Implementation of wireless power transfer and communications for an implantable ocular drug delivery system.

A wireless power transfer and communication system based on near-field inductive coupling has been designed and implemented. The feasibility of using such a system to remotely control drug release from an implantable drug delivery system is addressed. The architecture of the wireless system is described and the signal attenuation over distance in both water and phosphate buffered saline is studied. Additionally, the health risk due to exposure to radio frequency (RF) radiation is examined using a biological model. The experimental results demonstrate that the system can trigger the release of drug within 5 s, and that such short exposure to RF radiation does not produce any significant (

Development of a miniaturised drug delivery system with wireless power transfer and communication.

The development of an implantable system designed to deliver drug doses in a controlled manner over an extended time period is reported. Key performance parameters are the physical size, the power consumption and also the ability to perform wireless communications to enable the system to be externally controlled and interrogated. The system has been designed to facilitate wireless power transfer, which is very important for miniaturisation as it removes the need for a battery.

A pharmacokinetic model of intravitreal delivery of ganciclovir.

A pharmacokinetic model of intravitreal drug delivery was developed for describing the elimination and distribution of ganciclovir in the eye following intravitreous polymeric delivery. The model was based on Fick's second law of diffusion and assumed a cylindrical vitreous body. The model parameters such as the diffusion coefficient and the partition coefficient of the drug in the vitreous body and its surrounding tissues were determined from in vitro experiments using rabbit tissues. The time course of in vivo mean concentration of ganciclovir in the rabbit vitreous body agreed well with the profile calculated from the present pharmacokinetic model for both membrane-controlled polymeric devices and biodegradable rod-matrix systems. The clinical vitreous concentration following implantation of the membrane-controlled delivery system was the same order of magnitude but approximately four times lower than that predicted from the present model. This may indicate the metabolism of ganciclovir and/or the facilitated transport across the retina/choroid membrane in the human eye.

Intravitreous delivery of dexamethasone sodium m-sulfobenzoate from poly(DL-lactic acid) implants.

Biodegradable intravitreal rod-shaped implants containing dexamethasone sodium m-sulfobenzoate (DMSB) were prepared from blends of poly(DL-lactic acid) (PLA) with number-average molecular weight 2000 (PLA2000) and 4000 (PLA4000). The effect of the fraction of PLA2000 on the release of DMSB from the implant was investigated after implantation in the vitreous body of rabbit eyes. After the initial burst, the drug was released slowly from the blended PLA implants with a PLA2000 fraction of below 30 wt% in normal eyes within a period of 28 d. For the implants with a higher PLA2000 fraction of over 50 wt%, the drug was released following approximately first order kinetics. In the vitrectomized eyes, the release of DMSB from the PLA2000/PLA4000 (5/5) implant was 2.5 times more rapid than in normal eyes, and the clearance of drug was also appreciably accelerated as compared with that in normal eyes.

Pharmacokinetic model of intravitreal drug injection.

A dynamic mathematical model is developed to describe the distribution and elimination behavior of a drug in the vitreous body following intravitreal injection. The effects of three elimination pathways--the annular gap between the lens and the ciliary body (the posterior chamber), the lens, and the retina-choroid-sclera membrane--upon the concentration distribution in the vitreous body and the time course of the rate of elimination have been quantitatively demonstrated. The effects of metabolism in the vitreous body and the site of injection are also simulated. The annular gap between the lens and the ciliary body (the posterior chamber) is found to be a main route of elimination for large molecules injected into the vitreous body. For small or highly lipophilic molecules, however, both the posterior chamber and the retina-choroid-sclera membrane act as major routes of elimination. The lens pathway may contribute negligibly to the escape of drugs from the vitreous body. The concentration on the surface of the retina is appreciably affected by the site of injection or the initial distribution profiles, while the concentration gradient on the lens surface remains almost independent of the site of injection. To maintain the therapeutic concentration in the vitreous body or in the retina for a prolonged period of time, the drug must be injected into the posterior area of the vitreous body. When the drug is injected into the anterior segment of the vitreous body, the drug molecules quickly escape into the posterior chamber from the annular gap between the lens and the ciliary body. The present mathematical model describes well in vivo elimination profile of lomefloxacin following intravitreal injection.

In vivo/in vitro correlation of intravitreal delivery of drugs with the help of computer simulation.

The elimination of dexamethasone sodium m-sulfobenzoate, DMSB, following intravitreal injection, was measured in rabbit vitreous body under in vivo and in vitro conditions. The rate of elimination in vivo was appreciably greater than that in vitro, indicating that the in vivo data include not only the elimination due to metabolism/degradation in the vitreous humor, but also the elimination through the surrounding tissues such as the posterior aqueous humor, the retina/choroid/sclera membrane, and the lens. A general mathematical model based on Fick's second law of diffusion was developed for describing the pharmacokinetics of the intravitreal injection of DMSB. The model parameters were independently determined from a set of in vitro experiments. The in vivo data of elimination of DMSB following intravitreal injection agreed with the profiles calculated from the mathematical model, together with the model parameters determined from the in vitro experiments. The present in vivo/in vitro correlation, with the help of computer simulation, can be used for optimizing the therapeutic systems of intravitreal drug delivery.

Penetration and binding of aldose-reductase inhibitors in the lens.

Diffusion, partitioning, and binding of two aldose-reductase inhibitors (ARI) in the rat lens were investigated under in vitro conditions. A lipophilic ARI (CT-112) and a hydrophilic ARI (AD-5467) were used as model drugs. Under lens-uptake conditions, the drug concentration in the lens increased rapidly during the initial 10 hr and reached steady state (equilibrium) after 24 hr. Despite the equilibrium concentration of CT-112 in the lens which is approximately three times of that of AD-5467, the inhibition rate of CT-112 against the accumulation of sugar alcohols was appreciably lower than that for AD-5467. The equilibrium concentration in the lens after the penetration/binding experiment also suggested that AD-5467 may interact with the target sites of enzymes more than that for CT-112. The time course of the lens concentration during the uptake and desorption experiments was well described by a diffusion/binding model assuming a Langmuir binding. The diffusion coefficient, the partition coefficient, and binding parameters in the rat lens were determined for the two ARIs.

In vitro study of aldose reductase inhibitor concentrations in the lens and inhibitory effect on sugar alcohol accumulation.

Rat lenses were cultured in a medium containing either 30mM xylose or 30mM glucose. Inhibitory effects of two aldose reductase inhibitors, AD-5467 and CT-112, on the accumulation of sugar alcohols and the concentrations of the drugs in the lens were measured. Inhibitory effect of lens opacification by the drugs were also observed. Lens opacification was apparently inhibited in a medium containing each of the drugs. Inhibition rates for sugar alcohol accumulation by AD-5467 and CT-112 were unrelated to the kinds of added sugars. 50% inhibition-concentration in the medium was 0.82-1.02 x 10(-7) M for AD-5467 and 3.78-5.92 x 10(-7) M for CT-112, and the resulting concentration of drug in the lens was 2.33-3.08 nmole/g lens for AD-5467 vs. 21.19-24.63 nmole/g lens for CT-112. The results above indicated that the concentration of CT-112 should be 4.6-5.8 times of that of AD-5467 in the medium to attain the same inhibitory effect on sugar alcohol accumulation, and 8.0-9.1 times more CT-112 is needed in the lens. A linear correlation was found on a bilogarithmic graph of concentrations in the medium and in the lens for both drugs. This correlation is an empirical adsorption isotherm shown by Freundrich. So this suggested that both drugs were adsorbed into the lens. The rate of adsorption varied with the drugs. Even when the drug concentrations in the medium were the same, the concentration of CT-112 in the lens was 2-4 times higher than that of AD-5467.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of furosemide and trimethazidine on kinetic behavior and hypotensive effect of hydralazine in rats.

The pharmacokinetic and pharmacodynamic interactions between hydralazine (HP) and furosemide or trimethazidine were determined following single i.v. and repeated (7 d) oral administrations in rats. Both furosemide and trimethazidine caused a significant decrease in the level of plasma protein binding of HP in vivo after i.v. administration. However, in vitro there was no effect on binding. Coadministration of HP and furosemide at lower doses (1.67 mg/kg, i.v. and 5 mg/kg, oral) reduced the hypotensive effect, accompanying the enhanced elimination of HP from plasma after a single i.v. and repeated oral treatment when compared to the result obtained with HP alone. The elimination of HP accelerated by the lower doses of furosemide may be probably due to the increase in renal clearance by the diuretic effect of furosemide. On the contrary, a high dose (10 mg/kg, i.v.) of furosemide temporarily strengthened the hypotensive effect, probably due to the additional hypotensive action of furosemide itself. Trimethazidine (0.75 and 3.75 mg/kg) gave a small increase in the hypotensive effect of HP in spite of the partially enhanced clearance of HP. The pharmacodynamic analysis showed that the hypotensive effect of HP depended upon the plasma HP concentration in each treatment, although the response curves of HP were partly altered by the combined drugs. The present study also suggests a validity of co-administration of HP and diuretics for the therapy of hypertension and heart failure.

Encapsulation of dexamethasone in rabbit erythrocytes, the disposition in circulation and anti-inflammatory effect.

The application and usefulness of resealed erythrocyte as a cell carrier of dexamethasone were studied in rabbits. The erythrocytes were loaded with water soluble dexamethasone sodium phosphate by hypotonic dilution and dialysis methods. During in vitro incubation at 37 degrees C, the level of dexamethasone held within the resealed according erythrocytes declined according to first-order function. About one half of the dexamethasone-loaded cells, when returned to circulation, disappeared within the first 24 h. However, the survival of the remaining cells in circulation followed zero order function and declined for 7-8 d after administration. The apparent half-life of the remaining erythrocytes in circulation was 8.27 d by the hypotonic dilution method and 12.8 d by the dialysis method. This indicated that the encapsulated drug had a much longer half-life than when free drug (t 1/2, beta = 3.61 +/- 0.69 h) was administered intravenously. Dexamethasone phosphate entrapped within cells was slowly released from the loaded cells into plasma in in vivo circulation. When the encapsulated cells were administered to rabbits, the rabbits were protected from inflammation (the capillary permeability response) caused by histamine for approximately 2 to 5 d after administration. However by day 10 the protection was slight. This anti-inflammatory effect agreed reasonably well with the in vivo survival of loaded erythrocytes. Therefore, the results indicated that resealed erythrocytes act as a slow release system in vivo.

Effect of dicyclomine on intestinal absorption, disposition and biliary excretion of dexamethasone.

The effect of dicyclomine, a cholinergic blocking agent, on the in situ intestinal absorption, plasma clearance, biliary excretion of dexamethasone was examined in rats. The plasma concentrations and area under the plasma concentration-time curve (AUC) of dexamethasone after both a single and repeated oral coadministration with dexamethasone phosphate (4 mg/kg) and dicyclomine (4 mg/kg) were significantly reduced compared with those after dexamethasone alone, without the alteration of elimination rate. The in situ absorption study also indicated that the absorption of dexamethasone was reduced to about a half after repeated coadministration of the two drugs. The renal plasma flow (RPF) in coadministration group was significantly enhanced compared with that of dexamethasone alone. The biliary excretion of dexamethasone was reduced, in proportion to the plasma concentrations, by dicyclomine. Therefore, dicyclomine should be administered taking much care in the corticosteroid treatment, because of producing the decrease in absorption.