Effect of solid state transition on the physical stability of suspensions containing bupivacaine lipid microparticles

Bupivacaine lipid microparticles were prepared and evaluated as a parenteral sustained-release dosage form for postoperative pain management. Bupivacaine free base was incorporated into a molten tristearin matrix and lipid micro-particles were subsequently formed from this molten mixture by a spray-congealing process. A 3% injectable bupivacaine lipid microparticle suspension was prepared by dispersing 30% bupivacaine lipid microparticles in an aqueous medium containing carboxymethylcellulose (CMC), mannitol, and Tween 80. Upon room temperature storage, the fluid suspension gradually changed into a nonflowing semisolid (gelation) as a result of crystal growth of bupivacaine. However, suspensions prepared with bupivacaine lipid microparticles that were previously annealed at an elevated temperature remained fluid upon long-term storage. Differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD), and isoperibol solution calorimetry were used to investigate the changes in the solid-state properties of tristearin and bupivacaine in the lipid microparticles before and after the heat treatment. The DSC and XRPD results indicate that after 24 hours of heating at 40 degrees C, tristearin was completely converted from the unstable alpha form to the stable beta form. Using the isoperibol solution calorimetric method, bupivacaine was found to transform into a more stable form after the lipid microparticles were heated at 60 degrees C for 24 hours. The generation of the unstable solid forms of tristearin and bupivacaine was attributed to the resolidification of both components from the molten mixture during the spray-congealing process.     

Effect of Solid State Transition on the Physical Stability of Suspensions Containing Bupivacaine Lipid Microparticles

Bupivacaine lipid microparticles were prepared and evaluated as a parenteral sustained-release dosage form for postoperative pain management. Bupivacaine free base was incorporated into a molten tristearin matrix and lipid microparticles were subsequently formed from this molten mixture by a spray-congealing process. A 3% injectable bupivacaine lipid microparticle suspension was prepared by dispersing 30% bupivacaine lipid microparticles in an aqueous medium containing carboxymethylcellulose (CMC), mannitol, and Tween 80. Upon room temperature storage, the fluid suspension gradually changed into a nonflowing semisolid (gelation) as a result of crystal growth of bupivacaine. However, suspensions prepared with bupivacaine lipid microparticles that were previously annealed at an elevated temperature remained fluid upon long-term storage. Differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD), and isoperibol solution calorimetry were used to investigate the changes in the solid-state properties of tristearin and bupivacaine in the lipid microparticles before and after the heat treatment. The DSC and XRPD results indicate that after 24 hours of heating at 40°C, tristearin was completely converted from the unstable α form to the stable β form. Using the isoperibol solution calorimetric method, bupivacaine was found to transform into a more stable form after the lipid microparticles were heated at 60°C for 24 hours. The generation of the unstable solid forms of tristearin and bupivacaine was attributed to the resolidification of both components from the molten mixture during the spray-congealing process.     

Bupivacaine containing dry emulsion can prolong epidural anesthetic effects in rabbits.

To assess the prolongation of epidural bupivacaine by a novel lipid formulation, a physically stabilized bupivacaine containing dry emulsion was prepared by spray-drying. Bupivacaine release from the oil-in-water emulsion was studied using an in vitro two-phase stirred model, then the pharmacodynamic effects and the pharmacokinetics of bupivacaine from the spray-dried emulsion were evaluated and compared to a bupivacaine hydrochloride solution, following a two-period cross-over epidural administration in rabbits. The in vitro release characteristics suggested an extended release of bupivacaine from the emulsion compared to the solution. From the in vivo study, C(max) obtained with the emulsion (containing 5 mg bupivacaine) was not statistically different than from the solution (containing 2 mg bupivacaine) while T(max) was increased, suggesting a diminution of bupivacaine systemic absorption. The onset time of epidural anesthesia was similar for both formulations of bupivacaine used, while a significant blockade prolongation (360%) was observed with the emulsion compared to the solution, suggesting a controlled release of bupivacaine. Dry emulsions could be promising dosage forms to optimize the disposition of epidurally administered LAs.     

The formulation of Halofantrine as either non-solubilizing PEG 6000 or solubilizing lipid based solid dispersions: physical stability and absolute bioavailability assessment

A non-solubilizing solid dispersion formulation (polyethylene glycol 6000) and two solubilizing solid dispersions (Vitamin E TPGS and a Gelucire 44/14/Vitamin E TPGS blend) containing the antimalarial, Halofantrine (Hf), were formulated for bioavailability assessment in fasted beagles to determine if the oral absorption of Hf can be enhanced by these delivery systems. Solid dispersions comprising varying proportions of drug to carrier were prepared by the fusion method. Whilst the non-solubilizing formulation was assessed according to its dispersion characteristics, the solubilizing solid dispersions were assessed by their ability to form microemulsions upon dispersion. Studies in fasted beagles showed that the solid dispersions afforded a five- to seven-fold improvement in absolute oral bioavailability when compared with the commercially available tablet formulation. The delivery of Hf in either a solubilizing or non-solubilizing solid dispersion did not result in significant differences in oral bioavailability. The physical stability of the solid dispersions was studied using differential scanning calorimetry and X-ray powder diffraction.     

Poly(N-isopropylacrylamide) copolymers for constant temperature controlled drug delivery

To assess the prolongation of epidural bupivacaine by hyaluronic acid viscous formulations we designed a cross-over study in rabbits. Different doses of bupivacaine (3 or 6 mg) either as a solution (bupivacaine hydrochloride), or as viscous formulations with hyaluronic acid (bupivacaine base and bupivacaine hydrochloride) were administered in a rabbit model of epidural anesthesia. In the first part of the study, in vitro release characteristics were determined. Then pharmacodynamic effects and pharmacokinetic profiles of each bupivacaine formulation were studied. The rank order release rate of bupivacaine in vitro was always hydrochloride solution > viscous physical mixture of bupivacaine with hyaluronic acid > viscous ionic complex of bupivacaine base with hyaluronic acid. Onset time of epidural anesthesia was similar whatever the formulation of bupivacaine used. We did not find any blockade prolongation when 3mg bupivacaine was administered, but significant blockade prolongations were observed with viscous formulations incorporating 6 mg bupivacaine. The observed reduction in the absorption rate of bupivacaine into the systemic circulation for both viscous hyaluronic formulations after 6 mg of bupivacaine may explain the prolongation of spinal effects. Drug release and duration of action were found to be viscosity controlled as linear relationships were found between pharmacodynamic effects and viscosity. Our results were in accordance with those reported with bupivacaine-cyclodextrin complex, another formulation with a molecular dispersion of the drug, resulting in a moderate prolongation of action.     

Cardiotoxic local anesthetics increasingly interact with biomimetic membranes under ischemia-like acidic conditions

The cardiotoxic effects of local anesthetics increase in cardiac ischemia which is characterized by the tissue pH lowering to 6.5 or less. Apart from the cardiac channel blockade, the membrane interaction has been referred to as another mode of their cardiotoxic action. By using biomimetic membranes, we verified the hypothesis that bupivacaine and lidocaine may increasingly interact with cardiac mitochondrial membranes under ischemia-like acidic conditions. Biomimetic membranes were prepared with different phospholipids and cholesterol to be unilamellar vesicles suspended in buffers of pH 7.4, 6.9, 6.4 or 5.9. Bupivacaine and lidocaine were reacted with the membrane preparations at cardiotoxically relevant concentrations and their membrane interactivities were determined by measuring fluorescence polarization. Both drugs interacted with 100 mol% 1,2-dipalmitoylphosphatidylcholine, peripheral nerve cell-mimetic and cardiomyocyte-mimetic membranes to increase membrane fluidity, although lowering the reaction pH from 7.4 to 5.9 decreased their membrane-fluidizing effects. In cardiomyocyte mitochondria-mimetic membranes containing 20 mol% cardiolipin, however, bupivacaine and lidocaine reversely increased their membrane interactivities at pH 5.9-6.4 compared with pH 7.4. Such increases were greater in anionic phospholipid membranes which consisted of substantial amounts of cardiolipin and phosphatidylserine. Positively charged bupivacaine and lidocaine would form ion-pairs with the negatively charged head-groups of anionic phospholipids under acidic conditions, thereby increasing the induced membrane fluidization. The mitochondrial membrane interactions depending on pH lowering may be, at least in part, responsible for local anesthetic cardiotoxicity enhanced in acidosis associated with cardiac ischemia.     

Transfer of Lidocaine and Bupivacaine Across the Isolated Perfused Human Placenta *

Abstract: Drug permeability and pharmacokinetics through the placenta are important factors determining foetal drug exposure. The purpose of the present study was to establish a perfused human placental cotyledon system to assess the placental transfer of lidocaine and bupivacaine, widely used local anaesthetics in obstetric anaesthesia. Term placentas were obtained immediately after delivery with maternal consent and a two-hour recycling perfusion of a single placental cotyledon was performed. Bupivacaine or lidocaine with antipyrine as a reference compound were added to the maternal reservoir and their disappearance from the maternal circulation and appearance to the foetal circulation were followed in five experiments for each drug. Drug concentrations were measured by gas chromatography. Bupivacaine disappeared more rapidly from the maternal circulation than lidocaine. At 2 hr, bupivacaine foetal:maternal concentration ratio was 0.56±0.12 and 14.6%±2.99 of the total circulating amount was found in the foetal circulation. Lidocaine concentration increased more in the foetal circulation and the foetal: maternal concentration ratio at 2 hr was 0.90±0.09 (P<0.01), and 22.1%±2.21 (P<0.01) was found in the foetal circulation. The maternal to foetal transfer of bupivacaine and lidocaine were 67.2%±0.153 and 98.9%+0.07 (P<0.05) of that of freely diffusable antipyrine, respectively. Both amide local anaesthetics crossed the dually perfused human placenta rapidly. Bupivacaine disappeared faster than lidocaine from the maternal circulation but less was transferred to foetal circulation. This difference is probably explained by the greater lipophil-icity of bupivacaine and hence higher placental binding. These results suggest less foetal drug exposure with bupivacaine than lidocaine.     

The effect of physico-chemical properties of the drug on the pharmaceutical availability of piroxicam from pellets

The aim of this study was to develop the formulation of pellets with solid dispersions of piroxicam, and determine the effect of physico-chemical properties of the drug on pharmaceutical availability from solid dispersions and pellets. Two types of piroxicam, varying in crystal size, were used in this study. Presence of the amorphous form in solid dispersions depended on the method of their formulation, and type of piroxicam used. Based on the results of piroxicam release rate from pellets, it was established that the extrusion and spheronization process caused change in the drug release profile in comparison to powder systems, because during the pelletization process, the amorphous form of the piroxicam present in the solid dispersion recrystallizes, and a low-solubility type forms. Better results were obtained using the method, where microcrystalline cellulose cores were coated with solid dispersion.     

The effect of physico-chemical properties of the drug on the pharmaceutical availability of piroxicam from pellets

The aim of this study was to develop the formulation of pellets with solid dispersions of piroxicam, and determine the effect of physico-chemical properties of the drug on pharmaceutical availability from solid dispersions and pellets. Two types of piroxicam, varying in crystal size, were used in this study. Presence of the amorphous form in solid dispersions depended on the method of their formulation, and type of piroxicam used. Based on the results of piroxicam release rate from pellets, it was established that the extrusion and spheronization process caused change in the drug release profile in comparison to powder systems, because during the pelletization process, the amorphous form of the piroxicam present in the solid dispersion recrystallizes, and a low-solubility type forms. Better results were obtained using the method, where microcrystalline cellulose cores were coated with solid dispersion.     

肾上腺素在蛛网膜下腔麻醉中的价值

目的探讨在不同平面布比卡因腰麻时，局麻药中加入肾上腺素对麻醉效果的影响。方法选择腰麻下手术患者85例，随机分为肾上腺素组A（腹部手术），肾上腺素组B（下肢手术），布比卡因组A（腹部手术），布比卡因组B（下肢手术）。腰麻穿刺成功後注入0.6％布比卡因15mg（0.75％布比卡因2ml＋10％葡萄糖0.5ml），肾上腺素组另加入肾上腺素0.1mg。检测注药後血压，感觉阻滞时间，阻滞持续时间，恶心呕吐以及寒战例数。结果A组肾上腺素组较单纯应用布比卡因组血压波动小，感觉阻滞时间长较少发生恶心呕吐及寒战。B组之间无明显差异。结论肾上腺素在高位腰麻时可有效减轻、减缓局麻药对血流动力学的干扰，减少恶心呕吐及寒战例数，延长阻滞持续时间。     

Enhancing the bioavailability of ABT-963 using solid dispersion containing Pluronic F-68

Solid dispersions using Pluronic F-68 as a carrier were studied for improving the dissolution and bioavailability of ABT-963, a poorly water-soluble compound. The solid dispersions were prepared either by evaporation of the ethanol solutions containing ABT-963 and Pluronic, or by cooling the hot melt of the drug in the carrier. The dispersions were characterized using differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy, elemental mapping, and by constructing the melting point phase diagram. In vitro dissolution and in vivo oral bioavailability in fasted dogs were compared for the solid dispersion and a conventional IR capsule formulation. Results showed that, at a composition of approximately 7.5%, ABT-963 formed a eutectic mixture with Pluronic F-68. Both the drug and the polymer were crystalline in the solid dispersion with a wide range of composition of each component. The solid dispersion substantially increased the in vitro dissolution rate of ABT-963. Dosing of the dispersion to fasted dogs resulted in a significant increase of oral bioavailability compared with the conventional IR capsule formulation. These results show that solid dispersion is a promising approach for developing ABT-963 drug products.     

DRV Liposomal Bupivacaine: Preparation,Characterization, and In Vivo Evaluation in Mice

Purpose. To evaluate the dehydration-rehydration technique to prepare a formulation of liposomal bupivacaine, and to assess its analgesic efficacy. Methods. Bupivacaine hydrochloride (BUP) was encapsulated into dehydration-rehydration vesicles (DRV) of varying phospholipid (PL) compositions. Two bilayer-forming phospholipids were used, the fluid dimyristoyl-phosphatidylcholine and the solid dis- tearoyl-phosphatidylcholine (DSPC), with 20 or 40 mol% cholesterol, in the presence of bupivacaine at a 1.28 or 0.64 BUP/PL mole ratio. After rehydration, drug/lipid ratios were determined. The formulation with the highest drug/lipid ratio (DSPC/cholesterol in an 8:2 mole ratio prepared in the presence of bupivacaine in a 1.28 BUP/PL mole ratio) was adjusted to a final bupivacaine concentration of 3.5% or 0.5%. The duration of skin analgesia after subcutaneous injection in mice produced by these formulations was compared with the conventional administration of a plain 0.5% solution of BUP. In addition, the concentration of residual bupivacaine at the injection site was followed for 96 h. Results. The relatively low organic solvent/aqueous phase and membrane/aqueous phase partition coefficients, together with liposomal trapped volume and BUP/PL mole ratio, indicated that most of the drug was encapsulated in the intraliposome aqueous phase of the DRV. The DSPC/cholesterol 8:2 mole ratio had the best drug encapsulation (BUP/PL = 0.36). Compared to plain BUP, these BUP-DRV produced significant prolongation of analgesia, which is explained by longer residence time of the drug at the site of injection. Conclusions. Bupivacaine-DRV may have a role in achieving safe, effective, and prolonged analgesia in humans.     

Bupivacaine-loaded biodegradable poly(lactic-co-glycolic) acid microspheres I. Optimization of the drug incorporation into the polymer matrix and modelling of drug release

Bupivacaine has been encapsulated by solvent evaporation method based on O/W emulsion, using poly(DL-lactic-co-glycolic) acid (PLGA) 50:50. The particle size can be controlled by changing stirring rate and polymer concentration. The encapsulation efficiency was affected by polymer concentration and burst effect of bupivacaine released from particles was affected by drug/polymer mass ratio. Orthogonal design was used to optimize the formulation according to drug content, encapsulation efficiency and burst effect. The dissolution profile and release model were evaluated with two different bupivacaine microspheres (bupi-MS) groups including low drug loading (6.41%) and high drug loading (28.92%). It was observed that drug release was affected by drug loading especially the amount of drug crystal attached on surface of bupi-MS. The drug release profile of low drug loaded bupi-MS agreed with Higuchi equation and that of high drug loaded bupi-MS agreed with first order equation.     

Effects of bupivacaine on membrane currents of guinea-pig ventricular myocytes

The effects of bupivacaine on the membrane currents of single guinea-pig ventricular myocytes were investigated using the whole-cell patch-clamp technique. Bupivacaine decreased the inward calcium current in a concentration-dependent way at concentrations of 10 microM and higher. Bupivacaine also decreased the delayed outward current without modifying the inward-rectifying potassium current. From these results it can be concluded that bupivacaine, at concentrations lower than 10 microM, does not exert its negative inotropic effect by decreasing the calcium current. This mechanism may play a role at higher concentrations of the drug.     

Steady state bupivacaine plasma concentrations and safety of a femoral "3-in-1" nerve block with bupivacaine in patients over 80 years of age

OBJECTIVES: Fracture of the upper femur is a common injury in the elderly. Several anesthetic techniques exist for surgery of traumatic hip fracture. The aim of this investigation was to study plasma concentrations and safety of 2 mg/kg bupivacaine in a femoral "3-in-1" nerve block in patients older than 80 years of age. SUBJECTS AND METHODS: A 3-in-1 femoral nerve block, combined with a general anesthetic was used in 10 elderly patients aged over 80 years. They were undergoing emergency surgery for stabilization of their fractured femur. Bupivacaine plasma concentrations of radial artery blood samples were assessed over a 6-hour period after a femoral 3-in-1 injection of 2 mg/kg bupivacaine 0.375% with epinephrine (1:400,000). RESULTS: No toxic reactions to bupivacaine were seen. In 8 of the 10 patients per- and postoperative analgesia were adequate as a result of the nerve block. Patients experienced loss of sensation and analgesia for 26.6 +/- 4.6 hours (mean +/- SD). This was inversely related to the apparent steady state concentration of bupivacaine. The mean of the individual peak plasma concentrations of bupivacaine (C(max) was 0.74+/- 0.64 microg/ml. The highest plasma concentration was 1.83 microg/ml. Large variations in plasma concentrations were detected in these patients. Bupivacaine metabolites were not detected. CONCLUSIONS: A femoral 3-in-1 nerve block, using 2 mg/kg bupivacaine with epinephrine, provides prolonged pain reliefwithout local anesthetic toxicity in elderly patients. It is a satisfactory supplementary analgesic technique for hip and knee surgery in the elderly.     

Development of Extended-Release Solid Dispersions of Nonsteroidal Antiinflammatory Drugs with Aqueous Polymeric Dispersions: Optimization of Drug Release via a Curve-Fitting Technique

Extended-release solid dispersions of nonsteroidal antiinflammatory drugs were prepared by using aqueous polymeric dispersions of Eudragit RS30D and Eudragit RL30D as the inert carriers. The effects of different polymer ratios of Eudragit RS30D and Eudragit RL30D, different particle sizes, and different combination of various formulations of solid dispersions on the in vitro release kinetics of drugs from the dosage forms were investigated. A computer curve-fitting process was developed to choose the optimum formulation of the solid dispersion with the desired drug release profile. This process might offer the advantages of efficiency and simplicity in the formulation development of extended-release solid dispersions.     

Ibuprofen-phospholipid solid dispersions: improved dissolution and gastric tolerance

Solid dispersions of ibuprofen with various phospholipids were prepared, and the effect of phospholipids on the in vitro dissolution and in vivo gastrointestinal toxicity of ibuprofen was evaluated. Most phospholipids improved the dissolution of ibuprofen; dimyristoylphosphatidyl-glycerol (DMPG) had the greatest effect. At 45 min, the extent of dissolution of ibuprofen from the ibuprofen-DMPG system (weight ratio 9:1) increased about 69% compared to ibuprofen alone; the initial rate of dissolution increased sevenfold. Increasing the DMPG content from 9:1 to 4:1 in this system did not significantly increase the rate and the extent of dissolution. X-ray diffraction and scanning electron micrograph indicated a smaller crystallite size of ibuprofen with fairly uniform distribution in the ibuprofen-DMPG solid dispersion. A small amount of carrier phospholipid significantly increases the rate and the extent of dissolution, which may increase the bioavailability of ibuprofen. The number of ulcers >0.5mm in size formed in the gastric mucosa of rats following ibuprofen, DMPG, DMPC and DPPC solid dispersions (ibuprofen and phospholipid weight ratio 4:1) were 8.6 ± 6.2, 3.9 ± 5.3, 5.3 ± 4.9 and 9.1 ± 7.4, respectively. Solid dispersion of ibuprofen with DMPG was significantly less irritating to the gastric mucosa than ibuprofen itself (one-way ANOVA, p<0.05). Solid dispersion of ibuprofen and DMPG decreases the gastric side effects of ibuprofen.     

Oxidative metabolism of bupivacaine into pipecolylxylidine in humans is mainly catalyzed by CYP3A.

Bupivacaine is used to provide prolonged anesthesia and postoperative analgesia. The human cytochrome P450 (CYP) involved in bupivacaine degradation into pipecolylxylidine (PPX), its major metabolite, has, to our knowledge, never been described. Microsome samples were prepared from six human livers and incubated in the presence of bupivacaine. The concentrations of PPX in the microsomal suspensions were assessed, and K(m) and V(max) values were calculated. Bupivacaine incubations were then performed with specific CYP substrates and inhibitors. For each sample of hepatic microsomes, the correlation between the rate of PPX formation and the corresponding erythromycin N-demethylase activity was analyzed. Finally, an immunoinhibition study using an anti-rabbit CYP3A6 antibody and assays with cDNA-expressed human CYP were conducted. The apparent K(m) and V(max) values of bupivacaine were, respectively, 125 microM and 4.78 nmol/min/mg of microsomal protein. The strongest inhibition of bupivacaine metabolism was obtained for troleandomycin (-95% at 50 microM), a specific CYP3A inhibitor. The correlation between PPX formation and erythromycin N-demethylase activity showed an R value of 0.99 whereas anti-rabbit CYP3A6 antibody inhibited the degradation of bupivacaine into PPX by 99%. Finally, CYP1A2 and CYP2E1 cDNA-expressed forms of human CYP did not allow PPX formation, CYP2C19 and CYP2D6 produced only small amounts whereas CYP3A4 most efficiently metabolized bupivacaine into PPX. These results demonstrated that bupivacaine degradation into PPX was mediated in humans by CYP3A.     

Biopolymeric microparticles combined with lyophilized monophase dispersions for controlled flutamide release

Despite its short half-life, no controlled release formula of flutamide (FLT) was prepared until now. Therefore, 15 chitosan microparticle formulations were prepared for oral prolonged delivery of FLT via ionotropic gelation and emulsification-ionic gelation techniques then characterized for various parameters. FLT was successfully encapsulated into microparticles with loading capacity up to 39.98% and entrapment efficiency up to 97.16% using emulsification technique. Differential scanning calorimetry indicated that FLT was retained in a crystalline form in the microparticles prepared using ionotropic gelation whereas its crystallinity was significantly reduced using emulsification technique. Relationship between formulation variables and release behavior of FLT was explored. Chitosan microparticles prepared by ionotropic gelation showed a slower FLT release with a T(25%) of 7.9h whereas microparticles prepared by emulsification-ionic gelation under the same conditions showed a quick release profile with a T(25%) of 0.3h. Using 3 different hydrophilic carriers, immediate release FLT dispersions were prepared via lyophilization of monophase solution technique then combined with prolonged release chitosan microparticles to develop 6 controlled release formulae of FLT. A wide range of FLT release profiles were generated providing a prolonged release of drug after a suitable initial burst release.     

他达那非固体分散体的制备和性质研究

目的制备他达那非(tadalafil,TD)固体分散体并进行性质研究。方法利用喷雾干燥法制备固体分散体,以表观溶解度和溶出度为指标筛选处方,采用差示扫描量热(DSC)、粉末X-射线衍射(PXRD)和接触角测定等技术研究药物的存在状态和润湿性等理化性质。结果固体分散体将他达那非的表观溶解度提高22.6倍;20min内药物的累积溶出超过90%;固体分散体药物以分子或无定形状态存在;接触角减小,润湿性增大。结论采用十二烷基硫酸钠(SDS)和介孔硅为载体制备的他达那非固体分散体,能明显提高药物的表观溶解度和溶出度。