CN106344604B - Compound gentamicin film preparation technique - Google Patents
Compound gentamicin film preparation technique Download PDFInfo
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- CN106344604B CN106344604B CN201610742934.1A CN201610742934A CN106344604B CN 106344604 B CN106344604 B CN 106344604B CN 201610742934 A CN201610742934 A CN 201610742934A CN 106344604 B CN106344604 B CN 106344604B
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
- A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/722—Chitin, chitosan
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- 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
- A61K9/0012—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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Abstract
The invention discloses a kind of compound gentamicin film preparation techniques, it is formulated are as follows: 750-770 parts of gentamicin sulphate, 2000-2100 parts of tetracaine hydrochloride, 50-60 parts of dexamethasone acetate, polyvinyl alcohol (PVA) is appropriate, appropriate chitosan, appropriate sodium hydrogensulfite, appropriate Steviosin, appropriate tartaric acid, beautiful blue appropriate, appropriate lemon yellow；It is mixed with by the preparation of medicine film, the preparation of tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion and the dissolution of unclassified stores and obtains compound gentamicin film.Using technique of the invention, the rubber cement medical value in formula is fully used, the effective component of tetracaine hydrochloride more tends to stablize and preferably utilized in medicine film simultaneously, and compound gentamicin film loss of effective components is less, and quality is stablized.
Description
Technical field
The present invention relates to a kind of preparation processes of film (compound gentamicin film) for treating film for treating oral ulcer.
Background technique
Compound gentamicin film: the kind was Foochow Dao Shan pharmaceutical factory kind originally, and approval text is uniformly changed in the whole nation in 2003
Number, Foochow Dao Shan pharmaceutical factory is annexed by my company within 2004, which is also transferred to my company, obtains re-registration batch in June, 2015
Part.
Compound gentamicin film is mainly by compound gentamicin, tetracaine hydrochloride, dexamethasone acetate and other auxiliary materials
Deng 10 multiple materials, it is made by inclusion, dissolution, film etc..Wherein compound gentamicin is anti-for aminoglycosides wide spectrum
A variety of gram-negative bacterias and positive bacteria are all had antibacterial and bactericidal effect by raw element, and inhibiting bacteria and diminishing inflammation work is mainly played in said preparation
With；Tetracaine hydrochloride: local anesthetic can penetrate mucous membrane, play the role of narcotic analgesic；Dexamethasone acetate: adrenal cortex
Hormone drug can reduce and prevent reaction of the tissue to inflammation.
This patch is that traditional film is evolved, and tool has a better effect, and rubber cement is polyvinyl alcohol with dilute in original process
The diluted hydrochloric acid aqueous solution heating water bath dissolution released, is added glycerol, mixes thoroughly；Gentamicin sulphate and tetracaine hydrochloride, which are used, to be diluted
Diluted hydrochloric acid aqueous solution dissolution be added rubber cement；Dexamethasone acetate adds the ethyl alcohol dissolution that volume of molecular is 95% that rubber cement is added；Its
Remaining auxiliary material all with diluted diluted hydrochloric acid aqueous solution dissolution be added rubber cement stir evenly.Film packaging is made by the way that equipment plastic film mulch is dry
To obtain the final product.The compound made from this method celebrates the disadvantages of mycin film is unstable, degradable there are content, obtain product effect cannot
To substantially stabilized performance.So carrying out new research to the oral film preparation.
Summary of the invention
The purpose of the present invention is to provide a kind of formulation methods new about compound gentamicin film.
The traditional dissolving method of tetracaine hydrochloride is added the process of rubber cement that there are contents is unstable, easy in prescription
Degradation, therefore need to improve its stability using hydroxypropyl-β-cyclodextrin inclusion technique, after hydroxypropyl-β-cyclodextrin inclusion then
A kind of molecular complex is formed, mitigates oxidation, avoids reacting, light sensitivity and thermal sensitivity is passivated, promotes stable content to reach,
Avoid ingredient degradation.With orthogonal optimization compound celebrating mycin film in film-forming process, it is poly- that shell is added in filmogen
Sugar, chitosan itself are exactly fine a thickener, fruit glaze agent, can promote the stabilization of effective component, chitosan can promote blood coagulation
And wound healing, while can inhibit bacterial activity, to make rubber cement itself that there is medicinal efficacy, and compound gentamicin can be improved
Film quality of forming film, makes drug effect be greatly improved.
Compound gentamicin film preparation technique of the present invention, specific steps include the following:
(1) it weighs, ingredient
Get 750-770 parts of gentamicin sulphate by weight, 2000-2100 parts of tetracaine hydrochloride, dexamethasone acetate
50-60 parts, polyvinyl alcohol (PVA) is appropriate, appropriate chitosan, appropriate sodium hydrogensulfite, appropriate Steviosin, appropriate tartaric acid, beautiful
Blue appropriate, appropriate lemon yellow.The name of an article, specification, lot number, quantity are checked, is weighed up by material, and have special messenger's verification.
(2) preparation of tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion
It takes tetracaine hydrochloride and hydroxypropyl-β-cyclodextrin to get by weight 1:2, hydroxypropyl-β-cyclodextrin is taken to be placed in burning
In cup, adds a certain amount of purified water to be allowed to be saturated, dissolve by heating and cool down；Then the hydrochloric acid fourth card of half amount (weight ratio) is added
Because of magnetic agitation under the conditions of 60 DEG C, about 2h is included, it is cooling, it is freeze-dried up to tetracaine hydrochloride hydroxypropyl-β-cyclodextrin packet
Close object.
(3) preparation of rubber cement
Take Purified water that dilute hydrochloric acid is added to be configured to the diluted hydrochloric acid aqueous solution that pH value is 4.
By chitosan plus appropriate above-mentioned prepared diluted hydrochloric acid aqueous solution dissolution；It is spare.
By polyvinyl alcohol plus prepared diluted hydrochloric acid aqueous solution is stated, 100 DEG C of heating water baths make to dissolve, what addition had been dissolved
Chitosan and suitable glycerol, so that 3% chitosan: 1.5% polyvinyl alcohol: glycerol=4:10:1 stirs evenly molten to get rubber cement
Liquid.
(4) dissolution of other auxiliary materials
The prepared diluted hydrochloric acid aqueous solution of gentamicin sulphate is dissolved by heating, dexamethasone acetate adds the volume of molecular to be
95% ethyl alcohol dissolution, remaining auxiliary material sodium hydrogensulfite, Steviosin, tartaric acid, beautiful blue, lemon yellow add that prepare dilute hydrochloric acid water-soluble
Liquid dissolution.
(5) preparation of medicine film
Tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion is added stirring while adding in the rubber cement prepared.
It is stirred evenly to tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion, it is big mould that the sulfuric acid celebrating dissolved in (4) is added
The materials such as element, dexamethasone acetate, it is stirring while adding until color is uniform.
Defined medicine film is made in above-mentioned medicine slurry to pack to obtain the final product.Even compact, flexible is answered after gained film is to be dried.
(6) it packs
After the assay was approved, pass through equipment plastic film mulch, drying and pack up to compound gentamicin film.
Compound gentamicin film preparation technique of the present invention has two innovative points:
Innovative point one: the research of tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion
There are two the reason of improving its technique: one, tetracaine hydrochloride local anesthetic plays in compound gentamicin film
Important role.Two, the ingredient is likely to occur with tetracaine hydrochloride effective component in conventional method production medicine film to be not sufficiently stable, easily
The factors such as degradation.Therefore the present invention includes it with hydroxypropyl-β-cyclodextrin, to improve its stability, and hydroxy propyl-Beta-ring
Dextrin is a kind of glucose oligosaccharide annular in shape, 2-, 3-, 6- hydrogen atoms replaced by hydroxyl after title.Using it to salt
Sour totokaine can change the physics and chemical property of the drug into molecular complex is formed after inclusion.Mitigating it may be by oxygen
Change, avoid the effect of reaction, passivation light sensitivity and thermal sensitivity, to reach the stability work for improving tetracaine hydrochloride effective component
With.
Innovative point two: the preferential film-forming process of orthogonal film forming
Improve there are two its technological reasons: one, the film forming of prior art compound gentamicin film is less desirable, therefore this
Test optimizes its film forming using Orthogonal Experiment and Design research.Two, be added chitosan in filmogen, chitosan itself just
It is fine a thickener, fruit glaze agent, can promote the stabilization of effective component, chitosan can promote blood coagulation and wound healing, while can
Inhibit bacterial activity, to make rubber cement itself that there is medicinal efficacy, and quality of forming film can be made to be greatly improved.
Specific embodiment
1. the inclusion of tetracaine hydrochloride hydroxypropyl-β-cyclodextrin is studied
1.1 instruments and material: 7520 spectrophotometers；LGT0.5 freeze drier；Assay balance；Tetracaine hydrochloride；It is right
According to product；Hydroxypropyl-β-cyclodextrin；Magnetic stirrer.
1.2 experimental method
Hydroxypropyl-β-cyclodextrin inclusion.
1.3 orthogonal test
Through preliminary test, hydroxypropyl-β-cyclodextrin and tetracaine hydrochloride mixture feed ratio (A), agitator speed are selected
(B), including temperature (C) and mixing time (D) is influence factor (disregarding reciprocal effect), with inclusion compound recovery rate and hydrochloric acid fourth card
Because the comprehensive score of inclusion rate is index, and with the preferred clathrate process of orthogonal experiment, utilize L9(34) the orthogonal examination of orthogonal trial
It tests and finds optimal extraction conditions.
The inclusion compound rate of recovery (%)=inclusion compound weight/(tetracaine hydrochloride weight+hydroxypropyl-β-cyclodextrin weight) ×
L00%；
Tetracaine hydrochloride yield/(tetracaine hydrochloride input amount × sky in tetracaine hydrochloride inclusion rate (%)=inclusion compound
The white rate of recovery) × 100%；
Comprehensive score=inclusion compound yield × 30%+ tetracaine hydrochloride inclusion rate × 70%.
Each factor level table of orthogonal experiment is shown in Table 1,
1 each factor level table of tetracaine hydrochloride hydroxypropyl-β-cyclodextrin clathrate process of table
1.4 test level and it the results are shown in Table 2, the results of analysis of variance is shown in Table 3.The grade difference (R) of each factor in comparison sheet 2
Size, select optimum process condition be A2B1C2D3.I.e. solid-liquid ratio is 1:2, revolving speed 600rpm, includes 2h under the conditions of 60 DEG C.
2 orthogonal experiments of table and data processed result
3 variance analysis of table
1.5 verification test
To the optimised process A preferably gone out2B1C2D3Verification test is done, as a result inclusion rate is 58.10%, and yield is
95.22%.It can be seen that inclusion rate is higher than that orthogonal test is each as a result, recovery rate also has higher level compared with each result of orthogonal test,
Illustrate that selected clathrate process is feasible.
1.6 result
Include optimised process are as follows: take in tetracaine hydrochloride suitable device, the hydroxypropyl-of 2 times of tetracaine hydrochloride weight is added
Beta-cyclodextrin, magnetic agitation under the conditions of stirring intensity is 600rpm, inclusion temperature is 60 DEG C, includes 2h, cooling, freeze-drying
Gained tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion.
The calibrating of 1.7 tetracaine hydrochloride contents
1.7.1 the preparation of reference substance solution: it is appropriate that precision weighs tetracaine hydrochloride reference substance, is dissolved in water and is diluted to
0.1mg.mL-1Stock solution, mix, it is spare；Precision measures stock solution 1mL and sets in 20mL measuring bottle, is diluted with water to scale, mixes
It is even, it is spare.
1.7.2 the preparation of sample liquid: precision weighs the above-mentioned medicine film 1mg prepared and sets in 10mL measuring bottle, adds water ultrasound molten
Solution, and it is diluted to scale, it mixes；It takes above-mentioned solution 1mL in 20mL measuring bottle, is released with water weighing apparatus to scale, mixed spare.
1.7.3 prepared by blank sample solution: root Ju new process prepares the blank sample of without hydrochloric acid totokaine, according to " sample liquid
Preparation " method prepare blank sample solution.
1.7.4 the drafting of standard curve: selection measures tetracaine hydrochloride content at wavelength 312nm；Precision measures
0.1mg.mL-1Tetracaine hydrochloride reference substance solution is diluted with water to the series standard solution of 5,10,15,20,30 μ g/ml, to steam
Distilled water makees blank, measures trap respectively at wavelength 312nm.Linear regression is carried out with corresponding concentration with the trap measured,
Obtain tetracaine hydrochloride regression equation are as follows: C (μ g.mL-1)=14.9311A-0.1872, R2=0.9996.The result shows that in 5-30 μ
g.mL-1Sample concentration and trap linear relationship are good in range.
1.7.5 recovery test takes the sample liquid (0.1mg.mL of known concentration-1) 0.5,1.0,3.0mL in 3 10mL amounts
In bottle, it is diluted with water to scale, is mixed, wherein as a result tetracaine hydrochloride content, the calculating rate of recovery see the table below 4 for measurement.
4 recovery test result (n=5) of table
1.7.6 precision test: being measured the sample liquid of 3 kinds of concentration according to " recovery test " method, in weight in 1d
Multiple sample introduction 5 times, METHOD FOR CONTINUOUS DETERMINATION 5d, calculate in a few days, day to day precision, as a result see the table below 5.
In table 5 days, day to day precision investigate result (n=5)
1.7.7 sample size measures: compound gentamicin film 3 batches are taken, product liquid and preparation method thereof prepares sample liquid in the same old way, point
Not Ce Ding trap (every batch of measure 5 times), substituting into the content of regression equation calculation tetracaine hydrochloride, (the hydrochloric totokaine of this product is answered
For the 95%-105% of labelled amount) result the following table 6
6 sample size measurement result (n=5) of table
It is as a result reliable and stable by process certification three batches of this experiment.Illustrate that this technique can be used for the inclusion of tetracaine hydrochloride.
Innovative point two: the preferential film-forming process of orthogonal film forming
Improve there are two its technological reasons: one, the film forming of prior art compound gentamicin film is less desirable, therefore this
Test optimizes its film forming using Orthogonal Experiment and Design research.Two, be added chitosan in filmogen, chitosan itself just
It is fine a thickener, fruit glaze agent, can promote the stabilization of effective component, chitosan can promote blood coagulation and wound healing, while can
Inhibit bacterial activity, to make rubber cement itself that there is medicinal efficacy, and quality of forming film can be made to be greatly improved.
2. compound gentamicin film film forming technology optimization
2.1 materials prepare: appropriate chitosan, appropriate polyvinyl alcohol, appropriate glycerol.
The preparation of 2.2 rubber cements: take Purified water that dilute hydrochloric acid is added to be configured to the diluted hydrochloric acid aqueous solution that pH value is 4.Shell is gathered
Sugar plus appropriate above-mentioned prepared diluted hydrochloric acid aqueous solution dissolution；It is spare.Polyvinyl alcohol is water-soluble plus prepared dilute hydrochloric acid is stated
Liquid, 100 DEG C of heating water baths make to dissolve, and the chitosan dissolved is added and suitable glycerol stirs evenly to get rubber cement solution.
The calibrating of 2.3 rubber cements
2.3.1 the rubber cement prescription after chitosan is added is optimized using orthogonal experiment, observes its film-forming quality.
2.3.2 prescription screening: on the basis of single factor experiment, select glycerol, chitosan, polyvinyl alcohol dosage for
Investigation object selects L using film formation time as inspection target9(34) orthogonal test, it is for statistical analysis using intiutive analysis method(2),
Experimental factor and level, the level for taking film formation time short is as optimum condition.It is shown in Table 7
7 orthogonal test factor of table and level
2.3.3 film quality examination: main character, the quality difference for checking film.Take 20, diaphragm, it is accurately weighed its
Quality, after acquiring average quality, then accurately weighed each tablet quality respectively.Every tablet quality is more than of poor quality compared with average quality
The diaphragm of different limit (10%) must not be more than 2, and must not have 1 times of 1 overrun.
2.3.4 stability test: by film respectively at illumination (4500 ± 50) lx, high temperature (92.5% He of relative humidity
75.0%), high fever (30 DEG C) condition is placed 20 days.Observe its variation.
2.3.5 result and analysis are shown in Table 8
8 orthogonal experiments of table
By the very poor value R of upper table it is found that A factor is affected, B factor is taken second place, C factor influences minimum.Its optimum combination
For A2B3C3.That is 3% chitosan: 1.5% polyvinyl alcohol: film forming is most ideal when glycerol=4:10:1.
It is as a result almost the same with above-mentioned test using this process certification three batches, it is feasible to illustrate that this extraction process is stablized.
Implement first experiment
(1) it weighs, ingredient
Get 750 parts of gentamicin sulphate by weight, 2000 parts of tetracaine hydrochloride, 50 parts of dexamethasone acetate, poly- second
Enol (PVA) is appropriate, appropriate chitosan, appropriate sodium hydrogensulfite, appropriate Steviosin, appropriate tartaric acid, beautiful blue appropriate, lemon yellow
In right amount.The name of an article, specification, lot number, quantity are checked, is weighed up by material, and have special messenger's verification.
(2) preparation of tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion
It takes tetracaine hydrochloride and hydroxypropyl-β-cyclodextrin to get by weight 1:2, hydroxypropyl-β-cyclodextrin is taken to be placed in burning
In cup, adds a certain amount of purified water to be allowed to be saturated, dissolve by heating and cool down；Then the hydrochloric acid fourth card of half amount (weight ratio) is added
Because of magnetic agitation under the conditions of 60 DEG C, about 2h is included, it is cooling, it is freeze-dried up to tetracaine hydrochloride hydroxypropyl-β-cyclodextrin packet
Close object.
(3) preparation of rubber cement
Take Purified water that dilute hydrochloric acid is added to be configured to the diluted hydrochloric acid aqueous solution that pH value is 4.
By chitosan plus appropriate above-mentioned prepared diluted hydrochloric acid aqueous solution dissolution；It is spare.
By polyvinyl alcohol plus prepared diluted hydrochloric acid aqueous solution is stated, 100 DEG C of heating water baths make to dissolve, what addition had been dissolved
Chitosan and suitable glycerol, so that 3% chitosan: 1.5% polyvinyl alcohol: glycerol=4:10:1 stirs evenly molten to get rubber cement
Liquid.
(4) dissolution of other auxiliary materials
The prepared diluted hydrochloric acid aqueous solution of gentamicin sulphate is dissolved by heating, dexamethasone acetate adds the volume of molecular to be
95% ethyl alcohol dissolution, remaining auxiliary material sodium hydrogensulfite, Steviosin, tartaric acid, beautiful blue, lemon yellow add that prepare dilute hydrochloric acid water-soluble
Liquid dissolution.
(5) preparation of medicine film
Tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion is added stirring while adding in the rubber cement prepared.
It is stirred evenly to tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion, it is big mould that the sulfuric acid celebrating dissolved in (4) is added
The materials such as element, dexamethasone acetate, it is stirring while adding until color is uniform.
Defined medicine film is made in above-mentioned medicine slurry to pack to obtain the final product.Even compact, flexible is answered after gained film is to be dried.
(6) it packs
After the assay was approved, pass through equipment plastic film mulch, drying and pack up to compound gentamicin film.
The second batch of embodiment 2 is tested:
(1) it weighs, ingredient
Get 760 parts of gentamicin sulphate by weight, 2050 parts of tetracaine hydrochloride, 55 parts of dexamethasone acetate, poly- second
Enol (PVA) is appropriate, appropriate chitosan, appropriate sodium hydrogensulfite, appropriate Steviosin, appropriate tartaric acid, beautiful blue appropriate, lemon yellow
In right amount.The name of an article, specification, lot number, quantity are checked, is weighed up by material, and have special messenger's verification.
(2) preparation of tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion
It takes tetracaine hydrochloride and hydroxypropyl-β-cyclodextrin to get by weight 1:2, hydroxypropyl-β-cyclodextrin is taken to be placed in burning
In cup, adds a certain amount of purified water to be allowed to be saturated, dissolve by heating and cool down；Then the hydrochloric acid fourth card of half amount (weight ratio) is added
Because of magnetic agitation under the conditions of 60 DEG C, about 2h is included, it is cooling, it is freeze-dried up to tetracaine hydrochloride hydroxypropyl-β-cyclodextrin packet
Close object.
(3) preparation of rubber cement
Take Purified water that dilute hydrochloric acid is added to be configured to the diluted hydrochloric acid aqueous solution that pH value is 4.
By chitosan plus appropriate above-mentioned prepared diluted hydrochloric acid aqueous solution dissolution；It is spare.
By polyvinyl alcohol plus prepared diluted hydrochloric acid aqueous solution is stated, 100 DEG C of heating water baths make to dissolve, what addition had been dissolved
Chitosan and suitable glycerol, so that 3% chitosan: 1.5% polyvinyl alcohol: glycerol=4:10:1 stirs evenly molten to get rubber cement
Liquid.
(4) dissolution of other auxiliary materials
The prepared diluted hydrochloric acid aqueous solution of gentamicin sulphate is dissolved by heating, dexamethasone acetate adds the volume of molecular to be
95% ethyl alcohol dissolution, remaining auxiliary material sodium hydrogensulfite, Steviosin, tartaric acid, beautiful blue, lemon yellow add that prepare dilute hydrochloric acid water-soluble
Liquid dissolution.
(5) preparation of medicine film
Tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion is added stirring while adding in the rubber cement prepared.
It is stirred evenly to tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion, it is big mould that the sulfuric acid celebrating dissolved in (4) is added
The materials such as element, dexamethasone acetate, it is stirring while adding until color is uniform.
Defined medicine film is made in above-mentioned medicine slurry to pack to obtain the final product.Even compact, flexible is answered after gained film is to be dried.
(6) it packs
After the assay was approved, pass through equipment plastic film mulch, drying and pack up to compound gentamicin film.
The third of embodiment 3 batch experiment:
(1) it weighs, ingredient
Get 770 parts of gentamicin sulphate by weight, 2100 parts of tetracaine hydrochloride, 60 parts of dexamethasone acetate, poly- second
Enol (PVA) is appropriate, appropriate chitosan, appropriate sodium hydrogensulfite, appropriate Steviosin, appropriate tartaric acid, beautiful blue appropriate, lemon yellow
In right amount.The name of an article, specification, lot number, quantity are checked, is weighed up by material, and have special messenger's verification.
(2) preparation of tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion
It takes tetracaine hydrochloride and hydroxypropyl-β-cyclodextrin to get by weight 1:2, hydroxypropyl-β-cyclodextrin is taken to be placed in burning
In cup, adds a certain amount of purified water to be allowed to be saturated, dissolve by heating and cool down；Then the hydrochloric acid fourth card of half amount (weight ratio) is added
Because of magnetic agitation under the conditions of 60 DEG C, about 2h is included, it is cooling, it is freeze-dried up to tetracaine hydrochloride hydroxypropyl-β-cyclodextrin packet
Close object.
(3) preparation of rubber cement
Take Purified water that dilute hydrochloric acid is added to be configured to the diluted hydrochloric acid aqueous solution that pH value is 4.
By chitosan plus appropriate above-mentioned prepared diluted hydrochloric acid aqueous solution dissolution；It is spare.
By polyvinyl alcohol plus prepared diluted hydrochloric acid aqueous solution is stated, 100 DEG C of heating water baths make to dissolve, what addition had been dissolved
Chitosan and suitable glycerol, so that 3% chitosan: 1.5% polyvinyl alcohol: glycerol=4:10:1 stirs evenly molten to get rubber cement
Liquid.
(4) dissolution of other auxiliary materials
The prepared diluted hydrochloric acid aqueous solution of gentamicin sulphate is dissolved by heating, dexamethasone acetate adds the volume of molecular to be
95% ethyl alcohol dissolution, remaining auxiliary material sodium hydrogensulfite, Steviosin, tartaric acid, beautiful blue, lemon yellow add that prepare dilute hydrochloric acid water-soluble
Liquid dissolution.
(5) preparation of medicine film
Tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion is added stirring while adding in the rubber cement prepared.
It is stirred evenly to tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion, it is big mould that the sulfuric acid celebrating dissolved in (4) is added
The materials such as element, dexamethasone acetate, it is stirring while adding until color is uniform.
Defined medicine film is made in above-mentioned medicine slurry to pack to obtain the final product.Even compact, flexible is answered after gained film is to be dried.
(6) it packs
After the assay was approved, pass through equipment plastic film mulch, drying and pack up to compound gentamicin film.
(1) present invention investigates the compound gentamicin produced by the present invention of three batches by above three embodiments respectively
Film product, is described below in detail:
First takes 5 box compound gentamicin film products to carry out character, identification, uniformity of dosage units, dissolve the time limit, to fourth ammonia
Yl benzoic acid, gentamicin sulphate, tetracaine hydrochloride, dexamethasone acetate and the inspection of microbial limit measurement specifically see the table below
Second batch takes 5 box compound gentamicin film products to carry out character, identification, uniformity of dosage units, dissolve the time limit, to fourth ammonia
Yl benzoic acid, gentamicin sulphate, tetracaine hydrochloride, dexamethasone acetate and the inspection of microbial limit measurement specifically see the table below
Third batch takes 5 box compound gentamicin film products to carry out character, identification, uniformity of dosage units, dissolve the time limit, to fourth ammonia
Yl benzoic acid, gentamicin sulphate, tetracaine hydrochloride, dexamethasone acetate and the inspection of microbial limit measurement specifically see the table below
5 box of compound gentamicin film product obtained by traditional handicraft is taken to carry out character, identification, uniformity of dosage units, dissolve
The inspection in time limit, P-butylaminobenzoic acid, gentamicin sulphate, tetracaine hydrochloride, dexamethasone acetate and microbial limit measurement
It looks into and is specifically shown in Table 9
The related data of 9: four batches of compound gentamicin film products of table compares:
| Inspection project | First | Second batch | Third batch | Traditional handicraft |
| Character | Meet regulation | Meet regulation | Meet regulation | Meet regulation |
| Identify | Meet regulation | Meet regulation | Meet regulation | Meet regulation |
| Dissolve the time limit | 9 | 10 | 8 | 14 |
| Microbial limit | Meet regulation | Meet regulation | Meet regulation | Meet regulation |
| Uniformity of dosage units | Meet regulation | Meet regulation | Meet regulation | Meet regulation |
| P-butylaminobenzoic acid | 0.02% | 0.03% | 0.02% | 0.3% |
| Gentamicin sulphate | 101.65% | 102.83% | 101.96% | 92.10% |
| Tetracaine hydrochloride | 99.34% | 98.67% | 98.79% | 91.69% |
| Dexamethasone acetate | 98.57% | 99.25% | 99.62% | 91.54% |
| Conclusion | It is qualified | It is qualified | It is qualified | It is qualified |
Analyze according to above data: compound gentamicin film obtained through the invention measures data and traditional handicraft is made
Compound gentamicin film product compare, dissolve that the time limit is shorter, gentamicin sulphate, tetracaine hydrochloride, dexamethasone acetate
Content is higher, and impurity P-butylaminobenzoic acid is less.
Product stability produced by the present invention is investigated:
Acceleration study continuously investigates three batches；Experiment condition: after product is packed by market sale packing specification requirement,
It is put into Acceleration study equipment, 40 DEG C ± 2 DEG C of set temperature；Humidity 75% ± 5% is placed 6 months, by 1 month, 2 months, 3
A month, 6 the end of month were separately sampled primary, the character of high spot reviews compound gentamicin film product, identification, uniformity of dosage units, molten
Change time limit, P-butylaminobenzoic acid, gentamicin sulphate, tetracaine hydrochloride, dexamethasone acetate and microbial limit measurement, number
According to being shown in Table 10
Table 10: the related data of the compound gentamicin film product accelerated test of three batches is investigated
Long-term experiment continuously investigates 3 batches: experiment condition: after product is packed by market sale packing specification, being put into
In experimental facilities, 25 DEG C ± 2 DEG C of set temperature；Humidity 60% ± 10% is placed 24 months, by 0 month, 3 months, 6 months, 9
A month, 12 months, 18 months, 24 the end of month were separately sampled primary, the character of high spot reviews compound gentamicin film product, mirror
Not, uniformity of dosage units, dissolve the time limit, P-butylaminobenzoic acid, gentamicin sulphate, tetracaine hydrochloride, dexamethasone acetate and
Microbial limit measurement, data are shown in Table 11
Table 11: the related data of the compound gentamicin film product accelerated test of three batches is investigated
By study on the stability, analysis comparison is carried out to the data, the results showed that compound gentamicin produced by the present invention
Film stable product quality, method is reliable, on the basis of original prescription, passes through the matter for the product of the present invention that the improvement of technique obtains
Amount has sufficient guarantee.
Claims (1)
1. a kind of preparation process of compound gentamicin film, includes the following steps
(1) it weighs, ingredient
Get 750-770 parts of gentamicin sulphate by weight, 2000-2100 parts of tetracaine hydrochloride, dexamethasone acetate 50-
60 parts, polyvinyl alcohol (PVA) is appropriate, appropriate chitosan, appropriate sodium hydrogensulfite, appropriate Steviosin, appropriate tartaric acid, beautiful indigo plant
In right amount, appropriate lemon yellow；The name of an article, specification, lot number, quantity are checked, is weighed up by material, and have special messenger's verification；
(2) preparation of tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion
It takes tetracaine hydrochloride and hydroxypropyl-β-cyclodextrin to get by weight 1:2, hydroxypropyl-β-cyclodextrin is taken to be placed in a beaker,
Add a certain amount of purified water to be allowed to be saturated, dissolve by heating and cools down；Then tetracaine hydrochloride magnetic force under the conditions of 60 DEG C is added to stir
It mixes, includes about 2h, it is cooling, it is freeze-dried up to tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion；
(3) preparation of rubber cement
Take Purified water that dilute hydrochloric acid is added to be configured to the diluted hydrochloric acid aqueous solution that pH value is 4；
By chitosan plus appropriate above-mentioned prepared diluted hydrochloric acid aqueous solution dissolution；It is spare；
By polyvinyl alcohol plus prepared diluted hydrochloric acid aqueous solution is stated, 100 DEG C of heating water baths make to dissolve, and it is poly- that the shell dissolved is added
Sugared and suitable glycerol, so that 3% chitosan: 1.5% polyvinyl alcohol: glycerol=4:10:1 stirs evenly to get rubber cement solution；
(4) dissolution of other auxiliary materials
The prepared diluted hydrochloric acid aqueous solution of gentamicin sulphate is dissolved by heating, dexamethasone acetate adds volume of molecular to be 95%
Ethyl alcohol dissolution, remaining auxiliary material sodium hydrogensulfite, Steviosin, tartaric acid, beautiful blue, lemon yellow add that prepare diluted hydrochloric acid aqueous solution molten
Solution；
(5) preparation of medicine film
Tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion is added stirring while adding in the rubber cement prepared；
It is stirred evenly to tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion, the middle gentamicin sulphate dissolved of addition (4),
The materials such as dexamethasone acetate, it is stirring while adding until color is uniform；
Defined medicine film is made in above-mentioned medicine slurry to pack to obtain the final product；Even compact, flexible is answered after gained film is to be dried；
(6) it packs
After the assay was approved, pass through equipment plastic film mulch, drying and pack up to compound gentamicin film.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109953984A (en) * | 2019-03-01 | 2019-07-02 | 哈尔滨医科大学 | A kind of compound hydrochloric acid totokaine film and preparation method thereof |
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