Spheroids, preparation method thereof and pharmaceutical compositions

Abstract

The invention relates to a directly-compressible gastro-resistant spheroid. The spheroid comprises: (i) a core containing one or more active substances; (ii) a flexible, deformable film which directly coats the aforementioned core and which comprises an enteric polymer and a mixture of saturated and/or unsaturated polyglycosylated glycerides, the fatty acids of which include at least 8 carbon atoms; and (iii) an outer water-dispersible layer containing at least one disintegrating agent.

1 . A directly tabletable gastroresistant spheroid, which comprises: 
 (i) a core comprising one or more active principles, directly coated with    (ii) a flexible and deformable film comprising an enteric polymer and a mixture of saturated and/or unsaturated polyglycosylated glycerides whose fatty acids contain at least 8 carbon atoms,    (iii) a water-dispersible outer layer comprising at least one disintegrant.    
   
   
       2 . The spheroid of  claim 1 , wherein the core comprises one or more active principles selected from the group consisting of gastro-intestinal sedatives, antacids, analgesics, anti-inflammatories, coronary vasodilators, peripheral and cerebral vasodilators, antiinfection agents, antibiotics, antivirals, antiparasitics, anticancer agents, anxiolytics, neuroleptics, central nervous system stimulants, antidepressants, antihistamines, anti-diarrheals, laxatives, nutritional supplements, immuno-depressants, hypocholesterolemics, hormones, enzymes, antispasmodics, antianginal agents, medicinal products which influence heart rate, medicinal products for treating arterial hypertension, antimigraine agents, medicinal products which influence blood clottability, antiepileptics, muscle relaxants, medicinal products for treating diabetes, medicinal products for treating thyroid dysfunctions, diuretics, anorexigenic agents, antiasthmatics, expectorants, antitussives, muco-regulators, decongestants, hypnotics, antinausea agents, hematopoietic agents, uricosuric agents, plant extracts, and contrast agents.  
   
   
       3 . The spheroid of  claim 1 , wherein the active principle is selected from proton pump inhibitors, preferably omeprazole, lansoprazole, pantoprazole, pariprazole, leminoprazole or rabeprazole, in their racemic form or in the form of pure enantiomers, themselves in base form or in the form of alkali metal salts; nonsteroidal anti-inflammatories, preferably diclofenac, in the form of bases or of salts; and antibiotics, preferably erythromycin and its derivatives, in the form of bases or of salts.  
   
   
       4 . The spheroid of  claim 1 , wherein the binder is selected from the group consisting of cellulosic polymers, acrylic polymers, povidones, copovidones, polyvinyl alcohols, alginic acid, sodium alginate, starch, pregelatinized starch, sucroses and derivatives thereof, guar gum, polyethylene glycols, and mixtures thereof.  
   
   
       5 . The spheroid of  claim 1 , wherein the core optionally comprises a diluent, an antistat and/or a lubricant.  
   
   
       6 . The spheroid of  claim 1 , wherein the enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylcellulose and shellac, which are used alone or in a mixture.  
   
   
       7 . The spheroid of  claim 6 , wherein the enteric polymer is a methacrylic acid copolymer.  
   
   
       8 . The spheroid of  claim 1 , wherein the fatty acids of the mixture of saturated and/or unsaturated polyglycosylated glycerides contain from 8 to 18 carbon atoms (C8-C18).  
   
   
       9 . The spheroid of  claim 8 , wherein said mixture is a mixture of mono-, di- and triglycerides and of polyethylene glycol monoester and diester, with a molecular weight of between 200 and 1500, and optionally of glycerol and of free PEG, and predominantly comprises palmitostearic acid, said mixture having a melting point of between 46.0° C. and 51.0° C. and a hydrophilic/lipophilic balance (HLB) of 13.  
   
   
       10 . The spheroid of  claim 8 , wherein said mixture is Gélucire®, in particular Gélucire 50/13.  
   
   
       11 . The spheroid of  claim 1 , wherein the flexible and deformable film optionally comprises a plasticizer selected from the group consisting of triethyl citrate, acetyl tributyl citrate, triacetin, tributyl citrate, diethyl phthalate, polyethylene glycols, polysorbates, and monoacetylated and diacetylated glycerides, preferably triethyl citrate.  
   
   
       12 . The spheroid of  claim 1 , wherein the coating composition optionally comprises a surfactant, an antistat and/or a lubricant.  
   
   
       13 . The spheroid of  claim 1 , wherein the disintegrant is selected from the group consisting of the crosslinked sodium carboxymethylcellulose denoted in the art by the term croscarmellose, crospovidone, sodium carboxymethyl starch, and mixtures thereof.  
   
   
       14 . The spheroid of  claim 1 , wherein the dispersible outer layer optionally comprises a binder and an auxiliary substance, in particular mannitol.  
   
   
       15 . A method of preparing a spheroid of  claim 1 , comprising the following steps: 
 (i) preparing a core comprising one or more active principles and at least one binder;    (ii) coating the core thus obtained by spraying it with a coating composition comprising an enteric polymer and a mixture of saturated and/or unsaturated polyglycosylated glycerides whose fatty acids contain at least 8 carbon atoms, preferably from 8 to 18 carbon atoms (C8-C18);    (iii) coating the spheroid thus obtained with a water-dispersible outer layer comprising at least one disintegrant; and    (iv) drying the spheroid.    
   
   
       16 . The method of  claim 15 , wherein the core comprising the active principle(s) is prepared by granulation, by application to a neutral substance, or by extrusion with spheronization.  
   
   
       17 . The method of  claim 15 , wherein the spheroid is prepared in a fluidized-air bed.  
   
   
       18 - 22 . (canceled)