EP1597318A1 - Preparations sous forme d'emulsions a base de poloxameres - Google Patents

Preparations sous forme d'emulsions a base de poloxameres

Info

Publication number
EP1597318A1
EP1597318A1 EP04712958A EP04712958A EP1597318A1 EP 1597318 A1 EP1597318 A1 EP 1597318A1 EP 04712958 A EP04712958 A EP 04712958A EP 04712958 A EP04712958 A EP 04712958A EP 1597318 A1 EP1597318 A1 EP 1597318A1
Authority
EP
European Patent Office
Prior art keywords
composition
copolymer
oil
emulsion
weight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04712958A
Other languages
German (de)
English (en)
Other versions
EP1597318A4 (fr
Inventor
Steen Boye Jorsal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novasel Australia Pty Ltd
Original Assignee
Novasel Australia Pty Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novasel Australia Pty Ltd filed Critical Novasel Australia Pty Ltd
Publication of EP1597318A1 publication Critical patent/EP1597318A1/fr
Publication of EP1597318A4 publication Critical patent/EP1597318A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K8/04—Dispersions; Emulsions
    • A61K8/06—Emulsions
    • A61K8/068—Microemulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K8/90—Block copolymers
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C08L71/02—Polyalkylene oxides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
    • C08G2650/58—Ethylene oxide or propylene oxide copolymers, e.g. pluronics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to microemulsions and compositions useful in a variety of pharmaceutical and personal care products and applications.
  • it provides microemulsions and compositions useful for topical and/or mucosal application of water insoluble or sparingly soluble active agents to oesophageal, otic, vaginal, rectal or ophthalmic surfaces or for application to the epidermis of an animal (such as skin in human) and/or to treat disorders and imperfections of the skin.
  • It also provides a method for making the microemulsions and compositions comprising water insoluble or sparingly soluble active agents.
  • active agents in pharmaceutical and cosmetic preparations comprise oils or are immiscible or insoluble in water. It can be difficult to deliver an effective amount of these active agents in order to provide the desired therapeutic effect, due to their lack of water solubility. It is therefore often desirable to provide such agents in water-based compositions (eg. for oral administration, topical application, intravenous injection, intramuscular injection, subcutaneous injection etc).
  • One of the methods for preparing such compositions is to form an emulsion.
  • An emulsion is a heterogeneous system consisting of at least two immiscible liquids (such as a water phase and an oil phase), one of which is dispersed in the other in the form of droplets, with continuous and discontinuous phases.
  • the discontinuous phase is referred to variously as the dispersed or internal phase, whereas the phase in which the dispersion occurs is referred to as the continuous or external phase.
  • O/W oil-in-water
  • W/O water-in-oil
  • O/W emulsions are the most frequently used emulsions.
  • W/O emulsions are desirable for many applications and would be more extensively used if problems with instability could be overcome.
  • Macroemulsions are defined as being formed by high shear mixing and normally having particles of 1 micron to 10 microns in size. Such emulsions are difficult to achieve and possess minimal stability, as the oil and water components separate into distinct phases over time. In addition, the droplet size of the macroemulsion increases with time.
  • additives such as emulsifiers and finely divided solids.
  • microemulsion systems consisting of oil, water, and appropriate emulsifiers can form spontaneously (i.e. form with minimal agitation) and are therefore thermodynamicaily stable. This level of thermodynamic stability is highly desirable, but seldom achieved.
  • Microemulsion systems theoretically have an infinite shelf life under normal conditions without separating, in contrast to the limited life of macroemulsions.
  • the size of the droplets in such microemulsions remains constant and is typically less than 150 nm (in general between 10-50 nm) and the microemulsion has very low oil/water interfacial tension.
  • Emulsions such as microemulsions are important for the development of new and effective active agent delivery systems that allow water insoluble or sparingly soluble active agents to be provided in aqueous solutions appropriate for human use.
  • the preparation of such microemulsions represents a major technological hurdle for pharmaceutical delivery systems as one must choose materials that are biocompatible, non-toxic, clinically acceptable and form stable microemulsions.
  • emulsion formulations for delivery of active agents that are multi-purpose and can be applied to, for example, topical or mucosal tissues.
  • Such emulsions should preferentially have high bioadhesion capability to ensure contact for a prolonged time. Further they should preferentially be able to carry a high amount of active agent to the site of application for a controlled and prolonged release to the desired tissue.
  • compositions typically require the use of high temperatures to melt all ingredients of the oil phase to uniformly disperse the particles of one phase through the particles of the other one.
  • Microemulsions are usually formed at temperatures in excess of 75°C, typically about 90°C, and the composition is then cooled slowly over a period of hours or days to room temperature in order to create the emulsion. For large batches this is a costly and time consuming procedure. There is also the risk that the emulsions will be overheated resulting, for example, in the degradation of some of the ingredients.
  • surfactants and emulsifiers for the preparation of emulsions are selected from the group consisting of hydrophilic surfactants and mixtures thereof.
  • hydrophilic surfactants and mixtures thereof are selected from the group consisting of hydrophilic surfactants and mixtures thereof.
  • a compound must necessarily include polar or charged hydrophilic moieties as well as non-polar lipophilic (hydrophobic) moieties; that is, a surfactant compound must be amphiphilic.
  • An empirical parameter commonly used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value).
  • HLB values Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
  • Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. It should be appreciated that the HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
  • a group of compounds that have been successfully used as surfactants in the production of macro- and microemulsions are the block copolymers of ethylene oxide and propylene oxide, the poloxamers.
  • a number of these compounds have the unusual property that they become liquid when chilled, but harden when warmed, a characteristic known as thermo-reversibility.
  • thermo-reversibility is useful in pharmaceutical compounding wherever it is desirable to handle a material in a fluid state, but performance is preferably in a gelled or more viscous state.
  • Such compounds can be drawn into a syringe for accurate dose measurement or easily applied from a bottle or squirted from a dispenser when cold.
  • the poloxamer warms to body temperature (eg. when applied to skin or mucosal surfaces) it thickens to a suitable consistency to facilitate proper inunction and adhesion.
  • the desired gelling temperature can be regulated by adjusting the concentration of the block copolymer, with the lower copolymer concentrations giving higher gelling temperatures.
  • Concentrations of the copolymer of at least 18% to 20% by weight are needed to produce a composition which exhibits such a transition at commercially or physiologically useful temperatures.
  • incorporating high concentrations of copolymer causes the composition to become extremely viscous or "gelatinised” and solutions containing 18%- to 20% by weight of poloxamer typically have high viscosity even in the "liquid” phase, so that these solutions can not function under conditions where low viscosity, free- flowing is required prior to transition.
  • typical copolymer emulsions usually contain less than 10% copolymer.
  • Active agents are chemical materials or compounds which, when administered to an organism (human or animal, generally human) induce a desired pharmacologic effect.
  • Many of the active agents in pharmaceutical and cosmetic preparations comprise oils or are immiscible or insoluble in water.
  • An example of such an active agent is Tea Tree Oil (TTO).
  • TTO is isolated by distilling the oil from the stems and leaves of the paperbark tree Melaleuca alternafolia.
  • TTO has medicinal properties including antimicrobial, antiviral, anti-inflammatory and antifungal characteristics. Additionally, TTO provides a soothing sensation when in contact with a person's skin.
  • the properties of TTO can only be exploited by formulating delivery systems suitable to the various conditions required.
  • TTO products in the form of aqueous creams, are exposed to air, the TTO component oxidates and some of the chemical components can change their characteristics, affecting the medicament's effectiveness and safety.
  • the presence of many of the emulsifying agents used to solubilize TTO in water also inhibit or inactivate the activity of TTO.
  • TTO tends to separate from the gel base formula, particularly when the suspension contains concentrations of TTO higher than 2%, a process accentuated by changes in temperature (eg. temperatures over 30°C) and/or applying physical shear forces, such as kneading the gel suspension.
  • Microemulsion formulations are therefore highly desirable as they are thermodynamicaily stable.
  • This invention has as its objective the formation of safe and effective pharmaceutical microemulsion delivery systems that can be manufactured without the need for the high temperature preparation.
  • Other aims and aspects of the present invention will be apparent from the following description of the present invention.
  • composition or more specifically a microemulsion for delivery of water-insoluble active agents comprising: an aqueous component and a non-ionic block copolymer, and at least an oil that is the active agent or has a water-insoluble active agent dissolved therein.
  • emulsion includes both macroemulsions and microemulsions.
  • compositions of the present invention will desirably possess bioadhesive or mucoadhesive properties.
  • the composition will be in the form of a liquid or a gel.
  • the microemulsion composition will exist as a gel or will be a liquid that is capable of gelatinising upon contact with dermal or mucosal tissue.
  • the invention provides a microemulsion or a composition for delivery of water-insoluble active agents, comprising an aqueous component and a non-ionic block copolymer, a hydrophilic, non-ionic short chain fatty acid emulsifier, and at least a oil that is the active agent or has a water- insoluble active agent dissolved therein.
  • the invention provides a method for preparing the microemulsion composition, comprising the steps of: (a) Mixing a copolymer with an aqueous solution at a suitable temperature to substantially dissolve the copolymer in the aqueous solution; and (b) Mixing, at cold temperature, an oil that is the active agent or has a water-insoluble active agent dissolved therein, with the aqueous copolymer solution prepared in step (a) to form a microemulsion.
  • the invention provides a method for preparing the microemulsion composition, comprising the steps of:
  • step (c) Mixing the solution prepared in step (a) with the solution prepared in step (b) at a low temperature to form a microemulsion.
  • microemulsion compositions formed by the above methods.
  • composition of the invention will have a wide variety of applications.
  • the compositions When applied topically to the dermal layer of an animal the compositions may include agents to promote bodily attractiveness or to mask the physical manifestations of a disorder or disease, in lieu or in addition to the treatment of a physical disorder.
  • the same agent may have either a cosmetic or pharmaceutical effect, depending upon the amounts used and the manner of administration.
  • compositions of the invention may be incorporated into other compositions to impart thickening properties to the final composition.
  • thickening properties include enhanced overall viscosity, as well as a desirable viscosity response with temperature.
  • the composition may be useful as a thickener in pH ranges where other thickeners are not effective.
  • compositions of the invention may be incorporated into other compositions to impart emolliency to the composition.
  • the composition may also act as a film-forming bioactive agent after it has been applied to the skin or other mucosal membrane. This film-forming bioactive agent may be used as a barrier to prevent water loss from the skin while treating biological challenges.
  • the present invention provides a microemulsion composition
  • a microemulsion composition comprising at least 10% by weight of a copolymer that preferentially has thermo-reversible properties. Copolymer levels of this magnitude exceed, to the best of the applicant's knowledge, those found in other oil-copolymer based microemulsion.
  • oil-copolymer combinations may be prepared at a cold temperature. The applicant has found, however, that the combination of an emulsifier with the oil before addition of the copolymer surprisingly allows the microemulsion to be prepared at a low temperature.
  • composition or more specifically a microemulsion for delivery of water-insoluble active agents comprising: an aqueous component and a non-ionic block copolymer, and at least an oil that is the active agent or has a water-insoluble active agent dissolved therein.
  • Microemulsions as described herein will comprise an amount by weight of block copolymer of about 10% to about 50% by weight, more preferably the amount by weight block copolymer will be between about 10.1% and 40% by weight of the emulsion while an amount by weight of the block copolymer between any of the following ranges will be highly desirable: 10.5% to 35%, 11 % to 30%, 12% to 25%, 13% to 20% or 14% to 18% by weight of the emulsion.
  • the block copolymer may comprise 15% by weight of the emulsion.
  • block copolymer being present in the aforementioned weight ranges in the microemulsion, it will also desirably be a thermo-reversible copolymer.
  • the microemulsion or composition will possess bioadhesive or mucoadhesive properties. Such properties will be consistent with the microemulsion or composition being prepared in either a liquid or more preferably a gel form.
  • the microemulsion or composition will be useful for topical and/or mucosal application of water insoluble or sparingly soluble active agents to oesophageal, otic, vaginal, rectal or ophthalmic surfaces, or for application to the epidermis of an animal (such as skin in human) and/or to treat disorders and imperfections of the skin.
  • the microemulsion or composition will either exist as a gel or will be prepared in such a manner that it is capable of gelatinising upon contact with dermal or mucosal tissue.
  • the oil and the thermo-reversible copolymer will be mixed at a cold temperature.
  • the composition forms a stable microemulsion capable of application to dermal or mucosal tissue.
  • the invention provides a composition or more specifically a microemulsion for delivery of water-insoluble active agents, comprising: an aqueous component and a non-ionic block copolymer, a hydrophilic non-ionic short chain fatty acid emulsifier and at least an oil that is the active agent or has a water-insoluble active agent dissolved therein.
  • the oil and the emulsifier will be mixed and then applied to the thermo-reversible copolymer.
  • the composition rapidly forms a stable microemulsion capable of application to dermal or mucosal tissue.
  • the copolymer for use in the present invention is preferably a block copolymer of ethylene oxide and propylene oxide (poloxamer) preferably those represented by the formula:
  • 'b' is between 15 and 67 and 'a' is between 2 and 130, and the total proportion of 'a' units amounts to from 20% to 90% by weight of the poloxamer.
  • the molecular weight of the poloxamer ranges from preferably about 1 ,000 to 20,000 and it will preferentially have thermo-reversible properties.
  • the block copolymer may be poloxamer 407, such as that sold as Pluronic ® F127 (BASF Corporation) or Synperonic PE/F127 (Uniqema).
  • the preferred emulsifier is a fatty acid component with a polyethoxylated side chain.
  • suitable emulsifiers might be Laureth-4, Laureth-9, Laureth-23, PPG-26-Buteth-26/PEG-40 Hydrogenated castor oil or PEG-40 Hydrogenated castor oil.
  • the amount by weight of the emulsifier will vary generally from about 0.5% to about 50% by weight of the microemulsion.
  • the physico-chemical characteristics of the present invention make the microemulsion suitable as a delivery vehicle for water insoluble or sparingly soluble active agents. It is particularly well-suited for transdermal or transmucosal delivery.
  • the oil phase may comprise oils commonly used in the food, cosmetic and pharmaceutical industries for example, oils of natural or synthetic origin, long chain alcohols, glyceryl esters of fatty acids or fatty esters of monohydric alcohols.
  • the esters and alcohols can be straight or branch chained, saturated or unsaturated and liquids at room temperature.
  • the oil phase may also contain active agents that are soluble in or miscible with the oil phase.
  • the oil of the present invention may have inherent pharmaceutical properties and constitute the active agent of the microemulsion and/or may contain dissolved active agents that are soluble or miscible in the oil.
  • the active agents may include, but are not limited to, antimicrobials (such as antibiotics, antifungals and antivirals), anti-inflammatories, antihistaminics, antidepressants, anaesthetics antineoplastics, enzymes, cardiovascular agents, polynucleotides, genetic material, viral vectors, immunoactive agents, imaging agents, immunosuppressive agents, peptides, proteins etc and combinations thereof.
  • Pharmaceutically effective amounts of the selected active agents may be determined using techniques well known in the art.
  • the amount by weight of the oil used in the microemulsion will comprise from about 0.1% to about 80% by weight of the emulsion, more preferably 1% to 30% by weight of the emulsion, with a range of 3% to 15% by weight of the emulsion being highly desirable.
  • the oil will constitute about 6% of the total weight of the emulsion.
  • the oil is tea tree oil (TTO).
  • TTO tea tree oil
  • the active agent is TTO
  • the microemulsion will have microbicide activity.
  • Such a composition can be used to treat for example; diseases such as sexually transmitted disease (eg. HIV) by vaginal delivery; impetigo and cold sores by topical preparation, elimination of MRSAs by intranasal application and diseases such as otitis media, otitis externa, acne, periodontitis, gingivitis, paronychia, onychomycosis and secondary infections in connection with operations, dermatitis, burns, etc.
  • diseases such as sexually transmitted disease (eg. HIV) by vaginal delivery; impetigo and cold sores by topical preparation, elimination of MRSAs by intranasal application and diseases such as otitis media, otitis externa, acne, periodontitis, gingivitis, paronychia, onychomycosis and secondary infections in connection with operations
  • the invention provides a method for preparing the microemulsion composition, comprising the steps of:
  • step (a) Mixing a copolymer with an aqueous solution at a suitable temperature to substantially dissolve the copolymer in the aqueous solution; and (b) Mixing, at cold temperature, an oil that is the active agent or has a water-insoluble active agent dissolved therein, with the aqueous copolymer solution prepared in step (a) to form a microemulsion.
  • the co-polymer is mixed with an aqueous solution at a suitable temperature to substantially dissolve the copolymer in the aqueous solution. Dissolution of the co-polymer with an aqueous solution will occur almost instantaneously at temperatures of around 6°C.
  • the co-polymer may be mixed with the aqueous solution at room temperature if left over night with semi-continuous or continuous stirring.
  • cold temperature refers to temperatures less than about 15°C, preferably from about 4°C to about 12°C and most preferably less than about 10°C.
  • the invention provides a method for preparing the microemulsion composition, comprising the steps of: (a) Mixing a copolymer with an aqueous solution at a suitable temperature to substantially dissolve the copolymer in the aqueous solution; (b) Mixing a hydrophilic, non-ionic short chain fatty acid emulsifier with an oil that is the active agent or has a water-insoluble active agent dissolved therein, at a low temperature to form an oil mixture; and (c) Mixing the solution prepared in step (a) with the solution prepared in step (b) at a low temperature to form a microemulsion.
  • Low temperature refers to temperatures less than about 60°C, preferably from about 15°C to about 40°C, more preferably from about 20°C to about 30°C and most preferably at about room temperature.
  • Low temperature refers to temperatures less than about 60°C, preferably from about 15°C to about 40°C, more preferably from about 20°C to about 30°C and most preferably at about room temperature.
  • the ability to manufacture microemulsions of the present invention at these temperatures is highly significant as it provides a distinguishing feature from most other methods of manufacture of microemulsions which demand the microemulsions be made at about 90°C.
  • a microemulsion composition prepared according to the present invention has the surprising feature that the addition of the oil/emulsifier mixture to the aqueous poloxamer solution at room temperature changes the thermo-reversible nature of the poloxamer by altering the temperature at which solidification occurs. This effect is most evident at high ratios of poloxamer to oil.
  • Microemulsion compositions of the present invention provide clear, colourless gels that are particularly well suited to pharmaceutic and personal care applications. For example, very little residue is formed upon dehydration, which may be important in some applications, such as in optically applied pharmaceutics.
  • An additional advantage of the microemulsion composition of the invention is that they remain clear and translucent before and after the triggering environmental change. These characteristics of the reversibly gelling microemulsion composition make it well suited for use in pharmaceutic compositions.
  • microemulsion composition can be administered as a flowing liquid at ambient temperatures. Upon contact with body tissues it viscosifies, thus changing its flow properties, and more importantly, its clearance from the site of application is dramatically reduced.
  • microemulsion composition of the present invention may be utilized for a wide variety of pharmaceutic and personal care applications.
  • an effective amount of pharmaceutically active agent(s) which imparts the desirable pharmaceutic effect is incorporated into the reversibly gelling composition of the present invention.
  • the microemulsion composition can further include one or more pharmaceutically acceptable additives, excipients carriers and diluents.
  • additives, excipients carriers and diluents include, without limitation, water, saline, ethanol, dextrose, glycerol, lactose, dextrose, sucrose sorbitol, mannitol, starches, gum acacia, calcium phosphates, alginate, tragacanth, gelatine, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose,, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate and mineral oil or combinations thereof.
  • the formulations can additionally include lubricating agents, pH buffering agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents, antifoaming agents, polymers, antioxidants, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • lubricating agents pH buffering agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents, antifoaming agents, polymers, antioxidants, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • the particular selection of constituent that can be included in the compositions described herein will generally depend on the type of preparation.
  • an acid or a base may be incorporated into the microemulsion composition to facilitate processing, to enhance stability, or for other reasons.
  • pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminium hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminium silicate, synthetic aluminium silicate, synthetic hydrocalcite, magnesium aluminium hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris (hydroxymethyl) aminomethane (TRIS) and the like.
  • bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.
  • a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids
  • Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used.
  • the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Preferred cations include sodium, potassium, lithium, magnesium, calcium and ammonium.
  • Suitable acids are pharmaceutically acceptable organic or inorganic acids.
  • suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.
  • suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic
  • the present compositions can also include an enzyme inhibiting agent.
  • Enzyme inhibiting agents are shown for example, in Bernskop-Schnurch (1998),"The use of inhibitory agents to overcome enzymatic barrier to perorally administered therapeutic peptides and proteins," Controlled Release 52: 1-16.
  • inhibitory agents can be divided into the following classes: inhibitors that are not based on amino acids (such as P-aminobenzamidine, FK-448, camostat mesylate and sodium glycocholate); amino acids and modified amino acids (such as aminoboronic acid derivatives and n-acetylcysteine); peptides and modified peptides (such as bacitracin, phosphinic acid dipeptide derivatives, pepstatin, antipain, leupeptin, chymostatin, elastatin, bestatin, hosphoramindon, puromycin, cytochalasin potatocarboxy peptidase inhibitor, and amastatin); polypeptide protease inhibitors (such as aprotinin, Bowman-Birk inhibitor, soybean trypsin inhibitor, chicken egg white trypsin inhibitor, chicken ovoinhibitor, and human pancreatic trypsin inhibitor); complexing agents (such as EDTA, EGTA, 1
  • Esophageal, oral cavity and buccal applications One indication for the use of this microemulsion composition would be to provide a suitable vehicle for delivering a pharmaceutic effect within the oesophageal lining.
  • the mucoadhesive properties of the microemulsion composition of the invention make that composition desirable for controlling and facilitating a pharmaceutic effect to the oesophageal lining.
  • the shear sensitivity of the microemulsion composition could also be taken advantage of in applications in which a liquid treatments is sprayed under high shear conditions onto the oral cavity, where the solution adheres and viscosities to provide a reservoir for antibacterial agents, such as chlorohexadine, or a breath freshener.
  • Ophthalmic applications Most ophthalmic drugs are applied to the eye, typically to the precorneal area. The most common dosage form is a liquid drop. Drug bioavailability is generally low because liquid formulations are quickly cleared from the eye by tearing and blinking, resulting in the need for frequent dosing and uneven drug delivery.
  • microemulsion composition described herein provides a new vehicle for achieving greater bioavailability of topically administered insoluble or partially soluble ophthalmic active agents.
  • Formulations containing such active agents can be applied as drops that viscosity or gel upon contact with eye. Since gelling can be accomplished with low concentrations of the polymer, blurring can be minimized upon drop instillation.
  • microemulsion composition When used in this manner the microemulsion composition would preferentially be used for delivering bioactive materials, such as anaesthetics, mydriatics and cycloplegics, antimicrobial agents (antibacterial, antifungal, antiviral), anti- inflammatory agents, agents for the treatment of glaucoma, ocular decongestants, diagnostic agents, and wound healing agents.
  • bioactive materials such as anaesthetics, mydriatics and cycloplegics, antimicrobial agents (antibacterial, antifungal, antiviral), anti- inflammatory agents, agents for the treatment of glaucoma, ocular decongestants, diagnostic agents, and wound healing agents.
  • Microemulsion compositions of the invention may also be used for delivery of drugs to the nasal cavity.
  • Nasal drug delivery has been considered as an alternative to parenteral routes of administration of drugs that demonstrate low oral bioavailability.
  • efforts have been made to increase the residence time of formulations in the nasal cavity.
  • Nasal delivery of drugs can offer advantages over other methods of delivery, including rapid systemic absorption, lower dosing, more rapid onset of desired therapeutic effects, and improved pharmacokinetics.
  • it provides an alternative route for administering peptide drugs, which generally have low bioavailability via the oral route and are normally administered parenterally.
  • Microemulsion composition would potentially be useful for delivering agents such as decongestants, antihistamines, anti-osteoporosis agents, hormones, antineoplastic agents, Parkinsonism drugs, etc.
  • the composition may also be used for the application of vaccines, such as those against the influenza virus.
  • Microemulsion compositions of the invention are also indicated for the delivery of bioactive agents (such as TTO) to the vaginal or the rectal cavity.
  • bioactive agents such as TTO
  • TTO bioactive agents
  • These delivery routes have been considered as an alternative to parenteral routes of administration of bioactive agents that demonstrate low oral bioavailability.
  • efforts have been made to increase the residence time of formulations in these cavities.
  • These routes offer advantages over other methods of delivery, including rapid systemic absorption, lower dosing, more rapid onset of desired therapeutic effects, and improved pharmacokinetics.
  • Microemulsion compositions of the invention may also be useful in the treatment of not only human conditions but in providing treatments for animal care.
  • the microemulsion compositions is indicated for the preparation of topical dermal products, such as antibacterials, antifungals, antipruritics, and antiseborrheia, antiodor, and antiseptic/wound healing preparations.
  • Otic products would include ear cleaners with or without actives, such as, antifungals.
  • Ophthalmic products would include eye moisturizers or antimicrobial preparations.
  • Microemulsion compositions of the invention may also be particularly well suited for cosmetic applications. For example, very little residue is formed upon dehydration, which may be important in some applications, such as in topically applied cosmetics.
  • An additional advantage of the composition of the invention is that it remains clear and translucent above and below the critical temperature or pH. These characteristics of the microemulsion compositions make it well suited for use in cosmetic compositions.
  • an effective " amount of cosmetically active agent(s) that imparts the desirable cosmetic effect is incorporated into the microemulsion composition of the present invention.
  • the selected agent lends itself to a homogeneous dispersion through out the microemulsion composition. It is contemplated as within the scope of the invention that the reversibly gelling composition compositions of the present invention may be prepared under sterile conditions.
  • Exemplary cosmetic and personal care applications in which the microemulsion composition may be used include, but are not limited to, baby products, bath preparations, eye makeup preparations, fragrance preparations, noncolouring hair preparations, colour cosmetics, hair colouring preparations, makeup preparations, manicuring preparations, oral hygiene products, shaving preparations, skin care preparations, and suntan preparations such as suntan creams, gels and lotions, indoor tanning preparations.
  • the cosmetic composition may be in any form. Suitable forms include but are not limited to lotions, creams, sticks, roll-ons formulations, mousses, aerosol sprays, pad-applied formulations, and film-forming formulations.
  • Preparation of pharmaceutic compositions may be accomplished with reference to any of the pharmaceutic formulation guidebooks and industry journals which are available in the pharmaceutic industry. These references supply standard formulations which may be modified by the addition or substitution of the microemulsion compositions of the present invention. Suitable guidebooks include Pharmaceutics and Toiletries Magazine, Vol. 111 (March, 1996); Formulary: Ideas for Personal Care; Croda, Inc, Parsippany, N.J. (1993); and Pharmaceuticon: Pharmaceutic Formulary, BASF, which are hereby incorporated in their entirety by reference.
  • Exemplary drugs or therapeutics delivery systems which may be administered using the aqueous responsive compositions of the invention include, but are in no way limited to, mucosal therapies, such as esophageal, otic, rectal, buccal, oral, vaginal, and urological applications; topical therapies, such as wound care, skin care and teat dips; and intravenous/subcutaneous therapies, such as intramuscular, intrabone (e.g., joints), spinal and subcutaneous therapies, tissue supplementation, adhesion prevention and parenteral drug delivery.
  • mucosal therapies such as esophageal, otic, rectal, buccal, oral, vaginal, and urological applications
  • topical therapies such as wound care, skin care and teat dips
  • intravenous/subcutaneous therapies such as intramuscular, intrabone (e.g., joints), spinal and subcutaneous therapies, tissue supplementation, adhesion prevention and parenteral drug delivery.
  • animal used herein is taken to mean mammals, such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats, mice; it also includes, birds, reptiles, and fish.
  • Part A Add 15.6 g Lutrol ® F127 to 84.4 g deionised water, which is held at a temperature of 6°C. Combine with slow mixing to reduce air entrapment and place under vacuum for a few minutes to remove any trapped air after Lutrol ® F127 is dissolved.
  • Part C Combine 3.0 g Tea Tree oil, 5.0 g propylene glycol and 2.0 g undecylenic acid and mix to dissolve all ingredients. Cool the solution to 10°C.
  • the products were tested using macrodilution and microdilution methods, using a 96-well microtitre tray. The highest concentration of gel tested was 50% product.
  • test organisms were Staphylococcus aureus NCTC 6571 , Escherichia coli NCTC 10418, Pseudomonas aeruginosa NCTC 10662 and the yeast Candida albicans ATCC 10231.
  • Inocula were prepared in double strength Mueller Hinton broth, resulting in a final concentration of single strength broth and organisms at a final concentration of approximately 5 x 10 5 cfu/mL. Tests were incubated at 37°C for 24 hours. After this time, trays were subcultured by removing 5 ⁇ L from tray wells and spot 5 inoculating onto Mueller Hinton agar. All subcultures were incubated for 24 hours and the colonies counted.
  • the minimum inhibitory concentration (MIC) was defined as the lowest concentration of product resulting in the maintenance or reduction of the inoculum.
  • the minimum cidal concentration (MCC) was defined as the lowest 0 concentration of product resulting in the death of 99.9% of the inoculum.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Dermatology (AREA)
  • Birds (AREA)
  • Polymers & Plastics (AREA)
  • Urology & Nephrology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Gynecology & Obstetrics (AREA)
  • Reproductive Health (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Preparation (AREA)
  • Colloid Chemistry (AREA)
  • Processes Of Treating Macromolecular Substances (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Cosmetics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Composition sous forme d'émulsion, qui contient un constituant aqueux, un copolymère séquencé non ionique et une huile, le copolymère représentant au moins 10 % en poids de la composition.
EP04712958A 2003-02-27 2004-02-20 Preparations sous forme d'emulsions a base de poloxameres Withdrawn EP1597318A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
AU2003900887A AU2003900887A0 (en) 2003-02-27 2003-02-27 Poloxamer emulsion preparations
AU2003900887 2003-02-27
PCT/AU2004/000218 WO2004076561A1 (fr) 2003-02-27 2004-02-20 Preparations sous forme d'emulsions a base de poloxameres

Publications (2)

Publication Number Publication Date
EP1597318A1 true EP1597318A1 (fr) 2005-11-23
EP1597318A4 EP1597318A4 (fr) 2006-06-14

Family

ID=31499933

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04712958A Withdrawn EP1597318A4 (fr) 2003-02-27 2004-02-20 Preparations sous forme d'emulsions a base de poloxameres

Country Status (9)

Country Link
EP (1) EP1597318A4 (fr)
JP (1) JP2006519272A (fr)
CN (1) CN100591721C (fr)
AU (3) AU2003900887A0 (fr)
BR (1) BRPI0408056A (fr)
CA (1) CA2516863C (fr)
EA (1) EA017434B1 (fr)
NO (1) NO20054395L (fr)
WO (1) WO2004076561A1 (fr)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2721927C (fr) * 2008-04-21 2014-01-28 Otonomy, Inc. Preparations auriculaires de traitement de maladies et etats otiques
WO2010076730A1 (fr) * 2009-01-02 2010-07-08 Donald, Jenny Méthode de traitement d'une infection par le vih
SG184071A1 (en) * 2010-04-01 2012-10-30 Pharmanest Ab Thermogelling anaesthetic compositions
WO2012126140A1 (fr) 2011-03-21 2012-09-27 博任达生化科技（上海）有限公司 Composition d'hydrogel réciproquement thermoréversible
ITMI20131927A1 (it) * 2013-11-20 2015-05-21 Cosmo Technologies Ltd Emulsions or microemulsions for use in endoscopic mucosal resectioning and/or endoscopic submucosal dissection. emulsioni o microemulsioni per uso nella resezione mucosale endoscopica e/o dissezione submucosale endoscopica
EP3778702B1 (fr) * 2014-03-25 2023-06-28 F. Hoffmann-La Roche AG Procédé de préparation de poloxamère pour une utilisation dans milieu de culture cellulaire
US10351750B2 (en) * 2017-02-03 2019-07-16 Saudi Arabian Oil Company Drilling fluid compositions with enhanced rheology and methods of using same
KR101852718B1 (ko) * 2017-04-04 2018-05-18 주식회사 제네웰 외과수술 후 절개부위 통증 감소를 위한 키트
KR102544922B1 (ko) * 2017-12-21 2023-06-16 시그마-알드리치 컴퍼니., 엘엘씨 폴록사머 조성물 및 이의 제조 및 사용 방법
IT201900018752A1 (it) * 2019-10-14 2021-04-14 Alessandro Tosetti Composizione a base di olii essenziali ad uso odontoiatrico per il trattamento della periodontite e della mucosite perimplantare
RU2762506C1 (ru) * 2021-01-20 2021-12-21 Общество С Ограниченной Ответственностью «Диамед-Фарма» Средство для аппликации полости рта и носа и способ его применения в составе комплексной терапии инфекционно-воспалительных заболеваний носовой и ротовой полости
CN114455621B (zh) * 2022-01-11 2023-10-27 兰州交通大学 一种针状碳酸钙的制备方法

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990003429A1 (fr) * 1988-09-23 1990-04-05 Cetus Corporation Micro-emulsions de lipides pour milieux de culture
US5698219A (en) * 1994-08-08 1997-12-16 Laboratorios Cusi, S.A. Nanoemulsion of the oil water type, useful as an ophthalmic vehicle and process for the preparation thereof
DE19723308A1 (de) * 1997-06-04 1998-12-10 Wolfgang A Prof Dr Wohlrab Neue Mikroemulsionen zur topischen Anwendung von Arzneimittelwirkstoffen
US5952004A (en) * 1994-03-18 1999-09-14 Shire Laboratories Inc. Emulsified drug delivery systems
EP1018363A1 (fr) * 1999-01-05 2000-07-12 L'oreal Nanoémulsion à base de copolymères blocs d'oxyde d'éthylène et d'oxde de propylène, et ses utilisations dans les domaines cosmétique, dermatologique et/ou phtalmologique
WO2000051550A1 (fr) * 1999-03-01 2000-09-08 Basf Corporation Emulsions eau dans huile traitees a froid
WO2000078301A1 (fr) * 1999-06-21 2000-12-28 Kuhnil Pharm. Co., Ltd. Composition d'anesthesiant en injection intraveineuse comprenant du propofol
WO2001066087A1 (fr) * 2000-03-08 2001-09-13 Astrazeneca Ab Nouveau systeme de delivrance d'un medicament auto-emulsifiant
WO2002009671A2 (fr) * 2000-08-01 2002-02-07 University Of Florida Nouveaux systemes de micro-emulsions et de tensioactifs destines a la solubilisation de medicaments

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0791555B2 (ja) * 1989-12-22 1995-10-04 株式会社資生堂 洗浄剤組成物
SE9601421D0 (sv) * 1996-04-12 1996-04-12 Astra Ab New composition

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990003429A1 (fr) * 1988-09-23 1990-04-05 Cetus Corporation Micro-emulsions de lipides pour milieux de culture
US5952004A (en) * 1994-03-18 1999-09-14 Shire Laboratories Inc. Emulsified drug delivery systems
US5698219A (en) * 1994-08-08 1997-12-16 Laboratorios Cusi, S.A. Nanoemulsion of the oil water type, useful as an ophthalmic vehicle and process for the preparation thereof
DE19723308A1 (de) * 1997-06-04 1998-12-10 Wolfgang A Prof Dr Wohlrab Neue Mikroemulsionen zur topischen Anwendung von Arzneimittelwirkstoffen
EP1018363A1 (fr) * 1999-01-05 2000-07-12 L'oreal Nanoémulsion à base de copolymères blocs d'oxyde d'éthylène et d'oxde de propylène, et ses utilisations dans les domaines cosmétique, dermatologique et/ou phtalmologique
WO2000051550A1 (fr) * 1999-03-01 2000-09-08 Basf Corporation Emulsions eau dans huile traitees a froid
WO2000078301A1 (fr) * 1999-06-21 2000-12-28 Kuhnil Pharm. Co., Ltd. Composition d'anesthesiant en injection intraveineuse comprenant du propofol
WO2001066087A1 (fr) * 2000-03-08 2001-09-13 Astrazeneca Ab Nouveau systeme de delivrance d'un medicament auto-emulsifiant
WO2002009671A2 (fr) * 2000-08-01 2002-02-07 University Of Florida Nouveaux systemes de micro-emulsions et de tensioactifs destines a la solubilisation de medicaments

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2004076561A1 *

Also Published As

Publication number Publication date
CA2516863C (fr) 2011-12-06
EP1597318A4 (fr) 2006-06-14
AU2009202265B2 (en) 2012-02-16
AU2009202265A1 (en) 2009-07-02
AU2003900887A0 (en) 2003-03-13
AU2004215921A1 (en) 2004-09-10
JP2006519272A (ja) 2006-08-24
CA2516863A1 (fr) 2004-09-10
EA200501368A1 (ru) 2006-02-24
WO2004076561A1 (fr) 2004-09-10
BRPI0408056A (pt) 2006-02-14
NO20054395L (no) 2005-09-22
EA017434B1 (ru) 2012-12-28
CN100591721C (zh) 2010-02-24
CN1753949A (zh) 2006-03-29

Similar Documents

Publication Publication Date Title
US8802116B2 (en) Poloxamer emulsion preparations
AU2009202265B2 (en) Poloxamer Emulsion Preparations
JP7369683B2 (ja) 水溶性超分子複合体
US8865143B2 (en) Reversely thermo-reversible hydrogel compositions
US20030215418A1 (en) Hydroalcoholic compositions thickened using polymers
JP2002514220A (ja) 熱傷処置および感染防止のための局部スプレー
CN101522165A (zh) 个人护理组合物
CA2180755A1 (fr) Base pour onguent pharmaceutique
JP2003183157A (ja) 眼科用組成物
JPH08310959A (ja) 非水性皮膚軟化剤入りヨードフォア製剤
US5137718A (en) Infection fighting composition for topical application
CA1063515A (fr) Tretinoin dans un excipient en gel pour le traitement de l'acne
JP2005162728A (ja) 局所用途のためのムピロシン組成物、これを作成する改良プロセス、およびこれを用いる方法
KR20230021981A (ko) 난용성 효능성분의 안정도가 개선된 다중유화 조성물
MX2007003700A (es) Composiciones para enfriar la piel.
EP3638219B1 (fr) Composition comprenant le terpinen-4-ol pour le traitement de la démodécie
JP7546113B1 (ja) 水中油型乳化化粧料
JP7555683B2 (ja) 乳化化粧料組成物
JP2011507942A (ja) 新規なエステル及び組成物、並びにこれらの使用
KR20230021979A (ko) 난용성 효능성분의 안정도가 개선된 다중유화 조성물
JPH10182312A (ja) 防腐系とそれを含有する化粧品用または製薬用組成物
KR20230021978A (ko) 난용성 효능성분의 안정도가 개선된 다중유화 조성물
JP3005219B1 (ja) 外用剤
US20230085380A1 (en) Method for Treating Pruritus
JPH11269023A (ja) 外用組成物

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20050826

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

A4 Supplementary search report drawn up and despatched

Effective date: 20060428

17Q First examination report despatched

Effective date: 20060816

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1089197

Country of ref document: HK

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1089197

Country of ref document: HK

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 47/34 20170101ALI20170421BHEP

Ipc: B01F 17/42 20060101ALI20170421BHEP

Ipc: C08L 71/02 20060101AFI20170421BHEP

Ipc: A61K 9/107 20060101ALI20170421BHEP

Ipc: C08J 3/075 20060101ALI20170421BHEP

INTG Intention to grant announced

Effective date: 20170519

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20170930

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 47/34 20170101ALI20170421BHEP

Ipc: C08J 3/075 20060101ALI20170421BHEP

Ipc: A61K 9/107 20060101ALI20170421BHEP

Ipc: B01F 17/42 20060101ALI20170421BHEP

Ipc: C08L 71/02 20060101AFI20170421BHEP