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WO1993012797A1 - Compositions pharmaceutiques contenant de la progesterone naturelle a disponibilite biologique elevee - Google Patents

Compositions pharmaceutiques contenant de la progesterone naturelle a disponibilite biologique elevee 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
Authority
WO
WIPO (PCT)
Prior art keywords
progesterone
pyrrolidone
cross
compositions according
cyclodextrin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1992/002982
Other languages
English (en)
Inventor
Sergio Rosini
Fabio Carli
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Istituto Gentili SpA
Vectorpharma International SpA
Original Assignee
Istituto Gentili SpA
Vectorpharma International SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Istituto Gentili SpA, Vectorpharma International SpA filed Critical Istituto Gentili SpA
Publication of WO1993012797A1 publication Critical patent/WO1993012797A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nanotechnology (AREA)
  • Biotechnology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biophysics (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • General Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention se rapporte à des compositions pharmaceutiques contenant de la progestérone naturelle à disponibilité biologique élevée. La progestérone naturelle est supportée sur un matériau sélectionné dans le groupe comprenant de la cyclodextrine β et de la polyvinylpyrrolidone réticulée avec des excipients utilisés généralement dans les techniques pharmaceutiques et utiles en thérapie dans des formes de déficience en progestérone.
PCT/EP1992/002982 1991-12-31 1992-12-23 Compositions pharmaceutiques contenant de la progesterone naturelle a disponibilite biologique elevee Ceased WO1993012797A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI913510A IT1252867B (it) 1991-12-31 1991-12-31 Composizioni farmaceutiche contenenti progesterone ad elevata biodisponibilita'
ITMI91A003510 1991-12-31

Publications (1)

Publication Number Publication Date
WO1993012797A1 true WO1993012797A1 (fr) 1993-07-08

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/002982 Ceased WO1993012797A1 (fr) 1991-12-31 1992-12-23 Compositions pharmaceutiques contenant de la progesterone naturelle a disponibilite biologique elevee

Country Status (3)

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AU (1) AU3257893A (fr)
IT (1) IT1252867B (fr)
WO (1) WO1993012797A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998026762A1 (fr) * 1996-12-16 1998-06-25 Jenapharm Gmbh & Co. Kg Preformulations homogenes, a forte concentration en steroides, servant a produire des preparations pharmaceutiques solides et semi-solides faiblement dosees
WO1999025322A3 (fr) * 1997-11-19 1999-08-19 Vectorpharma S P A Compositions pharmaceutiques ayant la forme de poudres de polymeres reticules charges de medicaments et procede de preparation correspondant au moyen de fluides supercritiques
JP2014521721A (ja) * 2011-08-05 2014-08-28 リポカイン インコーポレーテッド プロゲステロン含有の経口剤形及び関連する方法
US9358299B2 (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

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0364944A1 (fr) * 1988-10-17 1990-04-25 Vectorpharma International S.P.A. Médicaments peu solubles fixés sur des substances polymères sous une forme susceptible de modifier leur taux de solubilité
EP0446753A1 (fr) * 1990-03-06 1991-09-18 Vectorpharma International S.P.A. Compositions thérapeutiques à libération contrôlée de médicaments supportés par des polymères réticulés et revêtus de films polymères, et leur procédé de préparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0364944A1 (fr) * 1988-10-17 1990-04-25 Vectorpharma International S.P.A. Médicaments peu solubles fixés sur des substances polymères sous une forme susceptible de modifier leur taux de solubilité
EP0446753A1 (fr) * 1990-03-06 1991-09-18 Vectorpharma International S.P.A. Compositions thérapeutiques à libération contrôlée de médicaments supportés par des polymères réticulés et revêtus de films polymères, et leur procédé de préparation

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2178694C2 (ru) * 1996-12-16 2002-01-27 Йенафарм Гмбх & Ко. Кг Гомогенная преформция, содержащая стероиды для изготовления твердых фармацевтических препаратов, способ ее изготовления
WO1998026762A1 (fr) * 1996-12-16 1998-06-25 Jenapharm Gmbh & Co. Kg Preformulations homogenes, a forte concentration en steroides, servant a produire des preparations pharmaceutiques solides et semi-solides faiblement dosees
WO1999025322A3 (fr) * 1997-11-19 1999-08-19 Vectorpharma S P A Compositions pharmaceutiques ayant la forme de poudres de polymeres reticules charges de medicaments et procede de preparation correspondant au moyen de fluides supercritiques
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
US9358299B2 (en) 2011-07-28 2016-06-07 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
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 (fr) * 2011-08-05 2015-03-25 Lipocine Inc Formes de posologie orale contenant de la progestérone et procédés associés
JP2014521721A (ja) * 2011-08-05 2014-08-28 リポカイン インコーポレーテッド プロゲステロン含有の経口剤形及び関連する方法
US11590147B2 (en) 2015-06-22 2023-02-28 Lipocine Inc. 17-hydroxyprogesterone ester-containing oral compositions and related methods

Also Published As

Publication number Publication date
AU3257893A (en) 1993-07-28
ITMI913510A1 (it) 1993-07-01
ITMI913510A0 (it) 1991-12-31
IT1252867B (it) 1995-06-28

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