Transdermal, transcutaneous and topical delivery

Transdermal drug delivery system utilises intact skin as the port for continuous drug infusion as well as for rate controlled transdermal therapy bypassing the liver and GI metabolism of most of drugs, say Prof Vivek Ranjan Sinha, Jayant Rajaram Bhinge and Aman Trehan in the second part of the article

Several transdermal therapeutic systems have recently been developed for topical application on the intact skin surface to achieve systemic medication. Transdermal drug delivery system utilises intact skin as the port for continuous drug infusion as well as for rate controlled transdermal therapy bypassing the liver and GI metabolism of most of drugs.

With advent of biotechnology and recombinant DNA technology, various macromolecules are synthesised which are difficult to administer through skin because of poor skin permeability. But various techniques are coming into action to improve the permeability of such drugs such as sonophoresis, iontophoresis, electroporation, sonomacrophoresis along with permeability enhancers.

Sonophoresis utilises acoustic wave of frequency 20KHz to 20MHz, iontophoresis utilises small electric current, electroporation utilises a high-voltage (more than 100 V) pulse for a very short period of time (micro sec) and sonomacroporation utilises ultra sound waves (20KHz) of intensity in the range between two to 50 w/cm. All above techniques increases the permeability of skin through cavitation and makes delivery of large size molecules easier. Some of successful technologies are discussed as follows:

Macroflux technology

Alza Corporation has taken its leadership position in transdermal research and development to a new level with its latest innovation: Macroflux transdermal technology. Macroflux systems can be drug-coated for direct administration or can be used in combination with passive transdermal or electrotransport systems to significantly expand the delivery opportunities for synthetic drugs, therapeutic proteins and vaccines.

Macroflux transdermal technology incorporates a thin titanium screen with precision microprojections that, when applied to the skin, creates superficial pathways through the skin’s dead barrier layer allowing transport of macromolecules.

The screen has an area up to 8 cm2 with less than 300 micro-projections per cm2. Each microprojection having length of less than 200 mm with adhesive patch size 10 cm2. Figure 3 shows macroflux system.

Macroflux technology is a needle-free alternative for fast and efficient bolus drug delivery.

Macroflux promotes high drug utilisation and rapid drug onset in preclinical tests. Macroflux has shown peak therapeutic drug plasma levels equivalent to injections within one hour after administration.

Macroflux can provide reproducible, uniform drug delivery through an efficient tip-coating process and a reusable applicator. Preclinical testing has shown optimal skin tolerability with Macroflux.

Phoresor PM 850 &900

IOMED Inc’s Phoresor Iontophoretic Drug Delivery System is indicated for the administration of soluble salts and other drugs into the body for medical purposes as an alternative to hypodermic injection in situations when it is advisable to avoid the pain that may accompany needle insertions and drug injection, minimise the infiltration of carrier fluids and avoid the damage caused by needle insertion when tissue is traumatised.

The PM850 allows the user to deliver a specific dose from 0 to 80 mA-minutes and to control the current from 0 to 4 mA. The Phoresor II Auto automatically calculates required time for the selected dose, even if the current setting is changed during treatment.

Current ramp-up and down, shut-off, error messages and safety checks are also performed automatically.

The built-in option for manual current shut-off is an added safety feature. The large display provides a continuous update of dose delivered, time remaining and current setting. The PM900 is a new, compact iontophoretic dose controller that makes administering iontophoretic treatments as simple as pressing a button. The PM900 is easy to operate, fast to set-up and effective. In as little as 10 minutes, the PM900 delivers a therapeutic dose.

Thermophobic Mousse

In collaboration with Soltec Research Pty Ltd, Miparm has developed a thermophobic mousse as a new transcutaneous delivery system.

The technology uses a temperature activated mousse which, when applied to the skin, rapidly melts and evaporates allowing sustained penetration of the active compound.

The mousse has significantly lower evaporation time than lotion and experimental studies have shown that the thermophobic mousse allows a six-fold increase in transcutaneous penetration of the active compound in comparison with lotions. This improvement in pharmacokinetics results in significantly higher clinical efficacy when compared to lotion formulations.

Mipharm has already marketed two products based on the thermophobic mousse technology: Milice for the treatment of head lice, and Bettamousse for the treatment of scalp dermatoses. In trials comparing Bettamousse with standard betamethasone treatments, the thermophobic mousse product showed significantly higher cutaneous absorption and clinical efficacy.

Thermophobic mousse formulations also underpin four of Mipharm’s pipeline products: a clobetasol based mousse for the treatment of moderate to severe corticosteroid-responsive scalp dermatoses; a new formulation for the treatment of androgenic alopecia; new vitamin E formulation for the treatment of dry skin; and a ketoconazole mousse for the treatment of dandruff and seborrheic dermatitis.

Liquipatch

This technology developed jointly by Mipharm and Soltec Research Pty Ltd utilities a novel, multipolymer film-forming gel matrix system for topical and transdermal delivery of active drugs. When applied to the skin, Liquipatch quickly dries to an invisible water-resistant film. Liquipatch improves pharmacokinetics producing a six-fold times increase in the cutaneous penetration of active compounds. Mipharm’s Acyclovir Liquipatch for the cold sores treatment is under developmental stages.

Crystalip

Crystalip technology by Mipharm consists of two monoglycerides forming multilamellar crystals including a selected active ingredient. The organisation of this structure changes depending on temperature. At ambient temperature the structure is rigid preserving the active ingredient from alteration. At skin temperature, after the application, the crystal structure partially loses its rigidity releasing the active ingredient.

Based on Crystalip technology it is possible to obtain a product with high stability and controlled active release. Mipharm is already marketing a Crystalip formulation including hydrogen peroxide for the topical treatment of skin bacterial and fungal infections.

FloGel (Alliance)

FloGel is a thermo-reversible gel technology based on the use of biocompatible poloxamers made up of polyoxyethylene and polyoxypropylene units. FloGel, which contains poloxamer 407 as a primary ingredient, can be manufactured in a variety of formulations with specific physical and chemical properties.

The most significant physical characteristic of FloGel is its ability to change from a liquid to a gel upon warming to body temperature. This characteristic allows for manipulation of the polymer product in its liquid state and conversion to a desired solid state (gel) in or on the body of the patient.

FloGel in the liquid state will mold to body/tissue contours before gelling in place. Thus, FloGel maintains contact with the tissue surface and serves as a physical, protective barrier. It has the potential to serve as a depot for an included drug that would be available to the adjacent tissue(s).

FloGel has been demonstrated in preclinical and early clinical studies to be non-toxic, non-irritating and pharmacologically inert. It dissolves in the body and is cleared by the normal excretory processes. FloGel is osmotically controlled, adjusted to body pH, sterile, manufactured from commercially available National Formulary Grade polymer, and has good storage stability. FloGel is currently being developed for the reduction of postsurgical adhesions in gynaecologic surgeries. Alliance is investigating other applications of FloGel, including: reduction of adhesions related to other surgeries, drug delivery, wound healing.

WEDD

Wearable Electronic Disposable Drug delivery (WEDD) from Birch Point Medical Inc is a self-contained, portable and disposable patch designed to be worn on the surface of the skin and to deliver medication across the skin (ie, transdermally) into the body. This process is commonly called iontophoresis.

The primary enabling feature of WEDD is a proprietary, ultra thin, flexible and low cost battery technology that provides an electric field to propel medication across the skin. The battery technology can deliver a range of adjustable energy profiles that, in turn, produce a range of drug delivery rate profiles, including the potential for patient control. WEDD strengths include; Efficacy, safety, convenience/compliance, cost-effective.

SEPA

Soft Enhancement of Percutaneous Absorption technology (SEPA) developed by MacroChem Corporation consists of a novel skin permeation enhancer, SEPA, which has been shown to possess broad-spectrum absorption-enhancement activity and appears to be tolerated at effective concentrations. Extensive chemical, pharmacology, toxicology and carcinogenicity studies have demonstrated that SEPA is an inert excipient that does not chemically interact or otherwise alter any known drug or compound with which it has been combined.

SEPA is an acronym for “Soft Enhancement of Percutaneous Absorption,” where “soft” refers to the reversibility of the skin effect, and “percutaneous” means “through the skin.” MacroChem synthesises SEPA by condensing ethylene glycol and decyl aldehyde (decanal).

MacroChem’s SEPA is an absorption enhancer that works with a wide range of drugs that are otherwise absorbed only minimally or not at all when applied to the skin. SEPA enhances skin penetration by altering the fluidity of the lipid layers in the stratum corneum. Those lipids surround the skin cells of the stratum corneum the way mortar surrounds bricks in a wall. SEPA temporarily alters the alignment of those lipids allowing drug molecules to slip through.

Dermastick

Sky Pharmaceuticals’ DermaStick presents the active ingredient in a wax stick, which facilitates controlled application to the affected skin. One of the general problems of topical products is that they are often accidentally applied to unaffected areas of the skin as well as the area requiring treatment. This can lead to increased side effects such as skin irritation.

The DermaStick technology offers a convenient formulation for high potency or irritant drugs and allows treatment of the infected area only. A major problem with other stick technologies is to achieve a homogenous product. The active is usually suspended in the molten vehicle, which can lead to sedimentation of the drug during the solidification process. Dermastick in contrast keeps the active solubilised thereby allowing manufacture of homogenous sticks with uniform drug distribution throughout the matrix. Table No. 3 gives glimpse of other novel topical technologies.

Technologies for insoluble drugs

Most of the potentially useful drugs suffer from the problem of the solubility, which may be the rate limiting step in absorption (eg. drug from class BCS II i.e. drugs with good permeability but poor solubility), therefore the problem of solubility affects the rate and extent of drug in plasma and at receptor site. Now-a-days, most of the pharmaceutical companies are developing innovative technologies to over come the problem of solubility. These technologies improve the solubility of insoluble drugs.

SMP technology

The SMP technology from Atrix Laboratories allows the topical delivery of highly water-insoluble drugs. The product combines a dissolved drug with a microparticle suspension of the drug to allow a controlled amount of the dissolved drug to permeate the epidermal layer of the skin. Drug permeates by partitioning and diffusion mechanism. The SMP system works in four stages:

• Product is applied to the skin surface
• Product near follicle concentrates at the skin pore
• Drug readily partitions into skin oils
• Drug diffuses throughout the area

Atrix is currently conducting additional phase III trials for Atrisone, dapsone topical gel in SMP technology, for moderate to severe acne. Dapsone is a highly water insoluble drug that formerly was not bio-available topically.

The SMP delivery system makes topical delivery of this antibiotic possible. In addition to these applications, SMP is well suited for delivering nucleoside analogues as antiviral therapies, antifungals, and any active compound that would be delivered optimally by targeting the pilosebaceous follicle.

Ocular drug delivery

Ocular drug delivery is one of the most interesting and challenging fields. When drug is delivered to eye, it gets drained away from precorneal area. In a non-blinking state cul-de-sac of eye can occupy 30 ml of solution but natural tendency reduces its volume to 7-10 ml. Also the drug is lost through nasolacrimal drainage. It is a challenge for drug delivery scientists to extend the release of drug by ocular delivery.

Various techniques are developed by number of companies and following gives a glimpse of some of them.

OcuPhor

Eye drops are useful in treating conditions affecting either the exterior surface of the eye or tissues in the front of the eye, but cannot penetrate to the back of the eye for treatment of retinal diseases.

To meet these needs, Iomed Inc has developed a novel ocular iontophoresis system (OcuPhor) to deliver drugs safely and noninvasively to the back of the eye. The OcuPhor system consists of drug applicator, dispersive electrode, and an electronic iontophoresis dose controller.

The drug applicator is a small silicone shell that contains a patented silver-silver chloride ink conductive element; a hydrogel pad to absorb the drug formulation; and a small, flexible wire to connect the conductive element to the dose controller.

The drug pad is hydrated with drug solution immediately prior to use, and the applicator is placed on the sclera of the eye under the lower eyelid. Preliminary clinical studies in human volunteers have shown that the OcuPhor system is well tolerated over a wide range of both positive and negative polarity currents and does not produce any ophthalmic changes as measured by a series of standard tests.

(To be concluded)

The writers are with the University Institute of Pharmaceutical Sciences Punjab University, Chandigarh. Email: vrsinha@yahoo.com