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Author(s): J.J. Escobar-Chávez et al.Article title: Article no: LPDT 458999

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Introduction

It was more than four decades ago when the first Surgeon General’s Report on Smoking and Health provided irrefu-table evidence that smoking causes cancer and other diseases.[1] Nowadays, the smoking of tobacco remains the single most preventable cause of death in the world, being responsible for the death of one in 10 adults annually.[2] Despite success on both, public health and legislative fronts,[3] hundreds of millions of smokers suffer from the consequences of their habit. Different studies

have suggested that the cumulative risks of death due to cardiovascular and lung diseases can be drastically reduced if smokers abandon their habit, even if late in life.[4,5] In this way, smoking cessation is a means to reduc-ing health risks and to improving quality of life.

Nicotine, the primary component of tobacco, is responsible for reward and reinforcement and the effects of withdrawal of tobacco consumption.[6–8] Nicotine replacement products are first-line treatments for nicotine dependence, having been approved by the U.S. Federal Drug Administration (FDA) and the European

Pharmaceutical Development and TechnologyPharmaceutical Development and Technology, 2010; 00(00): 000–000

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Address for Correspondence: Dr José Juan Escobar-Chávez, PhD, Facultad de Estudios Superiores Cuautitlán-Universidad Nacional Autónoma de México, Química Analítica, Av 1o. de Mayo s/n, Cuautitlán Izcalli, 54704 Mexico. Email: josejuanescobarchavez@gmail.com

27 September 2009

18 November 2009

18 December 2009

1083-7450

1097-9867

© 2010 Informa UK Ltd

10.3109/10837450903584902

R E S E A R C H A R T I C L E

Transdermal nortriptyline hydrocloride patch formulated within a chitosan matrix intended to be used for smoking cessation

José Juan Escobar-Chávez1,2, Virginia Merino1, Octavio Díez-Sales1, Amparo Nácher-Alonso1, Adriana Ganem-Quintanar2, Marina Herráez1, and Matilde Merino-Sanjuán1

1Departamento de Farmacia y Tecnología Farmacéutica, Universidad de Valencia, Av. Vicente Andrés Estellés s/n, Burjassot, Valencia, Spain, and 2División de Estudios de Posgrado (Tecnología Farmacéutica), Facultad de Estudios Superiores Cuautitlán-Universidad Nacional Autónoma de México, Cuautitlán Izcalli, Estado de México, México

AbstractObjective: The aim of this study was to prepare and characterize both physically and biopharmaceutically, a nortriptyline hydrochloride (NTP-HCl) patch formulated in chitosan.

Methods: 16 g of each chitosan patch formulation (I, II and III, see Table 1) was poured onto rectangular glass plates (64 cm2) at a height of 1 mm and dried for 24 h at room temperature. In order to characterize the chitosan patches, polarized microscopy, in vitro skin permeation studies by passive diffusion and ion-tophoresis and rheological and bioadhesion studies were performed.

Results: Polarized microscopy revealed the absence of aggregates and crystal forms of NTP-HCl in all transder-mal patches after 30 days of storage. The rheological behavior of Patches I, II and III was predominantly elastic. The low level of adhesion of Patch III (containing PF-127 + 1-dodecanol) could be a result of the interactions between chitosan and PF-127 in the presence of 1-dodecanol. Patches I and II had approximately the same value of adhesion (≈ 60 mN.mm). The transdermal patch with chitosan, PF-127 and 1-dodecanol (Patch III) provided a reasonable flux of NTP-HCl across the skin compared with Patches I and II. Iontophoresis applied to the patches did not increase the penetration of NTP-HCl across the skin.

Conclusions: The data suggest that Patch III is suitable for use in clinical practice pending further studies.

Keywords: Nortriptyline hydrochloride; skin; transdermal patch; smoking cessation; iontophoresis; PF-127; passive diffusion

PHD

458999

(Received 27 September 2009; revised 18 November 2009; accepted 18 December 2009)

ISSN 1083-7450 print/ISSN 1097-9867 online © 2010 Informa UK LtdDOI: 10.3109/10837450903584902 http://www.informahealthcare.com/phd

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Medicines Agency (EMEA). Currently, there are many nicotine delivery devices available on the market – these include gum, the transdermal patch, the vapour inhaler, the nasal spray, the lozenge, and the sublingual tablet.[9] These treatments aid cessation by delivering nicotine without exposing the subject to the carcinogenic com-pounds that are present in cigarette smoke. These nico-tine replacement products have afforded varying degrees of success in long-term smoking cessation,[10,11] which has been reviewed extensively elsewhere.[12,13]

The only non-nicotine medications for smoking cessa-tion approved by the FDA and the EMEA are the antide-pressant bupropion (Zyban, Wellbutrin) and the nicotinic receptor partial antagonist varenicline (Chantix). In addition to these therapies, other pharmacological com-pounds are also being developed as adjuncts to tools for smoking cessation. New approaches, including nico-tine vaccines, rimonabant and nortriptyline, are under development.[14]

Nortriptyline is a noradrenergic tricyclic anti-depressant that inhibits serotonin and noradrenalin reuptake. Its effi-cacy in smoking cessation has been demonstrated,[15–18] and seems to work by reducing withdrawal symptoms. In four studies, odds ratios for smoking cessation using nortriptyline alone ranged from 1.2–5.5.[16,18,19] The smok-ing cessation rates achieved with nortriptyline are com-parable to those achieved with bupropion.[20]

One of the most important reasons for the failure of treatment is the number of drugs that the patient has to ingest in one single day, which often causes patients to abandon the therapy. One possible approach to tackling this problem is to develop transdermal formulations that administer the necessary drugs over several days in a more convenient manner. Accordingly, a transdermal formulation for nortriptyline would doubtlessly help to improve patient compliance.

In a previous study we tested the effect of different chemical enhancers on NTP-HCl transdermal absorp-tion in order to select the most effective one for its incorporation into a transdermal system. Among the enhancers tested we selected 1-dodecanol. The objec-tive of the present work was to prepare and evaluate different transdermal systems containing NTP-HCl and dodecanol.

Materials and methods

Chemicals and materials

Nortriptyline hydrochloride (NTP-HCl), chitosan-medium molecular weight, Pluronic F-127 (PF-127), Silver Chloride 99%, one millimetre diameter silver and platinum wire 99.9% (used for the manufacture of Ag/AgCl electrodes) and HEPES buffer were obtained from Sigma Aldrich

(Spain). Propylene glycol and acetic acid were purchased from Merck (Germany). Acetonitrile, 1-dodecanol and methanol were obtained from Scharlau (Scharlab, Spain), and Poly(ethylene glycol) 400 Monoestearate (PEG 400 ME) was provided by Guinama (Spain). Deionized water (resistivity ≥ 18 M Ωcm−1) purified by a Millipore System (Milli-Q UFplus) was used to prepare the mobile phase for High Performance Liquid Chromatography (HPLC) analysis. The Spectrum molecular filter T-C100 MWCO was obtained from Vertex Technics SL (Spain).

Film preparations

Chitosan solutions were prepared by dissolving the appropriate amount of chitosan in an acetic acid solution (0.1 M). The solution was homogenized (Teflon pestle, 1000 rpm) and left to stand for 24 h at room temperature in order to allow the complete hydration of the polymer. The rest of the ingredients were then added (Table 1) and the preparation gently stirred and sonicated to eliminate air bubbles. The final content of NTP-HCl in the formu-lation was 2% (w/w). The pH of all formulations was adjusted to 5.5. To obtain films, 16 g of each solution was poured onto rectangular glass plates (64 cm2) at a height of 1 mm (Bio-Rad laboratories, Italy) and dried for 24 h at room temperature. The thickness of the films was meas-ured at different locations (center and corners) by means of a micrometer. To assess the uniformity of drug content among the different transdermal chitosan patches, 1 cm2 samples were dissolved in a solution of acetic acid (0.1 M) and analyzed for drug content.

Polarized microscopy

The different NTP-HCl transdermal patches were stored in an aluminum laminate and sealed polyethylene bags for 30 days at 20°C, at a relative humidity (RH) of 65% fol-lowing the guideline of declaration of storage conditions of the Committee for Human Medicinal Products (CHMP) of the European Medicine Agencies (EMEA).[21] Three cir-cular patches of 3.6 cm in diameter were examined for drug crystallization by means of polarized microscopy, using a Microscopic Nikon (Eclipse E800, Japan) with a digital camera DXM1200F and multiple sensor system

Table 1. Composition of the NTP-HCl transdermal patches.

Components

Concentration (%, w/w)

Patch I Patch II Patch III

Chitosan 1 1 1

Propylene glycol 15 15 15

PEG400ME - 5 -

Acetic acid solution 84 74 69

1-dodecanol - 5 5

PF-127 - - 10

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U-III immediately after the manufacturing process and after 30 days storage.

Rheological characterization

A Haake Rheostress 1 rheometer (Thermo Haake, Germany) with data acquisition software (RheoWin 2.94) and a circulator for sample temperature control was employed. The oscillatory tests for transdermal patches were measured with serrated parallel plates (35 mm diameter, 0.1 mm gap) to avoid slippage dur-ing oscillation. Samples were allowed to rest for at least 300 s prior to analysis. All measurements were performed in triplicate at 25°C. To determine the linear viscoelastic range, stress sweeps at 25°C and at a fre-quency of 1 Hz were performed for all systems studied. Frequency sweep tests were carried out for all patches from 0.01–10 Hz, at 10 Pa. The oscillatory rheological parameters used to compare the viscoelastic proper-ties of all the systems were storage modulus (G'), loss modulus (G") and complex viscosity (η*).

Bioadhesive test

The bioadhesion study was carried out using a tensiom-eter (Nima Technology Ltd, DTS 9005 model, UK). One stainless steel plate (L-shape) was fitted into the upper jaw of the instrument and another into the lower jaw so that the two plates were facing each other. Human skin was fixed with glue to the surface of the upper plate, and the transdermal patch was attached to the surface of the lower plate. Distilled water (50 µL) was spread over the surface of the film. The upper jaw was lowered slowly so that the tissue came into contact with the patch (attached to the lower jaw). No external force was applied. The transdermal patch was kept in con-tact with the tissue for 10 min and the upper jaw was slowly moved upward at a speed of 3 mm/min. The total amount of forces involved in the probe withdrawal from the tissue (work of adhesion, W

ad) was then calculated

from the area under the force versus distance curves. This parameter was used to compare the different for-mulations tested. All experiments were performed in triplicate.

In vitro skin permeation studies by passive diffusion

Permeation experiments were performed on Caucasian abdominal skin samples obtained from three randomly assigned female donors aged 38–48 years who had undergone cosmetic surgical procedures in the Hospital Clínico Universitario (Valencia, Spain). Informed con-sent was previously obtained from the patients and their identity was masked to the researchers to guarantee

their anonymity. Excess fatty and connective tissues were removed and the samples (full thickness skin) were stored in a freezer at −40°C for no more than 1 month.

For the passive diffusion experiments the skin mem-branes were placed in Franz-type diffusion cells with an effective area available for diffusion of 0.78 cm2 and a receiver compartment capacity of 6 mL. The full thick-ness skin sample was mounted between the donor and receptor compartment, and the patch was placed on the skin and covered with an occlusive film (3M Scotchpak™ 9733 backing, 3M UK). The receptor compartment was filled with HEPES buffer pH 5.5. The whole assembly was fixed on a magnetic stirrer. The solution of the receptor compartment was continuously stirred using magnetic bars, at 50 rpm. The receptor temperature was maintained at 37°C in order to maintain skin temperature at 32°C, following the guidances of the expert group ECVAM[22] for assessing percutaneous absorption. Skin tempera-ture was confirmed at 32°C prior to patch application by measuring it with an Optris minisight® thermometer. In a previous work in which we studied transdermal absorp-tion of nortriptyline from a solution we had observed that the lag time for steady state diffusion was about 3 h, and when the skin was pretreated with 1-dodecanol the time to reach steady state was about 7 h. For this reason we decided to extend the absorption studies for 32 h. We did not consider adequate to further extend the permeation studies because skin integrity may be compromised after 48 h of diffusion experiments.

Samples were withdrawn at different time intervals over the following 32 h, and analyzed for drug content by HPLC. The cumulative amounts of drug permeated per cm2 of skin were plotted against time, and the equation derived from the application of the Fick’s Second Law to the diffusion process was fitted to the data:

(1)

Q1

6

2 1

t 2

2

2

21

2 2

( )

( )∑

= ⋅ ⋅ ⋅ ⋅ ⋅ −

−−

⋅ − ⋅ ⋅ ⋅=

∞

A K L C Dt

L

nExp

D n t

Lnp

p22

where Q(t) is the quantity of NTP-HCl passing across the membrane and reaching the receptor solution at a given time, t; A is the actual diffusion surface area (0.78 cm2); K is the partition coefficient of the permeant between the membrane and the donor vehicle; L is the diffusion path-way; D is the diffusion coefficient of the permeant in the membrane; and C is the concentration of the permeant in the donor solution.

By fitting the equation to our results we calculated with an estimation of precision t

L, the lag time corresponding

to L2/6D, and the permeability coefficient, Kp = K.D/L. The fitting procedures were carried out by means of

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nonlinear regression using Win Nonlin 5.0.1 (Pharsight corp). The flux values (J) were obtained by employing the expression J = Kp·C

In vitro skin permeation studies with iontophoresis

For iontophoresis, we employed vertical diffusion cells with the donor compartment divided into two chambers.[23] After placing the patch without the occlu-sive layer directly in contact with the human skin, it was covered by a membrane with a pore size of 100 Dalton and isolated from the electrodes. Subsequently, the elec-trodes (Ag/AgCl) were inserted into a sodium chloride (0.12%) solution. The solution of the receptor compart-ment was constantly and continuously stirred at 500 rpm using magnetic bars. A constant current of 0.5 mA cm−2 was administered. Samples from the receptor compart-ment were taken every hour for 8 h. When a steady state is reached, Equation 1 becomes a linear expression (Equation 2), which was used to calculate the flux of NTP-HCl in these assays, since the plot of amounts versus time was clearly linear from the beginning:

Q t( ) [ ]= ⋅ ⋅ ⋅ −A Kp C t tL (2)

Fitting procedures were also carried out using Win Nonlin 5.0.1 (Pharsight corp).

Analytical method

The HPLC method used for the NTP-HCl determination is based on the one proposed by Ghahramani and Lennard (1996).[24] Samples were eluted through a Kromasil 100 C

18 column (5 µm particle size, 4.6 × 150 mm) (Scharlab,

Spain) at a flow rate of 1 mL/min. The mobile phase con-sisted of 50% of acetonitrile HPLC grade and 50% of 25 mM phosphate-buffer solution pH 3.0. NTP-HCl was detected at 240 nm. Retention time was approximately 2.5 min. The HPLC equipment consisted of an isocratic pump (Waters 1515), a spectrophotometric detector (Waters 2487) and Breeze® software (Waters, Barcelona, Spain).

The analytical method validation was based on accu-racy and precision. Accuracy, defined as the relative error of known concentration solutions, was within ±10%, and thus the method was considered acceptable. Precision of the method was tested as within-day and between day reproducibilities of the assay. Precision of the method was expressed as the residual standard deviation of rep-licate measurements, which was lower than 10% in all the concentrations analyzed.[25]

Results and discussion

In a previous report Merino et al.,[26] tested 1-dodecanol, Span® 20, Azone®, R-(+)- limonene, isopropyl myristate

and propylene glycol as possible enhancers of NTP-HCl transdermal permeation. The highest enhancement ratio of flux (approximately 9) was obtained with 1-dodecanol. For this reason, we decided to incorporate it and NTP-HCl into a transdermal patch based on chitosan. The selection of chitosan was based on its bioadhesive properties.[27] Since 1-dodecanol and chitosan cannot be directly com-bined we have tested two different substances – Pluronic® F-127 and PEG 400 ME – each of which was used at the minimum concentration to interpose 1-dodecanol in the transdermal system. We have selected propylen glycol as a plasticizer because previous studies,[26] have demonstrated that this compound enhances transdermal absorption of nortriptyline hydrochloride.

All the combinations generated homogeneous and flexible films. All films were easily removed from the cast plate and no pores or cracks were detected. The ana-lyzed patch samples of 1 cm2 to determine nortriptyline hydrochloride recovery showed a good uniformity of drug content in all three formulations. Drug recovery was 108.6 ± 4.6, 104.0 ± 7.4 and 98.2 ± 6.7% for patch I, II and III, respectively (n = 12). These results indicate that the process employed to prepare the patches was adequate and did not cause aggregation of the drug at localized points. Thickness of films (mm) varied between 0.17 ± 0.01 (Patch I), 0.19 ± 0.01 (Patch II) and 0.22 ± 0.01 (Patch III), values which confirm the homogeneous dis-tribution of the dispersions in the plates used as molds.

All the transdermal NTP-HCl Patches (I, II and III) were shown to be free of crystals directly after manufac-turing (Figure 1) and after 30 days of storage (Figure 2) according to polarized microscopy, which is the method of choice for detecting crystals within matrix transdermal drug delivery systems.[28] These findings suggest that NTP-

A

C D

B

Figure 1. Microscopic view of (A) NTP-HCl crystals, (B) Patch I, (C) Patch II (PEG400ME+1-dodecanol), and (D) Patch III (PF-127 + 1-dodecanol) following manufacturing process. (See colour version of this figure online at www.informahealthcare.com/phd)

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HCl possesses a good physical stability in the chitosan matrix patch and that the use of crystallization inhibitors is not necessary.

The viscoelastic properties of trandermal patches were studied to analyze the influence of the different compounds in the formulations obtained. Figure 3 shows storage modulus (G') and loss modulus (G") as a function of angular frequency (ω, rad/s) for the all systems evalu-ated. We observed the behavior to be predominantly more elastic than viscous because G' was greater than G" in the entire frequency interval studied. This behavior is typical of a three-dimensional network. Therefore, the loss tangent (tan δ = G"/G') was less than 1 for all cases. The prevalence of an elastic nature over a viscous nature

can be considered an advantage for the development of bioadhesive systems.[29]

For all systems studied complex viscosity η* = f(ω) decreases as the frequency increases. The complex viscosity values obtained for transdermal systems were fitted to power law functions

* A B= ω− (3)

where the power index, B, was close to 1 (straight lines in Figure 4) for Patches I and II but not for Patch III (B = 0.73). The storage modulus G' was much greater than the loss modulus G" (therefore η* is almost G'/ω), which is a behavior characteristic of structured systems.[30] This confirms that a matrix structure has been formed, as explained above. Nevertheless, Patch III was not as elastic as Patch I and II.

On the order hand, the complex viscosity η* decreased in the presence of PEG 400 ME, PF-127 and 1-dodecanol (Figure 4). Patch III showed a lower complex viscosity than Patch I and II. This could be due to the presence of PF-127, as it is known that the addition of alcohol (i.e. 1-dodecanol) to aqueous solutions of PF-127 decreases the rigidity of the system and increases the transition temperature, causing a reduction in both viscosity values and hydrophobic interactions.[31]

In order to determine the bioadhesion of the transder-mal NTP-HCl patches, the work of adhesion was also determined, and gave bioadhesion values ranging between 36 and 60 mN/mm (Figure 5). The low value of the work of adhesion of patch III (containing PF-127 + 1- dodecanol) may be a result of the interaction of the chitosan with surface-active polyoxyethylene-polyoxypropylene- polyoxyethylene (POE-POP-POE, Pluronic) block copolymer PF-127 in the presence of 1-dodecanol. This phenomenon

B

C

A

Figure 2. Microscopic view of NTP-HCl patches after storage: (A) Patch I, (B) Patch II (PEG400ME+1-dodecanol) and (C) Patch III (PF-127 + 1-dodecanol). (See colour version of this figure online at www.informahealthcare.com/phd)

105

104

103

102

0.01 0.1G′ (

stor

age

mod

ulus

) and

G″

(loss

mod

ulus

)

1Angular frequency (ω, rad. S−1)

10 100

Figure 3. Frequency dependence of storage modulus (G', filled sym-

bols) and loss modulus (G", open symbols): Patch I (-•- , -°-), Patch II (-- , --) and Patch III (-- , -•-).

105

Patch IPatch IIPatch III104

103

102

101

0.01 0.1

Com

plex

vis

cosi

ty (P

a s)

1

Angular frequency (ω, rad. S−1)

10 100

Figure 4. Frequency dependence of complex viscosity (n*) for the three transdermal patches.

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produces a reduction in both bioadhesive properties and complex viscosity values.

The permeation profiles obtained from the different patches are shown in Figure 6. In order to compare the transdermal fluxes (J) of each of the formulated Patches (I, II and III) for the passive diffusion studies, an analysis of variance (ANOVA) and Tukey’s test were performed. Significant differences between the value fluxes (F = 6.52; F

0.05/2; 2,21 = 3.46) of the three Patches (I, II and III) were

detected. The patches showed NTP-HCl flux in the fol-lowing order: Patch III > Patch II > Patch I, as depicted in Figure 6 and Table 2.

The patch formulated with PF-127 + 1-dodecanol showed the highest flux value for the passive diffusion studies (43.6 ± 18.6 μg/h/cm2); it was about 18 times higher than that of Patch I (2.36 ± 1.28 ug/h/cm2), and four times higher than the patch with PEG400ME + 1-dodecanol (10.46 ± 3.42 ug/h/cm2). These results are in accordance with different permeation studies of drugs formulated with enhancers and PF-127.[28,32–39] Although PF-127 is not a skin permeation enhancer, its combination with skin penetration enhancers promotes the delivery across the skin of drugs such as arginine-vasopressin,[28] insulin[35] and sodium naproxen,[36–38] suggesting that a synergistic effect takes place between 1-dodecanol and PF-127 in Patch III. Though the lag time (about 30 h) is a limitation of these systems, it does not constitute a serious problem, as treatment is long term. The permeability coefficient (Kp) of NTP-HCl in patch III was 6.05·10−7 cm/sec, which is approximately ten times higher than that obtained by Melero et al.[40] with a transdermal patch consisting of an (hydroxypro-pyl)methyl-cellulose matrix in which polisorbate 80 and oleic acid were used as enhancers. With our transdermal system we have improved the NTP-HCl transdermal flux.

Given that nortriptyline clearance in humans is 36 L/h[41] and that a plasma level of less than 50 ng/mL[42]

(slightly lower than that required in the treatment of depression) is necessary for an optimal response, a maximal entrance of 1.8 mg/h would be required if the patch were to be effective. In the case of patch III that could be accomplished with a reasonable size (around 40 cm2).

Iontophoresis constitutes an important means of improving the transport of ionized species (cati-ons) across the skin,[23,43–45] and for this reason it was applied to the patches. Iontophoretic experiments were intended principally to reduce the lag time of diffusion. The flux of NTP-HCl from Patch II was slightly higher than the passive diffusion during the 8 hours that the experiment lasted. Unfortunately, the flux values for Patches, II and III were only 2.8 ± 0.7 µg/h/cm2 and 2.1 ± 1.3 µg/h/cm2, respectively (Table 2). Iontophoresis applied to a solution of the molecule acted synergis-tically with the chemical enhancers;[26] nevertheless, applied to the patches, iontophoresis does not repre-sent an effective alternative to reducing the lag time of transdermal absorption. The statistical comparison (one-way ANOVA) of the data, which was followed by the Tukey’s test, confirmed no significant differences between the flux values of patches II and III when iontophoresis was used (F = 0.88; F

0.05/2; 1,6 = 5.98). These

fluxes were of the same magnitude as those obtained during the first 8 h of the experiment, when no current was applied to the patches.

80

Patch I Patch II Patch III

60

40

20

0

60 mN .mm 59.9 mN .mm

Wor

k of

adh

esio

n (m

N .m

m)

36 mN .mm

Figure 5. Effect of human skin on work of adhesion (mN.mm) for the three different films (n = 3).

500

Patch IPatch IIPatch III

400

300

200

100

00 10 20

NTP

-HC

I Acc

umul

ated

am

ount

(µg/

cm2 )

Time (hours)30 40

Figure 6. Permeation profiles of NTP-HCl for the three transdermal patches (mean ± SD).

Table 2. Permeation data for NTP-HCl in respect to passive diffusion and iontophoresis studies across human skin.

Passive diffusion Iontophoresis

J(µg/cm2/h) tL (h) J(µg/cm2/h)

Patch I 2.36 ± 1.28 35 ± 9 -

Patch II 10.46 ± 3.42 25 ± 5 2.8 ± 0.7

Patch III 43.6 ± 18.6 31 ± 5 2.1 ± 1.3

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Conclusions

Crystallization was not observed in the patches after storage and NTP-HCl was homogeneously distributed throughout the chitosan matrix. The addition of chemi-cal enhancers to the patches increased the skin per-meation of NTP-HCl. According to our results, Patch III, containing PF-127 + 1-dodecanol, was the least bioad-hesive and presented the lowest complex viscosity val-ues. The low value of the work of adhesion of patch III may be a result of the interaction of the chitosan with surface-active block copolymer (PF-127) in the pres-ence of 1-dodecanol. The lower complex viscosity value appears to be responsible for the higher rate of NTP-HCl release. In this way, of the three patches, this one pro-vides the highest NTP-HCl transdermal flux. However, further research about skin irritancy and tolerance is required to consider the patches adequate However further research about skin irritancy and tolerance is required to consider the patches adequate. The formula-tion of nortriptyline within a transdermal system seems to offer great potential as a highly effective treatment for tobacco addiction.

Acknowledgments

The authors wish to thank Conselleria d’Empresa, Universitat i Ciència (Generalitat Valenciana) for their financial support (GV06/163). José Juan Escobar-Chávez wishes to acknowledge the PROFIP/UNAM grant of which he was a recipient and PAPIIT 209709. The authors also thank Pharsight Corp for granting the academic license of Win Nonlin 5.0.1.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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1. Accessed from the website: http://www.cdc.gov/Tobacco/sgr/sgr_1964/sgr64.htm

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