Influence of chitosan and polycarbophil on permeation of a model hydrophilic drug into the urinary bladder wall
Introduction
Intravesical instillation of a drug solution is a common way of treating superficial bladder cancer (Witjes, 1997, Nseyo and Lamm, 1996) and, in catheterized patients, also urinary bladder infections (Getliffe, 1996, Gubbins et al., 1999). Due to the anatomical and physiological characteristics of the lower urinary tract there are several advantages of the local over systemic drug administration. As with other regional approaches intravesical pharmacotherapy aims to optimize drug delivery near the site of action while minimizing systemic exposure (Highley et al., 1999). The current approach is instillation of a drug solution using an empirical dosage regimen. To optimize treatment parameters Wientjes (Wientjes et al., 1993) developed a mathematical model to predict drug exposure in bladder tumors and to correlate the exposure with antitumor effect. The model was based on pharmacokinetic data in patients treated with intravesical mitomycin C, drug penetration data in the bladder wall of patients undergoing cystectomy and on data on the chemosensitivity of the patient’s bladder tumor. By the use of computer simulation he assessed that 8.5-fold increase in tissue exposure can be achieved by dosage regimen optimization compared to standard treatment. This would result in a 20% improvement in recurrence-free rate.
Drug concentrations in the bladder tissue are frequently subtherapeutic due to short retention times in the bladder lumen, continuous dilution as a result of urine formation, low permeability of the bladder mucosa and systemic absorption in the lamina propria and underlying muscular layers (Highley et al., 1999). Prolongation of drug retention near the site of action and maintenance of relatively constant drug concentration by controlled drug delivery are the main motives for developing an intravesical drug delivery system (Johnson et al., 1989, Frangos et al., 1990, Singh et al., 1996, Ueda et al., 1992, Ueda et al., 1994). There is an immense potential in mucoadhesion (Bogataj et al., 1999).
In the last decade, considerable attention has been focused on the mucoadhesive polymers chitosan (CH) and polycarbophil (PC). In addition, it has been demonstrated, “in vitro” as well as “in vivo”, on intestinal, bucal and nasal mucosa, that both polymers enhance permeability by modulating paracellular transport pathways. The mechanism involves epithelial tight junctions and is calcium-dependent (Schipper et al., 1997, Kriwet and Kissel, 1996, Lueßen et al., 1996). We recently showed for PC (Kerec et al., 2002) that probably the same calcium-dependent mechanism exists also in the urinary bladder. It is anticipated that utilization of CH and PC in intravesical therapy would improve efficacy by a combination of mucoadhesion and permeation enhancing effects.
To test this concept in intravesical delivery, PC and CH were used as mucoadhesive polymers, and pipemidic acid (PPA) as a model hydrophilic drug. The permeation enhancing effect was determined in isolated porcine urinary bladder wall. Furthermore, a mathematical model was developed on the basis of obtained results to get an insight into the mechanisms of permeation enhancement and to explore the potential benefits of the use of CH and PC in intravesical therapy.
Section snippets
Chemicals
PPA trihydrate was provided by Lek, d.d. (Ljubljana, Slovenia). Chitosan hydrochloride—Protasan CL213 was purchased from Pronova (Oslo, Norway). According to the certificate of analysis, degree of deacetylation was 86%. Polycarbophil—Noveon AA1 was a gift from BF Goodrich (Brecksville, USA). For determining PPA in tissue samples, chromatography grade methanol (MeOH) and acetonitrile (ACN) (Merck, Darmstadt, Germany) and analytical grade trichloroacetic acid (TCA) (Kemika, Zagreb, Croatia) were
Results
The in vitro PPA concentration versus bladder wall tissue depth at four different experimental conditions are shown in Fig. 1.
These results indicate that higher PPA concentrations are obtained in the bladder wall in the presence of CH and PC. Diffusion model (Eq. (1)) was fitted to individual concentration profiles. In general, good agreement between the model response and observed concentrations was achieved. In many cases, careful observation of the tissue concentration profiles revealed two
Discussion
Intravesical chemotherapy is widely used for more than 40 years in patients with superficial bladder cancer as adjuvant to surgical removal. It aims to optimize drug delivery in the tumor and its vicinity and reduce systemic toxicity. Commonly applied agents are mitomycin C, thiotepa, etoglucid, doxorubicin, bacilli Calmette-Guérin and recently taxol (Highley et al., 1999). Although there is sparse information on the uptake from the bladder lumen, models for drug distribution in the bladder
Conclusion
CH and PC increase permeability of the bladder wall by diffusion enhancement in the urothelium. The proposed experimental model may be applied to evaluate the results of experiments with drugs employed in intravesical therapy.
References (22)
- et al.
Influence of physicochemical and biological parameters on drug release from microspheres adhered on vesical and intestinal mucosa
Int. J. Pharm.
(1999) - et al.
The development of liposomes containing interferon alpha for the intravesical therapy of human superficial bladder cancer
J. Urol.
(1990) - et al.
The enhancement of pipemidic acid permeation into the pig urinary bladder wall
Int. J. Pharm.
(2002) - et al.
Interactions between bioadhesive poy(acrylic acid) and calcium ions
Int. J. Pharm.
(1996) - Burjak, M., Bogataj, M., Pšeničnik, M., Mrhar, A., 2000. Development of an experimental model for the evaluation of...
- et al.
Permeability properties of the mammalian bladder apical membrane
Am. J. Physiol.
(1994) - Crank, J., 1985. The mathematics of diffusion, 2nd ed. Clarendon Press,...
Bladder instillations and bladder washouts in the management of catetherized patients
J. Adv. Nurs.
(1996)- et al.
Current management of funguria
Am. J. Health Syst. Pharm.
(1999) - et al.
Intravesical drug delivery Pharmacokinetic and clinical considerations
Clin. Pharmacokinet.
(1999)
Identification of proteoglycans present at high density on bovine and human bladder luminal surface
J. Urol.
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