UA119684C2 - TABLET FORM OF ANTI-VIRUS MEDICINAL PRODUCT - Google Patents

Abstract

According to the description describes a dosage form of an antiviral drug intended for topical use in the oral cavity, the following composition, mg / table: human interferon recombinant alpha-2a or alpha-2b from 1000 to 1,000,000 IU talc 0,1-12,0 magnesium stearate 2.0-12.0 binding agent 50.0-3000.0. The binding agent may be selected from the group consisting of sorbitol, mannitol, xylitol, lactose, glucose, sucrose, starch, polydextrin, macrogol 4000, or a combination thereof. The dosage form may further comprise pharmaceutically acceptable flavoring and flavoring agents. The tablet form is made in the form of lozenges, buccal or sublingual tablets.

Description

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

Interferon alpha-2 is a polypeptide consisting of 165 amino acid residues.

Subtypes alpha-2a and alpha-2B differ by an amino acid residue in position 23: lysine in the case of interferon alpha-ha, arginine in the case of interferon alpha-2B5 GP.

Interferon has nonspecific antiviral, immunomodulatory and antiproliferative activity (1, 2, ZI.

The antiviral effect of interferon is manifested during the period of virus reproduction. Interferon interacts with specific receptors on the surface of cells, initiates a number of intracellular changes, including activating the synthesis of cytokines and enzymes (2-5-adenylate synthetase, protein kinase), the action of which inhibits the synthesis of viral protein and viral ribonucleic acid in the cell (21.

The immunomodulatory effect of interferon consists in increasing the phagocytic activity of macrophages, strengthening the specific cytotoxic effect of lymphocytes, and changing the functional activity of immunocompetent cells |21.

Antiproliferative activity determines the use of interferon in the treatment of some oncological diseases |21.

Interferon in medicinal forms for systemic use (solution for injections, lyophilized powder for preparation of solution for injections) is used to treat hepatitis B and C, kidney cancer, hairy cell leukemia, malignant lymphomas of the skin, sarcoma

Kaposi, skin cancer, keratoacanthoma, chronic myeloid leukemia, histiocytosis, subleukemic myelosis, essential thrombocythemia (2). However, the indicated dosage forms can provoke the development of systemic adverse reactions to the administration of interferon (often - a flu-like syndrome: chills, fever, asthenia, fatigue, myalgia, arthralgia, headache; rarely - arrhythmia, dry mouth, insomnia, hair loss, pharyngitis, systemic lupus erythematosus, hearing impairment, hyperglycemia, etc.), as interferon is absorbed into the systemic bloodstream (21.

Zo Interferon in medicinal forms for local use (ointment, gel, solution for external use, eye drops, spray, including nasal) is used for the treatment of viral keratitis, treatment and prevention of influenza and respiratory viral infections, herpetic lesions of the skin and mucous membranes shell The disadvantages of these dosage forms are the patient's lack of an opportunity to take the exact dose of the drug, which can negatively affect the effectiveness of the treatment, and the inconvenience of using it in the oral cavity. Also, after opening the package, contamination of the undosed medicinal product with infectious agents and subsequent reinfection of the person using this medicinal product is possible.

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

A tablet form of an antiviral drug containing interferon, intended for local use in the oral cavity, is unknown from the prior art.

Local use of interferon in the oral cavity in the form of tablets has certain advantages compared to intravenous, intramuscular administration or administration in medicinal forms for local use. Diseases that require treatment with painful injectable formulations are considered more serious than those conditions that can be treated with oral dosage forms. A great advantage of the tablet form is the possibility of self-administration by patients, unlike parenteral forms, which in most cases must be administered by a doctor or a representative of the middle level of medical personnel.

The task of this invention is to create an antiviral drug containing interferon, which provides therapeutic effectiveness in the prevention and treatment of human viral diseases when applied locally in the oral cavity.

The task is solved by a tablet form of an antiviral drug intended for local use, containing human recombinant or leukocyte interferon of subtypes alpha-2a or alpha-2p in amounts from 1000 international units of action (IU) to 2,000,000 IU per unit of dosed medicinal product.

According to the invention, a dosage form of an antiviral drug is claimed, because it is intended for local use in the oral cavity, with the following composition, mg/cap.:

human interferon from 1000 to recombinant alpha-2a 1000000 IU or alpha-25 talc 0.1-12.0 magnesium stearate 2.0-12.0 binding agent 50.0-3000.0.

The binding agent can be selected from the group consisting of sorbitol, mannitol, xylitol, lactose, glucose, sucrose, starch, polydextrin, macrogol 4000, or a combination thereof.

In a preferred embodiment of the invention, the claimed dosage form may additionally contain taste correctors and flavorings. It is clear to the expert that the taste correctors and aromas in this composition can be any of those used in pharmaceuticals.

In another preferred embodiment of the invention, anhydrous citric acid is used as a taste corrector with the following ratio of ingredients in the stated form, mg/tablet: human interferon Y from 1000 to recombinant alpha-2a 1000000 IU or alpha-25 macrogol 4000 4.0-400 talc 0.1-12.0 magnesium stearate 2.0-12.0 anhydrous citric acid 1.0-15 sorbitol 50-3000.0.

This medicine can be made in the form of lozenges, buccal or sublingual tablets.

Unexpectedly, it was found that the proposed combination of auxiliary substances is able to ensure the stability of interferon in tablet form during the stated shelf life, as well as to ensure the manifestation of the therapeutic effect of interferon when applied locally in the oral cavity and the absence of toxic and other undesirable effects in the finished medicinal product.

The advantages of the proposed dosage form in the form of tablets for absorption, buccal or sublingual tablets containing interferon, compared to known underdosed dosage forms, which allow the possibility of local application in the oral cavity, are as follows: 1) accuracy of the dose of interferon taken by the patient; 2) longer contact of the mucous membrane of the oral cavity with interferon due to the presence of a dissolution period in the oral cavity in the proposed dosage form; 3) convenience of storage, transportation and use of the proposed dosage form.

The therapeutic and preventive effectiveness of the use of the proposed dosage form of interferon is confirmed by the following examples.

Example 1

Data from preclinical studies

Zo Determination of 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 with the following composition, mg/tablet, was studied: interferon human recombinant alpha-2a 100,000 IU or alpha-25 macrogol 4000 90.0 talc 6.0 magnesium stearate 6.0 anhydrous citric acid 7.0 sorbitol 491.0 relative influenza viruses and herpes simplex 1 and 2 types of HIV.

Antiviral properties of these tablets were studied on monolayer cultures of dog kidney cells (MSCs) overgrown with the influenza virus A(H7MI) (ERM/Koviosk/34 (H7MI) strain), and human rhabdomyosarcoma (KO) cell lines - with herpes viruses simple 1 and 2 types (HPV-1, strain 1 C and HPP-2; strain US, respectively) by the method of evaluating the inhibition of the cytopathic effect of viruses.

Monolayer cultures of cells grown in vials were washed from the culture medium, a support medium containing different concentrations of the sample of the drug under study was introduced, they were left for a day in a thermostat, after which infection of 0.01-0.0001 TsDP5O/cells was carried out by viruses applying to the cells a dilution of the virus-containing suspension in a volume of 0.1 ml for 1 hour at 37 "С and again applying a support medium containing the same concentrations of the studied drug. In the other part of the vials, infection was carried out immediately after washing the cells from the culture medium, then the virus-containing liquid was removed and the cells were covered with a support medium containing different concentrations of the drug under study. After 48-72 g of incubation at 37 "C, morphological changes in the monolayer of cells were recorded (cytopathic effect (CPD) of the virus, magnification x80).

The decrease in the titer of viruses in the presence of the studied medicinal product is shown in Table 1.

Table 1

Dilution of interferon difference with difference with difference with ;

I4 TsPD5O/ml I4 TsPD5O/ml TsPD5O/ml week | Lyu"! 001 tallow" | zeyumi virus 01 | 664:046 | 066 | 639033 | 061 575043 | 048 001 | 721х041 | 009 | bulochom3 | 03 | 575043 | 048 same | Lyu"! 01 tallow") | invyuhi virus

The obtained data indicate a high antiviral effect of the studied sample of the research agent against viruses containing RNA and DNA. The lower limit of dilution of the drug with high activity (reduction of the virus titer by more than 1 IU TSPD5O/ml) relative to the most sensitive viruses of influenza A and herpes simplex type 1 corresponds to 1 IU, relative 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 EC90O value, more than 20,000 for more sensitive viruses and more than 700 for the more resistant herpes simplex type 2 virus. A higher activity during the previous exposure of the cell culture to the drug before infection indicates the typical "interferon" mode of action observed.

Example 2

Study of the pharmacokinetics of the studied medicinal product during oral administration.

The investigational medicinal product in the form of a tablet for absorption, containing 100,000

IU of interferon was administered to rabbits orally once in the form of 60 95 aqueous suspension in the following doses: 1. Daily therapeutic - 10,000 IU per 1 kg of animal body weight.

From 2. Three-fold daily therapeutic dose - 30,000 IU per 1 kg of the animal's body weight. 3. 5-fold daily therapeutic dose - 50,000 IU per 1 kg of the animal's body weight.

Saliva and blood samples were collected at the following time intervals: initial data (before drug administration), 30 minutes, 1, 2, 4, and 8 hours after drug administration |4|.

The route of administration chosen in the experiment provides the necessary duration of contact of the investigated medicinal product with the mucous membrane of the oral cavity of rabbits.

The developers and reviewers of the preclinical research program consider this approach acceptable.

Determination of the content of interferon in the saliva and blood plasma of rabbits was carried out by the method of immunoenzymatic analysis.

Interferon was not detected in the blood plasma of rabbits after a single oral administration of the studied medicinal product at any time point of the study.

The content of interferon (pg/ml) in the saliva of experimental animals (rabbits) by series and time points of the experiment is presented in the table.

Table 2

Series

After a single oral administration of the studied medicinal product to rabbits in the entire range of studied doses (10,000 IU/kg, 30,000 IU/kg, 50,000 IU/kg), the following was established: - no traces of interferon were detected in the blood plasma, which is due to its destruction by proteolytic enzymes; - the amount of interferon in the saliva of rabbits was correlated with the dose of the injected drug; the maximum concentration was recorded at the time point of 30 min. after oral administration to animals of all experimental series; - the increased content of interferon in the saliva of experimental animals is registered within 4 hours after the oral administration of the studied medicinal product.

Example C

Study of the stability of the investigated medicinal product.

The medicinal product with the following composition was studied:

The most . Quantity per tablet of the name of the ingredient, mg

Human interferon Y 100,000 IU recombinant alpha-2r

Macrogol 4000 90.0

Talc 6.0

Magnesium stearate 6.0

Anhydrous citric acid 7.0

Sorbitol 491.0

The study of the stability of this finished medicinal product was carried out on experimental and industrial series.

The stability study program included long-term stability studies of the medicinal product when stored at (5:53)"C for 24 months.

The results of the study of the stability of the medicinal product "tablets for absorption, 100,000

MO" (Series 19 0514, Series 20 0514, 21 0514) are presented in Tables 3-5, respectively.

Table C

Series 19 0514 tires Duration of storage, months.

Controlled shi TE53 C indicator specification | 0 | with | 6 | 9 | 12 | 18 | 24

Description according to FOV

RB

Validity: interferon according to FSV RB

The average weight of the tablet is from 570 to 630 mg (600 mg in bo 6oZ 605 bo 607 6o5 6oZ o in accordance with FSV RB

Specific activity from 80,000 IU to 140,000 IU 110,000 110,000 110,000 110,000 110,000 100,000 100,000 (Microbiological purity) 7777711 total number of aerobes less than 2 2 2 2 o! less than 2 (ZKA) not more than 102 CFU-04/g less than 10| less than 10 102 less than 10 total number of mushrooms 4 4 4 4 and less than 4

ZKP no more than 101 CFU/H less than 10"! less than 10") less than 10th less than 10"! less than 10 101 less than 10

Rzeidotopaz aeegidipoz . : . . . . . . . . . . . .

Ziarpuiosossiv aygetsv| , . . . . . . . . . . . . .

Table 4

Series 20 0514 tires Duration of storage, months. o Controlled.d/ | ; | te5zh3 with indicator specification | 0 | 3 | 6 | 9 | 12 | 18 | 24

Description according to FOV

RB

Validity: interferon in accordance with FSOV of the Republic of Belarus

The average weight of the tablet is from 570 to 630 mg (600 mg in 604 602 602 605 604 5 9 according to FSV RB

Specific activity from 80,000 IU to 140,000 IU 110,000 110,000 110,000 110,000 110,000 100,000 110,000

Ide) (Microbiological purity | ОЙ 77С7Ї1711117Ї1111111111111111111111111111Ї11 total number of aerobes 2 2 2 2 2 | less (ZKA) no more than 102KUO/G less than 10-| less than 10-| less than 10-| less than 10-| less than 10-| less than 10-| less than 10 of mushrooms 1 1 1 1 1 1 less (ZK) no more than 10! cotton wool

Ziarpuiosossiv aygetsv| . . . . . . . . . . . . . .

Table 5 Series 210514. | (| ////// Duration of storage, average//// About Controlled

Berman SNY SSZ SSZ SSZ SSZ SSZ

FSV RB

Validity: interferon according to FSV RB

Average tablet weight from 570 to 605 6o8 god god 607 605 630 mg (600 mg 5 5 95

Specific activity from 80,000 IU to 140! 110000 | 110000 | 110000 | 110000 | 110000 | 100000 | 110,000,000 IU, the total amount is more than 102 CFU/G 10 10 10 10 10 10 10 total amount. I'm less |less |less less less less |less 10! CFU/g

Rzepdotopav aegidiposis are absent in 1| absent | absent | absent | absent | absent | absent | absent d

During long-term studies of the stability of the finished medicinal product "tablets for absorption, 100,000 IU" for 24 months, no significant changes were found.

The results of the stability study confirm a shelf life of 2 years.

Sources of information: 1. Ipenegop aiga-2 sopsepigayed voIshiop, topodgari 07/2015:1110: EEpgoreap Rpaptasoroviia 8.5. - R. 4989-4985. 2. Reaferon-ES: Instructions for use of the medicinal product, ND RB 7399-2015. 3. Naumova, L.M. Application of new form! of liposomal interferon alpha-2p5 in the treatment of influenza and other acute viral respiratory diseases. - L. M. Naumova and others:

Polyclinic, May 4, 2012. - P. 102-106. 4. Guide to conducting preclinical studies of medicinal products / Ed. Myronova A.N. - M., 2012. - part one, p. 846.

Claims (4)

FORMULA OF THE INVENTION 1. The tableted form of an antiviral drug, intended for local use in the oral cavity, with the following composition, mg/tablet: human interferon. recombinant alpha guy! 0000 IU to or alpha-25 talc 0.1-12.0 magnesium stearate 2.0-12.0 binding agent 50.0-3000.0. 2. The tablet form according to claim 1, which is characterized by the fact that the binding agent is selected from the group including sorbitol, mannitol, xylitol, lactose, glucose, sucrose, starch, polydextrin, macrogol 4000 or their combination. 3. The tablet form according to claim 1, which is characterized by the fact that it additionally contains pharmaceutically acceptable flavoring agents and flavoring agents. 4. The tablet form according to claim 1, which differs in that it is made in the form of lozenges, buccal or sublingual tablets.