WO2014009434A1 - Système d'administration de médicament auto-microémulsifiant à base d'abiratérone ou d'acétate d'abiratérone - Google Patents

Système d'administration de médicament auto-microémulsifiant à base d'abiratérone ou d'acétate d'abiratérone Download PDF

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Publication number
WO2014009434A1
WO2014009434A1 PCT/EP2013/064618 EP2013064618W WO2014009434A1 WO 2014009434 A1 WO2014009434 A1 WO 2014009434A1 EP 2013064618 W EP2013064618 W EP 2013064618W WO 2014009434 A1 WO2014009434 A1 WO 2014009434A1
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Prior art keywords
drug delivery
self
delivery system
fatty acid
microemulsifying drug
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PCT/EP2013/064618
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English (en)
Inventor
Igor Legen
Luka Peternel
Mateja Novak Stagoj
Miha Homar
Tanja Rozman Peterka
Uros Klancar
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Sandoz Ag
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Publication of WO2014009434A1 publication Critical patent/WO2014009434A1/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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present invention relates to a self-microemulsifying drug delivery system comprising a compound of formula (I), preferably abiraterone or abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof, at least one fatty acid ester and at least one surfactant.
  • the invention further relates to a method of preparing the same and to a pharmaceutical composition comprising the self- microemulsifying drug delivery system.
  • Abiraterone is a selective inhibitor of 17 a-hydroxylase/C17,20 lyase (CYP17A1 ), an enzyme which is known to be essential for the biosynthesis of androgens and oestrogens.
  • CYP17 is expressed in testicular, adrenal, and prostatic tumor tissues.
  • Said enzyme complex catalyzes the conversion of pregnenolone and progesterone to their 1 7-a- hydroxy derivatives by its 17 a- hydroxylase activity, and the subsequent formation of the androgens dehydroepiandrosterone (DHEA) and androstenedione, by its C17,20 lyase activity.
  • DHEA dehydroepiandrosterone
  • the androgens DHEA and androstenedione are precursors of testosterone.
  • inhibition of CYP17 activity by abiraterone decreases circulating levels of testosterone and other androgens in cancer patients.
  • Abiraterone is poorly bioavailable such that the prodrug abiraterone acetate which is rapidly deacetylated to abiraterone in vivo is used.
  • Abiraterone acetate (INN, CB7630; JNJ-212082; Zytiga ® ) is a pregnenolone analog used in castration-resistant prostate cancer (CRPC).
  • Abiraterone acetate i.e 17- (pyridin-3-yl)androsta-5,16-dien-33-yl acetate) is absorbed through the gut when administered orally and then deacetylated in the liver to the active drug abiraterone.
  • Abiraterone acetate was first approved by the FDA in April 201 1 for the treatment of patients with metastatic CRPC, who have received prior chemotherapy containing docetaxel.
  • Abiraterone acetate was launched in USA and Europe by
  • Abiraterone acetate is a white to off-white, non-hygroscopic, crystalline powder. Its molecular formula is C26H33NO2 and it has a molecular weight of 391 .55 g/mol.
  • Abiraterone acetate (Zytiga ® ) is being marketed as an immediate-release tablet containing 250 mg of abiraterone acetate. Zytiga ® is administered at a daily dose of 1000 mg abiraterone acetate once daily in combination with 5 mg prednisone twice daily.
  • BCS Biopharmaceutics Classification System
  • drugs are classified on the basis of the parameters solubility, permeability and dissolution.
  • BCS class IV compounds exhibit low permeability and low solubility. Those compounds have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected.
  • Abiraterone acetate has an aqueous solubility of ⁇ 0.01 mg/mL. According to the definition of the United States Pharmacopeia (USP) drugs exhibiting an aqueous solubility ⁇ 100 ⁇ g/mL (0.1 mg/mL) are classified as insoluble or practically insoluble.
  • USP United States Pharmacopeia
  • the low solubility of abiraterone acetate in water is one of the factors leading to a low bioavailability of abiraterone acetate for Zytiga ® .
  • steady-state values (mean ⁇ SD) of Cmax were 226 ⁇ 178 ng/mL and of AUC were 1 1 73 ⁇ 690 ng.hr/ml_.
  • the absolute bioavailability of abiraterone acetate for Zytiga ® is reported to be no more than 10%, as the drug is mainly metabolized to abiraterone and then excreted by feces (-88%) and urine (-5%) with a terminal half life of 12 ⁇ 5 hours.
  • Zytiga ® prescribing information This means in consequence that, from the 4 Zytiga ® tablets of 250 mg each, adding up to 1 g, which the patient has to take each day at once, only 10% of the drug can develop a therapeutic effect.
  • abiraterone acetate as currently used in Zytiga ® is known to exhibit a very strong food effect, when administered orally (Zytiga ® prescribing information).
  • administration with food increases absorption of the drug and thus potentially results in increased and highly variable exposures.
  • the drug uptake may vary up to 5- to 10-fold between fasted and fed state, depending on the fat content of the meal.
  • Zytiga ® is labeled to be taken fasting, i.e. patients must take abiraterone acetate on empty stomach only. No food should have been consumed for 2 h prior to dosing and for 1 h afterwards.
  • this object is achieved by a self-microemulsifying drug delivery system comprising abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof, a fatty acid ester or a mixture of fatty acid esters and at least one surfactant.
  • Said self-microemulsifying drug delivery system is not only suitable for abiraterone acetate but also generally for the compound abiraterone and its derivatives.
  • the present invention relates to a self-microemulsifying drug delivery system comprising:
  • FT represents H, unsubstituted or substituted CrC 6 alkyl or unsubstituted or substituted C C 6 acyl
  • R represents H or unsubstituted or substituted CrC 6 alkyl
  • a fatty acid ester or a mixture of fatty acid esters (c) at least one surfactant.
  • SMEDDS self-emulsifying drug delivery system
  • SEDDS self-emulsifying drug delivery system
  • SMES self-microemulsifying system
  • lipids and surfactants optionally with one or more solubilizers.
  • SMES self-microemulsifying system
  • These systems can form oil-in-water microemulsions instantaneously upon dilution with aqueous media, e.g. water or gastrointestinal fluids, if taken orally. The dissolved drug does not precipitate upon dilution.
  • Self- microemulsifying drug delivery systems typically produce microemulsions with a droplet size of less than 1000 nm.
  • SEDDS self- emulsifying drug delivery systems
  • SEDDS self- emulsifying drug delivery systems
  • the self-emulsifying drug delivery systems contain no aqueous components, a high concentration of the hydrophobic drug may be incorporated into the vehicle.
  • the following factors, influencing the self- emulsification properties have to be considered: the physicochemical nature and concentration of the lipophilic phase, surfactant and co-emulsifier or co-surfactant or solubilizer, if included; the ratio of the components, particularly the oil-to-surfactant ratio; the temperature, ionic strength and pH of the aqueous phase where emulsification would occur; and physicochemical properties of the drug to be included in the SEDDS such as hydrophilicity/lipophilicity, pKa and polarity.
  • WO 2008/073731 discloses a microemulsion dosage form of valsartan.
  • WO 2007/067593 relates to self-emulsifying and self-microemulsifying formulations of CETP inhibitors.
  • SMEDDS self-microemulsifying drug delivery system
  • SMES self-microemulsifying system
  • SEDDS self-emulsifying drug delivery system
  • drug delivery system drug delivery system
  • a Treating "AM”) is generally recognized as a micellar system of lipid, surfactant and water. It is formed spontaneously upon addition of water to lipid/surfactant or lipid/surfactant/cosurfactant mixtures.
  • a microemulsion is a homogeneous system showing no phase separation when stored at room conditions (25 °C, 65% relative humidity (RH)) for one week.
  • Microemulsions generally exhibit a droplet size of ⁇ 1000 nm, preferably ⁇ 500 nm, more preferably ⁇ 250 nm, more preferably ⁇ 200 nm, even more preferably ⁇ 150 nm, measured by photon correlation spectroscopy (PCS) at 25 °C.
  • PCS photon correlation spectroscopy
  • the self-microemulsifying drug delivery system of the present invention results in an increased solubility and dissolution rate of the compound of formula (I), preferably of abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof compared to conventional compositions. Further, the self-microemulsifying drug delivery system also advantageously exhibits a reduced food effect and an increased stability of the drug.
  • formulation of the compound of formula (I), preferably of abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof in the form of the self-microemulsifying drug delivery system of the invention surprisingly results in an increased dissolution rate of the compound of formula (I), preferably of abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof independent of the tested dissolution media, compared to conventional compositions such as the commercially available product Zytiga ® .
  • the increased dissolution rate of the compound of formula (I), preferably of abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof results in an increased bioavailability and improved pharmacokinetic profile of the drug. This results in a reduction of the required daily dose of the compound of formula (I), preferably of abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • a 2-fold, preferably a 3-fold, more preferably a 4-fold, more preferably a 5-fold, even more preferably a 6-fold reduction of the required daily dose of the compound of formula (I), preferably of abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof can be achieved by the self-microemulsifying drug delivery system of the invention or a pharmaceutical composition comprising the self-microemulsifying drug delivery system of the invention.
  • the invention therefore also relates to the use of from 166 mg to 500 mg, in particular, from 166 mg to 250 mg, preferably from 166 mg to 200 mg abiraterone acetate per day for the treatment of cancer, preferably metastatic prostate cancer.
  • the self-microemulsifying drug delivery system results in a 6-fold reduction of the required daily dose of the compound of formula (I), preferably of abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • the compound of formula (I) preferably of abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • a microemulsion maximizes the absorption of the compound of formula (I), preferably of abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof, such that the food effect is significantly reduced.
  • the compound of formula (I), preferably abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof is dissolved in the carrier, and then after oral administration, finely dispersed within the fluids of the gastrointestinal tract before it is adequately absorbed.
  • the self-microemulsifying drug delivery system of the invention also abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • inventive self-microemulsifying drug delivery system comprising the compound of formula (I), preferably of abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition comprising the self-microemulsifying drug delivery system can thus be taken with or without food, i.e. without having regard to the meals.
  • the present invention also relates to the use of abiraterone acetate or a pharmaceutical salt, hydrate or solvate thereof for the treatment of cancer, preferably metastatic prostate cancer, wherein abiraterone acetate can be taken without regards to a prior fasting regimen.
  • Benefits of a dosage form which substantially eliminates the effect of food include an increase in patient convenience, thereby increasing patient compliance, as the patient does not need to ensure that they are taking a dose either with or without food. This is significant, as with poor patient compliance an increase in the medical condition for which the drug is being prescribed may be observed.
  • the stable self-microemulsifying drug delivery system of the invention at least 90 wt% of the compound of formula (I), preferably of abiraterone acetate or a
  • pharmaceutically acceptable salt, hydrate or solvate thereof based on the total weight of the compound of formula (I), preferably of abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof is not degraded, preferably at least 95 wt%, more preferably at least 97 wt%, more preferably at least 98 wt%, even more preferably at least 99 wt%, most preferably at least 99.5 wt% of the compound of formula (I), preferably of abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof, based on the total weight of the compound of formula (I), preferably of abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof is not degraded.
  • the product is stable when it meets the above requirements after storage at long- term storage conditions of 25 ⁇ 2°C and 60 ⁇ 5% relative humidity or more preferably at storage conditions of 30 ⁇ 2°C and up to 75 ⁇ 5% relative humidity after 2 years, more preferably after 3 years, even more preferably after 4 years, most preferably after at least 5 years of storage at storage conditions of 25 ⁇ 2°C and 60 ⁇ 5% relative humidity, more preferably at 30 ⁇ 2°C and up to 75 ⁇ 5% relative humidity.
  • the product is stable when it meets the above requirements after 6 months of storage at accelerated stability conditions of 40 ⁇ 2°C and 75 ⁇ 5% relative humidity (in that case label of storage conditions is not required for some of the markets, i.e. EU).
  • the self-microemulsifying drug delivery system of the invention has excellent water mixing properties.
  • the self-microemulsifying drug delivery system according to the invention is liquid and forms a microemulsion when contacted with an aqueous medium such as a gastrointestinal fluid, e.g. gastric juice.
  • an aqueous medium such as a gastrointestinal fluid, e.g. gastric juice.
  • the self-microemulsifying drug delivery system itself does not comprise any aqueous compound such as water.
  • the mean droplet size is a crucial factor in self-emulsification because it determines the rate and extent of drug release, as well as the stability of the emulsion.
  • the self-microemulsifying drug delivery system preferably forms a microemulsion when contacted with water in an amount of 95% water and 5% SMES at 25 °C comprising droplets having a mean particle size of less than 1000 nm, preferably less than 500 nm, less than 250 nm, less than 200 nm, more preferably less than 150 nm when mixed/shaked by means of magnetic stirrer or hand for one minute, measured by a suitable PCS method at 25 °C.
  • mean particle size refers to the volume average diameter of the droplets formed upon microemulsification of the inventive self-microemulsifying drug delivery system.
  • the particle size is measured using photon correlation spectroscopy (PCS) with a Malvern Zetasizer machine (manufactured by Malvern, UK) at 25°C.
  • a crucial factor for the formulation of a drug in a self-microemulsifying drug delivery system is the drug load/content of the drug in the system. Often only in a very limited concentration of less than 5% of the drug is soluble in the system, such that a relatively high amount of excipients is needed.
  • the dosage form When formulated as a solid oral dosage form (e.g. as a tablet or capsule), the dosage form cannot exceed about 1000 mg, as otherwise the size of the dosage form would become too big to be swallowed by a patient. The smaller the dosage form, the better patient compliance. It is therefore important to achieve a high drug load of the drug in the self- microemulsifying drug delivery system.
  • the self-microemulsifying drug delivery system comprises at least 5%, preferably at least 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5% more preferably at least 10% by weight of the compound of formula (I), based on the weight of the drug delivery system.
  • the self-microemulsifying drug delivery system comprises up to 10%, preferably up to 1 5%, preferably up to 20%, more preferably up to 25%, even more preferably up to 30% by weight of the compound of formula (I), based on the weight of the drug delivery system.
  • the self-microemulsifying drug delivery system comprises 5-30%, 5.5-30%, 6-25%, 6.5-25%, 7-20%, 7.5-20%, 8-20%, 8.5- 15%, 9-15%, 9.5-15% by weight of the compound of formula (I), based on the weight of the drug delivery system.
  • the present invention therefore also relates to a high drug load formulation comprising abiraterone acetate or any pharmaceutically acceptable salt, hydrate or solvate thereof.
  • component (a), i.e. the compound of formula (I), is dissolved in components (b) and (c).
  • the self-microemulsifying drug delivery system of the invention preferably comprises 50-100 mg of the compound of formula (I) per 1 g of the self-microemulsifying drug delivery system.
  • the compound of formula I is selected from the group consisting of abiraterone, abiraterone acetate and any
  • abiraterone acetate is present as the compound of formula (I) in the self-microemulsifying drug delivery system of the invention and it is further preferred that the abiraterone acetate is in the form of the free base or the mesylate salt.
  • the self-microemulsifying drug delivery system of the invention further comprises a fatty acid ester or a mixture of fatty acid esters, i.e. a lipophilic component or a mixture of lipophilic components.
  • a fatty acid ester or a mixture of fatty acid esters, i.e. a lipophilic component or a mixture of lipophilic components.
  • fatty acid ester equally relates to fatty acid monoesters and fatty acid polyesters such as fatty acid diesters or fatty acid triesters.
  • a "mixture of fatty acid esters” means a mixture of at least two different fatty acid esters.
  • fatty acid relates to a carboxylic acid with an aliphatic moiety, which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28.
  • fatty acids are:
  • the lipophilic phase has great importance in the formulation of the self- microemulsifying drug delivery system.
  • a lipophilic component which has maximum solubilizing potential for the selected drug candidate is selected for the formulation of the self-microemulsifying drug delivery system so as to achieve the maximal drug loading in the self-microemulsifying drug delivery system.
  • a mixture of lipophilic components can also be used in order to obtain optimum properties of the lipophilic phase.
  • the amount of the fatty acid ester present in the self-microemulsifying drug delivery system of the invention is from 30 to 80%, preferably from 40 to 70% by weight, based on the weight of components (b) and (c).
  • the fatty acid ester or mixture of fatty acid esters comprises at least one medium or long chain fatty acid.
  • the term "medium or long chain fatty acid” refers to a fatty acid comprising from 6 to 22 carbon atoms.
  • a “medium chain fatty acid” should be understood as a fatty acid comprising from 6 to 12 carbon atoms
  • a “long chain fatty acid” should be understood as a fatty acid comprising from 14 to 22 carbon atoms.
  • the "medium chain fatty acid” and/or the “long chain fatty acid” is linear fatty acid, either saturated or unsaturated.
  • the fatty acid ester is a fatty acid glycerol ester.
  • the fatty acid glycerol ester may thus be a mono-, di- or triglyceride.
  • the mixture of fatty acid esters is a mixture of fatty acid glycerol esters.
  • the fatty acid glycerol esters may thus be a mono-, di- or triglyceride.
  • Fatty acid glycerol esters which are suitable according to the invention are selected from the group consisting of natural oils (e.g. castor oil, linseed oil, corn oil, olive oil, sunflower oil), medium chain triglycerides (e.g. Miglyol 812 ® , Captex 355 ® , Labrafac lipophile WL 1349 ® ), medium chain mono- and diglycerides (e.g. Capmul MCM ® ), long chain monoglycerides (e.g. glyceryl monooleate (Peceol @) , glyceryl
  • natural oils e.g. castor oil, linseed oil, corn oil, olive oil, sunflower oil
  • medium chain triglycerides e.g. Miglyol 812 ® , Captex 355 ® , Labrafac lipophile WL 1349 ®
  • medium chain mono- and diglycerides e.g. Capmul MCM
  • propylene glycol diester of caprylic and caprinic acid propylene glycol dipelagonate, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol dicaprylocaprate), long chain mono- and diesters with propylene glycol (e.g.
  • propylene glycol monopalmitostearate fatty acid esters with isopropyl alcohol (e.g. isopropyl myristate, isopropyl palmitate, isopropyl isostearate, isopropyl linolate, isopropyl monooleate) and other fatty acid esters (e.g. ethyl oleate, diisooctyl ester of adipic acid) and any mixtures thereof.
  • isopropyl alcohol e.g. isopropyl myristate, isopropyl palmitate, isopropyl isostearate, isopropyl linolate, isopropyl monooleate
  • other fatty acid esters e.g. ethyl oleate, diisooctyl ester of adipic acid
  • a mixture of mono-, di- and triglycerides is preferred. In a further embodiment a mixture of mono- and triglycerides is preferred.
  • the mixture of fatty acid glycerol esters is a mixture of at least one long chain (Ci 4 -C 2 2) triglyceride and at least one medium chain (C 6 -Ci 2 ) mono- or diglyceride.
  • the mixture of fatty acid glycerol esters is a mixture of at least one long chain (Ci 4 -C 2 2) triglyceride, at least one medium chain (C 6 -Ci 2 ) monoglyceride and at least one medium chain (C 6 -Ci 2 ) diglyceride.
  • the mixture of fatty acid glycerol esters is a mixture of at least one long chain (Ci 4 -C 22 ) triglyceride and at least one long chain (Ci 4 -C 22 ) mono- or diglyceride.
  • the mixture of fatty acid glycerol esters is a mixture of at least one long chain (Ci 4 -C 22 ) triglyceride, at least one long chain (Ci 4 -C 22 ) monoglyceride and at least one long chain (Ci 4 -C 22 ) diglyceride.
  • the most preferred fatty acid esters according to the invention are castor oil, Capmul MCM ® and Peceol ® , alone or in combination with another fatty acid ester.
  • a mixture of fatty acid esters is used.
  • Preferred mixtures of fatty acid esters are castor oil/Capmul MCM ® , castor oil/Peceol ® and Captex 355 ® /Capmul MCM ®
  • the fatty acid esters are preferably present in a weight ratio of 1 :10 to 1 0:1 , preferably 1 :5 to 5:1 , more preferably 1 :2 to 2:1 , even more preferably 1 :1
  • the fatty acid esters are preferably present in a weight ratio of 1 :10 to 10:1 , preferably 1 :5 to 5:1 , more preferably 1 :35 to 3:1 even more preferably 1 :2.
  • the self-microemulsifying drug delivery system of the invention further comprises at least one surfactant.
  • surfactant is critical for the formulation of the self-microemulsifying drug delivery system. In certain cases also a mixture of surfactants can be used in the self-microemulsifying drug delivery system.
  • the amount of the surfactant present in the self-microemulsifying drug delivery system of the invention is from 20 to 70%, preferably from 30 to 60% by weight, based on the weight of components (b) and (c).
  • Suitable surfactants for use according to the invention are non-ionic surfactants and selected from the group consisting of polyoxyethylene products of hydrogenated vegetable oils, polyoxyethylene-sorbitan-fatty acid esters, polyoxyethylene castor oil derivatives, sorbitan esters (e.g. Tween ® , Span ® ), castor oil derivatives (e.g.
  • Cremophor EL ® Cremophor RH40 ® , Cremophor RH60 ®
  • macrogol 15 Cremophor EL ® , Cremophor RH40 ® , Cremophor RH60 ®
  • sucrose esters e.g. sucrose palmitate
  • poloxamers polyglycolyzed glycerides (e.g. caprylocaproly macrogol glyceride (Labrasol ® ), linoleaoyl macrogol glycerides (Labrafil ® ), polyglyceryl oleate (Plurol oleique ® ), Gelucires ® or a combination thereof.
  • polyglycolyzed glycerides e.g. caprylocaproly macrogol glyceride (Labrasol ® ), linoleaoyl macrogol glycerides (Labrafil ® ), polyglyceryl oleate (Plurol oleique ® ), Gelucires ® or a combination thereof.
  • the at least one surfactant has a hydrophilic-lipophilic balance (HLB) of 4 to 18, preferably 10 to 18, more preferably 1 2 to 16.
  • HLB hydrophilic-lipophilic balance
  • the self-microemulsifying drug delivery system comprises at least one further surfactant with a HLB value of 4 to 18, preferably 10 to 1 8, more preferably 12 to 16 and additionally at least one surfactant with a HLB value of 4 to 8.
  • the self- microemulsifying drug delivery system additionally comprises at least one further surfactant with a HLB value of 4 to 18, preferably 10 to 18, more preferably 12 to 16 and additionally at least one surfactant with a HLB value of 12 to 1 8.
  • hydrophilic-lipophilic balance of a surfactant is a measure of the degree to which it is hydrophilic or lipophilic, determined by calculating values for the different regions of the molecule, as described by Griffin in 1954.
  • HLB values range from 0 to 20, with an HLB value of 0 corresponding to a completely lipophilic molecule, and a value of 20 corresponding to a completely hydrophilic molecule.
  • HLB values for a broad range of surfactants have been disclosed e.g. by Sigma-Aldrich Materials Science.
  • HLB values of surfactants are presented in Table 1 .
  • Preferred surfactants according to the invention are Cremophor EL , Cremophor RH40 ® , Solutol HS ® , Span 80 ® , Tween 20 ® and Tween 80 ® Cremophor EL ® , Cremophor RH40 and Span 80 are the most preferred surfactants according to the invention.
  • Cremophor EL ® is a particularly preferred surfactant, alone or in combination with Span 80 ® , Tween 80 ® or Cremophor RH40 ® .
  • Cremophor EL ® is used in combination with another surfactant and both surfactants are preferably present in a weight ratio of 1 :10 to 10:1 , preferably 1 :5 to 5:1 , more preferably 1 :2 to 2:1 , even more preferably 1 :1 .
  • solubilizers may be incorporated in self-microemulsifying drug delivery systems in order to increase the drug loading to the self-microemulsifying drug delivery systems, to modulate self-microemulsification time of the self- microemulsifying drug delivery systems or to modulate droplet size of the
  • microemulsion refers to any substance that increases the solubility of abiraterone acetate in the self-microemulsifying drug delivery system.
  • the self-microemulsifying drug delivery system according to the invention further comprises a solubilizer.
  • Suitable solubilizers for use according to the invention include short-chain alcohols such as methanol, ethanol and benzyl alcohol; alkane diols and triols such as propylene glycol and glycerol; polyethylene glycols such as PEG 400; glycol ethers such as diethylene glycol monoethyl ether (e.g. Transcutol); and propylene carbonate.
  • Preferred solubilizers according to the invention are methanol, ethanol, propylene glycol, polyethylene glycol, propylene carbonate and benzyl alcohol.
  • the self-microemulsifying drug delivery system according to the invention further comprises an antioxidant.
  • an antioxidant refers to any substance that inhibits the oxidation of other molecules, especially the oxidation of abiraterone acetate.
  • Suitable antioxidants for use according to the invention include butylated
  • BHT hydroxytoluene
  • BHA butylated hydroxyanisole
  • AP ascorbyl palmitate
  • propyl gallate alpha tocopherol or any mixtures thereof.
  • the antioxidant is preferably present in an amount of 0.0001 to 5% by weight, preferably 0.001 to 0.5% by weight, more preferably 0.01 to 0.1 % by weight, even more preferably 0.05% by weight of the drug delivery system.
  • the fatty acid ester is a fatty acid glycerol ester, preferably selected from a mixture of at least one long chain (Ci 4 -C 2 2) triglyceride and at least one medium chain (C 6 -Ci 2 ) mono- or diglyceride or a mixture thereof or a mixture of at least one long chain (Ci 4 -C 2 2)- triglyceride and at least one long chain (Ci 4 -C 2 2)-mono- or diglyceride or a mixture thereof.
  • Particularly preferred fatty acid esters are castor oil, Capmul MCM ® and Peceol ® , alone or in combination with another fatty acid ester. It is further preferred that the surfactant has a HLB of 4 to 18, preferably 10 to 18, more preferably 12 to 16.
  • the self-microemulsifying drug delivery system additionally comprising at least one surfactant with a HLB value of 4-8 or/and at least one surfactant with a HLB value of 12-18.
  • a particularly preferred surfactant is Cremophor EL ® , alone or in combination with Span 80 ® , Tween 80 ® or Cremophor RH40 ®
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a self- microemulsifying drug delivery system as described hereinabove.
  • the pharmaceutical composition comprising a self-microemulsifying drug delivery system preferably is an oral dosage form.
  • Said oral dosage form may be selected from the group consisting of a capsule, e.g. a soft gelatin capsule, a hard gelatin capsule or a hydroxypropylmethyl cellulose capsule; a powder or a tablet.
  • the self-microemulsifying drug delivery system of the invention is liquid and may be filled into a capsule such as a soft gelatin capsule, a hard gelatin capsule or a hydroxypropylmethyl cellulose capsule.
  • the self-microemulsifying drug delivery system of the invention may also be converted to the solid state. This can be achieved by adsorption of the liquid self-microemulsifying drug delivery system onto the surface of carriers or by granulation using the liquid self-microemulsifying drug delivery system as a binder.
  • the final dosage form of the solid self-microemulsifying drug delivery system is a tablet, a pellet or a capsule.
  • the pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients.
  • the excipients may be selected from fillers, diluents, lubricants, binders,
  • disintegrating agents colorants, flavoring agents, sweeteners, glidants,
  • compositions according to the present invention may optionally comprise an external coating.
  • Said external coating may provide a function such as enteric coating or oxygen protection. Suitable enteric coatings are known in the art.
  • oxygen protection i.e. in order to prevent oxidation degradation, oxygen scavengers may be used in the coating.
  • the pharmaceutical composition in the form of a solid dosage form e.g. a tablet, comprises 10-250 mg of the compound of formula (I) per unit dosage form, preferably 1 00-200 mg of the compound of formula
  • the pharmaceutical composition in the form of a soft gelatine capsule comprises 10-500 mg of the compound of formula (I) per unit dosage form, preferably 50-250 mg of the compound of formula (I).
  • the pharmaceutical composition comprising a self-microemulsifying drug delivery system may be administered one to three times per day, preferably one to two times per day, more preferably once per day.
  • the pharmaceutical composition comprising a self- microemulsifying drug delivery system is administered three times a day with a dosing interval of 6 to 9 hours, preferably 7 to 9 hours, more preferably 7.5 to 8.5 hours.
  • the pharmaceutical composition comprising a self- microemulsifying drug delivery system is administered two times a day with a dosing interval of 10 to 1 3 hours, preferably 1 1 to 13 hours, more preferably 1 1 .5 to 12.5 hours.
  • the pharmaceutical composition comprising the inventive self- microemulsifying drug delivery system exhibits a dissolution profile such that more than 80%, preferably 85%, more preferably 90% of 250 mg of the compound of formula (I), preferably of abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof is released within 1 5 minutes, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 900 ml of FaSSIF (pH 6.5) and FeSSIF (pH 5.0) media at 37°C ⁇ 0.5°C.
  • FaSSIF relates to the "Fasted State Simulated Intestinal Fluid", a dissolution medium developed by Prof. Dr. Dressman (Goethe-Univ. Frankfurt).
  • the "FeSSIF” relates to the "Fed State Simulated Intestinal Fluid", a dissolution medium developed by Prof. Dr. Dressman (Goethe-Univ. Frankfurt). The preparation of both dissolution media has been widely published (e.g. in Margreth Marques, Dissolution Technologies, page 1 6, May 2004).
  • abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof from about 900 to about 1 1 00 ng/ml; preferably 950 to 1050 ng/ml, more preferably about 1000 ng/ml after application of 1000 mg of abiraterone acetate;
  • Tmax a time to reach maximum plasma concentration
  • an area under the concentration time curve (AUCO-t) from about 4000 to about 5000 ng.h/mL, preferably 4250 to 4750 ng.h/mL, more preferably about 4500 ng.h/mL.
  • the invention further relates to a process for preparing a self-microemulsifying drug delivery system comprising the compound of formula (I), preferably abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof, the process comprising the following steps: (a) providing a surfactant or mixture of surfactants, if more than one surfactant is used;
  • the invention further relates to a process for preparing a microemulsion of the compound of formula (I), preferably abiraterone acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof, the process comprising the following steps:
  • the invention further relates to a process for preparing a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), preferably abiraterone acetate or a
  • step (b) adding one or more pharmaceutically acceptable excipients; and (c) converting the mixture obtained in step (b) into an oral dosage form, preferably selected from the group consisting of a capsule, e.g. a soft gelatin capsule, a hard gelatin capsule or a hydroxypropylmethyl cellulose capsule; a powder or a tablet.
  • a capsule e.g. a soft gelatin capsule, a hard gelatin capsule or a hydroxypropylmethyl cellulose capsule
  • a powder or a tablet preferably selected from the group consisting of a capsule, e.g. a soft gelatin capsule, a hard gelatin capsule or a hydroxypropylmethyl cellulose capsule; a powder or a tablet.
  • the self-microemulsifying drug delivery system as described hereinabove or the pharmaceutical composition comprising a self-microemulsifying drug delivery system as described hereinabove is for use in the treatment of cancer, preferably metastatic prostate cancer.
  • Figure 1 Stability evaluation of self-emulsifying drug delivery systems from Example 5 under different storage conditions. Storage at elevated temperature of 60 °C for 7 days without (A) and with antioxidants (B).
  • Figure 2 Stability evaluation of self-emulsifying drug delivery systems from Example 5 under different storage conditions. Storage at accelerated temperature of 40 °C for 1 month without (A) and with antioxidants (B).
  • Figure 3 Percentage of abiraterone acetate dissolved in Fassif media versus time for self-microemulsifying drug delivery system samples 200X1 , 200X3 and 200X4 compared to samples containing a Zytiga ® reference tablet tested with the presence of the corresponding self-microemulsifying system in the dissolution medium and Zytiga ® without use of lipid excipients.
  • the dissolution of the self-emulsifying drug delivery system samples 200X1 , 200X3 and 200X4 are significantly faster, the solubility of abiraterone acetate in the presence of self-emulsifying drug delivery systems is significantly improved.
  • Figure 4 Percentage of abiraterone acetate dissolved in Fessif media versus time for self-emulsifying drug delivery system samples 200X1 , compared to samples containing a Zytiga ® reference tablet tested with the presence of the self- microemulsifying system in the dissolution medium and Zytiga ® without use of lipid excipients.
  • the dissolution of abiraterone acetate in the self-emulsifying drug delivery system was shown to be very fast, the solubility of abiraterone acetate in the presence of self-microemulsifying system was significantly improved.
  • Figure 5 Percentage of abiraterone acetate dissolved in FaSSGF media versus time for self-emulsifying drug delivery system samples 200X1 , 200X3, 200X4 compared to samples Zytiga ® reference tablet tested with the presence of the self- microemulsifying system in the dissolution media and Zytiga ® without use of lipid excipients.
  • the dissolution of the self-emulsifying drug delivery system samples 200X1 , 200X3, 200X4 is significantly faster than the dissolution of the Zytiga ® reference product, the solubility of abiraterone acetate in the presence of self- emulsifying systems was significantly improved.
  • Miglyol (20% w/w in regard to final mixture) was added to the mixture, resulting in a homogeneous self-microemulsifying system.
  • Abiraterone acetate (6% w/w in regard to the final dispersion) was added to the self- microemulsifying system and mixed for 24 hours.
  • IPM Isopropyl myristate
  • Abiraterone acetate 6% w/w in regard to the final dispersion was added to the self-microemulsifying system and mixed for 24 hours.
  • excipients suitable for the preparation of self-microemulsifying drug delivery systems were prepared based on our previous experience, regulatory acceptance, low irritability and toxicity, melting temperature, self-dispersing properties, digestibility, expected solubilization capacity, compatibility with other excipients and purity.
  • Table 2 Table 2
  • compositions were prepared.
  • the preparation procedure was the same in all cases: surfactants were mixed in the prescribed ratio (if there were two surfactants) and oil phases (fatty acid ester) were added.
  • the mixture was mixed on a magnetic stirrer after each addition to form a homogeneous mixture.
  • Final compositions were mixed until a homogeneous mixture was obtained.
  • the final self-microemulsifying drug delivery systems did not exhibit any phase separation under room conditions.
  • the respective compositions of the self-emulsifying drug delivery systems and the respective maximum solubility of abiraterone acetate in the systems are shown in Table 4. All prepared self- microemulsifying systems could be mixed with water in any ratio without observing any phase separation, indicating excellent water mixing properties.
  • the self-emulsifying drug delivery systems from example 5 were saturated with abiraterone acetate and put on different storage conditions for stability evaluation.
  • the self-emulsifying drug delivery systems with abiraterone acetate were stored at elevated temperature of 60° C for 7 days and at accelerated temperature of 40° C for 1 month. Samples were stored under air and nitrogen atmosphere.
  • Results demonstrate that abiraterone acetate dissolved in majority of tested self- microemulsifying drug delivery systems is prone to degradation during storage under air.
  • the stability of abiraterone acetate in all tested systems was significantly improved when stored under nitrogen. Nevertheless the stability of abiraterone acetate prepared in SMES 1 was surprisingly good at all tested conditions, even under air atmosphere.
  • the worst stability of abiraterone acetate was detected in SMES 8 and SMES 9 in spite of the low solubility of abiraterone acetate in both systems (solubility of AA ⁇ 5%).
  • antioxidants to some of the self- microemulsifying drug delivery systems with abiraterone acetate could improve stability and prevent degradation of abiraterone acetate.
  • SMES1 , SMES 5 and SMES 7 from example 5 were mixed with 6% of abiraterone acetate (w/w in regard to final mixture) until all abiraterone acetate was dissolved.
  • the self-microemulsifying drug delivery systems with abiraterone acetate were tested for solubility and dissolution. All the dissolution tests were performed using a dissolution tester in paddle method (USP Apparatus 2) at 50 rpm with 900 ml of media.
  • the dissolution media were chosen to reflect in vivo gastro intestinal conditions at three different states: fasted stomach, fasted intestine and fed state.
  • FaSSGF Fested state simulation gastric fluid
  • FaSSIF Fested state simulation intestine fluid
  • FeSSIF Fed state simulation intestine fluid
  • All the media were prepared according to literature data, since bio relevant dissolution testing, especially for drugs with low solubility has been established (M. Vertzoni, N. Fotaki, E. Kostewicz, E. Stippler, C. Leuner, E. Nicolaides, J. Dressman, C. Reppas, Dissolution media simulating the intralumenal composition of the small intestine: physiological issues and practical aspects, J. Pharm. Pharmacol, 56 (2004) 453-462.; E. Jantratid, N.
  • the prepared self-microemulsifying drug delivery systems containing abiraterone acetate were simultaneously tested against self-microemulsifying drug delivery systems without abiraterone acetate, Zytiga ® reference tablet tested in dissolution medium containing the self- microemulsifying systems and Zytiga ® reference tablets as such.
  • Self-microemulsifying drug delivery systems form a stable emulsion after contact with the media and abiraterone acetate is not salted out throughout the dissolution time period (2h). This may be expected also in vivo since bio relevant dissolution media were used, and high solubility of abiraterone acetate was shown also in presence of lipid digestion enzymes (hog lipase).
  • Example 7 shows that the dose of abiraterone acetate in SMES system may be significantly reduced compared to the Zytiga ® reference product.

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Abstract

La présente invention concerne un système d'administration de médicament auto-microémulsifiant comprenant un composé de formule (I), de préférence de l'abiratérone ou de l'acétate d'abiratérone ou un sel, un hydrate ou un solvate pharmaceutiquement acceptable associé, au moins un ester d'acide gras et au moins un tensioactif. L'invention concerne en outre un procédé de préparation associé ainsi qu'une composition pharmaceutique comprenant ledit système d'administration de médicament auto-microémulsifiant.
PCT/EP2013/064618 2012-07-11 2013-07-10 Système d'administration de médicament auto-microémulsifiant à base d'abiratérone ou d'acétate d'abiratérone WO2014009434A1 (fr)

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