# Patent

## Title
Human immunodeficiency virus decoy

## Abstract

The present invention relates to a sustained-release tablet, characterized in that it comprises as active principle isosorbide 5-mononitrate (5-ISMN) in the form of a powder having a particle size of 80 .mu.m to 500 .mu.m, in homogeneous dispersion in a hydrophilic matrix based on at least one swelling component and at least one diluent component.

## Background
The present invention relates to a pharmaceutical composition based on isosorbide 5-mononitrate, and having a dosage form which is suitable for prolonged release of this active principle over time.

Isosorbide 5-mononitrate (5-ISMN), an active metabolite of ISDN, is the first representative of a new generation of nitrated vasodilators. It permits an effective preventive treatment of anginal disease, and the absence of a hepatic first-pass effect endows it with advantageous properties in cardiac insufficiency.

However, 5-ISMN has drawbacks which make it difficult to prepare it in a sustained-release dosage form, namely: impossible as a result of a virtually zero flowability, conditions (60.degree. C.-75% relative humidity), and it difficult to control the release of the active principle from the dosage form.

The object of the present invention is to develop a suitable dosage form of 5-ISMN enabling the abovementioned drawbacks to be eliminated.

Thus, it was demonstrated that a well-defined particle size fraction of 5-ISMN in the form of a powder had the appropriate qualities for such a formulation, namely a low level of electrostatic phenomena, a far less marked tendency to sublime and qualities of flowability and compressibility.

More specifically, the present invention relates to a tablet, characterized in that it comprises as active principle isosorbide 5-mononitrate (5-ISMN) in the form of a powder of particle size 80 .mu.m to 500 .mu.m, determined by the air-Jet sieve method, in homogeneous dispersion in a hydrophilic matrix based on at least one swelling component and at least one diluent component.

The use of a powder of such particle size, namely having particles between 80 .mu.m and 500 .mu.m in size, and preferably having 70% of these particles between 80 .mu.m and approximately 250 .mu.m in size, has, moreover, a further advantage. It makes it possible to avoid the use, during the manufacture of said composition, of the wet granulation technique which is a common method but one which has drawbacks.

The air-Jet sieve method used according to the invention to define the particle size of the 5-ISMN is a technique widely used by those skilled in the art on account of its great sensitivity and reliability, and is consequently very familiar to them. The operating conditions employed in the context of the invention will be clarified in greater detail below.

The preferred particle size profile for the 5-ISMN according to the invention and determined according to this technique corresponds to approximately: 100 .mu.m, .mu.m, and

the residue consisting of 5-ISMN having a particle size smaller than 80 .mu.m.

As regards the hydrophilic matrix, this comprises at least one swelling component and one diluent component in a swelling/diluent weight ratio of between 0.2 and 0.7, and preferably equal to 0.5.

The diluent component (diluent) contains at least one intrinsic diluent and one thickening diluent, in a thickening diluent/diluents ratio of between 0.1 and 0.6, and preferably equal to 0.3.

This combination makes it possible to stabilize the in vitro release of the 5-ISMN essentially during the terminal stage of the two-phase release.

According to the present invention, the intrinsic diluent is preferably chosen from one or more substances comprising lactose, sorbitol, mannitol, calcium phosphate or sulfate, colloidal silica and/or microcrystalline cellulose. On the other hand, this intrinsic diluent may not be chosen from polyvinylpyrrolidone and the close derivatives thereof.

The thickening diluent (thickener) is preferably chosen from one or more substances comprising starches, starch derivatives, microfine cellulose, xanthan gums, natural or semi-synthetic, and/or dextrins.

As regards the swelling component (swelling agent), this is preferably chosen from one or more hydrophilic polymeric substances of apparent viscosity, at a concentration of 2% by weight relative to the weight at 20.degree. C., between 0.1 Pa.s and 100 Pa.s. These hydrophilic polymer substances are preferably chosen from the family of proteinaceous or cellulosic hydrocolloids, and in particular from alginic derivatives, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose and/or methylhydroxypropylcellulose. Preferably, methylhydroxypropylcellulose of viscosity in the region of 15 Pa.s will be used.

These polymers may be used alone or in combination with one another.

As a result of the intrinsic qualities of the 5-ISMN thus selected and the characteristics of the hydrophilic matrix form used, a dosage form having excellent cohesion and characterized by two-phase and pH-independent kinetics of release in vitro is thereby obtained.

The tablets thereby obtained contain from 5% to 20% by weight of active principle relative to the total weight of the tablet. This content will preferably be equal to approximately 10% by weight of the active principle relative to the total weight of the tablet.

Finally, according to a preferred embodiment, an aqueous film-coating, preferably based on compatible cellulose derivatives of the hydroxypropylcellulose or methylhydroxypropylcellulose type, with the addition, where appropriate, of a plasticizer of the glycerin and/or polyethylene glycol type, is applied to the matrix base described above.

This film-coating of hydrophilic matrices using an aqueous solvent proves to meet the requirements of maintenance of resistance to crushing without significant modification of the profile of release.

This same film-coating can naturally be colored by the addition of pigment suspensions prepared at the time of use.

The tablets according to the invention may also contain a lubricant such as stearic acid or derivatives, and/or a colorant, preferably pink in color, in the form of a synthetic organic shellac, for example erythrosine shellac.

The present invention also relates to a process for manufacturing said tablets, characterized in that: sieved and then mixed; mixture thereby obtained;

The tablets thereby obtained may be oval in shape and optionally divisible.

Such a dosage formulation of isosorbide 5-mononitrate hence has the advantages of reducing the number of daily doses, of decreasing the side effects characteristic of nitrated derivatives and which are linked to excessively high plasma concentrations, and consequently of obtaining a mean plasma level which is stable over several hours after administration. A tablet based on isosorbide 5-mononitrate according to the invention hence enables a sustained and regular release of this active principle to be secured over a time period of approximately 6 to 18 hours.

The tablets obtained according to the invention are especially useful for the treatment of anginal disease and cardiac insufficiency.

The examples and figures given below without implied limitation will enable other advantages and characteristics of the present invention to be demonstrated.

FIG. 1 shows the kinetics of release of 5-ISMN contained in a composition according to the invention, in vitro as a function of time.

FIG. 2 shows the kinetics of release of 5-ISMN contained in a tablet according to the invention, in vitro as a function of different pH values.

FIG. 3 shows the mean curve for the plasma 5-ISMN levels obtained after administration of the compound in the form of tablets according to the invention.

FIG. 4 shows the mean curve for the percentages of 5-ISMN absorbed. Tablet No. 1     2       3       4     5 ______________________________________ Isosorbide 5-mono- 50.0    40.0    20.0  80.0  60.0 nitrate Lactose      140.0   170.0   60.0  200.0 200.0 Mannitol     50.0 Corn starch,         69.0    50.0        75.0 pregelatinized Xanthan gum  60.0                  100.0 MHPC 4 Pa.s                  20.0 MHPC 15 Pa.s 107.0   115.0   40.0  150.0 100.0 Magnesium stearate 4.35    3.88    2.6   4.45  4 Colloidal silica, 2.5     2.0     1.34  2.35  2.5 anhydrous Erythrosine shellac 0.15    0.12    0.06  0.2 E 127 Intermediate Unit 414.0   400.0   194.0 537.0 441.5 Mass MHPC, partially 13.95   13.955  5.975 11.65 substituted Polyoxyl 8 stearate Sodium lauryl sulfate 0.05    0.045   0.025 0.05 Glycerin Codex 2.0     2.0     1.0   2.3 Final Unit Mass 430.0   416.0   201.0 551.0 441.5 ______________________________________ invention by the air-jet sieve, type ALPIN JET SIEVE, method

Under these conditions, three batches of 5-ISMN, A, B and C, were tested. The results are presented in the following table: A          B      C Desired profile %          %      % ______________________________________ 80 .mu.m 40 .ltoreq.  .ltoreq. 60 47.5     48.2 49.2 100 .mu.m 20 .ltoreq.  .ltoreq. 50 26       34.4 34.85 250 .mu.m .ltoreq. 5          0.0      0.9  0.0 500 .mu.m .ltoreq. 0.5        0.0      0.0  0.0 ______________________________________

These three batches clearly have the desired particle size profile.

The study of the changes in the percentage of 5-ISMN dissolved was performed as a function of time. This test was carried out using a rotating paddle apparatus (100 rpm/900 ml of water). The results obtained are as follows, and are shown in FIG. 1:

This study was carried out at pH values of 1.5, 4.25 and 7.2 and variable values. The results obtained are shown in FIG. 2.

The three kinetic profiles of release at constant pH do not differ significantly from one another. As regards the dissolution profile obtained at variable pH, on being superposed on the above profiles, it attests to a pH-independent mode of release.

FIG. 3 shows the mean curve for the plasma levels of 5-ISMN observed after administration to 3 subjects at a single dose of a tablet No. 2; the pharmacokinetic parameters calculated during this pilot screening study are as follows: Tmax        Cmax      T 1/2  MRT    AUC o-oo h           ng .multidot. ml.sup.-1 h      h      ng .multidot. ml.sup.-1 .multidot. ______________________________________ h MEAN    4.67    386.27    4.72 10.02  4670.33 S.D     1.53     35.44    2.06  1.46   470.08 ______________________________________

On this mean plasma curve, taking into account the existence of a recorded minimal effective concentration value of 100 ng.ml.sup.-1 (=C.sub.eff), the maintenance of plasma levels above this value, without a significant latency time, during a time period t C C.sub.eff (sic) in the region of 16 hours, is noted.

FIG. 4 shows the mean curve for the percentages of 5-ISMN absorbed. The absorption profile obtained is characterized by a zero order entry up to approximately the fifth hour following administration; in consequence, the constant mean flux of in vivo absorption calculated from this curve is of the order of 13.37% h.sup.-1.

## Claims

1. Sustained-release tablet, characterized in that it comprises as active principle, isosorbide 5-mononitrate (5-ISMN) in the form of a powder having the following particle size profile: and smaller than 100 .mu.m, .mu.m and smaller than 250 .mu.m, 250 .mu.m and smaller than 500 .mu.m, 500 .mu.m, size smaller than 80 .mu.m, swelling agent and at least one diluent, at a swelling agent to diluent weight ratio of between 0.2 and 0.7, said swelling agent containing a hydrophilic polymeric substance of apparent viscosity between about 0.1 and 100 Pa.s.

2. Sustained-release tablet according to claim 1, characterized in that the powder is preferably an isosorbide 5-mononitrate powder in which at least 70% of the particles are between 80 .mu.m and approximately 250 .mu.m in size.

3. Sustained-release table according to claim 1 or 2, characterized in that the active principle is present in the proportion of 5 to 20% by weight, and preferably in the proportion of approximately 10% by weight, relative to the total weight of said tablet.

4. Sustained-release tablet according to claim 1, characterized in that the swelling agent and the diluent are present in the said tablet according to a swelling agent/diluent ratio of between 0.2 and 0.7, and preferably equal to approximately 0.5.

5. Sustained-release table according to claim 4, characterized in that the swelling agent contains a hydrophilic polymeric substance of apparent viscosity between about 0.1 and 100 Pa.s.

6. Tablet according to claim 5, characterized in that the hydrophilic polymeric substance is chosen from the family of proteinaceous or cellulosic hydrocolloids, and preferably from alginic derivatives, natural gums, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose and/or ethylhydroxypropylcellulose.

7. Sustained-release tablet according to claim 6, characterized in that the polymeric substance is preferably methylhydroxypropylcellulose of viscosity of about 15 Pa.s.

8. Sustained-release tablet according to claim 1 or 2, characterized in that the diluent contains at least one intrinsic diluent and one thickener.

9. Sustained-release tablet according to claim 8, characterized in that the thickener/-diluents ratio is between 0.1 and 0.6, and preferably equal to approximately 0.3.

10. Sustained-release tablet according to claim 9, characterized in that the intrinsic diluent is preferably chosen from lactose, sorbitol, mannitol, calcium phosphate or sulfate, colloidal silica and/or microcrystalline cellulose.

11. Sustained-release tablet according to claim 8 or 9, characterized in that the thickener is preferably chosen from starches, starch derivatives, xanthan gums, microfine cellulose and/or dextrins.

12. Sustained-release tablet according to claim 1 or 2, characterized in that it comprises, in addition, an aqueous film-coating based on cellulose derivatives.

13. Sustained-release tablet according to claim 1 or 2, characterized in that the tablet also comprises other additives chosen from lubricants or coloring substances.

14. Process for manufacturing a tablet according to claim 1 or 2, characterized in that the following are carried out: principle, mixture,