Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1998-09-01
2001-04-24
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S474000, C424S464000, C424S468000
Reexamination Certificate
active
06221395
ABSTRACT:
FIELD OF THE INVENTION AND STATE OF THE ART
Biological active agents poorly soluble in water or in biological fluids have always represented remarkable problems of bioavailability when they are administered in pharmaceutical formulations for oral use.
This problem happens both in the case of preparation of fast release tablets and, mostly, in the case of tablets and/or whatever of therapeutic systems from which the active principle has to be released in an extended interval of time.
In fact, in the case of so-called “retard” tablets, the very low solubility of the drug produces a very changeable release speed of the active principle from the pharmaceutical formulation and, as consequence, a changeable and wrong absorption and, therefore, therapeutical effect.
Practically the dissolution speed of the active principle results as the restrictive factor of the absorption process and the followed therapeutic activity.
Many attempts have been carried out to modify the parameters which influence the dissolution speed of a biological active and poorly soluble agent.
The employment of micronized active agents, which show so wide superficial area, results widely utilized and well known by the expert of the art.
In fact, the process of dissolution of an active agent is regulated of the Noyes and Withney law which is usually expressed in the following form:
ⅆ
c
ⅆ
t
=
DS
(
Cs
-
C
)
h
wherein
dc/dt=dissolution speed; it is the quantity of agent that dissolves in the unit of time
D=diffusion coefficient of the substance (depending from the molecular weight, from the viscosity of the medium, from the temperature, etc.)
h=thickness of the diffusion layer
S=total superficial area exposed to the medium of dissolution
Cs=concentration of the agent in the diffusion layer
C=concentration of the drug in solution in mass.
Procedures of micronization have been used to increase the dissolution speed of a lot of active principles like, for example: chloramphenicol palmitate, terfenadine, nitrofurantoine, naftazone, griseofulvine, even if, in this last case, an increase of the dissolution speed gives a great increase both of the activity but mostly of the toxicity of the product.
Also in the case of nifedipine, a drug widely used in the treatment of hypertension, it is known that a rapid effect of the drug can be obtained by using the micronized product, while by using the active principle in a greater granulometry or more precisely with a superficial area lower than 5 m
2
/g it is obtained a retard in the dissolution speed and therefore a slower absorption speed and, consequently, a retarded therapeutical effect. This last procedure to obtain slow release pharmaceutical formulations has been claimed in German patents 2,209,526 and DE A1 3,033,991 even if the active agent with a precise granulometry and/or with a superficial area under the limits described in the quoted patent is particularly complex and not easily standardizable to obtain.
Different methods have been carried out to increase the dissolution speed of poorly soluble active agents like, for example, the transformation of the active substances from a crystalline to an amorphous state which represents, usually, an increase of the solubility and so of the dissolution speed too, for example the 1-acetoxy-ethyl-cefuroxime (axetylcefuroxime) (v. Gouda M. W. et al: Drug Develop. & Ind: Pharm. 3, 273, 1977).
To obtain similar results clathrates or inclusion complexes with polymers like polyvinylpyrrolidone, polyoxyethylenglycol, polyvinylalcohols, celluloses and derivatives have been prepared and in particular the complexes with cyclodextrins have provoked a lot of interest, even if it has to be underlined that these modifications involve a great increase of weight of the pharmaceutical formulation because at least a ratio of 1:1 molar between the drug and the polymer is usually utilized.
A wide series of possibilities to increase the dissolution speed of poorly active principles is described in the test “Technique of solubilization of drugs” of S. H. Yalkowsky-M. Dekker New York 1985.
A different technique to increase the dissolution speed of not very soluble active agent is claimed in the Italian patent no 1.188.165 (see application no 20474 A/85) and in the Italian patent no 1.246.188 and in the U.S. Pat. No. 5,476,654 in which it is used a procedure to load the poorly soluble drug on a support formed by hydrophylic swollen polymers or through a co-mixing and/or co-grinding process.
Nevertheless, all these methods allow to obtain an increase of the dissolution speed of an active principle but they don't guarantee a better bioavailability of the same, in particular, when this poorly soluble active principle, is carried out in a pharmaceutical formulation for oral use.
Like above mentioned, an increase of the dissolution speed of a poorly soluble drug is necessary for the preparation of fast-release tablets, but mostly for modified-release tablets, in order to allow that the absorption of the drug is not limited from the speed of its solubilization.
In the particular field of the controlled or modified release, the systems able to release the active principle at constant speed during time, namely systems that are usually defined with zero-release kinetics, are great important.
In fact, for example, in the case of hydrophilic matrixes, which form the class of the most utilized and diffused pharmaceutical formulations, the release of the drug shows at the beginning the fast release of a dose fraction (“burst effect”), phenomenon which has to be avoided because it can determine the outbreak of toxic effects linked to excessive absorption.
To avoid the “burst effect” different solutions have been proposed and adopted like to save a fraction of the matrix surface with a waterproof layer, at least for a determined interval of time, like described in the U.S. Pat. No. 4,839,177 and U.S. Pat. No. 5,422,123.
A different solution to the problem of the “burst effect” is the suggestion to add, in the formulation of the hydrophilic matrix, ionizable, pharmaceutically acceptable, compounds.
This last solution is reported in the U.S. Pat. No. 5,419,917 in which it is described that the employment of polar substances in an hydrophilic matrix shows a great reduction of the dissolution speed of the active principle carried in the hydrophylic matrix.
DESCRIPTION OF THE INVENTION
Now we have unexpectedly found, and it is the object of the present industrial patent, that, the use of particular concentrations of surface-active agents in a hydrophilic matrix, allow to obtain an increase of the dissolution speed of a poorly soluble drug and, in this way, also an improvement of the absorption and bioavailability of the active principle carried in this matrix.
These systems of matrix release, composed by pharmaceutical tablets of one or more layers, one of which contains the active principle, can be produced by using precise productive and high industrial reproducible technologies. Moreover, we have, unexpectedly found that these systems do not determine “burst effect” and especially, they allow to eliminate the variability of the absorption caused by differences in the granulometry of the poorly soluble active principle.
In this way we have carried out and experimentally proved a new therapeutic system, with modified and controlled release, that solves the problem of the “burst effect” bound to the matrix systems. This system shows innovative advantages of safety and therapeutic efficacy, because the release of the active principle happens in a complete and reproducible way and the absorption results effective and high, like it is showed by the data relative to the plasma concentrations (C
max
), obtained after the administration to the healthy volunteer, as it will be reported in the examples of the present patent.
Object of the present invention is a tablet of one or more layers one of which, at least, carries the active principle while the other one, or the others layers, have mostly the function of barrier wi
Conte Ubaldo
Grenier Pascal
Maggi Lauretta
Vergnault Guy
Zimmer Robert
Jagotec AG
Leydig , Voit & Mayer, Ltd.
Page Thurman K.
Seidleck Brian K.
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