Oral pharmaceutical composition with controlled release and prolonged absorption

Abstract

A galenic system with prolonged/controlled release of the medicinal and/or nutritional active principle, for oral administration. A composition including two controlled release systems associated in series, namely: individualised coated microcapsules of active principle forming an internal phase, the coating including a film-forming polymer P 1 , a nitrogenous polymer, a softener, and a lubricant, and an external phase of functional carriers: polyelectrolytic hydrophilic polymer; neutral hydrophilic polymer, and a gelling agent, the composition spontaneously forming in the presence of water, a cohesive and stable composite macroscopic solid, where the external continuous phase is a gelled matrix including the active principle microcapsules. The invention is useful for delayed oral galenic formulation of metformin.

1 - . An oral pharmaceutical composition comprising at least one active principle (AP) and excipients capable of conferring, on this composition, properties of controlled release and of prolonged absorption of the AP in the gastrointestinal tract, this composition being of the type of those comprising: 
 first, a plurality of individual particles comprising AP and excipients,    and, secondly, a continuous external phase of excipients, in which phase is dispersed this plurality of individual and coated particles, characterized in that: 
 -a- it comprises two systems for the controlled release of the AP combined in series, namely: individual and coated particles, first, and the continuous external phase, secondly;  
 -b- the individual and coated particles of AP are microcapsules having the following characteristics: 
 (i) their coating film has the composition below: 
 1—at least one film-forming polymer (P1) which is insoluble in the fluids of the tract, present in a proportion of 50 to 90% by weight, preferably 50 to 80% by weight, on a dry basis with respect to the total mass of the coating composition and composed of at least one water-insoluble cellulose derivative, ethylcellulose and/or cellulose acetate being particularly preferred;  
 2—at least one nitrogenous polymer (P2), present in a proportion of 2 to 25% by weight, preferably of 5 to 15% by weight, on a dry basis with respect to the total mass of the coating composition and composed of at least one polyacrylamide and/or one poly-N-vinylamide and/or one poly-N-vinyllactam, polyacrylamide and/or polyvinylpyrrolidone being particularly preferred;  
 3—at least one plasticizer, present in a proportion of 2 to 20% by weight, preferably of 4 to 15% by weight, on a dry basis with respect to the total mass of the coating composition and composed of at least one of the following compounds: glycerol esters, phthalates, citrates, sebacates, esters of cetyl alcohol, castor oil, salicylic acid and cutin, castor oil being particularly preferred;  
 4—and optionally at least one surface-active agent and/or lubricating agent, present in a proportion of 2 to 20% by weight, preferably of 4 to 15% by weight, on a dry basis with respect to the total mass of the coating composition and chosen from anionic surfactants, preferably alkali metal or alkaline earth metal salts of fatty acids, stearic and/or oleic acid being preferred, and/or from nonionic surfactants, preferably polyoxyethylenated sorbitan esters and/or polyoxyethylenated derivatives of castor oil, and/or from lubricating agents, such as stearates, preferably calcium, magnesium, aluminum or zinc stearate, or such as stearylfumarate, preferably sodium stearylfumarate, and/or glyceryl behenate; it being possible for said agent to comprise just one or a mixture of abovesaid products;  
 
 (ii) they have a particle size of between 50 and 1 000 microns, preferably between 100 and 750 microns and more preferably still between 200 and 500 microns;  
 
 -c- The continuous phase of functional excipients comprises: 
 (i) at least one polyelectrolytic hydrophilic polymer (PEP) capable of gelling and/or crosslinking, preferably an acrylic or cellulose polymer or a polysaccharide and more preferably still an alginate;  
 (ii) at least one neutral hydrophilic polymer (NP), preferably chosen from the group consisting of celluloses, more especially hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose (HPC) and their derivatives;  
 (iii)and optionally a gelling/crosslinking additive (ADD) for the PEP polymer, preferably a compound based on a cation with a valency≧2, preferably a calcium-based compound and more preferably still calcium acetate;  
 
 -d- the mixture formed from the individual particles according to -b- and from the continuous phase according to -c- above spontaneously forms, in the presence of water in a dissolution test D, a composite macroscopic solid comprising a continuous external phase in the gel form in which is included a noncontinuous internal phase formed from the individual and coated AP particles, this composite macroscopic solid being formed spontaneously in a time of less than 30 minutes and preferably of between 1 and 20 minutes.  
   
     
     
         2 - . The composition as claimed in  claim 1 , characterized in that it exhibits an in vitro dissolution curve in a test D having a sigmoidal appearance defined in the following way: 
 there exists a point T on the dissolution curve, the tangent to which passes through the origin without cutting the curve and the abscissa t T  of which is such that:   t T ≧1 H   20% of the AP is released within a time t≧1.5 H.    
     
     
         3 - . The composition as claimed in  claim 1  or  2 , characterized in that the polymer NP has a viscosity η at 25° C.≧10 000 mPa·s at a concentration of 2% and according to the conditions set by USP 2208.  
     
     
         4 - . The composition as claimed in any one of  claims 1  to  3 , characterized in that the composition of the coating film of the discrete AP particles is as follows: 
 1-60 to 80% weight of P1=ethylcellulose  
 2-5 to 10% weight of P2=PVP  
 3-5 to 10% weight of plasticizer=castor oil  
 4-2 to 8% weight of lubricant/surfactant=magnesium stearate  
 
     
     
         5 - . The composition as claimed in any one of  claims 1  to  3 , characterized in that the composition of the continuous external phase is as follows: 
 i—60 to 90% by weight, preferably from 70 to 90% by weight, of gelling/crosslinking polyelectrolytic hydrophilic polymer PEP, advantageously of alginate;  
 ii—5 to 40% by weight, preferably from 10 to 30% by weight, of neutral hydrophilic polymer NP, advantageously of HPMC;  
 iii—1 to 5 by weight, preferably from 2 to 4% by weight, of a gelling/crosslinking additive ADD, advantageously calcium acetate.  
 
     
     
         6 - . The composition as claimed in any one of  claims 1  to  5 , characterized in that it comprises: 
 from 50 to 80% by weight, preferably from 60 to 70% by weight, of continuous external phase,  
 and 50 to 20% by weight, preferably from 40 to 30% by weight, of individual and coated particles of AP and of excipients.  
 
     
     
         7 - . The composition as claimed in any one of  claims 1  to  6 , characterized in that it is provided in the form of a pulverulent mixture capable of being converted in the gastrointestinal tract into a system comprising a gelled matrix based on the continuous external phase including the individual and coated particles of AP and of excipients.  
     
     
         8 - . The composition as claimed in  claim 7 , characterized in that it is present in a gelatin capsule which, in an in vitro dissolution test D, spontaneously forms a cohesive solid which maintains its cohesion in the test D for at least 3 h.  
     
     
         9 - . The composition as claimed in any one of  claims 1  to  8 , characterized in that it is provided in the form of a tablet capable of being converted in the gastrointestinal tract into a system comprising a gelled matrix based on the continuous external phase including the individual and coated particles of AP+excipients.  
     
     
         10 - . The composition as claimed in any one of claims  1  to  9 , characterized in that the AP belongs to at least one of the following families of active substances: 
 antiulcer drugs, antidiabetics, anticoagulants, antithrombics, hypolipemics, antiarrhythmics, vasodilators, antianginals, antihypertensives, vasoprotectants, fertility promoters, uterine labor inducers and inhibitors, contraceptives, antibiotics, antifungals, antivirals, antineoplastics, antiinflammatories, analgesics, antiepileptics, antiparkinsonians, neuroleptics, hypnotics, anxiolytics, psychostimulants, antimigraines, antidepressants, antitussives, antihistaminics or antiallergics;  
 and is preferably chosen from the following compounds:  
 metformin, pentoxyfylline, prazosin, diltiazem, ketoprofen, metoprolol, captopril, atenolol, salbutamol, ranitidine, quinidine, perindopril, morphine, verapamil and their mixtures.  
 
     
     
         11 - . The composition as claimed in any one of  claims 1  to  10 , characterized in that the AP is present in a proportion of at least 10% by weight, preferably in a proportion of 15 to 50% by weight and more preferably still in a proportion of 20 to 40% by weight.  
     
     
         12 - . A pharmaceutical dosage system, preferably in the form of a gelatin capsule, characterized in that it comprises of the composition as claimed in any one of  claims 1  to  10 , preferably in an amount of between 300 and 1 000 mg, and more preferably still between 400 and 700 mg.  
     
     
         13 - . Use of the composition as claimed in any one of  claims 1  to  12  in the preparation of pharmaceutical or dietary forms which are preferably pulverulent and are present in gelatin capsules.