Link: Pharm/Biotech Resources
Title: Particles coated with granulated crystalline
ibuprofen
United States Patent: 6,951,657
Issued: October 4, 2005
Inventors: Zuccarelli; Jean-Marc (Antibes, FR); Chauveau; Charles André (Valbonne, FR); DeMichelis; Gilles (Grasse, FR); Jean; Karine (Cagnes sur Mer, FR)
Assignee: Laboratoires des produits Ethiques Ethypharm SA (Houdan, FR)
Appl. No.: 830101
Filed: November 3, 1999
PCT Filed: November 3, 1999
PCT NO: PCT/FR99/02682
371 Date: March 5, 2002
102(e) Date: March 5, 2002
PCT PUB.NO.: WO00/27368
PCT PUB. Date: May 18, 2000
Abstract
The invention concerns coated particles based on granulated microcrystals of ibuprofen, its pharmaceutically acceptable isomers and salts, characterized in that they comprise a coating obtained in a fluidized bed apparatus with a hydroalcoholic dispersion consisting of a mixture comprising (A) 5 to 50% by weight of ethylcellulose relative to ibuprofen; (B) 10 to 60% by weight of hydroxypeopylmethylcellulose relative to the ethylcellulose; and (C) 1 to 40% by weight of silica with antistatic and permeabilizing properties relative to the ethylcellulose, the resulting coating, whereof at least one of the constituents can be used for granulating the ibuprofen microcrystals resulting in said particles, thereby masking the unpleasant taste of ibuprofen and significantly reducing its irritating effect on the throat after deglutition and substantially immediate release of ibuprofen when the particles are placed in an aqueous medium.
Description of the Invention
The invention relates to coated particles based on granulated crystalline
ibuprofen or its pharmaceutically acceptable salts or esters, which have a
coating obtained in a fluidized bed apparatus with an aqueous-alcoholic
dispersion, said coating masking the unpleasant taste of the ibuprofen,
significantly reducing its irritant effect on the throat after swallowing,
and releasing said ibuprofen substantially immediately when the particles
reach the gastric medium.
It further relates to the process for the preparation of said particles.
The coated particles in question consist of granulated microcrystals of
ibuprofen.
Patent U.S. Pat. No. 5,215,755 describes tablets in which the ibuprofen is
present in the form of granules having a coating based on hydroxyethyl
cellulose or a hydroxyethyl cellulose/hydroxypropyl methyl cellulose
mixture. This coating affords a better compromise between taste masking and
bioavailability, which could not be achieved by the use of ethyl cellulose
on its own or mixed with other, already known coating polymers.
Patent U.S. Pat. No. 5,814,332 describes ibuprofen particles encapsulated by
coacervation of the active principle with cellulosic polymers and gelatin.
Patents U.S. Pat. No. 4,835,186 and U.S. Pat. No. 4,835,187 describe
ibuprofen powders obtained by a method in which suspensions of colloidal
silica in solutions, in organic solvents, of ibuprofen and a cellulosic
material such as ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl
methyl cellulose or cellulose acetophthalate are dried by atomization, said
method is better known as nebulization.
The object of the invention is to provide novel particles based on
crystalline ibuprofen which have a neutral palatability, are tasteless and
mask the irritant effect of the active principle. Their particle size
distribution and their physical characteristics enable them to be used
especially in the manufacture of multiparticulate tablets disintegrating
rapidly in the mouth under the action of the saliva, according to patent FR
2679451, and are such that the active principle is released substantially
immediately.
As a result of in-depth researches, the Applicant succeeded in discovering
that this object was achieved by using a process of granulation and coating
in a fluidized bed apparatus with a mixture essentially based on ethyl
cellulose, hydroxypropyl methyl cellulose and silica with antistatic and
permeabilizing properties, in defined proportions.
Thus the particles according to the invention, based on granulated
microcrystals of ibuprofen, its isomers and its pharmaceutically acceptable
salts, are characterized in that they have a coating consisting of a mixture
comprising
said coating—of which at least one of the constituents can be used for the granulation of the ibuprofen microcrystals to produce said particles—masking the unpleasant taste of the ibuprofen, significantly reducing its irritant effect on the throat after swallowing, and releasing the ibuprofen substantially immediately when the particles are placed in an aqueous medium.
The active principle consists of crystalline ibuprofen or one of its pharmaceutically acceptable salts or esters.
The active principle is commercially available in the form of microcrystals with a mean size of between 20 and 80 μm.
The disadvantage of this particle size is that coating by methods which consist in spraying a coating solution onto these microcrystals in a fluidized bed apparatus is difficult and lengthy.
According to the invention, to overcome this disadvantage, the ibuprofen microcrystals are granulated and coated to produce particles whose size is such that at least 80% of the particles are between 100 and 500 μm and less than 15% of the particles are smaller than 100 μm.
In the coated particles according to the invention, the ibuprofen preserves its physicochemical integrity, the intrinsic properties of the active principle being totally unchanged by granulation and coating.
The silica with antistatic and permeabilizing properties (C) can be selected from the group comprising especially colloidal silica, particularly the one marketed under the trade mark AEROSIL®, and preferably precipitated silica, particularly the one marketed under the trade mark SYLOID® FP244, and mixtures thereof.
Advantageously, it is also possible to use an agent (D) which directly or indirectly favours the solubilization of the ibuprofen, said agent being selected from the group comprising especially mannitol, starch, pharmaceutically acceptable self-emulsifying bases, polyvinylpyrrolidones, stearic macrogol glycerides, which are better known as gélucire, alkali metal salts of organic origin such as sodium bicarbonate, surfactants such as sodium laurylsulfate, and mixtures thereof. This agent (D) is present in proportions which can range up to 50% by weight, preferably up to 35% by weight, based on the ibuprofen.
In one advantageous embodiment, the ibuprofen particles are granulated with at least one agent favouring the solubilization of the ibuprofen, said agent preferably being selected from the group comprising stearic macrogol glycerides and hydroxypropyl methyl cellulose, and are coated with an ethyl cellulose/hydroxypropyl methyl cellulose mixture in proportions which make it possible to mask the taste and the irritant effect of the ibuprofen, and with a silica having antistatic and permeabilizing properties, especially precipitated silica, this embodiment optimizing the bioavailability of the ibuprofen.
This achieves a masking of the taste and the irritant effect which is just as satisfactory as with the other method of preparing the particles, but the rate of release of the active principle into aqueous media is optimized.
In another advantageous embodiment, the ibuprofen microcrystals are granulated in the presence of microcrystals of an alkali metal salt of organic origin as an agent favouring the solubilization of ibuprofen, and a solution comprising hydroxypropyl methyl cellulose and/or polyvinylpyrrolidone. This alkali metal salt is preferably sodium bicarbonate, which, by dissolving in the gastrointestinal fluids, creates an alkaline micro-pH favouring the solubilization of the ibuprofen particles.
The particles of this constitution are then coated with the coating mixture according to the invention.
In another advantageous embodiment, again in the case where at least one of the constituents of the coating is used for the granulation of the ibuprofen microcrystals, said coating contains an agent favouring solubilization, which can be a soluble agent such as mannitol or a swelling agent such as starch. If a soluble agent is used, it crystallizes on the surface of the ibuprofen particles and, in an acid medium, it solubilizes to leave pores which allow the physiological fluids to enter inside the particle. If a swelling agent is used, a complementary particle bursting phenomenon takes place.
The particles according to the invention optimize the dissolution of the ibuprofen in aqueous media. The rate of dissolution of the particles is such that, in a buffer solution of pH 7.2, 80% of the ibuprofen is released in 30 minutes and preferably in 15 minutes.
The invention further relates to a process for the preparation of coated particles based on ibuprofen microcrystals. This process comprises, simultaneously or successively, a phase consisting in granulating the ibuprofen microcrystals and a phase consisting in coating them with a coating made up of a mixture of
at least one of the constituents of the mixture used for the coating can be used for the granulation of the ibuprofen microcrystals.
In the granulation and/or coating phases, it is also possible to use an agent (D) favouring the solubilization of the ibuprofen, said agent being selected from the group comprising mannitol, starch, pharmaceutically acceptable self-emulsifying bases, polyvinylpyrrolidones, stearic macrogol glycerides, alkali metal salts of organic origin, surfactants and mixtures thereof. In this case said agent (D) is present in proportions which can range up to 50% by weight, preferably up to 35% by weight, based on the ibuprofen.
The process according to the invention is carried out in a fluidized bed under temperature conditions such that the temperature of the ibuprofen is always kept below the melting and sublimation points of ibuprofen. In one particular embodiment of the process of the invention, the temperature of the ibuprofen is always kept below 45° C., preferably below 30° C.
Because the granulation and coating process used is carried out in a fluidized bed, the ibuprofen is not brought into solution, so it preserves its physicochemical integrity in optimal manner. Furthermore, the use of low temperatures enables any change of state and any risk of degradation of the active principle to be avoided.
In a first embodiment, the granulation and coating phases take place simultaneously by wetting the ibuprofen microcrystals with an aqueous-alcoholic suspension comprising especially ethyl cellulose and hydroxypropyl methyl cellulose and a silica with antistatic and permeabilizing properties.
In another embodiment of the process according to the invention, the first step, or granulation phase, is carried out using at least one agent favouring solubilization, selected from the group comprising especially stearic macrogol glycerides and hydroxypropyl methyl cellulose, and the second step, or coating phase, is then carried out using a silica with antistatic and permeabilizing properties and a mixture of ethyl cellulose and hydroxypropyl methyl cellulose in proportions which make it possible to mask the taste and the irritant effect of the ibuprofen and to release the ibuprofen substantially immediately.
In another advantageous embodiment of the process according to the invention, in the first step, or granulation step, ibuprofen microparticles are mixed with microcrystals of an alkali metal salt of organic origin as an agent favouring the solubilization of the ibuprofen, and the resulting mixture is granulated with an aqueous-alcoholic dispersion comprising hydroxypropyl methyl cellulose and/or polyvinylpyrrolidone. The coating phase is then carried out with a coating mixture according to the invention.
Claim 1 of 9 Claims
1. Coated particles based on granulated microcrystals of ibuprofen, its
isomers and its pharmaceutically acceptable salts, wherein they have a
coating consisting of a mixture consisting of:
A) from 5 to 50% by weight, of ethyl cellulose, based on the ibuprofen,
B) from 10 to 60% by weight, of hydroxypropyl methyl cellulose, based on
the ethyl cellulose,
C) from 0.1 to 40% by weight, of silica with antistatic and permeabilizing
properties, based on the ethyl cellulose, and
D) from 0 to 50% by weight of an agent favoring the solubilization of the
ibuprofen, based on the ibuprofen, said agent being selected from the
group comprising mannitol, starch, pharmaceutically acceptable
self-emulsifying bases, polyvinylpyrrolidones, stearic macrogol glycerides,
alkali metal salts of organic origin, surfactants and mixtures thereof,
whereby said coating—of which at least one of the constituents can be used
for the granulation of the ibuprofen microcrystals to produce said
particles—allows the masking of the unpleasant taste of the ibuprofen, the
significantly reduction of its irritant effect on the throat after
swallowing, and the release of 80% of the ibuprofen in 30 minutes in 900
ml of a buffer solution of pH 7.2, using a type 4 apparatus described in
USP XXIII p. 1794.
____________________________________________
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