Drug Delivery Trends for Parenteral Therapeutics

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Pharmaceutical Technology, Pharmaceutical Technology-10-02-2006, Volume 30, Issue 10

There is a growing need for patient-compliant dosage forms within the cancer therapeutics and biotechnology areas. Ease of administration, enhanced therapeutic efficacy, and reduced side effects are factors that differentiate drug delivery products from conventional dosage forms and provide a competitive advantage. This article reviews salient trends in the parenteral drug delivery sector within the realms of a changing regulatory environment, drivers to growth, and recent advances in this field. Challenges associated with bringing parenteral drug delivery concepts to commercialization are discussed.

The global pharmaceutical industry has grown at an average annual rate of 7–12% during the past several years, with the worldwide market estimated at approximately $602 billion dollars in 2005 (1). Nonetheless, pharmaceutical companies are challenged in sustaining this growth rate because of higher costs of drug development, higher regulatory scrutiny for new molecular entities, and economic threats from the surge of generic drugs entering the market (2). When a drug patent expires, it is not unusual for sales to decline as much as 90% because of competition from generic drugs (3).

Drug delivery technologies offer a viable option for pharmaceutical companies to maintain a healthy drug pipeline and effectively manage the life cycle of a drug. Drug delivery products often demand less development time and costs, especially when the active ingredient has been previously well characterized for safety and toxicity. In addition, as depicted in Figure 1, drug delivery-based products can be designed to have reduced side effects (by means of local or targeted delivery), improved bioavailability, product stability, enhanced patient compliance, and technology to reduce medication errors. Furthermore, drug delivery technologies can be used for new chemical entities, enabling them to be formulated in spite of challenging pharmaceutical properties (4).


Alza Corporation, founded in 1968, was perhaps one of the earliest, true drug delivery companies. The company started working on oral drug delivery concepts ("OROS" osmotic technology) as well as controlled-release implants and transdermal systems ("D-TRANS"). A few other companies such as Elan and R.P. Scherer (now part of Cardinal Healthcare) also focused mainly on oral drug delivery. The commercial potential of drug delivery technologies, however, came into the limelight with highly successful products approved in the late 1980s and 1990s, including "Lupron Depot" and "Cardizem." These products demonstrated how drug delivery can be used with an existing drug to significantly expand its appeal by improving patient compliance. Lupron Depot was formulated from a once-daily injection to a monthly sustained-release dosage form, and Cardizem was formulated from a multiple-doses-per-day regimen to a once-a-day pill.

Figure 1: Utility of drug delivery technologies in early development and in the life cycle management of drugs. "PC" denotes "proof of concept."

As pharmaceutical companies took notice of the advantages of this concept, a whole new segment of the industry was formed consisting of companies that focused primarily on novel drug delivery technologies. Drug delivery companies serve the advanced formulation needs of innovator pharmaceutical companies. At the same time, they have evolved to become specialty pharmaceutical companies by taking generic drugs and reformulating them to enhance their value (e.g., Anesta, a drug delivery company that reformulated fentanyl into an oral transmucosal formulation for pain management).

During the past 20 years, drug delivery technologies and the specialty companies developing such technologies have changed significantly. Drug delivery technologies have been credited with the commercial success of many drugs. At the same time, several drug delivery companies have had to terminate programs at various stages of development because of failures or significant challenges. Oral drug delivery technologies are in a mature phase, with such technologies now being used fairly routinely by pharmaceutical companies for life cycle management. In contrast, drug delivery for parenteral drugs has significant room for growth, but the associated challenges are more pronounced.

Drivers for parenteral drug delivery

Parenteral drug delivery technologies have roots in transdermal delivery patches that were first developed by Alza Corporation. In 1981, the US Food and Drug Administration approved the first commercial transdermal patch, "Transderm Scop" (scopolamine). This passive transdermal technology also was used to develop the most successful parenteral drug delivery product, "Duragesic," which had peak sales of $2.1 billion in 2004.

In recent years, parenteral therapeutics have grown significantly (see Figure 2). According to some estimates, the parenteral therapeutic market will outpace that of oral drugs. This growth has been primarily driven by biotechnology products and novel therapies for cancer, most of which are administered parenterally.

Figure 2: Anticipated growth of injectable therapeutic agents.

Biotechnology products. The biotechnology industry has matured in recent years, leading to a number of breakthrough products and the approval of several first-in-class products. For example, in 2006, FDA approved "Rituxan" (rituximab) as a treatment for rheumatoid arthritis. Rituxan has a unique mechanism of action by targeting B-cells (as compared with the conventional tumor necrosis factor antagonist therapies) (5). As another example, in 2003, "Xolair" became the first humanized therapeutic antibody for the treatment of asthma and the first approved therapy designed to target the antibody IgE, a key underlying cause of the symptoms of asthma that has an allergic component. In 2004, FDA approved "Erbitux," the first monoclonal antibody for the treatment of colorectal cancer. Erbitux is a chimeric antibody that works by specifically blocking an epidermal growth factor receptor protein, which is overexpressed in cancer cells. Drugs such as these are capable of action without the side effects commonly associated with nonspecific small-molecule treatments.

Currently, biotechnology products account for close to $50 billion in annual sales (6) and account for the majority of parenteral drugs that are in clinical trials (see Figure 3). Hence this number is expected to keep increasing at a rate higher than that of the conventional pharmaceutical industry. Furthermore, no generic pathway yet exists for biotechnology drugs within FDA, so the revenue stream generated by biotechnology drugs is sustained even beyond patent expiration. A number of marketed recombinant proteins, including insulin and human growth hormone, continue to be successful even though their patents have long expired. This is expected to change as biosimilar proteins are submitted to regulatory agencies for approval. For example, "Omnitrope," a biogeneric version of human growth hormone, was approved for marketing in Europe and Australia. The advent of such biogenerics will pose a challenge for biotechnology companies, driving a need for differentiated products.

Figure 3: Estimated number of chemical and biologic products expected to reach the market. Biotechnology and biologic entities include monoclonal antibodies, recombinant proteins, viral agents, nucleic acids, and bacterial (vaccines) therapies. Chemical entities include small-molecule products.

At present, most biotechnology products are administered as injections. Because of the short half-life of proteins, treatments with a number of these molecules require frequent injections. Therefore, these molecules are ideal candidates for drug delivery where injection frequency could be reduced. Noninvasive routes of administration for systemic delivery of proteins have seen significant advances, including the first inhaled insulin product, "Exubera," which was approved by FDA earlier this year. A number of active transdermal technologies also are being explored for the systemic delivery of proteins.

Novel treatments for cancer. The second driver for parenterals is the novel treatments for managing cancer, including chemotherapeutic drugs and the drugs to manage side effects of chemotherapy such as pain and nausea. Application of drug delivery technologies has been very successful for conventional drugs, including transdermal delivery of fentanyl (Duragesic for pain management) and sustained-release formulations of leuprolide (Lupron Depot, "Eligard," for treating prostate cancer). New molecules approved for chemotherapy in recent years include "Alimta" (pemetrexed), which was approved in 2004 for treating non-small cell lung cancer; "Vidaza" (azacitidine), which was approved in 2004 for treating myelodysplastic syndrome; and "Velcade" (bortezomib), which was approved in 2003 for treating refractory multiple myeloma. All these molecules are administered as injections and could benefit significantly from enhanced solubilization, stabilization, and targeting technologies.

Formulation-based technologies

Drug delivery technologies can be exploited to reformulate existing molecules or to enable the formulation of difficult discovery molecules (see Figure 1). Drug delivery technologies also have been used to impart targeting functionality to small-molecule drugs. Advances in nanotechnology have opened additional opportunities to exploit targeting opportunities further.

Formulation of poorly soluble drugs. Early drug-candidate screening does not differentiate compounds based on their solubility. Therefore, there is an increasing bias toward lipophilic (and consequently poorly soluble) molecules entering and progressing through the drug development pipeline (7). Indeed, more than 40% of drugs in recent years have been classified as poorly soluble. A number of drug delivery technologies have emerged to address this need within the pharmaceutical industry. Multiple oral drug delivery–based products have reached the market in spite of their poor solubility. Within the parenteral space, cyclodextrins and nanoparticles represent two key approaches to formulate poorly soluble drugs, and many injectable formulations using cyclodextrins for solubilization have been approved in the United States, Japan, and Europe (see Table I).

Table I: List of injectable products containing cyclodextrins (10).

If a drug is not suitable for complexation with cyclodextrins, other formulation approaches are sought. For example, liposomal technologies have resulted in more than five FDA-approved products (see Table II). Advances in nanotechnology have led to several drug delivery platforms that are designed specifically for the formulation of poorly soluble drugs as injectable nanoparticles (8). A nanoparticulate technology was used in development of "Abraxane," a novel formulation of paclitaxel that does not contain "Cremophor EL," a toxic excipient known to cause hypersensitivity reactions. By using a nanoparticulate formulation, the drug could be infused at a higher rate, without any need for premedication and with a higher maximum tolerated dose (9).

Table II: Examples of lipid-based products approved by FDA.

Targeted drug delivery. Concepts in active and passive targeting have been explored with the aid of liposomal drug formulations. Conventional liposomes, when injected intravenously, are taken up by the reticuloendothelial system. Such dosage forms can thus be used to target macrophage residing and propagating disorders. Macrophage targeting has been exploited further using nanoparticles, which can provide a significantly higher drug payload while delivering the drug in its crystalline form, thus allowing sustained release at and from the macrophages (11, 12).

Tumor targeting for chemotherapeutic agents is desirable to enhance the efficacy of the drug while reducing systemic toxicity. An enhanced permeability and retention (EPR) effect has been exploited for passive targeting of doxorubicin to tumors ("Doxil," Johnson and Johnson) (13). Passive targeting via the EPR effect has also been used by polymer–drug conjugates (14). Styrene maleic acid–conjugated neocarzinostatin, or SMANCS, is an example of an approved product based on the polymer–drug conjugation targeting approach (15).

High-concentration protein formulations. Recent advances in protein research have led to a large number of monoclonal antibodies that now are being clinically tested. These monoclonal antibodies have high plasma-circulation half lives on the order of several days. Furthermore, several monoclonal antibodies demonstrate stability to proteolytic enzymes present in subcutaneous areas, thereby providing an opportunity for the subcutaneous administration of such therapeutics. Subcutaneous injections reduce the frequency of injections and allow the convenience of self-administration. The volume that can be administered subcutaneously is typically limited to less than 1 mL, however, and the desired therapeutic dose may range from 100 to 800 mg. Hence, in recent years there has been an interest in developing novel approaches to formulate monoclonal antibodies at high concentration (100–800 mg/mL). Challenges for high-concentration protein formulations include a lack of syringeability owing to high viscosity and the self-association effects of the protein (16). Monoclonal antibodies could be formulated with some excipients, such as histidine, that in certain cases reduce the viscosity of solutions (17). Novel concepts such as protein crystals and suspensions also are being explored to formulate high-concentration monoclonal antibodies without compromising syringeability (18).

Sustained circulation and release (reduced frequency of injections). Sustained release was the basis for some of the early breakthrough research and development in parenteral drug delivery. Using biodegradable polymers has led to a number of highly successful products (see Table III). Polymeric drug delivery recently has been revived by the need for local delivery of medication to reduce restenosis (discussed in further detail in a subsequent section).

Table III: Examples of polymer microsphere products approved by FDA.


For protein drugs, PEGylation has been used to enhance circulation half-life and thereby reduce frequency of injections. In the case of interferon-alfa, the half-life of the protein increases from 3–5 hours for the native protein to 30–50 hours for the protein conjugated with polyethylene glycol (19). The technology has resulted in six FDA-approved products. Early-stage PEGylation involved nonspecific conjugation of the protein with linear poly(ethylene glycol) chains. The product was typically heterogeneous with higher propensity toward activity loss. In recent years, a number of novel concepts have been introduced in the field of PEGylation. For instance, using branched poly(ethylene glycol) was shown to increase circulation half-life as compared with the linear version. Site-specific PEGylation has been achieved using mutagenesis techniques, resulting in homogeneous product with retention of bioacitivity (20).

Table IV: Examples of combination products approved by FDA.

Device-based technologies

Advances in drug delivery technologies have led to an increasing number of products that involve both medical devices and drug therapies. To address the growing demand for such highly specialized technologies, FDA created the Office of Combination Products in December 2002. Several products classified as combination products have been approved by this office and others are in development (see Table IV).

Device-based drug delivery technologies are developed for one of the following reasons:

  • to reduce the invasiveness of the therapy (e.g., switching from injection to inhalation);

  • to reduce the potential for administration errors (e.g., prefilled syringes) (21);

  • to prevent needle-stick injuries (e.g., needle-free devices);

  • to provide added therapeutic value (e.g., drug-eluting stents, in which the drug reduces inflammation at the site of implantation).

Device technologies offer significant promise in a number of areas for parenteral drugs. For instance, injection devices can be used to administer accurately intradermal injections that may lead to enhanced vaccine performance. Injection devices also are useful for intramuscular administration of drugs in an emergency setting and have found applications for biodefense and anaphylaxis treatments (22). Injection devices help address formulation challenges such as those for the delivery of highly concentrated protein solutions. Devices designed for less invasive delivery (e.g., inhalation, transdermal) would enhance patient compliance and the outcome of therapy.

Inhaled insulin could change diabetes treatment by eliminating the need for daily injections. The first inhaled insulin product, Exubera, recently gained FDA approval, paving the way for other inhaled insulin products that promise even further convenience and product performance. Inhaled insulin products currently in the clinic include Novo Nordisk and Aradigm's liquid formulation of insulin for inhalation, Eli Lilly and Alkermes's porous dry-powder formulation, and Baxter Healthcare's uniform insulin microspheres (Promaxx) (see Figure 4) (23). Commercial success of inhaled insulin also could lead to the systemic delivery of other therapeutic proteins.

Figure 4: Scanning electron micrograph of uniform microparticles of insulin, produced by Baxter Healthcare's "Promaxx" process.

Potential interaction between the drug and container of a combination product is an important consideration. Leachables from the container may cause unexpected side reactions or adverse-stability concerns for the drug product. Hence drug–excipient–container compatibility considerations should be addressed up front during formulation development, and stability studies should be designed carefully to explore these factors. Drug–container interactions have received more attention recently, after concerns were raised for an erythropoietin product in prefilled syringe ("Eprex") that resulted in increased occurrences of pure red-cell aplasia (24). Another area of research has been the effect of silicone leachables from glass prefilled syringes and the stability of protein formulations in such syringes (25, 26). Although both of these examples refer to formulation concepts, as opposed to devices or combination products, it is anticipated that similar considerations should be explored for combination products.

Drug-eluting stents are one of the biggest areas of combination products. Currently, there are two FDA-approved drug eluting stents in the market: "Cypher" (Johnson and Johnson) and "Taxus" (Boston Scientific). These drug-eluting stents release drugs at the implantation site, prevent inflammation, and reduce the occurrence of restenosis. This concept is expected to be applicable in other medical devices as well. For example, ongoing clinical studies already are using drug-eluting vascular grafts during coronary bypass surgeries (27).

Advanced technologies for devices are being explored, including combination coatings, where multiple polymers are combined to provide a tailored release profile for one or more drugs (28). Another concept is biodegradable polymers as materials for medical devices or their coatings such as using lactide and caprolactone-based polymers as biodegradable stents (29). Other device concepts that have received attention in drug delivery include the development of better, improved inhalation and nasal devices for effective delivery (30), microarray needles for intradermal delivery of drugs and vaccines (31), and single-use, prefilled needle-free injector devices (32).

Formulation and device technologies for effective life cycle management

The previously described formulation and device technologies can be used in tandem toward a very effective strategy for life cycle management. For example, Roche's interferon-alfa product, "Roferon," was first introduced to the market in 1986 as a lyophilized powder of the protein and contained human serum albumin as a stabilizer (see Figure 5) (33). Subsequent generations of the product included a solution formulation without human serum albumin, using prefilled syringe devices, and subsequently branched poly(ethylene glycol), for extending the circulatory half-life of the protein (PEGasys). In 2004, the PEGylated protein was presented in a prefilled syringe to enhance patient convenience.

Figure 5: Example of formulation technologies for life cycle management of interferon-alfa. ("HSA" denotes "human serum albumin," "PFS" denotes "prefilled syringe," and "PEG" denotes "poly(ethylene glycol)."

Challenges for drug development

The challenges faced in development of parenteral drugs formulated using drug delivery technologies can be broadly classified as relating to manufacturing, product performance, or regulatory areas.

Manufacturing. Typically drug delivery technologies involve more complex manufacturing steps compared with conventional dosage forms. This increased complexity can lead to the following issues:

  • scale-up: A number of drug delivery technologies have been conceptualized in an academic setting, and scaling up these complex processes to pilot or production scales can be challenging (34);

  • drug stability (e.g., maintenance of protein activity during encapsulation into polymer microspheres) (35);

  • producing a consistent quality product;

  • sterility (e.g., protein microspheres cannot be terminal sterilized and must be produced in an aseptic manner).

Product performance. Drug delivery products are designed to enhance existing products. Hence, clinical studies are typically designed with a control arm of the existing product. This presents a challenge, especially when the drug delivery concept is intended for enhancing a patient's quality of life, rather than the drug's efficacy. For such situations, designing a clinical trial that captures and quantifies such product features is important. For devices, consistent performance in terms of dose delivery is of paramount importance for the success of the device.

Regulatory related. Novel parenteral dosage forms present regulatory challenges because the dosage forms are unique, and, therefore, the testing methodologies may not be well developed. The safety profile of novel dosage forms also may be unique, requiring additional testing to convince the agency of the product's safety. FDA is addressing this challenge by issuing guidance for the testing of various novel dosage forms (e.g., liposomes ) (36), as well as novel excipients used in formulations (37). Furthermore, the agency has facilitated discussions between FDA, the US Pharmacopeia, and the industry for the testing of complex dosage forms, including parenteral sustained-release products (38).


Opportunities and future directions

Parenteral, especially biotechnology drugs, are ideal candidates for drug delivery technologies. The success of next generation biotechnology molecules, including DNA-based drugs as well as small interfering RNA molecules, depends on the effectiveness by which such molecules are delivered to the desired site of action (39). In the protein delivery area, there is a need for novel technologies to deliver high-dose monoclonal antibodies to the subcutaneous space. Noninvasive technologies (e.g., inhalation, transdermal) are advancing rapidly toward realization (40). These technologies use breakthroughs in both the formulation and device areas to provide noninvasive routes of drug administration. The recent approval of Exubera for pulmonary delivery of insulin shows how novel formulation and device technologies can be combined to produce a product that shifts the paradigm of conventional therapy.

It is important to understand that the development of parenteral drug delivery products requires a detailed understanding and integration of experience in several core technical competencies associated with parenteral science, including formulation science, manufacturing, sterilization expertise, and regulatory requirements. These traditional concepts of parenteral science are required to be fully integrated in the development of novel drug delivery technologies. Because a number of drug delivery technologies involve complex processing steps or novel dosage forms, product development becomes challenging. Having a product with consistent quality through the various stages of development is essential to avoid product delays in market introductions.

Mahesh V. Chaubal, PhD, is the associate director of product development, and Theodore J. Roseman, PhD,* is the vice-president of scientific affairs at Baxter Healthcare Corporation, Route 120 & Wilson Road, Round Lake IL 60073, ted_roseman@baxter.com.

*To whom all correspondence should be addressed.

Submitted: June 12, 2006. Accepted: Aug. 4, 2006.

Keywords: drug delivery, formulation, parenterals

This article updates a manuscript previously published in Drug Delivery Systems, Japan 21 (4) (July 2006).


1. IMS Health, "IMS Health Reports Global Pharmaceutical Market Grew 7% in 2005 to $602 Billion," March 2006, www.imshealth.com, accessed Sept. 4, 2006.

2. R. Mullin, "Drug Development Costs About $1.7 Billion," Chem. Eng. News 81 (50) 8, 2003 .

3. S. Class, "Health Care in Focus," Chem. Eng. News 82 (49), 18–29 (2004).

4. M.V. Chaubal, "Application of Drug Delivery Technologies in Lead Candidate Selection and Optimization," Drug Discovery Today 9 (14), 603–609 (2004).

5. M.J. Leandro et al., "Reconstitution of Peripheral Blood B Cells after Depletion with Rituximab in Patients with Rheumatoid Arthritis," Arthritis Rheum. 54 (2), 613–620 (2006).

6. G. Hamilton, The Biotech Market Outlook (Business Insights Ltd., London, UK, 2005).

7. K.R. Horspool and C.A. Lipinsky, "Advancing New Drug Delivery Concepts to Gain the Lead," Drug Deliv. Technol. 3 (7), 34–44, (2003).

8. J.E. Kipp, "The Role of Solid Nanoparticle Technology in the Parenteral Delivery of Poorly Water-Soluble Drugs," Int. J. Pharm. 284 (1–2), 109–22 (2004).

9. N.K. Ibrahim et al., "Phase I and Pharmacokinetic Study of ABI-007: A Cremophor-Free Protein Stabilized, Nanoparticle Formulation of Paclitaxel," Clin. Cancer Res. 8 (5), 1038–1044 (2002).

10. D.O. Thompson and M.V. Chaubal "Cyclodextrins (CDS)—Excipients by Definition, Drug Delivery Systems by Function, Part I: Injectable Applications," Drug Deliv. Technol. 2 (7), 34–38, (2002).

11. B.E. Rabinow, "Nanosuspensions in Drug Delivery." Nat. Rev. Drug Discov. 3 (9), 785–796 (2004).

12. F. Chellat et al., "Therapeutic Potential of Nanoparticulate Systems for Macrophage Targeting," Biomaterials 26 (35), 7260–7275 (2005).

13. Y. Tsukioka et al., "Pharmaceutical and Biomedical Differences between Micellar Doxorubicin (NK911) and Liposomal Doxorubicin (Doxil)," Jpn. J. Cancer Res. 93 (10), 1145–1153 (2002).

14. Y. Chau et al., "Antitumor Efficacy of a Novel Polymer-Peptide-Drug Conjugate in Human Tumor Xenograft Models," Int. J. Cancer 118 (6), 1519–1526 (2006).

15. J. Fang, T. Sawa, and H. Maeda, "Factors and Mechanism of EPR Effect and the Enhanced Antitumor Effects of Macromolecular Drugs including SMANCS," Adv. Exp. Med. Biol. 519, 29–49 (2003).

16. J. Liu et al., "Reversible Self-Association Increases the Viscosity of a Concentrated Monoclonal Antibody in Aqueous Solution," J. Pharm. Sci. 94 (9), 1928–1940 (2005).

17. B. Chen et al., "Influence of Histidine on the Stability and Physical Properties of a Fully Human Antibody in Aqueous and Solid Forms," Pharm. Res. 20 (12), 1952–1960 (2003).

18. M.X. Yang et al., "Crystalline Monoclonal Antibodies for Subcutaneous Delivery," Proc. Natl. Acad. Sci. 100 (12), 6934–6939 (June 10, 2003).

19. S. Zeuzem, C. Welsch, and E. Herrmann, "Pharmacokinetics of Peginterferons," Semin. Liver Dis. 23 (suppl. 1), 23–28 (2003).

20. Y. Yamamoto et al., "Site-Specific PEGylation of a Lysine-Deficient TNF-alpha with Full Bioactivity," Nat. Biotechnol. 21 (5), 546–552 (2003).

21. D. French, "Market Trends in Injection Devices for Pharmaceuticals," in Future Drug Delivery 2006 (Touch Briefings, London, UK), pp. 20–24.

22. J.S. Kim, J.M. Sinacore, and J.A. Pongracic, "Parental Use of EpiPen for Children with Food Allergies," J. Allergy Clin. Immunol. 116 (1), 164–168 (July 2005).

23. L. Bromberg and S.T. Rashba-Step J, "Insulin Particle Formation in Supersaturated Aqueous Solutions of Poly(ethylene glycol)," Biophys. J. 89 (5), 3424–3433 (Nov. 2005).

24. A.P. Villalobos, S.R. Gunturi, and G.A. Heavner, "Interaction of Polysorbate 80 with Erythropoietin: A Case Study in Protein–Surfactant Interactions," Pharm. Res. 22 (7), 1186–1194 (July 2005).

25. L.S. Jones, A. Kaufmann, C.R. Middaugh, "Silicone Oil Induced Aggregation of Proteins," J. Pharm. Sci. 94 (4), 918–927 (April 2005).

26. A. Rosenberg and A. Worobec, "A Risk-Based Approach to Immunogenicity Concerns of Therapeutic Protein Products, Part 2: Considering Host-Specific and Product-Specific Factors Impacting Immunogenicity," Biopharm Intl. (12), (2004).

27. Angiotech Pharmaceuticals Inc., Website, http://www.angiotech.com.

28. A.B. Anderson, L.W. Duran, and N.M. Hupfer, "Combination Coatings Unlock Medical Device Potential," Med. Device Technol. 16 (1), 12–14, 16 (Jan–Feb. 2005).

29. I. Uurto et al., "Drug-Eluting Biodegradable Poly-D/L-Lactic Acid Vascular Stents: An Experimental Pilot Study," J. Endovasc. Ther. 12 (3), 371–379 (June 2005).

30. M. Knoch and Keller, "The Customised Electronic Nebuliser: A New Category of Liquid Aerosol Drug Delivery Systems," Expert Opin. Drug Deliv. 2 (2), 377–390 (March 2005).

31. M. Cormier et al., "Transdermal Delivery of Desmopressin Using a Coated Microneedle Array Patch System," J. Controlled Release 97 (3), 503–511 (2004).

32. O.A. Shergold, N.A. Fleck, and T.S. King, "The Penetration of a Soft Solid by a Liquid Jet, with Application to the Administration of a Needle-Free Injection," J. Biomech. (Nov. 5, 2005).

33. W.A. Mallick, "The Evolution of Biopharmaceutical Formulations," presented at IBC's 2nd International Biopharmaceutical Conference, Miami, FL, 2002.

34. M.A. Tracy, "Development and Scale-Up of a Microsphere Protein Delivery System," Biotechnol. Prog. 14 (1), 108–115 (Jan.–Feb. 1998).

35. G. Zhu, S.R. Mallery, and S.P. Schwendeman, "Stabilization of Proteins Encapsulated in Injectable Poly(lactide-co-glycolide)," Nat. Biotechnol. 18 (1), 52–57 (2000).

36. US Food and Drug Administration, Guidance for Industry, Liposome Drug Products, August 2002, http://www.fda.gov.

37. FDA, Guidance for Industry, Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients, May 2005, http://www.fda.gov.

38. D.J. Burgess et al., "Assuring Quality and Performance of Sustained and Controlled Release Parenterals: EUFEPS Workshop Report," AAPS PharmSci. 6 (1), E11 (Mar. 22, 2004).

39. M. Sioud, "On the Delivery of Small Interfering RNAs into Mammalian Cells," Expert Opin. Drug Deliv. 2 (4), 639–651 (2005).

40. S. White et al., "Exubera: Pharmaceutical Development of a Novel Product for Pulmonary Delivery of Insulin," Diabetes Technol. Ther. 7 (6), 896–906 (2005).