CN115252799A - Ultrahigh drug-loading compound prepared based on phase transfer inhibition principle and method thereof - Google Patents

Ultrahigh drug-loading compound prepared based on phase transfer inhibition principle and method thereof Download PDF

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CN115252799A
CN115252799A CN202210891544.6A CN202210891544A CN115252799A CN 115252799 A CN115252799 A CN 115252799A CN 202210891544 A CN202210891544 A CN 202210891544A CN 115252799 A CN115252799 A CN 115252799A
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acid
drug
derivatives
reactant
phase transfer
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刘东飞
霍青青
高玥
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China Pharmaceutical University
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China Pharmaceutical University
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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
    • A61K47/30—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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A61K38/1722—Plasma globulins, lactoglobulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/38—Albumins
    • A61K38/385—Serum albumin
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Abstract

The invention discloses an ultrahigh drug-loading compound prepared based on a phase transfer inhibition principle and a method thereof. The pharmaceutical composition comprises colloidal particles of an active pharmaceutical ingredient and a phase transfer inhibiting carrier material; wherein the mass of the water-soluble medicine component accounts for 1-90% of the mass of the whole compound; the encapsulation rate of the compound is 1% -100%; the particle size range of the compound is 50nm-1000 μm; the compound can obviously improve the encapsulation efficiency and the drug-loading rate of the drug, and has extremely high application value in the aspects of reducing the dosage of drug auxiliary materials, reducing immunoreaction and improving the compliance of patients; the carrier material can resist violent external force interference and effectively inhibit phase transfer of water-soluble polypeptide and protein. The invention also discloses a preparation method of the ultrahigh drug-loaded compound prepared based on the phase transfer inhibition principle.

Description

Ultrahigh drug-loading compound prepared based on phase transfer inhibition principle and method thereof
Technical Field
The invention relates to an ultrahigh drug-loading compound prepared based on a phase transfer inhibition principle and a method thereof, belonging to the technical field of pharmaceutical preparations.
Technical Field
With the rapid development of biotechnology, polypeptide and protein drugs have great potential in disease treatment. The medicaments are widely applied to the treatment of diseases such as tumors, cardiovascular diseases, endocrine metabolism and the like, the market growth speed of the medicaments is far higher than that of small molecular medicaments, and the medicaments occupy larger market share in the future[1]. By the end of 2020, about 80 peptide drugs are approved all over the world, the market scale of bioengineering protein drugs is estimated to increase from $ 817.7 hundred million in 2020 to $ 1107.8 million in 2026, the annual composite increasing speed reaches 4%, and the development space is extremely wide[2,3]. However, most of polypeptide and protein drugs have the problems of short half-life, low bioavailability, poor stability and the like, and particularly when the drugs are used for treating chronic diseases, the drugs are often required to be injected and administered for a long time and frequently, so that not only can serious inflammatory reaction be brought, but also the patient compliance is low[4]。
In order to solve the problems of short half-life period, low bioavailability and the like of polypeptide and protein medicines, in recent years, the development of the polypeptide and protein medicines in clinical application is promoted to a certain extent by technical means of preparing the polypeptide and protein medicines into polymers and packaging the polymers in lipid materials, high-molecular block polymers and other biological materials to prepare nano or micron preparations and the like, but the development of the polypeptide and protein medicines in clinical application is also promoted to a certain extent by the technical means of preparing the polypeptide and protein medicines into the polymers, packaging the polymers in lipid materials, high-molecular block polymers and other biological materials and the like[5]. For example, the strict requirements on drug-polymer interaction lead to poor universality of the method, and the problems of low encapsulation efficiency and drug loading rate caused by leakage of water-soluble drugs in the wrapping process, severe immune response caused by high auxiliary material consumption, severe burst release and the like limit the clinical application of the drugs.
To solve these problems, researchers are continuously conducting related research. In the research of water-in-oil-in-water (w/o/w) disclosed in CN102988301A, firstly, the medicine is dissolved in water, and is prepared into colostrum with an oil phase, and then, the colostrum is subjected to secondary emulsification to prepare a multiple emulsion method of water-in-oil-in-water (w/o/w), so that the process is complicated, the production cost is high, and the drug-loading rate is low; in the research disclosed in CN107537038a, a certain proportion of gelatin is added into the water phase in the emulsification process, and polypeptide and protein drugs are fixed in the water phase in the emulsification process by improving the viscosity of the water phase, so as to improve the encapsulation efficiency and the drug loading capacity of the microsphere preparation, but the research result shows that the encapsulation efficiency and the drug loading capacity of the microsphere preparation prepared by the method are only 72.9% and 2.3%; in the technical method disclosed by CN102302455A, a water-in-oil-in-water (w/o/o) method is adopted to prepare a hydrophilic drug-encapsulated microsphere preparation, wherein a water-soluble drug is dissolved in water or a phosphate buffer solution, a carrier material is dissolved in an organic solvent, water-in-oil type colostrum is obtained after vortex, then the colostrum is mixed with liquid paraffin containing an emulsifier, water-in-oil type compound emulsion is obtained by vortex, and the hydrophilic drug-encapsulated microsphere preparation is obtained after petroleum ether washing. The high adjuvant dosage and the multiple administration frequency caused by the lower drug loading are disadvantageous to the clinical application of the pharmaceutical preparation.
Therefore, for water-soluble polypeptide and protein drugs, a simple, efficient and universal encapsulation method is needed to improve the encapsulation efficiency and drug loading capacity, avoid drug burst release, prolong the in-vitro and in-vivo release cycle, improve patient compliance, and further promote the clinical application of water-soluble polypeptide and protein drugs.
Disclosure of Invention
The invention aims to solve the technical problem of providing an ultrahigh drug-loading compound prepared based on a phase transfer inhibition principle, which is used for improving the encapsulation efficiency and the drug loading capacity of nano and micron compounds.
The technical problem to be solved by the invention is to provide a preparation method of the drug compound.
In order to solve the problems, the invention adopts the following technical scheme:
an ultrahigh drug-loading compound prepared based on a phase transfer inhibition principle is characterized by comprising an active drug component colloid and a carrier material which inhibits phase transfer and wraps a drug; wherein, the mass of the active medicine component accounts for 1 to 90 percent of the mass of the whole compound; the encapsulation rate of the drug-loaded compound is 1-100%; the particle size range of the medicine-carrying compound is 50nm-1000 mu m; the carrier material can resist violent external force interference and effectively inhibit phase transfer of water-soluble polypeptide and protein. The invention also discloses a preparation method of the ultrahigh drug-loaded compound prepared based on the phase transfer inhibition principle.
Wherein, the active pharmaceutical ingredient is one or a mixture of several of water-soluble protein and polypeptide substances.
<xnotran> , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 8978 zxft 8978, , , , , , , , , , , , , , , , , , , , , , β - , </xnotran> Zein, pepsin, streptokinase, thromboplastin, interferon, prolactin, asparaginase, anakinra, collagenase, streptokinase, mivampicin, pranopal Luo Lintai, cothrelin, enfuvirtide, carfilzomib, cobicistat, lirantide, dulaglutide, buserelin, ghrelin, carbitol, corticotropin, bone morphogenetic protein, dinil, reteplase, sha Ge statin, blood coagulation factors, secretin, aximab, growth hormone antagonists, botulinum toxin, feggastine, enfuvirdi, or vasoactive intestinal peptide.
Wherein, the carrier material comprises one or a mixture of several of polymer and lipid material.
Wherein the polymer material comprises: the polymer comprises but is not limited to hydrophobic chitosan and derivatives thereof, hypromellose acetate succinate and derivatives thereof, polymethacrylate and derivatives thereof, polyvinyl acetate phthalate and derivatives thereof, polyethylcellulose and derivatives thereof, acetalized dextran and derivatives thereof, polylactic acid-glycolic acid copolymer and derivatives thereof, poly-N-isopropylacrylamide) and analogues and derivatives thereof, polycaprolactone and derivatives thereof, polyalkyl-cyanoacrylate and derivatives thereof, polystyrene and derivatives thereof, polylactic acid/polyethylene glycol block copolymer and derivatives thereof, polylactic acid glycolic acid/polylysine block copolymer and derivatives thereof, polylactic acid glycolic acid/polyaspartic acid block copolymer and derivatives thereof, polylactic acid glycolic acid/polyglutamic acid block copolymer and derivatives thereof, polyethylene glycol/polylysine block copolymer and derivatives thereof, polyethylene glycol/polyglutamic acid block copolymer and derivatives thereof, or polymethacrylic acid/polymethyl methacrylate block copolymer and derivatives thereof, one or a mixture of several of the polymethacrylic acid/polymethyl methacrylate block copolymer and derivatives thereof; the lipid material comprises one or more of fatty acid and derivatives thereof, glyceride and derivatives thereof, waxy materials and derivatives thereof, steroid materials and derivatives thereof, and phospholipid materials and derivatives thereof.
Wherein, the external force interference comprises but is not limited to the mixing action of one or more of stirring, shearing, high-pressure homogenization, extrusion, centrifugation and ultrasound.
The preparation method of the ultrahigh drug-loaded compound based on the phase transfer inhibition principle comprises the following steps: mixing a first reactant and a second reactant to enable a water-soluble drug active ingredient to form drug colloid particles; adding a third reactant; centrifuging, removing the supernatant, and dispersing in a fourth reactant to obtain an oil phase containing the drug colloid particles and the carrier material; and (3) preparing the oil phase and the water phase into oil-in-water emulsion droplets through a microfluidic device, and curing the emulsion droplets by a solvent diffusion method to obtain the drug-loaded compound.
Wherein, the first reactant is a solution formed by a medicinal active ingredient and a solvent I; the second reactant is a poor solvent II of the active pharmaceutical ingredient; the third reactant is a poor solvent III of the active pharmaceutical ingredient; the fourth reactant is a solution formed by a carrier material and a poor solvent IV of a medicine active ingredient.
Wherein, the solvent I and the solvent II are mutually soluble, and the solvent II and the solvent III are mutually soluble.
Wherein, the solvent I is water or aqueous solution containing acidic, alkaline and organic solvents; the solvent II is an organic solvent; the solvent III is an organic solvent; the solvent IV is an organic solvent.
Wherein the acidic solution includes but is not limited to any one or a mixture of any more of the substances including high chloric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid, sulfuric acid, nitric acid, chloric acid, phosphoric acid, oxalic acid, sulfurous acid, nitrous acid, pyruvic acid, hydrofluoric acid, formic acid, lactic acid, benzoic acid, propionic acid, glacial acetic acid, acrylic acid, acetic acid, oleic acid, carbonic acid, hydrosulfuric acid, hypochlorous acid, boric acid, metasilicic acid, silicic acid, lactic acid, or stearic acid; the alkaline solution comprises any one or a mixture of more of sodium hydroxide, potassium hydroxide, ammonia water, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium acetate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate or dipotassium hydrogen phosphate.
Wherein, the organic solvent II includes but is not limited to any one or a mixture of several of methanol, ethanol, ethylene glycol, diethylene glycol, isopropanol, 1-propanol, 1,2-propanediol, 1,3-propanediol, butanol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 1,5-pentanediol, 2-butoxyethanol, glycerol, methyldiethanolamine, diethanolamine, acetone, acetonitrile, diethylenetriamine, dimethoxyethane, ethylamine, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetaldehyde, pyridine, triethylene glycol, ethyl acetate, dimethyl carbonate, dichloromethane, trichloromethane, cyclohexane or n-octanol.
The solvent III comprises but is not limited to benzene, n-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, cyclopentane, dichloromethane, trichloromethane, dichloroethane, diethyl ether, n-heptane, n-hexane, methyl ethyl ketone, isooctane, pentane, dipropyl ether, tetrachloroethane, toluene, trichloroethane, xylene, ethyl acetate or a mixture of any one or more of dimethyl carbonate.
The solvent IV comprises, but is not limited to, one or a mixture of more of benzene, n-butanol, carbon tetrachloride, chloroform, cyclohexane, cyclopentane, dichloromethane, trichloromethane, dichloroethane, diethyl ether, n-heptane, n-hexane, methyl ethyl ketone, isooctane, pentane, dipropyl ether, tetrachloroethane, toluene, trichloroethane, xylene, ethyl acetate or dimethyl carbonate.
Wherein the aqueous phase includes, but is not limited to, any one or a mixture of several of alkyl benzene sulfonate, alpha-olefin sulfonate, alpha-sulfo monocarboxylic acid ester, succinate sulfonate, sodium dodecylbenzene sulfonate, oleic soap, stearic soap, lauric soap, rosin oil soap, alkyl sulfonate, alkyl sulfate, alkyl benzyl sulfonate, alkyl naphthyl sulfonate, alkyl glyceryl ether sulfonate, lignosulfonate, phosphate ester salt, sulfate ester salt, quaternary ammonium salt, octadecyl trimethyl ammonium chloride, hexadecyl trimethyl ammonium chloride and other alkyl ammonium salts, lecithin, fatty acid glyceride, sucrose fatty acid ester, sorbitan fatty acid, polysorbate, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, polyoxyethylene-polyoxypropylene block copolymer, fluorocarbon surfactant, silicon-containing surfactant, biosurfactant, crown ether type surfactant, gum arabic, tragacanth, gelatin, apricot gum, egg yolk, polyvinylpyrrolidone, or solid particulate emulsifier.
The invention has the following function principle:
the invention provides a universal drug-loaded compound capable of effectively improving the encapsulation efficiency and the drug-loaded capacity, and a preparation method of the compound. At present, the mode of improving the half-life, bioavailability and stability of water-soluble polypeptides and protein drugs mostly depends on carrying out molecular modification (amino acid substitution, PEG modification, glycosylation or fusion long-acting fragment) on the polypeptides and proteins and preparing a nano-scale and micro-scale drug delivery system by adopting a preparation method (utilizing interaction and covalent modification between drugs and polymers). However, the molecular structures of the drugs are various, and the properties are complex, so that the traditional strategy is difficult to realize the universal improvement on the half-life period, the bioavailability and the stability of the water-soluble polypeptide and protein drugs, and simultaneously, the encapsulation efficiency and the drug loading rate are lower due to the rapid phase transfer of the water-soluble drugs in the preparation wrapping process.
Compared with drug molecules, the colloidal particles have limited surface properties and are easy to regulate and control, so that the ultrahigh drug-loaded compound prepared by the phase transfer inhibition method slows down the thermal motion of the drug molecules in a bulk phase by converting the water-soluble drug molecules into the colloidal particles; meanwhile, by utilizing the enrichment activity of the amphiphilic polymer (block polymer and graft polymer) and the lipid material at the interface, the enrichment amount of the amphiphilic polymer material and the lipid material at the interface is increased along with the increase of the content of the amphiphilic polymer material and the lipid material in the system, the arrangement of molecules at the interface is changed from a flat state to a vertical state, the hydrophobic ends are mutually wound, and a layer of dense three-dimensional interface film is formed at the interface to prevent colloidal particles from crossing an oil-water interface (figure 14). The strategy can effectively inhibit the phase transfer of water-soluble polypeptide and protein medicines, remarkably improve the encapsulation efficiency and drug-loading rate of the medicines and avoid the sudden release of the medicines.
Has the advantages that: the invention has the following advantages:
1. the ultrahigh drug-loading compound prepared based on the phase transfer inhibition principle comprises water-soluble drug component colloid particles and a carrier material which inhibits phase transfer and wraps a drug; the water-soluble medicine component is dispersed in the oil phase in the form of colloid particles, a carrier material for inhibiting phase transfer and wrapping the medicine is adsorbed on an oil-water interface, and a three-dimensional interface film formed by the carrier material adsorbed on the interface is utilized to inhibit the phase transfer of the water-soluble medicine component in the emulsification process, so that effective encapsulation is realized; has the characteristics of universality, simplicity, high encapsulation efficiency and high drug-loading rate.
2. The ultrahigh drug-loading compound prepared based on the phase transfer inhibition principle can realize about 100% of encapsulation effect in the preparation process, and particularly, the particle size of the compound can realize about 100% of encapsulation in the range of micron and nanometer; in particular, encapsulation of about 100% can still be achieved when the ratio of drug to polymer is high. Effectively reduces the dosage of the medicinal auxiliary materials, and further reduces the inflammatory reaction caused by high auxiliary material dosage.
3. The ultrahigh drug-loading compound prepared based on the phase transfer inhibition principle can effectively control the release of drugs, avoid the burst release of the drugs, prolong the release period of the drugs, reduce the administration frequency, further improve the inflammatory reaction caused by multiple administration frequencies, improve the compliance of patients and have good clinical application prospect.
4. The ultrahigh drug-loading compound prepared based on the phase transfer inhibition principle has no essential requirement on whether the drug-polymer has interaction or not, can be applied to water-soluble drug components with various structures, and has strong universality.
5. The ultrahigh drug-loading compound prepared based on the phase transfer inhibition principle has no essential requirement on whether the interaction between the drug and the polymer exists, and the polymer has wide selection range and strong universality.
6. The ultrahigh drug-loading compound prepared based on the phase transfer inhibition principle has strong capacity of resisting external force interference and is easy for industrial scale-up production.
7. The ultrahigh drug-loading compound prepared by the phase transfer inhibition method has the advantages of simple process, small batch difference and easy industrial amplification production.
Drawings
Figure 1, ability of spermine modified Acetalized Dextran (ADS) to inhibit phase transfer of Insulin (Insulin) nanoparticles under the conditions of example 1.
FIG. 2 shows the ability of methoxypolyethylene glycol polylactic acid-glycolic acid copolymer (mPEG-b-PLGA) to inhibit phase transfer of Insulin (Insulin) nanoparticles under the conditions of example 10.
FIG. 3 shows the ability of spermine-modified poly (lactic-co-glycolic acid) (PLS) to inhibit phase transfer of Exenatide (Exenatide) nanoparticles under the conditions of example 21.
FIG. 4, optical microscope photograph of Insulin (Insulin) and spermine modified Acetalized Dextran (ADS) Insulin @ ADS micro-complex prepared under the conditions of example 1.
FIG. 5 optical microscope photo of Insulin (Insulin) and spermine modified Acetalized Dextran (ADS) Insulin @ ADS micro-complex prepared under the conditions of example 2.
Figure 6, optical microscope photograph of Insulin (Insulin) and spermine modified Acetalized Dextran (ADS) Insulin @ ADS micron complex prepared under the conditions of example 3.
FIG. 7 is an optical micrograph of Exenatide (Exenatide) and spermine-modified poly (lactic acid-co-glycolic acid) Exenatide @ PLS nanocomposite prepared under the conditions of example 20.
FIG. 8 is an optical micrograph of Exenatide (Exenatide) and spermine-modified poly (lactic acid-co-glycolic acid) Exenatide @ PLS nanocomposite prepared under the conditions of example 21.
FIG. 9 shows the ability of amphiphilic polymer spermine modified Acetalized Dextran (ADS) to resist external force interference and inhibit phase transfer of Insulin (Insulin) under the conditions of example 1.
FIG. 10 shows the ability of amphiphilic polymer spermine modified Acetalized Dextran (ADS) to resist external force interference and inhibit phase transfer of Bovine Serum Albumin (BSA) under the conditions of example 4.
FIG. 11, the ability of amphiphilic polymer spermine modified Acetalized Dextran (ADS) to resist external force interference and inhibit phase transfer of beta-lactoglobulin (beta-LG) under the conditions of example 7.
Figure 12 encapsulation efficiency under the conditions of examples 1,2, 3.
FIG. 13 shows the drug loading under the conditions of examples 1,2 and 3.
Fig. 14, amphiphilic material self-assembles at the interface to form a three-dimensional interface membrane to block colloidal particle phase transfer.
Detailed Description
The invention will be better understood from the following examples. However, it is easily understood by those skilled in the art that the contents described in the embodiments are only for illustrating the present invention and should not be limited to the invention described in detail in the claims.
Example 1
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: spermine modified Acetalized Dextran (ADS) wrapped Insulin (Insulin) micron compound (Insulin @ ADS) and preparation method thereof.
Taking a medicinal active ingredient insulin and 0.02M hydrochloric acid solution as a first reactant, and adding a second reactant acetone under the stirring condition to obtain insulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing ADS (20 mg/mL). The resulting mixture (Insulin: ADS =10: 20mg/mL) was mixed with a 2% (W/v) polyvinyl alcohol solution to prepare O/W emulsion droplets by a microfluidic device, and the emulsion droplets were solidified by a solvent diffusion method to obtain an Insulin @ ADS microcomposite.
Example 2
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: an Insulin (Insulin @ ADS) compound coated by spermine modified Acetalized Dextran (ADS) and a preparation method thereof.
Taking a medicinal active ingredient insulin and 0.02M hydrochloric acid solution as a first reactant, and adding a second reactant acetone under the stirring condition to obtain insulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing ADS (40 mg/mL). The resulting mixture (Insulin: ADS =60: 40mg/mL) was mixed with a 2% (W/v) polyvinyl alcohol solution by a microfluidics apparatus to prepare O/W emulsion droplets, and the emulsion droplets were solidified by a solvent diffusion method to obtain an Insulin @ ADS microcomposite.
Example 3
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: spermine modified Acetalized Dextran (ADS) wrapped Insulin (Insulin) micron compound (Insulin @ ADS) and preparation method thereof.
Taking a medicinal active ingredient insulin and 0.02M hydrochloric acid solution as a first reactant, and adding a second reactant acetone under the stirring condition to obtain insulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing ADS (50 mg/mL). The resulting mixture (Insulin: ADS =100: 50mg/mL) was mixed with a 2% (W/v) polyvinyl alcohol solution by a microfluidics apparatus to prepare O/W emulsion droplets, and the emulsion droplets were solidified by a solvent diffusion method to obtain an Insulin @ ADS microcomposite.
Example 4
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: spermine modified Acetalized Dextran (ADS) coated Bovine Serum Albumin (BSA) micro-composite (BSA @ ADS) and preparation method thereof.
Taking a water solution of a pharmaceutical active ingredient bovine serum albumin as a first reactant, and adding a second reactant acetonitrile under the stirring condition to obtain bovine serum albumin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing ADS (20 mg/mL). The resulting mixture (BSA: ADS =10: 20mg/mL) was mixed with a 2% (W/v) polyvinyl alcohol solution to prepare an O/W emulsion droplet by a microfluidic device, and the emulsion droplet was solidified by a solvent diffusion method to obtain a micro-composite of BSA @ ADS.
Example 5
The embodiment discloses a super-high entrapped protein and polypeptide micron composite: spermine modified Acetalized Dextran (ADS) coated Bovine Serum Albumin (BSA) micro-composite (BSA @ ADS) and preparation method thereof.
Taking a water solution of a pharmaceutical active ingredient bovine serum albumin as a first reactant, and adding a second reactant acetonitrile under the stirring condition to obtain bovine serum albumin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing ADS (40 mg/mL). And (3) mixing the obtained mixture (BSA: ADS =60: 40mg/mL) with a 2% (W/v) polyvinyl alcohol solution to prepare O/W emulsion droplets through a microfluidic device, and solidifying the emulsion droplets through a solvent diffusion method to obtain the BSA @ ADS micron composite.
Example 6
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: spermine modified Acetalized Dextran (ADS) coated Bovine Serum Albumin (BSA) micro-composite (BSA @ ADS) and preparation method thereof.
Taking a water solution of a pharmaceutical active ingredient bovine serum albumin as a first reactant, and adding a second reactant acetonitrile under the stirring condition to obtain bovine serum albumin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing ADS (30 mg/mL). And (3) mixing the obtained mixture (BSA: ADS =70: 30mg/mL) with a 2% (W/v) polyvinyl alcohol solution to prepare an O/W emulsion drop through a microfluidic device, and solidifying the emulsion drop through a solvent diffusion method to obtain a BSA @ ADS micron composite.
Example 7
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: spermine modified Acetalized Dextran (ADS) wrapped beta-lactoglobulin (beta-LG) micron compound (beta-LG @ ADS) and preparation method thereof.
Taking a water solution of a pharmaceutical active ingredient beta-lactoglobulin as a first reactant, and adding a second reactant tetrahydrofuran under the stirring condition to obtain beta-lactoglobulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with a fourth reactant dimethyl carbonate solution containing ADS (20 mg/mL). Preparing O/W emulsion droplets from the obtained mixture (beta-LG: ADS =10: 20mg/mL) and 2% (W/v) polyvinyl alcohol solution through a microfluidic device, and solidifying the emulsion droplets through a solvent diffusion method to obtain a beta-LG @ ADS micron composite.
Example 8
The embodiment discloses a protein and polypeptide micro-composite with ultrahigh entrapment: spermine modified Acetalized Dextran (ADS) wrapped beta-lactoglobulin (beta-LG) micron compound (beta-LG @ ADS) and preparation method thereof.
Taking an aqueous solution of a pharmaceutical active ingredient beta-lactoglobulin as a first reactant, and adding a second reactant tetrahydrofuran under the stirring condition to obtain beta-lactoglobulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with a fourth reactant dimethyl carbonate solution containing ADS (40 mg/mL). And (3) preparing O/W emulsion droplets from the obtained mixture (beta-LG: ADS =60: 40mg/mL) and a 2% (W/v) polyvinyl alcohol solution through a microfluidic device, and solidifying the emulsion droplets through a solvent diffusion method to obtain the beta-LG @ ADS micron composite.
Example 9
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: spermine modified Acetalized Dextran (ADS) wrapped beta-lactoglobulin (beta-LG) micron compound (beta-LG @ ADS) and a preparation method thereof.
Taking an aqueous solution of a pharmaceutical active ingredient beta-lactoglobulin as a first reactant, and adding a second reactant tetrahydrofuran under the stirring condition to obtain beta-lactoglobulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing ADS (30 mg/mL). And (3) preparing O/W emulsion droplets from the obtained mixture (beta-LG: ADS =70: 30mg/mL) and a 2% (W/v) polyvinyl alcohol solution through a microfluidic device, and solidifying the emulsion droplets through a solvent diffusion method to obtain the beta-LG @ ADS micron composite.
Example 10
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: a methoxypolyethylene glycol polylactic acid-glycolic acid copolymer (mPEG-b-PLGA) Insulin (Insulin) -coated micro-composite (Insulin @ mPEG-b-PLGA) and a preparation method thereof.
Taking insulin as a medicinal active ingredient and 0.02M hydrochloric acid solution as a first reactant, and adding acetone as a second reactant under the stirring condition to obtain insulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing mPEG-b-PLGA (40 mg/mL). The resulting mixture (Insulin: mPEG-b-PLGA =10: 40mg/mL) was mixed with a 2% (W/v) polyvinyl alcohol solution by a microfluidics apparatus to prepare O/W emulsion droplets, and the emulsion droplets were solidified by a solvent diffusion method to obtain an Insulin @ mPEG-b-PLGA micro-composite.
Example 11
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: a methoxypolyethylene glycol polylactic acid-glycolic acid copolymer (mPEG-b-PLGA) Insulin (Insulin) -coated micro-composite (Insulin @ mPEG-b-PLGA) and a preparation method thereof.
Taking insulin as a medicinal active ingredient and 0.02M hydrochloric acid solution as a first reactant, and adding acetone as a second reactant under the stirring condition to obtain insulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing mPEG-b-PLGA (40 mg/mL). The resulting mixture (Insulin: mPEG-b-PLGA =60: 40mg/mL) was mixed with a 2% (W/v) polyvinyl alcohol solution by a microfluidics apparatus to prepare O/W emulsion droplets, and the emulsion droplets were solidified by a solvent diffusion method to obtain an Insulin @ mPEG-b-PLGA micro-composite.
Example 12
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: methoxy polyethylene glycol polylactic acid-glycolic acid copolymer (mPEG-b-PLGA) coated Bovine Serum Albumin (BSA) micro-composite (BSA @ mPEG-b-PLGA) and a preparation method thereof.
Taking a water solution of a pharmaceutical active ingredient bovine serum albumin as a first reactant, and adding a second reactant acetonitrile under the condition of stirring to obtain bovine serum albumin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing mPEG-b-PLGA (40 mg/mL). The resulting mixture (BSA: mPEG-b-PLGA =10 40mg/mL) was mixed with a 2% (W/v) polyvinyl alcohol solution to prepare O/W emulsion droplets by a microfluidic device, and the emulsion droplets were solidified by a solvent diffusion method to obtain BSA @ mPEG-b-PLGA micro-composites.
Example 13
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: methoxy polyethylene glycol polylactic acid-glycolic acid copolymer (mPEG-b-PLGA) wraps the micro-complex (BSA) @ mPEG-b-PLGA) of Bovine Serum Albumin (BSA) and the preparation method thereof.
Taking a water solution of a pharmaceutical active ingredient bovine serum albumin as a first reactant, and adding a second reactant acetonitrile under the stirring condition to obtain bovine serum albumin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing mPEG-b-PLGA (40 mg/mL). The resulting mixture (BSA: mPEG-b-PLGA =60 40mg/mL) was mixed with a 2% (W/v) polyvinyl alcohol solution to prepare O/W emulsion droplets by a microfluidic device, and the emulsion droplets were solidified by a solvent diffusion method to obtain BSA @ mPEG-b-PLGA micro-composites.
Example 14
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: methoxy polyethylene glycol polylactic acid-glycolic acid copolymer (mPEG-b-PLGA) wraps beta-lactoglobulin (beta-LG) micron compound (beta-LG @ mPEG-b-PLGA) and preparation method thereof.
Taking an aqueous solution of a pharmaceutical active ingredient beta-lactoglobulin as a first reactant, and adding a second reactant tetrahydrofuran under the stirring condition to obtain beta-lactoglobulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate and collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing mPEG-b-PLGA (40 mg/mL). The resulting mixture (β -LG: mPEG-b-PLGA =10: 40mg/mL) was mixed with a 2% (W/v) polyvinyl alcohol solution by a microfluidic device to prepare O/W emulsion droplets, and the emulsion droplets were solidified by a solvent diffusion method to obtain a micro-composite of β -LG @ mPEG-b-PLGA.
Example 15
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: methoxy polyethylene glycol polylactic acid-glycolic acid copolymer (mPEG-b-PLGA) wraps beta-lactoglobulin (beta-LG) micron compound (beta-LG @ mPEG-b-PLGA) and a preparation method thereof.
Taking a water solution of a pharmaceutical active ingredient beta-lactoglobulin as a first reactant, and adding a second reactant tetrahydrofuran under the stirring condition to obtain beta-lactoglobulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing mPEG-b-PLGA (40 mg/mL). And (3) preparing O/W emulsion drops by a microfluidic device by using the obtained mixture (beta-LG: mPEG-b-PLGA = 60) and a 2% (W/v) polyvinyl alcohol solution, and solidifying the emulsion drops by a solvent diffusion method to obtain the beta-LG @ mPEG-b-PLGA micron compound.
Example 16
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: spermine modified polylactic acid-glycolic acid copolymer (PLS) Insulin-encapsulated micron complex (Insulin @ PLS) and preparation method thereof.
Taking a medicinal active ingredient insulin and 0.02M hydrochloric acid solution as a first reactant, and adding a second reactant acetone under the stirring condition to obtain insulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing PLS (40 mg/mL). The resulting mixture (Insulin: PLS =60: 40mg/mL) was mixed with a 2% (W/v) polyvinyl alcohol solution by a microfluidics apparatus to prepare O/W emulsion droplets, and the emulsion droplets were solidified by a solvent diffusion method to obtain an Insulin @ PLS microcomposite.
Example 17
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: spermine modified polylactic acid-glycolic acid copolymer (PLS) coated Insulin (Insulin) micro-complex (Insulin @ PLS) and a preparation method thereof.
Taking insulin as a medicinal active ingredient and 0.02M hydrochloric acid solution as a first reactant, and adding acetone as a second reactant under the stirring condition to obtain insulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate and collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing PLS (30 mg/mL). The resulting mixture (Insulin: PLS =70: 30mg/mL) was mixed with a 2% (W/v) polyvinyl alcohol solution by a microfluidics apparatus to prepare O/W emulsion droplets, and the emulsion droplets were solidified by a solvent diffusion method to obtain an Insulin @ PLS microcomposite.
Example 18
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: spermine modified polylactic acid-glycolic acid copolymer (PLS) coated with Bovine Serum Albumin (BSA) micron complex (BSA @ PLS) and a preparation method thereof.
Taking a water solution of a pharmaceutical active ingredient bovine serum albumin as a first reactant, and adding a second reactant acetonitrile under the stirring condition to obtain bovine serum albumin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with a solution of the fourth reactant dimethyl carbonate, PLS (30 mg/mL). The resulting mixture (BSA: PLS =70 30mg/mL) was mixed with a 2% (W/v) polyvinyl alcohol solution by a microfluidics apparatus to prepare O/W emulsion droplets, and the emulsion droplets were solidified by a solvent diffusion method to obtain a micro-complex of BSA @ PLS.
Example 19
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: spermine modified polylactic acid-glycolic acid copolymer (PLS) coated beta-lactoglobulin (beta-LG) micron complex (beta-LG @ PLS) and a preparation method thereof.
Taking a water solution of a pharmaceutical active ingredient beta-lactoglobulin as a first reactant, and adding a second reactant tetrahydrofuran under the stirring condition to obtain beta-lactoglobulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing PLS (30 mg/mL). The resulting mixture (β -LG: PLS =70: 30mg/mL) was mixed with a 2% (W/v) polyvinyl alcohol solution by a microfluidic device to prepare an O/W emulsion droplet, and the emulsion droplet was solidified by a solvent diffusion method to obtain a micro-composite of β -LG @ PLS.
Example 20
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: exenatide (Exenatide @ PLS) micron compound (Exenatide @ PLS) of Exenatide encapsulated by spermine modified polylactic acid-glycolic acid copolymer and a preparation method thereof.
Taking an aqueous solution of the pharmaceutical active ingredient exenatide as a first reactant, and adding a second reactant acetonitrile under the stirring condition to obtain exenatide colloid particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate and collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing PLS (20 mg/mL). The resulting mixture (Exenatide: PLS =20:20 mg/mL) was mixed with a 2% (W/v) polyvinyl alcohol solution by a microfluidic device to prepare an O/W emulsion droplet, and the emulsion droplet was solidified by a solvent diffusion method to obtain a micro-complex of Exenatide @ PLS.
Example 21
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: an Exenatide (Exenatide) micron compound (Exenatide @ PLS) coated by spermine modified polylactic acid-glycolic acid copolymer (PLS) and a preparation method thereof.
Taking an aqueous solution of an active pharmaceutical ingredient exenatide as a first reactant, and adding a second reactant acetonitrile under the condition of stirring to obtain exenatide colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing PLS (40 mg/mL). The resulting mixture (Exenatide: PLS =60: 40mg/mL) was mixed with a 2% (W/v) polyvinyl alcohol solution by a microfluidic device to prepare an O/W emulsion droplet, and the emulsion droplet was solidified by a solvent diffusion method to obtain an Exenatide @ PLS nanocomposite.
Example 22
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: spermine modified Acetalized Dextran (ADS) wrapped Insulin (Insulin) nano-composite (Insulin @ ADSN) and a preparation method thereof.
Taking a medicinal active ingredient insulin and 0.02M hydrochloric acid solution as a first reactant, and adding a second reactant acetone under the stirring condition to obtain insulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing ADS (20 mg/mL). Performing probe ultrasonic treatment on the obtained 0.3mL mixture (Insulin: ADS =10: 20mg/mL) and 0.6mL 1% (w/v) poloxamer 407 aqueous solution to obtain colostrum; under magnetic stirring, adding 6mL of 1% (w/v) poloxamer 407 aqueous solution at constant speed by using an injection pump to solidify the emulsion droplets to obtain the Insulin @ ADS nano composite (Insulin @ ADSN).
Example 23
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: spermine modified Acetalized Dextran (ADS) coated Bovine Serum Albumin (BSA) nano-composite (BSA @ ADSN) and preparation method thereof.
Taking a water solution of a pharmaceutical active ingredient bovine serum albumin as a first reactant, and adding a second reactant acetonitrile under the stirring condition to obtain bovine serum albumin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution (20 mg/mL) containing ADS. Performing ultrasonic treatment on the obtained 0.3mL mixture (BSA: ADS =10: 20mg/mL) and 0.6mL of 1% (w/v) poloxamer 407 aqueous solution by using a probe to obtain colostrum; under magnetic stirring, using injection pump to add 6mL of 1% (w/v) poloxamer 407 aqueous solution at constant speed to solidify the emulsion drop, and obtaining BSA @ ADS nano-composite (BSA @ ADSN).
Example 24
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: spermine modified Acetalized Dextran (ADS) wrapped beta-lactoglobulin (beta-LG) nano-composite (beta-LG @ ADSN) and a preparation method thereof.
Taking an aqueous solution of a pharmaceutical active ingredient beta-lactoglobulin as a first reactant, and adding a second reactant tetrahydrofuran under the stirring condition to obtain beta-lactoglobulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing ADS (20 mg/mL). Performing ultrasonic treatment on the obtained 0.3mL mixture (beta-LG: ADS =10: 20mg/mL) and 0.6mL of 1% (w/v) poloxamer 407 aqueous solution by a probe to obtain colostrum; and under the magnetic stirring, a 6mL 1% (w/v) poloxamer 407 aqueous solution is added at a constant speed by adopting an injection pump to solidify the emulsion drop to obtain the beta-LG @ ADS nano composite (beta-LG @ ADSN).
Example 25
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: spermine modified polylactic acid-glycolic acid copolymer (PLS) coated Insulin (Insulin) nano-composite (Insulin @ PLSN) and a preparation method thereof.
Taking a medicinal active ingredient insulin and 0.02M hydrochloric acid solution as a first reactant, and adding a second reactant acetone under the stirring condition to obtain insulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing PLS (20 mg/mL). Performing ultrasonic treatment on the obtained 0.3mL mixture (Insulin: PLS =10: 20mg/mL) and 0.6mL of 1% (w/v) poloxamer 407 aqueous solution by a probe to obtain colostrum; under magnetic stirring, a syringe pump is adopted to add 6mL of 1% (w/v) poloxamer 407 aqueous solution at a constant speed to solidify emulsion droplets, and the Insulin @ PLS nano-composite (Insulin @ PLSN) is obtained.
Example 26
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: spermine modified polylactic acid-glycolic acid copolymer (PLS) coated Bovine Serum Albumin (BSA) nano-composite (BSA @ PLSN N) and a preparation method thereof.
Taking a water solution of a pharmaceutical active ingredient bovine serum albumin as a first reactant, and adding a second reactant acetonitrile under the stirring condition to obtain bovine serum albumin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing PLS (20 mg/mL). Performing ultrasonic treatment on the obtained 0.3mL mixture (BSA: PLS =10: 20mg/mL) and 0.6mL of 1% (w/v) poloxamer 407 aqueous solution by using a probe to obtain colostrum; and under the magnetic stirring, a syringe pump is adopted to add 6mL of 1% (w/v) poloxamer 407 aqueous solution at a constant speed to solidify the emulsion drop, so as to obtain the BSA @ PLS nano composite (BSA @ PLSN).
Example 27
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: a spermine modified polylactic acid-glycolic acid copolymer (PLS) coated beta-lactoglobulin (beta-LG) nano-composite (beta-LG @ PLSN N) and a preparation method thereof.
Taking a water solution of a pharmaceutical active ingredient beta-lactoglobulin as a first reactant, and adding a second reactant tetrahydrofuran under the stirring condition to obtain beta-lactoglobulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate and collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing PLS (20 mg/mL). Performing ultrasonic treatment on the obtained 0.3mL mixture (beta-LG: PLS =10: 20mg/mL) and 0.6mL of 1% (w/v) poloxamer 407 aqueous solution by a probe to obtain colostrum; and adding 6mL of 1% (w/v) poloxamer 407 aqueous solution into the mixture at a constant speed by using an injection pump under magnetic stirring to solidify the emulsion droplets to obtain the beta-LG @ PLS nano composite (beta-LG @ PLSN).
Example 28
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: a methoxypolyethylene glycol polylactic acid-glycolic acid copolymer (mPEG-b-PLGA) Insulin-encapsulated nano-composite (Insulin @ mPEG-b-PLGAN) and a preparation method thereof.
Taking insulin as a medicinal active ingredient and 0.02M hydrochloric acid solution as a first reactant, and adding acetone as a second reactant under the stirring condition to obtain colloidal particles of the medicinal active ingredient; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing mPEG-b-PLGA (20 mg/mL). Performing ultrasonic treatment on 0.3mL of the obtained mixture (Insulin: mPEG-b-PLGA = 10; and under the magnetic stirring, adding 6mL of 1% (w/v) poloxamer 407 aqueous solution into the solution at a constant speed by using an injection pump to solidify the emulsion droplets to obtain the Insulin @ mPEG-b-PLGA nano compound (Insulin @ mPEG-b-PLGAN).
Example 29
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: methoxy polyethylene glycol polylactic acid-glycolic acid copolymer (mPEG-b-PLGA) coated Bovine Serum Albumin (BSA) nano-composite (BSA @ mPEG-b-PLGAN) and a preparation method thereof.
Taking a water solution of a pharmaceutical active ingredient bovine serum albumin as a first reactant, and adding a second reactant acetonitrile under the stirring condition to obtain bovine serum albumin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing mPEG-b-PLGA (20 mg/mL). Performing ultrasonic treatment on the obtained 0.3mL mixture (BSA: mPEG-b-PLGA =10: 20mg/mL) and 0.6mL of 1% (w/v) poloxamer 407 aqueous solution by a probe to obtain colostrum; and under the magnetic stirring, a syringe pump is adopted to add 6mL of 1% (w/v) poloxamer 407 aqueous solution at a constant speed to solidify the emulsion drop, and the BSA @ mPEG-b-PLGA nano composite (BSA @ mPEG-b-PLGAN) is obtained.
Example 30
The embodiment discloses an ultrahigh drug-loaded compound prepared based on a phase transfer inhibition principle: a methoxy polyethylene glycol polylactic acid-glycolic acid copolymer (mPEG-b-PLGA) coated beta-lactoglobulin (beta-LG) nano composite (beta-LG @ mPEG-b-PLGA) and a preparation method thereof.
Taking an aqueous solution of a pharmaceutical active ingredient beta-lactoglobulin as a first reactant, and adding a second reactant tetrahydrofuran under the stirring condition to obtain beta-lactoglobulin colloidal particles; the colloidal particles were flocculated by adding the third reactant dimethyl carbonate, collected by centrifugation and mixed with the fourth reactant dimethyl carbonate solution containing mPEG-b-PLGA (20 mg/mL). Performing probe ultrasonic on the obtained 0.3mL mixture beta-LG, mPEG-b-PLGA =10, 20mg/mL) and 0.6mL of 1% (w/v) poloxamer 407 aqueous solution to obtain colostrum; under the magnetic stirring, 6mL (1%w/v) of poloxamer 407 aqueous solution is added at a constant speed by using an injection pump to solidify the emulsion drop, and the beta-LG @ mPEG-b-PLGA nano compound (beta-LG @ mPEG-b-PLGAN) is obtained.
Examples 31 to 45
Specific raw material selection is shown in table 1. Table 1 shows the results of the preparation processes of 1 st to 21 st according to the present invention.
TABLE 1
Figure BDA0003767747180000181
Figure BDA0003767747180000191
Examples 46 to 60
Specific raw material selection is shown in table 2. Table 2 shows the results of the preparation according to the invention using the preparation methods described in the 22 nd to 30 th.
TABLE 2
Figure BDA0003767747180000201
Figure BDA0003767747180000211
TABLE 3 drug encapsulation efficiency and drug loading rate of drug delivery systems prepared by conventional methods
Figure BDA0003767747180000212
Figure BDA0003767747180000221
TABLE 4 drug encapsulation efficiency and drug loading rate of drug delivery system prepared by the invention
Figure BDA0003767747180000222
Figure BDA0003767747180000231
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Claims (9)

1. An ultrahigh drug-loading compound prepared based on a phase transfer inhibition principle is characterized by comprising active drug ingredient colloidal particles and a carrier material which inhibits phase transfer and wraps a drug; wherein, the mass of the active medicine component accounts for 1 to 90 percent of the mass of the whole compound; the encapsulation efficiency of the compound is 1-100%; the particle size range of the drug compound is 50nm-1000 μm; the carrier material can effectively resist external force interference and effectively inhibit phase transfer of water-soluble polypeptide and protein.
2. The ultrahigh drug-loading compound prepared based on the phase transfer inhibition principle according to claim 1, wherein the active drug component is one or a mixture of water-soluble polypeptide and protein substances.
3. <xnotran> 2 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 8978 zxft 8978, , , , , , , , , , , , , , , , </xnotran> Keratin, mucin, casein, hemocyanin, serum albumin, ovalbumin, beta-lactoglobulin, zein, pepsin, streptokinase, thromboplastin, interferon, prolactin, asparaginase, anakinra, collagenase, streptokinase, mivawood peptide, pra Luo Lintai, coterelin, enfuvirtide, carfilzomib, cobicistat, lirana peptide, dulaglutide, buserelin, somatrelin, carbitol, corticotropin, bone morphogenetic protein, dinilukins, reteplase, sha Ge statin, blood coagulation factors, secretin, asimumab, growth hormone antagonists, botulinum toxin, feggastine, enfuvirdine, or vasoactive intestinal peptide.
4. The ultra-high drug-loaded complex prepared based on the phase transfer inhibition principle according to claim 1, wherein the carrier material comprises one or a mixture of several of polymer and lipid materials.
5. The ultra-high drug-loaded composite prepared based on the phase transfer inhibition principle according to claim 4, wherein the polymer and lipid materials comprise: the polymer comprises but is not limited to one or a mixture of more of hydrophobic chitosan and derivatives thereof, hypromellose acetate succinate and derivatives thereof, polymethacrylate and derivatives thereof, polyvinyl acetate phthalate and derivatives thereof, polyvinyl acetate polyethylene cellulose and derivatives thereof, acetalized dextran and derivatives thereof, polylactic acid-glycolic acid copolymer and derivatives thereof, polyethylene glycol polylactic acid-glycolic acid copolymer and derivatives thereof, N-isopropylacrylamide and analogues and derivatives thereof, polycaprolactone and derivatives thereof, polyalkyl-cyanoacrylate and derivatives thereof, polystyrene and derivatives thereof, polylactic acid/polyethylene glycol block copolymer and derivatives thereof, polylactic acid/polylysine block copolymer and derivatives thereof, polylactic acid/polyaspartic acid block copolymer and derivatives thereof, polyethylene glycol/polylysine block copolymer and derivatives thereof, polyethylene glycol/polyaspartic acid block copolymer and derivatives thereof, polyethylene glycol/polyglutamic acid block copolymer and derivatives thereof, or polymethacrylic acid/polymethyl methacrylate block copolymer and derivatives thereof; the lipid material includes, but is not limited to, any one or a mixture of several of fatty acid and its derivatives, glyceride and its derivatives, waxy materials and their derivatives, steroid materials and their derivatives, and phospholipid materials and their derivatives.
6. The ultrahigh drug-loading compound is prepared based on the phase transfer inhibition principle, and is characterized in that external force comprises but is not limited to mixing action of one or more of stirring, shearing, high-pressure homogenization, extrusion, centrifugation and ultrasound.
7. The method for preparing the ultra-high drug-loading complex based on the phase transfer inhibition principle according to any one of claims 1 to 6, wherein the first reactant and the second reactant are mixed to form the water-soluble pharmaceutical active ingredient into the drug colloidal particles; adding a third reactant; centrifuging, removing the supernatant, and dispersing in a fourth reactant to obtain an oil phase containing the drug colloid particles and the carrier material; preparing the oil phase and the water phase into oil-in-water emulsion droplets through a microfluidic device, and curing the emulsion droplets by a solvent diffusion method to obtain a drug-loaded compound;
the first reactant is a solution formed by a medicinal active ingredient and a solvent I;
the second reactant is a poor solvent II of the active pharmaceutical ingredient;
the third reactant is a poor solvent III of the active pharmaceutical ingredient;
the fourth reactant is a solution formed by a carrier material and a poor solvent IV of a pharmaceutical active ingredient;
the solvent I and the solvent II are mutually soluble, and the solvent II and the solvent III are mutually soluble.
8. The method for preparing the ultra-high drug-loading compound based on the phase transfer inhibition principle of claim 7, wherein the solvent I is water or an aqueous solution containing an acidic, basic and organic solvent; the solvent II is an organic solvent; the solvent III is an organic solvent; the solvent IV is an organic solvent.
9. The method of claim 8, wherein the acidic solution comprises one or more of high chloric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid, sulfuric acid, nitric acid, chloric acid, phosphoric acid, oxalic acid, sulfurous acid, nitrous acid, pyruvic acid, hydrofluoric acid, formic acid, lactic acid, benzoic acid, propionic acid, glacial acetic acid, acrylic acid, acetic acid, oleic acid, carbonic acid, bisulfic acid, hypochloric acid, boric acid, metasilicic acid, silicic acid, lactic acid, and stearic acid; the alkaline solution comprises any one or a mixture of more of sodium hydroxide, potassium hydroxide, ammonia water, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium acetate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate or dipotassium hydrogen phosphate;
the organic solvent II comprises but is not limited to any one or a mixture of more of methanol, ethanol, ethylene glycol, diethylene glycol, isopropanol, 1-propanol, 1,2-propanediol, 1,3-propanediol, butanol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 1,5-pentanediol, 2-butoxyethanol, glycerol, methyldiethanolamine, diethanolamine, acetone, acetonitrile, diethylenetriamine, dimethoxyethane, ethylamine, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetaldehyde, pyridine, triethylene glycol, ethyl acetate, dimethyl carbonate, dichloromethane, chloroform, cyclohexane or n-octanol;
the solvent III comprises but is not limited to benzene, n-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, cyclopentane, dichloromethane, trichloromethane, dichloroethane, diethyl ether, n-heptane, n-hexane, methyl ethyl ketone, isooctane, pentane, dipropyl ether, tetrachloroethane, toluene, trichloroethane, xylene, ethyl acetate or a mixture of more than one of any of dimethyl carbonate;
the solvent IV comprises but is not limited to benzene, n-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, cyclopentane, dichloromethane, trichloromethane, dichloroethane, diethyl ether, n-heptane, n-hexane, methyl ethyl ketone, isooctane, pentane, dipropyl ether, tetrachloroethane, toluene, trichloroethane, xylene, ethyl acetate or a mixture of any one or more of dimethyl carbonate;
the aqueous phase comprises one or more of alkyl benzene sulfonate, alpha-olefin sulfonate, alpha-sulfo monocarboxylic ester, succinate sulfonate, sodium dodecyl benzene sulfonate, oleic soap, stearic soap, lauric soap, rosin oil soap, alkyl sulfonate, alkyl sulfate, alkyl benzyl sulfonate, alkyl naphthyl sulfonate, alkyl glyceryl ether sulfonate, lignin sulfonate, phosphate ester, sulfate ester, quaternary ammonium salt, octadecyl trimethyl ammonium chloride, hexadecyl trimethyl ammonium chloride and other alkyl ammonium salts, lecithin, fatty glyceride, sucrose fatty acid ester, sorbitan fatty acid, polysorbate, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, polyoxyethylene-polyoxypropylene block copolymer, fluorocarbon surfactant, silicon-containing surfactant, biosurfactant, crown ether surfactant, arabic gum, tragacanth, gelatin, apricot gum, egg yolk, polyvinylpyrrolidone or solid particle emulsifier.
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CN102988301A (en) * 2012-12-26 2013-03-27 温州医学院 Preparation method of long-acting sustained-release microspheres containing bevacizumab
CN107375238A (en) * 2016-05-16 2017-11-24 刘东飞 A kind of superelevation medicine-carried nano particles and preparation method thereof
CN112603892A (en) * 2020-12-18 2021-04-06 中国药科大学 Drug-loaded microsphere and preparation method thereof
CN114081867A (en) * 2021-11-08 2022-02-25 中国药科大学 Method for improving drug loading capacity of microspheres
CN114146647A (en) * 2021-12-03 2022-03-08 中国药科大学 Continuous flow preparation method of high drug-loading microspheres

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Publication number Priority date Publication date Assignee Title
CN102302455A (en) * 2011-07-25 2012-01-04 浙江大学 Method for preparing microsphere preparation coated with hydrophilic medicaments
CN102988301A (en) * 2012-12-26 2013-03-27 温州医学院 Preparation method of long-acting sustained-release microspheres containing bevacizumab
CN107375238A (en) * 2016-05-16 2017-11-24 刘东飞 A kind of superelevation medicine-carried nano particles and preparation method thereof
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