CN104306408B - A kind of polysaccharide nucleic acid pharmaceutical composition for treating infantile eczema - Google Patents
A kind of polysaccharide nucleic acid pharmaceutical composition for treating infantile eczema Download PDFInfo
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- CN104306408B CN104306408B CN201410605276.2A CN201410605276A CN104306408B CN 104306408 B CN104306408 B CN 104306408B CN 201410605276 A CN201410605276 A CN 201410605276A CN 104306408 B CN104306408 B CN 104306408B
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- nucleic acid
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- 102000039446 nucleic acids Human genes 0.000 title claims abstract description 51
- 108020004707 nucleic acids Proteins 0.000 title claims abstract description 51
- 229920001282 polysaccharide Polymers 0.000 title claims abstract description 48
- 239000005017 polysaccharide Substances 0.000 title claims abstract description 48
- -1 polysaccharide nucleic acid Chemical class 0.000 title claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- 201000008937 atopic dermatitis Diseases 0.000 title claims abstract description 15
- 206010014198 Eczema infantile Diseases 0.000 title claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 22
- XVPBINOPNYFXID-JARXUMMXSA-N 85u4c366qs Chemical compound C([C@@H]1CCC[N@+]2(CCC[C@H]3[C@@H]21)[O-])N1[C@@H]3CCCC1=O XVPBINOPNYFXID-JARXUMMXSA-N 0.000 claims abstract description 18
- 229930015582 oxymatrine Natural products 0.000 claims abstract description 18
- 239000007924 injection Substances 0.000 claims abstract description 16
- 238000002347 injection Methods 0.000 claims abstract description 16
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- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 14
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 10
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- 238000002360 preparation method Methods 0.000 claims abstract description 10
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims abstract description 8
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- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims abstract description 8
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
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- ZSBXGIUJOOQZMP-UHFFFAOYSA-N Isomatrine Natural products C1CCC2CN3C(=O)CCCC3C3C2N1CCC3 ZSBXGIUJOOQZMP-UHFFFAOYSA-N 0.000 claims description 5
- ZSBXGIUJOOQZMP-JLNYLFASSA-N Matrine Chemical compound C1CC[C@H]2CN3C(=O)CCC[C@@H]3[C@@H]3[C@H]2N1CCC3 ZSBXGIUJOOQZMP-JLNYLFASSA-N 0.000 claims description 5
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- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention relates to a kind of polysaccharide nucleic acid pharmaceutical compositions for treating infantile eczema, it is using BCG polysaccharide nucleic acid and oxymatrine as active pharmaceutical ingredient, slow-release microshpere formulation for injection is made, the preparation is made of BCG polysaccharide nucleic acid, oxymatrine, poly (lactide-co-glycolide), polyvinyl alcohol, Tween 80 and trehalose.The drug, which can cooperate with, effectively plays curative effect of medication, preferably treatment infantile eczema, enhances therapeutic effect, shortens medication cycle, improves medication compliance.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of polysaccharide nucleic acid pharmaceutical composition for treating infantile eczema.
Background technique
Infantile eczema is a kind of allergic skin disease.It is complicated for causing the cause of disease of eczema, wherein being most importantly
Intolerance factors are, so there is the children of allergic constitution family history to be easier that eczema occurs.Main cause is to ingestant, inhalation (inhalatio)
Contactant do not tolerate or allergy caused by.
The major clinical feature of infantile eczema is that fash pleomorphism, often has exudation tendency, distribution at violent scratchiness
Compare symmetrical and easy recurrent exerbation, if be effectively treated makes protracted course be likely to that disease is caused to develop to chronicity not in time.One
Denier, which suffers from eczema, will seriously affect rest, appetite and the sleep of infant, and infant scratches also easy secondary bacterial infection repeatedly makes disease
Feelings deteriorate.
The treatment means of existing infantile eczema mainly remove anaphylactogen；Using symptomatic treatments such as externally used pastes；For
The infant of acute general hair wants active treatment general disease, removes lesion, the main means using oral hormone treatment.However, existing
For example outer paste of some treatment means etc. is easy to be scratched by children, or even eats by mistake, there is some potential safety problems.And oral hormone
Then there is the common adverse effect of hormone therapy in treatment, injure to children very big.Therefore it is badly in need of developing new treatment means and medicine
Object.
BCG vaccine is that ox type is attenuated tulase, and no pathogenicity has immunogenicity, replaces tulase first with BCG vaccine inoculation
It infects and obtains to immunity lungy, be one of current vaccine most widely used in the world.China's researcher into
It has gone the research of BCG vaccine extract, bacterium protein has been removed using hot phenol method, then extract mycelial polysaccharides and core with ethanol precipitation
Sour and a small amount of protein mixture and be made.
By the raising of process modification and quality standard, the side reaction of BCG vaccine extract is effectively reduced, and is entered
" Products in China regulation ", is made BCG polyose nuclear acid injection, is clinically used for immunological regulation, feels preventing and treating
It emits, the skin diseases such as respiratory diseases and eczema, nettle rash, verruca plana, verruca vulgaris, condyloma acuminatum such as asthma, allergic rhinitis
It has a better effect.The existing part research in this field treats chronic eczema (" Chinese leprosy using BCG polyose nuclear acid injection
Skin disease magazine ", Wu Xiaojin etc., the 10th phase of volume 29, the 677-679 pages).
Clinically another new selection, this kind of therapy peace are become using BCG polyose nuclear acid injection treatment infantile eczema
Good perfection, curative effect is reliable, can effectively treat infantile eczema.However this kind of therapy needs are at least primary every intramuscular injection in 1 day,
Infant compliance is poor, and family burden is heavier.
On this basis, inventor has developed a kind of BCG polysaccharide nucleic acid slow-release injection, can effectively delay drug
Release extends drug treating time, increases shot to shot turnaround, improves the compliance of infant.In addition, by injection
Active pharmaceutical ingredient is further added, drug effect can be made synergistic, improve therapeutic effect, shorten administration time.
Summary of the invention
The invention reside in a kind of polysaccharide nucleic acid pharmaceutical composition for treating infantile eczema is provided, by increasing pharmaceutical activity
Slow-release injection is made in ingredient, and therapeutic effect can be enhanced, and improves the compliance of infant.
The polysaccharide nucleic acid pharmaceutical composition that the present invention treats infantile eczema is a kind of slow-release microshpere formulation for injection, drug
Active constituent is BCG polysaccharide nucleic acid and oxymatrine.
Wherein, the composition that active constituent BCG polysaccharide nucleic acid is made of bacillus calmette-guerin polysaccharide and BCG vaccine nucleic acid,
The mass percentage of middle polysaccharide is 15%~55%, and the mass percentage of the composition amplifying nucleic acid is 45%~85%, excellent
Selection of land, polysaccharide 40%, nucleic acid 60%.
Two kinds of active pharmaceutical ingredients in injection of the present invention, the weight proportion of BCG polysaccharide nucleic acid and oxymatrine
It is 3: 1~1: 3, further preferably 1-3: 1, more preferably 1.7: 1.By drug efficacy study of the present invention, the drug of the proportion
Active constituent, which can cooperate with, effectively plays curative effect of medication, preferably treatment infantile eczema, enhances therapeutic effect, shortens medication week
Phase improves medication compliance.
The pharmaceutical composition of injection BCG polysaccharide nucleic acid co-oxidation matrine slow-release microballoon of the invention is situated between by card
Granulose nucleic acid, oxymatrine, poly (lactide-co-glycolide), polyvinyl alcohol, Tween 80 and trehalose are made.With weight
The each group of number meter is grouped as are as follows:
As a preferred solution of the present invention, the injection BCG polysaccharide nucleic acid co-oxidation matrine slow-release microballoon
Pharmaceutical composition, each group by weight is grouped as are as follows:
The pharmaceutical composition of injection BCG polysaccharide nucleic acid co-oxidation matrine slow-release microballoon of the invention is using such as
Lower preparation method, specific steps include:
(1) BCG polysaccharide nucleic acid of recipe quantity and oxymatrine are dissolved in containing at recipe quantity trehalose and half
Aqueous phase solution (W1) is made in the PBS buffer solution for the Tween 80 just measured；
(2) hand over rouge/co-glycolide methylene chloride dissolution that oil-phase solution (O), the concentration of oil-phase solution is made for third
For 0.1-0.5 grams per milliliter；The aqueous phase solution (W1) of above-mentioned drug containing active constituent is added in oil-phase solution (O), oil mixes
The ratio of liquid (O) liquid compatible with water (W1) is 20: 1 to 2: 1, is uniformly mixed both solution at 5-30 DEG C of temperature,
Colostrum W1/O is made, is saved at 4-10 DEG C；
(3) by the Tween 80 of the polyvinyl alcohol of recipe quantity and the other half recipe quantity, it is completely dissolved in water, aqueous phase solution is made
(W2), the weight concentration of polyvinyl alcohol is 5-20%；Above-mentioned colostrum W1/O is added to aqueous phase solution (W2) to stir evenly, colostrum
The ratio of W1/O liquid compatible with water (W2) is 1: 50 to 1: 200, and emulsion W1/O/W2 is made, saves at 4-10 DEG C；
(4) emulsion W1/O/W2 is transferred in NaCl aqueous solution, is stirred evenly, organic solvent is made to volatilize, be then centrifuged for receiving
Collect microballoon.
Whipping temp in the step (2) is 25 DEG C, and mixing speed is 500-8000 revs/min, mixing time 0.02-
0.2 hour.
Whipping temp in the step (3) is 15 DEG C, and mixing speed is 100-3000 revs/min, mixing time 0.2-
0.5 hour.
Whipping temp in the step (4) is 15 DEG C, and mixing speed is 500-3000 revs/min, mixing time 0.2-
0.5 hour.
The bacillus calmette-guerin polysaccharide and BCG vaccine nucleic acid for forming active pharmaceutical ingredient, by the following method from BCG vaccine culture
Extraction obtains:
(1) bacterium is collected when BCG vaccine bacteria to be inoculated in culture to logarithmic phase in the culture medium of suitable mycobacterium growth
Body；
(2) supernatant is collected by centrifugation in above-mentioned thallus after crushing；
(3) supernatant removes organic solvent by dialysis or gel chromatography after organic solvent extracts, and obtains card and is situated between
Granulose, mixtures of nucleic acids；
(4) bacillus calmette-guerin polysaccharide of acquisition, mixtures of nucleic acids are separated by the column chromatography of anionic exchange medium, on
Sample washes column with physiology salt, and column liquid is washed in collection；
(5) desalination is carried out with desalting column, obtains bacillus calmette-guerin polysaccharide；
(6) step (4) uses concentration to be eluted for the sodium chloride solution of 0.1~2mol/L after washing column, and collection is washed
De- liquid；
(7) eluent of collection is subjected to desalination using desalting column, obtains BCG vaccine nucleic acid；
(8) bacillus calmette-guerin polysaccharide being prepared and BCG vaccine nucleic acid are mixed in proportion, it is mixed obtains BCG polysaccharide nucleic acid
Close object.
According to the report that the prior art studies microballoon, microball preparation is described poly- generally using polymer as framework material
Closing object can be the biodegradable or biological nondegradable or biodegradable and nondegradable combination of biology.Generally
Using biodegradable but be not readily dissolved in the pharmaceutical acceptable polymer of water and prepare microsphere for injection, including but not limited to poly- third is handed over
Ester-glycolide, polylactic acid, polyglycolic acid, poly- 3-hydroxybutyrate ester, polylactic acid-glycollic acid, poly lactide-glycolide acid
(PLGA), gather adjacent ester, polylactone, polyanhydride, polyvinyl alcohol (PVA), polyethylene glycol (PEG), Polyhydroxybutyrate-co-hydroxyvalerate
Copolymer, polypropylene glucan, polyglycolic acid, polylactic acid-polyglycol, polyglycolic acid-polyethylene glycol, gelatin, albumin,
One of mannitol, trehalose or in which two or more mixture etc..
Use above-mentioned when can be with biodegradable polymer, molecular weight is preferably in 5,000~500,000 dalton
Range.Molecular weight be greater than 500,000 molecular weight it is excessive, into vivo after do not allow it is degradable, it is possible to be difficult to realize blood appropriate
Concentration, and release time can become too long.Molecular weight is too small lower than 5000 molecular weight, it is possible to be difficult to realize the mesh of sustained release
's.Release profiles expected from degradation rate and inventive compound expected from polymer may depend on monomer used type,
The different mixtures of homopolymer or copolymer and polymer used used.
Inventor have passed through the experiment largely screened, it was surprisingly found that: poly (lactide-co-glycolide) and polyethylene
Alcohol cooperation, is particularly suited for preparing polyoses nucleic acid sustained release microsphere agents of the invention than above-mentioned other polymer.Bacillus calmette-guerin polysaccharide
Nucleic acid and oxymatrine and poly (lactide-co-glycolide) and polyvinyl alcohol are prepared by multi-emulsion method, have excellent balling-up
Performance and excellent medicine stability.
For currently preferred poly (lactide-co-glycolide), molecular weight 5,000-100,000 dalton it
Between, preferred molecular weight is between 5000-20000, most preferably between 5000-10000.The wherein polymerization of lactide and glycolide
Than between about 95: 5-5: 95, preferably from about 40: 60-75: 25, most preferably about 50: 50.Most preferably lactide/glycolides are total
The molecular weight of polymers be 5000-10000, for example, about 5000, about 6000, about 7000, about 8000, about 9000 and about 10,000.This
The polyvinyl alcohol that preferred polyvinyl alcohol is low polymerization degree is invented, molecular weight is between 20,000-150,000, preferably from about
20,000, about 25,000, about 30,000.
Microballoon of the invention may further include other auxiliary materials, such as: polyvinylpyrrolidone, Tween 80, carboxymethyl are fine
Tie up one of plain sodium, dextrin, polyethylene glycol, glycerol, glucose and NaGC or in which two or more
Mixture etc..The preferred Tween 80 of the present invention and trehalose.
By continuously attempting to and concentrating on studies, pharmaceutical composition of the invention, active constituent BCG polysaccharide nucleic acid with
The compatibility of oxymatrine achieves synergistic therapeutic effect.Sustained release preparation can extend dosing interval, and it is suitable to promote infant
Ying Xing improves therapeutic effect.
Detailed description of the invention
Attached drawing 1 is the In-vitro release curves of microballoon prepared by embodiment 1, and curve A is the BCG vaccine simulated in release liquid
The release in vitro of polysaccharide；Curve B is the release in vitro for simulating the BCG vaccine nucleic acid in release liquid；Curve C is in simulation release liquid
Oxymatrine release in vitro.
Attached drawing 2 is the In-vitro release curves of microballoon prepared by embodiment 2, and curve A is the BCG vaccine simulated in release liquid
The release in vitro of polysaccharide；Curve B is the release in vitro for simulating the BCG vaccine nucleic acid in release liquid；Curve C is in simulation release liquid
Oxymatrine release in vitro.
Specific embodiment
The present invention is further illustrated below with reference to embodiment.It should be understood that these embodiments be merely to illustrate the present invention without
For limiting the scope of the invention.
Embodiment 1
(1) BCG polysaccharide nucleic acid and oxymatrine are dissolved in 1 milliliter of PBS containing trehalose and half Tween 80
Aqueous phase solution (W1) is made in buffer solution；
(2) third friendship rouge/co-glycolide is dissolved in 4 milliliters of methylene chloride and oil-phase solution (O) is made；
(3) above-mentioned aqueous phase solution (W1) is added in oil-phase solution (O), makes both solution at 25 DEG C of temperature, stirs
It mixes that speed is 8000 revs/min, mixing time is 0.05 hour, is stirred, colostrum W1/O is made, saved at 4-10 DEG C；
(4) in the polyvinyl alcohol that above-mentioned colostrum W1/O is added to 300ml under 1500 revs/min of stirring states, stirring temperature
Degree is 15 DEG C, and mixing time is 0.2 hour, and emulsion W1/O/W2 is made, saves at 4-10 DEG C；
(5) emulsion W1/O/W2 is added in the 1%NaCl aqueous solution of 3 times of emulsion volumes, is stirred by 1500 revs/min
So that organic solvent is volatilized, then 2000 revs/min, is centrifuged 15 minutes, collects microballoon, deposit in refrigerator and refrigerate.
Obtained microballoon form rounding, even particle size distribution, average grain diameter at 18.2 microns, drugloading rate up to 7.9%,
Encapsulation rate is 47.9%.
Embodiment 2
(1) BCG polysaccharide nucleic acid and oxymatrine are dissolved in 2 milliliters of PBS containing trehalose and half Tween 80
Aqueous phase solution (W1) is made in buffer solution；
(2) third friendship rouge/co-glycolide is dissolved in 6 milliliters of methylene chloride and oil-phase solution (O) is made；
(3) above-mentioned aqueous phase solution (W1) is added in oil-phase solution (O), makes both solution at 25 DEG C of temperature, stirs
It mixes that speed is 8000 revs/min, mixing time is 0.2 hour, is stirred, colostrum W1/O is made, saved at 4-10 DEG C；
(4) in the polyvinyl alcohol that above-mentioned colostrum W1/O is added to 400ml under 1500 revs/min of stirring states, stirring temperature
Degree is 15 DEG C, and mixing time is 0.2 hour, and emulsion W1/O/W2 is made, saves at 4-10 DEG C；
(5) emulsion W1/O/W2 is added in the 1%NaCl aqueous solution of 4 times of emulsion volumes, is stirred by 1500 revs/min
So that organic solvent is volatilized, then 2000 revs/min, is centrifuged 25 minutes, collects microballoon, deposit in refrigerator and refrigerate.
Obtained microballoon form rounding, even particle size distribution, average grain diameter at 19.6 microns, drugloading rate up to 7.9%,
Encapsulation rate is 35.6%.
The extracorporeal releasing test of 3 microballoon of embodiment
Test specimen: the microballoon of method preparation described in 1-2 according to embodiments of the present invention.
Laboratory apparatus: water-bath constant temperature oscillator, centrifuge.
Experiment condition: temperature: 37 ± 0.5 DEG C, revolving speed: 100rpm.
Experimental method: precision weighs laboratory sample about 10mg, is placed in the clear bottle of tool lid that volume is 100ml, 90ml is added to release
Medium (0.02% Tween-80) is put, is placed in water-bath constant temperature oscillator, certain temperature and revolving speed is kept to sample on time.
Sampling method: essence takes 5ml solution, and 10min is centrifuged under the conditions of 3000 turns, then adds the dissolution medium of 5ml, takes out liquid
It is detected with HPLC.
Sampling time point (hour): 1,8,16,24,48,3 days, 5 days.
Test result: the release bacillus calmette-guerin polysaccharide accumulation in 8 hours of microballoon prepared by the embodiment of the present invention 1, embodiment 2 is released
The rate of putting is respectively 13.8%, 14.6%, and 5 days preparations are respectively 94.7%, 95.1%；BCG vaccine nucleic acid 8 hours
Preparation is respectively 12.6%, 11.5%, and 5 days preparations are respectively 95.2%, 95.5%；Oxymatrine 8
The preparation of hour is respectively 20.3%, 18.5%, and 5 days preparations are respectively 93.6%, 89.5%.
Microballoon release test result is referring to attached drawing 1 and attached drawing 2.
4 pharmacodynamic test of embodiment
46 infants are all from outpatient service, and male 22, female 24, treatment did not took glucocorticosteroid and swashs in first 1 month
Element does not take antihistamine drug in 1 week, is not in the mood for liver and kidney disease, there is the fash and violent itch etc. such as erythema, papule, exudation, general hair
Symptom.Age is 2~6 years old, and average out to 4.1 years old, the course of disease was 2d~2 year.Skin injury happening part: Head And Face 2, neck 3
Example, trunk 14, four limbs 25, the general hair 2 of whole body.Clinical diagnosis meets dermatitis and eczema diagnostic criteria.46 patients are random
It is divided into treatment group and control group, wherein treatment group 25, control group 21, two groups of patients are tight in gender, age, the course of disease and disease
Equal no difference of science of statistics in weight degree, is comparable.
Treatment method: treatment group is slow-release injected using BCG polysaccharide nucleic acid co-oxidation matrine of the invention
(using 1 prescription of embodiment), intramuscular injection, 1ml is each, and every intramuscular injection in 5 days 1 time.Control group uses commercially available bacillus calmette-guerin polysaccharide core
Acid injection (Si Qikang), intramuscular injection, 1ml is each, and every intramuscular injection in 2 days is primary.Two groups of courses for the treatment of are 4 weeks, after treatment
10, further consultation in 28 days.
Curative effect determinate standard: before the treatment, erythema, papule, erosion, exudation, infiltration are recorded respectively within the 10th, 28 day after treatment
Or mossization, angling furfur etc. and itch degree, each index are carried out in assessment by 4 grades of point systems.Pruritis: 0=is without itching
Sense, itch that 1=is slight but can endure at 2=moderate itch, and 3=severe itch is impatient at.Rash sign: 0=is without 1=is light
Degree, 2=moderate, 3=severe refer to according to symptom integral decline is calculated with the total mark of follow up time corresponding after treatment before treatment
Number, decline index are divided into recovery from illness, effective, effective and invalid 4 grades of assessments curative effect, and calculation formula is as follows: symptom integral declines index
=(pre-treatment score-post treatment integral)/pre-treatment score × 100%.Recovery from illness: symptom integral decline index is greater than or equal to
90%；Effective: symptom integral declines index and is greater than or equal to 60%, but less than 90%；Effective: symptom integral decline index is greater than
Or it is equal to 20%, but less than 60%；Invalid: symptom integral declines index less than 20%.Total effective rate is recovery from illness and effective trouble
The sum of person's percentage.
Clinical efficacy is shown in Table 1.Treatment group starts effective time most short 5d, and longest 10d, it is most short that control group starts effective time
9d, longest 14d.Two groups of curative effects compare when 10d, treatment group's total effective rate 52%, control group total effective rate 47.6%, and two groups always show
There were significant differences for efficiency (χ 2=6.215, P < 0.05).Two groups of curative effects compare when 28d, treatment group's total effective rate 92%, control group
Total effective rate 55.6%, two groups of total effective rate differences have significant (χ 2=11.616, P < 0.01).Wherein 28d is checked
When, control group has 3 people lost to follow-up, and treatment group all adheres to treating.
1 Clinical efficacy comparison of table
5 pharmacodynamic test of embodiment
Using rat subacute eczema model, BCG polysaccharide nucleic acid and oxymatrine proportion are studied.Modeling
Method is as follows: SD rat, 220g or so are taken, yellow Jackets anesthesia is marked in rat back, and 1 × 1cm of area removes deratization hair,
It is pasted with 6% vulcanized sodium mixing starch, is removed to form shaving area with water after five minutes.7% 2,4- dinitro-chlorine is smeared in shaving area
Propiophenone sensitization, control group smear equivalent amount of water, and for the first time after sensitization, it is (the abdominal cavity 30mg/kg that drug dose, which is given once daily, in administration group
Injection), equivalent amount of water is injected intraperitoneally in model group and control group, and repeatedly sensitization is primary weekly, continues surrounding.According to eczema area and sternly
Severe index (EASI) scores respectively to groups of animals shaving area in terms of erythema, hard swelling and excoriation three, each
The severity score of aspect performance refers to the region sign atopic dermatitis point system of berth-Jones, and 0=is without 1=is light, 2=
In, 3=weight, each symptom score can remember half score value.
The weight percent of each administration group BCG polysaccharide nucleic acid and oxymatrine is referring to following table
| BCG polysaccharide nucleic acid | Oxymatrine | |
| Administration group 1 | 100% | 0% |
| Administration group 2 | 0% | 100% |
| Administration group 3 | 50% | 50% |
| Administration group 4 | 62.5% | 37.5% |
| Administration group 5 | 66.6% | 33.4% |
| Administration group 6 | 75% | 25% |
As a result
(1) influence (n=8) of the administration group to rat Eczema Model skin lesion
(2) influence of the administration group to horn cell (KC) and lymphocyte (LYM) apoptosis and IL-4 in rat Eczema Model
After administration 2 weeks, the partial rat in each group is put to death respectively, separates rat eczema skin lesion tissue block, paraformaldehyde
Paraffin section after fixation, using ImmunohistochemistryMethods Methods, the content of the apoptosis to KC in slice and LYM and IL-4 are detected respectively,
Concrete outcome is as follows:
| Kc apoptosis rate (%) | LYM apoptosis rate (%) | The IOD value of IL-4 | |
| Control group | - | - | 79±6 |
| Model group | 9.3±0.9 | 10.3±1.1 | 173±8 |
| Administration group 1 | 29.5±1.6 | 28.7±1.8 | 121±7 |
| Administration group 2 | 18.2±1.2 | 15.4±1.4 | 169±9 |
| Administration group 3 | 41.6±2.3 | 38.4±0.6 | 104±6 |
| Administration group 4 | 58.9±1.8 | 56.7±1.1 | 82±5 |
| Administration group 5 | 51.4±1.6 | 48.7±0.7 | 91±4 |
| Administration group 6 | 44.7±0.9 | 41.2±0.8 | 113±8 |
The content of present invention merely illustrates claimed some specific embodiments, one of them or more skill
Documented technical characteristic can be combined with arbitrary one or more technical solutions in art scheme, these are combined and obtain
Technical solution also in the application protection scope, the technical solution just as obtained from these are combined is disclosed in the present invention
It is specifically recorded in content the same.
Claims (6)
1. a kind of polysaccharide nucleic acid pharmaceutical composition for treating infantile eczema, it is characterised in that the composition is that a kind of injection is slow
Release microball preparation, active pharmaceutical ingredient is BCG polysaccharide nucleic acid and oxymatrine, BCG polysaccharide nucleic acid and oxidation
The weight proportion of matrine is 3:1~1:3, and the composition is by BCG polysaccharide nucleic acid, oxymatrine, lactide/glycolides
Copolymer, polyvinyl alcohol, Tween 80 and trehalose composition；
The prescription of the composition is, based on parts by weight:
The polymerization ratio of the poly (lactide-co-glycolide), lactide and glycolide is 50: 50.
2. pharmaceutical composition according to claim 1, it is characterised in that the prescription of the composition is, with parts by weight
Meter:
3. pharmaceutical composition according to claim 1, it is characterised in that in the composition BCG polysaccharide nucleic acid be by
The composition of bacillus calmette-guerin polysaccharide and BCG vaccine nucleic acid composition, wherein the mass percentage of polysaccharide is 15%-55%, the matter of nucleic acid
Amount percentage composition is 45%-85%.
4. pharmaceutical composition according to claim 1, it is characterised in that form active pharmaceutical ingredient bacillus calmette-guerin polysaccharide and
BCG vaccine nucleic acid is extracted from BCG vaccine culture obtain by the following method:
(1) thallus is collected when BCG vaccine bacteria to be inoculated in culture to logarithmic phase in the culture medium of suitable mycobacterium growth；
(2) supernatant is collected by centrifugation in above-mentioned thallus after crushing；
(3) supernatant removes organic solvent by dialysis or gel chromatography, it is more to obtain BCG vaccine after organic solvent extracts
Sugar, mixtures of nucleic acids；
(4) bacillus calmette-guerin polysaccharide of acquisition, mixtures of nucleic acids are separated by the column chromatography of anionic exchange medium, loading is used
Physiology salt washes column, and column liquid is washed in collection；
(5) desalination is carried out with desalting column, obtains bacillus calmette-guerin polysaccharide；
(6) step (4) uses concentration to be eluted for the sodium chloride solution of 0.1~2mol/L after washing column, collects eluent；
(7) eluent of collection is subjected to desalination using desalting column, obtains BCG vaccine nucleic acid；
(8) bacillus calmette-guerin polysaccharide being prepared and BCG vaccine nucleic acid are mixed in proportion, obtains BCG polysaccharide nucleic acid mixture.
5. pharmaceutical composition according to claim 1, it is characterised in that its molecular weight of poly (lactide-co-glycolide) exists
Between 5000-10000 dalton.
6. pharmaceutical composition according to claim 1, it is characterised in that polyvinyl alcohol is the polyvinyl alcohol of low polymerization degree,
Molecular weight is 25,000.
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| Title |
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| 卡介菌多糖核酸注射液治疗慢性湿疹疗效观察;吴晓金等;《中国麻风皮肤病杂志》;20131031;第29卷(第10期);第677页 "3 讨论"段 |
| 氧化苦参碱注射液治疗慢性湿疹48例疗效观察;滕瑞芝等;《山东医药》;20071231;第47卷(第11期);第79页 |
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