Alternative systems will play a greater role in biopharmaceutical delivery by the year 2005

Alternative systems will play a greater role in biopharmaceutical delivery by the year 2005

Liposomes, MAbs, transdermal patches and other approaches eyed for growth

Delivering drugs by alternative routes is becoming increasingly important in the pharmaceutical industry. Drug companies, faced with generic competition and the advent of new biopharmaceutical compounds, need new methods of introducing their products into the body in a targeted and controlled manner. Such new methods include liposomes, monoclonal antibodies, needleless injections, oral controlled-release drugs, polymer-based, pulmonary, transdermal, and transmucosal delivery systems. The market for alternative drug delivery systems (ADDS) has experienced especially strong growth due to significant breakthroughs and refinements since the early 1990s. Table 1 on page 203 shows market share data for the segments of alternative drug delivery systems in 1995 and their projected shares in 2005.

Several factors have promoted the growth of the alternative drug delivery industry:

* A large number of products reaching the end of their patent life cycle require new modes of delivery to maintain market share and product line profitability.

* R & D efforts and approvals of biopharmaceuticals – namely proteins, oligonucleotides, and polysaccharides – need delivery methods that maintain molecule integrity.

* Continuous recognition of the limitations of conventional routes and the need for improved drug efficacy and tolerance.

Some delivery systems attempt to deliver therapeutics directly to affected or diseased tissues. Site delivery bypasses digestive degradation and hepatic metabolism and reduces the need for excessive dosing, which can lead to undesirable side effects and toxicity. Other systems employ sophisticated and rational approaches to delivery. These technologies take into account pharmacokinetic principles, specific drug characteristics, and response variability between individuals and within the same individual under different conditions.

The benefits of alternative drug delivery systems compared to conventional immediate-release oral drugs, topical, rectal, ophthalmic, and parenteral delivery systems include:

* Lower total volume of administered drug.

* Increased patient comfort and compliance.

* Reduced incidence of adverse side-effects.

* Potential improved pharmacoeconomic value.

Sales from alternative drug delivery are expected to grow at an average annual rate of about 20% between 1995 and 2000, and nearly 30% between 2000 and 2005. By 2005, alternative drug delivery systems are expected to reach $100 billion in worldwide sales and may account for about half of total drug delivery sales [ILLUSTRATION FOR TABLE 2 OMITTED].

Strong role seen for liposomes

Many companies developing biotherapeutics, which traditionally are administered by injection, see liposomes as one of their best hopes for improved product value and profitability. Liposomes are comprised of lipid molecules which resemble natural cell membranes, with a lipid exterior shell and aqueous interior core. This structure lends itself well to the packaging and delivery of water soluble and insoluble molecules, as well as amphipathic molecules. Of particular value is the liposome’s ability to enter the body and seek out target tissue and cells without inducing an immediate immune response that would lead to destruction of the liposome and its drug product.

Surface modifications, such as the STEALTH technology developed by Sequus Pharmaceuticals (Menlo Park, California), have made liposomes a more viable delivery vehicle for biotherapeutics. The attachment of a hydrophilic polymer, such as polyethylene glycol (PEG), can be employed to help stabilize the liposome and shield it from the host’s defense system. PEG-surfacing significantly extends the lipo-some’s circulation half-life and improves its ability to target specific tissues and cells.

Liposomal delivery’s first revenues were generated in 1990, following the approval in Ireland of AmBisome (amphotericin B), a treatment for systemic fungal infections developed by NeXstar Pharmaceuticals (Boulder, Colorado). The first U.S. approvals of liposomal products were Sequus’s Doxil (doxorubicin) for treatment of refractory Kaposi’s sarcoma in AIDS patients and The Liposome Co.’s (Princeton, New Jersey) ABLC (ampho-tericin B), indicated for second-line treatment of systemic fungal infections. Worldwide revenues of liposomal products totaled $120 million in 1995. Growth between 1996 and 2000 is expected to be fast-paced, averaging 58% a year. Between 2000 and 2005, BBI believes growth will average about 25% a year.

Major developers of liposomal technology are The Liposome Co., Sequus Pharmaceuticals, and NeXstar. The Liposome Co. expects to earn revenues of $50 million in 1996 for ABLC, and also has D-99 (doxorubicin) in Phase III trials with Pfizer (New York) for metastatic breast cancer. Its C-53 (prostaglandin E1) compound is in Phase II/III trials for acute respiratory distress syndrome. NeXstar’s DaunoXome (daunorubicin), approved this year, is a chemotherapeutic indicated for Kaposi’s sarcoma. Amphocil, Sequus’s version of amphotericin B, is approved in European markets.

Liposomes also are being used as vectors for gene therapy. Carrying genes to correct a specific disorder, the liposomes can be coated with antibodies to direct the liposome to a specific cell type. Theragen (Princeton, New Jersey), Parke-Davis (Morris Plains, New Jersey), Vical (San Diego, California), Applied Immune Sciences (Santa Clara, California), and GenVec (Rockville, Maryland), are among the firms developing lipid-based carriers and liposome vectors for gene therapy.

Monoclonal antibodies are site-specific

Antibodies are one of the body’s natural defense mechanisms that have been engineered by biotechnology and pharmaceutical companies to have therapeutic, diagnostic, and delivery uses. Monoclonal antibodies (MAb) are ideal candidates as carriers of therapeutic substances for targeted delivery to specific sites in the body because they will attach only to specific antigens found on the surfaces of diseased cells. High specificity binding allows lower dosing, which is particularly advantageous when delivering chemotherapeutics with toxic profiles.

Estimated 1996 world sales of MAb delivery systems are about $100 million. Revenues through 2000 will be driven primarily from sales of ReoPro, developed by Centocor (Malvern, Pennsylvania), an anti-platelet drug used as an adjunct to angioplasty. Contributing to the total will be OncoScint, an imaging agent for colorectal and ovarian cancer developed by Cytogen (Princeton, New Jersey). Use of OncoScint is limited to technicians with proven expertise in nuclear medicine; as a result, this product’s 1996 sales are estimated at $2 million. Cytogen’s second product, ProstaScint, likely will gain FDA approval late this year. This MAb will be the first prostate cancer diagnostic approved for use in soft tissue. It will be used to determine if a confirmed cancer will be treated with local therapy, surgery, or radiation. At $1,000 per scan, ProstaScint will be almost as expensive as ReoPro ($1,350 per dose), but its sales also will be limited by restricted use.

NeoRx Corp. (Seattle, Washington) is another key player. It has developed a “pre-targeting” system whereby tumor cells are first targeted with MAbs attached to a non-toxic protein called streptavidin. The excess anti-body-streptavidin is cleared from the body and a radioactive isotope (yttrium-90), which is complexed with biotin protein, is injected. This multi-phase approach is very effective, as the biotin binds strongly with streptavidin. Delivery of the anti-cancer agent yttrium-90 in this precise manner reduces harmful radiation exposure in healthy tissue. Avicidin, the product employing this technology, will begin Phase II clinical trials this year for treatment of chemotherapy-resistant solid tumors.

Also in development are monoclonal antibodies with surface modifications and bi-specific binding sites. Surface modifications reduce immunogenicity by masking murine antibodies to appear human while bi-specific antibodies improve targeting to diseased sites. These developments, as well as the continued success of current products, will help grow this market rapidly. Compound annual growth will be over 100% between 1995 and 2000. Between 2000 and 2005, growth likely will slow to 55% per year, yielding $6 billion in worldwide revenues by 2005.

Advantages seen with needleless injectors

Needleless injectors propel aqueous or dry powder drug formulations at high speed through intact skin. These “jet injectors” offer significant advantages over conventional needle injections:

* Less-invasive administrations.

* Precise dosing.

* Compact, portable, and easy-to-use systems.

* Reduced risk of accidental needle sticks.

* Reusable and disposable injectors which do not require sharp instrument disposal.

The market for needleless injectors is quite small, with only $3 million in revenues for 1995. The three major players are Medi-Ject Corp. (Minneapolis, Minnesota), Bioject Inc. (Portland, Oregon), and Oxford Biosciences (Burlingame, California). Medi-Ject is the world leader in needleless injection, licensing its product on an indication basis. Its Medi-Jector device delivers aqueous solutions through the skin in less than 1/3 of a second. Medi-Jector is powered by a simple internal spring which forces the drug through a microfine hole in the tip of the nozzle. Medi-Jector is used to deliver insulin and human growth hormone to patient populations that require frequent injections.

Bioject also is developing a jet injector for multiple sclerosis. The company has filed a new drug application with Berlex (Wayne, New Jersey) for approval of its needleless injection method for use with Betaseron. Bioject’s device, called Biojector, uses pressurized carbon dioxide to drive a blunt plunger that forces a liquid suspension of the drag out a tiny hole and through the patient’s skin. It has been widely used since 1994 for subcutaneous and intramuscular injections of vaccines and local anesthetics.

Oxford Biosciences’ products are unlike the Medi-Jector or Biojector. Oxford’s devices, the Powder-Ject and Oral-Ject, deliver dry powder drug formulations. Use of smaller massed particles allows the patient to target the drug to a specific skin layer. Smaller dry particles also reduce pain, bruising, and bleeding, effects often seen with liquid jet-injectors. The Powder-Ject uses a compressed gas source to accelerate drug particles through the skin, while the Oral-Ject uses shock waves to accelerate the drug through the skin in the oral cavity. Both are in Phase I clinical trials.

With approval for multiple sclerosis treatments and other indications, needleless injections will gain wider acceptance in the medical community. The jet injector market will grow at a compound annual rate of 46% between 1995 and 2000, slowing to an average of 20% a year between 2000 and 2005, with sales of $50 million by 2005.

Oral controlled-release

Oral controlled-release delivery systems account for the largest segment of the ADDS market, with 54% market share and 1995 worldwide sales of $5.8 billion. The compound annual growth rate is expected to be 21% through the year 2000, and sales will grow by 30% through 2005. Worldwide sales are estimated at $56 billion by 2005. Growth will be driven by generic competition and the need for more effective products than conventional immediate-release oral drugs.

A drug that is administered in a controlled-release form will be delivered at a slower rate and for a longer period than conventional tablets, resulting in a more consistent and effective level of medication in the bloodstream. An area of intense research and development, this segment will continue to dominate the ADDS market since many applicable drugs are coming off patent. With the increasing loss in sales due to generic competition, many of the major drug companies are looking to new patentable formulations and delivery systems to extend product life, retain market share, and prevent sales erosion. The key benefits of oral controlled-release systems are both therapeutic and compliance related. Less frequent dosing and sustained-release mechanisms offer several advantages:

* Increased patient compliance.

* Fewer drug variations in the bloodstream.

* Fewer side effects.

Major developers of oral controlled-release systems are ALZA Corp. (Palo Alto, California), and Elan Corp. (Gainesville, Georgia). Table 3 lists the major oral controlled-release products on the market and in late stage development, their indication, and the company marketing the product. Many products on the market are to treat cardiovascular diseases like angina and hypertension. This is a highly competitive field and current leaders like Pfizer’s Procardia, Bayer’s (West Haven, Connecticut) Adalat, and Hoechst Marion Roussel’s (Kansas City, Missouri) Cardizem are offering controlled-release formulations not only to provide more efficacious drugs with better side-effect profiles, but also to retain market share of their best-selling products. The antiarthritic market also is seeing an increase in controlled-release formulations, due in part to the loss of patent exclusivity for many antiarthritic products and the need for longer and more sustained dosing to relieve symptoms.

Polymer-based delivery systems

Polymer-based delivery systems are designed, in part, for the targeted and sustained release of drugs. One of the sophisticated ways to deliver drugs in a timed-released manner is to encapsulate them within layers of microspheres. As each microsphere layer dissolves, it releases a specific amount of drug. Dosing can be more precisely controlled over time with a single oral or injected administration. Although 1995 worldwide sales were about $3 million, polymer-based delivery systems are expected to grow by 180% annually between 1995 and 2000 and 20% between 2000 and 2005, with sales reaching almost $1.4 billion by 2005.

The players in polymer-based systems include Enzon Inc. (Piscataway, New Jersey), Alkermes Inc. (Cambridge, Massachusetts), and Guilford Pharmaceutical (Baltimore, Maryland). Enzon’s Oncaspar (PEG-L-asparaginase) relies on the attachment of proteins to improve stability and reduce immunogenicity of its polymer implant used to treat acyute lymphoblastic leukemia. Alkermes is in Phase I with its ProLease delivery system, which encapsulates fragile protein drugs in porous microspheres. Designed for subcutaneous injection, ProLease will deliver human growth hormone and interferon alpha. Guilford’s Gliadel wafers, approved in September, are polyanhydride disks which are implanted at the site where a brain tumor was surgically removed. As the wafers erode over a period of two to three weeks, they release the chemotherapeutic carmustine in the tumor cavity to prevent malignant cancer from recurring. Rhone-Poulenc Rorer (Collegeville, Pennsylvania) markets Oncaspar and will market Gliadel when the product is launched in early 1997.

Table 3

Oral Controlled-Release Formulations

Brand Name Indication Manufacturing/

Marketing Company

Adalat CC Hypertension Bayer

Calan SR Hypertension Searle

Cardene SR Hypertension Roche Laboratories

Cardizem SR/CD Hypertension Hoechst Marion

Roussel

DayPro Arthritis Searle

DynaCir SR Hypertension Novartis

Efidac-24 Decongestant/antihistamine Novartis

Isoptin SR Hypertension Knoll

Minipress XL Hypertension Pfizer

Naprelan Analgesic Wyeth-Ayerst

Procardia XL Hypertension Pfizer

Sinemet SR Parkinson’s disease DuPont

Timoptic Intra-ocular pressure Merck

Awaiting Approval

Carbatrol Epileptic seizures Elan

Erythelan Antibiotic Elan

Glucotrol XL Hyperglycemia Pfizer

Hismanal Antihistamine KV Pharmaceuticals

Teczem Hypertension Hoechst Marion

Roussel

Source: The BBI Newsletter

Growth in pulmonary delivery systems

Current pulmonary delivery systems account for 33% of the alternative drug delivery market and posted $3.6 billion in global sales for 1995. The world pulmonary delivery systems market segment is expected to grow at an average rate of 20% per year, reaching $22 billion by 2005. This growth will be due, in part, to the development of technologies that can take advantage of the better drug-absorbing characteristics of the lung tissues versus other tissues like the skin or the gut epithelia. Pulmonary delivery systems are well suited to treat many respiratory diseases including asthma, bronchitis, emphysema, respiratory allergies, and cystic fibrosis. The pulmonary system is an ideal route for non-invasive drug delivery as larger molecules are able to pass easily through the deep lung tissues into the bloodstream. Early clinical trials have proven that the lung is permeable to many peptides and proteins. Novel pulmonary delivery systems also may be applied for the delivery of therapeutics needed for disorders not centered in the lungs, broadening the potential market.

After introducing the first metered dose inhaler in 1956, 3M Pharmaceuticals (St. Paul, Minnesota) became a leader in the pulmonary delivery field. The company unveiled its first non-CFC propelled metered dose inhaler in 1995. The product, Airomir, delivers the anti-asthmatic salbutamol. Numerous pulmonary delivery systems are on the market and more are in development. Inhale Therapeutic Systems (Palo Alto, California), which went public in May 1994, and Dura Pharmaceuticals (San Diego, California) are developing new aerosol formulations to increase efficacy and duration of aerosol therapy. Inhale is developing 1 micron to 5 micron particles to be delivered as aerosols or powders for inhalation. This delivery system has technological advantages over conventional inhalers:

* Deposits inhaled particles into the deep lung tissue, where they are absorbed more effectively.

* Drug dosages can be delivered more efficiently.

* Not using propellants obviates environmental concerns and complications with formulations.

* More long-term stability than existing liquid formulations of protein-based therapeutics.

Inhale is developing a dry powder formulation of insulin with partner Pfizer. The product is in Phase II clinical trials. Dura has created a novel dry powder inhaler drug delivery system called Spiros, which also is propellant free and easier to use than conventional inhalers. Spiros is in Phase II clinical trials, delivering salmon calcitonin to prevent bone loss.

Strong competition in transdermal delivery

Transdermal drug delivery, the delivery of drugs directly into the bloodstream via intact skin, is a growing but highly competitive market segment. The worldwide transdermal drug market reached $1.2 billion in 1995, with growth rates estimated at 20% through 2005 and sales of $10 billion by that year. Current market share for this segment is 11%, with an expected decline to less than 10% due to entry of other alternative drug delivery systems by 2005. Advantages of transdermal delivery include:

* Avoidance of “first-pass” or hepatic metabolism before becoming therapeutically available to the body.

* Increased patient compliance, compared to oral delivery formulations.

* Ability to dose short-lived therapeutics.

* Sustained, long-term drug delivery which can be easily terminated by patch removal.

The leader in transdermal delivery is ALZA Corp., with seven transdermal products on the market for pain, smoking cessation, and hypertension. Cygnus Therapeutic Systems (Redwood City, California) has a smoking cessation patch, approved for the non-prescription market and it anticipates the approval of two more transdermal products in 1997. One of these products, a 7-day estrogen transdermal therapy called FemPatch, will help Cygnus become a key player in the male and female hormone replacement market. Driven by an aging population this market is valued at $1 billion worldwide. Other participants include Noven Pharmaceuticals (Miami, Florida) and Theratech (Salt Lake City, Utah).

Aside from creating thinner, less-irritating transdermal patches, with better control, companies also are investigating the use of electricity to aid in transdermal delivery. Passive transdermal systems are limited in scope because the skin’s outer protective layer, the stratum corneum, effectively keeps out most molecules. Iontophoresis, an FDA-approved method for transdermal drug delivery, uses electric potential (a low-voltage, long-duration current) to enhance drug efficiency. Cygnus has combined iontophoresis with electrophoresis (a high voltage, short duration current) to significantly enhance drug entry through the skin. The procedure will provide better control of drug delivery, and site-specific delivery in peripheral tissues. Elan and Genetronics (San Diego, California) also are developing electrically assisted trans-dermal systems. Their products are in Phase III for delivery of calcitonin and Phase II for basal cell carcinoma and breast adenocarcinoma, respectively.

Transmucosal delivery a new segment

The more efficient delivery of drugs to the bloodstream, via the mucous membranes in the nose, rectal, vaginal, and buccal areas, offers potential opportunities to deliver sustained release of drugs normally administered parenterally. Transmucosals are a new segment, with the first product developed by Anesta Corp. (Salt Lake City, Utah), approved for marketing in 1993. Expected annual growth rates of 30% through 2000 and 40% through 2005 would yield annual worldwide sales of $1.7 billion dollars by 2005. Transmucosals are a less-threatening and useful alternative to injections given to patients before oral surgery Noven Pharmaceuticals and Anesta are developing delivery systems to administer anesthetics and sedatives. Noven’s DentiPatch, an oral transmucosal lidocaine patch approved in 1996, allows for deep cleanings and even limited drilling without a needle injection of anesthetic. Anesta’s product, Fentanyl Oralet, is a solid lozenge on a handle that contains the anesthetic fentanyl citrate. Advantages of administering an anesthetic via an oral transmucosal delivery system include:

* Rapid drug absorption into the bloodstream.

* Non-invasive medication of patients at lower cost.

* More accurate dosing of patients.

Nastech Pharmaceuticals (Hauppauge, New York) is a leader in nasal spray drug formulations. Stadol NS, a narcotic analgesic, was its first product and is marketed by Bristol-Meyers Squibb (Princeton, New Jersey). Nastech also has a Vitamin B-12 nasal gel under FDA review. Theratech is developing a rapid, sustainable transmucosal delivery system featuring mucosal enhancers together with bioadhesive polymers and the desired drug.

Ideal candidates for drug delivery systems

The next generation of biopharmaceuticals includes recombinant peptides and proteins, monoclonal antibodies, and antisense DNA and RNA. These cannot be delivered through traditional oral methods because they are rapidly degraded by the digestive system and thus are administered intravenously. However, par-enteral delivery often is uncomfortable for the patient and usually requires administration by a physician. With several hundred protein and peptide-based therapeutics in development or awaiting approval, the worldwide market for biopharmaceuticals was valued at $15 billion in 1995 and is expected to grow to almost $50 billion by 1998. The success of these new products will be dependent, in part, on the development of effective delivery systems, so drug makers are establishing licensing agreements with drug delivery companies.

Alternative drug delivery systems will continue to grow as companies, patients, and managed care organizations push for drugs with more therapeutic and pharmacoeconomic value.

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