WO2000067726A1 - Procedes et formulations hote-invites pour l'administration de composes bioactifs - Google Patents

Procedes et formulations hote-invites pour l'administration de composes bioactifs Download PDF

Info

Publication number
WO2000067726A1
WO2000067726A1 PCT/US2000/012743 US0012743W WO0067726A1 WO 2000067726 A1 WO2000067726 A1 WO 2000067726A1 US 0012743 W US0012743 W US 0012743W WO 0067726 A1 WO0067726 A1 WO 0067726A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
process according
group
host
compounds
Prior art date
Application number
PCT/US2000/012743
Other languages
English (en)
Other versions
WO2000067726A8 (fr
Inventor
Charles Walton Champ
Karen June Kinzer
Original Assignee
Charles Walton Champ
Karen June Kinzer
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 Charles Walton Champ, Karen June Kinzer filed Critical Charles Walton Champ
Priority to AU51293/00A priority Critical patent/AU5129300A/en
Priority to US10/019,859 priority patent/US6676951B1/en
Priority to CA002373630A priority patent/CA2373630A1/fr
Publication of WO2000067726A1 publication Critical patent/WO2000067726A1/fr
Publication of WO2000067726A8 publication Critical patent/WO2000067726A8/fr

Links

Classifications

    • 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
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N27/00—Biocides, pest repellants or attractants, or plant growth regulators containing hydrocarbons
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N61/00—Biocides, pest repellants or attractants, or plant growth regulators containing substances of unknown or undetermined composition, e.g. substances characterised only by the mode of action
    • 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
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/26—Aluminium; Compounds thereof
    • 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
    • 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
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • 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
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • 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
    • A61K2800/52—Stabilizers
    • A61K2800/522—Antioxidants; Radical scavengers

Definitions

  • the present invention relates to processes and formulations capable of protecting, stabilizing, and/or delivering one or more bio-affecting compounds More particularly, the invention relates to processes of making a composition having a host compound capable of accepting one or more bio-affecting guest compounds and new compositions formed by the processes.
  • the processes are particulai ly useful in formulating compositions for the topical delivery of the bio-affecting compounds
  • compositions capable of delivering a compound to a cell membrane and in a structural form or environment that will encourage the transfer of the compound across the cell membrane into the biological system has been the subject of considerable research using many different approaches.
  • ascorbic acid can be beneficial for healing the sk .
  • a relatively high concentration of ascorbic acid preferably at least 8% by weight of the composition, is desirable, and perhaps necessary, to be effective in penetrating the dermal layer and activating collagen in the skin
  • the ascorbic acid composition is exposed to air, however, and particularly at such high concentrations, the ascorbic acid tends to rapidly oxidize A stabilizing environment for the ascorbic acid is necessary to protect it from oxidation or the composition will lose its effectiveness
  • alpha tocopherol can be beneficial for healing and/or preventing damage to the skin by scavenging free radicals in the biological system
  • a relatively high concentration of alpha tocopherol preferably at least 5% by weight of the composition, is desirable, and perhaps necessary, to be effective in penetrating the dermal layer and
  • compositions for topical application contain low concentrations of both ascorbic acid (as a preservative) and alpha tocopherol (as an antioxidant) at levels below 0 5% by weight At these low concentrations, however, the ascorbic acid and alpha tocopherol are much less effective in repai ⁇ ng skin damage
  • compositions having high concentrations of certain bio-affecting compounds, such as ascorbic acid have been particularly difficult to stabilize
  • standard stability test procedures that are used to determine the shelf life of a product do not tell the whole story
  • a standard stability test is conducted at elevated temperatures and humidity is commonly used for determining the shelf life of a composition Because the rates of chemical reactions and the growth of bacte ⁇ a tend to double with each 10°C (18°F) increase in temperature, testing the stability of a product at elevated temperatures can be used to calculate its expected shelf life at ordinary temperatures with a reasonable degree of confidence
  • the standard test requires the compound to be placed in the sealed container in which it is to be sold or stored, for 30, 60, and 90 days at 31 °C (87°F) and at 45°C (113°F) in a chamber at 80% relative humidity.
  • bio-affecting ingredients for ultraviolet sun block protection include zinc oxide (ZnO) and/or titanium dioxide (T ⁇ O 2 ), which can be used for blocking UV-A and/or UV-B radiation, respectively.
  • compositions according to the invention depend on the initial formation of a host composition having a host capable of accepting a guest in host-guest coordination
  • One or more bio-active compounds can then be mixed with the host composition for creation of a stable molecular environment, that is, according to a process of molecular stacking.
  • the formulation processes preferably include establishing a desired pH range to help maintain the stability of pH-sensitive compounds.
  • a wide range of bio-affecting compositions can be made according to the general approach of the invention.
  • specific formulation processes and compositions are provided
  • a process for making a host composition having a host for at least one guest comprising mixing, in any order:
  • R a and R h are hydrocarbons that can be the same or different, where at least one of the R a and R b hydrocarbons includes an epoxide group within 3 carbons ofthe hydrocarbon attachment to contnbute to the desired hydro-hpid balance of 7 - 9, where R c is hydrogen or a methyl group, and where R d is a methylene group (-CH 2 -), an ethyl group (-CH 2 -CH 2 -), or a structurally equivalent link with a bond length range about the same as or shorter than that provided by an ethyl group, and having a hydro-hpid balance in the range of 7 - 9, or any combination of two or more thereof; (n) in a stoichiomet ⁇ c proportion of at least 1 :6 relative to the non-ionic surfactant, an amphoteric surfactant selected from the group consisting of organic compounds having the chemical formula NH3
  • R is a straight, branched, or aromatic hydrocarbon structure having 6 - 24 carbons, or any combination of two or more thereof;
  • the solvent compnsmg one or more compounds selected from the group consisting of water, alcohols having straight or branched hydrocarbon structure having up to 6 carbons, glycosamionoglucans, or any combination of two or more of the foregoing;
  • a five- or six-member aromatic nng structure is of the appropriate molecular size and provides the appropnate electron orbitals to coordinate in the formation of the host complex.
  • nonoxyl-9 which includes a phosphate group that can be considered to be a Lewis acid but not a Bronsted-Lowry acid, can be used for providing both the aromatic and the Lewis acid.
  • Nonoxyl-9 has the further advantage of being a well-known germicide.
  • aluminum sulfate which in water forms a small amount of sulfu ⁇ c acid, can be used for providing both the aluminum cation and the Bronsted-Lowry
  • one or more compounds are selected to be sequentially mixed with the host composition to form a stable molecular environment, which is sometimes referred to herein as a process of molecular stacking
  • the sequence of mixing the additional bio-affecting compounds is based on the following factors:
  • the process preferably includes establishing a desired pH range to help maintain the stability of pH-sensitive compounds Establishing the desired pH range often has a substantial influence on the selection of one or more additional compounds to be mixed with the host composition and the mixing sequence
  • bio-affectmg compositions can be made according to the general approach of the invention
  • specific formulation processes and compositions are provided for various bio- affecting compositions, which compositions are highly effective for certain biological purposes, such as skin exfoliation, collagen activation in the skm, the topical delivery of salicylic acid, and other pain relievers to local areas of pain and/or inflammation, to promote skin healing processes, and other purposes, such as the delivery of plant growth hormones, such as diterpenes, or even the topical dispersion of UV radiation blocking compounds
  • the formulation processes according to the invention are expected to be useful in the production of a wide a ⁇ ay of compositions having bio-affecting purposes
  • water soluble means that a compound or mixture of compounds has a solubility characteristic of at least 0 2 g/lOOg of distilled water at standard temperature and pressure To the extent the compound or mixture of compounds does not meet this solubility cntena, it would be expected to be lipid soluble It is to be understood that this bright-line cntena between water solubility and lipid solubility is arbitra ⁇ ly assigned as a matter of clan ty of definition, and that the solubility charactenstics in relation to complex mixtures can be blurred by factors such as temperature, pressure, pH, chemical reaction, complex coordination, and mutual solubility Of course, some compounds, particularly inorganic compounds, can be nearly or completely insoluble in both water and lipids
  • a process according to the invention can be used to formulate specific compositions including one or more compounds that can be considered to be water soluble selected from the group consisting of ascorbic acid, ascorbyl salts, 7- dehydroxy cholesterol, alpha-hydroxy acids, beta-hydroxy acids, glycohc acids, isoprenoids, bioflav oids, fatty acids, glycosaminoglucans, flavin mono nucleotides, flavin mono nucleotide de ⁇ vatives, diterpenes, glycerophosphohpids, beta-carotene, trans retinol, trans retinoic acid, allontom, nonoxyl-9, betaine, and any combination of two or more of the foregoing.
  • a process according to the invention can be used to formulate specific compositions including one or more compounds that can be considered to be hpid-soluble selected from the group consisting of. alpha tocopherol, alpha tocopherol ester, co- enzymes, ubiquinones, menaqumones, phylloquinones, 7-dehydroxy cholesterol, steroids, bioflavmoids, terpenes, saponified fatty acids, unsapomfied fats, glycerophospho pids, and any combination of two or more of the foregoing
  • the host complexes can be used for a vanety of formulations that do not require direct activation of ingiedients in response to the system in which they are introduced. Rather, the stabilization of crown complexes can provide an alternative at the other end of the spectrum of products
  • a process according to the invention can be used to formulate specific compositions including one or more compounds that can be considered to be nearly or completely insoluble in either water and lipids, such as inorganic compounds, and more particularly, titanium dioxide and/or zinc oxide
  • the processes according to the invention allow for the inclusion of non- hydrocarbon chemicals that are bio-affecting as not only resistant to external forces (like UV radiation) within mammalian systems, but also provide the consistent ability to release other organic products as a resultant of the interacting system It is important to note, however, that solubility charactenstics of chemical compounds are typically reported based on studies of a purified form of the particular chemical Many naturally-occur ⁇ ng chemicals are found and extracted in conjunction with denvatives that substantially affect solubility
  • the invention has one or more of the following illustrative objects, which are not intended to limit the invention to being able to accomplish all of the following objects:
  • compositions according to the invention depend on the initial formation of a host composition capable of accepting a guest in host-guest coordination Thereafter, one or more bio-active compounds can be mixed with the host composition according to the formulation process for creation of a stable molecular environment for the bio-active compounds, that is, according to a process of molecular stacking.
  • Crown ethers were first discovered by Charles Pederson in 1967. Crown ethers act as lonophores trapping guest atoms or molecules that would otherwise not be able to transfei across membranes because the trapped molecule is not soluble in the fatty compounds found in the membrane Traditionally, the guest has been a transition metal. Crown ethers tend to mimic enzymes in function because they act as carriers of other compounds across membranes.
  • crown ether structure in biological systems is fe ⁇ echrome which has hemoglobin at the center of a C-N-O ether ring
  • Other forms of host molecules include, for example, crystahemispherands, cahxarenes, carcerands, and rotoxanes It is important to iecogmze that all these host compounds are not necessarily cyclic in nature, but many are actually open crowns that are generally horseshoe shaped With the presence of transitional metals, crown ethers are more rigid and interlocking similar to amino acid building blocks in DNA Without the presence of a transitional metal, the crown ethers tend to be flat and soft, more like a rubber band, and without the presence of a well-defined cavity To act as a host, a guest molecule must be present to give the crown ether or other host compound its shape and function Crown ethers are typically formed and stabilized with transitional metals and acyl or acetyl groups by establishing a catalytic reaction which allows for synthesis of a
  • Surfactants in water can create lamellar configurations, vesicles, micelles, and reverse micelles which will incorporate compounds that have the opposite solubility ofthe chemical system, water in oil, oil in water. These configurations align the polar end of a molecule in one direction and the non-polar end in the opposite direction.
  • the specific configuration will vary dependent upon the type of suifactant, the concentration of the surfactant, the compound(s) involved, temperature, and mix order of the compounds.
  • surfactants will create an emulsion or a micro-emulsion Surfactants also alter the mterfacial tension of the chemical system Low temperatures and/or elevated pressures will cause separation of the oil and water phases in a sui ctant system.
  • surfactant systems are found naturally in biological systems, the most prominent is the lung surfactant containing 50% to 60% dipalrmtoylphosphatidyl cho ne.
  • the lung surfactant maintains high surface tension preventing collapse ofthe alveoli upon air expulsion from the lungs.
  • the phophatidyl chohne is a phophohpid which will also create electron orbitals that will share with both hpid and water-soluble compounds In combination with certain bio-affecting compounds, the stability of that compound is lessened.
  • a transitional crown ether "host” can be formed in a what is refened to herein as a "host composition.”
  • the tdiversely-solublensitional crown ether allows foi electrophihc attachment of diversely-soluble compounds.
  • a host complex is created by using a combination of non-ionic and amphote ⁇ c surfactant in an aqueous environment with aluminum sulfate.
  • the non-ionic surfactant is selected from the group consisting of compounds having the following chemical structure:
  • R a and R b are hydrocarbons that can be the same or different, where at least one of the R a and R b hydrocarbons includes an epoxide group within 3 carbons of the hydrocarbon attachment to contribute to the desired hydrolypid balance of 7 - 9, where R c is hydrogen or a methyl group, and where R d is a methylene group (-CH 2 -), an ethyl group (-CH 2 -CH 2 -), or a structudiversely-solublelly equivalent link with a bond length diversely-solublenge about the same as or shorter than that provided by an ethyl group, and having a hydro-hpid balance in the diversely-solublenge of 7 - 9, or any combination of two or more thereof
  • R a includes the required epoxide group
  • R c is a hydrogen
  • R c is most preferably hydrogen
  • hydrocarbon generally refers to a chemical structure made up of hydrogen and carbon atoms Unless the context clearly requnes otherwise, however, it is to be understood that the term does not exclude hydiocarbon structures having other atoms or chemical functionalities, so long as such variations do not interfere with the chemistry of the formulation processes and compositions
  • the presently most prefened components for the formation of the host composition are.
  • nonoxyl-9 which is an aromatic compound with a single phosphate group, and where the phosphate group provides a Lewis acid
  • aluminum sulfate which m the presence of water piovides both the aluminum cation and a small quantity of sulfu ⁇ c acid, which is a Bronsted- Lowry acid
  • the non-ionic surfactant is made from naturally-occurnng compositions and is sometimes commercially refened to as a "dodecat ⁇ ethoxylate" or "EO3" type composition, which is presently commercially available from Hoechst under the trade name "Genapol UDO79 "
  • the attachment process includes va ⁇ ous intermediate steps which can lead to one of several resultant chemical structures including a pure crown ether without a transitional metal, a crystahemispherand, a cahxarene, a carcerand, a rotoxane, or another form of a host-guest complex
  • the presence of the chemical unit -C-O-C- can be immediately attached to an aromatic or cyclic compound as long as the end resultant complex completes a cyclic configuration This reaction stages into repetitive additions of that unit The larger the (-C-O-C-) n host molecule, the larger the guest molecule that coordinates with the host.
  • Non-ionic surfactants with 12 to 16 carbons and three epoxides having a hydrolipid balance factor of 7 - 9 will yield an -C-O-C- ether unit
  • Non-ionic surfactants are formed from alcohols By treating the alcohol with potassium hydroxide, 96% of the alcohol bonds will form into epoxide groups By final treatment with aluminum hydroxide, the remaining 4% alcohols will also yield epoxide bonds
  • aluminum sulfate providing the Bronsted-Lowry acid
  • the reaction yields relatively large percentages of the ether link.
  • the water is preferably in a stoichiometnc proportion of at least 1: 1.2 relative to the non-ionic surfactant.
  • the host complex is formed by cleaving the branched chain of the non-ionic surfactant
  • the branched chain contains an epoxide group
  • the key components for cleaving the branched chain and forming the host complex are the presence of an amphoteric surfactant (zwitte ⁇ on) dissolved in a solvent such as a short chain alcohol, a phosphate group (Lewis acid), an aromatic aryl hydrocarbon (e g , attached to phosphate group), aluminum sulfate, and water
  • the aluminum sulfate has two roles in this reaction First, aluminum sulfate in the presence of water and a phosphate group will generate sufficient sulfu ⁇ c acid to cleave the epoxide branch chain of the non-ionic surfactant Second, the aluminum sulfate acts as a temporary binding site for the formation of the host complex unit ( -C-O-C-)n, where n is at least 3. In the presence of alcohol, the epoxide gioup breaks between the C-C bond.
  • the alcohol participates in the formation of the host complex unit by sharing electrons while the temperature is ramped up to about 49°C (120°F)
  • the host complex unit at lower temperatures of 21 °C - 32°C (70°F - 90°F) can join together by producing an 18- crown-6 ether with a single aromatic nng in the middle to provide rigidity
  • the internal diameter of 18-crown-6 ether is 7.86A, whereas the external diameter ofthe benzene nng
  • the less polar end of the aromatic aryl hydrocarbon is at a 75 degree to 90 degree angle from the plane of the host complex.
  • the shape of the host complex is that of calixarenes and carcerands without a transition metal m the middle of the structure. Due to the presence of nnged structures in calixarenes and carcerands, several compounds with an aromatic group can provide the ⁇ gidity for the host complex.
  • the zwitterion adds stability to the reaction by partial sharing of electrons during the formation of the host complex.
  • aromatic compounds with repeating isoprenoid units become the guest in the host complex.
  • the repeating units, whether isoprenoids or polymeric units, provide for subsequent molecular stacking of additional ingredients into the host composition.
  • At least three molecules of the branched chain non-ionic surfactant is required for the formation of a host complex molecule.
  • at least about one weight percent of the host complex in the total composition is formed for the purpose of stabilizing diversely-soluble compounds.
  • one host complex provides inter- molecular attachment sites for three diversely-soluble molecules. This, in turn, provides three or more stacking sites for other like molecules. The stacked molecules are then sandwiched between non-ionic surfactant layers.
  • phosphate-sulfate balance is the balance of electrons available from different orbitals due to the molecular configuration of the anions.
  • the crown ethers that are formed are extremely unstable until they become attached within the system based on both nucleophilic and electrophihc reaction.
  • the key to the reaction is the cleavage of the branched chain non-ionic surfactant, i.e., the separation of the -(CH 2 ) n -3,4-epoxide-R" group.
  • Calixerands, crystahemispherands, calixarenes, carcerands, rotoxanes, or other host molecules can be formed in the process of producing a crown by introducing aromatic compounds prior to full cyclization of the crown ether. Because of greater electron affinity to the paired electrons found in the oxygen molecule and, similarly, in double-bonded shared electrons in cyclic and aromatic compounds, other host complexes can be formed. Refer to Figure 1.
  • the subsequent sequence of mixing additional compounds with the host composition allows for stabilization of the one or more host compounds, which then allows for molecular stacking of diversely-soluble compounds.
  • Host compositions begin to stabilize the first addition of the aromatic to the center of the host compound.
  • the host compositions become more stable as more guest compounds are added because the host becomes entrapped rather than entrapping as in the first step of host-guest complex formation.
  • the remaining system is balanced with assorted surfactants (lamellar layenng) allowing for other compounds to be added in a hydro-hpid balanced environment.
  • assorted surfactants lamellar layenng
  • the apolar ends of the guest molecules will first be directed toward the aqueous phase with the polar ends directed to the crown ether type structure, which also is polar.
  • the isoprenoid unit extends into the aqueous phase, there will be lamellar layer of similar compounds, especially those that have a ubiqionone structure attached to the hydrocarbon chain.
  • the pnmary stabilizing component of this compounding method is the introduction of selected compounds during the formation of either the pure 18-crown-6 ether or any resultant compound where the introduced substrate binds to the (- C-O-C) n complex
  • the resultant host-guest complex creates an electronic environment where hydrogen bonding, Van Der Waal forces, and inter-molecular adhesion occurs. And, by partial electron polarity and sharing, the various molecules will align through a process of molecular stacking and layering It is important to note that this is not the same as forming a 'liposome' system, which requires the presence of what can be various phosphatidyl cholmes. Nor is this an emulsion, which is genei ally created in cold compounding procedures by utilizing high revolutions-per-minute (RPM) mixing, rather than the relatively low RPM mixing prefened according to the inventive formulation processes.
  • RPM revolutions-per-minute
  • a process of molecular stacking of one or more bio-acti ve compounds is used in the further formulation of stabilized compositions
  • the bio-acti ve compounds are selected based on the desired function of the final product and the desired activity level of each of the selected ingredients.
  • the identification and desired bio-active compounds to be stabilized and delivered by the formulation can be determined from the known uses and effectiveness of the bio-effective compound Numerous classes of compounds are available, including synthetic and natural compounds, as well as natural essential compounds.
  • Major factors governing the addition of compounds to the host composition environment include: (I) the one or more desired bio-affecting compounds desired to be added to create a desired composition for a specific application, and (n) the desired point of attachment to the host complexes
  • the systematic addition, 1 e , molecular stacking, of the bio-affecting and other desirable ingredients into the host composition is also based on a consideration of the following factors
  • the initial molecular structure required for maintaining stability for diversely- soluble compounds is based on partial polanzation of long chain hydrocarbons and the electron protection of aromatic, cyclomatic, and suspected non-metal-contaming crown- like ether compounds in the host composition
  • the initial molecular structure is established through mixing non-ionic surfactants (epoxide groups configured inward protecting the oxygen molecules), establishing divalent charges with the addition of an amphote ⁇ c (zwittenon) surfactant, an aromatic group (such as provided by the germicide nonoxyl-9) for initially coordinating with the molecular structure of the host
  • the molecular infrastructure although similar to a liposome, is not reliant on phosphate compounds such as found in phosphatydal chohne
  • the molecular infrastructure is reliant on the structure of qumones, ubiqinones, menaquinones, and hydroquinones Although a broad classification of compounds, the molecular structure of qumones and similar structures allow for a molecular stacking
  • the key is to select compounds that in later steps are compatible in structuie with at least one structural component of the compounds to be later added This is similar to solubility standards in batch mixing The difference is that the form of the compound must be able to stack into the host-guest environment of the host composition
  • the mix order depends on the molecular stacking concept
  • the long hydi ocarbon chain will easily affiliate or coordinate with the hydrocarbon component (less polar component) of the crown ether host-guest complex or the short branch from the cyclic component of the selected compound will electronically associate with the oxygen component of the crown ether.
  • many natural products can be added pnor to a specific compound. For instance, canot seed oil which is high in Beta-carotene needs to be added pnor to highly punfied Beta-carotene
  • canot seed oil do not attach to the crown ether environment, but allow for later components (chemicals) to be added.
  • Canot seed oil for instance, has flavinoids and fatty acids which allow for later addition through mutual solubility of a wide variety of both natural products like St. John's Wort and other highly-purified chemicals like vitamin B's.
  • the molecular stacking process is continued on the basis of both attachment to the crown ether and maintaining the hydro-hpid balance as well as future chemicals necessary for an effective bio-affectmg compound.
  • This system is based on quinone structures with repeating hydrocarbon units There is an alternating requirement for the attachment to the crown ether system; if the first compound attached is water soluble, then the next compound must be hpid soluble to maintain the hydro-hpid balance as well as the electrophihc and nucleophihc balance. Nowhere in this process should a compound or series of compounds be added that would substantially diminish that balance. For instance, compounds high in redox potential added in significantly high quantity can disrupt that balance.
  • co-enzymes with a quinone structure can be added, but high concentration of flavinoids cannot be added without pre - treatment that would create a reduced compound
  • the inter-molecular polarity of the host composition is preferably controlled to be between about 1.8 debye to about 20 debye at 21 °C (70°F).
  • the process includes the steps of:
  • the inter-molecular pola ⁇ ty of the host composition can be easily controlled by adding water to the composition
  • the process includes the steps of (a) controlling the mter-molecular polanty of the host composition to be between about 8 debye to about 20 debye at 21 °C (70 °F), and (b) mixing at least one water soluble compound with the second composition to obtain a hydro-guest composition
  • this process more preferably further includes the steps of (a) controlling the inter-molecular polarity ofthe hydro-guest composition to be between about 1 8 debye to about 8 debye at 21 °C (70 °F), and (b) mixing at least one hpid-soluble compound with the host composition to obtain a hpi- and hydio-guest composition
  • a buffer compound such as betaine is pieferably added at some point during the formulation process to help control the pH within a desired range
  • an amphoteric surfactant NH3-R-COOH is included because of its ability to allow for creation of an electron sha ⁇ ng neutral envnonment where electrophihc or nucleophihc compounds can be added without substantially alternativeng the established pH
  • This amphotenc compound being a zwittenon, allows for prolonged additions of the above-mentioned types of compounds
  • the pH stabilizing (l e , buffe ⁇ ng) effects of the amphoteric surfactant may need to be overcome
  • one or more other zwitte ⁇ ons can be added du ⁇ ng the formulation process. The choice ofthe other zwitte ⁇ ons is based on the pH range required to stabilize a pH-sensitive bio-affectmg compound.
  • the desired pH range is preferably maintained by buffenng
  • the pH must be maintained below the pKa of any additional compound or the pKa of any potential bond reaction within the compound to maintain stability within the molecular system.
  • This pKa factor becomes very evident when L-ascorbic acid is one of the compounds to reside in the stable molecular environment Compounds ai e added in ratio with their salt form such that the pH is below the pKa
  • Vitamin C which should be stabilized in a composition having a pH of less than 4 5, a small concentration of a short-length zwitte ⁇ on, like a betaine, helps adjust and maintain the pH in an acidic range below 4 5
  • a zwittenon such as allantoin can be preferably added for its additional benefit of having desirable bio-effecting properties, such as softening of the skin
  • Allantoin has both cyclic and ring structures included, which structures can be taken advantage of for the purposes of selecting the molecular stacking sequence, as well as the zwitte ⁇ on effect.
  • the temperature must be increased to allow for the complete attachment of the selected first compound.
  • the temperature of the host composition is preferably adjusted (typically heated) to be at least as high as the melting point of the first bio-affectmg compound to be added to the mixture to cieate a molecular environment in which the first bio-affectmg compound to be added can be set into the host molecule
  • a hpid-soluble compound such as alpha tocopherol or a watei -soluble compound such as 7-dehydroxy cholesterol.
  • the temperature of the host composition is increased to at least about 49 °C ( 120°F)
  • the temperature is reduced to below the melting point of the next compound to be added
  • the resultant mix sets the diverse compounds in a configuration that allows for the first addition of compound containing electrophihc and neuclophihc compound, e.g., ascorbyl palmitate.
  • compound containing electrophihc and neuclophihc compound e.g., ascorbyl palmitate.
  • this addition with temperature control
  • the pH must be maintained below the pKa of any additional compound or the pKa of any potential bond reaction within the compound to maintain stability within the molecular system This pKa factor becomes very evident when L-ascorbic acid is one of the compounds to reside in the stable molecular environment.
  • Compounds are added ratio with their salt form such that the pH is below the pKa.
  • the next compound to be added is preferably a hpid-soluble denvative of one of the active ingredients in order to begin the basis for molecular stacking of like molecules and reduction of pH, especially in the case of stabilizing the molecular environment for L-ascorbic acid.
  • ascorbyl palmitate is selected because the palmitate group is hpid soluble and the tail of the ascorbic acid group can electronically attach to the oxygen group of the crown ether system
  • the system has to be reduced in temperature to accept the ascorbyl palmitate, as it would for other compounds that are bio-affecting, but not necessarily for stabilization of the system
  • a pH buffenng compound such as betaine should be added soon after the temperature decreases to about 46°C (115°F) The temperature is maintained at about 45 °C (112°F) until all the remaining pH stabilizing ingredients have been mixed together
  • temperature must be adjusted to allow for the compound to inter-molecularly bind with the complex.
  • aloe used for dry skin, because of its mucopolysaccha ⁇ de components must be combined with a beta-hydroxy acid to attach with the complex.
  • Shea Butter the temperature of the Shea Butter has to be adjusted to become soluble with the complex Most additional ingredients are present for effectiveness and bio-affecting applications. Not all ingredients can be added without considering solubility, pH, and temperature.
  • the resulting composition is highly stable, and certain formulations have been tested to be capable of remaining stable until the air-to-composition ratio in the container is 6: 1. At that time there is a 14-day period before one or more of the composition's active ingredients begin to degrade to the point the product composition may become ineffective for one or more of its intended purposes
  • the formulations are based on host-guest formation and chemical strategycture addition It is necessary to have similar hpid- oi watei -soluble components to the compounds so that the chemicals can either attach to the crown ether type structure or layer by molecular stacking between the compounds
  • a pH-sensitive bio- affectmg compound such as vitamin C
  • calcium ascorbate 3:2: 1
  • Salicylic acid'sodium sahcylate 2' 1.
  • the molecular configuration for qumones requires balancing the attached chain groups to the available electron orbitals from other compounds with similar chain groups
  • the principle involved is the stacking of compounds with similar aromatic and cyclic structures through the lamellar layer created in the process.
  • the nng structures will tend to stack one upon the other with the apolar ends acting as tails.
  • the isoprenoid units become the apolar end and are aligned in the opposite direction from the polar cyclics
  • Some cyclics will exhibit a partial pola ⁇ ty based on hydroxylation to the nng.
  • each ofthe following formulations are examples of mixture formulations and steps that can be used to produce a stable composition for the delivery of one or more bio- affecting compounds to a target biological system.
  • the first 10 of the following formulation examples are from actual mixes
  • the temperatures can vary with reasonable ranges ofthe precise temperatures used in the examples without departing from the scope and spint of the examples.
  • the initial ' phase of the mix preferably includes the step of increasing the temperature to help drive the formation of the host complex. Although the maximum mixing temperature can exceed 49 °C (120°F), there is a point where the complex will not accept the initial substrate for setting the rigidity of the host-guest complex. This temperature point will vary depending ofthe guest chemical, but typically is expected to be a maximum of about 54°C (130°F)
  • the RPM of the mix motor can vary depending of the equipment and the type of propeller used the procedure. However, it is important that the mixing not be unnecessarily fast to minimize the introduction of air (i.e., oxygen) into the composition. Excessive mixing forces may also tend to destabilize the molecular stacking within the mixtures.
  • This formulation is designed to promote skm sloughing
  • trans- ret oic acid a form of retinol (Vitamin A) at the 1 0 % or greater level will increase the rate of exfoliation
  • the first step sets the molecular environment as well as establishes the crown ether host complex.
  • the 6% ammo dodecacarboxyhc acid is an ethanol solution.
  • the ethanol provides a solubility factor allowing for the formation of the host complex and the stage for lamellar layering. As the temperature is increased du ⁇ ng the mixing steps of the process, the ethanol gradually evaporates.
  • the alpha tocopherol at 41 °C is for the purpose of establishing an attachment to the host-guest complex.
  • the host-guest complex does not go to completion in the procedure until 49 °C (120°F).
  • this temperature can vary dependent on the desired guest chemical and the pnmary decision on which is the first compound to be added to the host composition.
  • the first solubility decision dnves the mix order and the following decisions as to molecular stacking of additional compounds.
  • the other natural extracts in this formulation example contain natural solubhzing compounds allowing for protection from other factors like pH and salt content.
  • These natural products are preferably mixed mto the composition before the desired specific compound for biochemical function, in this case, the ascorbic acid
  • This formulation is designed to maximize the production of collagen I in skin. Therefore, the percentages of ascorbic acid and ascorbic acid de ⁇ vati ves are increased so as to produce a composition having above 8% by weight of water-soluble ascorbic acid. Likewise, the balance needed in the molecular complexmg for alpha tocopherol is increased to be above 5% to act in balance to the ascorbic acid and for free radical reduction within the body. With the co-enzyme Q 10 being part of the free radical reduction system, the complex requires a very small, but active, percentage to accelerate the free radical reduction. The same concept as in Formulation 1 is required for the molecular stacking. In
  • Formulation 1 only betaine is used for creating a pH buffering balance.
  • Allantoin which is a longer chained compound and has better molecular stacking properties, is added due to the increased amounts of active ingredients and additional compounds like orange oil which contains limonene. Allantoin also has properties that increase the integrity of the lipid membrane in the dermal layer. Limonene, found in orange oil, is very penetrating in the dermal layer and aids in canying other compounds across the dermal layer. These additions alone do not count for the complete penetration of the dermal layer and the hyperdermal layer.
  • Lavender is added in the complex because its natural components contain bioflavinoids that are compatible in ring structure and has been reported to promote healing in the skin as does cholecalciferal, a form of Vitamin D.
  • the phosphatidyl chohne can be added at the end of the order without disrupting the balance within the complex because the phosphate ions will not form liposomes which adsorb oxygen rapidly.
  • This formulation is designed to be able to penetrate the dermal and hyperdermal layers to deliver a se ⁇ es of compounds to fibroblast and osteoblast found in joints, tendons, and muscles.
  • the ascorbic acid activates the production of Collagen I, bnngmg collagen complex back to balance.
  • Shea Butter which contains a relatively high amount of unsaponifiable fats as compared to other natural oil extracts.
  • the presence of the ratio of unsaponifiable fats to saponifiable fats allows for the stability of the complex without cleaving the Ca bond in the calcium ascorbate due to the reducing capability of unsaponifiable fats.
  • the Shea Butter tends to hold the complex in place on the dermis for a longer period of time allowing for the active components to penetrate the hyperdermal layer and reach the fibroblast, osteoblast, and other tissues. Note that the Shea Butter needs to be heated to be able change from a granular form to a liquid so that the unsaponifiable fats can molecularly stack within the formulation.
  • Salicylic acid derivatives acetyl salicylic acid and methyl salicylate, have been shown to decrease inflammation when taken internally.
  • the delivery system in this complex allows for the salicylic acid and the sodium salicylate to reach the inflamed area, thereby reducing inflammation and swelling.
  • This formulation is designed to provide relief from procedures that remove layers of skin from the face.
  • the combination of the Shea Butter and the Aloe provide this relief.
  • the ammo polyglycans in the Aloe are added first to provide additional buffenng before adding the unsaponifiable fats since the amount of the salicylic acid has been reduced to a level similar to previous formulations.
  • the molecular configuration within the lamellar layenng is subject to partial reversal of the micelles that are created if added in a different order
  • This formulation is designed as an acid peel.
  • the pH is lower than the regular pH of 3.5 to 3.0.
  • This formulation illustrates that the use to the host composition for the stabilization and delivery of a single active ingredient, in that this formulation need not contain alpha tocopherol as the host-guest setting compound. Instead, a mucopolysaccaha ⁇ de complex containing amino polyglycans and glycohc acid can be substituted and the mix order changed based on solubility The different components like glycine are present to stabilize the polar ends of the complex so that the ascorbic acid stability is maintained.
  • This formulation is designed as a delivery system for plant growth hormones, dite ⁇ enes
  • This formulation also illustrates that the use to the host composition for the stabilization and delivery of a single active ingredient, m that this formulation need not contain alpha tocopherol as the host-guest setting compound Instead, a mucopolysaccahande complex containing ammo polyglycans and glycohc acid can be substituted and the mix order changed based on solubility.
  • the host complex is first attached to the polar end ofthe amino polyglycans.
  • the nitrogen complex within the ammo group creates a molecular attachment point for the diterpenes
  • these isoprenoid units are directed 90 degrees from the crown ether complex providing for lamellar layer of the Co-enzyme Q 10 and the betaine.
  • the chlorophyll, a po ⁇ horm compound attaches parallel to the crown ether complex. Upon penetration ofthe plant membrane, the dite ⁇ ene is released into the plant cell.
  • This formulation is designed to penetrate the dermal layer when it has become 'sequacious' , which is an overlaye ⁇ ng condition ofthe skm. This formulation illustrates the ability of the formulation process to provide a stable complex with primarily hpid-soluble components.
  • This formulation is designed to penetrate the dermal layer acting as a chemical peel.
  • This formulation illustrates the ability of the formulation process to provide a stable composition by first mixing a watei -soluble bio-affecting compound with the host composition
  • This formulation is designed to provide sun protection from UV-A/UV-B wave lenghts by including metallo complexes known to provide in vivo and in vitro coverage, i.e., zinc oxide and titanium dioxide. Additional ingredients are preferably added for antioxidant benefits, occlusion, and moistunzmg capabilities.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Engineering & Computer Science (AREA)
  • Plant Pathology (AREA)
  • Environmental Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Dermatology (AREA)
  • Wood Science & Technology (AREA)
  • Dentistry (AREA)
  • Zoology (AREA)
  • Pest Control & Pesticides (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Emergency Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention se rapporte à des procédés de fabrication d'une composition comportant un composé hôte susceptible de recevoir un ou plusieurs composés invités bioactifs, ainsi qu'à des compositions formées selon ces procédés. Les procédés consistent à mélanger, dans un ordre indifférent: (i) un tensioactif non ionique sélectionné dans le groupe constitué par les composés représentés par la formule générale (I), dans laquelle '-CHO-O-CH-' représente un groupe époxy; Ra et Rb sont des hydrocarbures qui peuvent être identiques ou différents, l'un au moins des hydrocarbures que sont Ra et Rb comportant un groupe époxy à moins de 3 atomes de carbones du point de fixation de l'hydrocarbure de manière à participer à l'équilibre hydrolipidique souhaité de valeur comprise entre 7 et 9; Rc est hydrogène ou un groupe méthyle et Rd est un groupe méthylène, un groupe éthyle ou une liaison structurellement équivalente dotée d'une longueur approximativement identique ou inférieure à celle d'un groupe éthyle, et possédant un équilibre hydrolipidique de valeur comprise entre 7 et 9; (ii) un tensioactif amphotère sélectionné dans le groupe constitué par des composés organiques représentés par la formule chimique NH3-R-COOH, où R est une structure hydrocarbonée droite, ramifiée ou aromatique ayant 6 à 24 atomes de carbone; (iii) un solvant destiné au tensioactif amphotère; (iv) un composé aromatique sélectionné dans le groupe constitué par des composés ayant au moins un anneau aromatique à cinq ou six éléments; (v)un cation aluminium; (vi) un acide de Lewis qui n'est pas un acide de Bronsted-Lowry; et (vii) un acide de Bronsted-Lowry.
PCT/US2000/012743 1999-05-11 2000-05-10 Procedes et formulations hote-invites pour l'administration de composes bioactifs WO2000067726A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU51293/00A AU5129300A (en) 1999-05-11 2000-05-10 Host-guest processes and formulations for delivering bio-affecting compounds
US10/019,859 US6676951B1 (en) 1999-05-11 2000-05-10 Host-guest processes and formulations for delivering bio-affecting compounds
CA002373630A CA2373630A1 (fr) 1999-05-11 2000-05-10 Procedes et formulations hote-invites pour l'administration de composes bioactifs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13355299P 1999-05-11 1999-05-11
US60/133,552 1999-05-11

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US10/019,859 A-371-Of-International US6676951B1 (en) 1999-05-11 2000-05-10 Host-guest processes and formulations for delivering bio-affecting compounds
US10/756,177 Continuation-In-Part US20040228887A1 (en) 1999-05-11 2004-01-13 Host-guest processes and formulations for delivering bio-affecting compounds

Publications (2)

Publication Number Publication Date
WO2000067726A1 true WO2000067726A1 (fr) 2000-11-16
WO2000067726A8 WO2000067726A8 (fr) 2001-02-15

Family

ID=22459169

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/012743 WO2000067726A1 (fr) 1999-05-11 2000-05-10 Procedes et formulations hote-invites pour l'administration de composes bioactifs

Country Status (3)

Country Link
AU (1) AU5129300A (fr)
CA (1) CA2373630A1 (fr)
WO (1) WO2000067726A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1379223A1 (fr) * 2001-03-27 2004-01-14 C.S. Bioscience, Inc. Preparation dentaire
US7105691B2 (en) 2003-06-26 2006-09-12 Colgate-Palmolive Company Aluminum / zirconium / glycine antiperspirant actives stabilized with Betaine
WO2007059530A3 (fr) * 2005-11-16 2007-07-19 Colgate Palmolive Co Compositions d’antitranspirants
JP2010248211A (ja) * 2010-06-10 2010-11-04 Rohto Pharmaceut Co Ltd コラーゲン合成促進用組成物
WO2011018501A3 (fr) * 2009-08-12 2011-10-20 Laboratoires Expanscience Composition comprenant une fraction non saponifiable

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5326567A (en) * 1991-04-10 1994-07-05 Capelli Christopher C Antimicrobial compositions useful for medical applications
US5518730A (en) * 1992-06-03 1996-05-21 Fuisz Technologies Ltd. Biodegradable controlled release flash flow melt-spun delivery system
US5770453A (en) * 1993-10-19 1998-06-23 The Secretary Of State For Defence In Her Britannic Majesty's Government Of The United Kingdom Of Great Britain And Northern Ireland Sensors for neutral molecules

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5326567A (en) * 1991-04-10 1994-07-05 Capelli Christopher C Antimicrobial compositions useful for medical applications
US5518730A (en) * 1992-06-03 1996-05-21 Fuisz Technologies Ltd. Biodegradable controlled release flash flow melt-spun delivery system
US5770453A (en) * 1993-10-19 1998-06-23 The Secretary Of State For Defence In Her Britannic Majesty's Government Of The United Kingdom Of Great Britain And Northern Ireland Sensors for neutral molecules

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1379223A1 (fr) * 2001-03-27 2004-01-14 C.S. Bioscience, Inc. Preparation dentaire
EP1379223A4 (fr) * 2001-03-27 2005-09-07 C S Bioscience Inc Preparation dentaire
US7105691B2 (en) 2003-06-26 2006-09-12 Colgate-Palmolive Company Aluminum / zirconium / glycine antiperspirant actives stabilized with Betaine
WO2007059530A3 (fr) * 2005-11-16 2007-07-19 Colgate Palmolive Co Compositions d’antitranspirants
AU2006315119B2 (en) * 2005-11-16 2010-01-28 Colgate-Palmolive Company Antiperspirant compositions
WO2011018501A3 (fr) * 2009-08-12 2011-10-20 Laboratoires Expanscience Composition comprenant une fraction non saponifiable
US9282759B2 (en) 2009-08-12 2016-03-15 Laboratoires Expanscience Composition including an unsaponifiable fraction
JP2010248211A (ja) * 2010-06-10 2010-11-04 Rohto Pharmaceut Co Ltd コラーゲン合成促進用組成物

Also Published As

Publication number Publication date
AU5129300A (en) 2000-11-21
CA2373630A1 (fr) 2000-11-16
WO2000067726A8 (fr) 2001-02-15

Similar Documents

Publication Publication Date Title
US7588747B2 (en) Singlet oxygen quencher and composition using the same
JP2020515635A (ja) 医薬組成物
WO2013178752A1 (fr) Procédé de préparation d'une composition dermatologique comprenant des oléosomes
JP2003026604A (ja) トコフェロール誘導体を用いてナノ乳化粒子を安定化させる方法及びナノ乳化粒子を含有する皮膚外用剤組成物
WO2001085156A1 (fr) Compositions dermiques ayant la coenzyme q comme principe actif
US6676951B1 (en) Host-guest processes and formulations for delivering bio-affecting compounds
WO2000067726A1 (fr) Procedes et formulations hote-invites pour l'administration de composes bioactifs
US20040228887A1 (en) Host-guest processes and formulations for delivering bio-affecting compounds
Gunda et al. Formulation and evaluation of tolnaftate loaded topical liposomal gel for effective skin drug delivery to treat fungal diseases
KR20200049592A (ko) 나노리포솜을 포함하는 수중유형 화장료 조성물
CN106726643A (zh) 一种包覆水溶性光甘草定的多囊泡脂质体及其制备方法
CN117379337A (zh) 一种视黄醇衍生物超分子微脂囊、其制备方法及应用
EP1933812A1 (fr) Liposomes chargés de fullerène et procédé pour la préparation de ceux-ci
CN115554175A (zh) 一种基于生育酚及其衍生物的超分子纳米乳液及其制备方法和应用
KR20150121409A (ko) 아스코빅애씨드 2-글루코사이드를 안정화시키는 방법 및 안정화된 아스코빅애씨드 2-글루코사이드를 함유하는 화장료 조성물
EP1360958B1 (fr) Formulation liposomique de propionate de clobetasol
JP3656197B2 (ja) 皮膚外用剤
US20030198654A1 (en) Cosmetic formulation that provides for a suspension of beads
CA2123585A1 (fr) Composition lipidique polaire d'origine vegetale
KR101457182B1 (ko) 수용성 성분을 함유하는 ｓ／ｏ형 에멀젼 파우더 화장료 조성물 및 이의 제조방법
APRIANI et al. EFFECT OF STIRRING SPEED AND STIRRING TIME ON CHARACTERIZATION OF CLINDAMYCIN HCL ETHOSOMAL AND ICH Q1A (R2) STABILITY TEST.
JPH0873311A (ja) 皮膚外用剤
EP0350438B1 (fr) Composition à usage cosmétique ou pharmaceutique
KR100473716B1 (ko) 7-디하이드로콜레스테롤 및 사이클로덱스트린의 포접복합체, 이를 포함하는 화장료 조성물 및7-디하이드로콜레스테롤의 안정화방법
EP0391754B1 (fr) Composition pour favoriser la cicatrisation

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

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

AL Designated countries for regional patents

Kind code of ref document: A1

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

121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: C1

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

AL Designated countries for regional patents

Kind code of ref document: C1

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

WR Later publication of a revised version of an international search report
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 10019859

Country of ref document: US

ENP Entry into the national phase

Ref document number: 2373630

Country of ref document: CA

Ref country code: CA

Ref document number: 2373630

Kind code of ref document: A

Format of ref document f/p: F

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP