CN1927390A - Compound recipe interferon vaginal spray for preventing and treating human viral infection - Google Patents

Abstract

The invention relates to a formula of compound interferon vaginal mist, and relative production, and packing device. Wherein, it can treat papilloma virus (HPV), herpes simplex virus (HSV-2), etc, which will caused original cancer, etc. And the invention is formed by following components as interferon, herpes simplex virus, polysaccharide, and other cell factors, baffle solution and salt. And via special long ejector vaginal mist device can directly disperse the drug to needed part.

Description

A kind of compound interferon vagina spray of preventing and treating the novelty of Human virus's infection

The present invention relates to a kind of prevention and treatment women human papillomavirus (HPV), herpes simplex virus I I type (HSV-2), the novel prescription and the device of the YC compound interferon vagina spray that cytomegalovirus (CMV) infects belong to the field of pharmaceutical preparations of pointed treatment indication.

Background technology:

1. human papillomavirus (HPV) infects

The papillomatosis viral disease is the modal sexually transmitted disease (STD) in the whole world.Report that recently whole world adult over half is infected by human papillomavirus.Human papillomavirus (HPV) has many types, and that has identified at present reaches 100 more than the type, and it infects specific part or causes the specific clinical symptom, has 30% trafficability characteristic to propagate approximately.Have report to point out, 77%HIV is positive, and the women also is the HPV positive simultaneously.Different with other sexually transmitted disease (STD), HPV is very easy to be propagated by directly contacting with the skin that infects or with the article that pollute.U.S.'s data shows that nearly 1,000 ten thousand American Women have activeness HPV and infect, and wherein great majority are more than 10 year old and more than 20 year old.

At present, from different people's lesion tissue, the HPV that has cloned reaches 100 more than the type.The form of HPV virion is shown in Figure of description 1.The relation of HPV and human diseases sees the following form:

Table 1 HPV and disease relationship catalog

Disease	Carcinogenecity	The HPV type
			The height maldevelopment of genitals mucous membrane; Intraepithelial neoplasia forms and cervical carcinoma nasal cavity papilloma; Unusual and the cancer anus of epithelial development, (epithelial development is unusual, intraepithelial neoplasia formation (I and II degree) verruca vulgaris oral cavity, penis wart oral cavity kitchen range epithelial proliferation for genitals condyloma acuminatum (Condylomata acuminata) (property wart) chronic cervicitis	A:carcinogenecity height; B: C in the carcinogenicity: carcinogenicity is low often be optimum 6,11 often be optimum 16 carcinogenicity height often be optimum often be optimumly may develop into cancer	A：16，18 B：31，33，35，39，45，51，52，56，58，59， 68，C：6，11，26，40，42，43，44，53，54，55，62，66 6，11，57； 6，11，2，40，57 6.11.16. 6，11 6，11，57 13，32；

The sick sample papule of (HeckShi disease) young people and the sudden larynx papilloma lip wart venereal disease kitchen range papilloma of conjunctiva of adult deep toe and palm myrmecia skin verruca vulgaris teenager's flat wart (Verrucae planae) epidermodysplasia verruciformis disease (Epidemodysplasia verruciformis) toe wart and verruca vulgaris pityriasis versicolor spot (Pityriasis versicolor macules) meat and the care of animal personnel's verruca vulgaris BowenShi; Larynx, esophageal carcinoma, some bronchogenic carcinoma wart, immunodeficiency patient skin wart is accepted renal transplantation person's skin, the sick keratoacanthoma of the non-genitals BowenShi of middle wart laryngeal carcinoma (Kerato-acanthoma) multiple condyloma latum of Bowenoid focus and skin verruca plana genital wart in a melanoma

Often be optimum often be optimum often be optimum optimumly seldom to worsen at least 12,17 and 20 and can worsen and optimumly have 30% can to worsen often be that the unknown carcinoma in situ of optimum pernicious the unknown is optimum pernicious optimum optimum

11，6 2 6，11 1 2，3，10，28，40，57 3，10，28 3，5，8，9，10，12，14，15，17，19，25，28，36，40 4 5，8 7 16，18，31，35，39 16，18，31，35，39 26 27 29 30，40 34 37 38 40 41 42

2. the main pathogen of chronic cervicitis is human papillomavirus (HPV), human herpes simplex vicus II type (HSV-1) and human cytomegalic inclusion disease virus (CMV) etc.

In the human diseases that above-mentioned HPV causes, the HPV of woman uterus infects the most common, and hazardness is also maximum.At the band place, district of cervical mucosa columnar epithelium and squamous epithelial cancer transformation, be the position of having a liking for the breeding of mucosa human papillomavirus, also be the predilection site of chronic cervicitis.HPV is the main pathogen of chronic cervicitis.

Chinese Key State Laboratories Virogene Engineering For Virogene Engineering in 1989 and Beijing Tiantan Hospital's joint study are found, chronic cervicitis (cervical erosion) and human papillomavirus (HPV), herpes simplex virus (HSV), cytomegalovirus (CMV) and chlamydia infection relation are very close.From chronic cervicitis patient's cervix uteri, the recall rate of three kinds of viruses all is higher than normal cervix significantly, and the generation of these three kinds of viruses and chronic cervicitis is described, particularly infects relevant with human papillomavirus 16 types (HPV16).Thereby be the object of interferon therapy.

In 1987 ends dimension and waits employing recombinant human interferon-alpha treatment cervical erosion, finds that interferon has fairly obvious curative effect to this commonly encountered diseases.146 routine patients of cervical ruin reach 93.8% with the total effective rate of human interferon-alpha treatment, and wherein obvious effective rate is 60%, and are suitable with natural LeIF with dosage; Obvious effective rate with conventional medicine FUYANLING treatment is 37.7%, and interferon therapy still keeps obvious curative effects after 12 months.The recall rate of virus also obviously descends behind the interferon therapy.

3. cervical HPV infection and cervical cancer are in close relations

At present, the human papillomavirus be the human tumor virosis because of in an of paramount importance viroid.Optimum and the malignant tumor relation of it and human skin and mucosa is the closest.

The main diseases that cervical HPV infection is not only chronic cervicitis is because of, or the original cause of disease of cervical cancer.At present, a large amount of studies show that, before cervical cancer takes place a series of abnormal cell change is arranged, these abnormal cell changes (dysplasia) are called CIN I, II, III (cervical intraepithelial neoplasia), wherein CIN III promptly is a cancer in situ.Past just thinks that HPV infects and CIN I, II, and III is in close relations, is called HPV-associated CIN I, II, III.

Check that the conventional method that changes before the cancer of cervical HPV infection and cervical cancer is the Pap plate coating checking.Many evidences are arranged in recent years, illustrate that HPV can cause CIN, under the effect of cofactor, can develop into cervical cancer:

1. change before Zu Zhi the cancer relevantly with the human papillomavirus of some type regularly, as anogenital BowenShi disease, the Intradermal tumor forms (CIN) etc. on the cervix uteri.

Cervix uteri Pap plate coating checking is divided into 3 degree with CIN: mainly be the degree of depth that enters the epithelium of cervix uteri layer according to undesired cell, and mitotic active degree and atypical nuclear:

CIN 1: 1/3 thickness of only invading the cervix uteri top layer;

CIN 2: 2/3 thickness of invading the cervix uteri top layer;

CIN 3: the through thickness of invading the cervix uteri top layer.

But all CIN I, II, III often invade the sub-fraction of cervix uteri.CIN I, II are equivalent to gently, the abnormal development of moderate (dysplasia); CIN III is equivalent to serious abnormal development, or is called cancer in situ (carcinoma-in-situ); But not cervical cancer.Cervical smear can illustrate whether there is CIN, but can not affirm the degree of depth that undesired cell is invaded sometimes, need carry out the cervix uteri biopsy in case of necessity.

2. around uterus carcinoma, cloudy neck cancer, pudendum and anus, can detect the HPV DNA sequence regularly in the cancerous tissue.Have in 97.9% the cervical cancer tissues and can find the HPV DNA sequence, mainly be HPV16 or HPV18, but zonal difference is arranged.The year morbidity number of World Health Organization's report whole world cervical cancer is 450,000 people.

The dimension of ending money waits (1986) to find that in chronic cervicitis patient's the cervical tissue and washing liquid, the recall rate of HPV16 can be up to 20-50%.

3. be not only cervical cancer tissues and all contain the HPV DNA of HPV16, HPV18 or other type from the cell strain of cervical cancer such as HeLa, SIHA and CASKI, the latter site or whole being associated with of a plurality of site on chromosome are transcribed.

4. histology's pathological change before the cancer of human reproduction's device, caused pathological change is corresponding to when infecting with the animal teat tumor virus, as usual have a recessed ghost (Koilocytosis).

5.HPV having necessarily, the existing way of DNA and canceration process get in touch.In the precancerosis kitchen range, HPV DNA is free state, then is integrated state in the infiltrating carcinoma histiocyte, and certain integration site is arranged, promptly between E1-E2.

6. the district occurred frequently of cervical cancer, the generation of carcinoma of penis is also higher.

In view of the above, be diagnosed as CIN after, have time enough to treat intervention, the HPV that in time treats cervix uteri infects and also can think to prevent a kind of measure of cervical cancer.

Recent study person has identified that the HPV that 18 types are arranged is relevant with cervical cancer.Most of type past knows wherein have 3 types to classify as in the list of " possibility ".Data is published on " The New England Journal ofMedicine " magazine of publishing February 6.

In fact all cervical cancers are caused by HPV that all the latter spreads through sex intercourse.The type of having identified at present surpasses 80, wherein only has about 30 relevant with canceration.Point out that by the article that the Dr.Thomas Wright of Columbia university department of medicine and surgery institute delivers simultaneously most cervical cancers all contain a kind of among the HPV DNA of 18 types.

Cervical cancer is second modal cancer of women in the world, sees in developed country more.

Nineteen ninety-five cancer research international body (IARC) points out have enough evidences to classify HPV 16 and 18 as carcinogen.Last Nov, it is highly effective to suppressing HPV 16 that researcher declares to develop a kind of vaccine, and the cervical cancer to 50% is all effective.

Now, the author of research, except that 4 pieces of past (IARC nineteen ninety-five bulletin the basis), collected 7 pieces of research papers again, in addition reductive analysis.These 11 parts of research reports are from cervical cancer women and 1,928 cervical cancer women of 9 countries and 1,918 conclusive evidence.The result shows that 91% cervical cancer patient can detect HPV DNA, and the contrast women is 13%.

The modal type of cancer patient is followed successively by: 16,18,45,31,33,52, the 58 and 35. modal types that detect of matched group women are: 16,18,45,31,6,58,35 and 33.

According to these data, there is the HPV of 15 types to incorporate into to high-risk.These are: 16,18,31,33,35,39,45,51,52,56,58,59,68,73 and 82.3 types in addition: 26,53 and 66 classify as may be high-risk type.It is other that 12 types are divided into low risk.

4. human interferon

According to interferon (interferons, IFNs) definition, interferon is that a class has broad-spectrum antiviral, anti-cell division, immunoregulatory activity and influence the protein of metabolism, growth and the differentiation of cell on different approaches at least on the allogenic cell, and its active performance needs new synthetic RNA and protein.It is the important cytokines of a class.Basis and clinical research through nearly half a century illustrate that it is a kind of important broad-spectrum antiviral, antineoplaston medicine.

Interferon at first with the specific cell receptors bind, by the signal transmission, active cell gene expression, thereby the performance interferon biologic activity:

1. antiviral activity: suppress duplicating of viral gene.

2. cell proliferation activity: the change of cell membrane; The change of cytoskeleton; The irritation cell differentiation; Regulate the expression of somatomedin; Suppress the expression of oncogene; Reverse the phenotype that worsens cell; Activate the p53 expression of gene.

3. immunoregulatory activity: the expression of inducing other cytokines; Activating macrophage, the NK cell; Raise the expression of HLA I and II; Regulate the expression of tumor associated antigen.

So far, there are a plurality of types in human interferon: interferon-' alpha ', and β, δ, γ, ε, κ, λ, τ, ω, types such as limitin, their main feature and possible clinical practice are different.

At present, study more and be used for the α that has of clinical treatment, beta, gamma; Whether other type interferon has clinical value still among research.

5. Human Inter Leukin-2 (IL-2)

IL-2 is produced by the TH1 cell, can promote the growth of T cell, strengthens the NK cytoactive, induces or promotes the toxic activity of various kinds of cell, collaborative B cell proliferation and the secretion Ig etc. of stimulating.Drugs approved by FDA IL-2/125S mutant treatment renal carcinoma in late period and melanoma.China SDA ratifies plan far away glad (IL-2/125C) treatment late period renal carcinoma, melanoma, cancer ascites and tuberculosis.Gene mapping: people: 4q26-28; Mus: 3B-C.

Extrasin beta 4 (Thymosin-beta-4, TB4):

TB4 is made up of 43 aminoacid, and N holds acetylation, extracts from cattle thymus gland the earliest.Some cell line also can produce TB4, comprises sarcoplast, fibroblast; Some people's medullary substance thyroid carcinoma also can produce.By inducing TB4 in the atomization of the inductive medullary cell of GM-CSF.The 6-26 homology that people TB4 and human interferon induce is also with the Fx homology that relates to actin polymerization.

The fusion rotein of TB4 and TNF is observed obvious antineoplastic after injecting and having the animal of experimental tumor.The half-life of fusion rotein in serum is longer than TNF, can also cause dwindling of tumor under the concentration of TNF non-activity.

TB4 can promote the epidermis wound healing significantly, and mechanism is different from epidermal growth factor, does not cause canceration.

7. the HPV that spreads through sex intercourse of interferon therapy infects

Up to now, delivered many bibliographical informations both at home and abroad, proved that interferon forms treatment chronic cervicitis, Cervical intraepithelial neoplasia and the prevention cervical cancer has certain effect.

The document that the applicant delivers:

1. money ends dimension ... Hou Yunde: the curative effect China journal of obstetrics and gynecology 22:335 of people r α D type interferon therapy chronic cervicitis, 1987

2. money ends dimension ... Hou Yunde: people's recombinant alpha D type interferon and Radix Astragali use in conjunction treatment cervical erosion combination of Chinese and Western medicine magazine 7:268,1987

3. money ends dimension ... Hou Yunde: the due to illness malicious journal 3:18 of the virosis of chronic cervicitis, 1987

4.Qian Zhiwei，Hou Yunde et al：A study on the efficacy of a recombinant human alphaD type interferon in treatment of chronic cervicitis J.Interferon Res.6：suppl.1：34，1986

5. money ends dimension ... Hou Yunde: the cervical HPV viral infection is to the experiment of therapeutic response China and clinical virology magazine 1:60,1987 of Radix Astragali interferon

6.Qian Zhiwei…Hou Yunde et al：Viral Etiology of Chronic Cervicitis and itsTherapeutic Response to A Recombinant Interferon Chinese Medical Journal103(8)：647-651，1990

7. interferon cooperative groups: the routine observation of curative effect of the α 1 type genetic engineering interferon treatment chronic cervicitis of choosing outward 673 China Journal of Immunology 1990,6:21

8. money ends dimension ... Hou Yunde etc.: the research China journal of obstetrics and gynecology 25 (5): 266,1990 of cervix uteri common virus and chlamydia trachomatis infection

9. money ends dimension, Li Yuying, and Hou Yunde etc.: the cause of disease research sex medicine of cervical virus and chlamydia trachomatis infection and sexually transmitted disease (STD) progress, p.1-2,1990

10. money ends dimension, Li Yuying, Yang Xin section, Hou Yunde etc.: the virosis of chronic cervicitis because of and to the therapeutic response sex medicine and the sexually transmitted disease (STD) progress of recombinant interferon, p.3-6, nineteen ninety

11. money ends dimension, Zhang Jinghua, and Wu Guangqin ... Hou Yunde: the mother-to-baby transmission China journal of obstetrics and gynecology of cervix uteri HPV 16 infection, 28 (45): 242-2

End dimension 12. open elegant imperial money: the achievement in research China journal of obstetrics and gynecology 32 (1), 1997 of cervical erosion area measuring method

13. Shu Lili, Hou Yunde etc.: in the woman uterus condyloma latum, find a kind of HPV correlated series virus journal 5:268,1989

18. the king is gentle greatly etc.: the observation of curative effect Chinese biological goods of external α 1 type genetic engineering interferon treatment chronic cervicitis are learned magazine 6:(special edition 1), 24,1993

19. Hu Minhua, Zhang Jinghua, money ends dimension ... Hou Yunde: wait the blocking effect of recombinant human alpha 1b interferon to the mother-to-baby transmission of cervix uteri HPV 16.Beijing medical science 20 (4): 276-278,1998

20. Li Yu English, Yang Xin section, Hou Yunde etc.: the virosis of chronic cervicitis because of and to the therapeutic response sex medicine and the sexually transmitted disease (STD) progress of recombinant interferon, p.3-6, nineteen ninety

21. section is refined quick, Yang Xin section, Guo Jinjin etc.: the infection between the mother and baby of HPV 16 and cytomegalovirus and experiment of propagation China and clinical virology magazine, 10 (4): 389,1996

22 Yang Xin sections, Duan Shumin, Hou Yunde: anemia of pregnant woman-neonate HPV-16 birth canal is propagated experiment of research China and clinical virology magazine, 6 (4): 334-336,1992

23. Yang Xin section, Duan Shumin, Guo Jinjin etc.: interferon is to the experiment of inhibitory action China and the clinical virology magazine of anemia of pregnant woman's birth canal virus, 10 (2): 122-123,1996

24. the refined quick Yang Xin of section section, # Guo Jin Tianjin: experiment of influence China and clinical virology magazine 10 that interferon therapy is propagated through birth canal mature anemia of pregnant woman's cervix uteri HPV 16,2:189,1996

25. open beautiful blue Liu # Yongqing, # Yu Zhi love etc.: the experiment of effect China and the clinical virology magazine 12 of the Radix Astragali and interferon mixture anti-herpes simplex virus, 3:269-271,1998

8. the problem that current interferon therapy cervical HPV infection exists

In inventor's's eighties clinical trial, in view of having a liking for the junction (also being the predilection site of cervical cancer) that mucosa HPV infects the columnar epithelium and the phosphorus columnar epithelium that mainly occur in cervix uteri, in order to judge curative effect exactly, adopt the mode of hospital doctor administration, under the help of vaginal dilator, have the gauze of 1 milliliter of interferon liquid (1,000,000 unit) directly to stick on the cervix uteri infiltration, expose outside vagina with a cotton thread, pulled out by patient oneself next day.But this administering mode does not become a kind of dosage form of medicine.So we are considering to develop suitable dosage form always, interferon directly can be rendered to the cervix uteri part.

After our work was delivered, since the nineties, there were many producers in China, had developed the multiple dosage form of interferon therapy chronic cervicitis in succession, comprised suppository, gel, effervescent etc.But above-mentioned dosage form is not really desirable, and according to a series of research work (seeing document in addition) that we carried out in the eighties, also there are the following problems:

1. vagina is about 7-9 centimetre from vestibule to preceding arched roof; Be about 10-12 centimetre from vestibule to the back arched roof; When above-mentioned dosage form pushed vagina with finger, most of at the middle part of vagina, because the area maximum of vagina upper end, the major part of administration was difficult for directly arriving cervix uteri.

2. patient oneself advances administration with finger, if patient without sterile glove or fingerstall, is easy to pollute.

3. in the present dosage form, interferon dosage is on the low side: the contained interferon of dose is mostly below 500,000 units; And we are studies show that of the carrying out eighties, and the effect that one time 500,000 unit interferon all sticks on cervix uteri only is half of 1,000,000 units.

4. interferon and other effect of cytokines mechanism roughly the same, it is not duplicating of direct blocking virus; But,, activate series of genes through the signal transmission by combining with cell receptor, make cell produce a series of so-called anti-viral proteins again, the effect that the performance antiviral duplicates; Suppository, gel dosage form slowly discharge interferon in a small amount, just might produce the physiological low reaction phase, are unfavorable for treatment.

Though in international literature, have the author to report that the interferon therapy cervical HPV infection has certain effect, but effect and not really desirable mainly is that administering mode is undesirable.

Content of the present invention:

1. the prescription of a YC compound interferon vagina spray

The present invention provides a kind of YC compound interferon vagina spray prescription of novelty, the preparation method and the device of product for the problem that overcomes current interferon therapy cervix uteri parillomarvirus infections existence, be used for the treatment of chronic cervicitis, the epithelium of cervix uteri dysplasia, comprise that Cervical intraepithelial neoplasia forms I, II, III degree (cancer in situ), suppress HPV, herpes simplex virus I I type (HSV-2), the breeding of cytomegalovirus (CMV) etc., the prevention cervical cancer.Described novel YC compound interferon vagina spray contains following component: human interferon, and human albumin matter, natural polysaccharides etc. can contain or not contain other human cell factor and buffer.

1.1., it is characterized in that described human interferon is various interferon and a hypotype thereof natural and reorganization as summary of the invention 1 described YC vagina spray component, as α 1b, α 2a, α 2b, β 1a, β 1b, γ etc.

1.2. as the described natural human interferon of summary of the invention 1.1., it is characterized in that, described natural human interferon by on people's cell culture (human blood leukocyte or primitive cell culture or diploid cell strain cultivate or the cell line cultivation of immortalization etc.) by inductive human interferons of other all interferon induceres such as any virus or double-stranded RNAs.

1.3., it is characterized in that described recombinant human interferon alpha 2 is by antibacterial (as escherichia coli) as the described recombinant human interferon alpha 2 of summary of the invention 1.1., fungus (as yeast) or the various recombinant human interferon alpha 2 of producing by mammalian cell.

1.4., it is characterized in that described human albumin is from the human albumin of people's blood extraction on every side purification or the human albumin of being produced by recombinant technique as summary of the invention 1. described YC vagina spray components.

1.5. as summary of the invention 1. described YC vagina spray components, it is characterized in that, described natural polysaccharide comprises hypromellose, hyaluronic acid, cellulose, starch, chitin, chitosan and derivant thereof, can be wherein a kind of, or the combination in any of these natural polysaccharides.

1.6. as summary of the invention 1. described YC vagina spray components, it is characterized in that also can contain other cytokine, comprise the various types of cells factor that can promote the local immunity reaction and promote wound healing, comprise Human Inter Leukin-2 natural or reorganization, 12, natural or recombinate thymosin-β 4, lactoferrin natural or reorganization etc.

1.7., it is characterized in that also can contain certain density estrogen, as estradiol, ethinylestradiol, diethylstilbestrol etc. as the described YC compound interferon of summary of the invention 1.6. vagina spray.

1.8. as summary of the invention 1. described YC compound interferon vagina sprays, it is characterized in that also can contain certain density buffer solution, these comprise acetate buffer solution, citrate buffer solution, phosphate buffer etc., and pH is 3.5 ~ 5.5, are complementary with the sour environment of vagina.

1.9., it is characterized in that this product is a sterile product, wherein contains the human albumin, and does not contain any to vaginal mucosa antiseptic excitatory as summary of the invention 1. described vagina sprays.

2. because the human interferon among the present invention, other cytokine and human albumin and natural polysaccharide exist highly effective synergism in the prescription of medicine, the special medicine of Cai Yonging is sent mode in addition, increased the time of staying of interferon, thereby increased the effectiveness of interferon anti-reflecting virus significantly at cervix uteri and vagina epithelium.Disclosed YC compound interferon composition proposal of the present invention and can be good at being applied to vagina and send biopharmaceutical macromolecular drug, human papilloma virus infection has been had good prevention effect.

3. the indication of YC compound interferon vagina spray of the present invention is characterized by prevention and treats human papillomavirus, human herpes simplex vicus, the human cytomegalovirus infection of female sex organs.

3.1. the indication of content 3 described YC compound interferon vagina sprays is characterized by and comprises other HPV of all models, and particularly relevant 6,11,16 with cervical cancer and condyloma acuminatum, 18,26,31,33,35,39,40,42,43,44,45,51,52,53,54,55,56,58,59,62,66,68 types such as grade.

3.2. infect as the described HPV of summary of the invention 3.1., the position that it is characterized by the HPV infection is at positions such as women's cervix uteri, vaginal wall, vestibule, labia, perineums.

3.3. as the described indication of summary of the invention 3.1., its feature also is to form (Cervical Intraepithelial Neoplasia, I, II, III) with the closely-related Cervical intraepithelial neoplasia of HPV.

3.4. as summary of the invention 3 described indications, its feature also is the cervix uteri chronic infection that is caused by HPV, HSV, CMV etc. or claims chronic cervicitis or cervical erosion.

4, as summary of the invention 1. described YC vagina sprayer units, it is characterized in that it being a kind of special, that be suitable for the cervix uteri anatomical structure, disposable, quantitative long nozzle type vagina sprayer unit, can medicine directly be delivered to the pathological changes part by patient oneself.

5, YC compound interferon vagina spray treatment genitals viral infection, the international initiative of prevention cervical cancer system.

Characteristics of the present invention:

1. the characteristics of vagina spray prescription are:

(1) dosage of interferon has scientific basis: according to our clinical trial of 1985-89; Directly stick at cervix uteri, be at least 1,000,000 units at every turn.

(2) contain finite concentration IL-2 in the spray, its effect has 2:

1. expand blood capillary, be beneficial to the effect of medicine;

2. stimulate the body cell immunoreation, the latter is relevant closely with viral infection.

(3) spray contains 0.1% chitosan or other polysaccharide, increased the viscosity of spray, prolonged spray, can expand the intercellular substance of epithelium layer simultaneously in the time that mucomembranous surface stops, interferon is entered in the mucous epithelium, give full play to the effect of interferon.

(4) contain certain density TB4 in the spray, can promote the reparation of epithelium of cervix uteri.

(5) spray is acid, does not destroy the sour environment of vagina;

(6) do not contain in the spray any may be to vaginal mucosa antiseptic excitatory;

(7) spray Production and Packaging under aseptic condition, the possibility of polluting because of using has repeatedly been got rid of in every bottle of disposable use.

2.YC the characteristics of vagina spray vagina administration:

(1) the YC vagina spray can directly be sprayed to cervix uteri with interferon, i.e. the position of virus breeding according to the anatomical characteristics of vagina and uterus.

(2) disposable medicine bottle, safety not only, and also dispensing dosage is accurate.

(3) if when labia and perineal position have HPV to infect simultaneously, be easy to expand new indication.

(4) the spray nozzle length of YC vagina spray is 7 centimetres, and patient oneself can guarantee that in the calculi position administration medicine arrives cervix uteri mouth and cervix uteri arched roof district on every side.

The specific embodiment:

Embodiment 1: according to the spray of vagina anatomic characteristic design

Female internal genital organs be per vaginam, cervix uteri, uterus, fallopian tube and ovary form.

Vagina: vagina is the garden cylindricality, is one and has tube chamber highly expansionary, muscle, divides front and rear wall, two ends up and down; Antetheca is shorter, is about 7-9 centimetre; Rear wall is longer, about 10-12 centimetre.The upper end broad surrounds cervix uteri.Part around cervix uteri is called the vagina arched roof, divides front, rear, left and right 4 parts, and vaginal part of cervix protrudes from the vagina upper end.Lower ending opening is in the vaginal vestibule rear portion.Narrow than the upper end.The vagina front and rear wall pastes mutually at ordinary times, makes transverse section, vagina bottom be H shape.From vestibule up to the uterus.The mucosa that the vagina tube chamber covers, color is light red, is covered by stratified squamous epithelium.

Cavity of uterus and cervix uteri: uterine cavity is a triangle wide at the top and narrow at the bottom.Form the narrowest part and be called isthmus uteri between body of uterus and cervix uteri, be about 1 centimetre in the non-pregnancy period, its lower end links to each other with the cervix uteri inner chamber.The upper end of isthmus uteri because of narrower anatomically, is called anatomical internal os again; The lower end of isthmus is organized in this and changes cervical mucous membrane into by endocorvix, claims histological internal os again.The cervix uteri inner chamber is fusiformis, claims cervical canal, and it is 3 centimetres that the adult women is about, and its lower end is called the external os of vervix, connects vaginal vault, so cervix uteri is the boundary with the vagina facies posterior hepatis, is divided into two parts, i.e. portio supravaginalis and portio vaginalis.The lower part that is the uterus protrudes in the vagina tube chamber, and there is mouth the centre, and menses can flow out, and sperm can enter the uterus.The columnar epithelium of cervix uteri and squamous epithelial cancer junction are the locations of HPV breeding.

When the human body bed, when being in calculi position, cervix uteri is the most approaching with the back arched roof, and when being in this position, the atomizer spray thing can reach around the cervix uteri.

According to the anatomical features more than the cervix uteri, we have developed the vagina spray device, see Figure of description 8.Form by 3 parts altogether: drug bottle, atomizing pump and spray arm.

Embodiment 2: the every bottled amount labelled amount 1.0ml of vagina spray of our invention, and it is as follows to write out a prescription:

Recombinant human interferon alpha 2 b (escherichia coli): 3,000,000 IU/ml

Human albumin: 0.5%

Sodium chloride: 0.7%

Chitosan: 0.1%

Acetate buffer (pH4.5): 50mM

With the chitosan dissolving, be mixed with 1% mother solution, and the acetate buffer (pH4.5) of preparation 1M, according to prescription concentration each component is mixed then, stir evenly, after the aseptic filtration, divide to be filled in the sterilized above-mentioned sprayer unit.

Embodiment 3: the every bottled amount labelled amount 1.0ml of vagina spray, and prescription can be as follows:

Recombinant human interferon beta: 1,000,000 IU/ml

Human albumin: 0.5%

Recombination human interleukin-2 20 ten thousand IU/ml

Sodium chloride: 0.6%

Hydroxypropyl emthylcellulose: 0.5%

Citrate buffer (pH5.0): 50mM

With the hydroxypropyl emthylcellulose dissolving, be mixed with 2% mother solution, and the citrate buffer (pH5.0) of preparation 1M, according to prescription concentration each component is mixed then, stir evenly, after the aseptic filtration, divide to be filled in the sterilized above-mentioned sprayer unit.Embodiment 4: the every bottled amount labelled amount 1.0ml of vagina spray, and prescription can be as follows:

Recombinant human interferon alpha 1 b: 10 μ g/ml

Human albumin: 0.5%

Extrasin beta 4 20 μ g/ml

Sodium chloride: 0.6%

Chitin: 0.5%

Phosphate buffer (pH5.5): 50mM

With the chitin dissolving, be mixed with mother solution, and the phosphate buffer (pH5.5) of preparation 1M, according to prescription concentration each component is mixed then, stir evenly, after the aseptic filtration, divide to be filled in the sterilized above-mentioned sprayer unit.

Embodiment 5: the every bottled amount labelled amount 1.0ml of vagina spray, and prescription can be as follows:

Recombinant human interferon alpha 2 b (Chinese hamster ovary celI): 3,000,000 IU/ml

Human albumin: 0.5%

Sodium chloride: 0.7%

Genuine milk ferritin 20 μ g

Chitosan: 0.05%

Cellulose: 0.1%

Acetate buffer (pH4.0): 50mM

With chitosan and cellulose dissolution, be mixed with mother solution, and the acetate buffer (pH4.0) of preparation 1M, according to prescription concentration each component is mixed then, stir evenly, after the aseptic filtration, divide to be filled in the sterilized above-mentioned sprayer unit.

Embodiment 6: the every bottled amount labelled amount 1.0ml of vagina spray, and prescription can be as follows:

Recombinant human interferon alpha-2: 3,000,000 IU/ml

Human albumin: 0.5%

Extrasin beta 4 20 μ g/ml

Human IL-2: 200,000 IU/ml

Sodium chloride: 0.6%

Hyaluronic acid: 0.1%

Acetate buffer (pH3.8): 50mM

Each solid constituent is dissolved respectively, be mixed with mother solution, and the vinegar salt buffer (pH3.8) of preparation 1M, according to prescription concentration each component is mixed then, stir evenly, after the aseptic filtration, divide to be filled in the sterilized above-mentioned sprayer unit.

Embodiment 7: the using method of this spray is: 2-3 time weekly; Each 1.0 milliliters; 2-3 week is a course of treatment continuously.Patient's self-administer before sleeping, takes calculi position that spray nozzle is directly pointed to cervix uteri every night.Medicine is sprayed into; Every bottle of medicine is disposable use.Use 6 bottles a course of treatment.

Embodiment 8: this spray curative effect judging standard:

The cervical erosion case:

The recovery from illness: cervix uteri is smooth, rotten to the corn reduction of area little 2 the degree (promptly transferring the I degree well to) by the III degree or more than.

Produce effects: rotten to the corn area dwindles 1 degree (promptly transfer the I degree well to by the II degree, the III degree transfers the II degree well to);

Effectively: rotten to the corn area dwindles or the not enough I degree that takes a turn for the better.Or rotten to the corn area do not have and dwindles and granule becomes simple type, and the nipple type becomes granular pattern.

Invalid: rotten to the corn area does not dwindle or enlarges;

Calculate two groups of cure rates, obvious effective rate.

The CIN case:

Recovery from illness: HPV is cloudy to be changeed, and the Pap smear is cloudy to be changeed.

Produce effects: HPV is cloudy to change the Pap smear: the CIN rank reduces the I degree; Or the cloudy commentaries on classics of HPV, the CIN rank reduces the II degree

Effectively: HPV is cloudy to be changeed, and the Pap smear: the CIN rank does not have change; Or the cloudy commentaries on classics of HPV, but the Pap smear: the CIN rank reduces the I level.

Invalid: HPV lasting masculin and Pap plate coating checking, CIN rank no change or increase the weight of.

Have cervical erosion and CIN patient concurrently, two kinds of situations are added up respectively.

Claims (16)

1, a kind of compound interferon vagina spray, contain following component: human interferon, human albumin, natural polysaccharide etc., its packing adopts long nozzle type vagina sprayer unit a kind of uniqueness, that be suitable for the cervix uteri anatomical structure, disposable, quantitative, can medicine directly be delivered to the pathological changes part by patient oneself.Infect the epithelium of cervix uteri dysplasia that causes owing to the human papillomavirus (HPV) who spreads through sex intercourse in order to treatment, comprise that Cervical intraepithelial neoplasia forms I, II, III degree (cancer in situ), and HPV, herpes simplex virus I I type (HSV-2), the cervix uteri chronic infection that cytomegalovirus (CMV) causes (chronic cervicitis or cervical erosion), the prevention cervical cancer.

2, YC compound recipe vagina spray component as claimed in claim 1 is characterized in that, described human interferon is various and hypotype of natural human interferon or the various and hypotype of recombinant human interferon alpha 2 that makes up by gene recombination technology, as α 1b, α 2a, α 2b, β 1a, β 1b, γ etc.

3, the various and hypotype interferon of natural people as claimed in claim 2, it is characterized in that described natural human interferon is (the cell line cultivation of human leukocyte or primitive cell culture or diploid cell strain cultivation or immortalization etc.) various and hypotype interferon by inductive people of other all interferon induceres such as any virus or double-stranded RNAs on people's cell culture.

4, the various and hypotype interferon of recombined human as claimed in claim 2, it is characterized in that, described recombinant human interferon alpha 2 for the recombined human of being produced by antibacterial (as escherichia coli) or fungus (as yeast) etc.s or produce by mammalian cell various with the hypotype interferon.

5, YC vagina spray component as claimed in claim 1 is characterized in that, described human albumin is from the human albumin of people's blood extraction on every side purification or the human albumin of being produced by recombinant technique.

6, YC vagina spray component as claimed in claim 1, it is characterized in that, described natural polysaccharide comprises hypromellose, hyaluronic acid, cellulose, starch, chitin, chitosan and derivant thereof, can be wherein a kind of, or the combination in any of these natural polysaccharides.

7, YC vagina spray component as claimed in claim 1, it is characterized in that to contain other cytokine, comprise the various types of cells factor that can promote the local immunity reaction and promote wound healing, comprise Human Inter Leukin-2 natural or reorganization, 12, natural or recombinate thymosin-β 4, lactoferrin natural or reorganization etc.

8, YC compound interferon vagina spray as claimed in claim 7 is characterized in that also can contain certain density estrogen, as estradiol, ethinylestradiol, diethylstilbestrol etc.

9, YC compound interferon vagina spray as claimed in claim 8, it is characterized in that also can contain certain density buffer solution, comprise acetate buffer solution, citrate buffer solution, phosphate buffer etc., pH is 3.5 ~ 5.5, is complementary with the sour environment of vagina.

10, YC compound interferon vagina spray as claimed in claim 9 is characterized in that this product is a sterile product, wherein contains the human albumin, and does not contain any to vaginal mucosa antiseptic excitatory.

11, vagina spray as claimed in claim 10, it is characterized in that, the delivery apparatus of its medicine is to be suitable for the cervix uteri anatomical structure, disposable, quantitative long nozzle type vagina sprayer unit, can directly be delivered to the cervical lesions part from being about to medicine by the patient.

12, YC compound interferon vagina spray as claimed in claim 10, being characterized as its indication is Human virus's infection of prevention and treatment female sex organs, comprises HPV, HSV, CMV etc.

13, human papillomavirus as claimed in claim 12 (HPV) infects, and it is characterized by to comprise other HPV of all models, and particularly relevant 6,11,16 with cervical cancer and condyloma acuminatum, 18,26,31,33,35,39,40,42,43,44,45,51,52,53,54,55,56,58,59,62,66,68 types such as grade.

14, HPV as claimed in claim 12 infects, and the position that it is characterized by the HPV infection is at positions such as women's cervix uteri, vaginal wall, vestibule, labia, perineums.

15, indication as claimed in claim 12, its feature also are to form (Cervical Intraepitheliai Neoplasia, I, II, III) and chronic cervicitis with the closely-related Cervical intraepithelial neoplasia of HPV.

16, indication as claimed in claim 12, its feature also are the cervix uteri chronic infection that is caused by HPV, HSV, CMV etc. or claim chronic cervicitis or cervical erosion.

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