JP2013545498A - Apparatus and method for loading a drug eluting medical device - Google Patents

Abstract

A method for loading a therapeutic substance or drug into a lumen space of a hollow wire having a plurality of side openings along its length forming a hollow drug eluting stent having a plurality of side drug delivery openings And an apparatus are disclosed. Loading the drug within the lumen space of the hollow stent includes a drug filling step in which the drug is mixed with a solvent or dispersion medium. The lumen space may be filled with a drug solution or suspension in a reverse filling process and / or a forward filling process. After the drug loading term, a solvent or dispersion medium extraction step is performed to extract the solvent or dispersion medium from within the lumen space, so that only the drug remains in the hollow stent. A stent cleaning step may be performed on the outer surface of the hollow stent.
[Selection] Figure 1

Description

  Embodiments herein relate to tubular implantable medical devices that release therapeutic substances, and to devices and methods for filling such medical instruments with therapeutic substances.

  Drug eluting implantable medical devices have become commonplace in recent years due to their ability to perform their main functions, such as structural support, as well as their ability to medically treat the area in which they are implanted. Has become popular. For example, drug eluting stents have been used to prevent recurrent stenosis in coronary arteries. Drug eluting stents can administer therapeutic agents such as anti-inflammatory compounds that block local invasion / activation of mononuclear cells, thereby preventing secretion of growth factors that induce VSMC proliferation and metastasis. Other potential anti-restenotic compounds include antiproliferative agents such as chemotherapeutic agents including sirolimus and paclitaxel. Other classes of agents such as antithrombogenic agents, antioxidants, platelet aggregation inhibitors and cytostatics have also been proposed for anti-restenosis applications.

  The drug eluting medical device is coated with a polymer material and then the polymer material is impregnated with the drug or combination of drugs. Once the medical device is implanted at the target location, single or multiple agents are released from the polymer for the treatment of local tissue. For biostable polymers, single or multiple agents are released by the process of diffusion through the polymer layer and / or for biodegradable polymers, as the polymer material degrades.

  Controlling the dissolution rate of the drug from the drug-impregnated polymer material is largely based on the nature of the polymer material. However, in some cases, at the end of the elution process, the remaining polymeric material is associated with adverse reactions with blood vessels, resulting in small but dangerous thrombi. Furthermore, the drug-impregnated polymer coating on the exposed surface of the medical device may delaminate during delivery or otherwise be damaged, which prevents the drug from reaching the target site. To do. Still further, in drug-impregnated polymer coatings, the amount of drug delivered by the polymer coating and the size of the medical device limits the amount of drug delivered. Control of the dissolution rate using a polymer coating is also difficult.

  Accordingly, there is a need to improve drug eluting medical devices that can deliver increased amounts of drug by the medical device and improve control of the drug elution rate, as well as methods for manufacturing such medical devices. Co-pending US patent application Ser. No. 12 / 500,359 filed Jul. 9, 2009, filed Sep. 20, 2009, each incorporated herein by reference in its entirety. U.S. Provisional Application No. 61 / 244,049, U.S. Provisional Application No. 61 / 244,050 filed September 20, 2009, and co-pending U.S. Patent Application No. 12 / 884,343. Discloses a method for producing a drug eluting stent having hollow struts. In some applications, such as coronary stents, the diameter of the lumen of hollow struts filled with drugs or therapeutic substances is very small, for example about 0.0015 inches, which makes it difficult to fill the cavity. ing. What is needed is an apparatus and method for loading a drug into the lumen of the hollow strut of a stent.

  Embodiments herein form a therapeutic substance within a lumen space of a hollow wire having a plurality of side openings along its length that forms a drug eluting hollow stent with a plurality of side drug delivery openings. Or relates to a method and apparatus for loading a medicament. Loading the drug into the lumen space of the hollow stent comprises a drug filling step in which the drug is mixed with a solvent or dispersion medium for flow into the lumen space of the hollow wire. The lumen space is filled with a drug solution or suspension in the reverse filling process through the drug delivery opening of the hollow stent and / or the drug solution or suspension in the forward filling process through the open end of the hollow stent. Filled with suspension. After the lumen space has been filled with the drug solution or suspension, a solvent or dispersion medium extraction step is performed, so that the lumen is primarily retained within the hollow stent, mainly the drug alone or in addition to the drug, one or more excipients. Extract the solvent or dispersion medium from within the space. A stent cleaning process is performed on the outer surface of the hollow stent.

  The foregoing and other features and advantages of the present invention will become apparent from the following description of the embodiments herein as illustrated in the accompanying drawings. The accompanying drawings, which are incorporated in and form a part of this specification, illustrate the principles of the invention and further help those skilled in the relevant arts to make and use the invention. This drawing is not to scale.

1 is a side view of a drug eluting stent formed from a hollow wire according to an embodiment herein. FIG. It is a cross-sectional view along line 2-2 in FIG. FIG. 3 is a cross-sectional view taken along line 3-3 at the end of the hollow wire in FIG. 1. Figure 5 is a dissolution rate chart for a hollow drug eluting stent. 2 is a flow chart showing the three main steps of a process for loading a hollow wire of the stent of FIG. 1 with a drug or therapeutic substance. It is a more detailed flowchart of the medicine filling process of FIG. It is a more detailed flowchart of the solvent extraction process of FIG. 6 is a more detailed flowchart of the stent cleaning process of FIG. 3 is a chart illustrating the effect of viscosity on drug loading. FIG. 7A illustrates a hexane-based dispersant homogenized to nano-sized drug particles, while FIG. 7B illustrates a hexane-based dispersant system that has not been homogenized. 1 is a schematic view of an apparatus for forward filling a drug eluting stent using high pressure gas. FIG. 1 is a schematic view of an apparatus for forward filling a drug eluting stent using high pressure gas. FIG. 1 is a schematic view of an apparatus for forward filling a drug eluting stent using disk rotation. FIG. 1 is a schematic view of an apparatus for forward filling a drug eluting stent using disk rotation. FIG. FIG. 6 is a schematic diagram of an apparatus for forward filling a plurality of straight hollow wires using high G centrifugal force. FIG. 6 is a schematic diagram of an apparatus for forward filling a plurality of straight hollow wires using high G centrifugal force. 1 is a schematic view of an apparatus for forward filling a drug eluting stent using high G centrifugal force. FIG. 1 is a schematic diagram of an apparatus for forward filling a drug eluting stent using supercritical CO ₂ to settle the drug within the drug eluting stent. FIG. 1 is a schematic view of an apparatus for forward filling a drug eluting stent using a syringe. FIG. 1 is a schematic diagram of an apparatus for forward filling a drug eluting stent using vibration. FIG. 1 is a cross-sectional view of a drug eluting stent having a biodegradable liner to assist in the forward filling of the stent. FIG. FIG. 19 is a schematic diagram of a method used to form the biodegradable liner of FIG. FIG. 19 is a schematic diagram of a method used to form the biodegradable liner of FIG. 1 is a cross-sectional view of a drug eluting stent having a biodegradable plug to assist in forward filling of the stent. FIG. 1 is a schematic view of an apparatus for reverse filling a drug eluting stent using a vacuum pump. FIG. 1 is a schematic view of an apparatus for reverse filling a drug eluting stent using a vacuum pump and pressure differential. FIG. 1 is a schematic view of an apparatus for reverse filling a drug eluting stent using a vacuum pump and pressure differential. FIG. 1 is a schematic view of an apparatus for reverse filling a drug eluting stent using vibration. FIG. 2 is a flow chart of a method for precipitating a drug within the hollow wire of a drug eluting stent, which method uses azeotrope formation. FIG. 26 is a cross-sectional view illustrating the method of FIG. 25 for illustrating the formation of an azeotrope in the hollow wire of a drug eluting stent. FIG. 26 is a cross-sectional view illustrating the method of FIG. 25 for illustrating the formation of an azeotrope in the hollow wire of a drug eluting stent. FIG. 26 is a cross-sectional view illustrating the method of FIG. 25 for illustrating the formation of an azeotrope in the hollow wire of a drug eluting stent. ₂ is a flow chart of a method for extracting solvent from a drug eluting stent, which method uses static supercritical CO ₂ extraction. ₂ is a flow chart of a method for extracting solvent from a drug eluting stent, which method uses dynamic supercritical CO ₂ extraction. 1 is a schematic diagram of an apparatus for extracting solvent from a drug eluting stent via cryovac sublimation. FIG. FIG. 32 is a schematic diagram of an apparatus for extracting solvent from a drug eluting stent, the method using the cryovac sublimation apparatus of FIG. FIG. 3 is an image of cleaning the outer surface of a stent via a histobrushed. FIG. 3 is an image of cleaning the outer surface of a stent via a histobrushed. 2 is a flow chart illustrating various combinations of the methods described herein for drug filling, solvent extraction, and stent cleaning. 2 is a flow chart illustrating various combinations of the methods described herein for drug filling, solvent extraction, and stent cleaning. 2 is a flow chart illustrating various combinations of the methods described herein for drug filling, solvent extraction, and stent cleaning.

  Particular embodiments of the present invention will now be described with reference to the drawings, wherein like reference numerals refer to elements that are identical or not functionally different. The terms “distal” and “proximal” are used in the following description with respect to position or orientation relative to the treating clinician. “Distal” or “distal” is a position in a direction away from or away from the clinician. “Proximal” and “proximal” are positions in a direction close to or toward the clinician.

  The following detailed description is exemplary only and is not intended to limit the invention or the application and uses of the invention. The drug eluting stents described herein are used in the treatment of blood vessels such as coronary arteries, carotid arteries, renal arteries, or any other body passages deemed useful. In particular, drug-eluting stents loaded with therapeutic substances by the methods described herein are applied to deployment at various treatment sites within a patient's body and are used for vascular stents (eg, coronary stents and cerebral stents). Peripheral vascular stents), urinary tract stents (eg, urethral and ureteral stents), biliary stents, tracheal stents, gastrointestinal stents and esophageal stents. Furthermore, there is no intention to be bound by any expressed or implied theory presented in the preceding technical field, background, brief summary or the following detailed description.

Hollow Wire Drug Eluting Stent One embodiment of a stent 100 for loading with a drug according to embodiments herein is shown in FIGS. In particular, the stent 100 is formed from a hollow wire 102 and may hereinafter be referred to as a hollow stent or a hollow core stent. The hollow wire 102 defines a lumen or lumen space 103, which is formed before or after being shaped into the desired stent pattern. In other words, as used herein, a “stent formed from a hollow wire” is a straight hollow wire shaped into a desired stent pattern, a solid wire having a core through it. To have a discontinuous lumen or lumen space, after the solid wire has been shaped into the desired stent pattern, its core is at least partially removed, or a tubular component formed in the desired stent pattern Stents constructed from any suitable manufacturing method that results in the tubular component having a lumen or lumen space extending continuously or discontinuously therethrough. As shown in FIG. 1, the hollow wire 102 is formed into a series of generally sinusoidal waveforms including a generally straight portion 106 joined by a bent portion or crown 108, passing through a central blood flow passage or lumen therethrough. A defining generally tubular stent 100 is formed. Selected longitudinally adjacent sinusoidal crowns 108 are joined, for example, by a weld 110 as shown in FIG. The method of loading a drug into a hollow stent according to embodiments herein is not limited to hollow stents having the pattern shown in FIG. Hollow stents formed in any pattern suitable for use as a stent are loaded with a drug by the methods disclosed herein. For example, but not limited to, US Pat. No. 4,800,082 to Gianturco, US Pat. No. 4 to Wiktor, each of which is incorporated herein by reference in its entirety. No. 5,886,062, U.S. Pat. No. 5,133,732 to Wiktor, U.S. Pat. No. 5,782,903 to Wiktor, U.S. Pat. No. 6,136,023 to Boyle. The hollow stent formed in the pattern disclosed in the specification, as well as in US Pat. No. 5,019,090 to Pinchuk, is loaded with a drug by the methods disclosed herein.

As shown in FIG. 12, the hollow wire 102 of the stent 100 allows a therapeutic substance or drug 112 to be deposited within the lumen or lumen space 103 of the hollow wire 102. The lumen 103 may extend continuously from the first end 114 to the second end 114 ′ of the hollow wire 102, or discontinuous only within the straight portion 106 and not the crown 108. Or may be discontinuous, such as on a portion of the straight portion 106 and crown 108. Although the hollow wire 102 is shown as having a generally circular cross section, the hollow wire 102 may be oval or rectangular in cross section. The hollow wire 102, with the inner diameter or lumen diameter I _D in the range of 0.0005 to 0.02, having a wall thickness W _T in the range of from 0.0004 to 0.005 inches. The hollow wire 102 forming the stent 100 is made of a metallic material that provides artificial radial support to the wall tissue, which includes stainless steel, nickel-titanium (Nitinol), nickel-cobalt alloys such as MP35N, cobalt -Chromium, tantalum, titanium, platinum, gold, silver, palladium, iridium, etc. are mentioned, but not limited thereto. Alternatively, the hollow wire 102 may be made from a hypotube, which is a very small diameter hollow metal tube of the type typically used in the manufacture of hypodermic needles, as is known in the art. Alternatively, the hollow wire 102 is formed from a non-metallic material such as a polymer material. This polymeric material is biodegradable or bioabsorbable so that the stent 100 is absorbed into the body after being used to restore lumen patency and / or to provide drug delivery. It is good.

  The hollow wire 102 further includes a drug delivery side opening or port 104 distributed along its length to allow the therapeutic substance or drug 112 to be released from the lumen 103. The side openings 104 are disposed only on the generally straight portion 106 of the stent 100, only on the crown 108 of the stent 100, or on both the generally straight portion 106 and the crown 108. The side openings 104 can be sized and shaped as desired to control the dissolution rate of the drug 112 from the hollow stent 100. In particular, the side opening 104 may be a slit or a hole having any suitable cross section including, but not limited to, a circular, elliptical, rectangular, or any polygonal cross section. Larger sized side openings 104 generally allow for faster elution rates, as well as smaller sized openings 104 generally result in slower elution rates. Further, the size and / or amount of the side opening 104 is varied along the hollow stent 100 to change the amount and / or rate of the drug 112 that is eluted from the stent 100 at different portions of the hollow stent 100. . For example, the side opening 104 is not limited, but may be 5 to 30 μm in width or diameter. The side openings 104 are provided only on the outside of the hollow stent 100 or on the lumen outer surface 116, or on the inside of the hollow stent 100 or on the lumen surface 118, as shown in FIG. Provided on both of these surfaces, or provided anywhere along the circumference of the wire 102.

  In various embodiments herein, a wide range of therapeutic agents are readily determined by those of ordinary skill in the art, and ultimately, for example, the condition being treated, the nature of the therapeutic agent itself, and the mode of administration are introduced. It is used as a dissolvable therapeutic substance or drug 112 contained in the lumen 103 of the hollow wire 102 in a pharmaceutically effective amount that depends on the tissue and the like. Furthermore, it will be appreciated by those skilled in the art that one or more therapeutic substances or agents are loaded into the hollow wire 102. The drug 112 supplied to the region of the stenosis affected area is of a type that dissolves the plaque substance that forms this stenosis, or is an antiplatelet-forming agent, antithrombotic agent, or antiproliferative agent. Examples of such agents include TPA, heparin, urokinase, or sirolimus. Of course, the stent 100 is used to deliver any suitable medicament, including one or more of the following agents, to the walls and interior of the body vessel, which are antithrombotic, antiproliferative, anti-inflammatory agents. , Anti-metastatic agents, agents that affect extracellular matrix formation and organization, antitumor agents, anti-mitotic agents, anesthetic agents, anticoagulants, vascular cell growth promoters, vascular cell growth inhibitors, cholesterol lowering agents Vasodilators, and agents that interfere with endogenous vasoactive mechanisms.

  According to embodiments herein, the hollow stent 100 is loaded or filled with a therapeutic substance or agent 112 prior to implantation into the body. As shown in the cross-sectional view of FIG. 3 along line 3-3 of FIG. 1, the open end 114, 114 ′ of the wire 102 is either before or after the drug is loaded into the passage 103. It may be closed or sealed. Once placed in the body at the desired location, the hollow stent 100 is for permanent or temporary implantation within the body cavity so that the therapeutic substance 112 elutes from the lumen 103 through the side opening 104. Be expanded.

  FIG. 4 shows a dissolution rate chart for a drug-eluting hollow stent. This chart shows the percentage of therapeutic substance eluted as a function of time. The lines labeled 1 and 2 represent commercially available drug eluting stents with therapeutic substances placed in a polymer on the surface of the stent that produced the desired clinical efficacy data. Lines labeled 3, 4, 5, and 6 are tested with a stent having a lumen filled with a therapeutic material according to the method described herein where no polymer is present on the surface of the stent. is there. In particular, for the lines marked 3, 4, 5, and 6, the lumen of the hollow stent is used for an azeotrope filling process as described in more detail herein, followed by solvent extraction. Filled using vacuum drying and stent cleaning via histobrush. The lines marked 3 and 4 are tests using a hollow stent with one 6 μm hole on each strut, and the lines marked 5 and 6 have three 10 μm holes on each strut. It is a test using the hollow stent which has. In particular, the hollow stent used in the tests marked by lines 3 and 5 is filled with a solution of sirolimus and tetrahydrofuran, followed by the addition of hexane to precipitate sirolimus and then the solvent is extracted from the hollow stent lumen. And the outside of the stent was cleaned. The hollow stent used in the tests marked by lines 4 and 6 is filled with a solution of sirolimus, tetrahydrofuran and excipients, followed by the addition of hexane to precipitate sirolimus, and then the solvent and non-solvent Extracted from the hollow stent lumen and the outside of the stent was washed. The dissolution rate chart shows that controlled release is achieved through a hollow stent filled with therapeutic substance and a hollow stent filled with therapeutic substance plus excipients, and that the hollow stent is It shows that an elution curve similar to that of a drug eluting stent having a therapeutic substance disposed in a polymer on the surface is achieved. Hollow-filled stents with a dissolution curve similar to drug-polymer coated stents are expected to be safer without polymer coating while having similar clinical effectiveness. Furthermore, the dissolution rate chart shows that various dissolution curves are possible from hollow stents filled with therapeutic substances or hollow stents filled with excipients in addition to therapeutic substances.

Overview of Stent Filling Process A general method for loading a drug into the lumen 103 of the hollow stent 100 according to embodiments herein is shown in FIG. 5 including drug filling 520, solvent extraction 538, and stent cleaning 546. Yes. Particularly in the drug filling step 520, the therapeutic substance 112 is typically mixed with a solvent or dispersion medium / dispersant for loading into the lumen 103 of the hollow wire 102. Furthermore, the therapeutic substance 112 is mixed with excipients to aid dissolution in addition to the solvent or dispersion medium / dispersant for loading into the lumen 103 of the hollow wire 102. Hereinafter, the term “pharmaceutical composition” is used to refer generally to therapeutic substances, solvents or dispersion media, and optional excipients / additives / regulators added to them. After the lumen 103 of the hollow stent 100 is filled with the pharmaceutical composition, a solvent / dispersion medium extraction step 538 is performed to extract the solvent or dispersion medium from within the lumen space, thereby being eluted into the body. Only the therapeutic substance 112, or the therapeutic substance 112 and one or more excipients remain in the hollow stent 100. Finally, a stent cleaning step 546 is performed on the hollow stent 100 such that the outer surface of the hollow stent 100 is substantially free of therapeutic agent 112 except where the side openings 104 are present. Depending on the apparatus and method used herein, one or more of the steps of drug filling, solvent / dispersion medium extraction, and / or stent cleaning may be performed before or after the hollow wire 102 is formed into the stent 100. May be implemented. For example, some of the processes described below require the hollow wire 102 to be straight in order to load a therapeutic substance into the lumen space, while other processes described below are It can also be used to fill the hollow wire 102 after the 102 has been formed into the desired sinusoidal, helical, or other stent shape.

Drug Filling Process FIG. 5A shows a more detailed flowchart of the drug filling process 520. In particular, according to embodiments herein, the pharmaceutical composition is loaded into the hollow wire 102 by either the forward filling method 522 or the reverse filling method 536. The forward-filling method involves the drug delivery opening 104 being substantially blocked or occluded in several ways to prevent leakage therethrough and simultaneously through one or both of the open ends 114, 114 ′. Filling the hollow wire 102. The reverse filling method includes filling the hollow wire 102 through a plurality of side openings 104. In some reverse filling methods, the hollow wire 102 is also filled via one or both of its open ends 114, 114 ′ in addition to the side openings 104. Therefore, the reverse filling method utilizes the drug delivery port 104 as an access point for filling the lumen space of the hollow stent 100. By using a plurality of access points spaced along the length of the hollow wire 102, the drug composition is more uniformly introduced into the lumen 103, thereby filling the entire length of the lumen 103 with the drug composition. Further, if a partial blockage of the lumen 103 or side opening 104 occurs during the reverse filling process, the filling of the remaining portion of the lumen 103 is not dependent on the filling of the lumen space from end to end. Since the filling continues through the remaining side opening 104, there is no significant influence.

  As described above, in some stent configurations, the lumen 103 is discontinuous along the length of the hollow wire 102. For example, to make hollow stent 100 more radiopaque, as described in co-pending US patent application Ser. No. 12 / 884,343, previously incorporated herein by reference, The core of the hollow wire 102 is on the left in the crown of the hollow stent 100. It is not possible to fill the drug form through the lumen 103 of the hollow wire 102 from one and / or the other open end 114, 114 'in a forward filling manner due to the discontinuous nature of the lumen. Thus, the filling in the reverse filling method is formed from a hollow wire with a discontinuous lumen, so that the drug form simultaneously fills the lumens separated via the drug delivery side openings or ports 104 simultaneously. This is particularly advantageous for stents.

  As shown in FIG. 5A, regardless of whether forward filling method 522 or reverse filling method 536 is utilized, therapeutic substance 112 is loaded as solution 524 before being loaded into hollow wire 102. Mixed with solvent or solvent mixture or mixed with dispersion medium as slurry / suspension 530. Solution 524 is a homogeneous mixture in which therapeutic substance 112 is dissolved in a solvent or solvent mixture. In one embodiment, the solution 524 contains a high volume solvent 528 that is an organic solvent having a high volume that dissolves the therapeutic substance 112. High volume solvent as used herein is defined as the ability to dissolve therapeutic substance 112 at a concentration of more than 500 mg substance per milliliter of solvent. Examples of high volume drug dissolution solvents for sirolimus and similar materials include, but are not limited to, tetrahydrofuran (THF), dichloromethane (DCM), chloroform, and dimethyl sulfoxide (DMSO). In addition to the high volume solvent, the solution 524 may contain an excipient 526 to aid drug elution. In one embodiment, excipient 526 includes sorbitan fatty acid esters such as sorbitan monooleate and sorbitan monolaurate, polysorbates such as polysorbate 20, polysorbate 60, and polysorbate 80, 2-hydroxypropyl-β-cyclodextrin and 2, Surfactants such as, but not limited to, cyclodextrins such as 6-di-O-methyl-β-cyclodextrin, sodium dodecyl sulfate, octyl flucoside, and low molecular weight poly (ethylene glycol) s. In another embodiment, excipient 526 may be a hydrophilic agent such as, but not limited to, salts such as sodium chloride and other substances such as urea, citric acid, and ascorbic acid. In yet another embodiment, excipient 526 may be a stabilizer such as butylated hydroxytoluene (BHT), but is not limited thereto. Depending on the desired drug loading, a low dose solvent is also selected for its reduced solubility of the therapeutic substance 112. Low volume is typically defined as the ability to dissolve therapeutic substance 112 at a concentration of 500 mg or less of drug per milliliter of solvent. Examples of low volume drug dissolution solvents for sirolimus and similar materials include solvent mixtures such as methanol, ethanol, propanol, acetonitrile, ethyl lactate, acetone, and tetrahydrofuran / water (9: 1 weight ratio) It is not limited to this. After the solution 524 is loaded into the hollow stent 100, the therapeutic substance 112 is precipitated from the solution, eg, converted to a solid phase, with the remaining solvent and, if present, the majority of any non-solvent present mostly in the hollow wire. By being extracted from the lumen space of 102, mainly the therapeutic substance 112 alone or the therapeutic substance 112 and one or more excipients 526 remain and are eluted in the body.

  In the slurry / suspension form 530, the therapeutic substance 112 is not dissolved, but rather dispersed as solid particulates in a dispersion medium, which is a continuous in liquid form in which the solid particulates are dispersed. Refers to the medium. The use of a suspension eliminates the need to precipitate the therapeutic substance 112 from a solvent as is the case with solutions, because when mixed together, the therapeutic substance 112 remains solid in the dispersion medium. To do. Examples of dispersion media that are unable to dissolve the therapeutic substance 112 depend on the properties of the therapeutic substance 112. For example, suitable dispersion media that do not dissolve sirolimus include, but are not limited to, water, hexane, and other simple alkanes, such as C5-C10. In order to aid suspension and stabilization, to further ensure the dispersion of the drug throughout the suspension and / or to increase the surface lubricity of the drug particles, certain excipients, suspending agents, Surfactants and / or other additives / conditioning agents are added to the drug slurry / suspension. Thus, the surfactant generally prevents the therapeutic substance 112 from floating at the top of the dispersion medium or settling to the bottom of the dispersion medium. Examples of surfactants include sorbitan fatty acid esters such as sorbitan monooleate and sorbitan monolaurate, polysorbates such as polysorbate 20, polysorbate 60, and polysorbate 80, 2-hydroxypropyl-β-cyclodextrin and 2,6-di- Examples include, but are not limited to, cyclodextrins such as -O-methyl-β-cyclodextrin. In one embodiment, the targeted amount of therapeutic substance 112 is suspended in the dispersion medium and the appropriate additive / conditioning agent is added at 0.001-10% by weight based on the total drug form. The In addition, excipients such as urea or 2,6-di-O-methyl-β-cyclodextrin may be added to the slurry / suspension 530 to aid drug elution.

  One advantage of using the slurry / suspension 530 as opposed to the solution 524 is that the opening 104 is blocked with a dry drug solution because the therapeutic substance 112 is already in solid form in the dispersion medium. There is no end to it. In particular, when the hollow stent 100 is filled with the solution 524, the fraction of the solution 524 in the lumen 103 may flow out or leak through the opening 104 to the outer surface of the hollow stent 100. This leakage occurs due to surface tension / capillary action or outflow from the migration process. The solution 524 on the outer surface of the stent dries faster than the solution 524 contained in the lumen 103 of the hollow wire 102. The substantial effect is a cast layer of drug that can occlude the side openings 104, which further makes solvent extraction more difficult. Residual solvent trapped in the lumen space has a negative impact on biocompatibility and causes complications in predicting effective drug loading. By utilizing the slurry / suspension 530 rather than the solution 524, the drug and dispersion medium remain separated and no drug casting layer is formed.

  When suspended in the slurry / suspension 530, the particle size of the therapeutic substance 112 means how long the particles remain suspended prior to precipitation and the suspension viscosity and suspension stability. Affects a variety of factors, including In one embodiment, labeled standard slurry / suspension 532, drug particle diameters ranging from 1 μm to 50 μm are utilized. The therapeutic substance 112 is pelletized prior to filling the lumen of the hollow wire. Control of the particle size distribution or pelleting of the drug occurs via various routes including mechanical means such as a grinding process and non-mechanical means such as a precipitation process. When the forward filling method is used, drug particles can pass through the end of the pellet because it is smaller than the lumen space of the stent strut. If reverse filling is used, the pellets are smaller than the stent strut openings 104 so that drug particles can pass through them. The pelletized drug in slurry / suspension 532 is loaded into the lumen of the stent by vibration / sonication, pressure filling, or any other suitable technique described herein. Pelletizing the therapeutic substance results in approximately uniform dimensions of the particles for improved consistency in administration and easier loading.

  In another embodiment, labeled small particles and nanoparticle slurries / suspensions 534, drug particle sizes ranging from 1 nanometer to 1000 nanometers are used. Particles in a particle size range of less than 100 nanometers are commonly referred to as nanoparticles. Small particle size drugs, and in particular nanoparticles, are attractive candidates for use in drug delivery as smaller particles that allow more effective loading of the drug into the stent. In particular, the drug particles are much smaller than the lumen space 103 and the side openings 104. Thus, in the forward filling method, small particles of the drug can be easily transferred to the lumen 103 of the hollow wire 102 via the open ends 114, 114 'of the stent. In the reverse filling method, the drug can easily cross the side opening 104 and fill the lumen 103 of the hollow wire 102.

  In addition to the efficiency described above, small and nanoparticulate drugs have advantages in drug delivery. Specifically, as the particle size is reduced, the drug stability is increased in situ. This advantage becomes even more apparent when the particle size is reduced from μm sized particles to nm diameter particles. Nanometer range particles also have the ability to diffuse as a whole particle from the stent to the tissue by using a concentration gradient that exists between the drug source and the target tissue. As a result, the speed of transport from the lumen of the stent 100 to the tissue is increased.

Small and nanoparticulate drugs are produced by any suitable method including, but not limited to, homogenization / microfluidic processing, precipitation, supercritical CO ₂ , ball milling, and rod milling. When producing a slurry / suspension with nanoparticles, it is important that the viscosity of the slurry / suspension is low enough to allow it to be transported across the opening 104 to the stent. FIG. 6 is a chart showing how drug loading is affected when the particle size is well matched below the size of the side opening 104 and the viscosity is changed. In this example, the side opening 104 size is 6 μm, the particle size is 300 nm, and the percent fill weight is defined as the ratio of the amount of drug loaded into the stent to the theoretical maximum amount. In one embodiment, small and nanoparticulate drugs are produced through a multi-pass homogenization process using a surfactant stabilized dispersant such as hexane or water. For example, hexane-based dispersants are produced by mixing hexane with 1% (v / v) SPAN® 80, and water-based dispersants are water containing 1% (v / v) Tween ( (Registered trademark) 80 and mixed. The therapeutic substance 112 is added to the slurry / suspension, which is 10% (v / v). This mixture is sonicated for a predetermined time, eg, 1-60 minutes, and the ingredients are mixed prior to homogenization. A microfluidic homogenizer or microfluidic processor is then used for the homogenization process at a setting of 28000 psi and 860 passes. FIG. 7A shows a hexane-based dispersant (5% (v / v)) homogenized into nanoparticulate drug particles, while FIG. 7B shows a non-homogenized hexane-based dispersant system (5% (v / v)). v)). After homogenization, dynamic light scattering (DLS) and / or SEM is used to measure the particle distribution that confirms that the particles are homogeneous. The slurry / suspension is then diluted to the desired slurry / suspension volume fraction and the stent is suspended by vibration / sonication, pressure filling, or any other suitable technique described herein. Loaded into the lumen.

Drug Filling: Forward Filling High Pressure Gas Embodiment FIGS. 8 and 9 are schematic views of an apparatus 860 for loading a lumen of a hollow stent with a therapeutic substance in a forward filling method according to embodiments herein. Apparatus 860 is a high pressure loading cylinder that is used to take advantage of established capillary column loading techniques, modified for slurry / suspension formulations and / or loading technique (s). In particular, the device 860 includes a pressure source 862, a three-way valve 864 having a pressure vent 866, a pressure gauge 868, a high pressure loading unit or cylinder 870, and tubing 872 connecting these items together. As shown in FIG. 9, the loading unit 870 includes a body 878, a cap lock 880, a vial or container 882 for holding a suspension of therapeutic substance and dispersion medium, a side port 886 to which tubing 872 is attached, And a nut 884. As shown in FIG. 8, the loading unit 870 further includes a cap seal 888. Pressurized gas enters the loading unit 870 via tubing 872 and pressurizes the therapeutic substance suspension held in the vial 882. On the exit side of the loading unit 870, fluid is received at the first end of the hollow stent 100 such that the lumen space of the hollow wire 102 is in fluid communication with the vial 882 for receiving a therapeutic substance suspension from the vial. There is a high-pressure fitting 874 for mechanical connection. An end fitting 876 having a frit disposed therein is connected to the second end of the hollow stent 100 to prevent release of the therapeutic substance from the hollow stent 100. The frit pore size ranges from 0.2 μm to 20 μm, depending on the slurry / suspension density of the therapeutic substance and the particle size of the therapeutic substance. The above-described portions of the device 860, except for the hollow stent 100, are available from Western Fluids Engineering + MFG, LLC of Wildermar, CA.

  In operation, vial 882 is filled with a slurry / suspension containing therapeutic substance 112. In one embodiment, a fixed mass of drug therapeutic substance 112 is added to vial 882, followed by the dispersion medium, such that the drug concentration per unit volume is in the range of 0.5 mg / ml to 50 mg / ml. Thus, the vial 882 is filled with the slurry / suspension. A first end of the hollow stent 100 is connected to a high pressure loading unit 870 using a high pressure connection 874. In one embodiment, a microstir bar (not shown) may be added to the vial 882, and after the vial 882 is placed inside the loading unit 870 and sealed therein, the high pressure loading unit 870 Located at the top of the magnetic stir plate. Inert high pressure gas enters the loading unit 870 through the tubing 872 through the side port 886, pushes the slurry / suspension of the therapeutic substance 112 out of the vial 882, exits the nut 884, passes through the high pressure fitting 874, and is a hollow stent. The wire 102 forming 100 is directed to the lumen space. The pressurized drug slurry / suspension passes through the lumen space of the hollow stent 100 and solid particles of the therapeutic substance 112 are captured by the frit of the end fitting 876. In particular, so that the solid drug or therapeutic substance 112 is held or captured behind or upstream of the frit, while the dispersion medium can be pushed through or through the frit, ie downstream thereof. The size of the frit hole is selected, thereby filling / loading the lumen space of the hollow stent 100 from its second end to its first end.

  The initial loading pressure ranges from 100 to 10,000 psi, depending on the desired loading rate, the drug concentration in the slurry / suspension, and the ratio between the inner diameter of the hollow wire 102 and the drug particle size. In one embodiment, a 6 inch long hollow tube having an inner diameter of 0.004 ″ was filled with sirolimus having a median diameter of approximately 5 μm in diameter. This sirolimus was suspended in hexane-isopropanol. A 90:10 hexane: isopropanol (v / v) mixture was obtained and a 0.5 μm frit was used at the end fitting 876. The loading cylinder 870 was pressurized to 500 psi and left in that state for approximately 55 minutes. The cylinder 870 was then depressurized to ambient pressure and then repressurized to 600 psi, gradually increasing pressure from 600 to 900 psi over an additional 20 minutes, and then increasing to 1500 psi over 30 minutes with an increase of 100 psi. The hollow tube of 4 inches or more was filled with sirolimus. In form, the diameter of the therapeutic agent particles is selected in the range of 1 μm to 50 μm In one embodiment, uniform loading of the hollow stent is such that a periodic pulsatile pressure process or cycle is used. By successively decreasing the loading pressure to or near ambient pressure, i.e. by decreasing the loading unit 870 to or near ambient pressure and subsequently increasing the loading pressure, That is, it is aided by repressurizing the loading unit 870 to the loading pressure, hi another embodiment, the uniform loading is such that the hollow stent 100 moves from the furthest second end of the loading unit 870 to the first end. At the same time as the loading is initiated, the loading pressure is assisted by gradually raising or increasing the pressure, hi another embodiment, the vacuum is low pressure or downstream of the frit. Applied to the system on the side to assist in pumping the slurry / suspension through the lumen space of the hollow wire 102 toward the frit, as well as assisting in pushing / pulling the dispersion medium through the frit.

  In one embodiment, the high pressure gas pushes the slurry / suspension through the lumen space of the hollow wire 102 to minimize slurry / suspension leakage and the drug delivery opening 104 of the hollow stent 100. Are temporarily blocked or occluded during the forward filling process. In addition, as shown in FIG. 8, high pressure gas for forward filling the lumen space of the hollow wire may be used to fill the previously shaped hollow stent 100, or subsequently hollow. It may be used to fill a straight hollow wire or tube 102 that is shaped into the stent 100.

Drug Filling: Forward Filling Embodiment via Centrifugal Force FIGS. 10 and 11 illustrate an apparatus 1090 and method for filling the lumen of a hollow stent with a therapeutic substance using centrifugal force according to another embodiment herein. FIG. Apparatus 1090 includes a rotatable disk 1092 and a central fill tube 1094. Filling tube 1094 is filled with dry therapeutic substance 112. Alternatively, the fill tube 1094 is filled with a solution or slurry / suspension containing a therapeutic substance. The central filling tube 1094 is connected to the lumen 103 of the hollow stent 100. As can be seen, a plurality of hollow stents 100 are connected to the central fill tube 1094. As indicated by the arrow, the disk 1092 is rotated at a high speed, thereby pushing the therapeutic substance radially from the central filling tube 1094 into the lumen 103 of the hollow stent 100.

  12 and 13 are schematic views of another embodiment using centrifugal force to fill a plurality of hollow stent lumens with a therapeutic substance. The loading device 1291 includes two upper and lower segments 1297A, 1297B that combine along a longitudinally extending surface to form a cylindrical structure. As shown in the side view of FIG. 12, segments 1297A, 1297B are approximately equal halves of cylindrical loading device 1291. FIG. 13 shows a top view of segment 1297A. The loading device 1291 is formed from polycarbonate, stainless steel, and similar materials and is designed to hold an array or a plurality of linear hollow wires 102 to be filled with the therapeutic substance 112. The straight hollow wire 102 is disposed in a loading compartment 1280 having a plurality of grooves 1295 formed on the flat surface of each segment 1297A, 1297B. Groove 1295 is precisely machined to a size and shape sufficient to securely accommodate a plurality of straight hollow wires 102 so that the wire is securely held in place during filling. The bisected design of the loading device 1291 facilitates loading of the stent to be filled. The device 1291 comprises a wedge-shaped reservoir 1293 for containing a drug slurry / suspension loaded into the lumen of the straight hollow wire 102. The loading partition chamber 1280 is disposed downstream of the liquid storage tank 1293 and is in fluid communication with the liquid storage tank 1293. The device 1291 further comprises a filtration restraint plate 1299 that allows the drug to be retained upstream while facilitating the flow of the dispersion medium therethrough. In one embodiment, the filtration restraint plate is a sintered glass insert that constrains the drug within the lumen of the straight hollow wire 102 while allowing fluid to flow therethrough. A drain chamber 1296 downstream of the filtration restraint plate 1299 captures and contains the dispersion medium flowing through the device 1291 during the filling process, as described in more detail herein. A rubber gasket 1298 seals the device 1291 so that the segments 1297A, 1297B are closed together and no slurry / suspension leaks from the device during the filling process. Further, a screw cap 1289 with a rubber septum (not shown) and a base ring 1287 hold the segments 1297A, 1297B together firmly.

  The filling process begins by placing a plurality of straight hollow wires 102 or tube blanks in the groove 1295 in one half of the loading device 1291. The straight hollow wire 102 is then sandwiched between the segments 1297A, 1297B of the device 1291 so that the loading device 1291 is closed and the base ring 1287 and cap 1289 are screwed into a position to seal the unit. Conveniently, a compliant rubber coating is applied to one or more surfaces of the loading compartment 1280 to minimize leakage so that when the loading device 1291 is closed, the rubber coating can be Leakage through the drug delivery opening 104 formed therein is sealed or prevented. Once sealed, the reservoir 1293 is filled with the slurry / suspension containing the therapeutic substance by injecting the slurry / suspension through the rubber septum of the cap 1289. The device 1291 is then placed in a standard centrifuge rotor, and a high G centrifugal force drives the drug slurry / suspension into the lumen of the hollow wire 102 and volume the drug particles in a fast and efficient manner. Fill with. Centrifugal rotor speed and time parameters depend on various factors including slurry / suspension composition, slurry / suspension viscosity, drug particle size or diameter, coefficient of friction, and desired degree of packing. To do. Centrifugal force acts along the entire length of the hollow tube 102 and the slurry / suspension moves through the hollow wire 102. The slurry / suspension dispersion medium flows through or through the filtration restraint plate 1299 and is contained in the drainage chamber 1296, while the slurry / suspension therapeutic material is contained in the hollow wire 102. Remains in the lumen. After filtration, the straight hollow wire 102 is shaped into the desired stent shape or configuration.

  Although described above with respect to the slurry / suspension, the device 1291 may also be utilized to fill the lumen space of the hollow wire 102 with a solution of a therapeutic substance. When used with a solution, the drain chamber 1296 may be omitted and the restraint plate 1299 need not allow the passage of liquid therethrough, but rather functions to block the passage of the solution, thereby , Allowing the hollow wire 102 to fill the lumen space. After filtration, the lumen of the straight hollow wire is filled with the drug solution and the solvent must be subsequently extracted therefrom by any suitable method described herein. In general, filling a hollow wire with a solution requires a shorter duration and a lower speed of the centrifuge rotor.

  Referring to FIG. 14, an embodiment for loading a hollow stent via high G centrifugal force is shown. Similar to loading device 1291, loading device 1491 is generally cylindrical and combines upper and lower longitudinal segments that combine along a longitudinally extending surface to form a generally cylindrical structure (not shown). Prepare. Apparatus 1491 includes a wedge-shaped reservoir 1493 for containing a drug slurry / suspension, a constraining plate or sintered glass insert 1499 that facilitates the flow of the dispersion medium therethrough as well as the drug upstream thereof, a filling process. A drainage chamber 1496 for trapping and containing the dispersion medium flowing through the device 1491 therein, a rubber gasket 1498 for sealing the device 1491, and a cap 1489 and a base ring 1487 for closing the device 1491 are provided. However, rather than having a groove for receiving a straight hollow wire, the device 1491 includes a cylindrical loading compartment 1480 formed therein for receiving a single hollow stent 100. Cylindrical loading compartment 1480 is a specific diameter and length to accommodate the hollow stent. In one embodiment, a rod or core (not shown) may be inserted through the hollow stent during the drug filling process to securely hold the hollow stent in place. The filling process in which high G centrifugal forces are applied throughout the length of the stent to drive the drug slurry / suspension or solution therein into the lumen space of the stent is similar to that described above with respect to device 1291. It is.

Drug Filling: Forward Filling Embodiment Using Supercritical CO ₂ for Drug Precipitation FIG. 15 illustrates an apparatus 1585 and method for filling a hollow stent lumen with a therapeutic drug according to another embodiment herein. FIG. Apparatus 1585 includes a pressure chamber 1583 (shown in phantom), a supply 1581 for supercritical carbon dioxide (SCCO ₂ ), a supply line 1579 for introducing a solution of a therapeutic substance in a solvent such as ethanol, And a recirculation system 1577. Supercritical carbon dioxide is carbon dioxide whose critical temperature is higher than the critical temperature of carbon dioxide (31.1 ° C.) and whose critical pressure is higher than the critical pressure of carbon dioxide (72.9 atm / 7.39 MPa). A hollow stent 100 is placed in the pressure chamber 1583. Supercritical carbon dioxide enters the lumen of the hollow stent 100 through the opening 104 as the solution is pushed through the lumen of the hollow stent 100. Supercritical carbon dioxide interacts with the solution to precipitate the therapeutic material, so that the therapeutic material remains within the lumen of the hollow stent 100 and a solvent such as ethanol continues to be recirculated through the recirculation system 1577. In this embodiment, the SCCO ₂ properties are thus utilized as part of the drug loading process to precipitate the therapeutic substance from solution. A filter 1573 may be positioned on the outlet side of the pressure chamber to capture any therapeutic substance pushed through the hollow stent 100. The therapeutic substance supply unit 1575 is connected to the recirculation system 1577 so that the therapeutic substance and the solvent are mixed and introduced into the pressure chamber 1583 through the supply line 1579 as a solution.

  In one embodiment, supercritical carbon dioxide for forward filling the stent may be used to fill a hollow stent 100 shaped as shown in FIG. May be used to fill a straight hollow tube 102 shaped as follows.

Drug Filling: Forward Filling Syringe Embodiment FIG. 16 is a schematic diagram of an apparatus 1671 and method for filling a lumen of a hollow stent with a therapeutic drug according to another embodiment herein. The device 1671 includes a syringe luer connector 1669 and a small diameter tube joint 1667 for coupling the syringe luer connector to the hollow stent 100. A syringe (not shown) injects a therapeutic substance into the lumen of the hollow stent 100 through a syringe luer connector and a small diameter tube joint. This therapeutic substance is mixed with a solvent or dispersion medium to form a solution or slurry / suspension, respectively. Examples of solvents or dispersion media include ethanol, chloroform, acetone, tetrahydrofuran, dimethyl sulfoxide, ethyl lactate, isopropyl alcohol, acetonitrile, water, and others that may be known to those skilled in the art, and / or herein. The thing described in is mentioned. In one embodiment, the drug delivery opening 104 of the hollow stent 100 is blocked or occluded to minimize leakage as the syringe injects therapeutic material and solvent / dispersion medium through the lumen of the stent. Further, a syringe for forward filling the stent may be used to fill the hollow stent 100 as shown in FIG. 16, or a straight hollow tube 102 subsequently formed into the hollow stent 100. May be used to fill.

Drug Filling: Forward Filling Embodiment Using Vibration Forward packing of the stent is assisted by vibration. The vibration is applied directly or through a liquid bath. The vibration assists in moving the therapeutic substance through the lumen of the stent. FIG. 17 shows a schematic representation of one embodiment that uses vibration to assist in drug loading. The hollow stent 100 is placed in a container 1765 filled with a liquid 1762 such as water. A hopper 1761 containing the drug form is connected to one end of the hollow stent 100 and the opposite end of the stent is closed. The pharmaceutical form is a solution or slurry / suspension containing a therapeutic substance or a dry therapeutic substance. A pump 1759 is connected to the hopper 1761 to push the drug form through the lumen 103 of the hollow stent 100. An sonicator 1757 or similar vibration generator is placed in the liquid 1762. The ultrasonic processing apparatus 1757 is held at a predetermined position by the support structure 1755 and is connected to the power supply 1753. While the drug form is being filled through the lumen 103 of the hollow stent 100, the ultrasonic treatment device 1757 vibrates the liquid 1863 to vibrate the hollow stent 100. This ultrasonic processing apparatus is vibrated at about 20 to 100 KHz. It will be appreciated by those skilled in the art that vibration techniques may be used with other loading methods and various means for vibrating the stent. For example, the sonicator 1757 or similar vibration device may be in direct contact with a portion of the stent.

  The drug delivery opening 104 of the hollow stent 100 prevents liquid 1762 from entering the hollow stent 100 through the opening 104 and pumps the therapeutic substance and solvent / dispersion medium into the lumen of the stent. In order to further minimize leakage at the same time, it is blocked or plugged during the forward filling process. Further, the vibration to forward-fill the stent may be used to fill a hollow stent 100 shaped as shown in FIG. 17 or linearly shaped into the hollow stent 100 subsequently. It may be used to fill the hollow tube 102.

Drug Filling: Forward Filling Embodiment Using a Biodegradable Liner or Plug In one embodiment, the stent assists in filling the stent with a therapeutic substance or drug and the rate of drug delivery after stent implantation. Contains a liner to further control In particular, referring to the cross-sectional view of FIG. 18, the stent 1800 includes a bioabsorbable / biodegradable liner 1851 that conforms to the inner surface 1849 of the hollow wire 1802. In one embodiment, the liner 1851 has a thickness that ranges between 0.001 and 0.002 inches. The liner 1851 prevents the therapeutic substance 1812 from leaking through the side opening 1804 during the drug filling step of the manufacturing process. After the liner is deployed as described below, the stent 1800 is filled or loaded with the therapeutic material 1812 using any of the forward filling methods described herein. Regardless of the type of filling method used, the liner 1851 ensures that the therapeutic material 1812 does not leach or leak through the opening 1804 while the lumen 1803 of the hollow wire 1802 is filled.

  In addition to blocking the opening 1804 during the manufacturing process, the liner 1851 also acts as a mechanism for controlling the release of the therapeutic substance 1812 into the body vessel after the stent 1800 has been implanted into the body vessel. To do. The liner 1851 is formed from a bioabsorbable / biodegradable polymer that dissolves or breaks in the blood vessel so that the therapeutic substance 1812 can be eluted into the blood lumen. In one embodiment, the liner 1851 is made from polylactic acid (PLA), a biodegradable plastic that has long been used for medical applications such as biodegradable sutures. Other biodegradable polymers suitable for use in constructing the liner 1851 include, for example, polyglycolic acid, collagen, polycaprolactone, hyaluronic acid, copolymers of these materials, and compositions and mixtures thereof. It is done. Bioabsorbable polymers suitable for use in constructing liner 1851 include polylactide [poly-L-lactide (PLLA), poly-D-lactide (PDLA)], polyglycolide, polydioxanone, polycaprolactone, poly Polymers or copolymers such as gluconate, polylactic acid-polyethylene oxide copolymer, modified cellulose, collagen, poly (hydroxybutyrate), polyanhydride, polyphosphoester, poly (amino acids), poly (α-hydroxy acid), or Two or more polymerisable monomers such as lactide, glycolide, trimethylene carbonate, ε-caprolactone, polyethylene glycol, caprolactone derivatives such as 4-tert-butylcaprolactone and N-acetylcaprolactone A conductor, poly (ethylene glycol) bis (carboxymethyl) ether is mentioned. Each type of biodegradable polymer has a characteristic degradation rate in the body. Some substances are relatively fast bioabsorbable materials (weeks to months), while others are relatively slow bioabsorbable materials (months to years). The dissolution rate of the liner 1851 is adjusted by controlling the type of bioabsorbable polymer, the thickness and / or density of the bioabsorbable polymer, and / or the nature of the bioabsorbable polymer. Furthermore, increasing the thickness and / or density of the polymeric material generally slows the dissolution rate of the liner. Properties such as the chemical composition and molecular weight of the bioabsorbable polymer are also selected to control the dissolution rate of the liner.

  After the stent 1800 is implanted within the blood vessel, the bioabsorbable / biodegradable liner 1851 collapses due to exposure to blood flowing through the blood vessel, thereby releasing the therapeutic substance 1812 at the treatment site. And enter the bloodstream. Compared to the bioabsorbable / biodegradable coating on the outer surface used to control the release of therapeutic substance 1812 into the blood vessel after stent 1800 is implanted, liner 1851 is a balloon catheter (not shown). It is more protected during further processing steps such as crimping the stent 1800 onto the balloon. Furthermore, the polymer coating on the exposed surface of the medical device can be peeled off or damaged during delivery. In comparison, the liner 1851 is protected from being peeled off or damaged during delivery because it is inside the hollow wire 102.

  19 and 20 show an exemplary method of manufacture for liner 1851. FIG. In particular, in one embodiment, a bioabsorbable / biodegradable polymer hollow tube 1947 is fed into the lumen 1803 of the hollow wire 1802. The hollow wire 1802 may be straight or shaped into a stent structure. Similar to the balloon forming technique, the tube 1947 is clamped to either end, and at the same time, internal pressure and external heating are applied, causing the tube 1947 to blow out and the liner 1851 to coincide with the inner surface 1849 of the hollow wire 1802. Form. That is, this blowing process stretches and thins the tube 1947 into the liner 1851. Other manufacturing processes may be used to form the liner 1851, which will allow the bioabsorbable / biodegradable polymer to be in liquid form with or without masked areas on the outer surface of the stent. Examples include, but are not limited to, gas-assisted injection molding and dip molding or pumping into and out of hollow stents.

  Referring to FIG. 21, another embodiment is shown in which the drug delivery opening 2104 of the stent 2100 is filled with a plug 2145 of bioabsorbable / biodegradable polymer. Similar to the liner 1851 described above, the plug 2145 serves to assist in filling the stent 2100 with therapeutic material or drug 2112 as well as to control the rate of drug delivery after stent implantation. The plug 2145 substantially encloses the drug delivery side opening and thus extends approximately from the outer surface to the inner surface of the hollow wire 2102. Plug 2145 has an uppermost surface that is coplanar with the outer surface of stent 2100, or is slightly protruding or uneven. Plug 2145 prevents therapeutic substance 2112 from leaking through the drug delivery opening during the drug filling step of the manufacturing process. After placement of the plug 2145, the stent 2100 is filled or loaded with the therapeutic substance 2112 using any of the forward filling methods described herein. In addition to blocking the drug delivery side opening during manufacture, the plug 2145 is bioabsorbable / biodegradable that dissolves or disintegrates in the blood vessel so that the therapeutic substance 2112 is released or emitted into the blood lumen. Because it is formed from a functional polymer, the plug 2145 also acts as a mechanism to control the release of the therapeutic material 2112 into the blood vessel after the stent 2100 is implanted.

  Plug 2145 is formed from any of the bioabsorbable / biodegradable polymers described above with respect to liner 1851. In one embodiment, the plug 2145 is formed from the outer surface of the hollow wire 2102 and is formed from any suitable method, which is liquid-shaped with or without masked areas on the outer surface of the stent. Injecting the bioabsorbable / biodegradable polymer into the side opening for drug delivery, manually pushing a solid plug having the same shape as the side opening for drug delivery into the side opening, and the hollow stent in liquid form Although it is immersed in a bioabsorbable / biodegradable polymer, a hollow stent is formed, but it is not limited to this.

Drug Filling: Drug Forward Filling Embodiment Using Drug Shaped in Solid Rod or Cylinder In another embodiment, the therapeutic substance is a rod having a diameter smaller than the diameter of the lumen 103 of the hollow wire 102 or Made into a solid cylinder. The therapeutic substance can be formed into a solid cylinder by combining it with a binder such as lactose powder, dibasic calcium phosphate, sucrose, corn starch, microcrystalline cellulose and modified cellulose, and combinations thereof. is there. The therapeutic substance and binder are mixed uniformly and compressed into the desired shape, such as the rod or cylindrical shape in this embodiment. The rod is then inserted into the lumen 103 of the hollow wire 102 before the hollow wire is bent into the stent pattern, ie when the wire is straight. A hollow wire 102 having a therapeutic substance disposed thereon is then shaped into a stent shape as described above. The therapeutic material in solid form provides support to the hollow wire while the hollow wire is formed into a stent pattern.

Drug Filling: Reverse and Forward Filling Embodiments Using Pressure and / or Vacuum Pumps FIG. 22 is a schematic diagram of an apparatus 2243 and method for loading a hollow wire lumen with a solution or suspension of a therapeutic substance. It is. The device 2243 includes a vacuum pump 2241, a manifold 2239, and a liquid storage tank 2237. The reservoir 2237 is filled with a pharmaceutical form in a solution or suspension containing the therapeutic substance 112. The vacuum pump 2241 is connected to the manifold 2239 by tubing 2235 or other suitable connection mechanism. The manifold 2239 can be in fluid communication with the lumen space 103 of each hollow wire 102 that forms the hollow stent 100 using a fitting 2233 or other suitable fluid coupling mechanism to connect the second plurality of hollow stents 100. 1 open end 114, 114 '. The hollow stent 100 extends from the manifold 2239 to a reservoir 2237 filled with a solution or suspension. In operation, the vacuum pump 2241 draws vacuum through the manifold 2239 and the lumen space 103 of the hollow stent 100 and draws the drug form through the side opening 104 of the hollow stent 100 and through the opposing open second ends 114, 114 ′. . In this way, the lumen space 103 of the hollow stent 100 is filled with the drug form.

  FIG. 23 is a schematic diagram of an apparatus 2331 and method for loading a lumen of a hollow stent with a therapeutic material according to another embodiment herein. Apparatus 2331 includes a pressure chamber or vessel 2329 (shown in phantom) and a vacuum pump 2327. The pressure chamber 2329 is a pressure controlled container that is suitable for containing a hollow stent submerged in a drug suspension. A pressure source 2322 is fluidly connected to the interior of the pressure chamber 2329 to control the pressure in the chamber 2329. Other pressure chamber structures suitable for use herein include, but are not limited to, the apparatus of FIG. 23A described below and the filling cylinder described above with respect to FIGS. 8-9.

  A hollow stent is placed in pressure chamber 2329 and therapeutic substance 112 in suspension is provided or supplied to the pressure chamber. The open end of the hollow stent extends beyond the pressure chamber 2329 and may be sealed to the pressure chamber 2329 by a pressure fitting (not shown) such as, but not limited to, a nut and ferrule combination. The vacuum pump 2327 is coupled to the lumen 103 of the hollow stent 100 via respective opposed open ends 114, 114 '. In one embodiment, the pressure inside the pressure chamber 2329 is higher than atmospheric pressure, and the resulting inward force indicated by the arrow 2325 causes the suspension of the therapeutic substance 112 to pass through the side opening 104 and the hollow stent. Or push into the lumen 103 of At the same time, the vacuum pump 2327 generates an outward force as indicated by the arrow 2323 so that the suspension and especially the therapeutics are directed outwardly toward the respective open ends 114, 114 ′ and the vacuum pump 2327. Assist by drawing solid particles of material 112. In another embodiment, the pressure inside the pressure chamber 2329 can be equilibrated with atmospheric pressure, so that the pressure differential created by the vacuum pump 2327 is external to the lumen space of the stent as well as toward the vacuum pump 2327. Acts to pull solid particles of therapeutic substance 112 in the direction. The filter 2321 may be provided at either end of the hollow stent 100 so that the dispersion medium can pass through the filter 2321 while the therapeutic substance is “stacked” on the filter. The lumen space 103 of the hollow stent 100 is tightly filled. In the method and apparatus described above, a vacuum is supplied along the surface of the hollow stent 100 through the side opening 104 and the therapeutic substance in solution or suspension is lumen space from the open ends 114, 114 ′ of the hollow stent 100. It will be appreciated by those skilled in the art that it may be modified to be pushed inwardly. In particular, the same assembly or device may be used, except that a vacuum is applied to the side opening 104 of the hollow stent 100 by creating a vacuum in the pressure chamber 2329. In this embodiment, the vacuum pump 2327 may be drawn directly from the pressure chamber 2329 to create a vacuum. The open end 114, 114 ′ of the stent 100 is immersed in a therapeutic agent solution or slurry / suspension, thereby being pulled or pushed into the lumen space of the stent 100 due to a pressure differential. It is done. In one embodiment, the solution / suspension is pressurized so that the vacuum from the pressure chamber 2329 and the pressure applied to the solution / suspension pushes the solution / suspension, and the lumen space of the stent 100 Fill.

  FIG. 23A is another embodiment of a pressure controlled container that is suitable for encapsulating a hollow stent submerged in a drug suspension. Apparatus 2331A, which functions similarly to apparatus 2331 described above, includes a pressure chamber or container 2329A and a pressure source 2322A fluidly connected within pressure chamber 2329A to control the pressure in chamber 2329A. In one embodiment, the pressurized gas from pressure source 2322A assists in moving the drug suspension. The pressure chamber 2329A includes a removably sealable cap or lid 2321 that can place the hollow stent 100 in the pressure chamber 2329A. The hollow stent 100 is placed in the pressure chamber 2329A and the therapeutic substance 112 in suspension is provided or supplied to the pressure chamber. The open end of the hollow stent extends beyond the pressure chamber 2329A and is sealed to the pressure chamber 2329A by a compression fitting 2326A such as, but not limited to, a nut and ferrule combination. A frit or filter 2321A is placed in a line between each end of the stent 100 and the vacuum pump 2327A so that the therapeutic substance can be “with respect to the filter” while the dispersion medium can pass through the filter 2321A. Stacked ”and tightly packed into the lumen space 103 of the hollow stent 100. A tube adapter 2328 is also placed in line between each end of the stent 100 and the vacuum pump 2327A so that the size of the tubing from the frit / compression fitting to the vacuum pump can be varied. As described above with respect to FIG. 23, a pressure differential and vacuum pump 2327A pushes or pushes the suspension of therapeutic substance 112 through side opening 104 and into lumen 103 of the hollow stent.

  A pressure chamber and / or vacuum pump for reverse or forward filling of the stent may be used to fill a hollow stent 100 shaped as shown in FIGS. 22, 23, and 23A. Alternatively, or may be used to fill a straight hollow wire or tube 102 that is subsequently shaped into a hollow stent 100.

Drug Filling: Reverse Filling Embodiment Using Vibration In another embodiment, vibration is used to reverse fill the stent 100. The vibration is applied directly or through a liquid bath. The vibration assists in the solution or suspension of the therapeutic substance moving across the drug delivery side opening 104 and into the lumen 103 of the hollow wire 102 forming the stent 100. FIG. 24 shows a schematic diagram of one embodiment using a sonication bath to assist drug loading. A container or tube 2419 is filled with a drug solution or suspension having the therapeutic substance 112, and the shaped shaped hollow stent 100 is submerged therein. A tube 2419 is placed in the chamber 2465 of the sonication bath. Chamber 2465 is filled with a liquid 2463 such as water or other solution. The sonication bath typically generates an ultrasonic wave in the liquid 2463 by changing its size in cooperation with an electrical signal that oscillates at an ultrasonic frequency, and an internal ultrasonic wave generation transformation built into the chamber 2465. 2457 is provided. Alternatively, an external ultrasonic generator transducer such as the ultrasonic processing horn 1757 described above with respect to FIG. 17 may be placed in the liquid 2463 to generate vibration. An internal ultrasound generation transducer 2457 vibrates the liquid 2463, thereby causing the drug solution or suspension to vibrate into the drug delivery opening 104 of the hollow stent 100. In one embodiment, the drug solution or suspension is oscillated with a duration of 1 hour to 4 hours. The internal ultrasound generation transducer 2457 is oscillated at about 20-100 kHz. It will be appreciated by those skilled in the art that vibration techniques may be used with other loading methods and various means for vibrating the stent may be used. In one embodiment, ice or another coolant may be added to the sonication bath as needed to ensure that the hollow stent 100 does not warm above room temperature during sonication.

  After sonication, the hollow stent 100 includes a lumen space 103 containing a therapeutic substance 112, a solvent or dispersion medium, and / or any modifier / additive such as one or more surfactants or excipients. Removed from container 2419, filled with drug solution or suspension, and at least partially dried to remove most of the outer solvent or dispersion medium. After drying, the outer surface of the hollow stent 100 may be coated with the same solution or suspension component, either as a layer of cast drug solution or as a dry drug residue. The hollow stent 100 is described herein to remove residual solvent or dispersion medium from the lumen space and / or to remove a cast layer or drug residue of drug solution from the outer surface of the stent. Further solvent extraction steps and / or washing steps as described herein are further performed. The vibration to reverse-fill the stent may be used to fill the shaped hollow stent 100 shown in FIG. 24, or a straight hollow tube that is subsequently shaped into the hollow stent 100. May be used to fill 102.

Solvent extraction: azeotrope for precipitating the drug FIGS. 25-28 are used in which the precipitation method is used to separate the drug from the solvent after the solution is loaded into the lumen space of the hollow wire. One embodiment is shown. In particular, as shown in the first step 2520 of FIG. 25 and the cross-sectional view of FIG. 26, the hollow wire 2602 of the stent 2600 is first filled with a solution 2617 of therapeutic agent or drug 112 and a first solvent. The The therapeutic substance 112 is soluble in the first solvent and forms a solution 2617. The first solvent is a high capacity or low capacity solvent. In one embodiment, the first solvent is tetrahydrofuran (THF), although other solvents suitable for dissolving the therapeutic substance 112 may be used. THF is a high volume solvent that dissolves large amounts of various drugs such as sirolimus. As will become apparent from the description below, the first solvent should also be capable of forming an azeotrope with the solvent being the second or precipitation separator added after the process. Stent 2600 is filled or loaded with solution 2617 using any of the filling methods described herein, but the plurality of apertures where evaporation of the first solvent is spaced along the length of stent 2600. A reverse filling method such as vibration through a sonication bath is preferred because it can occur quickly through section 2604.

  In the second step 2521 of FIG. 25, a second or settling solvent solvent is added to the lumen of the stent 2600. The second solvent has the following characteristics to perform these important functions: (1) The second solvent does not dissolve the therapeutic substance 112, ie, the therapeutic substance 112 The therapeutic substance 112 is insoluble in the second solvent so that it precipitates from the solution 2617, and (2) the second solvent is miscible with the first solvent to ensure proper homogeneous mixing. And being able to form an azeotrope with the first solvent. With respect to the first feature of the second settling solvent solvent described above, it is noted that the second settling solvent solvent is referred to as a non-solvent that cannot dissolve the therapeutic substance 112 within the solution 2617. . With respect to the second feature of the second settling solvent, the azeotrope changes its composition when boiled because the resulting vapor has the same composition ratio as the original mixture. A mixture of two or more liquids in such a ratio that they are not. A second or settling solvent solvent is added until the two solvents, the first solvent and the settling solvent, reach the azeotrope point. For example, when THF is used as the first solvent, hexane is used as the second settling solvent. Various drugs, including sirolimus, are insoluble in hexane. Furthermore, THF and hexane are miscible and form an azeotrope with 46.5% THF and 53.5% hexane by weight (w / w). Since the azeotrope point of the THF / hexane mixture requires 53.5% hexane, a large amount of hexane is added to solution 2617 to ensure that therapeutic substance 112 precipitates from solution 2617. The In another embodiment, ethanol is used as the first solvent to dissolve the therapeutic substance, and ethanol as the first solvent to dissolve in the therapeutic substance as long as the therapeutic substance is insoluble in water. And water may be used as the second settling agent solvent to form an azeotrope with ethanol. As shown in the cross-sectional view of FIG. 27, after precipitation, the therapeutic substance 112 is present in the solid phase, while the two solvents are present as a mixture 2715 in the liquid phase, namely the first solvent and the settling solvent. To do.

  The second settling solvent may be added to the lumen space of the stent 2600 in any suitable manner. For example, if vibration is used in a reverse filling method to load the hollow stent 100, the second settling solvent solvent may be used in the ultrasonic / ultrasonic phase while the stent 100 is still submerged in the solution 2617. It may simply be added to the sonication bath, and the second sedimentation solvent will enter the lumen space through the drug delivery side opening of the immersed stent. The second settling solvent solvent precipitates the therapeutic substance 112 from the first solvent both within the lumen space of the hollow wire 2602 and outside the stent 2600. Precipitation of the therapeutic substance 112 from the solution 2617 separates the drug and solvent, does not form a dried drug casting layer, and is believed to block the opening 2604 during drying.

Referring now to the third step 2538 of FIG. 25, to remove the two solvents present in the lumen space of the hollow wire 2602 as the liquid mixture 2715, namely the first solvent and the settling agent solvent. Solvent extraction is performed. A stent 2600 that is still immersed in or removed from the mixture 2715 is placed on a vacuum oven. The temperature and pressure are controlled so that the azeotrope formed between the first solvent and the settling agent solvent becomes volatile and moves to the gas phase. For example, the ambient pressure may be reduced to approximately 5 torr and the temperature may be increased between 30 ° C. and 40 ° C. to rapidly evaporate THF-hexane into the solvent. The specific values required for temperature and pressure depend on the particular solvent system selected, but typical values range between 1 × 10 ⁻⁸ torr and 760 torr for pressure, and for temperature It is the range of 25 degreeC-40 degreeC. As shown in the cross-sectional view of FIG. 28, the mixture 2715 evaporates or separates from the stent 2600, leaving substantially only the therapeutic substance 112 in solid form within the lumen space of the hollow wire 2602. Only a small portion of the solvent remains in the hollow wire 2602 or no solvent remains at all. Because the first solvent and the precipitating agent solvent form an azeotrope, the solubility of the therapeutic substance 112 does not change because the mixture 2715 evaporates but remains in solid form during solvent extraction. Because the composition of the azeotrope does not change during boiling, the therapeutic material 112 does not dissolve in any remaining solvent as the azeotrope 2715 evaporates. Forming an azeotrope to precipitate the drug within the hollow stent may be used within the shaped stent or to fill a straight hollow tube that is subsequently shaped into the hollow stent. May be used.

  In one embodiment, the first solvent and the sedimentation agent solvent form a positive azeotrope, meaning that the combination is more volatile than the individual components. It is believed that the volatile azeotrope provides a relatively low boiling point for mixture 2715 so that mixture 2715 evaporates or separates from stent 2600 quickly and easily. The THF and hexane described in the previous embodiment are used as the first solvent and the precipitation separator solvent to form a positive azeotrope having a relatively low boiling point.

  In another embodiment, water is added to the hollow stent 100 prior to the solvent extraction step 2538 described above, because the addition of water to the THF / hexane / sirolimus system can create a hard shell. This hard shell is used to cap the stent 2600 so that no drug is lost from the inside of the stent during handling of the stent.

Solvent / Dispersion Medium Extraction Step of Stent Loading Process Referring back to FIG. 5, the second step of the drug loading process after the stent is filled with the drug is solvent or dispersion medium extraction 538. After the lumenal space of the hollow wire 102 is filled with the drug form, primarily the therapeutic substance 112 or one or more excipients in addition to the therapeutic substance 112 are dissolved in the hollow stent 100 for elution into the body. In order to be located, any remaining solvent / dispersion medium must be extracted from within the lumen space. Thus, the end result of solvent / dispersion medium extraction is a drug filled with a hollow stent with no appreciable solvent / dispersion medium remaining in the lumen, or drug and excipient. Solvent / dispersion medium extraction preferably occurs without affecting or altering the composition of the therapeutic substance 112. Solvent / dispersion medium extraction is necessary to make the hollow stent 100 into a biocompatible implant and is desirable to ensure consistent dissolution of the therapeutic substance 112.

FIG. 5B shows a more detailed flowchart of the solvent / dispersion medium extraction step 538 of the loading process, which includes removal of the solvent from the solution of therapeutic material retained in the lumen space of the hollow stent and the hollow stent lumen space. It refers to both removal of the dispersion medium from the slurry / suspension of the retained therapeutic substance within. In particular, the solvent / dispersion medium extraction step 538 is generally performed via one or more of a supercritical CO ₂ extraction 540 method, a vacuum oven drying 542 method, and / or a cryovac sublimation 544 method. After solvent / dispersion medium extraction has been performed, the lumen space of the hollow wire is filled with only a small amount of solvent / dispersion medium and mainly with the drug alone or drugs and excipients. Each method is described in more detail below.

Solvent / Dispersion Medium Extraction: Vacuum Oven Drying Embodiment Hollow stent 100 was filled or loaded with drug form, either in solution or suspension, via any of the filling methods described herein. Later, the stent is dried in a vacuum oven to evaporate any solvent / dispersion medium contained within the lumen space of the hollow wire 102 and deposit the therapeutic material. The temperature used for drying is high enough to facilitate solvent removal while not causing drug degradation during drying. In particular, the stent was placed in an oven and dried at a temperature between 25 ° C. and 40 ° C. and a pressure between 1 torr and 760 torr for a maximum of 24 hours and loaded into most of the external solvent / dispersion medium and the lumen space. Evaporate a portion of the solvent / dispersion medium. After vacuum oven drying, a dry drug residue or drug cast often remains on the outer surface of the stent, and the residual solvent / dispersion medium often remains in the lumen space.

Solvent / Dispersion Medium Extraction: Supercritical CO ₂ Embodiment Referring to FIGS. 29 and 30, supercritical carbon dioxide (SCCO ₂ ) extraction is used to reduce residual solvent or dispersion medium in the lumen space of the hollow stent to a negligible amount. Two embodiments are shown for use. These embodiments use the properties of SCCO ₂ to extract residual solvent or dispersion medium without removing previously loaded therapeutic substance / drug from the lumen space of the stent. In the first step 2920 of the static extraction method of FIG. 29, the stent 100 is passed through any of the filling methods described herein such that at least the lumen space of the hollow wire 102 is filled in drug form. , Filled or loaded in drug form, either in solution or suspension. In one embodiment, the stent may be dried in a vacuum oven prior to performing supercritical carbon dioxide (SCCO ₂ ) extraction.

In a second step 2938A of the method of FIG. 29, a hollow stent 100 filled with a solution / suspension is placed inside the extraction vessel. The extraction vessel is a pressure vessel that can hold the hollow stent 100 and can withstand the temperatures and pressures required for supercritical carbon dioxide. The usual structure for the extraction vessel is a stainless steel cylinder with caps and fittings that are removable at each end to allow the flow of supercritical carbon dioxide, but other shapes and structures are used. Also good. The extraction vessel is heated to a temperature between 31 ° C. and 40 ° C., and then supercritical carbon dioxide (SCCO ₂ ) expands to fill the extraction vessel at a density such as that of a gas but liquid. And filled with carbon dioxide (CO ₂ ) pressurized to a pressure between 1100 psi and 9000 psi until the temperature and pressure in the extraction vessel are above the critical conditions for CO ₂ to act as a supercritical fluid. Is done. A supercritical fluid is one that is defined at a temperature and pressure above or equal to the critical temperature and pressure of the fluid. Since the critical temperature of carbon dioxide is 31.1 ° C. and the critical pressure is 1070.9 psi (72.9 atm), supercritical carbon dioxide (SCCO ₂ ) is at a temperature higher than 31.1 ° C. and 1070. Applies to carbon dioxide at pressures higher than 9 psi. In the supercritical state, CO ₂ has a unique gas-like vapor diffusivity and liquid-like density. Unlike normal liquid organic solvents, SCCO ₂ has zero surface tension and can therefore penetrate small voids or spaces. SCCO ₂ also has solvent properties similar to organic solvents that are capable of dissolving the same organic solvents used in solvent / dispersion media including simple alcohols, alkanes, DCM, THF, and DMSO. In the third step 2938B of the method of FIG. 29, there is sufficient time, such as a retention period or equilibration time, to penetrate the SCCO ₂ through the lumen space of the stent 100 and dissolve any residual solvent / dispersion media left from the filling process. Over time, supercritical conditions are maintained in the extraction vessel. In one embodiment, the equilibration time is between 15 minutes and 60 minutes.

In the fourth step 2938C of the method of FIG. 29, after the SCCO ₂ penetrates the lumen space of the stent 100 and the residual solvent / dispersion medium is dissolved, the extraction vessel is gradually depressurized to ambient pressure. This depressurization is controlled by an expansion valve, which comprises an upstream inlet valve attached to the extraction vessel and a downstream outlet valve attached to the extraction vessel. Opening the expansion valve encompasses opening the outlet valve while maintaining the inlet valve closed, which allows the flow of SCCO ₂ and residual solvent / dispersion medium from the extraction chamber, Reduce the pressure in the extraction vessel. SCCO ₂ flow occurs because the expansion valve outlet is at a lower pressure than the extraction chamber. In one embodiment, the outlet of the expansion valve is at ambient pressure. The reduced pressure or pressure drop that occurs across the expansion valve is referred to as an expansion valve because it results in a volume expansion of the material flowing therethrough. The outward flow of SCCO ₂ and solvent / dispersion medium from the extraction vessel results in extraction of the solvent / dispersion medium from the lumen space of the stent with the solid form of the therapeutic substance remaining. SCCO ₂ returns to gas and evaporates as the pressure is reduced. Depending on the particular solvent / dispersion medium used and the geometry of the nozzle of the expansion valve, the extracted solvent / dispersion medium is also changed to a gaseous state and evaporated at the outlet of the expansion valve, or in a liquid state Extracted. In one embodiment, additional heating / pressurization, holding and decompression steps or duty cycles, i.e., steps 2938A-2938C, are provided to effectively remove residual solvent / dispersion medium in the lumen to a minute amount. May be used repeatedly or periodically.

In addition to the removal of residual solvent / dispersion medium from the lumen of the stent, SCCO ₂ also showed a low capacity for dissolving certain drugs such as sirolimus. SCCO ₂ is therefore useful in removing any drug residue located on the outer surface of the stent after the filling process. In particular, during the retention period, SCCO ₂ also dissolves a small fraction of any external residual solvent and external drug residue, thereby providing a substantial cleaning effect on the stent external surface.

In the dynamic extraction method shown in FIG. 30, method steps 3020, 3038A and 3038B are similar to those described above with respect to method 2920, 2938A and 2938B of FIG. In a first step 3020, the stent is filled or loaded in drug form, either in solution or suspension, via any of the filling methods described herein. In a second step 3038A, a solution / suspension filled stent is placed inside the extraction vessel and heated to a temperature between 31 ° C. and 40 ° C., then the temperature and pressure in the extraction vessel are changed to CO. ₂ relates to higher than the critical condition, are filled with carbon dioxide which is pressurized to a pressure of between 1100psi~9000psi (CO _2). In the third step 3038B, the retention time is maintained to penetrate the SCCO ₂ through the lumen space of the stent and dissolve any residual solvent / dispersion media left from the filling process. In one embodiment, the retention time is between 15 and 60 minutes. In the fourth step 3038C of the method of FIG. 30, after the SCCO ₂ has penetrated the lumen space of the hollow stent 100 and dissolved the residual solvent / dispersion medium, the extraction vessel pressure is maintained through a continuous inflow of a fresh supply of SCCO _2. At the same time, the extraction valve is allowed to flow dynamically by restricting the expansion valve. The continuous inflow of SCCO ₂ is achieved by continuously adding pressurized carbon dioxide to the extraction vessel and by restricting the expansion valve to control the outflow of material from the extraction vessel. In this embodiment, the extraction vessel is never depressurized during the extraction process because both the upstream inlet valve and the downstream outlet valve remain open. In order to provide a fresh supply of SCCO ₂ during dynamic extraction, the CO ₂ pump continuously adds fresh SCCO ₂ to the extraction vessel.

In embodiments herein, the static and / or dynamic SCCO ₂ extraction method is performed with one or more stents loaded at a pressure between 2000 and 6000 psi for a total time between 30 and 120 minutes. Used in cycle. The SCCO ₂ extraction method reduces the solvent level in the lumen to a small amount. Further, in various embodiments, one or more cleaning methods described herein may be used after the SCCO ₂ extraction method to clean the outer surface of the hollow stent.

Solvent Extraction; Cryovaclo Sublimation Embodiment Referring to FIGS. 31 and 32, there is shown a method in which cryovac sublimation is used to extract residual solvent in the lumen according to embodiments herein. In particular, as shown in the first step 3220 of the method of FIG. 32, the stent is filled or loaded with a solution containing a therapeutic substance via a filling method described herein that is suitable for the solution. As a result, the lumen space of the hollow wire 102 is filled with the drug solution. In one embodiment, the drug solution contains acetonitrile and sirolimus.

  The second step 3238A of the method of FIG. 32 after being filled is to cool the hollow stent 100 to precipitate the drug from the solution. In particular, referring to FIG. 31, there is shown an apparatus 2713 suitable for performing the cryovac sublimation steps 3238A-3238C of the method of FIG. One or more filled stents are placed in the sample holder 2711. In one embodiment, additional drug solution may be added to the sample holder 2711 to keep the filled stent immersed in the drug solution. Soaking the filled stent in the drug solution prevents the surface of the stent from drying, which can create a dry drug casting layer across the drug delivery side opening 104. To block the opening and prevent solvent removal.

  Next, the sample holder 2711 is attached to the cooling plate 2701 located in the processing chamber 2709 of the apparatus 2713 and cooled through the coolant circulating through the coolant supply line 2706 and the coolant return line 2708. In one embodiment, to minimize solvent evaporation during mounting of the sample holder 2711 on the cooling plate 2701, the device 2713 is a pressurized inert gas, i.e., a pressure above atmospheric pressure, which is higher than atmospheric pressure. Special preconditioning steps such as those introduced in 2709 may be included. Examples of inert gases include, but are not limited to, argon, helium, and nitrogen. This preconditioning process continues until the sample holder 2711 is attached to the cooling plate 2701 and the processing chamber 2709 is closed to the atmosphere. In another embodiment, the preconditioning process may continue further until the sample holder 2711 is cooled by the cooling plate 2701 and the drug precipitates from the drug solution. The temperature and pressure of the processing chamber 2709 are controlled and manipulated so that the temperature of the drug solution is sufficient for the drug to precipitate from the solvent. In particular, temperature is an important factor for precipitation, but pressure control is also required to reach the temperature required for precipitation to occur, thus controlling both the temperature and pressure of the processing chamber 2709. It is necessary to The temperature of the cooling plate 2701 is controlled by the coolant temperature and by how much coolant is supplied through the coolant supply line 2706 and coolant return line 2708, and the pressure in the processing chamber 2709 is controlled by a vacuum pump. 2707. In addition, a thermocouple 2704 is used to monitor the temperature of the cooling plate 2701 and a pressure sensor 2705 is used to monitor the pressure in the processing chamber 2709. In one embodiment, drug precipitation occurs for acetonitrile and sirolimus solutions at a temperature of approximately −20 ° C. for cooling plate 2701 and at a pressure of 600 torr for processing chamber 2709. The cooling rate provided by the cooling plate 2701 ensures that the precipitated drug settles or is spatially separated from the solvent prior to freezing the solvent so that splashing of the drug is minimized during solvent sublimation. Can be controlled to be slow enough. Control of the cooling rate is more important as the solution approaches the conditions under which the drug precipitates.

After precipitation, the therapeutic agent or drug is present in the solid phase, while the solvent is present in the liquid phase, both on the lumen space of the stent and on the outer surface of the stent. By precipitating the drug from the solvent, the drug and the solvent are separated, and the dried drug casting layer does not form to block the opening 104 during drying. As shown in FIG. 32, the third step 3238B of the process further includes cooling the stent 100 to solidify or freeze the solvent. Thus, further cooling of the stent to freeze the solvent locks the relative position of the precipitated drug and the solvent portion. In order to freeze the solvent, the sample holder 2711 must reach a temperature below the melting point of the solvent. Depending on the solvent, the temperature of the sample holder 2711 is required to reach a temperature between −150 ° C. and 0 ° C. Examples of the solvent include, but are not limited to, methanol, ethanol, isopropanol, acetonitrile, acetone, ethyl lactate, tetrahydrofuran, dichloromethane, hexane, and water. The following table lists the melting point temperatures of these representative solvents.

After the solvent has solidified, the fourth step 3238C of the method of FIG. 32 is for sublimating the frozen solvent from the stent. Sublimation is a phase transition of a substance from a solid phase that does not pass through an intermediate liquid phase to a gas phase. In ^particular, 1.0E ^{- 3~1.0E} - deep vacuum on the order of 8Torr is that applied to the process chamber 2709 via a vacuum pump 2707, the solvent sublimes, only solid drug lumen space of the stent Leave. After solvent removal, the temperature and pressure of the processing chamber 2709 is increased to atmospheric conditions and the stent is removed from the device 2713.

In one example, a hollow stent was sonicated for more than 1 hour to backfill the stent with a solution of sirolimus and acetonitrile. After filling the stent with the drug solution, the stent was placed in the sample holder 2711, additional drug solution was added, and the filled stent was completely immersed. The sample holder was then placed on the cooling plate 2701. Next, the processing chamber 2709 was evacuated to 600 torr, and the cooling plate 2701 was rapidly cooled to about −17 ° C. The cooling rate was then controlled at approximately 3 ° C./min until drug precipitation and solvent solidification were observed. Precipitation of the drug was observed at about -20 ° C and solidification of the solvent was observed at about -30 ° C. Next, the processing chamber 2709 was evacuated to less than 1 × 10 ⁻³ torr, and the cooling plate 2701 was cooled to approximately −45 ° C. Next, the processing chamber 2709 was continuously evacuated, and the cooling plate 2701 was heated at a rate of approximately 0.5 ° C./min. About 45 minutes after the temperature of the cooling plate 2701 was about −20 ° C., the sample holder 2711 was taken out. As a criterion for determination, the temperature of the cooling plate 2701 and the temperature of the sample need not be the same. Differences in temperature are due to cooling plate design, thermocouple position, sample holder position, coolant supply and return line position, as well as other factors. In this embodiment, the cooling plate 2701 is made of copper and has a larger area than the sample holder 2711. The thermocouple 2704 was positioned near one end of the cooling plate 2701, and the cooling holder 2711 was positioned near the center of the cooling plate 2701. The coolant supply line 2706 and the coolant return line 2708 were oriented to contact the cooling plate 2701 near the center. In this configuration, the indicated temperature of the cooling plate 2701 from the thermocouple 2704 resulted in a warmer temperature than that of the sample holder 2711. Thus, rapid cooling of the cooling plate 2701 to approximately −17 ° C. during the cooling process also means that the sample holder, ie the drug solution, was at a lower temperature. Similarly, the solidification of the solvent observed at −30 ° C. and the indicated temperature of the cooling plate 2701 means that the sample holder 2711 and even the sample were at a lower temperature. Assuming that the melting point of acetonitrile was −45 ° C., the temperature offset between the cooling plate 2701 and the sample was approximately 15 ° C.

  In one embodiment, vibrational energy may be applied to the device 2713 at any point in the process to facilitate solvent removal. During the precipitation and subsequent solvent freezing steps, the drug and solvent are separated into specific areas where the volume of drug is surrounded by frozen solvent or vice versa. If the volume of frozen solvent is surrounded by the drug, the trapped solvent cannot sublime. The addition of vibrational energy moves the drug so that it no longer completely surrounds the solvent to allow sublimation. Such vibrational energy is applied via a piezoelectric transducer, a vibrating magnet, or any suitable technique compatible with cryogenic and high vacuum processes.

Stent Cleaning Step of Stent Loading Process Referring to the method shown in FIG. 5, after solvent is extracted from the lumen space of the stent, the third step of the drug loading method is stent cleaning 546. The above methods used to fill hollow stents in drug form include all of the stents including the lumen, the lumen exterior, the inter-strut surface and the inter-crown surface coated with the drug form used to fill the stent. Resulting in an outer surface. All outer surfaces of the stent should be substantially drug free in areas where there are no drug delivery side openings. Preferably, the stent cleaning process removes external surface drug residues without physical manipulation of the stent and without interfering with drug filling inside the lumen space of the stent.

FIG. 5C shows a more detailed flowchart of stent cleaning 546 of the drug loading process. In particular, the stent cleaning 546 may include a solventless cleaning method 548, such as a method 550 using a CO ₂ dry ice snow spray device, and / or a solvent-based spray method 554, a mechanically operated cleaning method 556 using a histoblast, and / or Performed by one or more of the solvent-based cleaning methods 552, including the solvent-based rinsing method 558. Any combination of the cleaning methods described above can be used to clean the stent. Selection of the cleaning method (s) will include the drug form component, the viscosity of the dry component on the stent surface, the degree of unwanted drug removed from the stent as a result of cleaning, and the unnecessary trapped within the stent lumen. It is governed by factors such as the degree of the correct solvent. Each method is described in more detail below.

In one embodiment of solventless stent cleaning , a CO ₂ spray cleaning system, also known as a CO ₂ dry ice snow spray device, is used for removal of drug residues on the intended outer surface. Suitable CO ₂ spray washer is available from Applied Surface Technologies, is required additional modification for use in a stent. The CO ₂ spray washer takes a high purity liquid CO ₂ and expands it at high speed across a specially designed orifice expansion nozzle. Expansion causes both a temperature drop and a pressure drop, which converts liquid CO ₂ into solid microparticles CO ₂ , also known as dry ice snow. After expansion, high speed dry ice snow is directed to the area of the stent containing the drug residue. The surface of the stent that is in contact with the dry ice causes a temperature drop at the stent surface, after which water vapor from the surrounding air condenses. Continuous application of dry ice will freeze the condensed water. The frozen water effectively shields the stent surface from further cleaning with dry ice. A modification to minimize the formation of frozen water is the addition of an enclosure member to heat the stent. In addition, the enclosure member may be purged with an inert gas such as argon or nitrogen to minimize the amount of water vapor present. Cleaning of the stent surface occurs by momentum transfer of dry ice snow to drug residues similar to bead blasting. After contact of the stent, the dry ice snow particles are heated by the ambient temperature and the CO ₂ eventually returns to the gaseous state. The net effect is a solventless cleaning process that removes external drug residues from the stent.

Stent cleaning with solvent-based spray systems Solvent spray systems are designed based on an ejector system, where air or nitrogen acts as a working fluid that carries the solvent and atomizes the solvent into fine droplets or mists . This mist is directed to the stent at high speed. Depending on the solvent used in the spray system, a high speed mist dissolves or displaces the drug form residue from the outer surface of the stent. Various ejector systems may be used. An exemplary ejector system may be a nitrogen pen or airbrush, usually used for blowing dust particles, connected to a small reservoir of solvent.

  The solvent used in the solvent spray system is selected to minimize the amount of drug dissolution and subsequent removal from the lumen space of the stent. Thus, the solvent is selected based on the limited ability or inability to dissolve the drug. Examples of solvents with limited ability to dissolve various therapeutic agents including sirolimus include ethanol, isopropyl alcohol, butanol, and combinations of these alcohols with water in any mass ratio. However, the present invention is not limited to this. The addition of water serves to suppress the ability of these simple alcohols to dissolve in therapeutic agents such as sirolimus that are insoluble in water. When using low drug solubility solvents, drug form residues on the outer surface are removed primarily by dissolution, followed by movement by spray rate. Examples of solvents that cannot dissolve various therapeutic agents including sirolimus include, but are not limited to, water and simple alkanes (C5-C10). When non-drug soluble solvents are used, drug form residues on the outer surface are mainly removed by movement with spray speed.

Stent cleaning by mechanical manipulation via Histobrus FIG. 33 shows another embodiment of stent cleaning in which the outer surface of the stent is cleaned by mechanical manipulations via histobrush 333. FIG. The histobrush method is manual and requires a high degree of stenting. The user must clean the stent vigorously enough to remove all external contaminants while ensuring that the mechanical integrity is not compromised during the cleaning process. As shown in FIG. 34, solvent 335 may be added to the brush to aid in cleaning, but excess solvent may remove the drug from the internal portion of the stent and / or add residual solvent. Can lead to large variations in the drug loading procedure.

Stent cleaning with a solvent-based rinsing system The solvent rinsing and cleaning system is a complete solution of the hollow stent 100 into a solvent system with or without limited ability to dissolve a drug or drug and excipient. It has dipping or dipping. The solvent rinse cleaning system must strictly control the time that the stent is fully immersed. Vortexing, mixing, convolution, or other means of total fluid agitation is used to shear bulk fluid across the stent surface, thereby cleaning the stent outer surface.

  The solvent used in the solvent rinsing system should minimize the amount of drug dissolution and subsequent removal from the lumen space of the hollow stent 100. Thus, the solvent is selected based on the limited ability or inability to dissolve the drug. Examples of solvents with limited ability to dissolve various therapeutic agents including sirolimus include ethanol, isopropyl alcohol, butanol, and combinations of these alcohols with water in any mass ratio. However, the present invention is not limited to this. The addition of water serves to suppress the ability of these simple alcohols to dissolve in therapeutic agents such as sirolimus that are insoluble in water. When using low drug solubility solvents, drug form residues on the outer surface are removed primarily by dissolution, followed by movement with total fluid agitation. Examples of solvents that cannot dissolve various therapeutic agents including sirolimus include, but are not limited to, water and simple alkanes (C5-C10). When non-drug soluble solvents are used, drug form residues on the outer surface are mainly removed by movement with total fluid agitation.

Exemplary Combination / Process In summary, a drug eluting stent, such as the hollow stent 100, can be loaded with a drug by a method comprising three main parts or steps as shown in FIG. An extraction step 538 and a stent cleaning step 546 are provided. Various methods for each of the three main steps of the drug loading process are described herein, and a complete loading process according to embodiments herein can include one or more types of drug loading, one of solvent extractions. It will be apparent to those skilled in the art that the above types and one or more types of stent cleaning are provided and that the methods described herein are used in various combinations.

For example, FIG. 35 shows one exemplary combination of devices and methods described herein for drug loading, solvent extraction, and stent cleaning. For the drug filling step 3520, the hollow stent 100 is reverse filled using vibration / sonication, as described above, eg, with reference to the apparatus of FIG. The drug is dissolved in a high volume solvent and / or a low volume solvent with one or more excipients. For the solvent extraction step 3538, supercritical carbon dioxide (SCCO ₂ ) extraction is used to reduce the residual solvent in the lumen to a small amount. A static SCCO ₂ extraction method as described with reference to FIG. 29 may be used. Alternatively, a dynamic SCCO ₂ extraction method as described with reference to FIG. 30 may be used. Finally, the stent is cleaned through a cleaning step 3546 using a CO ₂ dry ice snow spray system as described above.

FIG. 36 illustrates another exemplary combination of devices and methods described herein for drug loading, solvent extraction, and stent cleaning. For the drug filling step 3620, the stent is reverse filled using vibration / sonication, as described above, eg, with reference to the apparatus of FIG. The drug is dissolved in a high volume solvent having one or more excipients containing at least urea. For the solvent Nakatsu process 3638, cryovac sublimation as described herein with reference to FIGS. 31 and 32 is used to reduce the residual solvent in the lumen to a small amount. Finally, the stent is cleaned through a cleaning step 3646 using a CO ₂ dry ice snow spray system as described above.

FIG. 37 illustrates another exemplary combination of devices and methods described herein for drug loading, solvent extraction, and stent cleaning. For the drug filling step 3720, the stent is reverse filled using vibration / sonication as described above, eg, with reference to the apparatus of FIG. The drug is suspended in a solvent to form a slurry / suspension, and the size of the drug particles is preferably in the nanometer range. For the solvent extraction step 3738, the stent is dried in a vacuum oven to evaporate any solvent contained within the lumen space of the hollow wire. Finally, the stent is cleaned through a cleaning step 3746 using a CO ₂ dry ice snow spray system as described above.

  The above combinations of drug filling, solvent extraction, and stent cleaning are merely for illustrative purposes. It will be apparent to those skilled in the art that various combinations of the above methods are used herein to load a drug eluting stent.

  While various embodiments of the invention have been described above, it should be understood that these have been presented by way of illustration and example only and are not limiting. It will be apparent to those skilled in the art that various changes in form and detail can be made therein without departing from the spirit and scope of the invention. Accordingly, the general scope and scope of the present invention should not be limited by any of the above-described exemplary embodiments. Each embodiment described herein, as well as each feature of each reference cited herein, may be used in combination with the features of any other embodiment. Furthermore, there is no intention to be bound by any expressed or implied theory presented in the preceding technical field, background, brief summary or mode for carrying out the invention. All patent documents and publications discussed herein are hereby incorporated by reference in their entirety.

Claims (32)

A method of loading a therapeutic substance into a lumen space of a hollow wire having a plurality of side openings forming a hollow stent, comprising:
Immersing the hollow stent in a solution of therapeutic substance and solvent;
Vibrating the hollow stent and the solution to assist in moving the solution through the plurality of side openings and into the lumen space of the hollow stent;
Removing the hollow stent from the solution when the lumen space is substantially filled with the solution, thereby creating a filled hollow stent;
By using supercritical carbon dioxide extraction to extract almost all residual solvent from the lumen space of the filled hollow stent while the therapeutic substance remains in the hollow stent, Allowing the hollow stent to be loaded with the therapeutic material for delivery into a body cavity;
A method characterized by that. Using the supercritical carbon dioxide extraction comprises:
Placing the filled stent in an extraction container;
Filling the extraction vessel with carbon dioxide pressurized to a pressure above the critical pressure;
Heating the extraction vessel with the filled hollow stent to a temperature above the critical pressure with respect to carbon dioxide to produce supercritical carbon dioxide;
The supercritical carbon dioxide and the filled hollow stent are sufficient for the supercritical carbon dioxide to penetrate the lumen space of the hollow stent and dissolve the residual solvent in the lumen space of the hollow stent. Holding at a critical condition for a certain period of time;
Further comprising
The method of claim 1. Using the supercritical carbon dioxide extraction comprises:
Further extracting the dissolved residual solvent and supercritical carbon dioxide from the lumen space of the filled hollow stent by depressurizing the extraction vessel to ambient pressure.
The method of claim 2. The heating, adding pressurized carbon dioxide, holding and depressurizing steps are repeated to extract substantially all residual solvent from the lumen space of the filled hollow stent.
The method of claim 3. Using the supercritical carbon dioxide extraction comprises:
The hollow stent filled with the dissolved residual solvent and supercritical carbon dioxide by maintaining the pressure in the extraction container with a continuous inflow of supercritical carbon dioxide and simultaneously throttle the expansion valve of the extraction container. Extracting from the lumen space of
The method of claim 2. The solvent of the solution is a high volume solvent, the solution also contains an excipient to assist in elution of the therapeutic substance, and the excipient and therapeutic substance are the residual solvent Stays in the hollow stent after extraction from the hollow stent;
The method of claim 1. The excipient is a hydrophilic drug;
The method of claim 6. The high volume solvent is tetrahydrofuran, the therapeutic substance is sirolimus, and the excipient is urea;
The method of claim 7. The excipient is a surfactant;
The method of claim 6. The high volume solvent is dichloromethane, the therapeutic substance is sirolimus, and the excipient is cyclodextrin;
The method of claim 9. Further comprising cleaning an outer surface of the hollow stent loaded with the therapeutic material using a carbon dioxide spray cleaning system;
The method of claim 6. The solvent of the solution is a low volume solvent, the solution also contains an excipient to assist in elution of the therapeutic substance, and the excipient and therapeutic substance are the residual solvent of the residual solvent. Stays in the hollow stent after extraction from the hollow stent;
The method of claim 1. The excipient is a surfactant;
The method of claim 12. The low volume solvent is methanol, the therapeutic substance is sirolimus, and the excipient is cyclodextrin;
The method of claim 13. The excipient is a hydrophilic drug;
The method of claim 12. The low volume solvent is methanol, the therapeutic substance is sirolimus, and the excipient is urea;
The method of claim 15. A method of loading a therapeutic substance into a lumen space of a hollow wire having a plurality of side openings forming a hollow stent, comprising:
Immersing the hollow stent in a suspension of therapeutic material and dispersion medium;
Vibrating the hollow stent and the suspension to assist in moving the suspension through the plurality of side openings to the lumen space of the hollow stent;
Removing the hollow stent from the suspension when the lumen space is substantially filled with the suspension, thereby creating a filled hollow stent;
By using supercritical carbon dioxide extraction to extract almost all residual solvent from the lumen space of the filled hollow stent while the therapeutic substance remains in the hollow stent, Allowing the hollow stent to be loaded with the therapeutic substance for delivery into a body cavity.
A method characterized by that. Using the supercritical carbon dioxide extraction comprises:
Placing the filled stent in an extraction container;
Filling the extraction vessel with carbon dioxide pressurized to a pressure above the critical pressure;
Heating the extraction vessel with the filled hollow stent to a temperature above the critical temperature for carbon dioxide to produce supercritical carbon dioxide;
The supercritical carbon dioxide and the filled hollow stent are sufficient for the supercritical carbon dioxide to penetrate the lumen space of the hollow stent and dissolve the residual dispersion medium in the lumen space of the hollow stent. Further comprising the step of holding at critical conditions for a certain period of time,
The method of claim 17. Using the supercritical carbon dioxide,
Further comprising extracting the dissolved residual dispersion medium and supercritical carbon dioxide from the lumen space of the filled hollow stent by depressurizing the extraction vessel to ambient pressure.
The method of claim 18. The heating, holding and extracting steps are repeated to extract substantially all residual dispersion medium from the lumen space of the filled hollow stent;
The method of claim 19. Using the supercritical carbon dioxide,
The pressure in the extraction vessel is maintained by continuous inflow of supercritical carbon dioxide, and at the same time, the dissolved residual dispersion medium and supercritical carbon dioxide are filled in the filled hollow by restricting the expansion valve of the extraction vessel. Further comprising extracting from the lumen space of the stent;
The method of claim 18. The dispersion medium of the suspension is selected from the group consisting of water and C5-C10 alkanes, and the suspension is also a surfactant for stabilizing the dispersion of the therapeutic substance in the suspension Including agents,
The method of claim 17. The dispersion medium is water, the therapeutic substance is sirolimus, and the surfactant is polysorbate,
The method of claim 22. The dispersion medium is hexane, the therapeutic substance is sirolimus, and the surfactant is a sorbitan fatty acid ester,
The method of claim 22. Cleaning the outer surface of the hollow stent loaded with the therapeutic material using a carbon dioxide spray cleaning system;
The method of claim 17. A method of loading a therapeutic substance into a lumen space of a hollow wire having a plurality of side openings forming a hollow stent, comprising:
Immersing the hollow stent in a suspension of small particles of therapeutic material in a dispersion medium;
Vibrating the hollow stent and the suspension to assist in moving the suspension through the plurality of side openings and into the lumen space of the hollow stent;
Removing the hollow stent from the suspension when the lumen space is substantially filled with the suspension, thereby creating a filled hollow stent;
By using vacuum oven drying to extract substantially all the remaining dispersion medium from the lumen space of the filled hollow stent while the therapeutic substance remains in the hollow stent, it is subsequently placed in the body cavity. Allowing said hollow stent to be loaded with said therapeutic substance for delivery to
A method characterized by that. Cleaning the outer surface of the hollow stent loaded with the therapeutic material using a carbon dioxide spray cleaning system;
27. The method of claim 26. The suspension also includes a surfactant to stabilize the dispersion of the therapeutic substance in the suspension, the dispersion medium is water, the therapeutic substance is sirolimus, and the The surfactant is polysorbate,
27. The method of claim 26. The suspension also includes a surfactant to stabilize the dispersion of the therapeutic substance in the suspension, the dispersion medium is hexane, the therapeutic substance is sirolimus, and the The surfactant is a sorbitan fatty acid ester,
27. The method of claim 26. Homogenization of the suspension is used to create nanoparticles of the therapeutic substance therein
27. The method of claim 26. The diameter of the small particles is less than 1 μm,
27. The method of claim 26. The diameter of the small particles is less than 100 nm,
27. The method of claim 26.