1. TRANSDERMAL DRUG DELIVERY SYSTEMS (TDDS) Percutaneous Absorption The absorption of substances from outside the skin to positions beneath the skin, including entrance into the blood stream. The main mechanism is passive diffusion through epidermis and shunts. Advantages Reasonably constant dosage can be maintained (as opposed to peaks and valleys associated with oral dosage) Improved absolute bioavailabilityFirst pass metabolism in the liver and GI tract is avoided, Improved absolute bioavailability Reduced need for frequent administration (some patches can last 7 days) The patch is noninvasive and dosage can be stopped by removal More convenient and improved patient compliant dosing regimen. Limitations Skin structure poses a barrier for drug permeation Usually reserved for drugs which are extremely potent (thus requiring a dosage of only a few mg). The largest daily dose of a drug from a patch is the nicotine patch, with delivers a daily dose of only 21 mg.

2. Transepidermal Absorption Stratum corneum (keratinized tissue: major rate limiting barrier of TDDS): Composed of 15-25 layers of acutely flattened metabolically inactive dry cells that lack nuclei. Despite being soft, It has surprisingly high density (1.3-1.4 gm/cm 3 ). Stratum corneum has two distinct phases as 1. Intracellular proteins: The cells composed mainly of proteins (75- 85%), most of which is keratin, which is an insoluble protein, with a high proportion of disulfide bridges (from cysteine), and also a high level of glycine and alanine residues that allow strong H-bonds to neighboring amino acids. 2. The Intercellular lipoidal medium: lipoidal substances lie mainly between sells as lipid bilayer and this route occupies only 1% of the stratum corneum diffusion area. It lacks any blood supply. Its thickness varies from 0.2 to 0.5  m depending on location. Most substances diffused across the stratum corneum via the intercellular lipoidal route.

3. Epidermis: Unlike the dry composition of stratum corneum, epidermis consists of wet mass of cells. The cells are viable with nuclei and filled with aqueous cytoplasm that is surrounded by the lipoidal cytoplasmic membrane. The cells are separated by very tight junction that does not all even ions to pass through. It can be viewed as alternating lipoidal and aqueous phases. Frequent crossing of hydrophilic drugs through the lipoidal membranes is thermodynamically prohibitive, while too lipophilic are constrained from dissolving in the watery cytoplasm. Thus balanced hydrophilic-lipophilic character is needed for efficient permeation through the epidermis. It lacks capillaries and blood supply and thus delivery through this layer is not enough for the reach to the systemic circulation. Thickness varies from 50 to 100  m. Dermis: Consist of bundle of collagen fibers as woven mesh-like network, that is filled with a watery gel (mucopolysacharide) called ground substance. Permeation is through interlocking channels of the ground substance between fibers. The gaps between fibers are too large to filter even large molecules and thus diffusion through the dermis is facile with no molecular selectively. The dermis receives rich blood supply from the capillaries in the subcutaneous tissues. Thus passage through the dermis is the final hurdle to systemic entry. The blood supply act as sink for diffusing molecules keeps penetrate concentration in the dermis as minimum, which maximize the concentration gradient with respect to epidermis. Transepidermal Absorption

4. Trans follicular (Shunt Pathway) Absorption Ecrine or sweat glands: numerous (up to 400 gland per cm 2. However, their orifice is tiny with limited surface area. In addition they are evacuated by the watery secretion that it is unlikely that molecules can diffuse inward through against gland input. For these reasons they are discounted as significant rout for percutaneous absorption. Pilosbaceous glands: located and the base of hair follicles. Are filled with soft slowly extruded lipoidal medium (sebum), in which lipophilic drugs are soluble and should diffuse easily. Less numerous than ecrine gland (50 to 100 per cm 2. However, their opening is larger. They remain possibly important avenue for percutaneous absorption Both ecrine gland and sebaceous glands are of epidermal origin, but they go deep into the dermis where blood supply can take any pen entrant,

5. In Vitro Transdermal Permeation Study: Franz Diffusion Cells Franz Diffusion Cells The Franz diffusion cell was an in vitro model that is used as a standard for measuring the permeability of compounds into and across skin or other biological membranes. The major components of a diffusion cell included a donor chamber, a receptor chamber, a sampling port, a cell clamp, and a jacket that was connected to a water source for maintaining the temperature at 32 degree. The membrane is usually hairless rat skin. Human skin after plastic surgery can be used. Samples are assayed by HPLC because of the release of skin components and possible drug metabolism during permeation, that may cause interference with drug assay and requires separation of the drug from the released materials and related substances. Sink condition is achieved by replacing the receiving medium with fresh medium to keep the drug concentration in the receptor chamber less than 10% of that in donor compartment. Data are tabulated as time (0 to 24 hr) and drug concentration. Drug concentration are obtained using a calibration curve, converted to amounts and cumulative amounts (  g or  g/cm 2 ), which are used of the membrane to give the plot in the next slide.

6. The curve has to regions: A. Lag time region during which the flux increases gradually and this is due to the increase of the drug concentration in the membrane, and B. the steady state region, which starts when the membrane become saturated with the penetrate leading to constant permeation rate. The equation that describes the whole curve is Where, Mt is the flux (  g/cm 2 ) K is the partition coefficient between formulation vehicle and membrane (stratum corneum of skin), D is the diffusion constant in the membrane, Cs is the dissolved penetrate concentration in the vehicle and h is the thickness of the membrane. When the steady-state line is extrapolated to the time axis, the value oft at M = 0 is called the lag time (TL), which is equal to The steady-state flux rate, dM,/dt, which is equal to the slope of the extrapolated, line is readily obtained by differentiating M, with respect to t, i.e.:

7. The equation during the linear steady state (for extrapolated line) can be simplified as Where P is the permeability coefficient and is given as Choosing candidate for TDD and prediction of delivery rate 1.Potency of the drug: Daily systemic dose should be less than 20 mg 2. Diffusioin coeffcient and T-lag: 2. Diffusioin coeffcient and T-lag: the lag time for penetration becomes longer as the effective diffusivity, D, becomes smaller (irrespective of how it is calculated). Normally one wants the lag time to be a negligible fraction of the projected time of use of a transdermal system. If the prescribed period of application is to be a day, as it is with current nitroglycerine patches, the lag time should be no more than a tenth of a day or 2-3 hrs at the most. Any lag time longer than this Raises questions about the utility of the patch, for the patch will not be delivering drug over a significant part of the time it is in use. In vitro diffusion cell studies suggest that the values of D for the stratum corneum (one uses the stratum corneum’s 10  m thickness in the calculation) range from 10 -9 down to 10 -12 cm 2 /sec. At the larger diffusivities, lag times of several minutes are expected. On the other hand, multiple-day lag times are suggested by the smallest reported diffusivities. the more polyfunctional and polar a compound is, the longer its lag time seems to be. For example, lag times across cadaver skin membranes for the permeation of fentanyl and sufentanil, both narcotics of low polarity based on partitioning data, have consistently been less than 3 hours. In contrast, lag times for morphine and hydromorphone, both relatively polar narcotics, have consistently exceeded 6 hours, well over than twice those of fentanyl and sufentanil.

8. 3. Concentration gradient: T he previous discussion indicates that the transdermal delivery rate of a drug can be forecast providing one knows the drug’s solubility in and permeability coefficient from a given solvent medium. It is suggested that the logical solvent medium on which to base such projections is water. The highest concentration in water to give the highestconcentration gradient for diffusion is the saturated concentration or solubility. Highest flux is obtained at this concentration. Relatively, dilute concentrations gives lower flux and higher total (dissolved and solid) concentrations with suspended drug particles will no longer increase the flux as it should become constant. However, the exess solid when fast dissolving and significant change in the concentration occurs, maintainace of the saturated concentration can be achieved. 4. Permeability and partition coefficients: Permeability coefficients are not easily determined; there is no immediately obvious means of estimating them that does not involve permeation experiments. However, on careful examination of the literature, one finds prediction-useful relationships between the permeability coefficients of drugs and their partitioning tendencies. For example it has been found that permeation of test compounds through hairless mouse skin relate to the ether/water partition coefficients of the compounds. Then reported data are displayed in the next slide. It can be seen that compounds all seem to lie on a sigmoidal Line stretching over ten logarithmic orders of partition coefficient. *

9. At partition coeffcient higher than 500 (log = 2.7), plateu with the highest permeability coefcient, slightly higher than 0.01 ( log -2) Over the range of partition coefficients from 0.01 (log = -2) to 100 (log = +2), the permeability coefficients increase by three logarithmic orders from -5 to -2. compounds with log (permeability coefficients) less than - 2 all fall on a line just above partition coeffcient of 10 -5 log = -5)

10. Similar correlation results were obtained for octanol/water partition coeffcient (K) as the following: For compounds with log K < -2.301, a lower limit of 1x 10 -6 cm/hr was assigned to the permeability coefficient. In this regionthe compounds were considered polar enough to preferentially pass through the aqueous region of the stratum corneum For compounds with log K values lying between - 2.301 and + 2.000, the permeability coefficients were determined from the empirically derived relationship: For compounds with log K values > 2.000, an upper limit permeability coefficient of 1 x 10 -2 cm/hr was assigned. Compounds fitting into this partitioning range were considered sufficiently nonpolar for their permeation rates to be controlled within aqueous phase of the epidermis and dermis

11. Examples Calculated the predicted and actual transdermal delivery rate (mg/cm 2 /day) for the following, tabulate your results and judge the prediction (home work due next lecture) 1. Fentanyl has K (octanol/water) of 9550, water solubility of 0.2 mg/ml, and actual permeability coeffcient of 0.01. 2. Scopoalamine has K (octanol/water) of 15.8, water solubility of 75 mg/ml, and actual permeability coeffcient of 0.00005. 3. Estradiol has K (octanol/water) of 1259, water solubility of 0.003 mg/ml, and actual permeability coeffcient of 0.0052.

12. Calculation of the surface area neede to deliver reccomended drug dose Using the solubilities and permeability coefficients, the cumulative amount of drug thatcan be made to pass through a 1-cm 2 area of skin from a saturated solution in a day, M24hr, in milligrams can be calculated from: M24hr ((mg/cm 2 ) = P estimated  Cs  24 Estimated transdermal dose can be calculated as the following: Dose 24 hr.transdermal (mg)= Dose 24.oral  (100  %extracted first pass) Patch size (cm 2 ) = Dose 24 hr.transdermal (mg) M24hr ((mg/cm2) The batch size required to deliver some drug daily is reported in the table next slide

14. Home work By showing calculations, try to obtaine the patch size area in the previous table for the following drugs 1. Estrone sulfate 2. Dexamethasone 3. Nitroglycerine