CN101375845B - Podophyllotoxin external-use formulation prescription for treating pointed condyloma and herpes genitalis, dosage form series and preparation method - Google Patents
Podophyllotoxin external-use formulation prescription for treating pointed condyloma and herpes genitalis, dosage form series and preparation method Download PDFInfo
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- CN101375845B CN101375845B CN2007101211601A CN200710121160A CN101375845B CN 101375845 B CN101375845 B CN 101375845B CN 2007101211601 A CN2007101211601 A CN 2007101211601A CN 200710121160 A CN200710121160 A CN 200710121160A CN 101375845 B CN101375845 B CN 101375845B
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- podophyllotoxin
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- liniment
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940116423 propylene glycol diacetate Drugs 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 229940083037 simethicone Drugs 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a podophyllotoxin preparation formula for external use for the treatment of condyloma acuminatum and genital herpes, a series of formulations and a preparation method, and belongs to the field of pharmacy. The weights or the volumes of all the ingredients of the formula of 100ml of the podophyllotoxin preparation for external use are as follows: 0.5g of podophyllotoxin, 20ml-80ml of main solvent, 1ml-3ml of penetration enhancer 1, 0.5g-2.5g of penetration enhancer 2, 20ml-80ml of cosolvent and 0.03-0.5g of preservative. The podophyllotoxin preparation for external use has the advantages that the types and the amount of excipients and the proportion of main drugs are reasonable, the drug administration is carried out by a liniment, a spray or other formulations which are applicable to the external use, the main drug can be rapidly absorbed by the horny layer and the epidermis, the efficacy is significant, the local toxicity or side effects are small, the skin acute toxicity is very low, and the podophyllotoxin preparation has no irritation and weak allergy and does not hinder the skin normal functions; the podophyllotoxin preparation has no systemic toxicity or side effects, thereby being safe and effective. The preparation prepared by the formula has the advantages of good appearance, moderate viscosity, easy coating, spraying drug administration, feasible process, controllable quality, simple preparation process, and suitability for industrial batch production.
Description
Technical field
The present invention relates to treat externally applied podophyllotoxin preparation prescription, dosage form series and the method for preparing of condyloma acuminatum and genital herpes; Exactly be with podophyllotoxin as effective ingredient treatment condyloma acuminatum and the preparation prescription of genital herpes, serial exterior-applied formulation and preparation method thereof, belong to the pharmaceutics field.
Background technology
Condyloma acuminatum is to infect the genitals sexually transmitted disease (STD) that causes by human papillomavirus (HPV).The condyloma acuminatum number of patients has increased nearly 10 times over nearly 15 years.Detect according to China sexually transmitted disease (STD), genitals HPV recall rate is 30.69/10 ten thousand, and its sickness rate is in second of sexually transmitted disease (STD), be only second to gonorrhea (Xu Wenyan. the sexually transmitted disease (STD) prevention with treat. Shanghai: publishing house of The 2nd Army Medical College, 2001.3-5).And should the disease relapse rate high, difficult radical cure brings great misery for patient physiological and psychology.The treatment condyloma acuminatum has physiotherapy and chemotherapy and physiotherapy fiting chemical therapy (Ruan Jianbo, a Deng Minzhi in the prior art; Zhu Ruiqing; Deng. the electron ion art cooperates imiquimod treatment urethral orifice condyloma acuminatum. Guangdong medical science, 2006,27 (1): 89-90).But the common relapse rate of physiotherapy is higher, and more or less to normal mucosa have the damage and relapse rate higher (30%-90%) (Hu Weiyi, Qian Yihong, Zhang Wei, etc.The efficacy analysis of condyloma acuminatum different treatment methods. Chinese combination of Chinese and Western medicine skin cypridology magazine, 2005,4 (2): 101-102).And chemotherapeutics mainly contains inhibition hypertrophy medicine, like fluorouracil, podophyllotoxin etc.; The enhance immunity medicine is like interferon, imiquimod etc.At present, the most frequently used external used medicine of this disease is 0.5% podophyllotoxin and 5% imiquimod.(Yan Jun, Chen Shengli, king sea sodium, etc.The cost-effectiveness analysis of 5% imiquimod and 0.5% podophyllotoxin treatment condyloma acuminatum, China Dispensary, 2004,15 (12), 735-737).Main dosage form has the podophyllotoxin tincture, ointment, imiquimod cream agent, and compound Chinese medicinal preparation.
Imiquimod is a kind of new immunomodulator, be proved to be to have antivirus action, but its antivirus action is not direct; But produce interferon-' alpha ' and other cytokine (interleukin-1, interleukin-6, interleukin 8 and tumor necrosis factor-alpha) through inducing; Improve the immunity of Skin Cell by this, thereby reach antiviral purpose (Tyring SK, Arany I; Stanley MA; Et al 1A randomised, controlled, molecular st udy of condylomata acuminataclearance during t reatmentwit h imiquimod [J] 1J I nf ectDis; 1998,178 (2): 5511).Though this medicine therapeutic effect is good; Untoward reaction is lighter, but treatment cycle is longer relatively, the effect of treatment---and the higher (Yan Jun of cost; Chen Shengli, the cost-effectiveness analysis of king's sea sodium 5% imiquimod and 0.5% podophyllotoxin treatment condyloma acuminatum. China Dispensary 2,004 15 (12) 735-737); Composition is more in the compound Chinese medicinal preparation, difficult quality control, and adverse reaction rate is also higher.Therefore, the medicine of the treatment condyloma acuminatum of research high-efficiency low-toxicity economy has remarkable economic efficiency and social benefit.
Podophyllotoxin is that (ZUYECAO, podophylliumpeltatium) Chinese podophyllum root with ground such as China Tibet gets rhizome portion extract to the geographic shield Rhizoma Dysosmae Versipellis in North America.The eighties, abroad the someone found that low concentration podophyllotoxin (0.5%) treatment condyloma acuminatum curative effect is obvious, and it can suppress the in vitro tests proof cell proliferation process of normal epithelial cells and cervical cancer cell and suppress these cells to the picked-up of nucleotide and synthesizing of DNA.The outer time spent makes it necrosis and comes off through suppressing the division birth process of human papillomavirus HPV infection cell, thereby plays the effect of treatment condyloma acuminatum.Owing to use through the podophyllotoxin after highly purified in the preparation, improved curative effect, reduced the concentration of podophyllotoxin simultaneously significantly, significantly reduced the systemic absorption of this medicine.And toxicology proof podophyllotoxin does not have teratogenesis, and is carcinogenic, mutagenic action.
At present, and a line medicine of the treatment condyloma acuminatum that the podophyllotoxin tincture is recommended as WHO (Zhu Xuejun, the hole is flourishing, and Ji Suzhen waits the curative effect comparison of. You Tuoxin and YOUDI treatment condyloma acuminatum. and Chinese journal of dermatology, 1994,27 (3): 199.) therapeutic effect is good.China began to carry out the research of homemade high-purity podophyllotoxin and preparation thereof from 1988; And attain the results expected; Podophyllotoxin and preparation 0.5% podophyllotoxin tincture thereof obtained national two kind new medicine certificates in 1993, got into the domestic market, had created significant social and economic benefit.
The podophyllotoxin physicochemical property is stable, but water insoluble, employed primary solvent is a high concentration ethanol in the tincture; Cause said preparation that vulvar mucous membrane is had stronger zest; This not only brings misery to the patient, and directly influences medication, and has the safety issue in producing and transporting.Ointment mainly is to use inconvenience, can not absorb very soon smearing the back medicine, behind the administration certain hour, also must flush away attached to the drug matrices of mucomembranous surface, and certain mucous membrane irritation is arranged also.Recently disclosed patent [Li Lisha; Externally applied podophyllotoxin ointment and preparation method thereof; Publication number 1771937A] 122 routine clinical practice results among the embodiment also show: externally applied podophyllotoxin ointment has certain mucous membrane irritation and side effect the patient, pain (12.5%) wherein, erythema (65%); Edema (35%), rotten to the corn (52.5).
Summary of the invention
The technical problem that the present invention will solve provides the little externally applied podophyllotoxin preparation of a kind of toxic and side effects evident in efficacy, local.
Another technical problem that the present invention will solve provides a kind of method for preparing of externally applied podophyllotoxin preparation of simple, quality controllable, suitable suitability for industrialized production.
For realizing above-mentioned purpose, the present invention adopts following technical scheme:
A kind of externally applied podophyllotoxin preparation, the quality of each composition or volume were during 100mL should write out a prescription:
Podophyllotoxin 0.5g
Main solvent 20mL-80mL
Penetrating agent 1 1mL-3mL
Penetrating agent 2 0.5g-2.5g
Cosolvent 20mL-80mL
Antiseptic 0.03g-0.5g.
Described externally applied podophyllotoxin dosage form, the quality of each composition or volume were during 100mL should write out a prescription:
Podophyllotoxin 0.5g
Main solvent 30mL-50mL
Penetrating agent 1 2.5mL
Penetrating agent 2 2.5g
Cosolvent 50mL-70mL
Antiseptic 0.03g.
Said main solvent is selected from one or more in ethanol, ethylene glycol, glycerol, propylene glycol, isopropyl alcohol, liquid polyethylene glycol, liquid glycerin acid esters, propylene glycol acid esters, polyoxyethylene castor oil, benzyl acetate, diacetyl list glyceride, diacetyl tartaric acid (single, double) glycerol, oxalic acid glycerine ester, Emulphor FM, triglycerin caprylate, triglycerin decanoin, benzyl butyrate and the simethicone; Penetrating agent is selected from one or more of azone, Oleum menthae, Mentholum, cyclodextrin and derivant thereof and surfactant apoplexy due to endogenous wind; Cosolvent is selected from one or more in organic acid and salt, amide or aminated compounds, inorganic salt, polymer, esters and the polyhydric alcohol; Antiseptic is selected from one or more of benzoic acid and sodium benzoate, parabens and sorbic acid apoplexy due to endogenous wind.
Liquid polyethylene glycol is Macrogol 200, PEG400 or Macrogol 600 in the said main solvent; The liquid glycerin acid esters is acetin, diacetine, glyceryl triacetate, glyceryl monooleate, NOFABLE GO-902P or glycerol trioleate; The propylene glycol acid esters is propylene glycol monoacetate or propylene-glycol diacetate; Polyoxyethylene castor oil is polyoxyethylene castor oil (10), polyoxyethylene castor oil (35), polyoxyethylene castor oil (40), polyoxyethylene castor oil (60), polyoxyethylene castor oil (80) or polyoxyethylene castor oil (100); Cyclodextrin and derivant thereof are 2-HP-, methyl-beta-schardinger dextrin-or DM-in the penetrating agent; Organic acid and its esters are benzoic acid, salicylic acid and sodium salt thereof or glycyrrhizic acid in the cosolvent; Amide or aminated compounds are nicotiamide, acetamide, diethylamine, ethanolamine etc., and inorganic salt has potassium iodide or sodium phosphate; Polymer is PVP or PEG-400, and esters is glycinate or ethyl succinyl ester; Polyhydric alcohol is glycerol or propylene glycol; Antiseptic is an ethyl hydroxybenzoate.
Said main solvent is a glyceryl triacetate; Cosolvent is a propylene glycol; Penetrating agent 1 is an azone; Penetrating agent 2 is the 2-HP-; Antiseptic is an ethyl hydroxybenzoate.
The externally applied podophyllotoxin dosage form, the quality of each composition or volume were during 100mL should write out a prescription:
Podophyllotoxin 0.5g
Azone 2.5mL
Propylene glycol 60mL
2-HP-2.5g
Glyceryl triacetate 37.5mL
Ethyl hydroxybenzoate 0.03g
.
The preparation technology of externally applied podophyllotoxin dosage form; Get azone, propylene glycol, 2-dihydroxypropyl-beta-schardinger dextrin-, the ethyl hydroxybenzoate of recipe quantity, add an amount of glyceryl triacetate, fully behind dissolving and the mix homogeneously; The podophyllotoxin that adds recipe quantity again stirs and makes dissolving; Add all the other glycerol triacetates at last, stir, promptly get medicinal liquid.
Above-mentioned medicine liquid tank is installed in the packing container of liniment, obtain the externally applied podophyllotoxin liniment; Canned in the packing container of spray, obtain the externally applied podophyllotoxin spray; Canned in the packing container of other exterior-applied formulation, then can make other exterior-applied formulation of podophyllotoxin.
Through the enforcement of technical scheme of the present invention, not only solved the solubility of podophyllotoxin, and can be good at solving the strong problem of podophyllotoxin tincture zest in the past; The present invention is through changing main solvent and adding penetrating agent; Podophyllotoxin is processed liniment or spray, not only easy to use, and eliminated in original tincture ethanol and reduced medicine itself to Mucocutaneous zest; Improve the compliance of drug use, and guaranteed the safety of transportation and production process.As add azone etc. as penetrating agent; Make the subcutaneous osmotic effect of medicine obvious, and for example be incorporated as 2-HP-penetrating agent, form the compound system of oozing that helps with main solvent; Thereby make podophyllotoxin see through epidermis and horny layer rapidly; Thereby reduce the zest of medicine itself, and stability is increased, improve the compliance of patient's medication skin and mucosa.But and for example add prolong drug such as propylene glycol in the cuticular holdup time, thereby play prolong drug action time.
The present invention provides the prescription of externally applied podophyllotoxin preparation, serial exterior-applied formulation and preparation method thereof; Be intended to further improve the therapeutic effect of this medicine to condyloma acuminatum; Its purpose mainly is to stimulate the problem that influences therapeutic effect because of local mucous membrane for solving the prescription and the dosage form of treating the original external preparation of condyloma acuminatum medicine podophyllotoxin; Especially podophyllotoxin tincture; Strong to mucous membrane irritation during condyloma acuminatum in treatment, and problems such as potential safety hazard because of using a large amount of ethanol to cause in process of production.
Advantage of the present invention is: supplementary product kind of the present invention, consumption and principal agent reasonable mixture ratio; Be suitable for the dosage form administration of external with liniment, spray or other, principal agent can absorb rapidly and get into horny layer and epidermis, and is evident in efficacy; Local toxic and side effects is little; The skin acute toxicity is very low, and nonirritant and weak sensitization do not hinder the skin normal function; And the unsystematic toxicity, safe and effective.By the present invention write out a prescription the preparation the preparation outward appearance good, viscosity is moderate, be easy to the coating and spray delivery.Preparation process among the present invention is feasible, and is quality controllable, and preparation technology is simple, is fit to industrialized mass production.
Below in conjunction with the specific embodiment the present invention is described further; Be not to qualification of the present invention; According to prior art well known in the art; Embodiment of the present invention is not limited to this, therefore all this areas of having done according to the disclosure of invention be equal to replacement, all belong to protection scope of the present invention.
The specific embodiment
Embodiment 1: the externally applied podophyllotoxin spray
One. prescription: the quality of each composition or volume were during 100mL should write out a prescription:
Podophyllotoxin 0.5g
Azone 2.5mL
Propylene glycol 20mL
2-HP-2.5g
Glyceryl triacetate 77.5mL
Ethyl hydroxybenzoate 0.03g
Two. method for preparing:
Press the above-mentioned prescription of externally applied podophyllotoxin spray, it is subsequent use to take by weighing each component, gets the azone of recipe quantity earlier; Propylene glycol, 2-HP-, ethyl hydroxybenzoate; Add and fit glyceryl triacetate, fully behind dissolving and the mix homogeneously, the podophyllotoxin that adds recipe quantity again stirs and makes dissolving; Add all the other glyceryl triacetate at last, stir, promptly get medicinal liquid.Above-mentioned medicine liquid tank is installed in the packing container of spray, obtain the externally applied podophyllotoxin spray.
Embodiment 2: the externally applied podophyllotoxin spray
One. prescription: the quality of each composition or volume were during 100mL should write out a prescription:
Podophyllotoxin 0.5g
Azone 2.5mL
Propylene glycol 40mL
Methyl-beta-schardinger dextrin-2.5g
Glyceryl triacetate 57.5mL
Ethyl hydroxybenzoate 0.03g
Two. method for preparing:
Press the above-mentioned prescription of externally applied podophyllotoxin spray, it is subsequent use to take by weighing each component, gets the azone of recipe quantity earlier; Propylene glycol, methyl-beta-schardinger dextrin-, ethyl hydroxybenzoate; Add an amount of glyceryl triacetate, fully behind dissolving and the mix homogeneously, the podophyllotoxin that adds recipe quantity again stirs and makes dissolving; Add all the other glyceryl triacetate at last, stir, promptly get medicinal liquid.Above-mentioned medicine liquid tank is installed in the packing container of spray, obtain the externally applied podophyllotoxin spray.
Embodiment 3: the externally applied podophyllotoxin spray
One. prescription: the quality of each composition or volume were during 100mL should write out a prescription:
Podophyllotoxin 0.5g
Azone 2.5mL
Propylene glycol 60mL
DM-2.5g
Glyceryl triacetate 37.5mL
Ethyl hydroxybenzoate 0.03g
Two. method for preparing:
Press the above-mentioned prescription of externally applied podophyllotoxin spray, it is subsequent use to take by weighing each component, gets the azone of recipe quantity earlier; Propylene glycol, DM-, ethyl hydroxybenzoate; Add an amount of glyceryl triacetate, fully behind dissolving and the mix homogeneously, the podophyllotoxin that adds recipe quantity again stirs and makes dissolving; Add all the other glyceryl triacetate at last, stir, promptly get medicinal liquid.Above-mentioned medicine liquid tank is installed in the packing container of spray, obtain the externally applied podophyllotoxin spray.
Embodiment 4: the externally applied podophyllotoxin liniment
One. prescription: the quality of each composition or volume were during 100mL should write out a prescription:
Podophyllotoxin 0.5g
Azone 2.5mL
Propylene glycol 20mL
2-HP-2.5g
Glyceryl triacetate 77.5mL
Ethyl hydroxybenzoate 0.03g
Two. method for preparing:
Press the above-mentioned prescription of externally applied podophyllotoxin liniment, it is subsequent use to take by weighing each component, gets the azone of recipe quantity earlier; Propylene glycol, 2-HP-, ethyl hydroxybenzoate; Add an amount of glyceryl triacetate, fully behind dissolving and the mix homogeneously, the podophyllotoxin that adds recipe quantity again stirs and makes dissolving; Add all the other glyceryl triacetate at last, stir, promptly get medicinal liquid.Above-mentioned medicine liquid tank is installed in the packing container of liniment, obtain the externally applied podophyllotoxin liniment.
Embodiment 5: the externally applied podophyllotoxin liniment
One. prescription:
The quality of each composition or volume were during 100mL should write out a prescription:
Podophyllotoxin 0.5g
Azone 2.5mL
Propylene glycol 40mL
Methyl-beta-schardinger dextrin-2.5g
Glyceryl triacetate 57.5mL
Ethyl hydroxybenzoate 0.03g
Two. method for preparing:
Press the above-mentioned prescription of externally applied podophyllotoxin liniment, it is subsequent use to take by weighing each component, gets the azone of recipe quantity earlier; Propylene glycol, methyl-beta-schardinger dextrin-, ethyl hydroxybenzoate; Add an amount of glyceryl triacetate, fully behind dissolving and the mix homogeneously, the podophyllotoxin that adds recipe quantity again stirs and makes dissolving; Add all the other glyceryl triacetate at last, stir, promptly get medicinal liquid.Above-mentioned medicine liquid tank is installed in the packing container of liniment, obtain the externally applied podophyllotoxin liniment.
Embodiment 6: the externally applied podophyllotoxin liniment
One. prescription: the quality of each composition or volume were during 100mL should write out a prescription:
Podophyllotoxin 0.5g
Azone 2.5mL
Propylene glycol 60mL
2-HP-2.5g
Glyceryl triacetate 37.5mL
Ethyl hydroxybenzoate 0.03g
Two. method for preparing:
Press the above-mentioned prescription of externally applied podophyllotoxin liniment, it is subsequent use to take by weighing each component, gets the azone of recipe quantity earlier; Propylene glycol, 2-HP-, ethyl hydroxybenzoate; Add an amount of glyceryl triacetate, fully behind dissolving and the mix homogeneously, the podophyllotoxin that adds recipe quantity again stirs and makes dissolving; Add all the other glyceryl triacetate at last, stir, promptly get medicinal liquid.Above-mentioned medicine liquid tank is installed in the packing container of spray, obtain the externally applied podophyllotoxin liniment.
Embodiment 7: embodiment 6 preparations are to rabbit skin irritation test
One. single is smeared the skin irritation test:
6 of New Zealand's large ear rabbits.24h shaves clean belly wool with shaver before the experiment, depilation scope left and right sides Ge Yue 5 * 10cm2.Mark three skin areas with marking pen during experiment, each about 3 * 3cm.Three receive the examination district to have one for damaged skin, embrocate 0.5% podophyllotoxin liniment 0.5ml among the embodiment 6; Two normal skins are coated with 0.5% podophyllotoxin liniment and prescription blank solvent each 0.5ml of system among the embodiment 6 in addition.(2.5cm * 2.5cm) skin is smeared in covering, and medical proof fabric is fixed, and continues 24h, in 1,24,48 and 72 h observation dermoreaction and recovery situations with two layers of gauze.Table 1 and table 2 are seen in the criterion of skin irritation intensity, and result of the test is seen table 3.
Table 1 skin irritation reaction standards of grading
The IR score value
Erythema
No erythema 0
Slight erythema (visible reluctantly) 1
Moderate erythema (obviously visible) 2
Severe erythema 3
The aubergine erythema forms 4 to slight eschar
Edema
No edema 0
Mild edema (visible reluctantly) 1
Intermediate edema (obviously protuberance) 2
Severe edema (skin 1mm, profile is clear) 3
Serious edema (skin 1mm above and have expansion) 4
Highest point total value 8
Table 2 skin irritation intensity evaluation standard
Score value is estimated
0-0.49 nonirritant
0.5-2.99 slight zest
3.0-5.99 moderate zest
6.0-8.0 strong and stimulating
Table 3 skin single zest scoring synthesis result (n=6)
Two. repeatedly skin irritation test
6 of New Zealand's large ear rabbits.24h shaves clean belly wool with shaver earlier before the experiment, depilation scope left and right sides Ge Yue 5 * 10cm
2Indicate each group zone with marking pen with dotted line during experiment, each about 3 * 3cm size.Three receive the examination district to have one for damaged skin, embrocate 0.5% podophyllotoxin liniment 0.5ml among the embodiment 6; Two normal skins are coated with 0.5% podophyllotoxin liniment and prescription blank solvent each 0.5ml of system among the embodiment 6 in addition.With two layers of gauze (2.5cm * 2.5cm) cover medical proof fabric to fix.Whenever together once, after continuous ten days, in 1,24,48 and 72 h observation dermoreaction and recovery situations.Table 1 and table 2 are seen in the criterion of skin irritation intensity, and result of the test is seen table 4.
Table 4 skin is zest scoring synthesis result (n=6) repeatedly
The result shows: to the basic nonirritant of New Zealand's large ear rabbit skin, select rationally by pharmaceutical dosage form and concentration under people's normal use concentration (0.5%) for liniment of the present invention.
Embodiment 8: embodiment 6 preparations are to testing the guinea pig skin allergy
One. material and method
30 of healthy albefaction Cavia porcelluss, 250g～300g is divided into totally three groups of pastille sample sets, solvent control group and positive controls at random, and 10 every group, male and female half and half.Test adopts partial closure to be coated with pico farad, and (Buehler test, BT), whole process is divided into sensitization (inducing) and excites two stages.
1. sensitization stage:
24h before the test, shaver is subsequent use with the depilation of Cavia porcellus rib abdominal part 3 * 3cm zone.Get the 0.5% podophyllotoxin liniment 1mL or 2 of the blank solvent 1mL of system or 1% of writing out a prescription among the embodiment 6,4-dinitrochlorobenzene (positive controls) 1mL drops on four layers of gauze of 2 * 2cm, is applied on the skin of unhairing; Immobilization with adhesive tape; Behind the 6h, warm water flush away debris, 7d, 14d repeat with method.
2. excitation phase:
After the last sensitization 14 days, with 2 of 0.5% podophyllotoxin liniment 1ml among the embodiment 6 or prescription blank solvent 1mL or 0.1%, 4-dinitrochlorobenzene 1mL dropped on four layers of gauze of 2 * 2cm; Be applied to (24h depilation before the contact) on the skin of unhairing; Immobilization with adhesive tape, behind the 6h, warm water flush away debris; At once observe, behind 24h, 48h, 72h, observe dermoreaction then once more.The irritated dermatitis of the contact that chemical substance causes belongs to IV type (delaying type) allergy, and animal shows as skin erythema and edema, and evaluation criteria is seen table 5, table 6.
Table 5 skin erythema evaluation criteria
Erythema and eschar form grade scoring
No erythema 0
It is thus clear that erythema is reluctantly 1
Obvious erythema 2
Moderate～serious erythema 3
The aubergine erythema also forms 4 with eschar
Table 6 hydroderma forms evaluation criteria
Edema forms grade scoring
No edema 0
It is thus clear that edema is reluctantly 1
Skin profile clear 2
The about 1mm 3 of edema protuberance
The edema protuberance surpasses 1mm, expanded range 4
Carry out the classification of sensitization intensity by the judgment criteria in the new drug toxicologic study guideline of Ministry of Public Health promulgation.
Two. it is following that each organizes appraisal result:
The pastille sample sets: reaction meansigma methods=0, sensitization rate=0, the ametaboly reaction occurs.
Solvent control group: reaction meansigma methods=0, sensitization rate=0, the ametaboly reaction occurs.
Positive controls: reaction meansigma methods=4.05, sensitization rate=100% belongs to the intensity sensitizer.
The result shows: after guinea pig skin repeated to contact 0.5% podophyllotoxin liniment 1ml or prescription blank solvent, body did not produce the dermoreaction that immunity is transmitted.Said preparation and blank solvent are not all had a sensitization.
Embodiment 9: liniment treated condyloma acuminatum 120 routine curative effects and side effect are observed in the embodiment of the invention 6
One. divide into groups: with the Dermatology & STD Dept. integration and cooperation observation of treatment unit; After signing Informed Consent Form with the patient and putting on record through Ethics Committee of hospital; Adopt unified standard to select case; All clinical symptoms typical cases and acetic acid are tested positive or clinical doubtful case in vain, meet CA as the treatment object of observation through tissue pathology checking.Treat 120 examples altogether, male 76 examples, women 44 examples.21 years old～66 years old age, 35.7 years old mean age; Stadium is the longest 13 months, the shortest 2 weeks, average 2.3 months.The wart body is maximum like Semen Glycines, little person such as foxtail millet grain size.The maximum persons of wart body have 18, general 2～4.
Two. Therapeutic Method and curative effect are judged
1. method: with 0.5% podophyllotoxin liniment among the embodiment 6 be coated in the wart body and around, medication every day 2 times, for three days on end, the observation that continues 4 days was 1 course of treatment.If the wart body does not disappear, can count the course of treatment with the method repetitive therapy.Be no more than 3 courses of treatment at most.
2. curative effect judging standard:
Recovery from illness: all disappear after the medication, a month nothing is sent out again after the drug withdrawal.
Produce effects: 3 of continuous uses disappear or residual a little person of not disappearing the course of treatment fully.
Invalid: 3 courses of treatment of continuous use, the wart body does not disappear or 1～2 week of drug withdrawal, the affected part recidivist.
Local irritation and untoward reaction are observed: mainly observe medication local skin and untoward reaction such as mucosa pain, erythema, edema and erosion.
The result: through the present invention's treatment of 1 ~ 3 course of treatment, the efficacy result brief summary sees 7, and table 8 is seen in local irritation and the brief summary of untoward reaction observed result.
The 120 routine curative effect brief summaries of table 7 liniment treatment of the present invention condyloma acuminatum
Brief summary is observed in the 120 routine untoward reaction of table 8 liniment treatment of the present invention condyloma acuminatum
Annotate: liniment of the present invention is to normal mucocutaneous no obvious adverse reaction, and medication is after 1～2 day, wart body periphery or white membranoid substance all takes place; After with 2～3 days, the atrophy of wart body or the something lost that disappears have flushing face and edema, and with mild pain; Slight erosion takes place in a little patient, and incidence rate is 9.2%, but does not form ulcer; Need not to handle, drug withdrawal 3～5 light can recover normal.
Above clinical treatment observation result shows: podophyllotoxin liniment therapeutic effect of the present invention is good, and mucous membrane irritation and side effect are slight, and patient tolerability is good.
Claims (2)
1. externally applied podophyllotoxin dosage form, it is characterized in that: the quality of each composition or volume are in this dosage form of 100mL:
Said exterior-applied formulation is a liniment.
2. the preparation technology of externally applied podophyllotoxin dosage form according to claim 1; It is characterized in that: get azone, propylene glycol, 2-HP-, the ethyl hydroxybenzoate of recipe quantity, add an amount of glyceryl triacetate, fully behind dissolving and the mix homogeneously; The podophyllotoxin that adds recipe quantity again stirs and makes dissolving; Add all the other glyceryl triacetate at last, stir, promptly get medicinal liquid; The gained medicine liquid tank is installed in the packing container of liniment, make the externally applied podophyllotoxin liniment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007101211601A CN101375845B (en) | 2007-08-30 | 2007-08-30 | Podophyllotoxin external-use formulation prescription for treating pointed condyloma and herpes genitalis, dosage form series and preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007101211601A CN101375845B (en) | 2007-08-30 | 2007-08-30 | Podophyllotoxin external-use formulation prescription for treating pointed condyloma and herpes genitalis, dosage form series and preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101375845A CN101375845A (en) | 2009-03-04 |
| CN101375845B true CN101375845B (en) | 2012-07-04 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007101211601A Expired - Fee Related CN101375845B (en) | 2007-08-30 | 2007-08-30 | Podophyllotoxin external-use formulation prescription for treating pointed condyloma and herpes genitalis, dosage form series and preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101375845B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113274342B (en) * | 2016-11-08 | 2023-06-02 | 北京天衡军威医药技术开发有限公司 | Colchicine external composition |
| CN108098458B (en) * | 2017-08-09 | 2019-12-24 | 徐先顺 | Gel for resisting HPV6/11 |
| CN111671900A (en) * | 2020-06-19 | 2020-09-18 | 任新军 | Compound preparation for photodynamic therapy and preparation method thereof |
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2007
- 2007-08-30 CN CN2007101211601A patent/CN101375845B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
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| CN101375845A (en) | 2009-03-04 |
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