TW202038925A - Lipid, composition containing the lipid, method of producing the lipid, and method of enhancing thermal-stability of retinol - Google Patents
Lipid, composition containing the lipid, method of producing the lipid, and method of enhancing thermal-stability of retinol Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/07—Retinol compounds, e.g. vitamin A
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- 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
Abstract
Description
本發明是有關於一種內包視黃醇（retinol）的脂質體（liposome）及含有所述脂質體的組成物以及所述脂質體的製造方法等。The present invention relates to a liposome containing retinol, a composition containing the liposome, and a method for producing the liposome.
脂質體是由作為生物膜的主要構成成分的磷脂質等構成的人工膠囊（capsule）。磷脂質為兩親性結構，並形成脂質雙分子層（lipid bilayer）（換句話說，雙分子膜）。在雙分子膜內可吸收進油溶性物質。利用所述性質，對於若干油溶性物質，以提高其穩定性等為目的而進行使所述油溶性物質內包於脂質體中的操作。Liposomes are artificial capsules composed of phospholipids and the like, which are the main components of biological membranes. Phospholipids have an amphiphilic structure and form a lipid bilayer (in other words, a bilayer). Oil-soluble substances can be absorbed into the bimolecular membrane. Using these properties, for some oil-soluble substances, the operation of encapsulating the oil-soluble substances in liposomes is performed for the purpose of improving the stability thereof.
另外，用於製備脂質體的磷脂質可經氫化（即，可為氫化磷脂質）。其中，為了使用氫化磷脂質來製備脂質體，要求經過磷脂質的相轉變溫度以上的加熱攪拌步驟。另一方面，在使用未經氫化的磷脂質來製備脂質體的情況下，即便並不加熱地進行攪拌亦可無問題地製備脂質體，但未進行氫化的磷脂質大多是其結構中具有碳-碳雙鍵的磷脂質（換句話說，構成的脂肪酸為不飽和脂肪酸），因此，磷脂質容易氧化，所製作的脂質體溶液亦容易分離。即，所形成的脂質體的經時穩定性差。In addition, the phospholipids used to prepare liposomes may be hydrogenated (ie, may be hydrogenated phospholipids). Among them, in order to prepare liposomes using hydrogenated phospholipids, it is required to pass through a heating and stirring step above the phase transition temperature of the phospholipids. On the other hand, when liposomes are prepared using non-hydrogenated phospholipids, liposomes can be prepared without any problems even if they are stirred without heating, but most of the non-hydrogenated phospholipids have carbon in their structure. -Phospholipids with carbon double bonds (in other words, the constituent fatty acids are unsaturated fatty acids). Therefore, the phospholipids are easy to oxidize, and the prepared liposome solution is easy to separate. That is, the liposomes formed have poor stability over time.
根據以上情況，通常在為了提高內包物質的穩定性而利用脂質體的情況下，大多是使用氫化磷脂質來製備脂質體。但是，如上所述，在使用氫化磷脂質來製備脂質體的情況下需要加熱操作，因此，在內包物質對熱不穩定的情況下，在製備脂質體的階段中會大量損失。 [現有技術文獻] [專利文獻]Based on the above, when liposomes are generally used to improve the stability of the encapsulated substance, hydrogenated phospholipids are often used to prepare liposomes. However, as described above, in the case of using hydrogenated phospholipids to prepare liposomes, a heating operation is required. Therefore, when the inner encapsulating substance is unstable to heat, a large amount of loss will occur during the preparation of liposomes. [Prior Art Literature] [Patent Literature]
[專利文獻1]日本專利特開2009-256268號公報[Patent Document 1] Japanese Patent Laid-Open No. 2009-256268
[發明所欲解決之課題][The problem to be solved by the invention]
本發明者等人為了提供一種使熱穩定性低的作為油溶性物質的視黃醇穩定且效率良好地內包於使用氫化磷脂質來製備的脂質體中的方法，而反覆進行了研究。 [解決課題之手段]The inventors of the present invention have repeatedly studied in order to provide a method for stably and efficiently encapsulating retinol, which is an oil-soluble substance with low thermal stability, in liposomes prepared using hydrogenated phospholipids. [Means to solve the problem]
本發明者等人發現，藉由使用純度高的氫化磷脂醯膽鹼（hydrogenated phosphatidylcholine）來製備內包視黃醇的脂質體，而有如下可能性、即、即便在製備步驟中進行加熱視黃醇亦不會變得不穩定，並且進一步反覆進行改良，從而完成了本發明。The inventors of the present invention found that by using hydrogenated phosphatidylcholine with high purity to prepare liposomes encapsulating retinol, there is a possibility that even if retinol is heated during the preparation step Alcohol does not become unstable, and further improvements have been made repeatedly, thus completing the present invention.
本發明例如包含以下項中記載的主題。 項1. 一種脂質體，其為內包視黃醇的脂質體，且 包含氫化磷脂醯膽鹼作為膜成分，並且 所述氫化磷脂醯膽鹼為純度70%以上的氫化磷脂醯膽鹼。 項2. 如項1所述的脂質體，其中作為膜成分而包含的磷脂質僅為純度70%以上的氫化磷脂醯膽鹼。 項3. 一種醫藥品組成物、化妝品組成物、食品組成物、或口腔用組成物，含有如項1或項2所述的脂質體。 項4. 一種方法，其為內包視黃醇的脂質體的製造方法，並且包括： 製備包含視黃醇、水、及純度70%以上的氫化磷脂醯膽鹼的脂質體原料液的步驟；以及 對所述原料液進行加熱及攪拌的步驟。 項5. 如項4所述的方法，其中 對所述原料液進行加熱及攪拌的步驟為將所述原料液加熱至40℃以上並且進行攪拌的步驟。 項6. 一種方法，其為提高視黃醇的熱穩定性的方法，並且包括： 至少將視黃醇、水、及純度70%以上的氫化磷脂醯膽鹼混合的步驟。 項7. 一種方法，其為提高視黃醇的熱穩定性的方法，所述視黃醇用於內包於經過加熱及攪拌步驟而製備的脂質體中，並且所述方法包括： 至少將視黃醇、水、及純度70%以上的氫化磷脂醯膽鹼混合而製備脂質體原料液的步驟。 [發明的效果]The present invention includes, for example, the subjects described in the following items. Item 1. A liposome, which is a liposome containing retinol, and Contains hydrogenated phospholipid choline as a membrane component, and The hydrogenated phospholipid choline is hydrogenated phospholipid choline with a purity of more than 70%. Item 2. The liposome according to item 1, wherein the phospholipid contained as a membrane component is only hydrogenated phospholipid choline having a purity of 70% or more. Item 3. A pharmaceutical composition, a cosmetic composition, a food composition, or a composition for oral cavity, which contains the liposome according to Item 1 or Item 2. Item 4. A method, which is a method for manufacturing liposomes encapsulating retinol, and includes: The step of preparing a liposome raw material liquid containing retinol, water, and hydrogenated phospholipid choline with a purity of more than 70%; and The step of heating and stirring the raw material liquid. Item 5. The method according to item 4, wherein The step of heating and stirring the raw material liquid is a step of heating the raw material liquid to 40°C or higher and stirring. Item 6. A method, which is a method for improving the thermal stability of retinol, and includes: At least a step of mixing retinol, water, and hydrogenated phospholipid choline with a purity of 70% or more. Item 7. A method, which is a method for improving the thermal stability of retinol, wherein the retinol is used to be encapsulated in liposomes prepared through heating and stirring steps, and the method includes: A step of mixing at least retinol, water, and hydrogenated phospholipid choline with a purity of 70% or more to prepare a liposome raw material liquid. [Effects of the invention]
本發明可使視黃醇穩定地內包於製備時需要加熱、且包含氫化磷脂質作為膜成分的脂質體中。In the present invention, retinol can be stably contained in liposomes that require heating during preparation and contain hydrogenated phospholipids as a membrane component.
以下，進一步詳細地說明本發明中所包含的各實施形態。本發明較佳地包含：內包視黃醇的特定的脂質體、所述脂質體的製造方法、含有所述脂質體的組成物、及提高視黃醇的熱穩定性的方法等，但並不限定於該些，本發明包含本說明書中所公開且本領域技術人員能夠理解到的全部內容。Hereinafter, each embodiment included in the present invention will be described in further detail. The present invention preferably includes: specific liposomes encapsulating retinol, a method for manufacturing the liposomes, a composition containing the liposomes, and a method for improving the thermal stability of retinol, etc., but not Not limited to these, the present invention includes all the contents disclosed in this specification and understood by those skilled in the art.
本發明中所包含的內包視黃醇的脂質體包含氫化磷脂醯膽鹼作為膜成分。以下，有時將本發明中所包含的所述脂質體稱為「本發明的脂質體」。另外，有時將含有本發明的脂質體的組成物稱為「本發明的脂質體組成物」。The liposome containing retinol contained in the present invention contains hydrogenated phospholipid choline as a membrane component. Hereinafter, the liposome contained in the present invention may be referred to as the "liposome of the present invention". In addition, a composition containing the liposome of the present invention may be referred to as the "liposome composition of the present invention".
本發明的脂質體為內包視黃醇的脂質體，且為包含氫化磷脂醯膽鹼作為膜成分、並且所述氫化磷脂醯膽鹼為純度70%以上的氫化磷脂醯膽鹼的脂質體。The liposome of the present invention is a liposome containing retinol, and contains hydrogenated phospholipid choline as a membrane component, and the hydrogenated phospholipid choline is a hydrogenated phospholipid choline with a purity of 70% or more.
氫化磷脂醯膽鹼較佳純度可為71%以上、72%以上、73%以上、74%以上、75%以上、76%以上、77%以上、78%以上、79%以上、80%以上、81%以上、82%以上、83%以上、84%以上、85%以上、86%以上、87%以上、88%以上、89%以上、90%以上、91%以上、92%以上、93%以上、94%以上、95%以上、96%以上、97%以上、98%以上、或99%以上。再者，氫化磷脂醯膽鹼可購入市售品來使用，市售品大多是規定純度來銷售。例如，市售有純度55%～65%的氫化磷脂醯膽鹼、純度70%的氫化磷脂醯膽鹼、或純度95%的氫化磷脂醯膽鹼等。本發明中使用的氫化磷脂醯膽鹼例如可自利博得考斯麥提庫（Lipoidkosmetik）公司等購入。The preferred purity of hydrogenated phospholipid choline can be 71% or more, 72% or more, 73% or more, 74% or more, 75% or more, 76% or more, 77% or more, 78% or more, 79% or more, 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% Above, above 94%, above 95%, above 96%, above 97%, above 98%, or above 99%. Furthermore, the hydrogenated phospholipid choline can be purchased and used as a commercially available product, and most of the commercially available products are sold at a predetermined purity. For example, hydrogenated phospholipid choline with a purity of 55% to 65%, hydrogenated phospholipid choline with a purity of 70%, or hydrogenated phospholipid choline with a purity of 95% are commercially available. The hydrogenated phospholipid choline used in the present invention can be purchased, for example, from Lipoidkosmetik Company and the like.
再者，純度低（小於100%）的氫化磷脂醯膽鹼中包含與氫化磷脂醯膽鹼不同的磷脂質或氫化磷脂質。換句話說，在本說明書中，純度小於100%的氫化磷脂醯膽鹼是指氫化磷脂醯膽鹼與其他磷脂質和/或氫化磷脂質的混合物。本發明中使用的純度小於100%的氫化磷脂醯膽鹼中所含的其他磷脂質和/或氫化磷脂質並無特別限制，較佳為卵磷脂（lecithin）和/或氫化卵磷脂（例如，大豆卵磷脂、氫化大豆卵磷脂、玉米卵磷脂、氫化玉米卵磷脂、棉籽油卵磷脂、氫化棉籽油卵磷脂、蛋黃卵磷脂、氫化蛋黃卵磷脂、蛋清卵磷脂、氫化蛋清卵磷脂等），其中較佳為大豆卵磷脂和/或氫化大豆卵磷脂。作為本發明中使用的純度小於100%的氫化磷脂醯膽鹼，可較佳地使用卵磷脂中在提高了磷脂醯膽鹼的純度後進行氫化而獲得的氫化卵磷脂，尤其是可更佳地使用大豆卵磷脂中提高了磷脂醯膽鹼含有率（即，提高了純度）、進而進行了氫化而成者。Furthermore, the hydrogenated phospholipid choline with low purity (less than 100%) contains phospholipids or hydrogenated phospholipids that are different from the hydrogenated phospholipid choline. In other words, in this specification, hydrogenated phospholipid choline with a purity of less than 100% refers to a mixture of hydrogenated phospholipid choline and other phospholipids and/or hydrogenated phospholipids. The other phospholipids and/or hydrogenated phospholipids contained in the hydrogenated phospholipid choline with a purity of less than 100% used in the present invention are not particularly limited, and preferably lecithin and/or hydrogenated lecithin (for example, Soy lecithin, hydrogenated soybean lecithin, corn lecithin, hydrogenated corn lecithin, cottonseed oil lecithin, hydrogenated cottonseed oil lecithin, egg yolk lecithin, hydrogenated egg yolk lecithin, egg white lecithin, hydrogenated egg white lecithin, etc.), of which Preferably, it is soybean lecithin and/or hydrogenated soybean lecithin. As the hydrogenated phospholipid choline with a purity of less than 100% used in the present invention, hydrogenated lecithin obtained by hydrogenating the phospholipid choline after increasing the purity of the phospholipid in lecithin can be preferably used, and in particular, it can be more preferably used. Soy lecithin is used to increase the content of phospholipid choline (that is, to increase the purity), and then hydrogenated.
再者，在本發明的脂質體中，膜中所含的磷脂質更佳為僅為純度70%以上的氫化磷脂醯膽鹼。Furthermore, in the liposome of the present invention, the phospholipid contained in the membrane is more preferably only hydrogenated phospholipid choline having a purity of 70% or more.
本發明的脂質體例如可藉由如下方式製備：對至少將視黃醇、水、及純度70%以上的磷脂醯膽鹼混合而獲得的脂質體原料液進行加熱及攪拌。較佳為在所述原料液中調配多元醇。作為多元醇，例如可列舉：丙三醇（glycerine）、1,3-丁二醇、丙二醇、二丙二醇等，特佳為丙二醇。另外，亦可在所述原料液中調配此外的在脂質體領域中所調配的公知的成分。例如，亦可調配甾醇（sterol）或防腐劑等。作為甾醇，例如可較佳地列舉膽固醇（cholesterol）。另外，作為防腐劑，例如可較佳地列舉對羥基苯甲酸甲酯（羥苯甲酯（methylparaben））。The liposome of the present invention can be prepared, for example, by heating and stirring a liposome raw material liquid obtained by mixing at least retinol, water, and phospholipid choline with a purity of 70% or more. Preferably, a polyol is blended in the raw material liquid. Examples of polyols include glycerine, 1,3-butanediol, propylene glycol, and dipropylene glycol, and propylene glycol is particularly preferred. In addition, other well-known ingredients formulated in the liposome field may also be formulated in the raw material liquid. For example, sterol or preservatives can also be formulated. As the sterol, for example, cholesterol (cholesterol) is preferably mentioned. In addition, as the preservative, for example, methyl paraben (methylparaben) can be preferably cited.
脂質體原料液中的各成分的含量若為無損本發明的效果的範圍，則並無特別限制。例如，相對於純度70%以上的氫化磷脂醯膽鹼4質量份，較佳為包含0.01質量份～1質量份左右、更佳為包含0.05質量份～0.5質量份左右、進而佳為包含0.08質量份～0.2質量份左右的視黃醇；較佳為包含5質量份～20質量份左右、更佳為包含8質量份～17質量份左右、進而佳為包含10質量份～15質量份左右的多元醇。另外，在包含甾醇的情況下，相對於純度70%以上的氫化磷脂醯膽鹼4質量份，例如可包含0.5質量份～2質量份左右。另外，例如，相對於純度70%以上的氫化磷脂醯膽鹼4質量份，較佳為包含80質量份以上左右的水。另外，較佳為包含脂質體原料液整體的80質量%以上左右的水。The content of each component in the liposome raw material liquid is not particularly limited as long as it is a range that does not impair the effects of the present invention. For example, with respect to 4 parts by mass of hydrogenated phospholipid choline having a purity of 70% or more, the content is preferably 0.01 parts by mass to 1 part by mass, more preferably 0.05 parts by mass to 0.5 parts by mass, and still more preferably 0.08 parts by mass. Parts to about 0.2 parts by mass of retinol; preferably about 5 parts by mass to about 20 parts by mass, more preferably about 8 parts by mass to about 17 parts by mass, and more preferably about 10 parts by mass to about 15 parts by mass Polyol. In addition, when a sterol is contained, it may contain, for example, about 0.5 to 2 parts by mass relative to 4 parts by mass of hydrogenated phospholipid choline having a purity of 70% or more. In addition, for example, it is preferable to contain about 80 parts by mass or more of water with respect to 4 parts by mass of hydrogenated phospholipid choline having a purity of 70% or more. In addition, it is preferable to contain about 80% by mass or more of water in the entire liposome raw material liquid.
藉由對脂質體原料液進行加熱及攪拌而製備脂質體。較佳為在所述操作中一邊進行加熱一邊進行攪拌。加熱較佳為以脂質體原料液成為40℃以上的方式進行，更佳為以成為41℃以上、42℃以上、43℃以上、44℃以上、45℃以上、46℃以上、47℃以上、48℃以上、49℃以上、50℃以上、51℃以上、52℃以上、53℃以上、54℃以上、55℃以上、56℃以上、57℃以上、58℃以上、59℃以上、60℃以上、61℃以上、62℃以上、63℃以上、64℃以上、65℃以上、66℃以上、67℃以上、68℃以上、69℃以上、70℃以上、71℃以上、72℃以上、73℃以上、74℃以上、或75℃以上的方式進行。作為更具體的加熱及攪拌操作的一例，可列舉如下操作：將脂質體原料液放入燒杯中，在將所述燒杯放入至高溫槽中的狀態下，使用例如均質混合器等對所述燒杯中的原料液進行攪拌。所述情況下，攪拌槽的溫度可以脂質體原料液成為所述溫度以上的方式適宜設定，例如，較佳為50℃以上、55℃以上、60℃以上、65℃以上、70℃以上、75℃以上、或80℃以上左右。The liposome is prepared by heating and stirring the liposome raw material liquid. It is preferable to stir while heating during the operation. The heating is preferably carried out so that the liposome raw material liquid becomes 40°C or higher, more preferably 41°C or higher, 42°C or higher, 43°C or higher, 44°C or higher, 45°C or higher, 46°C or higher, 47°C or higher, Above 48℃, above 49℃, above 50℃, above 51℃, above 52℃, above 53℃, above 54℃, above 55℃, above 56℃, above 57℃, above 58℃, above 59℃, 60℃ Above, above 61℃, above 62℃, above 63℃, above 64℃, above 65℃, above 66℃, above 67℃, above 68℃, above 69℃, above 70℃, above 71℃, above 72℃, Performed at a temperature above 73°C, above 74°C, or above 75°C. As an example of a more specific heating and stirring operation, the following operations can be cited: the liposome raw material liquid is put into a beaker, and the beaker is put into a high-temperature tank, and for example, a homomixer is used to treat the The raw material liquid in the beaker is stirred. In this case, the temperature of the stirring tank can be appropriately set so that the liposome raw material liquid becomes the above-mentioned temperature or higher. For example, it is preferably 50°C or higher, 55°C or higher, 60°C or higher, 65°C or higher, 70°C or higher, 75°C or higher. Above ℃, or above 80℃.
另外，本發明還包含提高視黃醇的熱穩定性的方法。所述方法包括至少將視黃醇、水、及純度70%以上的氫化磷脂醯膽鹼混合的步驟。所述步驟相當於製備所述脂質體原料液的步驟。因此，所述步驟中所混合的成分可較佳為所述脂質體原料液的材料。另外，在所述方法中，亦可直接較佳地應用此外的所述脂質體原料液及脂質體製造方法的內容。In addition, the present invention also includes a method for improving the thermal stability of retinol. The method includes the step of mixing at least retinol, water, and hydrogenated phospholipid choline with a purity of more than 70%. The step is equivalent to the step of preparing the liposome raw material liquid. Therefore, the components mixed in the step may preferably be the material of the liposome raw material liquid. In addition, in the method, the contents of the other liposome raw material liquid and liposome manufacturing method can also be directly applied.
本發明亦包含含有本發明的脂質體的脂質體組成物。所述脂質體組成物較佳為水性組成物。另外，所述組成物可作為例如醫藥品組成物（尤其是外用醫藥品組成物）、化妝品組成物、食品組成物、及口腔用組成物等來使用。該些組成物例如可利用常規方法來製備。The present invention also includes liposome compositions containing the liposomes of the present invention. The liposome composition is preferably an aqueous composition. In addition, the composition can be used as, for example, a pharmaceutical composition (especially an external pharmaceutical composition), a cosmetic composition, a food composition, and an oral composition. These compositions can be prepared by conventional methods, for example.
再者，如上所述，藉由對脂質體原料液進行加熱及攪拌來製備脂質體，此時，可自脂質體原料液獲得脂質體懸浮液。如此獲得的脂質體懸浮液亦可直接作為含有本發明的脂質體的脂質體組成物來使用。另外，亦可在所述脂質體懸浮液中進一步適宜地調配外用醫藥品組成物、口腔用組成物、及化妝品組成物中公知的成分，並作為脂質體組成物來使用。Furthermore, as described above, the liposomes are prepared by heating and stirring the liposome raw material liquid. In this case, the liposome suspension can be obtained from the liposome raw material liquid. The liposome suspension thus obtained can also be directly used as a liposome composition containing the liposome of the present invention. In addition, well-known components in the external pharmaceutical composition, oral composition, and cosmetic composition may be further suitably formulated in the liposome suspension, and used as a liposome composition.
在無損本發明的效果的範圍內，本發明的脂質體及脂質體組成物中亦可含有所述成分以外的成分。例如可列舉：油性成分、脂質、水溶性物質、生理活性物質等。可特別較佳地使用外用醫藥品或化妝品中使用的公知的成分。雖然並無特別限制，例如，可列舉：殺菌劑（尤其是，異丙基甲基苯酚等酚系殺菌劑）；乳酸、檸檬酸等有機酸；氫氧化鉀、氫氧化鈉等鹼性化合物；磷脂醯甘油、磷脂醯乙醇胺等脂質；殼聚糖（chitosan）、褐藻醣膠（fucoidan）、玻尿酸（hyaluronic acid）等天然高分子；聚乙二醇、羧基乙烯基聚合物等合成高分子；海藻糖（trehalose）、乳果糖（lactulose）、麥芽糖醇（maltitol）等醣類；丙三醇等多元醇等。The liposome and liposome composition of the present invention may contain components other than the above-mentioned components within a range that does not impair the effects of the present invention. For example, oily components, lipids, water-soluble substances, physiologically active substances, etc. can be cited. Particularly, well-known ingredients used in external medicines or cosmetics can be preferably used. Although it is not particularly limited, for example, there may be mentioned: fungicides (especially, phenolic fungicides such as isopropyl methylphenol); organic acids such as lactic acid and citric acid; alkaline compounds such as potassium hydroxide and sodium hydroxide; Lipids such as phospholipid glycerol and phospholipid ethanolamine; natural polymers such as chitosan, fucoidan, and hyaluronic acid; synthetic polymers such as polyethylene glycol and carboxyvinyl polymers; seaweed Sugar (trehalose), lactulose (lactulose), maltitol (maltitol) and other sugars; glycerol and other polyols.
再者，在本說明書中，所謂「包含」，亦包含「本質上由……所組成」與「由……所組成」（The term "comprising" includes "consisting essentially of" and "consisting of."）。另外，本發明包含所有的本說明書中所說明的構成要件的任意組合。Furthermore, in this specification, the term "comprising" also includes "consisting essentially of" and "consisting of" (The term "comprising" includes "consisting essentially of" and "consisting of." ). In addition, the present invention includes any combination of all the constituent elements described in this specification.
另外，針對所述本發明的各實施形態而說明的各種特性（性質、結構、功能等）在特別指定本發明中所包含的主題時，可任意組合。即，本發明中包括所有的由本說明書中所記載的能夠組合的各特性的所有組合所組成的主題。 [實施例]In addition, the various characteristics (property, structure, function, etc.) described for each embodiment of the present invention can be combined arbitrarily when specifying the subjects included in the present invention. That is, the present invention includes all themes composed of all combinations of the various features described in this specification that can be combined. [Example]
以下，更具體地對本發明進行說明，但本發明並不限定於下述例子。Hereinafter, the present invention will be described more specifically, but the present invention is not limited to the following examples.
按照表1所示的組成來製備脂質體原料液，並對其進行加熱及攪拌，製備實施例1、實施例2、及比較例1的脂質體。表1的各成分的值表示質量%。表1中，PG表示丙二醇，PC表示磷脂醯膽鹼。另外，90H表示作為市售的氫化磷脂醯膽鹼的豪斯佛裡朋（Phospholipon）90H（利博得考斯麥提庫（Lipoidkosmetik）公司），80H表示作為市售的氫化磷脂醯膽鹼的豪斯佛裡朋（Phospholipon）80H（利博得考斯麥提庫（Lipoidkosmetik）公司），S-10M表示作為市售的氫化磷脂醯膽鹼的萊西諾魯（Lecinol）S-10M（日光化學股份有限公司）。90H為純度95%以上的氫化磷脂醯膽鹼，80H為純度70%以上的氫化磷脂醯膽鹼，S-10M為純度55%～65%的氫化磷脂醯膽鹼。The liposome raw material liquid was prepared according to the composition shown in Table 1, and heated and stirred to prepare liposomes of Example 1, Example 2, and Comparative Example 1. The value of each component in Table 1 represents mass %. In Table 1, PG represents propylene glycol, and PC represents phospholipid choline. In addition, 90H means Phospholipon 90H (Lipoidkosmetik) which is a commercially available hydrogenated phospholipid choline, and 80H means Phospholipon which is a commercially available hydrogenated phospholipid choline. Phospholipon 80H (Lipoidkosmetik), S-10M means Lecinol S-10M (Nikko Chemical Co., Ltd.) as a commercially available hydrogenated phospholipid choline Limited). 90H is hydrogenated phospholipid choline with a purity of more than 95%, 80H is hydrogenated phospholipid choline with a purity of more than 70%, and S-10M is hydrogenated phospholipid choline with a purity of 55% to 65%.
更詳細而言，按照表1記載的組成，向設置於80℃的恒溫槽中的燒杯中添加丙二醇、氫化磷脂醯膽鹼、視黃醇、膽固醇、及羥苯甲酯，並加以溶解（80℃加熱），向其中添加加熱至80℃的水，並利用80℃的恒溫槽加熱1小時，同時以5000 rpm進行攪拌，製備各實施例及比較例的脂質體懸浮液。再者，所述攪拌處理是使用均質混合器（均質混合器馬克II（Homomixer MARK II）：普裡密庫斯（PRIMIX）公司）進行。In more detail, according to the composition described in Table 1, propylene glycol, hydrogenated phospholipid choline, retinol, cholesterol, and methyl paraben were added to a beaker set in a thermostat at 80°C, and dissolved (80 Heating at ℃), water heated to 80°C was added thereto, and the mixture was heated in a thermostat at 80°C for 1 hour while stirring at 5000 rpm to prepare liposome suspensions of the Examples and Comparative Examples. Furthermore, the stirring process is performed using a homomixer (Homomixer MARK II: PRIMIX).
[表1]
對於所獲得的各脂質體，測定所含的視黃醇量。視黃醇的定量是利用高效液相色譜法（high performance liquid chromatography）（沃特世阿萊恩斯（WATERS Alliance）HPLC系統）進行。（管柱：聖賽爾（SunShell）C18 2.1×100 mm（2.6 μm）；管柱溫度：40℃；移動相：0.1%乙酸甲醇溶液：0.1%乙酸水溶液=90：10；流速：0.3 mL/min；注入量10 μL；檢測器：325 nm）。視黃醇標準液是最初稱量視黃醇0.01 g，並定容為甲醇100 mL（100 ppm）來製備。其後，將其稀釋為10 ppm、5 ppm、1 ppm，並將所述3點作為校準曲線。對於脂質體，採取10 μL加溫後的脂質體溶液，添加異丙醇（isopropyl alcohol，IPA）990 μL並加以溶解，製成測定樣品。For each liposome obtained, the amount of retinol contained was measured. The quantification of retinol is carried out using high performance liquid chromatography (Waters Alliance HPLC system). (Column: SunShell (SunShell) C18 2.1×100 mm (2.6 μm); column temperature: 40℃; mobile phase: 0.1% acetic acid methanol solution: 0.1% acetic acid aqueous solution = 90: 10; flow rate: 0.3 mL/ min; injection volume 10 μL; detector: 325 nm). The retinol standard solution is prepared by initially weighing 0.01 g of retinol and distilling it to 100 mL (100 ppm) of methanol. Thereafter, it was diluted to 10 ppm, 5 ppm, and 1 ppm, and the 3 points were used as a calibration curve. For liposomes, take 10 μL of warmed liposome solution, add 990 μL of isopropyl alcohol (IPA) and dissolve it to prepare a measurement sample.
將各脂質體的視黃醇含量測定結果作為將各脂質體製備時使用的視黃醇量設為100%時的相對值示於圖1中。得知，在使用純度70%以上的氫化磷脂醯膽鹼的情況下，視黃醇殘存量超過75%，視黃醇的熱穩定性提高；以及使用的氫化磷脂醯膽鹼的純度越高，視黃醇的熱穩定性越提高。The measurement result of the retinol content of each liposome is shown in FIG. 1 as a relative value when the amount of retinol used in the preparation of each liposome is set to 100%. It is known that when hydrogenated phospholipid choline with a purity of more than 70% is used, the residual amount of retinol exceeds 75%, and the thermal stability of retinol is improved; and the higher the purity of the hydrogenated phospholipid choline used The thermal stability of retinol is improved.
無no
圖1是將各脂質體的視黃醇含量測定結果作為將各脂質體製備中使用的視黃醇量設為100%時的相對值來表示。Fig. 1 shows the measurement result of the retinol content of each liposome as a relative value when the amount of retinol used in the preparation of each liposome is set to 100%.
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