Lipid-polymer hybrid nanoparticles

Abstract

This disclosure describes lipid polymer hybrid nanoparticles and methods for synthesizing such nanoparticles or compositions containing such nanoparticles. The nanoparticles are prepared in a biodegradable polymer micelle core surrounded by a lipid shell, and the majority of the pharmaceutical product is present on the inner periphery of such nanoparticles due to physical adhesion with lipid molecules. Only a small amount of the pharmaceutical product is encapsulated in the micelle core. Thus, the lipid shell becomes the primary excipient portion of the nanoparticle, and the biodegradable polymer-containing core becomes the secondary excipient portion of the nanoparticle.

Description

[Technical Field]

[0001] The present invention relates to lipid-polymer hybrid nanoparticles and methods for preparing pharmaceutical compositions containing lipid-polymer hybrid nanoparticles, as well as to such nanoparticles and nanoparticle-containing compositions. Specifically, the present invention relates to nanoparticles for pharmaceutical compositions, and to coating compositions for medical devices, drug delivery, and diagnostics. [Background technology]

[0002] Nanoparticle-based drug delivery systems offer several advantages compared to conventional drug delivery systems. The main advantages are control over drug release in tissues, higher drug transfer for specific amounts of drug used in the delivery system, longer drug retention in nanoparticles (which in turn increases longer drug delivery to tissues), and lower drug efflux into biological fluids. Biodegradable polymers are a preferred choice for use as substrates to prepare nanoparticles for implantable medical devices. They not only help control drug release but also leave the body of the organism for a period of time after degradation. Lipids help form micelles, which are the basis for nanoparticle formation, and also help stabilize dispersion during the nanoparticle formation process.

[0003] This disclosure focuses on utilizing the properties of lipids and biodegradable polymers and developing unique lipid-polymer hybrid nanoparticles to overcome several drug delivery challenges related to drug release control, drug retention, and drug loss during transport. Therefore, it is an object of the present invention to provide lipid-polymer hybrid nanoparticles that achieve longer-term drug release control, reduced drug loss due to blood flow, and increased drug transfer and retention in biological tissues after application.

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

[0005] The above embodiments are further illustrated in the drawings and described in the corresponding descriptions below. It should be noted that the descriptions and drawings merely illustrate the principles of the present invention. Therefore, various configurations encompassing the principles of the present invention, which are not explicitly described or illustrated herein, can be derived from the descriptions and are included within their scope. [Brief explanation of the drawing]

[0006] Detailed explanations are provided with reference to the attached diagrams. [Figure 1] A schematic diagram illustrating a pharmaceutical product supporting lipid-polymer hybrid nanoparticles according to an embodiment of the present invention is provided. [Figure 2] The in vitro drug release profiles of lipid-polymer hybrid nanoparticles containing pharmaceuticals, according to embodiments of the present invention, are illustrated. [Figure 3] Two embodiments of the present invention illustrate the ex vivo drug delivery and retention profiles of pharmaceuticals carrying two different lipid-polymer hybrid nanoparticles in tissue over a 24-hour duration. [Figure 4] Embodiments of the present invention illustrate the ex vivo drug delivery and retention profiles of a pharmaceutical product carrying lipid-polymer hybrid nanoparticles containing a coating composition in tissue over a 72-hour duration, and compare them with similar profiles of competing products (commercially available). [Modes for carrying out the invention]

[0007] This disclosure, along with the disclosed drawings, describes the embodiments presented, but is not intended to be the only embodiments to be constructed from this disclosure. This disclosure describes the applications or uses of the embodiments and a set of steps for achieving the embodiments. The same applications or uses and a set of steps may be employed by different embodiments.

[0008] As described herein, any concentration range, percentage range, ratio range, or integer range is understood to include any integer value within the listed range, and, where appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer), unless otherwise indicated.

[0009] As used herein, the term “pharmaceutical” refers to any biologically active compound or drug molecule that can be used in formulations or compositions suitable for administration to mammals, including humans.

[0010] As used herein, the term “nanoparticles” refers to lipid-polymer hybrid nanoparticles having a nanoscale structure in which at least one dimension (length, width, or thickness) of the nanoparticle is in the nanometer range. Nanoparticles can be any shape, such as spherical, elliptical, disc-shaped, cylindrical, or hexagonal.

[0011] According to the present invention, as used herein, the term “primary excipient” refers to the phospholipid region within the structure of a nanoparticle in which the pharmaceutical is densely accumulated in the range of 51% to 99% by weight of the total pharmaceutical, more specifically in the range of 70% to 97% by weight of the total pharmaceutical, and more specifically in the range of 80% to 95% by weight of the total pharmaceutical.

[0012] According to the present invention, as used herein, the term “secondary excipient” refers to a biodegradable polymer core region in the structure of a nanoparticle, in which the amount of pharmaceutical product is smaller compared to the primary excipient.

[0013] According to embodiments of the present disclosure, the nanoparticles are micelles comprising a lipid shell encapsulating a polymer core, the lipid shell comprising at least one amphiphilic lipid, and the polymer core comprising at least one biodegradable polymer, at least one pharmaceutical, and optionally at least one surfactant. Furthermore, the lipids may be bound to a functionalized moiety comprising an organic functional group, and specifically functionalized with polyethylene glycol (PEG). The polymer core has a uniformly distributed biodegradable polymer. However, the pharmaceutical may or may not be uniformly dispersed in the biodegradable polymer matrix.

[0014] The nanoparticles according to this disclosure are designed to store the majority or primary weight percentage of the pharmaceutical product around the nanoparticle, specifically inside the periphery. The pharmaceutical product is densely stored closest to the periphery, and its concentration decreases towards the center of the nanoparticle. Therefore, relatively small portions or weight percent of the pharmaceutical product are located towards the center of the core or distributed within the primary biodegradable polymer core. Thus, upon exposure of such nanoparticles to tissue, the pharmaceutical product trapped or concentrated around the nanoparticle becomes the primary and readily available source of the pharmaceutical product. Thus, the periphery of the nanoparticle, specifically the inner periphery, becomes the primary excipient portion of the nanoparticle, while the polymer core containing the smaller portion of the pharmaceutical product becomes the secondary excipient portion of the nanoparticle. This nanoparticle design is achieved using solvent and antisolvent combinations for the specific pharmaceutical product, along with other basic raw materials, while forming the nanoparticles. The hydrophobic and lipophilic properties of the pharmaceutical product are also utilized in designing such nanoparticles.

[0015] According to the present invention, the lipid shell of the nanoparticles is The material comprises at least one amphiphilic lipid selected from, but not limited to, phospholipids, lipid-polyethylene glycol conjugates, cholesterol, PEGylated phospholipids, cationic lipids, soybean phospholipids, egg phospholipids, lecithin, DC-cholesterol, chemically modified cholesterol, cholesterol conjugates, or combinations thereof.

[0016] According to the present invention, the micelle core of the nanoparticles is a polymer of L-lactide, glycolide, or a combination thereof, poly(L-lactide-co-caprolactone) (PLCL), polydl lactide (PDLLA), polydl lactide-co-glycolide (PLGA), polydl lactide-co-caprolactone (polydl The material comprises at least one biodegradable polymer selected from, but not limited to, 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.

[0017] According to the present invention, the solvent for the biodegradable polymer having a Hansen solubility parameter value in the range of 18 to 25 is selected from, but is not limited to, acetone, acetonitrile, tetrahydrofuran, nitromethane, chloroform, dichloromethane, and ethyl acetate.

[0018] According to the present invention, antisolvents having a Hansen solubility parameter value that should not be in the range of 18 to 25 for biodegradable polymers are selected from, but are 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 to 15 or in the range of 25 to 40. More specifically, the Hansen solubility parameter value of the solvent is in the range of 25 to 40. Furthermore, the volume percentage ratio of the solvent-antisolvent mixture varies within the range of 0.01 to 3.5.

[0019] According to one embodiment of the present invention, the pharmaceutical is selected from, but not limited to, anti-cancer agents, anti-proliferative agents, anti-restenosis agents, neurolytic agents, quaternary ammonium salts, sodium channel blockers, anesthetics, amino acids, amines, calcium channel blockers, diuretics, vasoconstrictors, neurotransmitter chemicals, poisons, sclerosing agents, anti-nerve growth agents, amino steroids, neurotoxins, antithrombotic agents, antioxidants, anticoagulants, antiplatelet agents, thrombolytic agents, anti-proliferative agents, anti-inflammatory agents, anti-mitotic agents, antibacterial agents, anti-restenosis agents, smooth muscle cell inhibitors, antibiotics, fibrinolytic agents, immunosuppressive agents, anti-angiogenic agents, anti-restenosis agents, anti-migration agents, antigenic substances, or combinations thereof. More specifically, examples of the pharmaceutical include, but are not limited to, everolimus, sirolimus, pimecrolimus, tacrolimus, zotarolimus, biolimus, paclitaxel, rapamycin, and combinations thereof.

[0020] According to one embodiment of the present invention, 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.

[0021] According to one embodiment of the present disclosure, the ratio of the biodegradable polymer to the pharmaceutical is in the range of 90:10 to 10:90.

[0022] According to one embodiment of the present disclosure, the ratio of the phospholipid-based molecule to the pharmaceutical is in the range of 90:10 to 10:90.

[0023] One aspect of this disclosure provides lipid-polymer hybrid nanoparticles in which the pharmaceutical is not uniformly dispersed within the polymer core of the micelle but is accumulated around it. Specifically, the pharmaceutical molecule is concentrated within the shell structure of the nanoparticle, both around the inner periphery of the shell and in close proximity to it. Thus, the lipid-based shell and proximal inner region become the primary excipient portion of the nanoparticle, and the biodegradable polymer-containing core become the secondary excipient portion of the nanoparticle. The shell structure is made of lipid molecules, which are either one type of lipid or a mixture of different types of lipids. Only a small amount of the pharmaceutical is dispersed within the main biodegradable polymer core. While the micelle is created by mixing an organic liquid phase and an aqueous phase in the presence of a surfactant, the distribution of a particular compound between these two phases can be controlled using its solubility in these two phases. In addition, the hydrophobic nature of the pharmaceutical, as well as its interaction with the biodegradable polymer and lipid, causes the pharmaceutical to concentrate near the periphery of the nanoparticle. Furthermore, the added surfactant, mixing rate, and mixing time are other variables that can determine the degree of nanoparticle formation and the size distribution of the nanoparticles.

[0024] Furthermore, as discussed above, careful selection of solvents (solvents and antisolvents) and surfactants is involved in controlling the areas of drug migration and accumulation within nanoparticles in drug delivery systems. These migration and accumulation areas within nanoparticles determine the drug release profile of the drug delivery system.

[0025] According to another embodiment of the present disclosure, a primarily organic non-aqueous solvent is selected for the biodegradable polymer, pharmaceutical, and phospholipid, having different solubility or different Hansen solubility parameters. Furthermore, the phospholipid acts as a surfactant in the system, providing stability to the nanoparticles or micelles, preventing their aggregation during preparation and storage, and maintaining their character as nanoparticles. The difference in solubility between the solvents biases the movement of pharmaceutical molecules toward micelles in the biodegradable polymer matrix, while the lipophilic nature of the pharmaceutical drives them toward phospholipid molecules, which also have an affinity for hydrophobic pharmaceuticals. Thus, the selected solvent-antisolvent interacts with this biaffinity, driving the majority of the pharmaceutical toward the periphery, where it is concentrated near the phospholipid molecules forming the periphery of the micelles or nanoparticles, while a small amount of the pharmaceutical remains inside the micelles and is distributed within the biodegradable polymer core.

[0026] Furthermore, in the process of preparing nanoparticles, the hydrophilic portion of the micelle-forming surfactant faces outward around the nanoparticles. During nanoparticle formation and accumulation of pharmaceuticals near phospholipid molecules, the majority of the accumulated pharmaceuticals adhere to the phospholipids and accumulate inside the nanoparticles formed by the phospholipids. In some modifications, the phospholipids are functionalized with hydrocarbon chains containing hydrophilic compounds, e.g., PEGylated phospholipids. In such cases, the inherently hydrophilic PEG chains are also located on the outer periphery of the nanoparticles. Optionally, these hydrocarbon chains can also hold small amounts of pharmaceuticals due to the physical adhesion between the pharmaceutical molecules and the hydrocarbon chains. In addition, during the nanoparticle formation process, some of the pharmaceuticals are not captured inside the nanoparticles and remain in the system as free pharmaceuticals. Upon solvent removal or separation of the formed nanoparticles from the process medium, some of the free pharmaceuticals remain on or between the nanoparticles. Nonionic phospholipids, anionic phospholipids, cationic phospholipids, amphoteric phospholipids, or combinations thereof can also be used in the preparation of nanoparticles according to this disclosure.

[0027] When such nanoparticles are exposed to biological tissue, the combined hydrophilic and lipophilic properties of the surrounding phospholipids help the nanoparticles adhere to the tissue boundary and facilitate their penetration. Due to the enhanced compatibility between the nanoparticles and the tissue, a considerable amount of the drug is transferred to the tissue and retained within it. Upon exposure of the tissue to the nanoparticles, an initial burst of drug release occurs, lasting approximately 1 day. This initial burst of drug is due to the drug present between the nanoparticles as free drug molecules from the manufacturing process and / or due to the drug loosely adhering to the outer periphery of the nanoparticles. Drug release over the next few days is slower and more controlled. This release is controlled due to adhesion between the drug and the phospholipid boundary of the nanoparticles. This controlled release lasts for 5–7 days. Thus, from the exposure time, the first two phases together are completed 6–8 days from the exposure time. After the controlled release, a sustained release of the drug is observed over the next 18–22 days. When a drug-containing biodegradable polymer core is exposed to tissue, a sustained release profile occurs.

[0028] Therefore, the nanoparticles according to this disclosure enable controlled drug release, followed by sustained drug release. The nanoparticle boundary composition increases the transfer of the drug through tissue and the longer retention of the drug within the tissue. This novel nanoparticle-based drug delivery system of the present invention provides sustained drug release with a lower polymer load compared to conventional polymer matrix-based drug delivery systems. In the present invention, formulated nanoparticles exhibit a controlled release profile in the first few days and subsequently exhibit a sustained release profile. The controlled release profile results from the drug being encapsulated and accumulated near the inner periphery of the nanoparticle. The sustained release profile results from the drug being dispersed within the polymer core of the nanoparticle.

[0029] In some embodiments, the phospholipids used in the preparation of nanoparticles are functionalized with polyethylene glycol chains. These functionalized phospholipids or PEGylated phospholipids present in the nanoparticles further enhance tissue interactions due to the hydrophilic nature of the PEG chains. Furthermore, in other possible embodiments, other hydrophilic moiety-containing compounds can be used to functionalize the phospholipids. Such compounds include poly(carboxybetaine) (PCB), branched PEG, poly(sarcosine), polyglycerol, poly(hydroxyethyl-1-asparagine) (PHEA), poly(vinylpyrrolidone) (PVP), poly(N,N-dimethylacrylamide) (PDMA), and poly(N-acryloylmorpholine) (N-acryloyl Examples include, but are not limited to, morpholine (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 their functionality, the drug release behavior of nanoparticles containing functionalized phospholipids may have different effects in different embodiments.

[0030] According to another embodiment, nanoparticles prepared in accordance with this disclosure are applied to a target lesion alone or in combination with a substrate. The substrate is selected from at least polymer materials, nonpolymer materials, or a combination thereof. In addition, these nanoparticles can also be used in conjunction with other drug delivery methods such as pills, eye drops, nasal sprays, ointments, intravenous routes, intramuscular routes, intranasal routes, sublingual administration, transdermal, oral, vaginal, mucosal, or through drug pumps positioned in desired organs or conduits.

[0031] According to yet another embodiment, the nanoparticles prepared according to the present disclosure can be used in pure form, in pharmaceutical formulation form, in composition form, together with a polymeric or non-polymeric medium. Additionally, these nanoparticles can also be used in fluid form, as an aerosol, as a gel, as a powder, in a colloidal solution, in a curable mixture, in semi-solid form, or in solid form.

[0032] According to one embodiment of the present disclosure, the nanoparticles prepared according to the present disclosure are used in a coating composition coated on the surface, and the loading of the pharmaceutical in the coating is about 0.05 μg / mm 2 ~5.0 μg / mm 2 Preferably about 0.5 μg / mm 2 ~4.0 μg / mm 2 More preferably about 1.0 μg / mm 2 ~3.0 μg / mm 2 within the range of.

[0033] According to one embodiment of the present invention, the nanoparticles prepared according to the present invention are used in a coating composition coated on the surface, and the loading of the biodegradable polymer in the coating is about 0.1 μg / mm 2 ~10.0 μg / mm 2 Preferably about 0.5 μg / mm 2 ~7.0 μg / mm 2 More preferably about 1.0 μg / mm 2 ~5.0 μg / mm 2 within the range of.

[0034] According to one embodiment of the present disclosure, the nanoparticles prepared according to the present disclosure are used in a coating composition on the surface, and the amount of phospholipid-based molecules present in the coating is about 0.1 μg / mm 2 ~10.0 μg / mm 2 Preferably about 0.5 μg / mm 2 ~7.0 μg / mm 2 More preferably about 0.5 μg / mm 2 ~5.0 μg / mm 2 within the range of.

[0035] Lipid-based shells ensure better adhesion to biological tissues, and nano-sized particles more easily pass through cell boundaries in biological tissues, resulting in better drug delivery and lower drug loss due to leaching in the bloodstream. When applied, compositions containing such nanoparticles first provide controlled release with a slower release rate, then sustained release with a higher release rate, enhanced tissue absorption, longer tissue retention, and better therapeutic efficacy with smaller amounts of drug. In addition, due to the organic nature of the drug delivery system, these nanoparticles or nanoparticle-based coating compositions are easier to coat.

[0036] According to one embodiment, the drug delivery system of the present invention comprises a medical device that can be placed inside a lumen, tube, or conduit of a human or animal, selected from, but not limited to, arteries, veins, bile ducts, urinary tracts, gastrointestinal tracts, tracheobronchial trees, cerebral aqueducts, or the urogenital system. Specifically, the medical device can be used intravascularly in the 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, or neuroartery.

[0037] In yet another embodiment, the nanoparticles or nanoparticle composition according to the present invention are used as agents coated onto a medical device for drug delivery, the medical device being embedded in a lumen, tube or conduit selected from the bile duct, urinary tract, gastrointestinal tract, tracheobronchial tree, cerebral aqueduct, urogenital 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, neuroartery, or any vein.

[0038] Another aspect of the present disclosure provides a method for preparing nanoparticles by a solvent-antisolvent method that provides control and increase over a longer period of time of drug release, reduction of drug loss due to blood flow, and increased drug transfer and longer retention in biological tissue after application. The method comprises (1) preparing a solution A of a pharmaceutical 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) slowly adding solution A to solution B while solution B is being stirred by a magnetic stirrer to form a micelle core in the nanometer range at ambient temperature, 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, more preferably 1:25; and (4) using a mixture containing nano-sized micelle cores or nanoparticles for application or further processing. The organic solvents used in solutions A and B have different solubility or Hansen solubility parameters for the pharmaceutical and biodegradable polymer. The organic solvent used to prepare solution A has good solubility for the pharmaceutical and biodegradable polymer, while the other organic solvent used to prepare solution B has good solubility for lipids. However, for micelle formation, the pharmaceutical and biodegradable polymer should not have good solubility in the other organic solvent. In this disclosure, the other organic solvent is carefully selected to which the pharmaceutical is somewhat soluble, but this solubility is significantly lower than that of the pharmaceutical in the organic solvent. Therefore, when solution A is added to solution B with stirring, micelles are formed in which the inner core contains the biodegradable polymer and pharmaceutical solution in the organic solvent. The micelle shell is formed from lipids present in solution B. Initially, the pharmaceutical is uniformly dispersed in the micelles, but as the process progresses, a solubility gradient is formed due to the difference in solubility of the pharmaceutical between the inner core phase and the solution B phase outside the lipid boundary, causing some of the pharmaceutical molecules to migrate toward the lipid boundary. The adhesive forces between the pharmaceutical, biodegradable polymer, and phospholipids also play a role in the accumulation of the pharmaceutical near the inner periphery of the nanoparticles.Some of the pharmaceutical molecules present in this system also accumulate on the outer periphery of the micelles, and some of these are also trapped within the molecular structure of the lipids present at the boundary, specifically toward the interior. Thus, through careful selection of materials and process parameters, lipid polymer hybrid nanoparticles that provide the properties required at application are formed according to this disclosure.

[0039] According to one embodiment of the present invention, solution B is prepared using a plurality of phospholipids selected from natural phospholipids, synthetic phospholipids, or combinations thereof. Examples of phospholipids include lecithin, soy lecithin, egg yolk lecithin, synthetic phospholipids, PEGylated phospholipids, phosphatidylcholine, phosphatidic acid, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), and 1,2-dipalmitoyl-sn-glycero 1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (1,2-Dioleoyl-sn-glycero-3-phosph oethanolamine, DOPE), 1,2-Dimyristoyl-rac-glycero-3-phospho-rac-(l-glycerol, DMPG), 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phospho-(1'-rac-glycerol)(1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phospho-(1'-rac-g lycerol), DOPG), 1,2-distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol), DSPG), 1,2-dimyristoyl-sn-glycero-3-phosphocholine, DMPC, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (1,Examples include, but are not limited to, 2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-Dioleoyl-sn-Glycero-3-Phosphocholine (DPOC), 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-Dierucoyl-sn-glycero-3-phosphocholine (DEPC), or combinations thereof.

[0040] According to one embodiment of the present disclosure, the method further comprises the step of removing a nanoparticle-rich phase from a solvent mixture using a suitable unit operation such as centrifugation, gravity sedimentation, ultracentrifugation, electrophoresis, nanofiltration, chromatography, colloidal suspension, and selective precipitation.

[0041] According to one embodiment of the present disclosure, the method further comprises the step of adding an antifreeze agent to provide stability to the nanoparticles before freeze-drying. The antifreeze agent may be selected from, but is not limited to, polyols, sucrose, trehalose, lactose, mannitol, or a combination thereof.

[0042] According to one embodiment of the present invention, the method further includes the step of removing the solvent from the nanoparticle-rich phase to obtain nanoparticles in powder form by using a suitable unit operation such as freeze-thaw or evaporation. Upon application, the obtained nanoparticle powder is redispersed alone in a suitable solvent or in combination with a suitable surfactant.

[0043] By combining the different materials and process modifications described above, various configurations with diverse structural-property relationships can be obtained.

[0044] According to one embodiment of the present disclosure, a drug delivery system comprises a medical device coated with nanoparticles or a nanoparticle-based composition. The medical device may be selected from the group consisting of, but not limited to, stents, guidewires, catheters, shunts, balloons, heart valves, vena cava filters, vascular grafts, stent grafts, artificial bone, artificial spine, artificial hip joint, artificial rib, artificial skull, sutures, staples, anastomotics, bone pins, suture anchors, hemostatic barriers, vascular implants, tissue scaffolds, bone substitutes, and intraluminal devices.

[0045] According to another embodiment of the present disclosure, nanoparticles or nanoparticle compositions or formulations can be coated by spray coating, immersion coating, chemical vapor deposition, physical vapor deposition, plasma-assisted chemical vapor deposition, vapor deposition, sputtering deposition, ion plating, atmospheric pressure plasma deposition, sol-gel method, and 3D printing.

[0046] According to another embodiment of the present invention, the nanoparticles or nanoparticle-based compositions according to the present invention are disposed on a medical device made of a material made of a metal, a metal alloy, a nonmetal, a polymer, a polymer composite material, or a combination thereof. According to yet another embodiment of the present invention, the nanoparticles or nanoparticle-based compositions according to the present invention are used in a medical device which may be an implantable medical device, a temporary implantable device, or a non-implantable medical device.

[0047] Herein, refer to the accompanying drawings, which form part of this specification and illustrate specific embodiments in which the present invention can be put into practice. It should be understood that other embodiments may be used and structural modifications may be made without departing from the scope of the present invention.

[0048] Figure 1 illustrates a schematic diagram of an embodiment of nanoparticles (100) according to the present disclosure. The nanoparticles (100) comprise a biodegradable polymer, specifically a PLGA-based polymer core (108), which also comprises a pharmaceutical, 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, more specifically, the lipid-based shell structure is made of phospholipids (106) and PEGylated lipids (102). The majority of the pharmaceutical is accumulated inside the lipid shell structure and is not uniformly dispersed within the biodegradable polymer-based polymer core. These nanoparticles enable controlled pharmaceutical release, followed by sustained release with a higher release rate, better penetration into biological tissues, longer retention in tissues, and reduced leaching due to blood flow. [Examples]

[0049] Two examples are given below, describing a process for preparing such nanoparticles that can be used in the preparation of two compositions and coating compositions. Furthermore, a set of graphs illustrates the drug release profile, as well as the drug transfer and retention profiles, of such nanoparticle-containing compositions. In one graph, the drug transfer and retention profiles are compared with commercially available competing products. The following table shows the composition of the main components of the two compositions.

[0050] [Table 1] Table 1: Compositions for the preparation of sirolimus-containing nanoparticles containing PLGA as a core and natural phosphatidylcholine and PEGylated synthetic phospholipids as lipid shells

[0051] Example 1: The antiproliferative drug sirolimus is used as a pharmaceutical product encapsulated in a micelle core. Referring to the process described in the above embodiment for preparing drug nanocarriers, solution A is prepared using sirolimus and PLGA in acetonitrile. The concentration of sirolimus in the solution is 0.08% w / v, and the concentration of PLGA in the solution is 0.22% w / v. Another solution B is prepared using PEGylated synthetic phospholipids and natural phosphatidylcholine in methanol. The concentration of PEGylated synthetic phospholipids in the solution is 0.05% w / v, and the concentration of natural phosphatidylcholine in the solution is 0.05% w / v. While solution B is stirred at a speed of 500 RPM (revolutions per minute) for 1 hour, solution A is added to solution B at a rate of 1 mL / min to form a nano-sized micelle core. This process is carried out at ambient temperature and pressure.

[0052] Example 2: The antiproliferative drug sirolimus is used as a pharmaceutical product encapsulated in a micelle core. Referring to the process described in the above embodiment for preparing drug nanocarriers, solution A is prepared using sirolimus and PLGA in acetonitrile. The concentration of sirolimus in the solution is 0.08% w / v, and the concentration of PLGA in the solution is 0.22% w / v. Another solution B is prepared using PEGylated synthetic phospholipids and natural phosphatidylcholine in methanol. The concentration of PEGylated synthetic phospholipids in the solution is 0.075% w / v, and the concentration of natural phosphatidylcholine in the solution is 0.05% w / v. While solution B is stirred at a speed of 500 RPM (revolutions per minute) for 1 hour, solution A is added to solution B at a rate of 1 mL / min to form a nano-sized micelle core. This process is carried out at ambient temperature and pressure.

[0053] Furthermore, the release of pharmaceuticals from nanoparticles prepared according to the present invention and the embodiments described above was measured in a simulated physiological environment, and the results are depicted in Figure 2. For this measurement, 1.5–2.5 mg of such nanoparticle samples were placed in a 1.5 mL centrifugation vial containing 1.5 mL of release medium (pH 7.4). The vial was incubated at 37°C with gentle mixing at 200 rpm. The release medium was withdrawn from the vial at regular time intervals, and the amount of released pharmaceutical was measured by liquid chromatography. This measurement was performed for each sample over a period of 28 days. Figure 2 shows the pharmaceutical release profile over this 28-day period. After an initial burst of pharmaceutical on day 1 or day 2, controlled release was observed for the next 6 or 7 days. Subsequently, sustained release was observed over the next 3 weeks.

[0054] Furthermore, in a separate experimental setting, drug transfer and retention profiles (ex vivo) were studied, and the results are depicted in Figure 3. In this study, the balloon portion of a typical balloon catheter is coated with nanoparticles prepared according to the present invention and the embodiments described above. The coated balloon is navigated through a traceable pathway and inflated in biological tissue. The amount of drug loss during navigation, the amount of drug transferred to the biological tissue, and the amount of drug remaining on the balloon are measured. For drug retention measurements, a biological tissue-containing compartment is attached to a pulsating pump, and a biological medium passes through the compartment for one hour. The amount of drug adhering to or retained within the walls of the biological tissue, and the amount of drug leaching into the biological medium are measured at the end of the first hour after balloon inflation in the biological tissue, and again at the end of 24 hours. Figure 3 shows the amount of drug transferred during balloon inflation in the biological tissue, followed by the absorption and retention of the drug in the biological tissue at the end of the first hour and 24 hours after balloon inflation in the biological tissue. The graph clearly demonstrates the sustained availability of pharmaceuticals in biological tissues over a 24-hour period for nanoparticles prepared according to Example 1 and Example 2.

[0055] In addition, under the same experimental setup, drug transfer and retention profiles (ex vivo) were continuously studied for nanoparticles prepared according to Example 1 over a period of 72 hours from balloon inflation in biological tissue, and the results are depicted in Figure 4. Furthermore, similar studies were conducted for commercially available products from competitors (for comparison or as reference products). The graph in Figure 4 clearly shows sustained drug retention in biological tissue over a 72-hour period. Moreover, the graph also distinguishes the present invention from comparative commercially available products in terms of higher drug transfer and higher drug retention in biological tissue.

[0056] Figures 2, 3, and 4 clearly demonstrate that nanoparticles prepared according to embodiments of this disclosure are prepared using a biodegradable polymer core, with lipid molecules forming a boundary or shell. A large amount of drug is accumulated around the inner periphery of the shell structure formed by lipid molecules around such nanoparticles, while a small amount of drug is dispersed within the main polymer core. This drug distribution enables controlled and sustained drug release over a period of 3–4 weeks. A significant increase in drug transfer and retention in biological tissues is also demonstrated.

[0057] Nanoparticles prepared as described in the exemplary embodiments above, or compositions containing such nanoparticles, can be used directly in applications. Furthermore, such nanoparticles may undergo other process steps, such as the addition of additives to improve their properties, for example, antifreeze agents to enhance stability, or dry freezing (freeze-thawing) to form nanoparticles in powder form for storage and subsequent applications.

[0058] This disclosure mitigates the problem of high drug leakage by applying novel nanoparticle compositions. Furthermore, the nano-sized particles and lipid-based shell surfaces enable them to adhere to and penetrate biological tissues, allowing them to be administered not only intravenously but also via various routes, including subcutaneous, transdermal, oral, mucosal, sublingual, and ocular, in order to enable new application platforms for future drug delivery.

[0059] The above description includes specific details for explanatory purposes to provide an understanding of the disclosure. However, it will be apparent to those skilled in the art that the disclosure can be implemented without these details. Those skilled in the art will recognize that embodiments of the disclosure (one of which is described below) can be incorporated into several systems. Furthermore, the structures and processes shown in the figures are illustrative of exemplary embodiments of the disclosure and are intended to avoid obscuring the disclosure.

Claims

1. Nanoparticles for drug delivery, Nanoparticles for drug delivery comprising a peripheral primary excipient made of a phospholipid molecule, and an inner biodegradable polymer core which is a secondary excipient, wherein at least one pharmaceutical product is distributed across 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 comprising lactose, glycol, glycolide, lactide, caprolactone, or a combination thereof.

3. The nanoparticle according to claim 1, wherein the phospholipid molecule is selected from phospholipids, functionalized phospholipids, nonionic phospholipids, anionic phospholipids, cationic phospholipids, amphoteric phospholipids, or combinations thereof.

4. The nanoparticle according to claim 3, wherein the phospholipid molecule is an amphiphilic lipid selected from natural phospholipids, synthetic phospholipids, lipid-polyethylene glycol conjugates, cholesterol, PEG-modified phospholipids, cationic lipids, soybean phospholipids, egg 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 nanoparticle according to claim 1, wherein the ratio of the amount of biodegradable polymer to the amount of pharmaceutical is 90:10 to 10:

90.

7. The nanoparticle according to claim 1, wherein the ratio of the amount of phospholipid molecules to the amount of pharmaceutical product is 90:10 to 10:

90.

8. The nanoparticles according to claim 1, wherein the pharmaceutical product is selected from antithrombotic agents, antioxidants, anticoagulants, antiplatelet agents, thrombolytic agents, antiproliferative agents, anti-inflammatory agents, antimitotic agents, antirestenotic agents, smooth muscle cell inhibitors, antibiotics, fibrinolytic agents, immunosuppressants, anti-angiogenic agents, antirestenotic antitumor agents, anti-migration agents, antigenic substances, anticancer agents, antiproliferative agents, lipophilic drugs, antirestenotic agents, neurodestroying agents, quaternary ammonium salts, sodium channel blockers, anesthetics, amino acids, amines, calcium channel blockers, diuretics, vasoconstrictors, neurotransmitters, toxins, sclerosing agents, anti-nerve growth agents, aminosteroids, neurotoxins, or combinations thereof.

9. The nanoparticles according to claim 1, wherein the pharmaceutical product is selected from paclitaxel, sirolimus, rapamycin, everolimus, pimecrolimus, tacrolimus, zotarolimus, biolimus, or a combination thereof.

10. The coating of the aforementioned nanoparticle composition is approximately 0.05 μg / mm ２ ~5.0 μg / mm³ ２ Nanoparticles for drug delivery according to claim 1, comprising the pharmaceutical in an amount such that the pharmaceutical is contained within a range.

11. The coating of the aforementioned nanoparticle composition is approximately 0.1 μg / mm ２ ~10.0 μg / mm³ ２ Nanoparticles for drug delivery according to claim 1, comprising the biodegradable polymer in an amount such that the biodegradable polymer is contained within an amount within a certain range.

12. The coating of the aforementioned nanoparticle composition is 0.1 μg / mm ２ ~10.0 μg / mm³ ２ Nanoparticles for drug delivery according to claim 1, comprising the phospholipid molecule in an amount such that the phospholipid molecule is contained in an amount within the range of [amount].

13. A drug delivery system comprising a medical device coated with nanoparticles as described in claim 1, wherein the medical device is selected from balloons, stents, shunts, catheters, heart valves, guidewires, vena cava filters, vascular grafts, stent grafts, artificial bone, artificial spine, artificial hip joint, artificial rib, artificial skull, sutures, staples, anastomotic devices, bone pins, suture anchors, hemostatic barriers, vascular implants, tissue scaffolds, bone substitutes, and intraluminal devices.

14. Nanoparticles according to claim 1 for use as a drug to be coated onto a medical device for drug delivery, wherein the medical device is implanted into a lumen, tube or duct selected from the bile duct, urinary tract, gastrointestinal tract, tracheobronchial tree, cerebral aqueduct, urogenital 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, neuroartery, or any vein.

15. A method for preparing nanoparticles for drug delivery, The first solution A of a biodegradable polymer and a pharmaceutical in a first solvent, The process involves preparing a second solution B of at least one surfactant in a second solvent, This includes mixing the first solution into the second solution in an excess of the second solution while continuously stirring, A method wherein the second solvent has higher solubility with respect to the pharmaceutical product compared to the first solvent.

16. A method for preparing nanoparticles for drug delivery according to claim 13, wherein the first solvent and the second solvent are selected from acetonitrile, methyl chloride, ethylene dichloride, acetophenone, ethylene carbonate, 1,2-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. A method for preparing nanoparticles for drug delivery according to claim 13, wherein the first solvent is acetonitrile and the second solvent is methanol.

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

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

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

21. A method for preparing nanoparticles for drug delivery according to claim 13, further comprising the step of adding an antifreeze agent to provide stability to the nanoparticles.

22. A method for preparing nanoparticles for drug delivery according to claim 13, wherein the antifreeze agent is selected from polyols, sugars, sucrose, trehalose, lactose, mannitol, or a combination thereof.

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