EP2094275A2 - Procédés et formulations pour une biodisponibilité améliorée des antiprogestines - Google Patents

Procédés et formulations pour une biodisponibilité améliorée des antiprogestines

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Publication number
EP2094275A2
EP2094275A2 EP07869940A EP07869940A EP2094275A2 EP 2094275 A2 EP2094275 A2 EP 2094275A2 EP 07869940 A EP07869940 A EP 07869940A EP 07869940 A EP07869940 A EP 07869940A EP 2094275 A2 EP2094275 A2 EP 2094275A2
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Prior art keywords
composition
alkyl
group
patient
compound
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EP07869940A
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German (de)
English (en)
Inventor
Joseph Podolski
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Repros Therapeutics Inc
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Repros Therapeutics Inc
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Publication of EP2094275A2 publication Critical patent/EP2094275A2/fr
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    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • 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

Definitions

  • the present invention relates generally to compositions with improved bioavailability comprising at least one antiprogestin. More particularly, the present invention relates to compositions with potent antiprogestational activity, minimal antiglucocorticoid activity and improved bioavailability, comprising a 19- norprogesterone I derivative and optionally a pharmaceutically acceptable exicipient.
  • the compounds are steroid derivatives, and more specifically they are structural modifications of 19-norprogesterone I, such as 17- ⁇ - substituted-1 1 - ⁇ -substituted-4-aryl and 21 -substituted 19-norpregnadienedione, and are poorly soluble in water. Therefore, a need remains in the art to develop formulations comprising antiprogestins, in particular steroid derivatives, with increased solubility and improved bioavailability.
  • 19-norprogesterone I such as 17- ⁇ - substituted-1 1 - ⁇ -substituted-4-aryl and 21 -substituted 19-norpregnadienedione
  • the present invention provides new formulations with potent antiprogestational activity, preferably minimal antiglucocorticoid activity and improved bioavailability.
  • the new formulations are produced by finely- spraying a non-aqueous solution of the antiprogestin onto a carrier substrate.
  • the resulting formulation comprises antiprogestin particles deposited on relatively larger particles of carrier substrate.
  • the new formulations comprise micronized antiprogestin particles.
  • the antiprogestin is a compound having the following general formula I:
  • R 1 is a functional group including, but not limited to, —
  • R 2 is a functional group including, but not limited to, hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (e.g., methoxy, ethoxy, vinyloxy, ethynyloxy, cyclopropyloxy, etc.), acyloxy (e.g., formyloxy, acetoxy, propionyloxy, heptanoyloxy, glycinate, etc.), alkylcarbonate, cypionyloxy, S-alkyl, — SCN, S-acyl and —
  • compositions comprising particles of an antiprogestin, such as any compound of general formula I, and a surfactant.
  • the surfactant is preferably a polyglycolysed glyceride, such as an unsaturated polyglycolysed glyceride, a saturated polyglycolysed glyceride, GELUCIRE 33/01, GELUCIRE 35/10, GELUCIRE 37/02, GELUCIRE 44/14, LABRAFIL and LABRASOL.
  • the composition may further comprise a polyethylene glycol (PEG).
  • polyethylene glycols include, but are not limited to, PEG200, PEG400, PEG600 and PEG2000.
  • a weight ratio of polyglycosylated glyceride to polyethylene glycol (PEG) of from 5: 1 to 1 : 1 is preferred
  • compositions comprising particles of an antiprogestin, preferably any compound of general formula I, a polyglycolysed glyceride and peceol (glyceryl monooleate).
  • a weight ratio of polyglycolysed glyceride to peceol of from 9: 1 to 1 :4 is preferred.
  • compositions may possess potent antiprogestational activity with minimal antiglucocorticoid activity in combination with improved bioavailability. Therefore, the compositions may be suitable for long term use in the treatment of human endocrinological disorders or other conditions in steroid-sensitive tissues. Specific conditions for treatment include, but are not limited to, endometriosis, dysmenorrhea, uterine leiomyoma, uterine fibroid, meningioma and metastatic breast cancer. Other uses include, but are not limited to, contraception, including emergency post-coital contraception and inducement of cervical ripening.
  • compositions of the present invention in the manufacture of a medicament for treatment of human endocrinological disorders or other conditions in steroid-sensitive tissues as described herein, including but not limited to, endometriosis, dysmenorrhea, uterine leiomyoma, uterine fibroid, meningioma and metastatic breast cancer.
  • the present invention provides a composition
  • a composition comprising a carrier substrate and a deposit on said carrier substrate, said deposit comprising particles of an antiprogestin, preferably a steroid derivative with the following general formula I:
  • R 1 is a functional group including, but not limited to, — OCH 3 , -SCH 3 , —N(CH 3 ) 2 , -NHCH 3 , -NC 4 H 8 , -NC 5 Hi 0 , -NC 4 H 8 O, -CHO, -CH(OH)CH 3 , -C(O)CH 3 , — O(CH 2 ) 2 , — N(CH 3 ) 2 , — O(CH 2 ) 2 NC 4 H 8 , and -0(CHa) 2 NC 5 H] O .
  • R 2 is a functional group including, but not limited to, hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (e.g., methoxy, ethoxy, vinyloxy, ethynyloxy, cyclopropyloxy, etc.), acyloxy (e.g., formyloxy, acetoxy, propionyloxy, heptanoyloxy, glycinate, etc.), alkylcarbonate, cypionyloxy, S-alkyl, — SCN, S-acyl and — OC(O)R 6 , wherein R 6 is a functional group including, but not limited to, alkyl (e.g., methyl, ethyl, etc.), alkoxyalkyl (e.g., -CH 2 OCH 3 ) and alkoxy (-0CH 3 ).
  • alkyl e.g., methyl, ethyl, etc.
  • R 1 is a functional group including, but not limited to, alkyl, hydroxy, alkoxy and acyloxy.
  • R is a functional group including, but not limited to, hydrogen and alkyl.
  • the present invention provides a composition comprising micronized particles of an antiprogestin, preferably a steroid derivative with general formula I.
  • alkyl refers to a branched, unbranched, monovalent hydrocarbon radical having from 1-12 carbons.
  • alkyl group When the alkyl group has from 1-6 carbon atoms, it may be referred to as a "lower alkyl.”
  • Representative alkyl radicals include, for example, methyl, ethyl, n-propyl, i-propyl, 2-propenyl (or allyl), n-butyl, t-butyl, i- butyl (or 2-methylpropyl), etc.
  • alkyl encompasses "substituted alkyls.”
  • a substituted alkyl refers to alkyl further containing one or more functional groups such as lower alkyl, aryl, aralkyl, acyl, halogen (i.e., alkylhalos, e.g., CF 3 ), hydroxy (e.g., hydroxymethyl), amino, alkylamino, acylamino, acyloxy, alkoxy (e.g., methoxymethyl), mercapto and the like. These groups may be attached to any carbon atom of the lower alkyl moiety.
  • alkoxy may refer to a — OR group, where R is a lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl.
  • Suitable alkoxy radicals include, for example, methoxy, ethoxy, phenoxy, t-butoxy (e.g., methoxyethoxy, methoxymethoxy, etc.), etc.
  • acyloxy may refer to an organic radical derived from an organic acid by the removal of a hydrogen.
  • the organic radical can be further substituted with one or more functional groups such as alkyl, aryl, aralkyl, acyl, halogen, amino, thiol, hydroxy, alkoxy, etc.
  • An example of such a substituted organic radical is glycinate (e.g., -OC(O)CH 2 NH 2 ).
  • Suitable acyloxy groups include, for example, acetoxy, i.e., CH3COO — , which may be derived from acetic acid, formyloxy, i.e., H(CO)O — , which may be derived from formic acid and cypionyloxy, which may be derived from 3-cyclopentylpropionic acid.
  • halogen may refer to fluorine, bromine, chlorine and iodine atoms.
  • hydroxyl may refer to the group — OH.
  • acyl may denote groups — C(O)R, where R is alkyl or substituted alkyl, aryl or substituted aryl as defined herein.
  • aryl may refer to an aromatic substituent which may be a single ring or multiple rings which are fused together, linked covalently, or linked to a common group such as an ethylene or methylene moiety.
  • the aromatic ring(s) may include phenyl, naphthyl, biphenyl, diphenylmethyl, 2,2-diphenyl-l -ethyl, and may contain a heteroatom, such as thienyl, pyridyl and quinoxalyl.
  • the aryl group may also be substituted with halogen atoms, or other groups such as nitro, carboxyl, alkoxy, phenoxy, and the like. Additionally, the aryl group may be attached to other moieties at any position on the aryl radical which would otherwise be occupied by a hydrogen atom (such as 2-pyridyl, 3-pyridyl and 4-pyridyl).
  • alkyl carbonate may refer to the group — OC(O)OR, where R is alkyl, substituted alkyl, aryl, or substituted aryl as defined herein.
  • S-alkyl may refer to the group — SR, where R is lower alkyl or substituted lower alkyl.
  • S-acyl may refer to a thioester derived from the reaction of a thiol group with an acylating agent. Suitable S-acyls include, for example, S-acetyl, S-propionyl and S-pivaloyl. S-acyl may refer to such thioesters regardless of their method of preparation.
  • the oximes can consist of the syn-isomer, the anti-isomer or a mixture of both the syn- and anti-isomers.
  • Additional compounds include those in which R 1 is -N(CHa) 2 ; R 2 is halogen; R 3 is acyloxy; and R 4 is alkyl, such where R 2 is F, Br or Cl; and R 4 is methyl.
  • Additional compounds are those in which R is methoxy or ethoxy; and R is acetoxy or methoxy.
  • Exemplar compounds include, but are not limited to, 17 ⁇ -acetoxy-l l ⁇ -[4- (N,N-dimethylamino)phenyl]-21 -methoxy- 19-norpregna-4,9( 10)-diene-3 ,20-dione (CDB-4124) with the following structural formula:
  • Another exemplar compound is 17 ⁇ -acetoxy-l l ⁇ -[4-(N,N- dimethylamino)phenyl]-19-no ⁇ regna-4,9-diene-3,20-dione (CDB-2914) with the following structural formula:
  • Other exemplar compounds include, but are not limited to, 17 ⁇ -acetoxy-21- chloro- 11 ⁇ -(4-N,N-dimethylaminophenyl)- 19-norpregna-4,9-diene-3 ,20-dione; 17 ⁇ -acetoxy-21 -bromoro- 11 ⁇ -(4-N,N-dimethylaminophenyl)- 19-norpregna-4,9- diene-3,20-dione; 17-,21-diacetoxy-l l ⁇ -(4-N,N-dimethylaminophenyl) 19-norpregna- 4,9-diene-3,20-dione; 17 ⁇ -hydroxy-21-acetylthio-l l ⁇ -(4-N,N-dimethylaminophenyl)- 19-norpregna-4,9-diene-3 ,20-dione; 17 ⁇ -acetoxy-21 -acetylthio- 1 1 1
  • R 1 is — N(CHa) 2 , — NC 4 Hs, -NC 4 H 10 , -NC 4 H 8 O, -C(O)CH 3 , — O(CH 2 ) 2 N(CH 3 ) 2 , — O(CH 2 )2NC 4 H 8 , ⁇ O(CH 2 ) 2 NC 3 Hi 0 , and — O(CH 2 ) 2 NC 5 Hi 0 ; those in which R 2 is hydrogen, alkyloxy, alkoxy, -SAc, -SCN, — OC(O)CH 2 N(CH 3 ) 2 , and -OC(O)R 6 , wherein R 6 is a functional group including, but not limited to, alkyls (e.g., — CH 2 CH 3 ), alkoxy esters (e.g., — CH 2 OMe) and alkoxys (e.g., — OCH 3 ); those in which R 3
  • R 1 is — N(CH 3 ) 2 or — NCsH 10 ;
  • R 2 is hydrogen;
  • R 3 is methoxy;
  • R 4 is methyl;
  • R 1 is -NC 5 Hi 0 or -C(O)CH 3 ;
  • R 2 and R 3 are both acetoxy;
  • R 4 is methyl;
  • X 0.
  • R 1 is — C(O)CH 3 ;
  • R 2 is — SAc;
  • R 3 is acetoxy;
  • R 4 is methyl; and
  • X O.
  • R 1 is — N(CH 3 ) 2 ;
  • R 3 is acetoxy;
  • R 4 is methyl;
  • R 1 is -N(CH 3 ) 2 ;
  • R 2 is -OC(O)H;
  • R 3 is -OC(O)H;
  • R 4 is methyl; and
  • X 0.
  • Exemplar compounds also include, but are not limited to, 17 ⁇ -acetoxy-l 1 ⁇ -[4- (N,N-dimethylamino)phenyl]-21 -methoxy- 19-norpregna-4,9( 10)-diene-3,20-dione; 17 ⁇ -formyloxy- 1 1 ⁇ -[4-(N,N-diethylamino)phenyl]- 19-norpregna-4,9-diene-3 ,20- dione; 17 ⁇ -propionoxy-l l ⁇ -[4-(N,N-dimethylamino)phenyl]-19-norpregna-4,9-diene- 3,20-dione; 17 ⁇ -heptanoyloxy-l l ⁇ -[4-(N,N-dimethylamino)phenyl]-19-norpregna- 4,9-diene-3,20-dione; 17 ⁇ -methoxymethyl-l l ⁇ -[4-N-N-
  • any known antiprogestin can be used in the practice of this invention for its known antagonist effect on the progesterone receptor.
  • antiprogestins include, but are not limited to, onapristone (1 l ⁇ -(p-(dimethylamino)phenyl)-17 ⁇ -hydroxy-17-(3- hydroxypropyl)-13 ⁇ -estra-4,9-dien-3-one), mifepristone (1 l ⁇ -(4- dimethylaminophenyl)-17 ⁇ -hydroxy-17-(prop-l-ynyl)-estra-4,9-dien-3-one), lilopristone (l l ⁇ -(p-(dimethylamino)phenyl)-17 ⁇ -hydroxy-17-((Z)-3- hydroxypropenyl)estra-4,9-dien-3-one) and ZK 230 211.
  • antiprogestins include those disclosed in U.S. Patent Nos. 4,814,327, 4,829,060, 5,089,635, 6,339,098, 6,391,907 and 6,417,214, the contents of which are hereby incorporated by reference in their entirety.
  • an antiprogestin preferably a compound having general formula I
  • the absorption of an antiprogestin, preferably a compound having general formula I, into the bloodstream of a mammal may be significantly improved when the compound is administered to the mammal in the form of particles spray-deposited on a solid substrate or in the form of micronized particles.
  • the particles may be relatively small, thus providing a large surface area which leads to increased dissolution and bioavailability.
  • a composition comprising particles of an antiprogestin, preferably a compound of formula I, deposited on a carrier substrate,
  • the average diameter of a particle may be from about 50 nanometers (nm) to about 20,000 nm, although particles of any size having favorable dissolution and/or bioavailability profiles are within the scope of the invention.
  • the average particle diameter is from about 50 nm to about 1000 nm, more preferably from about 200 nm to about 900 nm, most preferably from about 300 nm to about 800 nm.
  • the average particle diameter may fall anywhere within the range of 50 nm and 20,000 nm, or may be less than 50 nm or greater than 20,000 nm.
  • at least 90% of the particles have a diameter less than 10,000 nm.
  • a composition comprising particles of an antiprogestin, preferably a compound having general formula I, deposited on a carrier substrate, is formed by spraying a solution of said compound in at least one solvent onto carrier substrate particles under conditions that allow for a substantial amouni of solvent to be removed from said solution, such that particles of said compound having the desired size, preferably an average particle diameter of less than about 20,000 ran, are deposited on the carrier substrate.
  • a surfactant may be present in the solution to be sprayed.
  • a surfactant is a surface active agent which displays wetting, detergent or soap-like qualities as those agents are understood by those of ordinary skill in the art.
  • surfactant represents ionic and nonionic surfactants or wetting agents commonly used in the formulation of pharmaceuticals, such as ethoxylated castor oil, benzalkonium chloride, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene fatty acid esters, polyoxyethylene derivatives, monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, sodium docusate, sodium lauryl sulfate, magnesium lauryl sulfate, triethanolamine, cetrimide, sucrose laurate and other sucrose esters, glucose (dextrose) esters, simethicone, ocoxynol, dioctyl sodium sulfosuccinate, sodium dodecylbenzene sulfonate, dialkyl sodium sulfosuccinate,
  • the surfactant if present, is a polyglycolyzed glyceride.
  • the carrier substrate is preferably a water-soluble compound or polymer.
  • Carrier substrates useful in the present invention include, but are not limited to, saccharides, such as sugars (for example, lactose or sucrose) and sugar alcohols (for example, mannitol, or sorbitol), starches, flour, cellulose preparations and/or salts such as carbonates, bicarbonates and phosphates, for example tricalcium phosphate or calcium hydrogen phosphate.
  • Sugars and sugar alcohols useful as carrier substrates include xylitol, mannitol, sorbitol, arabinose, ribose, xylose, glucose, mannose, galactose, sucrose, lactose and the like.
  • the sugar or sugar alcohol has a molecular weight less than 500 and is capable of easily dispersing and dissolving in water, thus improving the dissolution rate of the antiprogestin, preferably a compound of general formula I. More preferably, the sugar is lactose having particle size range from about 10 ⁇ m to about 3 mm.
  • Polymers suitable as carrier substrates include, without limitation, polymers and copolymers of polyvinyl acohol, polyvinyl pyrrolidinone, polysaccharide polymers, acrylate polymers, methyacrylate polymers, phthalate polymers, polyvinyl acetate, polyethylene oxide, polypropylene, polyester and polyamide films.
  • Cellulose preparations suitable as carrier substrates include, without limitation, methyl cellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and ethyl cellulose.
  • one part by weight of an antiprogestin preferably a compound having general formula I
  • a carrier substrate preferably a compound having general formula I
  • antiprogestins preferably compounds of general formula I
  • a non-aqueous solvent or mixed solvents including mixtures of non-aqueous solvents as well as mixtures of non-aqueous and aqueous solvents.
  • Useful non-aqueous solvents include, without limitation, alcohols, halogenated alkanes, dialkylketones and aromatic solvents.
  • Particularly useful solvents include ethanol, preferably 95% ethanol, isopropyl alcohol, methylene chloride, chloroform, acetone, methylethyl ketone and toluene.
  • Suitable solvents have the property of dissolving the antiprogestin, preferably a compound of general formula I, to a useful concentration, which should be at least about 0.5% (w/v), preferably at least about 2% (w/v), more preferably in the range of 5% to 10% (w/v) or greater than 10% (w/v).
  • an antiprogestin preferably a compound of general formula I
  • Spray deposition of antiprogestins, preferably compounds having general formula I may be performed by any method known in the art.
  • the design and operation of the sprayer can vary many characteristics of the final product, such as particle size and size distribution, bulk and particle densities, porosity, moisture content, flowability and friability.
  • the design and operation of the sprayer is such to ensure that the dried particles of the compound have an average particle size of less than or equal to about 20 microns.
  • spray deposition of antiprogestins preferably compounds having general formula I, may be performed by electrostatic jet spray deposition.
  • the solution comprising an antiprogestin, preferably a compound of general formula I, and optionally comprising a surfactant is metered into an apparatus which projects a fine spray of droplets which are concentrated on a particular area of the substrate through the use of a defined area electrostatic field.
  • an antiprogestin preferably a compound of general formula I
  • a surfactant is metered into an apparatus which projects a fine spray of droplets which are concentrated on a particular area of the substrate through the use of a defined area electrostatic field.
  • Also useful are commercially available fluid-bed apparatus equipped with an insert for top spray (droplets are sprayed from the top) or bottom spray using a Wurster-type column, or tangential spray using a rotor disk (droplets are sprayed from a side of the bottom).
  • carrier substrate particles are entrained in a high velocity gas and pass through the Wurster column where fine droplets of solution comprising an antiprogestin, preferably a compound of general formula I, and optionally a surfactant are sprayed from a jet nozzle.
  • the gas stream is heated to allow the evaporation of the solvent from the sprayed solution.
  • the result is to deposit a plurality of particles of an antiprogestin, preferably a compound of general formula I, (and optionally a surfactant) onto a carrier substrate.
  • Particularly useful is the Vector FL-M-I fluid bed system equipped with a 6 inch Wurster column.
  • the diameter of the droplets of solution that is sprayed and the speed at which the droplets collide with the carrier substrate during spraying and drying should be controlled so as to minimize aggregation of the sprayed particles as well as aggregation of the carrier substrate.
  • the amount of compound, solvent(s) and optional surfactant used for spraying are optionally chosen so that the resulting compound particles have the desired particle size which is preferably no more than 20 microns, more preferably less than or equal to 2 microns, most preferably less than or equal to 1 micron.
  • the solution to be sprayed may comprise a surfactant such as a polyglycolysed glyceride.
  • a surfactant such as a polyglycolysed glyceride.
  • the absorption of spray deposited particles of an antiprogestin, preferably a compound having general formula I, into the bloodstream of a mammal may be significantly improved when the compound is administered to the mammal as a formulation with a polyglycolysed glyceride.
  • a composition comprising a carrier substrate and a deposit on said carrier substrate, wherein said deposit comprises particles of an antiprogestin, preferably a compound of formula I, and a polyglycolysed glyceride.
  • the composition may further comprise a polyethylene glycol (PEG), such as a polyethylene glycol with molecular weight in a range from 200 to 35000 or such as PEG with molecular weight 400 (PEG400).
  • PEG polyethylene glycol
  • the composition may further comprise Peceol, a readily dispersible, solubilizing agent comprised primarily of a mixture of mono- and diglycerides of oleic acid that closely resembles the end products of intestinal lipid digestion (Hauss et al. 1998. J. Pharm. ScL 87: 164-169).
  • Polyglycolysed glycerides may be a mixture of mono-, di- and triglycerides and polyethylene glycol (PEG) mono- and diesters, which may be of molecular weight between 200 and 600, where appropriate of free glycerol and free PEG, whose HLB (Hydrophile-Lipophile Balance) value may be adjusted by the length of the PEG chain, and whose melting point is adjusted by the length of the chains of the fatty acids, of the PEG and by the degree of saturation of the fatty chains, and hence of the starting oil; examples of such mixtures are GELUCIRE.
  • Another suitable saturated polyglyocylsed glyceride is LABRASOL, a mixture of polyoxyethylene glyceryl caprylate and polyoxyethylene glyceryl caproate.
  • the present invention provides compositions comprising micronized particles of an antiprogestin, preferably a compound of general formula I, wherein the average particle diameter is less than 20 microns.
  • the average particle diameter is between 0.5 and 20 microns.
  • the average particle diameter may be 0.5, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 1 1, 1 1.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5 or may fall anywhere within the range of 0.5 and 20 microns. More preferably, at least 90% of the particles have a diameter less than 10 microns.
  • Micronization of compounds having general formula I may be performed by any method known in the art.
  • micronization of compounds having general formula I may be performed in a radiator mill (jet air micronizer). Pinned disc mills or hammer mills can also be used.
  • U.S. Patent Nos.: 2,032,827 and 4,018,388 disclose micronization techniques and machines and are hereby incorporated by reference in their entirety. The time of milling or grinding will be a function of the capacity and type of apparatus used.
  • micronization useful in the present invention include the aerosol solvent extraction system (ASES) described, for example, in Steckel, et al, "Micronizing Steroids for Pulmonary Delivery by Supercritical Carbon Dioxide,” Int. J. of Pharmaceutics, (1997), Vol. 152, No. 1, pp. 99-1 10 (incorporated herein by reference), which describes the preparation of a number of steroids in a spraying solution containing 1% (w/w) of the drug in an organic solvent such as dichloromethane, methanol or a mixture of both.
  • the spraying solution was sprayed into supercritical dioxide and median particle size was determined to be in most cases under 5 microns.
  • the addition of a surface active agent added to the spraying solution resulted in larger sized particles.
  • Such micronized particles may be administered by any available route of administration.
  • micronized drugs of the present invention are described in the U.S. Patent Nos.: 7,148,212; 7,029,700; 5,952,008; 5,855,913; 5,851 ,453; 5,874,064; 5,874,029; 5,833,891 ; 5,043,280; and 4,384,975, all of which are incorporated herein by reference in their entirety.
  • Particle size analysis may be carried out using any technique known in the art. For example, a Coulter Counter, Model TA 2, which is an automatic apparatus for analyzing particle size distribution of powders, may be used.
  • Micronization may be performed in the presence of a surfactant such as a polyglycolysed glyceride.
  • a surfactant such as a polyglycolysed glyceride.
  • the absorption of micronized particles of a compound having general formula I into the bloodstream of a mammal may be significantly improved when the compound is administered to the mammal as a formulation with a surfactant.
  • the present invention provides a composition comprising micronized particles of a compound of general formula I, a polyglycolysed glyceride and optionally a pharmaceutically acceptable carrier.
  • compositions may further comprise a polyethylene glycol (PEG), such as a PEG with molecular weight in a range from 200 to 35000 or such as a PEG with molecular weight 400 (PEG400).
  • PEG polyethylene glycol
  • the composition may further comprise ethanol or Peceol.
  • Micronization in the presence of an oily excipient such as a polyglycolysed glyceride may be carried out more easily than in the dry or aqueous phase in that overheating of the compound is avoided, as is the need for cooling and lubricating during the micronization process.
  • compositions may possess potent antiprogestational activity and minimal antiglucocorticoid activity, combined with improved absorption, which may render these compositions suitable for oral administration.
  • compositions can be advantageously used, inter alia, to antagonize endogenous progesterone; to induce menses; to treat endometriosis; to treat dysmenorrhea; to treat endocrine hormone-dependent tumors; to treat meningioma; to treat uterine leiomyonas, to treat uterine fibroids; to inhibit uterine endometrial proliferation; to induce labor; to induce cervical ripening, for hormone therapy; and for contraception.
  • compositions having antiprogestational activity may also be characterized by antagonizing the effects of progesterone.
  • the compositions may be of particular value in the control of hormonal irregularities in the menstrual cycle, for controlling endometriosis and dysmenorrhea, and for inducing menses.
  • the compositions can be used as a method of providing hormone therapy either alone or in combination with estrogenic substances in postmenopausal women, or in women whose ovarian hormone production is otherwise compromised.
  • the compositions can be used for control of fertility during the whole of the reproductive cycle.
  • the compositions can be administered either continuously or periodically depending on the dose.
  • the compositions may be of particular value as post-coital contraceptives, for rendering the uterus inimical to implantation, and as "once a month" contraceptive agents.
  • compositions can be administered to any warm-blooded mammal such as humans, domestic pets, and farm animals. Domestic pets include dogs, cats, etc. Farm animals include cows, horses, pigs, sheep goats, etc.
  • the amount of active ingredient that can be combined with an optimal carrier material to produce a single dosage form will vary depending upon the disease treated, the mammalian species, and the particular mode of administration.
  • a unit dose may comprise between 0.1 milligram and 1 gram of the active ingredient or between 0.001 and 0.5 grams.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy.
  • compositions can be administered by a variety of methods.
  • the compositions can be administered via the oral route in a form of solutions, suspensions, emulsions, tablets, including sublingual and intrabuccal tablets, soft gelatin capsules, including solutions used in soft gelatin capsules, aqueous or oil suspensions, emulsions, pills, lozenges, troches, tablets, syrups or elixirs and the like.
  • the compositions can be also administered as an implant including SILASTIC and biodegradable implants or via intramuscular and intravenous injections.
  • the compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents.
  • Tablets containing the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients are acceptable.
  • excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid and talc.
  • Tablets can be uncoated or, alternatively, they can be coated by known methods to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the particles of the active ingredient deposited on a carrier substrate are mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein particles of the active ingredient deposited on a carrier substrate are mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions may contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (erg., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial phosphat
  • the aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin.
  • Oil suspensions can be formulated by suspending particles of the active ingredient deposited on a carrier substrate in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water can be formulated from the active ingredients in admixture with a dispersing, suspending and/or wetting agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.
  • the pharmaceutical composition can also be in the form of oil-in- water emulsions.
  • the oily phase can be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion can also contain sweetening and flavoring agents.
  • Syrups and elixirs can be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations can also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • the pharmaceutical composition can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension can be formulated using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.
  • the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride.
  • sterile fixed oils can be employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can likewise be used in the preparation of injectables.
  • the compound can also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • They can also be administered by in intranasal, intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations.
  • Compounds administered by the topical route can be administered as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • the invention will be described in greater detail by way of the following specific, but not limiting, examples.
  • Example 1 Preparing a Composition Comprising Particles of a Compound of General Formula I in Admixture with Lactose
  • a biologically effective amount of a compound of general formula I e.g. CDB-4124 or CDB-2914
  • a suitable solvent e.g., ethanol
  • the solution is sprayed onto 1 kg of lactose in, e.g., a Vector FL-
  • inlet pressure and inlet temperature are adjusted such that particles of the compound of general formula I have the desired average particle diameter, preferably less than 20 microns, as measured by e.g, laser diffraction technique using photo correlation
  • Example 2 Preparing a Composition Comprising Particles of a Compound of General Formula I in Admixture with Lactose and GELUCIRE 44/14,
  • a biologically effective amount of a compound of general formula I e.g.,
  • CDB-4124 or CDB-2914 is dissolved in a suitable solvent, e.g., ethanol, with slight
  • particles of the compound of general formula I have the desired average particle diameter, preferably less than 20 microns, as measured by e.g, laser diffraction technique using photo correlation spectroscopy.
  • Example 3 Preparing a composition comprising micronized particles of a compound of general Formula I
  • a jet air pulverizer such as a Spiral-Mill (fluid energy mill) manufactured by
  • Milling occurs due to a strong continuous acceleration and decelaration of the feed stock by expanding nitrogen gas within the cylindrical milling chamber. Collisions occur constantly between the particles, resulting in comminution. A cyclone separator is used to internally classify the material.
  • the fineness of the micronized material is controlled by adjusting the feed rate, milling gas pressure, and the angle of the gas jets.
  • the air speed in the mill is about 300-500 meters per
  • Micronized compound consisting of particles preferably have an average particle diameter of less than 20 microns are optionally combined with pharmaceutically acceptable excipients.
  • Example 4 Preparing a composition comprising GELUCIRE 44/14, PEG400 and micronized particles of a compound of general Formula I in a capsule form
  • PEG400 is heated to 50 0 C, GELUCIRE 44/14 is then added in the 2.87:1 ratio of GELUCIRE 44/14 to PEG400. The mixture is then heated with good mixing until GELUCIRE 44/14 is melted to completion. Micronized particles of a compound of general Formula I are then added to the concentration of 3.42%. The solution is then held at 50 0 C for 30 minutes. Empty pre-weighted capsules were then filled with the solution at the target weight of net fill of 365 mg per capsule. Example 5.
  • Antiprogestins may be prepared by using the aerosol solvent extraction system (ASES) described, for example, in Steckel, et al., "Micronizing Steroids for Pulmonary Delivery By Supercritical Carbon Dioxide,” Int. J. of Pharmaceutics, (1997), Vol. 152, No. 1, pp. 99-1 10, (incorporated herein by reference).
  • the compounds of the present invention are prepared in a spraying solution containing 1 % (w/w) of the drug in an organic solvent such as dichloromethane, methanol or a mixture of both. Other suitable organic solvents are also well known in the art.
  • the spraying solution is then sprayed into supercritical carbon dioxide and median particle size is determined. In most cases particle size is expected to be around 5 microns.
  • the addition of a surface active agent added to the spraying solution will result in larger sized particle.

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Abstract

L'invention concerne des compositions comprenant une antiprogestine et ayant une biodisponibilité améliorée. Dans un aspect, l'invention concerne des compositions comprenant des particules d'une antiprogestine déposée sur un substrat vecteur. Dans un autre aspect, l'invention propose des compositions comprenant une antiprogestine micronisée. L'invention concerne également l'utilisation de compositions comprenant une antiprogestine et ayant une biodisponibilité améliorée pour le traitement de l'endométriose, des fibromyomes utérins, des dysménorrhées, et des méningiomes.
EP07869940A 2006-12-28 2007-12-27 Procédés et formulations pour une biodisponibilité améliorée des antiprogestines Withdrawn EP2094275A2 (fr)

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US88242306P 2006-12-28 2006-12-28
US88537207P 2007-01-17 2007-01-17
PCT/US2007/088891 WO2008083192A2 (fr) 2006-12-28 2007-12-27 Procédés et formulations pour une biodisponibilité améliorée des antiprogestines

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US8299050B2 (en) * 2008-01-29 2012-10-30 Laboratoire Hra-Pharma Method for treating uterine fibroids
US8512745B2 (en) * 2008-12-08 2013-08-20 Laboratoire Hra Pharma Ulipristal acetate tablets
RS55331B1 (sr) 2009-04-14 2017-03-31 Hra Pharma Lab Postupak za kontracepciju po potrebi
EP2471537A1 (fr) * 2010-12-30 2012-07-04 PregLem S.A. Traitement de la douleur associé à la dislocation de l'endomètre de base
EP2545922A1 (fr) 2011-07-12 2013-01-16 PregLem S.A. Traitement des saignements menstruels excessifs associés aux fibromes utérins
EP2775831A4 (fr) * 2011-10-21 2015-08-12 Seachaid Pharmaceuticals Inc Compositions pharmaceutiques et leurs utilisations
FR2997628B1 (fr) * 2012-11-08 2015-01-16 Hra Pharma Lab Produit de co-micronisation comprenant un modulateur selectif des recepteurs a la progesterone
FR2997627B1 (fr) * 2012-11-08 2015-01-16 Hra Pharma Lab Produit de co-micronisation comprenant de l'ulipristal acetate
FR2999081B1 (fr) * 2012-12-06 2015-02-27 Hra Pharma Lab Dispersion solide d'un modulateur selectif du recepteur a la progesterone
HK1221169A1 (zh) 2013-04-10 2017-05-26 Preglem S.A. 孕酮受体调节剂在子宫肌瘤疗法中的用途
WO2018106914A1 (fr) * 2016-12-09 2018-06-14 Repros Therapeutics Inc. Compositions pharmaceutiques orales comprenant un récepteur de progestérone sélectif non micronisé en tant qu'agent actif
WO2017216637A2 (fr) 2017-08-04 2017-12-21 Alvogen Malta Operations (Row) Ltd Forme de comprimé comprenant de l'acétate d'ulipristal et ses procédés de préparation
US11878025B2 (en) 2021-09-06 2024-01-23 Slayback Pharma Llc Pharmaceutical compositions of mifepristone

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WO1997041145A1 (fr) * 1996-05-01 1997-11-06 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Derives de progesterone substitues 21 pouvant etre utilises comme nouveaux agents antiprogestatifs
US6248363B1 (en) * 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
FR2821555B1 (fr) * 2001-03-01 2003-05-16 Besins Int Lab Progestatif co-micronise avec un tensioactif, composition pharmaceutique le comprenant, leurs procedes de fabrication et leurs utilisations
US20050220825A1 (en) * 2004-03-10 2005-10-06 Adrian Funke Molecular dispersions of drospirenone
WO2007038796A1 (fr) * 2005-09-29 2007-04-05 Repros Therapeutics Inc. Formulations a biodisponibilite amelioree, contenant un derive steroidien et une glyceride polyglycolysee

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WO2008083192A3 (fr) 2008-11-27
EA200970646A1 (ru) 2009-12-30
WO2008083192A2 (fr) 2008-07-10
JP2010514793A (ja) 2010-05-06
WO2008083192A8 (fr) 2009-07-09
ECSP099536A (es) 2009-08-28
MX2009006912A (es) 2009-08-12
CA2672888A1 (fr) 2008-07-10
AU2007339820A1 (en) 2008-07-10
TW200831110A (en) 2008-08-01
CO6190605A2 (es) 2010-08-19
AR064697A1 (es) 2009-04-22
CL2007003855A1 (es) 2008-03-14
KR20090086470A (ko) 2009-08-12

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