RU2587782C1 - Stable pharmaceutical composition lamivudine - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics. Described is a stable pharmaceutical composition for oral consumption contains lamivudine in amount of 10 mg/ml, free of ethanol and parabens. Composition contains a hydrophilic carrier composed of water, preserving agent, complexing agent and process additives. Preserving agent is cetylpyridinium chloride in amount from 0.1 mg/ml to 0.2 mg/ml. Complexing agent is disodium edetate in amount from 0.11 mg/ml to 0.2 mg/ml. Correctives of taste, colour, odour and pH regulators are used as process additives, wherein the formulation has pH from 5.5 to 7.0.

EFFECT: invention provides implementation of the above application, as well as wider range of drugs.

1 cl, 1 dwg, 9 tbl, 1 ex

Description

The invention relates to medicine, in particular to the pharmaceutical industry, and describes a pharmaceutical composition comprising lamivudine.

Prevention of infection with human immunodeficiency viruses (HIV) and hepatitis B, as well as the treatment of acquired immunodeficiency syndrome (AIDS) and hepatitis B are some of the most relevant medical and sociological problems.

HIV / AIDS is the world's leading infectious cause of death. Every year, 2 million people die from HIV / AIDS, and today this disease has claimed the lives of more than 27 million people. Every day, 7,000 people become infected with HIV.

Viral hepatitis B is a worldwide widespread disease that causes acute and chronic hepatitis.

Despite the availability of a highly effective vaccine, there are currently 350 million people with chronic HBV infection worldwide.

According to the results of studies, 6-13% of HIV-infected people have HBV co-infection. HIV co-infection is most common in people living in regions where both viruses are endemic, such as in South Africa. People with HBV / HIV co-infection typically have a higher level of HBV DNA, a lower frequency of spontaneous HBeAg seroconversion, a more severe liver damage, and a higher rate of fatal outcomes associated with liver disease [Care of patients with chronic hepatitis B and HIV co-infection: recommendations from an HIV-HBV International Panel / Soriano V., Puoti M., Bonacini M., Brook G., Cargnel Α., Rockstroh J., et al. // AIDS. - 2005. - No. 19. P. 221-240].

Lamivudine, emtricitabine, and tenofovir are ANs with activity against both HIV and HBV. However, patients with HBV / HIV co-infection have a high incidence of HBV resistance to lamivudine, which reaches 90% in 4 years [Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patitents / Benhamou Y., Bochet M ., Thibault V. et al. // HEPATOLOGY. - 2000. - No. 31. - P. 1030-1031]. Tenofovir in combination with lamivudine or emtricitabine is widely prescribed as a component of HAART in patients with HBV / HIV co-infection. In addition, tenofovir has activity against lamivudine-resistant strains of HBV and reduces the frequency of resistance to lamivudine when used in combination.

Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI). In November 1995, it was first approved by the United States Food and Drug Administration (FDA).

According to WHO recommendations for therapy in adults, adolescents and children, lamivudine is widely used in first and second line treatment regimens. This medicinal substance is an important component of combination drugs.

The 2010 WHO Guidelines recommend first-line therapy in adults and adolescents with lamivudine or emtricitabine along with tenofovir or zidovudine and efivarenz or nevirapine [World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: Recommendations for a public health approach. 2010 Revision. [Online] Health (San Francisco), 2010. [Cited 2012 June 25]].

From the prior art the following registered in the Russian Federation drugs lamivudine (table 1).

From the presented data in table 1 shows that in the market there is only one RF preparation in a solution form with lamivudine - Epivir ^®, oral solution (GlaxoSmithKline Inc., Canada.).

The drug Epivir - oral solution of 10 mg / ml, has the following composition, mg:

Lamivudine 10.00 Sucrose 200.00 Propylene glycol 20.00 Methyl Parahydroxybenzoate 1,50 Propyl parahydroxybenzoate 0.18 Artificial Strawberry Flavor 0.80 Artificial Banana Flavor 0.60 Anhydrous Citric Acid 1.00 Sodium Citrate 11.00 Diluted hydrochloric acid up to pH 6.0 or sodium hydroxide solution Purified water up to 1.0 ml

Thus, the preparation is prepared on a hydrophilic basis, in which excipients fulfill the following functional purpose: methyl parahydroxybenzoate and propyl parahydroxybenzoate - antimicrobial preservatives; sucrose - flavor flavoring; propylene glycol is a hydrophilic non-aqueous solvent; artificial strawberry flavor and artificial banana flavor - flavorings; anhydrous citric acid and sodium citrate - buffer substances; diluted hydrochloric acid and sodium hydroxide - pH regulators; purified water - solvent. All excipients included in the preparation, except flavorings, meet the requirements of the European Pharmacopoeia.

The prior art is aware of the existence of a Eurasian patent (EA 001990, publ. 10/22/2001) for the above composition, which is the closest analogue to the claimed invention. The said patent describes a pharmaceutical composition substantially free of ethanol and containing less than 0.005% ethylenediaminetetraacetic acid, including lamivudine or a pharmaceutically acceptable derivative, carrier and preservative system that includes parabens, said composition having a pH above 5.5.

It is also known from the prior art that the pH of the solution is important for the stability of lamivudine, and a pH of 5.5 is a critical parameter, upon lowering which lamivudine decomposes.

Therefore, it was of interest to study the effect of pH on the stability of lamivudine in its hydrophilic bases. In this regard, the dependence of the formation of lamivudine impurities on the pH of its solutions was investigated. Samples of the solutions were adjusted to a specific pH using a 10% sodium hydroxide solution or 0.1 M hydrochloric acid solution and stored for two weeks at a temperature of 60 ° C.

Table 2 shows the compositions of the investigated solutions, and in table 3 the total content of impurities, which was determined according to the methodology included in the draft FSP. In FIG. Figure 1 shows the dependence of the total content of decomposition products (impurities) on the pH of solutions of lamivudine.

As can be seen from the data presented in table 3 and in FIG. 1, with an increase in pH from 4.0 to 5.5, the sum of the resulting impurities decreases and practically reaches a plateau at pH 5.5. There are no significant differences in the total content of impurities that are formed in the pH range of solutions from 5.5 to 7.0 during storage at a temperature of 60 ° C.

In patent No. 001990 B1, the authors solve the problem of replacing ethanol by increasing the concentration of parabens by 20-25%, which provides the necessary level of preservative effectiveness with a pH> 5.5 in a lamivudine solution. In particular, in the composition of this pharmaceutical composition, said parabens are present in a concentration of from 0.96 to 2 mg / ml of methyl paraben and in a concentration of from 0.1 to 0.2 mg / ml of propyl paraben, respectively.

However, to date, the scientific community can not give a definite answer about the harmlessness of parabens to humans. There are different points of view about the safety of parabens in the food industry, pharmaceuticals and cosmetology. Opinions of scientists on this issue differ.

Thus, several expert studies have shown that there is an indirectly confirmed correlation between the presence of parabens and breast cancer. A high level of parabens was found in a cancerous tumor, more precisely, in a British study, a high concentration of parabens was obtained in 18 of 20 cases of breast cancer [Harvey PW, Everett DJ (2004). "Significance of the detection of esters of p-hydroxybenzoic acid (parabens) in human breast tumors." Journal of Applied Toxicology 24 (1): 1-4. DOI: 10.1002 / jat.957. PMID 14745840., Darbre PD, Aljarrah A, Miller WR, Coldham NG, Sauer MJ, Pope GS (2004 Jan-Feb). "Concentrations of parabens in human breast tumors." J Appl Toxicol 24 (1): 5-13. DOI: 10.1002 / jat.958. PMID 14745841].

Direct evidence of a causal relationship between parabens and cancer, however, has not been provided. In 2005, after additional studies of the available data [Golden R, Gandy J, Vollmer G (2005). "A review of the endocrine activity of parabens and implications for potential risks to human health." Critical Reviews in Toxicology 35 (5): 435-58. DOI: 10.1080 / 10408440490920104. PMID 16097138], The American Cancer Society has concluded that there is insufficient scientific evidence to argue that the use of cosmetics such as antiperspirants increases the individual risk of developing breast cancer and the need for further research on the possible effects of parabens on breast cancer [The American Cancer Society Antiperspirants and Breast Cancer Risk].

At the same time, the European Scientific Commission on Consumer Products (ECPP, SCCP) established in 2006 that the available data on parabens do not provide a decisive answer to the question of whether propyl, butyl and isobutyl parabens can be used safely in cosmetic products for individual concentrations up to 0.4% of the EU limit. [SCCP: Opinion on Parabens. Colipa No P82 10 Oct 200]

Since 2014, France has banned the use of parabens such as isopropyl, isobutyl, pentyl and benzyl paraben. The Commission for the Safety of Cosmetic Products considered that despite numerous confirmations of the safety of the use of parabens in established concentrations, additional studies are needed [Yana Zubtsova, Tiina Orasmäe-Meder Beauty myths: The whole truth about Botox, stem cells, organic cosmetics and much more. - M .: Alpina Publisher, 2015 .-- 296 p. - ISBN 978-5-9614-4887-0.].

In Russia, in 2005, by the Decree of the Chief Sanitary Doctor of the Russian Federation, a ban was introduced on the import into the Russian Federation of food products made using additives Ε 216 (para-hydroxybenzoic acid propyl ether) and Ε 217 (para-hydroxybenzoic acid propyl ether, sodium salt) , as well as the use of these additives in the manufacture of food products.

Since the question of the safety of parabens is currently under discussion, when developing a pharmaceutical composition of lamivudine, the authors of the present invention set the task of excluding ethanol and parabens from the composition of the preparation, while maintaining the necessary preservation efficiency and pH level.

An object of the present invention is to expand the list of drugs and to develop a domestic preparation, pharmaceutically equivalent to Epivir, oral solution, 10 mg / ml, while eliminating the use of undesirable (unsafe) agents in the composition to achieve preservative efficacy.

The technical result of the invention is to obtain a stable preparation in the form of an oral solution containing a safe, therapeutically effective amount of lamivudine, free of ethanol and not containing parabens, with a composition that ensures the creation and maintenance of preserving efficacy at pH from 5.5 to 7.0.

The authors of the present invention experimentally selected the composition of the drug Lamivudine, a solution for oral administration, with a possible concentration of lamivudine 1-50 mg / ml in accordance with the claimed technical result.

As part of the developed product, there are no such pH regulators as hydrochloric acid and sodium hydroxide; instead of them, sodium citrate and citric acid monohydrate act as pH regulators, the content of which can be varied if necessary. Other substances forming buffer solutions with pH greater than 5.5 can be used as pH regulators.

Also, the developed product does not contain parabens. Instead of methyl parahydroxybenzoate and propyl parahydroxybenzoate, cetylpyridinium chloride (CPC) was used as an antimicrobial preservative. To enhance the antimicrobial effect of cetylpyridinium chloride, disodium edetate (DNE) complexing agent in a concentration of up to 0.2% can be introduced into the composition of the drug.

Cetylpyridinium chloride, which is a cationic antiseptic and used in pharmacy as an antimicrobial drug and antimicrobial preservative, was chosen as a suitable antimicrobial preservative. Cetylpyridinium chloride is used in preparations for the treatment of skin diseases, infections of the oral cavity and throat, and in preparations for oral and inhalation use. In preparations for oral and inhalation use, it is used in concentrations of 0.02-1.5 mg / ml. The daily dose of cetylpyridinium chloride for adults and children over the age of 12 years is 8 mg, and for children from 6 to 12 years old - 4 mg.

As a result of these studies, the authors obtained a pharmaceutical composition of lamivudine, corresponding to the claimed technical result (free from ethanol and parabens, at pH from 5.5 to 7.0). This composition contains a hydrophilic carrier, a preservative agent in the form of cetylpyridinium chloride in an amount of 0.1 mg / ml to 0.2 mg / ml and processing aids, which can be used flavoring agents, colors, odors and pH adjusters. It is also possible to include in the composition of the complexing agent in the form of disodium edetate in an amount of up to 0.2 mg / ml.

Example 1: A specific example of the composition of the developed drug Lamivudine oral solution of 10 mg / ml are presented in table 4.

A method of manufacturing said composition is preferably, but not necessarily, as follows:

- sequentially dissolve propylene glycol, buffers, cetylpyridinium chloride and disodium edetate, sucrose, flavors and lamivudine in purified water;

- filter the solution;

- dispense the solution into vials, seal and label.

The authors of the present invention conducted screening studies on the choice of the composition of the preserving system using cetylpyridinium chloride and disodium edetate. When choosing the concentration of cetylpyridinium chloride, the fact that a single and daily dose of the drug for children and adults up to 30 ml was also taken into account.

The methodology for testing the effectiveness of antimicrobial preservatives is given in general article 34 (OFS 42-0069-07) “Determining the effectiveness of antimicrobial preservatives of medicines” of the RF State Pharmacopoeia XII ed., As well as in the European Pharmacopoeia (EF) RF XII ed. and EF are not significantly different.

According to the requirements of general article 34 of the RF Civil Code XII, in medicines for oral administration, the decimal 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. This criterion is less stringent than the criterion given in the European Pharmacopoeia (5.1.3).

In accordance with the requirements of the European Pharmacopoeia (5.1.3) in medicines for oral administration, the decimal logarithm of reducing the number of viable bacterial cells after 14 days should be at least 3, after 28 days the number of viable bacterial cells should not increase. The logarithm of reducing the number of viable fungal cells after 14 days should be at least 1, in the future, the number of viable fungal cells should not increase.

The research results for example 1 are shown in tables 5-8.

At a concentration of cetylpyridinium chloride (CPC) of 0.2 mg / ml, the effectiveness of the antimicrobial preservative effect is very high with and without disodium edetate (DNE) 0.2 mg / ml (Tables 5 and 6).

With a 2-fold decrease in the concentration of cetylpyridinium chloride (CPC) to 0.1 mg / ml and disodium edetate to 0.1 mg / ml, the effectiveness of the antimicrobial preservative effect slightly decreases against P. aeruginosa, S. aureus and A. niger, but remains high enough. From the data presented in table 8, 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 4.75, after 7 days and subsequent seeding, no viable cells of this test microorganism were detected.

No viable cells of the test microorganism E. coli ATCC 8739 were found in the initial plating, and no viable cells of this test microorganism were also found during subsequent plating.

In the initial seeding, the logarithm of the decrease in the number of the test microorganism P. aeruginosa ATCC 9027 was 3.86, after 7 days - 3.68, after 14 days and subsequent seeding, no viable cells of this test microorganism were detected.

In relation to fungi, the studied drug also showed high antimicrobial preservative effect. In the initial seeding, the logarithm of the decrease in the number of the test microorganism C. albicans ATCC 10231 was 4.18, after 7 days - 4.43, 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 16404 did not change significantly, after 7 days the logarithm of the decrease in the number of test microorganism A. niger ATCC 16404 was 4.95, after 14 days, and after subsequent seeding, viable cells of this test microorganism were not detected.

This antimicrobial preservative efficacy complies with the requirements of EF 8 (5.1.3) for oral medication [European Pharmacopoeia 8.0. - 5. General Texts. - 5.1.3. Efficacy of Antimicrobial Preservation] and significantly exceeds the requirements of article 34 (OFS 42-0069-07) “Determining the effectiveness of antimicrobial preservatives of drugs” of the RF Civil Fund of the XII edition to category 3 drugs [State Pharmacopoeia of the Russian Federation. - M.: Publishing House "Scientific Center for Expertise of Medical Applications", 2008. - 704 p.].

Next, the study of solutions of lamivudine with different composition was carried out by a similar method. For research, several versions of a solution were prepared with different pH and with a lamivudine content from 1 mg / ml to 50 mg / ml. The lower limit of the content of 1 mg / ml is due to the fact that at a lower content, even to provide an effective daily daily dose of 30 mg lamivudine, 30 ml of solution is required, which is unacceptable. The upper limit of 50 mg / ml is due to the solubility of lamivudine in hydrophilic solvents.

Table 9 shows the results of studies of the effectiveness of the antimicrobial preservative effect on the 14th day for preparations of lamivudine with different pH and active substance content.

The data obtained indicate that for all the given variants of the composition of the effectiveness of the antimicrobial preservative effect, the requirements of EF 8 (5.1.3) for oral medicines

Claims (1)

A stable pharmaceutical composition for oral use containing 10 mg / ml lamivudine, free of ethanol and parabens, including a hydrophilic carrier, which is water, a preservative agent, a complexing agent and processing aids, where the preservative is cetylpyridinium chloride in an amount of 0.1 mg / ml to 0.2 mg / ml, complexing agent - disodium edetate in an amount of from 0.11 mg / ml to 0.2 mg / ml, and as technological additives contains flavoring agents, colors, odors and p N, and this composition has a pH level of from 5.5 to 7.0.

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