UA60328C2 - Pharmaceutical formulations - Google Patents

Abstract

The present invention relates to novel pharmaceutical formulations containing (2R, cis)-4-amino-l-(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

Description of the invention

The invention relates to new pharmaceutical compositions containing 2 (2K,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one ((-) -2,3-dideoxy, 3-thiacytidine, ErimigF), lamivudine) and their use in medical therapy.

Retroviruses form a subgroup of RNA viruses, which for replication must first carry out "reverse transcription" of the RNA of their genome into DNA (transcription is called the synthesis of RNA from DNA). Having assumed the form of DNA, the viral genome can be embedded in the genome of the host cell and use the cellular mechanisms 70 of transcription/translation for replication. After such incorporation, the viral DNA is practically indistinguishable from the host's DNA, and in this state the virus can exist throughout the life of the cell,

One of the retroviruses, namely HIV (human immunodeficiency virus), capable of reproduction, was isolated from patients with AIDS or with symptoms often preceding AIDS. AIDS is an immunosuppressive or immunodestructive disease that makes patients prone to opportunistic, fatal infections. 12 A characteristic feature of AIDS is that it is associated with a progressive decrease in the number of T-cells, in particular, those of them that are helper-inducers and carry the surface marker CO4. HIV is cytopathic and appears to preferentially infect and destroy T-cells with the CO4 marker. It is now generally accepted that HIV is the etiological agent

AIDS. Such clinical conditions as AIDS-related complex, progressive general lymphadenopathy, sarcoma

Karposi, thrombocytopenic purpura, AIDS-related neurological conditions such as those associated with

AIDS dementia, multiple sclerosis or tropical paraparesis, as well as antibodies positive for antibodies and

HIV-positive conditions, including such conditions in asymptomatic patients, are conditions for which appropriate anti-viral therapy can be applied. Another RNA virus that has been recognized as a causative agent of serious internal diseases is the non-A hepatitis and non-B hepatitis viruses. At least 8,095 cases of chronic post-infusion non-A hepatitis were reported Non-hepatitis B is caused by a virus now identified as hepatitis C virus, and it is possible that this virus is the cause of almost all cases of post-infusion hepatitis in the world (In the clinical setting, when blood samples are tested for hepatitis B. Although about half of cases of acute hepatitis C ends in recovery After a few months, the rest become chronic, and in many cases, chronic active hepatitis progresses to cirrhosis and hepatocellular carcinoma. The genome structure of hepatitis C virus has been studied and this virus has been classified as a single-stranded RNA virus similar to flaviviruses.

Hepatitis B virus (HBV) is a small virus that contains DNA and infects humans. It belongs to a class of closely related viruses known as hepadDNAviruses, each of which selectively infects mammals or birds, such as marmots and ducks. Recent studies of the genome replication mechanism of the hepadDNA virus point to the importance of reverse transcription of the RNA intermediate and to the fact that the reverse "3 transcriptase is a logical target of chemotherapy. HBV is a viral pathogen of great global significance and is etiologically associated with primary hepatocellular carcinoma. It is believed to be the cause of 8090 of all liver cancer cases. at

Clinical symptoms of HBV infection may include headache, fever, malaise, nausea, vomiting, anorexia, and abdominal pain. Replication of the virus is usually suppressed by the immune response, recovery in a person occurs after several weeks or months, but in severe cases the infection leads to the chronic disease of the liver, mentioned above. C 70 US Patent 5,047,407 describes c (2K,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (Erimyk, lamivudine) and his

From" application in the therapy and prevention of viral infections. Lamivudine has been shown to have antiviral activity against HIV and other viruses such as HBV. Liquid compositions with lamivudine, which are used in the clinic, contain disodium (ethylene dinitrilo) tetraacetate dihydrate (disodium edetate, EDTC) and beans (volume) of ethanol. However, desirable, in particular, in pediatrics or in the treatment of adults with kidney or liver impressions

Me are considered liquid compositions without ethanol or other sedatives and EDTC or other unnecessary antioxidants. av | It is considered necessary to add alcohol and EDTC to maintain resistance against bacteria, yeast and mold. It has been shown that EDTC is a chelating agent that enhances the action of many antibacterial agents by chelating Ma 2: and Ca ions, which are usually responsible for the stability of the cell wall of gram-negative organisms. Studying the factors affecting the preservative ability of lamivudine solution for of oral co-administration, Maiuep ei a!. noted that this ability increases with increasing concentrations of EDTC and an increase in pH from 4.5 to 7.5 (Mdiuep M-AT. 14, 1671-1682, 1995). It was also noted that the chemical resistance of lamivudine increases with an increase in pH from 4.5 to 7.5. The preservative capacity is greatest at pH 7.5, but an increase in pH from 4.5 to 7, 5 causes severe destruction of such preservatives as 59 esters of hydroxybenzoates (hereinafter referred to as parabens). All compositions were effective against bacteria and

GF) yeast, but not mold. 7 In the work on the assessment of the effect of alcohol concentration on the preservative capacity of a lamivudine solution for oral administration, it was shown that reducing the amount or removing alcohol from such solutions leads to an unacceptable decrease in the preservative capacity (uUeiYi5 ei ai., Rnagtaseciisa! Kezeagsy, 10 (10), 5171, 1993). because Lamivudine in compositions is used at pH 5.5 together with 0.0195 EDTC, 0.1295 (w/v) methylparaben, 0.01595 propylparaben and 695 ethanol. In this composition, EDTC maintains both the pH and the preservative capacity. At these concentrations of parabens and pH, ethanol is required to meet the requirements of the Antimicrobial test

Preservative capacity according to the standard of the United States Pharmacopoeia (Opiedy 5iafevs RIagtasoreia, 23:51", r.1681, 1995), the standard of the British Pharmacopoeia (EPisasu oi Apiitisgoria! Rgezegmaiop, Arr. KhMI S, 1005) and the standard of the European Pharmacopoeia (EPisasu oi Apiitisgoria !Rgezeghmayop, SPparieg MY. 14, 1992). pH 55 is maintained to preserve the chemical stability of parabens. We found a sharp increase in the preservative capacity of lamivudine compositions at pH 5.5 (Fig. 1) and with an increase in the concentration of parabens by 20-2590o compared to their concentrations in ethanol-containing compositions.

It was found that the oral lamivudine compositions according to the invention retain their preservative ability and chemical stability without ethanol and EDTC.

The task of the invention is to create pharmaceutical compositions containing lamivudine canning system that allows you to do without ethanol and EDTC while preserving the canning ability.

The invention includes a pharmaceutical composition, substantially free of ethanol and EDTC, which contains a safe and 7/0 pharmaceutically effective amount of lamivudine or a pharmaceutically acceptable derivative thereof, and a preservative system, which contains parabens in concentrations sufficient to maintain preservative capacity and pH »5 ,5.

The term "safe and therapeutically effective amount" means an amount of a drug, compound, composition, product, or pharmaceutical agent sufficient to attenuate or reverse the development of a disorder in a human or other mammal without serious damage to the tissues of the mammal to which the drug or pharmaceutical agent is administered. .

The term "pharmaceutically acceptable derivative" means a pharmaceutically acceptable salt, solvate, ester or salt of such an ester or any other compound capable of forming (directly or indirectly) the desired active ingredient or any active metabolite or residue thereof after administration to a patient.

The term "substantially free from" means present in amounts that have less than a material effect on the pharmaceutical composition. A pharmaceutical composition substantially free of ethanol" will contain less than 390, preferably less than 195, of ethanol. A pharmaceutical composition substantially free of EDTC may contain, for example, less than 0.00595 EDTC.

The term "preservative capacity" or "preservative efficacy" means that the composition meets the standards defined in Protocol "51", p. 1681, document MOpiyez Z (Afiez Ragtasoreia, 1995). A preservative in a product is considered effective if (a) the concentration of viable bacteria on the 14th day is reduced to no more than 0.195 of the initial concentration, (b) the concentration of viable yeast and mold and) remains at the same level or decreases during the first 14 days and (c) the concentration of each of the test organisms remains below the specified levels for the remainder of the 28-day test period. Similar criteria are defined in the standards of the British Pharmacopoeia (EPisasu oi Apiitisgobiai so zo Rtezegmaiop, Arr. KhMI S, 1005) and the European Pharmacopoeia (EPisasu oi ApiitisgoriaI Rgezegmaiop, SNarieg

E. 14, 1992). with

The term "preservative system" refers to the ingredients and conditions (for example, to maintain the pH) that provide the preservative ability.

For a specialist, it is clear that treatment includes both prevention and actual treatment of the diagnosed disorder, infection or their symptoms. "at

The term "EDTC"' means ethylenediaminetetraacetic acid and includes disodium EDTC (disodium edetate, disodium salt of (ethylenedinitrilo)tetraacetic acid, disodium ethylenediaminetetraacetate), calcium disodium EDTC, sodium iron(11) EDTC, etc.

Compositions according to the invention contain a safe and pharmaceutically effective amount of lamivudine or its pharmaceutically acceptable salts, solvates and derivatives together with an effective amount of pharmaceutically acceptable carriers.

In particular, the invention includes a pharmaceutical composition substantially free of ethanol and EDTC and formulated at a pH of 5.5, which contains lamivudine and parabens.

The pH of the composition according to the invention can be 5.56 - 7.4, preferably 5.56 - 6.5, best 5.8 - 6.2,

In particular, about 6.0. According to the invention, it is possible to use esters of hydroxybenzoates (parabens) or combinations of such esters, including methyl and propyl parabens and combinations of butyl and propyl parabens. o The invention also includes lamivudine compositions that contain methyl and propyl parabens. In oral 2) solutions and suspensions, the concentration of methyl parabens can be in the range from 0.096 to 0.295 (0.096 - 5 or 2 mg/ml), and the concentration of methyl parabens - in the range from 0.01 to 0.0290 (0.1 - 0.2 mg /ml). It is desirable to have concentrations of methyl parabens in the range from 0.15 to 0.295 (1.5-2 mg/ml), and concentrations of methyl parabens - in the range from 0.018 to 0.01995 (0.18-0.19 mg/ml).

Any suitable buffer that provides a pH of 25.5 can be used according to the invention. It is preferable to use citrate or sodium phosphate.

In the compositions according to the invention, as an option, diluents, solubilizers, flavoring agents, viscosity-increasing agents (eg, polyethylene glycol), sweeteners, buffers or

F) any other fillers used in the industry. Methods of preparation of lamivudine are described in UUO92/20669 and MUO95/29174, which are included here by reference.

The invention includes pharmaceutically acceptable salts, esters or salts of esters of lamivudine or any other compound capable of forming (directly or indirectly) its antivirally active metabolite or residue after administration to a human patient in a safe and therapeutically effective amount.

The methods of preparation of the compositions according to the invention should correspond to the physical and chemical properties of the compositions and are well known to specialists familiar with the preparation of oral dosage forms (Ketipdiop, Te

Zsiepse apa Rgasiise oi Rpagtasu, 19-(p eay., 1995). 65 The compositions according to the invention can have various forms suitable for direct oral administration, including liquid forms, for example, syrups, suspensions or solutions. They may include other pharmaceutically acceptable carrier-fillers that are commonly used for compositions. For example, syrups may include sugar syrup, sorbitol, or hydrogenated glucose syrup. Suspensions may include suspending agents, for example, methylcellulose, microcrystalline cellulose, croscarmellose sodium, or dispersed cellulose. Solutions

May include sweeteners such as liquid glucose, levulose, xylitol, maltitol or lysazine. If desired, artificial or natural flavor additives can be added to the compositions.

The compositions include those suitable for oral administration, and may be prepared as dosage forms in any manner known in the pharmaceutical industry. Such methods include the step of combining the active ingredient with a carrier, which may contain one or more auxiliary ingredients. In general, 7/0 compositions are prepared by introducing the active ingredient into a homogeneous and close connection with the carriers.

Compositions according to the invention, suitable for oral administration, can be prepared in the form of aqueous or non-aqueous liquid solutions or suspensions, or oil-in-water or water-in-oil emulsions.

For the production of compositions according to the invention, it is possible to use methods and procedures that are usually used for this in the pharmaceutical industry.

The amount of lamivudine in the compositions of the invention depends on many factors, including the severity of the disorder to be treated, the age and condition of the patient and is determined by the physician. In general, a suitable effective daily dose may be from 0.1 to 20 mg/kg, preferably from 0.1 to bmg/kg. Such a dose can be composed of one, two, three, four or more subdoses, each amounting from 0.1 to 100 mg/ml, preferably 5 to 20 mg/ml.

Compositions according to the invention can be used for the treatment or prevention of human retroviral diseases, including HIV infections and conditions caused by such infections, for example, AIDS or pre-AIDS symptoms, progressive generalized lymphadenopathy, and HIV-seropositive and AIDS-antibody-positive conditions.

Compositions according to the invention can also be used to treat or prevent human hepatitis B infections and subsequent clinical conditions resulting from such infections. high school

Compositions according to the invention can be used in medical therapy in combination with other therapeutic agents suitable for the treatment of HIV infections, for example, with such inhibitors of i) nucleoside reverse transcriptase as zidovudine, zalcitabine, didanosine, stavudine, 5-chloro-2,3 '-dideoxy-3-fluorouridine and (2K,55)-5-fluoro-1-(2-hydroxymethyl)-1,3-oxathiolan-5-yl|cytosine, 1592C89; with non-nucleoside reverse transcriptase inhibitors, for example, TIVO and 9o-ARA; with HIV co-protease inhibitors, for example, saquinavir, indinavir, ritonavir, 141UuU94; with other antiViL agents, for example, soluble CO4; with immune modulators, for example, interleukin II, erythropoietin, with tucaresol; and with interferons, for example, o-interferon. co

The compositions according to the invention can also be used in medical therapy in combination with other therapeutic agents suitable for the treatment of HBV infections, for example, with o-interferon. at

The components of such compositions can be introduced simultaneously individually or in combinations, or at different times, (Se) for example, in a certain sequence that gives the desired effect.

The following examples illustrate the invention without limiting it.

Example 1. Preparation of a liquid composition « 1) Composition:

Ingredient Quantity in a 1000-liter portion - with Lamivudine" 10.0Okg and Sucrose 200.Okg "» Methyl pdroxybenzoate 1.5kg

Propyl hydroxybenzoate 180g

Artificial strawberry flavoring 800g

Ge) Artificial banana flavor additive bO0g o Sodium citrate dihydrate 11g

Anhydrous citric acid 1 g

Ge) Propylene glycol "7" 19.4 l of 50 Maon/nHsi for pH adjustment pH 6.0

Purified water up to 1000 l

IR e) t - the amount can be adjusted depending on the purity and - the volume of propylene glycol is calculated by mass, based on the actual density of 1.03 Zg/ml. 2) Method of preparation

Add 19.4 liters of propylene glycol to a tank of suitable volume and add 1.50 kg of methyl hydroxybenzoate and 180 g of propyl hydroxybenzoate with stirring and continue stirring until dissolved. Purified water is poured into a stainless steel vessel with a built-in mixer. With stirring, add a solution of parabens in glycol, 200,000 kg of sucrose, 1 g of anhydrous citric acid, 11 g of sodium citrate dihydrate, 800 g of artificial strawberry flavoring, 100 g of artificial banana flavoring and 10 kg of lamivudine. Add 60 purified water to obtain 201.65 kg and mix. Take a sample, measure the pH and adjust the pH to 6.0.

The solution is poured into a suitable tank with filtration through a cleaning filter.

Example 2. Antimicrobial preservative effectiveness test according to the procedure according to MOP.5ia(ez)

Rpagtasoreia, 23,:51", 1995, Opiei 5ia(ez Rpagtasoreia! Sopmepiyop, KoskKmiMPe, Ma., 1994, r, 1682.

TABLE 1. Antimicrobial preservative efficacy test results for an ethanol-free solution of 65 lamivudine (1Omg/ml) for oral administration (Example 1).

Results:

Yeast and mold (A.pideg, S.aiIrisapv): decrease by 1 order on the 14th day, no increase until the 28th day. and

Organism Inoculum per ml o GI tt in

Worth 00100 o Be 00000001

Reedotyaee 1000010 ba

I

Aereshishe 17777111

Example 3. Antimicrobial preservative effectiveness test according to the procedure according to Opieai bia(ez Rnaptasoreia, 23.51", 1995, Opiea Ziaiez Rinaptasoreia! Sompemiop, Boskmey, Ma., 1994, p. 1682.

TABLE 2. Logarithmic reduction over 14 days for lamivudine formulations (1Omg/ml).

Results:

Yeast and mold (A.pideg, S.aiIrisapv, 7.goikhii): decrease by 1 order on the 14th day, no growth until the 28th day. s o so zo sch

Fo o vo1800 020 vho (BYU 50 515 b. Bl BIV zv F

My name is 00003600

Iov sla 1ott 11111 " - placebo ch yah - the numbers given in bold represent the 10095th decrease. o) c z

Claims (8)

The formula of the invention 1. A pharmaceutical composition, substantially free of ethanol, which contains less than 0.00590 (o) ethylenediaminetetraacetic acid and lamivudine or a pharmaceutically acceptable derivative thereof, and a preservative system that includes parabens, and the composition has a pH greater than 5.5. 2. Pharmaceutical composition according to claim 1, which differs in that the concentration of methylparaben is from (95) 0.96 mg/ml to 2 mg/ml, and the concentration of propylparaben is from 0.1 mg/ml to 0.2 mg/ml . 7 50 3. Pharmaceutical composition according to claim 1 or 2, which differs in that its pH is in the range from 5.56 to 7 4. 4. The pharmaceutical composition according to item C, which is characterized by the fact that its pH is 6.0. and42) 5. The pharmaceutical composition according to any of the previous items, which differs in that the amount of lamivudine in it is from 0.1 mg/ml to 100 mg/ml. 6. Pharmaceutical composition according to claim 5, which differs in that the amount of lamivudine in it is from 5 mg/ml to 20 mg/ml. at 7. A pharmaceutical composition according to any of the previous items, which is characterized by the fact that it additionally contains a second therapeutic agent. co 8. A pharmaceutical composition according to any of the previous items, which differs in that it is intended for oral administration. 60 b5