CN112569208B - Pramipexole dihydrochloride pharmaceutical composition and preparation method thereof - Google Patents
Pramipexole dihydrochloride pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN112569208B CN112569208B CN201910934085.3A CN201910934085A CN112569208B CN 112569208 B CN112569208 B CN 112569208B CN 201910934085 A CN201910934085 A CN 201910934085A CN 112569208 B CN112569208 B CN 112569208B
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- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 230000000152 swallowing effect Effects 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/428—Thiazoles condensed with carbocyclic rings
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- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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Abstract
The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a pramipexole dihydrochloride oral film-dissolving agent pharmaceutical composition and a preparation method thereof. The composition provided by the application comprises a polymer film forming material, a plasticizer and the like. The film agent is taken without water, has convenient administration, good taste and quick dissolution, is very suitable for parkinsonism patients, especially patients with mastication, dysphagia and tremor of hands, greatly improves the compliance of the patients, and has better economic and social benefits.
Description
Technical Field
The application belongs to the field of pharmaceutical preparations, and in particular relates to a pramipexole dihydrochloride oral dissolved film pharmaceutical composition and a preparation method thereof.
Background
Pramipexole dihydrochloride (Pramipexole) is a new generation of non-ergot dopamine receptor agonists developed by German Boehringer Ingelheim company, can highly selectively act on dopaminergic D2 and D3 receptors, excite release of dopamine in brain, improve motor symptoms, and is a first-line medicament for treating parkinsonism.
Pramipexole has the chemical name S-2-amino-4, 5,6, 7-tetrahydro-6- (propylamino) -benzothiazole, formula C 10 H 17 N 3 S, relative molecular weight 211.33. Pramipexole dihydrochloride is a white or off-white crystalline powder, is readily soluble in water, methanol, poorly soluble or slightly soluble in ethanol, is practically insoluble in methylene chloride, is very stable in the solid state, and is photosensitive when in solution or mixed with other excipients. The chemical formula is as follows:
only common tablets and sustained release tablets exist in the market at present. The common tablet of month 1 in 1997 was approved by the FDA in the united states and marketed under the trade name "Sifrol", and the common tablet of month 12 in 2005 was approved for the chinese market and marketed under the trade name "forest formol". The sustained-release tablets of 2 months in 2010 are marketed in the United states in batches, and the sustained-release tablets of 8 months in 2014 are marketed in China. At present, oral solvent film dosage forms are not marketed.
Because parkinsonism patients usually accompany symptoms of hand tremble, when the tablets are used for administration, the tablets are not easy to take and are easy to scatter; for dysphagia patients, especially for elderly patients, the tablet is unfavorable for swallowing, and has difficult administration and low compliance; in addition, the conventional tablet can be better taken by matching with water, and is more troublesome and complicated for Parkinson patients. Therefore, there is a need to develop a new dosage form to address the medication compliance problem of parkinson patients.
Patent CN201210323670.8 "pramipexole oral liquid and preparation method thereof" discloses a formula of oral liquid and preparation method thereof, the oral liquid can solve the problem of dysphagia of patients, but the oral liquid is often poor in stability due to water, difficult to store, and needs to be added with preservative or bacteriostatic agent to control microorganism growth. The oral liquid is inconvenient to take, has the defect of inconvenient operation of sub-dosage for the multi-dosage packaged oral liquid, and has inaccurate sub-dosage, and particularly has poor compliance for patients suffering from parkinsonism. For single-dose packaged oral liquid, the hand-held bottle can absorb all liquid medicine, a certain time is needed for shaking the patient, and the operation is inconvenient. In addition, the oral liquid has the problems of oversized size, overweight, inconvenient carrying and the like.
Patent 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 the swallowing action, and do not need to take medicine with water, thus improving the compliance of patients to a certain extent. However, the preparation process of the orally disintegrating tablet is complex, and usually requires special production equipment and production conditions, and the cost is high. And the orally disintegrating tablet is low in hardness, fragile and poor in folding resistance, and has relatively strict requirements on packaging, storage and transportation.
Therefore, the development of a new pramipexole dihydrochloride dosage form is urgently needed in the market, and the pramipexole dihydrochloride dosage form is convenient for Parkinson patients to administer, accurate in dosage and convenient to carry and transport.
The instant oral film is a new form of fast dissolving in oral cavity, and is one kind of film-shaped solid preparation prepared through dissolving or dispersing medicine homogeneously in film forming material. The oral instant film has the advantages and characteristics of (1) being capable of dissolving, rapidly releasing and rapidly taking effect in a few seconds; (2) The medicine is convenient to take without chewing and taking with water, has better patient compliance, does not have the danger of blocking the throat, and can be used as a substitute for traditional oral tablets, capsules and the like to be applied to the elderly or postoperative patients with children and dysphagia; (3) the volume is light and small, the package is independent, and the carrying is convenient; (4) Compared with freeze-dried orally disintegrating tablets, the preparation method has the advantages of less auxiliary material consumption, 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 application provides an oral membrane pharmaceutical composition of pramipexole dihydrochloride and a preparation method thereof, and aims to provide a medicament which is convenient to take and good in compliance for patients with dysphagia in middle and late stages of Parkinson, and provides more choices for the patients.
Disclosure of Invention
In order to solve the problems, the pramipexole dihydrochloride oral solution film provided by the application has the advantages of excellent product quality, high bioavailability and convenience in taking medicine, and can greatly improve the medication compliance of parkinsonism patients.
In a first aspect, the application provides a pramipexole dihydrochloride oral solution pharmaceutical composition, comprising the following components:
the oral film has small volume, light weight and soft shape, ensures enough drug loading, and ensures that the oral film can be rapidly disintegrated into fine particles or further dissolved into solution in the oral cavity, and the selection of auxiliary materials is important.
The film forming material is a key component of an oral film, and the property of the film forming material directly influences the drug loading rate, the film stripping property, the disintegration time, the mechanical strength and the like of the film agent. Common polymer film-forming materials are methylcellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyoxyethylene, polyvinyl alcohol-polyethylene glycol graft copolymer, pullulan, gelatin, acacia, modified starch, carageenan, gum arabic, guar gum, locust bean gum, xanthan gum, gellan gum, agar and the like.
The application is screened by a large number of tests, and one or more of polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer are preferable as film forming materials.
More preferably, the film-forming material is polyvinyl alcohol or a polyvinyl alcohol-polyethylene glycol graft copolymer. The prepared oral film has good film forming property, toughness, folding resistance and stripping property, and can be rapidly disintegrated or dissolved.
Wherein the dosage of the polyvinyl alcohol is 5-60 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 a partially preferred embodiment, the polyvinyl alcohol fraction represents 25% to 75% of the total weight of the graft copolymer and the polyethylene glycol fraction represents 75% to 25% of the total weight of the graft copolymer.
In a partially preferred embodiment, the polyvinyl alcohol fraction represents 50% to 75% of the total weight of the graft copolymer and the polyethylene glycol fraction represents 50% to 25% of the total weight of the graft copolymer.
In a partially preferred embodiment, the polyvinyl alcohol-polyethylene glycol graft copolymer of the present application has a polyvinyl alcohol fraction of 75% by weight of the total graft copolymer and a polyethylene glycol fraction of 25% by weight of the total graft copolymer and a molecular weight of about 45,000 daltons.
In a partially preferred embodiment, the polyvinyl alcohol-polyethylene glycol graft copolymer of the application has a polyvinyl alcohol fraction of 50% by weight of the total graft copolymer and a polyethylene glycol fraction of 50% by weight of the total graft copolymer and a molecular weight of about 45,000 daltons.
The molecular weight of the polyvinyl alcohol is 16,000-20,000 daltons, and the viscosity is 4.6-6.3 mPa.s.
The plasticizer can reduce the glass transition temperature of the film and reduce brittleness, thereby increasing the toughness of the film agent and being beneficial to split charging and cutting of the film agent. Examples of the plasticizer include polyethylene glycol, diethylene glycol, tripropylene glycol, ethylene glycol, triethylene glycol, 1, 3-butanediol, 1, 4-butanediol, and polysorbate.
Preferably, the plasticizer is selected from one or more of the group consisting of polyethylene glycol 400 and glycerin.
More preferably, the plasticizer is a mixture of the polyethylene glycol 400 and glycerin.
Wherein the dosage of polyethylene glycol 400 is 2-12mg, and the dosage of glycerol is 1-6mg.
In some embodiments, the mass ratio of film-forming material to plasticizer is 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 orodispersible film needs to disintegrate rapidly, and a disintegrating agent may be optionally added to promote disintegration, as needed. The usual disintegrants may be selected from croscarmellose sodium, sodium carboxymethyl starch, crospovidone, etc. Preferably, the disintegrant is crospovidone.
Wherein, the dosage of the crosslinked povidone is 3-15 parts,
the oral film pharmaceutical composition provided by the application further optionally comprises a filler, wherein the filler is microcrystalline cellulose.
Wherein the microcrystalline cellulose is used in an amount of 0-100 parts.
In some embodiments, the oral film provided by the application comprises 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 crosslinked povidone, 0-100 parts of microcrystalline cellulose, 2-12 parts of polyethylene glycol 4002 and 1-6 parts of glycerol.
In some embodiments, the oral film provided by the application comprises 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 crosslinked povidone, 0-100 parts of microcrystalline cellulose, 2-12 parts of polyethylene glycol 4002 and 1-6 parts of glycerol.
The weight of the unit piece of the oral film provided by the application is 20-150mg.
The oral dissolving film disintegrates or dissolves rapidly in the oral cavity, has high demand on the mouth feel, and often needs to be added with flavoring agents and the like to improve the mouth feel. The common flavoring agent is selected from aspartame, saccharin sodium, sucrose, glucose, fructose, sucralose, menthol, nutmeg oil, vanilla essence, cocoa essence, chocolate essence, apple essence, cherry essence, pineapple, etc. Preferably, the flavoring agent is selected from sucralose and orange flavor.
The oral film is also important in terms of appearance in addition to its inherent quality. Depending on how pleasing the patient is to the color, the orosol film often needs to be colored, and the colorant may be selected from food grade, pharmaceutical grade pigments such as indigo, sunset yellow, red iron oxide, and the like. Sunset yellow is preferred as the colorant in the present application.
In some embodiments, the oral films provided herein further optionally comprise flavoring and/or coloring agents.
Furthermore, the oral film provided by the application, the corrigent is selected from sucralose and orange essence, and the toner is tartrazine.
Further, the oral film provided by the application comprises 0.1-2 parts of sucralose, 1-2 parts of orange essence and 0.03-0.08 part of sunset yellow.
Besides the orosol excipients, other excipients known in the art can be added according to the characteristics of the product requirements.
In a second aspect of the present application, there is provided a method for preparing the above oral film, comprising the steps of:
(1) Heating polyvinyl alcohol or polyvinyl alcohol-polyethylene glycol graft copolymer in purified water to 75-85 ℃, stirring and dissolving, standing and cooling to room temperature to supplement volatilized water to obtain solution I;
(2) Dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange essence into a solution I to obtain a solution II;
(3) Adding crosslinked povidone, microcrystalline cellulose and sunset yellow into the solution II, and stirring and mixing uniformly to obtain a matrix solution III;
(4) And (3) coating the matrix liquid III by using a coating machine, and drying and rolling at 60-75 ℃.
(5) Cutting the winding film agent, and controlling the deviation difference within +/-6% to obtain a finished product.
In the preparation method of the oral film provided by the application, the solid content (i.e. the mass percentage concentration of solid materials) in the matrix liquid III in the step (3) is controlled to be 15-60%.
The preparation method of the oral film provided by the application further comprises the operation of vacuumizing and evacuating bubbles, wherein the vacuum degree is controlled between-0.05 Mpa and-0.08 Mpa.
In the preparation method of the oral film provided by the application, the coating wet thickness in the step (4) is controlled to be 100-600um; the film cutting width in the step (5) is as follows: 1-4X 2-5cm 2 。
The pramipexole dihydrochloride oral solution film provided by the application has the following advantages:
(1) The pramipexole dihydrochloride has the advantages of adding a new formulation for pramipexole dihydrochloride, filling the market blank, providing more formulation choices for parkinsonism patients, especially for patients with psychological resistance to traditional medicaments, along with the stamp film shape, and being capable of well protecting privacy.
(2) The medicine is convenient to take, does not need water for taking, does not need chewing, does not have the danger of blocking the throat, has better patient compliance than common tablets or capsules, and is particularly suitable for parkinsonism patients, dysphagia patients or postoperative patients.
(3) Rapid disintegration and quick action. The oral film can be rapidly disintegrated in the mouth within 30 seconds, so that the medicine is rapidly dissolved out, the disintegration and dissolution time is greatly shortened compared with the common tablet or capsule, and the medicine is similar to a solution, and can be rapidly absorbed and has special effect.
(4) The taste is good, no obvious peculiar smell exists, no gritty feel exists, and the compliance of the medicine taking place of patients is improved;
(5) Compared with freeze-dried orally disintegrating tablets, the preparation method has the advantages of simple and convenient process, low cost, uneasy breakage and convenient storage and transportation; and the process has no dust flying, and is beneficial to personnel health protection.
Detailed Description
The present application will be described in further detail with reference to the following examples, in order to make the objects, technical solutions and advantages of the present application more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the application.
In the following screening experiments and examples, a polyvinyl alcohol-polyethylene glycol graft copolymer was used, with a polyvinyl alcohol fraction of 75% of the total weight of the graft copolymer and a polyethylene glycol fraction of 25% of the total weight of the graft copolymer, having a molecular weight of about 45,000 daltons.
1. Film forming material screening
The film-forming material is critical to the quality of the orosol film. On the one hand, orofilms need to disintegrate rapidly into fine particles or further into a solution state in the oral cavity; on the other hand, the carrier material is peeled off by the mouth-soluble film, the peelability is required to be proper, and the carrier material has certain viscosity after drying, is not easy to fall off, and is favorable for cutting and packaging of the subsequent process; if the peelability is poor, the film is not easy to peel, and the separation of the film and the carrier material during cutting is affected, so that the cutting is not facilitated; if the peelability is too good, the film and the carrier material are separated when the cutting machine is used, which is unfavorable for the cutting process and influences the process smoothness, so the peelability should be kept proper, and the smoothness of the cutting process is ensured.
The application screens and inspects hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone K30 and polyvinyl alcohol or polyvinyl alcohol-polyethylene glycol graft copolymer. According to the prescription composition of the following table 1, water is respectively added, the mixture is mechanically stirred and swelled to prepare glue solution with proper viscosity, the glue solution is coated on PET (namely polyester film), and the PET is dried in an oven at 60-75 ℃ and cut into films with the size of 3cmx4cm, thus obtaining the finished product. The film forming material is comprehensively evaluated by taking appearance, peeling property and toughness as investigation indexes.
TABLE 1 formulation for screening test of film forming materials
The film made of prescription 1 (hypromellose) is transparent, the toughness basically meets the requirements, but the carrier material is difficult to peel off, which is not beneficial to the production operation; prescription 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 prescription 4 (povidone K30) has transparent appearance, but poor toughness, and is difficult to peel off the carrier material, and the film forming requirement is not met. The film made of prescription 3 (sodium carboxymethyl cellulose) had a clear appearance and suitable peelability, but the toughness of the film was not ideal, and further examination revealed that the film of prescription 3 had a longer disintegration time. The film prepared by the prescription 5 (polyvinyl alcohol) and the prescription 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, and the disintegration time limit is about 30 seconds, thereby being very beneficial to the rapid disintegration and dissolution of the film in the oral cavity.
2. Plasticizer screening
The plasticizer can ensure the toughness of the mouth-soluble film and increase the tensile strength and the folding endurance. The application prepares the diaphragm according to the prescription of the following table 2, takes appearance property, stripping property and toughness as investigation indexes, and comprehensively evaluates the influence of the plasticizer on the diaphragm. The amounts of polyethylene glycol 400 and glycerin used in formulation 13 were 0.5g each.
Table 2 plasticizer screening test recipe composition
The film prepared by the prescription 7 (glycol) and the prescription 9 (polysorbate) has poor toughness, does not meet the film forming requirement, and the film of the prescription 9 is difficult to strip the carrier material, thus being not beneficial to industrial production; the film made in prescription 10 (poly ethanol 4000) has good stripping property, which is unfavorable for cutting process; when 1,3 butanediol (prescription 8) or polyethylene glycol 400 (prescription 11) is used as a single plasticizer, the prepared film has transparent appearance and proper peeling property, but the toughness of the film is general; when glycerin (prescription 12) is adopted as a single plasticizer or glycerin and polyethylene glycol 400 (prescription 13) are adopted as mixed plasticizers in combination, the film forming property, toughness and peeling property of the oral dissolving film are all very excellent, and the product requirement and industrial production are met.
3. Disintegrating agent screening
Films were prepared according to the recipe of table 3 below, and the effect of the use of different disintegrants on disintegration time, film forming properties, toughness and peelability was examined.
Table 3 disintegrant screening prescriptions
The cross-linked sodium carboxymethyl cellulose (formula 14) is adopted as a disintegrating agent, the disintegration time limit of the prepared film reaches hundreds of seconds, and the carrier material is difficult to peel; sodium carboxymethyl starch (formula 15) is adopted as a disintegrating agent, and the prepared film has 100 seconds of disintegration time limit, less ideal toughness and easy stripping; the cross-linked povidone (formula 6) is adopted as the disintegrating agent, and the prepared membrane has transparent appearance, good toughness and proper stripping property, and the disintegration time limit is only 31 seconds, and all indexes meet the requirements. Microcrystalline cellulose was not used in formulation 16 and the resulting film had a disintegration time of 60s and a peeling property inferior to that of formulation 6. It can be seen that the combination of crospovidone and microcrystalline cellulose in the formulation accelerates the disintegration of the film.
The orosity of the present application is further illustrated by the following examples
Example 1
Prescription composition (1000 tablets)
| Raw and auxiliary material composition | Dosage (g) |
| Pramipexole dihydrochloride | 0.1 |
| Polyvinyl alcohol | 12.77 |
| Crosslinked povidone | 3 |
| Polyethylene glycol 400 | 2 |
| Glycerol | 1 |
| Sucralose | 0.1 |
| Orange essence | 1 |
| Sunset yellow | 0.03 |
| Unit film weight (total) | 20 |
Preparation process
(1) Heating polyvinyl alcohol in 100-130g of purified water to 75-85 ℃, stirring and dissolving, standing and cooling to room temperature to supplement volatilized water to obtain a solution I;
(2) Dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange essence into a solution I to obtain a solution II;
(3) Adding crospovidone and sunset yellow into the solution II, stirring and mixing uniformly to obtain matrix liquid III, vacuumizing to-0.05 Mpa-0.08 Mpa for degassing bubbles for more than 20 minutes, and controlling the solid content to be 15-20%;
(4) Coating the substrate liquid III by a coating machine, controlling the thickness of the coating wet 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: 1X 2cm 2 Controlling the deviation difference to +/-6%, and obtaining the finished product.
Example 2
Prescription composition (1000 tablets)
| Raw and auxiliary material composition | Dosage (g) |
| Pramipexole dihydrochloride | 0.25 |
| Polyvinyl alcohol-polyethylene glycol graft copolymer | 16 |
| Crosslinked povidone | 4 |
| Microcrystalline cellulose | 13 |
| Polyethylene glycol 400 | 3 |
| Glycerol | 2 |
| Sucralose | 0.11 |
| Orange essence | 1.6 |
| Sunset yellow | 0.04 |
| Unit film weight (total) | 40 |
Preparation process
(1) Heating the polyvinyl alcohol-polyethylene glycol graft copolymer to 75-85 ℃ in 160-200g of purified water, stirring and dissolving the polyvinyl alcohol-polyethylene glycol graft copolymer, standing and cooling the polyvinyl alcohol-polyethylene glycol graft copolymer to room temperature to supplement volatilized water to obtain a solution I;
(2) Dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange essence into a solution I to obtain a solution II;
(3) Adding crosslinked povidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain matrix liquid III, vacuumizing for more than 20 minutes under the conditions of-0.05 Mpa to-0.08 Mpa, and controlling the solid content to be 20-25%;
(4) Coating the substrate liquid III by a coating machine, controlling the thickness of the coating wet to be 150-200 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 multiplied by 3cm < 2 >, and controlling the deviation difference to +/-6%, thus obtaining the finished product.
Example 3
Prescription composition (1000 tablets)
Preparation process
(1) Heating polyvinyl alcohol in 200-240g of purified water to 75-85 ℃, stirring and dissolving, standing and 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 aroma in the solution I to obtain a solution II;
(3) Adding crospovidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain matrix liquid III, vacuumizing to-0.05 Mpa-0.08 Mpa for removing bubbles for more than 20 minutes, and controlling the solid content to 25-30%;
(4) Coating the substrate liquid III by a coating machine, controlling the coating wet 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: 2X 4cm 2 Controlling the deviation difference to +/-6%, and obtaining the finished product.
Example 4
Prescription composition (1000 tablets)
| Raw and auxiliary material composition | Dosage (g) |
| Pramipexole dihydrochloride | 0.75 |
| Polyvinyl alcohol-polyethylene glycol graft copolymer | 25 |
| Crosslinked povidone | 10 |
| Microcrystalline cellulose | 32 |
| PEG400 | 5 |
| Glycerol | 5 |
| Sucralose | 1.1 |
| Orange essence | 1.1 |
| Sunset yellow | 0.05 |
| 75 unit 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 and dissolving the polyvinyl alcohol-polyethylene glycol graft copolymer, standing and cooling the polyvinyl alcohol-polyethylene glycol graft copolymer to room temperature to supplement volatilized water to obtain a solution I;
(2) Dissolving a unit dose of pramipexole dihydrochloride raw material, polyethylene glycol 400, glycerol, sucralose and orange flavor into a solution I to obtain a solution II;
(3) Adding crospovidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain matrix liquid III, vacuumizing to-0.05 Mpa-0.08 Mpa for removing bubbles for more than 20 minutes, and controlling the solid content to be 30-40%;
(4) Coating the substrate liquid III by a coating machine, controlling the coating wet 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: 3X 4cm 2 Controlling the deviation difference to +/-6%, and obtaining the finished product.
Example 5
Prescription composition (1000 tablets)
| Raw and auxiliary material composition | Dosage (mg) |
| Pramipexole dihydrochloride | 1.25 |
| Polyvinyl alcohol | 30 |
| Crosslinked povidone | 8 |
| Microcrystalline cellulose | 41 |
| PEG400 | 10 |
| Glycerol | 6 |
| Sucralose | 2 |
| Orange essence | 1.67 |
| Sunset yellow | 0.08 |
| Unit film weight (total) | 100 |
Preparation process
(1) Heating polyvinyl alcohol in 220-250g of purified water to 75-85 ℃, stirring and dissolving, standing and cooling to room temperature to supplement volatilized water to obtain a solution I;
(2) Dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange aroma in the solution I to obtain a solution II;
(3) Adding crospovidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain matrix liquid III, vacuumizing to-0.05 Mpa-0.08 Mpa for removing bubbles for more than 20 minutes, and controlling the solid content to 40-45%;
(4) Coating the substrate liquid III by a coating machine, controlling the coating wet thickness to be 400-450um, 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 4cm 2 Controlling the deviation difference to +/-5%, and obtaining the finished product.
Example 6
Prescription composition (1000 tablets)
| Raw and auxiliary material composition | Dosage (g) |
| Pramipexole dihydrochloride | 1.5 |
| Polyvinyl alcohol-polyethylene glycol graft copolymer | 40 |
| Crosslinked povidone | 15 |
| Microcrystalline cellulose | 51 |
| PEG400 | 10 |
| Glycerol | 4 |
| Sucralose | 1.5 |
| Orange essence | 1.95 |
| Sunset yellow | 0.05 |
| Unit film weight (total) | 125 |
Preparation process
(1) Heating the polyvinyl alcohol-polyethylene glycol graft copolymer in 250-280g of purified water to 75-85 ℃, stirring and dissolving the polyvinyl alcohol-polyethylene glycol graft copolymer, standing and cooling the polyvinyl alcohol-polyethylene glycol graft copolymer to room temperature to supplement volatilized water to obtain a solution I;
(2) Dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange aroma in the solution I to obtain a solution II;
(3) Adding crospovidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain matrix liquid III, vacuumizing to-0.05 Mpa-0.08 Mpa for removing bubbles for more than 20 minutes, and controlling the solid content to be 45-50%;
(4) Coating the substrate liquid III by a coating machine, controlling the coating wet thickness to be 450-500um, 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 5cm 2 Controlling the deviation difference to +/-5%, and obtaining the finished product.
Example 7
Prescription composition (1000 tablets)
| Raw and auxiliary material composition | Dosage (g) |
| Pramipexole dihydrochloride | 2.5 |
| Polyvinyl alcohol | 50 |
| Crosslinked povidone | 10 |
| Microcrystalline cellulose | 57 |
| PEG400 | 8 |
| Glycerol | 4 |
| Sucralose | 2 |
| Orange essence | 1.45 |
| Sunset yellow | 0.05 |
| Unit film weight (total) | 135 |
Preparation process
(1) Heating polyvinyl alcohol in 245-300g of purified water to 75-85 ℃, stirring and dissolving, standing and 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 aroma in the solution I to obtain a solution II;
(3) Adding crospovidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain matrix liquid III, vacuumizing to-0.05 Mpa-0.08 Mpa for removing bubbles for more than 20 minutes, and controlling the solid content to 45-55%;
(4) Coating the substrate liquid III by a coating machine, controlling the coating wet thickness to be 450-550um, and drying and rolling at 60-75 ℃;
(5) Cutting the rolled film agent, wherein the cutting width of the film agent is as follows: 4X 4cm 2 Controlling the deviation difference to +/-6%, and obtaining the finished product.
Example 8
Prescription composition (1000 tablets)
Preparation process
(1) Heating the polyvinyl alcohol-polyethylene glycol graft copolymer in 250-300g of purified water to 75-85 ℃, stirring and dissolving the polyvinyl alcohol-polyethylene glycol graft copolymer, standing and cooling the polyvinyl alcohol-polyethylene glycol graft copolymer to room temperature to supplement volatilized water to obtain a solution I;
(2) Dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange aroma in the solution I to obtain a solution II;
(3) Adding crospovidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain matrix liquid III, vacuumizing to-0.05 Mpa-0.08 Mpa for removing bubbles for more than 20 minutes, and controlling the solid content to be 50-60%;
(4) Coating the substrate liquid III by a coating machine, controlling the thickness of the coating wet to be 500-600um, and drying and rolling at 60-75 ℃;
(5) Cutting the rolled film agent, wherein the cutting width of the film agent is as follows: 4X 5cm 2 Controlling the deviation difference to +/-6%, and obtaining the finished product.
Example 9
Prescription composition (1000 tablets)
| Raw and auxiliary material composition | Dosage (g) |
| Pramipexole dihydrochloride | 4.5 |
| Polyvinyl alcohol | 23 |
| Crosslinked povidone | 5 |
| MicrocrystalCellulose | 100 |
| PEG400 | 9.45 |
| Glycerol | 4 |
| Sucralose | 2 |
| Orange essence | 2 |
| Sunset yellow | 0.05 |
| Unit film weight (total) | 150 |
Preparation process
(1) Heating polyvinyl alcohol in 300-330g of purified water to 75-85 ℃, stirring and dissolving, standing and 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 aroma in the solution I to obtain a solution II;
(3) Adding crospovidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain matrix liquid III, vacuumizing to-0.05 Mpa-0.08 Mpa for removing bubbles for more than 20 minutes, and controlling the solid content to 15-60%;
(4) Coating the substrate liquid III by a coating machine, controlling the thickness of the coating wet to be 500-600um, and drying and rolling at 60-75 ℃;
(5) Cutting the rolled film agent, wherein the cutting width of the film agent is as follows: 4X 5cm 2 Controlling deviation and weight differenceAnd (5) obtaining the finished product by +/-6 percent.
Example 10
1) Prescription composition (1000 tablets)
| Raw and auxiliary material composition | Dosage (g) |
| Pramipexole dihydrochloride | 5 |
| Polyvinyl alcohol-polyethylene glycol graft copolymer | 6 |
| Crosslinked povidone | 3 |
| Microcrystalline cellulose | 1.45 |
| PEG400 | 2 |
| Glycerol | 1 |
| Sucralose | 0.5 |
| Orange essence | 1 |
| Sunset yellow | 0.05 |
| Unit film weight (total) | 20 |
2) Preparation process
(1) Heating the polyvinyl alcohol-polyethylene glycol graft copolymer in 60-70g of purified water to 75-85 ℃, stirring and dissolving the polyvinyl alcohol-polyethylene glycol graft copolymer, standing and cooling the polyvinyl alcohol-polyethylene glycol graft copolymer to room temperature to supplement volatilized water to obtain a solution I;
(2) Dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange aroma in the solution I to obtain a solution II;
(3) Adding crospovidone, microcrystalline cellulose and sunset yellow into the solution II, stirring and mixing uniformly to obtain matrix liquid III, vacuumizing to-0.05 Mpa-0.08 Mpa for removing bubbles for more than 20 minutes, and controlling the solid content to be 30-35%;
(4) Coating the substrate liquid III by a coating machine, controlling the thickness of the coating wet to be 200-300um, and drying and rolling at 60-75 ℃;
(5) Cutting the rolled film agent, wherein the cutting width of the film agent is as follows: 2X 3cm 2 Controlling the deviation difference to +/-6%, and obtaining the finished product.
Comparative example 1 pramipexole dihydrochloride orally disintegrating tablets
1) Prescription composition (1000 tablets)
| Raw and auxiliary material composition | Dosage (g) |
| Pramipexole dihydrochloride | 0.5 |
| Lactose and lactose | 100 |
| Microcrystalline cellulose | 49.6 |
| Low substituted hydroxypropyl cellulose | 39.9 |
| Stevioside (stevioside) | 5 |
| Talc powder | 4 |
| Unit piece weight (in total) | 199 |
2) Preparation method
(1) Pulverizing pramipexole dihydrochloride as main medicine, sieving with 100 mesh sieve, and sieving lactose and microcrystalline cellulose with 100 mesh sieve respectively for use;
(2) Mixing the main medicine with lactose 4 times of the main medicine, sieving with a 50 mesh sieve for 2 times, adding 45g lactose for mixing, and finally adding the rest lactose and microcrystalline cellulose for mixing;
(3) Adding low-substituted hydroxypropyl cellulose, stevioside, and pulvis Talci into the above (2), and mixing;
(4) Tabletting, wherein the hardness is controlled within 30-40N.
Comparative example 2 pramipexole dihydrochloride capsules
1) Prescription composition (1000 tablets)
2) Preparation process
(1) Mannitol, starch and polylactic acid are sieved by a 80-mesh sieve according to a prescription and then uniformly mixed to obtain mixed powder;
(2) Adding povidone k30 into the aqueous solution, dissolving, and then adding pramipexole dihydrochloride to dissolve to obtain an adhesive solution;
(3) Adding the adhesive solution in the step (2) into the mixed powder in the step (1), sieving by a wet method, and granulating;
(4) Drying the wet particles in the step (3) at 55-60 ℃ for 3 hours;
(5) Taking dried particles, adding silicon dioxide and magnesium stearate, and uniformly mixing;
(6) And (5) filling the capsules to obtain the finished product.
Experimental example 1 determination of physical Properties of film products of the application
1. Measurement method
(1) Strippability of
After drying of the film, the film was peeled off easily from the coated carrier material PET (i.e., mylar). The film was gently peeled off by hand from 40mm by 50mm film, and the degree of peeling difficulty was evaluated.
(2) Tensile Strength and elongation
The prepared pramipexole dihydrochloride oral solution film is cut into strips with the size of 20mmx 5mm, the strips are measured by a universal DE material tester at the speed of 50mm.min < -1 >, the tensile stress and the tensile length when the oral solution film is longitudinally stretched to fracture are recorded, and the measurement is repeated for 3 times. The tensile strength and elongation were calculated according to the formula: tensile Strength (N.mm) -2 ) =tensile stress/cross-sectional area; extension (%) =stretched length/initial length x100%.
(3) Folding endurance
Taking 10x 20mm pramipexole dihydrochloride oral solution films with proper size, manually repeatedly folding the same position until the pramipexole dihydrochloride oral solution films are broken, recording folding times, and evaluating the folding resistance of the oral solution films.
2. Measurement results
In the embodiment 1 to the embodiment 10 of the application, the appearance property, the peeling property, the tensile strength, the ductility and the folding endurance are all good, and the requirements of the film agent are met.
Table 4 example oral film sample mass measurement results
| Appearance characteristics | Strippability of | Tensile Strength | Extensibility rate | Folding endurance | Comprehensive evaluation | |
| Example 1 | Has smooth appearance and good film forming property | Is easy to be peeled from PET film | 6.82±0.32 | 24.2±1.6 | 208±2 | 1 |
| Example 2 | Has smooth appearance and good film forming property | Is easy to be peeled 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 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 PET film | 8.82±0.23 | 28.4±1.8 | 241±2 | 2 |
| Example 5 | Has smooth appearance and good film forming property | Is easy to be peeled from PET film | 9.32±0.45 | 32.7±2.3 | 255±3 | 4 |
| EXAMPLE 6 | Has smooth appearance and good film forming property | Is easy to be peeled 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 PET film | 7.25±0.14 | 23.3±1.5 | 212±2 | 1 |
| Example 8 | Has smooth appearance and good film forming property | Is easy to be peeled from PET film | 8.35±0.22 | 26.4±1.9 | 245±2 | 2 |
| Example 9 | Has smooth appearance and good film forming property | Is easy to be peeled from PET film | 9.81±0.42 | 33.3±1.2 | 260±2 | 4 |
| Example 10 | Has smooth appearance and good film forming property | Is easy to be peeled from PET film | 9.55±0.21 | 30.5±1.7 | 253±3 | 4 |
Note that: the score is integrated by the score, and the higher the score is, the more excellent the comprehensive index is.
Release properties: easy stripping is superior to strippable.
Experimental example 2 quality comparison of inventive film products with comparative example products
1. Measurement method
(1) Content determination
High performance liquid chromatography (appendix of China pharmacopoeia 2015 edition II), chromatographic conditions: octadecyl bonded silica gel is used as a filler, 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 lower than 2000 calculated according to pramipexole dihydrochloride peak. And calculating according to an external standard method and peak area to obtain the product.
(2) Content uniformity determination
According to the inspection of the content uniformity of the second appendix of 2015 edition of Chinese pharmacopoeia, 10 tablets of the product are taken, respectively placed in 25ml measuring flask, a proper amount of phosphate buffer is added, the mixture is shaken to disintegrate, and then the mixture is shaken for 15 minutes to dissolve pramipexole dihydrochloride, the mixture is diluted to a scale by using phosphate buffer, and the mixture is shaken uniformly and centrifuged, and the supernatant is taken as a solution of the product to be tested. And (3) measuring according to a method under the content measuring item, calculating the content of each tablet, calculating the relative content X of each tablet with the marked amount of 100%, and calculating the average value and standard deviation S of each tablet and the absolute value A of the difference between the marked content and the average 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 formulation was placed in a beaker containing 50ml of phosphate buffer at pH6.8, temperature (37.+ -. 0.5) C, gently shaken and the time to dissolve and collapse(s) was recorded.
(4) Dissolution measurement
Taking the sample, taking 100ml of citrate/phosphate buffer (pH 6.8) as a dissolution medium according to a dissolution rate measurement method (second method of second appendix of 2015 edition of Chinese pharmacopoeia), operating at 50rpm according to a law, taking a proper amount of solution when the sample is subjected to 5min, 10min, 20min and 30min, and filtering to obtain a subsequent filtrate as a sample solution; and precisely weighing appropriate amount of pramipexole dihydrochloride reference substance to prepare a solution containing 10.0ug per 1ml as reference substance solution. The content was measured by the content measuring method, and the elution amount of each tablet was calculated.
(5) Related substance measurement
Taking a pramipexole dihydrochloride preparation 1 tablet, adding a proper amount of phosphate buffer (pH 3.0), shaking to disintegrate, shaking for 15 minutes to dissolve pramipexole dihydrochloride, shaking uniformly, centrifuging, and taking a proper amount of supernatant as a sample solution; the method adopts a chromatographic column with octadecyl bonded silica gel as a filler, takes 0.1mol/L ammonium acetate (pH 5.0, containing 0.1 percent of triethylamine) -methanol (98:2) as a mobile phase A, takes methanol as a mobile phase B, carries out gradient elution, and has the detection wavelength of 264nm and the column temperature of 40 ℃ and the flow rate of 1.0m L/min; the content of the related substances is calculated according to an area normalization method.
2.0 day measurement results
The oral films prepared in the examples 1-10 have no obvious difference from the comparative examples in content and related substances, and meet the requirements; the content uniformity is slightly better than that of comparative example 1 and comparative example 2, the disintegration time limit is not more than 35 seconds, the content uniformity is obviously better than that of orally disintegrating tablets of comparative example 1, and the content uniformity is better than that of capsules of comparative example 2. In addition, the dissolution of the oral dissolving film is very rapid, namely more than 90% in 5 minutes, which is far faster than the gastric emptying speed, basically corresponds to the solution, and can rapidly promote the release, absorption and effect of the medicine.
TABLE 50 day mass measurement of orosol film samples according to the examples of the application
3. Stability (6 months of accelerated test) measurement results
Samples of the application and samples 1 and 2 of the comparative examples were placed at 40℃and 75% RH, respectively, and after 6 months, samples were taken to examine the quality change. The results are shown in the following table.
The results show that after the samples of the examples of the application 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 prolonged, and the dissolution rate is obviously slowed down, which is unfavorable for the dissolution of the main drug.
TABLE 6 results of 6 month quality inspection of the acceleration test of orosol film samples according to the examples of the present application
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Claims (10)
1. The pramipexole dihydrochloride oral dissolved film comprises the following components:
the film forming material is selected from one or more of polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer; the plasticizer is selected from glycerol or a mixture of polyethylene glycol 400 and glycerol; the disintegrating agent is crospovidone.
2. The orosol film according to claim 1, wherein the film-forming material is polyvinyl alcohol or a polyvinyl alcohol-polyethylene glycol graft copolymer.
3. The orosol film of claim 1, wherein the plasticizer is a mixture of polyethylene glycol 400 and glycerin.
4. The orosol film of claim 1, the filler being microcrystalline cellulose.
5. The orosol film according to claim 1, comprising pramipexole hydrochloride 0.1-5 parts, polyvinyl alcohol 5-60 parts or polyvinyl alcohol-polyethylene glycol graft copolymer 5-60 parts, crospovidone 3-15 parts, microcrystalline cellulose 0-100 parts, polyethylene glycol 400-12 parts, and glycerin 1-6 parts.
6. The orosol film according to claim 5, comprising pramipexole hydrochloride 0.1-5 parts, polyvinyl alcohol 20-40 parts or polyvinyl alcohol-polyethylene glycol graft copolymer 20-40 parts, crospovidone 3-15 parts, microcrystalline cellulose 0-100 parts, polyethylene glycol 400-12 parts, and glycerin 1-6 parts.
7. The orosol film according to any one of claims 1-6, further comprising a flavouring agent selected from sucralose and orange flavour and/or a colouring agent which is tartrazine.
8. The orosol film according to claim 7, comprising 0.1-2 parts of sucralose, 1-2 parts of orange essence, and 0.03-0.08 parts of sunset yellow.
9. A method of preparing the orosol film of claim 8, comprising the steps of:
(1) Heating polyvinyl alcohol or polyvinyl alcohol-polyethylene glycol graft copolymer in purified water to 75-85 ℃, stirring and dissolving, standing and cooling to room temperature to supplement volatilized water to obtain solution I;
(2) Dissolving pramipexole dihydrochloride, polyethylene glycol 400, glycerol, sucralose and orange essence into a solution I to obtain a solution II;
(3) Adding crosslinked povidone, microcrystalline cellulose and sunset yellow into the solution II, and stirring and mixing uniformly to obtain a matrix solution III;
(4) Coating the matrix liquid III by using a coating machine, and drying and rolling at 60-75 ℃;
(5) Cutting the winding film agent, and controlling the deviation difference within +/-6% to obtain a finished product.
10. The method of claim 9, further comprising evacuating the bubble operation, the vacuum being controlled at-0.05 Mpa to-0.08 Mpa.
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| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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