Prolonged Drug Delivery Research Articles

Percutaneous Permeation of Betamethasone 17-Valerate Incorporated in Lipid Nanoparticles

Corticosteroids are therapeutic agents widely used in the pharmacological treatment of skin diseases such as eczema or psoriasis. Unfortunately, their use is restricted by the side effects that frequently occur at the systemic level. The goal of the research described here was to develop and characterize a solid lipid nanoparticle (SLN) system containing corticosteroids for prolonged and localized delivery of the active drugs into the skin. In vitro measurements of Betamethasone 17-valerate (BMV) permeation through human epidermis were conducted using static Franz diffusion cells. The reservoir formation of the drug in the epidermal and dermal layers of the skin was also investigated. Monostearin SLN showed remarkable controlled release properties and a significant epidermis drug reservoir. On the other hand, beeswax SLN could not reduce the drug permeation through the skin, nor increase the drug content in the upper layers of the skin. The diffusion of corticosteroids into the skin appeared to be dependent on the lipid composition of the monostearin SLN. Topical SLN products show great potential for treating dermatological conditions by targeting corticosteroids to epidermal/upper dermal disease sites while minimizing systemic drug absorption.

Prolonged intragastric drug delivery mediated by Eudragit® E-carrageenan polyelectrolyte matrix tablets.

Interpolyelectrolyte (IPE) complexation between carrageenan (CG) and Eudragit E (EE) was studied in 0.1 M HCl and was used to develop floating matrix tablets aimed to prolong gastric-residence time and sustain delivery of the loaded drug. The optimum EE/CG IPE complexation weight ratio (0.6) was determined in 0.1 M HCl using apparent viscosity measurements. The IPE complex was characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. Metronidazole matrix tablets were prepared by direct compression using EE, CG, or hybrid EE/CG with ratio optimal for IPE complexation. Corresponding effervescent tablets were prepared by including Na bicarbonate as an effervescent agent. Tablets were evaluated for in vitro buoyancy and drug release in 0.1 M HCl. Both CG and EE-CG effervescent matrices (1:2 drug to polymer weight ratio, 60 mg Na bicarbonate) achieved fast and prolonged floating with floating lag times less than 30 s and floating duration of more than 10 h. The corresponding EE effervescent matrices showed delayed floating and rapid drug release, and completely dissolved after 3 h of dissolution. CG matrices showed an initial burst drug release (48.3±5.0% at 1 h) followed by slow drug release over 8 h. EE-CG matrices exhibited sustained drug release in almost zero-order manner for 10 h (68.2±6.6%). The dissolution data of these matrices were fitted to different dissolution models. It was found that drug release followed zero-order kinetics and was controlled by the superposition of the diffusion and erosion.

Ion-activated in situ gelling ophthalmic delivery systems of azithromycin

Gelation of pectin caused by divalent cations especially calcium ions has been applied to develop an ophthalmic formulation of azithromycin in the present study. Rapid elimination of drug on instillation into cul de sac would be minimal with in situ gelling ophthalmic solution leading to increased precorneal contact time and prolonged drug delivery. In the formulation development studies pectin was used in different concentrations (1-5% w/v) and different proportions of the hydrocolloids hydroxypropyl methylcellulose and sodium carboxymethyl cellulose of different grades of viscosity were used. The primary criteria for formulation optimization were gelling capacity and rheological behaviour. In addition, formulations were evaluated for pH, and antimicrobial efficacy and drug release. The clarity, pH, gelation in simulated tear fluid and rheological properties of the optimized formulations were satisfactory. The formulations inhibited the growth of Staphylococcus aureus effectively in cup–plate method and were proved to be safe and non irritant on rabbit eyes. The results indicate that pectin based in situ gels can be successfully used to prolong the duration of action of azithromycin.

Ionotropically Gelled Novel Hydrogel Beads: Preparation, Characterization and In vitro Evaluation.

Prolonged release drug delivery system of stavudine was made by ionotropic gelation and polyelectrolyte complexation technique. Cross-linking reinforced chitosan-gellan complex beads were prepared by gelation of anionic gellan gum, the primary polymer, with oppositely charged counter ion to form beads which were further complexed with chitosan as a polyelectrolyte. The effect of this polymer on release profile of drug was studied. Beads without chitosan complexation were also made. The reaction of chitosan-gellan complex dominates the formation of skin layer on the surface of beads. Stavudine an antiretroviral drug was selected as novel drug for the experiment. The final formulations were subjected to in vitro evaluation and several characterization studies. Batches with gellan gum shows Higuchi model, while chitosan-gellan shows zero order release. All the batches with copolymer showed sustained the drug release more than 12 h, whereas with gellan gum alone showed up to 10 h. Batches with chitosan showed maximum drug encapsulation efficiency.

Distribution of Dexamethasone and Preservation of Inner Ear Function following Intratympanic Delivery of a Gel-Based Formulation

Intratympanic (IT) delivery of drugs to the ear is increasingly used for both clinical and research purposes. One limitation of IT delivery is that drugs are rapidly lost from the middle ear by a number of processes, so that prolonged delivery of drug is technically difficult. In the present study, the delivery characteristics of a poloxamer hydrogel formulation containing dexamethasone (dex) were evaluated. The gel is liquid at room temperature, allowing IT injection, but transitions to a gel at body temperature, providing a prolonged residence time in the middle ear. A 50-µl volume of control or dex-containing gel (dex-gel) was injected through the tympanic membrane of guinea pigs. Cochlear function was assessed with cochlear action potential and acoustic emission thresholds measured immediately, 6 or 24 h after IT gel injection. After 6- or 24-hour treatment with dex-gel, perilymph drug gradients along the cochlea were assessed by taking samples sequentially from the apex, and endolymph was sampled from the basal turn. Control gel injections caused small changes in sound field calibrations and functional measures for low-frequency stimuli, consistent with an induced conductive loss. Within 24 h, responses returned to normal. Twenty-four hours after dex-gel injection, low-frequency changes remained as the dex-gel was retained better in the middle ear, but there was no indication of high-frequency loss. While perilymph sample data showed that dex gradients were substantially lower than after single injections of dex solution, quantitative analysis of this result suggests that some dex may have entered the perilymph through the thin bone in the apical region of the cochlea. Endolymph levels of dex remained lower than those in the perilymph. This study confirms that a poloxamer hydrogel-based dex formulation provides an effective method for a prolonged delivery, providing a more uniform distribution of drug in the inner ear.

Marqibo® (vincristine sulfate liposomes injection; VSLI) Optimizes the Dosing, Delivery, and Pharmacokinetic (PK) Profile of Vincristine Sulfate (VCR) In Adults with Relapsed and Refractory Acute Lymphoblastic Leukemia (ALL)

AbstractAbstract 2142 Background:VCR is an important component of the treatment of ALL, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma, and other adult and childhood cancers. In part, because of the cell cycle specific activity of VCR, its anti-cancer activity is believed to be very exposure time and concentration dependent. Standard dosing of conventional VCR (1.4 mg/m2 with a 2 mg cap) is limited because of early onset peripheral neuropathy and fails to achieve sustained VCR delivery. VSLI (Marqibo) is a nano-particle encapsulated formulation of VCR designed to facilitate dose intensification, prolonged drug delivery and enhanced cancer penetration and concentration. Methods:In a pivotal, Phase 2, multi-national study (RALLY Trial), 65 adults with Philadelphia chromosome negative ALL who were either in second or greater relapse or who had progressed after two or more prior lines of treatment received single-agent intravenous VSLI 2.25 mg/m2 (without any dose cap) weekly over 1 hour as salvage therapy. First-dose PK was investigated in a representative subset of 13 study subjects. Blood for analysis was collected at 8 time points ranging from 5 minutes to 48 hours following infusion. Total VCR plasma levels were determined by HPLC-MS/MS. PK parameters were calculated with Phoenix WinNonlin. Results:The PK subject subset had a median body surface area (BSA) of 1.92 m2 (range 1.47 to 2.45 m2) and received a median VSLI dose (VCR component) of 4.32 mg (range 3.3 to 5.51 mg). Based on BSA and the 2 mg dose cap, all subjects in this study group would have been dosed with 2.0 mg of conventional VCR. The median cumulative induction dose of VSLI (VCR component) that was administered in this study was 18.8 mg (range 3.5 to 70.1 mg). Total VCR plasma concentration decreased rapidly from Cmax after the VSLI infusion in 5 subjects (38%); 8 subjects (62%) exhibited a delay of 4 to 10 hours before the total VCR plasma concentration began to decrease. The calculated Tmax was 1.3 ± 0.4 hours (range 1.1 to 2.0 hours). The Cmax was 1214 ± 233 ng/mL (range 919 to 1720 ng/mL). The apparent mean half-life was 7.1 ± 3.2 hours. The mean AUCinf was 13,993 ± 6,588 ng hr/mL with a range from 7,167 to 27,233 ng hr/mL. The mean clearance (CL) was 6.4 ± 2.6 mL/min. The mean volume of distribution (Vd) was 0.051 ± 0.018 L/Kg. There were no significant differences in the PK parameters between the male and female subjects participating in this study. The table below presents VSLI PK parameters in addition to historical PK parameters for conventional VCR dosed at 2 mg. Conclusions:VSLI clearly provides dose intensification and prolonged VCR delivery compared to conventional, non-encapsulated VCR. VSLI, as dosed in this adult ALL clinical trial, delivered individual and cumulative amounts of VCR that exceed those achievable with standard and approved dosing of conventional VCR. This translated into a median dose intensification of 116% (range 65 to 176 percent) calculated as the percent change in VSLI dose from a standard VCR dose. This dose intensification is believed to have contributed to the 35% overall response rate including 20% complete responses (with or without full blood count recovery) reported in this heavily pre-treated, multiply-relapsed/refractory population without apparent enhanced toxicity [J Clin Oncol 28:15s, 2010 (suppl; abst 6507)]. VSLI has a distinctly different PK profile than conventional VCR. The larger VSLI Cmax and AUCinf reflect the dose intensification afforded by a larger mg/m2 dose and lack of dose capping. Even in the absence of dose capping, the 2.25 mg/m2 VSLI dose represents a 61% dose escalation above conventional VCR. While Cmax and AUCinf are dose-dependent PK parameters, the observed differences between VSLI and VCR control cannot be explained by dose alone. The larger AUCinf also reflects prolonged circulation afforded by the sphingomyelin:cholesterol liposome encapsulation. The modest VSLI mean CL and small Vd reflect the retention of encapsulated VCR within the plasma compartment for an extended period of time so that VCR can better penetrate and accumulate in sites of cancer through fenestrated vasculature. The enhanced delivery of encapsulated VCR contributes to maintenance of VCR concentrations above the effective concentration. Disclosures:Silverman: Hana Biosciences: Employment. Deitcher: Hana Biosciences: Employment.

Cyclodextrin solubilization of carbonic anhydrase inhibitor drugs: Formulation of dorzolamide eye drop microparticle suspension

Topically applied carbonic anhydrase inhibitors (CAIs) are commonly used to treat glaucoma. However, their short duration of action requiring multiple daily dosing can hamper patient compliance. The aim of this study was to develop novel aqueous CAI eye drop formulation containing self-assembled drug/cyclodextrin (D/CD) microparticles that enhance and prolong drug delivery to the eye. Phase-solubility of each drug tested (i.e. methazolamide, brinzolamide and dorzolamide HCl) was determined in either pure water or an aqueous eye drop medium. The pH was adjusted to maximize the fraction of unionized drug. Dorzolamide had the highest affinity for γ-cyclodextrin (γCD) and, thus, was selected for further investigation. Hydroxypropyl methylcellulose (HPMC) was the most effective polymer tested for stabilization of the dorzolamide/γCD complexes and gave the highest mucoadhesion at 0.5% w/v concentration. Thus, the dorzolamide eye drop vehicle containing γCD (18% w/v) and HPMC (0.5% w/v) was developed. The physicochemical properties of this formulation complied with the specifications of the eye drop suspension monograph of the European Pharmacopoeia. The in vivo testing of the formulation showed that the drug was delivered to the aqueous humor in rabbits for at least 24 h with the maximum drug concentration at 4 h. Furthermore, this formulation delivered the drug to the posterior segment of the eye after topical administration. These results indicate that this CAI eye drop formulation has the potential of being developed into a once-a-day product.

Formulation Evaluation and Optimization of Stomach Specific In situ Gel of Ranitidine Hydrochloride

The objectives of this research work were preparation, optimization and evaluation of in situ gelling system of Ranitidine. HCl based on sodium alginate that retains in the stomach by adherence to gastric wall providing an increased gastric residence time resulting in prolonged drug delivery in gastrointestinal tract. Sodium alginate was used as a polymer and CaCO3 as a cross-linking agent. The in situ formulation exhibited the expectations, viscosity, drug content and sustained drug release. This study reports that oral administration of aqueous solutions containing sodium alginate results in formation of in situ gel and such formulations are homogenous liquids when administered orally and become gel at the contact site. The results of a 32 full factorial design revealed that the concentrations of sodium alginate and CaCO3 significantly affected the dependent variables of viscosity, Q50 and Q80. These in situ gels are, thus, suitable for oral sustained release of Ranitidine HCL.

Investigation of the physicochemical and physicomechanical properties of a novel intravaginal bioadhesive polymeric device in the pig model.

The purpose of this study was to develop and evaluate the bioadhesivity, in vitro drug release, and permeation of an intravaginal bioadhesive polymeric device (IBPD) loaded with 3'-azido-3'-deoxythymidine (AZT) and polystyrene sulfonate (PSS). Modified polyamide 6,10, poly(lactic-coglycolic acid), polyacrylic acid, polyvinyl alcohol, and ethylcellulose were blended with model drugs AZT and PSS as well as radio-opaque barium sulfate (BaSO4) and then compressed into caplet devices on a tableting press. One set of devices was coated with 2% w/v pentaerythritol polyacrylic acid (APE-PAA) while another remained uncoated. Thermal analysis was performed on the constituent polymers as well the IBPD. The changes in micro-environmental pH within the simulated human vaginal fluid due to the presence of the IBPD were assessed over a period of 30 days. Textural profile analysis indicated that the bioadhesivity of the APE-PAA-coated devices (3.699 +/- 0.464 N; 0.0098 +/- 0.0004 J) was higher than that of the uncoated devices (1.198 +/- 0.150 N; 0.0019 +/- 0.0001 J). In addition, BaSO4-facilitated X-ray imaging revealed that the IBPD adhered to pig vaginal tissue over the experimental period of 30 days. Controlled drug release kinetics was obtained over 72 days. During a 24-h permeation study, an increase in drug flux for both AZT (0.84 mg cm(-2) h(-1)) and PSS (0.72 mg cm(-2) h(-1)) was realized up to 12 h and thereafter a steady-state was achieved. The diffusion and dissolution dynamics were mechanistically deduced based on a chemometric and molecular structure modeling approach. Overall, results suggested that the IBPD may be sufficiently bioadhesive with desirable physicochemical and physicomechanical stability for use as a prolonged intravaginal drug delivery device.

Dicyclomine-loaded Eudragit®-based Microsponge with Potential for Colonic Delivery: Preparation and Characterization

Purpose: The purpose of this work was to develop a prolonged microsponge drug delivery system containing dicyclomine. Methods: Dicyclomine-loaded, Eudragit-based microsponges were prepared using a quasi-emulsion solvent diffusion method. The compatibility of the drug with formulation components was established by differential scanning calorimetry (DSC) and Fourier transform infra-red (FTIR). Process parameters were modulated to optimise the formulation. Shape and surface morphology of the microsponges were examined using scanning electron microscopy. Results: The results of compatibility tests showed that no chemical interaction or changes took place during preparation of the formulations; furthermore, the drug was stable in all the formulations. In increase in drug:polymer ratio resulted in a reduction in the release rate of the drug from the microsponges. Kinetic analysis showed that the main mechanism of drug release was by Higuchi matrixcontrolled diffusion. Drug release was bi-phasic with an initial burst effect with 16 – 30 % of the drug was released in the first hour. Cumulative release for the microsponges over 8 hours ranged from 59 - 86 %. Conclusion: This study presents an approach for the modification of microsponges for prolonged drug release of dicyclomine. The unique compressibility of microsponges can be applied to achieve effective local action since microsponges may be taken up by macrophages present in colon.Keywords: Microsponge; Dicyclomine; Quasi-emulsion solvent diffusion; Eudragit RS-100; Colonic drug release

Development of bisphosphonates controlled delivery systems for bone implantation: influence of the formulation and process used on in vitro release

The present study investigates the development of controlled drug delivery devices by association of bisphosphonates (BPs) with calcium-deficient apatite (CDA) to obtain a prolonged drug delivery. In a first part, we studied the microencapsulation of methylene bisphosphonic acid, our model of BPs, in biodegradable PLGA by the double emulsion (w/o/w) solvent evaporation/extraction process. Secondly, we associated BPs, either in a free form or microencapsulated, with calcium phosphate biomaterials. The association of free BPs with CDA was performed by isostatic compression at 80 MPa and we tested the interest of adding a binder, HPMC, in the formulation to reinforce the association. In parallel, microparticles were associated with calcium-deficient apatite, either by simple mixture or by isostatic compression. To compare the different formulations, in vitro dissolution studies were performed. All the formulations tested appear to be efficient to produce BPs loaded biomaterials able to deliver the drug slowly and at a constant rate. The slowest release rate (2.7% in 14 days) was obtained with the blend of microencapsulated BPs with CDA.

Uptake and trafficking of liposomes to the endoplasmic reticulum

Liposomes are vesicular structures consisting of an aqueous core surrounded by a lipid bilayer. Apart from the cytosol and lysosomes, no other intracellular compartment has been successfully targeted using liposomal delivery. Here, we report the development of liposomes capable of specific targeting to the endoplasmic reticulum (ER) and associated membranes. Using competition and inhibitor assays along with confocal microscopy, we have determined that ER liposomes utilize scavenger and low-density lipoprotein receptors for endocytosis and enter cells through a caveolin- and microtubule-dependent mechanism. They traffic intact to the ER, where fusion with the ER membrane occurs after 22-25 min, which was confirmed by fluorescence-dequenching assays. Once inside the ER, tagged lipids intercalate with the ER membrane and are subsequently incorporated into ER-assembling entities, such as the ER-budding viruses hepatitis C virus (HCV) and bovine viral diarrhea virus (BVDV), lipid droplets, and secreted lipoproteins. ER liposomes are superior to cytosolic liposome formulations for the intracellular delivery of aqueous cargo, such as HIV-1 antivirals, and are especially suited for the prolonged delivery of lipids and lipophilic drugs into human cells.

Design and evaluation of liposomal formulation of pilocarpine nitrate.

Prolonged release drug delivery system of pilocarpine nitrate was made by optimizing thin layer film hydration method. Egg phosphatidylcholine and cholesterol were used to make multilamellar vesicles. Effects of charges over the vesicles were studied by incorporating dicetylphosphate and stearylamine. Various factors, which may affect the size, shape, encapsulation efficiency and release rate, were studied. Liposomes in the size range 0.2 to 1 µm were obtained by optimizing the process. Encapsulation efficiency of neutral, positive and negatively charged liposomes were found to be 32.5, 35.4 and 34.2 percent, respectively. In vitro drug release rate was studied on specially designed model. Biological response in terms of reduction in intraocular pressure was observed on rabbit eyes. Pilocarpine nitrate liposomes were lyophilized and stability studies were conducted.

Application of atomic force microscopy and ultrasonic resonator technology on nanoscale: Distinction of nanoemulsions from nanocapsules

Oily core nanocapsules were prepared by sequential addition of positively and negatively charged polyelectrolytes based on a nanoemulsion and transformation thereof into a core–shell structure. The capsules were well characterized by photon correlation spectroscopy, laser diffraction, ζ-potential and transmission electron microscopy and feature an average size of 150 nm and a negative surface charge. The aim of the current study was to improve the dispersion stability and mechanic rigidity of the capsule wall by depositing an increasing number of up to five layers. Therefore, atomic force microscopy (AFM) and ultrasonic resonator technology (URT) were applied to investigate the shell of the nanoemulsion, the intermediate and final nanocapsules in more detail. AFM was performed to investigate the shape, morphology and mechanic properties of the emulsion and capsule shell. It proved to be a feasible technique to distinguish nanoemulsions from nanocapsules by stiffness analysis. URT was utilized in order to observe the ultrasound velocity and could confirm the AFM results. Both techniques demonstrated that the shell around an oil droplet solidified with increasing number of polyelectrolyte layers. Since a solid wall might have the potential of a strong diffusion barrier, nanocapsules might present a feasible prolonged release drug delivery system in contrast to nanoemulsions.

Composite microparticles with in vivo reduction of the burst release effect

The aim of this study was to develop microparticles containing nanoparticles (composite microparticles) for prolonged drug delivery with reduced burst effect in vitro and in vivo. Such composite microparticles were prepared with hydrophobic and biodegradable polymers [poly(ε-caprolactone), poly(lactic-co-glycolic) acid]. Ibuprofen was chosen as the model drug, and microparticles were prepared by the extraction technique with ethyl acetate as the solvent. Nanoparticles and microparticles and an ibuprofen solution (Pedea ®) were administered subcutaneously at the dose of 1 mg of ibuprofen per kg to overnight-fasted rats (male Wistar). Composite microparticles showed prolonged ibuprofen release and less burst effect when compared to simple microparticles (without nanoparticles inside) or nanoparticles both in vitro (PBS buffer) and in vivo. Moreover, ibuprofen was still detected in the plasma after 96 h with composite microparticles. Consequently, it has been demonstrated that composite microparticles were able to reduce burst release and prolong the release of ibuprofen for a long period of time.

Microspheres based on poly(3-hydroxy)butyrate for prolonged drug release

The kinetics of the controlled release of the antiproliferative drug dipyridamole from microspheres based on the biocompatible and biodegradable polymer poly(3-hydroxy)butyrate is studied. As carriers for dipyridamole, microspheres prepared from a solution of poly(3-hydroxy)butyrate by single emulsion method are used. Under in vitro conditions, the kinetic curves describing the release of dipyridamole from microspheres with diameters of 19, 63, and 92 μm show two characteristic regions: the region of fast drug release within a short time period and a well-pronounced continuous linear region. For microspheres with a diameter of 4 μm, the linear region is missing. Analysis of the kinetic curves illustrating controlled drug release together with the measurements on polymer degradation shows that their kinetic profiles depend on the diffusion-controlled process and hydrolytic degradation of poly(3-hydroxy)butyrate. The diffusion kinetic equation describing both linear and nonlinear regions of dipyridamole released from the microspheres involves the sum of two terms: desorption from the sphere via the diffusion-controlled mechanism and drug release via the zero-order reaction. The linear region of the drug release curve is explained by the zero-order hydrolysis of poly(3-hydroxy)butyrate. The diffusion coefficients and kinetic constants are calculated. For bigger microspheres, the existence of the continuous linear region in the corresponding kinetic curves makes it possible to use microsystems based on poly(3-hydroxy)butyrate and dipyridamole as novel systems for local prolonged drug delivery.

Epidural Granuloma Arising From Epidural Catheter Placement

Indwelling epidural catheter placement for prolonged drug delivery or is commonplace. Epidural catheter placement leading to a subsequent epidural mass is infrequently symptomatic and thus not often sought after or uncovered. Such masses can mimic lesions causing tumor, infection, and inflammation, and when found, the etiology of granuloma formation is unclear. This article describes a case of a benign epidural granuloma masquerading as an epidural tumor thought to be caused by epidural catheter placement for postoperative total hip replacement pain control. After symptoms of mechanical and radiculopathic pain arose, the patient underwent an open biopsy, spinal decompression, and intradural exploration as an MRI evaluation identified a mass in the spinal canal. Pathologic examination identified a benign fibrous granuloma. At 36-month follow-up, there was no evidence of symptom or tumor recurrence.

Pharmacokinetics of a granisetron transdermal system for the treatment of chemotherapy-induced nausea and vomiting

To determine the pharmacokinetic (PK) profile of granisetron transdermal formulation and examine its possible relationship with age, gender, and renal function. This article describes a Phase I PK study and a post hoc pooled population PK analysis. The Phase I study was a randomized, cross-over study that assessed PK parameters of three granisetron patch sizes and oral granisetron. The pooled population PK analysis included data from three trials in healthy subjects (n = 48) and from Phase II and III studies in patients with cancer (n = 793). The population PK model was used to investigate granisetron exposure and its possible relationship with age, gender, and renal function. Following oral dosing, plasma granisetron concentration was quantifiable at 1 h, and maximal mean concentration (4.7 ng/mL) was reached 2 h after administration. With transdermal application, maximal concentration was reached 48 h post-application; t(1/2) was 36 h. With oral dosing, overall exposure after 5 days was 306 ng/mL.h, and C(avg) 2.6 ng/mL. This corresponded to an AUC(0-infinity) for the 52 cm(2) patch of 420 ng/mL.h and C(avg) 2.2 ng/mL over 6 days. Clearance was not affected by age, gender, weight, or renal function. The 52 cm( 2) granisetron patch achieves a similar exposure to that of a 2 mg oral dose and provides continuous delivery of granisetron over 6 days. The patch may have utility in treating chemotherapy-induced nausea and vomiting where prolonged drug delivery is advantageous. No dose adjustments would be needed based on age or renal function.

Dexamethasone-containing biodegradable superparamagnetic microparticles for intra-articular administration: Physicochemical and magnetic properties, in vitro and in vivo drug release

Compared with traditional drug solutions or suspensions, polymeric microparticles represent a valuable means to achieve controlled and prolonged drug delivery into joints, but still suffer from the drawback of limited retention duration in the articular cavity. In this study, our aim was to prepare and characterize magnetic biodegradable microparticles containing dexamethasone acetate (DXM) for intra-articular administration. The superparamagnetic properties, which result from the encapsulation of superparamagnetic iron oxide nanoparticles (SPIONs), allow for microparticle retention with an external magnetic field, thus possibly reducing their clearance from the joint. Two molecular weights of poly(lactic-co-glycolic acid) (PLGA) were used, 12 and 19 kDa. The prepared batches were similar in size (around 10 μm), inner morphology, surface morphology, charge (neutral) and superparamagnetic behaviour. The SPION distribution in the microparticles assessed by TEM indicates a homogeneous distribution and the absence of aggregation, an important factor for preserving superparamagnetic properties. DXM release profiles were shown to be quite similar in vitro (ca. 6 days) and in vivo, using a mouse dorsal air pouch model (ca. 5 days).

Hyaluronan-Tethered Opioid Depots: Synthetic Strategies and Release Kinetics In Vitro and In Vivo

We proposed the use of opioid drug bound covalently to hyaluronan (HA) via ester linkages as a method to prolong drug delivery and to possibly increase the quality of perioperative pain management. The in vitro release profile of morphine conjugated to HA (1.3 million MW) was studied. The influence of parameters such as conjugation site and steric protection of the labile ester bonds was investigated in phosphate buffered saline (PBS) medium. HA--codeine and HA--naloxone conjugates were used as structural controls. Codeine and morphine conjugated via the allylic hydroxyl group had a release half-life of 14.0 days in PBS. Naloxone conjugated via the phenolic hydroxyl group showed a half-life of 0.3 days, and all drugs admixed in HA showed half-lives of 0.1 days. Methyl, ethyl, or n-propyl introduced in vicinal position to the ester bond prolonged release of naloxone with half-lives of 0.5, 4.0, and 4.0 days in PBS, respectively. Incorporation of a methyl group prolonged codeine release with a half-life of 55.0 days in PBS. Drugs were released chemically unaltered from the conjugates as confirmed by LC-MS/MS. Further, morphine was conjugated to divinylsulfone cross-linked HA (Hylan B) particles and the release profiles in rat plasma were studied in vitro and in vivo. Release in rat plasma was faster than in PBS with a half-life of 2.5 days, but the release was similar (ca. 12 days) when a cocktail of protease inhibitors was added to the plasma. Sustained release of morphine was observed in a rat surgical model over 30 h. Morphine was released chemically unaltered from the conjugate and morphine intermediates were not detected in significant amounts as confirmed by LC-MS/MS. These results suggest that the morphine release profile from the HA conjugates depends on the alkyl groups vicinal to the ester and the nature of the leaving group. In rat plasma, hydrolysis seems to be controlled by esterase activity.