CN101190184A - Micronizing solid external application local anesthetic and preparation method thereof - Google Patents
Micronizing solid external application local anesthetic and preparation method thereof Download PDFInfo
- Publication number
- CN101190184A CN101190184A CNA2006101295886A CN200610129588A CN101190184A CN 101190184 A CN101190184 A CN 101190184A CN A2006101295886 A CNA2006101295886 A CN A2006101295886A CN 200610129588 A CN200610129588 A CN 200610129588A CN 101190184 A CN101190184 A CN 101190184A
- Authority
- CN
- China
- Prior art keywords
- local anesthetic
- surfactant
- compositions
- additives
- matrix materials
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention relates to a medicine compound, in particular to a micro-powder local anesthesia medicine compound and a preparation method of the medicine compound; the medicine compound consists of solid local anesthesia medicines which has the average granule-diameter of being less than 50Mum and medical subsidiary substance, with the optimized average granule-diameter which is less than 1000nm. The medicine compound is characterized in that absorbing effect of the local anesthesia medicine is better; the used medicine dose is less and reaction time is quick.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, especially relate to micropowder local anesthetic combination and preparation method thereof.
Background technology
Jenning Gysler A, people (Eur J Pharm Biopharm such as Schafer-Korting M, 2000,49 (3): 211-218) with Sivaramakrishnan R, Nakamura C, people (J Controlled Release such as Mehnert W, 2004,97 (3): 493-502) all introduce solid lipid nanoparticle (solid lipid nanoparticles, SLN) mean that with natural or synthetic high melting solid lipid be carrier, medicine is adsorbed, be wrapped in the lipid core, making particle diameter is the solid micelle of 50～1000nm, is a kind of faster novel nano drug-supplying system of development in recent years.Easily be attached on during the administration of SLN local skin and form thin film on the skin, this thin film can pass through blocking effect (occlusion properties) and reduce the skin surface water loss, improves medicine to cuticular penetrance by the aquation that strengthens skin simultaneously.In addition, SLN can impel medicine directly to pass through the appendages transdermal of skin surface; Particle diameter is little, has certain bioadhesive, and the medicine hold-up of local skin is increased.
Local anesthetic is that a class can take place and the medicine that conducts in the impulsion of medication local reversible ground blocking-up sensory nerve, mainly is to alleviate the local pain that produces.Local pain often occurs such as having an injection, all can occurring in the acupuncture process in the daily life, especially the situation of having an injection can appear being reluctant because fearing pain in child and minority adult, the child often cries and screams, and mismatches the nurse, and severe patient also the situation of having a fainting spell during acupuncture treatment can occur.In order to reduce the appearance of the local pain sensation, can use the external preparation of local anesthetic to alleviate pain.There have been at present spray, the ointment of local anesthetic to come out, but owing to use local anesthetic spray, the general consumption of ointment big, generally all more than 10 milligrams/time; Onset is slower, and general onset time (is seen the compound lidocaine emulsifiable paste description) greatly about about 1 hour, and patient's toleration, the convenience of use are all influenced.
Local anaesthetics has two kinds of forms, water miscible salt and uncharged base.The fat-soluble height of uncharged base ratio salt, be easy to see through skin (Qiu Yu, Zhou Guanhuai. local anesthetic percutaneous Absorption Study and prospect thereof. foreign medical science anesthesia and recovery fascicle, 1996,17 (5): 274-275).Lignocaine is the strongest a kind of of permeability in local anaesthetics, and anesthetic action rapid-action (imperial illuminate, Li Wanhai. the clinical pharmacology handbook. Beijing: Golden Shield publishing house, 2000.389).
Summary of the invention
By local anesthetic being made the micronized medication compositions, with promoting the absorption of local anaesthetics, reduce drug dose, accelerate onset time.
A kind of micronized medication compositions is made up of less than solid local anesthetic and the pharmaceutic adjuvant of 50 μ m mean diameter, and preferred mean diameter is less than 1000nm.
Local anesthetic is preferably one or more in lignocaine, procaine, tetracaine, proparacaine, oxybuprocaine, benzocaine, cinchocaine, bupivacaine, mepivacaine, etidocaine, ropivacaine, benzyl alcohol, dyclonine, cocaine, chloroprocaine, prilocaine, trimecaine and the medicinal salt or ester thereof.
Pharmaceutic adjuvant in the said preparation wherein contains one or more in Percutaneous absorption enhancer, surfactant, other matrix materials, phospholipid, the additives.The preferred dimethyl sulfoxide of Percutaneous absorption enhancer that contains at pharmaceutic adjuvant, lauryl alcohol, propylene glycol, laurocapram (azone), carbamide, one or more of oleic acid etc., phospholipid is preferably as soybean phospholipid, lecithin, Ovum Gallus domesticus Flavus lecithin, one or more of synthetic phospholipid, the poly-hydrocarbon oxygen ester of the above acid of preferred 12 carbon of surfactant, poloxamer, soil temperature, Pu Lang flows the Buddhist nun, Brij, one or more of Myrij, the preferred stearic acid of other matrix materials, Palmic acid, arachidic acid, myristic acid, octadecanol, the monoglyceride of 12 above acid of carbon, one or more of diester or three esters, the preferred propylene glycol of additives, glycerol, ethanol, or in the mannitol one or more.
The micronized medication compositions is by weight by 1 part of the local anesthetic of treatment effective dose, phosphatidase 12-200 part, and other matrix materials 2-400 part, surfactant 1-400 part, Percutaneous absorption enhancer 0-100 part is formed, additives 0-50 part.
The micronized medication compositions is by weight by 1 part of the local anesthetic of treatment effective dose, phosphatidase 11 0-100 part, and other matrix materials 10-200 part, surfactant 5-100 part, Percutaneous absorption enhancer 1-10 part is formed, additives 0-10 part.
The micronized medication compositions is by weight by 1 part of the local anesthetic of treatment effective dose, phosphatidase 12 0-50 part, and other matrix materials 100-150 part, surfactant 10-50 part, Percutaneous absorption enhancer 1-5 part is formed, additives 0-1 part.
Micronized medication preparation of compositions technology is: local anesthetic, phospholipid, other matrix materials are dissolved in organic solvent such as acetone, ethanol, isopropyl alcohol, oxolane, the dioxane constitute organic facies; surfactant, cutaneous permeable agent, additives are added constitute water in the entry; organic facies and water are heated to the 60-90 degree; both temperature difference are not more than 5 degree; stir down biphase rapid mixing; form transparent system; this transparent system decompression is removed away organic solvent to be concentrated once more; right or be diluted in the water of 0-10 degree, form the micronized medication compositions.
Micronized medication preparation of compositions technology can also for: with machinery local anesthetic is pulverized, is added in surfactant, the cutaneous permeable agent one or more and stir, form the micronized medication compositions.
Mentioning meso-position radius in " pharmaceutics " the 5th edition (People's Health Publisher) is the most frequently used average diameter, also cries the intermediate value footpath, and accumulated value just in time is 50% pairing particle footpath in cumulative distribution, and D50 commonly used represents.Mean diameter described in this patent refers to meso-position radius.
The assay of local anaesthetics
It is an amount of that precision takes by weighing local anaesthetics, is made into the solution of 10 μ g/ml.With the distilled water is blank, draws uv absorption spectra in the interscan of 200-400nm wave-length coverage, obtains absorption maximum, is to measure wavelength with the absorption maximum.The preparation of standard curve: it is an amount of that precision takes by weighing local anaesthetics, prepares the local anaesthetics storing solution of 100 μ g/ml, and this solution of reuse is mixed with the liquid to be measured of 5,10,15,20,25,30,35,40,45,50 μ g/ml. measure absorbance in the absorption maximum place.With local anaesthetics concentration absorbance is carried out linear recurrence, basis of calculation curve is in order to measure the content of local anaesthetics.
Precision is measured: by the preparation method compound concentration of standard curve be respectively 5,15, the 30ml sample solution, carry out in a few days and day to day precision, in a few days in 1,2,4,6,8,24h measures 5 times, in the daytime METHOD FOR CONTINUOUS DETERMINATION is 5 times, and calculate precision by same timing 1 time every day.
Determination of recovery rates: the preparation method compound concentration by standard curve is respectively 5,15,30 μ g/ml sample solutions, and in locating to measure trap, the sample of each concentration repeats 5 times, carries out the response rate for people's regression equation and calculates.
The assay method of Transdermal absorption
The preparation of isolated mouse skin:
Get Kunming kind healthy mice, disconnected neck is put to death, and cuts most belly wool with shears, peels off skin of abdomen, removes subcutaneous fat, checks that the integrity of skin is placed in the normal saline, and is standby 4 ℃ of cold preservations, uses in the 3d.
The transdermal test in vitro test:
Adopt Franz diffusion Xiao Chi, last chamber is a diffuser casing, and following chamber is a receiving chamber.Receiving chamber's internal capacity is 20ml, and infiltrating area is 2cm
2Get mouse skin and place between diffuser casing and the receiving chamber, the skin keratin aspect contacts with acceptable solution, and the dress normal saline is as acceptable solution in the receiving chamber.Start TP-2A type intelligence Transdermal absorption and pass the rate instrument, make temperature maintenance 37,200rmin
-1Constant speed stirs, balance 1h.The compositions (content of dispersion is equivalent to 1mg) that will contain the micronize local anaesthetics then is coated in the mouse skin surface equably; sampling 4ml puts in vitro in setting-up time; all add the fresh acceptable solution of equal volume and preheating after each sampling, and get rid of the bubble in the receiving chamber.The acceptable solution that takes out is compared with the blank solution that extracts with method, measure trap in the absorption maximum place of this medicine, for people's regression equation calculation concentration.According to formula: Q=C
n+ V
0/ V ∑ C
N-1, obtain drug per unit area accumulation infiltration capacity Q.Be receiving chamber's volume in the formula, be the volume of each sampling, C
nBe n the actual drug level that records of sample, ∑ C
N-1Mensuration concentration sum for this sample point.With the accumulation infiltration capacity time is carried out linear recurrence, try to achieve infiltration rate K, be the lag time of medicine in the intercept of X-axis.
Yon Frey analgesic test places mice on the wire netting, covers a transparent organic glass box, makes its quiet about 30min.After treating that mice conforms, with Von Frey cellosilk (is diameter, one group of nylon yarn that grammes per square metre is different) stimulates the mice plantar surfaces of toe, make the bending of Von Frey cellosilk reach 90 degree, begin to occur in 10 seconds hiding to stimulate to light pressure, shout, attack and metapedes are lifted 1 positive performance of foot 1 time, if stimulate positive performance below 2 times or 2 times arranged in 5 times, then changing thick No. one Von Frey cellosilk measures, cause the silk that positive performance more than 3 times or 3 times is arranged in 5 stimulations until finding, record quantity of stimulus at this moment, its grammes per square metre is the pain threshold of reaction to stimulating.Repeat 3 times, 5min at least at interval at every turn gets 3 times meansigma methods.Each position that stimulates will change a little to some extent, and medication side and non-medication top-cross are for stimulating, in order to avoid mouse sensitization.The pain sensation suppresses percentage rate: (medication side quantity of stimulus one non-medication side quantity of stimulus)/non-medication side quantity of stimulus * 100%.
The specific embodiment
Below will the invention will be further described by embodiment, these descriptions are not that content of the present invention is done further to limit.One skilled in the art will understand that to be equal to replacement to what technical characterictic of the present invention was done, or corresponding the improvement, still belong within protection scope of the present invention.
Embodiment one
Lignocaine 10 grams, soybean phospholipid 200 grams, stearic acid 1500 grams are dissolved in entirely and constitute organic facies in the acetone; poloxamer 10 grams, laurocapram 40 grams, propylene glycol 5 are restrained to add and constitute water in the entry; organic facies and water all are heated to 75 degree; stir down biphase rapid mixing; form transparent system; this transparent system decompression is removed away organic solvent concentrate once more, right or be diluted in the water of 5 degree formation micronized medication compositions.
Mean diameter is 287nm, percutaneous absorption rate 6.9 ± 1.1 μ gcm
-2Min
-1, pain sensation suppression ratio reached 70% in the time of 1 minute, and summit reaches 94%.
Embodiment two
With tetracaine 10 gram, lecithin 100 grams,, glycerol trioleate 1500 grams are dissolved in entirely and constitute organic facies in the dioxane; 10 gram soil temperatures 80, dimethyl sulfoxide 40 grams, glycerol 2 are restrained to add and constitute water in the entry; organic facies and water all are heated to 85 degree; stir down biphase rapid mixing; form transparent system; this transparent system decompression is removed away organic solvent concentrate once more, right or be diluted in the water of 0 degree formation micronized medication compositions.
Mean diameter is 225nm, percutaneous absorption rate 7.2 ± 0.8 μ gcm
-2Min
-1, pain sensation suppression ratio reached 65% in the time of 1 minute, and summit reaches 96%.
Embodiment three
Prilocaine 10 grams, egg yolk lecithin 500 grams, 2000 are restrained Precirol ATO 5, and (main component is stearic acid and Palmic acid; 60 ℃ of mp) be dissolved in entirely and constitute organic facies in the oxolane; poloxamer 200 gram added constitute water in the entry; organic facies and water all are heated to 65 degree; with biphase rapid mixing, form transparent system under stirring, this transparent system decompression is removed away organic solvent concentrate once more; right or be diluted in the water of 10 degree, form the micronized medication compositions.
Mean diameter is 421nm, percutaneous absorption rate 3.9 ± 2.1 μ gcm
-2Min
-1, pain sensation suppression ratio reached 35% in the time of 1 minute, and summit reaches 80%.
Embodiment four
With etidocaine 10 gram, 300 gram synthetic phospholipids, 1000 gram Compritol, 888 ATO (main component is behenic acid monoglyceride and diester thereof, three esters, mp 70 degree) (the happy Kanggong of Shanghai card department); Be dissolved in entirely and constitute organic facies in the ethanol; with poly-hydrocarbon (40) [polyoxyethylene (40) stearate of stearic acid; trade name s-40; Nanjing WeiEr chemical engineering Co., Ltd] 150 grams, laurocapram 100 gram add and constitute water in the entry, and organic facies and water all are heated to 80 degree, stir down biphase rapid mixing; form transparent system; this transparent system decompression is removed away organic solvent concentrate once more, right or be diluted in the water of 0 degree formation micronized medication compositions.
Mean diameter is 421nm, percutaneous absorption rate 3.9 ± 2.1 μ gcm
-2Min
-1, pain sensation suppression ratio reached 35% in the time of 1 minute, and summit reaches 80%.
Embodiment five
Lignocaine 10 grams, soybean phospholipid 250 grams, stearic acid 1250 grams are dissolved in entirely and constitute organic facies in the acetone; poloxamer 150 grams, laurocapram 50 grams, ethylene glycol 1 are restrained to add and constitutes water in the entry; organic facies and water all are heated to 75 degree; stir down biphase rapid mixing; form transparent system; this transparent system decompression is removed away organic solvent concentrate once more, right or be diluted in the water of 0 degree formation micronized medication compositions.
Mean diameter is 192nm, percutaneous absorption rate 7.3 ± 1.1 μ gcm
-2Min
-1, pain sensation suppression ratio reached 74% in the time of 1 minute, and summit reaches 98%.
Claims (10)
1. a micronized medication compositions is characterized in that being made up of less than solid local anesthetic and the pharmaceutic adjuvant of 50 μ m mean diameter.
2. as described in the claim 1, the mean diameter that it is characterized in that the solid local anesthetic is less than 1000nm.
3. as described in the claim 1, it is characterized in that local anesthetic is one or more in lignocaine, procaine, tetracaine, proparacaine, oxybuprocaine, benzocaine, cinchocaine, bupivacaine, mepivacaine, etidocaine, ropivacaine, benzyl alcohol, dyclonine, cocaine, chloroprocaine, prilocaine, trimecaine and the medicinal salt or ester thereof.
4. as described in the claim 1, it is characterized in that pharmaceutic adjuvant in said preparation wherein contains one or more in Percutaneous absorption enhancer, surfactant, other matrix materials, phospholipid, the additives.
5. as described in the claim 4, it is characterized in that pharmaceutic adjuvant contains the preferred dimethyl sulfoxide of Percutaneous absorption enhancer, lauryl alcohol, propylene glycol, laurocapram (azone), carbamide, one or more of oleic acid etc., phospholipid is preferably as soybean phospholipid, lecithin, Ovum Gallus domesticus Flavus lecithin, one or more of synthetic phospholipid, the poly-hydrocarbon oxygen ester of the above acid of preferred 12 carbon of surfactant, poloxamer, soil temperature, Pu Lang flows the Buddhist nun, Brij, one or more of Myrij, the preferred stearic acid of other matrix materials, Palmic acid, arachidic acid, myristic acid, octadecanol, the monoglyceride of 12 above acid of carbon, one or more of diester or three esters, the preferred propylene glycol of additives, glycerol, ethanol, or in the mannitol one or more.
6. as described in the claim 1, it is characterized in that the micronized medication compositions by weight by 1 part of the local anesthetic of treatment effective dose, phosphatidase 12-200 part; other matrix materials 2-400 part; surfactant 1-400 part, Percutaneous absorption enhancer 0-100 part is formed, additives 0-50 part.
7. as described in the claim 1, it is characterized in that the micronized medication compositions is by weight by 1 part of the local anesthetic of treatment effective dose, phosphatidase 11 0-100 part; other matrix materials 10-200 part; surfactant 5-100 part, Percutaneous absorption enhancer 1-10 part is formed, additives 0-10 part.
8. as described in the claim 1, it is characterized in that the micronized medication compositions is by weight by 1 part of the local anesthetic of treatment effective dose, phosphatidase 12 0-50 part; other matrix materials 100-150 part; surfactant 10-50 part, Percutaneous absorption enhancer 1-5 part is formed, additives 0-1 part.
9. as described in the claim 1-8; it is characterized in that micronized medication preparation of compositions technology is: with local anesthetic; phospholipid; other matrix materials are dissolved in organic solvent such as acetone; ethanol; isopropyl alcohol; oxolane; constitute organic facies in the dioxane; with surfactant; cutaneous permeable agent; additives add and constitute water in the entry; organic facies and water are heated to the 60-90 degree; both temperature difference are not more than 5 degree; stir down biphase rapid mixing; form transparent system; this transparent system decompression is removed away organic solvent to be concentrated once more; right or be diluted in the water of 0-10 degree, form the micronized medication compositions.
10. as described in the claim 1-8, it is characterized in that micronized medication preparation of compositions technology is: with machinery local anesthetic is pulverized, added in surfactant, the cutaneous permeable agent one or more and stir, form the micronized medication compositions.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101295886A CN101190184A (en) | 2006-11-24 | 2006-11-24 | Micronizing solid external application local anesthetic and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101295886A CN101190184A (en) | 2006-11-24 | 2006-11-24 | Micronizing solid external application local anesthetic and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101190184A true CN101190184A (en) | 2008-06-04 |
Family
ID=39485481
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006101295886A Pending CN101190184A (en) | 2006-11-24 | 2006-11-24 | Micronizing solid external application local anesthetic and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101190184A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103933041A (en) * | 2014-04-21 | 2014-07-23 | 王寿世 | Composition containing bupivacaine for local anaesthesia and application thereof |
| CN105769839A (en) * | 2016-05-17 | 2016-07-20 | 山西远扬医药科技有限公司 | Compound lidocaine medicine composition and preparation method thereof |
| CN108159170A (en) * | 2018-02-06 | 2018-06-15 | 重庆医科大学附属永川医院 | Piece and preparation method and application is released for the freeze-drying sudden strain of a muscle of local skin anesthesia |
-
2006
- 2006-11-24 CN CNA2006101295886A patent/CN101190184A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103933041A (en) * | 2014-04-21 | 2014-07-23 | 王寿世 | Composition containing bupivacaine for local anaesthesia and application thereof |
| CN103933041B (en) * | 2014-04-21 | 2016-03-16 | 青岛市中心医院 | A kind of local anesthetic composition and application thereof comprising bupivacaine |
| CN105769839A (en) * | 2016-05-17 | 2016-07-20 | 山西远扬医药科技有限公司 | Compound lidocaine medicine composition and preparation method thereof |
| CN105769839B (en) * | 2016-05-17 | 2019-06-11 | 山西远扬医药科技有限公司 | A kind of compound lidocaine pharmaceutical composition and preparation method thereof |
| CN108159170A (en) * | 2018-02-06 | 2018-06-15 | 重庆医科大学附属永川医院 | Piece and preparation method and application is released for the freeze-drying sudden strain of a muscle of local skin anesthesia |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPH0564125B2 (en) | ||
| RU2117490C1 (en) | Transdermal composition for local administration of therapeutic and/or prophylactic active agent, band or bandage for transdermal delivery | |
| Buchbauer et al. | Aromatherapy: evidence for sedative effects of the essential oil of lavender after inhalation | |
| CN106999598A (en) | Stable Cannabinoids compound formulation | |
| RU2761342C2 (en) | Delivery of therapeutic agents to the central nervous system | |
| WO2014160016A2 (en) | Peptide systems and methods for metabolic conditions | |
| CN108379269A (en) | A kind of sustained release preparation and preparation method thereof for Postoperative Analgesia After | |
| CN106267218A (en) | 4 terpinol aliphatic ester derivatives and application thereof and preparation method | |
| CN114980890A (en) | Injectable long-acting analgesic pharmaceutical composition and preparation method and application thereof | |
| CN105853421B (en) | The new application of FoxO1 selective depressant AS1842856 | |
| US6677361B2 (en) | Topical formulations for the transdermal delivery of niacin and methods of treating hyperlipidemia | |
| CN104447313B (en) | α-terpinol aliphatic ester derivatives and application | |
| CN101190184A (en) | Micronizing solid external application local anesthetic and preparation method thereof | |
| US10517835B2 (en) | Composition and methods of treatment | |
| US5371104A (en) | Compositions containing forskolin | |
| US20100331812A1 (en) | Pharmaceutical Formulations for Iontophoretic Delivery of an Immunomodulator | |
| CN101669986A (en) | Compound gel preparation containing sophora alopecuroide oil | |
| CN101891751B (en) | Method for preparing tetrodotoxin | |
| CN102232925A (en) | Hydrochloric acid lidocaine transdermal agent and its preparation method | |
| US8779003B2 (en) | Method and composition for prolonging analgesic effect of local anesthetic | |
| AU2016390920B2 (en) | New use of isoquinoline derivatives for diabetic wound healing | |
| CN109289041B (en) | Vitamin D-insulin nano sustained-release transdermal preparation and preparation method thereof | |
| CN117356588A (en) | Plant preparation stock solution, plant preparation and preparation method thereof | |
| US8895623B2 (en) | Intrathecal or epidural administration of 3-[(1S,25)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol | |
| WO2022105720A1 (en) | Glibenclamide pharmaceutical composition and preparation method therefor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Open date: 20080604 |