BB&T Contributing Writer

NEW YORK — One of the most varied and interesting areas of medical technology is the recent proliferation of new device systems for the delivery of drugs, an area traditionally dominated by pills and capsules. This variety is being augmented by the need to develop systems for the delivery of newly emerging therapies such as biologics, stem cells and RNAi.

The range of these systems and strategies was showcased at the late-November Rodman & Renshaw healthcare conference, its 8th annual event. More than 350 public and private companies were on hand to tout their novel drug delivery technologies and drug development pipelines, including new developments in RNAi and stem cells. A distinguishing feature of many of the drugs being reviewed was their proprietary delivery technologies, frequently presented as enhancing either product differentiation or improved therapeutic performance, or both.

Oral spray and inhalers

Sprays and inhalers have long been used for the delivery of throat sprays, other over-the-counter medications and asthma drugs, and they are now being more frequently employed for more complex pharmaceuticals.

Pharma (Flemington, New Jersey) used the conference to report its recent FDA approval, via the 505(b)(2) regulatory pathway, of NitroMist, a nitroglycerine lingual aerosol for acute relief of an attack or acute prophylaxis of angina pectoris due to coronary artery disease. This is the company's first product approval utilizing its oral spray technology. Par Pharmaceutical (Newton, Massachusetts) has licensed North American rights to NitroMist.

Other oral spray products in NovaDel Pharma's pipeline are Sumatriptan and Zolpiderm which target patients suffering from migraines and insomnia, respectively. The benefits of the oral spray system are more rapid delivery of drugs to the bloodstream resulting in a faster therapeutic effect, increased bioavailability by avoiding metabolism by the liver, improved drug safety from a reduced dosage requirement and obviating the need to swallow.

Generex Biotechnology (Toronto) uses its RapidMist metered dose inhaler for oral delivery of its Ora-lyn insulin spray. The drug is absorbed through the inner walls of the check (buccal mucosa), thereby entering directly into the bloodstream. The product is sold only in Ecuador but is in various stages of clinical development throughout the world. Glucose RapidSpray is used to treat minor symptoms of low blood sugar and is sold in the U.S. and Canada. Metformin medicinal chewing gum for treating Type II diabetes is in Phase II trials and spray formulations of fentanyl and morphine for pain management are in Phase I trials.

Mannkind (Calencia, California) is enrolling patients in three pivotal Phase III clinical trials in the U.S. and Europe for use of its inhaled dry powder insulin Technospheres for the treatment of Type 1 and Type 2 diabetes. A proprietary inhaler is used to deliver insulin deep into the lungs. Efficacy is being evaluated on the basis of changes in HbA1c levels and in blood glucose levels after a standardized mixed meal. An impassioned presentation was given by Alfred Mann, the company's CEO and chairman, who has personally invested $369 million in Mannkind.

Nastech Pharmaceutical (Bothell, Washington) is utilizing its proprietary technology for the intransal delivery of compounds, ranging from small molecules to peptides, for treating a variety of disease conditions. It is in a Phase II trial of a morphine gluconate nasal spray for treating breakthrough pain, a Phase I trial of a rapid-acting insulin nasal spray for diabetes, and a Phase II trial of Peptide YY for treating obesity that was previously a collaborative program with Merck (Whitehouse Station, New Jersey). Nastech has strategic alliances for several of its nasal delivery programs.

These include a Phase I trial using parathyroid hormone (PTH1-34) for osteoporosis with Procter & Gamble Pharmaceuticals (Cincinnati), a Phase I trial using exenatide for Type 2 diabetes with Amylin (San Diego), and a calcitonin-salmon nasal spray for osteoporosis with Par Pharmaceuticals that received a non-approvable letter from the FDA.

Nastech also is a new entrant in the emerging class of therapeutics utilizing RNAi technology. The RNAi mechanism provides researchers with the ability to specifically silence the expression of individual genes and prevent protein synthesis. Nastach recently has licensed intellectual property rights from City of Hope (Duarte, California) for Dicer-Substrate RNA interference technology. This effort is pursuing the hope of developing small interfering (si)RNAs that could have improved pharmacological properties important for drug development and delivery when compared to conventional, first generation RNAi technology.

The field of RNA interference received a major boost with the announcement by Merck at the end of October of its $1.1 billion acquisition of Sirna Therapeutics (San Francisco), a leading company in this rapidly growing area of research and drug development.

Anlylam Pharmaceuticals (Cambridge, Massachusetts) also has corporate alliances for RNAi therapeutics with Merck, Novartis (Basel, Switzerland), Medtronic (Minneapolis) and Biogen Idec (Cambridge, Massachusetts), and CytRx (Los Angeles) is pursuing RNAi programs for treating obesity, Type 2 diabetes, ALS and CMV which are based on a license and research ongoing at the University of Massachusetts Medical School (Amherst) and Advanced BioScience Laboratories (Kensington, Maryland).

Electroporation and iontophoresis

Inovio Biomedical (San Diego) utilizes electroporation technology for drug and gene delivery by locally applying electrical pulses to create permeability in cell membranes. It has developed devices consisting of pulse generators and needle electrode applicators that are used together with a drug or a gene. Preclinical studies have shown that the company's electroporation technology enhances the cellular uptake of DNA plasmids, increases expression 100-fold compared to naked DNA, and generates immune responses with prophylactic or therapeutic benefits. Thus, it provides an alternative to viral and other gene delivery vectors. The company recently reported that Wyeth (Madison, New Jersey) will use Inovio's delivery technology with its DNA vaccines in development.

Transport Pharmaceuticals (Framingham, Massachusetts) is developing iontophoretic systems for enhancing the delivery of topically applied drugs. Its lead product, SoloVir, is for the treatment of herpes labialis (cold sores). Positive results from a Phase IIb clinical trial were published in August 2006 in Clinical Infectious Diseases. The device is reusable and consists of a microprocessor-driven control unit and a unit-dose drug cartridge that contains a proprietary formulation of acyclovir. The therapy entails a single treatment with the device (about the size of a nickel) held pressed against the cold sore for about 10 minutes. Another product under development is an iontophoretic patch that releases terbinafine for the treatment of onychomycosis (nail fungus).

The FDA has approved two single-use iontophoretic products. One is the LidoSite patch developed by Vyteris Holdings (Fair Lawn, New Jersey) that employs its Actyve transdermal drug delivery technology and is being sold by B. Braun Medical (Bethlehem, Pennsylvania), a subsidiary of B. Braun (Melsungen, Germany). The second is the Ionysis fentanyl delivery patch for treating acute postoperative pain on adult patients that utilizes the E-Trans electrotransport technology from ALZA (Mountain View, California), a Johnson & Johnson (J&J; New Brunswick, New Jersey) subsidiary. This product is currently in production scaleup for launch in 2007. It will be sold in the U.S. by Ortho-McNeil and in Europe by Janssen-Cilag, both J&J subsidiaries.

Microspheres for IV and catheter delivery

Acusphere (Watertown, Massachusetts) uses porous microsphere technology for improved formulations of existing drugs. Its microparticles have controlled aerodynamic properties for quick or slow pulmonary delivery. Its lead product, Imagify, is in a Phase III trial. It employs gas-filled microparticles for intravenous delivery that act as tracers of blood flow for improved ultrasound imaging used to detect coronary artery disease. Its technology can convert hydrophobic drugs into tiny sponge-like microspheres for rapid dissolution. Acusphere has completed a Phase I study with a currently marketed drug reformulated with its technology and has demonstrated sustained drug release in the lungs.

BioSphere Medical (Rockland, Massachusetts) markets an embolotherapy system for treating uterine fibroids. Uterine artery embolization (UAE) is an image-guided, minimally invasive procedure that entails an injection through a small catheter of Embosphere microspheres that occlude arteries feeding the vascularized uterine fibroids. Symptomatic fibroids afflict 5 million women in the U.S. UAE is gaining acceptance as a fibroid treatment within the U.S. medical community.

BioSphere is using microspheres in combination with Avastin to treat liver cancer patients in a Phase II trial underway at Johns Hopkins University School of Medicine (Baltimore, Maryland). The company has just received notification from the FDA of 510(k) clearance of QuadraSphere microspheres for treating uterine fibroids, hypervascularized tumors and vascular malformations. This product is sold in Europe. Biocompatibles (Farnham, UK) is also conducting Phase I/II chemoembolization trials at hospitals in Barcelona, Spain and Hong Kong on liver cancer (hepatocellular carcinoma) patients. It uses doxorubicin-loaded microspheres.

Drug/polymer combinations

Columbia Laboratories (Livingston, New Jersey) markets products that utilize its patented bioadhesive system which consists of a mucoadhesive polymer, polycarbophil, and an active ingredient. Prochieve 4% progesterone gel is used for the treatment of secondary amenorrhea and Prochieve 8% for the treatment of infertile women with progesterone deficiency. A pivotal Phase III trial is being conducted for use of Prochieve 8% to prevent preterm birth. This product would compete against Gestiva from Adeza Biomedical (Sunnyvale, California), a long-acting synthetic progestin used to prevent recurrent preterm birth which recently received an approvable letter from the FDA contingent on completion of an additional animal study.

Columbia Laboratories also markets Striant, a testosterone buccal delivery system for the treatment of male hypogonadism which it licensed for sale in Europe to Ardana (Edinburgh, UK) and Mipharm (Milan, Italy). In a competing development, BioSante Pharmaceuticals (Lincolnshire, Illinois) is in clinical trials with a transdermal testosterone gel for male hypogonadism. Columbia Laboratories has recently reported that it has initiated a 42-patient clinical study of vaginally administered lidocaine for use in preventing and treating dysmenorrhea.

Access Pharmaceuticals (Dallas) is using its polymer-drug delivery technology for the enhanced delivery of chemotherapeutic agents to tumors. The company's lead product, ProLindac, is a polymer prodrug of oxaliplatin, currently in a Phase II clinical trial. The company has a preclinical research program that combines its polymer expertise and vitamin-targeting technologies to enhance the tumor delivery of other cancer drugs. Its polymer know-how is also being used in MuGard, an oral rinse that was developed for treating oral mucositis. It forms an adhesive protective film in the oral cavity but does not contain a biologically active agent.

The company recently submitted a 510(k) application to the FDA for MuGard. Access has R&D collaborations with UCB-Celltech (Slough, UK) and Hunter-Fleming (Bristol, UK) and with a U.S. company, undisclosed, for the development of oral drug delivery formulations utilizing its vitamin B12 mediated oral drug delivery technology.

Oral controlled release of solid dosages

Depomed (Menlo Park, California) uses its AcuForm drug delivery technology to develop novel oral products and extended-release formulation of existing oral drugs. This technology allows for prolonged gastric retention and is designed for drugs that are preferentially absorbed in the upper portion of the gastrointestinal tract. It is used in two products marketed in the U.S. and Canada. ProQuin XR is a once-daily tablet of ciprofloxacin used for the treatment of uncomplicated urinary tract infection. It is licensed for sale in the U.S. to Esprit Pharma (East Brunswick, New Jersey) and in Europe to Madaus (Cologne, Germany). Glumetza is extended release metformin used for the treatment of adult Type 2 diabetes. Gabapentin is in a Phase III trial for the treatment of postherpetic neuralgia. It is licensed for co-promotion in the U.S. to King Pharmaceuticals (Bristol Tennnessee) and in Canada to Biovail (Mississauga, Canada).

Elite Pharmaceuticals (Northvale, New Jersey) is developing oral controlled-release versions of generic drugs with high barriers to entry. Its lead product, ELI-216, is a once-daily oxycodone that has completed a Phase I bioavailability study and is formulated to discourage illegal diversion and abuse of the drug. This is accomplished by combining an opiod antagonist with an agonist in such a way that when administered as an intact product, only the agonist will be absorbed in a sustained manner. When the product is physically damaged with the intent of abusing it, the antagonist is also released and thereby antagonizes the effect of the agonist.

Elite has a pipeline of six products under development in the therapeutic areas of cardiovascular, pain, allergy and infection. It has partnered with ECR Pharmaceuticals (Richmond, Virginia) for the sale of its allergy medications, Lodrane 24, a once-daily dose of an antihistamine formulation, and Lodrane 24D which also contains a decongestant.

Light-activated and topical delivery

DUSA Pharmaceuticals (Toronto) markets Levulan which uses photodynamic therapy for the treatment of pre-cancerous actinic keratoses. It also is being developed for the treatment of acne and photodamaged skin. Additional marketed products that came with its acquisition in March 2006 of Sirius Laboratories (Vernon Hills, Illinois) are Nicomide, a vitamin-based oral supplement for treating acne, Nicomide-T, a vitamin -based topical cream or gel for acne, and Avar a drug for rosacea.

Antares Pharma (Ewing, New Jersey) has a variety of drug delivery platforms. These include its Advanced Transdermal Delivery (ATD) system and the related TecTix system for topical and transmucosal delivery, Easy Tec oral fast-melt technology, and Medi-Jector needle-free injection devices. Medi-Jector Vision is currently marketed for delivering insulin and growth hormone.

The company has a development and licensing agreement with Eli Lilly (Indianapolis) for use of its Medi-Jector Valeo device for delivery of drugs to treat diabetes and obesity. It also recently reported an agreement with Teva Pharmaceutical Industries (Petach Tikvah, Israel) to provide its needle-free injection system for use with an unnamed product in the U.S. and also has signed two other commercial development agreements with Teva for its disposable mini-needle injector.

Antares Pharma has completed a Phase II trial of oxybutynin gel for treating an overactive bladder. It has licensed its ATD technology to BioSante Pharmaceuticals (Lincolnshire, Illinois) for use in its Bio-E-Gel transdermal estradiol gel for treating hot flashes in menopausal women. Market clearance from the FDA is expected shortly. BioSante has just disclosed an exclusive license for Bio-E-Gel to Bradley Pharmaceuticals (Fairfield, New Jersey). BioSante uses the ATD technology in its Libi-Gel low-dose testosterone gel that has completed a Phase II trial for treating female sexual dysfunction. The Intrinsa patch from Procter & Gamble Pharmaceuticals (Cincinnati, Ohio) also uses testosterone for this indication and recently received marketing approval for this product in Europe.

Injectable therapeutic, aesthetic materials

Anika Therapeutics (Woburn, Massachusetts) has developed products based on hyaluronic acid aned licensed out. OrthoVisc a synovial fluid replacement for the treatment of joint pain from osteoarthritis, is sold in the U.S. by DePuy Mitek (Raynham, Massachusetts), a subsidiary of J&J, and Amvisc, a viscoelastic gel used in cataract surgery, is sold worldwide by Bausch & Lomb (Rochester, New York).

In July of last year, Anika signed a worldwide marketing and distribution agreement with Galderma Pharma (Fort Worth, Texas) for its cosmetic tissue augmentation (dermal filler) product with expectations of launching the product in mid-2007. It will compete with other hyaluronic acid-based dermal fillers currently marketed by Medicis Pharmaceuticals (Scottsdale, Arizona) and Allergan Medical (Irvine, California).

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