CN102614497A - Usage of human interferon in preparation of medicines for treatment or prevention of HPV (human paillomavirus) related diseases - Google Patents
Usage of human interferon in preparation of medicines for treatment or prevention of HPV (human paillomavirus) related diseases Download PDFInfo
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Abstract
The invention relates to the medical field, and discloses the usage of human interferon in preparation of medicines for treatment or prevention of HPV (human paillomavirus) related diseases. According to clinical tests, human interferon has curative effects on HPV infection, and particularly has remarkable curative effects on simple type HPV infection and high-risk type HPV continuous genital tract infection. The usage of human interferon is significant to preventive treatment of HPV infection, particularly the simple type HPV infection, and prevention and reduction of cervical erosion and cervical cancers, and has bright clinical application prospect.
Description
Technical field
The present invention relates to field of medicaments, particularly the purposes of human interferon in the medicine of preparation treatment HPV relevant disease.
Background technology
Cervical erosion is the modal a kind of disease of gynecological clinic, is a kind of common pathological change of chronic cervicitis.The ectocervical outward appearance that shows as cervix uteri collar extension place is the red color area of fine particulate.In recent years it is relevant with the morbidity of cervical erosion that research both at home and abroad shows that human papillomavirus (HPV) infects; And cervical HPV infection is the main pathogenesis of cervical cancer; Therefore, the cervical erosion that merges the HPV infection gets along with to the possibility of cervical cancer, and is closely related with the morbidity of cervical cancer.Clinical research shows that patients of cervical ruin HPV infects and cervix uteri local patholoic change weight, and it is relevant whether to merge many factors such as other infection and patient's age, occupation, childbearing history.The treatment of traditional cervical erosion is main with physiotherapy mainly, and cervical erosion face columnar epithelium is destroyed, and makes it come off necrosis and is covered by new life's stratified squamous epithelium, cures cervical erosion.And for the cervical erosion that is associated with viral infection, newer Therapeutic Method is that topical application antiviral drugs such as interferon etc. are treated at present, has obtained certain therapeutic effect.Interferon is through its specific antivirus action, and when effectively removing cervix uteri part viral infection, the human body immunity improving function promotes the healing of cervical erosion.Cervical cancer reaches the change that cervical dysplasia all shows as chronic cervicitis clinically in early days, and the persistence cervical HPV infection finally possibly cause the generation of cervical cancer.Therefore, be combined the cervical erosion that HPV infects and carry out early stage efficacious therapy, can prevent further developing of pathological changes, make pathological changes in early days the stage promptly obtain medical treatment, maybe prevention its to working aspect the further transformation of cervical cancer.
Cervical cancer (cervical cancer) is one of modal gynecologic malignant tumor, in global woman cancer mortality rate, occupies the second, and women's Health and Living quality in serious threat.Its incidence and development has demonstrated the trend of rejuvenation; 500,000 new cases are arranged every year approximately, and wherein 80% in developing country, because interlocal different cervical cancer morbidity has very big-difference; China accounts for the world 1/3, and China women's health and life security in serious harm.
Find that in research in recent years HPV (human papillomavirus) is related closely with cervicitis, especially the HPV of some high-risk-types is the key factors that cause cervical cancer, in the biopsy of cervical cancer, almost can both find HPV to infect.On average there is 132300 routine new cases every year the hotspot that China is cervical cancer as a developing country, and total incidence is 0.27 ‰.Massive epidemiology investigation and molecular biology research show; Human papillomavirus (Human Papillomavirus; HPV), especially high-risk HPV (high-risk HPV, hr-HPV) the reproductive tract persistent infection be cause cervical cancer and the important nosetiology factor of CIN.According to statistics, in the case of all cervical cancers, surpass 99% and can be detected high-risk HPV DNA.
It is the process of multifactor participation, progressive development from the normal cervix cell to the conversion of Cervical intraepithelial neoplasia change and cervical cancer that HPV infects the back, and the high-risk human mammilla papillomavirus persistent infection is the necessary factor in the cervix cells vicious transformation.Massive epidemiology and molecular biology research data show that HPV and cervical cancer and precancerous lesion are closely related, and especially (high-risk HPV, hr-HPV) the reproductive tract persistent infection is the important nosetiology factor that causes cervical cancer and CIN to high-risk HPV.Most of HPV infects no clinical symptoms or subclinical infection, but can cause serious consequence, and HPV infects the existence that the indication Cervical intraepithelial neoplasia becomes (CIN).Also discover, continue to carry HPV and point out strongly in the highly dangerous that the infected is in the secondary precancerous lesion.According to statistics, in the case of all cervical cancers, surpass 99% and can be detected high-risk HPV DNA.Research shows that the Cervical intraepithelial neoplasia change of infecting with HPV (CIN) further can develop into cervical cancer.
Human papillomavirus (HPV) belongs to human papillomavirus family, is special DNA viruses, has the ability of normal cell immortalization and height species specificity and special had a liking for epithelium property, and viral DNA is present in the host cell to integrate to form.HPV is a kind of nonencapsulated double-stranded closed loop small molecule DNA virus, belongs to the papovaviridae Papillomavirus.Its infection has species specificity, and HPV and multiple disease are closely related, is so far by one of sure DNA oncovirus, and the skin of the main infected person of HPV or mucomembranous epithelial cell cause good, the malignant change of infection site.Present known HPV6,11,42,43,44 etc. relevant with spread through sex intercourse wart or condyloma acuminatum belongs to low risk, does not generally bring out canceration; And HPV16,18,31,33,35,39,45,51,52,56,58,59,68 belongs to high-risk-type, and is relevant with the generation of cervical cancer and cervical intraepithelial neoplasia (CIN).The molecular biology research result shows that 90% above cervical cancer infects with HPV, is mainly HPV16,18 hypotypes.
Owing to infect Cervical intraepithelial neoplasia a changes-cervical cancer from HPV, need a comparatively very long process, be generally for 10 years, and the Cervical intraepithelial neoplasia change is the pathological changes that can reverse, and 5 years cure rates of early cervical carcinoma are up to 90%.Therefore, actively prevent and treat HPV and infect, particularly high-risk HPV infect to prevention and reduce cervical cancer have an important clinical meaning.
Summary of the invention
The technical problem that the present invention will solve is that the purposes of human interferon in the medicine of preparation treatment HPV relevant disease is provided.
Preferably, said human interferon is selected from human interferon-alpha, human interferon beta and human interferon gamma.
Preferably, said human interferon-alpha is selected from human interferon alpha 1 b, human interferon-alpha 2a, human interferon-alpha-2 b and said three kinds of proteic derivants and analog.
Preferably, said human interferon is natural human interferon or recombinant human interferon alpha 2.
Preferably, said HPV relevant disease infects for simple type HPV.
In the specific embodiment of the present invention; Infect to simple type HPV; Study compound preparation group according to the invention and the matched group difference between the negative conversion rate in the time of 6th month; The result shows: simple type HPV infects after treatment in 6 months, and the total effective rate of compound preparation group and negative conversion rate are apparently higher than matched group.Total effective rate: FAS collection, compound preparation group are 69.81%, and matched group is 57.89%, and the compound preparation group is greater than matched group; And PPS collection matched group is greater than the compound preparation group, and the compound preparation group is 77.62%, and matched group is 62.26%, and compound preparation group and matched group have obvious significant difference.Negative conversion rate: FAS collection, compound preparation group are 69.18%, and matched group is 52.63%; PPS collection, compound preparation group are 76.92%, and matched group is 56.60%.It is thus clear that compound preparation group according to the invention infects simple type HPV notable therapeutic effect is arranged.
Preferably, said HPV relevant disease is the persistent infections of high-risk HPV reproductive tract.
More preferably, said HPV relevant disease is cervical erosion, condyloma acuminatum, genital herpes or herpes labialis, herpes zoster, skin carcinoma, cervical cancer, verruca plana, the change of cervical epithelial cells tumor.
In the specific embodiment of the present invention, the method for preparing of said medicine is following:
Step 1: in human interferon stock solution, add the human albumin and obtain mixed solution, making the albumin final concentration is 1%-5%, adds and the isopyknic stabilizing agent mixing of mixed solution heating in water bath 0.5-3min, lyophilization powdered; Said stabilizing agent is selected from SDS, the mixture of carbamide and mercaptoethanol, glycine, heparin, trehalose, vitamin C or reduced glutathion.
Step 2: after taking by weighing sodium carboxymethyl cellulose 50-200g, glycerol 500-1500ml, sorbic acid 10-20g mixing, add the injection water, be heated to 60-100 ℃ of mixing, when treating that substrate is cooled to 10-40 ℃, transfer pH to 4.0-9.5 to 10000g, subsequent use;
Step 3: step 1 human interferon powder is added to the substrate mix homogeneously that step 2 prepares, and packing promptly gets.
Preferably, add interferon powder 1.0 * 10 in the method for preparing of said medicine in every 1000g substrate
6-1.0 * 10
9Iu.
Preferably, said human interferon is a human interferon-alpha-2 b.
The preparation of embodiment of the invention preparation is a human interferon, has antiviral, antitumor and immunoregulatory activity, and the enhancing body anti-virus ability also has the function of eliminating the dna structure damage simultaneously, thereby causes the recovery of cytogenetics mechanism, makes injury repairing.It produces antiviral protein through activating the antiviral gene of target cell, suppresses duplicating of viral DNA and transcribing of mRNA, thereby plays the effect that suppresses virus.And interferon still can activate natural killer cell, macrophage, the expression of regulation and control major histocompatibility antigen.Clinical trial shows that the pharmaceutical preparation treatment HPV that the present invention makes infects certain curative effect is arranged, and high-risk-type and simple type HPV viral infection are had notable therapeutic effect.
Compare with existing injection interferon, advantage such as that preparation according to the invention has is painless, convenient, effective, have no side effect, its percutaneous absorbability is good, can reach the effect that topical antiviral effectively suppresses cell proliferation; In addition, its stability is good, and room temperature is preserved to tire in 3 months and almost do not changed, and has good potential applicability in clinical practice.The present invention infects for control HPV, and particularly high-risk HPV infects, prevention and reduce cervical cancer have an important clinical meaning.
The specific embodiment
The invention discloses the purposes of human interferon in the medicine of preparation treatment HPV relevant disease, those skilled in the art can use for reference this paper content, suitably improve technological parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are regarded as and are included in the present invention.Application of the present invention is described through preferred embodiment, and the related personnel obviously can change or suitably change and combination methods and applications as herein described in not breaking away from content of the present invention, spirit and scope, realizes and use technology of the present invention.
In order to make those skilled in the art understand technical scheme of the present invention better, the present invention is done further detailed description below in conjunction with specific embodiment.
Embodiment 1, preparation prescription technology:
(1) processing of human interferon stock solution:
Add the human albumin according to human interferon stock solution volume, making human albumin's final concentration is 5% (W/V), adds isopyknic stabilizing agent SDS according to the cumulative volume that added albuminous human interferon solution then; Mixing; Heating in water bath 0.5-3min, the lyophilization powdered is carried out in cooling after the packing.
(2) substrate preparation:
After accurately taking by weighing sodium carboxymethyl cellulose 200g, glycerol 500ml, sorbic acid 20g mixing, add the injection water, be heated to 100 ℃ of abundant stirring and evenly mixings, when treating that substrate is cooled to 40 ℃, transfer pH to 7.5 to 10000g, subsequent use.
(3) preparation of human interferon preparation:
The human interferon powder is added to (adding human interferon powder 1.0 * 10 in every 1000g substrate in the substrate
9Iu), constantly be stirred to complete mix homogeneously.
Embodiment 2, preparation prescription technology:
(1) processing of human interferon stock solution:
Add the human albumin according to human interferon stock solution volume; Making human albumin's final concentration is 1% (W/V); Add isopyknic stabilizing agent reduced glutathion, mixing, heating in water bath 0.5min according to the cumulative volume that added albuminous human interferon solution then; The lyophilization powdered is carried out in cooling after the packing.
(2) substrate preparation:
After accurately taking by weighing sodium carboxymethyl cellulose 50g, glycerol 1500ml, sorbic acid 10g mixing, add the injection water, be heated to 60 ℃ of abundant stirring and evenly mixings, when treating that substrate is cooled to 10 ℃, transfer pH to 4.0 to 10000g, subsequent use.
(3) preparation of human interferon preparation:
The human interferon powder is added to (adding human interferon powder 1.0 * 10 in every 1000g substrate in the substrate
6Iu), constantly be stirred to complete mix homogeneously.
Embodiment 3 preparation prescription technologies:
(1) processing of human interferon stock solution:
Add the human albumin according to human interferon stock solution volume, making human albumin's final concentration is 3% (W/V), adds isopyknic stabilizing agent vitamin C according to the cumulative volume that added albuminous human interferon solution then; Mixing; Heating in water bath 2min, the lyophilization powdered is carried out in cooling after the packing.
(2) substrate preparation:
After accurately taking by weighing sodium carboxymethyl cellulose 100g, glycerol 750ml, sorbic acid 15g mixing, add the injection water, be heated to 80 ℃ of abundant stirring and evenly mixings, when treating that substrate is cooled to 30 ℃, transfer pH to 9.5 to 10000g, subsequent use.
(3) preparation of human interferon preparation:
The human interferon powder is added to (adding human interferon powder 1.0 * 10 in every 1000g substrate in the substrate
8Iu), constantly be stirred to complete mix homogeneously.
Embodiment 4 preparation prescription technologies:
(1) processing of human interferon stock solution:
Add the human albumin according to human interferon stock solution volume, making human albumin's final concentration is 2% (W/V), adds isopyknic stabilizing agent heparin according to the cumulative volume that added albuminous human interferon solution then; Mixing; Heating in water bath 2.5min, the lyophilization powdered is carried out in cooling after the packing.
(2) substrate preparation:
After accurately taking by weighing sodium carboxymethyl cellulose 80g, glycerol 600ml, sorbic acid 18g mixing, add the injection water, be heated to 90 ℃ of abundant stirring and evenly mixings, when treating that substrate is cooled to 20 ℃, transfer pH to 6.0 to 10000g, subsequent use.
(3) preparation of human interferon preparation:
The human interferon powder is added to (adding human interferon powder 1.0 * 10 in every 1000g substrate in the substrate
7Iu), constantly be stirred to complete mix homogeneously.
Embodiment 5, the clinical research of HPV negative conversion rate
1. test master-plan
This test adopt multicenter, at random, open, parallel, blank design.The ratio that test group (the preparation group of embodiment 1) and matched group (placebo group) go into to organize the patient is 2: 1.
The selected altogether 432 routine cases of plan, wherein test group is 288 examples, matched group is 144 examples.
The usage of the trial drug of embodiment 1 preparation is: one time one, the next day medication once, using 10 times continuously is 1 course of treatment.
2. treatment cycle confirms
Test objective mainly is to explore the influence of human interferon for the HPV negative conversion rate, is 8-12 week according to the viral replicative cycle of bibliographical information HPV, so the medication cycle is 3 months.
3. sample size estimation
3.1 the selected altogether 432 routine cases of plan, wherein test group is 288 examples, and matched group is 144 examples.The research implementation step is carried out according to following table.
3.2 the selection of object of study
1. inclusion criteria
(1) 30～65 years old age is married or the female patient of sexual life arranged;
(2) liquid based cytology (TCT) inspection is not gone up Intradermal sick cell and malignant cell for seeing;
(3) HPV dna typing detection (comprising that single high-risk-type is positive, the positive and mixed type positive of just endangering of many high-risk-types) is that high-risk HPV is positive.15 kinds of high-risk-types comprise HPV16,18,31,33,35,39,45,51,52,53,56,58,59,66,68;
2. exclusion standard
(1) cervical intraepithelial neoplasia;
(2) be associated with serious mycotic trichomonal vaginitis person;
(3) be associated with serious primary disease such as cardiovascular, liver, kidney and hemopoietic system;
(4) allergic constitution or to the known composition allergy sufferers of this medicine.
(5) in 30 days, accepted other clinical trial medicines or participating in other clinical trial person;
(6) pregnancy, women breast-feeding their children and the conceived women of plan;
(7) researcher is thought and should not carry out clinical trial person.
3. reject/withdraw from standard
If an experimenter has gone into anthology research, but learns afterwards that this experimenter had terms hereinafter, from the consideration to experimenter's secure context, this experimenter must withdraw from this research immediately.
(1) researcher is thought has any discomfort should continue to participate in the situation of test;
(2) women of child-bearing age person of becoming pregnant during studying;
(3) to research drug allergy person;
(4) experimenter initiatively requires to withdraw from research;
(5) serious adverse reaction occurs, need stop researcher;
(6) experimenter no longer accepted medication or detection and loses visit before not accomplishing all treatments;
(7) experimenter's compliance is poor.
3.3 process of the test
3.3.1 research medicine
1. study the specification and the source of medicine
(1) trial drug
The human interferon of title: embodiment 1 preparation
(2) adopt placebo
3.3.2 it is blind that randomization and medicine are compiled
This test adopt multicenter, at random, the clinical study design of open, parallel, placebo.
3.3.3 drug combination
Experimenter's long-term drug combination should remain unchanged during the research, and should not increase other interim drug combinations as far as possible.
Ban use of following Drug therapy during the medication:
(1) other interferons medicines outside this research medication.
(2) other can treat medicine or method that HPV infects.
3.3.4 research implementation step
The test cycle of following up a case by regular visits to is 12 months, divides two stages.
I stage: 1-6 month, test group was used the preparation 30 times (3 courses of treatment) of embodiment 1 continuously at 1-3 month, and matched group uses placebo, does observation.Follow up a case by regular visits in the time of 6th month 1 time, and detect HPV,, do not turn out cloudy and then continue to get into the II stage and treat if turn out cloudy then finish clinical research.
II stage: 7-12 month, test group continued to use continuously the preparation 30 times (3 courses of treatment) of embodiment 1 at 7-9 month, and matched group still uses placebo, does observation.Followed up a case by regular visits to 1 time at 12nd month, and detect HPV, no matter how testing result finishes research.
3.4 effectiveness and safety indexes
3.4.1 observation index and observing time
● routine blood test (erythrocyte, leukocyte, platelet count, neutrophilic granulocyte, eosinophilic granulocyte, basophilic granulocyte, lymphocyte, monocyte count, hemoglobin);
● hepatic and renal function (total protein, albumin, STB, glutamate pyruvate transaminase, glutamic oxaloacetic transaminase, GOT, alkali phosphatase, gamma glutamyl transpeptidase, blood urea nitrogen, creatinine, uric acid)
special examined:
● liquid based cytology (TCT) inspection
● the HPV dna typing detects
3.4.2 validity evaluation index
(1) hr-HPV DNA negative conversion rate: analytical test group and matched group in the time of the 6th, 12 month, the difference between two groups of negative conversion rates;
(2) hr-HPV DNA total effective rate: analytical test group and matched group in the time of the 6th, 12 month, the difference between two groups of total effective rates;
Criterion:
Turn out cloudy: the positive high-risk HPV hypotype of all when going into to organize all transfers feminine gender to;
Effectively: the positive high-risk HPV hypotype of the part when going into to organize transfers feminine gender to, still has 1 high-risk HPV hypotype positive at least;
Invalid: the positive high-risk HPV hypotype of all when going into to organize does not all transfer negative total effective rate=negative conversion rate+effective percentage to.
Annotate: the male type of high-risk-type that only occurs when going into to organize is judged, and the new high-risk-type type of appearance only carries out record during following up a case by regular visits to, does not include efficacy analysis in.
(1) infect to simple type HPV, analytical test group and matched group be the difference between the negative conversion rate in the time of the 6th, 12 month;
(2) distribution and the Susceptible population's characteristics of analysis HPV.
3.5 statistical disposition
1. the selection of statistical data analysis
● the complete analysis collection (Full Analysis Set, FAS)
● meet scheme set (Per-Protocol Set, PPS)
● FAS and PPS all are used for the statistical analysis to curative effect of medication.
● safety analysis collection (Safety Analysis Set), all go into to organize case, use the single test medication at least, and whole patients of safety record after the medication are arranged, and all belong to the safety analysis collection.This data set is used for safety analysis.
2. statistical analysis plan
Statistical analysis will adopt the SAS9.2 statistical analysis software to analyze.Do not make specified otherwise, statistical test all adopts two-sided test, and inspection level is 0.05.
All safeties and efficacy result are all described by group, when statistical analysis, to the estimation of major variable missing values, adopt (Last Observation Carry Forward, LOCF) method of carrying down near an observed value.
For comparing between continuous variable's group, for comparing between the group of group data, according to total number and minimum expectation number selection χ
2Check or definite probabilistic method.If orderly group data then adopts CMH-χ
2Check.
3.6 experimental result
Because of the curative effect data of the December of collecting very little, 12 examples only, expulsion rate reaches 96% (313/325), so 12 months efficacy analysis is not done in this analysis.Only to June curative effect analyze.Concrete outcome is following:
3.6.1 experimenter's typing situation
The selected altogether 432 routine cases of this clinical trial plan, actual typing case 325 examples, FAS collection 315 examples, PPS collection 285 examples, SS collection 315 examples.Case withdraws from reason and is and does not do inspection, directly withdraws from.
3.6.2 experimenter's dropping situations
Two routine patient's medication loss of learnings are included in and are analyzed 323 examples, blank control group 90 examples, experimental group 233 examples.Two groups of expulsion rate indifferences see table 1 for details.
Table 1 liang group expulsion rate analysis
3.6.3 efficiency evaluation
Efficacy analysis
Negative conversion rate: treat after 6 months, FAS collection and PPS collection, negative conversion rate has significant difference between two groups, p=0.0459; The total effective rate zero difference, but the effective percentage between two groups has notable difference, P=0.0361.See table 2 for details.
The analysis of table 2 curative effect index
1. simple type HPV infects (only one type viral infection)
FAS concentrates, and curative effect between two groups, negative conversion rate are variant, the effective percentage zero difference; PPS concentrates, and curative effect, negative conversion rate, effective percentage are all variant between two groups.See table 3 for details.
Table 3 simple type HPV infects the curative effect index analysis
2 compound HPV infect (only two types viral infection)
Curative effect, negative conversion rate, the equal zero difference of effective percentage between two groups.See table 4 for details.
The compound HPV of table 4 infects the curative effect index analysis
3. multiple type HPV infects (three types or above HPV viral infection)
Curative effect, negative conversion rate, the equal zero difference of effective percentage between two groups.See table 5 for details.
The multiple type HPV of table 5 infects the curative effect index analysis
Safety analysis
The adverse events tabulation
Adverse events all appears at test group, and adverse events is mainly the waist abdomen aches and pruritus, and analysis possibly be an individual variation, or the primary disease syndrome.See table 6 for details.
The tabulation of table 6 adverse events
The adverse events incidence rate
Though adverse events all occurs in experimental group, incidence rate is merely 1.3%, compares no difference of science of statistics with matched group, P=0.563, two groups of adverse events incidence rate indifferences.It is thus clear that the safety of embodiment 1 medicine medication.See table 7 for details.
Table 7 a liang group adverse events incidence rate is analyzed (SS collection)
3.7 discuss and conclusion
This test is according to testing program, and main curative effect index is negative conversion rate and hr-HPV DNA the total effective rate 6th, 12 month time of hr-HPV DNA in the time of the 6th, 12 month.
The selected altogether 432 routine cases of this test plan, actual typing case 325 examples, FAS collection 315 examples, PPS collection 285 examples, SS collection 315 examples.The characteristic equilibrium of two groups of population sociologies is comparable when selected.
Therapeutic evaluation:
Main therapeutic evaluation standard is negative conversion rate and the total effective rate of 6th month treatment back hr-HPV: treats after 6 months, and FAS collection and PPS collection, negative conversion rate has significant difference between two groups, p=0.0459; Though the total effective rate zero difference, the effective percentage between two groups has notable difference, P=0.0361.The preparation for treating high-risk HPV infection that shows embodiment 1 has certain effect.
Secondary efficacy is estimated: one of secondary efficacy standard is for infecting to simple type HPV, and analytical test group and matched group be the difference between the negative conversion rate in the time of 6th month.Simple type HPV infects after treatment in 6 months, blank control group and experimental group obvious significant difference arranged, we can see that the total effective rate of experimental group and negative conversion rate are apparently higher than blank control group.Total effective rate: the FAS collection, the preparation group of embodiment 1 is 69.81%, and the blank group is 57.89%, and the preparation group of embodiment 1 is greater than blank control group; And PPS collection matched group is greater than experimental group, and the preparation group of embodiment 1 is 77.62%, and the blank group does, 62.26%, and preparation group and the blank control group of embodiment 1 have tangible significant difference.Negative conversion rate: the FAS collection, the preparation group of embodiment 1 is 69.18%, the blank group is 52.63%; The PPS collection, the preparation group of embodiment 1 is 76.92%, the blank group is 56.60%.It is thus clear that experimental group infects simple type HPV notable therapeutic effect is arranged.
Safety evaluatio: in the test that the high-risk property of the preparation for treating cervix uteri HPV of embodiment 1 infects, though adverse events all occurs in experimental group, incidence rate is merely 1.3%, compares no difference of science of statistics with matched group, P=0.563.Adverse events is mainly the waist abdomen aches and pruritus, and analysis possibly be an individual variation, or the primary disease syndrome.Two groups of adverse events incidence rate indifferences.It is thus clear that the safety of the preparation medication of embodiment 1.
The clinical research of embodiment 6, treatment cervical erosion
1, case is selected
(1), inclusion criteria:
23～49 years old age, the women of sexual life is arranged;
Be ready also can require give the partner according to scheme;
Clinical diagnosis cervical erosion person;
Cervical smear is normal range and optimum reactive changer according to the TBS system classification.
(2), exclusion standard:
All patients with following arbitrary condition must get rid of this clinical research of entering:
Known to the interferon allergy sufferers;
Gestation or women breast-feeding their children;
Immunologic hypofunction, or take corticosteroid hormone and immunosuppressant person for a long time;
The serious heart, liver, renal function injury person;
Once accepted system or topical antiviral Drug therapy person in 1 week;
Used in 4 weeks and acted on immune medicine person;
There is unusual pap test cytologist in cervical scraping smear;
Menstrual period or menstrual cycle preceding 7 days;
(2 week in) or accepting the treatment of transvaginal administration in the recent period.
(3), cervical erosion diagnostic criteria: according to the classification of the 5th edition cervical erosion of high medical college " obstetrics and gynecology " teaching material.
Be divided into according to rotten to the corn area:
Slight rotten to the corn (I degree): rotten to the corn area is less than 1/3 of whole cervix uteri area;
Moderate rotten to the corn (II degree): rotten to the corn area accounts for 1/3～2/3 of whole cervix uteri;
Severe rotten to the corn (III degree): rotten to the corn area accounts for more than 2/3 of whole cervix uteri area.
Be divided into according to rotten to the corn type:
Simple type: the surface of rotten to the corn face is a slice red light sliding surface, and erosion is more shallow, has one deck columnar epithelium to cover;
Granular pattern: the hamartoplasia of rotten to the corn face forms granule;
The nipple type: rotten to the corn hamartoplasia is more obvious, forms a mamillary.
2, test medication and method
(1). the human interferon of medicine: embodiment 1 preparation
(2). administrated method:
The patient who meets inclusion criteria is in menstruation beginning in clean back 3 days medication.After cleaning pudendum before patient sleeps evening, with drug to vagina fornix portion.The next day once, 10 times is a course of treatment.Forbid demibain and sexual life during the medication, finish the back course of treatment in the clean back further consultation in 3～7 days of next menstruation, make observation of curative effect, severe patient suitably increases a course of treatment.
3, curative effect assessment
Researcher should be assessed according to the change result of following standard to experimenter's rotten to the corn area.
Time: be the 3rd～7 day before the medication, after the treatment end after menstruation is clean, accept for totally 2 times to observe and therapeutic evaluation.
4, criterion of therapeutical effect: adopt the percentage rate of rotten to the corn area to compare.
Recovery from illness: rotten to the corn area disappears.
Produce effects: rotten to the corn face dwindles 50% or take a turn for the better and reach more than the I degree before the treatment; Or two-stage falls in rotten to the corn type.
Effectively: rotten to the corn face dwindles before the treatment less than 50% or the not enough I degree that takes a turn for the better; Or one-level falls in rotten to the corn type.
Invalid: rotten to the corn area and type no change before and after the treatment.
5, statistical disposition scheme
(1) the case sample size confirms
Selected 250 routine experimenters, i.e. test group 125 example and matched group 125 examples of amounting to.
(2) statistical analysis crowd
A purpose treatment (Intent-to-treat, ITT) crowd
B meets scheme (Per-Protocol, PP) crowd
C safety (Safety) crowd
(3) data management and statistical analysis
All datas are carried out typing and after audit under the blind attitude is errorless, taken off blind.Adopt SAS8.2 to carry out statistical analysis, all statistical test are all used two-sided test, and the P value is less than or equal to 0.05 difference that will be considered to checked has statistical significance.The dosage data adopts the t check, does not possess the parametric test conditional indicator and adopts rank test, and counting dosage adopts X 2 test, does not possess the X 2 test conditional indicator and adopts accurate probabilistic method; Do not meet the parametric test conditional indicator with the rank test of many groups and compare in twos, ranked data are analyzed with rank test.
To main curative effect index: the relative baseline of rotten to the corn area changes, and adopts analysis of covariance model to carry out two groups relatively, must be divided into covariant with baseline in the model, considers minute, the effect at center.Simultaneously, be the basis, calculate the least square mean and 95% credibility interval thereof of two groups difference with this model.
For observing the concordance at center, also with analysis of covariance model of independent match, except that considering above-mentioned factor, also consider the reciprocal action of center and grouping in the model, and judge in 0.10 level whether mutual item is meaningful, whether has reciprocal action that is:.
6, clinical test results
The randomization crowd comprises experimenter's 250 examples; The safety crowd comprises experimenter's 240 examples; ITT crowd comprises experimenter's 240 examples; PP crowd comprises experimenter's 235 examples.
Efficacy analysis (main curative effect and less important result and analysis, efficacy evaluation) and curative effect brief summary
Variation from main research index-rotten to the corn area; The covariance result of rotten to the corn area change carried out when a variation, each time point that comprises the rotten to the corn area of time point finished with respect to the variation of baseline and treatment ITT and PP analyze; After the influence of removing baseline and each branch center; Have significant significant difference between experimental group and matched group, wherein test group reduces 17.83% and 17.91% (ITT) and obvious 7.44% and 7.56% (PP) greater than matched group.The covariance ITT analysis result that slight Asia group crowd rotten to the corn, that moderate is rotten to the corn and severe is rotten to the corn treats the rotten to the corn area change when finishing shows that also the rotten to the corn area of treatment group reduces greater than matched group.
The clinical research of embodiment 7 treatment condyloma acuminatum
Research method
1. randomized, double-blind, placebo, multi-center clinical trial are adopted in the clinical trial design, and observer's interferon is treated the clinical efficacy of condyloma acuminatum with fixed attention.
2. case is selected
(1) inclusion criteria: 18～65 years old men and women patient, the condyloma acuminatum patient of clinical definite does 5% acetic acid test (vinegar is tested in vain) in case of necessity and examines and examine; Be ready and can the partner; The written Informed Consent Form person of signature before the treatment.
(2) exclusion standard: known to interferon or placebo composition allergy sufferers; Gestation and women breast-feeding their children; Known patient immune function is low, or takes corticosteroid hormone and immunosuppressant person for a long time; Severe cardiac, liver, renal function injury person; Be selected in and preceding 1 week once accepted system or topical antiviral Drug therapy person; Act on immune medicine person with crossing in 4 weeks; The clinical trial person who participated in other in 30 days; Single wart body diameter＞0.5cm or wart body agglomerate diameter＞1cm person or wart body number are greater than 10 persons; Merge other STD persons.
(3) rejecting standard: during being tried, merge and use other antiviral drugs person; Not by regulation medication person; Further consultation person on time not; Because of untoward reaction stopped treatment person, this case is not counted in therapeutic evaluation, but counts the safety evaluatio case.
3. test drug, administrated method and the course of treatment
(1) test drug
The human interferon of investigational agent: embodiment 1 preparation
(2) administrated method
The patient gets into test according to random number, medicine is applied to wart body place, external every day 4 times.6 weeks of logotype.
(3) course of treatment
6 weeks, per 2 all further consultations 1 time.4 all nonresponders are if the patient requires to withdraw from then by invalidation.
4. observation item
(1) clinical observation
The profile (comprising mamillary, cockscomb, cauliflower, agglomerate) and the target wart body size (the wide mm of long mmX) of record wart body happening part, number, wart body before the treatment.Wart body region, number and size are write down in patient's per 2 all further consultations 1 time respectively, select some cases to take a picture.
(2) untoward reaction is observed
Record is tried any untoward reaction that the phase patient is taken place; Be recorded on the observation table; Is described, lasting time, the time of disappearance, the order of severity (light, in, heavy), the measure of handling, with the dependency of medicine (irrelevant, possibility is uncorrelated, possibly be correlated with, relevant) and lapse to the time that occurs.If serious adverse reaction takes place, no matter whether relevant with the research medicine, drug withdrawal immediately.
(3) drug combination
The used medicine of patient should be recorded in the drug combination table during being tried, and the title, dosage, medication of record drug combination is by way of, Start Date, date of expiry, indication.
5. curative effect is judged
According to recovery from illness, produce effects, progress, invalid level Four standard evaluation.
Recovery from illness: the wart body disappears fully.
Produce effects: wart body number or area reduce more than 60%.
Progressive: wart body number or area reduce 20～59%.
Invalid: wart body number or area reduce＜20% or continue to increase the weight of.
When doing therapeutic evaluation, the case of will fully recovering and produce effects case add up to effective case, calculate effective percentage.
6. data analysis and statistical procedures
Relatively with t check or rank test, the curative effect rate is relatively used X for test group and matched group physical data
2Check or accurate probabilistic method, p＜0.05 has statistical significance.
7, clinical research result
(1) comparison of wart body number before and after human interferon and the placebo treatment condyloma acuminatum
The result shows the variation of two groups of treatment condyloma acuminatum front and back average ranks of wart body and average number.Average wart body number is 3.64 ± 2.82 before the 64 example treatments of human interferon group, and it is 4.03 ± 2.45 that placebo group is treated average wart body number, and there was no significant difference on two groups of comparative statistics explains that both have comparability.Along with the prolongation of treatment time, the average rank of wart body number of human interferon treatment group reduces gradually, and average wart body number reduces gradually; During to the 4th week; With significant difference relatively appears before the treatment, in the 6th when week, notable difference appears in statistics; And relatively change not obvious before average rank of placebo group and average wart body number and the treatment; More all there were significant differences in average wart body number statistical of treatment group simultaneously and each time period of placebo group, thereby analyze from the total trend that changes of wart body number, and human interferon treatment group is being superior to placebo group aspect the minimizing wart body number.
(2) comparison of wart bulk area before and after human interferon and the placebo treatment condyloma acuminatum
The result shows the variation of the average rank of area of area and the wart body of average wart bodies before and after two groups of treatment condyloma acuminatum.Along with treatment time prolongs, average wart bulk area is organized in the human interferon treatment and the average rank of wart bulk area reduces gradually, significant difference relatively occurs during to 4 weeks with before the treatment; The 6th week the time notable difference occurred, and that placebo group wart bulk area changes before and after treatment is not obvious, and the wart bulk area between two groups during the 2nd, 4,6 weeks relatively; When the 4th week, has significant difference; Difference is more obvious during the 6th week, and after The above results showed the human interferon treatment, the area of the average wart body of 64 routine patients reduced before the treatment; Comparatively obvious during especially with the 4th week and the 6th week, placebo group is then not obvious to the change of wart bulk area.
(3) human interferon and placebo treatment condyloma acuminatum total effective rate are relatively
When testing for the 6th week,, count the total effective rate of human interferon and placebo treatment condyloma acuminatum respectively through calculating the change of each patient treatment front and back wart body number of contrast and area.Human interferon group total effective rate is 64.1% (26/64), and placebo group is 21.9% (14/64), and two groups relatively, on p value＜0.0001 statistics significant difference arranged, and explains that human interferon treatment condyloma acuminatum effective percentage obviously is superior to placebo group.
(4) cure rate of human interferon and placebo treatment condyloma acuminatum relatively
When testing for the 6th week; The cure rate of human interferon and placebo treatment condyloma acuminatum compares, and human interferon group cure rate is 40.6% (26/64), and placebo group is 9.4% (6/64); Two groups relatively; The p value is 0.0004, and significant difference is arranged on the statistics, explains that the cure rate of human interferon treatment condyloma acuminatum obviously is superior to placebo group.
(5) subjective symptoms compares before and after human interferon and the placebo treatment condyloma acuminatum
The variation of two groups of patient treatment front and back subjective symptomss.It is all lower to treat preceding two groups of patient's subjective symptoms incidence rates, does not more all have significant difference between two groups before and after the medication.
Safety evaluatio
In the course of treatment in 6 weeks, two groups of patients all do not find system's untoward reaction.The human interferon group has 4 examples local untoward reaction to occur, wherein the 3 example persons of being studied be judged as maybe be relevant with medication, mainly show as Mild edema, causalgia and pruritus; Need not special handling and alleviate; Disappear in about 2-6 days, do not influence treatment, placebo group is not found any untoward reaction.
The clinical research of embodiment 8 treatment herpes zoster
1, design principle: this test is the clinical trial of multicenter, randomized, double-blind, placebo.Intend and accomplish eligibility 100 (200 example).The experimenter goes into two parallel-group with random assortment, and end user's interferon and placebo external are 10 days respectively.Two groups of experimenter while oral vitamin B
12(methycobal is defended material (China) pharmaceutcal corporation, Ltd) 7 days.
2, go into group at random: every experimenter obtains a medicine sequence number in strict accordance with selected time sequencing; Two groups of selected experimenters' medicine sequence number adopts the computer random coded system to number in 1: 1 ratio, is acceptor's interferon or placebo to determine this experimenter.
3, test arrangement:
Local topical: D
0-9 days
4, test plan: this clinical research plan was accomplished from year March in May, 2003 to 2004.Each patient the accepts 21 days experimental observation of (maximum 28 days), experiment process sees the following form.
The ※ skin lesion disappears the back if any post herpetic neuralgia, need observe the 28th day.
5, case is selected
(1) inclusion criteria
The patient of all this clinical researches of participation must meet following whole standard:
● the skin lesion time of occurrence was less than 5 days;
● the men and women patient of age 18-60 one full year of life;
● clinical diagnosis meets the patient of herpes zoster;
● be ready and can be according to the timely further consultation of the requirement of scheme.
(2) exclusion standard
All patients with following arbitrary condition must get rid of this clinical research of entering:
● do not fill in Informed Consent Form and can not accurately narrate state of an illness person;
● head, herpes zoster facialis, blood blister and downright bad and obvious pain and influence work and the sleeper appear;
● the affected part is accompanied with other skin disease patients that significantly may have influence on therapeutic evaluation;
● local serious antibacterial of merging of erythra or fungal infection person;
● known counterweight human interferon and the similar medicine of chemical constitution have allergies person;
● known have serious immunologic hypofunction, or need take 17-hydroxy-11-dehydrocorticosterone and immunosuppressant person for a long time;
● suffer from the serious heart, liver, renal function and the disease patient of system;
● treat preceding 4 all interior system applies and cross antiviral drugs; Treat preceding 2 all interior topical application and cross antiviral drugs;
● gestation or women breast-feeding their children;
● once participated in other drug clinical trial person in 4 weeks.
6, trial drug
The human interferon of
investigational agent: embodiment 1 preparation
Commercially available vitamin B
12Sheet: trade name " methycobal ", each 500 micrograms (1), every day 3 times.
The administrated method and the course of treatment
Selected patient is by the prescription on individual diagnosis serial number.The patient embrocates the affected part with medicine, every day 4 times.Drug treatment: 10 days.While oral vitamin B
12Sheet (trade name " methycobal "), each 500 micrograms, serve on 7 days at every day 3 times.
Drug combination:
The patient does not allow to use the listed medicine of exclusion standard at duration of test.As really make medicament because of other diseases need merge, should on the case notes table, write down its title, dosage, indication, beginning and Close Date etc.In addition, generally should not give analgesic, can use analgesic (ibuprofen) or tranquilizer (estazolam), but necessary itemized record are in the case notes table pain especially severe person to the experimenter.
7, curative effect assessment
Researcher should be assessed score to experimenter's sings and symptoms according to following standard.The experimenter accepted to observe and therapeutic evaluation (cure can stop observing as 14 days or 21 days) after medication the 3rd, 7,10,14 in 21,28 days, and same experimenter's observation should be carried out strict record by same position researcher as far as possible.
(1) observation index and standards of grading
Objective indicator
1=pimple number≤25
2=pimple number＞25 ,≤50
3=pimple number＞50
1=vesicle number≤25
2=vesicle number＞25 ,≤50
3=vesicle number＞50
1=1～3 places are rotten to the corn, or rotten to the corn face diameter＜3mm, have slightly and ooze out
2=4～6 places are rotten to the corn, or rotten to the corn face 3mm≤diameter＜5mm, have moderate to ooze out
3=＞6 places are rotten to the corn, or rotten to the corn face diameter >=5mm, have severe to ooze out
The 1=skin color is light red
The red skin of 2=
3=has tangible flushing and with swelling
Subjective index
The 1=idol causes mild pain by stimulation
2=walks or causes pain when movable
The obvious pain of 3=or influence work
Time index
Each time point below the record (my god):
The therapeutic evaluation standard
Curative effect index improves percentage rate and evaluation
Calculate main, the total mark of objective indicator before and after treatment respectively, draw curative effect at last and improve percentage rate.
Base is healed: skin lesion disappears basically, and transference cure improves >=90%
Produce effects: sings and symptoms improves >=60%,＜90%
Take a turn for the better: sings and symptoms improves >=20%,＜60%
Invalid: sings and symptoms improves＜20%
Case loads * 100% of effective percentage=(produce effects example number+base heal routine number)/all
(3) compare the experimental group and the control group in terms of the difference:?
Comparative test group and matched group are in the difference of post herpetic neuralgia: the persistent period and the pain degree that have or not post herpetic neuralgia, post herpetic neuralgia
8, statistical method
The test initial data of all clinical case observation tables carries out statistical analysis with the SPSS statistical package.All case employing purpose treatment fractional analysis (Intent to Treat, principle ITT) is carried out efficiency analysis to data, and relatively a situation arises for improvement of two groups curative effect and adverse events.
Comparability for two groups of basic conditions should be carried out statistical test; Two groups curative effects are relatively carried out rank test, t check or X 2 test and definite probabilistic method (Fisher method); Can carry out U check or X 2 test to the incidence rate of adverse events, with P value＜0.05 for having statistical significance.
9, clinical research result
Human interferon treatment group and matched group compare: for the majority parameters in the objective indicator and two groups of comparison difference of subjective index all is to appear at 4-10 days, and test group obviously is better than matched group; For more preceding 14 days of two groups of erythema in the objective indicator, test group was superior to matched group, and two groups are not had significant difference after 14 days, and 21 days all objective indicators and subjective index more all do not have significant difference for two groups.
The effective percentage of comparative test group and matched group; Two groups are respectively 51.28% and 28.81% in the time of the 7th day; Two groups are respectively 80.34% and 54.24% (p=0.001) in the time of the 10th day; Two groups are respectively 90.60% and 73.73% (P=0.001) in the time of the 14th day, but have all reached more than 93% to the 21st day later two groups effective percentage, and two groups are compared not statistically significant.
The clinical research of embodiment 9 treatment herpes simplexes
The clinical efficacy and the safety of appraiser's interferon therapy recurrent herpes simplex, and and placebo.
1, design
Adopt multicenter, at random, double blinding, placebo clinical verification.
2, case choice criteria
18-65 year patient, the men and women does not limit.
The herpes simplex of clinical definite, the course of disease is within 24 hours.
Be ready and can require the partner according to scheme
Be ready and written Informed Consent Form person can be provided
The case exclusion standard
Trimester of pregnancy and women breast-feeding their children.
Known to the interferon allergy sufferers.
Immunologic hypofunction, or take corticosteroid hormone and immune formulation person for a long time
Severe cardiac, liver, renal insufficiency and central nervous system disease patient
Once accepted system or topical antiviral Drug therapy person in 1 week
Used in 4 weeks and acted on immune medicine
Participated in other clinical trial in 30 days
Other dermatological preparations person was used in merging at the skin lesion place
Get rid of other STD
Culling level
During being tried, merge and use other antiviral drugs person
Not by regulation medication person
Further consultation person on time not
Because of untoward reaction stopped treatment person, this case is not counted in the therapeutic evaluation case, but counts the safety evaluatio case
3, medicine, administrated method and the course of treatment:
The human interferon of (1) investigational agent: embodiment 1 preparation
(2) administrated method
The patient gets into test by random number, will receive the reagent thing to be applied to the skin lesion place with disinfecting cotton swab, external every day 4 times, 1 week of logotype.
(3) course of treatment
In 1 week of the course of treatment, followed up a case by regular visits to for 1 week.
4, clinical observation project:
(1). clinical observation
Clinical symptoms and sign are all with 4 grades of point system scorings
That the observation of a clinical symptoms (subjective symptom) comprises is scorching hot, twinge, pruritus, tight sense.
The observation of b clinical sign (nbjective symptom) comprises skin lesion area, herpes number, erythema swelling, erosion, incrustation time started, all forms a scab the time, beginning decrustation time, all decrustation time, no new breakout date.
(2) untoward reaction
Period in a medicine is strict observe and the kind of record adverse effect and with take medicine, the relation of drug withdrawal.For the case that stops studying because of untoward reaction, do not make the curative effect statistics, but need make the untoward reaction statistics.
5, curative effect judging standard
(1) symptom variation situation
Observe the symptom of different time,, relatively treat the 3rd, 5,6,7 day two groups of scoring situation, to judge the symptom variation situation with the average mark addition of four symptoms.
(2) sign situation of change:
Calculate the time that incrustation and decrustation begin and finish respectively, relatively two groups difference.
(3) calculating of curative effect rate
With time of whole decrustations as the recovery from illness index.Calculate the 3rd, 5,6,7 day two groups of cure rates of treatment, relatively whether two groups have difference.
6, statistical procedures
The physical data comparison of test group and matched group, curative effect rate are relatively with t check, rank test or X
2Check.
7, clinical research result
(1) physical data
66 examples are organized in treatment, male 35 examples, women 31 examples, age 18-60 year, average 34.06 ± 10.48 years old.Course of disease 0-24 hour, average 13.67 ± 8.94 hours.Morbidity part is distributed in upper lip, lower lip, bicker, lower jaw, nose, cheek, cheekbone, near the eyes, glans penis, and penis, in the foreskin, outside the foreskin, perineum, vaginal vestibule.Morbidity first is so far: 8.76 ± 19.16 years, and the number of times 3.07 ± 2.95 times of falling ill last year.Skin lesion area 93.52 ± 119.60mm
2
Matched group 56 examples, male 33 examples, women 23 examples.Age 18-65 year, average 32.8 ± 8.9 years old.Course of disease 0-24 hour, average 14.1 ± 7.8 hours.Lesion portion is distributed in upper lip, lower lip, bicker, lower jaw, nose, cheek, cheekbone, near the eyes, glans penis, and penis, in the foreskin, outside the foreskin, perineum, vaginal vestibule.Morbidity first is so far: 4.47 ± 5.9 years, and the number of times 2.8 ± 2.7 times of falling ill last year.Skin lesion area 109.4 ± 126.2mm
2Two groups of basic conditions are similar, have comparability (p＞0.05).
(2) curative effect
Treatment group and matched group be relatively: the 3rd day symptom (branchs) change amplitude, begin the incrustation time (hour), form a scab the time fully (hour), the beginning decrustation time (hour), fully the decrustation time (hour) equal not statistically significant.5th, 6,7 days symptom score change amplitude treatment groups are big, have statistical significance
(3) untoward reaction
4 examples are organized in treatment has untoward reaction, 1 routine had slight edema wherein, 1 routine moderate causalgia, the slight pruritus of 1 example; Maybe be relevant with medicine, feeling sick (patient's medication first day) appears in 1 example in addition, maybe be irrelevant with medicine; Matched group 1 routine moderate causalgia continues 1-3 days, all stopped treatment not.
The above only is a preferred implementation of the present invention; Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; Can also make some improvement and retouching, these improvement and retouching also should be regarded as protection scope of the present invention.
Claims (10)
1. the purposes of human interferon in the medicine of preparation treatment or prevention HPV relevant disease.
2. purposes according to claim 1 is characterized in that said human interferon is selected from human interferon-alpha, human interferon beta and human interferon gamma.
3. purposes according to claim 2 is characterized in that, said human interferon-alpha is selected from human interferon alpha 1 b, human interferon-alpha 2a, human interferon-alpha-2 b and said three kinds of proteic derivants and analog.
4. purposes according to claim 1 is characterized in that, said human interferon is natural human interferon or recombinant human interferon alpha 2.
5. purposes according to claim 1 is characterized in that, said HPV relevant disease infects for simple type HPV.
6. purposes according to claim 1 is characterized in that, said HPV relevant disease is the persistent infections of high-risk HPV reproductive tract.
7. purposes according to claim 1 is characterized in that, said HPV relevant disease is cervical erosion, condyloma acuminatum, genital herpes or herpes labialis, herpes zoster, skin carcinoma, cervical cancer, verruca plana, the change of cervical epithelial cells tumor.
8. purposes according to claim 1 is characterized in that, the method for preparing of said medicine is following:
Step 1: in human interferon stock solution, add the human albumin and obtain mixed solution, making the albumin final concentration is 1%-5%, adds and the isopyknic stabilizing agent mixing of mixed solution heating in water bath 0.5-3min, lyophilization powdered;
Step 2: after taking by weighing sodium carboxymethyl cellulose 50-200g, glycerol 500-1500ml, sorbic acid 10-20g mixing, add the injection water, be heated to 60-100 ℃ of mixing, when treating that substrate is cooled to 10-40 ℃, transfer pH to 4.0-9.5 to 10000g, subsequent use;
Step 3: step 1 human interferon powder is added to the substrate mix homogeneously that step 2 prepares, and packing promptly gets.
9. purposes according to claim 1 is characterized in that, adds interferon powder 1.0 * 10 in the method for preparing of said medicine in every 1000g substrate
6-1.0 * 10
9Iu.
10. according to Claim 8 or 9 described purposes, it is characterized in that said human interferon is a human interferon-alpha-2 b.
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Application publication date: 20120801 |