RU2491087C1 - Multifunctional combined drug preparation for correcting immune deficiencies and treating severe infectious-inflammatory diseases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, and concerns a new multifunctional combined interferon drug preparation of broad spectrum of action. A preparation in the form of a suppository contains a synergistic combination of the immunomodulator interferon alpha-2b and the herbal biostimulant aloe extract; it contains vitamin E, glycine, buffer salts, tysol, lecithin and solid fat as a base in the specified proportions.

EFFECT: invention provides preparing the combined drug preparation in the form of long storage-stable suppository having the standard physical-chemical, structural and mechanical, multifunctional biological properties, higher bioavailability and synergistic therapeutic efficacy of interferon alpha-2b with the herbal biostimulant aloe extract.

1 cl, 5 tbl, 3 dwg

Description

The invention relates to medicine and the pharmaceutical industry and relates to a new multifunctional combined drug of a wide spectrum of action based on interferon, namely a rectal suppository for the correction of immunodeficiency states and the treatment of infectious viral diseases. The drug contains a synergistic combination of an immunomodulator interferon alpha-2b with a natural biostimulant aloe extract. The composition of this tool also includes glycine, tizol, lecithin, vitamin E, a buffer solution and solid fat as a suppository base.

The immune system is one of the most important systems of our body. It is difficult to overestimate its role, because it is the immune system that protects our body from harmful factors of both the external and internal environment, helps us cope with many diseases.

The modern rhythm of life, the state of ecology and a number of other factors negatively affect immunity. It is known that a decrease in immunity leads to the emergence of infectious diseases that are difficult to treat and often aggravated by the development of complications or the formation of life-threatening conditions.

In the treatment of various infectious diseases, a fairly wide range of drugs that affect the immune system is used, among the most promising are interferon preparations. Interferons are widely used for the correction and treatment of chronic viral diseases of the liver and are the only antiviral drugs that reduce the risk of cirrhosis and its transformation into hepatocellular carcinoma [N. Blokhina. New strategies for interferon therapy in patients with chronic hepatitis C // Viral hepatitis. 1999.V.2. No. 6. S.11-18; Arinenko R.Yu., Anikin V.B., Golovkin V.I. Interferon system: the first line of defense // Terra Medica. 1997. No4. S.11-14].

Significant progress in the treatment of immunodeficiency conditions aggravated by various clinical pathologies has been achieved in the field of drug development based on human interferon alfa-2b, the production of which uses recombinant DNA technology, which significantly reduces the cost of production and also reduces to zero the likelihood of transmission of any infection from the donor.

It is recognized that the number of side effects decreases with rectal use of drugs. In particular, with this method of administration, the production of antibodies to interferon does not occur, significantly reducing the effectiveness of therapy.

Known drug Kipferon based on interferon human recombinant alpha type with a complex immunoglobulin preparation containing immunoglobulins of classes A, M, G, and having antiviral and immunomodulating activity that can be used in the treatment of a wide range of viral diseases [Patent No. 2073522 RU, IPC A61K 9/02. Antiviral drug].

The drug contains antibodies derived from human blood, which can lead to potential contamination with human viruses or other donor agents.

Known drug Genferon, containing natural interferon or recombinant interferon alpha, or beta, and / or gamma types and taurine (taufon), as well as excipients in a certain ratio [Patent No. 2201212 RU, IPC A61K 9/00. Suppositories with immunomodulatory, antiviral, antibacterial, regenerative, reparative, membrane and hepatoprotective effects].

Genferon contains anesthesin, which can cause allergic reactions and a persistent decrease in sensitivity at the site of use.

Known drug for the treatment of severe forms of infectious diseases and mixed infections. It contains human recombinant interferon alpha, and / or beta, and / or gamma types, an antioxidant complex, a vitamin complex, as well as orotic acid and / or ornithine or its derivative citruline malate, or glutoxime, antibacterial, antimycotic substances [ Patent No. 2366450 RU, IPC A61K 38/21, A61K 31/195, A61K 31/355, A61K 31/375, A61K 31/525, A61P 31/00, A61P 37/04. A remedy for the treatment of severe infectious and inflammatory diseases and mixed infections].

The composition is complex, which increases the risk of individual intolerance to the drug. Its effect is due to biologically active components that increase the activity and provide a synergistic effect of the drug, includes antibiotics and other synthetic biologically active substances that have a number of side effects. The suppository form, although it reduces side effects, does not exclude the formation of antibiotic-resistant microflora strains.

However, it should be noted the advantages of the combined dosage form, which, in turn, can be divided into subjective and objective.

“Subjective” benefits include:

- ease of use for the patient (eliminates his memory and attention from the need to make complex combinations of various dosage forms and take them "handfuls", etc.);

- psychological and social comfort (it is much easier to use one unit of the dosage form than several, during work, in a public place, etc.);

- economic factor - in most cases, the price of combination drugs is lower than the total price of single drugs.

"Objective" advantages of combined drugs - potentiation of action due to:

- unidirectional effect of the ingredients;

- reducing the inactivation of a drug substance in the body (suppression of biotransformation);

- the creation of one ingredient conditions for the manifestation of the effect of another;

- reduced risk of side effects;

- modeling of natural processes in the body.

Problems in the treatment of infectious and inflammatory diseases associated with a decrease in immunity and the development of complications determine the feasibility of developing new complex drugs with a synergistic effect.

Known drug Viferon containing genetically engineered interferon alpha-2, antioxidants - ascorbic acid and alpha-tocopherol [Patent No. 2024253 RU, IPC A61K 9/02. Rectal suppositories and a device for introducing rectal suppositories into the body cavity]. The tool can be used to treat various diseases in which interferon preparations are effective, including viral hepatitis, acute respiratory viral infections, rheumatoid arthritis, meningitis. It was shown that the specific activity of interferon increases significantly in the presence of antioxidants. This drug is taken as the closest analogue (prototype).

The second object claimed in the patent - the device provides three functions at once: it is a form for casting candles, their storage and administration to the patient.

The disadvantages of the group of solutions include: the complication of the preparative form of the drug for manufacturing purposes and the cost of the drug due to the use of a disposable special device for its administration, which, although it prevents the product from reaching the skin and helps to reduce the microbial contamination of the patient’s body during drug administration, solves the problems of an inevitable decrease in the resistance of the mucous membranes to the action of damaging agents (most often of synthetic origin) and does not have a natural resource of antimicrobial action. At the same time, the storage periods of the claimed composition (i.e., compliance with the requirements of the pharmacopeia) outside the use of the claimed device are not indicated.

Currently, clinical medicine is showing increasing interest in herbal medicines with sufficient efficacy and minimally toxic effects. Biogenic stimulants are found to be widely used in the complex therapy of many diseases, which, when introduced into the body, can have a stimulating effect and accelerate the regeneration processes and, at the same time, are low toxic.

Based on the foregoing, the feasibility of developing suppository forms with improved specific activity of immunomodulators in conjunction with natural plant biostimulants for the treatment of severe infectious diseases is obvious.

The objective of the present invention is to develop a multifunctional combined drug for the correction of immunodeficiency conditions and the treatment of severe infectious and inflammatory diseases based on the combination of interferon alpha-2b with a biostimulant of plant origin, which has given physico-chemical, structural-mechanical and biological properties that meet and meet the requirements of the pharmacopeia improved specific activity and effectiveness of the drug, with increased bioavailability Tew.

The essence of the invention consists in experimentally sound selection of components and their concentrations that have the necessary properties to provide the drug with the specified characteristics, confirming the technological capabilities of the real implementation of the solution found.

The technical result is the preparation of a combined drug in the form of a suppository that is stable during long-term storage and has standard physicochemical, structural-mechanical, multifunctional biological properties, increased bioavailability and synergistic therapeutic efficacy of interferon alpha-2b with a plant-derived biostimulator of aloe extract.

The technical result is achieved in that the suppository mass also contains effective amounts of a natural antioxidant and emulsifier and auxiliary substances having a certain therapeutic activity and the ability to improve the technological characteristics of active substances. As auxiliary substances, the composition of the claimed funds includes a promoter of absorption of active substances, a stabilizer of interferon activity, a natural emulsifier and a buffer solution of salts. The resulting drug is characterized by the stability of physico-chemical and biological properties, their multifunctionality, improved tolerance, reduced toxicity, increased bioavailability, effectiveness, increased shelf life.

A multifunctional preparation based on a synergistic combination of an immunomodulator interferon alpha-2b and a biostimulator of aloe extract, as well as vitamin E, contains interferon-stabilizing auxiliary substances, such as glycine and salt buffers, tizol and emulsifier lecithin, which increase the bioavailability of the drug, and solid fat as a suppository the basics in the following ratios of components to obtain a suppository weighing 1.45 g (g):

Human recombinant interferon alpha 2b 400000 ME-675000 ME Dry aloe extract 0.05-0.07 Vitamin E 0.04-0.06 Glycine 0.014-0.016 Buffer solution 0,100-0,104 Lecithin 0.012-0.016 Tizol 0.04-0.06 Solid fat rest

The description of the invention is illustrated in tables 1-5 and figure 1-3.

Figure 1 - ¹ H NMR spectrum of solid fat (manufactured by Loders Croklaan, Holland).

Figure 2 - NMR spectrum of ¹ H suppositories combined composition.

Figure 3 - curves "dose - response" differential (a) and integral (b); on the left is the pharmacological response; on the right is a toxic response.

Table No. 1 presents the compositions of model mixtures of the claimed funds.

Recombinant human interferon alpha-2b is a water-soluble protein with a molecular weight of about 19,300 Da. It is obtained from a clone of Escherichia coli containing a plasmid hybrid obtained by genetic engineering, which includes the interferon alpha-2b gene from human leukocytes. Interferon acts in several directions. Firstly, it affects the cells adjacent to the infected one, triggering a chain of events in them leading to a suppression of the synthesis of viral proteins. The second direction of action of interferons is the stimulation of the immune system to fight viruses. Interferon also causes a number of other biological effects, including inhibiting cell reproduction. Recent studies have shown that under certain conditions it can inhibit the development of malignant neoplasms.

High prophylactic and therapeutic effect against many viral and bacterial infections showed drugs with the main active ingredient - interferon alpha. It turned out that interferon alpha has the unique ability to almost instantly trigger the destruction of viruses, pathogenic bacteria and fungi, allergens and other antigens. Thanks to alpha interferon, the coordination of the actions of various cells of the immune system that stop the growth and reproduction of infectious agents is ensured. Interferon alpha prevents and slows down the action of T-suppressors, which suppress the immune response of B-lymphocytes and other T-lymphocytes to antigens. Interferon alpha, by increasing the number of receptors on the membrane of immune cells, enhances the capture and absorption of foreign agents by them, and activates the production of specific antibodies that destroy antigens. Interferon alfa is involved in the formation of a defense mechanism against intracellular pathogens. Under its influence, the formation of proteins on the cell membrane is enhanced, thereby improving the process of recognition and destruction of antigens by T cells. Alpha interferon activates factors that increase the likelihood that foreign agents will be recognized by immune cells, and also contribute to the rapid elimination of antigens from the body. As a result, immunity is strengthened and the body's resistance to infection increases, and the oncological process slows down or stops.

To date, it is generally accepted that alpha interferons are most effective in the treatment of chronic viral diseases, they are the only antiviral drugs that reduce the risk of liver cirrhosis and its transformation into hepatocellular carcinoma. Recombinant alpha-2b interferon preparations are in demand in the treatment of patients with influenza and other acute respiratory diseases [Interferon status, interferon preparations in the treatment and prevention of infectious diseases and patient rehabilitation / Ed. S.S. Afanasyev [et al.]. M., 2005].

The most commonly used biogenic stimulant is aloe extract. It has an adaptogenic, tonic, laxative, antiseptic and choleretic effect. It improves cellular metabolism, trophism and tissue regeneration, increases the general nonspecific resistance of the body and the resistance of mucous membranes to the action of damaging agents, and accelerates the regeneration process. Aloe acts on the immune system, activating macrophages, causing the release of interferons and interleukins. It has some antimicrobial activity against streptococci, staphylococci, typhoid and dysenteric rods, Proteus. Stimulates the protective function of granulocytes, stimulates appetite. Increases energy reserves in sperm and enhances their motility. Aloe-containing preparations are widely used in many fields of medicine (gynecology, dentistry, dermatology, surgery, therapy, immunology) [Oleinikov D.N., Zilfikarov I.N., Ibragimov T.A. The study of the chemical composition of aloe tree (AloeArborescensMill.), 2010. No. 3. S.77-82].

The composition of the claimed funds aloe extract is introduced as a substance that increases the specific activity of interferon. A study was made of the specific activity depending on the composition of the combined suppositories in comparison with suppositories containing as an active substance only interferon alpha-2b. In the experiment, it was found that the antiviral activity of the sample of the claimed drug is almost 40% higher than the antiviral activity of sample No. 1, containing only interferon alpha-2b (See table 2).

Determination of specific antiviral activity

Standard sample:

- the international standard Interferon alpha 2b, (Human r DNA derived), NIBSC Code: 95/566, or the standard sample of the enterprise (SOP), the antiviral activity of which is established relative to the International standard Interferon alpha 2b, (Human r DNA derived), NIBSC Code: 95/566 with a confidence level of 0.95.

Indicator virus:

- Vesicular stomatitis virus, Indiana strain, deposited at the Institute of Virology. D.I. Ivanovskii (number in the collection of GKV-29).

The antiviral activity of the drug is determined in comparison with a standard sample. Dilution of the International Standard Interferon alpha 2b is carried out in accordance with the instructions.

To determine the specific activity of the drug, 96-well culture plates with cell culture for titration are prepared.

For the titer of interferon, take the value inverse to the dilution of the drug, in which the cell culture in 50% of the holes was completely protected from the cytopathic effect of the virus.

Vitamin E includes a group of compounds (tocopherols and tocotrienols) that have α-tocopherol activity [Blazheevich N.V., 1984].

A fat-soluble vitamin whose function remains unclear to the end. As an antioxidant, it inhibits the development of free radical reactions, prevents the formation of peroxides that damage cell and subcellular membranes, which is important for the development of the body, normal function of the nervous and muscular systems, prevents the hemolysis of red blood cells, and inhibits the oxidation of unsaturated fatty acids. A lack of vitamin E can be one of the causes of lethargy and anemia.

The composition of the claimed drug, vitamin E is introduced as a substance that prevents the negative effect of free radicals in the body and the occurrence of solid fat oxidation processes during storage of suppositories. We studied the stability of the physico-chemical parameters of suppositories depending on the concentration of vitamin E. The results of the experiments are presented in table No. 3.

The data in table 3 indicate the effect of glycine and vitamin E on the stability of active substances in suppositories. As can be seen from the table, interferon alfa-2b tends to decrease activity during storage. After six months of storage, its activity drops by 10% in composition No. 1, which contains the minimum amounts of glycine and vitamin E. The best preservation of interferon alpha-2b and glycosides of anthracene derivatives of aloe extract in terms of aloe emodin is provided by a combination of glycine and vitamin E in combination 0.015 g and 0.05 g, respectively. So after 15 months of storage in compositions No. 3 and No. 10, the content of interferon alpha-2b compared to the original decreased slightly. A similar relationship has been identified for aloe emodin.

Glycine - the simplest aliphatic amino acid, is a metabolic regulator, normalizes and activates the processes of protective inhibition in the central nervous system, reduces psychoemotional stress, increases mental performance. In the composition of the claimed medicinal product, in addition to therapeutic properties, glycine is introduced as a stabilizer of the activity of interferon (see table 1).

Lecithin is a natural emulsifier that allows you to get stable emulsions in oil-water systems. Consists of esters of amino alcohol choline and diglyceride phosphoric acids; is an essential representative of phospholipids. Lecithin has a powerful antioxidant effect, prevents the formation of highly toxic free radicals in the body. With a lecithin deficiency, the effectiveness of the effects of drugs decreases. The composition of the claimed drug lecithin is introduced as an emulsifier. In vitro experiments studied the effect of lecithin on the rate of release of active substances from suppositories. It should be noted that when developing the composition and technology for preparing combined suppositories, the target concentration of interferon alpha-2b in the finished product is very small (500,000 IU / suppository, which corresponds to 0.001182 g). Determining the concentration of interferon alpha-2b in the dialysate is difficult, since quantification by specific activity is expensive and time-consuming, and the sensitivity of the NMR spectroscopy technique is insufficient. Therefore, when choosing the concentration of lecithin in suppositories, the degree of release of the active substances (aloe emodin) of the aloe extract into the dialysate was evaluated, and sampling was carried out 60 minutes after the start of dialysis. This is also due to the low content of aloe extract in suppositories and the sensitivity of the quantification method. In addition, physicochemical quality indicators of suppositories were also evaluated depending on the type of emulsifiers used. The results of the study are presented in table 4.

Tizol ^® is an original domestic drug that has no analogues. It is a conductor of drugs, provides conductivity through the skin, mucous membranes and other biological tissues to a depth of 8 cm. It serves as the basis for the preparation of soft dosage forms, combines well with medicinal substances, delivers the medicinal substance introduced into the pathological focus without destroying it, and completely releasing unchanged. Tizol ^® has anti-inflammatory, dehydrating, protective, decongestant, local analgesic, moisturizing, antipruritic effect, accelerates reparative processes. An important technological feature of thysol is the provision of microbiological purity and sterility of medicinal compositions, which eliminates the need for the introduction of antimicrobial preservatives, which can cause unwanted side effects. In addition, tizol significantly increases the shelf life of medicinal compositions and reduces the treatment time compared to traditional treatment methods (see tables No. 3 and No. 5).

Given the physico-chemical and therapeutic properties of the components used and due to experimentally found their original combination and ratio when developing the inventive drug in the form of suppositories, it becomes possible to achieve high efficiency and stability of the claimed medicinal product.

Thus, a distinctive feature of the proposed drug in the form of suppositories is precisely the combination of an immunomodulator interferon alpha-2b and a natural biostimulant of plant origin of aloe extract, as well as a complex of substances with certain properties that increase the specific activity, therapeutic efficacy and stability of the dosage form during storage, and which has not previously been used in medical practice.

This combination made it possible to obtain a stable multifunctional agent for the correction of immunodeficiency conditions and for the treatment of a number of serious infectious diseases with complications of varying severity, including oncological ones.

The drug is made in the form of suppositories by the traditional method in accordance with the "Pharmaceutical Technology: Technology of dosage forms", 2nd ed., Moscow: Publishing Center "Academy", 2006.

The technology of production of suppositories is reduced to the sequential addition of active components to the base, which greatly simplifies the production process and ensures the quality of the resulting product due to the reduction in the number of critical process parameters.

To ensure the stability of human recombinant interferon alfa-2b, it is necessary to use a buffer solution containing sodium hydrogen phosphate dodecahydrate (GOST 4172-76) and sodium dihydrogen phosphate dihydrate (GOST 245-76).

Given the research results when choosing the composition, the production technology of the developed suppositories was based on the pouring method. The method of pouring is currently used in Russia more often than others due to uncomplicated technological equipment.

Ancillary stages regarding the preparation of purified water and preparation of production are carried out in accordance with the rules of GMP.

The sterile components of the suppository were used: the base was sterilized by autoclaving, aqueous solutions of the active substances and the buffer solution were sterilized by sterilizing filtration.

The claimed tool was studied by NMR spectroscopy of a solid (Figure 1, Figure 2). The possibility of interaction of the active components with the specified base and with each other was studied. The observed absence of signal shifts of the proton components in the spectra of suppositories can be considered evidence of the absence of interaction between all active and auxiliary components of the finished dosage form, which in turn indicates the stability of the claimed funds during long-term storage.

A preclinical study of the claimed drug was carried out. In the preclinical drug research system, the first step is to evaluate the toxicity of the compound for cell culture and laboratory animals [Guide to the experimental (preclinical) study of new pharmacological substances. 2nd ed., Revised. and add. M .: Medicine, 2005].

Assessment of the toxicity of the claimed funds was carried out on laboratory animals: mice weighing from 19 g to 21 g and rats. The total duration of observation of the animals was 2 weeks, and on the first day after administration, the animals were under continuous observation. Regularly recorded the general condition of animals, their behavior, the intensity and nature of motor activity, the presence and nature of seizures, coordination of movements, the frequency and depth of respiratory movements, the condition of the hair and skin, tail position, feed and water consumption, and body weight change. The timing of the development of intoxication and death of animals was recorded.

A study of the claimed toxicity agent was carried out at the Center for Diagnostic Research of the PSC of RUDN University with financial support from the Ministry of Education and Science.

In laboratory conditions, acute and chronic toxicity of the claimed drug was established. The studies were strictly regulated by the relevant regulatory documents, which determine the experimental design and procedure, conditions of keeping and ration of animal feeding, their number, methods of drug administration, time, amount of drug administered, duration of observation, description of the condition of animals, etc.

In the study of acute toxicity, the dependence of the proportion of dead mice,% of the dose of the test drug (Figure 3), was established. The experimental dose-response curve determined the following indicators: LD10 (the dose at which 10% of the experimental mice die) and LD50 (the dose at which 50% of the experimental mice die). In our studies for the claimed means LD50 to determine for these animals was not possible. So we injected the mice intravenously with an aqueous extract from the suppository. An extract was prepared as follows: one suppository was dissolved in 1 ml of water for injection at a temperature of 37 ° C for 15 minutes. The resulting mixture was then filtered through a paper filter and injected into mice intravenously and intraperitoneally at an interferon dose of more than 10,000,000 IU per mouse. In this case, the mice remain alive for more than 5 days. (The test dose for monitoring interferon toxicity is 1,000,000 IU / 0.5 ml saline per mouse).

The determination of the chronic toxicity of the claimed drug was carried out on 56 male and 56 female rats with its daily administration for 14 days in high dose (4 suppositories) and in small dose (1 suppository). Animals were divided into 8 groups. Table 3 presents the study of chronic toxicity of the claimed drug. During the experiment, the following indicators were taken: the volume of animal consumption of feed and water; the dynamics of changes in body weight, changes in general condition and behavior; hematological and biochemical parameters, etc.

From the results of the experiment it follows that the claimed drug is a non-toxic drug, well tolerated by laboratory animals, since when it was introduced, there were no visible deviations in the behavior of the animal and its physiological state.

Thus, the distinguishing feature of the proposed drug in the form of suppositories is precisely the combination and quantitative ratio of the immunomodulator interferon alpha-2b and the natural biostimulant of plant origin of aloe extract, as well as a complex of substances with certain properties that increase the specific activity, therapeutic effectiveness and stability of the dosage form in the process storage, providing low toxicity of the drug. The drug does not include antimicrobial preservatives, contains natural antioxidant vitamin E and emulsifier lecithin. The original domestic drug tizol increases the bioavailability and stability of suppositories during storage.

The drug is sold in an experimentally selected ratio of components, meets the requirements of the pharmacopeia and has not been previously used in medical practice.

Table 1 The compositions when choosing the recipe of the claimed funds name of raw materials Composition number one 2 3 four 5 6 7 8 9 10 IFN alpha-2b human recombinant, thousand ME 500 500 500 500 500 500 500 500 500 500 Aloe extract dry, g 0.015 0.015 0.015 0.015 0.015 0.015 0.015 0.250 0.06 0.06 Glycine, g 0.005 0.01 0.015 0.005 0.005 0.01 0.015 0.015 0.015 0.015 Vitamin E, g 0.005 0.01 0.05 0.05 0.01 0.005 0.005 0.01 0.01 0.05 Tizol, g 0 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Buffer solution *, g 0.012 0.012 0.012 0.012 0.012 0.012 0.012 0.012 0.012 0.012 Lecithin, g 0.014 0.014 0.014 0.014 0.014 0.014 0.014 0.014 0.014 0.014 Solid fat, g 1,399 1,384 1,294 1,304 1,344 1,339 1,334 1,104 1,289 1,249 Note: * Buffer solution of sodium hydrogen phosphate dodecahydrate and sodium dihydrogen phosphate dihydrate

table 2 Antiviral activity of drugs in one suppository Sample No. Name of ingredients Activity, ME * one Interferon alfa-2b (buffer solution), lecithin, solid fat 606000 2
(Claim-
volume
means) Interferon alfa-2b, (buffer solution), dry aloe extract, tizol, glycine, vitamin E, lecithin, hard fat 849333

Table 3 The dependence of stability on the composition of the composition (on the concentration of the stabilizer, antioxidant and promoter of absorption) Term
observing
niya The determined amount of interferon alpha-2b in one suppository should be 500 (400 to 675) thousand ME (Determination of antiviral activity in cell culture) Determined amount of aloe-emodin (HPLC) *, mg / suppository Composition number Composition number one 2 3 four 5 6 7 8 9 10 8 9 10 Svezheprig. 435 465 510 490 450 450 460 450 450 500 250 63.0 65.0 6 months 400 438 500 485 420 410 425 430 420 500 210 62.0 62,4 12 months 370 395 500 480 390 380 387 400 400 500 210 61.7 62.3 15 months 350 385 500 475 380 345 342 400 388 495 200 61.5 62.3 * the limits of the quantitative content of aloe-emodin in the suppository are not indicated, since it is different depending on the composition

Table 4 Surfactant Selection Name of surfactant Quality indicators Melting point, ° С The time of complete deformation, min Hardness, kg / suppository. % Release of active substances (aloe-emodin) from suppositories 2 hours after the start of dialysis through a semipermeable membrane in experiments (in vitro) (HPLC method) Emulsifier number 1 37.2 ± 0.1 12.4 ± 0.15 4.2 ± 0.2 51.3 ± 1.3 Emulsifier number 2 37.1 ± 0.3 13.23 ± 0.17 4.2 ± 0.4 54.6 ± 1.8 Twin 80 36.2 ± 0.2 4.15 ± 0.26 3.2 ± 0.1 65.0 ± 1.2 Ceteareth-25 36.6 ± 0.5 6.46 ± 0.14 4.0 ± 0.5 63.9 ± 0.9 Gelucire 44/14 36.7 ± 0.2 5.10 ± 0.54 3.5 ± 0.2 62.2 ± 1.1 Lanette sx 36.8 ± 0.5 4.26 ± 0.31 3.7 ± 0.1 68.2 ± 0.8 Lecithin 36.2 ± 0.1 3.17 ± 0.22 2.9 ± 0.1 75.2 ± 0.5 Without emulsifier 36.9 ± 0.3 9.35 ± 0.47 3.9 ± 0.8 49.2 ± 1.6

Claims (1)

A multifunctional combined drug for the correction of immunodeficiency conditions and the treatment of severe infectious and inflammatory diseases based on interferon alpha-2b, characterized in that it is made in the form of suppositories, including interferon human recombinant alpha-2b, aloe extract dry, buffer solution, vitamin E, glycine, lecithin, tizol and solid fat in the following ratios of components to obtain a suppository weighing 1.45 g (g):
Human recombinant interferon alpha 2b 400000 ME-675000 ME Dry aloe extract 0.05-0.07 Vitamin E 0.04-0.06 Glycine 0.014-0.016 Buffer solution 0,100-0,104 Lecithin 0.012-0.016 Tizol 0.04-0.06 Solid fat rest

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