Preparation, characterization and pharmacological evaluation of tolterodine hydrogels for the treatment of overactive bladder

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Abstract

In this study, transdermal gel formulations for tolterodine were developed to investigate the effects of gel matrix and chemical enhancers on drug skin permeation from tolterodine hydrogels. In vitro permeation studies of tolterodine through excised mouse skin were carried out using Franz-type diffusion cells. In the optimum gel formulation, Carbopol 940 was selected as the gel matrix. Compared to gels without enhancer, tolterodine hydrogels with N-methyl pyrrolidone (NMP) showed significant enhancing effect on transdermal permeation of tolterodine (p < 0.05). The results of in vitro percutaneous delivery experiment showed that the relationship of the steady accumulative percutaneous amount (Q, μg cm−2) of tolterodine hydrogels and time was Q4–12h = 770.19t1/2  966.99. Tolterodine permeated at the steady-state speed of 770.19 μg cm−2 h−1 and its release coincided with Higuchi Equation. The pharmacokinetic properties of the optimized tolterodine formulation were studied in rabbits. The absolute bioavailability of tolterodine was 11.47%. Since the absence of hepatic first-pass metabolism, only a single active compound-tolterodine was detected in the plasma. A skin irritation study was also carried out on rabbits, and the results showed tolterodine hydrogels had no skin irritation. In the pharmacodynamic study, the significant effects of tolterodine hydrogels on the inhibition of pilocarpine-induced rat urinary bladder contraction were last to 12 h, indicating that tolterodine hydrogels could produce prolonged pharmacological responses. In conclusion, tolterodine hydrogels were formulated successfully using Carbopol 940 and NMP and these results helped in finding the optimum formulation for percutaneous drug release. It is quite evident that tolterodine hydrogels may offer a possibility to avoid the first-pass effect, resulting in a single active compound of tolterodine in plasma, which may profit on the patient under the dose control and the reduction of potential adverse effect from two active compounds in the body.

Graphical abstract

Effects of tolterodine hydrogels and tolterodine tablets on the cumulative urinary output in rats.

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Introduction

Muscarinic receptors mediate the bladder contraction of normal voiding and the main part of contraction in bladder overactivity associated with urge and urge incontinence. Consequently, muscarinic antagonists are mainly used to treat bladder overactivity (Andersson et al., 1998). Tolterodine (Fig. 1), a potent and competitive muscarinic receptor antagonist, is extensively used for the treatment of urge incontinence and other symptoms of unstable bladder (Dmochowski and Appell, 2000). This drug has more specificity for the M2 receptor in clinical development for overactive bladder and less M3 receptor activity with a direct correlate of less dry mouth (Modiri et al., 2002). Tolterodine is rapidly absorbed, and an approximate dose-proportional increase in peak serum levels is observed after about 1 h. Basic pharmacokinetic parameters are: half-life 2–3 h, systemic clearance about 30 l/h and volume of distribution about 110 1 (Oishi et al., 2011).

The recommended oral dosage of tolterodine immediate-release tablets in adult patients with overactive bladder is 2 mg twice daily, which may be lowered to 1 mg twice daily based on individual response and tolerability. Recently, an extended-release capsule formulation of tolterodine (4 mg once daily) has recently been approved by regulatory authorities. It was developed that provides sustained release of the drug for 24 h, producing a flatter serum concentration–time profile versus the immediate-release tablet formulation (Delyth and Blair, 2001). Hydrogels are three-dimensional materials which can absorb large amounts of water and maintain their dimensional stability. Because of the high water content, hydrogels resemble natural living tissue more than any other type of synthetic biomaterial (Yaszemski et al., 2003). In 2009, Food and Drug Administration (FDA) approved Gelnique™ (oxybutynin chloride) Gel 10% for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and frequency (Staskin and Robinson, 2009).

After oral administration, tolterodine is metabolized through the liver, resulting in the formulation of 5-hydroxymethyl derivative (DD01), a major pharmacologically active metabolite. With the exception of tolterodine, however, most drugs lack functional bladder selectivity, and side effects may limit their usefulness (Brynne et al., 1999). Therefore, there is a great interest to develop the topical dosage forms of tolterodine to avoid the oral side effects and to provide relatively consistent drug levels at the application site for prolonged periods. Tolterodine hydrogels were designed to provide steady plasma tolterodine levels with daily application, favorably altering DD01:tolterodine ratio, and to utilize a biocompatible delivery system, thus reducing both the anti-muscarinic adverse effects of oral formulations. Tolterodine patches and nanosized microemulsion for transdermal delivery of tolterodine tartrate have been reported, however, preparation methods of those formulations are more complex than hydrogels and no skin irritation evaluation and pharmacodynamic of the transdermal delivery of tolterodine has been studied.

The aims of this study were to evaluate the effects of enhancers and Carbopol on drug skin permeation from gels, and to investigate pharmacokinetics, skin irritation and pharmacodynamics of tolterodine hydrogels using N-methyl pyrrolidone (NMP) as skin enhancer and Carbopol 940 as gel matrix.

Section snippets

Drugs and reagents

Tolterodine tartrate was obtained from Beijing Gaobo Pharm-Chemicals Tech. Co. Ltd. Carbopol 934, 940 and 980 were purchased from Beijing Guoren Yikang Technology Co. Ltd. (China). Tolterodine free base was synthesized in our laboratory. All other chemicals were of reagent grade. Deionized water was purified using a Milli-Q system (Millipore, Milford, MA, USA).

Healthy Kunming mice weighing 18–22 g and healthy New Zealand male rabbits weighing 1.5–2.0 kg were supplied by Experimental Animal Center

Effect of Carbopol on the skin permeation of tolterodine

The in vitro transdermal permeation of tolterodine hydrogels was studied in skin of mice, which is widely used in research of transdermal drug system (Mohammad et al., 2006). The cumulative percutaneous amounts of tolterodine from the hydrogels using Franz diffusion cell were shown in Fig. 2. All the formulations showed a low initial burst release. From 1st to 12th h, tolterodine release rates were relatively constant. The gel matrix, Carbopol 940 could significantly improve the cumulative

Conclusions

Carbopol 940 as gel matrix and NMP as chemical enhancers showed significant enhancing effects on transdermal permeation of tolterodine from hydrogels. It is quite evident that tolterodine hydrogels may offer a possibility to avoid the first-pass effect, resulting in a single active compound of tolterodine in plasma, which may profit on the patient under the dose control and the reduction of potential adverse effect from two active compounds in the body.

Acknowledgement

This work was supported by the Key Project of Science and Technology Development Plan for Jilin Province (20100435).

References (22)

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