CN101693069B - Composition for preparing external preparation for treating soft tissue injuries and preparation method thereof - Google Patents
Composition for preparing external preparation for treating soft tissue injuries and preparation method thereof Download PDFInfo
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Abstract
The invention relates to an external preparation for treating soft tissue injuries, belonging to the technical field of medicaments for treating orthopedic diseases. The external preparation is prepared from a water or alcohol extract of raw material medicines and pharmaceutically acceptable carriers. The raw material medicines comprise pubescent holly roots, Chinese aralis, oblongleaf Chinese sweetspire roots and flowers, ardisia crenata, syzygium grijsii roots, goldhair hedyotis herbs, earthworms, rinus massoniana roots, ampelopsis sinica roots, ormosia henryi roots, kuh-seng, cuscuta japonica, drynaria rhizome, thinleaf adina fruit roots and cudrania cochinchinensis. The carriers comprise oleaginousbase, an emulsifier and a preservative, wherein the weight percentage of the oleaginousbase is 10-21 percent, and the oleaginousbase is selected from one or a mixture of glyceryl monostearate, hexadecanol-octadecanol, vaseline and liquid paraffin; the weight percentage of the emulsifier is 0.5-5 percent, and the emulsifier is a polyoxyethylene fatty alcohol ether non-ionic emulsifier compound; the preservative is Jemaa BP accounting for 0.05-1.0 percent of the total weight of the preparation. The external preparation eliminates the irritability and the foreign odor of preparations of the prior art, obviously improves the viscosity of paste and improves the stability of emulsifiable paste.
Description
Technical field
The invention belongs to set a broken bone section disease class technical field of pharmaceuticals, particularly be used for the treatment of the Chinese medicine compound external preparation of the diseases such as local swelling due to the human soft tissue injury, blood stasis, pain, dysfunction.
Background technology
Soft tissue injury is commonly encountered diseases, the frequently-occurring disease of orthopedics department, belong to motherland's medical science dialectical in the category of " muscle and tendon injury ".How because of tumbling down, clash into, fall, sprain and contusion, pressure rolling, the external violence such as wrestle directly or indirectly act on body, cause the damage at the positions such as body skin, subcutaneous tissue, fascia, muscle, tendon ligament, periosteum, joint capsule, synovial bursae, a series of pathological change occurs.Clinical manifestation is local pain, tenderness, swelling, livid purple ecchymosis, limb activity dysfunction etc.Modern medicine has the primary treatment method of soft tissue injury: wrapping, partial closure or physical therapy, but these method curative effects are not good enough, and rehabilitation duration is longer.
Soft tissue injury belongs to " injury of tendon and muscle " category in orthopedics and traumatology of Chinese medicine, motherland's medical science is thought its pathogenesis for " stagnation of QI and blood stasis " and seen.The Chinese traditional treatment soft tissue injury has long history, in long-term medical practice, formed be association of activity and inertia, muscles and bones is laid equal stress on, internal and external application, the Comprehensive Treatment system of medication by stages, especially show unique characteristics with external treatment of tcm.The ointment that cures the wound is exactly the representative drugs with external treatment of tcm treatment soft tissue injury, its main pharmacological is control and slows down inflammatory reaction, absorption is by oozing out due to the inflammatory reaction, congested and red and swollen, reparation by the concentration of the soft tissue due to the damage and blood vessel wall, reduction algogenic substance, alleviate the stimulation to free nerve endings, improve simultaneously pain threshold, play the effect of blood circulation promoting and blood stasis dispelling, reducing swelling and alleviating pain, fundamentally eliminate " stagnation of QI and blood stasis ".
Country of National Drug Administration standard for traditional Chinese medicines compilation, Chinese patent medicine provincial standard rising national standard part, the orthopedics department fascicle standard ointment standard (WS-11421 (ZD-1421)-2002) that cures the wound, prescription and the method for making of the ointment that cures the wound are disclosed, adopt newborn soap method, newborn triethanolamine soap that neutralization reaction generates occuring as emulsifying agent take stearic acid and triethanolamine, makes O/W type emulsifiable paste at the interface that contacts.According to the investigation that keeps sample, little by the ointment stickiness that cures the wound of this formulation and technology production, tool is mobile, is difficult for adhering to the affected part; Particularly pass through torridity summer in effect duration, mastic can breakdown of emulsion, oil-water separation occurs, becomes sour, variable color iso-metamorphism phenomenon.Therefore the inventor wishes to improve its stability, produces evenly, exquisiteness, soft cunning, denseness be suitable, and property is stable, preserves the product that stay-in-grade satisfies clinical requirement more in effect duration.
Compound Chinese medicinal preparation about the treatment damage, the applicant in first to file, publication number is CN1939480A, denomination of invention is " a kind of compound Chinese medicinal preparation for the treatment of damage " (open day is 2007.04.04), take crude drug as Radix Ilicis Pubescentis Cortex araliae chinensis, Flos Iteae oblongae, Radix Ardisiae Crenatae, root of Syzygiumgrijsii (Hance) Merr.etPerry, Herba Hedyotidis Chrysotrichae, Pheretima, Pinus massoniana root, Radix ampelopsis brevipedunculatae, the Lignum pterocarpi indici root, Radix Sophorae Flavescentis, cuscuta japonica Choisy, Rhizoma Drynariae, Radix Gei japonici and Radix Cudraniae, add the adjuvant stearic acid, dimethyl sulfoxine, Yellow Vaselin, lanoline, liquid Paraffin, glycerol and triethanolamine, this scheme antiinflammatory action and analgesic activity are obvious, especially the component of embodiment 3 and content proportioning, compare the orthopedics department fascicle standard disclosed technology of ointment standard that cures the wound, the swelling rate of its ointment administration has reduced by 10%, the inhibitory action that xylol causes mice auricular concha inflammation also has enhancing, and the zest of intact skin and damaged skin is reduced.But also there is following deficiency in it:
(1) its oil phase substrate is Yellow Vaselin, liquid paraffin, lanoline.Lanoline has one foreign odor, and in use, anaphylaxis often occurs, and this may be to cause owing to containing alcohol moiety in the lanoline, and in the ointment of topical application, lanoline is put into the secondary allergic agent.
(2) without thickening agent, the product viscosity that makes is inadequate, and extruding in flexible pipe can not be into strips, and the pollution clothes that easily becomes to drip during use is made troubles to patient's use.
(3) less stable, summer, meeting oil-water separation produced demulsifying phenomenon.
(4) penetration enhancer is dimethyl sulfoxine.Dimethyl sulfoxine (DMSO) is because its general toxicity reaches the zest to skin, and U.S. FDA has not allowed to sell the goods that contain DMSO.Report that topical application DMSO can cause hepatic injury, skin erythema, edema, Pruritus, burn feeling, and have unhappy stink etc.When the DMSO of high concentration uses in a organized way amine discharge and the report of the side effect such as local tissue damage; Large-area applications may affect the optic nerve function and cause haemolysis.Dimethyl sulfoxine has been listed in the substrate of careful usefulness at present.
(5) existence of microorganism is to be unable to do without water, so the concentration of aqueous phase antiseptic is the key that affects growth of microorganism.The antiseptic ethyl hydroxybenzoate is oil-soluble in the invention technical scheme of CN1939480A, and is lower at the aqueous phase dissolubility.
Summary of the invention
The present invention seeks in order to overcome the defective of above-mentioned prior art, provide a kind of soft cunning, denseness to suit, have Chinese medicine compound external preparation and the preparation technology thereof of the treatment soft tissue injury of high stable performance.
The technical solution adopted for the present invention to solve the technical problems is:
A kind of external preparation that is used for the treatment of soft tissue injury, said preparation is comprised of the water of crude drug or alcohol extract and pharmaceutically acceptable carrier, and described crude drug is Radix Ilicis Pubescentis, Cortex araliae chinensis, Flos Iteae oblongae, Radix Ardisiae Crenatae, root of Syzygiumgrijsii (Hance) Merr.etPerry, Herba Hedyotidis Chrysotrichae, Pheretima, Pinus massoniana root, Radix ampelopsis brevipedunculatae, Lignum pterocarpi indici root, Radix Sophorae Flavescentis, cuscuta japonica Choisy, Rhizoma Drynariae, Radix Gei japonici and Radix Cudraniae; Described pharmaceutically acceptable carrier comprises greasing base, emulsifying agent and antiseptic, the percentage by weight that greasing base accounts for the preparation total amount is 10%-21%, and this oleaginous base is selected from one of glyceryl monostearate, hexadeca-octadecyl alcohol, vaseline and liquid paraffin or their mixture;
Described emulsifying agent is the polyoxyethylene aliphatic alcohol ether nonionic emulsifier compound that accounts for total formulation weight amount 0.5%-5%;
Described antiseptic is the germall BP that accounts for total formulation weight amount 0.05%-1.0%.
Pharmaceutically acceptable carrier also comprises thickening agent and pH adjusting agent described in the external preparation of the present invention.
Described thickening agent is carbomer, and the percentage by weight that accounts for the preparation total amount is 0.05%-1.5%.
The described greasing base of external preparation of the present invention is selected from one of glyceryl monostearate, hexadeca-octadecyl alcohol, vaseline and liquid paraffin or their mixture.Can be weight percentage and be the glyceryl monostearate of 0.5%-5%.Perhaps being weight percentage is the hexadeca-octadecyl alcohol of 0.5%-15%, or the vaseline of 0.5%-8%, or is the liquid paraffin of 2%-15%.But be not to be defined as a kind of oleaginous base, its two kinds or two or more mixing interworkings also can play preferably effect, as with Yellow Vaselin and liquid paraffin, and add hexadeca-octadecyl alcohol, can effectively improve flexibility and the lubricity of ointment.If composite following mode is mixed best:
The percentage by weight that accounts for the preparation total amount is the glyceryl monostearate of 0.5%-5%;
The percentage by weight that accounts for the preparation total amount is the hexadeca-octadecyl alcohol of 0.5%-15%;
The percentage by weight that accounts for the preparation total amount is the vaseline of 0.5%-8%;
The percentage by weight that accounts for the preparation total amount is the liquid paraffin of 2%-15%.
The PH regulator that described adjusting denseness is used is selected from triethanolamine, sodium hydroxide or potassium hydroxide.
The percentage by weight of the following component of the preferred pharmaceutical carrier of external preparation of the present invention forms, and wherein wt percentage ratio refers to that the fractions that accounts for the total formulation weight amount is:
Carbomer 0.3%
Polyoxyethylene aliphatic alcohol ether 2.0%
Hexadeca-octadecyl alcohol 8.0%
Glyceryl monostearate 2.0%
Liquid paraffin 8.0%
Yellow Vaselin 3.0%
Triethanolamine 0.5%～1.2%
Germall BP 0.3%
Described medicine original material forms by following percentage by weight: 30-125 weight portion Radix Ilicis Pubescentis; 30-125 Chong Liang Fen Cortex araliae chinensis; 19-75 weight portion Flos Iteae oblongae; 37-150 weight portion Radix Ardisiae Crenatae; 13-50 weight portion root of Syzygiumgrijsii (Hance) Merr.etPerry; 13-50 weight portion Pheretima; 25-100 weight portion Herba Hedyotidis Chrysotrichae; 30-125 weight portion Pinus massoniana root; 64-150 weight portion Radix ampelopsis brevipedunculatae; 50-200 weight portion Lignum pterocarpi indici root; 44-175 weight portion Radix Sophorae Flavescentis; 25-100 weight portion cuscuta japonica Choisy; 19-75 weight portion Rhizoma Drynariae; 19-75 weight parts water Radix Myricae rubrae; 25-100 weight portion Radix Cudraniae.
More preferably, described medicine original material forms by following percentage by weight:: 62.5 weight portion Radix Ilicis Pubescentiss; 65.2 Chong Liang Fen Cortex araliae chinensis; 37.5 weight portion Flos Iteae oblongae; 75 weight portion Radix Ardisiae Crenataes; 25 weight portion root of Syzygiumgrijsii (Hance) Merr.etPerrys; 25 weight portion Pheretimas; 50 weight portion Herba Hedyotidis Chrysotrichaes; 62.5 weight portion Pinus massoniana root; 75 weight portion Radix ampelopsis brevipedunculataes; 100 weight portion Lignum pterocarpi indici roots; 87.5 weight portion Radix Sophorae Flavescentis; 50 weight portion cuscuta japonica Choisies; 37.5 weight portion Rhizoma Drynariae; 37.5 weight parts water Radix Myricae rubrae; 50 weight portion Radix Cudraniaes.
Preparation viscosity of the present invention is 10Pas-30Pas, is preferably approximately 10Pas-20Pas.
The preparation pH value is 4.0-8.0, is preferably 5.5-6.5.
External preparation of the present invention, described dosage form are ointment, ointment, gel, Emulsion or emplastrum.
Another object of the present invention is to provide the preparation method of described external preparation, it is characterized in that may further comprise the steps:
(1) prepares water or the alcohol extract of active constituents of medicine by the raw medicinal material proportioning;
(2) getting thickening agent adds water-soluble swollen, for subsequent use;
(3) get oleaginous base and polyoxyethylene aliphatic alcohol ether, be heated to 70～80 ℃, make oil phase substrate, for subsequent use;
(4) add an amount of purified water and thickening agent colloid in the emulsion tank, be heated to 70～80 ℃; Under stirring condition, oil phase substrate is sucked emulsion tank by oil phase tank vacuum, reinforcedly finishes to mix after 20 minutes, stir 10 minutes with the 2500rpm homogenizing after, change low rate mixing into, stir borehole cooling to 50 ℃-70 ℃;
(5) add in the blank mastic after the extracting solution of step (1) is heated to 50～60 ℃, mixing, stir 10 minutes with the 2500rpm homogenizing after, change low rate mixing into;
(6) be cooled to 50 ℃, add again pH adjusting agent and antiseptic, stir evenly, cooling.
Further, the extracting method of step (1) is with ten five tastes medical materials of described recipe quantity, is ground into coarse powder, and ethanol extraction, extracting solution are concentrated into the clear paste that relative density is 1.10～1.15 (85 ℃), filters filtrate for later use; Medicinal residues decoct with water secondary, and each 1～2 hour, collecting decoction filtered, and filtrate is concentrated into the clear paste that relative density is 1.05～1.10 (85 ℃), filters;
Concentration of alcohol is 45%～95%, and described ethanol extraction is one of percolation, cold-maceration or water bath reflux method.
Preparation method of the present invention comprises step: with the ointment mastic that the prepares medicinal compound ointment tube of packing into, before fill, be filled with nitrogen, fill again nitrogen one time after being filled into the ointment mastic that cures the wound, after immediately sealing.
External preparation of the present invention compared to existing technology, beneficial effect is embodied in:
(1) the present invention discards prior art preparation lanoline,, eliminated the anaphylaxis and the foreign odor that are prone to when using.
(2) the present invention adopts polyoxyethylene aliphatic alcohol ether to make emulsifying agent, and polyoxyethylene aliphatic alcohol ether is the nonionic emulsifier compound that different molal quantity polyoxyethylene aliphatic alcohol ethers are main component.Emulsifying effectiveness obviously improves, and when adopting glyceryl monostearate to make coemulsifier, can increase oil phase viscosity, prevents the merging of drop, has improved the stability of emulsifiable paste.
Effect embodies in the preparation in addition: the prior art preparation is when stirring and emulsifying, and saponification can produce a large amount of foams and be raised to the vacuum mouth of pipe of emulsion tank and be sucked away, and the present patent application produces foam when stirring and emulsifying few, the situation that can not run material.
(3) add thickening agent, the product viscosity that prior art makes is inadequate, extruding in flexible pipe can not be into strips, pollution clothes easily becomes to drip during use, make troubles to patient's use, the present invention adds thickening agent, can significantly improve the mastic viscosity when especially increasing by 0.05%～1.5% carbomer.
(4) the penetration enhancer dimethyl sulfoxine of prior art has been listed in the substrate of careful usefulness.For this reason, the applicant has carried out adding the CN1939480A of dimethyl sulfoxine and the application carries out release in vitro and transdermal penetration is tested, experiment entrusts pharmaceutical college of Zhejiang University medicament institute to finish, by release in vitro and transdermal penetration experimentation, the present patent application product and CN1939480A situation aspect release in vitro and Transdermal absorption is basically identical, without significant difference.Because preparation of the present invention is the local topical medicine, under the prerequisite that does not affect Transdermal absorption, does not preferably add penetration enhancer, the present patent application is left out the penetration enhancer dimethyl sulfoxine.
(5) when the present patent application antiseptic be germall BP, it is the mixture of diazonium imidazolidinyl urea and IPBC (IPBC), has broad spectrum antibiotic activity, can suppress gram negative bacteria, positive bacteria, yeast and mycete, the adding of IPBC more strengthens it and presses down the mycete effect, and its bacteriostasis is not subjected to the impact of surfactant.The emulsifying agent of the present patent application is non-ionic surface active agent, also be added in oil phase so that larger chance solubilising antiseptic is arranged, by the ethyl hydroxybenzoate of surfactant micella solubilising to microorganism with ineffective, therefore the present patent application is selected suitable antiseptic, experimental results show that its effect is excellent.
Description of drawings
Fig. 1 is the outer release profiles of soft paste:
Among Fig. 1 :-◆-: the ointment that cures the wound (prior art sample, the preparation of public technology preparation among the CN1939480A)-■-: the ointment that cures the wound (preparation of the embodiment of the invention 1 preparation).
Fig. 2 is the outer transdermal penetration curve of soft paste::
Among Fig. 2 :-◆-: the ointment that cures the wound (prior art sample, the preparation of public technology preparation among the CN1939480A)-■-: the ointment that cures the wound (preparation of the embodiment of the invention 1 preparation).
The swelling rate of each experimental group in the experiment of Fig. 3 anti-inflammatory activity:
I among the figure: positive control II: negative control III: the ointment that cures the wound (prior art sample, the preparation of public technology preparation among the CN1939480A) IV: the ointment that cures the wound (preparation of the embodiment of the invention 1 preparation).
Fig. 4 is the skin electron micrograph of histopathological examination single-dose experiment:
A wherein: the present invention's ointment single-dose group intact skin (* 400 that cures the wound, HE) b: the present invention's blank substrate single-dose of ointment group intact skin (* 400 that cures the wound, HE) c: the present invention's ointment single-dose group damaged skin (* 400 that cures the wound, HE) d: the present invention cure the wound the blank substrate single-dose of ointment group damaged skin (* 400, HE).
Fig. 5 is the skin electron micrograph of histopathological examination experiment multiple dosing:
A wherein: the ointment multiple dosing group that cures the wound intact skin (* 400, HE) b: the blank substrate multiple dosing of the ointment group that cures the wound intact skin (* 400, HE) c: the ointment multiple dosing group that cures the wound damaged skin (* 400, HE) d: the blank substrate multiple dosing of the ointment group that cures the wound damaged skin (* 400, HE).
The specific embodiment
Come the present invention is further specified below in conjunction with specific embodiment, but do not limit the invention to these specific embodiment.One skilled in the art would recognize that the present invention contained all alternatives, improvement project and the equivalents that may comprise in claims scope.
Embodiment 1: ointment formulation and technology I
Raw medicinal material (to make 1000g ointment):
Radix Ilicis Pubescentis 62.5g Cortex araliae chinensis 65.2g Flos Iteae oblongae 37.5g
Radix Ardisiae Crenatae 75g root of Syzygiumgrijsii (Hance) Merr.etPerry 25g Pheretima 25g
Herba Hedyotidis Chrysotrichae 50g Pinus massoniana root 62.5g Radix ampelopsis brevipedunculatae 75g
Lignum pterocarpi indici root 100g Radix Sophorae Flavescentis 87.5g cuscuta japonica Choisy 50g
Rhizoma Drynariae 37.5g Radix Gei japonici 37.5g Radix Cudraniae 50g
Extraction process:
With ten five tastes raw medicinal materials, be ground into coarse powder, the ethanol with 75% is evenly moistening, airtight placement 2 hours, reinstall in the percolator, should be closely even when packing into, degree of tightness is consistent, the alcohol dipping of adding 75% 2 hours, then begin percolation, collect the liquid of filtering of 8 times of medical material amounts, the liquid of filtering is concentrated into the clear paste that relative density is 1.10～1.15 (85 ℃), filter filtrate for later use; The decocting that medicinal residues add 6 times of medical material amounts boils secondary, and each 1～2 hour, collecting decoction filtered, and filtrate is concentrated into the clear paste that relative density is 1.05～1.10 (85 ℃), filters filtrate for later use.
Pharmaceutical carrier (to make 1000g ointment):
Carbomer 3g polyoxyethylene aliphatic alcohol ether (OLI-9022) 20g
Hexadeca-octadecyl alcohol 80g glyceryl monostearate 20g
Liquid paraffin 80g Yellow Vaselin 30g
An amount of germall BP3g of triethanolamine
Preparations shaping technique:
1. getting carbomer adds water-soluble swollen, for subsequent use.
2. get glyceryl monostearate, hexadeca-octadecyl alcohol, Yellow Vaselin, liquid paraffin, polyoxyethylene aliphatic alcohol ether (OLI-9022), be heated to 70～80 ℃, make oil phase substrate, for subsequent use;
3. add an amount of purified water and carbomer colloid in the emulsion tank, be heated to 70～80 ℃;
4. under stirring condition, oil phase substrate is sucked emulsion tank by oil phase tank vacuum, reinforcedly finishes to mix after 20 minutes, stir 10 minutes with the 2500rpm homogenizing after, change low rate mixing into, stir borehole cooling to 50～70 ℃;
5. add after the raw medicinal material extracting solution being heated to 50～60 ℃ in the blank mastic, mixing after 10 minutes, changes low rate mixing with the stirring of 2500rpm homogenizing into;
6. be cooled to 50 ℃, add an amount of triethanolamine, regulate pH to 5.5～6.5;
7. add again germall BP, stir evenly, cooling, recording viscosity is 10Pas～20Pas;
8. the medicinal compound ointment tube of at last mastic being packed into is filled with nitrogen before fill, be filled with nitrogen after being filled into mastic again, immediately sealing and get final product.
Embodiment 2: ointment formulation and technology II
Raw medicinal material (to make 1000g ointment): with embodiment 1.
Extraction process:
With ten five tastes raw medicinal materials, cutting was extracted 2 hours with 60% alcohol heat reflux of 10 times of medical material amounts, and extracting solution is concentrated into the clear paste that relative density is 1.10～1.15 (85 ℃), filters filtrate for later use; The decocting that medicinal residues add 6 times of medical material amounts boils secondary, and each 1～2 hour, collecting decoction filtered, and filtrate is concentrated into the clear paste that relative density is 1.05～1.10 (85 ℃), filters filtrate for later use.
Pharmaceutical carrier (to make 1000g ointment):
Carbomer 1g polyoxyethylene aliphatic alcohol ether (OLI-9022) 5g
Glyceryl monostearate 50g liquid paraffin 110g
Yellow Vaselin 5g sodium hydroxide is an amount of
Germall BP3g
Preparations shaping technique:
1. getting carbomer adds water-soluble swollen, for subsequent use.
2. get glyceryl monostearate, Yellow Vaselin, liquid paraffin, polyoxyethylene aliphatic alcohol ether (OLI-9022), be heated to 70～80 ℃, make oil phase substrate, for subsequent use;
3. add an amount of purified water and carbomer colloid in the emulsion tank, be heated to 70～80 ℃
4. under stirring condition, oil phase substrate is sucked emulsion tank by oil phase tank vacuum, reinforcedly finishes to mix after 20 minutes, stir 10 minutes with the 2500rpm homogenizing after, change low rate mixing into, stir borehole cooling to 50～70 ℃.
5. add after the raw medicinal material extracting solution being heated to 50～60 ℃ in the blank mastic, mixing after 10 minutes, changes low rate mixing with the stirring of 2500rpm homogenizing into.
6. be cooled to 50 ℃, add an amount of sodium hydroxide, regulate pH to 4.0.
7. add again germall BP, stir evenly, cooling, recording viscosity is 10Pas.
8. the medicinal compound ointment tube of at last mastic being packed into is filled with nitrogen before fill, be filled with nitrogen after being filled into mastic again, immediately sealing and get final product.
Embodiment 3: ointment formulation and technology III
Raw medicinal material (to make 1000g ointment):
Radix Ilicis Pubescentis 30g Cortex araliae chinensis 30g Flos Iteae oblongae 19g
Radix Ardisiae Crenatae 37g root of Syzygiumgrijsii (Hance) Merr.etPerry 13g Pheretima 13g
Herba Hedyotidis Chrysotrichae 25g Pinus massoniana root 30g Radix ampelopsis brevipedunculatae 150g
Lignum pterocarpi indici root 200g Radix Sophorae Flavescentis 175g cuscuta japonica Choisy 100g
Rhizoma Drynariae 75g Radix Gei japonici 75g Radix Cudraniae 100g
Extraction process:
With ten five tastes raw medicinal materials, be ground into coarse powder, add the alcohol dipping 24 hours of 10 times of medical material amounts 95%, impregnation liquid is concentrated into the clear paste that relative density is 1.10～1.15 (85 ℃), filters filtrate for later use; The decocting that medicinal residues add 6 times of medical material amounts boils secondary, and each 1～2 hour, collecting decoction filtered, and filtrate is concentrated into the clear paste that relative density is 1.05～1.10 (85 ℃), filters filtrate for later use.
Pharmaceutical carrier (to make 1000g ointment):
Carbomer 10g polyoxyethylene aliphatic alcohol ether (OLI-9022) 50g
Hexadeca-octadecyl alcohol 150g glyceryl monostearate 50g
An amount of germall BP0.5g of potassium hydroxide
Preparations shaping technique:
1. getting carbomer adds water-soluble swollen, for subsequent use.
2. get glyceryl monostearate, hexadeca-octadecyl alcohol, polyoxyethylene aliphatic alcohol ether (OLI-9022), be heated to 70～80 ℃, make oil phase substrate, for subsequent use;
3. add an amount of purified water and carbomer colloid in the emulsion tank, be heated to 70～80 ℃;
4. under stirring condition, oil phase substrate is sucked emulsion tank by oil phase tank vacuum, reinforcedly finishes to mix after 20 minutes, stir 10 minutes with the 2500rpm homogenizing after, change low rate mixing into, stir borehole cooling to 50～70 ℃;
5. add after the raw medicinal material extracting solution being heated to 50～60 ℃ in the blank mastic, mixing after 10 minutes, changes low rate mixing with the stirring of 2500rpm homogenizing into;
6. be cooled to 50 ℃, add an amount of potassium hydroxide, regulate pH to 8;
7. add again germall BP, stir evenly, cooling, recording viscosity is 30Pas;
8. the medicinal compound ointment tube of at last mastic being packed into, sealing and get final product.
Embodiment 4: ointment formulation and technology IV
Raw medicinal material (to make 1000g ointment):
Radix Ilicis Pubescentis 125g Cortex araliae chinensis 125g Flos Iteae oblongae 75g
Radix Ardisiae Crenatae 150 root of Syzygiumgrijsii (Hance) Merr.etPerry 50g Pheretima 50g
Herba Hedyotidis Chrysotrichae 100g Pinus massoniana root 125g Radix ampelopsis brevipedunculatae 64g
Lignum pterocarpi indici root 50g Radix Sophorae Flavescentis 44g cuscuta japonica Choisy 25g
Rhizoma Drynariae 19g Radix Gei japonici 19g Radix Cudraniae 25g
Extraction process:
With ten five tastes raw medicinal materials, be ground into coarse powder, the ethanol with 45% is evenly moistening, airtight placement 2 hours, reinstall in the percolator, should be closely even when packing into, degree of tightness is consistent, the alcohol dipping of adding 75% 2 hours, then begin percolation, collect the liquid of filtering of 8 times of medical material amounts, the liquid of filtering is concentrated into the clear paste that relative density is 1.10～1.15 (85 ℃), filter filtrate for later use.
Pharmaceutical carrier (to make 1000g ointment):
Carbomer 3g polyoxyethylene aliphatic alcohol ether (OLI-9022) 20g
Glyceryl monostearate 50g liquid paraffin 150g
An amount of germall BP3g of triethanolamine
Preparations shaping technique:
1. getting carbomer adds water-soluble swollen, for subsequent use.
2. get glyceryl monostearate, liquid paraffin, polyoxyethylene aliphatic alcohol ether (OLI-9022), be heated to 70～80 ℃, make oil phase substrate, for subsequent use;
3. add an amount of purified water and carbomer colloid in the emulsion tank, be heated to 70～80 ℃;
4. under stirring condition, oil phase substrate is sucked emulsion tank by oil phase tank vacuum, reinforcedly finishes to mix after 20 minutes, stir 10 minutes with the 2500rpm homogenizing after, change low rate mixing into, stir borehole cooling to 50～70 ℃
5. add after the raw medicinal material extracting solution being heated to 50～60 ℃ in the blank mastic, mixing after 10 minutes, changes low rate mixing with the stirring of 2500rpm homogenizing into;
6. be cooled to 50 ℃, add an amount of triethanolamine, regulate pH to 5.5～6.5;
7. add again germall BP, stir evenly, cooling, recording viscosity is 10Pas～20Pas;
8. the medicinal compound ointment tube of at last mastic being packed into is filled with nitrogen before fill, be filled with nitrogen after being filled into mastic again, immediately sealing and get final product.
Embodiment 5: ointment formulation and technology V
Raw medicinal material (to make 1000g ointment):
Radix Ilicis Pubescentis 62.5g Cortex araliae chinensis 65.2g Flos Iteae oblongae 37.5g
Radix Ardisiae Crenatae 75g root of Syzygiumgrijsii (Hance) Merr.etPerry 25g Pheretima 50g
Herba Hedyotidis Chrysotrichae 100g Pinus massoniana root 125g Radix ampelopsis brevipedunculatae 150g
Lignum pterocarpi indici root 200g Radix Sophorae Flavescentis 44g cuscuta japonica Choisy 25g
Rhizoma Drynariae 19g Radix Gei japonici 19g Radix Cudraniae 25g
Extraction process:
With ten five tastes raw medicinal materials, be ground into coarse powder, the ethanol with 60% is evenly moistening, airtight placement 2 hours, reinstall in the percolator, should be closely even when packing into, degree of tightness is consistent, the alcohol dipping of adding 75% 2 hours, then begin percolation, collect the liquid of filtering of 8 times of medical material amounts, the liquid of filtering is concentrated into the clear paste that relative density is 1.10～1.15 (85 ℃), filter filtrate for later use.
Pharmaceutical carrier (to make 1000g ointment):
Carbomer 0.5g polyoxyethylene aliphatic alcohol ether (OLI-9022) 20g
Hexadeca-octadecyl alcohol 5.0g glyceryl monostearate 5.0g
Liquid paraffin 20g Yellow Vaselin 80g
An amount of germall BP10g of triethanolamine
Preparations shaping technique:
1. getting carbomer adds water-soluble swollen, for subsequent use.
2. get glyceryl monostearate, liquid paraffin, hexadeca-octadecyl alcohol, Yellow Vaselin, polyoxyethylene aliphatic alcohol ether (OLI-9022), be heated to 70～80 ℃, make oil phase substrate, for subsequent use;
3. add an amount of purified water and carbomer colloid in the emulsion tank, be heated to 70～80 ℃;
4. under stirring condition, oil phase substrate is sucked emulsion tank by oil phase tank vacuum, reinforcedly finishes to mix after 20 minutes, stir 10 minutes with the 2500rpm homogenizing after, change low rate mixing into, stir borehole cooling to 50～70 ℃;
5. add after the raw medicinal material extracting solution being heated to 50～60 ℃ in the blank mastic, mixing after 10 minutes, changes low rate mixing with the stirring of 2500rpm homogenizing into;
6. be cooled to 50 ℃, add an amount of triethanolamine, regulate pH to 5.5～6.5;
7. add again germall BP, stir evenly, cooling, recording viscosity is 20Pas～30Pas;
8. the medicinal compound ointment tube of at last mastic being packed into is filled with nitrogen before fill, be filled with nitrogen after being filled into mastic again, immediately sealing and get final product.
Embodiment 6: the Emulsion formulation and technology
Raw medicinal material (to make 1000ml Emulsion): with embodiment 1.
Extraction process: with embodiment 1.
Pharmaceutical carrier (to make 1000g Emulsion):
Liquid paraffin 100g
Polyoxyethylene aliphatic alcohol ether (OLI-9022) 20g
Germall BP3g
Preparations shaping technique:
1. get liquid paraffin, polyoxyethylene aliphatic alcohol ether (OLI-9022), be heated to 70～80 ℃, for subsequent use;
2. add an amount of purified water and raw medicinal material extracting solution in the emulsion tank, be heated to 70～80 ℃;
3. under stirring condition oil phase substrate is sucked emulsion tank by oil phase tank vacuum, reinforced end mixed after 20 minutes, stirred 10 minutes with the 2500rpm homogenizing;
4. be cooled to 50 ℃, add germall BP, stir evenly again, cooling;
5. emulsion is packed in the plastic bottle, seal and get final product.
Embodiment 7: the gel formulation and technology
Raw medicinal material (to make the 1000g gelometer): with embodiment 1
Extraction process: with embodiment 1
Pharmaceutical carrier (to make 1000g ointment):
Carbomer 15g
Triethanolamine is an amount of
Germall BP3g
Preparations shaping technique:
1. getting carbomer adds water-soluble swollen, for subsequent use.
2. with an amount of purified water, carbomer colloid and raw medicinal material extracting solution, be heated to while stirring 70～80 ℃;
3. be cooled to 50 ℃, add an amount of triethanolamine, regulate pH to 5.5～6.5;
4. add again germall BP, stir evenly, cooling;
5. the flexible pipe of at last mastic being packed into, sealing and get final product.
Test example:
The present invention is through stability experiment, and the result is as follows
Embodiment 1 carries out stability with the disclosed prior art contrast of the CN1939480A that adopts ionic emulsifying agent, through comparative study, and external preparation of the present invention, good stability.
When take carbomer as thickening agent, the carbomer consumption is 0.3%, regulates pH value as 5.5～6.5 o'clock take triethanolamine, and mastic has optimum denseness 10Pas-20Pas.
The present invention compares as the prior art ointment of antiseptic with adopting ethyl hydroxybenzoate, sodium benzoate, the ointment that makes torn off behind the sealed membrane cover back with moulding lid, put in the constant incubator, 27～30 ℃ of temperature, relative humidity 90% continues 30 days, allow it naturally grow bacterium, check antibacterial total viable count and the mycete total viable count situation of change of ointment after 0 o'clock and 30 days,, the antiseptic effect of 0.3% germall BP is best as a result.
One, accelerated test
1, press the product sample of CN1939480A disclosed embodiment 1 explained hereafter, label is C.
2, the preparation for preparing of the embodiment of the invention 1, label is respectively: I, II, III
3, centrifugal test: sample thief is respectively extruded 10g, places the centrifuge tube with scale, with rotating speed 2500rpm, observes behind the centrifugal 30min.Result of study sees Table 1:
Table 1
| Label | Before centrifugal | After centrifugal |
| C | The yellowish-brown emulsifiable paste, mastic is rarer, and uniform and smooth is easy to coating, does not melt, easily trickling | The profit layering |
| I | Faint yellow emulsifiable paste, the ropy milk shape, Consistency is suitable, and uniform and smooth is easy to coating, does not melt, and does not trickle | Unchanged |
| II | Faint yellow emulsifiable paste, the ropy milk shape, Consistency is suitable, and uniform and smooth is easy to coating, does not melt, and does not trickle | Unchanged |
| III | Faint yellow emulsifiable paste, the ropy milk shape, Consistency is suitable, and uniform and smooth is easy to coating, does not melt, and does not trickle | Unchanged |
4, heat resistant test: 10 of the every batch of sample thiefs are observed after 6 hours in 55 ℃ of incubator constant temperature; Low temperature resistant test: investigate every batch of 10 of sample thief is placed 24h in-20 ℃ of refrigerators after.The results are shown in following table 2:
Table 2
| Label | Room temperature | 55℃ | -20℃ |
| C | The yellowish-brown emulsifiable paste, mastic is rarer, and uniform and smooth is easy to coating, does not melt, easily trickling | The profit layering | Send out thick |
| I | Faint yellow emulsifiable paste, the ropy milk shape, Consistency is suitable, and uniform and smooth is easy to coating, does not melt, and does not trickle | Breakdown of emulsion is not stratified | Unchanged |
| II | Faint yellow emulsifiable paste, the ropy milk shape, Consistency is suitable, and uniform and smooth is easy to coating, does not melt, and does not trickle | Breakdown of emulsion is not stratified | Unchanged |
| III | Faint yellow emulsifiable paste, the ropy milk shape, Consistency is suitable, and uniform and smooth is easy to coating, does not melt, and does not trickle | Breakdown of emulsion is not stratified | Unchanged |
5, test is preserved in circulation: every batch of 10 of sample thief places 40 ℃ of baking ovens to take out after 12 hours and put into 0 ℃ of refrigerator 12 hours again, and circulation is preserved and investigated afterwards in 10 days, the results are shown in following table 3.
Table 3
| Label | Room temperature | After circulation is preserved |
| C | The yellowish-brown emulsifiable paste, mastic is rarer, and uniform and smooth is easy to coating, does not melt, easily trickling | The profit layering |
| I | Faint yellow emulsifiable paste, the ropy milk shape, Consistency is suitable, and uniform and smooth is easy to coating, does not melt, and does not trickle | Unchanged |
| II | Faint yellow emulsifiable paste, the ropy milk shape, Consistency is suitable, and uniform and smooth is easy to coating, does not melt, and does not trickle | Unchanged |
| III | Faint yellow emulsifiable paste, the ropy milk shape, Consistency is suitable, and uniform and smooth is easy to coating, does not melt, and does not trickle | Unchanged |
6, exposure experiments to light: sample thief 30g, uncovered placement places under 4500lx ± 500lx illuminance, shines 10 days, compares with illumination sample not, the results are shown in following table 4.
Table 4:
| Label | According to front | According to rear |
| C | The yellowish-brown emulsifiable paste, mastic is rarer, and uniform and smooth is easy to coating, does not melt, easily trickling | Color burn, surface sclerosis, chap |
| I | Faint yellow emulsifiable paste, the ropy milk shape, Consistency is suitable, and uniform and smooth is easy to coating, does not melt, and does not trickle | Color burn, surface sclerosis, chap |
| II | Faint yellow emulsifiable paste, the ropy milk shape, Consistency is suitable, and uniform and smooth is easy to coating, does not melt, and does not trickle | Color burn, surface sclerosis, chap |
| III | Faint yellow emulsifiable paste, the ropy milk shape, Consistency is suitable, and uniform and smooth is easy to coating, does not melt, and does not trickle | Color burn, surface sclerosis, chap |
Other gets 10 in the sample of mastic filling and sealing in the 10ml ampoule, places under 4500lx ± 500lx illuminance, shines 10 days, compares with illumination sample not, the results are shown in following table 5.
Table 5
| Label | According to front | According to rear |
| C | The yellowish-brown emulsifiable paste, mastic is rarer, and uniform and smooth is easy to coating, does not melt, easily trickling | Color is little intensification, sends out thick |
| I | Faint yellow emulsifiable paste, the ropy milk shape, Consistency is suitable, and uniform and smooth is easy to coating, does not melt, and does not trickle | Unchanged |
| II | Faint yellow emulsifiable paste, the ropy milk shape, Consistency is suitable, and uniform and smooth is easy to coating, does not melt, and does not trickle | Unchanged |
| III | Faint yellow emulsifiable paste, the ropy milk shape, Consistency is suitable, and uniform and smooth is easy to coating, does not melt, and does not trickle | Unchanged |
7, conclusion: show by accelerated test results such as centrifugal test, heat-resisting low temperature resistant test, circulation preservation tests, the external preparation that the present patent application provides is more stable, and exposure experiments to light result and prior art are basically identical, and be insensitive to light.
Two, keep sample and investigate test
1, according to the product sample of CN1939480A disclosed embodiment 3 explained hereafter, label is respectively A, B, C
2, the present invention obtains pilot product by embodiment 1 preparation method, and label is respectively M1, M2, M3
3, accelerated stability test
Under 30 ℃ ± 2 ℃, the experimental condition of RH65% ± 5%, placed 6 months.Respectively at sampling in 0,1,2,3,6 month, measure study on the stability indices and 0 month sample relatively, the results are shown in following table 7 and table 8
Table 7: the ointment that cures the wound accelerates experimental result
| Label | Period of storage (moon) | Character | Uniformity | Content (mg) | Microbial | Conclusion |
| A | ||||||
| 0 1 2 3 6 | Yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment | Homogeneous is without the layering homogeneous, without the layering homogeneous, without the slight layering layering of layering | 0.32 0.31 0.33 0.34 0.33 | Up to specification up to specification | Up to specification up to specification |
| |
0 1 2 3 6 | Yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment | Homogeneous is without the layering homogeneous, without the layering homogeneous, without the slight layering layering of layering | 0.36 0.36 0.39 0.38 0.36 | Up to specification up to specification | Up to specification up to |
| C | ||||||
| 0 1 2 3 6 | Yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment | Homogeneous is without the layering homogeneous, without the layering homogeneous, without the slight layering layering of layering | 0.32 0.33 0.34 0.35 0.33 | Up to specification up to specification | Up to specification up to specification |
Table 8
| Label | Period of storage (moon) | Character | Uniformity | Content (mg) | Microbial | Conclusion |
| M1 | ||||||
| 0 1 2 3 6 | The faint yellow ointment yellowish-brown of the faint yellow ointment of the faint yellow ointment of faint yellow ointment ointment | Homogeneous is without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without layering | 0.29 0.30 0.30 0.32 0.31 | Up to specification up to specification | Up to specification up to | |
| M2 | ||||||
| 0 1 2 3 6 | The faint yellow ointment yellowish-brown of the faint yellow ointment of the faint yellow ointment of faint yellow ointment ointment | Homogeneous is without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without layering | 0.31 0.27 0.28 0.32 0.30 | Up to specification up to specification | Up to specification up to | |
| M3 | ||||||
| 0 1 2 3 6 | The faint yellow ointment yellowish-brown of the faint yellow ointment of the faint yellow ointment of faint yellow ointment ointment | Homogeneous is without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without layering | 0.30 0.29 0.31 0.31 0.31 | Up to specification up to specification | Up to specification up to specification |
4, long-term stable experiment
Sample is placed reserved sample observing indoor (25 ℃ ± 2 ℃, relative humidity 60% ± 10%), respectively at sampling in 0,3,6,9,12,18,24 month, detect by stable high spot reviews project, the results are shown in following table 9 and table 10.
Table 9
| Label | Period of storage (moon) | Character | Uniformity | Content (mg) | Microbial | Conclusion |
| A | ||||||
| 0 3 6 9 12 18 | Yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment | Homogeneous is without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without layering | 0.32 0.33 0.33 0.32 0.32 0.33 | Up to specification | Up to specification up to | |
| B | ||||||
| 0 3 6 9 12 | Yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment | Homogeneous is without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without layering | 0.36 0.35 0.36 0.35 0.35 | Up to specification | Up to specification up to | |
| C | ||||||
| 0 3 6 9 12 | Yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment yellowish-brown ointment | Homogeneous is without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without layering | 0.32 0.32 0.32 0.32 0.31 | Up to specification | Up to specification up to specification |
Table 10
| Label | Time (moon) | Character | Uniformity | Content (mg) | Microbial | Conclusion |
| M1 | ||||||
| 0 3 6 9 12 18 24 | The faint yellow ointment yellowish-brown of the faint yellow ointment of the faint yellow ointment of the faint yellow ointment of faint yellow ointment ointment yellowish-brown ointment | Homogeneous is without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without layering | 0.29 0.32 0.31 0.32 0.34 0.27 0.33 | Up to specification up to specification | Up to specification up to specification up to specification |
| |
0 3 6 9 12 18 24 | The faint yellow ointment yellowish-brown of the faint yellow ointment of the faint yellow ointment of the faint yellow ointment of faint yellow ointment ointment yellowish-brown ointment | Homogeneous is without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without layering | 0.31 0.32 0.29 0.32 0.32 0.31 0.32 | Up to specification up to specification | Up to specification up to specification up to |
| M3 | ||||||
| 0 3 6 9 12 18 24 | The faint yellow ointment yellowish-brown of the faint yellow ointment of the faint yellow ointment of the faint yellow ointment of faint yellow ointment ointment yellowish-brown ointment | Homogeneous is without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without the layering homogeneous, without layering | 0.30 0.32 0.30 0.32 0.32 0.31 0.33 | Up to specification up to specification | Up to specification up to specification up to specification |
5, conclusion:
(1) above-mentioned sample is preserved test, exposure experiments to light through centrifugal test, heat-resisting low temperature resistant test, circulation, and the result shows, preparation of the present invention is more stable.
(2) preparation of the present invention accelerates experiment 6 months under 30 ℃ ± 2 ℃, the experimental condition of RH65% ± 5%, 25 ℃ ± 2 ℃, relative humidity 60% ± 10% condition keeps sample and investigates 24 months, and the result shows indices without significant change, and is more stable than the product that CN1939480A public technology is produced.
Three, extracorporeal releasing test
1, detects the selection of wavelength
Get matrine an amount of, the water preparation is into about the solution of 20 μ g/ml, according to spectrophotography (2000 editions appendix IVA of Chinese Pharmacopoeia) in the interscan of 200～400nm scope, locating about 202nm all has absorption maximum, report and consider again the impact of end absorption according to pertinent literature, in this experimentation, select λ=220nm for detecting wavelength.
The selection of chromatographic condition
According to reported in literature, selecting chromatographic condition is Agilent ZORBAX Eclipse * DB-C18 chromatographic column (4.6mm * 150mm, 5 μ m), 25 ℃ of column temperatures, mobile phase is acetonitrile: water (be 2 with the phosphorus acid for adjusting pH)=3: 97, detect wavelength 220nm, flow velocity 1.0ml/min, sample size 20 μ l.Measure peak area behind the sample introduction, outer marking quantitative.The leaching component of skin histology has been eluted post in 2min, interference medicament is not measured.
The foundation of standard curve
Precision takes by weighing in matrine 2mg to the 100ml measuring bottle that is dried to constant weight, with water dissolution and be diluted to scale.Pipetting respectively 0.5,1.0,2.0,5.0, being diluted with water to scale in 7.5ml to the 10ml measuring bottle is standard solution, and by above-mentioned HPLC condition working sample, sample introduction 20 μ l return concentration (C) with peak area integrated value (A).The standard curve of matrine is: A=12.089C+1.1628 (r=0.9996), in the concentration range of 1～20 μ g/ml, the peak area of matrine and concentration have good linear relationship.
2, experimental provision
Adopt TK-12A type Franz diffusion cell, effectively diffusion area is 2.83cm
2, receiving chamber's capacity is 6.8ml.
3, extracorporeal releasing experiment
(1) test method
The microporous filter membrane of aquation 24h is fixed on the supply pool of diffusion cell and accepts drain bubble between the pond, recirculated water keeps (37 ± 0.5) ℃.Accept the pond with degassed distilled water accepting medium, add stirrer with the speed stirring of 300r/min.Supply House adds capacity ointment sample, respectively at 4,8,12,16,20h takes out the 3.5ml acceptable solution, and the acceptable solution of additional equivalent equality of temperature.
(2) the release in vitro sample concentration is measured
Sample thief 3ml adds ammonia 2ml, mixing respectively.Use chloroform extraction, each 4ml, totally 3 times.The combined chloroform layer volatilizes in 80 ℃ of water-baths.With an amount of dissolved in distilled water residue, ice bath 2h, 0.45 μ m filtering with microporous membrane, HPLC measures concentration.
(3) extracorporeal releasing experiment result
With the cumulative release amount to mapping release time, as shown in Figure 1.As can be seen from Figure, by drawing the release in vitro curve comparison, the release in vitro of prior art and the present patent application is basically identical, without significant difference.
4, transdermal permeation in vitro
(1) test method
Get body weight and be the SD rat about 200g, cut off the hair of abdominal part after the anesthesia, peel off skin, separate subcutaneous tissue, in normal saline, clean.The suitable size of clip is fixed on the diffusion cell, and recirculated water keeps (37 ± 0.5) ℃, adds stirrer and stirs with the speed of 300r/min.Continue to change a normal saline in per 30 minutes with normal saline flushing skin upper and lower surface, cleans three times after, the degassed normal saline of adding drains bubble as accepting medium in receiving chamber.Supply House adds capacity ointment sample, respectively at 12,24,36,48h takes out the 3.5ml acceptable solution, and the acceptable solution of additional equivalent equality of temperature.
(2) in-vitro percutaneous infiltration sample concentration is measured
Sample thief 3ml adds ammonia 2ml, mixing respectively.Use chloroform extraction, each 4ml, totally 3 times.The combined chloroform layer volatilizes in 80 ℃ of water-baths.With an amount of dissolved in distilled water residue, ice bath 2h, 0.45 μ m filtering with microporous membrane, HPLC measures concentration.
(3) transdermal permeation in vitro result
With the cumulative release amount to mapping release time, as shown in Figure 2.By drawing in-vitro percutaneous infiltration release profiles contrast, the ointment that cures the wound that the present patent application technology is produced is slightly large than the ointment transdermal penetration amount that cures the wound that prior art CN1939480A produces.
Four, cure the wound ointment anti-inflammatory activity experiment
1 laboratory animal
40 of ICR mices, male, body weight 18～20g, Zhejiang University zoopery center provides.
2 experimental techniques
The ICR mice evenly is divided into 4 groups, 10 every group.Be respectively positive controls I, negative control group II, prior art sample group III (pressing CN1939480A embodiment 3 preparations), the present patent application technology sample group IV (by the embodiment of the invention 1 preparation).It is as shown in table 11 that each organizes administration medicine, dosage and administering mode.Successive administration 3 days.1h wipes medicine with warm normal saline after the last administration, is coated with dimethylbenzene 10 μ L at the auris dextra positive and negative of every mice.Mice is put to death in the cervical vertebra dislocation behind the 4h, cuts two ears along the auricle baseline, and is wide with 7mm steel blunderbuss blunderbuss bottom left auris dextra, weighs.Calculate swelling rate, organize a t check.Ear swelling rate computing formula is as follows:
Table 11 is respectively organized administration medicine, dosage and administering mode
3 anti-inflammatory activity experimental results
Each organizes swelling rate as shown in Figure 3.The positive control swelling rate is less than negative control group (P＜0.05); The ointment prior art that cures the wound sample group is compared with negative control group with invention technology sample group all significant difference (P＜0.05), there was no significant difference (P＞0.05) then between the ointment prior art that cures the wound sample group and two groups of the ointment the present patent application sample groups of curing the wound.
4 conclusions
The result shows, the inflammation that prior art sample and the present patent application technology sample xylol cause the mice auricular concha has significant inhibitory action, and is relatively slightly stronger with the present patent application technology sample between two groups.
Five, the ointment irritation test that cures the wound
1. tested material
Ointment the technology of the present invention sample and blank substrate cure the wound.
2. experimental animal
16 of rabbit, New Zealand's strain, body weight 1.8～2.4kg, ♀
Half and half, by Zhejiang Academy of Agricultural Science animal and veterinary institute propagating and breeding, credit number: SCXK (Zhejiang) 2006-0025.Quality testing unit: Zhejiang Province's animal center.
3. test method
(1) irritation test of single percutaneous drug delivery
8 of rabbit, in spinal column both sides depilations, the depilation scope is 150cm2/ only (approximately be equivalent to body surface area 10%) approximately in front 24 hours of test.Wherein after the damaged skin group rabbit depilation again with the rubber skin that rubs, take slight oozing of blood as degree.By skin complete and breakage, be divided at random 2 groups, 4 every group, ♀
Half and half.Cure the wound ointment 1.0g/kg (by the crude drug amount in back left side depilation district's skin (complete or damaged) coating respectively, be 25 times of human clinical dosage), the right side is coated with blank substrate 1.0g/kg, the pan paper that does not absorb water with nonirritant behind the coating and gauze cover and are fixing, and every rabbit is divided equally cage and raises.Remove medicine and blank substrate with warm water after 24 hours, observation 1h, 24h, 48h, 72h smear the position reaction.
(2) irritation test of percutaneous drug delivery repeatedly
8 of rabbit, animal pretreatment, grouping, medication are all the same, and successive administration 14 days is observed skin erythema, edema, the colour of skin, petechia, skin fineness and the situation such as poor, continuous 7 days.
4. result of the test
Every animal test results is pressed table 12 scoring irritant reaction, calculates mean scores.Press table 13 and estimate stimulus intensity.The stimulus intensity evaluation is as the criterion with its highest stimulus intensity.Result's demonstration, the skin of the complete and damaged group rabbit of single-dose are without erythema, edema phenomenon, and hair, outward appearance, activity, food-intake, eyes are also all without unusual; After complete and damaged group of rabbit drug withdrawal of multiple dosing also all without skin erythema, edema, pigmentation, petechia, coarse and poor variation phenomenon, therefore think and cure the wound ointment to the skin nonirritant.
Histopathological examination
Through histopathological examination, the rabbit skin histology of above-mentioned two kinds of dosage regimens has no the obvious irritation reactions (seeing Fig. 4 a 4b 4c 4d, Fig. 5 a 5b 5c 5d) such as tissue inflammation, degeneration, necrosis.
5. conclusion
The ointment the technology of the present invention that cures the wound sample is through rabbit skin single-dose and multiple dosing, to intact skin and the equal nonirritant of damaged skin.
Table 12 skin irritation reaction score value standard
Table 13 skin irritation intensity evaluation standard
Claims (9)
1. external preparation that is used for the treatment of soft tissue injury, it is characterized in that said preparation is comprised of the water of crude drug or alcohol extract and pharmaceutically acceptable carrier, described crude drug is Radix Ilicis Pubescentis, Cortex araliae chinensis, Flos Iteae oblongae, Radix Ardisiae Crenatae, root of Syzygiumgrijsii (Hance) Merr.etPerry, Herba Hedyotidis Chrysotrichae, Pheretima, Pinus massoniana root, Radix ampelopsis brevipedunculatae, Lignum pterocarpi indici root, Radix Sophorae Flavescentis, cuscuta japonica Choisy, Rhizoma Drynariae, Radix Gei japonici and Radix Cudraniae; Described pharmaceutically acceptable carrier comprises greasing base, emulsifying agent and antiseptic, the percentage by weight that greasing base accounts for the preparation total amount is 10%-21%, and this greasing base is selected from one of glyceryl monostearate, hexadeca-octadecyl alcohol, vaseline and liquid paraffin or their mixture;
Described emulsifying agent is the polyoxyethylene aliphatic alcohol ether that accounts for total formulation weight amount 0.5%-5%;
Described antiseptic is the germall BP that accounts for total formulation weight amount 0.05%-1.0%;
Described pharmaceutically acceptable carrier also comprises thickening agent and pH adjusting agent, and described pH adjusting agent is selected from triethanolamine, sodium hydroxide or potassium hydroxide;
Described crude drug consist of 30-125 weight portion Radix Ilicis Pubescentis; 30-125 Chong Liang Fen Cortex araliae chinensis; 19-75 weight portion Flos Iteae oblongae; 37-150 weight portion Radix Ardisiae Crenatae; 13-50 weight portion root of Syzygiumgrijsii (Hance) Merr.etPerry; 13-50 weight portion Pheretima; 25-100 weight portion Herba Hedyotidis Chrysotrichae; 30-125 weight portion Pinus massoniana root; 64-150 weight portion Radix ampelopsis brevipedunculatae; 50-200 weight portion Lignum pterocarpi indici root; 44-175 weight portion Radix Sophorae Flavescentis; 25-100 weight portion cuscuta japonica Choisy; 19-75 weight portion Rhizoma Drynariae; 19-75 weight parts water Radix Myricae rubrae; 25-100 weight portion Radix Cudraniae; Said preparation is that pH value is the ointment of 4.0-8.0.
2. the external preparation for the treatment of soft tissue injury according to claim 1 is characterized in that described thickening agent is carbomer, and the percentage by weight that accounts for the preparation total amount is 0.05%-1.5%.
3. according to claim 1 and 2 the external preparation for the treatment of soft tissue injury is characterized in that greasing base is that following material consists of:
The percentage by weight that accounts for the preparation total amount is the glyceryl monostearate of 0.5%-5%;
The percentage by weight that accounts for the preparation total amount is the hexadeca-octadecyl alcohol of 0.5%-15%;
The percentage by weight that accounts for the preparation total amount is the Yellow Vaselin of 0.5%-8%;
The percentage by weight that accounts for the preparation total amount is the liquid paraffin of 2%-15%.
4. the external preparation for the treatment of soft tissue injury according to claim 1 is characterized in that the described pharmaceutically acceptable carrier following component that accounts for total formulation weight amount percentage ratio of serving as reasons forms:
Carbomer 0.3%
Polyoxyethylene aliphatic alcohol ether 2.0%
Hexadeca-octadecyl alcohol 8.0%
Glyceryl monostearate 2.0%
Liquid paraffin 8.0%
Yellow Vaselin 3.0%
Triethanolamine 0.5% ~ 1.2%
Germall BP 0.3%.
5. according to claim 1 the external preparation for the treatment of soft tissue injury is characterized in that consisting of of described crude drug: 62.5 weight portion Radix Ilicis Pubescentiss; 65.2 Chong Liang Fen Cortex araliae chinensis; 37.5 weight portion Flos Iteae oblongae; 75 weight portion Radix Ardisiae Crenataes; 25 weight portion root of Syzygiumgrijsii (Hance) Merr.etPerrys; 25 weight portion Pheretimas; 50 weight portion Herba Hedyotidis Chrysotrichaes; 62.5 weight portion Pinus massoniana root; 75 weight portion Radix ampelopsis brevipedunculataes; 100 weight portion Lignum pterocarpi indici roots; 87.5 weight portion Radix Sophorae Flavescentis; 50 weight portion cuscuta japonica Choisies; 37.5 weight portion Rhizoma Drynariae; 37.5 weight parts water Radix Myricae rubrae; 50 weight portion Radix Cudraniaes.
6. the external preparation of described treatment soft tissue injury according to claim 5 is characterized in that described preparation viscosity is 10 Pas-30Pas.
7. the external preparation for the treatment of soft tissue injury according to claim 6 is characterized in that described preparation viscosity is 10 Pas-20Pas.
8. the external preparation for the treatment of soft tissue injury according to claim 1 is characterized in that pH value is 5.5-6.5.
9. the preparation method of the external preparation for the treatment of soft tissue injury claimed in claim 1 is characterized in that the method may further comprise the steps:
(1) prepares water or the alcohol extract of active constituents of medicine by the crude drug proportioning;
(2) getting thickening agent adds water-soluble swollen, for subsequent use;
(3) get greasing base and polyoxyethylene aliphatic alcohol ether, be heated to 70～80 ℃, make oil phase substrate, for subsequent use;
(4) add an amount of purified water and thickening agent colloid in the emulsion tank, be heated to 70～80 ℃; Under stirring condition, oil phase substrate is sucked emulsion tank by oil phase tank vacuum, reinforcedly finishes to mix after 20 minutes, stir 10 minutes with the 2500rpm homogenizing after, change low rate mixing into, stir borehole cooling to 50 ℃-70 ℃;
(5) add in the blank mastic after the extracting solution of step (1) is heated to 50 ~ 60 ℃, mixing, stir 10 minutes with the 2500rpm homogenizing after, change low rate mixing into;
(6) be cooled to 50 ℃, add again pH adjusting agent and antiseptic, stir evenly, cooling.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1056298C (en) * | 1996-12-31 | 2000-09-13 | 佛山市中医院 | External use medicine for treating soft tissue injury and its producing method |
| CN1939480A (en) * | 2006-10-17 | 2007-04-04 | 浙江普洛康裕天然药物有限公司 | Chinese-medicinal compound preparation for treating injury |
| CN101462031A (en) * | 2007-12-17 | 2009-06-24 | 扬州市博升科技发展有限公司 | Active emulsifier and preparation method thereof |
-
2009
- 2009-08-06 CN CN200910101748XA patent/CN101693069B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1056298C (en) * | 1996-12-31 | 2000-09-13 | 佛山市中医院 | External use medicine for treating soft tissue injury and its producing method |
| CN1939480A (en) * | 2006-10-17 | 2007-04-04 | 浙江普洛康裕天然药物有限公司 | Chinese-medicinal compound preparation for treating injury |
| CN101462031A (en) * | 2007-12-17 | 2009-06-24 | 扬州市博升科技发展有限公司 | Active emulsifier and preparation method thereof |
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Address after: 322118 No. 398 Jiangnan Second Road, Hengdian Town, Dongyang City, Zhejiang Province Patentee after: Zhejiang Yousheng Meite Traditional Chinese Medicine Co.,Ltd. Address before: 321017 No. 1188 Jinpan Road, Jinhua City, Zhejiang Province Patentee before: PULUOKANGYU NATURAL DRUG Co.,Ltd. |
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Effective date of registration: 20230105 Address after: 322118 No.333 Jiangnan Road, Hengdian, Dongyang City, Jinhua City, Zhejiang Province Patentee after: ZHEJIANG APELOA KANGYU PHARMACEUTICAL Co.,Ltd. Patentee after: APELOA PHARMACEUTICAL CO.,LTD. Address before: No. 398, Jiangnan Second Road, Hengdian Town, Dongyang, Zhejiang 322118 Patentee before: Zhejiang Yousheng Meite Traditional Chinese Medicine Co.,Ltd. |