WO2003106382A2 - Phases cristallines liquides inversees comprenant des agents hydrophobes paraffiniques - Google Patents

Phases cristallines liquides inversees comprenant des agents hydrophobes paraffiniques Download PDF

Info

Publication number
WO2003106382A2
WO2003106382A2 PCT/US2003/018457 US0318457W WO03106382A2 WO 2003106382 A2 WO2003106382 A2 WO 2003106382A2 US 0318457 W US0318457 W US 0318457W WO 03106382 A2 WO03106382 A2 WO 03106382A2
Authority
WO
WIPO (PCT)
Prior art keywords
reversed
composition
surfactant
oil
compound
Prior art date
Application number
PCT/US2003/018457
Other languages
English (en)
Other versions
WO2003106382A3 (fr
Inventor
David M. Anderson
Original Assignee
Lyotropic Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lyotropic Therapeutics, Inc. filed Critical Lyotropic Therapeutics, Inc.
Priority to CA002488701A priority Critical patent/CA2488701A1/fr
Priority to EP03760279A priority patent/EP1539099A4/fr
Priority to AU2003243509A priority patent/AU2003243509B2/en
Priority to JP2004513218A priority patent/JP2005532366A/ja
Publication of WO2003106382A2 publication Critical patent/WO2003106382A2/fr
Publication of WO2003106382A3 publication Critical patent/WO2003106382A3/fr

Links

Classifications

    • 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 solubilization of compounds which are difficult to solubilize. i particular, the invention provides compositions, liquid crystalline solvent systems and methods for solubilizing such compounds. The invention also relates to the enhanced delivery of compounds through biomembrane absorption barriers, such as those found in cells, tissues, and organs.
  • solubilization of such compounds is made challenging by the very limited selection of solvents and structured liquids that are approved for injection at levels that would be required to solubilize the drug.
  • water-miscible liquid excipients most notably ethanol, are of limited value since, even when the drug is soluble in neat ethanol, it will often precipitate upon contact with water, either diluent water for injection or in the aqueous milieu of body fluids, such as blood.
  • Nanostructured liquid crystalline phases of the reversed type namely reversed cubic and reversed hexagonal phases
  • a number of techniques have been developed for encapsulating such phases. See, for example, U.S. Patent 6,482,571 to Anderson which is herein incorporated by reference.
  • Phosphatidylcholine suffers from two drawbacks in the present context: first, when combined with only water it does not form cubic phases at or near room temperature or body temperature, and second, its curvature properties limit its ability to promote the uptake of liquid crystalline particles containing the lipid, as discussed herein. Phosphatidylethanolamine, in contrast, does induce strong curvature in lipid bilayers containing the lipid, and thus can promote fusion between biomembranes and liquid crystalline particles containing the lipids (see below); however, PE is regarded as too toxic for general use in injectable or intraperitoneal products and is not even approved for use in orally-administered formulations.
  • each of these surfactants suffer from fundamental limitations from the point of view of drug-delivery, particularly when the approach to using them is limited to binary (or pseudobinary) matrices, and thus there is clearly a need for a larger stable of liquid crystalline phases employing other surfactants and lipids.
  • Matrices based on lamellar phases, such as liposomes can be of very low solubility, but generally rely on processes such as endocytosis or pinocytosis for interacting with cells, which are not only slow and inefficient but can result in an intact matrix trapped inside an endosome. Furthermore, the solubilization of difficultly-soluble pharmaceutical actives in liposomes has not met with great success.
  • Reversed hexagonal phase compositions and to an even larger extent reversed cubic phase compositions, are difficult enough to come by even without the constraint that they be pharmaceutically acceptable and useful, and especially difficult under that constraint. For a number of reasons, considerable insight is required to know how and where to look for these phases. Reversed hexagonal phases, and to an even greater extent reversed cubic phases, usually are found only in small regions of phase diagrams (with the exception of cubic phases based on certain monoglycerides; however, these have distinct disadvantages as described above), making them hard to locate. Finding them usually requires insight and the mixing and analysis of a large number of samples.
  • the inventor has demonstrated the relationship between curvature properties of lipids and their tendency to promote porosity in bilayers, and their tendency to form reversed cubic and other reversed phases including L3 and reversed hexagonal phases. See Anderson D.M., Wennerstrom, H. and Olsson, U., J. Phys. Chem. 1989, 93:4532- 4542.
  • the tendency to induce or form porous microstructures is viewed in the present context as being advantageous with respect to drug-delivery, in that it promotes the integration of the adieri concludedred lipidic microparticles with biomembranes that otherwise form barriers to absorption, in contrast with lamellar lipidic structures such as liposomes which show low curvature, and little or no porosity, and do not ordinarily show strong tendencies to integrate with biomembranes.
  • compositions comprising a structured fluid and a compound (the active, typically a pharmaceutical or nutriceutical active) present in the structured fluid, the compound being otherwise of sufficiently low solubility in water that more than about 100 ml of water are required to dissolve a therapeutic amount of the compound.
  • the nanostructured fluid comprises a polar solvent, a surfactant, and a non-paraffinic liquid with a high octanol-water partition coefficient which does not qualify as a surfactant.
  • the structured fluid comprises a reversed cubic phase or reversed hexagonal phase, or a combination thereof, composed of pharmaceutically acceptable components.
  • compositions each comprising a structured fluid for the solubilization of compounds of low solubility in water, viz., wherein more than about 100 ml of water are required to dissolve a therapeutic amount of such compound.
  • the nanostructured fluid comprises a polar solvent, a surfactant, and a non-paraffinic liquid with a high octanol-water partition coefficient which does not qualify as a surfactant.
  • the structured fluid is a reversed cubic or reversed hexagonal liquid crystalline phase, or a combination thereof, composed of pharmaceutically acceptable components.
  • the invention further provides an internally administerable solvent system comprising a polar solvent, a surfactant, and a non-paraffinic liquid with a high octanol-water partition coefficient which does not qualify as a surfactant.
  • the structured fluid is a reversed cubic or reversed hexagonal liquid crystalline phase, or a combination thereof, composed of pharmaceutically acceptable components.
  • the invention further provides an internally administerable solvent system comprising a polar solvent, a surfactant, and a non-paraffinic liquid with a high octanol-water partition coefficient which does not qualify as a surfactant, and a pharmaceutical active solubilized in this fluid.
  • the structured fluid is a reversed cubic or reversed hexagonal liquid crystalline phase, or a combination thereof, composed of pharmaceutically acceptable components.
  • the present invention further provides a method for solubilizing a compound, the compound being otherwise of sufficiently low solubility in water that more than about 100 ml of water are required to dissolve a therapeutic amount of the compound in a nanostructured fluid.
  • the nanostructured fluid comprises a polar solvent, a surfactant, and a non-paraffinic liquid with a high octanol-water partition coefficient which does not qualify as a surfactant.
  • the structured fluid is a reversed cubic or reversed hexagonal liquid crystalline phase, or a combination thereof, composed of pharmaceutically acceptable components.
  • the method comprises the steps of combining the compound with a solvent system and allowing the compound to be incorporated into said solvent system.
  • the present invention provides compositions, solvent systems and methods which are useful for solubilizing compounds that are otherwise difficult to solubilize (i.e. they otherwise require more than about 100 ml of water to dissolve a therapeutic amount of the compound).
  • the compositions, solvent systems and methods of the present invention are based on the surprising discovery that certain combinations of polar solvent, surfactant, and non-paraffinic liquid yield reversed cubic and reversed hexagonal phases that are pharmaceutically acceptable, capable of solubilizing difficultly-soluble compounds, and have porous microstructures that are capable of promoting absorption in the body.
  • compositions of the embodiments given herein were found through a combination of insight and a great deal of laborious work making and characterizing samples.
  • the insight that was applied came from a combination of two decades of experience in mapping phase behavior of three-component surfactant systems, and mathematical modeling that has been reported in a number of the current author's publications. See DM Anderson, SM Gruner and S Leibler, Proc. Nat. Acad. Sci. 1988, 85:5364-5368; DM Anderson, JCC Nitsche, HT Davis and EL Scriven, Adv. Chem. Phys., 1990, 77:337-396; P Strom and DM Anderson, Langmuir, 1992, 8:691-702; DM Anderson, H Wennerstrom and U.
  • Dissolution Is meant that a compound under consideration is dissolving or is undergoing dissolution.
  • Solubilize Is meant to be essentially synonymous with the term “dissolve” or “dissolution”, though with a different connotation; a compound under consideration is solubilized in a liquid or liquid crystalline material if and only if the molecules of the compound are able to diffuse within the liquid or liquid crystalline material as individual molecules, and that such material with the compound in it make up a single thermodynamic phase.
  • Solubility of a surfactant There has been some confusion in the literature as to what is meant by the solubility of a surfactant, in particular when low-solubility surfactants (such as long-chain monoglycerides or phospholipids, to cite well-known examples) form liquid crystals at high concentrations.
  • low-solubility surfactants such as long-chain monoglycerides or phospholipids, to cite well-known examples
  • the solubility of a surfactant in water is determined by the phase behavior that occurs when adding the surfactant to water: the first molecules of surfactant will go into solution, as required by thermodynamics (i.e., no surfactant has a solubility that is rigorously zero; the solubility is always a finite, non-zero value), but if a limit is reached beyond which a liquid crystalline phase splits out, then the solubility limit has been reached, and the solubility of the surfactant is this limiting value.
  • the solubility of glycerol monooleate is usually — and correctly, in accordance with this definition — given as of order 10 "13 M, despite the fact that it forms liquid crystalline phases in water at concentrations as high as 60%; indeed, a liquid crystalline phase forms with a composition of approximately 40% water and 60% monoolein as soon as the concentration of surfactant rises above the limiting concentration, or solubility, of 10 "13 M.
  • This low solubility fits intuitively with what is expected for a molecule such as monoolein, with its 18-carbon chain and relatively weak, uncharged polar head group.
  • a surfactant is said to be of low solubility in water, in this disclosure, if the solubility limit according to this definition is less than about 1% by weight.
  • Matrix In the present context, a "matrix” is meant to be a material that serves as the host material for an active compound or compounds.
  • the solubilizing properties of a matrix can be said to be "tunable” if the composition under consideration and/or structure of the matrix can be deliberately adjusted so as to substantially change the solubility of the active compound.
  • Difficultly-soluble In the present context, a compound (e.g., a pharmaceutical or nutritional active) can be said to be difficultly-soluble in water if a single therapeutic dose of the active requires more than about 100 ml of water or buffer to solubilize it; it can be said to be difficultly- soluble in oil if a single therapeutic dose of the active cannot be solubilized in less than about 10 ml of octanol; or if the compound is otherwise less than 5% by weight soluble in soybean oil.
  • octanol as one standard is based on its broad usage in connection with the octanol- water partition coefficient.
  • soybean oil is based on the broad usage of liquid triglycerides such as soybean oil, sesame oil, and peanut oil, in pharmaceutics and the fact that these liquid triglycerides all behave very similarly with respect to solubilization of actives.
  • Pharmaceutical active a compound or agent that exhibits biological activity, including nutritional, nutriceutical and/or pharmacological activity.
  • Excipients compound and mixtures of compounds that are used in pharmaceutical formulations that are not the active drugs themselves.
  • this listing includes, as approved for internal use (oral, injectable, intraperitoneal, etc.), such excipients as: benzyl benzoate, peppermint oil, orange oil, spearmint oil, ginger fluid extract (also known as essential oil of ginger), thymol, vanillin, anethole, cinnamon oil, cinnamaldehyde, clove oil, coriander oil, benzaldehyde, poloxamer 331 (Pluronic 101), polyoxyl 40 hydrogenated castor oil — indeed, a wide range of surfactants with polyethyleneglycol head groups — calcium chloride and docusate sodium.
  • excipients as: benzyl benzoate, peppermint oil, orange oil, spearmint oil, ginger fluid extract (also known as essential oil of ginger), thymol, vanillin, anethole, cinnamon oil, cinnamaldehyde, clove oil, coriander oil, benzaldehyde, poloxamer 331 (Plur
  • Absent from the list are a number of apolar or very weakly polar liquids that are more associated with applications as fuels or organic solvents: liquid hydrophobes including toluene, benzene, xylene, octane, decane, dodecane, and the like.
  • liquid hydrophobes including toluene, benzene, xylene, octane, decane, dodecane, and the like.
  • the hydrophobes and polar hydrophobes that are approved as excipients tend to be natural extracts which have a history of use in foods, nutriceuticals, or pharmaceutics — or early precursors to these disciplines.
  • Examples of compounds that are major components of approved excipients and known to be of low toxicity include: linalool, which is a major component of coriander oil and is the subject of extensive toxicity studies demonstrating its low toxicity; vanillin, which is a major component of the approved excipient 'flavor vanilla' and is one of the major taste components of vanilla- flavored foods and pharmaceutical formulations; and d-limonene, which is a major component of the approved excipient 'essence lemon' approved for use in oral formulations and has extensive everyday applications in which its low toxicity is important.
  • component we mean a molecule that is present as a distinct and individual molecule in a mixture, not as a chemical group in a larger molecule; for example, methanol (methyl alcohol) would not be considered to be a component of methyl stearate.
  • methanol methyl alcohol
  • liquids which have a greater value by far as the hydrophobe, for the obvious reason that liquids are far better solvents than solids (though this is not to say that solids are useless, since for example menthol (m.p. about 42°C) is soluble in many surfactant-water mixtures and can aid in the dissolution of many actives.
  • a compound will be considered to be a pharmaceutically-acceptable excipient if it can be created by a simple ion-exchange between two compounds that are on the FDA listing; thus, for example, calcium docusate is to be considered a pharmaceutically-acceptable excipient since it is a natural result of combining sodium docusate and calcium chloride (in the presence of water, for example).
  • Paraffinic, non-paraffinic a compound will be considered paraffinic in the context of this invention if and only if it contains an acyclic, uninterrupted saturated hydrocarbon chain segment at least 6 carbons in length, not counting any carbon atoms that are branched from this main chain. While the number 6 is to some extent arbitrary, it matches the criterion (cited below) given by Laughlin for the minimum chain length for self-association to occur; the shortest surfactant chains are 6 carbons in length discounting branches, as for example in sodium hexane sulfonic acid and in sodium 2-ethylhexyl sulfosuccinate (sodium docusate).
  • a compound is then considered non-paraffinic if it is free of such chain segments with length 6 or greater.
  • the presence of long, unsaturated hydrocarbon chains on a compound can still qualify the compound as paraffinic under this definition, if the unsaturation nonetheless leaves segments of saturated chain length greater than 6; for example, oleic acid would qualify as paraffinic because, although it contains a double bond at position 9, there is an uninterrupted segment of 8 carbons in a fully saturated configuration.
  • Amphiphile an amphiphile can be defined as a compound that contains both a hydrophilic and a lipophilic group. See D. H. Everett, Pure and Applied Chemistry, vol. 31, no. 6, p. 611, 1972. It is important to note that not every amphiphile is a surfactant. For example, butanol is an amphiphile, since the butyl group is lipophilic and the hydroxyl group hydrophilic, but it is not a surfactant since it does not satisfy the definition, given below. There exist a great many amphiphilic molecules possessing functional groups which are highly polar and hydrated to a measurable degree, yet which fail to display surfactant behavior. See R.
  • a surfactant is an amphiphile that possesses two additional properties. First, it significantly modifies the interfacial physics of the aqueous phase (at not only the air- water but also the oil-water and solid-water interfaces) at unusually low concentrations compared to non- surfactants. Second, surfactant molecules associate reversibly with each other (and with numerous other molecules) to a highly exaggerated degree to form thermodynamically stable, macroscopically one-phase, solutions of aggregates or micelles. Micelles are typically composed of many surfactant molecules (10's to 1000's) and possess colloidal dimensions. See R.
  • Lipids, and polar lipids in particular often are considered as surfactants for the purposes of discussion herein, although the term 'lipid' is normally used to indicate that they belong to a subclass of surfactants which have slightly different characteristics than compounds which are normally called surfactants in everyday discussion.
  • surfactants Two characteristics which frequently, though not always, are possessed by lipids are, first, they are often of biological origin, and second, they tend to be more soluble in oils and fats than in water.
  • lipids have extremely low solubilities in water, and thus the presence of a hydrophobic solvent may be necessary in order for the interfacial tension-reducing properties and reversible self-association to be most clearly evidenced, for lipids which are indeed surfactants.
  • a hydrophobic solvent may be necessary in order for the interfacial tension-reducing properties and reversible self-association to be most clearly evidenced, for lipids which are indeed surfactants.
  • such a compound will strongly reduce the interfacial tension between oil and water at low concentrations, even though extremely low solubility in water might make observation of surface tension reduction in the aqueous system difficult; similarly, the addition of a hydrophobic solvent to a lipid-water system might make the determination of self-association into nanostructured liquid phases and nanostructured liquid crystalline phases a much simpler matter, whereas difficulties associated with high temperatures might make this difficult in the lipid-water system.
  • any amphiphile which at very low concentrations lowers interfacial tensions between water and hydrophobe, whether the hydrophobe be air or oil, and which exhibits reversible self-association into nanostructured micellar, inverted micellar, or bicontinuous morphologies in water or oil or both, is a surfactant.
  • the class of lipids simply includes a subclass of surfactants which are of biological origin.
  • Lipid in the context of this invention, a lipid is considered to be a molecule formed by a hydrophilic moiety and a lipophilic moiety, the two linked together by bonds sufficiently flexible to yield a rather independent behavior. See Luzzati, in Biological Membranes, Chapter 3, page 72 (D. Chapman, ed. 1968).
  • the terms "lipid” and “surfactant” are utilized interchangeably herein.
  • Hydrophobe in the context of this invention, a compound is considered to be a hydrophobe if and only if it is a compound of high octanol-water partition coefficient — preferably about 10 greater or and more preferably about 100 or greater — and does not satisfy the definition of a surfactant given herein.
  • a compound can be a hydrophobe and still contain one or more polar groups, provided that the polar groups are not sufficiently dominant to yield true surfactant behavior.
  • a compound has a polar group that is operative as a surfactant head group according to Laughlin (see below), then this is not considered a lydrophobe in the present context.
  • sodium cholate is not a hydrophobe because it ;ontains a carboxylate ion, operative as a head group; indeed, sodium cholate is known to form surfactant microstructures such as micelles.
  • polar groups which are not operative as surfactant head groups — and thus, for example, an alkane chain linked to one of these polar groups would not be expected to form nanostructured liquid or liquid crystalline phases — are: aldehyde, ketone, carboxylic ester, carboxylic acid (in the free acid form), isocyanate, amide, acyl cyanoguanidine, acyl guanylurea, acyl biuret, N,N-dimethylamide, nitrosoalkane, nitroalkane, nitrate ester, nitrite ester, nitrone, nitrosamine, pyridine N-oxide, nitrile, isonitrile, amine borane, amine haloborane, sulfone, phosphine sulfide, arsine sulfide, sulfonamide, sulfonamide methylimine, alcohol (mono
  • Some polar groups which are operative as surfactant head groups, and thus, for example, an alkane chain linked to one of these polar groups would be expected to form nanostructured liquid and liquid crystalline phases, are: a. Anionics: carboxylate (soap), sulfate, sulfamate, sulfonate, thiosulfate, sulfinate, phosphate, phosphonate, phosphinate, nitroamide, tris(alkylsulfonyl)methide, xanthate; b. Cationics: ammonium, pyridinium, phosphonium, sulfonium, sulfoxonium; c.
  • Zwitterionics ammonio acetate, phosphoniopropane sulfonate, pyridinioethyl sulfate; d.
  • Semipolars amine oxide, phosphoryl, phosphine oxide, arsine oxide, sulfoxide, sulfoximine, sulfone diimine, ammonio amidate.
  • Laughlin also demonstrates that as a general rule, if the enthalpy of formation of a 1:1 association complex of a given polar group with phenol (a hydrogen bonding donor) is less than 5 kcal, then the polar group will not be operative as a surfactant head group.
  • a surfactant requires an apolar group, and again there are guidelines for an effective apolar group.
  • n is the number of carbons, then n must be at least 6 for surfactant association behavior to occur, although at least 8 or 10 is the usual case.
  • polybutadiene of very high MW is an elastomeric polymer at ambient temperature
  • block copolymers with polybutadiene blocks are well known to yield nanostructured liquid crystals.
  • hydrocarbon polymers such as polypropyleneoxide (PPO), which serves as the hydrophobic block in a number of amphiphihc block copolymer surfactants of great importance, such as the Pluronic series of surfactants.
  • Polar-apolar interface In a surfactant molecule, one can find a dividing point (or in some cases, 2 points, if there are polar groups at each end, or even more than two, as in Lipid A, which has seven acyl chains and thus seven dividing points per molecule) in the molecule that divide the polar part of the molecule from the apolar part.
  • the surfactant forms monolayer or bilayer films; in such a film, the locus of the dividing points of the molecules describes a surface that divides polar domains from apolar domains; this is called the "polar-apolar interface," or "polar-apolar dividing surface.”
  • polar-apolar interface or "polar-apolar dividing surface.”
  • this surface would be approximated by a sphere lying inside the outer surface of the micelle, with the polar groups of the surfactant molecules outside the surface and apolar chains inside it. Care should be taken not to confuse this microscopic interface with macroscopic interfaces, separating two bulk phases, that are seen by the naked eye.
  • Structured fluid Particularly useful mixtures from the point of view of microencapsulation and drug-delivery that occur in systems containing surfactant and polar solvents are structured fluids.
  • a structured fluid is taken to be a fluid that has structural features on a length scale much larger than atomic dimensions, in particular fluids such as nanostructured liquids, nanostructured liquid crystals, and emulsions. Examples include LI, L2 and L3 phases, lyotropic liquid crystalline phases, emulsions, and microemulsions.
  • Lyotropic liquid crystalline phases include the normal hexagonal, normal bicontinuous cubic, normal discrete cubic, lamellar, reversed hexagonal, reversed bicontinuous cubic, and reversed discrete cubic liquid crystalline phases, together with the less well-established normal and reversed intermediate liquid crystalline phases.
  • the nanostructured liquid crystalline phases are characterized by domain structures, composed of domains of at least a first type and a second type (and in some cases three or even more types of domains) having the following properties: a) the chemical moieties in the first type domains are incompatible with those in the second type domains (and in general, each pair of different domain types are mutually incompatible) such that they do not mix under the given conditions but rather remain as separate domains; (for example, the first type domains could be composed substantially of polar moieties such as water and lipid head groups, while the second type domains could be composed substantially of apolar moieties such as hydrocarbon chains; or, first type domains could be polystyrene-rich, while second type domains are poryisoprene-rich, and third type domains are 3olyvinylpyrrolidone-rich) ; b) the atomic ordering within each domain is liquid-like rather than solid-like, lacking attice-ordering of the atoms; (this would be evidence
  • Reversed hexagonal phase In surfactant-water systems, the identification of the reversed hexagonal phase differs from the above identification of the normal hexagonal phase in only two respects:
  • the viscosity of the reversed hexagonal phase is generally quite high, higher than a typical normal hexagonal phase, and approaching that of a reversed cubic phase.
  • the reversed hexagonal phase generally occurs at high surfactant concentrations in double-tailed surfactant / water systems, often extending to, or close to, 100% surfactant.
  • the reversed hexagonal phase region is adjacent to the lamellar phase region which occurs at lower surfactant concentration, although bicontinuous reversed cubic phases often occur in between.
  • the reversed hexagonal phase does appear, somewhat surprisingly, in a number of binary systems with single-tailed surfactants, such as those of many monoglycerides (include glycerol monooleate), and a number of nonionic PEG- based surfactants with low HLB.
  • Reversed cubic phase The reversed bicontinuous cubic phase is characterized by:
  • the identification of the reversed bicontinuous cubic phase differs from the above identification of the normal bicontinuous cubic phase in only one respect.
  • the reversed bicontinuous cubic phase is found between the lamellar phase and the reversed hexagonal phase, whereas the normal is found between the lamellar and normal hexagonal phases; one must therefore make reference to the discussion above for distinguishing normal hexagonal from reversed hexagonal.
  • a good rule is that if the cubic phase lies to higher water concentrations than the lamellar phase, then it is normal, whereas if it lies to higher surfactant concentrations than the lamellar then it is reversed.
  • the reversed cubic phase generally occurs at high surfactant concentrations in double-tailed surfactant / water systems, although this is often complicated by the fact that the reversed cubic phase may only be found in the presence of added hydrophobe ('oil') or amphiphile.
  • the reversed bicontinuous cubic phase does appear in a number of binary systems with single-tailed surfactants, such as those of many monoglycerides (include glycerol monooleate), and a number of nonionic PEG-based surfactants with low HLB.
  • a non-paraffinic hydrophobe must in fact be a hydrophobic compound (Kow>10, preferably >100) which is not a surfactant, i.e., in which any polar group on the molecule is on a par with the following groups listed by Laughlin as being not operative as a surfactant head group: aldehyde, ketone, carboxylic ester, carboxylic acid (in the free acid form), isocyanate, amide, acyl cyanoguanidine, acyl guanylurea, acyl biuret, N,N-dimethylamide, nitrosoalkane, nitroalkane, nitrate ester, nitrite ester, nitrone, nitrosamine, pyridine N-oxide, nitrile, isonitrile, amine borane, amine haloborane, sulfone, phosphine sulfide, ars
  • preferred groups for the polar group(s) are, given in approximate order from most preferred to less preferred: alcohol (monofunctional, including phenolic), carboxylic acid, aldehyde, amide, secondary amine, and tertiary amine.
  • alcohol monofunctional, including phenolic
  • carboxylic acid aldehyde
  • amide amide
  • secondary amine and tertiary amine.
  • tertiary amine tertiary amine
  • hydrophobe of the current invention there are a number of low-toxicity hydrophobic liquids with polar groups, many of which have a history of safe use in pharmaceutical and/or food products, that could be used. These include essential oils of plant origin, as well as a number of other liquids that are listed on FDA's list entitled Inactive Ingredients for Currently Marketed Drug Products and/or the appropriate sections of the Food Additives Status List.
  • benzyl benzoate cassia oil, castor oil, cyclomethicone, polypropylene glycol (of low MW), polysiloxane (of low MW), cognac oil (ethyl oenanthate), lemon balm, balsam of Peru, cardamom oleoresin, estragole, geraniol, geraniol acetate, menthyl acetate, eugenol, isoeugenol, petigrain oil, pine oil, rue oil, trifuran, annato extract, turmeric oleoresin, and paprika oleoresin.
  • Essential oils from plant sources comprise a rather large and chemically diverse group of liquids that include many low- toxicity hydrophobes with polar groups.
  • essential oils is intended to include essential oils from the following sources: allspice berry, amber essence, anise seed, arnica, balsam of Peru, basil, bay, bay leaf, bergamot, bois de rose (rosewood), cajeput, calendula (marigold pot), white camphor, caraway seed, cardamon, carrot seed, cedarwood, celery, german or hungarian chamomile, roman or english chamomile, cinnamon, citronella, clary sage, clovebud, coriander, cumin, cypress, eucalyptus, fennel, Siberian fir needle, frankincense (olibanum oil), garlic, rose geranium, ginger, grapefruit, hyssop, jasmine, jojoba, juniper
  • Especially preferred non-surfactant hydrophobes due to a favorable combination of good drug-solubilizing properties, low toxicity, low water solubility, useful temperature range as a liquid, history of use, and compatibilty with (or induction of) cubic phases, are: benzyl benzoate, estragole, eugenol, isoeugenol, linalool, and the following essential oils: balsam of Peru, basil, bay, bois de rose (rosewood), carrot seed, clovebud, eucalyptus, ginger, grapefruit, hyssop, lemon, mugwort, myrrh gum, bitter orange, oregano, palmarosa, patchouly, peppermint, petitgrain, rosemary, santalwood oil, spearmint, thuja (cedar leaf), thyme, vanilla, and ylang ylang (cananga).
  • Polar solvents employed in the practice of the present invention include but are not limited to: a. water; b. glycerol; c. ethylene glycol or propylene glycol; d. ethylammonium nitrate; e. one of the acetamide series: acetamide, N-methyl acetamide, or dimethylacetamide; f. low-molecular weight polyethylene glycol (PEG); g. a mixture of two or more of the above.
  • PEG low-molecular weight polyethylene glycol
  • Preferred polar solvents are water, glycerol, ethylene glycol, N-methylacetamide, dimethylacetamide, and polyethylene glycol, since these are considered of low toxicity.
  • PEGylated (ethoxylated) surfactants such as Arlatone and Pluronics
  • glycerol is generally not compatible. Advantages and unique properties.
  • cubic and hexagonal phases described herein have a number of unique properties, and significant advantages over cubic phases that have been described in the literature, particularly as relate to their potential application in drug-delivery, cosmeceutics, and nutriceuticals.
  • non-paraffinic hydrophobe particularly one containing at least one polar group
  • the ability of these cubic phases to solubilize difficultly-soluble drugs and actives is greatly improved.
  • most pharmaceutical compounds that are water-insoluble nevertheless contain at least one, usually several, and frequently four or more polar groups.
  • hydrophobe is of low molecular weight, about 500 or less, and especially if the MW is about 250 or less, so that it takes on more of a true "solventlike” nature, with entropic effects more strongly favoring dissolution of the hydrophobe in the bilayer, and the drug in the hydrophobe-lipid environment.
  • non-paraffinic hydrophobes in particular those that are more compact, such as aromatic compounds in particular (e.g., zingerone, a major component of ginger oil), or compounds such as carvone (a major component of oil of spearmint), which has a combination of low MW (150.2), unsaturation, branching, and polar groups.
  • hydrophobes that outperform all the other available hydrophobes in terms of solubilizing that active to a high loading
  • the available surfactants and lipids vary in their ability to tolerate the solubilizing effect of these hydrophobes (which often liquify what are otherwise liquid crystalline phases), and yield ternary liquid crystalline phases capable of solubilizing the active to a substantial loading.
  • This will vary from drug to drug, and call for a different liquid crystal composition as this varies. Beyond this are issues of enhancing absorption, toxicity, and compatibility with other features and processes in the overall formulation such as encapsulation with a particular coating, pH and ionic conditions, etc.
  • dantrolene For example, consider the structure of dantrolene. As one moves along the length of the molecular structure diagram of dantrolene, one finds: apolar group (nitro group), low-polarity group (aromatic ring), moderately-polar group (furanyl ring), polar group (methylamino), and finally a hydantoin group which is charged or uncharged depending on pH.
  • This compound has a solubility of approximately 150 mg/L in water, and even its sodium salt has a solubility on the order of 300 mg/L. Further, its solubility in simple phospholipid-water systems is also very low, too low to be of practical pharmaceutical importance. It is difficult to imagine a configuration of the drug in a lipid bilayer that would avoid direct contact between at least one of the polar groups with an acyl chain of the phospholipid.
  • paclitaxel is even more demonstrative of molecules that cannot be neatly divided into polar and apolar sections.
  • the molecule has 47 carbon atoms, includes 3 distinct aromatic rings, and has an exceedingly low solubility in water.
  • polar groups are present: one amide group, 3 hydroxyls, 4 ester bonds, another carbonyl group, and an cyclopropoxy ring.
  • Table 1 lists representative pharmaceutical compounds from some of the major therapeutic categories which are of low solubility in water, and tabulates the number of polar groups on the molecule.
  • the table demonstrates that many, if not most, water-insoluble drugs contain at least 3 polar groups, and would be expected to have low solubility in a simple lipid-water mixture.
  • the incorporation of a non-paraffinic hydrophobe in accordance with the present invention remedies this.
  • Examination of the chemical structure of each of these compounds furthermore reveals that the polar groups are spread througliout the molecule, so that only in rare cases would the molecule be able to situate itself in a simple (lipid-water) bilayer with an orientation analogous to that of a surfactant.
  • Table 2 also lists candidate pharmaceutical agents for use in the present invention.
  • the present invention provides for a range of lipid-based solubilization systems, and particularly liquid crystalline mixtures, and more particularly reversed hexagonal and reversed cubic phase mixtures, whose solubilization properties can be tuned over a broad range.
  • the property that is of importance in the solubilization of actives that have low solubilities in both water and simple lipid-water mixtures is recognized in the present invention to be the concentration and type of polar groups preferentially located in the lipid bilayer or at the polar-apolar interface.
  • a pharmaceutical active is taken to be of low water-solubility if a therapeutic dose of the active requires more than about 100 ml of water to solubilize it.
  • a pharmaceutical active is taken to be of low lipid- solubility if a therapeutic dose of the active requires more than about 10 ml octanol in order to solubilize it.
  • the choice of octanol is a natural one since it is the standard solvent in the definition of the important octanol-water partition coefficient, Kow
  • a compound is considered to be of low lipid-solubility if it is less than 5% by weight soluble in soybean oil.
  • non- paraffinic hydrophobes and approaches disclosed in herein can also serve another important role, that of providing a solubilizing matrix into which the pharmaceutically active compound partitions preferentially over water or body fluid (e.g., blood, etc.).
  • body fluid e.g., blood, etc.
  • certain drugs are not poorly water soluble, yet are more effective in certain situations when they are solubilized in a hydrophobic or amphiphilic environment, as opposed to solubilized in water.
  • solubilization in a more hydrophobic environment can yield sustained release, or targeted release by holding on to the drug until the matrix reaches the correct site or environment, and/or provide a protective milieu for the drug, or more generally provide a local microenvironment with more favorable chemical or physical properties for production, storage, or application.
  • the local anesthetic bupivicaine is solubilized — in its low-solubility, free base form — in a liquid crystal incorporating an essential oil as solubilizing agent, in spite of the fact that the more frequently used hydrochloride salt is water soluble (similar results should be achieved with other local anesthetics such as procaine, prilocaine, cocaine, and tetracaine).
  • This liquid crystal formulation with the free base form so solubilized provides an evironment into which the bupivicaine partitions strongly, since the value of Ko W is approximately 1500.
  • Certain compounds many of which are non-paraffinic liquids with high octanol- water partition coefficients which do not qualify as surfactants, and most of which in ton comprise at least one polar group that is not operative as a surfactant head group, have been found by the current inventor to induce reversed bicontinuous cubic phases in phosphatidylcholine-water systems. Furthermore, and quite surprisingly, these compounds have been found by the current inventor to show a remarkably strong correlation with the ability, as tablulated by Benet et al. in U.S. Patent No. 5,716,928, which is herein incorporated by reference, to inhibit the efflux and hydroxylation of cytochrome 3 A4 (Cyp3 A4) substrates such as cyclosporin.
  • the following essential oils have been determined by the current inventor to induce a bicontinuous cubic phase in a mixture of the high-PC lecithin "Epikuron 200" (Lucas-Meyer) and water, at a composition of approximately 39% Epikuron, 27% water, and 34% essential oil, at or a few degrees below room temperature: clove bud, ylang-ylang, santalwood, peppermint, eucalyptus, ginger, carrot seed, bay, myrrh, fir needle, patchouli, spearmint, and thyme.
  • the spearmint oil works better in this respect when a portion of the water is replaced by glycerol.
  • oils that are known to be the strongest inhibitors of the P-glycoprotein/Cyp3A4 efflux system.
  • the following oils induce discrete (i.e., non-bicontinuous) cubic phases at the same approximate composition (though typically at slightly lower water concentration): orange, tangerine, wintergreen, fennel, basil, and lemon; these oils are known to be poor inhibitors of the P-gp/Cyp3A4 system; the major components of these oils are either lacking in a polar group entirely (e.g., D-limonene), or have a weakly polar group such as an ester.
  • oils which liquify PC-water mixtures at the above composition, even at temperatures of about 15 C include: citronella, marjoram, and lemongrass; these are known to be poor inhibitors of the P-gp/Cyp3A4 system; typically these oils have aldehydes as their major components.
  • the essential oil component linalool is borderline between the first group and the third, able to induce either a bicontinuous cubic phase or a liquid phase in PC-water systems depending on small changes in composition, and similarly cinnamon (major component: cinnamaldehyde) can have several effects depending on small changes in composition and on the source of the oil.
  • oils which are the best inhibitors cloves, ylang-ylang, santalwood, peppermint, eucalyptus, ginger, carrot seed, bay, myrrh, fir needle, patchouli, spearmint, and thyme — reveals that each such oil has, as its major component or components, a compound which is a non-paraffinic liquid with a high octanol-water partition coefficient which does not qualify as a surfactant, and comprises at least one polar group that is not operative as a surfactant head group; and furthermore, in the case when the compound has an aldehyde group as the sole polar group, such a compound will not induce a bicontinuous cubic phase in PC- water systems near the above composition nor will it be an effective inhibitor of P-gp/Cyp3A4.
  • a pharmaceutically active compound which normally enhances many-fold the Cyp3A4-mediated hydroxylation of the compound
  • transient it is meant that the nanopores form and then close in preferably less than an hour and most preferably less than a minute.
  • this is a function of the nanostructure of the phase (the reversed bicontinuous cubic phase), not on the chemistry of the phase per se: in other words, independently of whether the reversed bicontinuous cubic phase contains essential oil components or hydrophobes with polar groups, the fact that it is in the reversed bicontinuous cubic phase nanostructure, whatever composition yields this, endows the material with the inherent ability to allow for this nanopore-based cell entry mechanism.
  • the presence of components, such as the bicontinuous cubic phase-inducing essential oils listed above, in the vehicle will be most effective and reliable in inducing nanopores in the cell membrane barrier.
  • Example 9 demonstrate this convincingly.
  • the delivery site is not intestinal but rather neuronal, and the drug, namely bupivacaine, is not subject to the P-gp/Cyp3A4 mechanism discussed in the previous subsection.
  • the enhancement of cell uptake due to the incorporation of the drug in a cubic phase containing linalool is very dramatic.
  • the fact that the uptake is enhanced is evidenced by the fact that bupivacaine can only exert its anesthetic effect if it is able to enter the cell, since it is known that the drug acts on the drug receptor only on the intracellular portion of the receptor.
  • Example 10 where the drug is paclitaxel, widely known to be a substrate of the P-gp/Cyp3A4 system, a single cubic phase can accomplish the inhibition of both proteins as well as the induction of nanopores by virtue of its cubic phase nanostructure and its specific composition.
  • a reversed cubic or reversed hexagonal phase to be formed in situ, from a composition containing a dissolved pharmaceutical active and suitably designed so as to form the desired reversed liquid crystalline phase at the site of cellular uptake.
  • a composition containing dissolved drug, but with less than full saturation with water could be designed that would swell in body fluids to a reversed cubic phase.
  • a material would be within the spirit, and at the site of delivery within the literal language, of this invention.
  • compositions of this invention can be of use in enhancing the delivery, particularly but not limited to the oral delivery, of peptides and proteins (e.g., insulin, erythropoietin, Interferon gamma- lb, Altepase, rh tPA, Darbepoeth alfa, Interferon beta- la, Coagulation factor LX, Coagulation factor Vila, rh TNF-alpha, Interferon beta- lb, rH factor VII, rH factor VIII, rH factor IX, Somatropin, Alemtuzumab, Imiglucerase, HbsAg, r TNFR-IgG fragment, rh EPO, Follitropin alpha, Follitropin beta,
  • peptides and proteins e.g., insulin, erythropoietin, Interferon gamma- lb, Altepase, rh tPA, Darbepoeth
  • the invention can be of utility in other routes of administration, including but not limited to buccal, intravenous, intramuscular, subcutaneous, intraperitoneal, sublingual, intrathecal, transdermal, intraocular, intranasal, pulmonary, and by direct instillation (e.g., bladder).
  • routes of administration including but not limited to buccal, intravenous, intramuscular, subcutaneous, intraperitoneal, sublingual, intrathecal, transdermal, intraocular, intranasal, pulmonary, and by direct instillation (e.g., bladder).
  • compositions of the present invention may be administered by any of a variety of means which are well known to those of skill in the art. These means include but are not limited to oral (e.g. via pills, tablets, lozenges, capsules, troches, syrups and suspensions, and the like) and non-oral routes (e.g. parenterally, intravenously, intraocularly, transdermally, via inhalation, and the like).
  • non-oral routes e.g. parenterally, intravenously, intraocularly, transdermally, via inhalation, and the like.
  • the compositions of the present invention are particularly suited for internal (i.e. non-topical) administration.
  • the present invention is especially useful in applications where a difficultly soluble pharmaceutical active is to be delivered internally (i.e.
  • non-topical including orally and parenterally, wherein said active is to be miscible with a water continuous medium such as serum, urine, blood, mucus, saliva, extracellular fluid, etc.
  • a water continuous medium such as serum, urine, blood, mucus, saliva, extracellular fluid, etc.
  • an important useful aspect of many of the structured fluids of focus herein is that they lend themselves to formulation as water continuous vehicles, typically of low viscosity.
  • the compounds can be administered in a form where they are associated with, and most preferably incorporated within, a said reversed cubic phase or reversed hexagonal phase material, or a combination thereof, that includes a polar solvent, a surfactant, and a non-paraffinic liquid with a high octanol-water partition coefficient which does not qualify as a surfactant.
  • the composition administered to a patient is present as a reversed bicontinuous cubic phase and allows delivery of a compound of interest through a biomembrane absorption barrier, such as could be present in a cell, tissue, or organ.
  • a biomembrane absorption barrier such as could be present in a cell, tissue, or organ.
  • co-administration or sequential administration of reversed bicontinous cubic phase materials together with compounds of interest might also be used, whereby the nanoporulation properties discussed in detail above are utilized to enhance delivery of a compound through the biomembrane absorption barrier.
  • each of these Examples demonstrates a novel cubic phase composition containing lipid or surfactant, polar solvent (usually water), and a non-paraffinic hydrophobe that does not qualify as a surfactant; furthermore, each Example reports the solubilization of a difficultly-soluble drug in the cubic phase.
  • the surfactant Pluronic 123 combined with water and a number of non-paraffinic hydrophobes, were found to form reversed cubic phases at specific compositions.
  • these cubic phases are capable of solubilizing drugs of low solubility.
  • Free base bupivacaine (solubility in water less than 0.1%) by wt) was made by dissolving 1.00 g of bupivacaine hydrochloride in 24 mL water. An equimolar amount of IN NaOH was added to precipitate free base bupivacaine.
  • 0.280 g free base bupivacaine, 0.685 g water, and 0.679 g linalool were combined and sonicated to break up bupivacaine particles. Then 0.746 g of the surfactant Pluronic PI 23 was added.
  • linalool is a major component of coriander oil, an excipient listed on the FDA list of approved inactive ingredients, and is also the subject of extensive toxicity studies demonstrating its low toxicity.
  • a second sample was also prepared using the same liquid crystal, then formulating it into microparticles coated with zinc tryptophanate. These bupivacaine- loaded microparticles are suitable for subcutaneous injection, as a slow-release formulation of the local anesthetic with the purpose of prolonging the drug's action and lowering its toxicity profile.
  • the detector has a range of 90 to 700 Angstroms.
  • the first material was loaded into a 1.5 mm i.d. x- ray capillary from Charles Supper Corp. The sample was run at 18 C.
  • the two- dimensional images from the 58 cm distance were integrated with a step size of 0.02 degrees two-theta.
  • Data from the 6-meter line were integrated with a step size of 0.002 degrees two-theta and those plots were overlaid with the runs at the shorter distance, and excellent agreement was obtained between the peak positions recorded with the two cameras.
  • the x-ray peak analysis software program JADE by Materials Data Analysis, Inc., was used to analyze the resulting data for the presence and position of peaks. Within that program, the "centroid fit" option was applied.
  • the SAXS data show Bragg peaks determined by JADE at positions 154.6, 80.6, 61.6, and 46.3 Angstroms. These peaks index to a cubic phase structure of the commonly-observed cubic phase space group of Pn3m (see Pelle Strom and D. M. Anderson, Langmuir, 1992, vol. 8, p. 691 for a detailed discussion of the most commonly observed cubic phase structures and their SAXs patterns). These four peaks in fact index as the (110), (211), (222) and (420) peaks of this space group (#229), with a lattice parameter of 210 Angstroms. The second sample exhibited one peak, at 104.6 Angstroms, which appears to index as the (200) peak of the same lattice. The second sample also showed three peaks with d-spacings less than 25 Angstroms which were clearly due to the crystalline zinc tryptophanate shell.
  • Isoeugenol is a major component of ylang-ylang oil and other essential oils, and has been the focus of a great deal of toxicity studies demonstrating its low toxicity.
  • Linalool is a major component of coriander oil as well as other essential oils such as cinnamon, and orange oils, and is considered non-paraffinic according to the definition given above because the maximum length of saturated hydrocarbon chain is only 5; the non-paraffinic nature of this compound is underscored by the presence of not only unsaturated bonds but also branching, tertiary carbons, and a hydroxyl group. Linalool has also been the subject of intensive toxicity studies that nearly universally show low toxicity and mutagenicity.
  • the Pluronics are a rich class of surfactants that include variants covering a wide range of molecular weights and HLBs. Those with low HLBs are of low water solubility, especially if they are of high MW, and PI 23 is an example of such a surfactant which nonetheless has a large enough PEG group to form self- association structures under a wide range of conditions. Furthermore its relatively high MW also encourages the formation of liquid crystalline (as opposed to liquid) phases, which is very favorable in the present context.
  • Pluronics are also known to interact strongly with biomembranes so as to enhance cellular absorption of drugs, and may in fact inhibit certain efflux proteins, such as P-glycoprotein and other MDR proteins that are responsible for multidrug resistance.
  • Phosphatidylcholine for example, has not been shown, or to this author's knowledge even speculated, as performing the latter function in drug-delivery.
  • Pluronics as a class are the subject of a Drug Master File with the FDA, and a number are listed explicitly on the 1996 Inactive Ingredient list as being approved for injectable formulations, indicating their low toxicity.
  • Bragg peaks were recorded at d-spacings of 123.6, 100.6, 68.8, 49.9, 45.6, and 33.4 Angstroms. These index with good accuracy to a cubic phase Pn3m lattice with a lattice parameter of 174 Angstroms, including the (110), (111), (211), and (222) peaks.
  • D-alpha tocopheryl polyethylene glycol 1000 succinate is itself water- soluble, variants of this molecule with shorter PEG chains are of much lower solubility.
  • These surfactants are of great interest in drug-delivery because of their low toxicity, and the fact that they can hydrolyze in the body to yield polyethylene glycol and vitamin E, a powerful antioxidant.
  • This surfactant clearly has advantages over, for example, monoglycerides, which take up very low percentages of oils such as ginger oil, and are thus of little value in solubilizing difficult actives such as Coenzyme Q10.
  • the calcium salt of docusate (2-ethyl hexyl sulfosuccinate) was made by dissolving 10.0 g of the sodium salt of dioctyl sulfosuccinate in 300 mL of water with heating and stirring. Then, 1.27 g of CaCl 2 dissolved in 10.0 g of water was added and a white precipitate formed — indicating the low water solubility of the calcium salt of docusate. This precipitate was dried by vacuum. This low-solubility surfactant was found to form a reversed cubic phase at a composition of: calcium docusate (74%) / linalool (9%) / water (17%).
  • SAXS peaks were recorded at 30.3, 27.8, and 25.1 Angstroms. This is consistent with a cubic phase of the common type Ia3d (space group #230), with lattice parameter 75 Angstroms, where the observed peak at 30.3 Angstroms compares well with the predicted position of the lowest-order reflection (211), namely 30.6 Angstroms; the next order reflection, (220), has a predicted position of 26.5 Angstroms, and this is probably interpreted as two peaks (27.5 and 25.1) by JADE.
  • An Ia3d cubic phase with lattice parameter 75 Angstroms is perfectly reasonable in view of the well-known cubic phase in the sodium-docusate water system, which also has an Ia3d lattice with lattice parameter of about 80 Angstroms.
  • Docusates have a long history of safe use in pharmaceutics and other fields, and their anionic charge opens up a range of possibilities in their applications, including enhanced adsorption properties, modulation of their solubilities by counterion substitution, etc.
  • a reversed hexagonal phase was found at a composition of: polyethylene glycol (5) oleyl ether (37%) / polyethylene glycol (2) oleyl ether (28.5%) / ginger oil (9%) / water (25.5%).
  • 0.008 g of menadione was dissolved in 0.096 g of ginger oil.
  • 0.410 g of polyethylene glycol (5) oleyl ether, 0.314 g of polyethylene glycol (2) oleyl ether, and 0.275 g of water were added. The sample was centrifuged to create a viscous, transparent, birefringent phase. Under the microscope, the sample appeared to have hexagonal textures, with a small amount of a liquid phase also being present.
  • Example 6 A mixture of 0.037g of menadione in 0.968 g of ginger oil was heated to dissolve. Then 0.306 of this solution was added to 0.598 g of polyoxyethylene (25) hydrogenated castor oil and 0.308 g water. The sample was stirred to mix and centrifuged for fifteen minutes, producing a viscous, transparent phase which was optically isotropic in polarizing microscopy. The same composition, minus the active menadione, was found to form a reversed cubic phase as well.
  • Ethoxylated castor oil derivatives such as this are strongly suspected to be inhibitors of certain efflux proteins, such as P-glycoprotein, that limit the absorption of drugs in a variety of cells and induce multidrug resistance. They may also have an effect on biomembranes that will, in a non-specific manner, increase the drug absorption.
  • the surfactant Pluronic 101 is a very low-HLB, low-solubility surfactant that is approved for internal use according to the 1996 FDA list.
  • a reversed cubic phase was found at a composition of: Pluronic 101 (60%) / ginger oil (15%) / (25%).
  • An amount 0.080 g menadione was heated gently with 1.919 grams of ginger oil to dissolve.
  • An amount 0.149 g of this solution was combined with 0.608 g of Pluronic LlOl and 0.250 g of water. After stirring, the sample was centrifuged for fifteen minutes, producing a viscous, clear phase which appeared optically isotropic in polarizing microscopy.
  • SAXS analysis recorded Bragg peaks in the small-angle range that confirmed the long-range liquid crystalline order of a reversed cubic phase.
  • the antineoplastic drug paclitaxel (obtained from LKT Labs), in the amount of 13 mg, was dissolved in a mixture of 0.1268 gm of santalwood oil (Cedarvale) and 0.2492 gm of strawberry aldehyde (also known as C-16 aldehyde). To this were added 0.3017 gm deionized water and 0.6179 gm of Pluronic L-122, a low water solubility Pluronic surfactant. This formed a stiff, isotropic cubic phase containing the paclitaxel in solubilized form, that is, in true solution.
  • Example 9 The cubic phase of Example 1 was formulated as coated microparticles (as per U.S. 6,482,517 which is herein incorporated by reference), and shown in tests on rats that the formulation strongly enhanced the cellular uptake of bupivacaine.
  • An amount 10.930 gm of Pluronic P123 was combined with 2.698 gm of free base bupivacaine, 10.912 gm of linalool, and 5.447 gm of sterile water, and stirred to form a reversed cubic phase.
  • Each tube was then centrifuged for 5 minutes in a 6000 rpm tabletop centrifuge.
  • the dispersion was then prefiltered, then filtered at 0.8 microns using Millex AA filters, then placed in a sealed vial and shipped to a facility for animal testing.
  • the formulation was tested on male Spraque-Dawley rats, weighing 220-250 gm. The animals were maintained under standard conditions, with access to food and water ad libitum. They were briefly anesthetized with halothane during the injection. Sciatic nerve blockage was then tested by administering either the standard 0.5% solution of bupivacaine hydrochloride, or the above cubic phase formulation, by a transcutaneous injection into the popliteal space of the hindlimb. Blockage of thermal nociception was determined by placing the rat on the glass surface of a thermal plantar testing apparatus (Model 336, IITC Inc.), with the surface maintained at 30 C. A mobile radiant heat source located under the glass was focused onto the hindpaw of the rat, and the paw- withdrawal latency recorded by digital timer. The baseline latency was found to be 10 seconds. The rats were tested for latency every 30 minutes.
  • the anticancer drug paclitaxel was solubilized in a Pluronic- essential oil-water cubic phase, which was encapsulated by a zinc-NAT shell as in Example 9.
  • the cubic phase was prepared by mixing 0.070 gm of gum benzoin, 0.805 gm of essential oil of sweet basil, and 0.851 gm of oil of ylang-ylang, heating to dissolve the gum benzoin, then adding 265 mg of paclitaxel, 3.257 gm of oil of spearmint, 0.640 gm of strawberry aldehyde, 0.220 gm of ethylhexanoic acid, 1.988 gm of deionized water, and finally 3.909 gm of Pluronic 103.
  • the encapsulating with zinc-NAT was done similarly as in the previous Example, except that short homogenizing was used instead of microfluidizing. The monopalmitin and Norit steps were skipped. The dispersion was placed in vials and sent for testing oral absorption in dogs.
  • Paclitaxel is known to exhibit very low absorption given orally or intraduodenally. Indeed, even in the Taxol R formulation, which includes a large volume of surfactant (Cremophor EL) and ethanol, both of which are membrane fluidizers, the bioavailability is less than about 10%. Blood levels of paclitaxel were measured at predose, 20 minutes, 40 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 10 hours, and 24 hours. The results for one experiment with the cubic phase formulation were as follows: Time point Blood concentration (ng/ml)

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des composés difficiles à solubiliser, de type principes actifs pharmaceutiques difficiles à absorber pour le corps, qui sont solubilisés en une composition au moyen d'un système de solvants qui est un fluide structuré. Ce fluide structuré est un matériau à phase cubique inversée ou à phase hexagonale inversée, ou une combinaison de celles-ci, qui comprend un solvant polaire, un tensioactif et un liquide non paraffinique présentant un coefficient de répartition octanol/eau élevé non qualifié de tensioactif. Les compositions ainsi obtenues peuvent améliorer l'absorption de médicaments par l'induction de nanopores locaux, transitoires dans des barrières d'absorption biomembraneuses, et en particulier ceux dont les mécanismes de libération, de type ceux associés à la P-glycoprotéine et/ou au cytochrome 3A4, sont actifs. Les compositions et les procédés utilisés pour solubiliser des principes actifs pharmaceutiques dans des fluides structurés peuvent permettre de solubiliser des médicaments difficilement solubles et d'améliorer leur absorption simultanément.
PCT/US2003/018457 2002-06-13 2003-06-13 Phases cristallines liquides inversees comprenant des agents hydrophobes paraffiniques WO2003106382A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002488701A CA2488701A1 (fr) 2002-06-13 2003-06-13 Phases cristallines liquides inversees comprenant des agents hydrophobes paraffiniques
EP03760279A EP1539099A4 (fr) 2002-06-13 2003-06-13 Phases cristallines liquides inversees comprenant des agents hydrophobes paraffiniques
AU2003243509A AU2003243509B2 (en) 2002-06-13 2003-06-13 Reversed liquid crystalline phases with non-paraffin hydrophobes
JP2004513218A JP2005532366A (ja) 2002-06-13 2003-06-13 非パラフィン系疎水性物による逆液晶相

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US38790902P 2002-06-13 2002-06-13
US60/387,909 2002-06-13

Publications (2)

Publication Number Publication Date
WO2003106382A2 true WO2003106382A2 (fr) 2003-12-24
WO2003106382A3 WO2003106382A3 (fr) 2004-07-22

Family

ID=29736379

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/018457 WO2003106382A2 (fr) 2002-06-13 2003-06-13 Phases cristallines liquides inversees comprenant des agents hydrophobes paraffiniques

Country Status (5)

Country Link
EP (1) EP1539099A4 (fr)
JP (1) JP2005532366A (fr)
AU (1) AU2003243509B2 (fr)
CA (1) CA2488701A1 (fr)
WO (1) WO2003106382A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015161139A1 (fr) * 2014-04-16 2015-10-22 Rapamycin Holdings, Llc Préparation orale de rapamycine et utilisation pour une stomatite
CN108548931A (zh) * 2018-05-09 2018-09-18 南京岚煜生物科技有限公司 基于微流控芯片检测游离甲状腺素fT4试剂盒及制备和检测方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990008537A1 (fr) * 1989-02-06 1990-08-09 Abbott Laboratories Compositions pharmaceutiques administrees oralement
WO1998047487A1 (fr) * 1997-04-17 1998-10-29 Dumex-Alpharma A/S Nouveau systeme bioadhesif d'administration de medicaments base sur des cristaux liquides
US6071524A (en) * 1994-11-10 2000-06-06 L'oreal Oily phase in aqueous phase dispersion stabilized by cubic gel particles and method of making
US6090800A (en) * 1997-05-06 2000-07-18 Imarx Pharmaceutical Corp. Lipid soluble steroid prodrugs

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE246039T1 (de) * 1997-09-09 2003-08-15 Select Release L C Beschichtete teilchen, methode zu ihrer herstellung und verwendung
US20020102280A1 (en) * 2000-11-29 2002-08-01 Anderson David M. Solvent systems for pharmaceutical agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990008537A1 (fr) * 1989-02-06 1990-08-09 Abbott Laboratories Compositions pharmaceutiques administrees oralement
US6071524A (en) * 1994-11-10 2000-06-06 L'oreal Oily phase in aqueous phase dispersion stabilized by cubic gel particles and method of making
WO1998047487A1 (fr) * 1997-04-17 1998-10-29 Dumex-Alpharma A/S Nouveau systeme bioadhesif d'administration de medicaments base sur des cristaux liquides
US6090800A (en) * 1997-05-06 2000-07-18 Imarx Pharmaceutical Corp. Lipid soluble steroid prodrugs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1539099A2 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015161139A1 (fr) * 2014-04-16 2015-10-22 Rapamycin Holdings, Llc Préparation orale de rapamycine et utilisation pour une stomatite
CN108548931A (zh) * 2018-05-09 2018-09-18 南京岚煜生物科技有限公司 基于微流控芯片检测游离甲状腺素fT4试剂盒及制备和检测方法

Also Published As

Publication number Publication date
JP2005532366A (ja) 2005-10-27
EP1539099A2 (fr) 2005-06-15
AU2003243509B2 (en) 2009-08-20
EP1539099A4 (fr) 2009-03-18
WO2003106382A3 (fr) 2004-07-22
CA2488701A1 (fr) 2003-12-24
AU2003243509A1 (en) 2003-12-31

Similar Documents

Publication Publication Date Title
US20040022820A1 (en) Reversed liquid crystalline phases with non-paraffin hydrophobes
AU2004280229B2 (en) Drug-delivery vehicles based on reversed liquid crystalline phase materials
EP1345589B1 (fr) Systemes de solvants pour agents pharmaceutiques
EP0790822B1 (fr) Composition a liberation regulee formant une structure micellaire inversee (l2) et une structure micellaire normale (l1)
JP4744875B2 (ja) パクリタキセルの可溶化用組成物及びその製造方法
KR0167696B1 (ko) 사이클로스포린-함유 연질캅셀제 조성물
US20040156816A1 (en) Lipid-drug complexes in reversed liquid and liquid crystalline phases
Otte et al. Liquid crystalline drug delivery vehicles for oral and IV/subcutaneous administration of poorly soluble (and soluble) drugs
WO2006041878A2 (fr) Procedes de traitement au moyen de formulations, agissant plus longuement et a faible dose, de produits anesthesiants locaux et d'autres agents
Saha et al. Interactions between loaded drugs and surfactant molecules in micellar drug delivery systems: A critical review
AU2003243509B2 (en) Reversed liquid crystalline phases with non-paraffin hydrophobes
JP5116306B2 (ja) タキソイドの経口投与用半固体製剤
Ritika et al. Formulation tactics for the delivery of poorly soluble drugs
da Costa Bernardo Port et al. Effect of vehicle composition on the preparation of different types of dapsone crystals for topical drug delivery
WO2002026324A2 (fr) Compositions a base de tocol contenant de l'amiodarone
KR101440726B1 (ko) 가용화제를 포함하는 림프계 약물전달 시스템용 조성물
AU2002219878B2 (en) Solvent systems for pharmaceutical agents
ES2357580T3 (es) Vehículos para la administración de farmacos basados en materiales de fase líquido-cristalina inversa.
AU2002219878A1 (en) Solvent systems for pharmaceutical agents

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2488701

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2003243509

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2004513218

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 2003760279

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2003760279

Country of ref document: EP