CA2182024C - Method for preparing dry pharmaceutical forms, and resulting pharmaceutical compositions - Google Patents

Abstract

A method is provided for use in the field of therapeutical chemistry and pharmaceutical technology in particular. Solid dispersions of medicinal agents in a hydrophilic carrier agent are provided, wherein the active principle is dissolved in a volatile organic solvent containing a highly hydrophilic cyclic amide, and the organic solution is sprayed and dried to give a coprecipitate that is crushed, screened and diluted with an excipient or a pharmaceutically acceptable carrier. The coprecipitate is useful as a starting material for preparing drugs.

Description

x, 182024 .
PROCESS FOR THE PREPARATION OF PHARMACEUTICAL FORMS
DRIED AND PHARMACEUTICAL COMPOSITIONS
ACHIEVED
The present invention relates to the field of therapeutic chemistry and more especially in the field of pharmacotechnics.
The subject of the invention is a process for the preparation of pharmaceutical forms whose resorption of the active ingredient by the digestive tract is improved.
More particularly, it relates to a method for preparing forms pharmaceutical products intended for digestive administration of which the resorption is faster or more important.
It relates specifically to a process for the preparation of dispersions drug agents in a hydrophilic carrier better solubility in aqueous media and better resorption in the digest'rf tract, a process in which the active ingredient (s) are dissolved in an organic solvent containing a very hydrophilic cyclic amide and in that 2o the organic solution thus obtained is evaporated to dryness and then ground and screened or possibly used as is.
When the organic solution brought to dryness is crushed, the powdered product in Resultant may be diluted with excipients or pharmaceutical vehicles z5 or subjected to a coating by a fluidized bed of air.
The dry dosage forms thus produced can be packaged tablets, lozenges, pills, capsules, capsules or sachets according to usual techniques of industrial galenics.
It is also possible to form, by coating in a fluidized air bed, a granule that can be broken, sifted and compressed or kept intact and spread in waterproof bags ready for use.
We have known for some years now, beside (classical exploration of pharmacological and toxicological properties of drugs, we care about more and more of the quantitative aspect of the resorption of the active principle.
this . ~ I ~~ 024 z becomes more and more the subject of systematic studies because the intensity, and sometimes the nature of the response, are a function of the concentration attained in level of the action site. The importance of pharmacokinetic and bioavailability has highlighted (interest changes made during of the preparation of galenic forms, especially those adapted for administration by the digestive tract.
Drugs that are poorly soluble in water or difficult to salt during passage in the stomach are only partially resorbed. Literature previous study showed that digestive resorption could be modified in a favorable sense by (study of the particle size, by the addition nonionic surfactants or by addition of an agent solubilizer.
Micronization that increases the external surface area of a product powder is already an approach to the problem, but is only suitable for some pharmaceutical forms such as suspensions or capsules. She does not can be a general solution to this problem.
The addition of surfactants can increase the solubility of the principle active and thereby improving the kinetics of resorption, but does not allow necessarily to obtain higher blood levels. fl is in addition, often necessary to add very large quantities (25 to 50%) agent surfactant to achieve a certain result. This improvement of the passage by digestive tract appears to result from a decrease in surface tension leading to an increase in the permeability of the digestive mucosa.
The beneficial effect obtained by adding an emulsifying agent and in particular of a carbohydrate fatty acid ester, follows from a different principle. This ester increases the lipophilicity of the molecule and makes the intestinal barrier more easily passable. Nevertheless, this type of process only gives results with very lipophilic molecules and requires high concentrations of esters acid fat and carbohydrate.
It is also known that for active substances whose absorption at the level of gastrointestinal tract is limited by their low solubility in the liquids biological, one of the possibilities offered to galenists for the improvement of their kinetics of dissolution is the preparation of solid dispersions. These solid dispersions (defined by CHIOU WL and RVEGELMAN S. in J. Pharm Sci. 60, 1281-1302, 1971) are systems which according to the method in use for their manufacture, can present various structures [see FORD
JL, Pharm. Acta. Helv. 61, 3, 69-88, (1986) BLOCH DW and SPEISER PP - Pharm.
Acta. Helv. 62, 23-27, (1987)), corresponding to crystallographic states The vitreous state, although a solid state, is approaching by its structural disorder of the liquid state. It is an unordered state, easy to break up and which significantly improves the dissolution rate of the least soluble.
Nevertheless, despite the large number of publications relating to the preparation of solid dispersions, especially in macrogols or poloxamers, this technique has not experienced significant development because of its lack of generality. In some cases, the dissolution rate is large. In In other cases, the dissolution rate is lower and tends towards a value asymptotic. For the same medicine and for the same concentration, shows very large variations in solubility rates in depending on the nature of the co-founder and even in some cases the impossibility of obtaining a complete solubilization of the active ingredient, even after prolonged contact time However, it turns out that resorption in the digestive tract occurs during a short time and on a small space. It is therefore important that in formulation according to the invention, the active ingredient is brought rapidly and completely under a solubilized form- The absorption rate depends on it.
It has been found that the best absorption kinetics are obtained with of the dispersions in very hydrophilic polymers and especially in a poly vinylpyrrolidinone as a co-precipitate. We obtain a rate of dissolution At least 80% in less than 10 minutes.
The Applicant's studies have shown that the dissolution rate was further increased the organic solvent contained, in addition, a area which further improves the wettability of the active ingredient and limits possibly the crystal growth phenomenon that occurs during conservation solid dispersions and which leads to a decrease in the kinetics of dissolution as a function of time.

~ 282Q24 ~, a Since 1961, when SEKIGUCHI and OBI proposed for the first time times the use of solid dispersions, about 300 publications on the how these systems are prepared and their physical characteristics.
chemicals, galenics and pharmaceuticals have appeared in the literature. This Pharmaceutical technique, widely described, concerns more than one hundred active ingredients dispersed in at least thirty carriers different hydrophilic substances and has, moreover, been the subject of a number Articles of synthesis.
Solid dispersions are systems in which one or more active ingredients are dispersed in the solid state (microparticulate, even molecular) in a solid inert vehicle. These solid dispersions are to be distinguished from simple powder blends commonly referred to as blends physical.
Two methods are commonly used for the preparation of dispersions solids: the fusion-solidification method which leads to the formation of and the dissolution-evaporation method which leads to the formation of of z0 coprecipitated. A mixed method, resulting from the combination of the two methods previous, is sometimes quoted, but is rarely used.
The process according to the invention uses the formation of co-precipitates by dissolution-evaporation. The highly hydrophilic polymer dissolved in the organic solvent is of preferably a polyvinylpyrrolidone of molecular weight ranging from 10,000 to 50,000, one (N-methylpyrrolidone), one (N-methylpiperidin-2-one) or N-methyl caprolactam. These cyclic lactams chosen are very soluble in water and make co-precipitates easily and completely soluble in water.
The organic solvent used is a solvent that dissolves both the principle active and the very hydrophilic polymer while having a sufficiently high degree of volatility large to be eliminated after dissolution of the whole without having use of physical means such as heat or vacuum, very powerful. Of such solvents are, for example, oxygenated solvents such as ethanol, isopropanol, tetrahydrofuran, isopropyl ether, acetone, methyl ethyl ketone, the tetrahydropyran, or chlorinated solvents such as methylene chloride or else mixtures in variable proportions of these same solvents.

The optionally added surfactant is preferably surfactant npn!
ionic. Preferably, the nonionic surfactant is chosen from lea ests polyoxyethyl ~ iquas of sorbitan and saturated or unsaturated fatty acids having at minus 8 carbon atoms, the polyoxyethylenic ethers of fatty alcohol having at least ;
8 carbon atoms and the styrene acid polyoxyethylenic esters.
The nonionic surfactant is selected from among those of character anctphiphile, but predominantly hydrophilic, an HLB? 12, as for example the esttrs Polyoxyethylenic sorbitan and fatty acid, such as Yween 20 to $ 0, the ' Polyoxyethylene ethers of fatty alcohol such as Bxi, j. 56-58-78-96-97-98-G3 $ 16 ct 3820,! 33910 and 39.0 or ET'H1'LAN * D234 Ä 257 or RENEX * Cremophor or labrafil or bulk copolymers, ethylene oxide / oxide of propylene such as PLIJkOI ~ IC * F68 or F87 or poloxaméze 188 at the synperonics 68 and 148.
The experiment showed that the TWEFNS "40 and 60 and the CREMOPHOR * EL are supplied ;
the best results. , Among the active ingredients poorly soluble in water, including formas, zo pharmaceutical according to! invention 8trc bridge restraint, orx will quote more especially:
-Anti-TNFLAMMATOIR15S and ANTAZ.C ~ TQUES ' salsalate ' bcnorylate ' oxametacine zs piroxicam, ninl.éSUlida floctafenine;
ethenzamide of I1VIM ~ TNO-SUPPRESSORS
3o cyclosporine -Of ANTI-HISTAMINIQUL?
te ~ 'enadine, * Marquc of ~ oerce ' ~ ~ 182U2 brompheniramine chlorpheniramine - ANTI-FUNGIC and ANTI-TRICHOMONAS
metronidazole ornidazole dapsone itraconazole - ANTI-VIRALS
cytarabine - ANTI-PSYCHOTICS
sulpiride i5 sultopride HORMONES
estradiol and esters estrone estriol progesterone and its derivatives - CARDIOVASCULAR agents dobutamine diltiazem nifedipine and the like ANTI-ULCEREUX agents pirenzepine - ANTIBACTERIAL agents erythromycin flumequin oxytetracycline piperacillin cefuroxime ~ 182 ~ 24 ~
ANTI-ARYTHMIOUI = S agents propafenone amiodarone cordarone ftécainide gallopamil verapamil dipyridamole düsopyramide io ANTI-MIGRAINE agents:
flunarizine Derivatives of (ergot of rye i5 - ANTIDEPRESSORS
fluvoxamine fluanisone - ANTI-HORMONES
2o flutamide BRONCHO-DILATATORS
tulobuterol talinolol 25 pre-altered ANXIOLYTICS
thiothixene trazodone 3o doxepin VASO-DILATATORS
ethaverine pentoxyphylline 5 eburnamonine DIURETIOUES
furosemide triamterene torasemide ANTI-SPASMODIC agents flavoxate trimebutine - inhibiting agents (excretion of calcium clodronate pamidronate - ANTI-COAGULANTS
pindione tromexan and / or HYPOCHOLESTEROILEMIANTS, and in particular, the derivatives of I ° CHOFIBRIQUE acid, as for example clofibrate the clofibride Fenofibrate gemfibrozil the bezafibrate The method also finds applications with metronidazole, fitraconazole, cyclosporine, piperacillin and cefuroxime.
In principle, the content of active ingredient in the compositions according to (invention is of the same order of magnitude as with the pharmaceutical compositions classics.
t5 A special interest is attached to products that are poorly or poorly absorbed in intestine such as progesterone, festradiol, festrone.
It is known that, in particular, a 17a substitution is necessary for the hormonosteroid agents are active orally (cyproterone acetate, I

Demegestone, Promegestone, Noreuiynodiol diacetate, Medroxyprogesterone, ethinyl estradiol), but this substitution has the effect of even , time, side effects (androgenic or anti-exert effect, effect estrogbne ..) çui zre are not necessarily sought after. It is therefore highly desirable to use them, s hormonal products in native form or in the form of a similar derivative (Dydrogesterone, 17a-hydroxy progesterone, ester or estradiol ether example) which does not carry these additional substituents in ~ 17a-. , Crr facilitates the resorption of such tti las molecules incorporating in form of, to solid dispexsians according to the invention, in the presence or in the fabaence of agents surfactants. , In such an environment, the active ingredient dissolves easily and rapidly in presence of water.

The amount of surfactant has ranged from 0.5 to 20% by weight total of the ts pharmacological form. In the particular case of drift progcst ~ eroniquos, we can make co-precipitates 9 from 10 to 60% by weight of principle assets, PRECIOUS CONTENTS range from 15 ~ 35 ° o o to ~ derived progestogenics and from 1 to 10%
of surfactant relative to the total mass of the pharmaceutical product.
In this way, progestational derivatives of the derivative 9 are obtained.
dissolve , almost completely in water or in an aqueous medium in 10 to 20 minutes with stirring according to the content of progesterone derivative.
The tests effcctubs by the Applicant have shown; .
-the presence of surfactant sum palysorbates and Cremophors ;
significantly improves the rate of release of the progesterone derivative.
whatever be the co-precipitate. This improvement is more important than the content ea, active ingredient increases in the sample. For example, rate ao means of dissolutiota of progesteranic derivative for the ca-precipitates to 3o and 50 °! 0 weight / weight with palysorbate, are xespoctively 95 and 60% in 10 minutes by 55 and 18 ° C for these samples prepared without polyaarbate. ~, ¿
that the dissolution rate of the progesterone derivative is independent of the pofysorbate content ~ 80 in coprecipitates at 2D and 30 °! °
weightlweight active ingredient, since the kinetics are practically superimposable. In however, this dissolution rate is dependent on the weight percentage of;
polysorbate 80 for coprecipitates at 50% w / w. The best kinetics is obtained with (sample containing 10% by weight of polysorbate $ 0 or, This result shows that a larger quantity of agent is surface is necessary to facilitate wetting and dissolution of derivative progesterone when its content is high in the coprecipitate.
>, o However, during their storage, solid dispersions although able to evolve towards thermodynamically more stable states, by recrystallization or enlargement of the size of the dispersed particles, factors time and temperature having a considerable impact on this transformation has appeared necessary to study the future of coprecies praesthesoneIPVP and proesterestheJPVPlpolyaorbate eo after ~ month of cvnseNation at different temperatures.
The test results showed that the dissolution kinetics of the derivative zo progesterone from preserved coprecipitate 8 three at ~ 4 ° C, 20'C and 3TC do not present no significant difference with respect to that established on the products freshly prepared, regardless of the storage temperature and whatever the concentration of active ingredient.
The coprecipits prepared according to (invention thus offer your guarantees the more complete with Stability.
The coprecipitate3 of active ingredient is dissolved in water quickly and However, it has subsequently proved desirable to obtain a form 3 o Galenic administered orally.
However, because of the particularly adherent nature of the mass, it is very difficult to obtain a powder active principle + pup sufficiently fluid, allowing to make galenic farms administrable per os.
This is why, according to the method of the invention, once obtained, the solution of active ingredient + PVP + solvanl. It is appropriate to remove the solvent spraying * Brand of Orne i this solution on neutral granules, in a stream of hot air, so get granules coated with active ingredient, in a perfectly homogeneous manner.
The granules according to the invention thus used are neutral granules. Those-this can be, according to a preferred embodiment of the invention, constituted of sucrose and lactose.
In order to spray this solution on the granules, a system of air bed 1o fluidized (GLATT) on which we can adjust the temperature, the air flow and the pressure.
The GLATT will be loaded with the neutral granules which are therefore in suspended in it and that perform ascending or descendants inside the airflow. These movements allow them to be coated throughout their surface by the active ingredient solution as and when measured that it is injected into the GLATT.
So that each particle is coated perfectly evenly by the 2o solution of active principle, the use of a film-forming agent will give this solution a plastic quality to perfectly coat each granule.
The agent Preferably, the film-forming agent used will be hydroxypropylmethyl cellulose (HPMC).
Since HPMC is not very soluble in ethanol, it is preferable to use solvent, an ethanol / methylene chloride mixture.
The granules thus coated will then be divided into capsules.
According to an advantageous embodiment, the coprecipitate obtained by evaporation at dry of the organic solution containing the active drug is so dispersed. This coprecipitate dispersion is sprayed onto microgranules neutrals, which are then film-coated with a cellulose derivative.

11a The following examples are provided by way of illustration of the invention without however limit it s EXAMPLES
The tests carried out therefore aimed at improving the kinetics of dissolution of an active ingredient, progesterone, with a view to improving the bioavailability of this hormone after oral administration.
In a first part, a number of dispersions were prepared solid by the fusion-solidification method and / or by the dissolution method.

~

'2182û24 i2 In a first portion. a number of dispersions have been prepared by the fusion-solidification method or by the dissolution-evaporation, using 5 hydrophilic excipients: the disfearate of sucrose, the polyoxyethylene glycol 4000, polyvinylpyrrolidone, citric acid and phospholipids. The techniques developed have made it possible to obtain reproducible, products with a marked improvement in kinetics of dissolution of progesterone. The optimal excipient for the pursuit of the study polyvinylpyrrolidone with which a coprecipitate containing 20%
weight / weight of progesterone has a dissolution rate of 80% in 10 minutes In a second part, we tried again to optimize the formulation of coprecipitated progesterone / PVP by modifying, on the one hand, the concentration of active principle in the samples and / or the evaporation conditions of the solvent, and studying, on the other hand, the influence of a surfactant incorporated into the formulation at different concentrations. It has been found that polysorbate 80 or the cremophor EL improved, very significantly, the speed of dissolution of progesterone. The best results are obtained with coprecipitates the more highly concentrated.
In a third part, it has been shown that the kinetics of dissolution of the progesterone after 6 months storage at 4 ° C, 20 ° C and 37 ° C were not significantly altered from those recorded on the products freshly prepared when the samples contained polysorbate 80.
However, for samples prepared without polysorbate 80, (raising the temperature may be a factor that is unfavorable to the good preservation of the samples, even if the modification observed has the effect a improvement of dissolution kinetics of progesterone. So we can assume that for temperatures close to 37 ° C, modifications of the 3o physical characteristics of the coprecipitates appear, as by example.
a glass transition, which promotes the release of the active ingredient.
In view of all these results, it appears that coprecipitation 30 to 50% w / w progesterone containing 5% w / w polysorbate 80 in PVP, has good galenic characteristics. Indeed, kinetics of dissolution of (hormone after conservation are superimposable to those obtained on freshly prepared product on the one hand, and on the other hand provide a dissolution rate greater than 95% in less than 10 minutes.
Another advantage of the process according to the invention lies in the fact that Its co-substances contain a high content of the active ingredient and that. from this done, we can make small pharmaceutical formulations and, sn particuliBr, small size capsules.
PRUGESTEFtONE
I ~ PFTPARATION OF WELDED DISPERSENTS ACCORDING TO INVEN110N
A - Preparation of physical mixtures physical mixtures containing 20, 30 and 50% w / w of progesterone in polyvinylpyrrolidons (xCa ~ .30 BASF) are prepared by stirring, for 10 minutes at the TURBULA '' merger. ~ For each sample, total quantity per manufacturing batch is 5 grams.
2a B - Preparation of progesterone coprecipitates The physical mixtures Gor ~ tertent variable proportions of progesterone are dissolved in a sufficient quantity of absolute alcohol. The dispersions solid sOrtt obtained by evaporation of the solvent under the following conditions - The speed of rotation of the balloon is 1b0 revolutions / minute - the temperature of the train-Marie is brought to SO ° C
the pressure inside the balloon is progressively brought to 200 miuibars to avoid too much boiling $ boiling of the alcohol and then, when the solution present 3o a viscous appearance :, the pressure is again down to 50 millibars.
The residual alcohol is thus rapidly eliminated and the coprecipitate which present the appearance of a very stable white mud is easily recoverable in scratching the bottom of the balloon using a spatula.
The samples thus obtained are placed in a desiccator for 48 hours.
AVAM
to be crushed and sieved (particle size ~ 100 um).
* Margin of ocmnez ~ oe C- Preparation of coprecipitates of progesterone-potylvinylpyrrolidone -potysorbate 80 s Physical mixtures containing 20, 30 and 50% ~~ po ~ ds / weight of progesterone were prepared with polyvinylpyrrotidone, (ico0 <.x. ~ cxi34 BASt =) in replace, respectively 1, 5 or tü ° ~ weight / pvids ds PVP by a quantity corresponding of poiysorbate 80. The manufacturing process for these coprecipitates is similar to that used for the preparation of samples without a surfactant, but you physical mixture is dissolved in a sufficient amount of absolute alcpot 1o containing polysorbate 80 in solution.
The conditions of evaporation of the gas are identical to those mentioned above.
previously and the caprésipités also have the appearance of a foam friable white and easily recoverable.

Solution of Progestron $ Potyvinyl polysorbate Alcohol;

absolute pyrrolidone80 ' dan $ ~ IcQOI

5 I, ___ aVBC% of I sorbate 1 3.95 10 ml 80 ml with 5/4 of ol sorbate 1 3 75 5Q ml 40 ml, with 1 d.6 of o! sorb ~ te 1 3,50 1b0 ml 0 1'abteau :
prpar: ~ tion of the coprcipits 20 ~
poidslpoids with polysortaate ;

, * Mango ae mame Sot ~ tlan of ProgestronePolyvinyl polysor4ate Alcoal absolute pyrrolldone8D

in alcohol ' 5;

with 1 ~ 6 of I sorbets 1.5 3.45 10 ml 100 ml with 5% of;

ol Sorbets 1 5 3 25 50 ml 60 ml $ 0 with 10%;
of ol sorbets 1 5 3 00 140 ml 10 ml Table 2: preparation of 3D coprecipiles ° / o weightlweight with Qolysorbate 80 , Solution;
of ProgestronePolyvinyl polysorbateAlaaol;

absolute pyrrdlldone80 in alco8l ' with 1%
of ol ort ~ te 2.5 2.45 10 ml 1 ~ 0 ml with 5 ~ of _ _ _, sorbets 80 2.5 a 2 25 50 mt 70 ml with i O ~ o of I sorbets 2 S 2 00 140 ml 20 ml ' Table 3: Preparation of coprecipitates 5U96 weight / weight with polysorbate $ 0 , 11- ~ TUDE OF DISSOLUTION GINETI4UES
A- Experimental technique The measurement chain used for galenic control of dispersions solids consists of 3 elements 15, - a dissolution device DISSdLUTESY DT6 ERWEKA *
a peristaltic pump 502 SR WAISBN-MARL ~ W *, a spetrophotom ~ (re GQUpIé to an automaton dissotulion SAFAS *
~ Marc3ue oo ~ merne Each dissolution test is carried out in one liter of degassed distilled water at 37 ° C and pH close to neutrality.
A test portion corresponding to 5 mg of progesterone (25 mg of or coprecipitate) is introduced into each of the six reactors at time To.
The stirring speed of the pallets is 100 rpm. Dosages by absorption in the ultraviolet (at 250 nm) are carried out continuously and in a closed circuit by the multichannel peristaluctic pump connecting the beakers of the Dissolutest to the vats of the spectrophotometer. The latter, coupled with a recorder 1o and to a printer, can measure at regular intervalBes (all minutes), variations in optical density, which are themselves proportional to the variations in concentration of the active ingredient in the dissolution medium.
B. Results B.1 Dissolution of the coorecies of orogesterone IPVP
The kinetics of dissolution of progesterone from dispersions solid containing 20, 30 and 50 °, 6 weightl of active ingredient are represented at table 1.
The results show that the rate of release of the hormone is dependent the content of active ingredient in the coprecipitate. We observe, indeed, a rate near 95% dissolution in 10 minutes for 20% w / w coprecipitate against respectively 55 and 18% for coprecipitates at 30 and 50% w / w.
This result shows that the best kinetics are obtained with the weakly concentrated solid dispersions, which is probably in relationship with greater dispersion of the active ingredient within the coprecipitate when its content is low in the sample.
3o Moreover, it is interesting to note that the kinetics of dissolution of the coprecipitated at 20% weight / weight are faster than those recorded during of preliminary study with samples of the same concentration. This result is due to changes in the preparation conditions, because by decreasing the pressure and by increasing the temperature of the water bath, it facilitates the evaporation of the solvent and prevents the crystallization of the active ingredient which remains poorly crystallized or in a more or less amorphous state and therefore more soluble.

B.2 Dissolution kinetics of coorecioities orooesterone / PVP /
Potvsorbate 80 The kinetics of dissolution of progesterone from dispersions solid containing 20, 30 and 50% w / w of active ingredient with proportions variables (1, 5 and 10% w / w of polysorbate 80) are shown in tables 11, III and IV.

, ~ ~ 1820 '~~ ~ x TABLE I
Time COPRECIPfTES
(minutes) PROGESTERONE-PVP
at manufacture 20 ~ 30% SO

3 77.22 '33.49 5.55 6 88.65 45.79 9.76 g 92.93 52.38 17.06 12 95.31 57.61 18.73 15 96.74 62.85 22.30 18 97.77 65.71 23.73 21 98.38 68.01 27.38 24 99.03 71.11 30.39 27 99.82 74.68 33.01 30 99.90 77.79 35.07 33 99.90 80.38 37.46 36 99.90 83.17 39.12 39 99.90 85.26 41.34 42 99.90 87.46 43.14 45 99.90 88.01 44.82 48 99.90 89.28 46.58 51 99.90 91.26 48.80 54 99.90 92.46 50.55 57 99.90 9420 51.11 60 99.90 94.92 52.06 ~ 18 ~ 02 ~~
TasLEaa II
Time COPRECIPffES
(minutes) PROGESTERONE-PVP
20%
at manufacture with ol sorbate 1% 5% 10%

3 87.30 86.54 80.26 6 94.20 94.55 92.09 g 97.15 98.90 97.40 12 99.50 99.60 100 15 99.80 100 100 30 100 ~ 100 ~ 100 TASLEAa III
Time COPRECIPfTES
(minutes) PROGESTERONE-PVP
30%
pol sorbate 80 a ms manufacturing ave 1% - 10%
5k 0 0 ~ 0 3 79.59 83_44 78.66 6 88.88 93.60 91.04 9 92.85 96.94 96.01 12 96.74 98.40 98 15 98.23 99.40 99.70 18 99.86 99.70 100 _ 100 100 100 ___ 100 100 100 30 100 100 ~ 100 ~ I ~~ 024 z ~
TABLE IV
Time COPRECIPfTES
(minutes) PROGESTERONE-PVP
50%
a xs manufacture with ol sorbate 20% 30 ~ 6 N / A

_- 0 0 0 0 3 22.38 36.82 44.91 6 37.93 51.90 60.10 g 46.42 61.50 69.70 12 54.12 67.22 74.40 15 58.65 71.98 78.90 18 62_38 76.36 83.50

2 i 65.15 80.47 89.84 24 68.49 81.66 93.96 27 70.63 83.04 95.55 30 72.38 84.52 96.79 33 74.28 86.31 98.25 36 75.39 87.49 99.49 39 77.14. 88.49 100 42 78.65 89.12 100 45 80.23 90.71 100 48 81.57 91.76 100 51 82.38 92.58 100 54 82.93 92.93 100 57 83.88 93.17 100 60 85 15 ~ 93 92 ~ 100 ~ $ 1 ~ U ~~~
Z.
III - STUDY OF KINETICS OF DISSOLUTION AFTER CONSERVATION
A. Kinetics of Dissolution of Progesterone-PVP Coprecipitates The kinetics of dissolution of progesterone from dispersions solid containing 20, 30 and 50% w / w of active ingredient after 6 months of at 4, 20 and 37 ° C are shown in Tables V, VI
and VII.
As previously, it is observed that the rate of release of the hormone is dependent on its content in the coprecipitate. However, the comparison of kinetics of dissolution after 6 months of storage, compared to those measured with these same freshly prepared products, shows that increasing conservation temperature seems to improve speed of dissolution of progesterone in the most strongly coprecipitated concentrated. The most significant result is obtained with the coprecipitate 50%
weights kept at 37 ° C for which we obtain a rate of dissolution of 95 ° ~
after one hour against 52 ° .6 for this same freshly prepared product.
B. Kinetics of dissolution of progesterone-PVP-coprecipitates Polysorbate 80 The kinetics of dissolution of progesterone from dispersions solid containing varying proportions of potysorbate 80 and after 6 months of at 4, 20 and 37 ° C are shown in Tables VIII
and IX.
These results show that the kinetics of release of the hormone from of the coprecipitate kept for 6 months at 4, 20 and 37 ° C does not present difference significant and is practically superimposable to that recorded on the products freshly prepared. The temperature does not seem to play a role determining in the conservation of samples containing polysorbate 80, 3d during the first 6 months.

~~ ~ I82, 4 TABLEAB V
COPRECIPITES time (minutes) PROGESTRONE-PVP
at conservation 6 months 4C

20% 30% 50

3 78.87 32.22 8.01 6 86.80 42.77 15 9 89.90 48.65 20.79 12 91 52.30 25.39 t 5 92.90 56.26 29.76 18 94.60 58.49 33.33 21 96 60.71 37.14 24 97.80 63.17 40.24 27 98.80 65.28 42.93 30 t 00 68.41 46.03 33 100 70.23 47.93 36 100 71.82 51. t 1 39 100 73.96 52.14 42 100 75.07 54.20 45 100 78.88 56.35 48 100 79.93 57.62 51 100 80.95 59.84 54 100 82.06 60.95 57 100 83.09 62.54 60 100 ~ 83.80 ~ 64.20 ~~ ~ 82U 4 , ~ zz TAHL ~ AB VI
COPRECIPITES time (minutes) PROGESTERONE-PVP
at conservation 6 months tem ambient erasure 20! 30% 50%

p 0 0 0 3 83.33 30.87 12.40 6 90.79 42.14 22.69 9 93.25 47.62 30.47 12 95.30 53.57 37.77 15 96.90 55.95 42.85 18 97.90 60.79 47.69 21 98.80 62.30 52.22 24 99.80 64.20 55.70 27 100 67.90 58.48 30 100 70.48 61.98 33 100 71.98 64.68 36 100 75.16 66.81 39 100 76.90 69.67 42 100 78.57 71.58 45 100 80.32 72-93 48 100 81.83 75.63 51 100 82.78 77.23 54 100 83.01 78.48 57 100 83.65 79.99 60 to 85.32 ~ 81.35 y'~ fi. $ 2U2 ~ 1 SABLEAD VII
COPRECIPITES time (minutes) PROGESTERONE-PVP
at conservation 6 months 37C

20% 30% 50 3 82.69 43.73 18.02 6 90.55 65.63 32.30 g 96.42 71.50 42.54 12 97.69 74.92 51.67 15 98.96 77.22 58.10 18 99.44 78.09 64.21 21 100 80.01 68.33 24 100 81.77 71.91 27 100 83.09 76.03 30 100 83.96 79.13 33 100 84.28 80.79 36 100 85.58 83.89 39 100 86.22 85.72 42 100 87.34 86.75 45 100 88.65 88.76 48 100 89.20 90.86 51 100 89.84 91.26 54 100 90.46 92.26 57 100 91.19 93.56 60 100 91.98 94.66 ~ 1 ~~~ 29'a ZS
TABLE VIII
COPRECIPITES time tminutes) PROGESTERONE-PVP

with ol sorbate 80 to 6 months 1% 5 ~ t 0 ~

3 78.65 84.85 69.95 6 90.70 93.70 87.10 9 93.40 96.50 93 12 95 98.20 95.80 15 96.70 99.30 97.50 18 97.70 100 98.40 21 98.20 100 99.30 24 99.20 100 100 27 99.90 100 100 30 to 100 to 100 , ~ ~ ~ i ~ 2 ~~ 4 'TABLEAO IX
COPRECIPITES time (minutes) PROGESTERONE-PVP
50%
with ol sorbate 80 to 6 months 1% 5% 10%

3 31.78 33.41 29.10 6 49.18 47.39 48.29 9 55.12 56.66 57.80 62.27 62.35 65.36 15 65.20 68.12 71.13 18 68.53 70.64 75.12 21 71.05 75.36 79.34 24 72.52 78.12 81.13 27 75.12 80.23 82.50 30 76.42 81.86 84.14 33 77.31 83.57 85.77 36 78.29 84.46 86.Oi 39 79.75 86.74 87.43 42 80.73 88.53 88.86 _ 82.27 89.42 90.08 48 82.60 89.67 90.80 83.08 91.29 91.38 54 85.04 91.70 92.35 57 85.12 92.35 92.84 60 85.60 93.81 93.41 - ~ ' Comparative study of plasma progesteroneemia (measurement by dosage radioimmunoassay after progesterone extraction by Chromatography) after fasting oral absorption in eight healthy volunteers ménauposées.
(Cross study in hospitalized volunteers and fasting since the day before at evening, meal taken after sampling taken at the fourth hour following ingestion of the product).
dts Cmax (nglml) Trrtax SSC (ng.nrf'.L) Report dt E (h) ntvy.

product tudit xpr gomfriquc of SSC vs Utrogestan results 100 m 46 0.69 144.71 5.66 FF 487 2x 100 average,, 0,09 34,28 mg 73 SEM, 0.50 1,0018.62 338.98 x 80 231.58 i 7 n - ma, 0 38 0 69 m 0 68 CV 25 0.75 73.99 3.90 EF 487 2x70 medium. , 0.09 22 46 mg 20 SEM, 0.50 1.0015.36 209.95 ax 39 167.62 i 6 n- m, 0 36 0.90 m 0 9l CV 10 82 0.69 13.39 0.56 EF 487 2x35 average, 24 0.09 3.80 mg 5 S, 0.50 1.005 47 40.07 i 82 n - max, 0 38 0.84 m, l 40 CV 8 2.06 23.51 Utrogestan 2x100mean,, 0.58 4.91 mg 3 SEM. 1 6 7.13 51.90 ~ 57 27.14 ~ 0 n 0, 0 80 0.65 CV

The esTRAOioL
i - PREPARAT1GN DISPERSIONS SfJI.II ~ ES ACCORDING TO THE INvENTiON.
i A ~ Raw materials The raw materials used are - Esbadial hemihydrate. Art.Nr. 680025. Charge 24056446. Schering AG, Berlin. t polyvinyl pirrolidana (~~. ~ moia * 30, N ~ r 56_0902), (BA $ F Aktierlgesellschaft, 67058 Ludwigshafen, Germeny).
80 (polyoxyethylene sorbitan monooleate, AB 39 ~
(ICi Chemicels, Niederlaasung der Deutsche ICI GmbH, Goldschmidtstr 100 t ~
4300 Essen 1).
- absolute ethyl alcohol (Na CEE 603-002-d0-5) (Distillery Hauguel, 76700 Gonfreville The Grcher).
R- The material The material used for the preparation of solid dispersions is used for - an electronic scale. At 120 seconds, there is no mention of bleaches.
75415 Bonds).
- a rotary evaporator RE 140 ~ * (Rauoaite, ~ 0 Av. Europe '78143.
Velezy).
C- preparation of solid dispersions by dlssolutlon-évaporatlan Physical mixtures containing 1 ~ J ° / b weight / weight of estradiol have the next composlttarr 0.5 g esiradiol

4.25 g PVP
0.25 gx! '80, ie 50 ml of ura ~ 5 glf solution in absolute alcohol 20 ml of alcohol soluble to dissolve astrediol and PVh 2, These mellanges are dissolved in sufficient quantified urge of absolute alcohol (it should about 50 ml of alcohol per gram of estradiol, 10 ml of alcohol per gram of, HVP). .
The solid dispersions are obtained by evaporation of the solvent under reduced pressure.
(P = 200 millibars) for 15 minutes then the pressure is reduced to a minimum * Mark of va ~ erve (about 40 millibars) for 1 minute. The temperature of the water bath is of 8 ° C and the rotation speed of the balloon is 100 rpm.
Recovered samples are placed in a desiccator for 48 hours9 then they are crushed and sieved. Galenic trials are carried out on samples with particle size less than 100 micrometers.
II - STUDY OF THE GINETICS OF DISSOLUTLQN
A- Experimental technique the drains of measurement used for the galenic control of dispersions solid consists of three elements - Dissolution device DISSOLUTEST DTS ERWEKA * (Euraf, 55 rue Deschanel, 92400 CaurtyevQie).
- a peristaltic pump 502 SR WATSON-MARL ~ W (Frolabo).
a spectrophotometer coupled to a dissolute automaton SA ~ AS ~ '(Prolabo).
Each dissolution test is carried out in one liter of degassed distilled water at PH of 3 ° C close to neutrality.
A test portion corresponding to 4 mg of estredtol (ie 25 mg of coprecipitate) is introduced into Ghacxrn six reactors at time t = 0. t ~ stirring speed of the pallets is 100 revolutions per minute. Absobtion assays in ultraviolet ( at 278 nm) are carried out continuously and in a closed circuit by the endtermedia of the multichannel peristaltic pump connecting the beds of dissolute, ttest to the a.wes of spectrophotometers. The latter, coupled with a recorder and a printer, allows you to measure at regular intervals (all variations optical density, which are themselves proportional to the variations in concentration of the active ingredient in the dissolution medium.
B- Results The kinetics of dissolution of featradiol from solid dispersions at 10 °! 0 Weights are shown in Figure 1.
* Brand of aammeme PROGESTERONE + ESTRADIOL J
1 - Preparation of Solid Dispersion According to the Invention A- Raw materials The raw materials used are the same as those used in the case of festardiol added to progeterone (USP D = P, lot 347 JA), UPJOHN
Company, Fine Chemical Division, Kalamazoo, Michigan 49001 USA.
B- The material The material is also the lead that used in the case of festradiol.
C-Preparation of solid dispersions by dissolution ~ vaporization The co-precipitates realized have the following coimposition 2.5 g of progesterone 0.05 g of estradiol 2.2 g of PVP
0.25 g or 50 ml of a 5 g / l solution of Tween 80 in absolute alcohol 103 ml of absolute alcohol necessary for the total dissolution of the various compounds (50 ml of absolute alcohol per 1 g of progesterone, 10 ml per 1 g estradiol).
The solid dispersions are obtained by evaporation of the solvent under vacuum (P
=
200 millibars) for 25 minutes then the pressure is reduced to a minimum (about 40 millibars) for 35 minutes. The temperature of the water bath is 60 ° C and the rotation speed of the balloon is 100 rpm.
The samples thus recovered are placed in a desiccator for 48 hours.
hours and then crushed and sifted. The galenic trials are carried out on of the samples with particle size less than 100 micrometers.

The coprecipitates obtained before the pass of the desiccator, are in the form of crystalline block, pale yellow or white and we also recover small cluster ~
crystallized II - STUDY OF KINETICS OF DISSOLUTION
These dissolution tests were carried out in water.
The coprecipitates used contain 50% progesterone and 1% estradiol.
Two tests were carried out: fun at 200 mg powder / liter of water and (other to 20 mg of powder per liter of water. The realization of these two tests are solved speak fact that festradiol is not detectable for a test portion of 20 mg of powder I liter of water and it was therefore necessary to carry out a test portion at 200mg powder / liter of water to detect estradiol.
RESULTS
1. Test 1 (200 mg powder / liter of water) Teaearm Tenear eslradiol had pxogestfrone Time P ~ fage Palescm (~ Paaroenge Paternal ~ I (pyr ppaxt By rappaxt mgJE by rsppazE by caypozf 1a h> s Ix b ~ thforiqae nc ~ armame benemtfiociqueKnearmescac 3 <0.3 <15 <25 0.78 0.8 1.0 6 <0.3 <75 <75 4.56 4b 6.0 9 0.4b 23 38.3 6.33 6.3 8.3 72 0.76 38 63.3 6.58 6.6 8.6 15 0.82 4I 68.3 6.30 6.3 8 ~

18 0.86 S3 7I, 7 6.43 6.4 8.4 2. Test 2 (20 ma of powder I liter of water) Tcacar cn Tcacur m idiot poogc ~ .rooc Ccmps Pontiffs Paurccntxgc Pu nPPt mbll ~ pu ~ appottpu npport i Ir pu i la ~ [i nppoK i It Crncat tfioriqoc tcnc ~ tizoriqnctracer dude trucar mc ~ xxfc a Dro - - o, v z7 as 6 Hp - - z49 29.9 39A

9 Np - - 3,87 38.7 50 ~

f1 t ~ ID - - 4t? 8 42.8 55.9 - - 4, 44.9 58.6 t9 (d ND - - 4.54 4 ~ 4 59.3 ND: Not detectable 3. Dissolution profiles The dissolution curves as a function of time are presented below.

FENOFIBRATE I
i - PREPARATION OF SOLID DISPER $ 10NS ACCORDING TO THE INVENTION
A- Raw materials - fenvfibrate (Iot FOD9 ~ (iD0);
(Schweizzefiall France Deshors, 57 bd of Montmorency, 75018 Paris) _ polyvinylpyrrolidone (~ 30, rtrr 56.0902 (BASF Aktlengesellachaft, 87066 Ludwigshafen, Germany).
- Bb (polyaxyethylene sorbitan monooleate) ~ lot AB 397 (IGI Chemicals, Niederlassuny dsr Deutsche ICI GmbH, Goldschmidtsfr 100 D.
4300 Essen 1), Falcoal absolute (Distillery HAUGUE ~ 76700 Gonfraville FOrcher). I, B- Hardware The material is exactly the same as the one used to make the coprecipitated precedents. , C- Preparation of solid dispersions by dissolution- &vaporation;
Five series of caprecipitates are performed, each series compora ~ ts.
samples. .
The sodium particles are obtoned by evaporation under vacuum (P = ~ ds millibar) for 24 minutes then the pressure is decreased to minimum (4D
millibars) for 25 minutes. The temperature of the water bath is 60 ° C
and the bellvn rotation speed is 100 revolutions per minute.
* Brand name ~~ ~ mexc ~ e The evaporation times are adapted according to the amount of absolute alcohol added to dissolve the products, so following the series of co-precipitates.
Samples at 2.5 g of fenofibrate have a yellowish appearance and form a ball more or less viscous after one hour of evaporation pressure minimum.
The more the fenofibrate content decreases (the amount of absolute alcohol added decreasing by this fact), the more the recovered samples are friable, under form of fine powder or granules. The color is white and shiny and the coprecipitates seem very dry.
The samples thus recovered are placed in a desiccator for 48 hours.
hours and then crushed and sifted. The galenic trials are carried out on of the samples with particle size less than 100 micrometers.
II - STUDY OF KINETICS OF DISSOLUTION
A-Experimental Technique This is identical to that used for studying the kinetics of dissolution co-precipitates of estradiol.
B- Results We previously measured the maximum solubility of fenofibrate in Skin. This is less than 3 mgll.
The coprecipitates manufactured above are successively at 50%, 40%, 30%, 20% and 10% by weight of fenofibrate. If it wants to introduce into éracteurs a quantity of fenofibrate allowing its total solubilization in 1 liter of water, he It is necessary to weigh 6 mg, 7.5 mg, 10 mg, 15 mg and 30 mg coprecipitates.
This precision in the measurement related to the minute but unavoidable losses by manipulation can not be obtained.
That's why we choose to make a standard range to 5 mgll as for progesterone and perform the kinetics of dissolution by introducing a equivalent amount of coprecipitates. This study will allow us to quantify the quality of the solubilized fenofibrate and we will observe a recrystallization of fenofibrate during the test.
Figure 3 and 4 respectively represent the standard range and the kinetic dissolution of fenofibrate in coprecipitates at 10% w / w (series , ~ ~ i82 ~ 29 ~
chosen at random and representative of a phenomenon common to others coprecipitated).
'TimeGnmmc (Miaules) Heel FEnofibcf: l; S ~ mpJl _ ____ _ .
glvC
i LLRC

.
Clvf3. ' -... 4-. ~.
. (~ K

Glve 3 95.26 95.26 98.96 93_6E 94.21 93.t5 6 9LI 92.1 95.78 91.05 92.1 90.52 9 87.89 87.89 91.05 E6.31 E7.E9 85.78 12 83.68 83.68 86.31 E2.1 E3.15 80.52 IS 80.52 80.52 83.15 TE.42 EO 76.86 I8 77.89 77.36 80 15.26 71.36 74.21 21 76.73 76.73 76.84 71.57 73.68 71.05 Zt 72.1 72.1 73.68 6E.94 11.05 68.42 27 70 70 71.57 66.84 68.94 66.31 30 68.12 67.89 69.47 64.73 67.36 64.73 The decay of this kinetics of dissolution is exclusively due to the sensitivity of the formulation to the light and to the fact that the dosage is realized by UV spectrophotometry at 278 nm, which leads to a degradation of the formulation. This degradation is therefore absolutely not due to the technique of coprécipité but with the technique of reading.

~ I82 ~ 24 Time Copreaprt (Minutes) Fnofibrate 10%
- PVP

- Polysorbate 80.5 % plp ' Priest t Cwe 2 Cwe 3 Cwe 4 tanks S Cuve 3 60.52 31.21 S9.t7 51.36 55.26 61.05 6 aS.26 t3.i5 tls7 12.63 23.15 3t.OS

9 36.31 SO.S2 31.21 36.And 10.52 t3.15 12 33.tS 9.17 3137 34.73 9.a7 11.57 IS 30 8.91 Z8_9tt 32_1 9. <7 St.57 18 '28.91 8.91 3052 31.05 8.9a to 2 t 2 7.89 8.12 2736 29.aT E.9a 10 2t 28.9a 8 <2 27.36 29.x7 E.9 <T t0 27.Sa 8.12 25.26 30.52 E.9 <10 30 25.78 8.12 26.31 2T.E9 E.9t 9 d7 33 25.26 8.42 2631 26.84 8.a2 9.47 36 25.26 8.42 24.73 27.89 8.42 9 a7 39 25.26 8.a2 13.68 29.47 8.42 9.47 a2 25.26 8.42 T3.68 2736 8.42 9.a7 a5 25.26 8.a2 12.63 2736 8.az 9.a7 as za.73 s.az 73.68 z736 s.a2 9.a7 ~

St 2x.73 8.42 24.73 26.8d 8 4t 9.47 Sa z6.31 8.a2 12_63 26.8a 8 a2 9.a7 51 23.68 8.9a 13.15 26.84 8 42 9.47 60 23.68 8.9a 13.15 1736 8.42 9.47 Here too, UV spectrophotometry is entirely responsible for the decay of the kinetics of dissolution.

V - SOLID DISPERSIONS CONTAINING ACETATE FROM
1 - Production of solid dispersions according to the invention Five sets of co-precipitates were made each consisting of six samples.
The amount of medroxyprogesterone acetate in each of them was 0.5 g and that of polyvinylpyrrolidone ranged from 2 to 5 g. The dispersions solids were prepared according to the procedure described in Example IV. The solubility of medroxyprogesterone acetate in water is very low. The determination of the concentration of medroxyprogesterone acetate thus dissolved in water was performed by UV spectrophotometry at 241 nm.
The percentage of compound dis:> out was almost total in 30 minutes at ordinary temperature.

gz z ~ ~~~
1. BLOCH DW - SPEISER PP
Solid dispersions. Fundamentalls and examples Pharm. Acta Helv. 62, 1, 1, 23 -: 7 (1987) 2. CHIOU CI - RIEGELMAN S.
Pharmaceutical applications of solid dispersion systems J. Pharm. Sci. 60, 9, 1281-1302 (1971) 3. DUCHENE D.
Solid dispersions. Stability and conservation STP Pharma. 1. (11) 1064-1073 (1985) 4. DUCHENE D.
Solid dispersions: interest and limits i5 The interviews of Carla, Volume VII, 99-107 (1986)

5. DUCLOS R.
Improvement of the bioavailability of natural progesterone by use of solid dispersions in polyoxyethylene glycol 6000. PhD Thesis zo State Pharmaceutical Sciences, University of ROUEN (1989)

6. FORD JL
The current status of solid dispersions Pharm. Acta. Helv. 6, 3, 69-88 (1986)

7. PUISIEUX F - HENRY S.
Solid dispersions Lab. Pharma Prob. etTech. 305. 11-20 (1981),

8. SEKIGUCHI K.-OBI N.
Studies on absorption of eutectic mixtures. A comparison of the behavior of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man.
Chem. Pharm. Bull. 9, 866-872 (1961)

Claims (26)

The embodiments of the invention, about which a exclusive right of ownership or privilege is claimed, are defined as following: 1. Process for obtaining solid dispersions of agents drug in a hydrophilic transport agent ensuring a better solubility in an aqueous medium and better resorption in the digestive tract of a patient, characterized in that:
a) a principle is dissolved in a volatile organic solvent medicinal active chosen from the group consisting of progesterone, estradiol and its salts, mixtures progesterone/estradiol and its salts, and fenofibrate, the solvent volatile organic containing highly cyclic amide polymer hydrophilic and a surfactant;
b) the organic solution obtained in step (a) is sprayed onto neutral granules in a current of hot air so as to obtain a coprecipitate; Where b′) the organic solution obtained in step (a) is evaporated to dryness so as to form a coprecipitate;
c) the coprecipitate obtained in step (b) or (b') is ground; and d) the ground coprecipitate obtained in step (c) is sieved. 2. Method according to claim 1, characterized in that the ground and sieved coprecipitate, obtained in step (d), is diluted with a excipient or a pharmaceutically acceptable vehicle. 3. Method according to claim 1 or 2, characterized in that step (b') is carried out by a fluidized air bed. 4. Method according to any one of claims 1 to 3, characterized in that the volatile organic solvent is a solvent oxygenated or chlorinated solvent, or a mixture of several solvents oxygenated or chlorinated. 5. Method according to any one of claims 1 to 4, characterized in that the volatile organic solvent is an alkanol. 6. Method according to one of claims 1 to 4, characterized in that that the volatile organic solvent is methylene chloride. 7. Method according to one of claims 1 to 5, characterized in that that the volatile solvent is ethanol, or isopropanol. 8. Method according to one of claims 1 to 7, characterized in that that the highly hydrophilic cyclic amide polymer is selected from the group consisting of polyvinylpyrrolidones having a weight molecular weight of 10,000 to 50,000, N-methylpyrrolidone, N-methyl caprolactam and N-methyl piperidinone-2. 9. Method according to claim 1, characterized in that the agent surfactant is a nonionic surfactant. 10. Method according to claim 9, characterized in that the agent nonionic surfactant is chosen from polyoxyethylenic esters of sorbitan and fatty acids, saturated or unsaturated, having at least 8 carbon atoms, polyoxyethylene fatty alcohol ethers having at least 8 carbon atoms and polyoxyethylenic acid esters stearic. 11. Method according to claim 1, characterized in that the agent surfactant is selected from the group consisting of polysorbates and the cremophors. 12. Method according to any one of claims 1 to 11, characterized in that the surfactant is used in a proportion from 0.5 to 20% by weight. 13. Method according to any one of claims 1 to 12, characterized in that the active principle is progesterone. 14. Method according to any one of claims 1 to 12, characterized in that the active principle is estradiol. 15. Method according to any one of claims 1 to 12, characterized in that the active principle is a mixture of progesterone and estradiol. 16. Method according to any one of claims 1 to 12, characterized in that the active principle is fenofibrate. 17. Solid dispersion obtained by a process as defined in one of claims 1 to 11, characterized in that the active principle is selected from the group consisting of progesterone, estradiol and its salts, progesterone/estradiol mixtures and its salts, and fenofibrate. 18. Solid dispersion according to claim 17, characterized in that that the active ingredient is progesterone. 19. Solid dispersion according to claim 18, characterized in that that progesterone is present in a concentration of 20 to 60% in weight, relative to the total weight of the dispersion. 20. Solid dispersion according to claim 17, characterized in that that the active ingredient is estradiol. 21. Solid dispersion according to claim 17, characterized in that that the active ingredient is a mixture of progesterone and estradiol. 22. Solid dispersion according to claim 17, characterized in that that the active ingredient is fenofibrate. 23. Solid dispersion according to claim 22, characterized in that that fenofibrate is present in a concentration of 10 to 50% in weight, relative to the total weight of the dispersion. 24. Solid dispersion according to any one of claims 17 to 23, characterized in that the surfactant is present in a concentration of 0.5 to 20% by weight, based on the total weight of the dispersion. 25. Pharmaceutical composition containing a solid dispersion as defined in any one of claims 17 to 24, characterized in that the solid dispersion of active principle is mixed with an inert, non-toxic excipient or diluent pharmaceutically acceptable. 26. A pharmaceutical composition according to claim 25, characterized in that the dispersion of coprecipitate obtained in step (b') is sprayed onto neutral microgranules which are then coated using a cellulose derivative.