CN108434437A - A kind of compound ointment preparation and preparation method thereof - Google Patents
A kind of compound ointment preparation and preparation method thereof Download PDFInfo
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- 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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- 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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Abstract
The present invention provides a kind of compound ointment preparation, and the weight of each component includes in every kilogram of ointment formulation in the compound ointment preparation：250 1,000 ten thousand unit of aerosporin, 300 400 ten thousand unit of neomycinsulphate, 25 75 ten thousand unit of bacitracin, 30 50g of lidocaine hydrochloride, matrix add to recipe quantity；Wherein, the matrix includes one or more in albolene, yellow petroleum jelly, ceresine, atoleine, α cyclodextrin, modification of chitosan, propylene glycol, methyl p-hydroxybenzoate, dibutyl hydroxy toluene.
Description
Technical field
The invention belongs to technical field of medicine, in particular it relates to a kind of compound ointment preparation and its preparation
Method.
Background technology
Transdermal drug delivery system refers to being administered in skin surface, so that drug is penetrated skin with certain rate, into human body blood
The effect of liquid cycle generates locally or systemically.Due to such preparation can effectively avoid liver first pass effect and gastrointestinal tract to medicine
The degradation of object reduces the adverse reaction of drug, is the hot spot of third generation pharmaceutical preparation research and development.Due to the knot of skin
Structure, drug are difficult to spread, penetrate, penetrate into absorption.Increase the effective area of transdermal drug delivery system and improves the scalp rate of drug
It can promote the Transdermal absorption of drug, but the limited area of transdermal drug delivery system, therefore the percutaneous rate for improving drug is to make clear of
The key of skin administration.
Lidocaine hydrochloride is clinically common amides local anesthetic, has that anesthetic effect is fast and strong, penetration power
Greatly, the feature of timeliness length, is a kind of ideal local anesthetic.Preparation capable of permeating skin related with lidocaine hydrochloride has patch, soft
Paste, gelling agent, mucilage.
A kind of ointment formulations of CN106075394A with and its preparation method and application all scholars in patent in ointment base
Woods uses as the matrix of excipient and making ointment, and the people that allergy is generated to it is few, almost without any side effects,
But the physiology moist environment for playing the protection surface of a wound in clinical application, keeping the surface of a wound, lubrication do not adhere to wound, are conducive to group
The self-regeneration knitted, vaseline play incomparable effect wherein.But in production technology, vaseline is as matrix
It is easily influenced by reaction temperature, and leads to lidocaine hydrochloride caking, is hardened, cannot be uniformly dispersed in matrix.
Therefore, in view of the above-mentioned problems, the present invention provides a kind of compound ointment preparation and preparation method thereof, not only antibacterial,
Good analgesic effect, the limitation for also overcoming matrix to be affected by temperature improve lidocaine hydrochloride and aerosporin, sulfuric acid
The dispersibility of neomycin, bacitracin in matrix.
Invention content
To solve the above-mentioned problems, first aspect present invention provides a kind of compound ointment preparation, the compound ointment preparation
In in every kilogram of ointment formulation the weight of each component include：Ten thousand units of aerosporin 250-1000, neomycinsulphate
Ten thousand units of 300-400, ten thousand units of bacitracin 25-75, lidocaine hydrochloride 30-50g, matrix add to recipe quantity；Wherein, the base
Matter includes albolene, yellow petroleum jelly, ceresine, atoleine, alpha-cyclodextrin, modification of chitosan, propylene glycol, P-hydroxybenzoic acid
It is one or more in methyl esters, dibutyl hydroxy toluene.
In one embodiment, the weight of each component includes in every kilogram of ointment formulation in the compound ointment preparation：
5,000,000 unit of aerosporin, 3,500,000 unit of neomycinsulphate, 500,000 unit of bacitracin, lidocaine hydrochloride 40g, base
Matter adds to recipe quantity.
In one embodiment, the matrix is albolene, atoleine, alpha-cyclodextrin, modification of chitosan, the third two
Alcohol, methyl p-hydroxybenzoate.
In one embodiment, albolene described in the matrix and the atoleine, the alpha-cyclodextrin, institute
It is 1 to state modification of chitosan, the propylene glycol, the weight ratio of the methyl p-hydroxybenzoate：(0.2-0.5)：(0.01-
0.05)：(0.01-0.3)：(0.05-0.1)：(0.001-0.01).
In one embodiment, albolene described in the matrix and the atoleine, the alpha-cyclodextrin, institute
It is 1 to state modification of chitosan, the propylene glycol, the weight ratio of the methyl p-hydroxybenzoate：(0.2-0.5)：(0.01-
0.03)：(0.05-0.2)：(0.05-0.1)：(0.001-0.005).
In one embodiment, the modification of chitosan includes that glycidyl methacrylate modified carboxy methyl shell is poly-
Sugar, glycidyl ether modified carboxymethyl chitosan, arginine and gluconic acid modified carboxymethyl chitosan.
In one embodiment, glycidyl methacrylate modified carboxy methyl shell described in the modification of chitosan
Glycan and the glycidyl ether modified carboxymethyl chitosan, the arginine and gluconic acid modified carboxymethyl chitosan sugar weight
Than being 1：(0.2-1)：(0.1-2).
In one embodiment, the glycidyl methacrylate modified carboxy methyl chitosan and the shrink are sweet
Oily ether modified carboxy methyl chitosan, the arginine and gluconic acid modified carboxymethyl chitosan weight ratio are 1：(0.3-0.7)：
(0.5-1.5)。
In one embodiment, the grain size of the lidocaine hydrochloride is 50-100 μm.
Another aspect of the present invention provides a kind of preparation method of compound ointment preparation, includes the following steps：
(1) matrix is added into vacuum mixer, is warming up to 42-48 DEG C, lidocaine hydrochloride is then added and stirs 6-
10min, be added aerosporin, neomycinsulphate, bacitracin, stir 10-30min, vacuumize, keep vacuum pressure-
0.04—-0.06Mpa；
(2) vacuum mixer lid is opened, the material scraper stirred on wall surrounding and blender is entered in blender, after
Stirrer cover is closed, is vacuumized, keeps vacuum pressure in-0.04-- 0.06Mpa, stirs 10-30min；
(3) it is again turned on vacuum mixer lid, the material scraper stirred on wall surrounding and blender is entered in blender, is tied
Stirrer cover is closed after beam, is vacuumized, and is kept vacuum pressure in-0.04-- 0.06Mpa, is stirred 10-30min；
(4) homogeneous after mixing, is cooled to 35-42 DEG C in step (3), stops stirring, preparation is filling, obtains described multiple
Square ointment formulation.
The above-mentioned of the application and other features, aspect and advantage is more readily understood with reference to following detailed description.
Specific implementation mode
The detailed description for preferred implementation method of the invention below of participating in the election of and including embodiment this hair can be more easily understood
Bright content.Unless otherwise defined, all technologies used herein and scientific terminology have common with fields of the present invention
The normally understood identical meaning of technical staff.When there is a conflict, the definition in this specification shall prevail.
As used herein term " by ... prepare " it is synonymous with "comprising".Term "comprising" used herein, " comprising ",
" having ", " containing " or its any other deformation, it is intended that cover non-exclusionism includes.For example, the combination comprising listed elements
Object, step, method, product or device are not necessarily limited to those elements, but may include not expressly listed other elements or
Such composition, step, method, product or the intrinsic element of device.
Conjunction " Consists of " excludes any element that do not point out, step or component.If in claim, this
Phrase will make claim be closed, so that it is not included the material in addition to the material of those descriptions, but relative normal
Except rule impurity.When being rather than immediately following after theme in the clause that phrase " Consists of " appears in claim main body,
It is only limited to the element described in the clause；Other elements are not excluded except the claim as a whole.
Equivalent, concentration or other values or parameter are excellent with range, preferred scope or a series of upper limit preferred values and lower limit
When the Range Representation that choosing value limits, this, which should be understood as, specifically discloses by any range limit or preferred value and any range
Any pairing of lower limit or preferred value is formed by all ranges, regardless of whether the range separately discloses.For example, when open
When range " 1 to 5 ", described range should be interpreted as including range " 1 to 4 ", " 1 to 3 ", " 1 to 2 ", " 1 to 2 and 4 to
5 ", " 1 to 3 and 5 " etc..When numberical range is described herein, unless otherwise stated, otherwise range intention includes its end
Value and all integers and score in the range.
Singulative includes that plural number discusses object, unless the context clearly dictates otherwise." optional " or it is " arbitrary
It is a kind of " refer to that the item described thereafter or event may or may not occur, and the description include situation that event occurs and
The situation that event does not occur.
Approximate term in specification and claims is used for modifying quantity, and it is specific to indicate that the present invention is not limited to this
Quantity further includes the modified part of the acceptable change without lead to related basic function close to the quantity.Phase
It answers, modifies a numerical value with " about ", " about " etc., mean that the present invention is not limited to the exact numericals.In some examples, approximate
Term likely corresponds to the precision of the instrument of measured value.In present specification and claims, range limits can be with
Combination and/or exchange, these ranges include all subranges contained therebetween if not stated otherwise.
In addition, indefinite article "an" before element of the present invention or component and "one" quantitative requirement to element or component
(i.e. occurrence number) unrestriction.Therefore "one" or "an" should be read as including one or at least one, and odd number
The element or component of form also include plural form, unless the apparent purport of the quantity refers to singulative.
First aspect present invention provides a kind of compound ointment preparation, in the compound ointment preparation in every kilogram of ointment formulation
The weight of each component includes：Ten thousand units of aerosporin 250-1000, ten thousand units of neomycinsulphate 300-400, bacitracin
Ten thousand units of 25-75, lidocaine hydrochloride 30-50g, matrix add to recipe quantity；Wherein, the matrix includes albolene, Huang Fan
Intellectual circle, ceresine, atoleine, alpha-cyclodextrin, modification of chitosan, propylene glycol, methyl p-hydroxybenzoate, dibutyl hydroxy toluene
In it is one or more.
In one embodiment, the weight of each component includes in every kilogram of ointment formulation in the compound ointment preparation：
5,000,000 unit of aerosporin, 3,500,000 unit of neomycinsulphate, 500,000 unit of bacitracin, lidocaine hydrochloride 40g, base
Matter adds to recipe quantity.
In one embodiment, the weight of each component includes in every kilogram of ointment formulation in the compound ointment preparation：
Ten thousand units of aerosporin 250-1000, ten thousand units of neomycinsulphate 300-400, ten thousand units of Bacitracin Zinc 25-75, hydrochloric acid
Lidocaine 30-50g, matrix add to recipe quantity；Wherein, the matrix includes albolene, yellow petroleum jelly, ceresine, liquid stone
It is one or more in wax, alpha-cyclodextrin, modification of chitosan, propylene glycol, methyl p-hydroxybenzoate, dibutyl hydroxy toluene.
In one embodiment, the weight of each component includes in every kilogram of ointment formulation in the compound ointment preparation：
5,000,000 unit of aerosporin, 3,500,000 unit of neomycinsulphate, 500,000 unit of Bacitracin Zinc, lidocaine hydrochloride 40g,
Matrix adds to recipe quantity.
In one embodiment, the matrix is albolene, atoleine, alpha-cyclodextrin, modification of chitosan, the third two
Alcohol, methyl p-hydroxybenzoate.
In one embodiment, albolene described in the matrix and the atoleine, the alpha-cyclodextrin, institute
It is 1 to state modification of chitosan, the propylene glycol, the weight ratio of the methyl p-hydroxybenzoate：(0.2-0.5)：(0.01-
0.05)：(0.01-0.3)：(0.05-0.1)：(0.001-0.01).
In one embodiment, albolene described in the matrix and the atoleine, the alpha-cyclodextrin, institute
It is 1 to state modification of chitosan, the propylene glycol, the weight ratio of the methyl p-hydroxybenzoate：(0.2-0.5)：(0.01-
0.03)：(0.05-0.2)：(0.05-0.1)：(0.001-0.005)；Preferably, the albolene and the atoleine,
The alpha-cyclodextrin, the modification of chitosan, the propylene glycol, the weight ratio of the methyl p-hydroxybenzoate are 1：0.3：
0.024：0.16：0.07：0.003.
In one embodiment, the modification of chitosan includes that glycidyl methacrylate modified carboxy methyl shell is poly-
Sugar, glycidol ether (CAS：13236-02-7) modified carboxy methyl chitosan, arginine and gluconic acid modified carboxymethyl chitosan
Sugar.
In one embodiment, glycidyl methacrylate modified carboxy methyl shell described in the modification of chitosan
Glycan and the glycidyl ether modified carboxymethyl chitosan, the arginine and gluconic acid modified carboxymethyl chitosan sugar weight
Than being 1：(0.2-1)：(0.1-2).
In one embodiment, the glycidyl methacrylate modified carboxy methyl chitosan and the shrink are sweet
Oily ether modified carboxy methyl chitosan, the arginine and gluconic acid modified carboxymethyl chitosan weight ratio are 1：(0.3-0.7)：
(0.5-1.5)；Preferably, the glycidyl methacrylate modified carboxy methyl chitosan and the glycidyl ether modified
Carboxymethyl chitosan, the arginine and gluconic acid modified carboxymethyl chitosan weight ratio are 1：0.5：1.3.
Carboxymethyl chitosan is purchased from Jiangsu again up to Pharmaceutical Technology Co., Ltd in the present invention.
The preparation method of the glycidyl methacrylate modified carboxy methyl chitosan includes the following steps：
Carboxymethyl chitosan, the purified water that number-average molecular weight is 9000 are added into reactor, is warming up to 50 DEG C, stirring
0.5h, is cooled to 30 DEG C, is added triethylamine, glycidyl methacrylate, tetrabutylammonium bromide, insulation reaction 72h, later
Absolute ethyl alcohol precipitation, deionized water dialysis 48h, 48h is lyophilized in -42 DEG C, and freeze-drying obtains the glycidyl methacrylate
Modified carboxy methyl chitosan；The carboxymethyl chitosan and the purified water, the triethylamine, the Glycidyl methacrylate are sweet
Grease, the tetrabutylammonium bromide, the weight ratio of the absolute ethyl alcohol are 1：50：3：5：5：50.
The preparation method of the glycidyl ether modified carboxymethyl chitosan includes the following steps：
Carboxymethyl chitosan, the purified water that number-average molecular weight is 10000 are added into reactor, is warming up to 50 DEG C, stirring
0.5h is cooled to 40 DEG C, triethylamine, glycidol ether, tetrabutylammonium bromide is added, insulation reaction 72h, absolute ethyl alcohol is heavy later
It forms sediment, deionized water dialysis 48h, 48h is lyophilized in -42 DEG C, freeze-drying obtains the glycidyl ether modified carboxymethyl chitosan；It is described
It is carboxymethyl chitosan and the purified water, the triethylamine, the glycidol ether, the tetrabutylammonium bromide, described anhydrous
The weight ratio of ethyl alcohol is 1：50：3：6：5：50.
The preparation method of the arginine and gluconic acid modified carboxymethyl chitosan includes the following steps：
Carboxymethyl chitosan, the 1mol/L HCl solutions that number-average molecular weight is 20000 are added into reactor, is warming up to 50
DEG C, 0.5h is stirred, is cooled to 30 DEG C, gluconic acid, EDC and NHS is added, and (NHS and EDC molar ratios are 1：4) 1mol/L, is used
The pH=5 of the solution tune solution of NaOH/1mol/L HCl, insulation reaction for 24 hours, the carboxymethyl chitosan and the HCl solution
Weight ratio be 1：50；The carboxymethyl chitosan is 1 with the gluconic acid, the EDC molar ratios：0.5：1.2；Essence is added
(NHS and EDC molar ratios are 1 by propylhomoserin, EDC and NHS：10), with the pH of the solution tune solution of 1mol/L NaOH/1mol/L HCl
=4.5, insulation reaction 48h, uses 1mol/L NaOH solutions to modulate pH=9, reaction solution is in bag filter after reaction at room temperature
It is dialysed 3 days with distilled water, the arginine and gluconic acid modified carboxymethyl chitosan is obtained after drying；The carboxymethyl chitosan
It is 1 with the arginine, the EDC molar ratios：1：0.5.
Arginine is alkaline positively charged amino acid, has excellent biocompatibility.Introducing arginine on main chain can
The biocompatibility of chitosan is effectively improved, arginine contains guanidino group, positively charged after protonation, can be negatively charged with surface
Bacterial action, to reach certain fungistatic effect.
In one embodiment, the grain size of the lidocaine hydrochloride is 50-100 μm；Preferably, the hydrochloric acid benefit
The grain size of cacaine is 50-75 μm.
The grain size of lidocaine hydrochloride is 50-75 μm in the present invention, and lidocaine hydrochloride grain size is less than 50 μm, hydrochloric acid benefit
Electrostatic interaction easily occurs between cacaine particle, reunites；Lidocaine hydrochloride grain size is more than 100 μm, influences product quality and treatment
Effect.
Another aspect of the present invention provides a kind of preparation method of compound ointment preparation, includes the following steps：
(1) matrix is added into vacuum mixer, is warming up to 42-48 DEG C, lidocaine hydrochloride is then added and stirs 6-
10min, be added aerosporin, neomycinsulphate, bacitracin, stir 10-30min, vacuumize, keep vacuum pressure-
0.04—-0.06Mpa；
(2) vacuum mixer lid is opened, the material scraper stirred on wall surrounding and blender is entered in blender, after
Stirrer cover is closed, is vacuumized, keeps vacuum pressure in-0.04-- 0.06Mpa, stirs 10-30min；
(3) it is again turned on vacuum mixer lid, the material scraper stirred on wall surrounding and blender is entered in blender, is tied
Stirrer cover is closed after beam, is vacuumized, and is kept vacuum pressure in-0.04-- 0.06Mpa, is stirred 10-30min；
(4) homogeneous after mixing, is cooled to 35-42 DEG C in step (3), stops stirring, preparation is filling, obtains described multiple
Square ointment formulation.
Active group amino and hydroxyl in chitosan molecule are both the activated centre of suction-operated, while being to hand over again
The active neutral of connection, chitosan and uncrosslinked chitosan after crosslinking acid-soluble, rigidity, adsorptivity, reusability and
Selectivity etc. all makes moderate progress.
Carboxymethyl chitosan is the general name of N- carboxymethyl chitosans, O-CMC, n,O-carboxymethyl chitosan, point
In subchain containing hydroxyl, amino, carboxyl isopolarity group, substantially improve its water solubility, have preferable moisture-absorbing moisture-keeping function,
Biological degradability, film forming and antibiotic property, the effective inducing cytotoxic macrophage of carboxymethyl chitosan energy, also can induce thermophilic
The accumulation of neutrocyte.
Glycidol ether has epoxy group in the present invention, can crosslink effect, glycidol with the amino of chitosan
Ether modified carboxy methyl chitosan has excellent hygroscopicity and moisture retention, inhibits to Escherichia coli and staphylococcus aureus
Property, while without skin irritation.
Glycidyl methacrylate modified carboxy methyl chitosan, glycidyl ether modified carboxymethyl chitosan in the present invention
Sugar, arginine and gluconic acid modified carboxymethyl chitosan, biological safety is improved while improving anti-microbial property again；Tool
There is biodegradability, it is less toxic, compared with of low pollution in production process；Preparation method reaction condition is mild, is not necessarily to high temperature high pressure process,
And organic solvent is not used, and it is environmentally protective, it can be used for mass producing.
Ointment formulation Multiple Classes of Antibiotics acts synergistically in the present invention, provides not only complementary antimicrobial spectrum, makes antibacterial range
Expand, cover the bacterial skin infections pathogen of the overwhelming majority, by collaboration between antibiotic and synergistic effect, and then makes to resist
Bacterium effect enhancing, is not likely to produce inducible resistance.For skins such as prevention and treatment skin cuts, scratch, burn and scald, wounds
The bacterium infection of the surface of a wound and interim release have excellent curative effect.In addition, this ointment formulation has local bacterial skin infections
There is preventive and therapeutic effect, there is analgesic, anastalsis to local skin wound, the pain of patient can be mitigated, increase patient medication
Compliance and comfort.
By collaboration between antibiotic and synergistic effect, glycidyl methacrylate modified carboxy methyl shell is poly- in matrix
Sugar, glycidyl ether modified carboxymethyl chitosan, arginine and gluconic acid modified carboxymethyl chitosan synergistic effect, meanwhile,
Alpha-cyclodextrin and glycidyl methacrylate modified carboxy methyl chitosan, glycidyl ether modified carboxymethyl chitosan, essence
It is cross-linked with each other to form firm three-dimensional network between propylhomoserin and gluconic acid modified carboxymethyl chitosan, the matrix tool being prepared
There is excellent breathable moisture permeability, the physiology moist environment for playing the protection surface of a wound, keeping the surface of a wound, lubrication does not adhere to wound, favorably
In the self-regeneration of tissue.
The present invention is specifically described below by embodiment.It is necessarily pointed out that following embodiment is only used
In the invention will be further described, it should not be understood as limiting the scope of the invention, professional and technical personnel in the field
Some the nonessential modifications and adaptations made according to the content of aforementioned present invention, still fall within protection scope of the present invention.
In addition, if without other explanations, it is raw materials used to be all commercially available, it is purchased from traditional Chinese medicines chemical reagent.
Embodiment 1
The weight of each component includes in every kilogram of ointment formulation in the compound ointment preparation：Aerosporin 5,000,000
Unit, 3,500,000 unit of neomycinsulphate, 500,000 unit of bacitracin, lidocaine hydrochloride 40g, matrix add to recipe quantity；
Wherein, the matrix is albolene, atoleine, alpha-cyclodextrin, modification of chitosan, propylene glycol, para hydroxybenzene
Methyl formate；The albolene and the atoleine, the alpha-cyclodextrin, the modification of chitosan, the propylene glycol, institute
The weight ratio for stating methyl p-hydroxybenzoate is 1：0.3：0.024：0.16：0.07：0.003；The modification of chitosan includes first
Base glycidyl acrylate modified carboxy methyl chitosan, glycidyl ether modified carboxymethyl chitosan, arginine and glucose
Sour modified carboxy methyl chitosan；The glycidyl methacrylate modified carboxy methyl chitosan changes with the glycidol ether
Property carboxymethyl chitosan, the arginine and gluconic acid modified carboxymethyl chitosan weight ratio be 1：0.5：1.3；The hydrochloric acid
The grain size of lidocaine is 50-75 μm；
The preparation method of the compound ointment preparation, includes the following steps：
(1) matrix is added into vacuum mixer, is warming up to 42 DEG C, lidocaine hydrochloride is then added and stirs 10min, adds
Enter aerosporin, neomycinsulphate, bacitracin, stir 20min, vacuumize, keeps vacuum pressure-0.04--
0.06Mpa；
(2) vacuum mixer lid is opened, the material scraper stirred on wall surrounding and blender is entered in blender, after
Stirrer cover is closed, is vacuumized, keeps vacuum pressure in-0.04-- 0.06Mpa, stirs 20min；
(3) it is again turned on vacuum mixer lid, the material scraper stirred on wall surrounding and blender is entered in blender, is tied
Stirrer cover is closed after beam, is vacuumized, and is kept vacuum pressure in-0.04-- 0.06Mpa, is stirred 20min；
(4) homogeneous after mixing, is cooled to 35 DEG C in step (3), stops stirring, preparation is filling, obtains the compound
Ointment formulation.
The preparation method of the glycidyl methacrylate modified carboxy methyl chitosan includes the following steps：
Carboxymethyl chitosan, the purified water that number-average molecular weight is 9000 are added into reactor, is warming up to 50 DEG C, stirring
0.5h, is cooled to 30 DEG C, is added triethylamine, glycidyl methacrylate, tetrabutylammonium bromide, insulation reaction 72h, later
Absolute ethyl alcohol precipitation, deionized water dialysis 48h, 48h is lyophilized in -42 DEG C, and freeze-drying obtains the glycidyl methacrylate
Modified carboxy methyl chitosan；The carboxymethyl chitosan and the purified water, the triethylamine, the Glycidyl methacrylate are sweet
Grease, the tetrabutylammonium bromide, the weight ratio of the absolute ethyl alcohol are 1：50：3：5：5：50.
The preparation method of the glycidyl ether modified carboxymethyl chitosan includes the following steps：
Carboxymethyl chitosan, the purified water that number-average molecular weight is 10000 are added into reactor, is warming up to 50 DEG C, stirring
0.5h is cooled to 40 DEG C, triethylamine, glycidol ether, tetrabutylammonium bromide is added, insulation reaction 72h, absolute ethyl alcohol is heavy later
It forms sediment, deionized water dialysis 48h, 48h is lyophilized in -42 DEG C, freeze-drying obtains the glycidyl ether modified carboxymethyl chitosan；It is described
It is carboxymethyl chitosan and the purified water, the triethylamine, the glycidol ether, the tetrabutylammonium bromide, described anhydrous
The weight ratio of ethyl alcohol is 1：50：3：6：5：50.
The preparation method of the arginine and gluconic acid modified carboxymethyl chitosan includes the following steps：
Carboxymethyl chitosan, the 1mol/L HCl solutions that number-average molecular weight is 20000 are added into reactor, is warming up to 50
DEG C, 0.5h is stirred, is cooled to 30 DEG C, gluconic acid, EDC and NHS is added, and (NHS and EDC molar ratios are 1：4) 1mol/L, is used
The pH=5 of the solution tune solution of NaOH/1mol/L HCl, insulation reaction for 24 hours, the carboxymethyl chitosan and the HCl solution
Weight ratio be 1：50；The carboxymethyl chitosan is 1 with the gluconic acid, the EDC molar ratios：0.5：1.2；Essence is added
(NHS and EDC molar ratios are 1 by propylhomoserin, EDC and NHS：10), with the pH of the solution tune solution of 1mol/L NaOH/1mol/L HCl
=4.5, insulation reaction 48h, uses 1mol/L NaOH solutions to modulate pH=9, reaction solution is in bag filter after reaction at room temperature
It is dialysed 3 days with distilled water, the arginine and gluconic acid modified carboxymethyl chitosan is obtained after drying；The carboxymethyl chitosan
It is 1 with the arginine, the EDC molar ratios：1：0.5.
Embodiment 2
The weight of each component includes in every kilogram of ointment formulation in the compound ointment preparation：Aerosporin 5,000,000
Unit, 3,500,000 unit of neomycinsulphate, 500,000 unit of bacitracin, lidocaine hydrochloride 40g, matrix add to recipe quantity；
Wherein, the matrix is albolene, atoleine, alpha-cyclodextrin, modification of chitosan, propylene glycol, para hydroxybenzene
Methyl formate；The albolene and the atoleine, the alpha-cyclodextrin, the modification of chitosan, the propylene glycol, institute
The weight ratio for stating methyl p-hydroxybenzoate is 1：0.3：0.024：0.05：0.07：0.003；The modification of chitosan includes first
Base glycidyl acrylate modified carboxy methyl chitosan, glycidyl ether modified carboxymethyl chitosan, arginine and glucose
Sour modified carboxy methyl chitosan；The glycidyl methacrylate modified carboxy methyl chitosan changes with the glycidol ether
Property carboxymethyl chitosan, the arginine and gluconic acid modified carboxymethyl chitosan weight ratio be 1：0.5：1.3；The hydrochloric acid
The grain size of lidocaine is 50-75 μm；
The preparation method of the compound ointment preparation, the glycidyl methacrylate modified carboxy methyl chitosan
Preparation method, the preparation method of the glycidyl ether modified carboxymethyl chitosan, the arginine and gluconic acid modified carboxylic
The preparation method is the same as that of Example 1 for methyl chitosan.
Embodiment 3
The weight of each component includes in every kilogram of ointment formulation in the compound ointment preparation：Aerosporin 5,000,000
Unit, 3,500,000 unit of neomycinsulphate, 500,000 unit of bacitracin, lidocaine hydrochloride 40g, matrix add to recipe quantity；
Wherein, the matrix is albolene, atoleine, alpha-cyclodextrin, modification of chitosan, propylene glycol, para hydroxybenzene
Methyl formate；The albolene and the atoleine, the alpha-cyclodextrin, the modification of chitosan, the propylene glycol, institute
The weight ratio for stating methyl p-hydroxybenzoate is 1：0.3：0.024：0.2：0.07：0.003；The modification of chitosan includes methyl
Glycidyl acrylate modified carboxy methyl chitosan, glycidyl ether modified carboxymethyl chitosan, arginine and gluconic acid
Modified carboxy methyl chitosan；The glycidyl methacrylate modified carboxy methyl chitosan and the glycidyl ether modified
Carboxymethyl chitosan, the arginine and gluconic acid modified carboxymethyl chitosan weight ratio are 1：0.5：1.3；The hydrochloric acid profit
The grain size of more cacaines is 50-75 μm；
The preparation method of the compound ointment preparation, the glycidyl methacrylate modified carboxy methyl chitosan
Preparation method, the preparation method of the glycidyl ether modified carboxymethyl chitosan, the arginine and gluconic acid modified carboxylic
The preparation method is the same as that of Example 1 for methyl chitosan.
Embodiment 4
The weight of each component includes in every kilogram of ointment formulation in the compound ointment preparation：Aerosporin 5,000,000
Unit, 3,500,000 unit of neomycinsulphate, 500,000 unit of bacitracin, lidocaine hydrochloride 40g, matrix add to recipe quantity；
Wherein, the matrix is albolene, atoleine, alpha-cyclodextrin, modification of chitosan, propylene glycol, para hydroxybenzene
Methyl formate；The albolene and the atoleine, the alpha-cyclodextrin, the modification of chitosan, the propylene glycol, institute
The weight ratio for stating methyl p-hydroxybenzoate is 1：0.3：0.024：0.16：0.07：0.003；The modification of chitosan includes first
Base glycidyl acrylate modified carboxy methyl chitosan, glycidyl ether modified carboxymethyl chitosan, arginine and glucose
Sour modified carboxy methyl chitosan；The glycidyl methacrylate modified carboxy methyl chitosan changes with the glycidol ether
Property carboxymethyl chitosan, the arginine and gluconic acid modified carboxymethyl chitosan weight ratio be 1：0.2：0.1；The hydrochloric acid
The grain size of lidocaine is 50-75 μm；
The preparation method of the compound ointment preparation, the glycidyl methacrylate modified carboxy methyl chitosan
Preparation method, the preparation method of the glycidyl ether modified carboxymethyl chitosan, the arginine and gluconic acid modified carboxylic
The preparation method is the same as that of Example 1 for methyl chitosan.
Embodiment 5
The weight of each component includes in every kilogram of ointment formulation in the compound ointment preparation：Aerosporin 5,000,000
Unit, 3,500,000 unit of neomycinsulphate, 500,000 unit of bacitracin, lidocaine hydrochloride 40g, matrix add to recipe quantity；
Wherein, the matrix is albolene, atoleine, alpha-cyclodextrin, modification of chitosan, propylene glycol, para hydroxybenzene
Methyl formate；The albolene and the atoleine, the alpha-cyclodextrin, the modification of chitosan, the propylene glycol, institute
The weight ratio for stating methyl p-hydroxybenzoate is 1：0.3：0.024：0.16：0.07：0.003；The modification of chitosan includes first
Base glycidyl acrylate modified carboxy methyl chitosan, glycidyl ether modified carboxymethyl chitosan, arginine and glucose
Sour modified carboxy methyl chitosan；The glycidyl methacrylate modified carboxy methyl chitosan changes with the glycidol ether
Property carboxymethyl chitosan, the arginine and gluconic acid modified carboxymethyl chitosan weight ratio be 1：1：2；The hydrochloric acid benefit
The grain size of cacaine is 50-75 μm；
The preparation method of the compound ointment preparation, the glycidyl methacrylate modified carboxy methyl chitosan
Preparation method, the preparation method of the glycidyl ether modified carboxymethyl chitosan, the arginine and gluconic acid modified carboxylic
The preparation method is the same as that of Example 1 for methyl chitosan.
Comparative example 1
The weight of each component includes in every kilogram of ointment formulation in the compound ointment preparation：Aerosporin 5,000,000
Unit, 3,500,000 unit of neomycinsulphate, 500,000 unit of bacitracin, lidocaine hydrochloride 40g, matrix add to recipe quantity；
Wherein, the matrix is albolene, atoleine, alpha-cyclodextrin, modification of chitosan, propylene glycol, para hydroxybenzene
Methyl formate；The albolene and the atoleine, the alpha-cyclodextrin, the modification of chitosan, the propylene glycol, institute
The weight ratio for stating methyl p-hydroxybenzoate is 1：0.3：0.024：0.16：0.07：0.003；The modification of chitosan is methyl
Glycidyl acrylate modified carboxy methyl chitosan；The grain size of the lidocaine hydrochloride is 50-75 μm；
The preparation method of the compound ointment preparation, the glycidyl methacrylate modified carboxy methyl chitosan
The preparation method is the same as that of Example 1.
Comparative example 2
The weight of each component includes in every kilogram of ointment formulation in the compound ointment preparation：Aerosporin 5,000,000
Unit, 3,500,000 unit of neomycinsulphate, 500,000 unit of bacitracin, lidocaine hydrochloride 40g, matrix add to recipe quantity；
Wherein, the matrix is albolene, atoleine, alpha-cyclodextrin, modification of chitosan, propylene glycol, para hydroxybenzene
Methyl formate；The albolene and the atoleine, the alpha-cyclodextrin, the modification of chitosan, the propylene glycol, institute
The weight ratio for stating methyl p-hydroxybenzoate is 1：0.3：0.024：0.16：0.07：0.003；The modification of chitosan is to shrink
Glycerin ether modified carboxy methyl chitosan；The grain size of the lidocaine hydrochloride is 50-75 μm；
The preparation method of the compound ointment preparation, the preparation method of the glycidyl ether modified carboxymethyl chitosan are same
Embodiment 1.
Comparative example 3
The weight of each component includes in every kilogram of ointment formulation in the compound ointment preparation：Aerosporin 5,000,000
Unit, 3,500,000 unit of neomycinsulphate, 500,000 unit of bacitracin, lidocaine hydrochloride 40g, matrix add to recipe quantity；
Wherein, the matrix is albolene, atoleine, alpha-cyclodextrin, modification of chitosan, propylene glycol, para hydroxybenzene
Methyl formate；The albolene and the atoleine, the alpha-cyclodextrin, the modification of chitosan, the propylene glycol, institute
The weight ratio for stating methyl p-hydroxybenzoate is 1：0.3：0.024：0.16：0.07：0.003；The modification of chitosan is smart ammonia
Sour and gluconic acid modified carboxymethyl chitosan；The grain size of the lidocaine hydrochloride is 50-75 μm；
The preparation of the preparation method, the arginine and gluconic acid modified carboxymethyl chitosan of the compound ointment preparation
Method is the same as embodiment 1.
Comparative example 4
The weight of each component includes in every kilogram of ointment formulation in the compound ointment preparation：Aerosporin 5,000,000
Unit, 3,500,000 unit of neomycinsulphate, 500,000 unit of bacitracin, lidocaine hydrochloride 40g, matrix add to recipe quantity；
Wherein, the matrix be albolene, atoleine, alpha-cyclodextrin, carboxymethyl chitosan, propylene glycol, to hydroxyl
Methyl benzoate；The albolene and the atoleine, the alpha-cyclodextrin, the carboxymethyl chitosan, described the third two
Alcohol, the methyl p-hydroxybenzoate weight ratio be 1：0.3：0.024：0.16：0.07：0.003；The lidocaine hydrochloride
Grain size be 50-75 μm；
The preparation method of the compound ointment preparation, the glycidyl methacrylate modified carboxy methyl chitosan
Preparation method, the preparation method of the glycidyl ether modified carboxymethyl chitosan, the arginine and gluconic acid modified carboxylic
The preparation method is the same as that of Example 1 for methyl chitosan.
Comparative example 5
The weight of each component includes in every kilogram of ointment formulation in the compound ointment preparation：Aerosporin 5,000,000
Unit, 3,500,000 unit of neomycinsulphate, 500,000 unit of bacitracin, lidocaine hydrochloride 40g, matrix add to recipe quantity；
Wherein, the matrix is albolene, atoleine, alpha-cyclodextrin, modification of chitosan, propylene glycol, para hydroxybenzene
Methyl formate；The albolene and the atoleine, the alpha-cyclodextrin, the modification of chitosan, the propylene glycol, institute
The weight ratio for stating methyl p-hydroxybenzoate is 1：0.3：0.024：0.16：0.07：0.003；The modification of chitosan includes first
Base glycidyl acrylate modified carboxy methyl chitosan, glycidyl ether modified carboxymethyl chitosan, arginine and glucose
Sour modified carboxy methyl chitosan；The glycidyl methacrylate modified carboxy methyl chitosan changes with the glycidol ether
Property carboxymethyl chitosan, the arginine and gluconic acid modified carboxymethyl chitosan weight ratio be 1：0.5：1.3；The hydrochloric acid
The grain size of lidocaine is 100 μm；
The preparation method of the compound ointment preparation, the glycidyl methacrylate modified carboxy methyl chitosan
Preparation method, the preparation method of the glycidyl ether modified carboxymethyl chitosan, the arginine and gluconic acid modified carboxylic
The preparation method is the same as that of Example 1 for methyl chitosan.
Comparative example 6
The weight of each component includes in every kilogram of ointment formulation in the compound ointment preparation：Aerosporin 5,000,000
Unit, 3,500,000 unit of neomycinsulphate, 500,000 unit of bacitracin, lidocaine hydrochloride 40g, matrix add to recipe quantity；
Wherein, the matrix is albolene；The grain size of the lidocaine hydrochloride is 50-75 μm；
The preparation method is the same as that of Example 1 for the compound ointment preparation.
Performance test：
1, the vitro antibacterial activity experiment of ointment
Method：By bacteria suspension 0.5ml and this product ointment (control group phosphate buffer) 4.5ml mixings.Effect is extremely
Predetermined time takes 0.5ml bacterium medicine mixed liquors, is added in the test tube for filling 4.5ml neutralizers, mixing.Neutralization 10min makees
Count plate calculates sterilization rate.
The preparation of bacteria suspension：Test organisms is Escherichia coli (8099), staphylococcus aureus (ATCC6538).Take its 3rd
~14 generation ordinary nutrient agars fresh cultured object for 24 hours, being diluted to bacteria containing amount with 0.03mol/L phosphate buffers (pH 7.2) is
106~107The bacteria suspension of cfu/ml.
Neutralizer：Phosphate buffer containing 0.5% lecithin, 3.0% Tween 80 and 0.1% histidine.
2, skin irritation test：
For 24 hours, using suitable depilatory agent or shaver, all tested rabbit back backbone both sides are gone before experiment for method
Hair is (per side about 3 × 3cm2, no erythema, oedema and breakage).20 rabbit are randomly divided into 5 groups, every group 4, if single has been smeared
Whole skin group, single smear damaged skin group, repeatedly smear intact skin group, repeatedly smear damaged skin group, smear administration
(damaged skin group, every family's rabbit back backbone both sides go hair-fields before the topical application of drug with syringe needle apply about area skin draw " well " word with
Oozing of blood is degree or is ground with sand paper), left side is tested area, and right side is check plot.0.02g/cm is pressed respectively2Ointment is given, with one
2.5 × 2.5cm of layer2Preservative film covers moisturizing, then adds gauze covering protection, finally suitably solid with nonirritant adhesive plaster and bandage
It is fixed.Single smearing group：6h after smearing washes away remaining ointment with warm water；Multiple smearing group：1 time/d, continuous 7d, last applies
Rear 6h is smeared, remaining ointment is washed away with warm water.Single smearing group remove tested material after 1h, for 24 hours, 48h, 72h observe spreader portion
Position situations such as whether there is or not erythema and oedema and recovery situation and the time of above-mentioned variation, multiple smearing group is in removal ointment every time
It 1h and observes and records before smearing again after agent and smears position erythema oedema and whether have pigmentation, blutpunkte, a pachylosis
Or situations such as epidermatic atrophy, occurs and its regression time, and score erythema oedema, after removing tested material after the last administration
1h, for 24 hours, 48h, 72h observation smear recovery situation and the time of situations such as whether there is or not erythema and oedema at position and above-mentioned variation.
Skin irritation reacts standards of grading：
Erythema：Without erythema (reluctantly visible), 0 point；Slight 1 point of erythema (clearly visible)；Moderate erythema, 2 points；Severe is red
Spot, 3 points；Aubergine erythema is formed to slight eschar, 4 points.Oedema：Without oedema, 0 point；Mild edema (visible reluctantly), 1 point；In
Degree oedema (apparent protuberance), 2 points；Severe edema (cutaneous protuberance about 1mm, be clearly outlined), 3 points；(cutaneous protuberance is about for Severe edema
1mm or more simultaneously has expansion), 4 points.
Skin irritation intensity evaluation standard：0-0.49 points of mean scores, it is nonirritant；0.5-2.99 points, slight stimulation
Property；3.0-5.99 points, moderate irritation；6.0-8.0 point, strong and stimulating.
3, moisture-absorbing moisture-keeping performance measures
1) moisture absorption determination of activity：The matrix that will be prepared in implementation is placed in 100 DEG C of baking ovens and dries 4h.0.5g accurately is weighed,
It is respectively placed in and maintains relative humidity (RH) to remain relatively wet for 81% and saturated aqueous sodium carbonate with saturated ammonium sulfate aqueous solution
Degree is moisture absorption in 43% drier, and 48h is weighed once, and parallel two parts are averaged.
Hydroscopicity (%)=(W1-W0) × 100/W0, W0 and W1 are respectively that matrix places forward and backward quality (g).
2) moisturizing determination of activity：The sample for being 10% with water content be placed in relative humidity be 81% and silica gel drier in
48h is weighed once, and parallel two parts are averaged.
Moisture survival rate (%)=100 × Hx/H0, H0, Hx are respectively the quality (g) for placing front and back moisture.
1 the performance test results of table
It is seen from the above data that a kind of compound ointment preparation provided by the invention and preparation method thereof, not only resists
Bacterium, good analgesic effect, the limitation for also overcoming matrix to be affected by temperature improve lidocaine hydrochloride and aerosporin, sulphur
The dispersibility of sour neomycin, bacitracin in matrix.
Example above-mentioned is merely illustrative, some features for explaining the method for the invention.Appended right is wanted
The range as wide as possible for being intended to require to be contemplated that is sought, and embodiments as presented herein is only according to all possible implementation
The explanation of the embodiment of the selection of the combination of example.Therefore, the purpose of applicant is that the attached claims are not illustrated this hair
The exemplary selectional restriction of bright feature.Some numberical ranges used also include sub- model in the claims
It encloses, the variation in these ranges should also be construed to be covered by the attached claims in the conceived case.
Claims (10)
1. a kind of compound ointment preparation, which is characterized in that each component in every kilogram of ointment formulation in the compound ointment preparation
Weight includes：Ten thousand units of aerosporin 250-1000, ten thousand units of neomycinsulphate 300-400, bacitracin 25-75 ten thousand are single
Position, lidocaine hydrochloride 30-50g, matrix add to recipe quantity；Wherein, the matrix include albolene, yellow petroleum jelly, ceresine,
It is a kind of or more in atoleine, alpha-cyclodextrin, modification of chitosan, propylene glycol, methyl p-hydroxybenzoate, dibutyl hydroxy toluene
Kind.
2. compound ointment preparation according to claim 1, which is characterized in that every kilogram of ointment system in the compound ointment preparation
The weight of each component includes in agent：5,000,000 unit of aerosporin, 3,500,000 unit of neomycinsulphate, bacitracin 500,000 are single
Position, lidocaine hydrochloride 40g, matrix add to recipe quantity.
3. compound ointment preparation according to claim 1, which is characterized in that the matrix is albolene, atoleine, α-
Cyclodextrin, modification of chitosan, propylene glycol, methyl p-hydroxybenzoate.
4. compound ointment preparation according to claim 3, which is characterized in that albolene described in the matrix and the liquid
Body paraffin, the alpha-cyclodextrin, the modification of chitosan, the propylene glycol, the weight ratio of the methyl p-hydroxybenzoate are
1：(0.2-0.5)：(0.01-0.05)：(0.01-0.3)：(0.05-0.1)：(0.001-0.01).
5. compound ointment preparation according to claim 4, which is characterized in that albolene described in the matrix and the liquid
Body paraffin, the alpha-cyclodextrin, the modification of chitosan, the propylene glycol, the weight ratio of the methyl p-hydroxybenzoate are
1：(0.2-0.5)：(0.01-0.03)：(0.05-0.2)：(0.05-0.1)：(0.001-0.005).
6. compound ointment preparation according to claim 1, which is characterized in that the modification of chitosan includes methacrylic acid contracting
Water glyceride modified carboxy methyl chitosan, glycidyl ether modified carboxymethyl chitosan, arginine and gluconic acid modified carboxylic first
Base enclosure glycan.
7. compound ointment preparation according to claim 6, which is characterized in that methacrylic acid described in the modification of chitosan
Ethylene oxidic ester modified carboxy methyl chitosan and the glycidyl ether modified carboxymethyl chitosan, the arginine and glucose
Sour modified carboxy methyl chitosan weight ratio is 1：(0.2-1)：(0.1-2).
8. compound ointment preparation according to claim 7, which is characterized in that the glycidyl methacrylate is modified carboxylic
Methyl chitosan and the glycidyl ether modified carboxymethyl chitosan, the arginine and gluconic acid modified carboxymethyl chitosan
Sugar weight ratio is 1：(0.3-0.7)：(0.5-1.5).
9. compound ointment preparation according to claim 7, which is characterized in that the grain size of the lidocaine hydrochloride is 50-100
μm。
10. according to the preparation method of any one of the claim 1-9 compound ointment preparations, which is characterized in that including following step
Suddenly：
(1) matrix is added into vacuum mixer, is warming up to 42-48 DEG C, lidocaine hydrochloride is then added and stirs 6-10min,
Be added aerosporin, neomycinsulphate, bacitracin, stir 10-30min, vacuumize, keep vacuum pressure-
0.04—-0.06Mpa；
(2) open vacuum mixer lid, the material scraper stirred on wall surrounding and blender entered in blender, after close
Stirrer cover vacuumizes, and keeps vacuum pressure in-0.04-- 0.06Mpa, stirs 10-30min；
(3) it is again turned on vacuum mixer lid, the material scraper stirred on wall surrounding and blender is entered in blender, after
Stirrer cover is closed, is vacuumized, keeps vacuum pressure in-0.04-- 0.06Mpa, stirs 10-30min；
(4) homogeneous after mixing, is cooled to 35-42 DEG C in step (3), stops stirring, preparation is filling, and it is soft to obtain the compound
Paste formulation.
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| CN112121146A (en) * | 2019-06-25 | 2020-12-25 | 山东瑞安药业有限公司 | A topical gel for treating skin wound, and its preparation method |
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| CN101225125A (en) * | 2008-01-18 | 2008-07-23 | 烟台海岸带可持续发展研究所 | Moisture absorption humectant and method for preparing same |
| CN103739862A (en) * | 2013-07-25 | 2014-04-23 | 天津大学 | Gelatin/carboxymethyl chitosan/POSS (polyhedral oligomeric silsesquioxane) photo-crosslinking hydrogel and preparation method |
| CN106075394A (en) * | 2016-06-15 | 2016-11-09 | 浙江日升昌药业有限公司 | A kind of ointment formulation with and its preparation method and application |
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2018
- 2018-06-12 CN CN201810619563.7A patent/CN108434437A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101225125A (en) * | 2008-01-18 | 2008-07-23 | 烟台海岸带可持续发展研究所 | Moisture absorption humectant and method for preparing same |
| CN103739862A (en) * | 2013-07-25 | 2014-04-23 | 天津大学 | Gelatin/carboxymethyl chitosan/POSS (polyhedral oligomeric silsesquioxane) photo-crosslinking hydrogel and preparation method |
| CN106075394A (en) * | 2016-06-15 | 2016-11-09 | 浙江日升昌药业有限公司 | A kind of ointment formulation with and its preparation method and application |
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| CN112121146A (en) * | 2019-06-25 | 2020-12-25 | 山东瑞安药业有限公司 | A topical gel for treating skin wound, and its preparation method |
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Address after: 322100 No. 209 Hulian West Street, Dongyang City, Jinhua City, Zhejiang Province Applicant after: Zhejiang Funuo Pharmaceutical Co., Ltd. Address before: 322100 No. 209 Hulian West Street, Dongyang City, Jinhua City, Zhejiang Province Applicant before: Zhejiang Reachall Pharmaceutical Co., Ltd. |
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Application publication date: 20180824 |