Eur J Drug Metab Pharmacokinet DOI 10.1007/s13318-014-0218-5
ORIGINAL PAPER
Ocular and systemic pharmacokinetics of lidocaine hydrochloride ophthalmic gel in rabbits after topical ocular administration Bing Liu • Li Ding • Xiaowen Xu • Hongda Lin Chenglong Sun • Linjun You
•
Received: 27 January 2014 / Accepted: 26 June 2014 Ó Springer International Publishing Switzerland 2014
Abstract Lidocaine hydrochloride ophthalmic gel is a novel ophthalmic preparation for topical ocular anesthesia. The study is aimed at evaluating the ocular and systemic pharmacokinetics of lidocaine hydrochloride 3.5 % ophthalmic gel in rabbits after ocular topical administration. Thirty-six rabbits were randomly placed in 12 groups (3 rabbits per group). The rabbits were quickly killed according to their groups at 0 (predose), 0.0833, 0.167, 0.333, 0.667, 1, 1.5, 2, 3, 4, 6, and 8 h postdose and then the ocular tissue and plasma samples were collected. All the samples were analyzed by a validated LC–MS/MS method. The test result showed that the maximum concentration (Cmax) of lidocaine in different ocular tissues and plasma were all achieved within 20 min after drug administration, and the data of Cmax were (2,987 ± 1814) lg/g, (44.67 ± 12.91) lg/g, (26.26 ± 7.19) lg/g, (11,046 ± 2,734) ng/mL, and (160.3 ± 61.0) ng/mL for tear fluid, cornea, conjunctiva, aqueous humor, and plasma, respectively. The data of the elimination half-life in these tissues were 1.5, 3.2, 3.5, 1.9, and 1.7 h for tear fluid, cornea, conjunctiva, aqueous humor, and plasma, respectively. The intraocular lidocaine levels were significantly higher than that in plasma, and the elimination half-life of Electronic supplementary material The online version of this article (doi:10.1007/s13318-014-0218-5) contains supplementary material, which is available to authorized users. B. Liu L. Ding (&) X. Xu H. Lin C. Sun Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China e-mail: [email protected] L. You Centre for New Drug Safety Evaluation and Research, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China
lidocaine in cornea, conjunctiva, and aqueous humor was relatively longer than that in tear fluid and plasma. The high intraocular penetration, low systemic exposure, and long duration in the ocular tissues suggested lidocaine hydrochloride 3.5 % ophthalmic gel as an effective local anesthetic for ocular anesthesia during ophthalmic procedures. Keywords Lidocaine gel Ocular pharmacokinetic Rabbits Anesthetic Ocular tissue
1 Introduction The majority of ophthalmic surgical procedures are performed under local anesthesia. Ocular anesthesia can be delivered by a variety of routes, including retrobulbar and peribulbar injection, sub-Tenon’s injection, subconjunctival injection and topical application (Wong 1993). Topical drug delivery has been reported to be a safe, efficacious, and noninvasive technique for intraoperative ocular procedures (Koevary 2003; Ghate and Edelhauser 2008), typically in the form of solution, suspension, or ointment (Mainardes et al. 2005). However, the disadvantages of these dosage forms are relatively short duration, repeated administration during the surgery, and potential for cumulative toxicity (Urtti and Salminen 1993; Young et al. 2009). Therefore, the efforts have been concentrated on new formulations to prolong precorneal residence time and enhance drug penetration as well as decrease systemic absorption (Mainardes et al. 2005). A novel gel preparation, which contains viscosity enhancers, has the potential advantage of increased contact time with the ocular surface, providing prolonged release of the drug, thus creating a sustained anesthetic effect at the target tissue (Paavola et al. 1995; Shin et al. 2004).
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Lidocaine gel, a local anesthetic, is widely used in upper airway (Chan and Tham 1995), dental (Donaldson et al. 2003), urogenital (Kafali et al. 2003), and gastrointestinal (Mallick et al. 2004) procedures. Recent clinical studies have evaluated the off-label use of lidocaine gel as the sole agent for ocular procedures (Page and Fraunfelder 2009; Barequet et al. 1999; Soliman et al. 2004; Sinha et al. 2013; Bardocci et al. 2003) and many of these ophthalmic studies support the idea that the gel formulation of lidocaine may enhance anesthetic effect, and therefore, be superior to the drop formulation for ocular anesthesia (Page and Fraunfelder 2009; Barequet et al. 1999; Soliman et al. 2004; Sinha et al. 2013; Bardocci et al. 2003). Lidocaine hydrochloride 3.5 % ophthalmic gel (AktenTM, Akorn Inc.) was approved by the Food and Drug Administration for all ophthalmic procedures in October 2008. Lidocaine 3.5 % gel has the benefit of being 50 % less viscous compared to the off-label lidocaine gel, allowing for the preparation to be more easily instilled into and washed off from the eye. These properties of lidocaine 3.5 % gel also maintain a homogeneous surface for unimpaired observation of anterior segment and retinal structures and provide a potential advantage against intraocular infection (Shah et al. 2010). In addition, lidocaine 3.5 % gel is well tolerated and has no corneal toxicity (Busbee et al. 2008). The lidocaine gel formulation is theorized to result in the relatively long duration, high tissue penetration and also negligible systemic exposure. To our knowledge, critical information regarding the pharmacokinetics of lidocaine gel preparation is not available in literatures. The objective of this investigation was to evaluate the pharmacokinetic properties of lidocaine hydrochloride 3.5 % ophthalmic gel in various intraocular tissues and plasma. Due to the destructive sampling, the ocular and systemic pharmacokinetic studies were characterized following a single topical ocular administration of the drug to rabbits.
purchased from Nanjing Chemical Reagent Co., Ltd. (Nanjing, China). 2.2 Instrumentation The LC–ESI–MS/MS method was performed using an Agilent 6410B triple quadrupole mass spectrometer (Agilent Technologies, Palo Alto, CA, USA), which included an Agilent 1200 G1312B binary pump; a vacuum degasser (model G1322A); an Agilent 1200 autosampler (model G1367C); a temperature-controlled column compartment (model G1330B); and an Agilent 6410 MSD triple quadrupole mass spectrometer equipped with a commercial electrospray ionization source (model G1956B). The signal acquisition and peak integration were performed using the Masshunter Qualitative Analysis Software (B.03.01Build 346) supplied by Agilent Technologies. The centrifuge purchased from Zonkia Science Ltd. (Hefei, China) was used for sample centrifugation and the refrigerator (-20 °C) purchased from Zkmeiling Science Ltd. (Hefei, China) was used for sample storage. 2.3 Animals Male New Zealand white rabbits weighting 2–2.5 kg were purchased from the Qinglongshan Experimental Animal Center (Nanjing, China) and were individually housed under controlled environmental conditions (temperature 16–26 °C, humidity 40–70 %, 12 h dark–light cycle) for 5 days before the experiment. Food and water were supplied ad libitum. A comprehensive health assessment, including an eye examination was performed on all rabbits, and only those confirmed to be in good physical condition and free from any overt ocular defects were used in the study. All animal experiments were approved by the Animal Ethical Committee of China Pharmaceutical University. 2.4 Administration and collection of samples
2 Materials and methods 2.1 Chemicals and reagents Lidocaine hydrochloride 3.5 % ophthalmic gel (AktenTM, containing 35 mg per mL of lidocaine hydrochloride) was purchased from Akorn Inc., Lake Forest, IL, USA. The reference standards of lidocaine (purity 99.9 %) and letrozole (the internal standard, purity 100.0 %) were purchased from National Institutes for Food and Drug Control. Methanol and acetonitrile (HPLC grade) were purchased from Merck KGaA (Darmstadt, Germany). Formic acid and ammonium acetate were all analytical grade purity and
Thirty-six animals were weighed and randomly divided into twelve groups corresponding to a total number of twelve sampling points at 0 (predose), 0.0833, 0.167, 0.333, 0.667, 1, 1.5, 2, 3, 4, 6, and 8 h postdose (n = 3 rabbits per time point). A single 15 lL of lidocaine hydrochloride 3.5 % ophthalmic gel was instilled into both eyes of each animal via a micropipette. Immediately after dosing, the eyelids were gently held closed for several seconds to facilitate even distribution of the test substance over the surface of the eye. At each sampling time point, the tear fluid was immediately collected by inserting a tear film into the lower conjunctival sac of each eye for 30 s. The amount of tear fluid collected was determined by
Eur J Drug Metab Pharmacokinet
subtracting the weight of the tear film before collection from the weight of the film after collection. Then, the rabbits were euthanized by injecting overdosed sodium pentobarbital into a marginal ear vein. Blood samples (3 mL each) were collected by a syringe around heart, then immediately heparinized and separated by centrifugation at 4,000 rpm for 10 min. Aqueous humor was removed from the treated eye via paracentesis. Then, conjunctiva and cornea were dissected, weighed, and homogenized in physiologic saline. All obtained samples were stored at -20 °C until analysis.
used the transitions of the protonated molecules at m/z 235.1 ? 86.1 for lidocaine and m/z 286.2 ? 217.1 for the IS. The full method validation experiments that include specificity, linearity, lower limit of quantitation (LLOQ), precision, accuracy, matrix effect, extraction recovery, and stability were carried on plasma, aqueous humor, tear fluid and cornea, conjunctiva homogenates, according to the guidelines set by the United States Food and Drug Administration (FDA) for bioanalytical method (US FDA 2001). 2.7 Pharmacokinetic analysis
2.5 Sample preparation An aliquot of 200 lL plasma sample was added with internal standard solution (IS). After a thorough vortex mixing for 30 s, the mixture was deproteinized with 400 lL of acetonitrile, and centrifuged at 15,600 rpm for 5 min. The supernatant was diluted twofold with distilled water, and an aliquot of 5 lL of the prepared solution was used to perform sample injection for analysis. An aliquot of 20 lL aqueous humor sample was added with IS solution, and then diluted with 1 mL methanol– water (50:50, v/v). The solution was vortex-mixed for 3 min, centrifuged at 15,600 rpm for 5 min, and 5 lL of the supernatant liquid was injected into the LC–MS/MS system. Cornea and conjunctiva samples were homogenized using a high-speed homogenizer by adding physiologic saline (sterile 0.9 % NaCl) at the ratio of 1:20 (g/mL). An aliquot of 50 lL cornea or conjunctiva homogenate was added with IS solution, and then treated with 200 lL of acetonitrile (protein precipitation reagent), followed by vortex mix for 5 min and centrifugation for 5 min at 15,600 rpm. The supernatant was diluted sixfold with methanol–water (50:50, v/v), and then transferred into an injection vial. After adding IS solution, lidocaine was extracted from the tear fluid on the film using methanol–water (50:50, v/v), then vortexed and centrifuged at 15,600 rpm for 5 min. The supernatant was diluted 40-fold with methanol– water (50:50, v/v), and then transferred into an injection vial. 2.6 LC–MS/MS analysis The chromatographic separation was achieved on a Hedara ODS-2 column, 5 lm, 150 9 2.1 mm i.d. (Hanbon Science and Technology) with a mobile phase of methanol– 0.1 % formic acid water solution with 20 mM ammonium acetate (55:45, v/v) at a flow rate of 0.3 mL/min. The column temperature was 35 °C and the run time for each sample was 4 min. Multiple-reaction monitoring (MRM)
Pharmacokinetic analysis of rabbit ocular tissue and plasma samples was performed using noncompartmental pharmacokinetic methods with DAS 2.0 software (DASÒ; professional edition version 2.0, Drug and Statistics, Shanghai, China). Because of destructive sampling, only the mean concentration data of lidocaine in each ocular tissue and plasma at each time point was calculated and subsequently used for pharmacokinetic evaluation. From these data, the mean concentration versus time profiles were generated. Pharmacokinetic parameters estimated in this study included maximum concentration (Cmax), time to reach Cmax (Tmax), area under the concentration–time curve (AUC) from time zero to 8 h postdosing (AUC0–8), AUC from time zero to infinity (AUC0–?), elimination rate constant (K), elimination half-life (t1/2), apparent clearance (CL/F), apparent volume of distribution (Vd/F). Cmax and Tmax were obtained directly from the observed data. The t1/2 was calculated as 0.693/K. AUC0–t was calculated by the linear trapezoidal method and was extrapolated to infinity (AUC0–?) according to the relationship: AUC0–? = AUC0–t ? Ct/K, where Ct was the concentration at the last measurable time point. CL/F was calculated as dose/ AUC0–? and Vd/F was derived from Vd/F = dose/ (K 9 AUC0–?).
3 Results and discussion 3.1 Determination of lidocaine in plasma and ocular tissues The concentration of lidocaine in various rabbit ocular tissues and plasma was determined by LC–MS/MS. Method validation assays were carried out in all ocular tissues and plasma. The specificity test showed that there was no endogenous interference in the determination of lidocaine. The concentration ranges for lidocaine in plasma, aqueous humor, cornea, conjunctiva, and tear fluid were 0.05–60 ng/mL, 2–10,000 ng/mL, 2.5–2,500 ng/mL, 2.5–2,500 ng/mL, and 2–10,000 ng, respectively, and the
Eur J Drug Metab Pharmacokinet Table 1 Precision, accuracy, recovery, and matrix effect data for the analysis of lidocaine in all ocular tissues and plasma Tissues
Concentration levels (ng/mL)
Plasma
Aqueous humor
Cornea
Conjunctiva
Tear fluid
Concentration added (ng/mL)
RSD (%) Intradaya
RE (%) Interdayb
Accuracya
LLOQ
0.104
9.1
8.4
-2.4
Low QC
0.207
5.4
13.1
2.3
Middle QC
5.175
6.9
2.5
-2.7
Recoverya (mean ± SD, %)
Matrix effectc (mean ± SD, %)
–
–
96.5 ± 1.5
93.4 ± 5.2
100.9 ± 7.3
101.9 ± 6.9
High QC
51.75
1.8
2.5
3.9
99.8 ± 3.6
101.0 ± 3.2
LLOQ
2.070
6.5
6.9
-1.8
–
–
Low QC
4.140
2.4
8.2
-4.0
100.2 ± 2.8
102.4 ± 3.5
Middle QC High QC
310.5 8,280
2.7 1.9
8.9 3.1
2.8 1.5
99.2 ± 1.6 98.9 ± 1.7
100.8 ± 1.5 99.4 ± 1.7
LLOQ
2.588
3.2
17.5
3.7
–
–
Low QC
5.175
2.6
14.9
-0.5
100.8 ± 4.2
104.5 ± 2.7
Middle QC
155.3
1.3
11.3
-2.1
104.7 ± 1.9
99.0 ± 1.0
High QC
2,070
1.2
10.7
5.1
98.6 ± 0.7
101.7 ± 2.6
LLOQ
2.588
5.8
17.8
0.5
–
–
Low QC
5.175
4.3
4.9
1.9
99.3 ± 3.1
96.1 ± 4.6
Middle QC
155.3
2.2
8.0
2.5
94.5 ± 1.5
103.5 ± 4.6
High QC
2,070
2.9
5.8
-1.4
LLOQ
2.070
5.4
5.5
3.7
104.3 ± 6.7
99.0 ± 2.3
–
–
Low QC
5.175
2.2
12.4
2.8
101.2 ± 2.5
99.6 ± 1.6
Middle QC
310.5
1.1
10.1
-7.3
100.5 ± 1.5
101.2 ± 1.5
High QC
8,280
1.7
3.8
1.5
101.6 ± 1.3
100.5 ± 1.7
RSD relative standard deviation, RE relative error a
Five replicates at each concentration level
b
Six replicates at each concentration level
Table 2 Lidocaine concentration in ocular tissues and plasma after topical ocular administration of lidocaine hydrochloride 3.5 % ophthalmic gel to rabbits Time (h)
Plasma (ng/mL, mean ± SD)
Aqueous humor (ng/mL, mean ± SD)
Cornea (lg/g, mean ± SD)
Conjunctiva (lg/g, mean ± SD)
Tear fluid (lg/g, mean ± SD)
0
0
0
0
0
0
0.0833
82.50 ± 6.73
9,849 ± 4455
44.67 ± 12.91
26.26 ± 7.19
2,987 ± 1814
0.167
160.3 ± 61.0
9,407 ± 3,380
33.69 ± 16.24
21.08 ± 10.21
1,326 ± 753
0.333
60.14 ± 14.97
11,046 ± 2,734
37.08 ± 10.45
19.30 ± 8.07
595.3 ± 404.8
0.667
19.38 ± 5.13
2,784 ± 2955
14.72 ± 22.63
6.624 ± 4.405
79.47 ± 80.48
1
19.34 ± 6.00
1,685 ± 1539
20.33 ± 12.71
9.662 ± 6.726
42.20 ± 23.77
1.5
16.05 ± 6.60
323.3 ± 181.9
7.715 ± 6.150
9.157 ± 10.034
22.36 ± 29.54
2
5.716 ± 2.256
652.4 ± 549.5
5.696 ± 1.578
6.196 ± 4.869
112.3 ± 108.5
3
2.437 ± 0.981
251.3 ± 243.5
3.989 ± 3.016
5.293 ± 2.655
15.65 ± 15.37
4
2.096 ± 1.097
294.2 ± 210.3
4.394 ± 2.646
3.934 ± 1.970
26.38 ± 22.52
6
1.147 ± 0.421
159.2 ± 169.2
1.954 ± 0.609
2.284 ± 0.756
16.32 ± 23.44
8
0.4982 ± 0.1646
74.49 ± 58.14
1.356 ± 1.014
1.071 ± 0.621
7.708 ± 6.350
calibration curves were linear with correlation coefficients r [ 0.997. Table 1 summarizes the intra- and interday precisions, accuracies, recoveries, and matrix effects for lidocaine in all ocular tissues and plasma evaluated by assaying the LLOQ and QC samples. These results
revealed that the method was accurate and precise and there were no obvious matrix effects for lidocaine in all ocular tissues and plasma. The stability results summarized in the table of the supplementary material (Online Resource 1) showed that lidocaine was stable in all ocular
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tissues and plasma samples under different storage conditions. Dilution integrity experiments were carried out when study sample concentrations were higher than the upper limit of calibration curve. The accuracy and precision for diluted sample were within ±15 %, suggesting that samples with concentration above upper limit of quantitation could be reanalyzed by appropriate dilution. 3.2 Ocular and systemic pharmacokinetics of lidocaine After topical ocular administration of 15 lL of lidocaine hydrochloride 3.5 % ophthalmic gel, the mean lidocaine concentration data in various rabbit ocular tissues and plasma are given in Table 2, and the concentration–time profiles of lidocaine in various rabbit ocular tissues and plasma are shown in Fig. 1. The ocular and systemic pharmacokinetic parameters of lidocaine are presented in Table 3. The results showed that the maximum concentration (Cmax) of lidocaine in different ocular tissue and plasma were all achieved within 20 min after drug administration. Based on Cmax and AUC0–8 values presented in Table 3, the exposure of lidocaine was the highest in tear fluid, followed by cornea, conjunctiva, aqueous humor, and plasma. Lidocaine intraocular levels were significantly higher than plasma level throughout the 8 h sampling period. In addition, the elimination half-life of lidocaine in cornea, conjunctiva, and aqueous humor was relatively longer than that in tear fluid and plasma. After ocular topical administration to the rabbit, the drug immediately mixes with the tear fluid and then penetrates into the intraocular environment through the cornea and conjunctiva. Meanwhile, the drug can enter into the systemic circulation through the nasal mucosa and the conjunctival blood capillaries and lymphatics. The conjunctival membrane is an important route of drug loss from the lachrymal fluid (Koevary 2003; Gaudana et al. 2010; Jarvinen et al. 1995). Upon instillation, the distributions of lidocaine were fast and the maximum concentrations of lidocaine were achieved at 5 min for tear fluid, cornea, and conjunctiva, 10 min for plasma, and 20 min for aqueous humor after dosing. Comparing with the lidocaine absorption rates in tear fluid, cornea, and conjunctiva, the absorption rates in plasma and aqueous humor were slower. This result is mainly owing to the unique anatomy and physiology of the eye. Based on an average tear volume of 7 lL in rabbits (Maurice 1995), the theoretical concentration of lidocaine in tear fluid at time zero following a 15 lL instillation of lidocaine 3.5 % gel is about 24,000 lg/g. At 5 min after dosing, the concentration of lidocaine measured in tear fluid was 2,987 lg/g. Therefore, only 12 % of the theoretical concentration in tear fluid at time zero was left on
Fig. 1 Lidocaine concentration–time profiles in ocular tissues and plasma. a–e The concentration–time profiles obtained from plasma, aqueous humor, cornea, conjunctiva, and tear fluid, respectively, after topical ocular administration of lidocaine hydrochloride 3.5 % ophthalmic gel
Eur J Drug Metab Pharmacokinet Table 3 Ocular and systemic pharmacokinetic parameters of lidocaine after topical ocular administration of lidocaine hydrochloride 3.5 % ophthalmic gel to rabbits Pharmacokinetic parameters
Plasmaa
Aqueous humorb
Cornea
Conjunctiva
Tear fluid
Cmax (lg/g)
160.3 ± 61.0
11,046 ± 2734
44.67 ± 12.91
26.26 ± 7.19
2,987 ± 1814
Tmax (h)
0.167
0.333
0.0833
0.0833
0.0833
t1/2 (h)
1.7
1.9
3.2
3.5
1.5
CL/F (lg/h)
13.4
0.1
8.7
10.2
0.6
Vd/F (lg)
33.0
0.2
39.8
50.8
1.4
AUC0–8 (lg h/g)
77.16
8125
54.56
42.42
798.6
AUC0–? (lg h/g)
78.39
8335
60.63
51.70
814.6
CL/F apparent clearance, Vd/F apparent volume of distribution a
Unit for plasma are ng/mL, L/h, L and ng h/mL for Cmax, CL/F, Vd/F, and AUC, respectively
b
Unit for aqueous humor are ng/mL, L/h, L and ng h/mL for Cmax, CL/F, Vd/F, and AUC, respectively
the ocular surface at 5 min after dosing. Moreover, tear levels of lidocaine decreased to 20 % of the Cmax at 20 min after dosing, which might be attributed to the precorneal clearance factors and distribution of lidocaine into the ocular tissues. The most important factor of the precorneal clearance is the nasolacrimal drainage and the major part (50–100 %) of the instilled dose will be absorbed into the systemic circulation through the nasolacrimal system (Mainardes et al. 2005; Jarvinen et al. 1995). Therefore, the low systemic exposure supported the premise that the decrease of lidocaine in the tear fluid was mainly due to penetration into the ocular tissues. Bardocci et al. (2003) compared intracameral levels of lidocaine 2 % gel with lidocaine 4 % unpreserved drops. All patients received the same amount of lidocaine (20 mg) and aqueous samples were taken to measure lidocaine intraocular levels. The result suggested that patients who received lidocaine 2 % gel had significantly higher intracameral lidocaine levels than those receiving lidocaine 4 % drops. Results from our studies were consistent with previous study demonstrating that lidocaine gel increase intraocular penetration compared with lidocaine unpreserved drops.
4 Conclusion This study evaluated the ocular and systemic pharmacokinetics of lidocaine hydrochloride 3.5 % ophthalmic gel in rabbits after ocular topical administration. The result demonstrated that the gel formulation had high intraocular penetration, low systemic exposure, and long duration in the ocular tissues, which may create a sustained anesthetic effect and reduce the potential for systemic toxicity. Acknowledgments All authors participated in the analysis and interpretation of data and in the writing of the manuscript, and approved the final manuscript. The authors thank the team at Centre
for New Drug Safety Evaluation and Research of China Pharmaceutical University for conducting the study.
References Bardocci A, Lofoco G, Perdicaro S, Ciucci F, Manna L (2003) Lidocaine 2% gel versus lidocaine 4% unpreserved drops for topical anesthesia in cataract surgery: a randomized controlled trial. Ophthalmology 110(1):144–149 Barequet IS, Soriano ES, Green WR, O’Brien TP (1999) Provision of anesthesia with single application of lidocaine 2% gel. J Cataract Refract Surg 25(5):626–631 Busbee BG, Alam A, Reichel E (2008) Lidocaine hydrochloride gel for ocular anesthesia: results of a prospective, randomized study. Ophthalmic Surg Lasers Imaging 39(5):386–390 Chan ST, Tham CS (1995) The effects of 2% lignocaine gel on incidence of retching with the use of the laryngeal mask airway. Anaesthesia 50(3):257–258 Donaldson D, Gelskey SC, Landry RG, Matthews DC, Sandhu HS (2003) A placebo-controlled multi-centred evaluation of an anaesthetic gel (Oraqix((R))) for periodontal therapy. J Clin Periodontol 30(3):171–175. doi:10.1034/j.1600-051X.2003. 00017.x Gaudana R, Ananthula HK, Parenky A, Mitra AK (2010) Ocular drug delivery. AAPS J 12(3):348–360. doi:10.1208/s12248-010-9183-3 Ghate D, Edelhauser HF (2008) Barriers to glaucoma drug delivery. J Glaucoma 17(2):147–156. doi:10.1097/IJG.0b013e31814b990d Jarvinen K, Jarvinen T, Urtti A (1995) Ocular absorption following topical delivery. Adv Drug Deliv Rev 16(1):3–19. doi:10.1016/ 0169-409x(95)00010-5 Kafali H, Cengiz M, Demir N (2003) Intrauterine lidocaine gel application for pain relief during and after hysterosalpingography. Int J Gynaecol Obstet 83(1):65–67 Koevary SB (2003) Pharmacokinetics of topical ocular drug delivery: potential uses for the treatment of diseases of the posterior segment and beyond. Curr Drug Metab 4(3):213–222 Mainardes RM, Urban MC, Cinto PO, Khalil NM, Chaud MV, Evangelista RC, Gremiao MP (2005) Colloidal carriers for ophthalmic drug delivery. Curr Drug Targets 6(3):363–371 Mallick S, Humbert M, Braud F, Fofana M, Blanchet P (2004) Local anesthesia before transrectal ultrasound guided prostate biopsy: comparison of 2 methods in a prospective, randomized clinical trial. J Urology 171(2):730–733. doi:10.1097/01.ju.0000108125. 96072.ff
Eur J Drug Metab Pharmacokinet Maurice D (1995) The effect of the low blink rate in rabbits on topical drug penetration. J Ocular Pharmacol Ther 11(3):297–304 Paavola A, Yliruusi J, Kajimoto Y, Kalso E, Wahlstrom T, Rosenberg P (1995) Controlled release of lidocaine from injectable gels and efficacy in rat sciatic nerve block. Pharm Res 12(12):1997–2002 Page MA, Fraunfelder FW (2009) Safety, efficacy, and patient acceptability of lidocaine hydrochloride ophthalmic gel as a topical ocular anesthetic for use in ophthalmic procedures. Clin Ophthalmol 3:601–609 Shah H, Reichel E, Busbee B (2010) A novel lidocaine hydrochloride ophthalmic gel for topical ocular anesthesia. Local Reg Anesth 3:57–63 Shin SC, Cho CW, Yang KH (2004) Development of lidocaine gels for enhanced local anesthetic action. Int J Pharm 287(1–2):73–78. doi:10.1016/j.ijpharm.2004.08.012 Sinha R, Chandralekha, Batra M, Ray BR, Mohan VK, Saxena R (2013) A randomised comparison of lidocaine 2% gel and proparacaine 0.5% eye drops in paediatric squint surgery. Anaesthesia 68(7):747–752. doi:10.1111/anae.12286
Soliman MM, Macky TA, Samir MK (2004) Comparative clinical trial of topical anesthetic agents in cataract surgery: lidocaine 2% gel, bupivacaine 0.5% drops, and benoxinate 0.4% drops. J Cataract Refract Surg 30(8):1716–1720. doi:10.1016/j.jcrs.2003.12.034 Urtti A, Salminen L (1993) Minimizing systemic absorption of topically administered ophthalmic drugs. Surv Ophthalmol 37(6):435–456 US FDA, DHHS, CDER (2001) Guidance for industry: bioanalytical method validation. U.S. Food and Drug Administration, Department of Health and Human Services, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CV). http://www.fda.gov/cder/guidance/index.htm Wong DH (1993) Regional anaesthesia for intraocular surgery. Can J Anaesth 40(7):635–657. doi:10.1007/BF03009701 Young AL, Leung GY, Cheng LL, Lau TT, Lam PT, Lam DS (2009) Randomised controlled trial on the effectiveness of lidocaine gel vs tetracaine drops as the sole topical anaesthetic agent for primary pterygium surgery. Eye 23(7):1518–1523. doi:10.1038/ eye.2008.319
ORIGINAL PAPER
Ocular and systemic pharmacokinetics of lidocaine hydrochloride ophthalmic gel in rabbits after topical ocular administration Bing Liu • Li Ding • Xiaowen Xu • Hongda Lin Chenglong Sun • Linjun You
•
Received: 27 January 2014 / Accepted: 26 June 2014 Ó Springer International Publishing Switzerland 2014
Abstract Lidocaine hydrochloride ophthalmic gel is a novel ophthalmic preparation for topical ocular anesthesia. The study is aimed at evaluating the ocular and systemic pharmacokinetics of lidocaine hydrochloride 3.5 % ophthalmic gel in rabbits after ocular topical administration. Thirty-six rabbits were randomly placed in 12 groups (3 rabbits per group). The rabbits were quickly killed according to their groups at 0 (predose), 0.0833, 0.167, 0.333, 0.667, 1, 1.5, 2, 3, 4, 6, and 8 h postdose and then the ocular tissue and plasma samples were collected. All the samples were analyzed by a validated LC–MS/MS method. The test result showed that the maximum concentration (Cmax) of lidocaine in different ocular tissues and plasma were all achieved within 20 min after drug administration, and the data of Cmax were (2,987 ± 1814) lg/g, (44.67 ± 12.91) lg/g, (26.26 ± 7.19) lg/g, (11,046 ± 2,734) ng/mL, and (160.3 ± 61.0) ng/mL for tear fluid, cornea, conjunctiva, aqueous humor, and plasma, respectively. The data of the elimination half-life in these tissues were 1.5, 3.2, 3.5, 1.9, and 1.7 h for tear fluid, cornea, conjunctiva, aqueous humor, and plasma, respectively. The intraocular lidocaine levels were significantly higher than that in plasma, and the elimination half-life of Electronic supplementary material The online version of this article (doi:10.1007/s13318-014-0218-5) contains supplementary material, which is available to authorized users. B. Liu L. Ding (&) X. Xu H. Lin C. Sun Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China e-mail: [email protected] L. You Centre for New Drug Safety Evaluation and Research, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China
lidocaine in cornea, conjunctiva, and aqueous humor was relatively longer than that in tear fluid and plasma. The high intraocular penetration, low systemic exposure, and long duration in the ocular tissues suggested lidocaine hydrochloride 3.5 % ophthalmic gel as an effective local anesthetic for ocular anesthesia during ophthalmic procedures. Keywords Lidocaine gel Ocular pharmacokinetic Rabbits Anesthetic Ocular tissue
1 Introduction The majority of ophthalmic surgical procedures are performed under local anesthesia. Ocular anesthesia can be delivered by a variety of routes, including retrobulbar and peribulbar injection, sub-Tenon’s injection, subconjunctival injection and topical application (Wong 1993). Topical drug delivery has been reported to be a safe, efficacious, and noninvasive technique for intraoperative ocular procedures (Koevary 2003; Ghate and Edelhauser 2008), typically in the form of solution, suspension, or ointment (Mainardes et al. 2005). However, the disadvantages of these dosage forms are relatively short duration, repeated administration during the surgery, and potential for cumulative toxicity (Urtti and Salminen 1993; Young et al. 2009). Therefore, the efforts have been concentrated on new formulations to prolong precorneal residence time and enhance drug penetration as well as decrease systemic absorption (Mainardes et al. 2005). A novel gel preparation, which contains viscosity enhancers, has the potential advantage of increased contact time with the ocular surface, providing prolonged release of the drug, thus creating a sustained anesthetic effect at the target tissue (Paavola et al. 1995; Shin et al. 2004).
Eur J Drug Metab Pharmacokinet
Lidocaine gel, a local anesthetic, is widely used in upper airway (Chan and Tham 1995), dental (Donaldson et al. 2003), urogenital (Kafali et al. 2003), and gastrointestinal (Mallick et al. 2004) procedures. Recent clinical studies have evaluated the off-label use of lidocaine gel as the sole agent for ocular procedures (Page and Fraunfelder 2009; Barequet et al. 1999; Soliman et al. 2004; Sinha et al. 2013; Bardocci et al. 2003) and many of these ophthalmic studies support the idea that the gel formulation of lidocaine may enhance anesthetic effect, and therefore, be superior to the drop formulation for ocular anesthesia (Page and Fraunfelder 2009; Barequet et al. 1999; Soliman et al. 2004; Sinha et al. 2013; Bardocci et al. 2003). Lidocaine hydrochloride 3.5 % ophthalmic gel (AktenTM, Akorn Inc.) was approved by the Food and Drug Administration for all ophthalmic procedures in October 2008. Lidocaine 3.5 % gel has the benefit of being 50 % less viscous compared to the off-label lidocaine gel, allowing for the preparation to be more easily instilled into and washed off from the eye. These properties of lidocaine 3.5 % gel also maintain a homogeneous surface for unimpaired observation of anterior segment and retinal structures and provide a potential advantage against intraocular infection (Shah et al. 2010). In addition, lidocaine 3.5 % gel is well tolerated and has no corneal toxicity (Busbee et al. 2008). The lidocaine gel formulation is theorized to result in the relatively long duration, high tissue penetration and also negligible systemic exposure. To our knowledge, critical information regarding the pharmacokinetics of lidocaine gel preparation is not available in literatures. The objective of this investigation was to evaluate the pharmacokinetic properties of lidocaine hydrochloride 3.5 % ophthalmic gel in various intraocular tissues and plasma. Due to the destructive sampling, the ocular and systemic pharmacokinetic studies were characterized following a single topical ocular administration of the drug to rabbits.
purchased from Nanjing Chemical Reagent Co., Ltd. (Nanjing, China). 2.2 Instrumentation The LC–ESI–MS/MS method was performed using an Agilent 6410B triple quadrupole mass spectrometer (Agilent Technologies, Palo Alto, CA, USA), which included an Agilent 1200 G1312B binary pump; a vacuum degasser (model G1322A); an Agilent 1200 autosampler (model G1367C); a temperature-controlled column compartment (model G1330B); and an Agilent 6410 MSD triple quadrupole mass spectrometer equipped with a commercial electrospray ionization source (model G1956B). The signal acquisition and peak integration were performed using the Masshunter Qualitative Analysis Software (B.03.01Build 346) supplied by Agilent Technologies. The centrifuge purchased from Zonkia Science Ltd. (Hefei, China) was used for sample centrifugation and the refrigerator (-20 °C) purchased from Zkmeiling Science Ltd. (Hefei, China) was used for sample storage. 2.3 Animals Male New Zealand white rabbits weighting 2–2.5 kg were purchased from the Qinglongshan Experimental Animal Center (Nanjing, China) and were individually housed under controlled environmental conditions (temperature 16–26 °C, humidity 40–70 %, 12 h dark–light cycle) for 5 days before the experiment. Food and water were supplied ad libitum. A comprehensive health assessment, including an eye examination was performed on all rabbits, and only those confirmed to be in good physical condition and free from any overt ocular defects were used in the study. All animal experiments were approved by the Animal Ethical Committee of China Pharmaceutical University. 2.4 Administration and collection of samples
2 Materials and methods 2.1 Chemicals and reagents Lidocaine hydrochloride 3.5 % ophthalmic gel (AktenTM, containing 35 mg per mL of lidocaine hydrochloride) was purchased from Akorn Inc., Lake Forest, IL, USA. The reference standards of lidocaine (purity 99.9 %) and letrozole (the internal standard, purity 100.0 %) were purchased from National Institutes for Food and Drug Control. Methanol and acetonitrile (HPLC grade) were purchased from Merck KGaA (Darmstadt, Germany). Formic acid and ammonium acetate were all analytical grade purity and
Thirty-six animals were weighed and randomly divided into twelve groups corresponding to a total number of twelve sampling points at 0 (predose), 0.0833, 0.167, 0.333, 0.667, 1, 1.5, 2, 3, 4, 6, and 8 h postdose (n = 3 rabbits per time point). A single 15 lL of lidocaine hydrochloride 3.5 % ophthalmic gel was instilled into both eyes of each animal via a micropipette. Immediately after dosing, the eyelids were gently held closed for several seconds to facilitate even distribution of the test substance over the surface of the eye. At each sampling time point, the tear fluid was immediately collected by inserting a tear film into the lower conjunctival sac of each eye for 30 s. The amount of tear fluid collected was determined by
Eur J Drug Metab Pharmacokinet
subtracting the weight of the tear film before collection from the weight of the film after collection. Then, the rabbits were euthanized by injecting overdosed sodium pentobarbital into a marginal ear vein. Blood samples (3 mL each) were collected by a syringe around heart, then immediately heparinized and separated by centrifugation at 4,000 rpm for 10 min. Aqueous humor was removed from the treated eye via paracentesis. Then, conjunctiva and cornea were dissected, weighed, and homogenized in physiologic saline. All obtained samples were stored at -20 °C until analysis.
used the transitions of the protonated molecules at m/z 235.1 ? 86.1 for lidocaine and m/z 286.2 ? 217.1 for the IS. The full method validation experiments that include specificity, linearity, lower limit of quantitation (LLOQ), precision, accuracy, matrix effect, extraction recovery, and stability were carried on plasma, aqueous humor, tear fluid and cornea, conjunctiva homogenates, according to the guidelines set by the United States Food and Drug Administration (FDA) for bioanalytical method (US FDA 2001). 2.7 Pharmacokinetic analysis
2.5 Sample preparation An aliquot of 200 lL plasma sample was added with internal standard solution (IS). After a thorough vortex mixing for 30 s, the mixture was deproteinized with 400 lL of acetonitrile, and centrifuged at 15,600 rpm for 5 min. The supernatant was diluted twofold with distilled water, and an aliquot of 5 lL of the prepared solution was used to perform sample injection for analysis. An aliquot of 20 lL aqueous humor sample was added with IS solution, and then diluted with 1 mL methanol– water (50:50, v/v). The solution was vortex-mixed for 3 min, centrifuged at 15,600 rpm for 5 min, and 5 lL of the supernatant liquid was injected into the LC–MS/MS system. Cornea and conjunctiva samples were homogenized using a high-speed homogenizer by adding physiologic saline (sterile 0.9 % NaCl) at the ratio of 1:20 (g/mL). An aliquot of 50 lL cornea or conjunctiva homogenate was added with IS solution, and then treated with 200 lL of acetonitrile (protein precipitation reagent), followed by vortex mix for 5 min and centrifugation for 5 min at 15,600 rpm. The supernatant was diluted sixfold with methanol–water (50:50, v/v), and then transferred into an injection vial. After adding IS solution, lidocaine was extracted from the tear fluid on the film using methanol–water (50:50, v/v), then vortexed and centrifuged at 15,600 rpm for 5 min. The supernatant was diluted 40-fold with methanol– water (50:50, v/v), and then transferred into an injection vial. 2.6 LC–MS/MS analysis The chromatographic separation was achieved on a Hedara ODS-2 column, 5 lm, 150 9 2.1 mm i.d. (Hanbon Science and Technology) with a mobile phase of methanol– 0.1 % formic acid water solution with 20 mM ammonium acetate (55:45, v/v) at a flow rate of 0.3 mL/min. The column temperature was 35 °C and the run time for each sample was 4 min. Multiple-reaction monitoring (MRM)
Pharmacokinetic analysis of rabbit ocular tissue and plasma samples was performed using noncompartmental pharmacokinetic methods with DAS 2.0 software (DASÒ; professional edition version 2.0, Drug and Statistics, Shanghai, China). Because of destructive sampling, only the mean concentration data of lidocaine in each ocular tissue and plasma at each time point was calculated and subsequently used for pharmacokinetic evaluation. From these data, the mean concentration versus time profiles were generated. Pharmacokinetic parameters estimated in this study included maximum concentration (Cmax), time to reach Cmax (Tmax), area under the concentration–time curve (AUC) from time zero to 8 h postdosing (AUC0–8), AUC from time zero to infinity (AUC0–?), elimination rate constant (K), elimination half-life (t1/2), apparent clearance (CL/F), apparent volume of distribution (Vd/F). Cmax and Tmax were obtained directly from the observed data. The t1/2 was calculated as 0.693/K. AUC0–t was calculated by the linear trapezoidal method and was extrapolated to infinity (AUC0–?) according to the relationship: AUC0–? = AUC0–t ? Ct/K, where Ct was the concentration at the last measurable time point. CL/F was calculated as dose/ AUC0–? and Vd/F was derived from Vd/F = dose/ (K 9 AUC0–?).
3 Results and discussion 3.1 Determination of lidocaine in plasma and ocular tissues The concentration of lidocaine in various rabbit ocular tissues and plasma was determined by LC–MS/MS. Method validation assays were carried out in all ocular tissues and plasma. The specificity test showed that there was no endogenous interference in the determination of lidocaine. The concentration ranges for lidocaine in plasma, aqueous humor, cornea, conjunctiva, and tear fluid were 0.05–60 ng/mL, 2–10,000 ng/mL, 2.5–2,500 ng/mL, 2.5–2,500 ng/mL, and 2–10,000 ng, respectively, and the
Eur J Drug Metab Pharmacokinet Table 1 Precision, accuracy, recovery, and matrix effect data for the analysis of lidocaine in all ocular tissues and plasma Tissues
Concentration levels (ng/mL)
Plasma
Aqueous humor
Cornea
Conjunctiva
Tear fluid
Concentration added (ng/mL)
RSD (%) Intradaya
RE (%) Interdayb
Accuracya
LLOQ
0.104
9.1
8.4
-2.4
Low QC
0.207
5.4
13.1
2.3
Middle QC
5.175
6.9
2.5
-2.7
Recoverya (mean ± SD, %)
Matrix effectc (mean ± SD, %)
–
–
96.5 ± 1.5
93.4 ± 5.2
100.9 ± 7.3
101.9 ± 6.9
High QC
51.75
1.8
2.5
3.9
99.8 ± 3.6
101.0 ± 3.2
LLOQ
2.070
6.5
6.9
-1.8
–
–
Low QC
4.140
2.4
8.2
-4.0
100.2 ± 2.8
102.4 ± 3.5
Middle QC High QC
310.5 8,280
2.7 1.9
8.9 3.1
2.8 1.5
99.2 ± 1.6 98.9 ± 1.7
100.8 ± 1.5 99.4 ± 1.7
LLOQ
2.588
3.2
17.5
3.7
–
–
Low QC
5.175
2.6
14.9
-0.5
100.8 ± 4.2
104.5 ± 2.7
Middle QC
155.3
1.3
11.3
-2.1
104.7 ± 1.9
99.0 ± 1.0
High QC
2,070
1.2
10.7
5.1
98.6 ± 0.7
101.7 ± 2.6
LLOQ
2.588
5.8
17.8
0.5
–
–
Low QC
5.175
4.3
4.9
1.9
99.3 ± 3.1
96.1 ± 4.6
Middle QC
155.3
2.2
8.0
2.5
94.5 ± 1.5
103.5 ± 4.6
High QC
2,070
2.9
5.8
-1.4
LLOQ
2.070
5.4
5.5
3.7
104.3 ± 6.7
99.0 ± 2.3
–
–
Low QC
5.175
2.2
12.4
2.8
101.2 ± 2.5
99.6 ± 1.6
Middle QC
310.5
1.1
10.1
-7.3
100.5 ± 1.5
101.2 ± 1.5
High QC
8,280
1.7
3.8
1.5
101.6 ± 1.3
100.5 ± 1.7
RSD relative standard deviation, RE relative error a
Five replicates at each concentration level
b
Six replicates at each concentration level
Table 2 Lidocaine concentration in ocular tissues and plasma after topical ocular administration of lidocaine hydrochloride 3.5 % ophthalmic gel to rabbits Time (h)
Plasma (ng/mL, mean ± SD)
Aqueous humor (ng/mL, mean ± SD)
Cornea (lg/g, mean ± SD)
Conjunctiva (lg/g, mean ± SD)
Tear fluid (lg/g, mean ± SD)
0
0
0
0
0
0
0.0833
82.50 ± 6.73
9,849 ± 4455
44.67 ± 12.91
26.26 ± 7.19
2,987 ± 1814
0.167
160.3 ± 61.0
9,407 ± 3,380
33.69 ± 16.24
21.08 ± 10.21
1,326 ± 753
0.333
60.14 ± 14.97
11,046 ± 2,734
37.08 ± 10.45
19.30 ± 8.07
595.3 ± 404.8
0.667
19.38 ± 5.13
2,784 ± 2955
14.72 ± 22.63
6.624 ± 4.405
79.47 ± 80.48
1
19.34 ± 6.00
1,685 ± 1539
20.33 ± 12.71
9.662 ± 6.726
42.20 ± 23.77
1.5
16.05 ± 6.60
323.3 ± 181.9
7.715 ± 6.150
9.157 ± 10.034
22.36 ± 29.54
2
5.716 ± 2.256
652.4 ± 549.5
5.696 ± 1.578
6.196 ± 4.869
112.3 ± 108.5
3
2.437 ± 0.981
251.3 ± 243.5
3.989 ± 3.016
5.293 ± 2.655
15.65 ± 15.37
4
2.096 ± 1.097
294.2 ± 210.3
4.394 ± 2.646
3.934 ± 1.970
26.38 ± 22.52
6
1.147 ± 0.421
159.2 ± 169.2
1.954 ± 0.609
2.284 ± 0.756
16.32 ± 23.44
8
0.4982 ± 0.1646
74.49 ± 58.14
1.356 ± 1.014
1.071 ± 0.621
7.708 ± 6.350
calibration curves were linear with correlation coefficients r [ 0.997. Table 1 summarizes the intra- and interday precisions, accuracies, recoveries, and matrix effects for lidocaine in all ocular tissues and plasma evaluated by assaying the LLOQ and QC samples. These results
revealed that the method was accurate and precise and there were no obvious matrix effects for lidocaine in all ocular tissues and plasma. The stability results summarized in the table of the supplementary material (Online Resource 1) showed that lidocaine was stable in all ocular
Eur J Drug Metab Pharmacokinet
tissues and plasma samples under different storage conditions. Dilution integrity experiments were carried out when study sample concentrations were higher than the upper limit of calibration curve. The accuracy and precision for diluted sample were within ±15 %, suggesting that samples with concentration above upper limit of quantitation could be reanalyzed by appropriate dilution. 3.2 Ocular and systemic pharmacokinetics of lidocaine After topical ocular administration of 15 lL of lidocaine hydrochloride 3.5 % ophthalmic gel, the mean lidocaine concentration data in various rabbit ocular tissues and plasma are given in Table 2, and the concentration–time profiles of lidocaine in various rabbit ocular tissues and plasma are shown in Fig. 1. The ocular and systemic pharmacokinetic parameters of lidocaine are presented in Table 3. The results showed that the maximum concentration (Cmax) of lidocaine in different ocular tissue and plasma were all achieved within 20 min after drug administration. Based on Cmax and AUC0–8 values presented in Table 3, the exposure of lidocaine was the highest in tear fluid, followed by cornea, conjunctiva, aqueous humor, and plasma. Lidocaine intraocular levels were significantly higher than plasma level throughout the 8 h sampling period. In addition, the elimination half-life of lidocaine in cornea, conjunctiva, and aqueous humor was relatively longer than that in tear fluid and plasma. After ocular topical administration to the rabbit, the drug immediately mixes with the tear fluid and then penetrates into the intraocular environment through the cornea and conjunctiva. Meanwhile, the drug can enter into the systemic circulation through the nasal mucosa and the conjunctival blood capillaries and lymphatics. The conjunctival membrane is an important route of drug loss from the lachrymal fluid (Koevary 2003; Gaudana et al. 2010; Jarvinen et al. 1995). Upon instillation, the distributions of lidocaine were fast and the maximum concentrations of lidocaine were achieved at 5 min for tear fluid, cornea, and conjunctiva, 10 min for plasma, and 20 min for aqueous humor after dosing. Comparing with the lidocaine absorption rates in tear fluid, cornea, and conjunctiva, the absorption rates in plasma and aqueous humor were slower. This result is mainly owing to the unique anatomy and physiology of the eye. Based on an average tear volume of 7 lL in rabbits (Maurice 1995), the theoretical concentration of lidocaine in tear fluid at time zero following a 15 lL instillation of lidocaine 3.5 % gel is about 24,000 lg/g. At 5 min after dosing, the concentration of lidocaine measured in tear fluid was 2,987 lg/g. Therefore, only 12 % of the theoretical concentration in tear fluid at time zero was left on
Fig. 1 Lidocaine concentration–time profiles in ocular tissues and plasma. a–e The concentration–time profiles obtained from plasma, aqueous humor, cornea, conjunctiva, and tear fluid, respectively, after topical ocular administration of lidocaine hydrochloride 3.5 % ophthalmic gel
Eur J Drug Metab Pharmacokinet Table 3 Ocular and systemic pharmacokinetic parameters of lidocaine after topical ocular administration of lidocaine hydrochloride 3.5 % ophthalmic gel to rabbits Pharmacokinetic parameters
Plasmaa
Aqueous humorb
Cornea
Conjunctiva
Tear fluid
Cmax (lg/g)
160.3 ± 61.0
11,046 ± 2734
44.67 ± 12.91
26.26 ± 7.19
2,987 ± 1814
Tmax (h)
0.167
0.333
0.0833
0.0833
0.0833
t1/2 (h)
1.7
1.9
3.2
3.5
1.5
CL/F (lg/h)
13.4
0.1
8.7
10.2
0.6
Vd/F (lg)
33.0
0.2
39.8
50.8
1.4
AUC0–8 (lg h/g)
77.16
8125
54.56
42.42
798.6
AUC0–? (lg h/g)
78.39
8335
60.63
51.70
814.6
CL/F apparent clearance, Vd/F apparent volume of distribution a
Unit for plasma are ng/mL, L/h, L and ng h/mL for Cmax, CL/F, Vd/F, and AUC, respectively
b
Unit for aqueous humor are ng/mL, L/h, L and ng h/mL for Cmax, CL/F, Vd/F, and AUC, respectively
the ocular surface at 5 min after dosing. Moreover, tear levels of lidocaine decreased to 20 % of the Cmax at 20 min after dosing, which might be attributed to the precorneal clearance factors and distribution of lidocaine into the ocular tissues. The most important factor of the precorneal clearance is the nasolacrimal drainage and the major part (50–100 %) of the instilled dose will be absorbed into the systemic circulation through the nasolacrimal system (Mainardes et al. 2005; Jarvinen et al. 1995). Therefore, the low systemic exposure supported the premise that the decrease of lidocaine in the tear fluid was mainly due to penetration into the ocular tissues. Bardocci et al. (2003) compared intracameral levels of lidocaine 2 % gel with lidocaine 4 % unpreserved drops. All patients received the same amount of lidocaine (20 mg) and aqueous samples were taken to measure lidocaine intraocular levels. The result suggested that patients who received lidocaine 2 % gel had significantly higher intracameral lidocaine levels than those receiving lidocaine 4 % drops. Results from our studies were consistent with previous study demonstrating that lidocaine gel increase intraocular penetration compared with lidocaine unpreserved drops.
4 Conclusion This study evaluated the ocular and systemic pharmacokinetics of lidocaine hydrochloride 3.5 % ophthalmic gel in rabbits after ocular topical administration. The result demonstrated that the gel formulation had high intraocular penetration, low systemic exposure, and long duration in the ocular tissues, which may create a sustained anesthetic effect and reduce the potential for systemic toxicity. Acknowledgments All authors participated in the analysis and interpretation of data and in the writing of the manuscript, and approved the final manuscript. The authors thank the team at Centre
for New Drug Safety Evaluation and Research of China Pharmaceutical University for conducting the study.
References Bardocci A, Lofoco G, Perdicaro S, Ciucci F, Manna L (2003) Lidocaine 2% gel versus lidocaine 4% unpreserved drops for topical anesthesia in cataract surgery: a randomized controlled trial. Ophthalmology 110(1):144–149 Barequet IS, Soriano ES, Green WR, O’Brien TP (1999) Provision of anesthesia with single application of lidocaine 2% gel. J Cataract Refract Surg 25(5):626–631 Busbee BG, Alam A, Reichel E (2008) Lidocaine hydrochloride gel for ocular anesthesia: results of a prospective, randomized study. Ophthalmic Surg Lasers Imaging 39(5):386–390 Chan ST, Tham CS (1995) The effects of 2% lignocaine gel on incidence of retching with the use of the laryngeal mask airway. Anaesthesia 50(3):257–258 Donaldson D, Gelskey SC, Landry RG, Matthews DC, Sandhu HS (2003) A placebo-controlled multi-centred evaluation of an anaesthetic gel (Oraqix((R))) for periodontal therapy. J Clin Periodontol 30(3):171–175. doi:10.1034/j.1600-051X.2003. 00017.x Gaudana R, Ananthula HK, Parenky A, Mitra AK (2010) Ocular drug delivery. AAPS J 12(3):348–360. doi:10.1208/s12248-010-9183-3 Ghate D, Edelhauser HF (2008) Barriers to glaucoma drug delivery. J Glaucoma 17(2):147–156. doi:10.1097/IJG.0b013e31814b990d Jarvinen K, Jarvinen T, Urtti A (1995) Ocular absorption following topical delivery. Adv Drug Deliv Rev 16(1):3–19. doi:10.1016/ 0169-409x(95)00010-5 Kafali H, Cengiz M, Demir N (2003) Intrauterine lidocaine gel application for pain relief during and after hysterosalpingography. Int J Gynaecol Obstet 83(1):65–67 Koevary SB (2003) Pharmacokinetics of topical ocular drug delivery: potential uses for the treatment of diseases of the posterior segment and beyond. Curr Drug Metab 4(3):213–222 Mainardes RM, Urban MC, Cinto PO, Khalil NM, Chaud MV, Evangelista RC, Gremiao MP (2005) Colloidal carriers for ophthalmic drug delivery. Curr Drug Targets 6(3):363–371 Mallick S, Humbert M, Braud F, Fofana M, Blanchet P (2004) Local anesthesia before transrectal ultrasound guided prostate biopsy: comparison of 2 methods in a prospective, randomized clinical trial. J Urology 171(2):730–733. doi:10.1097/01.ju.0000108125. 96072.ff
Eur J Drug Metab Pharmacokinet Maurice D (1995) The effect of the low blink rate in rabbits on topical drug penetration. J Ocular Pharmacol Ther 11(3):297–304 Paavola A, Yliruusi J, Kajimoto Y, Kalso E, Wahlstrom T, Rosenberg P (1995) Controlled release of lidocaine from injectable gels and efficacy in rat sciatic nerve block. Pharm Res 12(12):1997–2002 Page MA, Fraunfelder FW (2009) Safety, efficacy, and patient acceptability of lidocaine hydrochloride ophthalmic gel as a topical ocular anesthetic for use in ophthalmic procedures. Clin Ophthalmol 3:601–609 Shah H, Reichel E, Busbee B (2010) A novel lidocaine hydrochloride ophthalmic gel for topical ocular anesthesia. Local Reg Anesth 3:57–63 Shin SC, Cho CW, Yang KH (2004) Development of lidocaine gels for enhanced local anesthetic action. Int J Pharm 287(1–2):73–78. doi:10.1016/j.ijpharm.2004.08.012 Sinha R, Chandralekha, Batra M, Ray BR, Mohan VK, Saxena R (2013) A randomised comparison of lidocaine 2% gel and proparacaine 0.5% eye drops in paediatric squint surgery. Anaesthesia 68(7):747–752. doi:10.1111/anae.12286
Soliman MM, Macky TA, Samir MK (2004) Comparative clinical trial of topical anesthetic agents in cataract surgery: lidocaine 2% gel, bupivacaine 0.5% drops, and benoxinate 0.4% drops. J Cataract Refract Surg 30(8):1716–1720. doi:10.1016/j.jcrs.2003.12.034 Urtti A, Salminen L (1993) Minimizing systemic absorption of topically administered ophthalmic drugs. Surv Ophthalmol 37(6):435–456 US FDA, DHHS, CDER (2001) Guidance for industry: bioanalytical method validation. U.S. Food and Drug Administration, Department of Health and Human Services, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CV). http://www.fda.gov/cder/guidance/index.htm Wong DH (1993) Regional anaesthesia for intraocular surgery. Can J Anaesth 40(7):635–657. doi:10.1007/BF03009701 Young AL, Leung GY, Cheng LL, Lau TT, Lam PT, Lam DS (2009) Randomised controlled trial on the effectiveness of lidocaine gel vs tetracaine drops as the sole topical anaesthetic agent for primary pterygium surgery. Eye 23(7):1518–1523. doi:10.1038/ eye.2008.319
