Novel Drug Delivery Systems Leland Lou, MD, MPH

Address Texas Tech University Health Sciences Center, Department of Anesthesiology, 3601 4th Street, Lubbock, TX 79430, USA. Current Review of Pain 1999, 3:411–416 Current Science Inc. ISSN 1069–5850 Copyright © 1999 by Current Science Inc.

Interest in pain management is growing, with the emerging demand by our patients and colleagues, for pain relief. To meet that need, pharmaceutical and medical technology companies have provided the medical field with a variety of choices and options to deliver medication for pain control. Examination and review of the present systemic options are introduced. A more detailed look at the intrathecal route is necessary because of the tremendous potential for receptor-targeted drug delivery. The ability to treat nociceptive and neuropathic pain with drug-specific therapy makes this system all the more exciting. Because of this future, a wealth of new and old drugs are being found or reexamined for their use.

Drug delivery systems have evolved over time with increasingly sophisticated ways to make administration easier, more user-friendly, or reliable. These changes are driven by an ever-aging population and its interest in maintaining a more active lifestyle [1,2]. With the improvement in nutrition and health, the degenerative diseases of the spine and joints have resulted in a greater incidence of geriatric and chronic nonmalignant pain. Advances in research have shown that the pain mechanism is complex and can be affected at many levels. For this reason, a variety of drugs for specific receptors have been studied. Better ways to provide drugs for use with minimal side effects are being examined. The persistent concerns of society with addiction to opioids and their negative effects have been driving the research into nonopioid pain alternatives [3].

Drug Delivery Systems Enteral Oral medications are the preferred method for drug delivery because of ease-of-use and cost efficiencies compared with other routes. The ideal drug delivery system for an oral drug has to be dependent on its goal. If a fast onset time is sought, a drug must be quickly dissolved, easily transported through the gastrointestinal walls, and have a limited hepatic degradation.

For better pain control, the latest trends are moving toward a longer duration of action with a controlled, sustained release. It has been theorized that frequent oscillations of the serum drug levels have lead to a more rapid development of tolerance. Morphine is one of the first opioids to be formulated in a sustained-release form. Oxycodone was the next to follow, and hydromorphone is soon to come. One of the first oral sustained-release morphine pills to be successfully marketed was MS Contin (Purdue Frederick Co., Norwalk, CT) [4]. The Contin, or newer AcroContin, (for oxycodone) system is based on a wax cellulose matrix, which controls the release of the desired drug via the hydraulic drive [5]. This system is designed for use in 12hour intervals. Kadian (Faulding Laboratories, Elizabeth, NJ) is based on a methylacrylic polymerization of morphine, which is controlled for a sustained release over 24 hours [6,7]. As the capsule is dissolved, the pH-dependent microspheres are further differentially degraded to provide a controlled delivery in the small intestine. An experimental bioadhesive drug system has taken this concept a step further by adhering to the intestinal wall for several days for continuous drug delivery.

Transmucosal Oral transmucosal fentanyl citrate has been available for several years. It has proven useful for its ready bioavailability and quick onset (5 to 10 minutes). No mucosal deposit has been found, and rapid absorption through the mucosa bypasses the first-pass hepatic effect. This sweetened lozenge is attached to a handle to prevent swallowing and to dissuade chewing. Extensive testing in the clinical setting has shown it to be safe to use and well tolerated. Removal of the lozenge from the oropharynx stops delivery of the medication. Rectal Rectal suppositories, or rectal placement of heretofore oral drugs, have been examined. The few published papers available looked at its use clinically for patients with cancer [8,9]. Sustained-release oral pills have been placed in the rectum. They have shown a 30% to 40% decreased firstpass phenomen. For this reason, care must be taken to avoid overdosing of opioids. Negative reports on rectal administration are in reference to discomfort in placement, maintaining placement, and providing for a moist environment for proper drug delivery.

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Intranasal Butorphanol is presently the only commercially available intranasal opioid spray in the United States. Other drugs (oxycodone, meperidine, diamorphine, fentanyl, alfentantil, and sufentanil) have been given intranasally by introduction of a premixed intravenous form, or by a solution from a dissolved powder drug in saline or water. The key factor for this route is lipid solubility. The first-pass effect is nonexistent and compares well with intravenous administration [10]. Once again, this drug is advantageous in the acute pain management setting. It can be used in breakthrough pain situations. Although butorphanol given via this route has been identified as being addicting, an increased risk has yet to be determined Cutaneous and dermal Subcutaneous delivery of opioids was developed as an alternative to parenteral administration. With this route, the risk of septicemia is avoided while providing the patient an with an equipotent dose of medication. Continuous maintenance and bolus dosing are possible with this method. Because a needle is placed beneath the skin, cellulitis is a rare but obvious concern, which is managed by moving the needle to different parts of the body every 2 to 3 days. For patient comfort, the injectate should be concentrated as much as possible, limiting the total delivered rate to 1 mL/h or less. Overall, this route of administration of drugs is easily managed by ancillary care personnel [11]. Transdermal delivery and iontophoresis have the same advantages as subcutaneous infusion without the consequences of infection, but are dependent on drugs that are lipid soluble [12]. The transdermal route is an extension of the subcutaneous delivery, which has become a very popular choice for alternative opioid prescription. The transdermal therapeutic system is dependent on a low molecular weight drug, which is highly potent and lipid soluable. Each patch is composed of 4 layers: 1) a clear occlusive backing, 2) the drug reservoir with fentanyl dissolved in ethanol and gelled in cellulose, 3) a rate-controlling membrane, and 4) an adhesive base (Fig. 1). With this system, the amount of drug delivered is dependent on the surface area and is released over 72 hours. As expected, the adhesive is an integral factor in the effectiveness of this system. Oily skin, hyperhidrosis, vigorous activities, and excessive hydration of the skin may decrease the amount of drug delivered. Skin damage, occlusion of the skin, and hyperthermia (body temperature 40°C or greater) can increase the amount of delivered fentanyl by a third. Because it bypasses the gastrointestinal tract, there is a theoretic benefit of less constipation [13•]. Iontophoresis is an fascinating new method of transdermal drug delivery involving the use of electricity for introduction of the drug through the skin (Fig. 2). An electrical current with the same charge as the drug drives in the ionized drug for deposition in the deep subcutaneous tis-

Figure 1. Fentanyl transdermal, therapeutic system, consists of four layers: 1) clear plastic occlusive backing, 2) drug reservoir, 3) rate- limiting membrane, and 4) adhesive base. (Adapted from Eriator [12]; with permission.)

Figure 2. Hydromorphone disk consists of ethylene vinyl acetate and hydromorphone, with a bone cement coating (methyl-methacrylate). (Adapted from Lesser et al. [16]; with permission.)

sue [14]. Water-soluble and lipid-soluble opioids have been successfully administered with this method [15]. Presently, this is accomplished by an electrode, which must be applied directly to the skin. One last option, which is designed for 4 weeks of continuous release, is an subcutaneous hydromorphone implant. The disks are constructed of ethylene vinyl acetate solution, hydromorphone powder, and methyl-methacrylate coating (Fig. 3). These disks require implanting similar to the hormonal implants via skin incision. Increasing the diameter of the disks prolongs the duration to 8 weeks, and doubling the height of the disks increases the amount of drug delivered (Fig. 2) [16].

Central neuroaxis routes In some patients, oral medications are either not tolerated or an unacceptable option. For these reasons, other routes of drug administration have been sought. Rectal placement of oral medication has been studied and found to be very effective, but frequently poorly tolerated by patients. Intranasal and submucosal routes provide good alternatives for delivery of quick onset drugs, but are lacking in a long-act-

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route of administration is the ability to decrease the dose of drug delivered, as compared with the parenteral route, on the scale of a 3:1 ratio, respectively. Because of the epidural vasculature, systemic absorption from this technique is still a concern. Another factor affecting absorption is the presence of epidural fibrosis, which may effect the amount of drug diffusing through the dura.

Intrathecal Drug Delivery

Figure 3. Arrow Infusaid pump. A fixed-rate implanted pump driven by a gas-bellow compression. (From Arrow International, Reading, PA; with permission.)

ing option. The parenteral delivery of drugs has always proven to be an excellent choice for drug delivery in the acute setting, but comes with inherent risks of infection during long-term delivery, and added cost. An extension of parenteral drug delivery has been the use of subcutaneous infusion. From the database collected, two other innovations in drug delivery have evolved.

Epidural Drug Delivery The epidural space is a frequently used route for drug delivery. Epidural infusion is an easily accessed route for drug delivery, which has been very well studied. A variety of new drugs have been tested in this area for malignant and nonmalignant pain. For continuous infusion, a variety of catheters are also available for use. The DuPen catheter (BARD Access Systems, Salt Lake City, UT) is significant because of the use of a Dacron cuff (du Pont, Wilmington, DE) to prevent accidental withdrawal from the skin. Another system for long-term use is the Port-ACath system (SIMS Deltec, St. Paul, MN), which involves implantation of an indwelling port with a silicon access port connected to a catheter in the epidural space. With all of the available options, an external infusion pump is necessary for continuous infusion. The advantage of this

The ideal patient for intrathecal opioid therapy is one who has demonstrated opioid-responsive pain relief during a systemic opioid trial. Unfortunately, there are absolute and relative contraindications for intrathecal therapy. The absolute contraindications consist of aplastic anemia, systemic infection, known allergies to the metals or plastics on the pump or catheter, active intravenous drug abusers, and known allergies to the medications considered for infusion [17]. Relative contraindications include emaciated patients, active anticoagulant therapy [18], a growing child with unfused growth plates [19], possible occult infection, and recovering drug addiction [20,21]. Central neuroaxial drug delivery systems for epidural and intrathecal infusions can be divided into internal and external systems. Various systems have been devised to take advantage of this route of greater efficacy. For the internal system, two main pumping mechanisms exist. Likewise, the external central neuroaxial infusion system is usually represented by an external access catheter or a subcutaneous access port. The choice between the external and internal systems has mostly been based on cost, life expectancy, and medication requirement of the patient. This route for drug delivery has been a technical achievement stimulated by the discovery of opiate or µ-receptors in the spinal cord during the year 1976 [22]. The implantable pumps are based on two uniquely different technologies. The Infusaid pump (Arrow International, Reading, PA) (Fig. 3), the older of the two types, is based on a valve-controlled drug delivery, which is driven by a two-phased gas bellow. A mechanical varia b l e r a t e i m p l a n t a b l e p u m p i s m a n u f a c t u r e d by Medtronic (Minneapolis, MN) called the SynchroMed pump (Fig. 4). With the SynchroMed pump, a peristaltic pump has been minaturized and encased with a power source and drug reservoir. It is a programmable pump using radiowaves. This feature allows for variation of the delivered drug dose from a single concentration deposited in the drug reservoir. Because of the SynchroMed’s intricate construction, early problems with failure has been mostly resolved. There is an inherent theoretic benefit with the Infusaid, or set rate pump. With this gas driven pump, its simplicity of construction gives it an indefinite life expectancy. The rate is set by a fixed rate valve based on volume per day delivered. For titration of the drug delivered, the injectate must be changed. Cost of drug replacement and potential

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for multiple needle puncture comfort are negative factors, which must be considered prior to implantation.

[24,25]. Similar to opioids, the effects of clonidine appear to occur at the spinal level. It seems to act by inhibiting substance P release and causing postsynaptic action of the first- and second-order neurons. This presents the theoretic synergism of action with the presynaptic action of the spinal opioid receptors [26]. Unfortunately, there is also a cholinergic preganglionic sympathetic effect, which is closely associated with systemic hypotension. What one sees clinically with clonidine is orthostatic hypotension with the higher doses. It has also been associated with sedation, bradycardia, and nausea, especially during the inital titration stages. For decreased side effects and maximal benefit, intrathecal and epidural dosing have been studied. For intrathecal use, the side effects are most prevalent in the 17 to 25 µg/h range during the initial titration phase. A total dose no greater than 40 µg/h is recommended, because no additional benefit is obtained [27••]. Clonidine is available commercially in the United States in a 100 µg/mL concentration for epidural infusion. A 150 µg/mL concentration can be obtained for epidural administration in Europe and Australia (Catapresan, Boehringer Ingelheim, Ingelheim, Germany). If intrathecal infusion is planned, a higher concentration (recommended 1000 µg/ mL or 2000 µg/mL) injectate can be formulated from clonidine powder. This drug has been studied in combination with morphine and bupivacaine [28].

Drugs for Delivery

Local Anesthetics

Central neuroaxis compatible drugs Since the initial use of the pumps for infusion of Food and Drug Administration (FDA)-approved drugs, morphine and baclofen, other drugs have been used for infusion. These drugs have come from the commonly available drugs, such as clonidine and hydromorphone, to the more exotic drugs, such as SNX-III, ie ziconitide, and miscellaneous neuropeptides. An ideal infusion drug for pain must have a proven antinociceptive effect, a proven safety in profile, stability on the shelf and at body temperature, compatiblility for longterm infusion, and support for commercial development.

Local anesthetics have been used for several decades without serious sequelae. In particular, bupivacaine is a longacting local anesthetic, which has been studied alone and in combination with other drugs for long-term intrathecal delivery [29–35]. This addition of bupivacaine to opioid infusion has shown few serious side effects [33]. In spite of the successful use of bupivacaine, there are still concerns of motor blockade, sensory blockade, urinary retention, and hemodynamic instability with the higher doses [30,35]. An innovative process for intrathecal drug delivery systems has been developed, to decrease the toxic effects on the central nervous and cardiovascular systems, by using liposomal encapsulation [36]. It has been found that the encapsulation process also increases the anesthetic duration of bupivacaine sixfold in rats [37]. Human trials in postoperative epidural use of liposomal encapsulated bupivacaine show a twofold increase in the duration versus plain bupivacaine [38]. Presently, research is being directed to apply this process to other local anesthetics.

Figure 4. Medtronic SynchroMed pump. Programmable implanted pump with a peristaltic pumping mechanism, battery, and reservior. (From Medtronic, Minneapolis, MN; with permission.)

Morphine Morphine is the only FDA-approved opioid narcotic used in an intrathecal pump. It is a well-studied drug, which has been used safely by many routes. Recent literature cites potential problems with its metabolites causing hyperalgesia, edema, hormonal suppression, and so forth. Because of the side effects, the maximum limits for morphine are theoretically set at about 28 mg/d [23]. For this reason, other drugs have been considered as a single injectate or in combination with morphine. Clonidine Presently, clonidine is the best studied a2-adrenergic agonist for effective treatment in cancer and neuropathic pain

Somatostatin Analogs Somatostatin can be found in the periaqueductal gray, substantia gelatinosa, and in the descending pain control tracts from the brain. The presence of this tetradecapeptide in the afferent axons of the dorsal horn, spinal interneu-

Novel Drug Delivery Systems • Lou

rons, and descending and ascending spinal pathways suggests nociceptive inhibition [39]. What has sparked interest for possible long-term intrathecal infusion is octreotide, a somatostatin analog. Octreotide is a stable peptide, which has shown no signs of neurotoxicity [40]. In a study by Penn et al. [41], octreotide was successful in relieving pain in nonopioid-responsive patients at an infusion rate of 5 to 20 µg/h, for up to 91 days.

Calcium Channel Blockers The N-type calcium channel antagonists have shown consistent antinociceptive effects in animal models for acute, persistent, and neuropathic pain. One example of this group, which has received intense scrutinization is SNX-111, a synthetic form of ω-conopeptide MVIIA. The suspected mechanism of action is thought to occur by blocking primary nociceptive afferent fibers’ neurotransmitter release.

Conclusions The delivery systems discussed are by no means all-inclusive. As we understand the mechanisms of pain better, more specific drugs will be used to selectively block or stimulate receptors. To reach these targets, a whole new generation of devices will be developed. Presently, the technology being used is already evolving to accomodate the changes occurring in pain management. There is already research into implanting adrenal medullary tissue in the brain for pain control. It is possible that gene therapy may be applied to correct gene sequences involved in the pain response. Nanotechnology has been progressing to the point that tiny machines may someday repair individually damaged cells, or deliver receptor-specific drugs to their targets.

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