WO2022067336A1 - Compositions and methods for vasodilator delivery - Google Patents
Compositions and methods for vasodilator delivery Download PDFInfo
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- WO2022067336A1 WO2022067336A1 PCT/US2021/071589 US2021071589W WO2022067336A1 WO 2022067336 A1 WO2022067336 A1 WO 2022067336A1 US 2021071589 W US2021071589 W US 2021071589W WO 2022067336 A1 WO2022067336 A1 WO 2022067336A1
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- nanostructured
- formulation
- nonlamellar
- iloprost
- phase
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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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5578—Eicosanoids, e.g. leukotrienes or prostaglandins having a pentalene ring system, e.g. carbacyclin, iloprost
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
Definitions
- the present invention relates to the field of pharmaceutical compositions for administering a vasodilator (e.g., iloprost or a pharmaceutically acceptable salt thereof).
- a vasodilator e.g., iloprost or a pharmaceutically acceptable salt thereof.
- Other embodiments are directed to methods of treatment and methods of manufacturing the compositions disclosed herein.
- Constriction of blood vessels is a serious condition that prevents proper blood flow to surrounding tissues.
- pulmonary hypertension is an elevated blood pressure that affects the arteries in the lungs and the right side of the heart.
- PAH pulmonary arterial hypertension
- blood vessels in the lungs are narrowed, blocked or damaged which slows blood flow through the lungs, and blood pressure in the lung arteries becomes elevated. This causes the heart to work harder and results in cardiac complications.
- Pulmonary hypertension may become worse over time and can be life-threatening.
- Other diseases associated with constricted blood vessels include scleroderma and Raynaud’s syndrome.
- Iloprost is a vasodilator that can be used to treat diseases associated with constricted blood vessels.
- the chemical name for iloprost is (E)-(3aS, 4R, 5R, 6aS)-hexahydro-5-hydroxy-4- [(E)(3S,4RS)-3-hydroxy-4-methyl-l-octen-6-ynyl]- ⁇ 2(1H) ⁇ -pentalenevaleric acid.
- Racemic iloprost consists of a mixture of the 4R and 4S diastereoisomers at a ratio of approximately 50:50.
- Iloprost is commercially available as a solution for inhalation in 1 mL single-use glass ampules containing either 10 mcg/mL or 20 mcg/mL and is administered by a nebulized delivery system.
- the approved regimen includes dosing every 6-9 hours during waking hours. This is very inconvenient and difficult for compliance and may result in underdosing or overdosing by patients.
- vasodilator e.g., iloprost or a pharmaceutically acceptable salt thereof
- disease states such as arterial hypertension, pulmonary arterial hypertension, scleroderma and Reynaud’s disease.
- the vasodilator e.g., iloprost or a pharmaceutically acceptable salt thereof
- diseases associated with constriction of blood vessels arterial hypertension, pulmonary arterial hypertension, scleroderma and Reynaud’s disease
- the pharmaceutical compositions e.g., by an implantable pump
- a pharmaceutical composition comprising a vasodilator (e.g., iloprost or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient (e.g., a lipid material such as a lyotropic liquid crystal material).
- a vasodilator e.g., iloprost or a pharmaceutically acceptable salt thereof
- a pharmaceutically acceptable excipient e.g., a lipid material such as a lyotropic liquid crystal material.
- the pharmaceutical composition is contained in an implantable pump.
- the present invention is directed to the use of a vasodilator (e.g., iloprost or a pharmaceutically acceptable salt thereof) in the preparation of a medicament for the treatment of a disease requiring vasodilatory therapy such as hypertension (e.g., pulmonary hypertension).
- a vasodilator e.g., iloprost or a pharmaceutically acceptable salt thereof
- the medicament is contained in an implantable pump.
- vasodilator includes a single vasodilator as well as a mixture of two or more different vasodilators
- excipient includes a single excipient as well as a mixture of two or more different excipients, and the like.
- the term “about” in connection with a measured quantity or time refers to the normal variations in that measured quantity or time, as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement.
- the term “about” includes the recited number ⁇ 10%, such that “about 10” would include from 9 to 11, or “about 1 hour” would include from 54 minutes to 66 minutes.
- the terms "therapeutically effective” and an “effective amount” refer to that amount of an active agent or the rate at which it is administered needed to produce a desired therapeutic result.
- treatment of and “treating” include the administration of an active agent(s) with the intent to lessen the severity of a condition.
- prevention of and “preventing” include the avoidance of the onset of a condition by a prophylactic administration of the active agent.
- parenteral means administration by injection, implantation or infiltration by a route such as intravenous, inhalation, intrarterial, intracardiac, intraspinal, intraosseous, intrarticular, intrasynovial, intracutaneous, subcutaneous or intramuscular.
- injection means administration to a discrete site through the skin or into tissue of a human or animal.
- implantation means embedding a device and/or pharmaceutical composition into the skin, tissue, muscles, tendons, joints, or other body parts of a human or animal.
- the term refers to a surgical procedure where a device and/or pharmaceutical composition is put into the body and the skin is closed over it.
- aqueous formulation refers to a water base formulation or compositionwithout a lipid material.
- formulation and composition are used interchangeably.
- FIG. 1 is a graphic illustration of Mean (SD) Plasma Concentrations (pg/mL) of Iloprost versus Time Post Start of Infusion in Female Dogs Following a Single Continuous Intravenous Infusion of Aqueous Formulation or Aqueous lipid-based Formulation for up to 24
- FIGS. 2 to 6 are a graphic illustration of Individual PK Profiles of Log-transformed
- FIGS. 7 to 11 are a graphic illustration of Individual PK Profiles of Log-transformed Concentration Values vs Time and Linear Regression to Estimate the Elimination Rate in Dog Plasma after IV Infusion of Iloprost Aqueous lipid-based for up to 24 Hours at 5760 ng/kg of the Pharmokinetic (PK) study.
- PK Pharmokinetic
- FIG. 12 is an image of the optical microscopcy of the blank aqueous lipid mixture of the Preparation example.
- FIG. 13 is an image of the optical microscopy of the Manufacturing Example.
- FIG. 14 is a bargraph illustrating intracellular cAMP levels in isolated hPASMCs upon treatment with Iloprost in an aqueous lipid formulation and aqueous lipid dispersion.
- FIG. 15 is a bargraph illustrating intracellular cAMP levels in isolated hPASMCs upon treatment with Iloprost Trometamol solution.
- FIG. 16 is a line graph illustrating intracellular cAMP levels in isolated hPASMCs upon treatment with Iloprost in an aquous lipid formulation with Iloprost Trometamol formulation.
- the invention is directed to a pharmaceutical composition
- a vasodilator e.g., iloprost or a pharmaceutically acceptable salt thereof
- a pharmaceutical composition comprising a vasodilator (e.g., iloprost or a pharmaceutically acceptable salt thereof) that can be administered (e.g., by implantable pump) to facilitate the treatment of relevant disease states.
- the pharmaceutical composition comprises iloprost or a pharmaceutically acceptable salt thereof and a lipid material (e.g., a lyotropic liquid crystal material).
- a lipid material e.g., a lyotropic liquid crystal material
- the pharmaceutical composition is an aqueous lipid solution).
- the lyotropic liquid crystal material comprises both polar and non-polar nano-domains.
- the material comprises nanostructured nonlamellar liquid crystalline phases.
- the material comprises reversed nanostructured liquid crystalline phases.
- the material comprises distinct nanostructured nonlamellar liquid crystalline material and a liquid phase embedded within said distinct nanostructured nonlamellar liquid crystalline material, said liquid phase being selected from the group consisting of a hydrophobe-rich phase and a polar solvent-rich phase.
- the pharmaceutical composition disclosed herein is contained in an implantable pump that can deliver the active agent for a time period of, e.g., at least 3 days, at least 7 days, at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 45 days, at least 60 days, at least 90 days, at least 100 days, at least 120 days, at least 150 days, at least 180 days, at least 200 days, at least 210 days, at least 240 days, at least 270 days, at least 300 days, or at least one year.
- a time period of e.g., at least 3 days, at least 7 days, at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 45 days, at least 60 days, at least 90 days, at least 100 days, at least 120 days, at least 150 days, at least 180 days, at least 200 days, at least 210 days, at least 240 days, at least 270 days, at least 300 days, or at least one year.
- the pharmaceutical composition disclosed herein is contained in an implantable pump that can deliver the active agent for a time period of, e.g., about 3 days, about 7 days, about 10 days, about 14 days, about 21 days, about 28 days, about 30 days, about 45 days, about 60 days, about 90 days, about 100 days, about 120 days, about 150 days, about 180 days, about 200 days, about 210 days, about 240 days, about 270 days, about 300 days, or about one year.
- the pharmaceutical composition disclosed herein is contained in an implantable pump that can deliver the active agent for a time period of, e.g., from about 3 days to about 400 days, from about 7 day to about 200 days, or from about 30 days to about 180 days.
- the formulation e.g., a lipid formulation such as a lyotropic liquid crystal formulation
- the vasodilator e.g., iloprost or pharmaceutically acceptable salt thereof
- the formulation disclosed herein increases the potency of the drug.
- it may increase the potency of iloprost or pharmaceutically acceptable salt thereof on prostaglandin receptors. This may decrease the minimum effective dose and result in less drug being administered and/or decrease the frequency of dosing.
- the formuation dislcosed herein may have a pH of about 6 to about 10, about 7 to about 9 or about 7.5 to 8.5.
- the formulation disclosed herein may have a density of about 0.8 to about 1.2 g/mL, about 0.9 to about 1.1 g/mL or about 1 g/mL.
- the formulation disclosed herein may have a particle size distribution (D90) of the drug of about 0.1 nm to about 10 nm, about 0.5 nm to about 5 nm about 1 nm to about 3 nm, about 1.25 nm to about 2.75 nm, about 1.5 nm to about 2.5 nm, or about 1.75 nm to about 2.25 nm.
- D90 particle size distribution
- the formulation disclosed herein provides iloprost or pharmaceutically acceptable salt thereof to the patient in a daily amount from about 1000 ng/kg to about 10,000 ng/kg, from about 2000 ng/kg to about 8000 ng/kg, from about 5000 ng/kg to about 6500 ng/kg, from about 5250 ng/kg to about 6250 ng/kg, from about 5500 ng/kg to about 6000 ng/kg, or from about 5700 ng/kg to about 5800 ng/kg.
- the formulation disclosed herein is administered daily, twice daily, three times daily, 4 times daily, 6 times daily, once weekly, twice weekly, three times weekly, 4 times weekly or any oyjer suitable disong mitin.
- the administration is continuous (e.g., by intravenous infusion) over a time period of about 30 minutes to about 7 days, about 1 hour to about 3 days, about 2 hours to about 2 days, or about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours or about 24 hours.
- formulation disclosed herein provides a maximum plama concentration (C max ) of iloprost that is higher when compared to the adminsitartiion of a comparable aqueous formulation.
- C max maximum plama concentration
- the Cmax provided by the present formulation is up to about 100% higher, up to about about 90% higher, up to about 80% higher, up to about 75% higher, up to about 65% higher, up to about 50% higher, up to about 40% higher, up to about 25% higher, up to about 15% higher, up to about 10% higher or up to about 5% higher than a comparable aqueuous formulation.
- the formulation disclosed herein provides a half-life of iloprost that decreases as compared to a comparable aqueous formulation.
- the decrease is about 75% or less, about 50% or less, about 35% or less, about 25% or less, about 10% or less or about 5% or less as compared to an aqueous formulation.
- the formulation disclosed herein provides a total clearance of iloprost that increases when compared to an aqueous formulation.
- the total clearance provided by the present formulation is up to about 100% higher, up to about about 90% higher, up to about 80% higher, up to about 75% higher, up to about 65% higher, up to about 50% higher, up to about 40% higher, up to about 25% higher, up to about 15% higher, up to about 10% higher or up to about 5% higher than a comparable aqueuous formulation
- the formulation disclosed herein has a relative mean plasma exposure (AUC 0-48 ) that increases as compared to a comparable aqueous formulation.
- the (AUC 0-48 ) provided by the present formulation is up to about 100% higher, up to about about 90% higher, up to about 80% higher, up to about 75% higher, up to about 65% higher, up to about 50% higher, up to about 40% higher, up to about 25% higher, up to about 15% higher, up to about 10% higher or up to about 5% higher than a comparable aqueuous formulation.
- the formulation may be used to treat any condition to provide vasodilator therapy or iloprost therapy such as pulmonary arterial hypertension, or hypertension.
- the iloprost lipid formulation of the present invention provides intracellular cAMP levels in isolated hPASMCs of from about 10 nM to about 40 nM, or about 20 nM to about 30 nM at a concentration of about 1950 nM iloprost.
- the iloprost lipid formulation of the present invention provides intracellular cAMP levels in isolated hPASMCs of from about 2 nM to about 15 nM, or about 4 nM to about 12 nM at a concentration of about 650 nM iloprost.
- the iloprost lipid formulation of the present invention provides intracellular cAMP levels in isolated hPASMCs of from about 2 nM to about 15 nM, or about 4 nM to about 12 nM at a concentration of about 195 nM iloprost.
- the iloprost lipid formulation of the present invention provides intracellular cAMP levels in isolated hPASMCs of from about 2 nM to about 15 nM, or about 4 nM to about 12 nM at a concentration of about 65 nM iloprost.
- the formulation disclosed herein provides an increase in cAMP in human PASMCs when compared to an aqueous formulation iloprost.
- the iloprost lipid formulation of the present invention provides intracellular cAMP levels in isolated hPASMCs of from about 5 nM to about 30 nM, or about 10 nM to about 20 nM at a concentration of about 2310nm iloprost.
- the iloprost lipid formulation of the present invention provides intracellular cAMP levels in isolated hPASMCs of from about 2 nM to about 20 nM, or about 5 nM to about 15 nM at a concentration of about 770 nM iloprost.
- the iloprost lipid formulation of the present invention provides intracellular cAMP levels in isolated hPASMCs of from about 2 nM to about 12 nM, or about 5 nM to about 10 nM at a concentration of about 231 nM iloprost.
- the iloprost lipid formulation of the present invention provides intracellular cAMP levels in isolated hPASMCs of from about 2 nM to about 12 nM, or about 5 nM to about 10 nM at a concentration of about 77 nM iloprost.
- the iloprost lipid formulation of the present invention provides intracellular cAMP levels in isolated hPASMCs of at least about 15 nM, at at least about 20 nM, from about 15 nM to about 50 nM, from about 20 nM to about 30 nM, or from about 22 nM to about 28 nM at a concentration of about 1000 nM to about 3000 nM, about 1500 nM to about 2500 nM, about 1900 nM to about 2400 nM or about 1950 nM or about 2310 nM iloprost.
- the composition disclosed herein can be contained in an implantable pump.
- the pump may provide a continuous release or a pulsed release of the drug.
- the pulses may be, e.g., about every 2 hours, about every 4 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 48 hours, about every 72 hours or about every 168 hours.
- the implantable pump may be implanted in any suitable body space such as the abdomen, neck area (e.g., under the collarbone), buttock, thigh or upper arm.
- the composition is released from the pump into the surrounding tissue and the drug (e.g., iloprost or pharmaceutically acceptable salt thereof) is subsequently absorbed into the circulatory system.
- a catheter delivers the composition from the device (e.g., implanted in the abdomen or under the collarbone) directly into the circulatory system (e.g., to the venous system such as subclavian vein or the subjugular vein).
- the pump is in the form of an implantable infusion device that comprises a lightweight, inert housing that contains a pharmaceutical composition disclosed herein for administration to a patient, and an enclosed, gas-impermeable variable volume chamber which contains a pressure source, such as a propellant or mechanical spring.
- the variable volume chamber may be in the form of a rigid-walled expandable bellows structure or a nonstretchable flexible bag and is attached to the housing so as not to obstruct the entry port.
- a recharging fluid flow path may be provided adjacent to where the variable volume chamber is attached to the housing.
- the composition is delivered from the device via a catheter in response to expansion of the variable volume chamber against the volume of infusate in the housing.
- a separate bolus injection port is provided which allows infusate to be safely introduced directly into the catheter and overrides the controlled pressure-driven delivery.
- the lightweight housing may include integrally formed needle stops and suture fastening loops.
- the device is in the form of an implantable infusion device comprising a housing including an inner wall and having an interior region defined at least in part by the inner wall, at least a portion of the interior region defining an pharmaceutical composition reservoir adapted to store a pharmaceutical composition as disclosed herein for delivery to a patient; a closed variable volume chamber having an outer wall, the variable volume chamber disposed within the interior region of the housing with the outer wall of the variable volume chamber being spaced from the inner wall of the housing, the variable volume chamber being supported within the interior region from an internal portion of the inner wall of the housing; a pressure source contained within the variable volume chamber; a pharmaceutical composition recharging fluid flow path adapted to recharge the infusate reservoir by carrying infusate to the infusate reservoir through the internal portion of the housing from which the variable volume chamber is supported within the interior region; and an exit fluid flow path adapted to deliver infusate from the infusate reservoir out of the housing, e.g., directly into the circulatory system.
- the implantable pump comprises a filter for microbial agents.
- the filter can comprise a material such as, e.g., plastic, ceramic, glass or fiber.
- the filter comprises plastic and does not comprise polyvinylidene fluoride. In other embodiments, the filter does not comprise plastic.
- Exemplary infusion pumps that can be adapted for use in the devices, systems (device/pharmaceutical composition combinations) and methods disclosed herein are described in US2003/0208184; US2014/0228765; US2014/0194851; US2013/0023857; US3, 840,009; US5,167,633; US5, 514103; US3,951,147; US5,045,064; US5,395,324; US5,769,823; US5,575,770; US10, 173,004; US10, 010670; US9,968,734; US9,700,669, US9, 180,282; US9, 125,982; US8,551,044; US8,545,477 and US 8,273,058, the disclosures of which are hereby incorporated by reference for all purposes.
- the pharmaceutical formulation comprising iloprost or a pharmaceutically acceptable salt thereof; a carrier; and a particle or material comprising a distinct nanostructured nonlamellar liquid crystalline material; and one or more pockets or droplets of a liquid phase embedded within said distinct nanostructured nonlamellar liquid crystalline material, said liquid phase being selected from the group consisting of an oil-rich liquid phase and a polar solvent-rich liquid phase.
- the distinct nanostructured nonlamellar liquid crystalline material is a reversed phase nonlamellar liquid crystalline material.
- the distinct nanostructured nonlamellar liquid crystalline material comprises a reversed hexagonal phase material, a reversed bicontinuous cubic phase material, a reversed discrete cubic phase material, or a reversed intermediate phase material.
- the distinct nanostructured nonlamellar liquid crystalline material is polymerized.
- the pharmaceutical formulation further comprises a stabilizing layer exterior to said particle or material.
- the stabilizing layer is selected from the group consisting of a charged moiety, a polymer, and a surfactant.
- the particle or material further comprises a coating comprising the vasodilator (e.g., iloprost or pharmaceutically acceptable salt thereof).
- the vasodilator e.g., iloprost or pharmaceutically acceptable salt thereof.
- the liquid phase is an oil and said oil is selected from the group consisting of benzyl benzoate, estragole, eugenol, isoeugenol, linalool, and the essential oils of basil, bay, bois de rose (rosewood), carrot seed, clovebud, eucalyptus, ginger, grapefruit, hyssop, lemon, balsam of Peru, mugwort, myrrh gum, biter orange, oregano, palmarosa, patchouly, peppermint, petitgrain, rosemary, santalwood oil, spearmint, thuja (cedar leaf), thyme, vanilla, and ylang ylang (cananga).
- said oil is selected from the group consisting of benzyl benzoate, estragole, eugenol, isoeugenol, linalool, and the essential oils of basil, bay, bois de rose (rosewood), carrot seed, clovebud, eucalyptus
- the liquid phase is a polar solvent and said polar solvent is selected from the group consisting of water, glycerol, and N,N-dimethylacetamide.
- the vasodilator e.g., iloprost or pharmaceutically acceptable salt thereof
- the vasodilator is dissolved or dispersed in the liquid phase or in the distinct nanostructured nonlamellar liquid crystalline material.
- the one or more pockets or droplets have a diameter of 50 nm or greater.
- the liquid phase includes at least one of an oil and a polar solvent.
- the liquid phase is a hydrophobe-rich phase or a polar solvent- rich phase.
- the distinct nanostructured nonlamellar liquid crystalline material consists essentially of a reversed bicontinuous cubic phase material.
- the distinct nanostructured nonlamellar liquid crystalline material comprises or consists essentially of a reversed discrete cubic phase material.
- the distinct nanostructured nonlamellar liquid crystalline material comprises a water insoluble lipid or surfactant.
- the pharmaceutical formulation comprises a vasodilator (e.g., iloprost or a pharmaceutically acceptable salt thereof) and a coated particle comprising a) an interior core comprising a matrix comprising of i) at least one nanostructured liquid phase or a dehydrated variant thereof, ii) at least one nanostructured liquid crystalline phase or a dehydrated variant thereof or iii) a combination of (1) at least one nanostructured liquid phase or a dehydrated variant thereof and (2) at least one nanostructured liquid crystalline phase or a dehydrated variant thereof and b) an exterior coating comprising nonlamellar domains wherein the iloprost or pharmaceutically acceptable salt thereof is in a), b) or a combination thereof.
- a vasodilator e.g., iloprost or a pharmaceutically acceptable salt thereof
- a coated particle comprising a) an interior core comprising a matrix comprising of i) at least one nanostructured liquid phase or a dehydrated variant thereof, i
- the nanostructured liquid phase material comprises a nanostructured LI phase material, a nanostructured L2 phase material, a microemulsion that is nanostructured, or a nanostructured L3 phase material.
- the nanostructured liquid phase material comprises a nanostructured normal or reversed cubic phase material, a nanostructured normal or reversed hexagonal phase material, a nanostructured normal or reversed intermediate phase material, or nanostructured lamellar phase material.
- the nanostructured liquid phase material comprises a polar solvent and a surfactant or a lipid.
- the nanostructured liquid phase material comprises a polar solvent, a surfactant or a lipid and an amphiphile or hydrophobe.
- the nanostructured liquid phase material comprises a block copolymer.
- the nanostructured liquid phase material comprises a block copolymer and a solvent.
- the nanostructured liquid phase material comprises a polar solvent and a surfactant.
- the nanostructured liquid phase material comprises a polar solvent, a surfactant and an amphiphile or hydrophobe.
- the interior core comprises the vasodilator (e.g., iloprost or pharmaceutically acceptable salt thereof) disposed within said matrix.
- the vasodilator e.g., iloprost or pharmaceutically acceptable salt thereof
- the interior core comprises a reversed cubic phase material.
- the nonlamellar domain is amorphous.
- the nonlamellar domain is a polymer such as polylactic glycolic acid.
- the nonlamellar domain comprises a sugar such as trehalose.
- the exterior coating comprises a semi-crystalline nonlamellar material.
- the exterior coating comprises at least 2% nonlamellar domains, at least 10% nonlamellar domains or at least 50% nonlamellar domains.
- the exterior coating comprises the vasodilator (iloprost or pharmaceutically acceptable salt thereof).
- compositions and implants disclosed herein include iloprost or a pharmaceutically acceptable salt thereof.
- Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as arginate, asparginate, glutamate and the like, and metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, tromethamine salt, triethanolamine salt, dicyclohexylamine salt
- vasodilators that can be utilized in the present invention (alone or in combination with iloprost) include an alpha-adrenergic receptor antagonist (a-blocker), an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a beta 2 -adrenergic receptor agonist ( 2 -agonist), Calcium channel blocker (CCB), centrally acting sympathetic blocker, direct acting vasodilator, endothelin receptor antagonist, ganglion blocker, nitrodilator, phosphodiesterase inhibitor, potassium channel opener, renin inhibitor or combination thereof.
- a-blocker alpha-adrenergic receptor antagonist
- ACE angiotensin converting enzyme
- ARB angiotensin receptor blocker
- 2 -agonist beta 2 -adrenergic receptor agonist
- CB Calcium channel blocker
- centrally acting sympathetic blocker direct acting vasodilator, endothelin receptor antagonist, ganglion blocker,
- Particular agents include prazosin, terazosin, doxazosin, trimazosin, phentolamine, phenoxybenzamine, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril, candesartan, eprosartan, irbesartan, irbesartan, irbesartan, irbesartan, irbesartan, irbesartan, irbesartan, irbesartan, irbesartan, epinephrine, norepinephrine, dopamine, dobutamine, isoproterenol, amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nitrendipine, clonidine
- compositions according to the present invention may comprise one or more pharmaceutically acceptable carriers and excipients appropriate for parenteral administration.
- pharmaceutically acceptable carriers and excipients are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (6 th Edition, 2009 Publication), which is incorporated by reference herein.
- Carriers and excipients suitable for parenteral compositions include antioxidants, buffering agents, diluents, surfactants, solubilizers, stabilizers, hydrophilic polymers, additional absorption or permeability enhancers, preservatives, osmotic agents, isotonicity agents, pH adjusting agents, solvents, co-solvents, viscosity agents, gelling agents, suspending agents or combinations thereof.
- Suitable surfactants for the formulations disclosed herein include, but are not limited to Polysorbate 80 NF, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitan monoisostearate, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trilaurate, sorbitan trioleate, sorbitan tristearate, and the like, and combinations thereof.
- the pharmaceutical composition is used in an implantable pump, implantable depot or similar implantable device that can provide administration of the active agent over an extended period of time.
- it may be necessary to have a concentrated formulation in order to have the a suitable amount of active agent in a practical size for implant.
- the iloprost is in a concentration from about 5 mg/mL to about 50 mg/mL, about 6 mg/mL to about 40 mg/mL, about 7 mg/mL to about 40 mg/mL, about 8 mg/mL to about 30 mg/mL, about 10 mg/mL to about 20 mg/mL, about 5 mg/mL to about 15 mg/mL or about 15 mg/mL to about 25 mg/mL.
- the concentration is about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mL about 12 mg/mL.
- the device for implant can contain from about 5 mL to about 30 mL, about 10 mL to about 20 mL or about 15 mL to about 25 mL. In other embodiments the device for implant can contain about 10 mL, about 15 mL, about 20 m, about 25 mL, about 30 mL, about 40 mL or about 50 mL.
- solubilizing agent such as an alcohol (e.g., benzyl alcohol or ethyl alcohol), a polyethylene glycol or dimethylsulfoxide (DMSO).
- alcohol e.g., benzyl alcohol or ethyl alcohol
- DMSO dimethylsulfoxide
- the lipid mixture of the present disclosure may be prepared according to the following method.
- a cubic phase is first prepared.
- the cubic phase is prepared by mixing one or more of the following ingredients: vitamin E, a phospholipid and/or a lecithin.
- the vitamin E may be a tocopherol, such as D,L-a-tocopherol.
- the phospholipid may be derived from soybean, rapeseed (canola), egg or sunflower.
- the lecithin may be naturally occurring and/or hydrogenated lecitihin fractions.
- the phospholipid and/or lecithin may be Phospolipon ®, such as Phospholipon 90G, or Phospholipon 85G, LIPOID SI 00 or LIPOID E80.
- the phospholipid may be from LIPOID ®, such as LIPOID SI 00 or LIPOID E80.
- the phospholipid and/or lecithin may include one or more of the following ingredients: phosphatidylcholine (PC), lyso-phosphati-dycholine (LPC) and phosphatidylethanolamine (PE).
- PC phosphatidylcholine
- LPC lyso-phosphati-dycholine
- PE phosphatidylethanolamine
- the phospholipid and/or lecithin may include about 80 to 85% phosphatidylcholine (PC) + lyso-phosphati-dycholine (LPC), about 7 to about 9.5% phosphatidylethanolamine (PE), and about 2 to about 3 wt% sphingomyelin (SPM).
- the phospholipid and/or lechithin may include greater than 95% phosphatidylcholine (PC).
- the ratio of vitamin E 90 (e.g., D,L-a- tocopherol) to one or both of the phospholipid and lecithin may be from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3 to about 3:1, from about 1:2 to about 2:1, or about 1: 1.
- the mixture may be heated to fully dissolve one or both of the phospholipid and lecithinat a temperature of about 60°C to about 250°C, or any one of about about 70°C, about 80°C, about 90°C, about 100°C, or about 120°C to any one of about 130°C, about 140°C, about 150°C, about 160°C, about 170°C, about 180°C, about 190°C, or about 200°C.
- the temperature should be set to facilitate lipid dissolution without burning.
- a deoxycholic acid may be added to the above mixture before preparation, after preparation or during preparation.
- the deoxycholic acid is dissolved in water and added to the mixture above.
- the deoxycholic acid may be sodium deoxycholate.
- the resultant composition may be mixed to homogenize the composition, e.g., from about 1 minute to about 30 minutes. After homogenization, the mixture may be hydrated, e.g., from about 15 minutes to about 24 hours, or any of about 1 hour, 2 hours, 4 hours, 6 hours, 8 hours or 10 hours to any of about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, or about 24 hours, to form the cubic phase.
- a separate mixture of a deoxycholic acid may be incorporated.
- a deoxycholic acid is dissolved in water and incorporated with the cubic phase and mixed until no lamellar phase is observed (e.g. for about 30 minutes to about 8 hours). Once no lamellar phase is observed, glycine and/or water may be added. The final mixture may be microfluidized to form a nano-dispersion.
- PK pharmacokinetic
- Ten female beagle dogs were assigned to one of two treatment groups using a standard, by weight, randomization procedure.
- Iloprost formulated as Aqueous formulation or Aqueuous lipid-based formulation was administered by a single IV infusion to two groups of female beagle dogs (5 animals per group), Group 1 administered with Aqueous formulation, and Group 2 administered with Aqueous lipid-based formulation.
- Each formulation was administered to animals via a surgically implanted catheter into the femoral vein by a single continuous intravenous infusion for up to 24 hours at a dose level of 5760 ng/kg and a dose volume of 3.6 mL/kg, see Table 1.
- Plasma samples were analyzed for Iloprost using the validated analytical method based on a liquid-liquid extraction, followed by LC-MS/MS analysis.
- the bioanalytical assay provided a linear range from 20.0 to 20,000 pg/mL (LLOQ: 20.0 pg/mL) for plasma based on a 200 pL sample volume. Plasma concentrations were reported to three significant figures and exported from the Watson® LIMS.
- Non-compartmental methods were used to calculate the plasma PK parameters of Iloprost using the PhoenixTM WinNonlin software (version 8.1, Pharsight Corp., Mountain View, CA).
- PK analysis for individual animals in Groups 1 and 2 were performed using Iloprost plasma concentration data at nominal time points. Mean plasma concentration for each time point was calculated using Watson® LIMS (version 7.4.2). For data below the limit of quantitation (BLQ) before dosing at time zero, a value of zero was assigned for mean calculations. Of note, one sample (animal 2501 at 27-hour point) was not received by MBL, and one sample (animal 2504 at 25.5 hour) was not processed for analysis due to quantity not sufficient for testing. Therefore, these two time points were omitted from PK calculations.
- AUC 0- ⁇ Reliability of AUC 0- ⁇ were evaluated by the coverage of AUC 0-48 in relation to AUC 0- ⁇ for individual animals and the number of samples used to fit a good regression line in the terminal log-linear phase of the individual concentration-time profiles by PhoenixTM WinNonlin software.
- Iloprost Aqueous formulation 5760 ng/kg, IV Infusion for up to 24 hours
- Iloprost Aqueous lipid-based formulation 5760 ng/kg, IV Infusion for up to 24 hours a. Time post start of infusion;
- Iloprost Aqueous formulation 5760 ng/kg, IV Infusion for up to 24 hours a: Dose normalized C max is calculated as C max Dose b: Dose normalized AUC 0-48 is calculated as AUCo-rs Dose
- Aqueous lipid-based formulation 5760 ng/kg, IV Infusion for up to 24 hours a: Dose normalized C max is calculated as C max Dose b: Dose normalized AUCo-rs is calculated as AUCo-rs Dose
- Iloprost formulated as Aqueous formulation and Aqueous lipid-based formulation was administrated in dogs by IV infusion for up to 24 hours. Following an initial of infusion, the plasma C max was observed at 24.03 hours (median T max ) for Group 1 (Aqueous formulation) and at 24.08 hours for Group 2 (Aqueous lipid-based formulation).
- Mean plasma exposure ( AUC 0-48 ) was 4286 hr*pg/mL for Group 1 and 5359 hr*pg/mL for Group 2.
- Mean C max was 2602 pg/mL for Group 1 and 3969 pg/mL for Group 2.
- Estimated elimination half-life (ti/2) in plasma ranged from 0.0303 to 0.797 hour for Group 1 and from 0.0289 to 0.437 hour for Group 2.
- Total clearance (CL) ranged from 292 to 184111 mL/hr/kg for Group 1 and from 7708 to 292462 mL/hr/kg for Group 2.
- Apparent volume of distribution (Vd) ranged from 335 to 8038 mL/kg for Group 1 and from 322 to 89971 mL/kg for Group 2.
- the relative mean plasma exposure ( AUC 0-48 ) and mean C max of Group 2 to Group 1 were 125% and 153%, respectively (Table 5), indicating improved pharmacokinetics characterized by approximate 25% higher exposure (AUC 0-48 ) and 53% higher C max in Aqueous lipid-based formulation compared with Aqueous formulation. It should be noted that small numbers of animals or insufficient qunatificable data points for some animals caused large variations (%CVs of AUC 0-48 and C max ranging from 191.4% to 218.8% in the two groups) and impacted the results.
- Iloprost peak or near peak concentrations were achieved at 24.03 hours (median T max ) for Group 1 (Aqueous formulation) and at 24.08 hours for Group 2 (Aqueous lipid-based formulation).
- Mean plasma exposure ( AUC 0-48 ) was 4286 hr*pg/mL for Group 1 and 5359 hr*pg/mL for Group 2.
- Mean C max was 2602 pg/mL for Group 1 and 3969 pg/mL for Group 2.
- Estimated elimination half-life (ti/2) in plasma ranged from 0.0303 to 0.797 hour for Group 1 and from 0.0289 to 0.437 hour for Group 2.
- Total clearance (CL) ranged from 292 to 184111 mL/hr/kg for Group 1 and from 7708 to 292462 mL/hr/kg for Group 2
- apparent volume of distribution (Vd) ranged from 335 to 8038 mL/kg for Group 1 and from 322 to 89971 mL/kg for Group 2.
- the relative mean plasma exposure (AUC 0-48 ) and mean C max of Group 2 to Group 1 were 125% and 153%, respectively.
- a cubic phase was first prepared.
- D To prepare the cubic phase, 47.24 g of D, L-a-tocopherol and 34.25 g of Phospholipon 90G were mixed to form a lipid mix.
- the lipid mix was heated on a hot plate set to 90°C to fully dissolve the Phospholipon 90G.
- 2.68 g of sodium deoxy cholate was dissolved in 27.42 g of sterile water for injection into the lipid mix.
- the sodium deoxy cholate injection was added to the lipid mix, which was vigorously mixed to form a cubic gel.
- the cubic gel was then observed under polarized light under a microscope and images were recorded. If lamellar phase is observed, then continue homogenization or kneading using mortar-pestle until most of the lamellar phase disappears. An image of the final cubic gel was recorded before hydration start time and after hydratation completion if necessary. The adjustments should be recorded. The beaker was then covered with parafilm and hydrated overnight for about 18 hours.
- a blank aqueous lipid dispersion was prepared.
- a 4L glass beaker 1432.0 g of WFI water and 4.0 g of sodium deoxy cholate was added.
- the beaker was transferred under a Silverson homogenizer (L5M-A) using a square slot high shear screen, and the stirring speed was set to 5,000 rpm.
- the solution was mixed until the sodium deoxy cholate was dissolved, about 4-5 minutes.
- Amount of water Sum of the formulation component added to the beaker (amount of cubic gel + amount of DI water + amount of Sodium deoxycholate + amount of glycine) - amount of dispersion
- aqueous lipid mixture is prepared accoding to the following process, where the aqueous lipid mixture has a concentration of about 2 mg/mL.
- a 400 mL beaker 1.103 g of iloprost and 125 g of an aqueous lipid mixture was added.
- the beaker was secured under a Silverson homogenizer (L5M-A).
- the small-scale square hole screen homogenizing head was lowered into the solution in the beaker and the solution was mixed at 5,000 rpm. This was performed until all the iloprost was dissolved, i.e. until the iloprost was no longer visible.
- a magnetic stir bar should be used instead of the homogenizer and the solution should be mixed for a longer interval, at least 2 days, but at a lower speed then was used with the homogenizer.
- the solution was filter using a Meissner 0.2 pm polypropylene vanguard filter into a 100 mL beaker.
- a 2mL sample was then prepared for assay to test the concentration of the solution.
- the sample was found to have a concentration of 6.4 mg/mL.
- 60.31 g of the 6.4 mg/mL of the solution was diluted to 193.0 g by adding 132.69 g of the aqueous lipid mixture to prepare a 2 mg/mL solution. This was then mixed for about 30 minutes.
- hPASMCs were isolated from small-resistance arteries obtained from nonimplanted human Caucasian donor lungs. These cells were plated in 96-well plates the day before the experiment, and the cells were serum-starved overnight. The hPASMCs were treated with 3-isobutyl-l -methylxanthine (IBMX lOOpM; an inhibitor of both extracellular and intracellular phosphodiesterases) prior to the exposure with the different Iloprost formulations and respective vehicle controls.
- IBMX lOOpM 3-isobutyl-l -methylxanthine
- the Iloprost in an aqueous lipid formulation was used in the concentration range of 1.9nM - 1950nM, while the Iloprost Trometamol solution was used in the concentration range of 2.3nM - 2310 nM.
- Forskolin (5pL) a permanent cAMP activator, was used as a positive control.
- the cells were treated, and after 15 minutes, the hPASMCs were rinsed twice with ice-cold PBS (200 ⁇ l), and then IX lysis buffer was added (100 ⁇ l/well). The samples were then stored at -80°C until the cAMP levels were measured using the Cyclic AMP XP® Assay Kit.
- An “upper solution”, is obtained by dissolving Pluronic F-68 (a polvpropyleneoxide-polvethyleneoxide block copolymer surfactant commercially available from BASF), and acetic acid together and adding to the test tube as a layer of solution above the previous solution that includes the iloprost. Immediately the test tube containing the liquid crystalline mixture and the upper solution is shaken and sonicated for in a small, table-top ultrasonicator (Model FS6, manufactured by Fisher Scientific) to form a dispersion.
- Pluronic F-68 a polvpropyleneoxide-polvethyleneoxide block copolymer surfactant commercially available from BASF
- acetic acid acetic acid
Abstract
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US6638621B2 (en) * | 2000-08-16 | 2003-10-28 | Lyotropic Therapeutics, Inc. | Coated particles, methods of making and using |
US6991809B2 (en) * | 2001-06-23 | 2006-01-31 | Lyotropic Therapeutics, Inc. | Particles with improved solubilization capacity |
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