Strategies for meloxicam delivery to and across the skin: a review

Figures & data

Figure 1. Structure of meloxicam.

Table 1. MX approved by US FDA, PMDA and CFDA^a.

Drug name	Strengths	Dosage form/Route	Companies^b	Approving authorities
Meloxicam	7.5 and 15 mg	Tablet; Oral	Apotex INC, Carlsbad, Breckenridge Pharm, Zydus Pharms USA, Mylan, Roxane, Unichem, Strides Pharma, Cipla LTD, etc.	US FDA
Mobic	7.5 and 15 mg	Tablet; Oral	Boehringer Ingelheim	US FDA
Mobic	7.5 mg: 5 ml	Suspension; Oral	Boehringer Ingelheim	US FDA
Vivlodex	5 and 10 mg	Capsule; Oral	Iroko Pharms LLC	US FDA
Meloxicam tablets	5 and 10 mg	Orally disintegrating  tablets; Oral	Nippon Zoki	PMDA
Meloxicam tablets	5 and 10 mg	Tablet; Oral	Kyowa chemical industry, Kaken Pharma, Kokando, Chemiphar group, Sawai Pharma, Teva Pharma, Takata Seiyaku, etc.	PMDA
Meloxicam tablets	7.5 mg	Tablet; Oral	Xiuzheng Pharma, Qilu Pharma, Simcere Pharma, Yangtze river Pharma, Shanghai Boehringer Ingelheim, etc.	CFDA
Meloxicam dispersible tablets	7.5 mg	Dispersible tablet; Oral	Hainan quanxing Pharma and Jiangsu yabang Pharma	CFDA
Meloxicam gel	50 mg	Gel; Topical	Jiangsu jibeier Pharma	CFDA
Meloxicam granules	7.5 mg	Granule; Oral	Hainan selection Pharma	CFDA
Meloxicam capsules	7.5 mg	Capsule; Oral	Xiuzheng Pharma, Simcere Pharma, Shandong xinhua Pharma, Sichuan kelun Pharma and Yaopharm	CFDA
Meloxicam injection	1.5 ml: 15 mg	Injectable; Injection	Shanghai Boehringer Ingelheim	CFDA

^aThis list includes MX approved by the US Food and Drug Administration (US FDA), Japan Pharmaceuticals and Medical Devices Agency (PMDA) and China Food and Drug Administration (CFDA).

^b Only the first five approved product manufacturers are shown.

Figure 2. Cumulative number of publications on skin delivery of MX. The number of publications was determined by searching the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed/) on 16 November 2015.

Table 2. Physicochemical properties of idea drug for skin delivery and MX^a.

Items	Ideal candidate	MX	Fit or not
Aqueous solubility	>1 mg/ml	7.15 mg/L at 25 °C	Not
Lipophilicity	1 < Log P < 3	Log P = 3.54	Not
Molecular weight	<500 Da	351.4 Da	Fit
Melting point	<200 °C	254 °C (decomposes)	Not
Dose deliverable	<10 mg/day	7.5-15 mg/day	Fit

^aData were collected from the website: http://pubchem.ncbi.nlm.nih.gov/compound/54677470#section=Top.

Figure 3. Pie chart of the proportion of approaches applied on skin delivery of MX.

Table 3. Summary of the key findings of studies involving in vitro skin delivery of MX.

Compound	Delivery system	Drug loading	Skin model	Optimal flux or cumulative amount	Key findings	Reference
MX potassium	Mesomorphic phases	50 mg (1 g, 5%)	Rat abdominal skin	38.42 μg/cm^2/h	The permeation rate was significantly increased on using mesomorphic phases as a vehicle.	(Huang et al., 2011)
MX ion-pairing	Suspension	280.63 mg (2.5 ml, 112.25 mg/ml)	Rat abdominal skin	19.54 μg/cm^2/h	The cumulative permeation was markedly increased in the presence of a counter ion and chemical enhancers	(Zhang et al., 2009)
MX	Solution	12.4 mg (1 ml, 12.4 mg/ml)	Rat skin	407.65 μg/cm^2/h	5% menthol performed best among a series of terpenes as enhancers.	(Chang et al., 2007b)
MX	Gels	90 mg (3 g, 3%)	Rat skin	339.81 μg/cm^2/h	Gels consisted of 12% azone, 12% SDS and 6% menthol obtained the highest penetration rate.	(Chang et al., 2006)
MX	Nanoemulsion based gel(NE gel)	11.79 mg (250 mg, 4.72%)	Rat abdominal skin	6.41 μg/cm^2/h	Percutaneous absorption studies demonstrated a 1.85-fold higher permeation of MX from NE gel, than the drug solution.	(Khurana et al., 2013b)
MX	Nanostructured lipid carriers gels	11.79 mg (250 mg, 4.72%)	Rat abdominal skin	7.05 μg/cm^2/h	MX- nanostructured lipid carriers based gel demonstrated sustained release and enhanced the skin permeation.	(Khurana et al., 2013a)
MX	Niosomal hydrogels	2.5 mg	Rat skin	69.38 μg/cm^2/h	Niosomal poloxamer-407 gel showed the superior drug release over the other formulations.	(El-Badry et al., 2014)
MX	Nanoethosomes	1 ml	Rat skin	10.42 μg/cm^2/h	Nanoethosomes proved to be significantly superior with an enhancement ratio of 3.77 when compared to rigid liposomes.	(Ahad et al., 2014)
MX	Microemulsions	7.5 mg (2 g, 0.375%)	Rat abdominal skin	5.40 μg/cm^2/h	The optimum formulation with the highest skin permeation rate consisted of 0.375% MX, 5% IPM, 50% Tween 85/ethanol (1:1) and water.	(Yuan et al., 2006)
MX	Nanoemulsion	0.75 mg (100 μl,7.5 mg/ml)	Rat abdominal skin	10.10 μg/cm^2/h	The permeated amount of MX from ultra-fine selfnanoemulsifying drug delivery system was increased up to 11.89-fold.	(Badran et al., 2014)
MX/Ethanolamine  salt	Suspension	300 μl (saturated solution with excess amount of MX)	Hairless mouse skin	23.57 μg/cm^2/h	MX/Ethanolamine Salt had greater solubilities and permeation rates than MX alone in various vehicles.	(Ki & Choi, 2007)
MX	Freeze-dried solid dispersions	7.15 mg (3 ml,2.38 mg/ml)	Hairless mouse skin	82.04 μg/cm^2/h	The permeation rate of MX was significantly increased in the case of solid dispersions.	(El-Badry and Fathy, 2006)
MX	Menthosomes	1.9 mg (3 ml, 634.8 μg/ml)	Hairless mouse skin	0.31 μg/cm^2/h	The difference in physicochemical characteristics affected the skin permeability, and menthosomes showed higher flux of MX than others.	(Duangjit et al., 2014a)
MX	Patch	1.35 mg (2.25 cm^2, 0.6 mg/cm^2)	Hairless mouse skin	350 μg/cm^2(24h)	The formulation composed of diisopropanolamine as cosolvent and polyoxyethylene cetylether as enhancer performed best with the highest skin permeation of MX	(Ah et al., 2010)
MX sodium  or potassium	Solution	8.79 mg (2 ml,12.5 mM)	Human cadaver skinRat skin	29.07 μg/cm^2/ h47.05 μg/cm^2/h	Iontophoresis and the combination protocol enhanced the skin permeation of MX salts.	(Ren-Jiunn Wang, 2008)
MX	Gels	1.5 mg (0.5 g, 0.3%)	Human cadaverSkin	2.43 μg/cm^2/h	The gel consisting of 2.5% Klucel, propylene glycol, ethanol, and water (1:1:1) showed superior permeability properties.	(Jantharaprapap & Stagni, 2007)
MX	Transfersomes	1.54 mg (3 ml, 514.41 μg/ml)	Shed snake skin	2.2 μg/cm^2/h	Transfersomes provided 8.8-fold and 22-fold greater MX skin permeation than conventional liposomes and MX suspensions.	(Duangjit et al., 2013)

Huang CT, Tsai CH, Tsou HY, et al. (2011). Formulation optimization of transdermal meloxicam potassium-loaded mesomorphic phases containing ethanol, oleic acid and mixture surfactant using the statistical experimental design methodology. J Microencapsul 28:508–14

 PubMed Web of Science ®Google Scholar

Zhang JY, Fang L, Tan Z, et al. (2009). Influence of ion-pairing and chemical enhancers on the transdermal delivery of meloxicam. Drug Dev Ind Pharm 35:663–70

 PubMed Web of Science ®Google Scholar

Chang JS, Tsai YH, Wu PC, et al. (2007b). The effect of mixed-solvent and terpenes on percutaneous absorption of meloxicam gel. Drug Dev Ind Pharm 33:984–9

 PubMed Web of Science ®Google Scholar

Chang J, Wu P, Huang Y, et al. (2006). In-vitro evaluation of meloxicam permeation using response surface methodology. J Food Drug Anal 14:236--41

 Web of Science ®Google Scholar

Khurana S, Jain NK, Bedi PM. (2013b). Development and characterization of a novel controlled release drug delivery system based on nanostructured lipid carriers gel for meloxicam. Life Sci 93:763–72

 PubMed Web of Science ®Google Scholar

Khurana S, Bedi P, Jain N. (2013a). Preparation and evaluation of solid lipid nanoparticles based nanogel for dermal delivery of meloxicam. Chem Phys Lipids 175:65–72

 PubMed Web of Science ®Google Scholar

El-Badry M, Fetih G, Fathalla D, et al. (2014). Transdermal delivery of meloxicam using niosomal hydrogels: in vitro and pharmacodynamic evaluation. Pharm Dev Technol 20:820–6

 PubMed Web of Science ®Google Scholar

Ahad A, Raish M, Al-Mohizea AM, et al. (2014). Enhanced anti-inflammatory activity of carbopol loaded meloxicam nanoethosomes gel. Int J Biol Macromol 67:99–104

 PubMed Web of Science ®Google Scholar

Yuan Y, Li SM, Mo FK, et al. (2006). Investigation of microemulsion system for transdermal delivery of meloxicam. Int J Pharm 321:117–23

 PubMed Web of Science ®Google Scholar

Badran MM, Taha EI, Tayel MM, et al. (2014). Ultra-fine self nanoemulsifying drug delivery system for transdermal delivery of meloxicam: dependency on the type of surfactants. J Mol Liq 190:16–22

 Web of Science ®Google Scholar

Ki HM, Choi HK. (2007). The effect of meloxicam/ethanolamine salt formation on percutaneous absorption of meloxicam. Arch Pharm Res 30:215–21

 PubMed Web of Science ®Google Scholar

El-Badry M, Fathy M. (2006). Enhancement of the dissolution and permeation rates of meloxicam by formation of its freeze-dried solid dispersions in polyvinylpyrrolidone K-30. Drug Dev Ind Pharm 32:141–50

 PubMed Web of Science ®Google Scholar

Duangjit S, Obata Y, Sano H, et al. (2014a). Comparative study of novel ultradeformable liposomes: menthosomes, transfersomes and liposomes for enhancing skin permeation of meloxicam. Biol Pharm Bull 37:239–47

 PubMed Web of Science ®Google Scholar

Ah YC, Choi JK, Choi YK, et al. (2010). A novel transdermal patch incorporating meloxicam: in vitro and in vivo characterization. Int J Pharm 385:12–19

 PubMed Web of Science ®Google Scholar

Ren-Jiunn W, Pao-Chu W, Huang Y-B, Yi-Hung T. (2008). The effects of iontophoresis and electroporation on transdermal delivery of meloxicam salts evaluated in vitro and in vivo. J Food Drug Anal 16:41–8

 Web of Science ®Google Scholar

Jantharaprapap R, Stagni G. (2007). Effects of penetration enhancers on in vitro permeability of meloxicam gels. Int J Pharm 343:26–33

 PubMed Web of Science ®Google Scholar

Duangjit S, Opanasopit P, Rojanarata T, et al. (2013). Evaluation of meloxicam-loaded cationic transfersomes as transdermal drug delivery carriers. AAPS PharmSciTech 14:133–40

 PubMed Web of Science ®Google Scholar