Stock material or miscellaneous articles – Coated or structually defined flake – particle – cell – strand,... – Particulate matter
Reexamination Certificate
2002-01-08
2003-12-09
Kiliman, Leszek (Department: 1773)
Stock material or miscellaneous articles
Coated or structually defined flake, particle, cell, strand,...
Particulate matter
C428S407000, C427S212000, C427S213300, C427S213310, C427S213360, C424S465000, C424S480000, C424S482000, C424S499000, C514S772200, C514S781000
Reexamination Certificate
active
06660382
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation of PCT application PCT/FR00/01855 filed Jun. 30, 2000, and published under PCT Article 21(2) in French as WO 01/03672 on Jan. 18, 2001. PCT/FR00/01855 claimed the priority of French application FR/99 09047, filed Jul. 8, 1999. The entire disclosures of both are incorporated herein by reference.
The invention relates to a process for manufacturing coated granules with masked taste and immediate release of active principle. The invention also relates to the granules coated with active principle which may be obtained by this process, and also to any presentation form incorporating said coated granules.
In the description hereinbelow and in the claims, the expression “immediate release of active principle” means that the release kinetics of the active molecule are not substantially modified by the formulation and/or by the parameters of the manufacturing process (see in particular the document from the European Drug Agency “note for guidance on modified release oral and transdermal dosage forms” dated Apr. 22, 1998). Consequently, the dissolution profile of the active principle depends essentially on its intrinsic properties.
To obtain an immediate release of the active principle, document EP-A-0 237 506 proposes a complex process for manufacturing a fast-disintegrating granule, in which a solution of an active principle in a mixture of water and alkanol is first prepared and an emulsifier is then added thereto, the mixture obtained being vigorously homogenized. The composition thus obtained is sprayed onto a bed of powder comprising an inert support consisting of a microcrystalline cellulose and a disintegrant. The resulting aggregate is finally dried and then presented in more or less spherical form. The main object of this process is not to produce granules of active principle with masked taste.
Specifically, it is well known that a certain number of active principles have an unpleasant taste, such that it is essential to mask the taste of these active principles at least while they are in the oral cavity, so as to make them more pleasant to take and to optimize the patient's compliance with the treatment.
One of the solutions proposed consists in coating the particles of active principle with a cellulose polymer. However, although the taste of the active principle present in the granules is satisfactorily masked, the low permeability and low solubility of all the pH values of the cellulose polymer leads to a slow release of the active principle, which is unsuitable for immediate-release kinetics.
To solve this problem, the Applicant has proposed, in French patent application FR 98/14033 which is unpublished at the date of filing of the present application, to coat ibuprofen particles by spraying with a solution based on ethylcellulose and hydroxypropylmethylcellulose, also comprising an agent for promoting the dissolution of the ibuprofen.
Another solution consists in coating the particle of active principle with a polymer of the acrylic type. Among these polymers that may be distinguished are pH-dependent polymers, that is to say polymers whose solubility depends on the pH, and pH-independent polymers, that is to say polymers whose solubility is independent of the pH.
Depending on their solubility range, pH-dependent polymers may bring about a delayed release of the active principle just until it is into the distal portion of the intestine. In other words, such a coating is incompatible with an immediate release of the active principle.
pH-independent acrylic polymers are, by definition, insoluble, such that even though they are entirely satisfactory in terms of masking the taste, they too are unsuitable, on the basis of their permeability properties, for an immediate release of the active principle.
The use of this type of polymer is more particularly described in documents U.S. Pat. No. 4,726,966 and WO 98/47493.
Document U.S. Pat. No. 4,726,966 describes a process for manufacturing ibuprofen microspheres by dissolving ibuprofen particles in an aliphatic alcohol, followed by recrystallization in the form of microspheres with the aid of various solvents and acrylic resins. This manufacturing process, performed by means of a very specific technique, makes it possible to obtain a masking of the taste that is, in principle, satisfactory.
Similarly, document Wo 98/47493 describes a pharmaceutical composition in the form of granules coated with a polymer film of the acrylic type, which, as expressly indicated, leads to a delayed release of the active principle.
Similarly, document EP-A-0 255 725 describes the use of formulation adjuvants (binders and disintegrants) in the outer layer of sustained-release granules, presented in the form of tablets. In this case, the formulation adjuvants, including crosslinked sodium croscarmellose and povidone derivatives, are used to give the sustained-release granules sufficient cohesion during the tabletting procedure while at the same time ensuring rapid disintegration of the tablet.
Document EP-A-0 525 389 describes a process for producing multiparticulate tablets with rapid disintegration, which is imparted by using granules of active principle coated in particular with crospovidone. This compound is introduced here with the aim of giving the tablet rapid disintegration while at the same time maintaining sufficient cohesion.
However, for both these documents, the rapid disintegration of the tablet does not automatically mean immediate release of active principle.
In other words, the object of the invention is to propose a process for manufacturing coated granules, the taste of the active principle of which is masked, and the release of the active principle of which is immediate, irrespective of the nature of the coating polymer.
To do this, the invention proposes a process for manufacturing coated granules with masked taste, and immediate release of the active principle, according to which:
the constituents of a powder comprising at least the active principle and a granular disintegrant are first dry-mixed;
the powder obtained is then granulated, in the presence of a mixture of excipients comprising at least one binder capable of binding the particles together to give grains;
the grains thus formed are then coated by spraying with a suspension comprising at least one coating agent and a membrane disintegrant;
finally, the coated granules obtained are dried.
In the description hereinbelow and in the claims, the expression “membrane disintegrant” denotes an excipient that is capable of increasing the speed of disintegration of the coating layer of the granules, obtained after the coating step.
Similarly, the expression “granule disintegrant” denotes an excipient capable of accelerating the speed of separation of the particles of active principle from each other after dissolving the coating layer of the granule.
“Superdisintegrants”, also known as high-performance disintegrants, are used as external disintegrant (AGM) and internal disintegrant (AGG). Superdisintegrants are widely known to those skilled in the art, and are more particularly described in the publication Journal of Pharmaceutical Sciences (Volume 85, No. 11, November 1996).
In the process of the invention, the granular and membrane disintegrants are advantageously chosen from the group comprising sodium carboxymethylcellulose, crospovidone and carboxymethylstarch.
The process of the invention makes it possible, surprisingly and unexpectedly, to solve the two problems with diametrically opposed solutions, namely those of achieving the masking of the taste of the active principle by coating, while not, however, delaying the dissolution of the active principle, and in doing so by incorporating both at the granular level and at the membrane level, not only a binder and a coating agent, respectively, but also (granular and membrane) disintegrants.
The distinction between the actual granulation and coating steps is relatively theoretical, insofar as, even though the primary function of the binder used in t
Bruna Etienne
Chauveau Charles
Nouri Noureddine
Zuccarelli Jean-Marc
Ethypharm
Heslin Rothenberg Farley & & Mesiti P.C.
Kiliman Leszek
LandOfFree
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