Development and characterization of PLGA-Bupivacaine and PLGA-S75: R25 Bupivacaine (Novabupi®) biodegradable implants for postoperative pain

Abstract In the hospital environment, postoperative pain is a common occurrence that impairs patient recovery and rehabilitation and lengthens hospitalization time. Racemic bupivacaine hydrochloride (CBV) and Novabupi® (NBV) (S (-) 75% R (+) 25% bupivacaine hydrochloride) are two examples of local anesthetics used in pain management, the latter being an alternative with less deleterious effects. In the present study, biodegradable implants were developed using Poly(L-lactide-co-glycolide) through a hot molding technique, evaluating their physicochemical properties and their in vitro drug release. Different proportions of drugs and polymer were tested, and the proportion of 25%:75% was the most stable for molding the implants. Thermal and spectrometric analyses were performed, and they revealed no unwanted chemical interactions between drugs and polymer. They also confirmed that heating and freeze-drying used for manufacturing did not interfere with stability. The in vitro release results revealed drugs sustained release, reaching 64% for NBV-PLGA and 52% for CBV-PLGA up to 30 days. The drug release mechanism was confirmed by microscopy, which involved pores formation and polymeric erosion, visualized in the first 72 h of the in vitro release test. These findings suggest that the developed implants are interesting alternatives to control postoperative pain efficiently.

Determination of bupivacaine tissue concentration in human biopsy samples using high-performance liquid chromatography with mass spectrometry.

In the present study, we developed a simple and rapid analytical method for the quantification of bupivacaine hydrochloride in human biopsy samples of adipose, muscle, neural, connective and cartilage tissue using liquid chromatography-mass spectrometry. Anesthetics were extracted from the tissue samples using 0.1% formic acid in acetonitrile for protein denaturation and hexane for removal of lipophilic impurities. Analytes were separated adequately on Phenomenex Luna Omega polar C18 column using a gradient mobile phase 0.1% formic acid in water and 0.1% formic acid in acetonitrile. The lower limits of quantification were ≤ 97 ng g-1 tissue for all studied tissues. Intra-day recoveries were between 48.2% and 82.1% with relative standard deviations (RSDs) between 1.47% and 14.28%, whereas inter-day recoveries were between 52.2% and 77.6% with RSDs between 2.98% and 14.79%. The calibration curve showed a linear fit with R2 higher than 0.99 in the concentration range from 0.16 to 100 µg g-1 . Lidocaine hydrochloride was tested as internal standard because its recoveries and matrix effects were comparable to bupivacaine hydrochloride. Post-analytical corrections of measured bupivacaine tissue concentrations can accordingly be made based on recovery of lidocaine as internal standard, with recoveries between 51.2% and 86.9% and RSDs between 1.99% and 16.88%. The developed method could be used to study time-dependent spread of bupivacaine locally or to more distant locations across tissue barriers.

Development and evaluation of a novelty single-step cleanup followed by HPLC-QTRAP-MS/MS for rapid analysis of tricaine, tetracaine, and bupivacaine in fish samples.

A novelty single-step cleanup method combined with HPLC coupled with triple quadrupole-linear ion trap MS/MS (HPLC-QTRAP-MS/MS) was developed for the analysis of tricaine, tetracaine, and bupivacaine in fish tissue. The target analytes were extracted using acetonitrile based on the modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) method under ultrasound irradiation. A cheap analytical filtration syringe (CAFS) cleanup column for single-step purification was proposed first; 300 mg of primary/secondary amino was proposed as the optimum purification sorbent; 1 mL of acetonitrile extract was transferred into a CAFS cleanup column and purified for analysis using HPLC-QTRAP-MS/MS. The limits of detection and the limits of quantification were 2.0 and 5.0 µg kg-1 , respectively. The recoveries were in the range of 88.73-108.72%. Inter-day and intra-day relative standard deviations were lower than 15% for all analytes. The developed method has been applied to measure real samples obtained from the local market.

Sterility and concentration of liposomal bupivacaine single-use vial when used in a multiple-dose manner.

OBJECTIVE: To evaluate the sterility of bupivacaine liposome injectable suspension (Nocita®) used in a multiple-dose fashion for 5 days. STUDY DESIGN: Triplicate liposomal bupivacaine vials were stored under two conditions, (1) room temperature (24°C) and (2) refrigerated temperature (5°C). A 3-mL aliquot was withdrawn from each vial daily. Samples were inoculated in tryptic soy broth in triplicate and then incubated for 24 hours at 37°C and subcultured every 48 hours onto blood agar and Sabouraud dextrose agar, respectively. Separate 1.5-mL aliquots of liposomal bupivacaine were centrifuged at 3500 g to separate liposome-encapsulated bupivacaine from the solution. Concentration of unencapsulated bupivacaine was analyzed via high-pressure liquid chromatography. Data were analyzed by using mixed effects procedure with multiple comparisons. SAMPLE POPULATION: Ten 20-mL vials of bupivacaine liposome injectable suspension stored under two conditions, (1) room temperature (24°C) and (2) refrigerated temperature (5°C). RESULTS: Five days of repeated withdrawal from the single-use vials yielded no bacterial growth. One control vial, which was opened and punctured once on the last day of the experiment, yielded fungal growth of an Aspergillus spp, likely an environmental contaminant. The concentration of free bupivacaine did not significantly differ until the fifth day of sampling. CONCLUSION: When aseptic technique was used, liposomal bupivacaine remained sterile for 5 days. Concentrations of free bupivacaine were unchanged from baseline for 4 days in both refrigerated and room temperature conditions. CLINICAL SIGNIFICANCE: Single-use liposomal bupivacaine vials can be used extralabel in a multiple-dose fashion for up to 4 days when stored either refrigerated or room temperature when sterile technique is used.

Quantification of bupivacaine hydrochloride and isoflupredone acetate residues in porcine muscle, beef, milk, egg, shrimp, flatfish, and eel using a simplified extraction method coupled with liquid chromatography-triple quadrupole tandem mass spectrometry.

In this study, a simple analytical approach has been developed and validated for the determination of bupivacaine hydrochloride and isoflupredone acetate residues in porcine muscle, beef, milk, egg, shrimp, flatfish, and eel using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A 0.1% solution of acetic acid in acetonitrile combined with n-hexane was used for deproteinization and defatting of all tested matrices and the target drugs were well separated on a Waters Xbridge™ C18 analytical column using a mobile phase consisting of 0.1% acetic acid (A) and 0.1% solution of acetic acid in methanol (B). The linearity estimated from six-point matrix-matched calibrations was good, with coefficients of determination ≥0.9873. The limits of quantification (LOQs) for bupivacaine hydrochloride and isoflupredone acetate were 1 and 2ngg-1, respectively. Recovery percentages in the ranges of 72.51-112.39% (bupivacaine hydrochloride) and 72.58-114.56% (isoflupredone acetate) were obtained from three different fortification concentrations with relative standard deviations (RSDs) of <15.14%. All samples for the experimental work and method application were collected from the local markets in Seoul, Republic of Korea, and none of them tested positive for the target drugs. In conclusion, a simple method using a 0.1% solution of acetic acid in acetonitrile and n-hexane followed by LC-MS/MS could effectively extract bupivacaine hydrochloride and isoflupredone acetate from porcine muscle, beef, milk, egg, shrimp, flatfish, and eel samples.

Probing the dynamics of complexed local anesthetics via neutron scattering spectroscopy and DFT calculations.

Since potential changes in the dynamics and mobility of drugs upon complexation for delivery may affect their ultimate efficacy, we have investigated the dynamics of two local anesthetic molecules, bupivacaine (BVC, C18H28N2O) and ropivacaine (RVC, C17H26N2O), in both their crystalline forms and complexed with water-soluble oligosaccharide 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD). The study was carried out by neutron scattering spectroscopy, along with thermal analysis, and density functional theory computation. Mean square displacements suggest that RVC may be less flexible in crystalline form than BVC, but both molecules exhibit very similar dynamics when confined in HP-ß-CD. The use of vibrational analysis by density functional theory (DFT) made possible the identification of molecular modes that are most affected in both molecules by insertion into HP-ß-CD, namely those of the piperidine rings and methyl groups. Nonetheless, the somewhat greater structure in the vibrational spectrum at room temperature of complexed RVC than that of BVC, suggests that the effects of complexation are more severe for the latter. This unique approach to the molecular level study of encapsulated drugs should lead to deeper understanding of their mobility and the respective release dynamics.

Identification of Drugs in Parenteral Pharmaceutical Preparations from a Quality Assurance and a Diversion Program by Direct Analysis in Real-Time AccuTOFTM-Mass Spectrometry (DART-MS).

In healthcare settings drug diversion and impairment of physicians are major concerns requiring a rapid and efficient method for surveillance and detection. A Direct Analysis in Real Time ion source coupled to a JEOL AccuTOFTM time-of-flight mass spectrometer (DART-MS) method was developed to screen parenteral pharmaceutical formulations for potential drug diversion. Parenteral pharmaceutical formulations are also known as injectable formulations and are used with intravenous, subcutaneous, intramuscular and intra-articular administration. A library was created using the mass spectra data collected by a DART-MS operated in switching mode at 20, 60 and 90 V settings. This library contained 17 commonly encountered drugs in parenteral pharmaceutical formulations that included the surgical analgesic: fentanyl, hydromorphone and morphine; anesthetic: baclofen, bupivacaine, ketamine, midazolam, ropivacaine and succinylcholine; and a mixture of other drug classes: caffeine, clonidine, dexamethasone, ephedrine, heparin, methadone, oxytocin and phenylephrine. Randomly selected 200 de-identified parenteral pharmaceutical formulations containing one or more drugs were submitted for analysis to the FIRM Toxicology Laboratory at Virginia Commonwealth University Health and were screened using the DART-MS. The drug contents of the de-identified formulations were previously confirmed by a published high performance liquid chromatography (HPLC) method. The drugs in the formulations were rapidly and successfully identified using the generated library. The DART-MS and HPLC results were in complete agreement for all 200 parenteral pharmaceutical formulations.

A fatal accidental subarachnoid injection of lidocaine and levobupivacaine during a lumbar paravertebral block.

Paravertebral block (PVB) is the technique of injecting a local anesthetic solution alongside the vertebral column, close to where the spinal nerves emerge, resulting in unilateral somatic and sympathetic nerve blockade. Here is reported a fatal case involving a 60-year-old woman with spondylitis arthropathy, who developed cardiac and respiratory arrest 40min after receiving an accidental subarachnoid injection (L5-S1 bilaterally) of depomedrol lidocaine and levobupivacaine. A complete autopsy including histological and toxicological analyses was performed in order to establish the cause of death. Liquid/liquid extraction (LLE) and GC-MS analysis were performed according to a previously published method. Lidocaine and bupivacaine were detected both in blood, at concentrations of 14.8mg/L and 13.3mg/L respectively, and in cerebrospinal fluid (CSF) at concentrations of 287.1mg/L and 464.2mg/L respectively. Both lidocaine and bupivacaine were also detected in the urine. The toxicological findings along with the autopsy allowed us to establish that the accidental subarachnoid injection of lidocaine and levobupivacaine had led to a progressive hypotension and normovolaemic shock caused by a severe ganglionic block, determining the patient's death.

Separation and determination of anesthetics by capillary electrophoresis with mixed micelles of sodium dodecyl sulfate and Tween 20 using electrochemiluminescence detection.

A simple and new method for the simultaneous determination of procaine (Pro), lidocaine (Lid), ropivacaine (Rop) and bupivacaine (Bup) was developed using capillary electrophoresis separation with mixed micelles and electrochemiluminescence detection. The use of mixed micelles of 2.0 × 10(-3) mol/L sodium dodecyl sulfate (SDS) and 8.0 × 10(-3) mol/L Tween 20 greatly improved separation selectivity. The detection sensitivities of four drugs with a Pt working electrode were increased by modification of the Pt electrode with europium(III)-doped Prussian Blue analog (Eu-PB). Under optimal conditions, the four local anesthetics were well separated and detected. The limits of detection (LOD, S/N = 3) of Pro, Lid, Rop and Bup in standard solution are 2.5 × 10(-8) , 1.3 × 10(-8) , 3.0 × 10(-8) and 4.1 × 10(-8) mol/L, respectively. The limits of quantitation (LOQ, S/N = 10) of Pro, Lid, Rop and Bup are 2.3 × 10(-7) , 1.2 × 10(-7) , 3.7 × 10(-7) and 5.6 × 10(-7) mol/L in a human urine sample, and 8.5 × 10(-7) , 6.9 × 10(-7) , 2.8 × 10(-6) and 1.1 × 10(-6) mol/L in a human serum sample, respectively. The recoveries of four drugs at different spiked concentrations in human urine and serum samples were between 86.5 and 107.6%. The proposed method has been successfully applied to determine local anesthetics in biofluids.

Selective discrimination of small hydrophobic biomolecules based on ion-current rectification in conically shaped nanochannel.

In this study, based on ion-current rectification in the conically shaped nanochannel embedded in polyethylene terephthalate (PET) membrane, we have selectively discriminated three small biomolecules. Because three positive biomolecules (Hoechst 33342, Propidium and Bupivacaine) have different hydrophobicities, their interactions with inside wall of the conical nanochannel are different and their binding affinities can be derived from Langmuir absorption model. Therefore, we can successfully discriminate these small biomolecules. The highest binding constant was obtained for the small molecule with highest hydrophobicity. Another interesting result is that the detection limit for the small molecule with the highest binding constant shifts to submicromole.

Fast detection of local anesthetic levobupivacaine by impedance method on PPy/SWCNT.

Fast response electrochemical impedance (EI) method was developed to detect concentrations of local anesthetic Levobupivacaine. It revealed the EI method possessed fast response and recovery times and the lowest detected concentration was 1 ppm. Pyrrole was electrochemically polymerized to polypyrrole and made a composite with single walled carbon nanotubes coated over gold electrodes for sensing studies. Ppy and Ppy/SWCNT composite materials were coated upon Au electrodes and characterized by UV/Vis, Fourier Transform Infrared (FTIR), Cyclic Voltammetry (CV) and Transmission Electron Microscope (TEM). Various concentrations of levobupivacaine in the range, 1 to 500 ppm were prepared in medically significant saline solution of 0.9% NaCI as test samples. A 10-kHz frequency was used for the calibration curve, and the short response and recovery time were tested as 5 s and 3 s, respectively. The Ppy/SWCNT material with R2 as 0.9971 showed better linearity than Ppy material. Using molecular dynamic simulation studies exothermic adsorption energies and bond lengths have been calculated and explained the fast response time and lower impedance of Ppy/SWCNT than Ppy.

Simultaneous determination of ropivacaine, bupivacaine and dexamethasone in biodegradable PLGA microspheres by high performance liquid chromatography.

A simple and rapid high-performance liquid chromatography method coupled with UV detector was developed and validated for the simultaneous determination of ropivacaine, bupivacaine and dexamethasone in biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres within 11 min. Chromatographic separation was performed on a XDB-C(18) column using a mobile phase comprised of acetonitrile-NaH(2)PO(4) buffer (pH 3.5, 30 mM) (30:70, v/v) with a flow rate gradient program. The method was in good linearity (r>0.999) over the range of 0.025-40.0 microg/ml for ropivacaine and bupivacaine, and 0.05-40 microg/ml for dexamethasone. The method was proved to be precise with intra- and inter-day precision less than 3.0% and 6.0% for all drugs and accurate with intra- and inter-day accuracy between -8.0% to 4.5% and between -5.0% to 5.5% for all drugs. The assay was rapid, simple and easy to apply. Therefore, it was very suitable for routine determination and quality control of ropivacaine, bupivacaine and dexamethasone in PLGA microspheres.

Determination of tramadol, metamizole, ropivacaine, and bupivacaine in analgesic mixture samples by HPLC with DAD detection.

A high-performance liquid chromatography-diode array detection method was developed and validated to simultaneously determine tramadol (TMD), metamizole (MTZ), ropivacaine (RPV), and bupivacaine (BPV) in the presence of 4-methylaminoantypirine (4-MAA), the metabolite of MTZ, in analgesic mixtures samples used in Patient Controlled Analgesia (PCA). Chromatographic separation is achieved with a C-18 column using a mixture of ACN-methanol-water adjusted to pH 3.0 with NaH(2)PO(4) 0.05M (10:25:65 v/v) in an isocratic mobile phase at a flow rate of 0.8 mL/min. 0.5 mg/mL of Na(2)SO(3) in the water of the mobile phase was necessary to prevent the fast MTZ hydrolysis process to 4-MAA. Ultraviolet-diode array detection was used and chromatograms were registered at the wavelength of 230 nm. The method was linear in the range of 2.2-80.0 mg/L for TMD, 4.1-140.0 mg/L for MTZ, 2.3-40.0 mg/L for RPV, and 2.9-40.0 mg/L for BPV. Validation of the method was made in terms of accuracy, intra- and interday precision, as well as quantification and detection limits. The hydrolysis of MTZ to 4-MAA was studied and verified by mass spectrometry. The developed method was used successfully to evaluate the chemical stability of binary analgesic TMD mixtures with MTZ, RPV, or BPV. The mixtures were tested at standard concentrations used in PCA and in different storage conditions. When mixtures contained MTZ, a chromatographic peak from the metabolite 4-MAA was always detected in the chromatograms.

Anestesia para miembro superior con la utilización del estimulador de nervio periférico: Hospital Vicente Corral Moscoso – 2007 / Anesthesia for upper limb with the use of peripheral nerve stimulator: Vicente Corral Moscoso Hospital - 2007

Con un diseño descriptivo longitudinal se incluyeron 105 pacientes de ambos sexos, ASA I - III, a quienes se realizó bloqueo de plexo braquial con bupivacaína, lidocaína o la mezcla de ambas con la ayuda de un neuroestimulador (Stimuplex Dig-RC™ de Braun™) para ser sometidos a cirugía de miembro superior en el Hospital Vicente Corral de Cuenca, Ecuador, en un período de dos años, se alcanzó un 97,2% de bloqueos exitosos y de éstos el 86.7% fueron completos y el 10,5% parciales. La edad promedio de la muestra fue de 29,4 ± 19,8 años con un rango entre 5 y 75 años. Los varones fueron el 71,4%. Artesanos y pacientes sin ocupación (estudiantes y preescolares) fueron el 76,1% del grupo, el 62.9% (n = 66) de las intervenciones fueron electivas. El acceso supraclavicular se utilizó en el 42,9% (n = 45), el interescalénico en el 41.% (n = 43) y el axilar en el 16.2% (n = 17),el tiempo quirúrgico tuvo una mediana de 90 min (rango 10 a 240), el tiempo anestésico de 120 min (rango 30 a 420) y el tiempo de analgesia de 250 min (rango 30 a 640), dos pacientes (1.9%) presentaron desorientación, ansiedad y diaforesis transitorias que se normalizaron en 20 – 30 min.

With a longitudinal descriptive design 105 patients of both sexes included themselves, ASA I - III, to those who blockade of brachial plexus with bupivacaine, lidocaine or mixture of both with aid of a neuroestimulator was made (Stimuplex Dig-RC™ Braun™) to be undergoing surgery of superior member in Vicente Corral Hospital of Cuenca, Ecuador, in a period of two years, a 97.2% of successful blockades were reached and of these the 86,7% were complete and 10.5% partisans. The age average of the sample was of 29.4 ± 19.8 years with a rank between 5 and 75 years. The men were 71.4%. Craftsmen and patients without occupation (students and prestudents) were 76.1% of the group, the 62,9% (n = 66) of the interventions were elective. The access to supraclavicular was used in 42.9% (n = 45), the interescalénico in (the 41,% n = 43) and the axillary one in the 16,2% (n = 17), the surgical time min had a medium one of 90 (rank 10 to 240), anesthetic time of 120 min (rank 30 to 420) and time of analgesia of 250 min (rank 30 to 640).Two patients (1,9%) showed transitory disorientation, anxiety and diaphoresis that were normalized in 20 - 30 min.

Application of a column selection system and DryLab software for high-performance liquid chromatography method development.

This paper describes a strategy for the development of chromatographic methods for drug candidates based upon the use of simple MS compatible mobile phases and optimization of the chromatographic selectivity through variations of the stationary phase and mobile phase pH. The strategy employs an automated column selection system and a series of HPLC columns, varying in hydrophobicity and silanol activity, in combination with DryLab software to develop chromatographic methods for the separation of mixtures of bupivacaine and its metabolites; acidic, basic, and neutral compounds; and atenolol, nitrendipine, and their degradation products.

Chiral separation of salbutamol and bupivacaine by capillary electrophoresis using dual neutral cyclodextrins as selectors and its application to pharmaceutical preparations and rat blood samples assay.

An attempt for the simultaneous separation of salbutamol (Sal) and bupivacaine (Bup) enantiomers was performed by capillary elecytrophoresis with a dual mixture of neutral cyclodextrins as chiral selector. The influence on the separation of several parameters such as buffer composition, pH, the concentration ratio of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) to dimethyl-beta-cyclodextrin (DM-beta-CD) was investigated. A better separation was obtained for Sal and Bup with the CD mixtures compared to the use of HP-beta-CD or DM-beta-CD alone. The best simultaneous separation of Sal and Bup enantiomers was achieved with a 20 mM HP-beta-CD and 20 mM DM-beta-CD at pH 2.5 in a triethanolamine (TEA)/phosphate buffer. This method-utilized chlorphenamine (Chl) as an internal standard was found to be linear in the range 0.5-100 microg/mL and 0.5-150 microg/mL for Sal and Bup enantiomers, respectively. The limits of detection for both enantiomers of Sal and Bup were 0.18 and 0.24 microg/mL, respectively. The proposed method was applied to monitor Sal and Bup enantiomers concentration change in rat blood samples obtained from a male rat after celiac doses administration 0-30 min of Sal and Bup racemate. The method could also be used to determine Sal enantiomers in a pharmaceutical aerosol.

Liquid-phase microextraction combined with high-performance liquid chromatography for the determination of local anaesthetics in human urine.

A simple liquid-phase microextraction (LPME) device combined with high-performance liquid chromatography (HPLC) is presented for the simultaneous analysis of local anaesthetics, lidocaine, bupivacaine, and tetracaine, from human urine sample. An organic solvent showed good compatibility with the mobile phase of the HPLC, o-dibutyl phthalate, was selected. Local anaesthetics are extracted from 6 ml of the feed aqueous solution and human urine sample into a water-immiscible organic solvent suspended at the needle tip of the microsyringe, then the organic solvent was directly introduced to a reversed-phase HPLC system. The kind of the organic extraction solvent, the stirring rate, the pH value of the aqueous feed solution, and the extraction time have been discussed. Under the optimized extraction conditions, high enrichment factors (more than 86.0-fold) and significant sample clean-up for all of studied local anaesthetics were achieved within 30 min. The detection limits (lower than 0.05 microg/ml) were comparable with previously reported gas chromatography methods. This method was applied to specimen of patient who was treated with extradural anaesthesia of lidocaine, bupivacaine, and tetracaine, and revealed that simultaneous determination of above three local anaesthetics in human urine was possible.

Sensitive bioassay of bupivacaine in human plasma by liquid-chromatography-ion trap mass spectrometry.

A sensitive high-performance liquid chromatography-tandem mass spectrometric (HPLC-MS-MS) method, using an ion trap spectrometer, was developed for quantitation of bupivacaine in human plasma. Bupivacaine and an internal standard (ropivacaine) were extracted in a single step from 100 microL of alkalinized plasma with diethyl-ether. The mobile phase consisted of acetonitrile with 0.1% formic acid (50:50, v/v), and was delivered at a flow rate of 0.3 mL/min. The effluent was detected by MS-MS in positive ion mode. Ionisation was performed, using an electrospray ion source, operating at 200 degrees C. The selected reaction monitoring transitions m/z 289-->m/z 140 and m/z 275-->m/z 126 were chosen for bupivacaine and ropivacaine, respectively. Calibration curves were linear over the concentration range of 3.90-500 microg/L with determination coefficients >0.996. The method is accurate (bias <10%) and reproducible (intra-assay and inter-assay precision <15%), with a quantitation limit of 3.90 microg/L, using only 100 microL of plasma. The high specificity and sensitivity, achieved by this fast method (total run-time <3 min), allowed the determination of bupivacaine plasma levels in pediatric patients, following epidural administration of bupivacaine.

Stability of admixture containing morphine sulfate, bupivacaine hydrochloride, and clonidine hydrochloride in an implantable infusion system.

Intrathecal infusion is often performed using drug combinations. This study was conducted to evaluate the stability of the admixture of morphine sulfate, bupivacaine hydrochloride, and clonidine hydrochloride when used in an implantable pump under simulated clinical use conditions. SynchroMed implantable pumps were filled with an admixture and incubated at 37 degrees C for a period of 90 days. Drug admixture stored in glass vials at 4 degrees C and at 37 degrees C served as controls. Samples which included pump reservoir and catheter delivered aliquots were collected every 30 days and analyzed for drug concentrations using a stability-indicating HPLC method. All drugs contained in the admixture were stable and the original concentrations remained greater than 96%. Over 90 days, and with the pump at the simulated body temperature of 37 degrees C, there were no evident heat catalyzed or device catalyzed reactions.

Solid-state NMR studies of pharmaceutical solids in polymer matrices.

Biodegradable drug-delivery systems can be formulated to release drug for hours to years and have been used for the controlled release of medications in animals and humans. An important consideration in developing a drug-delivery matrix is knowledge of the long-term stability of the form of the drug and matrix after formulation and any changes that might occur to the drug throughout the delivery process. Solid-state NMR spectroscopy is an effective technique for studying the state of both the drug and the matrix. Two systems that have been studied using solid-state NMR spectroscopy are presented. The first system studied involved bupivacaine, a local anesthetic compound, which was incorporated into microspheres composed of tristearin and encapsulated using a solid protein matrix. Solid-state 13C NMR spectroscopy was used to investigate the solid forms of bupivacaine in their bulk form or as incorporated into the tristearin/protein matrix. Bupivacaine free base and bupivacaine-HCl have very different solid-state NMR spectra, indicating that the molecules of these compounds pack in different crystal forms. In the tristearin matrix, the drug form could be determined at levels as low as 1:100 (w/w), and the form of bupivacaine was identified upon loading into the tristearin/protein matrix. In the second case, the possibility of using solid-state 13C NMR spectroscopy to characterize biomolecules lyophilized within polymer matrices is evaluated by studying uniformly 13C-labeled asparagine (Asn) in 1:250 (w/w) formulations with poly(vinyl pyrrolidone) (PVP) and poly(vinyl alcohol) (PVA). This work shows the capability of solid-state NMR spectroscopy to study interactions between the amino acid and the polymer matrix for synthetic peptides and peptidomimetics containing selective 13C labeling at the Asn residue.