Efficacy of Novel Acid Buffering Vaginal Tablet of Metronidazole for Bacterial Vaginosis

Patel Geeta M¹^*and Patel Madhabhai M²

¹Department of Pharmaceutics and Pharmaceutical Technology, S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Kherva-382711. Gujarat, India.

²Kalol Institute of Pharmacy, Kalol, Gujarat, India

ABSTRACT

To develop more effective treatment for bacterial vaginosis, metronidazole was formulated in acid buffering bioadhesive tablet formulations that increase the time of contact of drug with the vaginal mucosa. Oral metronidazole is still the drug of choice in the treatment of bacterial vaginosis. Yet, side effects have been reported, and dosage as well as duration of therapy is still controversial. This study presents a possible alternative treatment using a single dose of metronidazole administered in a vaginal bioadhesive table. Double blind, randomized, clinical trials with 24 patients was carried out. The cure rate in acid buffering bioadhesive metronidazole vaginal tablet group was higher (86.66%) than metronidazole vaginal tablet (60%). No side effects were reported. Treatment of bacterial vaginosis with a single application of metronidazole in a bioadhesive vaginal tablet was found to be a valid alternative. These results indicate that a new bioadhesive vaginal tablet formulations might be further developed for safe convenient and effective treatment of bacterial vaginosis.

KEYWORDS: Metronidazole, bioadhesion, inclusion-exclusion criteria, randomized clinical trial, vaginal retention

INTRODUCTION

Bacterial vaginosis (BV) is currently regarded as the most prevalent cause of vaginal infection in women of reproductive age (Eschenbach et al. 1988).The condition is characterized by vaginal discharge and has been associated with complications including preterm delivery of infants, pelvic inflammatory disease (PID), urinary tract infections (UTI) and acquisition/transmission of sexually transmitted diseases (STDs) including human immunodeficiency virus (HIV) (Amsel et al. 1983; Alesna et al. 1996). Control of BV has been advocated as a means of decreasing the prevalence of these complications. However, the etiology of BV remains unknown and the current treatment regimens are inadequate in terms of initial cure and recurrence rates. Bacterial vaginosis is a common cause of vaginitis, characterised by replacement of lactobacilli dominated flora with a mixed flora containing Gardnerella vaginalis, anaerobic bacteria and Mycoplasma hominis (Joesoef et al. 1995). Since bacterial vaginosis is a localized syndrome with no apparent inflammation of the vaginal epithelium, topical treatment provides an appealing alternative to systemic antimicrobial use. Metronidazole is the drug of a choice in the treatment of bacterial vaginosis. Metronidazole should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

A preliminary efficacy study of a bioadhesive vaginal metronidazole tablet was performed in 1995. In a double blind study, 30 outpatients were randomly allocated to a bioadhesive vaginal tablet (weight 1 g, diameter 20 mm) with 100 mg metronidazole or a placebo. Both groups were compared with a third arm where patients were given the conventional oral metronidazole treatment consisting of two 500 mg doses daily for 7 days.

The cure rate was significantly lower in the group receiving the placebo bioadhesive tablet as compared to the two other treatment groups. No significant difference in clinical efficacy was observed between the group treatment orally and the group treated with the bioadhesive carrier (Austin et al. 2005).The present study is a comparative efficacy study where acid-buffering metronidazole in a bioadhesive vaginal tablet was compared to a plain metronidazole vaginal tablet (without acid-buffering effervescent formula).

MATERIAL AND METHODS:

Composition of the tablets:

The bioadhesive tablet consisted of Metronidazole, Polyox WSR 301, HPMC K4M, MCC- PH 112, Sodium monocitrate, Sodium bicarbonate and Ac-di-sol. The total weight of the tablet was 1 g. To increase the adherence to the genital tract, the design of the tablet was further optimised and specially shaped to fit better to the uterine cervix. The tablet compositions were compressed directly on a 6-station single punch tablet machine by using 16 mm oval punches.

Study consideration:

Randomized, Double Group Assignment.

Study site:

Patients will be enrolled and followed at the Purvi Maternity Home, Mehsana District., and Gujarat, India.

Study population:

All eligible women attending the Purvi Maternity Home were approached and briefed about the study. Participants was asked to sign an informed consent form (in Gujarati) if the patient was able to sign, or give verbal consent which was witnessed and signed by a research nurse.

Eligibility:

Ages Eligible for Study: 18 Years to 45 Years

Genders Eligible for Study: Female

Accepts Healthy Volunteers: No

Study consideration:

Study Characteristics:

Statistically adequate and well-controlled trials establishing safety and effectiveness were recommended because there are no closely related indications and the microbiology for this infection is not well defined. In this infection, an evaluable patient should be expected to be clinically evaluable only.

Criteria:

Inclusion Criteria:

· Women be at least 18 years of age.

· Have symptoms of vaginal odor and or/discharge.

· Meet the clinical (Amsel) criteria for bacterial vaginosis.

· Willing to participate in research.

Exclusion Criteria:

· Presence of another vaginal infection or sexually transmitted diseases.

· Allergy to metronidazole.

· Pregnant or nursing.

· Use of oral or intravaginal antibiotics within the past 2 weeks.

· HIV or other chronic disease.

· Inability to keep return appointments.

Study procedures:

Eligible women who consent to participate were administered acid-buffering metronidazole bioadhesive vaginal tablets intravaginally in nonpregnent woman volunteers. The women were assigned to receive metronidazole acid- buffering bioadhesive vaginal tablets (n=12) intravaginally once daily for seven consecutive days. The second group was assigned to receive metronidazole vaginal tablet (n=12). Participants were evaluated in two follow-up visits (7–12 days and 28–35 days after treatment). At the first follow-up visit the women was check for recurrent bacterial vaginosis. For assessment of retention of formulation locally the time duration was note down during which the formulation came out due to self cleansing property of vagina (Bouckaert et al. 1995; Jody et al. 2002). The diagnosis of bacterial vaginosis was based on the following criteria: presence of clue cells (microscopic examination and gram staining), and two of the following criteria: history of a foul smelling vaginal flour; a thin vaginal discharge; a vaginal pH > 4: 5, and a positive amine test (KOH) (Schwebke et al. 1996).The protocol for this study was approved by Institutional Ethics Committee of SKPCPER and the document no was SKPCPER/IEC/2008/01.

Intervention:

The tablet was applied during the first visit by the gynaecologist. Women expecting their menstrual periods were asked to return after the periods in case of few symptoms. In case of clinical complaints women were treated with metronidazole orally and not included. The cervix was cleaned with a dry tamp, after which the tablet was applied with the concave site on the portio uteri, using tweezers or forceps. Signs and symptoms and the results of the direct microscopic examination were recorded on an evaluation sheet. Patients were asked to record the loss of the tablet. A clinical, microscopic and bacteriological evaluation was performed after 1–2 weeks, depending on the patients availability. No further follow-up was scheduled, and patients were instructed to return to the clinic in case problems persist.

Statistic evaluation of the results:

The data obtained for group A and B were evaluated by a two-tailed paired‘t’-test (Systat 2.03 software).Differences were considered statistically significant at P < 0.05.

RESULTS AND DISCUSSION:

A total of 30 outpatients were enrolled. Four patients did not fulfil the diagnostic criteria, two because of a doubtful clinical diagnosis, and two were lost to follow-up. The results of the study are shown in Table-1. The overall cure rate was 86.66 % in women who had been treated with acid-buffering bioadhesive metronidazole vaginal tablet (Group-A, n=9) and with metronidazole vaginal tablet (Group-B, with out bioadhesive acid-buffering formula, n=13). 6.66% of the women reported having lost the tablet within 6 days in group-A, whereas 26.67% of the women reported having lost the tablet within 2-3 days in group-A. There were significant differences in ‘lost tablets’ between the different groups. The patients reported no side effects, while no vaginal mucosal lesions were reported by the gynaecologists.

The current standard treatment of bacterial vaginosis with oral metronidazole or vaginal metronidazole has both advantages and disadvantages. High doses, systemic side effects, and difficult vaginal applications with poor patient compliance, are the most important disadvantages. A single treatment with a bioadhesive vaginal tablet with metronidazole would be ideal, since the tablet can be applied in the clinic, directly after the clinical diagnosis of bacterial vaginosis. As it concerns a local treatment, in a much lower dose than any oral treatment, less systemic side effects are to be expected. Cunningham et al., indeed showed that the systemic availability of a vaginal 0.75% metronidazole gel formulation was 47% lower than for an oral 500 mg tablet formulation,²⁰ resulting in less side effects. Ransom et al., recommend the routine treatment of bacterial vaginosis with a less expensive generic oral metronidazole, except when patients experience untoward side effects from the use of oral metronidazole, in which case a twice-daily dosing of a 0.75% metronidazole gel for 5 days was proposed.²¹In addition, also the once daily dose of 0.75% metronidazole gel for 5 days studied by Livengood et al. showed a good cure rate.²²

The overall cure rate in our study dealing with a single acid buffering bioadhesive vaginal metronidazole administration was 86.66%. Although the cure rate reported in our study is satisfactory. In our view the application of a single tablet loaded with metronidazole could have a place in the management of bacterial vaginosis. Side effects are not reported and patient compliance is optimal as the physician inserts the tablet during an outpatient visit. Comparing two groups the cure rate is higher in acid-buffering vaginal tablets (86.66%) to that of metronidazole vaginal tablet (60%). Of concern is the reported tablet loss, underlining the need for further research for optimal dose finding and vehiculum shaping to find the lowest effective dose in the best bioadhesive carrier.

CONCLUSION:

These preliminary data suggest that a single application with a low dose of metronidazole in a local bioadhesive carrier might become a useful alternative in the treatment of bacterial vaginosis. However, more research is needed to define the optimal dose of the active product as well as in tablet design and formulation, and further refinement is required before the method can be put into practice.

ACKNOWLEDGMENT:

The Authors are really very thankful to Dr. S. P. Patel, Gynecologist of the Poorvi maternity home for providing guidance as well as sound support to carry out the clinical trials.The authors are thankful to Institutional Ethics Committee of SKPCPER to approve the protocol to carry out clinical trials.

REFERENCES:

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Received on 11.02.2009

Accepted on 14.04.2009

Research Journal of Pharmaceutical Dosage Forms and Technology. 1(3): Nov. – Dec. 2009, 188-190