WO2021043145A1 - 阳离子纳米药物及其制备方法、载药植入医疗器械 - Google Patents

阳离子纳米药物及其制备方法、载药植入医疗器械 Download PDF

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WO2021043145A1
WO2021043145A1 PCT/CN2020/112899 CN2020112899W WO2021043145A1 WO 2021043145 A1 WO2021043145 A1 WO 2021043145A1 CN 2020112899 W CN2020112899 W CN 2020112899W WO 2021043145 A1 WO2021043145 A1 WO 2021043145A1
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cationic
drug
liquid flow
nanomedicine
liquid
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PCT/CN2020/112899
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French (fr)
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李猛
王钰富
李俊菲
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上海微创医疗器械（集团）有限公司
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Priority to EP20860383.7A priority Critical patent/EP4026536A4/en
Priority to US17/640,104 priority patent/US20220288285A1/en
Publication of WO2021043145A1 publication Critical patent/WO2021043145A1/zh

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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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Definitions

  • the invention relates to the technical field of medical devices, in particular to cationic nano-medicine, a preparation method thereof, and drug-carrying implanted medical devices.
  • Cardiovascular disease is the number one cause of death in the world, and coronary atherosclerotic heart disease (coronary heart disease) is one of the diseases with the highest mortality rate, which seriously endangers human life and health.
  • Percutaneous coronary intervention Percutaneouscoronary Intervention, PCI
  • PCI Percutaneouscoronary Intervention
  • drug eluting stent is still the first choice for PCI.
  • the implantation of DES can prevent vascular rebound and the loaded anti-proliferative drugs can inhibit the proliferation of vascular smooth muscle, prevent the occurrence of intimal hyperplasia, and effectively reduce In-stent restenosis rate.
  • Implanted medical devices with drug coatings are mainly obtained by coating the surface of the device with drug coatings containing anti-proliferative drugs. After the implanted medical device containing the drug coating is delivered to the diseased location, the drug coating releases the drug within a short expansion time (30s-60s) to inhibit the proliferation of vascular smooth muscle cells. Therefore, the design of the drug coating on the implanted medical device is of great significance.
  • the current design of drug coatings on implanted medical devices is mainly focused on reducing delivery loss and improving drug uptake by target lesions.
  • drug coatings with different hydrophilic base layers have been designed and manufactured.
  • This type of drug coating also has a hydrophilic top layer for delaying dissolution, which can greatly reduce the loss of the drug coating during the delivery process.
  • the ingestion and retention of this type of drug coating is not good, and it is unable to achieve a sustained release effect.
  • How to increase the uptake and retention of drugs, and thereby improve the slow-release effect of the drug coating on implanted medical devices has always been an important factor restricting the development of implanted medical devices.
  • the present invention provides a cationic nanomedicine, comprising a carrier and a drug loaded on the carrier, the carrier contains one or more of a cationic amphiphilic compound and a cationic modifier; the cationic amphiphilic compound contains A cationic amphiphilic compound of an amino group and/or an acyl group, and the cationic modifier is a cationic modifier containing an amino group and/or an acyl group.
  • the carrier further includes a hydrophobic nanocore
  • the cationic amphiphilic compound and/or the cationic modifier includes a hydrophilic end and a hydrophobic end, and the hydrophobic end is bound to the hydrophobic nanocore, And the hydrophilic end is at least partially exposed.
  • the cationic modifier is selected from: polyamino acids, polysaccharides, polypeptides, cholesterol derivatives or cationic copolymers.
  • the cationic modifier is selected from: polyarginine, polylysine, diethylaminoethyl-dextran, hydroxypropyltrimethylammonium chloride chitosan, chitosan One of sugar hydrochloride, N,N,N-trimethylchitosan, TAT polypeptide, and 3 ⁇ -[N-(N',N'-dimethylaminoethyl)carbamoyl]cholesterolkind or more.
  • the cationic amphiphilic compound is selected from one or more of the following cationic surfactants: (2,3-dioleoyl-propyl)trimethylammonium chloride, 1,2 -Dioleoyl-SN-glycerol-3-phosphoethanolamine, (2,3-distearoyl-propyl)trimethylamine, (2,3-dimyristoyl-propyl)trimethylmethanesulfonic acid Salt, (2,3-dipalmitoyl-propyl) trimethylamine and (2,3-distearoyl-propyl) trimethylamine, amphiphile based on poly(N,N-dimethylaminoethyl methacrylate) Polymer, chitosan-based amphiphilic polymer, chitosan quaternary ammonium salt-based amphiphilic polymer, chlorinated chitosan-based amphiphilic polymer, sulfhydryl
  • the carrier when the carrier includes a cationic modifier, the carrier also includes an emulsifier.
  • the emulsifier is one or more of D- ⁇ -tocopherol polyethylene glycol succinate, polyvinyl alcohol, polysorbate, poloxamer, and carbomer.
  • the carrier further contains a sustained-release copolymer.
  • the surface charge of the cationic nanomedicine is 10mV-60mV; and/or
  • the particle size of the cationic nanomedicine is 3nm-300nm.
  • the morphology of the cationic nanomedicine is spherical, rod-shaped, worm-shaped or disc-shaped.
  • the drug loaded on the carrier is selected from one or more of the following antiproliferative drugs: paclitaxel, sirolimus and sirolimus derivatives. Described sirolimus derivative is Zotamus, Everolimus, Biomus, 7-O-desmethylrapamycin, Tesirolimus, Desirolimus and Tacrolimus Division.
  • the anti-proliferative drug is in a crystalline state, an amorphous state or a mixture of the two.
  • the present invention also provides a medical device, comprising a device substrate and a drug coating loaded on the device substrate, and the drug coating contains the above-mentioned cationic nano drug.
  • the present invention also provides a method for preparing cationic nanomedicine, which includes the following steps:
  • the instant nanoprecipitation method is used to make the first liquid flow and the second liquid flow collide to form a vortex to obtain a nanosuspension formed by mixing, collect the nanosuspension, and dialyze the nanosuspension to obtain the Cationic nanomedicine;
  • At least one of the first liquid stream and the second liquid stream has a drug dissolved in it, and at least one of the first liquid stream and the second liquid stream has a carrier dissolved in it;
  • One of the first liquid stream and the second liquid stream has an organic phase that is miscible with water, and the other of the first liquid stream and the second liquid stream has an aqueous phase;
  • in the carrier Contains one or more of a cationic amphiphilic compound and a cationic modifier;
  • the cationic amphiphilic compound is a cationic amphiphilic polymer containing an amino group and/or an acyl group, and the cationic modifier is a cationic modification containing an amino group and/or an acyl group Agent.
  • the cationic modifier is selected from cationic phospholipids, polyamino acids, polysaccharides, polypeptides or cholesterol derivatives or cationic copolymers.
  • the cationic modifier is selected from: polyarginine, polylysine, diethylaminoethyl-dextran, hydroxypropyltrimethylammonium chloride chitosan, chitosan One of sugar hydrochloride, N,N,N-trimethylchitosan, TAT polypeptide, and 3 ⁇ -[N-(N',N'-dimethylaminoethyl)carbamoyl]cholesterolkind or more.
  • the cationic amphiphilic compound is selected from the following cationic surfactants: (2,3-dioleoyl-propyl)trimethylammonium chloride, 1,2-dioleoyl-SN- Glycerol-3-phosphoethanolamine, (2,3-distearoyl-propyl) trimethylamine, (2,3-dimyristoyl-propyl) trimethyl methanesulfonate, (2,3- Dipalmitoyl-propyl) trimethylamine, (2,3-distearoyl-propyl) trimethylamine, amphiphilic polymer based on poly(N,N-dimethylaminoethyl methacrylate), based on chitosan Amphiphilic polymer based on chitosan quaternary ammonium salt, amphiphilic polymer based on chlorinated chitosan, amphiphilic polymer based on sulfhydryl modified chitosan
  • a sustained-release copolymer is dissolved in at least one of the first liquid stream and the second liquid stream;
  • At least one of the first liquid stream and the second liquid stream has an emulsifier dissolved in it.
  • the sustained-release copolymer is a polylactic acid-glycolic acid copolymer
  • the emulsifier is one or more of D- ⁇ -tocopherol polyethylene glycol succinate, polyvinyl alcohol, polysorbate, poloxamer and carbomer.
  • the step of using the instantaneous nanoprecipitation method to cause the first liquid stream to collide with the second liquid stream to form a vortex includes the following steps:
  • the first liquid flow and the second liquid flow are collided and mixed in the vortex mixer to form a vortex.
  • the step of using the instantaneous nanoprecipitation method to cause the first liquid flow and the second liquid flow to collide to form a vortex flow further includes passing water into the remaining channels of the vortex mixer as an additional liquid flow And making the first liquid flow, the second liquid flow, and the additional liquid flow collide and mix in the vortex mixer to form a vortex.
  • the additional liquid flow may include a third liquid flow and a fourth liquid flow.
  • the flow rates of the third liquid stream and the fourth liquid stream may be the same.
  • the flow rates of the first liquid flow, the second liquid flow, and the third liquid flow are 1 mL/min to 12 mL/min; and the first liquid flow and the second liquid flow
  • the flow rate ratio of is 1:1, and the flow rate of the third liquid flow is 1 to 5 times the flow rate of the first liquid flow or the second liquid flow.
  • the present invention also provides a drug-carrying implanted medical device, which includes the cationic nano-medicine prepared by the above-mentioned preparation method.
  • the cationic amphiphilic compounds and/or cationic modifiers used can make the surface of the cationic nano-medicine positively charged, the cationic nano-medicine can effectively bind to the blood vessel wall cells whose surface charge is negative, thereby greatly improving the tissue cell’s resistance to the nano-medicine particles.
  • the above-mentioned cationic amphiphilic compound and/or cationic modifier contains amino or acyl groups, which can help nano-drug particles escape from cell lysosomes through "proton pumping" and prevent the drug from being degraded by lysosomes or transported to cells. outer.
  • the above-mentioned cationic nanomedicine has an excellent tissue retention time, obtains a better sustained release effect, and is beneficial to inhibit the proliferation of vascular smooth muscle for a long time.
  • the cationic nanomedicine has good biocompatibility and can avoid additional cytotoxicity.
  • the above-mentioned cationic nanomedicine is a nanometer-level drug, which can increase the drug loading, and can effectively avoid the embolism problem caused by the shedding of large particles of the traditional drug coating, and greatly improve the safety.
  • the cationic nano-drug particles can increase the affinity of the carrier and the drug under the action of the cationic amphiphilic compound containing amino or acyl groups and/or the cationic modifier, thereby greatly increasing the drug loading of the cationic nano-drug particles, namely Under the same drug concentration, the cationic nano drug particles can reduce the use of excipients and reduce the thickness of the coating, thereby improving the crossability of drug implanted medical devices.
  • the instantaneous nano-precipitation method can quickly prepare cationic nano-drug particles with ultra-high drug loading.
  • the instantaneous nanoprecipitation method has the advantages of simple operation, very short preparation time (a few seconds), high drug loading, good repeatability, adjustable nanoparticle size, and linear industrial amplification. .
  • the instantaneous nanoprecipitation method to prepare the cationic nanomedicine can obtain nanoparticles with a particle size of about 200 nm.
  • the cationic nano-drug prepared by the instantaneous nanoprecipitation method can enhance the penetration of the nano-particles and increase the uptake of the drug by the tissue.
  • the added cationic amphiphilic compound and/or cationic modifier makes the surface charge of cationic nano-drug particles positive, the cationic nano-drug prepared by the instantaneous nanoprecipitation method can effectively bind to the blood vessel wall cells with negative surface charge.
  • the surface potential of the cationic nanomedicine can be adjusted, which is more conducive to promoting the combination of the cationic nanomedicine and the blood vessel wall cells, and regulating the residence time of the cationic nanomedicine in the tissue to obtain excellent Slow-release effect.
  • Fig. 1 is a schematic diagram of a vortex mixer according to an embodiment.
  • Fig. 2 is a graph showing the zeta potential distribution on the surface of the cationic nanomedicine of Example 1 and Comparative Example 1.
  • Fig. 3 is a particle size distribution diagram of the cationic nanomedicine of Example 1 and Comparative Example 1.
  • FIG. 4 is a morphology diagram of the cationic nanomedicine of Example 1.
  • Example 5 is a morphology diagram of the cationic nanomedicine of Example 13.
  • the present invention provides a cationic nanomedicine, including a carrier and a drug loaded on the carrier.
  • the carrier contains one or more of a cationic amphiphilic compound and a cationic modifier; the cationic amphiphilic compound is an amino and/or acyl-containing compound
  • the cationic amphiphilic compound, the cationic modifier is a cationic modifier containing an amino group and/or an acyl group.
  • the amino or acyl-containing cationic amphiphilic compound and/or cation modifier used in the present invention can help nano-medicine particles escape from the cell lysosome through the "proton pump action", and prevent the drug from being degraded by the lysosome or transported to the outside of the cell . Therefore, the cationic nanomedicine of the present invention has excellent tissue retention time, is beneficial to inhibit the proliferation of vascular smooth muscle for a long time, has good biocompatibility, and can avoid additional cytotoxicity.
  • the carrier in the above-mentioned cationic nanomedicine further includes a hydrophobic nanocore
  • the cationic amphiphilic compound and the cationic modifier include a hydrophilic end and a hydrophobic end.
  • the hydrophobic end is adsorbed on the hydrophobic nanocore, and a small part of the hydrophilic end is exposed. .
  • the hydrophilic end can be at least partially exposed to protect the outside of the particles and prevent the nanoparticles from agglomerating each other, which is conducive to the formation of small and uniform nanoparticles. .
  • the hydrophilic end is exposed refers to the hydrophobic nanocore at the core position, that is, with respect to the hydrophobic end, the hydrophilic end is exposed to the outside of the nanocore.
  • the interaction between the nanoparticle and the nanoparticle, or with other molecules (such as solvent molecules) to wrap the hydrophilic end should be understood as falling within the protection scope of the present invention.
  • the reagents (such as cationic amphiphiles, cationic modifiers, etc.) used in the present invention are all acceptable reagents in the pharmaceutical field.
  • the hydrophobic nanocore can be a material acceptable in the art, such as a hydrophobic nanocore formed by a supersaturated organic solute, which is not particularly limited herein.
  • the cationic amphiphilic compound and the cationic modifier are reagents containing an amino group or an acyl group, that is, they only need to contain an amino group or an acyl group. It is understandable that reagents containing only amino groups or only acyl groups, and reagents containing both amino groups and acyl groups are all within the protection scope of the present invention.
  • the cationic modifier is selected from one or more of cationic phospholipids, cationic copolymers, polyamino acids, polysaccharides, polypeptides and cholesterol derivatives.
  • the cationic modifier is a copolymer that is biodegradable and non-toxic and harmful substances accumulate after degradation.
  • polyamino acids, polysaccharides, polypeptides or cholesterol derivatives are biological analogues in the human body, and have no toxic side effects after degradation. Higher application value.
  • the cationic modifier is selected from: polyarginine, polylysine, diethylaminoethyl-dextran, hydroxypropyltrimethylammonium chloride chitosan, chitosan hydrochloride, One or more of N,N,N-trimethylchitosan, TAT polypeptide, and 3 ⁇ -[N-(N',N'-dimethylaminoethyl)carbamoyl]cholesterol.
  • the cationic amphiphilic compound is selected from one or more of the following cationic surfactants: (2,3-dioleoyl-propyl) trimethylammonium chloride (DOTAP), 1,2-di Oleoyl-SN-glycerol-3-phosphoethanolamine (DOPE), (2,3-distearoyl-propyl) trimethylamine (DSTAP), (2,3-dimyristoyl-propyl) trimethyl Methanesulfonate (DMTAP), (2,3-dipalmitoyl-propyl) trimethylamine (DPTAP) and (2,3-distearoyl-propyl) trimethylamine (DSTAP), based on polymethyl Amphiphilic polymer of N,N-dimethylaminoethyl acrylate, chitosan-based amphiphilic polymer, chitosan quaternary ammonium salt-based amphiphilic polymer, chlorinated chitosan-based
  • cationic surfactants and cationic modifiers have good biocompatibility, and have high safety, and are not easy to produce toxic and side effects. Compared with reagents such as didodecyldimethylamine bromide (DMAB), the safety performance of the cationic surfactants and cationic modifiers has been significantly improved.
  • DMAB didodecyldimethylamine bromide
  • the concentration of cationic amphiphilic compounds and/or cationic modifiers the surface potential of cationic nanomedicine can be adjusted, which is more conducive to promoting the binding of cationic nanomedicine to blood vessel wall cells and regulating the tissue residence time of cationic nanomedicine. Achieve a better sustained-release effect.
  • the carrier may also include an emulsifier.
  • the loading method of the emulsifier in the cationic nanomedicine is not particularly limited. It can be adsorbed on the nanocore by adsorption, and it can also be loaded on the cation by interacting with the cationic amphiphilic compound and/or the cationic modifier. Nano medicine. It should be understood that, depending on the selected reagent types and preparation methods, the loading methods are different, which are all within the protection scope of the present invention.
  • the emulsifier is one or more of D- ⁇ -tocopherol polyethylene glycol succinate, polyvinyl alcohol, polysorbate, poloxamer and carbomer.
  • the above reagent has no toxic and side effects, and can improve the safety of the prepared cationic nanomedicine.
  • the aforementioned carrier may also contain a sustained-release copolymer
  • the sustained-release polymer refers to a polymer that can slow the release of the drug from the nanoparticle after being loaded in the cationic nano-drug.
  • the loading method of the sustained-release copolymer in the cationic nanomedicine is not particularly limited. It can be adsorbed on the nanocore by adsorption, and it can also be loaded on the cationic amphiphilic compound and/or cationic modifier by interacting with it. Cationic nano-medicine. It should be understood that, depending on the selected reagent type and preparation method, the loading method is different, which is within the protection scope of the present invention. For example, when PLGA is used as a sustained-release copolymer, it may be embedded in the cationic nanomedicine due to its hydrophobic effect.
  • sustained-release copolymer has the effect of enhancing sustained-release.
  • the sustained-release copolymer in the present invention can be any biodegradable copolymer acceptable in the field of pharmacy, which is not particularly limited here, and is preferably capable of being degraded into non-toxic substances in the body to promote the sustained release of the drug.
  • the copolymer is polylactic acid-glycolic acid copolymer (PLGA), which can be degraded into lactic acid and glycolic acid in the body, both of which are by-products of human metabolic pathways, and have no toxic side effects.
  • PLGA polylactic acid-glycolic acid copolymer
  • the surface of the cationic nanomedicine can be positively charged.
  • the preferred potential of the surface charge ie, the zeta potential
  • the more preferred zeta potential is 10-60 mV, for example, 20-50 mV.
  • the cationic nanomedicine of the present invention is a nano-level (1-1000nm) drug, and the preferred size of the cationic nanomedicine is 3nm-300nm, and the more preferred size of the cationic nanomedicine is 50nm-250nm, for example, 70nm- 240nm, 80nm-230nm, 100nm-210nm.
  • Nanomedicine has the advantages of enhancing cell penetration, increasing drug loading, slow release, local retention, and preventing drug degradation. Therefore, when the coating containing the cationic nano drug is loaded on the implanted medical device, the embolism problem caused by the large particles of the traditional drug coating can be avoided, and the safety is greatly improved.
  • the morphology of the cationic nanomedicine of the present invention is not particularly limited, and is preferably spherical, rod-shaped, worm-shaped, or disc-shaped, and more preferably morphology is spherical to increase the drug loading.
  • the manifestation of the cationic nanomedicine can be a mixture of one or more of cationic micelles, cationic polymer nanoparticles and cationic liposomes, which can be selected according to specific processes.
  • the loading method of the drug loaded on the carrier of the present invention is not particularly limited. There will be differences according to the preparation method and the type of reagent.
  • the drug can be wrapped in the carrier or the drug can be loaded on the surface of the carrier.
  • the type of medicine is not particularly limited, and can be selected as necessary.
  • the drug is an anti-proliferative drug, such as paclitaxel, sirolimus and derivatives of sirolimus.
  • the sirolimus derivative is preferably zotamus, everolimus, biomos, 7-O-desmethylrapamycin, temsirolimus, desfoslimus and tacrolimus Moss.
  • the anti-proliferative drug may be in a crystalline state, an amorphous state, or a mixture of the two.
  • the cationic nano-medicine of the present invention is a nano-level medicine with a relatively large surface area, which can effectively increase the drug loading.
  • the cationic nanomedicine of the present invention uses cationic amphiphilic compounds with amino or acyl groups and/or cationic modifiers as carriers, which can effectively enhance the affinity between the carrier and the drug, and further increase the drug loading.
  • the drug loading can be controlled, which is convenient and quick.
  • the drug loading of the cationic nanomedicine is 1%-50% (w/w), for example, 10%-50%, 20%-50%.
  • the preparation method of the above-mentioned cationic nanomedicine is not particularly limited, and it is preferably prepared by the instantaneous nanoprecipitation method.
  • the method is simple, rapid, and scalable, and can continuously and rapidly prepare nanoparticles, and the prepared nanoparticles have a narrow size distribution and high drug loading rate.
  • the present invention also provides a method for preparing cationic nanomedicine, which includes the following steps:
  • S101 Provide a first liquid flow; provide a second liquid flow; wherein, at least one of the first liquid flow and the second liquid flow has a drug dissolved in it, and at least one of the first liquid flow and the second liquid flow
  • the carrier is dissolved in the stream, one of the first liquid stream and the second liquid stream has an organic phase that is miscible with water, and the other of the first liquid stream and the second liquid stream has an aqueous phase;
  • the carrier contains a cationic amphiphile
  • the cationic amphiphilic compound is a cationic amphiphilic compound containing an amino group and/or an acyl group
  • the cationic modifier is a cationic modifier containing an amino group and/or an acyl group.
  • the organic phase is not particularly limited, including but not limited to acetone, alcohol solvents, and the like.
  • the cationic modifier is selected from one or more of cationic phospholipids, cationic copolymers, polyamino acids, polysaccharides, polypeptides and cholesterol derivatives.
  • the preferred cationic modifiers are copolymers that are biodegradable and non-toxic and harmful substances accumulate after degradation.
  • polyamino acids, polysaccharides, polypeptides or cholesterol derivatives are biological analogs in the human body, and they have no toxic side effects after degradation and have high Application value.
  • the cationic modifier is selected from: polyarginine, polylysine, diethylaminoethyl-dextran, hydroxypropyltrimethylammonium chloride chitosan, chitosan hydrochloride, One or more of N,N,N-trimethylchitosan, TAT polypeptide, and 3 ⁇ -[N-(N',N'-dimethylaminoethyl)carbamoyl]cholesterol.
  • the cationic amphiphilic compound is selected from one or more of the following cationic surfactants: (2,3-dioleoyl-propyl) trimethylammonium chloride (DOTAP), 1,2-di Oleoyl-SN-glycerol-3-phosphoethanolamine (DOPE), (2,3-distearoyl-propyl) trimethylamine (DSTAP), (2,3-dimyristoyl-propyl) trimethyl Methanesulfonate (DMTAP), (2,3-dipalmitoyl-propyl) trimethylamine (DPTAP) and (2,3-distearoyl-propyl) trimethylamine (DSTAP), based on polymethyl Amphiphilic polymer of N,N-dimethylaminoethyl acrylate, chitosan-based amphiphilic polymer, chitosan quaternary ammonium salt-based amphiphilic polymer, chlorinated chitosan-based
  • the first liquid stream and the second liquid stream has an emulsifier dissolved in it.
  • the emulsifier may be one or more of D- ⁇ -tocopherol polyethylene glycol succinate, polyvinyl alcohol, polysorbate, poloxamer, and carbomer.
  • each reagent is specifically dissolved in the organic phase or the water phase needs to be determined according to the specific type of the reagent, which is not particularly limited here.
  • the specific type of the reagent which is not particularly limited here.
  • most drugs and cationic surfactants are easily soluble in organic solvents
  • sustained-release copolymers are easily soluble in the organic phase
  • cationic modifiers are easily soluble in water, so cationic surfactants and sustained-release copolymers can be added to the organic phase.
  • the cationic modifier is added to the water phase.
  • emulsifiers can also be added to the first liquid stream and/or the second liquid stream, such as D- ⁇ -tocopherol polyethylene glycol succinate (TPGS), polyvinyl alcohol One or more of, polysorbate, poloxamer and carbomer.
  • TPGS D- ⁇ -tocopherol polyethylene glycol succinate
  • polyvinyl alcohol One or more of, polysorbate, poloxamer and carbomer.
  • an emulsifier is added to the second liquid stream, and the emulsifier is selectively added to the first liquid stream according to the specific type of reagent.
  • each reagent can be adjusted as needed, and is not particularly limited here.
  • the adjustment of the content of the cationic amphiphilic compound and the cationic modifier can realize the adjustment of the surface potential of the cationic nanomedicine, which is of great significance for adjusting the affinity between the drug and the cell.
  • the type of loaded drug is not particularly limited and can be selected according to needs.
  • the drug is an anti-proliferative drug, such as paclitaxel, sirolimus and sirolimus derivatives.
  • the sirolimus derivative may be zotamus, everolimus, biomolus, 7-O-desmethylrapamycin, temsirolimus, desfolimus and other sirolimus derivatives. Cromos.
  • the anti-proliferative drug is in a crystalline state, an amorphous state or a mixture of the two.
  • S102 Use the instantaneous nano-precipitation method to make the first liquid stream and the second liquid stream collide to form a vortex to obtain a nano-suspension formed by mixing, collect the nano-suspension formed by mixing, and dialyze the nano-suspension to prepare cations Nano medicine.
  • the instantaneous nanoprecipitation method refers to the use of a multi-channel vortex mixer to quickly collide several liquid streams, resulting in the formation of a sufficiently high degree of supersaturation of organic solutes in a short time (subtle or even milliseconds), and then the formation of hydrophobic nano-nuclei.
  • the hydrophobic end of the amphiphilic cationic amphiphilic compound and/or cationic modifier is adsorbed on the hydrophobic nanocore to prevent the nanocore from continuing to grow, on the other hand, its hydrophilic end is exposed on the outside to avoid nanoparticles Convergence between them, and then achieve the purpose of forming uniform nanoparticles.
  • the selected multi-channel vortex mixer there will be a different number of channels, which is not particularly limited.
  • the selected multi-channel vortex mixer only needs to have more than two channels.
  • the four-channel vortex mixer shown in Fig. 1 can be used, in which the first channel is connected to the first liquid flow, the second channel is connected to the second liquid flow, and the third channel and the fourth channel are connected to water as the third channel. The liquid flow and the fourth liquid flow are sufficient.
  • the flow rate of the liquid in each channel can be adjusted as needed.
  • the flow rate of the liquid in the channel is between 1mL/min-12mL/min, for example, 2mL/min-11mL/min, 3mL/min-10mL/min, 5mL/min-9mL/min, 6mL/min- 8mL/min.
  • the speed of the liquid flow in each channel can be equal or different.
  • the flow rates of the third liquid stream and the fourth liquid stream are the same.
  • the ratio of the flow rates of the first liquid flow and the second liquid flow is 1:1, and the flow rates of the third liquid flow and the fourth liquid flow are 1 to 5 times the flow rate of the first liquid flow or the second liquid flow, For example, it is 1 to 4 times, preferably 1 to 3 times, to form a cationic nanomedicine with a smaller and uniform particle size.
  • the dialysis method can be a dialysis method commonly used in the art, which is not particularly limited here.
  • the suspension to be dialyzed is put into a dialysis bag for dialysis, and the water is changed every time. Subsequently, the prepared nano drug particle suspension is concentrated for use.
  • the present invention also provides a drug-loaded implant device, which includes a device substrate and a drug coating loaded on the device substrate.
  • the drug coating includes the above-mentioned cationic nano-medicine or the cationic nano-medicine prepared by the above-mentioned preparation method.
  • the above-mentioned drug-carrying implant device obtains good biocompatibility by adopting the above-mentioned cationic nano-drug or the cationic nano-drug prepared by the above-mentioned preparation method.
  • the drug-loaded implant device loaded with cationic nano-drugs can greatly increase the uptake of drugs by the target lesion through the charge effect and the high permeability of the nanoparticles during the implantation process.
  • the drug since the drug is coated in the cationic nano-drug particles, it has a slow-release effect, and the drug-carrying implant device loaded with the cationic nano-drug can also have the effect of inhibiting the proliferation of vascular smooth muscle for a long time.
  • the drug coating can be formed by spraying or other methods. After the drug concentration in the drug coating reaches the required drug concentration, it can be dried and sterilized.
  • the drug-carrying implant device of the present invention can be used in vivo or in vitro, and can be used for short-term or long-term permanent implantation.
  • the above-mentioned medical devices can provide medical treatment and/or diagnosis for arrhythmia, heart failure, valvular disease, vascular disease, diabetes, neurological diseases and disorders, plastic surgery, neurosurgery, oncology, ophthalmology, and ENT surgery Of equipment.
  • the medical devices involved in the present invention include but are not limited to the following devices: stents, stent grafts, anastomotic connectors, synthetic patches, leads, electrodes, needles, wires, catheters, sensors, surgical instruments, angioplasty balls, wound drainage tubes , Shunt, tube, infusion sleeve, urethral cannula, pellet, implant, blood oxygenation generator, pump, vascular graft, embedded interventional kit (vascular access port) ), heart valves, annuloplasty rings, sutures, surgical clips, surgical nails, pacemakers, implantable defibrillators, neurostimulators, orthopedic surgical instruments, cerebrospinal fluid shunt tubes, implantable Medicine pumps, vertebral cages, artificial intervertebral discs, replacement instruments for nucleus pulposus, ear tubes, intraocular lenses and any tubes used in interventional surgery.
  • the stents include, but are not limited to, coronary vascular stents, peripheral vascular stents, intracranial vascular stents, urethral stents, esophageal stents, and coronary vascular stents are preferred.
  • the device substrate is a balloon
  • the drug-loaded implant device is a drug-coated balloon.
  • the drug-carrying implant device containing a cationic nano drug coating in the present invention can greatly increase the uptake of drugs by the target lesion through the charge effect and the high penetration effect of the nano particles.
  • cationic nano-drugs can help nano-drug particles escape to the cytoplasm through "proton pumping", preventing the drug from being degraded by lysosomes or transported outside the cell. Because the drug in the nano drug particles that escape to the cytoplasm is coated in the polymer, it has a slow-release effect, which greatly prolongs the residence time of the drug in the tissue, so that the drug-loaded implant device containing the cationic nano drug coating can be obtained. The effect of inhibiting vascular smooth muscle proliferation for a long time.
  • nano-scale drug particles can avoid the problem of distal embolization and greatly improve safety.
  • the nano-medicine particles of the present invention have extremely high drug loading, which can reduce the use of excipients and surfactants, reduce the coating thickness of the drug balloon, and improve the passability of the drug balloon.
  • the cationic nanomedicine has a simple preparation method, short time-consuming, adjustable nanoparticle size, high drug loading, and convenient scale-up production, which has great industrial prospects.
  • TPGS D- ⁇ -tocopherol polyethylene glycol succinate
  • PLGA polylactic acid-glycolic acid copolymer
  • the concentrations are 10mg/mL, 2mg/mL and 5mg, respectively /mL, as stream 1.
  • TPGS and hydroxypropyltrimethylammonium chloride chitosan (HACC) were dissolved in water at concentrations of 0.3 mg/mL and 0.08 mg/mL, respectively, as stream 2. Both stream 3 and stream 4 are water.
  • liquid flow 1, liquid flow 2, liquid flow 3 and liquid flow 4 are injected into the four-channel vortex mixer at a flow rate of 10 mL/min to obtain the nano drug particle suspension formed by mixing liquid.
  • a suitable mixing time can be selected.
  • the mixing time is 10 s
  • the volume ratio of the aqueous phase and the organic phase in the finally obtained nano-medicine particle suspension is 1:3).
  • the mixed liquid obtained in the first 2 seconds is discarded and the mixed liquid obtained 8 seconds after collection is the nano-medicine particle suspension.
  • the collected nano-drug particle suspension was put into a dialysis bag for dialysis for 12 hours, and the water was changed every 2 hours. Subsequently, the prepared nano drug particle suspension is concentrated for use.
  • the size and surface charge of the nano-medicine particles were characterized by Malvern's ZS90 test, the drug loading of the nano-medicine particles was calculated by high performance liquid chromatography (HPLC), and the morphology of the nano-medicine particles was characterized by transmission electron microscopy (TEM).
  • Example 1 Take a balloon with a hydrophilic coating and spray the cationic nano drug particles prepared above on the surface of the balloon uniformly by ultrasonic spraying to make the drug concentration reach 1.3 mg/mm 2 , and then dry it naturally for 24 hours. After alkane sterilization, the drug-coated balloon of Example 1 was obtained.
  • Stream 2 Dissolve 1,2-dioleoyl-SN-glycerol-3-phosphoethanolamine (DOPE), DC-cholesterol, DOTAP, and sirolimus in ethanol at concentrations of 3mg/mL, 1mg/mL, 1mg/mL, respectively And 8mg/mL as stream 1.
  • Stream 2, Stream 3, and Stream 4 are all water.
  • four liquid streams (liquid flow 1, liquid flow 2, liquid flow 3 and liquid flow 4) are injected into a four-channel vortex mixer to obtain a cationic drug-carrying liposome suspension formed by mixing.
  • the flow rates of stream 1 and stream 2 are 10 mL/min, and the flow rates of stream 3 and stream 4 are 45 mL/min.
  • the volume ratio of the aqueous phase and the organic phase in the cationic drug-loaded liposome suspension is finally obtained It is 1:10 (v:v).
  • a suitable mixing time can be selected. In this embodiment, the mixing time is 10s.
  • the mixed solution obtained in the first 2 seconds is discarded and the mixed solution obtained 8 seconds after collection is the cationic drug-loaded liposome suspension. Collect the prepared cationic drug-loaded liposome suspension.
  • the above cationic drug-loaded liposome suspension was put into a dialysis bag for 10h dialysis, and the water was changed every 2h.
  • the size and surface charge of the cationic drug-loaded liposomes were characterized by Malvern's ZS90 test.
  • the drug-loading capacity of the cationic drug-loaded liposomes was calculated by high performance liquid chromatography (HPLC), and the morphology of the nano-drug particles was measured by transmission electron microscopy (TEM). Characterization.
  • DOTAP 2,3-dioleoyl-propyl
  • DC-cholesterol and sirolimus in ethanol at concentrations of 3mg/mL, 1mg/mL and 8mg/mL, As stream 1.
  • Stream 2, Stream 3, and Stream 4 are all water.
  • four liquid streams (liquid flow 1, liquid flow 2, liquid flow 3 and liquid flow 4) are injected into a four-channel vortex mixer at a flow rate of 10 mL/min to obtain a cationic drug carrier lipid formed by mixing Plasmid suspension.
  • a suitable mixing time can be selected.
  • the mixing time is 10 s, and the volume ratio of the aqueous phase and the organic phase in the cationic drug-loaded liposome suspension is 1:3.
  • the mixed solution obtained in the first 2 seconds is discarded and the mixed solution obtained 8 seconds after collection is the cationic drug-loaded liposome suspension.
  • the above cationic drug-loaded liposome suspension was put into a dialysis bag for 10h dialysis, and the water was changed every 2h.
  • the size and surface charge of the cationic drug-loaded liposomes were characterized by Malvern's ZS90 test.
  • the drug-loading capacity of the cationic drug-loaded liposomes was calculated by high performance liquid chromatography (HPLC), and the morphology of the nano-drug particles was measured by transmission electron microscopy (TEM). Characterization.
  • Example 3 Take a balloon with a hydrophilic coating and spray the cationic drug-loaded liposomes prepared above on the surface of the balloon uniformly by ultrasonic spraying to make the drug concentration reach 1.3 mg/mm 2 , and then dry naturally for 24 hours. Sterilized with ethylene oxide, the drug-coated balloon of Example 3 was obtained.
  • DMTAP (2,3-dimyristoyl-propyl) trimethylmethanesulfonate
  • mL as stream 1.
  • Polyvinyl alcohol is dissolved in water with a concentration of 0.4 mg/mL, which is used as stream 2. Both stream 3 and stream 4 are water.
  • four liquid streams (liquid flow 1, liquid flow 2, liquid flow 3 and liquid flow 4) are injected into a four-channel vortex mixer at a flow rate of 10 mL/min to obtain a cationic carrier lipid formed by mixing Plasmid suspension.
  • a suitable mixing time can be selected.
  • the mixing time is 10 s
  • the volume ratio of the aqueous phase and the organic phase in the cationic drug-loaded liposome suspension is 1:3.
  • the mixed solution obtained in the first 2 seconds is discarded and the mixed solution obtained 8 seconds after collection is the cationic drug-loaded liposome suspension.
  • the above cationic drug-loaded liposome suspension was put into a dialysis bag for 10h dialysis, and the water was changed every 2h.
  • the size and surface charge of the cationic drug-loaded liposomes were characterized by Malvern's ZS90 test.
  • the drug-loading capacity of the cationic drug-loaded liposomes was calculated by high performance liquid chromatography (HPLC), and the morphology of the nano-drug particles was measured by transmission electron microscopy (TEM). Characterization.
  • Example 4 Take a balloon with a hydrophilic coating and spray the cationic drug-loaded liposomes prepared above on the surface of the balloon uniformly by ultrasonic spraying to make the drug concentration reach 1.3 mg/mm 2 , and then dry naturally for 24 hours. Sterilized with ethylene oxide, the drug-coated balloon of Example 4 was obtained.
  • liquid flow 1, liquid flow 2, liquid flow 3 and liquid flow 4 are injected into a four-channel vortex mixer at a flow rate of 10 mL/min to obtain a cationic carrier lipid formed by mixing Plasmid suspension.
  • a suitable mixing time can be selected. In this embodiment, the mixing time is 10 s, and the volume ratio of the aqueous phase and the organic phase in the cationic drug-loaded liposome suspension is 1:3.
  • the mixed solution obtained in the first 2 seconds is discarded and the mixed solution obtained 8 seconds after collection is the cationic drug-loaded liposome suspension.
  • the above cationic drug-loaded liposome suspension was put into a dialysis bag for 10h dialysis, and the water was changed every 2h.
  • the size and surface charge of the cationic drug-loaded liposomes were characterized by Malvern's ZS90 test.
  • the drug-loading capacity of the cationic drug-loaded liposomes was calculated by high performance liquid chromatography (HPLC), and the morphology of the nano-drug particles was measured by transmission electron microscopy (TEM). Characterization.
  • Example 5 Take a balloon with a hydrophilic coating and spray the cationic drug-loaded liposomes prepared above on the surface of the balloon uniformly by ultrasonic spraying to make the drug concentration reach 1.3 mg/mm 2 , and then dry naturally for 24 hours. Sterilized with ethylene oxide, the drug-coated balloon of Example 5 was obtained.
  • DPTAP (2,3-Dipalmitoyl-propyl) trimethylamine
  • DC-cholesterol DC-cholesterol
  • sirolimus dissolved in ethanol at concentrations of 3 mg/mL, 1 mg/mL and 8 mg/mL, respectively, as liquid stream 1.
  • Poloxamer 188 is dissolved in water with a concentration of 0.4 mg/mL and used as stream 2. Both stream 3 and stream 4 are water.
  • four liquid streams (liquid flow 1, liquid flow 2, liquid flow 3 and liquid flow 4) are injected into a four-channel vortex mixer at a flow rate of 10 mL/min to obtain a cationic carrier lipid formed by mixing Plasmid suspension.
  • a suitable mixing time can be selected.
  • the mixing time is 10 s
  • the volume ratio of the aqueous phase and the organic phase in the cationic drug-loaded liposome suspension is 1:3.
  • the mixed solution obtained in the first 2 seconds is discarded and the mixed solution obtained 8 seconds after collection is the cationic drug-loaded liposome suspension.
  • the above cationic drug-loaded liposome suspension was put into a dialysis bag for 10h dialysis, and the water was changed every 2h.
  • the size and surface charge of the cationic drug-loaded liposomes were characterized by Malvern's ZS90 test.
  • the drug-loading capacity of the cationic drug-loaded liposomes was calculated by high performance liquid chromatography (HPLC), and the morphology of the nano-drug particles was measured by transmission electron microscopy (TEM). Characterization.
  • DSTAP Dissolve (2,3-distearoyl-propyl) trimethylamine
  • DC-cholesterol DC-cholesterol
  • DOTAP DOTAP
  • sirolimus in ethanol at concentrations of 3mg/mL, 1mg/mL, 1mg/mL and 8mg, respectively /mL, as stream 1.
  • Carbomer 940 was dissolved in water with a concentration of 0.4 mg/mL, adjusted to pH 7, and dissolved in water with a concentration of 0.4 mg/mL, as stream 2. Both stream 3 and stream 4 are water.
  • liquid flow 1, liquid flow 2, liquid flow 3 and liquid flow 4 are injected into a four-channel vortex mixer at a flow rate of 10 mL/min to obtain a cationic carrier lipid formed by mixing Plasmid suspension.
  • a suitable mixing time can be selected. In this embodiment, the mixing time is 10 s, and the volume ratio of the aqueous phase to the organic phase in the cationic drug-loaded liposome suspension is 1:3.
  • the mixed solution obtained in the first 2 seconds is discarded and the mixed solution obtained 8 seconds after collection is the cationic drug-loaded liposome suspension.
  • the cationic drug-loaded liposome suspension was put into a dialysis bag for 10 hours and the water was changed every 2 hours.
  • the size and surface charge of the cationic drug-loaded liposomes were characterized by Malvern ZS90 test, the drug-loading amount of the cationic drug-loaded liposomes was calculated by high performance liquid chromatography (HPLC), and the morphology of the nano-drug particles was characterized by transmission electron microscopy (TEM) .
  • Example 7 Take a balloon with a hydrophilic coating and spray the cationic drug-loaded liposomes prepared above on the surface of the balloon uniformly by ultrasonic spraying to make the drug concentration reach 1.3 mg/mm 2 , and then dry naturally for 24 hours. After sterilization with ethylene oxide, the drug-coated balloon of Example 7 was obtained.
  • TPGS D- ⁇ -tocopherol polyethylene glycol succinate
  • PLGA polylactic acid-glycolic acid copolymer
  • liquid flow 1, liquid flow 2, liquid flow 3 and liquid flow 4 were injected into a four-channel vortex mixer at a flow rate of 10 mL/min to obtain cationic nano-drug particles formed by mixing suspension.
  • a suitable mixing time can be selected.
  • the mixing time is 10 s
  • the volume ratio of the aqueous phase and the organic phase in the cationic nano-medicine particle suspension finally obtained is 1:3.
  • the mixed liquid obtained in the first 2 seconds is discarded and the mixed liquid obtained 8 seconds after collection is the cationic nano-medicine particle suspension.
  • the collected cationic nano drug particle suspension was put into a dialysis bag for dialysis for 12 hours, and the water was changed every 2 hours. Subsequently, the prepared nano drug particle suspension is concentrated for use.
  • the size and surface charge of the nano-medicine particles were characterized by Malvern's ZS90 test, the drug loading of the nano-medicine particles was calculated by high performance liquid chromatography (HPLC), and the morphology of the nano-medicine particles was characterized by transmission electron microscopy (TEM).
  • Example 8 Take a balloon with a hydrophilic coating and spray the cationic nano drug particles prepared above on the surface of the balloon uniformly by ultrasonic spraying to make the drug concentration reach 1.3 mg/mm 2 , and then dry it naturally for 24 hours. After alkane sterilization, the drug-coated balloon of Example 8 was obtained.
  • TPGS D- ⁇ -tocopherol polyethylene glycol succinate
  • PLGA polylactic acid-glycolic acid copolymer
  • the concentrations are 10mg/mL, 2mg/mL and 5mg, respectively /mL, as stream 1.
  • TPGS and N,N,N-trimethylchitosan (TMC) were dissolved in water at concentrations of 0.3mg/mL and 0.08mg/mL, respectively, as stream 2. Both stream 3 and stream 4 are water.
  • liquid flow 1, liquid flow 2, liquid flow 3 and liquid flow 4 were injected into a four-channel vortex mixer at a flow rate of 10 mL/min to obtain cationic nano-drug particles formed by mixing suspension.
  • a suitable mixing time can be selected.
  • the mixing time is 10 s
  • the volume ratio of the aqueous phase and the organic phase in the cationic nano-medicine particle suspension finally obtained is 1:3.
  • the mixed liquid obtained in the first 2 seconds is discarded and the mixed liquid obtained 8 seconds after collection is the cationic nano-medicine particle suspension.
  • the collected cationic nano-drug particle suspension was put into a dialysis bag for dialysis for 12 hours, and the water was changed every 2 hours. Subsequently, the prepared nano drug particle suspension is concentrated for use.
  • the size and surface charge of the nano-medicine particles were characterized by Malvern's ZS90 test, the drug loading of the nano-medicine particles was calculated by high performance liquid chromatography (HPLC), and the morphology of the nano-medicine particles was characterized by transmission electron microscopy (TEM).
  • Example 9 Take a balloon with a hydrophilic coating and spray the cationic nano drug particles prepared above on the surface of the balloon uniformly by ultrasonic spraying to make the drug concentration reach 1.3 mg/mm 2 , and then dry it naturally for 24 hours. After alkane sterilization, the drug-coated balloon of Example 9 was obtained.
  • TPGS D- ⁇ -tocopherol polyethylene glycol succinate
  • PLGA polylactic acid-glycolic acid copolymer
  • concentrations are 10mg/mL, 2mg/mL and 5mg, respectively /mL, as stream 1.
  • TPGS and DEAE-Dextran were dissolved in water at concentrations of 0.3 mg/mL and 0.08 mg/mL, respectively, as stream 2. Both stream 3 and stream 4 are water.
  • liquid flow 1, liquid flow 2, liquid flow 3 and liquid flow 4 were injected into a four-channel vortex mixer at a flow rate of 10 mL/min to obtain cationic nano-drug particles formed by mixing suspension.
  • a suitable mixing time can be selected.
  • the mixing time is 10 s
  • the volume ratio of the aqueous phase and the organic phase in the cationic nano-medicine particle suspension finally obtained is 1:3.
  • the mixed liquid obtained in the first 2 seconds is discarded and the mixed liquid obtained 8 seconds after collection is the cationic nano-medicine particle suspension.
  • the collected cationic nano-drug particle suspension was put into a dialysis bag for dialysis for 12 hours, and the water was changed every 2 hours. Subsequently, the prepared nano drug particle suspension is concentrated for use.
  • the size and surface charge of the nano-medicine particles were characterized by Malvern's ZS90 test, the drug loading of the nano-medicine particles was calculated by high performance liquid chromatography (HPLC), and the morphology of the nano-medicine particles was characterized by transmission electron microscopy (TEM).
  • Example 10 Take a balloon with a hydrophilic coating and spray the cationic nano drug particles prepared above on the surface of the balloon uniformly by ultrasonic spraying to make the drug concentration reach 1.3 mg/mm 2 , and then dry it naturally for 24 hours. After alkane sterilization, the drug-coated balloon of Example 10 was obtained.
  • TPGS D- ⁇ -tocopherol polyethylene glycol succinate
  • PLGA polylactic acid-glycolic acid copolymer
  • liquid flow 1, liquid flow 2, liquid flow 3 and liquid flow 4 were injected into a four-channel vortex mixer at a flow rate of 10 mL/min to obtain cationic nano-drug particles formed by mixing suspension.
  • a suitable mixing time can be selected.
  • the mixing time is 10 s
  • the volume ratio of the aqueous phase and the organic phase in the cationic nano-medicine particle suspension finally obtained is 1:3.
  • the mixed liquid obtained in the first 2 seconds is discarded and the mixed liquid obtained 8 seconds after collection is a cationic nano-medicine particle suspension.
  • the collected cationic nano-drug particle suspension was put into a dialysis bag for dialysis for 12 hours, and the water was changed every 2 hours. Subsequently, the prepared nano drug particle suspension is concentrated for use.
  • the size and surface charge of the nano-medicine particles were characterized by Malvern's ZS90 test, the drug loading of the nano-medicine particles was calculated by high performance liquid chromatography (HPLC), and the morphology of the nano-medicine particles was characterized by transmission electron microscopy (TEM).
  • Example 11 Take a balloon with a hydrophilic coating and spray the cationic nano drug particles prepared above on the surface of the balloon uniformly by ultrasonic spraying to make the drug concentration reach 1.3 mg/mm 2 , and then dry it naturally for 24 hours. After alkane sterilization, the drug-coated balloon of Example 11 was obtained.
  • DSPE Distearoylphosphatidylethanolamine
  • DC-cholesterol DC-cholesterol
  • DOTAP DOTAP
  • sirolimus were dissolved in ethanol at concentrations of 3 mg/mL, 1 mg/mL, 1 mg/mL, and 8 mg/mL, respectively, as liquid stream 1.
  • TPGS is dissolved in water with a concentration of 0.4 mg/mL, which is used as stream 2. Both stream 3 and stream 4 are water.
  • four liquid streams (liquid flow 1, liquid flow 2, liquid flow 3 and liquid flow 4) are injected into a four-channel vortex mixer at a flow rate of 10 mL/min to obtain a cationic carrier lipid formed by mixing Plasmid suspension.
  • a suitable mixing time can be selected.
  • the mixing time is 10 s
  • the volume ratio of the aqueous phase and the organic phase in the cationic drug-loaded liposome suspension is 1:3.
  • the mixed solution obtained in the first 2 seconds is discarded and the mixed solution obtained 8 seconds after collection is the cationic drug-loaded liposome suspension.
  • the above cationic drug-loaded liposome suspension was put into a dialysis bag for 10h dialysis, and the water was changed every 2h.
  • the size and surface charge of the cationic drug-loaded liposomes were characterized by Malvern's ZS90 test.
  • the drug-loading capacity of the cationic drug-loaded liposomes was calculated by high performance liquid chromatography (HPLC), and the morphology of the nano-drug particles was measured by transmission electron microscopy (TEM). Characterization.
  • Example 12 Take a balloon with a hydrophilic coating and spray the cationic drug-loaded liposomes prepared above on the surface of the balloon uniformly by ultrasonic spraying to make the drug concentration reach 1.3 mg/mm 2 , and then dry naturally for 24 hours. Sterilized with ethylene oxide, the drug-coated balloon of Example 12 was obtained.
  • the above cationic drug-loaded liposome suspension was put into a dialysis bag for 10h dialysis, and the water was changed every 2h.
  • the size and surface charge of the cationic drug-loaded liposomes were characterized by Malvern's ZS90 test.
  • the drug-loading capacity of the cationic drug-loaded liposomes was calculated by high performance liquid chromatography (HPLC), and the morphology of the nano-drug particles was measured by transmission electron microscopy (TEM). Characterization.
  • a suitable mixing time can be selected.
  • the mixing time is 10 s
  • the volume ratio of the aqueous phase and the organic phase in the cationic drug-loaded liposome suspension is 1:3.
  • the mixed solution obtained in the first 2 seconds is discarded and the mixed solution obtained 8 seconds after collection is the cationic drug-loaded liposome suspension.
  • the above cationic drug-loaded liposome suspension was put into a dialysis bag for 10h dialysis, and the water was changed every 2h.
  • the size and surface charge of the cationic drug-loaded liposomes were characterized by the Malvern ZS90 test, and the drug-loading capacity of the cationic drug-loaded liposomes was calculated by high performance liquid chromatography (HPLC).
  • a 2-channel mixer was used to prepare cationic nanomedicine.
  • a suitable mixing time can be selected.
  • the mixing time is 10 s, and the volume ratio of the aqueous phase and the organic phase in the cationic nano drug particle suspension finally obtained is 1:1.
  • the mixed liquid obtained in the first 2 seconds is discarded and the mixed liquid obtained 8 seconds after collection is the nano-medicine particle suspension.
  • the collected nano-drug particle suspension was put into a dialysis bag for dialysis for 12 hours, and the water was changed every 2 hours. Subsequently, the prepared nano drug particle suspension is concentrated for use.
  • the size and surface charge of the nano-medicine particles were characterized by Malvern's ZS90 test, the drug loading of the nano-medicine particles was calculated by high performance liquid chromatography (HPLC), and the morphology of the nano-medicine particles was characterized by transmission electron microscopy (TEM).
  • HPLC high performance liquid chromatography
  • TEM transmission electron microscopy
  • Example 15 Take a balloon with a hydrophilic coating and spray the cationic nano drug particles prepared above on the surface of the balloon uniformly by ultrasonic spraying to make the drug concentration reach 1.3 mg/mm 2 , and then dry it naturally for 24 hours. After alkane sterilization, the drug-coated balloon of Example 15 was obtained.
  • Embodiment 16 is basically the same as Embodiment 1, except that the flow rate ratios of the first liquid flow and the second liquid flow to the third liquid flow and the fourth liquid flow are different. specifically:
  • TPGS D- ⁇ -tocopherol polyethylene glycol succinate
  • PLGA polylactic acid-glycolic acid copolymer
  • the concentrations are 10mg/mL, 2mg/mL and 5mg, respectively /mL, as stream 1.
  • TPGS and hydroxypropyltrimethylammonium chloride chitosan (HACC) were dissolved in water at concentrations of 0.3 mg/mL and 0.08 mg/mL, respectively, as stream 2. Both stream 3 and stream 4 are water.
  • liquid flow 1, liquid flow 2, liquid flow 3 and liquid flow 4 are respectively injected into the four-channel vortex mixer, the flow rate of liquid flow 1 and liquid flow 2 is 10 mL/min, The flow rates of the liquid stream 3 and the liquid stream 4 are 40 mL/min, and a nano drug particle suspension formed by mixing is obtained.
  • a suitable mixing time can be selected. In this embodiment, the mixing time is 10 s, and the volume ratio of the aqueous phase and the organic phase in the cationic nano-medicine particle suspension finally obtained is 1:9.
  • the mixed liquid obtained in the first 2 seconds is discarded and the mixed liquid obtained 8 seconds after collection is the nano-medicine particle suspension.
  • the nano-drug particle suspension into a dialysis bag for dialysis for 12 hours, and change the water every 2 hours.
  • the prepared nano drug particle suspension is concentrated for use.
  • the size and surface charge of the nano-medicine particles were characterized by Malvern's ZS90 test, the drug loading of the nano-medicine particles was calculated by high performance liquid chromatography (HPLC), and the morphology of the nano-medicine particles was characterized by transmission electron microscopy (TEM).
  • Example 16 Take a balloon with a hydrophilic coating and spray the cationic nano drug particles prepared above on the surface of the balloon uniformly by ultrasonic spraying to make the drug concentration reach 1.3 mg/mm 2 , and then dry it naturally for 24 hours. After alkane sterilization, the drug-coated balloon of Example 16 was obtained.
  • Example 2 It is basically the same as Example 1, except that the second liquid stream does not contain a cationic modifier, specifically:
  • TPGS D- ⁇ -tocopherol polyethylene glycol succinate
  • PLGA polylactic acid-glycolic acid copolymer
  • a suitable mixing time can be selected.
  • the mixing time is 10 s
  • the volume ratio of the aqueous phase and the organic phase in the cationic nano-medicine particle suspension finally obtained is 1:3.
  • the mixed liquid obtained in the first 2 seconds is discarded and the mixed liquid obtained 8 seconds after collection is the nano-medicine particle suspension.
  • the collected nano-drug particle suspension was put into a dialysis bag for dialysis for 12 hours, and the water was changed every 2 hours. Subsequently, the prepared nano drug particle suspension is concentrated for use.
  • the size and surface charge of the nano-medicine particles were characterized by Malvern's ZS90 test, the drug loading of the nano-medicine particles was calculated by high performance liquid chromatography (HPLC), and the morphology of the nano-medicine particles was characterized by transmission electron microscopy (TEM).
  • HPLC high performance liquid chromatography
  • TEM transmission electron microscopy
  • Example 2 It is basically the same as Example 1, except that the cationic nanoparticles are not loaded with drugs, specifically:
  • TPGS D- ⁇ -tocopherol polyethylene glycol succinate
  • PLGA polylactic acid-glycolic acid copolymer
  • HACC hydroxypropyltrimethylammonium chloride chitosan
  • liquid flow 1, liquid flow 2, liquid flow 3 and liquid flow 4 were injected into a four-channel vortex mixer at a flow rate of 10 mL/min to obtain a nanoparticle suspension formed by mixing .
  • a suitable mixing time can be selected.
  • the mixing time is 10 s
  • the volume ratio of the aqueous phase and the organic phase in the cationic nanoparticle suspension finally obtained is 1:3.
  • the mixed liquid obtained in the first 2 seconds is discarded and the mixed liquid obtained 8 seconds after collection is the nanoparticle suspension.
  • TPGS D- ⁇ -tocopherol polyethylene glycol succinate
  • PLGA polylactic acid-glycolic acid copolymer
  • TPGS and DMAB were dissolved in water with concentrations of 0.3 mg/mL and 0.08 mg/mL, respectively, as stream 2. Both stream 3 and stream 4 are water.
  • liquid flow 1, liquid flow 2, liquid flow 3 and liquid flow 4 were injected into a four-channel vortex mixer at a flow rate of 10 mL/min to obtain a suspension of cationic nanoparticles formed by mixing liquid.
  • a suitable mixing time can be selected.
  • the mixing time is 10 s
  • the volume ratio of the aqueous phase and the organic phase in the cationic nanoparticle suspension finally obtained is 1:3.
  • the mixed liquid obtained in the first 2 seconds is discarded and the mixed liquid obtained 8 seconds after collection is the nanoparticle suspension.
  • the mixing time is 10 s
  • the volume ratio of the aqueous phase and the organic phase in the cationic drug-loaded liposome suspension is 1:3.
  • the mixed liquid obtained in the first 2 seconds is discarded and the mixed liquid obtained 8 seconds after collection is the cationic drug-loaded liposome suspension.
  • the above cationic liposome suspension was put into a dialysis bag for dialysis for 10 hours, and the water was changed every 2 hours.
  • the size and surface charge of cationic liposomes were characterized by Malvern ZS90 test.
  • Malvern ZS90 scattering angle 90°, temperature 25°C was used to test and characterize the size and surface charge of the nano-medicine particles of Examples 1-13 and Comparative Example 1, and passed high-performance liquid chromatography (HPLC) (C18 column, mobile phase: 16% acetonitrile: 24% water: 60% methanol, flow rate: 1.0 mL/min, temperature: 40° C., detector: UV 277 nm) Calculate the drug loading of the nano-drug particles, and the specific results are shown in Table 1.
  • HPLC high-performance liquid chromatography
  • Example 1 249.7 ⁇ 5.6nm 54.5 ⁇ 1.3mV 41%
  • Example 2 192 ⁇ 2.7nm 46.1 ⁇ 2.5mV 40%
  • Example 3 250.2 ⁇ 3.4nm 45.2 ⁇ 0.6mV 40%
  • Example 4 330.1 ⁇ 0.9nm 40.4 ⁇ 1.1mV 48%
  • Example 5 352.4 ⁇ 1.7nm 32.1 ⁇ 1.2mV 46%
  • Example 6 290.5 ⁇ 2.5nm 55.2 ⁇ 4.1mV 37%
  • Example 7 362.1 ⁇ 5.4nm 36.2 ⁇ 0.7mV 33%
  • Example 8 195.2 ⁇ 1.0nm 44.2 ⁇ 1.6mV 46%
  • Example 9 206.4 ⁇ 2.1nm 48.1 ⁇ 1.8mV 45%
  • Example 10 240.3 ⁇ 0.8nm 29.6 ⁇ 0.9mV 42%
  • Example 11 232.2 ⁇ 2.3nm 46.2 ⁇ 2.2mV 43%
  • Example 12 280.3 ⁇ 3.8nm 40.1 ⁇ 3.1mV 39%
  • Example 13 451.2 ⁇ 8.4nm 51.3 ⁇ 2.8mV twenty two%
  • Example 15 538.1 ⁇ 13.9nm 43.3 ⁇ 6.8mV 37%
  • Example 16 213.4 ⁇ 6.2nm 49.3 ⁇ 5.5mV 35%
  • Comparative example 1 195.8 ⁇ 4.5nm -14.2 ⁇ 0.9mV 41%
  • Comparative example 3 195.8 ⁇ 4.5nm -14.2 ⁇ 0.9mV -
  • FIG. 2 is the surface zeta potential distribution diagram of Example 1 and Comparative Example 1. It can also be clearly seen from FIG. 2 that the surface of Example 1 is positively charged, and Comparative Example 1 is negatively charged. This shows that by adding cationic amphiphilic compounds and/or cationic modifiers, the surface of the nano-drug particles can be positively charged.
  • Example 1 and Example 16 are basically the same.
  • Example 16 increases the flow rates of the third liquid stream and the fourth liquid stream, and the final prepared nanoparticles have a smaller particle size, indicating that the instantaneous nanoprecipitation method can effectively adjust the nanoparticle size.
  • the size of the particles are basically the same.
  • Example 3 is a particle size distribution diagram of Example 1 and Example 13.
  • Example 1 and Example 13 used the instantaneous nanoprecipitation method and the conventional stirring method to prepare cationic nano-medicine particles, respectively. It can be seen from FIG. 1 that the particle size of Example 1 is smaller than that of Example 13.
  • Figure 4 shows the morphology of the cationic nanomedicine of Example 1
  • Figure 5 shows the morphology of the nanomedicine prepared in Example 13. It can be seen that the cationic nanomedicine particles prepared by the instantaneous nanoprecipitation method have a better morphology.
  • Example 13 and Example 2 are basically the same, except that the preparation method is different. It can be seen from Table 1 that the drug loading of Example 2 is significantly higher than that of Example 13, indicating that the instantaneous nanoprecipitation method can significantly increase the drug loading of cationic nanomedicine.
  • Example 1 404.8 ⁇ 157.9
  • Example 2 507.5 ⁇ 230.3
  • Example 3 483.7 ⁇ 217.5
  • Example 4 303.4 ⁇ 110.5
  • Example 5 324.9 ⁇ 122.3
  • Example 6 284.2 ⁇ 140.1
  • Example 7 349.2 ⁇ 110.3
  • Example 8 286.7 ⁇ 87.6
  • Example 9 372.5 ⁇ 176.6
  • Example 10 384.8 ⁇ 88.7
  • Example 11 389.7 ⁇ 154.2
  • Example 12 325.2 ⁇ 91.3
  • Example 13 385.5 ⁇ 103.3 Comparative example 1 131.8 ⁇ 41.6
  • Example 3 It can be seen from Table 3 that the cationic nanomedicines of Examples 1-13 all have a better sustained-release effect and can prolong the drug release time, while Comparative Example 1 basically has no sustained-release effect. It can be seen from the comparison between Example 2 and Example 13 that the sustained-release effect of Example 2 is significantly better than that of Example 13.
  • SMC vascular smooth muscle cell
  • the cationic nanomedicine of Example 14 is basically non-cytotoxic and has a higher cell survival rate, while the DMAB of Comparative Example 3 has severe cytotoxicity and is not suitable for loading drugs.
  • the cationic amphiphilic compound DOTAP of Comparative Example 4 also has good biocompatibility and no obvious cytotoxicity.

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Abstract

一种阳离子纳米药物及其制备方法、载药植入医疗器械，其中，阳离子纳米药物包括载体和负载在载体上的药物，载体中包含有阳离子双亲化合物和阳离子修饰剂中的一种或多种；阳离子双亲化合物为含氨基和/或酰基的阳离子双亲化合物，阳离子修饰剂为含氨基和/或酰基的阳离子修饰剂。所述阳离子纳米药物大幅提高细胞对药物的摄取且具有较好的缓释效果。

Description

阳离子纳米药物及其制备方法、载药植入医疗器械 技术领域
本发明涉及医疗器械技术领域，特别涉及阳离子纳米药物及其制备方法、载药植入医疗器械。
背景技术
心血管疾病是全球的头号死因，而冠状动脉粥样硬化性心脏病(冠心病)又是其中死亡率最高的疾病之一，严重危害人类的生命健康。经皮冠脉介入(Percutaneouscoronary intervention，PCI)是其主要的治疗方案。目前，药物洗脱支架(Drug elutingstent，DES)仍是PCI的首选，DES的植入可防止血管回弹同时负载的抗增生药物能够抑制血管平滑肌的增生，防止内膜增生的发生，有效的降低支架内再狭窄率。最近，含药物涂层的植入医疗器械，特别是药物涂层球囊(Drug coated balloon，DCB)以其介入不植入、无血栓风险和治疗效果快等优点越来越受到人们的关注。含药物涂层的植入医疗器械作为一种新的介入治疗技术已被多项临床试验证实其在支架内再狭窄、小血管病变、分叉病变等方面具有疗效和安全性。
含药物涂层的植入医疗器械主要是通过在器械表面涂覆含抗增生药物的药物涂层获得。将含药物涂层的植入医疗器械输送至病变位置后，药物涂层在短暂的扩张时间内(30s-60s)释放药物，抑制血管平滑肌细胞的增生。故，植入医疗器械上的药物涂层的设计具有重要意义。
目前植入医疗器械上药物涂层的设计主要集中在降低输送损失和提高靶病变对药物的摄取。目前，已经设计并制造了具有不同亲水性基底层的药物涂层。该类药物涂层还具有用于延缓溶解的亲水性顶层，可大幅降低在输送过程中造成的药物涂层的损失。但是，该类药物涂层的摄取及滞留不佳，无法起到缓释作用。如何提高药物的摄取及滞留，进而提高植入医疗器械上的药物涂层的缓释作用也一直是限制植入医疗器械的发展的重要因素。
发明内容
基于此，有必要提供一种具有良好缓释效果的阳离子纳米药物及其制备方法、载药植入医疗器械。
本发明提供了一种阳离子纳米药物，包括载体和负载在所述载体上的药物，所述载体中包含有阳离子双亲化合物和阳离子修饰剂中的一种或多种；所述阳离子双亲化合物为含氨基和/或酰基的阳离子双亲化合物，所述阳离子修饰剂为含氨基和/或酰基的阳离子修饰剂。
在其中一个实施例中，所述载体还包括疏水纳米核，所述阳离子双亲化合物和/或所述阳离子修饰剂包括亲水端和疏水端，所述疏水端结合在所述疏水纳米核上，且所述亲水端至少部分裸露。
在其中一个实施例中，所述阳离子修饰剂选自：聚氨基酸、聚多糖、多肽、胆固醇衍生物或阳离子共聚物。
在其中一个实施例中，所述阳离子修饰剂选自：聚精氨酸、聚赖氨酸、二乙氨乙基-葡聚糖、羟丙基三甲基氯化铵壳聚糖、壳聚糖盐酸盐、N,N,N-三甲基壳聚糖、TAT多肽、和3β-[N-(N’,N’-二甲基胺乙基)胺基甲酰基]胆固醇中的一种或多种。
在其中一个实施例中，所述阳离子双亲化合物选自如下的阳离子表面活性剂中的一种或多种：(2,3-二油酰基-丙基)三甲基氯化铵、1,2-二油酰-SN-甘油-3-磷酰乙醇胺、(2,3-二硬脂酰-丙基)三甲胺、(2,3-二肉豆蔻酰基-丙基)三甲基甲磺酸盐、(2,3-二棕榈酰基-丙基)三甲胺和(2,3-二硬脂酰-丙基)三甲胺、基于聚甲基丙烯酸N,N-二甲基氨基乙酯的双亲聚合物、基于壳聚糖的双亲聚合物、基于壳聚糖季铵盐的双亲聚合物、基于氯化壳聚糖的双亲聚合物、基于巯基修饰壳聚糖的双亲聚合物、基于聚乙烯亚胺的双亲聚合物、和基于聚(β-氨基酯)的双亲聚合物。
在其中一个实施例中，所述载体中包含有阳离子修饰剂时，所述载体中还包括乳化剂。
在其中一个实施例中，所述乳化剂为D-α-生育酚聚乙二醇琥珀酸酯、聚乙烯醇、聚山梨酯、泊洛沙姆和卡波姆中的一种或多种。
在其中一个实施例中，所述载体中还包含有缓释共聚物。
在其中一个实施例中，所述阳离子纳米药物的表面电荷为10mV-60mV；和/或
所述阳离子纳米药物的粒径为3nm-300nm。
在其中一个实施例中，所述的阳离子纳米药物的形貌为球形、棒状、蠕虫状或圆盘状。
在其中一个实施例中，负载在所述载体上的药物选自以下抗增殖药物中的一种或多种：紫杉醇、西罗莫司和西罗莫司衍生物。所述西罗莫司衍生物为佐他莫司、依维莫司、比欧莫斯、7-O-去甲基雷帕霉素、替西罗莫司、地磷莫司和他克莫司。所述抗增生药物为结晶态、非结晶态或两者混合。
本发明还提供一种医疗器械，包括器械基底和负载在所述器械基底上的药物涂层，所述药物涂层中包含有上述阳离子纳米药物。
本发明还提供一种阳离子纳米药物的制备方法，包括以下步骤：
提供第一液流；
提供第二液流；
采用瞬时纳米沉淀法使所述第一液流和所述第二液流碰撞形成涡流以获得经混合形成的纳米悬浮液，收集所述纳米悬浮液，并透析所述纳米悬浮液以获得所述阳离子纳米药物；
其中，所述第一液流和所述第二液流中至少有一个液流中溶解有药物，所述第一液流和所述第二液流中至少有一个液流中溶解有载体；所述第一液流和所述第二液流中的一个具有能与水互溶的有机相，所述第一液流和所述第二液流中的另一个具有水相；所述载体中包含有阳离子双亲化合物和阳离子修饰剂中的一种或多种；所述阳离子双亲化合物为含氨基和/或酰基的阳离子双亲聚合物，所述阳离子修饰剂为含氨基和/或酰基的阳离子修饰剂。
在其中一个实施例中，所述阳离子修饰剂选自：阳离子磷脂、聚氨基酸、聚多糖、多肽或胆固醇衍生物或阳离子共聚物。
在其中一个实施例中，所述阳离子修饰剂选自：聚精氨酸、聚赖氨酸、二乙氨乙基-葡聚糖、羟丙基三甲基氯化铵壳聚糖、壳聚糖盐酸盐、N,N,N-三甲基壳聚糖、TAT多肽、和3β-[N-(N’,N’-二甲基胺乙基)胺基甲酰基]胆固醇中 的一种或多种。
在其中一个实施例中，所述阳离子双亲化合物选自如下的阳离子表面活性剂：(2,3-二油酰基-丙基)三甲基氯化铵、1,2-二油酰-SN-甘油-3-磷酰乙醇胺、(2,3-二硬脂酰-丙基)三甲胺、(2,3-二肉豆蔻酰基-丙基)三甲基甲磺酸盐、(2,3-二棕榈酰基-丙基)三甲胺、(2,3-二硬脂酰-丙基)三甲胺、基于聚甲基丙烯酸N,N-二甲基氨基乙酯的双亲聚合物、基于壳聚糖的双亲聚合物、基于壳聚糖季铵盐的双亲聚合物、基于氯化壳聚糖的双亲聚合物、基于巯基修饰壳聚糖的双亲聚合物、基于聚乙烯亚胺的双亲聚合物、和基于聚(β-氨基酯)的双亲聚合物中的一种或多种。
在其中一个实施例中，所述第一液流和所述第二液流中至少有一个液流中溶解有缓释共聚物；和/或
所述第一液流和所述第二液流中至少有一个液流中溶解有乳化剂。
在其中一个实施例中，所述缓释共聚物为聚乳酸-羟基乙酸共聚物；和/或
所述乳化剂为D-α-生育酚聚乙二醇琥珀酸酯、聚乙烯醇、聚山梨酯、泊洛沙姆和卡波姆中的一种或多种。
在其中一个实施例中，采用瞬时纳米沉淀法使所述第一液流和所述第二液流碰撞形成涡流的步骤包括以下步骤：
提供涡流混合器；
向所述涡流混合器中的一个通道通入所述第一液流；
向所述涡流混合器中的另一通道通入所述第二液流；以及
使所述第一液流和所述第二液流在所述涡流混合器中碰撞混合，形成涡流。
在其中一个实施例中，采用瞬时纳米沉淀法使所述第一液流和所述第二液流碰撞形成涡流的步骤还包括向所述涡流混合器的剩余通道中通入水，作为额外液流；以及使所述第一液流、所述第二液流、所述额外液流在所述涡流混合器中碰撞混合，形成涡流。
在其中一个实施例中，所述额外液流可包括第三液流和第四液流。
在其中一个实施例中，所述第三液流和所述第四液流的流速可相同。在其中一个实施例中，所述第一液流、所述第二液流和所述第三液流的流速为1mL/min至12mL/min；且所述第一液流、第二液流的流速比为1:1，所述第三液流的流速是第一液流或第二液流的流速的1至5倍。
本发明还提供一种载药植入医疗器械，包括由上述制备方法制备而成的阳离子纳米药物。
由于采用的阳离子双亲化合物和/或阳离子修饰剂可以使得阳离子纳米药物表面带正电荷，阳离子纳米药物可有效地与表面电荷为负电荷的血管壁细胞充分结合，从而大幅提高组织细胞对纳米药物颗粒的摄取。特别地，上述阳离子双亲化合物和/或阳离子修饰剂含有氨基或酰基，从而可通过“质子泵作用”帮助纳米药物颗粒从细胞溶酶体中逃逸出来，避免药物被溶酶体降解或转运至细胞外。因此，上述阳离子纳米药物具有极佳的组织滞留时间，获得较优的缓释作用，有利于长时间地抑制血管平滑肌的增生。此外，上述阳离子纳米药物生物相容性好，能够避免额外的细胞毒性。
此外，上述阳离子纳米药物为纳米级别药物，能够提高载药量，且能够有效地避免传统药物涂层的大微粒的脱落而造成的栓塞问题，极大地提高安全性。此外，上述阳离子纳米药物颗粒在含有氨基或酰基的阳离子双亲化合物和/或阳离子修饰剂的作用下，能够提高载体与药物的亲和力，进而大幅度地提高上述阳离子纳米药物颗粒的载药量，即在同等药物浓度下，上述阳离子纳米药物颗粒可减少辅料的使用，降低涂层的厚度，从而提高药物植入医疗器械的通过性(Crossability)。
此外，采用瞬时纳米沉淀法可快速制备具有超高载药量的阳离子纳米药物颗粒。与传统的纳米颗粒制备方法相比，瞬时纳米沉淀法具有操作简单、制备耗时极短(几秒钟)、载药量高、重复性好、纳米颗粒尺寸可调控、可线性工业放大等优点。
此外，采用瞬时纳米沉淀法制备上述阳离子纳米药物能够获得粒径在200nm左右的纳米颗粒。相比传统的方法制备得到的微米甚至毫米的药物颗粒，采用瞬时纳米沉淀法制备得到的阳离子纳米药物可增强纳米颗粒的渗透 作用，提高组织对药物的摄取。同时，由于添加的阳离子双亲化合物和/或阳离子修饰剂使得阳离子纳米药物颗粒表面电荷为正，采用瞬时纳米沉淀法制备得到的阳离子纳米药物可有效地与表面电荷为负电荷的血管壁细胞充分结合，从而大幅提高组织细胞对纳米药物颗粒的摄取。此外，通过调节阳离子表面活性剂的含量可以实现阳离子纳米药物的表面电位的调节，进而更有利于促进阳离子纳米药物与血管壁细胞的结合，调控阳离子纳米药物在组织内的滞留时间以获得优异的缓释效果。
附图说明
图1为一实施方式的涡流混合器的示意图。
图2为实施例1和对比例1的阳离子纳米药物的表面Zeta电位分布图。
图3为实施例1和对比例1的阳离子纳米药物的粒径分布图。
图4为实施例1的阳离子纳米药物的形貌图。
图5为实施例13的阳离子纳米药物的形貌图。
具体实施方式
为了便于理解本发明，下面将对本发明进行更全面的描述，并给出了本发明的较佳实施例。但是，本发明可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与本发明的技术领域的技术人员通常理解的含义相同。在本发明的说明书中所使用的术语只是为了描述具体的实施例，不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
本发明提供了一种阳离子纳米药物，包括载体和负载在载体上的药物，载体中包含有阳离子双亲化合物和阳离子修饰剂中的一种或多种；阳离子双亲化合物为含氨基和/或酰基的阳离子双亲化合物，阳离子修饰剂为含氨基和/或酰基的阳离子修饰剂。
本发明采用的含氨基或酰基的阳离子双亲化合物和/或阳离子修饰剂可通过“质子泵作用”帮助纳米药物颗粒从细胞溶酶体中逃逸出来，避免药物被溶酶体降解或转运至细胞外。因此，本发明的阳离子纳米药物具有极佳的组织滞留时间，有利于长时间地抑制血管平滑肌的增生，且生物相容性好，能够避免额外的细胞毒性。
进一步地，上述阳离子纳米药物中的载体还包括疏水纳米核，阳离子双亲化合物和阳离子修饰剂包括亲水端和疏水端，所述疏水端吸附在疏水纳米核上，所述亲水端少部分裸露。通过疏水端与疏水纳米核的吸附，可以防止纳米颗粒生长，同时所述亲水端至少部分裸露可在颗粒外部起保护作用并阻止纳米颗粒相互聚集，有利于形成粒径小且均一的纳米颗粒。可理解的是，本发明中“亲水端裸露”是指相对于处于核心位置的疏水纳米核而言，即相对于疏水端而言，亲水端暴露于纳米核的外部。纳米粒子与纳米粒子之间，或与其他分子(如溶剂分子)等相互作用而将亲水端包裹的情况应理解为在本发明的保护范围内。
可理解的是，本发明中所采用的各试剂(如阳离子双亲化合物、阳离子修饰剂等)均为药学领域可接受的试剂。在本发明中，疏水纳米核可以采用本领域可接受的物质，例如过饱和的有机溶质所形成的疏水纳米核，在此不做特别限定。
本发明中阳离子双亲化合物以及阳离子修饰剂为含有氨基或酰基的试剂，即只需其含有一个氨基或一个酰基即可。可理解的是，仅含氨基或仅含有酰基的试剂，以及同时含有氨基和酰基的试剂均在本发明的保护范围内。
进一步地，阳离子修饰剂选自：阳离子磷脂、阳离子共聚物、聚氨基酸、聚多糖、多肽和胆固醇衍生物中的一种或多种。优选地，阳离子修饰剂为能生物降解，且降解后无毒害物质累积的共聚物，其中，聚氨基酸、聚多糖、多肽或胆固醇衍生物均为人体内的生物类似物，降解后无毒副作用，具有较高的应用价值。
更进一步地，阳离子修饰剂选自：聚精氨酸、聚赖氨酸、二乙氨乙基-葡聚糖、羟丙基三甲基氯化铵壳聚糖、壳聚糖盐酸盐、N,N,N-三甲基壳聚糖、 TAT多肽、和3β-[N-(N’,N’-二甲基胺乙基)胺基甲酰基]胆固醇中的一种或多种。
更进一步地，阳离子双亲化合物选自如下的阳离子表面活性剂中的一种或多种：(2,3-二油酰基-丙基)三甲基氯化铵(DOTAP)、1,2-二油酰-SN-甘油-3-磷酰乙醇胺(DOPE)、(2,3-二硬脂酰-丙基)三甲胺(DSTAP)、(2,3-二肉豆蔻酰基-丙基)三甲基甲磺酸盐(DMTAP)、(2,3-二棕榈酰基-丙基)三甲胺(DPTAP)和(2,3-二硬脂酰-丙基)三甲胺(DSTAP)、基于聚甲基丙烯酸N,N-二甲基氨基乙酯的双亲聚合物、基于壳聚糖的双亲聚合物、基于壳聚糖季铵盐的双亲聚合物、基于氯化壳聚糖的双亲聚合物、基于巯基修饰壳聚糖的双亲聚合物、基于聚乙烯亚胺的双亲聚合物、和基于聚(β-氨基酯)的双亲聚合物中的一种或多种。
上述阳离子表面活性剂和阳离子修饰剂具有较好的生物相容性，且具有较高的安全性，不易产生毒副作用。相比于溴化双十二烷基二甲胺(DMAB)等试剂，上述阳离子表面活性剂和阳离子修饰剂的安全性能得到了显著的提高。此外，通过调节阳离子双亲化合物和/或阳离子修饰剂的浓度可实现对阳离子纳米药物的表面电位的调节，更有利于促进阳离子纳米药物与血管壁细胞的结合，调控阳离子纳米药物的组织滞留时间以达到较优的缓释效果。
进一步地，当上述载体为阳离子修饰剂时，载体中还可以包括乳化剂。可理解的是，乳化剂在阳离子纳米药物中的负载方式无特别限定，其可以通过吸附作用吸附在纳米核上，其还可以通过与阳离子双亲化合物和/或阳离子修饰剂相互作用而负载在阳离子纳米药物上。应理解的是，根据所选择的试剂种类及制备方法的不同，负载方式有所差异，其均在本发明的保护范围内。
更进一步地，乳化剂为D-α-生育酚聚乙二醇琥珀酸酯、聚乙烯醇、聚山梨酯、泊洛沙姆和卡波姆中的一种或多种。上述试剂无毒副作用，能够提高制得的阳离子纳米药物的安全性。
另外，上述载体中还可以包含有缓释共聚物，所述的缓释聚合物是指负载在阳离子纳米药物中后可减缓药物从纳米粒中的释放的聚合物。可理解的，缓释共聚物在阳离子纳米药物中的负载方式无特别限定，其可以通过吸附作用吸附在纳米核上，其还可以通过与阳离子双亲化合物和/或阳离子修饰剂相互作用而负载在阳离子纳米药物上。应理解的是，根据所选择的试剂种类及 制备方法的不同，负载方式有所差异，其在本发明的保护范围内。例如，当采用PLGA作为缓释共聚物，由于其具有一定的疏水作用，其可能被包埋在阳离子纳米药物内部。
缓释共聚物的添加具有增强缓释的作用。可理解的是，本发明中的缓释共聚物可以为任意药学领域可接受的生物可降解共聚物，在此不做特别限定，优选为能够在体内降解成无毒害物质，以促进药物的缓释作用。在一实施例中，共聚物为聚乳酸-羟基乙酸共聚物(PLGA)，其能够在体内降解为乳酸和羟基乙酸，均为人体代谢途径的副产物，无毒副作用。
本发明通过采用阳离子双亲化合物和/或阳离子修饰剂作为载体，可以使得阳离子纳米药物的表面带正电荷。优选的表面电荷的电位(即ζ电位)为1-80mV，更优选的ζ电位为10-60mV，例如为20-50mV。
可理解的是，本发明的阳离子纳米药物为纳米级别(1-1000nm)药物，优选的阳离子纳米药物的尺寸为3nm-300nm，更优选的阳离子纳米药物的尺寸为50nm-250nm，例如为70nm-240nm、80nm-230nm、100nm-210nm。纳米药物具有增强细胞渗透作用、提高载药量、缓释、局部滞留、防止药物降解等优点。故将含有上述阳离子纳米药物的涂层负载于植入医疗器械上时，可以避免传统药物涂层的大的微粒的脱落而造成的栓塞问题，极大地提高安全性。
本发明的阳离子纳米药物的形貌无特别限定，优选为球形、棒状、蠕虫状、圆盘状，更优选的形貌为球形，以提高载药量。阳离子纳米药物的表现形式可以为阳离子胶束、阳离子聚合物纳米粒和阳离子脂质体中的一种或多种的混合，根据具体工艺进行选择。
本发明的药物负载在载体上的负载方式无特别限定，根据制备方法及试剂种类会存在差异，例如：可以将药物包裹在载体内，也可以将药物负载在载体表面，应理解为均在本发明的保护范围内。另外，药物的种类无特别限定，可根据需要进行选择。在一实施例中，药物为抗增生药物，例如紫杉醇、西罗莫司(Sirolimus)和西罗莫司衍生物。所述西罗莫司衍生物优选为佐他莫司、依维莫司、比欧莫斯、7-O-去甲基雷帕霉素、替西罗莫司、地磷莫司和他克莫司。其中，抗增生药物可以为结晶态、非结晶态或两者的混合。
本发明的阳离子纳米药物为纳米级别药物，其相对表面积较大，可以有效地提高载药量。同时，本发明的阳离子纳米药物采用具有氨基或酰基的阳离子双亲化合物和/或阳离子修饰剂作为载体，可以有效地增强载体与药物之间的亲和作用，进一步提高载药量。此外，通过调节各试剂的浓度配比及所制得的阳离子纳米药物的粒径即可实现对载药量的控制，方便快捷。在一实施例中，上述阳离子纳米药物的载药量为1％-50％(w/w)，例如为10％-50％、20％-50％。
上述阳离子纳米药物的制备方法无特别限定，优选采用瞬时纳米沉淀法进行制备。该方法简单、快速、可规模扩大，且能够连续快速地制备纳米粒子，所制备得到的纳米粒子的尺寸分布窄且载药率高。
本发明还提供了一种阳离子纳米药物的制备方法，包括以下步骤：
S101：提供第一液流；提供第二液流；其中，第一液流和第二液流中至少有一个液流中溶解有药物，第一液流和第二液流中至少有一个液流中溶解有载体，第一液流和第二液流中的一个具有能与水互溶的有机相，第一液流和第二液流中的另一个具有水相；载体中包含有阳离子双亲化合物和阳离子修饰剂中的一种或多种；阳离子双亲化合物为含氨基和/或酰基的阳离子双亲化合物，阳离子修饰剂为含氨基和/或酰基的阳离子修饰剂。
在步骤S101中，有机相无特别限定，包括但不限于丙酮、醇类溶剂等。
进一步地，阳离子修饰剂选自：阳离子磷脂、阳离子共聚物、聚氨基酸、聚多糖、多肽和胆固醇衍生物中的一种或多种。优选的阳离子修饰剂为能生物降解，且降解后无毒害物质累积的共聚物，其中，聚氨基酸、聚多糖、多肽或胆固醇衍生物均为人体内生物类似物，降解后无毒副作用，具有较高的应用价值。
更进一步地，阳离子修饰剂选自：聚精氨酸、聚赖氨酸、二乙氨乙基-葡聚糖、羟丙基三甲基氯化铵壳聚糖、壳聚糖盐酸盐、N,N,N-三甲基壳聚糖、TAT多肽、和3β-[N-(N’,N’-二甲基胺乙基)胺基甲酰基]胆固醇中的一种或多种。
更进一步地，阳离子双亲化合物选自如下的阳离子表面活性剂中的一种或多种：(2,3-二油酰基-丙基)三甲基氯化铵(DOTAP)、1,2-二油酰-SN-甘油-3- 磷酰乙醇胺(DOPE)、(2,3-二硬脂酰-丙基)三甲胺(DSTAP)、(2,3-二肉豆蔻酰基-丙基)三甲基甲磺酸盐(DMTAP)、(2,3-二棕榈酰基-丙基)三甲胺(DPTAP)和(2,3-二硬脂酰-丙基)三甲胺(DSTAP)、基于聚甲基丙烯酸N,N-二甲基氨基乙酯的双亲聚合物、基于壳聚糖的双亲聚合物、基于壳聚糖季铵盐的双亲聚合物、基于氯化壳聚糖的双亲聚合物、基于巯基修饰壳聚糖的双亲聚合物、基于聚乙烯亚胺的双亲聚合物、和基于聚(β-氨基酯)的双亲聚合物。进一步地，第一液流和第二液流中至少有一个液流中溶解有缓释共聚物；更进一步地，缓释共聚物可以为聚乳酸-羟基乙酸共聚物。
进一步地，第一液流和第二液流中至少有一个液流中溶解有乳化剂。更进一步地，乳化剂可以为D-α-生育酚聚乙二醇琥珀酸酯、聚乙烯醇、聚山梨酯、泊洛沙姆和卡波姆中的一种或多种。
可理解的是，各试剂具体溶解在有机相还是水相中，需要根据试剂的具体种类来进行确定，在此不做特别限定。例如：目前大多数药物和阳离子表面活性剂易溶于有机溶剂，缓释共聚物易溶于有机相，阳离子修饰剂易溶于水，故可以将阳离子表面活性剂和缓释共聚物加入有机相中，阳离子修饰剂加入水相中。
另外，为了促进阳离子纳米药物的形成，还可以在第一液流和/或第二液流中添加乳化剂，例如D-α-生育酚聚乙二醇琥珀酸酯(TPGS)、聚乙烯醇、聚山梨酯、泊洛沙姆和卡波姆中的一种或多种。优选在第二液流中添加乳化剂，第一液流中根据试剂的具体种类选择性地添加乳化剂。
各试剂的添加比例可以根据需要进行调节，在此不做特别限定。特别地，阳离子双亲化合物和阳离子修饰剂的含量的调节可以实现阳离子纳米药物的表面电位的调节，对于调节药物与细胞之间的亲和作用具有重要意义。
负载的药物的种类无特别限定，可以根据需要进行选择，在一实施例中，药物为抗增生药物，例如紫杉醇、西罗莫司(Sirolimus)和西罗莫司衍生物。具体地，西罗莫司衍生物可以为佐他莫司、依维莫司、比欧莫斯、7-O-去甲基雷帕霉素、替西罗莫司、地磷莫司和他克莫司。其中，抗增生药物为结晶态、非结晶态或两者混合。
S102：采用瞬时纳米沉淀法使第一液流和第二液流碰撞形成涡流以获得经混合形成的纳米悬浮液，收集经混合形成的纳米悬浮液，并透析所述纳米悬浮液以制得阳离子纳米药物。
瞬时纳米沉淀法是指利用多通道涡流混合器等使几股液流快速碰撞，导致在短时间内(微妙甚至毫秒)，有机溶质形成足够高的过饱和度，进而形成疏水纳米核，此时，一方面，具有双亲性的阳离子双亲化合物和/或阳离子修饰剂的疏水端吸附在该疏水纳米核上以阻止纳米核继续长大，另一方面，其亲水端裸露在外侧以避免纳米颗粒之间的汇聚，进而达到形成均一的纳米颗粒的目的。
需要说明的是，根据所选择的多通道涡流混合器的种类，会有不同数目的通道，具体不做特别限定。在本发明中，所选择的多通道涡流混合器仅需具有大于两个通道即可。例如可以采用图1所示的四通道涡流混合器，在其中的第一通道通入第一液流，第二通道通入第二液流，第三通道和第四通道通入水，作为第三液流和第四液流即可。
各通道内的液体的流速可以根据需要进行调节。优选地，通道内的液体的流速在1mL/min-12mL/min之间，例如为2mL/min-11mL/min、3mL/min-10mL/min、5mL/min-9mL/min、6mL/min-8mL/min。各通道内的液流的速度可以相等或不同。优选地，第三液流和第四液流的流速相同。优选地，第一液流、第二液流的流速之比为1:1，第三液流和第四液流的流速是第一液流或第二液流的流速的1至5倍，例如为1至4倍，优选为1至3倍，以形成粒径较小且均一的阳离子纳米药物。
另外，透析的方法可以采用本领域常用透析方法，在此不做特别限定，例如：将待透析悬浮液装入透析袋中透析，每隔一段时间换一次水。随后将制备的纳米药物颗粒悬浮液浓缩备用。
本发明还提供了一种载药植入器械，包括器械基底和负载在器械基底上的药物涂层，药物涂层包括上述阳离子纳米药物或利用上述制备方法制备而成的阳离子纳米药物。
上述载药植入器械通过采用上述阳离子纳米药物或上述制备方法制备而 成的阳离子纳米药物而获得良好的生物相容性好。并且，由于纳米颗粒的表面电荷可调节，负载有阳离子纳米药物的载药植入器械在植入的过程中可通过电荷作用和纳米颗粒的高渗透作用大幅提高靶病变对药物的摄取。同时由于药物包覆在阳离子纳米药物颗粒中而具有缓释效果，负载有阳离子纳米药物的载药植入器械还可以获得长时间抑制血管平滑肌增生的效果。
可理解的是，可以通过喷涂等方法形成药物涂层。待药物涂层中的药物浓度达到所需药物浓度后，进行干燥、灭菌即可。
本发明的载药植入器械可以体内使用也可以体外使用，可以短期使用也可以长期永久性植入。此外，上述医疗器械是可以为心律失调、心力衰竭、瓣膜性疾病、血管病、糖尿病、神经疾病和失调症、整型外科、神经外科、肿瘤学、眼科学和ENT手术提供医疗和/或诊断的器械。本发明所涉及的医疗器械包括但不限于以下设备：支架、支架移植物、吻合连接器、合成贴片、引线、电极、针、导线、导管、传感器、手术仪器、血管成形球、创口引流管、分流管(shunt)、管子、输液套简(infusion sleeve)、尿道插管、小球、植入物、血液充氧发生器、泵、脉管移植物、埋入式介入药盒(vascularaccess port)、心瓣膜、瓣环成形术环、缝合线、手术夹、手术钉、起博器、可植入去纤颤器、神经刺激器、整型外科器械、脑脊髓液分流管、可植入药泵、椎笼、人造椎间盘、髓核的替代器械、耳管、眼内晶状体和在介入手术中使用的任何管。其中，支架包括但不限于，冠脉血管支架、外周血管支架、颅内血管支架、尿道支架、食道支架，优选冠脉血管支架。
在一实施例中，器械基底为球囊，载药植入器械为药物涂层球囊。
本发明中的包含有阳离子纳米药物涂层的载药植入器械，可通过电荷作用和纳米颗粒的高渗透作用大幅提高靶病变对药物的摄取。同时，阳离子纳米药物可通过“质子泵作用”帮助纳米药物颗粒逃逸至细胞质，避免药物被溶酶体降解或转运至细胞外。由于逃逸至细胞质的纳米药物颗粒中药物被包覆在聚合物中而具有缓释效果，极大地延长了药物在组织中的滞留时间，使包含有阳离子纳米药物涂层的载药植入器械获得长时间抑制血管平滑肌增生的效果。此外，纳米尺度的药物颗粒可以避免远端栓塞问题，极大地提高安全性。 相比以往的纳米药物颗粒，本发明的纳米药物颗粒具有极高的载药量，可减少辅料和表面活性剂的使用，降低药物球囊的涂层厚度，提高药物球囊的通过性。此外，该阳离子纳米药物的制备方法简单、耗时短、纳米颗粒尺寸可调控、载药量高，同时可方便的放大生产，极具工业前景。
下面列举具体实施例对本发明进行说明。
实施例1
取西罗莫司、D-α-生育酚聚乙二醇琥珀酸酯(TPGS)和聚乳酸-羟基乙酸共聚物(PLGA)充分溶于丙酮，浓度分别为10mg/mL、2mg/mL和5mg/mL，作为液流1。TPGS和羟丙基三甲基氯化铵壳聚糖(HACC)溶于水中，浓度分别为0.3mg/mL和0.08mg/mL，作为液流2。液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)以10mL/min的流速注入到四通道的涡流混合器中，获得通过混合形成的纳米药物颗粒悬浮液。根据所需的纳米药物颗粒悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的纳米药物颗粒悬浮液中水相和有机相的体积比为1：3)。其中，为获得均匀的纳米药物颗粒悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为纳米药物颗粒悬浮液。然后将所收集的纳米药物颗粒悬浮液装入透析袋中透析12h，每隔2h换一次水。随后将制备的纳米药物颗粒悬浮液浓缩备用。纳米药物颗粒的尺寸和表面电荷使用Malvern ZS90测试表征，纳米药物颗粒的载药量通过高效液相色谱(HPLC)计算，纳米药物颗粒的形貌使用透射电子显微镜(TEM)表征。
取一根具有亲水涂层的球囊，使用超声喷涂方法将上述制备的阳离子纳米药物颗粒均匀喷涂在球囊表面，使药物浓度达到1.3mg/mm 2，然后自然干燥24h后，环氧乙烷灭菌，即得实施例1的药物涂层球囊。
实施例2
取1,2-二油酰-SN-甘油-3-磷酰乙醇胺(DOPE)、DC-胆固醇、DOTAP和西罗莫司溶于乙醇，浓度分别为3mg/mL、1mg/mL、1mg/mL和8mg/mL，作为液流1。液流2、液流3和液流4皆为水。通过注射泵，将四股液流(液流1、 液流2、液流3和液流4)注入到四通道的涡流混合器中，获得通过混合形成的阳离子载药脂质体悬浮液。其中，液流1和液流2的流速为10mL/min，液流3和液流4的流速为45mL/min，最终获得的阳离子载药脂质体悬浮液中水相和有机相的体积比为1:10(v:v)。根据所需的阳离子载药脂质体悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s。其中，为获得均匀的阳离子载药脂质体悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为阳离子载药脂质体悬浮液。收集制备得到的阳离子载药脂质体悬浮液。将上述阳离子载药脂质体悬浮液装入透析袋透析10h，每隔2h换一次水。阳离子载药脂质体的尺寸和表面电荷使用Malvern ZS90测试表征，阳离子载药脂质体的载药量通过高效液相色谱(HPLC)计算，纳米药物颗粒的形貌使用透射电子显微镜(TEM)表征。
取一根具有亲水涂层的球囊，使用超声喷涂方法将上述制备的阳离子载药脂质体均匀喷涂在球囊表面，使药物浓度达到1.3mg/mm 2，然后自然干燥24h后，环氧乙烷灭菌，即得实施例2的药物涂层球囊。
实施例3
取(2,3-二油酰基-丙基)三甲基氯化铵(DOTAP)、DC-胆固醇和西罗莫司溶于乙醇，浓度分别为3mg/mL、1mg/mL和8mg/mL，作为液流1。液流2、液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)以10mL/min的流速注入到四通道的涡流混合器中，获得经混合形成的阳离子载药脂质体悬浮液。根据所需的阳离子载药脂质体悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的阳离子载药脂质体悬浮液中水相和有机相的体积比为1：3。其中，为获得均匀的阳离子载药脂质体悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为阳离子载药脂质体悬浮液。将上述阳离子载药脂质体悬浮液装入透析袋透析10h，每隔2h换一次水。阳离子载药脂质体的尺寸和表面电荷使用Malvern ZS90测试表征，阳离子载药脂质体的载药量通过高效液相色谱(HPLC)计算，纳米药物颗粒的形貌使用透射电子显微镜(TEM)表征。
取一根具有亲水涂层的球囊，使用超声喷涂方法将上述制备的阳离子载 药脂质体均匀喷涂在球囊表面，使药物浓度达到1.3mg/mm 2，然后自然干燥24h后，环氧乙烷灭菌，即得实施例3的药物涂层球囊。
实施例4
取(2,3-二肉豆蔻酰基-丙基)三甲基甲磺酸盐(DMTAP)、DC-胆固醇和西罗莫司溶于乙醇，浓度分别为3mg/mL、1mg/mL和8mg/mL，作为液流1。聚乙烯醇溶于水中，浓度为0.4mg/mL，作为液流2。液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)以10mL/min的流速注入到四通道的涡流混合器中，获得通过混合形成的阳离子载药脂质体悬浮液。根据所需的阳离子载药脂质体悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的阳离子载药脂质体悬浮液中水相和有机相的体积比为1：3。其中，为获得均匀的阳离子载药脂质体悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为阳离子载药脂质体悬浮液。将上述阳离子载药脂质体悬浮液装入透析袋透析10h，每隔2h换一次水。阳离子载药脂质体的尺寸和表面电荷使用Malvern ZS90测试表征，阳离子载药脂质体的载药量通过高效液相色谱(HPLC)计算，纳米药物颗粒的形貌使用透射电子显微镜(TEM)表征。
取一根具有亲水涂层的球囊，使用超声喷涂方法将上述制备的阳离子载药脂质体均匀喷涂在球囊表面，使药物浓度达到1.3mg/mm 2，然后自然干燥24h后，环氧乙烷灭菌，即得实施例4的药物涂层球囊。
实施例5
取N-[1-(2,3-二油酰氧)丙基]-,N,N-二甲铵(DODMA)、DC-胆固醇、DOTAP和西罗莫司溶于乙醇，浓度分别为3mg/mL、1mg/mL、1mg/mL和8mg/mL，作为液流1。吐温80溶于水中，浓度为0.4mg/mL，作为液流2。液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)以10mL/min的流速注入到四通道的涡流混合器中，获得通过混合形成的阳离子载药脂质体悬浮液。根据所需的阳离子载药脂质体悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的阳离子载药脂质 体悬浮液中水相和有机相的体积比为1：3。其中，为获得均匀的阳离子载药脂质体悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为阳离子载药脂质体悬浮液。将上述阳离子载药脂质体悬浮液装入透析袋透析10h，每隔2h换一次水。阳离子载药脂质体的尺寸和表面电荷使用Malvern ZS90测试表征，阳离子载药脂质体的载药量通过高效液相色谱(HPLC)计算，纳米药物颗粒的形貌使用透射电子显微镜(TEM)表征。
取一根具有亲水涂层的球囊，使用超声喷涂方法将上述制备的阳离子载药脂质体均匀喷涂在球囊表面，使药物浓度达到1.3mg/mm 2，然后自然干燥24h后，环氧乙烷灭菌，即得实施例5的药物涂层球囊。
实施例6
取(2,3-二棕榈酰基-丙基)三甲胺(DPTAP)、DC-胆固醇和西罗莫司溶于乙醇，浓度分别为3mg/mL、1mg/mL和8mg/mL，作为液流1。泊洛沙姆188溶于水中，浓度为0.4mg/mL，作为液流2。液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)以10mL/min的流速注入到四通道的涡流混合器中，获得通过混合形成的阳离子载药脂质体悬浮液。根据所需的阳离子载药脂质体悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的阳离子载药脂质体悬浮液中水相和有机相的体积比为1：3。其中，为获得均匀的阳离子载药脂质体悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为阳离子载药脂质体悬浮液。将上述阳离子载药脂质体悬浮液装入透析袋透析10h，每隔2h换一次水。阳离子载药脂质体的尺寸和表面电荷使用Malvern ZS90测试表征，阳离子载药脂质体的载药量通过高效液相色谱(HPLC)计算，纳米药物颗粒的形貌使用透射电子显微镜(TEM)表征。
取一根具有亲水涂层的球囊，使用超声喷涂方法将上述制备的阳离子载药脂质体均匀喷涂在球囊表面，使药物浓度达到1.3mg/mm 2，然后自然干燥24h后，环氧乙烷灭菌，即得实施例6的药物涂层球囊。
实施例7
取(2,3-二硬脂酰-丙基)三甲胺(DSTAP)、DC-胆固醇、DOTAP和西罗莫司溶于乙醇，浓度分别为3mg/mL、1mg/mL、1mg/mL和8mg/mL，作为液流1。卡波姆940溶于水中，浓度为0.4mg/mL，并将pH调至7，溶于水中，浓度为0.4mg/mL，作为液流2。液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)以10mL/min的流速注入到四通道的涡流混合器中，获得通过混合形成的阳离子载药脂质体悬浮液。根据所需的阳离子载药脂质体悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的阳离子载药脂质体悬浮液中水相和有机相的体积比为1：3。其中，为获得均匀的阳离子载药脂质体悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为阳离子载药脂质体悬浮液。将上述阳离子载药脂质体悬浮液装入透析袋透析10h，每隔2h换一次水。阳离子载药脂质体的尺寸和表面电荷使用MalvernZS90测试表征，阳离子载药脂质体的载药量通过高效液相色谱(HPLC)计算，纳米药物颗粒的形貌使用透射电子显微镜(TEM)表征。
取一根具有亲水涂层的球囊，使用超声喷涂方法将上述制备的阳离子载药脂质体均匀喷涂在球囊表面，使药物浓度达到1.3mg/mm 2，然后自然干燥24h后，环氧乙烷灭菌，即得实施例7的药物涂层球囊。
实施例8
取西罗莫司、D-α-生育酚聚乙二醇琥珀酸酯(TPGS)和聚乳酸-羟基乙酸共聚物(PLGA)充分溶于丙酮，浓度分别为10mg/mL、2mg/mL和5mg/mL，作为液流1。TPGS和壳聚糖盐酸盐溶于水中，浓度分别为0.3mg/mL和0.08mg/mL，作为液流2。液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)以10mL/min的流速注入到四通道的涡流混合器中，获得通过混合形成的阳离子纳米药物颗粒悬浮液。根据所需的阳离子纳米药物颗粒悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的阳离子纳米药物颗粒悬浮液中水相和有机相的体积比为1：3。其中，为获得均匀的阳离子纳米药物颗粒悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为阳离子纳米药物颗粒悬浮液。然后将所收集的阳 离子纳米药物颗粒悬浮液装入透析袋中透析12h，每隔2h换一次水。随后将制备的纳米药物颗粒悬浮液浓缩备用。纳米药物颗粒的尺寸和表面电荷使用Malvern ZS90测试表征，纳米药物颗粒的载药量通过高效液相色谱(HPLC)计算，纳米药物颗粒的形貌使用透射电子显微镜(TEM)表征。
取一根具有亲水涂层的球囊，使用超声喷涂方法将上述制备的阳离子纳米药物颗粒均匀喷涂在球囊表面，使药物浓度达到1.3mg/mm 2，然后自然干燥24h后，环氧乙烷灭菌，即得实施例8的药物涂层球囊。
实施例9
取西罗莫司、D-α-生育酚聚乙二醇琥珀酸酯(TPGS)和聚乳酸-羟基乙酸共聚物(PLGA)充分溶于丙酮，浓度分别为10mg/mL、2mg/mL和5mg/mL，作为液流1。TPGS和N,N,N-三甲基壳聚糖(TMC)溶于水中，浓度分别为0.3mg/mL和0.08mg/mL，作为液流2。液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)以10mL/min的流速注入到四通道的涡流混合器中，获得通过混合形成的阳离子纳米药物颗粒悬浮液。根据所需的阳离子纳米药物颗粒悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的阳离子纳米药物颗粒悬浮液中水相和有机相的体积比为1：3。其中，为获得均匀的阳离子纳米药物颗粒悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为阳离子纳米药物颗粒悬浮液。然后将所收集的阳离子纳米药物颗粒悬浮液装入透析袋中透析12h，每隔2h换一次水。随后将制备的纳米药物颗粒悬浮液浓缩备用。纳米药物颗粒的尺寸和表面电荷使用Malvern ZS90测试表征，纳米药物颗粒的载药量通过高效液相色谱(HPLC)计算，纳米药物颗粒的形貌使用透射电子显微镜(TEM)表征。
取一根具有亲水涂层的球囊，使用超声喷涂方法将上述制备的阳离子纳米药物颗粒均匀喷涂在球囊表面，使药物浓度达到1.3mg/mm 2，然后自然干燥24h后，环氧乙烷灭菌，即得实施例9的药物涂层球囊。
实施例10
取西罗莫司、D-α-生育酚聚乙二醇琥珀酸酯(TPGS)和聚乳酸-羟基乙酸共 聚物(PLGA)充分溶于丙酮，浓度分别为10mg/mL、2mg/mL和5mg/mL，作为液流1。TPGS和二乙氨乙基-葡聚糖(DEAE-Dextran)溶于水中，浓度分别为0.3mg/mL和0.08mg/mL，作为液流2。液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)以10mL/min的流速注入到四通道的涡流混合器中，获得通过混合形成的阳离子纳米药物颗粒悬浮液。根据所需的阳离子纳米药物颗粒悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的阳离子纳米药物颗粒悬浮液中水相和有机相的体积比为1：3。其中，为获得均匀的阳离子纳米药物颗粒悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为阳离子纳米药物颗粒悬浮液。然后将所收集的阳离子纳米药物颗粒悬浮液装入透析袋中透析12h，每隔2h换一次水。随后将制备的纳米药物颗粒悬浮液浓缩备用。纳米药物颗粒的尺寸和表面电荷使用Malvern ZS90测试表征，纳米药物颗粒的载药量通过高效液相色谱(HPLC)计算，纳米药物颗粒的形貌使用透射电子显微镜(TEM)表征。
取一根具有亲水涂层的球囊，使用超声喷涂方法将上述制备的阳离子纳米药物颗粒均匀喷涂在球囊表面，使药物浓度达到1.3mg/mm 2，然后自然干燥24h后，环氧乙烷灭菌，即得实施例10的药物涂层球囊。
实施例11
取西罗莫司、D-α-生育酚聚乙二醇琥珀酸酯(TPGS)和聚乳酸-羟基乙酸共聚物(PLGA)充分溶于丙酮，浓度分别为10mg/mL、2mg/mL和5mg/mL，作为液流1。TPGS和聚精氨酸(9肽)溶于水中，浓度分别为0.3mg/mL和0.08mg/mL，作为液流2。液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)以10mL/min的流速注入到四通道的涡流混合器中，获得通过混合形成的阳离子纳米药物颗粒悬浮液。根据所需的阳离子纳米药物颗粒悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的阳离子纳米药物颗粒悬浮液中水相和有机相的体积比为1：3。其中，为获得均匀的阳离子纳米药物颗粒悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为阳离子纳米药物颗粒悬浮液。然后将所收集的阳 离子纳米药物颗粒悬浮液装入透析袋中透析12h，每隔2h换一次水。随后将制备的纳米药物颗粒悬浮液浓缩备用。纳米药物颗粒的尺寸和表面电荷使用Malvern ZS90测试表征，纳米药物颗粒的载药量通过高效液相色谱(HPLC)计算，纳米药物颗粒的形貌使用透射电子显微镜(TEM)表征。
取一根具有亲水涂层的球囊，使用超声喷涂方法将上述制备的阳离子纳米药物颗粒均匀喷涂在球囊表面，使药物浓度达到1.3mg/mm 2，然后自然干燥24h后，环氧乙烷灭菌，即得实施例11的药物涂层球囊。
实施例12
取二硬脂酰基磷脂酰乙醇胺(DSPE)、DC-胆固醇、DOTAP和西罗莫司溶于乙醇，浓度分别为3mg/mL、1mg/mL、1mg/mL和8mg/mL，作为液流1。TPGS溶于水中，浓度为0.4mg/mL，作为液流2。液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)以10mL/min的流速注入到四通道的涡流混合器中，获得通过混合形成的阳离子载药脂质体悬浮液。根据所需的阳离子载药脂质体悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的阳离子载药脂质体悬浮液中水相和有机相的体积比为1：3。其中，为获得均匀的阳离子载药脂质体悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为阳离子载药脂质体悬浮液。将上述阳离子载药脂质体悬浮液装入透析袋透析10h，每隔2h换一次水。阳离子载药脂质体的尺寸和表面电荷使用Malvern ZS90测试表征，阳离子载药脂质体的载药量通过高效液相色谱(HPLC)计算，纳米药物颗粒的形貌使用透射电子显微镜(TEM)表征。
取一根具有亲水涂层的球囊，使用超声喷涂方法将上述制备的阳离子载药脂质体均匀喷涂在球囊表面，使药物浓度达到1.3mg/mm 2，然后自然干燥24h后，环氧乙烷灭菌，即得实施例12的药物涂层球囊。
实施例13
取1,2-二油酰-SN-甘油-3-磷酰乙醇胺(DOPE)、DC-胆固醇、DOTAP和西罗莫司溶于乙醇，浓度分别为3mg/mL、1mg/mL、1mg/mL和8mg/mL。然后 取1mL上述溶液缓慢滴加到搅拌的水溶液中(10mL)，继续搅拌过夜，获得阳离子载药脂质体悬浮液。此时，所获得的阳离子载药脂质体悬浮液中水相和有机相的体积比为1：10。将上述阳离子载药脂质体悬浮液装入透析袋透析10h，每隔2h换一次水。阳离子载药脂质体的尺寸和表面电荷使用Malvern ZS90测试表征，阳离子载药脂质体的载药量通过高效液相色谱(HPLC)计算，纳米药物颗粒的形貌使用透射电子显微镜(TEM)表征。
实施例14
取1,2-二油酰-SN-甘油-3-磷酰乙醇胺(DOPE)、DC-胆固醇和DOTAP溶于乙醇，浓度分别为3mg/mL、1mg/mL和1mg/mL，作为液流1。TPGS溶于水中，浓度为0.4mg/mL，作为液流2。液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)以10mL/min的流速注入到四通道的涡流混合器中，获得通过混合形成的阳离子载药脂质体悬浮液。根据所需的阳离子载药脂质体悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的阳离子载药脂质体悬浮液中水相和有机相的体积比为1：3。其中，为获得均匀的阳离子载药脂质体悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为阳离子载药脂质体悬浮液。将上述阳离子载药脂质体悬浮液装入透析袋透析10h，每隔2h换一次水。阳离子载药脂质体的尺寸和表面电荷使用Malvern ZS90测试表征，阳离子载药脂质体的载药量通过高效液相色谱(HPLC)计算。
实施例15
使用2通道的混合器制备阳离子纳米药物。
取西罗莫司、泊洛沙姆407和聚乳酸-羟基乙酸共聚物(PLGA)充分溶于丙酮，浓度分别为10mg/mL、2mg/mL和5mg/mL，作为液流1。TPGS和羟丙基三甲基氯化铵壳聚糖(HACC)溶于水中，浓度分别为0.3mg/mL和0.08mg/mL，作为液流2。通过注射泵，将两股液流(液流1和液流2)以10mL/min的流速注入到两通道的混合器中，获得通过混合形成的纳米药物颗粒悬浮液。根据所需的纳米药物颗粒悬浮液的体积，可选择合适的混合时间。在本实施例中， 混合时间为10s，最终获得的阳离子纳米药物颗粒悬浮液中水相和有机相的体积比为1：1。其中，为获得均匀的纳米药物颗粒悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为纳米药物颗粒悬浮液。然后将所收集的纳米药物颗粒悬浮液装入透析袋中透析12h，每隔2h换一次水。随后将制备的纳米药物颗粒悬浮液浓缩备用。纳米药物颗粒的尺寸和表面电荷使用Malvern ZS90测试表征，纳米药物颗粒的载药量通过高效液相色谱(HPLC)计算，纳米药物颗粒的形貌使用透射电子显微镜(TEM)表征。
取一根具有亲水涂层的球囊，使用超声喷涂方法将上述制备的阳离子纳米药物颗粒均匀喷涂在球囊表面，使药物浓度达到1.3mg/mm 2，然后自然干燥24h后，环氧乙烷灭菌，即得实施例15的药物涂层球囊。
实施例16
实施例16与实施例1基本相同，不同之处在于第一液流和第二液流与第三液流和第四液流的流速比不同。具体地：
取西罗莫司、D-α-生育酚聚乙二醇琥珀酸酯(TPGS)和聚乳酸-羟基乙酸共聚物(PLGA)充分溶于丙酮，浓度分别为10mg/mL、2mg/mL和5mg/mL，作为液流1。TPGS和羟丙基三甲基氯化铵壳聚糖(HACC)溶于水中，浓度分别为0.3mg/mL和0.08mg/mL，作为液流2。液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)分别注入到四通道的涡流混合器中，液流1和液流2的流速为10mL/min，液流3和液流4的流速为40mL/min，获得通过混合形成的纳米药物颗粒悬浮液。根据所需的纳米药物颗粒悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的阳离子纳米药物颗粒悬浮液中水相和有机相的体积比为1：9。其中，为获得均匀的纳米药物颗粒悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为纳米药物颗粒悬浮液。然后将纳米药物颗粒悬浮液装入透析袋中透析12h，每隔2h换一次水。随后将制备的纳米药物颗粒悬浮液浓缩备用。纳米药物颗粒的尺寸和表面电荷使用Malvern ZS90测试表征，纳米药物颗粒的载药量通过高效液相色谱(HPLC)计算，纳米药物颗粒的形貌使用透射电子显微镜(TEM)表征。
取一根具有亲水涂层的球囊，使用超声喷涂方法将上述制备的阳离子纳米药物颗粒均匀喷涂在球囊表面，使药物浓度达到1.3mg/mm 2，然后自然干燥24h后，环氧乙烷灭菌，即得实施例16的药物涂层球囊。
对比例1
与实施例1基本相同，不同之处在于，第二液流中不含有阳离子修饰剂，具体地：
取西罗莫司、D-α-生育酚聚乙二醇琥珀酸酯(TPGS)和聚乳酸-羟基乙酸共聚物(PLGA)充分溶于丙酮，浓度分别为10mg/mL、2mg/mL和5mg/mL，作为液流1。TPGS溶于水中，浓度为0.3mg/mL，作为液流2。液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)以10mL/min的流速注入到四通道的涡流混合器中，获得通过混合形成的纳米药物颗粒悬浮液。根据所需的纳米药物颗粒悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的阳离子纳米药物颗粒悬浮液中水相和有机相的体积比为1：3。其中，为获得均匀的纳米药物颗粒悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为纳米药物颗粒悬浮液。然后将所收集的纳米药物颗粒悬浮液装入透析袋中透析12h，每隔2h换一次水。随后将制备的纳米药物颗粒悬浮液浓缩备用。纳米药物颗粒的尺寸和表面电荷使用Malvern ZS90测试表征，纳米药物颗粒的载药量通过高效液相色谱(HPLC)计算，纳米药物颗粒的形貌使用透射电子显微镜(TEM)表征。
取一根具有亲水涂层的球囊，使用超声喷涂方法将上述制备的阳离子纳米药物颗粒均匀喷涂在球囊表面，使药物浓度达到1.3mg/mm 2，然后自然干燥24h后，环氧乙烷灭菌，即得对比例1的药物涂层球囊。
对比例2
与实施例1基本相同，不同之处在于，阳离子纳米颗粒不负载药物，具体地：
取D-α-生育酚聚乙二醇琥珀酸酯(TPGS)和聚乳酸-羟基乙酸共聚物(PLGA)充分溶于丙酮，浓度分别为2mg/mL和5mg/mL，作为液流1。TPGS 和羟丙基三甲基氯化铵壳聚糖(HACC)溶于水中，浓度分别为0.3mg/mL和0.08mg/mL，作为液流2。液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)以10mL/min的流速注入到四通道的涡流混合器中，获得通过混合形成的纳米颗粒悬浮液。根据所需的纳米颗粒悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的阳离子纳米颗粒悬浮液中水相和有机相的体积比为1：3。其中，为获得均匀的纳米颗粒悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为纳米颗粒悬浮液。然后将所收集的纳米颗粒悬浮液装入透析袋中透析12h，每隔2h换一次水。随后将制备的纳米颗粒悬浮液浓缩备用。纳米颗粒的尺寸和表面电荷使用Malvern ZS90测试表征。
对比例3
与对比例2基本相同(即，不负载药物)，不同之处在于，采用双十二烷基二甲基溴化铵(DMAB)代替阳离子修饰剂羟丙基三甲基氯化铵壳聚糖(HACC)，具体地：
取D-α-生育酚聚乙二醇琥珀酸酯(TPGS)和聚乳酸-羟基乙酸共聚物(PLGA)充分溶于丙酮，浓度分别为2mg/mL和5mg/mL，作为液流1。TPGS和双十二烷基二甲基溴化铵(DMAB)溶于水中，浓度分别为0.3mg/mL和0.08mg/mL，作为液流2。液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)以10mL/min的流速注入到四通道的涡流混合器中，获得通过混合形成的阳离子纳米颗粒悬浮液。根据所需的纳米颗粒悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的阳离子纳米颗粒悬浮液中水相和有机相的体积比为1：3。其中，为获得均匀的纳米颗粒悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为纳米颗粒悬浮液。然后将所收集的纳米颗粒悬浮液装入透析袋中透析12h，每隔2h换一次水。随后将制备的纳米颗粒悬浮液浓缩备用。纳米颗粒的尺寸和表面电荷使用MalvernZS90测试表征。
对比例4
取(2,3-二油酰基-丙基)三甲基氯化铵(DOTAP)和DC-胆固醇溶于乙醇，浓度分别为3mg/mL和1mg/mL，作为液流1。液流2、液流3和液流4皆为水。通过注射泵，将四股液流(液流1、液流2、液流3和液流4)以10mL/min的流速注入到四通道的涡流混合器中，获得经混合形成的阳离子脂质体悬浮液。根据所需的阳离子载药脂质体悬浮液的体积，可选择合适的混合时间。在本实施例中，混合时间为10s，最终获得的阳离子载药脂质体悬浮液中水相和有机相的体积比为1：3。其中，为获得均匀的阳离子脂质体悬浮液，将前2s获得的混合液舍弃并收集后8秒获得的混合液为阳离子载药脂质体悬浮液。将上述阳离子脂质体悬浮液装入透析袋透析10h，每隔2h换一次水。阳离子脂质体的尺寸和表面电荷使用Malvern ZS90测试表征。
效果验证实验
(1)粒径、表面电荷和载药量测试
采用Malvern ZS90(散射角90°，温度25℃)测试表征实施例1-13和对比例1的纳米药物颗粒的尺寸和表面电荷，并通过高效液相色谱(HPLC)(C18柱，流动相：16％乙腈：24％水：60％甲醇，流速：1.0mL/min，温度：40℃，检测器：UV 277nm)计算纳米药物颗粒的载药量，具体结果如下表1。
表1
  粒径(nm) 表面电荷(mV) 载药量％，w/w
实施例1 249.7±5.6nm 54.5±1.3mV 41％
实施例2 192±2.7nm 46.1±2.5mV 40％
实施例3 250.2±3.4nm 45.2±0.6mV 40％
实施例4 330.1±0.9nm 40.4±1.1mV 48％
实施例5 352.4±1.7nm 32.1±1.2mV 46％
实施例6 290.5±2.5nm 55.2±4.1mV 37％
实施例7 362.1±5.4nm 36.2±0.7mV 33％
实施例8 195.2±1.0nm 44.2±1.6mV 46％
实施例9 206.4±2.1nm 48.1±1.8mV 45％
实施例10 240.3±0.8nm 29.6±0.9mV 42％
实施例11 232.2±2.3nm 46.2±2.2mV 43％
实施例12 280.3±3.8nm 40.1±3.1mV 39％
实施例13 451.2±8.4nm 51.3±2.8mV 22％
实施例15 538.1±13.9nm 43.3±6.8mV 37％
实施例16 213.4±6.2nm 49.3±5.5mV 35％
对比例1 195.8±4.5nm -14.2±0.9mV 41％
对比例3 195.8±4.5nm -14.2±0.9mV -
从表1可以看出，实施例1-16的阳离子纳米药物表面呈正电性，而对比例1呈负电性。另外，图2为实施例1和对比例1的表面Zeta电位分布图，从图2也能明显看出，实施例1的表面呈正电性，而对比例1呈负电性。这说明通过添加阳离子双亲化合物和/或阳离子修饰剂能够使纳米药物颗粒的表面呈正电性。
另外，实施例1和实施例16基本相同，实施例16提高了第三液流和第四液流的流速，最终制备的纳米颗粒的粒径更小，说明瞬时纳米沉淀法能够有效的调节纳米颗粒的尺寸。
图3为实施例1和实施例13的粒径分布图。实施例1和实施例13分别采用了瞬时纳米沉淀法和常规搅拌方法制备阳离子纳米药物颗粒。从图1可以看出，实施例1相比于实施例13的粒径更小。图4为实施例1的阳离子纳米药物的形貌，图5为实施例13制备的纳米药物的形貌，可以看出，瞬时纳米沉淀法制备的阳离子纳米药物颗粒具有较优的形貌。
另外，实施例13和实施例2基本相同，不同之处在于，制备方法不同。从表1可以看出，实施例2的载药量明显高于实施例13，说明瞬时纳米沉淀法能够显著提高阳离子纳米药物的载药量。
(2)组织吸收测试
取离体的猪动脉血管段，保持37℃恒温，取灭菌的裸球囊扩张血管1min， 6atm，随后泄压取出。将上述实施例1-12和对比例1制备的药物球囊置入扩张过的血管，扩张1min，6atm，随后泄压取出。立即使用磷酸缓冲盐溶液(PBS)冲洗3次，每次1mL。然后通过气相色谱-质谱联用仪(GC-MS)测组织内的药物浓度，测试结果如表2。
表2
  组织浓度(ng/mg)
实施例1 404.8±157.9
实施例2 507.5±230.3
实施例3 483.7±217.5
实施例4 303.4±110.5
实施例5 324.9±122.3
实施例6 284.2±140.1
实施例7 349.2±110.3
实施例8 286.7±87.6
实施例9 372.5±176.6
实施例10 384.8±88.7
实施例11 389.7±154.2
实施例12 325.2±91.3
实施例13 385.5±103.3
对比例1 131.8±41.6
从表2可以看出，实施例1-13的阳离子纳米药物均具有较优的组织吸收，且明显优于对比例1，说明正电性的纳米药物更利于组织吸收。
(3)组织滞留时间测试
取离体的猪动脉血管段，保持37℃恒温，取灭菌的裸球囊扩张血管1min，6atm，随后泄压取出。将上述实施例1-12和对比例1制备的药物球囊置入扩张过的血管，扩张1min，6atm，随后泄压取出。立即使用磷酸缓冲盐溶液(PBS) 冲洗3次，每次1mL。然后将植入有药物球囊的猪动脉血管段放置在培养基中培养，培养7天、14天和28天，每个时间点取3个重复样，样品取样后，使用气相色谱-质谱联用仪(GC-MS)测组织内的药物浓度，测试结果如表3。
表3
Figure PCTCN2020112899-appb-000001
BQL:低于检测限
从表3可以看出，实施例1-13的阳离子纳米药物均具有较优的缓释效果，能够延长药物释放时间，而对比例1基本无缓释效果。通过实施例2和实施例13的对比可以看出，实施例2的缓释效果明显优于实施例13。
(4)阳离子材料的细胞毒性测试
收集血管平滑肌细胞(SMC)细胞，使用血球计数板计算细胞浓度，用细胞 培养液将细胞浓度调整为105个/mL。向96孔板中的每孔加入100细胞悬液(每孔104个细胞)，设置4组(空白对照组和4个不同实施例组)，每组4个重复孔，正常细胞培养条件下培养24h。然后，吸去培养基，分别替换为新鲜培养基和含上述实施例14和对比例2和对比例3的不载药纳米颗粒悬浮液(各实施例中的阳离子材料的浓度保持一致)的培养基。继续培养24h后，向每个孔中加入50μL MTT试剂，再重新放入CO 2培养箱中培养4h。小心吸去培养基，每个孔加入150μL二甲基亚砜，轻微摇晃以充分溶解甲瓒，然后使用酶标仪测试每个孔在490nm下的吸光值。细胞存活率按照以下公式计算：
Figure PCTCN2020112899-appb-000002
测试结果如下表4。
表4
  细胞存活率％
对照组 100
实施例14 97
对比例2 91
对比例3 68
对比例4 96
从表4可以看出，实施例14的阳离子纳米药物基本无细胞毒性，具有较高的细胞存活率，而对比例3的DMAB具有严重的细胞毒性，不适宜用于负载药物。对比例4的阳离子双亲化合物DOTAP本身也具有很好的生物相容性，无明显的细胞毒性。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本 领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (18)

  1. 一种阳离子纳米药物，其特征在于，包括载体和负载在所述载体上的药物，所述载体中包含有阳离子双亲化合物和阳离子修饰剂中的一种或多种；所述阳离子双亲化合物为含氨基和/或酰基的阳离子双亲化合物，所述阳离子修饰剂为含氨基和/或酰基的阳离子修饰剂。
  2. 根据权利要求1所述的阳离子纳米药物，其特征在于，所述载体还包括疏水纳米核，所述阳离子双亲化合物和/或所述阳离子修饰剂包括亲水端和疏水端，所述疏水端结合在所述疏水纳米核上，所述亲水端至少部分裸露。
  3. 根据权利要求1或2所述的阳离子纳米药物，其特征在于，所述阳离子修饰剂选自：阳离子磷脂、聚氨基酸、聚多糖、多肽、胆固醇衍生物和阳离子共聚物中的一种或多种。
  4. 根据权利要求3所述的阳离子纳米药物，其特征在于，所述阳离子修饰剂选自：聚精氨酸、聚赖氨酸、二乙氨乙基-葡聚糖、羟丙基三甲基氯化铵壳聚糖、壳聚糖盐酸盐、N,N,N-三甲基壳聚糖、TAT多肽、和3β-[N-(N’,N’-二甲基胺乙基)胺基甲酰基]胆固醇中的一种或多种。
  5. 根据权利要求1或2所述的阳离子纳米药物，其特征在于，所述阳离子双亲化合物选自如下的阳离子表面活性剂中的一种或多种：(2,3-二油酰基-丙基)三甲基氯化铵、1,2-二油酰-SN-甘油-3-磷酰乙醇胺、(2,3-二硬脂酰-丙基)三甲胺、(2,3-二肉豆蔻酰基-丙基)三甲基甲磺酸盐、(2,3-二棕榈酰基-丙基)三甲胺、(2,3-二硬脂酰-丙基)三甲胺、基于聚甲基丙烯酸N,N-二甲基氨基乙酯的双亲聚合物、基于壳聚糖的双亲聚合物、基于壳聚糖季铵盐的双亲聚合物、基于氯化壳聚糖的双亲聚合物、基于巯基修饰壳聚糖的双亲聚合物、基于聚乙烯亚胺的双亲聚合物、和基于聚(β-氨基酯)的双亲聚合物。
  6. 根据权利要求1所述的阳离子纳米药物，其特征在于，所述载体中包含有阳离子修饰剂时，所述载体中还包括乳化剂。
  7. 根据权利要求6所述的阳离子纳米药物，其特征在于，所述乳化剂为D-α-生育酚聚乙二醇琥珀酸酯、聚乙烯醇、聚山梨酯、泊洛沙姆和卡波姆中 的一种或多种。
  8. 根据权利要求1或2所述的阳离子纳米药物，其特征在于，所述载体中还包含有缓释共聚物。
  9. 根据权利要求1或2所述的阳离子纳米药物，其特征在于，所述阳离子纳米药物的表面电荷为10mV-60mV；和/或
    所述阳离子纳米药物的粒径为3nm-300nm。
  10. 根据权利要求1或2所述的阳离子纳米药物，其特征在于，所述的阳离子纳米药物的形貌为球形、棒状、蠕虫状或圆盘状。
  11. 根据权利要求1所述的阳离子纳米药物，其特征在于，负载在所述载体上的药物选自以下抗增殖药物中的一种或多种：紫杉醇、西罗莫司和西罗莫司衍生物。
  12. 一种医疗器械，其特征在于，包括器械基底和负载在所述器械基底上的药物涂层，所述药物涂层中包含有如权利要求1-11中任一项所述的阳离子纳米药物。
  13. 一种阳离子纳米药物的制备方法，其特征在于，包括以下步骤：
    提供第一液流；
    提供第二液流；以及
    采用瞬时纳米沉淀法使所述第一液流和所述第二液流碰撞形成涡流以获得经混合形成的纳米悬浮液，收集所述纳米悬浮液，并透析所述纳米悬浮液以获得所述阳离子纳米药物；
    其中，所述第一液流和所述第二液流中至少有一个液流中溶解有药物，所述第一液流和所述第二液流中至少有一个液流中溶解有载体；所述第一液流和所述第二液流中的一个具有能与水互溶的有机相，所述第一液流和所述第二液流中的另一个具有水相；所述载体中包含有阳离子双亲化合物和阳离子修饰剂中的一种或多种；所述阳离子双亲化合物为含氨基和/或酰基的阳离子双亲化合物，所述阳离子修饰剂为含氨基和/或酰基的阳离子修饰剂。
  14. 根据权利要求13所述的制备方法，其特征在于，所述第一液流和所述第二液流中至少有一个液流中溶解有缓释共聚物；和/或
    所述第一液流和所述第二液流中至少有一个液流中溶解有乳化剂。
  15. 根据权利要求14所述的制备方法，其特征在于，所述缓释共聚物为聚乳酸-羟基乙酸共聚物；所述乳化剂为D-α-生育酚聚乙二醇琥珀酸酯、聚乙烯醇、聚山梨酯、泊洛沙姆和卡波姆中的一种或多种。
  16. 根据权利要求13-15中的任一项所述的制备方法，其特征在于，采用瞬时纳米沉淀法使所述第一液流和所述第二液流碰撞形成涡流的步骤包括以下步骤：
    提供涡流混合器；
    向所述涡流混合器中的一个通道通入所述第一液流；
    向所述涡流混合器中的另一通道通入所述第二液流；以及
    使所述第一液流和所述第二液流在所述涡流混合器中碰撞混合，形成涡流。
  17. 根据权利要求16所述的制备方法，其特征在于，采用瞬时纳米沉淀法使所述第一液流和所述第二液流碰撞形成涡流的步骤方法还包括向所述涡流混合器的剩余通道中通入水，作为额外液流；以及
    使所述第一液流、所述第二液流和所述额外液流在所述涡流混合器中碰撞混合，形成涡流。
  18. 根据权利要求17所述的制备方法，其特征在于，所述第一液流、所述第二液流和所述第三液流的流速为1mL/min至12mL/min；且所述第一液流、第二液流的流速之比为1:1，每一剩余通道中的所述额外液流的流速是所述第一液流或第二液流的流速的1至5倍。
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