Lipid-polymer hybrid nanoparticles

Abstract

The present disclosure describes a lipid-polymer hybrid nanoparticle and a method of synthesizing such a nanoparticle or a composition containing such a nanoparticle. These nanoparticles are made from a biodegradable polymer-based micellar core surrounded by a lipid-based shell, wherein a majority of the agent is present on the inner periphery of such nanoparticles due to physical adhesion to lipid molecules. Only a small amount of medicament is encapsulated in the micelle core. Thus, the lipid-based shell becomes the primary excipient part of the nanoparticle, and the core containing the biodegradable polymer becomes the secondary excipient part of the nanoparticle.

Description

Technical Field

[0001] This invention relates to lipid-polymer hybrid nanoparticles and pharmaceutical compositions containing lipid-polymer hybrid nanoparticles, as well as methods for preparing such nanoparticles and compositions containing nanoparticles. Specifically, this invention relates to nanoparticles for pharmaceutical compositions, and coating compositions for medical devices, drug delivery, and diagnostics. Background Technology

[0002] Nanoparticle-based drug delivery systems offer several advantages over conventional drug delivery systems. Key benefits include controlled drug release within tissues, higher drug transfer for specific amounts of drug used in the delivery system, longer drug retention within nanoparticles leading to longer-term drug delivery to tissues, and lower drug elution in biofluids. Biodegradable polymers are a preferred choice as base materials for preparing nanoparticles for implantable medical devices. They not only help control drug release but also degrade and leave the body over time. Lipids help form micelles, which are the basis for nanoparticle formation, and they also help stabilize the dispersion during nanoparticle formation. Summary of the Invention

[0003] This disclosure focuses on utilizing the properties of lipids and biodegradable polymers to develop unique lipid-polymer hybrid nanoparticles to overcome some of the drug delivery challenges associated with controlled drug release, drug retention, and drug loss during transport. Therefore, one object of the present invention is to provide lipid-polymer hybrid nanoparticles that enable controlled drug release over extended periods, reduce drug loss due to blood flow, and increase drug transfer and retention in biological tissues after administration.

[0004] Furthermore, another object of the present invention is to provide a method for preparing the above-described lipid-polymer hybrid nanoparticles and compositions having the above-described properties.

[0005] The foregoing aspects are further illustrated in the accompanying drawings and described in the corresponding description below. It should be noted that the specification and drawings only illustrate the principles of the invention. Therefore, various arrangements that encompass the principles of the invention, although not explicitly described or shown herein, can be devised from the description and are included within its scope. Attached Figure Description

[0006] Please refer to the accompanying drawings for a detailed description.

[0007] Figure 1 A schematic diagram of a lipid-polymer hybrid nanoparticle carrying a drug is illustrated according to one embodiment of the present invention.

[0008] Figure 2 An in vitro drug release profile of lipid-polymer hybrid nanoparticles containing a pharmaceutical agent is illustrated according to one embodiment of the present invention.

[0009] Figure 3 Ex vivo drug transfer and retention curves in tissue over a 24-hour period are illustrated by two embodiments of the invention, showing the drug transfer and retention curves of two different lipid-polymer hybrid nanoparticles carrying the drug.

[0010] Figure 4 An example is provided of an embodiment of the invention, illustrating the in vitro drug transfer and retention curves of a drug-carrying lipid-polymer hybrid nanoparticle containing a coating composition in a tissue over a duration of 72 hours, and a comparison with similar curves of a competitor's product (commercially available). Detailed Implementation

[0011] This disclosure, together with the accompanying drawings, explains the presented embodiments, but is not intended to be the only embodiment that can be constructed from this disclosure. This disclosure sets forth the application or utility of the embodiments and the sequence of steps for implementing the embodiments. Different embodiments may employ the same application or utility and sequence of steps.

[0012] As stated herein, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range shall be understood to include any integer value within the range stated, and, where appropriate, its fractions (such as one-tenth and one-hundredth of an integer).

[0013] As used herein, the term "pharmaceutical" refers to any biologically active compound or pharmaceutical molecule that is suitable for administration in mammals, including humans.

[0014] As used herein, the term "nanoparticle" refers to lipid-polymer hybrid nanoparticles with a nanoscale structure, wherein at least one or more dimensions (length, width, or thickness) of the nanoparticle are in the nanometer range. Nanoparticles can be of any shape, such as spherical, elliptical, disk-shaped, cylindrical, or hexagonal.

[0015] According to the present invention and as used herein, the term "major excipient" refers to a phospholipid-based peripheral region in a nanoparticle structure, wherein the agent is densely accumulated in the range of 51% to 99% by weight of the total agent, specifically in the range of 70% to 97% by weight of the total agent, and more specifically in the range of 80% to 95% by weight of the total agent.

[0016] According to the present invention and as used herein, the term "secondary excipient" refers to a biodegradable polymer core region in a nanoparticle structure, wherein the amount of the agent is lower than that of the primary excipient.

[0017] According to one embodiment of this disclosure, the nanoparticles are micelles comprising a lipid shell containing a closed polymer core, wherein the lipid shell comprises at least one amphiphilic lipid, and the polymer core comprises at least one biodegradable polymer, at least one pharmaceutical agent, and optionally at least one surfactant. Furthermore, the lipid may be attached to a functionalized portion containing organic functional groups, particularly polyethylene glycol (PEG) functionalization. The polymer core has a uniformly distributed biodegradable polymer. However, the pharmaceutical agent may be uniformly or non-uniformly dispersed within the biodegradable polymer matrix.

[0018] According to the nanoparticle design of this disclosure, most or a large weight percentage of the drug is stored on the periphery of the nanoparticle, particularly on the inner side of the periphery. The drug is densely stored near the periphery, and its concentration decreases towards the center of the nanoparticle. Therefore, a relatively small portion or a small weight percentage of the drug is present or distributed towards the center of the core in the main biodegradable polymer core. Thus, when such nanoparticles are exposed to tissue, the drug trapped or concentrated on the periphery of the nanoparticle becomes the main and readily available source of the drug. Therefore, the periphery of the nanoparticle, especially the inner periphery, becomes the main excipient portion of the nanoparticle, while the polymer core containing a small portion of the drug becomes the secondary excipient portion of the nanoparticle. This nanoparticle design is achieved by using a combination of solvents and antisolvents for the specific drug, as well as other basic raw materials, when forming the nanoparticles. Furthermore, the hydrophobicity and lipophilicity of the drug are utilized in the design of such nanoparticles.

[0019] According to the present invention, the lipid shell of the nanoparticles comprises at least one amphiphilic lipid selected from, but not limited to: phospholipids, lipid-polyethylene glycol conjugates, cholesterol, polyethylene glycol-modified phospholipids, cationic lipids, soybean phospholipids, egg yolk phospholipids, lecithin, DC-cholesterol, chemically modified cholesterol, cholesterol conjugates, or combinations thereof.

[0020] According to the present invention, the micelle core of the nanoparticles comprises at least one biodegradable polymer selected from, but not limited to, polymers of L-lactide, glycolide, or combinations thereof, poly(L-lactide-co-caprolactone) (PLCL), polydl-lactide (PDLLA), polydl-lactide-co-glycolide (PLGA), polydl-lactide-co-caprolactone (PLLCL), poly(hydroxybutyrate), polyorthoester, polyanhydride, poly(glycolic acid), poly(glycolide), poly(L-lactic acid), poly(L-lactide), poly(D-lactic acid), poly(D-lactide), poly(caprolactone), poly(trimethylene carbonate), polyesteramide, polyester, polyolefin, polycarbonate, polyoxymethylene, polyimide, polyether, and copolymers and combinations thereof.

[0021] According to the present invention, for biodegradable polymers, the solvent has a Hansen solubility parameter value in the range of 18 to 25, and the solvent is selected from, but not limited to, acetone, acetonitrile, tetrahydrofuran, nitromethane, chloroform, dichloromethane, and ethyl acetate.

[0022] According to the present invention, for biodegradable polymers, the antisolvent has a Hansen solubility parameter value that should not be in the range of 18-25, and the antisolvent is selected from, but not limited to, methanol, ethanol, allyl alcohol, ethanolamine, hexane, heptane, cyclohexane, 1-octanol, pentane, and xylene. Specifically, the Hansen solubility parameter value of the antisolvent is in the range of 10-15 or in the range of 25-40. More specifically, the Hansen solubility parameter value of the solvent is in the range of 25-40. Furthermore, the volume percentage of the solvent and antisolvent mixture varies from 0.01 to 3.5%.

[0023] According to one embodiment of this disclosure, the agent is selected from, but not limited to, anticancer drugs, antiproliferative drugs, antirestenosis drugs, neurodestructive agents, quaternary ammonium salts, sodium channel blockers, anesthetics, amino acids, amines, calcium channel blockers, diuretics, vasoconstrictors, neurotransmitter chemicals, venom, sclerosing agents, antinerve growth agents, amino steroids, neurotoxins, antithrombotic agents, antioxidants, anticoagulants, antiplatelet agents, thrombolytic agents, antiproliferative agents, anti-inflammatory agents, antimitotic agents, antimicrobial agents, antirestenosis agents, smooth muscle cell inhibitors, antibiotics, fibrinolytic agents, immunosuppressants, antiangiogenic agents, antirestenosis antitumor agents, antimyotrophic agents, antigens, or combinations thereof. More specifically, examples of pharmaceutical agents include, but are not limited to, everolimus, sirolimus, pimecrolimus, tacrolimus, zotarolimus, biolimus, paclitaxel, rapamycin, and combinations thereof.

[0024] According to one embodiment of this disclosure, the diameter of the nanoparticles of the present invention is in the range of about 10 nm to about 950 nm, preferably about 100 nm to about 900 nm, and more preferably about 200 nm to about 800 nm.

[0025] According to one embodiment of the invention, the ratio of the biodegradable polymer to the agent is in the range of 90:10 to 10:90.

[0026] According to one embodiment of this disclosure, the ratio of phospholipid molecules to the reagent is in the range of 90:10 to 10:90.

[0027] One aspect of this disclosure is to provide lipid-polymer hybrid nanoparticles in which the agent is not uniformly dispersed in the polymer core of the micelles, but rather accumulates on its periphery. Specifically, the agent molecules are concentrated in the shell structure of the nanoparticles, in and near the inner periphery of the shell. Thus, the lipid-based shell and proximal inner region become the primary excipient portion of the nanoparticles, and the core containing the biodegradable polymer becomes the secondary excipient portion of the nanoparticles. The shell structure is made of lipid molecules, which may be a single lipid or a mixture of different types of lipids. Only a small amount of the agent is dispersed in the primary biodegradable polymer core. Micelles are generated by mixing an organic liquid phase and an aqueous phase in the presence of a surfactant, and the distribution of a particular compound between these two phases can be controlled by its solubility in both phases. Furthermore, the hydrophobic properties of the agent and its interaction with the biodegradable polymer and lipids cause the agent to concentrate near the periphery of the nanoparticles. In addition, the added surfactant, mixing rate, and mixing time are other variables that can determine the degree of nanoparticle formation and the nanoparticle size distribution.

[0028] Furthermore, as discussed above, careful selection of solvents (solvents and antisolvents) and surfactants helps control drug movement and the accumulation area of ​​the drug within the nanoparticles of the drug delivery system. This movement and accumulation area within the nanoparticles determines the drug release profile of the drug delivery system.

[0029] According to another embodiment of this disclosure, a primary organic non-aqueous solvent is selected that has different solubilities or different Hansen solubility parameters for the biodegradable polymer, the pharmaceutical agent, and the phospholipid. Furthermore, the phospholipid acts as a surfactant in this system, providing stability to the nanoparticles or micelles and preventing their aggregation during preparation and storage to maintain their nanoparticle characteristics. The solubility difference between the solvents causes pharmaceutical molecules to migrate towards micelles within the biodegradable polymer matrix, but the lipophilic nature of the pharmaceutical agent pushes them towards the phospholipid molecules, which also have an affinity for the hydrophobic pharmaceutical agent. Therefore, the selected solvent-antisolvent interacts with this dual affinity, pushing most of the pharmaceutical agent to the periphery, where it concentrates near the phospholipid molecules forming the periphery of the micelles or nanoparticles, while a small amount of the pharmaceutical agent remains within the micelles and distributed within the biodegradable polymer core.

[0030] Furthermore, during the preparation of nanoparticles, the hydrophilic portion of the micelle-forming surfactant faces outwards from the periphery of the nanoparticles. During the formation of the nanoparticles and the accumulation of the agent near the phospholipid molecules, most of the accumulated agent adheres to the phospholipids and accumulates on the inner side of the periphery of the nanoparticles formed by the phospholipids. In some variants, the phospholipids are functionalized with hydrophilic compounds containing hydrocarbon chains, such as polyethylene glycol-modified phospholipids. In such cases, the inherently hydrophilic PEG chains are also located on the outer periphery of the nanoparticles. Optionally, these hydrocarbon chains may also retain a small amount of agent due to the physical adhesion between the agent molecules and the hydrocarbon chains. In addition, during the nanoparticle formation process, some agent is not trapped inside the nanoparticles but remains in the system as free agent. A portion of the free agent remains on or between the nanoparticles during solvent removal or separation from the process medium. Nonionic phospholipids, anionic phospholipids, cationic phospholipids, zwitterionic phospholipids, or combinations thereof can also be used to prepare nanoparticles according to this disclosure.

[0031] When such nanoparticles are exposed to biological tissue, the hydrophilic and lipophilic combination of phospholipids on their peripheral outer surface facilitates adhesion to and easy penetration of the tissue boundary. Due to the enhanced biocompatibility between the nanoparticles and the tissue, a significant amount of the agent is transferred to and retained within the tissue. An initial burst of agent release occurs upon exposure of the nanoparticles to the tissue, lasting nearly a day. This initial burst is due to the presence of the agent as free agent molecules from the manufacturing process and / or due to the loose adhesion of the agent to the periphery of the nanoparticles. The agent release over the following days is slower and proceeds in a controlled manner. This release is controlled due to adhesion between the agent and the phospholipid-based boundary of the nanoparticles. This controlled release lasts 5 to 7 days. Thus, the first two phases are completed together within 6 to 8 days from the start of exposure. Following the controlled release, sustained release of the agent is observed over the next 18–22 days. A sustained release profile emerges once the biodegradable polymer core containing the agent is exposed to the tissue.

[0032] Therefore, the nanoparticles according to this disclosure enable controlled drug release, followed by sustained drug release. The nanoparticle boundary composition increases drug transfer within tissues and prolongs drug retention. Compared to conventional polymer-matrix-based drug delivery systems, this novel nanoparticle-based drug delivery system of the present invention provides sustained drug release with a lower polymer loading. In this invention, the formulated nanoparticles exhibit a controlled release profile in the first few days and subsequently a sustained release profile. The controlled release profile occurs because the drug is encapsulated and accumulates near the inner periphery of the nanoparticles. The sustained release profile occurs because the drug is dispersed within the polymer core of the nanoparticles.

[0033] In one embodiment, the phospholipids used to prepare the nanoparticles are functionalized with polyethylene glycol chains. Due to the hydrophilic nature of the PEG chains, this functionalized phospholipid or PEGylated phospholipid present in the nanoparticles further enhances tissue interactions. Furthermore, in other possible embodiments, another compound containing a hydrophilic moiety can be used to functionalize the phospholipids. Such compounds include, but are not limited to, poly(carboxybetaine) (PCB), branched PEG, poly(sarcosine), polyglycerol, poly(hydroxyethyl-1-asparagine) (PHEA), poly(vinylpyrrolidone) (PVP), and poly(… N , N PDMA (dimethylacrylamide), poly( N -Acryloylmorpholine (PAcM), poly[ N [(2-hydroxypropyl))methacrylamide] (HPMA) and poly(2-methyl-2-oxazoline) (PMOX), poly(2-ethyl-2-oxazoline), poly(acrylic acid), or combinations thereof. Based on functionality, the drug release behavior of nanoparticles containing functionalized phospholipids can have different effects in different embodiments.

[0034] According to another embodiment, the nanoparticles prepared according to this disclosure are applied to a target lesion alone or in combination with a base material. The base material is selected from at least polymeric materials, non-polymeric materials, or combinations thereof. Furthermore, these nanoparticles can also be used with other drug delivery methods, such as pills, eye drops, nasal sprays, ointments, intravenous routes, intramuscular routes, intranasal routes, sublingual administration, transdermal administration, oral administration, intravaginal administration, intramucosal administration, or via a drug pump placed in a desired body organ or tube.

[0035] According to yet another embodiment, the nanoparticles prepared according to this disclosure can be used with polymeric or non-polymeric media in pure form, formulation form, or compositional form. Furthermore, these nanoparticles can also be used in fluid form, aerosol form, gel form, powder form, colloidal solution form, curable mixture form, semi-solid form, or solid form.

[0036] According to one embodiment of this disclosure, the nanoparticles prepared according to this disclosure are used in a coating composition coated on a surface, and the loading of the agent in the coating is about 0.05 μg / mm². 2 Up to 5.0 μg / mm 2 Preferably about 0.5 μg / mm 2 Up to 4.0 μg / mm 2 More preferably about 1.0 μg / mm 2 Up to 3.0 μg / mm 2 Within the range.

[0037] According to one embodiment of this disclosure, nanoparticles prepared according to this disclosure are used in a coating composition coated on a surface, and the loading of biodegradable polymer in the coating is about 0.1 μg / mm². 2 Up to 10.0 μg / mm 2 Preferably about 0.5 μg / mm 2 Up to 7.0 μg / mm 2 More preferably about 1.0 μg / mm 2 Up to 5.0 μg / mm 2 Within the range.

[0038] According to one embodiment of this disclosure, the nanoparticles prepared according to this disclosure are used in a coating composition on a surface, and the amount of phospholipid-based molecules present in the coating is about 0.1 μg / mm². 2 Up to 10.0 μg / mm 2 Preferably about 0.5 μg / mm 2 Up to 7.0 μg / mm 2 More preferably about 0.5 μg / mm 2 Up to 5.0 μg / mm 2 Within the range.

[0039] The lipid-based shell ensures better adhesion to biological tissues, and the nanoparticles more easily cross cell boundaries within biological tissues, resulting in better drug transfer and less drug loss due to blood elution. Upon application, compositions containing such nanoparticles initially provide a controlled release at a slower rate, followed by sustained release at a higher rate, offering enhanced tissue absorption, longer tissue retention, and better therapeutic efficacy at lower drug doses. Furthermore, the organic nature of the drug delivery system facilitates the coating of these nanoparticles or nanoparticle-based coating compositions.

[0040] According to one embodiment, the drug delivery system of the present invention includes a medical device that can be placed within a lumen, tube, or channel in a human or animal, the lumen, tube, or channel being selected from, but not limited to, arteries, veins, bile ducts, urethra, digestive tract, tracheobronchial tree, cerebral aqueduct, or genitourinary system. Specifically, the medical device can be used intravascularly in renal arteries, femoral arteries, superficial femoral arteries, popliteal arteries, tibial arteries, genicular arteries, cerebral arteries, carotid arteries, vertebral arteries, subclavian arteries, radial arteries, brachial arteries, axillary arteries, coronary arteries, peripheral arteries, iliac arteries, or neural arteries.

[0041] According to yet another embodiment, the nanoparticles or nanoparticle compositions according to the invention are used as a drug to be coated onto a medical device for drug delivery, wherein the medical device is to be implanted in a lumen or tract or tube selected from: bile duct, urethra, digestive tract, tracheobronchial tree, cerebral aqueduct, genitourinary system, renal artery, femoral artery, superficial femoral artery, popliteal artery, tibial artery, genitourinary artery, cerebral artery, carotid artery, vertebral artery, subclavian artery, radial artery, brachial artery, axillary artery, coronary artery, peripheral artery, iliac artery, neural artery or any vein.

[0042] Another aspect of this disclosure is to provide a method for preparing nanoparticles via a solvent-antisolvent approach, the nanoparticles providing controlled and increased drug release over a longer period of time, reduced drug loss due to blood flow, and increased drug transfer and longer retention in biological tissues after application. The method comprises: (1) preparing a solution A of a drug and a biodegradable polymer in an organic solvent; (2) preparing a solution B of at least one lipid in a mixture of another organic solvent and water; (3) at ambient temperature, slowly adding solution A to solution B while stirring solution B with a magnetic stirrer to form nanoscale micelle cores, wherein the volume of solution B exceeds that of solution A, and the ratio of solution A to solution B is in the range of 1:50, preferably 1:40, and more preferably 1:25; and (4) applying or further processing the mixture containing nanoscale micelle cores or nanoparticles. The organic solvents used in solutions A and B have different solubilities or Hansen solubility parameters for the drug and the biodegradable polymer. The organic solvent used to prepare solution A has good solubility for both the pharmaceutical agent and the biodegradable polymer, while another organic solvent used to prepare solution B has good solubility for the lipids. However, for micelle formation, the pharmaceutical agent and the biodegradable polymer should not have good solubility in the other organic solvent. In this disclosure, the pharmaceutical agent is carefully selected to be soluble in another organic solvent to a certain extent, but this solubility is significantly less than the solubility of the pharmaceutical agent in the organic solvent. Therefore, when solution A is added to solution B under stirring, micelles are formed, with the inner core containing the biodegradable polymer and the solution of the pharmaceutical agent in the organic solvent. The shell of the micelle is formed by the lipids present in solution B. Initially, the pharmaceutical agent is uniformly dispersed in the micelles, but as the process proceeds, a solubility gradient is formed due to the solubility difference of the pharmaceutical agent between the inner core phase and the solution B phase outside the lipid boundary, and some pharmaceutical agent molecules move toward the lipid boundary. The adhesive forces between the pharmaceutical agent, the biodegradable polymer, and the phospholipids also play a role in the accumulation of the pharmaceutical agent near the inner periphery of the nanoparticles. Some of the drug molecules present in the system also accumulate on the periphery of the micelles, and some of them are also trapped in the molecular structure of the lipids present at the boundary, specifically towards the inside. Therefore, by carefully selecting materials and process parameters, lipid-polymer hybrid nanoparticles that provide the desired properties upon application are formed according to this disclosure.

[0043] According to one embodiment of the present invention, solution B is prepared using a variety of phospholipids selected from natural phospholipids, synthetic phospholipids, or combinations thereof. Examples of phospholipids include, but are not limited to, lecithin, soybean lecithin, egg yolk lecithin, synthetic phospholipids, polyethylene glycol-modified phospholipids, phosphatidylcholine, phosphatidic acid, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, 1,2-dimyristoyl-sn-glycerol-3-phosphate ethanolamine (DMPE), 1,2-dipalmitoyl-sn-glycerol-3-phosphate ethanolamine (DPPE), 1,2-distearate-sn-glycerol-3-phosphate ethanolamine (DSPE), 1,2-dioleoyl-sn-glycerol-3-phosphate ethanolamine (DOPE), 1,2-dimyristoyl-rac-glycerol-3-phosphate-rac-(l-glycerol) (DMPG), and 1,2-di-(9Z-octadecene). Acyl)-sn-glycerol-3-phosphate (1'-rac-glycerol) (DOPG), 1,2-distearyl-sn-glycerol-3-phosphate (1'-rac-glycerol) (DSPG), 1,2-dimyristoyl-sn-glycerol-3-phosphate choline (DMPC), 1,2-dipalmitoyl-sn-glycerol-3-phosphate choline (DPPC), 1,2-distearyl-sn-glycerol-3-phosphate choline (DSPC), 1,2-dioleoyl-sn-glycerol-3-phosphate choline (DPOC), 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphate choline (POPC), 1,2-disorcinoyl-sn-glycerol-3-phosphate choline (DEPC), or combinations thereof.

[0044] According to one embodiment of this disclosure, the method further includes the step of removing the nanoparticle-rich phase from the solvent mixture using suitable unit operations such as centrifugation, gravity sedimentation, ultracentrifugation, electrophoresis, nanofiltration, chromatography, colloidal suspension, and selective precipitation.

[0045] According to one embodiment of this disclosure, the method further includes the step of adding a cryoprotectant to provide stability to the nanoparticles prior to freeze-drying. The cryoprotectant may be selected from, but is not limited to, polyols, sugars, including sucrose, trehalose, lactose, mannitol, or combinations thereof.

[0046] According to one embodiment of the invention, the method further includes the step of removing the solvent from the nanoparticle-rich phase using a suitable unit operation such as freeze-thaw drying or evaporation to obtain nanoparticles in powder form. Upon application, the obtained nanoparticle powder is redispersed in a suitable solvent, either alone or in combination with a suitable surfactant.

[0047] By combining the different materials and processes mentioned above, various configurations with different structure-property relationships can be obtained.

[0048] According to one embodiment of this disclosure, the drug delivery system includes a medical device coated with nanoparticles or a nanoparticle-based composition. The medical device may be selected from, but is not limited to, the group consisting of: stents, guidewires, catheters, shunts, balloons, heart valves, vena cava filters, vascular grafts, stent grafts, bone prostheses, spinal prostheses, hip prostheses, rib prostheses, skull prostheses, sutures, staples, anastomotic devices, bone needles, suture anchors, hemostatic barriers, vascular implants, tissue scaffolds, bone substitutes, and endoluminal devices.

[0049] According to another embodiment of this disclosure, nanoparticles or nanoparticle-based compositions or formulations can be coated by spraying, dip coating, chemical vapor deposition, physical vapor deposition, plasma-enhanced chemical vapor deposition, evaporation deposition, sputtering deposition, ion plating, atmospheric pressure plasma deposition, sol-gel method and 3D printing.

[0050] According to another embodiment of the invention, nanoparticles or nanoparticle-based compositions according to the invention are placed on a medical device made of a material made of metal, metal alloy, non-metal, polymer, polymer composite material, or a combination thereof. According to yet another embodiment of the invention, nanoparticles or nanoparticle-based compositions according to the invention are used in a medical device, which may be an implantable medical device, a temporary implantable device, or a non-implantable medical device.

[0051] Reference is now made to the accompanying drawings, which form a part of the invention, and specific embodiments in which the invention can be practiced are illustrated by way of explanation. It should be understood that other embodiments can be utilized and structural changes can be made without departing from the scope of the invention.

[0052] Figure 1 A schematic diagram illustrating one embodiment of the nanoparticles (100) according to this disclosure is shown. The nanoparticles (100) comprise a polymer core (108) based on a biodegradable polymer (specifically PLGA), which also comprises an agent (specifically sirolimus) (104). The polymer core is surrounded by a lipid-based shell structure. The lipid-based shell structure is made of lipids, preferably a mixture of natural and synthetic lipids, and more specifically, the lipid-based shell structure is made of phospholipids (106) and polyethylene glycol-modified lipids (102). Most of the agent accumulates inside the lipid shell structure, rather than being uniformly dispersed within the biodegradable polymer core. These nanoparticles allow for controlled release of the agent, followed by sustained release with a higher release rate, allowing for better penetration into biological tissues, longer retention in tissues, and reduced elution due to blood flow.

[0053] Example : Two examples are given below, describing two compositions and a method for preparing such nanoparticles that can be used to prepare coating compositions. In addition, a set of graphs illustrates the agent release of compositions containing such nanoparticles.

[0054] Drug transfer and retention curves are shown. Similarly, the drug transfer and retention curves are compared to those of a commercially available competitor product in a single graph. The composition of the main components of the two compositions is shown below: Table 1: Phospholipids prepared using PLGA as the core and natural phosphatidylcholine and polyethylene glycol-modified synthetic phospholipids as lipids. Composition of shell-containing sirolimus nanoparticles Example 1: The antiproliferative drug sirolimus was used as a drug agent encapsulated in a micelle core. Following the method for preparing drug nanocarriers described in the above embodiments, solution A was prepared in acetonitrile using sirolimus and PLGA. The concentration of sirolimus in the solution was 0.08% w / v, and the concentration of PLGA in the solution was 0.22% w / v. Another solution B was prepared in methanol using polyethylene glycol-modified synthetic phospholipids and natural phosphatidylcholine. The concentration of polyethylene glycol-modified synthetic phospholipids in the solution was 0.05% w / v, and the concentration of natural phosphatidylcholine in the solution was 0.05% w / v. Solution A was added to solution B at a rate of 1 ml / min, while solution B was stirred at 500 RPM (revolutions per minute) for one hour to form nanoscale micelle cores. This process was carried out at ambient temperature and pressure.

[0055] Example 2: The antiproliferative drug sirolimus was used as a drug agent encapsulated in a micelle core. Following the method for preparing drug nanocarriers described in the above embodiments, solution A was prepared in acetonitrile using sirolimus and PLGA. The concentration of sirolimus in the solution was 0.08% w / v, and the concentration of PLGA in the solution was 0.22% w / v. Another solution B was prepared in methanol using polyethylene glycol-modified synthetic phospholipids and natural phosphatidylcholine. The concentration of polyethylene glycol-modified synthetic phospholipids in the solution was 0.075% w / v, and the concentration of natural phosphatidylcholine in the solution was 0.05% w / v. Solution A was added to solution B at a rate of 1 ml / min, while solution B was stirred at 500 RPM (revolutions per minute) for one hour to form nanoscale micelle cores. This process was carried out at ambient temperature and pressure.

[0056] Furthermore, the drug release from the nanoparticles prepared according to the present invention and the above embodiments was measured in a simulated physiological environment, and the results were plotted. Figure 2For this measurement, a sample of these nanoparticles, weighing between 1.5 mg and 2.5 mg, was placed in a 1.5 ml vial containing 1.5 ml of release medium (pH 7.4). The vial was incubated at 37°C while being gently mixed at 200 rpm. The release medium was removed from the vial at regular time intervals, and the amount of released agent was measured by liquid chromatography. This measurement was performed for 28 days for each sample. Figure 2 The release curve of the agent is shown over this 28-day period. Following the initial burst of the agent on the first or second day, controlled release was observed over the next six or seven days. Sustained release was then observed over the next three weeks.

[0057] In addition, in another experimental setting, drug transfer and retention curves (in vitro) were studied, and the results were plotted on... Figure 3 In this study, the balloon portion of a typical balloon catheter was coated with nanoparticles prepared according to the present invention and the embodiments described above. The coated balloon navigated through a traceable path and inflated in biological tissue. The amount of drug loss during navigation, the amount of drug transferred to biological tissue, and the amount of drug retained on the balloon were measured. For the measurement of drug retention, a compartment containing biological tissue was attached to a pulsatile pump, and biological media were passed through the compartment for 1 hour. At the end of the first hour of balloon inflation in biological tissue and at the end of the 24th hour, the amount of drug adhering to or retained in the biological tissue wall and the amount of drug washed away in the biological media were measured. Figure 3 The amount of drug transferred during balloon inflation in biological tissue is shown, as well as the absorption and retention of the drug in biological tissue at the end of the first hour and the end of the 24th hour after balloon inflation. This graph clearly illustrates the sustained availability of the drug in biological tissue over a 24-hour period for the nanoparticles prepared according to Examples 1 and 2.

[0058] Furthermore, in the same experimental setup, for the nanoparticles prepared according to Example 1, drug transfer and retention curves (in vitro) were continuously studied for a period of 72 hours from the start of balloon inflation in biological tissue, and the results were plotted on [the graph]. Figure 4 In addition, similar research was conducted on commercially available products from competitors (used for comparison or as reference products). Figure 4 The graph clearly illustrates the sustained drug retention in biological tissue over a 72-hour period. Furthermore, the graph distinguishes the present invention from comparative commercial products based on higher drug transfer and higher drug retention in biological tissue.

[0059] Figure 2 , Figure 3 and Figure 4It is clearly demonstrated that the nanoparticles prepared according to the embodiments of this disclosure are prepared using a core based on a biodegradable polymer, with lipid molecules forming the boundary or shell. A large amount of drug is aggregated on the inner periphery of the shell structure formed by lipid molecules at the periphery of such nanoparticles, while a small amount of drug is dispersed within the main polymer core. This distribution of the drug allows for controlled and sustained drug release over a period of three to four weeks. Furthermore, a significant increase in drug transfer and retention in biological tissues has been demonstrated.

[0060] Nanoparticles prepared as described in the exemplary embodiments above, or compositions containing such nanoparticles, can be used directly for application. Furthermore, such nanoparticles can undergo additional processing steps, such as the addition of additives to improve properties, for example, to enhance stability or to provide cryoprotectants for lyophilization (freeze-thaw), to form nanoparticles in powder form for storage and later application.

[0061] This disclosure reduces the problem of high drug elution by applying novel nanoparticle compositions. Furthermore, the nanoscale particles and lipid-based shell surface enable them to adhere to and penetrate biological tissues, allowing for administration not only via intravenous routes but also via a variety of routes, including subcutaneous, dermal, oral, mucosal, sublingual, and ocular, thus enabling a new delivery platform for future drug delivery.

[0062] In the foregoing description, specific details have been set forth for purposes of explanation to provide an understanding of this disclosure. However, it will be apparent to those skilled in the art that this disclosure may be practiced without these details. Those skilled in the art will recognize that embodiments of this disclosure (one of which is described below) can be incorporated into multiple systems. Furthermore, the structures and methods illustrated in the accompanying drawings are illustrative of exemplary embodiments of this disclosure and are intended to avoid obscuring this disclosure.

Claims

1. A nanoparticle for drug delivery, said nanoparticle comprising: A peripheral primary excipient made of phospholipid-based molecules; an internal biodegradable polymer core as a secondary excipient, wherein at least one agent is distributed in both the primary and secondary excipients.

2. The nanoparticles for drug delivery according to claim 1, wherein the biodegradable polymer core comprises at least one polymer selected from the group consisting of lactose, ethylene glycol, glycolide, lactide, caprolactone, or combinations thereof.

3. The nanoparticles according to claim 1, wherein the phospholipid-based molecule is selected from phospholipids, functionalized phospholipids, nonionic phospholipids, anionic phospholipids, cationic phospholipids, zwitterionic phospholipids, or combinations thereof.

4. The nanoparticles according to claim 3, wherein the phospholipid-based molecule is selected from the following amphiphilic lipids: natural phospholipids, synthetic phospholipids, lipid-polyethylene glycol conjugates, cholesterol, polyethylene glycol-modified phospholipids, cationic lipids, soybean phospholipids, egg yolk phospholipids, lecithin, DC-cholesterol, chemically modified cholesterol, cholesterol conjugates, or combinations thereof.

5. The nanoparticles according to claim 1, wherein the size of the nanoparticles is in the range of about 10 nm to about 950 nm.

6. The nanoparticles according to claim 1, wherein the ratio of the amount of biodegradable polymer to the amount of the agent is 90:10 to 10:

90.

7. The nanoparticles according to claim 1, wherein the ratio of the amount of phospholipid-based molecules to the amount of the reagent is 90:10 to 10:

90.

8. The nanoparticles according to claim 1, wherein the pharmaceutical agent is selected from antithrombotic agents, antioxidants, anticoagulants, antiplatelet agents, thrombolytic agents, antiproliferative agents, anti-inflammatory agents, antimitotic agents, antimicrobial agents, anti-restenosis agents, smooth muscle cell inhibitors, antibiotics, fibrinolytic agents, immunosuppressants, anti-angiogenic agents, anti-restenosis antitumor agents, anti-migration agents, antigens, anticancer drugs, antiproliferative drugs, lipophilic drugs, anti-restenosis drugs, neurodestructive agents, quaternary ammonium salts, sodium channel blockers, anesthetics, amino acids, amines, calcium channel blockers, diuretics, vasoconstrictors, neurotransmitter chemicals, venom, sclerosing agents, anti-nerve growth agents, amino steroids, neurotoxins, or combinations thereof.

9. The nanoparticles according to claim 1, wherein the pharmaceutical agent is selected from paclitaxel, sirolimus, rapamycin, everolimus, pimecrolimus, tacrolimus, zotamolimus, eucomolimus, or combinations thereof.

10. The nanoparticles for drug delivery according to claim 1, wherein the nanoparticles contain an amount of the pharmaceutical agent such that the coating of the nanoparticle composition will contain about 0.05 μg / mm². 2 Up to 5.0 μg / mm 2 The amount of the drug within the specified range.

11. The nanoparticles for drug delivery according to claim 1, wherein the nanoparticles comprise an amount of the biodegradable polymer, such that the coating of the nanoparticle composition comprises about 0.1 μg / mm². 2 Up to 10.0 μg / mm 2 Amounts of biodegradable polymers within the specified range.

12. The nanoparticles for drug delivery according to claim 1, wherein the nanoparticles comprise an amount of the phospholipid-based molecules such that the coating of the nanoparticle composition will contain 0.1 μg / mm². 2 Up to 10.0 μg / mm 2 The amount of the phospholipid-based molecules within the specified range.

13. A drug delivery system comprising a medical device coated with nanoparticles according to claim 1, wherein the medical device is selected from balloons, stents, shunts, catheters, heart valves, guidewires, vena cava filters, vascular grafts, stent grafts, bone prostheses, spinal prostheses, hip prostheses, rib prostheses, skull prostheses, sutures, staples, anastomotic devices, bone needles, suture anchors, hemostatic barriers, vascular implants, tissue scaffolds, bone substitutes, and endoluminal devices.

14. The nanoparticles of claim 1, wherein the nanoparticles are used as a drug to be coated onto a medical device for drug delivery, wherein the medical device is to be implanted in a lumen or tract or tube selected from: bile duct, urethra, digestive tract, tracheobronchial tree, cerebral aqueduct, genitourinary system, renal artery, femoral artery, superficial femoral artery, popliteal artery, tibial artery, genitourinary artery, cerebral artery, carotid artery, vertebral artery, subclavian artery, radial artery, brachial artery, axillary artery, coronary artery, peripheral artery, iliac artery, neural artery, or any vein.

15. A method for preparing nanoparticles for drug delivery, the method comprising: A first solution A of a biodegradable polymer and a pharmaceutical agent in a first solvent is prepared. Prepare a second solution B in a second solvent containing at least one surfactant; The first solution is mixed with the second solution under continuous stirring and in the presence of an excess of the second solution; The second solvent has a higher solubility for the drug compared to the first solvent.

16. The method for preparing nanoparticles for drug delivery according to claim 13, wherein the first solvent and the second solvent are selected from acetonitrile, chloromethane, dichloroethane, acetophenone, ethylene carbonate, propylene carbonate, methanol, ethanol, allyl alcohol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, benzyl alcohol, cyclohexanol, 1-decanol, acetonitrile, acetone, heptane, hexane, ethanolamine, nitromethane, and combinations thereof.

17. The method for preparing nanoparticles for drug delivery according to claim 13, wherein the first solvent is acetonitrile and the second solvent is methanol.

18. The method of claim 13 for preparing nanoparticles for drug delivery, wherein the first solvent has a Hansen solubility parameter value between 18 and 25 and the second solvent has a Hansen solubility parameter value in the range of 25 to 40.

19. The method for preparing nanoparticles for drug delivery according to claim 13, wherein the first solvent has a Hansen solubility parameter value between 18 and 25 and the second solvent has a Hansen solubility parameter value in the range of 10 to 15.

20. The method for preparing nanoparticles for drug delivery according to claim 13, the method further comprising the step of removing the nanoparticle-rich phase from the solvent mixture.

21. The method for preparing nanoparticles for drug delivery according to claim 13, the method further comprising the step of adding a cryoprotectant to provide stability to the nanoparticles.

22. The method for preparing nanoparticles for drug delivery according to claim 13, wherein the cryoprotectant is selected from polyols, sugars, sucrose, trehalose, lactose, mannitol, or combinations thereof.

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