Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-12-08
2002-04-30
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S470000, C424S465000, C514S784000, C514S785000
Reexamination Certificate
active
06379700
ABSTRACT:
The invention relates to a process for manufacturing tablets for the sustained release of active principle(s), as well as to the tablets thus obtained.
In the description and in the claims, the expression “tablet for the sustained release of an active principle” denotes a tablet which can extend the therapeutic effect of the active principle in tissues or in the blood over a sustained period of time (see in particular “The Science and Practice of Pharmacy”, 19th edition, Remington 1975).
Several processes have been proposed for manufacturing tablets of this type.
Thus, for example, documents, FR-A-2 417 982 and HU-A-9960 disclose a process for manufacturing delayed-action tablets by wet granulation. More specifically, the powder mixture comprising the active principle and the various adjuvants is blended with a granulation liquid consisting of an aqueous emulsion based on a hydrophobic component such as stearic acid and nonionic hydrophilic components such as polysorbates. The resulting wet mass is then dried, after which it is passed through a screen and the granules obtained are then pelletized so as to obtain tablets. The steps of blending, screening, drying and pelletizing the powder mixture make this process long and expensive.
Similarly, document WO 94/06416 discloses tablets consisting of a core coated with a double layer, respectively a first layer containing at least one immediate-release or modulated-release active principle, a second layer for the delayed release of active principle and an additional layer of low permeability. By means of a relatively long process, a tablet is thus obtained which has a complex structure and for which the release kinetics of the active principle are predetermined during manufacture.
Moreover, document WO 87/04070 discloses a process for spraying onto tablets an aqueous dispersion prepared by redissolving a dried lipid emulsion, based on wax or on hydrogenated oils, in water.
Document JP-A-53 062 821 discloses a process consisting in emulsifying a lipophilic substance melted in an aqueous phase and then in coating a pharmaceutical preparation by spraying with this emulsion at elevated temperature, above the melting point of the lipophilic substance (technique known as dry-spraying). Besides the fact that nothing is indicated regarding the nature of the coated pharmaceutical preparation, this technique has the drawback of resulting in, during spraying, an evaporation of the aqueous phase and thus in a modification of the coating conditions.
Document WO 98/14176 discloses a process for manufacturing tablets for the sustained release of active principle which are obtained by tableting granules that are hot-coated with a lipid matrix agent. This hot-coating technique not only has the drawback of giving rise to an additional energy expenditure, but also of requiring an adaptation of the standard equipment.
The problem which the invention proposes to solve is thus that of developing tablets for the sustained release of active principle(s) and whose manufacturing process is simple to carry out, potentially shorter and consequently less expensive than the processes proposed in the prior art.
To do this, the invention proposes a process for manufacturing tablets for the sustained release of active principles), in which:
an oil-in-water fluid emulsion is prepared;
the emulsion obtained is sprayed onto a powder mixture comprising at least the active principle;
the powder thus treated is subjected to a tableting step, in order to obtain tablets.
Specifically, it has been found, entirely surprisingly, that although the coated particles have no sustained-release properties, a subsequent conventional step of tableting these particles produces tablets that have sustained-release characteristics.
In one advantageous embodiment of the invention, the powder mixture comprises not only the active principle but also the formulation excipients.
The expression “formulation excipient” denotes the excipients required to formulate the desired presentation form.
Similarly, the tableting step can be carried out using any known excipient intended to promote the said tableting.
According to a first characteristic of the invention, the spraying-air temperature is between 20° C. and 60° C., advantageously 25° C., the temperature of the emulsion being set at between 20° C. and 25° C.
At a temperature above 60° C., the process becomes economically less viable. Moreover, a considerable risk of degradation of heat-sensitive active principles is noted.
In other words, besides the fact that this process makes it possible to obtain sustained-release tablets, it also has the advantage of being carried out at room temperature (the temperature of the spraying air and of the emulsion is advantageously equal to 25° C.) and is thus less expensive.
In one specific embodiment, the initial powder mixture is subjected beforehand to a granulation step in order to obtain granules.
To facilitate the spraying of the emulsion onto the powder mixture, the said emulsion is advantageously prepared by phase inversion, so as to modify the particle size distribution, thus making it possible to reduce the particle size and hence the viscosity of the emulsion.
According to another important characteristic of the invention, the oil-in-water fluid emulsion comprises from 5% to 35% by weight of fatty substance.
For a concentration of less than 5%, the concentration of fatty substance is insufficient to ensure sustained release of the active principle.
For a concentration of more than 35%, the viscosity is too high to obtain a fluid emulsion. In addition, the tableting step is difficult.
Moreover, to allow tableting of the particles, the said particles are coated in a proportion of from 3% to 100% by weight with fluid emulsion, advantageously from 10% to 60%.
For a coating of less than 3%, only partial coating of the particles is observed.
Similarly, for a coating of greater than 100%, the tablet becomes too big to be a suitable presentation form.
In order to obtain a sustained release of the active principle, the fatty substances are chosen from the group comprising fatty acids, hydrogenated oils, fatty acid esters of glycerol or of polyols, and natural waxes.
According to a first embodiment, the fatty substance chosen is glyceryl behenate sold by the Applicant under the trade name Compritol® 888 Ato.
According to another embodiment of the invention, the fatty substance is glyceryl palmitostearate sold by the Applicant under the trade name Precirol® Ato 5.
To prepare the fluid emulsion at room temperature, the emulsion also contains an emulsifier or surfactant.
The surfactant used is chosen from nonionic and/or ionic surfactants.
More specifically, the emulsifier will be chosen so as to make the emulsion fluid and stable and to ensure the absence of formation of a foam. In addition, the emulsifier must be pharmaceutically acceptable.
The emulsifier advantageously chosen is polyethylene glycol 4000 palmitostearate.
According to another embodiment, the emulsifier is sodium lauryl sulfate used in a proportion of from 0.5% to 1% relative to the weight of the emulsion. Beyond 1%, no improvement of the emulsion is obtained and the formation of a foam is observed.
Similarly, so as not to obstruct the tubes and nozzle of the spraying machine, the viscosity of the oil-in-water fluid emulsion is set at between 10 and 70 centipoises.
The invention also relates to the tablet for the sustained release of active principle(s) which can be obtained by the process described hereinabove.
The invention and the advantages arising therefrom will emerge more clearly from the implementation examples which follow, in support of the attached figures, in which:
REFERENCES:
patent: 4199560 (1980-04-01), Gyarmati et al.
patent: 4684632 (1987-08-01), Schulz et al.
patent: 8-198776 (1996-06-01), None
patent: 87/04070 (1987-07-01), None
patent: 94/06416 (1994-03-01), None
patent: 94/12180 (1994-06-01), None
patent: 98/14176 (1998-04-01), None
Gyarmati et al. “Solid oral pharmaceutical compositions of regulated rate of release”
Farah Nabil
Joachim Joseph
Prindirre Pascal
Gattefosse S.A.
Heslin Rothenberg Farley & & Mesiti P.C.
Spear James M.
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