Pharmacokinetic study of ginsenoside Re after vaginal administration in rabbits by UPLC-MS/MS determination (original) (raw)
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Effect of suppository bases on the release properties of a potent antimicrobial agent (C31G)
Pharmazie
C31G is a specific formulation which contains equal molar concentrations of alkyi N-betaine and alkyl N.N-dimethylamine oxide. Vaginal suppositories containing 500 mg of C31G, this potent antimicrobial substance, were prepared by the fusion method in a variety of Suppocire ® and Witepsol ® bases with different melting points and hydroxyl values. In vitro release and diffusion characteristics of C31G from different suppository bases were investigated using two different systems. The release from suppositories was determined by using a system without a membrane and the diffusion rate of the released agent was determined through a semipermeable dialyzing tubing. Diffusion kinetics from suppositories were evaluated in terms of the apparent dialytic rate constants using the equation developed by Davis et al. From the results of in vitro studies, Witepsol H 15 and Suppocire CM bases were selected as the most suitable ones for the formulations of C31G vaginal suppositories, since it is imperative for topical formulations to release the active substance in high proportions which are not absorbable by the mucosal membranes. Freisetzung der antimikrobiellen Substanz C31G aus verschiedenen Suppositoriengrundlagen Vaginalsuppositorien mit 500 mg C31G (Gemisch gleicher molekularer K-onzentrationen von Alkyl-Nbetain und Alkyl-N.N-dimethylaminoxid) wurden mit Suppocire ®-und Witepsol ®-Suppositorienmassen unterschiedlicher Schmeiztemperaturen und Hydroxylgehalte hergestellt. Die Erfassung der Freisetzung von C31G erfolgte in einem System ohne Membran, die der Diffusionsrate mit einem semipermeablen Dialysierschlauch. Fur Vaginalsuppositorien mit C31G erwiesen sich Witepsol H 15 und Suppocire CM als am geeignetsten.
A Review on Vaginal Route as a Systemic Drug Delivery
Exhaustive efforts have been made to the administration of drugs, via alternative routes, that are poorly absorbed after the oral administration. The vaginal route of drug delivery has been known since ancient times. In recent years, the vaginal route has been rediscovered as a potential route for systemic delivery of peptides and other therapeutically important macromolecules. However, successful delivery of drugs through the vagina remains a challenge, primarily due to the poor absorption across the vaginal epithelium. The rate and extent of drug absorption after intra vaginal administration may vary depending on formulation factors, vaginal physiology, age of the patient and menstrual cycle. Suppositories, creams, gels, tablets and vaginal rings are commonly used vaginal drug delivery systems. The purpose of this communication is to provide the reader with a summary of advances made in the field of vaginal drug delivery. This report, therefore, summarizes various vaginal drug delivery systems and factors affecting drug absorption from the vaginal route. The objective of this paper is to provide an overview of various vaginal drug delivery systems currently in development stages are available in the market, immunization via the vagina and special emphasis on the challenges and difficulties associated with systemic delivery of drugs via the vaginal route.
ISRN Obstet Gynecol, 2012
Vaginal infection and inflammation with or without vulvar involvement are very common gynecologicaly clinical conditions associated with morbidity and reduced quality of life. Vaginal infections are commonly treated with causal antimicrobial treatments. In addition to specific antimicrobial treatment, anti-inflammatory therapy, both systemic or topical (vaginal douche), could be useful in the integrated treatment approach of these conditions reducing symptoms and speeding up the recovery in vulvovaginitis. Ibuprofen is a well-known effective and well-tolerated anti-COX (anti-COX1 and COX2) compound. In addition, several in vitro studies suggest that Ibuprofen shares antimicrobial and antifungal activities. Ibuprofen isobutanolammonium (Ib-isb) (Ginenorm) is a soluble salt from formulation suitable for external and intravaginal use. This salt completely dissociates in aqueous solution. Ib-isob is available in sachet and vaginal douche pharmaceutical formulations. Clinical efficacy of Ib-isob has been documented in 10 clinical studies (6 controlled and 4 open trials) which have enrolled in total 399 women with vulvovaginitis. The six controlled clinical trials were performed both versus placebo (2 studies) or versus active comparators such as benzydamine. In these studied, Ib-Isb has been used in general for 7 consecutive days with a twice application daily regimen at the dose of 1 g per application. Topical application of Ib-isob induced a marked and rapid reduction in signs (erythema, oedema) and symptoms (itching and burning sensation) of vulvovaginitis. In head-to-head studies carried out in comparison with other topical products, Ib-isob induced a more rapid reduction in both subjective and objective symptoms. In particular a remarkable significant improvement of all the symptoms has been observed in the group of patients treated with Ib-isob in comparison with women receiving benzydamine. The clinical data available for Ib-isob confirm that this salt, specifically developed for gynecological use, is effective and well tolerated in vulvovaginal inflammation conditions. Efficacy of Ib-isob was greater in comparison with commonly used products. Ibuprofen-isob may be considered a useful and effective tool for the topical treatment of nonspecific vaginal diseases.
Formulation and in vitro study of antibacterial vaginal suppositories
Pharmaceutica Acta Helvetiae, 1994
Vaginal suppositories frequently used in gynaecological therapy were studied. Several antibacterial pharmacons are used for the topical treatment of vaginitis of various origins. In view of the fact that the liberation of the given active substance and the subsequent therapeutic effect may be improved or inhibited by the vehicle, our aim was to find the optimal suppository base for vaginal suppositories containing sulfadimidine, chloramphenicol and gentamicin sulfate by means of in vitro experiments. On the basis of breaking hardness, disintegration time and spreading properties the French Suppocire NA product, and compositions of macrogols with lower molecular weight proved to be the best lipophilic and hydrophilic bases, respectively. Among the lipophilic bases the in vitro drug liberation of Suppocire NA was significantly better (P < 0.05) than the other lipophilic bases. This vehicle is recommended for the topical treatment of vaginitis, as these suppositories have the further advantage that they can easily be produced on a magistral, galenical or industrial scale as well.
Journal of Chromatography B, 2008
A sensitive and rapid liquid chromatography-mass spectrometric method for the simultaneous determination of ginsenoside Rg1, Re, Rd, Rb1 and ophiopogonin D in rat plasma was developed and validated. Chromatographic separation was performed on a C 18 column using a step gradient program with the mobile phase of 0.5 mmol/L ammonium chloride solution and acetonitrile. The analytes and I.S. were detected using an electrospray negative ionization mass spectrometry in the selected ion monitoring (SIM) mode. The method was linear over the investigated concentration range with a good correlation coefficient higher than 0.997. The lower limits of detection (LLOD) of these analytes were all lower than 2.0 ng/mL. The intra-and inter-day precisions were all no more than 7.5% and accuracies were within the range of 97.5-107.0%. The validated method was successfully applied to investigate the pharmacokinetics of ginsenoside Rg1, Re, Rd, Rb1 and ophiopogonin D in rat after intravenous administration of 'SHENMAI' injection.
Non-clinical pharmacokinetic behavior of ginsenosides
Journal of Ginseng Research, 2019
Ginsenosides, the major active ingredients of ginseng and other plants of the genus Panax, have been used as natural medicines in the East for a long time; in addition, their popularity in the West has increased owing to their various beneficial pharmacological effects. There is therefore a wealth of literature regarding the pharmacological effects of ginsenosides. In contrast, there are few comprehensive studies that investigate their pharmacokinetic behaviors. This is because ginseng contains the complicated mixture of herbal materials as well as thousands of constituents with complex chemical properties, and ginsenosides undergo multiple biotransformation processes after administration. This is a significant issue as pharmacokinetic studies provide crucial data regarding the efficacy and safety of compounds. Moreover, there have been many difficulties in the development of the optimal dosage regimens of ginsenosides and the evaluation of their interactions with other drugs. Therefore, this review details the pharmacokinetic properties and profiles of ginsenosides determined in various animal models administered through different routes of administration. Such information is valuable for designing specialized delivery systems and determining optimal dosing strategies for ginsenosides.
Contraception, 2009
Background-The Population Council studied a pre-coital contraceptive microbicide vaginal product containing levonorgestrel (LNG) as active component and Carraguard® gel as a vehicle (Carra/LNG gel) for couples who engage in occasional unplanned intercourse. The objective of this study was to evaluate the effect of sexual intercourse after vaginal application of Carra/LNG gel on serum levels of LNG in women and to assess LNG absorption by the male partner. Study Design-This was a randomized, cross-over, pharmacokinetic study including an abstinence arm and an arm in which couples engaged in sexual intercourse between 2 and 4 h after gel application. In each study arm, each woman received a single application of Carra/LNG gel (0.75 mg in 4 mL gel) followed by serial blood samples taken at 0, 1, 2, 4, 8, 24 and 48 h after gel application for LNG measurements. In the intercourse arm, LNG was measured in blood samples taken from the male partner before intercourse and at 4, 8 and 24 h after gel application in the female partner. Results-Time concentration curves for serum LNG levels showed a mean C max of 7.8±5.5 and 8.3±5.7 nmol/L, a mean T max of 6.2±5.9 and 7.5±5.7, and comparable area under the curve for the intercourse and abstinence arm, respectively. Pharmacokinetic parameters presented large variability between subjects, but excellent reproducibility within each subject. LNG was undetectable in 10 out of 12 male partners. Conclusion-Sexual intercourse does not appear to interfere with vaginal absorption of LNG after application of a Carra/LNG gel. A vaginal pre-coital contraceptive gel is feasible.
Contraception, 2004
Background: C31G is an antimicrobial and spermicidal agent that contains two surface-active compounds, cetyl betaine and myristamine oxide. It is being developed as a vaginal microbicide and contraceptive. Method: Three C31G concentrations (0.5%, 1.0% and 1.7%) were tested and compared with Extra Strength Gynol II, a marketed spermicide containing 3% nonoxynol-9 (N-9), in a randomized, double-blinded, Phase I, dose-escalation study to assess genital irritation (by subject report, visual examination at pelvic examination and colposcopy), plasma and vaginal lavage levels of C31G, product leakage, systemic safety and acceptability. Women were randomized to use 3.5 mL of one of the three C31G products or the N-9 gel at night for 7 days then twice daily for another 7 days. Pelvic and colposcopic evaluations were performed after 7 and 14 days of product use. Results: The percent of women experiencing irritation in the 0.5% and 1.0% C31G groups in the study were similar to each other and were lower than the percent experiencing irritation in the 1.7% and N-9 groups, which were also similar to each other. Differences were statistically significant between 1.0% C31G vs. N-9 at 7 days and between 0.5% C31G and 1.0% C31G vs. N-9 at 14 days. There was no significant difference between groups in leakage or acceptability. No C31G was detected in the plasma of any volunteer. Conclusions: These results suggest that 0.5% and 1.0% C31G are less irritating to the female genital tract than 1.7% C31G or Extra Strength Gynol II.
International Journal of Pharmaceutics, 2012
Background: For any new vaginal dosage form, the distribution and retention in the vagina has to be assessed by in vivo evaluation. We evaluated the vaginal distribution and retention of starch-based pellets in sheep as live animal model by gamma scintigraphy (using Indium-111 DTPA as radiolabel) and in women via magnetic resonance imaging (MRI, using a gadolinium chelate as contrast agent). A conventional cream formulation was used as reference in both studies. Method: Cream and pellets were administered to sheep (n = 6) in a two period-two treatment study and to healthy female volunteers (n = 6) via a randomized crossover trial. Pellets (filled into hard gelatin capsule) and cetomacrogol cream, both labeled with Indium-111 DTPA (for gamma scintigraphy) or with gadolinium chelate (for MRI) were evaluated for their intravaginal distribution and retention over a 24 h period. Spreading in the vagina was assessed based on the part of the vagina covered with formulation (expressed in relation to the total vaginal length). Vaginal retention of the formulation was quantified based on the radioactivity remaining in the vaginal area (sheep study), or qualitatively evaluated (women study). Results: Both trials indicated a rapid distribution of the cream within the vagina as complete coverage of the vaginal mucosa was seen 1 h after dose administration. Clearance of the cream was rapid: about 10% activity remained in the vaginal area of the sheep 12 h post-administration, while after 8 h only a thin layer of cream was detected on the vaginal mucosa of women. After disintegration of the hard gelatin capsule, the pellet formulation gradually distributed over the entire vaginal mucosa. Residence time of the pellets in the vagina was longer compared to the semi-solid formulation: after 24 h 23 ± 7% radioactivity was detected in the vaginal area of the sheep, while in women the pellet formulation was still detected throughout the vagina. Conclusion: A multi-particulate system containing starch-based pellets was identified as a promising novel vaginal drug delivery system, resulting in complete coverage of the vaginal mucosa and long retention time.
Journal of Chromatography B, 2014
Nonoxynol-9 (N-9), a microbicidal spermicide, has been in use as an over-the-counter contraceptive since the 1960s. A detailed account of its pharmacokinetic profile using highly sensitive detection method has not been reported yet. We developed and validated a rapid, selective and sensitive high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method for N-9 detection in plasma and simulated vaginal fluid. The analytes were quantified using reverse phase Thermo Accucore C 18 (150 mm × 4.6 mm, 5 m) column with isocratic elution using acetonitrile: 0.1% formic acid in triple distilled water (90:10, v/v) as mobile phase. The ionization was optimized using ESI (+) and selectivity was achieved by tandem mass spectrometric analysis using MRM transition, m/z 617.4 → 133.2 for N-9 and m/z 180.1 → 138.1 for phenacetin. The method was linear over the range 0.195-100 ng/mL. The method was accurate and precise with intra-batch and inter-batch accuracy (% bias) of less than ±15% and precision (% CV) of <15% for N-9. The mean peak plasma concentration (C max ) 4.87 ± 0.37 ng/mL was achieved 1.0 h after vaginal application with terminal half-life 1.45 ± 0.07 h in rabbits. The validated method was successfully applied for pharmacokinetic study of N-9 in rabbits after vaginal administration.