Patent Grant
7867548
Many types of medical devices have drugs coated on them prior to their being implanted or inserted into people. Such medical devices include stents, heart implants, and needles, as well as other types of medical devices. Current approaches for coating drugs onto medical devices include dip coating, ultrasonic spray coating, brushing, as well as piezoelectric fluid ejection, among other types of approaches.
All of these approaches, however, are disadvantageous to some degree. Dip coating and ultrasonic spray coating lack precision in both placement and quantity applied. Brushing is tedious, and also lacks precision. Piezoelectric fluid ejection of drugs is usually achieved by using a single piezoelectric fluid-ejection nozzle, which can mean that coating takes a relatively long time, since the entire coating is ejected from a single nozzle.
The term active pharmaceutical ingredient is used in a general and broadly encompassing sense herein. For instance, such an active pharmaceutical ingredient may be a drug. Another type of active pharmaceutical ingredient is a bioactive substance, such as a protein, a biologic, or another type of active pharmaceutical ingredient.
The solute has a large molecular weight in that it has a molecular weight of at least 50,000 atomic mass units (AMU's). The large molecular weight solute may be or include a large molecular weight material like a large molecular weight polymer, a monomer, or a monomer and a polymer. For instance, the solute may include an active pharmaceutical ingredient within a monomer and/or a polymer. The monomer may be capable of being converted to a fully formed polymer. Examples of large molecular weight polymers include homo- and co-polymers of polylactic acid, polyethylene glycol, polyglycolic acid/polylactic acid, polycaprolactone, polyhydroxybutarate valerate, polyorthoester, polyethylenoxide/polybutylene terepthalate, and polyurethane. Additional examples include silicone, polyethylene terephthalate, phosphorylcholine-based polymers and acrylic homo and copolymers of hydroxyethylmethylacrylate, methylacrylate, ethyl acrylate, methyl methacrylate and ethyl methacrylate. Further examples include polycaprolactam, polystyrene-butadiene, chitosan, and alginate-based polymers.
The active pharmaceutical ingredient is disposed within the solute, and may be a drug, or another type of active pharmaceutical ingredient. The presence of the active pharmaceutical ingredient within the solute is typically that which provides the desired benefits of the coating on the device medium when the device medium is implanted or inserted into the human body. By comparison, the purpose of the large molecular weight polymer or other large molecular weight material is primarily to control the time-release profile of the active pharmaceutical ingredient, and ensure that the coating properly adheres to the device medium.
A thermal-fluid ejection mechanism is provided that has multiple fluid-ejection nozzles and that is capable of ejecting the solution (104). An advantage of thermal-fluid ejection mechanisms, as compared to piezoelectric fluid-ejection mechanisms, is that the former can typically have more densely packed fluid-ejection nozzles than the latter can. This is partly why, for instance, prior art piezoelectric fluid-ejection mechanisms for coating device media typically employ just single-nozzle piezoelectric fluid-ejection mechanisms. It can be stated that in general, a thermal-fluid ejection mechanism of an embodiment of the invention can have a greater number and/or more densely packed fluid-ejection nozzles than piezoelectric fluid-ejection mechanisms have for a given device medium-coating application.
Typical thermal-fluid and piezoelectric ejection mechanisms used to eject ink onto paper or other media, as in inkjet-printing devices, are not amenable to thermal ejection of large molecular weight solutes dissolved within non-aqueous organic solvents, as in embodiments of the invention. Rather, such existing thermal-fluid ejection mechanisms have thermal fluid-ejection nozzles that have orifices too small in diameter to properly eject large molecular weight materials without difficulty. Therefore, in one embodiment, the thermal fluid-ejection nozzles of the thermal-fluid ejection mechanism have diameters of at least thirty microns, as compared to, for instance, diameters of at least ten-to-fifteen microns as in modern conventional thermal fluid-ejection nozzles used in inkjet-printing devices.
Furthermore, because the solutions ejected by thermal-fluid ejection mechanisms of embodiments of the invention are non-aqueous and organic, existing thermal-fluid ejection mechanisms used to eject ink, as in inkjet-printing devices, are not inherently suited for thermally ejecting such solutions. That is, while the basic technology for thermal ejection may be the same in both embodiments of the invention and in conventional inkjet-printing applications, the thermal-fluid ejection mechanisms of embodiments of the invention can be considerably and novelly different. Besides the orifices of the thermal fluid-ejection nozzles being larger to manage premature drying within the nozzle, other components of thermal-fluid ejection mechanisms of embodiments of the invention may also differ, as compared to conventional inkjet-printing thermal-fluid ejection mechanisms, to ensure that they can accommodate non-aqueous and organic solvent-based solutions.
For example, because less energy is needed for low-boiling point solvents, which can be employed in embodiments of the invention, the width of the firing pulse may be reduced and the size of resistors within thermal fluid-ejection mechanisms may be increased in embodiments of the invention for such solvents. The materials employed within the fluid-ejection mechanisms may be specific to organic solvents. Other components may also be adjusted or differ as compared to conventional thermal-fluid ejection mechanisms to accommodate non-aqueous and organic solvent-based solutions.
A device medium is provided that has a three-dimensional surface on which the solution in question is to be ejected (106). A device medium is a medium in that it receives the solution as ejected by the thermal fluid-ejection nozzles of the thermal fluid-ejection mechanism. A device medium is further a device in that it has functionality beyond that which is commonly ascribed to media and that the device can perform in relation to the coating ejected thereon, without assistance from other devices.
For example, one type of a device medium is a medical device medium, like a stent, heart implant, or a needle. A stent in particular is inserted into an artery to ensure that the artery stays open, and thus is a device performing this functionality. A drug coating assists in this functionality, by for instance, helping to ensure that the stenosis does not reform, among other things. By comparison, what is commonly referred to as media includes paper, optical media like compact discs, and so on. These types of media are not devices, in that they are incapable of performing any functionality by themselves without the assistance of devices. For example, paper may have human-readable information printed on it, but the paper cannot perform any function related to this information by itself. As another example, an optical disc may have machine-readable data situated on it, but the optical disc cannot perform any function related to this information by itself, and has to be inserted into an optical disc drive in order for the data to be read.
The device medium further has a three-dimensional surface. Such a surface compares to more conventional media that have two-dimensional surfaces. For example, paper, optical media like compact discs, and so on, have flat, planar two-dimensional surfaces. Fluid, such as ink, is ejected onto these types of conventional media based on the presumption that the surfaces thereof on which the fluid is to be ejected are flat. Stated another way, such fluid ejection takes into account the x and y directions of the surfaces of these conventional media, and presumes that the surfaces have no features of interest in the z direction extending upwards or downwards from them. That is, the distance from the point of fluid ejection to the surface is at least substantially constant at all times with such conventional media.
By comparison, the device media in relation to which embodiments of the invention are performed have three-dimensional surfaces on which solutions are to be thermally ejected. These three-dimensional surfaces are non-planar surfaces, such as cylindrical or round surfaces, or more complex types of surfaces. A stent, for example, is cylindrically shaped in general. Furthermore, a stent can be made with a wire mesh, where the individual loops of the mesh are themselves cylindrically shaped. Such a complex surface is three-dimensional because solution ejection has to take into account the z direction extending upwards or downwards from the surface, in addition to the x and y directions of the surface. That is, the distance from the point of solution ejection to the surface varies with such device media.
The fluid-ejection nozzles of the thermal fluid-ejection mechanism are controlled to eject the solution onto the three-dimensional surface of the device medium in accordance with a desired pattern (108). The desired pattern can be the pattern of the resultant coating on the device medium. Generally, the non-aqueous organic solvent evaporates rapidly after being thermally ejected onto the three-dimensional surface of the device medium. Thereafter, just the solute, including the large molecular weight polymer and the active pharmaceutical ingredient, remain as the coating.
The desired pattern can be simple, such as a complete coating of the three-dimensional surface of the device medium, or more complex. For example, the coating may have multiple layers of the same or different polymers and/or active pharmaceutical ingredients, at the same or different concentrations. Some portions of the surface of the device medium may remain uncoated. The coating may have a particular shape or topography. The coating may be smooth or rough. Different manners by which the fluid-ejection nozzles of the thermal fluid-ejection mechanism are controlled to eject the solution onto the three-dimensional surface of the device medium are described in the following sections of the detailed description.
The device medium 206 of
It is noted that embodiments of the invention are described in relation to the situation where there is a solute having a polymer containing an active pharmaceutical ingredient. However, other embodiments of the invention are not so limited. For example, the coating 216 may include a number of layers, one or more of which may be formed from solutes that are pure polymer without any active pharmaceutical ingredients. As another example, the coating 216 may itself just include one or more layers of solute, all of which are pure polymer without any active pharmaceutical ingredients.
General Approaches for Moving the Thermal Fluid-Ejection Mechanism
The thermal fluid-ejection mechanism 202 can be moved relative to the three-dimensional surface 207 of the device medium 206 in one of two ways. First, the fluid-ejection mechanism 202 can be moved in accordance with a vector mode of operation. In the vector mode, the mechanism 202 is freely moved in any direction within an x-y plane over the three-dimensional surface 207 until the desired pattern has been formed on the surface 207. Second, the fluid-ejection mechanism 202 can be moved in accordance with a scanning mode of operation. In the scanning mode, the mechanism 202 is moved, or scanned, along an x direction over the three-dimensional surface 207. The mechanism 202 or the three-dimensional surface 207 is then moved in a perpendicular, y direction, and the mechanism 202 is again moved, or scanned, along the x direction over the surface 207. This process is repeated until the desired pattern has been formed on the three-dimensional surface 207.
The fluid-ejection mechanism 202 is then scanned one or more times along a second dimension relative to the three-dimensional surface 207, over the current swath thereof (404). The second dimension is perpendicular to the first dimension. For example, the first dimension may correspond to the y-axis of a plane, and the second dimension may correspond to the x-axis of the plane. While the fluid-ejection mechanism is being scanned over the current swath, the fluid-ejection nozzles 204 are caused to selectively eject the solution 208 onto the three-dimensional surface 207 in accordance with a corresponding swath of the desired pattern (406). If there are more swaths of the three-dimensional surface 207 that need to have the solution 208 ejected thereon to realize the desired pattern (408), then the method 400 repeats at part 402. Otherwise, the method 400 is finished (410), such that the desired pattern has been formed on the three-dimensional surface 207.
The three-dimensional surface 207 of the device medium 206 can be considered as being logically divided into a number of swaths 452A, 452B, 452C, . . . , 452N, collectively referred to as the swaths 452. Each swath extends from one side of the surface 207 to another side of the surface 207 along the x-axis. Each swath has a height corresponding to a distance over the surface 207 along the y-axis over which the fluid-ejection mechanism 202 is capable of ejecting the solution 208 at any given time.
Representative performance of the method 400 is particularly described in relation to swaths 452A, 452B, and 452C of
Thereafter, the fluid-ejection mechanism 202 is advanced along the y-axis relative to the three-dimensional surface 207, as indicated by the arrow 454B, until it is incident to the swath 452B, as the new currently swath. The fluid-ejection mechanism 202 is scanned over the swath 452B along the x-axis, and the fluid-ejection nozzles 204 caused to eject the solution 208 as needed to realize the portion of the desired pattern 356 lying within the swath 452B. Next, the fluid-ejection mechanism 202 is advanced along the y-axis relative to the three-dimensional surface 207, as indicated by the arrow 454C, until it is incident to the swath 452C, as the new currently swath. The fluid-ejection mechanism 202 is scanned over the swath 452BC along the x-axis, and the fluid-ejection nozzles 204 caused to eject the solution 208 as needed to realize the portion of desired pattern 356 lying within the swath 452C. This process is repeated for all of the remaining swaths 452, until the desired pattern 356 has been formed on the three-dimensional surface 207 of the device medium 206.
Alternatively, each of the swaths 452 may be traversed a large number of times along the x-axis prior to advancement along the y-axis. For example, there may just be four swaths for a given surface 207. However, the fluid-ejection mechanism 202 may pass back and forth over each of these swaths as many as one hundred times, for instance, ejecting fluid each time. In one embodiment, each pass may be considered a swath. Thus, in one embodiment, successive swaths may be considered coincidental, or “on top of” one another, such that there is no motion along the y-axis in-between some of the swaths, which is not particularly depicted in
In such an embodiment, as well as other embodiments, each of the swaths 452 may be considered as corresponding to one of the fluid-ejection nozzles 204 of the fluid-ejection mechanism 202. Thus, the fluid-ejection mechanism 202 moves back and forth over the surface 207. Each of the nozzles 204 is responsible for ejecting the solution 208 onto a different y-position of the surface 207.
Decapping, and Preventing Plugging of the Fluid-Ejection Nozzles
The solution 208 is situated within the cavity 508 and the fluid-ejection nozzle 204A. The solution 208 includes solvent 510, within which the large molecular weight solute 212 is disposed, the latter indicated by circles in
First, the Reynolds Number value of the fluid-ejection nozzles 204 relative to the solution 208, times a Euler Number value of the fluid-ejection nozzles 204 relative to the solution 208, can be specified such that it is greater than a predetermined threshold product (514). It has been determined that, where the Reynolds Number value times the Euler Number value are greater than a predetermined threshold product of ten, for instance, plugging up of the fluid-ejection nozzles 204 with the solution 208 is substantially less likely to occur. The Reynolds Number value is the ratio of the inertial force to the viscous force within a fluid flow. The Euler Number value is the ratio of the pressure force generated by phase change (in this case, the transient boiling or nucleation of the liquid) to the inertial force in a flow.
In one embodiment using a circular nozzle, the product of the Reynolds Number value and the Euler Number value can be approximated as:
In equation (1), Re is the Reynolds Number value and Eu is the Euler Number value. R is the radius of the fluid-ejection nozzle, which is half the distance of the diameter indicated by the line 503 in
The product of equation (1) can also be considered the ratio of nucleation force to viscous force. The nucleation force within a thermal fluid-ejection process is the pressure in the vapor bubble created by suddenly heating the solution 208 multiplied by the projected area of the bubble. The viscous force is a function of the flow resistance of the solution 208 through the nozzle. Thus, for ejection to result, the nucleation force has to be much larger than the viscous force, such as by a factor of ten.
Specifying the product of equation (1) so that it is greater than ten can be achieved in a number of different ways. Δp can be increased by increasing the temperature employed during the thermal fluid-ejection process, or by changing the solvent to one that has a higher critical temperature and other appropriate thermophysical properties, for instance. Increasing the diameter of the fluid-ejection nozzle increases its radius R, which has a very strong effect on the product in equation (1). The effective viscosity in the jetting chamber μ can be decreased by adding a humectant to the solution 208 to reduce the rate of evaporation of the solvent 510.
Still referring to
Therefore, for a given distance between ejection locations (i.e., between ejection pixel locations), a predetermined threshold rate of movement of the fluid-ejection mechanism 202 can be experimentally determined, corresponding to the maximum allowable idle time, corresponding to the time above which plugging of the fluid-ejection nozzles 204 of the thermal fluid-ejection mechanism 202 is likely to occur. Thereafter, moving the fluid-ejection mechanism 202 in the vector mode of operation or in the scanning mode of operation at a rate greater than or equal to this predetermined threshold rate makes plugging of the fluid-ejection nozzles less likely to occur. For instance, in the scanning mode in particular, the fluid-ejection mechanism 202 is scanned over the three-dimensional surface 207 at a rate greater than or equal to the predetermined threshold rate.
Still referring to
For example, consider the scanning mode of operation of
Referring back to
Spitting involves sending a number of fluid-ejection pulses to each of the fluid-ejection nozzles 204. The fluid-ejection pulses sufficiently heat the solution 208 to ultimately cause the fluid-ejection nozzles 204 to eject the solution 208, breaking through and thus expelling any of the solute 212 that may have skinned over the nozzles 204, and thus ensuring that drop ejection onto the target will reliably occur, because the idle time between nozzle servicing and actual coating/ejection has been minimized. Desirably each pulse causes the ejection of a droplet of the solution 208 from a fluid-ejection nozzle. However, where the fluid-ejection nozzle has been plugged a number of pulses may be needed to break through the solute 212 that has skinned over the nozzle.
The fluid-ejection nozzles 204 of the thermal fluid-ejection mechanism 202 are calibrated in relation to the solution 208 to determine a profile that is particular to both the specific nozzles 204 that are being used and the specific solution 208 that is being used (532). A profile specifies the number of fluid-ejection pulses that have to be sent to a plugged fluid-ejection nozzle to unplug the fluid-ejection nozzle, as a function of the length of time in which the nozzle has remained unused. For example, the longer a fluid-ejection nozzle has remained unused, the stronger the solute 212 that has skinned over and plugged the nozzle is, and, as a result, the greater number of pulses that have to be successively sent to the fluid-ejection nozzle to clear, or unplug, it.
Calibration of the fluid-ejection nozzles 204 in relation to the solution 208 to determine the particular profile is an experimental process. For example, droplets may be ejected from the fluid-ejection nozzles 204, and then a predetermined amount of time waited. Where the nozzles 204 become plugged after this predetermined amount of time, the number of fluid-ejection pulses that have to be sent to the nozzles 204 to unplug them are counted. This process is repeated a number of times, for different predetermined amounts of time, in order to construct the resulting profile.
Therefore, referring back to
Where the fluid-ejection nozzle has been plugged by the solution 208, a number of fluid-ejection pulses are sent to the fluid-ejection nozzle to unclog or clear the nozzle (536). For example, the fluid-ejection mechanism 202 may be moved to one of the spit receptacles 524A and 524B. Thereafter, the number of pulses needed to clear the fluid-ejection nozzle is determined using the previously constructed profile, and then sent to the nozzle. Verification of effective nozzle servicing may be performed by using a drop detector, in another way, or no nozzle function verification may be performed.
Accelerating Evaporation of Solvent from Three-Dimensional Surface
The coating 216, including the large molecular weight solute 212 with the active pharmaceutical ingredient 214 therein, is established on the three-dimensional surface 207 of the device medium 206 by first thermally ejecting the solution 208 on the surface 207. Thereafter, the solvent 510 evaporates from the solution 208, leaving primarily the solute 212 and the active pharmaceutical ingredient 214 to form the coating 216. To limit movement of the solution 208 prior to evaporation of the solvent 510, and to otherwise better control the topography of the coating 216 on the three-dimensional surface 207 of the device medium 206, evaporation of the solvent 510 may be actively accelerated.
First, gas may be forced to flow over the three-dimensional surface 207 of the device medium 206 after the solution 208 has been thermally ejected onto the surface 207 (604). The gas may be nitrogen gas, or another type of gas. The gas may be preheated, and may be dry. Flowing such a gas over the three-dimensional surface 207 accomplishes forced convective heat and mass transfer, accelerating evaporation of the solvent 510 from the solution 208 thermally ejected onto the surface 207.
Second, the device medium 206 may itself be directly heated, either by radiation, convection, and/or conduction (606). For example, a heating element may be positioned near the three-dimensional surface of the device medium 206. The heat emanating from the heating element conductively heats the device medium 206. Such conductive and/or radiative heating is direct in that the heat emanating from the heating element directly heats the device medium 206, as opposed to first heating an intermediary component such that the heat from the heating element indirectly conductively heats the device medium 206. Directly conductively heating the device medium 206 accelerates evaporation of the solvent 510 from the solution 208 thermally ejected on the three-dimensional surface 207 of the device medium 206.
Third, gas or liquid may be forced to flow through a mandrel around which the device medium 206 is disposed (608). For example, the device medium may be a stent, or otherwise substantially cylindrically shaped and hollow. In such an embodiment, the stent can be wrapped around a mandrel. Where the mandrel itself is hollow, gas, such as nitrogen gas or another type of gas, and which may be preheated, is flowed through the mandrel. Flowing such a gas through the mandrel heats the device medium and the solvent on it, increasing the solvent's vapor pressure and thus accelerating evaporation of the solvent 510 from the solution 208 thermally ejected onto the surface 207.
Fourth, the mandrel around which the device medium 206 is disposed may be directly conductively heated (610). For example, a heating element may be positioned near the mandrel. The heat emanating from the heating element conductively heats the mandrel. In turn, heating of the mandrel causes heating of the device medium 206. That is, direct conductive heating of the mandrel indirectly conductively heats the device medium 206, which also accelerates evaporation of the solvent 510 from the solution 208 thermally ejected on the three-dimensional surface 207 of the device medium 206.
Fifth, the mandrel itself may be employed as a heating element (612). For instance, the mandrel may be fabricated from or include a resistive heating material, around which an electrical insulator is wrapped, such that the device medium 206 is disposed around the electrical insulator of the mandrel. Where the mandrel includes or is such a resistive heating material, the mandrel itself can function as a heating element. The heat emanating from the mandrel thus conductively heats the device medium 206. Such conductive heating is direct in that the heat emanating from the mandrel directly heats the device medium 206. Employing the mandrel as a heating element that directly conductively heats the device medium 206 accelerates evaporation of the solvent 510 from the solution 208 thermally ejected on the three-dimensional surface 207 of the device medium 206.
In part 604, a gas-blowing element 654 is positioned relative to the device medium 206. Warm and dry gas, indicated by arrows 656, is flowed over the device medium 206 to achieve accelerated evaporation. The gas-blowing element 654 may be revolved around the device medium 206, or the device medium 206 itself may be rotated relative to the gas-blowing element 654. It is noted that furthermore the gas flow may be periodically interrupted to ensure that the droplets being ejected onto the surface 207 are not blown off-course by this gas flow. In part 606, a resistive heating element 658 is connected to a power supply 660 to resistively heat the heating element 658. Heat emanating from the heating element 658 directly conductively heats the device medium 206 to achieve accelerated evaporation. That is, heat rises from the heating element 658, convectively heating the device medium 206.
In part 608, a gas-blowing element 662 is at a positive pressure relative to the mandrel 652. Warm and dry gas, indicated by arrow 664, is flowed through the mandrel 652, which is hollow. The heat increases the solvent temperature, increasing its vapor pressure and thus increasing the evaporation rate. In part 610, a resistive heating element 666 is connected to the power supply 660 to resistively heat the heating element 666. Heat emanating from the heating element 666 directly conductively heats the mandrel 652, which indirectly conductively heats the device medium 206 to achieve accelerated evaporation.
Finally, in part 612, the mandrel 652 itself functions as a resistive heating element that is connected to the power supply 660, as indicated by lines 668 and 670. The mandrel 652 may have an electrically insulated material surrounding it (not shown in
It is noted that while just one power supply 660 is depicted in
Thickness Control of Coating
Besides having the desired pattern 356, the coating 216, including the large molecular weight solute 212 with the active pharmaceutical ingredient 214 therein, that is established on the three-dimensional surface 207 of the device medium 206 may have a desired thickness. The thickness of the coating 216 after the solution 208 has been thermally ejected onto the three-dimensional surface 207, and after the solvent 510 has evaporated from the solution 208. The thickness of the coating 216 in this respect can be considered the thickness of the solute 212 after thermal ejection of the solution 208 and after evaporation of the solvent 510 from the thermally ejected solution 208.
First, the thickness of the coating 216 can be controlled by specifying the thickness in accordance with an equation, where the various parameters of the equation are themselves controllable (704). This equation in one embodiment is:
It is noted that equation (2) is for multiple nozzles within an array, where Nnozz is greater than one. By comparison, for single nozzle fluid ejection on a surface, the corresponding equation is
In equations (2) and (3), t is the thickness of the solute 212 (i.e., the coating 216), and Npass is the number of passes of the thermal fluid-ejection mechanism 202 over the three-dimensional surface 207 in which the solution 208 is ejected onto the surface 207. Furthermore, c is the concentration of the solute 212 within the solvent 510, Vdrop is the volume of a droplet of the solvent 510 ejected by a fluid-ejection nozzle, Nnozz (in just the former equation) is the number of the fluid-ejection nozzles 204 actively ejecting the solution 208 onto the three-dimensional surface 207, and ρ is the density of the solute 212 on the three-dimensional surface 207 after evaporation of the solvent 212. Finally, Δx and Δy together are spatial resolutions of the droplets ejected along dimensions x and y, and M is a spreading margin factor, as will be described. Thus, by controlling one or more of these parameters, the thickness of the coating 216 is correspondingly controlled.
Once a droplet of the solution 208 has been thermally ejected onto the three-dimensional surface 207 of the device medium 206, it can spread to cover a larger area of the surface 207. Thus, with respect to the solution droplet 710B, the droplet 710B covers a particular area of the three-dimensional surface 207 as shown in
Referring back to
Furthermore, the three-dimensional surface 207 may be designed to be selectively non-wettable, such that locations thereof that are not to receive the solution 208, based on the desired pattern 356, are treated with a material that renders them substantially non-wettable. Examples of such a material include polymers (e.g., parylene), silane coupling agents, etchants (e.g., nitric-phosphoric acid), or other surface modification techniques, such as grit blasting and the deposition of other materials via electrolysis. Alternatively, the three-dimensional surface 207 may not be intrinsically uniformly wettable, such that locations thereof that are to receive the solution 208, based on the desired pattern 356, are treated with a material that renders them substantially uniformly wettable, such as polymers (e.g., parylene), silane coupling agents, etchants (e.g., nitric-phosphoric acid), or other surface modification techniques, such as grit blasting and the deposition of other materials via electrolysis, as noted above.
Finally, the thickness of the coating 216 may be controlled by specifying within a predetermined range (708) the Weber value of the droplets of the solution 208 ejected onto the three-dimensional surface 207 of the device medium 206. The Weber value of the solution droplets is the ratio of the kinetic energy of a droplet to the surface energy of the droplet. Droplets having too high of a Weber value “splat” upon contacting the three-dimensional surface 207, in that they undesirably spread more than the spreading margin factor M of equation (2), because these droplets impact the surface 207 with too much kinetic energy. By comparison, droplets having too low of a Weber value can bounce off the three-dimensional surface 207 one or more times before landing on the surface 207 or elsewhere, such that the droplets do not ultimately rest at their intended destination.
In one embodiment, the Weber value for a droplet of the solution 208 may be determined via:
In equation (4), the Weber value We for a solution droplet is specified by the density of the solution Dsol, multiplied by the radius of the droplet Rdrop, times the square of the velocity at which the droplet impacts the three-dimensional surface Vdroplet, and divided by six times the surface tension of the solution Tsol. In one embodiment, the Weber value should be within a range of three to thirty, so that the droplets of the solution 208 neither “splat” nor bounce. The Weber value can be controlled, or specified, by adjusting one or more of the parameters of equation (4).
Scaling Desired Pattern Resolution to Fluid-Ejection Resolution
The desired pattern 356 of the coating 216 to be established on the three-dimensional surface 207 of the device medium 206 may have a resolution that is expressed in dots-per-inch (DPI) or pixels-per-inch (PPI). The fluid-ejection nozzles 204 of the fluid-ejection mechanism 202 likewise have a resolution, which may be expressed in DPI or PPI, at which they are capable of ejecting droplets of the solution 208 onto the three-dimensional surface 207. In some situations, the resolution of the desired pattern 356 may be equal to the resolution of the fluid-ejection nozzles 204. However, in other situations, the resolution of the desired pattern 356, which may be referred to as R1, may be greater than the resolution of the fluid-ejection nozzles 204, which may be referred to as R2.
In this latter situation, the pixels of the desired pattern 356 are not easily mapped to pixels ejectable by the fluid-ejection nozzles 204, since R1 is greater than R2. In such a case, a pixel ejectable by the fluid-ejection nozzles 204 maps to
pixels of the desired pattern 356. Therefore, one embodiment of the invention employs a scaling threshold number to determine whether a pixel of the fluid-ejection nozzles 204 is on (i.e., whether a droplet of the solution 208 is to be ejected for the pixel for that pass), or off (i.e., no solution droplets are ejected for the pixel for that pass) for a given corresponding group of
pixels of the desired pattern 356. In particular, if the number of pixels within such a group of pixels of the desired pattern 356 is equal to or greater than the scaling threshold number, than the corresponding pixel of the fluid-ejection nozzles 204 is on, and otherwise the corresponding pixel is off.
For any given group of four pixels of the desired pattern 356, there are five different possibilities: no pixels on, as in pixel group 806A; one pixel on, as in pixel group 806B; two pixels on, as in pixel group 806C; three pixels on, as in pixel group 806D; and, all four pixels on, as in pixel group 806E. Which of the pixels of the groups 806B, 806C, and 806D are on and which are off does not matter in one embodiment. For example, in the pixel group 806C, the upper left-hand pixel and the lower right-hand pixel are on, and the other two pixels are off. However, the pixel group 806C also represents and exemplifies the scenario where the top two pixels are on and the bottom two pixels are off (or vice-versa); the left two pixels are on and the right two pixels are off (or vice-versa); and, the upper right-hand pixel and the lower left-hand pixel are on, and the other two pixels are off.
Four different scaling threshold numbers 1, 2, 3, and 4, are represented in
The scaling threshold numbers of 2, 3, and 4, represented by the lines 810A, 810B, and 810C, means that at least two, three, or four pixels, respectively, of any of the pixel groups 806 have to be on for the corresponding pixel of the fluid-ejection nozzles 204 to be on. For example, in relation to the scaling threshold number of 3, the pixel groups 806A, 806B, and 806C correspond to the off pixel 808A, because they have just zero, one, and two constituent pixels on, respectively. By comparison, in relation to the scaling threshold number of 3, the pixel groups 806D and 806E both correspond to the on jetting pixel 808B, since they each have at least three image pixels on.
In different embodiments of the invention, different scaling thresholds can be selected. For example, if a more-saturated pattern 356 is desired to be coated on the device medium 206, a lower scaling threshold number is selected, because less pixels of any given group of pixels of the pattern 356 have to be on for the corresponding pixel of the fluid-ejection nozzles 204 to be on. By comparison, if a less-saturated pattern 356 is desired to be coated on the device medium 206, a higher scaling threshold number is selected, because more pixels of any given group of pixels of the pattern 356 have to be on for the corresponding pixel of the fluid-ejection nozzles 204 to be on.
pattern pixels of the desired pattern 356. The pattern pixels of the desired pattern 356 are therefore divided into groups, and the method 820 is performed in relation to these groups of pixels.
The method 820 starts with the first group of pixels of the desired pattern 356 as corresponding to a single fluid-ejection pixel (822). If the number of pixels within this group of pattern pixels is greater than the scaling threshold number (824), then the corresponding single fluid-ejection pixel is turned on (826). That is, the solution 208 is ejected by the fluid-ejection nozzles 204 for this pixel. Otherwise (824), the corresponding single-fluid ejection pixel is turned off (828), such that none of the solution 208 is ejected by the fluid-ejection nozzles 204 for this pixel.
In either case, if the desired pattern 356 has been completely formed on the three-dimensional surface 207 of the device medium 206 (830), such that all of the groups of pixels of the pattern 356 have been evaluated in part 824, then the method 820 is finished (832). Otherwise, the method 820 advances to the next group of pixels within the desired pattern 356, corresponding to the next single fluid-ejection pixel (834). The method 820 then repeats at part 824 with respect to this group of pixels.
Satisfaction of Flux Constraint
When applying the coating 216 to the three-dimensional surface 207 of the device medium 206, there is a flux limit past which an acceptable coating cannot be established for topography or “drippage” reasons. That is, the flux limit relates to the overall rate at which the solution can be applied to the three-dimensional surface 207, considering both the solution per time per area on a given pass and the time between passes of the fluid-ejection mechanism 202 over this location before the coating 216 becomes unacceptable, from the standpoint of coating uniformity or spreading. Unacceptability may mean that the coating 216 is too rough or coarse, too widely spread, or has some other undesired topography. The flux limit itself is thus the number of times a given location on the three-dimensional surface 207 can receive the solution 208 during successive passes of the fluid-ejection mechanism 202 thereover before the resultant coating 216 becomes too rough or coarse, too widely spread, or otherwise has an undesired topography in relation to the desired pattern 356.
First, the coarseness of the desired pattern 356, as ejected by the fluid-ejection nozzles 204 onto the three-dimensional surface 207, may itself simply be increased (904). That is, the flux constraint, or limit, specifies the overall solution mass per unit time per unit area (or per pixel), considering both the material deposited per pass and the time between passes, before the resultant coating 216 becomes too rough or coarse, or too widely spread, in relation to the desired pattern 356. Therefore, if the desired pattern 356 is itself made rougher or coarser or more widely spread even if ejection of the solution 208 results in a rough coating 216, the flux constraint is satisfied in relation to the desired pattern 356, because the dictates of the pattern 356 are relaxed in relation to roughness, coarseness or spreading
Second, the saturation of the solution 208 as fluidically ejected onto the three-dimensional surface 207 may be non-randomly and deterministically controlled to satisfy the flux constraint (906). Saturation refers to the percentage of fluid-ejection pixels which are executed/ejected in a given pass, or the number of times a given location on the three-dimensional surface 207 is to maximally receive the solution 208 during successive passes of the fluid-ejection mechanism 202 thereover, divided by the total number of passes. For example, if a given location is passed over by the fluid-ejection mechanism 202 eight times, 50% saturation means that at most the location can receive the solution 208 four of these times. As another example, if a given location is passed over eight times, 25% saturation means that at most the location can receive the solution is two of these times.
The saturation is non-random and deterministic in that in which of the passes of the fluid-ejection mechanism 202 over a given location on the three-dimensional surface 207 the surface 207 receives the solution 208 is non-randomly and deterministically controlled. For example, if the fluid-ejection mechanism 202 passes over a given location eight times at 50% saturation, then the location receives the solution 208 four of these times, but which of the four passes the location receives the solution 208 is not dictated by the saturation setting of 50% itself. A random and non-deterministic saturation is ill suited to satisfy the flux constraint on a pixel basis or length-scale, and even apart from that may not cover the part uniformly when a small number of passes is involved.
Therefore, embodiments of the invention instead employ a non-random and deterministic approach to achieve a given saturation. In one embodiment, a regular approach is employed, such that a regular pattern of solution ejection is achieved to satisfy a given saturation. For example, for 50% saturation, every other pass of the fluid-ejection mechanism 202 may result in the solution 208 being ejected onto a given location of the three-dimensional surface 207. This pattern of eject solution-do not eject solution-eject solution-do not eject solution is a regular pattern, and thus a non-random and deterministic approach to saturation control. As another example, for 25% saturation, every fourth pass of the fluid-ejection mechanism 202 may result in the solution 208 being ejected onto a given location of the three-dimensional surface 207.
Thus, to satisfy a flux constraint, the number of times M that the solution 208 is actually ejected onto a given location of the three-dimensional surface 207 within a number of successive passes N that the fluid-ejection mechanism 202 is scanned over the location is decreased, such that M≦N. Stated another way, the saturation of any location on the three-dimensional surface 207 can be reduced to satisfy the flux constraint. If the saturation is initially at 100%, for instance, and if the flux constraint is not satisfied, then the saturation may be reduced to 75%, 50%, 25%, and so on, until the flux constraint becomes satisfied.
The table 920 is thus followed each time any location on the three-dimensional surface 207 is to receive the solution 208, for a given saturation. For example, for 50% saturation, a given location may always receive the solution 208 on the first and third passes, and may never receive the solution 208 on the second and fourth passes. This is why this approach to 50% saturation is deterministic and non-random; there is no chance, using the approach of the table 920, that a given location, at 50% saturation, will ever receive the solution on the second or fourth pass.
Coating Control Parameters
The thickness of the coating 216 on the three-dimensional surface 207 of the device medium 206—that is, the thickness of the solute 212 thereon after the solvent 512 has evaporated—can be controlled as has been described in a preceding section of the detailed description. Furthermore, however, the uniformity of the thickness of the coating 216 can be optimized so that it does not undesirably vary. Optimizing thickness uniformity in turn optimizes edge sharpness of the desired pattern 356 as fluidically realized on the three-dimensional surface 207. That is, edges within the desired pattern 356 are desirably and optimally as sharp upon the realization of the pattern 356 on the three-dimensional surface 207 as they are when the pattern 356 is first abstractly generated.
The first parameter 1004 is the spatial resolution of the droplets ejected by the fluid-ejection nozzles 204 of the fluid-ejection mechanism 202. The spatial resolution of a droplet of the solution 208 is the distance along the x-axis and the distance along the y-axis that the solution droplet extends over when impacting the three-dimensional surface 207, before the droplet spreads, as has been described in relation to
The second parameter 1006 is droplet size of the droplets ejected by the fluid-ejection nozzles 204 of the fluid-ejection mechanism 202, which is related to the first parameter 1004. The droplet size, such as the droplet volume, also contributes to thickness uniformity and pattern edge sharpness. In general, the smaller the droplet size, the greater the thickness uniformity and pattern edge sharpness.
The third parameter 1008 is the temperature of the device medium 206 while the three-dimensional surface 207 thereof receives the solution 208. The temperature is desirably within a nominal range, such as between 22 and 40 degrees Celsius (° C.). If the device medium temperature is too hot, the solution 208 may not properly spread, negatively affecting coating thickness uniformity. Likewise, if the device medium temperature is too cold, the solution 208 may spread too much, which also negatively affects coating thickness uniformity.
The fourth parameter 1010 is the delay time between scans, or passes, of the fluid-ejection mechanism 202 over locations on the three-dimensional surface 207. For example, as has been described in relation to
The fifth parameter 1012 is the type of the solvent 512 that is used within the solution 208. Different types of solvents, for instance, have different vapor pressures and resultant rates of evaporation, as well as other different physical properties. With respect to evaporation rate, a solvent having a faster rate may require less delay time between scans—meaning it has a higher flux limit) as compared to a solvent having a slower rate—to achieve the same coating thickness uniformity and pattern edge sharpness optimization.
The sixth parameter 1014 is the concentration of the solute (i.e., the active pharmaceutical ingredient plus the polymer) in the solution. Driving this concentration as high as possible is of value in putting less solvent on the part for a given mass of solute to be delivered; this helps the process stay within its flux limit and increases throughput; reliable jetting and decap behavior end up being the constraint on how high one can take this concentration. Two related parameters include the specific concentration of the polymer, and the specific concentration of the active pharmaceutical ingredient.
Finally, the seventh parameter is the cleanliness of the three-dimensional surface 207 of the device medium 206 (1016). The cleaner the three-dimensional surface 207 is, the easier it generally is to optimize coating thickness uniformity and pattern edge sharpness. Likewise, the less clean the three-dimensional surface 207 is, the more difficult it generally is to optimizing coating thickness uniformity and pattern edge sharpness.
Coating Surface Roughness
Besides controlling the thickness of the coating 216 on the three-dimensional surface 207 of the device medium 206, and the uniformity of this thickness, the surface roughness of the coating 216 on the surface 207 can be controlled. In some applications, a rougher surface of the coating 216 on the three-dimensional surface 207 of the device medium 206 may be desired. In other applications, a smoother surface may be desired. In general, the fewer passes of the fluid-ejection mechanism 202 over the three-dimensional surface 207, where the mechanism 202 ejects fluid over each of these passes, and with more of the solution 208 deposited in each pass, the greater the surface roughness, as compared to having more passes with less of the solution 208 deposited in each pass.
Increasing the fluid-ejection flux increases surface roughness of the coating 216 on the three-dimensional surface 207 (1104), whereas decreasing the flux decreases surface roughness of the coating 216 (1106). Flux refers to the volume of liquid dispensed over a given period of time per unit area. Use of a lower fluid-ejection, or dispense, flux when ejecting the solution 208 from the fluid-ejection nozzles 204 onto the three-dimensional surface 207 generally allows the resultant layer to dry more quickly, before migration of the solute 212 can occur, leading to a smoother surface of the coating 216. Likewise, utilization of a higher fluid-ejection, or dispense, flux when ejecting the solution 208 onto the surface 207 generally means that the resultant layer dries more slowly, such that migration of the solute 212 is more likely to occur, leading to a rougher and less well confined surface of the coating 216.
Once the coating 216 has been established on the three-dimensional surface 207—that is, after evaporation of the solvent 510 from the deposited solution 208 on the surface 207—the coating 206 may be heated above the glass-transition temperature of the solute 212 to reduce surface roughness (1108). The glass-transition temperature of the solute 212 is the temperature at which the solute 212 becomes a glass. This is why heating the coating 216 past this temperature results in the coating 216 becoming less rough.
Furthermore, placing the device medium 206, before the solvent 510 has completely evaporated, within an environment that is saturated with vapor of the solvent 510 can reduce surface roughness (1110). Such placement reduces the rate of evaporation of the solvent 510. Reducing the evaporative rate of the solvent 510 reduces surface roughness, because the resultant coating 216 is permitted to dry in a more orderly and controlled fashion.
Layer-by-Layer and Intra-Layer Thickness and Composition Control
On a layer-by-layer basis, the composition of the solution 208 may be varied in relation to the three-dimensional surface 207 of the device medium 206 (1202). For instance, for a first pass over the three-dimensional surface 207, the solution 208 may include at least a particular type of the polymer, a particular type of the active pharmaceutical ingredient 214, a particular concentration of the active pharmaceutical ingredient 214 within the polymer, and a particular concentration of the polymer within the solvent 510. For a second pass over the three-dimensional surface 207, the composition of the solution 208 may vary insofar as the solute type, the active pharmaceutical ingredient type, the solvent type, and/or the concentration of the active pharmaceutical ingredient within the solute may be varied.
In addition, on an intra-layer basis, the composition of the solution 208 may be varied in relation to the three-dimensional surface 207 of the device medium 206 (1204). For example, during a given pass over the three-dimensional surface 207, the concentration of the active pharmaceutical ingredient 214 within the polymer may not be homogeneous. Rather, there may be localized greater concentrations of the ingredient 214 within the solute 212, as well as localized lesser concentrations of the ingredient 214 within the solute 212. As a result, during dispensing of the solution 208 onto the three-dimensional surface 207 to realize a given, single layer of the coating 216, some locations of the surface 207 may receive solution 208 that has greater concentrations of the active pharmaceutical ingredient 214 within the polymer 212, and other locations may receive solution 208 that has lesser concentrations of the ingredient 214 within the solute 212.
Finally, on either an inter-layer basis (i.e., a layer-by-layer basis) or on an intra-layer basis, the thickness of the solute 212 of the resultant coating 216 may be varied (1206). For example, some layers, corresponding to the different number of passes over the three-dimensional surface 207 by the fluid-ejection mechanism 202, may be thinner or thicker than other layers. Furthermore during dispensing of the solution 208 during a given pass, more of the solution 208 may be ejected onto the surface 207 in some locations than in other locations, such that a given layer may purposefully not have uniform thickness.
The different shapes of the active pharmaceutical ingredients or bioactive substances 214 within the layers 1252 denote different active pharmaceutical ingredients 214. Likewise, the different shadings of the polymer within the layers 1252 denote different types of the polymer. As such, the composition of the layers 1252 is varied on a layer-by-layer basis. In addition, the layer 1252B does not have any active pharmaceutical ingredient 214 therein, and thus includes just the polymer. Furthermore, the composition of the layer 1252C in particular varies on an intra-layer basis, insofar as the concentration of the active pharmaceutical ingredient 214 within the polymer 212 decreases from left to right. Finally, the layers 1252 have different thicknesses, and the layer 1252D is thicker to the left than it is to the right.
Topographical Coating Control
Finally, besides thickness and composition, the topography of the layers of the coating 216 on the three-dimensional surface 207 of the device medium 206 can also be varied, among other characteristics of the coating 216.
First, the cross-sectional surface shape of the coating 216 on the three-dimensional surface 207 may be controlled (1302). For example, grooves within the coating 216 can be formed by varying the dispense, or fluid-ejection, flux of the solution 208 in a particular way. More specifically, where the dispense flux exceeds the flux corresponding to a smooth, flat surface, it has been found that such grooves are created within the resultant coating 216. Such grooves or craters can result from various fluidic evaporation effects. Other types of topographies may also be generated in this manner.
Second, periodic and discrete modules of the solute 212 may be purposefully formed as the coating 216 on the three-dimensional surface 207 (1304). That is, instead of a continuous layer of the coating 216 resulting from continuous ejection or dispensation of the solution 208 from the fluid-ejection nozzles 204 of the fluid-ejection mechanism 202, the solute 212 may instead mound periodically within the resultant coating 216. This effect occurs by leveraging the Rayleigh instability of the solution 208 as the solution 208 is continuously ejected onto the three-dimensional surface. The Rayleigh instability is the surface tension-driven instability of the thin film of the liquid solution 208 that lines a cylindrical surface in particular. For thinly dispensed layers of the solution 208, the periodic mounds form approximately with spacing every πD to 4.5 D along the length of the device medium 206, where D is the diameter of the medium 206 and where the medium 206 is cylindrically shaped.
| Number | Name | Date | Kind |
|---|---|---|---|
| 4069084 | Miodozeniec et al. | Jan 1978 | A |
| 4197289 | Sturzenegger et al. | Apr 1980 | A |
| 4322449 | Voss et al. | Mar 1982 | A |
| 4349529 | Morcos et al. | Sep 1982 | A |
| 4548825 | Voss et al. | Oct 1985 | A |
| 4905589 | Ackley | Mar 1990 | A |
| 5025325 | Hudson | Jun 1991 | A |
| 5609908 | Voss | Mar 1997 | A |
| 5714007 | Pletcher et al. | Feb 1998 | A |
| 5881716 | Wirch et al. | Mar 1999 | A |
| 5925732 | Ecker et al. | Jul 1999 | A |
| 6086942 | Carden, Jr. et al. | Jul 2000 | A |
| 6143353 | Oshlack et al. | Nov 2000 | A |
| 6395326 | Castro et al. | May 2002 | B1 |
| 6645547 | Shekalim et al. | Nov 2003 | B1 |
| 6692738 | MacLaughlin et al. | Feb 2004 | B2 |
| 20010016177 | Pelc et al. | Aug 2001 | A1 |
| 20020149641 | Du et al. | Oct 2002 | A1 |
| 20030223546 | McGregor et al. | Dec 2003 | A1 |
| 20060217801 | Rosenthal | Sep 2006 | A1 |
| Number | Date | Country |
|---|---|---|
| 0369445 | May 1990 | EP |
| 10016208 | Apr 1998 | JP |
| 03005950 | Jan 2003 | WO |
| 2004026182 | Apr 2004 | WO |
| 2006-102524 | Sep 2006 | WO |
| WO 2006102524 | Sep 2006 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20080100685 A1 | May 2008 | US |
