Home > Subjects > Drug Delivery > Formulation and Evaluation of Lidocaine Base Ethosomes for T...
Anesthesia & Analgesia:
doi: 10.1213/ANE.0b013e3182937b74
Anesthetic Pharmacology: Research Report

Formulation and Evaluation of Lidocaine Base Ethosomes for Transdermal Delivery

Zhu, Xiaoliang PhD; Li, Fuli MM; Peng, Xuebiao MD; Zeng, Kang MM

Free Access
Article Outline
Collapse Box

Author Information

From the Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China.

Accepted for publication March 8, 2013.

Published ahead of print June 6, 2013.

Funding: This work was supported by the National Natural Science Foundation of China (grant no. 30902019).

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Xiaoliang Zhu, PhD, Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, People’s Republic of China. Address e-mail to nfnpfk@163.com.

Collapse Box

Abstract

BACKGROUND: Although transdermal preparations of local anesthetics have been used to reduce pain caused by skin surgery, these preparations cannot effectively penetrate through the epidermis because of the barrier formed by the stratum corneum and the thick epidermis. Ethosomes can effectively transport drugs across the skin because of their thermodynamic stability, small size, high encapsulation efficiency, and percutaneous penetration. We evaluated lidocaine base ethosomes by measuring their loading efficiency, encapsulation efficiency, thermodynamic stability, and percutaneous penetration capability in vitro, and their effectiveness and cutaneous irritation in vivo.

METHODS: Lidocaine base ethosomes were prepared using the injection-sonication-filter method. Size, loading efficiency, encapsulation efficiency, and stability were evaluated using a Zetasizer and high performance liquid chromatography. Formulation was determined by measuring the maximum encapsulation efficiency in the orthogonal test. Percutaneous penetration efficiency in vitro was analyzed using a Franz-type diffusion cell experiment. In vivo effectiveness was analyzed using the pinprick test. Cutaneous irritancy tests were performed on white guinea pigs, followed by histopathologic analysis. The results were compared with lidocaine liposomes as well as lidocaine delivered in a hydroethanolic solution.

RESULTS: Lidocaine base ethosomes composed of 5% (w/w) egg phosphatidyl choline, 35% (w/w) ethanol, 0.2% (w/w) cholesterol, 5% (w/w) lidocaine base, and ultrapure water had a mean maximum encapsulation of 51% ± 4%, a mean particle size of 31 ± 3 nm, and a mean loading efficiency of 95.0% ± 0.1%. The encapsulation efficiency of lidocaine base ethosomes remained stable for 60 days at 25°C ± 1°C (95% confidence interval [CI], −1.12% to 1.34%; P = 0.833). The transdermal flux of lidocaine base differed significantly for the 3 preparations (F = 120, P < 0.001), being significantly greater from ethosomes than from liposomes (95% corrected CI, 1129–1818 µg/(cm2·h); P < 0.001), and from hydroethanolic solution (95% corrected CI, 1468–2157 µg/(cm2·h); P < 0.001). Lidocaine base ethosomes had a shorter onset time and longer duration in vivo than did lidocaine base liposomes or lidocaine delivered in a hydroethanolic solution. Lidocaine base ethosomes showed no evidence of dermal irritation in guinea pigs.

CONCLUSIONS: Ethosomes are potential carriers of local anesthetics across the skin and may have applicability for other percutaneous drugs that require rapid onset.

Many types of skin surgery, such as curettage of molluscum, laser cosmetic surgery, and electrosurgery, require topical anesthetics with a rapid onset and long duration of activity. Direct injection of lidocaine, the most commonly used local anesthetic, has the advantages of instant onset and simple administration. Direct injection is also painful and may be poorly tolerated, especially in children. Anatomic marks, which are very important in facial surgery, may be altered by direct injection. Percutaneous delivery systems for lidocaine base, such as ointment, tincture, and liposomes, have been developed for clinical use,1 but each has drawbacks.

Ethosomes are an innovative vesicular delivery system, with advantages that include thermodynamic stability, small particle size, high loading efficiency (LE), and high encapsulation efficiency.2 Ethosomal formulations have been used for the administration of several drugs, including finasteride and matrine.3,4 Due to their deformability, ethosomes can effectively penetrate the epidermis, and even into deeper layers of the skin.5–7

We hypothesized that lidocaine base in an ethosomal formulation may be superior to the existing percutaneous preparations of lidocaine base, especially in thermodynamic stability, onset time, and duration. We therefore prepared 5% (w/w) lidocaine base ethosomes and measured their size, LE, encapsulation efficiency, and percutaneous penetrating efficiency in vitro, their effectiveness in vivo, and their ability to irritate the skin of guinea pigs.

Back to Top | Article Outline

METHODS

Preparation of Lidocaine Base Formulations

The orthogonal test L9 (34) table was used to design the formulations of lidocaine base ethosomes. The vesicular system was composed of 3% to 5% (w/w) egg phosphatidyl choline, 0.15% to 0.2% (w/w) cholesterol, 35% to 45% (w/w) anhydrous ethanol, drug (5% lidocaine base, w/w), and ultrapure water. The egg phosphatidyl choline and cholesterol were dissolved in anhydrous ethanol with lidocaine base, followed by the slow addition of ultrapure water and vortexing at 1500 rpm for 10 minutes (Haimen Instruments, Jiangsu, China). The mixture was sonicated with a pulse of 105 W for 2 minutes in an Ultrasonic Processor (Cole-Parmer Instruments, Vernon Hills, IL) and filtered through a 0.22-μm filter. The lidocaine base ethosomes were stored in sealed vials at 25°C ± 1°C.

As a control, lidocaine base liposomes containing the same amounts of egg phosphatidyl choline, cholesterol, and drug (5% lidocaine base, w/w) as mentioned earlier were prepared using a film-dispersing method.8 We also prepared a second control formulation consisting of lidocaine base hydroethanolic solution containing 5% (w/w) lidocaine base and 35% (w/w) anhydrous ethanol.

Back to Top | Article Outline
Characterization of Lidocaine Base Ethosomes
Loading Efficiency

A 50-μL aliquot of ethanol base ethosomes was added to a 10-mL measuring flask, which was subsequently filled with methanol to the calibration tail, followed by sonication for 10 minutes. The amount of lidocaine base in the flask was determined by a high performance liquid chromatography (HPLC) analytic method, and the LE was calculated as:

Equation (Uncited)
Equation (Uncited)
Image Tools

where Wtest is the amount of lidocaine base determined by HPLC and Wtotal is the theoretical amount of lidocaine base in the 50-μL sample.

Back to Top | Article Outline
Encapsulation Effectiveness

Encapsulation efficiency was measured as previously described.9 Briefly, a dialysis bag with a molecular weight cutoff of 8000 to 14,000 Da was precut into 10-cm lengths. One end of each dialysis bag was sealed, and 2-mL lidocaine base ethosomes were added. The other end of each dialysis bag was sealed, and the bags were placed in a beaker containing 250 mL 2% (w/w) anhydrous ethanol and mixed with a magnetic stirrer (Yangyinpu Instrument Ltd., Shanghai, China) at the rate of 60 rpm. The concentration of lidocaine base in the solution outside the bag was analyzed every hour by HPLC, until equilibrium was reached. Encapsulation efficiency was calculated as:

Equation (Uncited)
Equation (Uncited)
Image Tools

where Wfree is the concentration of lidocaine base in the solution outside the bag, and Wtotal is the theoretical concentration of lidocaine base.

Back to Top | Article Outline
Vesicular Size and Range

The vesicular size of lidocaine base ethosomes was determined using a Zetasizer (3000HAS, Malvern Instrument, London, UK) at 25°C ± 1°C. A 2-mL aliquot of lidocaine base ethosomes was added to a glass test tube without dilution for visualization, and the intensity of laser light scattered by samples was detected at a 90° angle with a photomultiplier. The vesicular size range of lidocaine base ethosomes was described by the parameter of polydispersity.

Back to Top | Article Outline
Stability

The stability of lidocaine base ethosomes was evaluated by comparing encapsulation efficiency values determined on days 0 and 60 after ethosomes preparation, the preparations having been sealed in vials at 25°C ± 1°C.

Back to Top | Article Outline
In Vitro Percutaneous Penetration

All experimental procedures involving animals were approved by the Institutional Animal Care and Use Committee of Southern Medical University, Guangzhou, Guangdong, China. Healthy Sprague-Dawley rats, weighing 250 to 300 g, were anesthetized by peritoneal injection of carbrital. The abdominal hairs on each rat were carefully trimmed (<1 mm) with an electric razor, and the abdominal skin was carefully dissected from the underlying connective tissue with a scalpel. The excised skin was placed on aluminum foil. Any adhering fat or subcutaneous tissue was gently removed from the dermal side of the skin.

The in vitro percutaneous penetrating capability of lidocaine base ethosomes was evaluated using Franz-type diffusion cells, with an effective permeability area of 2.92 cm2 and a receptor of 7 mL. The receptor compartment was filled with 7 mL physiologic saline containing 2% (w/w) anhydrous ethanol at 37°C ± 0.5°C, and the solution was constantly stirred by a magnetic stirrer at 300 rpm. Lidocaine base preparations of ethosomes, liposomes, and hydroethanolic solution and their blank preparations (1.5 mL each) were applied onto the epidermal surface of the skin. Samples of 0.4 mL were withdrawn through the sampling port of the diffusion cell at 0.5, 1, 2, 3, 6, 9, and 11 hours after each sampling, and an equal volume of physiologic saline containing 2% anhydrous ethanol was added to the receptor compartment.

Back to Top | Article Outline
HPLC Determination of Lidocaine Base

The amount of lidocaine base in the receptor compartment of Franz cells was determined using a model LC-20A liquid chromatographic system (Shimadzu, Kyoto, Japan). Methanol and 0.0257 M ammonium acetate (70: 30, v/v) were used as the mobile phase and delivered by a pump at 0.8 mL/min. Each 10 µL aliquot of sample was eluted by the mobile phase in a C-8 column (4.6 × 250 mm, 5 μm, Shimadzu) at 30°C and was monitored using a UV detector at a wavelength of 270 nm.

Back to Top | Article Outline
In Vivo Effectiveness

The in vivo effectiveness of lidocaine base ethosomes was evaluated by pinprick tests on guinea pigs. Guinea pig skin has an instinctive response to pinprick, as shown by the appearance of a shivering reflex. Application of local anesthetic prevents this response. Observers were blinded to the treatment of experimental animals.

Guinea pigs weighing 250 to 300 g and with a normal response to pinprick were randomly divided into 4 groups containing 6 pigs each. The hair on the back of each guinea pig was shaved with an electric razor. The remaining fuzz was cleared by a depilatory 24 hours before the assay. Aliquots (200 µL each) of lidocaine base ethosomes, liposomes, and hydroethanolic solution were applied to the skin. The area of skin covered by drugs was 3 cm2. The degree of shivering reflex response induced by acupuncture was recorded after 30, 40, 50, 60, 80, 100, and 120 minutes. The durations of anesthetic of 3 lidocaine base preparations (ethosomes, liposomes, and hydroethanolic solution) were compared. The shivering reflex response of guinea pigs treated with drugs for 1 hour was recorded at 10, 20, 40, 60, 80, 100, and 120 minutes. As a control, we also used the respective blank preparations (no lidocaine base).

Back to Top | Article Outline
In Vivo Cutaneous Irritancy

The potential for skin irritation (erythema and swelling) of lidocaine base ethosomes was evaluated as described.10 Cutaneous irritation by lidocaine base ethosomes was evaluated in male white guinea pigs, which were housed in an air-conditioned room (25°C). The hair on the back of each animal was trimmed 24 hours before the test. The skin on 6 animals was damaged by pinpricks, whereas the skin on 6 other animals was left intact. All animals were treated with 200-μL lidocaine base ethosomes for 24 hours. The skin was scored for erythema and swelling 1, 24, 48, and 72 hours after application. As a negative control, guinea pigs were treated with normal saline. Erythema was scored as 0 to 3, with 0 indicating no erythema, 1 indicating very slight erythema (barely perceptible; light pink in color), 2 indicating well-defined erythema (dark pink in color), and 3 indicating moderate to severe erythema (light red in color). Swelling was scored as 0 to 3, indicating no, light, moderate, and serious swelling, respectively. Skin treated with lidocaine base ethosomes was also examined histopathologically.

Back to Top | Article Outline
Data Analysis

All quantitative data were expressed as mean ± SD and analyzed using SPSS software (version 13.0, SPSS Inc, Chicago, IL). The stability of lidocaine base ethosomes at 0 and 60 days was compared using independent sample t tests; 95% confidence intervals (CIs) were also calculated. Transdermal flux, onset time, and duration of lidocaine base ethosomes, liposomes, and hydroethanolic solution were compared by using repeated-measures analysis of variance. When the spherical assumption was violated, the Greenhouse–Geisser correction was applied. The Bonferroni correction was used in multiple comparisons if the data met the homogeneity of variance; otherwise, we used the Dunnett T3 test. A P value <0.05 was considered statistically significant.

Back to Top | Article Outline

RESULTS

The formulation of lidocaine base ethosomes was determined by the maximum encapsulation efficiency, as described.11 The R values in Table 1 indicate that encapsulation efficiency was affected most by egg phosphatidyl choline (ingredient B), followed by ethanol (ingredient A) and cholesterol (ingredient C). The 5% (w/w) lidocaine base ethosomes were prepared with 5% (w/w) lidocaine base, 5% (w/w) egg phosphatidyl choline, 0.2% (w/w) cholesterol, 35% (w/w) ethanol, and ultrapure water, to yield the maximum encapsulation efficiency.

Table 1
Table 1
Image Tools

The mean LE of 5% (w/w) lidocaine base ethosomes was 95.0% ± 0.06% (n = 6). As determined by the Zetasizer, the mean particle diameter of these ethosomes was 31.33 ± 2.63 nm (n = 6), and their mean polydispersity index was 0.42± 0.21. The mean encapsulation efficiency of lidocaine base ethosomes was 52.96% (95% lower CI, 51.73%). After storage at 25°C ± 1°C for 60 days, the mean encapsulation efficiency was 52.84% (95% lower CI, 52.47%). Equal variance was not assumed (F = 120.060, P < 0.001). The mean encapsulation efficiency at 0 and 60 days did not differ significantly (95% CI, −1.12% to 1.34%; P = 0.833).

The cumulative transdermal penetration profiles of the 3 investigated formulations are shown in Figure 1. The sphericity assumption was violated (Mauchly W = 0.000, P < 0.001), so the Greenhouse–Geisser correction was used to correct the violation (ε = 0.402), resulting in a significant group × time interaction (F = 158, P < 0.001). We found that the percutaneous flux of lidocaine base in vitro differed significantly (F = 121, P < 0.001) among the 3 preparations, being significantly higher from ethosomes than from liposomes (95% corrected CI, 1129–1818 µg/(cm2·h); P < 0.001) and from hydroethanolic solution (95% corrected CI, 1468–2157 µg/(cm2·h); P < 0.001). However, it did not show the significant difference between liposomes and hydroethanolic solution (95% corrected CI, −6.21 to 683 µg/(cm2·h); P = 0.055).

Figure 1
Figure 1
Image Tools

The negative responses of guinea pig in the pinprick test to lidocaine base from ethosomes, liposomes, and hydroethanolic solution are shown in Figure 2. The sphericity assumption was violated (Mauchly W = 0.014, P < 0.001), so the Greenhouse–Geisser correction was used to correct the violation (ε = 0.545), resulting in a significant group × time interaction (F = 2.769, P = 0.019). The negative responses induced by lidocaine base ethosomes were significantly greater than those for lidocaine base liposomes (95% corrected CI, 0.52–2.67 times; P = 0.003) and hydroethanolic solution (95% corrected CI, 1.14–3.27 times; P < 0.001). However, there was no significant difference between lidocaine base liposomes and hydroethanolic solution (95% corrected CI, −0.45 to 1.69 times; P = 0.422).

Figure 2
Figure 2
Image Tools

The anesthetic duration of the 3 lidocaine base formulations is shown in Figure 3. Because the sphericity assumption was violated (Mauchly W = 0.077, P = 0.041), the Greenhouse–Geisser correction was used to correct the violation (ε = 0.515), resulting in a significant group × time interaction (F = 3.538, P = 0.005). The duration of anesthesia was significantly longer for lidocaine base ethosomes than for liposomes (95% corrected CI, 2.25–4.23 times; P < 0.001) and hydroethanolic solution (95% corrected CI, 3.32–5.30 times; P < 0.001) and was significantly longer for lidocaine base liposomes than for hydroethanolic solution (95% corrected CI, 0.08–2.06 times; P = 0.032). We found no evidence of erythema or swelling of the skin. The lack of cutaneous irritation was confirmed by histopathologic examination.

Figure 3
Figure 3
Image Tools
Back to Top | Article Outline

DISCUSSION

Over the past 150 years, percutaneous preparations of anesthetics have evolved from simple solutions to creams, ointments, gels, liposomes, and sophisticated patches.12 These formulations are characterized by slow onset and short duration of action. Ethosomes were shown to act as carriers of drugs13 and to promote their percutaneous penetration.14,15 Among the agents used to date in ethosomal preparations are cannabidiol, azelaic acid, and bacitracin. Ethosomal preparations have many excellent characteristics, including small particle size, good encapsulation efficiency stability, rapid percutaneous penetration, and low irritation,16–18 suggesting that ethosomes could be used as percutaneous carriers of lidocaine base.

Although ethanol can increase membrane fluidity of ethosomes and improve their stability,19 an ethanol concentration >45% (w/w) has been shown to decrease the value of encapsulation efficiency, perhaps because the membrane may leak in the presence of high concentrations of ethanol.20 Thus, ethanol concentrations in ethosomes should be controlled within a certain range. Encapsulation efficiency may also be affected by many other factors, including changes in the proportions of ethosomal ingredients, as shown in the orthogonal test. We found that membrane dialysis was more appropriate than ultracentrifugation in the determination of ethosomal encapsulation efficiency, perhaps because the kinetic energy created during ultracentrifugation could destroy the structure of the ethosomes, leading to leakage of drug from the ethosomal membrane.21

The percutaneous flux of lidocaine base was much higher from ethosomes than from liposomes and hydroethanolic solution. Ethanol may enhance penetration through stratum corneum lipids22 and effectively promote the mobility of the ethosomal membrane. The role of ethanol in percutaneous penetration was confirmed by our in vivo experiments, which showed that the onset time of ethosomes was shorter than that of liposomes containing the same ingredients except for ethanol. In addition, ethosomes can be stored in the skin, making the anesthetic duration of ethosomes longer than that of the other 2 lidocaine base preparations.

Because the structure and function of skin are complex, the results obtained from in vivo experiments may be more accurate than those from in vitro assays. Therefore, the irritation and effectiveness of drugs on skin have been generally evaluated by animal experiments in vivo, despite their subjective interpretation. Objectivity may be enhanced by using a sufficient number of experimental animals, by evaluations performed by ≥2 observers blinded to treatment, and, for skin irritation, by histopathologic examination.

Our results confirm previous findings that the high encapsulation efficiency, stability, and excellent percutaneous penetration of drugs by ethosomes are due to the presence of ethanol. Further research should include the use of other types of phospholipids and short-chain alcohols to prepare ethosomes and to determine whether these ethosomes further enhance percutaneous penetration of drugs. Ethosomes are promising drug carriers for topical administration of local anesthetics, especially when a rapid onset of effect is desired.

Back to Top | Article Outline

DISCLOSURES

Name: Xiaoliang Zhu, PhD.

Contribution: This author helped write the manuscript.

Attestation: Xiaoliang Zhu has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Fuli Li, MM.

Contribution: This author helped write the manuscript.

Attestation: Fuli Li has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Xuebiao Peng, MD.

Contribution: This author helped write the manuscript.

Attestation: Xuebiao Peng has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Kang Zeng, MM.

Contribution: This author helped write the manuscript.

Attestation: Kang Zeng has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

This manuscript was handled by: Steven L. Shafer, MD.

Back to Top | Article Outline

REFERENCES

1. Tadicherla S, Berman B. Percutaneous dermal drug delivery for local pain control. Ther Clin Risk Manag. 2006;2:99–113

2. Touitou E, Dayan N, Bergelson L, Godin B, Eliaz M. Ethosomes - novel vesicular carriers for enhanced delivery: characterization and skin penetration properties. J Control Release. 2000;65:403–18

3. Rao Y, Zheng F, Zhang X, Gao J, Liang W. In vitro percutaneous permeation and skin accumulation of finasteride using vesicular ethosomal carriers. AAPS PharmSciTech. 2008;9:860–5

4. Zhaowu Z, Xiaoli W, Yangde Z, Nianfeng L. Preparation of matrine ethosome, its percutaneous permeation in vitro and anti-inflammatory activity in vivo in rats. J Liposome Res. 2009;19:155–62

5. Chen JG, Liu YF, Gao TW. Preparation and anti-inflammatory activity of triptolide ethosomes in an erythema model. JLiposome Res. 2010;20:297–303

6. Mishra D, Mishra PK, Dabadghao S, Dubey V, Nahar M, Jain NK. Comparative evaluation of hepatitis B surface antigen-loaded elastic liposomes and ethosomes for human dendritic cell uptake and immune response. Nanomedicine. 2010;6:110–8

7. Dubey V, Mishra D, Nahar M, Jain V, Jain NK. Enhanced transdermal delivery of an anti-HIV agent via ethanolic liposomes. Nanomedicine. 2010;6:590–6

8. Fang YP, Tsai YH, Wu PC, Huang YB. Comparison of 5-aminolevulinic acid-encapsulated liposome versus ethosome for skin delivery for photodynamic therapy. Int J Pharm. 2008;356:144–52

9. Dubey V, Mishra D, Jain NK. Melatonin loaded ethanolic liposomes: physicochemical characterization and enhanced transdermal delivery. Eur J Pharm Biopharm. 2007;67:398–405

10. Jain S, Jain N, Bhadra D, Tiwary AK, Jain NK. Transdermal delivery of an analgesic agent using elastic liposomes: preparation, characterization and performance evaluation. Curr Drug Deliv. 2005;2:223–33

11. Dubey V, Mishra D, Dutta T, Nahar M, Saraf DK, Jain NK. Dermal and transdermal delivery of an anti-psoriatic agent via ethanolic liposomes. J Control Release. 2007;123:148–54

12. Pathak P, Nagarsenker M. Formulation and evaluation of lidocaine lipid nanosystems for dermal delivery. AAPS PharmSciTech. 2009;10:985–92

13. Ainbinder D, Paolino D, Fresta M, Touitou E. Drug delivery applications with ethosomes. J Biomed Nanotechnol. 2010;6:558–68

14. Dayan N, Touitou E. Carriers for skin delivery of trihexyphenidyl HCl: ethosomes vs. liposomes. Biomaterials. 2000;21:1879–85

15. Touitou E, Godin B, Dayan N, Weiss C, Piliponsky A, Levi-Schaffer F. Intracellular delivery mediated by an ethosomal carrier. Biomaterials. 2001;22:3053–9

16. Lodzki M, Godin B, Rakou L, Mechoulam R, Gallily R, Touitou E. Cannabidiol-transdermal delivery and anti-inflammatory effect in a murine model. J Control Release. 2003;93:377–87

17. Esposito E, Menegatti E, Cortesi R. Ethosomes and liposomes as topical vehicles for azelaic acid: a preformulation study. JCosmet Sci. 2004;55:253–64

18. Godin B, Touitou E. Mechanism of bacitracin permeation enhancement through the skin and cellular membranes from an ethosomal carrier. J Control Release. 2004;94:365–79

19. Jain S, Tiwary AK, Sapra B, Jain NK. Formulation and evaluation of ethosomes for transdermal delivery of lamivudine. AAPS PharmSciTech. 2007;8:E111

20. Bendas ER, Tadros MI. Enhanced transdermal delivery of salbutamol sulfate via ethosomes. AAPS PharmSciTech. 2007;8:E107

21. López-Pinto JM, González-Rodríguez ML, Rabasco AM. Effect of cholesterol and ethanol on dermal delivery from DPPC liposomes. Int J Pharm. 2005;298:1–12

22. Godin B, Touitou E. Erythromycin ethosomal systems: physicochemical characterization and enhanced antibacterial activity. Curr Drug Deliv. 2005;2:269–75

Cited By:

This article has been cited 1 time(s).

Expert Opinion on Drug Delivery
Strategies for delivering local anesthetics to the skin: focus on liposomes, solid lipid nanoparticles, hydrogels and patches
de Araujo, DR; da Silva, DC; Barbosa, RM; Franz-Montan, M; Cereda, CMS; Padula, C; Santi, P; de Paula, E
Expert Opinion on Drug Delivery, 10(): 1551-1563.
10.1517/17425247.2013.828031
CrossRef
Back to Top | Article Outline

© 2013 International Anesthesia Research Society

Login

Become a Society Member