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WO1993012797A1 - Pharmaceutical compositions containing natural progesterone having a high biological availability - Google Patents

Pharmaceutical compositions containing natural progesterone having a high biological availability Download PDF

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Publication number
WO1993012797A1
WO1993012797A1 PCT/EP1992/002982 EP9202982W WO9312797A1 WO 1993012797 A1 WO1993012797 A1 WO 1993012797A1 EP 9202982 W EP9202982 W EP 9202982W WO 9312797 A1 WO9312797 A1 WO 9312797A1
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WO
WIPO (PCT)
Prior art keywords
progesterone
pyrrolidone
cross
compositions according
cyclodextrin
Prior art date
Application number
PCT/EP1992/002982
Other languages
French (fr)
Inventor
Sergio Rosini
Fabio Carli
Original Assignee
Istituto Gentili S.P.A.
Vectorpharma International S.P.A.
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Filing date
Publication date
Application filed by Istituto Gentili S.P.A., Vectorpharma International S.P.A. filed Critical Istituto Gentili S.P.A.
Publication of WO1993012797A1 publication Critical patent/WO1993012797A1/en

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the invention relates to pharmaceutical compositions containing natural progesterone having a high biological availability.
  • the feminine ovulatory cycle is ruled by the concerted secretion of estrogens and progesterone, which in its turn is modulated by the output of the hypophyseal hormones FSH and LH.
  • the progesterone secretion is particularly high during the luteal phase of the ovulatory cycle.
  • the therapy of the postmenopausal disorders is therefore relying on the pharmacological reintegration of both the hormonal components, as to reach the physiological haematic levels typical of the childbearing period.
  • the complicating diseases coming from the reduced secretion of the sexual hormones during the menopause the loss of osteal matrix (osteoporosis) assumes a prominent role.
  • a combined treatment based on estrogens and progesterone
  • the combination of the two hormones shows also other implications.
  • the administration of the sole estrogens exerts a beneficial action on the lipidic haematic profile, in terms of cardiovascular diseases, along with an increase of the HDL fraction of cholesterol, but a prolonged treatment makes register an increased risk of mammary and endometrial tumor .
  • This last consequence of the estrogens can be antagonized by a contemporaneous administration of progesterone [J. Jensen; Am. J. Obstet. Gynecol. (1987) ; 156:66] .
  • progestational agents are normally utilized in the combined therapy based on estrogens .
  • progestogens are synthesized steroids deriving from progesterone.
  • compositions consist of natural progesterone supported on a material selected from the group consisting of ⁇ - cyclodextrin and cross-linked polyvinyl-pyrrolidone along with excipient substances normally used in the pharmaceutical technique, said progesterone being admixed with said carrier material by means of a high energy co-grinding under an atmosphere substantially consisting of the vapour of a solvent apt to solubilize the drug or to be adsorbed onto the surface of the carrier material.
  • the incorporation of progesterone into the cross- linked polyvinyl-pyrrolidone can be carried out by swelling the polymer with a solution of the drug, by a subsequent removal of the solvent at a controlled rate and by an end activation by solvent spraying.
  • compositions allow to obtain the desired haematic concentrations of progesterone by administering a drug dose definitely lower with respect to the prior art and can be advantageously applied in the hormonal replacement therapy of menopause, in the prevention and in the treatment of the osteoporosis and in all other forms of progesterone deficiency.
  • compositions consist of natural progesterone and of a carrier material selected from the group consisting of ⁇ -cyclodextrin and
  • the progesterone amount is between 2 and 50 b.w. and preferably between 5 and 20. b.w.; the amount of ⁇ - cyclodextrin or of polyvinyl-pyrrolidone is between 10 and 80% b.w.
  • lactose crystalline and spray dried
  • microcrystalline cellulose cellulose ethers
  • dibasic calcium phosphate mannitol
  • starch modified starch
  • linear povidone polyvinyl-pyrrolidone
  • sodium carboxymethylcellulose sodium carboxymethylcellulose
  • cross-linked polyvinyl-pyrrolidone 15 cross-linked polyvinyl-pyrrolidone; sodium carboxymethylstarch; croscaramellose; stearic acid; alkaline earth stearates; polyethyleneglycols having various molecular weight.
  • the incorporation of progesterone into ⁇ -cyclodextrin and into cross-linked polyvinyl-pyrrolidone is performed by the high energy on co-grinding technique, in the presence of the vapour of a solvent, such technique being based on the use of high-energy mills; in the grinding chamber of said mills there is introduced, beyond the drug/carrier mixture, a stream of a solvent apt to solubilize the drug or to be adsorbed onto the ' surface of the carrier material, 5 like for instance water, methylene chloride and methanol.
  • the incorporation of progesterone into cross-linked polyvinyl-pyrrolidone is performed by the technique comprising the swelling of the polymer by means of a drug-containing solution, suitable for the swelling of the polymer, subsequent removal of the solvent by con rolled-rate evaporation, and final activation by solvent spraying; it may be advantageous to add to such solvent a linear polymer, like linear polyvinyl-pyrrolidone, in order to grant the product better technological features, like miscibility and a high flow. Said solvent removal is carried out at a rate between 0.2 - and 10 ml/min per liter of solvent to be removed.
  • compositions according to the invention can be prepared in the form of a powder or as a granular product, which can be subsequently employed as such (e.g. as a granular product, suitable for suspensions and so on) or converted into tablets or capsules.
  • Said compositions were tested not only in dissolution tests, but also in bioavailability tests and in pharmacokinetic tests on the woman; such tests showed that an administration of 50 mg of progesterone allows to reach a haematic concentration of 10-12 ng/ml.
  • hormonal replacement therapy of menopause in combination with estrogens either during the whole space of the ovarial cycle or during the last 7 ⁇ 10 days, at a dosage between 25 and 200 mg/d of progesterone, said dosage being supplied either as a sole administration or in a subdivided form (2-3 daily doses) in order to maintain an optimum concentration during the 24 hours;
  • compositions according to the invention are supplied for merely illustrative but not limitative purposes.
  • Progesterone (50 g) was supported on ⁇ -cyclodextrin (250 g) by means of the high energy co-grinding technique , by co-grinding for lh under a water vapour atmosphere , whereas the other components , consisting of cross-linked polyvinyl-pyrrolidone ( 10 g) , microcrystalline cellulose (20 g) , calcium dibasic phosphate (30 g) , colloidal silica (8 g) and magnesium stearate (2 g) , were subsequently admixed with the co-ground product. The thus obtained product was then subdivided into tablets and capsules .
  • EXAMPLE 2 EXAMPLE 2
  • TOTAL 710 Progesterone (50 g) was supported on ⁇ -cyclodextrin (500 g) by means of the high-energy co-grinding technique, by co-grinding for lh, under a water vapour atmosphere , whereas the other components , consisting of : cross-linked polyvinyl-pyrrolidone ( 60 g) , microcrystalline cellulose (46 g) , calcium dibasic phosphate (45 g) , colloidal silica ( 7 g) and magnesium stearate ( 2 g) , were subsequently admixed with the co-ground product .
  • the mixture was then subdivided into tablets .
  • EXAMPLE 3 A composition was prepared having the following unitary content per each single dose ( tablet) : mg
  • Progesterone 50 g was supported on cross-linked polyvinyl- pyrrolidone (250 g) by a swelling of the same with 500 ml of a 10J. w.w. solution of the drug in methylene chloride, followed by a removal of the solvent by means of an evaporation at a rate of 2 ml/minute. On the product there were then sprayed 200 ml of a 10 b.w.
  • EXAMPLE 4 It was prepared a composition having the following unitary content per each single dose (tablet or capsule): mg Natural Progesterone 50
  • Progesterone (50 g) was supported on cross-linked polyvinyl- pyrrolidone (500 g) by a swelling of the same with 500 ml of a 10 b.w. solution of the drug in methylene chloride, followed by a removal of the solvent by means of evapouration at a rate of 2 ml/minute.
  • Onto the thus obtained powder there were then sprayed 400 ml of a 15% b.w. solution of linear polyvinyl-pyrrolidone in methylene chloride; then there was a drying step and the thus obtained powder was admixed with the other components, consisting of: linear polyvinyl-pyrrolidone (70 g) , microcrystalline cellulose (75 g) .
  • calcium dibasic phosphate (48 g) colloidal silica (4 g) and magnesium stearate (3 g) •
  • Cross-linked polyvinyl-pyrrolidone (micronized) 500 Cross-linked polyvinyl-pyrrolidone 50 Sodium carboxymethylstarch 0
  • Progesterone (50 g) was supported on micro cross-linked polyvinyl- pyrrolidone (500 g) by the high energy co-grinding technique under an atmosphere of methylene chloride vapour, whereas the other components, consisting of cross-linked polyvinyl-pyrrolidone (50 g) , sodium carboxymethylstarch (50 g) , lactose (22 g) , colloidal silica (35 ⁇ ) and magnesium stearate (3 g) • were subsequently admixed with the co-ground product. The mixture was then subdivided into tablets.
  • compositions prepared according to the invention prepared two compositions based on complex compounds of the progesterone with ⁇ - cyclodextrine and cross-linked polyvinyl-pyrrolidone; the first composition was prepared according to the known spray-drying technique and the second one was prepared by simply loading by means of a swelling.
  • Progesterone 50 g was supported on cross-linked polyvinyl- pyrrolidone by swelling the same with 500 ml of a 10% w/w solution of the drug in methylene chloride and subsequent drying in an oven under vacuum.
  • the thus obtained powder was admixed with the other components according to the modalities of example 3-
  • compositions of examples 1, 3 and 5 ⁇ there were performed pharmacokinetic tests on the woman, while administering 50 mg of progesterone by oral administration.
  • table 3 reports the results obtained by administering a composition of the known art, based on a micronized progesterone available on the market, containing 200 mg of progesterone.
  • Table 2 Plasmatic concentration of progesterone (ng/ml) after administration of compositions according to the present invention.
  • P/PVP Composition according to example 3-
  • P/ ⁇ -CDX Composition according to example 1.
  • P/PVP Composition according to example 5-
  • Example 3 Example 1
  • Example 5 Time P/PVP P/ ⁇ -CDX P/PVP

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Abstract

Pharmaceutical compositions containing natural progesterone having a high biological availability, consisting of natural progesterone supported on a material selected from the group consisting of β-cyclodextrin and cross-linked polyvinyl-pyrrolidone along with excipient substances normally employed in the pharmaceutical technique, useful in the therapy of the forms of progesterone deficiency.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING NATURAL PROGESTERONE HAVING A HIGH BIOLOGICAL AVAILABILITY BACKGROUND OF THE INVENTION
1) FIELD OF THE INVENTION The invention relates to pharmaceutical compositions containing natural progesterone having a high biological availability.
2) PRIOR ART
The feminine ovulatory cycle is ruled by the concerted secretion of estrogens and progesterone, which in its turn is modulated by the output of the hypophyseal hormones FSH and LH.
The progesterone secretion is particularly high during the luteal phase of the ovulatory cycle. At the end of the childbearing period there is a deficiency in the secretion of the sexual hormones, either estrogens or progesterone; the therapy of the postmenopausal disorders is therefore relying on the pharmacological reintegration of both the hormonal components, as to reach the physiological haematic levels typical of the childbearing period. Amongst the complicating diseases coming from the reduced secretion of the sexual hormones during the menopause, the loss of osteal matrix (osteoporosis) assumes a prominent role.
It has now long been known the beneficial action of the estrogens on the prevention and on the treatment of the osteoporosis, such action consisting of the inhibition of the excessive osteal reabsorption performed by the osteophages. A few experimental evidences, on the other hand, show that progesterone performs its activity by stimulating the osteoblasts , which represent the cellular population responsible for the neoformation of osteal matrix [J. C . Prior ; Endocrine Reviews (1990) ; 11 (2) ; 386] . From such statements it can be inferred that a combined treatment, based on estrogens and progesterone , is suitable for both the hormonal replacement therapy of menopause and the prevention and the treatment of osteoporosis, where also progesterone alone can be utilized. The combination of the two hormones shows also other implications. In fact, the administration of the sole estrogens exerts a beneficial action on the lipidic haematic profile, in terms of cardiovascular diseases, along with an increase of the HDL fraction of cholesterol, but a prolonged treatment makes register an increased risk of mammary and endometrial tumor . This last consequence of the estrogens can be antagonized by a contemporaneous administration of progesterone [J. Jensen; Am. J. Obstet. Gynecol. (1987) ; 156:66] .
Because of the poor absorbability of natural progesterone by oral administration, a different class of progestational agents is normally utilized in the combined therapy based on estrogens . Such class consists of progestogens , which are synthesized steroids deriving from progesterone.
Although these steroids decrease the impact of mammary and endometrial carcinoma, they however reduce the protection supplied by the estrogens against cardiovascular diseases.
It is thus desirable to use natural progesterone in combination with the estrogens in the therapy of the pathologies hereinabove. The benefits supplied by the natural progesterone, with respect to the synthetic progestogens, can be summarized as follows:
- It has no harmful effect on the lipidic metabolism;
- It doesn't modify the blood-clotting factors;
- It has no impact on the metabolism of carbohydrates;
- It causes a stimulating effect on breathing (PCO2, in fact, is lower in the women in luteal phase, with respect to men);
- It has an antiandrogen activity and therefore it doesn't give rise either to any weight increase or to any engendering of seborrhea, acne or hypertrichosis;
- It blocks the aldosterone action on the kidneys, giving rise to a sodium engendered diuresis and lowering the water retention;
- It shows a tranquillizing physiological effect.
The oral preparations nowadays available, based on natural progesterone, show, as already mentioned, a poor biological availability; it is thus necessary to administer a high dose of the product, equal to 200 mg/d, in order to reach the physiological haematic concentrations. There are available also injectable preparations either in a vegetable oil or in water; they did however prove to be locally irritant and particularly painful. SUMMARY The Applicants found new pharmaceutical compositions, by oral administration, containing natural progesterone having a high biological availability, which allow to overcome the drawbacks of the prior art. Said compositions consist of natural progesterone supported on a material selected from the group consisting of β- cyclodextrin and cross-linked polyvinyl-pyrrolidone along with excipient substances normally used in the pharmaceutical technique, said progesterone being admixed with said carrier material by means of a high energy co-grinding under an atmosphere substantially consisting of the vapour of a solvent apt to solubilize the drug or to be adsorbed onto the surface of the carrier material.
Alternatively, the incorporation of progesterone into the cross- linked polyvinyl-pyrrolidone can be carried out by swelling the polymer with a solution of the drug, by a subsequent removal of the solvent at a controlled rate and by an end activation by solvent spraying.
Said compositions allow to obtain the desired haematic concentrations of progesterone by administering a drug dose definitely lower with respect to the prior art and can be advantageously applied in the hormonal replacement therapy of menopause, in the prevention and in the treatment of the osteoporosis and in all other forms of progesterone deficiency. DETAILED DESCRIPTION OF THE INVENTION
The features and the advantages of the pharmaceutical compositions suitable for oral administration and containing natural progesterone having high biological availability according to the present invention, will be more widely illustrated during the following detailed description.
Said compositions consist of natural progesterone and of a carrier material selected from the group consisting of β-cyclodextrin and
5 cross-linked polyvinyl-pyrrolidone and of the excipients normally used in the pharmaceutical technique.
In said compositions the progesterone amount is between 2 and 50 b.w. and preferably between 5 and 20. b.w.; the amount of β- cyclodextrin or of polyvinyl-pyrrolidone is between 10 and 80% b.w.
10 and preferably between 30 and J0% b.w.
As an excipient there can be used: lactose (crystalline and spray dried); microcrystalline cellulose; cellulose ethers; dibasic calcium phosphate; mannitol; starch; modified starch; linear povidone (polyvinyl-pyrrolidone); sodium carboxymethylcellulose;
15 cross-linked polyvinyl-pyrrolidone; sodium carboxymethylstarch; croscaramellose; stearic acid; alkaline earth stearates; polyethyleneglycols having various molecular weight. The incorporation of progesterone into β-cyclodextrin and into cross-linked polyvinyl-pyrrolidone is performed by the high energy on co-grinding technique, in the presence of the vapour of a solvent, such technique being based on the use of high-energy mills; in the grinding chamber of said mills there is introduced, beyond the drug/carrier mixture, a stream of a solvent apt to solubilize the drug or to be adsorbed onto the' surface of the carrier material, 5 like for instance water, methylene chloride and methanol. Alternatively, the incorporation of progesterone into cross-linked polyvinyl-pyrrolidone is performed by the technique comprising the swelling of the polymer by means of a drug-containing solution, suitable for the swelling of the polymer, subsequent removal of the solvent by con rolled-rate evaporation, and final activation by solvent spraying; it may be advantageous to add to such solvent a linear polymer, like linear polyvinyl-pyrrolidone, in order to grant the product better technological features, like miscibility and a high flow. Said solvent removal is carried out at a rate between 0.2 - and 10 ml/min per liter of solvent to be removed.
The compositions according to the invention can be prepared in the form of a powder or as a granular product, which can be subsequently employed as such (e.g. as a granular product, suitable for suspensions and so on) or converted into tablets or capsules. Said compositions were tested not only in dissolution tests, but also in bioavailability tests and in pharmacokinetic tests on the woman; such tests showed that an administration of 50 mg of progesterone allows to reach a haematic concentration of 10-12 ng/ml. These results allow the application of the compositions according to the invention, following the prescriptions and the posology hereinbelow:
1) hormonal replacement therapy of menopause: in combination with estrogens either during the whole space of the ovarial cycle or during the last 7~10 days, at a dosage between 25 and 200 mg/d of progesterone, said dosage being supplied either as a sole administration or in a subdivided form (2-3 daily doses) in order to maintain an optimum concentration during the 24 hours;
2) prevention and treatment of osteoporosis, in combination with the estrogens, according to the therapeutical cycle hereinabove, and without estrogens, according to the following prescriptions: during 10-11 days/month or during the whole month, at a dosage between 25 and 200 mg/d of progesterone;
3) therapy of the progesterone deficiency: premenstrual syndrome, menstrual irregularities, caused by ovulation disorders or anovulation, different kinds of benign mastopathy or of mastodynia, hormonal sterility coming from ovulation disorders, according to the posologic pattern defined under item 1).
The following examples of compositions according to the invention are supplied for merely illustrative but not limitative purposes.
EXAMPLE 1
It was prepared a composition having the following unitary content per each single dose (tablet or capsule): mg
Natural Progesterone 0 β-cyclodextrin 20
Cross-linked polyvinyl-pyrrolidone 10
Microcrystalline cellulose 20
Calcium dibasic phosphate 30
Colloidal silica 8 Magnesium stearate
TOTAL 370
Progesterone (50 g) was supported on β-cyclodextrin (250 g) by means of the high energy co-grinding technique , by co-grinding for lh under a water vapour atmosphere , whereas the other components , consisting of cross-linked polyvinyl-pyrrolidone ( 10 g) , microcrystalline cellulose (20 g) , calcium dibasic phosphate (30 g) , colloidal silica (8 g) and magnesium stearate (2 g) , were subsequently admixed with the co-ground product. The thus obtained product was then subdivided into tablets and capsules . EXAMPLE 2
There was prepared a composition having the following unitary content per each single dose (tablet) : mg Natural Progesterone 50 β-cyclodextrin 500
Cross-linked polyvinyl-pyrrolidone 60
Microcrystalline cellulose 46
Calcium dibasic phosphate 45 Colloidal silica 7
Magnesium stearate 2
TOTAL 710 Progesterone (50 g) was supported on β-cyclodextrin (500 g) by means of the high-energy co-grinding technique, by co-grinding for lh, under a water vapour atmosphere , whereas the other components , consisting of : cross-linked polyvinyl-pyrrolidone ( 60 g) , microcrystalline cellulose (46 g) , calcium dibasic phosphate (45 g) , colloidal silica ( 7 g) and magnesium stearate ( 2 g) , were subsequently admixed with the co-ground product .
The mixture was then subdivided into tablets .
EXAMPLE 3 A composition was prepared having the following unitary content per each single dose ( tablet) : mg
Natural Progesterone 50
Cross-linked polyvinyl-pyrrolidone 250
Linear polyvinyl-pyrrolidone 27-5 Microcrystalline cellulose 30
Calcium dibasic phosphate 35-5
Colloidal silica 5
Magnesium stearate 2
TOTAL 400
Progesterone (50 g) was supported on cross-linked polyvinyl- pyrrolidone (250 g) by a swelling of the same with 500 ml of a 10J. w.w. solution of the drug in methylene chloride, followed by a removal of the solvent by means of an evaporation at a rate of 2 ml/minute. On the product there were then sprayed 200 ml of a 10 b.w. solution of linear polyvinyl-pyrrolidone in methylene chloride; then there was a drying step and the thus obtained powder was admixed with the other components, consisting of: polyvinyl- pyrrolidone (27-5 g) , microcrystalline cellulose (30 g), calcium dibasic phosphate (33-5 g) » colloidal silica (5 g) and magnesium stearate (2 g) .
The mixture was then subdivided into tablets. EXAMPLE 4 It was prepared a composition having the following unitary content per each single dose (tablet or capsule): mg Natural Progesterone 50
Cross-linked polyvinyl-pyrrolidone 500
Linear polyvinyl-pyrrolidone 70 Microcrystalline cellulose 75
Calcium dibasic phosphate 48
Colloidal silica 4
Magnesium stearate 3
Total 750
Progesterone (50 g) was supported on cross-linked polyvinyl- pyrrolidone (500 g) by a swelling of the same with 500 ml of a 10 b.w. solution of the drug in methylene chloride, followed by a removal of the solvent by means of evapouration at a rate of 2 ml/minute. Onto the thus obtained powder there were then sprayed 400 ml of a 15% b.w. solution of linear polyvinyl-pyrrolidone in methylene chloride; then there was a drying step and the thus obtained powder was admixed with the other components, consisting of: linear polyvinyl-pyrrolidone (70 g) , microcrystalline cellulose (75 g) . calcium dibasic phosphate (48 g) , colloidal silica (4 g) and magnesium stearate (3 g) •
The mixture was then subdivided into tablets or capsules. EXAMPLE It was prepared a composition having the following unitary content per each single dose (tablet): mg Natural Progesterone 50
Cross-linked polyvinyl-pyrrolidone (micronized) 500 Cross-linked polyvinyl-pyrrolidone 50 Sodium carboxymethylstarch 0
Lactose 22
Colloidal silica 35
Magnesium stearate 3
Total 710
Progesterone (50 g) was supported on micro cross-linked polyvinyl- pyrrolidone (500 g) by the high energy co-grinding technique under an atmosphere of methylene chloride vapour, whereas the other components, consisting of cross-linked polyvinyl-pyrrolidone (50 g) , sodium carboxymethylstarch (50 g) , lactose (22 g) , colloidal silica (35 ε) and magnesium stearate (3 g) • were subsequently admixed with the co-ground product. The mixture was then subdivided into tablets. COMPARATIVE EXAMPLES (AS FROM THE KNOWN TECHNOLOGY) In order to better evaluate the effectiveness of the compositions prepared according to the invention in comparison with the compositions of the prior art, the Applicant prepared two compositions based on complex compounds of the progesterone with β- cyclodextrine and cross-linked polyvinyl-pyrrolidone; the first composition was prepared according to the known spray-drying technique and the second one was prepared by simply loading by means of a swelling.
The preparation methods and the corresponding compositions are indicated in the examples A and B hereinbelow, whereas Table 1 is reporting the dissolution rate values, compared with the ones of the analogous formulations containing the complex compounds prepared according to the present invention. The data obtained from the preparations according to the present invention proved to be sharply superior, with respect to the ones of the preparations obtained according to the known technologies.
EXAMPLE A
Progesterone (50 g) was dissolved into a solution of β-cyclodextrine (250 g) in 4 00 ml of a water/ethanol mixture and the product was recovered by spray-drying (using an apparatus known as NYRO ATOMIZER) . The powder of the resulting complex compound was then added under mixing conditions to the other components, as per example 1. EXAMPLE B
Progesterone (50 g) was supported on cross-linked polyvinyl- pyrrolidone by swelling the same with 500 ml of a 10% w/w solution of the drug in methylene chloride and subsequent drying in an oven under vacuum. The thus obtained powder was admixed with the other components according to the modalities of example 3-
Table 1 Dissolution rate at 37 °C of progesterone into water (+ 0.5% of sodium lauryl-sulphate) , resulting from compositions with β-cyclo- dextrine and cross-linked polyvinyl-pyrrolidone prepared according to the invention and according to the prior art.
Concentration in the solution (μg/ml) Time P/Cross- P/β-CDX P/β-CDX P/Cross- ( in) linked PVP linked PVP
(as per Ex.3) (as per Ex. 1) (as per Ex.A) (as per Ex. B)
1-9 3-5
53.2
56.1
Figure imgf000016_0001
56.2
Figure imgf000016_0002
PHARMACOKINETIC TESTS
By using the compositions of examples 1, 3 and 5 < there were performed pharmacokinetic tests on the woman, while administering 50 mg of progesterone by oral administration.
The thus obtained results, concerning the plasmatic concentration of progesterone from the time of the administration to a time 24 h later, are recorded on table 2.
As a comparison, table 3 reports the results obtained by administering a composition of the known art, based on a micronized progesterone available on the market, containing 200 mg of progesterone. Table 2 Plasmatic concentration of progesterone (ng/ml) after administration of compositions according to the present invention. P/PVP: Composition according to example 3- P/β-CDX: Composition according to example 1. P/PVP: Composition according to example 5-
Example 3 Example 1 Example 5 Time P/PVP P/β-CDX P/PVP
(hours) (50 mg of (50 mg of (50 mg of progesterone) progesterone) progesterone)
Figure imgf000017_0001
Figure imgf000017_0002
Table 3 Plasmatic concentration of progesterone (ng/ml) after administration of a product present on the market, based on micronized natural progesterone. Time Composition present on the market (h) (200 mg of progesterone)
0.0 1.3
2.0 10.85
4.0 7-75 6.0 2.05
8.0 1.65
24 0.54
From the comparison of table 3 with table 2 it is to be remarked that by using the compositions according to the invention and administering 50 mg of progesterone, it is possible to reach a plasmatic concentration at a level similar to the one which can be obtained by administering one of the usual compositions on the market containing 200 mg of progesterone.

Claims

1 1) Pharmaceutical compositions containing natural progesterone
2 having a high biological availability, characterized in that they
3 contain natural progesterone supported on a material selected from
4 the group consisting of β-cyclodextrin and cross-linked polyvinyl-
5 pyrrolidone along with pharmaceutical acceptable excipients usually _ employed in the pharmaceutical technique.
D
1 2) Compositions according to claim 1, wherein the progesterone
2 content is between 2 and 50% b.w.
1 3) Compositions according to claim 1, wherein the progesterone
2 content is between 5 and 20% b.w.
. 4) Compositions according to claim 1, wherein the β-cyclodextrin
2 content is between 10 and 80% b.w.
5) Compositions according to claim 1, wherein the β-cyclodextrin
2 content is between 30 and 70% b.w.
1 6) Compositions according to claim 1, wherein the cross-linked
2 polyvinyl-pyrrolidone content is between 10 and 80% b.w.
1 7) Compositions according to claim 1, wherein the cross-linked
2 polyvinyl-pyrrolidone content is between 30 and 70% b.w.
1 8) Compositions according to claim 1, wherein progesterone is
2 supported on β-cyclodextrin and on cross-linked polyvinyl-
3 pyrrolidone by means of the high-energy co-grinding technique, under
4 an atmosphere substantially consisting of the vapour of a solvent g which is apt to solubilize the drug or to be adsorbed onto the 6 surface of the carrier material. 1 9) Compositions according to claim 1, wherein progesterone is
2 supported on cross-linked polyvinyl-pyrrolidone by swelling the
3 polymer with a drug solution, by subsequent removal of the solvent
4 at a controlled rate and by end activation by means of solvent
5 spraying.
1 10) A method for the treatment of the progesterone deficiencies,
2 wherein there are employed pharmaceutical compositions by oral ^ administration, consisting of natural progesterone having a high
4 biological availability and of a carrier material selected from the
5 group consisting of β-cyclodextrin and cross -linked polyvinyl- 5 pyrrolidone along with excipient substances normally used in the 7 pharmacological technique, at a dosage between 25 and 200 mg/d of g progesterone, administered only once a day or subdivided into 2-3 9 daily doses .
1 11) A method according to claim 10, characterized in that it is
2 employed for the hormonal replacement therapy of menopause and for
3 the prevention and the treatment of osteoporosis.
PCT/EP1992/002982 1991-12-31 1992-12-23 Pharmaceutical compositions containing natural progesterone having a high biological availability WO1993012797A1 (en)

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ITMI913510A IT1252867B (en) 1991-12-31 1991-12-31 PHARMACEUTICAL COMPOSITIONS CONTAINING HIGH-BIOAVAILABILITY PROGESTERONE

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WO1998026762A1 (en) * 1996-12-16 1998-06-25 Jenapharm Gmbh & Co. Kg Homogeneous preformulations containing wigh concentrations of steroids, for producing low-dose solid and semi-solid pharmaceutical preparations
WO1999025322A3 (en) * 1997-11-19 1999-08-19 Vectorpharma S P A Pharmaceutical compositions having the shape of powders of cross-linked polymers loaded with drugs and related preparation process by supercritical fluids
JP2014521721A (en) * 2011-08-05 2014-08-28 リポカイン インコーポレーテッド Progesterone-containing oral dosage forms and related methods
US9358298B2 (en) 2011-07-28 2016-06-07 Lipocine Inc. 17-hydroxyprogesterone ester containing oral compositions and related methods
US9375437B2 (en) 2010-06-18 2016-06-28 Lipocine Inc. Progesterone containing oral dosage forms and kits
US11590147B2 (en) 2015-06-22 2023-02-28 Lipocine Inc. 17-hydroxyprogesterone ester-containing oral compositions and related methods

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EP0364944A1 (en) * 1988-10-17 1990-04-25 Vectorpharma International S.P.A. Poorly soluble medicaments supported on polymer substances in a form suitable for increasing their dissolving rate
EP0446753A1 (en) * 1990-03-06 1991-09-18 Vectorpharma International S.P.A. Therapeutic compositions with controlled release of medicaments supported on crosslinked polymers and coated with polymer films and their preparation process

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EP0364944A1 (en) * 1988-10-17 1990-04-25 Vectorpharma International S.P.A. Poorly soluble medicaments supported on polymer substances in a form suitable for increasing their dissolving rate
EP0446753A1 (en) * 1990-03-06 1991-09-18 Vectorpharma International S.P.A. Therapeutic compositions with controlled release of medicaments supported on crosslinked polymers and coated with polymer films and their preparation process

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2178694C2 (en) * 1996-12-16 2002-01-27 Йенафарм Гмбх & Ко. Кг Steroid-containing homogeneous substance for solid pharmaceutical preparations preparing, method of its making
WO1998026762A1 (en) * 1996-12-16 1998-06-25 Jenapharm Gmbh & Co. Kg Homogeneous preformulations containing wigh concentrations of steroids, for producing low-dose solid and semi-solid pharmaceutical preparations
WO1999025322A3 (en) * 1997-11-19 1999-08-19 Vectorpharma S P A Pharmaceutical compositions having the shape of powders of cross-linked polymers loaded with drugs and related preparation process by supercritical fluids
US9375437B2 (en) 2010-06-18 2016-06-28 Lipocine Inc. Progesterone containing oral dosage forms and kits
US9399069B2 (en) 2011-07-28 2016-07-26 Lipocine Inc. 17-Hydroxyprogesterone ester containing oral compositions and related methods
US9358298B2 (en) 2011-07-28 2016-06-07 Lipocine Inc. 17-hydroxyprogesterone ester containing oral compositions and related methods
US9358299B2 (en) 2011-07-28 2016-06-07 Lipocine Inc 17-hydroxyprogesterone ester-containing oral compositions and related methods
US9364547B2 (en) 2011-07-28 2016-06-14 Lipocine Inc. 17-hydroxyprogesterone ester containing oral compositions and related methods
US10022384B2 (en) 2011-07-28 2018-07-17 Lipocine Inc. 17-hydroxyprogesterone ester-containing oral compositions and related methods
US10709716B2 (en) 2011-07-28 2020-07-14 Lipocine Inc. 17-hydroxyprogesterone ester-containing oral compositions and related methods
US11471470B2 (en) 2011-07-28 2022-10-18 Lipocine Inc. 17-hydroxyprogesterone ester-containing oral compositions and related methods
EP2739288A4 (en) * 2011-08-05 2015-03-25 Lipocine Inc Progesterone containing oral dosage forms and related methods
JP2014521721A (en) * 2011-08-05 2014-08-28 リポカイン インコーポレーテッド Progesterone-containing oral dosage forms and related methods
US11590147B2 (en) 2015-06-22 2023-02-28 Lipocine Inc. 17-hydroxyprogesterone ester-containing oral compositions and related methods

Also Published As

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ITMI913510A1 (en) 1993-07-01
IT1252867B (en) 1995-06-28
AU3257893A (en) 1993-07-28

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