Non-invasive Drug Delivery System Research Articles

Hollow microspheres fabricated from instant adhesive

Non-invasive surgery techniques and drug delivery system with acoustic characteristics of ultrasound contrast agent have been studied intensively in recent years. Many ultrasound contrast agents are commercially available, and they are usually composed of a microbubble coated by a surfactant or lipid bilayer, i.e., a hollow microsphere. We show that the hollow microsphere with polymer shell can be fabricated just blowing vapor of commonly-used instant adhesive into water as microbubbles. The hollow microspheres are composed of cyanoacrylate, a biocompatible material used for adhesion to human tissue such as skin, blood vessels, and organs. Moreover these are less than 10 μm in diameter, which is smaller than a blood capillary (approximately 10 μm). Therefore, with their stable polymer shells, the hollow microspheres are possible ultrasound contrast agents, and are expected to be generated at low cost on the medical frontline, and not in a pharmaceutical factory.

Drug accumulation by means of noninvasive magnetic drug delivery system

The medication is one of the most general treatment methods, but drugs diffuse in the normal tissues other than the target part by the blood circulation. Therefore, side effect in the medication, particularly for a drug with strong effect such as anti-cancer drug, are a serious issue. Drug Delivery System (DDS) which accumulates the drug locally in the human body is one of the techniques to solve the side-effects. Magnetic Drug Delivery System (MDDS) is one of the active DDSs, which uses the magnetic force. The objective of this study is to accumulate the ferromagnetic drugs noninvasively in the deep part of the body by using MDDS. It is necessary to generate high magnetic field and magnetic gradient at the target part to reduce the side-effects to the tissues with no diseases. The biomimetic model was composed, which consists of multiple model organs connected with diverged blood vessel model. The arrangement of magnetic field was examined to accumulate ferromagnetic drug particles in the target model organ by using a superconducting bulk magnet which can generate high magnetic fields. The arrangement of magnet was designed to generate high and stable magnetic field at the target model organ. The accumulation experiment of ferromagnetic particles has been conducted. In this study, rotating HTS bulk magnet around the axis of blood vessels by centering on the target part was suggested, and the model experiment for magnet rotation was conducted. As a result, the accumulation of the ferromagnetic particles to the target model organ in the deep part was confirmed.

Advancements in ocular drug delivery

This review covers both noninvasive and invasive ophthalmic drug delivery systems that can have application to therapy of veterinary ophthalmic diseases. Noninvasive approaches include gel technologies, permeation enhancement via pro-drug development, solubilization agents and nanoparticle technologies, iontophoresis, microneedles, drug-eluting contact lenses and eye misters, and microdroplets. More invasive systems include both eroding implants and noneroding technologies that encompass diffusion based systems, active pumps, intraocular lenses, suprachoroidal drug delivery, and episcleral reservoirs. In addition to addressing the physiologic challenges of achieving the necessary duration of delivery, tissue targeting and patient compliance, the commercial development factors of biocompatibility, sterilization, manufacturability and long-term stability will be discussed.

Noninvasive and persistent transfollicular drug delivery system using a combination of liposomes and iontophoresis

Iontophoresis is a promising technique for enhancing transdermal administration of charged drugs. However, conventional iontophoresis is not sufficient for effective delivery of large, hydrophilic, or electrically neutral molecules. In this study, we utilized charged liposomes as carriers, focused on a transfollicular route for delivery of the liposomes, and optimized iontophoretic conditions and lipid composition for this method in both in vitro and in vivo conditions. As a result, we identified the optimum condition (lipid composition: DOTAP/EPC/Chol=2:2:1, current supply: 0.45mA/cm2, duration: 1h) for effective iontophoretic delivery of aqueous solution, which cannot be transferred into the skin without charged liposomes. We also examined the pharmacological effects of iontophoresis of liposomes encapsulating insulin (INS-lipo) using a rat model of type I diabetes. Interestingly, iontophoresis of INS-lipo onto a diabetes rat skin resulted in a gradual decrease in blood glucose levels, with levels reaching 20% of initial values at 18h after administration. These lower blood glucose levels were maintained for up to 24h. Significant amount of insulin were also detected in plasma 18h after iontophoresis of INS-lipo. We succeeded in developing a non-invasive and persistent transfollicular drug delivery system that used a combination of liposomes and iontophoresis.

Biphasic Vesicles: A Novel Topical Drug Delivery System

Non-invasive drug delivery systems provide alternative routes of administration and improved delivery of drugs to localized target sites in the body. Topically applied dermal and transdermal delivery systems could replace needles required to administer many of the new biologics-based drugs and vaccines, in addition to other significant advantages such as avoiding first-pass hepatic metabolism, gastric degradation and frequent dosing. However, the limited dermal and transdermal delivery of many small and large molecules is a significant challenge because of the unyielding barrier properties of the skin. This paper reviews the application of a novel topical delivery system, biphasic vesicles built from nanoscale components, to the delivery of several therapeutic agents and vaccine antigens and discusses progress toward clinical use.

Cannabidiol bioavailability after nasal and transdermal application: effect of permeation enhancers

Context: The nonpsychoactive cannabinoid, cannabidiol (CBD), has great potential for the treatment of chronic and ‘breakthrough’ pain that may occur in certain conditions like cancer. To fulfill this goal, suitable noninvasive drug delivery systems need to be developed for CBD. Chronic pain relief can be best achieved through the transdermal route, whereas ‘breakthrough’ pain can be best alleviated with intranasal (IN) delivery. Combining IN and transdermal delivery for CBD may serve to provide patient needs-driven treatment in the form of a nonaddictive nonopioid therapy. Objective: Herein we have evaluated the IN and transdermal delivery of CBD with and without permeation enhancers. Materials and Methods: In vivo studies in rats and guinea pigs were carried out to assess nasal and transdermal permeation, respectively. Results: CBD was absorbed intranasally within 10 minutes with a bioavailability of 34–46%, except with 100% polyethylene glycol formulation in rats. Bioavailability did not improve with enhancers. The steady-state plasma concentration of CBD in guinea pigs after transdermal gel application was 6.3 ± 2.1 ng/mL, which was attained at 15.5 ± 11.7 hours. The achievement of a significant steady-state plasma concentration indicates that CBD is useful for chronic pain treatment through this route of administration. The steady-state concentration increased by 3.7-fold in the presence of enhancer. A good in vitro and in vivo correlation existed for transdermal studies. Conclusion: The results of this study indicated that CBD could be successfully delivered through the IN and transdermal routes.

Cell‐penetrating peptide TAT‐mediated delivery of acidic FGF to retina and protection against ischemia–reperfusion injury in rats

The development of non-invasive ocular drug delivery systems is of practical importance in the treatment of retinal disease. In this study, we evaluated the efficacy of transactivator of transcription protein transduction domain (TAT-PTD, TAT49–57) as a vehicle to deliver acidic FGF (aFGF) to retina in rats. TAT-conjugated aFGF-His (TAT-aFGF-His) exhibited efficient penetration into the retina following topical administration to the ocular surface. Immunochemical staining with anti-His revealed that TAT-aFGF-His proteins were readily found in the retina (mainly in the ganglion cell layer) at 30 min. and remained detectable for at least 8 hrs after administration. In contrast, His+ proteins were undetectable in the retina after topical administration of aFGF-His, indicating that aFGF-His cannot penetrate the ocular barrier. Furthermore, TAT-aFGF-His, but not aFGF-His, mediated significant protection against retinal ischemia–reperfusion (IR) injury. After IR injury, retina from TAT-aFGF-His-treated rats showed better-maintained inner retinal layer structure, reduced apoptosis of retinal ganglion cells and improved retinal function compared to those treated with aFGF-His or PBS. These results indicate that conjugation of TAT to aFGF-His can markedly improve the ability of aFGF-His to penetrate the ocular barrier without impairing its biological function. Thus, TAT49–57 provides a potential vehicle for efficient drug delivery in the treatment of retinal disease.

Ocular Drug Delivery

Ocular drug delivery has been a major challenge to pharmacologists and drug delivery scientists due to its unique anatomy and physiology. Static barriers (different layers of cornea, sclera, and retina including blood aqueous and blood-retinal barriers), dynamic barriers (choroidal and conjunctival blood flow, lymphatic clearance, and tear dilution), and efflux pumps in conjunction pose a significant challenge for delivery of a drug alone or in a dosage form, especially to the posterior segment. Identification of influx transporters on various ocular tissues and designing a transporter-targeted delivery of a parent drug has gathered momentum in recent years. Parallelly, colloidal dosage forms such as nanoparticles, nanomicelles, liposomes, and microemulsions have been widely explored to overcome various static and dynamic barriers. Novel drug delivery strategies such as bioadhesive gels and fibrin sealant-based approaches were developed to sustain drug levels at the target site. Designing noninvasive sustained drug delivery systems and exploring the feasibility of topical application to deliver drugs to the posterior segment may drastically improve drug delivery in the years to come. Current developments in the field of ophthalmic drug delivery promise a significant improvement in overcoming the challenges posed by various anterior and posterior segment diseases.

Targeted drug delivery system for oral cancer therapy using sonoporation

Ultrasound-mediated destruction of microbubbles has been proposed as an innovative non-invasive drug delivery system for cancer therapy. We developed a specific drug delivery system for squamous cell carcinoma that uses sonoporation with the anti-epidermal growth factor receptor (EGFR) antibody. Administration of a low dose of bleomycin (BLM) by sonoporation with the anti-EGFR antibody produced a marked growth inhibition of Ca9-22 cells in vitro. In addition, scanning electron microscopic analysis revealed apparent surface deformation of Ca9-22 cells treated with sonoporation in the presence of the antibody. Interestingly, the population of apoptotic cells was remarkably increased when a low dose of BLM was delivered using sonoporation with the Fab fragment of the anti-EGFR antibody. These findings indicate that sonoporation with the Fab fragment makes it possible to administer drugs into cells more efficiently and specifically, suggesting a novel application for chemotherapy and gene therapy treatments for oral squamous cell carcinoma.

Investigation of In Vitro Iontophoresis Facilitated Transdermal Delivery of Glycine

The research presented in this paper discusses the potential of iontophoresis facilitated transdermal delivery of glycine. Iontophoresis has been widely investigated as a noninvasive transdermal drug delivery system. Iontophoresis is the use of a low electric current to carry ionized as well as unionized drug molecules across tissues (like skin) in a noninvasive technique. In the present paper, a custom made low cost, battery powered, portable transdermal iontophoretic system has been investigated for the various parameters of transdermal iontophoretic drug delivery namely drug density in donor formulation, current density, current profile, presence of competitive ions and type of electrode material. In vitro release studies of glycine, as a drug, were done using a modified Franz type glass diffusion cell through excised mouse skin. Factors affecting the delivery of glycine (a non-essential amino acid used to treat schizophrenia, anxiety, insomnia, hypoglycemia etc.) by iontophoresis include concentration of glycine in donor solution, ionic strength of donor solution, density of applied current & its aspect ratio. The change in frequency and electrode type (Ag/AgCl & stainless steel) did not have any significant effect on glycine delivery. In conclusion it could be stated that it is possible to achieve appreciable control over the transdermal delivery of glycine by the low-cost portable iontophoretic drug delivery system developed.

Mucoadhesive drug carriers and polymers for effective drug delivery

The concept of mucoadhesion for the design of non-invasive drug delivery systems has gained increasing attention in recent years. Within the current review, various mucoadhesive polymers, including poly(acrylates), chitosan, thiolatedpolymers and others, as well as their use in mucosal drug delivery are discussed. An emphasis has been put on the development of mucoadhesive formulations, and in particular on recently developed micro-and nanoparticulate systems. Moreover, the applications of the mucoadhesive carrier systems for different administration routes such as the oral, nasal, pulmonary and ocular route are discussed.

The Management of Pain

The Management of Pain

Ocular toxicity of iontophoretic foscarnet in rabbits.

Transscleral iontophoresis of foscarnet is a noninvasive drug delivery system for the local treatment of cytomegalovirus (CMV) retinopathy. We determined the retinotoxic effects of transscleral iontophoresis of foscarnet. Slit-lamp biomicroscopy revealed no toxic effects for any of the treated eyes. Indirect ophthalmoscopy showed retinal and choroidal burns 1-3 mm in diameter at the site of iontophoresis in both foscarnet-treated eyes and saline-treated control eyes. Light and electron microscopy revealed focal retinal, retinal pigment epithelial, and choroidal necrosis at the site of iontophoresis but no abnormalities elsewhere. Ganzfeld electroretinographic studies revealed no response differences between foscarnet-treated eyes vs. controls.