Classifications

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  • 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
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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  • A61B17/0485—Devices or means, e.g. loops, for capturing the suture thread and threading it through an opening of a suturing instrument or needle eyelet
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  • A61K31/12—Ketones
  • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
  • A61K31/355—Tocopherols, e.g. vitamin E
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• • A—HUMAN NECESSITIES
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  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
• • A—HUMAN NECESSITIES
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  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• • A—HUMAN NECESSITIES
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  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
  • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
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  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• • A—HUMAN NECESSITIES
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  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
  • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
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  • 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
• • A—HUMAN NECESSITIES
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  • 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
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
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  • 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
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P5/30—Oestrogens
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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• • A—HUMAN NECESSITIES
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  • A61B17/0469—Suturing instruments for use in minimally invasive surgery, e.g. endoscopic surgery
  • A61B2017/0474—Knot pushers
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates generally to the delivery of hydrophobic drugs, such as steroids and benzoquinones. More specifically, the invention relates to novel pharmaceutical compositions in which a therapeutically effective amount of a hydrophobic active agent is combined with a vitamin E substance and a surfactant to form a uniform dispersion wherein the active agent is solubilized in the aqueous environment in a readily absorbable form.
• compositions for oral delivery of progesterone comprising micronized particles of crystalline progesterone in triglyceride vehicles.
• Such suspensions are difficult to manufacture, may be physically unstable, and may still suffer from poor dissolution and low and/or highly variable absorption.
• compositions utilizing solid dispersions such as the approach in FR 2, 647,366 which discloses a solid dispersion of the metastable progesterone JJ polymorph in a hydrophilic excipient, are difficult to manufacture consistently and may suffer from physical stability problems.
• micellar formulations can solubilize a variety of hydrophobic therapeutic agents, the loading capacity of conventional micelle formulations is limited by the solubility of the therapeutic agent in the micelle surfactant. For many therapeutic agents, such solubility is too low to offer formulations that can deliver therapeutically effective doses.
• Another approach is to solubilize the active substance in a triglyceride solvent, such as a digestible vegetable oil.
• a triglyceride solvent such as a digestible vegetable oil.
• U.S. Patent No. 4,900,734 to Maxson et al. discloses a composition in which progesterone is dissolved in a highly unsaturated edible oil.
• triglycerides are water insoluble themselves and do not normally disperse in aqueous environments such as the gastrointestinal tract. Typically, they must by emulsified by high shear or high temperature homogenization and stabilized with emulsifiers.
• a triglyceride-containing formulation suitable for delivering hydrophobic agents through an aqueous environment is an oil-in-water emulsion.
• the colloidal oil particles are relatively large and will often spontaneously agglomerate, eventually leading to complete phase separation. The large size slows the rate of transport of the colloidal particle and hence the rate of absorption of the therapeutic agent.
• triglyceride compositions are subject to a number of significant limitations and disadvantages, such as physical instability and lack of homogeneity, and are likely to suffer from poor and variable absorption.
• a further disadvantage of triglyceride-containing compositions is the dependence of the therapeutic agent absorption on the rate and extent of lipolysis (e.g. see WO 9524893 and WO 9740823).
• solubilizers of particular utility for hydrophobic active agents are described in U.S. Patent Application No. 09/716,029 to Chen et al.
• the vitamin E substances disclosed therein include fatty acid esters of glycerol, such as mono-, di-, and triglycerides and acetylated mono- and diglycerides, and mixtures thereof, fatty acid esters of propylene glycol, such as mono- and di-fatty acid esters of glycerol and mixtures thereof, trialkyl citrate, glyceryl acetate and lower alcohol fatty acid esters.
• WO 01/49262; U.S. Patent No. 6,458,373; and U.S. Patent No. 6,193,985 disclose the use of solubilizers that require high levels of hydrophilic surfactants, high shear, or high temperature homogenization to disperse the solubilizers sufficiently to form even a coarse dispersion in an adequate medium. Formation of a fine dispersion, which would make an effective carrier for oral delivery of the active agent, is often difficult or impossible to achieve.
• compositions for the delivery of therapeutic levels of active agents that overcome the solubility, physical stability, and absorption limitations of conventional approaches using micronization, emulsification, or solubilization.
• a pharmaceutical composition comprising a therapeutically effective amount of an active agent, a vitamin E substance and a surfactant, wherein upon dilution of the composition, the active agent increases the extent of dispersion of the vitamin E substance by at least 20% relative to the dispersion of the composition without the active agent.
• a pharmaceutical composition comprising a therapeutically effective amount of an active agent, a vitamin E substance and a surfactant, wherein after a 100X dilution of the composition in an aqueous medium, at least 30% of the active agent or the vitamin E substance is dispersed in an aqueous phase.
• the present invention also encompasses methods of improving the bioavailability of active agents, and steroids in particular, in patients through the administration of the claimed pharmaceutical compositions in suitable dosage forms.
• the present invention overcomes the problems associated with the conventional approaches for preparing formulations containing hydrophobic active agents by providing unique pharmaceutical compositions comprising a therapeutically effective amount of an active agent, a solubilizer and, optionally, a dispersing aid, that are more readily dispersed upon mixing with an aqueous medium than those which would be obtained without the particular combination of solubilizer and active agent.
• the present inventors have found that with a composition of an active agent, such as a steroid or benzoquinone; a solubilizer, such as a vitamin E substance; and a dispersion aid, such as a surfactant, a synergistic combination results wherein upon dilution in aqueous media at an appropriate dilution factor the dispersion of both the active agent and the solubilizer is improved and thus the active agent is solubilized in the aqueous environment in a readily absorbable form.
• a synergistic combination of an appropriate active agent and solubilizer is observed, such that the presence of the active agent improves the dispersion of the solubilizer (i.e.
• the term "dispersion” is used to refer to the extent to which the composition, in particular the active agent and the solubilizer, are uniformly distributed in the aqueous phase after dilution in an aqueous medium, such as water, simulated gastric fluid, or simulated intestinal fluid, i general, it is expected that aqueous dispersion of the active agent is critical for oral absorption.
• the extent of dispersion of the composition can be indirectly measured by diluting the composition in an aqueous medium at a selected dilution factor, preferably 10X to 1000X, most preferably 100X; gently mixing the dilution for a physiologically realistic duration, sampling from the aqueous phase; and assaying for either active agent or the solubilizer.
• the extent of dispersion is then defined as the fraction of the total drug or solubilizer which is distributed in the aqueous phase and thus readily available for absorption.
• the undispersed fraction is the fraction of the total drug or solubilizer would then typically be present in separate oil or solid layers and non-uniformly distributed large globules, or large aggregates of particulates which would be then unavailable for absorption.
• the characteristics of the dispersion can be further assessed by separating out larger particles or globules by filtration or centrifugation, then assaying for either the active agent or the solubilizer (e.g. vitamin E) or both in the filtrate or supernatant.
• the active agent or the solubilizer e.g. vitamin E
• the composition forms a "fine dispersion" in which the composition is dispersed such that at least 30% of the active agent or vitamin E substance solubilizer is in particles which will pass through a filter with 0.45 ⁇ nominal pore size.
• aqueous dispersion of the active agent is critical for absorption and that the more finely dispersed the active agent is, the more effectively it will be absorbed.
• Other techniques for characterizing the effectiveness of the dispersion may also be used, such as filtration of the aqueous dispersion with varying nominal pore size and demonstrating an increase in the fraction of active agent or solubilizer in the filtrate of any given size, or centrifugation to demonstrate an increase in the fraction of active agent or solubilizer in aqueous layer.
• a similar comparison may be made based on measuring the volume-weighted particle size distribution by photon correlation spectroscopy (dynamic laser light scattering) and showing an increase in the fraction of particles with particle diameter below a certain threshold, a decrease in the fraction of particles with diameter above a certain threshold, or a reduction in the volume-weighted mean particle size.
• an increase in the effectiveness of the dispersion may be shown by a reduction in the absorbance of light by an aqueous dilution at visual wavelengths (e.g. 400 nm).
• a pharmaceutical composition comprising a therapeutically effective amount of an active agent, a vitamin E substance and a surfactant, wherein upon dilution of the composition, the active agent increases the extent of dispersion of the vitamin E substance by at least 20% relative to the dispersion of the composition without the active agent.
• a pharmaceutical composition comprising a therapeutically effective amount of an active agent, a vitamin E substance and a surfactant, wherein after a 100X dilution of the composition in an aqueous medium, at least 30% of the active agent or the vitamin E substance is dispersed in an aqueous phase.
• a pharmaceutical composition comprising a therapeutically effective amount of an active agent, a solubilizer and, optionally, a dispersing aid, wherein the amount of active agent improves the dispersion of the solubilizer over that which would be achieved with the same solubilizer without the active agent upon contact with an aqueous medium.
• a pharmaceutical composition comprising a therapeutically effective amount of an active agent, a solubilizer and a dispersing aid, wherein the solubilizer is present in an amount such that more of the active agent is dispersed in aqueous medium than that which would be achieved with the same active agent and dispersing aid without the solubilizer.
• a pharmaceutical composition comprising a therapeutically effective amount of an active agent, a solubilizer and a dispersing aid, wherein the active agent is present in an amount such that at least 30% of the active agent and/or the solubilizer present in the composition is dispersed upon dilution with an aqueous medium.
• a pharmaceutical composition comprising a therapeutically effective amount of an active agent, a solubilizer and a dispersing aid, wherein the active agent and the solubilizer are present in amounts such that the composition forms a more effective aqueous dispersion than that which would be achieved without the active agent.
• the improvement of the dispersion of either the active agent or the solubilizer or the improvement in the effectiveness of the dispersion is on the order of at least 20%, preferably at least 30%, more preferably at least
• the dispersion of the active agent or the solubilizer is at least 30%, with a dispersion of at least 50% preferred, a fine dispersion of at least 30%) more preferred, and a fine dispersion of at least 50% most preferred.
• a pharmaceutical composition comprising a therapeutically effective amount of an active agent, a solubilizer, and optionally, a dispersing aid, wherein the active agent is present in an amount of from about 0.1 to 30 %> w/w of the composition; the solubilizer in the composition is present in an amount of from about 1 to 99 % w/w of the composition; and the dispersing aid is present in an amount from about 1 to 99%> of the composition
• the concentrations of each of the active agent, solubilizer, and surfactant of the claimed pharmaceutical composition will have the following ranges: active agent from 0.01% to 30% w/w; solubilizer (vitamin E substance) from 1-95% w/w; and surfactant from 5-85% w/w.
• concentrations of some exemplary steroids are provided as follows: progesterone - 1-300 mg/dosage form (0.1 %> to 30%> w/w); testosterone - 10 mg to 300 mg/dosage form ( at least 1% w/w); and DHEA - 50 to 300 mg/dosage form (at least 5%> w/w).
• Tables 1-2, 2-2, 3-2, 4-2, 5-2, 6-3, 7-2, 8-3 and 9-2 from Examples 1-9 show that the synergy between the active agents and the vitamin E substances results in a pharmaceutical composition with a very high percent of dispersion of the active agent and/or the vitamin E substance solubilizer.
• Table 1-2 shows that as the concentration of active agent is increased from 0% to 15%, the dispersion of both the active agent and the vitamin E substance increase.
• Table 8-3 also shows that the careful selection of a solvent or cosolubilizer may further increase the dispersion of the composition.
• Examples 10-25 set forth exemplary compounds that fall within the scope of the pharmaceutical compositions of the present invention.
• the active agent of the present invention is characterized by the fact that it is solubilized in aqueous dispersion by the solubilizer and has a synergistic role in improving the dispersibihty of the solubilizer (and consequently of the active agent itself) upon dilution in aqueous media.
• the active agent can be said to "improve" the dispersibihty of the solubilizer if it is present at levels such that at the selected dilution factor it increases the extent of dispersion of the solubilizer by at least about 20% relative to the same composition without the active agent.
• a pharmaceutical composition comprising a therapeutically effective amount of an active agent, a solubilizer and, optionally, a dispersing aid, wherein upon dilution of the composition, the active agent is present in an amount to increase dispersion of the solubilizer by at least 20% more than that which would be achieved with the same composition without the active agent.
• the active agent is present such that after a 100X dilution of the composition the active agent is at least 30% dispersed in the aqueous phase, with an active agent dispersion of at least 50% being preferred. More preferably, the active agent is present such that as least 30% of the drug is in fine dispersion. Most preferably the active agent is present such that at least 50% of the drug is in a fine dispersion.
• Steroids are compounds based on the cyclopenta[ ⁇ ]phenanthrene structure.
• Examples of steroids which have been shown to be suitable for the current invention include those with the androstane structure.
• Examples of such androstane steroids include cetadiol, clostebol, danazol, dehydroepiandrosterone (DHEA) (also, prasterone or dehydroisoandrosterone), DHEA sulfate, dianabol, dutasteride, exemestane, finasteride, nerobol, oxymetholone, stanolone, stanozolol, testosterone, 17-alpha-methyltestosterone, and methyltestosterone enanthate.
• DHEA dehydroepiandrosterone
• steroids which have been shown to be suitable, are those based on the cholane or cholesterol structure.
• steroids are brassicasterol, campesterol, chenodeoxycholic acid, clionasterol, desmosterol, lanosterol, poriferasterol, ⁇ - sitosterol, stigmasterol, and ursodeoxycholic acid.
• Another suitable class of steroids for use in the present invention are those steroids based on the estrane structure.
• estranes include desogestrel, equilin,
• estradiol ethinyl estradiol, estriol, estrone, levonorgestrel, lynestrenol, mestranol, mibolerone, mifegyne, mifepristone, nandrolone, norethindrone (or norethistrone), norethindrone acetate (or norethisterone acetate), nortestosterone.
• steroid class based on the pregnane structure.
• pregnanes include alfaxalone, beclomethasone, budesonide, clobetasol, clobetasone, corticosterone, desoxycorticosterone, cortisol, cortisone, dihydrocortisone, cyproterone, desonide, dexamethasone, eplerenone, epoxypregnenolone, flumethasone, megestrol, melengestrol, prednisolone, prednisone, pregnanediol, pregnanolone, pregnenolone, allopregnanolone, epiallopregnanolone, progesterone, medroxyprogesterone, spironolactone, and tibolone.
• steroids suitable for the present invention are not limited to those disclosed herein and include any secondary steroids, such as for example, vitamin D.
• Steroid esters such as the acetate, benzoate, cypionate, decanoate, enanthate, hemisuccinate, hexahydrobenzoate, 4-methylvalerate, propionate, stearate, valerate, and undecanoate esters would also be suitable for the present invention.
• Suitable benzoquinones include ubiquinones, such as coenzyme
• Examples of other active agents which may be suitable for this invention include, without limitation: abecarnil, acamprostate, acavir, acebutolol, aceclofenac, acemetacin, acetaminophen, acetaminosalol, acetanilide, acetohexamide, acetophenazine maleate, acetophenazine, acetoxolone, acetoxypregnenolone, acetretin, acrisorcin, acrivastine, acyclovir, adinazolam, adiphenine hydrochloride, adrafinil, adrenolone, agatroban, ahnitrine, akatinol, alatrofloxacin, albendazole, albuterol, aldioxa, alendronate, alfentanil, alibendol, alitretinoin, all
• a pharmaceutical composition comprising a therapeutically effective amount of an active agent, a solubilizer and a dispersing aid.
• the solubilizer is present in an amount such that more of the active agent is dispersed in aqueous medium than that which would be achieved with the same active agent and dispersing aid without the solubilizer.
• the active agent and the solubilizer act synergistically to improve the dispersibihty of the solubilizer itself and the active agent upon dilution in an aqueous media, thus greatly increasing the amount of active agent which can be dispersed in a readily absorbably form.
• the solubilizer is present such that after a
• the active agent and/or the solubilizer is at least 30% dispersed in the aqueous phase, with a dispersion of at least 50%> being preferred. It is more preferred that the solubilizer, like the active agent is at least 30% finely dispersed in the aqueous phase, with a fine dispersion of at least 50% being most preferred.
• the preferred solubilizer of the present invention is a "vitamin E substance,” which includes substances with the tocol structure [2-methyl-2-(4,8,12 ⁇ trimethyltridecyl)chroman-6-ol] or the tocotrienol structure [2-methyl-2-(4,8,12-trimethyltrideca-
• vitamin E substances include the mono-, di-, trimethyl- tocol derivatives, commonly known as tocopherols, such as ⁇ -tocopherol [5,7,8-trimethyl-], ⁇ -tocopherol [5,8-dimethyl-], ⁇ -tocopherol
• tocotrienols such as ⁇ -tocotrienol (or ⁇ i-tocopherol) [5,7,8-trimethyl-], ⁇ -tocotrienol (or ⁇ - tocopherol) [5,8-dimethyl-], ⁇ -tocotrienol [7,8-dimethyl], and ⁇ -tocotrienol [8-methyl-].
• vitamin E substances for use in the present invention include tocopherols, tocotrienols and tocopherol derivatives with organic acids such as acetic acid, propionic acid, bile acid, lactic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, polyethylene glycol succinate and salicylic acid.
• Particularly preferred vitamin E substances include alpha-tocopherol, alpha- tocopherol acetate, alpha-tocopherol acid succinate, alpha-tocopherol polyethylene glycol succinate and mixtures thereof.
• Preferred solubilizers that are not vitamin E substances for use in the present invention include fatty acid esters of glycerol, acetylated mono- and diglycerides, fatty acid esters of propylene glycol, trialkyl citrate, glycerol acetate, and lower alcohol fatty acid esters.
• the surfactant in the present invention may be any compound containing polar or charged hydrophilic moieties as well as non-polar hydrophobic (lipophilic) moieties; i.e. a surfactant compound must be amphiphilic.
• the hydrophilic surfactant can be any hydrophilic surfactant suitable for use in pharmaceutical compositions. Such surfactants can be anionic, cationic, zwitterionic or non-ionic. Mixtures of hydrophilic surfactants are also within the scope of the invention.
• the hydrophobic surfactant can be any hydrophobic surfactant suitable for use in pharmaceutical compositions.
• hydrophobic surfactants are also within the scope of the invention.
• suitable hydrophilic surfactants will have an HLB value greater than about 10 and suitable hydrophobic surfactants will have an HLB value less than about 10.
• the choice of specific hydrophobic and hydrophilic surfactants should be made keeping in mind the particular hydrophobic therapeutic agent to be used in the composition, and the range of polarity appropriate for the chosen therapeutic agent. With these general principles in mind, a very broad range of surfactants is suitable for use in the present invention.
• surfactants examples include polyethoxylated fatty acids such as PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG- 10 laurate,
• PEG-32 dilaurate and PEG-32 dioleate PEG-fatty acid mono- and di-ester mixtures; polyethylene glycol glycerol fatty acid esters such as PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate; alcohol - oil transesterification products such as PEG-35 castor oil (Lncrocas-35), PEG-40 hydrogenated castor oil (Cremophor® RH40), polyoxyl 35 castor oil (Cremophor EL), PEG-25 trioleate
• PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil (Emalex C-50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8 caprylic/capric glycerides (Labrasol®), and
• PEG-6 caprylic/capric glycerides Softigen® 767
• transesterification products of oils and alcohols polyglycerized fatty acids such as polyglyceryl oleate (Plurol® Oleique), polyglyceryl-
• polyglyceryl-10 trioleate examples include polyglyceryl-10 laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn
• polyglyceryl-10 mono, dioleate Caprol® PEG 860
• propylene glycol fatty acid esters such as propylene glycol monolaurate (Lauroglycol FCC), propylene glycol ricinoleate
• propymuls propylene glycol monooleate (Myverol® P-06), propylene glycol dicaprylate/dicaprate (Captex® 200), and propylene glycol dioctanoate (Captex 800); mixtures of propylene glycol esters and glycerol esters such as a mixture of oleic acid esters of propylene glycol and glycerol (Arlacel 186); mono- and diglycerides such as glyceryl monooleate (Peceol), glyceryl ricinoleate, glyceryl laurate, glyceryl dilaurate (Capmul® GDL), glyceryl dioleate
• Capmul GDO glyceryl mono/dioleate
• Capmul GMO-K glyceryl caprylate/caprate
• MCM caprylic acid mono/diglycerides
• Myvacet® 9-45 mono- and diacetylated monoglycerides
• sterol and sterol derivatives such as PEG-24 cholesterol ether
• Solulan® C-24 polyethylene glycol sorbitan fatty acid esters such as PEG-20 sorbitan monolaurate (Tween® 20), PEG-20 sorbitan monopalmitate (Tween 40), PEG-20 sorbitan monostearate (Tween 60), and PEG-20 sorbitan monooleate (polysorbate 80 or Tween 80); polyethylene glycol alkyl ethers such as PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether
• sorbitan fatty acid esters such as sorbitan monolaurate
• lower alcohol fatty acid esters such as hydrophobic surfactants include ethyl oleate (Crodamol EO), isopropyl myristate (Crodamol IPM), and isopropyl palmitate (Crodamol JPP); ionic surfactants such as sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate, lauroyl carnitine, palmitoyl carnitine, and myristoyl carnitine; unionized ionizable surfactants such as free fatty acid, particularly C 6 -C 22 fatty acids, and bile acids.
• PEG-400 succinate PEG 3350, tocopherol polyethyleneglycol (200-8000 MW) succinate, tocopherol polyethylene glycol 400 succinate, tocopherol polyethyleneglycol 1000 succinate
• solubilizer may be used.
• ethanol may be used in conjunction with Cremophor to improve the solubility of active agent.
• Preferred surfactants for use with particular active agents are illustrated in the Examples.
• compositions of the present invention may also include one or more additional components, i.e., additives.
• additives include, but are not limited to, solvents, absorbents, acids, adjuvants, anticaking agent, glidants, antitacking agents, antifoamers, anticoagulants, antimicrobials, antioxidants, antiphlogistics, astringents, antiseptics, bases, binders, chelating agents, sequestrants, coagulants, coating agents, colorants, dyes, pigments, compatiblizers, complexing agents, softeners, crystal growth regulators, denaturants, dessicants, drying agents, dehydrating agents, diluents, dispersants, emollients, emulsifiers, encapsulants, enzymes, fillers, extenders, flavor masking agents, flavorants, fragrances, gelling agents, hardeners, stiffening agents, hum
• the pharmaceutical composition of the present invention can be prepared by mixing the active agent, the solubilizer, the surfactant, and optional additives according to methods well known in the art.
• the active agent, the solubilizer, and the surfactant may be prepared in separate dosage forms or separated within one dosage form to form a dispersion in situ upon administration and dissolution in the aqueous environment of the gastrointestinal tract.
• the claimed pharmaceutical compositions can be further processed according to conventional methods known to those skilled in the art, such as lyophilization, encapsulation, compression, melting, extrusion, balling, drying, chilling, molding, spraying, spray congealing, coating, comminution, mixing, homogenization, sonication, cryopelletization, spheronization and granulation to produce the desired dosage form.
• Excess solvent added to facilitate incorporation of the active agent and/or mixing of the formulation components, can be removed before administration of the pharmaceutical dosage form.
• compositions in liquid, semi- solid or paste form can be filled into hard gelatin or soft gelatin capsules using appropriate filling machines.
• the composition can also be extruded, merumerized, sprayed, granulated or coated onto a substrate to become a powder, granule or bead that can be further encapsulated or tableted with or without the addition of appropriate solidifying or binding agents.
• This approach also allows for the creation of a "fused mixture,” a "solid solution” or a "eutectic mixture.”
• the dosage forms of the present invention are not limited with respect to size, shape or general configuration, and may comprise, for example, a capsule, a tablet or a caplet, or a plurality of granules, beads, powders, or pellets that may or may not be encapsulated, hi addition, the dosage form may be a drink or beverage solution or a spray solution that is administered orally.
• the drink or beverage solution may be formed by adding a therapeutically effective amount of the composition in, for example, a powder or liquid form, to a suitable beverage, e.g., water or juice.
• compositions and dosage forms of the current invention may be immediate release, releasing the active agent and/or excipients in an uncontrolled fashion, or may be controlled release. Included in the term "controlled release” are dosage forms or compositions which release the drug and/or excipients with various release profiles such as extended or sustained release, delayed release, pulsitile release, or combinations of the above such as multistage release achieved by a combination of delayed release compositions with variable delay times.
• the pharmaceutical compositions and dosage forms have utility in the treatment of patients that may benefit from the therapeutic administration of hydrophobic drugs.
• Such therapies include, for example, steroid therapy or hormone therapy.
• Patients suffering from any condition, disease or disorder that can be effectively treated with any of the active agents disclosed herein can benefit from the administration of a therapeutically effective amount of the pharmaceutical compositions and dosage forms described herein.
• An advantage of the claimed pharmaceutical composition is improvement in the oral absorption and bioavailability of the active agent thereby ensuring that the patient will in fact benefit from the prescribed therapy.
• the improved bioavailability of the active agent is a result of the improved dispersion of the active agent in the claimed pharmaceutical composition.
• solubility of drug substances in the compositions was determined using conventional techniques. For example, solubility was in some cases determined gravimetrically by incrementally adding drug until the composition could no longer solubilize additional added drug. Solubility could also be determined by equilibration of the composition with excess drug during gentle mixing at a controlled temperature (25 ⁇ 0.5°C), centrifugation of the resulting mixture (15 min at 15,000*g; Beckmann Microfuge Lite), and assay of the clear supernatant.
• the dispersibihty of the composition was determined by diluting the composition in an aqueous medium such as water, simulated gastric fluid, or simulated intestinal fluid, at a selected dilution factor, preferably 10X to 1000X, most preferably 100X.
• the dilution was then gently mixed, for example with a rotator at 10 rpm, at an appropriate controlled temperature (typically 37°C).
• a selected duration typically 1 hour, but any physiologically realistic duration could be appropriate
• the aqueous phase was sampled, taking care not to include undispersed oil globules, or non-uniformly dispersed particulates.
• the aqueous phase was filtered through Nylon or Tuffryn ® membrane filters with the appropriate nominal pore size (Whatman or Gelman). In all cases, the initial 1-3 ml of filtrate were discarded, and the absence of significant filter absorption was confirmed by filtration of standard solutions of known active agent or vitamin E substance concentration in the appropriate matrix, collection of the filtrate, and assay of the filtrate to confirm that there was no change in drug concentration. Other techniques to characterize the extent of dispersion could also be used, such as centrifugation to separate larger particles from the uniform aqueous dispersion.
• Assay for vitamin E substance content in most cases was by UN spectrophotometry with quantification at a wavelength of 291 nm for tocopherol and 285 nm for tocopherol acetate tocopherol succinate, and tocopherol polyethyleneglycol succinate. Samples were diluted 100X in methanol, then scanned in a quartz cuvette using an Agilent 8453 UV/Vis
• Spectrophotometer Calibration was by linear regression of absorbance at the indicated wavelengths with standards of the relevant Vitamin E substance of known concentration.
• assay for Vitamin E substances was by reversed phase HPLC using a Symmetry C18 3.6 X 150 mm column, 5 ⁇ , with a mobile phase of Methanol 98/2%v/v and detection at 285 nm.
• Assay of the active agents was by reversed-phase HPLC with the column indicated above, a mobile phase of acetonitrile/water 63/57%v/v, and detection at 204 nm.
• Particle size of aqueous dispersions was determined using a ⁇ icomp 380 ZLS laser-scattering particle sizer (Particle Sizing Systems), with a He- ⁇ e laser at 632.8 nm, fixed
• This example shows the solubilization and dispersion behavior of a composition including a pregnane steroid, progesterone, a vitamin E substance (dl-alpha-tocopherol, Spectrum Chemicals) and a surfactant (polyoxyl 35 castor oil USP/ ⁇ F, Cremophor EL, BASF).
• a pregnane steroid a pregnane steroid
• progesterone a vitamin E substance
• a vitamin E substance dl-alpha-tocopherol, Spectrum Chemicals
• a surfactant polyoxyl 35 castor oil USP/ ⁇ F, Cremophor EL, BASF
• compositions were dispersed in simulated gastric fluid without enzyme (USP).
• the improved dispersibihty is also shown by the increase in the fraction of the solubilizer dispersed as a fine dispersion, increasing from 14% without drug to
• EXAMPLE 2 shows the solubilization and dispersion of a pregnane steroid, progesterone, in compositions consisting of vitamin E substances (dl-alpha-tocopherol, Spectrum Chemicals; or d-alpha-tocopherol, Archer Daniels Midland Company), a surfactant (polyoxyl 35 castor oil USP/NF, Cremophor EL, BASF), and a low-molecular weight alcohol (dehydrated alcohol, USP/NF, Quantum).
• vitamin E substances dl-alpha-tocopherol, Spectrum Chemicals; or d-alpha-tocopherol, Archer Daniels Midland Company
• a surfactant polyoxyl 35 castor oil USP/NF, Cremophor EL, BASF
• a low-molecular weight alcohol dehydrated alcohol, USP/NF, Quantum
• compositions were dispersed in simulated gastric fluid without enzyme (USP).
• compositions shown in the tables below were prepared by combining the components and mixing gently at room temperature. The corresponding placeboes (without drug) are described in Example 2, compositions 2-1 and 2-3.
• compositions were dispersed in simulated gastric fluid without enzyme (USP
• E/surfactant compositions for additional model steroids an androstane steroid, finasteride; and a cholane steroid, ursodiol.
• the compositions shown in the tables below were prepared by combining the components and mixing gently at room temperature.
• compositions were dispersed in simulated gastric fluid without enzyme (USP
• EXAMPLE 5 shows the solubilization and dispersion of progesterone in compositions containing two different tocopherol esters (d-alpha-tocopherol acetate and d-alpha- tocopherol succinate, Archer Daniels Midland Company).
• the compositions shown in the tables below were prepared by combining the components and mixing gently at room temperature.
• compositions were dispersed in simulated gastric fluid without enzyme (USP
• EXAMPLE 6 shows the effect of solubilization and dispersion of progesterone in compositions with varying surfactants and surfactant levels.
• the vitamin E substances are d- alpha tocopherol or d-alpha tocopherol acetate (both from Archer Daniels Midland) with the following surfactants: polyoxyl 35 castor oil (Cremophor EL, BASF); caprylocaproyl macrogolglycerides (Labrasol, Gattefosse); polysorbate 80 (Tween 80, ICI), medium chain monoglycerides (Capmul MCM, Abitec), and tocopherol polyethyleneglycol 1000 succinate (Vitamin E-TPGS, Eastman).
• the compositions shown in the tables below were prepared by combining the components and mixing gently at room temperature.
• compositions were dispersed in simulated gastric fluid without enzyme (USP
• compositions were dispersed in simulated gastric fluid without enzyme (USP).
• EXAMPLE 8 shows the effect of solubilization and dispersion of progesterone in a compositions consisting of a vitamin E substance (d-alpha-tocopherol), a surfactant (polyoxyl 35 castor oil USP/NF) and various hydrophilic and hydrophobic solvents (ethanol, triethyl citrate; glycerol triacetate (triacetin)).
• a vitamin E substance d-alpha-tocopherol
• a surfactant polyoxyl 35 castor oil USP/NF
• various hydrophilic and hydrophobic solvents ethanol, triethyl citrate; glycerol triacetate (triacetin)
• compositions were dispersed in simulated gastric fluid without enzyme (USP).
• EXAMPLE 9 shows the solubilization and dispersion of a water insoluble benzoquinone, Coenzyme Q 10, in a composition consisting of a vitamin E substance (dl-alpha- tocopherol, BASF), and surfactant (Cremophor EL, BASF). Results are shown in Table 9-1. The corresponding composition without drug is in Example 1, Composition 1-1.
• compositions were dispersed in simulated gastric fluid without enzyme (USP

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