Microcapsules with modified release of active principles with low solubility for oral delivery

Abstract

The invention concerns microcapsules for reliably modified release and adapted to industrial reproduction of an active principle hardly water-soluble, other than anti-hyperglycemia agents Each of said microcapsules comprises a core of hardly soluble active principle and a coating film applied on the core. Their mean diameter is less than 1000 microns. The coating film contains a film-forming polymer (P1) insoluble in gastrointestinal tract fluids, a water-soluble polymer (P2), a plasticizer (PL), and optionally a lubricating surfactant (TA). Said coating film represents at least 4% p/p of dry mraner of their total weight. and its components P1, P2. PL satisfy the following characteristics: dry weight mass fraction of PI relative to the total coating weight ranging between 40 and 90%; dry matter weight fraction of PL/P1+P2 ranging between 15 and 60%: dry matter weight fraction of PL/P1+P2 ranging between 1 and 30%. The invention also concerns the uses of said microcapsules in galenic formulation.

1 . A microcapsule for the modified release of at least one AP with low water solubility, with the exclusion of blood glucose-lowering agents, intended to be administered orally and of the type of those: 
 each consisting of a core comprising at least one active principle and of a coating film applied onto the core and controlling the modified release of the AP(s),    the mean diameter of which is less than 1000 microns, preferably between 800 and 50 microns, and even more preferably between 600 and 100 microns,    in which the coating film of each microcapsule contains the following components: 
 -I—at least one film-forming polymer (P1) insoluble in gastrointestinal tract fluids,  
 -II—at least one water-soluble polymer (P2),  
 -III—at least one plasticizer (PL),  
 -IV—and, optionally, at least one lubricating surfactant (TA);  
   with the exclusion of coating films consisting of enteric compositions and of coating films having the composition below:    1—at least one film-forming polymer (P1) insoluble in the fluids of the tract, present in a proportion of 50 to 90, preferably 50 to 80% by weight on a dry basis relative to the total mass of the coating composition and consisting of at least one water-insoluble derivative of cellulose, i.e. ethylcellulose and/or cellulose acetate;    2—at least one nitrogenous polymer (P2) present in a proportion of 2 to 25, preferably 5 to 15% by weight on a dry basis relative to the total mass of the coating composition and consisting of at least one polyacrylamide and/or one poly-N-vinyl-amide and/or one poly(N-vinyl lactam), i.e. polyacrylamide and/or polyvinylpyrrolidone;    3—at least one plasticizer present in a proportion of 2 to 20, preferably 4 to 15% by weight on a dry basis relative to the total mass of the coating composition and consisting of at least one of the following compounds: glyceryl esters, phthalates, citrates, sebacates, cetyl alcohol esters, castor oil, salicylic acid and cutin;    4—and at least one surfactant and/or lubricant, present in a proportion of 2 to 20, preferably 4 to 15% by weight on a dry basis relative to the total mass of the coating composition and chosen from anionic surfactants, i.e. alkali metal salts or alkaline-earth metal salts of fatty acids, stearic acid and/or oleic acid being preferred, and/or from nonionic surfactants, i.e. polyoxyethylenated sorbitan esters and/or polyoxyethylenated castor oil derivatives, and/or from lubricants such as calcium stearate, magnesium stearate, aluminum stearate or zinc stearate, or such as sodium stearyl fumarate and/or glyceryl behenate; it being possible for said agent to comprise just one or a mixture of the abovementioned products;    characterized: 
 in that their coating film represents at least 3% dry weight/dry weight, preferably at least 5% dry weight/dry weight of their total mass,  
 and in that the components P1, P2 and PL of the coating film satisfy the following characteristics: 
 mass fraction by dry weight of P1 relative to the total mass of the coating of between 40 and 90%, and preferably of between 50 and 80%;  
 mass fraction by dry weight P2/P1+P2 of between 15 and 60%, and preferably of between 15 and 55%;  
 mass fraction by dry weight PL/P1+PL of between 1 and 30%, and preferably of between 5 and 25%.  
 
   
   
   
       2 . The microcapsule as claimed in  claim 1 , without the exclusion relating to blood glucose-lowering agents and without the exclusion relating to coating films consisting of enteric compositions and to coating films having the composition 1, 2, 3 and 4 as defined in  claim 1 .  
   
   
       3 . The microcapsule as claimed in  claim 1  or  2 , characterized in that the coating film comprises component TA in a proportion of 2 and 20%, and preferably of between 4 and 15% of the total mass of the dry coating.  
   
   
       4 . The microcapsule as claimed in any one of claims  1  to 3, characterized in that P1 is selected from the group of products below: 
 water-insoluble derivatives of cellulose, preferably ethylcellulose and/or cellulose acetate,    acrylic derivatives,    poly(vinyl acetates),    and mixtures thereof.    
   
   
       5 . The microcapsule as claimed in any of one of  claims 1  to  4 , characterized in that P2 is selected from the group of products below: 
 water-soluble derivatives of cellulose,    polyacrylamides,    poly-N-vinylamides,    poly(N-vinyl lactams),    polyvinyl alcohols (PVAs),    polyoxyethylenes (POEs),    polyvinylpyrrolidones (PVPs) (the latter being preferred),    and mixtures thereof.    
   
   
       6 . The microcapsule as claimed in any one of  claims 1  to  5 , characterized in that PL is selected from the group of products below: 
 glycerol and esters thereof, preferably from the following subgroup: 
 acetylated glycerides, glyceryl mono-stearate, glyceryl triacetate, glyceryl tributyrate,  
   phthalates, preferably from the following subgroup: 
 dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate,  
   citrates, preferably from the following subgroup: 
 acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, triethyl citrate,  
   sebacates, preferably from the following subgroup: 
 diethyl sebacate, dibutyl sebacate,  
   adipates,    azelates,    benzoates,    plant oils,    fumarates, preferably diethyl fumarate,    malates, preferably diethyl malate,    oxalates, preferably diethyl oxalate,    succinates, preferably dibutyl succinate,    butyrates,    cetyl alcohol esters,    salicylic acid,    triacetin,    malonates, preferably diethyl malonate,    cutin,    castor oil (this being particularly preferred),    and mixtures thereof.    
   
   
       7 . The microcapsule as claimed in any one of claims  1  to 6, characterized in that TA is selected from the group of products below: 
 anionic surfactants, preferably from the subgroup of alkali metal salts or alkaline-earth metal salts of fatty acids, stearic acid and/or oleic acid being preferred,    and/or nonionic surfactants, preferably from the following subgroup: 
 polyoxyethylenated oils, preferably polyoxyethylenated hydrogenated castor oil,  
 polyoxyethylene-polyoxypropylene copolymers,  
 polyoxyethylenated sorbitan esters,  
 polyoxyethylenated castor oil derivatives,  
 stearates, preferably calcium stearate, magnesium stearate, aluminum stearate or zinc stearate,  
 stearyl fumarates, preferably sodium stearyl fumarate,  
 glyceryl behenate,  
 and mixtures thereof.  
   
   
   
       8 . The microcapsule as claimed in any one of claims  1  to 7, characterized in that the APs with low solubility are chosen from at least one of the major varieties of active substances below: antiulcer agents, antidiabetic agents, anticoagulants, antithrombics, blood lipid-lowering agents, anti-arrhythmics, vasodilators, antiangina agents, anti-hypertensives, vasoprotective agents, fertility promoters, inducers and inhibitors of uterine labor, contraceptives, antibiotics, antifungal agents, anti-viral agents, anticancer agents, anti-inflammatories, analgesics, antiepileptics, antiparkinsonian agents, neuroleptics, hypnotics, anxiolytics, psychostimulants, antimigraine agents, antidepressives, antitussives, antihistamines or antiallergic agents.  
   
   
       9 . The microcapsule as claimed in  claim 8  characterized in that the AP(s) with low solubility is (are) chosen from the following compounds: prazosine, acyclovir, nifedipine, naproxen, ibuprofen, ketoprofen, fenoprofen, indomethacine, diclofenac, sulpiride, terfenadine, carbamazepine, fluoxetine, alprazolam, famotidine, ganciclovir, spironolactone, acetylsalicyclic acid, quinidine, morphine, amoxicillin, paracetamol, metoclopramide, verapamil and mixtures thereof.  
   
   
       10 . A medicinal product comprising the microcapsules as claimed in any one of  claims 1  to  9 .  
   
   
       11 . The medicinal product as claimed in  claim 10 , characterized in that it is in solid form, preferably: tablet, gelatin capsule or powder, or in liquid form, preferably: an aqueous suspension.  
   
   
       12 . The use of microcapsules for the modified release of at least one AP with low water solubility, with the exclusion of blood glucose-lowering agents, intended to be administered orally, these microcapsules having the following characteristics: 
 they each consist of a core comprising at least one active principle and of a coating film applied onto the core and controlling the prolonged release of the AP(s),    their mean diameter is less than 1000 microns, preferably between 800 and 50 microns, and even more preferably between 600 and 100 microns,    their coating film contains the following components: 
 -I—at least one film-forming polymer (P1) insoluble in gastrointestinal tract fluids,  
 -II—at least one water-soluble polymer (P2),  
 -III—at least one plasticizer (PL),  
 IV—and, optionally, at least one lubricating surfactant (TA);  
 components P1, P2 and P1 of the coating film satisfying the following characteristics: 
 mass fraction by dry weight of P1 relative to the total mass of the coating of between 40 and 90%, and preferably of between 50 and 80%;  
 mass fraction by dry weight P2/P1+P2 of between 15 and 60%, and preferably of between 15 and 55%;  
 mass fraction by dry weight PL/P1+PL of between 1 and 30%, and preferably of between 5 and 25%;  
 
 and this coating film represents at least 4% w/w, preferably at least 5% w/w of their total mass;  
   with the exclusion of coating films consisting of enteric compositions and of coating films having the composition below:    1—at least one film-forming polymer (P1) insoluble in the fluids of the tract, present in a proportion of 50 to 90, preferably 50 to 80% by weight on a dry basis relative to the total mass of the coating composition and consisting of at least one water-insoluble derivative of cellulose, i.e. ethylcellulose and/or cellulose acetate;    2—at least one nitrogenous polymer (P2) present in a proportion of 2 to 25, preferably 5 to 15% by weight on a dry basis relative to the total mass of the coating composition and consisting of at least one polyacrylamide and/or one poly-N-vinyl-amide and/or one poly(N-vinyl lactam), i.e. polyacrylamide and/or polyvinylpyrrolidone;    3—at least one plasticizer present in a proportion of 2 to 20, preferably 4 to 15% by weight on a dry basis relative to the total mass of the coating composition and consisting of at least one of the following compounds: glyceryl esters, phthalates, citrates, sebacates, cetyl alcohol esters, castor oil, salicylic acid and cutin;    4—and at least one surfactant and/or lubricant, present in a proportion of 2 to 20, preferably 4 to 15% by weight on a dry basis relative to the total mass of the coating composition and chosen from anionic surfactants, i.e. alkali metal salts or alkaline-earth metal salts of fatty acids, stearic acid and/or oleic acid being preferred, and/or from nonionic surfactants, i.e. polyoxyethylenated sorbitan esters and/or polyoxyethylenated castor oil derivatives, and/or from lubricants such as calcium stearate, magnesium stearate, aluminum stearate or zinc stearate, or such as sodium stearyl fumarate and/or glyceryl behenate; it being possible for said agent to comprise just one or a mixture of the abovementioned products;    for producing a medicinal product based on at least one AP with low solubility which can be administered orally, which can be readily swallowed, and which is released in vivo in a controlled, prolonged and, optionally, delayed manner.    
   
   
       13 . The use as claimed in  claim 12 , without the exclusion relating to blood glucose-lowering agents and without the exclusion relating to coating films consisting of enteric compositions and to coating films having the composition 1, 2, 3 and 4 as defined in  claim 12.