Patent Application
20230106928
The present disclosure generally relates to the fields of drug delivery and drug coated balloons. In particular, the present disclosure is directed to undulating balloon systems and methods for nanoparticle-based drug delivery.
Drug coated balloons (DCB) have been used for treatment of coronary artery disease and peripheral artery disease (PAD) for many years. In a conventional DCB, the drug payload is coated on the balloon using a wide variety of coating techniques. In use, similar to a plain old balloon angioplasty (POBA) procedure, the DCB is placed across the lesion and expanded to compress, and force drugs into, the lesion. While some success has been achieved to date with DCBs, one limitation is challenges in drug delivery from the balloon to the arterial wall and adequate retention of the initially delivered drug for a time sufficient to have a lasting beneficial effect.
A number of different devices or techniques have been proposed in an attempt to improve results of angioplasty procedures. In one proposal, the PTA balloon is configured to vibrate at a relatively high frequency with a goal of fracturing or breaking up plaque forming the lesion. However, a drawback of vibrating balloons is believed to be stimulation of intimal thickening and proliferation of smooth muscle cells in the vessel wall as a result of the forceful, high frequency vibrations applied to break up the plaque of the lesion. Smooth muscle cell proliferation is undesirable because it can be a significant cause of stenosis or narrowing. Such high frequency vibrations may also impede rather than promote drug uptake via drug carrying media such as nanoparticles if implemented in a DCB.
Another limitation with conventional DCBs for treatment of PAD is limitation of the available drugs. For example, while both paclitaxel and sirolimus are known to show efficacy in limiting restenosis in PAD, to date sirolimus has not been generally accepted for use with DCBs because it has a much slower uptake by cells as compared to paclitaxel-rendering delivery via DCB far more challenging.
However, functionalized nanoparticles have shown significant promise as vehicles for delivery of a wide variety of drug compounds, including sirolimus. Examples of such nanoparticles are disclosed in US Pat. No. 8,865,216 to Labhasetwar et al., granted Oct. 21, 2014, and entitled “Surface-Modified Nanoparticles for Intracellular Delivery of Therapeutic Agents and Composition for Making Same, which is incorporated by reference in its entirety herein. There is, however, a need for effective delivery devices for drug carrying nanoparticles, particularly as regards to delivery of sirolimus and other drugs intravascularly, alone or in combinations for multiple drug treatments.
In one implementation, the present disclosure is directed to an undulating balloon PTA system. The system includes a balloon catheter having preset maximum inflation pressure, an oscillating fluid pressure source communicating with the balloon catheter, and a controller configured to cause the oscillating fluid pressure source to deliver controlled pressure oscillations to the balloon catheter between a maximum pressure equal to the preset maximum inflation pressure and a set minimum pressure at a selected cycle time. In some embodiments the set minimum pressure is not more than 50% less than the maximum pressure. In other embodiments, the controller is further configured to deliver the pressure oscillations at a cycle time of 10 seconds to about 0.25 seconds. In still other embodiments, the set minimum pressure is not more than 30% less than the maximum pressure and the controller is configured to deliver pressure oscillations at a cycle time of 1 second to about 0.25 seconds. In a further embodiment, the controller is configured to deliver pressure oscillations with a minimum cycle time setting of 0.5 seconds.
In another implementation, the present disclosure is directed to an undulating balloon PTA system comprising an inflatable balloon member with a drug-carrying nanoparticle matrix disposed on an outer surface of the balloon member. The drug-carrying nanoparticle matrix preferably contains microchannels, whereby blood may circulate in the microchannels to increase hydration of the nanoparticle matrix. In another embodiment, the nanoparticle matrix comprises drug-carrying nanoparticles and interstitial bonding agent, wherein the interstitial bonding agent is configured to release the drug-carrying nanoparticles in response to predetermined stimulus or conditions. In yet another embodiment, the balloon member is a part of a balloon catheter and the system further comprises an oscillating fluid pressure source communicating with the balloon catheter, and a controller configured to cause the oscillating fluid pressure source to deliver controlled pressure oscillations to the balloon member between a maximum pressure equal to the preset maximum inflation pressure and a set minimum pressure at a selected cycle time.
In yet another implementation, the present disclosure is directed to a method of inflating a PTA balloon. The method includes inflating the balloon using an inflation fluid to a selected maximum pressure; delivering controlled pressure oscillations to the balloon through the inflation fluid, the controlled pressure oscillations oscillating at a cycle time of 10 seconds to 0.25 seconds with a pressure reduction between the selected maximum pressure and a set minimum pressure not more than 50% less than the selected maximum pressure.
In still another implementation, the present disclosure is directed to a method of treating vascular disease. The method includes placing a balloon across a lesion in a vessel, the balloon having an outer surface with a nanoparticle matrix disposed thereon, the nanoparticle matrix including drug-carrying nanoparticles; inflating the balloon using an inflation fluid to a selected maximum pressure; delivering controlled pressure oscillations to the balloon through the inflation fluid, the controlled pressure oscillations oscillating between the selected maximum pressure and a set minimum pressure, the oscillations provided at a selected cycle time; and releasing the drug-carrying nanoparticles from the nanoparticle matrix during the delivering, whereby the pressure oscillations facilitate ingress of the drug-carrying nanoparticles into the lesion and surrounding tissue.
In another implementation, the present disclosure is directed to an undulating balloon PTA system. The system includes a balloon catheter including at least one balloon having a preset maximum inflation pressure; a manually actuatable fluid pressure source communicating with the balloon catheter and comprising a syringe body and plunger received in the syringe body; an oscillating fluid pressure source communicating with the balloon catheter; a drive motor powering the oscillating pressure source; and a controller configured to control the drive motor to cause the oscillating pressure source to deliver controlled pressure oscillations to the balloon catheter, the control comprising - delivering fluid pressure oscillations between a maximum pressure equal to the preset maximum inflation pressure and a set minimum pressure not more than 50% less than the maximum pressure; and delivering the fluid pressure oscillations at a selected cycle time in the range of about 10 seconds to about 0.25 seconds.
In still yet another implementation, the present disclosure is directed to an undulating balloon PTA system. The system includes a balloon catheter including a balloon member comprising a double balloon with a first inner balloon inside a second outer balloon, the balloon member having a preset maximum inflation pressure; a manually actuatable fluid pressure source communicating with the first inner balloon and second outer balloon; an oscillating fluid pressure source communicating with second outer balloon; and a controller configured to cause the oscillating fluid pressure source to deliver controlled pressure oscillations to the second outer balloon between a maximum pressure equal to the preset maximum inflation pressure and a set minimum pressure at a selected cycle time.
In a further implementation, the present disclosure is directed to a balloon PTA system. The system includes a multi-segmented balloon catheter. The balloon catheter includes an inflatable balloon member having plural balloon segments arranged along its length; and a catheter body defining a guidewire lumen and plural inflation lumens with one inflation lumen for each the balloon segment, each inflation lumen having at least one inflation port providing fluid communication between a balloon segment and the corresponding inflation lumen, whereby each balloon segment is independently inflatable via separate inflation lumens in the balloon catheter.
In yet another implementation, the present disclosure is directed to an undulating PTA balloon system. The system includes a self-oscillating balloon catheter. The self-oscillating balloon catheter includes a catheter body; a balloon member disposed at a distal end of the catheter body; at least one plunger disposed inside the balloon member; and an actuatable biasing element acting on the at least one plunger configured to cause oscillations of the at least one plunger when actuated.
For the purpose of illustrating the disclosure, the drawings show aspects of one or more embodiments of the disclosure. However, it should be understood that the present disclosure is not limited to the precise arrangements and instrumentalities shown in the drawings, wherein:
Systems and methods for localized drug delivery via drug coated balloons (DCB), in particular using functionalized nanoparticles as a drug delivery medium in combination with an undulating balloon, are disclosed. In various disclosed embodiments, a nanoparticle matrix is adhered to an external substrate-surface, such as the balloon surface, and is activated for release once at the treatment site. Activation for release may be enhanced through the use of an undulating balloon system including methodologies for precise control of timing, waveform and extent of undulations. Certain aspects of the present disclosure may also have applicability in non-undulating drug-coated balloons, plain old balloon angioplasty (POBA), and/or other medical devices placed in the vasculature, such as, for example, stents. Another aspect of the oscillations described herein is to create microchannels in the vessel lumen to enable released nanoparticles to diffuse into the underlying tissue.
An example of an embodiment of an undulating DCB system is shown in
In some embodiments, undulating PTA balloon 104 oscillates within a diameter range of about +/-50%, with a preferable diameter oscillation range between a ratio of about 1:1 to 1:2.5 of the initial vessel diameter. In an illustrative example, if the vessel is measured at 6.0 mm, the diameter of the balloon would have a maximum oscillation range between 4.5 mm and 7.5 mm. In smaller vessels, the upper diameter ratio may be about 1: 1.2 or less and in more moderately sized vessels, such as some peripheral arteries, the upper diameter ratio may be about 1:3 to about 1:6. While some degradation or destruction of the plaque may be a beneficial side effect, the oscillations need not be sufficient to break calcium in atherosclerotic plaque. In fact, excessive frequency or amplitude may promote intimal thickening or induce proliferation of smooth muscle cells in the vessel wall tissue, which is to be avoided. Instead, oscillation frequency and amplitude is controlled to more gently introduce microchannels for drug delivering nanoparticles to diffuse through the endothelium and into the underlying vessel wall. Low amplitude pressure cycles comprising a fraction of the maximum inflation pressure are preferred. For example, in a balloon with a 20 atm maximum inflation pressure (burst pressure may be higher), low amplitude pressure cycles would cycle between about maximum pressure of 20 atm and a minimum cycle pressure of not more than a 50% pressure reduction, or about 10 atm minimum pressure. In some embodiments, the maximum pressure reduction should be about 30%, for a minimum cycle pressure of about 14 atm in 20 atm maximum pressure balloon. In other embodiments the maximum pressure reduction should not exceed about 20%, to give a minimum cycle pressure of about 16 atm in the same balloon. Cycle times may exceed times achievable by conventional manual inflation techniques, but should not significantly exceed those levels, and high frequency cycles are to be avoided due to the likelihood of triggering proliferation of smooth muscle cells in the vessel wall at or around the treatment site. Therefore lower frequency pressure cycles are preferred, with typical cycle times, i.e., time between adjacent maximum pressure peaks, typically not below about 0.25 seconds per cycle. In general, the applicable range of cycle times is about 10 seconds down to about 0.25 seconds per cycle. In certain embodiments, it will be desirable to limit the minimum cycle time to be greater than about 0.5 second per cycle. In some embodiments, drug uptake may be increased with greater numbers of cycles, in which case it may be desirable to reduce maximum cycle time to about 1 cycle per second. In such embodiments cycle time may range from 1 to 0.25 seconds per cycle or in others from about 1 to about 0.5 seconds per cycle. With the described relatively lower frequency and pressure amplitude changes, devices disclosed herein are configured to impart micro or nanochannels into the endothelium, while minimizing or eliminating triggering of undesirable cell proliferation (e.g. smooth muscle cells), to allow increased uptake of drug cargo (for example via functionalized nanoparticles as described below) into the underlying tissue while not adding significant injury to the angioplasty procedure.
In another embodiment, fluid displacement is provided by a modified inflator device with a moving piston that changes the pressure automatically for a certain period of time using a mechanized leadscrew and internal pressure sensor. A variety of different balloon types may be used.
PAD may occur over relatively lengthy sections of arteries, sometimes lengths of 200 mm or more. The characteristics or extent of lesions across lengthy sections of PAD, however, may not be uniform or consistent. Therefore, in the treatment of PAD, it may be desirable to provide lengthy devices, i.e., lengths of 50 mm, 100 mm, or 200 mm or more. Also, due to nonuniformity of lesions in such lengthy sections of disease, it may be desirable to provide a treatment device that offers different levels or characteristics of treatment in different segments of the device. Multi-segmented balloon 104F, as shown in
In another alternative embodiment, as shown in
In another embodiment, the fluid oscillations are created through fluid displacement inside the balloon itself. Such an embodiment may have essentially the same structure as balloon 104C, shown in
One example of an oscillating fluid pressure source to drive balloon undulation according to the present disclosure is shown in
Another example of an oscillating fluid pressure source is shown in
Drive motors 172/172A are controlled by controller 110 as shown in
A further alternative embodiment of a periodic fluid pressure source is shown in
In some embodiments, controllers 110, 618 may comprise a user interface that permits user selection of motor drive parameters.
In specific embodiments, the ranges of rest and hold times may be more narrowly set than the overall ranges shown in Table 2. For example, in some embodiments, rest time may not exceed 1000 ms.
In another aspect of the present disclosure, a method for deployment and treatment with undulating balloon embodiments as disclosed herein includes steps as illustrated in
After spanning the lesion at the treatment site, the balloon is then first inflated to an initial pressure 194 as determined by compliance charts per standard clinical practice based on factors such as vessel size, lesion characteristics and/or balloon size. Such information may optionally be stored in memory or a storage module of controller 110. The initial pressure is typically selected by the physician to correspond to a clinically appropriate maximum balloon diameter as determined by the physician based on measurements made prior to balloon placement. The maximum inflation pressure will not exceed the burst pressure for the balloon. In some embodiments, inflation to the initial pressure may be done manually by the physician using a manual actuator on the indeflator, in others it may be part of the automated control algorithm. In preferred embodiments, the system senses when the initial pressure is reached and sets that pressure as Pmax196. After holding at Pmax for a set hold time, the system then controls pressure delivered by the indeflator to oscillate down to either a pre-set reduced value or a physician-determined value, Pmin, before returning to Pmax and then oscillating between max and min pressure over selected cycle, hold and rest times 197. Pmin may be determined from the DCB compliance chart to maintain contact between the balloon and the vessel wall to prevent blood flow across the lesion during undulations. Pmin may also be determined angiographically. Pmin may also be determined by the undulating inflator based on pressure or another measurement of balloon-tissue contact such as tissue strain or conductivity. Pmin may also be set to enable blood flow between balloon and vessel wall to aid with rehydration of the nanoparticle coating and thus improve transfer between balloon and vessel wall. Once set cycles are completed, the physician removes the balloon in accordance with standard PTA best practices 198.
Controller 110 also may be configured with different treatment algorithms employing a variety of different undulation waveforms as shown in
The undulation algorithms are preferably configured to optimize disruption of the endothelial layer in different disease profiles. The arterial wall is composed of a plurality of layers, with the endothelial layer being the innermost layer. The undulations are designed to disrupt the endothelial layer (the endothelium and subendothelium). The internal elastic lamina should deform and also form microchannels with more undulations. The combination of these microchannels are believed to increase nanoparticle transport to the smooth muscle cell layer and thus increase tissue concentrations of cargo drug without triggering an intimal thickening response or proliferation of the smooth muscle cells. Specific waveform can be derived to optimally address these factors in each patient/clinical situation by persons skilled in the art based on teachings contained herein.
An important aspect of DCBs is adherence and release of the drug compound on the balloon substrate. Functionalized nanoparticles, for example, as described in the above-incorporated Labhasetwar patent, address the well-known problem of poor uptake of many drugs (e.g. sirolimus), However, such nanoparticles are readily water soluble and therefore require delivery solutions to get past the endothelium to reside in the underlying tissue. The above-disclosed undulating balloons and balloon systems are configured to impart more micro or nanochannels into the endothelium, while minimizing or eliminating triggering of undesirable cell proliferation (e.g. smooth muscle cells), to allow more functionalized nanoparticles into the underlying tissue while not adding significant injury to the angioplasty procedure. Embodiments disclosed herein provide improved coatings and coating techniques for use with disclosed systems and balloons to maximize drug delivery using functionalized nanoparticles as a delivery vehicle. Disclosed devices have characteristics to sustain user-handling while releasing the nanoparticle-carrying matrix or coating when it arrives at the treatment location.
Adhesion of the nanoparticle matrix onto a substrate is dependent on a number of factors, such as particle surface modification and the interface between the substrate and coating. Device manipulation is possible during delivery, but the nanoparticle matrix should remain intact when dry, and then only release within the body (e.g., in vessel or contact with body fluid) due to hydration or other controlled processes as disclosed herein. With respect to hydration, the hydrating characteristics may be selected to achieve such release during an applicable allotted time selected as clinically desirable for a particular patient or treatment. As an illustrative example, DCBs in PAD treatment are typically inflated over about 3 mins, whereas DCBs in coronary disease treatments may be typically inflated for approximately 1 min. In another example, a coronary stent is typically permanently deployed, and has a drug elution time in a range around 90 days. Thus, devices to meet each of these three applications may have multiple different coatings with different hydrating characteristics specific to the application and elution time. The drug elution time designed into a product also may be achieved in whole or in part through the use of an interstitial agent or agents as further described hereinbelow.
In some embodiments, drug elution from the nanoparticle carrier matrix is controlled with the use of one or more interstitial bonding agents between the nanoparticles. Depending on the rate of interstitial bonding agent hydration, a slow or fast release of the drug-carrying nanoparticle coating from the substrate may be achieved. This allows the elution time to be carefully controlled and tailored to the clinical need and, as a result, the nanoparticle coating could be used on a DCB requiring a fast release, or a stent for a slow release by employing the teachings of the present disclosure.
A number of different characteristics of the interstitial bonding agent may be used to tailor the elution time. However, in general, the interstitial bonding agent is selected so as to not degrade the nanoparticles and to preserve the shape, charge, or surface modifier designed into the nanoparticle to create the functionalization of the particles. For example, a water-soluble hydrogel or ductile material bonding agent may be selected with properties such that when dried it allows for bending of the coating without fragmenting the nanoparticle matrix. Examples of materials that may be used as an interstitial bonding agent include PVA, PEG and its co-polymers, PVP, poly-e-caprolactone, chitosan, poly(N-isopropylacrylamide) (NIPAAM), gelatin, poloxamer, alginate, and other similar materials with similar material properties. Such materials may serve as an interstitial excipient for holding the nanoparticle coating together without necessarily interacting with particle transfer to the vessel wall or with cellular uptake of the drug-carrying nanoparticles. However, further modification of the coating material may allow the coating to also serve as an excipient for drug elution, nanoparticle transfer and/or cellular uptake.
Another characteristic of the interstitial bonding agent that may be modulated is its chemical sensitivity to factors such as proteins in the blood, plasma, pH, and cationic and ionic imbalance as means for initiating or promoting degradation. Such a protein-based nanoparticle carrying film may be made out of resilin, elastins including elastin-like polypeptides, silk, collagens, keratins, and bee silks. Protein-based films may employ multiple protein sources with different protein rations to modulate the degradation response initiating factors such as identified above. Multi-layers of hydrophilic and hydrophobic protein materials may be used to create a bond-interface to allow nanoparticles to reside and be released once degraded through pH change, or temperature change or other factors.
Release mechanisms pH sensitivity may employ interstitial bonding agents comprising pH sensitive polymers having a pH critical point designed to obtain a desired change in material behavior - e.g. polyacids with a pH critical point < 7.4 (physiological) would result in a net negative charge on the interstitial bonding agent, such as a non-loaded nanoparticle, causing the polymer to swell and detach from the substrate. Conversely, with polybases if the pKa (i.e. critical point) of the polymer is > 7.4, the polymer will swell upon exposure to blood causing the coating to detach from the substrate. Alternatively, linear block copolymers may be designed to undergo a sol-gel transition such that the properties go from a stiff gel to a soft gel at physiological pH capable of releasing from the substrate. Multi-stimuli polymers may also be used that respond to a combination of both pH and temperature.
Interstitial bonding agents also may be made sensitive to body-temperature by using temperature-responsive polymers within the matrix to change phase when achieving body temperature. A variety of temperature-responsive polymers are available. such as, but not limited to, gelatin, poloxamers (e.g. 407, 127), poly(N-isopropylacrylamide) (NIPAAM), poly(vinylcaprolactame), polyoxazolines (such as poly-2-isopropyl-2-oxazoline), polyvinyl methyl ether, poly[2-dimethylamino)ethyl methacrylate] (pDMAEMA), cellulose-derived polymers (hydroxypropyl myethylcellulose, methyl cellulose, carboxymethylcellulose, ethy (hydroxyethyl) cellulose and the like); xyloglucans, dextrans, poly(g-glutamate), elastin, elastin-like polypeptice/oligopeptide; poly (organophosphazenes), PEG/biodegradable polyester copolymers, PEG-PCL-PEG.
In a further alternative, as illustrated in
Blank nanoparticles 204 may be functionalized to provide specific release characteristics using functionalizing elements such as cationic polymers, e.g., poly(ethyleneimine) (PEI), poly-l-(lysine) (PLL), poly-l-arginine, poly[2-dimethylamino)ethyl methacrylate] (pDMAEMA), chitosan, cellulose such as hydroxyethylcellulose, cationic gelatin, dextran, poly(amidoamines), cyclodextrin. Other functionalizing elements for blank nanoparticles 204 may include anionic polymers such as, for example, alginate, carboxymethylcellulose. Functionalized blank nanoparticles 204 may be comprised of dendrimers such as poly(amidoamine) (PAMAM). Dendrimers may be cationic or anionic depending on the surface charge of the nanoparticles. Opposite charged blank nanoparticles 204 will form charge-based interactions with the drug-loaded nanoparticles 200. Degradation of the blank dendrimer will then enable release of the nanoparticle-containing drug. In further alternative embodiments, hydrophobic molecules may be included to encourage hydrophobic interactions between blank nanoparticles 204 and drug loaded nanoparticles 200. Alternatively, hydrophilic molecules encourage hydrophilic interactions between blank nanoparticles 204 and drug loaded nanoparticles 200.
In further alternative embodiments, illustrated in
In other alternative embodiments, as illustrated in
In other embodiments, as illustrated in
In yet another embodiment, an example of which is illustrated in
Using a sensor such as formed by conductive filaments 223, the physician also may obtain information via controller 232 indicating when to deflate or remove the device because the nanoparticle matrix has fully degraded. Therefore, with such a sensor underlying the nanoparticle matrices as described herein, and measurement of the impedance change, one can determine when the coating has completely eluted out of a device such as a DCB. Such information, previously unavailable with existing devices, will help adjust the inflation time to either shorten it or extend it as permissible in order to optimize treatment delivery. Currently, DCB inflation time is typically fixed, without real-time feedback on possible effectiveness of drug delivery. For instance, instead of having a fixed time of 3 min during the delivery of the DCB balloon, such time could either increase or decrease depending on the in vivo elution time and the medical decision to do so.
Nanoparticle hydration is another parameter that can be modulated to beneficial effect in embodiments of the disclosed devices. The rate of nanoparticle matrix hydration is a factor in releasing the nanoparticle from the substrate during the desired application time. If duration of an application is of a short time, the nanoparticle matrix should have that brief time to degrade and elute the nanoparticle. At a basic level, the nanoparticle matrix is applied against a vessel wall and drawing water from the environment, which causes the coating to re-hydrate and degrade. Various factors may be employed to modulate the rate of hydration as the mechanism of degradation and thus application times may be manipulated and enhanced. For example, a salt-based polymer embedded with the nanoparticle matrix will augment the ability to attract water faster into coating. Also, controlling blood flow over the substrate surface between pressure cycles can contribute to hydration.
In another alternative, as illustrated in
Devices disclosed herein are not limited to delivery of individual drugs. Disclosed devices may employ nanoparticles carrying multiple therapeutic or diagnostic (e.g. cellular tagging) cargo. The conjugation of drug and biodegradable nanoparticles could be done through standard nanoparticle formulation and fabrication as it is known in the field. Employing known techniques as modified by the teachings of the present disclosure, various embodiments may deliver cargos such as, but not limited to anti-inflammation, anti-arrhythmic, anti-proliferative, anti-restenosis, Botox®, cortisone, cytotoxic drugs, and cytostatic drugs. For example, the desired cargo may be mixed with a biodegradable material such as a PLLA/PLGA mixture or other biodegradable material known in the art. The cargo type in such embodiments may be multi-drug in one nanoparticle or a slurry of multiple nanoparticles with a single drug each.
A further aspect of the present disclosure are coating processes for creating nanoparticle layers as described above. In one embodiment, the coating process employs an aqueous solution and uses a lyophilized nanoparticle recombined into a water-based interstitial bonding agent (as described above) or just an interstitial non-bonding agent (water) to form a slurry. The nanoparticles may include a surface modifier to help connect with the substrate’s surface, such surface modification is substrate-dependent and designed to interact with one surface at a time. The slurry is applied to a device surface by deposition, for example using an ink-jet type of deposition, where it is sputtered on to the device surface (e.g., balloon) one layer at a time. In one embodiment, illustrated in
The slurry with a water-based interstitial bonding or non-bonding agent when deposed using inkjet or inkdot technology may not require an additional drying mechanism (e.g. air flow or heat). In one process embodiment, the coating machine and the catheters are placed in an extremely low humidity environment to extract the water from the coating. Alternatively, the product is placed in a vacuum chamber to extract water out of the coating. Further drying processes such as lyophilization may be employed, i.e. subjecting the coating to a freezing temperature environment or freezing fluid inside the balloon to drive off moisture.
In a further alternative embodiment, during the coating process, the balloons or substrate are purposely undersized. As an illustrative example, for instance, a 6 mm nominal balloon is coated at 4 mm diameter instead of at its nominal diameter. Thus when the device is applied in the clinical setting, the coating is overstretched further from the original coating diameter, providing additional mechanical degradation of the surface layers that allows for water absorption. Alternatively, the balloon may be oversized during coating, e.g. the 6 mm balloon inflated to 8 mm, to create small gaps between lines/dots of the coating to facilitate/channel water ingress.
In another embodiment, the deposition of the coating lines on the substrate is performed with an ink-jet deposition using either an ultrasound-nozzle or a non-ultrasound nozzle with just a spray pattern. With the use of either nozzles, the nanoparticles are designed to sustain the shear stresses during the coating process. For instance, with the nanoparticles are fabricated a solid nanosphere, the surface-modifiers are also designed to sustain high shear stresses. The deposited lines are differentiated such that when the substrate is rotated, there is no effect of gravity in drooping the material from the balloon. This is achieved through a combination of nanoparticle design, interstitial (bonding or non-bonding) agent, viscosity manipulation, and temperature. In a further alternative, using inkjet line deposition, after applying the coating lines the balloon is then frozen to enable use of lower viscosity NP solutions. Thereafter the coating can either slowly thaw to dry or lyophilize, which may impart microchannels for water to invade the coating and enhance release/transfer.
During the coating process, single or multiple sprays from depositing nozzles could be used. The spray nozzles may operate to sputter continuously or intermittently. Using multiple spray nozzles, the content delivered by the nozzles could be the same or different depending on the spraying need. For instance, one nozzle could have a nanoparticle with drug cargo, and the other nozzle could have a topcoat for re-hydration manipulations. Also, a nozzle could have a nanoparticle with Drug A and the other nozzle(s) with a nanoparticle with Drug B or C, etc., netting a balloon with multiple drugs, for instance depositing both Paclitaxel and Sirolimus on the same balloon at different ratios. In one embodiment, a low quantity of paclitaxel and a large quantity of sirolimus. A combination of multiple nozzles also may be employed, for example, one spraying continuously and the other intermittently to create channels for water ingress.
In alternative embodiments, a robotic coating machine may be used with the ability to coat the substrate selectively leaving some areas without any coating. In one example, in a PTA balloon, the cones are not part of the therapy and therefore could be excluded from the coating process. In another alternative, the non-therapeutic area is coated with a hydration-promoting agent, such as a hydrophilic coating. In a further alternative, the topcoat is a degradable hydrophilic coating applied either after folding or before folding the PTA balloon. In yet another alternative embodiment, a dip coating process is used to coat devices such as DCBs, wherein a multiple dip in a same solution or multiple dip in different solutions of distinct actions can be employed.
The foregoing has been a detailed description of illustrative embodiments of the disclosure. It is noted that in the present specification and claims appended hereto, conjunctive language such as is used in the phrases “at least one of X, Y and Z” and “one or more of X, Y, and Z,” unless specifically stated or indicated otherwise, shall be taken to mean that each item in the conjunctive list can be present in any number exclusive of every other item in the list or in any number in combination with any or all other item(s) in the conjunctive list, each of which may also be present in any number. Applying this general rule, the conjunctive phrases in the foregoing examples in which the conjunctive list consists of X, Y, and Z shall each encompass: one or more of X; one or more of Y; one or more of Z; one or more of X and one or more of Y; one or more of Y and one or more of Z; one or more of X and one or more of Z; and one or more of X, one or more of Y and one or more of Z.
Various modifications and additions can be made without departing from the spirit and scope of this disclosure. Features of each of the various embodiments described above may be combined with features of other described embodiments as appropriate in order to provide a multiplicity of feature combinations in associated new embodiments. Furthermore, while the foregoing describes a number of separate embodiments, what has been described herein is merely illustrative of the application of the principles of the present disclosure. Additionally, although particular methods herein may be illustrated and/or described as being performed in a specific order, the ordering is highly variable within ordinary skill to achieve aspects of the present disclosure. Accordingly, this description is meant to be taken only by way of example, and not to otherwise limit the scope of this disclosure.
Exemplary embodiments have been disclosed above and illustrated in the accompanying drawings. It will be understood by those skilled in the art that various changes, omissions and additions may be made to that which is specifically disclosed herein without departing from the spirit and scope of the present disclosure.
This application claims the benefit of priority of U.S. Provisional Pat. Application Serial No. 62/983,921, filed Mar. 2, 2020, and titled Nanoparticle-Based Drug Delivery Therapeutic Devices and Methods, which is incorporated by reference herein in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2021/020545 | 3/2/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 62983921 | Mar 2020 | US |
