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New developments improve transdermal delivery of drugs.(Brief Article) (english)
16 Feb 2003
The commercialization of transdermal patches for controlled drug delivery began two decades ago and has resulted in diverse products. Among them are nitroglycerine for angina, scopolamine for motion sickness, fentanyl for pain control, nicotine for smoking cessation, estrogen for hormone replacement therapy, testosterone for male hypogonadism, clonidine for hypertension, lidocaine for topical anesthesia and the recently approved ethinylestradiol and norelgestromin combination for contraception
New developments improve transdermal delivery of drugs.(Brief Article)
Author; Himadri Chatterjee,B.Pharm.
Currently working with Ranbaxy laboratories limited and is a member of Karnataka pharmacy council.
The commercialization of transdermal patches for controlled drug delivery began two decades ago and has resulted in diverse products. Among them are nitroglycerine for angina, scopolamine for motion sickness, fentanyl for pain control, nicotine for smoking cessation, estrogen for hormone replacement therapy, testosterone for male hypogonadism, clonidine for hypertension, lidocaine for topical anesthesia and the recently approved ethinylestradiol and norelgestromin combination for contraception. Three techniques are used to control drug delivery in these "passive" transdermal patches: Solid matrix, reservoir with rate-controlling membrane and drug-in-adhesive systems.
Transdermal drug patches offer the advantages of ease of use, painlessness, disposability, control of drug delivery and avoidance of first-pass metabolism by the liver. However, current transdermal patch designs are not capable of transporting large molecular drug through the skin barrier, especially peptides and proteins, which includes many drugs that are marketed or will emerge from the biotechnology industry. Consequently, a variety of approaches are being investigated by companies for enhancing transdermal drug delivery. They include the use of iontophoresis, ultrasound (sonophoresis), electroporation, heat and microneedles. Needleless jet gas injection devices are sold for drug and vaccine delivery through the skin. They provide immediate drug release, but not controlled delivery. They are reusable and costly and represent a small market niche.
Skin penetration enhancers are used to permeate the skin but are of limited benefit due to skin irritation caused by prolonged exposure. Two companies with proprietary skin penetration enhancers -- MacroChem (Lexington, Massachusetts) and NexMed (Robbinsville, New Jersey) -- are developing cream-based formulations of alprostadyl for use in treating erectile dysfunction. Their skin penetration enhancers cannot be used to deliver macromolecules through the skin. Transdermics (Zichron Yaakov, Israel) claims to have achieved the transdermal delivery of insulin in a Phase II trial on Type 1 diabetics by using novel compounds that temporarily alter the cell membranes.
Active transdermal patches
Developers of transdermal drug delivery systems have turned to external sources of energy to increase movement (flux) of large molecular drugs in order to push them through the skin. Two approaches that are used to develop "active" transdermal patches are iontophoresis (low intensity electric current) and ultrasound (sonic energy), called sonophoresis. The iontophoretic technique is suited for drugs that are polar or ionic. lontophoretic devices have been used for many years as a topical treatment for edema and sports injuries. These devices discharge an electrical impulse and are connected by wires to skin-interfacing electrodes. The leading marketers of these products are Iomed (Salt Lake City, Utah) and Empi (St. Paul, Minnesota).
Alza (Palo Alto, California), which was acquired last year by Johnson & Johnson (New Brunswick, New Jersey), initiated in 1988 the development of a self-contained, disposable and electrically-driven transdermal patch. To date, no products have been commercialized using this electrotransport system, dubbed e-Trans. The most advanced e-Trans development program is for delivering fentanyl to treat acute and post-operative pain, which is in a Phase III clinical trial. The patient pushes a button on the device, causing current to flow between two electrodes and a predetermined amount of drug is released through the skin. This product is aimed at expanding the use of Alza's highly successful Duragesic brand transdermal fentanyl patch, which had estimated sales of $600 million in 2001 but is contraindicated for post-operative analgesia. Elan (Athione, Ireland) had undertaken to develop a disposable iontophertic patch, called PowerPatch, for delivering calcitonin to treat osteoporosis. However, work on this device was discontinued after a decade of development and was licensed to lomed. Similarly, BD (Franidin Lakes, New Jersey) had been developing an iontophoretic patch but exited the program. It was acquired by Vyteris (Fair Lawn, New Jersey), which is in a Phase III trial with an iontophoretic patch that is preprogrammed for the controlled delivery of lidocaine for rapid dermal anesthesia. It is projected to reach the market in about 15 months. This product is targeted at the pediatric population to quickly numb the site for inserting an IV or a syringe needle.
The concept behind use of ultrasound for transdermal drug delivery is that acoustic energy vibrates molecules to generate flux and also causes cavitation which creates tiny holes in the skin surface through which drugs can pass. Sontra Medical (Cambridge, Massachusetts), founded on research from the laboratory of Professor Robert Langer at Massachusetts Institute of Technology (also Cambridge), is developing the SonoPrep transdermal system for delivery of large molecules. It uses low frequency ultrasound for skin permeation as well as for extracting a sample of interstitial fluid for biochemical diagnosis, especially for monitoring glucose in blood. The company plans to conduct clinical trials for the transdermal delivery of a drug for pain control and for delivering insulin for diabetics.
ImaRx Therapeutics (Tucson, Arizona) is planning to develop an ultrasound-assisted transdermal system using its SonoRelease technology, an outgrowth of its work on ultrasound contrast agents. The company will use a conventional ultrasound transducer to activate a drug and open skin pores for enhanced transdermal delivery. ImaRx is collaborating with Elan on the development of an oncology product, the HydroPlex "smart bubble" drug delivery system, that wraps water soluble drugs in polymer strands to make them more soluble.
The ability to drive large molecules through intact skin using external energy sources has proven to be a more difficult challenge than was originally conceived. There are no products on the market after more than a dozen years of research and development on disposable transdermal drug delivery systems utilizing iontophoresis. Early expectations that this technology could be used to deliver large molecules haven't been realized. A principal shortcoming of iontophoresis is that the current levels need to be kept sufficiently low to avoid skin irritation or sensitization, thereby limiting its ability to drive large molecules through the skin surface. It is too early to draw any conclusions about the utility of ultrasound for this application.
Electroporation for producing transient pores
The application of a brief, carefully controlled, pulsed electric field to living cells causes a transient permeability in their outer membrane and the opening of pores that close a few minutes after the electric field is withdrawn. Genetronics Biomedical (San Diego, California) has developed the MedPulser electroporation therapy system for use in delivering pharmaceuticals and genes. The company's most advanced development program is a completed Phase II trial for treating head and neck cancer patients who were resistant to prior therapy or had a recurrence. Genetronics has approval to do a Phase Ill trial and is seeking a corporate partner. The electroporation procedure takes about 30 minutes. The MedPulser system received the CE mark in Europe in April 2001. An advantage of electroporation for cancer therapy is that a smaller dose of a chemotherapy drug is needed, thereby causing fewer and less severe side effects.
Thermal and RF energy
Zars (Salt Lake City, Utah) is developing a controlled heat-aided drug delivery (CHADD) system to enhance the transdermal passage of drugs. Skin permeability is increased by the application of heat. The CHADD system uses a thin heating device which is attached to the top of a transdermal patch. The temperature and heat duration are highly controlled and can be used with a drug depot to deliver a bolus or to match circadian rhythms. Zars has licensed its initial two anesthetic products, S-Caine and S-Caine Peel, to Ortho Dermatological, a division of Johnson & Johnson (New Brunswick, New Jersey). S-Caine is a proprietary formulation of lidocaine and tetracaine that uses CHADD technology for attaining a dense anesthetic effect in 15 to 20 minutes and is targeted for pediatric use. S-Caine Peel is an anesthetic cream that is applied to a large surface. It forms a rubbery mask that can be peeled off. It does not use heat and is being tested for use in pain relief from facial skin resurfacing procedures. A third unlicensed product, Titragesia, has completed a Phase I trial. It uses the CHADD system to deliver fentanyl for treating breakthrough pain that occurs with the use of the fentanyl transdermal patch. Other applications under consideration for the CHADD system are for delivering nicotine, testosterone and scopolamine. Zars also is developing a drug encased in a polymer that is implanted and external heat is used to release the drug.
Altea (Tucker, Georgia) has developed a method for passing drugs through microscopic openings in the stratum corneum that are created using its MicroPor system. The minuscule pores are made using an array of elements that are pulsed at a high temperature for a few milliseconds. The thermal energy is emitted by an electrically heated filament and can be precisely controlled. The MicroPor system can be used for the controlled delivery of large molecules. Initial applications to be developed are: an opiate for pain control, a-interferon for hepatitis B and C and insulin for Type 1 and Type 2 diabetics. Clinical studies using a prototype device have been conducted under institutional review board approval for each of these drugs and have demonstrated clinical feasibility. Altea is collaborating with Elan for the use of the MicroPor system to deliver DNA vaccines and for gene therapy. Altea's technology has application for use in biomedical diagnostics and was licensed in to SpectRx (Norcross, Georgia) for develo pment of a noninvasive glucose monitor in collaboration with Abbott Laboratories (Abbott Park, Illinois).
TransPharma Medical (Yehud, Israel) uses microscopic passageways for the controlled transdermal delivery of macromolecules. Radiofrequency energy is used to ablate the outer layer of skin (stratum corneum and upper epidermis), thereby creating microchannels of precise dimensions, called RFMicroChannels, that enable the controlled passage of small and large molecules through the skin via an applied adhesive patch. The initial product to be developed, ViaDerm, is a two-stage system consisting of a reusable handheld device that incorporates a disposable microelectrode array that transmits RE energy and a patch containing the drug that is applied after creating the microchannels. Its safety has been demonstrated in a human trial for single and repeat applications. Also under development is MicroDerm, an integrated, one-stage, disposable patch system containing both the mechanism for forming microchannels and the reservoir for the drug to be delivered.
Microneedles and microknives
Another approach for delivering large molecules through skin is to mechanically create holes in the stratum corneum. Several methods are under development, including hollow microneedles, solid microknives, a single tiny retractable needle and, as discussed above, thermally generated micropores.
NanoPass Technologies (Haifa, Israel) is using MEMS (microelectro-mechanical systems) technology to develop hollow microneedle devices for painless transdermal drug delivery and diagnostics. The devices were found to be suitable for delivery of large molecules in tests on rats. The microneedle array is mounted on a chip for use in its products which include: NanoSet, a chip integrated with an insulin pump for painless transdermal release of insulin, and NanoVac, a chip integrated with a drug reservoir for transdermal delivery of vaccines.
Biovalve (Worcester, Massachusetts) is developing products that are microfabricated using MEMS technology, based on the research of Professor Mark Prausnitz at the Georgia Institute of Technology (Atlanta, Georgia). Arrays of microneedles having a length of 150 [mu]m and a thickness of 3-5 [mu]m have been produced. The dimensions of the array can be varied to fit the end-use application such as for hypodermic syringes (in place of a long needle) or as a transdermal drug delivery device. Biovalve also is developing a transdermal patch, called e-Patch, that employs an electrochemical reaction that can push a large dose of drug contained in a reservoir through a microneedle array. The company says it has several strategic alliances with pharmaceutical companies.
Professor Dorian Liepmann at the University of California at Berkeley (Berkeley, California) has published his research on the use of MEMS to fabricate polysilicon microneedles and on continuous onchip micropumping through a microneedle. BD was a sponsor of his research.
Alza is developing Macroflux, a thin screen with precision microprojections (190 microprojections per sq. cm. with each knife of 330 [mu]m length). The screen is stamped from a sheet of titanium foil. The microprojections (microknives) can be coated with a drug or used in combination with a passive transdermal patch or with Alza's active e-Trans device. The solid microknives create channels through which a drug is transported. Macroflux is claimed to be painless when applied to the skin and to be suitable for delivering macromolecules such as proteins and vaccines. In preclinical trials, Macroflux used with e-Trans was found to deliver therapeutic levels of recombinant growth hormone and to deliver human insulin with retention of biological activity. When used alone, Macroflux has limited applications because it can only be used to deliver a small amount of a drug at a high concentration level. Alza, in collaboration with Theratechnologies (Montreal, Quebec), is in a Phase II trial using the Macroflux device to deliver ThGRF peptide for treating endocrine and metabolic disorders. Theratechnologies has FDA clearance to initiate a Phase II trial of ThGRF in patients with Type 2 diabetes.
Minimally invasive subcutaneous delivery
Elan has developed the MediPad, a minimally invasive, disposable transdermal device that contains a 5 mm needle for prolonged subcutaneous delivery of injectable compounds. The needle is designed with side orifices for uniform flow and to reduce back pressure, thereby preventing the drug from leaking to the skin surface. The MediPad uses controlled gas generation as the mechanism to initiate drug delivery. The gas compresses a membrane that forces the drug through a tiny needle and into the subcutaneous tissue. The Medipad provides continuous zero-order delivery for up to 48 hours. When the button on top of the MediPad is pushed, a tiny needle is inserted through the skin, and when the MediPad is removed, the needle collapses back into the device so it is not seen by the user. The most advanced program using the MediPad is a Phase II trial on more than 2,000 patients that is being conducted in collaboration with a major pharmaceutical company. The drug, which was not been disclosed, is released over two days . Elan had earlier announced two studies that use the MediPad device. They are a Phase I trial in a joint venture with Ribozyme Pharmaceuticals (Boulder, Colorado) for delivery of Herzyme ribozyme EGF receptor type 2, and a collaboration with MiniMed (Northridge, California), subsequently acquired by Medtronic (Minneapolis, Minnesota), for delivering insulin.
Transcutaneous immunization
Iomai (Gaithersburg, Maryland) is using trancutaneous immunization technology for delivering vaccines through a skin patch. The system uses cholera toxin, a potent adjuvant that induces an immune response, mixed with vaccine components such as diphtheria and tetanus toxoids and is applied to the skin surface. It produces an immune response without penetrating or disrupting the skin. This mixture is targeted at the Langerhans cells, immune cells that are located in the epidermis just below the stratum corneum. Iomai formed a joint venture with Elan in 1998 to develop vaccines and is in clinical trials on the transdermal delivery of flu and pertusis vaccines.

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Re: New developments improve transdermal delivery of drugs.(Brief Article) (english)
09 Jan 2005
kINDLY CONATCT ME AT himadri (at)