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CN118948808A - A kind of milobarlin besylate orodispersible film preparation and preparation method thereof - Google Patents

A kind of milobarlin besylate orodispersible film preparation and preparation method thereof Download PDF

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Publication number
CN118948808A
CN118948808A CN202411079481.XA CN202411079481A CN118948808A CN 118948808 A CN118948808 A CN 118948808A CN 202411079481 A CN202411079481 A CN 202411079481A CN 118948808 A CN118948808 A CN 118948808A
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besylate
film
solution
agent
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翟光喜
卢慧嫒
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Shandong University
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Shandong University
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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Abstract

本发明公开了一种苯磺酸米洛巴林口溶膜剂及其制备方法，属于药物制剂技术领域。按质量份数计，其包括：乙醇水溶液80～105份，苯磺酸米洛巴林0.1～0.75份，羟丙甲纤维素5～12份，表面活性剂0.1～5份，增塑剂3～10份，崩解剂0或0.1～2份。相对于片剂不易吞咽、口崩片口感差，易吐出等现有剂型的缺点，本发明制备的口溶膜剂药物在口腔中接触少量唾液即可迅速粘附于口腔粘膜上不易吐出，快速崩解，易于吞咽，且无需咀嚼和水送服，无砂砾感。The invention discloses an orodispersible film preparation of milobarline besylate and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. According to the mass fraction, it comprises: 80 to 105 parts of ethanol aqueous solution, 0.1 to 0.75 parts of milobarline besylate, 5 to 12 parts of hydroxypropyl methylcellulose, 0.1 to 5 parts of surfactant, 3 to 10 parts of plasticizer, and 0 or 0.1 to 2 parts of disintegrant. Compared with the shortcomings of the existing dosage forms such as tablets being difficult to swallow, orodispersible tablets having a poor taste, and being easy to spit out, the orodispersible film preparation drug prepared by the invention can quickly adhere to the oral mucosa when in contact with a small amount of saliva in the oral cavity, is not easy to spit out, disintegrates quickly, is easy to swallow, and does not require chewing and water delivery, and has no sense of gravel.

Description

Melobalin besylate oral film agent and preparation method thereof
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a milabalin besylate oral film agent and a preparation method thereof.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Milobulin besylate (Mirogabalin) is a novel selective calcium channel alpha 2 delta ligand, can be preferentially and selectively combined with the alpha 2 delta-1 subunit of the voltage-dependent calcium channels (1 and 2) to play a role in easing pain, and is mainly used for treating diabetic peripheral neuralgia, postherpetic neuralgia and fibromyalgia. At present, the research on the formulation of the milbelin benzenesulfonate mainly focuses on oral preparations such as sustained release tablets and orally disintegrating tablets. Oral formulations have limitations and are difficult to take by elderly persons, children and dysphagia patients, and there is a need to develop an oral film which rapidly disintegrates in the mouth or in water.
Patent CN 110917164A discloses a amisulprin besylate sustained-release tablet and a preparation method thereof. However, the patent does not describe an orosol film formulation containing milbelin benzenesulfonate.
Patent CN 116509811A discloses a sulbactam besylate slow-release tablet and a preparation method thereof, the preparation process is simple, and the obtained sulbactam besylate slow-release tablet has good stability. However, the patent does not describe an orosol film formulation containing milbelin benzenesulfonate.
Patent CN 115803020A discloses an orally disintegrating tablet containing milabalin benzenesulfonate, which rapidly disintegrates when contained in the mouth or placed in water, showing excellent solubility. However, the patent does not describe an orosol film formulation containing milbelin benzenesulfonate.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide the amisulpride besylate oral film agent and the preparation method thereof, the preparation method provided by the invention is simple and efficient, the obtained sulbactam oral film agent is quickly adhered to the oral mucosa in the oral cavity, is not easy to spit out, is not easy to break, is quickly dissolved and is easy to swallow.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
the invention provides a milabalin besylate oral film agent, which comprises the following components in parts by mass:
80 to 105 parts of ethanol aqueous solution, 0.1 to 0.75 part of milbelin benzenesulfonate, 5 to 12 parts of hypromellose, 0.1 to 5 parts of surfactant, 3 to 10 parts of plasticizer and 0 to 2 parts of disintegrating agent.
In some embodiments of the invention, the hypromellose is a film forming material.
In some embodiments of the present invention, the milbelin besylate oral film uses an ethanol aqueous solution as a solvent, and each 100mL of solvent (ethanol aqueous solution) contains: 0.1 to 0.75g of milbelin benzenesulfonate, 5 to 12g of hypromellose, 0.1 to 5g of surfactant, 3 to 10g of plasticizer and 0 to 2g of disintegrating agent.
In some embodiments of the invention, the surfactant is selected from at least one of poloxamer, polysorbate, polyoxyethylene sorbitan monooleate, sodium dodecyl sulfate, polyethylene glycol-15 hydroxystearate, polyethylene glycol, vitamin E, and polyethylene glycol succinate, preferably poloxamer and polysorbate, further preferably poloxamer 188 and polysorbate 80 (i.e., tween 80). Wherein, poloxamer 188 can be used as a solid dispersion carrier besides being used as a surfactant for improving the dissolution rate of medicine (milbelin benzenesulfonate).
In some embodiments of the invention, the plasticizer is selected from at least one of glycerol, propylene glycol, polyethylene glycol 400, glycerol monooleate and glycerol citrate, preferably glycerol, propylene glycol or polyethylene glycol 400, further preferably glycerol.
In some embodiments of the present invention, the disintegrant is at least one selected from lactose, soluble starch, maltodextrin, mannitol, low substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and sodium alginate, preferably lactose.
In some embodiments of the present invention, the millbalin besylate oral film further comprises a flavoring agent selected from at least one of sucralose, citric acid hydrate, sucrose, mannitol, maltitol, stevioside, aspartame, acesulfame k and cyclamate, preferably a combination of sucralose and citric acid hydrate, further preferably sucralose.
In some embodiments of the present invention, the milabalin besylate oral film comprises the following components in parts by weight:
80 to 105 parts of ethanol aqueous solution, 0.1 to 0.75 part of milbelin benzenesulfonate, 5 to 12 parts of hypromellose, 0.1 to 5 parts of surfactant, 3 to 10 parts of plasticizer, 0 to 2 parts of disintegrant and 0.1 to 1.2 parts of flavoring agent.
Preferably, the disintegrant is 0 or 0.1 to 2 parts.
In some embodiments of the present invention, the milabalin besylate oral film uses ethanol water solution as a solvent, and each 100mL of solvent contains: 0.1 to 0.75g of milbelin benzenesulfonate, 5 to 12g of hypromellose, 0.1 to 5g of surfactant, 3 to 10g of plasticizer, 0 or 0.1 to 2g of disintegrating agent and 0.1 to 1.2g of flavoring agent.
In some embodiments of the invention, the volume ratio of water to ethanol in the aqueous ethanol solution is 4:1 to 1:4, preferably 1:1;
the amisulprine besylate oral film comprises the following components in parts by mass:
85-90 parts of 50% ethanol water solution, 0.1-0.75 part of milbelin benzenesulfonate, 5-12 parts of hypromellose, 0.5-2.5 parts of poloxamer 188, 0.1-0.3 part of polysorbate, 3-9 parts of glycerin, propylene glycol or polyethylene glycol 400, 0-2 parts of lactose and 0.1-1.2 parts of sucralose.
Preferably, lactose is 0 or 0.1-2 parts.
In some embodiments of the present invention, the milabalin besylate oral film comprises the following components in parts by weight:
85-90 parts of 50% ethanol water solution, 0.1-0.75 part of milbelin benzenesulfonate, 9-11 parts of hypromellose, 0.5-2.5 parts of poloxamer 188, 0.1-0.3 part of polysorbate, 5-9 parts of glycerin, propylene glycol or polyethylene glycol 400, 0-0.6 part of lactose and 0.2-0.6 part of sucralose.
Preferably, lactose is 0 or 0.1 to 0.6 parts.
In some embodiments of the present invention, the milabalin besylate oral film comprises the following components in parts by weight:
85-90 parts of 50% ethanol water solution, 0.1-0.75 part of milbelin benzenesulfonate, 9-11 parts of hypromellose, 0.5-2.5 parts of poloxamer 188, 0.1-0.3 part of polysorbate, 5-9 parts of glycerin, 0 or 0.1-0.6 part of lactose and 0.2-0.6 part of sucralose.
In some embodiments of the invention, the sulbactam besylate oral film is a film-like preparation, and the content of the drug active ingredient in each film is 2.5 mg-15 mg calculated by the sulbactam besylate.
In a second aspect of the invention, a preparation method of the amisulpride besylate oral film agent is provided, which comprises the following steps:
adding hydroxypropyl methylcellulose into a part of ethanol water solution, and stirring until the hydroxypropyl methylcellulose is completely swelled;
Adding a surfactant, the sulbactam besylate, a plasticizer, a disintegrating agent and a flavoring agent into the residual ethanol water solution, and dissolving to obtain a medicine-containing solution;
adding the medicine-containing solution into the completely swelled hypromellose, homogenizing, and removing bubbles to obtain medicine-containing slurry;
and (3) coating the medicine-containing slurry on the surface of a mold, drying, demolding and cutting to obtain the medicine-containing slurry.
In some embodiments of the present invention, the surfactant, the milbelin besylate, the plasticizer, the disintegrant and the flavoring agent are added to the remaining aqueous ethanol solution to be completely dissolved and dispersed for 0.5 to 2 hours.
In some embodiments of the invention, the drug-containing solution is added to the fully swollen hypromellose, stirred and homogenized, and left to stand for foam removal; the stirring time is 0.5-2 h, and the standing time is 0.1-2 h.
Amino and carboxyl exist in the molecule of the milbelin benzenesulfonate at the same time, impurities can be generated by dehydration when the temperature is too high, and the drying temperature is not too high. In some embodiments of the invention, the drying is at a temperature of 40-60 ℃ for a drying time of 0.5-4 hours;
except for the drying step, other preparation steps of the amisulprin besylate oral film agent are all carried out at room temperature or 30 ℃.
The beneficial effects of the invention are as follows:
In view of the fact that the existing sulbactam preparation does not relate to an oral film agent, the invention provides the sulbactam oral film agent and a preparation method thereof. The invention adopts hydroxypropyl methylcellulose as a film forming material; the ethanol water solution is used as a solvent, so that the medicine can be fully dissolved, the film-forming material can be fully swelled and dispersed, excessive bubbles generated by medicine-containing slurry can be avoided, the production efficiency can be improved, and the appearance of the film agent is smoother and smoother; poloxamer 188 is used as a dispersion carrier, and is prepared into a solid dispersion with the milbelin benzenesulfonate, so that the granular medicine can be prevented from being separated out from the surface of the film agent after the solvent is volatilized, and the disintegration behavior of the medicine can be improved. Compared with the defects of the existing dosage forms such as difficult swallowing, poor taste of orally disintegrating tablets, easy spitting and the like, the orally dissolving film medicament prepared by the invention can be quickly adhered to the oral mucosa in the oral cavity by contacting a small amount of saliva, is difficult to spit, is quickly disintegrated, is easy to swallow, does not need chewing and water for taking, and has no gritty feel.
The preparation process of the sulbactam besylate oral film provided by the invention is simple and efficient, the sulbactam besylate oral film has flexible dosage, and the sulbactam besylate oral film can be prepared into different sizes and dosages.
Detailed Description
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail with reference to specific embodiments.
The reagents, methods and apparatus used in the examples which follow are conventional in the art unless otherwise indicated.
Examples
The preparation method of the milbelin besylate oral film comprises the following steps:
(1) The prescribed amount of hydroxypropyl methylcellulose was dissolved in 50ml of 50% ethanol aqueous solution at room temperature, and stirred for 30min until it was completely swollen.
(2) The preparation method comprises the steps of adding poloxamer 188, tween 80, milbelin besylate, glycerol, lactose and sucralose into 50mL of 50% ethanol water solution at room temperature, and stirring for 40min to fully dissolve and disperse to obtain a medicine-containing solution.
(3) And (3) adding the drug-containing solution obtained in the step (2) into the swelled film-forming material at room temperature, stirring for 30min, dispersing uniformly, standing for 30min, and removing bubbles to obtain drug-containing slurry.
(4) And uniformly coating the medicine-containing slurry on a surface dish at room temperature, drying at 60 ℃ for 45min, demolding, and cutting into the size of 2.0cm multiplied by 3.0cm to obtain the medicine-containing slurry.
Specific prescriptions are given in examples 1 to 24.
Examples 1 to 3
The preparation method comprises the steps of taking hypromellose as a film forming material, taking glycerol as a plasticizer, taking poloxamer 188 as a solid dispersion carrier, taking tween 80 as a surfactant, taking lactose as a disintegrating agent, taking sucralose as a flavoring agent, taking ethanol water solution with concentration of 20%, 50% and 80% as a solvent, and using 100mL to screen the solvent. The prescription is shown in table 1.
Table 1 examples 1 to 3 preparation of Melobalin besylate oral film
Examples 4 to 6
Hydroxypropyl methylcellulose is used as a film forming material, glycerol is used as a plasticizer, poloxamer 188 is used as a solid dispersion carrier, tween 80 is used as a surfactant, lactose is used as a disintegrating agent, sucralose is used as a flavoring agent, and 50% ethanol is used as a solvent; the types of hydroxypropyl methylcellulose are HPMC E3, HPMC E5 and HPMC E15 respectively, the dosage is 5.0g, and the type of hydroxypropyl methylcellulose is screened, and the prescription is shown in Table 2.
Table 2 examples 4 to 6 Milobulin besylate oral film formulations
Composition of the components Example 4 Example 5 Example 6
Milobulin benzenesulfonate 0.25g 0.25g 0.25g
HPMC E3 5.0g - -
HPMC E5 - 5.0g -
HPMC E15 - - 5.0g
Glycerol 8.0g 8.0g 8.0g
Poloxamer 188 2.0g 2.0g 2.0g
Tween 80 0.2g 0.2g 0.2g
Lactose and lactose 0.5g 0.5g 0.5g
Sucralose 0.5g 0.5g 0.5g
50% Ethanol 100mL 100mL 100mL
Examples 7 to 9
Hydroxypropyl methylcellulose is used as a film forming material, glycerol is used as a plasticizer, poloxamer 188 is used as a solid dispersion carrier, tween 80 is used as a surfactant, lactose is used as a disintegrating agent, sucralose is used as a flavoring agent, and 50% ethanol is used as a solvent; the dosage of HPMC E5 is 6.0-12.0 g, and the dosage of hypromellose is screened. The prescription is shown in table 3.
Table 3 examples 7 to 9 Milobulin besylate oral film formulations
Composition of the components Example 7 Example 8 Example 9
Milobulin benzenesulfonate 0.25g 0.25g 0.25g
HPMC E5 6.0g 8.0g 12.0g
Glycerol 8.0g 8.0g 8.0g
Poloxamer 188 2.0g 2.0g 2.0g
Tween 80 0.2g 0.2g 0.2g
Lactose and lactose 0.5g 0.5g 0.5g
Sucralose 0.5g 0.5g 0.5g
50% Ethanol 100mL 100mL 100mL
Examples 10 to 12
Hydroxypropyl methylcellulose is used as a film forming material, poloxamer 188 is used as a solid dispersion carrier, tween 80 is used as a surfactant, lactose is used as a disintegrating agent, sucralose is used as a flavoring agent, and 50% ethanol is used as a solvent; the types of the plasticizers were selected by using 5.0g of glycerin, propylene glycol and polyethylene glycol 400 as plasticizers. The recipe is shown in Table 4.
Table 4 examples 10 to 12 preparation of Melobalin besylate oral film
Examples 13 to 15
Hydroxypropyl methylcellulose is used as a film forming material, poloxamer 188 is used as a solid dispersion carrier, tween80 is used as a surfactant, lactose is used as a disintegrating agent, sucralose is used as a flavoring agent, and 50% ethanol is used as a solvent; the glycerol is taken as a plasticizer, the dosage is 3.0-9.0 g, and the dosage of the glycerol is screened. The prescription is shown in table 5.
Table 5 examples 13 to 15 preparation of Melobalin besylate oral film
Composition of the components Example 13 Example 14 Example 15
Milobulin benzenesulfonate 0.25g 0.25g 0.25g
HPMC E5 10.0g 10.0g 10.0g
Glycerol 3.0g 6.0g 9.0g
Poloxamer 188 2.0g 2.0g 2.0g
Tween 80 0.2g 0.2g 0.2g
Lactose and lactose 0.5g 0.5g 0.5g
Sucralose 0.5g 0.5g 0.5g
50% Ethanol 100mL 100mL 100mL
Examples 16 to 18
Hydroxypropyl methylcellulose is used as a film forming material, glycerol is used as a plasticizer, tween 80 is used as a surfactant, lactose is used as a disintegrating agent, sucralose is used as a flavoring agent, and 50% ethanol is used as a solvent; poloxamer 188 is taken as a solid dispersion carrier, the dosage is 1.0-3.0 g, and the dosage is screened. The prescription is shown in table 6.
Table 6 examples 16 to 18 preparation of Melobalin besylate oral film
Composition of the components Example 16 Example 17 Example 18
Milobulin benzenesulfonate 0.25g 0.25g 0.25g
HPMC E5 10.0g 10.0g 10.0g
Glycerol 8.0g 8.0g 8.0g
Poloxamer 188 0g 1.0g 3.0g
Tween 80 0.2g 0.2g 0.2g
Lactose and lactose 0g 1.0g 2.0g
Sucralose 0.5g 0.5g 0.5g
50% Ethanol 100mL 100mL 100mL
Examples 19 to 21
Hydroxypropyl methylcellulose is used as a film forming material, glycerol is used as a plasticizer, poloxamer 188 is used as a solid dispersion carrier, tween 80 is used as a surfactant, sucralose is used as a flavoring agent, and 50% ethanol is used as a solvent; lactose is used as disintegrating agent, the dosage of the disintegrating agent is 0-2.0 g, and the disintegrating agent dosage is screened. The recipe is shown in Table 7.
Table 7 examples 19 to 21 preparation of Melobalin besylate oral film
Examples 22 to 24
Hydroxypropyl methylcellulose is used as a film forming material, glycerol is used as a plasticizer, poloxamer 188 is used as a solid dispersion carrier, tween80 is used as a surfactant, lactose is used as a disintegrating agent, and 50% ethanol is used as a solvent; the sucralose is used as the flavoring agent, the dosage is 0.2-1.0 g, and the flavoring agent dosage is screened. The prescription is shown in table 8.
Table 8 examples 19 to 21 preparation of Milobulin Benzenesulfonate oral film preparation
The appearance, peeling property, folding endurance and disintegration time of the milabalin besylate orosol films prepared in examples 1 to 24 were examined. The appearance evaluation criteria are shown in table 9.
TABLE 9 appearance evaluation criteria
The peeling property evaluation criteria are shown in table 10.
Table 10 evaluation criteria for exfoliation
Folding endurance: taking self-made sulbactam sodium mouth-dissolving film agent, repeatedly folding the film agent to the same side at an angle of 180 degrees until the film agent breaks, and recording the folding times during breaking, namely the folding resistance.
Disintegration time limit: the self-made sulbactam sodium sulfonate oral film is fixed on paper clips and put into 30mL distilled water at 37 ℃ to gently oscillate, and the time of complete disintegration of the film at the temperature is recorded as the disintegration time limit.
The appearance, folding endurance, peeling property and disintegration time of examples 1 to 24 are shown in table 11.
Table 11 results of the tests of examples 1 to 24
The detection results of examples 1-3 show that the concentration of the solvent influences the appearance, the peeling property and the disintegration time limit of the film agent, when the ethanol water solution with proper concentration is used as the solvent, the medicine can be fully dissolved, and excessive bubbles generated after the polymer material is swelled can be prevented, so that the film agent has good appearance and proper folding resistance and disintegration time limit; the detection results of examples 4-9 show that the model and the dosage of the film forming agent influence the folding endurance and the disintegration time limit of the film forming agent, and the selection of the proper film forming agent is an important factor in the preparation process of the oral dissolving film; the detection results of examples 10-12 show that the type of the plasticizer influences the folding endurance of the orosol film, and when glycerol is taken as the plasticizer, the appearance is smooth and flat, no obvious bubbles are generated, and compared with propylene glycol and polyethylene glycol 400, no oily matter oozes out from the surface of the film; the test results of examples 13-15 and example 2 show that the plasticizer can increase the folding endurance of the film agent, but the addition of excessive plasticizer can lead to prolonged disintegration time, so that the dosage should be taken into consideration during use; the test results of examples 16 to 18 and example 2 show that poloxamer 188 affects the appearance and disintegration time of the film agent, and when the amount of the poloxamer 188 is too large, the property of the film agent is affected to deteriorate the film forming property, and a proper amount of poloxamer 188 can prevent the precipitation of drug particles on the surface of the film agent after the volatilization of the solvent, and improve the disintegration time of the film agent, and further improve the dissolution behavior of the drug (herein, "improving the dissolution behavior of the drug" means improving the disintegration behavior of the film agent, which is reflected in that the film agent is better dispersed in water due to the reduction of aggregation of the drug in the form of particles or agglomerates, so that the disintegration time is shortened, and the disintegration time results of examples 16, 17, 2 and 18 are shortened with the increase of the use amount of poloxamer 188); the test results of examples 19 to 21 and example 2 show that the disintegrating agent can shorten the disintegration time limit within a certain range, but when the dosage of the disintegrating agent is too large, the disintegrating agent is not fully compatible with the drug-containing slurry, so that the appearance of the film agent is rough, the disintegration time limit is prolonged, and the dosage should be taken care of when in use; the test results of examples 22 to 24 and example 2 show that the taste of the film agent is improved and the use amount of the taste modifier slightly influences the appearance and other properties of the film.
In summary, the invention relates to a sulbactam besylate oral film and a preparation method thereof, the preparation process of the method is simple and efficient, the sulbactam besylate oral film obtained by the method is rapidly adhered to an oral mucosa in an oral cavity and is not easy to spit out, and the sulbactam besylate oral film has flexible dosage, is not easy to crack, is rapidly and rapidly dispersed, and is easy to swallow.
The preparation of the sulbactam besylate oral film prepared in the example 2 comprises 5 mg/tablet of the sulbactam besylate, wherein examples 25 to 26 are added for the preparation of 10 mg/tablet of the sulbactam besylate oral film.
The recipe for example 25 is the same as that for example 2, except that: the added amount of the milbelin benzenesulfonate is 0.5g.
The recipe for example 26 is the same as that of example 2, except that: the film was cut to a size of 3cm by 4 cm.
The test results are shown in Table 12.
Table 12 results of the tests of example 25 and example 26
Table 12 shows that adjusting the amount of milabalin benzenesulfonate or changing the cut size of the film has negligible effect on the film folding endurance, disintegration time, etc.
The drug loading range of the invention is 2.5-15mg, and the invention can be made into various specifications, thereby adapting to the drug demands of different drug groups.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. The amisulprin besylate oral film is characterized by comprising the following components in parts by mass:
80 to 105 parts of ethanol aqueous solution, 0.1 to 0.75 part of millbalin benzenesulfonate, 5 to 12 parts of hypromellose, 0.1 to 5 parts of surfactant, 3 to 10 parts of plasticizer and 0 to 2 parts of disintegrating agent.
2. The milbelin besylate oral film according to claim 1 wherein the surfactant is selected from at least one of poloxamer, polysorbate, polyoxyethylene sorbitan monooleate, sodium lauryl sulfate, polyethylene glycol-15 hydroxystearate, polyethylene glycol, vitamin E and polyethylene glycol succinate, preferably poloxamer and polysorbate;
Preferably, the plasticizer is at least one selected from glycerol, propylene glycol, polyethylene glycol 400, glycerol monooleate and glycerol citrate, preferably glycerol, propylene glycol or polyethylene glycol 400, and more preferably glycerol;
preferably, the disintegrating agent is at least one selected from lactose, soluble starch, maltodextrin, mannitol, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose and sodium alginate, preferably lactose;
Preferably, the milbelin besylate oral film further comprises a flavoring agent, wherein the flavoring agent is at least one selected from the group consisting of sucralose, citric acid hydrate, sucrose, mannitol, maltitol, steviosin, aspartame, acesulfame potassium and cyclamate, preferably a combination of sucralose and citric acid hydrate, and further preferably sucralose.
3. The milabalin besylate oral solution film according to claim 2, wherein the milabalin besylate oral solution comprises the following components in parts by weight:
80 to 105 parts of ethanol aqueous solution, 0.1 to 0.75 part of milbelin benzenesulfonate, 5 to 12 parts of hypromellose, 0.1 to 5 parts of surfactant, 3 to 10 parts of plasticizer, 0 to 2 parts of disintegrant and 0.1 to 1.2 parts of flavoring agent;
preferably, the disintegrant is 0 or 0.1 to 2 parts.
4. The milabalin of benzenesulfonic acid oral film according to claim 2, characterized in that the volume ratio of water to ethanol in the aqueous ethanol solution is 4:1-1:4, preferably 1:1;
the amisulprine besylate oral film comprises the following components in parts by mass:
85-90 parts of 50% ethanol water solution, 0.1-0.75 part of millbalin benzenesulfonate, 5-12 parts of hypromellose, 0.5-2.5 parts of poloxamer 188, 0.1-0.3 part of polysorbate, 3-9 parts of glycerin, propylene glycol or polyethylene glycol 400, 0-2 parts of lactose and 0.1-1.2 parts of sucralose;
Preferably, lactose is 0 or 0.1-2 parts.
5. The milabalin besylate oral solution film according to claim 2, wherein the milabalin besylate oral solution comprises the following components in parts by weight:
85-90 parts of 50% ethanol water solution, 0.1-0.75 part of millbalin benzenesulfonate, 9-11 parts of hypromellose, 0.5-2.5 parts of poloxamer 188, 0.1-0.3 part of polysorbate, 5-9 parts of glycerin, propylene glycol or polyethylene glycol 400, 0-0.6 part of lactose and 0.2-0.6 part of sucralose;
preferably, lactose is 0 or 0.1 to 0.6 parts.
6. The milabalin besylate oral solution film according to claim 2, wherein the milabalin besylate oral solution comprises the following components in parts by weight:
85-90 parts of 50% ethanol water solution, 0.1-0.75 part of milbelin benzenesulfonate, 9-11 parts of hypromellose, 0.5-2.5 parts of poloxamer 188, 0.1-0.3 part of polysorbate, 5-9 parts of glycerin, 0 or 0.1-0.6 part of lactose and 0.2-0.6 part of sucralose.
7. The amisulbactam besylate oral film according to claim 1, wherein the amisulbactam besylate oral film is a film-like preparation, and the content of the pharmaceutical active ingredient in each film is 2.5 mg-15 mg calculated by the amisulbactam besylate.
8. A process for the preparation of an orally dissolving film of milabalin besylate according to any of the claims 1 to 7, characterized in that it comprises the following steps:
adding hydroxypropyl methylcellulose into a part of ethanol water solution, and stirring until the hydroxypropyl methylcellulose is completely swelled;
Adding a surfactant, the sulbactam besylate, a plasticizer, a disintegrating agent and a flavoring agent into the residual ethanol water solution, and dissolving to obtain a medicine-containing solution;
adding the medicine-containing solution into the completely swelled hypromellose, homogenizing, and removing bubbles to obtain medicine-containing slurry;
and (3) coating the medicine-containing slurry on the surface of a mold, drying, demolding and cutting to obtain the medicine-containing slurry.
9. The method for preparing the film dissolving agent for the mouth of milbeverine besylate according to claim 8 wherein the surfactant, the milbeverine besylate, the plasticizer, the disintegrating agent and the flavoring agent are added into the residual ethanol water solution to be completely dissolved and dispersed for 0.5 to 2 hours;
Or adding the drug-containing solution into the completely swelled hypromellose, stirring and homogenizing, and standing for removing bubbles; the stirring time is 0.5-2 h, and the standing time is 0.1-2 h.
10. The method for preparing the film dissolving agent for the mouth of milbelin besylate according to claim 8 wherein the drying temperature is 40-60 ℃ and the drying time is 0.5-4 h;
except for the drying step, other preparation steps of the amisulprin besylate oral film agent are all carried out at room temperature or 30 ℃.
CN202411079481.XA 2024-08-07 2024-08-07 A kind of milobarlin besylate orodispersible film preparation and preparation method thereof Pending CN118948808A (en)

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