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ABSTRACT: Intra-articular injection of oil solutions of lipophilic prodrugs that rapidly degrade to their parent compound in synovial fluid may constitute a feasible approach to increase the joint residence time of non-steroidal anti-inflammatory drugs. In this in vivo study, oil solutions of the N,N-diethyl glycolamide ester prodrug of naproxen (16mg/ml) were injected into the rat knee joint by dosing 6μL formulation per 100g body weight. The sustained release properties were compared to those of intra-articularly injected aqueous and oil solutions of naproxen by monitoring the naproxen serum concentrations over time. Two oils, medium-chain triglycerides and castor oil, differing with respect to viscosity were tested. After intra-articular administration of oil prodrug solutions, a significant increase in the time to maximum naproxen serum concentration from around 40 to 245min, an increase in the MRTj from around 0.11 to 3.3h and a 30% reduction in the maximum serum concentration were observed compared to that of the parent naproxen. The similar serum profiles obtained using the two oils indicate that the release was not affected by the oil viscosity. A prolonged naproxen joint residence time in rats was shown by intra-articular injection of an oil prodrug solution.
International journal of pharmaceutics 04/2013; · 2.96 Impact Factor
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Fengbin Ye,,
Yuanyi, Xie,,
Henrik Jensen,, Susan Weng Larsen,,
Anan, Yaghmur,,
Claus Larsen,,
Jesper Østergaard
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ABSTRACT: Interactions of drug candidates with the bio-macromolecules of the synovial fluid affect drug targeting to the articular cartilage as well as clearance from the synovial space upon intra-articular administration. Hyaluronic acid (HA) and human serum albumin (HSA) are two main components existing in the synovial fluid. To this end, we investigated the affinity of seven cationic amino acid and dipeptide b-naphthylamide derivatives towards HA and HSA in order to shed light on possible relationships between physicochemical properties, in particular charge state, and biomacromolecular interactions to increase the joint resi-dence time. Capillary electrophoresis frontal analysis was used for characterization of the binding of the derivatives to hyaluronic acid and HSA at 25 °C in acetate buffer (pH 4.65) and phosphate buffer (pH 7.40), respectively. Linear binding isotherms were observed for the ligand– hyaluronic acid interactions and the obtained binding con-stants ranged from 43 to 133 M -1 . The average fraction of bound ligand towards hyaluronic acid increased with increasing the net charge of the ligands but was less than 67 % for all investigated ligands. The obtained binding constants of the ligands with HSA varied in the range of 10 3 –10 6 M -1 . The interactions of low-molecular weight derivatives with hyaluronic acid were highly dependent on the ligand charge state. This trend was not observed for the interactions with HSA. The obtained affinity data may provide useful information in the design of cartilage adhesive prodrugs with extended residence time in the synovial cavity.
Chromatographia 12/2012; · 1.20 Impact Factor
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ABSTRACT: Intra-articular injection of two drugs in a sustained drug delivery system combining the use of lipophilic solution with the prodrug approach may provide efficient and prolonged postoperative pain treatment after arthroscopic procedures. In the present study, the concomitant release of N,N-diethyl glycolamide ester of naproxen and ropivacaine from an oil vehicle consisting of medium-chain triglycerides were investigated in vitro. The release into both phosphate buffer and 80% (v/v) synovial fluid at pH 7.4 was examined in two dialysis membrane-based release models. The ester prodrug exhibited high solubility in medium-chain triglyceride, a high partition coefficient and was rapidly converted to naproxen in synovial fluid. Compared to naproxen, the release of the prodrug from the oil was sustained. In synovial fluid, the reconversion to naproxen resulted in faster release compared to that observed using buffer. In both release models, the use of ropivacaine-prodrug combination provided concomitant release from the oil into synovial fluid with ropivacaine being released faster than naproxen. The use of lipophilic prodrugs that are converted fast to the parent drug in synovial fluid seems to be a feasible approach to obtain prolonged joint residence time.
International journal of pharmaceutics 09/2012; · 2.96 Impact Factor
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ABSTRACT: Upon subcutaneous administration, the distribution of drug between the delivery vehicle and the biological tissue critically affects the absorption of drug substances. Utilization of physical models resembling the native tissues appears promising for obtaining a detailed understanding of the performance of drug delivery systems based on in vitro experiments. The objective of this study was to evaluate a UV imaging-based method for real-time characterization of the release and transport of piroxicam in hydrogel-based subcutaneous tissue mimics/surrogates. Piroxicam partitioning from medium chain triglyceride (MCT) into 0.5% (w/v) agarose or 25% (w/v) F127-based hydrogels was investigated by monitoring the concentration profiles of the drug in the gels. The effect of pH on piroxicam distribution and diffusion coefficients was studied. For both hydrogel systems, the diffusion of piroxicam in the gels was not affected significantly by the pH change from 4.0 to 7.4 but a considerable change in the oil-gel distribution coefficients was found (24 and 34 times less at pH 7.4 as compared those observed at pH 4.0 for F127 and agarose gels, respectively). In addition, the release and transport processes of piroxicam upon the injection of aqueous or MCT solutions into an agarose-based hydrogel were investigated by UV imaging. The spatial distribution of piroxicam around the injection site in the gel matrix was monitored in real-time. The disappearance profiles of piroxicam from the injected aqueous solution were obtained. This study shows that the UV imaging methodology has considerable potential for characterizing transport properties in hydrogels, including monitoring the real-time spatial concentration distribution in vitro after administration by injection.
Journal of pharmaceutical and biomedical analysis 07/2012; 71:27-34. · 2.45 Impact Factor
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ABSTRACT: The present study was designed to evaluate the effect of the negatively charged food-grade emulsifier citrem on the internal nanostructures of oil-free and oil-loaded aqueous dispersions of phytantriol (PHYT) and glyceryl monooleate (GMO). To our knowledge, this is the first report in the literature on the utilization of this charged stabilizing agent in the formation of aqueous dispersions consisting of well-ordered interiors (either inverted-type hexagonal (H(2)) phases or inverted-type microemulsion systems). Synchrotron small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM) were used to characterize the dispersed and the corresponding nondispersed phases of inverted-type nonlamellar liquid-crystalline phases and microemulsions. The results suggest a transition between different internal nanostructures of the aqueous dispersions after the addition of the stabilizer. In addition to the main function of citrem as a stabilizer that adheres to the surface of the dispersed particles, it has a significant impact on the internal nanostructures, which is governed by the following factors: (1) its penetration between the hydrophobic tails of the lipid molecules and (2) its degree of incorporation into the lipid-water interfacial area. In the presence of citrem, the formation of aqueous dispersions with functionalized hydrophilic domains by the enlargement of the hydrophilic nanochannels of the internal H(2) phase in hexosomes and the hydrophilic core of the L(2) phase in emulsified microemulsions (EMEs) could be particularly attractive for solubilizing and controlling the release of positively charged drugs.
Langmuir 07/2012; 28(32):11755-66. · 4.19 Impact Factor
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ABSTRACT: A novel real-time UV imaging approach for non-intrusive investigation of the diffusion and partitioning phenomena occurring during piroxicam release from medium chain triglyceride (MCT) solution into two hydrogel matrices is described. Two binary polymer/buffer gel matrices, 0.5% (w/v) agarose and 25% (w/v) Pluronic F127, were applied as simple models mimicking the subcutaneous tissue. The evolution of the absorbance maps as a function of time provided detailed information on the piroxicam release processes upon the exposure of the gel matrices to MCT. Using calibration curves, the concentration maps of piroxicam in the UV imaging area were determined. Regression of the longitudinal concentration-distance profiles, which were obtained using expressions derived from Fick's second law, provided the diffusivity and the distribution coefficients of piroxicam penetrated into the gels. The obtained MCT-agarose (pH 7.4) distribution coefficient of 1.4 was identical to the MCT-aqueous (pH 7.4) distribution coefficient determined by the shake-flask method whereas that of the MCT-Pluronic F127 system was four times less. The experimental data show that UV imaging may have considerable potential for investigating the transport properties of drug formulations intended for the subcutaneous administration.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 02/2012; 46(1-2):72-8. · 2.61 Impact Factor
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ABSTRACT: This report details the structural characterization and the in vitro drug-release properties of different local anesthetic bupivacaine (BUP)-loaded inverted-type liquid crystalline phases and microemulsions. The effects of variations in the lipid composition and/or BUP concentration on the self-assembled nanostructures were investigated in the presence of the commercial distilled glycerol monooleate Myverol 18-99K (GMO) and medium-chain triglycerides (MCT). Synchrotron small-angle X-ray scattering (SAXS) and rotating dialysis cell model were used to characterize the BUP formulations and to investigate the in vitro BUP release profiles, respectively. The evaluation of SAXS data for the BUP-loaded GMO/MCT formulations indicates the structural transition of inverted-type bicontinuous cubic phase of the symmetry Pn3m → inverted-type hexagonal (H(2)) phase → inverted-type microemulsion (L(2)) with increasing MCT content (0-40 wt %). In the absence of MCT, the solubilization of BUP induces the transition of Pn3m → H(2) at pH 7.4; whereas a transition of Pn3m → (Pn3m + H(2)) is detected as the hydration is achieved at pH 6.0. To mimic the drug release and transport from in situ formed self-assembled systems after subcutaneous administration, the release experiments were performed by injecting low viscous stimulus-responsive precursors to a buffer in the dialysis cell leaving the surface area between the self-assembled system and the release medium variable. Our results suggest that the pH-dependent variations in the lipidic partition coefficient, K(l/w), between the liquid crystalline nanostructures and the surrounding buffer solution are significantly affecting BUP release rates. Thus, a first step toward understanding of the drug-release mechanism of this drug-delivery class has been undertaken tackling the influence of drug ionization as well as the type of the self-assembled nanostructure and its release kinetics under pharmaceutically relevant conditions.
Langmuir 02/2012; 28(5):2881-9. · 4.19 Impact Factor
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ABSTRACT: Most in vitro methods for evaluating parenteral oil based depots are focusing on intramuscular or subcutaneous injection. For intra-articular injection other mechanisms may control the overall drug release rate due to a relatively smaller interfacial area and longer transport distance of the drug substance in the oil to the oil-synovial fluid interface. In the current work, an in vitro model for testing drug release from oil solutions intended for intra-articular injection was evaluated. The release of the model drugs naproxen, piroxicam and ropivaciane from a well-defined surface area of the lipophilic solutions were followed using an in vitro model based on a modified USP II paddle apparatus with modest agitation (50rpm) of the oil formulation. By alteration of the viscosity of the oil, the oil-water interfacial area, the oil volume and the stirring efficiency of the release medium, it was shown that the drug release rate was dependent on the drug diffusivity in the oil and the degree of agitation generated in the oil vehicle. In addition, the partitioning of the drug between the oil vehicle and the release media was found to influence the release rate. In combination with an improved understanding of in vivo drug release and distribution, the present work may form a promising foundation for future in vivoin vitro correlations.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 12/2011; 45(3):351-7. · 2.61 Impact Factor
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ABSTRACT: The objective of the present study was to explore the potential of using an in situ suspension forming drug delivery system of celecoxib to provide sustained drug exposure in the joint cavity following intra-articular administration. In vitro, precipitates were formed upon addition of a 400 mg/mL solution of celecoxib in polyethylene glycol 400 (PEG 400) to phosphate buffer, pH 7.4, or synovial fluid. The in vitro release profiles of the in situ formed suspensions were characterized by an initial fast release followed by a slower constant flux. In buffer solutions, these fluxes were comparable to those determined for a preformed suspension containing celecoxib in its most stable crystal form despite the in situ formed precipitates contained a mixture of two crystal forms of celecoxib as determined by X-ray powder diffraction. In situ suspension formation in synovial fluid was subject to considerable variation. A relatively high dose of celecoxib, corresponding to 1.25 mg/kg, in the form of PEG 400 solution (400 mg/mL) was injected into the radiocarpal joint in four horses. Celecoxib was present in serum samples taken over 10 days and in the joint tissue (post mortem), strongly indicating that joint sustained celecoxib exposure can be achieved using in situ suspension formation. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4330–4337, 2011
Journal of Pharmaceutical Sciences 05/2011; 100(10):4330 - 4337. · 3.06 Impact Factor
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ABSTRACT: Dissolution critically affects the bioavailability of Biopharmaceutics Classification System class 2 compounds. When unexpected dissolution behaviour occurs, detailed studies using high information content technologies are warranted. In the present study, an evaluation of real-time ultraviolet (UV) imaging for conducting single-crystal dissolution studies was performed. Using lidocaine as a model compound, the aim was to develop a setup capable of monitoring and quantifying the dissolution of lidocaine into a phosphate buffer, pH 7.4, under stagnant conditions. A single crystal of lidocaine was placed in the quartz dissolution cell and UV imaging was performed at 254 nm. Spatially and temporally resolved mapping of lidocaine concentration during the dissolution process was achieved from the recorded images. UV imaging facilitated the monitoring of lidocaine concentrations in the dissolution media adjacent to the single crystals. The concentration maps revealed the effects of natural convection due to density gradients on the dissolution process of lidocaine. UV imaging has great potential for in vitro drug dissolution testing.
Journal of Pharmaceutical Sciences 03/2011; 100(8):3405-10. · 3.06 Impact Factor
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ABSTRACT: In the area of parenteral depots, a strong need exists for the development of suitable in vitro drug release models that might enable establishment of in vitro-in vivo relations (IVIVRs).
The objective of this study was to investigate the possibility of establishing an IVIVR between morphine disappearance from the joint cavity and in vitro release data obtained employing the rotating dialysis cell model.
In vitro release experiments were conducted using the rotating dialysis cell model. For establishment of an IVIVR, data from a previous study on pharmacokinetics of intra-articular (IA) morphine in horses with lipopolysaccharide-induced synovitis were used (Lindegaard et al., (2009). Vet Anaesth Analg, 37, 186-195).
A rate constant of morphine disappearance from the donor phase of the in vitro model of 1.8 × 10(-2) min(-1) was calculated, independently of the different release media used. The in vivo synovial fluid disappearance rate constants were in the range of 1.0 × 10(-2)-1.7 × 10(-2) min(-1). An IVIVR (R(2) = 0.89) was established between the calculated disappearance data and the joint disappearance data.
The results indicate that the IA fate of morphine administered in the form of a solution can be predicted from the in vitro release data obtained in the rotating dialysis cell model. Thus, this model might be a valuable tool in the establishment of IVIVRs after IA administration of drugs with similar properties.
Drug Development and Industrial Pharmacy 03/2011; 37(9):1043-8. · 1.49 Impact Factor
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ABSTRACT: RESULTS: Basic physicochemical properties including their apparent solubility in aqueous buffer and vegetable oils of a series of 11 peptidomimetics varying with respect to chain length and degree of N-methylation were estimated. It was observed that the compounds in contact with water transformed into sticky, slowly dissolving semisolid materials. Based on these observations, the in vitro release behavior of selected peptide derivatives from oil solutions and in situ formed precipitates was investigated using a validated in vitro release model. CONCLUSION: The results of this investigation suggest that both types of oil-based drug delivery systems might constitute alternative sustained release formulation principles of such amorphous peptide derivatives for the intra-articular route of administration.
Drug Development and Industrial Pharmacy 01/2011; 37(1):62-71. · 1.49 Impact Factor
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ABSTRACT: This study was conducted to characterize UV imaging as a platform for performing in vitro release studies using Nicorette® nicotine patches as a model drug delivery system.
The rate of nicotine release from 2 mm diameter patch samples (Nicorette®) into 0.067 M phosphate buffer, pH 7.40, was studied by UV imaging (Actipix SDI300 dissolution imaging system) at 254 nm. The release rates were compared to those obtained using the paddle-over-disk method.
Calibration curves were successfully established which allowed temporally and spatially resolved quantification of nicotine. Release profiles obtained from UV imaging were in qualitative agreement with results from the paddle-over-disk release method.
Visualization as well as quantification of nicotine concentration gradients was achieved by UV imaging in real time. UV imaging has the potential to become an important technology platform for conducting in vitro drug release studies.
Pharmaceutical Research 12/2010; 27(12):2614-23. · 4.09 Impact Factor
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ABSTRACT: Development of suitable in vitro release models for formulation development as well as quality control purposes has to be initiated in the early design phase of injectable depots. Optimally, construction of an in vitro release model may lead to the establishment of in vitro in vivo correlations. By using a model compound (sodium diatrizoate, DTZ), the purpose of this study was to investigate the possibility of establishing in vitro in vivo relations between the DTZ disappearance profile obtained from the donor compartment of the rotating dialysis cell model and the joint disappearance profile following intra-articular administration. In vitro experiments were conducted by applying solutions of DTZ to the donor compartment. In the in vivo experiments, five horses were subjected to both intravenous and intra-articular administration of an aqueous solution of 3.9 mg DTZ/kg. A strong relation (R(2)=0.99) was obtained between the disappearance data from the donor compartment of the in vitro model and the disappearance data from the synovial fluid after intra-articular administration of DTZ. Furthermore, a relation (R(2)=0.91) between the appearance data obtained from the acceptor compartment and the deconvolved appearance serum data upon intra-articular administration of DTZ was obtained. The correlations obtained in this study hold promise that the rotating dialysis cell model has a role in the prediction of the intra-articular fate of drugs injected as solutions.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 09/2010; 41(1):10-5. · 2.61 Impact Factor
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ABSTRACT: This review article provides an assessment of advantages/limitations of the use of current in vitro release models to predict in vivo performance of parenteral sustained release products (injectable depots). As highlighted, key characteristics influencing the in vivo drug fate may vary with the route of administration and the type of sustained release formulation. To this end, an account is given on three representative injection sites (intramuscular, subcutaneous and intra-articular) as well as on in vitro release mechanism(s) of drugs from five commonly investigated depot principles (suspensions, microspheres, hydrogels, lipophilic solutions, and liposomes/other nano-size formulations). Current in vitro release models are, to a different extent, able to mimic the rate, transport and equilibrium processes that the drug substance may experience in the environment of the administration site. Their utility for the purpose of quality control including in vitro-in vivo correlations and formulation design is discussed.
Expert Opinion on Drug Delivery 12/2009; 6(12):1283-95. · 4.90 Impact Factor
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ABSTRACT: Parenteral long-acting lipophilic solutions have been used for decades and might in the future be used in the design of depots with tailored delivery characteristics. The present review highlights major factors influencing the in vivo performance of lipophilic solutions. Furthermore, an account is given of the characteristics of employed in vitro release methods with a focus on the "state" of sink condition, the stirring conditions, and the oil-water interfacial area. Finally, the capability of in vitro release data to predict the in vivo performance of drug substances administrated in the form of lipophilic solutions is discussed. It is suggested that as long as the major rate-limiting in vivo release mechanism is governed by the drug partitioning between the oil vehicle and the tissue fluid, the use of in vitro release testing in quality control appears to be realistic. With increasing lipophilicity of the drug substances and longer duration of action, the in vivo drug release process may become more complex. As discussed, practical analytical problems together with the inability of release methods to mimic two or more concomitant in vivo events may constitute severe impediments for establishment of in vitro in vivo correlations.
The AAPS Journal 11/2009; 11(4):762-70. · 5.09 Impact Factor
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ABSTRACT: The potential of using CE frontal analysis (CE-FA) for the study of low-molecular-weight drug-liposome interactions was assessed. The interaction of bupivacaine, brompheniramine, chlorpromazine, imipramine, and ropivacaine with net negatively charged 80/20 mol% 1-oleoyl-2-palmitoyl-sn-glycero-3-phosphocholine/egg yolk phosphatidic acid liposome suspensions in HEPES buffer at pH 7.4 was investigated. The fraction of free drug as a function of lipid concentration was measured and apparent liposome-buffer distribution coefficients were determined for the basic drug substances. The distribution coefficients increased in the order ropivacaine, bupivacaine, brompheniramine, imipramine, and chlorpromazine. The developed CE method was relatively fast allowing estimates of drug-liposome affinity to be obtained within 15 min. CE-FA may have the potential to become a valuable tool for the characterization of drug-liposome interactions in relation to estimation of drug lipophilicity and for the evaluation of drug distribution in liposomal drug delivery systems.
Electrophoresis 08/2008; 29(16):3320-4. · 3.30 Impact Factor
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ABSTRACT: The objective of this study was to gain insight into factors influencing the drug release kinetics from oil suspensions. The in vitro drug release from suspensions was investigated at pH 7.4 using the local anesthetics, bupivacaine and ropivacaine, as model drug compounds. Two dialysis membrane-based in vitro release models differing with respect to stirring of the donor compartment were employed to study the release characteristics of oil suspensions comprising the free base or the corresponding drug hydrochloride salt. In the rotating dialysis cell model identical release profiles from aqueous and oil suspensions of the base form were obtained for both ropivacaine and bupivacaine. From the steady state fluxes, drug concentrations in the aqueous donor compartment were found to be in agreement with drug solubilities at pH 7.4. Also relatively fast transformation of a sesame oil suspension of the oil insoluble ropivacaine hydrochloride salt into an aqueous suspension of ropivacaine base was observed. Collectively, these observations indicate a lability of the oil film surrounding the solid particles eventually caused by rotation of the donor cell. In the Float A Lyzer model, which operates at much less intensive stirring, significantly slower release rates from aqueous and oil suspensions of ropivacaine base were obtained. In the latter model, ropivacaine was released faster from oil suspensions containing the hydrochloride salt than from the corresponding oil suspensions of the free base form. These findings suggest that the oil film surrounding the particles also is instable in the absence of significant shear forces.
European Journal of Pharmaceutical Sciences 06/2008; 34(1):37-44. · 3.21 Impact Factor
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ABSTRACT: In vitro drug release and transport rates from oil depot formulations under nonsink conditions have been investigated in the rotating dialysis cell model. Eight model drug compounds and eight oil vehicle compositions were used for the releaseexperiments. The experimentally obtained apparent first-order rate constants related to the drug appearance in the acceptor phase after initial instillation of a drug-containing oil solution were found to be in excellent agreement with the rate constants obtained from a theoretically derived expression. It was observed that the drug oil-water distribution coefficient was the key parameter influencing the release characteristics. As compared with ketoprofen, flurbiprofen exhibited a higher affinity for the oil, resulting in a significantly lower and more slowly decreasing drug concentrations in the aqueous donor compartment. Release profiles for prilocaine and the more lipophilic agent bupivacaine after incorporation of both drugs in fractionated coconut oil were characterized by a fast release of prilocaine, whereas bupivacaine was liberated much slower to the acceptor phase. The high oil-buffer interfacial area generated in vitro by rotation of the donor cell tends to overestimate release rates in comparison to those expected in vivo, for example, after intra-articular administration of oil solutions. The present in vitro method may constitute a valuable tool in accelerated in vitro release testing of parenteral oil depot formulations in areas comprising formulation design and product quality control.
Drug Development and Industrial Pharmacy 04/2008; 34(3):297-304. · 1.49 Impact Factor
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ABSTRACT: In vitro drug release rates from aqueous and oil solutions as well as preformed and in situ formed aqueous and oil suspensions intended for intra-articular delivery have been investigated using the rotating dialysis cell model. Using lidocaine as a model drug substance the release kinetics from aqueous and oil suspensions have been compared and the sustained release properties from such suspensions formed in situ has been evaluated. The appearance of lidocaine in the acceptor phase after instillation of preformed and in situ formed aqueous and oil suspensions into the small aqueous donor compartment applied to zero-order kinetics as long sufficient amounts of solid lidocaine remained in the donor cell. The obtained data indicate that oil solutions and oil suspensions of lidocaine possess prolonged release properties equal to or better than those of aqueous counterparts. Also the release properties of preformed aqueous and oil suspensions are identical to such suspension types formed in situ. The present in vitro model appears useful in quality control and formulation development in the field of parenteral depots.
Drug Delivery 02/2008; 15(1):23-30. · 1.46 Impact Factor
