Transdermal Delivery of Cimetidine Across Microneedle-Treated Skin: Effect of Extent of Drug Ionization on the Permeation.

The objective of this work was to optimize a gel formulation of cimetidine to maximize its transdermal delivery across microporated skin. Specifically, the effect of extent of ionization in formulation on permeation of cimetidine across microporated skin was studied. Cimetidine was formulated into a gel using propylene glycol, water, and carbopol 980NF. Three strengths of gels (0.1% w/w, 0.5% w/w, and 0.8% w/w) were made and Tris base was used to adjust the pH of formulations to pH 5, pH 6.8, and pH 7.5. In vitro permeation testing was performed on vertical Franz cells with dermatomed porcine ear skin. Permeation studies suggested that pH 5 gels showed highest permeation through microchannels. This trend was more prominent with an increase in drug loading. The total amount of cimetidine delivered from 0.8% w/w gel at pH 5 at 24 h was 28.20 ± 4.63 µg, which was significantly higher than that from pH 6.8 (16.89 ± 3.56 µg) and pH 7.5 (12.03 ± 1.66 µg) gels. Cimetidine permeation across microporated skin was found to be pH dependent, with lower pH/highest ionization resulting in greatest permeation. The effect of ionization contributing to faster release was more pronounced when drug concentration was increased.

Formulation optimization of a drug in adhesive transdermal analgesic patch.

CONTEXT: Conventional pain management approaches have limitations such as gastrointestinal side effects, frequent dosing, and difficulties in swallowing medications. Hence, to overcome these limitations, we developed a transdermal analgesic patch. OBJECTIVE: This study was designed to formulate a drug in adhesive transdermal patch with codeine (CDB) and acetaminophen (APAP) that may potentially treat moderate pain in children. MATERIALS AND METHODS: Three analgesic drugs hydrocodone bitartrate, CDB and APAP were screened by a slide crystallization study using polarized light microscope and their permeation profiles were studied using vertical Franz diffusion cells across porcine ear skin, dermatomed human skin and epidermis for 24 h, and the samples were quantified by high performance liquid chromatography. Patches used for permeation studies were prepared by dissolving sub-saturation concentration of the drug(s) in adhesive (with/without 5% w/w oleic acid [OA]), cast with a film casting knife. RESULTS AND DISCUSSION: Among the three drugs screened, CDB demonstrated the best permeation profile (660.21 µg/cm(2)), and shortest lag time (4.35 ± 0.01 h), and hence was chosen for patch studies. The highest concentration of CDB in the patch at which drug does not crystallize was determined as 40% of its saturation solubility (Cs) and that of APAP was determined as 200% of its Cs. CDB standalone patch delivered 105.48 µg/cm(2) of CDB, while the CDB-APAP combination patch with 5% w/w OA delivered 151.40 µg/cm(2) CDB and 58.12 µg/cm(2) APAP in 24 h. CONCLUSION: Drug-in-adhesive patches using CDB and APAP were developed for infants and children. Addition of OA enhanced solubility and permeation of drugs.

Formulation optimization of a drug in adhesive transdermal analgesic patch.

CONTEXT: Conventional pain management approaches have limitations such as gastrointestinal side effects, frequent dosing, and difficulties in swallowing medications. Hence, to overcome these limitations, we developed a transdermal analgesic patch. OBJECTIVE: This study was designed to formulate a drug in adhesive transdermal patch with codeine (CDB) and acetaminophen (APAP) that may potentially treat moderate pain in children. MATERIALS AND METHODS: Three analgesic drugs hydrocodone bitartrate, CDB and APAP were screened by a slide crystallization study using polarized light microscope and their permeation profiles were studied using vertical Franz diffusion cells across porcine ear skin, dermatomed human skin and epidermis for 24 h, and the samples were quantified by high performance liquid chromatography. Patches used for permeation studies were prepared by dissolving sub-saturation concentration of the drug(s) in adhesive (with/without 5% w/w oleic acid [OA]), cast with a film casting knife. RESULTS AND DISCUSSION: Among the three drugs screened, CDB demonstrated the best permeation profile (660.21 µg/cm2), and shortest lag time (4.35 ± 0.01 h), and hence was chosen for patch studies. The highest concentration of CDB in the patch at which drug does not crystallize was determined as 40% of its saturation solubility (Cs) and that of APAP was determined as 200% of its Cs. CDB standalone patch delivered 105.48 µg/cm2 of CDB, while the CDB-APAP combination patch with 5% w/w OA delivered 151.40 µg/cm2 CDB and 58.12 µg/cm2 APAP in 24 h. CONCLUSION: Drug-in-adhesive patches using CDB and APAP were developed for infants and children. Addition of OA enhanced solubility and permeation of drugs.

Development of Disposal Systems for Deactivation of Unused/Residual/Expired Medications.

PURPOSE: The objective of this work was to identify deactivation agents and develop a disposal system for unused/ residual/ expired medications. METHODS: Deactivation agents screened included oxidizing agent-sodium percarbonate, hydrolysis agent- sodium carbonate and adsorbants- zeolite and activated carbon. Deactivation studies using these agents were performed on four active pharmaceutical agents (APIs) including ketoprofen, dexamethasone sodium phosphate, metformin hydrochloride and amoxicillin trihydrate. Disposal systems were also designed for deactivation studies on dexamethasone pills, amoxicillin trihydrate capsules and fentanyl transdermal patches (Duragesic®). Briefly, APIs/ dosage forms were allowed to be in close contact with deactivation agents for a specified period of time and percentage decrease in the amount of API from the initial amount was measured. RESULTS: Sodium percarbonate and sodium carbonate were only successful in deactivation of amoxicillin trihydrate API. Adsorption agents resulted in more universal deactivation with activated carbon resulting in efficient deactivation of most APIs and all dosage forms tested. Also adsorption of oral dosage medications on activated carbons was maintained even on dilution and shaking and no desorption was observed. CONCLUSIONS: Deactivation systems containing activated carbon are promising for efficient, safe and environment friendly disposal of unused/residual/expired medications.

Transcending the skin barrier to deliver peptides and proteins using active technologies.

Peptides and proteins have been investigated as promising therapeutic agents over the past decade. These macromolecules are conventionally administered by the parenteral route because oral delivery is associated with degradation in the gastrointestinal tract. Transdermal delivery presents a promising alternative route of drug delivery, avoiding pain associated with parenteral administration and degradation issues associated with oral delivery. However, the barrier properties of skin limit delivery to only small, moderately lipophilic molecules. Hence, hydrophilic macromolecules like peptides and proteins cannot passively permeate across skin. Active physical enhancement approaches such as iontophoresis electroporation, microneedles treatment, and sonophoresis have been developed to assist transdermal delivery of peptides and proteins. This review describes active physical transdermal enhancement approaches for transdermal delivery of peptides and proteins. The mechanisms associated with each technique and important parameters governing transdermal delivery of peptides and proteins are discussed in detail. Combinations of enhancement techniques for synergistic enhancement in protein and peptide delivery are also discussed.

An update on the application of physical technologies to enhance intradermal and transdermal drug delivery.

A large number of biopharmaceuticals and other macromolecules are being developed for therapeutic applications. Conventional oral delivery is not always possible due to first-pass metabolism and degradation in the GI tract. Parenteral delivery is invasive and has poor patient compliance. Transdermal delivery provides one attractive route of administration. Transdermal administration can achieve the continuous and non-invasive delivery of drugs. However, passive transdermal delivery is restricted to small lipophilic molecules. Active physical-enhancement technologies are being investigated to increase the scope of transdermal delivery to hydrophilic molecules and macromolecules. Recent developments in transdermal technologies, such as microporation, iontophoresis and sonophoresis can enable therapeutic delivery of many drug molecules, biopharmaceuticals, cosmeceuticals and vaccines. This review provides an update of recent developments in transdermal delivery focusing on physical-enhancement technologies.

In vivo iontophoretic delivery of salmon calcitonin across microporated skin.

The purpose of this study was to determine the effect of microneedle (MN) technology and its combination with iontophoresis (ITP) on the in vivo transdermal delivery of salmon calcitonin (sCT). Maltose MNs (500 µm) were used to porate skin prior to application of the drug, with or without ITP. Micropores created by maltose MNs were characterized by histological sectioning and calcein imaging studies, which indicated uniformity of the created micropores. In vivo studies were performed in hairless rats to assess the degree of enhancement achieved by ITP (0.2 mA/cm² for 1 h), MNs (81 MNs), and their combination. In vivo studies indicate a serum maximal concentration of 0.61 ± 0.42 ng/mL, 1.79 ± 0.72 ng/mL, and 5.51 ± 0.32 ng/mL for ITP, MNs, and combination treatment, respectively. MN treatment alone increased serum concentration 2.5-fold and the combination treatment increased the concentration ninefold as compared with iontophoretic treatment alone. Combination treatment of ITP and MNs resulted in the highest delivery of sCT and therapeutic levels were achieved within 5 min of administration.

Low frequency sonophoresis mediated transdermal and intradermal delivery of ketoprofen.

The objective of this study was to test low frequency sonophoresis at 20 kHz for delivery of ketoprofen into and across the skin. Permeation studies were carried out in vitro on excised hairless rat skin over a period of 24h using Franz diffusion cells after which, skin samples were subjected to skin extraction to quantify the amount of drug present in skin. Parameters like ultrasound application time, duty cycle coupling medium and distance of ultrasound horn from skin were optimized. Transepidermal water loss (TEWL) was measured to indicate the extent of barrier disruption following sonophoresis. Confocal microscopy was used to visualize dye penetration through sonophoresis treated skin. Application of ultrasound significantly enhanced permeation of ketoprofen from 74.87 ± 5.27 µg/cm(2) for passive delivery to 491.37 ± 48.78 µg/cm(2) for sonophoresis. Drug levels in skin layers increased from 34.69 ± 7.25 µg following passive permeation to 212.62 ± 45.69 µg following sonophoresis. TEWL increased from 31.6 ± 0.02 (passive) to 69.5 ± 12.60 (sonophoresis) indicating disruption of barrier properties. Confocal microscopy images depicted enhanced dye penetration through sonophoresis treated skin confirming barrier disruption. Low frequency sonophoresis with optimized ultrasound parameters can be effectively used to actively enhance transdermal and topical delivery of ketoprofen.