WO2022098121A1 - 고상의 물질 및 이를 포함하는 분산 조성물 - Google Patents
고상의 물질 및 이를 포함하는 분산 조성물 Download PDFInfo
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- WO2022098121A1 WO2022098121A1 PCT/KR2021/015911 KR2021015911W WO2022098121A1 WO 2022098121 A1 WO2022098121 A1 WO 2022098121A1 KR 2021015911 W KR2021015911 W KR 2021015911W WO 2022098121 A1 WO2022098121 A1 WO 2022098121A1
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- 230000008025 crystallization Effects 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229960001048 fluorometholone Drugs 0.000 description 1
- FAOZLTXFLGPHNG-KNAQIMQKSA-N fluorometholone Chemical class C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@]2(F)[C@@H](O)C[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FAOZLTXFLGPHNG-KNAQIMQKSA-N 0.000 description 1
- 235000012041 food component Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229910021485 fumed silica Inorganic materials 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000013335 mesoporous material Substances 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 229960003632 minoxidil Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- RJMUSRYZPJIFPJ-UHFFFAOYSA-N niclosamide Chemical compound OC1=CC=C(Cl)C=C1C(=O)NC1=CC=C([N+]([O-])=O)C=C1Cl RJMUSRYZPJIFPJ-UHFFFAOYSA-N 0.000 description 1
- 229960001920 niclosamide Drugs 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 229960000639 pazopanib Drugs 0.000 description 1
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical class O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002028 silica xerogel Inorganic materials 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000008259 solid foam Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
- A23L29/206—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin
- A23L29/262—Cellulose; Derivatives thereof, e.g. ethers
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
- A61K8/86—Polyethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- 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
- A61K2800/10—General cosmetic use
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/59—Mixtures
- A61K2800/592—Mixtures of compounds complementing their respective functions
- A61K2800/5922—At least two compounds being classified in the same subclass of A61K8/18
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Definitions
- the present invention relates to a solid material having improved dispersibility and a dispersion composition exhibiting improved dispersibility by dispersing the same.
- a typical known technique for solving this is a micelle solubilization technique for solubilizing a poorly soluble drug with a surfactant (solubilization).
- a surfactant is a substance having both a hydrophilicity and a hydrophobicity in one molecule, and is mainly distributed at the interface between the target substance (eg, drug) and the dispersion medium (eg, water) to form the target substance.
- the target substance eg, drug
- the dispersion medium eg, water
- the micelle solubilization technology selectively selects a target substance that is poorly soluble in the dispersion medium in nanometer-sized micelles formed by self-assembly of the surfactant contained in the dispersion medium exceeding a specific concentration (critical micelle concentration) It is a technique of distributing the target substance in a dispersion medium with a high content exceeding the saturation solubility.
- bioavailability refers to the amount and rate of delivery of a drug from the site of administration to the site of action in vivo where the drug produces a therapeutic effect. As a concept, if the bioavailability is low, even if the drug has high therapeutic efficacy outside the body, the actual amount delivered to the in vivo organ that needs to act is low, and thus the therapeutic effect in the body remains low or at a minimal level.
- Bioavailability refers to the flow rate (FLUX) through biological barriers in vivo, such as cornea, skin, blood-brain-barrier, and blood-retina barrier. It can be understood as Equation 8 below).
- Equation 8 it can be seen that in order to increase the flow rate (FLUX), both solubility and permeability must be balanced and high. According to the Biopharmaceutics Classification System, 70% of all drugs belong to Class II with high permeability and low solubility, and 20% belong to Class IV with low permeability and low solubility. (Reintjes, T., Solubility enhancement with BASF Pharma polymers: Solubilizer Compendium. BASF, (2021) pp.9-10.).
- micellar solubilization technique When the micellar solubilization technique is applied to a polar dispersion medium such as water, the outer surface of the drug surrounded by the surfactant is changed to be hydrophilic compared to the state in which the drug is independently present.
- a polar dispersion medium such as water
- the permeability of the pharmaceutical composition implemented by the micellar solubilization technology to the biological barrier is generally lowered.
- the micellar solubilization technology has a limitation in that it is difficult to obtain a pharmaceutical composition that improves the bioavailability to the extent that the therapeutic efficacy is improved because the improvement in solubility and the increase in permeability are trade-off.
- most surfactants also have problems such as causing environmental pollution or causing toxicity or side effects in the body, so there is a need to minimize the amount used.
- a dispersion medium comprising particles comprising a target material
- the dispersion composition comprises at least one surfactant having a critical micelle concentration or higher,
- the dispersion composition does not contain a solubilizer
- the S-parameter of Equation 3 calculated by Equations 1 and 2 satisfies S-parameter > 1,
- Equation 1 S w is a concentration corresponding to the saturated solubility of the target material in the dispersion medium, and S surf is calculated by Equation 2 below.
- Equation 2 k is the molar solubilization capacity defined by the number of moles of the target substance that can be dispersed in the dispersion medium by one type of surfactant above the critical micelle concentration of 1 mole, C surf is the molar concentration of the surfactant component in the composition, and CMC is the critical micelle molar concentration of the surfactant in the composition.
- Equation 3 S tot is the total molar content of the target material contained in the dispersion composition.
- Equation 4 k surf(i) is the molar solubilization capacity (molar) defined by the number of moles of the target substance that can be dispersed in the dispersion medium by any one of the surfactant components above the critical micelle concentration of 1 mole solubilization capacity), C surf(i) is the concentration of any one of the surfactant components above the critical micelle concentration, and CMC surf(i) is the dispersion medium of any one type of the surfactant component above the critical micelle concentration. is the critical micelle concentration at
- Equation 5 m is the total number of types of surfactant components above the critical micelle concentration.
- the dispersion composition is obtained by applying the solid substance as the target substance.
- the dispersion composition In the field of dispersion compositions such as drugs and cosmetics, stably dispersing a high content of an active substance is an important task for easy absorption of the active substance. Therefore, the dispersion composition can be innovatively applied to various industrial fields requiring high content and dispersion stability. For example, when the dispersion composition embodied in the present invention contains a poorly soluble drug, it expands the possibility of using previously unusable drugs, minimizes the side effects of additives such as surfactants, and achieves breakthrough in disease treatment will be able
- the dispersion composition embodied in the present invention has a surfactant content lower than that of the existing technology, and improves not only solubility but also permeability of the target substance, resulting in improved bioavailability and excellent therapeutic efficacy.
- a surfactant content lower than that of the existing technology, and improves not only solubility but also permeability of the target substance, resulting in improved bioavailability and excellent therapeutic efficacy.
- by lowering the content of the surfactant than the existing technology there is an effect of reducing or preventing problems such as environmental pollution or toxicity/side effects in the body caused by the surfactant.
- Polyoxyl 35 castor oil Kerphor EL or Cremophor EL
- Cremophor EL which is mainly used as a surfactant in pharmaceutical compositions, is highly toxic.
- the dispersion composition of the present invention can reduce or avoid the side effects of toxic surfactants because it maintains a stable dispersion state while the content of the surfactant is low.
- the cosmetic product prepared with the dispersion composition embodied in the present invention is a composition in which the content of additives such as a surfactant is minimized, and the cosmetic effect can be improved by improving the spreadability and permeability.
- “Target ingredient” is a substance to be dispersed in the dispersion composition to be implemented, and may be an active pharmaceutical ingredient for pharmaceutical use, and an active substance effective for skin aesthetics if it is for cosmetic use.
- the pharmacologically active substance of the present invention includes tyrosine kinase inhibitor (Tyrosine) such as Sunitinib, Axitinib, and Pazopanib. Kinase Inhibitor), Cyclosporine, Niclosamide, Adenosine, Deoxycholic acid, Paclitaxel, or a pharmaceutically acceptable salt or derivative thereof ), but is not limited thereto.
- the target material may be one type of material or a mixture of two or more types of target materials.
- the dispersion composition according to an embodiment of the present invention includes the target material in a dispersion medium.
- a soluble substance it is commercially valuable, and examples of drugs among these poorly soluble substances are pi (practically insoluble), vss (very slightly soluble), ss (slightly soluble), in "United States Pharmacopeia (USP) Solubility Criteria” It may be a substance classified as sps (sparingly soluble), etc. (O.Wolk, et al, Drug Design, Development and Therapy, 8 (2014) pp 1563-1575).
- paclitaxel Paclitaxel
- Deoxycholic acid Cyclosporine
- Minoxidil Finasteride (Fina) steride
- latanoprost miconazole
- prednisolone fluorometholone
- prostaglandin analogs such as insoluble or poorly-soluble drugs
- the target material may be an active material having a cosmetic effect or a nutritional component that is poorly soluble in water, such as curcumin, and may be a variety of materials depending on the use or purpose of the dispersion composition.
- “Medium with a plurality of surface” is composed of porous materials or non-porous materials or a mixture thereof, and includes intraparticle pores or interparticle pores ( interparticle pores) or a mixture thereof. That is, the pores in the multi-surface body may be intra-particle pores or inter-particle pores.
- the multi-surface body for example, contains pores in the material.
- the pores in the polysurface body may be the pores in the particles included in the porous material, for example, an aggregate or aggregate (secondary particles, powder or filling layer, etc.), the voids in the multi-surface body may be inter-particle voids.
- an aggregate or aggregate formed by agglomeration or stacking of the multi-surface body by mixing porous particles and non-porous particles (2). tea particles, powder or filling layer, etc.
- the pores in the multi-surface body may be intra-particle voids or inter-particle voids, that is, the multi-surface body may be formed of various types of porous materials or any porous or non-porous particles. It may be an aggregate or aggregate composed of
- the average size of the pores of the polysurface body may be about 1 nm to about 1 ⁇ m.
- the average size of the pores of the polysurface body may be about 1 nm to about 100 nm.
- the average size of the pores of the polysurface body may be about 1 nm to about 50 nm.
- the average size of the pores of the polysurface body may be about 1 nm to about 30 nm.
- the polysurface may have a porosity of about 5 to about 97% (v/v).
- the porosity of the multi-surface body may be about 20 to about 60% (v/v).
- the porosity may be about 90 to about 97% (v/v).
- the multi-surface body may be silica gel, silica xerogel, mesoporous silica, fumed silica, mesoporous alumina, mesoporous.
- Mesoporous metal oxides, Mesoporous material, Charcoal, Activated Carbon, aerogel, Zeolite, Molecular Sieve, metal-organic framework ( Metal-Organic Framework), an organic/inorganic hybrid porous material, etc. may be a natural material, a synthetic material, or a biological material, and may be crystalline or amorphous, and has a composition, material, and structure , synthesis / manufacturing method, etc. are not limited.
- the pores in the multi-surface body may have various shapes, sizes, production methods, arrangement structures (regular or irregular), and the like.
- the multi-surface body is a particle form having an arbitrary size and shape, a secondary particle form in which a plurality of particles are gathered, a powder form consisting of particles having an arbitrary size and shape, and a filling formed by stacking the particles It may be in the form of a packed bed, a solid foam, a membrane or a sheet, but is not limited thereto.
- the multi-surface body may include not only a single material but also at least two or more materials, or a mixture thereof.
- the material is a non-porous material or the like.
- the “solvent for preparing a mixture” is a solvent capable of dissolving the target substance in a desired content, and may be selected in consideration of solvent properties such as saturation solubility or polarity to dissolve the target substance in a target content.
- the target substance can be dissolved in a higher content in the solvent for preparing the mixed solution than the dispersion medium.
- the solubility of the target substance in the solvent for preparing the mixed solution is greater than the solubility of the target substance in the dispersion medium.
- the solvent for preparing the mixed solution is water, alcohol (methanol, ethanol, etc.), acetone, acetic acid, acetonitrile, ethyl acetate, methylene chloride, chloroform, an organic solvent such as dimethyl sulfoxide (DMSO), polyethylene glycol (PEG), mannitol, May contain sugars such as sorbitol, and may include a combination of two or more thereof, but is not limited thereto.
- DMSO dimethyl sulfoxide
- PEG polyethylene glycol
- mannitol May contain sugars such as sorbitol, and may include a combination of two or more thereof, but is not limited thereto.
- the solvent for preparing the mixed solution may be friendly or incompatible with the dispersion medium.
- the solvent for preparing the mixed solution is in the dispersion medium Can be miscible, immiscible, or partially miscible.
- the solvent for preparing the mixed solution may be a hydrophilic material, a hydrophobic material or an amphiphilic material.
- the solvent for preparing the mixed solution is polar, non-polar or amphiphilic.
- the solvent for preparing the mixed solution may be a volatile compound.
- “Mixture” is a solution obtained by mixing the target substance with the solvent for preparing the mixed solution, and the target substance is dissolved in the solvent for preparing the mixed solution.
- the mixed solution may contain the target material in an amount of about 0.01% (w/v) to about 50% (w/v).
- the mixed solution (A) may contain the target material in an amount of about 0.1% (w/v) to about 10% (w/v).
- the content of the target substance in the mixed solution may be determined in consideration of the solubility of the target substance in the solvent for preparing the mixed solution, and the type of the solvent for preparing the mixed solution may be selected accordingly.
- Process fluid is a fluid used together with the mixed solution when contacting the mixed solution with the multi-surface body for the purpose of facilitating contact, increasing productivity, or controlling the residence time of the mixed solution in the multi-surface body when the mixed solution is brought into contact with the multi-surface body.
- the process fluid is selected in consideration of viscosity or surface tension, etc. in order to control the ease of contact, productivity, or residence time of the mixed solution, and the target material is precipitated or solidified in the process of contacting the mixed solution with the multi-surface body. ), the type can be selected by appropriately considering the solubility of the target substance or miscibility with the solvent for preparing the mixed solution.
- the process fluid may be the same as or different from the solvent for preparing the mixed solution, or may be a mixture with a solvent different from the solvent for preparing the mixed solution.
- the “dispersion medium” corresponds to a continuous phase among the components of the dispersion composition, and various materials may be used depending on the purpose.
- the pharmaceutical composition may be water, saline solution or a buffered aqueous solution.
- the content of the target substance in the dispersion composition of the present invention may exceed the saturated solubility in the dispersion medium.
- the dispersion medium may be a polar or hydrophilic solvent.
- the polar or hydrophilic solvent may be water, methanol, ethanol, glycerol, polyol, or the like.
- the dispersion medium may be water, and the target substance may be poorly soluble paclitaxel, deoxycholic acid, cyclosporine, latanoprost, miconazole, curcumin, or the like in water.
- the dispersion medium may be a non-polar or hydrophobic solvent.
- the non-polar or hydrophobic solvent may be hydrocarbon, silicone oil, ethyl acetate, acetone, tetrahydrofuran (THF), or the like.
- the dispersion medium may be hexane, and the target substance may be saccharides or glucose that are sparingly soluble in hexane.
- the dispersion medium may be an amphiphilic solvent.
- an amphiphilic solvent may be added to a polar or non-polar solvent.
- the type or composition of the dispersion medium may be selected in various ways in consideration of the solubility of the target material, the difference in physicochemical properties, the use of the dispersion composition, and the like, and may be used as one type or a mixture of two or more types.
- the dispersion medium may be an organic solvent.
- Particle is defined as an association of multiple molecules, having any composition, shape, size or structure, the dispersed phase being the discrete phase in the dispersed composition.
- the particles in the dispersion composition may further include auxiliary agents and additive materials in addition to the target material.
- the “dispersion composition” is a composition in which particles containing the target substance are dispersed in a dispersion medium that is a continuous phase as a discrete phase distinct from the dispersion medium.
- the dispersion composition is the target substance Since the particles containing It is a state that is distinct from a single phase solution existing in a dissolved state.
- the dispersion composition is used for the purpose of viscosity, osmotic pressure, pH, ionic strength, surface tension, color, taste, flavor, etc.
- Additives or adjuvants may be additionally included to control the properties and quality required according to the intended use or route of administration.
- “Surfactant” has a structurally hydrophilic head and a hydrophobic tail in a molecule, and a surface activity that lowers surface tension or interfacial tension in a dispersion medium As a (surface active), amphiphilic material, it is added to the dispersion composition in a smaller amount than the dispersion medium and is mainly distributed at the interface between the target material and the dispersion medium to help the dispersion of the target material or to stabilize the dispersion state. Or, it is a generic term for substances that perform this function Surfactant is also referred to as an emulsifier or detergent, depending on the use or industry, etc. The surfactant is a monomer, an oligomer, etc.
- the surfactant may be cationic, anionic, nonionic or zwitterionic, and the ionic state is pH
- the surfactant may be a natural material, a synthetic material, or a biological material, and a plurality of materials may be mixed and used, but is not limited thereto.
- CMC Critical Micelle Concentration
- micelles colloidal size (1 nm - 1 um) particles
- the solubility of the target substance in the dispersion medium is, when the surfactant is less than the critical micelle concentration, the saturated solubility of the target substance (saturated solubility, the saturated solubility of a specific target substance in a specific dispersion medium, the type, composition, It is determined as an intrinsic value according to conditions including phase and content, type and composition of dispersion medium, temperature and pressure, etc.
- the saturated solubility of the target substance in the dispersion medium is a well-known database.
- NASH National Institutes of Health
- M.J. Rosen, J.T. Kunjappu Surfactants and Interfacial Phenomena, Fourth edition, 2012, Wiley.
- M. J. Rosen & J. T. Kunjappu “Surfactants and Interfacial Phenomena", 4th Ed, Wiley (2012), pp141-143, p155 describe the values of the critical micelle concentration of various surfactants.
- Molar Solubilization Capacity ( ⁇ ) is the number of moles of a target substance solubilized in the dispersion medium per mole of surfactant exceeding the critical micelle concentration (CMC), and is defined by Equation 9 below and usually has a value less than 1.
- S w is the molar saturated solubility, which is an intrinsic value of the target substance in the dispersion medium
- S tot is the total molar content of the target substance contained in the dispersion composition
- C surf is the content of the target substance in the dispersion composition.
- Indicates the total molar content of the surfactant (Rangel-Yagui CO, Pessoa A Jr, Tavares LC., J Pharm Pharm Sci.
- the content of the target substance is the surfactant When measured along the content (x-axis) and graphed, if there is no surfactant or the content is below CMC, the content of the target substance is either the saturated solubility or does not deviate significantly from the saturated solubility.
- the target substance It shows a behavior that the content of is linearly increased in proportion to the content of surfactant (micelle solubilization, solubilization by micelle or micellar solubilization)
- Molar solubilization capacity ( ⁇ ) corresponds to the slope of the straight line section in the graph above, ,
- a surfactant with a high molar solubilization capacity ( ⁇ ) means high solubilization efficiency. and physical properties having intrinsic values depending on the dispersion medium.
- Solubilizer is a substance different from the target substance and dispersion medium, and is added in a smaller amount than the dispersion medium to the dispersion composition in which the target substance is dispersed in the dispersion medium, so that the content of the target substance exceeds the saturation solubility of the target substance in the dispersion medium It is a generic term for substances that play a role in increasing the content of It may be metal/organic/inorganic nanoparticles, porous medium, water-soluble polymer, antibody, etc., and may include a combination of two or more thereof.
- the target substance may be contained in an amount exceeding the saturation solubility in the dispersion medium through the solubilizer and various physicochemical mechanisms.
- These physicochemical mechanisms include complexation, inclusion (inclusion), encapsulation (encapsulation), conjugation (conjugation), adsorption (adsorption), absorption (absorption), dissolution (dissolution), etc., but are not limited thereto, etc.
- Surfactants have a surface active ability (surface/interface tension of the dispersion medium) decreases), and shows a characteristic concentration of critical micelle concentration in the dispersion medium, and when the concentration in the dispersion medium exceeds the critical micelle concentration, it self-assembles to form micelles, and physical and chemical properties (osmotic pressure, turbidity) as micelles are formed , diffusion coefficient, surface tension, electrical conductivity, etc.) are different from before the formation of micelles, and are clearly distinguished from solubilizers with different mechanisms or physical properties, such as selectively distribution in micelles where the target material is formed. It is treated as a separate substance by being distinguished from the solubilizer and is referred to separately from the solubilizer.
- the dispersion composition according to an embodiment of the present invention provides a dispersion composition containing a target material stably dispersed in a dispersion medium in excess of the maximum amount (S micelle ) that can be solubilized by micellar solubilization technology.
- S micelle maximum amount
- a product of a separated solid target material obtained by removing a solvent and a process fluid for preparing a mixed solution.
- the separated solid target substance is mixed with a separately prepared dispersion medium, surfactant, and necessary additives, and the separated solid target substance is dispersed in a dispersion medium, and the dispersion composition is micelles It is a dispersion composition containing a target substance stably dispersed in a dispersion medium in excess of the maximum amount (S micelle ) that can be solubilized by solubilization technology.
- One embodiment of the present invention is to provide a dispersion composition having a high content of the target material (ie, increased solubilization efficiency) while lowering the content of the surfactant than the amount required in the existing micellar solubilization technology.
- One embodiment of the present invention provides a dispersion composition containing a target material in excess of the content that can be solubilized by conventional micellar solubilization technology.
- One embodiment of the present invention provides a pharmaceutical composition having improved bioavailability or therapeutic efficacy by lowering the content of the surfactant than the amount required in the existing micellar solubilization technology.
- the present invention is not limited to drugs, and can be equally applied to the field of increasing solubility or in vivo bioavailability.
- various additives are added to the final formulation because many of the substances having excellent cosmetic effects have poor solubility.
- the cosmetic product made in this way has an opaque formulation, so the aesthetics is not good, and the touch on the skin is not excellent.
- excessively added additives clog pores, preventing easy absorption of active substances.
- the present invention is not limited to a specific target substance, a specific dispersion medium, or a specific efficacy/function.
- the maximum content of the target substance that can be solubilized by the existing micelle solubilization technique is determined by the S micelle value obtained through Equations 1 and 2 below.
- Equation 1 S w is a concentration corresponding to the saturated solubility of the target material in the dispersion medium, and S surf is calculated by Equation 2 below.
- Equation 2 k is the known molar solubilization capacity ( ⁇ ) measured in the dispersion medium with respect to the surfactant and the target substance used, C surf is the molar concentration of the surfactant component added to the composition, and CMC is the dispersion medium is the critical micelle molar concentration of a known surfactant specified in S surf can therefore be calculated using the measured and known properties ( ⁇ , CMC) for the target material, surfactant and dispersion medium.
- the S-parameter is a value obtained by dividing the total content (S tot ) of the target substance contained in the dispersion composition according to an embodiment of the present invention by the maximum content of the target substance that can be solubilized by the existing micellar solubilization technology (S micelle ) It is calculated by Equation 3 below.
- the content of the target substance that can be stably contained in the dispersion composition is the S micelle (Equation 1 and 2) Exceeds the value. That is, the S-parameter of the dispersion composition containing one type of surfactant embodied in the present invention is greater than 1.
- the S-parameter value may be 1.05 or more, 1.06 or more, 1.1 or more, 1.2 or more, 1.5 or more, 2 or more, 3 or more.
- the S-parameter is implemented as a value greater than 1.
- the S-parameter is implemented as a value greater than 1.
- S micelle is a value calculated using experimentally measured physical properties for the target substance, surfactant, and dispersion medium
- the content of the target substance in the dispersion composition implemented with the existing micellar solubilization technology cannot exceed S micelle .
- the S-parameter of the dispersion composition implemented by the solubilization technique is 1 or less.
- the present invention is a dispersion containing a higher content of the target substance beyond the limit of solubilization with the existing micellar solubilization technology. composition can be implemented.
- the present invention can implement a dispersion composition containing the content of the specific target substance even with a surfactant in an amount smaller than the surfactant required to solubilize the specific target substance content with the existing micellar solubilization technology. it means
- micellar solubilization technology cannot stably disperse the target substance in the dispersion medium at a content higher than the maximum amount (S micelle ) that the surfactant can solubilize the target substance. It is natural in terms of conceptual definition that the S-parameter cannot exceed 1 for the dispersion composition prepared including
- the S-parameter when the S-parameter is experimentally measured for a dispersion composition prepared including a surfactant by the existing micellar solubilization technology, the S-parameter may be measured/calculated as a value exceeding 1 due to measurement error. there is.
- the present invention is not intended to cover the case of a dispersion composition prepared including a surfactant by an existing micelle solubilization technique, in which the S-parameter is obtained to a value greater than 1 due to experimental error or measurement error.
- Equation 4 k surf(i) is the known molar solubilization capacity ( ⁇ ) measured in the dispersion medium with respect to any one kind of surfactant and the target substance, and C surf(i) is the interface above the critical micelle concentration is the concentration of any one of the active ingredients, and CMC surf(i) is the known critical micelle concentration measured in the dispersion medium of any one of the surfactant ingredients above the critical micelle concentration.
- Equation 5 m is the total number of types of surfactant components above the critical micelle concentration. Equation 5 is the sum of the solubilizing capacities of the surfactants used when following the rule (additivity rule, that is, the content of the target material solubilized with a plurality of surfactants is equal to the simple sum of the amounts solubilized with each surfactant) If it is, a plurality of surfactants are effectively applied regardless of whether they form pure micelles or mixed micelles, respectively, in the dispersion medium.
- additive rule that is, the content of the target material solubilized with a plurality of surfactants is equal to the simple sum of the amounts solubilized with each surfactant
- non-ionic surfactants based on PEG include polysorbates (eg, Tween 20, 40, 60, 80, etc.), polyethoxylated castor oil (eg Polyoxyl 35 castor oil, Kolliphor EL or Cremophor EL, Marlowet 40, Emulgin RO 40, etc.), polyethoxylated hydrogenated castor oil (eg Cremophor RH40, etc.), poly ethoxylated fatty alcohols (fatty alcohol. eg Brij 30, Brij 35, etc.), polyethoxylated fatty acids (fatty acid.
- polysorbates eg, Tween 20, 40, 60, 80, etc.
- polyethoxylated castor oil eg Polyoxyl 35 castor oil, Kolliphor EL or Cremophor EL, Marlowet 40, Emulgin RO 40, etc.
- polyethoxylated hydrogenated castor oil eg Cremophor RH40, etc.
- the maximum amount of the target substance that can be solubilized by the micellar solubilization technology can be calculated using the known physical properties ( ⁇ , CMC, etc.)
- the content of the target substance that can be contained in the existing composition in which the target substance is solubilized by micellar solubilization technology cannot exceed the S micelle .
- the maximum content of the target substance that can be solubilized with the two or more surfactants is the above Equations 1 and 4, It is determined by the S micelle value obtained through 5.
- the content of the target substance that can be stably contained in the dispersion composition is the S micelle (Equations 1 and 4, 5) exceeds the value. That is, the S-parameter of the dispersion composition containing two or more surfactants embodied in the present invention is greater than 1.
- the S-parameter value may be 1.05 or more, 1.06 or more, 1.1 or more, 1.2 or more, 1.5 or more, 2 or more, 3 or more.
- S micelle is a value calculated using experimentally measured physical properties for the target substance, surfactant, and dispersion medium
- the content of the target substance in the dispersion composition implemented with the existing micelle solubilization technology cannot exceed S micelle .
- the S-parameter of the dispersion composition implemented by the solubilization technique is 1 or less.
- the dispersion composition embodied in the present invention has an S-parameter greater than 1, the present invention can implement a dispersion composition containing a higher content of the target substance beyond the limit that can be solubilized by conventional micellar solubilization technology.
- the dispersion composition of the present invention when the dispersion composition of the present invention includes two or more surfactants, the dispersion composition embodied in the present invention may have an S-parameter of greater than 1, regardless of the type or total number of surfactants used or the type of target material.
- the present invention can implement a dispersion composition containing the content of the specific target substance even using a surfactant in an amount smaller than the surfactant required to solubilize the specific target substance content with the existing micellar solubilization technology. it means
- micellar solubilization technology cannot stably disperse the target substance in the dispersion medium at a content higher than the maximum amount (S micelle ) that the surfactant can solubilize the target substance. It is natural in terms of conceptual definition that the S-parameter cannot exceed 1 for the dispersion composition prepared including
- the S-parameter when the S-parameter is experimentally measured for a dispersion composition prepared including a surfactant by the existing micellar solubilization technology, the S-parameter may be measured/calculated as a value exceeding 1 due to measurement error. there is.
- the present invention is not intended to cover the case of a dispersion composition prepared including a surfactant by an existing micelle solubilization technique, in which the S-parameter is obtained to a value greater than 1 due to experimental error or measurement error.
- the present invention can implement a dispersion composition containing a higher content of the target material beyond the limit that can be solubilized by the existing micellar solubilization technology. This is due to the physicochemical interaction described below that induces/promotes/causes the multi-surface body in contact with the mixed solution in the process of the present invention, which will be described later. It is presumed that it is due to the change in the surface properties of the solid target material that is induced/promoted/caused and then formed.
- the present invention can implement a dispersion composition containing a higher content of the target substance beyond the limit of solubilization with the existing micellar solubilization technology, and this can be achieved through the above-described S-parameter analysis. It can be confirmed through a numerical comparison with the composition.
- a dispersion medium comprising particles comprising a target material
- the dispersion composition comprises at least one surfactant having a critical micelle concentration or higher,
- the dispersion composition does not contain a solubilizer
- the S-parameter of Equation 3 calculated by Equations 1 and 2 satisfies S-parameter > 1,
- Equation 1 S w is a concentration corresponding to the saturated solubility of the target material in the dispersion medium, and S surf is calculated by Equation 2 below.
- Equation 2 k is the molar solubilization capacity defined by the number of moles of the target substance that can be dispersed in the dispersion medium by one type of surfactant above the critical micelle concentration of 1 mole, C surf is the molar concentration of the surfactant component in the composition, and CMC is the critical micelle molar concentration of the surfactant in the composition.
- Equation 3 S tot is the total molar content of the target material contained in the dispersion composition.
- Equation 4 k surf(i) is the molar solubilization capacity (molar) defined by the number of moles of the target substance that can be dispersed in the dispersion medium by any one of the surfactant components above the critical micelle concentration of 1 mole solubilization capacity), C surf(i) is the concentration of any one of the surfactant components above the critical micelle concentration, and CMC surf(i) is the dispersion medium of any one type of the surfactant component above the critical micelle concentration. is the critical micelle concentration at
- Equation 5 m is the total number of types of surfactant components above the critical micelle concentration.
- the total content of the target substance that can be dispersed is in accordance with the sum of the content of the target substance that can be dispersed by type of each surfactant.
- the type of surfactant may be selected.
- the dispersion composition may include the target material in an amount exceeding a content corresponding to a saturated solubility in the dispersion medium.
- Particles that are the dispersed phase of the dispersion composition of the present invention may include one or more target substances.
- the particles include a plurality of types of target substances
- “the content of the target substance exceeds a content corresponding to the saturated solubility of the target substance in the dispersion medium” means at least one of the plurality of types of substances This means that it is included in an amount exceeding the content corresponding to the saturated solubility in the dispersion medium.
- the particles may further include additives in addition to the target material.
- the particles may be crystalline, amorphous, or a mixture thereof.
- the target substance is a drug, and the particles are amorphous or crystalline.
- the particles may be single component or multicomponent.
- the particles may be single phase or multiphase.
- the number average diameter of the particles including the target material in the dispersion composition embodied in the present invention has a size of about 100 nm or less.
- the number average diameter may be about 80 nm or less.
- the number average diameter may be about 50 nm or less.
- the number average diameter may be about 1 nm to about 20 nm.
- the number average diameter may be about 1 nm to about 10 nm.
- the number average diameter may be about 1 nm to about 5 nm .
- the dispersion composition is transparent. If the particle size is small and does not agglomerate or settle, the permeability of the dispersion composition is maintained high. Since the particles are formed in a nanometer unit size, the dispersion composition is formed to be transparent, and the transmittance is high. Transmittance can be measured by transmittance or turbidity for a specific wavelength, and transparency can be confirmed by visual inspection.
- the dispersion composition has excellent dispersion stability.
- the dispersion composition is stably dispersed while including the target material in an amount exceeding the saturated solubility in the dispersion medium.
- the stability of the dispersion composition can be confirmed by visual inspection by observing that transparency is maintained or precipitation does not occur over time.
- physical properties sensitive to particle size such as transmittance or turbidity obtained by optical measurement, or particle size (Z-avg or mean particle diameter) measured by Dynamic Light Scattering (DLS), etc.
- DLS Dynamic Light Scattering
- dispersion stability can also be measured by the change in the content of the target substance over time.
- the content of high performance liquid chromatography (HPLC) measured after filtering decreases over time. Therefore, dispersion stability can be confirmed by examining whether the high-performance liquid chromatography content measured after filtering is maintained at a value immediately after the composition is created over time.
- the dispersion composition may stably maintain a dispersion state in which the number average diameter of the particles has a size of 100 nm or less for about 24 hours or more.
- the dispersion composition may stably maintain a dispersed state in which the number average diameter of the particles has a size of 100 nm or less for about 1 week or more.
- the dispersion composition may stably maintain a dispersed state in which the number average diameter of the particles has a size of 100 nm or less for about 1 month or more.
- the dispersion composition may stably maintain a dispersed state in which the number average diameter of the particles has a size of 100 nm or less for about 3 months or more.
- the dispersion composition may stably maintain a dispersed state in which the number average diameter of the particles has a size of 100 nm or less for about 12 months or more.
- a solid material obtained by removing the dispersion medium from the dispersion composition.
- the above-described dispersion composition can be obtained by applying the solid material as the target material.
- the dispersion composition is obtained by applying the solid substance as the target substance.
- the solid material can be stably dispersed in the dispersion medium in excess of the maximum amount (S micelle ) that can be solubilized by micelle solubilization technology.
- S micelle maximum amount that can be solubilized by micelle solubilization technology.
- the solid material may be a powder.
- the dispersion composition according to an embodiment of the present invention has a surfactant content lower than that of the conventionally known technology, and improves not only solubility but also permeability of the target substance, resulting in improved bioavailability and excellent therapeutic efficacy.
- a surfactant content lower than that of the conventionally known technology improves not only solubility but also permeability of the target substance, resulting in improved bioavailability and excellent therapeutic efficacy.
- by lowering the content of the surfactant than the conventional known technology there is an effect of reducing or preventing problems such as environmental pollution or body toxicity/side effects caused by the surfactant.
- Polyoxyl 35 castor oil Kerphor EL or Cremophor EL
- a cosmetic product manufactured using the dispersion composition according to an embodiment of the present invention is a composition that minimizes the content of additives such as surfactants, and can improve the cosmetic effect by improving spreadability and permeability. .
- the dispersion composition or solid material may be prepared by the manufacturing method described below.
- the manufacturing method is: by mixing the target material and the solvent for preparing the mixed solution preparing a mixed solution; preparing a polysurface; It may include; contacting the mixed solution with the multi-surface body.
- intraparticle pores or interparticle pores of the multi-surface body, or the surface inside/outside of the pores Physico-chemical interactions such as shear, spatial constraints, and surface effects can be induced/promoted/caused between the mixture and the mixed solution.
- the mixed solution is subjected to a high shear rate while passing through the nanometer or micrometer-sized particles of the multi-surface body or between the pores between particles. Clustering or arrangement/alignment or conformation may be induced/promoted/caused.
- the target substance molecules are spatially constrained (confinement effect) within the pores (within or between particles) of several tens of nanometers or less contained in the multi-surface body during the process of contacting the mixed solution with the multi-surface body (confinement effect), the target substance in the mixed solution Molecular clustering or arrangement/alignment or conformation of a specific type of molecules may be induced/promoted/caused.
- a specific type of molecular clustering of the target substance molecules in the mixed solution depends on the surface properties of the multi-surface body (for example, polarity, hydrophilicity, or type of surface functional group, etc.) or arrangement or formation of morphology, etc. can be induced/promoted/caused.
- the time during which the mixed solution interacts with the multi-surface body changes.
- Molecular clustering, arrangement, or morphogenesis can be easily induced/promoted/caused.
- the step of contacting the mixed solution with the multi-surface body is a process of inducing/promoting/inducing the various physicochemical interactions described above. contacting or mixing with
- the process fluid can be flowed to the multi-surface body together with the mixed solution sequentially or in parallel.
- the mixed solution is impregnated into the pores in the multi-surface body, and then the multi-surface body containing the liquid mixed solution is brought into contact with a dispersion medium (it may be in various ways such as simple mixing) and the mixed solution is discharged into the dispersion medium. (release) step.
- the mixed solution and the process fluid are passed together sequentially or in parallel through a multi-surface body in the form of a filling layer or membrane or sheet made of a porous or non-porous material, and directly collect to obtain a flowthrough. All of the solvent and the process fluid for preparing the mixed solution from the flow-through liquid are removed by freeze-drying, atmospheric pressure/reduced pressure/vacuum drying, distillation, or the like to obtain a solid target material (or the above-mentioned solid material).
- the separated solid target material (or solid material) may be a powder.
- the dispersion medium for example, it may be water
- one or more surfactants for example, it may be water
- additives osmotic pressure regulator, thickener, pH buffer, etc.
- the target material may be poorly soluble in the dispersion medium
- the target material may be supersaturated and dispersed in the dispersion medium.
- the residence time is adjusted by adjusting the pressure (pressure difference between the inlet and outlet) or temperature during the process as needed, or physicochemical interaction You can adjust the degree/strength of
- the process according to the present invention aims to apply the physicochemical interaction to target material molecules while bringing the mixture into contact with the multi-surface body, and solidification (crystallization) of the target material in the multi-surface body (possibly in the pores) or amorphization) or precipitation (precipitation), etc., are not intended to induce / promote / cause a thermodynamic phase transition (phase transition).
- the target material undergoes a phase change such as solidification or precipitation in the multi-surface body and remains, it is difficult to realize the result of the present invention (solid target material (or solid material) or dispersion composition) or the effect/efficacy according to the present invention. Therefore, during the process according to the present invention, it is important to adjust/control process conditions (eg, residence time or flow rate, etc.) so that the target material does not remain in the multi-surface body.
- process conditions eg, residence time or flow rate, etc.
- the residence time (t ret ) corresponding to the total contact time of the mixed solution and the multi-surface body is calculated by Equation 7 below.
- q is the Darcy flux, which is the volume of fluid passing through the polysurface unit cross-sectional area per unit time
- L is the dimension of the polysurface in the direction in which the fluid passes through the polysurface (Da Corresponds to the height of the fill layer if the surface body is a fill layer).
- the advection rate causing ordering is disordered ( It should dominate over the diffusion rate that causes randomization Since this becomes difficult, it is undesirable if the residence time is too large.
- the flow rate is too large and the residence time is too short, turbulent flow occurs, which also interferes with molecular clustering, arrangement, or shape formation of the target material. Therefore, when implementing the present invention by passing the mixed solution through the multi-surface body, an appropriate range exists in the residence time, and in order to implement the present invention, the residence time is adjusted to more than about 30 sec and less than about 390 sec.
- the residence time is proportional to the height of the filling layer (L), the height (L) of the filling layer, more precisely, the aspect ratio (height/diameter) of the height of the filling layer and the diameter of the filling layer (height/diameter) ) greater than about 0.01 and less than about 1 helps to obtain the appropriate residence time.
- the surface properties of the solid target material (or solid material) obtained by removing all of the solvent or process fluid for preparing the mixed solution from the penetrating solution are changed due to the physicochemical interaction that occurs while the mixed solution passes through the multi-surface body. It is presumed that the molecules change more affinity with the dispersion medium due to molecular clustering, arrangement, or morphogenesis. Accordingly, the content of the solid target material (or solid material) according to an embodiment of the present invention is higher than the maximum amount (S micelle ) that can be solubilized by conventional micellar solubilization technology in a dispersion medium containing a surfactant can be stably dispersed.
- the surface properties of the particles containing the target material are changed to be more friendly with the dispersion medium, and the dispersibility in the dispersion medium is improved, , it is presumed to result in a decrease in the amount of surfactant required for solubilization.
- the solid target material (or solid material) obtained by removing the dispersion medium from the dispersion composition maintains the surface properties of these particles even when dispersed in the dispersion medium again, the dispersibility in the dispersion medium is similarly improved, and accordingly, the solubilization It is assumed that this results in a decrease in the amount of surfactant required.
- the step of contacting the mixed solution and the multi-surface body as described above is referred to as a unit operation.
- a dispersion composition in which particles including the target material (or the material) are dispersed can be obtained by performing the unit process several times while changing/adjusting the process conditions for each unit process. In this case, the process conditions of each unit process may be individually or gradually changed/adjusted.
- the solid target material obtained by removing all of the solvent or process fluid for preparing the mixed solution from the penetrating liquid by freeze drying, atmospheric pressure/reduced pressure/vacuum drying or distillation, etc. is mixed with a dispersion medium 1
- a desired final dispersion composition can be obtained by mixing more than one type of surfactant and various additives (osmotic pressure regulator, thickener, pH buffer, etc.) according to the purpose and use of the final composition.
- a dispersion medium and one or more surfactants are mixed with the penetrating liquid, and then, a solvent or a process fluid for preparing the mixed solution is selectively (preferentially) separated/removed, and then necessary additives are added to achieve a predetermined desired result.
- a final dispersion composition can be obtained.
- the solvent or process fluid for preparing the mixed solution when the boiling point of the solvent or process fluid for preparing the mixed solution is lower than the boiling point of the dispersion medium, the solvent or process fluid for preparing the mixed solution is heated to a temperature above the boiling point of the solvent or process fluid for preparing the mixed solution and less than the boiling point of the dispersion medium. can be selectively separated/removed.
- the dispersion composition may contain a small amount of a solvent or process fluid for preparing the mixed solution remaining because some are not removed.
- the content of the solvent or process fluid for preparing the mixed solution can be determined.
- the dispersion composition may contain less than about 0.5% (w/w) ethanol (United States Pharmacopoeia Residual Solvents, December 1, 2020).
- the method for preparing the dispersion composition may further include separating and removing the multi-surface body.
- the multi-surface body may be separated by, for example, a filtration method using a filter, and in addition, various separation methods such as physical removal, centrifugation, coagulation, precipitation, and electrostatic attraction may be used, but is not limited thereto.
- the method for preparing the dispersion composition may further include the step of selectively removing or adding a predetermined amount of the dispersion medium of the dispersion composition in order to determine/control the final content/concentration of the target substance.
- It provides a method for preparing a solid target material (or solid material) comprising a; separating the target material from the mixture to obtain a solid target material.
- the dispersion composition according to an embodiment of the present invention is a dispersion medium, one or more surfactants and / as described above after obtaining the solid target material (or solid material) Alternatively, it may be a dispersion composition prepared by mixing necessary additives and the like.
- a pharmaceutical product for animals or humans containing the solid material (or solid target material).
- a cosmetic comprising the solid substance (or solid target substance).
- a food and beverage comprising the solid material (or solid target material).
- a pharmaceutical for animals or humans comprising the dispersion composition.
- a cosmetic comprising the dispersion composition.
- a food and beverage comprising the dispersion composition.
- % (w/v) Percentage of the mass (g) of the substance to be measured with respect to the volume (mL) of the whole system. For example, the mass of the target substance (g)/the volume of the dispersion composition (mL)*100 or the mass of the solute (g)/the volume of the solution (mL)*100
- % (w/w) the percentage of the mass of the substance to be measured relative to the mass of the whole system.
- % (v/v) the percentage of the volume of the substance to be measured relative to the volume of the whole system. For example, volume of process fluid/volume of solution*100.
- ethanol (hereinafter, 95% v/v ethanol) prepared in a volume ratio of ethanol and water of 95:5 was prepared.
- cyclosporine A Purity 99.1%. TEVA company lot no. 7414004320. hereinafter referred to as CsA
- CsA Cyclosporine A
- the mesoporous silica was sufficiently wetted with ethanol by stirring sufficiently using a spoon so that the mesoporous silica powder and the ethanol were well mixed.
- the mesoporous silica supported in 95% v/v ethanol was slowly poured into a Buchner funnel with a paper filter while maintaining a pressure difference of 0.8 bar with a suction pump.
- the flowthrough collected through the mesoporous silica was filtered using a 0.45 ⁇ m membrane filter.
- Example 1-1 The percentage obtained by dividing the amount of solid CsA (4.84 g) obtained through the above process by the amount of CsA (5 g) input to the process was defined as the yield (yield), and the value was calculated as 96.8%. That is, it was found that most of CsA (95% or more) passed through the mesoporous silica filling layer.
- This process is referred to as Example 1-1.
- the process in which the residence time was changed by varying the average volumetric flow rate was referred to as Examples 1-2, 1-3, and 1-4, and the main process conditions of each Example are described in Table 1.
- Example Amount of CsA added to the process (g) Solvent for preparing mixed solution process fluid Average volumetric flow rate (ml/min) Darcy Flux (cm/min) dwell time (sec) - Equation 7 Amount of CsA obtained after the process (g) Recovery (%) 1-1 5 95% v/v ethanol 95% v/v ethanol 13.76 0.216 222 4.84 96.8 1-2 5 95% v/v ethanol 95% v/v ethanol 12.67 0.199 241 4.75 95.0 1-3 2 95% v/v ethanol 95% v/v ethanol 13.15 0.207 232 1.93 96.5 1-4 2 95% v/v ethanol 95% v/v ethanol 12.47 0.196 245 1.90 95.0
- Examples 2-1 to 2-3 CsA aqueous dispersion composition
- Kolliphor EL manufactured BASF, lot no. 55573988Q0
- polysorbate 80 Teween 80, manufacturer Croda, lot no.45971
- CsA powder embodied in Example 1-1 was described in Table 2 Add them sequentially according to the input amount and mix thoroughly by stirring at room temperature 300 rpm for 12 hours.
- 5 ml of purified water is added to the CsA/Kolliphor EL/Tween80 mixture that is being stirred, and then thoroughly mixed by stirring at 600 rpm for 30 minutes.
- a CsA aqueous phase dispersion composition in which CsA particles are dispersed in continuous phase water was prepared.
- CsA aqueous dispersion composition of the present invention Example 2-1
- Example 2-2 Example 2-3
- CsA aqueous dispersion composition composition (% w/v) CsA: 0.02 (nominal) Tween 80: 0.1 Kolliphor EL: 0.1 CsA: 0.02 (nominal) Tween 80: 0.1 Kolliphor EL: 0.08 CsA: 0.02 (nominal) Tween 80: 0.16 Kolliphor EL: 0.04
- Example 1-1 As a comparison group (control) for comparing / contrasting the difference with the existing known technology, using a commercial CsA powder (manufacturer TEVA, lot no. 7414004320) instead of the CsA powder implemented in Example 1-1, the above table According to 2, each component was added in the same amount as the CsA aqueous dispersion composition of Examples 2-1, 2-2, and 2-3 to prepare a CsA aqueous dispersion composition prepared as a commercial CsA powder (hereinafter, Comparative Group) 2-1, 2-2, 2-3).
- Comparative Groups 2-1, 2-2, and 2-3 prepared with commercial CsA powder, precipitation was observed immediately after preparation and was observed to be translucent or opaque, indicating that the dispersion composition was not implemented.
- the CsA aqueous dispersion composition of the same composition prepared in Examples 2-1, 2-2, and 2-3 precipitation was not observed after preparation and all were observed to be transparent, indicating that the dispersion composition was implemented.
- the CsA aqueous dispersion composition prepared in Examples 2-1, 2-2, 2-3 and Comparative Groups 2-1, 2-2, 2-3 was filtered through a 0.22 ⁇ m PES (Polyethersulfone) filter to obtain a filter filtrate. .
- the filter filtrate was subjected to HPLC analysis under the following conditions to measure CsA content/concentration, and is described in Table 3, respectively.
- the CsA content/concentration in Table 3 is the same as in Examples 2-1, 2-2, 2-3 and CsA actual content/concentration stably dispersed in the CsA aqueous dispersion composition prepared in Comparative Groups 2-1, 2-2, and 2-3.
- the actual content of CsA in the CsA aqueous dispersion composition prepared in Examples 2-1, 2-2, and 2-3 is within +-5% of the nominal content of 0.02% w/v in Table 2. It can be seen that all have been implemented.
- the actual content of CsA in the CsA aqueous dispersion composition prepared in Comparative Groups 2-1, 2-2, and 2-3 fell short of the nominal content of 0.02% w/v, and 0.02% w/v CsA was dispersed in the dispersion composition. It was found that this was not implemented.
- the calculated value is the number of moles of CsA Therefore, it is converted back to CsA % w/v using the molecular weight of CsA to obtain Ssurf.
- the contents/composition in Tables 5 and 6 are all % w/v obtained through this conversion process.
- the S-parameters of the CsA dispersion compositions implemented in Examples 2-1, 2-2, and 2-3 are 1.12, 1.18, and 1.17, respectively, and all exceed 1. This is the existing limit (S micelle ) amount that CsA in the CsA dispersion composition implemented in Examples 2-1, 2-2, and 2-3 can be solubilized with two surfactants (Tween 80 and Kolliphor EL), respectively. 12%, 18%, and 17% over.
- the S-parameters of the dispersion compositions of Comparative Groups 2-1, 2-2, and 2-3 implemented by the known technology are all 1 or less.
- CsA aqueous dispersion composition of the present invention Elapsed time since dispensing Example 2-1
- Example 2-2 Example 2-3 sedimentation appearance sedimentation appearance sedimentation appearance 1 week doesn't exist Transparency doesn't exist Transparency 2 weeks doesn't exist Transparency doesn't exist Transparency doesn't exist Transparency 3 weeks doesn't exist Transparency doesn't exist Transparency 4 weeks doesn't exist Transparency doesn't exist Transparency
- the CsA aqueous dispersion composition prepared in Examples 2-1, 2-2, and 2-3 In order to check the stability of the CsA aqueous dispersion composition prepared in Examples 2-1, 2-2, and 2-3, it is stored for 2-4 weeks at 25 ⁇ 2° C. and 60 ⁇ 5% relative humidity after preparation.
- the CsA content over time was determined by HPLC.
- the CsA aqueous dispersion composition prepared in Examples 2-1, 2-2, and 2-3 was filtered with a 0.22 ⁇ m PES (Polyethersulfone) filter, and then the filter filtrate HPLC analysis was performed under the following conditions to measure the rate of change over time of the CsA content (setting the HPLC content to 100% immediately after preparation and calculating the content change rate over time) was shown in Table 8.
- PES Polyethersulfone
- Example 2-1 Example 2-2 Example 2-3 immediately after dispensing 100% 100% 1 week 100.5% 100.2% 98.4% 2 weeks 100.8% 100.7% 100.7% 4 weeks 100.4% 99.9%
- the content of the CsA aqueous dispersion composition prepared in Examples 2-1, 2-2, and 2-3 is maintained at the content immediately after preparation even after 2-4 weeks have elapsed. Therefore, it can be seen that CsA is stably dispersed without precipitation in the CsA aqueous dispersion composition prepared in Examples 2-1, 2-2, and 2-3 during this period.
- Example 2-4 CsA aqueous dispersion composition
- ethanol (hereinafter, 95% v/v ethanol) prepared in a volume ratio of ethanol and water of 95:5 was prepared.
- CsA cyclosporine A (purity 99.1%. Manufacturer TEVA, lot no.7414004320, hereinafter referred to as CsA) as the target substance was 30 at 500 rpm using a magnetic bar and a magnetic stirrer. It was dissolved with stirring for a minute to finally obtain a CsA mixture having a concentration of 0.2% w/w.
- 95% v/v ethanol was prepared in the same manner as the solvent for preparing the mixed solution, 120 g and 80 g of purified water were mixed, and 200 g of the mixed solution was further poured into the Buchner funnel. 205 g of the flowthrough collected through the mesoporous silica was filtered using a 0.45 ⁇ m membrane filter.
- Ethanol was selectively removed from the mixed solution using a rotary vacuum concentrator (Eyela, OSB-2200) at 25° C., 150 rpm, 20 mbar for 2 hours and 20 minutes, and some purified water was distilled to finally obtain 15.8 mL of a CsA aqueous dispersion composition. .
- the obtained solution was filtered through a 0.45 ⁇ m (manufacturer FUTECS, PVDF) syringe filter and a 0.22 ⁇ m (manufacturer FUTECS, PTFE) filter to obtain a filter filtrate.
- the obtained filter filtrate was subjected to HPLC analysis under the following conditions to measure CsA content/concentration, and is shown in Table 9 .
- Example 2-5 CsA aqueous dispersion composition
- ethanol (hereinafter, 95% v/v ethanol) prepared in a volume ratio of ethanol and water of 95:5 was prepared.
- CsA cyclosporine A (purity 99.1%. Manufacturer TEVA, lot no.7414004320, hereinafter referred to as CsA) as the target substance was 30 at 500 rpm using a magnetic bar and a magnetic stirrer. It was dissolved with stirring for a minute to finally obtain a CsA mixture having a concentration of 0.2% w/w.
- 95% v/v ethanol was prepared in the same manner as the solvent for preparing the mixed solution, 120 g and 80 g of purified water were mixed, and 200 g of the mixed solution was further poured into the Buchner funnel. 205 g of the flowthrough collected through the mesoporous silica was filtered using a 0.45 ⁇ m membrane filter.
- Ethanol was selectively removed from the mixed solution using a rotary vacuum concentrator (Eyela, OSB-2200) at 25° C., 150 rpm, 20 mbar for 1 hour and 20 minutes, and some purified water was distilled to finally obtain 15.6 mL of a CsA aqueous dispersion composition. .
- the obtained solution was filtered through a 0.45 ⁇ m (manufacturer FUTECS, PVDF) syringe filter and a 0.22 ⁇ m (manufacturer FUTECS, PTFE) filter to obtain a filter filtrate.
- the obtained filter filtrate was subjected to HPLC analysis under the following conditions to measure CsA content/concentration, and is shown in Table 9 .
- composition of the final CsA aqueous dispersion composition of Examples 2-4 and 2-5 is shown in Table 9.
- CsA aqueous dispersion composition
- Example 2-4 Composition (% w/v) CsA: 0.015 Tween 80:0.038 Polyoxyl 35 Castor oil: 0.038 CsA: 0.018 Tween 80:0.019 Polyoxyl 35 Castor oil:0.058
- the S-parameters of the CsA aqueous dispersion compositions implemented in Examples 2-4 and 2-5 are 1.90 and 2.19, respectively, and both exceed 1.
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Abstract
Description
실시예 | 공정에 투입된 CsA 양 (g) | 혼합액 제조용 용매 | 공정 유체 | 평균 부피유속 (ml/min) | 달시 플럭스 (cm/min) | 체류 시간 (sec) - 수학식 7 | 공정 후 얻어진 CsA 양 (g) | 회수율 (%) |
1-1 | 5 | 95% v/v 에탄올 | 95% v/v 에탄올 | 13.76 | 0.216 | 222 | 4.84 | 96.8 |
1-2 | 5 | 95% v/v 에탄올 | 95% v/v 에탄올 | 12.67 | 0.199 | 241 | 4.75 | 95.0 |
1-3 | 2 | 95% v/v 에탄올 | 95% v/v 에탄올 | 13.15 | 0.207 | 232 | 1.93 | 96.5 |
1-4 | 2 | 95% v/v 에탄올 | 95% v/v 에탄올 | 12.47 | 0.196 | 245 | 1.90 | 95.0 |
조성 |
본 발명의 CsA 수상 분산 조성물
|
||
실시예 2-1 | 실시예 2-2 | 실시예 2-3 | |
CsA (mg) | 40.0 | 40.0 | 40.0 |
Tween 80 (mg) | 200.0 | 200.0 | 320.0 |
Kolliphor EL (mg) | 200.0 | 160.0 | 80.0 |
정제수 (ml) | 199.56 | 199.60 | 199.56 |
총 부피 (ml) | 200 | 200 | 200 |
CsA 수상 분산 조성물 조성 (% w/v) |
CsA: 0.02 (명목)
Tween 80: 0.1 Kolliphor EL: 0.1 |
CsA: 0.02 (명목)
Tween 80: 0.1 Kolliphor EL: 0.08 |
CsA: 0.02 (명목)
Tween 80: 0.16 Kolliphor EL: 0.04 |
HPLC 분석 | 본 발명의 CsA 수상 분산 조성물 | 공지기술로 구현된 CsA 수상 분산 조성물 | ||||
실시예 2-1 | 실시예 2-2 | 실시예 2-3 | 비교군 2-1 | 비교군 2-2 | 비교군 2-3 | |
CsA 함량/농도 (% w/v) |
0.02 | 0.019 | 0.02 | 0.014 | 0.016 | 0.016 |
CsA | Tween 80 | Kolliphor EL | |
분자량 (g/mol) | 1202.6 | 1310 | 2500 |
물에서 포화 용해도, Sw (% w/v) | 0.0027 | n/a | n/a |
CMC (% w/v) | n/a | 0.0018 | 0.009 |
몰 가용화 용량, k | n/a | 0.0806 | 0.1800 |
함량/조성 (% w/v) S-파라미터 (무차수) |
본 발명의 CsA 수상 분산 조성물 | ||
실시예 2-1 | 실시예 2-2 | 실시예 2-3 | |
CsA, Stot (% w/v) | 0.02 | 0.019 | 0.02 |
Tween 80, Csurf (Tween 80), % w/v | 0.1 | 0.1 | 0.16 |
Kolliphor EL, Csurf (Kolliphor EL), % w/v |
0.1 | 0.08 | 0.04 |
Ssurf (Tween 80) - 수학식 4 | 0.00726 | 0.00726 | 0.0117 |
Ssurf (Kolliphor EL) - 수학식 4 | 0.00788 | 0.00615 | 0.00268 |
Ssurf = Ssurf (Tween 80) + Ssurf (Kolliphor EL) - 수학식 5 | 0.01514 | 0.01341 | 0.01439 |
Smicelle = Sw + Ssurf - 수학식 1 | 0.0178 | 0.016 | 0.0171 |
S-파라미터 (=Stot/ Smicelle) - 수학식 3 | 1.12 | 1.18 | 1.17 |
함량/조성 (% w/v) S-파라미터 (무차수) |
공지기술의 CsA 수상 분산 조성물 | ||
비교군 2-1 | 비교군 2-2 | 비교군 2-3 | |
CsA, Stot (% w/v) | 0.014 | 0.016 | 0.016 |
Tween 80, Csurf (Tween 80), % w/v | 0.1 | 0.1 | 0.16 |
Kolliphor EL, Csurf (Kolliphor EL), % w/v |
0.1 | 0.08 | 0.04 |
Ssurf (Tween 80) - 수학식 4 | 0.00726 | 0.00726 | 0.0117 |
Ssurf (Kolliphor EL) - 수학식 4 | 0.00788 | 0.00615 | 0.00268 |
Ssurf = Ssurf (Tween 80) + Ssurf (Kolliphor EL) - 수학식 5 | 0.01514 | 0.01341 | 0.01439 |
Smicelle = Sw + Ssurf - 수학식 1 | 0.0178 | 0.016 | 0.0171 |
S-파라미터 (=Stot/ Smicelle) - 수학식 3 | 0.79 | 1.0 | 0.94 |
본 발명의 CsA 수상 분산 조성물 | ||||||
조제이후 경과 시간 | 실시예 2-1 | 실시예 2-2 | 실시예 2-3 | |||
침전 | 성상 | 침전 | 성상 | 침전 | 성상 | |
1주 | 없음 | 투명 | 없음 | 투명 | 없음 | 투명 |
2주 | 없음 | 투명 | 없음 | 투명 | 없음 | 투명 |
3주 | 없음 | 투명 | 없음 | 투명 | ||
4주 | 없음 | 투명 | 없음 | 투명 |
조제이후 경과 시간 | 본 발명의 CsA 수상 분산 조성물 함량 변화 | ||
실시예 2-1 | 실시예 2-2 | 실시예 2-3 | |
조제직후 | 100% | 100% | 100% |
1주 | 100.5% | 100.2% | 98.4% |
2주 | 100.8% | 100.7% | 100.7% |
4주 | 100.4% | 99.9% |
조성 | CsA 수상 분산 조성물 | |
실시예 2-4 | 실시예 2-5 | |
조성 (% w/v) | CsA: 0.015 Tween 80:0.038 Polyoxyl 35 Castor oil:0.038 |
CsA: 0.018 Tween 80:0.019 Polyoxyl 35 Castor oil:0.058 |
함량/조성 (%w/v) S-파라미터 (무차수) |
CsA 수상 분산 조성물 | |
실시예 2-4 | 실시예 2-5 | |
CsA, Stot (% w/v) | 0.015 | 0.018 |
Tween 80, Csurf (Tween 80), % w/v | 0.038 | 0.019 |
Polyoxyl-35 Castor oil, Csurf (Polyoxyl-35 Castor oil), % w/v | 0.038 | 0.058 |
Ssurf (Tween 80) - 수학식 4 | 0.00268 | 0.00127 |
Ssurf (Polyoxyl-35 Castor oil) - 수학식 4 | 0.00251 | 0.00424 |
Ssurf = Ssurf (Tween 80) + Ssurf (Polyoxyl-35 Castor oil) - 수학식 5 | 0.00519 | 0.00551 |
Smicelle = Sw + Ssurf - 수학식 1 | 0.0079 | 0.0082 |
S-파라미터 (=Stot/ Smicelle) - 수학식 3 | 1.90 | 2.19 |
Claims (12)
- 분산매; 및 목적물질을 포함하는 입자를 포함하는 분산 조성물이고,상기 분산 조성물은 임계 미셀 농도 이상의 계면활성제를 적어도 1종을 포함하고,상기 분산 조성물은 가용화제를 포함하지 않고,상기 분산 조성물이 계면활성제 1종을 포함하는 경우, 수학식 1 및 수학식 2에 의해 계산되는 수학식 3의 S-파라미터가 S-파라미터 > 1 를 만족하고,상기 분산 조성물은 임계 미셀 농도 이상의 계면활성제를 적어도 2종을 포함하는 경우, 계면활성제의 각 종류별로 하기 수학식 4에 의해 얻은 Ssurf(i)를 계산하여, 하기 수학식 5에 의해 이들의 합으로서 Ssurf 값을 얻고, 이렇게 계산된 Ssurf 값을 상기 수학식 1 에 적용하여 얻은 수학식 3의 S-파라미터가 S-파라미터 > 1 를 만족하는분산 조성물.<수학식 1>Smicelle = Sw + Ssurf상기 수학식 1에서, Sw는 상기 목적물질의 상기 분산매에 대한 포화 용해도에 해당하는 농도이고, Ssurf는 하기 수학식 2에 의해 계산된다.<수학식 2>Ssurf = k(Csurf - CMC)상기 수학식 2에서, k는 1몰의 상기 임계 미셀 농도 이상의 1종의 계면활성제의 의해 상기 분산매에 분산될 수 있는 상기 목적물질의 몰수로 정의되는 몰 가용화 용량 (molar solubilization capacity)이고, Csurf는 상기 조성물에서 계면활성제성분의 몰 농도이고, CMC는 상기 조성물에서 계면활성제의 임계 미셀 몰 농도이다.<수학식 3>S-파라미터 = Stot / Smicelle상기 수학식 3에서, Stot은 분산 조성물에 함유된 상기 목적물질의 총 몰 함량이다.<수학식 4>Ssurf(i) = ksurf(i) (Csurf(i) - CMCsurf(i))상기 수학식 4에서, ksurf(i)는 1몰의 상기 임계 미셀 농도 이상의 계면활성제 성분의 임의의 1종에 의해 상기 분산매에 분산될 수 있는 상기 목적물질의 몰수로 정의되는 몰 가용화 용량 (molar solubilization capacity)이고, Csurf(i)는 상기 임계 미셀 농도 이상의 계면활성제 성분의 임의의 1종의 농도이고, CMCsurf(i)는 상기 임계 미셀 농도 이상의 계면활성제 성분의 임의의 1종의 상기 분산매에서의 임계 미셀 농도이다.<수학식 5>상기 수학식 5에서, m은 상기 임계 미셀 농도 이상의 계면활성제 성분의 종류의 총 개수이다.
- 제1항에 있어서,상기 분산 조성물은 상기 목적물질을 상기 분산매에 대한 포화 용해도에 해당하는 함량을 초과하는 함량으로 포함하는분산 조성물.
- 제1항에 있어서,상기 임계 미셀 농도 이상의 계면활성제를 2종 이상 포함하는 경우, 총 분산시킬 수 있는 상기 목적물질의 함량은 각 계면활성제의 종류별 분산시킬 수 있는 상기 목적물질의 함량의 합산에 따르도록 상기 계면활성제의 종류가 선택된분산 조성물.
- 제1항에 있어서,상기 입자의 수평균 직경이 100 nm 이하 크기를 가진분산 조성물.
- 제1항에 있어서,상기 입자의 수평균 직경이 50 nm 이하 크기를 갖는분산 조성물.
- 제1항에 따른 분산 조성물을 포함하는 동물용 또는 인체용 의약품.
- 제1항에 따른 분산 조성물을 포함하는 화장품.
- 제1항에 따른 분산 조성물을 포함하는 식음료.
- 고상의 물질로서,상기 물질을 제1항의 목적물질로서 적용하여 제1항에 따른 분산 조성물이 얻어지는고상의 물질.
- 제9항에 따른 고상의 물질을 포함하는 동물용 또는 인체용 의약품.
- 제9항에 따른 고상의 물질을 포함하는 화장품.
- 제9항에 따른 고상의 물질을 포함하는 식음료.
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JP2007126423A (ja) * | 2005-11-07 | 2007-05-24 | Mitsubishi Chemicals Corp | エマルション並びにそれを用いた目的物質粒子の製造方法及び医薬品 |
WO2018152334A1 (en) * | 2017-02-15 | 2018-08-23 | Molecular Infusions, Llc | Formulations |
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- 2021-11-04 WO PCT/KR2021/015911 patent/WO2022098121A1/ko active Application Filing
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JP2007126423A (ja) * | 2005-11-07 | 2007-05-24 | Mitsubishi Chemicals Corp | エマルション並びにそれを用いた目的物質粒子の製造方法及び医薬品 |
WO2018152334A1 (en) * | 2017-02-15 | 2018-08-23 | Molecular Infusions, Llc | Formulations |
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LODHA A, LODHA M, PATEL A, CHAUDHURI J, DALAL J, EDWARDS M, DOUROUMIS D: "Synthesis of mesoporous silica nanoparticles and drug loading of poorly water soluble drug cyclosporin A", JOURNAL OF PHARMACY AND BIOALLIED SCIENCES, MUMBAI : MEDKNOW PUBLICATIONS, IN, vol. 4, no. 5, 1 January 2012 (2012-01-01), IN , pages 92, XP055928343, ISSN: 0975-7406, DOI: 10.4103/0975-7406.94153 * |
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EP4241760A1 (en) | 2023-09-13 |
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