WO2010054495A2 - Formulation colloïdale non-aqueuse - Google Patents

Formulation colloïdale non-aqueuse Download PDF

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Publication number
WO2010054495A2
WO2010054495A2 PCT/CH2009/000361 CH2009000361W WO2010054495A2 WO 2010054495 A2 WO2010054495 A2 WO 2010054495A2 CH 2009000361 W CH2009000361 W CH 2009000361W WO 2010054495 A2 WO2010054495 A2 WO 2010054495A2
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formulation
component
gel
surfactant
gels
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PCT/CH2009/000361
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English (en)
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WO2010054495A3 (fr
Inventor
Vaclav Velkoborsky
Sankha Ghosh
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Profimed S.R.O.
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Priority to EP09756130A priority Critical patent/EP2355806A2/fr
Publication of WO2010054495A2 publication Critical patent/WO2010054495A2/fr
Publication of WO2010054495A3 publication Critical patent/WO2010054495A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/14—Liposomes; Vesicles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A61K8/375—Esters of carboxylic acids the alcohol moiety containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86—Polyethers
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/06—Preparations for care of the skin for countering cellulitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/59—Mixtures
    • A61K2800/596—Mixtures of surface active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses

Definitions

  • the invention relates to formulations, such as a gel, which are non-aqueous, colloidal, containing tubulosomes as defined herein; methods of manufacturing such formulations; oral care compositions and topical / transdermal compositions containing such formulations; methods of manufacturing such compositions and to the use of these formulations and compositions in cosmetics, pharmaceuticals, nutrition and dietary.
  • Vesicles have become the vehicle of choice in drug and cosmetic delivery. Different types of carriers of pharmaceutical and cosmetic importance are known in the art. They are particulate, polymeric, macromolecular and cellular carrier. Particulate type carrier, which is also known as colloidal carrier system, includes lipid particles (low and high density lipoprotein-LDL and HDL, respectively), microspheres, nanoparticles , polymeric micelles and vesicles.
  • Particulate type carrier which is also known as colloidal carrier system, includes lipid particles (low and high density lipoprotein-LDL and HDL, respectively), microspheres, nanoparticles , polymeric micelles and vesicles.
  • hydrogels require substantial amounts of preservatives, which is disadvantageous, e.g. in case of oral administration.
  • the present invention aims to overcome one or more or of the problems associated with known formula ⁇ tions containing active ingredients. Particularly, they leak additives / active ingredients from the vesicles (liposomes / niosomes) of such formulations, they can't efficiently solubilize and transport difficult hydro- philic and liphilic substances/additives, they can't form gels, they need aqueous gel / emulsion.
  • US 4812306 and US5264205 disclose certain anhydrous gel formulations, and teach that the main challenge towards composing a non-aqueous dentifrice gel/cream is to form an anhydrous gel/cream/emulsion, which is consistent in nature, stable in storage, and has appropriate flow properties (viscosity, thioxotroy, yield value) and a pleasant surface-texture.
  • a "formulation” relates to a combination of two or more components which are not intended as a product to the end-user but rather a commercial intermediate to manufacture such end-products.
  • the nature of the formulation basically determines the appearance of the end-product, i.e. gel or emulsion.
  • compositions relate to a combination of two or more components which are intended as a product to the end-user.
  • Compositions according to this invention contain a formulation as described herein and one or more additives. Such additives basically determine the nature of the composition, i.e. a topical / transdermal composi ⁇ tion or an oral care composition.
  • additive is any component, other than used for obtaining the formulation as defined above, which is useful in obtaining a composition as defined above .
  • colloid also in the context of colloidal formulation, is well known in the field.
  • a colloid is a broad category of mechanical mixtures where one substance is dispersed evenly throughout another giving rise to a bi-phase non-crystalline substance consisting of nano-particles .
  • a colloidal system comprises of two separate phases: a dispersed phase (inter- nal phase) and a continuous phase (dispersion medium) .
  • the average diameter of the dispersed phase particles approximately ranges between 5 and 200 nanometers. Such particles are normally invisible to an optical microscope, but their presence can be confirmed by ultra- microscopy or electron microscopy.
  • Some colloids are translucent due to the Tyndall effect, which is the scattering of the visible light by particles in the colloid.
  • colloids may be opaque or have a slight color.
  • the dispersed phase particles or droplets are largely affected by the surface chemistry present in the colloid. Because the average size of the dispersed phase particles may be difficult to measure, and because colloids have the appearance of solutions, colloids are sometimes identified and characterized by their proper- ties.
  • a gas suspended in a liquid or solid is called foam.
  • a liquid dispersed in a different liquid is called an emulsion.
  • a liquid dispersed in a solid is called a solid emulsion.
  • a solid or liquid suspended in a gas is called an aerosol.
  • a solid suspended in a liquid is called a sol although a high concentration of solid is also called a paste.
  • a solid suspended in a solid is called a solid suspension.
  • Major forces are as follows: i) Excluded Volume Repulsion; ii) Electrostatic interaction; iii) van der Waals forces; iv) entropic forces; v) Steric forces.
  • surfactant is well known in the field. Surfactants are surface active compounds that reduce the surface tension of a liquid and interfacial tension between two liquids by adsorbing at the interfaces of liquid-gas and liquid-liquid, respectively.
  • Surfactants are usually organic compounds that are amphiphilic due to coexistence of hydrophilic and lipophilic groups, often referred to as “heads” and “tails”, respectively.
  • Surfactant solutions may contain a disordered phase of free monomers (molecules and/or ions, "nM") and an ordered phase of aggregates (micelles, vesicles, etc., "M” n ) , through self-assembling above a critical concentration and temperature, in equilibrium.
  • a surfactant can be classified by the presence of formally charged groups in its head.
  • a non-ionic surfactant has no charge groups in its head.
  • surfactant family refers to a group of surfactants belonging to a given set of H x T y , where H and T denote particular head and tail groups that are extended by digital numbers of x and y, restively, to form a family in which each surfactant is indentified as a member of it.
  • H and T denote particular head and tail groups that are extended by digital numbers of x and y, restively, to form a family in which each surfactant is indentified as a member of it.
  • Exemplary surfactants which may be used for the inventive formulations are identified in table 1 (see end of specification) .
  • a micelle is well known in the field.
  • a micelle is an aggregate of surfactant molecules dispersed in a liquid colloid. Geometrical orientation of the head-tail groups in monomers in such an aggregate depends on the polarity of the dispersing medium.
  • monomer units In an aqueous or polar medium, monomer units assembles in such a fashion that the head groups forms the outer surface, surrounded by the polar solvent molecules, while the liophilic tails are sequestered inner core or centre region.
  • This type of micelle is called normal phase or typical micelle.
  • the hydrophilic heads are sequestered in the core/centre region and the liophilic tails are extended away from the core region.
  • a micelle may form when surfactant molecules aggregate to form particles suspended in solution, which is a colloid, nonetheless. Since micelle forms colloid by the association of a discrete number of components, it is often called an "association colloid".
  • Vesicle is well known in the field. Vesicles are uni- or multi-lamellar aggregates composed of bi-layers of amphiphilic molecules. They are, in general, spheroid. Phospholipids, cholesterols and surfactants are known to form vesicles in aqueous medium. Surfactant vesicles are analogous to surfactant micelles in molecular structural sense.
  • the bi-layer comprises of either typical (head groups are pointing towards both the exterior as well as interior polar solvent, while tail groups of both layers are sequestered face one another) arrangement of the amphiphilic molecules or reverse.
  • "Liposomes" and “niosomes” are vesicles that have been used as carriers of various drugs.
  • Liposomes are simple microscopic vesicles in which lipid bilayer structures are present with an aqueous volume entirely enclosed by a membrane, composed of lipid molecules with double liophilic tails. There are a number of components present in liposomes, with phospholipid and cholesterol being the main ingredients. The type of phospholipids includes phosphoglycerides and sphingolipids, and together with their hydrolysis products. Niosomes are similar vesicular aggregates that stems from non-ionic surfactants instead of phospholipids in an aqueous medium.
  • gel is well known in the field. Generally, gels are an intermediate state of matter, containing both solid and liquid components.
  • the solid component comprises a three-dimensional network of interconnected aggregates (typical/reverse vesicles) or molecules which immobilizes the liquid continuous phase.
  • Hydrogels have an aqueous continuous phase
  • organo- gels have an organic solvent as the liquid continuous phase. Gels may also be classified based on the nature of the bonds involved in the three-dimensional network. In chemical gels, strong covalent bonds comprise the gel network, and in physical gels, the hydrogen bonds, electrostatic and van der Waals interactions, which are relatively weaker.
  • Fig. 1 shows an idealized inverse tubulosome structure of an inventive formulation, wherein the dispersing medium is substantially non-polar or liophilic.
  • 1 shows a tubulosome vesicle in perspective view
  • 2 shows the cross section of this tubulosome
  • 3 shows an enlarged view of this cross section identifying a stacked, bi-layered surfactants
  • n denotes the number of stacking.
  • Fig. 2 shows an idealized typical tubulosome structure of an inventive formulation, wherein the dispersing medium is substantially polar or hydrophilic.
  • 1 shows a tubulosome vesicle in perspective view
  • 2 shows the cross section of this tubulosome
  • 3 shows an enlarged view of this cross section identifying stacked, bi-layered surfactants
  • n denotes the number of stacking
  • 4 denotes hydrophilic interior.
  • Fig. 3 shows a known spherical liposome / ni- osome vesicle 1; its idealialized 3D strucutre 2, its 2D cross-section 3.
  • typical bilayer lamella e.g. phospholipid nonionic surfactant
  • hydrophilic core liophilic interior 6
  • surrounding aqueous medium 7 are shown.
  • the invention relates to a non-aqueous colloidal formulation comprising of a first and a second component wherein said first component is an amphiphilic, non-ionic surfactant; said second component is a water-free, liquid, organic dispersing medium.
  • the invention relates to a formulation which is a gel (i.e. solid / liquid phase) or an emulsion (i.e. liquid / liquid phase) .
  • the formulation may be a gel selected from the class of i) organogels, ii) pure amphiphilic gels, iii) mixed amphiphilic gels and iv) co-gels.
  • This inventive formulation is engineered to accommodate various additives either solubilizing over a wide range of solubility or suspending, retain the chemical functionalities of additives, transport and deliver the additives to target site through a range of possible administration methods. Without being bound to theory, it is believed that this is due to the formation of a stable isotropic, visco-elastic association colloid.
  • Such colloid comprises multi-lamellar bi-layer stacked tubular vesicle (tubulosome) carriers of amphiphilic surfactants.
  • tubulosome carriers constitute the skeleton of a three dimensional gel network to immobilize the solvent/liquid medium thereby, which is consistent, stable on storage with high shelf-life.
  • colloids are easy to manufacture at industrial scale, offer broad range of adjustable viscosity and gel-flow properties (rehology, yield point/value, thixotropy) , are capable to accommodate various additives (through solubilizing the hydrophilic ones in the hydrophilic interior of tubu- losomes, the liophilic ones in the liophilic interior of tubulosomes as well as in the continuous solvent and suspending the particles of the insoluble ones within the 3D gel network) , are suitable towards oral-care / dentifrice applications and topical / transdermal applications onto skin.
  • the swollen tubulosomes are capable in transporting the entrapped additives / drugs through osmotic diffusion, and hence ensure / stipulate sustained release at site-specific target.
  • This non- aqueous tubulosome based gel / association colloid technology thus offers a unique way to preserve the chemical functionalities of the ingredients thereby, and to selectively as well as sustainably deliver them to the target site through a number of administration methods.
  • the first component is also referred to as the "gelator” or “gelling agent”.
  • the invention particularly relates to a formulation as described herein, wherein said first component is a solid, amphiphilic, non-ionic surfactant.
  • Preferred is one or a combination of solid surfactants, belonging to non-ionic, zwitterionic, anionic and cationic classes of surfactants, with a melting point (MP) ranging between 35 - 80 0 C, more preferably between 45 - 70 0 C, and most preferably between 50 - 65°C.
  • MP melting point
  • Non-ionic and zwitterionic surfactant classes are more preferable, while the non- ionic class is most preferable.
  • Said surfactant is particular preferably selected from the mono- and poly ⁇ ester families of Sorbitan, Glycerol, Glycol, polyalkyl- glycol and fatty alcohols (with hydrocarbon chain with at least 12 carbon atoms and higher) with fatty acids such as lauric acid, palmitic acid, stearic acid, oleic acid, cocoic acid, ricinolic acid, tallic acid, etc; mono- and poly-substituted amine oxides of fatty alcohols, mono- and poly-substituted alkanolamides; Ethylene Oxide (EO) /Propylene Oxide (PO) block copolymers (such as [EO] x [PO] y [EO] x , [PO] ⁇ [EO] y [PO] x ) ; alkylamine ethoxylates (such as CH3- [CH2] !
  • said solid, amphi- philic non-ionic surfactant may be selected from the group consisting of mono- and poly-esters, wherein the acid component of said ester is selected from the group consisting of behenic acid, eicosadic acid and isostearic acid ; the alcohol component of said ester is selected from the group consisting of glycol, glycerol, poly- glycols and poly-glycerols; particularly Polyglyceryl-10 Behenate / Eicosadioate; Glyceryl Behenate / Eicosadioate and Glyceryl tribehenate / Isostearate / Eicosadioate.
  • dispersing medium includes liquids without surfactant properties as well as liquids with surfactant properties.
  • Liquids with surfactant properties A wide variety of liquid surfactants / classes of surfactants may be used as a second component. Such surfactants include non-ionic, anionic, cationic, zwitterionic surfactants .
  • Non-ionic surfactants are preferably based on the mono- and poly- ester families of Sorbitan, Glycerol, Glycol, polyalkyl-glycol and fatty alcohols (with hydrocarbon chain with at least 12 carbon atoms and higher) with fatty acids such as lauric acid, palmitic acid, stearic acid, oleic acid, cocoic acid, ricinolic acid, tallic acid, etc; mono- and poly-substituted amine oxides of fatty alcohols, mono- and poly-substituted alkanolamides; Ethylene Oxide (EO) /Propylene Oxide (PO) block copolymers (such as [EO] x [PO] y [EO] x
  • Anionic surfactants are preferably based on sulfate, sulfonate and carboxylate anions. Particular preferred are Alkali metal salts of fatty acids, such as Sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, other alkyl sulfate salts, Sodium laureth sulfate (also known as sodium lauryl ether sulfate SLES), Alkyl benzene sulfonate, Sodium Lauroyl Sarcosinate.
  • SDS Sodium dodecyl sulfate
  • ammonium lauryl sulfate other alkyl sulfate salts
  • Sodium laureth sulfate also known as sodium lauryl ether sulfate SLES
  • Alkyl benzene sulfonate Sodium Lauroyl Sarcosinate.
  • Cationic surfactants are preferably based on quaternary ammonium cations. Particular preferred are Cetylpyridinium chloride (CPC) and other halides, Benzalkonium chloride (BAC) and other halides, Benzetho- nium chloride (BZT) and other halides, Cetyl trimethylam- monium bromide (CTAB) (hexadecyl trimethyl ammonium bromide), and other alkyltrimethylammonium salts, Polyethoxylated tallow amine (POEA) .
  • CPC Cetylpyridinium chloride
  • BAC Benzalkonium chloride
  • BZT Benzetho- nium chloride
  • CAB Cetyl trimethylam- monium bromide
  • POEA Polyethoxylated tallow amine
  • Zwitterionic surfactants Particular preferred are Dodecyl betaine; Cocamidopropyl betaine; Dodecyl dimethylamine oxide; Coco ampho glycinate; betaine oxides, alkyl amine oxides.
  • Organic liquids without surfactant properties A wide variety of organic liquids without surfactant properties may be used as a second component in the inventive formulations.
  • Such organic liquids include vegetable oils such as corn oil, cottonseed oil, soybean oil, olive oil, sesame oil, sunflower oil and castor oil.
  • Such organic liquids also include derivatives of vegetable oils (such as alcohols, esters, alkoxylates of vegetable oils) ; particularly long chain synthetic esters such as isopro- pyl myristate, ethyl oleate, ethyl myristate, etc.;
  • Such organic liquids also include acyclic and cyclic alkanes (higher than five carbon) such as hexane, octane, decane, dodecane, tetradecane, hexadecane, octadecane, cyclohex- ane, cis and trans decalines,
  • Such organic liquids also include polyalkenes, such as poylisodecene, polyisobu- tene, polybutene, etc.;
  • Such organic liquids also include cyclic and acyclic alkenes such as squalene.
  • the structure of the inventive gels may be described as (1) pure amphiphilic gel; (2) Organogel; (3) Mixed amphi- philic gel; and (4) Co-gel.
  • Pure amphiphilic gel This type comprises gels where the first component comprises one or more solid amphiphilic surfactants and the second component comprises or consists of a liquid amphiphilic surfactant.
  • Organogel This type com- prises gels where the first component comprises one or more solid amphiphilic surfactants and the second component comprises one or more liquids without surfactant properties.
  • (3) Mixed amphiphilic gel This type comprises gels where the first component comprises one or more solid amphiphilic surfactants and the second component comprises two or more liquid amphiphilic surfactants.
  • Co-gel This type comprises those gels wherein the second component is a mixture of an organic liquid without surfactant properties and a liquid amphiphilic surfactant.
  • Organogels (2) have revealed the surfactant aggregates to form rod-like tubular clusters. The clusters associate with each other through junction points due to van der Waals and electrostatic dispersion interactions (including weak to strong hydrogen bondings) constructing a 3-D network that immobilizes the solvents and acts as the skeleton of the gel.
  • the toroids are short-lived structures, existing only at the gelation temperature. Further cooling results in their conversion into tubules.
  • Gel microstructure is affected upon incorporation of a relatively higher hydrophilic surfac ⁇ tant, such as polysorbate 20, polysorbate 40, pluronic, PEG-80 Sorbitan Laurate, etc.
  • Organogels spiked with the hydrophilic surfactants comprise star-shaped clusters of the surfactant tubules.
  • the molecules of spiking hydro- philic surfactants are revealed to participate in formation of mixed inverse bi-layers, which is comparable to mixed reverse micelle, and thus formation of tubular aggregates, tubulosomes, by stacking.
  • Amphiphilic gels (1) ; (3) consist of tubules that become more numerous with increasing gelator concentration.
  • the tubulosomes are clustered into star- or flower-shaped structures with a diameter of order 8-100 ⁇ m in the amphiphilic gels as in cases of organogels spiked with a hydrophilic surfactant.
  • tubules are revealed to be the aggregates of concentrically stacked sheets of mixed surfactant bi-layers with solvent embedded interiors.
  • the mixed typical tubulosomes possess higher number of binding sites that stipulate multidimensional clusterification through inter-vesicular association interactions to produce star or flower shaped clusters in amphiphilic gels, compared to mono-dimensional clusterification to rod-like clusters in organogels. Higher binding sites attribute to more compact structure of the gel network and hence to greater stability.
  • the clusterification proceeds through fractal growth yielding a 3D gel network, which is essentially a volume fractal, as sol phase cools down. Fractal growth through higher binding sites gives rise to higher fractal dimensionality to the offspring clusters, and hence to the resulting gel network as well.
  • the toroids and rod-like clusters in organo- gels, and tubular/fibrous and star/flower shaped clusters in amphiphilic gels are composed of stacked bi-layer lamella of surfactant molecules, in a fashion similar to well-known vesicles, liposomes and niosomes. This arrangement is retained upon gelation and therefore, the tubules in gel network are comprised of concentric sheets of bi-layers ("Tubulosome”) . This is a unique feature of present invention.
  • the disclosed tubulosomes exactly match to the functional properties of the liposomes and niosomes, although they are more efficient to solubilize the hydrophilic as well as liophilic substances/additives and do not require sophisticated and expensive preparation routes.
  • the active ingredients can be swollen by the tubulosomes which span the entire skeleton of the organo- and amphiphilic-gels, giving rise to swollen tubulosomes and thus attributing to huge enhancement in solubilizing power and stability of the disclosed gel formulations.
  • these swollen tubulosomes largely boost the bioavailability of the active ingredients as well as enable the disclosed gels permeating the active ingredi ⁇ ents into and/or through the skin. These make them attractive carrier vehicles in cosmetic and drug industry for oral, topical and transdermal applications.
  • the closed association model states that above a critical temperature (Krafft temperature) and a critical concen- tration (critical aggregation concentration, CAC) monomers nM of a surfactant in a given bulk solution / medium / sol-phase spontaneously self-assembles / aggregates to form aggregates (either typical in which head groups point toward aggregate-solvent interface, or reverse/inverse in which tail groups point towards aggregate-solvent interface) of equal size, but below CAC and/or Krafft temperature monomers are retained in the bulk phase.
  • Krafft temperature critical temperature
  • CAC critical concen- tration
  • ⁇ ing properties including CMC, aggregation number (N) , melting point, molecular packing parameter (P) and hydrophilic-liophilic balance (HLB) of a surfactant are forumulated towards its appropriate application. Tailoring a particular trade-off combination of these proper ⁇ ties casts a surfactant to yield the desired associated colloid system with satisfactory properties and stabil ⁇ ity.
  • HLB hydrophilic-liophilic balance
  • HLB 20 * MH / M
  • MH is the sum of molecular weights of the hydrophilic portion of the molecule
  • M is the total molecular weight of the whole molecule, giving a result on an arbitrary scale of 0 to 20.
  • An HLB value of 0 corresponds to a completely hydrophobic/liophilic molecule
  • a value of 20 corresponds to a molecule totally hydrophilic.
  • HLB value can be used to select a surfactant molecule for a particular func ⁇ tional role:
  • HLB value 0 to 3 an anti-foaming agent HLB value 4 to 6 : a W/0 emulsifier HLB value 7 to 9 : a wetting agent HLB value 8 to 18 : an 0/W emulsifier
  • HLB value 10 to 19.5 solubilizer or 0/W microemulsifier
  • Each lipophilic ingredient used in 0/W emul- sion/sol has a "required" HLB number, which can be determined through a simple experiment of forming stable emulsion with a standard surfactant of known HLB number.
  • HLB value of the surfactant that provides the lowest interfacial tension between the unique oil and water phases is the "required” HLB of the oil.
  • HLB number of the surfactants can be alternatively measured through chromatographic experiments. In table 1 and 2 we report the HLB numbers and required HLB numbers of various surfactants and liophilic substances, respec- tively.
  • a mixture of surfactants (surfactant blend) of different families and/or classes (with different HLB values) is known to be advantageous, over a single surfactant, in practical formulation of stable associa- tion colloid systems, especially in industrial end uses, since an appropriate surfactant blend is often able to provide lowest interfacial tensions.
  • concentration fraction three situations can arise:
  • the molecules of the surfactant (B) which is present in low concentration, can adsorb at the interface of the aggregates (vesicles, micelles) of the other surfactant (A) , which is present in solution / dispersion in much higher concentration.
  • This adsorption also results in lowering aggregate-aggregate repulsion, which enhances the over kinetic stability of the colloid system against coalescence.
  • a and B are present in bulk solution with comparable concentration and above the CMC, they often increase the resulting CMC of the blend and produce mixed aggregates (vesicles, micelles) with lower size, which are thermodynamically, as well as kinetically more stable than the bigger aggregates.
  • Formation of smaller aggre ⁇ gate promotes formation of more aggregates in solution / dispersion. If one of these surfactants has lower HLB due to its larger liophilic tail group, it promotes in-core solvation of the liophilic materials in liophilic interior of vesicles and typical micelles and raises overall attractive aggregate-aggregate and aggregate- solvent interactions in a liophilic or substantially low polar solvent / medium.
  • the surfactant with higher HLB in this pair promotes aggregate-solvent (solvation) interactions in substantially hydrophilic solvent /medium, while in liophilic or substantially low polar solvent/medium it promotes formation of more reverse/inverse aggregates (vesicles, micelles) with smaller size.
  • HLB number of a surfactant blend can be easily computed through summing the concentration fraction times the HLB number of the surfactant components. Likewise, total "required" HLB number of a mixture of liophilic ingredients can be calculated by summing the concentration fraction times its required HLB number for all liophilic components. HLB numbers of the components can either be theoretical or experimentally measured. Matching total HLB number of surfactant (surfactant blend) with total HLB requirement of a liophilic substance (a mixture of liophilic substances) yields largest entrapment of the additives within vesicles as well as most stable swollen aggregates (swollen tubulosomes) in sol phase association colloids.
  • HLB was meant to be a specific property based solely on the chemical structure of a surfactant. Each functional group was assigned a specific value based on correlation of emulsion properties for various surfactants. Thus, HLB was thought to be independent of intensive variables such as temperature or ionic strength. However heating a gel phase of an association colloid leads to sol phase and cooling a sol phase leads to gel phase back; the temperature at which this phase transition occurs is called phase transition temperature.
  • phase inversion or formation of a water-in-oil emulsion/reverse sol phase; the temperature at which this occurs is the phase inversion temperature, and is common to many nonionic surfactant emulsions and sols.
  • phase transition and inversion can be interpreted as a consequence of the increase in relative hydrophobicity of nonionic surfac ⁇ tants (the surfactant starts to get dissolved in the oil or liophilic interior of vesicle/micelle) with tempera- ture or ionic strength, which in turn leads to a change in aggregate curvature and ultimately packing about the aggregate-solvent interface.
  • HLB may include specific structural information about a given surfactant, its interpretation in terms of other physical properties is somewhat limited.
  • P molecular packing parameter
  • the properties of the chain are not greatly influenced by the type of head group for a given surfac- tant, and thus these correlations hold reasonably well for a wide range of ionic, zwitterionic, and nonionic surfactants.
  • the head groups are always located at the hydrophilic solvent- hydrocarbon interface, but some solvent-hydrocarbon contact remains and cannot be avoided. Complete coverage by head groups would require a close proximity between them which is incompatible with their mutual repulsion. Because of its minimum area for a given volume, the spherical shape is the best way to minimize this contact area. Aggregates are thus expected to be spherical whenever it is sterically possible. To avoid this solvent-hydrocarbon contact, solvent molecules are expelled from the liophilic interior which is composed of dry hydrocarbon of constant density. It has been shown that spherical micelles can grow up to a maximum value of aggregation number (N sph ) and any further growth induces a shape deformation.
  • N sph maximum value of aggregation number
  • a value of P higher than 1 indicates a spontaneous bending of the interface towards oil (hydrophobic / liophilic medium / solvent)
  • a value lower than 1 indicates a spontaneous bending towards water/hydrophilic medium/solvent (typical micelles) .
  • the qualitative estimate of R ShP is no longer sufficient, since oil-water (hydrophilic-liophilic) has to be characterized by two curvatures on each point. P depends on the surfactant chemical structure (1 and v) and on surface repulsions between the head groups (a) .
  • the desired curvature (and thus type of aggregate) may be obtained upon a correct choice of the surfactant molecule and solvent conditions (type of solvent, ionic strength, etc), using P as a guide.
  • P values can be used to estimate the aggregate shape based on the geometry of the monomer, such as a value between 0 and 1/3 corresponds to spherical shape, 1/3 and 1/2 corresponds to cylindrical shape (for single chain tail groups, and the aggregate can be flexible) , 1/2 and 1 corresponds to lamellar shape (for single as well as double chain tail groups, and the aggregate can be flexible) , and a value higher than 1 corresponds to reverse/inverse micelles in substantially liophilic or non-polar solvent/medium.
  • Small aggregates are obtained with ionic and zwitterionic surfactants, while large ones are made up with non-ionic or ionic surfactants under conditions of high ionic strength, since size is controlled by the repulsion interactions between head groups at the interface. When repulsions increase, “a” increases and hence P decreases resulting in generation of smaller aggregates.
  • size and critical aggrega ⁇ tion concentration are related: surfactants with low CAC aggregate into large aggregates, the higher the CAC, the smaller the aggregates. Therefore, a continuous size increase (and CAC decrease) is observed as salt is added in ionic surfactant sol phase. The same effect is obtained when surfactant solution is concentrated.
  • Energetically unfavorable edges can be avoided upon formation of toroids from cylinders or vesicles from lamellae, but the energy reduction may be compensated by a decrease of deformation entropy.
  • the transition from rigid to flexible aggregates as well as the persistence length of coiled aggregates depends on the nature of the surfactant molecules.
  • the strength of interfacial interactions governs the variation of area per head group and thus flexibility. When flexibility is strongly hindered as in during non-ionic gel formation from sol phase, interacting rods are observed, resulting in a viscoelastic behavior of the medium.
  • Solvation solvent penetration in the vesicular interiors and interface thickness:
  • High HLB Amphi- philic solvent molecules surround typical vesicles ( tubulosomes) and some solvent molecules are bound to the hydrophilic groups at the surface as well as in the hydrophilic interiors of the multi-lamellar structure of the vesicle. Therefore, lamellar embedded as well as interfacial solvent molecules attribute greatly to the stability of tubulosomes and to overall stability of the gels.
  • Low HLB solvent molecules though surround and bind to liophilic surface of the reverse/inverse vesicles (tubulosomes), their embedding into the liophilic interiors of the lamellar structure is rather fewer.
  • tubulosome On a micro-level, the inventive formulation according to this aspect may be considered an isotopic association colloid wherein tubulosomes furnish a three-dimensional network, particularly a network of linked clusters that spans the entire volume as a skeleton.
  • the term tubulosomes is chosen to describe tubular shaped, multi-lamellar vesicles comprising of stacked bi-layers of amphiphilic surfactant molecules. Idealized tubulosome structures are shown in figures 1 and 2.
  • the surfactant molecules form a "sol" phase, which upon gradual cooling with vortexing stipulates tubular shaped, concentric stacked bi-layer vesicles (“tubulosomes”), of the surfactant molecules near the phase transition temperature.
  • tubulosomes which remain soluble in the sol phase within the range of phase transition, aggregate further into clusters, which establish linkage through junction points to construct a 3D network over the volume, as temperature drops down further, giving rise to viscoelastic/thickening property to the formulation .
  • association colloid such as a gel
  • tubulosomes are the structural unit of such association colloid. It is believed that tubulosomes aggregate / associate through van der Waals and electrostatic interactions to form clusters which are tubular shaped in Organogels, and star- or flower- shaped in all disclosed amphiphlic classes of gels (pure gels, mixed gels and co-gels) and in organogels spiked with one or more solid and / or liquid hydrophilic surfactants.
  • the first component has to be a) insoluble (or substantially insoluble) in the second component at room temperature
  • first and second component form a sol phase (due to solubility
  • tubulosomes can be either "typi- cal” (or “regular”), in which head groups in bi-layer point towards the polar/substantially hydrophilic liquid continuous medium, or "inverse” (“reverse") , in which lipophilic tail groups in bi-layer point towards lio- philic (hydrophobic) /substantially low polar continuous medium/solvent.
  • the tubulosomes of the formulation exhibit inverse geometrical orientation of the surfactant molecules in organo gels, while typical orientation in all classes of amphiphilic gels.
  • inventive compositions comprising such tubulosome structure, prove to be superior when compared to other formulations comprising known vesicles, such as niosomes.
  • inventive formulations are thus useful to replace the known formulations containing Liposomes and Niosomes; particular in pharmaceutical and cosmetic compositions.
  • tubulosomes are considered a self gel forming agent, while niosomes are incapable of forming a gel or thicken a formulation. This avoids the addition of a further component.
  • the entrapment of additives into tubulosomes does not require an extra step (it occurs in the sol phase) , while niosomes must be loaded in an extra step. This avoids one manufacturing step, which is often sensitive and difficult for scale- up.
  • the in ⁇ vention relates to a formulation as described herein wherein said first component is a liquid, amphiphilic, non-ionic surfactant.
  • the in ⁇ vention relates to a formulation as described herein wherein said second component is selected from the group consisting of vegetable oils, and derivatives of vegetable oils, such as alcohols, esters, alkoxylates; long chain synthetic esters such as isopropyl myristate, ethyl oleate, ethyl myristate, etc.; acyclic and cyclic alkanes
  • Particularly preferred are vegetable oils selected from the group of cottonseed oil, soybean oil, corn oil, sesame oil, olive oil, castor oil and sunflower oil, and the long chain synthetic esters selected from the group consisting of ethyl olate and ethyl myristate and isopropyl myristate.
  • Such formulations may be referred to as an "Qrgano-Gel" .
  • the invention relates to a formulation as described herein wherein said second component is selected from the group consisting of liquid, non-ionic surfactants.
  • Said liquid non-ionic surfactant is preferably selected from the mono- and poly- ester families of Sorbitan, Glycerol, Glycol, polyalkyl-glycol and fatty alcohols (with hydrocarbon chain with at least 12 carbon atoms and higher) with fatty acids such as lauric acid, palmitic acid, stearic acid, oleic acid, cocoic acid, ricinolic acid, tallic acid, etc; mono- and poly-substituted amine oxides of fatty alcohols, mono- and poly-substituted alkanolamides; Ethylene Oxide (EO) /Propylene Oxide (PO) block copolymers (such as [EO] x [PO] y [EO] x, [PO] x [EO] y [PO] x, ); al
  • the invention relates to a formulation as described herein wherein said second component is a combination of (i) organic solvents/liquids as defined herein, and (ii) liquid, non-ionic surfactants as defined herein.
  • said formulations may be referred to as a "Co-Gel”.
  • the in- vention relates to a formulation as described herein wherein the said first component is present in concentration rage of 0.1 to 50, preferably 1 to 40, more preferably 5 to 35, and most preferably 10 to 30 %weight/weight (%first/second w/w) to the said second component.
  • the invention relates to a formulation as described herein wherein a low net HLB value of the first component (3.5- 7.5, more preferably 4.5-7) and higher net HLB value (4- 20, more preferably 8-18, most preferably 15-17) of the second component (wherein a liquid surfactant or a blend of surfactants comprises the solvent) are combined.
  • a low net HLB value of the first component 3.5- 7.5, more preferably 4.5-7
  • higher net HLB value 4- 20, more preferably 8-18, most preferably 15-17
  • a liquid surfactant or a blend of surfactants comprises the solvent
  • the in ⁇ vention relates to a formulation as described herein wherein the second component is selected from the group of vegetable oils, synthetic esters, acyclic and cyclic alkanes (with more than 6 carbon atoms) , alkene sequale- nes and liquid non-ionic surfactant with HLB ranging between 15 and 20.
  • the second component is selected from the group of vegetable oils, synthetic esters, acyclic and cyclic alkanes (with more than 6 carbon atoms) , alkene sequale- nes and liquid non-ionic surfactant with HLB ranging between 15 and 20.
  • liquid non- ionic surfactants are a member from polyoxyethelene PEG (O-CH2-CH2) 2o sorbitan ester family (including monolaurate (Polysorbate 20/ Tween 20), monopalmitate (Polysorbate 40/ Tween 40), and monoolate (Polysorbate 80/Tween 80) with concentration ranging between 1 and 5%.
  • Such formulations may be referred to as a "spiked-gel”.
  • the in ⁇ vention relates to a formulation as described herein comprising an additional viscosity modifier, preferably selected from the group consisting of natural clays, synthetic clays and combinations thereof, such as Thixogel.
  • an additional viscosity modifier preferably selected from the group consisting of natural clays, synthetic clays and combinations thereof, such as Thixogel.
  • Such modifier may be added to enhance the viscosity, if required.
  • compositions comprising a formulation as described herein.
  • compositions according to the invention contain a formulation as described herein and one or more additional components ("additives”). Such additives are known per se in the field. The type and amount of additives determines the intended use of the composition. Thus, such compositions may relate to the field of cosmetics, pharmaceuticals, nutrition and / or dietary. Particularly, such compositions are oral care compositions or topical / transdermal compositions. Further, such compositions may be in the form of a gel or an emulsion .
  • compositions as described herein do only contain small amounts of water (“essentially water free composi ⁇ tion”) or do not contain water (“water free composi ⁇ tion”) .
  • water free composi ⁇ tion water free composi ⁇ tion
  • a composition according to the invention thus contains preferably less than 5wt% water, preferably less than lwt% much preferred less than 0.2wt%.
  • the invention relates to an oral care composition, such as a dental cream, dental gel, dental/oral ointments and dental lozzanes, comprising a formulation as described herein.
  • Such composition typically contains additives, including an abrasive, a mild detergent or foam forming/stabilizing agent, an anhydrous humectants, a thickening agent, a flavouring agent, a sweetening agent, a colouring agent, an anti-tarter agent, a nutrient agent, an oral isotonic agent, a polishing agent, an anti-carious agent, an anti- plaque agent, a bleaching/oxidizing agent, an enzyme.
  • additives including an abrasive, a mild detergent or foam forming/stabilizing agent, an anhydrous humectants, a thickening agent, a flavouring agent, a sweetening agent, a colouring agent, an anti-tarter agent, a nutrient agent, an oral isotonic agent, a polishing agent,
  • such oral care composition additionally comprises anti-microbial, anti- fungal, anti-bacterial, dental mineralizing agents and / or preservatives.
  • the invention relates to an oral care composition as described herein additionally comprising bleaching agents, in particular peroxides .
  • Preferred peroxides are Hydrogen Peroxide, PVP-Hydrogen Peroxide, Alkaline Earth Metal Peroxides, group 12 metal peroxides, Urea Peroxide (Carbamide Peroxide) , Alkali Metal Percarbonates, Alkali Metal Persulfates, Alkali Metal Perborates and alkali metal and alkali earth metal Monoperthalates .
  • bleach ⁇ ing/oxidising agents are Hypochlorites, such as alkali metal hypochlorites, alkaline earth metal hypochlorites and group 12 metal hypochlorites; Chlorites, such as alkali metal chlorites, alkaline earth metal chlorites and group 12 metal chlorites; Chlorates, such as alkali metal chlorates, alkaline earth metal chlorates and group 12 metal chlorates; Clathrates of Chlorine dioxide (C102) and alkali metal oxoborates.
  • Hypochlorites such as alkali metal hypochlorites, alkaline earth metal hypochlorites and group 12 metal hypochlorites
  • Chlorites such as alkali metal chlorites, alkaline earth metal chlorites and group 12 metal chlorites
  • Chlorates such as alkali metal chlorates, alkaline earth metal chlorates and group 12 metal chlorates
  • Clathrates of Chlorine dioxide (C102) and alkali metal oxoborates Clathrates of Chlorine dioxide (C102) and alkali
  • the invention relates to an oral care composition as described herein additionally comprising enzymes.
  • the enzymes useful in the practice of this invention are catalyti- cally active protein substances within the class of hydrolases, which break down or hydrolyze proteins
  • protease a useful protease
  • carbohydrates such as soybean meal, and glucose
  • proteolytic enzyme suitable for use in accordance with the invention.
  • One useful protease thus prepared has an activity of about 2.4 million units per gram at pH 7 when assayed against a casein substrate as described hereinafter.
  • proteases useful in accordance with this invention are: Alcalase (trademark) a hydrolytic enzyme preparation whose major activity is proteolytic. It is derived from Bacillus subtilis and is obtainable from Novo Industri A/S. Purification of the commercial detergent- grade material is desirable before use in an oral preparation. Maxatase (trademark) obtainable from Chas. Pfizer, Inc. Protease AP-100 (trademark) obtainable from Monsanto Chemical Company. Prolase 300 a trademark of the Wallerstein Company, trypsin may be derived from bovine or porcine pancreas, chymotrypsin may be derived from bovine, chicken, or turkey pancreas.
  • Papain may be obtained from the milky latex of the Papaya tree, ficin may be obtained by extraction from the fruit of a tropical fig tree. bromelin produced by the family Bromeliaceae obtainable from pineapple and pineapple plant. M-Zyme derived from a microbiological source. Has keratinase activity. Rhozyme P-Il (trademark) derived from fungal sources. Obtainable from Rohm and Hass.
  • dextra- nase may be derived from Aspergillus sp.
  • cellulase may be derived from Myrothecium verrucaria
  • Cellzyme A a crude cellulolytic enzyme system, alpha-amylase, beta-amylase, and mixtures thereof may be obtained from Bacillum subtilis.
  • Mylase 100 (trademark) derived from Aspergillus oryzae. Obtainable from the Waller- stein Company.
  • Mylase W (trademark) a mixture of amylase, dextranase and other enzymes derived from a fungal source. Obtainable from the Wallerstein Company.
  • Amylase L-661 (trademark) obtainable from Premier Malt Products, Inc.
  • Lipase 4000 (trademark) may be derived from Aspergillus oryzae.
  • Lipase B (trademark)
  • Lipase 448 (trademark) a relatively pure lipolytic enzyme derived from hog pancreas.
  • One gm digests 448 gm of fat (av. mw 840) per hour at pH 7.8 and a temperature of 37° C.
  • Obtainable from Nutritional Biochemicals Corp. are gastric lipase, pancreatic lipase and plant lipases.
  • Preferred concentration of enzyme (a mixture of them) ranges between 0.001% and 20%, preferably 0.1% and 10%, more preferably 0.5% and 5%, most preferably 1% and 3%.
  • the in ⁇ vention relates to an oral care composition as described herein additionally comprising a source of zinc ions and enzymes, particularly a source of zinc ions and a protease, a carbohydrase, and / or a lipase.
  • a source of zinc ions and enzymes particularly a source of zinc ions and a protease, a carbohydrase, and / or a lipase.
  • the invention relates to an oral care composition as described herein additionally comprising lytic Bacterio-phages of oral bacterias.
  • lytic Bacterio-phages of oral bacterias Preferred are bacterio-phage of Streptococcus mutans, such as Phage M102, Phage ElO, Phage Fl, or mixtures thereof.
  • bacterio-phage of Streptococcus mutans such as Phage M102, Phage ElO, Phage Fl, or mixtures thereof.
  • the disclosed dentifrice composition containing disclosed co-gel and lytic bacterio-phages provide an effective means in controlling / subsiding oral plaque (S. Mutan/Plauq count) and hence a new remedy against tooth disorder and discolouration problems due to well known acid dissolution of HCA.
  • additives may be added to the inventive oral care compositions are explained below:
  • Preferred abrasives are anhydrous fumed silica, anhydrous silica, Brushite (CaHPO 4 • 2H 2 O) , Kaolin, Aragonite, Calcite, white Pearl powder, Baking Soda and Calciaum carbonate.
  • Preferred anhydrous humectants are anhydrous
  • Glycerol anhydrous Propylene Glycol, Polyethylene Glycols (PEG 400, 600, 800, 1000, 1200, etc.), hydrogen- ated vegetable oils, D-Sorbitol, vegatable oils, etc.
  • Preferred mild detergent is Zwitterionic Sur- factant such as Cetyl Betain, Cocamidopropyl betaine, Dodecyl betaine, betaine oxides, alkyl amine oxides, etc., or a Nonionic Surfactant such as Alkyl poly (ethylene oxide), Poloxamer, Cetyl Alcohol, Oleyl Alcohol, Cocamide MEA, cocamide DEA, cocamide TEA.
  • Preferred mild detergent is a polysorbate ester such as Polysorbate 20, Polysorbate 60, Polysorbate 80, etc.
  • Preferred mild detergent is a poloxamer (Pluronic, Synperonic) .
  • Preferred thickening agents are Carbopol or Carober, fatty acid mono- and poly- ester of mono- and poly-glycols and their amide or oxide derivatives, such as Glyceryl MonoStearate, Ceto Stearyl Stearate, Ethylene Glycol MonoStearate, Poly Glyceryl Stearate, Glyceryl Mono Laurate, Glyceryl Mono Palmitate, Glyceryl Mono Oleate, Coco Mono Ethanolamide, Ethylene Glycol Di Stearate, Propylene Glycol MonoStearate, PEG Mono Laurate, PEG Mono Stearate, Cetyl Palmitate, Stearyl Stearate, Coco Di Ethanolamide, Butyl Stearate, 2 Ethyl Hexyl Stearate, 2 Ethyl Hexyl Palmitate, etc. Said abrasive agents with low abrasivity serve as thickening agents .
  • Preferred flavoring agents are Peppermint Oil, Spearmint Oil, Orange Oil, Anise Oil, Wintergreen Oil, Birch Oil, Freshmint flavor, Herbal Flavor, Lemon oil, Green Apple flavor, etc.
  • Preferred sweetening agents are either natural such as xylitol, Dihydrochalcones, Cyclamate, Dextrose, Sorbitol, Levulose Thaumatine, D-Tryptophan, etc., or synthetic such as Potassium Acesulfame, Sodium Saccaharin, Aspartame, etc.
  • Preferred anti-tarter agents are Alkali Metal Pyrophosphates, Disodium dihydrogen Pyrophospahtes, Dipotassium dihydrogen Pyrophosphates, 1-Azocycloheptane- 2, 2-diphosphonate (AHP), Ethane-l-hydroxy-1, 1- diphosphonate, Alkali metal salts of Polyphosphate, Phosphocitrate salts, Polyacrylates, Polycarboxylates, Alkali Metal Alkali-Earth Metal salts of EDTA, Zinc Chloride, Polyphosphonates, Polyepoxysuccinates, Ni- trilotriacetic Acid and its Salts of Alkali Metals, Ethylenediamintetraacetic acid (EDTA) , Alkali Earth Metal Salts of Citrate etc., or a mixture thereof.
  • Preferred nutrient agents are Ascorbic Acid
  • Vitamin C and it salts of Alkali Metals and Alkali Earth Metals, Tocopherol (Vitamin E) and its acetate precursors, Phyloguinone (Vitamin K), Vitamin B (Bl, B5, B6, B12), Vitamin A and its Retinoid precursors, Vitamin P, Vitamin H, etc., or a mixture thereof.
  • Preferred oral isotonic agent is sodium chlo ⁇ ride (NaCl) .
  • Preferred polishing agents are titanium oxide, zirconium oxide, zinc oxide, aluminum oxide, etc.
  • Preferred anti-carious agents are a fluoride agent such as alkali metal fluorides, ammonium fluoride, alkali metal monofluorophosphates, etc., dental mineral ⁇ izing agents such as water soluble salts of calcium, incuding glycerophosphate, nitrate, propionate, maleate, etc.
  • Preferred anti-plaque agent is Polyamino- propyl Biguanide, which is a gentle and effective antimicrobial substance that acts against tough gram negative bacteria as well as gram positive bacteria, yeast and fungi over a wide range of pH, 4-10.
  • anti-plauqe agents are said bleaching/oxidizing agents, naturally occurring substance such as Xylitol, Thymol, Eucalyptol, Euganol, Oil of Colve, Sweet Birch Oil, Wintergreen Oil, D-Limonene, Mentha Paprita L oil, Spearmint oil, etc., synthetic substances such as Methyl Paraben, Ethyl Paraben, Propyl Paraben, Domiphene Bromide, Salicylanide, Zinc ions, Stannous ions, Octenidine, Delmopione, Octapinol, etc.
  • Preferred pH Buffering agents are Alkali Metal Salt of mono-, di- and tri-basic Phosphate or mixtures thereof.
  • the invention re ⁇ lates to skin care composition, such as a skin cream, beauty cream, shower gel, shampoo, lozzanes, and oint ⁇ ments comprising a formulation as described herein (collectively: "cosmetic compositions").
  • skin care compositions such as a skin cream, beauty cream, shower gel, shampoo, lozzanes, and oint ⁇ ments comprising a formulation as described herein (collectively: "cosmetic compositions").
  • non-ionic surfactants are preferred over ionic surfactants. It is believed that they are less skin irritant, less allergic and more pharmaceutically accepted.
  • Such skin care composition may contain rheol- ogy modifiers.
  • the viscosity, surface texture, thixotro- py, surface-feeling, etc., of the inventive compositions can further be optionally modified by incorporation of such rheology modifier, such as Carbopols or Carbomers, natural and synthetic waxes, gums and clays, and diluting by a suitable humcetant.
  • the invention relates to a topical and/or transdermal delivery vehicle gel composition as described herein additionally comprising one or more pharmaceutically active ingredients.
  • the disclosed topical / transdermal compositions are capable in accommodating, transporting and delivering to the target liophilic as well as hydrophilic active ingredients, such as enzymes, co-enzymes, vitamins, precursors of vitamins, anti-bacterial/anti-microbial agents (collectively: "pharmaceutical compositions")
  • Such composition may also contain additives, e.g. oxidizing/bleaching, flavoring, coloring agents, etc.
  • Preferred active ingredients are in particular one or more folate antagonists, immunosuppressive, disease-modifying antirheumatic drug (DMARD) , in particular Methotrexate and its pharmaceutically accepted derivatives such as orotate, - ⁇ -glycine-tris, - ⁇ -glycine- tris monopalmitate, - ⁇ -glycine-tris dipalmitate, ⁇ - glycine-tris tripalmitate, etc.
  • Preferred concentration ranges between 0.01 and 10%, more preferably 0.1 and 5% and most preferably 0.25 and 1%.
  • Compositions may additionally (but not limited to) contain another DMARDs drugs such as azathioprine, ciclosporin (cyclosporine A) , Cyclophosphamide, D-penicillamine, leflunomide, minocycline, sulfasalazine, gold salts, hydroxychloroquine, etc., tumor necrosis factor alpha (TNF- ⁇ ) blockers such as, etanercept, infliximab, adalimumab, etc., Interleukin 1 (IL-I) blockers such as anakinra, monoclonal antibodies against B cells such as rituximab, T cell activation blocker such as abatacept, Anti-inflammatory agents
  • DMARDs drugs such as azathioprine, ciclosporin (cyclosporine A) , Cyclophosphamide, D-penicillamine, leflunomide, minocycline, sulfasalazine
  • glucocorticoids such as glucocorticoids, non-steroidal anti-inflammatory drug NSAIDs (salicylates, arylalkanoic acids, 2-arylpropionic acids, N- arylanthranilic acids, pyrazolidine derivatives, oxicams, COX-2 inhibitors, Sulphonanilides, Licofelone, Omega-3 fatty acids, etc.
  • analgesic agents such as opiates, acetaminophen, diproqualone, lidocaine, an A 3 adenosine receptor (A 3 AR) agonist such as N 6 - (3-iodobenzyl) - adenosine- 5 ' -N-methyl-uronamide, 2-chloro-N - (3- iodobenzyl) -adenosine- 5 ' -N-methyl-uronamide, etc.
  • a 3 AR A 3 adenosine receptor
  • the disclosed topical transdermal vehicle compositions provides an excellent delivery system for Methotrexate to treatment for autoimmune disorder diseases, in particular RA, psoriatic arthritis, psoriasis, scleroderma, polymyosi ⁇ tis, lupus and systemic lupus erythematosus, directly on the local diseased spots / sites with much enhanced topical bioavailability, as compared to niosomal and emulsion composition of prior art, overcoming most of the major side-effects as well as risk of cytotoxicity / tissue-toxicity / organ-toxicity, which are associated with oral route administration of Methotrexate including anemia, neutropenia, nausea, vomiting, renal disorders, hepatitis, gastrointestinal disorders, mucositis, lung disorder, etc.
  • autoimmune disorder diseases in particular RA, psoriatic arthritis, psoriasis, scleroderma, polymyosi ⁇ tis, lupus and
  • the in ⁇ vention relates to a topical transdermal gel vehicle compositions as described herein additionally comprising a non-steroidal anti-inflammatory drug NSAID, in particular but not limited nimesulide, which targets a number of key mediators of the inflammatory process such as, COX-2 mediated prostaglandins, free radicals, proteolytic enzymes and histamine.
  • NSAID non-steroidal anti-inflammatory drug
  • concentration of NSAID is 0.01-20%, more preferably 0.5-10%, most preferably 1- 6%.
  • an A 3 adenosine receptor (A 3 AR) agonist such as N 6 - (3-iodobenzyl) -adenosine- 5'-N-methyl- uronamide, 2-chloro-N 6 - (3-iodobenzyl) -adenosine- 5 ' -N- methyl-uronamide, etc., can be incorporated to composi- tion with preferred concentration 0.001-0.1%.
  • TNF- ⁇ blockers such as, etanercept, infliximab, adalimumab, etc.
  • Inter- leukin 1 (IL-I) blockers such as anakinra with 0.001- 0.1%
  • monoclonal antibodies against B cells such as rituximab 0.001-0.1%
  • T cell activation blocker such as abatacept with concentration 0.001-0.1% may be incorpo ⁇ rated.
  • the disclosed topical transdermal gel vehicle compositions can also be used in treatment to RA and related inflammatory conditions, such as psoriatic arthritis, psoriasis, SLE, etc.
  • the invention relates to a topical transdermal gel/ointment composition as described herein additionally comprising lipolysis agent Lipase, an activator of lipolysis and a blocker of dephosphorylation of cyclic adenosine monophosphate (cAMP) .
  • lipase agent is from Candida rugosa, Candida cylindracea, Lipase B, etc., with concentration 0.001-20%.
  • Preferred activator is cAMP with concentration 0.001-10%.
  • Preferred cAMP-Phosphodiesterase blocker is paraxanthine with concetration 0.001-10%.
  • cAMP-Phosphodiesterase blockers such as pheophylline, Caffeine, Aminophylline, etc.
  • a phosphate donor which also activates Lipase
  • an appetite suppressant agent such as Ephedrine
  • an inhibitor of glucose- ⁇ -phosphate • dehydrogenase such as extract of Andiroba can be incorporated in concentration 0.01-10%.
  • a promoter of cellular cAMP such as Forskolin, which acts through activating protein kinase A (PKA) and hence adenylyl cyclase enzyme, can be incorporated in concentration 0.01-10%.
  • PKA protein kinase A
  • transdermal gel / ointment composition is suitable for the reduction of unwanted fat, particular for unwanted fat located in the hypodermis. Therefore, such compositions are suitable for therapeutic treatment of obesity, adiposis and / or for cosmetic shaping of the body, particular for shaping abdomen, hip and/or buttock of a person in need thereof. This is achieved by fat reduction / burning.
  • the invention thus also relates to the use of such compositions and to the manufacture of a medicament for such indications.
  • said composition when topically applied onto the skin, is being absorbed by the epidermis, followed by osmotic spreading through the dermis and hypodermis, respectively, as a result of which the swollen tubulosomes, encapsulating the ingredients, permeate through the epidermis and dermis, and delivers the entrapped ingredients into hypodermis due to osmotic dilution and subsequent selective absorption by the adipocytes, which are called fat cells.
  • the absorbed lipase molecules thereby are being activated by an activator and locally stimulate the lipolysis of trigly- crides (break/hydrolyze the lipid bonds of triglyceride) to produce mono-glycerides and free fatty acids which subsequently enter into the oxidative citric acid cycle in mitochondria to yield ultimately Adenosine Triphosphate (ATP) and carbon dioxide and water as bi-products and release energy.
  • ATP Adenosine Triphosphate
  • an activator of lipolysis such as, cyclic adenosine monophosphate (cAMP) , which is believed to be an activator of Lipase enzyme through the protein kinase mediated phosphate group transfer, and hence stimulate overall lipolysis.
  • Blocker of dephosphorylation/promoter of cAMP inhibits the action of cAMP-Phosphodiesterase enzyme and activates adenylyl cyclase which promotes formation of cAMP from ATP/GTP.
  • the present invention provides a composition that supports lipolysis and the use of such compositions in the treatment of lipolysis - related diseases, disorders and/or conditions.
  • the invention relates to a topical vehicle pharmaceutical composition as described herein additionally comprising an analgesic/local anesthetic/antiarrhythmic agent/drug, in particular Lidocaine (Lidocaine hydrochloride monohy- drate) .
  • Lidocaine alters depolarization in neurons, by blocking the fast voltage gated sodium (Na + ) channels in the cell membrane. With sufficient blockade, the membrane of the presynaptic neuron will not depolarize and therefore fails to transmit an action potential, leading to its anesthetic effects. Careful titration allows for a high degree of selectivity in the blockage of sensory neurons, whereas higher concentrations will also affect other modalities of neuron signaling.
  • Disclosed Lidocaine gel compositions have shown to have improved bioavail- ability, as compared with 3% topical bioavailability in prior art, towards topically relieve itching, burning and pain from skin inflammations and towards topical dental anesthesia in minor dental surgeries.
  • Other such analgesic agents are prilocaine, bupivacaine and ropivacaine.
  • Preferred concentration of Lidocaine (hydrochloride monohydrate derivative) is 0.001-25%, more preferably 0.01-10%, most preferably 0.25-5%.
  • the disclosed topical gel compositions can also be used in treatment to early stage of RA and related inflammatory conditions, such as psoriatic arthritis, psoriasis.
  • the invention relates to a topical transdermal gel / ointment vehicle composition as described herein additionally comprising Omega-3 fatty acids in concentration 0.1-20%.
  • Such composition is particularly suitable for the treatment of atopic dermatitis and RA.
  • the invention relates to the manufacture of formulations as described herein.
  • Formulation according to this invention may be prepared by processes that, though not applied hitherto for the components of the present invention where they thus form new processes, are known per se.
  • the invention relates to a method for manufacturing a formulation as described herein comprising the steps of: combining component 1 and 2, preferably by vortexing; heating the obtained mixture at least 5°C above the melting point of component 1, preferably over a water-bath suited with a thermostat; maintaining the temperature for a period from 10 min to 10 hrs, preferably with occasional vortexing; slowly cooling down the obtained mixture.
  • a general procedure for manufacturing the inventive formulation may be given as follows: (1) The solid gelators and the liquid medium are mixed, (2) The mixture is heated to a fixed temperature, at least 5 0 C above the melting point of the gelators, by means of thermostat regulated water-bath until the gelator has completely dissolved/dispersed to give a sol phase, (3) The sol phase is then kept at the same temperature for time span ranging from 30 minutes to 2 hour, allowing the stable formation of the sol phase, (4) The resulting sol is then allowed to cool down by standing at room temperature for overnight (preferable cooling time is from 8 to 36 hours), (5) At gelator concentrations above a minimum threshold, which is called minimum gelation concentration (MCG) , the sol phase sets to an opaque, smooth, semisolid gel as it cools down to room temperature.
  • MCG minimum gelation concentration
  • Gelation which is defined as the transition from a sol to a gel state, is considered successful in this context, if, upon inversion of the vial, sample does not flow perceptibly.
  • MGC Minimum Gelation Concentration
  • the gelator solubility in the solvent is reduced, resulting in reduced gelator- solvent affinity and enhanced aggregate-aggregate interactions, which conduce formation of a coherent network of interconnected clusters throughout the liquid phase, thus immobilizing it.
  • aggregate- aggregate interactions are stronger than solvent- aggregate affinities, resulting in a preferential ordered flocculation of the clusters to form a 3-D network within the solvent.
  • Such a gel network which is anisotropically dispersed in the solvent, is then able to gel the solvent only in parts, and a fibrous gel mesh is observed within the excess solvent, which is not accommodated in or immobilized by the gel network.
  • organo-gels wherein a second sur ⁇ factant with relatively high HLB is incorporated in low amount ( ⁇ 5% w/w) , it has reduced the CGC (critical gelling concentration) and MGC of the surfactant gelator, presumably due to enhancing the solubility of the gelators in the solvent via forming mixed reverse tubulosomes .
  • CGC critical gelling concentration
  • compositions according to this invention may be prepared by processes that, though not applied hitherto for the the components of the present invention where they thus form new processes, are known per se.
  • the invention relates to a method for manufacturing a composition as described herein comprising the steps of providing a formulation as described herein and combining it with one or more additives to obtain the desired composition.
  • A. Disperse a non-aqueous gelling agent (and optionally a thickener agent, if required) into the liquid dispersion medium, which is either with or without surfactant property , or a mixture thereof, containing humectants, flavoring, sweetening and coloring agents.
  • the stirring is withdrawn to let the obtained gel settle down for 10 minutes to 10 hours, preferably for 30 minutes to 5 hours, most preferably for 1 to 2 hours.
  • D. Add the abrasives during vacuum milling, if required.
  • F. Add foaming agent during milling, if required.
  • G. Add polishing agent, oral isotonic agent and the oxidizing/bleaching agent as a batch process, if required.
  • A. Disperse a non-aqueous gelling agent (and optionally a thickener agent, if required) into the liquid dispersion medium, which is either a liquid (non-ionic) surfactant or a vegetable oil, or a mixture thereof, containing humectants, flavoring agent, sweetening agent, coloring agent and the enzyme (a mixture of enzymes) .
  • a non-aqueous gelling agent and optionally a thickener agent, if required
  • the liquid dispersion medium which is either a liquid (non-ionic) surfactant or a vegetable oil, or a mixture thereof, containing humectants, flavoring agent, sweetening agent, coloring agent and the enzyme (a mixture of enzymes) .
  • polishing agent and oral isotonic agent as a batch process, if required.
  • the invention relates to the use of formulations and compositions as described herein .
  • the invention relates in one embodi- ment to the use of a formulation as described herein for manufacturing a composition as describes herein, in particular for the manufacture of a cosmetic product, pharmaceutical product, nutrition product or dietary product, very particularly a topical / transdermal product or an oral care product.
  • the invention relates in a further embodiment to the use of a composition as described herein in cosmetics, pharmaceuticals, nutrition and/or dietary.
  • the invention relates in a further embodiment to a composition as described herein as pharmaceutical.
  • the inventive organogels and amphiphilic gels are thermoreversible . They melt on heating to the sol phase which can once again be gelled upon cooling without any appreciable change in gel properties.
  • the gel-to-sol and/or sol-to- gel phase transition temperatures have been obtained through measuring the melting points using a standard melting point apparatus.
  • the gel is introduced into the capillary tube of lOOmm length and 1.4mm outer diameter, by dipping the tube into the gel to obtain a sample of approximately 0.5cm in length within the tube. The sample is then drawn up the tube to approximately 0.3cm from the lower end of the tube using a syringe.
  • the gel filled tubes are then placed in the melting point apparatus, and the temperature is increased with a constant rate of l°C/min.
  • the gel phase transition temperature is taken as the temperature at which the gels melt into an isotropic liquid (sol) that flows down the capillary tube.
  • isotropic liquid sol
  • five samples of a gel are used to obtain an average.
  • phase transition does not take place at a single temperature but over a range, typically 3-5 0 C, for a gel belonging to organogel or amphiphilic gel-class disclosed herein. Consequently, broad phase transition temperatures correspond to homogeneous microstructure within the gel for organogels and amphiphilic gels.
  • phase transition temperature of all organogels and amphiphilic gels are below the melting point of the gelators. This is a universal property of the organogels and amphiphilic gels, and can be understood by the fact that relatively much higher energy is required to break the close-pack lattice in solid state than to break the supra-molecular associations in gel state of a gelator. Increasing the gelator concentration leads to an increase in phase transition temperature, reflecting more cohesive 3D network of gelator aggregates and the number of crosslinks between aggregates such that more energy is required for the sol-to-gel transition.
  • phase transition temperature with increased HLB of solvent reflects a stronger network, and is due to higher gelator-gelator affinities compared to gelator-solvent affinities as the solvent HLB increases.
  • phase transition temperature does not correlate to solubility- insolubility balance of the gelator in a solvent based on HLB.
  • Span 40 gels possess lower phase transition energy than Span 60 gels, although the latter is more insoluble in a hydrophilic solvent. Therefore, the phase transition temperature correlates much better to the melting point of the solid surfactant gelator, while the melting points of the solid surfactant gelators correlate well to their HLB numbers; lower the HLB, higher the melting point.
  • phase transition temperature on storage for organogels and amphiphilic gels attributes from a greater number of and/or stronger junction points. Often a stronger gel network is formed among the tubular clusters over the time.
  • Gel lifetime is taken herein as the duration between gel preparation and gel syneresis. Syneresis is a result of the contraction of the solid network of tubulosome clusters stipulating the release of the trapped liquid solvent, which was initially accommodated within the gel network, and thus the separation of two phases. Syneresis is expected to take place in the gels comprising larger aggregates. The larger pore size that exists between the large aggregates indicates that the liquid phase is not held very tightly/efficiently within the gel network by capillary (cohesion) forces and that it may separate out (get un-enveloped) . Five samples of each gel have been placed in glass vials at constant room temperature to weekly observe for syneresis.
  • organogels have lifetime of 3-6 weeks, while the organogels spiked with a hydrophilic surfactant possess lifetime of range 4 to 8 months, and most of the amphiphilic gels possess lifetime more than a year.
  • the pure and mixed amphiphilic gel did not undergo syneresis on storage at room temperature for more than two years. While some of the co-gels exhibit syneresis after one year storage, most of them possess lifetime of about two years and more. Most of the amphiphilic gels show betterment in consistency over storage, while their properties remain nearly unchanged.
  • Gel flow properties and rheology are important to fit in personal-care, cosmetic and pharmaceutical systems of commercial value, such as creams, pastes, ointments and gels.
  • the viscosity of the disclosed organogels and amphiphilic gels are found to fall with externally applied shear rate, since the physical 3D gel-network breaks to a large part when the gels are subjected to shear. Removal of shear stress initiates rapid reformation of the 3D gel network, restoring most of the junction points of the clusters that were ruptured due to external shear.
  • the yield point/value is an indication of the level of resistance to external forces before the system starts to flow, and thus an indication of the strength of the gel network.
  • Yield point/value with low thixotropy provides for a clean, non-stringing ribbon/thread of the delivery vehicle composition (pastes, gels, ointments, creams, etc.) coming out the package (squeezebility, pumpability: important parameters for delivery systems for commercial toothpaste, gel, dermal creams/gel/ointment, etc.).
  • Yield value/point is also required to suspend insoluble additives, such as abrasive particles and any insoluble additives, which are often incorporated in dentifrice compositions and skin-care/dermal compositions.
  • the shear rate of rubbing formulations onto skin is known to approach 10 5 s "1 . It is therefore expected that the viscosities of the disclosed gels at such a shear rate would allow easy application onto skin as their viscosities fall with increasing shear.
  • the shear rate approaches to a much higher number during brushing the teeth with both manual and electric toothbrushes. Therefore, the disclosed gels with yield point and low thixotropy largely facilitate to suspend the debris loosened, and hence removal of them, during brushing the teeth.
  • Flow properties of the gels are influenced by parameters such as gel age, gelator concentration, nature of liquid solvent phase, etc.
  • a significant difference is found between the viscosities of the disclosed gels containing different liquid phases. A major contribution to this stems from the different viscosities of the liquid phases (solvents) .
  • a viscous solvent for example, Span 20, produces a gel with harder consistency, a high viscosity, as well as a yield point at lower gelator concentrations, whereas less viscous solvents, for example, vegetable oils, polysorbate 20, etc., produce softer gels with lower viscosities .
  • the gels in which the liquid phases are composed of polysorbate 20 or polysorbate 80, have shown an increment in viscosity and consistency over the storage- time, due to formation of more junction points on storage .
  • the dis- closed gel formulations are "thermo-reversible", i.e. they melt upon heating over the gel-to-sol phase transition temperature to the sol phases that once again produce the gels on cooling below the sol-to-gel phase transition temperature without any appreciable change in the gel-properties. Therefore, the conventional procedure for industrial stability-check, which is associated with preserving the compositions at elevated temperature, such as 60 0 C, 90 0 C, for weeks to examine for any change in the composition, does not apply to the disclosed gel composi- tions, especially the ones that contain any suspended additives such as abrasives, insoluble thickeners, and the like.
  • the stability test for any composition which is based on the disclosed gels herein, should be done keeping at room temperature for the desired period of examination.
  • Example 1 Preparation of formulations General process 1 for examples Al to DlO: The first and the second components were weighted and mixed, heated until the first component dissolved/dispersed in the latter, followed by cooling to room temperature by standing in room temperature. As the sol phase cooled to room temperature, it set to an opaque, smooth, semi-solid gel .
  • compositions El - G5 may be prepared according to general process 2 or 3
  • compositions Hl - 13 may be prepared accoding to general process 4 as described below.
  • the obtained suspension / mixture / dispersion was heated to a constant temperature 5 0 C greater than the melting point of first component (gelling agent) with constantly stirring at a moderate propeller speed ranging between 100 rpm and 1200rm (preferably 300rpm and 1000 rpm, most preferably between 600 and 800 rpm) for 10 minutes to 5 hours.
  • the obtained composition was allowed to cool down to room temperature while constantly stirring with lower propelling speed ranging between 100 rpm and 600rpm, preferably between 300 and 400rmp to obtain a gel. Any additives not compatible to high temperature were added at this stage when during cooling the temperature reaches to about 40 0 C as a batch. D. The stirring was withdrawn to let the obtained gel settle down for 10 minutes to 10 hours.
  • General process 3 A. The first component and optionally a thickener agent, were dispersed into the second component. B. The obtained suspension / mixture / dispersion was heated to a constant temperature 5 0 C greater than the melting point of first component (gelling agent) with constantly stirring at a moderate propeller speed ranging between 100 rpm and 1200rm for 10 minutes to 5 hours. C. The obtained composition was allowed to cool down to room temperature while constantly stirring with lower propelling speed ranging between 100 rpm and 600rpm, to obtain a gel. D. The stirring was withdrawn to let the obtained gel settle down for 10 minutes to 10 hours. D.
  • Additives were added during vacuum milling, first with low propeller speed ranging between 100 and 300rpm for 10 minutes to 1 hour as to incorporate the additives into the tubulosomes, and then with higher propeller speed ranging between 400 and 1200rpm for 10 minute to 5 hours.
  • General process 4 A. The first component and optionally a thickener agent, is dispersed into the second component. B. The obtained suspension / mixture / dispersion is heated at a constant temperature 5 0 C greater than the melting point of first component (gelling agent) with constantly stirring at a moderate propeller speed ranging between 100 rpm and 1200rm for 10 minutes to 5 hours. C. The obtained composition was allowed to cool down to room temperature while constantly stirring with lower propelling speed ranging between 100 rpm and 600rpm, to obtain a gel. D. The stirring was withdrawn to let the obtained gel settle down for 10 minutes to 10 hours. D.
  • the additives were added during vacuum milling, first with low propeller speed ranging between 100 and 300rpm for 10 minutes to 1 hour as to incorporate the additives into the tubulosomes structure, and then with higher propeller speed ranging between 400 and 1200rpm for 10 minute to 5 hours.
  • E2, E3 and E4 contain Methotrexate in 0.1%, 0.5% and 1%, respectively.
  • E6, E7 and E8 contain Methotrexate in 0.1%, 0.5% and
  • ElO, Ell and E12 contain Methotrexate- ⁇ -glycine-tris tnpalmitate in 0.1%, 0.5% and 1%, respectively.
  • E14, E15 and E16 contain Methotrexate- ⁇ - glycine-tris tripalmitate in 0.1%, 0.5% and 1%, respectively.
  • Examples E provide compositions suitable for treatment of Autoimmune disorders.
  • Examples F provide compositions suitable for treatment of Autoimmune disorders.
  • Examples G provide compositions suitable for treatment of anit-inflammatory disorders.
  • Examples H provide compositions suitable for transdermal fat catabolizmg.
  • Examples I provide compositions suitable for transdermal analgesics.
  • Example 3 Preparation of transdermal compositions:
  • the compositions Kl - KIl may be prepared according to general process 5, as described below.
  • Examples K provide compositions suitable as dentifice gel / cream.

Abstract

L'invention concerne des formulations, telles qu'un gel, qui sont colloïdales non-aqueuses, se composant d'un premier et un second constituant tels que définis dans la description et ayant une structure particulière telle que définie dans la description ; des procédés de fabrication de ces formulations ; des compositions d'hygiène buccale et des compositions topiques/transdermiques contenant ces formulations ; des procédés de fabrication de ces compositions et l'utilisation de ces formulations et compositions dans des produits cosmétiques, des produits pharmaceutiques et l'alimentation et en diététique.
PCT/CH2009/000361 2008-11-14 2009-11-13 Formulation colloïdale non-aqueuse WO2010054495A2 (fr)

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Cited By (5)

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EP2811968A1 (fr) * 2012-02-10 2014-12-17 Stepan Company Systèmes de tensioactifs structurés ayant la capacité de mise en suspension
KR101664877B1 (ko) * 2015-06-26 2016-10-12 주식회사 코리아나화장품 니트로지방산을 함유하는 니오좀을 포함하는 화장료 조성물
US9668474B2 (en) 2012-02-10 2017-06-06 Stepan Company Structured surfactant suspending systems
CN113350381A (zh) * 2021-06-07 2021-09-07 浙江爱诺生物药业股份有限公司 一种提高珍珠水解液蛋白比例的方法和处理液
US11291201B2 (en) 2013-11-22 2022-04-05 Marizyme, Inc. Solutions for increasing the stability and shelf life of an organ and tissue preservation solution

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EP2811968A1 (fr) * 2012-02-10 2014-12-17 Stepan Company Systèmes de tensioactifs structurés ayant la capacité de mise en suspension
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US11291201B2 (en) 2013-11-22 2022-04-05 Marizyme, Inc. Solutions for increasing the stability and shelf life of an organ and tissue preservation solution
KR101664877B1 (ko) * 2015-06-26 2016-10-12 주식회사 코리아나화장품 니트로지방산을 함유하는 니오좀을 포함하는 화장료 조성물
CN113350381A (zh) * 2021-06-07 2021-09-07 浙江爱诺生物药业股份有限公司 一种提高珍珠水解液蛋白比例的方法和处理液

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