Assessment of Drug Delivery Kinetics to Epidermal Targets In Vivo.

It has proven challenging to quantify 'drug input' from a formulation to the viable skin because the epidermal and dermal targets of topically applied drugs are difficult, if not impossible, to access in vivo. Defining the drug input function to the viable skin with a straightforward and practical experimental approach would enable a key component of dermal pharmacokinetics to be characterised. It has been hypothesised that measuring drug uptake into and clearance from the stratum corneum (SC) by tape-stripping allows estimation of a topical drug's input function into the viable tissue. This study aimed to test this idea by determining the input of nicotine and lidocaine into the viable skin, following the application of commercialised transdermal patches to healthy human volunteers. The known input rates of these delivery systems were used to validate and assess the results from the tape-stripping protocol. The drug input rates from in vivo tape-stripping agreed well with the claimed delivery rates of the patches. The experimental approach was then used to determine the input of lidocaine from a marketed cream, a typical topical product for which the amount of drug absorbed has not been well-characterised. A significantly higher delivery of lidocaine from the cream than from the patch was found. The different input rates between drugs and formulations in vivo were confirmed qualitatively and quantitatively in vitro in conventional diffusion cells using dermatomed abdominal pig skin.

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.

Mucoadhesive thin films for the simultaneous delivery of microbicide and anti-inflammatory drugs in the treatment of periodontal diseases.

There is an unmet clinical need for new products to address the high percentage of the populous who present with periodontal diseases. Drug dose retention at the point of application would facilitate sustained release and more efficacious treatments. The aim of this study was to evaluate mucoadhesive polymeric thin films for simultaneous in situ delivery chlorhexidine and anti-inflammatory and analgesic drugs. Mucoadhesive thin films were prepared using a polymer mixture containing chlorhexidine (25 mg) ± diclofenac sodium (10 and 50 mg), and lidocaine hydrochloride (10 mg) or betamethasone dipropionate (10 and 50 mg). The films were assessed for in vitro drug release and localised tissue delivery, followed by determination of modulated prostaglandin E2 (PGE2) levels in ex vivo tissue and cytotoxicity using a HaCaT keratinocyte cell line. Antibacterial activity of the chlorhexidine/diclofenac film was determined against planktonic and biofilm bacteria associated with periodontal disease and dental plaque. Chlorhexidine release was consistently low (up to 10% of initial loading) from all films, whereas the release of diclofenac, betamethasone and lidocaine exceeded 50% within 30 min. The 50 mg betamethasone film released up to 4-fold more than the 10 mg film. Statistically significant reduction of PGE2 was observed in ex vivo porcine gingival tissue for films containing chlorhexidine with or without diclofenac, and betamethasone. No cytotoxicity was observed for any film, apart from 50 mg betamethasone at 24 h. Films loaded with chlorhexidine and diclofenac were inhibitory against relevant test bacteria. Between 3 and 6 log10 reductions in bacterial cell recovery was observed after biofilm exposure to the chlorhexidine films irrespective of the presence of the anti-inflammatory or anaesthetic. This work demonstrated that thin film formulations have the potential to simultaneously counter key causative factors in periodontal diseases, namely associated bacteria biofilm and chronic local inflammation.

Articaine Versus Lidocaine Concentration in the Palatal Tissues After Supraperiosteal Buccal Infiltration Anesthesia.

PURPOSE: Palatal local anesthetic injection is a painful procedure. Previous studies have reported successful extraction of maxillary teeth using only buccal infiltration of 4% articaine without palatal anesthesia. The aim of the present study was to determine levels of 4% articaine solution in palatal bone and mucosal tissues after buccal injection and compare those levels with 2% lidocaine solution in New Zealand white rabbits. MATERIALS AND METHODS: Eight rabbits received 2 different injections of 0.6 mL of 4% articaine with 1:100,000 epinephrine and 0.6 mL of 2% lidocaine with 1:100,000 epinephrine buccal to the right and left maxillary first molar, respectively, in a split-mouth study design using quantitative syringes. All injections were administered using the buccal infiltration technique without any palatal injection. Ten minutes later, palatal bone and mucosa specimens were collected for analysis. Levels of the 2 local anesthetic agents were measured in palatal tissues using high-performance liquid chromatography (HPLC). RESULTS: HPLC analysis showed markedly higher 4% articaine solution values (0.319 ± 0.037) in palatal mucosal tissues compared with palatal mucosal concentrations of 2% lidocaine solution (0.0839 ± 0.017). In palatal bone, the mean concentration of 2% lidocaine solution was markedly lower than the mean concentration of 4% articaine solution (0.085 ± 0.012 vs 0.155 ± 0.012, respectively). There was no relevant difference between levels of 2% lidocaine in the palatal bone and mucosal tissues. However, the mean concentration of 4% articaine in the palatal mucosa was markedly higher than its concentration in palatal bone. CONCLUSIONS: The buccal vestibule-palatal diffusion of 4% articaine solution with 1:100,000 epinephrine is greater than 2% lidocaine solution with 1:100,000 epinephrine in a rabbit model.

Preparation and characterization of textile-based carrier systems for anal fissure treatment.

Anal fissure is common and painful disease of anorectum. In this study, microparticles containing nifedipine and lidocaine HCl were prepared by spray drying and applied to bio-degradable and bio-stable tampons. Characterization of microparticles was determined by visual analyses, mass yield, particle size measurement, encapsulation efficiency, drug loading and in vitro drug release. Mass yield was between 5.5 and 45.9%. The particle size was between 15.1 and 26.8 µm. Encapsulation efficiency were 96.142 ± 5.931 and 85.571 ± 3.301; drug loading were 65.261 ± 3.914% and 37.844 ± 4.339% of L2 and N1, respectively. Well-separated, mainly spherical microparticles with suitable properties were obtained. Optimum microparticles were applied to tampons. Physical properties and visual characteristics of tampons were investigated before and after binder application. In vitro drug release from tampons were also examined. According to the results, textile-based carrier systems loaded microparticles containing nifedipine and lidocaine HCl will be an effective and promising alternative for current anal fissure treatment.

Natural lipids-based NLC containing lidocaine: from pre-formulation to in vivo studies.

In a nanotechnological approach we have investigated the use of natural lipids in the preparation of nanostructured lipid carriers (NLC). Three different NLC composed of copaiba oil and beeswax, sweet almond oil and shea butter, and sesame oil and cocoa butter as structural matrices were optimized using factorial analysis; Pluronic® 68 and lidocaine (LDC) were used as the colloidal stabilizer and model encapsulated drug, respectively. The optimal formulations were characterized by different techniques (IR-ATR, DSC, and TEM), and their safety and efficacy were also tested. These nanocarriers were able to upload high amounts of the anesthetic with a sustained in vitro release profile for 24h. The physicochemical stability in terms of size (nm), PDI, zeta potential (mV), pH, nanoparticle concentration (particles/mL), and visual inspection was followed during 12months of storage at 25°C. The formulations exhibited excellent structural properties and stability. They proved to be nontoxic in vitro (cell viability tests with Balb/c 3T3 fibroblasts) and significantly improved the in vivo effects of LDC, over the heart rate of zebra fish larvae and in the blockage of sciatic nerve in mice. The results from this study support that the proper combination of natural excipients is promising in DDS, taking advantage of the biocompatibility, low cost, and diversity of lipids.

Estimated Maximal Safe Dosages of Tumescent Lidocaine.

BACKGROUND: Tumescent lidocaine anesthesia consists of subcutaneous injection of relatively large volumes (up to 4 L or more) of dilute lidocaine (≤1 g/L) and epinephrine (≤1 mg/L). Although tumescent lidocaine anesthesia is used for an increasing variety of surgical procedures, the maximum safe dosage is unknown. Our primary aim in this study was to measure serum lidocaine concentrations after subcutaneous administration of tumescent lidocaine with and without liposuction. Our hypotheses were that even with large doses (i.e., >30 mg/kg), serum lidocaine concentrations would be below levels associated with mild toxicity and that the concentration-time profile would be lower after liposuction than without liposuction. METHODS: Volunteers participated in 1 to 2 infiltration studies without liposuction and then one study with tumescent liposuction totally by local anesthesia. Serum lidocaine concentrations were measured at 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, and 24 hours after each tumescent lidocaine infiltration. Area under the curve (AUC∞) of the serum lidocaine concentration-time profiles and peak serum lidocaine concentrations (Cmax) were determined with and without liposuction. For any given milligram per kilogram dosage, the probability that Cmax >6 µg/mL, the threshold for mild lidocaine toxicity was estimated using tolerance interval analysis. RESULTS: In 41 tumescent infiltration procedures among 14 volunteer subjects, tumescent lidocaine dosages ranged from 19.2 to 52 mg/kg. Measured serum lidocaine concentrations were all <6 µg/mL over the 24-hour study period. AUC∞s with liposuction were significantly less than those without liposuction (P = 0.001). The estimated risk of lidocaine toxicity without liposuction at a dose of 28 mg/kg and with liposuction at a dose of 45 mg/kg was ≤1 per 2000. CONCLUSIONS: Preliminary estimates for maximum safe dosages of tumescent lidocaine are 28 mg/kg without liposuction and 45 mg/kg with liposuction. As a result of delayed systemic absorption, these dosages yield serum lidocaine concentrations below levels associated with mild toxicity and are a nonsignificant risk of harm to patients.

New insights into eutectic cream skin penetration enhancement.

The manner in which the eutectic cream EMLA enhances the percutaneous penetration of lidocaine and prilocaine into human skin is still not fully understood. The purpose of this study was to investigate if the modification of drug aggregation played a role in the way EMLA facilitates delivery. Light scattering analysis of lidocaine alone in water gave a critical aggregation concentration (CAC) of 572 µM and a mean aggregate size of 58.8 nm. The analysis of prilocaine in identical conditions gave a CAC of 1177 µM and a mean aggregate size of 105.7 ± 24.8 nm. When the two drugs were mixed at their eutectic 1:1 ratio in water the CAC reduced to 165.8 µM and the aggregate size was 43.82 nm. This lidocaine-prilocaine interaction in water was further modified upon addition of polyoxyethylene hydrogenated castor oil, the surfactant in the EMLA aqueous phase, to produce aggregates of <20 nm. The physical characterisation data suggested that it was the EMLA cream's surfactant that modified the drug molecular interactions in the aqueous continuous phase and caused a 6 fold higher drug penetration through human epidermal tissue compared to the oil formulations tested in this study.

Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial.

Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart-rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart-rate corrected J-Tpeak (J-Tpeak c) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from hERG potassium channel block and assessment of J-Tpeak c may add value beyond only assessing QTc.

Awakening properties of isoflurane, sevoflurane, and desflurane in pediatric patients after craniotomy for supratentorial tumours.

BACKGROUND: The aim of this prospective, comparative, randomized study was to compare the inhalational anesthetics isoflurane, sevoflurane, and desflurane in pediatric patients undergoing craniotomy for excision of supratentorial tumors. We assessed early postoperative recovery outcome, intraoperative hemodynamics, and degree of brain swelling, as well as postoperative vomiting and shivering. METHODS: Sixty patients scheduled for supratentorial brain tumor excision, were randomly allocated into 1 of 3 groups (20 patients each); isoflurane, sevoflurane, and desflurane group. After IV induction of anesthesia, maintenance was achieved using the inhalational anesthetic according to the allocated group. Tracheal extubation time was the primary endpoint. The secondary endpoints included: emergence time and the interval time needed to reach Aldrete score ≥9, intraoperative degree of brain swelling, intraoperative heart rate and mean arterial blood pressure, as well as postoperative vomiting and shivering. RESULTS: The mean emergence time, extubation time, and the interval required to reach Aldrete score 9 were significantly shorter in the desflurane and sevoflurane groups than the isoflurane group. No statistically significant changes in the 3 groups regarding intraoperative brain swelling, hemodynamics, and postoperative shivering or vomiting were noted. CONCLUSIONS: Desflurane and sevoflurane can be used to facilitate early emergence from anesthesia in neurosurgical pediatric patients. Emergence times are shorter with desflurane or sevoflurane than with isoflurane. The patients who received desflurane or sevoflurane have similar intraoperative and postoperative incidence of adverse effects compared with those who received isoflurane. Thus, desflurane and sevoflurane can be considered as suitable for emergence in pediatric neurosurgical anesthesia.

Topical anesthetics for cosmetic dermatologic procedures.

AIM: The aim of our study is to value the vasoconstrictor effect of two most utilized topical anesthetics, the first one containing a mixture 2.5% lidocaine and 2.5% prilocaine and the second one containing 4% liposomal lidocaine, in the treatment of vascular lesion during cosmetic dermatologic procedures. METHODS: Ten healthy volunteers were enrolled in our department. They showed telangiectasias, measuring between 0.5 and 1 millimeter in diameter on their face and limbs. Five volunteers were randomized to receive topical 4% liposomal lidocaine and five to receive 2.5% lidocaine and 2.5% prilocaine. In all treated areas, the 4% liposomal lidocaine was left for at least 30 minutes and the 2.5% lidocaine and 2.5% prilocaine was left for at least 60 minutes. RESULTS: Clinically, the volunteers who received the 4% liposomal lidocaine showed minimal vasoconstrictor difference between before and after treatment; while the others who received the 2.5% lidocaine and 2.5% prilocaine showed a major vasoconstrictor effect. Furthermore the 4% liposomal lidocaine cream has the advantage of an anesthetic effect after 30 minutes, rather than 60 minutes for the 2.5% lidocaine and 2.5% prilocaine cream. CONCLUSION: This study demonstrated that the 4% liposomal lidocaine has relatively minor vasoconstrictor effect when compared to the other anesthetic, and it shows how this type of anesthetic allows a clear vision of the lesion during the dermatologic procedures. Furthermore, this cream achieves an anesthetic effect in 30 minutes rather than the 60 minutes required for the other cream, making the first one more suitable for cosmetic dermatologic procedures and for the emergency.

Topical lidocaine enhanced by laser pretreatment: a safe and effective method of analgesia for facial rejuvenation.

BACKGROUND: Injectable forms of anesthesia for nonsurgical facial rejuvenation, although efficacious, are uncomfortable for the patient. Preclinical studies have demonstrated that laser pretreatment at low energies enhances absorption of topical lidocaine. OBJECTIVES: The authors assess the safety and efficacy of laser-assisted transdermal delivery of topical anesthetic. METHOD: Ten patients were split into 2 groups (A and B). All patients received 15 g of BLT (20% benzocaine, 6% lidocaine, and 4% tetracaine triple anesthetic cream) for 20 minutes with no occlusion. Then the cream was removed and the first blood draw taken. Group A patients were pretreated with the full ablative laser and group B patients with a fractional ablative laser to the full face. A further 15 g BLT was applied for another 20 minutes. Group A patients then underwent full ablative laser treatment, and group B received fractionated ablative laser treatment. Blood draws were taken at 60, 90, 120, 180, and 240 minutes after the initial topical anesthetic application, and the serum was analyzed for lidocaine and monoethylglycinexylidide (MEGX) levels. Patients were asked to rate the pain felt at intervals during the procedure. RESULTS: No patient required supplemental nerve blocks. Pain scores were equivalent at the end of the first pass for both groups (P = .436). Group A patients had significantly lower pain scores at the start of the second laser treatment (P = .045), but pain scores became equivalent by the end (P = .323). Combined serum lidocaine and MEGX levels were significantly higher in group A patients up to 90 minutes (peak average of 0.61 µg/mL for group A and 0.533 µg/mL for group B; P = .0253), which corresponded to greater initial analgesic effect. CONCLUSIONS: Data from this study demonstrate that topical anesthetic for facial rejuvenation can be enhanced with laser pretreatment while maintaining safe blood serum levels. Further studies should examine optimal application amount and time to allow safe multipass facial rejuvenation without the need for invasive nerve blocks.

Local anesthetics in liposuction: considerations for new practice advisory guidelines to improve patient safety.

The Practice Advisory on Liposuction published by the American Society of Plastic Surgeons provides a thorough review of anesthetic techniques and guidelines for surgeons who perform liposuction. However, there is evidence to support several changes to the anesthetic infiltrate guidelines that will improve patient safety. These proposed recommendations will have the most impact on patients undergoing office-based procedures, where dedicated anesthesia providers may not be present, but they should also guide practice in both ambulatory care centers and hospitals. The primary foci of the proposed changes include restrictions on bupivacaine use and creation of lidocaine concentration guidelines.

Preclinical experiments on the release behavior of biodegradable nanofibrous multipharmaceutical membranes in a model of four-wall intrabony defect.

Guided tissue regeneration (GTR) therapy has been widely used to regenerate lost periodontium from periodontal disease. However, in terms of regenerative periodontal therapy, a multidrug-loaded biodegradable carrier can be even more promising in dealing with periodontal disease. In the current study, we fabricated biodegradable nanofibrous collagen membranes that were loaded with amoxicillin, metronidazole, and lidocaine by an electrospinning technique. The in vitro release behavior and the cytotoxicity of the membranes were investigated. A four-wall intrabony defect was created in rabbits for in vivo release analysis. The bioactivity of the released antibiotics was also examined. The experimental results showed that the drug-loaded collagen membranes could provide sustainable release of effective amoxicillin, metronidazole, and lidocaine for 28, 56, and 8 days, respectively, in vivo. Furthermore, the bioactivity of the released antibiotics remained high, with average bioactivities of 50.5% for amoxicillin against Staphylococcus aureus and 58.6% for metronidazole against Escherichia coli. The biodegradable nanofibrous multipharmaceutical membranes developed in this study may provide a promising solution for regenerative periodontal therapy.

Anatomic distribution of gadolinium contrast medium by high-resolution magnetic resonance imaging after peribulbar and retrobulbar injections.

OBJECTIVE: To examine the anatomic distribution of gadolinium contrast medium by high-resolution surface-coil magnetic resonance imaging after peribulbar and retrobulbar injection. METHODS: Comparative case series in which 4 healthy volunteers were randomized to peribulbar (n = 2) or retrobulbar (n = 2) injection of gadolinium and lidocaine hydrochloride, 2%, without epinephrine. Magnetic resonance imaging was performed before injection and at 5 minutes and 90 minutes after injection. RESULTS: The peribulbar injection technique resulted in contrast medium primarily in the extraconal space, with no gadolinium observed at the orbital apex; surprisingly, a small amount of contrast medium was observed in the pterygopalatine fossa immediately after peribulbar injection. The retrobulbar injection technique resulted in gadolinium signal diffusely enhancing the intraconal space, orbital apex, optic nerve sheath, and optic canal. The signal intensity was clearly observed in the cavernous sinus surrounding the cavernous portion of the internal carotid artery. A small amount of contrast medium was detected in the pterygopalatine fossa. CONCLUSIONS: The retrobulbar injection technique localizes to the intraconal space, with access to intracranial and central nervous system structures via the optic canal, superior orbital fissure, and cavernous sinus. In contrast, the peribulbar injection technique produces a mostly extraconal distribution; however, intraconal solution may communicate with the central nervous system via the inferior orbital fissure and pterygopalatine fossa. This novel finding suggests that peribulbar anesthesia has a readily accessible route for central nervous system toxic effects. Magnetic resonance imaging with gadolinium contrast medium administration provides an important methodological advantage over previously described techniques and is a safe, reproducible, and superior method of orbital imaging.

The local pharmacokinetics of ³H-ropivacaine and ¹4C-lidocaine after maxillary infiltration anesthesia in rats.

The effects of infiltration anesthesia with ropivacaine on the dental pulp are considered to be weak. This may be partly associated with its permeation into the oral tissue. With the objective of investigating the local pharmacokinetics of ropivacaine and lidocaine following infiltration anesthesia, we injected (3)H-ropivacaine or (14)C-lidocaine to the palatal mucosa in rats, measured distributions of radioactivity in the maxilla, and compared the local pharmacokinetics of these agents. The animals were sacrificed at various times and the maxillas were removed. The palatal mucosa and maxillary nerve were resected, and the bone was divided into 6 portions. We measured radioactivity in each tissue and calculated the level of each local anesthetic (n  =  8). Lidocaine diffused to the surrounding tissue immediately after the injection, whereas ropivacaine tended to remain in the palatal mucosa for a longer period. Lidocaine showed a higher affinity for the maxillary bone than ropivacaine. There was a correlation between the distribution level of local anesthetics in the maxillary bone and that in the maxillary nerve. The lower-level effects of infiltration anesthesia with ropivacaine on the dental pulp may be because ropivacaine has a high affinity for soft tissue, and its transfer to bone is slight.

Development of lidocaine-coated microneedle product for rapid, safe, and prolonged local analgesic action.

PURPOSE: To demonstrate rapid (~1 min) lidocaine delivery using 3M's solid microstructured transdermal system (sMTS) for prolonged, local analgesic action. METHODS: Polymeric microneedles were fabricated via injection molding and then dip-coated using an aqueous lidocaine formulation. The amount of lidocaine coated onto the microneedles was determined by high performance liquid chromatography (HPLC). To assess drug delivery and dermal pharmacokinetics, lidocaine-coated microneedles were inserted into domestic swine. Skin punch biopsies were collected and analyzed to determine lidocaine concentration in skin using HPLC-mass spectrometry (LC-MS). Commercial lidocaine/prilocaine EMLA (Eutectic Mixture of Local Anesthetic) cream was used as comparative control. RESULTS: Lidocaine dissolves rapidly off the microneedles and into skin such that the 1-min wear time achieves or exceeds lidocaine tissue levels needed to cause analgesia. This therapeutic threshold (100 ng/mg) was estimated by measuring the total amount of lidocaine and prilocaine in skin following a 1 h EMLA application. When co-formulated with 0.03 wt% vasoconstrictor-epinephrine, the concentration of lidocaine in tissue was maintained above 100 ng/mg for approximately 90 min. CONCLUSIONS: 3M's sMTS can be used to provide rapid delivery of lidocaine for local analgesia up to 90 min.