Systemic delivery of ß-blockers via transdermal route for hypertension.

Hypertension is the most common cardiovascular disease worldwide. Moreover, management of hypertension requires long-term treatment that may result in poor patient compliance with conventional dosage forms due to greater frequency of drug administration. Although there is availability of a plethora of therapeutically effective antihypertensive molecules, inadequate patient welfare is observed; this arguably presents an opportunity to deliver antihypertensive agents through a different route. Ever since the transdermal drug delivery came into existence, it has offered great advantages including non-invasiveness, prolonged therapeutic effect, reduced side effects, improved bioavailability, better patient compliance and easy termination of drug therapy. Attempts were made to develop the transdermal therapeutic system for various antihypertensive agents, including ß-blockers, an important antihypertensive class. ß-blockers are potent, highly effective in the management of hypertension and other heart ailments by blocking the effects of normal amounts of adrenaline in the heart and blood vessels. The shortcomings associated with ß-blockers such as more frequent dose administration, extensive first pass metabolism and variable bioavailability, make them an ideal candidate for transdermal therapeutic systems. The present article gives a brief view of different ß-blockers formulated as transdermal therapeutic system in detail to enhance the bioavailability as well as to improve patient compliance. Constant improvement in this field holds promise for the long-term success in technologically advanced transdermal dosage forms being commercialized sooner rather than later.

Formation of a Controllable Diffusion Barrier Layer on the Surface of Polydimethylsiloxane Films by Infrared Laser Irradiation.

Developing a diffusion barrier layer on material interfaces has potential applications in various fields such as in packaging materials, pharmaceuticals, chemical filtration, microelectronics, and medical devices. Although numerous physical and chemical methods have been proposed to generate the diffusion barrier layer, the complexity of fabrication techniques and the high manufacturing costs limit their practical utility. Here, we propose an innovative approach to fabricate the diffusion barrier layer by irradiating poly(dimethylsiloxane) (PDMS) with a mid-infrared (λ = 10.6 µm) CO2 laser. This process directly creates a diffusion barrier layer on the PDMS surface by forming a heavily cross-linked network in the polymer matrix. The optimal irradiation conditions were investigated by modulating the defocusing distance, laser power, and number of scanning passes. The barrier thickness can reach up to 70 µm as observed by the scanning electron microscope (SEM). The attenuated total reflectance (ATR), electron dispersive X-ray (EDX), and X-ray photoelectron spectroscopy (XPS) analyses collectively confirmed the formation of the SiOx structure on the modified surface based on the decreased methyl group signal and the increased oxygen/silicon ratio. The diffusion test with the model drugs (rhodamine B and donepezil) demonstrated that the modified surface exhibits effective diffusion barrier properties and the rate of drug diffusion through the modified barrier layer can be controlled by the optimization of the irradiation parameters. This novel approach provides the possibility to develop a controllable diffusion barrier layer in a biocompatible polymer with prospective applications in the fields of pharmaceuticals, packing materials, and medical devices.

Transdermal Therapeutic Systems for the Treatment of Alzheimer's Disease: A Patent Review.

BACKGROUND: Two classes of medications are used to treat Alzheimer's disease (AD); donepezil, galantamine, and rivastigmine are acetylcholinesterase inhibitors, and memantine is a non-competitive antagonist of the N-methyl-D-aspartate receptor. Although these are typically taken orally, there are transdermal therapeutic systems (TTSs) commercially available for rivastigmine and donepezil. The transdermal route has been preferable for guardians/caregivers due to ease of use, reduced side effects, and improved adherence to therapy. OBJECTIVE: The study aimed to obtain knowledge of the properties of these drugs and to search for patents relating to the TTS for AD using the Espacenet platform. METHODS: The search terms were "rivastigmine AND transdermal AND skin delivery AND Alzheimer's", changing the drugs "memantine", "donepezil", and "galantamine", between January 2015 and January 2022. Title and abstract were used to choose patents. RESULTS: TTSs present some limit factors in terms of absorption due to skin physiology and the size of the molecules with established limits of percutaneous penetration (molecular mass of 500 g/mol and log P of 5). We found 1, 4, 4, and 2 patents for galantamine, rivastigmine, donepezil, and memantine, respectively. Galantamine TTS seems to be more challenging due to the molecular mass of 287.35 g/mol and logP of 1.8. The permeator of absorption is necessary. Memantine, rivastigmine, and donepezil present logP of 3.28, 2.3, and 4.27 and molecular weights of 179.30, 250.34, and 415.96 g/mol, respectively. CONCLUSION: TTSs are primarily effective for delivering small molecules. The use of absorption enhancers and irritation mitigators can be necessary to enhance the performance. The development of these technologies is essential for the convenience of patients and caregivers.

Aminodihydrophthalazinedione Sodium Transdermal Therapeutic System Specific Activity on an ExperimentalModel of Extensive Liver Resection.

Previously, the authors showed that the application of the aminodihydrophthalazinedione sodium (ADPS) immunomodulator transdermal therapeutic system (TTS) to laboratory animals provides bioavailability analogous to the intramuscular administration of this drug at the same dose. At the same time, its maximum blood concentration is significantly reduced, and the retention time of the drug in the body is increased more than 10-fold, which can contribute to prolonging the drug effect. The aim of the work was to identify a possible positive effect of the transdermal administration of the ADPS immunomodulator on reparative liver regeneration on an experimental model of extensive liver resection (ELR). It has been shown that at a period of 48 h after ELR, the percutaneous administration of the immunomodulator has a pronounced stimulating effect on the mitotic activity of rat liver cells; by 72 h after ELR, an accelerated rate of recovery of hepatic homeostasis in the body was observed in laboratory animals in groups with the application of the ADPS TTS versus the control group.

Development of Capsaicin-Containing Analgesic Silicone-Based Transdermal Patches.

Transdermal therapeutic systems (TTSs) enable convenient dosing in drug therapy. Modified silicone-polymer-based patches are well-controlled and cost-effective matrix diffusion systems. In the present study, we investigated the substance release properties, skin penetration, and analgesic effect of this type of TTS loaded with low-dose capsaicin. Release properties were measured in Franz diffusion cell and continuous flow-through cell approaches. Capsaicin was detected with HPLC-UV and UV spectrophotometry. Raman spectroscopy was conducted on human skin samples exposed to the TTS. A surgical incision or carrageenan injection was performed on one hind paw of male Wistar rats. TTSs were applied to the epilated dorsal skin. Patches were kept on the animals for 6 h. The thermal hyperalgesia and mechanical pain threshold of the hind paws were detected. Patches exhibited controlled, zero-order kinetic capsaicin release. According to the Raman mapping, capsaicin penetrated into the epidermis and dermis of human skin, where the target receptors are expressed. The thermal pain threshold drop of the operated rat paws was reversed by capsaicin treatment compared to that of animals treated with control patches. It was concluded that our modified silicone-polymer-based capsaicin-containing TTS is suitable for the relief of traumatic and inflammatory pain.

Successful Treatment of Alopecia Areata Patches with Triamcinolone Acetonide Using MMP®: Report of 2 Cases.

Intralesional (IL) injection of corticosteroids is an effective treatment of alopecia areata (AA). A novel drug delivery technique that uses a tattoo machine (MMP®) has been successfully used to treat other skin disorders. We tested this technique to treat AA. We used the Cheyenne dermopigmentation machine (Anvisa 80281110016; Germany) with a 27 Magnum needle cartridge (Anvisa 80281110015) at a frequency of 70 Hz and needle depth of 1.0 mm. A triamcinolone acetonide (TAC) solution was placed in a sterile receptacle and loaded onto the cartridge by capillarity. We produced micropunctures of the skin with the medication-soaked needles until the affected area was covered by a bloody dew. Case 1: J.C.V., a male, with a diagnosis of AA in patches was treated with 1-monthly session with 2.5 mg/mL TAC delivered by MMP® (4 sessions in total). Case 2: L.M.V., a 78-year-old female with a diagnosis of AA was treated with 1-monthly session with 10 mg/mL TAC delivered by MMP® (4 sessions in total). MMP® is a novel technique that combines microneedling with drug delivery, and it could be used to deliver IL TAC to AA patients. This technique promotes a more uniform absorption of corticosteroids than traditional treatment methods of AA.

Allergic Contact Dermatitis to Fentanyl TTS with Good Tolerance to Systemic Fentanyl.

BACKGROUND: Fentanyl is primarily an opioid agonist. It is frequently used in general anesthesia as a potent analgesic. It can be administered either orally, transdermally or systemically. Adverse effects due to opium alkaloids are usually because of a non-specific histamine release. Only in a few cases, a true allergy mechanism could be involved. Immediate reactions to opioids are most frequent than delayed reactions. In the past years, delayed reactions have increased in frequency because of the wide use of Transdermal Therapeutic System (TTS) with several opioids for its potent analgesic properties. OBJECTIVE: The objective was to study delayed reaction to fentanyl TTS and cross-reactivity with other opioids. METHODS: A 52-year-old man with a diagnosis of pancreatic cancer who began treatment for a bone metastases pain with fentanyl TTS, at a dose of 50 micrograms per hour (mcg/h) is the subject of the study. After 10-15 days of treatment, he developed an itchy papulovesicular rash in the application site of the fentanyl TTS. Afterward, eczema and superficial desquamation just on the application site of the patch were observed. He changed several times the site of application, but always developing the same symptoms in every single application. Later on, he tolerated other opioids such as oral morphine or tramadol. An allergy workout was performed. We performed Patch Tests (PT) with fentanyl at a concentration of 10% in aqua (aq) and with buprenorphine 10% aq., in order to investigate probable crossreactivity among other topical opioids. RESULTS: Readings were recorded at day 2 (D2) and day 4 (D4), with positive PT only with fentanyl at D2 (+++) and D4 (+++). We decided to perform a single-blind challenge test with buprenorphine 35 mcg/h in TTS, with a negative result. At this moment, fentanyl TTS was replaced by buprenorphine TTS, with good tolerance. CONCLUSION: We present the case of Allergic Contact Dermatitis (ACD) due to hypersensitivity to fentanyl with good tolerance to buprenorphine. Positive PT in this patient suggests a type IV hypersensitivity mechanism. Allergic reactions to opioids are frequently immediate, but delayed reactions could appear, especially when the drug is administered topically.

Transdermal delivery of angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) and others for management of hypertension.

CONTEXT: Angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) are some of the most commonly prescribed medications for hypertension. OBJECTIVE: Most of all conventional dosage forms of ARBs and ACEIs undergo extensive first-pass metabolism, which significantly reduces bioavailability. Majority of ARBs and ACEIs are inherently short acting due to a rapid elimination half-life. In addition, oral dosage forms of ARBs and ACEIs have many high incidences of adverse effects due to variable absorption profiles, higher frequency of administration and poor patient compliance. METHODS: Many attempts have been made globally at the laboratory level to investigate the skin permeation and to develop transdermal therapeutic systems of various ARBs, ACEIs and other anti-hypertensives, to circumvent the drawbacks associated with their conventional dosage form. RESULTS: This manuscript presents an outline of the transdermal research specifically in the area of ARBs, ACEIs and other anti-hypertensives reported in various pharmaceutical journals. CONCLUSION: The transdermal delivery has gained a significant importance for systemic treatment as it is able to avoid first-pass metabolism and major fluctuations of plasma levels typical of repeated oral administration. As we can experience from this review article that transdermal delivery of different ARBs and ACEIs improves bioavailability as well as patient compliance by many folds. In fact, the rationale development of some newer ARBs, ACEIs and other anti-hypertensives transdermal systems will provide new ways of treatment, circumventing current limitations for conventional dosage forms.

Therapeutic effects of transdermal systems containing zinc-related materials on thermal burn rats.

OBJECTIVE: The aim of the present study is to evaluate the efficacy of slow zinc (Zn) release from ß-tricalcium phosphate powder (ZnTCP) containing 10 mol% Zn on rats with thermal burns. METHODS: The first-aid tapes were contained zinc sulfate (ZnSO4) solution, ZnTCP suspensions or zinc oxide ointment. After thermal burn treatments were performed on Zn-deficient rats, the groups D1, D2 and D3 were treated with tapes containing ZnTCP, ZnSO4 and zinc oxide ointment. The effects of the tapes on wound area, plasma Zn levels and alkaline phosphatase activity (Alp) were investigated. RESULTS: The wound area profiles of all rat groups could be separated into before and after the scab formation at around day 6. The area under the curve (Aw-AUC) for wound area profiles, therefore, was evaluated as an index of therapeutic scores for the thermal wound. The order of Aw-AUC was D3>C>D2>D1. The degree of expansion at the initial stage by thermal burns of group D1 was the lowest and that of group D2 was the highest, and the order was D1

Corticosteroid transdermal delivery to target swelling, edema and inflammation following facial rejuvenation procedures.

BACKGROUND AND AIM: The use of transdermal therapeutic systems has spread worldwide since they allow effective local drug delivery. In the present study, we investigated the efficacy and safety of a new betamethasone valerate medicated plaster (Betesil®) to manage facial swelling, edema, inflammation, ecchymosis, and hematoma, when applied immediately after a facial rejuvenation procedure. MATERIALS AND METHODS: We applied the plaster to the skin of 20 healthy patients for 12 hours immediately after hyaluronic acid-based procedure performed with the aim of erasing facial wrinkles of perioral and nasolabial folds and improving chin and eye contour. A further 20 patients underwent the same cosmetic procedure, but they were treated with an aescin 10% cream (applied immediately after the procedure, in the evening, and the morning after) and served as control group. RESULTS: Betesil® application resulted in a significant improvement in swelling/edema/inflammation score, if compared with aescin 10% cream (P < 0.01). As for facial ecchymosis and hematoma around the needle injection track, only two patients in the active treatment group displayed minimal ecchymosis and hematoma. In the control group, two patients presented minimal ecchymosis and three slight hematoma. However, using the ecchymosis/hematoma score, no significant difference between Betesil® and aescin 10% cream groups was observed. Patients' satisfaction was significantly higher among subjects receiving Betesil®, if compared to patients receiving aescin 10% cream (P < 0.01). CONCLUSION: The present study supports the use of Betesil® plaster immediately after facial cosmetic procedures in order to safely control swelling, edema, and inflammation.

The effectiveness of transdermal opioid in the management multiple rib fractures: randomized clinical trial.

BACKGROUND: The most commonly observed pathology in chest traumas is rib fracture, and the most important clinical symptom is severe pain. AIMS: To investigate the effectiveness of intramuscular opioid (IMO), intravenous patient-controlled analgesia (IVPCA) and the Fentanyl transdermal therapeutic system (TTS) in the management of rib fracture pain. STUDY DESIGN: Prospective randomized clinical trial. METHODS: In our prospective and randomised study, we included 45 patients with a diagnosis of multiple rib fractures. There were three groups and intercostal nerve blockage (ICB) in the first day and oral paracetamol for five days was administered to each group as standard. In Group IMO (n=15), 4×40 mg pethidine HCl was administered to the patients, while in Group IVPCA (n=15) this was 5 µg/mL continuous intravenous fentanyl and was 50 µg fentanyl TTS in Group TTS (n=15). The demographics, injury data and vital signs of the patients were recorded. Pain was scored using Visual Analogue Scale (VAS). The pain during lying down (VASl) and mobilisation (VASm) was detected. RESULTS: There were no differences between the three groups regarding age, sex, the trauma pattern, the number and distribution of costal fracture localisations, the presence of additional pathology, complications, thoracal catheter and the duration of thoracal catheter. No significant difference between the groups regarding systolic and diastolic arterial tension, number of breaths and beats in a minute was observed (p>0.05). We observed an improvement in the mean VAS score after treatment in all three groups. The mean VASl score significantly decreased after treatment in each group (p<0.05). The mean VASl and VASm scores measured on the 1(st), 2(nd), 3(rd), 4(th) and 5(th) days were found to be higher in Group IMO than in Groups IVPCA and TTS; however, these differences were not statistically significant (p>0.05). CONCLUSION: In the analgesia of patients with multiple rib fractures, TTS administration with ICB showed similar effectiveness with IVPCA administration with ICB. In the management of pain due to multiple rib fractures, TTS administration is a safe, non-invasive and effective procedure.

Iontophoresis: a potential emergence of a transdermal drug delivery system.

The delivery of drugs into systemic circulation via skin has generated much attention during the last decade. Transdermal therapeutic systems propound controlled release of active ingredients through the skin and into the systemic circulation in a predictive manner. Drugs administered through these systems escape first-pass metabolism and maintain a steady state scenario similar to a continuous intravenous infusion for up to several days. However, the excellent impervious nature of the skin offers the greatest challenge for successful delivery of drug molecules by utilizing the concepts of iontophoresis. The present review deals with the principles and the recent innovations in the field of iontophoretic drug delivery system together with factors affecting the system. This delivery system utilizes electric current as a driving force for permeation of ionic and non-ionic medications. The rationale behind using this technique is to reversibly alter the barrier properties of skin, which could possibly improve the penetration of drugs such as proteins, peptides and other macromolecules to increase the systemic delivery of high molecular weight compounds with controlled input kinetics and minimum inter-subject variability. Although iontophoresis seems to be an ideal candidate to overcome the limitations associated with the delivery of ionic drugs, further extrapolation of this technique is imperative for translational utility and mass human application.