Impact of Different Mixing Methods on the Performance of Suspension-Based Transdermal Delivery Systems.

Suspension-based matrix transdermal delivery systems (TDSs) are specialized systems that maintain a continuous driving force for drug delivery over prolonged wear. The pressure-sensitive adhesive (PSA) is the most critical constituent of such systems. Our study aimed to determine the effect of different mixing methods on the performance of silicone PSA-based suspension TDSs. Lidocaine suspension TDSs were prepared using conventional slow rotary mixing, high-speed homogenization, bead-mill homogenization, vortex shaking, and by an unguator. Resultant TDSs were tested for tack, shear, and peel properties and correlated to coat weight, content uniformity, microstructure, and in vitro permeation across dermatomed human skin. Every mixing method tested caused a significant reduction in peel. However, bead-mill homogenization resulted in significant loss of all adhesive properties tested, while unguator-mixed TDSs retained most properties. Good linear correlation (R2 = 1.000) between the shear properties of the TDSs with the average cumulative amount of lidocaine permeated after 24 h was observed, with no significant difference between percutaneous delivery from slow rotary-mixed systems (1334 ± 59.21 µg/cm2) and unguator-mixed systems (1147 ± 108.3 µg/cm2). However, significantly lower delivery from bead-mill homogenized systems (821.1 ± 28.00 µg/cm2) was noted. While many factors affect TDS performance, careful consideration must also be given to the processing parameters during development as they have been shown to affect the resultant system's therapeutic efficacy. Extensive mixing with bead-mill homogenization demonstrated crystallization of drug, loss in adhesive properties, coat weight, and film thickness, with reduced transdermal delivery of lidocaine from the prepared system.

In vitro and in vivo studies of micro-depots using tailored microemulsion for sustained local anaesthesia.

In clinical practice, lidocaine is used as local anesthetic for the management of post-operative pain. The commercial formulation including gels, injections and ointments showed short duration of action (1 to 2 h). In this paper, the efforts have being made to develop tailored lidocaine-microemulsion (o/w), which on penetration in the skin layer cause micro-depots formation due to destabilization of the microemulsion system. To identify the microemulsion region, pseudo ternary diagrams were constructed using Capmul MCM as oil, Pluronic F68 as tri-block surfactant, polyethylene glycol 200 as co-surfactant at 1:4 and 1:6 ratios (S:Co-S). The selected 5%w/v lidocaine loaded microemulsion [Ld-ME-2(1:4)] was stable in thermodynamic test and during shelf life period (3 months). In ex vivo permeability study, the lidocaine release from Ld-ME-2(1:4) microemulsion was sustained in comparison to the marketed lidocaine ointment. The skin irritation study confirmed the safety of lidocaine loaded microemulsion. Tail flick test showed improved and sustain local anaesthetic effect in comparison to the market ointment. The improved efficacy of microemulsion system, was due to high penetration in the skin layer due to local precipitation of lidocaine from microemulsion. The findings suggest that the tailored microemulsion could be a potential strategy to prolong the local anaesthesia.

Across-the-World Automated Optimization and Continuous-Flow Synthesis of Pharmaceutical Agents Operating Through a Cloud-Based Server.

The power of the Cloud has been harnessed for pharmaceutical compound production with remote servers based in Tokyo, Japan being left to autonomously find optimal synthesis conditions for three active pharmaceutical ingredients (APIs) in laboratories in Cambridge, UK. A researcher located in Los Angeles, USA controlled the entire process via an internet connection. The constituent synthetic steps for Tramadol, Lidocaine, and Bupropion were thus optimized with minimal intervention from operators within hours, yielding conditions satisfying customizable evaluation functions for all examples.

Local Anaesthetic Effect of Methanolic Leaves Extract of Lannea schimperi (Hoschst. Ex Rich) Eng.

BACKGROUND: Local anaesthetics provide relief from pain when applied locally to nerve tissue by blocking conduction of sensory nerve impulse from the receptor to the brain cortex. OBJECTIVE: This study aimed at evaluating local anaesthetic activity of the methanolic leaves extract of Lannea schimperi. METHODS: Six groups of five animals were used; groups I-IV were used for intracutaneous wheal test in guinea pigs for infiltration anaesthesia, while group V and VI were used for guinea pig corneal reflex method of surface anaesthesia. RESULTS: The result indicated a significant ( 0.05) dose dependent local anaesthetic activity of the methanolic leaves extract of Lannea schimperi with faster onset and longer duration of action at 24 mg/ml than at 12 mg/ml of the extract. Additions of 5 µg of adrenaline into the 24 mg/ml preparation also prolonged the duration of local anaesthetic activity of the extract. The extract at 24 mg/ml significantly (0.05) inhibited corneal reflex, lidocaine was used as a standard drug in positive control group, while normal saline was used as negative control in all the treated groups. CONCLUSION: The patent data therefore revealed that the methanolic leaves extract Lannea schimperi possess local anaesthetic principles that may require further scientific elucidation.

Synthesis of C2-Symmetric Benzimidazolium Salts and Their Application in Palladium-Catalyzed Enantioselective Intramolecular α-Arylation of Amides.

A series of C2-symmetric chiral benzimidazolium salts, the precursor of N-heterocyclic carbene ligands, were designed and synthesized from 1,2-dibromobenzene. In situ prepared corresponding carbenes were tested in the asymmetric palladium-catalyzed intramolecular α-arylation of amides, affording chiral diarylmethanols with high yields and moderate enantioselectivities.

ß-Cyclodextrin-Propyl Sulfonic Acid Catalysed One-Pot Synthesis of 1,2,4,5-Tetrasubstituted Imidazoles as Local Anesthetic Agents.

Some functionalized 1,2,4,5-tetrasubstituted imidazole derivatives were synthesized using a one-pot, four component reaction involving 1,2-diketones, aryl aldehydes, ammonium acetate and substituted aromatic amines. The synthesis has been efficiently carried out in a solvent free medium using ß-cyclodextrin-propyl sulfonic acid as a catalyst to afford the target compounds in excellent yields. The local anesthetic effect of these derivatives was assessed in comparison to lidocaine as a standard using a rabbit corneal and mouse tail anesthesia model. The three most potent promising compounds were subjected to a rat sciatic nerve block assay where they showed considerable local anesthetic activity, along with minimal toxicity. Among the tested analogues, 4-(1-benzyl-4,5-diphenyl-1H-imidazol-2-yl)-N,N-dimethylaniline (5g) was identified as most potent analogue with minimal toxicity. It was further characterized by a more favourable therapeutic index than the standard.

Rapid Vortex Fluidics: Continuous Flow Synthesis of Amides and Local Anesthetic Lidocaine.

Thin film flow chemistry using a vortex fluidic device (VFD) is effective in the scalable acylation of amines under shear, with the yields of the amides dramatically enhanced relative to traditional batch techniques. The optimized monophasic flow conditions are effective in ≤80 seconds at room temperature, enabling access to structurally diverse amides, functionalized amino acids and substituted ureas on multigram scales. Amide synthesis under flow was also extended to a total synthesis of local anesthetic lidocaine, with sequential reactions carried out in two serially linked VFD units. The synthesis could also be executed in a single VFD, in which the tandem reactions involve reagent delivery at different positions along the rapidly rotating tube with in situ solvent replacement, as a molecular assembly line process. This further highlights the versatility of the VFD in organic synthesis, as does the finding of a remarkably efficient debenzylation of p-methoxybenzyl amines.

Carborane-derived local anesthetics are isomer dependent.

Clinically there is a need for local anesthetics with a greater specificity of action on target cells and longer duration. We have synthesized a series of local anesthetic derivatives we call boronicaines in which the aromatic phenyl ring of lidocaine was replaced with ortho-, meta-, C,C'-dimethyl meta- and para-carborane clusters. The boronicaine derivatives were tested for their analgesic activity and compared with lidocaine using standard procedures in mice following a plantar injection. The compounds differed in their analgesic activity in the following order: ortho-carborane = C,C'-dimethyl meta-carborane > para-carborane > lidocaine > meta-carborane derivative. Both ortho-boronicaine and C,C'-dimethyl meta-boronicaine had longer durations of analgesia than lidocaine. Differences in analgesic efficacies are rationalized by variations in chemical structure and protein binding characteristics.

Synthesis of ¹³C-lidocaine as a probe of breath test for the evaluation of cytochrome P450 activity.

(13)C-Labeled lidocaine, 2-di[1-(13)C]ethylamino-N-(2,6-dimethylphenyl)acetamide (1), was synthesized from [1-(13)C]acetic acid in six steps, as a probe for a breath test to evaluate in vivo cytochrome P450 activity. The measurement of (13)CO2 in breath was successfully performed following oral administration of (13)C-lidocaine 1 to mice.

Synthesis, local anaesthetic and antiarrhythmic activities of N-alkyl derivatives of proline anilides.

We describe here the design, synthesis and evaluation of in vivo local anaesthetic and antiarrhythmic activities of a series of N-alkylproline anilides. Most of the compounds demonstrated surface anaesthetic activity higher than that of lidocaine, ropivacaine and bupivacaine. We established that the local anaesthetic activity was sensitive to structural variations in the substitution pattern at the aromatic ring and the type of alkyl group at the proline nitrogen atom. Some of the prepared N-alkylproline anilides possessed significant antiarrhythmic activity with higher therapeutic indexes than the reference drugs.

Synthesis and characterization of two homologous series of diastereomeric 2-alkoxyphenylcarbamates.

Two homologous series of racemic diastereomeric cis- and trans-(2-dimethylaminomethylcycloheptyl)-2-alkoxyphenylcarbamates with alkyl chain lengths ranging from C1 to C8 were synthesized by stereoselective reactions. The chemical structures of these compounds were confirmed by ¹H-NMR, ¹³C-NMR and IR spectroscopy and their physico-chemical properties were characterized. The two new series of diastereomeric compounds were tested for their local anesthetic activity and parabolic relationship between the local anesthetic activity and lipophilicity was found for both cis- and trans-series. Interestingly, cis-stereoisomers exhibited higher local anesthetic activity.

Synthesis, biological evaluation, and docking studies of gigantol analogs as calmodulin inhibitors.

Several analogs of gigantol (1) were synthesized to evaluate their effect on the complexes Ca(2+)-calmodulin (CaM) and Ca(2+)-CaM-CaM sensitive phosphodiesterase 1 (PDE1). The compounds belong to four structural groups including, 1,2-diphenylethanes (2-11), diphenylmethanes (13-15), 1,3-diphenylpropenones (16-18), and 1,3-diphenylpropanes (20-22). In vitro enzymatic studies showed that all compounds except 11 inhibited the complex Ca(2+)-CaM-PDE1 with IC(50) values ranging from 9 to 146 µM. On the other hand, all analogs but 11, 12 and 15 quenched the extrinsic fluorescence of the CaM biosensor hCaM-M124C-mBBr to different extent, then revealing different affinities to CaM; their affinity constants (K(m)) values were in the range of 3-80 µM. Molecular modeling studies indicated that all these compounds bound to CaM at the same site that the classical inhibitors trifluoperazine (TFP) and chlorpromazine (CPZ). Some of these analogs could be worthy candidates for developing new anti-tumor, local anesthetics, antidepressants, antipsychotic, or smooth muscle relaxant drugs, with anti-CaM properties due to their good affinity to CaM and the straightforwardness of their synthesis. In addition they could be valuable tools for the study of Ca(2+)-CaM functions.

Evaluation of the local anaesthetic activity of 3-aminobenzo[d]isothiazole derivatives using the rat sciatic nerve model.

On the basis of computer prediction of biological activity by PASS and toxicity by DEREK, the most promising 32-alkylaminoacyl derivatives of 3-aminobenzo[d]isothiazole were selected for possible local anaesthetic action. This action was evaluated using an in vitro preparation of the isolated sciatic nerve of the rat and compared with lidocaine which was used as a reference compound. QSAR studies showed that the polarizability, polarity and molecular shape of molecules have a positive influence on their local anaesthetic activity, while contributions of aromatic CH and singly bonded nitrogen are negative. Since the estimated PASS probabilities to find local anaesthetic activity in the most active compounds are less than 50%, these compounds may be considered to be possible NCEs.

Synthesis of lidocaine-loaded PLGA microparticles by flow focusing. Effects on drug loading and release properties.

In the present work, two methods for the preparation of lidocaine-loaded PLGA microparticles are compared. The differences between the polymeric particles obtained by solvent evaporation (SEVM) or flow focusing (FF) were studied by means of scanning electron microscopy and surface thermodynamics determinations. A detailed investigation of the capabilities of the polymer particles to load this drug is described. The physical state of the drug in the polymeric particles and the existence of interactions between both entities were studied by differential scanning calorimetry. The main factors determining the lidocaine incorporation and the release kinetics were the synthesis procedure followed, the amount of drug dissolved in the organic phase during the synthesis routine, the type of polymer (molecular weight and end chemical groups) and the size and the hydrophobic/hydrophilic properties of the particles. The FF technology allowed higher drug incorporations and slower release kinetics. The release studies showed a biphasic profile probably due to diffusion-cum-degradation mediated processes.

Synthesis and local anesthetic activity of some novel N-[5-(4-substituted)phenyl-1,3,4-oxadiazol-2-yl]-2-(substituted)-acetamides.

A novel series of acetamides carrying substituted-1,3,4-oxadiazole moiety were synthesized from reaction of 5-aryl-2-chloroacetamido-1,3,4-oxadiazoles with different secondary amines. The local anesthetic potential of the compounds was investigated using rabbit corneal reflex method and guinea pig's wheal derm method. The present work is the only one of its kind reporting local anesthetic activity in acetamide system combined with 1,3,4-oxadiazole nucleus. Lidocaine was selected as standard drug in evaluation of local anesthetic activity of synthesized oxadiazole analogues. Compound 19 was found to possess significant local anesthetic activity in both the models employed for evaluation of local anesthetic activity. Compound 20, 23, 28, 29 and 35 also demonstrated marked local anesthetic activities. Structure-activity relationships among synthesized compounds were also established.

Synthesis and antispasmodic activity of lidocaine derivatives endowed with reduced local anesthetic action.

The present structure-activity relationship (SAR) study focused on chemical modifications of the structure of the local anesthetic lidocaine, and indicated analogues having reduced anesthetic potency, but with superior potency relative to the prototype in preventing anaphylactic or histamine-evoked ileum contraction. From the SAR analysis, 2-(diethylamino)-N-(trifluoromethyl-phenyl) and 2-(diethylamino)-N-(dimethyl-phenyl) acetamides were selected as the most promising compounds. New insights into the applicability of non-anesthetic lidocaine derivatives as templates in drug discovery for allergic syndromes are provided.

Synthesis and local anesthetic activity of fluoro-substituted imipramine and its analogues.

A series of fluoro-substituted imipramines and its analogues, 6a-6e, were synthesized and evaluated for their in vitro local anesthetic activity. Compound 6b was found to have potency, onset, and duration of action comparable to those of lidocaine (lidocaine hydrochloride, CAS:6108-05-0). Dissociation constants (pK(a)) of these compounds have been determined to be 7.6-7.9.

Synthesis and biological evaluation of novel 6-nitro-5-substituted aminoquinolines as local anesthetic and anti-arrhythmic agents: molecular modeling study.

A series of 6-nitro-5-[1-oxo-2-(substituted amino)ethylamino and 2-(substituted amino)propylamino] quinoline was synthesized and evaluated for their local anesthetic and anti-arrhythmic activity. The detailed synthesis, spectroscopic, and biological data are reported. Molecular modeling methods are used to study the local anesthetic activity of lidocaine and the active compounds by means of the AM1 method. The superposition of the stable conformations of these compounds was studied using the HyperChem 5.11 program.