Pharmaceutical composition

Abstract

Pharmaceutical composition presented in a galenic form of spheroid, absorbable by oral route, said spheroid internalizing, as the sole active ingredient with anti-malarial activity, a therapeutically effective quantity of at least 200 mg of artesunate, for use as a medicinal product.

Description

Title of the invention: Pharmaceutical composition

[0001] The present invention falls within the field of pharmaceutical compositions with anti-malarial activity.

[0002] The invention relates specifically to a pharmaceutical composition in the form of a spheroid galenic tablet for oral administration comprising as the sole active ingredient with anti-malarial activity at least 200 mg of artesunate, as well as the use of this composition in a method of treating malaria.

[0003] The invention also relates to the use of said pharmaceutical composition as a parasiticide composition against parasites of the genus Plasmodium, in particular Plasmodium falciparum.

[0004] The present invention also relates to a method for manufacturing a pharmaceutical composition of the invention.

[0005] Malaria is a disease affecting many countries including France, for which severe imported malaria mainly involves P. falciparum, more rarely P. vivax or P. knowlesi, and exceptionally P. mal a riae and P. ovale.

[0006] Currently, the clinical manifestations of malaria are mainly the presence of fever; however, no specific association of symptoms allows for a reliable differentiation between malaria and other conditions.

[0007] That is why in all cases of suspected malaria, a parasitological test must confirm the diagnosis.

[0008] The diagnosis of parasitology can be established either by an examination in optical microscopy, allowing identification and enumeration of the plasmodies present in a sample of thick drops of blood or blood smears, or by a rapid diagnostic test of the immuno-chromatographic type detecting the presence of specific antigens of the parasite in a blood sample taken by finger prick.

[0009] In a patient, severe P. falciparum malaria is defined by parasitemia detected by a positive parasitological test for P. falciparum with the presence of asexual form of P. falciparum, accompanied by at least one clinical or biological criterion of severity, belonging to the following list: - impaired consciousness: a Glasgow Coma Scale score <11 in adults or a Blantyre score <3 in children; - prostration: inability to sit, stand or walk without assistance; - repeated seizures in large numbers, involving more than two episodes of seizures within 24 hours; - acidosis: a base deficit >8 meq / 1 or a plasma bicarbonate level <15 mmol / 1 or a venous lactate level >5 mmol / 1, in case of severe acidosis: respiratory distress; - hypoglycemia involving a blood glucose level <2.2 mmol / l (<40 mg / dl); - severe malarial anemia with a hemoglobin concentration <5 g / dl or hematocrit <15% in children <12 years (<7 g / dl and <20% respectively, in adults), with a parasite count >10,000 / pl; - renal insufficiency with serum or plasma creatinine >265 pmol / 1 (3 mg / dl) or blood urea >20 mmol / 1; - jaundice with serum or plasma bilirubin >50 pmol / l (3 mg / dl) with a parasite count >100,000 / pl; - pulmonary edema confirmed by radiological examination, or an oxygen saturation <92% in room air with a respiratory rate >30 / min, often accompanied by chest retractions and crackles on auscultation; - significant, recurrent or prolonged bleeding from the nose, gums or venipuncture sites; hematemesis or melena; - a state of shock: either decompensated shock defined by a capillary refill time >3 s or a temperature gradient in the legs, but without hypotension: or decompensated shock defined by a systolic pressure <70 mmHg in children or <80 mmHg in adults, accompanied by signs of circulatory disorders (cold extremities or prolonged vascular refill time); - hyper-parasitemia: parasitemia with p. falciparum >10%.

[0010] A patient presenting with parasitemia detected by a positive parasitological test for Plasmodium and symptoms of malaria (fevers) without the aforementioned characteristics of severe malaria, will be diagnosed as suffering from uncomplicated malaria.

[0011] As a substance with anti-malarial activity, artesunate is a chemical compound widely used in the treatment of malaria.

[0012] Artesunate is a derivative of artemisinin, obtained by semi-synthesis of extracts from an Artemisia annua plant, having a sesquiterpene lactone chemical structure with an endoperoxide bridge, with a schizonticidal action on all intra-erythrocytic parasitic stages of Plasmodium.

[0013] The schizonticidal action of artesunate is due to the cleavage by organic iron of the endoperoxide bridge, which generates the release of free radicals having a direct toxicity on the developing parasite and its nutritive vacuole (inhibition of parasite calcium ATPase pumps).

[0014] Artesunate is a prodrug hydrolyzed in the systemic circulation by an esterase to dihydroartemisinin (DHA), the active metabolite responsible for the antimalarial activity. DHA acts on intraerythrocytic parasites, from early asexual stages (ring stage) to late stages (old trophozoites and schizonts responsible for cytoadherence) and immature sexual forms (gametocytes).

[0015] To treat uncomplicated malaria, it is known to use therapeutic combinations based on artemisinin, such as orally administered tablets comprising mixtures of artesunate-amodiaquine (AS+AQ); artesunate-mefloquine (ASMQ); artesunate + sulfadoxine-pyrimethamine (AS+SP); or artesunate-pyronaridin (ASPY).

[0016] These combination therapy tablets have various disadvantages.

[0017] First of all, these tablets are known to have significant side effects in some patients with malaria, making their use as an anti-malarial treatment dangerous or even impossible.

[0018] For example, it is known that the ASPY tablet should be avoided in patients with liver disease because it generates an elevation of hepatic transaminases.

[0019] It is also known that treatment with the As+AQ tablet is associated with severe neutropenia and is therefore contraindicated in patients co-infected with HIV or already treated with zidovudine, efavirenz or cotrimoxazole.

[0020] Similarly, treatment with the ASMQ tablet is known to cause nausea, vomiting, dizziness, dysphoria and sleep disturbances.

[0021] Moreover, the widespread and continuous use of these artemisinin-based combination therapy tablets has contributed to increasing the resistance of certain species of Plasmodium that cause malaria and makes these combination treatments less and less functional.

[0022] In addition, artesunate is known to exhibit physico-chemical incompatibility with many other molecules with antimalarial activity, responsible for its degradation or systemic inactivity, which is why, faced with the rising resistance of Plasmodium species, it is becoming increasingly complex to find malaria treatment tablets based on therapeutic combinations of molecules with antimalarial activity.

[0023] Furthermore, studies have shown that after oral administration of a combination therapy tablet containing artesunate, the peak systemic exposure to DHA is observed within 2 hours of oral administration of the tablet, this which may seem quite long to combat plasmodia in patients with malaria.

[0024] As is known, for the treatment of severe malaria caused by P. falciparum, it is currently recommended to administer artesunate immediately as first-line therapy in adults via intravenous parenteral injection. The recommended dosage is 2.4 mg of artesunate / kg of the adult patient at the time of diagnosis, then at 12 and 24 hours, and then every 24 hours thereafter, with a maximum of 9 intravenous doses, i.e., 7 days of treatment.

[0025] In France, intravenous artesunate is an injectable specialty, marketed under the name Malacef®, which is presented in the form of a vial of powder containing 60 mg of artesunate and a vial of solvent containing 1 ml of sodium bicarbonate solution. The artesunate solution for intravenous injection is prepared by mixing 1 ml of sodium bicarbonate solution with the 60 mg of artesunate powder and 5 ml of 5% glucose solution or 0.9% saline solution.

[0026] The artesunate solution should be administered intravenously immediately after reconstitution at a slow injection rate using an electric syringe pump at a rate of 3 ml / minute.

[0027] This treatment of malaria with intravenous artesunate presents several disadvantages:

[0028] - risks of microbial contamination during reconstitution of the solution injectable intravenously,

[0029] - problems with the preservation of the reconstituted artesunate solution, which does not It does not exceed 6 hours and therefore requires systematic and immediate reconstitution before each intravenous injection.

[0030] - undesirable side effects such as digestive problems, dizziness and convulsions, hematotoxicity to be monitored for 4 weeks after the start of treatment involving delayed and persistent hemolytic anemia or neutropenia, reticulocytopenia, potential embryo toxicity, liver toxicity in 4% of cases,

[0031] - the requirement for immediate availability of the reconstituted injectable solution As soon as the diagnosis is made, in order to administer the treatment intravenously,

[0032] - a limitation to 9 doses over a maximum of 7 days, requiring in the event of persistence of malaria, a follow-up antimalarial treatment administered orally.

[0033] - a systemic peak of DHA that varies between patients, averaging 25 minutes.

[0034] The emergence of Plasmodium parasites resistant to antimalarials, the constraints of administration, bioavailability in the body of certain antimalarial agents, as well as the risks of side effects related to their administration are major drawbacks and obstacles to improving methods of treating malaria and to eradicating the disease.

[0035] Thus, in order to overcome all the aforementioned drawbacks, it is necessary to find an alternative solution for the treatment of Malaria, involving artesunate, which allows: - to avoid the adverse effects observed with current treatments, and to minimize the overall toxicity of artesunate treatment for the body, - to limit the risk of contamination for patients, - to delay the emergence of parasite resistance to antimalarial molecules, - to make the treatment easy to use and accessible for patients, for example those with seizures or reduced mobility, and accessible for caregivers, - a lower cost galenic form, with long shelf life and acceptable pharmacokinetics without compromising the clinical efficacy and bioavailability of artesunate to fight malaria.

[0036] Thus the present invention aims to overcome the drawbacks of the prior art by proposing a pharmaceutical composition in the form of a spheroid galenic, absorbable orally, said spheroid internalizing, as the sole active ingredient with anti-malarial activity, a therapeutically effective quantity of at least 200 mg of artesunate, for use as a medicinal product.

[0037] The term “pharmaceutical composition” means a pharmaceutically acceptable composition comprising all excipients which are useful in the preparation of the composition and which is safe, stable, non-biologically toxic, nor otherwise undesirable and which is acceptable for human or animal pharmaceutical use.

[0038] The term "spheroid galenic form" means the form in which the composition is presented which is specially designed for oral administration and which is obtained according to the manufacturing process of the pharmaceutical composition of the invention described later.

[0039] The term "active ingredient with antimalarial activity" means at least one molecule, a substance having an antimalarial therapeutic effect on the body, that is to say, eliminating the development and proliferation of all forms of the parasite, in a particular species of the genus Plasmodium which participates in or promotes the improvement of the health of a patient with malaria.

[0040] The term "therapeutically effective quantity" means the quantity of artesunate present in the pharmaceutical composition of the invention that is sufficient or effective to administer to prevent, treat (stop, prevent progression, inhibit, reduce or slow down) malaria in a subject, including the resulting symptoms.

[0041] For the purposes of the invention, "artesunate" means an artemisinin derivative obtained by semi-synthesis of extracts from an Artemisia annua plant, having a sesquiterpene lactone chemical structure with an endoperoxide bridge, which is presented in powder galenic form.

[0042] According to a preferred embodiment of the invention, the artesunate used is an artesunate identical to that marketed in powder form before reconstitution of the solution under the trade name Malacef®.

[0043] According to the invention, said pharmaceutical composition is for use in the treatment of malaria in an affected subject, in particular in a subject with Plasmodium falciparum malaria, preferably in a subject with Plasmodium falciform malaria with a parasitemia of at least 2000 asexual forms / mm3 of blood.

[0044] Preferably, the term "subject" refers to a human person, who is an adult or a minor over 15 years of age.

[0045] According to a particular embodiment of the invention, parasitemia in the blood is measured either by optical microscopy, allowing the identification and enumeration of parasites present in a sample of thick blood drops or blood smears, or by a rapid diagnostic test such as immunochromatographic techniques detecting the presence of parasite-specific antigens in a blood sample obtained by finger prick, as recommended by the WHO. Any other technique known to those skilled in the art for measuring parasitemia in the blood is also applicable.

[0046] According to a preferred embodiment of the composition of the invention, said spheroid internalizing at least 200 mg of artesunate is obtained by successively carrying out the following steps:

[0047] A) At least 200 mg of artesunate is mixed with an absorbent and adsorptive substance having plastic properties, and optionally the mixture is moistened with a humidifying liquid, such as ultrapure water,

[0048] B) The mixture is extruded until an extruded product is obtained,

[0049] C) The extruded product is spheronized until a monolayer spheroid internalizing at least 200 mg of artesunate is obtained.

[0050] D) Optionally, the spheroid is dried and / or the spheroid is calibrated and / or the spheroid is film-coated and / or the spheroids obtained are grouped into a capsule, a softgel, sachets or tablets.

[0051] According to the invention, said absorbent and adsorbent substance must possess plastic properties compatible with the extrusion and spheronization steps of the continuation of the process for obtaining the artesunate internalizing spheroid.

[0052] The absorbent and adsorptive substance is preferably of polymer type, such as a natural polymer or synthetic polymer, generally in the form of a powder.

[0053] For example, examples of polymers exhibiting suitable absorbing and adsorbing properties and satisfactory plastic characteristics include microcrystalline celluloses, microfine celluloses, starches, modified starches and polysaccharides.

[0054] Another example is a technical excipient formed from a dry, homogeneous mixture of a low-substituted hydroxypropyl cellulose polymer, in particular a low-substituted hydroxypropyl cellulose ether at the 13-O-glucopyranosil ring groups. This absorbent substance is particularly useful as a polymer when it is desired to obtain rapidly dispersible artesunate spheroids in the blood.

[0055] To confer additional properties to the artesunate spheroid, auxiliary substances, such as for example other excipients, including binders, glides, lubricants, surfactants or others, can also be added to the mixture in step a).

[0056] These auxiliary substances may also be compounds intended to improve the results or the quality of the spheroids or to give them new properties.

[0057] These may include vitamins, minerals and / or other organic components. Examples include simple sugars with low energy value, mineral and organic substances which may correspond in particular to lactose, sorbitol, mannitol, maltodextrins, carbonates, citrates, gelatin, polyvinylpyrrolidone or a cellulosic derivative (ethyl, methyl or carboxy) and in particular cross-linked sodium carboxymethylcellulose.

[0058] All these auxiliary substances can be mixed simultaneously or successively in any order during step A) of mixing.

[0059] Optionally, a humidifying liquid is used in step A). ​​A person skilled in the art will choose any humidifying liquid capable of transporting and depositing the artesunate active ingredient to the core of the absorbent and adsorptive substance, in the microcavities of the polymer. Thus, the distribution of artesunate to The interior of the spheroid is uniform, and its dissemination after oral ingestion by the body will be facilitated.

[0060] According to the invention, none of the elements of the mixture interacts synergistically to the detriment of the anti-malarial activity of artesunate and none of the elements of the mixture alters the properties of artesunate by diminishing its anti-malarial therapeutic effect.

[0061] A person skilled in the art will choose the elements of the mixture, other than artesunate, to achieve the physico-chemical properties of the galenic form of the spheroid without chemically impacting the properties of use of artesunate and its antimalarial activity.

[0062] According to the invention, step B) consists, in other words, of extruding the mass, advantageously wet, of the mixture through a die with calibrated orifices, then making it spherical, that is to say, spheronizing the extruded product.

[0063] During the extrusion process, the mass, preferably moistened, is compacted and transformed by stretching into compact filaments of generally cylindrical and defined cross-section called "extrudate".

[0064] To obtain spheroids, the "extrudates" are placed in a cylindrical device called a "spheronizer" containing, in its lower part, a disk rotating at a variable and controlled speed. Under the effect of the centrifugal force exerted by the rotation of the rotating disk, the "extrudates" fragment regularly, then transform into spheres by a rolling-binding effect.

[0065] It has been observed that the possibility of transforming the "extrudates" into spheroids of homogeneous sphericity, of regular granulometry previously defined, depends as much on the plastic characteristics of the extrudates, therefore on the plastic characteristics of the moistened mass, as on the characteristics related to the spheronization operation itself, that is to say the speed of rotation of the rotating disk and the duration of its rotation.

[0066] According to a feature of the invention, to obtain a suitable plasticity, compatible with the extrusion and then spheronization techniques, the mass of humidification liquid is preferably between 3 and 5 times the mass of absorbent substance used.

[0067] A particular feature of the invention cited by way of example consists of preparing spheroids with a particle size between 350 microns and 1250 microns, for a yield of at least 95% of the mass of the spheroids produced.

[0068] In this case, the extruder die has orifices with an opening diameter of 1000 microns and a length of 1000 microns (die thickness). The extrusion speed is 100 rpm for a twin-screw front-mounted extruder or similar type.

[0069] The spheronization cycle for a spheronization device of 25 cm in diameter or other is then of a duration of 5 minutes with a rotation speed of 1040 rpm.

[0070] According to a preferred embodiment, after step C) of spheronization, the spheroids can then undergo a step D) of drying, preferably at a temperature close to 35°-40° C. Alternatively, they can simply be left in the open air for a certain time.

[0071] Step D) of drying the spheroid allows, by eliminating moisture, to increase its preservation by limiting the risk of microbiological contamination

[0072] According to another embodiment, optionally, the spheroids can be calibrated during step D), i.e. passed through a calibration device, consisting for example of a set of sieves, in order to obtain spherical multi-particle systems of controlled particle size.

[0073] Calibration step D) produces spheroids, each containing 200 mg of artesunate, with a controlled and identical particle size. Controlled particle size of the 200 mg artesunate spheroids facilitates their packaging.

[0074] The spheroids, according to the present invention, can be presented as such or coated in bulk, in dosing dispensers, in capsules, tablets, sachets or any other suitable form.

[0075] Preferably, they are grouped into capsules or softgels, corresponding to a quantity of active ingredient determined according to the specific dosage of the composition and allowing easier unit intake.

[0076] Before their packaging, for example in the form of capsules, these spheroids can, in addition, be film-coated in an optional additional step.

[0077] The film-coating step of the 200 mg artesunate spheroids increases their stability and preservation over time, while facilitating their packaging in capsules, caplets or other forms.

[0078] This film coating operation consists of covering them with a resistant coating film to protect the active ingredient of artesunate from any undesired degradation and to promote only its systemic biodispersion.

[0079] The film coating also allows for the regulation of the release of the active ingredient artesunate in the body. Release can thus be delayed or controlled in order to deliver artesunate selectively to certain levels of the digestive system, for example, to the gastric region and the upper parts of the small intestine for faster systemic action.

[0080] By using coatings of different kinds for the spheroids of the same capsule, it is also possible to deliver several doses of artesunate successively by means of a single dose of composition.

[0081] Advantageously, the process according to the invention makes it possible to obtain a pharmaceutical dosage form for solid artesunate alone that is easy to use and, in particular, can be administered orally. Furthermore, this dosage form ensures the physical and chemical stability of the artesunate used over time, even under unfavorable storage conditions. Thus, the pharmaceutical composition in spheroid form is free from all the constraints indicated (storage, contamination, need for reconstitution before use) for the treatment of malaria with intravenous artesunate alone.

[0082] Advantageously, the pharmaceutical composition in the form of a monolayer spheroid internalizing at least 200 mg of artesunate, of the present invention, is stable over time, easy to control and reproducible, simple and practical to use, and can be stored without precaution or special care and is easily transportable because the spheroids are light, compact and not fragile.

[0083] According to a particular embodiment of the composition of the invention, said spheroid is a multilayer spheroid.

[0084] According to this embodiment, each additional layer of a multilayer spheroid can be produced by carrying out the same steps A) to C) as described above, with or without artesunate, on an existing internalizing spheroid that has already undergone a drying step and contains at least 200 mg of artesunate. Each layer can be chosen according to a physicochemical composition so as to allow the differential release of its constituents over time.

[0085] Thus, according to this embodiment, it is possible, for example, to have as a pharmaceutical composition of the invention a multilayer spheroid with at least one layer internalizing 200 mg of artesunate and at least one other layer also capable of internalizing 200 mg of artesunate, so as to have a pharmaceutical composition with a total of 400 mg of artesunate. According to this embodiment, each 200 mg layer can be provided with a physicochemical nature allowing for differential or prolonged release of the artesunate, thereby affecting the bioavailability of the artesunate.

[0086] According to a preferred embodiment of the composition of the invention, the therapeutically effective amount of at least 200 mg of artesunate consists of 200 mg of artesunate powder.

[0087] According to a preferred embodiment of the composition of the invention, the therapeutically effective amount of at least 200 mg of artesunate consists of a mixture of 200 mg of artesunate in solution in 5% sodium bicarbonate and 0.9% sodium chloride.

[0088] According to this latter embodiment, since the 200 mg of artesunate is already in solution, the humidification liquid is not necessary to wet the mixture but remains possible.

[0089] According to another aspect of the invention, said pharmaceutical composition of the invention, being in galenic form of internalizing spheroid, at least 200 mg of artesunate, is for use in a method of treating malaria in an affected subject, in particular in a subject over 15 years of age suffering from acute uncomplicated Plasmodium falciparum malaria with a parasitemia of at least 2000 asexual forms / mm3 of blood.

[0090] Advantageously, in the context of use in a malaria treatment method, said composition is administered orally, according to a dosage of 400 mg of artesunate on day 1, then 200 mg on days 2, 3, 4, and 5. Day 1 corresponds to the first day of implementation of the treatment method and the first day of administration of the composition of the invention. Preferably, day 1 corresponds to the day of the actual diagnosis of malaria in a subject, in particular the day on which the diagnosis of uncomplicated acute malaria due to Plasmodium falciparum with a parasitemia of at least 2000 asexual forms / mm³ of blood is given for a subject.

[0091] The dosage of 400 mg of artesunate on day 1 consisting of taking orally once in the morning and once in the evening a pharmaceutical composition of the invention.

[0092] The present invention also relates to the use of a pharmaceutical composition of the invention as a parasiticide composition, in particular as a parasiticide composition against parasites of the genus Plasmodium, such as Plasmodium falciparum, Plasmodium vivax, Plasmodium knowlesi, Plasmodium malariae and Plasmodium ovale, particularly in an in vivo context of the presence of the parasite in its human or animal host, but also in an in vitro context of parasite culture.

[0093] For the purposes of the invention, the expression "in vivo context" means the use of the composition of the invention on a living being, whose organism is complete and in its natural living environment.

[0094] For the purposes of the invention, the expression "in vitro context" means a use of the composition of the invention, outside of the complete living organism, in an artificial environment, in particular in a laboratory, which corresponds to all experimental activities carried out on cells, tissues, organs or other components of a living being outside of their natural living context.

[0095] According to another aspect, the present invention also relates to a method for manufacturing a pharmaceutical composition of the invention, in which the following steps are carried out:

[0096] A) 200 mg of artesunate is mixed with an absorbent and adsorptive substance having plastic properties, and optionally the mixture is moistened with a humidifying liquid,

[0097] B) The mixture is extruded until an extruded product is obtained,

[0098] C) The extruded product is spheronized until a spheroid is obtained, a monolayer internalizing at least 200 mg of artesunate,

[0099] D) Optionally, the spheroid is dried and / or the spheroid is calibrated and / or the spheroid is film-coated and / or the spheroids obtained are grouped into a capsule, a softgel, sachets or tablets so as to obtain said pharmaceutical composition.

[0100] Advantageously, in the manufacturing process of a pharmaceutical composition of the invention:

[0101] - In step A), the absorbent and adsorptive substance is a natural polymer or synthetic, such as microcrystalline cellulose, microfine celluloses, modified starches, polysaccharides or a dry homogeneous mixture of low-substituted hydroxypropyl cellulose polymer of the low-substituted hydroxypropyl cellulose ether type at the 13-O-glucopyranosil ring groups.

[0102] Other features and advantages of the invention will become apparent from the results of the following experiments, with reference to the accompanying figures, in which

[0103] [Fig-1] [Fig.1] shows a curve of the evolution of the average temperature in °C of a population of patients with malaria, having been treated with said pharmaceutical composition of the invention, as a function of time in days,

[0104] [Fig.2] [Fig.2] shows a curve of the evolution of the average parasitemia of a population of patients with malaria, having been treated with said pharmaceutical composition of the invention, as a function of time in days,

[0105] [Fig.3] [Fig.3] shows the cure rate of a population of patients with malaria, 14 days and 28 days after diagnosis of malaria and start of anti-malarial treatment with a pharmaceutical composition according to the invention.

[0106] A clinical study to show the efficacy and tolerability of a pharmaceutical composition internalizing 200 mg of artesunate in a monolayer spheroid was carried out on a population of 50 patients suffering from acute uncomplicated Plasmodium falciparum malaria.

[0107] The patients in the study are men or women at least 15 years of age suffering from acute uncomplicated Plasmodium falciparum malaria, with fever as a symptom and with a parasitemia between 2000 and 20000 asexual forms / mm3 of blood diagnosed according to the parasitology test, performed either by examination by optical microscopy or by a rapid diagnostic test of the immuno-chromatographic type in a blood sample taken by finger prick.

[0108] The study patients did not receive any antimalarial or other medication in the 7 days prior to the start of the study.

[0109] In the study, patients were administered, orally, with a sufficient quantity of water, a pharmaceutical composition according to the invention. More specifically, the administered composition was in the form of a monolayer spheroid internalizing 200 mg of artesunate obtained after mixing 200 mg of powdered artesunate with an absorbent and adsorptive substance formed of a dry homogeneous mixture of low-substituted hydroxypropyl cellulose polymer, in particular a low-substituted hydroxypropyl cellulose ether at the 13-O-glucopyranosil ring groups, and with ultrapure water as the humidifying liquid.

[0110] In the study, treatment was administered at a dosage of 400 mg of artesunate on day 1, in 2 doses (one in the morning and the other in the evening), then 200 mg of artesunate / day on days 2, 3, 4 and 5 after the start of the study.

[0111] A patient vomiting a dose of the treatment within 30 to 60 min after oral administration was withdrawn from the study.

[0112] During the study, a safety assessment was carried out by recording through regular biological and biochemical measurements, and by monitoring the clinical condition (vital signs, physical examination) of the patient, any adverse events that may occur during treatment.

[0113] The patient safety assessment of the study was based, in particular, on monitoring vital signs such as pulse, blood pressure and auxiliary temperature, and examinations of different systems such as, for example, the cardiovascular system or the digestive system.

[0114] In addition, the patient safety assessment was also based on the control, by all methods known to those skilled in the art, of hematological parameters (hemoglobin level, red or white blood cell, hematocrit, platelet, reticulocyte) and biochemical parameters (total bilirubin, urea, creatinine, transaminase, alkaline phosphatases).

[0115] To evaluate the effectiveness of malaria treatment with the pharmaceutical composition of the invention, the following parameters were measured in each patient during the 28 days following the start of treatment: thermal clearance time, parasite clearance time and cure rate at 14 days and 28 days post-treatment.

[0116] The thermal clearance time ([Fig. 1]) corresponds to the time elapsed between the first dose and the moment when the temperature of the patient with malaria is below 37.5°C for at least 24 additional hours.

[0117] The parasite clearance time ([Fig.2]) corresponds to the time elapsed between the first administration and the first total and continuous disappearance of the asexual forms of the parasite and persisting for at least 24 additional hours, observed by the parasitology test by microscopy or by rapid diagnostic test.

[0118] The cure rate at 14 or 28 days ([Fig.3]) corresponds to the proportion of patients for whom elimination of parasitemia is achieved within 7 days of the study without relapse within 14 days, respectively 28 days following the start of study treatment.

[0119] Relapse is defined as a new clinical manifestation of infection after initial clearance of parasites from peripheral blood.

[0120] The results of the thermal clearance time, the parasite clearance time and the cure rate are given respectively in [Fig.1], [Fig.2] and [Fig.3].

[0121] The results of the study showed in particular that the average temperature of the patient population was less than 37.5°C after 24 hours of treatment with the pharmaceutical composition of the invention, and that the average parasitemia was zero 48 hours after the start of treatment.

[0122] Only 6% of recurrence or re-infestation of parasites was observed in the treated population after 28 days. The cure rate was 100% at 14 days and 94% after 28 days of treatment with the pharmaceutical composition of the invention.

[0123] The adverse effects observed were dominated by nausea (12%), asthenia (12%) and vomiting (10%), but without a clear link between these effects and the study treatment.

[0124] This study therefore shows that the pharmaceutical composition of the invention in the form of a spheroid containing 200 mg of artesunate is an effective and well-tolerated antimalarial when administered orally. The pharmaceutical composition of the invention is a good candidate as an alternative to intravenous malaria treatment with artesunate alone.

[0125] The pharmaceutical composition of the invention, in particular its particular galenic form, constitutes an original galenic formulation of artesunate freeing itself from the problems of packaging, reconstitution or complexity of administration of an anti-malarial treatment by intravenous artesunate or even from the problems of bioavailability or reduction of its systemic action of artesunate in molecular combination by a treatment in tablet form.

Claims

Demands

1. Pharmaceutical composition in the form of a spheroid galenic, absorbable orally, said spheroid internalizing, as the sole active ingredient with anti-malarial activity, a therapeutically effective amount of at least 200 mg of artesunate, for use as a medicinal product.

2. Pharmaceutical composition, according to claim 1 for use in the treatment of malaria in an affected subject, in particular in a subject with Plasmodium falciparum malaria, preferably in a subject with Plasmodium falciparum malaria with a parasitemia of at least 2000 asexual forms / mm3 of blood.

3. A pharmaceutical composition according to any one of the preceding claims, characterized in that said spheroid, internalizing at least 200 mg of artesunate, is obtained by successively carrying out the following steps: - A) At least 200 mg of artesunate is mixed with an absorbent and adsorptive substance having plastic properties, and optionally said mixture is moistened with a humidifying liquid such as ultrapure water, - B) said mixture is extruded until an extruded product is obtained, - C) said extruded product is spheronized until a monolayer spheroid internalizing at least 200 mg of artesunate is obtained, - D) Optionally, the spheroid is dried and / or calibrated and / or film-coated and / or the spheroids obtained are grouped into a capsule, a softgel, sachets, or tablets.

4. Pharmaceutical composition, according to any one of the preceding claims, characterized in that said spheroid is a multilayer spheroid.

5. A pharmaceutical composition in the form of an internalizing spheroid, containing at least 200 mg of artesunate, according to any one of claims 1 to 4, for use in a method of treating malaria in an infected subject, in particularly in a subject over 15 years of age suffering from acute uncomplicated Plasmodium falciparum malaria with a parasitemia of at least 2000 asexual forms / mm3 of blood.

6. Pharmaceutical composition, according to the preceding claim, characterized in that it is in a form suitable for oral administration.

7. Use of a pharmaceutical composition, according to any one of claims 1 to 6, as a parasiticide composition, in particular as a parasiticide composition against parasites of the genus Plasmodium, such as Plasmodium falciparum, Plasmodium vivax, Plasmodium knowlesi, Plasmodium malariae and Plasmodium ovale, particularly in an in vivo context of parasite presence.

8. A method for manufacturing a pharmaceutical composition according to any one of claims 1 to 6, wherein the following steps are carried out: - A) 200 mg of artesunate is mixed with an absorbent and adsorptive substance having plastic properties, and optionally said mixture is moistened with a humidifying liquid, - B) said mixture is extruded until an extruded product is obtained, - C) said extruded product is spheronized until a monolayer spheroid internalizing at least 200 mg of artesunate is obtained, - D) optionally, the spheroid is dried and / or calibrated and / or filmed and / or the spheroids obtained are grouped into a capsule, softgel, sachets or tablets to obtain said pharmaceutical composition.

9. A process according to the preceding claim, characterized in that: - In step A), the absorbent and adsorptive substance is a natural or synthetic polymer, such as microcrystalline cellulose, microfine celluloses, modified starches, polysaccharides, or a dry homogeneous mixture of a weakly substituted hydroxypropyl cellulose ether-type polymer. hydroxypropyl cellulose weakly substituted at the 13-O-glucopyranosil core groups.

Images