1 Copyright © 2008 by ASME

Proceedings of the 2008 International Manufacturing Science And Engineering Conference (MSEC2008) MSEC/ICMP2008

October 7-10, 2008, Evanston, Illinois, USA

MSEC/ICMP2008-72248

INK-JET AS A MANUFACTURING METHOD FOR DRUG DELIVERY APPLICATIONS

Bogdan V. Antohe MicroFab Technologies, Inc.

Plano, TX 75074, USA bogdan.antohe@microfab.com

David B. Wallace MicroFab Technologies, Inc.

Plano, TX 75074, USA david.wallace@microfab.com

ABSTRACT

Recent drug delivery applications have stressed the need for precise dosage in the context of complex delivery vehicles. Ink-jet technology incorporates data-driven, non-contact techniques that enable precise, picoliter volumes of material to be deposited with high speed and accuracy at target sites (even onto non-planar surfaces) and thus has emerged as a front runner for drug delivery applications. Being data-driven, ink-jet dispensing is highly flexible and can be readily automated into manufacturing lines. Moreover, the ability to precisely target the delivery location reduces waste, an important factor when the active biological materials to be deposited are high value / high cost.

Some of the applications that have made use of ink-jet methods for dosage and distribution of biologically active agents are: loading of active agents onto drug eluting stents (DES); generation of drug loaded microspheres; fabrication of polymeric nerve conduits loaded with nerve growth factor; and coating of the active components onto patches for transdermal delivery.

This paper provides details on the manufacturing applications of ink-jet technology in drug delivery and discusses future potential uses and opportunities.

INTRODUCTION Localized Drug Delivery

In order to minimize the side effects of systemic drug administration, a new approach has emerged: the delivery of the drugs or active components locally, close to where the drug is needed. This approach has been taken for coating of the cardiovascular stents implanted to open up narrowed arteries and thus to prevent reclosure of the blood vessels (restenosis) [1,2]; for the treatment of the cancerous tumors [3,4]; and the delivery of the growth factor(s) next to damaged nerves to promote their regeneration [5]. Each of these applications, due to its constraints and geometric configuration, has a preferred design for the delivery instrument. Some of these applications make use of materials that are biodegradable and disappear as they release the active agent.

The cardiovascular stents require a permanent cylindrical structure, but need some mechanism to prevent the body’s rejection of the implant which could result in vessel reclosure. Treating the stents with an antiproliferative drug embedded in a biodegradable coating that releases the drug over the 3-6 months after the intervention will reduce the cell growth that leads to restenosis. More recent research has been exploring the use of stents that are made entirely from biodegradable materials.[6,7]

In case of the cancerous tumors, the ideal configuration consists of biodegradable microspheres that are loaded with anticancer drug(s). If the spheres are of specific and controlled diameters they can be delivered by injection next to or within the tumor stroma. Besides reducing the systemic (blood) toxicity level, the drug encapsulated in the microspheres acts as a depot system with additional benefits: lengthened duration of drug exposure through a continuous, sustained release and delivery of locally higher, more efficient drug concentrations.

The nerve regeneration also favors a cylindrical configuration, but, unlike the cardiovascular stents, does not require the presence of the structure after the delivery of the growth factor is ended. This has led to the use of the biodegradable materials that incorporate the active agent, similar to the approach discussed at microspheres.

Other applications of the local delivery methods are related to tissue engineering where the scaffolds are used to provide an optimal microenvironment for cell proliferation and guidance for cellular in-growth from host tissue. These scaffolds can be also used as drug delivery vehicles to release bioactive molecules, such as growth factors, DNA, or drugs, in a sustained manner to facilitate tissue regeneration.[8]

Ink-Jet Microdispensing

In the case of the drop on demand (DOD) ink-jet printing systems, a volumetric change in the fluid is induced either by the displacement of a piezoelectric material that is coupled to the fluid [9], or by the formation of a vapor bubble in the ink, caused by heating a resistive element [10]. This volumetric change causes pressure/velocity transients to occur in the fluid and these are directed to produce a drop that issues from an

2 Copyright © 2008 by ASME

orifice (Figure 1).[11,12] Demand mode ink-jet printing systems produce a droplet only when desired. Figure 2 illustrates a piezoelectric based DOD system, in which a droplet is generated only when a voltage pulse is applied to the piezoelectric actuator. The drops are targeted to specific locations on the paper/substrate (stent struts – drug eluting stents, mandrel – nerve conduits) by moving it such that the desired location is brought under the dispenser.

For drug eluting microspheres, a pressure assisted DOD

(closer to continuous ink-jet processes) is used. In this case pressure is applied to the fluid reservoir by the means of a regulator and pneumatic switch to create a stream that is broken into individual droplets by a signal that acts as a perturbation. The droplets are collected in a liquid bath where the solvent is extracted.

DRUG ELUTING STENTS Background

Vascular diseases are the leading causes of death in the United States. In addition, vascular diseases have major impacts on quality of life including chronic pain, disability and unemployment. Coronary bypass surgery can be used successfully for the treatment of closed arteries, but it is a highly invasive and expensive procedure that necessitates a long recovery time. Angioplasty is found to be a viable alternative to the coronary bypass being less invasive, less expensive and less traumatic to the patient. The use of stents after angioplasty has increased the efficiency of the procedure and significantly reduced post-procedure closing of the vessels.

The stents inhibit the two problems that could appear following an angioplasty: the abrupt reclosure of the artery by elastic recoil, arterial dissection and/or thrombosis and restenosis, and the slower (6 months to one year) re-narrowing

of an artery.[1] A stent is typically a scaffold device fabricated from metals, alloys, or polymers having the surface treated or covered with materials that reduce the rejection mechanisms.[13,14] It is usually delivered into the body lumen in reduced size form using a catheter. The stent is expanded and released from the catheter, so that it engages the lumen wall when it reaches the desired location. A comprehensive review of existing stent platforms is presented in the Handbooks of Coronary Stents [15,16], but new programs have emerged since publication especially in the area of drug eluting stents.

Angioplasty followed by stent implantation has almost eliminated the problem of elastic recoil and vessel remodeling, but still presents a significant restenosis risk. A wide variety of therapeutic agents that can effectively inhibit inflammation and smooth-muscle cell growth are available, but administration of these agents systemically may lead to adverse effects. To reduce the restenosis occurrence and to limit the side effects, the therapeutic agents can be delivered locally by coating the stents with these agents. In most cases this therapeutic agent is a drug that is coated and attached to the stent or coated onto the stent as a drug-polymer combination. The composition of the drug-polymer solution used to coat stents is selected not only to enhance reservoir characteristics, but also to control the release of the drug. Ideally, the release time of the beneficial agent will be close to the time in which the restenosis risk is the greatest: three to six months.

A drug-eluting stent, sometimes referred to as a “coated” or “medicated” stent, is a metal or, in some cases, a polymeric stent coated with a therapeutic agent that is known to reduce restenosis. The concept of using stents as vehicles for prolonged intraluminal drug delivery is very appealing. The stents can be used as a drug reservoir where medications can be released from various coatings at controlled time intervals.[2]

Emphasis has been placed on the development of the coating materials that consist of the therapeutic agent(s) (drug) and of the polymer used to control the drug release rate. The therapeutic agents typically fall in one of the following groups: antiproliferative agents, immunomodulators, antithrombotics, and growth factor inhibitors.[13,16,17] Ongoing research is exploring other drugs like ABT-578 which is a new synthetic analog of rapamycin, designed to inhibit smooth muscle cell proliferation.[18] Exploration of possible therapeutic agents is expanding to other bioactive elements including cells [19] and oligonucleotides [20] as well as antibodies (e.g. anti-CD34 [21]). The polymer controlling the drug reservoir and release rate has typically been developed in conjunction with the drug.

Reports on the clinical trials confirm the beneficial effect of DES compared to bare stents and other surgical procedures (bypass, angioplasty) [16,17,22,23], but also indicate possible limitations regarding the patients that would benefit most of DES use and present post surgical therapy requirements [24] to reduce the thrombosis risk. A consensus has emerged that drug eluting stents are the best choice when used for important categories of patients when proper follow up procedures are employed.[25] Blood clotting has been shown to have somewhat higher occurrences in DES patients. While this can be addressed in most cases with follow-up medication it remains an issue under scrutiny.

Simultaneous with the evaluation of the implanted stents the research continues in the development of more complex drug coated stents by using multiple drugs and polymers [2,26].

Figure 1. Drop formation sequence with synchronized

lighting. 50µm drops of isopropyl alcohol are generated at 4000 per second.

Data Pulse TrainInk at atmospheric pressure

Driver

Transducer

Orifice

Paper

Character Data Figure 2. Drop on demand printing system.

3 Copyright © 2008 by ASME

With the latest questions raised on DES employing antiproliferative drugs it is expected that the stent manufacturers will explore other active components like anti-CD34, which allows the early and controlled stent endothelialization.[21]

Conventional processes used to apply drug or drug/polymer solutions to stents are based on one of the following methods: dipping, ultrasonic spray coating, painting (air brush) and deposition along the struts using syringes. These methods have a number of problems, such as variability in drug concentration from device to device, inability to tightly control and maintain drug concentration, inability to vary drug distribution in a controlled and predetermined manner for a more desirable drug loading profile, and inability to control the local area density of the drug, (e.g., inability to apply multiple drugs/compounds to individual areas on the stent).

DES Fabrication Using Ink-jet

The need for efficient fabrication methods to provide control of the loading of drugs onto vascular stents has been recognized. Recently, there has been a significant effort in the process development of stent coating using ink-jet microdispensers.[27,28,29,30,31]

The main advantage brought by an ink-jet based coating system is the excellent process control. The drug and polymer solutions can be deposited very precisely (location and amount) onto the stent. These coatings could be multilayer and use different drug and polymer solutions in each layer to achieve different release kinetics. The direct targeting of the struts eliminates polymeric bridges between the struts. For stents having drug loading wells, ink-jet is the only efficient method to dispense the drug into the wells.

Ink-jet Coating Process and System

The ink-jet coating process uses mechanical stages to move the stent, mounted on a mandrel, along its axis and rotate it around its axis (Figure 3). The combined axial (X) and rotational (θ) motion of the stent under the microdispenser can place the microdispensers above all strut locations. Once the microdispenser is at the desired position the piezoelectric actuator receives the signal that generates one or more drops. The stent printing pattern is obtained by unwrapping the cylindrical surface and is programmed in terms of location along the stent axis and position along the circumference. A vertical (Z) stage is used to mount the printhead (can

incorporate up to four dispensers, each with its different solution) and to compensate for different stent diameters. All stages are computer controlled through a PC-104 motion controller (Delta Tau) integrated into the system control computer.

The stents were precoated with a PC polymer (Biocompatibles, UK) to increase the adhesion between the drug which was dissolved into a diluted polymer solution.

When using this ink-jet system to deposit the polymer-drug solution onto stents we have employed two methods: 1) dispense of the coating solution in the cylindrical area of the strut thickness (Figure 4) without targeting a specific strut and 2) dispense of the coating solution specifically targeting the struts’ outer surface.

In our preliminary work with non-targeted drops [31,32] the stent was moved axially such that the dispenser (which was continuously producing drops) axis was tangent to the cylinder passing through the half strut thickness (Figure 4). For this coating method we have achieved drug (ABT-578) loading efficiency above 89% for coronary stents. In comparison, spray coating of stents have 20-30% loading efficiency. The CV of the drug loading of the stents produced by ink-jet was demonstrated to be as low as 2% [27] and release characteristics were similar to the ones for stents coated using spraying [32].

When targeting the center of the strut, the drug polymer

solution is deposited only on the struts and the drug loading efficiency becomes 100%. Figure 5 shows the dispenser producing droplets of the coating solution while the stent, mounted on the mandrel, is moving such that the droplets land on the center of the struts. Figure 6 illustrates the capability of the ink-jet coating system of targeting individual locations of the struts. This capability facilitates the fabrication of coating with different drug distributions along the axis and the ability to incorporate multiple drugs on a single stent.

Figure 3. Stent coating system using ink-jet.

Drop trajectories

Figure 4. Dispensing tangent to a cylindrical surface

passing through the middle of the strut.

Figure 5. Stent coating by ink-jet targeting the struts.

Emerging droplet (solution of PC and paclitaxel in isobutanol) is visualized using synchronized lighting.

4 Copyright © 2008 by ASME

Another type of the DES that has been explored lately

makes use of wells along the struts. In this configuration the drug (or drug and polymer solution) is no longer deposited on the whole strut, but localized either in the wells [30,33] or at discrete positions along the strut [34]. Considering the size of the struts (150µm or less), the wells are even smaller (under 60µm) and thus make ink-jet the only viable alternative to deposit the drug only inside the wells. The other coating technologies that are currently employed (spray coating or dipping) cannot target individual wells.

DRUG LOADED MICROSPHERES In another application that targets the reduction of the side

effects in chemotherapy, monodisperse polymeric microspheres for localized delivery of anticancer drugs were obtained by using pressure assisted drop-on-demand ink-jetting. The microsphere desired size and monodispersity were achieved by controlling the pressure and the electrical signal applied to the piezoelectric actuator.

In the fabrication of the microspheres we have used paclitaxel which is a taxoid, a relatively new class of anticancer drugs reported to be effective against various types of cancers, including head and neck.[35,36] At subnanomolar concentrations, paclitaxel inhibits the disassembly of microtubules, whose principal function is the formation of mitotic spindle during cell division. The microtubules formed in the presence of paclitaxel are extraordinarily stable and dysfunctional, thereby causing cell death by disrupting the normal microtubule dynamics required for cell division.[37]

Paclitaxel also has potent antiangiogenic [38,39,40] and antimetastatic effects [41]. Paclitaxel attacks all the underlying mechanisms involved in tumor pathogenesis: tissue proliferation, angiogenesis and metastasis and thus is an ideal molecule for this application.

Unfortunately, paclitaxel shows dose-limiting toxic side effects when given systemically. The side effects (hypersensitivity reactions, neutropenia, mucositis, peripheral

neuropathy [37,42]) can become so debilitating that many patients have to be removed from the chemotherapeutic protocols.[35] The concept of local delivery via polymeric delivery systems injected next to or within the tumor stroma becomes a better alternative.

Microsphere size not only dictates a particular route of administration and drug’s biodistribution, but also the release rates. The ability to manufacture monodispersed microspheres and to control their size facilitates a delivery system that can be tuned to mimic various therapy regimens.

The ink-jet method employed to manufacture the microspheres used the DOD pressure assisted drop generation. In this approach, the orifice of the microdispenser was immersed in the extraction bath (a solution of polyvinyl alcohol alcohol – PVA – in phosphate buffer saline – PBS) that removed the solvent from the spheres.[43] Microspheres were fabricated using poly(lactide-co-glycolide) (PLGA) dissolved in 1,2-dichlorethane. Figure 7 illustrates the uniformity of the microspheres produced using ink-jet as compared to microspheres obtained using traditional methods. By employing microdipspensers or various orifice diameters and by adjusting the applied pressure and electrical signal applied to the piezoelectric actuator, we have obtained microspheres in the range of 50-100µm.

The final product has to be presented as a free-flowing

powder. To achieve this, microspheres were frozen and lyophilized. During lyophilization, eventual solvent traces are removed (via sublimation), the final microspheres containing just the drug and the biodegradable polymer. Figure 8 presents microspheres after lyophilization indicating that the uniformity was preserved.

The functional evaluation of the microspheres consisted in the analysis of the eluted drug (after the microspheres went through the whole process) and of the drug release rate.

The analysis of the drug was done by first extracting the

drug from the microspheres. Paclitaxel was reconstituted in High Performance Liquid Chromatography (HPLC) mobile

Figure 6. Mock-up stent coated at MicroFab with two

paclitaxel solutions containing different fluorescent dyes (Coumarin and Rhodamine) simulating two drugs.

Figure 7. Paclitaxel loaded PLGA microspheres; right: single emulsion method (36µm average diameter, 22µm standard deviation) and left: ink-jetted (50µm average diameter, 1µm standard deviation).

Figure 8. SEM’s of lyophilized microspheres.

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Figure 9. Comparison between HPLC data for standard

paclitaxel and paclitaxel that was extracted out of polymer microspheres created by ink-jet microdispensing.

5 Copyright © 2008 by ASME

phase. External standards of paclitaxel were obtained from a commercial source (Sigma). The chromatogram comparing the external standard with the extracted sample shows there is no change in the HPLC profile of the paclitaxel (Figure 9). This indicates that there is no structural change to the paclitaxel molecule, which suggests retention of pharmacological efficacy.

HPLC was also used to determine the release kinetics of

the drug from the microspheres. The microspheres were incubated in phosphate buffer saline and well mixed samples from the bath were analyzed by HPLC. The concentration of the solution was then converted into total amount of drug released. Figure 10 presents the cumulative amount of drug released over a two month period. The plot indicates that the microspheres are capable of producing a sustained release over this time period.

More recent work in the area of microspheres included the

reduction of the size and the possibility of fabrication of multilayered microspheres. Figure 11 depicts PLGA microspheres that are between 8 and 14 microns in diameter. Figure 12 shows ink-jet produced hollow microspheres. These hollow microspheres used a jet-in-jet technique with the outer jet being the polymer solution and inner jet being nitrogen. If

the inner jet is replaced by a second polymer-drug solution double layered microspheres can be obtained.

CONDUITS FOR NERVE REGENERATION To date, the only method employed in successful

peripheral nerve repair is autografting. In order to provide autograft material to repair peripheral nerve damage, a separate deficit of nerve tissue must be created at the donor site. This presents a situation where not enough material is available to repair the priority deficit without further risking the condition of the patient.[44]

So far, the most successful techniques for the manufacture of guidance conduits are limited to mold casting, extrusion methods, or dipping which allow for the formation of simple shapes as long as they reside in the macroscale. Experimental outcomes of generating nerve conduits for peripheral nerve repair have not been as successful as existing methods of autografting.

Current attempts focus on bridging the gap between laboratory research and clinical practice for peripheral nerve regeneration. Applied tissue engineering theories for tissue regeneration proliferate throughout the literature[45] as newer and more elaborate methods evolve for creating tissue-supporting scaffolds. Although many protocols exist for peripheral nerve regeneration, there has yet to be a single, uniformly applied method that insures a result comparable to autologous nerve grafting - the current gold standard in peripheral nerve repair.

Research on peripheral nerve repair has centered on the development of tissue generating scaffolds constructed of various materials. These materials mainly consisting of natural, [46,47,48] synthetic or hybridized [49] substances have been employed to act as cell seeding scaffolds into which cells of different lines would infiltrate and proliferate, ultimately constructing an endogenously derived tissue mass. A separate research direction has identified and characterized the type and actions of various biomolecules present in endogenous tissue. In order to be fully effective, the nerve conduits must be rendered bioactive by providing the necessary growth factor(s) and support cell(s) required for successful regeneration [50]. Schwann cells have been demonstrated to play a key role in axonal migration and release of nerve growth factor (NGF) to enhance nerve regeneration.[51,52,53] Previous studies [50,54,55] have demonstrated that human embryonic kidney cells (hNGF-EcR-293) can be genetically modified to mimic Schwann cell function by delivering bioactive NGF both in vitro and in vivo.

By combining both areas of research, laboratories have created the technology that has allowed for limited peripheral nerve repair on a small scale. The most current and successful techniques for the manufacture of guidance conduits are limited to mold casting, extrusion methods, or dipping which allow for the formation of simple shapes as long as they reside in the macroscale.

The control over various factors such as conduit micro-texture, dimensions, permeability, growth factor distribution and directional control of a regenerative nerve scaffold are tools in the selection of the optimum configurations of the nerve conduits. The application of the ink-jet microdispensing technology to the generation of nerve guidance conduits has the

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Figure 10. Example of release kinetics determined for

polymer microspheres manufactured by ink-jet.

Figure 11. PLGA microspheres produced by ink-jet. The

grid distance is 10µm.

Figure 12. Hollow microsphere 240µm in diameter

produced by ink-jet.

6 Copyright © 2008 by ASME

potential to allow manipulation of many of these variables currently disallowed by present manufacturing techniques.

Our work in this area has focused on enhancing nerve regeneration in two ways. The first involves increasing the level of precision and control in the basic manufacturing process for conduits by employing the ink-jet deposition. This increased control is further reflected in the degradation time and release of NGF. The second approach focuses on the creation of an NGF gradient using high-precision ink-jet deposition within the conduit itself.[56]

The conduit material was selected based on its ability to be

shaped in a 3D structure, to biodegrade after the completion of the healing process, to sustain cell viability and to not interfere with the bioactivity. The ink-jet printing system used is similar to the one used for stents in which the printing is done in angular and axial coordinates on a rotating mandrel. We have used both PLGA and poly (D,L-lactic acid) (PLA) for the conduit structure. Figure 13 shows an example of an ink-jet printed polymeric conduit. To increase the structural strength, more material was deposited at certain axial location forming reinforcement ribs.

Figure 14 depicts the ability to construct a gradient by

using a fluorescent dye. Figure 15 shows a planar gradient by ink-jet printing. In this case, the variation of the density was

achieved by varying the space between the locations where the droplets are deposited on the substrate.

TRANSDERMAL PATCHES A more recent drug delivery application has emerged in the

delivery of active components through transdermal patches which can maintain prolonged release of drugs to attain optimal blood concentrations. Drug delivery through the skin is limited by the strong barrier properties of skin’s outer layer so the latest patch configurations are provided with microneedles. [57,58,59] These microneedles have been adopted to deliver drugs across the barrier layer in a minimally invasive and pain-free manner.

A review [57] of different microneedle configurations indicate that they could have cylindrical, conical and pyramidal shapes and can be hollow, forming pockets where drug can be loaded [58]. The outer dimensions range from 0.2 to 0.5 millimeters while the inner dimensions range between 0.1 to 0.26 millimeters.

The active component (drug, DNA, protein or any other bioactive molecule) can be either coated on the outer surface of the microneedle or deposited in the hollowed area of the microneedle which can act as a drug pocket/reservoir. The reservoir approach is more attractive as it prevents the drug being wiped off during insertion through the skin.

The loading of the drug onto the microneedles is currently limited to dip coating. This procedure is acceptable as long as all needles are coated with the same solution. Filling the hollow part of the needles is also possible by dip coating, but could produce non-uniform loading.

Due to the size, shape and distribution of the microneedles, the use of ink-jet for filling is a good match for this application, too. Besides the accurate dosage of the active element per needle, an additional benefit of the ink-jet (through the individual targeting) is that each microneedle can be custom filled with a different amount or even a different drug.

Figure 16 depicts a picture of conical holes that were filled

by ink-jet with a polymer solution containing a florescent dye. The amount of solution deposited increases from top to bottom thus the higher intensity of the dye in the bottom row.

FUTURE DIRECTIONS The local drug delivery will continue to be expanded in all

the areas described above. Drug eluting stents will continue to evolve in terms of complexity: multiple drugs, with possible

1 mm1 mm1 mm

Figure 13. Polymeric conduit fabricated by ink-jet

printing.

Figure 14. Rhodamine gradient (increasing left to

right) incorporated into rib-supported polymeric conduit.

Figure 15. Jetted Nerve Growth Factor unidirectional

gradient - variation by spacing.

Figure 16. Array of conical holes similar to an array of

hollow microneedles. The holes are conical with a top diameter of 90µm and a bottom diameter of 30µm. Fluorescent dye solution was dispensed in the odd rows with 14 drops in the 1st row, 12 drops in the 3rd row and 8 drops in the 5th row.

7 Copyright © 2008 by ASME

varying distribution along the stent, multilayer coating (either on the strut or in the well) to control the release of one or more drugs. Microspheres could also include multiple layers with the outer “shell” layer containing the drug that needs to be released immediately while the inner spherical region containing a second drug needed in the later parts of the treatment. Alternatively, both layers could have the same drug but at different amounts per unit volume. Microneedles could also consist of layered drugs with possible intermediate layers between them.

The future of localized drug delivery systems will, at one point, include active feedback delivery [60] where a sensor will measure a quantity of interest and an actuator will increase/decrease the amount of released drug.

Drug delivery will also be combined with tissue engineering.[8] Similar to the nerve conduits, the bioactive agent will be used to create features onto 3D scaffolds. These features could change the surface texture, gradients of the active molecule, or layered structures that will embed the active molecules or drugs.

Ink-jet will very likely have a role in some of the developments described above due to its data control, high accuracy, flexibility and the results to date.

ACKNOWLEDGMENTS This work was sponsored in part by NIH grants

1R43NS40625 and 1R43HL081999 and NSF grant DMI-0109462.

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