WO2020203808A1 - Novel method for producing lecithin organogel - Google Patents

Novel method for producing lecithin organogel Download PDF

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WO2020203808A1
WO2020203808A1 PCT/JP2020/014114 JP2020014114W WO2020203808A1 WO 2020203808 A1 WO2020203808 A1 WO 2020203808A1 JP 2020014114 W JP2020014114 W JP 2020014114W WO 2020203808 A1 WO2020203808 A1 WO 2020203808A1
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lecithin
water
active ingredient
organogel
soluble active
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PCT/JP2020/014114
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French (fr)
Japanese (ja)
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壮一 門馬
畑中　大輔
恵子 一丸
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日産化学株式会社
国立大学法人九州大学
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Priority to JP2021512022A priority Critical patent/JPWO2020203808A1/ja
Publication of WO2020203808A1 publication Critical patent/WO2020203808A1/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23J—PROTEIN COMPOSITIONS FOR FOODSTUFFS; WORKING-UP PROTEINS FOR FOODSTUFFS; PHOSPHATIDE COMPOSITIONS FOR FOODSTUFFS
    • A23J7/00—Phosphatide compositions for foodstuffs, e.g. lecithin
    • 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
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • 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
    • A61K8/41—Amines
    • 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
    • A61K8/55—Phosphorus compounds
    • 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
    • A61K8/67—Vitamins
    • 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
    • A61K8/73—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q1/00—Make-up preparations; Body powders; Preparations for removing make-up
    • 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

Definitions

  • the present invention relates to a new method for producing lecithin organogel.
  • Lecithin organogel is an organogel in which oil is retained in a three-dimensional network structure formed of lecithin inverted string-shaped micelles, and since the inside of the micelles has a hydrophilic environment, it can contain water-soluble active ingredients such as drugs.
  • An object of the present invention is to find a method for producing a lecithin organogel that efficiently and widely incorporates a water-soluble active ingredient in or a part of a lecithin inverted string-shaped micelle.
  • a method for producing a lecithin organogel consisting of the following three steps.
  • a first step a step of forming a lecithin gel emulsion containing a water-soluble active ingredient;
  • a second step a step of self-assembling into lecithin reverse string-shaped micelles while removing water from the lecithin gel emulsion obtained in the previous step;
  • the third step comprises a step of adding an oil-based base material to the lecithin inverted string-shaped micelle obtained in the previous step to form a lecithin organogel.
  • the lecithin organogel obtained by the production method of the present invention can contain a higher volume of a water-soluble active ingredient than before, and is excellent in transparency and dispersion stability, leading to the completion of the present invention. It was.
  • the present invention is as follows.
  • a step of preparing a lecithin gel emulsion containing a water-soluble active ingredient a step of self-assembling while removing water from the lecithin gel emulsion to form a lecithin reverse string-shaped micelle, and an oil-based substrate on the lecithin reverse string-shaped micelle.
  • a method for producing a lecithin organogel which comprises a step of forming a lecithin organogel.
  • the production method of the present invention can be produced using only water without dissolving the water-soluble active ingredient in an organic solvent such as alcohol, it is possible to provide a lecithin organogel containing a wide range of water-soluble active ingredients. .. Another feature is that it can be manufactured without using a heating process or a special shearing device or crusher. It is considered that this production method has a higher amount of water-soluble active ingredient incorporated into the lecithin organogel than the conventional method, and has expanded the possibility as a dispersion form in oil at a practical level.
  • the lecithin organogel obtained by this production method is uniformly dispersed on an oil-based substrate and has an excellent appearance, so that it can be suitably used as a pharmaceutical preparation, a quasi-drug, a cosmetic product, or the like.
  • the present invention relates to a method for producing a lecithin organogel that efficiently and widely incorporates a water-soluble active ingredient in or as a part of a lecithin inverted string-shaped micelle.
  • the water-soluble active ingredient that can be taken up in or as a part of the lecithin reverse-string micelle is a substance known as an active ingredient of pharmaceuticals, quasi-drugs, cosmetics, dietary supplements or pesticides, and There is no particular limitation as long as it is a substance that dissolves in water. Dissolving in water means, for example, when shaking vigorously every 5 minutes at 20 ⁇ 5 ° C. for 30 seconds, the amount of water required to dissolve 1 g or 1 mL of the water-soluble active ingredient is less than 100 mL to the extent that it dissolves within 30 minutes. Means that Examples of such a water-soluble active ingredient include "slightly soluble", “slightly soluble", “easily soluble” or "extremely soluble” agents specified in the Japanese Pharmacopoeia.
  • water-soluble active ingredients include low-molecular-weight pharmaceutical compounds such as tranexamic acid, diclofenac or salts thereof, water-soluble vitamins such as vitamin Bs, ascorbic acid (vitamin Cs) or derivatives thereof, hyaluronic acid or derivatives thereof, and the like. Sugars are mentioned.
  • the water-soluble active ingredient may be used alone or in combination of two or more.
  • the oil-based base used in the lecithin organogel of the present invention is a substance known as a base for pharmaceuticals, quasi-drugs, cosmetics, dietary supplements or pesticides, and is liquid at room temperature (20 ⁇ 5 ° C.). There is no particular limitation as long as it is a fat-soluble substance.
  • oily bases examples include alcohol esters of fatty acids having 8 to 20 carbon atoms such as cetyl 2-ethylhexanoate, isopropyl myristate (IPM) and isopropyl palmitate (IPP), and terpenes such as squalane and squalane.
  • Vegetable oils such as jojoba oil, almond oil and olive oil, animal oils such as horse oil, synthetic oils such as silicone oil, and mineral oils such as liquid paraffin and vaseline.
  • Preferred examples of the oily base are alcohol esters of fatty acids having 8 to 20 carbon atoms, vegetable fats and oils, animal fats and oils or mineral oils, and more preferable examples are alcohol esters of fatty acids having 10 to 16 carbon atoms.
  • Classes or mineral oils, a particularly preferred example is isopropyl myristate (IPM).
  • the oily base may be used alone or in combination of two or more.
  • the water-soluble active ingredient is incorporated in or as a part of the inverted string-shaped micelle, and they are uniformly dispersed in the oil-based base to form a dispersion liquid.
  • the amount of the oil-based substrate in which the inverted string-shaped micelles are dispersed affects the concentration of the active ingredient and the viscosity of the preparation, and the smaller the amount of the oil-based substrate, the higher the concentration.
  • the fact that the water-soluble active ingredient is uniformly dispersed in the oil-based base to form a dispersion means that the water-soluble active ingredient is taken into the inverted string-shaped micelle or a part thereof and is contained in the oil-based base. Refers to a dispersed state without agglomeration.
  • the lecithin used in the lecithin organogel of the present invention has the following formula:
  • residues of saturated or unsaturated fatty acids having 12 to 20 carbon atoms are residues of saturated or unsaturated fatty acids having 16 to 18 carbon atoms, and particularly preferably independent of each other.
  • It contains at least one phosphatidylcholine represented by [myristoyl group, palmitoyl group, stearoyl group, oleoyl group or linoleoyl group] in an amount of about 80% or more, preferably about 90% or more, particularly preferably 94% or more. Things are good.
  • the lecithin used in the lecithin organogel of the present invention is not particularly limited as long as it contains at least one phosphatidylcholine represented by the above formula in an amount of about 94% or more.
  • soybean lecithin, egg yolk lecithin, synthetic lecithin, and enzyme treatment examples include lecithin and enzymatically decomposed lecithin.
  • Preferred examples of lecithin are soybean lecithin, egg yolk lecithin or synthetic lecithin. These lecithins can be appropriately obtained from reagent suppliers such as LIPOID AG and NOF CORPORATION.
  • the blending amount of lecithin is about 1 to about 200 times, preferably about 1 to about 100 times the total amount of the water-soluble active ingredient.
  • the lecithin organogel of the present invention self-forms into an inverted string-shaped micelle while (a) forming a lecithin gel emulsion containing a water-soluble active ingredient, and (b) removing water from the lecithin gel emulsion obtained in the previous step. It is obtained through three steps: a step of assembling and (c) a step of adding an oil-based substrate to the inverted string-shaped micelles obtained in the previous step to form a lecithin organogel.
  • An aqueous solution of the water-soluble active ingredient is prepared by a known method.
  • the concentration of the active ingredient in the aqueous solution is not particularly limited and is appropriately adjusted according to the solubility, the desired content in the lecithin organogel, etc., but is, for example, about 0.01% by mass or more and about 30% by mass or less. It is preferably about 0.5 to about 20% by mass.
  • the step of forming the lecithin gel emulsion is carried out by kneading the aqueous solution of the water-soluble active ingredient and lecithin. Kneading is carried out by a known method until a uniform lecithin gel emulsion is formed.
  • the instruments / equipment used for kneading are not particularly limited, and any method usually carried out by those skilled in the art may be used.
  • an instrument / machine used for kneading there are a spatula, a mortar, a stirrer, a mechanical stirrer, a mixer, a rotation / revolution mixer, a multi-bead shocker and the like.
  • the lecithin gel emulsion in the present invention is composed of only an aqueous solution of lecithin and a water-soluble active ingredient, and refers to a gel-solid state in which the water-soluble active ingredient is contained in lecithin.
  • the weight ratio of lecithin to the aqueous solution used for kneading is about 1: 1 to 1: 5, preferably about 1: 2 to 1: 3.
  • the kneading is carried out at room temperature, for example, after adding an aqueous solution of the water-soluble active ingredient to lecithin until a gel emulsion having a uniform appearance is obtained.
  • the lecithin gel emulsion thus obtained is then subjected to a step of removing water (drying step). Moisture removal is carried out by natural drying or vacuum drying, and the obtained inverted string micelles are oil-soluble.
  • Natural drying or vacuum drying is carried out by a known method, but it is preferably carried out under mild conditions. For example, it is carried out at an ambient temperature (for example, 10 to 40 ° C., preferably room temperature (about 25 ° C.)) under normal pressure or reduced pressure conditions for several hours to several days until the desired moisture removal rate is reached.
  • the lecithin gel emulsion may undergo an aging step before being naturally dried or dried under reduced pressure. The aging step can be carried out by allowing the lecithin gel emulsion to stand, for example, at about 1 to about 48 hours, about 1 to about 20 ° C., preferably about 12 to about 24 hours, about 5 to 10 ° C.
  • the water removal rate from the lecithin gel emulsion is preferably about 85 to about 95% by mass, more preferably about 87 to about 93% by mass, and the obtained dried product self-assembles to form an inverted string-like micelle.
  • the amount of the oil-based substrate to be added is, for example, 1 to 100 times, preferably 5 to 50 times the amount of the lecithin used.
  • a lecithin organogel can be obtained by adding an oil-based substrate and then mixing until the inverted string-shaped micelles are completely dispersed.
  • the present invention is a method for producing a lecithin organogel that efficiently and widely incorporates a water-soluble active ingredient in or as a part of a lecithin inverted string-shaped micelle, thereby providing a practically dispersed form in oil.
  • lecithin organogels can be provided.
  • the lecithin organogel of the present invention can be used as a pharmaceutical product, a quasi drug, a cosmetic product, a dietary supplement or a pesticide, or as a raw material or stock thereof.
  • pharmaceuticals such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, diluents, etc., as long as the dispersibility of the dispersion of the present invention is not impaired. It may contain additives that are acceptable in the field of cosmetics.
  • Soy lecithin containing 94% or more of phosphatidylcholine
  • Phospholipon (R) 90G trade name “Phospholipon (R) 90G”, manufactured by Lipoid AG
  • IPM Isopropyl Myristate
  • Example 1 Preparation of APM-containing lecithin organogel
  • Water 2.0 mL was added to APM (20 mg) to completely dissolve it.
  • the obtained aqueous solution and lecithin (1.0 g) were kneaded at room temperature for about 30 minutes, and the obtained kneaded product was aged at about 10 ° C. for 12 hours to obtain a lecithin gel emulsion.
  • isopropyl myristate (9.0 g) was added to the obtained lecithin inverted string micelles, and the mixture was completely dispersed in oil to obtain an APM-containing lecithin organogel.
  • the evaluation results of viscosity and transparency are shown in Table 1 below. No white turbidity or precipitation was confirmed (see FIG. 1).
  • Examples 2 to 6 Confirmation of substrate generality of production method
  • a lecithin organogel was prepared in substantially the same manner as in Example 1 except that the water-soluble active ingredients shown in Table 1 below were used. At that time, the evaluation results of the water-soluble active ingredient used, the content, the viscosity and the transparency are shown in Table 1 below. No white turbidity or precipitation was confirmed (see FIG. 1).
  • an aqueous solution of a water-soluble active ingredient and lecithin are kneaded until they become uniform to form a lecithin gel emulsion, and then a reverse string-shaped micelle obtained by removing water is placed in an oil-based base. It is a technology to disperse evenly. Unlike the conventional method, since it is once passed through the lecithin gel emulsion, it is a production method under mild conditions without abrupt self-assembly, so that the active ingredient can be included in a high content. ..
  • the water-soluble active ingredient can be produced without being dissolved in an organic solvent such as alcohol, it is possible to provide a wide range of water-soluble active ingredient lecithin organogels regardless of the solubility of the water-soluble active ingredient in the organic solvent.
  • the lecithin organogel of the present invention can be suitably used as a pharmaceutical product, a quasi-drug, a cosmetic product, etc. because the water-soluble active ingredient is uniformly dispersed in oil, the dispersion stability is high, and the appearance is excellent.

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Abstract

The present invention addresses the problem of discovering a method for producing a lecithin organogel in which a water-soluble active ingredient is efficiently and widely incorporated into the interior of a lecithin reverse wormlike micelle or as a part thereof.　The problem was solved by discovering a method for producing a lecithin organogel comprising the three steps indicated below. In a first step, a lecithin gel emulsion including a water-soluble active ingredient is formed. In a second step, water is removed from the lecithin gel emulsion obtained in the previous step while the result self-organizes into lecithin reverse wormlike micelles. In a third step, an oily base material is added to the lecithin reverse wormlike micelles obtained in the previous step and a lecithin organogel is obtained.

Description

レシチンオルガノゲルの新規製造方法New manufacturing method of lecithin organogel
　本発明は、レシチンオルガノゲルの新規製造方法に関する。 The present invention relates to a new method for producing lecithin organogel.
　レシチンオルガノゲルはレシチン逆紐状ミセルで形成された３次元網目構造中にオイルを保持したオルガノゲルであり、ミセル内部は親水的環境となるため薬物等の水溶性有効成分を内包することができる。 Lecithin organogel is an organogel in which oil is retained in a three-dimensional network structure formed of lecithin inverted string-shaped micelles, and since the inside of the micelles has a hydrophilic environment, it can contain water-soluble active ingredients such as drugs.
　古くから逆紐状ミセルを形成する代表的な系として、レシチン／水／各種オイルの３成分混合系の報告例がある。これはレシチンをオイルに溶解し、そこに水を少量添加することで逆紐状ミセルの形成を促進するというものである。 Since ancient times, there have been reports of a three-component mixed system of lecithin / water / various oils as a typical system for forming inverted string micelles. This is to dissolve lecithin in oil and add a small amount of water to it to promote the formation of inverted string micelles.
　しかしながらこの系では極少量の水により急激にゲル化を引き起こしてしまうため、ミセル内部への有効成分の取り込みは極めて少ないことが課題となっている。 However, in this system, a very small amount of water causes gelation rapidly, so the problem is that the uptake of the active ingredient into the micelle is extremely small.
　一方、レシチン／極性成分／有機溶媒／各種オイルを用いてレシチン逆紐状ミセルを形成する方法も報告されている（特許文献１～８参照）。これらは水に代わる極性物質の報告例となる。実際にはレシチン及び極性成分を有機溶媒に溶解後、有機溶媒を除去することによりオルガノゲル形成剤とし、そこにオイル成分を添加混合させることで増粘ゲル状組成物とするものである。 On the other hand, a method of forming lecithin inverted string micelles using lecithin / polar component / organic solvent / various oils has also been reported (see Patent Documents 1 to 8). These are reported examples of polar substances that replace water. Actually, after dissolving lecithin and the polar component in an organic solvent, the organic solvent is removed to obtain an organogel forming agent, and an oil component is added and mixed therewith to obtain a thickening gel-like composition.
　上記方法ではレシチン／極性成分／水溶性有効成分のすべてが溶解する有機溶媒の選択が必要となり、結果内包可能な有効成分は限定されてしまう。特に、水へのみ可溶な塩等の有効成分に関してはこの技術では油溶化することができない。 In the above method, it is necessary to select an organic solvent in which all of lecithin / polar component / water-soluble active ingredient is dissolved, and as a result, the active ingredient that can be included is limited. In particular, active ingredients such as salts that are soluble only in water cannot be oil-solubilized by this technique.
　以上のように、レシチン逆紐状ミセル内又はその一部として水溶性有効成分を効率的かつ幅広く取り込み、レシチンオルガノゲルを形成する技術はこれまでに報告例がなく、それゆえ実用化レベルでの油中分散形態としての可能性は閉ざされてきた。 As described above, there has been no report on a technique for efficiently and widely incorporating a water-soluble active ingredient in or a part of a lecithin inverted string-shaped micelle to form a lecithin organogel, and therefore an oil at a practical level. The potential as a medium-dispersed form has been closed.
特開２０１０－２７０２９９号公報Japanese Unexamined Patent Publication No. 2010-270299 国際公開２０１０／０８２４８７号International Release 2010/082487 国際公開２０１０／１２２６９４号International Publication 2010/122694 国際公開２０１２／００８２７１号International Publication 2012/008271 国際公開２０１２／１６５１４５号International Release 2012/1651445 国際公開２０１３／０５８０８０号International release 2013/058080 国際公開２０１３／０８１１２０号International release 2013/081120 国際公開２０１３／１７６２４３号International Publication 2013/176243
　本発明は、レシチン逆紐状ミセル内又はその一部に水溶性有効成分を効率的かつ幅広く取り込むレシチンオルガノゲルの製造方法を見出すことを課題とする。 An object of the present invention is to find a method for producing a lecithin organogel that efficiently and widely incorporates a water-soluble active ingredient in or a part of a lecithin inverted string-shaped micelle.
　本発明者らは、鋭意研究の結果、以下の３つの工程からなるレシチンオルガノゲルの製造方法を見出した。
　第１工程として水溶性有効成分を内包したレシチンゲルエマルションを形成する工程；第２工程として前工程で得られたレシチンゲルエマルションから水分を除去しながらレシチン逆紐状ミセルに自己組織化する工程；第３工程として前工程で得られたレシチン逆紐状ミセルに油性基材を加え、レシチンオルガノゲルとする工程からなる。本発明の製造方法で得られたレシチンオルガノゲルには従来よりも高容量の水溶性有効成分を内包することが可能であり、さらに透明性及び分散安定性に優れることから本発明を完成させるに至った。 As a result of diligent research, the present inventors have found a method for producing a lecithin organogel consisting of the following three steps.
As a first step, a step of forming a lecithin gel emulsion containing a water-soluble active ingredient; as a second step, a step of self-assembling into lecithin reverse string-shaped micelles while removing water from the lecithin gel emulsion obtained in the previous step; The third step comprises a step of adding an oil-based base material to the lecithin inverted string-shaped micelle obtained in the previous step to form a lecithin organogel. The lecithin organogel obtained by the production method of the present invention can contain a higher volume of a water-soluble active ingredient than before, and is excellent in transparency and dispersion stability, leading to the completion of the present invention. It was.
　本発明は、以下のとおりである。
［１］水溶性有効成分を内包したレシチンゲルエマルションを作製する工程、レシチンゲルエマルションから水分を除去しながら自己組織化しレシチン逆紐状ミセルとする工程、及びレシチン逆紐状ミセルに油性基材を加えレシチンオルガノゲルとする工程を含む、レシチンオルガノゲルの製造方法。
［２］レシチンゲルエマルションの作製工程が、レシチンと水溶性有効成分の水溶液とを混練することで実施される、［１］に記載の製造方法。
［３］レシチンゲルエマルションからの水分除去と自己組織化の工程が、自然乾燥または減圧乾燥により実施される、［１］又は［２］に記載の製造方法。
［４］レシチンゲルエマルションからの水分除去率が８０質量％以上で実施される、［１］から［３］のいずれかに記載の製造方法。 The present invention is as follows.
[1] A step of preparing a lecithin gel emulsion containing a water-soluble active ingredient, a step of self-assembling while removing water from the lecithin gel emulsion to form a lecithin reverse string-shaped micelle, and an oil-based substrate on the lecithin reverse string-shaped micelle. A method for producing a lecithin organogel, which comprises a step of forming a lecithin organogel.
[2] The production method according to [1], wherein the step of producing a lecithin gel emulsion is carried out by kneading lecithin and an aqueous solution of a water-soluble active ingredient.
[3] The production method according to [1] or [2], wherein the steps of removing water from the lecithin gel emulsion and self-assembling are carried out by natural drying or vacuum drying.
[4] The production method according to any one of [1] to [3], wherein the water removal rate from the lecithin gel emulsion is 80% by mass or more.
　本発明の製造方法は、水溶性有効成分をアルコール等の有機溶媒に溶解させることなく、水のみを用いて製造可能なため、幅広い水溶性有効成分を含むレシチンオルガノゲルを提供することが可能である。また、加熱工程や特殊なせん断装置・粉砕機等を使用せずに製造できるのも特徴である。
　本製造方法は従来法に比較してレシチンオルガノゲル中への水溶性有効成分の取り込み量が高く、実用化レベルでの油中分散形態としての可能性を広げたものと考える。
　本製造方法により得られるレシチンオルガノゲルは、油性基材に均一分散し、外観にも優れることから医薬品製剤、医薬部外品、化粧品などとして好適に使用できる。 Since the production method of the present invention can be produced using only water without dissolving the water-soluble active ingredient in an organic solvent such as alcohol, it is possible to provide a lecithin organogel containing a wide range of water-soluble active ingredients. .. Another feature is that it can be manufactured without using a heating process or a special shearing device or crusher.
It is considered that this production method has a higher amount of water-soluble active ingredient incorporated into the lecithin organogel than the conventional method, and has expanded the possibility as a dispersion form in oil at a practical level.
The lecithin organogel obtained by this production method is uniformly dispersed on an oil-based substrate and has an excellent appearance, so that it can be suitably used as a pharmaceutical preparation, a quasi-drug, a cosmetic product, or the like.
実施例１、２で作製した、本発明に係るＡＰＭ含有レシチンオルガノゲルの外観を示した写真である。It is a photograph showing the appearance of the APM-containing lecithin organogel according to the present invention prepared in Examples 1 and 2. 比較例において、水１００μL滴下時点で、液面が上がりゲル化が確認できた様子を示した写真である。In the comparative example, it is a photograph showing how the liquid level rose and gelation was confirmed at the time of dropping 100 μL of water. 左から比較例１、２、３、４で作製した、既存技術によるＡＰＭ含有レシチンオルガノゲルの外観を示した写真である。From the left, it is a photograph showing the appearance of the APM-containing lecithin organogel produced by Comparative Examples 1, 2, 3 and 4 by the existing technique.
　本明細書において「～」を用いて示された数値範囲は、「～」の前後に記載される数値をそれぞれ最小値及び最大値として含む範囲を示す。 The numerical range indicated by using "-" in the present specification indicates a range including the numerical values before and after "-" as the minimum value and the maximum value, respectively.
　本発明は、レシチン逆紐状ミセル内又はその一部として水溶性有効成分を効率的かつ幅広く取り込むレシチンオルガノゲルの製造方法に関する。 The present invention relates to a method for producing a lecithin organogel that efficiently and widely incorporates a water-soluble active ingredient in or as a part of a lecithin inverted string-shaped micelle.
　本発明においてレシチン逆紐状ミセル内又はその一部として取り込むことのできる水溶性有効成分は、医薬品、医薬部外品、化粧品、栄養補助食品または農薬の有効成分として公知の物質であって、かつ水に溶解する物質であれば特に限定はない。水に溶解するとは、例えば、２０±５℃で５分ごとに強く３０秒間振り混ぜるとき、３０分以内に溶ける度合で、水溶性有効成分１gまたは１mLを溶かすのに要する水の量が１００mL未満であることを意味する。そのような水溶性有効成分として、例えば、日本薬局方に規定される「やや溶けにくい」、「やや溶けやすい」、「溶けやすい」または「極めて溶けやすい」薬剤が挙げられる。 In the present invention, the water-soluble active ingredient that can be taken up in or as a part of the lecithin reverse-string micelle is a substance known as an active ingredient of pharmaceuticals, quasi-drugs, cosmetics, dietary supplements or pesticides, and There is no particular limitation as long as it is a substance that dissolves in water. Dissolving in water means, for example, when shaking vigorously every 5 minutes at 20 ± 5 ° C. for 30 seconds, the amount of water required to dissolve 1 g or 1 mL of the water-soluble active ingredient is less than 100 mL to the extent that it dissolves within 30 minutes. Means that Examples of such a water-soluble active ingredient include "slightly soluble", "slightly soluble", "easily soluble" or "extremely soluble" agents specified in the Japanese Pharmacopoeia.
　水溶性有効成分の例としては、トラネキサム酸、ジクロフェナクまたはその塩などの低分子医薬化合物、ビタミンＢ類、アスコルビン酸（ビタミンＣ類）またはその誘導体などの水溶性ビタミン類、ヒアルロン酸またはその誘導体などの糖類が挙げられる。本発明では、前記の水溶性有効成分を、単独で使用してもよいし、２種以上を組み合わせて使用してもよい。 Examples of water-soluble active ingredients include low-molecular-weight pharmaceutical compounds such as tranexamic acid, diclofenac or salts thereof, water-soluble vitamins such as vitamin Bs, ascorbic acid (vitamin Cs) or derivatives thereof, hyaluronic acid or derivatives thereof, and the like. Sugars are mentioned. In the present invention, the water-soluble active ingredient may be used alone or in combination of two or more.
　本発明のレシチンオルガノゲルで用いられる油性基剤は、医薬品、医薬部外品、化粧品、栄養補助食品または農薬の基剤として公知の物質であって、かつ常温（２０±５℃）で液体である脂溶性物質であれば特に限定はない。 The oil-based base used in the lecithin organogel of the present invention is a substance known as a base for pharmaceuticals, quasi-drugs, cosmetics, dietary supplements or pesticides, and is liquid at room temperature (20 ± 5 ° C.). There is no particular limitation as long as it is a fat-soluble substance.
　油性基剤の例としては、２－エチルヘキサン酸セチル、ミリスチン酸イソプロピル（ＩＰＭ）、パルミチン酸イソプロピル（ＩＰＰ）などの炭素原子数８乃至２０の脂肪酸のアルコールエステル類、スクワラン、スクワレンなどのテルペン類、ホホバオイル、アーモンドオイル、オリーブオイルなどの植物性油脂、馬油などの動物性油脂、シリコーンオイルなどの合成油、及び流動パラフィン、ワセリンなどの鉱物油が挙げられる。油性基剤の好ましい例は、炭素原子数８乃至２０の脂肪酸のアルコールエステル類、植物性油脂、動物性油脂または鉱物油であり、より好ましい例は、炭素原子数１０乃至１６の脂肪酸のアルコールエステル類または鉱物油であり、特に好ましい例は、ミリスチン酸イソプロピル（ＩＰＭ）である。本発明では、前記の油性基剤を、単独で使用してもよいし、２種以上を組み合わせて使用してもよい。 Examples of oily bases include alcohol esters of fatty acids having 8 to 20 carbon atoms such as cetyl 2-ethylhexanoate, isopropyl myristate (IPM) and isopropyl palmitate (IPP), and terpenes such as squalane and squalane. , Vegetable oils such as jojoba oil, almond oil and olive oil, animal oils such as horse oil, synthetic oils such as silicone oil, and mineral oils such as liquid paraffin and vaseline. Preferred examples of the oily base are alcohol esters of fatty acids having 8 to 20 carbon atoms, vegetable fats and oils, animal fats and oils or mineral oils, and more preferable examples are alcohol esters of fatty acids having 10 to 16 carbon atoms. Classes or mineral oils, a particularly preferred example is isopropyl myristate (IPM). In the present invention, the oily base may be used alone or in combination of two or more.
　上記水溶性有効成分は、逆紐状ミセル内又はその一部として取り込まれ、かつそれらが油性基剤中に均一に分散して分散液を形成している。逆紐状ミセルを分散させる油性基材の量により有効成分濃度や製剤の増粘性に影響を与え、油性基材の量が少ないといずれも高くなる。
　また水溶性有効成分が、油性基剤中に均一に分散して分散液を形成しているとは、水溶性有効成分が、逆紐状ミセル内又はその一部として取り込まれ、油性基剤中に凝集することなく分散した状態を指す。 The water-soluble active ingredient is incorporated in or as a part of the inverted string-shaped micelle, and they are uniformly dispersed in the oil-based base to form a dispersion liquid. The amount of the oil-based substrate in which the inverted string-shaped micelles are dispersed affects the concentration of the active ingredient and the viscosity of the preparation, and the smaller the amount of the oil-based substrate, the higher the concentration.
Further, the fact that the water-soluble active ingredient is uniformly dispersed in the oil-based base to form a dispersion means that the water-soluble active ingredient is taken into the inverted string-shaped micelle or a part thereof and is contained in the oil-based base. Refers to a dispersed state without agglomeration.
　本発明のレシチンオルガノゲルで用いられるレシチンは、下記式： The lecithin used in the lecithin organogel of the present invention has the following formula:
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
［式中、Ｒ１Ｃ（＝Ｏ）－及びＲ２Ｃ（＝Ｏ）－基は、互いに独立して、炭素原子数２乃至２２の飽和または不飽和脂肪酸の残基（アシル基）であり、好ましくは、炭素原子数１２乃至２０の飽和または不飽和脂肪酸の残基であり、より好ましくは炭素原子数１６乃至１８の飽和または不飽和脂肪酸の残基であり、特に好ましくは、互いに独立して、ミリストイル基、パルミトイル基、ステアロイル基、オレオイル基またはリノレオイル基である］で表される少なくとも１種のホスファチジルコリンを約８０％以上、好ましくは約９０％以上、特に好ましくは９４％以上含有するものがよい。 [In the formula, the R 1 C (= O)-and R 2 C (= O) -groups are independent of each other and are residues (acyl groups) of saturated or unsaturated fatty acids having 2 to 22 carbon atoms. , Preferred are residues of saturated or unsaturated fatty acids having 12 to 20 carbon atoms, more preferably residues of saturated or unsaturated fatty acids having 16 to 18 carbon atoms, and particularly preferably independent of each other. It contains at least one phosphatidylcholine represented by [myristoyl group, palmitoyl group, stearoyl group, oleoyl group or linoleoyl group] in an amount of about 80% or more, preferably about 90% or more, particularly preferably 94% or more. Things are good.
　本発明のレシチンオルガノゲルで用いられるレシチンは、上記式で表わされる少なくとも１種のホスファチジルコリンを約９４％以上含むものであれば特に限定はないが、例えば、大豆レシチン、卵黄レシチン、合成レシチン、酵素処理レシチン、酵素分解レシチンが挙げられる。レシチンの好ましい例は、大豆レシチン、卵黄レシチンまたは合成レシチンである。これらのレシチンは、LIPOID AG及び日油株式会社などの試薬供給会社より適宜入手することができる。レシチンの配合量は、水溶性有効成分の総量に対して約１～約２００倍量であり、好ましくは約１～約１００倍量である。 The lecithin used in the lecithin organogel of the present invention is not particularly limited as long as it contains at least one phosphatidylcholine represented by the above formula in an amount of about 94% or more. For example, soybean lecithin, egg yolk lecithin, synthetic lecithin, and enzyme treatment. Examples include lecithin and enzymatically decomposed lecithin. Preferred examples of lecithin are soybean lecithin, egg yolk lecithin or synthetic lecithin. These lecithins can be appropriately obtained from reagent suppliers such as LIPOID AG and NOF CORPORATION. The blending amount of lecithin is about 1 to about 200 times, preferably about 1 to about 100 times the total amount of the water-soluble active ingredient.
　本発明のレシチンオルガノゲルは、（a）水溶性有効成分を内包した、レシチンゲルエマルションを形成する工程、（b）前工程で得られたレシチンゲルエマルションから水分を除去しながら逆紐状ミセルに自己組織化する工程、（c）前工程で得られた逆紐状ミセルに油性基材を加えレシチンオルガノゲルとする工程、の３つの工程を経て得られる。 The lecithin organogel of the present invention self-forms into an inverted string-shaped micelle while (a) forming a lecithin gel emulsion containing a water-soluble active ingredient, and (b) removing water from the lecithin gel emulsion obtained in the previous step. It is obtained through three steps: a step of assembling and (c) a step of adding an oil-based substrate to the inverted string-shaped micelles obtained in the previous step to form a lecithin organogel.
　水溶性有効成分の水溶液は、公知の方法により調製される。水溶液における有効成分の濃度は、特に限定はなく、溶解度やレシチンオルガノゲル中の所望の含有量などに応じて適宜調整されるが、例えば、約０．０１質量％以上、約３０質量％以下であり、好ましくは約０．５～約２０質量％である。 An aqueous solution of the water-soluble active ingredient is prepared by a known method. The concentration of the active ingredient in the aqueous solution is not particularly limited and is appropriately adjusted according to the solubility, the desired content in the lecithin organogel, etc., but is, for example, about 0.01% by mass or more and about 30% by mass or less. It is preferably about 0.5 to about 20% by mass.
　レシチンゲルエマルションを形成する工程は、水溶性有効成分の水溶液とレシチンとを混練することにより実施される。混練は公知の方法により実施され、均一なレシチンゲルエマルションを形成するまで行われる。混練に用いられる器具・機器は、特に限定はなく、当業者が通常実施する方法であればよい。例えば、混練に用いられる器具・機械として、スパーテル、乳鉢、スターラー、メカニカルスターラー、ミキサー、自転公転ミキサー、マルチビーズショッカー等がある。なお、本発明におけるレシチンゲルエマルションとは、レシチンと水溶性有効成分の水溶液のみで構成されたものであり、レシチン中に水溶性有効成分が内包されたゲル～固体状態のものを指す。
　混練に用いられるレシチンと水溶液の重量比は、約１：１～１：５であり、好ましくは約１：２～１：３である。
　混練は、例えば、水溶性有効成分の水溶液をレシチンへ添加後、外観上均一なゲルエマルションが得られるまで、室温にて実施される。 The step of forming the lecithin gel emulsion is carried out by kneading the aqueous solution of the water-soluble active ingredient and lecithin. Kneading is carried out by a known method until a uniform lecithin gel emulsion is formed. The instruments / equipment used for kneading are not particularly limited, and any method usually carried out by those skilled in the art may be used. For example, as an instrument / machine used for kneading, there are a spatula, a mortar, a stirrer, a mechanical stirrer, a mixer, a rotation / revolution mixer, a multi-bead shocker and the like. The lecithin gel emulsion in the present invention is composed of only an aqueous solution of lecithin and a water-soluble active ingredient, and refers to a gel-solid state in which the water-soluble active ingredient is contained in lecithin.
The weight ratio of lecithin to the aqueous solution used for kneading is about 1: 1 to 1: 5, preferably about 1: 2 to 1: 3.
The kneading is carried out at room temperature, for example, after adding an aqueous solution of the water-soluble active ingredient to lecithin until a gel emulsion having a uniform appearance is obtained.
　このようにして得られたレシチンゲルエマルションは、次いで水分を除去する工程（乾燥工程）に付される。水分の除去は、自然乾燥又は減圧乾燥により実施され、得られた逆紐状ミセルは油溶性を示す。 The lecithin gel emulsion thus obtained is then subjected to a step of removing water (drying step). Moisture removal is carried out by natural drying or vacuum drying, and the obtained inverted string micelles are oil-soluble.
　自然乾燥または減圧乾燥は、公知の方法により実施されるが、緩和な条件で実施されるのが好ましい。例えば、周囲温度（例えば１０～４０℃、好ましくは室温（約２５℃））にて、常圧または減圧条件下にて、数時間から数日間かけて、所望の水分除去率に達するまで実施される。またレシチンゲルエマルションを自然乾燥または減圧乾燥に付す前に、熟成工程を経てもよい。熟成工程は、レシチンゲルエマルションを、例えば、約１～約４８時間、約１～約２０℃で、好ましくは約１２～約２４時間、約５～１０℃で静置することにより実施できる。 Natural drying or vacuum drying is carried out by a known method, but it is preferably carried out under mild conditions. For example, it is carried out at an ambient temperature (for example, 10 to 40 ° C., preferably room temperature (about 25 ° C.)) under normal pressure or reduced pressure conditions for several hours to several days until the desired moisture removal rate is reached. To. Further, the lecithin gel emulsion may undergo an aging step before being naturally dried or dried under reduced pressure. The aging step can be carried out by allowing the lecithin gel emulsion to stand, for example, at about 1 to about 48 hours, about 1 to about 20 ° C., preferably about 12 to about 24 hours, about 5 to 10 ° C.
　レシチンゲルエマルションからの水分除去率は、好ましくは約８５～約９５質量％、より好ましくは約８７～約９３質量％であり、得られた乾燥物は自己組織化し逆紐状ミセルを形成する。 The water removal rate from the lecithin gel emulsion is preferably about 85 to about 95% by mass, more preferably about 87 to about 93% by mass, and the obtained dried product self-assembles to form an inverted string-like micelle.
　得られた逆紐状ミセルに油性基材を加え、レシチンオルガノゲルとする工程において、加える油性基材の量は、使用したレシチン量の、例えば、１～１００倍量、好ましくは５～５０倍量である。油性基材を添加後、逆紐状ミセルが完全に分散するまで混合することでレシチンオルガノゲルを得ることができる。 In the step of adding an oil-based substrate to the obtained inverted string-shaped micelle to obtain a lecithin organogel, the amount of the oil-based substrate to be added is, for example, 1 to 100 times, preferably 5 to 50 times the amount of the lecithin used. Is. A lecithin organogel can be obtained by adding an oil-based substrate and then mixing until the inverted string-shaped micelles are completely dispersed.
　以上のように本発明は、レシチン逆紐状ミセル内又はその一部として水溶性有効成分を効率的かつ幅広く取り込むレシチンオルガノゲルの製造方法であり、これにより実用化レベルでの油中分散形態としてのレシチンオルガノゲルを提供することができるものと考える。 As described above, the present invention is a method for producing a lecithin organogel that efficiently and widely incorporates a water-soluble active ingredient in or as a part of a lecithin inverted string-shaped micelle, thereby providing a practically dispersed form in oil. We believe that lecithin organogels can be provided.
　本発明のレシチンオルガノゲルは、医薬品、医薬部外品、化粧品、栄養補助食品または農薬として、あるいはそれらの原料もしくはストックとして使用することができる。またその目的に応じて、本発明の分散液の分散性を損なわない範囲で、賦形剤、滑沢剤、結合剤、崩壊剤、乳化剤、安定剤、矯味矯臭剤、希釈剤等の医薬品や化粧品の分野で許容される添加剤を含んでもよい。 The lecithin organogel of the present invention can be used as a pharmaceutical product, a quasi drug, a cosmetic product, a dietary supplement or a pesticide, or as a raw material or stock thereof. In addition, depending on the purpose, pharmaceuticals such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, diluents, etc., as long as the dispersibility of the dispersion of the present invention is not impaired. It may contain additives that are acceptable in the field of cosmetics.
　次に実施例を挙げ本発明の内容を具体的に説明するが、本発明はこれらに限定されるものではない。 Next, the contents of the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.
［透明性の評価］
　本製法を用いて作製したレシチンオルガノゲルの透明性は、３９℃の恒温槽に１時間静置後、目視により観察したもので、以下のように評価した。
◎：透明、○：半透明、△：白濁、×：二相分離もしくは沈殿が認められる [Evaluation of transparency]
The transparency of the lecithin organogel produced by this production method was evaluated by visual observation after standing in a constant temperature bath at 39 ° C. for 1 hour and evaluated as follows.
⊚: transparent, ○: translucent, Δ: cloudy, ×: two-phase separation or precipitation is observed.
［粘度の評価］
　本製法を用いて作製したレシチンオルガノゲルの粘度は、コーンプレート型（コーンロータ1°34′×R24）回転粘度計（TVE-22L、東機産業株式会社）を用いて２５℃恒温下で測定した。
　サンプルカップに試料を入れ、粘度計本体に取り付けてから約５分置いた後、回転速度０．５rpmで測定し、最高粘度に達した時の粘度を測定した。 [Evaluation of viscosity]
The viscosity of the lecithin organogel produced using this manufacturing method was measured at a constant temperature of 25 ° C. using a cone plate type (cone rotor 1 ° 34'× R24) rotational viscometer (TVE-22L, Toki Sangyo Co., Ltd.). ..
The sample was placed in a sample cup, attached to the viscometer body, and then left for about 5 minutes, and then measured at a rotation speed of 0.5 rpm to measure the viscosity when the maximum viscosity was reached.
試薬は以下のものを使用した。
・大豆レシチン（ホスファチジルコリン９４％以上含有）：商品名「ホスフォリポン90G（Phospholipon(R) 90G）」、Lipoid AG製
・ミリスチン酸イソプロピル（Isopropyl Myristate：IPM）：東京化成工業（株）製
・Ｌ－アスコルビン酸リン酸エステルマグネシウム塩（L-Ascorbic Acid Phosphate Magnesium Salt：ＡＰＭ）：昭和電工（株）製
・ジクロフェナクナトリウム塩：東京化成工業（株）製
・加水分解ヒアルロン酸：キューピー（株）製
・ヒアルロン酸ナトリウム塩（分子量８５万～１６０万）：商品名「ヒアルロンHA-LQ」、キューピー（株）製 The following reagents were used.
・ Soy lecithin (containing 94% or more of phosphatidylcholine): trade name “Phospholipon (R) 90G”, manufactured by Lipoid AG ・ Isopropyl Myristate (IPM): manufactured by Tokyo Kasei Kogyo Co., Ltd. ・ L-ascorbin L-Ascorbic Acid Phosphate Magnesium Salt (APM): Showa Denko Co., Ltd., Diclofenac Sodium Salt: Tokyo Kasei Kogyo Co., Ltd., Hydrolyzed Hyaluronic Acid: Cupy Co., Ltd., Hyaluronic Acid Sodium salt (molecular weight 850,000 to 1.6 million): Brand name "Hyaluronic HA-LQ", manufactured by Cupy Co., Ltd.
［実施例１：ＡＰＭ含有レシチンオルガノゲルの作製］
　ＡＰＭ（２０mg）に水（２．０mL）を加え、完全に溶解した。得られた水溶液とレシチン（１．０g）を室温で均一になるまで約３０分間混練し、得られた混練物を約１０℃で１２時間熟成させ、レシチンゲルエマルションとした。室温下、６日間減圧乾燥器で乾燥後、得られたレシチン逆紐状ミセルにミリスチン酸イソプロピル（９．０g）を加え、完全に油中分散させることで、ＡＰＭ含有レシチンオルガノゲルを得た。粘度及び透明性の評価結果を以下の表１に示す。また白濁・沈殿は確認されなかった（図１参照）。 [Example 1: Preparation of APM-containing lecithin organogel]
Water (2.0 mL) was added to APM (20 mg) to completely dissolve it. The obtained aqueous solution and lecithin (1.0 g) were kneaded at room temperature for about 30 minutes, and the obtained kneaded product was aged at about 10 ° C. for 12 hours to obtain a lecithin gel emulsion. After drying in a vacuum drier for 6 days at room temperature, isopropyl myristate (9.0 g) was added to the obtained lecithin inverted string micelles, and the mixture was completely dispersed in oil to obtain an APM-containing lecithin organogel. The evaluation results of viscosity and transparency are shown in Table 1 below. No white turbidity or precipitation was confirmed (see FIG. 1).
［実施例２～６：製造方法の基質一般性の確認］
　以下の表１に示す水溶性有効成分を使用した以外は、実質的に実施例１と同様の方法でレシチンオルガノゲルを作製した。その際、使用した水溶性有効成分、含有量、粘度及び透明性の評価結果を以下の表１に示す。また白濁・沈殿は確認されなかった（図１参照）。 [Examples 2 to 6: Confirmation of substrate generality of production method]
A lecithin organogel was prepared in substantially the same manner as in Example 1 except that the water-soluble active ingredients shown in Table 1 below were used. At that time, the evaluation results of the water-soluble active ingredient used, the content, the viscosity and the transparency are shown in Table 1 below. No white turbidity or precipitation was confirmed (see FIG. 1).
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
［比較例１～４：既存技術によるＡＰＭ含有レシチンオルガノゲルの作製］
　レシチン（１．０g）にミリスチン酸イソプロピル（９．０g）を加え、６０℃で３０分間撹拌し均一な溶液にした後、溶液を室温に戻した。得られた溶液に下記表２に示すＡＰＭ水溶液を２０μLずつ１００μLまで滴下し、ゲル化させることで、それぞれ比較例１～４とした。
　使用した水溶液の濃度、実質投与量、粘度及び透明性の評価結果を下記表２に示す。 [Comparative Examples 1 to 4: Preparation of APM-containing lecithin organogel by existing technology]
Isopropyl myristate (9.0 g) was added to lecithin (1.0 g), and the mixture was stirred at 60 ° C. for 30 minutes to form a uniform solution, and then the solution was returned to room temperature. 20 μL of each of the APM aqueous solutions shown in Table 2 below was added dropwise to 100 μL of the obtained solution and gelled to obtain Comparative Examples 1 to 4, respectively.
Table 2 below shows the evaluation results of the concentration, parenchymal dose, viscosity and transparency of the aqueous solution used.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　既存の方法では、水１００μL滴下時点で、液面が上がりゲル化が確認できた（図２参照）。またＡＰＭ実質投与量３．０mgで白濁が起こり、実質投与量１０mgでは沈殿が確認できた（図３参照）。 With the existing method, when 100 μL of water was dropped, the liquid level rose and gelation was confirmed (see Fig. 2). In addition, cloudiness occurred at a parenchymal dose of APM of 3.0 mg, and precipitation was confirmed at a parenchymal dose of 10 mg (see FIG. 3).
　本発明のレシチンオルガノゲル製造方法は、水溶性有効成分の水溶液とレシチンを均一になるまで混練し、レシチンゲルエマルションとした後、水分を除去することで得られる逆紐状ミセルを油性基剤中に均一に分散させる技術である。従来法とは異なり、一旦レシチンゲルエマルションを経由するため、急激な自己組織化を伴わず、緩和な条件下での製造方法となるため、有効成分を高い含有量で内包させることが可能である。また、水溶性有効成分をアルコール等の有機溶媒に溶解させることなく製造できるため、水溶性有効成分の有機溶媒への溶解性にかかわらず、幅広い水溶性有効成分のレシチンオルガノゲルを提供することが可能である。本発明のレシチンオルガノゲルは、水溶性有効成分を油中に均一分散させ、分散安定性が高く、さらに外観に優れることから、医薬品、医薬部外品、化粧品などとして好適に使用できる。 In the method for producing lecithin organogel of the present invention, an aqueous solution of a water-soluble active ingredient and lecithin are kneaded until they become uniform to form a lecithin gel emulsion, and then a reverse string-shaped micelle obtained by removing water is placed in an oil-based base. It is a technology to disperse evenly. Unlike the conventional method, since it is once passed through the lecithin gel emulsion, it is a production method under mild conditions without abrupt self-assembly, so that the active ingredient can be included in a high content. .. Further, since the water-soluble active ingredient can be produced without being dissolved in an organic solvent such as alcohol, it is possible to provide a wide range of water-soluble active ingredient lecithin organogels regardless of the solubility of the water-soluble active ingredient in the organic solvent. Is. The lecithin organogel of the present invention can be suitably used as a pharmaceutical product, a quasi-drug, a cosmetic product, etc. because the water-soluble active ingredient is uniformly dispersed in oil, the dispersion stability is high, and the appearance is excellent.

Claims (4)

  1. 　水溶性有効成分を内包したレシチンゲルエマルションを作製する工程、レシチンゲルエマルションから水分を除去させながら自己組織化させレシチン逆紐状ミセルとする工程、及びレシチン逆紐状ミセルに油性基材を加えレシチンオルガノゲルとする工程を含む、レシチンオルガノゲルの製造方法。 A step of preparing a lecithin gel emulsion containing a water-soluble active ingredient, a step of self-assembling while removing water from the lecithin gel emulsion to form a lecithin reverse string-shaped micelle, and a step of adding an oil-based base material to the lecithin reverse string-shaped micelle to make lecithin. A method for producing a lecithin organogel, which comprises a step of forming an organogel.
  2. 　レシチンゲルエマルションの作製工程が、レシチンと水溶性有効成分の水溶液とを混練することで実施される、請求項１に記載の製造方法。 The production method according to claim 1, wherein the step of producing the lecithin gel emulsion is carried out by kneading lecithin and an aqueous solution of a water-soluble active ingredient.
  3. 　レシチンゲルエマルションからの水分除去と自己組織化の工程が、自然乾燥または減圧乾燥により実施される、請求項１又は２に記載の製造方法。 The production method according to claim 1 or 2, wherein the steps of removing water from the lecithin gel emulsion and self-assembling are carried out by natural drying or vacuum drying.
  4. 　レシチンゲルエマルションからの水分除去率が８０質量％以上で実施される、請求項１から３のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 3, wherein the water removal rate from the lecithin gel emulsion is 80% by mass or more.
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WO2022071481A1 (en) * 2020-09-30 2022-04-07 日産化学株式会社 WATER-SOLUBLE COMPLEX CONTAINING β BLOCKER AND LECITHIN

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WO2013081120A1 (en) * 2011-11-30 2013-06-06 学校法人日本大学 Lecithin-organogel-forming agent
WO2013176243A1 (en) * 2012-05-25 2013-11-28 学校法人日本大学 Lecithin organogel formation agent

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WO2010122694A1 (en) * 2009-04-23 2010-10-28 学校法人日本大学 Oil gel comprising reverse thread-like micelle
WO2013058080A1 (en) * 2011-10-21 2013-04-25 株式会社ダイセル Oily gel composition
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WO2022071481A1 (en) * 2020-09-30 2022-04-07 日産化学株式会社 WATER-SOLUBLE COMPLEX CONTAINING β BLOCKER AND LECITHIN

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