 100 μ l precisely, injected into a liquid chromatograph, and the chromatogram is recorded (measured by HPLC method of the invention). Calculating according to the peak area by an external standard method to obtain the product.
Table: blonanserin tablets (131101) same as
Figure BDA0001285581300000153
(ロナセン) comparison of results of dissolution Curve measurements in five media
Figure BDA0001285581300000154
Figure BDA0001285581300000161
Figure BDA0001285581300000171
Blonanserin tablets (131101) same as
Figure BDA0001285581300000172
(ロナセン) comparison of dissolution profile measurements in five media figures 1 to 5, respectively.
From the cumulative dissolution curves of five dissolution media, the blonanserin tablets prepared by the invention and
Figure BDA0001285581300000173
the in vitro dissolution behavior of the composition is substantially consistent. Calculation of dissolution Properties f of the two formulations according to methods well known in the art2Similar factors, results are given in the following table:
Figure BDA0001285581300000174
f2comparison of similarity factors takes points to illustrate that: the point 6 of the dissolution curve in water and phosphate buffer solution with pH6.8 is taken for 5min, 10min, 15min, 30min, 60min and 120min to calculate f2A similarity factor. The difference in the average cumulative release at each time point on the release curves of the test and reference formulations is minimal in the plateau region (if extrapolated to 100% release, the difference would be 0) where an increase in the sampling point would directly result in f2The value is too large. Therefore, the cumulative drug release of the tested or reference preparation should be no more than 85% of the sampling points, and f is calculated from 5 points of 5min, 10min, 15min, 30min and 60min in the dissolution curve of phosphate buffer solution with pH6.02A similarity factor. Dissolution rates of over 85% at 5min in the hydrochloric acid solution of pH1.2 and acetate buffer solution of pH4.0 were directly considered to be similar to those of the reference formulation.
And (4) conclusion: inventive samples and
Figure BDA0001285581300000175
dissolution curves f in5 different dissolution media2The similarity factors all meet the requirements, which indicate that the sample is prepared by self and
Figure BDA0001285581300000176
dissolution profiles are similar.
It is generally required in the art that each of f in the above 5 types of dissolution media2The in vitro dissolution performance of both formulations was considered similar when the similarity factor was greater than 65, and it is evident from the above results that the tablet of example 1 of the present invention has very good similarity to the original commercially available formulation.
In a supplementary test in the manner described above, dissolution tests were conducted on all tablets obtained in examples 2 to 11 and the similarity factor with the original commercial reference was calculated, and the results show that f, which is the dissolution factor of all tablets obtained in examples 2 to 5 in five dissolution media2The similarity factors are all substantially the same as those of the tablet of example 1, e.g. in water f2The similarity factor values are all in the range of 79-83, and f is in a medium with the pH value of 6.82The similarity factor value is in the range of 87-91, and f is in the medium with pH4.0 and pH1.22All similarity factor values are greater than 90, f in a medium with pH6.02The similarity factor values are all in the range of 74-77. Unfortunately, however, all tablets obtained in examples 6-11 differ significantly from the original ground commercial control by similar factors, e.g. they were in pH4.0 and pH1.2 medium f2The similarity factor value is in the range of 79-88, and f is in three media of water, pH6.0 and pH6.82Similarity ofThe factor values are respectively in the range of 54-62, 49-58 and 59-67; for example, the example 11 tablet has f in five media of pH4.0, pH1.2, water, pH6.0, pH6.82The similarity factor values were 83, 87, 58, 53, 61, respectively. The similarity of all tablets obtained in the above examples 6 to 11 to the original ground commercial product in three media of water, pH6.0 and pH6.8 is obviously unacceptable, and the similarity in the media of pH4.0 and pH1.2 is also obviously worse than that in example 1 of the present invention.
Test example 2: determination of tablet content and inspection of related substances
The change of impurities in the tablet was measured according to the method carried in "pharmacopoeia of the people's republic of China" 2015, fourth part, page 59, "0512 high performance liquid chromatography".
(1) Chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent; the method comprises the following steps of mixing methanol: acetonitrile: 0.05M sodium acetate buffer solution (30: 30: 40) with pH4.0 as a mobile phase; the detection wavelength is 254 nm; the number of theoretical plates is not less than 5000 according to blonanserin peak;
(2) preparation of control solutions: taking a proper amount of blonanserin reference substance, precisely weighing, and adding a mobile phase to prepare a solution containing 20 mu g of the blonanserin reference substance per 1ml, so as to obtain the blonanserin reference substance which can be used as a reference substance solution for content measurement; [ precisely measuring 10ml of reference substance solution for content determination, placing the reference substance solution in a 50ml measuring flask, and diluting with a mobile phase to a constant volume to obtain a reference substance solution for dissolution determination; ]
(3) Preparation of a test solution: taking tablets, grinding, mixing uniformly, taking powder containing blonanserin about 10mg, precisely weighing, placing in a 50ml measuring flask, carrying out ultrasonic treatment (power 250W, frequency 40kHz) for 5 minutes, fixing volume with a mobile phase, filtering, and taking a subsequent filtrate to obtain a test sample solution for detecting related substances;
precisely measuring 10ml of a test sample solution for detecting related substances, putting the test sample solution into a 100ml measuring flask, and diluting with a mobile phase to a constant volume to obtain a test sample solution for measuring the content;
precisely measuring 1ml of a sample solution for content measurement, placing the sample solution in a 100ml measuring flask, and diluting with a mobile phase to a constant volume to obtain a reference solution for detecting related substances;
(4) the determination method comprises the following steps: precisely sucking 20 μ l of each of the reference solution or the sample solution, injecting into a liquid chromatograph, and recording chromatogram; [ in the case of dissolution test, the dissolution liquid can be directly injected into an HPLC apparatus after filtration to test by this method ]
(5) And (4) calculating a result:
calculating the content of the active ingredient in the tablet by peak area according to an external standard method by using a reference substance solution for content measurement, peak area in a chromatogram of a test substance solution for content measurement and drug concentration of the reference substance solution;
calculating the content of various impurities in the test sample and the total impurity content thereof according to the main peak area in the chromatogram of the reference solution for detecting the related substances and the impurity peak area in the test sample solution for detecting the related substances;
the percent dissolution is calculated by comparing the peak areas obtained by the reference substance solution for dissolution determination and the dissolution solution determination solution according to the peak area of an external standard method.
The raw material medicines used for preparing the tablets in the above embodiments of the invention are the same batch, so that the chemical stability of the tablets can be reflected by the difference of related substance changes of the tablets when the related substances are checked.
The blonanserin tablets prepared in examples 1-11 herein and the commercially available primary grinding tablets were mixed
Figure BDA0001285581300000191
(ロナセン, 2054F) was packaged in an aluminum-plastic bag and tested at 45 + -2 deg.C/RH 75 + -5% accelerated for 5 months to determine the tablet content and related substances at 0 month and 5 months for each batch of tablet samples.
In terms of content, for each batch of tablet samples, the percentage obtained by dividing the content of 5 months by the content of 0 months and multiplying the result by 100% is taken as the residual percentage of the active ingredient after the accelerated test, and the results show that all the tablets obtained in examples 1-11 and the 2054F tablet have no obvious difference in content change, and the residual percentage is in the range of 95-97%, which is a relatively ideal result.
When relevant substances of the tablets are measured by the method, the HPLC method conditions can effectively separate blonanserin from other chromatographic peaks, the separation degree of the blonanserin from other chromatographic peaks is more than 4.0, and by the HPLC method, the unknown impurity peak (the impurity can be marked as RRT1.88 impurity) appears in each tablet (comprising 2054F) at the relative retention time of about 1.88 relative to the blonanserin peak, the impurity can increase in the tablet along with the prolonging of the storage time of the tablet, and the impurity is not introduced by the auxiliary materials but introduced by the medicine blonanserin through blank tablets, namely mixed auxiliary materials and bulk drug comparison. All tablets obtained in examples 1 to 11 herein and 2054F tablets were subjected to a relevant material check at 0 months and at 45 ℃ for 5 months, and the results showed: examples 1-11 all tablets and 2054F tablets had a maximum individual impurity at month 0 (including RRT1.88 impurity) of less than 0.03%, a total impurity of less than 0.075%, and no significant difference between the batches of tablets; all of the tablets of examples 1-11 and the 2054F tablet had a maximum individual impurity of less than 0.05% at 5 months, a total impurity of less than 0.15%, and no significant difference between the individual batches of tablets; the results of all of the tablets of examples 6-11 and the 2054F tablets showed a significant increase in the RRT1.88 impurity at 5 months and a significantly higher increase than the tablets of examples 1-5, and the percentage increase in the RRT1.88 impurity at 5 months minus the RRT1.88 impurity at 0 months divided by the RRT1.88 impurity at 0 months multiplied by 100% for a batch of tablets was found to be the percentage increase in the RRT1.88 impurity, which represents the growth of the RRT1.88 impurity in the tablets, and the results showed that the percentage increase in the RRT1.88 impurity was in the range of 263 to 327% for all of the tablets of examples 6-11 and the 2054F tablets, for example, the percentage increase in the RRT1.88 impurity was 296% for the tablet of example 11, and the percentage increase in the RRT1.88 impurity was in the range of 39 to 62% for all of the tablets of examples 1-5, which was significantly lower than the other tablets.
The above-mentioned embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of the present invention is not limited thereto. The equivalent substitution or change made by the technical personnel in the technical field on the basis of the invention is all within the protection scope of the invention. The protection scope of the invention is subject to the claims.

Claims (10)

1. Blonanserin tablet pharmaceutical composition, which comprises the following components: 4 parts of blonanserin, 60-200 parts of diluent, 5-20 parts of disintegrating agent, 1-5 parts of adhesive, 0.1-2 parts of flow aid and 0.1-1 part of lubricant; the diluent is lactose and microcrystalline cellulose both in a weight ratio of 1: 0.5-2, the disintegrant is low-substituted hydroxypropyl cellulose, the binder is hydroxypropyl cellulose, the glidant is silicon dioxide, and the lubricant is magnesium stearate; the tablet is prepared by the method comprising the following steps:
(i) pre-grinding the raw materials and the auxiliary materials into fine powder of 120 meshes;
(ii) carrying out micronization treatment on blonanserin and microcrystalline cellulose which is 1-2 times of blonanserin in weight until the particle size is less than 10 mu m, then adding half of disintegrating agent in the prescription, mixing, and continuously crushing until the particle size of all particles is less than 25 mu m to obtain micronized powder;
(iii) (iii) uniformly mixing the micronized powder obtained in the step (ii) with the balance of diluent, the balance of disintegrant and half of the flow aid in the formula, placing the mixture in a fluidized bed granulator, preparing the adhesive into an adhesive solution with the concentration of 2-3% by using water, performing fluidized bed granulation on the mixed solid material by using the adhesive solution, and drying until the water content is less than 5%;
(iv) and uniformly mixing the granules prepared by the fluidized bed with the lubricant and the balance of the glidant to obtain a final mixed material, and pressing the final mixed material into tablets to obtain the tablet.
2. Blonanserin tablet pharmaceutical composition according to claim 1, consisting of: 4 parts of blonanserin, 80-150 parts of diluent, 5-15 parts of disintegrating agent, 1-3 parts of adhesive, 0.2-1 part of glidant and 0.2-0.5 part of lubricant.
3. The blonanserin tablet pharmaceutical composition according to claim 1, wherein in step (ii) blonanserin and microcrystalline cellulose are micronized together until more than 90% of the particles have a diameter in the range of 3-10 μm.
4. Blonanserin tablet pharmaceutical composition according to claim 1, comprising 2-8 mg of blonanserin per tablet.
5. Blonanserin tablet pharmaceutical composition according to claim 1, comprising 2-6 mg of blonanserin per tablet.
6. Blonanserin tablet pharmaceutical composition according to claim 1, comprising 4mg of blonanserin per tablet.
7. A process for preparing the blonanserin tablet pharmaceutical composition of any one of claims 1 to 6, comprising the steps of:
(i) pre-grinding the raw materials and the auxiliary materials into fine powder of 120 meshes;
(ii) carrying out micronization treatment on blonanserin and microcrystalline cellulose which is 1-2 times of blonanserin in weight until the particle size is less than 10 mu m, then adding half of disintegrating agent in the prescription, mixing, and continuously crushing until the particle size of all particles is less than 25 mu m to obtain micronized powder;
(iii) (iii) uniformly mixing the micronized powder obtained in the step (ii) with the balance of diluent, the balance of disintegrant and half of the flow aid in the formula, placing the mixture in a fluidized bed granulator, preparing the adhesive into an adhesive solution with the concentration of 2-3% by using water, performing fluidized bed granulation on the mixed solid material by using the adhesive solution, and drying until the water content is less than 5%;
(iv) and uniformly mixing the granules prepared by the fluidized bed with the lubricant and the balance of the glidant to obtain a final mixed material, and pressing the final mixed material into tablets to obtain the tablet.
8. A process according to claim 7, wherein the blonanserin and microcrystalline cellulose are micronised together in step (ii) until more than 90% of the particles have a diameter in the range of 3 to 10 μm.
9. Use of the blonanserin tablet pharmaceutical composition of any one of claims 1-6 in the manufacture of a medicament for the treatment of a psychiatric disorder.
10. Use according to claim 9, wherein the psychiatric disorder is schizophrenia.
CN201710305669.5A 2017-05-03 2017-05-03 Blonanserin tablet pharmaceutical composition and preparation method thereof Active CN107028903B (en)

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CN108392481A (en) * 2018-05-21 2018-08-14 威海贯标信息科技有限公司 A kind of Blonanserin tablet composition
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CN115364062B (en) * 2022-09-30 2025-07-25 北京新领先医药科技发展有限公司 Blonanserin orally disintegrating tablet composition and preparation method thereof

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