Long-acting microneedle formulations.

The minimally-invasive and painless nature of microneedle (MN) application has enabled the technology to obviate many issues with injectable drug delivery. MNs not only administer therapeutics directly into the dermal and ocular space, but they can also control the release profile of the active compound over a desired period. To enable prolonged delivery of payloads, various MN types have been proposed and evaluated, including dissolving MNs, polymeric MNs loaded or coated with nanoparticles, fast-separable MNs hollow MNs, and hydrogel MNs. These intricate yet intelligent delivery platforms provide an attractive approach to decrease side effects and administration frequency, thus offer the potential to increase patient compliance. In this review, MN formulations that are loaded with various therapeutics for long-acting delivery to address the clinical needs of a myriad of diseases are discussed. We also highlight the design aspects, such as polymer selection and MN geometry, in addition to computational and mathematical modeling of MNs that are necessary to help streamline and develop MNs with high translational value and clinical impact. Finally, up-scale manufacturing and regulatory hurdles along with potential avenues that require further research to bring MN technology to the market are carefully considered. It is hoped that this review will provide insight to formulators and clinicians that the judicious selection of materials in tandem with refined design may offer an elegant approach to achieve sustained delivery of payloads through the simple and painless application of a MN patch.

Microneedle-mediated drug delivery for cutaneous diseases.

Microneedles have garnered significant interest as transdermal drug delivery route owing to the advantages of nonselective loading capacity, minimal invasiveness, simple operation, and good biocompatibility. A number of therapeutics can be loaded into microneedles, including hydrophilic and hydrophobic small molecular drugs, and macromolecular drugs (proteins, mRNA, peptides, vaccines) for treatment of miscellaneous diseases. Microneedles feature with special benefits for cutaneous diseases owing to the direct transdermal delivery of therapeutics to the skin. This review mainly introduces microneedles fabricated with different technologies and transdermal delivery of various therapeutics for cutaneous diseases, such as psoriasis, atopic dermatitis, skin and soft tissue infection, superficial tumors, axillary hyperhidrosis, and plantar warts.

Promising Strategies for Transdermal Delivery of Arthritis Drugs: Microneedle Systems.

Arthritis is a general term for various types of inflammatory joint diseases. The most common clinical conditions are mainly represented by rheumatoid arthritis and osteoarthritis, which affect more than 4% of people worldwide and seriously limit their mobility. Arthritis medication generally requires long-term application, while conventional administrations by oral delivery or injections may cause gastrointestinal side effects and are inconvenient for patients during long-term application. Emerging microneedle (MN) technology in recent years has created new avenues of transdermal delivery for arthritis drugs due to its advantages of painless skin perforation and efficient local delivery. This review summarizes various types of arthritis and current therapeutic agents. The current development of MNs in the delivery of arthritis drugs is highlighted, demonstrating their capabilities in achieving different drug release profiles through different self-enhancement methods or the incorporation of nanocarriers. Furthermore, the challenges of translating MNs from laboratory studies to the clinical practice and the marketplace are discussed. This promising technology provides a new approach to the current drug delivery paradigm in treating arthritis in transdermal delivery.

Translational Value of the Transdermal Administration of Bergamot Essential Oil and of Its Fractions.

The essential oil of bergamot (BEO) has consistently proven antinociceptive and antiallodynic properties. Accordingly, the analgesic efficacy of the decolored essential oil (DEC), with higher levels of limonene, and the deterpenated (DET) fraction, with higher levels of linalool and linalyl acetate, was investigated using a formalin test after inhalation. The present study was aimed at characterizing the effects of BEO, its components with the highest pharmacological activity (represented by linalool, limonene, and linalyl acetate), and its DEC and DET fractions on the formalin test after transdermal administration relevant to clinical translation through topical application. To this aim, the schedule of intervention involved administration immediately after formalin injection or as a 5 min pretreatment followed by washout in ddY-strain mice. This study demonstrates, for the first time, the significant analgesic effect of all three constituents in the first and second phases, accounting for the efficacy of the essential oil in the formalin test. While all fractions revealed equal activity toward the phytocomplex in the early phase, the reduction in time of licking/biting during the late phase was more markedly induced by DEC. Moreover, pretreatment with BEO and its fractions followed by washout did not produce a significant reduction in licking/biting time in both phases of formalin-induced nociceptive response.

Pain management with transdermal drug administration: A review.

Pain management is an urgent issue to solve with complex mechanisms. Localized acute pain requires rapid and accurate delivery of drugs with less distribution in the blood circulation while chronic pain requires controlled release of drugs with long drug retention time. The transdermal route, a promising way with high patient compliance was known for painless delivery, long drug retention time, stable blood concentration, easily controlled dosage and release rate as well as the fewer side effects. This review presents transdermal route for pain management according to the different sites of action which drugs aim to reach, and illustrates different analgesic mechanisms, dosage forms, transdermal enhancements and clinical applications. In addition, the review concludes the difference of pain types and presents the future aims of pain management, thereby providing a reference for researches focusing on percutaneous analgesia.

Current trends in polymer microneedle for transdermal drug delivery.

Transdermal drug delivery using microneedles is increasingly gaining interest due to the issues associated with oral drug delivery routes. Gastrointestinal route exposes the drug to acid and enzymes present in the stomach, leading to denaturation of the compound and resulting in poor bioavailability. Microneedle transdermal drug delivery addresses the problems linked to oral delivery and to relieves the discomfort of patients associated with injections to increase patient compliance. Microneedles can be broadly classified into five types: solid microneedles, coated microneedles, dissolving microneedles, hollow microneedles, and hydrogel-forming microneedles. The materials used for the preparation of microneedles dictate the different applications and features present in the microneedle. Polymeric microneedle arrays present an improved method for transdermal administration of drugs as they penetrate the skin stratum corneum barrier with minimal invasiveness. The review summarizes the importance of polymeric microneedle and discussed some of the most important therapeutic drugs in research, mainly protein drugs, vaccines and small molecule drugs in regenerative medicine.

Microneedle-Mediated Transdermal Delivery of Tizanidine Hydrochloride.

Tizanidine hydrochloride is a skeletal muscle relaxant used for the treatment of spasm, a sudden involuntary muscle contraction leading to pain. The presently available oral dosage form has limitations such as high first pass metabolism resulting in low oral bioavailability. The short half-life necessitates its frequent administration to maintain the required plasma concentration. Transdermal delivery of drug avoids its first pass hepatic metabolism and gives controlled release, making it possible for reduction in dosing frequency. Drug delivery through transdermal route is severely limited by the presence of a tough stratum corneum barrier. A penetration enhancement approach is often necessary to achieve desired plasma concentrations. Microneedles are very short and sharp needles which do not cause pain. Thus, in the present investigation, preparation and evaluation of a transdermal delivery system for tizanidine hydrochloride based on microneedles are described.

Taxifolin: Evaluation Through Ex vivo Permeations on Human Skin and Porcine Vaginal Mucosa.

BACKGROUND: Taxifolin (TAX) is a flavonoid that has numerous pharmacological properties, including an antioxidant ability superior to that of other flavonoids due to its particular structure. Nevertheless, it has low oral bioavailability, which limits its therapeutic application. In this context, potentially important approaches for systemic drug delivery could be by alternative routes such as skin and vaginal mucosa, once both routes have a variety of advantages compared with the oral route, including the ability to bypass both first-pass hepatic metabolism and the consequent degradation in the gastrointestinal tract. Vaginal delivery could also account for a local effect, or an effect on circumvent microregion. OBJECTIVE: The major objective of this study was to develop and validate a high-performance liquid chromatography (HPLC) method for the determination of TAX in a semisolid dosage forms and then to evaluate ex vivo permeations across porcine vaginal mucosa and human skin. METHODS: TAX was incorporated into an oil-in-water emulsion developed previously by our group. Method for quantification was developed and validated using HPLC. Permeation through human skin and vaginal porcine mucosa were conducted in Franz-type cells. RESULTS: The method was precise (CV < 5%), accurate (recovery between 98% and 102%), linear (R2> 0.99), specific, and robust. Permeation experiments through porcine vaginal mucosa and human skin presented permeated percentages equal to 87.43% and 48.09% (per dose), respectively. CONCLUSION: The results suggest that, in the matrixes studied, TAX may be able to exert its biological activities systemically when applied by these routes. Furthermore, it exhibits greater permeability potential when administered by intravaginal route.

Copaiba Oil: Chemical Composition and Influence on In-vitro Cutaneous Permeability of Celecoxib.

BACKGROUND: Use of topical or transdermal administration of Celecoxib (Cxb) is an interesting strategy in cutaneous treatments since it reduces or avoids side effects of the oral route. However, Cxb´s high lipophilicity and the stratum corneum (SC) barrier impair cutaneous penetration. OBJECTIVE: Evaluation of copaiba oil (C.O) as a potential skin penetration enhancer (P.E) for Cxb. METHODS: The chemical composition of C.O was evaluated by GC-MS. Both in-vitro release and permeability assay of Cxb in Polyethylene glycol 400/ propylene glycol (PEG 400/PG) vehicle associated to C.O (1-50% w/w) were determined in a modified diffusion cell fitted with a synthetic hydrophobic membrane and pig ear skin as model, respectively. RESULTS: GC-MS analysis of C.O showed that it is composed of sesquiterpenes (68.65%) and diterpenes (22.26%). Formulations containing 25% C.O (F4) and 50% C.O (F5) have shown in-vitro burst release in the first 2 h, but only F4 released 100% of drug after 24 h. The highest Cxb permeation across skin was obtained from F4 and the highest skin retentions for F4 and F5 in the stratum corneum and epidermis plus dermis. CONCLUSION: The increased Cxb permeability through skin and its retention for an extended time (24h) at 25% C.O suggest that it could be a promising adjuvant for the development of transdermal formulations of Cxb.

Design and Development of Repaglinide Microemulsion Gel for Transdermal Delivery.

Microemulsion formulation of repaglinide, a BCS class II hypoglycemic agent with limited oral bioavailability, was developed considering its solubility in various oils, surfactants, and cosurfactants. The pseudo-ternary phase diagrams for microemulsion regions were constructed by water titration method at K m 1:1 and characterized for optical birefringence, percentage transmittance, pH, refractive index, globule size, zeta potential, viscosity, drug content, and thermodynamic stability. To enhance the drug permeation and residence time, the optimized microemulsions having mean globule size of 36.15 ± 9.89 nm was gelled with xanthan gum. The developed microemulsion-based gel was characterized for globule size, zeta potential, pH, and drug content. All evaluation parameters upon gelling were found to be satisfactory. Ex vivo permeability study across rat skin demonstrated higher steady-state flux (P < 0.05) for microemulsion of repaglinide in comparison to the repaglinide microemulsion gel. At the end of 24 h, the cumulative drug permeation from microemulsion and microemulsion gel was found to be 229.19 ± 24.34 and 180.84 ± 17.40 µg/cm2, respectively. The microemulsion formulation showed 12.30-fold increase in flux as compared to drug suspension with highest enhancement ratio (E r ) of 12.36. Whereas microemulsion gel exhibited 10.97-fold increase in flux (with highest E r , 11.78) as compared to repaglinide (RPG) suspension. In vivo efficacy study was performed in normal Sprague-Dawley rats by using oral glucose tolerance test. Results of RPG transdermal microemulsion gel demonstrated remarkable advantage over orally administered RPG by reducing the glucose level in controlled manner. Hence, it could be a new, alternative dosage form for effective therapy of type 2 diabetes mellitus.

Pharmacokinetics of a novel spot-on formulation of praziquantel for dogs.

Praziquantel (PZQ) is an anthelmintic drug used both in humans and animals that can be administered through various routes. There are transdermal formulations for cats, but only oral or subcutaneous dosage forms for dogs. Given the fact that the cat's skin and the dog's skin have different characteristics, which in turn affect bioavailability, we developed a PZQ spot-on formulation for dogs. This study was aimed at determining the plasmatic behavior of topically administered PZQ (Labyes®) in adult dogs. Dogs were administered PZQ (14.5mg/kg PZQ, from a solution of 100mg/ml). Blood samples were drawn before treatment onset and at the following time points after PZQ administration: 1, 2, 4, 6, 12, 24 and 48h. PZQ plasma concentration was determined by ultra-high performance liquid chromatography (UPLC) coupled to tandem mass spectrometry (MS/MS). Observed maximum concentration (Cmax), area under the concentration-time curve from the time of drug administration to infinity (AUCinf) and time to maximum concentration (Tmax) were calculated for each animal, and mean±SD for each parameter was obtained. Results were as follows: Cmax=56.0±15ng/ml; AUCinf=910.2±220ng*h/ml, Tmax=5.0±1.1h. This is the first study to provide pharmacokinetic data of a praziquantel spot-on formulation for dogs.

Permeação cutânea: desafios e oportunidades / Skin permeation: challenges and opportunities

O transporte de fármacos pela via transdérmica tem vindo a despertar um grande interesse, uma vez que constitui uma alternativa para ultrapassar as limitações de outras vias, como a oral e parenteral. No entanto, esta via ainda se destina apenas a um grupo restrito de fármacos, devido ao fato de que a pele apresenta uma baixa permeabilidade ao movimento de moléculas estranhas, como consequência da função barreira desempenhada pela camada córnea. Diversas estratégias têm sido desenvolvidas para contornar a barreira da pele com o objetivo de aumentar a permeação de fármacos, abrangendo métodos passivos ou ativos. O presente trabalho visa à revisão dessas estratégias, abordando os respetivos mecanismos de ação, bem como algumas combinações entre os diferentes métodos que têm demonstrado um efeito sinérgico e abordando, ainda, o problema da irritação da pele que pode advir da administração de fármacos por esta via.

Transdermal drug delivery has shown to be an interesting alternative to overcome limitations of conventional routes, such as the oral and parenteral ones. Nonetheless, the practical applications still remains limited to a narrow range of drugs, due to the skin barrier layer of the stratum corneum, which provides a low permeability to exogenous molecules. This review focuses on the strategies developed to enhance drug permeation, which include passive and active methods, and their respective mechanisms of action, as well as the combination of different methods that have shown to work in synergy. The problem of skin irritation that may result from the administration of drugs by this route is also addressed.

How to overcome the limitations of current insulin administration with new non-invasive delivery systems.

Non-invasive insulin delivery systems have potential to overcome the most pressing problem regarding effective treatment of diabetic patients: therapy compliance. To overcome this disadvantage, non-invasive routes such as oral, buccal, pulmonary, nasal and transdermal have been proposed. These new routes of insulin administration may help to suppress hypoglycemia episodes and aid to control weight gain and post-meal glucose. Despite all efforts the invasive route remains preferential, since studies on insulin administration by non-invasive routes conducted to date have not demonstrated clinical efficacy and safety, including some products introduced in the market. Therefore, the aim of this review is to make an update of the current state of administration of insulin by non-invasive routes as alternatives to the conventional invasive route.

Polymer-drug conjugates: recent progress on administration routes.

INTRODUCTION: Polymer-drug conjugates are an important part of polymer therapeutics. Recently, they have been used as an appealing platform for drug delivery. As a delivery vector, the route of administration performs a serious impact on the accessibility of drug molecules to their respective target site and therapeutic index. Furthermore, the physicochemical and biological properties of conjugates also correlate distinctly with the route of administration. AREAS COVERED: This article reviews the recent advances of polymer-drug conjugates as drug delivery systems through parenteral, enteral and topical routes. In particular, it mainly focuses on the classical and emerging routes such as injection, oral, transdermal, pulmonary and ocular routes using polymer-drug conjugates as delivery systems. EXPERT OPINION: Although polymer-conjugated drug delivery systems reported so far face severe shortcoming of being incomplete methodology and limited routes for administration (mostly concentrated in injection), some polymer carriers like poly(amidoamine) and hyaluronic acid still offer an appealing platform to deliver drug. Acquiring the particular characteristics of each polymer carrier, exploiting novel biodegradable polymer, expanding classical drug administration ways by emerging routes and developing a rational and systematic methodology to design administration routes will be the promising directions.

Rapid and sensitive controlled release monitoring method of biomedical combined products with IDM for pain management and cancer treatment.

New designed combined products and its determination for pain management and cancer treatment were studied. A rapid and sensitive stability indicating HPLC method had been developed and validated for the determination of Indomethacin(IDM) in a transdermal patch. This analytical method was successfully applied to the determination of Indomethacin in a transdermal patch and can be used for routine quality control analysis. Chromatographic separation was achieved isocratically on an Inertsil® C8-3 column utilizing a mobile phase of acetonitrile / 0.01 M monobasic sodium phosphate and 0.01 M dibasic sodium phosphate buffer (pH 3) (65:35, v/v) at the flow rate of 1 mL/min with UV detection at the wavelength of 210 nm. The system suitability was performed, and the result showed that Indomethacin(IDM) and its impurity were separated. The calibration curve of Indomethacin(IDM) was linear in the range of 0.1~15 ppm (r = 0.9989, n = 3).

Eficácia e tolerabilidade da associação transdérmica matricial de estradiol e noretisterona em regime combinado contínuo na pós-menopausa / Continuous combined transdermal matrix patch delivering estradiol-norethisterone acetate in post menopause: efficacy and tolerability

Objetivos: Avaliar a eficácia e tolerabilidade da associação transdérmica de estradiol e noretisterona, em regime combinado contínuo, em mulheres na pós-menopausa. Casuística e Métodos: Foram estudadas 40 pacientes, com média etária de 56,7 anos em estudo prospectivo, aberto e não comparativo. As pacientes receberam a associação de estradiol e noretisterona em regime combinado contínuo pelo período de seis meses, seguidos de extensão por período de mais um ano. Avaliaram-se os sintomas menopausais por meio do índice de Kupperman, além de parâmetros clínicos e ultra-sonográficos (peso, pressão arterial, espessura endometrial) e aspectos relacionados aos eventos adversos e às manifestações cutâneas, através de exame dermatológico. Resultados: Houve melhora global dos sintomas menopausais avaliados pelo índice de Kupperman. A análise detalhada dos sintomas moderados e graves demonstrou melhora significativa dos fogachos, sudorese, parestesia, fadiga, irritabilidade e psicolabilidade, com início ao terceiro mês de tratamento, mantendo-se até o final do período de avaliação. Eritema e prurido no local da aplicação do adesivo foram os eventos cutâneos mais comuns, ocorrendo em 12,1% e 3,0% das pacientes, respectivamente. Discreta taxa de eventos adversos foi observada. Conclusão: A TH transdérmica, contendo estradiol e noretisterona de uso contínuo, mostrou-se efetiva no alívio sintomático em mulheres climatéricas, associando-se a uma discreta taxa de eventos adversos e boa tolerabilidade.