CN103816110A - Preparation method of drug transdermal absorbent promoting fracture healing - Google Patents
Preparation method of drug transdermal absorbent promoting fracture healing Download PDFInfo
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- CN103816110A CN103816110A CN201310359008.2A CN201310359008A CN103816110A CN 103816110 A CN103816110 A CN 103816110A CN 201310359008 A CN201310359008 A CN 201310359008A CN 103816110 A CN103816110 A CN 103816110A
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Abstract
The invention relates to a preparation method of a peracetylated sodium alga acid transdermal preparation. A drug for curing and preventing fracture is prepared by performing a peracetylated reaction on sodium alga acid, and then sodium alga acid peracetylated derivatives, adhesives, humectants, excipients and softeners form a drug combination for curing fracture, bone ununion, femoral head necrosis and osteoporosis in a transdermal way. The method has the advantages that the method is simple, the source of raw material is wide, the cost is low, and the drug has no side effects.
Description
Technical field
The invention belongs to clinical medicine medication, relate to specifically a kind of medicine that is applicable to fracture, bone does not connect, femur head necrosis, osteoporotic treatment and prevention.
Background technology
How early promotion union of fracture is the emphasis problem of orthopedics department area research always, along with the continuous expansion of people to union of fracture mechanism understanding, in recent years inquire into promote union of fracture method and machine-processed aspect research obtained the progress attracting people's attention.
Transdermal drug delivery system (transdermal delivery system, TDS), or claim Transcutaneous Therapeutic System (GGN) to refer to the controlled release preparation that causes whole body therapeutic effect through percutaneous drug delivery, be the third generation preparation growing up the eighties.Due to structure, the character of medicine and the physiological status effect of human body of skin, medicine is difficult to spread, penetrates, infiltrates absorption.Increase the Transdermal absorption that effective release area of transdermal drug delivery system and the percutaneous rate of raising medicine can promote medicine, but the area of transdermal drug delivery system is limited, therefore requires to have certain percutaneous rate.The percutaneous rate that improves medicine is the key of research transdermal drug delivery system.Promote the method for Drug Percutaneous Absorption to have practice of pharmacy, chemical method and physical method.
Practice of pharmacy use Percutaneous absorption enhancer Percutaneous absorption enhancer refers to the material of suffered resistance can penetrate into skin and reduce medicine by skin time.They should be able to reversibly reduce the barrier properties of skin, and don't damage other functions of skin.The condition that desirable Percutaneous absorption enhancer should possess is: drug absorption is not affected by the factors such as the interior pH of digestive tract, food, transhipment time; Avoid liver first-pass effect; Overcome because absorbing the too high untoward reaction causing of too fast generation blood drug level; Sustainable control injection speed, flexible administration etc., common transdermal drug delivery system comprises cataplasma, ointment, liniment, gel etc.
Percutaneous absorption enhancer is of a great variety, can be divided into two large classes: nonpolar class: comprise hydrocarbon, fatty acid, oleic acid and lauryl alcohol etc. by its physicochemical property; Polarity class: comprise ethanol, dimethyl sulfoxine, ethylene glycol, propylene glycol, glycerol, sulfated lauryl alcohol and water etc.Can be divided three classes by its mechanism of action: lipotropy solvent class, comprises dimethyl sulfoxine, dimethyl formamide, ketopyrrolidine etc.; Surfactant-based, comprise oleic acid, linoleic acid, sulfated lauryl alcohol and dodecyl methyl sulfoxide etc.; Two-component system class, comprises propylene glycol-oleic acid, linoleic acid-butanediol, azone-propylene glycol and oleic acid-azone etc.
Laurocapram, is called for short azone, is a kind of research on novel penetration enhancers, and amphipathic property medicine is all had to facilitation.This product has the strong facilitation that penetrates, and large 13 times than 50% dimethyl formamide of 1% azone transdermal facilitations are also larger than the effect of 50% dimethyl sulfoxide.Azone all has transdermal facilitation to a lot of medicines, and it may be to make lipoids in horny layer produce irregular arrangement and the lipoid that dissolves skin increases the absorption of medicine.There is report azone to promote that the mechanism of peptide medicament Transdermal absorption is mainly the arrangement that changes Cell membrane lipids bilayer, forms soupspoon shape structure.Azone is significantly increased the ability of medicine transdermal.
The algae sea-plant of being rich in sodium alginate can promote union of fracture (application number 201110298817.8) fast through chemical modification.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of full acetylated sodium alginate preparation capable of permeating skin.Be to provide a kind of preparation method simple, the medicine of fracture is treated and prevented to raw material sources widely.
Advantage of the present invention is that preparation method is simple, and raw material sources are wide, with low cost, have no side effect.
Object of the present invention can realize by following technique measures:
The medicine for the treatment of of the present invention and prevention fracture is that sodium alginate is made through full acetylated reaction.Then the compositions such as full acetylated sodium alginate derivant and adhesive, wetting agent, excipient, softening agent are there is to the drug regimen of Transdermal absorption treatment fracture.
The full acetylated derivant of sodium alginate preparation: by sodium alginate 100g, acetic anhydride 50ml and sulfamic acid 1g, be mixed under room temperature and react 30min, then temperature is continued to rise to 60-90 ℃ of reaction 20min complete reaction.To the end that reacts completely, in product, add sodium bicarbonate to be neutralized to PH7-7.5.Then dry, filter, concentrating under reduced pressure obtains product
Described preparation capable of permeating skin pharmaceutical composition, is characterized in that described water-soluble pharmaceutic adjuvant comprises one or more in pH adjusting agent, adhesive, wetting agent, softening agent, penetrating agent, surfactant or stabilizing agent.Preferably include one or more in penetrating agent, surfactant.
PH adjusting agent in described water-soluble pharmaceutic adjuvant is one or more in phosphoric acid and salt, boric acid and salt thereof, citric acid and salt thereof, acetic acid and salt thereof, tartaric acid and salt thereof, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, tromethane.Preferably one or more in acetic acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.
Described adhesive is water-soluble high-molecular substance, comprises carboxymethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, and its consumption is 0.5%-50% (percentage by weight, lower same), is preferably 2%-5%.
Described wetting agent has: glycols or saccharide, and as ethylene glycol, diethylene glycol (diglycol), Polyethylene Glycol, glycerol, sorbitol, propylene glycol, 1,3 butylene glycol etc.Choose any one kind of them, wetting agent usual range is 1%-70%, is preferably 10%-60%.
[0012] described softening agent is often selected Oleum Ricini and other oils and fatss.Its consumption is the 1%-10% of medicine total amount.Softening agent can strengthen flexibility and the tolerance to cold of cataplasma.
Other additives if desired also can be with some traditional absorbent, for example, salicylic acid, hyaluronic acid, oleic acid, N, N-diethyl-m-Benzoylamide, n-butyl stearate, benzyl alcohol, isopropyl myristate, isopropyl palmitate, polypropylene glycol, crotamiton, lauryl alcohol etc.Also can in gel-type vehicle, use surfactant, for example, polyoxyethylene sorbitan monooleate dehydration, polyethenoxy sorbitan monostearate, Arlacel-80, Arlacel-40 etc.In addition, antiseptic, antioxidant etc. also can add in right amount, and its consumption and type depend on whether affect the control of medicine release and the zest to skin.
Described preparation capable of permeating skin pharmaceutical composition, its composition prescription is: the full acetylated derivant 10g of sodium alginate, carboxymethyl cellulose 2-10g, glycerol 1g, Oleum Ricini 1g, azone 1-2g.Take the full acetylated derivant 10g of sodium alginate, add water 100ml, carboxymethyl cellulose 2-10g is stirred to clear and bright glue.Under stirring, add successively azone 2-4g, glycerol 1g, Oleum Ricini 1g, mix, regulating pH value with sodium bicarbonate is 7-7.5 left and right, ultrasonic 15min.When use, coat on gauze, cover therapentic part.
Described pharmaceutical composition, the application in the treatment of preparation promotion human or animal union of fracture.
In order further to verify the curative effect of finished product preparation of the present invention, the medicine of preparing in above-mentioned concrete preparation method 1-3 has been carried out corresponding animal experiment by we, existing that report the test is as follows.
Reagent: bone morphogenesis protein-2 (BMP-2) antibody is purchased from Beijing Bo Aosen Bioisystech Co., Ltd
Animal: 30 of kunming mices, body weight 18-22g, male.
Method: 30 body weight 20～30g, 2～3 monthly age Kunming white mice femur bones are made animal fracture model, is divided into treatment A group, and blank B organizes two groups.A group is covered near fracture site with full acetylated sodium alginate preparation capable of permeating skin every every day, and B group white mice is not processed, and every group of mice put to death 5 respectively at 7 14 28d are each.Get white mice femur pathological section processed.Specimen decalcification after 10% formaldehyde is fixing, immunohistochemical staining.Two groups of significant differences of result, can there is a large amount of BMP-2 albumen for 1 week in A group white mice, within 2 weeks, can form seriality callus, clinical healing.
Result: the immune positive products of BMP-2 albumen is expressed in bone matrix and in osteoblast kytoplasm, is brown color.Adopt semiquantitative method judge the expression of BMP-2 albumen: select 10 high power fields, the positive reaction cell number < 25% of colour developing be+, 25～50% are ++, > 75% is +++, the obvious positive reaction cell of nothing is-.The statistical analysis of enumeration data adopts X 2 test.Touchstone α=0.05.
The postoperative 7d of table 1,15d, the expression comparison (n=15) of two groups of BMP-2 albumen of 21d
Since nearly 3 years, we successively treat 500 many cases fracture, bone does not connect, femur head necrosis, osteoporotic patient with this preparation capable of permeating skin, all obtain good effect.
The specific embodiment
Be below the specific embodiment of content of the present invention, want the technical scheme of technical solution problem for setting forth present specification.
Embodiment 1
The full acetylated derivant preparation of sodium alginate: by sodium alginate 100g, acetic anhydride 50ml and sulfamic acid 1g, be mixed under room temperature and react 30min, then temperature is continued to rise to 60-90 ℃, and reaction 20min completes reaction.To the end that reacts completely, in product, add sodium bicarbonate to be neutralized to PH7-7.5.Then dry, filter, concentrating under reduced pressure obtains the full acetylated derivant product of sodium alginate.Composition prescription is: the full acetylated derivant 10g of sodium alginate, carboxymethyl cellulose 2-10g, glycerol 1g, Oleum Ricini 1g, azone 2-4g.Take the full acetylated derivant 10g of sodium alginate, add water 100ml, carboxymethyl cellulose 2-10g is stirred to clear and bright glue.Under stirring, add successively azone 1-2g, glycerol 1g, Oleum Ricini 1g, mix, regulating pH value with sodium bicarbonate is 7-7.5 left and right, and ultrasonic 15min, obtains the full acetylated derivant preparation capable of permeating skin of sodium alginate.
Embodiment 2
Sodium alginate is prepared through full acetylated derivant: by sodium alginate 100g, acetic anhydride 50ml and sulfamic acid 1g, be mixed under room temperature and react 30min, then temperature is continued to rise to 60-90 ℃, and reaction 20min completes reaction.To the end that reacts completely, in product, add sodium bicarbonate to be neutralized to PH7-7.5.Then dry, filter, concentrating under reduced pressure obtains the full acetylated derivant product of sodium alginate.Composition prescription is: the full acetylated derivant 10g of sodium alginate, polyvinyl alcohol 2-10g, glycerol 1g, Oleum Ricini 1g, azone 2-4g.Take the full acetylated derivant 10g of sodium alginate, add water 100ml, polyvinyl alcohol 2-10g is stirred to clear and bright glue.Under stirring, add successively azone 1-2g, glycerol 1g, Oleum Ricini 1g, mix, regulating pH value with sodium bicarbonate is 7-7.5 left and right, and ultrasonic 15min, obtains the full acetylated derivant preparation capable of permeating skin of sodium alginate.
Claims (5)
1. the invention relates to a kind of medicine that is applicable to fracture, bone does not connect, femur head necrosis, osteoporotic treatment and prevention.
2. according to the preparation method of a kind of transdermal pharmaceutical that promotes union of fracture described in claims 1; It is characterized in that: treatment and prevention fracture, bone does not connect, femur head necrosis, osteoporotic medicine are that sodium alginate is made through full acetylated reaction.Then the compositions such as full acetylated sodium alginate derivant and adhesive, wetting agent, excipient, softening agent are there is to the drug regimen of Transdermal absorption treatment fracture.
3. according to the preparation method of a kind of transdermal pharmaceutical that promotes union of fracture described in claims 1; Its composition prescription is: the full acetylated derivant 10g of sodium alginate, carboxymethyl cellulose 2-10g, glycerol 1g, Oleum Ricini 1g, azone 2-4g.Take the full acetylated derivant 10g of sodium alginate, add water 100ml, carboxymethyl cellulose 2-10g is stirred to clear and bright glue.Under stirring, add successively azone 1-2g, glycerol 1g, Oleum Ricini 1g, mix, regulating pH value with sodium bicarbonate is 7-7.5 left and right, ultrasonic 15min.
4. according to the preparation method of a kind of transdermal pharmaceutical that promotes union of fracture described in claims 1; Its composition prescription is: the full acetylated derivant 10g of sodium alginate, polyvinyl alcohol 2-10g, glycerol 1g, Oleum Ricini 1g, azone 2-4g.Take the full acetylated derivant 10g of sodium alginate, add water 100ml, polyvinyl alcohol 2-10g is stirred to clear and bright glue.Under stirring, add successively azone 1-2g, glycerol 1g, Oleum Ricini 1g, mix, regulating pH value with sodium bicarbonate is 7-7.5 left and right, ultrasonic 15min.
5. according to a kind of transdermal pharmaceutical and preparation method that promotes union of fracture described in claims 1,2,3; When use, coat on gauze, cover therapentic part.Within 12 hours, change once, one the course for the treatment of two weeks.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310359008.2A CN103816110A (en) | 2013-08-19 | 2013-08-19 | Preparation method of drug transdermal absorbent promoting fracture healing |
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| CN201310359008.2A CN103816110A (en) | 2013-08-19 | 2013-08-19 | Preparation method of drug transdermal absorbent promoting fracture healing |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104288219A (en) * | 2014-10-14 | 2015-01-21 | 新乡医学院 | Preparation method and clinical application of fructus psoraleae derivative transdermal absorbent |
| CN108938671A (en) * | 2018-08-02 | 2018-12-07 | 苏州红冠庄国药股份有限公司 | A kind of preparation method and applications of harts horn carbon |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1579450A (en) * | 2003-08-05 | 2005-02-16 | 陈建华 | She medicinal composition for treating bone fracture and relieving pain, and its cataplasm and preparation process thereof |
| CN102349929A (en) * | 2011-09-28 | 2012-02-15 | 郭宏昌 | Drug for treating and preventing fracture |
| CN103110668A (en) * | 2013-03-01 | 2013-05-22 | 俞忠明 | Transdermal sustained-release drug delivery system and preparation and application method thereof |
-
2013
- 2013-08-19 CN CN201310359008.2A patent/CN103816110A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1579450A (en) * | 2003-08-05 | 2005-02-16 | 陈建华 | She medicinal composition for treating bone fracture and relieving pain, and its cataplasm and preparation process thereof |
| CN102349929A (en) * | 2011-09-28 | 2012-02-15 | 郭宏昌 | Drug for treating and preventing fracture |
| CN103110668A (en) * | 2013-03-01 | 2013-05-22 | 俞忠明 | Transdermal sustained-release drug delivery system and preparation and application method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104288219A (en) * | 2014-10-14 | 2015-01-21 | 新乡医学院 | Preparation method and clinical application of fructus psoraleae derivative transdermal absorbent |
| CN108938671A (en) * | 2018-08-02 | 2018-12-07 | 苏州红冠庄国药股份有限公司 | A kind of preparation method and applications of harts horn carbon |
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Application publication date: 20140528 |