Process for obtaining a modafinil-based pharmaceutical composition, resulting pharmaceutical composition and use thereof

Abstract

The present invention relates to a novel method for obtaining a pharmaceutical composition based on modafinil. This method consists of solubilizing S modafinil in a fluid in the supercritical state and then after expansion of said fluid, recovering S modafinil by causing it to be absorbed at the surface by a support appearing as granules. Said fluid may be CO.sub.2 or another solvent and the support, anhydrous lactose or mannitol. Application of the pharmaceutical composition in the cases when increased short term alertness and over a short period is required for the consumer of the pharmaceutical composition.

Claims

1. A method for obtaining a S modafinil-based pharmaceutical composition, the method consisting of the following acts, which are performed successively: solubilizing S modafinil in a fluid in the supercritical state in order to form a solution; expanding the solution such that S modafinil is precipitated; and absorbing the precipitated S modafinil on an inert support in order to obtain granules.

2. The method according to claim 1, wherein the supercritical fluid is CO.sub.2.

3. The method according to claim 1, wherein the supercritical fluid is tetrafluoroethane.

4. The method according to claim 1, wherein the inert support is mannitol.

5. The method according to claim 1, wherein the inert support is anhydrous lactose.

6. A pharmaceutical composition obtained according to the method according to claim 3, the pharmaceutical composition comprising S modafinil, wherein upon administration of the pharmaceutical composition to a patient the S modafinil of the pharmaceutical composition is released from the pharmaceutical composition in less than 1 hour, and a therapeutic effect of the pharmaceutical composition lasts for a duration of between 3 and 4 hours.

7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is in an oral form.

8. The pharmaceutical composition according to claim 7, wherein the oral form contains from 25 to 200 mg of the S modafinil.

9. The pharmaceutical composition according to claim 8, wherein the oral form contains from 50 to 100 mg of the S modafinil.

10. The pharmaceutical composition according to claim 7, wherein the oral form is a tablet.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING

(1) FIG. 1 is illustration of data relating to the solubility of modafinil in CO.sub.2;

(2) FIG. 2 is illustration of data relating to dissolution studied via HPLC;

(3) FIG. 3 is illustration of DSC profiles of formulations of the S-modafinil/mannitol type prepared with the supercritical CO.sub.2 or tetrafluoroethane methods;

(4) FIG. 4 is a micrograph of mannitol (Pearlitol 200SD) (X3500) obtained via scanning electron microscope (SEM);

(5) FIG. 5 is a micrograph of Sample 1 obtained via SEM X3500:

(6) FIG. 6 is a micrograph of Sample 2 obtained via SEM X3500

(7) FIG. 7 is a micrograph of Sample 3 obtained via SEM X3500:

(8) FIG. 8 is a micrograph of Sample 4 obtained via SEM X3500;

(9) FIG. 9 is a micrograph of Sample 5 obtained via SEM X3500;

(10) FIG. 10 is illustration of data relating to the comparison of the dissolution kinetics of the 30% S modafinil/mannitol formulations;

(11) FIG. 11 is illustration of data relating to the comparison of the dissolution kinetics of the 30% S modafinil/mannitol formulations; and

(12) FIG. 12 is illustration of dissolution results where Modiodal, Formulation 4 (powder) and compound DASC 00512 (tablets dissolved in baskets) are compared.

(13) Modafinil appears as a crystalline white powder practically insoluble in water and partly soluble in methanol and acetone. The result of this is low bioavailability of modafinil; it is estimated to be about 40%; indeed the solubility of modafinil is too low, the absolute bioavailability was not able to be determined.

(14) Thus, it was sought to improve the solubility of modafinil; in particular, and this is one of the objects of the invention, the solubility of modafinil was studied in supercritical fluids.

(15) From among these supercritical fluids, mention may be made of CO.sub.2: the technology of supercritical CO.sub.2 is based on the solvent power of CO.sub.2 which may be modulated at will depending on the pressure and temperature conditions applied to it.

(16) In the supercritical state (more than 74 bars and 31° C.), CO.sub.2 has very particular properties. The obtained fluid is characterized by great diffusivity (of the order of that of gases), which gives its good capability for diffusion, and a high density which provides it with a significant transport and extraction capacity.

(17) A method for extraction with supercritical CO.sub.2 operates in a closed circuit. It includes pressurizing units (pumps) and a temperature-setting unit (exchangers) in order to bring CO.sub.2 above its critical point.

(18) The product to be treated is placed in an extractor crossed by the supercritical CO.sub.2 flow. Molecules which are soluble in supercritical CO.sub.2, therefore extractable, are not very polar compounds with a low molecular mass.

(19) The supercritical fluid has several advantages as compared with a liquid fluid:

(20) a great diffusivity coefficient and a small viscosity coefficient;

(21) an absence of surface tension, which increases the penetration power of the supercritical fluid.

(22) A supercritical fluid has another advantage as compared with other solvents: its solubility changes depending on whether its temperature or its pressure is varied. Thus it is possible to ensure that it be a solvent for certain substances at a given moment and not at all, at the next instant. This facilitates recovery of the substance which has been dissolved.

(23) Thus, it has been realized that modafinil has acceptable solubility in CO.sub.2 as shown in FIG. 1.

(24) It was then sought to spray the dissolved active ingredient onto an inert support so as to have granules consisting of said support, at the surface of which particles of modafinil obtained according to the aforementioned method were absorbed. The grain size of these particles as well as the crystalline form of these same particles was subject to extensive study.

(25) Several tests were conducted, first by using anhydrous lactose as a support.

(26) Different samples were made by varying the parameters: extraction temperature and pressure, pre-expansion temperature, expansion pressure, percentage of liquid CO.sub.2.

(27) By studying the crystalline forms of the powders obtained by differential thermal analysis or X-ray diffraction and by comparing these same data with those of the literature, it may therefore be concluded that the profiles are identical and correspond to anhydrous lactose and to the IV form of racemic modafinil.

(28) Dissolution was then studied in HPLC, baskets 50 rpm; dissolution medium: HCl 0.1 N; bath temperature: 37° C.; volume: 450 ml; test sample equivalent to about 50 mg of S modafinil; Formulations put into gelatin capsules of size 000 (2 gelatin capsules).

(29) The obtained results appear in FIG. 2:

(30) An increase of the dissolution in vitro as compared with the mixture alone (SAD P1/lactopress) is observed.

(31) Different parameters were then modified:

(32) changing the support for mannitol,

(33) increasing the loading level up to 30% of an active ingredient load

(34) using S modafinil

(35) a solvent other than CO.sub.2, notably tetrafluoroethane, more specifically 1,1,1,2-tetrafluoroethane.

(36) The table below repeats the result when using S modafinil, and mannitol instead of anhydrous lactose; further the loading level was increased to about 30%.

(37) TABLE-US-00001 Amount of Amount of Theoretical extracted collected Collection load levels Test modafinil (g) Solubility (g/g) formulation (g) yield (%) (%) Formulations prepared with supercritical CO.sub.2 Formulation 1 10.0 1.0.E−04 29.54 96 32.65 Formulation 2 9.5 9.3.E−05 29.40 98 31.52 Formulation 3 9.7 9.9.E−05 29.62 98 32.18 Formulations prepared with tetrafluoroethane Formulation 4 11.4 2.5.E−04 28.81 86 31.38 Formulation 5 11.5 1.9.E−04 26.68 80 31.66 Formulation 6 11.5 2.7.E−04 30.36 91 34.27

(38) The curves in FIG. 3 illustrate the comparison of the DSC profiles of formulations of the S-modafinil/mannitol type prepared with the supercritical CO.sub.2 or tetrafluoroethane methods with the reference physical mixture. The operating procedure for obtaining the modafinil entering these formulations is that of international application WO 2010/112702.

(39) FIGS. 4-9 are different micrographs of S modafinil particles were obtained by means of a scanning electron microscope (SEM) from 30% S-modafinil/mannitol formulations; Sample 2 having been obtained with CO.sub.2 as a supercritical solvent and Sample 4 with tetrafluoroethane.

(40) FIGS. 10 and 11 illustrate the comparison of the dissolution kinetics of the 30% S modafinil/mannitol formulations prepared with the supercritical CO.sub.2 method (medium HCl 0.1N)—Sample 2—and by the method using tetrafluoroethane—Sample 4.

(41) The analytical results of the formulations confirm the results obtained during the previous studies although the capture excipient has been changed:

(42) preparation of uniform titer formulations with good capture efficiency for S-modafinil particles;

(43) the DSC profiles are similar to the profiles of formulations prepared under the same operating conditions during the previous tasks;

(44) SEM observations of the formulations seem to indicate that S modafinil is crystallized in the form of particles with a size of the order of one micrometer;

(45) the dissolution kinetics are reproducible for both types of formulations and similar to the results obtained earlier. The dissolution rate of the supercritical CO.sub.2 formulations is rather slow. Formulations with tetrafluoroethane have a faster dissolution profile.

(46) The preparations obtained earlier were formulated so as to obtain tablets with a dose of 2 mg of S modafinil, these tablets being intended to be administered to the rat during a pharmacokinetic study.

(47) The method used is the following:

(48) after weighing each of the components, the excipients are successively introduced in an increasing weight order into a mixer;

(49) the mixture is then sifted for removing the possible clusters;

(50) the obtained mixture is then compacted and calibrated on a grid with an aperture of 1.25 mm at 250 rpm;

(51) it is then proceeded with compression on a SVIAC compressing machine.

(52) Formulation

(53) DASC00512:

(54) TABLE-US-00002 Raw materials g % Echantillon 4 5.000 55.64 Aerosil 200 1.250 13.91 PVP XL 0.358 3.99 PVP K30 0.765 8.51 Pearlitol 400 DC 1.523 16.95 Magnesium stearate 0.090 1.00 TOTAL 8.987 100.00

(55) The dissolution results are shown in FIG. 12 where Modiodal, Formulation 4 (powder) and compound DASC 00512 (tablets dissolved in baskets) are compared.

(56) The S modafinil formulation obtained according to the supercritical fluid method actually confirms that it allows both very fast release (less than 1 hour) and an effect with limited duration (between 3 and 4 hours): it is this dual feature which makes the formulation according to the present invention, interesting.

(57) This formulation consists in granules forming a support, for example mannitol or anhydrous lactose, or any other inert support on the surface of which S modafinil particles obtained with the supercritical fluid technology have been absorbed.

(58) Advantageously, the obtained tablets from this formulation will be dosed between 25 and 200 mg of S modafinil, and even more advantageously between 50 and 100 mg. The aforementioned feature allows the use of these tablets as soon as the consumer needs increased alertness in the short term, i.e. very rapidly (less than one hour) for a short period (3 to 4 hours for example).