Linear delivery of verapamil via nanofibrous sheet-based system.

PURPOSE: To achieve linear delivery of a highly water-soluble oral drug, verapamil, with a nanofibrous sheet-based system. METHODS: The nanofibrous sheets made of poly (lactic-co-glycolic acid) were used as a diffusion barrier to cap a tablet containing verapamil. For controlled drug delivery, we varied the sheet thickness to 20 µm, 50 µm and 80 µm to give the capped drug tablets, 20CT, 50CT and 80CT, respectively. RESULTS: Drug release was more sustained as the sheet thickness increased. Thus, the periods for almost complete drug release could be extended up to 14 h with the 80 µm-thick sheets. As we assessed the linear least square fits to the in vitro drug release data from the capped tablets, 20CT and 50CT showed a fairly good correlation with linear release. The periods of linear release were 6 h and 8 h for 20CT and 50CT, respectively, both releasing more than 85% drug during this period. CONCLUSION: We conclude that a drug tablet capped with nanofibrous sheets is a promising system for linear delivery of a highly water-soluble oral drug.

Brimonidine-montmorillonite hybrid formulation for topical drug delivery to the eye.

Brimonidine (BMD) is often prescribed as an eye drop to reduce the intraocular pressure (IOP) for glaucoma treatment. However, eye drops are limited by rapid clearance from the preocular surface, and hence a low ocular drug bioavailability. Therefore, in this study, we propose montmorillonite (MMT), as a delivery carrier, hybridized with BMD (BMD-MMT) for topical drug delivery to the eye. The BMD-MMT hybrid was prepared by intercalating the BMD molecules in the interlayer space of the MMT lattice via ion-exchange reaction; it was then formulated with polyvinyl alcohol (PVA) to produce a dry tablet (i.e., BMD-MMT@PVA). The BMD-MMT@PVA hybrid drug released BMD in a sustained manner for more than 5 h under in vitro conditions. When the hybrid drug was administered to rabbit eyes in vivo, 43% and 18.5% BMD-MMT still remained on the preocular surface for 10 and 60 min after administration, respectively. Thus, the BMD-MMT@PVA hybrid drug exhibited a prolonged decrease in IOP, that is, for 12 h, which was approximately two times longer than that observed with the commercially available BMD eye drop, Alphagan® P.

Nanoparticle coating on the silane-modified surface of magnesium for local drug delivery and controlled corrosion.

In this study, we proposed a potential method for the preparation of a magnesium-based medical device for local drug delivery and controlled corrosion. A magnesium surface was modified with 3-aminopropyltrimethoxy silane, and the resulting surface was then coated with drug-loaded nanoparticles made of poly (lactic-co-glycolic acid) via electrophoretic deposition. The drug-loaded nanoparticles (i.e., Tr_NP) exhibited a size of 250 ± 67 nm and a negative zeta potential of -20.9 ± 2.75 mV. The drug was released from the nanoparticles in a sustained manner for 21 days, and this did not change after their coating on the silane-modified magnesium. The silane-modified surface suppressed magnesium corrosion. When immersed in phosphate buffered saline at pH 7.4, the average rate of hydrogen gas generation was 0.41-0.45 ml/cm(2)/day, compared to 0.58-0.6 ml/cm(2)/day from a bare magnesium surface. This corrosion profile was not significantly changed after nanoparticle coating under the conditions employed in this work. The in vitro cell test revealed that the drug released from the coating was effective during the whole release period of 21 days, and both the silane-modified surface and carrier nanoparticles herein were not cytotoxic.

Theranostic Bioabsorbable Bone Fixation Plate with Drug-Layered Double Hydroxide Nanohybrids.

A bioabsorbable polymeric bone plate enabled with both diagnostic and therapeutic functionalities (radiopacity and sustained drug release, respectively) is proposed. To this end, a drug-inorganic nanohybrid (RS-LDH) is examined as a theranostic agent by intercalating an anti-resorptive bone remodeling drug, risedronate (RS) into a layered double hydroxide (LDH) via an ion-exchange reaction. The RS-LDH is prepared as a sheet with a biodegradable polymer, poly(lactic-co-glycolic acid), and is then attached onto the clinically approved bioabsorbable bone plate to produce the theranostic plate. Because of the presence of the metals in the LDH, the theranostic plate results in discernible in vivo X-ray images for up to four weeks after implantation. Concurrently, bone regeneration is also significantly improved compared with the other control groups, likely because of this material's sustained drug-release property. The theranostic plate is also largely biocompatible, similar to the plate already approved for clinical use. It is concluded that the combination of a biodegradable bone plate with RS-LDH nanohybrids can constitute a promising system with theranostic ability in both X-ray diagnosis and expedited bone repair.

Acute suppression of TGF-ß with local, sustained release of tranilast against the formation of fibrous capsules around silicone implants.

We propose the acute, local suppression of transforming growth factor beta (TGF-ß), a major profibrotic cytokine, to reduce fibrosis around silicone implants. To this end, we prepared silicone implants that were able to release tranilast, a TGF-ß inhibitor, in a sustained manner for 5 days or 15 days. We performed histologic and immunohistochemical analyses for 12 weeks after the implantation of the implants in living rats. The capsule thicknesses and collagen densities significantly decreased compared with those around the non-treated silicone implants. Notably, early suppression of TGF-ß affected the fibrogenesis that actually occurs at the late stage of wound healing. This change may be ascribed to the decrease in monocyte recruitment mediated by early TGF-ß during the acute inflammatory reaction. Thus, a significant decrease in differentiated macrophages was observed along with a decrease in the quantity of TGF-ß and fibroblasts during the subsequent inflammation stage; these changes led to a diminished fibrotic capsule formation.

Mucoadhesive microparticles with a nanostructured surface for enhanced bioavailability of glaucoma drug.

Topical drug administration to the eye is limited by low drug bioavailability due to its rapid clearance from the preocular surface. Thus, multiple daily administrations are often needed, but patient compliance is low, hence a high chance of unsatisfactory treatment of ocular diseases. To resolve this, we propose mucoadhesive microparticles with a nanostructured surface as potential carriers for delivery of brimonidine, an ocular drug for glaucoma treatment. For sustained drug delivery, the microparticles were composed mainly of a diffusion-wall material, poly(lactic-co-glycolic acid) and a mucoadhesive polymer, polyethylene glycol, was used as an additive. Due to their nanostructured surface, the microparticles with a mucoadhesive material exhibited a 13-fold increase in specific surface area and could thus adhere better to the mucous layer on the eye, as compared with the conventional spherical microparticles. When loaded with brimonidine, the mucoadhesive microparticles with a nanostructured surface increased both drug bioavailability and its activity period by a factor of more than 2 over Alphagan P, a marketed eye drop of brimonidine.

Bioabsorbable bone fixation plates for X-ray imaging diagnosis by a radiopaque layer of barium sulfate and poly(lactic-co-glycolic acid).

Bone fixation systems made of biodegradable polymers are radiolucent, making post-operative diagnosis with X-ray imaging a challenge. In this study, to allow X-ray visibility, we separately prepared a radiopaque layer and attached it to a bioabsorbable bone plate approved for clinical use (Inion, Finland). We employed barium sulfate as a radiopaque material due to the high X-ray attenuation coefficient of barium (2.196 cm(2) /g). The radiopaque layer was composed of a fine powder of barium sulfate bound to a biodegradable material, poly(lactic-co-glycolic acid) (PLGA), to allow layer degradation similar to the original Inion bone plate. In this study, we varied the mass ratio of barium sulfate and PLGA in the layer between 3:1 w/w and 10:1 w/w to modulate the degree and longevity of X-ray visibility. All radiopaque plates herein were visible via X-ray, both in vitro and in vivo, for up to 40 days. For all layer types, the radio-opacity decreased with time due to the swelling and degradation of PLGA, and the change in the layer shape was more apparent for layers with a higher PLGA content. The radiopaque plates released, at most, 0.5 mg of barium sulfate every 2 days in a simulated in vitro environment, which did not appear to affect the cytotoxicity. The radiopaque plates also exhibited good biocompatibility, similar to that of the Inion plate. Therefore, we concluded that the barium sulfate-based, biodegradable plate prepared in this work has the potential to be used as a fixation device with both X-ray visibility and biocompatibility.

Drug-inorganic-polymer nanohybrid for transdermal delivery.

For transdermal drug delivery, we prepared a drug-inorganic nanohybrid (FB-LDH) by intercalating a transdermal model drug, flurbiprofen (FB), into the layered double hydroxides (LDHs) via coprecipitation reaction. The X-ray diffraction patterns and FT-IR spectra of the FB-LDH indicated that the FB molecules were successfully intercalated via electrostatic interaction within the LDH lattices. The in vitro drug release revealed that the Eudragit(®) S-100 in release media could facilitate the drug out-diffusion by effectively replacing the intercalated drug and also enlarging the lattice spacing of the FB-LDH. In this work, a hydrophobic gel suspension of the FB-LDH was suggested as a transdermal controlled delivery formulation, where the suspensions were mixed with varying amounts of Eudragit(®) S-100 aqueous solution. The Frantz diffusion cell experiments using mouse full-skins showed that a lag time and steady-state flux of the drug could be controlled from 12.8h and 3.28µgcm(-2)h(-1) to less than 1h and 14.57µgcm(-2)h(-1), respectively, by increasing the mass fraction of Eudragit(®) S-100 solution in gel suspensions from 0% to 20% (w/w), respectively. Therefore, we conclude gel formulation of the FB-LDH have a potential for transdermal controlled drug delivery.

Biodegradable internal fixation plates enabled with X-ray visibility by a radiopaque layer of ß-tricalcium phosphate and poly (lactic-co-glycolic acid).

Biodegradable polymer plates can be clinically used as an alternative to metal plates (e.g., titanium) for internal fixation, which, however, are not visible with X-ray imaging, often used for post-operative diagnostics. In this study, therefore, we prepared a biodegradable plate enabled with X-ray visibility by attaching a radiopaque layer on a biodegradable fixation plate in clinical use (Inion, Finland). A radiopaque layer was made of a fine powder of a radiopaque agent, ß-tricalcium phosphate (TCP) and a biodegradable binder material, poly (lactic-co-glycolic acid) (PLGA), which were physically mixed without change in their chemical structure. The radiopacity increased as we increased the layer thicknesses from 0.5 mm to 1.3 mm. Regardless of layer thickness, however, the radiopacity decreased with time both in vitro and in vivo due to decreasing density of TCP in the layer by swelling and degradation of a binder material, PLGA. The in vivo study with rabbits revealed that a discernible image of the radiopaque plate could be obtained by X-ray for up to 21 days, also showing the overall biocompatibility 6 months after implantation. Therefore, we conclude that the radiopaque plate prepared in this work is a promising fixation device enabled with both X-ray visibility and biodegradability.

Surgical suture assembled with polymeric drug-delivery sheet for sustained, local pain relief.

Surgical suture is a strand of biocompatible material designed for wound closure, and therefore can be a medical device potentially suitable for local drug delivery to treat pain at the surgical site. However, the preparation methods previously introduced for drug-delivery sutures adversely influenced the mechanical strength of the suture itself - strength that is essential for successful wound closure. Thus, it is not easy to control drug delivery with sutures, and the drug-delivery surgical sutures available for clinical use are now limited to anti-infection roles. Here, we demonstrate a surgical suture enabled to provide controlled delivery of a pain-relief drug and, more importantly, we demonstrate how it can be fabricated to maintain the mechanical strength of the suture itself. For this purpose, we separately prepare a drug-delivery sheet composed of a biocompatible polymer and a pain-relief drug, which is then physically assembled with a type of surgical suture that is already in clinical use. In this way, the drug release profiles can be tailored for the period of therapeutic need by modifying only the drug-loaded polymer sheet without adversely influencing the mechanical strength of the suture. The drug-delivery sutures in this work can effectively relieve the pain at the surgical site in a sustained manner during the period of wound healing, while showing biocompatibility and mechanical properties comparable to those of the original surgical suture in clinical use.

Long-term efficacy and rotational stability of AcrySof toric intraocular lens implantation in cataract surgery.

PURPOSE: To evaluate the long-term efficacy and rotational stability of the AcrySof toric intraocular lens (IOL) in correcting preoperative astigmatism in cataract patients. METHODS: This prospective observational study included 30 eyes from 24 consecutive patients who underwent implantation of an AcrySof toric IOL with micro-coaxial cataract surgery between May 2008 and September 2008. Outcomes of visual acuity, refractive and keratometric astigmatism, and IOL rotation after 1 day, 1 month, 3 months, and long-term (mean, 13.3+/-5.0 months) follow-up were evaluated. RESULTS: At final follow-up, 73.3% of eyes showed an uncorrected visual acuity of 20/25 or better. The postoperative keratometric value was not different from the preoperative value; mean refractive astigmatism was reduced to -0.28+/-0.38 diopter (D) from -1.28+/-0.48 D. The mean rotation of the toric IOL was 3.45+/-3.39 degrees at final follow-up. One eye (3.3%) exhibited IOL rotation of 10.3 degrees, the remaining eyes (96.7%) had IOL rotation of less than 10 degrees. CONCLUSIONS: Early postoperative and long-term follow-up showed that implantation of the AcrySof toric IOL is an effective, safe, and predictable method for managing corneal astigmatism in cataract patients.