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Pharmaceutical Manufacturing and Packing Sourcer

Under The Skin

Robert Falcone of the New Jersey Institute of Technology and Bozena Michniak-Kohn of the State University of New Jersey discuss current technologies for transdermal delivery and highlight its clinical benefits as a means of providing controlled release formulations

Many drugs have a high hepatic extraction ratio – also known as first pass metabolism – and therefore the amount in the systemic circulation is much lower than the required dose needed to achieve the desired therapeutic effect (1). This effect is seen as a temporary increase of the drug level in the bloodstream and is followed by its decrease until the next time the drug is re-administered as shown in Figure 1a (2).

The main objective when administering medications is to maintain the drug levels in the bloodstream between the maximum value (toxic level), and the minimum value (below the effective level). The most effective way to achieve the delivery of the active ingredient at the effective therapeutic level is with controlled delivery systems (see Figure 1b) (2).

The skin is the largest organ in the human body with a surface area between 1-2m2 and is therefore the most accessible drug administration site. Administering drugs transdermally can avoid first pass metabolism along with gastrointestinal effects, and results in greater patient compliance, hence making it the best alternative for drug delivery. The skin has been successfully used as a means of achieving local pharmacological action (topical) or systemic effects (transdermal delivery) for a limited set of drugs. In order to extend the application of transdermal delivery to more agents for different therapeutic areas, various techniques have been investigated over the years. These techniques range from chemical enhancement to transdermal patches; an overview of these systems is provided in this article.

CHEMICAL PERMEATION MODIFIERS (CPM)

Several physical and chemical methods have been used with varying success to deliver therapeutic agents across the layers of the skin (3,4). However, CPMs are seen as the best economical alternatives for drug delivery (5). Their mechanism of action is thought to rely on the fact that they can act as modifiers to the intercellular lipid arrangement of the stratum corneum (SC) or the protein composition of skin.

Within CPMs there is a class of compounds that limits rather than enhances the permeation of actives across the skin – these are referred to as retardants (6). Retardants are used when there is an undesirable degree of transdermal permeation leading to serious toxic systemic effects. Examples range from household chemicals to cosmetic products (7). The mechanism of action of retardants is still not well understood.

The applications for CPMs extend to many topical and transdermal formulations. Enhancers have been used to improve the delivery of therapeutic agents ranging from anti-hypertensives (such as clonidine) to hormone replacement drugs (8). However, the use of retardants is limited to fields where permeants show systemic toxicity or undesired systemic absorption.

VESICLES

Liposomes One of the most studied forms of vesicles for drug delivery is liposome-lipid based carriers. Conventional liposomes are composed of phospholipids and cholesterol (CH), and the composition of these lipids can affect the properties of the resulting dosage forms. Typically, liposomes can range from 0.02 to 10μm in diameter, and can either form small or large unilamellar or multilamellar vesicles containing concentric lipid bilayers that encapsulate aqueous compartments (9).

Transfersomes

Transfersomes or ultradeformable liposomes were the earliest elastic vesicles investigated by Cevc and Blume in the 1990s. These vesicles consist of phospholipids, water and surfactants such as sodium cholate (10). They are deformable and can squeeze through water channels in the SC, resulting in transdermal delivery of the encapsulated agent. In non-occluded conditions, the transfersomes dehydrate on the skin’s surface producing a hydration gradient between the dry skin surface and the hydrated skin tissue beneath. This gradient, in addition to xerophobia (tendency to avoid dry surroundings) and the extreme deformability incorporated by the surfactants, enables the intact vesicles to squeeze between the cells in the SC (11).

Ethosomes

Ethosomes are another form of lipid vesicles that differ from other systems in terms of their composition, mechanism and structure. The ethosomal systems consist of phospholipids, water and ethanol, where the ethanol concentration can be as high as 20 to 45 per cent, thus conferring a negative net charge on the surface and leading to a decrease in vesicle size (12). The permeation enhancement for drugs from ethosomes has been shown to be higher than from hydroethanolic solutions, suggesting that the delivery mechanisms of ethosomes extend beyond the enhancement effects of ethanol in skin.

Niosomes

Niosomes are non-ionic surfactant vesicles that were initially proposed as delivery systems intended for the deposition of cosmetics onto the skin. Niosomes consist of amphiphiles and aqueous solvents containing lipid bilayers surrounded by aqueous cores. Though they primarily contain surfactants, the properties of these carriers can be altered by incorporation of excipients such as cholesterol.

Some of the notable clinical developments in vesicular skin delivery include the testing of new product candidates based on ultradeformable vesicles. Successful systemic delivery of macromolecules such as insulin by means of transfersomes has been reported (13). In 1996, the estimated worldwide sales share in the cosmetic market due to liposomal preparations was $3 to 4 billion and has been growing ever since. In terms of overall outlook, delivery to the skin using vesicular formulations has great potential, but final applications depend entirely on the type of vesicles used, other formulation excipients, drug of interest, the method of preparation and the effect desired.

IONTOPHORETIC TRANSDERMAL DRUG DELIVERY (TDD)

Physical enhancement methods constitute electrically (iontophoresis, electroporation), mechanically (microneedles) and velocity-based techniques (jet-propulsion), along with other methods such as ultrasound, laser and photomechanical waves (14). Transdermal iontophoresis uses low level electric current (~0.5mA/cm2) to enhance the transdermal delivery of charged substances through the skin, and has been studied extensively over the past few years.

As defined by 21 CFR Part 890 Sec 890.5525, an iontophoretic device is one that is intended to use a direct current to introduce ions of soluble salts or other drugs into the body as long as the labelling of the drug intended for use with the device bears adequate directions for the device’s use with the prescribed drug.

Over the years, iontophoretic devices for drug delivery and for non-invasive blood monitoring have been developed and successfully commercialised.

ULTRASOUND – SONOPHORESIS

Ultrasound, also commonly known as sonophoresis and phonophoresis, is the application of ultrasonic energy to enhance percutaneous drug delivery (16). The mechanical energy delivered by ultrasonic treatment is obtained by passing an alternating current through a piezoelectric crystal, causing it to vibrate. The stratum corneum consists of lipid/water bi-layers acting as a barrier that limits the penetration of substances through the skin. Drug molecules with a molecular weight less than 500 Daltons can pass through this barrier while others are repelled. This is due to the microscopic gaps between the lipid heads of the bilayers being too small to allow them through. Application of ultrasound to the skin increases the drug’s permeability enabling the delivery of various substances into and through the skin that would not be feasible with any other type of transdermal delivery system. There are several studies in progress that have shown great potential and this technology is being considered as the next generation of TDDs.

TRANSDERMAL FORMULATIONS: LIQUIDS, SEMI-SOLIDS, & SOLIDS

Transdermal formulations range from simple solutions to more sophisticated multiphasic emulsions. The vehicle, defined as the sum of all ingredients in which the drug resides when it comes into contact with the skin, must have certain important qualities such as ensuring solubility and stability of the active ingredient, providing proper release, and resisting microbial growth. In addition, it must have a cosmetically aesthetic look and feel. Selection of the proper vehicle can make an active ingredient more readily bioavailable. The vehicle can be monophasic, biphasic or multiphasic and divided into liquid, semisolid and solid groupings (17). Recent technological improvements have taken the guess work out of formulation as machines have been created for mass production, which use scientific endpoints until a few optimised formulations are found (17,18). Smith has classified the most common vehicles with the state of matter and the number of phases into two key variables (see Table 1) (17).

Table 1: Classification of transdermal formulations
Formulation Monophasic Diphasic Multiphasic 
Liquid Nonpolar solution (oil) Emulsion (lotion, shake) Emulsion (o/w/o, w/o/w)
Polar solution (paint, lotion) Suspension (paint, shake) Suspension
Semisolid Ointment Emulsion (creams) Emulsion with powder (cream pastes)
Gel Suspension (paste)
Solid  Powder Transdermal patch Transdermal patch

CLINICAL BENEFITS OF TRANSDERMAL FORMULATIONS

Apart from avoiding first-pass metabolism, the transdermal route of drug delivery has recently focused on providing controlled release formulations. These formulations can provide both increased patient convenience and compliance because they can be applied at far less regular intervals. Paediatric, surgical and geriatric patients who suffer from gastrointestinal side effects are often good candidates for transdermal therapies. Many drugs, mostly potent lipophilic drugs, ranging from analgesics to nicotine treatments, have been developed into sustained release products that have successfully gone through clinical trials into commercial use.

TRANSDERMAL PATCHES (TDPS)

The first TDP was approved by the FDA in 1979 to treat motion sickness. The main components of TDPs are adhesives, permeation enhancers and, in some cases, a rate-controlling polymeric membrane. Different groups have patented different adhesive resins, permeation enhancers, polymeric membranes and their combinations in formulations (see Table 2, page 28).

Table 2: Examples of commercially available transdermal patches
Active ingredient Product name Company  Dose delivered  Clinical indications/marketing status 
Fentanyl Duragesic Ortho McNeil Janssen  12.5, 25, 50, 75, 100mg/hour Analgesia/Prescription
Fentanyl Mylan Technologies 12.5, 25, 50, 75, 100μg/hour Analgesia/Prescription
Selegiline Emsam Somerset 3, 9, 12mg/hour  Major depression/Prescription
Oestrogen Climara Bayer Healthcare 0.0375, 0.025, 0.05, 0.06, 0.075, 0.1mg/24-hour Menopausal symptoms/Prescription
Estradiol Alora Watson Labs 0.025, 0.05, 0.075, 0.1mg/24-hour Menopausal symptoms/Prescription
Estraderm Novartis 0.05, 0.1mg/24-hour Menopausal symptoms/Prescription
Menostar Bayer Healthcare 0.014mg/24 hour Osteoporosis after menopause/Prescription
Rivastigimine Exelon Novartis 4.6mg, 9.5mg/24-hour Mild to moderate dementia/Prescription
Nicotine  Nicoderm CQ Sanofi Aventis US 7, 14, 21mg/24-hour Smoking cessation/Over the counter (OTC)
Habitrol

Novartis

7, 14, 21mg/24-hour Smoking cessation/OTC
Scopolamine Transderm Scop Novartis 1mg/72-hour Motion sickness/Prescription
Nitroglycerin  Nitro-dur Key Pharms 0.1, 0.2, 0.3, 0.4, 0.6, 0.8mg/24-hour Angina/Prescription

CONCLUSION

A Fuji-Keizai report estimated that the US drug delivery market would reach $91 billion by 2009-10 (19). The annual US market for transdermal devices is approximately 10 per cent of the entire drug delivery market, and this market is based on just a few drugs (shown in Table 2). Hence, pharmaceutical companies are continuously striving to develop more drugs that can be delivered by the transdermal route.

Acknowlegment

For their work on this article the authors would like to thank Brian Kilfoyle, Diksha Kaushik, Priya Batheja and Vishwas Vrai of The Ernesto Mario School of Pharmacy, Rutgers, The State University of New Jersey, and Longsheng Hu of Johnson & Johnson.

References

  1. Gibaldi M and Perrier D, Pharmacokinetics, Second Edition, Informa Healthcare, vol 15: p494, 2007
  2. Brannon-Peppas L, Polymers in Controlled Drug Delivery, Medical Plastics and Biomaterials Magazine, Nov 1997
  3. Kumar MG and Lin S, Transdermal iontophoresis: impact on skin integrity as evaluated by various methods, Crit Rev Ther Drug Carrier Syst 25(4): pp381-401, 2008
  4. Hakozaki T, Takiwaki H, Miyamoto K, Sato Y and Arase S, Ultrasound enhanced skin-lightening effect of vitamin C and niacinamide, Skin Res Technol 12(2): pp105-113, 2006
  5. Williams AC and Barry BW, Penetration enhancers, Adv Drug Deliv Rev 56(5): pp603-618, 2004
  6. Strekowski L, Henary M, Kim N and Michniak BB, N-(4-bromobenzoyl)-S,S-dimethyliminosulfurane, a potent dermal penetration enhancer, Bioorg Med Chem Lett 9(7): pp1,033-1,034, 1999
  7. Schlumpf M, Schmid P, Durrer S, Conscience M, Maerkel K, Henseler M, Gruetter M, Herzog I, Reolon S, Ceccatelli R, Faass O, Stutz E, Jarry H, Wuttke W and Lichtensteiger W, Endocrine activity and developmental toxicity of cosmetic UV filters – an update, Toxicology, 205(1-2): pp113-122, 2004
  8. Prausnitz MR, Mitragotri S and Langer R, Current status and future potential of transdermal drug delivery, Nat Rev Drug Discov 3(2): pp115-124 2004
  9. Moghimi SM and Patel HM, Current progress and future prospects of liposomes in dermal drug delivery, J Microencapsul 10(2): pp155-162, 1993
  10. Cevc G, Schatzlein A and Blume G, Transdermal drug carriers: basic properties, optimization and transfer efficiency in the case of epicutaneously applied peptides, J Controlled Release 36: pp3-16, 1995
  11. Cevc G and Blume G, Lipid vesicles penetrate into intact skin owing to the transdermal osmotic gradients and hydration force, Biochim Biophys Acta 1104(1): pp226-232, 1992
  12. Touitou E et al, Ethosomes – novel vesicular carriers for enhanced delivery: characterization and skin penetration properties, J Control Release 65(3): pp403-418, 2000
  13. Cevc G, Transdermal drug delivery of insulin with ultradeformable carriers, Clin Pharmacokinet 42(5): pp461-474, 2003
  14. Brown MB et al, Dermal and transdermal drug delivery systems: current and future prospects, Drug Deliv 13(3): pp175-187, 2006
  15. FDA, Drugs@FDA, Food and Drug Administration, 2008
  16. Kydonieus A, Treatise on Controlled Drug Delivery, p373, Marcel Dekker, 1992
  17. Smith E, Surber C, Tassopoulos T and Maibach H, Topical Dermatological Vehicles: An Holistic Approach, in Topical Absorption of Dermatological Products, Bronaugh R, Maibach H (eds), Marcel Dekker, vol 21, 2002 
  18. Bysouth S, Hite SI, Nettleton-Hammond J, Bergstrom K, Bohara A, Landham R and Lukkari I, Preparation and characterization of formulations in a high throughput mode, US Patent 7501094
  19. Fuji Keizai U, US Market Advanced Drug Delivery Systems54 Probing the Route to Growth, Fuji Keizai USA, p166, 2006

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Robert Falcone holds both a BSc in Physical Chemistry and an MSc in Chemical Engineering. He is presently completing a PhD in Materials Science and Engineering at the New Jersey Institute of Technology in the research area of transdermal patch technologies. He is also working as a Consulting R&D Director for several consumer products companies, and holds several patents (US and EU).

Bozena Michniak-Kohn obtained her PhD in Pharmacology in 1980 from DeMontfort University. Currently she is Professor of Pharmaceutics at the Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey and is the Director of the Laboratory for Drug Delivery of the New Jersey Center for Biomaterials (NJCBM). She holds a variety of industry positions and serves on several boards, as well as acting as the Engineering Research Center (ERC) Liaison to the FDA.

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