[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2020253709A1 - 一种脂溶性营养药透明水分散液的制备方法 - Google Patents

一种脂溶性营养药透明水分散液的制备方法 Download PDF

Info

Publication number
WO2020253709A1
WO2020253709A1 PCT/CN2020/096515 CN2020096515W WO2020253709A1 WO 2020253709 A1 WO2020253709 A1 WO 2020253709A1 CN 2020096515 W CN2020096515 W CN 2020096515W WO 2020253709 A1 WO2020253709 A1 WO 2020253709A1
Authority
WO
WIPO (PCT)
Prior art keywords
fat
vitamin
preparation
emulsifier
soluble
Prior art date
Application number
PCT/CN2020/096515
Other languages
English (en)
French (fr)
Inventor
乐园
钟杰
Original Assignee
宁波海奇合昇环能科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 宁波海奇合昇环能科技有限公司 filed Critical 宁波海奇合昇环能科技有限公司
Publication of WO2020253709A1 publication Critical patent/WO2020253709A1/zh

Links

Images

Classifications

    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals

Definitions

  • the invention relates to the field of biotechnology. More specifically, it relates to a method for preparing a transparent water dispersion of a fat-soluble nutritional medicine.
  • Fat-soluble nutritional medicine is an indispensable element to promote growth and development, maintain and promote immune function, and protect the heart and brain blood vessels. It has high biomedical value. However, due to its poor water solubility, it is difficult to achieve the required bioavailability after oral administration, or it is difficult to prepare a preparation for intravenous administration, which greatly limits its application. In order to improve the solubility and bioavailability of such drugs, various dosage forms such as solid dispersions, clathrates, and nanoemulsions have been researched and developed, but they all have problems such as low drug content, complex preparation processes and poor stability.
  • oil-in-water nanoemulsions with a particle size distribution between 1-100nm can increase the solubility of poorly soluble drugs, improve the stability and bioavailability of the drugs, and at the same time, due to their special structural composition, they can avoid the first Due to its over-effect, it has received more and more attention in improving drug bioavailability, increasing drug stability and efficacy.
  • solvent oils such as medium-chain fatty acid glycerides/soybean oil/olive oil/corn oil as the oil phase.
  • solvent oils have low solubility for some nutritional drugs, which limits the content of nutritional drugs in the nanoemulsion; second, the solvent oil increases the intake of fat after entering the body, which is not good for human health.
  • the object of the present invention is to provide a method for preparing a transparent water dispersion of a fat-soluble nutrient.
  • the particle size of the fat-soluble nutrient is less than 100 nm, which not only solves the problem of poor water solubility and low bioavailability of fat-soluble nutrient drugs such as vitamin A, vitamin D3, vitamin E and vitamin K, but also
  • the preparation process is simple, can be produced continuously, has no amplification effect, and is easy to industrialize.
  • the present invention adopts the following technical solutions:
  • a method for preparing a transparent water dispersion of a fat-soluble nutritional medicine includes the following steps:
  • the fat-soluble nutritional medicine is selected from one or more of vitamin A, vitamin D3, vitamin E and vitamin K.
  • the aforementioned vitamin K includes vitamins K1 and K2.
  • the heating and melting temperature is 0-10°C higher than the melting point of the fat-soluble nutrient.
  • the emulsifier is selected from Tween 20, Tween 80, Span 80, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, poloxamer, fatty acid monoglyceride, soybean phospholipid, egg yolk One or more of lecithin.
  • the aforementioned emulsifier has a strong compounding ability with the oil-phase fat-soluble nutritional drug, which helps to control the particle size and stability of the fat-soluble nutritional drug emulsion in the prepared dispersion.
  • the mixture also includes a co-emulsifier, the co-emulsifier is selected from one or more of absolute ethanol, 1,2-propylene glycol, glycerol, n-butanol, polyethylene glycol 400 Kind.
  • the weight ratio of the emulsifier to the co-emulsifier is 1:5-5:1. Further optionally, the weight ratio of the emulsifier to the co-emulsifier is 1:4-4:1, 1:3-3:1, 1:2-2:1, 1:1, etc.
  • the weight ratio of emulsifier to co-emulsifier also affects the stability and particle size of the resulting aqueous dispersion.
  • the stability of the aqueous dispersion is better, and the particle size can be controlled between 20-60nm, and the smaller the aforementioned ratio range, the better the stability, that is, 1:2-2
  • the stability in the range of :1 is better than the overall stability in the range of 1:5-5:1.
  • the weight ratio of the fat-soluble nutritional medicine to the emulsifier is 1:10-1:0.5, preferably 1:5-1:1.
  • the weight ratio of the two within this range can minimize toxic and side effects while ensuring the stability of the transparent water dispersion of the fat-soluble nutritional medicine.
  • the temperature at which the molten mixture is mixed with water is 20-100°C.
  • the mixing and stirring are performed in a supergravity rotating bed, a microchannel reactor, a stirred reactor or an ultrasonic generator.
  • the mass ratio of the molten mixture and the water is 1:10-1:200.
  • the feed volume ratio of the molten mixture to water is 1:10-1:200, preferably 1:20- 1:80.
  • the rotation speed of the high gravity rotating bed is 500-2800 r/min, preferably 1500-2500 r/min.
  • the stirring rate of the stirred reactor is 100-2000 r/m, preferably 500-1000 r/m.
  • the ultrasonic generator power is 600w-2400w, preferably 900w-1800w.
  • Any range recorded in the present invention includes an end value and any value between the end values, and any sub-range formed by the end value or any value between the end values.
  • the raw materials in the present invention can be purchased commercially, and the equipment used in the present invention can be made with conventional equipment in the field or with reference to the prior art in the field.
  • the preparation method of the fat-soluble nutritional medicine transparent water dispersion improves the problem of poor water solubility of the fat-soluble nutritional medicine, increases the content of the fat-soluble nutritional medicine in the water dispersion, and makes the fat-soluble nutritional medicine emulsion in the water dispersion
  • the particle size is less than 100nm, and at the same time, the bioavailability and stability of the fat-soluble nutritional medicine are improved; further, in the preparation method, the relationship between the addition amount of each component is limited, so as to better improve the fat-soluble
  • the stability of the nutritional medicine, and the particle size of the emulsion is controlled between 20-60nm.
  • the method is simple, easy to implement, low energy consumption, high efficiency, low cost, and is very easy to scale up, achieving the goal of industrial production.
  • FIG. 1 shows the electron microscope and particle size distribution diagram of the aqueous dispersion prepared in Example 1.
  • Example 2 shows the electron microscope and particle size distribution diagram of the aqueous dispersion prepared in Example 3.
  • Fig. 3 shows the change in particle size of the aqueous dispersion prepared in Example 5 after being placed at room temperature, 4°C ⁇ 2°C, and 40°C ⁇ 2°C for 14 days.
  • Example 4 shows the particle size distribution diagram of the aqueous dispersion prepared in Example 7.
  • Figure 5 shows the morphology of the aqueous dispersions prepared in Examples 1, 3, 5, 7 and Comparative Example 1 after being left at room temperature for 14 days.
  • the aqueous dispersion prepared in this example has a clear and transparent appearance, with an average particle size of 50 nm.
  • the aqueous dispersion prepared in this example has a clear and transparent appearance, with an average particle size of 55 nm.
  • the stability test was carried out according to the method of Example 1.
  • the aqueous dispersion prepared in this example was clear and transparent after being placed at room temperature, 4°C ⁇ 2°C, and 40°C ⁇ 2°C for 40 days.
  • the aqueous dispersion prepared in this example has a clear and transparent appearance, with an average particle size of 55 nm.
  • Example 1 The stability test was carried out according to the method of Example 1.
  • the aqueous dispersion prepared in this example was clear and transparent after being placed at room temperature, 4°C ⁇ 2°C, and 40°C ⁇ 2°C for 40 days.
  • the morphology after being placed at room temperature for 14 days is shown in Figure 5: the background can be clearly seen.
  • the aqueous dispersion prepared in this example has a clear and transparent appearance, with an average particle size of 30-40 nm.
  • the stability test was carried out according to the method of Example 1.
  • the aqueous dispersion prepared in this example is clear and transparent after being placed at room temperature, 4°C ⁇ 2°C, and 40°C ⁇ 2°C for 35 days.
  • the aqueous dispersion prepared in this example has a clear and transparent appearance, with an average particle size of 20 nm.
  • the stability test was carried out according to the method of Example 1.
  • the aqueous dispersion prepared in this example was placed at room temperature, 4°C ⁇ 2°C, 40°C ⁇ 2°C for 40 days, the appearance was clear and transparent, and the particle size remained basically unchanged .
  • the particle size changes of the aqueous dispersion after being placed at room temperature, 4°C ⁇ 2°C, and 40°C ⁇ 2°C for 14 days are shown in Figure 3, where the three curves are close to overlap.
  • Its morphology after being placed at room temperature for 14 days is shown in Figure 5: the background can be clearly seen, that is, the appearance of the aqueous dispersion remains clear and transparent.
  • the aqueous dispersion prepared in this example has a clear and transparent appearance, with an average particle size of 25 nm.
  • the stability test was carried out according to the method of Example 1.
  • the aqueous dispersion prepared in this example is clear and transparent after being placed at room temperature, 4°C ⁇ 2°C, and 40°C ⁇ 2°C for 35 days.
  • the aqueous dispersion has a concentration of 7.5 mg/ml.
  • the aqueous dispersion has a clear and transparent appearance with a particle size of about 20 nm.
  • the electron microscope and particle size distribution are shown in Figure 3.
  • Example 1 The stability test was carried out according to the method of Example 1.
  • the aqueous dispersion prepared in this example was clear and transparent after being placed at room temperature, 4°C ⁇ 2°C, and 40°C ⁇ 2°C for 40 days.
  • the morphology after being placed at room temperature for 14 days is shown in Figure 5: the background can be clearly seen.
  • Example 2 was repeated, except that the amount of vitamin A acetate was changed to 5 g, and the other conditions were unchanged, and the prepared aqueous dispersion had a concentration of 5 mg/ml.
  • the nanoemulsion prepared in this example has a clear and transparent appearance, with an average particle size of 52 nm.
  • the stability test was carried out according to the method of Example 1.
  • the aqueous dispersion prepared in this example is clear and transparent after being placed at room temperature, 4°C ⁇ 2°C, and 40°C ⁇ 2°C for 35 days.
  • Example 2 was repeated, except that the mixed oil phase and water were mixed under high-speed shearing conditions of 20000 rpm for 10 minutes to obtain an aqueous dispersion.
  • the nanoemulsion prepared in this comparative example has a turbid appearance and an average particle size of 165 nm.
  • the morphology after being left at room temperature for 14 days is shown in Figure 5, and it can be seen that the solution is cloudy.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Dispersion Chemistry (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Nutrition Science (AREA)
  • Biochemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

一种脂溶性营养药透明水分散液的制备方法，包括如下步骤：将包括脂溶性营养药和乳化剂的混合物加热熔化，得熔融态的混合物；将得到的熔融态的混合物与水混合，经搅拌均匀后，得所述脂溶性营养药透明水分散液；其中，所述脂溶性营养药选自维生素A、维生素D3、维生素E和维生素K中的一种或几种。该方法制备得到的水分散液中，脂溶性营养药的粒径小于100nm，不仅解决了脂溶性营养药水溶性差、生物利用度低的问题，且制备工艺简单，可连续化生产，无放大效应，易于工业化。

Description

一种脂溶性营养药透明水分散液的制备方法 技术领域
本发明涉及生物技术领域。更具体地，涉及一种脂溶性营养药透明水分散液的制备方法。
背景技术
脂溶性营养药是促进生长发育、维持和促进免疫功能、保护心脑血管不可缺少的元素，具有很高的生物医学价值。但由于其水溶性差，难以在口服后达到所要求的生物利用度，或难以制成供静脉给药的制剂，从而大大限制了应用。为了提高此类药物的溶解度和生物利用度，已经研究开发了固体分散体、包合物、纳米乳剂等多种剂型，但均存在药物含量低、制备工艺复杂及稳定性较差等问题。
研究表明，粒径分布于1-100nm之间的水包油型纳米乳可以增加难溶性药物的溶解度，提高药物的稳定性和生物利用度，同时因其特殊的结构组成，可以避免药物的首过效应，使得它在提高药物生物利用度，增加药物稳定性和药效方面受到越来越多的关注。目前公开的关于纳米乳液的专利多采用将营养药溶解在中链脂肪酸甘油酯/大豆油/橄榄油/玉米油等溶剂油中作为油相。但常用溶剂油脂一是对部分营养药溶解度较低，限制了纳米乳液中营养药的含量；二是溶剂油进入体内后增加了摄入脂肪量，不利于人体健康。
发明内容
本发明的目的在于提供一种脂溶性营养药透明水分散液的制备方法。该方法制备得到的水分散液中，脂溶性营养药的粒径小于100nm，不仅解决了维生素A、维生素D3、维生素E和维生素K等脂溶性营养药水溶性差、生物利用度低的问题，且制备工艺简单，可连续化生产，无放大效应，易于工业化。
为达到上述目的，本发明采用下述技术方案：
一种脂溶性营养药透明水分散液的制备方法，包括如下步骤：
将包括脂溶性营养药和乳化剂的混合物加热熔化，得熔融态的混合物；
将得到的熔融态的混合物与水混合，经搅拌均匀后，得所述脂溶性营养药透明水分散液；
其中，所述脂溶性营养药选自维生素A、维生素D3、维生素E和维生素K中的一种或几种。
进一步地，上述维生素K包括维生素K1、K2。
可选地，所述加热融化的温度高于所述脂溶性营养药熔点的0-10℃。
可选地，所述乳化剂选自吐温20、吐温80、司盘80、聚氧乙烯氢化蓖麻油、蓖麻油聚氧乙烯醚、泊洛沙姆、脂肪酸单甘油脂、大豆磷脂、蛋黄卵磷脂中的一种或多种。前述乳化剂与油相脂溶性营养药配合能力强，有助于控制制备得到的分散液中脂溶性营养 药乳液的粒径及稳定性。
可选地，所述混合物中还包括助乳化剂，所述助乳化剂选自无水乙醇、1,2-丙二醇、丙三醇、正丁醇、聚乙二醇400中的一种或多种。
可选地，所述乳化剂与助乳化剂的重量比为1:5-5:1。进一步可选的，所述乳化剂与助乳化剂的重量比为1:4-4:1、为1:3-3:1、1:2-2:1、1:1等。乳化剂与助乳化剂的重量比也影响得到的水分散液的稳定性及粒径。两者的比例在前述限定的范围内时水分散液的稳定性更好，且能控制粒径在20-60nm之间，且前述比例范围越小稳定性越好，也即1:2-2:1范围内的稳定性优于1:5-5:1范围内的整体稳定性。
可选地，所述脂溶性营养药与乳化剂的重量比为1:10-1:0.5，优选为1:5-1:1。限定在该范围内的两者的重量比能够在最大程度上减少毒副伤害的同时保证脂溶性营养药透明水分散液的稳定性。
可选地，所述熔融态的混合物与水混合的温度为20-100℃。
可选地，所述混合和搅拌均在超重力旋转床、微通道反应器、搅拌式反应器或超声波发生器中进行。采用在超重力旋转床、微通道反应器、搅拌式反应器或超声波发生器中混合，一方面能够实现获得粒度小且均一的纳米乳液，另一方面采用该混合手段有助于提高所得透明水分散液的稳定性。
可选地，所述熔融态的混合物与水混合的质量比为1:10-1:200。
可选地，当所述混合在超重力旋转床或微通道反应器中进行时，所述熔融态的混合物与水的进料体积比为1:10-1:200，优选为1:20-1:80。
可选地，所述超重力旋转床的转速为500-2800r/min，优选为1500-2500r/min。
可选地，当所述混合在搅拌式反应器中进行时，搅拌式反应器搅拌速率为100-2000r/m，优选500-1000r/m。
可选地，当所述混合在超声波发生器中进行时，超声波发生器功率600w-2400w，优选900w-1800w。
本发明所记载的任何范围包括端值以及端值之间的任何数值以及端值或者端值之间的任意数值所构成的任意子范围。
如无特殊说明，本发明中的各原料均可通过市售购买获得，本发明中所用的设备可采用所属领域中的常规设备或参照所属领域的现有技术进行。
本发明的有益效果如下：
本发明提供的脂溶性营养药透明水分散液的制备方法改善了脂溶性营养药水溶性差的问题，提高了水分散液中脂溶性营养药的含量、使得该水分散液中脂溶性营养药乳液粒径小于100nm，同时提高了脂溶性营养药的生物利用度和稳定性；进一步地，该制备方法中，通过对各组分间的添加量关系的限定，从而更好的改善了该脂溶性营养药的稳定性，且将该乳液粒径控制在20-60nm之间。此外，该方法简单，易于实现，能耗少，效率高，成本低，而且非常容易放大，达到工业化生产的发明目标。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细的说明。
图1示出实施例1制备得到的水分散液的电镜及粒径分布图。
图2示出实施例3制备得到的水分散液的电镜及粒径分布图。
图3示出实施例5制备得到的水分散液在室温、4℃±2℃、40℃±2℃条件下放置14天后的粒径变化情况。
图4示出实施例7制备得到的水分散液的粒径分布图。
图5示出实施例1、3、5、7以及对比例1制备得到的水分散液在室温放置14天后的形态。
具体实施方式
为了更清楚地说明本发明，下面结合优选实施例和附图对本发明做进一步的说明。附图中相似的部件以相同的附图标记进行表示。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
实施例1
称取6.9g维生素A醋酸酯，31g聚氧乙烯氢化蓖麻油，20g丙三醇加热至50℃熔融并涡旋振荡混合均匀，得到混合溶液。超重力旋转床转速为2000rpm，混合油相以6ml/min、提前预热的纯化水以420ml/min进料，控制体系温度为50℃，待混合溶液进料完毕后，关闭超重力旋转床，即得到维生素A醋酸酯水分散液，浓度为15mg/ml。其电镜及粒径分布图如图1所示。
本实施例制得的水分散液外观澄清透明，平均粒径为50nm。
稳定性测试方法：
取上述制备得到的水分散液样品置于棕色螺口瓶内，在室温、4℃±2℃、40℃±2℃条件下放置一个月，于7天、14天、30天、35天以及40天取样，用马尔文激光粒度仪测试水分散液粒径；用紫外可见光分光光度计测试水分散液透射率；用高效液相色谱测试水分散液药物含量。每个样品测试三次。
在室温、4℃±2℃、40℃±2℃条件下放置40天后，维生素A醋酸酯水分散液粒径、药物含量和透射率均无明显变化，稳定性较高，其在室温下放置14天后的形态如图5所示：溶液依旧澄清，能够清楚的看到背景上的字迹。
实施例2
称取0.3g维生素A醋酸酯，1.4g吐温80，0.7g PEG 400加热至50℃熔融并涡旋振荡混合均匀，得到混合溶液。在磁力搅拌条件下，控制水浴温度为40℃，将混合油相加入100g水中，搅拌10min，即得到维生素A醋酸酯水分散液，浓度为3mg/ml。
本实施例制得的水分散液外观澄清透明，平均粒径为55nm。
按实施例1的方法进行稳定性测试，本实施例制得的水分散液在室温、4℃±2℃、40℃±2℃条件下放置40天后外观澄清透明。
实施例3
称取6.6g维生素D3，24g吐温80，8g PEG 400加热至85℃熔融并涡旋振荡混合均匀，得到混合溶液。超重力旋转床转速为1500rpm，混合油相以5ml/min、提前预热的纯化水以300ml/min进料，控制体系温度为30℃，待混合溶液进料完毕后，关闭超重力旋转床，即得到维生素D3水分散液，浓度为6.67mg/ml，其电镜及粒径分布图如图2所示。
本实施例制得的水分散液外观澄清透明，平均粒径为55nm。
按实施例1的方法进行稳定性测试，本实施例制得的水分散液在室温、4℃±2℃、40℃±2℃条件下放置40天后外观澄清透明。其在室温下放置14天后的形态如图5所示：能够清楚的看到其后的背景。
实施例4
称取2.86g维生素D3，8.8g聚氧乙烯氢化蓖麻油，2.2g PEG 400加热至85℃熔融并涡旋振荡混合均匀，得到混合溶液。混合油相以5ml/min、提前预热的纯化水以200ml/min进料速度通入微通道反应器，控制体系温度为60℃，待混合溶液进料完毕后，即得到维生素D3水分散液，浓度为2.86mg/ml。
本实施例制得的水分散液外观澄清透明，平均粒径为30-40nm。
按实施例1的方法进行稳定性测试，本实施例制得的水分散液在室温、4℃±2℃、40℃±2℃条件下放置35天后外观澄清透明。
实施例5
称取0.2g维生素K，10.9g聚氧乙烯氢化蓖麻油，0.4g丙三醇加热至50℃熔融并涡旋振荡混合均匀，得到混合溶液。在55℃水浴下将混合溶液加入到60g纯化水中，以800rpm的转速磁力搅拌10min，即得到维生素K1水分散液，浓度为3.33mg/ml。
本实施例制得的水分散液外观澄清透明，平均粒径为20nm。
按实施例1的方法进行稳定性测试，本实施例制得的水分散液在室温、4℃±2℃、40℃±2℃条件下放置40天后外观澄清透明，且粒径基本维持不变。该水分散液在室温、4℃±2℃、40℃±2℃条件下放置14天后的粒径变化如图3所示，其中三条曲线接近重合。其在室温下放置14天后的形态如图5所示：能够清楚的看到其后的背景，也即，水分散液外观保持澄清透明。
实施例6
称取12g维生素K1，72g吐温80，18g 1,2-丙二醇加热至50℃熔融并涡旋振荡混合均匀，得到混合溶液。超重力旋转床转速为1800rpm，混合油相以5ml/min、提前预热的纯化水以350ml/min进料，控制体系温度为45℃，待混合溶液进料完毕后，关闭超重力旋转床，即得到维生素K1水分散液，浓度为12mg/ml。
本实施例制得的水分散液外观澄清透明，平均粒径为25nm。
按实施例1的方法进行稳定性测试，本实施例制得的水分散液在室温、4℃±2℃、40℃±2℃条件下放置35天后外观澄清透明。
实施例7
称取7.5g维生素E，30g吐温80，10g 1,2-丙二醇加热至40℃熔融并涡旋振荡混合均匀，得到混合溶液。超重力旋转床转速为2000rpm，混合油相以5ml/min、纯化水以350ml/min进料，控制体系温度为25℃，待混合溶液进料完毕后，关闭超重力旋转床，即得到维生素E水分散液，浓度为7.5mg/ml，该水分散液外观澄清透明，粒径20nm左右，其电镜及粒径分布图如图3所示。
按实施例1的方法进行稳定性测试，本实施例制得的水分散液在室温、4℃±2℃、40℃±2℃条件下放置40天后外观澄清透明。其在室温下放置14天后的形态如图5所示：能够清楚的看到其后的背景。
实施例8
重复实施例2，区别在于，将维生素A醋酸酯的量改为5g，其余条件不变，制备得到水分散液浓度为5mg/ml。本实施例制得的纳米乳液外观澄清透明，平均粒径为52nm。
按实施例1的方法进行稳定性测试，本实施例制得的水分散液在室温、4℃±2℃、40℃±2℃条件下放置35天后外观澄清透明。
对比例1
重复实施例2，区别在于，将混合油相与水在20000rpm高速剪切条件下混合10分钟，得到水分散液。本对比例制得的纳米乳液外观浑浊，平均粒径为165nm。其在室温下放置14天后的形态如图5所示，可知溶液浑浊。
显然，本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定，对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动，这里无法对所有的实施方式予以穷举，凡是属于本发明的技术方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之列。

Claims (10)

  1. 一种脂溶性营养药透明水分散液的制备方法，其特征在于，包括如下步骤：
    将包括脂溶性营养药和乳化剂的混合物加热熔化，得熔融态的混合物；
    将得到的熔融态的混合物与水混合，经搅拌均匀后，得所述脂溶性营养药透明水分散液；
    其中，所述脂溶性营养药选自维生素A、维生素D3、维生素E和维生素K中的一种或几种。
  2. 根据权利要求1所述的制备方法，其特征在于，所述加热融化的温度高于所述脂溶性营养药熔点的0-10℃。
  3. 根据权利要求1所述的制备方法，其特征在于，所述乳化剂选自吐温20、吐温80、司盘80、聚氧乙烯氢化蓖麻油、蓖麻油聚氧乙烯醚、泊洛沙姆、脂肪酸单甘油脂、大豆磷脂、蛋黄卵磷脂中的一种或多种。
  4. 根据权利要求1所述的制备方法，其特征在于，所述混合物中还包括助乳化剂，所述助乳化剂选自无水乙醇、1,2-丙二醇、丙三醇、正丁醇、聚乙二醇400中的一种或多种。
  5. 根据权利要求4所述的制备方法，其特征在于，所述乳化剂与助乳化剂的重量比为1:5-5:1，优选为1:4-4:1，更优选为1:3-3:1。
  6. 根据权利要求1所述的制备方法，其特征在于，所述脂溶性营养药与乳化剂的重量比为1:10-1:0.5，优选为1:5-1:1。
  7. 根据权利要求1所述的制备方法，其特征在于，所述熔融态的混合物与水混合的温度为20-100℃。
  8. 根据权利要求1所述的制备方法，其特征在于，所述混合和搅拌均在超重力旋转床、微通道反应器、搅拌式反应器或超声波发生器中进行。
  9. 根据权利要求1所述的制备方法，其特征在于，所述熔融态的混合物与水混合的质量比为1:10-1:200。
  10. 根据权利要求8所述的制备方法，其特征在于，当所述混合在超重力旋转床或微通道反应器中进行时，所述熔融态的混合物与水的进料体积比为1:10-1:200；优选地，所述超重力旋转床的转速为500-2800r/min，更优选为1500-2500r/min。
PCT/CN2020/096515 2019-06-17 2020-06-17 一种脂溶性营养药透明水分散液的制备方法 WO2020253709A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910523056.8 2019-06-17
CN201910523056.8A CN110237034A (zh) 2019-06-17 2019-06-17 一种脂溶性营养药透明水分散液的制备方法

Publications (1)

Publication Number Publication Date
WO2020253709A1 true WO2020253709A1 (zh) 2020-12-24

Family

ID=67887439

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/096515 WO2020253709A1 (zh) 2019-06-17 2020-06-17 一种脂溶性营养药透明水分散液的制备方法

Country Status (2)

Country Link
CN (1) CN110237034A (zh)
WO (1) WO2020253709A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110237034A (zh) * 2019-06-17 2019-09-17 宁波海奇合昇环能科技有限公司 一种脂溶性营养药透明水分散液的制备方法

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1546016A (zh) * 2003-12-04 2004-11-17 东南大学 天然维生素e纳米制剂及其制备方法
CN1720900A (zh) * 2004-07-14 2006-01-18 无锡杰西医药科技有限公司 一种适用于难溶性药物的药用乳剂及其制备方法
WO2011153513A2 (en) * 2010-06-03 2011-12-08 Latitude Pharma Nanoemulsion composition containing vitamin k
CN102389378A (zh) * 2011-11-23 2012-03-28 天津郁美净集团有限公司 一种用于化妆品的复合油脂微乳液及其制备方法
CN103053906A (zh) * 2013-01-20 2013-04-24 湖南奇异生物科技有限公司 猕猴桃籽油口服乳液的制备方法
CN103520102A (zh) * 2013-10-14 2014-01-22 陕西科技大学 一种维生素d纳米乳及其制备方法
CN104366508A (zh) * 2014-11-13 2015-02-25 天津禹王生物医药科技有限公司 一种叶黄素酯或叶黄素乳液及制备方法
CN106491520A (zh) * 2015-09-08 2017-03-15 黄慧健 一种辅酶q10注射液制剂及其制备方法
CN107744537A (zh) * 2017-09-15 2018-03-02 成都泠汐尚品科技有限公司 一种复方奥利司他纳米乳及其制备方法
CN110237034A (zh) * 2019-06-17 2019-09-17 宁波海奇合昇环能科技有限公司 一种脂溶性营养药透明水分散液的制备方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101647598B (zh) * 2009-08-25 2011-09-21 曹金党 纳米级维生素微乳液的制备方法
CN101803741B (zh) * 2010-04-20 2012-05-02 浙江新和成股份有限公司 超重力法制备纳米维生素e水分散粉体制剂的方法
CN102091080A (zh) * 2010-12-10 2011-06-15 上海恒丰强动物药业有限公司 一种脂溶性维生素的纳米乳及其制备方法
CN102551056A (zh) * 2012-01-10 2012-07-11 江南大学 一种o/w型碳链长<15的脂溶性营养素的微乳模型及其制备方法
CN105127439B (zh) * 2014-05-27 2017-05-17 北京化工大学 一种油相银纳米颗粒的制备方法
CN106727310A (zh) * 2016-12-29 2017-05-31 陕西科技大学 一种维生素a纳米乳及其制备方法

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1546016A (zh) * 2003-12-04 2004-11-17 东南大学 天然维生素e纳米制剂及其制备方法
CN1720900A (zh) * 2004-07-14 2006-01-18 无锡杰西医药科技有限公司 一种适用于难溶性药物的药用乳剂及其制备方法
WO2011153513A2 (en) * 2010-06-03 2011-12-08 Latitude Pharma Nanoemulsion composition containing vitamin k
CN102389378A (zh) * 2011-11-23 2012-03-28 天津郁美净集团有限公司 一种用于化妆品的复合油脂微乳液及其制备方法
CN103053906A (zh) * 2013-01-20 2013-04-24 湖南奇异生物科技有限公司 猕猴桃籽油口服乳液的制备方法
CN103520102A (zh) * 2013-10-14 2014-01-22 陕西科技大学 一种维生素d纳米乳及其制备方法
CN104366508A (zh) * 2014-11-13 2015-02-25 天津禹王生物医药科技有限公司 一种叶黄素酯或叶黄素乳液及制备方法
CN106491520A (zh) * 2015-09-08 2017-03-15 黄慧健 一种辅酶q10注射液制剂及其制备方法
CN107744537A (zh) * 2017-09-15 2018-03-02 成都泠汐尚品科技有限公司 一种复方奥利司他纳米乳及其制备方法
CN110237034A (zh) * 2019-06-17 2019-09-17 宁波海奇合昇环能科技有限公司 一种脂溶性营养药透明水分散液的制备方法

Also Published As

Publication number Publication date
CN110237034A (zh) 2019-09-17

Similar Documents

Publication Publication Date Title
WO2020253710A1 (zh) 一种辅酶q10透明水分散液的制备方法
Liu et al. A novel liposome-encapsulated hemoglobin/silica nanoparticle as an oxygen carrier
AU2010312021B2 (en) A submicron emulsion of paclitaxel using steroid complex as intermediate carrier
CN101658494B (zh) 一种石杉碱甲固体脂质纳米粒及其制备方法
WO2022222683A1 (zh) 一种辅酶q10微乳液及其制备方法和应用
CN104337851B (zh) 鸦胆子油纳米结构脂质载体及其冻干粉的制备方法
WO2022160971A1 (zh) 一种含有难溶性药物的浓缩液以及由其制备的乳剂
CN108741080B (zh) 一种微藻dha-花青素双相纳米脂质体及其制备方法
Li et al. Preparation and properties of water-in-oil shiitake mushroom polysaccharide nanoemulsion
CN104523606B (zh) 自组装法制备棉酚及其衍生物普朗尼克纳米粒子的方法
WO2020253709A1 (zh) 一种脂溶性营养药透明水分散液的制备方法
CN103768103B (zh) 一种蜂胶纳米乳口服液及其制备方法
CN113117091B (zh) 一种姜黄素水溶性制剂及其制备方法
CN101411686A (zh) 克拉霉素亚微乳注射液及其制备方法
CN111643451A (zh) 一种注射用和厚朴酚自乳化微乳制剂及其制备方法
CN109157549A (zh) Egcg灵芝孢子油软胶囊及其制备方法
CN106309515A (zh) 鸦胆子油溶致液晶纳米粒分散体、原料组合物及制备方法
CN110721155B (zh) 一种长效载药脂肪乳制剂及其制备方法
CN103690556B (zh) 一种羟基喜树碱长循环脂质体
WO2016119114A1 (zh) 一种葛根素纳米晶胶囊剂及其制备方法
CN101912388B (zh) 逆向蒸发-高压微射流制备中链脂肪酸-维生素c脂质体
CN101632635A (zh) 一种抗肿瘤乳剂及其制备方法
CN101732231A (zh) 青蒿素固体脂质纳米颗粒及其制备方法
CN103908432B (zh) 一种伊沙匹隆白蛋白的冻干组合物及其制备方法
CN103768132B (zh) 一种含注射用水溶性维生素、脂溶性维生素注射液和中/长链脂肪乳注射液的药物组合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20825745

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20825745

Country of ref document: EP

Kind code of ref document: A1