Climara (Estradiol). Matrix. 7 days. CombiPatch. (Estradiol/-Norethindrone acetate). Matrix. 3 to 4 days. Duragesic. (Fentanyl). Membrane. 72 hours. Esclim.
International Journal of Advances in Pharmaceutical Sciences 1 (2010) 201-211 http://www.arjournals.org/ijoaps.html Review
ISSN: 0976-1055
Transdermal Drug Delivery System- Design and Evaluation 1
Eseldin Keleb , Rakesh Kumar Sharma2*, Esmaeil B mosa2, Abd-alkadar Z aljahwi2
*Corresponding author: Rakesh Kumar Sharma 1. Faculty of Pharmacy, Al-Fateh University, Tripoli, Libya 2. Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, AL-Mergeb University, AL-khooms, Libya. E mail: rks19761(at)rediffmail.com
Abstract The human skin is a readily accessible surface for drug delivery. Skin of an average adult body covers a surface of approximately 2 m 2 and receives about one-third of the blood circulating through the body. Over the past three decades, developing controlled drug delivery has become increasingly important in the pharmaceutical industry. The human skin surface is known to contain, on an average, 10-70 hair follicles and 200-250 sweat ducts on every square centimeters of the skin area. It is one of the most readily accessible organs of the human body. The potential of using the intact skin as the port of drug administration to the human body has been recognized for several decades, but skin is a very difficult barrier to the ingress of materials allowing only small quantities of a drug to penetrate over a period of time. During the past decade, the number of drugs formulated in the patches has hardly increased, and there has been little change in the composition of the patch systems. Modifications have been mostly limited to refinements of the materials used. The present article reviews the selection of drug candidates suitable to be formulated as Transdermal system and the methods of evaluation. Keywords:Transdermal; Drug Delivery; TDDS
Introduction Optimum therapeutic outcomes require not only proper drug selection but also effective drug delivery. The human skin is a readily accessible surface for drug delivery. Over the past three decades, developing controlled drug delivery has become increasingly important in the pharmaceutical industry. The pharmacological response, both the desired therapeutic effect and the undesired adverse effect, of a drug is dependent on the doi:10.5138/ijaps.2010.0976.1055.01026
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concentration of the drug at the site of action, which in turn depends upon the dosage form and the extent of absorption of the drug at the site of action. Skin of an average adult body covers a surface of approximately 2 m 2 and receives about one-third of the blood circulating through the body. Skin contains an uppermost layer, epidermis which has morphologically distinct regions; basal layer, spiny layer, stratum granulosum and upper most stratum corneum, it consists of highly cornified (dead) cells
Keleb et al. International Journal of Advances in Pharmaceutical Sciences 1 (2010) 201-211 embedded in a continuous matrix of lipid membranous sheets. These extracellular membranes are unique in their compositions and are composed of ceramides, cholesterol and free fatty acids. The human skin surface is known to contain, on an average, 10-70 hair follicles and 200250 sweat ducts on every square centimeters of the skin area. It is one of the most readily accessible organs of the human body. The potential of using the intact skin as the port of drug administration to the human body has been recognized for several decades, but skin is a very difficult barrier to the ingress of materials allowing only small quantities of a drug to penetrate over a period of time. Transdermal drug delivery—the delivery of drugs across the skin and into systemic circulation—is distinct from topical drug penetration, which targets local areas. Transdermal drug delivery takes advantage of the relative accessibility of the skin. Advantages of Transdermal Drug Delivery Transdermal drug delivery offers several important advantages over more traditional dosage forms. The steady permeation of drug across the skin allows for more consistent serum drug levels, often a goal of therapy. Intravenous infusion also achieves consistent plasma levels, but it is more invasive than transdermal drug delivery. • The lack of peaks in plasma concentration can reduce the risk of side effects. Thus, drugs that require relatively consistent plasma levels are very good candidates for transdermal drug delivery. In addition, if toxicity were to develop from a drug administered transdermally, the effects could be limited by removing the patch. • Another advantage is convenience, especially notable in patches that require only once weekly application. Such a simple dosing regimen can aid in patient adherence to drug therapy. Transdermal drug delivery can be used as an alternative route of administration
to accommodate patients who cannot tolerate oral dosage forms. It is of great advantage in patients who are nauseated or unconscious. Drugs that cause gastrointestinal upset can be good candidates for transdermal delivery because this method avoids direct effects on the stomach and intestine. Drugs that are degraded by the enzymes and acids in the gastrointestinal system may also be good targets. First pass metabolism, an additional limitation to oral drug delivery, can be avoided with transdermal administration. Disadvantages of Transdermal Drug Delivery The first TDDS was developed for scopolamine for motion sickness in 1981. Since then many TDDS have appeared in market with great success. In spite of the therapeutic success achieved in last 28 years by using TDDS, the number of TDDS available in the market place is very few. This is mainly due to inherent limitations of the TDDS listed below One of the greatest disadvantages to transdermal drug delivery is the possibility that a local irritation will develop at the site of application. Erythema, itching, and local edema can be caused by the drug, the adhesive, or other excipients in the patch formulation. For most patients, site rotation can minimize irritation. However, some patients develop severe allergic reactions to transdermal patches, and, in these cases, therapy must be discontinued. Another significant disadvantage of transdermal drug delivery is that the skin's low permeability limits the number of drugs that can be delivered in this manner. Because the skin serves protective functions, it inhibits compounds from crossing it. Many drugs with a hydrophilic structure permeate the skin too slowly to be of therapeutic benefit. Drugs with a lipophillic character, however, are better suited for transdermal delivery. Many of the recent developments in transdermal drug
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Keleb et al. International Journal of Advances in Pharmaceutical Sciences 1 (2010) 201-211 delivery target the more hydrophilic compounds that were previously undeliverable via this method. In order to maintain consistent release rates, transdermal patches contain a surplus of active molecule. A stable concentration gradient is the mechanism used to maintain consistent release rates and constant serum drug levels. Most transdermal patches contain 20 times the amount of drug that will be absorbed during the time of application. Thus, after removal, most patches contain at least 95% of the total amount of drug initially in the patch. Therefore; patients must exercise care when disposing of patches. Each patch should be folded in half and the adhesive sides should be stuck together. As an additional precaution, patches may be flushed down the toilet rather than discarded in household trash, where children and pets may find them and ingest the remaining drug. Damage to a transdermal patch, particularly a membrane or reservoir patch, can result in poor control over the release rate. The release rate from a damaged patch would more likely be controlled by the skin than the patch, resulting in a higher, perhaps toxic, rate of drug delivery. Patients should be advised to discard a patch if the outer packaging or the patch itself appears damaged or altered in any way. Routes of Traditional Transdermal Drug Penetration [1,5,6] There are two main pathways by which drugs can cross the skin and reach the systemic circulation. The more direct route is known as the transcellular pathway. By this route, drugs cross the skin by directly passing through both the phospholipid membranes and the cytoplasm of the dead keratinocytes that constitute the stratum corneum. Although this is the path of shortest distance, the drugs encounter significant resistance to permeation. This is because the drugs must cross the lipophilic membrane of each cell, then the hydrophilic cellular contents containing
keratin, and then the phospholipid bilayer of the cell one more time. This series of steps is repeated numerous times to traverse the full thickness of the stratum corneum. Few drugs have the properties to cross via this method (FIGURE 1).
Fig 1: Diagram of skin structure The more common pathway through the skin is via the intercellular route. Drugs crossing the skin by this route must pass through the small spaces between the cells of the skin, making the route more tortuous. Although the thickness of the stratum corneum is only about 20 µm, the actual diffusional path of most molecules crossing the skin is on the order of 400 µm. The 20-fold increase in the actual path of permeating molecules greatly reduces the rate of drug penetration (FIGURE 2)
Fig 2: Various routes of drug absorption
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Keleb et al. International Journal of Advances in Pharmaceutical Sciences 1 (2010) 201-211 designed matrix patches, however, the decrease in release rate is so slight that it does not significantly affect the rate of drug absorption (FIGURE 4). The first transdermal patches incorporated the reservoir technology, and this type of patch maintains a reasonable share of the market. However, most transdermal patches reaching the market today use the matrix technology. Matrix patches may be smaller and thinner than their reservoir predecessors due to advances in design. Therefore, these new patches have the benefit of improved patient acceptability.
A less important pathway of drug penetration is the follicular route. Hair follicles penetrate through the stratum corneum, allowing more direct access to the dermal microcirculation. However, hair follicles occupy only 1/1,000 of the entire skin surface area. Consequently, very little drug actually crosses the skin via the follicular route. Reservoir/Membrane Transdermal Patches [6-8] There are two traditional designs for transdermal patches. With the membrane, or reservoir, system, a membrane that lies between the drug and the skin controls the rate of release from a reservoir. This patch design can provide a true zero-order release pattern to achieve a constant serum drug level (FIGURE 3).
Fig 4: Matrix System Product Development [1] [6] [9-10] Because of the uniqueness of this dosage form, the following questions need to be answered to define the final product
Fig 3: Reservoir/ Membrane system MATRIX TRANSDERMAL PATCHES The second type of traditional transdermal patch is the matrix system. The active drug in this type of patch is contained in a polymer matrix. The drug is released at a rate governed by the components in the matrix. In a matrix patch, the drug, adhesive, and polymer matrix are combined. Matrix patches are not designed to provide true zero-order release because as the drug closest to the skin is released, the drug deeper within the patch must travel a longer distance to reach the skin. The longer diffusional path slows the rate of absorption from the patch over time. For most well-
1. 2. 3. 4. 5.
Target therapeutic concentration Dose to be delivered Maximum patch size acceptable Preferred site of application Preferred application period (daily, biweekly, weekly, etc)
Once the preferred final product description has been established, an evaluation of the drug candidate begins. Because of the limitation of loading dose in a patch and a practical patch size, not all drugs can be candidate for transdermal drug delivery (Table 1)
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Keleb et al. International Journal of Advances in Pharmaceutical Sciences 1 (2010) 201-211 Table 1: Ideal Properties of a Transdermal Drug Delivery System Properties Shelf life Patch size Dose frequency Aesthetic appeal Packaging
Skin reaction Release
Comments Up to 2 years < 40 cm2 Once a daily to once a week Clear, tan or white color Easy removal of release liner and minimum number of steps required to apply Non irritating and nonsensitizing Consistent pharmacokinetic and pharmacodynamic profiles over time
The product development of a transdermal formulation generally includes the following stages: • Selection of drug candidate • Selection of the appropriate physical form (e.g., acid, base, or salt) • Selection of the desired design (e.g., reservoir, matrix, etc.) • Preparation of prototype formulations and testing of their physicochemical properties (tack, shear, peel adhesion, skin adhesion, etc.) • Evaluation of in vitro permeation • Development of analytical methods to quantitate drug in the formulation, skin layers, release medium, and blood (if applicable) • Evaluation of potential for systemic adverse events (e.g., carcinogenicity, teratogenicit mutagenicity, etc.) • Evaluation of skin toxicity (irritation, sensitization. etc.) in animals and humans • Microbial and preservative testing, if necessary • Phase I, 11, and III human clinical trials • Scale-up activities including development of specifications • Post approval market surveillance
Selection of Drug Candidate [11-12] The transdermal route of administration cannot be employed for a large number of drugs, only a small number of drug products are currently available via transdermal delivery. In many cases, a drug's physical properties, including molecular size and polarity, have limited its capacity to be delivered transdermally. Similarly, the biological properties of drug molecules, including dermal irritation and insufficient bioavailability, have been problematic. In the product development the focus must be on the rationality of drug selection based on pharmacokinetic parameters and physicochemical properties of the drug. Physiochemical factors such as solubility, crystallinity, molecular weight
