Pharmaceutical companies are turning to nanomaterials to develop new drug formulations for targeted delivery.
The pharmaceutical industry faces a number of technological and market challenges in the coming years including improving solubility, enhancing product effectiveness and exclusivity in the face of generic competition, active drug targeting, patient compliance, cost effectiveness (the cost of producing a new drug can be upwards of $800 million) and product life extension. To meet these challenges the industry has turned to nanotechnology.
Therapeutic drug delivery is one of the main markets for nanomaterials based applications, where the trend in recent years is for medical therapies tailored to specific diseases and patients, especially for cancer treatment. The unique properties of nanomaterials when combined with special high loading and controlled release provide superior performance for drugs. Nanomaterials are being utilised for treating cancer, inflammatory disorders, infectious disease and cardiovascular disease as they help drugs reach diseased tissues and release their payload in a controlled way.
Most drugs have primary targets within cells and tissues; ideally, these agents may be preferentially delivered to these sites of action within the cell. Selective subcellular delivery is likely to have greater therapeutic benefits, and this is where nanomaterials are useful due to their enhanced targeting and diffusion capability. Nanomaterials used in for drug delivery are mainly the following types:
• Nanoparticles, including inorganic, polymer-based and solid lipid nanoparticles
• Nanocrystals
• Liposomes.
There is over 150 companies currently developing nanomaterials based therapeutics and numerous products have been approved for clinical use, mainly liposome and polymer conjugates as anti-infective, anti-neoplastic and immune-modulating agents.
Other materials under development for drug delivery include:
• micelles
• nano-shells
• dendrimers
• engineered viral nanoparticles
• albumin-based nanoparticles
• polysaccharide-based-nanoparticle
• metallic nanoparticles.
• ceramic nanoparticles.
Polymer-based nanoparticles
Polymer-based nanoparticles are colloidal solid particles with a size range of 10 to 1000nm. They can be spherical, branched or shell structures and their nano-size enables them to penetrate capillaries and to be taken up by cells, thereby increasing the release capability of drugs at target sites. Drugs are incorporated into nanoparticles by dissolution, entrapment, adsorption, attachment or by encapsulation, and the nanoparticles provide sustained release of the drugs for periods of days or even weeks. Products on the market include:
• Adagen, for treating Adenosine deaminase (ADA) enzyme deficiency, produced by Enzon Pharmaceuticals, Inc.
• Onscaspar, for treating acute lymphoblastic leukaemia, produced by Sigma-Tau Pharmaceuticals, Inc.
• Copaxone, for treating relapsing-remitting multiple sclerosis, produced by Teva Pharmaceuticals
• Macugen, for treating neovascular age-related macular degeneration, produced by Nektar Therapeutics and OSI Pharmaceuticals
• Pegasys and PEG-INTRON, for treating Hepatitis C, produced by Nektar Therapeutics
• Neulasta, for treating Neutopenia, produced by Nektar Therapeutics
• Somavert, for treating Acromegaly, produced by Nektar Therapeutics.
Liposomes
Liposomes are artificial vesicles in the range of 50 – 100nm developed from phospholipids such as phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine and phosphatidylserine. As well as drug delivery, they also find application in food and cosmetics. They are used in drug delivery due to their ability to prevent degradation of drugs, improve targeting and thus reduce side effects. There are limitations to liposomes in drug delivery however, such as such as low encapsulation efficiency, rapid leakage of water-soluble drug in the presence of blood components and poor storage stability. Products on the market include:
• AmBisome, for fungal infections, produced by Astellas Pharma
• ABELCET, for fungal infections, produced by Sigma-Tau Pharmaceutical
• DOXIL/Caelyx, for chemotherapy agent for ovarian cancer, produced by Johnson and Johnson Inc.
• Daunoxome, Kaposi’s sarcoma, Galen Ltd.
• Myocet, Advanced breast cancer, made by Enzon Pharmaceuticals for Cephalon in Europe and for Sopherion Therapeutics in the United States
• Epaxal, Hepatitis A, Crucell NV
• Inflexal V, Influenza, Crucell NV
• DepoDur, Analgesia, EKR Therapeutics/Pacira
• Visudyne, Age-related macular degeneration, QLT Inc./Novartis
• Estrasorb, Hot flushes, Novavax/Allergan, Inc.
• Survanta, Respiratory distress syndrome, Abbott Laboratories
• Alveofact, Respiratory distress syndrome, Lyomark Pharma
• Curosurf, Respiratory distress syndrome, Takeda
• Mepact, high-grade resectable non-metastaic osteosarcoma, Takeda
• Depocyt, intrathecal treatment of lymphomatous meningitis , Sigma-Tau Pharmaceutical
• Octocogalfa, haemophilia, Bayer Pharma AG.
Nanocrystals
Approximately 60% of all synthesized drug candidates are poorly water-soluble. Nanocrystals are used to improve the solubility of poorly water-soluble drugs for oral delivery. Advantages of using nanocrystals in drug formulation include fast, simple and inexpensive formulation development, improved oral bioavailability, enhanced dose proportionality, increased drug loading, rapid effect, reduction in dosage, improved stability, increased reliability and administration via several routes. Nanocrystal drugs have been on the market since 2000 (Rapamune) and there are now a number available including:
• Rapamune, Immunosuppressant, produced by Elan Corporation/Pfizer
• Emend, Antiemetic, Elan Corporation/Merck
• Tricor, Hyperlipidemia, Elan Corporation/Abbott Labs
• Megace, Anorexia, Elan Corporation/Par Pharmaceuticals
• Semapimod, TNF-α inhibitor, Cytokine Pharmasciences
• PAXCEED, rheumatoid arthritis, Angiotech Pharmaceuticals Inc
• Theralux, Anti-cancer, Celmed Biosciences
• Triglide, Treatment of high cholesterol and high triglyceride levels, SkyePharma/First Horizon
• Invega Sustenna, Treatment of schizophrenia, Elan/ Johnson and Johnson.
Dendrimers
Dendrimers are nanosized three-dimensional polymers produced from macromolecules such as polyamidoamine (PAMAM), polypropyleneimine and polyaryl ether. They have a unique-tree branching architecture with an inner core. Particle size range is between 1 to 100nm although their sizes are mostly 1-15nm. Dendrimers are being developed by the pharmaceutical industry for anti-cancer drugs with desirable properties including high water solubility, monodisperse size, and uniform composition, which will lead to consistent batch-to-batch anti-cancer activity of dendrimers-based drug delivery systems. Dendrimer producer Starpharma has research collaboration with Eli Lilly and Stiefel (GlaxoSmithKline) for drug delivery applications. They recently demonstrated that their dendrimer-docetaxel formulation applied to chemotherapy drugs provided significant enhancements in efficacy. GlaxoSmithKline has also produced with NanoBio Corporation NB-001, an anti-herpes drug, and NB-002 an oil-in-water emulsion designed for use for the treatment of skin, hair, and nail infections incorporating dendrimers.
Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC)
Lipids and lipid nanoparticles are widely used for oral delivery of drugs and other active ingredients. They help to improve drug absorption and at the nanosize greatly improve mucosal adhesion due to their scale, increasing their effectiveness and longevity in the gastrointestinal tract. Lipid nanoparticles also protect the drug from degradation and gradually release their payload over time. Solid lipid nanoparticles (SLN) were developed over a decade ago due to their enhanced physiological and biodegradable properties. Advantages of SLNs include good tolerability, inexpensive and simple production, effective targeting and sustained controlled release and stability. However, they also have a number of advantages that have been overcome through nanostructuring the lipid matrix, which allows for increased drug loading and prevention of leakage, which were limitations with SLNs. These nanostructured lipid carriers (NLC) represent the second generation of lipid nanoparticles and as well as drug delivery have also been developed for application in cosmetics and dermatological preparations. There are a number of products incorporating SLNs and NLCs at various stages of clinical development include Nanobase for treating Hepatitis C.
Metallic nanoparticles
Metallic nanoparticles (silver, gold and magnetic nanoparticles) are being developed as carrier agents in cancer treatment. Gold nanoparticles/nanoshells are used in treatment of tumour cells, where they bind to the cells, allowing for cell death by laser activation. Companies developing products include Nanoprobes, Inc., Nanosphere, Inc., Strem Chemicals, Inc., Nucryst Pharmaceuticals, AcyMed and Antibodies Incorporated. Products under clinical development include:
• Aurimmune (CYT-6091), colloidal gold nanoparticles for tumour treatment, Cytimmune Sciences
• AuroShell, gold-coated nanoparticles for tumour treatment, Nanospectra Biosciences
• NUCRYST, Anti-bacterial, Nucryst Pharmaceuticals.
