Patent Grant
9909807
The present invention relates to drug-eluting medical devices; more particularly, this invention relates to processes for controlling the interaction among polymer, drug and solvent, and the release rate of a drug for drug eluting medical devices.
Strict pharmacological and good mechanical integrity of a drug eluting medical device are required to assure a controlled drug release. Significant technical challenges exist when developing an effective and versatile coating for a drug eluting medical device, such as a stent.
A coating may be applied by a spray coating process. A drug-polymer composition dissolved in a solvent is applied to the surface of a medical device using this method. The amount of drug-polymer to be applied has been expressed as a target coating weight, which corresponds to the weight of the coating after a substantial amount of the solvent is removed.
Previous efforts to produce a more consistent and stable drug release profile have been met with challenges. Prior efforts have focused on the type or structure of the polymer carrier for a drug, and the type of solvent used. However, these improvements have not been able to satisfactorily meet the needs for certain clinical applications, or provide a morphology that can be widely used.
A “drug release profile”, or “release profile” means the morphology, or characteristics of a drug-eluting matrix that delivers an expected therapeutic behavior after being placed within a body. A drug release profile, or release profile therefore informs one of such things as the predictability of the release rate, variation, if any, in the release rate over time or on a per unit area basis across a drug-eluting surface.
It has been previously discovered that a significant improvement in the ability to tailor a drug release profile to suit a particular objective such as producing a specific release rate, uniformity in the release rate over a drug eluting surface, and/or uniformity in a production setting (high throughput) lay in obtaining more precise control over the amount of solvent present, or rate of solvent removal. The criticality of solvent removal, distribution, etc. generally depends on the drug-polymer-solvent formulation and particular objectives. While it was already known that the morphology of a drug-polymer matrix is influenced by the presence of a solvent, it was later discovered that this interaction played a more significant role than previously thought. Based on this conclusion, a more effective process for controlling the amount of solvent-polymer-drug interaction was sought. It was found that the coating weight per spray cycle and manner in which solvent was removed, in connection with the coating thickness was an important consideration.
A relatively high coating weight per spray cycle has been sought in the past, because this minimizes process time and increases throughput. Maintaining control over the amount or rate of solvent removal is, however, challenging unless an applied coating layer is relatively thin. If the applied layer is too thick the removal of the solvent becomes more difficult to control or predict. When the solvent is removed from a thick layer, therefore, the potential for undesired interaction among the solvent, polymer and drug, and related problems begin to impair the ability to retain control over the release profile.
Process conditions can affect the desired morphology. For example, if there is excess residual solvent, i.e., solvent not removed between or after a spray cycle, the solvent can induce a plasticizing effect, which can significantly alter the release rate. Therefore, it can be critically important to have a process that produces a coating with consistent properties—crystallinity, % solvent residue, % moisture content, etc. If one or more of these parameters are not properly controlled, such that it varies over the thickness or across a surface of a drug-eluting device, then the release profile is affected. One or more of these considerations can be more critical for some drug-polymer-solvent formulations than for other formulations.
To facilitate the incorporation of a drug on a stent, spraying a low solid percent polymer/drug solution over the stent followed by removing the solvent has become feasible in controlling the amount of drug (in micrograms range) deposited on the stent and the release profile. A good coating quality benefits from using this spray technique, i.e., properties such as the crystallinity, % solvent residue, and % moisture content are more controllable as the coating weight is built up over several applied coatings.
Previous studies of the drying effect on drug release indicated a need for an optimal in-process or inter-pass drying technique to remove a solvent on the coated stent after each spray cycle. This is a critical step in producing more stable products while retaining a high throughput.
The properties of a solvent, e.g., surface tension, vapor pressure or boiling point, viscosity, and dielectric constant, used in dissolving a polymer have a dominant effect on the coating quality, coating process throughput, drug stability, and the equipment required to process it. A solvent can, of course, be removed by applying a heated gas over the stent. However, this drying step must be carefully controlled in order to achieve the desired end result. A uniform and efficient heat transfer from the gas to the coating surface must also take place.
The evaporation rate of a suitable solvent has an inverse relationship with the coating thickness (generally inversely proportional to the thickness) for a thin film coating. And the resistance increases non-linearly as the coating thickness increases. As alluded to earlier, this non-linearity should be avoided. When the coating thickness is not too high more uniformity and control can be achieved in removing the solvent. As a result, a more consistent drug release profile is obtained because there is the least drug-solvent-polymer interaction, solvent plasticizing and drug extraction rate. It is therefore desired to achieve more control over, not only the uniformity of properties across the coating thickness and along the length of the stent, but also the ability to remove solvent. This is because residual solvent on the drug eluting stent may induce adverse biological responses, compromise coating properties, induce drug degradation, and alter release profile.
Thus, it has been determined that a release rate can be better controlled by applying many coats of a low percentage solution, e.g., 5% of the final coating weight, with a drying step between each spray cycle. Thus, in this example 20 coats are needed to produce the target coating weight. In order to make this coating process more feasible as a production-level method, while maintaining control over the solvent and solvent-drug-polymer interaction, as just discussed, an efficient in-process drying step is needed.
Effective ways to remove residual solvent in the applied coating becomes more important for coating formulations that are more sensitive to a residual solvent level. As explained above, excessive remaining solvent impacts the coating morphology and property. For example, in the case of a coating formulation used for a polymer scaffold, e.g., PLLA, residual solvent left in the coating can induce phase separation between the drug and polymer because the drug and polymer are not miscible. This can cause variation of the drug release rate and adversely impact the physical properties of the coating. It is therefore desirable to achieve an optimized in-process dry nozzle design to ensure the removal of most of the residual solvent between successive spray cycles. Examples of dryers seeking to achieve this objective are described in US20110059228 and US20110000427.
For example, US20110000427 proposes using an external heat nozzle design having a narrow opening producing a drying gas exiting from the dryer plenum at relatively high velocity. This arrangement requires precise alignment between the stent and heat nozzle for uniform drying. The design can introduce extensive and interfering mixing of outside air into the gas stream before contacting the stent or scaffold; this mixing of outside air is uncontrolled and causes variation in the temperature across the drying area. Additionally, the high velocity gas causes the stent to oscillate, which can be problematic for longer-length stents, such as those intended for peripheral vessels.
There is a continuing need for obtaining a better control over the drug-eluting product. Specifically, there is a need to develop an inter-pass drying process that is better able to remove solvent to achieve improved rate of release of a drug, uniformity of release rate over the stent length and/or the effectiveness of a drug when released from the coating. It is also desirable to reduce processing time when applying a drug-eluting coating.
The invention proposes an in-process dryer for maximizing in-process drying efficiency and uniformity for improving the product quality (e.g. coating and its drug release consistency). A dryer and associated process according to the invention can also obviate the need for an oven step which has been relied on to remove residual solvent, thereby streamlining the manufacturing process.
A dryer nozzle according to the invention has a wider mouth or exit from the plenum than previously proposed stent dryer designs. With this design mean gas velocity at the dryer nozzle is reduced over earlier dryer designs, so that there is less or no influence by the surrounding ambient air and less oscillations of the stent during drying. In a preferred embodiment the dryer is constructed as a telescoping dryer assembly, although other designs are contemplated, e.g., a dryer nozzle that is moved into and out of position as a single unit connected to a flexible gas supply. A shield surrounds the drying region to isolate heated gas from surrounding cooler ambient air. The stent (or scaffold) is disposed within this drying region during the drying step. The dryer nozzle is retractable, which allows clearance for movement of the sent or scaffold between spraying and drying stations. The feature of a retractable dryer nozzle also simplifies drying operations, such as concerns aligning the stent with the mouth or exit.
A dryer according to the invention addresses alignment issues and uneven drying seen in prior designs by ensuring full coverage and uniform heat application. In addition, the influence of ambient air in the drying operation is effectively minimized or eliminated. Tests have shown that the temperature within the shielded area of the drying region and just above it is at a constant temperature, indicating that no ambient air is drawn into the drying region. Since the hot air within the drying region is at a slightly higher pressure than the surrounding ambient air, ambient air is prevented from being drawn into the drying region. The dryer nozzle includes internal diffusers, e.g., stacked spacer and screen assemblies, to uniformly mix the heated drying gas, resulting in a temperature uniformity of within 1 degree C. across the stent drying area.
Accordingly, an inter-pass dryer, according to the invention, that is used in a stent coating process improves on the art by providing an apparatus and method for forming a drug-eluting coating that offers greater control over the release rate for a drug and less undesired interaction between residual solvent and the drug-polymer matrix in the coating. The term “inter-pass drying” means drying, or removing solvent between one, two, three or more spray passes. The weight of material per coat is in some embodiments are very light, about 5% of the total coating weight according to one embodiment. This means, for this particular embodiment, 20 coats are needed to reach 100% of the coating weight.
In view of the foregoing, the invention provides one or more of the following additional improvements over the art.
According to one aspect of invention, a method for applying a composition to a stent, comprising the steps of spraying the composition on the stent; and drying the stent, including the steps of moving a shield, surrounding a drying region, over the stent, applying a drying gas to dry the stent, and after drying the stent, moving the shield away from the stent.
According to another aspect of invention, a dryer nozzle for drying a stent includes a first housing configured for being connected to a gas supply; a second housing movable within the first housing, the second housing including a drying region in fluid communication with a mouth of the dryer nozzle and configured to receive and support a mandrel, the mouth being located at a base of the drying region, and a diffusion chamber disposed below the mouth.
According to another aspect of invention, a stent coating system includes a sprayer; a telescoping dryer nozzle; and a linear actuator for moving a stent-supporting mandrel between the telescoping dryer nozzle and the sprayer. The system may further include a rotary actuator for rotating the stent-supporting mandrel to improve consistency and uniformity of solvent removal.
All publications and patent applications mentioned in the present specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. To the extent there are any inconsistent usages of words and/or phrases between an incorporated publication or patent and the present specification, these words and/or phrases will have a meaning that is consistent with the manner in which they are used in the present specification.
According to a preferred implementation of the invention, a sprayer and dryer nozzle is used to form a drug-eluting coat on a surface of a stent. A stent is an intravascular prosthesis that is delivered and implanted within a patient's vasculature or other bodily cavities and lumens by a balloon catheter for balloon expandable stents and by a catheter with an outer stent restraining sheath for self expanding stents. The structure of a stent is typically composed of scaffolding, substrate, or base material that includes a pattern or network of interconnecting structural elements often referred to in the art as struts or bar arms. A stent typically has a plurality of cylindrical elements having a radial stiffness and struts connecting the cylindrical elements. Lengthwise the stent is supported mostly by only the flexural rigidity of slender-beam-like linking elements, which give the stent longitudinal flexibility. Examples of the structure and surface topology of medical devices such as a stent and catheter are disclosed by U.S. Pat. Nos. 4,733,665, 4,800,882, 4,886,062, 5,514,154, 5,569,295, and 5,507,768.
As discussed earlier, one aspect of the stent coating process that has been simplified, or improved, as a result of the dryer according to the disclosure, is the ability to predict more consistently the rate of solvent removal and variation of that rate over the length of the stent. Increasing the predictability of a solvent's presence in the applied coating, or remaining when determining a final weight can greatly increase the ability and/or efficiency in which a predictable release rate for a drug can be provided in a medical device, in the form of an applied coating.
Moreover, as the design or desired loading of polymer-drug on the stent is determined from the measured weight, it will be readily appreciated that there needs to be an accurate, reliable and repeatable process for being able to determine the amount and distribution of solvent remaining over the length of the stent. This is especially true when less volatile solvents are used, e.g., DMAc as opposed to the more volatile solvent Acetone. Since it is expected that a greater percentage of solvent will remain after drying for solvents having higher boiling points, the coating is more susceptible to variations in a solvent's presence over the stent surface and/or across the coating thickness. Also when drying a polymer Acetone mixture, the rate and uniformity of drying affects the % crystallinity and thus the amount of locked in residual solvent.
The disclosure provides examples of spraying/drying components suited for addressing the previously discussed drawbacks and limitations in the art pertaining to a drug-eluting coating applied via a drug-polymer dissolved in a solvent.
Referring, briefly, to side views of the dryer 10 as depicted in
The stent, supported on the mandrel 15, is rotated by a rotary mechanism (not shown) coupled to the mandrel 15 as the sprayer applies a drug-polymer dissolved in a solvent, e.g., DMAc or Acetone, to the surface of the stent. This rotary mechanism is also used to rotate the stent while it is disposed within the shield 32 to facilitate uniform removal of solvent about the circumference of the stent during drying. A mass of heated gas exits from the mouth of the dryer (at a base of the shield 32) to accelerate the evaporation, or boiling-off of solvent from the coated stent surface. In a preferred embodiment, this sprayer-dryer coating process is repeated until a final coating weight of drug-polymer and remaining solvent is measured. During each drying stage the gas is capable of producing a uniform heat transfer across the surface of stents or scaffolds, even for stents or scaffolds having lengths of 100 mm, 150 mm, and 200 mm.
A coating process according to
A plenum of the dryer 10 is formed by internal volumes of the base housing 20, the diffuser housing 30 and a base cap 70. Perspective views of the base cap 70 and diffuser housing 30 are illustrated in
To account for any thermal energy loss for gas near the walls of the housings 20, 30 one or more mixing regions are provided within the diffuser housing 30 so that the gas entering the drying region surrounded by the shield 32 has a more uniform heat transfer across the length of the stent. Preferably three mixing regions are used for dryer 10. Each mixing region is formed by a diffuser screen 42 and spacer 40. Each screen and spacer are stacked on top of each other, as indicated in
As mentioned above, gas travels from the gas supply into the interior of the base cap 70, though the exit hole 72 and then through the diffuser housing 30. When the diffuser housing 30 is lifted up to position the stent within the drying region surrounded by the shield 32 (
As just alluded to, the aforementioned structure, i.e., housings 20, 30 and base cap 70, and mechanism 50 that form the plenum for the dryer 10 may be thought of as a telescoping dryer. Prior to the stent being positioned over the drying region, the diffuser housing 30 is retracted within the base housing 20 to provide clearance for the stent and mandrel 15 to be linearly displaced from the spray station to a position over the drying region. The dryer plenum is then essentially elongated or expanded to bring the stent into the drying region of the diffuser housing 30. Thus, a “telescoping dryer assembly” is intended to mean an arrangement of housings forming a plenum that slide inward and outward in overlapping fashion in a manner analogous to how a hand telescope slides inward and outward in an overlapping fashion, to thereby provide a variable length channel or internal passage for a pressurized fluid to pass through, i.e., a variable length plenum.
Referring to
The actuating mechanism 50 (e.g., one or more hydraulic actuators, such as air cylinders, operated as part of a servomechanism pre-programmed or controlled by a computer processor to produce the desired movement in the housing 30 in accordance with a drying/spraying process as shown in
The walls 30b forming the shield 32 include a first notch 36 disposed at one rounded end, and a second notch 38 disposed at a second or opposed rounded end. These notches 36, 38 are used to allow the mandrel that the stent sits on to lower the stent to within the shield 32 during the drying. When the gas exits, even at a low velocity the stent will oscillate since it rotates which presents a varying surface area to the gas exiting (in addition to the non-laminar or transient flow in and around the stent). The problem of oscillations is especially noted for stents that are 40 mm and longer, e.g., stents (or scaffolds) intended for the superficial femoral artery. To meet these needs the dryer 10 includes a support for the mandrel 15 distal end 15a, i.e., mandrel grippers 60, in addition to the notches 36, 38. With the additional support provided by grippers 60 the stent becomes effectively fixed-supported at the mandrel distal end 15a when disposed over the dryer mouth (exit of the plenum), yet is still capable of being rotated about the mandrel axis by a rotary mechanism coupled to the mandrel. This support may be achieved without interference with drying and prevents contact between the stent/scaffold and the walls 30b or mandrel 15 as the gas passes over the stent/scaffold.
The stent is mounted onto the mandrel 15 prior to the start of the stent coating process (
For the drying systems described in US20110059228 and US20110000427 there is preferably an oven step for removing residual solvent from the stent or scaffold. In an additional aspect of disclosure, the oven step may be skipped as tests show that the dryer 10 and process as shown and described may remove solvent at a sufficient rate during the process of
Twelve as-coated samples were collected to assess efficiency of the dryer 10 with and without a later oven step. Those samples were processed using inter pass dry temperature at 50 C. Those samples were divided into two groups—Group A and Group B. The six group A samples were kept in a tightly sealed vial and in the refrigerator prior to residual solvent testing, and while the six group B samples proceeded with an additional oven dry at 50 C for 30 minutes immediately after the final coating step, then kept in the vial.
The residual acetone data for the two groups are listed in the TABLE 1. The data shows that there is not much different between the average of the residual acetone level between the two groups (between 1 to 2 micrograms). This is because the actual amount of a residual solvent present in a coated stent can vary within a few micrograms of a measured amount, which is what TABLE 1 shows. Moreover, in some applications up to 5 μg of residual solvent remaining in the coating is considered acceptable. Accordingly, the test suggests there may be no need to have an oven bake step when using a dryer constructed in accordance with dryer 10.
A gas flow rate through the heater assembly 2 in
During a coating process, the dryer is not in use when the stent is being coated. If the dryer is shut down or the flow rate reduced the temperature of the gas at the entrance to the plenum 10 of the dryer 1 will decrease. If the stent is moved into position above the nozzle mouth for drying and the valve opened to increase the flow rate, there will be a period of transient flow. It is desirable to avoid a period of solvent removal by transient gas flow, since the rate or amount of solvent removal by transient flow can be difficult to predict. It is preferred, therefore, that the stent is dried only during steady state flow conditions.
If gas flow at the dryer is instead maintained at a constant rate, then the temperature may be maintained. However, this wastes gas resources. It would be desirable if the gas flow rate could be reduced when the dryer is not in use while holding the gas temperature at a constant value.
To meet this need, a closed loop control is preferably implemented with a stent dryer system according to the disclosure, so that the gas temperature may be maintained at variable flow rates. Referring to
As the flow rate is adjusted by opening/closing the adjustable valve 308, the controller senses a change in temperature from input received at the thermocouple 302, at which point it will increase/decrease the power delivered to the heating coils by affecting control 306 for power so that the temperature remains constant, regardless of the actual flow rate. Thus, according to this aspect of the disclosure, a dryer system may be operated at variable flow rates during a coating process while maintaining a substantially steady state gas flow during the drying stage, or a minimal period of transient flow conditions until a steady state condition is reached. This improves/maintains the predictability of solvent removal during drying, minimizes down time and allows gas resources to be conserved. The coated stent is almost immediately subject to the drying step and dried in a manner that allows the improved prediction of solvent removal. As discussed earlier, this is a critical step in the process of producing a predictable release rate for a drug-eluting stent and accurate assessment of whether the desired drug-polymer coating weight has been reached.
After, or just prior to completion of an application of coating composition on the stent, the controller 300 increases the gas flow temperature to the drying gas flow rate. While the gas flow is being increased, the controller 300 monitors the temperature at the plenum entrance 2c by input received from the thermocouple 302 and the power increased to the heating coils as necessary to maintain the temperature of the exiting gas flow. Once the gas flow has reached the operating flow rate and temperature, the stent is moved into position above the shield 32 and the housing 30 raised. The stent is rotated. After drying is complete, the gas flow is again returned to the idle state and the power to the heating coils decreased as necessary to maintain the same gas flow temperature (based on input received from the thermocouple 302) at/near location 2c. The process repeats until the desired coating weight is obtained.
The above description of illustrated embodiments of the invention, including what is described in the Abstract, is not intended to be exhaustive or to limit the invention to the precise forms disclosed. While specific embodiments of, and examples for, the invention are described herein for illustrative purposes, various modifications are possible within the scope of the invention, as those skilled in the relevant art will recognize.
These modifications can be made to the invention in light of the above detailed description. The terms used in claims should not be construed to limit the invention to the specific embodiments disclosed in the specification. Rather, the scope of the invention is to be determined entirely by claims, which are to be construed in accordance with established doctrines of claim interpretation.
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