WO2021258668A1 - 一种包裹疏水性固体粉末的p/h微球的制备方法 - Google Patents

一种包裹疏水性固体粉末的p/h微球的制备方法 Download PDF

Info

Publication number
WO2021258668A1
WO2021258668A1 PCT/CN2020/136163 CN2020136163W WO2021258668A1 WO 2021258668 A1 WO2021258668 A1 WO 2021258668A1 CN 2020136163 W CN2020136163 W CN 2020136163W WO 2021258668 A1 WO2021258668 A1 WO 2021258668A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogel
microspheres
solid powder
powder
solution
Prior art date
Application number
PCT/CN2020/136163
Other languages
English (en)
French (fr)
Inventor
许忠斌
刘聪
黄兴
郑素霞
徐宁涛
Original Assignee
浙江大学
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 浙江大学 filed Critical 浙江大学
Priority to PCT/CN2020/136163 priority Critical patent/WO2021258668A1/zh
Priority to JP2021571570A priority patent/JP7213520B2/ja
Publication of WO2021258668A1 publication Critical patent/WO2021258668A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals

Definitions

  • the invention relates to the technical field of powdered medicine/food packaging, in particular to a preparation method of P/H microspheres encapsulating hydrophobic solid powder.
  • microencapsulation technology can solve some of the above problems, by packaging or embedding the active ingredients in a single or complex secondary material matrix to form submicron to several hundred microns microspheres, thereby protecting the active ingredients.
  • the existing microencapsulation technology can be divided into two categories, one is the solvent dissolution method, and the other is the direct solid encapsulation method.
  • Solvent dissolution method dissolves the powder in a suitable organic solvent to obtain a uniform solution, and then disperses it into an emulsion, encapsulating the ingredients in a carrier such as particles, fibers, liposomes, and sponges.
  • the direct solid encapsulation method is to encapsulate the powder components in a matrix such as hydrogel or biopolymer, and then spray drying, freeze drying or grinding to make particles.
  • this method has the problem that the loading rate is not high, and the increase of the powder content in the solution will change the properties of the solution. For example, the viscosity of the solution increases exponentially, which greatly increases the difficulty of packaging.
  • Hydrogel is the best candidate material because of its high water absorption, flexibility, biocompatibility and biodegradability.
  • stimulus-responsive hydrogels have broad application prospects in the field of smart drug release.
  • hydrophilicity of hydrogels difficulties are encountered in encapsulating hydrophobic powders, which leads to the complexity of material design and limits its applicability.
  • the present invention proposes a method for preparing P/H microspheres encapsulating hydrophobic solid powders, which improves the loading rate of the solid powders, so that the formed powder/gel microspheres (Powder in hydrogel microspheres, P/H microspheres) have mechanical stability and the ability to release dual powder components.
  • a preparation method of P/H microspheres encapsulating hydrophobic solid powder includes the following steps:
  • microfluidic droplet separation is performed in the following manner:
  • adding a surfactant to the hydrogel solution reduces the interfacial tension of the solution, adding a high-molecular weight polymer to extend the existence time of the liquid film and bubbles, and adjusting the ratio of the hydrogel and additives to obtain different The diameter of the bubble.
  • the flow rate of the continuous phase or the hydrogel solution is adjusted to change the number of bubble nuclei in the P/H microspheres to form a single-core, dual-core or multi-core structure.
  • the ratio of the components in the hydrogel solution or the flow rate of the continuous phase or the flow rate of the hydrogel solution are adjusted to change the microsphere diameter, minimum wall thickness and average wall thickness of the P/H microspheres.
  • the frame has multiple rows and multiple columns to form a frame network, and each frame generates a bubble, and the frame network generates a large number of bubbles at the same time, so as to realize a large-flux powder package.
  • the temperature must be kept above 60° C. during the S1 to S3 process to prevent the hydrogel solution from gelling.
  • hydrogel solution is prepared from agarose, sodium dodecyl sulfate (SDS) and polyethylene oxide (PEO), wherein the concentration of the agarose is 2.5% to 4.5%.
  • the method of the present invention realizes powder encapsulation through hydrogel bubbles, avoiding the use of organic solvents in the microencapsulation process.
  • the method of the present invention directly encapsulates the powder in the bubble cavity, which can greatly increase the loading rate of the powder components.
  • the powder-gel microspheres formed by the method of the present invention have a core-shell structure, have dual loading capabilities, can release dual substances, and provide the possibility of controlled programmed release of drugs.
  • Figure 1 is a schematic diagram of the method for preparing P/H microspheres encapsulating hydrophobic solid powders of the present invention
  • Figure a represents the process of bubble formation
  • Figure b represents the process of bubble separation and P/H microsphere formation
  • Figure 2 is a physical picture of P/H microspheres, where the diameter of the microspheres is Dm, the bubble diameter is D b , and the minimum wall thickness is d min ;
  • Figure 3 is a side-by-side bubble frame structure provided by embodiment 4;
  • Figure 4 is a physical picture of P/H microspheres with different numbers of bubble nuclei, in which a picture is a single-core structure, b is a dual-core structure, and c is a three-core structure;
  • Figure 5 shows the adjustment of the bubble size by the ratio of the hydrogel solution
  • Figure 6 shows the control of the flow rate of the continuous phase and the ratio of the hydrogel solution to the size of the microspheres
  • Figure 7 is the test results of the mechanical properties of the P/H microspheres provided by the present invention.
  • Figures a and b are the stress-strain curves and fracture pressures of the P/H microspheres containing different concentrations of agarose.
  • Figures c and d are respectively The stress-strain curve and rupture pressure of P/H microspheres with different wall thicknesses;
  • Figure 8 is a schematic diagram of the drug release principle of P/H microspheres provided by the present invention.
  • Fig. 9 is a P/H microsphere drug release diagram provided in Example 1, wherein the left of the figure a is before ultrasound release, and the right is after ultrasound release; figure b is a graph of the cumulative release of the drug over time.
  • 1 is a solid powder
  • 2 is a hydrogel solution
  • 3 is a frame
  • 4 is a hydrogel liquid film
  • 5 is a hydrogel bubble loaded with powder
  • 6 is a T-shaped droplet generator
  • 7 is a hydrogel Glue drops
  • 8 is powder-gel microspheres (P/H microspheres)
  • 9 is a collecting pool.
  • the invention discloses a method for preparing P/H microspheres encapsulating hydrophobic solid powder. Hydrogel bubbles are generated to encapsulate the powder, and then the hydrogel bubbles are sheared by a microfluidic droplet generator to form the encapsulated powder. The hydrogel droplets are finally cross-linked by the hydrogel to form a powder-in hydrogel microsphere (P/H microsphere) with a core-shell structure covered with powder.
  • P/H microsphere powder-in hydrogel microsphere
  • hydrogel solution such as agarose, gelatin, etc.
  • the powder component is placed on the surface of the hydrogel solution, and the frame for generating bubbles is immersed in the hydrogel solution with the powder component on the surface.
  • the interfacial tension due to the hydrophobicity of the powder is balanced with the gravity of the powder, so that the powder stays on the surface without sinking.
  • the frame is lifted from the hydrogel solution, and a thin liquid film of hydrogel is attached to the frame at this time.
  • the frame rises the liquid film continues to stretch upwards until the liquid film necks down.
  • the Rayleigh platform is unstable and the seal is broken to form bubbles, which wrap the powder components inside the bubbles. Due to the Pickering effect, part of the powder also acts as a surfactant, which promotes the formation of bubbles and stabilizes them.
  • the generated powder-coated hydrogel bubbles are injected into the channels of the microfluidic droplet generating device, and the hydrogel bubbles are continuously sheared to form powder-coated hydrogel droplets.
  • the powder-coated hydrogel droplets are converted into solid P/H microspheres after cross-linking (cooling, light, etc.). Due to the buoyancy generated by the bubbles inside the P/H microspheres, the P/H microspheres have an eccentric structure.
  • the diameter of the obtained microspheres is Dm
  • the bubble diameter is Db
  • the minimum wall thickness is dmin
  • the average wall thickness is d.
  • the physical map of P/H microspheres is shown in Figure 2.
  • Adjusting the ratio of each component in the hydrogel solution can obtain different bubble diameters.
  • Adjusting the flow rate of the continuous phase or hydrogel solution can change the number of bubble nuclei in the P/H microspheres to form a single-core, dual-core or multi-core structure.
  • Adjusting the ratio of each component in the hydrogel solution or the continuous phase flow rate or the flow rate of the hydrogel solution can change the microsphere diameter, minimum wall thickness and average wall thickness of the P/H microspheres.
  • the frames used to generate bubbles are arranged side by side to form a frame network, which can generate a large number of bubbles to wrap the powder at the same time.
  • the preparation method of the P/H microspheres of the present invention can also achieve the effect of dual loading. In this case, it is necessary to dissolve another substance in the hydrogel solution first, and then after the above steps, the P/H microspheres are finally obtained. Another substance is contained in the shell.
  • the produced P/H microspheres have excellent mechanical properties and can withstand a certain external load, thereby protecting the inner packaging material from external interference and improving its stability.
  • the agarose concentration and minimum wall thickness have a great influence on the mechanical properties of P/H microspheres.
  • the frame for generating bubbles is immersed in the hydrogel solution with calcium carbonate powder on the surface, and then the frame is lifted from the hydrogel solution to wrap the powder components inside the bubbles. During this process, it is necessary to keep the hydrogel solution above 60°C to prevent its gelation.
  • the hydrogel bubble solution is injected into the T-shaped droplet generator.
  • the hydrogel channel part of the T-shaped droplet generator is equipped with a heating device to keep the temperature of the heating jacket above 60°C.
  • Use 50cSt silicone oil as For continuous phase adjust the flow rate of silicone oil to 120ml/h and the flow rate of hydrogel to 20ml/h.
  • the hydrogel bubble solution forms hydrogel droplets under the shearing action of the silicone oil.
  • the hydrogel droplets are cooled in a silicone oil environment at room temperature to be converted into solid P/H microspheres.
  • Table 1 The characteristic parameters of the prepared P/H microspheres are shown in Table 1.
  • the frame for generating bubbles is immersed in the hydrogel solution with calcium carbonate powder on the surface, and then the frame is lifted from the hydrogel solution to wrap the powder components inside the bubbles. During this process, it is necessary to keep the hydrogel solution above 60°C to prevent its gelation.
  • the hydrogel channel part of the T-shaped droplet generator is equipped with a heating device to keep the temperature of the heating jacket above 60°C.
  • the flow rate of the hydrogel to 25ml/h.
  • the hydrogel bubble solution forms hydrogel droplets under the shearing action of the silicone oil.
  • the hydrogel droplets are cooled in a silicone oil environment at room temperature to be converted into solid P/H microspheres.
  • the characteristic parameters of the prepared P/H microspheres are shown in Table 2.
  • the hydrogel solution Prepares the hydrogel solution. Choose 3% sodium alginate, 0.2% SDS and 0.1% PEO to prepare the hydrogel solution.
  • the nano calcium carbonate powder is used as the drug model inside the bubble.
  • Sodium alginate is used as the hydrogel base material, SDS is used as a surfactant, and PEO is mainly used to improve bubble stability.
  • the nanometer calcium carbonate powder is used as the drug model inside the bubble. Place calcium carbonate powder on the surface of the hydrogel solution.
  • the frame for generating bubbles is immersed in a hydrogel solution with calcium carbonate powder on the surface, and then the frame is lifted from the hydrogel solution to wrap the powder components inside the bubbles.
  • the hydrogel bubble solution is injected into the T-shaped droplet generator, and a 10% calcium chloride solution is selected as the continuous phase, and the flow rate of the calcium chloride solution is adjusted to 80 ml/h and the flow rate of the hydrogel to 20 ml/h.
  • the hydrogel bubble solution forms hydrogel droplets under the shearing action of the calcium chloride solution, and then crosslinks into solid P/H microspheres.
  • the characteristic parameters of the prepared P/H microspheres are shown in Table 3.
  • the hydrogel solution Prepares the hydrogel solution. Choose 3% agarose, 0.2% SDS and 0.01% PEO. Agarose is used as the hydrogel base material, SDS is used as a surfactant, and PEO is mainly used to improve bubble stability. After stirring the above three powders in deionized water uniformly, they were heated in a microwave oven until the solution was transparent, and then degassed under ultrasound for 30 seconds. The nanometer calcium carbonate powder is used as the drug model inside the bubble. Place calcium carbonate powder on the surface of the hydrogel solution. In order to achieve large-flux powder packaging, the frames used to generate bubbles are arranged side by side to form a frame network, which can generate a large number of bubbles to wrap the powder at the same time. The frame network is shown in Figure 3.
  • the method for preparing P/H microspheres provided by the present invention can also obtain P/H microspheres of different morphologies and sizes by adjusting operating parameters or solution ratio, which is specifically proved by the following experiments.
  • the number of bubble nuclei in the P/H microspheres can be changed to obtain P/H microspheres with different nuclei numbers to achieve multi-core packaging, so P/H H microspheres have the ability to load different powder components.
  • the flow rate of the hydrogel is adjusted to 18 ml/h, 54 ml/h and 80 ml/h, respectively, P/H microspheres with single-core, dual-core and tri-core structures can be formed, as shown in FIG. 4.
  • the bubble diameter D b of the P/H microspheres can be changed by controlling the ratio of the hydrogel solution (agarose concentration, SDS concentration or PEO concentration). The influence of each parameter on the bubble size is shown in FIG. 5.
  • the microsphere diameter D m of the P/H microspheres can be changed, With the minimum wall thickness d min and the average wall thickness d, P/H microspheres with different sizes are obtained.
  • the influence of each parameter on the size of the microspheres is shown in Figure 6.
  • the P/H microspheres prepared by the present invention have excellent mechanical properties and can bear a certain external load, thereby protecting the inner packaging materials.
  • the concentration of agarose has a great influence on the mechanical properties of the hydrogel.
  • the agarose concentration was changed between 2.5% and 4.5%, and the obtained P/H microspheres were mechanically compressed test.
  • Figure 7a shows typical compressive stress-strain curves of P/H microspheres with different agarose concentrations. As the agarose concentration increased from 2.5% to 4.5%, the compressive stress of P/H microspheres increased from 0.015 MPa to 0.12 MPa.
  • Figure 7b shows that the fracture pressure increased from 35 mN to 300 mN, which indicates A dense network is formed in the gel.
  • the minimum wall thickness of the P/H microspheres has a decisive influence on the mechanical strength, because this position is the weak point of the P/H microspheres.
  • the mechanical compression test was performed on P/H microspheres with different wall thicknesses.
  • Figure 7c shows the effect of the minimum wall thickness on the mechanical properties of P/H microspheres. When the minimum wall thickness increases from 50 ⁇ m to 250 ⁇ m, the compressive stress of P/H microspheres increases from 0.029 MPa to 0.10 MPa.
  • Figure 7d shows that the rupture pressure increases from 67 mN to 223 mN.
  • the P/H microspheres prepared by the method of the present invention have a core-shell structure, can be loaded with different powder components, and have dual release capabilities.
  • the release principle diagram is shown in Fig. 8.
  • the outer hydrogel shell releases powder component 1 in an aqueous environment at 37°C. Under the action of ultrasound, the hydrogel continuously breaks down into fragments, and the powder component 2 wrapped by the internal bubbles is released, and according to the ultrasound action time, intensity, and frequency, it appears Features of programmable control release.
  • Example 1 In order to demonstrate the dual drug loading and controlled release performance of P/H microspheres, a drug release experiment was carried out.
  • Example 1 during the preparation of the hydrogel solution, rhodamine B was dissolved in the hydrogel solution as a model for the release of small molecules in the microsphere shell. Other operations are the same as in Example 1. Accordingly, P/H microspheres containing rhodamine B in the hydrogel shell and nano-calcium carbonate powder in the hydrogel bubbles are obtained. Place the prepared P/H microspheres in 37°C water to test the release of rhodamine B. The P/H microspheres were placed in an ultrasonic environment to test the release of calcium carbonate. The release results are shown in Figure 9. The rhodamine contained in the hydrogel shell exhibits a burst release and then a slow release over time. The calcium carbonate powder wrapped in the bubble exhibits a controllable stepped release feature under the action of ultrasound. .

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Manufacturing Of Micro-Capsules (AREA)
  • Medicinal Preparation (AREA)
  • General Preparation And Processing Of Foods (AREA)

Abstract

一种包裹疏水性固体粉末的P/H微球的制备方法，该方法包括如下步骤：(1)将疏水性固体粉末置于水凝胶溶液表面上；(2)将用于产生气泡的框架浸入表面有所述固体粉末的水凝胶溶液中，然后将框架从水凝胶溶液中提起，此时框架上附着一层水凝胶液膜；随着所述框架的上升，液膜不断向上拉伸，直到液膜颈缩，断裂封口形成气泡，将粉末成分包裹在气泡内部；(3)将带有包裹固体粉末的气泡的水凝胶溶液进行微流体液滴分离，形成包裹有固体粉末的水凝胶液滴；(4)将包裹有固体粉末的水凝胶液滴进行交联，形成固体状的粉末-凝胶微球，即P/H微球。该方法将粉末直接封装在气泡空腔中，可大大提高粉末成分的装载率。

Description

一种包裹疏水性固体粉末的P/H微球的制备方法 技术领域
本发明涉及粉末药物/食品封装技术领域，具体涉及一种包裹疏水性固体粉末的P/H微球的制备方法。
背景技术
许多疏水性的药物成分、营养素或食品生物活性物质以粉末/固体形式存在，对人体健康非常重要。这些粉末成分广泛应用于医药工业和食品工程，如具有杀菌抗炎功效、可用于肿瘤癌症治疗的中药成分喜树碱、白藜芦醇、槲皮素等，一些水不溶性维生素，抗氧化剂和某些食品着色剂，特别是类胡萝卜素等。然而，这些粉末材料稳定性差、溶解性差、生物利用度低，在加工、储存和运输过程中极易受到光、氧、高温、湿度等环境外力的影响，大大限制了这些难溶性粉末成分发挥作用。
目前，采用微封装技术可以解决以上部分难题，通过将活性成分包装或包埋在单一或复杂的二次材料基质中，形成亚微米至几百微米的微球，从而保护活性成分。对于疏水性固体粉末的封装，现有的微封装技术主要可分为两大类，一是溶剂溶解法，二是直接固体包裹法。溶剂溶解法将粉末溶解在适当的有机溶剂中以获得均匀的溶液，然后将其分散到乳液中，将成分包裹在颗粒、纤维、脂质体和海绵等载体中。但是，考虑到各种粉体成分的多样性，寻找一种有效且相容的有机溶剂并非易事。为了解决这一问题，直接固体包裹法是将粉末成分包封在水凝胶或生物聚合物等基质中，后续经过喷雾干燥、冷冻干燥或研磨制成颗粒。然而，这种方法存在装载率不高的问题，并且溶液中粉末含量的增加会改变溶液的性质，例如溶液的粘度呈现指数级增加，大大增加封装难度。
另一方面，选择合适的材料进行微胶囊化对封装过程和后续的释放至关重要。水凝胶因其高吸水性、柔韧性、生物相容性和可生物降解而成为最佳候选材料。特别是，刺激响应性水凝胶，在智能药物释放领域具有广泛的应用前景。然而，由于水凝胶的亲水性，在封装疏水性粉末时遇到困难，导致材料设计的复杂性，限制了其适用性。
因此，对于疏水性固体粉末成分进行高装载率、无生物毒性的封装，并可进行可控释放仍有很大的发展空间。
发明内容
针对现有技术的不足，本发明提出一种包裹疏水性固体粉末的P/H微球的制备方法，提高了固体粉末的装载率，使形成的粉末/凝胶微球(Powder in hydrogel microsphere，P/H 微球)具有力学稳定性，且具有双重粉末成分释放的能力。
本发明的目的通过如下的技术方案来实现：
一种包裹疏水性固体粉末的P/H微球的制备方法，包括如下步骤：
S1：将疏水性固体粉末置于水凝胶溶液表面上；
S2：将用于产生气泡的框架浸入表面有所述固体粉末的水凝胶溶液中，然后将框架从水凝胶溶液中提起，此时框架上附着一层水凝胶液膜；随着所述框架的上升，液膜不断向上拉伸，直到液膜颈缩，断裂封口形成气泡，将粉末成分包裹在气泡内部；
S3：将带有包裹固体粉末的气泡的水凝胶溶液进行微流体液滴分离，形成包裹有固体粉末的水凝胶液滴；
S4：将包裹有固体粉末的水凝胶液滴进行交联，形成固体状的粉末-凝胶微球，即P/H微球。
进一步地，所述微流体液滴分离通过如下方式进行：
将带有包裹固体粉末的气泡的水凝胶溶液注入到微流体T型液滴发生器的一个通道中，利用连续相对水凝胶气泡的剪切作用，形成包裹有粉末的水凝胶液滴。
进一步地，向所述的水凝胶溶液中添加表面活性剂降低溶液的界面张力，添加高分子量的聚合物延长液膜及气泡存在的时间，通过调节水凝胶和添加剂的配比可获得不同的气泡直径。
进一步地，调节连续相或水凝胶溶液的流速，改变P/H微球内部的气泡核数，形成单核、双核或多核结构。
进一步地，调节水凝胶溶液中各组分的配比或连续相的流速或水凝胶溶液的流速，改变P/H微球的微球直径、最小壁厚和平均壁厚。
进一步地，所述框架为多排多列，形成框架网络，每个框架产生一个气泡，则框架网络同时产生大量气泡，实现大通量的粉末包裹。
进一步地，对于温度敏感性的水凝胶，所述S1～S3过程中需保持温度在60℃以上，防止所述水凝胶溶液凝胶化。
进一步地，在所述的S1之前，先在水凝胶溶液中溶解另一物质，从而经过S1～S4后，所述凝胶微球的外壳中装载有所述的另一物质，从而得到双重载物的效果。
进一步地，所述水凝胶溶液由琼脂糖、十二烷基硫酸钠(SDS)和聚氧化乙烯(PEO)配制而成，其中，琼脂糖的浓度为2.5％～4.5％。
本发明的有益效果如下：
(1)本发明的方法通过水凝胶气泡实现粉末包裹，避免了微封装过程中有机溶剂的使 用。
(2)本发明的方法将粉末直接封装在气泡空腔中，可大大提高粉末成分的装载率。
(3)本发明的方法形成的粉末-凝胶微球具有核壳结构，具备双重载物能力，可进行双重物质释放，为药物的可控编程释放提供可能。
附图说明
图1为本发明的包裹疏水性固体粉末的P/H微球的制备方法示意图；其中a图表示气泡形成的过程，b图表示气泡分离、P/H微球形成的过程；
图2为P/H微球实物图，其中微球直径为Dm，气泡直径为D b，最小壁厚为d min；
图3为实施例4提供的并排气泡框架结构；
图4为具有不同气泡核数的P/H微球实物图，其中a图为单核结构，b图为双核结构，c图为三核结构；
图5为水凝胶溶液的配比对气泡尺寸的调控；
图6为连续相的流速以及水凝胶溶液的配比对微球尺寸的调控；
图7为本发明提供的P/H微球力学性能测试结果，其中a图和b图分别为含不同浓度琼脂糖的P/H微球应力应变曲线和破裂压力，c图和d图分别为不同壁厚的P/H微球应力应变曲线和破裂压力；
图8为本发明提供的P/H微球药物释放原理示意图；
图9为实施例1提供的P/H微球药物释放图，其中a图左为超声释放前，右为超声释放后；b图为药物累积释放量随时间的变化曲线图。
图中：1为固体粉末，2为水凝胶溶液，3为框架，4为水凝胶液膜，5为装载粉末的水凝胶气泡，6为T形液滴发生器，7为水凝胶液滴，8为粉末-凝胶微球(P/H微球)，9为收集池。
具体实施方式
下面根据附图和优选实施例详细描述本发明，本发明的目的和效果将变得更加明白，应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。
本发明公开一种包裹疏水性固体粉末的P/H微球的制备方法，通过产生水凝胶气泡包裹粉末，随后通过微流控液滴发生装置将水凝胶气泡进行剪切形成包裹有粉末的水凝胶液滴，最后通过水凝胶交联形成包裹有粉末的核壳结构的粉末-凝胶微球(Powder in hydrogel microsphere，P/H微球)。
配置一定浓度的水凝胶溶液(如琼脂糖、明胶等)，并加入表面活性剂或添加剂。
如图1所示，将粉末成分置于水凝胶溶液表面上，将用于产生气泡的框架浸入表面有 粉末成分的水凝胶溶液中。由于粉体的疏水性而产生的界面张力与粉末的重力进行平衡，使粉末停留在表面而不下沉。然后将框架从水凝胶溶液中提起，此时框架上附着一层水凝胶薄液膜。随着框架的上升，液膜不断向上拉伸，直到液膜颈缩，最后由于瑞利平台不稳定而断裂封口形成气泡，将粉末成分包裹在气泡内部。由于Pickering效应，一部分粉末还起到表面活性剂的作用，它促进气泡的形成并使其稳定。
将产生的包裹有粉末的水凝胶气泡注入到微流控液滴发生装置的通道中，利用连续相对水凝胶气泡进行剪切，形成包裹有粉末的水凝胶液滴。
随后包裹有粉末的水凝胶液滴经过交联(降温、光照等)后转化为固体状的P/H微球。由于P/H微球内部气泡产生的浮力作用，P/H微球为偏心结构。所得微球直径为Dm，气泡直径为Db，最小壁厚为dmin，平均壁厚为d。P/H微球实物图如图2所示。
调节水凝胶溶液中各组分的配比可获得不同的气泡直径。
调节连续相或水凝胶溶液的流速，可改变P/H微球内部的气泡核数，形成单核、双核或多核结构。
调节水凝胶溶液中各组分的配比或连续相流速或水凝胶溶液的流速，可改变P/H微球的微球直径、最小壁厚和平均壁厚。
为实现大通量的粉末包裹，将用于产生气泡的框架进行并排排列，形成框架网络，可同时产生大量气泡包裹粉末。
本发明的P/H微球的制备方法也可以实现双重载物的效果，此时需要先在水凝胶溶液中溶解另一物质，然后经过上述步骤后，最后得到的P/H微球的外壳中则装载有另一物质。
产生的P/H微球具备优良的力学性能，可承受一定外部载荷，从而保护内部包裹物质不受外界干扰，提高其稳定性。琼脂糖浓度和最小壁厚对P/H微球的力学性能有很大影响。
实施例1
配置水凝胶溶液。选用3％琼脂糖、0.2％十二烷基硫酸钠(SDS)和0.01％聚氧化乙烯(PEO,M W＝4M g/mol)。琼脂糖作为水凝胶基底材料，SDS作为表面活性剂，PEO主要用于提高气泡稳定性。将上述三种粉末在去离子水中搅拌均匀后，在微波炉中加热至溶液透明，然后超声脱气30秒。以纳米碳酸钙粉末作为气泡内部药物模型。将碳酸钙粉末置于水凝胶溶液表面上。将用于产生气泡的框架浸入表面有碳酸钙粉末的水凝胶溶液中，然后将框架从水凝胶溶液中提起，将粉末成分包裹在气泡内部。在这一过程中，需要保持水凝胶溶液在60℃以上，以防止其凝胶化。
如图1b所述，将水凝胶气泡溶液注入T形液滴发生器中，T形液滴发生器的水凝胶通道部分设置加热装置，保持加热套温度在60℃以上，选用50cSt硅油为连续相，调节硅油 流速至120ml/h，水凝胶流速至20ml/h。水凝胶气泡溶液在硅油的剪切作用下形成水凝胶液滴。随后在室温环境下水凝胶液滴在硅油环境中冷却转化为固体状的P/H微球。制得的P/H微球特征参数如表1所示。
表1实施例1制得的P/H微球特征参数
微球直径D m/μm 气泡直径D b/μm 最小壁厚d min/μm 平均壁厚d/μm
1780 1060 150 295
实施例2
配置水凝胶溶液。选用12％明胶，0.2％SDS和0.1％PEO配置水凝胶溶液。以纳米碳酸钙粉末作为气泡内部药物模型。明胶作为水凝胶基底材料，SDS作为表面活性剂，PEO主要用于提高气泡稳定性。将上述三种粉末在去离子水中搅拌均匀后，在微波炉中加热至溶液透明，然后超声脱气30秒。以纳米碳酸钙粉末作为气泡内部药物模型。将碳酸钙粉末置于水凝胶溶液表面上。将用于产生气泡的框架浸入表面有碳酸钙粉末的水凝胶溶液中，然后将框架从水凝胶溶液中提起，将粉末成分包裹在气泡内部。在这一过程中，需要保持水凝胶溶液在60℃以上，以防止其凝胶化。
将水凝胶气泡溶液注入T形液滴发生器中，T形液滴发生器的水凝胶通道部分设置加热装置，保持加热套温度在60℃以上，选用50cSt硅油为连续相，调节硅油流速至100ml/h，水凝胶流速至25ml/h。水凝胶气泡溶液在硅油的剪切作用下形成水凝胶液滴。随后在室温环境下水凝胶液滴在硅油环境中冷却转化为固体状的P/H微球。制得的P/H微球特征参数如表2所示。
表2实施例2制得的P/H微球特征参数
微球直径D m/μm 气泡直径D b/μm 最小壁厚d min/μm 平均壁厚d/μm
2000 1140 150 330
实施例3
配置水凝胶溶液。选用3％海藻酸钠，0.2％SDS和0.1％PEO配置水凝胶溶液。以纳米碳酸钙粉末作为气泡内部药物模型。海藻酸钠作为水凝胶基底材料，SDS作为表面活性剂，PEO主要用于提高气泡稳定性。将上述三种粉末在去离子水中搅拌均匀后，在微波炉中加热至溶液透明，然后超声脱气30秒。以纳米碳酸钙粉末作为气泡内部药物模型。将碳酸钙粉末置于水凝胶溶液表面上。将用于产生气泡的框架浸入表面有碳酸钙粉末的水凝胶溶液 中，然后将框架从水凝胶溶液中提起，将粉末成分包裹在气泡内部。
将水凝胶气泡溶液注入T形液滴发生器中，选用10％氯化钙溶液为连续相，调节氯化钙溶液流速至80ml/h，水凝胶流速至20ml/h。水凝胶气泡溶液在氯化钙溶液的剪切作用下形成水凝胶液滴，然后交联成为固体状的P/H微球。制得的P/H微球特征参数如表3所示。
表3实施例3制得的P/H微球特征参数
微球直径D m/μm 气泡直径D b/μm 最小壁厚d min/μm 平均壁厚d/μm
1850 1100 90 325
实施例4
配置水凝胶溶液。选用3％琼脂糖、0.2％SDS和0.01％PEO。琼脂糖作为水凝胶基底材料，SDS作为表面活性剂，PEO主要用于提高气泡稳定性。将上述三种粉末在去离子水中搅拌均匀后，在微波炉中加热至溶液透明，然后在超声脱气30秒。以纳米碳酸钙粉末作为气泡内部药物模型。将碳酸钙粉末置于水凝胶溶液表面上。为实现大通量的粉末包裹，将用于产生气泡的框架进行并排排列，形成框架网络，可同时产生大量气泡包裹粉末。框架网络如图3所示。
本发明提供的P/H微球的制备方法还可以通过调节操作参数或溶液配比得到不同形貌和尺寸的P/H微球，具体通过如下的实验来证明。
通过控制T形液滴发生器内连续相或水凝胶溶液的流速，可改变P/H微球内部气泡核数，得到具有不同核数的P/H微球，实现多核包裹，因而P/H微球具有装载不同粉末成分的能力。在实施例1中，如调节水凝胶流速分别为18ml/h、54ml/h和80ml/h，可形成具有单核、双核和三核结构的P/H微球，如图4所示。
通过控制水凝胶溶液的配比(琼脂糖浓度、SDS浓度或PEO浓度)可改变P/H微球的气泡直径D b，各个参数对气泡尺寸的影响如图5所示。
通过控制T形液滴发生器内连续相(硅油)的流速以及水凝胶溶液的配比(琼脂糖浓度、SDS浓度或PEO浓度)，可改变P/H微球的微球直径D m，最小壁厚d min，平均壁厚d，得到具有不同尺寸的P/H微球，各个参数对微球尺寸的影响如图6所示。
本发明制备的P/H微球具备优良的力学性能，可承受一定外部载荷，从而保护内部包裹物质。琼脂糖浓度对水凝胶的力学性能有很大影响。针对由琼脂糖、SDS和PEO(M W＝4M g/mol))配制而成的水凝胶溶液，改变琼脂糖浓度在2.5％到4.5％之间，对所得P/H微球进行力学压缩测试。图7a显示了不同琼脂糖浓度的P/H微球的典型压缩应力-应变曲线。 随着琼脂糖浓度在2.5％到4.5％之间增加，P/H微球的压应力从0.015MPa增大到0.12MPa，图7b显示了其破裂压力从35mN增大到300mN，这表明在水凝胶中形成了致密的网络。当溶液配比确定时，P/H微球的最小壁厚对机械强度有决定性的影响，因为这个位置是P/H微球的薄弱点。对于不同壁厚的P/H微球进行力学压缩测试，图7c显示了最小壁厚对P/H微球力学性能的影响。当最小壁厚从50μm增加到250μm时，P/H微球的压应力从0.029MPa增大到0.10MPa，图7d显示了其破裂压力从67mN增加到223mN。
本发明的方法制备的P/H微球具有核壳结构，可装载不同的粉末成分，具有双重释放的能力。作为其中实施方式，释放原理图见图8。外部水凝胶壳在37℃水相环境中释放粉末成分1，在超声作用下水凝胶不断裂解成碎片，内部气泡包裹的粉末成分2释放出去，且根据超声作用时间、强度、频率，呈现出可编程操控释放的特点。
为展示P/H微球的双重载药和可控释放的性能，进行了药物释放实验。在实施例1中，在配置水凝胶溶液过程中，将罗丹明B溶解在水凝胶溶液中，作为微球壳中小分子释放模型。其他操作同实施例1。据此得到水凝胶壳体中装载罗丹明B、水凝胶气泡内装载纳米碳酸钙粉末的P/H微球。将制得的P/H微球置于37℃水中，测试罗丹明B的释放。将P/H微球置于超声环境中，测试碳酸钙的释放。对于释放结果见图9，水凝胶壳内装载的罗丹明随时间呈现出先爆发式释放后缓慢释放的特点，气泡内部包裹的碳酸钙粉末在超声作用下展现出可操控的阶梯式释放的特点。
本领域普通技术人员可以理解，以上所述仅为发明的优选实例而已，并不用于限制发明，尽管参照前述实例对发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实例记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在发明的精神和原则之内，所做的修改、等同替换等均应包含在发明的保护范围之内。

Claims (9)

  1. 一种包裹疏水性固体粉末的P/H微球的制备方法，其特征在于，该方法包括如下步骤：
    S1：将疏水性固体粉末置于水凝胶溶液表面上；
    S2：将用于产生气泡的框架浸入表面有所述固体粉末的水凝胶溶液中，然后将框架从水凝胶溶液中提起，此时框架上附着一层水凝胶液膜；随着所述框架的上升，液膜不断向上拉伸，直到液膜颈缩，断裂封口形成气泡，将粉末成分包裹在气泡内部；
    S3：将带有包裹固体粉末的气泡的水凝胶溶液进行微流体液滴分离，形成包裹有固体粉末的水凝胶液滴；
    S4：将包裹有固体粉末的水凝胶液滴进行交联，形成固体状的粉末-凝胶微球，即P/H微球。
  2. 根据权利要求1所述的包裹疏水性固体粉末的P/H微球的制备方法，其特征在于，所述微流体液滴分离通过如下方式进行：
    将带有包裹固体粉末的气泡的水凝胶溶液注入到微流体T型液滴发生器的一个通道中，利用连续相对水凝胶气泡的剪切作用，形成包裹有粉末的水凝胶液滴。
  3. 根据权利要求1所述的包裹疏水性固体粉末的P/H微球的制备方法，其特征在于，向所述的水凝胶溶液中添加表面活性剂降低溶液的界面张力，添加高分子量的聚合物延长液膜及气泡存在的时间，通过调节水凝胶和添加剂的配比可获得不同的气泡直径。
  4. 根据权利要求2所述的包裹疏水性固体粉末的P/H微球的制备方法，其特征在于，调节连续相或水凝胶溶液的流速，改变P/H微球内部的气泡核数，形成单核、双核或多核结构。
  5. 根据权利要求2所述的包裹疏水性固体粉末的P/H微球的制备方法，其特征在于，调节水凝胶溶液中各组分的配比或连续相的流速或水凝胶溶液的流速，改变P/H微球的微球直径、最小壁厚和平均壁厚。
  6. 根据权利要求1所述的包裹疏水性固体粉末的P/H微球的制备方法，其特征在于，所述框架为多排多列，形成框架网络，每个框架产生一个气泡，则框架网络同时产生大量气泡，实现大通量的粉末包裹。
  7. 根据权利要求1所述的包裹疏水性固体粉末的P/H微球的制备方法，其特征在于，对于温度敏感性的水凝胶，所述S1～S3过程中需保持温度在60℃以上，防止所述水凝胶溶液凝胶化。
  8. 根据权利要求1所述的包裹疏水性固体粉末的P/H微球的制备方法，其特征在于，在所述的S1之前，先在水凝胶溶液中溶解另一物质，从而经过S1～S4后，所述凝胶微球的外壳中装载有所述的另一物质，从而得到双重载物的效果。
  9. 根据权利要求1所述的包裹疏水性固体粉末的P/H微球的制备方法，其特征在于，所述水凝胶溶液由琼脂糖、十二烷基硫酸钠和聚氧化乙烯配制而成，其中，琼脂糖的浓度为2.5％～4.5％。
PCT/CN2020/136163 2020-12-14 2020-12-14 一种包裹疏水性固体粉末的p/h微球的制备方法 WO2021258668A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2020/136163 WO2021258668A1 (zh) 2020-12-14 2020-12-14 一种包裹疏水性固体粉末的p/h微球的制备方法
JP2021571570A JP7213520B2 (ja) 2020-12-14 2020-12-14 疎水性固体粉末を封入したｐ／ｈミクロスフェアの製造方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2020/136163 WO2021258668A1 (zh) 2020-12-14 2020-12-14 一种包裹疏水性固体粉末的p/h微球的制备方法

Publications (1)

Publication Number Publication Date
WO2021258668A1 true WO2021258668A1 (zh) 2021-12-30

Family

ID=79282773

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/136163 WO2021258668A1 (zh) 2020-12-14 2020-12-14 一种包裹疏水性固体粉末的p/h微球的制备方法

Country Status (2)

Country Link
JP (1) JP7213520B2 (zh)
WO (1) WO2021258668A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114376984A (zh) * 2022-01-17 2022-04-22 浙江大学 包裹水难溶性固体粉末的自漂浮mp/h微球的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101486799A (zh) * 2008-01-16 2009-07-22 中国科学院过程工程研究所 一种琼脂糖凝胶微球及其制备方法
CN107185029A (zh) * 2017-05-24 2017-09-22 南京大学 一种包裹载药纳米材料的高分子水凝胶栓塞微球及其制备方法和应用
CN107412877A (zh) * 2017-07-21 2017-12-01 王华楠 一种磷酸钙/明胶复合材料纳米颗粒的制备方法及其应用
CN109843332A (zh) * 2016-07-22 2019-06-04 华盛顿大学 两性离子微凝胶、其组件和相关制剂及其使用方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160271178A1 (en) 2013-10-18 2016-09-22 Agency For Science, Technology And Research Nanoparticle-containing hydrogels
CN110330980B (zh) 2019-07-12 2021-07-23 浙江尚瑞特科技股份有限公司 一种可降解的自修复保水固沙剂及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101486799A (zh) * 2008-01-16 2009-07-22 中国科学院过程工程研究所 一种琼脂糖凝胶微球及其制备方法
CN109843332A (zh) * 2016-07-22 2019-06-04 华盛顿大学 两性离子微凝胶、其组件和相关制剂及其使用方法
CN107185029A (zh) * 2017-05-24 2017-09-22 南京大学 一种包裹载药纳米材料的高分子水凝胶栓塞微球及其制备方法和应用
CN107412877A (zh) * 2017-07-21 2017-12-01 王华楠 一种磷酸钙/明胶复合材料纳米颗粒的制备方法及其应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MALIHE POORESMAEIL ET AL.: "Facile preparation of pH-sensitive chitosan microspheres for delivery of curcumin; characterization, drug release kinetics and evaluation of anticancer activity", INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, vol. 162, 20 June 2020 (2020-06-20), pages 501 - 511, XP086280630, ISSN: 0141-8130, DOI: 10.1016/j.ijbiomac.2020.06.183 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114376984A (zh) * 2022-01-17 2022-04-22 浙江大学 包裹水难溶性固体粉末的自漂浮mp/h微球的制备方法

Also Published As

Publication number Publication date
JP2022544731A (ja) 2022-10-21
JP7213520B2 (ja) 2023-01-27

Similar Documents

Publication Publication Date Title
CN112618517B (zh) 一种包裹疏水性固体粉末的p/h微球的制备方法
Yow et al. Formation of liquid core–polymer shell microcapsules
Mou et al. Trojan‐horse‐like stimuli‐responsive microcapsules
Parakhonskiy et al. Colloidal micro-and nano-particles as templates for polyelectrolyte multilayer capsules
Atkin et al. Preparation of aqueous core/polymer shell microcapsules by internal phase separation
JP2008540809A (ja) ヒドロゲルおよびヒドロゲル粒子
KR101591820B1 (ko) 마이크로입자 제조장치 및 방법
Liu et al. Preparation of monodisperse calcium alginate microcapsules via internal gelation in microfluidic-generated double emulsions
Lee et al. Harnessing interfacial phenomena to program the release properties of hollow microcapsules
US6495161B1 (en) Cytoprotective biocompatible containment systems for biologically active materials and methods of making same
Lima et al. Production methodologies of polymeric and hydrogel particles for drug delivery applications
CN105534952B (zh) 一种核壳结构复合多孔微球的制备方法
Zhai et al. Preparation and characterization of alginate microspheres for sustained protein delivery within tissue scaffolds
WO2021258668A1 (zh) 一种包裹疏水性固体粉末的p/h微球的制备方法
JP7082358B2 (ja) 中心コアを取り囲む架橋ヒドロゲルの外殻で作られたカプセルの製造方法
Huang et al. Engineering microcapsules for simultaneous delivery of combinational therapeutics
JP2010179095A (ja) 水又は水溶液を含有するマイクロカプセル及びその製造方法
Huang et al. Fabrication of multicore milli-and microcapsules for controlling hydrophobic drugs release using a facile approach
WO2009128476A1 (ja) 蓄熱シームレスカプセルおよびその製造方法
CN107875139A (zh) 一种壳核α‑生育酚微胶囊及其制备方法
JP2023549245A (ja) オイルコア包含マイクロカプセル
Yu et al. Hollow polyelectrolyte microcapsules as advanced drug delivery carriers
Ju et al. Lab-on-a-chip fabrication of polymeric microparticles for drug encapsulation and controlled release
CN105919944B (zh) 一种含凝胶内核的可降解聚合物微球及其制备方法和应用
de Silva et al. Preparation and timed release properties of self-rupturing gels

Legal Events

Date Code Title Description
ENP Entry into the national phase

Ref document number: 2021571570

Country of ref document: JP

Kind code of ref document: A

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

Ref document number: 20942397

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: 20942397

Country of ref document: EP

Kind code of ref document: A1