WO2002076938A2 - Carboxybenzopyran derivatives and compositions - Google Patents
Carboxybenzopyran derivatives and compositions Download PDFInfo
- Publication number
- WO2002076938A2 WO2002076938A2 PCT/US2002/011266 US0211266W WO02076938A2 WO 2002076938 A2 WO2002076938 A2 WO 2002076938A2 US 0211266 W US0211266 W US 0211266W WO 02076938 A2 WO02076938 A2 WO 02076938A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- compound
- hydrogen
- derivatives
- tocopherol
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring
Definitions
- the present invention relates to carboxybenzopyran derivatives and compositions including the derivatives.
- Benzopyrans are an important class of molecules that includes vitamin E, tocopherols and tocotrienols. These compounds have been developed to improve the water solubility of the oily vitamin so as to improve dietary or parenteral uptake of vitamin E in certain clinical and veterinary conditions, to discover novel medicaments, and to develop novel antioxidants. Only recently, the solubilization properties of tocopherols, tocopherol acetate, tocopherol succinate, TPGS and tocotrienols have been recognized. However, the chemistry of tocopherol derivatization for this purpose has not advanced much since the introduction of TPGS in 1951, and has not encompassed use of carboxylated, carbonated, or carbamated benzopyrans as efficient starting materials for derivatization. Previous work has not recognized the use of these derivatives as surfactants, or as pharmaceutical excipients in emulsions, nanoemulsions, microemulsions, liposomes or micellar solutions.
- the present invention seeks to fulfill this need and provides further related advantages.
- the present invention provides benzopyran derivatives.
- the benzopyran derivatives are carboxylate derivatives.
- the benzopyran derivatives are amide derivatives.
- the benzopyran derivatives are acetic acid derivatives.
- the benzopyran derivatives are acetamide derivatives.
- the benzopyran derivatives are carbonate derivatives.
- the benzopyran derivatives are carbamate derivatives.
- compositions that include the benzopyran derivatives are provided.
- FIGURES 1A-D are chemical structures of representative benzopyran carboxylate derivatives of the invention
- FIGURES 2A-D are chemical structures of representative benzopyran amide derivatives of the invention
- FIGURES 3A-D are chemical structures of representative benzopyran acetic acid derivatives of the invention.
- FIGURES 4A-D are chemical structures of representative benzopyran acetamide derivatives of the invention.
- FIGURE 5 is the chemical structure of vitamin E;
- FIGURE 6 is the chemical structure of d- ⁇ -tocotrienol;
- FIGURE 7 is the chemical structure of 5-carboxy-d- ⁇ -tocopherol;
- FIGURE 8 is the chemical structure of 6'-O-d- ⁇ -tocopherol acetic acid ester;
- FIGURE 9 is the chemical structure of a representative tocoglycinate of the present invention.
- FIGURE 10 is the chemical structure of a representative tocoglutamate of the present invention.
- FIGURE 11 is the chemical structure of a representative tocoglutamine of the present invention.
- FIGURE 12 is a schematic illustration of the synthesis of 5-bromo-d- ⁇ - tocopheryl-6-ol
- FIGURE 13 is a schematic illustration of the synthesis of 5-carboxy-d- ⁇ - tocopheryl-6-ol; and FIGURE 14 is a schematic illustration of the synthesis of RRR-d- -tocopheryl-6- carboxylic acid.
- the present invention provides benzopyran derivatives.
- the benzopyran derivatives are carboxylate derivatives.
- the benzopyran derivatives are amide derivatives.
- the benzopyran derivatives are acetic acid derivatives.
- the benzopyran derivatives are acetamide derivatives.
- the benzopyran derivatives are carbonate derivatives.
- the benzopyran derivatives are carbamate derivatives.
- FIGURES 1-4, 9-11, 13, and 14 The chemical structures of representative tocopherol succinic acid derivatives are illustrated in FIGURES 1-4, 9-11, 13, and 14.
- FIGURES 1A-D are chemical structures of representative benzopyran carboxylate derivatives of the invention.
- FIGURES 2A-D are chemical structures of representative benzopyran amide derivatives of the invention.
- FIGURES 3A-D are chemical structures of representative benzopyran acetic acid derivatives of the invention.
- FIGURES 4A-D are chemical structures of representative benzopyran acetamide derivatives of the invention.
- FIGURE 9 is the chemical structure of a representative tocoglycinate of the present invention.
- FIGURE 10 is the chemical structure of a representative tocoglutamate of the present invention.
- FIGURE 11 is the chemical structure of a representative tocoglutamine of the present invention.
- Rj, R2, R3, and R 4 are substituents selected independently from hydrogen, hydrocarbyl, amino, hydroxyl, and carboxyl. In one embodiment, these substiuents are selected from hydrogen, C C 4 hydrocarbyl, carboxyl, and hydroxyl. In another embodiment, the substiuents are selected from hydrogen, methyl, and ethyl.
- R 5 is a substituent that associates with water to form at least 2 hydrogen bonds, in one embodiment 3 hydrogen bonds, and in other embodiments from 2 to about 200 hydrogen bonds.
- R 5 can optionally form a salt in buffered water or saline, and may be selected from a carboxylate (such as sorbate, tartarate, succinate, citrate, gluconate, glucoheptonate, glycerate, itaconate, aconitate, galacturonate, galactarate, glutarate, creatine, fumarate and its polymers, ascorbate, lactate and its polymers, pangamate, pantothenate, or para-aminobenzoate), an amine (such as glucamine, glucosamine, thiamine or choline), a phosphate (such as glycerophosphate, fructose-6-phosphate or phosphocreatine), an amino acid, a purine (such as adenine and guanine), a
- n 1 to 100, and branched or block co-polymers of the same).
- R5 includes residues of carnitine, sarcosine, taurine, methionine, glutathione, ⁇ -alanine, glycine, glutamate, glutamine, aspartate, asparagine, ornithine, arginine, ⁇ -aminobutyrate (GABA), serotonin, adrenaline, histamine, melatonin, tryptamine, alanylglutamine, glycylglutamine, glycylsarcosine, valyl-lysine, aspartylalanine, glutamyltryptophane, lysyl-sarcosine, glycylproline, triglycine, polyglutamate (Glu) n , polyglutamine (Gln) n , polyglycine (Gly) n , polyalanine (Ala) n , polyproline (Pro) n , poly-(GlyProPro) n
- polyesters copolymers of succinate, glycerol, and polyethylene glycol, polyhydroxyalkonates, polyhydroxyproprionate, poly- (3-hydroxyvalerate), poly-(3-hydroxyhexanoate), poly-(4-hydroxyvalerate), poly-(5- hydroxyvalerate), generally R-3-hydroxyacid polymers and their derivatives, polyglycolides (PGA), polylactides (PLA), substituted polyhydroxybutyrates, folate, glycogen, chitosan, dextran, dextrin, gluconate, poly-N-substituted glycines, polyvinylpyrrolidinone, poloxamer, polyvinylalcohol, polyethylene glycol, 1-amino- polyethyleneglycol, or composites (co-polymers) of the above.
- PGA polyglycolides
- PLA polylactides
- substituted polyhydroxybutyrates folate, glycogen, chitosan, dextran, dextri
- R 5 provides a derivative that is not bonded or is weakly bonded by a C8 column packing, and most preferentially is not bonded or is weakly bonded by a C18 column packing (for example BondEluteTM). Bonding can be assessed by measuring retention times on an HPLC set up with a reverse phase column and a gradient solvent system progressing from relatively nonpolar to more polar. Those compounds that are poorly retained (i.e., have low retention times) are the preferred compounds for R 5 .
- Molecular weights for R 5 are typically between 20 Da to 5 kDa. In one embodiment, R 5 molecular weights are from about 80 Da to 5000 Da. In another embodiment, R5 molecular weights are from about 180 Da to 2500 Da.
- T j is a C] to Cgo hydrocarbyl, hydroxyhydrocarbyl, carboxyhydrocarbyl, oxyhydrocarbyl ketohydrocarbyl, oxohydrocarbyl, phosphohydroxy hydrocarbyl, saturated or unsaturated, branched or unbranched.
- T j is an isoprenoid, terpene, diglyceride, or phospholipid.
- Tj is a phytyl (4,8,12-trimethyl-tridecyl) or trienyl (4,8,12-trimethyl-3,7,l 1-tridecatrienyl).
- T 2 is hydrogen, or C ] to C 80 hydrocarbyl, optionally substituted, saturated or unsaturated, branched or unbranched, alkyl or aromatic.
- T 2 is a C j to C] 8 hydrocarbyl group.
- T 2 is methyl or ethyl.
- T is a carboxyl group, wherein the carboxyl group is optionally esterified or amidated, respectively, with a Cj to Cgo alcohol or amine, preferably a C j to C j g alcohol or amine, and the alcohol or amine is optionally substituted, saturated or unsaturated, branched or unbranched, cyclical or acyclic.
- the stereochemistry of T j and T 2 may be as d- or 1 -stereoisomers or as racemates, and the invention is not limited by the stereochemistry of any chiral centers.
- the benzopyran derivatives can be cationic, anionic, zwitterionic, multipolar or nonionic. Ionically charged derivatives can be formed and used as salts, for example as the sodium, hydrochloride, citrate, lactobionate, propionate, succinate, potassium, lithium or palmitate salt.
- the invention further relates to compositions in which a pharmaceutical, nutriceutical, cosmeceutical, vitamin, foodstuff, antigen, catalyst, cell, nanoparticle, oligonucleotide, gene, extract, cosmetic or fiber is solubilized, protected or dispersed in a solution, particle, emulsion, microemulsion, nanoemulsion, liposome, niosome, molecular matrix or coating comprising one or more of the benzopyran derivatives, optionally with other oils, co-solvents, surfactants and cosurfactants.
- the composition is a biocompatible or therapeutic formulation comprising one or more benzopyran derivatives for application to a human or to an animal by any of a variety of routes, including but not limited to oral, topical and parenteral administration.
- Such compositions include solutions, suspensions, emulsions, emulsion preconcentrates, liquigels, lotions, astringents, soaps, ointments, toothpastes, topicals, capsules, sustained release granules, powders, tablets, nosedrops, eyedrops, excipients, sunscreens, surgical dressings, intravenous infusions, depot or sustained release injections, and coatings for prosthetic devices.
- the benzopyran derivatives of the invention are 1 -benzopyran derivatives and can be synthesized by chemistry that is commercially attractive.
- the benzopyran derivatives have unexpected utility as surfactants, as biocompatible surfactants, as pharmaceutical excipients, and as bioavailability enhancers.
- typical commercial surfactants such as sodium oleate (a principal component soap), betaine, or SDS (sodium dodecyl sulfate) dissolve biological membranes and are corrosive to cells, so the utility of surfactants that, paradoxically and unexpectedly, serve both as detergents and as stabilizers of biocellular membranes is anticipated to be great.
- the benzopyran derivatives displayed surfactant properties of foaming and emulsion formation even before the protective groups on the "hydrophilic head" had been removed.
- biocompatible benzopyran derivatives are surfactants that may be anionic, cationic, zwitterionic, multipolar, or non- ionic.
- Vitamin E as used herein is the common name for RRR- ⁇ -tocopherol (d- ⁇ -tocopherol, sensu stricto 2,5,7,8-tetramethyl-2-(4',8',12'-trimethyltridecyl-6- benzopyranol), the vitamin named by Dr. George Calhoun and Dr. H.M. Evans in 1936. The suffix "-ol” denotes the presence of the 6-hydroxyl on the benzopyran ring. Vitamin E is a member of the family "tocopherols.” Vitamin E has a bioequivalence of 1.00 ⁇ TE units in biological assays for Vitamin E activity.
- Tocopherol(s) are a family of natural and synthetic compounds containing three key structural elements, a benzopyran ring, phenolic alcohol, and phytyl tail. Vitamin E is an important representative of the tocopherol family, and its molecular structure is shown in FIGURE 5. Not all tocopherols have three methyl groups on the chroman head. The simplest family member contains no methyl groups on the chroman ring, 6-hydroxy-2-methyl-2-phytylchroman), and is sometimes simply referred to as "tocol", although the term "tocol” is used herein to represent all tocopherols and tocotrienols. There are four tocopherol family members that are commonly encountered in food and natural products, and eight possible isomers in total (not including stereoisomers). The names of the family members are shown in the table below.
- Tocotrienol(s : Tocotrienols have structures related to the tocopherols, but possess a 3', 7', l l'-triene "tail" at the 2-position on the benzopyran ring.
- the structure of d- ⁇ -tocotrienol is shown in FIGURE 6.
- the tocopherols not all tocotrienol family members have three methyl groups on the chroman head. There are four family members that are commonly encountered in food, and eight possible members in total, more if the desmethyl forms are considered.
- Tocotrienol nomenclature is not fully consistent at the level of common names. However, all tocotrienols share the phenolic alcohol at the 6-position on the chroman head. Adding another layer of complexity, the double bonds at the 3, 7, and 11 positions of the tail may be "cis” or "trans”, but typically are all-trans in the natural products.
- Tocol-soluble refers to the property of certain molecules characterized as being soluble directly, or with the aid of a co-solvent, in a tocol. As an operative definition, the most useful way to determine tocol solubility is to dissolve the compound of interest in a tocol or to use a co-solvent such as ethanol.
- compositions can be incorporated into various types of pharmaceutical compositions, including multiphasic compositions or their precursors, such as emulsions, liquid crystalline gels, self-emulsifying drug delivery systems, or liposomal or niosomal dispersions, for oral or other (including parenteral) administration.
- multiphasic compositions or their precursors such as emulsions, liquid crystalline gels, self-emulsifying drug delivery systems, or liposomal or niosomal dispersions, for oral or other (including parenteral) administration.
- Tocan or Tocans are used herein in a broad sense to indicate the various members of the families of tocopherols and tocotrienols, their rarer natural and synthetic analogs, and in addition all benzopyran derivatives substituted at the 2- position by T j and T 2 , where Tj is a C j to Cgo hydrocarbyl, hydroxyhydrocarbyl, oxyhydrocarbyl, carboxyhydrocarbyl or phosphohydroxy hydrocarbyl, saturated or unsaturated, branched or unbranched, an isoprenoid, terpene, diglyceride, phospholipid, a phytyl (4,8,12-trimethyl-tridecyl), or trienyl (4,8,12-trimethyl-3,7,l l-tridecatrienyl), and T 2 is a hydrogen, halo, hydrocarbyl, carbonyl, methyl, ethyl, or carboxyl, as the
- Tocans also include tocols esterified at the 6-hydroxyl on the benzopyran ring.
- tocol esters include the acetate, succinate, maleate, phosphate, linoleate, nicotinate, ascorbate, retinoate, quinone, and a pegylated diester derivative known as TPGS (tocopherol polyethylene glycol succinate).
- a special case is the benzopyran derivative known as 6-hydroxy, 2,5,7,8- tetramethylchroman-2-carboxylic acid (commercially available as Trolox®), which has a reactive carboxyl functional group at the two position and is relatively hydrophobic despite lack of a lipid sidechain at T 2 .
- Trolox® 2,5,7,8- tetramethylchroman-2-carboxylic acid
- Tocol desmethyl analogs have been isolated or synthesized.
- Other synthetic tocols include Raloxifast.
- 5-d- ⁇ -tocopherol carboxylate has the chemical structure shown in FIGURE 7.
- 6'-O-d- ⁇ -tocopherol acetic acid ether has the chemical structure shown in FIGURE 8.
- Tocoglycinates representative benzopyran derivatives of the invention having the chemical structure shown in FIGURE 9, where R 1 ? R , R3, R 5 , Tj, and T 2 are as previously defined.
- Tocoglutamines representative benzopyran derivatives of the invention having the chemical structure shown in FIGURE 11, where Rj, R 2 , R3, R5, Tj, and T 2 are as previously defined.
- Linker In chemical synthesis, conjugations of two molecules A and B may take place using a linker "C" to modify the reactivity of a functional group so that the joining takes the form A+C+B in the final structure. Note the position of C between A and B.
- Linkers may be homo- or heterobifunctional, or multifunctional as in the synthesis of dendrimeric molecules.
- a spacer is a special class of linkers in which the separation of A and B is increased by the length of the spacer C.
- Surfactant An end group on a side chain, particularly on a polymer.
- Surfactants are bipolar molecules characterized by one simple property: they are driven to occupy interfaces between two phases, typically either liquid/gas phase interfaces, liquid/solid interfaces, or liquid/liquid phase interfaces (for immiscible liquids), so that the free energy of the boundary surface between phases is reduced.
- the "surfactanticity" of any molecule is not independent of the properties of the immiscible phases under study. With respect, for example, to water and oil, a surfactant will contain both a water-loving "head” and an oil-loving "tail".
- surfactants have fluorophilic "tails.” The basic principle is that the molecule is amphipolar with respect to the two phases with which it associates. Surfactants may be classed into five sub-groups: anionic, cationic, zwitterionic, multipolar and non-ionic on the basis of chemical structure and the presence or absence of electrostatically charged substituents. Surfactants are also sometimes termed "emulsifiers.” Catanionic, gemini, and bolaform surfactants are special cases.
- Co-surfactant A second surfactant that aids in reduction of the surface free energy between two phases, most typically that aids in fine emulsification of an oil and water or dirt and water system.
- Hydrophile-Lipophile Balance Is an empirical formula used to index the relative detergency of surfactants. Its value varies from 1 to about 45 and in the case of non-ionic surfactants from about 1-20. In general, for lipophilic surfactants the HLB is less than 10 and for hydrophilic ones the HLB is greater than 10.
- CMC Critical Micellar Concentration
- oils Any of a class of hydrocarbon derivatives that are hydrophobic and immiscible or poorly miscible with water. They may be synthetic or derived from plants, animals or microorganisms. Such oils include “grease,” waxes, "dirt,” triglycerides, diglycerides, derivatives of mono- and diglycerides, essential oils, Vitamin oils, nutrient oils, squalene, squalane, waxes, terpenes, ethers and crown ethers, and may be either synthetic or natural. In general, the melting points of oils are less than 100°C and most are in fact liquid at body temperature.
- Common oils include extracted and distilled oils from nuts and seeds, for example safflower, perrila, millet, niger, Ucu ⁇ ba, sesame, cimbopogon, mustard, canola, corn, caraway, soybean, sunflower, garlic, peanut, pumpkin seed, olive, almond, macadamia, palm, walnut, pistachio, coconut, evening primrose seed, black currant seed, rosemary, borage seed or flax seed oils, and from fish and phytoplankton, for example shark, cod, mackerel, sardine, salmon, scrod, or halibut oils, or from oleagenous microorganisms directly.
- tocols comprising the whole family of tocopherols and
- Vitamin A also called retinol
- retinoids menaquinones such as Coenzyme Q
- carotenoids such as carotenes
- lycopene and the related xanthophylls
- lutein lutein esters
- astaxanthin canthaxanthin and zeaxanthin
- Vitamin D Vitamin K
- vitamers of these Vitamin oils and their precursors and glycerides high in PUFAs such as triglycerides containing esterified docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).
- DHA docosahexaenoic acid
- EPA eicosapentaenoic acid
- oils are also contemplated as oils. These are often complex mixtures useful in enhancing bioavailability, and include extracts of (as in U.S. Patent No. 5,716,928) allspice berry, fennel, amber essence, anise seed, arnica, balsam of Peru, basil, bay leaf, parsley, peanut, benzoin gum, bergamot, rosewood, rosemary, rosehip, cajeput, marigold, turmeric, camphor, caraway, cardamom, carrot, cedarwood, celery, chamomile, cinnamon, citronella, palm kernels, avocado, macadamia, sage, clove, coriander, cumin, cypress, eucalyptus, aloe, fennel, fir, frankincense, garlic, geranium, rose, ginger, lime, grapefruit, orange, hyssop, jasmine, jojoba, juniper, lavender, lemon, lemongrass, marjoram, mugwort
- Colloidal System As used herein, this term refers to a system containing two or more immiscible phases, at least one of which takes the form of a particle or droplet and is termed a "dispersed” phase, and one phase is a liquid or a solution and is termed a “continuous” phase.
- colloidal systems are limited to those wherein the particles are larger than simple molecular or micellar solutes but are small enough that they remain suspended in a fluid medium without settling to the bottom.
- the vapor pressure of a liquid or solution containing a colloid is typically not influenced by the colloidal particles or droplets in suspension. Nor are other colligative properties affected, for example osmolarity.
- aspects of the invention also include precursors of colloidal systems, for example, SEDDS (self-emulsifying drug delivery systems), wherein the oily phase containing a therapeutic agent is administered as a preconcentrate, typically with surfactant(s), sometimes with solvents, but absent water.
- SEDDS self-emulsifying drug delivery systems
- Multiphase System As used herein, this term refers to a system where one or more phases is (are) dispersed throughout another phase, which is usually referred to as the continuous phase, or a precursor thereof.
- Complex emulsions, microemulsions and other multiphasic nanoparticulates, including liposomes, niosomes and crystalline suspensions in oil-in-water emulsions, are examples of multiphasic systems. These systems may be lyophilic or lyophobic.
- Biphasic systems are a subcategory of multiphasic systems.
- Emulsion A colloidal dispersion of two immiscible or poorly miscible liquid phases, such as oil and water, in the form of droplets.
- the internal phase is also termed the dispersed phase and the external phase is termed the continuous phase.
- the mean diameter of the dispersed phase in general, is between about 0.2 and about 50.0 microns ( ⁇ m), as is commonly measured by particle sizing methods, and the particles range broadly in size.
- Emulsions in which the dispersed phase and continuous phase have different refractive indexes are typically optically opaque. Emulsions in which the refractive indexes of the two phases are similar may be clear or translucent, and hence optical appearance is not a defining characteristic.
- Emulsions possess a finite or limited stability over time, and can be stabilized for days or weeks, sometimes for months, by the incorporation of surfactants and by viscosity modifiers.
- Microemulsion A thermodynamically stable, isotropically clear mixture of two immiscible liquids, stabilized by a relatively high concentration of surfactant molecules.
- Microemulsions have an apparent mean droplet diameter of less than about 200 nm, in general from about 10 to about 100 nm, and are typically self-assembling, or may be assembled using heat and/or solvents. Typically, microemulsions are more easily established with a co-surfactant. Microemulsions exist only within defined ratios of water, amphiphile and oil, as may be determined with a phase diagram for the system at a given temperature. Therefore, o/w microemulsions are inherently unstable when diluted with water.
- a class of microemulsions known as "swollen micelles" constitutes a system of special interest for drug delivery.
- Microemulsions of non-volatile oils decrease the vapor pressure of the continuous phase, and conversely, microemulsions of volatile oils may increase the vapor pressure of the continuous phase, a change that may involve substantial departures from ideal solute behavior, where ideality is taken as an approximately linear relationship between solute concentration and vapor pressure.
- Tocan Microemulsion A thermodynamically stable, isotropically clear mixture of two immiscible liquids, one of which contains a tocan oil or tocan surfactant, stabilized by a relatively high concentration of surfactant molecules.
- Tocan microemulsions have an apparent mean droplet diameter of less than about 200 nm, in general from about 10 to about 120 nm. Once manufactured, however, they are filter sterilizable and are highly stable in a defined temperature range. Typically, tocan microemulsions are more easily established with a co-surfactant.
- a class of tocan microemulsions known as "swollen micelles" constitutes a system of special interest for drug delivery.
- Nanoemulsions are colloidal systems distinct from microemulsions and emulsions. As used herein, this term refers to those systems having a mean particle size that is less than 200 nm (as Gaussian volumetric mean), preferably less than 120 nm, and most preferably from about 10 to 100 nm, and not displaying apparent growth in particle size as measured by a lack of increase in size of greater than 15% in Gaussian volumetric mean by photon correlation spectroscopy when incubated at 25°C under controlled conditions for at least 30 days, preferably for 6 months, and most preferentially for up to 2 years.
- Gaussian volumetric mean preferably less than 120 nm
- photon correlation spectroscopy when incubated at 25°C under controlled conditions for at least 30 days, preferably for 6 months, and most preferentially for up to 2 years.
- nanoemulsions are self-assembling, but others may require heat, solvent, and/or increased shear to assemble due to the high viscosity of certain nutrient oils.
- nanoemulsions however formed, share the common property of being terminally filter sterilizable, typically by passage through a compatible filter membrane of a pore size not to exceed 0.2 microns. And unlike o/w microemulsions, o/w nanoemulsions are robust when diluted with aqueous IV solutions, an important property when used for drug delivery.
- nanoemulsions are differentiated from microemulsions by their behavior upon dilution and from the broader category of emulsions by their size and stability.
- the relative insensitivity of the vapor pressure of the continuous phase to the presence of a nanoemulsion in suspension is a distinctive characteristic.
- Tocan nanoemulsion drug delivery vehicles contain a tocan surfactant or oil, optionally a cosurfactant, and an oil or oils and have a mean particle size that is less than 120 nm (as Gaussian volumetric mean), preferentially less than 100 nm, and do not display apparent growth in particle size (as measured by a lack of increase in size of greater than 15% in mean diameter by photon correlation spectroscopy) when incubated at 25°C under controlled conditions for at least 30 days, preferentially for 6 months, and most preferentially for up to 2 years. Many of these vehicles are optically translucent or clear, but display high levels of drug loading (a relative property that must be determined independently for each drug).
- tocan nanoemulsions are self-assembling, but others may require heat, solvent, and/or increased shear to formulate due to the high viscosity of certain tocan oils.
- tocan nanoemulsions share the common property of being terminally filter sterilizable, typically by passage through a compatible filter membrane of pore size 0.2 microns.
- Tocol oil nanoemulsions are further characterized by modest or negligible effect on the vapor pressure of the continuous phase.
- Liposome A lipid bilayer vesicle formed spontaneously upon dispersion of certain lipids, most commonly phospholipids, in water. "Liposome” is also defined as a vesicular structure consisting of hydrated bilayers.
- Tocan Liposome A bilayer vesicle formed spontaneously upon dispersion of certain highly polar tocans in water. "Liposome” is also defined as a vesicular structure consisting of hydrated bilayers.
- a niosome By analogy to a liposome, a niosome is a nonionic surfactant vesicle. Classes of commonly used non-ionic surfactants include polyglycerol alkylethers, glucosyl dialkylethers, crown ethers and polyoxyethylene alkyl ethers and esters.
- Tocan Niosome By analogy to a liposome, a tocan niosome is a nonionic tocan surfactant vesicle.
- Micelle These are organized dynamic molecular aggregates of one or more surfactants that exist only at a concentration above the critical micellar concentration (CMC) in water or buffer.
- CMC critical micellar concentration
- These molecular aggregates typically have a nominal diameter of 2 to 6 nm, and perhaps 15 or 20 nm in some systems.
- Micellar solutions of surfactants cause departures from non-ideality of the vapor pressure of the continuous phase and have other properties not characteristic of colloids.
- SEDDS Self-Emulsifying Drug Delivery Systems
- SEDDS self-emulsifying drug delivery systems
- SEDDS and the related SMEDDS self-microemulsifying drug delivery systems
- TSEDDS Tocan Self-Emulsifying Drug Delivery Systems
- SEDDS self-emulsifying drug delivery systems
- TSEDDS and the related TSMEDDS are useful to improve lipophilic drug dissolution and oral absorption.
- Biocompatible Capable of performing functions within or upon a living organism in a manner that does not terminate or excessively disable the life of the organism, i.e., without undue toxicity or harmful physiological or pharmacological effects.
- a prodrug is a chemical derivative of a therapeutic agent which, following administration, is cleaved or metabolized to release the therapeutic agent in situ.
- Hydrocarbyl By “hydrocarbyl” is meant moieties containing carbon and hydrogen atoms only, with the indicated number of carbon atoms. Hydrocarbyl groups may be straight-chain or branched-chain, aliphatic or aromatic, alkanes or alkenes.
- Unsaturated groups such as 1- and 2-butene and propargyl, including multiple unsaturated groups such as butadienyl and phenyl or polyphenyl, are included in this term.
- the present invention provides emulsion or liposome particles coated with a "stealth coat" so as to evade the phagocytic cells of the reticuloendothelial cell system (RES), comprising the liver, lungs, spleen and bone marrow.
- RES reticuloendothelial cell system
- particles that target particular cells where the therapeutic agent is needed for example cancer cells.
- polyoxyethylated derivatives have been used to form the "stealth coat" around the particles or liposomes.
- these agents include POLOXAMERS (also termed Pluronics®), which are block co-polymers of polyoxyethylene and polyoxypropylene, and pegylated surfactants such as Tween 80 and pegylated phospholipids. Particles coated with these molecules have been somewhat successful in evading the RES, but because of inherent toxicity or expense, have been less than satisfactory in clinical use. Furthermore, their corrosive detergency has rendered these compounds of little use in cosmetic applications.
- Tocopherol because of its gentle ability to stabilize biological membranes, is an excellent starting material to form a "stealth coat" surfactant for drugs and cosmetics.
- the chemical reactivity of the phenolic hydroxyl of tocopherol is limited and the ability to synthesize and screen tocol conjugates is substantially hampered by the strong reactants required to form a bond with the hydroxyl. Frequently, unacceptable side reactions occur or no reaction at all.
- a related compound, 8-carboxytocol which has been described in the literature, has been overlooked as a platform for the formation of prodrug and surfactant conjugates.
- This compound possesses excellent reactivity and versatility for synthesis of complex derivatives.
- the membrane insertion and stabilizing properties of this compound are expected to be retained and also expected to be biodegradable, albeit more slowly than esters or phosphate diesters.
- carboxytocans that retain the 6-hydroxyl were expected to be effective antioxidants.
- the present invention provides benzopyran derivatives, including carboxytocans (and other tocans) as a platform for covalently coupling biomolecules to benzopyrans.
- "stealth coat" surfactants comprising a hydrophilic "head” and a phytyl tail are provided.
- the very “greasy” phytyl or phytotrienyl tail can be used to position correspondingly large hydrophilic heads at a lipid/water interface.
- stearylamine has a molecular weight of 270 daltons
- the analogous carboxytocan has a molecular weight of about 450 daltons, a 65% increase.
- Betaine a good example of a corrosive and toxic detergent, has a CMC of about 0.0006 M, the CMC of TPGS is 0.0001 M, making TPGS a better detergent by a factor of six at low concentrations while gentle on cells.
- the large hydrophilic heads can also be used to prevent the interaction of the lipid droplets with phagocytic cells by "steric hindrance" and by binding of a layer of water to the particle through hydrogen bonds.
- the benzopyran derivative is a carboxytocan polyglutamate.
- Surfactants of this type are hydrophilic with high HLB values and are effective by steric hindrances to coalescence and by electrostatic repulsion in stabilizing emulsions during storage.
- Polyglutamate is an effective "stealth coat.”
- Bacillus anthracis a highly virulent bacterium which multiplies unchecked in the blood stream of mammals, including man, uses a capsule of polyglutamate (gamma-linked) to avoid triggering an immune response and to avoid phagocytosis.
- polyglutamate gamma-linked
- an artificial particle encapsulated in a polyglutamate coat could also evade the immune system, leading to prolonged circulation in the bloodstream, a highly desirable outcome.
- polyglutamate is covalently coupled to an appropriately substituted benzopyrans via mixed anhydride chemistry.
- the addition of the biomolecule or targeting agent (see, e.g., R 5 in
- FIGURES 1-4 and 9-1 1) is the last step of any synthesis.
- the first steps involve formation of the tocan and functional group (carbonyl or carboxyl). This is preferentially done directly from a preferred starting material, often a natural product, so that the stereochemistry of the product can be preserved.
- Vitamin E or Trolox is deoxygenated at the 6-position and then brominated so as to undergo Grignard mediated carboxylation at the 6-position to form 6-tocopherol carboxylate or 2,5,7,8- tetramethylchroman-2,6-dicarboxylic acid, respectively.
- ⁇ -tocotrienol may be brominated directly at any of the open positions on the chroman ring, and carboxylated by metallation to yield mixtures of 5-, 7-, and 5,7-d- ⁇ -tocotriene carboxylate.
- the 5- position is most reactive, comprising as much as 80% of the product.
- the 6'-O-tocol acetic acid ether can be formed by reacting a tocol with ethylbromoacetate and sodium ethoxide to alkylate the phenolic hydroxyl. Longer alkyl substituents may be introduced by analogous chemistry.
- a glycine linker can be introduced to form a tocoglycinate by first protecting the amine of the glycine with FMOC (9-fluorenylmethoxy-carbonyl) or t-BOC (tert-butoxy-carbonyl) and then activating the glycinate carboxyl with thionyl chloride to form the acid chloride.
- FMOC 9-fluorenylmethoxy-carbonyl
- t-BOC tert-butoxy-carbonyl
- This intermediate will then participate in the nucleophilic attack on the phenolic hydroxyl of the tocol when mixed in the presence of TEA or other basic amine and a catalytic amount of DMF in anhydrous methylene chloride or THF.
- carboxytocan derivatives thus formed may preferentially include "amide” (also called “peptide”) bonds of the form -NH-CO-.
- the amide bonds are preferentially formed by mixed anhydride chemistry, or may be formed with carbodiimides or phosgene as a condensing agent.
- the preferred amide bonds are biodegradable, but are more slowly degraded than ester, sulfhydryl, or diphosphoester bonds, and for that reason have surprising advantages as surfactants.
- ester bonds from the carbonyl are also suitable.
- the chemical bond is preferably a "zero linker" amide bond.
- the active functional group is the 5, 6, 7, or 8 carboxyl on the benzopyran ring.
- bifunctional or multifunctional linkers such as glycine, glutamate, aspartic acid, cysteine, lysine, arginine, or even succinate to the carboxyl, additional functional reactivity is obtained. Both homomultifunctional and heteromultifunctional linkers are provided.
- Carboxytocans as surfactants for example as soaps, detergents, and cosmetics, will have good environmental compatibility, be biodegradable, be gentle on the skin or mucosa, active in hard water, will absorb UV radiation, will adhere to skin, hair or fiber, and will be readily manufacturable. These are requirements that are advantages provided by the present invention.
- Carboxytocans can serve as biological detergents or as depot storage forms for the sustained-release delivery of drugs.
- Other multiphase systems include liquid crystalline structures such as liposomes, which are also suitable for drug delivery.
- the relatively nonpolar tocopherols have proved rather poor in forming liposomes, and only 20 mol % tocopherol could be incorporated into liposomes made from phospholipids (Fukuzawa, K. et al., 1992, "Location and dynamics of -tocopherol • in model phospholipid membranes with different charges" Chem. Phys.
- Lipids 63:69-75 with little surface association of the phenolic hydroxyl.
- Carboxytocans are particularly useful in forming anionic surfactants and anionic liposomes.
- ionic nanoparticles or nanocrystals are readily envisaged.
- the invention provides compositions in which a pharmaceutical, nutriceutical, cosmeceutical, vitamin, foodstuff, antigen, catalyst, cell, nanoparticle, oligonucleotide, gene, extract, cosmetic or fiber is solubilized, protected or dispersed in a solution, particle, emulsion, microemulsion, nanoemulsion, liposome, niosome, molecular matrix or coating that include the benzopyran derivatives of the invention, optionally with other oils, co-solvents, surfactants and co-surfactants.
- zero linker and linker-based carboxytocans and carboxybenzopyrans, and their derivatives, and the uses of carboxytocans as excipients, surfactants, as prodrugs, and as novel therapeutics, in creams, lotions, soaps, cosmetics, sunscreens, eyedrops, foodstuffs, toothpaste, detergents, emulsions, microemulsions, liposomes, capsules, nanosuspensions, nutriceuticals and injectables.
- the compositions may be administered orally, topically, or by other nonparenteral routes.
- compositions containing the benzopyran derivatives of the present invention many therapeutically useful drugs or other compounds are insoluble in water or poorly soluble, and must be administered in the form of an emulsion, microemulsion, or pre-emulsion concentrate, or as a micellar solution or liposome.
- the present invention provides a targeted therapeutic agent that can be direct to the desired cell.
- - 1 Q- can be used to modify the surface properties of emulsion droplets or liposomes so as to produce "stealth" or targeted medicament delivery formulations.
- the composition of the invention is a liposome that includes a tocan or derivative selected for its chemical stability and its ability to form bilayers alone and in mixtures with phospholipids and cholesterol or phytosterols.
- the tocans of the present invention form liposomes with novel surface properties.
- targeted benzopyran derivatives are provided.
- the hydrophilic substituent of the tocan surfactant is selected from a list of compounds, such as folate, that are preferentially bound, adhere to, or are taken up by particular types of cells. In this way, the contents of the drug delivery vehicle can be targeted to these cells. See, e.g., Reddy, J.A. and P.S. Low, 1998, "Folate-mediated targeting of therapeutic and imaging agents to cancers" Crit. Rev. Therapeutic Drug Carrier Systems 15(6):587-627.
- the benzopyran-containing compositions of the invention can be in the form of an emulsion, microemulsion, micellar solution, liquid crystalline system, self-emulsifying drug delivery system, or a liposomal formulation for parenteral administration.
- parenteral administration includes intravenous, pulmonary, intraocular, intrathecal, transmucosal, intratracheal, transdermal, subcutaneous, intraperitoneal or intramuscular administration.
- Oil-in-water, water-in-oil, and bicontinuous emulsions (Shinoda, K. et al, 1984, "Principle of attaining very large solubilization” J Phys. Chem. 88:5126), nanoemulsions, microemulsions, as well as liposomes, soaps, and detergents are suitable forms of the invention.
- TLC (95:5 hexane ethyl acetate) indicated no change. An additional 0.85 g of sodium ethoxide was added and stirring continued at ambient temperature. Two hours later, TLC (95:5 hexane ethyl acetate) indicated that the d- ⁇ -tocopherol was virtually gone. There was a major product spot and two minor spots: ⁇ -d-tocopherol and a faster moving spot that was in the d- ⁇ -tocopherol originally. The reaction mixture was concentrated in vacuo and the residue was triturated with 200 mL of hexanes. The hexane solution was filtered and concentrated in vacuo to afford 12.4 g of crude product.
- the light yellow oil was pumped on a Kugelrohr at 50°C and 0.2 Torr to remove solvent and excess ethyl bromoacetate.
- the crude product was loaded onto a 75 S Biotage column in 50 mL of hexane and eluted with 4 L of 12: 1 hexane ethyl acetate. Fraction two contained the fast moving spot, ethyl bromoacetate and some desired product based on NMR and weighed 2.9 g. Fractions three through five were pure.
- the ethyl ester was removed to provide the carboxylic acid.
- the resulting product can be derivatized at the terminal carboxyl with appropriately reactive R 5 groups selected as hydrophilic substituents (i.e., not adherent to a C18 column by HPLC) to provide the benzopyran derivatives of the invention.
- Example 2 The Synthesis of a Representative Benzopyran Derivative: 5-Carboxy-(d- ⁇ -tocopheryl-6-ol)
- a representative benzopyran derivative of the invention a 5-carboxytocopherol
- d- ⁇ -Tocopherol (10 g) was dissolved in 25 mL of carbon tetrachloride, cooled to 0-5°C in an ice bath and treated with 1.3 mL of bromine in 25 mL of carbon tetrachloride over 30 minutes. The reaction was stored overnight at ambient temperature.
- Example 3 The Synthesis of a Representative Benzopyran Derivative: RRPv-d- ⁇ -Tocopheryl-6-carboxylic acid
- RRPv-d- ⁇ -Tocopheryl-6-carboxylic acid the synthesis of a representative benzopyran derivative of the invention, a 6-carboxytocopherol, is described.
- FIGURE 14 Conversion of RRR-d- ⁇ -tocopherol to RRR-d- ⁇ -tocopherol-6-carboxylate is depicted in FIGURE 14.
- the advantage of this route is significant: all the necessary carbons and connectivity are present in the starting material (Vitamin E), which is abundant, inexpensive and readily available.
- Deoxygenation of a phenol begins by activating the phenolic oxygen as some derivative, such as tosylate, isourea, dimethylthiocarbonate, or triflate, followed by reduction (Sebok, P.; Timar, T.; Eszenyi, T., 1994, J. Org. Chem. 59:6318-6321 ; Wang, F.; Chiba, K.; Tada, M., 1992, J.
- the resulting hydrocarbon can be brominated (bromine, acetic acid). Because there is only one site on the aromatic ring that can react with bromine, the reaction is expected to be high yielding.
- the resulting bromide can then be converted to its corresponding Grignard reagent, which on treatment with carbon dioxide and then aqueous acidic workup should afford the desired product.
- 6-O-d- ⁇ -Tocopherol Acetic Acid Ether-Polyglutamate the synthesis of a representative benzopyran derivative of the invention, 6-O-d- ⁇ -tocopherol acetic acid ether-polyglutamate, is described.
- 6-O-d- ⁇ -tocopherol acetic acid ether -polyglutamate was carried out via mixed anhydride chemistry.
- 6'-O-d- ⁇ -Tocopherol acetic acid ether was activated by adding 1.00 equivalents-of isobutyl chloro formate (IBCF) and N-methylmorpholine (NMM) in anhydrous tetrahydrofuran
- 6-O-d- ⁇ -Tocopherol acetic acid ether (prepared as described in Example 1) was activated by adding 1.00 equivalents of isobutyl chloroformate (IBCF) and N-methylmorpholine (NMM) in anhydrous tetrahydrofuran (THF) medium at -5°C. The reaction mixture was stirred at -5°C for 64 mins. The mixed anhydride was filtered to remove the N-methylmorpholine hydrochloride salt
- Example 8 The Synthesis of a Representative Benzopyran Derivative: d- ⁇ -Tocopherol-5 -carboxylic Acid Taurine Amide
- a representative benzopyran derivative of the invention d- ⁇ -tocopherol-5-carboxylic acid taurine amide
- taurine amide of d- ⁇ -tocopherol-5-carboxylic acid conjugate is carried out via mixed anhydride chemistry.
- 1.00 equivalent of d- ⁇ -tocopherol-5- carboxylic acid is activated by adding 1.00 equivalents of isobutyl chloroformate (IBCF) and N-methylmorpholine (NMM) in 100 ml of anhydrous tetrahydrofuran (THF) medium at -5°C.
- IBCF isobutyl chloroformate
- NMM N-methylmorpholine
- THF anhydrous tetrahydrofuran
- the reaction mixture is stirred at -5°C for 60 mins.
- the mixed anhydride is filtered to remove the N-methylmorpholine hydrochloride salt (NMM:HC1).
- the filtrate is added dropwise to 1.00 equivalent solution of aminoethanesulfonic acid (Taurine,
- Example 9 The Synthesis of a Representative Benzopyran Derivative: d- ⁇ -Tocopherol-5-carboxylic Acid t-BOC-PEG Amide
- a representative benzopyran derivative of the invention d- ⁇ -tocopherol-5-carboxylic acid t-BOC PEG amide
- d- ⁇ -tocopherol-5-carboxylic acid is carried out via mixed anhydride chemistry.
- 0.9 Equivalent of d- ⁇ -tocopherol-5-carboxylic acid is activated by adding 0.9 equivalents of isobutyl chloroformate (IBCF) followed by addition of 0.9 equivalents of N-methylmorpholine (NMM) in 100 ml of anhydrous tetrahydrofuran (THF) medium at -5°C.
- IBCF isobutyl chloroformate
- NMM N-methylmorpholine
- THF anhydrous tetrahydrofuran
- the reaction mixture is stirred at -5°C for 60 mins.
- the mixed anhydride is filtered to remove the N-methylmorpholine hydrochloride salt (NMM:HC1).
- Examples 6 and 7 were tested for their properties as a surfactant by measuring surface tension at a standard concentration in comparison to other surfactants.
- the surface tension ( ⁇ s ) of a 0.1% solution in 20 mM phosphate buffer pH 7.4 was measured using a
- TPGS Eastman, Kingsport, TN
- Amisoft Ajinomoto, Tokyo, JP
- the tococarboxy monoglutamate derivative was superior to TPGS (a nonionic surfactant sold commercially), and tococarboxy triglutamate derivative was comparable to TPGS.
- the benzopyran derivatives of the invention can be evaluated as bioavailability enhancers in an in vitro CACO-2 tissue culture model.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2002307237A AU2002307237A1 (en) | 2001-03-23 | 2002-03-21 | Carboxybenzopyran derivatives and compositions |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US27846001P | 2001-03-23 | 2001-03-23 | |
US60/278,460 | 2001-03-23 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2002076938A2 true WO2002076938A2 (en) | 2002-10-03 |
WO2002076938A3 WO2002076938A3 (en) | 2003-03-06 |
Family
ID=23065058
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2002/011266 WO2002076938A2 (en) | 2001-03-23 | 2002-03-21 | Carboxybenzopyran derivatives and compositions |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU2002307237A1 (en) |
WO (1) | WO2002076938A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111635390A (en) * | 2020-06-30 | 2020-09-08 | 江南大学 | Low-foam alpha-tocopherol surfactant and preparation method thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5534536A (en) * | 1993-08-24 | 1996-07-09 | Ono Pharmaceuticals Co. Ltd. | Fused phenol derivatives |
US5917060A (en) * | 1997-12-17 | 1999-06-29 | Basf Aktiengesellschaft | Preparation of chromanyl derivatives |
US6239171B1 (en) * | 1991-11-22 | 2001-05-29 | Lipogenics, Inc. | Tocotrienols and tocotrienol-like compounds and methods for their use |
US6387882B1 (en) * | 1997-12-24 | 2002-05-14 | Senju Pharmaceutical Co., Ltd. | Vitamin E derivatives |
-
2002
- 2002-03-21 WO PCT/US2002/011266 patent/WO2002076938A2/en not_active Application Discontinuation
- 2002-03-21 AU AU2002307237A patent/AU2002307237A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6239171B1 (en) * | 1991-11-22 | 2001-05-29 | Lipogenics, Inc. | Tocotrienols and tocotrienol-like compounds and methods for their use |
US5534536A (en) * | 1993-08-24 | 1996-07-09 | Ono Pharmaceuticals Co. Ltd. | Fused phenol derivatives |
US5917060A (en) * | 1997-12-17 | 1999-06-29 | Basf Aktiengesellschaft | Preparation of chromanyl derivatives |
US6387882B1 (en) * | 1997-12-24 | 2002-05-14 | Senju Pharmaceutical Co., Ltd. | Vitamin E derivatives |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111635390A (en) * | 2020-06-30 | 2020-09-08 | 江南大学 | Low-foam alpha-tocopherol surfactant and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
AU2002307237A1 (en) | 2002-10-08 |
WO2002076938A3 (en) | 2003-03-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TW482685B (en) | Lipophilic carrier preparations comprising digalactosyldiacylglycerols | |
EP2579845B1 (en) | Ophthalmic compositions for the administration of liposoluble acitve ingredients | |
WO2002076970A2 (en) | Tocopherol succinate derivatives and compositions | |
TW200522978A (en) | Tocopherol-modified therapeutic drug compounds | |
KR960016908A (en) | Pharmaceutical carrier | |
JPH07502197A (en) | Particles, method of making the particles and their use | |
WO1999004787A1 (en) | Taxol emulsion | |
EP0514506B1 (en) | Lipid formulation system | |
CN107001303A (en) | The long-chain monoesters of 2,5 2 (methylol) tetrahydrofurans and diester, its purposes and preparation | |
US6679822B2 (en) | Polyalkylene oxide-modified phospholipid and production method thereof | |
US6683194B2 (en) | Tocopherol derivatives | |
JPH07108166A (en) | Liposome | |
Anil et al. | Microemulsion as drug delivery system for Peptides and Proteins | |
JP2002363278A (en) | Polyalkylene oxide-modified phospholipid and method for producing the same | |
WO2002076938A2 (en) | Carboxybenzopyran derivatives and compositions | |
CN1875022B (en) | Tocopherol-modified therapeutic drug compounds | |
WO2018159826A1 (en) | Absorption promoter and use for same | |
WO2002076937A2 (en) | Aminobenzopyran derivatives and compositions | |
WO1998013359A1 (en) | Ultramicroemulsion of spontaneously dispersible concentrates of esters of baccatin-iii compounds with antitumor and antiviral effect | |
JP4403303B2 (en) | Phospholipid derivative and method for producing the same | |
WO2002026324A2 (en) | Tocol-based compositions containing amiodarone | |
JP4008965B2 (en) | Preparation of lecithin-containing fat emulsion | |
JP2006265104A (en) | Phospholipid derivative for external preparation for skin, external preparation for skin, liposome and fat emulsion | |
JP2001025654A (en) | Surface active auxiliary | |
GB2285804A (en) | Terpinol esters & their use as biotenside solvents for pharmaceuticals and cosmetics |
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 NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ 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 CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE 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 | ||
AK | Designated states |
Kind code of ref document: A3 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 NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 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 CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase in: |
Ref country code: JP |
|
WWW | Wipo information: withdrawn in national office |
Country of ref document: JP |