Polyethyleneimine-treated xanthan beads for prolonged release of diltiazem: <Emphasis Type="Italic">in vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis> evaluation

The purpose of the study was to develop a multiunit sustained release dosage form of diltiazem hydrochloride using a natural polymer, sodium carboxymethyl xanthan gum and polyethyleneimine (PEI) from a completely aqueous environment. PEI treated diltiazem resin complex loaded beads were characterized by morphology, drug entrapment efficiency, in vitro and in vivo release behaviour. 40% and 80% drug was released in 2 hour in pH 1.2 and in 5 to 6 h in pH 6.8 respectively depending on the formulation variables. The prolonged release was attributed to decreased swelling of the beads due to PEI treatment. Maintaining the shape throughout the dissolution process, PEI treated diltiazem resin complex beads released the drug following non-Fickian transport phenomena. In vivo pharmacokinetic evaluation in rabbits shows slow and prolonged drug release when compared with diltiazem solution. The designed beads are suitable for prolonged release of a water soluble drug under a complete aqueous environment using natural gum.     

Equivalence-by-Design: Targeting <Emphasis Type="BoldItalic">In Vivo</Emphasis> Drug Delivery Profile

In the United States (U.S.), drug products are considered therapeutically equivalent if they meet regulatory criteria of pharmaceutical equivalence and bioequivalence. These requirements can be traced back to 1977 when the U.S. Food and Drug Administration (FDA) published the regulations on bioavailability and bioequivalence. Over the years, to keep up with the advancement in science and technology, the FDA has been constantly updating the regulatory approaches to assessing and ensuring equivalence. In view of the recent growth in novel pharmaceutical dosage forms and delivery systems, this paper examines the current framework for documentation of therapeutic equivalence and explores the opportunities of further advancing equivalence methods for complex drug products. It is proposed that equivalence may be established by matching the in vivo drug delivery profile (iDDP) between drug products in comparison. This can be achieved by characterizing the iDDP of the reference formulation with application of an equivalence-by-design approach for pharmaceutical development. Critical variables can be identified to serve as in vitro markers or biomarkers for mapping the desired drug delivery profile in vivo. A multidisciplinary approach may be necessary to develop these markers for characterization of iDDPs. The opinions expressed in this article do not necessarily represent the views or policies of the U.S. Food and Drug Administration     

Preclinical and Clinical <Emphasis Type="BoldItalic">In Vitro In Vivo</Emphasis> Correlation of an hGH Dextran Microsphere Formulation

Purpose To investigate the in vitro in vivo correlation of a sustained release formulation for human growth hormone (hGH) based on hydroxyethyl methacrylated dextran (dex-HEMA) microspheres in Pit-1 deficient Snell dwarf mice and in healthy human volunteers. Materials and Methods A hGH-loaded microsphere formulation was developed and tested in Snell dwarf mice (pharmacodynamic study) and in healthy human volunteers (pharmacokinetic study). Results Single subcutaneous administration of the microspheres in mice resulted in a good correlation between hGH released in vitro and in vivo effects for the hGH-loaded microsphere formulation similar to daily injected hGH indicating a retained bioactivity. Testing the microspheres in healthy volunteers showed an increase (over 7–8 days) in hGH serum concentrations (peak concentrations: 1–2.5 ng/ml). A good in vitro in vivo correlation was obtained between the measured and calculated (from in vitro release data) hGH serum concentrations. Moreover, an increased serum concentration of biomarkers (insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3) was found again indicating that bioactive hGH was released from the microspheres. Conclusions Good in vitro in vivo correlations were obtained for hGH-loaded dex-HEMA microspheres, which is an important advantage in predicting the effect of the controlled drug delivery product in a clinical situations.     

Spray-Dried Amorphous Solid Dispersions of Simvastatin,a Low T<Subscript>g</Subscript> Drug: <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">in Vivo</Emphasis> Evaluations

Purpose To obtain free flowing, stable, amorphous solid dispersions (SDs) of simvastatin (SIM), a drug with relatively lower glass transition temperature (T_g) by spray drying technique, and to perform comparative in vivo study in rats, which could justify the improvement in rate and extent of in vitro drug release.Methods Dichloromethane suspensions of SIM either alone or in combination with PVP (1:1 or 1:2 parts by weight) were spray dried with proposed quantity of Aerosil 200 (1:1, 1:1:1, 1:2:2 parts by weight of SIM, Aerosil 200 and PVP, respectively). SDs were characterized initially in comparison with pure drug and corresponding physical mixtures in same ratios by drug content, saturation solubility, SEM, DSC, XRPD, IR, and in vitro drug release. SD 1:2:2 was further subjected to accelerated stability testing and checked for in vitro drug release and presence of crystallinity using DSC and XRPD. In addition, improvement in rate and extent of in vitro drug release from SD 1:2:2 was justified by in vivo study in rats.Results Combination of SD and surface adsorption techniques has been attempted to overcome the limitations of spray drying technique for amorphization of low T_g drugs. Based on powder characteristics, drug content, saturation solubility, and feasibility of processing into tablets; SD 1:2:2 was selected as the optimized formulation. During initial characterization, SEM, DSC, and XRPD analyses confirmed the presence of amorphous form in SD 1:2:2. IR spectroscopy revealed possibility of hydrogen bonding interaction between SIM and PVP in SDs. Also, there was dramatical improvement in rate and extent of in vitro drug release of SD 1:2:2. Insignificant decrease in dissolution was observed with no evidence of crystallinity during accelerated stability studies of SD 1:2:2. Moreover in vivo study in rats also justified the improvement in therapeutic efficacy of SD 1:2:2 over pure SIM.Conclusions Thus, present study demonstrates high potential of spray drying technique for obtaining stable amorphous SDs of low T_g drugs.     

PEGylated PAMAM Dendrimer-Doxorubicin Conjugates: <Emphasis Type="BoldItalic">In Vitro</Emphasis> Evaluation and <Emphasis Type="BoldItalic">In Vivo</Emphasis> Tumor Accumulation

Purpose  

To investigate the effects of PEGylation degree and drug conjugation style on the in vitro and in vivo behavior of PEGylated polyamidoamine (PAMAM) dendrimers-based drug delivery system.     

Transmucosal delivery of domperidone from bilayered buccal patches: <Emphasis Type="Italic">In Vitro,Ex Vivo</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> characterization

Bilayered mucoadhesive buccal patches for systemic administration of domperidone (DOM), a dopamine-receptor (D₂) antagonist, were developed using hydroxy propyl methyl cellulose and PVPK30 as a primary layer and Eudragit RLPO and PEO as a secondary layer. Ex vivo drug permeation through porcine buccal membrane was performed. Bilayered buccal patches were developed by solvent casting technique and evaluated for in vitro drug release, moisture absorption, mechanical properties, surface pH, in vitro bioadhesion, in vivo residence time and ex vivo permeation of DOM through porcine buccal membrane from a bilayered buccal patch. Formulation DB4 was associated with 99.5% drug release with a higuchi model release profile and 53.9% of the drug had permeated in 6 h, with a flux of 0.492 mg/h/cm² through porcine buccal membrane. DB4 showed 5.58 N and 3.28 mJ peak detachment force and work of adhesion, respectively. The physicochemical interactions between DOM and the polymer were investigated by differential scanning calorimetry (DSC) and fourier transform infrared (FTIR) Spectroscopy. DSC and FTIR studies revealed no interaction between drug and polymer. Stability studies for optimized patch DB4 was carried out at 40°C/75% relative humidity. The formulations were found to be stable over a period of 3 months with respect to drug content, in vitro release and ex vivo permeation through porcine buccal membrane. The results indicate that suitable bilayered mucoadhesive buccal patches with desired permeability could be prepared.     

<Emphasis Type="Italic">In vitro / in vivo</Emphasis> evaluation of NCDS-micro-fabricated biodegradable implant

Using the nano-composite deposition system (NCDS) as a microfabrication technique, implantable scaffolds were prepared with poly(DL-lactide-co-glycolide)(85:15) [PLGA(85:15)] as a biodegradable polymer. 5-Fluorouracil (5-FU) was used as a model drug, and hydroxyapatite (HA) was incorporated as a release modifier. In vitro drug release was evaluated and we confirmed that HA could control the release of drug from the prepared scaffolds, especially in the initial phase of the release. Furthermore, in vivo tests demonstrated that the microfabricated scaffold with pores was useful in reducing immune response and maintained its original shape, indicating that the drug delivery system was highly biocompatible.     

Imperatorin sustained-release tablets: <Emphasis Type="Italic">In Vitro</Emphasis> and pharmacokinetic studies

We prepared and evaluated imperatorin (IMP) sustained-release tablets. IMP is an active compound in Angelica dahuricae, a Chinese herbal medicine. We used different polymers, such as hydroxypropyl methylcellulose (HPMC K4M, K15M, and K100M), carbopol 934P, sodium carboxymethyl cellulose (CMC-Na), and their combinations to prepare the matrix tablets and achieve the desired sustained release profile. The in vitro release profiles of these formulations were examined and fit to various kinetic release models. We also tested the effects of polymer combination ratios on the in vitro release rate. In vivo studies were performed for the optimized formulation in six beagle dogs, and pharmacokinetic parameters were compared with plain IMP tablets. IMP sustained-release tablets exhibited a more sustained plasma concentration than the plain tablets, with a relative bioavailability of 127.25%. The in vitro releases rates and in vivo absorption correlated for the initial 8 hours. These results demonstrate that the sustained-release tablet system can effectively control the release of IMP.     

Bioequivalence Methodologies for Topical Drug Products: <Emphasis Type="BoldItalic">In Vitro</Emphasis> and <Emphasis Type="BoldItalic">Ex Vivo</Emphasis> Studies with a Corticosteroid and an Anti-Fungal Drug

Objective

To examine whether in vitro and ex vivo measurements of topical drug product performance correlate with in vivo outcomes, such that more efficient experimental approaches can be reliably and reproducibly used to establish (in)equivalence between formulations for skin application.

Materials and Methods

In vitro drug release through artificial membranes, and drug penetration into porcine skin ex vivo, were compared with published human in vivo studies. Two betamethasone valerate (BMV) formulations, and three marketed econazole nitrate (EN) creams were assessed.

Results

For BMV, the stratum corneum (SC) uptake of drug in 6 h closely matched data observed in vivo in humans, and distinguished between inequivalent formulations. SC uptake of EN from the 3 creams mirrored the in vivo equivalence in man (both clinically and via similar tape-stripping experiments). However, EN clearance from SC ex vivo did not parallel that in vivo, presumably due to the absence of a functioning microcirculation. In vitro release of BMV from the different formulations did not overlap with either ex vivo or in vivo tape-stripping data whereas, for EN, a good correlation was observed. No measurable permeation of either BMV or EN was detected in a 6-h in vitro skin penetration experiment.

Conclusions

In vitro and ex vivo methods for topical bioequivalence determination can show correlation with in vivo outcomes. However, these surrogates have understandable limitations. A “one-size-fits-all” approach for topical bioequivalence evaluation may not always be successful, therefore, and the judicious use of complementary methods may prove a more effective and reliable strategy.

     

Dynamic Dissolution Testing To Establish <Emphasis Type="BoldItalic">In Vitro</Emphasis>/<Emphasis Type="BoldItalic">In Vivo</Emphasis> Correlations for Montelukast Sodium,a Poorly Soluble Drug

Purpose  The objectives of the study was to develop a dissolution test method that can be used to predict the oral absorption of montelukast sodium, and to establish an in vitro/in vivo correlation (IVIVC) using computer simulations. Methods  Drug solubility was measured in different media. The dissolution behaviour of montelukast sodium 10 mg film coated tablets was studied using the flow-through cell dissolution method following a dynamic pH change protocol, as well as in the USP Apparatus 2. Computer simulations were performed using GastroPlus™. Biorelevant dissolution media (BDM) prepared using bile salts and lecithin in buffers was used as the dissolution media, as well as the USP simulated intestinal fluid (SIF) pH 6.8 and blank FaSSIF pH 6.5. Dissolution tests in the USP Apparatus 2 were performed under a constant pH condition, while the pH range used in the flow through cells was pH 2.0 to 7.5. The in vitro data were used as input functions into GastroPlus™ to simulate the in vivo profiles of the drug. Results  The solubility of montelukast sodium was low at low pH, but increased as the pH was increased. There was no significant difference in solubility in the pH range of 5.0 to 7.5 in blank buffers, but the drug solubility was higher in biorelevant media compared with the corresponding blank buffers at the same pH. Using the flow through cells, the dissolution rate was fast in simulated gastric fluid containing 0.1% SLS. The dissolution rate slowed down when the medium was changed to FaSSIF pH 6.5 and increased when the medium was changed to FaSSIF medium at pH 7.5. In the USP Apparatus 2, better dissolution was observed in FaSSIF compared with the USP buffers and blank FaSSIF with similar pH values. Dissolution was incomplete with less than 10% of the drug dissolved in the USP-SIF, and was practically non existent in blank FaSSIF pH 6.5. The in vitro results of the dynamic dissolution test were able to predict the clinical data from a bioavailability study best. Conclusions  Dynamic dissolution testing using the flow through cell seems to be a powerful tool to establish in vitro/in vivo correlations for poorly soluble drugs as input function into GastroPlus.     

Structure formation and characterization of injectable drug loaded biodegradable devices: In situ implants versus in situ microparticles

The objective of the study was to investigate key formulation variables affecting the release of bupivacaine hydrochloride, a local anesthetic, from different in situ forming biodegradable drug delivery devices. The formulations included ISM systems [in situ microparticles, a poly(lactide)-solvent phase dispersed into an external oil phase] and poly(lactide) solutions (in situ implant systems). The solubility of the biodegradable polymer poly(d,l-lactide) (PLA) in various organic solvents was determined using the Hansen multicomponent solubility parameter concept. The solvent release from ISM and polymer solutions into phosphate buffer which influences the polymer precipitation rate was investigated as a function of the type of solvent, polymer concentration and polymer:oil phase ratio by using a HPLC assay. Scanning electron microscopy (SEM) was performed in order to relate the drug release to the surface properties of the precipitated implants or microparticles. Suitable solvents for the preparation of the in situ forming drug delivery systems, such as N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO) and 2-pyrrolidone were found using the Hansen multicomponent solubility parameter concept. The injection of the polymer solutions (in situ implants) into the aqueous medium led to a rapid solvent/non-solvent exchange. The resulting in situ implants were porous, thus explaining the rapid initial drug release. Upon contact with the release medium, the internal polymer phase of the ISM system solidified and formed microparticles as shown by SEM measurements. Due to the presence of an external oil phase the solvent release into the buffer medium from ISM was significantly slower compared to the polymer solutions. The solvent release of the ISM systems into the phosphate buffer decreased with increasing polymer concentration and decreasing polymer:oil phase ratio. The type of solvent used also affected the solvent release. A slower solvent release into the aqueous medium resulted in less porous microparticles, thus explaining the reduced initial drug release from ISM systems compared to the polymer solutions.     

A Semi-mechanistic Modeling Strategy to Link <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Drug Release for Modified Release Formulations

Purpose  

To develop a semi-mechanistic model linking in vitro to in vivo drug release.     

Two different approaches for the prediction of <Emphasis Type="Italic">In Vivo</Emphasis> plasma concentration-time profile from <Emphasis Type="Italic">In Vitro</Emphasis> release data of once daily formulations of diltiazem hydrochloride

The aim of this study was to employ two different mathematical approaches: first, a convolution approach using computer software; second, a mathematical calculation exploiting Wagner-Nelson calculation to predict in vivo plasma concentration — time profile from the in vitro release study for the once daily formulations of a model drug diltiazem hydrochloride. The once daily extended release tablets (120 mg) were prepared by the wet granulation technique. Ethanol or ethanolic solutions of ethylcellulose (N22), were used as granulating agents along with hydrophilic matrix polymers like hydroxypropyl methylcellulose (HPMC) (K 15M). The granules showed satisfactory flow properties, compressibility, moisture content and drug content. All the tablet formulations showed acceptable properties and complied with pharmacopeial limits. The in vitro drug release study revealed that formula F7-T which contains drug: HPMC ratio 1:1 and 20 mg of ethylcellulose was able to sustain the drug release for 24 h and satisfied the USP dissolution limits. Fitting the in vitro drug release data to Korsmeyer-Peppas equation indicated that the mechanism of drug release could be zero-order. The capsule formulation F14-C which consists of drug: HPMC ratio 1:2, 12 mg of ethylcellulose and 20 mg of polyox 100 showed in vitro drug release similar to the tablet F7-T using the similarity factor (f ₂). The mechanism of drug release could be coupled diffusion, and polymer matrix relaxation. The percent dissolved data from the two formulations were used as input function to predict the in vivo plasma data by the two approaches (Convolution by Kinetica® software and Wagner-Nelson calculation). The two methods were validated by prediction of plasma data from in vitro release data of FDA approved 300 mg extended release capsule. Prediction errors were estimated for C _max and area under the curve (AUC) to determine the validity of the methods. The percent prediction error for each parameter is not exceeding 15%.     

Design and <Emphasis Type="Italic">in vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis> characterization of mucoadhesive matrix pellets of metformin hydrochloride for oral controlled release: A technical note

The aim of the current work was to design and develop matrix pellets of hydroxy propyl methyl cellulose K200M and microcrystalline cellulose in an admixture for a mucoadhesive gastroretentive drug delivery system. Pellets containing metformin hydrochloride (500 mg) were prepared by the pelletization technique using an extruder-spheronizer. Pellets were characterized by differential scanning calorimetry (DSC), x-ray diffraction (XRD), scanning electron microscopy (SEM), circularity, roundness, percent drug content, percent production yield, in vitro swelling, ex vivo mucoadhesion, in vitro drug release and in vivo x-ray imaging studies. Optimized pellets were sufficiently porous spheroids, free flowing, had smooth surfaces, had yields up to 75.45 ± 0.52% and had drug content up to 96.45 ± 0.19%. The average particle size of formulations MF2 and MF6 were 1.13 ± 0.41 mm and 1.22 ± 0.18 mm, respectively. Formulation MF6 exhibited strong adhesion, about 94.67%, to goat mucosal tissue, and the desired in vitro swelling, with a sustained drug release profile for 12 h and with retention in the upper small intestine of rabbits for 10 h. We conclude that hydroxy propyl methyl cellulose K200M and microcrystalline cellulose at a 2.80:1.00 w/w ratio could be an effective carrier for multiple unit controlled delivery of metformin hydrochloride.     

Mechanistic Investigation of Drug Release from Asymmetric Membrane Tablets: Effect of Media Gradients (Osmotic Pressure and Concentration), and Potential Coating Failures on <Emphasis Type="BoldItalic">In Vitro</Emphasis> Release

Purpose An asymmetric membrane (AM) tablet was developed for a soluble model compound to study the in vitro drug release mechanisms in challenge conditions, including osmotic gradients, concentration gradients, and under potential coating failure modes. Porous, semipermable membrane integrity may be compromised by a high fat meal or by the presence of a defect in the coating that could cause a safety concern about dose-dumping. Methods The osmotic and diffusional release mechanisms of the AM tablet were independently shut down such that their individual contribution to the overall drug release was measured. Shut off of osmotic and diffusional release was accomplished by performing dissolution studies into receptor solutions with osmotic pressure above the internal core osmotic pressure and into receptor solutions saturated with drug, respectively. The effect of coating failure modes on in vitro drug release from the AM tablet was assessed through a simulated high-fat meal and by intentionally compromising the coating integrity. Results The predominant drug release mechanism for the AM tablet was osmotic and accounted for approximately 90–95% of the total release. Osmotic release was shutoff when the receptor media osmotic pressure exceeded 76 atm. Diffusional release of the soluble drug amounted to 5–10% of the total release mechanism. The observed negative in vitro food effect was attributed to the increased osmotic pressure from the high fat meal when compared to the predicted release rates in sucrose media with the same osmotic pressure. This suppression in drug release rate due to a high fat meal is not anticipated to affect in vivo performance of the dosage form, as the rise in pressure is short-lived. Conclusions Drug release from the AM system studied was determined to be robust to varying and extreme challenge conditions. The conditions investigated included varying pH, agitation rate, media osmotic pressure, media saturated with drug to eliminate the concentration gradient, simulated high fat meal, and intentionally placed film coating defects. Osmotic and diffusional shut off experiments suggest that the mechanism governing drug release is a combination of osmotic and diffusional at approximately 90–95% and 5–10%, respectively. In addition, the coating failure mode studies revealed this formulation and design is not significantly affected by a high fat meal or by an intentionally placed defect in the film coating, and more specifically, did not result in a burst of drug release.     

Structural Development of Self Nano Emulsifying Drug Delivery Systems (SNEDDS) During <Emphasis Type="BoldItalic">In Vitro</Emphasis> Lipid Digestion Monitored by Small-angle X-ray Scattering

Purpose To investigate the structural development of the colloid phases generated during lipolysis of a lipid-based formulation in an in vitro lipolysis model, which simulates digestion in the small intestine. Materials and Methods Small-Angle X-Ray scattering (SAXS) coupled with the in vitro lipolysis model which accurately reproduces the solubilizing environment in the gastrointestinal tract and simulates gastrointestinal lipid digestion through the use of bile and pancreatic extracts. The combined method was used to follow the intermediate digestion products of a self nano emulsified drug delivery system (SNEDDS) under fasted conditions. SNEDDS is developed to facilitate the uptake of poorly soluble drugs. Results The data revealed that a lamellar phase forms immediately after initiation of lipolysis, whereas a hexagonal phase is formed after 60 min. The change of the relative amounts of these phases clearly demonstrates that lipolysis is a dynamic process. The formation of these phases is driven by the lipase which continuously hydrolyzes triglycerides from the oil-cores of the nanoemulsion droplets into mono- and diglycerides and fatty acids. We propose that this change of the over-all composition of the intestinal fluid with increased fraction of hydrolyzed nanoemulsion induces a change in the composition and effective critical packing parameter of the amphiphilic molecules, which determines the phase behavior of the system. Control experiments (only the digestion medium) or the surfactant (Cremophor RH 40) revealed the formation of a lamellar phase demonstrating that the hexagonal phase is due to the hydrolysis of the SNEDDS formulation. Conclusions The current results demonstrate that SAXS measurements combined with the in vitro dynamic lipolysis model may be used to elucidate the processes encountered during the digestion of lipid-based formulations of poorly soluble drugs for oral drug delivery. Thus the combined methods may act as an efficient screening tool.     

<Emphasis Type="Italic">In vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis> evaluations of ketoprofen extended release pellets prepared using powder layering technique in a rotary centrifugal granulator

In the present study, an extended release pellet dosage form of ketoprofen was prepared using powder layering technique. A combination of ethyl cellulose (45 cps) and shellac polymers was used as a binder (12% w/w polymer) during drug layering and an extended release coating (1:3 ratio at 2%, 4% and 7% w/w polymer) within the same apparatus. The coated pellets were characterized for sphericity, Hardness-Friability Index, and drug content, and also underwent scanning electron microscopy. In vitro dissolution was performed in 900 mL of phosphate buffer (pH 6.8) using paddle apparatus at 100 rpm. Ethyl cellulose and shellac when used as binders during drug loading did not extend ketoprofen release beyond 3 h. However, coating of the drug loaded pellets using ethyl cellulose and shellac resulted in an extended release profile of about 10 h. Using Higuchi’s model and the Korsmeyer equation, the drug release mechanism from the pellets was found to be an anomalous type involving diffusion and erosion. Scanning electron microscopy was used to visualize the pellet morphology and drug release mechanism during dissolution testing. In vivo evaluations of the extended release pellets in rats indicated a significant increase in the time to reach maximum concentration (t_max) and extent of absorption (AUC_0-∞) compared to the ketoprofen immediate release tablet blend dispersed and dosed. In conclusion, extended release pellets of ketoprofen could perform therapeutically better than conventional dosage forms, leading to improved efficacy for a prolonged period.     

<Emphasis Type="Italic">In Vitro</Emphasis>/<Emphasis Type="Italic">in Vivo</Emphasis> Correlation of Transdermal Naltrexone Prodrugs in Hairless Guinea Pigs

Purpose The purpose of this investigation was to evaluate the in vitro and in vivo percutaneous absorption of the following prodrugs of naltrexone (NTX): 2-ethylbutyryl-3-O-ester-NTX (ETBUT-ester), methyl-3-O-carbonate-NTX (ME-carbonate), ethyl-3-O-carbamate-NTX (ET-carbamate), and N,N-dimethyl-3-O-carbamate-NTX (DME-carbamate) in hairless guinea pigs.Methods In vitro fluxes of NTX and its prodrugs through guinea pig skin were determined using a flow-through diffusion cell system. The pharmacokinetics of NTX prodrugs were determined after topical application of transdermal patches in guinea pigs.Results All the prodrugs hydrolyzed to NTX on passing through the skin, and ME-carbonate provided the highest NTX flux and had the highest apparent permeability coefficient (K_p). ME-carbonate and ET-carbamate underwent the highest extent of bioconversion to NTX upon passing through the skin as compared to ETBUT-ester and DME-carbamate. The results of the in vivo studies indicated that a significant amount of NTX was delivered after the application of transdermal patches of NTX prodrugs. A mean steady-state plasma concentration of 7.1 ng/ml was obtained after the application of transdermal patches of ME-carbonate. A good correlation was obtained between the in vitro and in vivo results.Conclusions The results of the in vivo studies indicated that the ME-carbonate prodrug of NTX was the most promising drug candidate for transdermal delivery.     

Transdermal therapeutic system of isradipine: Effect of hydrophilic and hydrophobic matrix on <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">Ex vivo</Emphasis> characteristics

Isradipine (ISDP) is an effective calcium channel blocker used in the treatment of hypertension. It undergoes extensive first pass metabolism and bioavailability through the oral route is only about 15 to 24%. Hence we attempted to develop a matrix type controlled transdermal drug delivery system for ISDP. Formulations A1, A2, A3 were composed of Eudragit RL100 and hydroxypropyl methyl cellulose (HPMC) in 1:3, 1:1, 3:1 ratios; A4, A5, A6 were composed of Eudragit RS100 and HPMC in 1:3, 1:1, 3:1 ratios. All six formulations carried 5 mg of ISDP/patch area, 5% v/w of D-limonene, 15 % v/w of propylene glycol in methanol:dichloromethane (1:1). The physicochemical compatibility of the drug and the polymers was studied by infrared spectroscopy and differential scanning calorimetry. The results suggested no physicochemical incompatibility between the drug and the polymers. The prepared transdermal drug delivery system were evaluated for physicochemical characteristics, mainly in vitro release and ex vivo permeation. The ex vivo permeation studies were carried out across excised rat skin using Franz diffusion cell. All the formulations exhibited satisfactory physicochemical characteristics. Cumulative amount of the drug released in 36 h from the six formulations were 1695.32, 1527.89, 1455.54, 1485.65, 1282.81 and 916.88 μg/cm² respectively. Corresponding values for the cumulative amounts of drug permeated across the rat skin for the above matrix films were 1456.29, 1284.70, 1182.99, 1212.72, 1046.05, and 782.60 μg/cm² respectively. By fitting the data into zero order, first order and Higuchi models, it was concluded that drug release from matrix films followed Higuchi model and the mechanism of drug release was diffusion mediated. Based on the physical evaluation, in vitro drug release and ex vivo permeation characteristics, it was concluded that for potential therapeutic use, monolithic drug matrix films A1, may be suitable for the development of a transdermal drug delivery system of ISDP.     

Local,Controlled Delivery of Local Anesthetics <Emphasis Type="BoldItalic">In Vivo</Emphasis> from Polymer - Xerogel Composites

Purpose

Polymer-xerogel composite materials have been introduced to better optimize local anesthetics release kinetics for the pain management. In a previous study, it was shown that by adjusting various compositional and nano-structural properties of both inorganic xerogels and polymers, zero-order release kinetics over 7 days can be achieved in vitro. In this study, in vitro release properties are confirmed in vivo using a model that tests for actual functionality of the released local anesthetics.

Methods

Composite materials made with tyrosine-polyethylene glycol(PEG)-derived poly(ether carbonate) copolymers and silica-based sol–gel (xerogel) were synthesized. The in vivo release from the composite controlled release materials was demonstrated by local anesthetics delivery in a rat incisional pain model.

Results

The tactile allodynia resulting from incision was significantly attenuated in rats receiving drug-containing composites compared with the control and sham groups for the duration during which natural healing had not yet taken place. The concentration of drug (bupivacaine) in blood is dose dependent and maintained stable up to 120 h post-surgery, the longest time point measured.

Conclusions

These in vivo studies show that polymer-xerogel composite materials with controlled release properties represent a promising class of controlled release materials for pain management.