WO2005007070A2

WO2005007070A2 - Stable pharmaceutical composition

Info

Publication number: WO2005007070A2
Application number: PCT/BR2004/000119
Authority: WO
Inventors: Ogari Pacheco; Elisa Russo; Valter Russo
Original assignee: Cristália Produtos Químicos Farmacêuticos Ltda.
Priority date: 2003-07-23
Filing date: 2004-07-19
Publication date: 2005-01-27
Also published as: BR0302523A; WO2005007070A3

Abstract

The present invention describes a soluble and stable pharmaceutical composition for the administration of HIV protease inhibitors. More specifically, the composition comprises a solution of one or two HIV protease inhibitors in a combination of pharmaceutical acceptable organic solvents, a surfactant and a bioavailability enhancer. It is also described a process for preparing concentrate pharmaceutical compositions for the administration of HIV protease inhibitors. The composition of the present invention is suitable to prepare oral solutions for the administration of active drugs and to be encapsulated in hard gelatin capsules or soft gelatin capsules.

Description

STABLE PHARMACEUTICAL COMPOSITION FOR THE ADMINISTRATION OF HIV PROTEASE INHIBITORS AND PROCESS FOR PREPARING A CONCENTRATE PHARMACEUTICAL COMPOSITION FOR THE ADMINISTRATION OF HIV PROTEASE INHIBITORS The present invention describes a soluble and stable pharmaceutical composition for the administration of HIV protease inhibitors. More specifically, the composition comprises a solution of one or two HIV protease inhibitors in a combination of pharmaceutical acceptable organic solvents, a surfactant and a bioavailability enhancer. It is also described a process for preparing concentrate pharmaceutical compositions for the administration of HIV protease inhibitors. The composition of the present invention is suitable to prepare oral solutions for the administration of active drugs and to be encapsulated in hard gelatin capsules or soft gelatin capsules . Nowadays, AIDS treatment (Acquired Immunodeficiency

Syndrome) uses medicines that must be administered every day many of them in high dosages and, which treatment can not be interrupted even a day for the rest of the infected individuals life. One of the main concerns from health professionals dealing with individuals infected by AIDS is the possibility of the development of virus resistance, a very plausible occurrence when the active drug does not reach the infected target tissue or tissues in a minimum amount necessary to the eradication and/or complete inactivation of the infectious agent. Resistance is without any doubt one of the biggest problems that may overcome during the treatment of diseases caused by infectious organisms and the efforts to avoid it are frequent . There are several issues that a drug must comply in order to be considered adequate as a therapeutic agent. Among them, a drug must present therapeutic efficacy and for that it has to possess adequate bioabsorption and bioavailability characteristics. Furthermore, the drug must have an administration route less invasive as possible in order not submitting the patient to painful and uncomfortable procedures during its administration and, another extremely important factor is that it has to stimulate or to induce the patient adherence or adhesion to the therapy. Adherence can be defined as the act, action or quality of being consistent with the administration of the prescribed medicaments. This issue is so more important as longer the time of duration of the therapy that the patient has to be submitted. The success of the therapy with antiretrovirals in AIDS treatment depends mainly on the patient adherence to the therapy, which consists in the administration of significant amounts of different medicines several times a day. Accordingly with the final report named "Avaliacao da Aderencia ao Tratamento por Anti-retrovirais em ϋsuarios de Ambulatόrios do Sistema Publico de Assistencia a AIDS no Estado de Sao Paulo" (a report evaluating the adherence of patients to antiretrovital therapy in the State of Sao Paulo - Brazil) , non-adherence to new AIDS medicines (antiretrovirals mainly and protease inhibitors in particular) is considered one of the most threatening dangers to the effectiveness of the treatment, in an individual level, and for the dissemination of virus-resistance, in a collective level. That is because new AIDS administration therapies seems to request from the "adherent" a complex integration between knowledge, ability and acceptance, besides other important issues related to the environment and to the health care. The report discloses the matter of non-adherence being a universal phenomenon in a certain rate, occuring either in rich and poor countries, even in cases of life threatening diseases. Adherence to antiretrovirals is a motive of apprehension among health professionals, once researches about it demonstrate that it is very low even in rich countries, where it reaches only 70% of the patients under treatment (Walsh J. , Dalton M., Gill J. , Wilkinson D. Burgess A. P., Gazzard B.G. - Adherence to protease inhibitor based highly effective anti- retroviral therapy (HAART) in 12^th World Aids Conference, Geneva 1998. Abstracts; Hecht F.M., Colfax G., Swanson M. , Chesney M.A. - Adherence and effectiveness of protease inhibitors in clinical practice in 5^th Conf. Retrovir. Oppor. Infect., San Francisco, 1998 Abstracts, e Eldred L. Adherence in the era of protease inhibitors - John Hopkins AIDS Service) . This percentage is considered very low for a fatal disease, especially when considering that those reports had exclusively disclosed the adherence from patients to the amount of medicines recommended. Particularly, one of the anti-aids cocktail components corresponds to a special medicine class, which acts inhibiting the retroviral protease, and they are called protease inhibitors. Protease inhibitors are substances with elevate molecular weight, normally lipophilic, slightly soluble in water and usually present low absorption rates and low bioavailability when administered in a solid state. Due these characteristics, high and frequent doses of these substances are needed to keep an ideal circulating therapeutic level of the drug in the organism. The physical-chemical characteristics from protease inhibitors difficult the development of concentrate compositions for the administration of these drugs. It is a consequence of the low solubility profile that these substances have in the pharmaceutical compositions proposed until now. As disclosed above, protease inhibitors present low absorption and low bioavailability when administered in a solid state. The administration of these substances as syrups or oral solutions was not well accepted by patients in treatment until now, once they have awful taste that is difficult to mask by adding suitable taste enhancers or flavoring substances. Another problem related to the administration of these substances as an oral solution involves the manipulation of administration devices, procedure that inhibit patients to follow the administration regime once in non-private places, avoiding the natural curiosity and prejudice inherent to the condition established by the disease. In order to offer a more discrete way of administration for protease inhibitors, recently there were developed compositions administered in soft gelatin capsules that consist in a liquid composition surrounded by a thin film of elastic gelatin. Because the elastic behavior of the capsule proportionates a smooth ingestion, its acceptance is higher than the conventional tablets or hard gelatin capsules. Another important property derived from this kind of composition is to allow the administration of medicines in a liquid state, wherein the pharmaceutical active ingredient is dissolved in a solution. Once ingested, the capsule breaks inside the gastrointestinal tract liberating its content in an homogeneous way, and as a liquid, it is not necessary to be dissolved first by the body in order to be absorbed. Although the pharmaceutical presentations had evoluted to deal with the need of supplying these substances in a soluble way and in a better acceptable form by patients, the final presentation of these compositions shows to be not very adequate to the adherence to these medicines. It is mainly because that the capsules used for the administration of the drug are very voluminous for oral administration, a direct consequence of the low solubility of the active ingredient in the excipients used to manufacture them. This fact is an aspect that directly interferes in the adherence of the patient to therapy. When considering cases where debilitated patients and those with several gastrointestinal diseases (a frequent problem among those patients) and also the infant patients, the need to ingest voluminous capsules is something that obstruct the adherence to the treatment. Protease inhibitors are substances with low solubility and frequently they present several different crystalline forms that interfere directly in the development of appropriate pharmaceutical compositions. For example, the development of the original composition wherein ritonavir was launched, just take into account one polymorphic form from ritonavir that was known at that time, being nominated polymorph I. Some years after its launch, it was observed that the original composition wasn't able to accomplish with the specifications of the "in vitro" dissolution test. It was resulting from the existence of a less soluble form of ritonavir, which was nominated as polymorph II. As ritonavir composition comprising this polimorphic form could compromise the medicine efficiency in suppressing the human immunodeficiency virus leading to virus-resistance to this substance, this composition was withdrawn from the market being temporarily substituted by the oral solution that could be easily inspected visually by patients certifying the absence of non-soluble crystals before taking the medicine. As it was not possible to control completely the precipitation of polymorph I only and avoid its interchange into polymorph II, the answer found to control the problem was the development of a new pharmaceutical composition that could be able to allow the presence of polymorph II in a solution. This new composition was developed for being administered as soft gelatin capsules. Despite this new composition had considerably suppressed the less soluble polymorph crystallization, it presents some disadvantages, i.e. low physical-chemical stability when stored at ambient temperatures, beeing possible to store the capsules without refrigeration for only two months. As a consequence of this physical-chemical instability, the final medicine must be stored under refrigeration, involving a complex design in the preservation of this medicine stock by distributing companies and implicate in one more difficulty for patients that have to keep their medicine under refrigeration, which limits considerably their liberty in traveling to places where there is no electricity or other means for keeping the medicine under refrigeration. Despite many efforts to proportionate a therapy more suitable to the patient life rhythm, adherence to treatment by HIV positives has some drawbacks. Protease inhibitor drugs are normally administered three times a day. Fear from disease's prejudice frequently interferes in the adherence to this treatment regime, the patient normally suppressing "the afternoon dose" eliminating the possibility to be recognized as HIV positive. To solve this problem, recently it was launched a medicine consisting in an association of ritonavir and a new protease inhibitor known by its generic name of lopinavir.

Lopinavir, which chemical name is [IS- [1R*, (R*) , 3R*, 4R*] ] -N-

[4- [ [ (2, 3-Dimethylphenoxy) acetyl] amino] - 3- hydroxy- 5- phenyl-1- (phenylmethyl) pentyl] tetrahydro - alfa-(l- methylethyl) -2-oxo-l- (2H) -pyrimidineacetamide, is a protease inhibitor that associated to a definite quantity of ritonavir, demonstrates its plasmatic levels increased due the inhibition by ritonavir of lopinavir mediated metabolism by enzyme CYP3A. Lopinavir is completely and essentially inhibited by enzyme CYP3A that is a part of hepatic cytochrome P450 system. The inhibition of this enzyme by ritonavir inhibits the metabolism of lopinavir increasing considerably its plasmatic level, and in consequence providing an extended activity of this inhibitor. Because this discovery, the commercially available composition can be administered twice a day. Because in fact it is used ritonavir and due its polymorphic problem presenting polymorphs of marked solubility differences, the pharmaceutical composition developed for the administration of lopinavir and ritonavir combination contains basically the same excipients of the composition in which ritonavir is delivered today. As a consequence the volume of the administered composition is high and the capsules are still voluminous, inhibiting the adherence from patients because of the difficulty in swallowing them. Another unfavorable issue is the physical-chemical instability of this composition that must be kept under refrigeration to avoid the degradation of the active ingredients, therefore possessing the disadvantages disclosed before in distributing, transporting and stocking this medicine. Because of these problems it is necessary the development of a liquid composition suitable for the administration of the combination lopinavir-ritonavir, which presents physical- chemical stability enough to be stored at ambient temperature for a long period of time and also a composition possible of being prepared containing an elevate concentration of those active ingredients in order for its size to be considerably reduced, making its swallowing easier for all treated individuals and, particularly allowing the treatment of the elder, the debilitate patients and the children. In the literature it is possible to find some references of pharmaceutical compositions developed for the administration of lopinavir-ritonavir combination. Among them there are patents US 5,914,332 and US 6,232,333 that describe a pharmaceutical composition comprising lopinavir and ritonavir. The pharmaceutical composition described is essentially similar to the pharmaceutical composition described in application WO 98/22,106 containing as the organic solvent a long chain fatty acid, combined or not to an alcohol and an acceptable pharmaceutical tensoactive. Another document is application WO 02/096,395, which describes a soft gelatin capsule in equilibrium with the pharmaceutical composition. The pharmaceutical composition disclosed in this application comprises a pharmaceutical agent (ritonavir) or a combination of pharmaceutical agents (ritonavir and lopinavir) , an alcohol and a fatty acid. As the alcohol, preferably substances are propylene glycol and ethanol. As fatty acid, the preferably substance is the oleic acid. The pharmaceutical composition includes additionally a surfactant agent, preferably the polyethoxylated castor oil 35 (Cremophor EL ™) . This application is a variant of the first two patents disclosed, wherein the composition presents an extra quantity of the alcoholic solvent that is consumed during the plasticizing process of the soft gelatin capsule, possessing self physical-chemical characteristics and adequate ingredients to the plasticizing process of producing the capsule, which involves a partial consumption of the alcoholic excipient that is within the fulfilled pharmaceutical composition. As the pharmaceutical excipients are essentially the same used in the earlier developed pharmaceutical compositions, the stability of the active ingredients is still limited to its storage under refrigeration. Application WO 01/34,119 describes a pharmaceutical formulation comprising a solid dispersion presenting the properties to inhibit the crystallization. As crystallization inhibitor it is used the polyvinylpirrolidone and hydroxypropyl cellulose. The dispersing solvent is a high molecular weight polyethyleneglycol (PEG 8000), being the product prepared and processed in mills to obtain a solid with suitable size to the final pharmaceutical product (tablets or hard gelatin capsules) . This composition is not yet available in the market and it is impossible to determinate its stability over crystallization on standing or its stability over different storage conditions. The product available today for administering lopinavir- ritonavir combination consists in a pharmaceutical preparation in a liquid form comprising basically oleic acid, polyethoxylated castor oil 35 and an alcohol. In accordance to the information disclosed in the label, this medicine must be kept under refrigeration over its validity date of 18 months. Its storage under ambient temperatures is allowed for only a maximum period of two months, demonstrating its short stability under this condition. Except by application WO 01/34,119, all references disclosed befor describe pharmaceutical compositions comprising the same excipients, therefore implicating in a short physical-chemical stability of the composition that can not be stored under ambient temperature because it can loose its efficacy in a short period of time. The disclosure of the solid dispertion (WO 01/34,119) does not provide any information that can allow to determinate its real efficacy and its stability behavior at room temperature on standing. In our earlier application, PI 0202252-4, we described a pharmaceutical composition presenting physical-chemical stability suitable to be stored at room temperature and capable of comprising an elevate concentration of ritonavir, being this composition better than the commercialized product. The composition described in that document comprises a combination of excipients capable of inhibiting ritonavir crystallization and demonstrating a suitable stability when stored under ambient temperature. The present invention describes a stable pharmaceutical composition suitable for the administration preferably of a combination of lopinavir-ritonavir in determined ratios, being also adequate to the administration of lopinavir by itself. The pharmaceutical composition of the present invention can be prepared in a high concentration of the active ingredients and furthermore it can be stored under no refrigeration. A second objective of the present invention is the process for preparing a stable pharmaceutical composition comprising a lopinavir-ritonavir combination, this process suitable for preparing pharmaceutical compositions using any polymorphic form from the active ingredients, avoiding previous treatments of the starting materials, micronizing processes or even the selection of batches composed by ideal polymorphs or solid forms suitable for the production. Accordingly with the present invention, the stable pharmaceutical composition comprises: (a) [IS- [1R* , (R*) ,3R* , 4R* ]] -N- [4- [ [ (2, 3-Dimethyl phenoxy) acetyl] amino] - 3- hydroxy- 5-phenyl-l- (phenylmethyl) pentyl] tetrahydro - alfa -(1- methylethyl) -2 - oxo- 1- (2H)- pyrimidineacetamide (lopinavir) , or its combination with [5S- (5R*,8R*,10R*,11R*) ] -10-hydroxy- 2-methyl -5-(l- methylethyl)-l-[2-(l-methylethyl) - 4 - tiazolyl] - 3,6- dioxo - 8,11-bis (phenylmethyl) - acid 2,4,7, 12-tetraazatridecan-13-oic 5-thiazolilmethyl ester (ritonavir) ; (b) A mixture between an alcoholic solvent and an alcoholic co-solvent (c) A mixture of medium chain mono/diglycerides of Cs-io; (d) A pharmaceutical acceptable surfactant; (e) An antioxidant; (f) Optionally, an emulsion stabilizer; (g) Optionally, a polarity corrector. The pharmaceutical composition of the present invention comprises as the active ingredient [IS- [1R*, (R*) , 3R*, 4R*] ] -N- [4- [ [ (2, 3-Dimethylphenoxy) acetyl] a ino]- 3- hydroxy- 5- phenyl-1- (phenylmethyl) pentyl] tetrahydro - alfa -(1- methylethyl) -2-oxo-l- (2H) -pyrimidineacetamide, known by its generic name as lopinavir, or preferably its combination with [5S- (5R*,8R*,10R*,11R*) ] -10-hydroxy- 2-methyl -5-(l- methylethyl) -1- [2- (1-methylethyl) - 4 - tiazolyl] - 3,6- dioxo

- 8,11-bis (phenylmethyl) - acid 2, 4, 7, 12-tetraazatridecan-13- oic 5-thiazolilmethyl ester (ritonavir) . When it is used the combination of the active ingredients lopinavir and ritonavir, the weight ratio between these substances can range from 9:1 to 1:9 respectively. The concentration of the combined therapeutic agents in the composition can range from 1.0% to 60% in weight of the final composition. More preferably the pharmaceutical agent or combination between pharmaceutical agents comprises a concentration ranging from 10% to 50% in weight of the final composition. In an ideal preparation of the present composition it is used a combination of the pharmaceutical agents lopinavir and ritonavir in a ratio of 4:1 in weight respectively, and this combination is used in a concentration ranging from 10% to 50% in weight of the final composition. The pharmaceutical composition described in the present invention also comprises a mixture of an alcoholic solvent and an alcoholic co-solvent suitable to prevent the active ingredient or preferably the combination of active ingredients lopinavir-ritonavir to precipitate. Among alcoholic solvents and co-solvents suitable for preparing the composition of the present invention there are the alcohols of chain C₂-₄. Preferably a mixture of alcohols that is used comprises the ethanol as the solvent and the propylene glycol as the co- solvent. Ethanol can be used in a concentration ranging from 5.0 to 20% in weight of the final composition, more preferable in a concentration ranging from 5.0% to 15% in weight of the final composition, while propylene glycol can be used in a concentration ranging from 5.0% to 20% in weight of the final composition or more preferably in a concentration ranging from 5.0% to 15% in weight of the final composition. Together, alcoholic solvent and co-solvent are used in a concentration ranging from 10% to 30% in weight in the final composition. The pharmaceutical composition of the present invention also comprises a mixture of medium chain mono/diglycerides of Cs-iO_f that possess the property of increasing the bioavailability of drugs that normally present low solubility. Its activity is expressed through an efficient dissolution and dispersion of the active ingredient or active ingredients combination, besides also exerting its property directly in the epithelial cells barrier from the gastrointestinal tract increasing the absorption and the transportation of the active ingredient or ingredients through this barrier. In the market there are some commercial preparations of this medium chain mono/diglycerides mixture. Among them there is the Akoline MCM™ that is highly pure and presents pharmaceutical quality suitable for preparing the composition of the present invention. In the composition of the present invention this medium chain mono/diglyceride mixture is used in a concentration ranging from 20% to 80% in weight of the final composition, more preferably it is used in a concentration ranging from 20% to 70% in weight of the final composition. A non-ionic surfactant can be added to the composition of the present invention, which is selected from the polyethoxylated castor oil derivatives, preferably polyethoxylated castor oil 35 (for example Cremophor EL™) and polyethoxylated hydrogenated castor oil 40 (for example Cremophor RH 40™) . Other suitable surfactants for the present invention are the polyoxyethylene sorbitan esters, compounds known as polysorbates . Among polysorbates possible of being used in the present invention there are the liquid polysorbates like polyssorbate 20, 40, 60 and 80. In the present invention surfactants are used in a concentration ranging from 0.1% to 20% in weight of the final composition. For increasing the stability of the pharmaceutical compositions of the present invention, substances known as antioxidants are used to avoid the decomposition of the active ingredient or the combination of active ingredients. Among antioxidants suitable for using with the ingredients of the present invention there are the alpha-tocopherol and the butylated hydroxytoluene (BHT) . In the composition of the present invention the antioxidant is used in a concentration ranging from 0.001% to 2.0% in weight of the final composition. Optionally, in the compositions of the present invention it is possible to use polyethyleneglycol 400 (PEG 400) as an emulsion stabilizer. Using of PEG 400 as an emulsion stabilizer is particularly important in systems that comprise water in small amount. In the present invention the presence of water in a small amount can be originating from the solvents used, as well it can be added to proportionate the minimum moisture necessary to keep the plasticity of soft gelatin capsules avoiding the dehydration of the thin gelatin film that surrounds the composition, which can turn this gelatin film into a friable pellicle that could break easily by friction. In the present invention polyethyleneglycol 400 is used in a concentration ranging from 0% to 60% in weight of the final composition. To guarantee a higher stability over precipitation, additionally there are used polarity correctors agents, capable of conferring to the medium a slight polarity in order to avoid ritonavir precipitation. Among suitable polarity correctors that are used in the present invention there are the pharmaceutical acceptable acids, especially citric acid and ascorbic acid. Polarity correctors are used in a concentration that ranges from 0% to 0.5% in weight of the final composition. The pharmaceutical composition disclosed in the present invention is a solution wherein the active ingredient lopinavir or lopinavir-ritonavir combination is completely dissolved. This composition consists in a clear and transparent solution in the form of an oil of low viscous consistence in most of its variants. The main feature of this composition is the possibility of being formulated comprising an elevate concentration of the active ingredient lopinavir or preferably a combination of lopinavir-ritonavir. When compared to the commercial available composition, which consists in a combination of lopinavir- ritonavir, its concentration can be considerably increased without the risk of precipitation or crystallization of the active substances. While the concentration of the marketed pharmaceutical composition used in the soft gelatin capsules is 16.6% of a combination of lopinavir-ritonavir in a ratio between these substances respectively of 4:1, the concentration of the pharmaceutical composition of the present invention can comprise concentrations up to 50% of this combination, for instance, it can reach a concentration three times higher than the composition used until now comprising a mixture between these active substances. Accordingly with the present invention the pharmaceutical composition disclosed comprises lopinavir in a concentration ranging from lO.Omg/l.Og of the final composition to 600mg/1.0g of the final composition. In a second variant, the composition of the present invention comprises a lopinavir- ritonavir combination, combined in a ratio ranging from 9:1 to 1:9 respectively, constituting a composition in which this combination has a concentration ranging from lO.Omg/lg of the final composition to 600mg/1.0g of the final composition. In an ideal variant, when used the combination of lopinavir- ritonavir, the ratio between these substances is 4:1 and the concentration used of the combination can range from lO.Omg/lg of the final composition to 600mg/lg of the final composition. Because of this improvement that allows obtaining higher concentrations from the active ingredients lopinavir-ritonavir combination, the administration regime of this composition can be considerably improved in order to facilitate the administration of this medicine that can be proportionate by the considerably reducing the size of the capsule containing the therapeutic amount of these substances. By this advance, it is possible to reduce in about 50% the size of the available capsules comprising a lopinavir-ritonavir combination. This miniaturization allows a more appropriate access to the pharmaceutical composition to all patients, making easier its ingestion and especially permitting the access of debilitate patients, the elder and the children, that were unlikely to start or to keep in this treatment regime with the composition now available because they were not able to swallow such huge existing capsules. A second important issue from the advance achieved by the present invention is the possibility of reducing the number of capsules ingested each time by patients that do not have restriction on ingesting capsules of that voluminous size. Adherence to treatment in those patients would be stimulated by the reduction of at least one third in the number of capsules taken in each dosage of the medicine. When considering that the number of capsules or tablets is an under stimulating issue to adherence, the reduction of the quantity of the medicine certainly will contribute very much in stimulating adhesion of patients to recommended therapeutic regime. Another objective of the present invention is the process for preparing a concentrate composition comprising lopinavir or preferably a combination of lopinavir and ritonavir. As we disclosed before, protease inhibitors normally present low solubility in several solvents (excipients) . The dissolution behavior of these substances is particularly critical when issues about polymorphic forms presenting different dissolution properties are involved. So, it is necessary the development of a manufacturing process that allows the use of the active ingredient or active ingredients combination independently from the crystalline form of the agent employed. In order to privilege the use of any crystalline form in the process for preparing the pharmaceutical composition of the present invention, its preparation is done by using an especial process, different from all the process proposed until now, that consist in the direct dissolution of ritonavir in the excipients used for preparing the final pharmaceutical composition. According to all processes for producing pharmaceutical compositions developed until now comprising lopinavir and its combination with ritonavir, the dissolution of these substances is done by a direct technique, where the active ingredient or ingredients are dissolved directly in one or more excipients of the pharmaceutical composition using heating. Due the low solubility of some polimorphic forms, it is necessary the selection of the more soluble polymorphs to reach the desired concentration without using too much elevate temperatures that are deleterious to the stability of the active ingredients. The process for preparing the pharmaceutical compositions of the present invention is extremely efficient to overcome polymorphism problem, allowing the preparation of a stable pharmaceutical composition with elevate concentration when compared to all alternatives existing today. The process for preparing pharmaceutical compositions of

[IS- [1R*, (R*) , 3R*, 4R*] ] -N- [4- [ [ (2, 3-Dimethylphenoxy) acetyl] amino] - 3- hydroxy- 5-phenyl-l- (phenylmethyl) pentyl] tetrahydro -alfa - (1-methylethyl) -2 -oxo -1-(2H)- pyrimidineacetamide (lopinavir) , or its combination with [5S-

(5R*,8R*,10R*,11R*) ] -10-hydroxy- 2-methyl -5- (1-methylethyl) -

1- [2- (1-methylethyl) - 4 - tiazolyl] - 3,6- dioxo - 8,11-bis (phenylmethyl) - acid 2, 4, 7, 12-tetraazatridecan-13-oic 5- thiazolilmethyl ester (ritonavir) comprises the following steps : (a2) Completely dissolving lopinavir or its combination with ritonavir in a sufficient amount of the alcoholic solvent of C₂-₄, under controlled temperature; (b2) Eliminating solid particles by filtration; (c2) Adding a mixture of mono/diglycerides, the antioxidant, the emulsion stabilizer and the polarity corrector in the appropriate amount for using in the composition; (d2) Removing the alcoholic solvent by distillation under reduced pressure until the remaining amount present in the composition corresponds to the final desired quantity in the composition; (e2) Adding the alcoholic co-solvent and the surfactant under constant stirring and stirring until its complete mixture with the composition; (f2) Correcting the final weight of the composition by adding the alcoholic solvent used in the initial dissolution of lopinavir/ritonavir, if necessary. Initially lopinavir or a combination of lopinavir and ritonavir is completely dissolved in a sufficient amount of the alcoholic solvent to obtain a completely clear solution. Preferably the alcoholic solvent used is ethanol. In order to avoid degradation of the active ingredient (s) , the dissolution is performed at a temperature ranging from 30°C to 50°C under stirring. To guarantee the absence of solid particles that could trigger a later precipitation process, this alcoholic solution is filtered using usual filtration techniques (particularly interesting is filtration through microporous membranes) . After filtration, it is added a mixture of medium chain mono/diglycerides, the antioxidant (butyl hydroxytoluene or alpha-tocopherol) and eventually the emulsion stabilizer (polyethyleneglycol 400 - PEG 400) and the polarity corrector (citric or ascorbic acid) , in the quantities desired in the final composition. After that, the alcoholic solvent (ethanol) is evaporated under reduced pressure in a maximum temperature of 50°C until the quantity remaining the solution corresponds to the final quantity desired in the composition. To this resulting liquid it is added the quantity used of the alcoholic co-solvent and the surfactant (polyethoxylated castor oil 35 and/or polyethoxylated hydrogenated castor oil 40, and/or polysorbate 20, 40, 60 or 80) to the composition and the liquid is kept under stirring until complete dissolution. Finally, the composition is weighted and if it is necessary to correct its weight ethanol is used to do this correction. Preferably the alcoholic solvent used in the initial dissolution of lopinavir or preferably lopinavir and ritonavir combination is ethanol that, besides being part of the composition, presents a low boiling point being possible its easy removal under considered low temperatures by reduced pressure distillation or evaporation procedures. By using this procedure it is possible to obtain a concentrate composition of lopinavir or its combination with ritonavir in a stable form, where the active ingredient (s) is (are) completely dissolved without the presence of microcrystalline forms or solid particles that can trigger the precipitation of the active ingredient (s) over time, interfering with the ideal characteristics of absorption and bioavailability of the final medicine. By using this procedure there is no need to control the crystalline form of the active ingredients used for preparing the final pharmaceutical composition, so excluding the need of eventual processing of the active ingredients before their use for preparing the pharmaceutical compositions. Additionally, by this technical advance it is possible to prepare highly concentrate compositions of lopinavir or lopinavir and ritonavir, impossible of being prepared through direct dissolution techniques without considerably degradation of the composition ingredients. In the pharmaceutical composition of the present invention, the combination of excipients demonstrates to be adequate to avoid the crystallization of lopinavir and its combination with ritonavir. The resulting pharmaceutical composition presents physical-chemical stability suitable for being stored under room temperature for more than 12 months, without any sign of significant degradation of the comprised active ingredients. When stored under refrigeration, the pharmaceutical composition of the present invention demonstrates to be efficient in inhibiting the crystallization of the active ingredients used during the same period of time. The stability presented by the composition of the present invention over crystallization of its active ingredients grants their delivery or liberation in a soluble way suitable for a prompt absorption by the organism. The soluble pharmaceutical composition of the present invention may be administered as an oral solution, being in this case fractioned by adequate fractionating devices. In case of oral solutions it is also possible to add flavoring excipients, coloring agents and other substances capable of masking and or giving to the composition a pleasant taste, odor and appearance. In a preferential realization of the present invention the concentrate pharmaceutical composition disclosed is encapsulated in soft gelatin capsules that present uniform liberation properties of its contents inside the gastrointestinal tract, and in addition presenting a better receptivity from the treated patients due its elastic properties that allows an easier ingestion. Besides all these factors, administration as capsules provides a better handling of the administered dosage exempting the patient of previous fractionating procedures, as well it also proportionates a tasteless administration. Because of the stability of the pharmaceutical composition of the present invention, costs related to storing, transportation and distribution of the final medicine are very reduced, besides being possible to store this medicine in places that do not have refrigeration chambers, increasing considerably the distribution of the drug and its access to patients. We previously described that the medicine consisting in the combination of lopinavir and ritonavir is available as a pharmaceutical presentation consisting in soft gelatin capsules of very voluminous size uncomfortable for their ingestion. This pharmaceutical composition, whose trade name is KALETRA™, comprises 133.3mg of lopinavir associated with 33.3mg of ritonavir per capsule containing about lg of the final composition. The size of the capsule has an average length of 22.0mm and a diameter of about 9.5mm, dimensions considerably voluminous that forbid the access of several patients to treatment due the unfeasability of swallowing the capsule. The present invention describes a technique suitable for preparing pharmaceutical compositions comprising higher concentration of these active ingredients, being possible the reduction of the capsule size at least by half of its original size. Besides allowing the inclusion of several individual in the therapy, this issue provides more comfort to patients already in treatment with this drug. The technique for preparing the soft gelatin capsule is very well known in the art, basically consisting on using gelatin, plasticizing agent and water in definite proportions.

Additionally the capsule material may contain additives like inks, pigments and flavors, among others. The manufacture of soft gelatin capsules comprises several techniques, like for example, a process with or without sewing, rotatory, using specific machinery, among others. Just as an example, soft gelatin capsules used in this invention as a thin film surrounding the pharmaceutical composition may consist in gelatin, glycerol as plasticizing agent, propylparabene, titanium dioxide, water, other substances like inks, and they may be prepared by using conventional techniques. As a general rule the composition of the present invention can be submitted to all of the existing processes of producing soft gelatin capsules since they do not considerably interfere with the composition, it means, that such process of producing does not considerably change the ratio among its ingredients by evaporation because heat exposition, drying processes or any other kind of processing. The following examples are illustrative, but not exhaustive about the possibilities of the composition of the present invention and the process for preparing it, as well the tests do demonstrate its stability and the maintaining of its properties of a soluble concentrate of lopinavir and ritonavir over time.

General procedure for preparing a concentrate pharmaceutical composition : The compositions of the present invention can be prepared according to the following procedure. The active ingredient comprised by lopinavir or by a combination of lopinavir and ritonavir is dissolved in a sufficient amount of ethanol for its complete dissolution in a temperature ranging from 30° to 50°C. The ethanolic clear solution is filtered and then are added the medium chain mono/diglycerides, the antioxidant and eventually the emulsion stabilizing agent and the polarity corrector. The system is kept under stirring until it turns to a clear solution, and then is placed in a under pressure rotatory evaporation equipment, being ethanol removed until its concentration reaches the concentration expected in the final composition. The surfactant and the organic co-solvent (propylene glycol) are added and the system is kept under stirring until it turns into a clear solution. The weight of the composition is measured and if necessary it is corrected by using ethanol. In the eventual addition of water to the composition, it is added together with the surfactant and the co-solvent . According to the procedure described above there were prepared several preparations of the pharmaceutical composition of the present invention disclosed in table 1 presented below:

TABLE 1:

POE 35: polyethoxylated castor oil 35; BHT: Butylated hydroxytoluene .

The compositions prepared in examples 1 to 19 disclosed in Table 1 above, where splitted into two portions, and there were prepared soft gelatin capsules of l,000mg of the composition per capsule and capsules of 500mg of the composition per capsule. The pharmaceutical composition of the present invention was stored under different conditions and the assay of the active ingredients was performed to follow their stability. The study under room temperature demonstrates a good stability of the compositions in this storage condition. All preparations present satisfactory results in the submitted tests. Table 2 below summarizes some of the studied examples for demonstration:

TABLE 2

TA = Ambient Temperature (25°C ± 2°C) AC = Accelerate Study (40°C ± 2°C) ; REF = Under refrigeration (5°C ± 3°C) LOIn = Lopinavir initial assay LOFi = Lopinavir final assay Rlln = Ritonavir initial assay RIFi = Ritonavir final assay The results disclosed in Table 2 demonstrate the stability of the composition of the present invention.

Claims

1. A stable pharmaceutical composition characterized by comprising: (a) [IS- [1R*, (R*) , 3R*, 4R*] ] -N- [4- [ [ (2, 3-Dimethylphenoxy) acetyl] amino] - 3- hydroxy- 5-phenyl-l- (phenylmethyl) pentyl] tetrahydro-alfa- (1-methylethyl) -2-oxo-l- (2H) - pyrimidineacetamide (lopinavir) , or its combination with [5S- (5R*,8R*,10R*,11R*) ] -10-hydroxy- 2-methyl -5- (1-methylethyl) -1- [2- (1-methylethyl) - 4 tiazolyl] - 3,6- dioxo - 8,11-bis (phenylmethyl) acid 2,4,7,12 - tetraazatridecan - 13-oic 5- thiazolilmethyl ester (ritonavir) ; (b) A mixture between an alcoholic solvent and an alcoholic co-solvent; (c) A mixture of medium chain mono/diglycerides of C₈-ιo; (d) A pharmaceutical acceptable surfactant; (e) An antioxidant; (f) Optionally, an emulsion stabilizer; (g) Optionally, a polarity corrector.

2. A pharmaceutical composition of claim 1, wherein [1S- [1R*, (R*) ,3R*,4R*] ] -N- [4- [ [ (2, 3-Dimethylphenoxy) acetyl] amino] - 3- hydroxy- 5-phenyl-l- (phenylmethyl) pentyl] tetrahydro-alfa- (1-methylethyl) -2-oxo-l- (2H) - pyrimidineacetamide (lopinavir) is used in a concentration from 1.0% to 60% in weight of the final composition, more preferably in a concentration from 10% to 50% in weight of the final composition;

3. A pharmaceutical composition of claim 1, characterized by comprising a combination between [IS- [1R*, (R*) , 3R*, 4R*] ] - N- [ 4- [ [ (2, 3-Dimethylphenoxy) acetyl] amino] - 3- hydroxy- 5-phenyl-l- (phenylmethyl) pentyl] tetrahydro- alfa- (1-methylethyl) -2-oxo-l- (2H) -pyrimidineacetamide (lopinavir) and [5S- (5R*, 8R*, 10R*, 11R*) ] -10-hydroxy- 2- methyl -5- (1-methylethyl) -1- [2- (1-methylethyl) - 4 - tiazolyl] - 3,6- dioxo - 8,11-bis (phenylmethyl) - acid 2,4,7,12 - tetraazatridecan - 13-oic 5-thiazolilmethyl ester (ritonavir) , which are present in a weight ratio ranging from 9:1 to 1:9 respectively, being the combination used in a concentration ranging from 1.0% to 60% in weight of the final composition, more preferably in a concentration ranging from 10% to 50% in weight of the final composition;

4. A pharmaceutical composition according to claim 1, characterized by the alcoholic solvent is used in a concentration from 5.0% to 20% in weight of the final composition, more preferably in a concentration from 5.0% to 15% in weight of the final composition;

5. A pharmaceutical composition according to claim 1, characterized by the alcoholic co-solvent is used in a concentration from 5.0% to 20% in weight of the final composition, more preferably in a concentration from 5.0% to 15% in weight of the final composition;

6. A pharmaceutical composition according to claim 1, characterized by the alcoholic solvent and co-solvent are used in a concentration from 10% to 40% in weight of the final composition, more preferably used in a concentration from 10% to 30% in weight of the final composition;

7. A pharmaceutical composition according to claim 1, characterized by the mixture of medium chain mono/diglycerides of C₈-ιo is used in a concentration from 20% to 80% in weight of the final composition, more preferably in a concentration from 20% to 70% in weight of the final composition;

8. A pharmaceutical composition according to claim 1, characterized by the surfactant is used in a concentration from 0.1% to 20%;

9. A pharmaceutical composition according to claim 1, characterized by the antioxidant is used in a concentration from 0.001% to 2.0% in weight of the final composition;

10. A pharmaceutical composition according to claim 1, characterized by the alcoholic solvent is ethanol and the alcoholic co-solvent is propylene glycol;

11. A pharmaceutical composition according to claim 1, characterized by the surfactant is polyethoxylated castor oil 35, and/or polyethoxylated hydrogenated castor oil 40, and or polysorbates 20, 40, 60 or 80;

12. A pharmaceutical composition according to claim 1, characterized by the antioxidant is the butylated hydroxytoluene and/or alpha-tocopherol;

13. A pharmaceutical composition according to claim 1, characterized by using an emulsion stabilizing agent in a concentration from 0% to 60% in weight of the final composition;

14. A pharmaceutical composition according to claim 1 , characterized by the emulsion stabilizing agent is the polyethyleneglycol 400 (PEG 400);

15. A pharmaceutical composition according to claim 1, characterized by using a polarity corrector agent in a . concentration from 0% to 0.5% in weight of the final composition;

16. A pharmaceutical composition according to claim 1, characterized by the polarity corrector agent used is citric acid and/or ascorbic acid;

17. A pharmaceutical composition according to claims 1 to 16, characterized by being used for oral administration as a solution, hard gelatin capsules and/or soft gelatin capsules;

18. A pharmaceutical composition according to claims 1 to 16, characterized by being preferably used for oral administration as soft gelatin capsules;

19. A pharmaceutical composition according to claim 1 to 16, characterized by being used in the treatment of viral infections;

20. A pharmaceutical composition according to claims 1 to 16, characterized by being used in medicine or veterinary.

21. A process for preparing pharmaceutical compositions of [1S-[1R*, (R*) ,3R*,4R*] ] - N- [4- [[ (2, 3-Dimethylphenoxy) acetyl] amino] - 3- hydroxy- 5-phenyl-l- (phenylmethyl) pentyl] tetrahydro -alfa- (1-methylethyl) -2-oxo-l- (2H) - pyrimidineacetamide (lopinavir) , or its combination with [5S- (5R*,8R*,10R*,11R*) ] -10-hydroxy- 2-methyl -5- (1- methylethyl) -1- [2- (1-methylethyl) - 4 - tiazolyl] - 3,6- dioxo - 8,11-bis (phenylmethyl) - acid 2,4,7,12 tetraazatridecan - 13-oic 5-thiazolilmethyl ester (ritonavir) , characterized by comprising the following steps : (a2) Completely dissolving lopinavir or its combination with ritonavir in a sufficient amount of the alcoholic solvent of C₂_₄, under controlled temperature; (b2) Eliminating solid particles by filtration; (c2) Adding a mixture of mono/diglycerides, the antioxidant, the emulsion stabilizer and the polarity corrector in the appropriate amount for using in the composition; (d2) Removing the alcoholic solvent by distillation under reduced pressure until the remaining amount present in the composition corresponds to the final desired quantity in the composition; (e2) Adding the alcoholic co-solvent and the surfactant under constant stirring and stirring until its complete mixture with the composition; (f2) Correcting the final weight of the composition by adding the alcoholic solvent used in the initial dissolution of lopinavir/ritonavir, if necessary.

22. A process for preparing pharmaceutical compositions according to claim 21, characterized by the alcoholic solvent used in (a2) is the ethanol;

23. A process for preparing pharmaceutical compositions according to claim 21, characterized by the dissolution described in (a2) is performed in a temperature preferably ranging from 30°C to 50°C;

24. A process for preparing pharmaceutical compositions according to claim 21, characterized by the mixture of medium chain mono/diglycerides used in (c2) is a mixture of medium chain mono/diglycerides of Cg-io;

25. A process for preparing pharmaceutical compositions according to claim 21, characterized by the antioxidant used in (c2) is the butylated hydroxytoluene or the alpha-tocopherol;

26. A process for preparing pharmaceutical compositions according to claim 21, characterized by the emulsion stabilizing agent used in (c2) is the polyethyleneglycol 400 (PEG 400) ;

27. A process for preparing pharmaceutical compositions according to claim 21, characterized by the corrector polarity agent used in (c2) is citric acid or ascorbic acid;

28. A process for preparing pharmaceutical compositions according to claim 21, characterized by the evaporation of the alcoholic solvent being performed under a maximum temperature of 50°C;

29. A process for preparing pharmaceutical compositions according to claim 21, characterized by the alcoholic co- solvent used in (e2) is propylene glycol; 30. A process for preparing pharmaceutical compositions according to claim 21, characterized by the surfactant used in (e2) is polyethoxylated castor oil 35, and/or polyethoxylated hydrogenated castor oil 40, and/or polysorbates 20, 40, 60 or 80; 31. A process for preparing pharmaceutical compositions according to claim 21, characterized by being used for preparing concentrate pharmaceutical compositions of ritonavir and lopinavir for oral administration.