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Recent Developments in Needle-Free Drug Delivery Samir mitragotri University of California, Santa Barbara Delivering medicines to patients in a safe, effective, and compliant way can be a major challenge (Langer, 2003). Pills and injections are the most common modalities for administering drugs. Although pills can only deliver small mol- ecules, they are generally accepted as a convenient mode of drug delivery (Mor- ishita and Peppas, 2006). Macromolecular drugs such as peptides and proteins, which cannot be taken orally, must be administered by injection. For some drugs, however, systemic administration to healthy tissues can be toxic, regardless of how they are administered. These drugs are only effective if they act directly on specific diseased tissues (Vasir and Labhasetwar, 2005). The ability of drugs to reach target tissues from the point of administration via pills or injections is limited by the body’s multiple barriers, including enzymatic degradation in the stomach, absorption across the intestinal epithelium, hepatic clearance, and accumulation in nontargeted tissues. These barriers have a range of lengths (from the tissue to the organelle level) and time scales. Collectively, these conditions have made the conversion of potent biomol- ecules into medical therapies very challenging. The field of drug delivery has 

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 FRONTIERS OF ENGINEERING Ocular delivery (drops) Nasal delivery (sprays and drops) Powder injections (gold particles, drug powders) Pulmonary delivery Liquid-jet injections (aerosol, dry powder) (liquid formulations) Transdermal patches (chemical, colloids, ultrasound, iontophoresis, microneedles) Oral delivery (liquid formulations and pills) Vaginal/rectal immunization (creams) FIGURE 1 Various modes of needle-free drug delivery. Source: Adapted from Mitragotri, 2005. grown in response to these challenges and is now a significant component of the overall drug development process. In the past several decades, tremendous progress has been made toward the development of safe, effective, and convenient means of drug administration. Advances have been possible, at least in part, because of our improved under- standing of the human body. This article focuses on some key developments in the field of drug delivery, especially those that deal with the development of pain- less, patient-friendly alternatives to injections for the delivery of macromolecules (Figure 1). THE NEED FOR BETTER METHODS OF DRUG DELIvERY Needles and syringes are the most common method of administering macro- molecular drugs; an estimated 12 billion injections are given annually worldwide (kermode, 2004). Despite their common use, needles have several limitations, including needle phobia (Nir et al., 2003) and accidental needle sticks (Rosen- stock, 2000). In addition, concerns have arisen about the unsafe use of needles,

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 RECENT DEVELOPMENTS IN NEEDLE-FREE DRUG DELIVERY as exemplified by the overwhelming number of HIV, hepatitis C, and hepatitis B infections that are thought to originate each year from the reuse of needles and syringes (kane et al., 1999). Noncompliance with medical treatment regimes is also a significant issue. It has been estimated that most patients do not adhere to prescribed dosing regi- mens, even in developed countries. Noncompliance is linked to several factors, including pain, needle phobia, and forgetfulness, and can result in serious medical complications. In fact, noncompliance is a leading cause of hospitalizations when the carefully designed drug concentration profile is altered in a way that becomes harmful to the patient. Typically, the blood concentration levels of both injectable and oral drugs that are administered repeatedly vary, depending on the schedule of their administra- tion and the speed at which they are absorbed and distributed by the body. Devia- tions from the therapeutic range of blood concentrations cause undesirable effects. For these reasons, it is important that drug developers, in addition to considering the efficacy and safety of a drug, must also carefully consider how a drug-delivery system may affect patient compliance. The limitations of conventional methods of drug delivery can potentially be overcome by needle-free delivery of drugs through the skin or mucosal surfaces of the mouth, nose, or lungs (Varmus et al., 2003). Although these represent viable alternatives to needle-based methods, these surfaces also present significant bar- riers to drug entry into the body, and breaching them in a safe, effective way is a major goal of drug-delivery research. This article provides a brief review of past efforts, a description of the current status, and prospects for the future, with an emphasis on transdermal and oral drug delivery. TRANSDERMAL DRUG DELIvERY Skin, the largest human organ, provides a painless, compliant interface for systemic drug administration (zaffaroni, 1991). However, because skin evolved to impede the flux of toxins into the body, it naturally has low permeability to the movement of foreign molecules (Wertz and Downing, 1989). A unique, hier- archical structure of lipid-rich matrix with embedded corneocytes in the stratum corneum (the upper strata [15 µm] of skin) is responsible for this barrier (Wertz and Downing, 1989). Corneocytes, cross-linked keratin fibers (about 0.2–0.4 µm thick and about 40 µm wide) held together by corneodesmosomes, provide structural stability to the stratum corneum. Lipids, which provide the primary barrier function in the stratum corneum, consist of several components; the primary constituents are ceramides, cholesterol, and fatty acids. The layer of lipids immediately adjacent to the corneocytes is covalently bound to them and plays an important role in maintaining the barrier function. The stratum corneum is continuously desqua- mated, with a renewal period of about one week, and is actively repaired by the

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 FRONTIERS OF ENGINEERING secretion of lamellar bodies following the disruption of the barrier properties or other environmental insults (Prausnitz et al., 2004). Transdermal drug delivery involves placing a drug on the skin in the form of a patch, cream, or lotion wherein the drug permeates across the skin and enters the bloodstream. key advantages of transdermal delivery include the easy acces- sibility of skin, which encourages patient compliance, avoidance of the gastro- intestinal tract, and sustained release over extended periods of time (Prausnitz et al., 2004). A number of drugs, including scopolamine, nitroglycerin, nicotine, cloni- dine, fentanyl, estradiol, testosterone, lidocaine, and oxybutinin, are routinely delivered transdermally by skin patches (Prausnitz et al., 2004). The patches, which generally last from one to seven days, depending on the drug, have enabled new therapies and reduced first-pass effects and severe side effects. For example, estradiol patches, which are widely used, have eliminated liver damage, which was a side effect of the drug when it was delivered orally. Trans- dermal clonidine, nitroglycerin, and fentanyl patches also have fewer adverse effects than the same drugs delivered orally. Nicotine patches have prevented, or at least reduced, smoking and increased lifespans (Prausnitz et al., 2004). Two classes of transdermal patches are currently available: (1) reservoir-type patches and (2) matrix-type patches. A reservoir-type patch holds the drug in a solution or gel, and the rate of delivery is governed by a rate-controlling mem- brane. Reservoir-type patches offer more flexibility in terms of drug formulation and tighter control over delivery rates than matrix-type patches. However, they are usually associated with greater design complexity. In matrix-type patches, the drug, adhesive, and mechanical backbone of the patch are combined into a single layer. Thus matrix-type patches are easier to fabricate, but they pose even more significant design constraints than reservoir-type patches (Prausnitz et al., 2004). Drugs that are currently administered transdermally have two common characteristics—low molecular weight and high lipophilicity. Opening the trans- dermal route to large hydrophilic drugs, a major challenge in the field of trans- dermal drug delivery, will require the development of technologies that enable the controlled, reproducible transdermal delivery of macromolecular drugs. Passive Methods Technologies that facilitate transdermal drug delivery can work either passively or actively, depending on whether an external source of energy is used to facilitate skin permeation (Figure 2). Passive methods include chemical enhancers, micelles, liposomes, and peptides (Chen et al., 2006; El Maghraby et al., 2006; karande et al., 2004; Schreier and Bouwstra, 1994; Schuetz et al., 2005). Examples of chemi- cal enhancers include fatty acids, fatty esters, solvents, and surfactants (Williams and Barry, 1992). These enhancers facilitate transdermal transport by making drugs

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 RECENT DEVELOPMENTS IN NEEDLE-FREE DRUG DELIVERY (v) (ii) (vii) (vi) (iv) (i) (viii) (iii) Stratum Corneum Epidermis Dermis A B C FIGURE 2 Various modes of transdermal drug delivery. (A) Liquid-jet injections deliver drugs into intramuscular, subcutaneous, or intradermal regions. (B) Permeability-based methods of transdermal drug delivery: (i) delivery through hair follicles; (ii) tape-strip- ping removes the stratum corneum and facilitates drug absorption; (iii) thermal or radio frequency wave-mediated ablation of the stratum corneum creates micropores that enhance drug delivery; (iv) colloidal carriers, such as microemulsions and transfersomes, enhance the dermal absorption of topically applied drugs; (v) low-frequency ultrasound increases drug delivery by making the skin more permeable; (vi) chemical enhancers or peptides for drug delivery; (vii) electroporation of the stratum corneum enhances drug delivery into the epidermis; (viii) microneedles penetrate into the epidermis to deliver drugs. (C) Powder injection delivers dry drug powders into superficial skin layers (epidermis and superficial dermis). Source: Adapted from Mitragotri, 2005. more soluble, increasing partitioning into the skin, fluidizing the crystalline struc- ture of the topmost layer of skin, or dissolving skin lipids. Although individual chemical enhancers have had some success, combina- tions of chemical enhancers are more effective. However, so far, the rational design of combinations of enhancers has been limited by the lack of information on interactions between individual chemical enhancers and the stratum corneum. The number of randomly generated formulations for binary mixtures is in the millions, and the number for higher order formulations (for example, ternary or quaternary mixtures) is even higher. Screening of these formulations is beyond the scope of traditional methods (e.g., Franz diffusion cells). High-throughput methods of screening transdermal formulations can open this bottleneck and may lead to the discovery of previously unknown mixtures. A new high-throughput method for screening transdermal formulations (karande et al., 2004) is greater than 100-fold more efficient than Franz diffusion cells (Bro-

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10 FRONTIERS OF ENGINEERING naugh, 1989); with this method, up to 1,000 experiments a day can be conducted, an experimental space well beyond the scope of traditional tools (karande and Mitragotri, 2001). Recent studies have also shown that peptides may effectively increase skin permeability. Specifically, peptides discovered using phage-display methodology have been shown to deliver macromolecules, such as insulin, in vivo (Chen et al., 2006). Chemical enhancers are relatively easy to incorporate into transdermal patches and can be calibrated to deliver predetermined amounts of a drug by changing the application area. However, passive methods cannot dynamically control the drug dose. Active Methods Active methods can be controlled in real time by varying appropriate param- eters. The device and application parameters can also be adjusted to match the patient’s skin properties. A growing number of researchers are now explor- ing transdermal devices with active mechanisms for skin permeation, such as microneedles, jet injectors, ultrasound, iontophoresis, and electrophoresis (Arora et al., 2007; Bashir et al., 2001; Doukas and kollias, 2004; Habash et al., 2006; kalia et al., 2004; karande et al., 2004; Mitragotri et al., 1995; Prausnitz et al., 1993; zhang et al., 1996). Microneedles are arrays of micrometer-sized shallow needles that penetrate only into the superficial layers of skin, thereby eliminating the pain associated with standard hypodermic needles (Prausnitz, 2004). Microneedles have been made from a variety of materials, including metals, semiconductors, polymers, and glass, and have been shown to be effective in drug delivery. They have also been produced in solid and hollow forms. Solid microneedles are used to render skin permeable, whereas hollow microneedles actively deliver drugs into the skin at a controlled rate. In contrast, jet injectors deliver a high-velocity liquid jet stream into the skin, delivering drugs into various skin layers, depending on the jet parameters (Mitragotri, 2006). Jet injectors have a long history, particularly in the delivery of vaccines, insulin, and growth hormone. Ultrasound enhances skin permeability by cavitation, which temporarily disrupts skin structure (Paliwal et al., 2006; Tezel and Mitragotri, 2003). Iontophoresis and electroporation use electric fields to alter skin structure and/or provide additional driving force for drug penetration through the skin (Banga and Prausnitz, 1998; Guy et al., 2000). Combined Technologies Although many individual technologies have been shown to facilitate trans- derml drug transport, combinations of technologies are often more effective than any of them alone (Mitragotri, 2000). A combination of two or more technologies

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11 RECENT DEVELOPMENTS IN NEEDLE-FREE DRUG DELIVERY may not only increase the enhancement, but may also potentially be safer. Under- standing the synergies between technologies and selecting the right combinations is a fruitful area for research that is still largely unexplored. Summary In the last decade, significant new insights have been developed into the structural organization and barrier formation of the skin. In the past, skin was considered primarily a barrier, but it is now known to be a smart material that controls its own structure and function in response to the environment (Menon, 2002). This new knowledge must be incorporated into the future development and evaluation of transdermal technologies. ORAL DRUG DELIvERY Oral drug delivery is the most common, and the preferred type, of drug administration. A large number of small molecules, including those prescribed for the treatment of pain, heart disease, and blood pressure, are already delivered orally. Drugs delivered orally are typically absorbed across the intestinal epithe- lium into the bloodstream via two mechanisms. The transcellular route involves the transport of drugs through the cell membrane to cross the barrier, either by partitioning of the drug into cell membranes or through the generation of small pores in the outer cell membrane, which allows entry into the cell. Alternatively, the drug may permeate through the paracellular pathway, which entails transport through the tight junctions between epithelial cells (Cano- Cebrian et al., 2005). A tight junction is a dynamic network of tightly packed proteins in the interstitial spaces of a cell monolayer. Tight junctions have been likened to gatekeepers, as their primary function is to maintain the barrier proper- ties of the epithelium and only permit the transport of very small molecules (< 4 nm in diameter). A third possibility is that drugs may be actively transported across the epi- thelium through receptor-mediated endocytosis (Figure 3). Proteins and Peptides The oral delivery of proteins and peptides has elicited a great deal of interest in recent years because of the availability of novel therapeutics through the advent of recombinant DNA technology. Proteins and peptides are macromolecules with a wide variety of functions in biological catalysis, the regulation of cellular pro- cesses, and immune-system protection. Effective oral delivery of a protein or peptide requires that a therapeutic mol- ecule be delivered to the site of interest and cross the intestinal epithelium barrier intact before being transported to the portal circulation system. Unfortunately, this

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12 FRONTIERS OF ENGINEERING Carriers (liposome, microsphere) Soluble drugs Lumen (intestine) Epithelial M-cell cells Epithelium Subepithelium FIGURE 3 Pathways of drug absorption across the intestinal epithelium. Source: Adapted from Mitragotri, 2005. process is difficult and results in only a small fraction of drug being absorbed in the bloodstream. The delivery of proteins and peptides is further limited by their susceptibility to enzymatic degradation in the gastrointestinal tract (Morishita and Peppas, 2006). The scientific community has made a major effort in recent years to overcome the obstacles to oral delivery through the development of a large number of new, innovative drug-delivery techniques (Hosny et al., 2002; Luessen et al., 1995; Lyu et al., 2004; Sinha et al., 2004; Whitehead and Mitragotri, 2008; Whitehead et al., 2004, 2008a,b). These methods include enzyme inhibitors, permeation enhancers, mucoadhesive polymers, chemical modification of drugs, targeted delivery, and encapsulation. Enzyme Inhibitors Enzyme inhibitors are used to counteract the natural functions of the enzymes of the gastrointestinal tract that break down ingested proteins. Many studies have been performed in which inhibitors were co-administered with a drug (Bernkop- Schnurch, 1998), but these strategies have seldom been successful unless they included absorption enhancers. Permeation enhancers have also been used, similar to the way they are used in transdermal drug delivery (Carino and Mathiowitz, 1999). Permeation enhanc- ers, such as surfactants, fatty acids, and bile salts, either disrupt the epithelial

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1 RECENT DEVELOPMENTS IN NEEDLE-FREE DRUG DELIVERY membrane of the intestine or loosen the tight junctions between epithelial cells. While numerous studies have demonstrated that certain enhancers can be very potent delivery aids, safety concerns abound (Aungst, 2000). Mucoadhesives Mucoadhesive strategies have also been used to localize drugs to a small, defined region of the intestine through attractive interactions between the carrier and the intestinal epithelium. This kind of localization results in a high concen- tration gradient of the drug across the epithelial barrier, which improves drug bioavailability. In addition, a strong adhesion force prolongs the residence time of the dosage at the site of drug absorption, which reduces the dosing frequency and, in turn, increases patient compliance. Certain mucoadhesive polymers, such as polycarbophil and chitosan deriva- tives, have been shown to simultaneously act as permeation enhancers and enzyme inhibitors (Luessen et al., 1995; Sinha et al., 2004). Encapsulation Technologies Encapsulation technologies are another alternative for the oral administration of drugs. Using commercially available pH-sensitive polymers, it is possible to target particular regions of the intestine (e.g., jejunum or colon) for drug delivery. Enteric coatings made from these pH-sensitive polymers enable drug-delivery devices to pass through the acidic environment of the stomach unscathed and rapidly dissolve in the intestine. Studies to evaluate these polymers for targeted oral delivery are ongoing in various laboratories (Hosny et al., 2002; Lyu et al., 2004). Other techniques involve the targeting of M-cells in the intestine to improve mucosal vaccine delivery. M-cells, which are present in the Peyer’s patches of the intestine, have the unique ability to take up antigens; targeting can be achieved by using M-cell-specific lectins in combination with a drug-delivery formulation. Other encapsulation strategies, including microparticles (Mathiowitz et al., 1997), nanoparticles (Carino et al., 2000), and liposomes (Iwanaga et al., 1999), have been developed. These strategies can protect proteins from enzymatic deg- radation in the intestine and/or facilitate protein uptake across the epithelium (Carino and Mathiowitz, 1999). AREAS FOR ONGOING RESEARCH Novel, painless, patient-friendly methods of drug delivery represent an unmet need in the field of health care. Discoveries in the last decade have demonstrated the feasibility of using several different methodologies for enhancing drug deliv- ery through skin and other mucosal surfaces. These methods have shown the

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14 FRONTIERS OF ENGINEERING potential to deliver several molecules, including macromolecules such as insulin and vaccines. The development of mathematical models to describe and predict transport across the skin and mucosal barriers is another area of active research that has provided useful insights into the development of novel strategies. With the variety of engineering tools at hand, the future of drug delivery looks brighter than ever. The challenge is to convert these discoveries into useful products. REFERENCES Arora, A., I. Hakim, J. Baxter, R. Rathnasingham, R. Srinivasan, D.A. Fletcher, and S. Mitragotri. 2007. Needle-free delivery of macromolecules across the skin by nanoliter-volume pulsed microjets. Proceedings of the National Academy of Sciences of the United States of America 104(11): 4255–4260. Aungst, B. 2000. Intestinal permeation enhancers. Journal of Pharmacological Science 89(4): 429–442. Banga, A.k., and M.R. Prausnitz. 1998. Assessing the potential of skin electroporation for the delivery of protein- and gene-based drugs. Trends in Biotechnology 16(10): 408–412. Bashir, S.L., A.L. Chew, A. Anigbogu, F. Dreher, and H.I. Maibach. 2001. Physical and physiological effects of stratum corneum tape stripping. Skin Research Technology 7(1): 40–48. Bernkop-Schnurch, A. 1998. The use of inhibitory agents to overcome the enzymatic barrier to per- orally administered therapeutic peptides and proteins. Journal of Controlled Release 52(1-2): 1–16. Bronaugh, R.L. 1989. Determination of Percutaneous Absorption by In Vitro Techniques. Pp. 239–259 in Percutaneous Absorption: Mechanisms, Methodology, and Drug Delivery, edited by R.L. Bronaugh and H.I. Maibach. New york and Basel: Marcel Dekker. Cano-Cebrian, M.J., T. zornoza, L. Granero, and A. Polache. 2005. Intestinal absorption enhancement via the paracellular route by fatty acids, chitosans and others: a target for drug delivery. Current Drug Delivery 2(1): 9–22. Carino, G.P., and E. Mathiowitz. 1999. Oral insulin delivery. Advanced Drug Delivery Reviews 35(2-3): 249–257. Carino, G.P., J.S. Jacob, and E. Mathiowitz. 2000. Nanosphere based oral insulin delivery. Journal of Controlled Release 65(1-2): 261–269. Chen, y., y. Shen, X. Guo, C. zhang, W. yang, M. Ma, S. Liu, M. zhang, and L.P. Wen. 2006. Transdermal protein delivery by a coadministered peptide identified via phage display. Nature Biotechnology 24(4): 455–460. Doukas, A.G., and N. kollias. 2004. Transdermal drug delivery with a pressure wave. Advanced Drug Delivery Reviews 56(5): 559–579. El Maghraby, G.M., A.C. Williams, and B.W. Barry. 2006. Can drug-bearing liposomes penetrate intact skin? Journal of Pharmacy and Pharmacology 58(4): 415–429. Guy, R.H., y.N. kalia, M.B. Delgado-Charro, V. Merino, A. López, and D. Marro. 2000. Iontophoresis: electrorepulsion and electroosmosis. Journal of Controlled Release 64(1-3): 129–132. Habash, R.W.y., R. Bansal, D. krewski, and H.I. Alhafid. 2006. Thermal therapy, part 1: an introduc- tion to thermal therapy. Critical Reviews in Biomedical Engineering 34(6): 459–489. Hosny, E.A., H.I. Al-Shora, and M.M. Elmazar. 2002. Oral delivery of insulin from enteric-coated capsules containing sodium salicylate: effect on relative hypoglycemia of diabetic beagle dogs. International Journal of Pharmacology 237(1-2): 71–76.

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