Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-03-23
2001-02-27
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S469000, C424S470000
Reexamination Certificate
active
06194005
ABSTRACT:
The invention relates to a process for the manufacture of a pharmaceutical composition with modified release of active principle comprising a matrix.
“Pharmaceutical composition with modified release of active principle” denotes the pharmaceutical compositions with accelerated, sustained and delayed release of active principle.
Various types of pharmaceutical compositions with modified release of active principle exist. Compositions comprising, on the one hand, uncoated granules constituting the dose of immediately available active principle and, on the other hand, coated granules providing for the modified release of active principle are particularly used.
Compositions comprising a matrix effect are also used.
The invention more particularly relates to the process for manufacturing the latter.
In this type of composition, the active principle is dispersed or coated in a solid system, known as a matrix. The release of the active principle from the matrix is achieved by contact of biological fluids with the said matrix. More specifically, biological fluids migrate through the matrix and dissolve the active principles and the latter are released by diffusion through the matrix which, simultaneously, modulates the release flow.
Hydrophilic matrices and hydrophobic matrices are distinguished.
In compositions comprising a hydrophilic matrix, the matrix is composed of an insoluble hydrophilic polymer, the concentration of which is between 25% and more than 50% of the weight of the composition, therefore high. This polymer is chosen from cellulose esters, carboxyvinyl esters, or acrylic or methacrylic esters. On contact with biological fluids, the matrix becomes hydrated and swells, forming a very dense network of polymers, through which polymers the soluble active principles diffuse. Furthermore, lipids, in particular glyceryl esters, as illustrated, for example, in the document FR-B-2,573,307, can be added in order to modulate the matrix swelling. In addition, these compositions include numerous adjuvants, often expensive adjuvants, at high concentrations, which greatly increases the cost of the composition.
These compositions are obtained by granulation and then compression of the mixture formed of the polymer, active principles and various adjuvants. These techniques often involve the use of organic solvents, which it is subsequently essential to recover in order to prevent them from dispersing into the atmosphere. In addition, traces of toxic solvents can remain in the final product, which traces necessarily have to be quantified.
In other words, the preparation of these compositions results in a high production cost, due to the cost of the various constituents of the composition, to their high proportions and to the technical constraints to be overcome.
In the compositions comprising a hydrophobic matrix, the matrix is composed of a lipid matrix agent of natural origin, for example beeswaxes, which is highly innocuous. However, its composition varies from one batch to another and its stability over time is not very satisfactory.
As above, these compositions are generally obtained by granulation, by a wet or solvent route, and then compression, involving high proportions of each of the constituents.
The aim of the invention is thus to provide a novel process for the manufacture of a pharmaceutical composition with modified release of active principle by having the object of significantly decreasing the number and the proportions of each of the constituents as well as the number of operations, thus making it possible to obtain a formulation which is simple to employ and of low and reproducible cost.
To overcome this combination of problems, the invention provides a process for the manufacture of a pharmaceutical composition with modified release of active principle comprising at least one active principle, a lipid matrix agent composed of an ester of at least one fatty acid and of alcohol, and at least one adjuvant.
This process is characterized in that:
a powder composed of at least one component selected from the group comprising the active principle and the adjuvant is mixed, while heating and fluidizing, in order to obtain individual grains,
the said lipid matrix agent is liquefied separately under warm conditions,
the said powder is then coated under warm conditions by spraying the said lipid matrix agent over the individual grains,
and, finally, the temperature of the combined product is lowered in order to allow the lipid matrix agent to solidify.
In other words, the invention lies in the employment of a specific process which makes it possible to decrease the number of adjuvants necessary for the preparation of the composition and thus to result in an extremely simple and low-cost formula.
In addition, the process of the invention does not require an evaporation phase or a drying phase, since it does not require a wet-route or solvent-route granulation step, thus making it possible to be freed from any risk due to the presence of toxic residues in the final product. Furthermore, it is no longer necessary to carry out the quantitative determination of the traces of solvents, an analysis which is very expensive.
According to the process of the invention, the spraying conditions and thus the coating characteristics can be modified, in order to vary the release profile of the active principle, by varying several parameters, the adjustment characteristics of which remain simple.
Thus, the spraying air pressure can be increased in order to promote the formation of a homogeneous film of lipid matrix agent around the grains.
Advantageously, the rate of spraying of the lipid matrix agent can simultaneously be decreased.
In this case, an active principle release profile, that is to say a percentage of dissolution as a function of the time, is obtained which is very low, corresponding to a slow release of the active principle.
Conversely, the spraying air pressure can be decreased in order to promote the agglomeration of the grains with one another.
Advantageously, the rate of spraying of the lipid matrix agent can simultaneously be increased.
In this case, a release profile of the grains obtained is obtained which is very high, corresponding to a rapid release of the active principle.
In practice and according to the mass of powder employed, the value of the rate of spraying of the lipid matrix agent is from two to four times higher when it is desired to promote the agglomeration of the grains with one another than when it is desired to promote the formation of a homogeneous film around the grains.
On the other hand, the value of the spraying air pressure is from one to two times lower when it is desired to promote the agglomeration of the grains with one another than when it is desired to promote the formation of a homogeneous film around the grains.
According to the process of the invention, it is possible, after having determined a given active principle release profile, to vary the values of spraying air pressure and of spraying rate throughout the coating stage, making it possible to promote the formation of a homogeneous film around the grains or to promote the agglomeration of the grains.
Once the sequence of the duration of the spraying air pressure and of the spraying rate has been determined, the coating operation can be carried out continuously and automatically.
According to another characteristic of the invention, the temperature of the mixture of liquefied matrix agent and of spraying air must be greater by 35° C. to 60° C. than the melting temperature of the lipid matrix agent.
Likewise, the temperature of the fluidization air and that of the powder must be equal to the melting temperature of the lipid matrix agent, plus or minus 10° C.
Furthermore, in order to obtain a mixture of individual grains, an air-operated fluidized bed device or a turbine device is used.
Furthermore, the lipid matrix agent can be sprayed by the air spray technique, that is to say liquid spraying under pressure in the presence of compressed air.
According to a first embodiment, use is made
Barthelemy Philippe
Farah Nabil
Joachim Joseph
Gattefosse S.A.
Norris & McLaughlin & Marcus
Page Thurman K.
Pulliam Amy E
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