Spraying device with improved tip and method of manufacture

The invention provides a precision spraying device having an improved atomizing end for reproducibly forming droplets from small amounts of liquid with improved operational stability and spray pattern quality as well as a method of manufacturing. The invention further provides a method for reproducibly coating substrates using the spraying device of the present invention.

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Description
CROSS-REFERENCE TO RELATED APPLICATIONS

This application relates to and claims priority from commonly owned U.S. patent Application Ser. No. 11/545,282, filed on Oct. 10, 2006 and is a continuation-in-part of U.S. patent application Ser. No. 11/408,421, filed on Apr. 21, 2006.

FEDERALLY SPONSORED RESEARCH

Not Applicable

SEQUENCE LISTING OR PROGRAM

Not Applicable

TECHNICAL FIELD

The present invention relates to improved multiple fluid spraying devices for the controlled atomization of small liquid amounts and a method for providing a repeatable spray performance in terms of droplet size and spatial droplet distribution. The invention is particularly suitable for drug delivery applications, such as for the production of coated medical implants in which batch to batch reproducibility is crucial.

BACKGROUND OF THE INVENTION

In pharmaceutical and biomedical applications, including drug coating of medical devices, tablet coating, oral drug delivery, and tissue engineering there is a trend to use multiple fluid spraying devices to atomize liquid compositions typically comprising one or more therapeutic substances as well as components used to modulate drug release kinetics, to stabilize a drug and/or to increase drug solubility. For example, medical devices including stents, vascular grafts, catheters, and the like are typically coated using multiple fluid spraying devices to deliver a therapeutic substance to a lumen that reduces smooth muscle tissue proliferation. The reproducible and homogeneous distribution of the therapeutic substance depends mainly on the performance of the spraying device in terms of droplet size and droplet size distribution, which, in turn, is crucial for the success of the particular drug delivery application.

A typical multiple fluid spraying device is adapted to externally atomize small liquid amounts in the order of 0.1 to 100 ml/h by a compressible fluid. It comprises a body having at least a liquid orifice and a tip defining a space for receiving the compressible fluid and having a central orifice for discharging the compressible fluid through an annular gap formed between the liquid orifice and the body for the compressible gas.

However, spraying devices known by the prior art have several drawbacks. Common problems associated with conventional spraying devices are imperfections of the orifices in terms of roundness and surface quality due to spiral marks and burrs that may require secondary procedures such as electropolishing which, in turn, may result in manufacturing tolerance variations and/or out-of-roundness of the orifice. In addition, an inhomogeneous width of the gas annulus will have a negative impact on the spray quality. Thus, any imperfection and eccentricity between the axes of the liquid orifice and the tip can cause the flow of the atomizing gas to be cylindrically asymmetric with respect to the axis of the liquid exiting from the liquid orifice and will lead to nebulization of the liquid composition by the atomizing gas that is different on different sides of the spray plume.

Despite stringent quality control of the surface quality and concentricity of liquid and gas orifices, the spray performance of conventional spraying devices for the fine atomization of small liquid amounts remains generally poor.

Consequently, devices, even of the same type, will have different spray characteristics and poor spray quality and/or stability despite of optimum roundness and concentricity of the liquid and gas orifices. Poor reproducibility, especially from one spraying device to the next, is a common problem in the production of coated medical implants, since poor spray stability and droplets that are too large and polydisperse in size may lead to an inhomogeneous distribution of the therapeutic substance within the coating, which may, in turn, have a negative impact on the performance of the medical implants.

OBJECT OF THE INVENTION

Accordingly, there is a need for an improved spraying device to disintegrate small liquid amounts into fine droplets that overcomes the aforementioned problems with the prior art and improves the stability and performance of precision spraying processes such as medical stent coating.

One object is to provide a spraying device that provides a homogeneous spatial droplet distribution, a tight droplet size distribution and a consistent spray performance over time.

Another object is to provide a spraying device to atomize small liquid amounts that can be manufactured reproducibly resulting in a repeatable performance from one spraying device to the next.

Yet another object is to provide a reproducible and precise manufacturing method for machining the atomizing end of the spraying device.

A further object is to provide a method to apply a homogeneous coating on a medical device using the spraying device of the present invention.

Still another object is to provide a method to apply a homogeneous and reproducible coating on multiple medical devices using a plurality of spraying device of the present invention.

These and additional features and advantages of the invention will be more readily apparent upon reading the following description of exemplary embodiment of the invention and upon reference to the accompanying drawings herein.

SUMMARY OF THE INVENTION

In one embodiment, a device to disintegrate a liquid into fine droplets using an atomizing gas comprising a body having at least a liquid conduit extending from a liquid inlet to a liquid orifice and a tip defining a space for receiving the atomizing gas and having an inner tapered section extending to an orifice is provide. The tip is essentially coaxial with the body and an annular gap through which the atomizing gas is expelled is formed between the body and the orifice of the tip and at least the orifice of the tip and a portion of the inner tapered section of the tip are machined to minimize the error of concentricity therebetween so that during operation a gas stream with a substantially uniform gas velocity distribution about the perimeter of the annular gap is formed. In one or more embodiments, the orifice of the tip has a diameter of less than 1.2 mm and the error of concentricity between the orifice and said portion of the inner tapered section is less than 20 microns. At least a portion of the inner section of the tip may be machined in the same setup as the orifice of the tip. The tip is preferably machined by a turning operation. The spaying device can further comprise a centering section, which may be machined in the same setting as the orifice of the tip, wherein the centering section is used to align the tip in relation to the body and the error of concentricity between the orifice of the tip and the centering section is smaller than 20 microns. The liquid conduit of the spraying device may be free of constrictions and preferably consists of a capillary. Furthermore, the spraying device may comprise a second liquid inlet extending to a second liquid orifice surrounding and being essentially coaxial with the first liquid orifice to separately supply a second liquid, wherein the second liquid is disintegrated by the atomizing gas upon exiting the second liquid orifice and mixed with the first liquid. The device may also comprise electrostatic means to atomize the liquid.

In another embodiment, a method for manufacturing the tip of a spraying device having a body with a liquid conduit extending from a liquid inlet to a liquid orifice and a tip being essentially coaxial with the body and defining a space for receiving a fluid, the tip having a section for aligning the tip in relation to the body and an inner tapered section extending to an orifice for discharging the fluid, is provided. The method comprises the steps of machining the orifice of the tip and at least a portion of the inner tapered section of the tip in the same setup so that the error of concentricity therebetween is minimized.

In one or more embodiments, the step of machining the section for aligning the tip so that the error of concentricity between the orifice of the tip and the section for aligning the tip is smaller than 20 microns is also provided. The orifice of the tip and the section for aligning the tip are preferably machined in the same setup.

In still another embodiment, a method for manufacturing the tip of a spraying device having a body with a liquid conduit extending from a liquid inlet to a liquid orifice and a tip being essentially coaxial with the body and defining a space for receiving a fluid, the tip having a section for aligning the tip in relation to the body and a inner tapered section extending to an orifice with a diameter of less than 1.2 mm for discharging the fluid, is provided. The method comprises the steps of machining the inner tapered section of the tip and at least a portion of the tip in the same setup, clamping the tip on said machined portion and machining the orifice of the tip by a turning operation so that the error of concentricity between the orifice of the tip and the inner tapered section of the tip is minimized.

In yet another embodiment, a method to apply a coating to a medical device using a spraying device having a body with a liquid conduit extending from a liquid inlet to a liquid orifice and a tip being essentially coaxial with the body and defining a space for receiving an atomizing gas, the tip having an inner section extending to an orifice with a diameter of less than 1.2 mm for discharging the atomizing gas through an annular gap formed between the body and the orifice of the tip, is provided. The method includes the steps of feeding a liquid into the liquid conduit and feeding a gas into the gas conduit and forming a gas stream having a substantially uniform gas velocity distribution about the perimeter of the annular gap, disintegrating the liquid into fine droplets through the momentum of the gas emerging from the annular gap, directing the droplets within the gas stream to the medical device so that the droplet trajectories are uniformly distributed around the extended longitudinal axis of the spraying device, and forming a coating on the medical device.

In one or more embodiments, the error of concentricity between the inner section of the tip and the orifice of the tip is less than 20 microns. The volume median diameter of the generated droplets is preferably less than 10 microns. Also, the liquid flow may be directed at a substantially constant velocity from the liquid inlet to the liquid orifice. The droplet size variation produced by the spraying device is preferably less than 1%. The liquid can comprise a therapeutic substance and/or a polymeric component. In addition, the step of feeding a second liquid through an additional orifice positioned between the first liquid orifice and the orifice for the atomizing gas and disintegrating and mixing the second liquid with the first liquid through the momentum of the atomizing gas emerging from the annular gap may be provided.

In still another embodiment, a method to form a reproducible coating on multiple stents using multiple spraying devices is provided. The method includes the steps of providing multiple stents, providing multiple spraying devices having a body with at least a liquid orifice and a tip being essentially coaxial with the body and defining a space for receiving an atomizing gas, the tip having an inner section extending to an orifice for discharging the atomizing gas through an annular gap formed between the body and the orifice of the tip, feeding a liquid into each spraying device and feeding a gas into each spraying device and forming a gas stream with a substantially uniform gas velocity distribution about the perimeter of the annular gap, disintegrating the liquid into fine droplets through the momentum of the gas emerging from the annular gap so that the variation of the volume median diameter of the sprays produced by the separate spraying devices is less than 2%, directing the droplets within the gas streams to the medical devices so that the droplet trajectories are uniformly distributed around the extended longitudinal axis of the spraying device, and forming a coating on the stents.

In one or more embodiments, the orifice of the tip has a diameter of less than 1.2 mm and the error of concentricity between the inner section of the tip and the orifice of the tip is less than 20 microns. Also, the error of concentricity between the inner section and the orifice of the tip is preferably less than 1.7% of the orifice diameter of the tip.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute a part of this specification, serve to explain the principles of the invention. The drawings are in simplified form and not to precise scale. In the drawings:

FIG. 1A is a longitudinal cross-sectional view of the spraying device of the present invention;

FIG. 1B is an expanded view of the atomizing end of the spraying device of FIG. 1A;

FIG. 2A is a longitudinal cross-sectional view of an alternative embodiment of the spraying device;

FIG. 2B is an expanded view of the spraying device of FIG. 2A;

FIG. 3A shows the machining operation of the tip of the spraying device of the present invention;

FIG. 3B is a expanded view of the tip region shown in FIG. 3A;

FIG. 4 is a longitudinal cross-sectional detail view of the tip of a spraying device;

FIG. 5 is a CFD simulation of the velocity distribution of the atomizing gas within the annular gap of a spraying device;

FIG. 6 is a droplet size distribution comparison (Invention vs. Prior Art);

FIG. 7 is a comparison of the coefficient of variation (Invention vs. Prior Art);

FIG. 8 shows droplet size distributions of various individual spraying devices (Prior Art);

FIG. 9 shows droplet size distributions of various individual spraying devices;

FIG. 10 is a comparison of the coefficient of variation of ten nozzles (Invention vs. Prior Art);

FIG. 11 is a CFD simulation of a stent coating process (Prior Art); and

FIG. 12 is a CFD simulation of a stent coating process (Invention).

 DETAILED DESCRIPTION OF THE INVENTION

The method and apparatus of the present invention were developed in response to the specific problems encountered with various apparatus for disintegration of small liquid amounts into fine droplets to produce coated medical implants. Examples of such medical implants include heart valves, pacemakers, tissues, sensors, catheters, needle injection catheters, blood clot filters, vascular grafts, stent grafts, biliary stents, colonic stents, bronchial/pulmonary stents, esophageal stents, ureteral stents, aneurysm filling coils, and other coil devices.

Use of the spray coating system model is not intended to limit the applicability of the method to that field. It is anticipated that the invention can be successfully utilized in other circumstances such as in the field of inhalation formulation and in-vitro diagnostics.

The present invention comprises an improved spraying device and method for reproducibly atomizing small liquid amounts into fine droplets having a uniform droplet size distribution that are preferably applied to medical devices to form a coating. The invention is directed to enhance medical implant coating processes in terms of coating quality and reproducibility by providing an improved spraying device, a manufacturing method and quality criteria that ensure a consistent spray performance of a plurality of spraying devices of the same series used in a medical implant production process.

When coating medial implants, the liquid to be atomized may be supplied through one or more orifices and disintegrated using an atomizing gas. The liquid or liquid composition may comprise one or more film-forming agents, such as polymers, oils and/or fats, one or more solvents, and therapeutic substances. The composition can also include beneficial agents, plastizers, buffers to adjust the pH of the composition, surfactants to enhance wettability of poorly soluble or hydrophobic materials, stabilizers, radiopaque elements, and radioactive isotopes.

The therapeutic substance may include, but is not limited to proteins, hormones, vitamins, anti-microbacterial agents, antioxidants, DNA, antimetabolite agents, anti-inflammatory agents, anti-restenosis agents, anti-thrombogenic agents, antibiotics, anti-platelet agents, anti-clotting agents, chelating agents, or antibodies. Specific examples include hyaluronic acid (HA), Omega-3 fatty acids (DHA/EPA), Acetylsalicylic acid, Dexamethasone, M-prednisole, Interferon y-1b, Leflunomide, sirolimus, tacrolimus, everolimus, mizoribine, ABT-578, QP-2, Paclitaxel, actinomycin, methothrexate, angiopeptin, vincristine, mitomycine, statins, PCNA Ribozyne, Batimastat, Prolyl hydroxylase inhibitors, C-proteinase inhibitors, Probucol, Re-Endothelialization, BCP671, VEGF Estradiols, NO donors, EPC antibodies; antioxidants such as probucol and retinoic acid; angiogenic and anti-angiogenic agents; agents blocking smooth muscle cell proliferation such as rapamycin, angiopeptin, and monoclonal antibodies capable of blocking smooth muscle cell proliferation; anti-inflammatory agents such as dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, acetyl salicylic acid, and mesalamine, lipoxygenase inhibitors; calcium entry blockers such as verapamil, diltiazem and nifedipine; antineoplastic/antiproliferative agents such as paclitaxel, methotrexate, doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine, vincristine, colchicine, epothilones, endostatin, angiostatin, Squalamine, and thymidine kinase inhibitors; L-arginine; antimicrobials such as triclosan, cephalosporins, aminoglycosides, and nitorfurantoin; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine; anticoagulants such as D-Phe-Pro-Arg chloromethyl ketone, heparin, antithrombin compounds, anti-thrombin antibodies, anti-platelet receptor antibodies, aspirin, prostaglandin inhibitors, platelet inhibitors; vascular cell growth promoters such as growth factors, growth factor receptor antagonists, transcriptional activators, and translational promoters; vascular cell growth inhibitors such as growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors; and cholesterol-lowering agents.

Examples of suitable biocompatible film-forming agents include, but are not limited to, synthetic polymers including polyethylen (PE), poly(ethylene terephthalate), polyalkylene terepthalates such as poly(ethylene terephthalate) (PET), polycarbonates (PC), Polyvinylpyrrolidone (PVP), polyvinyl halides such as polyvinyl chloride) (PVC), polyamides (PA), poly(tetrafluoroethylene) (PTFE), poly(methyl methacrylate) (PMMA), polysiloxanes, ethylene-vinyl acetate (EVAc), polyurethane polysiloxanes, and poly(vinylidene fluoride) (PVDF); biodegradable polymers such as poly(glycolide) (PGA), poly(lactide) (PLA) and poly(anhydrides) poly(lactic-co-glycolic acid) (PLGA), PEG-PLA-PEG, PEG-PLGA-PEG, PEG-PCL-PEG, PLA-PEG-PLA, PHB, P(PF-co-EG) ±acrylateend groups, P(PEG/PBO terephthalate), PEG-bis-(PLA-acrylate), PEG6CDs, PEG-g-P(AAm-co-Vamine), PAAm, P(NIPAAm-co-AAc), P(NIPAAm-co-EMA), PVAc/PVA, PNVP, P(MMA-co-HEMA), P(AN-co-allylsulfonate), P(biscarboxy-phenoxy-phosphazene), P(GEMA-sulfate); natural polymers and their derivatives including HA, alginic acid, pectin, carrageenan, chondroitin sulfate, dextrane, sulfate, chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, chitosan, fibrin, collagen, dextran, agarose, pullulan, sclerogluan, cellulose, albumin, silk; and combinations of natural and synthetic polymers including P(PEG-co-peptides), alginate-g-(PEO-PPO-PEO), P(PLGA-co-serine), collagen-acrylate, alginate-acrylate, P(HPMA-g-peptide), P(HEMA/Matrigel), HA-g-g-NIPAA. Alternatively or in addition, bio-compatible mineral, vegetable or animal oils may be used including fish oil, cod-liver oil, olive oil, linseed oil, sunflower oil, corn oil, and/or palm oil.

The solvents used for dissolving the film-forming component and the therapeutic substance are selected based on their biocompatibility and solubility of the material to be dissolved. Aqueous solvents can be used to dissolve water-soluble materials, such as Poly(ethylene glycol) (PEG) and organic solvents may be selected to dissolve hydrophobic and some hydrophilic materials. Examples of suitable solvents include methylene chloride, ethyl acetate, ethanol, methanol, dimethyl formamide (DMF), acetone, acetonitrile, tetrahydrofuran (THF), acetic acid, dimethyle sulfoxide (DMSO), toluene, benzene, acids, butanone, water, hexane, and chloroform, N-methylpyrrolidone (NMP), 1,1,2-trichloroethane (TCE), various freons, dioxane, ethyl acetate, cyclohexanone, and dimethylacetamide (DMAC). For the sake of brevity, the term solvent is used to refer to any fluid dispersion medium whether a solvent of a solution or the fluid base of a suspension, as the invention is applicable in both cases.

The spraying apparatus of the present invention, which is described in more detail in FIGS. 2 and 3 below, includes a body having at least a liquid conduit extending from a liquid inlet to a liquid orifice and a tip for receiving and defining a space for an atomizing gas that may be fed through one or more gas inlets. The tip is provided at the atomizing end of the spraying device and surrounds the liquid orifice such that an intermediate space (annular gap) is formed between the body and the tip through which an atomizing gas is expelled. The spraying device is designed to allow the precise and repeatable machining of the inner surface of the tip, the centering section between tip and body and the tip orifice to ensure optimized concentricity and surface quality of the atomizing end of the spraying device.

While the invention will be described in connection with certain embodiments, it will be understood that the invention is not limited to these embodiments. On the contrary, the invention includes all alternatives, modifications and equivalents as may be included within the spirit and scope of the present invention. Details in the Specification and Drawings are provided to understand the inventive principles and embodiments described herein, to the extent that would be needed by one skilled in the art to implement those principles and embodiments in particular applications that are covered by the scope of the claims. All dimensions used herein are suggestive and not intended to be restrictive.

FIG. 1A is a longitudinal cross-sectional view of an exemplary spraying device of the present invention. An expanded view of the atomizing end of the spraying device is provided in FIG. 1B.

The spraying device comprises a body 2 and a tip 3. The body 2 includes a central liquid conduit, which extends from liquid inlet 4 to liquid orifice 15 and gas passages 6 surrounding the fluid conduit in which gas is fed through gas inlets 5. The liquid orifice typically comprises an orifice having a diameter within the range from 0.05 to 0.5 mm. The tip 3 is mounted by securing ring 8 to the body 2 and a small annular gap 16 is provided to permit passage of gas therethrough from the gas passages 6. Tip 3 has typically a tapered inner section 72 having extending to orifice 16. The diameter of the atomizing end of the body and the orifice diameter of the tip define the width of the annulus. To ensure that the center of the liquid orifice 15 runs coaxial to the center of the annular gap 16 there is provided a centering section on the outer surface of the tip to align the tip in relation to the body, as depicted in FIG. 2B by arrow 7. Thus, tip 3 can be easily removed for maintenance and cleaning without the risk of misalignment between the tip and body during assembling and disassembling.

Alternatively, as shown in FIGS. 2A and 2B the tip of the spraying device may have a centering section 7 on the inner surface of the tip 3. The tip orifice 16, tapered inner section 72 and centering section 7 of the tip are substantially concentric to ensure a precise alignment between tip 3 and body 2. The liquid conduit is comprised of a capillary being stabilized within the body proximate to the liquid exit, as described in U.S. patent application Ser. No. 11/545,282, to ensure a constant liquid velocity along the fluid path of the spraying device and to minimize pulsation of the liquid flow. The tapered inner section of the tip is designed and manufactured such that a smooth high-precision surface is obtained and the error of concentricity between the axis of orifice and axis of inner tapered section is smaller than 20 microns, as described in more detail in FIGS. 3A and 3B below.

The spraying device may also include means to generate a vortical flow of the compressed gas. The body of the spraying device is preferably made from a metallic material such as stainless steel. Alternatively, a polymeric material such as PEEK can be used. The tip may be made from a metallic material such as stainless steel, titan and the like. The tip may further comprise additional bores to provide various spray patterns such as a flat spray.

The spraying device may be connected via liquid inlet 4 to means to supply the liquid to be atomized, and via gas inlets 5 to means to supply the atomizing gas (not shown). Typically, the gas used to disintegrate the liquid is chemically inert with respect to the liquid components. Suitable inert gases include, air, nitrogen, and the like. Pressurized air represents an economical atomizing gas, which may be supplied using pressurized tanks or cylinders as well as compressors. The liquid is preferably fed using a high-accuracy syringe pump to ensure precise control of the liquid supply.

In operation, the liquid to be atomized is supplied through inlet 4. The atomizing fluid (compressed gas) is fed into gas inlets 5, travels through gas passages 6 extending from gas inlets 5 via a portion substantially coaxial to the liquid line to a conical portion defined by the tip 3 and exits the atomizer trough annular gap 16. The liquid flows from liquid inlet port 4 through the liquid conduit to the atomizing end and is disintegrated into fine droplets by the atomizing gas outside the spraying device upon exiting orifice 15.

It may be desirable to furthermore provide electrostatic means to assist the liquid disintegration process. A high voltage source can be electrically connected to the liquid conduit of the spraying device while portions of the spraying devices are electrically isolated from the liquid conduit.

The present invention is particularly useful when mixing multiple liquids, since the quality of the tip of the spraying device is crucial for a uniform velocity distribution around the angular gap and a reproducible liquid disintegration and mixing process. In an alternative embodiment, the spraying may comprise an additional liquid inlet extending to a second liquid conduit to feed a second liquid separately to a second liquid orifice surrounding the first liquid orifice. An additional annular gap is provided between the body and the second orifice. The tip of the spraying device is designed and manufactured such that an optimized concentricity and surface quality as well as alignment to the liquid orifice are provided. The spraying apparatus is preferably connected to means to separately supply either simultaneously or consecutively at least two liquids, such as a composition comprising a polymeric component and a composition comprising a therapeutic agent, and an atomizing gas. In operation, a first liquid may be fed into the first liquid conduit and directed to the first orifice and a second liquid into second liquid conduit and directed to the second orifice. The atomizing gas may be supplied to one or more gas inlets, directed through passages to the gas orifice and discharged through the gas orifice with an equal velocity distribution around the gas annulus. The first and second liquids are disintegrated and homogeneously mixed by the aerodynamic forces upon exiting the liquid orifices and a fine spray is obtained.

In order to improve the spray performance and reproducibility beneath individual spraying devices and to assure a reproducible quality within a plurality of devices of the same type, a manufacturing procedure for machining the atomizing end of the spraying device has been developed.

The manufacturing procedure of the tip of the spraying device, which is schematically visualized in FIGS. 3A and 3B, consists in drilling a bore having a diameter smaller than the diameter of the finished orifice and machining tip orifice 16, inner surface 72 and centering section 35 in one setting. Tip orifice 16 and inner surface of the tip are preferably machined by internal turning and centering section 35 by external turning. Alternatively, the inner surface of the tip and the orifice may be bored out or grinded.

The manufacturing procedure of the tip of the spraying device, which is schematically visualized in FIGS. 3A and 3B, consists in drilling a bore having a diameter smaller than the diameter of the finished orifice and machining tip orifice 16 and at least a portion of the inner surface 72 and preferably centering section 7 to minimize the error of concentricity between orifice 16 and inner surface 72. The machining operations are preferably performed in the same setting. In one embodiment the tip orifice 16 and the inner surface of the tip are preferably machined by internal turning and centering section 7 by external turning. Alternatively, the inner surface of the tip and the orifice may be bored out or grinded.

As shown in FIG. 3B, a small bore tool 75 having cutting edge 74 may be moved along the final machining path illustrated by line 73. The machining path extends from the tapered inner section of the tip to orifice 16 such that a smooth transition between tapered section and orifice is ensured. By machining the inner surface of the tip 72 including the tip orifice in one setup an improved concentricity, roundness and smooth finish of tip inner surface and orifice as well as annular gap is obtained. The centering section 7 may preferably at least partially manufactured in the same setup as shown by machining path 76. By manufacturing the final shape of the orifice, the inner surface of the tip and the centering section in the same setup an improved concentricity is obtained resulting in a optimized alignment between body orifice 15 and tip 3 orifice.

Thus, the concentricity between the axis of body orifice 15 and the axis of orifice 16 of tip 3 is substantially improved compared to prior art atomizers. In addition, a repeatable and cost-effective manufacturing method of the tip of the spraying device which is crucial for the spray performance of the spraying apparatus is provided resulting in improved accuracy of the spraying device compared to conventional machining methods based on machining the tip in several setups.

In order to demonstrate the spray quality of the spraying device of the present invention as well as the spray performance of several spraying devices within a series with respect to prior art devices, various spray tests have been conducted as described below.

Droplet Size Consistency Comparison

To compare the performance of the spraying device of the present invention in terms of atomization consistency over time a droplet size analysis has been conducted.

The spray performance of the spraying device of the present invention shown in FIG. 2 with an orifice diameter of 0.8 mm has been compared to a prior art spraying device having an orifice diameter of 1.1 mm. The prior art spraying device has been inspected using a microscope and SEM to ensure that the annular gap has a homogeneous width and the orifices have an optimum concentricity and roundness. Thus, the prior art spraying device meets known quality criteria and is expected to produce a stable and homogenous spray.

A Laser Diffractometer (Sympatec, Lawrenceville, N.J.) which was located 30 mm downstream from the orifice of the spraying devices was used to measure the droplet distributions. A polymer solution comprising of 11 mg/ml PBMA dissolved in THF was supplied by a syringe pump (Hamilton Company, Reno, Nev.) at a flow rate of 15 ml/h to the liquid inlet of the spraying device. The atomizing gas was fed at a flow rate of 8 l/min into the gas inlet. Ten measurement runs have been conducted with a duration of 10 seconds per run.

Referring to FIG. 6, ten measurements of the droplet size distributions are shown for both the spraying device of the present invention and of the prior art. It can be seen, that the droplets generated by the prior art atomizing device have an inconsistent size compared to the spraying device of the present invention.

Furthermore, the coefficient of variation (COV) has been calculated for the ×10, ×50, ×90, ×99 and the volume median diameter (VMD) value as shown in Tables 1 and 2 below.

TABLE 1 PRIOR ART Droplet size measurement of one spraying device during 10 meas. runs Meas. ×10 [μm] ×50 [μm] ×90 [μm] ×99 [μm] VMD [μm] 1 1.46 8.29 16.93 25.8 8.82 2 1.45 8.21 16.81 25.44 8.73 3 1.45 8.14 16.75 25.41 8.67 4 1.47 8.22 17.11 28.24 8.88 5 1.47 8.28 17.15 28.17 8.92 6 1.48 7.92 17.10 28.20 8.68 7 1.46 8.18 17.09 28.46 8.89 8 1.46 8.20 17.12 28.47 8.91 9 1.46 8.20 17.1 28.16 8.85 10  1.45 8.27 17.43 32.99 9.13 Mean 1.46 8.19 17.06 27.93 8.85 COV [%] 0.7 1.3 1.1 7.9 1.5

TABLE 2 INVENTION Droplet size measurement of one spraying device during 10 meas. runs Meas. ×10 [μm] ×50 [μm] ×90 [μm] ×99 [μm] VMD [μm] 1 0.76 4.21 8.51 12.47 4.36 2 0.76 4.20 8.50 12.46 4.36 3 0.76 4.21 8.52 12.46 4.37 4 0.76 4.21 8.52 12.47 4.37 5 0.76 4.21 8.51 12.45 4.36 6 0.76 4.21 8.52 12.46 4.37 7 0.76 4.21 8.52 12.47 4.37 8 0.76 4.21 8.52 12.48 4.37 9 0.76 4.22 8.53 12.47 4.37 10  0.76 4.20 8.52 12.48 4.36 Mean 0.76 4.21 8.52 12.47 4.37 COV [%] 0.0 0.1 0.1 0.1 0.1

FIG. 7 illustrates the coefficient of variation of ten droplet size measurements of both the spraying device of the present invention and for the prior art spraying device. The droplet size variation over time of the prior art spraying device is 0.7% for the ×10 value and 1.3% for the ×50 value and 7.9% for the ×99 value. In contrast, the spraying device of the current invention generates droplets having a consistent size during the entire spray run that are significantly smaller than the values obtained for the prior art spraying device, resulting in a droplet size variation between 0% and 0.1%.

Droplet Size Variation Comparison

Droplet size distribution measurements for ten individual spraying devices for both the spraying device of the present invention and of the prior art have been conducted as described below.

Ten individual spraying devices of the present invention shown in FIG. 3 having an orifice diameter of 1.1 mm have been compared to ten individual prior art spraying device having an orifice diameter of 1.1 mm. The prior art spraying devices have been inspected using a microscope and SEM to ensure that the annular gap has a homogeneous width and the orifices have an optimum concentricity and roundness. Thus, the prior art spraying devices meet known quality criteria and are expected to produce a stable and homogenous spray.

A droplet size analysis has been performed using a Laser Diffractometer (Sympatec, Lawrenceville, N.J.), which was located 30 mm downstream from the orifice of the spraying devices. Deionized water was supplied by a syringe pump (Hamilton Company, Reno, Nev.) at a flow rate of 15 ml/h and the atomizing gas was fed at a flow rate of 8 l/min into the gas conduit of the atomizer.

FIG. 8 depicts ten individually measured droplet size distributions of ten prior art spraying devices and FIG. 9 ten individually measured droplet size distributions of ten spraying devices of the present invention. It can be seen, that there large performance deviations between the prior art devices. In contrast, the spraying devices of the present invention produce a consistent spray performance.

To quantify the performance deviations between the atomizers the coefficient of variation (COV) has been calculated for the ×10, ×50, ×90, ×99 and for the VMD value as shown in the Tables 3 and 4 below.

TABLE 3 PRIOR ART Droplet size measurement of 10 individual spraying devices Device ×10 [μm] ×50 [μm] ×90 [μm] ×99 [μm] VMD [μm] 1 2.50 11.98 23.61 46.65 13.06 2 1.99 10.01 20.10 31.80 10.82 3 2.53 11.90 22.09 33.68 12.35 4 2.72 13.01 23.99 35.29 13.41 5 2.31 11.80 20.71 31.51 11.97 6 3.35 12.85 20.68 30.54 12.75 7 2.26 11.17 22.99 40.71 12.31 8 2.13 10.70 21.14 35.22 11.54 9 2.40 11.65 22.88 37.09 12.47 10  2.23 11.10 21.88 35.81 11.93 Mean 2.44 11.62 22.01 35.83 12.26 COV [%] 15.6 7.9 6.1 13.5 6.1

TABLE 4 INVENTION Droplet size measurement of 10 individual spraying devices Device ×10 [μm] ×50 [μm] ×90 [μm] ×99 [μm] VMD [μm] 1 2.69 12.42 24.17 36.74 13.20 2 2.57 12.13 23.37 35.68 12.80 3 2.70 12.66 24.27 37.22 13.35 4 3.02 12.18 22.72 36.13 12.82 5 2.58 11.99 23.38 35.59 12.73 6 2.83 12.76 24.22 36.81 13.40 7 2.64 12.09 23.85 36.38 12.93 8 2.67 12.30 23.99 36.22 13.08 9 2.51 11.99 23.68 35.97 12.81 10  2.55 12.07 23.92 36.33 12.92 Mean 2.68 12.26 23.76 36.31 13.00 COV [%] 5.7 2.2 2.0 1.4 1.9

As shown in FIG. 10, the variation between the ten prior art spraying devices is 15.6% for the ×10 value, 7.9% for the ×50 value and 13.5% for the ×99 value and the variation between the ten spraying devices of the present invention is 5.7% for the ×10 value, 2.2% for the ×50 value and 1.9% for the ×99 value. It can be seen that the performance deviations between the spraying devices of the present invention are significantly smaller than the performance deviations between the prior art spraying devices.

The results of the spray tests described above outline the advantages of the design and manufacturing methodology adopted for the spraying device of the present invention in terms of droplet size and droplet size consistency during several spray runs and performance consistency between several spraying devices.

The prior art devices showed a poor performance and considerable performance deviation despite having a high quality atomizing end (annular gap with a homogeneous width about the perimeter and orifices with an optimum concentricity and roundness).

It has been demonstrated that the spray performance is considerably affected by an error in concentricity between the axis of the inner section of the tip and the axis of the tip orifice. FIG. 4 is a schematic representation of an exemplary error in concentricity resulting in an eccentricity between axis 71 of inner tapered section 72 and axis 70 of tip orifice 16.

To visualize the impact of the concentricity between the inner tapered surface of the tip and the tip orifice on a stent coating process, several computational fluid dynamics (CFD) simulations have been performed. FIG. 5 shows an inhomogeneous gas velocity within the annular gap resulting from an error in concentricity of the tip, which may lead as shown in FIG. 12 to a nebulization of the liquid composition by the atomizing gas that is inhomogeneous on different sides of the spray plume.

FIGS. 11 and 12 show the droplet trajectories with respect to the stent to be coated. The axis of the stent and the axis of the spraying device were located on the same plane at a distance of 14 mm downstream from the nozzle and the droplet trajectories were calculated for droplets having a diameter of 10 microns. Referring to FIG. 11, a model of the spraying apparatus of the present invention as shown in FIG. 3 and a substantially concentric alignment and a minimized error of concentricity between inner tapered section of tip and tip orifice is depicted. It can be seen, that the atomizing gas exits the gas orifice 16 and transports the droplets that are discharged from the liquid orifice to the stent 54 so that the droplet trajectories are uniformly distributed around the extended longitudinal axis of the spraying device resulting in a homogeneous droplet distribution in relation to the stent 54. This is due to the uniform velocity distribution of the atomizing gas about the perimeter of the annulus, which is the presumption for reproducible homogeneous coatings. FIG. 12 represents a model of the prior art spraying apparatus having an annular gap with a constant width and a small error of concentricity between inner tapered section of the tip and the tip orifice of about 20 microns. Due to the inhomogeneous gas velocities about the perimeter of the gas annulus 16 the droplet transport process is disturbed and the droplet trajectories are shifted in relation to the axis of the spraying device resulting in an inhomogeneous droplet distribution in relation to stent 54. It has been demonstrated that small imperfections of the tip have a considerable impact on the droplet disintegration and transportation process and will result in overspray (droplets don't reach spray target) and inhomogeneous coatings (stent is not homogeneously covered by droplet) leading to coating weight deviations and an inhomogeneous distribution of the therapeutic substance.

Thus, small imperfections of the tip have a considerable impact on the droplet disintegration and transportation process and will result in overspray (droplets don't reach spray target) and inhomogeneous coatings (stent is not homogeneously covered by droplet) which may result in coating weight deviations and an inhomogeneous distribution of the therapeutic substance used un the specific drug delivery application.

The following example has been provided to illustrate the advantages of the present invention in a stent coating application. Stents are tiny, expandable mesh tubes supporting the inner walls of a lumen used to restore adequate blood flow to the heart and other organs that were coated according to the method of the present invention.

Stent Coating Example

Multiple stents having a diameter of 2 mm and a length of 20 mm were inspected using a microscope and weighted with a microbalance before applying a coating composition comprising a polymer and a therapeutic agent to obtain a target coating weight of 320 μg as described below.

The stents were mounted on a holding device as described in U.S. Pat. App. No. 60/776,522 incorporated herein as a reference. The spraying device of FIG. 4 was used to disintegrate the coating composition into fine droplets and apply the coating to the stents.

For best results, the spraying device may be aligned in relation to the stent so that the spray axis of the atomizer is perpendicular to the rotation axis of the stent and both axes are in the same plane. The orifice of the spraying device is preferably positioned at a distance of approximately 12 to 35 mm from the outer surface of the stent.

The liquid inlet of the spraying device is connected to a liquid supply source. A syringe pump (Hamilton Inc., Reno, Nev.) is preferably used to feed the coating composition to the spraying device. The compressed gas is fed into the spraying device. The gas flow rate may range between 3 and 10 l/min and the flow rate of the coating solution may be in the order of 0.5 ml/h to 50 ml/h. The spraying device can disintegrate the coating solution into fine droplets.

The liquid is supplied to the liquid conduit of the spraying device having a constant diameter and the liquid is directed at a constant liquid velocity from the liquid inlet to the liquid orifice. The gas is fed into the gas conduit and flows through a tapered section to the gas annulus and a homogeneous gas velocity is produced about the perimeter of the annular gap. The expelled gas stream impinges on the liquid emerging from the liquid orifice and disintegrates the liquid into fine droplets.

The spraying process may be monitored using an optical patternator in order to ensure that the spatial droplet distribution of the generated spray plume is in the desired limits as described in U.S. Pat. App. No. 60/674,005 incorporated by reference herein.

During the application of the coating solution, rotary motion is transmitted to the stent to rotate the stent about its central longitudinal axis. The rotation speed can be from about 5 rpm to about 250 rpm. By way of example, the stent may rotate at 130 rpm. The stent is translated along its central longitudinal axis along the atomizer. The translation speed of the stent can be from about 0.2 mm/s to 8 mm/s. When applying the coating solution, the translation speed is preferably 0.5 mm/s. The stent can be moved along the atomizer one time to apply the coating in one pass or several times to apply the coating in several passes. Alternatively, the atomizer may be moved one time or several times along the stent length.

After application of the coating, the coated stents were inspected and weighted to determine the coating weight. The coefficient of variation of the coating weight was only 1.4% which outlines the superior performance and accuracy of the spraying device of the present invention.

It has been demonstrated, that using the spraying device of the present invention a stable coating process is obtained resulting in homogeneous high-accuracy coatings with a reproducible coating weight.

The stent coating example outlines the impact of the spray characteristics of the spraying device on the coating quality and reproducibility. Deviations of the quantity and of the distribution of the therapeutic agent in the coating, which may have a negative impact on the particular drug delivery application, can be therefore prevented.

Claims

1. A device to disintegrate a liquid into fine droplets using an atomizing gas comprising wherein

a body having at least a liquid conduit extending from a liquid inlet to a liquid orifice
and a tip defining a space for receiving the atomizing gas and having an inner tapered section extending to an orifice
the tip is essentially coaxial with the body and an annular gap through which the atomizing gas is expelled is formed between the body and the orifice of the tip
and at least the orifice of the tip and a portion of the inner tapered section of the tip are machined to minimize the error of concentricity therebetween so that during operation a gas stream with a substantially uniform gas velocity distribution about the perimeter of the annular gap is formed.

2. The device according to claim 1, wherein the orifice of the tip has a diameter of less than 1.2 mm and the error of concentricity between the orifice and said portion of the inner tapered section is less than 20 microns.

3. The device according to claim 1, wherein at least said portion of the inner section of the tip is machined in the same setup as the orifice of the tip.

4. The device according to claim 1, wherein the tip is machined by a turning operation.

5. The device according to claim 1, wherein the tip further comprises a centering section to align the tip in relation to the body and the error of concentricity between the orifice of the tip and the centering section is smaller than 20 microns.

6. The device according to claim 5, wherein the centering section is machined in the same setup as the orifice of the tip.

7. The device according to claim 1, wherein the liquid conduit is free of constrictions.

8. The device according to claim 7, wherein the liquid conduit is comprised of a capillary.

9. The device according to claim 1, further comprising a second liquid inlet extending to a second liquid orifice surrounding and being essentially coaxial with the first liquid orifice to separately supply a second liquid, wherein the second liquid is disintegrated by the atomizing gas upon exiting the second liquid orifice and mixed with the first liquid.

10. The device according to claim 1, further comprising electrostatic means to atomize the liquid.

11. (canceled)

12. (canceled)

13. (canceled)

14. (canceled)

15. Method to apply a coating to a medical device using a spraying device having a body with a liquid conduit extending from a liquid inlet to a liquid orifice and a tip being essentially coaxial with the body and defining a space for receiving an atomizing gas, the tip having an inner section extending to an orifice with a diameter of less than 1.2 mm for discharging the atomizing gas through an annular gap formed between the body and the orifice of the tip, comprising the following steps:

feeding a liquid into the liquid conduit and feeding a gas into the gas conduit and forming a gas stream having a substantially uniform gas velocity distribution about the perimeter of the annular gap;
disintegrating the liquid into fine droplets through the momentum of the gas emerging from the annular gap;
directing the droplets within the gas stream to the medical device so that the droplet trajectories are uniformly distributed around the extended longitudinal axis of the spraying device; and
forming a coating on the medical device.

16. The method of claim 15, wherein the error of concentricity between the inner section of the tip and the orifice of the tip is less than 20 microns.

17. The method of claim 15, wherein the volume median diameter of the generated droplets is less than 10 microns.

18. The method of claim 15, wherein the liquid flow is directed at a substantially constant velocity from the liquid inlet to the liquid orifice.

19. The method of claim 15, wherein the droplet size variation is less than 1%.

20. (canceled)

21. The method of claim 15, wherein the liquid comprises a polymeric component.

22. The method of claim 15, further comprising the step of feeding a second liquid through an additional orifice positioned between the first liquid orifice and the orifice for the atomizing gas and disintegrating and mixing the second liquid with the first liquid through the momentum of the atomizing gas emerging from the annular gap.

23. Method to form a reproducible coating on multiple stents using multiple spraying devices comprising the following steps:

providing multiple stents;
providing multiple spraying devices having a body with at least a liquid orifice and a tip being essentially coaxial with the body and defining a space for receiving an atomizing gas, the tip having an inner section extending to an orifice for discharging the atomizing gas through an annular gap formed between the body and the orifice of the tip;
feeding a liquid into each spraying device and feeding a gas into each spraying device and forming a gas stream with a substantially uniform gas velocity distribution about the perimeter of the annular gap;
disintegrating the liquid into fine droplets through the momentum of the gas emerging from the annular gap so that the variation of the volume median diameter of the sprays produced by the separate spraying devices is less than 2%;
directing the droplets within the gas streams to the medical devices so that the droplet trajectories are uniformly distributed around the extended longitudinal axis of the spraying device; and
forming a coating on the stents.

24. The method of claim 23, wherein the orifice of the tip has a diameter of less than 1.2 mm and the error of concentricity between the inner section of the tip and the orifice of the tip is less than 20 microns.

25. The method of claim 23, wherein the error of concentricity between the inner section and the orifice of the tip is less than 1.7% of the orifice diameter of the tip.

Patent History
Publication number: 20100075019
Type: Application
Filed: Oct 9, 2007
Publication Date: Mar 25, 2010
Inventor: Ingo Scheer (La Jolla, CA)
Application Number: 12/443,170
Classifications
Current U.S. Class: Liquid Conveying (e.g., Vascular, Arterial, Bile Duct, Urethra) (427/2.25); Rigid Fluid Confining Distributor (239/589); Electrostatic Type (239/690)
International Classification: B05D 7/00 (20060101); B05B 1/00 (20060101); B05B 5/00 (20060101);