August 1, 2005 (Vol. 25, No. 14)

Continued Success of Applications Should Help Ensure Future Growth

Drug delivery technology (DDT) is increasingly important as a component of drug development. An FDA survey found that only 9% of the 99 new small molecule drugs introduced between 1995 and 2001 were Class I high solubility and permeability, which facilitates conventional oral delivery.

With an increasing diversity of compounds addressing more drug targets, the available range and sophistication of DDTs has expanded with the goal of increasing the successful rate of new chemical entities. Peptides, proteins, and nucleic acids face similar delivery challenges.

Speakers at the recent “Drug Delivery World Conference,” sponsored by IBC, addressed both the importance of business strategies and collaborations for DDT and significant advances in the field.

Ravi Kiron, Ph.D., executive director, new technology assessment and planning, Alza (Mountain View, CA), a division of Johnson & Johnson, technology conference chairperson, said, “DDT is broadly defined as improving the efficacy, safety, or compliance of a drug through optimization strategies.

“Delivery technologies include methods that promote the uptake, absorption, and adequate bioavailability of molecules to optimize the balance between deliveries to the target site in the body.”

Most DDTs result in physical mixtures or entrapment of the active ingredient in a matrix within a dosage form, which can be solid, liquid (including topical creams), or adhesive (for most transdermal systems). PEGylation, the covalent attachment of a drug substance to polyethylene glycol ranging in weight from 5 to 60 kDa, is a notable exception.

Strategies and Collaborations

The use of advanced DDT to enable the development or enhance the utility of drug substances is a key component of what has come to be known as Life Cycle Management (LCM).

Richard DiCicco, president of Technology Catalysts International (Falls Church, VA), says he first applied the term LCM to the use of DDT in the development and implementation of strategy in 1992 after another party objected to the term “generic defense” for the use of a new DDT as a method of staving off generic competition for a pharmaceutical product.

Anne Hector, vp of the Analysis Group (Menlo Park, CA), addressed the broader issue of LCM strategies, including assessment of potential post-expiry strategies.

The goal of reformulation is to launch an improved patent-protected formulation in advance of expiration of the compound patent to prevent generic copies of the original product from almost immediately capturing virtually the entire market.

Implementation begins at least five years in advance to ensure launch before patent expiration. LCM is now firmly embedded in the strategies of pharmaceutical and many biotech companies. The importance of DDT as a component is not limited to the development and introduction of a new formulation shortly before the expiration of the compound patent.

The time when DDT was a “quick fix” to extend patent life is long since over, however. Competition has forced generic drug companies to “graduate” from seeking Abbreviated New Drug Approvals (ANDAs) for copies of the originator’s original dosage form to have their own sophisticated formulation groups.

Proper LCM will silence industry critics who say companies introduce improved new formulations when the drug substance patent expires solely to protect a franchise. Critics claim the new improved formulation that could have been of more benefit to patients if introduced much earlier in the product life cycle.

LCM strategy includes the introduction of a single isomer form of racemic mixtures and fixed combination products.

Single Isomer Products

Hector cited Lexapro, the once-daily oral controlled-release formulation of escitalopram the active enantiomer of citalopram/Celexa. “Lexapro has the potential to become the most widely used selective serotonin reuptake inhibitor (SSRI) because it offers high tolerability, strong efficacy, and low drug interactions at a 10% discount to Celexa,” she said.

Eli Lilly’s (Indianapolis, IN) once-weekly reformulation of fluoxetine/Prozac, launched well after loss of exclusivity for the original formulation, was less successful, achieving less than 10% of the sales of the original product.

Fixed Combination Products

The development of fixed combinations of two or more drugs has increased dramatically because of powerful driving forces and as a component of LCM. Jay S. Trivedi, director new products, Schwarz Pharma (Mequon, WI), posed the question, “Is this a fad or the future?”

Historically, the FDA was skeptical of fixed combinations, such as two or more drugs in the same dosage form, often citing titration difficulties and other technical challenges.

Trivedi says the rationale for combination products includes LCM and driving forces, which he calls “the three C’s”: clinical value greater than the sum of the component drugs; commercial value to the patient (lower co-payment) and provider; and compliance in the form of fewer pills to remember.

The result can be rational combinations that provide a significant medical advance and have commercial potential. He concluded that the commercial importance (14 of the top 200 selling prescription products are fixed combinations, increasing FDA responsiveness, broader acceptance, technical advances, and contribution to LCM) will continue to increase the importance of fixed combination drug products.

The industry has aggressively developed combination products for the cardiovascular market to take advantage of the significant overlap in patient populations. Five combinations of statins (e.g., Lipitor) have been introduced.

Pfizer (New York City) introduced Caduet, a fixed combination of Lipitor and amlodipine/ Norvasc, a calcium entry blocker, to address the significant overlap between the hypertension and dyslipidemia markets. Other combinations of statins with antihypertensives and other cardiovascular are in development.

Commercial Importance of DDT

The importance of DDT from a commercial perspective is apparent from the resources that pharmaceutical and biotech companies dedicate to the function.

According to Pfizer’s Michael Flakus, manager strategic alliances, the company has about a dozen business development personnel dedicated to the worldwide search for delivery technology to meet the need for external DDTs and a large network of specialists within R&D with expertise to participate in the evaluation and selection of the optimal technology for successful formulation of a new compound.

Pfizer often conducts multiple feasibility studies of candidate technologies to increase the probability of success and provide options for deal structure and negotiation with DDT companies.

Johnson & Johnson acquired Alza for close to $13 billion in the summer of 2001. According to Atul Ayer, Ph.D., of Alza, and an inventor on 86 oral controlled release patents, the acquisition was motivated not only by the desire to apply Alza’s established technologies to Johnson & Johnson’s portfolio of compounds, but for the general DDT expertise of its personnel.

Alza’s DDT capabilities and expertise is now applied to Johnson & Johnson compounds starting from the early stages of drug discovery leading to the development of compounds and macromolecules as therapeutic agents.

All Alza personnel are now dedicated to meeting the needs of Johnson & Johnson’s growing presence in pharmaceuticals, using their established technologies and complementary external technologies.

Dr. Kiron, who is responsible for establishing Alza’s drug delivery research and external strategy says, “Alza looks to partner with external DDT firms to complement its own internal research activities to enable the efficacious delivery of Johnson & Johnson compounds.

“A recent example was the search for technology to solubilize a compound at a particular pH to achieve uptake in a targeted section of the gastrointestinal (GI) tract.”

Improved Methodologies

A range of methods is used to study the characteristic of drug formulations.

Ian Wilding, Ph.D., co-founder and now scientific advisor of Pharmaceutical Profiles (Nottingham, U.K.), spoke on “Challenges and Opportunities in Drug Delivery.”

He presented data from an FDA/PhRMA study showing that 27% of marketed drugs failed to make commercial return due to poor bioavailability or pharmacokinetics and cited this as a key issue and opportunity for drug delivery. He demonstrated the importance of human studies by showing the poor correlation between animal and human data.

Pharmaceutical Profiles developed a novel technology, the Enterion capsule, to study absorption in the human intestines. Subjects swallow an Enterion capsule, which consists of a drug reservoir, release mechanism, and electronics. Location of the capsule in the gut is assessed in real time using a sophisticated imaging technique, and a radio frequency (RF) signal is used to release drug at the desired location in the GI tract to study uptake.

Enterion was used to identify technology to “rescue” a candidate drug with low oral bioavailability; drug delivery to the jejunum could be increased up to threefold with either nanoparticles or other DDTs.

Dr. Wilding says, “Technology to improve solubility is becoming a commodity, with over 80 DDT companies working in the lumenal availability’ area. Big Pharma is bringing technologies in-house to fix’ solubility problems at the time a compound moves from discovery to development.”

He sees permeability improvement as the biggest opportunity. “If you have realistic aspirations, there are a wide range of technologies to consider, including Xenoport’s receptor mediated transport systems, Emisphere’s carrier controlled approach, Nobex’ molecular stabilization, and Lipocine’s bioacceptable absorption promoters.”

Emerging and Novel DDTs

DDTs presented that have the potential to make significant contributions to the challenges imposed by insoluble and/or low-permeability compounds include: gastric-retention systems, protein PEGylation, microspheres, drug-device combinations for inhalation or enhanced transdermal delivery, and novel materials.

Although some of these technologies have been utilized for years, recent improvements have enhanced their utility.

Gastric retention, the use of DDT to prolong the residence and release of orally administered drug substance in the upper GI tract, has long been considered a desirable mechanism to increase the duration of action of small molecule therapeutics that have a narrow absorption window in the upper GI tract. Historical results have not met this need.

Bret Berner, Ph.D., vp, product development of DepoMed (Menlo Park, CA), says, “In the past, some gastric-retention technologies attempted to use large particles or devices, potentially resulting in adverse effects on GI function. Our formulations provide particles 1213 mm in diameter, just too large to cross the pylorus in the fed stomach.

“We obtain about six hours of gastric residence, which enables 89 hours of drug delivery and once-daily dosing for many drugs administered 34 times daily in other formulations.”

DepoMed’s most advanced products are once-daily formulations of metformin for type 2 diabetes and ciprofloxacin for urinary tract infections. Each has been studied in over 1,000 patients and both products have received approval by the FDA.

While no one was claiming oral delivery of peptides and proteins, the long-awaited inhaled formulation of insulin may be close to market. The NDA for Exubera developed by Nektar Therapeutics (San Carlos, CA) and Pfizer was submitted in March. Many other inhaled formulations of insulin and other peptides and proteins are in development.

Dr. Wilding is one of many who believe that the first approval of a protein delivered with a novel delivery will favorably impact the market. “A green light for Exubera could change the perceived risk profile for novel delivery technologies, leading to a resurgence of interest in pulmonary technology for systemic delivery and more investment in transdermal, nasal, and buccal technologies,” he said.

PEGylation technology has improved the delivery of injectable proteins. Annual worldwide sales of PEGylated drugs total about $6 billion. According to Mary Bossard, Ph.D., director of biopharmaceutical research, at Nektar, PEGylation has been shown to enhance bioavailability, optimize pharmacokinetics, reduce toxicity, and improve solubility and stability.

Nektar’s Advanced PEGylation is based on PEGs selected from a broader range of molecular weights (560 kDa), functional groups, and improvements in attachment chemistry. PEGASYS, once-weekly alpha-interferon for the treatment of hepatitis C, was developed by Roche using Nektar’s Advanced PEGylation to compete with Schering’s PEG INTRON, a PEGylated alpha interferon.

PEG Intron was one of the first PEGylated therapeutic proteins and was an improved formulation of non-PEGylated Intron A, recombinant interferon alpha 2b.

“PEGASYS is made with a 40 kDa branched mPEG-NHS reagent. One PEG molecule is bound to a lysine on each alpha-interferon, providing high in vivo efficacy. PEG INTRON is also mono-PEGylated, but uses a 12kDa PEG with binding to 14 different sites, primarily histidine residues.

PEGASYS provides higher and more uniform blood levels,” according to the firm. PEGASYS captured 60% of the market within two years of launch, virtually all at the expense of PEG INTRON.

Epic Therapeutics’ (Norwood, MA) Promaxx is an aqueous-based formulation technology that produces microspheres for inhalation or injection with over 95% drug loading. The manufacturing process can be controlled to produce microspheres from 0.4 to 50 microns in diameter within a narrow particle size range that can contain proteins, nucleic acids, or small molecules, says Larry Brown, Sc.D., CTO of Epic.

Epic has developed Promaxx formulations of insulin, alpha-1-antitrypsin, and hGH for pulmonary delivery. Most of the development has been conducted with dry powder inhalers, a limited amount with HFA-based inhalers.

The target particle size depends on the desired site of uptake. For example, microspheres 13 microns in diameter containing insulin are targeted to the alveoli for systemic delivery.

Advanced Transdermal Systems

Passive transdermal systems are widely used in hormone replacement, pain management, and cardiovascular indications, delivering small (typically less than 10 mg/day) quantities of hydrophobic small molecules across the intact stratum corneum (SC). Total annual worldwide sales of all patch products are about $5 billion.

Hydrophilic drugs, including some small molecules, peptides, and proteins, which cannot be delivered by conventional transdermal systems, provide much larger market opportunities.

According to Eric Tomlinson, Ph.D., CEO of Altea Therapeutics (Tucker, GA), who moderated what he described as the “Inaugural Microporation Conference,” the sweet spot is highly water-soluble small molecule therapeutics and biomolecules.

Companies developing advanced transdermal systems to deliver these drugs include Altea Therapeutics and TransPharm Medical (Lod, Israel).

Both companies use small handheld devices that impart painless electrical impulses to create pores in the SC. A patchlike reservoir containing the drug is placed over the treated area. The pores permit the passage of significantly larger quantities (up to 100 mg/day) of hydrophilic drugs to partition into and diffuse across the viable epidermis to enter the capillary bed and systemic circulation.

The broader capabilities of these technologies include delivery of larger molecules and those with physico-chemical characteristics that would preclude passive delivery. Each company has worked with both small molecules and proteins, including insulin.

Judith Kornfeld, vp, business development, TransPharma Medical, spoke on ViaDerm, which uses radio frequency current, to open microchannels in the SC, enabling transdermal delivery. RF current is commonly used in other medical applications such as electrosurgery.

TransPharma’s RF MicroChannels are temporary pores created by applying a painless electrical current for a few seconds in the SC. The pores provide many small passageways through which a dissolved drug can cross the SC. The low-cost device may be used for 1,000 applications, nearly three years of once-daily treatment.

The device currently has 150 microelectrodes per square centimeter, which may be modified for different delivery needs. In a recent clinical study, a patch of 8.4 square centimeters was sufficient to deliver 10 units of insulin over 10 hours, a therapeutically useful amount.

TransPharma has also shown therapeutically useful delivery rates for hGH. TransPharma has also worked on small molecules, including granisetron (Kytril) and testosterone.

David Enscore, Ph.D., senior vp, product R&D at Altea Therapeutics, described the firm’s skin microporation technology, which uses a painless two-millisecond electrical pulse to resistively heat metallic filaments to ablate skin to create pores in the stratum corneum.

The poration array is a disposable part of the delivery system and comprises 20120 filaments per square centimeter. The application device is reusable with a lifetime of up to two years. Altea’s insulin delivery system is targeted at delivery of a range of doses up to 30 U/day from patches between 1 and 8 cm2 for basal control of glucose levels.

pSivida (Perth, Australia) has a core focus on controlled release DDT based on BioSilicon, a nanostructure form of elemental silicon.


Roger Aston, Ph.D., director of strategy, says, “BioSilicon is engineered to create a porous honeycomb structure that is biodegradable, biocompatible, and made of low-cost raw materials. We have a range of procedures to load drugs into the honeycomb.

“Drugs stored in the honeycomb are released in a controlled manner as the honeycomb is hydrolyzed to silicic acid, a nontoxic substance present in common foods such as rice and wine,” he said.

Advantages of BioSilicon for drug delivery include: high drug loading (up to 95%), controlled release over hours to months, and delivery of everything from small molecules to proteins and nucleic acids.

PSivida is developing BrachySil as a brachytherapy device as its first commercial product. Brachytherapy is a radiation therapy in which radioactive material sealed in needles, seeds, or wires is placed directly into or near a tumor.

BrachySil is a suspension of 30-micron particles of highly purified BioSilicon containing immobilized 32P administered through a fine needle directly into the tumor and emitting beta radiation. A Phase IIa trial of patients with inoperable liver cancer showed no adverse effects or leakage of 32P from the implantation site.

BrachySil remains in the tumor, emitting beta radiation. Mean tumor regression was up to 80, some tumors of less than 4.2 mL showed complete regression.

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