CN108403668B - Valsartan orally disintegrating film and preparation method thereof - Google Patents
Valsartan orally disintegrating film and preparation method thereof Download PDFInfo
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- CN108403668B CN108403668B CN201710072235.5A CN201710072235A CN108403668B CN 108403668 B CN108403668 B CN 108403668B CN 201710072235 A CN201710072235 A CN 201710072235A CN 108403668 B CN108403668 B CN 108403668B
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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
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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
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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
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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
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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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
Abstract
The invention provides a valsartan orally disintegrating film for treating hypertension and a preparation method thereof. The valsartan orally disintegrating film is prepared from specific film forming materials, so that the stability of the medicine is good, the disintegration and the dissolution are fast, and unexpected effects are achieved. The valsartan orally disintegrating film has high dissolution rate, quick drug effect, good drug stability, convenient carrying and taking, simple production process, easy packaging, transportation, storage and the like.
Description
Technical Field
The invention provides a Valsartan (Valsartan) oral disintegrating film agent for treating hypertension and a preparation method thereof. Belongs to the technical field of pharmacy.
Background
Hypertension is one of the most common cardiovascular diseases in the world today and is the leading cause of death and disability in adults. Along with social progress, the living standard of people is increasingly improved, and the work rhythm is continuously accelerated, the number of people suffering from hypertension is greatly increased. The prevalence rate of hypertension in China is obviously increased, and statistics data in China show that the incidence rate of hypertension in the people of thirty-five to seventy-four years old in China is as high as about 27 percent, the number of patients is approximately one hundred million and thirty million, and the patients grow at a speed of more than three million every year, so that China becomes the country with the most serious harm to hypertension. Hypertension can cause damage to organs such as heart, brain, kidney and the like, and seriously threatens human health.
Valsartan is a new generation of high-efficiency antihypertensive drug developed and developed by Nowa company, is firstly applied to European countries such as Germany in 1996, is marketed in China in 1998, and is marketed in more than 70 countries in the world at present. Valsartan, chemical name: N-valeryl-N- [ [2' - (1H-tetrazole-5-yl) biphenyl-4-yl ] methyl ] -L-valine is a non-peptide angiotensin II (ATII) receptor antagonist, is used for treating light and medium essential hypertension, and has the advantages of brand new blood pressure reducing mechanism, stable blood pressure reduction, strong curative effect, long action time, good tolerance of patients and the like.
At present, the valsartan medicament clinically applied is a tablet and a capsule. Due to the limitation of the production process of the conventional preparation, the oral preparation has the defects of long disintegration time, poor absorption, slow effect, low bioavailability and the like, thereby influencing the exertion of the drug effect. The problems of unstable quality such as splintering, moisture absorption and discoloration easily occur during storage and carrying. And also difficult to adapt to patients with difficulty in swallowing.
The oral disintegrating film agent can be taken sublingually or buccally under anhydrous condition, is convenient to carry and take, and is especially suitable for patients with dysphagia. However, in the preparation of the film agent by using the valsartan, the valsartan is easy to rapidly settle in the preparation of slurry, the stability of the slurry cannot meet the requirement of the preparation of the film agent, and the prepared film agent is slow in disintegration and dissolution and has influence on the drug effect.
Disclosure of Invention
The invention aims to provide a component suitable for preparing a valsartan orally-dissolving film agent, in particular a film-forming material formula suitable for preparing a valsartan orally-disintegrating film, and further provides a stable valsartan orally-disintegrating film with quick disintegration and dissolution and a preparation method thereof.
The technical scheme of the invention is as follows:
the invention provides a valsartan oral disintegrating film for treating hypertension, which contains valsartan and a film forming material and is characterized in that the film forming material is a combination of pullulan and polyvinyl alcohol.
In the above-mentioned valsartan orally disintegrating film, the combination ratio of pullulan and polyvinyl alcohol is not particularly limited, and a suitable combination may be used. Preferably, the weight ratio of pullulan to polyvinyl alcohol is (1-10): 1-10), more preferably (1-5): 1-5), and particularly preferably (2: 1).
The valsartan orally disintegrating film may further comprise one or more of a plasticizer, a flavoring agent, a coloring agent and a flavoring agent. Wherein:
the plasticizer can be a pharmaceutically common pharmaceutical adjuvant used as a film plasticizer, such as one or more selected from polyethylene glycol (PEG), glycerol and triethyl citrate; preferably, the plasticizer is glycerol.
The flavoring agent can be one or more of pharmaceutical adjuvants commonly used as flavoring agent, such as sucralose, aspartame, mannitol, and saccharin.
The colorant or the aromatic can be a pharmaceutical adjuvant which is commonly used as a colorant in pharmacy, such as blue pigment and the like. The aromatic can be a pharmaceutically common pharmaceutical adjuvant used as an aromatic, such as orange essence and the like.
As a specific embodiment, the valsartan orally disintegrating film is characterized by comprising the following active ingredients and auxiliary materials in percentage by weight: 15-40% of valsartan, 10-30% of a film forming material, 0.1-5% of a plasticizer, 0.01-10% of a flavoring agent, 0.01-1% of an aromatic and 0.01-1% of a coloring agent.
Preferably, the valsartan orally disintegrating film described above is characterized by being prepared by a method comprising the following slurry formulation steps: firstly, mixing a solvent and a plasticizer, homogenizing uniformly, then adding a flavoring agent, continuing homogenizing uniformly, then adding valsartan, continuing homogenizing uniformly, then adding a film-forming material, continuing homogenizing uniformly, and finally adding an aromatic and/or a coloring agent, continuing homogenizing uniformly.
The valsartan orally disintegrating film can be prepared by using a solvent, such as an ethanol solution, and preferably an ethanol solution with the weight ratio of ethanol to water of 1: 1-1: 4.
In the valsartan oral disintegrating film, the particle size D90 of the valsartan raw material medicament is controlled to be less than 5 mu m.
As another object of the present invention, there is also provided a method for preparing the above-mentioned valsartan orally disintegrating film, comprising the steps of:
(1) crushing the raw material medicines: valsartan raw material medicine is crushed, and the particle size D90 is controlled below 5 mu m;
(2) homogenizing and preparing raw materials and auxiliary materials: firstly, mixing a solvent and a plasticizer, homogenizing uniformly, then adding a flavoring agent, continuing homogenizing uniformly, then adding valsartan, continuing homogenizing uniformly, then adding a film-forming material, continuing homogenizing uniformly, and finally adding an aromatic and/or a coloring agent, continuing homogenizing uniformly;
(3) coating, drying, cutting and packaging.
The above preparation method, wherein the homogeneous preparation of the raw and auxiliary materials is preferably homogeneous stirring at normal temperature to 30 ℃, and preferably, the bubbles are removed by vacuum.
As a specific embodiment of the present invention, there is provided the above-mentioned valsartan orally disintegrating film, which is characterized in that the orally disintegrating film is prepared from the following active ingredients and adjuvants in percentage by weight:
the valsartan orally disintegrating film can be prepared by the following method:
firstly, processing raw material medicines; homogenizing and emulsifying; thirdly, coating and drying; cutting and coiling; and fifthly, packaging.
Firstly, the treatment of raw material medicine
The valsartan bulk drug is mechanically crushed and then is crushed by air flow, and the particle size (D90) is controlled to be below 10 mu m.
② homogenizing and emulsifying process
The temperature of the water bath is set to be 30 ℃, the purified water, the ethanol and the plasticizer with the prescription amount are added into a homogenizing pot, and the homogenizing and the stirring are carried out uniformly (3000 rpm).
Slowly adding correctant, setting homogenizing temperature at 25 deg.C, homogenizing speed at 3500rpm, lowering cover, homogenizing and stirring for 30min, determining whether it is dissolved completely, or else, homogenizing, and vacuum degassing for about 20min to clarify the solution.
Lifting the cover, slowly adding the processed raw material valsartan, homogenizing at 3500rpm for about 30min, lowering the cover, continuing homogenizing and stirring for 30min, observing the dissolution and dispersion conditions, and properly prolonging the homogenizing time.
Removing bubbles in vacuum for about 30min, lifting the pot cover, slowly and gradually adding film-forming materials while homogenizing at a homogenizing speed of 3500rpm, putting down the pot cover, homogenizing and stirring for 1 hr (4000rpm)
The fragrance and colorant were poured from the viewing port and homogenization continued for 1-1.5 hours (4500rpm) depending on the mixing dispersion.
Manually removing bubbles in vacuum at pressure of 0.06-0.1bar for about 30-60 min, slowly stirring, and naturally degassing at low pressure overnight.
③ coating and drying process
Cutting and coiling
Fifthly, packaging
The invention mainly achieves the technical effects that:
in the development of the valsartan orally disintegrating film, for film forming materials, a single film forming material, such as pullulan, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose and the like, or a combination of several other film forming materials except the combination of pullulan and polyvinyl alcohol, is difficult to be used as a suitable material of the valsartan orally disintegrating film, and inevitable defects are as follows: 1. the film forming property is poor, and the film is easy to break after being dried; 2. the tackiness is too strong, resulting in adhesive tearing during peeling of the package; 3. the stability of the solution is poor, the main drug component valsartan is settled in the long-time standing process, and especially in the longer process of coating, the content uniformity can not meet the requirement directly; 4. slow disintegration and dissolution and slow effect.
The invention surprisingly finds through a great deal of experiments that the combined formula of the pullulan and the polyvinyl alcohol is used as a film forming material of the valsartan, solves all the problems, particularly has a very obvious improvement effect on the sedimentation problem of the main drug component of the valsartan, contributes to improving the stability of the solution, adopts coating and drying as a step with the longest time in the whole process flow, comprises a complete and continuous process of coating and drying, particularly has longer time consumption in industrial production, and has the advantages that in order to ensure the uniform content of the solution, the solution must be fully and uniformly mixed and degassed before being conveyed to a coating blade, and any vibration or stirring in the coating process can bring air bubbles to influence the uniform integrity of the coated film material, so that a very high requirement is provided for the long-term standing stability of the solution. The film material prescription adopted by the invention improves the stability of the solution, and then the content uniformity of the preparation is greatly improved, the requirement on time is relaxed, and the preparation has obvious practical significance for industrial production application. Meanwhile, the valsartan orally disintegrating film has the unexpected technical effects that the film forming material combination provided by the invention can be used for preparing the valsartan orally disintegrating film which is fast in disintegration and dissolution, fast in drug dissolution, high in dissolution rate and fast in effect.
In the invention, the valsartan raw material and the film forming auxiliary material are mixed and homogenized in a solution state, so that the medicament is dispersed in the film forming material in a molecular state or an extremely fine crystal state, the absorption by a human body is facilitated, the medicament effect is quickly exerted, the bioavailability is improved, the side effect is reduced, and the valsartan oral liquid is safe and reliable. The oral disintegrating film agent can be taken sublingually or buccally under anhydrous condition, is convenient to carry and take, and provides a new medicine selection for dysphagia patients. After the valsartan oral disintegrating film is orally taken, the film is rapidly melted after being contacted with saliva, and the medicament can be directly absorbed through oral mucosa and directly enters a circulatory system without passing through gastrointestinal tracts and liver, so that the first-pass effect of liver is avoided, the effect is rapidly achieved, the bioavailability is improved, and the side effect is reduced.
The valsartan orally disintegrating film has good drug stability and is convenient to carry and take. After the preparation is finished, the preparation can be packaged by an aluminum bag, external air and water vapor are completely blocked, the preparation is not easy to oxidize, the water content of the preparation is strictly controlled after a drying process, the medicine is not easy to hydrolyze, the stability of the medicine is improved, and the quality of the medicine is ensured. The size of single oral disintegrating film piece is 7.5cm2-10cm2The weight of the aluminum bag is added, the single piece is 1.2g-1.8g, the carrying is very convenient, and the aluminum bag can be directly taken without water.
Drawings
FIG. 1: comparison of stability of homogeneous sample of single film-forming material and composite film material
FIG. 2: comparison of the dissolution curves with reference preparations (pH1.2 hydrochloric acid solution)
FIG. 3: comparison of the dissolution curves with reference preparations (pH4.0 acetate buffer)
FIG. 4: comparison of the dissolution curves with the reference preparation (pH6.8 phosphate buffer)
FIG. 5: comparison of dissolution curves with reference formulation (water)
Detailed description of the preferred embodiments
The present invention is further illustrated by the following examples, but the scope of the present invention is not limited by the examples.
Example 1
Prescription:
the preparation method comprises the following steps:
treatment of the herbs
The valsartan bulk drug is mechanically crushed and then is crushed by air flow, and the particle size (D90) is controlled below 5 mu m.
② homogenizing and emulsifying process
The temperature of the water bath was set at 30 ℃, and 222.45g of purified water, 74.15g of ethanol and 5g of plasticizer were added in the prescribed amount to a homogenizer pan, and homogenized by stirring (3000 rpm).
Slowly adding 22g correctant, setting homogenizing temperature at 25 deg.C, homogenizing speed at 3500rpm, lowering cover, stirring for 30min, determining whether it is dissolved completely, or else, homogenizing, and vacuum degassing for about 20min until the solution is clear.
Lifting the cover, slowly adding 100g of the processed valsartan raw material, homogenizing at 3500rpm for about 30min, lowering the cover, continuing homogenizing and stirring for 30min, and observing the dissolution and dispersion conditions, wherein the homogenizing time can be properly prolonged.
Removing bubbles in vacuum for about 30min, lifting the pot cover, slowly and gradually adding film-forming materials (pullulan 50g, polyvinyl alcohol 25g) while homogenizing, homogenizing at 3500rpm, putting down the pot cover, homogenizing and stirring for 1 hr (4000rpm)
0.4g of an aromatic agent and 1g of a coloring agent were poured from a viewing port, and the mixture was further homogenized for 1 to 1.5 hours (4500rpm) depending on the mixing dispersion.
Manually removing bubbles in vacuum for about 30-60 min, slowly stirring, and naturally degassing overnight.
③ coating and drying process
Cutting and coiling
Fifthly, packaging (40 mg/tablet)
The packaging specification is 40 mg/tablet, and the area of each single piece is 7.5cm2。
Example 2
Prescription:
the preparation method comprises the following steps:
the preparation process was carried out as described in example 1, with a packaging specification of 80 mg/tablet and a 10cm area of the individual pieces2。
Test example 1: test of orally disintegrating film-Forming Material
1. The stability of the solution (example 1) of the film forming material prepared by the combination of pullulan and polyvinyl alcohol in the invention is compared with that of the solution of a single film forming material (the film forming material in the formula is 75g of single pullulan, and the rest is the same as that in example 1), the same preparation method is adopted, and the observation phenomenon is shown in the attached figure 1 after standing for 24 hours. The mixed homogeneous solution using pullulan alone as a film forming material showed a delamination phenomenon after 24 hours of standing, while the solution of example 1 was stable and showed no delamination after a long period of standing.
2. A series of film agents with different materials and composition ratios are prepared, in a formula 1-10, according to weight percentage, the content of a film forming material is 15%, the content of valsartan is 20%, glycerol is 1%, mannitol is 4%, sucralose is 0.4%, orange essence is 0.08%, blue pigment is 0.2%, ethanol is 14.83%, and water is 44.49%, film agent disintegration experiments are carried out, and disintegration time limit experiment results are shown in the following table.
| Film-forming material composition (weight ratio) | Disintegration time(s) | |
| Prescription 1 | 15 percent of hydroxypropyl methylcellulose | 452 |
| Prescription 2 | Polyvinyl alcohol 15% | 93 |
| Prescription 3 | 15 percent of polyvinylpyrrolidone | 97 |
| Prescription 4 | Pullulan 15% | 54 |
| Prescription 5 | 7.5% Pullulan + 7.5% hypromellose (1: 1) | 228 |
| Prescription 6 | 7.5% Pullulan + 7.5% polyvinylpyrrolidone (1: 1) | 73 |
| Prescription 7 | 7.5% Pullulan + 7.5% polyvinyl alcohol (1: 1) | 41 |
| Prescription 8 | 10% pullulan + 5% polyvinyl alcohol (2: 1) | 6 |
| Prescription 9 | 5% Pullulan + 10% polyvinyl alcohol (1: 2) | 34 |
| |
12% pullulan + 3% polyvinyl alcohol (4: 1) | 49 |
According to the experimental results, the pullulan disintegrating effect is the best when the film forming material is singly used for preparation, but the solution stability of the pullulan as the film forming material cannot meet the preparation requirement of the film agent, and the combination of the pullulan and the polyvinyl alcohol as the film forming material of the valsartan oral disintegrating film has the advantages of fast film agent disintegration and dissolution, good solution stability, film agent preparation and preparation requirements and unexpected effect.
Test example 2: reference formulation dissolution curve comparative test
In vitro dissolution comparison experiments were performed on the present invention (sample prepared in example 1) and the original research reference formulation (DIOVAN, Beijing Nowa pharmaceutical Co., Ltd.). Release profile measurements were performed on 3 batches of the valsartan orally disintegrating film and the reference formulation continuously prepared in example 1 under the conditions of a ph1.2 hydrochloric acid solution, a ph4.0 acetate buffer, a ph6.8 phosphate buffer and water, respectively. The results are shown in FIGS. 2-5, where the upper curve in FIGS. 2-5 is the oro-dissolution membrane of example 1 and the lower curve is the reference formulation. The result shows that the valsartan orally disintegrating film of the invention is dissolved more rapidly in four mediums compared with the original preparation, can achieve Cmax in a shorter time in vivo and has quicker effect.
Test example 3: reference formulation disintegration comparative test
Disintegration time-limit comparison experiments were carried out on the invention (samples prepared in examples 1 and 2) with the original research reference formulation (DIOVAN, Beijing Nowa pharmaceutical Co., Ltd.). The disintegration experiment device adopts a lifting disintegration tester, and has the main structure that a lifting metal support and a hanging basket with a screen embedded at the lower end are provided with baffles. The up-down moving distance of the lifting metal support is 55mm +/-2 mm, and the reciprocating frequency is 30-32 times per minute. During the experiment, 6 parts of each sample are respectively placed in a hanging basket glass tube, a transparent baffle is placed according to the requirement, a disintegration tester is started to check, the disintegration phenomenon is observed, and the disintegration time is recorded. The results are shown in the table below, and it can be seen that the orally disintegrating film disintegrates much faster than the capsule, and that the rapid disintegration is advantageous for the improvement of the dissolution rate.
Test example 4: oral absorption test
To confirm that the valsartan orally disintegrating film of the present invention was also absorbed by the human body in the oral cavity, 10 healthy adults, 5 men and 5 women were selected, and orally administered an orally disintegrating film containing 40mg of valsartan (sample prepared in example 1). After swallowing is not carried out within 1 minute, the residues in the mouth are completely spit out by rinsing with water, collected in a unified container, and the content of the valsartan in the container is measured, and the result shows that only about 70-78% of the total amount of the taken medicine can be recovered, which means that 22-30% of the taken medicine is absorbed by oral mucosa. The data are shown in the following table.
Claims (10)
1. The valsartan oral disintegrating film for treating hypertension contains valsartan and a film forming material, and is characterized in that the film forming material is a combination of pullulan and polyvinyl alcohol, and the weight ratio of the pullulan to the polyvinyl alcohol is (1-5) to (1-5).
2. The valsartan orally disintegrating film of claim 1 further comprising one or more of a plasticizer, a flavoring agent, a coloring agent, a fragrance.
3. The valsartan orally disintegrating film of claim 2, wherein the plasticizer is selected from one or more of polyethylene glycol (PEG), glycerol or triethyl citrate; the flavoring agent is one or more of sucralose, aspartame, mannitol or saccharin.
4. The valsartan orally disintegrating film according to claim 2, comprising the following active ingredients and excipients in weight ratio: 15-40% of valsartan, 10-30% of a film forming material, 0.1-5% of a plasticizer, 0.01-10% of a flavoring agent, 0.01-1% of an aromatic and 0.01-1% of a coloring agent.
5. The valsartan orally disintegrating film according to claim 4, characterized by being produced by a process comprising the steps of: firstly, mixing a solvent and a plasticizer, homogenizing uniformly, then adding a flavoring agent, continuing homogenizing uniformly, then adding valsartan, continuing homogenizing uniformly, then adding a film-forming material, continuing homogenizing uniformly, and finally adding an aromatic and/or a coloring agent, continuing homogenizing uniformly.
6. The valsartan orally disintegrating film of claim 5 wherein the solvent is an ethanol solution.
7. The valsartan orally disintegrating film according to claim 6, wherein the solvent is an ethanol solution with a weight ratio of ethanol to water of 1:1 to 1: 4.
8. The valsartan orally disintegrating film according to any one of claims 1 to 7, wherein the particle size D90 of the valsartan drug substance is controlled to be less than 5 μm.
9. A method for preparing a valsartan orally disintegrating film as claimed in any one of claims 1 to 8, comprising the steps of: (1) crushing the raw material medicines: valsartan raw material medicine is crushed, and the particle size D90 is controlled below 5 mu m; (2) homogenizing and preparing raw materials and auxiliary materials: firstly, mixing a solvent and a plasticizer, homogenizing uniformly, then adding a flavoring agent, continuing homogenizing uniformly, then adding valsartan, continuing homogenizing uniformly, then adding a film-forming material, continuing homogenizing uniformly, and finally adding an aromatic and/or a coloring agent, continuing homogenizing uniformly; (3) coating, drying, cutting and packaging.
10. The preparation method according to claim 9, wherein the homogeneous preparation of the raw and auxiliary materials is carried out by stirring at room temperature to 30 ℃ and removing bubbles by vacuum degassing.
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| CN102333526A (en) * | 2009-06-25 | 2012-01-25 | Cha生物&Diostech株式会社 | Fast-dissolving oral film for effectively concealing unpleasant tastes |
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| CN105581988A (en) * | 2014-11-12 | 2016-05-18 | 天津汉瑞药业有限公司 | Orally disintegrating tablet containing valsartan |
| CN105769825A (en) * | 2014-12-24 | 2016-07-20 | 广州朗圣药业有限公司 | Oral film and preparation method of montelukast sodium |
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