Non-invasive Drug Delivery System Research Articles

Numerical simulation of iontophoresis in the drug delivery system

The architecture and composition of stratum corneum act as barriers and limit the diffusion of most drug molecules and ions. Much effort has been made to overcome this barrier and it can be seen that iontophoresis has shown a good effect. Iontophoresis represents the application of low electrical potential to increase the transport of drugs into and across the skin or tissue. Iontophoresis is a noninvasive drug delivery system, and therefore, it is a useful alternative to drug transportation by injection. In this study, we present a numerical model and effects of electrical potential on the drug diffusion in the buccal tissue and the stratum corneum. The initial numerical results are in good comparison with experimental observation. We demonstrate that the application of an applied voltage can greatly improve the efficacy of localized drug delivery as compared to diffusion alone.

Recent advances in drug delivery to the retina

SummaryDrug delivery to the retina is presently one of the greatest challenges in ophthalmology due to the inherent limitations of ocular barriers. This therapeutic impediment affects many promising treatments including; anti‐VEGFs, which have revolutionised the management of age‐related macular degeneration, and have increasing indications for use as sight‐saving therapies in diabetes and retinal vascular disease. However, large molecular weight anti‐VEGF therapies such as ranibizumab and bevacizumab currently require invasive intravitreal (IVT) injections to bypass ocular barriers, and thus carry a risk of significant side effects. Despite this, the success of anti‐VEGF therapies has led to a dramatic increase in the number of IVT procedures, placing a high burden on healthcare resources. For these reasons, the development of non‐invasive ocular drug delivery systems has received considerable interest in recent years. This talk outlines the current understanding of anatomical barriers to ocular drug delivery and recent developments in overcoming these barriers for delivery of large drug cargo to posterior ocular tissues. Particular focus will be paid to the role of nanotechnology and annexin A5, which we recently reported to enhance the delivery of topically applied bevacizumab to the rabbit retina.

Development of a Nanoparticle-Embedded Chitosan Sponge for Topical and Local Administration of Chemotherapeutic Agents.

The following work describes the development of a novel noninvasive transmucosal drug delivery system, the chitosan sponge matrix (CSM). It is composed of cationic chitosan (CS) nanoparticles (NPs) that encapsulate cisplatin (CDDP) embedded within a polymeric mucoadhesive CS matrix. CSM is designed to swell up when exposed to moisture, facilitating release of the NPs via diffusion across the matrix. CSM is intended to be administered topically and locally to mucosal tissues, with its initial indication being oral cancer (OC). Currently, intravenous (IV) administered CDDP is the gold standard chemotherapeutic agent used in the treatment of OC. However, its clinical use has been limited by its renal and hemotoxicity profile. We aim to locally administer CDDP via encapsulation in CS NPs and deliver them directly to the oral cavity with CSM. It is hypothesized that such a delivery device will greatly reduce any systemic toxicity and increase antitumor efficacy. This paper describes the methods for developing CSM and maintaining the integrity of CDDP NPs embedded in the CSM.

Recent advances in the oral delivery of insulin.

Insulin was discovered over 90 years ago. However oral insulin still remains a challenging and elusive goal. Extensive efforts are being made worldwide for developing noninvasive drug delivery systems, mainly via oral route as it is the most widely accepted means of administration. The main barriers faced in oral protein delivery are the enzymatic degradation and poor permeability across the intestinal wall. The approaches for developing an oral insulin delivery system mainly focus on overcoming these barriers. To overcome the gastro-intestinal barriers various types of formulations such as insulin conjugates, permeation enhancers, micro/nanoparticles, liposomes etc. are investigated. In the recent years a number of advances have taken place in understanding the needs and workable mechanisms of improved oral peptide delivery systems. In this review the recent patents on oral insulin is focused. Emphasis is on the technologies based on permeation enhancers and nanoparticle based carrier systems.

Design and development of a safer non-invasive transungual drug delivery system for topical treatment of onychomycosis

Objective: The main objective of this study is to develop a safer non-invasive treatment for nail infections since the current treatment regimen has drawbacks like, incidence of systemic side-effects and higher cost. Proposed topical treatment on the other hand can drastically improve the situation, hence highly desirable. This work was undertaken with a hypothesis to develop a transungual microemulsion gel for topical treatment of onychomycosis.Methods: Benzyl alcohol and isopropyl myristate were used as oil, Pluronic F68 as surfactant and ethanol as co surfactant, in double-distilled water and loading itraconazole as the model antifungal drug. Pseudo-ternary phase diagram was developed by titrating different ratios of total oil and water with total surfactant, and Km ratio was fixed at 1:1. Microemulsion formulations were prepared based on the phase diagram and incorporated in gels by adding Carbopol 934P. Nail permeation enhancers like urea and salicylic acid were used to increase drug permeation through the nail plate. Parameters like drug loading, clarity, particle size distribution, drug entrapment efficiency (DEE), drug release profile, release kinetics and nail uptake were checked for the evaluation of the formulations.Results: Complete release of drug from the formulation varied from 60 to 120 min. The optimized formulation had DEE of 92.75%, complete drug release in 60 min and highest nail uptake of 0.386%/mm2 (39 µg of drug) with 5% urea as nail permeation enhancer.Conclusion: The formulation may prove beneficial in safer treatment of onychomycosis.

Topical Delivery of Avastin to the Posterior Segment of the Eye In Vivo Using Annexin A5‐associated Liposomes

Effective delivery to the retina is presently one of the most challenging areas in drug development in ophthalmology, due to anatomical barriers preventing entry of therapeutic substances. Intraocular injection is presently the only route of administration for large protein therapeutics, including the anti-Vascular Endothelial Growth Factors Lucentis (ranibizumab) and Avastin (bevacizumab). Anti-VEGFs have revolutionised the management of age-related macular degeneration and have increasing indications for use as sight-saving therapies in diabetes and retinal vascular disease. Considerable resources have been allocated to develop non-invasive ocular drug delivery systems. It has been suggested that the anionic phospholipid binding protein annexin A5, may have a role in drug delivery. In the present study we demonstrate, using a combination of in vitro and in vivo assays, that the presence of annexin A5 can significantly enhance uptake and transcytosis of liposomal drug carrier systems across corneal epithelial barriers. This system is employed to deliver physiologically significant concentrations of Avastin to the posterior of the rat eye (127 ng/g) and rabbit retina (18 ng/g) after topical application. Our observations provide evidence to suggest annexin A5 mediated endocytosis can enhance the delivery of associated lipidic drug delivery vehicles across biological barriers, which may have therapeutic implications.

J0260101 円筒水槽型ソノポレーションシステムにおけるディッシュ内の音場変化が生細胞残存率に及ぼす影響([J026]薬剤送達とバイオメカニクス,バイオエンジニアリング部門)

Transient cell membrane permeabilization by using ultrasound with the aid of microbubbles, i.e., sonoporation, is one of promising techniques for non-invasive drug delivery system. To improve the efficiency of successful sonoporation and the survival fraction of cells after the procedure, various in vitro sonoporation systems have been developed. Here, we report how experimental settings of the Well-on-Water-Surface (WWS) type in vitro sonoporation system affect the survival fraction of cells under sonoporation conditions. By changing the medium height of the cell culture dish by 0.1 mm, we measured the peak pressure amplitude in the dish during exposure to 1 MHz continuous wave ultrasound and counted the number of viable cells before and after exposure to the ultrasound with the aid of 0.1 ml/dish microbubbles SONAZOID[○!R]. Under the experimental condition, the peak pressure amplitude varied in the range from 0.4 to 0.6 MPa, and the survival fraction, the fraction of the number of viable cells after the procedure, from 25 to 85 %, which may be explained by the effects of standing wave in the dish. For the better estimation of sonoporation efficiency in the WWS type sonoporation system, the medium height in the dish should be set carefully.

English

Topical administration of gentamicin, a hydrophilic aminoglycoside antibiotic, is limited by membrane impermeability and toxicity concerns. The purpose of this study was to develop and evaluate the antimicrobial activities of an alternative non-invasive, convenient and cost-effective transdermal drug delivery system (TDDS) containing gentamicin in biodegradable polyester-based matrices. The patches were formulated by solvent evaporation technique using PURASORB® polymers and evaluated for thermal properties, drug content, physicochemical performance, stability, skin irritation on rat skin and antimicrobial activities against five micro-organisms: Staphylococcus aureus, Escherichia coli, Salmonella typhi,Pseudomonas aeruginosa, and Klebsiella pneumoniae. The differential scanning calorimetry(DSC) results indicated compatibilty between the drug and the polymers. In addition, theformulations showed good drug encapsulation, stability, physicochemical properties, tolerability on rabbit skin and higher zones of inhibition compared with a commercially available gentamicin sulphate cream against S. aureus, E. coli, S. typhi and P. aeruginosa, while K. pneumoniae was mildly susceptible. Compared with the rest of the formulations, patches of PURASORB® PL 32 exhibited the best stability, tolerability on rat skin and bioactivity. This study has shown that transdermal patches of PURASORB® PL 32 represent an alternative delivery system for gentamicin for treatment of infections caused by gentamicin-susceptible micro-organisms.   Key words: Antimicrobial activities, bioadhesive strength, gentamicin, PURASORB®polymers, transdermal patches.

Formulation, characterization and ex-vivo permeation studies on gentamicin-loaded transdermal patches based on PURASORB polymers

Topical administration of gentamicin, an aminoglycoside antibiotic commonly used for treatment of bacterial infections, is limited by toxicity and membrane impermeability. The purpose of this study was to develop an alternative non-invasive, convenient and cost-effective drug delivery system for enhanced skin delivery of gentamicin. The patches were formulated by solvent evaporation technique using PURASORB® polymers and evaluated for drug content, thermal properties, physicochemical performance, stability, skin irritability and ex-vivo drug permeation through rat skin using a modified Franz diffusion cell. The DSC results indicate absence of strong interaction between gentamicin and the polymers. Theformulations showed good drug encapsulation, stability, physicochemical properties, tolerability on rat skin and ex-vivo drug permeation through rat skin.Compared with a commercially available gentamicin sulphate cream the transdermal patches gave higher ex-vivo skin permeation through rat skin with patches of PURASORB® PL 32 showing highest permeation flux (5.161 µg/cm2.h) and permeation coefficient (1.032 × 10-6 cm/h). The results of this study indicates that patches of PURASORB® PL 32 represent a new delivery system for enhnaced skin delivery of gentamicin. Key words: Transdermal patches, gentamicin, PURASORB® polymers,bioadhesive strength, ex-vivo drug release.

Precise Control of the Drug Kinetics by Non-Invasive Magnetic Drug Delivery System

To solve the problems of side effects and medicinal lowering, studies on the magnetic drug delivery system (MDDS) have been applied. MDDS is a technique to accumulate drugs by using magnetic force as the physical driving force. It is necessary to apply a strong external magnetic field and high magnetic gradient to accumulate the ferromagnetic drugs to a deep diseased part noninvasively. However, by applying a static magnetic field from one direction, the drug accumulates only at the body surface near the magnet. In this study, we proposed a new method of MDDS in which a high-temperature superconducting (HTS) bulk magnet rotates around a target part. First, the particle trajectory simulation was conducted to examine the drug kinetics in a capillary blood vessel under the condition of rotating a magnet. Based on the results, the accumulation experiments of ferromagnetic particles with model blood vessels were conducted. As a result, the accumulation possibility of the ferromagnetic particles in the deep targeted part of the body was confirmed.

Lactoferrin-modified PEG-co-PCL nanoparticles for enhanced brain delivery of NAP peptide following intranasal administration

Development of effective non-invasive drug delivery systems is of great importance to the treatment of Alzheimer's diseases and has made great progress in recent years. In this work, lactoferrin (Lf), a natural iron binding protein, whose receptor is highly expressed in both respiratory epithelial cells and neurons is here utilized to facilitate the nose-to-brain drug delivery of neuroprotection peptides. The Lf-conjugated PEG-PCL nanoparticle (Lf-NP) was constructed via a maleimide-thiol reaction with the Lf conjugation confirmed by CBQCA Protein Quantitation and XPS analysis. Other important parameters such as particle size distribution, zeta potential and in vitro release of fluorescent probes were also characterized. Compared with unmodified nanoparticles (NP), Lf-NP exhibited a significantly enhanced cellular accumulation in 16HBE14o-cells through both caveolae-/clathrin-mediated endocytosis and direct translocation. Following intranasal administration, Lf-NP facilitated the brain distribution of the coumarin-6 incorporated with the AUC0–8h in rat cerebrum (with hippocampus removed), cerebellum, olfactory tract, olfactory bulb and hippocampus 1.36, 1.53, 1.70, 1.57 and 1.23 times higher than that of coumarin-6 carried by NP, respectively. Using a neuroprotective peptide – NAPVSIPQ (NAP) as the model drug, the neuroprotective and memory improvement effect of Lf-NP was observed even at lower dose than that of NP in a Morris water maze experiment, which was also confirmed by the evaluation of acetylcholinesterase, choline acetyltransferase activity and neuronal degeneration in the mice hippocampus. In conclusion, Lf-NP may serve as a promising nose-to-brain drug delivery carrier especially for peptides and proteins.

Ultrasound enhanced release of therapeutics from drug-releasing implants based on titania nanotube arrays

A non-invasive and external stimulus-driven local drug delivery system (DDS) based on titania nanotube (TNT) arrays loaded with drug encapsulated polymeric micelles as drug carriers and ultrasound generator is described. Ultrasound waves (USW) generated by a pulsating sonication probe (Sonotrode) in phosphate buffered saline (PBS) at pH 7.2 as the medium for transmitting pressure waves, were used to release drug-loaded nano-carriers from the TNT arrays. It was demonstrated that a very rapid release in pulsatile mode can be achieved, controlled by several parameters on the ultrasonic generator. This includes pulse length, time, amplitude and power intensity. By optimization of these parameters, an immediate drug-micelles release of 100% that spans a desirable time of 5-50 min was achieved. It was shown that stimulated release can be generated and reproduced at any time throughout the TNT-Ti implant life, suggesting considerable potential of this approach as a feasible and tunable ultrasound-mediated drug delivery system in situ via drug-releasing implants. It is expected that this concept can be translated from an in vitro to in vivo regime for therapeutic applications using drug-releasing implants in orthopedic and coronary stents.

Local use of iontophoresis with traditional Chinese herbal medicine, e.g., Gu-Sui-Bu (Rhizoma Drynariae) may accelerate orthodontic tooth movement

Introduction: Mechanical force is not the only means to cause tooth movement, but just one kind of stimuli for it. Biological stimuli, with potential of accelerating alveolar bone remodeling, other than mechanical force, have been attracted by orthodontists who are combating prolonged treatment duration. It has been approved that some traditional Chinese medicines, such as Gu-Sui-Bu (Rhizoma Drynaria), affect the process of bone remodeling. The Hypothesis: We make the hypothesis that local use of iontophoresis with Gu-Sui-Bu (Rhizoma Drynaria) as a non-invasive and safe drug delivery system with no trauma, risk of infection or damage to patients is a new potential approach for accelerating orthodontic tooth movement, and shorten the orthodontic treatment time. Evaluation of the Hypothesis: Gu-Sui-Bu is effective at inducing bone remodeling, and iontophoresis as a non-invasive technique for drug delivery, is suitable for the transmission of some traditional Chinese herbal medicines into periodontal tissues.

Precise control of the drug kinetics by means of non-invasive magnetic drug delivery system

In order to solve the problems of the side effects and medical lowering, has been advanced a study on the drug delivery system (DDS) to accumulate the drugs locally in the body with minimum dosage. The DDS is a system that controls the drug kinetics in the body precisely and accumulates the drug locally at the target part, keeping the drugs at high density. Among the DDS, the magnetic drug delivery system (MDDS) is the one that we studied. This is a technique to accumulate drugs by using the magnetic force as the physical driving force. Our previous researches showed the possibility of the technique of MDDS to accumulate the drugs with higher accumulation rate and locality than the traditional methods. It is necessary to apply a strong external magnetic field and a high magnetic gradient to accumulate the ferromagnetic drugs at a deep diseased part non-invasively. However, by applying a static magnetic field from one direction, the drug accumulates only at the surface of the body locates near the magnet. In this study, we tried to change the magnetic field applied by a superconducting bulk magnet with time, in order to make a constant and strong magnetic field applied in the center of the body and to accumulate the ferromagnetic drugs at the deep target part in the body.First of all, the effect of the surface treatment of the ferromagnetic drugs to prevent its absorption in the normal tissue was examined. Then, to increase the accumulation rate of the ferromagnetic drugs at the target part, the distribution of magnetic field was changed, and the optimum spatial and temporal conditions of magnetic field were examined.

Oral delivery of therapeutic protein/peptide for diabetes – Future perspectives

Diabetes is a metabolic disease and is a major cause of mortality and morbidity in epidemic proportions. A type I diabetic patient is dependent on daily injections of insulin, for survival and also to maintain a normal life, which is uncomfortable, painful and also has deleterious effects. Extensive efforts are being made worldwide for developing noninvasive drug delivery systems, especially via oral route. Oral route is the most widely accepted means of administration. However it is not feasible for direct delivery of peptide and protein drugs. To overcome the gastro-intestinal barriers various types of formulations such as polymeric micro/nanoparticles, liposomes, etc. are investigated. In the recent years lot of advances have taken place in developing and understanding the oral peptide delivery systems. Simultaneously, the development and usage of other peptides having anti-diabetic potentials are also considered for diabetes therapy. In this review we are focusing on the advances reported during the past decade in the field of oral insulin delivery along with the possibility of other peptidic incretin hormones such as GLP-1, exendin-4, for diabetes therapy.

PHOTOPNEUMATIC TECHNOLOGY IN ACNE TREATMENT AND SKIN REJUVENATION: HISTOLOGICAL ASSESSMENT

Recent reports indicate that a variety of light-based devices have been used for acne treatment and skin rejuvenation. A new technology combining intense pulsed light with negative pressure, photopneumatic technology, has recently attracted interest. The present study assessed acne treatment and skin rejuvenation with this novel approach Subjects and Methods: Acne, 450 nm tip. Five Japanese volunteers (1 male, 4 female; mean age 28.6 yr; skin type III) with mild to moderate/moderate active acne participated. The face was treated with 2 sessions, 2 weeks apart. Biopsies were obtained immediately after the first session and 1 week after the second session, and routinely processed for transmission electron microscopy (TEM). Rejuvenation, profusion tip with topical preparation . In 5 Japanese volunteers (3 male, 2 female; mean age 37.6 yr, skin type III), the volar aspect of both forearms was treated with the 530 nm head at P6 (around 12 J/cm(2)). The left arm was then treated with a pre-infused profusion tip and vacuum only. Four sessions were given, 14-day intervals. Biopsies were taken from both arms 2 weeks after the 2nd session and 3 weeks after the 4th session. One-half of each biopsy was assessed with histo-and immunohistochemistry, and the other with TEM. Acne trial: A combination of physical extraction of comedones, mild photothermal damage of the follicle and damage to identified bacilli was noted post-treatment, with macroscopic improvement of the skin. Rejuvenation with profusion: Significant morphological and immunohistochemical differences were seen between the control and profusion-treated arms at the first assessment. These differences became less significant at the 2nd assessment. Macroscopically and histologically, photopneumatic technology improved acne lesions, suggesting a synergistic effect between the components of the technology. In skin rejuvenation, the profusion therapy accelerated the regenerative process, and could have excellent additional potential as a noninvasive transepidermal drug delivery system.

A Non-invasive Drug Delivery System Using Claudin Binder

The intercellular spaces between adjacent epithelial cells are sealed by tight junctions (TJs). Modulation of TJ-seal is a potent strategy for drug absorption. Claudin is a key structural and functional component of TJ-seal. Claudin comprises a tetra-transmembrane protein family consisting of more than 20 members, whose expression profiles and barrier-function differ among tissues. For instance, claudin-1 plays roles in the epidermal and mucosal barriers, and claudin-4 regulates the mucosal barrier. Claudin forms homo- and hetero-type TJ strands. Properties of TJ-seal are determined by combination of the claudin family members. Some claudin strands work as size-selective or charge-selective paracellular routes for solutes. Thus, claudin modulators will make it possible to deliver drugs in a solute- and tissue-specific manner. The C-terminal fragment of the Clostridium perfringens enterotoxin (C-CPE) is the most characterized claudin modulator. In this review, we describe potency of claudin-targeting mucosal absorption, and we mentioned development of a novel claudin modulator using C-CPE as a prototype.

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.