ORAL FORMULATIONS OF EDARAVONE AND METHOD OF MANUFACTURING THEM.

Abstract

The present invention relates to an oral suspension dosage form of edaravone. The invention also relates to providing a cost-effective and technically advanced dosage form compared to existing dosage forms on the market. Furthermore, the solubility and stability of the patient-compatible edaravone formulation prepared according to the present invention have been shown to be superior compared to prior art inventions. Additionally, the present invention provides a suspension composition prepared by a process that is relatively simple, commercially easy to manufacture, and functionally reproducible.

Description

FIELD OF THE IWEMCXÓNi The present invention relates to an oral liquid formulation of Edaratone in the form of a suspension. Furthermore, the present invention relates to providing an economical and technically advanced dosage form that surpasses the existing dosage form. Edaravana (CAE: 89-25-8) is a member of the trigiogen group of substituted o-pyrasolin-i-one compounds. Edaravana is chemically named as (i-methyl-i-pyrasolin-i-one) and is structurally represented as follows: ά T'k ™ EDARAX^O^: 2U fB The osara vein was described earlier during 1925 in DE47 3214.. German company describes a process: for the preparation of idetóldr^^ by : of ΐ~· phenyl··3~meti 1 pinasalidone in aqueous solution of hydrochloric acid and in the presence of two metal salts transporting oxygen. p®.r di use of oxygen 1 9d^^ of: metallic: that contain pxídantss as agents. In the United States, edaratone is marketed... currently under the name of the drug. This intravenous infusion is indicated for the treatment of acute lateral sclerosis (ALS). The recommended dose of edaratone is 60 mg, administered as an intravenous infusion over 15 minutes. Prior to US approval, Mitsubishi Tanate Pharm Corp. (Osaka, Japan) lañad la edarevoca en Japón bajo la marca AAOTCbT'* .como el primer (tarmap® pt Ó tactor nédrcvaseultt del mundo. The recommended dose of edaravone is 60 mg, to be administered as two consecutive infusion bags containing 60 mg of edaravone, i.e., 30 mg per infusion bag, over a period of 60 minutes. Each 100 ml infusion bag of RADICAVA contains edaravone, L-cysteine ​​hydrochloride hydrate, and sodium bisulfate. The pH of the formulation is adjusted with phosphoric acid or sodium hydroxide, and isoprene is maintained by the addition of sodium chloride. The edaravone dosing regimen consists of two cycles. Cycle 1 includes an initial treatment cycle with daily dosing lasting 14 days, followed by a 14-day drug-free period. Subsequent treatment cycles consist of two subsequent cycles. wa de si ideación diario durante ID días.· de les perindua de 14 días; seguido de periodos: libres do drogas de .14 días. Edarawna is intended to inhibit the oxidation of ambient oxygen. Therefore, Edarawna is supplied in single-dose plastic bags, each wrapped in polyvinyl alcohol (PVA). In addition, the secondary packaging contains an oxygen absorber with an oxygen indicator, which must be readied to reflect the levels of adsorbed oxygen. The oxygen indicator will turn blue or purple if the oxygen has exceeded acceptable levels. i 5 Al dn cdman fco DO 93331 fí tele indio ® O t odo -to treat diseases: of the» neurons mgtnnas> lateral amniotic sclerosis (ALS) which consists, essentially, of administering an effective quantity of edaravone g. one of its salts that are readily acceptable to a patient, CN124í565C discloses a modified pharmaceutical composition of Edaravena to facilitate storage and transport. According to this patent, cbl.«a.,-:> suspends: pl gol va úe eetwe® in water; for 4nueuci.pn g / material a / alkalisn., followed by the addition of 25 other scaffolding agent to prepare the dosage form 1ÍW1 Used. Said invention is not Gpnsidura friendly for, the tratWentp a long piano from the panto of compliance; of the relative. >r Xg: tantpf; enlate the need for a comparable invention with the patient. The document; WQ2OOW041 describes w formulaeiS® de sa <a& en Xa que éatancaud^ alaciad ®X< agente quOante y Xos:agentes reductores. Además, el emulsionante sé elige entre fósfellpido de yema de huevo o £ssfól i pido de soga. Sin embargo, 10 durante el almacenamiento a largó placa, la mala estabilidad de esta torea de deOfícáqlph de emulsión liquida es hg dpstaculd y requiere una nueva Oro de dosificación estable. Dicha patenté divulga datos de estabilidad durante aproximadamente 3 meses, únicamente, cu lo tanto, los inventores de la presente invención consideraron· que·'· existe una necesidaíl Insatlsfedna.. de W composición farmOOs ce edarayona que sea estable y en forma oral para proporcionar un mayor cumplímiento por parte del parient e... W El ásswnm OfSWlMSI di vulga una campos roiga farmacia oral que contenido un complejo de inclusión de eóravcna y ciclodextrina. Esta patent compren asociar Edarawns sen OCHIMOBA en- agua durante 1 a 1 h.:Mís tiempo: de contacto con agua debe a la Edarayona a hídroliiars®. This invention improves the solubility of Edaravone; however, it does not reduce its inherent oxidation. Therefore, there is a "1 róquís.itd dé tna nflew Inww^ proppluló a improved solubility with significant stability. de Bdaravcna in the form of dea i fi cae fon oral. This patent has not informed the data; of stability and, therefore, proves that a prepared ee í^M-abX^ ppmpeeicicu ^formaceptica ^X^a· ,1a Edafovona, £1 document ^02017 / 157350 discloses a lipid-based phagocytic acminiphoration system. which c'ende fiáwaw®. íx una de sub salea formase úricamente aeepfoblesi, bha?solid dispersion comprises Edafovona and a polymeric vehicle. However, the preparation of a solid dispersion of Edafovona requires a focus on the API portion size and the focus on the size; of ddlllluM dfoduuu un afoa::de puperfíeie más crinde para la EdaraVohá>. for lo fonte, produc una mayor prueba de neidación á la Idaravoga porque a una mayor superficie dé piezas. Por luego, esta, invención tampoco lpgra< ndhidlfor al efocfo oxídativ®; sobre, la Edarawna.The absence of stability data indicates that the lipid-based compositions of Edaravana are not stable. dpfomepfo dóldll / lldldl claims a pomposlcídn fopmpfogtípa eóLxpa; dd-spernabie in water consisting of disperuae the pharmaceutical composition in an aqueous liquid to produce a This formulation can be administered via sterile route, containing 0.5% of the pharmaceutical composition and at least 23 g / L of edaravone, followed by whole administration of the liquid to a human patient in an amount that provides a dose of 30-300 mg of edaravone. This pharmaceutical composition contains 33503% of the components of the edaravone and 3% of the water-soluble alkalizing agent. This patent has not reported stability data and therefore proves that the solid pharmaceutical composition dispersible in water prepared for edaravone is not stable. £1 document 302 1$ '134143 discloses a liquid pharmaceutical composition that is an uncomplicated monophasic aqueous solution of Edaravone comprising at least 15% by weight of water and 0.2-3 mg / ml of Edaravone, wherein the treatment comprises the oral or gastric administration of 10-250 ml of the liquid pharmaceutical composition to provide 30-300 mg of Edaravone. This patent has not reported stability data, and therefore proves that the liquid composition prepared for Edaravone is not stable. Whisky Sato et al. (Pharmacology 1911 / 55; pp. 53-14) describes the pharmacokinetics of Edaravone using a complex solution of Edaravone / hydroxypropyl-O-cyclidextrin, which includes L-cysteine ​​(L-Cysteine) and sodium acid sulfate (SAS). This study suggested that L-Cysteine ​​and SAS were useful for rectal and oral mucosal administration of Edaravan. These types of compositions are already reported in prior inventions and, however, face similar stability difficulties to those addressed in document WO2CU2 / CHW. Parikh et al. (International Journal of Pharmaceuticals, 1110(525) / p. 49a-50a) discuss the development of an oral delivery system for edaravone. The new system The oral administration system (NODS) of Edaravone comprises a mixture of Labra sel and an acidic aqueous system optimized based on a solubility and stability study. The oral bioavailability of the NODS delivery system was found to be 5.7 times greater than that of an Edaravone suspension containing 30 mcg / ml of mcg / ml of sodium carboxymethylcellulose. A higher concentration of mcg / ml in the oral formulation increases gastric disturbances in the patient and, therefore, reduces patient compliance. Therefore, the inventors of the present invention have observed a need for an oral pharmaceutical composition of Edaravone that is stable and does not produce side effects such as gastric disturbances. Parikh es al« (Jrug Jelfwry 2917; 14(1) / pp. 952-979) describe a study that I aimed to enable oral use s of the Edafavene the development of a lipid building block (WS:) . The components of LNS?including oil# the tenSlcactives. and the corun if cacti you, if :ui&uc <n?ruF en función de su potencial para éaxímnax la solubilieacíón en ..gastrointestinal fluids^ (GIVfreduce. su. glucurw and pe. spurr transmembrane permeability. A 1W liquid (Ir-LRi) was prepared in the form of a micro-emulsion comprising Capcyol^- 1GMC (Aeaote)tCrumophur·' RH 40: Lab-rasóle TPGR 1000 11=018:0.2} (Surfactant) and Transcutol® R (Co-surfaéante}. It was discovered that the bdudíispoTiíbi.lidRd eral del s <w® de abela i si recaen de L-L® era casi 11 veces mayor que la de una suspensión de Edaravona ose contenía 30 w / ml de Edaravona y 0.§ % da oarboxi^ sódica,. Debido a ,1a presencia·, de tantos ingredientes costosos, el costo final dé dicha: formulación aumenta a un nivel muy alto. For 15 le tanto, los inventores de la presenté invención señalaron que existe una necesidad insatisfecha de una composición farmacéutica eral de Edaravona que sea estable y rentable para los pacientes y, por lo tanto, que sea asequible y compatible con el paciente. Furthermore, it can be noted that the efficacy of Edaravone has been undeniably successful since its inception in the therapeutic category of stroke management. Edaravone itself has broad applicability and potential for use in other therapeutic indications. The injectable dosage form has been a limiting factor in the case of wider use of this product. It is important to highlight that developing an oral dosage form of Edaravone is a challenging process due to its less soluble and permeable nature (BCS Class IV product). In addition, an injectable dosage form has inherent difficulties in terms of its post-hospital use. Furthermore, Edaravone is also quite sensitive to hydrolysis and oxidation, and therefore, it is more difficult to formulate an oral formulation.The inventors of the present invention identified with sufficient effectiveness the previous limitations and, therefore, have developed a stable and effective oral dosage form to meet the needs identified in the prior art publications. ha presente ihvehcióh descilbé la administrad^ de Idafavcha in the form of a single oral dosage form that does not use sophisticated injections and is economically affordable compared to the dosage form. (it would seem). Furthermore, the oral liquid suspension dosage form formulated and prepared according to the present invention provides greater stability in comparison with the liquid formulation of Edaravana. Moreover, the oral route is preferred for administration in patients with chronic neurodegenerative diseases. In addition, physicians also prefer the oral dosage form over injectable dosage forms due to advantages such as ease of administration, greater patient compliance, and reduced need for i. a sp 11 ¿iii 2 action . A suspension is a heterogeneous mixture containing sufficiently large solid particles for sedimentation. The suspended particles can be visible to the naked eye, and their size is usually greater than 1 micrometer. A suspension is a heterogeneous mixture in which the suspended particles do not dissolve, although they remain suspended in most of the liquid medium. In general, the solid part is dispersed by mechanical agitation using suspending agents. In contrast, a slurry has a homogeneously mixed solute in which no solid exists. The present invention incorporates Edaravna with stabilizers that reduce its oxidation. Furthermore, the smaller particle size of the suspension increases the solubility of Edaravna by providing a better dissolution profile. Additionally, the present invention resulted in greater stability of Edaravna compared to the [prescription] form.<m - > n ídíoiteía' Adv.oa;-, the solubility and éetpfeilidad of the formulation compatible with the patient, prepared sanan The present injection, has been shown to be superior in comparison with the inventions of the prior art. Furthermore, ., ρΎ^' te mvitc. popa 'no? ate composition 5 da: prepared suspension: by a process that is relatively simple, easy to manufacture commercially and functionally reproducible. In addition, the suspension composition of the present invention may also incorporate two or more active ingredients. 10 Despite extensive research on Edaravone as reported in technical publications, an oral composition of Edaravone is not commercially available worldwide. Therefore, there has been an unmet need to develop a patient-compatible oral composition with good stability for Edaravone. Accordingly, the present invention provides an oral composition of Edaravone, preferably in a formulation form, as a suspension with pharmaceutically acceptable excipients, and a method for preparing the same. The main objective of the present invention is that the pharmaceutical composition establishes a dual release pattern due to the type of solubique used in the formulation and, therefore, produces a sudden absorption followed by a delayed absorption. In general terms, a pharmaceutical composition according to the present invention is in the form of a liquid formulation. In another aspect, a pharmaceutical composition according to the present invention comprises a mouse luda and one or more pharmaceutically acceptable excipients® 10, wherein the composition is in the form of a suspension, In another general aspect, a pharmaceutical composition according to the presenter: invention includes Edaravone and one or more I| pharmaceutically acceptable excipients: in: les: that the composition is in the form of an oral suspension. In a single part of the present invention, the active ingredient incorporated in the pharmaceutical product comprises particles of size from 2 to 10 microns, preferably in the range of 2 to 80 microns. In one of the modalities, the pharmaceutical composition manufactured according to the present invention is a suspension. c η ' ' ” ' m ♦ ·. i: ' , in which the composition of the manufactured material has a particle size that varies from nanometer to micrometer, which results in a greater dissolution profile. Another modality according to the present invention, in which the manufactured formulated product has a particle size ranging from nanometers to micrometers, which results in an improvement in the in vitro dissolution profile of around 80% to 95%. Additional modality according to the present invention, in which the manufactured formulation has a particle size that varies from nanometer to micrometer, which results in an improvement in bioabsorption of around 40% to 90%. In another embodiment of the present invention, the pharmaceutical composition is manufactured by a number of steps in the manufacturing process that include homogenization, sonication, mixing and / or evaporation by spray drying. An 'Od.ij a rntm. mi :n la presante itven.nr os que el producto formulado· es una suspension homogénea stabilizeda. In another embodiment of the present invention, where the pH of the pharmaceutical composition is in the range of 2 to 6.5, more preferably in the range of 3.0 to 4.5. In Ciro aspeóte ®fiwalfana pharmaceutical upmpqsición según la presente invención, it comprises Edaravone or one of its pharmaceutically acceptable salts. In another embodiment of the present invention, in which the carrier proteins present in the light composition of Cesttta improve the absorption of Edáfavone due to their optimal hydrophilic and hydrophobic properties. In other forms of the present i-'vehción, the absorption of the active molecules is facilitated by passive absorption; due to the presence of excipients and adjuvants. The modalities of the pharmaceutical composition may include Edaravone as an active ingredient with one or more excipients: diluents, stabilizers / suspension agents / thickeners, chelating / complexing agents, solubility enhancers, permeability enhancers, preservatives, diluents, active vehicles, sweeteners. anti-caking agents, granulators, preservatives, agents: early, aromatizing agents, similar. In another embodiment of the present invention, Edaravone has a tartan particle feature from BOA nm to 3,000.0 erg, more preferably from 2000 nm to 3000 nm. In the present embodiment of the invention, to minimize the oxidation of the sensitive material, it is also desirable to remove the heat from the headspace and the moisture or both from the material as quickly as possible; the purging of inert gas is carried out using argon, helium or nitrogen or mixtures thereof. 15: In the third modality of the presented Invention,: the fields of pharmaceutical cloning are presented in the form of an oral suspension that comprises::.áj aund o: »$ stabil i zadnmrr vi© enrioeidantée pharmaceutical^ ácsptaMes as, part ©Ai b) Edaravone with one or more surfactants, surfactants, plasma enhancers and foaming agents acceptable for producing part B of the drug; c) one or more pharmaceutically acceptable thickening agents as part - C; d) ukq or more acceptable pharmaceutical sweeteners, flavorings and colorants as part ·· D; e) One or more pharmaceutically acceptable liquid vehicles for arspenalót as part - E> In one embodiment, the process for preparing an oral pharmaceutical composition according to the present invention 10 comprises the following steps: a) Dissolve antioxidants and / or stabilizers in purified water to prepare part A; b) Dissolve the tehsioactive, the costensioactive, the edaravone 15 micronized together with the permeability enhancer and the foaming agent to obtain a suspension; c) Dissolve the suspending agent and the thickening agent in the previously prepared suspension to provide the appropriate viscosity; a): Add a sweetening agent < na ·. » „ previously and mix it through a vortex or a high-speed homogenizer c by mechanical or sonic tension of the such lament to obtain a formulated form of the product <hanosuspendida uní fárme; e) prepare a volume of the previous nauesuspension non vehículm aeuoou.. The details of one or more embodiments of the invention are set forth in the following ox(:3]c„r:. The characteristics of the invention will be evident from the description. BRIEF DESCRIPTION OF THE DRAWINGS: Figure XA illustrates the particle size distribution graph for Edaravone used in the present invention; FIGURE-IB- Illustrates the particle size distribution graph for the oral suspension of Edarayone prepared according to the present invention; DETAILED DESCRIPTION OF THE INVENTION: The present invention will now be disclosed by describing certain preferred and optional modalities, to facilitate various :a.speci^ la: :misma¿:. 20. Edaravone, chemically known as 3-methyl-1-phenyl-2-phosphate-olin-S-one, is a small lipophilic molecule: with a molecular weight of 124.203 and a soluble content of 25 pg / mL. Édaravena sé cónsidéfa: ú:u fárWcs dé diáse IV del Sistema de Biopharmaceutical Classification (BCS) due to its low solubility in water and lower permeability to lipids. The mean terminal half-life of the Edaraypna is 4.1 a & b» According to the present invention, a pharmaceutical composition of Edaravone comprising Edaravone as an active ingredient with acceptable pharmaceutical ingredients. ΐ é r. ?> i no •'excipients f armanéut i carnenta aeeptan 1 es ” H) aecón is used in the present document, Sé refers to the excipients that are used in the laboratory combos:! clones i..- pharmaceutically acceptable excipients. They may include diluent vehicles, thickeners, suspension agents / antioxidants, chelating agents, solubility enhancers, and combinations thereof. At the time of preparation of the dosage form, the excipients of the oral suspension are mainly divided into the following parts according to their uses in the manufacturing process: (B) Enabling agents (W) Suspending agents, (D) Sweetening agents and flavorings, and (E) Diluent vehicle. The list of those used is shown in the tables below, although it is not limited to these excipients. The appropriate diluent vehicle may include one or more of the following aqueous vehicles: sugar, methylcellulose gel, citric acid, sucrose, sorbitol solution, sodium carboxymethylcellulose solution, xanthan gum solution, aqueous hydro-vegetarian vehicles such as refined fractionated coconut oil, hydrogenated castor oil, lecithin, phenyl stearate, and silicates. The inventors of the present invention observed during the development of the present invention that it was difficult to stabilize Edaravone for a long period of time. Edaravone has a tendency to decompose easily by oxidation in aqueous solution compared to powdered form. Taking these properties into account, the suspension can be further stabilized by the use of antioxidants. The antioxidants can be present at a concentration of approximately 5 to approximately 15 mg / ml, more preferably approximately 7 to approximately 12 mg / ml, most preferably approximately 10 mg / ml. Suitable cstfeilifedátes d aátioxldaát es may include one or more of titric acid, hi dioxl t ol üéno burilado. Hydroxy anisobutyl alcohol, sodium bisulfite, ascorbic acid, L-cysteine, magnesium bisulfite, sodium metabisulfite, thiazolidine, ubiquinone, rosin, glycine, lapoic acid, phosphate chalate, thallium urea, and similar substances. It is common in the technique that the surfactant reduces the interfacial tension. Two inventors of the present invention used the surfactant in such a way that it adsorbs onto the particles and minimizes flocculation due to the natural tension between the positively and negatively charged particles. The inventors of the present invention noticed that some particles that join together and form large particles do not have enough surface energy. To overcome this difficulty, the inventors of the present invention have added suspending agents, or thickeners, to increase the viscosity of the continuous phase so that the particles remain suspended for a sufficiently long time. These extruded vehicles trap the particles and reduce particle settling. However, these structured vehicles also reduce particle settling. cough. suitable suspension agents: thickeners: suitable may include one: or: more of alginab podium, methylcellulose, hydroxide iei i1ce1u1ose, hydroxiprop11me ti iceIulose, carboxymethylcallulose, sodium οηΓόοχΙηοϋΙοοίηΙοήη, cellulose mierocdstd ina, sorrel, tragacanth, xanthan gum, boaionite, saithe, carrageenan, gda:tlna and the like. The inventors of the present invention observed microbial growth in the prepared formulation during prolonged storage. Therefore, it was deemed unstable to provide susceptibility against a wide range of microorganisms. For this reason, preservatives that are non-toxic and compatible with other excipients were used in this formulation. The appropriate preservatives may contain one or more of the following: EDTA, benzoic acid, parabens, iodine, parabens, sodium benzoate, dimetal bisulfite, and the like. According to the Invadd standard, the alkali metal bisulfite may be composed of sodium bisulfite, potassium bisulfite, and combinations thereof. Most preferably, the alkali metal bisulfite used in the suspension is sodium bisulfite. Suitable anti-agglomerating agents may include one or more polyglycolic acid dioxide, tribasic calcium phosphate, magnesium silicate, starch and other similar substances. It is known in the art that wetting agents or substances reduce the interfacial tension between the particle and the solid-liquid interface, thus increasing the affinity of the particles for the surrounding medium and decreasing intra-solid forces. The particles, even high-density ones, float on the surface of the liquid until they completely displace the air layer. The use of a wetting agent allows this surface tension to be eliminated and facilitates the penetration of the vehicle into the surfaces. Suitable wetting agents may include one or more of the group comprising anionic, cationic, or ionotropic surfactants. Suitable examples of wetting agents include: sodium lauryl sulfate, sodium phosphate, cetrimide, polyethylene glycol, copal, polyoxyethylene-polyethylene block lipids such as poloxamers, polyglycerin fatty acid esters such as decaglyceryl monourate and decaglyceryl monomyristate, sorbitan fatty acid esters such as sorbitan monostearate, and fatty acid esters. of polyethylene sorbitan such as polyethylene sorbitan nonoolcate, esters of polyethylene sorbitan acids such as; eat wagesstearabo^ of pq:lioxi.et:.í.le:no7:áte rea al.qníXíooa of ppligrietá log: palea w» polyoxyethylene lauridiene ether, polyoxyethylene castor oil and the like. Suitable antibacterial agents may include one or more from the group that contains acid: chloride, citrate, sodium chloride, potassium nitrate, acetate buffer and the like, 5 Suitable permeability enhancers may include one or more of the group comprising alcohols, polysaccharides, short-chain glycerides, amines, amides, chloromethyls, fatty acids, pyrethroids, asses, sulfoxides, surfactants, turpentine and the like... Suitable arnica carrier molecules may include one or more from the group comprising piperine and the like. Lgg tcnsigaccivuá o CótensieaótidpS:· adecúa dos pueden 'rci:'' ”' . ' rs- yii'íU'üC ”,\,s > a ., : cs^, rn' nnumn o amphóteres. Non-limiting examples of surfactant can include polypropylenes, polyethylene glycol, and polypolymer blocks, sterinated and saturated, diluted from 20: vaccinia, g, ag. des:! vades· of the vitamin, t: such as the succinate of polyethylene glycol of Cocoterol C'PGS;, sodium dodecylsulfatg or lauryl.Indication of sodium; a bile acid is a salt of the same,, by: the use of epithelial acid, glycolic acid is a salt; and similar:.. Suitable flavoring agents may include one or more from the group consisting of mint, grapefruit, orange, lime, ileum, mandarin, pineapple, strawberry, raspberry, mango, passionfruit, kiwi, apple, porridge, peach, apricot, sloth, grape, banana, red berries, cranberry, blackcurrant, redcurrant, gooseberry, lingonberry, cumin, thyme, basil, camilla, valerian, binoje, parsley, chamomile, tarragon, lavender, dill, argan, sage, balsam of the refrigerator, spearmint, piparin, eucalyptus, and the like. Chelating agents that meet suitable requirements: they may include one or more of the group comprising odextrin, ethylenediaminetetraacetic acid and derivatives thereof, for example, sodium edecate, dihydroxyethylglycine, gluconate, citric acid, tartaric acid, glycol, phosphoric acid and the like. Suitable solubility enhancing agents may include one or more of the group comprising surfactants such as (1) non-ionic, for example, fatty acid esters of polyoxyethylsorbitan, sorbitan esters, gloriolin ethers, and (2) anionic, for example, sodium lauryl sulfate, sodium laurate, sodium sulfate, in particular bis-ethyl sulfate, sodium stearate, potassium stearate, and sodium oleate, (3) cationic, for example, L-al nonium chloride and bis-hydroxyethyl hydroxylaylamine, and (4) ionic ,α£chiok&; fatty alcohols such as lauryl, cetyl and stearyl alcohols; glyceryl esters such as mon-, di- and tri-glyceryl esters of natural origin; fatty acid esters of fatty alcohols and other alcohols such as: propylene glycol, polyethylene glycol; sucrose; ρ '1.,c¿s, for example, poloxamers, polyvinylpyrrolidones, glycerides, for example, triacetylene, glyceryl monocaprylate, glyceryl monodilate, glyceryl mennestearate; diethylene glycol monoethyl ether; and the like. Suitable antifoaming agents used in the present invention may include one or more of the group comprising linear siloxane polymers: motylated end-blocked with trimethyl units such as dimethylacetylene and glycol, as well as dimethylacetylene metals with an average chain length of 200 to 80 dimethylacetylene units and silica. The required amount of antifoaming agent is an amount sufficient to provide a concentration of about 1 mg / ml to about 8 mg / ml, preferably about 10 mg / ml. cough. pot'U' 'viscosity depressants' suitable for use: The ingredients in the present invention may include one or more of the group comprising xanthan gum, liquid sugars, starches, celluloses, and mixtures thereof. The xanthan gum is present in an amount of approximately 1 mg / ml and more; preferably the xanthan gum is present in an amount of approximately 3.7 mg / ml, the most common suspending agents are aqueous biological polymers including sodium methylcellulose (CMC), sodium bimethylcellulose (CMC), and hydropropyl methylcellulose (HPMC). A range of viscosity enhancers with different molecular weights are used in the range of 3 to 3 mg / ml. Ρ'Όί «í1alomen Le, $ r 'c1 ' nt <ή v <o edad de :^saimáwen¡t^ 10 mg / ml. ’ y. ene ^n? η ' fe \ .<v-,., j'ufe dé la presente invención facilitan la suspensión efe la formulación después de la confetución con una agitarlos mínima y evitan la 15 rápida sedimentación y apelmazamiento de la suspensión con el tlempo. The main objective of the present invention is that the pharmaceutical composition establishes a dual release pattern due to the type of soluhlliaa^ used in the formulation and, therefore, produces a sudden release followed by a follow-up release. One embodiment of the present invention may include a pharmaceutical composition comprising approximately 0.1 mg to 500 mg of Edaravcna apn and pharmaceutically acceptable excipients. Another embodiment of the present invention includes a pharmaceutical formulation comprising Edaravone with acceptable but non-adjustable pH adjusting agents or isotenoid agents. In another embodiment of the present invention, Edaravone is present in: an amount that: between 1 mg / ml and 30 mg / ml. In u'm modality re « where the Active ingredient: incorporated into the pharmaceutical product comprises: a particle in the range of: 2 to 100 mills, preferably, in the range of 2 to 100 mills. In another embodiment of the present invention, Edaravone has a particle size in the range of 800 nm to 10000 nm, preferably: 1000 nm to 8000 nm. In a preferred modality, the DxóO; of the size of the 3rd revena par!Ínula is Less than 8100 nm or S mis tas-. In one. of the modalities, the pharmaceutical laida compass manufactured according to the present invancidus ana nano~suapehsion.. In another embodiment of the present invention, in which the manufactured pharmaceutical compound is a nano-suspension, this results in a greater dissolution profile. Another modality according to the present invention, in which the product forms the manufactured side, is a nano “suspension”, which gives Id as a result .una: puj era in the dissolution profile a mitre: of around 8:5% to m. An additional modality according to the present invention, in which the manufactured formulation is a pahp-suspenaiqn, which gives 15 as: fédultado una: méipra óú la blg-abaélí^ dé- around 40% to 90%, preferably, 901, In another embodiment of the present invention, the pharmaceutical composition is manufactured by means of a number of 20 stages in the manufacturing process which includes homogenization, synthesis, mixing and / or evaporation by spray drying. An additional embodiment according to the present invention is that the formulated product is a stabilized homogeneous suspension. In another embodiment of the present invention, where the pH of the farmoltcm composition is in the range of 1 to i. i, more preferably in the range of 3.0 to 4.3, more preferably around 5. In another modality, the process comprises a step to provide Sears vana, in which the Edarawna is contained in part A which can be pr- t -v ose by mixing loara vería can one or more 10 pharmaceutically acceptable excipients. In another modality, the process includes a step to provide Edsravone, in that part B of the stabilizers can be prepared by mixing one or two pharmaceutically acceptable stabilizers. In one embodiment, part C means one or more pharmaceutically acceptable suspending agents or thickeners. In another embodiment, the process comprises a step to provide Sdaravona, in which part D can be prepared by mixing one or more acceptable pharmaceutical sweetening, flavoring, and coloring agents. In one modality, part E means one or more acceptable pharmaceutical vehicles. In another embodiment of the present invention, to minimize oxidation of the sensitive material, it is also desirable to remove oxygen from the space and moisture from the sealable container as quickly as possible. This can be achieved, for example, by purging the sealable container with a gas that is substantially oxygen-free, or substantially moisture-free, or substantially oxygen- and moisture-free before, during, or after the passage, or a combination thereof. It can be expected that the purge will reduce the oxygen level in the sealable container to approximately 0-5% to approximately 10%, typically around 5% or less, depending on the efficiency of the washing and the speed with which the container is sealed after washing. The gas used to purge the sealable container can be any suitable inert gas known to experts in the field; the most commonly used gases are argon, helium, or nitrogen, or mixtures thereof. However, the most preferred inert gas is nitrogen. The stability of the present pharmaceutical composition has been achieved by controlling the total oxygen content in the drug suspension and the headspace of the glass bottle using nitrogen. It may be important to note that the pharmaceutical formulation in suspension form is generally prepared by filling the contents into a glass bottle or vial and then replacing the ambient air in the headspace with an inert gas such as nitrogen gas to avoid any stability problems that may arise during storage. The purging of nitrogen gas was carried out continuously throughout the preparation procedure to maintain the stability of the suspension. The suspension was then filled into glass vials, and the headspace of the glass vials was covered with nitrogen to achieve the desired stability during the shelf life. In another modality, the process comprises a step to provide the formulation mentioned above, wherein the formulation is an oral suspension that can be prepared by means of the steps comprising: In one embodiment / "1 process for the preparation of an oral pharmaceutical composition according to the present invention, it comprises the following steps: a) Dissolve anti-orientants and / or stahilimators in purified water to prepare the parió or; b) dissolve the tenaipac^ the cotensÍQacpi^ the e <rwpa micrcnizada. junio con el potenciadpr de la permeabilidad y 5 el agente antiespumante para obtener una suspensión; c) Dissolve the suspending agent and the thickening agent in the previously prepared suspension to provide adequate viscosity; d) add a sweetening agent to the prepared suspension: previously and mix it through a vortex or a high-speed homogenizer or by mechanical tension c :sp'Sicada.:o of citation! lamiente to obtain a: form; of a uniform nanosuspended dosage; e) prepare a volume of the above nanosuspension with 15 aqueous vehicle. The advantages of the present invention include consistent homogeneity of the suspension and ease of dispersion. The solids that settle in the liquid suspension of the present invention do not form a solid cake that is difficult to rediaper. For a period of at least three days, there is practically no sedimentation of solids in the liquid suspension of this invention. This ensures patient compliance. The liquid suspensions of the present invention have a longer shelf life. Furthermore, after re-agitation, the liquid suspension provides substantially the same quantity and efficacy as the initially prepared suspension. These characteristics of the liquid suspensions of the present invention provide advantages for pharmaceutical, medical, and patient care. The invention will be further described with respect to the following examples; however, the scope of the invention is not limited to them. All percentages indicated in this specification are in step, unless otherwise specified. Although the present invention has been described in terms of specific embodiments, certain variations and equivalents will be evident to the various examples in the art and are intended to be included within the scope of the present invention. EXAMPLE 1; Table -1 Parres Serial No. Ingredients Weight Range (Hp / V) Part A (Part of oxidants and stabilizers) 1. Anhydrous citric acid 0.03-0J2 7 3. Sodium bisulfite L-Cyslein HC1 0J 0-030 0.10-0.30 Part B (Part of the drug) 4. Edaravone (micronized) PEG400 1.50-4.50 7.00-30.00 6. Sorbitan monooleate pohoxieWenado (Tween 80) 0.20-LOO *? Aerosdl 0.30-1.50 δ. 9. Labrad M 1944 is Black Pepper Oily Resin 0.50-3.00 0.15-0.45 10. Simefieone 100% 0.30-2.00 Part C (Suspending Agent and part of the wetting agent) 11. Hydroxypropane (E15 premium) 0.50-4.00 12. Xamua Gum 0.20 30 Part D (Part of the sweetening and flavoring agent) 13. Citric Acid 0.10-00 Part E _______________(Vehicle M 14. Purified Water Qs < 100 ml of ; I. Anhydrous citric acid, sodium bisulfite and L-cysteine ​​HCl were dissolved in purified water to prepare Part 2.To the previously prepared Pacté A, Tween 80, PEG 400 and aerosol were slowly added to form a suspension vehicle. 3. To the suspension vehicle prepared in step 2, Edaravone was slowly added, ensuring complete dissolution of the drug. 4. To improve the solubility of the drug, a potent antifoaming agent, Labrafil M 104, was slowly added to the suspension containing the drug, followed by the addition of black pepper urea, which was added to enhance the solubility. 3. In addition, all steps were carried out on a shaker, and to reduce foaming of the suspension prepared according to step 4, an antifoaming agent was added. €:.To trap part of the drug molecule; in order to maintain maintenance release just after explosive release, a polymer, HEME E15 premium, was slowly mixed into the previous suspension that was prepared in step 3.7. In addition, to increase the flocculation time and reduce the agglomeration time, a thickening agent, xanthan gum, was added to the suspension, as shown in step 6. a \ ο-. . « ι. n ^rera' en t eti -un 1 and was mixed through a vortex, high-speed homogenizer with mechanical, sonicated or shear stress at 810-00 RPM for approximately 15 minutes to obtain a uniform nanosuspended dosing mixture. 9. The suspension obtained in step 8 was completed to a volume of 100 ml using purified water.BJgMPLO 2 : Table -2 Part No. Series LagresOeate Weight Range (Hp / v) Part A (Antioxidants and Stabilizers Part) Part B (Drug Part) 1. Citric Acid 0.03-0.20 2 L-Cysterna 0.10-0.40 3. Sodium Bisulfite 0.40-0.40 4. Edaratona 1.00-5.00 5. Tween 80 0.10-2.00 Part C (Agent and part of the active ingredient) 6. Hydroxypropylmethyl Ichüose (3 cps) 0.25-5.00 Part D (Activating Agent Part and Part E (Vehicle) 7. Sucralose 0.10-4.00 8. Entrefina 0JM4Ó 9. 10. Piperita Dotted Water 0.10*0.50 Q;$. to 100 ml Common process for the preparation of Eawiplo-2 to Example-11: 1. S® disolph or Edaravone was mixed with other remaining ingredients of Part B to form the Drug part. All inactive ingredients of Part 1 were mixed geometrically to obtain an antioxidant part and is Lab: of nrmm. 3.The drug portion (prepared according to step 1; and the antioxidant and stabilizing portion (prepared according to step 2) were mixed by vortex or high speed or mechanical or sonic tension or shear to obtain mixture 2. 15: The mixture 1 (obtained according to step 3) and the mixture 2 (obtained according to step 4) were mixed together with water by vortex or high speed or mechanical or sonic tension or shear to obtain · a form of dosage for mu luda: ..suspended, Table ~3 Parts No.Serte Ingredients Ma»góde pm (Wp / v) Part A (Pan of oxidizing starches and maní nzadores) L Citric acid 0.03-0.30 ? WV 3. HWoxyanisoí Uidlated Ascorbic acid 05-0.75 0.10-0.50 HydroxitduemW 0.20-0.80 Part B (Part of fannaco) 5. Bhravona 1.00-5.00 ó. Polyethylene glycol 6.00-25.00 Part C (Sensitive agent and part of the preservative agent) Midroxipm (3 cps) 0.55P0 Part D (Part of the sensitive agent and coloring and flavoring*) 8. Sugar 10-11G 9. 10. En iris na Rpenna 0.20-0.40 0.10-0.50 Part E (Vehicle) 11. Purified water Qs a 100 EXAMPLE 4 or 5: -4 Parts Wte -5 ingredients Weight range (^p'v) Ingredients Weight range C*pA) Citric acid 9.03 0.30 Part A Antioxidant ^v saturated^ Citric acid 0.03- 9.20 L-Cysteine ​​0.10- 0.40 L-Cysteine ​​0.10- 0.40 Sodium bisulfite 0.10- 0.40 Sodium bisulfite 0.10- 0.40 Edarawaa Alcohol 1.00- 5.00 5.00- 40.00 Part B (Pare dd iarw Oí Edainvoua Alcoba 1.00- 5.00 5.00- 40.00 Hydrogenated (3 qn) 0.25- 5.00 Partó íAgente de SU-peí'Sme v parte del ageñu Hidras iptop í rnet ikei ulo>a (LS cps) 0.10- 3.00 Sucraiosa w- L00 PíirteD (Parfedel agiote ed'ík'arante s sK?wfetóte) ^ucraiosa 0.1 0- 1.00 Erythrosine Pipmna 0.20' 0.40 0.10o.so Prihxssina 0.29- 0.40 ^perina O.IO0.50 Purified water Qs to 190 wl Part £ (VehMo) ---A---------- Purified water Q,S. to 100 ñtí. Table -6 Parles Table -7 Ib gred totes Raugode weight (M*) I aggressions* Weight range (Wy) Citnco acid 0.03-0.15 Part A i Paris of as* ios. úfenles > estab:lizsdotesi Cuneo acid 0.03-0.15 L-Cistide 0.10*0.30 Butylated hydroxyanisole 0.10*0.70 Sodium bisulfite 0.WO..5Q Ascorbic acid 0.05'0.20 Butylated hydroxytoluene 0.10*0.70 Eda cavernous 1.00'5.06 Paite B (Parre del fármaco) Edaravone 1.00*5.00 ' Twem 80 1.00-16.00 Ween SO 1.00*10.00 Sodium cadmium 9>W. Part C (Suspension Agent) Sodium Ctómimetüeehüüsa 0.10-3.00 Su eral osa 0.10*0.80 Part D (Part of the sweetening agent that is effective.) 0.01-0.50 Entrance Ο.1ΟΌ.50 Water pmiScada Qs to 100 mi Part E (Verdculc) Water already supplied Qxa too mi EJEMPW 8 y 5' 10 15: -8 Parles Tabla-O Ingredients Mango by weight (^pA) Ingredients Rank by weight (^p / v) Acido dtiw 0.03-0.15 Fa ite A (Pane of an ti oxidants and stabilizers) Acido cúneo 0.03-0.15 L-Cisíeim 0.10-030 BHA 0 05-0.70 Bisulfite of sodium 0.10-030 Acido ascorísco 0.05-0.20 BHT 0.10-050 Edaravona 1.00-5,00 Parte B (Part of the drug) Edaravem 1.00-5.00 Tweea §0 1.00-16,00 Pcúietilengiicol 500 (PEG500) 7.00-30.00 Alginaio of sodium 0.20-4.00 Parte € (Assent of suspension) Al^aato of sodium 0.10-3.00 Snaab^ 0.10-030 ParteD (Parte of age eduleomte and ......amwtizaúté) Su eral osa 0.10-1.00 Entrbém 0.20-0.40 Eriirosíná O.2O-O.4O 0.10-050 Pipería» 0.01-030 Piperwa Aguapé Qs, a 100 mi Part E (Vehinrío) Agua purificada Qx a 100 mi EJEMPLO 10 γ 11; Mine 40 Parts Tato 41 Weight range (Wv) lagredimtes Weight range f^ep / v) Diric acid 033- 045 Part A (Part of smíaddasws stabilizers) Entic acid L^Cystem B isulnt sodium hydrotodylated 0.03015 o.w030 0.10030 0.100.70 L-Cystem 0.10030 sodium... Hidnfdprupilm^ 0.10- 3.00 PeneC (Asede * suspension'! Hydrtóptc^dm^ (3φ§) o.w330 Sucólcáa 044 030 Part D Pane ael asate sweetener v ammmúzatus.? Part £ (Vehicle) Sucralcsa 0. ΙΟΙ 30 Eríntsm 0.20« 0.40 Erythrosine Pipetin 030040 0400.50 Piperite 0.010.50 Cicated water Qs at 100 mi Puriscated water Qs at 100 mi EXAMPLE 12: In a particular fashion, the present invention can be prepared using the following exact formula: Table -12 Parts Number Series Vsar mg / mi Part e A 1. Anhydrous citric acid Antioxidant and lampón 0.0.5 8.5 ? Sodium bisulfite Preservative and stabilizer 20 3. L-Cystem HCl Antioxidant and stabilizer 1 10 4. Purifying water Vehicle 17 i 70 A Si meu with a 100 % .Agent ... antifuming O § 6< PEO 400 Solubilizer. 1. Humectant 15 150 X Sorbitan phosphate-erylated sorbitan (Tween 80 / HLB15) Solubilizer, wetting agent 0.7 8. Labrañ 1 M 1944 is Humectant 10 9. Edarávóha (micro-treated) API 3 30 .........io....... Aerosil Suspending agent 0.5 5 11. Peppercorn syrup Mask unpleasant taste Part 3® 12. HPMC Premium Viscosity enhancer, thickening agent........ 1 10 13. Tartar gum Viscosity enhancer, suspending agent $37 3.7 14. Purified water Vehicle 40 400 Part € 15. Suraíosa Sweetener 0.2 i tí. Purified water (QS) Vehicle 17 <2S 1^2.8 Process for preparing Example-12: 1, It was given, first solved the. cdarwoi^ 'ideaba in a tense oaut i re y uro agenté hWéótánOé; 2, all the other ingredients of part A were geometrically dissolved in the vehicle and added to the previous step I to obtain a smooth paste or suspension; 3. The suspension was transferred to a scalable mill or a disperser or any other suitable equipment to thoroughly soak the particles and make a uniform suspension; 4. The suspending agents or flocculants were then dissolved in an aqueous vehicle; or:, al vállenlo púd rentaniauél agenta da suspension flocculant agent: se anadió a la suspension del paso 3 anterior seguido de la adición Cal edulcorante; or. the volume was completed to the final dispersion volume and the vial was filled; 7. The ambient air in the vial's headspace was cleaned with an inert gas such as nitrogen gas to avoid the sterility tests that can be caused during long-term storage. EXAMPLE 13; The suspension prepared according to the present invention was subjected to a verification dissolution profile using a Ü3P type II (paddle) apparatus. Here, the dissolution medium used was 0.1 g HCl and the dissolution volume was 90 ml. ' and ep.rs a. pe <. .. mg of edaravone dissolved in 1 ml of the same. From the following results, the inventors of the present invention surprisingly obtained the dissolution of the suspension of not less than 90% in the initial 30 minutes. Table «13 Interval of i Composition prepared sega»... time | Example 2 gg^gΊ EXAMPLE 14; The suspension prepared according to the present invention was found to be stable and yielded the following results: Table -14 | Composition Time interval .{ prepared according to.,. ............. ; Example -1 Initial After 3 months After 0 | •month | 1005 | | Example -2 100.10 100.02 «ms§ | [ Example -12 100.55 _______100.35______ WbO j The previous results are representative data of the aumpóMciun 'prepared according to Examples 1, 1 and 12,..· The compositions prepared according to the present invention are subjected to pharmacokinetic studies in animals to establish the absorption by oral route and it is observed that the degree of absorption after oral administration ranges between 6 and 901. The invention described herein comprises several objects as mentioned above and their description in relation to the characteristics, compositions, and process adopted. While these aspects are emphasized in the invention, any variation of the invention described above should not be considered as a departure from the spirit and scope of the invention as described. Loó: njeOléd .menciópadós ónterlormepte. se .pbdpQidipúÁn:úní:camexité< con iínes ilustrativo y estos egomplós no son de ninguna modo limitativos de- la .proseóte invención.

Claims

I. A novel pharmaceutical composition of oral suspension of Edaravone comprising Edaravone or a pharmaceutically acceptable salt thereof and at least two or more pharmaceutically acceptable excipients are selected from: a. one or more of the antioxidants in the stabilizer portion in a concentration not exceeding 3.15% w / v; b. one or more humectants or thickeners in the solubilizing portion in a concentration not exceeding 20% ​​w / v; c. one or more of the suspending or thickening agents in a concentration not exceeding 2.1% w / v; d. either orally, one or more of the antifoaming agents in a concentration not exceeding 1.1% w / v; e. either orally, one or more of the sweetening, flavoring, and coloring agents in a concentration not exceeding 0.5% w / v; f. one © more of the van ions in a concentration not exceeding 0.5 lp / v; in which Edaravena is in a miaroni i rada form in a concentration not less than 2% w / v or not less than 25 rag / ml.

2. A novel pharmaceutical formulation of oral suspension of Edaravena according to claim 1, wherein the particle size of micronized Edaravena is less than 000 nc 5 3. A novel pharmaceutical composition: of an oral suspension of Edaravones according to claim 1, wherein the stabilizers are selected from one or more of anhydrous citric acid; sodium bisulfite, 1-ostein HCl, diethylhydroxytoluene, butylcorticoid, ascorbic acid and similar.

1. A novel pharmaceutical suspension composition of Edatavone according to claim 1, wherein the wetting or thickening agents are selected from one or more of PEG-15, ... CPSÍ,· Sodium tuina, xanthan gum, .Aereaíl, aarbgrimetólóe^ sódica: y simílareO:.

6. A new pharmaceutical competition for Edaravone suspension according to reivl® cacxon 1, in which the antifoaming agents are selected from one or more d® simeticen® al 19® , dimethiecne and the like.

7. A novel pharmaceutical composition of edaravone oral suspension according to claim 1, wherein the aromatic and flavoring agents are selected from one or more of the following: black pepper resin, stearate, ergot, and pine nuts.

8. A novel pharmaceutical composition of Edaravone oral suspension comprising the following formula: Inactive Ingredients (w / v) up to Anhydrous citric acid 0.05 Sodium bisulfite 2.00 100% <vV PEG-WD 15,00 Móndete de wbtán polioxíeíikaado (TweenSOÜLB 15) 0.70 Labrafil M 1944 es WO Aero&ü aso Okorresiua de pimienta negra OJO HPMC E15 premium LC® Goma tastana w Susralosu 0,20 Agua purificada 75.00 en el que la Edaravona está an forma miaron i nada en una conoenir ciclón no inferior al 2 i p / v o no inferior a 25 mg / ml y el tamaño de particwla DI 00 da la edaravona micr^ es inderior a> EdEO nm.

9. A novel pharmaceutical composition of Edaravone oral suspension according to claims 1 and 5, wherein the suspension formed during the preparation process of the fields is uniformly ground.

10. A novel pharmaceutical composition of Edaravone oral suspension according to claims 1 and 8, wherein the ambient air in the headspace of the vial is digitally replaced with an inert gas selected from one or more of the following: nitrogen, argon, or helium.