Pharmaceutical composition for the treatment and prevention of genital herpes, chronic papilloma virus infection and cervical cancer prevention (options)

 

(57) Abstract:

The invention relates to the field of medicine and pharmacology and applies to new effectors of interferon against viruses genital herpes and human papilloma. The invention lies in the fact that on the basis of the new current start, which is a mixture of interferon and aminocaproic acid, or a mixture of interferon, aminocaproic acid and Riboflavin, developed three new dosage forms: ointment, gel candles. The invention provides a composition possessing also prolonged action of interferon, longer retaining its original activity. Due to the fact that the active principle was effective against oncogenic viruses of the papilloma V-16 and V-18, and at their joint infection of cells by the virus of genital herpes SV-2, enabling use as a preventive means to prevent cancerous degeneration of the cells of the cervical epithelium. 2 S. and 3 C.p. f-crystals, 7 Il.

The invention relates to the field of medicine and pharmacology, particularly to pharmaceutical compositions and top-medicinal forms (local medications) for the treatment and prevention of diseases, clinical manifestations, as herpetic eruptions and lesions, as well as asymptomatic shedding virus, leading to dangerous consequences such as infection sexual partners, neonatal herpes in children, termination of pregnancy, and cervical cancer. The present invention provides for treatment of cervical cancer and its prevention the prevention, elimination of the possibility of malignant degeneration of genital herpetic lesions.

The most clinically approved drug for the treatment of genital herpes is acyclovir, an analogue of purine nucleoside. It is prescribed for the primary treatment of patients with recurrent simple herpes in the genital area or with a view to its prevention, usually by oral administration in the form of tablets. Local application in the form of a top dosage forms contributes to the formation of resistant strains (D. R. Lawrence. Clinical pharmacology, T. 1, page 403, 1978). In addition, the cost of treatment with acyclovir, for any of the used schemes is expensive - up to several hundreds of dollars, so the development of new effective and affordable for the consumer medicines this assignment remains an urgent task.

As you know, the interferon is a natural protein with complex biological properties. The most important of these are its anti-viral action, the ability to inhibit cell proliferatio and increase immune response. However, to obtain a therapeutic effect requires high doses of interferon, which gives unwanted side effects and is a limiting factor in therapeutic use.

In this regard, the development of drugs based on interferon are mainly 3 ways:

1. use drugs with similar mechanism of action;

2. the use of substances that are antagonists side effects interferon;

3. the use of substances that enhance the action of interferon (potentiator) or the creation of such physical conditions, for example, hyperthermia, laser radiation.

In addition, this disadvantage is largely overcome by the local use of interferon directly into the affected area or close to it.

Such approaches use the and drugs including for the treatment of uncomplicated genital herpes.

An interesting fact is that only for the last 4-5 years in Russia were created and patented more than 15 dosage forms for topical application for the treatment of various infectious diseases interferon-based (foreign patents generally protect pharmaceutical compositions with such General characteristics as for example: "pharmaceutical acceptable carrier"). This is primarily due to the fact that patent owners and investors, for known reasons, prefer to have patent protection directly to the manufactured product.

One of the first patents devoted to pharmaceutical compositions for the treatment and prevention of genital herpes and dosage forms based on them, are described in EP 0080032 AND 61 TO 45/02, and in PCT application 83/01198 And 61 To 45/02.

In EP 0080032 described pharmaceutical composition based on interferon, which may contain a stabilizer, such as albumin serum, other antiviral agents such as acyclovir, an anti-inflammatory agent such as aspirin or proteolytic enzyme, and an acceptable carrier. The composition is used in the form of Lekarstvo the P CLASS="ptx2">

In PCT application 83/01198 described dosage form for treatment and prevention of genital herpes interferon-based, representing a single-phase semi-transparent gel. As celebritysee component dosage form contains carboxylate or their derivatives, polysaccharides containing COO-groups, cellulose or its derivatives and other Gel may contain a stabilizer, and a number of substances that suppress the replication of herpes simplex virus type II.

Also known pharmaceutical composition for the treatment and prevention of genital herpes interferon-based and non-ionic surface-active antiviral substances (EP 077063), interferon derived methylguanine (EP 0109234), interferon and diatomic alcohol containing nitrogen-containing the bicyclic heterocycle (U.S. Pat. USA 4957733).

For all these pharmaceutical compositions are assumed to be relevant top dosage forms (some of them are given in the descriptions) in the form of ointments, candles, liniments, aseptic solutions, etc.

Any of the described invention may be adopted for the prototype, the applicant selected for the prototype patent EP 0080032, as it is more fully disclosed ka the adequate level primarily by the novelty of the approach in the creation of medicines for this purpose, that in turn allows us to solve new tasks.

Although all of the cited patents noted the relationship between infection by the virus HSV-2 and the probability of malignant transformation of cervical epithelium, none of them is the problem of prevention of cervical cancer, but only prevent the incidence of genital herpes. And the relevance of this problem is obvious. Thus according to the who, every year in the world there are nearly 600,000 cases of cervical cancer and despite ongoing treatment activities 45-50% of these patients die from this disease.

T. O. inventive task is to create an efficient, affordable, for industrial production of tools not only for treatment and prevention of genital herpes, but also for the prevention of cervical cancer.

For that purpose a pharmaceutical composition for the treatment and prevention of genital herpes and cervical cancer prevention, containing interferon and advanced-aminocaproic acid.

A variant of the invention is a pharmaceutical composition for the treatment and prevention of genital herpes and cervical cancer prevention, the dosage form for local application on the basis of the proposed composition, representing the ointment, which contains the interferon-aminocaproic acid, polyvinylpyrrolidone, aluminum oxide, lanolin in the following ratio of components:

Interferon - 100000-1000000 ME

-Aminocaproic acid - 0.1-0.5 g

Polyvinylpyrrolidone 0.05 to 0.15 g

Aluminum oxide is 0.5 to 1.5 grams

Lanolin - To 100 g

Another composition of the interferon-containing gel has the following composition:

Interferon - 50000-500000 ME in ml

Serum albumin 1-2 mg/ml

-Aminocaproic acid 0.05 to 0.15 g/ml

Riboflavin - 0.04-0.06 g/ml

Carboxymethylcellulose 8 grams

Glycerin - a 20 g

PBS-buffer - Up to 200 ml

Variant dosage forms for topical use is a candle that contain interferon-aminocaproic acid, Riboflavin, lanolin and cocoa butter in the following ratio of components:

Interferon - 100000-1000000 ME

-Aminocaproic acid is 0.05-0.5 g

Riboflavin - 0,04-0,1 g

Lanolin - 0.1-0.3 g

Cocoa butter - Up to 2 grams

The implementation of the present invention is made possible thanks to a new approach to testing compounds, their compositions, with the target activity. Based on the latest scientific data, the applicant made napreca (HSV-2), but also against viruses "high-risk" HPV-16 and HPV-18 HPV, especially while their presence, such an approach in drug development of this profile is applied, according to the applicant, for the first time.

We shall discuss it in more detail. In recent years, intensive studies on the analysis of factors contributing to the development of cervical cancer (see, for example, G. Gross et al. Genital papillomavirus intection, 1989; Olsen, A. O. et al. Magnus P/Armis, 1998, 106, 417-424. Herpes simplex virus and human papillomavirus in population - based cose-control study of cervical intraepithelial neoplasic grade II-IV; J. Hara et al. J. med.viral. 1987, 53(1), 4-12 Effect of herpes simplex virus on the DNA of human papilloma 18; Southern S. A. et al. Sex.Tronst intect. 1998. 78(2), 101-109. Storey, A. et al. Nature, 1998, 391, 229-234), including joint (combined) viral infection of the genital tract, chromosomal aberrations, telomerase activity, Smoking, hormonal and immune status, HLA type. From these findings indicate that a key role in the induction of tumor process is played by HPV-16 or HPV-18 and HSV-2 in their joint presence. Significant moments in neoplastic transformation may be the fact that the joint presence of HSV-2 (against HSV-1, this fact is not installed) and HPV-16 or HPV-18 contributes not only to increased viral replication, but also the introduction of the genome of the virus is the institutional capacity in relation to p53 protein-host cell - suppressor cell proliferatio.

Draws attention to the fact that the joint presence of these viruses leads to changes in their properties and/or conditions of existence in the body, so those drugs or those regularities that are known about these viruses in isolation, may not be effective or may not be respected in their joint presence, respectively.

For analysis of the distinctive features among the known prior art will note the following:

A group of patents is dedicated to the antiviral action of Riboflavin and other flavins: in PCT application 92/17173 And 61 To 31/25 described the use of Riboflavin with herpes, malaria, HIV-related diseases, in PCT application 95/11028 patented the use of Riboflavin as an antiviral agent, in particular for HIV infection.

Especially interesting is the information contained in patents EP 0659436, a 61 K 38/21 and U.S. Pat. USA 6020333, 514-251, 02.2000 (p. and. PCT 95/27491). In the patent 659436 described potentiation of the antiviral action of interferon Riboflavin, the mechanism is not disclosed, and it is shown that a given pharmaceutical activity of interferon is achieved when lower concentrations. The effect is shown in relation to belavina for local use for the prevention of viral infections, sexually transmitted diseases such as genital herpes and papillomavirinae infection. In the patent, however, no information about the effect of Riboflavin in the joint presence of the virus of genital herpes and human papilloma, especially about viruses "high-risk" HPV-16 and HPV-18.

The applicant is not known songs-aminocaproic acid (synthetic analogue of the natural amino acids) or interferon, or Riboflavin, nor in the joint presence of Riboflavin and interferon, which would be used as antiviral agents.

What about the use of-aminocaproic acid together with interferon, which is only to increase the water solubility of interferon in the process of its purification from cell culture at its microbiological methods of production (see U.S. Pat. USA 4675183,424-85). Although it is known the use of some natural aromatic amino acids, such as tryptophan, phenylalanine, tyrosine, etc. as effective stabilizers of interferon (Japan patent 102519/1980) or such natural amino acids like aspartic acid, cystine, cysteine, glycine, hydroxyproline, serine, tyrosine as potentiators its your anti-virus is Oh acid leads to stabilization, potenzirovania and prolongation of its antiviral action, while potentiation Riboflavin antiviral action of this complex interferon is saved. Such effects are not obvious and do not derive from the prior art, allow to solve a fundamentally new task, namely variants of the compositions, dosage forms based on them was effective not only against the virus of genital herpes, but in cases of joint infection by the virus of genital herpes and human papilloma virus high risk".

The examples given below illustrate the invention and describe it in more detail.

Example 1. Additive effect -2 and interferon-aminocaproic acid on reproduction of HSV-2 and HPV-16 (HPV-18) in tissue culture.

Cell culture of human fibroblast infected HSV-2 and HPV-16, and 30 min after infection contributed-2-interferon-and-aminocaproic acid in constant concentration in all samples is 0.5%.

As follows from the data presented in Fig. 1 and 2, -aminocaproic acid is almost twice as enhances the antiviral effect of interferon-2 against HSV-2 and HPV-16.

Dialogue is the Ktsia viruses HSV-2 and HPV-16 (HPV-18) in cell culture.

Experimental conditions analogous to example 1. As can be seen from Fig. 3, the inhibitory effect of Riboflavin on the reproduction of viruses HSV-2 and HPV-16 increases with increasing concentration of Riboflavin from 0.1 to 1% (similar results were obtained in respect of the HPV-18).

Example 3. The inhibiting effect of mixtures containing interferon-aminocaproic acid and Riboflavin, on the reproduction of viruses HSV-2 and HPV-16 in cell culture.

Experimental conditions analogous to example 1. -aminocaproic acid and Riboflavin contribute at constant concentrations of 0.5%, the concentration of interferon-2 is 1 and 2 ág/ml As shown in Fig. 4 and 5, aminocaproic acid and Riboflavin increase the action of interferon almost an order of magnitude compared with example 1.

Example 4.

Prepare the ointment of the following composition:

1. Interferon -2 recombinant - 500000 ME

-Aminocaproic acid 0.1 g

Polyvinylpyrrolidone - 0.5 g

Alumina - 0.5 g

Lanolin - To 100 g

2. Interferon -2 recombinant - 500000 ME

-Aminocaproic acid 3 g

Polyvinylpyrrolidone - 1,5

Alumina - 1.5 grams

Lanolin - to 100 g

Laboratory tests on cell cultures, HSV-2 and HPV-16 showed high protivo is the means retain their biological activity and physicochemical properties for at least 6 months.

Example 5. Prepare candles for the treatment of genital herpetic lesions following composition:

1. Interferon -2 recombinant - 500000 ME

-Aminocaproic acid, 0.05 g

Riboflavin - 0,025 g

Lanolin - 0.1 g

Cocoa butter - Up to 2 grams

2. Interferon -2 recombinant - 500000 ME

-Aminocaproic acid 0.15 g

Riboflavin - 0.075 g

Lanolin - 0.3 grams

Cocoa butter - Up to 2 grams

Candles showed a high level of antiviral activity in the same test systems, its conservation and physico-chemical properties for at least six months without use, as in the case of ointments, additional stabilizers.

Example 6. Prepare a gel of the following composition:

1. Interferon - ME in 50 ml

Serum albumin 1 mg/ml

-Aminocaproic acid, 0.05 g/ml

Riboflavin - 0.04 g/ml

Carboxymethylcellulose 8 grams

Glycerin - a 20 g

PBS-buffer - Up to 200 ml

2. Interferon - 500000 ME in ml

Serum albumin, 2 mg/ml

-Aminocaproic acid - 0.15 g/ml

Riboflavin - 0.06 g/ml

Carboxymethylcellulose 8 grams

Glycerin - a 20 g

PBS-buffer - Up to 200 ml

In these test systems, the gel showed activity at least 80% of the activity of aqueous compositions, GE is P> Example 7. Treatment of genital herpes infections.

Patient C. , 30 years. Turned 08.09.1999, over the past 5 years, suffering from recurrent genital herpes. With a frequency of 3-4 times a year, there are relapses that occur herpetic rash on genitals, accompanied by severe itching. Clinically: In the mouth of the urethra there is a pronounced erythema. On a background of erythema visible grouped blisters (vesicles) with a diameter up to 3 mm with serous clear content. Examination of material taken from the lesion by direct immunofluorescence and PCR analysis showed the presence of herpes simplex virus type 2.

The patient underwent a course of therapy, including a vaginal suppository (1 candle per day for 7 days) of the following composition: 2-interferon - 10000 ME-aminocaproic acid 0.1 g, Riboflavin, 0.05 g, lanolin - 0.2 g cocoa butter to 2 g and the application of an ointment containing: 2-interferon - 50000 ME, -aminocaproic acid 0.2 g, polyvinylpyrrolidone, 0.1 g, alumina - up to 1,

The result of therapy was observed rapid reduction of lesions within 3 days instead of the usual 6-7 days. The study of vaginarecent gave a negative result.

Example 8. Treatment of asymptomatic genital herpes and preventive monitoring of the "risk group".

The clinic CNIKVI was examined group of patients in quantities of 100 people suffering from recurrent genital herpes for at least 3 years.

Using the polymerase chain reaction was identified a group of patients women out of 10 people who have been diagnosed with asymptomatic genital herpes, and complaints and clinical signs of herpes infection in the survey were not found.

In addition, on the basis of the same group survey-based data on seropositivity against papillomaviruses 16 and 18 and data about the integrated form of the virus into the genome of epithelial cells was identified risk group of 7 people.

The first group of patients, the course of therapy, including a vaginal suppository (1 suppository per day for 10 days) composition:

2-Interferon - 500000 ME

-Aminocaproic acid 0.1 g

Riboflavin - 0.05 g

Lanolin - 0.2 g

Cocoa butter - Up to 2 grams

25 days after the start of treatment was carried out laboratory analysis of the vaginal discharge for the presence of DNA of herpes simplex virus type 2S="ptx2">

The second group of patients twice a year held therapy according to the same scheme as for group 1, or according to the scheme of example 5.

Monitoring of patients "at risk" for 1.5 years showed no signs of degeneration of the cervical epithelium.

The present invention is important in the framework of the new approach to the problem, which is due to the fact that the virus of genital herpes and HPV are the most common infectious agents, sexually transmitted diseases, relates to the field of dermatological services in the country. To resolve this problem, you must develop an effective diagnostic test system that allows the typing of HPV and HSV, to develop a fundamentally new drugs, preventive measures, which should lead to a significant reduction in the incidence of cancer of the cervix.

1. Pharmaceutical composition for the treatment and prevention of genital herpes, chronic papillomaviruses infection and cervical cancer prevention, containing interferon, characterized in that it additionally contains-aminocaproic acid.

2. The composition according to p. 1, characterized in that it is made and components g:

Interferon - 100000-1000000 IU

-Aminocaproic acid - 0,1-0,5

Polyvinylpyrrolidone is from 0.005 to 0.15

Aluminum oxide is 0.5 to 1.5

Lanolin - Up to 100.0

3. Pharmaceutical composition for the treatment and prevention of genital herpes, chronic papillomaviruses infection and cervical cancer prevention, containing interferon, characterized in that it additionally contains-aminocaproic acid and Riboflavin.

4. The composition according to p. 3, characterized in that it is made in the form of candles and additionally contains lanolin and cocoa butter in the following ratio of components, g:

Interferon - 100000-1000000 IU

-Aminocaproic acid - 0,05-0,5

Riboflavin - 0,04-0,1

Lanolin - 0,1-0,3

Cocoa butter - To 2.0

5. The composition according to p. 3, characterized in that it is made in the form of a gel, further comprises serum albumin, carboxymethyl cellulose, glycerin and S buffer in the following ratio of components:

Interferon - 50000-500000 IU per ml

Serum albumin 1-2 mg/ml

-Aminocaproic acid 0.05 to 0.15 g/ml

Riboflavin - 0.04-0.06 g/mi

Carboxymethylcellulose - 8,0

Glycerin - 20,0

S-buffer - 200 ml

 

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