RU2646812C1 - Liquid medicinal form risperidone and method for its manufacture - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: invention describes a liquid dosage form of risperidone in the form of an oral solution comprising an active substance and a combination of excipients having the following composition in mg/ml: Risperidone 1; Tartaric acid 7.5; Sodium benzoate 2.36; Sodium hydroxide to pH 3.0±0.2; Purified water to 1 ml.

EFFECT: invention provides a liquid dosage form that is stable in production and long-term storage, and involves a more technological method of production, consisting in the absence of the need to heat the aqueous solution by dissolving an antimicrobial preservative to be incorporated into the liquid dosage form.

2 cl, 1 tbl

Description

Technical field

The invention relates to medicine, in particular to the pharmaceutical industry, and describes a liquid oral dosage form containing risperidone and a method for its manufacture.

State of the art

Currently, there is an increase in mental illness and personality disorder in the world. According to the forecast of the World Health Organization (WHO), by 2020, mental disorders will be in the top five diseases leading to disability. The total incidence of mental disorders in the world averages 15% of the total population, while in Russia this indicator is 25%. The growth of mental illness is directly related to the increase in the number of people with disabilities and people who are unable to work. According to EU estimates, labor productivity losses associated with these diseases are estimated at 3-4% of GDP.

At the same time, despite the seriousness and scale of the problem, there is a large gap between the needs for treatment and care provided to patients with mental illnesses in the world. In low- and middle-income countries, between 76% and 85% of patients with mental disorders do not receive any treatment. In high-income countries, between 35% and 50% of people with such disorders are in this position [WHO Newsletter No. 396 April 2016, http://www.who.int/mediacentre/factsheets/fs396/en/] .

Currently, in the treatment of mental disorders, drugs belonging to the group of atypical antipsychotics (antipsychotics) are widely used. Like their predecessors - antipsychotics - atypical antipsychotics effectively eliminate delusional disorders, hallucinations, disorganization of thinking and other clinical manifestations of psychoses. However, compared with previous generations of drugs, atypical antipsychotics are less able to cause extrapyramidal symptoms and have greater clinical efficacy [Meltzer HY. Outcome in schizophrenia: Beyond symptom reduction. J Clin Psychiatry 1999; 60 (Suppl 3): 3-8].

Traditional antipsychotic drugs are effective against acute agitation and in controlling positive symptoms, and at the same time have little effect on cognitive impairment and negative symptoms in schizophrenia [Jibson MD, Tandon R. New atypical antipsychotic medications. J Psychiatr Res 1998; 32: 215-28]. Atypical antipsychotics, in contrast, have a very broad spectrum of efficacy, allowing treatment of both positive and negative symptoms, as well as cognitive impairment [Bilder RM, Goldman RS, Volavka J, et al. Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry 2002; 159: 1018-28].

Due to their high efficiency, atypical antipsychotics are rapidly being introduced into widespread clinical practice. Drugs such as risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole are recommended as first-line therapy in the treatment of patients with resistant schizophrenia [Marder SR, Essock SM, Miller AL, Buchanan RW, Davis JM, Kane JM, Lieberman J, Schooler NR . The Mount Sinai Conference on the Pharmacotherapy of schizophrenia. Schizophr Bull 2002; 28: 5-16].

One of the most widely used drugs in the practice of treating mental illness is risperidone. Risperidone has unique activity, acting on both D2-dopamine and 5HT2A-serotonin receptors. Currently risperidone is successfully used in the treatment of acute and chronic forms of schizophrenia in adult patients. At the same time, foreign psychiatrists use this drug in children for the treatment of hyperactivity, impulsivity, aggression, stereotypical behavior, obsessive-compulsive disorders. A number of foreign psychiatrists suggest that atypical antipsychotics, in particular risperidone, can play an important role in the treatment of severe autistic disorders [Shinaev NN, Akzhiginov RG, Volkova NP The use of atypical antipsychotic risplept in the clinic of borderline mental disorders // Psychiatry and psychopharmacotherapy. - 2000. - App. No. 2. - S. 8-10; Posey DJ, Walsh KN, Wilson GA, et al. Risperidon in the treatment of two very young children with autism // J Child Adolesc Psychopharmacol, 1999, 9, 273-276].

The relative safety of risperidone (the absence of toxic and mutagenic effects in the experiment, the absence of complications when taking average daily doses by middle-aged people), as well as the noted facts of overcoming therapeutic resistance in the treatment of severe forms of endogenous diseases in adults [Kozlovskaya G.V., Kalinina M.A. ., Goryunova A.V., Proselkova M.E. The experience of using risplept in the treatment of early childhood autism and schizophrenia in children // Psychiatry and psychopharmacotherapy. - 2000. - App. No. 2 - S. 10-12] make risperidone attractive for its use in pediatric practice.

Given the children's age of patients, as well as the symptoms of mental illness (behavioral disorders due to dementia, delirium, hallucinations, aggressiveness), the problem of difficulty swallowing drugs is relevant. In addition, a phenomenon such as dysphagia (difficulty swallowing) is widespread, especially among children and the elderly, and according to various estimates is observed in approximately 35% of the population. In this regard, the release of risperidone drugs in liquid form seems to be the most convenient and safe.

Risperidone preparations are available on the market in the form of film-coated tablets, lozenges, oral dispersible tablets, powders for the preparation of a suspension for intramuscular administration of a prolonged action, as well as oral solutions.

From the prior art, the only preparation of risperidone in liquid dosage form is known and presented on the domestic market, which is taken as a prototype of the proposed technical solution:

- "Risolept®" in the form of a solution for oral administration in a dosage of 1 mg / ml manufactured by Janssen Pharmaceuticals N.V., (Belgium), registration certificate P N012226 / 01 of July 14, 2011

Also known from the prior art is a method for preparing aqueous risperidone compositions according to patent RU 2161965 (published on January 20, 2001), in which, according to the description and claim 11 of the formula, the manufacture of solutions for oral administration is accompanied by the step of dissolving the preservative in a certain amount of heated water, which, according to the opinion of the authors of the present invention is redundant and complicates the production process.

In this regard, there is a need to develop high-quality and affordable atypical antipsychotic drugs of domestic production containing risperidone in the form of liquid dosage forms, preferably in the form of a solution for oral administration, convenient for use and stable during storage, as well as characterized by a more technologically advanced production method.

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 risperidone, preferably in the form of a solution for oral administration, stable upon receipt and long-term storage, pharmaceutically equivalent to the prototype, but characterized by a more technologically advanced production method, consisting in the absence of the need to heat the aqueous solution when dissolved an antimicrobial preservative for administration in a liquid dosage form.

To achieve this goal, the authors of the present invention attempted to develop an analogue drug - Risperidone oral solution 1 mg / ml (developed drug), which would not be inferior to Risolept® oral solution 1 in terms of effectiveness, safety and quality indicators mg / ml (Janssen Pharmaceutical N.V., Belgium) (reference preparation, comparative preparation, prototype).

Disclosure of invention

Based on the objective of the study, the authors of the present invention tried to develop a drug, pharmaceutically equivalent to the preparation “Risolept®” oral solution of 1 mg / ml, having comparable quality and properties.

A medicinal product is essentially similar to the original drug (generic preparation) if it meets the criteria of the same quantitative and qualitative composition with respect to the active substances, the same dosage form and is bioequivalent. Medicines are pharmaceutically equivalent if they contain the same amount of the same active substance in the same dosage forms that meet the requirements of the same or comparable standards (Pharmaceutical sector: Directive 2001/83 / EC of the European Parliament and Council of the EU .-- K .: MORION, 2013 .-- 120 s; CPMP / EWG / QWP / 1401 / 98. Note for guidance on the investigation of bioavailability and bioequivalence. - London: CPMP / EMEA, July 26, 2001). A medicinal product is therapeutically equivalent to another drug if it contains the same active substance or its therapeutically active part and clinically shows 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 reference preparation Risplept® oral solution of 1 mg / ml contains the following components (mg / ml):

The aim of the research was to develop a generic preparation of Risperidone oral solution 1 mg / ml, which is a true solution with excipients that have similar characteristics, which allows us to consider the change in the composition of excipients with respect to the reference drug as a change of type I and attribute the developed drug to generic drugs (Good manufacturing practice of medicines / Ed. by N.A. Lyapunov, V.A. Zagoria, V.P. Georgievsky, E.P. Bezugloy. - K .: MO ION, 1999. - 896 c)..

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 active substance in the reference preparation is risperidone, which is contained in a concentration of 1 mg / ml. Since the registered drug is a generic drug, the risperidone concentration of 1 mg / ml was also chosen for it, and the limits of the content of risperidone from 0.9 g to 1.1 mg per ml of solution were established (from 95% to 105% of the nominal amount of active substance )

Risperidone is practically insoluble in water and soluble in dilute acid solutions, therefore, the authors of the present invention have confirmed that the solubility of risperidone, as well as its stability (physical stability of the solution) increases with decreasing pH. The best solution stability is observed at pH values from 2.0 to 4.0, optimally at pH = 3.0 ± 0.2.

When developing the composition of excipients, the authors of the present invention faced the problem of including a preservative in the composition of the drug being developed. In the composition of the original drug, benzoic acid is such a preservative. In a pharmacopoeial article on this substance, it is stated that benzoic acid is “slightly soluble in water” [European Pharmacopoeia 7.0 Benzoic acid - p. 1467], which corresponds to the solubility of 1 g of the substance in 100-1000 ml of purified water at a temperature of 15 ° C to 25 ° C and "soluble in boiling water", which corresponds to the solubility of 1 g of the substance in 10-30 ml of boiling water.

Benzoic acid in the reference preparation is in the form of a true solution. The ratio between benzoic acid and purified water in the preparation is 1 g / 19.8 ml, which is 5 times less than 100 ml and 50 times less than 1000 ml. That is, the solubility of benzoic acid can affect the quality and physical stability of the solution. However, when the solution is heated to a temperature of 90 ° C (the state of boiling water), the solubility of benzoic acid in purified water increases, but requires significant energy consumption (heating and cooling the solution), which complicates the process and makes it longer.

In order to solve this problem, the authors managed to develop a rational composition of the generic preparation “Risperidone” oral solution 1 mg / ml, taking into account the composition and properties of the reference preparation “Rispolept®” oral solution 1 mg / ml, as well as the properties of risperidone 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 risperidone in a concentration corresponding to its content in the reference preparation - 1 mg / ml;

- the drug should have the dosage form “oral solution” and provide therapeutic equivalence with respect to the reference drug.

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

- risperidone and excipients should be in the preparation in the form of a true solution in the temperature range established for storage, for which a suitable composition of solvents should be selected;

- physico-chemical properties of the drug (pH) should be comparable with those of the reference drug;

- microbiological purity, which must comply with the requirements of the State Pharmacopoeia of the Russian Federation ed. XII, article 34 (OFS 42-0069-07) "Determining the effectiveness of antimicrobial preservatives in medicines."

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

The compatibility of risperidone with excipients has been proved by the stability of the drug during storage (see below the results of stability studies during storage).

The composition of the drug as a whole includes excipients, which for functional purpose are similar to excipients included in the composition of the reference drug. However, in order to reduce the energy consumption and process time required for the production of the generic preparation, the authors of the present invention decided to replace benzoic acid as an antimicrobial preservative and to include sodium benzoate in the dosage form. This substance is widely used in the pharmaceutical industry in concentrations of 0.2-0.3%, the permissible concentration is up to 0.5%. Benzoic acid is slightly soluble in water (0.34% in cold water, 6.8% in boiling water), while sodium benzoate is readily soluble in water (55.4% in cold water.) And its use instead of benzoic acid allows exclude the step of heating the solvent to dissolve the preservative and then cooling the resulting solution. In the original preparation, benzoic acid is used at a concentration of 0.2%, but it is known that undissociated benzoic acid, which exists in solution in sufficient quantities only at acidic values at pH≤4, has microbiological effectiveness. Sodium benzoate is converted in solution to undissociated benzoic acid at pH values less than 4.0. Based on the foregoing, sodium benzoate at a concentration of 0.236% was introduced into the developed drug, which corresponds to a content of 0.2% undissociated benzoic acid in the solution.

Thus, the authors of the present invention, was obtained the composition of the generic drug "Risperidone" oral solution 1 mg / ml, containing the following components:

In order to confirm the pharmaceutical equivalence of the developed drug, the efficacy was investigated.

antimicrobial preservative effect of samples of the laboratory series of the drug “Risperidone” oral solution of 1 mg / ml containing 0.095% risperidone and 0.212% sodium benzoate (lower limits of quantitative content according to the draft FSP). According to the requirements of general article 34 of the Civil Code of the Russian Federation XII ed. in drugs for oral administration, the logarithm of reducing the number of viable bacterial cells after 14 days should be at least 1, from 14 to 28 days the number of viable bacterial cells should not increase. The number of viable fungal cells should not increase after 14 and 28 days compared with the initial level. The research results are presented in table 1.

From the data presented in table 1, it is seen that in the drug there is a rapid death of bacteria. In the initial seeding, the logarithm of the decrease in the number of test microorganism S. aureus ATCC 6538 was 0.07, 4.44 after 7 days, and after 14 days and subsequent seeding, no viable cells of this test microorganism were detected.

In the initial seeding, the logarithm of the decrease in the number of test microorganism E. coli ATCC 25922 was 0.78, after 7 days and subsequent seeding, viable cells of this test microorganism were not detected.

In the initial seeding, the logarithm of the decrease in the number of test microorganism P. aeruginosa ATCC 9027 was 4.63, after 7 days and subsequent seeding no viable cells of this test microorganism were detected.

In relation to fungi, the studied drug also showed the effectiveness of antimicrobial preservative action. In the initial seeding, the logarithm of the decrease in the number of test microorganism C. albicans NCTC 885-653 was 0.11, after 7 days - 2.94, after 14 days and 28 days no viable cells of this test microorganism were found.

In the initial seeding, the number of viable cells of the test microorganism A. niger ATCC 9246 did not change significantly, after 7 days the logarithm of the decrease in the number of the test microorganism A. niger ATCC 9246 was 3.22, after 14 days and subsequent seeding, viable cells of this test microorganism were not detected.

Such an antimicrobial preservative efficacy complies with the requirements of Article 34 (OFS 42-0069-07) “Determining the Effectiveness of Antimicrobial Preservatives for Medicines” of the RF Civil Fund of the XII edition for category 3 medicines.

Thus, the studies showed that the effectiveness of the antimicrobial preservative in the “Risperidone” preparation, oral solution of 1 mg / ml corresponds to the requirements of the RF Civil Fund of the XII edition (Article 34) for category 3 drugs.

As follows from the research results, the developed drug exceeds the requirements of article 34 (OFS 42-0069-07) "Determining the effectiveness of antimicrobial preservatives of medicines" in the RF Civil Fund of the XII edition in terms of the effectiveness of the antimicrobial preservative effect.

To prepare a buffer solution in a reference preparation, tartaric acid at a concentration of 0.75% and sodium hydroxide are used to bring the resulting solution to a pH of 3.0 ± 0.1. In patent No. 2161965 “Aqueous compositions of respiridone” it is indicated that the pH of the solution is important for the physicochemical stability of risperidone, it is also indicated that at pH values from 2 to 6 in the present composition, the concentration of risperidone remains unchanged even under more severe conditions, in particular during longer storage at elevated temperatures.

In section 2.2, it was pointed out that the optimal solubility of respiridone is achieved at pH values of 3.0 ± 0.2, and it was also determined in the pharmacopoeial articles of the manufacturer of the substance that obtaining a clear, colorless solution with a concentration of 0.1% is achieved at 0, 75% tartaric acid solution.

From all of the above, it follows that tartaric acid at a concentration of 0.75% and sodium hydroxide is optimal for introducing into the composition of the drug to bring the pH to 3.0 ± 0.2.

Thus, these studies confirm that the replacement of a preservative does not affect the quality and stability of the drug throughout the shelf life.

The present invention also relates to a method for producing a liquid dosage form of risperidone.

According to paragraphs. 11-13 of the formula of patent RU No. 2161965 the following method is known for preparing an aqueous risperidone composition: “a) adding the acid component of the buffer and the active ingredient of risperidone to water; b) stirring the mixture until complete dissolution and cooling the solution to room temperature; c) trusting the pH using the main component of the buffer; and d) further diluting the solution with water to the desired final volume. ” Moreover, at the stage “a)”, the preservative is dissolved in a certain amount of heated water and the solution is diluted with an equal amount of water.

This method requires the use of special equipment and additional labor for introducing auxiliary substances into the mixture, which is economically inexpedient.

As a result of the research, the authors of the present invention were able to develop an optimal method for the manufacture of the generic preparation “Risperidone” oral solution 1 mg / ml, which, taking into account the properties of the components included in its composition, includes the following main technological processes:

- preparation of a 0.1 M alkali solution;

- dissolution of sodium benzoate, tartaric acid, risperidone in purified water;

- adjusting the pH of the solution to a value of 3.0 ± 0.2;

- dosing the solution into bottles.

Below is a brief description of the production process of the drug:

Stage 1. Preparation of a 0.1 M alkali solution

The technological capacity is weighed on a balance and sequentially loaded is purified water to prepare a 0.1 M alkali solution and sodium hydroxide. The solution is prepared according to GF XIII. Stirred with a stirrer until completely dissolved.

Stage 2. Preparation of the solution

The pre-weighed purified water and sodium benzoate are loaded into the reactor. The resulting solution is stirred with a mixer until the powder is completely dissolved, then pre-weighed tartaric acid is loaded and stirred with a mixer until it is completely dissolved, after which the pre-weighed risperidone is loaded and mixed with a mixer until it is completely dissolved, and finally, the prepared 0.1 M alkali solution is added until the pH of the solution is obtained 3.0 ± 0.2, mix and unload the resulting solution from the homogenizer into intermediate containers.

Stage 3. Dosing the solution into bottles

From the intermediate containers, the solution is unloaded and dispensed into vials.

Thus, the specified method for producing a liquid dosage form of risperidone differs significantly from the prior art and is characterized by the absence of the need for heating an aqueous solution to introduce antimicrobial preservatives into the liquid dosage form and, accordingly, the higher manufacturability of the manufacturing process.

The specified liquid dosage form of risperidone is stable upon receipt and long-term storage, and is also pharmaceutically equivalent to the prototype.

Claims (3)

1. A liquid dosage form of risperidone, made in the form of a solution for oral administration, comprising the active substance and a combination of excipients, having the following composition in mg / ml: Risperidone one Wine acid 7.5 Sodium benzoate 2,36 Sodium hydroxide Up to pH 3.0 ± 0.2 Purified water Up to 1 ml 2. The liquid dosage form of risperidone according to claim 1, obtained by the method in which the scales are weighed and purified water is loaded sequentially to prepare a 0.1 M alkali solution and sodium hydroxide and stirred with a stirrer until completely dissolved, then into the reactor pre-weighed purified water and sodium benzoate are loaded and the resulting solution is stirred until complete dissolution, after which pre-weighed tartaric acid is loaded and mixed until completely dissolved, then pre-loaded weighed risperidone and mix it until it is completely dissolved, after which the prepared 0.1 M alkali solution is added until a solution pH of 3.0 ± 0.2 is obtained, mix, the resulting solution is unloaded from the homogenizing reactor into intermediate containers and the solution is unloaded from intermediate containers and dosed in vials.