RESUMEN

In part I, we reported Hansen solubility parameters (HSP, HSPiP program), experimental solubility at varied temperatures for TOTA delivery. Here, we studied dose volume selection, stability, pH, osmolality, dispersion, clarity, and viscosity of the explored combinations (I-VI). Ex vivo permeation and deposition studies were performed to observe relative diffusion rate from the injected site in rat skin. Confocal laser scanning microscopy (CLSM) study was conducted to support ex vivo findings. Moreover, GastroPlus predicted in vivo parameters in humans and the impact of various critical factors on pharmacokinetic parameters (PK). Immediate release product (IR) contained 60% of PEG400 whereas controlled release formulation (CR) contained PEG400 (60%), water (10%) and d-limonene (30%) to deliver 2 mg of TOTA. GastroPlus predicted the plasma drug concentration of weakly basic TOTA as function of pH (from pH 2.0 to 9). The cumulative drug permeation and drug deposition were found to be in the order as B-VI˃ C-VI˃A-VI across rat skin. This finding was further supported with CLSM. Moreover, IR and CR were predicted to achieve Cmax of 0.0038 µg/ mL and 0.00023 µg/mL, respectively, after sub-Q delivery. Added limonene in CR extended the plasma drug concentration over period of 12 h as predicted in GastroPlus. Parameters sensitivity analysis (PSA) assessment predicted that sub-Q blood flow rate is the only factor affecting PK parameters in IR formulation whereas this was insignificant for CR. Thus, sub-Q delivery CR would be promising alternative with ease of delivery to children and aged patient.

Asunto(s)

Absorción Cutánea , Solubilidad , Tartrato de Tolterodina , Animales , Ratas , Humanos , Absorción Cutánea/efectos de los fármacos , Absorción Cutánea/fisiología , Tartrato de Tolterodina/administración & dosificación , Tartrato de Tolterodina/farmacocinética , Termodinámica , Solventes/química , Piel/metabolismo , Concentración de Iones de Hidrógeno , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/administración & dosificación , Terpenos/química , Terpenos/administración & dosificación , Terpenos/farmacocinética , Administración Cutánea , Limoneno/administración & dosificación , Limoneno/farmacocinética , Limoneno/química , Masculino , Polietilenglicoles/química , Sistemas de Liberación de Medicamentos/métodos , Química Farmacéutica/métodos , Ciclohexenos/química , Ciclohexenos/farmacocinética , Ciclohexenos/administración & dosificación , Ratas Sprague-Dawley

RESUMEN

OBJECTIVE: Tolterodine tartrate (TOTA) is a first-line therapy to treat overactive urinary bladder (OAB). Oral delivery causes high hepatic clearance, xerostomia, headache, constipation, and blurred vision. We addressed Hansen solubility parameter (HSP) and Design Expert oriented optimized cationic elastic liposomes for transdermal application. METHODS: The experimental solubility was conducted in HSPiP predicted excipients to tailor formulations using surfactants, stearylamine, ethanol, and phosphatidylcholine (PC). These were evaluated for formulation characteristics. The optimized OTEL1 and OTEL1-G (gel) were compared against the drug solution (DS) and liposomes. In vitro and ex vivo studies were accomplished to investigate the insights into the mechanistic understanding of TOTA release and permeation ability. Finally, confocal laser scanning microscopy (CLSM) supported ex vivo results. RESULTS: HSP values of TOTA were closely related to tween-80, stearylamine, and human's skin. The size (153 nm), %EE (87.6%), and PDI (0.25) values of OTEL1 were in good agreement to the predicted values (161 nm, 80.4%, and 0.31) with high desirability (0.963). Spherical and smooth OTEL1 (including OTEL1-G and liposomes) vesicles followed non-Fickian drug release as compared to DS (Fickian) as evidence with n > 0.5 (Korsmeyer and Peppas coefficient). OTEL1 (containing lipid and surfactant as 90 mg and 13.8 mg, respectively) exhibited 2.6 and 1.8-folds higher permeation flux than DS and liposomes, respectively. Biocompatible cationic OTEL1 was safe and non-hemolytic. CONCLUSIONS: OTEL1 was promised as a lead vesicular approach and an alternative to conventional oral therapy to treat OAB in children and advanced age patients.

Asunto(s)

Administración Cutánea , Cationes , Liposomas , Absorción Cutánea , Solubilidad , Tartrato de Tolterodina , Humanos , Animales , Tartrato de Tolterodina/administración & dosificación , Tartrato de Tolterodina/farmacocinética , Cationes/química , Piel/metabolismo , Liberación de Fármacos , Excipientes/química , Masculino , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Composición de Medicamentos/métodos , Aminas

RESUMEN

Tolterodine tartrate (TOTA) is associated with adverse effect, high hepatic access, varied bioavailability, slight aqueous solubility, and short half-life after oral delivery. Hansen solubility parameters (HSP, HSPiP program), experimental solubility (T = 298.2 to 318.2 K and p = 0.1 MPa), computational (van't Hoff and Apelblat models), and thermodynamic models were used to the select solvent(s). HSPiP predicted PEG400 as the most suitable co-solvent based on HSP values (δd = 17.88, δp = 4.0, and δh = 8.8 of PEG400) and comparable to the drug (δd = 17.6, δp = 2.4, and δh = 4.6 of TOTA). The experimental mole fraction solubility of TOTA was maximum (xe = 0.0852) in PEG400 confirming the best fit of the prediction. The observed highest solubility was attributed to the δp and δh interacting forces. The activity coefficient (ϒi) was found to be increased with temperature. The higher values of r2 (linear regression coefficient) and low RMSD (root mean square deviation) indicated a good correlation between the generated "xe" data for crystalline TOTA and the explored models (modified Apelblat and van't Hoff models). TOTA solubility in "PEG400 + water mixture" was endothermic and entropy-driven. IR (immediate release product) formulation can be tailored using 60% PEG400 in buffer solution for 2 mg of TOTA in 0.25 mL (dosing volume). The isotonic binary solution was associated with a pH of 7.2 suitable for sub-Q delivery. The approach would be a promising alternative with ease of delivery to children and aged patients.

Asunto(s)

Solubilidad , Solventes , Termodinámica , Tartrato de Tolterodina , Humanos , Tartrato de Tolterodina/administración & dosificación , Tartrato de Tolterodina/química , Tartrato de Tolterodina/farmacocinética , Solventes/química , Polietilenglicoles/química , Disponibilidad Biológica , Química Farmacéutica/métodos , Inyecciones Subcutáneas , Sistemas de Liberación de Medicamentos/métodos

RESUMEN

Background and purpose: The present study aimed to obtain a taste-masked oral disintegrating tablet (ODT) containing tolterodine tartrate (TT) intercalated into montmorillonite (MMT). Experimental approach: The TT-MMT hybrid was prepared by ion exchange reaction. The effect of the initial concentration of TT, MMT, temperature, and pH on the encapsulation efficiency (EE) % of the drug in MMT was evaluated. The selected TT-MMT hybrid was characterized by X-ray diffraction (XRD), Fourier transforms infrared (FTIR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Then, the optimized TT-MMT hybrid was incorporated in the ODT prepared by direct compression method and taste-masking assessment performed by a human test panel. Findings/Results: The EE% of TT was in the range of 22.67 to 71.06% in different formulations. It was found that increases in MMT concentration significantly increased EE%. DSC and XRD studies indicated that the TT was intercalated in the MMT interlayer space in an amorphous or molecular state. In-vitro release studies at pH 6.8 showed that the amount of the drug released from the TT-MMT hybrid was negligible for the first 3 min. The post-compression of ODT also showed satisfactory results in terms of friability, hardness, disintegration time, and taste. Conclusion and implications: MMT-ODT could be a suitable vehicle for the taste masking of TT, with the potential for use in patients with swallowing problems.

RESUMEN

OBJECTIVES: The impact of mirabegron on clinical outcome and urodynamic parameters may be important for clinical practice. Thus, the aim of this study was to compare the clinical outcomes and urodynamic effects of mirabegron (Betmiga 50 mg) versus tolterodine (Detrusitol ER 4 mg) treatment for women with overactive bladder syndrome (OAB). METHODS: Women with OAB were randomized to receive 12 weeks of mirabegron 50 mg, tolterodine extended-release 4 mg or placebo treatment. The clinical outcomes and urodynamic effects were compared between the subgroups. RESULTS: Thirty-three women completed 12 weeks of mirabegron (n = 12), tolterodine (n = 12) or placebo (n = 9) treatment. A significant increase in the volumes at strong desire to void and a decrease in the daytime frequency episodes were identified in the mirabegron and tolterodine groups (all P < 0.05). Nonetheless, a decrease in the total voided volume was identified following mirabegron treatment but not tolterodine (P = 0.02). CONCLUSIONS: Mirabegron and tolterodine exhibit similar changes in the urodynamics and bladder diary parameters. However, mirabegron may decrease the total voided volume. These findings may serve as an initial guide or assist in consultations regarding the treatment of OAB patients with mirabegron.

Asunto(s)

Acetanilidas/uso terapéutico , Tiazoles/uso terapéutico , Tartrato de Tolterodina/uso terapéutico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Agentes Urológicos/uso terapéutico , Acetanilidas/farmacología , Adulto , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Tiazoles/farmacología , Tartrato de Tolterodina/farmacología , Micción/efectos de los fármacos , Orina , Urodinámica/efectos de los fármacos , Agentes Urológicos/farmacología

RESUMEN

The purpose of the study was to develop a transdermal tolterodine tartrate (TT) patch and to analyse its efficacy for overactive bladder (OAB) treatment. Patches were prepared using various polymers and plasticizers via the solvent casting method. The patches were characterized for tensile strength, thickness, moisture content, modulus of elasticity and water absorption capacity. Differential scanning calorimetry and Fourier transform infrared analyses were also performed. To determine patch effectiveness, in vitro release, permeation and animal studies were performed. The patches showed satisfactory percentage of release, up to 89.9 %, and their mechanical properties included thickness (0.10-0.15 mm), tensile strength (4.62-9.98 MPa) and modulus of elasticity (20-29 MPa). There were no significant interactions between TT and other excipients. Animal studies indicated that the TT patch reduced the incidence of side effects; however, studies of longer duration are required to determine the effectiveness in treating OAB.

Asunto(s)

Tartrato de Tolterodina/administración & dosificación , Parche Transdérmico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Administración Cutánea , Animales , Masculino , Ratas Sprague-Dawley , Absorción Cutánea , Tartrato de Tolterodina/uso terapéutico

RESUMEN

ABSTRACT Introduction Overactive bladder (OAB) is a common condition, especially in middle aged women, requiring long term therapy with anticholinergics to maintain symptoms relief. The aim of the study was to determine the effect of tolterodine extended release (ER) used for OAB treatment on the sexual function of women. Materials and Methods Between August 2010 and August 2014, 220 women with confirmed OAB, attended Urogynecology Outpatient Clinic and were prospectively enrolled in this study. 158 women were evaluated, with a comprehensive history, physical examination, urodynamic studies and Female Sexual Function Index (FSFI) questionnaire. 73 patients of group A (control group) received no treatment and 85 patients of group B received an anticholinergic regimen - tolterodine ER 4mg once daily. Data were evaluated again in accordance with FSFI after three months, using SPSS software. Results A statistically significant increase was noted in group B in domains of desire (pre-treatment 2.5±0.2 to 4.5±0.2 post-treatment), arousal (3.1±0.2 to 3.1±0.2 respectively), lubrication (3.4±0.3 to 4.3±0.3 respectively), orgasm (3.5±0.3 to 4.5±0.3 respectively), satisfaction (2.6±0.2 to 4.2±0.3 respectively) and pain (2.4±0.2 to 4.6±0.4 respectively) after three months treatment with tolterodine ER. In group A there were no statistically significant changes in pre and post treatment values (p>0.05). Total FSFI score for group B was significantly higher after tolterodine treatment (26.5±1.5) compared to pre-treatment values (17.4±1.4, p<0.01) and to control group A (17.7±1.2 and 17.9±1.5, p>0,05) respectively. Conclusions This preliminary study demonstrates that treatment of OAB with tolterodine ER was found to have positive effect on sexual function of patients with OAB.

Asunto(s)

Humanos , Femenino , Adulto , Adulto Joven , Conducta Sexual/efectos de los fármacos , Disfunciones Sexuales Fisiológicas/tratamiento farmacológico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Agentes Urológicos/uso terapéutico , Tartrato de Tolterodina/uso terapéutico , Estudios Prospectivos , Encuestas y Cuestionarios , Preparaciones de Acción Retardada , Agentes Urológicos/efectos adversos , Tartrato de Tolterodina/efectos adversos , Persona de Mediana Edad

RESUMEN

Tolterodine tartrate belongs to the family of muscarinic receptor antagonists and is indicated for the treatment of overactive urinary bladder syndrome. This chapter provides an overview of physical, analytical, and ADME profiles; highlights methods of chemical synthesis; and discusses stability of tolterodine as a free base and/or its l-tartrate salt in solution and in the solid state. The information presented in this chapter is based on the peer-reviewed literature, compendial reports (USP, EP), and authors' data. Patent literature is included only in a few instances.

Asunto(s)

Antagonistas Muscarínicos , Tartrato de Tolterodina , Estabilidad de Medicamentos , Humanos , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/uso terapéutico , Tartrato de Tolterodina/química , Tartrato de Tolterodina/farmacocinética , Tartrato de Tolterodina/farmacología , Tartrato de Tolterodina/uso terapéutico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico

RESUMEN

INTRODUCTION: Overactive bladder (OAB) is a common condition, especially in middle aged women, requiring long term therapy with anticholinergics to maintain symptoms relief. The aim of the study was to determine the effect of tolterodine extended release (ER) used for OAB treatment on the sexual function of women. MATERIALS AND METHODS: Between August 2010 and August 2014, 220 women with confirmed OAB, attended Urogynecology Outpatient Clinic and were prospectively enrolled in this study. 158 women were evaluated, with a comprehensive history, physical examination, urodynamic studies and Female Sexual Function Index (FSFI) questionnaire. 73 patients of group A (control group) received no treatment and 85 patients of group B received an anticholinergic regimen - tolterodine ER 4mg once daily. Data were evaluated again in accordance with FSFI after three months, using SPSS software. RESULTS: A statistically significant increase was noted in group B in domains of desire (pre-treatment 2.5±0.2 to 4.5±0.2 post-treatment), arousal (3.1±0.2 to 3.1±0.2 respectively), lubrication (3.4±0.3 to 4.3±0.3 respectively), orgasm (3.5±0.3 to 4.5±0.3 respectively), satisfaction (2.6±0.2 to 4.2±0.3 respectively) and pain (2.4±0.2 to 4.6±0.4 respectively) after three months treatment with tolterodine ER. In group A there were no statistically significant changes in pre and post treatment values (p>0.05). Total FSFI score for group B was significantly higher after tolterodine treatment (26.5±1.5) compared to pre-treatment values (17.4±1.4, p<0.01) and to control group A (17.7±1.2 and 17.9±1.5, p>0,05) respectively. CONCLUSIONS: This preliminary study demonstrates that treatment of OAB with tolterodine ER was found to have positive effect on sexual function of patients with OAB.

Asunto(s)

Conducta Sexual/efectos de los fármacos , Disfunciones Sexuales Fisiológicas/tratamiento farmacológico , Tartrato de Tolterodina/uso terapéutico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Agentes Urológicos/uso terapéutico , Adulto , Preparaciones de Acción Retardada , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Encuestas y Cuestionarios , Tartrato de Tolterodina/efectos adversos , Agentes Urológicos/efectos adversos , Adulto Joven

RESUMEN

A short and sensitive stability-indicating gradient RP-UPLC method was developed for the quantitative determination of process-related impurities and degradation products of tolterodine tartrate in pharmaceutical formulations. The method was developed by using the Waters ACQUITY UPLC™ BEH shield RP18 (2.1 × 100 mm, 1.7 µm) column with a mobile phase containing a gradient mixture of solvent A and B at a detection wavelength of 210 nm. During the stress study, the degradation products of tolterodine tartrate were well-resolved from tolterodine and its impurities and the mass balances were found to be satisfactory in all the stress conditions, thus proving the stability-indicating capability of the method. The developed method was validated as per ICH guidelines with respect to specificity, linearity, limit of detection and quantification, accuracy, precision, ruggedness, and robustness. During the stability (40°C/75% RH, 3 months) analysis of the drug product, one unknown impurity was detected by the above stability-indicating method. The unknown impurity was isolated by preparative HPLC and subjected to mass and NMR studies. Based on the spectral data, the unknown impurity was characterised as 2-(3-amino-1-phenylpropyl)-4-methylphenol (des-N,N-diisopropyl tolterodine). Structural elucidation of the impurity by spectral data is discussed in detail.

RESUMEN

Objective:To establish a method for the determination of 8 residual organic solvents in tolterodine tartrate by capillary GC. Methods: The determination of methanol, ethanol, acetonitrile, acetone, ethyl acetate, trichloromethane and tetrahydrofuran in tolterodine tartrate dissolved in the solution of N, N-dimethylformamide-water ( 1∶ 4 ) was carried out on a CP-sil 5CB ( 60. 0 m × 0. 32 mm,5μm)column. The inlet temperature was 200℃ and the FID detector temperature was 250℃. The flow rate of carrier gas was 1. 2 ml·min-1 . The column temperature was 120℃. The headspace vial temperature was 85℃ and the time was 30min. The determina-tion of pyridine in tolterodine tartrate dissolved in the solution of dimethylsulfoxide-sodium hydroxide (17∶13) was carried out on an HP-1(30. 0 m × 0. 53 mm,5 μm) column. The inlet temperature was 220℃ and the FID detector temperature was 250℃. The column tem-perature was 80℃. The flow rate of carrier gas was 3. 0 ml·min-1 . The headspace vial temperature was 85℃ and the time was 30 min. Results:All peaks could be separated from each other under the chromatographic conditions. The linearity of the eight solvents was falrly good (r>0. 999). The average recovery was ranged from 86. 0% to 100. 2% with RSD of 1. 7%-3. 5% (n=9). The limit of detection was 0. 63, 0. 43, 0. 30, 0. 18, 0. 079, 0. 36, 0. 18 and 0. 89 μg·ml-1 , respectively. Conclusion:The methods can be applied in the determination of the eight residual organic solvents in tolterodine tartrate.

RESUMEN

During the stability study of Tolterodine tartrate drug product, two unknown impurities (Impurities I and II) were detected by ultra performance liquid chromatography (UPLC). Both impurities were isolated by preparative liquid chromatography and were subjected to mass and NMR spectral studies. Based on the spectral data, the Impurities I and II were characterized as N-(3-(2-hydroxy-5-methylphenyl)-3-phenylpropyl)-N,N-diisopropyl hydroxyl ammonium trifluoro acetate and 3-(2-hydroxy-5-methylphenyl)-N-isopropyl-3-phenylpropane-1-amine oxide respectively.

Asunto(s)

Compuestos de Bencidrilo/química , Cromatografía Líquida de Alta Presión/métodos , Cresoles/química , Contaminación de Medicamentos , Antagonistas Muscarínicos/química , Fenilpropanolamina/química , Compuestos de Bencidrilo/análisis , Cresoles/análisis , Estabilidad de Medicamentos , Espectroscopía de Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/normas , Espectrometría de Masas/métodos , Antagonistas Muscarínicos/análisis , Antagonistas Muscarínicos/normas , Fenilpropanolamina/análisis , Tartrato de Tolterodina

RESUMEN

Objective To evaluate the efficacy ofLingshao-Zaoren particle combined with Tolterodine Tartrate tablet in the treatment of overactive bladder in women.Methods A total of fifty female patients diagnosed with overactive bladder were randomized to receivingLingshao-Zaoren particle combined with Tolterodine Tartrate tablet group(treatment group,n=25) or only Tolterodine Tartrate tablet group(control group, n=25). Both groups were treated for 4 weeks. Changes of scores from the Overactive Bladder Symptom Scale (OBASS) and the Urgent Urination Scale were assessed.Results The scores from the OBASS improved significantly after treatment than those before treatment in both groups(in the treatment group: 3.24±0.61vs.12.16± 1.39,P<0.01; in the control group: 8.81±1.55vs.13.12±1.45,P<0.01) and so did the Urgent Urination Scale (in the treatment group: 1.04±0.72vs. 3.99±0.78,P<0.01; in the control group: 2.61±0.88vs.4.01±0.71,P<0.01) . There were significantly greater improvements in the scores from the OBASS and the Urgent Urination Scale in the treatment group than those in the control group(allP<0.01).ConclusionLingshao-Zaoren particle combined with Tolterodine Tartrate tablet was superior to only Tolterodine Tartrate tablet for the treatment of overactive bladder in women.

RESUMEN

A new rapid, simple, sensitive, selective and accurate reversed-phase stability-indicating Ultra Performance Liquid Chromatography (RP-UPLC) technique was developed for the assay of Tolterodine Tartrate in pharmaceutical dosage form, human plasma and urine samples. The developed UPLC method is superior in technology to conventional HPLC with respect to speed, solvent consumption, resolution and cost of analysis. Chromatographic run time was 6 min in reversed-phase mode and ultraviolet detection was carried out at 220 nm for quantification. Efficient separation was achieved for all the degradants of Tolterodine Tartrate on BEH C18 sub-2-µm Acquity UPLC column using Trifluoroacetic acid and acetonitrile as organic solvent in a linear gradient program. The active pharmaceutical ingredient was extracted from tablet dosage form using a mixture of acetonitrile and water as diluent. The calibration graphs were linear and the method showed excellent recoveries for bulk and tablet dosage form. The test solution was found to be stable for 40 days when stored in the refrigerator between 2 and 8 °C. The developed UPLC method was validated and meets the requirements delineated by the International Conference on Harmonization (ICH) guidelines with respect to linearity, accuracy, precision, specificity and robustness. The intra-day and inter-day variation was found be less than 1%. The method was reproducible and selective for the estimation of Tolterodine Tartrate. Because the method could effectively separate the drug from its degradation products, it can be employed as a stability-indicating one.