WO2013144356A1

WO2013144356A1 - Steroid, in particular a progestin, comicronized with a polymer having the pyrrolidone group, and compositions and uses

Info

Publication number: WO2013144356A1
Application number: PCT/EP2013/056840
Authority: WO
Inventors: Céline GNAKAMENE; Rachel LEVY-TOLEDANO
Original assignee: Effik
Priority date: 2012-03-30
Filing date: 2013-03-29
Publication date: 2013-10-03
Also published as: FR2988610B1; FR2988611B1; FR2988610A1; FR2988611A1

Abstract

The present invention relates to a steroid, in particular a progestin, comicronized with a polymer including one constitutional unit having the pyrrolidone group. The polymer is, in particular, polyvinylpyrrolidone, polyvinylpolylpyrrolidone, poly(1-vinylpyrrolidone-co-vinyl acetate), and the mixtures thereof. The invention also relates to a pharmaceutical composition including said steroid, in particular a progestin, comicronized with said polymer, and to a method for comicronizing a steroid, in particular a progestin, with a polymer including a constitutional unit having the pyrrolidone group. The invention finally relates to the resulting micronized product or the composition for the use thereof in the treatment or prevention of a physiological condition associated with an insufficiency in the secretion of progesterone, testosterone, or DHEA, or other conditions that require treatment with a steroid, in particular a progestin.

Description

Steroid, in particular a progestin, co-micronized with a polymer carrying the pyrrolidone group, compositions and uses

The subject of the present invention is, as a novel product, a steroid, in particular a progestogen, co-micronized with a polymer comprising a constituent unit carrying the pyrrolidone group, a pharmaceutical composition containing it, a process for their preparation as well as their uses.

The steroid is advantageously progesterone, testosterone or dehydroepiandrosterone (DHEA).

Progesterone is a hormone that is synthesized, in women, during the luteal phase mainly by the ovary, specifically by the corpus luteum cells, during pregnancy by the placenta and, to a lesser extent, by the adrenal glands. The plasma concentration of progesterone varies during the menstrual cycle.

Progesterone is secreted in greater quantity from the ^14th day of the cycle by the cells of the corpus luteum. It allows the maintenance and differentiation of the uterine lining, the development of the vascularization of the endometrium, and the appearance of uterine glands responsible for the serrated aspect of the uterine lining.

It is progesterone that allows the preparation of the endometrium for implantation of the egg in the uterus and implantation. During pregnancy, she also prepares the mammary gland for lactation and acts as a natural relaxant to prevent uterine contractions. If there is no fertilization, the progesterone level drops.

The deficiency in progesterone, called luteal insufficiency, can be responsible for many pathologies, including successive miscarriages, cycle disorders, and premenstrual syndrome.

The term "progestin" denotes any steroid having an affinity for progesterone receptors and capable of more or less completely reproducing the biological effects of progesterone.

Progestogens include progesterone as well as synthetic progestins. As an example of a synthetic progestin, mention may be made of:

synthetic progestins 1 (pregnanes), molecules close to progesterone in their chemical formula, for example retroprogesterone (isomer of progesterone, also known as dydrogesterone), medrogesterone, norprogesterone derivatives (such as demegestone or promégestone). These molecules have extragestative activity comparable to that of progesterone. They have no androgenic effect.

synthetic progestins 2 (pregnanes), which are derivatives of 17α-hydroxy-progesterone, for example cyproterone acetate, medroxyprogesterone acetate, chlormadidone acetate, nomegestrol acetate. They are substances that can be used by themselves, some of which have an anti-androgenic and anti-gonadotropic effect; they are also used as ovulation inhibitors. Their effect on the androgen receptor, verified in the laboratory animal, contraindicates by caution the administration during pregnancy, but not the use, even in prolonged cures, outside pregnancy.

synthetic progestins 3 (estranes or norandrostanes), which are norsteroids. These are derivatives of 19 nortestosterone. For example, norethindrone, norgestimate, levonorgestrel, desogestrel (3-keto desogestrel) and gestodene may be mentioned. They are highly antigonadotropic and are used as ovulation inhibitors.

Dehydroepiandrosterone (DHEA), also known as 3-β- hydroxyandrost-5-en-17-one, 15 dehydroisoandrosterone, trans déhydroandrostérone, A ⁵ -androsten-3 -ol-17-one, and prasterone.

DHEA is a naturally formed intermediate during the synthesis of various steroids from cholesterol. DHEA is the most abundant steroid hormone in humans and is produced primarily by the adrenal gland cortex as an inactive sulfate ester (DHEA-S). DHEA production also occurs in the testes, ovaries and brain.

DHEA has been implicated in a wide range of biological effects in humans and other mammals. It acts on the androgen receptor both directly and through its metabolites, which include androstanediol and androstenedione, which can undergo further conversion to produce androgen testosterone and estrogen estrone, estradiol and estriol. . DHEA has been proposed for use in the treatment of many diseases, such as systemic lupus erythematosus, primary adrenal insufficiency, Addison's disease, decreased libido, obesity, osteoporosis, fibromalgia, and Benign gynecological conditions such as endometriosis.

The issue of androgen loss, especially testosterone, is a potential problem known to all women using hormonal oral contraceptives. DHEA can be administered by a variety of routes. Unlike many other known androgens, DHEA is active orally.

Testosterone is a steroid hormone, from the group of androgens. In mammals, testosterone is secreted by the testes of males. It is the main male sex hormone and the "original" anabolic steroid.

Testosterone intervenes in the virilization via its receivers (the voice becomes more serious, the growth of the hairs is stimulated). Testosterone plays a role in sexual desire, certainly in men, and more or less in women. Its role in the activity, even aggressiveness, has been established. Testosterone also participates in men's hair loss with age.

Like other steroid hormones, testosterone is a derivative of cholesterol. It is in the testes that the largest amounts of testosterone are produced, but it is also synthesized in smaller amounts by thecal cells and ovaries, the reticular zone of the adrenal cortex, and the placenta. In women, a large part of testosterone is synthesized by "peripheral conversion", that is to say on the site of action, in the tissues. If we consider all sources of testosterone in women, by accounting for peripheral conversion, it is estimated that the production in women is about 60% of the testosterone produced in humans.

Like most hormones, testosterone is delivered to the target tissues through the blood, in which it is bound to a specific transport-specific plasma protein, sex hormone binding globulin (SHBG). There is a balance between the testosterone fraction attached to SHBG and the free fraction. Only free testosterone and that bound to albumin is biologically active.

Of the progestins suitable for hormone replacement therapy, micronized progesterone is preferred because of its lack of androgenic effect and its safety. metabolic. Supplementation with progesterone also helps to treat luteal insufficiency. However, its oral absorption is limited because of its low solubilization in intestinal environments. Progesterone is poorly absorbed by the intestine and is also subject to rapid gastrointestinal and hepatic degradation which gives it a relatively short plasma half-life. Oral progesterone has a low and inconsistent bioavailability that varies considerably with diet, especially because in current formulations, progesterone is suspended in an oily phase. Thus, to avoid excessive variability in progesterone levels, formulations of progesterone that would overcome the effect of meals are sought. In fact, routes of administration other than oral (eg vaginal, rectal, intramuscular, transdermal) seem more adequate to maintain for several consecutive hours a progesterone concentration at the physiological level of the luteal phase.

Similarly, testosterone is essentially formulated transdermally or injectably. The only oral formulation is, as for progesterone, a suspension in an oily phase.

However, the mode of oral administration presents, for the patient in particular, significant advantages over other methods of administration.

It is known in patent application FR 76 36007 a formulation containing micronized progesterone in oily suspension, which has increased the bioavailability of progesterone orally. This formulation is sold in France under the trademark UTROGESTAN®. The elevation of progesterone levels begins within the first hour and the highest plasma levels occur 1-3 hours after dosing. Pharmacokinetic studies in volunteers have shown that after the simultaneous ingestion of two UTROGESTAN® 100 mg capsules, progesterone levels rise from 0.13 ng / ml to 4.25 ng / ml after 1 hour, 11 , 75 ng / ml at 2 hours, 8.37 ng / ml at 4 hours, 2 ng / ml at 6 hours and 1.64 ng / ml at 8 hours. There are sensitive individual variations. In plasma, the main metabolites are allopregnanolone (3a-hydroxy-5a-pregnan-20-one), 5a-dihydro-progesterone and pregnanolone (3a-hydroxy-5P-pregnan-20-one) However, the excipients used are sunflower oil or peanut oil, and soy lecithin. However, peanut oil and soy lecithin have allergenic properties and significant hypersensitivity reactions.

There is therefore a need for a micronized progesterone formulation having no drawback in terms of allergenicity. There is a need to improve the absorption of progesterone in the digestive tract.

Patent application WO97 / 04749 describes pharmaceutical compositions comprising micronized progesterone and type II safflower oil. It has thus been possible to formulate compositions free of soy lecithin and peanut oil while maintaining the dispersions qualities of the micronized progesterone in the pharmaceutical composition.

Patent application WO 02/069978 describes pharmaceutical formulations comprising a progestogen, in particular progesterone, co-micronized with a surfactant, sodium lauryl sulphate. Such formulations make it possible to improve the bioavailability of the progestin. They also have good solubility.

However, the use of sodium lauryl sulphate has drawbacks, in particular related to its toxicity on tight junctions (Boulenc X, Breul T., Gautier JC, Saudemon P, Merry H, Roques C, and Sodium lauryl sulphate tiludronate paracellular transport using human epithelial Caco-2 monolayers Int J Pharm 1995; 123: 71-83).

As pointed out by the authors of the patent application WO 02/069978, it is perfectly well established that the properties of a substance treated by micronisation or grinding, in particular its solubility and bioavailability, are not predictable, contradictory results being possible. obtained, and that the same galenic formulation can give good results with one substance and result in a contrary result with another substance.

It has been shown that co-micronization of some poorly water-soluble compounds with excipients such as lactose and povidone can improve their solubility in the intestinal tract. In this study, it was demonstrated that the solubility in the intestinal medium (FASSIF-SLS media) of a steroid, danazol, can be improved by co-micronization with a lactose-povidone mixture (M. VOGT, K. KUNATH, JB DRESSMAN, "Dissolution improvement of four poorly water soluble drugs by cogrinding with commonly used excipients", 21 May 2007, EJPB 68 (2008) 330-337). This study gives no results on the solubilization in water of a steroid, in particular a progestin. In addition, the dissolution profile of danazol in FASSIF media shows a maximum dissolution of danazol of only 25%.

The inventors have discovered that it is possible to improve the bioavailability of a steroid, particularly a progestin, such as progesterone or testosterone or DHEA, by co-micronizing it with a particular polymer. In addition, co-micronization with said polymer improves the solubility of progesterone, testosterone or DHEA in aqueous media without transformation of the crystalline state of these steroids.

The steroid is selected from the group consisting of progesterone, dehydroepiandrosterone (DHEA), testosterone, estriol, estrone, estetrol, estradiol, androstanolone, androstenedione, retroprogesterone, and medrogesterone. , didrogesterone, demegestone, promespestone, medroxyprogesterone acetate, chlormadidone acetate, and nomegestrol acetate. The steroid is advantageously selected from the group consisting of progesterone, dehydroepiandrosterone (DHEA), and testosterone.

The polymer comprises a constituent unit carrying the pyrrolidone group. "Constitutive unit" is understood to mean the group of atoms that is repeated to form the macromolecule that is the polymer. The polymer may be formed of one or more constituent units. Preferably, the polymer is formed from one or two constituent units. To illustrate this, in a polymer of formula (A) n, the constitutive unit is A; in a polymer of formula (A) n (B) m, the two constituent units are A and B.

The term "pyrrolidone group-bearing unit" means that a carbon atom of the unit is substituted by the pyrrolidone group.

It is assumed by the inventors that the pyrrolidone groups present in the polymer help to solubilize the steroid, in particular the progestogen, by their three-dimensional structure, which, in particular because of the presence of the aliphatic rings, can be described as "porous". For this, it is preferable that the pyrrolidone groups in the polymer are accessible. To do this, it is possible to use a polymer having a satisfactory solubility in water (for example for polyvinylpyrrolidone a K value of less than 90, advantageously less than 60) or a molecular weight of less than 1,000,000 g / mol or a sufficiently porous three-dimensional structure. When the polymer is insoluble in water, as is the case with cross-linked polyvinylpyrrolidone, the polymer has sufficient porosity, in that the pyrrolidone groups are accessible.

More particularly, the polymer is chosen from the group consisting of polyvinylpyrrolidone (PVP), polyvinypolylpyrrolidone (crosslinked polyvinylpyrrolidone, called PVPP or crospovidone), poly (1-vinylpyrrolidone-co-vinyl acetate) (PVP-PA), and mixtures thereof. . Polyvinylpolypyrrolidone is preferred. The polyvinypolylpyrrolidone advantageously has an average particle size of between 25 and 50 μιη. The polyvinylpyrrolidone preferably has a molecular weight of less than 1,000,000 g / mol, more preferably between 10,000 and 50,000 g / mol. The polyvinylpyrrolidone advantageously has a K value of less than 90, more preferably less than 60, still more preferably between 17 and 30 or 29/32. The poly (1-vinylpyrrolidone-co-vinyl acetate) advantageously has a K value of less than 60, more preferably between 25 and 35.

Micronization is a well-known technique, which can be carried out either in hammer or ball mills or in gaseous micronizers. Micronization is a relatively simple process that allows large amounts of steroids, particularly progestins, to be introduced into the formulation (particularly in comparison with lipid based formulations or solid dispersions).

In the description, the term "micronizate" will be used to designate the steroid, in particular the progestogen, co-micronized with the polymer according to the invention.

In comparison with progesterone, or testosterone or non-micronized or micronized DHEA alone, co-micronization of progesterone or testosterone or DHEA with this type of polymer allows an improvement in the solubility of progesterone or testosterone or DHEA in aqueous media, allowing rapid in vitro dissolution profiles in aqueous media. Thus, it has been possible to obtain micronisates having a dissolution profile in vitro, in aqueous media comprising water and a few tenths of a percent of sodium lauryl sulfate, wherein the asymptotic plateau is reached in less than 100 minutes. more advantageously in less than 60 minutes, even more advantageously in less than 10 minutes. On the other hand, the solubility of progesterone or testosterone or DHEA in aqueous media is improved; advantageously, complete dissolution of progesterone or testosterone or DHEA is observed.

The steroid micronizate (in particular progestogen) -polymer thus makes it possible to improve the solubility of progesterone or of testosterone or of DHEA in aqueous media. The micronizate according to the invention also allows a better dissolution of progesterone or testosterone or DHEA in the digestive fluid; thus, by co-micronization with a polymer according to the invention, the absorption of the steroid, in particular the progestin, through the digestive tract is improved. Absorption through the gastrointestinal tract occurs for a short time and on a small space. It is therefore important that the steroid, in particular the progestin, be brought there quickly and completely in a solubilized form. What the invention allows. The micronizate according to the invention thus makes it possible to improve the rate of steroid absorption, in particular of the progestin (in particular progesterone or testosterone or DHEA) in the digestive tract.

Absorption of the steroid, particularly progesterone or testosterone through the gastrointestinal tract, is less subject to food-related variations than progesterone or micronized testosterone in oily suspension. The micronizate according to the invention (or the pharmaceutical composition containing it) can therefore be taken either on an empty stomach or after meals. The micronizate according to the invention thus makes it possible to reduce or even cancel the impact of the diet on exposure to the steroid, in particular to the progestin.

The micronizate according to the invention also allows:

An increase in the solubilization of progesterone or testosterone or DHEA in the intestinal medium;

- An increase in digestive absorption of the steroid, especially a progestogen;

- An increase in the bioavailability of the steroid, especially a progestin.

It follows that the use of micronisates according to the invention allows, in vivo, an increase in the steroids exposure rate. Thus, it becomes possible to ensure sufficient exposure while decreasing the dose of steroid administered. A decrease in the administered dose allows a reduction in the production of metabolites.

The dissolution profiles of micronisates according to the invention kept for several months, such as 12 months, at the usual temperature do not show any significant difference with respect to the freshly prepared micronisate dissolution profiles according to the invention.

It has been found that the micronization of the steroid, in particular of a progestin, with the polymer according to the invention leads to a reduction in the particle size, in comparison with the steroid, in particular a non-micronized progestogen and with the steroid, in particular a progestin, micronized alone (qualitative visual analysis of images obtained by SEM microscopy). The size of the micronised particles according to the invention advantageously varies from 5 μm to 300 μm, more advantageously from 5 μm to 200 μm, more advantageously from 5 μm to 100 μm, and even more advantageously from 5 μm to 50 μm.

It has been verified by X-ray diffraction and differential scanning calorimetry (DSC) analyzes that the micronization method of the invention has no effect on the crystalline structure of the steroid, in particular progestin, especially progesterone or testosterone or DHEA.

In the remainder of the description, unless otherwise indicated, the percentages are percentages by weight.

The micronizate according to the invention advantageously has a steroid content, in particular a progestin content, of between 50.0% and 95.0% by weight, more advantageously between 60.0% and 80.0% by weight, by weight. relative to the total weight of the micronisate.

In the steroid, in particular the co-micronized progestin, according to the invention, the steroid (in particular progestogen) mass ratio: polymer advantageously varies between 9.5: 0.5 and 5: 5, more advantageously between 8: 2 and 6: 4, still more advantageously the steroid mass ratio (in particular progestogen): polymer is 7: 3. The invention also relates to a pharmaceutical composition comprising the steroid, in particular the progestogen, co-micronized with a polymer as described above. The pharmaceutical composition according to the invention advantageously contains from 5% to 100% by weight, advantageously from 20% to 100% by weight, more preferably from 20% to 90% by weight of the micronizate according to the invention, relative to to the total weight of the composition.

The pharmaceutical composition according to the invention advantageously has a steroid content, in particular of progesterone, of between 10% and 95%, preferably between 10% and 90%, and still more preferably between 10% and 80% by weight. relative to the total weight of the composition. In particular, each dosage unit comprises between 2 mg and 600 mg of steroid. In particular, for progesterone, each dosage unit comprises between 20 mg and 450 mg, preferably between 50 mg and 200 mg, more preferably between 50 mg and 150 mg.

The pharmaceutical composition is particularly suitable for oral, transdermal, nasal or vaginal administration, according to the therapeutic indications; in particular, vaginal administration is preferred in case of side effects due to progesterone (somnolence after oral absorption) or contraindication to the oral route (hepatopathy).

In an advantageous embodiment, the pharmaceutical composition contains, in addition to the steroid, in particular the co-micronized progestin, an estrogen or one of these derivatives. In particular, estrogen is selected from the group consisting of 17-β-estradiol, estrone, 17-α-ethinyl estradiol, estradiol valerate or phytoestrogens, preferably 17-β-estradiol.

In such a case, an estrogen or derivative is present in the pharmaceutical composition in a content of between 0.05% and 5%, preferably between 0.1% and P / O, by weight relative to the total weight of the composition. In particular, each dosage unit comprises between 0.5 mg and 5 mg of estrogen, advantageously between 1 mg and 3 mg. The pharmaceutical composition may be formulated in any form suitable for administering the steroid, in particular the progestin, to humans or animals. It is in particular in dry or liquid form, such as for example: capsule soft, capsule, capsule containing microgranules, tablet (including gynecological tablet), lyophilisate, powder or granule, including microgranule, solution or oral suspension, suppository, ovum, patch, inhaled form spray, transdermal gel. The steroid, particularly the progestin, can be incorporated into a liposomal carrier. The capsule may comprise gelatin or the like. The composition may be formulated in a unitary form with immediate and / or prolonged release of steroid, in particular progestin. Thus, the unit form can incorporate an immediate release formulation of the steroid, particularly progestin, and / or a sustained release formulation of the steroid, particularly progestin. For example, a capsule comprising an immediate release tablet of the steroid, in particular progestin, and a sustained-release tablet of the steroid, in particular progestin, or a capsule comprising certain microgranules, some with immediate release, others with sustained release, or one multilayer tablet or equivalent allowing an immediate and prolonged mixed release modulation.

Steroids, particularly because of their low solubility in water, also pose difficulties in terms of galenic. Thus, the oral or vaginal formulations proposed to date are mainly soft capsules or capsules, which however have the drawback of including excipients with known effects such as gelatin. There is therefore a need for more varied and easy-to-manufacture steroid-based galenic formulations, particularly a need for tablets or transdermal gel. The inventors have discovered that co-micronization of the steroid with the polymer according to the invention allows wide access to different pharmaceutical formulations, without technical difficulties, and in particular allows the manufacture of tablets or transdermal gels. The co-micronization of progesterone or testosterone or DHEA with the polymer according to the invention makes it possible to formulate compositions, in particular tablets, the duration of dissolution of progesterone or testosterone or the DHEA by playing on the choice and ratios of excipients. The invention also makes it possible to be free from the use of excipients with known effects, in particular allergens, such as gelatin (used in the manufacture of the envelope of capsules / capsules), lecithin of soya, oils plant. The pharmaceutical composition according to the invention can be indifferently an aqueous or oily formulation. It may also comprise other excipients and adjuvants, in particular at least one excipient selected from the group consisting of disintegrating agents, diluents, binding agents, dyes, sustained-release agents, lubricants, solubilizing agents , absorption promoters, film-forming agents, gelling agents and mixtures thereof.

Of course, the pharmaceutical composition according to the invention has all the advantages observed for the micronizate according to the invention, in particular: rapid dissolution profile in aqueous media, improvement of the solubility of progesterone or testosterone or DHEA in aqueous media, improvement of the absorption rate of the steroid, in particular of the progestogen (in particular progesterone or testosterone or DHEA) in the digestive tract.

In one embodiment, the pharmaceutical composition according to the invention is formulated as an immediate release tablet, for oral or vaginal administration. Said tablet allows complete release of the steroid, particularly the progestin, in less than 20 minutes, more preferably in less than 15 minutes. The pharmaceutical composition, in addition to the steroid co-micronizate (especially a progestin) -polymer, also comprises at least one excipient selected from the group consisting of diluents, binders, dyes, and lubricants.

The diluents give the flow properties to the mixture and allow for homogeneous dilution in the mixture, progesterone or testosterone or DHEA. Among the diluents, there are sugars, advantageously lactoses, more preferably lactose monohydrate, cellulose derivatives, especially microcrystalline cellulose, calcium carbonate, magnesium carbonate, starches, polyols, sucroses, etc. The pharmaceutical composition according to the invention, in tablet form, advantageously contains from 20% to 95% by weight of diluent, relative to the total weight of the composition.

Binders improve the fluidity of progesterone or testosterone or

DHEA in the final mixture. Among the binding agents are anhydrous colloidal silica, alginic acid, sodium alginate, methylcellulose and sodium carboxymethylcellulose. The pharmaceutical composition according to the invention in tablet form advantageously comprises from 0.1% to 3% by weight of binding agent, relative to the total weight of the composition.

Lubricants help reduce friction during compression. They also prevent the adhesion of the compressed material to the punches. Lubricants include magnesium stearate, calcium stearate, glycerol monostearate and sodium stearyl fumarate. The pharmaceutical composition according to the invention, in tablet form, advantageously contains from 0.1% to 3% by weight of lubricant, relative to the total weight of the composition.

In one embodiment, the pharmaceutical composition according to the invention is formulated as a sustained-release tablet for oral or vaginal administration. Said tablet allows a total release of the steroid, in particular the progestin, in a time ranging from 120 minutes to 450 minutes, more preferably from 120 minutes to 400 minutes. The pharmaceutical composition, in addition to the steroid co-micronizate (especially a progestin) -polymer, also comprises at least one excipient, selected from the group consisting of disintegrants, diluents, binding agents, sustained-release agents , dyes, and lubricants.

The diluents are as defined above. The pharmaceutical composition according to the invention advantageously contains from 20% to 95% by weight of diluent, relative to the total weight of the composition.

The binding agents are as defined above. The pharmaceutical composition according to the invention, in tablet form, advantageously comprises from 0.1% to 3% by weight of binding agent, relative to the total weight of the composition.

Lubricants are as defined above. The pharmaceutical composition according to the invention, in tablet form, advantageously contains from 0.1% to 3% by weight of lubricant, relative to the total weight of the composition.

Sustained release agents are used as a sustained release tablet matrix. Amongst the sustained-release agents are: methacrylic copolymers, polyvinyl chlorides and acetates, methylcelluloses, sodium carboxymethylcellulose, hydroxypropyl methylcelluloses, hydroxypropylcelluloses, non-cellulosic polysaccharides such as guar gum, carob, carrageenan, agar-agar, modified starches, hydrophilic polymers such as xanthan, chitosan. Hydroxypropyl methylcellulose is advantageously used. The pharmaceutical composition according to the invention, in tablet form, advantageously comprises from 5% to 50% by weight of sustained-release agent, relative to the total weight of the composition.

In one embodiment, the pharmaceutical composition according to the invention is formulated as a hybrid composition, for oral or vaginal administration, containing an immediate release formulation and a sustained release formulation. The pharmaceutical composition may also contain the aforementioned excipients for immediate release and extended release tablets. Said formulations, immediate or prolonged release, may have a steroid dosage, in particular progestin, the same or different. In particular, the pharmaceutical composition can comprise:

An immediate release formulation containing between 2 mg and 600 mg of steroid, particularly progestin, preferably between 20 mg and 450 mg, more preferably between 50 mg and 200 mg.

A sustained release formulation containing between 2 mg and 600 mg of steroid, especially progestin, preferably between 20 mg and 450 mg, more preferably between 50 mg and 200 mg.

The composition may especially be in the form of capsule or tablet. The subject of the invention is also a process for the co-micronisation of a steroid, in particular a progestogen, with a polymer comprising a constituent unit bearing the pyrrolidone group, characterized in that a mixture of a steroid, in particular a progestin, with said polymer and then grinding of this mixture, preferably with a homogenizer mill.

Finally, the subject of the invention is a steroid, in particular a progestogen, co-micronized with a polymer comprising a constituent unit bearing the group pyrrolidone according to the invention for its use in the treatment of a physiological condition related to the insufficiency of the secretion of progesterone, testosterone or DHEA, or other conditions requiring treatment with a steroid, in particular progesterone, testosterone or DHEA. The invention also relates to a pharmaceutical composition according to the invention for its use in the treatment of a physiological condition related to the insufficiency of the secretion of progesterone, testosterone or DHEA, or other conditions requiring treatment with a steroid, especially progesterone, testosterone or DHEA.

Examples of physiological conditions related to inadequate secretion of progesterone include: luteal insufficiency, menstrual irregularity, premenstrual syndromes, mastodynia, benign mastopathies, premenopause, luteal insufficiency sterility, menopausal disorders, local contraception, prevention of repeated abortions in case of luteal insufficiency, threats of premature delivery, prevention of osteoporosis, hyperplasias, endometrial cancers and headaches.

Examples of conditions requiring treatment with testosterone include: androgen deficiency, male hypogonadism, sexual dysfunction, sexual function and feeling of well-being, as well as cases where supplementation with Androgenic hormones has shown therapeutic interest as for example, osteoporosis, some cancers, hormone replacement therapy, male fertility control. In combination with estrogen therapy, testosterone is used in the treatment of decreased sexual desire in women who have undergone bilateral oophorectomy and hysterectomy (surgically induced menopause)

Finally, examples of conditions requiring treatment with dehydroepiandrosterone (DHEA) include: the improvement of the keratinization of the epidermis, the fight against the papery appearance of the skin, the modulation of the pigmentation of the skin and hair, action against atrophy of the epidermis, prevention / delay / treatment of the appearance of signs of skin aging, increased proliferation of fibroblasts, prophylactic and curative treatment of lupus erythematosus . Treatment with DHEA can also treat Alzheimer's disease, obesity, diabetes, HIV syndrome, osteoporosis, decreased libido in women and some cancers, boost immunity, and promote weight loss.

The invention also relates to a pharmaceutical composition, in particular a tablet, immediate and prolonged release of steroid, in particular progesterone, DHEA or testosterone. Indeed, by the invention it is possible to administer in the same composition an immediate release steroid formulation and a sustained release steroid formulation. In each formulation, the steroid dose may be the same or different.

The steroid is advantageously progesterone, DHEA or testosterone.

In general, the dosage will be adapted according to the route of administration and the patient to be treated. The dosage may advantageously be from one to two dosage units per day. It may be particularly advantageous to administer a single dosage unit comprising formulations with different dissolution profiles, or even at different dosages.

Description of the figures:

Figure 1 shows the results of X-ray diffraction analyzes of non-micronized progesterone (bottom spectrum) in comparison with:

micronized progesterone (FIG. 1 A-spectrum above)

co-micronized progesterone co-micronisate - crospovidone ^® (Fig. 1B - spectrum above)

co-micronized co-micronisate progesterone - povidone ^® K29 / 32 (Fig. lC - spectrum above).

Figure 2 shows the results of differential scanning calorimetry (DSC) analyzes. Figure 2A shows micronized progesterone alone. Figure 2B shows co-micronized co-micronisate progesterone - crospovidone ^® (Polyvinylpolypyrrolidone). Figure 2C shows co-micronized progesterone co-micronized - povidone ^® K29 / 32.

Figure 3 shows the dissolution profile of an immediate release tablet (LI) according to the invention, containing 60 mg of progesterone. FIG. 4 represents the dissolution profiles of three prolonged-release tablets (LP) according to the invention:

the light gray curve / - corresponds to the CP1 tablet, containing 60 mg of progesterone and 11.50% of hydroxypropyl methylcellulose.

- The black curve / * corresponds to the CP2 tablet, also containing 60 mg of progesterone and 13.50% of hydroxypropyl methylcellulose.

The dark gray curve / ♦ corresponds to the CP3 tablet, also containing 75 mg of progesterone and 12.00% of hydroxypropyl methylcellulose.

Figure 5 shows the average curve of plasma progesterone concentrations (μg / ml) versus time for the tablets of the invention when administered orally. Figure 5A shows the linear plot of plasma concentration versus time. Figure 5B shows the semilogarithmic plot of plasma concentration versus time.

- The dashed curve / * corresponds to treatment A (1 LI tablet 60 mg + 1 LP CP1 60 mg tablet).

The black curve corresponds to treatment B (1 LI 60 mg tablet + 1 60 mg LP CP2 tablet).

The gray curve / corresponds to treatment C (1 LI tablet 60 mg + 1 LP CP3 75 mg tablet).

Figure 6 shows the average plasma progesterone concentration (μg / ml) versus time curve for the tablets according to the invention when administered vaginally. Figure 6A shows the linear plot of plasma concentration versus time. Figure 6B shows the semilogarithmic plot of plasma concentration versus time.

The black curve / * corresponds to treatment A (1 LI 60 mg tablet + 1 60 mg LP CP1 tablet).

The clear gray curve / ^β corresponds to treatment B (1 LI 60 mg tablet + 1 60 mg LP CP2 tablet).

- The curve in dark gray / ♦ corresponds to treatment C (1 tablet LI of

60 mg + 1 CP3 75 mg tablet). The following examples illustrate the invention but are not limiting.

Example 1 Co-Micronized Progesterone According to the Invention and Comparative Trials

The following co-micronisates, comprising 100 mg of progesterone, were prepared either without an excipient or with the excipients according to the invention or other excipients for comparison. Unless otherwise indicated, the products have been micronized.

Table 1: co-micronisates tested

Process for preparing the co-micronisates tested:

Progesterone is mixed with the chosen excipient. Mix until a mixture of homogeneous visual appearance. (NB: For test 0, no micronization is carried out and only the physical mixture obtained is tested after this step.) Then, the mixture is micronized in a Precellys 24® (mill-homogenizer) mill with metal balls (3 periods of 60 seconds at 6500 rpm, with a rest period of 120 seconds between each period). Dissolution profiles:

The dissolution profile of each co-micronizate of Table 1 is tested at a dose equivalent to 100 mg of progesterone. The dissolution medium comprises 1000 ml of 0.2% water of SLS (sodium lauryl sulfate).

The dissolution tests are conducted according to the following parameters:

- USPII apparatus, speed of the blades: 100 revolutions per minute

37 ° C

- 1000 ml of water, SLS 0.2%

- withdrawal of the samples: 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 90 min for some tests 120 min, 180 min for some tests, 300 min for some tests The dissolution rates of each co- micronisat tested are reported in the following tables:

Time 0 5 10 15 30 45 60 90 120 180 300 (min)

1 0 11.5 46.9 56.8 68.0 73.9 77.5 82.3 83.7 - -

2 0 14.3 41.2 58.5 75.5 82.4 86.6 - 94.2 97 98.1

35.5 67.0 80.1 90.5 94.3 93.8 - 97.6 98.2 98.3

4 0 36.2 87.5 100.8 101.4 101.1 101.2 - 101.1 101.8 101.4

5 0 35.5 68.8 74.2 81.6 91.7 93.4 - 95.8 95.9 96.2

Table 3: dissolution rates - tests according to the invention Time 0 5 10 15 30 45 60 90 120 180 300 (min)

6 0 21.2 51.3 65.5 80.7 85.7 87.7 90.6 91.2 - -

7 0 6.3 17.8 24.6 34.3 41.1 46.3 - 60.3 69.2 73.4

8 0 0.4 15.8 32.9 50.7 56.2 61.7 67.7 72.0 - -

9 0 32.0 55.5 61.1 68.0 69.6 70.8 72.1 72.1 - -

10 0 4.8 10.7 14.0 20.1 22.4 25.7 32.9 37.2 - -

11 0 1.3 2.0 3.8 21.2 40.0 54.8 - 76.3 80.4 82.6

12 0 10.2 42.6 48.3 60.3 67.2 71.6 - 78.6 81.7 84.3

Table ^L : dissolution rates - comparative tests (other excipient)

These results show that the only micronization of progesterone has no really significant effect on the dissolution profile (tests 0 and 0 '); only a slight improvement in dissolution is observed when the progesterone is in micronized form.

Very good results are obtained with polymers carrying the pyrrolidone group, in particular with polyvinylpyrrolidone with a molecular weight of approximately 50,000 g / mol (test 3) and polyvinylpyrrolidone-vinyl acetate (test 5) and crospovidone (test 4 ). It is found that when progesterone is co-micronized with crospovidone (test 4) complete dissolution of the 100 mg of progesterone is obtained in less than 15 minutes.

Tests with other super-disintegrants such as sodium croscarmelose and sodium starch glycolate show that the dissolution profile of progesterone is slower than that obtained when progesterone is co-micronized with crospovidone. This indicates that the only super-disintegrating effect of crospovidone does not explain the improvement in solubility and dissolution rate. These results demonstrate that it is the presence of pyrrolidone group on the polymer which is decisive.

Thus, it is noted that with other polymers which do not carry the pyrrolidone group the dissolution profile is not improved. In contrast, co-micronization with PEG6000 (Run 10) reduces the dissolution rate of progesterone. The dissolution profile obtained is even slower than that of non-micronized progesterone. Co-micronization with a combination of polyvinylpyrrolidone and sodium lauryl sulphate (test 7) shows a slower dissolution profile than each co-micronisate comprising either polyvinylpyrrolidone alone (test 1) or sodium lauryl sulphate alone (test 6).

The Applicant has also carried out dissolution tests directly from the physical mixtures (progesterone + excipient according to the invention) without a co-micronization step. The results obtained show that:

the physical mixtures alone already make it possible to improve the dissolution profile with respect to the non-micronized progesterone, the micronisates have a significantly faster dissolution profile than the respective physical mixtures.

The results are reported in the following table:

Table 5

In conclusion, these results show that the co-micronization of progesterone with a polymer comprising a constituent unit bearing the pyrrolidone group makes it possible to obtain micronates showing a dissolution profile in water that is faster than those obtained with progesterone alone ( micronized or not) or micronized with another polymer or a disintegrating agent other than crospividone.

The best results are obtained with polyvinypolylpyrrolidone.

Determination of crystalline state by X-ray diffraction and differential scanning calorimetry (DSC):

X-ray diffraction analysis:

Figure 1 shows the results of X-ray diffraction analysis of non-micronized progesterone compared with micronized progesterone and compared with two co-micronisates of progesterone co-micronized with a polymer 1 (crospovidone) or a polymer 2 (povidone K29 / 32).

The diffractograms show that the micronization of progesterone has no influence on the crystalline state of progesterone.

The co-micronization of progesterone with polymer 1 (crospovidone) or polymer 2 (povidone K29 / 32) does not influence the crystalline state of progesterone either. Their respective diffractogram is identical to that of non-micronized progesterone.

Differential scanning calorimetry (DSC) analyzes:

Figure 2 shows the results of differential scanning calorimetry (DSC) analyzes. Progesterone, micronized or not, has a peak temperature at about 140 ° C and a measured enthalpy of about 82 J / g. This demonstrates that micronization has no impact on the crystalline state of progesterone.

The results of DSC with co-micronisats show a slight decrease in melting point. This can be attributed to the dilution of progesterone in the co-micronisate.

These results, combined with the results of X-ray diffraction analysis, show that micronization or co-micronization with polymer 1 or 2 of progesterone has no influence on the crystalline state of progesterone. Progesterone remains intact, unmodified by co-micronization.

Example 2 Formulation of an immediate release tablet (LF) according to the invention

Formulation:

The composition of an immediate release compound according to the invention is presented in Table 7.

progesterone according to the invention The tablets are manufactured using a conventional compression method.

Dissolution profile:

The dissolution profile of the formulation of Table 7 is determined. The dissolution medium is a demineralized water solution containing 0.4% of SLS (sodium lauryl sulphate), and optionally an acid or a base to adjust the pH to 5.5. The results are reported in Table 8 and Figure 3 showing the dissolution profile of an immediate release tablet according to the invention containing 60 mg of progesterone.

containing 60mg of progesterone

Conclusion: The co-micronisat allows a very rapid dissolution of progesterone in an aqueous medium. It allows the solubilization of progesterone in water without transforming its crystalline state. Co-micronisat thus makes it possible to improve the bioavailability of progesterone.

Example 3: Formulation of sustained release tablets (LP) according to the invention

Formulation:

The compositions of three sustained-release compounds according to the invention comprise co-micronisate progesterone-crospovidone in a content such that the tablet contains 60 mg or 75 mg of progesterone and the following excipients: Lactose monohydrate, Colloidal anhydrous silica, Hydroxypropyl methylcellulose, Stearate magnesium. The content of hydroxypropylmethylcellulose is varied to obtain the desired dissolution profile. The three compounds are:

- CP1 = prolonged-release tablet in 120-250 minutes containing 60 mg of progesterone.

CP2 = 120-400 minute extended release tablet containing 60 mg of progesterone.

CP3 = 120-400 minute sustained-release tablet containing 75 mg of progesterone. The tablets are manufactured using a conventional compression method.

Dissolution profile:

The dissolution profile of the formulations CP1, CP2 and CP3 are determined. The dissolution medium is a demineralised water solution containing 0.4% of SLS (sodium lauryl sulfate), and optionally an acid or a base to adjust the pH to 5.5. The results are shown in FIG. 4 representing the dissolution profiles of 3 sustained-release tablets according to the invention.

Conclusion:

Co-micronization makes it possible to modify and control the duration of dissolution of the micronisate by excipients.

Co-micronization allows us to obtain a formulation that does not affect the release of progesterone.

In addition, it facilitates the manufacture of an immediate or sustained release tablet as well as a hybrid tablet comprising an immediate release formulation and a sustained release formulation.

Example 4 Evaluation of the Pharmacokinetics of Oral or Vaginal Progesterone Administration (Clinical Studies)

A randomized cross-open pilot study evaluated the pharmacokinetics of oral or vaginal progesterone administration according to the invention.

This study had objectives;

The evaluation of the pharmacokinetics of the single administration of three progesterone formulations, according to the invention.

- The evaluation of the safety and the tolerance of each formulation.

Each evaluated formulation consists of two tablets, one immediate release (LI) and one sustained release (LP). Both tablets being administered together. The three progesterone formulations tested are as follows:

Treatment A (A) = 1 60mg LI tablet + 1 60mg CP 60mg tablet B (B) treatment = 1 60mg LI tablet + 1 60mg LP CP2 tablet - C (C) treatment = 1 60mg LI tablet + 1 LP CP3 75 mg tablet

The study population, administered, consists of twelve women aged 18 to 65, in good health, after menopause or bilateral oophorectomy. The course of the clinical study is the same for both types of administration: each subject receives a dose of progesterone from one of the 3 formulations. 7 days later, they receive another dose of progesterone from another of the 3 formulations. Then, again 7 days later, they receive one more dose of progesterone from the remaining formulation. The administration of the 3 formulations is random and randomized. The pharmacokinetics of the three formulations are evaluated by determining the maximum concentration reached C _max , the time at which this maximum concentration is reached T _max , the half-life time Tm, the elimination rate constant k, the areas under the curve-AUC t and AUCo- _∞, and the absorption rate constant ka, the distribution volume Vd, the clearance C and the mean residence time of MRT. These data can be determined by the analysis of the plasma concentration of progesterone.

Example 4a: Orally Administered Compounds

Protocol of the study:

For each treatment, A, B and C, a dose of 120-135 mg of progesterone is administered orally with at least 240 ml of water in fasting subjects for at least 10 h and will remain so for at least 5 h after administration. Both intact tablets are administered simultaneously and swallowed.

The study consists of 3 periods, separated by 7 days between them. The subjects must arrive the day before (before 22h) of each of the 3 days of admissions (one for each period). The following table (Table 9) presents the series of analyzes carried out during these periods:

Clinical phase

Days 1st period 2nd period 3rd period

0 1 2-4 7 8 9-11 14 15 16-18

Physical examination X X X

Blood pressure and heart rate X X X

Electrocardiogram X X X

Progesterone Administration X X X

Blood samples (pharmacokinetics) X X X X X X

Blood samples (pharmacogenetics) X X X

Evaluation of adverse effects X X X X X X X X

Table 9: Analyzes performed during the clinical study of orally administered tablets For each volunteer, 22 blood samples are taken. For measurements of progesterone, a sample is taken 1h before administration and just before administration and then 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 , 12, 18, 24, 36, 48, 72h after progesterone administration.

Results:

Number of topics:

12 subjects completed the study, but subject 7 was excluded from pharmacokinetic and statistical analyzes because of the lack of measurable concentrations of the reference drug.

Results of pharmacokinetics:

Table 5: Pharmacokinetics of Oral Tablets Figure 5 shows the average plasma progesterone concentration (μg / ml) versus time curves for tablets according to the invention.

Safety results:

No serious adverse events or significant abnormalities in blood status attributable to any of the three study formulations were detected. The three formulations show a similar profile of safety and tolerance. Example 4b: Compounds with vaginal administration.

Protocol of the study:

For each treatment, A, B and C, a dose of 120-135 mg of progesterone is administered vaginally. Both intact tablets are administered simultaneously. Subjects are then kept awake while lying on their backs for 3 hours after administration. The study consists of 3 periods, separated by 7 days between them. Subjects must arrive by 7:30 am on admission days (one for each period). At 8am a standard breakfast is served and then, treatments are administered vaginally from 9am. The following table (Table 11) presents the series of analyzes performed during the clinical phase:

For each volunteer, 23 blood samples are taken. For progesterone measurements, a sample is taken 1h before administration and just before administration and then 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9 , 10, 12, 18, 24, 36, 48,

72 hours after the administration of progesterone.

Results:

Results of pharmacokinetics:

* median (amplitude)

Table 12: Pharmacokinetics of Vaginal Tablets

Figure 6 shows the average plasma progesterone concentration (pg / ml) versus time curves for the tablets according to the invention. Safety results:

No serious adverse events or significant abnormalities in blood status attributable to any of the three study formulations were detected. The three formulations show a similar profile of safety and tolerance.

Conclusion of clinical studies:

These studies first demonstrate that it is possible to manufacture tablets comprising progesterone using conventional compression methods. By the choice of excipients, the dissolution rate of progesterone can be controlled. These formulations are well absorbed both orally and vaginally. Orally, it is found that 24 hours after administration the measured plasma concentrations are still compatible with the production of a clinical effect. The same is true for vaginal administration where 36 hours after administration the measured plasma concentrations are still compatible with the production of a clinical effect.

The exposure is therefore sufficient, both orally and vaginally, to obtain an effective therapeutic effect for a dose of 120 mg or 135 mg.

These results suggest a frequency of administration of one to two times per day.

The effectiveness of the formulation is independent of the route of administration, oral or vaginal.

Claims

1. Steroid co-micronized with a polymer comprising a constituent unit carrying the pyrrolidone group, the steroid being chosen from the group consisting of progesterone, dehydroepiandrosterone (DHEA), testosterone, estriol, estrone, estetrol , estradiol, androstanolone, androstenedione, retroprogesterone, medrogesterone, didrogesterone, demegestone, promespestone, medroxyprogesterone acetate, chlormadidone acetate, nomegestrol acetate, advantageously among progesterone , dehydroepiandrosterone (DHEA), testosterone.

2. co-micronized steroid according to claim 1, characterized in that the polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinypolylpyrrolidone, poly (1-vinylpyrrolidone-co-vinyl acetate), and mixtures thereof.

3. Co-micronized steroid according to any one of claims 1 to 2, characterized in that it has a steroid content of between 50.0% and 95.0% by weight, preferably between 60.0% and 80.0% by weight, based on the total weight of the micronate.

4. Co-micronized steroid according to any one of claims 1 to 3, characterized in that the steroid: polymer mass ratio varies between 9.5: 0.5 and 5: 5, advantageously between 8: 2 and 6: 4, more advantageously the steroid mass ratio: polymer is 7: 3.

5. A pharmaceutical composition comprising the steroid co-micronized with a polymer according to any one of claims 1 to 4.

6. Pharmaceutical composition according to claim 5, characterized in that it has a steroid content of between 10% and 95%, preferably between 10% and

90%), and more preferably still between 10% and 80% by weight relative to the total weight of the composition.

7. Pharmaceutical composition according to any one of claims 5 and 6, characterized in that it is suitable for oral, transdermal, nasal or vaginal administration.

8. Pharmaceutical composition according to any one of claims 5 to 7, characterized in that it is in a unitary form immediate release and / or prolonged steroid.

9. Pharmaceutical composition according to any one of claims 5 to 8, characterized in that it contains, in addition to the micronized co steroid, an estrogen or one of these derivatives, selected from the group consisting of 17-β estradiol, estrone, 17-α-ethinyl estradiol, estradiol valerate or phytoestrogens, preferably 17β-estradiol.

10. Pharmaceutical composition according to claim 9, characterized in that it comprises an estrogen or derivative in a content of between 0.05% and 1%, preferably between 0.1% and 0.5% by weight by weight. relative to the total weight of the composition.

11. Pharmaceutical composition according to any one of claims 5 to 10, characterized in that it further comprises an excipient selected from the group consisting of disintegrating agents, diluents, binding agents, dyes, and lubricants .

12. A method for co-micronization of a steroid with a polymer comprising a constituent unit carrying the pyrrolidone group, characterized in that a mixture of a steroid is prepared with said polymer and then grinding is carried out. of this mixture, advantageously with a homogenizer mill.

13. A co-micronized steroid with a polymer comprising a constituent unit carrying the pyrrolidone group according to any one of claims 1 to 4, for its use in the treatment or prevention of a physiological condition related to insufficient secretion of progesterone, testosterone or DHEA, or other conditions requiring treatment with a steroid.

14. Pharmaceutical composition according to any one of claims 5 to 11, for its use in the treatment or prevention of a physiological condition related to the insufficiency of the secretion of progesterone, testosterone or DHEA, or other conditions requiring treatment with a steroid.

15. A co-micronized steroid with a polymer according to claim 13 or a pharmaceutical composition according to claim 14, characterized in that the condition is chosen from the group comprising luteal insufficiency, menstrual irregularity, premenstrual syndromes, mastodynies, mastinal mastopathies, premenopause, luteal insufficiency sterility, menopausal disorders, local contraception, prevention of repeated abortions in case of luteal insufficiency, threats of premature delivery, prevention of osteoporosis, hyperplasias, endometrial cancers and headaches.

16. A co-micronized steroid with a polymer according to claim 13 or a pharmaceutical composition according to claim 14, characterized in that the condition is selected from the group comprising androgen deficits, male hypogonadism, sexual dysfunction, decreased desire sexual dysfunction in women, improvement of sexual function and sense of well-being, osteoporosis, certain cancers, hormone replacement therapy, male fertility control.

17. A co-micronized steroid with a polymer according to claim 13 or a pharmaceutical composition according to claim 14, characterized in that the condition is chosen from the group comprising improving the keratinization of the epidemic, combating the appearance papery skin, modulation of pigmentation of the skin and hair, action against atrophy of the epidemic, prevention / delay / treatment of the appearance of signs of skin aging, increase of fibroblast proliferation, prophylactic and curative treatment of lupus erythematosus, treatment of Alzheimer's disease, obesity, diabetes, HIV syndrome, osteoporosis, decreased libido in women and some cancers, stimulation of immunity, weight loss.

18. Pharmaceutical composition, especially compressed, immediate and prolonged release of steroid, in particular progesterone, DHEA or testosterone.