Pharmaceutical Development and Technology, 2010; 15(3): 296–304

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

Eudragit-based transdermal delivery system of pentazocine: Physico-chemical, in vitro and in vivo evaluations

Ashok R. Chandak1,2 and Priya Ranjan Prasad Verma 2

1Alembic Research Centre Alembic Road, Vadodara and 2Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi, India

Address for Correspondence: Priya Ranjan Prasad Verma, MPharm, PhD, Professor (Pharmaceutics), Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi - 835215, India. E-mail: prpverma275730@yahoo.com

(Received 17 May 2009; revised 29 June 2009; accepted 14 July 2009)

Introduction

Pentazocine (PTZ), a benzomorphan derivative, is an opioid analgesic used for the relief of moderate to severe pain. It is considered to be a partial agonist or weak antagonist at the µ-receptor and a -receptor agonist.[1,2] Agonist/antagonist opiates, due to their ceiling effects and a low-flexibility dosing regimen, face many problems for administration in conventional dosage forms. Oral administration of PTZ has the disadvantage of low bioa-vailability (about 18–22%) due to the extensive first-pass metabolism. In addition, PTZ has a short half-life of 2–4 h and requires frequent dosing in order to maintain opti-mal therapeutic concentration.[1–3] Transdermal delivery is being extensively investigated as a viable alternative to deliver the drug with improved bioavailability. It offers many advantages such as elimination of first-pass effect,

sustained drug action, reduced dose, and frequency of dosing, self-administration and easy termination or interruption of treatment when necessary.[4–6]

The present study is aimed at the design and development of a matrix-dispersion-type transdermal drug delivery system for PTZ. Low molecular weight (285.4 g/mol), suitable pKa: 8.5, 10, log P (octanol/pH 7.4): 2.0, extensive oral first-pass metabolism and short biological half life strongly provide a rationale to develop a transdermal delivery system of PTZ.[3] Polymers play an important role in the design of such a delivery system.[7] Transdermal delivery for PTZ was designed and developed using mixed grades and ratios of rate controlling polymers; Eudragit RL100 and RS100, Eudragit RLPO and RSPO, Eudragit RLPM and RSPM, with a plasticizer, di-n-butylphthalate. Eudragit RL and RS, referred to as ammoniomethacrylate copolymers in

ISSN 1083-7450 print/ISSN 1097-9867 online © 2010 Informa UK LtdDOI: 10.3109/10837450903188501

AbstractThe present study was aimed to develop a matrix-type transdermal formulation of pentazocine using mixed polymeric grades of Eudragit RL/RS. The possible interaction between drug and polymer used were char-acterized by FTIR, DSC and X-RD. X-RD study indicates a change of state of drug from crystalline to amor-phous in the matrix films prepared. The matrix transdermal films of pentazocine were evaluated for physi-cal parameters and in vitro dissolution characteristic using Cygnus’ sandwich patch holder. Irrespective of the grades of Eudragit polymer used, the thickness and weight per patch were similar. In vitro dissolution study revealed that, with an increase in the proportion of Eudragit RS (slightly permeable) type polymer, dissolution half life (t50%) increases and dissolution rate constant value decreases. Selected formulations were chosen for these pharmacokinetic studies in healthy rabbits. The relevance of difference in the in vitro dissolution rate profile and pharmacokinetic parameters (Cmax, tmax, AUC(s), t1/2, Kel, and MRT) were evaluated statistically. In vitro dissolution profiles (DRC and t50%) and pharmacokinetic parameters showed a signifi-cant difference between test products (P < 0.01). Quantitatively good correlation was found between the percentage of drug absorbed from the transdermal patches and AUC(s).

Keywords: Pentazocine transdermal films; cygnus; sandwich patch holder; eudragit; in vitro and in vivo evaluation

http://www.informahealthcare.com/phd

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Eudragit-based transdermal delivery system of pentazocine 297

the USP/NF, are copolymers synthesized from acrylic acid and methacrylic acid esters, with Eudragit RL hav-ing 10% functional quaternary ammonium groups and Eudragit RS having 5% functional quaternary ammo-nium groups. All these polymers are water insoluble and films prepared from Eudragit RL are freely permeable to water while Eudragit RS films are only slightly permeable to water. These properties make the polymers, in mixed ratios, suitable for the preparation of matrix transdermal (TD) films.

Materials and methods

Materials

Pentazocine was a gift sample from Ranbaxy Research Laboratory, Gurgaon, India. Eudragits (RL100, RS100, RLPO, RSPO, RLPM and RSPM) were gift samples from Rohm Pharma, Germany. ScotchPak™ 1022 release liner and ScotchPak™ 1109 backing membrane were obtained from 3M Drug Delivery Systems, MN, USA. Other solvents and reagents used were of analytical rea-gent grade.

Preparation of pentazocine transdermal films

The transdermal films of PTZ were made by using mixed grades of Eudragits RL100:RS100, RLPO:RSPO and RLPM:RSPM each in the ratios of 100:00, 80:20, 60:40, 50:50, 40:60, 20:80, 00:100. Ten percent w/v polymer solution was made by dissolving the respec-tive amount of polymer in a mixture of methanol and dichloromethane (in the ratio 40:60) as casting solvent. The required amount of drug was dispersed separately in casting solvent. The two were then mixed and di- n- butylphthalate (15% w/w based on polymer weight) was incorporated as plasticizer. All the films were cast on mercury substrate using stainless steel rings in glass Petri plates. Films were cut into small patches containing equivalent of 10 mg of the drug per 3.5 cm2 area. Backing membrane was glued and patches were stored between sheets of wax paper in desiccators.

Thickness, weight variation and content uniformity

The thickness of the films was assessed using an elec-tronic digital instrument (FT-1000, Spectralab, India). The film was placed on iron surface and the probe was placed on the film surface. The apparatus was calibrated with calibration film of 103 ± 3 m (Spectralab, India). Ten randomly selected patches of each formulation were tested for their thickness. The thickness was meas-ured at five separate points of each patch in order to ensure uniform thickness. The patches were subjected to weight variation by individually weighing ten randomly

selected patches. Such determinations were carried out for each formulation.

Assay of each of the 10 randomly selected medicated patches was carried out to determine the drug content. The patches were dissolved in 2 mL of the methanol and the volume was adjusted to 100 mL with 0.1 N HCl. The solution was filtered, suitably diluted and content per film was estimated spectrophotometrically (UV-1700 PharmaSpec, Shimadzu, Japan) at 278.2 nm using standard curve [OD = 0.0074 × conc. + 0.0022 (r = 0.9999; P < 0.001)].

Folding endurance and flatness

This was determined by repeatedly folding of the patches at the same place until it showed a crack or break. The number of times the film could be folded without break-ing/cracking gave the value of folding endurance. Five randomly selected patches of each formulation were tested.

Longitudinal strips from the five randomly selected medicated films (1 × 4 cm2) of each formulation were cut out. The length of each strip was measured, and varia-tions in the length due to non-uniformity of flatness were measured. Flatness was calculated by measuring constriction of strips using the formula:

% constrictionl l

l1001 2

2

where l1 = initial film length; l

2 = final film length.

Percentage constriction was considered to be 100% flatness.

Moisture uptake

Accurately weighed films of each formulation (n = 3) were kept in a desiccator and exposed to an atmosphere of 98% relative humidity (saturated solution of lead nitrate) at room temperature and weighed periodically until the constant weight for the film was obtained. The percentage of moisture uptake was calculated as the dif-ference between final and initial weight with respect to initial weight.

Fourier transform infrared (FTIR) spectroscopic studies

FTIR spectrometer (IR Prestige-21 Shimadzu, Japan), equipped with attenuated total reflectance (ATR) acces-sory, was used to obtain the infrared spectra of drug matrix as well as placebo films. Analysis of pure drug, polymers and physical mixture of drug:polymer (1:1) was carried out using diffuse reflectance spectroscopy (DRS)-FTIR with KBr. All the powder samples were dried under vacuum prior to obtaining any spectra in

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298 A.R. Chandak and P.R.P. Verma

order to remove the influence of residual moisture. For each spectrum, 32 scans were obtained at a resolution of 4 cm−1 from 4000– 600 cm−1.

Differential scanning calorimetric studies

Thermal analysis was carried out using differential scan-ning calorimeter (DSC) (Q10, TA Instruments, Waters Inc., USA) with a liquid nitrogen cooling accessory. The analysis was performed under purge of dry nitrogen gas (50 cc min−1). High purity indium was used to calibrate the heat flow and heat capacity of the instrument. A sample (2.5– 5 mg) was placed in an aluminum crucible cell with the lid firmly crimped to provide an adequate seal. The samples were heated from ambient tempera-ture to 250°C at pre-programmed heating rate of 10°C min−1. All the samples were analyzed in the same man-ner. In the case of the three component systems, the physical mixture of the individual compounds (150 µm) in equal weight ratios, were prepared in glass pestle and mortar.

X-ray diffraction studies

X-ray diffraction (X-RD) patterns of pure drug, placebo films and drug-loaded matrix films were obtained using Rigaku-Miniflex (Regaku, Japan) diffractom-eter. Measurement conditions consisted of target Cu-K radiation anode, voltage 30 kV and current 15 mA. Diffraction patterns were obtained using a step width of 0.02° 2 between 2° and 60° 2 at a rate of 2° per min at ambient temperature.

In vitro dissolution studies

The in vitro dissolution study of each selected transder-mal patch was determined on USP dissolution appa-ratus equipped with a fractional collector (TDT-08L, Electrolab, India). A Cygnus’ sandwich patch holder, a slightly modified form of FDA’s sandwich patch holder was used to ensure patch-to-patch reproducibility of transdermal films.[8–10] The dissolution vessels contained 500 mL of phosphate buffer (pH 6.6) maintained at 32 ± 0.5°C (the skin surface temperature) and the paddle speed was set at 50 rpm. Patch assembly was carefully placed at the bottom of the vessel and was centered using a glass rod. Five mL sample was withdrawn at 1-h time intervals until the completion of drug release. The withdrawn sample was replenished with 5 mL of fresh media. The samples were analyzed at 278.2 nm using UV-visible spectrophotometer (UV-1700 PharmaSpec, Shimadzu, Japan). Three such determinations were carried out for each formulation. The content of pen-tazocine was calculated from the standard curve

[OD = 0.0074 × conc. + 0.0061 (r = 0.9998; P < 0.001)]. The in vitro dissolution profiles, namely, cumulative drug release, dissolution rate constant (K), and dissolution half life (t

50%) were calculated.

Skin irritation study

A skin irritation study was carried out on healthy rab-bits. The dorsal surface of the rabbit was cleared and hair was removed by shaving. The patch was placed over the skin with the help of surgical adhesive tape. They were removed after 48 h and the skin was examined for any untoward reaction.

In vivo studies

The formulations were tested for their bioavailability on six healthy rabbits weighing 1.917 ± 0.098 kg following balanced incomplete block design (BIBD). The protocol for the study in rabbit was approved by the institutional animal ethical committee (Reg. No. 621/02/ac/CPCSEA), Birla Institute of Technology, Mesra, Ranchi, India. The hair of skin area of around 50 cm2 was shaved, cover-ing both sides of the vertebral column of each rabbit, and care was taken to avoid the damage of skin during shaving. The formulation ( 10 mg/3.5 cm2 patch) was applied on the shaved surface 24 h after hair removal. Blood samples were collected from ear vein prior to application of films and then at 1, 2, 4, 6, 8, 24 and 48 h post application of films. Due to the small size of the ani-mal and damage to the ear vein, it was not advisable to withdraw the blood for more than the aforementioned intervals. The withdrawn blood sample were stored in well closed tubes under refrigeration (−20°C) until fur-ther analysis

PTZ was estimated in blood using previously reported spectrophotofluorometric method with some modification.[11] Acquisition of kinetic data and fluorescent measurement were made on a spectrofluor-ophotometer (RF 5301 PC, Shimadzu, Japan) equipped with RF-530XPC computer software. The samples were measured at excitation wavelength (

exc) = 280 nm and

emission wavelength (em

) = 311 nm, in a 10 mm quartz cell at an ambient temperature. The pharmacokinetic parameters were calculated using non-compartmental pharmacokinetics data analysis software, WinNonlin version 5.0.1™.

Statistical evaluations

The relevance of differences in the in vitro dissolution rate profile and pharmacokinetic parameters were evaluated statistically. The data were tested by two-way analysis of variance.

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Results and discussion

Physical properties

A matrix-dispersion-type transdermal drug delivery system containing pentazocine was prepared by using different ratios of mixed polymeric grades of Eudragit. The formulations made were evaluated for their physi-co-chemical characterization and in vitro/in vivo evalu-ations. The thickness, weight and drug content per patch are shown in Table 1. Irrespective of the grades and ratios of Eudragit polymer used, the thickness and weight per patch were similar. The drug content was found within 9.941 and 9. 986 mg per patch with low standard devia-tion indicating uniform distribution of drug in the matrix films prepared using different ratios of Eudragit RL100/RS100, RLPM/RSPM and RLPO/RSPO.

The mixture of Eudragit RL and Eudragit RS has been reported to provide hard films, but in the presence of the plasticizer, these mixed polymers form films with good elasticity. Folding endurance values of matrix films was found within 100 and 150, indicating good strength and elasticity. The endurance values decreased with the increase in Eudragit RS content of the matrix films. The flatness study showed that none of the formulations had the difference in the strip length before and after

longitudinal cut, indicating 100% flatness and thus they could maintain smooth surface when applied on the skin. The results of percentage moisture uptake studies of matrix TD films of PTZ are shown in Figure 1. The per-centage moisture uptake in the formulation was found to be low and ranges from 2.52 ± 0.07 to 5.05 ± 0.16 for Eudragit RL100/RS100 patches, 2.60 ± 0.09 to 5.12 ± 0.17 for Eudragit RLPM/RSPM patches and 2.56 ± 0.08 to 4.98 ± 0.21 for Eudragit RLPO/RSPO patches. The results revealed that moisture uptake was found to decrease with decreasing content of RL (permeable) type polymer in the matrix TD films of PTZ. Low moisture uptake pro-tects the TD films from microbial contaminations and reduces bulkiness.

Drug-polymer interaction studies

Apart from physical characteristics, compatibility between a drug and polymer is a factor in determining the effectiveness of polymeric delivery systems. Herein, to consider compatibility between polymer and drug, we refer to solubility and/or interaction with no alteration in the chemical structure of the polymer or the drug.[12] Because each drug has its own characteristic chemical and physical properties, no delivery vehicle prepared from a particular polymer will serve as universal carrier for all drugs. The possible drug-polymer interaction was studied by FTIR, DSC and X-RD analysis of pure substances, pla-cebo films and PTZ loaded TD matrix films.

DRS-FTIR is a simple and quick technique for obtaining the IR spectrum of powder samples with KBr. The DRS-FTIR spectral analysis of pure PTZ showed the principal peaks at about 1608, 1263, 1238, 1066, and 854 cm−1 confirming the purity of the drug as per established standards.[3] The DRS-FTIR spectrum of physical mixture of Eudragit RLPM/RSPM:PTZ (1:1 ratio) showed the major peaks which correspond to PTZ.

Table 1. Physical characterization of PTZ matrix transdermal patches prepared from mixed polymeric grades of Eudragit RL/RS.

Formulation PTZ Thickness (m)

Weight variation (mg)

Drug content (mg)

RL100:RS100

100:00 228.45 (0.516) 89.164 (0.239) 9.941 (0.041)

80:20 227.98 (0.527) 88.823 (0.221) 9.968 (0.041)

60:40 227.47 (0.516) 88.409 (0.326) 9.950 (0.504)

50:50 226.84 (0.483) 87.553 (0.174) 9.959 (0.031)

40:60 226.42 (0.516) 87.246 (0.133) 9.960 (0.042)

20:80 225.78 (0.516) 86.816 (0.129) 9.957 (0.048)

00:100 225.31 (0.483) 86.082 (0.155) 9.984 (0.038)

RLPM:RSPM

100:00 227.52 (0.527) 86.987 (1.179) 9.968 (0.033)

80:20 227.21 (0.527) 86.447 (0.213) 9.961 (0.027)

60:40 226.63 (0.516) 85.889 (0.141) 9.944 (0.026)

50:50 226.37 (0.527) 85.148 (0.213) 9.986 (0.015)

40:60 225.47 (0.516) 84.266 (0.272) 9.966 (0.017)

20:80 224.72 (0.421) 83.792 (0.212) 9.948 (0.015)

00:100 224.31 (0.483) 83.393 (0.169) 9.976 (0.023)

RLPO:RSPO

100:00 229.54 (0.527) 88.617 (0.208) 9.973 (0.021)

80:20 228.62 (0.516) 87.667 (0.184) 9.962 (0.029)

60:40 227.86 (0.675) 87.079 (0.196) 9.974 (0.015)

50:50 227.33 (0.483) 86.289 (0.175) 9.946 (0.013)

40:60 227.12 (0.527) 85.917 (0.154) 9.952 (0.029)

20:80 226.85 (0.421) 85.653 (0.200) 9.960 (0.034)

00:100 226.24 (0.421) 84.729 (0.171) 9.959 (0.035)

Values in parentheses indicate mean ± SD of 10 determinations.

100 80 60 50 40 20 00

1

2

3

4

5

6 RL100:RS100RLPM:RSPMRLPO:RSPO

Percent of Eudragit RL Content in Matrix Films

Per

cent

Moi

stur

e U

ptak

e

Figure 1. Percentage moisture uptake of pentazocine transdermal films containing different ratios of Eudragit RL and RS polymers.

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It can be inferred that there is no interaction between drug and polymer in physical mixture used, indicating their compatibility (Figure 2).

ATR-FTIR is a quick and non-destructive sampling technique for obtaining the IR spectrum of a mate-rial’s surface. Samples examined by ATR-FTIR generally require minimum, or no sample preparation, but an intimate optimal contact between the sample and the ATR crystal is crucial.[13] The ATR-FTIR spectra in the percentage transmittance mode for the placebo film of Eudragit RLPO/RSPO and drug loaded matrix films are shown in Figure 3. ATR spectra of the placebo film of Eudragit RL/RS produces characteristic band at 1724 cm−1 (C = O stretching), 1383 cm−1 (CH

3-asymmetric bend-

ing), 1143 cm−1 (C–CO–C– stretching) and 1445 cm−1 (CH

2– symmetric bending). In the ATR spectra of drug

loaded matrix films of PTZ-Eudragit RL/RS, principal peaks of PTZ and Eudragit RL/RS polymer have been pre-served. No new peaks were found in the spectra of drug loaded matrix films, which indicates that no interaction is there between drug and polymer. Furthermore, in drug loaded matrix films the intensity of peaks corresponding to drug were reduced, may be due to inhibition of PTZ crystal growth in the matrix films. The above ATR-FTIR spectrum data further confirms that Eudragit RL/RS does not alter the performance characteristics of the drug in the TD system under study.

The thermal analysis of PTZ, pure polymer (Eudragit RL100/RS100, RLPM/RSPM and RLPO/RSPO) and their physical mixture at ratio of 1:1 are shown in Figure 4. The sharp endothermic peak of PTZ appeared at 150.93°C, which corresponds to the drug melting point.[3,14] The appearance of sharp endothermic peak is due to its crystalline nature. In the ternary mixtures of PTZ:Eudragit RL100/RS100, RLPM/RSPM and RLPO/

RSPO the drug melting signal was clearly distinguish-able (Figure 4B, 4C, 4D), where as the pure Eudragit RL/RS (1:1) did not shown any peak in this region (Figure 4E, 4F, 4G). Since no other endothermic event was observed, one can state that no incompatibility was found between drug and polymer used. DSC study indicates that, these polymeric grades are well suited in formulating matrix type patches of PTZ.

The amorphous and crystalline nature of the drug within the TD films was confirmed using X-ray dif-fraction. Crystallinity of compound is indicated by the

2000 1800 1600 1400 1200 800 600

Wavenumber cm–1

% T

RLPM:RSPM

PTZ

RLPM:RSPM/PTZ

1000

Figure 2. DRS-FTIR spectra of pure PTZ, physical mixture with Eudragit RLPM/RSPM, and pure Eudragit RLPM:RSPM (1:1).

2000 1800 1600 1400 1200 800 600

Wavenumber cm–1

% T

RLPO-RSPO

RLPO-RSPO:PTZ

PTZ

RLPM-RSPM:PTZ

RL100-RS100:PTZ

1000

Figure 3. ATR-FTIR spectra of pure pentazocine, matrix films with Eudragit RL100/RS100, RLPM/RSPM and RLPO/RSPO and placebo film of Eudragit RLPO/RSPO.

50 100 150 200 250 Temperature (°C) Universal V4.2E TA

150.93 °C

A

B

C

D

E

F

G

148.14 °C 122.2 J/g

Figure 4. DSC thermograms of pure pentazocine(A), physical mix-ture at 1:1 ratio of pentazocine with RL100/RS100 (B), RLPM/RSPM (C) and RLPO/RSPO (D), and pure polymers RL100/RS100 (E), RLPM/RSPM (F), and RLPO/RSPO (G).

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Eudragit-based transdermal delivery system of pentazocine 301

presence of sharp peaks that were absent in case of amorphous compounds. X-ray diffractogram of pure PTZ, placebo films made of Eudragit RL/RS (1:1) and PTZ loaded matrix films made from Eudragit RL/RS are shown in Figure 5. X-RD pattern of pure PTZ from 2–60° 2 showed numerous sharp peaks, whereas distinctive sharp peaks occurred at approximately 2 angles of 27, 36, 39 and 45°. In contrast, Eudragit RL/RS placebo films exhibited just one broad peak with low intensity at 5–25° 2 that indicates an almost amorphous state of this polymer (Figure 5). This is in conformity with the pre-vious reports.[15] In the Eudragit RL/RS matrix TD films of PTZ the peaks corresponding to pure crystalline PTZ were not observed but similar pattern was observed as that of placebo films. Disappearance of the peaks cor-responding to pure crystalline PTZ indicated that drug was in an amorphous state in the transdermal films (Figure 5). Eudragit polymers were found successful in preventing crystallization of PTZ in transdermal films prepared using the drug-polymer ratio of 1:10 at the end of six months of storage at ambient condition. This is in agreement with the previous reports.[16,17]

In vitro dissolution

From the in vitro dissolution profiles data, the kinetics of drug release were evaluated for zero order, first order and Higuchi type release kinetics. Release rates were cal-culated from the slope of percentage cumulative release versus time (t), log percentage unreleased vs. time (t) and percentage cumulative release vs. square root of time (t0.5), respectively (Table 2). The coefficient of correlation of each of these release kinetics were calculated and compared. The percentage drug dissolved was found to be slightly higher in the formulations containing higher proportion of Eudragit RL type (freely permeable) polymer. In contrast with an increase in the proportion of Eudragit RS (slightly permeable) type polymer, dissolution half life (t

50%) increased and dissolution

rate constant (DRC) value decreased (Figure 6). The data revealed that in most of the formulations, release pattern are best fitted for Higuchi-type release kinetics as its coefficient of correlation (r) values pre-dominates over zero order and first order release kinet-ics. A significant linear correlation (P < 0.01) was found for Higuchi-matrix type release kinetics. For the formu-lations containing lower proportion of Eudragit RL type polymer or higher proportion of Eudragit RS type poly-mer, the release kinetics was best fitted for zero order release kinetics (Table 2).

In order to better characterize the drug release behavior, the Korsmeyer-Peppas semi-empirical model was also employed[18] given in the Equation:

Mt/M

= k tn

where, Mt/M

is the fractional release of drug in time

t, k is a constant incorporating structural and geomet-ric characteristics of the controlled-release device, and ‘n’ (the release exponent) is a parameter indicative of mechanism of drug release. The values of n = 0.5 indi-cates case-I transport (Fickian diffusion). The values of n between 0.5 and 1.0 indicates anomalous release pattern (non-Fickian transport). When n = 1.0, case-II transport drug release (zero order) mechanism and when n > 1 super case-II transport mechanism is indi-cated.[19] Based on the Korsmeyer-Peppas model, the order of drug release was best fitted with 0.5 < n < 1.0. With the increase in Eudragit RS content in the matrix films, the ‘n’ values were found more than 1.0,

PTZ

RL100:RS100

RL100:RS100-PTZ

RLPO:RSPO

IntensityRLPO:RSPO-PTZ

RLPM:RSPM

RLPM:RSPM-PTZ

2θ (°) scale 10 20 30 40 50 60

Figure 5. X-RD spectra of pure drug PTZ, drug loaded matrix films, and placebo Eudragit RL/RS (1:1) films.

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302 A.R. Chandak and P.R.P. Verma

indicating super case-II transport drug release mecha-nism. In swellable systems, mainly two factors affecting release kinetics are liquid diffusion rate and polymeric

chain relaxation rate. In the case of anomalous or non-Fickian type mechanism, liquid diffusion rate and poly-mer relaxation rate are of the same order of magnitude, whereas in case II transport, the relaxation process is very slow compared with the diffusion.[20] On the basis of these considerations, it is clear that the drug release from Eudragit-based formulations is controlled by both liquid diffusion and polymer chain relaxation.

The relevance of difference in dissolution rate con-stant and dissolution half life (t

50%) was evaluated sta-

tistically (Table 2). When examined by two-way analysis of variance, the DRC and t

50% data showed a significant

difference between the test products (P < 0.01), but within the test products non-significant difference was observed, indicating that the collected data differ signif-icantly. Hence, it can be inferred that the test products differ in their formulation compositions.

In vivo studies

Amongst the various formulations prepared using varying grades and ratios of Eudragit, four formula-tions were selected for their comparative in vivo studies

Table 2. In vitro release characteristics of the PTZ transdermal films prepared from mixed polymeric grades of Eudragit.

Sr. No. Formulation

Zero-order First-order Higuchi-matrix K-P t50%

K0(h−1) r K

1( h−1) r K

H (h−½) r n (h)

RL100:RS100

1 100:00 2.243 (0.017) 0.869 (0.014) 0.113 (0.007) 0.981 (0.018) 6.548 (0.055) 0.993 (0.010) 0.553 (0.019) 6.55 (0.331)

2 80:20 1.764 (0.023) 0.883 (0.007) 0.099 (0.007) 0.955 (0.024) 6.072 (0.036) 0.999 (0.008) 0.540 (0.026) 7.91 (0.533)

3 60:40 1.636 (0.008) 0.856 (0.024) 0.081 (0.005) 0.952 (0.011) 5.446 (0.044) 0.999 (0.009) 0.515 (0.018) 8.52 (0.422)

4 50:50 1.619 (0.013) 0.892 (0.007) 0.069 (0.006) 0.916 (0.016) 4.846 (0.046) 0.998 (0.008) 0.532 (0.009) 10.55 (0.812)

5 40:60 1.498 (0.031) 0.924 (0.018) 0.061 (0.003) 0.904 (0.009) 4.376 (0.032) 0.995 (0.006) 0.585 (0.022) 12.23 (0.862)

6 20:80 1.293 (0.028) 0.980 (0.009) 0.051 (0.005) 0.968 (0.030) 3.739 (0.042) 0.975 (0.005) 0.804 (0.017) 17.27 (1.221)

7 00:100 0.944 (0.011) 0.997 (0.004) 0.031 (0.004) 0.991 (0.016) 2.282 (0.024) 0.936 (0.007) 1.104 (0.019) 23.59 (0.911)

Two-way ANOVA ‘P’ < 0.01* < 0.01*

RLPM:RSPM

8 100:00 2.166 (0.023) 0.876 (0.012) 0.105 (0.007) 0.961 (0.032) 6.363 (0.038) 0.998 (0.013) 0.501 (0.022) 6.33 (0.213)

9 80:20 2.007 (0.037) 0.884 (0.008) 0.092 (0.005) 0.957 (0.014) 5.897 (0.046) 0.999 (0.009) 0.518 (0.009) 7.95 (0.331)

10 60:40 1.932 (0.018) 0.899 (0.011) 0.087 (0.004) 0.926 (0.023) 5.669 (0.026) 0.997 (0.008) 0.564 (0.014) 8.55 (0.532)

11 50:50 1.662 (0.016) 0.887 (0.027) 0.069 (0.005) 0.923 (0.031) 4.916 (0.054) 0.995 (0.009) 0.570 (0.018) 10.73 (0.634)

12 40:60 1.579 (0.028) 0.894 (0.011) 0.065 (0.006) 0.893 (0.012) 4.644 (0.062) 0.990 (0.004) 0.620 (0.024) 12.86 (0.933)

13 20:80 1.234 (0.025) 0.987 (0.016) 0.047 (0.004) 0.944 (0.018) 3.587 (0.039) 0.968 (0.008) 0.929 (0.018) 17.88 (0.825)

14 00:100 0.694 (0.013) 0.993 (0.013) 0.024 (0.003) 0.978 (0.015) 1.976 (0.033) 0.930 (0.014) 1.084 (0.015) 21.69 (1.232)

Two-way ANOVA ‘P’ < 0.01* < 0.01*

RLPO:RSPO

15 100:00 2.116 (0.033) 0.887 (0.018) 0.131 (0.006) 0.979 (0.021) 6.287 (0.038) 0.994 (0.013) 0.501 (0.015) 6.23 (0.341)

16 80:20 1.898 (0.036) 0.890 (0.009) 0.085 (0.005) 0.965 (0.016) 5.973 (0.052) 0.997 (0.011) 0.503 (0.021) 8.21 (0.452)

17 60:40 1.738 (0.008) 0.918 (0.013) 0.075 (0.003) 0.968 (0.007) 5.082 (0.063) 0.995 (0.009) 0.526 (0.018) 9.81 (0.346)

18 50:50 1.472 (0.026) 0.929 (0.012) 0.060 (0.005) 0.933 (0.014) 4.894 (0.059) 0.992 (0.003) 0.544 (0.014) 11.73 (0.776)

19 40:60 1.298 (0.019) 0.944 (0.007) 0.051 (0.004) 0.912 (0.024) 3.798 (0.032) 0.993 (0.004) 0.615 (0.022) 14.84 (0.112)

20 20:80 1.100 (0.021) 0.983 (0.008) 0.041 (0.005) 0.967 (0.013) 3.234 (0.045) 0.983 (0.003) 0.813 (0.013) 18.36 (0.812)

21 00:100 0.653 (0.021) 0.990 (0.004) 0.023 (0.004) 0.988 (0.016) 1.858 (0.036) 0.937 (0.006) 1.149 (0.015) 24.49 (1.281)

Two-way ANOVA ‘P’ < 0.01* < 0.01*

Values in parentheses indicate ± SD (n = 3). K0 = zero-order; K

1 = first-order; and K

H = Higuchi-type dissolution rate constant; K-P Korsmeyer-

Peppas release exponential (n) values.

0 20 40 60 80 100 0

4

8

12

t (50%

) (h)

KH (m

cg/c

m2 /

h0.5 )

16

20

24 7

6

5

4

3

2

Per Cent Eudragit RS Content in Matrix Films

RL100:RS100 RLPM:RSPM RLPO:RSPO

Figure 6. A correlation of dissolution rate constant (DRC) and dis-solution half life (t

50%) versus percentage Eudragit RS content in

transdermal films of Eudragit RL/RS of pentazocine.

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Eudragit-based transdermal delivery system of pentazocine 303

on the basis of film strength and elasticity and in vitro release profiles, namely percentage drug release, order and mechanism of drug release, t

50% and DRC. The com-

ponents of transdermal patches either alone or in com-bination with the drug may cause skin irritation; this in turn, may affect the efficacy or safety of the patches. The results of skin irritation tests carried out on healthy rabbits revealed that neither the polymer nor the drug caused any noticeable erythema, edema or inflam-mation on or around the patch area, either during the period of study or after removal of the patches.

For a comparative bioavailability study, whole blood data between all test products were considered. The pharmacokinetic parameters: C

max, t

max, AUC

(s),

t1/2,

Kel

, and MRT data are shown in Table 3. On the basis of t

1/2, AUC

(0-) and MRT values, the test products

could be ranked as follows: A > D > C > B (Table 3) [(A) Eudragit RL100/RS100 (80:20); (B) Eudragit RL100/RS100 (100:00); (C) Eudragit RLPO/RSPO (100:00) and (D) Eudragit RLPM/RSPM (100:00)]. The calculated parameters indicate that the biological half life (t

1/2) of

PTZ is prolonged from 2–4 h to 22.18 ± 3.37 h (transder-mal) in rabbits. Hence, the drug administered through transdermal patch is expected to remain for a longer period of time in the body and thus exert a sustained action. The significantly less elimination rate constant (0.032 ± 0.004 h−1) and high mean residence time values (22.96 ± 0.45 h) of PTZ further supports the sustained action of the drug from transdermal patches. The higher AUC(s) values observed with the transdermal patches also indicate increased bioavailability of the drug. This may be due to bypass of the hepatic first pass effects and avoidance of gastric degradation. These results are in accordance with the findings reported earlier.[21,22]

Upon statistical evaluation (two-way ANOVA), a significant difference was observed between the test products but not within the test products (P > 0.1), when C

max, AUC

(0–12), AUC

(0–24), AUC

(0-), t

1/2, K

el and MRT

data generated from plasma were taken into consid-eration (Table 3). On this basis, it can be inferred that

the selected four test products were not the same in their pharmacokinetic characteristics. Spearman rank correlation, a non-parametric statistical test, demon-strated a high degree of positive correlation showing a complete agreement in the order of ranks between the percentage of drug absorbed from patches and AUC

(0–

24) (P < 0.02; two-tail). The increase in the amount of

drug absorbed was thus associated with the increase in blood level and area under the plasma concentration curve (extent of absorption). This was further quantita-tively confirmed by regression analysis showing a good correlation between the percentage of drug absorbed and AUC

(0–12). A signifiant in vitro/in vivo correlation

was observed when the percentage of drug released at a given time was correlated with drug concentration in the blood at different time points.

Conclusion

The in vitro dissolution results of this study showed that the patches prepared using mixed polymeric grades of Eudragit can extend the release of pentazocine more than 24 hours. Amongst the various transdermal films of pentazocine, prepared with the different polymeric grades and ratios of Eudragit, four test formulations are better in their physico-chemical, in vitro dissolution. FTIR and DSC studies indicated no interaction between drug and polymer. The drug was distributed uniformly in the matrix and showed an amorphous nature which was confirmed by the X-RD study. The in vivo stud-ies in rabbit showed that the fabricated matrix films of pentazocine provided increased t

1/2, higher C

max, and

increased AUC0-

indicates increased bioavailability of the drug. Furthermore, the selected formulations, which have been duly screened, may be evaluated for their pharmacokinetic profiles in human to the best of their advantage.

Table 3. Pharmacokinetic parameters of PTZ after application of mixed grades of Eudragit RL/RS based transdermal patches in rabbits.

Code Formulation Tmax

(h)C

max

(ng/mL) t1/2

(h) Kel

(1/h)AUC

0-12

(h.ng/mL)AUC

0-24

(h.ng/mL)AUC

0-

(h.ng/mL) MRT (h)

RL100:RS100

A 80:20 8 321.58 (2.6) 27.21 (12.7) 0.026 (13.1) 2462.59 (3.9) 6283.85 (3.1) 19049.59 (7.3) 23.62 (1.9)

B 100:00 8 342.64 (4.3) 20.20 (8.7) 0.034 (9.1) 2766.46 (4.5) 6863.61 (4.5) 16967.57 (2.0) 22.65 (1.4)

RLPO:RSPO

C 100:00 8 335.40 (9.8) 20.44 (4.3) 0.034 (4.1) 2629.98 (4.9) 6796.75 (5.5) 16381.25 (3.0) 22.71 (1.5)

RLPM:RSPM

D 100-00 8 350.60 (8.1) 20.85 (4.2) 0.033 (4.1) 2668.67 (1.4) 6764.96 (1.6) 17096.86 (3.6) 22.87 (1.5)

Two-way ANOVA ‘P’ - < 0.01 HS < 0.05 S < 0.05 S < 0.01 HS < 0.01 HS < 0.05 S < 0.01 HS

Values in parentheses indicate % CV (n = 03). HS, highly significant; S, significant; NS, not significant. (A) Eudragit RL100/RS100 (80:20); (B) Eudragit RL100/RS100 (100:00); (C) Eudragit RLPO/RSPO (100:00) and (D) Eudragit RLPM/RSPM (100:00).

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304 A.R. Chandak and P.R.P. Verma

Acknowledgements

The authors wish to thank Vice-Chancellor, Birla Institute of Technology, Mesra, for providing the facili-ties and encouragement. The helpful discussions of Dr D. Sasmal, Dr G.M. Panpalia and Mrs S.M. Verma are highly acknowledged. Ashok R. Chandak gratefully acknowledges financial support in the form of a Senior Research Fellowship provided during the period of study by University Grants Commission, New Delhi, India UGC Grant F.No. 7-8/2004 (SR).

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