INVENTION TITLE

Method and apparatus to disintegrate liquids having a tendency to solidify

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Patent Application No. 11/541 ,833, filed October 02, 2006, the contents of which are herein incorporated by reference.

FEDERALLY SPONSORED RESEARCH

Not Applicable

SEQUENCE LISTING OR PROGRAM Not Applicable

BACKGROUND OF THE INVENTION - FIELD OF INVENTION

The present invention relates generally to a method and an apparatus for disintegration of small liquids amounts into fine droplets. More particularly the invention relates to an improved method for disintegrating and mixing of liquids comprising a therapeutic substance.

BACKGROUND OF THE INVENTION

In pharmaceutical and biomedical applications, such as drug coating of medical devices, tablet coating, oral drug delivery, and tissue engineering there is a trend to atomize liquid compositions comprising one or more therapeutic substances and at least a polymeric component to modulate drug release kinetics, work as stabilizing agent, increase drug solubility, and the like.

Such liquid compositions may be applied to medical implants including vascular grafts, catheters or stents to deliver a therapeutic substance to a lumen that reduces smooth muscle tissue proliferation. It is therefore crucial to ensure a homogeneous distribution of the coating composition and in particular of the therapeutic substance on the device to be coated to achieve the desired effect. Known technologies for applying compositions to a substrate include, among others, using a spraying device for depositing a previously mixed composition, using several spraying devices for mixing two or more compositions before deposition on the substrate and using a spraying device for mixing several separately delivered compositions being supplied through a plurality of circumferentially spaced individual orifices before deposition on the substrate. However, conventional devices and processes tend to provide inadequate mixing of the polymeric component and the therapeutic substance, especially in cases where small amounts of liquid compositions having a tendency to solidify are prepared. Spraying a composition comprising a polymeric

component and/or a therapeutic substance may lead to poor process reproducibility due to batch to batch variation in particle size resulting from particle sedimentation and/or aggregation. In addition, when using spraying devices having a plurality of circumferentially spaced individual orifices for the supply of several liquids and atomizing gas large droplet sizes and poor mixing of the liquids to be atomized are a common problem. Furthermore, when mixing two liquid compositions using separate spraying apparatuses being arranged such that the respective sprays intersect each other homogenous mixing of the liquids may be difficult to achieve. This will result in an inhomogeneous distribution of the separately supplied liquid composition as illustrated in FIG. 1.

Another drawback of conventional spraying apparatuses and processes is nozzle build-up due to drying and hardening of the liquid to be atomized. Build-up can occur at the tip of the spraying device and on the inner wall of the liquid and gas conduits. A film of dried product may narrow the conduits and orifices of the spraying device, particularly as the build-up increases overtime. As the dimension of the nozzle orifice is critical to produce homogeneous coatings, the coating typically becomes more irregular due to the deterioration of the spray performance resulting in larger and more unevenly sized droplets.

Thus, prior art systems have limitations when atomizing liquids comprising a fast drying component and a therapeutic substance in terms of process stability and spray quality. This may result not only in expensive maintenance and increased waste of hazardous and/or expensive material, but gives also rise to quality problems, which may have a negative impact on the performance of the particular drug delivery carrier.

OBJECT OF THE INVENTION

The principal aim of the present invention is to provide a new method and apparatus of atomizing at least a first liquid containing a film-forming or polymeric component and a second liquid preferably comprising one or more therapeutic substances, while ensuring an efficient and reproducible liquid disintegration and mixing process and preventing the crystallization and/or sedimentation of particles leading to nozzle clogging and the development of foreign matter.

One object is to provide a reproducible and flexible process to coat a substrate by mixing at least two compositions comprising on or more therapeutic substances during the spraying process while ensuring an efficient disintegration of the compositions into small droplets having a tight droplet size distribution and a homogeneous distribution of the therapeutic substance.

Still another object is to provide a new and improved method of preventing clogging of a spraying apparatus during spraying and non-spraying periods. Yet another object of the present invention is to reduce maintenance time and costs.

A further object of the present invention is to provide new and improved devices for carrying out the method of the present invention.

Other objects and advantages of the invention will become apparent from the description of the embodiments and the drawings and will be in part pointed out in more detail hereinafter.

75 The invention consists in the features of construction, combination of elements and arrangement of parts exemplified in the construction hereinafter described and the scope of the invention will be indicated in the appended claims.

SUMMARY OF THE INVENTION

80

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 small droplets, which comprise one or more therapeutic substances and have a tendency to solidify. A system for spray coating medical devices is used as the model for description of the method and apparatus of the 85 present invention. Examples of such medical implants include 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 90 the field of inhalation formulation, and in pharmaceutical production processes including spray drying and m icroencapsulation.

The present invention comprises an improved method and apparatus of disintegrating and mixing two or more liquids, and in particular two or more solutions, dispersions, suspensions, and/or emulsions. The liquids generally comprise a film-forming, generally comprising a polymeric component, and typically 95 a therapeutic substance.

In one embodiment, an apparatus to reproducibly form a spray having small droplets from at least two separately supplied and disintegrated liquids is provided. The apparatus comprises at least a first conduit to feed a small amount of a first liquid into a mixing conduit, a second conduit to feed a small amount of a second liquid into a mixing conduit; a mixing conduit extending from a first portion in which a

100 gas is introduced to a second portion in which an outlet aperture is provided, and means to respectively supply the first liquid, the second liquid and the gas to the dedicated conduit. The first and second liquid inlets are provided between the first and second portion of the mixing conduit. The first and second liquid conduits protrude into the mixing conduit to allow liquid break-up into droplets at the tip of the first and second liquid conduits by the gas stream. The droplets are mixed and transported by the gas stream to

105 the outlet aperture such that material build-up on the interior wall of the mixing conduit is prevented and a spray plume of thoroughly mixed droplets is produced. In one or more embodiments, the first liquid comprises a polymeric component and the second liquid comprises a beneficial agent. During spraying inactivity a liquid may be supplied to cover at least one liquid orifice such that nozzle clogging is prevented. Furthermore, an additional liquid may be supplied to prevent nozzle clogging during spraying

110 activity. The droplets may be transported within the gas stream to a substrate, such as a medical implant, and a coating is applied.

In another embodiment, an apparatus to reproducibly form a single spray having small droplets from at least two separately supplied and disintegrated liquids and to prevent nozzle clogging is provided. It comprises at least a first conduit having an orifice to feed a first liquid into a mixing conduit, at least a

115 second conduit having an orifice to feed a second liquid into a mixing conduit, a mixing conduit extending from a portion for receiving the first and second liquid via a portion for mixing the droplets of the first and second liquids to an exit aperture, at least one gas inlet to fed a gas stream into the apparatus, and means to respectively supply the first liquid, the second liquid and the gas stream to the dedicated conduits. The means to disintegrate the first and second liquids are respectively provided and the gas

120 inlet is oriented to establish a gas stream to direct the droplets towards the exit aperture such that a single spray plume of the mixture is formed and material build-up on the interior wall of the mixing conduit is avoided. In one or more embodiments, at least one of the liquids is disintegrated into droplets having a volumetric mean diameter of less than 10 microns. The first liquid may comprise a polymeric component and the second liquid comprises a beneficial agent. During spraying inactivity a liquid can be supplied to

125 cover at least one liquid orifice such that nozzle clogging is prevented. At least one liquid is disintegrated by pneumatic, vibrating means and/or electrostatic means. The angle between the spray axes of the first and second spray plume is typically smaller than 45 degrees. The gas stream may comprise a vortical flow. The droplets may be transported within the gas stream to a substrate, such as a medical device, and a coating is applied.

130 In still another embodiment, a method to reproducibly form a single spray plume with small droplets from at least two separately supplied liquids using a spraying device for receiving and mixing at least a first and a second liquid is provided. The method comprises the steps of disintegrating at least a first and a second liquid separately into droplets within the spraying device, directing a gas stream towards the outlet aperture of the spraying device to mix the generated droplets of the first and second

135 liquids within said gas stream and to prevent material build-up on the inner wall of the spraying device and forming a single spray plume comprising droplets of the first and second liquid. In one or more embodiments, at least one of the compositions may be disintegrated into droplets having a volumetric mean diameter of less than 10 microns to obtain an increased surface area and enhanced mixing efficiency. Also, the first liquid may comprise a polymeric component and the second liquid

140 comprises a beneficial agent. Furthermore, the step of providing an additional liquid during spraying activity to prevent solids build-up may be provided. In addition, the step of providing during spraying inactivity a small amount of liquid to form a film covering at least one liquid orifice such that solids build-up is prevented may be provided. The spray plume may be directed towards a substrate, such as a medical device, to apply a coating.

145 In yet another embodiment, a method to reproducibly coat a medical device with at least a coating composition having a tendency to solidify and to prevent nozzle clogging during spraying inactivity using a spraying device with at least first conduit having a first orifice and atomizing means to disintegrate said first liquid into fine droplets and a second conduit having a second orifice located in vicinity to the first

orifice to feed a second liquid is provided. The method comprises the steps of disintegrating the first liquid 150 into a plurality of small droplets, forming a spray plume and directing the droplets towards the medical device to form a coating on the medical device and supplying a small amount of the second liquid sufficient to cover and to separate the first liquid orifice from the external atmosphere during periods of spraying inactivity.

In certain embodiment, the first liquid comprises a polymeric component and the medical device is a 155 stent. The step of providing during the coating process a small amount of the second liquid to prevent solids build-up may be further provided.

In yet another embodiment, a method to apply a homogeneous and reproducible coating to a medical device from at least a first composition and a second composition including a beneficial agent is provided. The method comprises disintegrating at least a first and a second composition separately into 160 droplets, forming a single spray plume in which the droplets of both compositions are mixed and transporting the droplets of both compositions within said single spray plume to the medical device to form a coating, wherein at least the second composition is disintegrated into droplets having a volumetric mean diameter of less than 10 microns.

In a further embodiment, a method to apply a homogeneous and reproducible coating to a 165 medical device from at least a first composition and at least a second composition including at least a beneficial agent is provided. The method comprises the steps of disintegrating at least a first and a second composition separately into droplets and transporting the droplets of both compositions to the medical device to form a coating, wherein the variation of the droplet size of at least the second composition is less than 1 %. 170 In one or more embodiments, at least the second liquid is disintegrated into droplets having a volumetric mean diameter of less than 10 microns.

DRAWINGS

The accompanying drawings, which are incorporated herein and form a part of the specification, 175 illustrate the embodiments of the present invention and together with the description, serve to explain the principles of the invention. In the drawings:

FIG. 1 is a spray pattern produced by a conventional spraying apparatus. FIG. 2 is a flow chart illustrating the method of the present invention. FIG. 3 is a schematic representation of an exemplary spray coating setup.

180 FIG. 4A is a cross-sectional view of an exemplary spraying device of the present invention

(covered liquid orifice/non-spraying mode).

FlG. 4B is a cross-sectional view of an exemplary spraying device of , the present invention (open liquid orifice/spraying mode).

FIG. 5 is a CFD representation of the spraying process. 185 FIG. 6A is a cross-sectional view of an alternative spraying device

(covered liquid orifice/non-spraying mode).

FIG. 6B is a cross-sectional view of an alternative spraying device (open liquid orifice/spraying mode).

FIG. 7 is a further alternative embodiment of the spraying device of the present invention. 190 FIG. 8 is another alternative embodiment of the spraying device of the present invention.

FIG. 9 is a CFD representation of the spraying process. . FIG. 10 is a SEM image showing a coating defect on a portion of a stent. FIG. 11 is a SEM image showing a homogeneous coating of a portion of a stent. FIG. 12 is a droplet size distribution comparison (Invention vs. Prior Art). 195 FIG. 13 is a droplet size distribution produced by the spraying device of the present invention.

DETAILED DESCRIPTION OF THE DRAWINGS/PREFERRED EMBODIMENTS

200

The present invention comprises an improved method and apparatus for atomizing at least two liquids comprising a film-forming component and typically a therapeutic substance into fine droplets. The mixture is preferably applied to a medical device to form a homogeneous coating while preventing the formation of nozzle build-up of formerly suspended particles or formerly dissolved solute. In a preferred

205 embodiment, the film-forming agent (also referred to as first liquid) and the therapeutic substance (also referred to as second liquid) are each dissolved or suspended in separate solvent systems. The liquids are supplied through separate orifices to allow mixing of at least two substances during the spraying process. Particle aggregation or agglomeration is minimized due to the improved control of the disintegration and mixing process and the decreased exposure to environmental factors, such as

210 humidity, as described in more detail in the Figures below. This is particularly important when atomizing lipophilic substances, such as paclitaxel and rapamycin, which tend to crystallize when exposed to humidity.

The first liquid composition to be atomized may comprise one or more film-forming agents, such as polymers, oils and/or fats, and one or more solvents. The composition can also include beneficial

215 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 second liquid composition preferably includes one or more solvents and beneficial agents. The composition can also include a film-forming component such as a polymer. The amount of therapeutic substance dissolved will dependent upon the particular drug employed and

220 medical condition being treated. Typically, the amount of drug represents about 0.001 % to about 70%.

Depending on the particular formulation, an anti-clogging liquid (preferably the same solvent comprised in the first and/or second liquid composition) may be separately supplied during non-spraying and/or spraying periods such that material build-up at the nozzle tip, clogging of the spraying device and the development of foreign matter is prevented.

225 The term "beneficial agent" as used herein is intended to have its broadest possible interpretation and is used to include any therapeutic substance, active agent or drug hat is delivered to the body of a living being to produce a desired beneficial effect.

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

230 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, methotrexate, angiopeptin, vincristine, mitomycine, statins, PCNA Ribozyne, Batimastat, Prolyl hydroxylase inhibitors, C-proteinase inhibitors,

235 Probucol, Re-Endothelialization, BCP671 , VEGF Estradiols, NO donors, EPC antibodies; antioxidants

such as probucol and retinoic acid; angiogenic and anli-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

240 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 nitorfuirantoin; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine;

245 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 ceil 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

250 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), polyethylene terephthalate), polyalkylene terepthalates such as poly(ethylene terephthalate) (PET), polycarbonates (PC), polyvinyl halides such as polyvinyl chloride)

255 (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(PEGZPBO terephthalate), PEG-bis-(PLA-acrylate), PEG6CDs,

260 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

265 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

270 selected based on their bio-compatibility 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 fofmamide (DMF), acetone, acetoπitrile, tetrahydrofuran (THF), acetic acid, dimethyle sulfoxide (DMSO), toluene, benzene, 275 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.

Referring now to FIG. 2, the method to apply a homogeneous coating to a medical device and to 280 prevent nozzle clogging comprises the steps of disintegrating at least a first and a second liquid separately into droplets, forming a single spray plume in which the droplets of both liquids are mixed, directing the droplets within the single spray plume towards the medical device and supplying a small amount of liquid sufficient to cover at least one orifice of the spraying device to separate the orifice of the spraying device from the external atmosphere during spraying inactivity. 285 The protective liquid film is generally removed before starting the liquid disintegration process. It may be atomized using pneumatic, ultrasonic or electrostatic means. Alternatively, a suction force may be applied to force the liquid back into a reservoir. Other suitable mechanism to withdraw the anti-clogging liquid may also be provided. In addition, an anti-clogging liquid may be supplied during the spraying process to prevent solid build-up at the tip of the spraying device. 290 In another embodiment the second liquid may comprise an anti-clogging component to prevent solids build-up during spraying activity.

FIG. 3 is a spray coating setup comprising a spraying device having separate conduits for a first liquid composition, a second liquid composition and an atomizing gas as well as separate fluid supplies and a substrate to be coated located below the spraying device. 295 In operation, the liquids and the gas, which may be for example air or an inert gas such as Nitrogen, are supplied to the spraying apparatus. The first and second liquid compositions are atomized into fine droplets. The droplets are transported to the substrate within the gas stream.

The spray coating setup and method as well as the spraying device will be described in more detail below. FIG.4, 6, 7 and 8 are expanded views of exemplary spraying devices of the present 300 invention in the light of those the liquid disintegration and mixing process as well as the anti-clogging mechanism are illustrated.

The spraying devices include at least one liquid inlet and orifice for a first liquid generally comprising a film-forming component, at least one liquid inlet and orifice for a second liquid typically comprising a therapeutic substance and/or an anti-clogging component. Although two liquid inlets are 305 depicted in the following Figures, it should be recognized that the spraying device could include more than two separate liquid inlets in order to allow mixing of multiple fluids or to supply an anti-clogging liquid.

An atomizing gas is generally provided to disintegrate the liquids. Typically, the gas is chemically inert with respect to the fluid components. Suitable inert gases include, air, nitrogen, and the like. Pressurized

310 air represents an economical atomizing gas, which may be supplied using pressurized tanks or cylinders as well as compressors. Eξxact sizing of the spraying device, namely the size of the conduits and the orifices will depend on the liquid to be atomized and on the specific liquid flow rate. The orifice diameter of the liquid conduits may range from approximately 50 to 350 microns and the orifice diameter of the gas conduit from approximately 400 microns to 1.5 mm.

315 Each liquid is fed into a dedicated conduit and disintegrated separately into droplets at least partially within a conduit of the spraying device in which a gas stream is introduced using electrostatic, vibrating and/or pneumatic means. The droplets of the liquids are mixed within a gas stream inside and outside the spraying device as depicted in the Computational Fluid Dynamics (CFD) simulations of FIG. 5 and FIG. 9.

320 During non-spraying periods an anti-clogging liquid compatible with the composition to be atomized is preferably supplied through the second liquid orifice or through an additional orifice provided in vicinity to the first and second orifices to prevent clogging of the gas and liquid orifices by forming a protective film at the nozzle tip, which is held by surface forces. The film may cover the entire nozzle tip and may increase in thickness until reaching a hemispherical shape. To prevent dripping, it should be

325 ensured that the surface force of the film is greater than the weight force of the film. Depending on liquid type, length of non-spraying intervals and environmental factors influencing the liquid evaporation rate, the anti-clogging liquid may be supplied on an intermittent basis or continuously to maintain the sealing film at the nozzle tip. The anti-clogging liquid may also be supplied during the spraying process to prevent material build-up at the atomizer tip by wetting the orifices, thereby controlling the local environment

330 surrounding the atomizer tip.

Referring now to FIG. 4A and B, an exemplary spraying device of the present invention is shown in the state of spraying and non-spraying. The spraying device 1 includes at least a first conduit 4 having orifice 15 to supply a first liquid and at least a second conduit 30 having orifice 32 to supply a second liquid. The first and second conduits may protrude between 0.1 and 0.5 mm into the mixing conduit 6 at

335 opposite sides such that a constricted passage is formed therebetween.

The mixing conduit 6 comprises an upper portion in which an atomizing gas is introduced (not shown) and a lower slightly tapered portion extending to an exit aperture 16 located downstream from orifices 15, 32. The first and second liquids are supplied from separate liquid sources (not shown).

Referring to FIG. 4A in the state of non-spraying, a small amount of anti-clogging liquid is fed into

340 conduit 30. The anti-clogging liquid is supplied through orifice 32 such that it contacts the inner wall of the mixing conduit and forms film 35 covering orifices 15 and 32 as well as exit aperture 16.

FIG. 4B shows the state of liquid disintegration and mixing. In operation, the atomizing gas is fed into the mixing conduit 6. The gas flows through the mixing conduit 6 to the exit aperture. A small amount of liquid is supplied to conduits 4, 30 such that a liquid film is formed at the tips 61 of the protruding

345 conduits. The atomizing gas disintegrates the first and second liquids separately into droplets at tips 61 when it flows through the mixing conduit 6 to the exit aperture 16. The droplets 49 of the two liquids are

thoroughly mixed by the gas stream within the mixing conduit 6 and when expelled through the exit aperture 16. A fine spray 50 of small droplets 49 is obtained.

To better visualize the liquid disintegration and mixing process depicted in FIG. 4B a

350 computational fluid dynamics simulation has been conducted as shown in FIG.5. A model has been developed according to the spraying apparatus of FIG. 4. The droplet trajectories were calculated for droplets having a diameter of 10 microns. It can be seen that the droplet trajectories of the first and second liquids that emerge from the liquid orifices are oriented downward slightly towards each other. The droplets are disintegrated by aerodynamic forces of the atomizing gas near the tips of the liquid

355 conduits in a region where the gas stream has a high velocity. The liquids are thoroughly mixed in the mixing conduit, in particular within the constricted passage formed between the protruding tips of the liquid conduits, and when being expelled from the exit aperture. The gas stream directs the droplets to the outlet aperture and prevents material build-up at the inner wall of the mixing conduit. The extended mixing region and the elevated gas velocity near the protruding tips of the liquid conduits and in the mixing

360 region enhance the liquid disintegration and promote mixing efficiency.

FIG. 6A illustrates an alternative embodiment of a spraying device having a first liquid orifice 15 provided at the atomizing end of the spraying device and a second orifice 16 for supplying a second liquid, preferably an anti-clogging liquid, and/or an atomizing gas.

In the state of non-spraying, the gas supply is stopped and an anti-clogging liquid is supplied via

365 second liquid conduit 33 into mixing conduit 6. The anti-clogging liquid is expelled through orifice 16 to form film 35 covering orifice 15. Prior to the next spraying cycle, film 35 is typically removed by increasing the gas pressure within the mixing conduit to atomize the film and by feeding the remaining anti-clogging liquid back into the liquid reservoir (not shown).

As shown in FIG.6B in the state of liquid disintegration, the first liquid is fed into liquid conduit 4.

370 The atomizing gas is fed into gas inlet 5, flows through mixing conduit 6 to the exit end aperture and exits the spraying device 1 through orifice 16 to atomize the first liquid when it exits orifice 15. A fine spray 50 is obtained. It is desirable, to supply during spraying activity a small amount of anti-clogging liquid through second conduit 33 to prevent material build-up at the nozzle tip and within the mixing conduit. In an alternative embodiment, as shown in FlG. 7 below, a liquid may be disintegrated within the mixing

375 conduit and mixed with the first liquid when exiting orifice 16. With reference to FIG.7 in the state of spraying, a first liquid is fed into liquid conduit 4. A second liquid is fed through orifice 32 via liquid conduit 30 that protrudes into mixing conduit 6. The atomizing gas is supplied to the mixing conduit 6 through the gas inlet 5 being located in vicinity to the liquid orifice 32. The gas disintegrates the second liquid at tip 61 into fine droplets and directs the droplets within the gas stream to orifice 16 surrounding orifice 15. The

380 first liquid, which is expelled through orifice 15, is disintegrated by the atomizing gas exiting orifice 16 and mixed within the gas stream with the droplets of the second liquid. A fine spray 50 having small droplets 49 is obtained.

FIG. 8 is a further embodiment of the spraying device of the present invention including two spray ^• sources for atomizing two separately supplied liquids into fine droplets and an expanded mixing region for

385 thoroughly mixing the produced droplets. The spraying device 1 comprises a tapered mixing conduit 6 extending from a portion, in which inlets 63 for the transport gas stream and two spray sources are provided, to an exit aperture 16. The spray sources include dedicated liquid conduits 30, 4 and dedicated gas conduits, in which an atomizing gas is introduced through gas inlets 5. The liquid conduits 30, 4 are preferably surrounded by one or more gas conduits.

390 An anti clogging liquid may be supplied through the gas conduits to cover orifices 32 and 15 (not shown) during non-spraying intervals.

As shown in FIG. 8, the liquids are separately supplied to mixing conduit 6 and disintegrated into fine droplets 49 by the atomizing gas when exiting orifices 31 and 15. Alternatively, at least one liquid may be disintegrated using vibrating or electrostatic means and transported by the transport gas stream

395 to the exit aperture.

In order to visualize the spraying process, a computational fluid dynamics (CFD) simulation has been conducted and the resulting droplet trajectories, which have been calculated for droplets having a median droplet size of 10 microns, are illustrated in FIG. 9. As shown in FIG. 8 and FIG. 9, the droplets 49 are directed by the transport gas stream, which is fed through inlet 63 into mixing conduit 6, towards the

400 exit aperture. The droplets are mixed in the mixing zone 62 inside the mixing conduit and when exiting the spraying device through the exit aperture 16. A focused spray of thoroughly mixed droplets is produced and material adherence at the wall of the mixing chamber is prevented by the gas stream shielding the interior wall of the mixing conduit from the droplets.

The apparatus and method of the present invention allows efficiently disintegrating liquids into

405 small droplets having a homogeneous droplet size distribution and thoroughly mixing the generated droplets while preventing deterioration of the produced spray due to nozzle build-up and poor mixing.

This is achieved by pre-atomizing at least one liquid into fine droplets within a conduit separated from the external atmosphere and thereby improving mixing efficiency and minimizing environmental influence factors and mixing at least one liquid inside and outside the spraying device. Mixing is further

410 improved by the generation of droplets, which are preferably smaller than 10 microns and have a tight droplet size distribution with a droplet size variation of less than 1 % as shown in the Examples below.

Build-up on the interior wall of the mixing conduit is prevented by surrounding the produced droplets with a gas stream. To further enhance the robustness of the process and minimize cleaning and maintenance, an anti-clogging liquid is preferably supplied during periods of non-spraying.

415 Due to the new design of the spraying device which allows performing the disintegration and mixing step separately, the device can be easily adapted for mixing more than two liquids while ensuring the generation of small droplets having a homogeneous droplet size distribution and preventing nozzle build-up.

The following examples are presented to describe the apparatus and method of the present 420 invention in more detail and to illustrate the advantages of the present invention with respect to prior art devices. The examples are not intended in any way otherwise to limit the scope of the disclosure.

Example 1: Stent coating application

Stents having a diameter of 2 mm and a length of 20 mm were mounted on a holding device as 425 described in US Pat. App. No. 60/776,522 incorporated herein as a reference.

The spraying device of the present invention was used to disintegrate the coating composition with pneumatic means into fine droplets and apply the coating to the stents. Although gas was used to atomize the coating composition, it is to be understood that the liquid may be disintegrated using vibrating and/or electrostatic means as well.

430 The first liquid composition was composed of a polymeric component dissolved in Acetone, which was also used as anti-clogging liquid.

The spraying device has been 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. It may be positioned at a distance of approximately 12 to 35 mm from the outer surface of the stent. 435 The spraying device was coupled to two syringe pumps to feed the first and second liquid composition respectively and to a compressor to deliver an atomizing gas as shown in FIG.3. A syringe pump (Hamilton Inc., Reno, NV, USA) was used to feed the first liquid composition from a reservoir to the spraying device. The flow rate of the first liquid composition may range between 0.5 ml/h and about 50 ml/h and the atomizing pressure between 0.3 bar to about 1.5 bar. A second syringe pump was used to 440 supply the second liquid composition comprising the anti-clogging liquid. The flow rate of the anti-clogging liquid is generally between 0.5 ml/h to 20 ml/h depending on the particular process parameters such as length of non-spraying intervals, anti-clogging liquid type, orifice size and environmental factors.

In operation, liquid was fed at a flow rate of 5 ml/h. Gas was fed at a flow rate of 6.5 l/min and a fine spray was produced. During the application of the coating solution, rotary motion was transmitted to 445 the stent to rotate the stent about its central longitudinal axis. The stent was rotated at 130 rpm and translated along its central longitudinal axis along the spraying device at a translation speed of 0.5 mm/s and moved along the spraying device several times to apply the coating in several passes.

In a preferred embodiment, at least an additional liquid composition, typically comprising one or more beneficial agents and compatible solvents, may be supplied simultaneously with the first liquid 450 composition through a separate conduit to allow in-process mixing of the compositions. Furthermore, it may be desirable to supply a small amount of anti-clogging liquid during the spraying operation to control the local environment around the liquid orifice and prevent solid build-up.

Following the coating step, the coating liquid supply was stopped and the stent was removed from the spraying area. Next, the liquid composition comprising the anti-clogging liquid was fed at an 455 initial flow rate of 20 ml/h until a film was formed covering the liquid orifices of the spraying device. To

maintain the liquid film, the flow rate of the anti-clogging liquid was decreased to 1 ml/h. Thus, a liquid film lying on the tip of the atomizing end and separating the orifice from the external atmosphere was provided.

Before the next spraying cycle, the liquid supply was stopped and the liquid film was withdrawn

460 by suction by the syringe pump. To make sure that the anti-clogging liquid was completely removed, gas may be supplied to atomize the anti-clogging liquid.

The spray process was started again and the next stent was exposed to the spray plume. The coating process was continuously monitored using an Optica! Patternator as described in US. Pat. App. No. 60/674,005 incorporated by reference herein. Thus, nozzle build-up and other problems were

465 detected immediately.

Scanning electron microscope (SEM) images were taken to visualize the surface quality of stents coated with and without supplying an anti-clogging liquid. The stent shown in FIG. 10 was coated without covering the orifice during the state of non-spraying. Nozzle build-up due to evaporation of the solvent was observed after several spray runs. It can be therefore assumed that dried material became loose and

470 was deposited at the outer surface of the stent resulting in coating defects. The stent illustrated in FIG. 11 was coated using the method and the apparatus of the present invention described above. The formation of nozzle build-up of formerly suspended particles or dissolved solute could be prevented by means of closing the nozzle aperture when the spraying cycle was stopped. It can be seen that the coated stent has a homogeneous coating thickness covering the struts of the stent with a smooth coating layer.

475 In order to evaluate the mixing efficiency and process reproducibility of the apparatus of the present invention with respect to prior art devices, the droplet size distribution of the produced spray was measured using a Laser Diffractometer (Sympatec, Lawrenceville, USA) in the following examples. The droplets were measured at a distance of 30 mm from the spraying apparatus.

480 Example 2: In-situ mixing spraying process

Two polymer compositions were prepared, mixed in-situ and atomized using the spraying device and method of the present invention. The first liquid composition comprised 13 mg/ml Polyφutyl methacrylate) (PBMA) dissolved in THF. The second liquid composition was prepared by dissolving 23 mg/ml Polyethylene-co-vinyl acetate (PEVA) with 40% vinyl acetate in THF.

485 In operation, the first and second liquids were fed at a flow rate of 10 ml/h by a syringe pump (Hamilton Inc., Reno, NV, USA) and gas was fed at a flow rate of 7.2 l/min to the spraying device. The first and second liquids were separately disintegrated into droplets. A single spray plume was formed, in which the droplets of both liquids were mixed, and a fine spray was produced.

TABLE 1 Droplet size measurement

Meas. x10 [μm] x50 Tumi x90 \m] x99 [μm] VMD [μm]

1 0.70 3.17 8.83 13.86 4.09

490

Comparative example 3: In-situ mixing spraying process

Two polymer compositions were prepared as described in the Example 2, atomized and mixed in- situ using two B12 pneumatic spray nozzle (ioos systems, San Diego, CA). The nozzles were arranged at an angle of 30 degrees with respect to each other.

495 In operation, the first and second liquids were respectively supplied to the atomizers at a flow rate of 10 ml/h by a syringe pump (Hamilton Inc., Reno, NV, USA) and gas was fed at a flow rate of 8.2 l/min. Two spray plumes that intersect at a distance of approximately 30 mm downstream of the first and second nozzles were produced. The first and second compositions were atomized separately by the atomizing gas into droplets and mixed within the intersection region.

500

TABLE 2 Droplet size measurement

Meas. x10 [μm1 x50 [μm] x90 [μml x99 [μm] VMD [μml 1 1.44 9.86 19.03 29.18 10.30

The measurement data shown in FIG. 12 and in Table 1-2 illustrate that the apparatus and method of the present invention yields droplet sizes that are significantly smaller than the droplet sizes obtained in spraying processes known by the prior art. Referring to Table 1 , a volumetric median diameter 505 (VMD) of the droplet size distribution of 4.09 μm has been obtained. Thus, an increased surface area and enhanced mixing efficiency was achieved compared to the prior art apparatus and method.

Example 4: In-situ mixing spraying process

A drug and a polymer composition were prepared, atomized and mixed in-situ using the spraying 510 device and method of the present invention. Droplet size measurements were conducted for the polymer composition (Table 3), for the drug composition (Table 4) and for the polymer/drug mixture (Table 5).

The polymer composition was comprised of 7 mg/ml Poly(butyl methacrylate) and 11 mg/ml Polyethylene- co-vinyl acetate (PEVA) with 40% vinyl acetate dissolved in THF. The drug composition was comprised of

20 mg/ml Acetylsalicylic Acid dissolved in Ethanol. 515 In operation, the first and second liquids were fed at a flow rate of 10 ml/h by a syringe pump (Hamilton

Inc., Reno, NV, USA) and gas was fed at a flow rate of 7.2 l/min to the spraying device. The first and the second liquids were separately disintegrated into droplets. A single spray plume was formed, in which the droplets of both liquids were mixed, and a fine spray was produced.

TABLE 3

Droplet size measurement polymer composition

Meas. x10 [μm] xSO [μm] x90 fμm] x99 fμml VMP [μm]

1 0.71 3.49 10.21 16.74 4.58

TABLE 4 Droplet size measurement drug composition

Meas. x10 [μm] x50 [μm] x90 [μm] x99 [μm] VMD [μml

1 0.97 3.37 6.30 8.83 3.54

2 0.98 3.38 6.29 8.81 3.54

3 0.98 3.35 6.24 8.79 3.52

4 0.98 3.37 6.27 8.80 3.54

5 0.98 3.38 6.28 8.81 3.55

6 0.99 3.35 6.22 8.77 3.52

Mean 0.98 3.37 6.27 8.80 3.54.

COV (%) 0.3

TABLE 5 Droplet size measurement polymer/drug composition

Meas. x10 [μm] x50 [μm] x90 [μm] x99 [μm] VMP [μm]

1 0.83 3.47 7.07 10.88 3.75

As shown in FIG. 13 and in Table 5, small droplet sizes of 3.75 μm VMD and a narrow droplet size distribution were obtained when using the apparatus and method of the present invention to form a homogeneous spray comprising several polymeric components and a therapeutic substance.

The small droplet sizes of 3.54 μm VMD and the small droplet size variation of 0.3 % (COV) as shown in Table 4 highlight the droplet size consistency of the composition comprising the therapeutic substance, which is the presumption for a homogeneous distribution of the therapeutic substance within the resulting drug/polymer mixture.

Is has been demonstrated in the previous examples that the operational safety and repeatability of spraying processes, and in particular of stent coating processes, can be improved compared to prior art systems using the apparatus and method of the present invention. In particular, the spray quality in terms of droplet size and droplet size consistency can be enhanced while allowing improved flexibility and control in formulating pharmaceutical compositions. Thus, a reproducible and homogeneous distribution of the therapeutic substance to be delivered can be obtained.

While preferred embodiments of the foregoing invention have been set forth for purposes of illustration, the foregoing description should not be deemed a limitation of the invention herein. Accordingly, various modifications, adaptations and alternatives may occur to one skilled in the art without departing from the spirit and the scope of the present invention.