MX2014000463A - Stable dosage forms of arterolane and piperaquine. - Google Patents

Abstract

The field of the invention relates to stable oral dosage forms comprising, (a) cis-adamantane-2-spiro-3'-8'-[[[(2'-amino-2'-methylpropyl) amino]carbonyl]-methyl]-l',2',4'-trioxaspiro[4.5]decane hydrogen maleate (Active compound I); (b) piperaquine; and (c) one or more pharmaceutically acceptable excipients; and processes for their preparation, especially wherein the dosage form is prepared by a dry process.

Description

STABLE DOSING FORMS OF ARTEROLANE AND PIPERRAIN Field of the Invention The field of the invention relates to stable oral dosage forms comprising spiro or diespiro 1,2,4-trioxolane antimalarials or their pharmaceutically acceptable salts, prodrugs and analogs and processes for their preparation.

Background of the Invention Malaria, the parasitic disease much more common in humans, remains a major burden for health and economic in most tropical countries. Large areas of Central and South America, Hispaniola (Haiti and the Dominican Republic), Africa, the Middle East, the subcontinent of India, Southeast Asia and Oceania are considered areas at risk of malaria. This leads to a heavy burden of illness and death, especially among children and pregnant women. According to the World Health Organization, it is estimated that the disease infects approximately 400 million people each year, and around two to three million people die from malaria each year. There are four classes of malaria parasites that infect humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae.

Malaria is spread from one person to another by the bite of the mosquito, Anopheles gambiae, which It serves as a vector. When a mosquito sucks human blood, sporozoites are transfused into the human body along with mosquito saliva. The sporozoites enter the hepatocytes, reproduce asexually and finally enter the bloodstream. The parasites continue to multiply inside the red blood cells, until they break and release a large number of merozoites. This process continues, destroying a significant number of blood cells and causing the characteristic paroxysm ("chills and fever") associated with the disease. In red blood cells, some of the merozoites become male or female gametocytes. These gametocytes are ingested by the mosquito when it feeds on blood. The gametocytes fission in the intestine of the vector; Sporozoites are produced and migrated to the salivary glands of the vector.

The clinical symptoms of malaria are generally associated with the rupture of red blood cells that cause intense fever associated with chills that can leave the individual infected, exhausted and bedridden. The most severe symptoms associated with recurrent infections and / or Plasmodium falciparum infection include anemia, severe headaches, seizures, delirium and, in some cases, death.

Quinine, an antimalarial compound that is extracted from the bark of the chinchona tree, it is one of the oldest and most effective drugs in existence. Chloroquine and mefloquine are the synthetic analogues of quinine developed in the 1940s, which due to their effectiveness, ease of manufacture, and general lack of side effects, become the drugs of choice. The drawback of quinine and its derivatives is that they are short acting and have a bitter taste. In addition, they fail to prevent relapse of the disease and are also associated with side effects commonly known as "Chinchonism syndrome" characterized by nausea, vomiting, dizziness, vertigo and deafness. However, in recent years, with the emergence of drug-resistant strains of parasites and vector strains resistant to insecticide, the treatment and / or control of malaria is becoming difficult with these conventional drugs.

The malarial treatment also progressed with the discovery of Artemisinin (qinghaosu), a sesquiterpene lactone of endoperoxide that occurs naturally isolated from the Artemisia annua plant (Meshnick et al., Rev. Microbiol 1996, 60, p.301-315, Vroman et al, Curr Pharm Disign, 1999, 5, pp. 101-138; Dhingra et al., 2000, 66, pp. 279-300), and a number of its precursors, metabolites and semi-synthetic derivatives that have been shown to possess antimalarial properties. The antimalarial action of artemisinin is due to its reaction with iron in heme molecules free of the malaria parasite, with the generation of free radicals that lead to cell destruction. This initiated a substantial effort to make clear its mechanism of molecular action (Jefford, dv., Drug Res. 1997, 29, p 271-325, Cumming et al., Adv. Pharmacol 1997, 37, p 254-297) and for identifying novel antimalarial peroxides (Dong and Vennerstrom, Expert Opin. Ther.Patents 2001, 11, p.1753-1760).

Although clinically useful artemisinin derivatives are fast acting and potent antimalarial drugs, they have several disadvantages including recrudescence, neurotoxicity, (Wesche et al, Antimicrob Agents, Chemother, 1994, 38, p.1813-1819) and instability. metabolic (White, Trans.R Soc. Trop.Med. Hyg., 1994, 88, pp. 41-43). A major number of these compounds are very active in vitro, but most suffer from low oral activity (White, Trans.R Soc. Trop.Med. Hyg., 1994, 88, pp. 41-43 and van Agtmael et al. , Trends Pharmacol, Sci., 1999, 20, pp. 199-205).

In addition to all these artemisinin derivatives which are conventionally obtained from plant sources and are therefore expensive. As the cultivation of plant material is dependent on many factors, including weather conditions, the source of supply becomes thus finite and there are opportunities to vary the performance and power. This leads to quality inconsistencies and supply constraints. As malaria is more prevalent in developing countries, a change to the cheapest and most effective medicine is highly desirable.

Thus there is still a need in the art to identify new antimalarial peroxide agents, especially those that are not dependent on the plant source and can be easily synthesized, are free of neurotoxicity, and possess improved solubility, stability and pharmacokinetic properties.

Following that, many 1, 2, 4-synthetic antimalarial trioxanes (Jefford, Adv. Drug Res. 1997, 29, pp. 271-325, Cumming et al., Adv. Pharmacol 1997, 37, pp. 254-297), 1 2, 4, 5-tetraoxanes (Vennerstrom et al., J. Med. Chem., 2000, 43, p 2753-2758) and other endoperoxides have been prepared. Several patents / applications describe means and method for treating malaria using Spiro or Diespiro 1, 2, -trioxolanes for example, U.S. Patent Application No. 2004/0186168 and U.S. Patent No. 6,486,199 and U.S. Pat. 6,825,230. The present invention relates to solid dosage forms of the various antimalarial compounds of spiro or diespiro 1,2,4-trioxolanes described in these patents / applications and are incorporated herein by reference.

The active compounds that represent several Spiro and Diespiro 1, 2, 4-trioxolane derivatives have excellent potency, efficacy against Plasmodium parasites and a lower degree of neurotoxicity, in addition to their structural simplicity and ease of synthesis. In addition, these compounds have half-lives that are believed to allow short-term treatment regimens that compare favorably with other artemisinin-like drugs. In general, the therapeutic dose of trioxolane derivative can vary between about 0.1-1000 mg / kg / day, in particular between about 1-100 mg / kg / day. The previous dose can be administered as a single dose or can be divided into multiple doses. For the prevention of malaria, a typical dosage schedule could be, for example, 2.0-1000 mg / kg starting weekly 1-2 weeks before exposure to malaria, with continuation up to 1-2 weeks post-exposure.

Monotherapy with the artemisinin drug class (natural or synthetic) could cure patients within 3 days, however the potential threat of malaria parasite development resistance towards a very potent artemisinin drug class is perceived otherwise, those who have strictly called for an immediate impediment to the provision of single-drug artemisinin malaria pills. Combination therapy in the case of malaria delays the development of resistance, improve efficiency by decreasing the rate of recrudescence, provides synergistic effect and increased exposure of the parasite to drugs.

Artemisinin-based combinations are available in the market for a long time. Artemether-lumafentrine (Co-artem®) was the first fixed-dose antimalarial combination containing an artemisinin derivative and has been shown since 1999. This combination has passed the extensive safety and efficacy experiments and has been approved for more than 70 regulatory agencies. Co-artem® is recommended by WHO as the first line treatment for uncomplicated malaria.

Other artemisinin-based combinations include artesunate and amodiaquine (Coarsucam ®) and dihydroartemisin and piperaquine (Eurartesim®). Unfortunately, all available artemisinin-based combinations have complicated dosing regimens that make it difficult and inconvenient for a patient to fully comply with the total prescription duration. For example, the dosing regimen of Co-artem® for an adult who has a body weight of more than 35 kg includes 6 doses in three days. The first dose comprises four tablets initially, the second dose comprises four tablets after eight hours, the third to six doses comprises four tablets twice for another two days; making a total of 24 tablets. The dosing regimen of Coarsucam® for an adult who has a body weight of more than 36 kg or age above 14 years includes three doses for three days, each dose comprising two tablets, making a total of six tablets. The dosage regimen of Eurartesim® for an adult having a body weight between 36 kg - 75 kg includes 3 doses for three days, each dose comprising three tablets, with a total of nine tablets.

It is evident that the available artemisinin-based combinations have a high burden on patients since they need to consume too many tablets. As mentioned in the above, this may increase the possibility of losing a few doses, and consequently, could result in reduced efficacy due to non-compliance and may even lead to the development of resistance for the drug.

Therefore, there is an urgent and unmet need for anti-malarial combinations with a simplified daily dosage regimen that reduces the burden of pills and increases patient compliance.

Apart from simplifying the regimen, there are certain limitations for formulators who develop formulations with trioxolones, the first being their susceptibility to degradation in the presence of moisture that results reduced shelf lives. Another is its bitter taste, which can result in poor compliance with the regimen or the selection of another, possibly less effective, therapeutic agent.

The inventors have now discovered that a stable oral antimalarial solid dosage form comprising Spiro or Diespiro 1,2, -trioxolanes can be prepared to control the water content below a certain critical limit. In addition, the bitter taste can be masked by applying a film coating layer to the solid dosage form.

Brief Description of the Invention In a general aspect a stable solid oral dosage form is provided which includes a therapeutically effective amount of a compound having the structural Formula I, Formula I and its enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates, wherein: Ri and R2 are the same or different and are selected of hydrogen, linear or branched, substituted or unsubstituted alkyl, aryl and alkaryl groups and substituted or unsubstituted alicyclic groups which are optionally interrupted by one or more oxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromatic or heterocyclic groups which may be be interrupted by one or more oxygen atoms, sulfur or nitrogen, a hydroxy group, and a halogen, and further provides that the spirocyclohexyl rings linking Ri and R2 are optionally interrupted by one or more oxygen, sulfur or nitrogen atoms, and one or more pharmaceutically acceptable excipients, where no more than 5% w / w of total related substances are formed in storage at 40 ° C ± 2 ° C and 75% ± 5% relative humidity during a period of 6 months.

The modalities of the solid oral dosage form may include one or more of the following characteristics. For example, the dosage form may include one or more other antimalarial drugs. The other antimalarial drugs may include quinine, mefloquine, lumefantrine, sulfadoxine-pyrimethamine, dihydroartimisinin, piperaquine, chloroquine, amodiaquine, proguanil, atovaquone, chloroproguanil, dapsone, fosmidomycin, tetracycline, DB 289 (pafuramidine maleate), clindamycin or its salts and derivatives thereof. In particular, piperaquine, lumefantrine and DB 289 can be used.

In another general aspect, a method for the treatment of malaria is provided. The method includes administering a solid dosage form that includes a therapeutically effective amount of a compound of the structural Formula I; and one or more pharmaceutically acceptable excipients, wherein no more than 5% w / w of total related substances are formed storage at 40 ° C + 2 ° C and 75% ± 5% relative humidity for a period of 6 months.

In another aspect, a method of treating malaria is provided, the method includes administering a solid dosage form that includes a therapeutically effective amount of a structural Formula I compound formulated using a dry or non-aqueous process.

In another aspect, a stable solid oral dosage form is provided, wherein the dosage form includes a therapeutically effective amount of a compound of the structural Formula I; at least one other antimalarial drug selected from lumefantrine, piperaquine or DB 289; and one or more pharmaceutically acceptable excipients.

The modalities of the oral dosage form may include one or more of the following characteristics. For example, the water content of the dosage form It can not be more than 6.5% p / p.

In another general aspect, there is provided a stable oral solid dosage form comprising cis-adamantane-2-spiro-3 '-8' - [[(2'-amino-2'-methylpropyl) amino] carbonyl hydrogen maleate. ] -methyl] -1, 2 ', 4' -trioxaespiro [4.5] decane; piperaquine and one or more pharmaceutically acceptable excipients.

In another general aspect, a stable solid oral dosage form is provided comprising: (a) cis-adamantane-2-spiro-3 '-8' - hydrogen hydrogen [- [[(2'-amino-2'-methylpropyl) amino] carbonyl] -methyl] - 1 ', 2 4'-trioxaespiro [, 5] decane (Active compound I); (b) piperaquine, and (c) one or more pharmaceutically acceptable excipients wherein the dosage form is prepared by a dry process.

In another general aspect, a stable solid oral dosage form comprising Active compound I is provided; Y (b) piperaquine wherein the total drug content is within the range of from about 25% to about 85% w / w based on the total weight of the dosage form.

In another general aspect, a form of stable solid oral dosage comprising: (a) Active compound I in an amount of about 5% to about 25%; Y (b) piperaquine in an amount of about 40% to about 80%, w / w based on the total weight of the dosage form.

In another general aspect, a stable solid oral dosage is provided comprising: (a) active compound I in an amount of about 5% to about 25%, and (b) piperaquine in an amount from about 40% to about 80% wherein the total drug content does not exceed 85% w / w based on the total weight of the dosage form.

In another general aspect, a stable solid oral dosage of the compound Active I and piperaquine; wherein the dosage form has a dissolution performance such that more than 70% w / w of Active compound I dissolves within 45 minutes, in an acetate buffer solution of pH 4.5 with 2% tween 80 in the USP apparatus type II.

In another general aspect, a stable solid oral dosage form is provided comprising: (a) Active compound I and (b) piperaquine; in a weight ratio of about 1: 1 to about 1:10.

In another general aspect, there is provided a stable oral solid dosage form comprising Active compound I present in a dose range of about 100 to about 300 mg and piperaquine present in a dose range of about 700 mg to about 850 mg.

In another general aspect, a stable solid oral dosage form is provided comprising: (a) Active compound I in an amount of about 5% to about 25%; (b) piperaquine in an amount of about 40% to about 80%; (c) diluent in an amount of about 10% to about 40%; (d) disintegrant in an amount from about 1% to about 10%; Y (e) lubricant in an amount of about 1% to about 5%; p / p based on the total weight of the dosage form.

In another general aspect, a stable solid oral dosage form is provided comprising: (a) Active compound I; (b) piperaquine; (c) microcrystalline cellulose; (d) crospovidone; Y (e) magnesium stearate.

In another general aspect, a stable oral solid dosage is provided comprising: (a) The Active compound I in an amount of about 5% to about 25%; (b) piperaquine in an amount of about 40% to about 80%; Y (c) microcrystalline cellulose in an amount of about 10% to about 40%; p / p based on the total weight of the dosage form.

In another general aspect, there is provided a stable solid oral dosage form comprising Active compound I and microcrystalline cellulose in a weight ratio of from about 1: 1 to about 1: 5.

The pharmaceutically acceptable excipients may be selected from the group consisting of binders, diluents, glidants / lubricants, disintegrants, surfactants and coloring agents.

The solid dosage form can be in the form of a tablet, capsule, pellet, pill, pellet or powder. Particularly the dosage form is a tablet or a capsule. More particularly, the dosage form is a tablet.

In another general aspect, a form is provided of stable solid oral dosage, wherein the dosage form is processed and stored at a temperature below 27 ° C and relative humidity of 50%.

The modalities of the process may include one or more of the following characteristics. For example, the dosage form is formulated using a dry or non-aqueous process. The non-aqueous process may include a non-aqueous granulation liquid selected from ethanol, isopropyl alcohol, acetone, dichloromethane to prepare the binder solution. The dry process may include direct compression or dry granulation. The dry granulation can be compaction or compression. In particular, the dry granulation can be compaction, for example, compaction with dry roller.

In another general aspect, there is provided a process for the preparation of a stable solid oral dosage form, comprising the steps of: (a) mixing the active compound I, piperaquine and one or more intragranular excipients; (b) polishing, polishing or sifting the mixture by roller compaction to form granules; (c) mixing the granules with one or more extragranular excipients; (d) compress the mixture into tablets or fill in capsules.

In another general aspect, there is provided a process for the preparation of a stable solid oral dosage form, comprising the steps of: (a) mixing the active compound I, piperaquine and one or more intragranular excipients; (b) granulating the mixture by whipping; (c) mixing the granules with one or more extragranular excipients; (d) compress the mixture into tablets or fill in capsules.

In another general aspect, there is provided a process for the preparation of a stable solid oral dosage form, comprising the steps of: (a) mixing the active compound I, piperaquine and one or more pharmaceutically acceptable excipients; Y (B) directly compress the mixture into tablets or fill in capsules.

In another general aspect, there is provided a process for the preparation of a stable solid oral dosage form, comprising the steps of: (a) granulating a mixture of one or more excipients; (b) drying the granules with excipient; (c) mixing the granules with excipient with the compound Active I and piperaquine, and (d) compress the mixture into tablets or fill in capsules The tablet can be coated with layer (s) of one or more film-forming polymers.

In another general aspect, a method of treating malaria is provided. The method includes administering a stable oral solid dosage form comprising: (a) Active compound I; (b) piperaquine, and (c) one or more pharmaceutically acceptable excipients wherein the dosage form is prepared by a dry process.

In another general aspect, a stable solid oral dosage form is provided comprising: (a) 150 mg of Active compound I and (b) 750 mg piperaquine wherein the dosage form is administered once a day for three days.

In another general aspect, there is provided a method for treating malaria comprising administering a stable solid oral dosage form comprising: (a) 150 mg of Active compound I and (b) 750 mg piperaquine wherein the dosage form is administered once a day for three days.

The details of one or more modalities are set forth in the following description. Other features, objects and advantages of the invention will be apparent from the description in the claims.

Detailed description of the invention The inventors have now discovered that the stable solid oral dosage forms of Spiro or Diespiro 1,2, -trioxolane antimalarials can be prepared so that they do not degrade significantly and provide acceptable shelf life.

The term "stable" as used herein refers to the chemical stability of the active compound in solid dosage forms against the decomposition that occurs during shelf life due to hydrolysis, where no more than 5% w / w of total related substances are formed in storage at 40 ° C + 2 ° C and 75% ± 5% relative humidity during a period of 6 months.

The present invention provides stable solid oral dosage forms of the active compound, by using excipients that are low in water content and manufactured using dry or non-aqueous formulation processes.

The term "active compound" as used herein includes the spiro or diespiro 1,2,4-trioxolane compound of the structural Formula I Formula l wherein Ri and R2 are the same or different and are selected from hydrogen, substituted or unsubstituted linear or branched alkyl, aryl or alkaryl groups and substituted or unsubstituted alicyclic groups which are optionally interrupted by one or more oxygen, sulfur or oxygen atoms; nitrogen, substituted or unsubstituted aromatic or heterocyclic groups which can be interrupted by one or more oxygen, sulfur or nitrogen atoms, a hydroxy group, and a halogen and which further provide that the spirocyclohexyl rings linking Ri and R2 are optionally interrupted by one or more atoms of oxygen, sulfur or nitrogen. In particular, this includes the compounds of Formula I, wherein Rx is hydrogen, for example compounds of structural Formula II.

Formula II The active compound includes one or more of the various Spiro and Diespiro trioxolane derivatives described in U.S. Application No. 2004/0186168 and U.S. Patent Nos. 6,486,199 and 6,825,230, which are incorporated herein by reference. These trioxolanes are relatively sterically hindered on at least one side of the trioxolane heterocycle that provides better in vivo activity, especially with respect to oral administration. Particularly, spiro and dispyro 1,2, -trioxolane derivatives have excellent potency and efficacy against Plasmodium parasites and a lower degree of neurotoxicity.

The term "Active compound I" herein means cis-adamantane-2-spiro-3 '-8' - [[(2'-amino-2'-methylpropyl) amino] carbonyl] -methyl] -carbohydrate maleate. 1 ', 2', 4 '-trioxaespiro [4.5] decane. The active compound I that can present in an amount of about 5% to about 25%, w / w based on the total dosage form.

In addition, perceiving the potential threat of resistance developed by the malaria parasite to a class of otherwise potent artemisinin drugs, double HO has required an immediate impediment to the provision of single-drug artemisinin malaria polydrugs. In the case of malaria, combination therapy has been applied since around the 1990s. However, this strategy is being hampered because the Plasmodium parasite has developed resistance, as a result of monotherapy, to certain components of the combination drugs currently applied. Combination therapy is expected to retard the development of resistance, improve efficacy by decreasing the rate of recrudescence, provide synergistic effect and increase the exposure of the parasite to drugs.

The solid oral dosage forms of the present invention also include one or more of antimalarial drugs. Antimalarial drugs may include quinine, mefloquine, lumefantrine, sulfadoxine-pyrimethamine, dihydroart imisinin, piperaquine, chloroquine, amodiaquine, proguanil, atovaquone, chloroproguanil, dapsone, fosmidomycin, tetracycline, DB 289 (pafuramidine maleate), clindamycin or its salts and derivatives thereof. In particular, piperaquine, lumefantrine and DB 289 can be used; however, piperaquine remains the only preferred one.

The combination selection as an antimalarial therapy is based on certain attributes. Synthetic artemisinin derivatives exhibit their action through their reaction with iron in free heme molecules in the malaria parasite with the generation of free radicals that lead to cell destruction. On the other hand, bisquinoline derivatives such as piperaquine interfere with the detoxification of hemin in the digestive vacuole of the parasite to non-toxic malarial pigment, so that hemin can generate free radicals and consequently the damage of the membrane. The unrelated mode of action of the two drugs would provide improved therapy, and treatment against all stages of the parasites including gametocytes. Additionally, since the synthetic artemisinin derivatives are highly effective and highly potent, they would thus rapidly combat symptoms, exhibiting rapid recovery rates. The combination of synthetic artemisinin derivatives and bisquinoline derivatives such as piperaquine provide a short duration of treatment.

Piperaquine is a bisquinoline compound that has antimalarial activity against both P. vivax and P. falciparum, including strains of P. falciparum resistant to chloroquine. The tolerability, efficacy, pharmacokinetic profile, low cost and the longer acting piperaquine make it a very perfect candidate for use in combination with the short and fast active compound Activo I. The piperaquine of the present invention includes piperaquine phosphate. The piperaquine may be present in an amount of about 40% to about 80%, w / w based on the total dosage form.

The total drug content of the forms of Oral dosage of the present invention is within the range of about 25% to about 85%, and in particular does not exceed 85% w / w based on the total dosage form.

The oral dosage forms of the present invention comprise the compound Active I and piperaquine in a weight ratio of about 1: 1 to about 1:10.

Oral dosage forms of the present invention comprise Active compound I present in a dose range of about 100 mg to about 300 mg and piperaquine present in a dose range of about 700 mg to about 850 mg.

Oral dosage forms of the present invention comprise Active compound I present in a unit dose of 100 mg, 150 mg or 250 mg and piperaquine present in a unit dose of 750 mg.

Oral dosage forms of the present invention comprise Active compound I in a unit dose of about 100 mg and piperaquine present in a unit dose of about 750 mg.

Oral dosage forms of the present invention comprise Active compound I in a unit dose of about 150 mg and piperaquine present in a unit dose of about 750 mg.

Oral dosage forms of the present invention comprise Active compound I in a unit dose of about 200 mg and piperaquine present in a unit dose of about 750 mg.

The dosage regimen of the present invention includes administration of a fixed dose combination of 150 mg of Active compound I and 750 mg of piperaquine once a day for three days.

The dose of Active compound I herein means the dose equivalent to the free base of the active compound I.

The dosage regimen of the present invention includes three doses for three days.

The first dose is administered immediately in the diagnosis, the second dose approximately 24 hours after the first dose, and the third dose approximately 24 hours after the second dose.

The dosage regimen of the present invention is suitable for all patients aged 12 to 65 years and thus eliminates the need to calculate the dose based on individual weight parameters. In existing artemisinin-based combinations, the dose is calculated with respect to the patient's individual weight and in many cases the tablets are marked to adjust the dose. However, the dosing regime of this combination It is surprisingly simple and effective, both for patients and for people who prescribe.

Solid dosage form as used herein is selected from the group consisting of coated tablets or tablets, capsules, pellets, pills, granules and powders. A particularly suitable solid dosage form is that of compressed tablets.

In addition, it has been observed through exhaustive experimentation that when the active compound is formulated in a dosage form, including liquid or solid dosage forms, it is degraded by hydrolysis. The degradation may be due to the water associated with the excipients or added during the course of processing. Thus, forms of liquid oral dosages such as aqueous syrups, suspensions or solutions having desired shelf life could not be prepared successfully. In addition, the preparation of solid oral dosage forms of the active compound using techniques involving the use of water, such as wet granulation, spray drying or extrusion-spheronization processes resulted in dosage forms with varying stability results. However, acceptable stability results were obtained when the solid dosage forms were formulated using appropriate excipients with low water content and a process in which the water was absent, such as dry granulation, direct compression or non-aqueous granulation. In case where the excipients were granulated using water, the granules of excipients were properly dried prior to mixing with the active compound as such or with the granules containing active compound, and processed into solid dosage forms of acceptable stability.

The function of the excipients and the water content are evaluated by conducting compatibility studies of the active compound with various excipients in different proportions, and by evaluating the degree of degradation by forced degradation at 60 ° C during the 2-week period. 50 ° C for 4 weeks. The water content was analyzed using the Karl Fischer method and the total related substances (% w / w) were determined by the HPLC method. The results of the study are shown below in Table 1.

Table 1: Compatibility studies of the active compound (Active compound I) with various excipients The study clearly indicates the importance of the use of excipients having low water or moisture content in solid dosage forms stabilizing the active compound. In the present invention, the inventors have discovered that the use of excipients having water content of less than 6.5% w / w surprisingly increases the stability of the active compound, and thus provides reasonably long shelf life. The starch was found to be incompatible with the active compound when used in higher amounts. In addition, lactose was also found to be incompatible due to degradation by other mechanisms such as the Maillard reaction, and dicalcium phosphate was not preferred due to an increase in related substances at 60 ° C. However, microcrystalline cellulose gave the most satisfactory results.

The stable solid oral dosage forms of the present invention may further comprise one or more pharmaceutically acceptable excipients, including all physiologically inert excipients used in the art for the preparation of solid dosage forms. Examples include binders, diluents, glidants / lubricants, disintegrants, surfactants, coloring agents and the like. The excipients can be use either intragranularly or extragranularly, or both. The weight ratio of the active compound and excipients in the dosage forms may vary from about 1.5: 1 to about 1:30.

Examples of binders include methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, agar, tragacanth, and sodium alginate or mixtures thereof.

Examples of diluents include cellulose powder, microcrystalline cellulose, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, mannitol, sorbitol, sucrose, compressible sugar and sugar confectionery, in particular microcrystalline cellulose. The diluents can be present in an amount of about 10% to about 40% w / w based on the total weight of the dosage form. In addition, the weight ratio of Active compound I to microcrystalline cellulose can vary from about 1: 1 to about 1: 5.

Examples of disintegrants include clays, celluloses, alginates, gums, cross-linked polymers (such as crosslinked polyvinylpyrrolidone and crosslinked sodium carboxymethylcellulose), sodium starch glycolate, low substituted hydroxypropyl cellulose and soybean polysaccharide, in particular crospovidone. The disintegrant may be present in an amount of about 1% to about 10% w / w based on the total weight of the dosage form.

Examples of lubricants or glidants include talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, magnesium carbonate, magnesium oxide, calcium silicate, microcrystalline cellulose, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium benzoate, sodium acetate , sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate and hydrogenated vegetable oils, sucrose fatty acid esters, microcrystalline wax, yellow beeswax, white beeswax, in particular magnesium stearate. The lubricant may be present in an amount of about 1% to about 5%, w / w based on the total weight of the dosage form.

Examples of surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) suitable for use in sweetener compositions. These include polyethoxylated fatty acids and their derivatives, for example, polyethylene glycol distearate 400, polyethylene glycol-20 dioleate, 4-150 polyethylene glycol mono-dilaurate, polyethylene glycol-20 glyceryl stearate; alcohol-oil transesterification products, for example, polyethylene glycol-6 corn oil; fatty acids polyglycerized, for example polyglyceryl-6-pentaoleate; fatty acid esters of propylene glycol, for example, propylene glycol monocaprylate; mono- and diglycerides, for example glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and their derivatives, for example polyethylene glycol 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example polyethylene glycol-20 cetyl ether, polyethylene glycol-10-100 nonyl phenol; sugar esters, for example sucrose monopalmitate; copolymers of polyoxyethylene-polyoxypropylene blocks known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, disodium octyl sulfosuccinate and palmitoyl carnitine.

Coloring agents include any of the colors approved by the FDA for oral use.

The solid dosage forms can additionally be coated with one or more functional and / or non-functional layers comprising film-forming polymers, and other coating additives.

Examples of film-forming polymers include cellulose derivatives such as ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, partially hydrolyzed polyvinyl alcohol, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; and methacrylic acid polymers such as Eudragit® RL and RS. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry®, can also be used for coating.

The coating additives comprise one or more plasticizers, glidants or flow regulators, opacifiers and lubricants.

The pharmaceutically acceptable excipients and / or film-forming polymers and coating additives may be selected to provide an immediate release profile or a modified release profile.

The solid dosage forms of the Active compound I can be prepared by densifying Active compound I and one or more excipients, and processing in solid dosage forms. The densification can be carried out using the conventional method known in the art. In particular, granulation or extrusion-spheronization can be used.

In one of the modalities, the oral tablets Active compound I compounds can be prepared by a process comprising the steps of mixing the active compound I and the intragranular portion of a diluent, lubricant and disintegrant; when passing the mixture through a roller compactor to form a compact mass; by reducing the compact mass in granules of adequate size; by mixing the granules with the extragranular portion of a lubricant, disintegrant and diluent in a double cone mixer and finally compressing into tablets using the appropriate tools.

In another embodiment, the stable oral capsules of Active compound I can be prepared by a process comprising the steps of mixing the active compound I and the intragranular portion of a diluent, lubricant, and disintegrant; compressing the mixture in a heavy tablet forming press to form debris; reduce those reduced in granules of adequate size; Mix the granules with the extragranular portion of a lubricant, disintegrant and diluent in a double cone mixer, and finally compress into tablets using the appropriate tools.

In another embodiment, the stable oral capsules of the Active compound I can be prepared by a process comprising the steps of mixing the active compound I and the intragranular portion of a diluent, lubricant, and disintegrating; passing the mixture through a roller compactor to form a compact mass; reduce the compact in granules of a suitable size; mix the granules with the extragranular portion of a double cone mixer lubricant and finally fill in capsules of a suitable size.

In another embodiment, the stable oral capsules of Active compound I can be prepared by a process comprising the steps of mixing the active compound I and the intragranular portion of a diluent, lubricant, and disintegrant; compress the mixture in a press to form dense tablets to form waste; reduce waste in granules of an adequate size; mix the granules with the extragranular portion of lubricant in a double cone mixer and finally fill in capsules of a suitable size.

In another embodiment, the stable oral tablets of the active compound I can be prepared by a process comprising the steps of mixing the active compound I, a diluent, a lubricant and a disintegrant; and directly compress into tablets using the right tools.

In another embodiment, the stable oral capsules of Active compound I can be prepared by a process comprising the steps of mixing the active compound I, a diluent and a lubricant; and fill in capsules of an appropriate size.

In another embodiment, the stable oral tablets of the active compound I can be prepared by a process comprising the steps of mixing the active compound I and intragranular portion of a diluent, and disintegrating; wet granulating the mixture with a non-aqueous granulation fluid or a solution / dispersion of pharmaceutically acceptable excipients in the non-aqueous granulation fluid; dry and reduce the granules of a suitable size, mix the granules with the extragranular portion of a lubricant, disintegrant and diluent in a double cone mixer, and finally compress into tablets using the appropriate tools.

In yet another embodiment, the stable oral capsules of the Active compound I can be prepared by a process comprising the steps of mixing the Active compound I and the intragranular portion of diluent, and disintegrant; wet granulating the mixture with a non-aqueous granulation fluid or a solution / dispersion of pharmaceutically acceptable excipients in the non-aqueous granulation fluid; dry and reduce the granules to a suitable size; mix the granules with the extragranular portion of lubricant in a double cone mixer, and finally fill in capsules of a suitable size.

Examples of the non-aqueous granulation fluid include organic solvents such as methanol, ethanol, isopropyl alcohol, dichloromethane, acetone or mixtures thereof.

In yet another embodiment, tablets prepared by any of the processes described above can also be coated with film-forming polymers and one or more coating additives, using techniques well known in the art such as spray coating on a tray. conventional coating or a processor or fluidized bed or dip coating. Alternatively, the coating can also be made using a hot melt technique.

The coating layers on the tablet can be applied as a solution / dispersion of coating components in a suitable solvent. Examples of solvents used to prepare a solution / dispersion of the coating ingredients include methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water and the like and mixtures thereof.

In still another embodiment, one or more of the antimalarial drugs selected from piperaquine, lumefantrine and DB 289 (pafuramidine maleate) may be added in the mixture comprising the active compound, in any of the above embodiments.

The dosage form of the present invention It is processed and stored at a temperature below 27 ° C and a relative humidity of 50%.

The invention described herein is further illustrated by the following examples, which should not be considered as limiting the scope of the invention.

EXAMPLES Example 1 : Process : 1. The active compound I and the intragranular portion of microcrystalline cellulose were screened through the BSS # 44 screen and mixed together in a double cone mixer to form a uniform mixture. 2. To the mixture from step 1, the intragranular portion of sieved magnesium stearate was added and mixed for about 5 minutes. 3. The mixture from step 2 was compacted in a roller compactor and sieved through the BSS # 22 screen to form granules.

. The extragranular portion of microcrystalline cellulose, croscarmellose sodium and magnesium stearate were sieved through the BSS # 44 screen and mixed with the granules of step 3. 5. The mixture from step 4 was compressed using punches of suitable size to obtain compressed tablets. 6. Tablets as obtained from step 5 were coated with Opadry® using conventional coating techniques.

The tablets prepared according to Example 1 were subjected to stability studies at 25 ° C / 60% RH, 30 ° C / 65% RH and 40 ° C / 75% RH over a period of 6 months. The results are summarized in Table 2. The results of the in vitro drug release analyzed in periods of predetermined time are given in Table 3.

Table 2: Total related substances * (Percent p / p) % Total Related Substance should not be more than Table 3: Percentage (%) of drug release in vitro in the USP II * device (medium: 2% tween 80 in water, 900 ml at 75 rpm, in 45 min) * In vitro drug release (% w / w) should not be less than 70% (Q) of the marked amount dissolved in 45 minutes.

As is evident from the previous studies, the tablets prepared by the. process of the present invention in which the water is absent show acceptable shelf stability.

Example 2: Process : 1. Active compound I, microcrystalline cellulose, croscarmellose sodium and magnesium stearate were sieved through the BSS # 44 screen. 2. The active compound I, the microcrystalline cellulose, and the sifted croscarmellose sodium were mixed in a double cone mixer for approximately 15 minutes to form a uniform mixture. 3. To the mixture of step 2, the sieved magnesium stearate was added and mixed for about 5 minutes. 4. The mixture obtained in step 3 was compressed directly using punches in the form of a capsule of suitable size to obtain compressed tablets.

Examples 3 and 4: Process : 1. Active compound I, piperaquine phosphate and the intragranular portion of microcrystalline cellulose and crospovidone were screened through the BSS # 44 screen and mixed together in a double cone mixer to form a uniform mixture. 2. To the mixture from step 1, the intragranular portion of sieved magnesium stearate was added and mixed for about 5 minutes. 3. The mixture from step 2 was compacted in a roller compactor and sieved through the BSS # 18 screen to form granules. 4. The extragranular portion of microcrystalline cellulose and crospovidone were screened through the BSS # 44 screen and mixed with the granules of step 3. 5. The extragranular portion of magnesium stearate was sieved through the BSS # 44 screen and mixed with the mixture from step 4 in a double cone mixer for about 5 minutes. 6. The mixture from step 5 was compressed using punches of suitable size to obtain compressed tablets. 7. Tablets as obtained from step 6 were coated with Opadry® using conventional coating techniques and weight accumulation of up to 2.5% w / w.

The tablets prepared according to Example 3 and 4 were subjected to stability studies at 40 ° C / 75% RH over a period of 3 months, as shown in Table 4.

Table 4: Percent of total related substances * *% Total related substance percent should not be Example 5 Process: 1. The active compound I, piperaquine phosphate and the intragranular portion of microcrystalline cellulose and crospovidone were screened through the BSS # 44 screen and mixed together. 2. To the mixture from step 1, the intragranular portion of sieved magnesium stearate was added and mixed for about 5 minutes. 3. The mixture from step 2 was compacted and the compacts were sieved through the BSS # 18 screen to form granules. . The extragranular portion of microcrystalline cellulose and crospovidone were sifted through the BSS # 44 screen and mixed with the granules of step 3. 5. The extragranular portion of magnesium stearate was screened through the BSS # 44 screen and mixed with the mixture from step 4 in a double cone mixer for about 5 minutes. 6. The mixture from step 5 was compressed using finches of suitable size to obtain compressed tablets. 7. The tablets as obtained from step 6 are coated with Opadry® using conventional coating techniques and weight accumulation of up to 2.4% w / w. Table 5: Percentage (% w / w) of drug release In vitro of the active compound I, of example 5, in the apparatus * USP II (medium: t een 80% 2% in water, 900 ml, 75 rpm) * The release of the drug in vitro (% w / w) should not be less than 70% (Q) of the marked amount dissolved in 45 minutes.

A Phase II, double-blind, randomized, randomized dose discovery study was conducted to determine the safety and efficacy of three dose levels (50 mg, 100 mg and 200 mg) of Active compound I administered for three days in patients with uncomplicated P. falciparum malaria. Preliminary data showed that the mean parasite evacuation time for the patient at 50 mg was 52 hours, and all 3 patients who were followed for up to 28 days showed reappearance of the parasites. The patients receiving 100 mg had a parasite evacuation time of 46.6 hours and 5 of the 6 total patients showed reappearance of the parasites. The patients who receive 200 mg had a parasite evacuation time of 30.4 hours and 4 of 5 patients showed adequate clinical and parasitological response (ACPR) on day 28. Only 1 patient showed reappearance of the parasites. The results obtained so far indicate that the active compound I was a short-acting drug and produced rapid evacuation of the parasites. The relatively high rate of recrudescence with the active compound I after three days of monotherapy highlighted the need to combine the drug with a long-acting drug.

Piperaquine phosphate was chosen as an associated drug and a parallel, randomized, double-blind, Phase I controlled, placebo-controlled study was conducted in young healthy male subjects to investigate the safety, tolerability and pharmacokinetic profile of the active compound I and the piperaquine phosphate after co-administration of multiple oral doses. The study comprised three groups. Group I received an oral daily dose of 100 mg of Active compound I and 750 mg of piperaquine phosphate, Group II received a daily oral dose of 200 mg of Active compound I and 750 mg of piperaquine phosphate and Group III received a oral daily dose of 200 mg of Active compound I and 1000 mg of piperaquine phosphate. All three doses were administered once a day for three days in each group. No adverse event related with the drug up to dose levels of 200 mg of Active compound I and 750 mg of piperaquine phosphate. However, drowsiness and vomiting were reported at a dose level of 200 mg of Active compound I and 1000 mg of piperaquine phosphate. The systemic exposure to Active compound I after repeated dosing was not appreciably different from those after the single dose, therefore no accumulation was observed for Active compound I in the repeated 3-day dosing of the active compound combination I - piperaquine phosphate. Active compound I exposures were increased in a proportional dose manner by doubling the dose from 100 mg to 200 mg, when the piperaquine phosphate dose remained constant (Table 6).

O O Table 6: Pharmacokinetic parameters of geometric mean of active compound I (free base) after co-administration of active compound I and piperaquine phosphate to healthy young male subjects (n = 6).

"= Degree of accumulation calculated as (AUCo-24 (-> ia 3) / AUCo-24 (Day 1)) Comparative Bioavailability Study of the fixed dose combination of the active compound I 150 mg + piperaquine phosphate 750 mg and co-package formulations.

A parallel-design, two-treatment, single-dose study comparing the bioavailability of the fixed-dose combination tablets of Active compound I 150 mg + piperakine phosphate of 750 mg with the active compound I co-administered 150 mg and Piperaquine phosphate 750 mg was conducted as a parallel, two-treatment, single-dose, randomized, open-label release in 36 healthy, adult, human subjects under fasting conditions. The pharmacokinetic parameters are presented in Tables 7 and 8. The results of this study suggest that the pharmacokinetics of the active compound I remained unchanged when administered in fixed dose combination with piperaquine phosphate as compared to its co-administration as tablets. individual Table 7: Pharmacokinetic parameters of the geometric mean of Active compound I (free base) after administration of the fixed dose combination (FDC) and co-pack formulations of the active compound I and piperaquine phosphate to healthy, young male subjects .

FDC: Fixed dose combination tablet of Active compound I 150 mg and piperaquine phosphate 750 mg as a tablet (n = 16); Co-pack: Three tablets of active compound I 50 mg and one tablet of piperaquine phosphate 750 mg as individual tablets (n = 17), AUCo-t = AUC 0 at the last measurable concentration (sampling up to 96 h).

Table 8: Pharmacokinetic parameters of the geometric mean of piperaquine after administration of the fixed dose combination (FDC) and the co-pack formulations of the active compound I and piperaquine phosphate to healthy, young male subjects.

FDC: Fixed dose combination tablet of Active compound I 150 mg and piperaquine phosphate 750 mg as a tablet (n = 16); Co-pack: Three tablets of active compound I 50 mg and one piperaquine phosphate tablets 750 mg as individual tablets (n = 17), AUC0-t = AUC 0 at the last measurable concentration (sampling up to 96 h).

While several particular compositions are have described, it will be evident that several modifications combinations of the detailed compositions in the text can do without departing from the spirit and scope of invention.

Claims (24)

1. A stable solid oral dosage form, characterized in that it comprises: (a) cis-adamantane-2-spiro-3'-8 '- [[[(2'-amino-2'-methylpropyl) amino] carbonyl] -methyl] -1', 2 ', 4' hydrogen maleate -trioxaspiro [4.5] decane (Active compound I); (b) piperaquine, and (c) one or more pharmaceutically acceptable excipients; wherein the dosage form is prepared by a dry process.

2. The stable solid oral dosage form according to claim 1, characterized in that the dosage form comprises: (a) Active compound I in an amount of about 5% to about 25%, and (b) piperaquine in an amount of about 40% to about 80%, w / w based on the total weight of the dosage form.

3. The stable solid oral dosage form according to claim 1, characterized in that the pharmaceutically acceptable excipient is selected from the group consisting of binders, diluents, glidants / lubricants, disintegrants, surfactants and coloring agents.

4. The stable solid oral dosage form of according to claim 3, characterized in that the diluent is microcrystalline cellulose.

5. The stable solid oral dosage form according to claim 1, characterized in that the dosage form has a dissolution performance such that, more than 70% w / w of the active compound I dissolves within 45 minutes, in a buffer solution of pH 4.5 acetate with 2% tween 80, in the USP type II device.

6. The stable solid oral dosage form according to claim 1, characterized in that the Active compound I and the piperaquine are present in a weight ratio of from about 1: 1 to about 1:10.

7. The stable solid oral dosage form according to claim 1, characterized in that the Active compound I is present in a dose range of about 100 mg to about 300 mg and piperaquine present in a dose range of about 700 mg to about 850 mg.

8. The stable solid oral dosage form according to claim 1, characterized in that the dosage form comprises: (a) Active compound I in an amount of about 5% to about 25%; (b) piperaquine in an amount of about 40% to approximately 80%; (c) diluent in an amount of about 10% to about 40%; (d) disintegrant in an amount from about 1% to about 10%; Y (e) lubricant in an amount of about 1% to about 5%, w / w based on the total weight of the dosage form.

9. The stable solid oral dosage form according to claim 1, characterized in that the dosage form comprises: a) Active compound I; (b) piperaquine; (c) microcrystalline cellulose; (d) crospovidone; Y (e) magnesium stearate.

10. The stable solid oral dosage form according to claim 1, characterized in that the dosage form comprises: (a) Active compound I in an amount of about 5% to about 25%; (b) piperaquine in an amount of about 40% to about 80%, and (c) microcrystalline cellulose in an amount of about 10% to about 40%; p / p based on total weight of the dosage form.

11. The stable solid oral dosage form according to claim 1, characterized in that the dosage form comprises the Active compound I and microcrystalline cellulose in a weight ratio of about 1: 1 to about 1: 5.

12. The stable solid oral dosage form according to claim 1, characterized in that the dosage form is selected from a group consisting of tablet, capsule, pill, granule and powder.

13. The stable solid oral dosage form according to claim 12, characterized in that the tablet is coated with one or more functional and / or non-functional coating layers comprising film-forming polymers and coating additives.

14. The stable solid oral dosage form according to claim 13, characterized in that the coating additives comprise one or more of plasticizers, glidants or flow regulators, opacifiers and lubricants.

15. The stable solid oral dosage form according to claim 1, characterized in that the dosage form is processed and stored at a temperature below 27 ° C and 50% relative humidity.

16. The stable solid oral dosage form of according to claim 1, characterized in that the dry process comprises direct compression or dry granulation.

17. The stable solid oral dosage form according to claim 1, characterized in that the dosage form is prepared by a process comprising the steps of: (a) mixing the active compound I, piperaquine, and one or more intragranular excipients; (b) grinding, pulverizing or sifting the mixture by roller compaction to form granules; (c) mixing the granules with one or more extragranular excipients, and (d) compress the mixture into tablets or fill in capsules.

18. The stable solid oral dosage form according to claim 1, characterized in that the dosage form is prepared by a process comprising the steps of: (a) mixing the active compound I, piperaquine, and one or more intragranular excipients; (b) granulating the mixture by whipping; (c) mixing the granules with one or more extragranular excipients, and (d) compress the mixture into tablets or fill in capsules

19. The stable solid oral dosage form according to claim 1, characterized in that the dosage form is prepared by a process comprising the steps of: (a) mixing the active compound I, piperaquine and one or more pharmaceutically acceptable excipients; Y (b) directly compress the mixture into tablets or fill in capsules.

20. The stable solid oral dosage form according to claim 1, characterized in that the dosage form is prepared by a process comprising the steps of: (a) qranulating a mixture of one or more excipients; (b) drying the excipient granules; (c) mixing the excipient granules with the active compound I and piperaquine; Y (d) compress the mixture into tablets or fill in capsules.

21. A stable solid oral dosage form, characterized in that it comprises: (a) 150 mg of Active compound I and (b) 750 mg piperaquine, wherein the dosage form is administered once a day for three days.

22. The stable solid oral dosage form according to claim 21, characterized in that the first dose of the dosage form is administered immediately in the diagnosis, the second dose approximately 24 hours after the first dose and the third dose approximately 24 hours after of the second dose.

23. A method of treating malaria, the method characterized in that it comprises administering a stable oral solid dosage form comprising: (a) an Active compound I; (b) piperaquine, and (c) one or more pharmaceutically acceptable excipients wherein the dosage form is prepared by a dry process.

24. A method for treating malaria, characterized in that it comprises administering a stable solid oral dosage form comprising: (a) 150 mg of Active compound I and (b) 750 mg piperaquine wherein the dosage form is administered once a day for three days.