CN112569208A - Pramipexole dihydrochloride medicine composition and preparation method thereof - Google Patents
Pramipexole dihydrochloride medicine composition and preparation method thereof Download PDFInfo
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- CN112569208A CN112569208A CN201910934085.3A CN201910934085A CN112569208A CN 112569208 A CN112569208 A CN 112569208A CN 201910934085 A CN201910934085 A CN 201910934085A CN 112569208 A CN112569208 A CN 112569208A
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- film
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- polyvinyl alcohol
- polyethylene glycol
- solution
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Links
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A61K9/00—Medicinal preparations characterised by special physical form
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Abstract
The invention belongs to the technical field of medicinal preparations, and particularly relates to a pramipexole dihydrochloride oral soluble film agent medicinal composition and a preparation method thereof. The composition provided by the application comprises a high-molecular film-forming material, a plasticizer and the like. The film agent is taken without water, is convenient to take, has good taste and quick dissolution, is very suitable for Parkinson patients, especially patients with chewing difficulty, swallowing difficulty and hand tremor, greatly improves the compliance of the patients, and has better economic benefit and social benefit.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to a pramipexole dihydrochloride oral soluble film medicinal composition and a preparation method thereof.
Background
Pramipexole dihydrochloride (Pramipexole) is a new generation of non-ergot dopamine receptor agonist developed by Boehringer Ingelheim, germany, can highly selectively act on dopaminergic D2 and D3 receptors, stimulate the release of dopamine in brain, improve motor symptoms, and is a first-line medicament for treating parkinson disease.
Pramipexole has the chemical name of S-2-amino-4, 5,6, 7-tetrahydro-6- (propylamino) -benzothiazole and the molecular formula C10H17N3S, relative molecular weight 211.33. Pramipexole dihydrochloride is a white or off-white crystalline powder, readily soluble in water, soluble in methanol, poorly soluble or slightly soluble in ethanol, practically insoluble in methylene chloride, very stable in the solid state, yet photosensitive when in solution or mixed with other excipients. The chemical formula is as follows:
at present, only common tablets and sustained-release tablets exist in the market. The common tablets were marketed after approval by the FDA in the United states in 1997 under the trade name "Sifrol", and in 2005 in 12 months were approved for entry into the Chinese market under the trade name "Senforo". The slow release tablets for 2 months in 2010 are sold on the market in the United states, and the slow release tablets for 8 months in 2014 are sold on the market at home. At present, the oral film dissolving dosage form is not on the market.
The Parkinson patients usually have hand trembling symptoms, so the Parkinson patients are not easy to take and are easy to fall off when taking tablets; for dysphagia patients, especially for the elderly patients, the tablet is not beneficial to swallowing, the medicine taking is difficult, and the compliance is not high; in addition, the conventional tablet can be better taken only by being matched with water, and is troublesome and fussy for Parkinson patients. Therefore, a new dosage form needs to be developed to solve the problem of compliance of patients with Parkinson's disease.
Patent CN201210323670.8 "pramipexole oral liquid and its preparation method" discloses a formulation and a preparation method of an oral liquid, which can solve the problem of dysphagia of patients, but the oral liquid contains water, is often poor in stability and difficult to store, and needs to add preservative or bacteriostatic agent to control the growth of microorganisms. The oral liquid is inconvenient to take, and has the defects of inconvenient operation of divided dosage for the oral liquid packaged by multiple dosages, the divided dosage is possibly inaccurate, and the compliance is poor especially for patients with Parkinson hand trembling. For the oral liquid packaged by single dose, the bottle is held by hand to suck all the liquid medicine, a certain time is needed, the patient is shaken by hands, and the operation is inconvenient. In addition, the oral liquid has the problems of overlarge size, overweight, inconvenient carrying and the like.
Patents CN200810226593.8 and CN201410169359.1 disclose a pramipexole dihydrochloride orally disintegrating tablet, which can be rapidly disintegrated in the oral cavity, enter the digestive tract along with swallowing, and need not to take medicines with water, thus improving the compliance of patients to a certain extent. However, the preparation process of orally disintegrating tablets is complex, usually requires special production equipment and production conditions, and has high cost. Furthermore, orally disintegrating tablets tend to be relatively low in hardness, brittle, and relatively weak in folding resistance, and have relatively stringent requirements for packaging, storage, and transportation.
Therefore, the market urgently needs to develop a new pramipexole dihydrochloride preparation which is convenient for the administration of the Parkinson patients, accurate in dosage and convenient to carry and transport.
The oral instant film agent is a new preparation which can be quickly dissolved in oral cavity, and is a film-shaped solid preparation prepared by dissolving or uniformly dispersing a medicine in a film-forming material. The oral instant film agent has the advantages and characteristics that (1) the film agent can be dissolved within seconds, is rapidly released and takes effect rapidly; (2) the oral liquid does not need to be chewed or taken with water, is convenient to take, has better patient compliance, does not have the risk of blocking throat, and can be used as a substitute dosage form of the traditional oral tablet, capsule and the like to be applied to children, old people with dysphagia or postoperative patients; (3) the volume is light and small, and the packaging is independent and convenient to carry; (4) compared with freeze-dried orally disintegrating tablets, the preparation method has the advantages of small using amount of auxiliary materials, simple and convenient process, low cost, difficult friability and convenient storage and transportation. (5) Compared with the common tablet, the process has no dust pollution and no noise.
Therefore, the pramipexole dihydrochloride oral soluble film medicine composition and the preparation method thereof are provided, and the medicine which is convenient to take by patients with intermediate and late stage dysphagia in Parkinson and has good compliance is provided, so that more choices are provided for the patients.
Disclosure of Invention
In order to solve the problems, the pramipexole dihydrochloride oral soluble film provided by the application has the advantages of excellent quality, high bioavailability and convenience in taking medicine, and can greatly improve the medication compliance of patients with Parkinson's disease.
In a first aspect, the present application provides a pramipexole dihydrochloride oral soluble film pharmaceutical composition, which comprises the following components:
the orally dissolving film has small volume, light weight and soft shape, and has enough medicine carrying capacity, capacity of fast disintegrating into fine grains or further dissolving into solution, and important supplementary material selection.
The film forming material is a key component of the orally dissolving film, and the property of the film forming material directly influences the drug loading rate, the film release property, the disintegration time, the mechanical strength and the like of the film agent. Commonly used polymeric film-forming materials include methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyoxyethylene, polyvinyl alcohol-polyethylene glycol graft copolymer, pullulan, gelatin, gum arabic, modified starch, carageenan, gum arabic, guar gum, locust bean gum, xanthan gum, gellan gum, and agar.
Through a large number of experimental screens, one or more of polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer are preferably selected as film-forming materials.
More preferably, the film-forming material is polyvinyl alcohol or a polyvinyl alcohol-polyethylene glycol graft copolymer. The prepared mouth dissolving film has good film forming property, toughness, folding resistance and stripping property, and can be quickly disintegrated or dissolved.
Wherein, the dosage of the polyvinyl alcohol is 5 to 60 parts; the dosage of the polyvinyl alcohol-polyethylene glycol graft copolymer is 5-60 parts.
In the polyvinyl alcohol-polyethylene glycol graft copolymer, the polyvinyl alcohol part accounts for 15-85% of the total weight of the graft copolymer, and the polyethylene glycol part accounts for 85-15% of the total weight of the graft copolymer.
In some preferred embodiments, the polyvinyl alcohol moieties comprise from 25% to 75% by weight of the total graft copolymer and the polyethylene glycol moieties comprise from 75% to 25% by weight of the total graft copolymer.
In some preferred embodiments, the polyvinyl alcohol moiety comprises 50% to 75% by weight of the total graft copolymer and the polyethylene glycol moiety comprises 50% to 25% by weight of the total graft copolymer.
In some preferred embodiments, the polyvinyl alcohol-polyethylene glycol graft copolymer of the present invention has a polyvinyl alcohol moiety comprising 75% of the total weight of the graft copolymer and a polyethylene glycol moiety comprising 25% of the total weight of the graft copolymer and having a molecular weight of about 45,000 daltons.
In some preferred embodiments, the polyvinyl alcohol-polyethylene glycol graft copolymer of the present invention has a polyvinyl alcohol moiety comprising 50% of the total weight of the graft copolymer and a polyethylene glycol moiety comprising 50% of the total weight of the graft copolymer and having a molecular weight of about 45,000 daltons.
The molecular weight of the polyvinyl alcohol is 16,000-20,000 daltons, and the viscosity of the polyvinyl alcohol is 4.6-6.3 mPa.s.
The plasticizer can reduce the glass transition temperature of the film and reduce the brittleness, thereby increasing the toughness of the film and being beneficial to the split charging and cutting of the film. Common plasticizers include polyethylene glycol, diethylene glycol, tripropylene glycol, ethylene glycol, triethylene glycol, 1, 3-butanediol, 1, 4-butanediol, polysorbate, etc.
Preferably, the plasticizer is selected from one or more of the group consisting of polyethanol 400 and glycerol.
More preferably, the plasticizer is a mixture of polyethanol 400 and glycerol.
Wherein, the dosage of the polyethylene glycol 400 is 2-12mg, and the dosage of the glycerol is 1-6 mg.
In some embodiments, the mass ratio of film-forming material to plasticizer is from about 1: 1-5: 1.
in some embodiments, the mass ratio of film-forming material to plasticizer is 1: 1. 1.5: 1. 1.7: 1. 1.9: 1. 2: 1. 2.5: 1. 2.9: 1. 3: 1. 3.2: 1. 3.3: 1. 4: 1. 4.2: 1 or 5: 1.
the orally dissolving film is required to be rapidly disintegrated, and a disintegrant may be optionally added as needed to facilitate disintegration. Commonly used disintegrants may be selected from croscarmellose sodium, sodium carboxymethyl starch, crospovidone, and the like. Preferably, the disintegrant is crospovidone.
Wherein the usage amount of the crospovidone is 3-15 parts,
the oral film-dissolving pharmaceutical composition provided by the invention optionally comprises a filler, and the filler is microcrystalline cellulose.
Wherein the dosage of the microcrystalline cellulose is 0-100 parts.
In some embodiments, the oral dissolving film provided by the invention comprises 0.1-5 parts of pramipexole dihydrochloride, 5-60 parts of polyvinyl alcohol or 5-60 parts of a polyvinyl alcohol-polyethylene glycol graft copolymer, 3-15 parts of crospovidone, 0-100 parts of microcrystalline cellulose, 2-12 parts of polyethylene glycol 400and 1-6 parts of glycerol.
In some embodiments, the oral dissolving film provided by the invention comprises 0.1-5 parts of pramipexole dihydrochloride, 20-40 parts of polyvinyl alcohol or 20-40 parts of a polyvinyl alcohol-polyethylene glycol graft copolymer, 3-15 parts of crospovidone, 0-100 parts of microcrystalline cellulose, 2-12 parts of polyethylene glycol 400and 1-6 parts of glycerol.
The unit weight of the oral dissolving film provided by the invention is 20-150 mg.
The orally dissolving film can be quickly disintegrated or dissolved in oral cavity, has high requirement on mouth feel, and often needs to be added with a flavoring agent and the like to improve the mouth feel. The common correctant is selected from aspartame, saccharin sodium, sucrose, glucose, fructose, sucralose, menthol, nutmeg oil, vanilla essence, cocoa essence, chocolate essence, apple essence, cherry essence, pineapple essence, etc. Preferably, the flavoring agent is selected from sucralose and orange flavor.
In addition to the inherent quality, the appearance of the oromelt film is also important. The orodispersible film is often colored according to the pleasure of the patient with respect to color, and the coloring agent may be selected from food, pharmaceutical grade pigments such as indigo, sunset yellow, red iron oxide, etc. Sunset yellow is preferred as a colorant in the present invention.
In some embodiments, the present invention provides an orally dissolving film that further optionally comprises a flavoring and/or coloring agent.
Further, the taste modifier is selected from sucralose and orange essence, and the toner is sunset yellow.
Furthermore, the oral dissolving film provided by the invention comprises 0.1-2 parts of sucralose, 1-2 parts of orange essence and 0.03-0.08 part of sunset yellow.
In addition to the above-mentioned orodispersible film excipients, other excipients known in the art may also be added depending on the desired characteristics of the product.
In a second aspect of the present invention, there is provided a method for preparing the above oromelt film, comprising the steps of:
(1) heating polyvinyl alcohol or polyvinyl alcohol-polyethylene glycol graft copolymer in purified water to 75-85 ℃, stirring for dissolving, standing, cooling to room temperature to complement volatilized water to obtain solution I;
(2) dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange essence in the solution I to obtain a solution II;
(3) adding polyvinylpolypyrrolidone, microcrystalline cellulose and sunset yellow into the solution II, and uniformly stirring and mixing to obtain a matrix solution III;
(4) coating the substrate liquid III by a coating machine, and drying and rolling at 60-75 ℃.
(5) Cutting the rolled film agent, and controlling the weight difference within +/-6% to obtain a finished product.
In the preparation method of the oral dissolving film, the solid content (namely the mass percentage concentration of the solid material) in the matrix liquid III in the step (3) needs to be controlled to be 15-60%.
The preparation method of the oral dissolving film further comprises the operation of vacuumizing and bubble exhausting, wherein the vacuum degree is controlled to be-0.05 Mpa to-0.08 Mpa.
In the preparation method of the oral dissolving film, the wet thickness of the coating in the step (4) is controlled100-; the cutting width of the film agent in the step (5) is as follows: 1-4X 2-5cm2。
The pramipexole dihydrochloride orally-dissolvable film provided by the application has the following advantages:
(1) the pramipexole dihydrochloride drug is added with a new dosage form, the market blank is filled, more dosage form choices are provided for Parkinson patients, and particularly for patients with resistance to traditional drugs, the pramipexole dihydrochloride drug is stamped into a film form, so that privacy can be well protected.
(2) The capsule is convenient to take, does not need to be taken with water, does not need to be chewed, does not have the risk of blocking throat, has better patient compliance compared with the common tablet or capsule, and is particularly suitable for patients with Parkinson's disease, patients with dysphagia or postoperative patients.
(3) Has quick disintegration and rapid action. The orally dissolving film can be quickly disintegrated in 30 seconds in the mouth, so that the medicine is quickly dissolved, the disintegration and dissolution time is greatly shortened compared with that of a common tablet or capsule, and the medicine is similar to a solution and can be quickly absorbed with special effect.
(4) The taste is good, no obvious peculiar smell exists, no gravel feeling exists, and the compliance of a patient in taking medicine is favorably improved;
(5) compared with freeze-dried orally disintegrating tablets, the preparation method has the advantages of simple process, low cost, low probability of being fragile, and convenience in storage and transportation; and no dust flies in the process, which is beneficial to the health protection of personnel.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below by way of examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In the following screening experiments and examples, polyvinyl alcohol-polyethylene glycol graft copolymers were used having a polyvinyl alcohol moiety of 75% by weight of the total graft copolymer and a polyethylene glycol moiety of 25% by weight of the total graft copolymer and a molecular weight of about 45,000 daltons.
1. Screening of film-Forming Material
The film-forming material is critical to the quality of the oromelt film. On the one hand, the orally dissolving film needs to be rapidly disintegrated into fine particles or further dissolved into a solution state in the oral cavity; on the other hand, the oral dissolving film is suitable for stripping the carrier material, has a certain viscosity to the carrier material after being dried, is not easy to fall off, and is beneficial to cutting and packaging of subsequent processes; if the stripping property is poor, the film is not easy to strip, the separation of the film and the carrier material during cutting is influenced, and the cutting is not facilitated; if the stripping property is too good, the film and the carrier material are separated when the cutting machine cuts, so that the cutting process is not facilitated, and the smoothness of the process is influenced, so that the stripping property is kept appropriate, and the smoothness of the cutting process is ensured.
The application screens and surveys hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, povidone K30 and polyvinyl alcohol or polyvinyl alcohol-polyethylene glycol graft copolymer. According to the formula composition of the following table 1, water is respectively added, mechanically stirred and swelled to prepare glue solution with proper viscosity, the glue solution is coated on PET (polyester film), dried in an oven at 60-75 ℃, and cut into films with the size of 3cmx4cm, and the finished products are obtained. The film-forming material was evaluated comprehensively using the appearance, peelability, and toughness as the index of investigation.
TABLE 1 film-Forming Material screening test recipe composition
The film prepared by the formula 1 (hydroxypropyl methylcellulose) is transparent, the toughness basically meets the requirement, but the carrier material is difficult to strip, so that the production operation is not facilitated; the formula 2 (low substituted hydroxypropyl cellulose) is difficult to form a film in the preparation process, has poor toughness and does not meet the film forming requirement; the film prepared by the formula 4 (povidone K30) is transparent in appearance, but poor in toughness, difficult to strip the carrier material and not capable of meeting the film forming requirement. The film prepared by the formula 3 (sodium carboxymethyl cellulose) has transparent appearance and proper stripping performance, but the toughness of the film is not ideal, and further investigation finds that the disintegration time limit of the formula 3 film is longer. The film prepared by the formula 5 (polyvinyl alcohol) and the formula 6 (polyvinyl alcohol-polyethylene glycol graft copolymer) has transparent appearance, good toughness and proper stripping property, all indexes meet the film forming requirement and the industrial production requirement, the disintegration time is about 30 seconds, and the film is very favorable for the rapid disintegration and dissolution of the film in the oral cavity.
2. Plasticizer screening
The plasticizer can ensure the toughness of the mouth dissolving film and increase the tensile strength and the folding resistance. The film is prepared according to the formula of the following table 2, the appearance, the stripping property and the toughness are taken as investigation indexes, and the influence of the plasticizer on the film is comprehensively evaluated. The amounts of PEG 400 and glycerol used in formula 13 are each 0.5 g.
TABLE 2 plasticizer screening test recipe compositions
The films prepared by the formula 7 (ethylene glycol) and the formula 9 (polysorbate) have poor toughness and cannot meet the requirement of film formation, and the carrier material is difficult to strip from the film of the formula 9, so that the industrial production is not facilitated; the film made by the prescription 10 (the polyethanol 4000) has too good stripping performance, which is not beneficial to the cutting process; when 1, 3-butanediol (formula 8) or polyethanol 400 (formula 11) is used as a single plasticizer, the prepared film has transparent appearance and proper stripping property, but the toughness of the film is general; when glycerin (formula 12) is used as a single plasticizer or glycerin and polyethylene glycol 400 (formula 13) are used in combination as a mixed plasticizer, the film-forming property, toughness and peeling property of the oral dissolving film are all excellent, and the product requirements and industrial production are met.
3. Disintegrant screening
The film was prepared according to the recipe in table 3 below and the effect of the use of different disintegrants on disintegration time, film forming, toughness and peelability was examined.
Table 3 disintegrant screening formulations
The prepared film has disintegration time of hundreds of seconds by adopting the croscarmellose sodium (formula 14) as a disintegrant, and is difficult to strip carrier materials; sodium carboxymethyl starch (formula 15) is used as a disintegrating agent, the disintegration time of the prepared film is 100 seconds, the toughness is not ideal, and the film is easy to strip; the cross-linked povidone (formula 6) is adopted as the disintegrant, and the prepared film has transparent appearance, good toughness and proper stripping property, the disintegration time is only 31 seconds, and all indexes meet the requirements. The formulation 16 does not use microcrystalline cellulose, and the obtained film has disintegration time of 60s and stripping property inferior to that of formulation 6. It can be seen that the combination of crospovidone and microcrystalline cellulose in the formula can accelerate the disintegration of the film.
The orodispersible films of the invention are further illustrated by the following examples
Example 1
Prescription composition (made into 1000 tablets)
| Raw and auxiliary materials | Dosage (g) |
| Pramipexole dihydrochloride | 0.1 |
| Polyvinyl alcohol | 12.77 |
| Cross-linked polyvidone | 3 |
| Polyethylene glycol 400 | 2 |
| Glycerol | 1 |
| Sucralose | 0.1 |
| Orange essence | 1 |
| Sunset yellow | 0.03 |
| Weight of unit film (totality) | 20 |
Preparation process
(1) Heating polyvinyl alcohol in 100-130g of purified water to 75-85 ℃, stirring for dissolving, standing, cooling to room temperature to complement volatile water to obtain a solution I;
(2) dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange essence in the solution I to obtain a solution II;
(3) adding polyvinylpolypyrrolidone and sunset yellow into the solution II, stirring and mixing uniformly to obtain a matrix solution III, and removing bubbles under the condition of vacuum pumping of-0.05 Mpa to-0.08 Mpa for more than 20 minutes, wherein the solid content is controlled to be 15-20%;
(4) coating the substrate liquid III by a coating machine, controlling the wet coating thickness to be 100-150 mu m, and drying and rolling at 60-75 ℃;
(5) cutting the rolled film agent, wherein the cutting width of the film agent is as follows: 1 x 2cm2Controlling the weight difference to be +/-6 percent to obtain a finished product.
Example 2
Prescription composition (made into 1000 tablets)
| Raw and auxiliary materials | Dosage (g) |
| Pramipexole dihydrochloride | 0.25 |
| Polyvinyl alcohol-polyethylene glycol graft copolymer | 16 |
| Cross-linked polyvidone | 4 |
| Microcrystalline cellulose | 13 |
| Polyethylene glycol 400 | 3 |
| Glycerol | 2 |
| Sucralose | 0.11 |
| Orange essence | 1.6 |
| Sunset yellow | 0.04 |
| Weight of unit film (totality) | 40 |
Preparation process
(1) Heating the polyvinyl alcohol-polyethylene glycol graft copolymer in 160-200g of purified water to 75-85 ℃, stirring for dissolving, standing, cooling to room temperature to complement the volatilized water to obtain a solution I;
(2) dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange essence in the solution I to obtain a solution II;
(3) adding polyvinylpolypyrrolidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain a matrix solution III, and degassing under the condition of vacuum-0.05 Mpa-0.08 Mpa for more than 20 minutes to control the solid content to be 20-25%;
(4) coating the substrate liquid III by a coating machine, controlling the wet coating thickness to be 150-;
(5) cutting the rolled film agent, wherein the cutting width of the film agent is as follows: 2 × 3cm2, and controlling the weight difference to be +/-6% to obtain the finished product.
Example 3
Prescription composition (made into 1000 tablets)
Preparation process
(1) Heating polyvinyl alcohol in 200-240g of purified water to 75-85 ℃, stirring for dissolving, standing, cooling to room temperature to complement volatile water to obtain a solution I;
(2) dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange fragrance in the solution I to obtain a solution II;
(3) adding polyvinylpolypyrrolidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain a matrix solution III, and degassing under the condition of vacuum-0.05 Mpa-0.08 Mpa for more than 20 minutes to control the solid content to be 25-30%;
(4) coating the substrate liquid III by a coating machine, controlling the wet coating thickness to be 200-250 mu m, and drying and rolling at 60-75 ℃;
(5) cutting the rolled film agent, wherein the cutting width of the film agent is as follows: 2 x4cm2Controlling the weight difference to be +/-6 percent to obtain a finished product.
Example 4
Prescription composition (made into 1000 tablets)
| Raw and auxiliary materials | Dosage (g) |
| Pramipexole dihydrochloride | 0.75 |
| Polyvinyl alcohol-polyethylene glycol graft copolymer | 25 |
| Cross-linked polyvidone | 10 |
| Microcrystalline cellulose | 32 |
| PEG400 | 5 |
| Glycerol | 5 |
| TrichlorocaneCandy | 1.1 |
| Orange essence | 1.1 |
| Sunset yellow | 0.05 |
| 75 units film weight (total) | 80 |
Preparation process
(1) Heating the polyvinyl alcohol-polyethylene glycol graft copolymer in 200-270g of purified water to 75-85 ℃, stirring for dissolving, standing, cooling to room temperature to complement the volatilized water to obtain a solution I;
(2) dissolving pramipexole dihydrochloride raw materials, polyethylene glycol 400, glycerol, sucralose and orange fragrance in unit dose into the solution I to obtain a solution II;
(3) adding polyvinylpolypyrrolidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain a matrix solution III, and degassing under the condition of vacuum-0.05 Mpa-0.08 Mpa for more than 20 minutes to control the solid content to be 30-40%;
(4) coating the substrate liquid III by a coating machine, controlling the wet coating thickness to be 250-350 mu m, and drying and rolling at 60-75 ℃;
(5) cutting the rolled film agent, wherein the cutting width of the film agent is as follows: 3 x4cm2Controlling the weight difference to be +/-6 percent to obtain a finished product.
Example 5
Prescription composition (made into 1000 tablets)
| Raw and auxiliary materials | Dosage (mg) |
| Pramipexole dihydrochloride | 1.25 |
| Polyvinyl alcohol | 30 |
| Cross-linked polyvidone | 8 |
| Microcrystalline cellulose | 41 |
| PEG400 | 10 |
| Glycerol | 6 |
| Sucralose | 2 |
| Orange essence | 1.67 |
| Sunset yellow | 0.08 |
| Weight of unit film (totality) | 100 |
Preparation process
(1) Heating polyvinyl alcohol in 250g of purified water 220-85 ℃ to 75-85 ℃, stirring for dissolving, standing, cooling to room temperature to complement volatile water to obtain a solution I;
(2) dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange fragrance in the solution I to obtain a solution II;
(3) adding polyvinylpolypyrrolidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain a matrix solution III, and degassing under the condition of vacuum-0.05 Mpa-0.08 Mpa for more than 20 minutes to control the solid content to be 40-45%;
(4) coating the matrix liquid III by a coating machine, controlling the wet coating thickness to be 400-450 mu m, and drying and rolling at 60-75 ℃;
(5) cutting the rolled film agent, wherein the cutting width of the film agent is as follows: 3 x4cm2Controlling the weight difference to be +/-5 percent to obtain a finished product.
Example 6
Prescription composition (made into 1000 tablets)
| Raw and auxiliary materials | Dosage (g) |
| Pramipexole dihydrochloride | 1.5 |
| Polyvinyl alcohol-polyethylene glycol graft copolymer | 40 |
| Cross-linked polyvidone | 15 |
| Microcrystalline cellulose | 51 |
| PEG400 | 10 |
| Glycerol | 4 |
| Sucralose | 1.5 |
| Orange essence | 1.95 |
| Sunset yellow | 0.05 |
| Weight of unit film (totality) | 125 |
Preparation process
(1) Heating the polyvinyl alcohol-polyethylene glycol graft copolymer in 250-280g of purified water to 75-85 ℃, stirring for dissolving, standing, cooling to room temperature to complement the volatilized water to obtain a solution I;
(2) dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange fragrance in the solution I to obtain a solution II;
(3) adding polyvinylpolypyrrolidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain a matrix solution III, and degassing under the condition of vacuum-0.05 Mpa-0.08 Mpa for more than 20 minutes to control the solid content to be 45-50%;
(4) coating the matrix liquid III by a coating machine, controlling the wet coating thickness to be 450-500 mu m, and drying and rolling at 60-75 ℃;
(5) cutting the rolled film agent, wherein the cutting width of the film agent is as follows: 3X 5cm2Controlling the weight difference to be +/-5 percent to obtain a finished product.
Example 7
Prescription composition (made into 1000 tablets)
| Raw and auxiliary materials | Dosage (g) |
| Pramipexole dihydrochloride | 2.5 |
| Polyvinyl alcohol | 50 |
| Cross-linked polyvidone | 10 |
| Microcrystalline cellulose | 57 |
| PEG400 | 8 |
| Glycerol | 4 |
| Sucralose | 2 |
| Orange essence | 1.45 |
| Sunset yellow | 0.05 |
| Weight of unit film (totality) | 135 |
Preparation process
(1) Heating polyvinyl alcohol in 245-300g of purified water to 75-85 ℃, stirring for dissolving, standing, cooling to room temperature to complement volatile water to obtain a solution I;
(2) dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange fragrance in the solution I to obtain a solution II;
(3) adding polyvinylpolypyrrolidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain a matrix solution III, and degassing under the condition of vacuum-0.05 Mpa-0.08 Mpa for more than 20 minutes to control the solid content to be 45-55%;
(4) coating the matrix liquid III by a coating machine, controlling the wet coating thickness to be 450-;
(5) cutting the rolled film agent, wherein the cutting width of the film agent is as follows: 4 x4cm2Controlling the weight difference to be +/-6 percent to obtain a finished product.
Example 8
Prescription composition (made into 1000 tablets)
Preparation process
(1) Heating the polyvinyl alcohol-polyethylene glycol graft copolymer in 300g of purified water of 250-85 ℃, stirring for dissolving, standing, cooling to room temperature to complement the volatilized water to obtain a solution I;
(2) dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange fragrance in the solution I to obtain a solution II;
(3) adding polyvinylpolypyrrolidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain a matrix solution III, and degassing under the condition of vacuum-0.05 Mpa-0.08 Mpa for more than 20 minutes to control the solid content to be 50-60%;
(4) coating the substrate liquid III by a coating machine, controlling the wet coating thickness to be 500-600 mu m, and drying and rolling at 60-75 ℃;
(5) cutting the rolled film agent, wherein the cutting width of the film agent is as follows: 4 x 5cm2Controlling the weight difference to be +/-6 percent to obtain a finished product.
Example 9
Prescription composition (made into 1000 tablets)
| Raw and auxiliary materials | Dosage (g) |
| Pramipexole dihydrochloride | 4.5 |
| Polyvinyl alcohol | 23 |
| Cross-linked polyvidone | 5 |
| Microcrystalline cellulose | 100 |
| PEG400 | 9.45 |
| Glycerol | 4 |
| Sucralose | 2 |
| Orange essence | 2 |
| Sunset yellow | 0.05 |
| Weight of unit film (totality) | 150 |
Preparation process
(1) Heating polyvinyl alcohol in 330g of purified water of 300-85 ℃ to 75-85 ℃, stirring for dissolving, standing and cooling to room temperature to complement the volatile water to obtain a solution I;
(2) dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange fragrance in the solution I to obtain a solution II;
(3) adding polyvinylpolypyrrolidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain a matrix solution III, and degassing under the condition of vacuum-0.05 Mpa-0.08 Mpa for more than 20 minutes to control the solid content to be 15-60%;
(4) coating the substrate liquid III by a coating machine, controlling the wet coating thickness to be 500-600 mu m, and drying and rolling at 60-75 ℃;
(5) cutting the rolled film agent, wherein the cutting width of the film agent is as follows: 4 x 5cm2Controlling the weight difference to be +/-6 percent to obtain a finished product.
Example 10
1) Prescription composition (made into 1000 tablets)
| Raw and auxiliary materials | Dosage (g) |
| Pramipexole dihydrochloride | 5 |
| Polyvinyl alcohol-polyethylene glycol graft copolymer | 6 |
| Cross-linked polyvidone | 3 |
| Microcrystalline cellulose | 1.45 |
| PEG400 | 2 |
| Glycerol | 1 |
| Sucralose | 0.5 |
| Orange essence | 1 |
| Sunset yellow | 0.05 |
| Weight of unit film (totality) | 20 |
2) Preparation process
(1) Heating polyvinyl alcohol-polyethylene glycol graft copolymer in 60-70g of purified water to 75-85 ℃, stirring for dissolving, standing, cooling to room temperature, and complementing volatile water to obtain solution I;
(2) dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange fragrance in the solution I to obtain a solution II;
(3) adding polyvinylpolypyrrolidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain a matrix solution III, and degassing under the condition of vacuum-0.05 Mpa-0.08 Mpa for more than 20 minutes to control the solid content to be 30-35%;
(4) coating the substrate liquid III by a coating machine, controlling the wet coating thickness to be 200-300 mu m, and drying and rolling at 60-75 ℃;
(5) cutting the rolled film agent, wherein the cutting width of the film agent is as follows: 2 x 3cm2Controlling the weight difference to be +/-6 percent to obtain a finished product.
Comparative example 1 pramipexole dihydrochloride orally disintegrating tablets
1) Prescription composition (made into 1000 tablets)
| Raw and auxiliary materials | Dosage (g) |
| Pramipexole dihydrochloride | 0.5 |
| Lactose | 100 |
| Microcrystalline cellulose | 49.6 |
| Low-substituted hydroxypropyl cellulose | 39.9 |
| Stevioside | 5 |
| Talcum powder | 4 |
| Unit weight (totality) | 199 |
2) Preparation method
(1) Crushing the main drug pramipexole dihydrochloride and sieving the crushed pramipexole dihydrochloride by a 100-mesh sieve, and respectively sieving lactose and microcrystalline cellulose by a 100-mesh sieve for later use;
(2) mixing the main drug with lactose 4 times of the weight of the main drug, sieving for 2 times by a 50-mesh sieve, adding 45g of lactose for mixing, and finally adding the rest lactose and microcrystalline cellulose for mixing;
(3) adding low-substituted hydroxypropyl cellulose, stevioside and talcum powder into the mixture obtained in the step (2) and mixing;
(4) tabletting, and controlling the hardness within 30-40N.
Comparative example 2 pramipexole dihydrochloride capsules
1) Prescription composition (made into 1000 tablets)
2) Preparation process
(1) Sieving mannitol, starch and polylactic acid with 80 mesh sieve, and mixing to obtain mixed powder;
(2) adding povidone k30 into the aqueous solution, dissolving, adding pramipexole dihydrochloride, and dissolving to obtain an adhesive solution;
(3) adding the binder solution obtained in the step (2) into the mixed powder obtained in the step (1), and sieving and granulating by a wet method;
(4) drying the wet granules obtained in the step (3) at 55-60 ℃ for 3 hours;
(5) adding silicon dioxide and magnesium stearate into the dried granules, and uniformly mixing;
(6) and (5) filling the mixture into capsules to obtain the capsule.
Experimental example 1 measurement of physical Properties of film agent product of the present invention
1. Measurement method
(1) Peelability of
Ease of stripping the film from the coated support material PET (i.e., polyester film) after the film has dried. A film of 40mm x 50mm was taken, and the film was peeled off gently by hand to evaluate the ease of peeling.
(2) Tensile strength and elongation
The prepared pramipexole dihydrochloride oral solution film is cut into thin strips with the size of 20mmx 5mm, a universal DE material tester is adopted to measure the strips at the speed of 50mm.min < -1 >, the tensile stress and the tensile length of the oral solution film when the oral solution film is longitudinally stretched to be broken are recorded, and the measurement is repeated for 3 times. Calculating the tensile strength and the elongation according to the formula: tensile Strength (N.mm)-2) Tensile stress/cross-sectional area; elongation (%) — stretched length/initial length x 100%.
(3) Folding strength
Repeatedly folding the pramipexole dihydrochloride orolysis film with the size of 10x 20mm at the same position by hand until the film is broken, recording the folding times, and evaluating the folding resistance of the orolysis film.
2. Measurement results
The invention of examples 1-10, from the appearance, stripping, tensile strength, ductility, folding resistance is good, meet the film requirements.
TABLE 4 quality measurement results of oromelt film samples
| Appearance character | Peelability of | Tensile strength | Elongation rate | Folding endurance | Comprehensive evaluation | |
| Example 1 | Has smooth appearance and good film forming property | Easy to be stripped from PET film | 6.82±0.32 | 24.2±1.6 | 208±2 | 1 |
| Example 2 | Has smooth appearance and good film forming property | Easy to be stripped from PET film | 8.16±0.51 | 26.9±1.4 | 235±2 | 2 |
| Example 3 | Has smooth appearance and good film forming property | Can be peeled from the PET film | 8.61±0.35 | 25.4±1.7 | 252±3 | 2 |
| Example 4 | Has smooth appearance and good film forming property | Can be peeled from the PET film | 8.82±0.23 | 28.4±1.8 | 241±2 | 2 |
| EXAMPLE 5 | Has smooth appearance and good film forming property | Easy to be stripped from PET film | 9.32±0.45 | 32.7±2.3 | 255±3 | 4 |
| EXAMPLE 6 | Has smooth appearance and good film forming property | Easy to be stripped from PET film | 8.81±0.33 | 26.2±2.1 | 233±1 | 2 |
| EXAMPLE 7 | Has smooth appearance and good film forming property | Can be peeled from the PET film | 7.25±0.14 | 23.3±1.5 | 212±2 | 1 |
| EXAMPLE 8 | Has smooth appearance and good film forming property | Easy to be stripped from PET film | 8.35±0.22 | 26.4±1.9 | 245±2 | 2 |
| EXAMPLE 9 | Has smooth appearance and good film forming property | Easy to be stripped from PET film | 9.81±0.42 | 33.3±1.2 | 260±2 | 4 |
| EXAMPLE 10 | Has smooth appearance and good film forming property | Easy to be stripped from PET film | 9.55±0.21 | 30.5±1.7 | 253±3 | 4 |
Note: and (4) comprehensively scoring according to the degree of the score, wherein the higher the score is, the more excellent the comprehensive index is.
Stripping property: easy peeling is preferred over peeling.
Experimental example 2 quality comparison of film agent product of the present invention with those of comparative examples
1. Measurement method
(1) Determination of content
High performance liquid chromatography (appendix of the second part of chinese pharmacopoeia 2015 edition), chromatographic conditions: octadecane bonded silica gel is used as a filling agent, and acetonitrile-ammonium carbonate buffer solution pH10.0(20:80) is used as a mobile phase; the detection wavelength is 264nm, and the theoretical plate number is not less than 2000 calculated according to the pramipexole dihydrochloride peak. Calculating according to the peak area by an external standard method to obtain the product.
(2) Content uniformity measurement
Checking according to content uniformity inspection method in appendix of the second part of the year edition of Chinese pharmacopoeia 2015, taking 10 tablets of the product, respectively placing the tablets in 25ml measuring bottles, adding a proper amount of phosphate buffer solution, shaking to disintegrate, shaking for 15 minutes to dissolve pramipexole dihydrochloride, diluting to a scale with the phosphate buffer solution, shaking uniformly, centrifuging, and taking supernatant as a sample solution. And (3) measuring according to a method under a content measuring item, calculating the content of each piece, calculating the relative content X of each piece with the marked amount as 100%, calculating the mean value and the standard deviation S of each piece, and calculating the absolute value A of the difference between the marked content and the mean value, wherein if A +2.2S is less than or equal to 15.0, the content uniformity of the sample meets the requirement.
(3) Determination of disintegration time
The unit preparation was placed in a beaker containing 50ml of pH6.8 phosphate buffer at a temperature of 37. + -. 0.5 ℃ with gentle shaking and the time(s) of dissolution and disintegration was recorded.
(4) Dissolution determination
Taking the product, taking 100ml citrate/phosphate buffer solution (pH6.8) as dissolution medium according to dissolution determination method (appendix second method of second part of Chinese pharmacopoeia 2015 edition), rotating at 50rpm, operating according to the method, taking appropriate amount of solution after 5min, 10min, 20min and 30min, filtering, and taking the subsequent filtrate as sample solution; in addition, a proper amount of pramipexole dihydrochloride reference substance is precisely weighed and prepared into a solution containing 10.0ug of pramipexole dihydrochloride reference substance in each 1ml serving as a reference substance solution. Measuring according to a content measuring method, and calculating the dissolution amount of each tablet.
(5) Determination of related substances
Taking 1 tablet of pramipexole dihydrochloride preparation, adding a proper amount of phosphate buffer solution (pH3.0), shaking to disintegrate, shaking for 15 minutes to dissolve pramipexole dihydrochloride, shaking uniformly, centrifuging, and taking a proper amount of supernatant as a test solution; the method adopts a chromatographic column which takes octadecane bonded silica gel as a filling agent, takes 0.1mol/L ammonium acetate (pH5.0, containing 0.1% triethylamine) -methanol (98: 2) as a mobile phase A and takes methanol as a mobile phase B, and the method adopts gradient elution, the detection wavelength is 264nm, the column temperature is 40 ℃, and the flow rate is 1.0m L/min; and calculating the content of the related substances according to an area normalization method.
2.0 day measurement
The content and related substances of the oral dissolving film prepared in the embodiment 1-the embodiment 10 of the invention have no obvious difference from those of the comparative embodiment and all meet the requirements; the content uniformity is slightly better than that of comparative example 1 and comparative example 2, the disintegration time is not more than 35 seconds, and the content uniformity is significantly better than that of the orally disintegrating tablet of comparative example 1 and is more better than that of the capsule of comparative example 2. In addition, the oral dissolving film is very quick in dissolving, reaches more than 90% in 5 minutes, is much faster than the gastric emptying speed, is basically equivalent to a solution, and can quickly promote the release, absorption and effect of the medicine.
TABLE 5 oral film sample 0 day Mass measurement of the inventive examples
3. Stability (6 months of accelerated test)
The samples of the inventive example and the samples of the comparative examples 1 and 2 were placed at 40 ℃ and RH 75%, respectively, and after 6 months, they were sampled to examine the change in mass. The results are shown in the following table.
The results show that after the samples of the embodiments of the invention are placed for 6 months under the test conditions, the content and related substances are not obviously changed, the stability is good, and the product quality requirements are met. The disintegration time of the samples of comparative example 1 and comparative example 2 is long, and the dissolution rate is remarkably slow, which is not favorable for the dissolution effect of the main drug.
TABLE 6 results of quality investigation of mouth-dissolving film samples in accelerated tests for 6 months in the examples of the present invention
Claims (10)
1. The pramipexole dihydrochloride oral solution film comprises the following components:
0.1-5 parts of pramipexole dihydrochloride
5-60 parts of film forming material
3-18 parts of plasticizer
3-15 parts of disintegrating agent
0-100 parts of a filler.
2. The orodispersible film of claim 1, wherein the film-forming material is selected from one or more of polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer.
3. The oro-dissolving film according to claim 1, wherein the plasticizer is selected from one or more of polyethylene glycol 400 and glycerin.
4. The orodispersible film of claim 1, the disintegrant being crospovidone, and the filler being microcrystalline cellulose.
5. The orodispersible film according to claim 1, comprising 0.1-5 parts of pramipexole dihydrochloride, 5-60 parts of polyvinyl alcohol or 5-60 parts of polyvinyl alcohol-polyethylene glycol graft copolymer, 3-15 parts of crospovidone, 0-100 parts of microcrystalline cellulose, 2-12 parts of polyethylene glycol 4002 and 1-6 parts of glycerol.
6. The orodispersible film according to claim 5, comprising 0.1-5 parts of pramipexole dihydrochloride, 20-40 parts of polyvinyl alcohol or 20-40 parts of polyvinyl alcohol-polyethylene glycol graft copolymer, 3-15 parts of crospovidone, 0-100 parts of microcrystalline cellulose, 2-12 parts of polyethylene glycol 4002 and 1-6 parts of glycerol.
7. The orodispersible film of any one of claims 1-6, further optionally comprising a flavoring agent selected from sucralose and orange flavor and/or a coloring agent, the hueing agent being sunset yellow.
8. The orodispersible film of claim 7, comprising sucralose 0.1-2 parts, orange essence 1-2 parts, sunset yellow 0.03-0.08 part.
9. A method of making an oro-dissolvable film according to any of claims 1-8, comprising the steps of:
(1) heating polyvinyl alcohol or polyvinyl alcohol-polyethylene glycol graft copolymer in purified water to 75-85 ℃, stirring for dissolving, standing, cooling to room temperature to complement volatilized water to obtain solution I;
(2) dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange essence in the solution I to obtain a solution II;
(3) adding polyvinylpolypyrrolidone, microcrystalline cellulose and sunset yellow into the solution II, and uniformly stirring and mixing to obtain a matrix solution III;
(4) coating the substrate liquid III by using a coating machine, and drying and rolling at 60-75 ℃;
(5) cutting the rolled film agent, and controlling the weight difference within +/-6% to obtain a finished product.
10. The method of claim 9, further comprising a bubble evacuation operation, wherein the vacuum is controlled to be between-0.05 Mpa and-0.08 Mpa.
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| CN114886874A (en) * | 2022-04-07 | 2022-08-12 | 沈阳信达泰康医药科技有限公司 | Oral instant film agent and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120195955A1 (en) * | 2010-12-16 | 2012-08-02 | Arx, Llc | Sublingual films |
| CN105682639A (en) * | 2013-07-31 | 2016-06-15 | 兰色制药医药工业股份有限公司 | Oral dispersible films |
| CN109331175A (en) * | 2018-10-15 | 2019-02-15 | 袁海龙 | A kind of sublingual film of spearhead haemocoagulase and preparation method thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120195955A1 (en) * | 2010-12-16 | 2012-08-02 | Arx, Llc | Sublingual films |
| CN103476372A (en) * | 2010-12-16 | 2013-12-25 | Cynapsus疗法有限公司 | Sublingual films |
| CN105682639A (en) * | 2013-07-31 | 2016-06-15 | 兰色制药医药工业股份有限公司 | Oral dispersible films |
| CN109331175A (en) * | 2018-10-15 | 2019-02-15 | 袁海龙 | A kind of sublingual film of spearhead haemocoagulase and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114886874A (en) * | 2022-04-07 | 2022-08-12 | 沈阳信达泰康医药科技有限公司 | Oral instant film agent and preparation method thereof |
| CN114886874B (en) * | 2022-04-07 | 2023-11-17 | 沈阳信达泰康医药科技有限公司 | Oral instant film and preparation method thereof |
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