EA030197B1 - Tableted form of an antiviral medicament - Google Patents

Abstract

According to the invention described is an antiviral medicament in the form of a tablet for topical administration in oral cavity, of the following composition: human recombinant interferon - 100000 ME, α-2a or α-2b auxiliary substances, mg/tablet: talc - 6.0, magnesium stearate - 6.0, macrogol 4000 - 90.0, sorbitol - 491.0. The medicament may further comprise pharmaceutically acceptable flavors and fragrances. The medicament is produced in the form of a tablet for resorption, buccal or sublingual tablet.

Description

The invention relates to medicine, specifically to an antiviral drug based on human recombinant or leukocyte interferon subtypes a-2a or a-2b, used for the prevention and / or treatment of human viral diseases by local use in the mouth and nasopharynx, and can be used in pharmaceutical industry and health care.

Interferon α-2 is a polypeptide consisting of 165 amino acid residues. The subtypes a-2a and a-2b differ in amino acid residue at position 23: lysine in the case of interferon a-2a, arginine in the case of interferon a-2b [1].

Interferon has non-specific antiviral, immunomodulatory and antiproliferative activity [1, 2, 3].

The antiviral effect of interferon is manifested during the reproduction of the virus. Interferon interacts with specific receptors on the cell surface, initiates a number of intracellular changes, including activates the synthesis of cytokines and enzymes (2-5-adenylate synthetase, protein kinase), which inhibits the synthesis of viral protein and viral ribonucleic acid in the cell [2].

The immunomodulatory effect of interferon consists in increasing the phagocytic activity of macrophages, enhancing the specific cytotoxic effect of lymphocytes, and altering the functional activity of immunocompetent cells [2].

Aniproliferative activity causes the use of interferon in the treatment of certain oncological diseases [2].

Interferon in systemic dosage forms (solution for injection, lyophilized powder for solution for injection) is used to treat hepatitis B and C, kidney cancer, hairy cell leukemia, malignant skin lymphomas, Kaposi's sarcoma, skin cancer, keratoacanthoma, chronic myeloid leukemia, histiocytosis , sublabemic myelosis, essential thrombocythemia [2]. However, these dosage forms can provoke the development of systemic adverse reactions to the introduction of interferon (often - flu-like syndrome: chills, fever, asthenia, fatigue, myalgia, arthralgia, headache; rarely - arrhythmia, dry mouth, insomnia, hair loss, pharyngitis, systemic lupus erythematosus, hearing loss, hyperglycemia, etc.), since interferon is absorbed into the systemic circulation [2].

Interferon in topical dosage forms (ointment, gel, topical solution, eye drops, spray, including nasal) is used to treat viral keratitis, treat and prevent influenza and respiratory viral infections, herpes lesions of the skin and mucous membranes. The disadvantages of these dosage forms is the lack of the patient's ability to take the exact dose of the drug, which may adversely affect the effectiveness of treatment, and the inconvenience of use in the oral cavity. Also, after the package has been opened, contamination of the non-dosed drug with infectious agents and subsequent reinfection of the person using the drug is possible.

Interferon in the form of suppositories and capsules for systemic use is used to treat influenza and other respiratory viral infections [3]. Capsules and suppositories are dosage forms of drugs containing interferon, but are intended for systemic use with appropriate systemic use of undesirable effects.

The tablet form of the antiviral drug containing interferon intended for topical use in the oral cavity is unknown in the prior art.

Topical application in the oral cavity of interferon in the form of tablets has certain advantages compared with the intravenous or intramuscular administration of dosage forms. Diseases requiring treatment with painful injectables are regarded as more serious diseases than those conditions that can be treated with oral dosage forms. The big advantage of the tablet form is the possibility of self-administration by patients, unlike parenteral formulations, which in most cases must be administered by a doctor or middle-level medical personnel.

The objective of the present invention is the creation of an interferon-containing antiviral drug in tablet form, which provides therapeutic efficacy in the prevention and treatment of human viral diseases when applied topically in the oral cavity.

The problem is solved intended for topical application of antiviral drug in tablet form, containing interferon human recombinant subtypes a-2a or a-2b in the amount of 100,000 international units of action (IU) per unit dosage of the drug and pharmaceutically acceptable excipients.

In accordance with the invention, an antiviral drug in the form of a tablet is described for topical use in the oral cavity, of the following composition:

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human recombinant interferon alpha-2a or alpha-2b excipients, mg / tabl .: talc

magnesium stearate

macrogol 4000

sorbitol

100,000 IU

6.0

6.0

90.0

491.0

In a preferred embodiment of the invention, the claimed antiviral drug in the form of a tablet may further contain flavoring agents and flavoring agents. The skilled person will appreciate that flavors of flavor and flavors in this composition can be any of those used in the pharmaceutical industry.

The specified drug can be made in the form of lozenges, buccal or sublingual tablets.

Unexpectedly, it was found that the proposed combination of excipients is able to ensure the stability of interferon in pill form for the stated shelf life, as well as to ensure the manifestation of the therapeutic effect of interferon when applied topically in the oral cavity and the absence of toxic and other undesirable effects in the finished drug.

The advantages of the proposed antiviral drug in the form of an interferon-containing resorption tablet, a buccal or sublingual tablet over known non-dosed dosage forms that allow the possibility of topical use in the oral cavity are as follows:

1) the accuracy of the dose of interferon taken by the patient,

2) a longer contact of the mucous membrane of the oral cavity with interferon due to the fact that the proposed dosage form has a period of dissolution in the oral cavity,

3) ease of storage, transportation and use of the proposed dosage form.

Therapeutic and prophylactic efficacy of the proposed antiviral drug in the form of tablets for local use in the mouth is confirmed by the following examples.

Example 1. These preclinical studies.

1. Determination of the antiviral properties of lozenges containing interferon against influenza A virus, herpes simplex virus type 1, herpes simplex virus type 2.

The specific antiviral activity of tablets of the following composition, mg / tabl has been studied: Recombinant human interferon 100,000 IU

alpha 2a or alpha 2b

Macrogol 4000 90.0

Talc 6.0

Magnesium stearate 6.0

Anhydrous citric acid 7.0

Sorbitol 491.0

in relation to influenza viruses and herpes simplex 1 and 2 types ίη νίΐΓΟ.

The antiviral properties of these tablets were tested on monolayer cultures of transplanted dog kidney cells (MOSC) with influenza virus Α (Η 7-1) (strain of HRE / Kozosk / 34 (Η 7-1), and human rhabdomyosarcoma cell lines (KO) - with herpes viruses of types 1 and 2 (AIV-1, strain 1 C and AIV-2; strain US, respectively) using the method for evaluating the inhibition of the cytopathic effect of viruses.

Monolayer cell cultures grown in vials washed from the growth medium, added a support medium containing different concentrations of the sample of the studied drug, left them in a thermostat for a day, after which 0.01-0,0001 TCID50 / cell viruses were infected by applying to dilution cells of the virus-containing suspension in a volume of 0.1 ml for 1 h at 37 ° C and the support medium with the same concentrations of the test drug was applied again. In another part of the vials, the infection was carried out immediately after the cells were washed from the growth medium, then the vaccinated liquid was removed and the cells were coated with support medium containing various concentrations of the test drug. After 48-72 hours of incubation at 37 ° C, morphological changes in the cell monolayer (cytopathic effect (CPD) of the virus, increase x80) were recorded.

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Table 1

Reducing the titer of viruses in the presence of the test drug_

Breeding Inferon, IU Virus influenza Α (Η7Ν1) VGP-1 VGP-2 titer, TCID50 / ml difference with control. 1y TCID50 / ml titer, 1y TCIDZO / ml difference with control, 1y TCID50 / ml titer, one§ TCID50 / ml difference with control, 1§ TCID50 / ml Group 1 (infection after preprocessing by the test agent) 1,000 <5.0 > 2.3 <5.0 > 2.0 <4.0 > 1.48 100 <5.0 > 2.3 <5.0 > 2.0 <4.0 > 1.48 ten <5.0 > 2.3 <5.0> 2.0 <4.0 > 1.48 one <5.0 > 2.3 <5.0> 2.0 4.48 + 0.34 one 0.1 6.05 + 0.52 1.25 5.70 + 0.43 1,3 5.00 + 0.53 0.48 Control virus 7.3 + 0.32 - 7.00 + 0.53 - 5.48 + 0.34 - Group 2 (infection without pretreatment with the test agent) 1,000 6.05 + 0.52 1.25 5.48 + 0.34 1.52 4.48 + 0.34 1.7 100 6.18 + 0.26 1.12 5.48 + 0.34 1.52 5.00 + 0.53 1.0 ten 6.41 + 0.37 0.89 6.00 + 0.53 1.0 5.3 + 0.43 0.88 one 6.48 + 0.34 0.82 6.15 + 0.46 0.85 5.54 + 0.40 0.64 one 6.6 4 + 0.46 0.66 6.39 + 0.33 0.61 5.7 + 0.43 0.48 0.01 7.21 ± 0.41 0.09 6.70 + 0.43 0.3 5.7 + 0.43 0.48 Control virus 7.3 + 0.32 - 7.00 + 0.53 - 6.18 + 0.26 -

The data obtained indicate a high antiviral effect of the tested sample of the test product against RNA and DNA containing viruses. The lower limit of dilution of the drug with a high activity (lower virus titer more than 1 1d TCID50 / ml) in relation to the most sensitive influenza A viruses and herpes simplex type 1 corresponds to 1 IU, and in relation to the more resistant herpes simplex virus type 2 - 10 IU. The range of effective concentrations, non-toxic for cell cultures, is, based on the EC90 value, more than 20,000 for more sensitive viruses and more than 700 for the more resistant herpes simplex virus of type 2. Higher activity during pre-exposure of the cell culture with the drug before infection indicates a typical "interferon" method of the observed action.

Example 2. The study of the pharmacokinetics of the studied drugs when administered orally.

The investigational drug in the form of a resorption tablet containing 100,000 IU of interferon was administered orally to the rabbits once as a 60% aqueous suspension in the following doses.

1. Daily therapeutic - 10,000 IU per 1 kg of body weight of the animal.

2. 3-fold daily therapeutic - 30,000 IU per 1 kg of body weight of the animal.

3. 5-fold daily therapeutic - 50,000 IU per 1 kg of body weight of the animal.

Samples of saliva and blood were taken at the following time intervals: baseline data (before the start of drug administration), 30 minutes, 1, 2, 4, and 8 hours after drug administration [4].

Selected in the experience route of administration provides the necessary duration of contact of the investigational medicinal product with the mucous membrane of the oral cavity of rabbits. Developers and reviewers of the preclinical testing program consider this approach acceptable.

The content of interferon in the saliva and blood plasma of rabbits was performed by enzyme immunoassay.

In the blood plasma of rabbits after a single oral administration of the test drug, interferon was not detected at any time point of the study.

The content of interferon in the saliva of experimental animals is presented in table. 2

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table 2

The content of interferon (PG / ml) in the saliva of rabbits by series and time points of the experiment

Series experiment The time point of the experiment baseline data 30 min 1 hour 2 hours 4 hours 8 ocloc'k 1 series, 10,000 IU / kg 13.1 + 4.1 183.2 + 44.5 71.8 + 20.8 31.4 + 10.9 12.8 + 3.0 12.7 + 2.5 2 series, 30000 IU / kg 11.4 + 2.5 252.2 + 52.4 146.2 + 36.8 28.3 + 6.0 6.6 + 1.7 16.7 + 5.2 3 series. 150000 IU / kg 19.9 + 4.8 418.3 + 53.1 275.8 + 45.7 51.3 + 15.3 17.6 + 4.5 17.8 + 6.1

After a single oral administration to the rabbits of the test drug in the whole range of doses studied (10,000 IU / kg, 30,000 IU / kg, 50,000 IU / kg), the following was established:

did not detect traces of interferon in the blood plasma, due to its destruction by proteolytic enzymes,

the amount of interferon in rabbit saliva correlated with the dose of the injected drug; the maximum concentration was recorded at a time point of 30 minutes. after oral administration for animals of all experimental series,

the increased content of interferon in the saliva of experimental animals is recorded within 4 hours after oral administration of the investigational medicinal product.

Used sources of information.

1. £ £ £ £ £ a1 £ a-2 sssep1ga! To her δοϊιιΐίοη. PododgarE 07/2015: 1110: Eigoreup Reagshasoroe1a 8.5. R. 4989-4985.

2. IFN-EU: Instructions for use of the drug, ND RB 7399-2015.

3. Naumova, L.M. The use of a new form of liposomal interferon alpha-2b in the treatment of influenza and other acute viral respiratory diseases. L.M. Naumova et al .: Polyclinic, № 4, 2012. Pp. 102-106.

4. Guidelines for conducting preclinical studies of drugs / ed. Mironova A.N. M., 2012, part one, p. 846.

Claims (3)

CLAIM 1. Antiviral drug in the form of tablets for local use in the mouth, the following composition: recombinant human interferon a-2a or a-2b - 100,000 IU, excipients, mg / tabl .: talc - 6.0, magnesium stearate - 6.0, macrogol 4000 - 90.0, sorbitol - 491.0. 2. The tool according to claim 1, characterized in that it additionally contains pharmaceutically acceptable flavors of taste and flavors. 3. The tool according to claim 1, characterized in that it is made in the form of a tablet for resorption, buccal or sublingual tablets.