Pharmaceutical Formulation with Improved Solubility and Bioavailability

Abstract

The present invention relates to a pharmaceutical formulation comprising at least one active pharmaceutical ingredient (API) having low aqueous solubility or a pharmaceutically acceptable salt thereof in the form of particles of a size between 1 and 800 nm, wherein said particles are encapsulated within a large microparticle of a size between 1 and 100 μm formed by a matrix comprising at least an excipient. Therefore, the API is entrapped or encapsulated in the microparticles of excipients. This pharmaceutical formulation contains the pharmaceutical active ingredient having improved solubility and subsequently supra-bioavailability.

1 . A pharmaceutical formulation characterized in that it comprises:
 at least one active pharmaceutical ingredient (API) having low aqueous solubility or a pharmaceutically acceptable salt thereof in the form of particles of a size between 1 and 800 nm, wherein said particles are encapsulated within a large microparticle of a size between 1 and 100 μm formed by a matrix comprising at least an excipient, wherein the active pharmaceutical ingredient having low aqueous solubility is selected from the group of Biopharmaceutical Classification System classes II and IV.   
     
     
         2 . A pharmaceutical formulation, according to  claim 2 , wherein the active pharmaceutical ingredient is selected form the list comprising: abiraterone, albendazole, axitinib, atovaquone, acetazolamide, atorvastatin calcium, amphotericin, aceclofenac, betamethasone, candesartan cilexetil, carbamazepine, carisoprodol, cefixime, ceritinib, crizotinib, celecoxib, cephalexin, clopidogrel, cefuroxime axetil, danazole, dapsone, diclofenac, dronabinol, etodolac, etoposide, ezetimib, fenofibrate, felodipine, furosemide,
 griseofulvin, irbesartan, itrconazole, ibufrofen, valsartan, ritonavir, paclitaxel, nilotinib, omega 3 polyunsaturated fatty acids, simvastatin, lamotrigine, lansoprazole, ketoconazole, troglitazone, nimesulide, loratadine, probucol, ubiquinone, ketoprofen, tinidazole, mesalamine, metaxalone, loperamide, methylphenidate, methylprednisolone, mycophenolate, nabumetone, nelfinavir mesylate, pioglotazone HCl, piroxicam, rifabutin, rifampin, risperidone, ritonavir, tadalafil, tacrolimus, telmisartan, vitamin D, vardenafil, triamcinolone acetonide, ofloxacin, nevirapine. or combinations thereof.   
     
     
         3 . A pharmaceutical formulation, according to  claim 1  or  2  comprises at least one active pharmaceutical ingredient having low aqueous solubility or a pharmaceutically acceptable salt thereof in the form of particles of a size between 1 and 500 nm, wherein said particles are encapsulated within a large microparticle of a size between 1 and 20 μm formed by a matrix comprising at least an excipient. 
     
     
         4 . A pharmaceutical formulation, according to any of  claims 1  to  4  wherein each microparticle encapsulating the API or a pharmaceutically acceptable salt thereof comprises between 20-85% by weight of the API or a pharmaceutically acceptable salt thereof and between 15-80% by weight of one or more excipients. 
     
     
         5 . A pharmaceutical formulation, according to any of  claims 1  to  4 , comprising:
 a) 10-85% by weight of microparticles encapsulating the API or a pharmaceutically acceptable salt thereof; 
 b) 15-90% by weight of additional excipients. 
 
     
     
         6 . A pharmaceutical formulation, according to any of  claims 1  to  5 , wherein the excipients are selected from diluents, binders, lubricants, disintegrants, glidants, surfactants, thickeners or combinations thereof. 
     
     
         7 . A pharmaceutical formulation, according to  claim 6 , wherein the excipients comprise at least one disintegrant selected from natural, modified or pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, effervescent disintegrating systems or any combination thereof. 
     
     
         8 . A pharmaceutical formulation, according to any of  claims 6  to  7 , wherein the excipients comprise at least one binder selected from: starch, pregelatinized starch, polyvinyl pyrrolidone, copovidone, cellulose derivatives, such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose and carboxymethyl cellulose or any combination thereof. 
     
     
         9 . A pharmaceutical formulation, according to any of  claims 6  to  8 , wherein the excipients comprise at least one diluent selected from: starch, microcrystalline cellulose, lactose, xylitol, mannitol, maltose, polyols, fructose, guar gum, sorbitol, magnesium hydroxide, dicalcium phosphate or any combination thereof. 
     
     
         10 . A pharmaceutical formulation, according to any of  claims 6  to  9 , wherein the excipients comprise at least one lubricant selected from: magnesium stearate, calcium stearate, stearic acid, talc, sodium stearyl fumarate or any combination thereof. 
     
     
         11 . A pharmaceutical formulation, according to any of  claims 6  to  10 , wherein excipients comprise at least one glidant selected from: colloidal silica, silica gel, precipitated silica, talc or any combination thereof. 
     
     
         12 . A method to prepare sub-micron particles between 1 and 800 nm of at least one active pharmaceutical ingredient or pharmaceutical acceptable salt thereof encapsulated into microparticles between 1 and 100 μm comprising excipients, characterized in that it is carried out in a facility comprising:
 an injection unit, which is preferably a nebuliser or an electronebuliser, 
 a drying unit, which is arranged after the injection unit, and 
 a collection unit, arranged after the drying unit. 
 
       The method comprises the following stages: 
       a) preparing of an emulsion comprising:
 at least one active pharmaceutical ingredient or pharmaceutically acceptable salt thereof to be encapsulated, 
 one or more excipients; 
 at least two non-miscible or partially miscible solvents or two miscible solvents that by solubilizing the API or the excipients become non-miscible or partially miscible, 
 
       b) forming droplets from the solution obtained in stage (a) in the presence of an injection gas flow; 
       c) drying the droplets obtained in stage (b) in the drying unit at a controlled temperature to obtain microparticles; and 
       d) collecting the microparticles obtained in stage (c) by means of the collection unit. 
     
     
         13 . A method according to  claim 12  wherein the excipient used in stage a) comprises a surfactant to stabilize the emulsion. 
     
     
         14 . A method according to any of  claims 12  to  13  wherein the solvents used in step a) are selected from the list comprising: water, alcohol, toluene, ethyl acetate, methylene chloride, chloroform, dimethyl sulfoxide, dimethyl formamide, tetrahydrofuran, deep eutectic solvents, natural deep eutectic solvents and combinations thereof. 
     
     
         15 . The method, according to any of  claims 12  to  14  wherein stage c) is carried out at a temperature between 1 and 45° C. 
     
     
         16 . The method, according to any of  claims 12  to  15 , wherein the stage b) of forming droplets is carried out by applying a voltage of between 0.1 kV and 500 kV to the solution and injection gas flow at the outlet of the injection unit.