CN115252585A - Brexpiprazole oral solution membrane-coated composition, preparation method and application thereof - Google Patents

Brexpiprazole oral solution membrane-coated composition, preparation method and application thereof Download PDF

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Publication number
CN115252585A
CN115252585A CN202210436803.6A CN202210436803A CN115252585A CN 115252585 A CN115252585 A CN 115252585A CN 202210436803 A CN202210436803 A CN 202210436803A CN 115252585 A CN115252585 A CN 115252585A
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brexpiprazole
oral
cyclodextrin
mass percentage
film composition
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Inventor
郭桢
王璇
王婷婷
应述欢
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Bozhiyan New Taizhou Pharmaceutical Technology Co ltd
Shanghai Yunshengyan Neoplasm Technology Co ltd
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Shanghai Bocimed Pharmaceutical Co Ltd
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A—HUMAN NECESSITIES
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    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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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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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The invention providesA brexpiprazole oral soluble membrane composition, a preparation method and application thereof. The invention discloses a brexpiprazole oral soluble film composition, which comprises one or more of an active medicament, a film forming material, a plasticizer, a sweetening agent and an organic acid, wherein the active medicament is 7- [4- (4-benzo [ B ] B shown as a formula I]Thien-4-yl-1-piperazine) butoxy]-2 (1H) -quinolinone and/or a pharmaceutically acceptable salt thereof, said brexpiprazole orosol composition having a pH of 2.5-4.5. The brexpiprazole oral membrane composition obtained by the invention has good dissolution rate, does not have gritty feeling after being dissolved in the oral cavity, has uniform appearance and good flexibility, does not generate sedimentation in the membrane liquid preparation process, and meets the requirement on content uniformity.

Description

Brexpiprazole oral solution membrane-coated composition, preparation method and application thereof
The application claims priority of the invention patent application with application number CN202110395944.3 entitled "a brexpiprazole oral soluble film composition, its preparation method and application" filed to Chinese intellectual property office in 2021, 4, 13. The entire disclosure of this application is incorporated herein by this reference.
Technical Field
The invention relates to a brexpiprazole oral soluble film composition, a preparation method and application thereof.
Background
Brexpiprazole tablets were co-developed by tsukamur pharmaceutical co-company of japan and north pharmaceutical limited of denmark, and were approved by the FDA for marketing in 2015 at 7 months, and were in the dosage forms of 0.25mg, 0.5mg, 1mg, 2mg, 3mg, and 4mg.
The brexpiprazole tablet is used as a 5-HT1A receptor and dopamine D2 receptor agonist and a 5-HT2A receptor antagonist and is clinically used for treating major depressive disorder and schizophrenia. When the composition is used for treating major depression, the initial dose is 0.5 mg/day or 1 mg/day, then the initial dose is increased to the target dose of 2mg once a day, and the maximum recommended dose is 3 mg/day; for schizophrenia treatment, the initial dose is 1 mg/day, the recommended target dose is 2mg to 4mg once daily, and the maximum recommended dose is 4 mg/day. The brexpiprazole has wide activity in a plurality of monoamine systems, reduces the activity of partial agonist of dopamine D2 receptor, improves the affinity of specific 5-HT receptors (such as 5-HT1A, 5-HT2A and 5-HT 7), has better curative effect and tolerance, and can reduce adverse reactions of patients such as incapability of sitting still, uneasiness or insomnia and the like.
Brexpiprazole is white or off-white crystalline powder, is almost insoluble in water, has a bitter and tingling stimulus sensation, and can cause a remarkable stimulus sensation on the oral mucosa.
The common brexpiprazole tablet is required to be disintegrated in the stomach at present to start releasing the medicine, and the effect is slow, so that the bioavailability is limited. The medicine is inconvenient to take, is poor in the aspect of matching treatment as a treatment medicine for mental diseases, and is easy to cause the situations of refusal of treatment, tibetan medicine, vomiting medicine and the like.
Patent CN105078910A discloses a preparation method of brexpiprazole orally disintegrating tablets, which is to prepare the brexpiprazole-containing freeze-dried orally disintegrating tablets by adopting a freeze-drying technology, so that the disintegration speed is accelerated, and the dissolution is improved. However, the technology is relatively complicated, special equipment is needed for production, the manufacturing cost of the product is high, the prepared preparation is easy to crack and is not suitable for transportation, and the packaging and transportation difficulty is increased. And the medicine can not be stained with water when being taken, thereby improving the requirements of patients and being not beneficial to the compliance of patients with schizophrenia.
Patent CN105395528A discloses a brexpiprazole oral instant membrane, but since brexpiprazole is almost insoluble in water and is difficult to disperse in hydrophilic glue solution, in the knife coating and drying process, the drug is easy to agglomerate, thereby affecting the content uniformity of the main drug. Meanwhile, the patient also has uncomfortable taste after taking the medicine, which affects the compliance.
Therefore, the development of a preparation form of brexpiprazole which is convenient to take, good in patient compliance, high in bioavailability and suitable for industrial production is urgently needed.
Disclosure of Invention
The invention aims to solve the technical problem that the brexpiprazole oral soluble film composition can be used for overcoming the defects that the common brexpiprazole tablets in the prior art can start to release medicines only by being disintegrated in the stomach at present, the effect is slow, the bioavailability is limited, the taking is inconvenient, the compliance of patients is poor and the like, and provides a brexpiprazole oral soluble film composition, a preparation method and application thereof.
The invention provides a brexpiprazole oral soluble film composition which is characterized by comprising the following components: one or more of an active drug clathrate compound, a film forming material, a filling agent, a plasticizer and a sweetening agent, wherein the active drug is 7- [4- (4-benzo [ B ] thiophene-4-yl-1-piperazine) butoxy ] -2 (1H) -quinolinone shown in a formula I and/or pharmaceutically acceptable salt thereof; the active drug inclusion compound is formed by inclusion of active drugs and cyclodextrin;
Figure BDA0003595100050000031
in the invention, the molar ratio of the active drug to the cyclodextrin is preferably 2:1-1:4.
In the invention, the cyclodextrin is preferably alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin or sulfobutyl-beta-cyclodextrin.
In the present invention, the active drug is preferably 1% to 30%, for example, 3.4% by mass, and the mass percentage refers to the mass percentage of the active drug in the total mass of the brexpiprazole oral soluble film composition.
In the invention, the film-forming material is one or more of a carrier of a medicament selected from gelatin, shellac, acacia, starch, dextrin, agar, sodium alginate, zein, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, polyoxyethylene, an acrylic acid copolymer, povidone, polylactic acid and silicone rubber.
In the present invention, the mass percentage of the film-forming material is preferably 30% to 70%, for example 51.6%, and the mass percentage refers to the mass percentage of the film-forming material in the total mass of the brexpiprazole oral solution film-forming composition.
In the present invention, the plasticizer is one or more selected from the group consisting of polyethylene glycol, glycerin, propylene glycol, silicone oil, dimethicone, polypropylene glycol and hexylene glycol for lowering the glass transition temperature of the film, increasing the plasticity, toughness and increasing the elongation.
In the present invention, the mass percentage of the plasticizer is preferably 5% to 30%, for example, 8.6%, 8.8% or 17.4%, and the mass percentage refers to the mass percentage of the plasticizer in the total mass of the brexpiprazole oral solution film-forming composition.
In the invention, the sweetening agent is a substance which plays a role in flavoring in the film agent and is selected from one or more of aspartame, sucralose, fructose, sucrose, stevioside, glycyrrhizin, essence, spice, saccharin and saccharin sodium.
In the invention, the mass percentage of the sweetener is preferably 0.05-0.5%, for example 0.2%, and the mass percentage refers to the mass percentage of the sweetener to the total mass of the brexpiprazole oral solution film-coating composition.
In the invention, the filler is a solid substance which is added into the material and can improve the material performance, or can increase the volume, increase the weight and reduce the cost of the material. Is selected from one or more of mannitol, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin and trehalose.
In the present invention, the mass percentage of the filler is preferably 5% to 30%, for example, 25.8%, and the mass percentage refers to the mass percentage of the filler to the total mass of the brexpiprazole orally-dissolving film-coating composition.
The brexpiprazole oral film composition of the present invention preferably further comprises a disintegrant, or a combination of a disintegrant with one or more of a saliva stimulating agent and a coloring agent.
In the invention, the disintegrant is an auxiliary material for promoting the rapid disintegration of the drug in the gastrointestinal tract into small particles, and is selected from one or more of low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, starch, microcrystalline cellulose and pregelatinized starch.
In the present invention, the saliva stimulating agent is a substance for stimulating saliva production, and is selected from one or more of citric acid, tartaric acid, malic acid and mannitol.
In the present invention, the coloring agent is a substance capable of improving the appearance color of the preparation, and can be used for identifying the concentration of the preparation, distinguishing the application method and reducing the patient's aversion to taking medicine, and is selected from one or more of titanium dioxide, pigment and lake.
The brexpiprazole oral soluble film composition can be any one of the following formulas:
the formula I is as follows: 3.4% of brexpiprazole, 10.3% of beta-cyclodextrin, 34.4% of hydroxypropyl methylcellulose, 17.2% of polyvinyl alcohol, 25.8% of mannitol, 8.6% of glycerol and 0.2% of sucralose;
and a second formula: 3.4% brexpiprazole, 10.3% alpha-cyclodextrin, 34.4% polyvinyl alcohol, 17.2% gelatin, 25.8% mannitol, 8.6% glycerol, 0.2% dimethicone, 0.2% sucralose;
and the formula III: 3.4% of brexpiprazole, 10.3% of hydroxypropyl-beta-cyclodextrin, 8.6% of hydroxypropyl methylcellulose, 42.9% of gelatin, 17.2% of mannitol, 17.2% of glycerol, 0.2% of simethicone and 0.2% of sucralose;
the formula four: 3.4 percent of brexpiprazole, 10.3 percent of sulfobutyl-beta-cyclodextrin, 51.5 percent of polyvinyl alcohol, 17.2 percent of mannitol, 17.2 percent of glycerin, 0.2 percent of simethicone and 0.2 percent of sucralose.
The invention also provides a preparation method of the brexpiprazole oral solution film composition, which comprises the following steps:
1) Preparing the active drug and cyclodextrin into an active drug cyclodextrin inclusion compound;
2) Mixing filler, plasticizer and sweetener with purified water, stirring, adding the cyclodextrin inclusion compound of the active drug obtained in the step 1) after the mixture is completely dissolved, and uniformly stirring to obtain a solution A;
3) Uniformly stirring the film forming agent and distilled water, and cooling to be completely dissolved to obtain a glue solution B;
4) Adding the glue solution B obtained in the glue solution step 3) into the solution A obtained in the step 2), and stirring and defoaming under a vacuum condition to obtain a medicine-containing glue solution;
5) Defoaming the medicine-containing glue solution obtained in the step 4), uniformly coating the medicine-containing glue solution on a polyester belt by using a scraper, heating and drying the polyester belt, and cutting the polyester belt into a certain size to obtain the risperidone oral soluble film composition.
The invention also provides a brexpiprazole oral film agent which comprises the brexpiprazole oral film-dissolving composition.
The invention also provides application of the brexpiprazole oral soluble film composition in preparation of a medicament for treating central nervous system diseases. The central nervous system disease can be major depressive disorder or schizophrenia.
The present invention also provides a method for treating central nervous system diseases, which comprises administering a therapeutically effective amount of the briprazole oral film agent to a patient in need thereof.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The invention has the beneficial effects that: the brexpiprazole oral soluble film composition prepared by the invention has good dissolution rate, does not have gritty feeling after being dissolved in the oral cavity, has uniform appearance and good flexibility, does not generate sedimentation in the film liquid preparation process, and meets the requirement on content uniformity.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Examples 1 to 5:
Figure BDA0003595100050000061
* Removed during the draw down drying.
The preparation process comprises the following steps:
1) Carrying out pretreatment on brexpiprazole and cyclodextrin to obtain an active drug cyclodextrin inclusion compound;
2) Weighing a filling agent, a plasticizer and a sweetening agent, mixing with purified water, stirring, adding the cyclodextrin inclusion compound of the active drug obtained in the step 1) after the mixture is completely dissolved, and uniformly stirring to obtain a solution A;
3) Uniformly stirring the film forming agent and distilled water, and cooling to be completely dissolved to obtain a glue solution B;
4) Adding the glue solution B obtained in the glue solution step 3) into the solution A obtained in the step 2), and stirring and defoaming under a vacuum condition to obtain a medicine-containing glue solution;
5) Defoaming the medicine-containing glue solution obtained in the step 4), uniformly coating the medicine-containing glue solution on a polyester belt by using a scraper, heating and drying the polyester belt, and cutting the polyester belt into a certain size to obtain the risperidone oral soluble film composition.
The result of the detection
Figure BDA0003595100050000071
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made without departing from the spirit and principle of the present invention shall fall within the protection scope of the present invention.

Claims (10)

1. A brexpiprazole oral soluble film composition is characterized by comprising the following components: one or more of an active drug clathrate compound, a film forming material, a filling agent, a plasticizer and a sweetening agent, wherein the active drug is 7- [4- (4-benzo [ B ] thiophene-4-yl-1-piperazine) butoxy ] -2 (1H) -quinolinone shown in a formula I and/or pharmaceutically acceptable salt thereof; the active drug inclusion compound is formed by inclusion of active drugs and cyclodextrin;
Figure FDA0003595100040000011
2. the brexpiprazole oral film composition of claim 1, wherein: the molar ratio of the active drug to the cyclodextrin is 2:1-1:4.
3. The brexpiprazole oral film composition according to claim 1 or 2, wherein: the cyclodextrin is alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin or sulfobutyl-beta-cyclodextrin.
4. The brexpiprazole oral film composition according to any one of claims 1 to 3, wherein: the mass percentage of the active drug is 1-30%, and the mass percentage refers to the mass percentage of the active drug in the total mass of the brexpiprazole oral soluble film composition.
Preferably, the film-forming material is selected from one or more of gelatin, shellac, gum arabic, starch, dextrin, agar, sodium alginate, zein, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, polyoxyethylene, acrylic acid copolymer, povidone, polylactic acid and silicone rubber;
and/or the presence of a gas in the gas,
the mass percentage of the film forming material is 30-70%, and the mass percentage refers to the mass percentage of the film forming material in the total mass of the brexpiprazole oral soluble film composition.
Preferably, the plasticizer is selected from one or more of polyethylene glycol, glycerol, propylene glycol, silicone oil, dimeticone, polypropylene glycol and hexylene glycol;
and/or the presence of a gas in the gas,
the mass percentage of the plasticizer is 5-30%, and the mass percentage refers to the mass percentage of the film forming material in the total mass of the brexpiprazole oral soluble film composition.
Preferably, the sweetener is selected from one or more of aspartame, sucralose, fructose, sucrose, stevioside, glycyrrhizin, essence, spice, saccharin and saccharin sodium;
and/or the presence of a gas in the gas,
the mass percentage of the sweetener is 0.05-0.5%, and the mass percentage refers to the mass percentage of the sweetener to the total mass of the brexpiprazole oral soluble film composition.
Preferably, the bulking agent is selected from one or more of mannitol, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin and trehalose;
and/or the presence of a gas in the atmosphere,
the mass percentage of the filler is 5-30%, and the mass percentage refers to the mass percentage of the filler in the total mass of the brexpiprazole oral soluble film composition.
Preferably, the brexpiprazole oral film composition further comprises a disintegrant, or a combination of a disintegrant with one or more of a saliva stimulating agent and a colorant.
5. The brexpiprazole orally disintegrating film composition of claim 4, wherein:
the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, starch, microcrystalline cellulose and pregelatinized starch;
and/or the presence of a gas in the gas,
the saliva stimulating agent is one or more selected from citric acid, tartaric acid, malic acid and mannitol;
and/or the presence of a gas in the gas,
the colorant is selected from one or more of titanium dioxide, pigment and lake.
6. The brexpiprazole oral film composition according to any one of claims 1 to 5, wherein:
the brexpiprazole oral soluble film composition is any one of the following formulas:
the formula I is as follows: 3.4% of brexpiprazole, 10.3% of beta-cyclodextrin, 34.4% of hydroxypropyl methylcellulose, 17.2% of polyvinyl alcohol, 25.8% of mannitol, 8.6% of glycerol and 0.2% of sucralose;
and a second formula: 3.4% brexpiprazole, 10.3% alpha-cyclodextrin, 34.4% polyvinyl alcohol, 17.2% gelatin, 25.8% mannitol, 8.6% glycerol, 0.2% dimethicone, 0.2% sucralose;
and the formula III: 3.4% brexpiprazole, 10.3% hydroxypropyl-beta-cyclodextrin, 8.6% hypromellose, 42.9% gelatin, 17.2% mannitol, 17.2% glycerol, 0.2% simethicone, 0.2% sucralose;
the formula four: 3.4 percent of brexpiprazole, 10.3 percent of sulfobutyl-beta-cyclodextrin, 51.5 percent of polyvinyl alcohol, 17.2 percent of mannitol, 17.2 percent of glycerin, 0.2 percent of simethicone and 0.2 percent of sucralose.
7. The process for preparing a brexpiprazole oral film-coating composition according to any one of claims 1 to 6, characterized by comprising the steps of:
1) Preparing the active drug and cyclodextrin into an active drug cyclodextrin inclusion compound;
2) Mixing filler, plasticizer and sweetener with purified water, stirring, adding the cyclodextrin inclusion compound of the active drug obtained in the step 1) after the mixture is completely dissolved, and uniformly stirring to obtain a solution A;
3) Uniformly stirring the film forming agent and distilled water, and cooling to be completely dissolved to obtain a glue solution B;
4) Adding the glue solution B obtained in the glue solution step 3) into the solution A obtained in the step 2), and stirring and defoaming under a vacuum condition to obtain a medicine-containing glue solution;
5) Defoaming the medicine-containing glue solution obtained in the step 4), uniformly coating the medicine-containing glue solution on a polyester belt by using a scraper, heating and drying the polyester belt, and cutting the polyester belt into a certain size to obtain the risperidone oral soluble film composition.
8. The briprazole oral film agent is characterized in that: comprising the brexpiprazole oro-film composition as defined in any one of claims 1 to 7.
9. Use of the brexpiprazole oral membrane-dissolving composition as defined in any one of claims 1 to 7 for the preparation of a medicament for the treatment of central nervous system diseases.
10. The use of claim 9, wherein: the central nervous system disease is major depression or schizophrenia.
CN202210436803.6A 2021-04-13 2022-04-13 Brexpiprazole oral solution membrane-coated composition, preparation method and application thereof Pending CN115252585A (en)

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JPH10194996A (en) * 1996-12-25 1998-07-28 Janssen Pharmaceut Nv Acylated cyclodextrin-containing pharmaceutical composition
TW201332572A (en) * 2011-12-28 2013-08-16 Otsuka Pharma Co Ltd Pharmaceutical preparation comprising substituted β -cyclodextrin
CN103784426B (en) * 2014-02-19 2015-11-18 上海现代药物制剂工程研究中心有限公司 Molten membrane of Aripiprazole mouth and preparation method thereof
CN105395528A (en) * 2015-12-25 2016-03-16 北京康立生医药技术开发有限公司 Brexpiprazole oral fast dissolving film
CN106580902A (en) * 2017-02-24 2017-04-26 佛山市弘泰药物研发有限公司 Brexpiprazole oral disintegrating tablet and preparation method thereof
CN107375945B (en) * 2017-08-29 2020-10-13 沈阳药科大学 Donepezil cyclodextrin inclusion compound and oral instant film agent containing same
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