CN103182070B - External composition, and preparation and application thereof - Google Patents
External composition, and preparation and application thereof Download PDFInfo
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- CN103182070B CN103182070B CN201310127192.8A CN201310127192A CN103182070B CN 103182070 B CN103182070 B CN 103182070B CN 201310127192 A CN201310127192 A CN 201310127192A CN 103182070 B CN103182070 B CN 103182070B
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Abstract
The invention relates to an external composition, and a preparation and an application thereof and belongs to the field of medicines. The external composition provided by the invention is a medicine composition which contains chlorhexidine or officinal salt thereof, or benzalkonium bromide or officinal salt thereof and a recombinant human epidermal growth factor or a recombinant cattle alkali fibroblast growth factor. According to the invention, the medicine composition is also further prepared into gel, liniment, ointment or paste, and the gel further comprises chitosan or officinal salt thereof and hyaluronic acid or officinal salt thereof. When being used for treating vagina inflammation, the external composition disclosed by the invention can improve a vagina microenvironment, promote growth of granulation tissue and repair vagina micro damage; and when being used for skin wound atraumatic restorative treatment, the external composition also can speed up restoration and regeneration of a wound tissue, promote healing and reduce scar formation, so that the external composition has a wide medical application prospect.
Description
Technical field
The present invention relates to a kind of topical composition, preparation and application thereof, be specially a kind of pharmaceutical composition that contains recombinant human epidermal growth factor and for the preparation of the medical usage for the treatment of colpitis or skin wound reparation, belong to field of medicaments.
Background technology
Colpitis is the general name of the multiple vaginal mucosa inflammatory diseases that causes of different pathogeny, is commonly encountered diseases and the frequently-occurring disease of Out-patient Clinic of Department of Gynecology, and its morbidity is how relevant with microecology in vaginas imbalance.Colpitis is mainly caused by antibacterial, mycete, chlamydia, virus, protozoon etc., vaginal infection source of disease is as treated and can go upward to cavity of uterus, fallopian tube, ovary and pelvic cavity not in time, thereby cause endometritis, salpingitis, oophoritis or the pelvic inflammatory disease of acute and chronic, chronic infection person is except inflammation symptom, even may cause to advocate and block and infertile, make a big impact to women and kinsfolk's thereof physical and mental health.
Though it is many to be used for the treatment of in the market the medicine of colpitis, ubiquity therapeutic effect is poor, the defect that relapse rate is high.Treatment for colpitis adopts antibiotic and antibacterial anti-inflammatory treatment more clinically, but uses in a large number antibiotic and antibacterial more easily to cause dysbacteriosis.This is because healthy women intravaginal exists many kinds of microbiologic populations, mainly contain lactobacillus, staphylococcus epidermidis, escherichia coli, corynebacterium, anhemolytic streptococcus, Gardnerella, bacteroid etc., wherein the most important thing is lactobacillus, lactobacillus is the dominant microflora in microecology in vaginas system, current research shows,, up to 50%～80%, its quantity accounts for the more than 95% of vagina microorganism to the separation rate of lactobacillus in healthy women vagina.Lactobacillus adheres to vaginal epithelial cell by alternative, the machine-processed prevention pathogenic microorganism of competition exclusion, simultaneously, also can secrete hydrogen peroxide, bacteriocin, bacterioid element and biosurfactant etc. and suppress pathogenic microorganism growth, to maintaining vaginal environment microbial balance, there is important function.As can be seen here, carry out effectively treatment and maintain the microbial environment balances such as vagina simultaneously only depending on abuse of antibiotics and antifungal drug to colpitis, actively find antibiotic alternative medicine treatment colpitis tool be of great significance.
The shallow table scratch of skin surface, is wound type common in orthopedic clinical work, especially common with body exposure positions such as facial areas; Have that wound area is large, easy infection, operative effect is poor and the conventional course for the treatment of of changing dressings is long, curative effect is sure not; After healing, focus easily forms the sequela such as cicatrix, pigment alteration, and the harm that the body and mind of sufferer is caused is very large.Wound healing is one of hot issue of current clinical research, and skin wound reparation is a complicated biological process, comprising pathophysiological processes such as inflammatory reaction, cell proliferation, collagenic supersession, hair follicle formation and pigmentation.Generally believed in the past that wound healing was uncontrollable, can only be the process of body oneself healing always, and people often in passive state, are difficult to make regulation and control and the effort of effective active to the processing of wound healing.The appearance of tissue engineering, makes wound surface skin transplantation have new breakthrough.
All there is new technology in application and the Chinese medical and herbal therapy of the development of skin transplantation at present, new pattern compress and application, cultured cell transplanting and artificial skin transplanting, gene therapy, cytokine.Be applied at present clinical skin tissue engineering product and still have certain immunological rejection, therapeutic effect is not good enough.Conventional treatment is on wound surface, to be coated with medicine for external use sterilization, to expose or to wrap up, but effect is unsatisfactory, and the lighter patient feels wound pain, redness, empyema under severe one crust, and limb activity is limited, the normal work of impact then.The time relationship of the formation of cicatrix and the order of severity and wound repair is close, and wound healing time is longer, and collagen deposition is more, causes the cicatrix that forms more serious and affect local function.Therefore urgent clinical needs are at present a kind of safe, short treating period, sure Therapeutic Method and the supporting preparation of curative effect.Therefore how can rapid Cover wound repairing, there is clinically important researching value and treatment prospect.
Chinese patent CN101342354A, CN1626189A, CN1413683A and CN1418660A just disclose Chinese medicine decoction, tablet or the capsule of different formulations for the treatment of colpitis especially cervicitis respectively, but this class medicine is because medicament effective component is uncertain and the defect of purifying technique, the therapeutic effect of its medicine is not good, the risk that even has the inflammation of making to increase the weight of.
The < < recombinant human epidermal growth factor that is published in < < Chinese Journal of Clinical Pharmacy > > 03 phase in 2003 on cervical erosion naturopathy after the > > mono-that affects of wound healing the article pointed out that rhEGF can promote wound healing after cervical erosion naturopathy, improves cure rate.The clinical observation > > mono-that is published in < < contemporary Chinese medical journal > > 17 phase < < recombinant human epidermal growth factor treatment burn woundes in 2005 the article pointed out that recombinant human epidermal growth factor can effectively promote the healing of shallow II degree wound surface, dark II degree wound surface, remaining granulation wound and the chronic routed wound surface of dieing young, and does not find obvious adverse effect.But recombinant human epidermal growth factor can not sterilizing, the diffusion that can not effectively control inflammation, causes inflammation difficult for a long time.Therefore, in the urgent need to research, can control inflammation and can repair external curing medicine.Meet clinical demand.
Chinese patent CN102939097A discloses for the preparation of for preventing and treat the new synergistic pharmaceutical combination of the topical formulations of wound, burn, skin graft, pressure ulcer and diabetic ulcer of foot, comprise short Cyclin, antibacterial and antibacterial, wherein short Cyclin is recombinant human epidermal growth factor (rh-EGF of Bharat Biotech InternationalLimited), antibacterial is silver sulfadiazine (SSD), and antibacterial is chlorhexidine gluconate (CHG).Be that said composition comprises recombinant human epidermal growth factor, silver sulfadiazine and chlorhexidine gluconate.Said composition better and faster cicatrizes a wound.But it has been applied because silver sulfadiazine silver sulfadiazine has bone marrow toxicity, the wound of ulceration is smeared said composition, silver sulfadiazine be absorbed cause poisoning, leukopenic danger.Therefore, need to develop a kind of topical composition eliminates simultaneously and reduces toxicity at treatment and prevention of inflammation and reparation wound.
Summary of the invention
Poor in order to overcome the destruction vagina microenvironment balance and the therapeutic effect that exist in existing colpitis therapeutic process, the defect that relapse rate is high, with skin wound repair process Chinese medicine toxic action drawback, the invention provides a kind of new pharmaceutical composition for colpitis and skin wound reparation use
The present invention adopts following technical scheme to realize: a kind of topical composition, and described topical composition is pharmaceutical composition, it contains following active component:
(1) chlorhexidine or its officinal salt or benzalkonium bromide or its officinal salt; With
(2) recombinant human epidermal growth factor or bFGF bovine basic fibroblast growth factor.
Chlorhexidine is white crystalline powder, is a kind of surfactant with great broad-spectrum antibacterial effect, and it is to most gram positive bacterias and gram negative bacteria tool killing action.The antibacterial principle of chlorhexidine, be mainly destroy permeability barrier on antibacterial endochylema film (but not former hypothesis, ATP enzyme lose activity and reach cause bactericidal effect), low concentration can cause part endochylema seepage, high concentration can cause endochylema cohesion degeneration, thereby antibacterial.Its advantage is that zest is low, the less anaphylactic reaction that occurs compared with other externally used antimicrobial agent.Chlorhexidine toxicity is low, zest is little, non-corrosiveness, is applicable to disinfecting of skin mucosa and wound surface, is widely used in the sterilization of mucosa, skin, operation, wound surface, apparatus, apparatus etc.
Benzalkonium bromide is cationic surfactant class broad-spectrum antibacterial agent, can change antibacterial endochylema membrane permeability, makes thalline endochylema extravasation, hinders its metabolism and a killing action.Stronger to gram-positive bacteria effect, but invalid to bacillus pyocyaneus, acid-fast bacilli and bacterial spore.Can with the rapid combination of protein, meet blood, Cotton Gossypii, cellulose and Organic substance and exist, effect significantly reduces.To 0.1% following concentration skin nonirritant.Be applicable to pre-surgical skin disinfection, mucosa and wound disinfection, surgical instrument disinfection.
Recombinant human epidermal growth factor is comprised of 53 amino acid residues, is a kind of multi-functional somatomedin, and external in vivo all have strong short splitting action to Various Tissues cell.It is for multiple epithelial cell, as: squamous cell, mucomembranous epithelial cell, corneal epithelial cell, glandular epithelium and endotheliocyte etc., have powerful promotion growth, it can also promote the synthetic of the extracellular matrixs such as hyaluronic acid, fibronectin, glycoprotein and hydroxyproline simultaneously.Epidermal growth factor (EGF) is factor indispensable in wound healing and process of tissue reparation.
BFGF bovine basic fibroblast growth factor is the efficient growth promoter of fibroblast, vascular endothelial cell and vascular smooth muscle cell, can strongly promote the formation of new capillary vessel, significantly increase granulation tissue blood capillary quantity and blood flow, improve wound surface microcirculation, for tissue repair provides necessary oxygen and abundant nutrient substance; The regeneration of damaged tissue position nerve fiber is also had to significant facilitation, the recovery of acceleration loss injured tissue function simultaneously; Fibroblast is also the main cell of synthetic collagen, and collagen is the Main Ingredients and Appearance of intercellular substance in granulation tissue, recombinant human epidermal growth factor constantly synthesizes, secretes, changes structure and renewal by regulation and control collagen, and constantly improves structure and the intensity of repair tissue.
Preferably, in pharmaceutical composition described above, contain following active component: chlorhexidine or its officinal salt and recombinant human epidermal growth factor.
Further, pharmaceutical composition described above comprises chlorhexidine that mass ratio is 1000-6000 part and the recombinant human epidermal growth factor of 0.1-5 part, and preferred mass is than being the chlorhexidine of 2000 parts and the recombinant human epidermal growth factor of 0.4 part.
Above-mentioned chlorhexidine officinal salt is chlorhexidine diacetate, chlorhexidine citrate or chlorhexidine gluconate.
The present invention also provides a kind of preparation that comprises above-mentioned topical composition, and said preparation is gel, liniment, ointment or unguentum.Wherein patient or doctor can select suitable preparation according to concrete indication.
When aforementioned pharmaceutical compositions is prepared into liniment, the adjuvant in described drug composition liniment comprises one or more of propylene glycol, glycerol, carbamide, sodium chloride or water.
When aforementioned pharmaceutical compositions is prepared into unguentum or ointment, in described pharmaceutical composition ointment, contain one or more of stearic acid, white vaseline, glyceryl monostearate, polysorbate, propylene glycol, methylcellulose and ethyl hydroxybenzoate, described pharmaceutical composition unguentum contains one or more of white vaseline, glycerol, liquid paraffin and anhydrous lanolin.
The present invention also provides above-mentioned gel, when aforementioned pharmaceutical compositions is prepared into gel, in gel, by mass fraction, comprise: the recombinant human epidermal growth factor of 10000-60000 part chitosan, 500-5000 part hyaluronate sodium, 1000-6000 part chlorhexidine and 0.1-5 part.
Preferably, in gel, by mass fraction, comprise: 40000 parts of chitosans, 1000 parts of hyaluronate sodiums, the chlorhexidine of 2000 parts and the recombinant human epidermal growth factor of 0.4 part.
The pH value of described gel is between 5.0-6.0.
In the preparation of pharmaceutical composition described above, during for colpitis and skin wound repairing and treating.Gel preparation in colpitis and skin wound repairing and treating process except bringing into play the synergistic therapeutic effect of two kinds of medicine diseases, also there is following technical advantage:
(1) chitosan and hyaluronate sodium are all macromolecule polyalcohols; strand disperse is stretched; be great swelling state; and there is viscosity; can form the gelatinous mass of the thickness of clarification, gel is attached to vaginal mucosa, cervical erosion wound surface or skin wound, forms protecting film; wound surface is isolated from the outside, avoids secondary cross infection.
(2) feature of the equal tool water-soluble base of chitosan and hyaluronate sodium, can slowly discharge parcel chlorhexidine and hEGF wherein, so that medicine is permanently effective.
Gel of the present invention is ionic, subacidity by force, be not subject to microbiological effect, antibiotic property is strong, thereby suppress pathogen breeding, strengthen resistivity and the immunocompetence of diseased region to pathogenic bacteria, virus, during in particular for treatment cervical erosion, can simulate environment in the normal soda acid of vagina, promote the growth of vagina probiotic bacteria.
Gel of the present invention can absorb the transudate of wound surface, allows free gas infiltration, and metabolite can be discharged by gel, and then improves the microenvironment of lesion, meets the method for excretion Regeneration and Repair in modern wound moisture treatment principle one moist environment; Recombinant human epidermal growth factor can promote the histiocytic regeneration of ectoderm, reparation; Gel and mucosa glycoprotein interact, and formation rationality is tangled, and forms stronger mucus gel networks, at Mucosal system, keep longer adhesion time, the pathogen such as the pathogenic bacteria of absorption parcel wound surface, virus.
The present invention also provides a kind of above-mentioned topical composition to treat and/or prevent the application in the medicine of colpitis relevant disease in preparation.Wherein colpitis relevant disease mainly refers to the diseases such as vaginitis, cervicitis or cervical erosion.During for colpitis treatment, administering mode is that administration is smeared in intravaginal external, and dosage can be adjusted according to disease situation.
The present invention also provides the application of another kind of above-mentioned topical composition in the medicine of preparation treatment skin wound reparation.Wherein said skin wound is the wound surface that burn, scald, decubital ulcer, otch or ulcer cause.Its administering mode is that administration is smeared in external, and dosage can suitably be adjusted according to skin injury degree.The present composition significantly promotes the granulation tissue growth of skin injury part, smears and can fully recover for medication 3-5 days.
When topical composition of the present invention is used for the treatment of colpitis or skin wound repairing and treating, compared with prior art there is following technical advantage:
(1) the present invention can either improve vagina microenvironment, promotes granulation tissue growth, repair all kinds of colpitis, the auxiliary treatment of cervicitis and the treatment of cervical erosion that vagina micro-damage causes, can solve again the treatment problem of skin wound, otch and the routed wound surface of dieing young, so pharmaceutical composition of the present invention has very wide medical application prospect.
(2) topical composition of the present invention and significantly promote injury of human or ulcer spot granulation tissue growth
,as repair micro-damage and the ulcer such as vagina, cervix uteri, promote this position granulation tissue growth, maintain vagina microorganism environment, stop sticking, breeding of pathogenic bacterium, fundamentally blocking inflammation process is target, has also avoided drug resistance, superinfection, anaphylaxis and the drawbacks such as toxic and side effects to body of using antibiotic to cause.
(3) topical composition of the present invention can be prepared multiple exterior-applied formulation, when it is repaired for colpitis and skin wound, medicine irritation is little, when not damaging wound surface, effectively bring into play its antiphlogistic effects, and medication is convenient, can significantly improve patient's compliance and the therapeutic effect of medicine.
(4) topical composition of the present invention, through test of many times and clinical verification, can either improve vagina microenvironment, promote granulation tissue growth, repairs all kinds of colpitis, the auxiliary treatment of cervicitis and the treatment of cervical erosion that vagina micro-damage causes; Can solve again treatment problem, the minimizing cicatrization of skin wound, otch and the routed wound surface of dieing young.Two kinds of effective ingredient in pharmaceutical composition of the present invention have significant synergistic therapeutic effect with treatment skin wound reparation aspect aspect antiinflammatory, this can accelerate the healing time of wound surface to a certain extent, improves the therapeutic effect of medicine and patient's quality of life.
In a word, the repair mechanisms that the present invention is directed to the principal character of vaginal mucosa, cervical mucosa and skin are come screening formula and proportioning, can be simultaneously lasting antibacterial and promote epithelial tissue and mucosal tissue reparation, regeneration, healing time is short, recovery is rapid, reduce the advantages such as cicatrix,, nonirritant nontoxic to skin and mucosa, without allergy, be worthy of popularization.
The specific embodiment
By specific embodiment, further illustrate content of the present invention below, but those skilled in the art should be able to know, described embodiment also limits the present invention never in any form.
(1) pharmaceutics embodiment part
embodiment 1: gel of the present invention
For repairing a gel for vaginal mucosa, cervical mucosa or skin wound, composition comprises chitosan, hyaluronate sodium, chlorhexidine, recombinant human epidermal growth factor.Mass percent meter comprises: the chitosan of 30000 parts, the hyaluronate sodium of 3000 parts, the chlorhexidine of 3000 parts, the recombinant human epidermal growth factor of 0.1 part.
Take that to prepare one kilogram of gel be example,
30g chitosan
3g hyaluronate sodium
3g chlorhexidine
0.1mg recombinant human epidermal growth factor
Preparation method:
(1) chitosan, hyaluronate sodium are added in 960 milliliters of purified water, with dispersion machine, make its dissolving;
(2) chlorhexidine is scattered in 5 milliliters of propylene glycol;
(3) chlorhexidine propylene glycol suspension is added in the solution of above-mentioned chitosan and hyaluronate sodium, stirs and make each component mix homogeneously,
(4) pH value of regulator solution, between 5.0 to 6.0, continues to stir and treats that sample becomes gel;
(6) recombinant human epidermal growth factor is added water to dissolving, with the aseptic filtration of 0.22um microporous filter membrane;
(7) recombinant human epidermal growth factor solution is added in gel and stir and make finished product.
embodiment 2: gel of the present invention
For repairing a gel for vaginal mucosa, cervical mucosa or skin wound, comprise by mass percentage: the chitosan of 50000 parts, the hyaluronate sodium of 1000 parts, the chlorhexidine diacetate of 1000 parts, the recombinant human epidermal growth factor of 5 parts.
Take that to prepare one kilogram of gel be example,
50g chitosan
1g hyaluronate sodium
1g chlorhexidine diacetate
5mg recombinant human epidermal growth factor
Preparation method:
(1) chitosan, hyaluronate sodium are added in 960 milliliters of purified water, with dispersion machine, make its dissolving;
(2) chlorhexidine diacetate is scattered in 5 milliliters of propylene glycol;
(3) chlorhexidine diacetate propylene glycol suspension is added in the solution of above-mentioned chitosan and hyaluronate sodium, stir and make each component mix homogeneously;
(4) pH value of regulator solution, between 5.0 to 6.0, continues to stir and treats that sample becomes gel;
(6) recombinant human epidermal growth factor is added water to dissolving, with the aseptic filtration of 0.22um microporous filter membrane;
(7) recombinant human epidermal growth factor solution is added in gel and stir and make finished product.
embodiment 3: gel of the present invention
For repairing a gel for vaginal mucosa, cervical mucosa or skin wound, comprise by mass percentage: the chitosan of 40000 parts, the hyaluronate sodium of 1000 parts, the chlorhexidine gluconate of 2000 parts, the recombinant human epidermal growth factor of 0.4 part.
Take that to prepare one kilogram of gel be example,
40g chitosan
1g hyaluronate sodium
2g chlorhexidine gluconate
0.4mg recombinant human epidermal growth factor
Preparation method:
(1) chitosan, hyaluronate sodium are added in 960 milliliters of purified water, with dispersion machine, make its dissolving;
(2) chlorhexidine gluconate is scattered in 5 milliliters of propylene glycol;
(3) chlorhexidine gluconate propylene glycol suspension is added in the solution of above-mentioned chitosan and hyaluronate sodium, stirs and make each component mix homogeneously,
(4) pH value of regulator solution, between 5.0 to 6.0, continues to stir and treats that sample becomes gel;
(6) recombinant human epidermal growth factor is added water to dissolving, with the aseptic filtration of 0.22um microporous filter membrane;
(7) recombinant human epidermal growth factor solution is added in gel and stir and make finished product.
embodiment 4: gel of the present invention
For repairing a gel for vaginal mucosa, cervical mucosa or skin wound, comprise by mass percentage: the chitosan of 30000 parts, the hyaluronate sodium of 5000 parts, the chlorhexidine of 3000 parts, the recombinant human epidermal growth factor of 0.4 part.
Take that to prepare one kilogram of gel be example,
30g chitosan
5g hyaluronate sodium
3g chlorhexidine
0.4mg recombinant human epidermal growth factor
Preparation method:
(1) chitosan, hyaluronate sodium are added in 960 milliliters of purified water, with dispersion machine, make its dissolving;
(2) chlorhexidine is scattered in 5 milliliters of propylene glycol;
(3) chlorhexidine propylene glycol suspension is added in the solution of above-mentioned chitosan and hyaluronate sodium, stirs and make each component mix homogeneously,
(4) pH value of regulator solution, between 5.0 to 6.0, continues to stir and treats that sample becomes gel;
(6) recombinant human epidermal growth factor is added water to dissolving, with the aseptic filtration of 0.22um microporous filter membrane;
(7) recombinant human epidermal growth factor solution is added in gel and stir and make finished product.
embodiment 5: gel of the present invention
For repairing a gel for vaginal mucosa, cervical mucosa or skin wound, comprise by mass percentage: the chitosan of 60000 parts, the hyaluronate sodium of 500 parts, the chlorhexidine of 4000 parts, the recombinant human epidermal growth factor of 3 parts.
Take that to prepare one kilogram of gel be example,
60g chitosan
0.5g hyaluronate sodium
4g chlorhexidine
3mg recombinant human epidermal growth factor
Preparation method:
(1) chitosan, hyaluronate sodium are added in 960 milliliters of purified water, with dispersion machine, make its dissolving;
(2) chlorhexidine is scattered in 5 milliliters of propylene glycol;
(3) chlorhexidine propylene glycol suspension is added in the solution of above-mentioned chitosan and hyaluronate sodium, stirs and make each component mix homogeneously,
(4) pH value of regulator solution, between 5.0 to 6.0, continues to stir and treats that sample becomes gel;
(6) recombinant human epidermal growth factor is added water to dissolving, with the aseptic filtration of 0.22um microporous filter membrane;
(7) recombinant human epidermal growth factor solution is added in gel and stir and make finished product.
embodiment 6: gel of the present invention
For repairing a gel for vaginal mucosa, cervical mucosa or skin wound, comprise by mass percentage: the chitosan of 10000 parts, the hyaluronate sodium of 10000 parts, the chlorhexidine of 6000 parts, the recombinant human epidermal growth factor of 4 parts.
Take that to prepare one kilogram of gel be example,
10g chitosan
10g hyaluronate sodium
6g chlorhexidine
4mg recombinant human epidermal growth factor
Preparation method:
(1) chitosan, hyaluronate sodium are added in 960 milliliters of purified water, with dispersion machine, make its dissolving;
(2) chlorhexidine is scattered in 5 milliliters of propylene glycol;
(3) chlorhexidine propylene glycol suspension is added in the solution of above-mentioned chitosan and hyaluronate sodium, stirs and make each component mix homogeneously,
(4) pH value of regulator solution, between 5.0 to 6.0, continues to stir and treats that sample becomes gel;
(6) recombinant human epidermal growth factor is added water to dissolving, with the aseptic filtration of 0.22um microporous filter membrane;
(7) recombinant human epidermal growth factor solution is added in gel and stir and make finished product.
embodiment 7: ointment of the present invention
A kind of ointment of repairing vaginal mucosa, cervical mucosa or skin wound, the concrete following prescription (percentage by weight) that adopts: chlorhexidine 0.3%, recombinant human epidermal growth factor 0.0003%, stearic acid 10%, white vaseline 9%, glyceryl monostearate 6%, polysorbate65 %, propylene glycol 6%, methylcellulose 0.07%, ethyl hydroxybenzoate 0.02%, distilled water are appropriate.
Preparation technology:
(1) stearic acid, white vaseline and glyceryl monostearate are contained in container, 70-80 ℃ of heat fused, as oil phase;
(2) Tween-80, propylene glycol, ethyl hydroxybenzoate, recombinant human epidermal growth factor and chlorhexidine are added in the distilled water that is dissolved with methylcellulose, be heated to 70-80 ℃, as water;
(3) water is under agitation joined in oil phase, constantly stir until cool off, form emulsion bases type ointment, be sub-packed in and in pipe, obtain gynecological external use of the present invention or skin wound reparation ointment.
embodiment 8: liniment of the present invention
A kind of liniment of repairing vaginal mucosa, cervical mucosa or skin wound, the concrete following prescription (percentage by weight) that adopts: chlorhexidine citrate 0.3%, recombinant human epidermal growth factor 0.0003%, glycerol 50%, sodium chloride 3%, carbamide 9%, surplus is distilled water.
Preparation technology:
At normal temperatures and pressures, weigh recipe quantity chlorhexidine citrate and recombinant human epidermal growth factor, be dissolved in appropriate distilled water, then add wherein respectively according to the proportioning of each component in prescription.Last adding distil water standardize solution, fully mixes 10% appropriate sodium hydroxide solution of rear use and regulates pH to 6.0 can obtain gynecological external use of the present invention or skin wound reparation liniment.
embodiment 9: unguentum of the present invention
Repair an ointment for vaginal mucosa, cervical mucosa or skin wound, the concrete following prescription (percentage by weight) that adopts: chlorhexidine 0.6%, recombinant human epidermal growth factor 0.0004%, white vaseline 60%, distilled water is appropriate.
Preparation technology is: chlorhexidine and recombinant human epidermal growth factor are placed in to sterilizing mortar, after adding sterilizing, distilled water is ground into fine and smooth pasty state in right amount, the gradation equivalent recipe quantity white vaseline that progressively increases, grinds well packing and can obtain gynecological external use of the present invention or skin wound reparation ointment.
reference embodiment is with reference to formula and the preparation method preparation of Chinese patent CN102939097A embodiment 8 ointment-4
The pharmaceutical preparation of all the other dosage groups can prepare with reference to above-described embodiment, and preparation technology suitably adjusts according to above-mentioned technique, and this is that appearance is facile to those skilled in the art.
(2) pharmacodynamics embodiment part
embodiment 10: gynecological external use of the present invention or skin wound are repaired pharmaceutical composition xylol and caused mice ear impact
Get 108 of Kunming mouses, body weight 18-22g, is divided into 9 groups at random, 12 every group, be respectively to following tested medicine:
Blank group: do not use any dressing or smear to give distilled water;
High group of chlorhexidine: smear the Chlorhexidine Gel agent that gives 0.6%, 0.2 gram/only;
Low group of chlorhexidine: smear the Chlorhexidine Gel agent that gives 0.1%, 0.2 gram/only;
High group of somatomedin: smear and give 0.00006% recombinant human epidermal growth factor gel agent, 0.2 gram/only;
Low group of somatomedin: smear and give 0.00001% recombinant human epidermal growth factor gel agent, 0.2 gram/only;
1 group of compositions: smear the chlorhexidine and the 0.00001% recombinant human epidermal growth factor gel agent that give 0.6%, 0.2 gram/only;
2 groups of compositionss: smear the chlorhexidine diacetate and the 0.00001% recombinant human epidermal growth factor gel agent that give 0.1%, 0.2 gram/only;
3 groups of compositionss: smear the chlorhexidine citrate and the 0.00006% recombinant human epidermal growth factor gel agent that give 0.6%, 0.2 gram/only;
4 groups of compositionss: smear the chlorhexidine gluconate and the 0.00006% recombinant human epidermal growth factor gel agent that give 0.1%, 0.2 gram/only;
Each administration group is administered once every day, continuous 7 days, after last administration 1h, every mouse right ear outside was evenly coated with dimethylbenzene 1ml/10g, left ear is contrast, after 1h, the de-neck of mice is put to death, at the same position of left and right ear, by the sclerotic ring of diameter 9mm, sweep away auricle, with electronic balance, divide another name auricle weight, the difference of two auricle weight of take is swelling, calculate and respectively organize mice ear degree average and standard deviation, and calculate swelling suppression ratio, the results are shown in Table 2; Suppression ratio=(the average ear swelling degree of the average ear swelling degree-administration of matched group group) average ear swelling degree * 100% of/matched group;
Table 1 gel xylol of the present invention causes the antiinflammatory action of ear swelling model
Compare with matched group, * P < 0.05, * * P < 0.01, compares #P < 0.05, ##P < 0.01 with high group of chlorhexidine
Compare ▲ P < 0.05, ▲ ▲ P < 0.01 with high group of somatomedin;
As can be seen from Table 1, present composition gel and recombinant human epidermal growth factor group all have remarkable result aspect the ear swelling of reduction mice ear model, wherein pharmaceutical composition group of the present invention is compared with matched group and is had utmost point significant difference, and compare with chlorhexidine list medicine group or compare with somatomedin list medicine group, pharmaceutical composition of the present invention all has the difference of significance or utmost point significance aspect the ear swelling of reduction mice ear model.This shows that pharmaceutical composition of the present invention has good antiphlogistic effects, and two kinds of medicines have synergism aspect the ear swelling of reduction mice ear model, and this has great importance for treatment gynaecologic vaginal inflammation relevant disease and skin wound reparation.
embodiment 11: gynecological external use of the present invention or skin wound are repaired the therapeutical effect of pharmaceutical composition to colpitis
Inventor has carried out system clinical observation to 500 routine intractable gynecological inflammations, wherein select female vulva inflammation, vaginitis, cervical erosion, cervicitis, each 100 examples of pelvic inflammatory disease, each is organized patient and is vagina and smears administration (according to the liniment of the embodiment of the present invention 8 preparation), sooner or later each medication once, each about 3-5g, after continuous use one week, the therapeutic effect after statistics medication.Its curative effect statistical result of medication is as follows: table 2 is treated front and back for gynecological inflammation and contrasted wherein, intractable gynecological inflammation age of onset reckling 20 years old, the maximum 55 years old.
Table 2 gynecological external use of the present invention or skin wound reparation be the therapeutical effect to colpitis with liniment
Above-mentioned clinical statistics data shows, the present invention, to controlling the state of an illness, alleviates patient's symptom and complication successful, and zest is little, can not increase the weight of colpitis patient's the state of an illness.When gynecological external use of the present invention or skin wound reparation are used for the treatment of colpitis with liniment, applicable disease is extensive, and treated effect is high, can improve preferably patient's compliance and quality of life.
embodiment 12: the therapeutical effect that the pharmaceutical composition of gynecological external use of the present invention or skin wound reparation use is repaired skin wound
1. experimental technique
With the mice of 18-22g, build wound repair model, male and female half and half, random packet.First adopt 20% urethane as the anesthetis of experiment mice, dosage is 0.01ml/g.Adopt the mode of intraperitoneal injection to anaesthetize mice, fix 10 minutes after narcotism, cuts off the hair at experiment mice back until mice, and the region of cropping can be determined according to the size of wound.After having cut, with alcohol swab, mice is carried out disinfection without hair-fields, simultaneously to surgical instrument disinfections such as operating scissors, tweezers.With tweezers, pick up the skin that mouse back had been cut hair, with operating scissors, cut the circular wound that diameter is 5mm.In wound, apply the aerogel dressing (about 10mg) of having sterilized.Change once tested medicine to mice every day, by wound area being measured to record the variation of wound.It is as follows respectively that each organizes tested medicine:
Blank group: do not use any dressing or smear to give distilled water;
High group of chlorhexidine: smear the Chlorhexidine Gel agent that gives 0.6%, 0.6 gram/only;
Low group of chlorhexidine: smear the Chlorhexidine Gel agent that gives 0.1%, 0.6 gram/only;
High group of somatomedin: smear and give 0.00006% recombinant human epidermal growth factor gel agent, 0.6 gram/only;
Low group of somatomedin: smear and give 0.00001% recombinant human epidermal growth factor gel agent, 0.6 gram/only;
1 group of compositions: smear the chlorhexidine and the 0.00001% recombinant human epidermal growth factor gel agent that give 0.6%, 0.6 gram/only;
2 groups of compositionss: smear the chlorhexidine and the 0.00001% recombinant human epidermal growth factor gel agent that give 0.1%, 0.6 gram/only;
3 groups of compositionss: smear the chlorhexidine and the 0.00006% recombinant human epidermal growth factor gel agent that give 0.6%, 0.6 gram/only;
4 groups of compositionss: smear the chlorhexidine and the 0.00006% recombinant human epidermal growth factor gel agent that give 0.1%, 0.6 gram/only;
Each administration group is all raised under equivalent environment, freely drinks water.Respectively at the wound area of time point determining shown in table 3, and calculate wound healing rate.Wound healing rate=1-testing time wound area/initial wound area
2. experimental result
Table 3 is the evaluation of gel of the present invention to skin wound repair function, result shows after medication, chlorhexidine list medicine group, somatomedin list medicine group and the wound healing rate of pharmaceutical composition administration group after administration are compared the difference with significance or utmost point significance with blank group, the 1st day after medication wherein, 25% of the wound healing rate of the high group of somatomedin, a little less than the wound healing rate of 1,2,3,4 groups of compositions administrations.Along with the continuity of administration time, the wound healing rate that the present composition is 1,2,3,4 groups is obviously better than chlorhexidine list medicine group and somatomedin list medicine group, has the difference of significance or utmost point significance.Wound healing rate is all higher than more than 85% after 120h for medicine group of the present invention, and after 168 hours, wound healing rate is more than 95 in medication, and wound heals substantially.This shows in pharmaceutical composition of the present invention that chlorhexidine and recombinant human epidermal growth factor breeding composition have significant synergism impelling aspect wound healing.
The evaluation of table 3 gel of the present invention to skin wound repair function
Compare with blank group, * P < 0.05, * * P < 0.01, compares #P < 0.05, ##P < 0.01 with high group of chlorhexidine
Compare ▲ P < 0.05, ▲ ▲ P < 0.01 with high group of somatomedin
embodiment 13: the dark II degree of medicine composite for curing of gynecological external use of the present invention or skin wound reparation use burns and III degree burned patient clinical experimental study
1, data and method
1.1 physical data
Year October Jingzhou City, Hubei Province in October, 2006 to 2009 burned patient 125 examples, male 85 examples, female's 40 examples, 5～70 years old age, 35 years old mean age; According to burn and scald reason, be divided into: boiling water burn 67 examples, fire burn 58 examples; According to burn and scald degree, be divided into: dark II degree burn and scald 75 examples, III degree burn and scald 50 examples.
1.2 grouping and medications
Dark II degree burned patient 75 examples, are divided into 5 groups, every group of 15 people, and contrast SHAOSHANG PENWUJI administration group is set.
The concrete medication of each administration group is as follows:
Reference embodiment group: the outer ointment being coated with according to described in reference embodiment prepared by prescription and technique;
Drug composition liniment group: the drug composition liniment that is coated with the embodiment of the present invention 8 preparations outward.
Pharmaceutical composition ointment group: the pharmaceutical composition ointment that is coated with the embodiment of the present invention 7 preparations outward.
Pharmaceutical composition unguentum group: the pharmaceutical composition unguentum that is coated with the embodiment of the present invention 9 preparations outward.
Pharmaceutical composition gel group: the pharmaceutical composition gel that is coated with embodiment 6 preparations outward.
III degree burned patient 50 examples, are divided into 5 groups, every group of 10 people, and concrete medication is as follows:
Reference embodiment group: the outer ointment being coated with according to described in reference embodiment prepared by prescription and technique;
Drug composition liniment group: the drug composition liniment that is coated with embodiment 8 preparations outward.
Pharmaceutical composition ointment group: the pharmaceutical composition ointment that is coated with embodiment 7 preparations outward.
Pharmaceutical composition unguentum group: the pharmaceutical composition unguentum that is coated with embodiment 9 preparations outward.
Pharmaceutical composition gel group: the pharmaceutical composition gel that is coated with embodiment 6 preparations outward.
Each administration group patient is according to burn and scald area definition dosage, with whole flap coverages, is as the criterion.
1.3 Therapeutic Method
Under sterile working, the wound surface routine disinfection of burn will be scalded, first with povidone iodine and the normal saline of low concentration, simply clean wound surface, remove attachment and the elephant skin that come off, the vesicle tap that tension force is high, keep residual epithelium as far as possible, wipe out and come off or downright bad epidermis, the capable thorough debridement of infective wound surface is coated with or sprays corresponding medicinal liquid outside wound surface, every 3-4 hour daytime 1 time, every day, coating was 3-4 time.After medication, fully expose wound surface, can not cover, prevent that, into water, note warming winter.
Recovery from illness criterion of therapeutical effect: after medication, swelling disappears, and pain disappears, and wound surface is without infection, and subcrustal healing, has epidermal growth, wound surface is substantially repaired or is all repaired.After medication, record recovery from illness number in 7d, 14d, 21d, calculate 14d cure rate, recovery from illness number/case total number of persons * 100% in 14d cure rate=14d; The definition wound surface required time of complete epithelization is healing time, records each patient's healing time, and healing time is carried out to t check relatively; Record the wound surface cicatrix situation of burned patient, record patient's number of cases of scar, calculate cicatrix rate, patient's number of cases/case total number of persons * 100% of cicatrix rate=scar; Applied statistics software SPSS 11.0 carries out the χ of each treatment group cure rate and cicatrix rate
2check.If χ
2> χ
2 0.05,1=3.84, with p<0.05, there is significant difference.The results are shown in Table 4.
2, result of the test
Result of the test shows (in Table 4):
1) no matter for dark II degree or III degree burned patient, pharmaceutical composition of the present invention is being obtained significant progress aspect raising 14d cure rate and shortening healing time, and aspect 14d cure rate and healing time, pharmaceutical composition group is compared with SHAOSHANG PENWUJI group has significance or significant difference extremely;
2) from the cicatrix rate of pharmaceutical composition of the present invention and SHAOSHANG PENWUJI treatment burn and scald, along with increasing the weight of of burn and scald degree, burn and scald spraying group cicatrix rate increases thereupon, and from 48.27% to 76.92%.As can be seen here, along with the increase of burn and scald degree, the effect of SHAOSHANG PENWUJI treatment burn and scald weakens.But the cicatrix rate discovery from medicine composite for curing of the present invention burn and scald in various degree, treats dark II degree burn and scald cicatrix rate and treatment III degree burn and scald cicatrix is extremely low.Obviously, pharmaceutical composition of the present invention staying after treatment burn obtained unforeseeable technique effect in scar problem.
3) the treatment situation to burned patient from pharmaceutical composition different pharmaceutical dosage form of the present invention, each pharmaceutical composition different dosage form effect aspect cure rate is remarkable.
the clinical treatment situation of table 4 pharmaceutical composition of the present invention to burned patient
Note:
★with the comparison of reference embodiment group, p<0.05;
★ ★p<0.01.
embodiment 14 pharmaceutical composition toxicity test of the present invention
1, grouping
Blank
Reference embodiment group: outer spray is according to the SHAOSHANG PENWUJI of writing out a prescription described in reference embodiment and prepared by technique;
Pharmaceutical composition gel group: the pharmaceutical composition gel that is coated with embodiment 6 preparations outward.
2, test method:
In Mus back of the body system, defend the full thick-layer of 10% area and burn, excision skin ambustion, until appear sound of a bird chirping layer, leave open wound, excise each group of latter 0.5 hour and 1.5 hours be coated with respectively correspondingly to reagent thing at skin, blank group is only done skin excision and is not told medicine, to be coated with l time every day, totally 1,4 or 7 day.From tail venous hemorrhage place, total white blood cells and granulocyte value are measured in blood sampling.Computational fields blank group is compared total white blood cells and granulocyte value slip.
the impact of table 5 pharmaceutical composition of the present invention on leukocyte and granulocyte
Experiment points out the Mus wound surface external reference embodiment group of burning that total white blood cells and granulocyte number are significantly reduced, pharmaceutical composition group of the present invention slightly reduces, to after administration the 4th day, the above-mentioned cell number of pharmaceutical composition group of the present invention is significantly gone up, and reference embodiment group still continues to reduce, to administration the 7th day, pharmaceutical composition group total white blood cells of the present invention and granulocyte value were recovered substantially, and reference embodiment group is compared with blank group to still have significantly and reduced.Illustrate that coating pharmaceutical composition of the present invention occurs that the prompting of temporary leucocytes reduction phenomenon needn't stop using, and the pharmaceutical composition of reference embodiment is lasting to leukocyte reduced toxicity.
To sum up statement is only several preferred embodiment of the present invention, and for the principle scheme of the art, under the premise without departing from the principles of the invention, some pin improvement of the present invention and the modification made, be also considered as protection scope of the present invention.
Claims (4)
1. a gel for topical composition, is characterized in that, in described gel, by mass fraction, comprises: 40000 parts of chitosans, 1000 parts of hyaluronate sodiums, the chlorhexidine of 2000 parts and the recombinant human epidermal growth factor of 0.4 part.
2. preparation as claimed in claim 1, is characterized in that, the pH value of described gel is between 5.0-6.0.
3. topical composition as claimed in claim 1 or 2 treats and/or prevents the application in the medicine of colpitis relevant disease in preparation, and described colpitis relevant disease is vulvitis, vaginitis, cervicitis, cervical erosion or pelvic inflammatory disease.
4. the application in the medicine that topical composition as claimed in claim 1 or 2 is repaired at preparation treatment skin wound, described skin wound is the wound surface that burn, scald, decubital ulcer, otch or ulcer cause.
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| CN104013966B (en) * | 2014-05-31 | 2017-06-16 | 符耿哲 | A kind of lotion and application thereof |
| CN104623635B (en) * | 2015-01-19 | 2017-01-11 | 天津冠勤生物科技有限公司 | Pharmaceutical composition for preventing and treating cerebral ischemia |
| US11110071B2 (en) | 2015-06-19 | 2021-09-07 | Global Health Solutions Llc | Petrolatum-based PHMB compositions and methods of treatment for onychomycosis |
| CA2990170A1 (en) * | 2015-06-19 | 2016-12-22 | Global Health Solutions, Llc | Petrolatum-based compositions comprising cationic biocides |
| CN106580871B (en) * | 2017-02-16 | 2020-03-27 | 浙江因诺泰医疗器械有限公司 | Vaginal gel and preparation method thereof |
| CN107158363A (en) * | 2017-05-16 | 2017-09-15 | 张莎莎 | A kind of reparation liquid for being used to treat cervical erosion |
| CN108261562A (en) * | 2017-08-11 | 2018-07-10 | 上海建华精细生物制品有限公司 | A kind of Sodium Hyaluronate skin sparing film and its preparation method and application |
| KR101924894B1 (en) * | 2018-07-25 | 2018-12-04 | 베네브바이오랩 주식회사 | Skin ointment for treating skin of the labia minora |
| CN115192518B (en) * | 2022-09-01 | 2024-10-11 | 多氟多新材料股份有限公司 | Pharmaceutical gel preparation for treating skin burn caused by hydrofluoric acid and preparation method thereof |
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