MXPA99008690A - Pharmaceutical compositions - Google Patents

Abstract

The present invention relates to novel pharmaceutical formulations containing (2R, cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one ((-)-2', 3'-dideoxy,3'-thiacytidine, Epivir®, lamivudine) and their use in medical therapy.

Description

LIQUID COMPOSITIONS COMPRISING LAMIVUDINA Field of the Invention The present invention relates to novel pharmaceutical compositions containing (2R, cis) -4-amino-1- (2-hydroxymethyl-1, 3-oxathiolan-5-yl) - (1H) -pyrimidin-2-one ( (-) -2 ', 3' -dideoxy, 3'-thiacytidine, Epivir®, lamivudine) and its use in medical therapy.

Background of the Invention Retroviruses form a subset of the RNA viruses which, in order to replicate, must first "reverse transcribe" the RNA of their genome in DNA ("transcription" conventionally describes the synthesis of RNA from DNA). Once in the DNA form, the viral genome can be incorporated into the genome of the host cell, allowing it to take advantage of the transcription / translation machinery of the host cell for the purposes of replication. Once incorporated, viral DNA is virtually indistinguishable from host DNA and, in this state, the virus can persist for the life of the cell. Ref.031357 A species of retrovirus, the human immunodeficiency virus (HIV) has been reproducibly isolated from patients with AIDS (acquired immune deficiency syndrome) or with the symptoms that often precede AIDS. AIDS is an immunosuppressive or immuno-destructive disease that predisposes subjects to deadly opportunistic infections. Characteristically, AIDS is associated with progressive depletion of T cells, especially those that carry the inducer-helper subset of the CD4 surface marker. HIV is cytopathic and appears to preferentially infect and destroy T cells carrying the CD4 marker, and it is now generally recognized that HIV is the etiological agent of AIDS. Clinical conditions such as the AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), Karposi's sarcoma, thrombocytopenic purpura, neurological conditions related to AIDS, such as the AIDS dementia complex, the Multiple sclerosis or tropic paraparesis, and also the positive conditions of anti-HIV and HIV-positive antibodies, including such conditions in asymptomatic patients, are also conditions which can be treated by appropriate antiviral therapy.

Another RNA virus which has been recognized as the causative agent of a serious growing international health problem is the hepatitis virus different from both A and B. At least 80% of cases of hepatitis differ from both A and B, postransfusional, chronic, has been shown to be due to the virus now identified as hepatitis C and this virus is probably taken into account for virtually all cases of transfunctional hepatitis in clinical environments where blood products are protected from hepatitis B. While about half of the cases of acute hepatitis C infection resolve spontaneously over a period of months, the rest becomes chronic and in many cases, if not all, Chronic active hepatitis results with the potential of cirrhosis and hepatocellular carcinoma. The genome structure of the hepatitis C virus has been clarified and the virus has been characterized as a single-stranded RNA virus with similarities with flaviviruses. The hepatitis B virus (HBV) is a small DNA that contains the virus that infects humans. It is an element of the class of closely related viruses known as the hepadnaviruses, each element of which selectively infects hosts of either mammals or poultry, such as the marmot and the ducks. Recent insights into the replication mechanism of the hepadnavirus genome indicate the importance of reverse transcription of an RNA intermediate compound, suggesting that reverse transcriptase is a logical therapeutic target. HBV is a viral pathogen of major importance throughout the world. The virus is associated etiologically with primary hepatocellular carcinoma and is thought to cause 80% of global liver cancer. The clinical effects of infection with HBV vary from headaches, fever, headache, nausea, vomiting, anorexia and abdominal pain. The replication of the virus is usually controlled by the immune response, with a course of recovery that lasts for weeks or months in humans, but the infection can be more severe leading to persistent chronic liver disease, described above. The U.S. Patent No. 5,047,407 describes (2R, cis) -4-amino-1- (2-hydroxymethyl-1, 3-oxathiolan-5-yl) - (1H) -pyrimidin-2-one (Epivir®, lamivudine) and its use in the treatment and prophylaxis of viral infections. Lamivudine has tested antiviral activity against HIV and other viruses such as HBV. The common liquid formulations of lamivudine used in the clinic contain the disodium (ethylenedinitrile) tetraacetate dihydrate (disodium edetate, EDTA) and 6% ethanol (v / v). However, liquid formulations without ethanol or other sedatives and EDTA or other unnecessary antioxidants are considered advantageous, particularly for pediatric use and in kidney or liver damaged adults. The addition of alcohol and EDTA is thought to be necessary to maintain the preservative efficacy against bacteria, yeasts, and molds. EDTA, a chelating agent, has been shown to potentiate the activity of many antimicrobial agents by chelating the Mg2 + and Ca2 + ions which are normally responsible for the cell wall stability of Gram-organisms. negative In a study of the factors that affect the preservative efficacy of the lamivudine oral solution, Nguyen et. al., reported that improved preservative efficacy with increasing EDTA concentrations and with pH increasing from 4.5 to 7.5 (Nguyen, NA, T., et al., Drug Development and Industrial Pharmacy 21, 14, 1671-1682. , nineteen ninety five) . The same study reported that the chemical stability of lamivudine increased with an increasing pH from 4.5 to 7.5. The preservative efficacy was higher at pH 7.5, but increasing the pH from 4.5 to 7.5 led to extensive biodegradation of preservatives such as the hydroxybenzoate esters (hereinafter referred to as parabens). All the formulations were effective against bacteria and yeasts, but not against mold, Aspergillus niger. In a study evaluating the effects of alcohol concentration on the preservative efficacy of oral lamivudine solutions, Wells et. al., reported that the reduction or elimination of alcohol from oral lamivudine solutions led to an unacceptable preservative efficacy (Wells et al., Pharmaceutical Research, 10 (10), S171, 1993). Lamivudine is commonly formed at a pH of 5.5 with 0.01% EDTA, 0.12% (w / v) of methyl paraben, 0.015% of propyl paraben, and 6% of ethanol. In this formulation, EDTA works both to maintain pH and to preserve efficacy. At this concentration of parabens and pH, ethanol is necessary to pass the Antimicrobial Preservatives Effectiveness Test (APE) according to the standards of the United States of America Pharmacopeia (USP) (United States P armacopeia 23 , <; 51 > , p. 1681, 1995), the BP standards (Efficacy of Antimicrobial Preservation, Appendix XVI, 1995), and the PhEur standards (Efficacy of Antimicrobial Preservation, Chapter VIII.14, 1992). The pH was maintained at 5.5 to preserve the chemical stability of the parabens. It has surprisingly been found that there is an acute increase in preservative efficacy when lamivudine is formulated at a pH > 5.5 (Fig. 1) and the concentrations of the parabens are increased by 20 25% of the concentration of the parabens in the formulation containing ethanol. It has been found that oral formulations of lamivudine according to the present invention surprisingly maintain preservative efficacy and chemical stability while eliminating ethanol and EDTA An object of the present invention is to provide pharmaceutical compositions comprising lamivudine and a preservative system that allows the elimination of ethanol and EDTA, while maintaining the preservative efficacy.

Brief Description of the Invention The present invention relates to a pharmaceutical composition, substantially free of ethanol and EDTA, comprising a safe and therapeutically effective amount of lamivudine or a pharmaceutically acceptable derivative thereof and a preservative system comprising parabens in concentrations sufficient to confer and maintain the preservative efficacy and a pH greater than 5.5.

Detailed description of the invention The phrase "a safe and therapeutically effective amount" as used herein, means a sufficient amount of a drug, compound, composition, product or pharmaceutical agent to kill or reverse or treat a disease in a human or other mammal without severely harming it. the tissues of the mammal to which the drug or pharmaceutical agent is administered. The phrase "pharmaceutically acceptable derivative" ', as used herein, means any salt, solvate, ester, or salt of such pharmaceutically acceptable ester or any other compound which, during administration to the recipient, is capable of providing (directly or indirectly ) the proposed active ingredient or any active metabolite or residue thereof. The term "substantially free of," as used herein, means present in amounts that have less than a material effect on, or confer less than a material advantage to, the pharmaceutical composition. A substantially ethanol-free pharmaceutical composition may contain, for example, less than 3% ethanol, advantageously 0-1% ethanol. A substantially EDTA-free pharmaceutical composition may contain, for example, less than 0.005% EDTA. The term "preservative efficacy" or "preservative effectiveness", as used herein, means that the composition satisfies USP standards as defined in the protocol < 51 > , p. 1681, Uni ted States Pharmacopeia, 1995). The condom effect is effective on the product examined if (a) the concentrations of the viable bacteria are reduced to no more than 0.1% of the initial concentrations by the fourteenth day; (b) the concentrations of the viable yeasts and molds remain at or below the initial concentrations during the first 14 days; and (c) the concentration of each test microorganism remains at or below these designated levels for the remainder of the 28-day trial period. Similar criteria are defined for the BP (Efficacy of Antimicrobial Preservation, Appendix XVI C, 1995) standards, and the PhEur standards (Efficacy of Antimicrobial Preservation, Chapter VIII, 14, 1992).

The term "preservative system," as used herein, means ingredients and conditions (eg, pH) which lead to preservative efficacy. It will be appreciated by those skilled in the art that the reference herein to "treatment" extends to both prophylaxis and treatment of an established disease, infection or its symptoms. The term "EDTA", as used herein, means ethylenediaminetetraacetic acid, and includes the disodium EDTA (edetate disodium, (disodium salt of (ethylenedinitrile) tetraacetic acid, sodium ethylenediaminetetraacetate), calcium disodium EDTA, sodium iron (III) EDTA, and the like The compositions of the present invention employ a therapeutically safe and effective amount of lamivudine or pharmaceutically acceptable salts, solvates and derivatives thereof together with a safe and effective amount of pharmaceutically acceptable carriers. The present invention provides a pharmaceutical composition, substantially free of ethanol and EDTA, comprising lamivudine and parabens, wherein the composition is formulated at a pH> 5.5.

The pH of the formulation of the present invention can be in the range of 5.56 - 7.4, advantageously in the range of 5.56 - 6.5, and even more advantageously in the range of 5.8 - 6.2, particularly approximately 6.0. In accordance with the present invention, any hydroxybenzoate ester (parabens) or combination of such esters can be used, including combinations of methyl and propyl paraben and butyl and propyl paraben. In a further aspect of the present invention, formulations of lamivudine containing methyl paraben and propyl paraben are provided. For oral solutions and suspensions, the concentration range of methyl paraben may be 0.096 - 0.2% (0.96 mg / ml up to 2 mg / ml) and the concentration range of propyl paraben may be 0.01% to 0.02% ( 0.1 up to 0.2 mg / ml). Advantageously, the concentration range of methyl paraben can be 0.15 - 0.2% (1.5 mg / ml to 2 mg / ml) and the concentration range of propyl paraben can be 0.018% to 0.19% (0.18 to 0.19 mg / ml). According to a further aspect of the present invention, any suitable buffer solution can be used to provide a pH > 5.5 Advantageously, sodium citrate or phosphate can be used. The compositions of the present invention may optionally employ diluents, solubilizers, seasoning agents, viscosity increase agents (eg, polyethylene glycol), sweeteners, buffer solutions, or any other excipients commonly used in the art. Methods for the preparation of lamivudine are described in WO92 / 20669 and W095 / 29174 both incorporated herein by reference. Included in the invention are the salts, esters, or salts of such pharmaceutically acceptable lamivudine esters, or any other compound which, during administration of a safe and therapeutically effective amount of the compound to a human subject, is capable of providing ( directly or indirectly) the antivirally active metabolite or the residue thereof. The compositions of the present invention can be formulated using methods and techniques suitable for the physical and chemical characteristics of the compositions and which are commonly employed by those skilled in the art of preparing oral dosage forms (Remington, The Science and Practice of Pharmacy, 19 / a ed., 1995). The formulations according to the invention can be presented in various forms adapted for direct oral administration including liquid forms, for example, syrups, suspensions, or solutions. The formulations according to the invention may include other pharmaceutically acceptable carriers or excipients conventionally used in such formulations. Accordingly, for example, the syrups may include sugar syrup, sorbitol or hydrogenated glucose syrup. The suspensions may include suspending agents such as methylcellulose, microcrystalline cellulose, croscarmellose sodium or dispersible cellulose. Solutions may include sweeteners such as liquid glucose, levulose, xylitol, maltitol, or licasine. The formulations can be optionally flavored with artificial or natural flavors. The formulations include those suitable for oral administration. The formulations can be conveniently presented in the unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations can be prepared by uniformly and intimately bringing into association the active ingredient with the carriers. Formulations of the present invention suitable for oral administration can be presented as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water emulsion or a water-in-oil emulsion. The formulations of the present invention can be made using the methods and techniques that are commonly employed in obtaining preparations within the pharmaceutical industry. In the formulations according to the invention, the required amount of lamivudine will depend on several factors including the severity of the condition to be treated and the age and condition of the recipient and ultimately will be at the discretion of the attending physician. Attention. In general, however, an effective, adequate dose may be in the range of 0.1-20 mg / kg of body weight of the receptor per day, advantageously 0.1-5 mg / kg / day. The desired dose may be presented preferably as one, two, three, four or more sub-doses, containing for example 0.1-100 mg / ml, advantageously 5-20 mg / ml. The formulations according to the invention can be used for the treatment of human retroviral infections including HIV infections, and the consequent clinical conditions resulting from such infections, for example, AIDS, ARC, progressive generalized lymphadenopathy (PGL) and conditions HIV seropositive and positive AIDS antibody conditions. The formulations according to the invention can be used for the treatment or prophylaxis of human hepatitis B infections (HBV) and the consequent clinical conditions resulting from such infections. The formulations according to the invention can be used in medical therapy in combination with other suitable therapeutic agents in the treatment of VHI infections, such as inhibitors of nucleoside reverse transcriptase eg zidovudine, zalcitabine, didanosine, stavudine, 5-chloro-2 ', 3'-dideoxy-3' -fluorouridine and (2R, 5S) -5-fluoro-l- [2- (hydroxymethyl) -1,3-oxathiolan-5-yl] cytosine, 1592U89; reverse transcriptase inhibitors other than the nucleoside eg neviparin, TIBO, and α-APA; HIV protease inhibitors, for example saquinavir, indinavir, 141W94; other anti-HIV agents for example soluble CD4; immune modulators for example interleukin II, erythropoietin, tucaresol; and interferons, for example a-interferon. The formulations according to the present invention can be used in medical therapy in combination with other suitable therapeutic agents in the treatment of HBV infections, such as α-interferon. The components of such combination therapy can be administered simultaneously, either in separate or combined formulations or at different times, for example sequentially in such a way that a combined effect is achieved. The following non-limiting examples are included to illustrate the present invention but are not proposed to limit the reasonable scope thereof.

Example 1 A liquid formulation was prepared as follows: 1) Composition Ingredient Quantity / Lot of 1000 1 Lamivudine® 10.00 kg Sucrose 200.00 kg Methyl hydroxybenzoate 1.50 kg Propyl hydroxybenzoate 180 g Artificial strawberry flavor 800 g Artificial banana flavor 600 g Citrate dihydrate 11 g sodium Anhydrous citric acid 1 g Propylene glycol ** 19.4 1 NaOH / HCl , adjust when pH 6.0 necessary Purified water up to 1000 1 The quantity can be corrected by purity.

** The volume of Propylene Glycol is calculated by weight using the true density of 1.033 g / ml. 2) Preparation Method To a suitably sized auxiliary vessel, 19.4 1 of propylene glycol are added. While being mixed, 1.50 kg of methyl hydroxybenzoate and 180 g of propyl hydroxybenzoate were added to the propylene glycol and mixed until dissolved. The purified water was distributed in a stainless steel container with a fixed mixer. While mixing, parabens and glycol solution, 200.0 kg of sucrose, 1 g of anhydrous citric acid, 11 g of sodium citrate dihydrate, 800 g of artificial strawberry flavor, 600 g of banana flavor were added. artificial and 10 kg of lamivudine and mixed. A sufficient amount of purified water to make 201.65 kg was added and mixed. The solution was sampled and the pH was measured and adjusted to pH 6.0. The solution was filtered through a lightening filter into an appropriately sized receiving container.

Example 2 The antimicrobial preservative effectiveness test was carried out using the method described in The Uni ted States Pharmacopeia 23 < 51 > (1995), Pharmacopoeia Convention of the United States of America, Rockville, Md., 1994, p. 1681 Table 1. Antimicrobial Preservative Efficacy Test Results for the Ethanol-free Oral Solution of 10 mg / ml of Lamivudine (Example 1) Specifications Yeast and mold (A. niger, C. albicans,): 1 log reduction by day 14, no increase until day 28. Bacteria: 3 log reduction by day 14, no increase until day 28. pH 6.0 Example 3 The antimicrobial preservative effectiveness test was carried out using the method described in The Uni ted Sta tes Pharmacopoeia 23 < 51 > (1995), Pharmacopoeia Convention of the United States of America, Rockville, Md., 1994, p. 1681 Table 2. Log reduction values on day 14 for lamivudine formulations (10 mg / ml).

Specifications Yeast and mold (A. niger, C. albicans, Z rouxii): 1 log reduction on day 14, no increase until day 28. Bacteria: 3 log reduction on day 14, no increase until day 28.

* Placebo ** The numbers with bold letters represent a reduction of 100% It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following

Claims (17)

1. A pharmaceutical composition, substantially free of ethanol and containing less than 0.005% of ethylenediaminetetraacetic acid, comprising lamivudine or a pharmaceutically acceptable derivative thereof, and a preservative system, characterized in that the preservative system also comprises the parabens, the composition has a pH greater than 5.5.

2. A pharmaceutical composition comprising lamivudine, the composition is substantially free of ethanol and contains less than 0.005% of ethylenediaminetetraacetic acid and exhibits antimicrobial preservative efficacy, characterized in that it also comprises parabens, the composition has a pH greater than 5.5.

3. A pharmaceutical composition comprising lamivudine, the formulation is characterized in that it is substantially free of ethanol and ethylenediaminetetraacetic acid and satisfies the PhEur / BP / USP specifications.

4. A pharmaceutical composition, substantially free of ethanol and containing less than 0.005% ethylenediaminetetraacetic acid, characterized in that it comprises lamivudine or a pharmaceutically acceptable derivative thereof, methyl paraben, and propyl paraben, the composition has a pH greater than 5.5.

5. A pharmaceutical composition according to any of claims 1-4, characterized in that the concentration of methyl paraben is 0.96 mg / ml to 2 mg / ml and the concentration of propyl paraben is 0.1 mg / ml to 0.2 mg / ml.

6. A pharmaceutical composition according to any of claims 1-5, characterized in that the pH is in the range of 5.56-7.4.

7. A pharmaceutical composition according to claim 6, characterized in that the pH is 6.0.

8. A pharmaceutical composition according to any preceding claim, characterized in that the amount of lamivudine is in the range of 0.1-100 mg / ml.

9. A pharmaceutical composition according to claim 8, characterized in that the amount of lamivudine is in the range of 5-20 mg / ml.

10. A pharmaceutical composition according to any preceding claim, characterized in that it also comprises a second therapeutic agent.

11. A pharmaceutical composition according to any preceding claim, characterized in that it is for oral administration.

12. A method of treating viral infections by administering a safe and pharmaceutically effective amount of a pharmaceutical composition according to claims 1-11.

13. The use of lamivudine or a pharmaceutically acceptable derivative thereof, for the manufacture of a pharmaceutical composition according to any of claims 1-11, for use in the treatment or prophylaxis of viral infections.

14. The use of lamivudine according to claim 13, for the treatment or prophylaxis of HIV.

15. The use of lamivudine according to claim 13, for the treatment or prophylaxis of HBV.

16. A process for the preparation of a pharmaceutical composition according to any of claims 1 to 11, characterized in that it comprises the step of carrying in association the lamivudine or a pharmaceutically acceptable derivative thereof with a carrier.

17. A pharmaceutical composition, characterized in that it is as described here above.