RU2607965C1 - Liquid dosage form of fenspiride and production method thereof - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and represents liquid dosage form of fenspiride hydrochloride in form of syrup, including fenspiride hydrochloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, potassium sorbate, sodium citrate, citric acid monohydrate, sodium saccharinate, noncrystallizing liquid sorbitol, glycerin, honey flavoring agent, fruit flavoring agent, dye E110 and purified water, wherein ingredients of the dosage form are taken in certain proportions, g/100 ml.

EFFECT: invention provides extending range of medications, which are liquid dosage forms of fenspiride hydrochloride, stable and long-term storable without use of sucrose.

2 cl, 14 dwg, 9 tbl

Description

Technical field

The invention relates to medicine, in particular to the pharmaceutical industry, and describes a liquid oral dosage form in the form of a syrup, including fenspiride hydrochloride.

State of the art

Respiratory diseases account for up to 80% of diseases diagnosed in children and adolescents [Experience of using the drug fenspiride hydrochloride in the treatment of acute respiratory diseases in children in outpatient practice / Yu.V. Chernenkov, O.I. Gumenyuk, I.Yu. Popova, E.E. Raskina, N.N. Doblo // Pediatrics. - 2010. - Volume 89 - No. 1. - S. 95-98]. Along with a high incidence rate, there is an increase in the number of recurrent and chronic forms of respiratory diseases in the general population, often leading to disability [Mechanisms of bronchial obstruction and therapeutic tactics for bronchitis in children]. Sereda, O.F. Lukina, L.R. Selimzyanova // Pediatrics. - 2008. - No. 87 (6). - S. 146-149. Children's health in Russia (state and problems). Ed. A.A. Baranova. M.: Union of Pediatricians of Russia, 1999. White Paper: Pulmonology / Chuchalin A.G. // Pulmonology. - 2004. - No. 1. - S. 7-34]. These diseases pose the greatest danger to the child in the first three years of life [Fenspirida hydrochloride: experience of using ARI in children // Information and analytical newspaper Pharmaceutical Bulletin. 10/27/2010].

At the same time, according to statistics, 20-25% of children in Russia can be classified as often sick, i.e. carrying 6 to 12 episodes of upper respiratory tract infections per year. Diseases of the respiratory organs of children of the first year of life lead to death in 7.8% of cases [Rational antibacterial therapy in the intensive care units and intensive care / M.A. Georgyants, Yu.A. Vinnik, V.A. Korsunov // Clinical antibiotic therapy. - 2003. - No. 2. - S. 8].

The high prevalence of upper respiratory tract infections is partly due to inadequate treatment, including the simultaneous prescription of an unjustifiably large number of drugs, mainly symptomatic therapy [Fenspirida hydrochloride: experience of using ARI in children // Information and analytical newspaper Pharmaceutical Bulletin. - 10.27.2010].

In recent years, fenspiride hydrochloride (Erespal ^® syrup, Labs Servier Industry, France) has been successfully used as an anti-inflammatory drug in acute, recurrent and chronic respiratory diseases, which has a pronounced anti-inflammatory effect and tropism to the mucous membrane of the respiratory tract [Mechanisms of bronchial obstruction and therapeutic tactics for bronchitis in children / E.V. Sereda, O.F. Lukina, L.R. Selimzyanova // Pediatrics. - 2008. - No. 87 (6). - S. 146-149. Efficiency and safety of fenspiride hydrochloride (Erespal) in the treatment of children and adolescents in the early rehabilitation period of community-acquired pneumonia / N.D. Soroka, E.V. Korshunova, S.P. Gomozova, T.G. Vlasova, V.N. Kotelnikova // Pediatrics. - 2010. - Volume 89. - No. 2. - S. 120 127].

Fespirid hydrochloride - 8- (2-phenylethyl) -1-oxa-3,8-diazaspiro (4,5) -decane-2-OH is an anti-inflammatory drug that has an antiexudative effect that prevents the development of bronchospasm. It shows antagonism with mediators of inflammation and allergies: serotonin, histamine (at the level of H1-histamine receptors), bradykinin {Anti-inflammatory drug fenspiride / A.A. Vizel, I.Yu. Vizel, I.Yu. Pronina // Pulmonology. - 2007. - No. 2. - S. 80-88].

Fespirid hydrochloride (Erespal syrup) has proven itself in the treatment of bronchial asthma in children [Pathogenetic rationale for the use of fenspiride (erespal) in bronchial asthma in children / C.V. Lukyanov [et al.] // Pulmonology. - 2001. - No. 4. - P. 59-64], acute respiratory viral infection [Results of a multicenter study of the effectiveness of fenspiride hydrochloride (erespal) in the treatment of acute respiratory infection in children / G.A. Samsygina, S.B. Fitilev, A.M. Levin // Pediatrics. - 2003. - No. 2. - S. 81-85], chronic bronchitis [The effectiveness of fenspiride in patients with chronic obstructive bronchitis / T.D. Shorokhov [et al.] // Clinical Medicine. - 2001. - No. 8. - S. 55-57], diseases of the broncho-pulmonary system and ENT organs [Erespal (fenspiride) in the treatment of diseases of the broncho-pulmonary system and ENT organs / А.S. Sokolov // Pulmonology. - 2003. - No. 5. - S. 122-127]. There are reports of the effectiveness of fenspiride in chronic obstructive pulmonary disease [Clinical and functional status and quality of life of patients with chronic obstructive pulmonary disease before and after treatment with fenspiride in an outpatient setting / S.I. Butorov [et al.] // Therapeutic Archive. - 2008. - T. 80. - No. 3. - S. 24-28].

Currently, the high clinical effectiveness of fenspiride hydrochloride has been proven in the treatment of almost all diseases of the upper respiratory tract, various clinical options for bronchitis, exacerbations of chronic obstructive pulmonary disease.

Fenspiride is included in the list of vital and essential medicines (Vital and Essential Drugs).

The use of fenspiride hydrochloride in the treatment of acute respiratory infections (ARI) in children of the first months of life allows you to stop the main symptoms of ARI (rhinitis, pharyngitis, cough). In addition, monotherapy of fenspiride with hydrochloride in the treatment of ARI allows avoiding polypharmacy (prescribing sick children several drugs at the same time - mucolytics, mukokinetics, bronchodilators and antihistamines).

The highest incidence of influenza and ARVI are observed in children of the first 6 years of life. It is known that childhood, especially early and preschool, is characterized by a significantly higher sensitivity of the child's body to viral and viral-bacterial agents that penetrate the respiratory tract, and, accordingly, a significantly higher incidence of ARI. Hence it is obvious that the high risk group for the incidence of viral and viral-bacterial infections of the respiratory tract are children of the first years of life [G. Samsygina Anti-inflammatory therapy for acute respiratory infections in children. Pediatrics - 2011. - Volume 90. - No. 1. - S. 102-105].

Given the children's age of patients, as well as the symptoms of ARI (inflammation and swelling of the respiratory tract), the problem of difficulty swallowing drugs is relevant. Dysphagia (difficulty swallowing) is widespread, especially among children and the elderly, and according to various estimates, approximately 35% of the population. In this regard, the release of fenspiride drugs in liquid form seems to be the most convenient and safe.

Fenspiride preparations are marketed in the form of film-coated tablets and syrups.

The following liquid dosage forms of fenspiride hydrochloride are widely known and presented on the domestic market from the prior art:

- "Erispirus®" in the dosage form of syrup in a dosage of 2 mg / ml in a bottle of 150 ml, manufactured by Sandoz D. (Slovenia), registration certificate No. LP-002715 dated November 14, 2014

- “Syres” in the dosage form of syrup in a dosage of 2 mg / ml in a bottle of 150 ml, manufactured by Pharmaceutical Plant Polfarma AO (Poland), registration certificate No. LP-002683 dated 10.29.2014.

- “Erespal®" in the dosage form of syrup in a dosage of 2 mg / ml in bottles of 150 and 250 ml, produced by the company Servier Laboratory (France), registration certificate No. P N012547 / 02 of 06/28/2010

These preparations, in addition to the active active ingredient (fenspiride hydrochloride) also contain: antimicrobial preservatives (methyl parahydroxybenzoate, propyl parahydroxybenzoate, potassium sorbate), hydrophilic solvent (glycerin), flavoring agents (saccharin, licorice root extract), colorants and flavoring agents, water in the main solvent, water . Also, the composition of all the above preparations contains flavor flavoring simultaneously performing the function of a thickener - sucrose.

At the same time, the concentration of sucrose in syrups is about 60-65% or 600-650 mg / ml. This amount of sucrose is optimal because syrups with a sugar concentration higher than 66%, when stored and slightly cooled, are sugared, forming large, hardly soluble sucrose crystals. At the same time, syrups with a sugar concentration below 60% are fermented and soured.

At the same time, the use of sucrose contributes to the development of hyperglycemia, increased insulin release into the bloodstream, and the depletion of the insular apparatus, which contributes to the development of diabetes mellitus. For patients with this disease, the use of sucrose is contraindicated or permissible in small quantities with increased caution. The increased amount of sucrose that enters the human body cannot be fully deposited in the form of glycogen and converted into triglyceride, which contributes to the development of living tissue, an increase in blood cholesterol and the development of a number of severe cardiovascular diseases. It is also known about the destructive effect of sucrose on tooth enamel and its high cariogenic effect.

In this regard, there is a need to develop high-quality and affordable domestic H1 antihistamines containing fenspiride hydrochloride in the form of liquid dosage forms, preferably in the form of syrups, convenient for use, stable during storage and having a masking sweet taste, and, in addition, without disadvantages known drugs containing sucrose in their composition.

The closest analogue adopted as a prototype is the widely distributed and well-known on the market drug Erespal® manufactured by Servier Laboratory (France), in the dosage form of syrup in a dosage of 2 mg / ml in 150 and 250 ml bottles (registration certificate No. P N012547 / 02 of 06/28/2010).

The technical task of the present invention is to expand the list of domestic drugs.

The technical result (goal) of the invention is the creation of a liquid dosage form of fenspiride, preferably in the form of a syrup, stable upon receipt and long-term storage, pharmaceutically equivalent to the prototype, but excluding the content of sucrose in its composition.

To achieve this goal, the authors of the present invention attempted to develop an analogue drug - “Fenspiride syrup” 2 mg / ml (the drug being developed), which would not be inferior to the innovative drug “Erespal®” syrup 2 mg / ml in efficiency, safety and quality indicators (“Servier Laboratories”, France), (reference preparation, comparative preparation, prototype).

Disclosure of invention

Based on the objectives of the study, the authors of the present invention, tried to develop a drug pharmaceutically equivalent to the drug "Erespal®" syrup 2 mg / ml, which has comparable indicators of quality and properties, including specific types of action and safety. In this case, it will be possible to predict that the developed drug will also be therapeutically equivalent to the comparison drug.

Medicines are pharmaceutically equivalent if they contain the same amount of the same active substance (the same active substances) in the same dosage forms that meet the requirements of the same or comparable standards. Therapeutically equivalent to another drug is a drug containing the same active substance or its therapeutically active part and clinically showing the same efficacy and safety as the drug whose efficacy and safety has been established [CPMP / EWG / QWP / 1401/98. Note for guidance on the investigation of bioavailability and bioequivalence. - London: CPMP / EMEA, July 26, 2001].

The requirements for a syrup preparation containing fenspiride hydrochloride are not described in the leading pharmacopoeias. General requirements for syrups are described in the monograph “Liguid preparations for oral use” of the European Pharmacopoeia [European Pharmacopoeia 7th Edition. - Strassbourg: European Directorate for the Quality of Medicines & Health Care (EDQM) - Council of Europe, 67075 Strasbourg Cedex, France 2010. - Vol. 1, Vol. 2. - 3536 p.], In the monograph "Liguid preparations for oral use" of the British Pharmacopoeia [British Pharmacopoeia. - 2013, vol. III], in the monograph “Pharmaceutical Dosage Forms: Solutions}) of the United States Pharmacopeia [The United States Pharmacopeia, 36 ed. (NF 31) / Rochiville: United States Pharmacopeia Convention Inc],

Reference drug "Erespal®" syrup 2 mg / ml, contains the following components g / 100 ml:

Components g fenspiride hydrochloride 0.2 licorice root extract 0.2 vanilla tincture 0.4 methyl parahydroxybesoate 0.09 propyl parahydroxybenzoate 0,035 saccharin 0,045 sucrose 60.0 potassium sorbate 0.190 glycerol 22.5 aroma with hints of honey smell 0.5 dye sunny sunset yellow (Sunset Yellow S) 0.01 purified water up to 100 ml

Excipients in the composition of the drug "Erespal ^® " syrup 2 mg / ml perform the following functions:

- licorice root extract - flavor flavoring;

- vanilla tincture, flavoring composition with honey tones - flavors;

- methyl parahydroxybenzoate, propyl parahydroxybenzoate, potassium sorbate - antimicrobial preservatives;

- saccharin - flavor flavoring;

- sucrose - flavor flavoring, thickener;

- glycerol is a hydrophilic solvent;

- dye sunny sunset yellow (Sunset yellow S) - dye;

- purified water - solvent.

The experimental design for the pharmaceutical development of Fenspiride Syrup 2 mg / ml was based on pharmacopoeial and regulatory requirements. It was supposed to develop a preparation in the form of a syrup containing fenspiride hydrochloride as an active substance, an inhibitor of phospholipase A ₂ (PLA ₂ ), a blocker of H1-histamine and α1-adrenergic receptors.

Given the physico-chemical properties of the active and excipients that make up the drug, it was necessary to choose their qualitative and quantitative composition according to the results of physico-chemical, microbiological, technological and analytical studies.

The difficulty of achieving a technical result lies in the exclusion (or replacement) of sucrose from the composition of the drug while preserving its physicochemical, organoleptic, pharmaceutical and therapeutic properties, provided that the sucrose in the reference preparation is not only a flavoring agent, but also a thickener, and given its amount in the composition of the syrup, in fact, along with water, is its basis.

In order to solve this problem, the authors managed to develop a rational composition of the Fenspiride Syrup preparation 2 mg / ml taking into account the composition and properties of the reference preparation Erespal ^® syrup 2 mg / ml, as well as the properties of fenspiride hydrochloride and excipients. At the same time, choose the composition of the drug so that changes in it with respect to the reference drug can be classified as minor changes of type I [The rules governing medicinal products in the European Union. - V. 2. - Notice to Applicants. - V. 2C. - Regulatory Guidelines. - Guideline on Dossier Requirements for Type IA and IB Notifications. - EC. - July 2003. Good Manufacturing Practice for Medicines / Ed. ON. Lyapunova, V.A. Zagoria, V.P. Georgievsky, E.P. Angleless. - K: MORION, 1999 .-- 896 p. The rules governing medicinal products in the European Union. - V. 2. - Notice to Applicants. - V. 2C. - Regulatory Guidelines. - Guideline on the Categorization of new Applications (NA) versus Variations Applications (V). - European Comission. - January 2002. - 11 p.]. The development of the composition must be carried out so that the drug being developed can be qualified as pharmaceutically equivalent relative to the reference drug, as well as taking into account the biomedical requirements for drugs for systemic treatment of the upper respiratory tract, for which:

- the preparation should contain fenspiride hydrochloride in a concentration corresponding to its content in the reference preparation - 2 mg / ml;

- the drug must have the dosage form “syrup” and provide therapeutic equivalence with respect to the reference drug.

In this regard, the critical characteristics for the drug under development are:

- physical stability of the syrup (including a similar pH level);

- microbiological purity, which must comply with pharmacopoeial requirements [5.1.4. Microbiological guality non-sterile pharmaceutical preparations and substances for pharmaceutical use. - European Pharmacopoeia 8.0. - P. 559. State Pharmacopoeia of the Russian Federation. - M.: Publishing House "Scientific Center for Expertise of Medical Applications", 2008. - 704 p.].

In order to achieve the above technical result, the authors of the present invention conducted studies on the selection of flavoring agents, pH flavoring agents (buffering substances), flavors and antimicrobial preservatives of the developed composition.

For the manufacture of laboratory samples used the mixer "Polytron" company "Kinematica" (Switzerland). The experimental series of the preparation were developed in a RP 500 vacuum homogenizer reactor manufactured by Promvit (Ukraine), which models industrial equipment.

For weighing we used EUROPE-C500 and CRYSTAL 200 scales from Gibertini S.A. (Italy).

The pH of the syrups was determined potentiometrically on a 744 pH Meter (Metrohm, Switzerland) with an electrode of the Porotrode type [European Pharmacopoeia 7th Edition. - Strassbourg: European Directorate for the Quality of Medicines & Health Care (EDQM) - Council of Europe, 67075 Strasbourg Cedex, France 2010. - Vol. 1, Vol. 2. - 3536 p.].

The structural viscosity was determined by rotational viscometry on a rotational viscometer with coaxial Reolab-QC cylinders from Anton Paar (Austria), at a temperature of (25.0 ± 0.1) ° С or at other temperatures indicated in the text. Rheograms were constructed reflecting the dependence of the shear stress τ _r on the shear rate gradient D _r , which was used to determine the type of system flow, the presence of thixotropic properties, and the lower, upper, and extrapolated yield stresses. The structural viscosity was calculated by the formula: η = τ _r / D _r [State Pharmacopoeia of the Russian Federation. - M.: Publishing House "Scientific Center for Expertise of Medical Applications", 2008. - 704 p.].

», Германия).Particle size was determined using an MBL-2100 microscope ("

", Germany).

The kinetics of water absorption by syrups, characterizing their osmotic activity, was determined in experiments in vitro by dialysis through a semipermeable cellophane membrane (GOST 7730-89) at a temperature of (25.0 ± 0.1) ° С [GNSSLS work on the creation, implementation and standardization soft drugs and suppositories / N.A. Lyapunov, E.P. Bezuglaya, N.G. Kozlova and others // Farmakom. - 1999. - No. 3. - S. 61-64. Lugano A.S. Etude du transport de principles actifs incorpores dans des emulsions liquides de type huile dans eau: These doct. pharm. sci. - 1793. - Zurich, 1977 .-- 117 s. Guidelines for experimental (preclinical) study of drugs for local treatment of wounds / B.M. Datsenko, S.V. Biryukova, T.I. Tamm et al. - M., Ministry of Health of the USSR, 1989. - 47 p.].

The main flavoring agent in the composition of the reference preparation is sucrose in a concentration of 60.0 g / 100 ml of syrup.

For the preparation of syrups, either sucrose at a concentration of not less than 45 wt.%, Or other polyalcohols or sweeteners can be used.

Currently, sorbitol is also used as a sweetener and thickener for syrups.

Sorbitol has a masking sweet taste, but at the same time it is not toxic, does not cause rapid changes in the amount of sugar in the blood and does not provoke additional production of insulin by the pancreas. Being a caloric sugar substitute, sorbitol is absorbed from the gastrointestinal tract, practically without affecting blood glucose, which allows the drug to be used to treat patients with diabetes mellitus (Russian Drug Register, Radar. Encyclopedia of drugs. - 14th issue / red G.L. Vyshkovsky. - M.: Radar - 2006, 2005).

Sorbitol, as a chemical substance, is a six-atom alcohol with the empirical formula C ₅ H ₁₄ O ₆ . It is a stereoisomer of mannitol. Sorbitol is used as a sugar substitute [Reference - Vidal.

Medicines in Russia / M.: AstraPharmService, 2010. Handbook of Pharmaceutical Excipients: 6th Edition / Ed. by Anley Wade and Paul J. Weller. - Washington / London: Amer. Pharm. Association / The Pharm. Press, 2009. - 888 p.].

Non-crystallizing liquid sorbitol was chosen as the main flavoring agent in the developed product.

Since the rheoparameters of sorbitol-based syrups depend on its concentration, rheological studies of syrup samples were carried out depending on the concentration of non-crystallizing liquid sorbitol. The composition of the syrups are shown in table 1.

In FIG. 1 shows rheograms of fenspiride hydrochloride syrups containing non-crystalline liquid sorbitol non-crystallizing in different concentrations and a rheogram of the Erespal ^® syrup 2 mg / ml. In FIG. 2 is a graph of the structural viscosity of syrups versus the concentration of liquid non-crystallizing sorbitol with a shear rate gradient of 41.64 s ^-1 . Table 2 shows the values of the structural viscosity of the indicated syrups at different shear rate gradients in comparison with the structural viscosity of the reference preparation.

As can be seen from the data presented in FIG. 1, all syrups have a flow type close to Newtonian, they have no lower yield strength and thixotropic properties. The structural viscosity of syrups increases with increasing concentration of liquid non-crystallizing sorbitol (Fig. 2). The rheological closest to the reference drug is a syrup containing 85.2 g of liquid non-crystallizing sorbitol in 100 ml (Table 2).

When examining the pH level of the reference drug, the following pH values were established: 5.03; 5.28 5.48; 5.50; 5.53; 5.89. Accordingly, for the developed product, pH limits from 5.0 to 6.0 should be set.

The pH of the developed syrup, which did not contain pH flavors (buffering agents), was 6.25. To create a pH of about 5.5, buffers were included in the syrup. A nitrate buffer consisting of sodium citrate and citric acid monohydrate was selected.

Syrups containing buffering substances in various ratios were developed at a total concentration of 0.50 g per 100 ml, which corresponds to 0.40 wt.%. The compositions of these syrups are presented in table. 3. In FIG. 3 shows the dependence of the pH of the drug on the ratio of buffer substances.

As can be seen from the data presented in FIG. 3, with an increase in the concentration of citric acid monohydrate and, accordingly, with a decrease in the concentration of sodium citrate, the pH of syrups decreases. The optimum pH value of 5.5 is achieved when the content of 100 ml of citric acid syrup monohydrate and sodium citrate is about 0.10 g and 0.40 g, respectively.

The next step in our research was to study the dependence of the pH of syrups on the concentration of buffer substances at a selected ratio of citric acid monohydrate and sodium citrate (1: 4). In the table. 4 shows the compositions of the studied syrups, and in FIG. 4 - research results.

As can be seen from the data presented in table. 4 and in FIG. 4, with an increase in the concentration of buffer substances at a selected ratio of citric acid monohydrate and sodium citrate, the pH of the syrup decreases.

Based on the data obtained, the composition of the buffer substances of the preparation under development was selected: citric acid monohydrate 0.15 g in 100 ml of syrup, which corresponds to 0.12 wt.% And sodium citrate 0.60 g in 100 ml of syrup, which corresponds to 0.48 wt. .%.

The composition of the reference drug "Erespal" as fragrances

includes a flavoring composition with hints of honey smell, tincture of vanilla and licorice root extract in concentrations of 0.5 g / 100 ml, 0.4 g / 100 ml and 0.2 g / 100 ml, respectively.

The composition of the developed product as fragrances included honey flavoring and fruit flavoring. Syrups containing these flavors in different concentrations were prepared. Organoleptic evaluation of each syrup was performed on volunteers. The results are presented in table 5.

According to the results of organoleptic studies, the composition of the developed drug included honey flavoring at a concentration of 0.10 g / 100 ml and fruit flavoring at a concentration of 0.01 g / 100 ml, which corresponds to 0.080 wt.% And 0.008 wt.%, Respectively.

As a result of research on the development of the drug "Fenspiride Syrup" 2 mg / ml, the authors of the present invention came to the following conclusions regarding the composition of excipients included in its composition:

1. The choice of flavoring flavor. Non-crystallizing liquid sorbitol was chosen as the main flavoring agent for the taste. Based on experimental data and the study of the physicochemical properties of syrups containing non-crystalline liquid sorbitol non-crystallizing in different concentrations (rheological properties of syrups and their density), its concentration of 85.2 g in 100 ml of syrup was selected, which corresponds to 68.16 wt.%.

2. The choice of pH flavors (buffer substances). The replacement of sucrose, which is part of the reference preparation, with non-crystallizing liquid sorbitol caused a change in the pH of the preparation. In this regard, a citrate buffer was introduced into the preparation, including sodium citrate and citric acid monohydrate at a concentration of 0.60 g / 100 ml and 0.15 g / 100 ml, respectively (0.48 wt.% And 0.12 wt. % respectively).

The selected qualitative and quantitative composition of the buffer substances provides the pH of the drug in the established range from 5.0 to 6.0.

3. The choice of flavorings. Based on the results of organoleptic studies, the composition of the drug included honey flavoring at a concentration of 0.1 g / 100 ml and fruit flavoring at a concentration of 0.01 g / 100 ml, which corresponds to 0.080 wt.% And 0.008 wt.%, Respectively.

4. The choice of antimicrobial preservatives. The composition of the developed product included methyl parahydroxybenzoate (0.090 g / 100 ml or 0.072 wt.%), Propyl parahydroxybenzoate (0.035 g / 100 ml or 0.028 wt.%) And potassium sorbate (0.19 g / 100 ml or 0.152 wt.%) . The selected qualitative and quantitative composition of preservatives provides an antimicrobial preservative effect that complies with the requirements of EF 8.0 (5.1.3) for drugs for oral administration and the requirements of the RF Civil Fund of the XII edition (Article 34) for category 3 drugs.

Thus, based on the results of the studies, the composition of the drug “Fenspiride syrup” 2 mg / ml, which is presented in table 6, was substantiated.

As a result of comprehensive studies, experimentally, the authors of the present invention obtained a liquid dosage form of fenspiride in the form of a syrup, physico-chemical and biological properties, as well as quality indicators of which confirm the rationality of the selected composition, to achieve the purpose of the present invention and solve the problem of sucrose substitution .

Below are the comparative results of the analysis of the developed drug "Fenspiride syrup" 2 mg / ml and the drug "Erespal®" syrup 2 mg / ml, claimed by the authors of the present invention as a prototype.

Rheological properties

To determine the storage conditions of the drug, the effect of temperature fluctuations on the rheological and physical properties of the drug being developed was investigated.

The drug was stored for 2 months. at a temperature of -8 ° C, after which it was kept at a temperature of 25 ° C to a constant temperature of the preparation and its rheogram was taken, as well as a rheogram of a preparation of the same series stored after operating time at a temperature of 25 ° C (Fig. 5). In addition, photographs were taken of these samples of the drug (Fig. 6).

As can be seen from the data presented in FIG. 5 and 6, freezing and subsequent thawing of the drug does not violate its physical stability, all components remain in a dissolved state. The rheograms of the preparations subjected to and not subjected to freezing practically coincide, the structural viscosity at different shear rate gradients is practically the same.

In FIG. 7 shows rheograms of the preparation “Fenspiride syrup” 2 mg / ml at different temperatures, and in FIG. 8 - dependence of the structural viscosity of the syrup on temperature.

As can be seen from the rheograms shown in FIG. 7, the drug in the temperature range from 15 to 45 ° C has a flow type close to Newtonian; the drug has no thixotropic properties at all temperatures studied. As for structural viscosity, it decreases with increasing temperature (Fig. 8). So, with an increase in temperature from 15 to 45 ° С, the values of structural viscosity decrease by ~ 80%. Changes in rheoparameter with temperature change are reversible.

In FIG. Figure 9 shows the rheograms of the developed and reference preparations, and Table 7 shows the values of their structural viscosity at different shear stress gradients.

As can be seen from the data presented in FIG. 9 and tab. 7, the reoparameters of the developed and reference drugs are practically the same.

Hyperosmolar properties

Comparative studies of the kinetics of water absorption by developed and reference drugs were carried out. The research results are presented in FIG. 10. As can be seen from the data presented, the osmotic activity of the developed and reference drugs is practically the same.

Stability

The compatibility of fenspiride hydrochloride with excipients and its stability in the developed preparation "Fenspiride Syrup" 2 mg / ml are confirmed by the results of a study of its stability, given below.

The studies were carried out on three experimental series (011113, 021113 and 031113) of the Fenspiride Syrup preparation 2 mg / ml. Samples of the experimental series were prepared for storage. They were made in a RP-500 homogenizer reactor simulating industrial equipment and packaged in 100 ml bottles. The weight of each batch of bulk products was 3.75 kg (3.0 L).

For these three series, long-term tests were carried out during storage of samples at a temperature of (25 ± 1) ° C and accelerated tests during storage of samples at a temperature of (40 ± 1) ° C.

Long-term and accelerated testing of the 011113, 021113 and 031113 series were planned in accordance with the recommendations of CPMP / ICH / 2736/99 (ICH Topic Q1A (R2)) (Note for Guidance on Stability Testing: Stability Testing of New Drug Substances and Products)) ; the protocol included an initial analysis of three series, analysis after 3 months in the first year of storage, after 6 months in the second year of storage.

Stability data are presented in tables 8 and 9 and in FIG. 11-14.

As a result of long-term stability tests at 25 ° C for 6 months (stability study period), there were no significant changes in the quality indicators of the drug; the drug passed the tests for all indicators of the specification.

The present invention also relates to a method for producing a liquid dosage form of fenspiride, which, given the properties of the components included in its composition, includes the following basic processes:

- preparation of a solution;

- dissolution of fenspiride hydrochloride in purified water;

- preparation of a solution of buffer substances, sodium saccharinate and dye in purified water;

- the introduction of prepared solutions and fruit flavoring in sorbitol, homogenization and unloading of bulk syrup from the homogenizing reactor;

According to the invention, a method for producing a liquid dosage form of fenspiride is as follows:

Glycerin is loaded into container No. 1, heated, then pre-weighed methyl parahydroxybenzoate, propyl parahydroxybenzoate, potassium sorbate and honey flavor are loaded and mixed until the components are completely dissolved; at the same time, a previously weighed portion of purified water and fenspiride hydrochloride are loaded into a container No. 2, which is stirred until complete dissolution; in container No. 3 load pre-weighed part of purified water, sodium citrate, citric acid monohydrate, sodium saccharinate, dye E 110 and mix the mixture until the substances are completely dissolved; then pre-weighed sorbitol non-crystallizing liquid is loaded into the homogenizing reactor, and a solution of excipients is quantitatively transferred from tank No. 3, after which the mixture is stirred for 5-10 minutes at a temperature of 20-25 ° C until a homogeneous mass is obtained; then, the solution is quantitatively transferred to the homogenizer from tank No. 1 and the mixture is stirred for 5-10 minutes at a temperature of 20-25 ° C until a homogeneous mass is obtained; also, the solution of fenspiride hydrochloride is quantitatively transferred from the container No. 2 to the homogenizer reactor and the pre-weighed fruit flavor is loaded, which mix the mixture for 5-10 minutes at a temperature of 20-25 ° C until a homogeneous syrup is obtained; in intermediate containers, bulk syrup is transported to the dosing room and unloaded in parts into the hopper of the dosing machine, after which the syrup is dosed into bottles, sealed with lids and packaged in packs.

Claims (3)

1. A liquid dosage form of fenspiride hydrochloride, made in the form of a syrup, comprising the active substance and a combination of excipients, having the following composition in g / 100 ml: Fenspiride hydrochloride 0,200 Methyl Parahydroxybenzoate 0,090 Propyl parahydroxybenzoate 0,035 Potassium sorbate 0.190 Sodium Citrate 0,600 Citric Acid Monohydrate 0.150 Sodium saccharin 0,045 Sorbitol liquid non-crystallizing 85,200 Glycerol 22,500 Honey flavor 0,100 Fruit flavor 0.010 Dye E 110 0.010 Purified water up to 100,000 ml 2. The liquid dosage form of fenspiride hydrochloride according to claim 1, for the preparation of which a solution of the active and auxiliary substances is prepared, for which glycerin is loaded, then pre-weighed methyl parahydroxybenzoate, propyl parahydroxybenzoate, potassium sorbate and honey flavor are mixed and mixed until the components are completely dissolved. , as well as in container No. 2 pre-weighed

part of the purified water and fenspiride hydrochloride, which is stirred until complete dissolution, then pre-weighed are loaded into container No. 3

part of purified water, sodium citrate, citric acid monohydrate, sodium saccharinate, dye E 110 and the mixture is stirred until the substances are completely dissolved, then pre-weighed sorbitol liquid non-crystallizing is loaded into the homogenizer and quantitatively the excipient solution is transferred quantitatively, and then mixed the mixture until a homogeneous mass is obtained, then the solution is quantitatively transferred to the homogenizing reactor from tank No. 1 and the mixture is stirred until a homogeneous mass is obtained; also, the solution of fenspiride hydrochloride is quantitatively transferred to the homogenizer reactor from vessel No. 2 and the previously weighed fruit flavor is loaded, the mixture is stirred until a homogeneous syrup is obtained.

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