US 2011 0135719A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0135719 A1 Besins et al. (43) Pub. Date: Jun. 9, 2011

(54) PHARMACEUTICAL COMPOSITION BASED (30) Foreign Application Priority Data ON MICRONIZED PROGESTERONE, PREPARATION METHOD AND USES Nov. 13, 2001 (FR) ...... O1 (14653 THEREOF Publication Classification (75) Inventors: Antoine Besins, Bruxelles (BE); (51) Int. Cl. Jerome Besse, Listrac Medoc (FR) A 6LX 3/57 (2006.01) A69/48 (2006.01) (73) Assignee: Besins Manufacturing A6IP5/24 (2006.01) (21) Appl. No.: 12/916,795 (52) U.S. Cl...... 424/451; 514/177; 514/170 (22) Filed: Nov. 1, 2010 (57) ABSTRACT Related U.S. Application Data The present invention relates to a pharmaceutical composi tion comprising micronized progesterone, soya bean lecithin, (63) Continuation of application No. 12/071,822, filed on and at least one selected from the group consisting of Feb. 27, 2008, now Pat. No. 7,829,115, which is a , , sesame see oil, colza oil, oil, continuation of application No. 10/495,242, filed on to the method for the preparation thereof and to the uses May 6, 2004, now Pat. No. 7,431,941, filed as appli thereof for treating a physiological condition linked to insuf cation No. PCT/FR02/03879 on Nov. 13, 2002. ficiency of progesterone secretion. Patent Application Publication Jun. 9, 2011 Sheet 1 of 4 US 2011/0135719 A1

FIG. 1

I III UI II I III. Y. H || ||N|N II|| || NA I IVNA IN I I \\ I III VIII

HAHII MRIVN 0 1 0, 1 1 10 100 1000 3000 PARTICLE SIZE

GAL 221.01 CAPS START BATCH QBO1249020, 10/15/01 10:48:30

T. PFO098 CAPS BATCH 5439. 10/02/01 11:33:35 (UTROGESTANG) CAPSULE) Patent Application Publication Jun. 9, 2011 Sheet 2 of 4 US 2011/0135719 A1

FIG. 2

100 90 80 70 60 50 40 BO 20 10

30 60 90 120 150 180 210 2.0 20 300 330 360 TIME (MINUTES)

-- UTROGESTAN 100 mg - BATCH 5604 -É3-- 100 mg SOFT PROGESTERONE CAPSULE - BATCH QBO 1187020 Patent Application Publication Jun. 9, 2011 Sheet 3 of 4 US 2011/0135719 A1

FIG. 3

PROGESTERONE: MEAN CONCENTRATION - TIME N - 60

mem CAPSULE ACCORDING TO THE INVENTION

-- UTROGESTANE 20000 15000 10000 5000 0 0.0 3,0 6.0 9.0 120 15,0 18.0 21.0 24,0 27.0 300 33,0 36,0 TIME (hrs) Patent Application Publication Jun. 9, 2011 Sheet 4 of 4 US 2011/0135719 A1

FIG. 4

PROGESTERONE: Lin (MEAN CONCENTRATION) - TEMPS N = 60 1200

c -- CAPSULE ACCORDING TO THE INVENTION 3. 10,00+ 1"444N -- UTROGESTAN& 2 k 8.00 Z z 6.00 O 2. O O 4,00 a. t O S 2.00

- 0.0 30 6,0 90 120 150 18.0 210 240 27.0 30,0 33,O 360 TIME (hrs) US 2011/0135719 A1 Jun. 9, 2011

PHARMACEUTICAL COMPOSITION BASED 0012. The oil which serves as a basis for the oily suspen ON MICRONIZED PROGESTERONE, sion in UTROGESTANR) is . PREPARATION METHOD AND USES 0013 Peanut (Arachis hypogae) is a leguminous plant, a THEREOF bushy annual plant with yellow flowers, of the Papilionacea family. CROSS-REFERENCE TO RELATED 0014. In the last 15 years, peanut allergy has become a APPLICATIONS considerable allergological problem. (0015. Dutau et al. (La Presse Médicale Medical Press), 0001. This application is a continuation of U.S. applica vol. 28, p. 1553) observe that the prevalence of peanut allergy tion Ser. No. 12/071,822, filed Feb. 27, 2008, which is a has recently been estimated at 1.3% in the general population. continuation of U.S. application Ser. No. 10/495,242, filed The increased use of peanut in food, very often in a masked May 6, 2004, which is the U.S. National Stage of PCT/FR02/ form, perhaps explains this development. 03879, filed Nov. 13, 2002, the entire contents of which are 0016 Early sensitizations have been described in infants incorporated herein by reference in its entirety. The applica who have never consumed peanuts in conventional form, but tion also claims priority to FR 01/14653, filed Nov. 13, 2001. who were apparently sensitized in utero or via maternal milk, through maternalized milks having contained plant (pea BACKGROUND nut oil) or through medicinal preparations in oily solution. 0002 The present invention relates to a pharmaceutical (0017 UTROGESTANR) may be prescribed in many cases composition containing micronized progesterone, Soya bean of therapeutic indications, including as a Supplement to the lecithin, and at least one oil selected from the group consist luteal phase during cycles of in vitro fertilization (IVF), and ing of Sunflower oil, olive oil, Sesame , colza oil and in the case of a danger of abortion or of prevention of repeat almond oil. It also relates to pharmaceutical products com abortion due to luteal insufficiency, up to the 12th week of prising said pharmaceutical composition. pregnancy. It is therefore possible, in theory, for a fetus to be 0003. The invention also relates to the method for manu exposed to UTROGESTANR) in utero. facturing this pharmaceutical composition, as well as to the 0018 To date, while the allergenic effects of peanut are uses thereof. definite, a controversy still exists regarding the ability of 0004 Progesterone is a hormone which is synthesized, in peanut oil to engender allergenic reactions. Many publica women, essentially by the ovary during the postovulation or tions may be cited on this subject, including: Taylor et al., J. luteal phase (more precisely by the cells of the corpus luteum) Allergy Clin. Immunol. Vol. 68, p. 372 (1981); Moneret and, to a lesser degree, by the adrenal glands and the placenta Vautrinet al., Pediatr. Allergy Immunol. Vol. 5, p. 184 (1994); during the second part of pregnancy. Non-endocrine synthe Sabbah and Lauret, Allergie et Immunologie, vol. 26, p. 380 sis of progesterone, in particular in neurons, is also possible. (1994); de Montis et al., Arch. Pediatr., vol. 2. p. 25 (1995)). 0005. A consequence of insufficiency of progesterone 0019 Given this fact, the applicant company devoted itself secretion in a woman is a loss of its biological effects: proges to developing a novel pharmaceutical composition, replacing tative effect, anti-androgen effect (action on the skin) and the peanut oil with other which do not have high risks of anti-Oestrogen effect (the consequence being hyperoestro allergenicity, while at the same time endeavouring to con genemia: hot flushes, psychogenic difficulties of the anxious serve the advantages of the prior formula. or depressive type, weight gain, etc.). This progesterone insufficiency may lead to functional difficulties and diverse BRIEF DESCRIPTION OF THE DRAWINGS clinical manifestations, in particular: 0020 FIG. 1 illustrates the results of a comparative par 0006 premenstrual syndromes, ticle size study between UTROGESTANR) capsules (dashed 0007 menstrual irregularities due to disovulation or line) and capsules described herein containing Sunflower oil anovulation, (solid line). 0008 benign mastopathies, 0021 FIG. 2 illustrates the results of a comparative disso 0009 perimenopause and menopause. lution study between UTROGESTANR) capsules (0) and 0010. However, oral administration of progesterone suf capsules described herein containing sunflower oil (). fers from a serious handicap due to the poor intestinal absorp 0022 FIG. 3 illustrates the results of a bioequivalence tion and to the intense hepatic metabolism (short plasmatic study between UTROGESTANR) capsules (+) and capsules half-life) of this hormone. Only the vaginal, rectal and intra described herein containing sunflower oil (), with respect to muscular pathways would, to date, make it possible to main mean plasma concentration (pg/ml). tain blood progesterone level at the physiological level of the 0023 FIG. 4 illustrates the results of a bioequivalence luteal phase, for several hours. study between UTROGESTANR) capsules (+) and capsules 0011. The LABORATOIRES BESINS-ISCOVESCO described herein containing sunflower oil (), with respect to have already proposed a solution in order to improve the the natural log (Ln) of mean plasma concentration (pg/ml). quality and intensity of the digestive absorption of natural progesterone, in Patent Application FR 76 36007. Specifi DETAILED DESCRIPTION cally, they have developed a formulation of soft capsules containing micronized progesterone in oily suspension. The 0024. After much study and research, during which sev synergistic effect of the micronization and the use of mol eral plant oils were tested, sunflower oil, olive oil, sesame ecules containing long-chain fatty acids has made it possible seed oil, colza oil and almond oil were selected. Specifically, to indisputably increase the bioavailability of progesterone the use of these oils makes it possible to rule out the risks of taken orally. This formulation has known a great deal of allergic reactions, while at the same time conserving all of the success worldwide. It is sold in under the trade mark physicochemical and kinetic characteristics of the prior UTROGESTANCR). UTROGESTANR) formulation, characteristics which were US 2011/0135719 A1 Jun. 9, 2011

the cause of its success. Given that the method manufacturing micronized progesterone in Suspension became apparent the prior UTROGESTANR) formulation on an industrial scale between the composition based on peanut oil and that con comprise steps which are very delicate to carry out, it is to the taining the oils used in accordance with the invention. credit of the applicant company to have Succeeded in modi 0033. With regard to the other oils tested, the particle size fying the formulation without increasing the production dif was not the same in the presence or absence of the Soya bean ficulties. lecithin. The main advantage of the oils selected according to 0025. In the context of the present invention, the oils can the invention in physicochemical terms compared to the pea be refined or not. A refined oil is an oil which is obtained from nut oil is to simultaneously ensure: raw oil and which has undergone a set of refining operations. 0034 comparable solubilities at saturation of the micron The refined oil is a purified oil having a very low impurity ized progesterone; content and especially devoid of highly allergenizing proteins 0035 comparable particle sizes of the suspension; Such as gluten. 0036) and comparable in vitro dissolution profiles. 0026. In the pharmaceutical composition according to the 0037 Now, particle size and solubility at saturation sig invention, the micronized progesterone is preferably in Sus nificantly influence the in vivo bioavailability of the proges pension in Sunflower oil, olive oil, Sesame seed oil, colza oil, terOne. almond oil, or in a mixture of some or all these oils. 0038. The choice of these oils therefore makes it possible 0027. The applicant company is aware of U.S. Pat. No. to have better control of the particle size distribution of the 5,140,021 in the name of GENESIS SYSTEMS CORPORA micronized progesterone in the oily suspension, and also the TION (Maxson et al.) which describes a soft capsule contain amount of progesterone solubilized in the oil, and therefore to ing a micronized progesterone in Suspension in a highly bring together all of the conditions required for maintaining unsaturated oil. Sunflower oil appears among the oils cited in an in vivo bioavailability similar to that obtained with this patent. However, the inventors of this patent U.S. Pat. No. UTROGESTANCR). 5,140,021 have taken the greatest care to distinguish them 0039. According to an advantageous embodiment of the selves from the pharmaceutical product UTROGESTANR, pharmaceutical composition according to the invention, the i.e. the formulation developed and currently marketed by the progesterone/oil(s) ratio is between 0.15/1 and 3/1, prefer applicant company, based on peanut oil. Thus, the micronized ably between 0.25/1 and 2/1, preferentially between 0.40/1 progesterone used in the GENESIS SYSTEMS patent is and 1/1, and even more preferentially is 0.67/1. described as having a particular particle size distribution 0040. According to an advantageous embodiment of the which is different from that used in UTROGESTANR). pharmaceutical composition of the invention, the Soya bean 0028 U.S. Pat. No. 5,140,021 only describes a laboratory lecithin/oil(s) ratio is between 0.005/1 and 0.3/1, preferably scale preparation of the progesterone capsules and provides between 0.01/1 and 0.2/1, preferentially between 0.040/1 and no teaching regarding the preparation of capsules on an indus 0.1/1, and even more preferentially is 0.067/1. In other trial scale. In addition, the progesterone capsules according to embodiments, the ratio of soya bean lecithin/oil(s) is 0.0067/ saidAmerican patent do not contain soya bean lecithin, which 1. is an essential element of the pharmaceutical composition 0041. The pharmaceutical composition according to the according to the present invention. Specifically, the Soya bean invention may also comprise an oestrogen or an ester-type lecithin plays the role of an agent for Suspending the proges derivative thereof, preferably selected from the group con terone particles in the sunflower oil and of a during sisting of 17-3-oestradiol, oestrone, 17-O-ethinyl oestradiol encapsulation of the content on an industrial scale. and oestradiol Valerianate, or phyto-Oestrogens and even 0029. The invention therefore relates to a pharmaceutical more preferentially is 17-B-oestradiol. composition comprising micronized progesterone, soya bean 0042. The pharmaceutical composition according to the lecithin and at least one oil selected from the group consisting invention may be in the form, interalia, of a soft capsule, of a of Sunflower oil, olive oil, Sesame seed oil, colza oil and hard capsule, of a tablet, or a drinkable Suspension. almond oil. 0043. When the pharmaceutical composition according to 0030. According to an advantageous embodiment of the the invention is integrated into a pharmaceutical product, pharmaceutical composition according to the invention, the each dosage unit advantageously comprises between 2 mg micronized progesterone is in Suspension in oil or in a mixture and 600 mg of micronized progesterone, preferably between of some or all these oils. 30 mg and 300 mg, and even more preferentially between 100 0031. In the context of the present invention, the term mg and 200 mg. “micronized progesterone' is intended to mean a progester 0044) The pharmaceutical composition according to the one in which at least 80% of the particles have a particle size invention may be administered orally or vaginally, depending of between 1 and 15um, preferably 50% of the particles have on the therapeutic indications. a particle size of between 1 and 10 um, and even more pref 0045 Vaginal administration also represents an alterna erentially 25% of the particles have a particle size of between tive to oral administration in the case of side effects due to the 1 and 5um, these particle sizes being measured using a laser progesterone (drowsiness after oral absorption) or of con particle sizer of the Malvern type, by the procedure described traindication to oral administration (hepatopathy). in the examples of the present patent application. 0046 According to an advantageous embodiment of the 0032. During the studies prior to choosing the oil, the pharmaceutical composition according to the invention, the applicant company was able to observe, Surprisingly and capsule comprises gelatin or an equivalent. unexpectedly, that the combination of soya bean lecithin with 0047. The invention also relates to a method for preparing the oils selected according to the invention was very advan a pharmaceutical composition comprising micronized tageous since it did not modify the particle size of the micron progesterone, soya bean lecithin, and at least one oil selected ized progesterone in Suspension in the oil. In addition, no from the group consisting of Sunflower oil, olive oil, Sesame significant difference in the particle size distribution of the seed oil, colza oil and almond oil. US 2011/0135719 A1 Jun. 9, 2011

0048 This method comprises the following Successive steps: TABLE I-continued 0049 mixing of oil(s) and of soya bean lecithin is car ried out, with stirring, in order to obtain a mixture; Percentage formula References to 0050 the micronized progesterone is added, with stir Compound name (%) per unit (mg) Function standards ring, to the mixture thus obtained in order to obtain a Excipients homogeneous Suspension. Oil or mixture 59.60 149.00 Diluent Ph.Eur. 0051. This suspension may be administered as such, in the of oils 3rd Ed. form of a drinkable suspension, or be presented in the form of according to Soft capsules or hard capsules, but may also be used to the invention impregnate an absorbent Support presented in the form of Soya bean O.40 1.00 Emulsifier USP 24, powder. lecithin NF 19. 0052. This absorbent support may be of the maltodextrin p. 2471 and/or derivatives, silica and/or derivatives, cyclodextrin and/ or derivatives or cellulose powder and/or derivatives type, or 0059. The applicant company has also prepared 500 mg a combination thereof, or any other pharmaceutical raw mate capsules which are homothetic with the 250 mg capsules rial which possesses equivalent properties. described above. Thus, the 500 mg capsules contain 200 mg 0053. The powder thus obtained may then be presented in the form of hard capsules or tablets. The hard capsules or of micronized progesterone, 2 mg of Soya bean lecithin, and tablets containing the powder may also comprise binding as an example, 298 mg of Sunflower oil. agents, disintegrating agents, diluents and/or . 0054 The invention also relates to the use of the micron Example 2 ized progesterone, of the Soya bean lecithin, and of at least one oil selected from the group consisting of Sunflower oil, Study of Solubility of Micronized Progesterone in olive oil, sesame seed oil, colza oil and almond oil in the Various Oils preparation of a medicinal product for treating a physiologi cal condition linked to insufficiency of progesterone secre 0060. In order to select the optimum oily vehicle to replace tion. the peanut oil, while at the same time conserving the physi 0055 As examples of such physiological conditions, men cochemical properties of the prior formulation, the following tion may be made of: luteal insufficiency, menstrual irregu larity, premenstrual syndromes, mastodynia, benign masto plant oils were tested with regard to the solubility of proges pathies, premenopause, sterility due to luteal insufficiency, terone in these oils: disorders due to menopause, local contraception, for preven 0061 peanut oil tion of repeated abortions in the case of luteal insufficiency, 0062 olive oil danger of premature birth, acne, alopecia, for prevention of 0063 sunflower oil osteoporosis, endometrial cancers and epilepsy. 0056. The invention also relates to the use of the micron 0.064 Sunflower oil with a high oleic acid content ized progesterone, of the Soya bean lecithin, and of at least 0065 colza oil one oil selected from the group consisting of Sunflower oil, 0066 almond oil olive oil, sesame seed oil, colza oil and almond oil and also of 0067 soya bean oil an oestrogen, in the preparation of a medicinal product for treating a physiological condition linked to insufficiency of 0068 sesame seed oil progesterone secretion. The oestrogen is preferably selected 0069 from the group consisting of 17-B-Oestradiol, oestrone, 17-O- 0070 Standard solutions were prepared as follows: ethinyloestradiol, oestradiol Valerianate, orphyto-Oestrogens and even more preferentially is 17-3-oestradiol. 0057 The invention will be more clearly understood using concentrated Solution: progesterone batch AO098 10 mg the nonlimiting examples described below. oil qs for 20 ml diluted solution: concentrated Solution 1 ml Example 1 tetrahydrofuran (THF) 10 ml acetonitrile qs for 20 ml Pharmaceutical Composition in the Form of a Soft magnetic stirring: 5 minutes. Capsule According to the Invention 0058. The content of a soft capsule according to the inven 0071. The saturated solutions were then prepared as fol tion is described in Table I below. lows: 0072 The saturated solutions in each oil were maintained TABLE I for one hour with stirring at room temperature, and were then Percentage formula References to filtered on a nylon filter syringe with a diameter of 25 mm, at Compound name (%) per unit (mg) Function standards 0.45 Lum. Active Substance 0073 Saturated solutions were diluted 200-fold: 0074 saturated solution: 0.5 ml Micronized 40.00 100.00 Active Ph.Eur. progesterone substance 3 ed. 0075 THF: 50 ml 0.076 acetonitrile qs for 100 ml US 2011/0135719 A1 Jun. 9, 2011

0077. The results are given in Table II below: I0089. The mixer is again placed under vacuum (between 0.7 bar and 0.9 bar), followed by stirring at low speed between TABLE II 10 rpm and 15 rpm. 0090 The progesterone is added under vacuum, followed RELATIVE CONCENTRATION DIFFERENCE* ON by the remaining quarter of sunflower oil, and the temperature AT SATURATION THE CONCENTRATION is brought to 23° C.3°C. OIL TESTED (mg/ml) AT SATURATION (%) 0091 Next, vigorous stirring is carried out until homog enization is obtained. Peanut oil 16.77 Colza oil 1814 +8.2% 0092. The mixer with vigorous stirring is placed under a Sunflower oil 17.50 +4.4% pressure up to a maximum of 1 bar. Sunflower oil 8.29 -50.6% 0093 Continuous sieving using a 500 um sieve is carried with a high oleic acid content out and the mixture is transferred into a storage container. Olive oil 1746 +4.1% 0094. The storage containers are placed under vacuum and then stirred at between 2400 and 2000 rpm for 15 minutes. They are again placed under vacuum and restirred for 30 minutes at a speed of between 2000 and 2500 rpm. TABLE III 0.095 The stirring is stopped and the containers are left to RELATIVE stand for 5 minutes under vacuum. CONCENTRATION DIFFERENCE* ON 0096. The encapsulation is carried out in a conventional AT SATURATION THE CONCENTRATION manner known to those skilled in the art. OIL TESTED (mg/ml) AT SATURATION (%) Peanut oil 1880 Example 4 Almond oil 18.98 +1.0% Soya bean oil 16.19 -13.9% Determination of the Particle Size of a Capsule Sesame seed oil 1980 +5.3% Corn oil 15.60 -17.0% According to the Invention

Peanut oil = reference oil 0097. A comparative particle size study was carried out between UTROGESTRANR) capsules and capsules accord 0078. The colza oil, sunflower, olive oil, sesame seed oil ing to the invention containing Sunflower oil. and almond oil were selected following this study of solubil 0098. The material used is as follows: ity at Saturation. 0099 Mastersizer 2000 laser particle sizer 0079 Among the various suppliers of oils mention may be 0100 Hydro 2000 SM measuring cell made, by way of example, of: according to the following method: 0080 for the olive oil: LESSIEUR: 0101. Amount of sample per measurement: 1 or 2 drops 0081 for the sunflower oil: HENRY LAMOTTE. deposited using a pipette 0102 Medium: filtered saturated sunflower oil. This oil is Example 3 prepared with magnetic stirring, maintaining the temperature at 37°C., for 1 hour, and then filtered on filter paper. Manufacturing of Soft Micronized Progesterone (0103) Refractive index: (oil average) 1.4671 Capsules According to the Invention 01.04 Medium volume: 100 ml 0105 Stirring rate: 1800 rpm 0082. The manufacturing of soft capsules based on 0106 Percentage obscuration: between 10 and 20% micronized progesterone according to the invention is carried 0107 Weighted residual percentage: <3% out as follows: 0108) Number of measurements per preparation: 2. The 0083. The capsules are prepared according to one of the measurements begin after the percentage obscuration has methods known perse to those skilled in the art. been stable for 30 min. 0084. For a batch of 2300 000 capsules, each containing 0109 The results given in FIG. 1 hereinafter demonstrate 100 mg of progesterone, the following procedure is carried that the particle sizes of the two capsules are highly compa Out: rable. I0085. The atmosphere is controlled at 22°C.-3°C. and at 0110. Further studies carried out by the Applicant Com a relative humidity of 35%+10%. pany have shown that the size distribution of progesterone in I0086. The following ingredients are weighed: sesame seed oil, olive oil, colza oil or almond oil, is also comparable to that obtained in peanut oil.

Progesterone 230.00 kg Example 5 Sunflower oil 342.70 kg Soya bean lecithin 2.30 kg Comparative In Vitro Dissolution Study Between a UTROGESTRANR) Capsule and a Capsule Accord ing to the Invention I0087. A mixer with a volume of 600 litres is placed under WaCUU. 0111 ASOTAX AT7 dissolution machine with rotating 0088. Three quarters of the amount of sunflower oil is baskets was used. introduced under vacuum into this mixer and the Soya bean 0112 20 mg of exactly weighed progesterone are dis lecithin is added. solved in 2 ml of ethanol, in a 200 ml volumetric flask (class US 2011/0135719 A1 Jun. 9, 2011

A), this is then treated with ultrasound and the volume is made 18. The pharmaceutical composition according to claim up to the capacity line using the dissolution medium (1% 11, wherein the progesterone/oil ratio is between 0.15/1 and Kleptose). 3/1. 0113. The control solution is filtered on a fiberglass 19. The pharmaceutical composition according to claim Syringe filter with a porosity of 1 Jum. 11, wherein the soybean lecithin/oil ratio is between 0.005/1 0114 7 tanks are placed in a waterbath at constant tem and 0.3/1. perature, and then 1000 ml of dissolution medium are trans 20. The pharmaceutical composition according to claim ferred into each of the 7 tanks. 11, wherein the progesterone/oil ratio is between 0.25/1 and 0115 1 capsule is placed in 6 tanks, and then the baskets 2/1. are immersed in the dissolution medium at a distance of 25 21. The pharmaceutical composition according to claim Mimit2 Mm between the basket and the bottom of the tank. 11, wherein the progesterone/oil ratio is between 0.40/1 and 0116. The baskets are stirred, and then a control solution is 1/1. prepared. 22. The pharmaceutical composition according to claim 0117. At each time interval planned (5, 10, 15, 30, 45, 60, 11, wherein the progesterone/oil ratio is 0.67/1. 90, 120, 150, 180, 225, 270, 315 and 360 minutes), the samples are collected and then analysed by UV spectropho 23. The pharmaceutical composition according to claim tometry (X: 248 nm). 11, wherein the soybean lecithin/oil ratio is between 0.01/1 0118. The results given in FIG. 2 hereinafter demonstrate and 0.2/1. that the in vitro dissolution curves for an UTROGESTANR) 24. The pharmaceutical composition according to claim capsule and for a capsule according to the invention contain 11, wherein the soybean lecithin/oil ratio is between 0.04.0/1 ing sunflower oil are virtually identical. and 0.1/1. 0119 The physicochemical characteristics of the prior 25. The pharmaceutical composition according to claim formulation are therefore conserved in the formulation 11, wherein the soybean lecithin/oil ratio is 0.0067/1. according to the invention. 26. The pharmaceutical composition according to claim 11, further comprising an estrogen or an ester-type derivative Example 6 thereof. 27. The pharmaceutical composition according to claim Bioeduivalence Study Between UTROGESTANR) 26, wherein the estrogen, or the ester-type derivative thereof Capsules and the Pharmaceutical Composition is selected from the group consisting of 17-beta-estradiol. According to the Invention estrone, 17-alpha-ethinyl estradiol and estradiol valerianate, 0120 A bioequivalence study was carried out in order to or phyto-estrogens. compare capsules according to the invention containing 100 28. The pharmaceutical composition according to claim mg progesterone in Suspension in Sunflower oil with 26, wherein the estrogen, or the ester-type derivative thereof UTROGESTANR) capsules. is 17-beta-estradiol. 0121 The study was carried out on a representative 29. The pharmaceutical composition according to claim sample of 60 women, in starvation conditions. 11, wherein at least the progesterone is in Suspension in the 0122) The results of the study showed a bioequivalence oil. between the capsules according to the invention and 30. The pharmaceutical composition according to claim UTROGESTANR) (see FIGS. 3 and 4 thereafter). 11, in the form of a soft capsule. 1-10. (canceled) 31. The pharmaceutical composition according to claim 11. A pharmaceutical composition comprising micronized 11, in unit dosage form comprising between 2 mg and 600 mg progesterone, soybean lecithin, and at least one oil selected of micronized progesterone. from the group consisting of , colza oil, and almond oil. 32. The pharmaceutical composition according to claim 12. The pharmaceutical composition of claim 11, wherein 31, comprising between 30 mg and 300 mg of micronized the oil is sesame oil. progesterone. 13. The pharmaceutical composition of claim 11, wherein 33. The pharmaceutical composition according to claim the oil is colza oil. 31, comprising between 100 mg and 200 mg of micronized 14. The pharmaceutical composition of claim 11, wherein progesterone. the oil is almond oil. 34. A method for preparing a pharmaceutical composition 15. The pharmaceutical composition of claim 11, wherein according to claim 11, comprising: at least about 80% of the particles of said micronized proges mixing at least one oil selected from the group consisting of terone are characterized by a particle size of between 1 and 15 Sesame oil, colza oil, and almond oil with Soy bean um, as measured in the composition. lecithin in order to obtain a mixture; and 16. The pharmaceutical composition according to claim adding micronized progesterone to said mixture to obtain a 11, wherein at least 50% of the particles of said micronized homogeneous Suspension. progesterone have a particle size of between 1 and 10 um, as 35. A method for the treatment of a physiological condition measured in the composition. linked to insufficiency of progesterone secretion comprising 17. The pharmaceutical composition according to claim the step of administering to the patient a pharmaceutical 11, wherein at least 25% of the particles of said micronized composition according to claim 11. progesterone have a particle size of between 1 and 5um, as measured in the composition. c c c c c