CN106344604A - Preparation process of compound gentamicin film - Google Patents
Preparation process of compound gentamicin film Download PDFInfo
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- CN106344604A CN106344604A CN201610742934.1A CN201610742934A CN106344604A CN 106344604 A CN106344604 A CN 106344604A CN 201610742934 A CN201610742934 A CN 201610742934A CN 106344604 A CN106344604 A CN 106344604A
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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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- 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
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- 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
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- 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 preparation process of a compound gentamicin film, made from, according to the formula, 750-770 parts of gentamicin sulfate, 2000-2100 parts of tetracaine hydrochloride, 50-60 parts of dexamethasone acetate, suitable polyvinyl alcohol (PVA), suitable chitosan, suitable sodium hydrogen sulfite, suitable steviosin, suitable tartaric acid, suitable indigo, and suitable of lemon yellow; the compound gentamicin film is prepared through the preparation of a drug film, the preparation of tetracaine hydrochloride hydroxypropyl-Beta-cyclodextrin inclusion, and the preparation of dissolution and mixing of other materials. By using the process of the invention, gel pharmaceutical value in the formula is made full use, effective ingredients of tetracaine hydrochloride tend to be more stable in the drug film and are better utilized, and the compound gentamicin film has low loss of effective ingredients and stable quality.
Description
Technical field
The present invention relates to a kind of preparation technology of the membrane (compound gentamicin film) treating film for treating oral ulcer.
Background technology
Compound gentamicin film: this kind was Foochow Dao Shan pharmaceutical factory kind originally, approval literary composition is changed in whole nation unification in 2003
Number, Foochow Dao Shan pharmaceutical factory is annexed by my company within 2004, and this kind is also transferred to my company, and in June, 2015 obtains re-registration and criticizes
Part.
Compound gentamicin film is mainly by compound gentamicin, tetracaine hydrochloride, dexamethasone acetate and other adjuvants
Deng 10 multiple materials, it is made by inclusion, dissolving, masking etc..Wherein compound gentamicin resists for aminoglycosides wide spectrum
Multiple gram-negative bacterias and positive bacteria are all had antibacterial and bactericidal action by raw element, act primarily as inhibiting bacteria and diminishing inflammation and make in said preparation
With；Tetracaine hydrochloride: local anesthetic, mucosa can be passed through, play narcotic analgesic effect；Dexamethasone acetate: adrenal cortex
Hormone drug, can mitigate and prevent the reaction to inflammation for the tissue.
This membranous patch develops for traditional membrane, has preferable curative effect, in former technique rubber cement for polyvinyl alcohol with dilute
The diluted hydrochloric acid aqueous solution heating in water bath dissolving released, adds glycerol, mixes thoroughly；Gentamycin sulfate and tetracaine hydrochloride are with diluting
Diluted hydrochloric acid aqueous solution dissolving add rubber cement；Dexamethasone acetate adds the ethanol dissolving that volume of molecular is 95% and adds rubber cement；Its
Remaining adjuvant all adds rubber cement to stir with having diluted diluted hydrochloric acid aqueous solution dissolving.Membrane packaging is made by the drying of equipment plastic film mulch
Obtain final product.With the method be obtained compound recipe celebrating mycin film there are content unstable, degradable the shortcomings of, make this product act on can not obtain
To substantially stabilized performance.So new research is carried out to this oral film preparation.
Content of the invention
It is an object of the invention to provide a kind of formulation method new with regard to compound gentamicin film.
In prescription, to there are content unstable, easy for the tetracaine hydrochloride process that traditional dissolving method adds rubber cement
Degraded, therefore need to improve its stability using HP-β-CD inclusion technique, after HP-β-CD inclusion then
Form a kind of molecular complex, mitigate oxidation, it is to avoid reaction, be passivated heliosensitivity and thermal sensitivity, thus reach promoting stable content,
Avoid ingredient degradation.With orthogonal optimization compound recipe celebrating mycin film in film-forming process, shell is added to gather in filmogen
Sugar, shitosan itself is exactly fine thickening agent, a fruit glaze agent, can promote stablizing of effective ingredient, shitosan can promote blood coagulation
And wound healing, simultaneously can Antibacterial activity so that rubber cement has medicinal efficacy in itself, compound gentamicin can be improved again
Film quality of forming film, makes drug effect be greatly improved.
Compound gentamicin film preparation technique of the present invention, its concrete steps includes the following:
(1) weighing, dispensing
Get gentamycin sulfate 750-770 part, tetracaine hydrochloride 2000-2100 part, dexamethasone acetate by weight
50-60 part, polyvinyl alcohol (pva) is appropriate, appropriate shitosan, appropriate sodium sulfite, appropriate steviosin, appropriate tartaric acid, beautiful
Blue appropriate, appropriate lemon yellow.The verification name of an article, specification, lot number, quantity, weigh up by material, and have special messenger to check.
(2) preparation of tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion
Take tetracaine hydrochloride to get by weight 1:2 with HP-β-CD, take HP-β-CD to be placed in burning
In cup, plus a certain amount of purified water is allowed to saturation, and heating for dissolving simultaneously cools down；Then add the hydrochloric acid fourth card of half amount (weight ratio)
Because of magnetic agitation under the conditions of 60 DEG C, inclusion about 2h, cooling, lyophilization obtains final product tetracaine hydrochloride HP-β-CD bag
Compound.
(3) preparation of rubber cement
Take Purified water to add dilute hydrochloric acid and be configured to the diluted hydrochloric acid aqueous solution for 4 for the ph value.
By shitosan plus the above-mentioned diluted hydrochloric acid aqueous solution dissolving preparing in right amount；Standby.
Polyvinyl alcohol is added and states the diluted hydrochloric acid aqueous solution preparing, 100 DEG C of heating in water bath make dissolving, addition has been dissolved
Shitosan and appropriate glycerol are so that 3% shitosan: 1.5% polyvinyl alcohol: glycerol=4:10:1, stir evenly, obtain final product rubber cement molten
Liquid.
(4) dissolving of other adjuvants
The diluted hydrochloric acid aqueous solution heating for dissolving that gentamycin sulfate is prepared, dexamethasone acetate adds volume of molecular and is
95% ethanol dissolving, remaining adjuvant sodium sulfite, steviosin, tartaric acid, beautiful blue, lemon yellow add that to prepare dilute hydrochloric acid water-soluble
Liquid dissolves.
(5) preparation of medicine film
Tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion is added stirring while adding in the rubber cement preparing.
Treat that tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion stirs, add the sulphuric acid celebrating dissolved in (4) mould greatly
The materials such as element, dexamethasone acetate, stirring while adding until color even.
The medicine film packaging that above-mentioned medicine slurry is made regulation obtains final product.Even compact, flexible is answered after gained film is to be dried.
(6) pack
After the assay was approved, by equipment plastic film mulch, drying and pack and obtain final product 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
The reason improve its technique has two: one, tetracaine hydrochloride local anesthetic, plays in compound gentamicin film
Important effect.2nd, make tetracaine hydrochloride effective ingredient in medicine film with traditional method and be likely to occur this composition and be not sufficiently stable, easily
The factors such as degraded.Therefore the present invention carries out inclusion with HP-β-CD to it, to improve its stability, and hydroxy propyl-Beta-ring
Dextrin is a kind of oligomeric glucose annular in shape, its 2-, 3-, 6- position hydrogen atom replaced by hydroxyl after title.Using it to salt
Sour tetracaine forms molecular complex after entering inclusion, can change physics and the chemical property of this medicine.Mitigating it may be by oxygen
Change, avoid reacting, be passivated heliosensitivity and the effect of thermal sensitivity, thus reaching the stability work improving tetracaine hydrochloride effective ingredient
With.
Innovative point two: the preferential film-forming process of orthogonal film forming
Improving its technological reason has two: one, the film property of existing process compound gentamicin film is less desirable, therefore this
Test optimizes its film property using Orthogonal Experiment and Design research.2nd, in filmogen add shitosan, shitosan itself just
It is fine thickening agent, a fruit glaze agent, stablizing of effective ingredient can be promoted, shitosan can promote blood coagulation and wound healing, may be used simultaneously
Antibacterial activity, so that rubber cement has medicinal efficacy in itself, can make quality of forming film be greatly improved again.
Specific embodiment
1. the inclusion research of tetracaine hydrochloride HP-β-CD
1.1 instruments and material: 7520 spectrophotometers；Lgt0.5 freezer dryer；Analytical balance；Tetracaine hydrochloride；Right
According to product；HP-β-CD；Magnetic stirrer.
1.2 experimental technique
HP-β-CD inclusion.
1.3 orthogonal test
Through preliminary test, selected HP-β-CD and tetracaine hydrochloride mixture rate of charge (a), agitator speed
B (), inclusion temperature (c) and mixing time (d) are influence factor's (disregarding reciprocal effect), with clathrate recovery rate and hydrochloric acid fourth card
Comprehensive grading because of inclusion rate is index, and with the preferred clathrate process of orthogonal experiment, using l9(34) the orthogonal examination of orthogonal trial
Test and find optimal extraction conditions.
The clathrate response rate (%)=clathrate weight/(tetracaine hydrochloride weight+HP-β-CD weight) ×
L00%；
Tetracaine hydrochloride yield/(tetracaine hydrochloride input amount × sky in tetracaine hydrochloride inclusion rate (%)=clathrate
The white response rate) × 100%；
Comprehensive grading=clathrate yield × 30%+ tetracaine hydrochloride inclusion rate × 70%.
The each factor level table of orthogonal experiment is shown in Table 1,
The each factor level table of table 1 tetracaine hydrochloride HP-β-CD clathrate process
1.4 test level and the results are shown in Table 2, the results of analysis of variance is shown in Table 3.Level difference (r) of each factor in comparison sheet 2
Size, select optimum process condition be a2b1c2d3.I.e. solid-liquid ratio is 1:2, rotating speed 600rpm, inclusion 2h under the conditions of 60 DEG C.
Table 2 orthogonal experiments and data processed result
Table 3 variance analyses
1.5 checking test
To the optimised process a preferably going out2b1c2d3Do checking test, result inclusion rate is 58.10%, yield is
95.22%.It can be seen that inclusion rate is higher than each result of orthogonal test, compared with recovery rate result each with orthogonal test, also there is higher level,
Selected by explanation, clathrate process is feasible.
1.6 result
Inclusion optimised process is: take in tetracaine hydrochloride suitable device, add 2 times of tetracaine hydrochloride weight hydroxypropyl-
Beta-schardinger dextrin-, stirring intensity be 600rpm, inclusion temperature be 60 DEG C under the conditions of magnetic agitation, inclusion 2h, cooling, lyophilization
Gained tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion.
The calibrating of 1.7 tetracaine hydrochloride contents
1.7.1 the preparation of reference substance solution: precision weighs tetracaine hydrochloride reference substance in right amount, is dissolved in water and is diluted to
0.1mg.ml-1Storing solution, mix, standby；Precision measures storing solution 1ml and puts in 20ml measuring bottle, is diluted with water to scale, mixes
Even, standby.
1.7.2 the preparation of sample liquid: precision weighs above-mentioned medicine film 1mg preparing and puts in 10ml measuring bottle, adds water ultrasonic molten
Solution, and it is diluted to scale, mix；Take above-mentioned solution 1ml in 20ml measuring bottle, released to scale with water weighing apparatus, mix standby.
1.7.3 blank sample solution preparation: root Ju new technology prepares the blank sample of without hydrochloric acid tetracaine, shines " sample liquid
Preparation " method prepare blank sample solution.
1.7.4 the drafting of standard curve: select to measure 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 at wavelength 312nm respectively.Linear regression is carried out with corresponding concentration with the trap recording,
Obtaining tetracaine hydrochloride regression equation is: c (μ g.ml-1)=14.9311a-0.1872, r2=0.9996.Result shows, in 5-30 μ
g.ml-1In the range of sample concentration good with trap linear relationship.
1.7.5 recovery test takes the sample liquid (0.1mg.ml of concentration known-1) 0.5,1.0,3.0ml measure in 3 10ml
In bottle, it is diluted with water to scale, mixes, measure wherein tetracaine hydrochloride content, calculate the response rate, result see table 4.
Table 4 recovery test result (n=5)
1.7.6 precision test: according to " recovery test " method, the sample liquid of 3 kinds of concentration is measured, weight in 1d
Multiple sample introduction 5 times, METHOD FOR CONTINUOUS DETERMINATION 5d, calculate in a few days, day to day precision, result see table 5.
In table 5 days, day to day precision investigate result (n=5)
1.7.7 sample size measures: take compound gentamicin film 3 batches, in the same old way product liquid and preparation method thereof preparation sample liquid, point
Not Ce Ding trap (every batch measure 5 times), (the hydrochloric tetracaine of this product should to substitute into the content of regression equation calculation tetracaine hydrochloride
95%-105% for labelled amount) result table 6 below
Table 6 sample size measurement result (n=5)
The process certification three batches tested by this, result is reliable and stable.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
Improving its technological reason has two: one, the film property of existing process compound gentamicin film is less desirable, therefore this
Test optimizes its film property using Orthogonal Experiment and Design research.2nd, in filmogen add shitosan, shitosan itself just
It is fine thickening agent, a fruit glaze agent, stablizing of effective ingredient can be promoted, shitosan can promote blood coagulation and wound healing, may be used simultaneously
Antibacterial activity, so that rubber cement has medicinal efficacy in itself, can make quality of forming film be greatly improved again.
2. compound gentamicin film film property technology optimization
2.1 materials prepare: appropriate shitosan, appropriate polyvinyl alcohol, appropriate glycerol.
The preparation of 2.2 rubber cements: take Purified water to add dilute hydrochloric acid and be configured to the diluted hydrochloric acid aqueous solution for 4 for the ph value.Shell is gathered
Sugar plus the in right amount above-mentioned diluted hydrochloric acid aqueous solution dissolving preparing；Standby.Polyvinyl alcohol is water-soluble plus stating the dilute hydrochloric acid preparing
Liquid, 100 DEG C of heating in water bath make dissolving, add the shitosan having dissolved and appropriate glycerol to stir evenly, obtain final product rubber cement solution.
The calibrating of 2.3 rubber cements
2.3.1 using orthogonal experiment to adding the rubber cement prescription after shitosan to be optimized, observe its film-forming quality.
2.3.2 prescription screening: on the basis of single factor experiment, selection glycerol, shitosan, the consumption of polyvinyl alcohol are
Investigate object, with film formation time as inspection target, from l9(34) orthogonal test, statistical analysiss are carried out using intiutive analysis method(2),
Experimental factor and level, take the short level of film formation time as optimum condition.It is shown in Table 7
Table 7 orthogonal test factor and level
2.3.3 membrane quality examination: the main character checking membrane, mass discrepancy.Take 20, diaphragm, accurately weighed its
Quality, after trying to achieve average quality, more accurately weighed each tablet quality respectively.Every tablet quality is compared with average quality, exceedes of poor 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 membrane respectively at illumination (4500 ± 50) lx, high temperature (relative humidity 92.5% He
75.0%), hyperpyrexia (30 DEG C) condition is placed 20 days.Observe its change.
2.3.5 result and analysis in table 8
Table 8 orthogonal experiments
From extreme difference value r of upper table, the impact of a factor is larger, b factor is taken second place, and the impact of c factor is minimum.Its optimum combination
For a2b3c3.I.e. 3% shitosan: 1.5% polyvinyl alcohol: during glycerol=4:10:1, film property is the most preferable.
Using this process certification three batches, result is basically identical with above-mentioned test, illustrates that this extraction process is stablized feasible.
Implement first experiment
(1) weighing, dispensing
Get 750 parts of gentamycin sulfate, 2000 parts of tetracaine hydrochloride, 50 parts of dexamethasone acetate, poly- second by weight
Enol (pva) is appropriate, appropriate shitosan, appropriate sodium sulfite, appropriate steviosin, appropriate tartaric acid, beautiful blue appropriate, lemon yellow
In right amount.The verification name of an article, specification, lot number, quantity, weigh up by material, and have special messenger to check.
(2) preparation of tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion
Take tetracaine hydrochloride to get by weight 1:2 with HP-β-CD, take HP-β-CD to be placed in burning
In cup, plus a certain amount of purified water is allowed to saturation, and heating for dissolving simultaneously cools down；Then add the hydrochloric acid fourth card of half amount (weight ratio)
Because of magnetic agitation under the conditions of 60 DEG C, inclusion about 2h, cooling, lyophilization obtains final product tetracaine hydrochloride HP-β-CD bag
Compound.
(3) preparation of rubber cement
Take Purified water to add dilute hydrochloric acid and be configured to the diluted hydrochloric acid aqueous solution for 4 for the ph value.
By shitosan plus the above-mentioned diluted hydrochloric acid aqueous solution dissolving preparing in right amount；Standby.
Polyvinyl alcohol is added and states the diluted hydrochloric acid aqueous solution preparing, 100 DEG C of heating in water bath make dissolving, addition has been dissolved
Shitosan and appropriate glycerol are so that 3% shitosan: 1.5% polyvinyl alcohol: glycerol=4:10:1, stir evenly, obtain final product rubber cement molten
Liquid.
(4) dissolving of other adjuvants
The diluted hydrochloric acid aqueous solution heating for dissolving that gentamycin sulfate is prepared, dexamethasone acetate adds volume of molecular and is
95% ethanol dissolving, remaining adjuvant sodium sulfite, steviosin, tartaric acid, beautiful blue, lemon yellow add that to prepare dilute hydrochloric acid water-soluble
Liquid dissolves.
(5) preparation of medicine film
Tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion is added stirring while adding in the rubber cement preparing.
Treat that tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion stirs, add the sulphuric acid celebrating dissolved in (4) mould greatly
The materials such as element, dexamethasone acetate, stirring while adding until color even.
The medicine film packaging that above-mentioned medicine slurry is made regulation obtains final product.Even compact, flexible is answered after gained film is to be dried.
(6) pack
After the assay was approved, by equipment plastic film mulch, drying and pack and obtain final product compound gentamicin film.
The second batch experiment of embodiment 2:
(1) weighing, dispensing
Get 760 parts of gentamycin sulfate, 2050 parts of tetracaine hydrochloride, 55 parts of dexamethasone acetate, poly- second by weight
Enol (pva) is appropriate, appropriate shitosan, appropriate sodium sulfite, appropriate steviosin, appropriate tartaric acid, beautiful blue appropriate, lemon yellow
In right amount.The verification name of an article, specification, lot number, quantity, weigh up by material, and have special messenger to check.
(2) preparation of tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion
Take tetracaine hydrochloride to get by weight 1:2 with HP-β-CD, take HP-β-CD to be placed in burning
In cup, plus a certain amount of purified water is allowed to saturation, and heating for dissolving simultaneously cools down；Then add the hydrochloric acid fourth card of half amount (weight ratio)
Because of magnetic agitation under the conditions of 60 DEG C, inclusion about 2h, cooling, lyophilization obtains final product tetracaine hydrochloride HP-β-CD bag
Compound.
(3) preparation of rubber cement
Take Purified water to add dilute hydrochloric acid and be configured to the diluted hydrochloric acid aqueous solution for 4 for the ph value.
By shitosan plus the above-mentioned diluted hydrochloric acid aqueous solution dissolving preparing in right amount；Standby.
Polyvinyl alcohol is added and states the diluted hydrochloric acid aqueous solution preparing, 100 DEG C of heating in water bath make dissolving, addition has been dissolved
Shitosan and appropriate glycerol are so that 3% shitosan: 1.5% polyvinyl alcohol: glycerol=4:10:1, stir evenly, obtain final product rubber cement molten
Liquid.
(4) dissolving of other adjuvants
The diluted hydrochloric acid aqueous solution heating for dissolving that gentamycin sulfate is prepared, dexamethasone acetate adds volume of molecular and is
95% ethanol dissolving, remaining adjuvant sodium sulfite, steviosin, tartaric acid, beautiful blue, lemon yellow add that to prepare dilute hydrochloric acid water-soluble
Liquid dissolves.
(5) preparation of medicine film
Tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion is added stirring while adding in the rubber cement preparing.
Treat that tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion stirs, add the sulphuric acid celebrating dissolved in (4) mould greatly
The materials such as element, dexamethasone acetate, stirring while adding until color even.
The medicine film packaging that above-mentioned medicine slurry is made regulation obtains final product.Even compact, flexible is answered after gained film is to be dried.
(6) pack
After the assay was approved, by equipment plastic film mulch, drying and pack and obtain final product compound gentamicin film.
3rd batch of experiment of embodiment 3:
(1) weighing, dispensing
Get 770 parts of gentamycin sulfate, 2100 parts of tetracaine hydrochloride, 60 parts of dexamethasone acetate, poly- second by weight
Enol (pva) is appropriate, appropriate shitosan, appropriate sodium sulfite, appropriate steviosin, appropriate tartaric acid, beautiful blue appropriate, lemon yellow
In right amount.The verification name of an article, specification, lot number, quantity, weigh up by material, and have special messenger to check.
(2) preparation of tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion
Take tetracaine hydrochloride to get by weight 1:2 with HP-β-CD, take HP-β-CD to be placed in burning
In cup, plus a certain amount of purified water is allowed to saturation, and heating for dissolving simultaneously cools down；Then add the hydrochloric acid fourth card of half amount (weight ratio)
Because of magnetic agitation under the conditions of 60 DEG C, inclusion about 2h, cooling, lyophilization obtains final product tetracaine hydrochloride HP-β-CD bag
Compound.
(3) preparation of rubber cement
Take Purified water to add dilute hydrochloric acid and be configured to the diluted hydrochloric acid aqueous solution for 4 for the ph value.
By shitosan plus the above-mentioned diluted hydrochloric acid aqueous solution dissolving preparing in right amount；Standby.
Polyvinyl alcohol is added and states the diluted hydrochloric acid aqueous solution preparing, 100 DEG C of heating in water bath make dissolving, addition has been dissolved
Shitosan and appropriate glycerol are so that 3% shitosan: 1.5% polyvinyl alcohol: glycerol=4:10:1, stir evenly, obtain final product rubber cement molten
Liquid.
(4) dissolving of other adjuvants
The diluted hydrochloric acid aqueous solution heating for dissolving that gentamycin sulfate is prepared, dexamethasone acetate adds volume of molecular and is
95% ethanol dissolving, remaining adjuvant sodium sulfite, steviosin, tartaric acid, beautiful blue, lemon yellow add that to prepare dilute hydrochloric acid water-soluble
Liquid dissolves.
(5) preparation of medicine film
Tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion is added stirring while adding in the rubber cement preparing.
Treat that tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion stirs, add the sulphuric acid celebrating dissolved in (4) mould greatly
The materials such as element, dexamethasone acetate, stirring while adding until color even.
The medicine film packaging that above-mentioned medicine slurry is made regulation obtains final product.Even compact, flexible is answered after gained film is to be dried.
(6) pack
After the assay was approved, by equipment plastic film mulch, drying and pack and obtain final product compound gentamicin film.
(1) present invention investigates, by above three embodiment, the compound gentamicin that the present invention of three batches is obtained respectively
Film product, is described below in detail:
First takes 5 box compound gentamicin film products to carry out character, discriminating, uniformity of dosage units, dissolve the time limit, to fourth ammonia
The inspection that yl benzoic acid, gentamycin sulfate, tetracaine hydrochloride, dexamethasone acetate and microbial limit measure specifically see table
Second batch takes 5 box compound gentamicin film products to carry out character, discriminating, uniformity of dosage units, dissolve the time limit, to fourth ammonia
The inspection that yl benzoic acid, gentamycin sulfate, tetracaine hydrochloride, dexamethasone acetate and microbial limit measure specifically see table
3rd batch takes 5 box compound gentamicin film products to carry out character, discriminating, uniformity of dosage units, dissolve the time limit, to fourth ammonia
The inspection that yl benzoic acid, gentamycin sulfate, tetracaine hydrochloride, dexamethasone acetate and microbial limit measure specifically see table
Compound gentamicin film product 5 box obtained by traditional handicraft is taken to carry out character, discriminating, uniformity of dosage units, dissolve
The inspection that time limit, P-butylaminobenzoic acid, gentamycin sulfate, tetracaine hydrochloride, dexamethasone acetate and microbial limit measure
Look into and be 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 | 3rd batch | Traditional handicraft |
| Character | Meet regulation | Meet regulation | Meet regulation | Meet regulation |
| Differentiate | 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% |
| Gentamycin sulfate | 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 | Qualified | Qualified | Qualified | Qualified |
Go up data analysiss: the compound gentamicin film being obtained by the present invention according to this, measure data and be obtained with traditional handicraft
Compound gentamicin film product compare, dissolve that the time limit is shorter, gentamycin sulfate, tetracaine hydrochloride, dexamethasone acetate
Content is higher, and impurity P-butylaminobenzoic acid is less.
The product stability that the present invention is obtained is investigated:
Acceleration study continuously investigates three batches；Experiment condition: after product is packed by market sale packing specification requirement,
Put in Acceleration study equipment, 40 DEG C ± 2 DEG C of design temperature；Humidity 75% ± 5%, places 6 months, by 1 month, 2 months, 3
Individual month, 6 the end of month were separately sampled once, the character of high spot reviews compound gentamicin film product, discriminating, uniformity of dosage units, molten
Change time limit, P-butylaminobenzoic acid, gentamycin sulfate, tetracaine hydrochloride, dexamethasone acetate and microbial limit to measure, number
According to being shown in Table 10
Table 10: investigate the related data of the compound gentamicin film product accelerated test of three batches
Long-term experiment continuously investigates 3 batches: experiment condition: product is pressed after market sale packing specification packaging, puts into
In experimental facilitiess, 25 DEG C ± 2 DEG C of design temperature；Humidity 60% ± 10%, places 24 months, by 0 month, 3 months, 6 months, 9
Individual month, 12 months, 18 months, 24 the end of month were separately sampled once, the character of high spot reviews compound gentamicin film product, mirror
Not, uniformity of dosage units, dissolve the time limit, P-butylaminobenzoic acid, gentamycin sulfate, tetracaine hydrochloride, dexamethasone acetate and
Microbial limit measures, and data is shown in Table 11
Table 11: investigate the related data of the compound gentamicin film product accelerated test of three batches
By study on the stability, this data is analyzed comparing, result shows the compound gentamicin that the present invention is obtained
Film product quality is stable, and method is reliable, on the basis of original prescription, by the matter improving the product of the present invention obtaining of technique
Amount has sufficient guarantee.
Claims (1)
1. a kind of preparation technology of compound gentamicin film comprises the steps
(1) weighing, dispensing
Get gentamycin sulfate 750-770 part, tetracaine hydrochloride 2000-2100 part, dexamethasone acetate 50- by weight
60 parts, polyvinyl alcohol (pva) is appropriate, appropriate shitosan, appropriate sodium sulfite, appropriate steviosin, appropriate tartaric acid, beautiful indigo plant
In right amount, appropriate lemon yellow；The verification name of an article, specification, lot number, quantity, weigh up by material, and have special messenger to check；
(2) preparation of tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion
Take tetracaine hydrochloride to get by weight 1:2 with HP-β-CD, take HP-β-CD to be placed in beaker,
Plus a certain amount of purified water is allowed to saturation, heating for dissolving simultaneously cools down；Then tetracaine hydrochloride magnetic force under the conditions of 60 DEG C is added to stir
Mix, inclusion about 2h, cooling, lyophilization obtains final product tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion；
(3) preparation of rubber cement
Take Purified water to add dilute hydrochloric acid and be configured to the diluted hydrochloric acid aqueous solution for 4 for the ph value；
By shitosan plus the above-mentioned diluted hydrochloric acid aqueous solution dissolving preparing in right amount；Standby；
Polyvinyl alcohol is added and states the diluted hydrochloric acid aqueous solution preparing, 100 DEG C of heating in water bath make dissolving, add the shell having dissolved to gather
Sugared and appropriate glycerol is so that 3% shitosan: 1.5% polyvinyl alcohol: glycerol=4:10:1, stirs evenly, obtains final product rubber cement solution；
(4) dissolving of other adjuvants
The diluted hydrochloric acid aqueous solution heating for dissolving that gentamycin sulfate is prepared, it is 95% that dexamethasone acetate adds volume of molecular
Ethanol dissolves, and remaining adjuvant sodium sulfite, steviosin, tartaric acid, beautiful blue, lemon yellow add that to 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 preparing；
Treat that tetracaine hydrochloride hydroxypropyl-beta-cyclodextrin inclusion stirs, the middle gentamycin sulfate having dissolved of addition (4),
The materials such as dexamethasone acetate, stirring while adding until color even；
The medicine film packaging that above-mentioned medicine slurry is made regulation obtains final product；Even compact, flexible is answered after gained film is to be dried；
(6) pack
After the assay was approved, by equipment plastic film mulch, drying and pack and obtain final product compound gentamicin film.
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