Compositions and methods for treatment of vaginitis

Abstract

Compositions and methods for treatment of vaginitis (including refractory or recurrent vaginitis conditions) are provided. In particular, this disclosure relates to the treatment of vaginitis conditions and compositions for use in such treatment. In embodiments, treatment compositions include two active ingredients (such as an imidazole compound and boric acid), formulated into a vaginal delivery vehicle (such as a suppository) that provides controlled release of the active ingredient(s) over 24 hours, for instance. The rate of release of the active ingredients may be similar or different. Example controlled release suppositories are made by combining oleaginous excipient(s) with different polymer(s) and surfactant(s) at selected concentrations, thereby enabling intentional modulation of the rate(s) of release of therapeutic active agent(s) delivered in the composition.

Description

COMPOSITIONS AND METHODS FOR TREATMENT OF VAGINITISCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to, and benefit of the earlier filing date of, U.S. Provisional Patent Application No. 63 / 591 ,422 filed October 18, 2023, the entire contents of which are incorporated herein by reference.FIELD

[0002] The present disclosure relates to compositions and methods for the treatment of vaginitis. In particular, this disclosure relates to the treatment of vaginitis conditions and compositions for use in such treatment including refractory or recurrent vaginitis conditions.BACKGROUND

[0003] Vaginitis is characterized by inflammation of the vulva or vagina, with an estimated 7.4 million new cases annually. The vast majority of cases of vaginitis are caused by three characteristic infections, bacterial vaginosis (BV) (>50%), vulvovaginal candidiasis (VVC) (<25%), and trichomoniasis (<25%). Treatment of vaginitis may include oral, topical and / or intravaginal administration of compositions such as nitroimidazole, imidazole, and lincosamide compounds, antifungal agents, and hormonal medications. However, BV and VVC both produce biofilms and trichomoniasis is frequently accompanied by dysbiotic microbacteria which produce biofilms that provide adhesion (Hinderfeld et al., Microb Pathog. 2020 Jan;138:103820), creating infections that are resistant to current treatments and leading to recurrent and refractory infections.

[0004] Bacterial vaginosis (BV) is the most common cause of vaginitis and mostly affects women of reproductive age. Global prevalence of BV in the general population ranges between 23-29% (Peebles et al., Sex. Transm. Dis. 2019 May; 46(5): 304-31 1) and is responsible for considerable and persistent discomfort. If left untreated, BV can lead to serious complications such as chorioamnionitis, pre-term labor, and enhanced susceptibility to sexually transmitted diseases including HIV infections, N. gonorrhoeae, C. trachomatis, and HSV-2.

[0005] BV is characterized by high bacterial species diversity, increased loads of facultative anaerobes and their subgroups, including Gardnerella vaginalis, Provetella spp., Atopobium vaginae, Megasphaera, Sneathia, and Clostridiales species; increased production of volatile amines; and a rise in vaginal pH to> 4.5. These changes are accompanied by a marked depletion of key commensal bacteria such as Lactobacillus species including Lactobacillus crispatus, whichproduces lactic acid, bacteriocins, and other antimicrobial molecules, and which is thought to play an important role in host defense against pathogens.

[0006] Although anti-microbial therapy is effective in relieving symptoms in the short term, BV is associated with high post-treatment recurrence rates (30% in 3 months, 30-50% within 6 months, and rising to 80% within one year) and incidence of refractory disease (15-20%). The emotional and economic consequences of recurrent BV are enormous, and a source of considerable frustration to both physicians and women.

[0007] Previous treatments of bacterial vaginosis such as oral tinidazole or metronidazole therapy in combination with vaginal boric acid have produced suboptimal results due to the inability of patients to tolerate the oral therapy, resulting in recurrence rates as high as 31% between two and six months after administration (Surapaneni et al., Sexually Transmitted Diseases 2021 ; 48(10): 761 -765). Further, such treatments frequently resulted in other forms of vaginitis, such as those caused by vulvovaginal candidiasis (VVC). There remains a need for an alternative treatment for BV. In particular, there remains an urgent need for an effective treatment which can at least control and potentially cure recurrent BV.

[0008] Yeast infections are the second most common type of vaginitis. Typical symptoms of VVC include pruritus, vaginal soreness, dyspareunia, external dysuria, and abnormal vaginal discharge. VVC is characterized by yeast colonization, most frequently by Candida albicans (C. albicans) and occasionally caused by other Candida species or yeasts. Approximately 50% of women with VVC test positive for non-C. albicans, and successful treatment is often difficult. Further, the optimal treatment of non-albicans VVC remains unknown, particularly for recurrent VVC (RVVC).

[0009] VVC can be classified as either uncomplicated or complicated depending on factors including infection severity, yeast species, and immune system integrity. In general, complicated VVC is less likely to respond to treatment and requires more aggressive regimens to resolve. Given the significant prognostic differences between uncomplicated and complicated VVC, differentiation between these two conditions is necessary.

[0010] The majority of C. albicans infections form biofilms (Jabra-Rizk et al., Emerg. infect. Dis., 10(1 ):14-19, 2004; Nett & Andes, Curr. Opin. Microbiol. 9: 340-345 2006; Finkel & Mitchell Nat. Rev. Microbiol. 9:109-118, 2011 ; Tournu & Van Dijck, Int. J. Microbiol., 845352, 2012; Mathe & Van Dijck, Curr. Genet. 59: 251 -64, 2013). Biofilms formed by C. albicans are inherently tolerant to antimicrobial therapy and therefore, the susceptibility of Candida biofilms to the current therapeutic agents remains low. Short courses of vaginal boric acid have been investigated as part of treatments for VVC and are considered first line treatment alternatives to azoles in thecontext of resistance and refractory VVC ((RVVC); defined as three or more symptomatic episodes of VVC over 12 months). However, boric acid by itself is insufficient to treat vaginitis.

[0011] The third most common cause of vaginitis is trichomoniasis, where a protozoan Trichomonas vaginalis (T. vaginalis) is responsible for infecting the host. Trichomoniasis is one of the most prevalent non-viral sexually transmitted infections (STIs) in the United States. Women with trichomoniasis will often present with vaginal discharge, painful intercourse, urinary tract infection symptoms, vaginal itching, or pelvic pain. Of concern is that trichomoniasis increases the risk of transmission of human immunodeficiency virus (HIV) and the infection is also associated with adverse outcomes during pregnancy.

[0012] Currently, nitroimidazoles (metronidazole and tinidazole) are recommended drugs for treating trichomoniasis. Trichomoniasis is often accompanied by dysbiotic microbiota of pathogenic potential and specifically demonstrated T. vaginalis adhesion to the biofilms of such, enhancing the pathogenic potential capabilities of the parasite (Hinderfeld et al., Microb Pathog 138:103820, 2020).

[0013] Current methods of treatment for vaginitis are insufficient, particularly for refractory or recurrent disease. Extended therapy including maintenance administration of antibiotics, faces issues with patient compliance, and even in compliant patients is not effective in a significant portion of the population. The efficacy of oral administration is limited as increasing dosages to the levels needed to eradicate disease may be toxic to the patient. There remains a need for alternative treatments for vaginitis. In particular, there remains an urgent need for a safe and effective treatments which can treat vaginitis including refractory vaginitis.SUMMARY

[0014] Provided herein are vaginal compositions combining an imidazole therapeutic agent with boric acid and methods of use therein to provide disruption, decimation and / or eradication of biofilms and associated pathogenic species and subgroups present in vaginitis. The described compositions and methods of administration provide not only short-term (e.g., 30 day), but also long-term control of recurrent vaginitis, for example, beyond the 30-day limitation in currently approved products.

[0015] The use of the compositions described herein provides simultaneous local application of both a imidazole therapeutic agent and boric acid in a combined formulation in which the therapeutic agent and the boric acid are administered together in a single composition . The formulations may be immediate release, as well as modified release formulations including sustained (extended) release, controlled release, pulsatile release, or delayed release. In someaspects, the described compositions can provide therapeutic agent release up to 24 hours. The extended release is particularly advantageous in view of current treatments.

[0016] Specifically, embodiments described herein allow for the use of higher doses of imidazole therapeutic agents such as nitroimidazole in combination with boric acid in a single unit composition for the effective treatment of vaginitis. In contrast to previous studies with boric acid which required prolonged intravaginal therapy for 21 -30 days, it was unexpectedly determined that the optimal duration of the provided combination intravaginal therapy is much shorter, for example 7 days, leading to improved patient compliance. The compositions and methods described herein may also be used for prophylactic treatment of patients prone to recurrent vaginitis.

[0017] In some aspects, the compositions described herein may be administered in a modified release formulation. Such modified release formulations include sustained (or extended) release in which therapeutic agents are released at a predetermined rate over a period of time; controlled release, in which a same amount of the therapeutic agents is released over time; delayed release in which the therapeutic agents are released at a later time than administration; and pulsatile release in which the therapeutic agents are released in a predetermined pattern over a specific time.

[0018] Modified release of a therapeutic agent reduces the frequency at which the drug needs to be administered, improving patient compliance and reducing adverse effects. In some embodiments, this method and compositions described herein provide an intravaginal dosage formulated for a controlled release within 24 hours.

[0019] As described in further detail in the examples, vaginally administered compositions demonstrate advantages in the inhibition of pathogens and associated biofilms. In vitro studies documented herein confirm the unexpected and synergistic effect of combining the imidazole therapeutic agent with boric acid in inhibiting the growth of planktonic cells and inhibiting the biofilm of the dominant pathogen responsible for different manifestations of vaginitis. These results support the notion that the combined vaginal administration of an imidazole therapeutic agent with boric acid can provide an improved treatment for vaginitis, in particular a treatment that is of short duration (< 7 days) thereby increasing patient compliance and reducing post-treatment recurrence rates and refractory disease.

[0020] In an embodiment, the composition is provided in the form of a cream, ointment, foam, or vaginal suppository. In an embodiment, the vaginal suppository is a lipophilic vaginal ovule including oil soluble excipient pessary base substantially free of water. In some aspects, the composition may be administered as a suppository ovule delivering a substantially water-insolublenitroimidazole or imidazole therapeutic agent; and a water-soluble boric acid, in one physically stable dosage unit, wherein the therapeutic agent and boric acid are delivered sequentially or simultaneously at a modified release rate over 24 hours.

[0021] In some embodiments, the suppository contains 100 to 1 ,000 mg of an imidazole such as nitroimidazole, and from 300 to 900 mg boric acid. In some embodiments, the vaginal suppository contains 500 to 1 ,000 mg metronidazole. In some embodiments, the vaginal suppository contains 100 to 400 mg tinidazole. In some embodiments, the vaginal suppository contains 100 to 400 mg imidazole (e.g., miconazole or tioconazole).

[0022] In one aspect, provided herein is a composition and method for the treatment of bacterial vaginosis in which a nitroimidazole therapeutic agent and boric acid are used in the treatment of G. vaginalis when simultaneously administered to the patient by vaginal application in a modified release composition. In one aspect, a modified release therapy can be customized or personalized according to phases of disease (pH variation, inflammation severity, acute-chronic). In some embodiment, a nitroimidazole therapeutic agent active against G. vaginalis, together with boric acid and at least one pharmaceutically acceptable excipient, provide therapeutic modified release suitable for vaginal 24 hour administration as part of a personalized medical protocol. In one embodiment, the nitroimidazole therapeutic agent is a 5-nitroimidazole or a pharmaceutically acceptable salt thereof. In one embodiment, the 5-nitroimidazole is selected from metronidazole or tinidazole. In some embodiments, the nitroimidazole is present in the composition in the amount from 4 to 40 wt.% based on the total weight of the composition. In some embodiment, the boric acid is present in an amount of from 10 to 30 wt.% based on the total weight of the composition.

[0023] In an embodiment, the patient is a female having recurrent BV. In some embodiments, the method is effective to prevent recurrence of BV in the patient for a period of at least 30 days, preferably at least 45 days e.g., at least 60 days from the start of the treatment. In an embodiment, the treatment is effective to prevent the recurrence of BV in the patient without the need for conventional antibiotic maintenance therapy in which lower doses of the antibiotic are administered for sustained periods of time. In an embodiment, the patient is a female patient having refractory BV. In an embodiment, the patient is refractory to an FDA-approved treatment for BV, for example oral or vaginal treatment with clindamycin or metronidazole. In some embodiments, the method includes administration of the composition for a treatment period of up to 14 days, e.g., up to 7 days. In one embodiment, the composition is provided in the form of a vaginal suppository that contains 750 mg metronidazole and 600 mg boric acid, and the method includes administration of the vaginal suppository once a day for a period of 7 days.

[0024] In one aspect, provided herein is a method for the treatment of VVC with an imidazole therapeutic active agent and boric acid in a controlled release composition. In some embodiments, the imidazole therapeutic agent is miconazole, tioconazole, and clotrimazole, or pharmaceutically available salts thereof. In some embodiments, the imidazole therapeutic agent effective against C. albicans is present in the composition in an amount of from 2 to 10 wt.% based on the total weight of the composition. In some embodiment, the boric acid of the therapeutic composition is present in an amount of from 10 to 30 wt.% based on the total weight of the composition.

[0025] In an embodiment, the patient is a female having recurrent VVC (RVVC). In some embodiments, the method is effective to prevent RVVC in the patient for a period of at least 30 days, preferably at least 45 days e.g., at least 60 days from the start of the treatment. In an embodiment, the treatment is effective to prevent the recurrence of RVVC in the patient without the need for conventional antibiotic maintenance therapy. In an embodiment, the patient is a female patient having refractory VVC. In an embodiment, the patient is refractory to an FDA- approved treatment for VVC, for example, vaginal treatment with miconazole or oral treatment with Fluconazole. In some embodiments, the method includes administration of the composition for a treatment period of up to 14 days, e.g., up to 7 days. In one embodiment, the composition is provided in the form of a vaginal suppository that contains 100 mg miconazole and 300 mg boric acid, and the method includes administration of the vaginal suppository once a day for a period of 7 days.

[0026] In one aspect, the disclosure provides a method of treating VVC in a patient in need thereof, the method of including vaginal administration to the patient of a composition including of imidazole therapeutic agent and boric acid is active against C. albicans, wherein a therapeutically effective amount of the composition is administered. In some aspects, the therapeutic agent is a imidazole therapeutic agent.

[0027] In one aspect, the disclosure provides a pharmaceutical composition for vaginal administration including an imidazole therapeutic agent and boric acid is active against C. albicans, together with at least one pharmaceutically acceptable excipient are suitable for vaginal administration. In one embodiment, the imidazole therapeutic is selected from miconazole or tioconazole, or a pharmaceutically acceptable salt thereof. In some embodiment, the imidazole therapeutic agent is present in the pharmaceutical composition in an amount from 2 to 10 wt.% based on the total weight of the composition. In some embodiment, the boric acid is present in the pharmaceutical composition in an amount 10 to 30 wt.% based on the total weight of the composition.

[0028] In one aspect, provided herein is a method for the treatment of trichomoniasis in which an imidazole therapeutic agent such as a nitroimidazole therapeutic agent and boric acid are active against T. vaginalis when simultaneously administered to the patient by vaginal application in a modified release composition. In one embodiment, the nitroimidazole therapeutic agent is a 5- nitroimidazole selected from metronidazole or tinidazole, or a pharmaceutically acceptable salt thereof. In some embodiments, the nitroimidazole therapeutic agent is present in the composition in the amount from 4 to 40 wt.% based on the total weight of the composition. In some embodiment, the boric acid is present in an amount of from 10 to 30 wt.% based on the total weight of the composition.

[0029] In an embodiment, the patient is a female having recurrent trichomoniasis. In some embodiments, the method is effective to prevent recurrence of trichomoniasis in the patient for a period of at least 30 days, for instance at least 45 days, e.g., at least 60 days from the start of the treatment. In an embodiment, the treatment is effective in preventing the recurrence of trichomoniasis in the patient without the need for conventional antibiotic maintenance therapy. In one aspect, the patient is a female patient having refractory trichomoniasis. In an embodiment, the patient is refractory to an FDA-approved treatment for trichomoniasis, for example oral or vaginal treatment with metronidazole. In some embodiments, the method includes administration of the composition for a treatment period of up to 14 days, e.g., up to 7 days. In one embodiment, the composition is provided in the form of a vaginal suppository that contains 750 mg metronidazole and 600 mg boric acid, and the method includes administration of the vaginal suppository once a day for a period of 7 days.

[0030] In one aspect, the disclosure provides a method of treating trichomoniasis in a patient in need thereof, the method of including vaginal administration to the patient of a composition including of nitroimidazole therapeutic agent and boric acid is active against T. vaginalis, wherein a therapeutically effective amount of the composition is administered.

[0031] In one aspect, the disclosure provides a pharmaceutical composition for vaginal administration including a nitroimidazole therapeutic agent active against T. vaginalis and boric acid, together with at least one pharmaceutically acceptable excipient suitable for vaginal administration. In one embodiment, the nitroimidazole therapeutic agent is a 5-nitroimidazole or a pharmaceutically acceptable salt thereof. In one embodiment, the 5-nitroimidazole therapeutic agent is selected from metronidazole or tinidazole. In some embodiment, the nitroimidazole therapeutic agent is present in the pharmaceutical composition in an amount from 4 to 40 wt.% based on the total weight of the composition. In some embodiment, the boric acid is present inthe pharmaceutical composition in an amount 10 to 30 wt.% based on the total weight of the composition.

[0032] In one aspect, the disclosure provides a pharmaceutical composition for vaginal administration including a customized or personalized medical treatment protocol for two or more compositions to treat acute or chronic vaginitis conditions with compositions delivering compositions over 24 hours.

[0033] In one aspect, the imidazole therapeutic agent such as nitroimidazole or pharmaceutically acceptable salt thereof, present in an ointment composition in amount from 2 to 40 wt.% based on the total weight of the composition. In some embodiment, the boric acid is present in the pharmaceutical composition in an amount 10 to 30 wt.% based on the total weight of the composition,

[0034] In one aspect, the imidazole therapeutic agent such as nitroimidazole or pharmaceutically acceptable salt thereof, present in the cream, ointment, or foam composition in amount capable of delivering therapeutic dosage described herein, in a 5 gram cream, ointment, or foam medicament to be administered. In some embodiments, the boric acid is present in the same cream, ointment, or foam composition accordingly, in amount capable of delivering therapeutic dosages described herein, in a 5 gram cream, ointment, or foam medicament to be administered.

[0035] Thus, in particular aspects, provided herein are compositions wherein two active ingredients at high strengths are formulated into a small, easy to administer vaginal suppository. The suppository can be used to deliver two drugs (one water-soluble and the other waterinsoluble) in a small (2500 mg ovule), physically stable dosage unit, wherein the drugs are delivered at a modified release rate over 24 hours sequentially or simultaneously. This is achieved by combining excipients including oleaginous excipients with different polymer(s) and surfactants at selected concentrations, which enables intentional modulation of the rate(s) of release of therapeutic active agent(s) delivered in the composition. In embodiments, the rate of release is modulated by changing the proportion of lower and higher melting point oils, polymer(s), and surfactant(s) in the composition.

[0036] Another embodiment is a method for modified release of boric acid and an imidazole therapeutic agent, essentially as describe herein. By way of example, the imidazole therapeutic agent can include one or more of nitroimidazole, metronidazole, tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazol, azaindole, secnidazole, or benznidazole.

[0037] Another embodiment is a kit including: (i) a composition including a nitroimidazole active or imidazole active agent in combination with boric acid, and (ii) an applicator adapted for delivery (e.g., to the vaginal cavity of a human subject) of a modified release including a controlled release(or delayed release) composition of any embodiment described herein, for instance for treatment of bacterial vaginosis.

[0038] Also described are modified release pharmaceutical compositions for vaginal administration, which compositions includes: at least one imidazole therapeutic agent; boric acid; an oleaginous excipient, a polymer, and a surfactant, wherein the rate of release of the at least one imidazole therapeutic agent and / or the boric acid is controlled by using a specific concentration of the oleaginous excipient, the polymer, and / or the surfactant.BRIEF DESCRIPTION OF THE DRAWINGS

[0039] FIG. 1 : Isobologram for the combination treatment of boric acid and metronidazole against planktonic cells of G. vaginalis ATCC 14018. FIGs. 1-8 are reproduced from co-pending WO2023201341 , which is incorporated herein by reference in its entirety.

[0040] FIG. 2: Isobologram for the combination treatment of boric acid and tinidazole against planktonic cells of G. vaginalis ATCC 14018

[0041] FIG. 3: Relative biofilm mass following combination treatments of boric acid and metronidazole for the inhibition of biofilm formation by G. vaginalis ATCC 14018. Single drug treatments are shown (BA MIC-B90and metronidazole MIC-B90) and compared to effective combination treatments (as determined by FICI90calculations). Concentrations for the displayed FICgo values are marked with * in Table 8.

[0042] FIG. 4: Relative Biofilm mass following combination treatment of boric acid and tinidazole for the inhibition of biofilm formation of G. vaginalis ATCC 14018. Single drug treatments are shown (BA MIC-B90and tinidazole MIC-B90) and compared to effective combination treatments (as determined by FIC l90calculations). Concentrations for the displayed FIC90values are marked with * in Table 9.

[0043] FIG. 5: Isobologram for the combination of boric acid and metronidazole against biofilm formation by G. vaginalis ATCC 14018.

[0044] FIG. 6: Isobologram for the combination of boric acid and tinidazole against biofilm formation by G. vaginalis ATCC 14018.

[0045] FIG. 7: Isobologram for the combination of boric acid and metronidazole against biofilm- associated G. vaginalis ATCC 14018.

[0046] FIG. 8: Isobologram for the combination of boric acid and tinidazole against biofilm- associated G. vaginalis ATCC 14018.

[0047] FIGs. 9-15: Graphs of boric acid and metronidazole release in different formulations over time.DETAILED DESCRIPTION

[0048] Provided are methods and compositions for the treatment of vaginitis including the use of vaginal suppositories to provide a combined delivery of boric acid and an imidazole therapeutic agent. Such compositions may be used for immediate and long-term treatment of acute, recurrent, and refractory vaginitis.

[0049] Vaginitis is characterized by inflammation in the vulva or vagina. The vast majority of cases of vaginitis are caused by three characteristic infections, bacterial vaginosis (BV) (>50%), vulvovaginal candidiasis (VVC) (<25%), and trichomoniasis (<25%). BV occurs when the balance of vaginal bacteria is disrupted. It is characterized by increased loads of facultative anaerobes and their subgroups, including Gardnerella vaginalis, Provetella spp., Atopobium vaginae, and other fastidious BV-associated bacteria, such as Megasphaera, Sneathia, and Clostridiales species; increased production of volatile amines; and a rise in vaginal pH to > 4.5. These changes are accompanied by a marked depletion of key Lactobacillus species such as Lactobacillus crispatus, which produces lactic acid, bacteriocins, and other antimicrobial molecules, and which is thought to play an important role in host defense against pathogens. VVC is characterized by yeast colonization, most frequently by Candida albicans (C. albicans) though occasionally caused by other Candida species or yeasts. Trichomoniasis is caused by the protozoan Trichomonas vaginalis ( T. vaginalis).

[0050] Vaginitis is currently treated with antibiotics such as metronidazole, clindamycin, and tinidazole as well as antifungals such as triazole and imidazole. However, the microbes involved in BV, VVC, and Trichomonas either create or work with biofilms, making them resistant to antibiotics and antifungal drugs. Current FDA-approved treatment options frequently fail, leading to a high rate of refractory disease as well as high recurrence rates. For example, BV is associated with recurrence rates of 30% in 3 months, 30-50% within 6 months, and rising to 80% within one year, and 15-20% of patients have refractory BV. As used herein, the term “refractory bacterial vaginosis” is intended to define bacterial vaginosis in a patient that does not respond to conventional antibacterial therapy such as a 5-7 day course of oral or vaginal treatment with clindamycin or metronidazole, or with any other antibiotic.

[0051] Previous studies have evaluated a long-term maintenance antimicrobial regimen of twice weekly metronidazole 0.75% gel for the treatment of BV (Sobel et al., Am. J. Obstet. Gynecol. 2006; 194: 1283-1289). However, the regimen was only effective while prophylaxis continued, and long-term efficacy or cure was uncommon. Similar relapses were discussed in Reichman et al., (2009) which notes that after a total treatment time of 6 months, only 77% of patients wereclinically cured, i.e., asymptomatic and negative for Amsel’s clinical criteria for BV. Only 67% of patients remained cured at 9 months, i.e., 3 months after maintenance therapy. The median duration of remission was 8.7 months.

[0052] More recently, simultaneous administration of oral nitroimidazole and vaginal boric acid therapy followed by long-term twice weekly vaginal metronidazole gel for 5 months was used to treat recurrent BV (Surapaneni etal., Sexually Transmitted Diseases 2021 ; 48(10): 761 -765). The treatment regimen consisted of oral tinidazole or metronidazole 500 mg twice daily for 7 days starting on the same day as vaginal boric acid (600 mg) which was given for 30 days. Follow-up visits occurred on days 30 and 35 and, if asymptomatic and with < 3 Amsel criteria for BV, twice weekly metronidazole gel 0.75% was then prescribed for 5 months. The initial regimen of a short course of oral nitroimidazole and simultaneous longer course of vaginal boric acid was reported to achieve a satisfactory response in 87 out of 88 patients. Thereafter, the maintenance metronidazole gel prevented symptomatic BV recurrence in 70% of compliant patients. Long-term cure at a 12-month follow up was demonstrated in 50% of the patient population. The duration of the initial treatment (30 days) and the need for long-term maintenance therapy resulted in frequent patient follow-up loss. Even in compliant patients, recurrence rates of BV rates were still prevalent.

[0053] As discussed in further detail below, in vitro studies confirm the unexpected synergistic effect of combining metronidazole or tinidazole (nitroimidazole drugs) with boric acid in inhibiting the growth of planktonic cells and inhibiting biofilms of Gardnerella vaginalis, the dominant bacterial pathogen responsible for BV. These results support the notion that the vaginal administration of a combination of a nitroimidazole and boric acid can provide an improved treatment for bacterial vaginosis, in particular a treatment that is short in duration (thereby maximizing patient compliance), yet highly effective in eradicating the disease and in reducing post-treatment recurrence rates. In embodiments, the compositions and methods herein are used in refractory patients.

[0054] The treatment methods herein described pertain to vaginal administration of a composition containing boric acid in combination with a nitroimidazole therapeutic agent(s); or a composition containing boric acid in combination with an imidazole therapeutic agent(s), in a single medicament to be administered as an effective treatment for vaginitis. Nitroimidazole compounds that may be used herein include both metronidazole and tinidazole. Imidazole compounds that may be used herein include miconazole, clotrimazole, butoconazole, tioconazole and terconazole. Significantly, co-administration of a composition containing both therapeutically active agents (an antibiotic such as an imidazole and boric acid) provides an enhanced synergisticeffect in the treatment of the condition and is effective to reduce (e.g., to prevent) vaginitis recurrence.

[0055] Nitroimidazole antibiotics are known to eradicate G. vaginalis and other anaerobic pathogens involved in BV. They are classified according to the position of the nitro group on the imidazole ring. 5-nitroimidazoles are particularly suitable for use in the composition and methods described herein. Nitroimidazoles which may be used in the compositions and methods disclosed herein include, but are not limited to, metronidazole, tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazol (CL 64855), azinidazole, secnidazole and benznidazole. Examples of 5-nitroimidazoles that find use in the compositions and methods disclosed herein include metronidazole and tinidazole. Preferably, the nitroimidazole effective against G. vaginalis is metronidazole. Metronidazole is also effective against trichomonas vaginalis.

[0056] The compositions and methods described herein may be used in the prophylactic and therapeutic treatment of individuals with vaginitis or suspected of having vaginitis including BV. As used herein, the term “BV” encompasses both symptomatic and asymptomatic BV. Common symptoms of BV include malodorous vaginal discharge that may be white or grey in color and burning associated with urination. BV is routinely diagnosed by physical examination and by tests carried out on vaginal secretions. The diagnostic tests may include the following, though other tests may also be performed:Gram stain-, a gram stain of vaginal secretions which shows the depletion of lactobacilli and overgrowth of G. vaginalis bacteria usually confirms bacterial vaginosis. pH test e.g. using pHydrion® paper): to control bacterial growth the vagina is normally slightly acidic with a pH of 3.8-4.2. A pH greater than 4.5 is indicative of bacterial vaginosis and other inflammatory and infective vaginal processes.Saline microscopy: some of the vaginal discharge sample is diluted with one or two drops of normal saline and examined under a microscope, first at x10 magnification, then at x40. The sample is searched for epithelial cells, blood cells, “clue” cells (i.e., epithelial cells with borders studded or obscured by bacteria), and mobile trichomonads. The presence of “clue” cells is indicative of bacterial vaginosis.10% KOH whiff test (also known as the “amine test”): a small amount of 10% potassium hydroxide (KOH) is added to some of the vaginal discharge and is sniffed. Any amine or fishy odor is considered a positive whiff test and a sign of bacterial vaginosis. The sample is then examined under a microscope of fungal elements.

[0057] In clinical practice, bacterial vaginosis may be diagnosed according to Amsel criteria (Amsel et al., Am J Medi. 74(1 ):14-22, 1983) including vaginal pH greater than 4.5; positive whiff test (amine test); abnormal vaginal discharge (i.e., a thin, white yellow, homogenous, discharge); and at least 20% clue cells on microscopy. Alternatively, a diagnosis of BV may be made based on the observation of certain bacteria from a vaginal swab on Gram stain microscopy. The Gram stain can be scored using the Nugent criteria to give a “Nugent score” (Nugent et al., J. Clin. Microbiol. 29(2):297-301 , 1991 ). A Nugent score > 7 is considered indicative BV.

[0058] The compositions and methods described herein may be used in the treatment of female patients suspected of having BV, patients having physical symptoms of BV such as malodorous vaginal discharge that is white or grey in color, as well as patients who test positive in diagnostic tests. For example, in one embodiment, the patient is a female that exhibits 3 out of the 4 Amsel criteria. In another embodiment, the patient is a female that exhibits all 4 Amsel criteria. In another embodiment, the patient is a female that exhibits a Nugent score > 7 In another embodiment, the patient is a female that exhibits 3 out of the 4 Amsel criteria and a Nugent score > 7.

[0059] In one set of embodiments, the patient for treatment is a female having recurrent bacterial vaginosis. As used herein, the term “recurrent bacterial vaginosis” or “RBV” is intended to define bacterial vaginosis in a patient having BV that meets > 3 Amsel criteria and that has a history of at least 3 episodes of BV in the previous 12 months. In one embodiment, a female that is frequently infected with bacterial vaginosis is one who has had at least 4 episodes of BV in the previous 12 months. In one set of embodiments, the patient is a female having recurrent bacterial vaginosis and that has previously undergone treatment with conventional antibacterial therapy. Conventional antibacterial therapy may, for example, include oral or vaginal treatment with clindamycin or metronidazole, or with any other antibiotic.

[0060] Advantageously, the treatment method herein described is effective to prevent recurrence of BV post-treatment. In one set of embodiments, the treatment method prevents recurrence of BV for a period of at least 30 days, preferably at least 45 days, more preferably at least 60 days from the start of the treatment.

[0061] In one embodiment, the treatment described herein is a method for the prevention of BV. In this embodiment, the patient may be a female patient that is asymptomatic for BV and / or that has a negative diagnosis for BV according to one or more of the clinical criteria set out herein. In one embodiment, the patient is a female that is frequently infected with BV. A female that is frequently infected with bacterial vaginosis may be one who has had at least four episodes of BV in the previous 12 months.

[0062] For therapeutic treatment, the method may include applying the composition to the vagina from once a day to three times a day, preferably once or twice daily. Advantageously, it will be applied once daily. Once daily administration at night (ideally immediately before bedtime) will generally be preferred in order to maximize contact of the active agents with the pathogens present in the vagina and in order to enhance the efficacy of the treatment. A once daily administration is considered particularly beneficial to aid in patient compliance.

[0063] In embodiments, the duration of the therapeutic treatment ranges from 5 to 14 days, for example it may be 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 days. Advantageously, the treatment period will be short in duration in comparison to standard treatments whilst still effective to achieve the desired clinical outcome for the patient and clinician. A treatment period of 5 to 10 days, preferably 6 to 9 days, e.g. 7 days, is considered particularly beneficial.

[0064] In one set of embodiments, therapeutic treatment may be carried out once or twice a day for 5 to 14 days, preferably for 5 to 10 days, more preferably 6 to 9 days, e.g. 7 days. In some embodiments, treatment may be carried out once a day for 5 to 14 days, preferably for 5 to 10 days, more preferably 6 to 9 days, e.g., 7 days. A treatment that is carried out once a day for 7 days is particularly preferred.

[0065] Therapeutic treatment in accordance with the methods disclosed herein may be followed by maintenance therapy in order to prevent recurrence of the condition. For example, it may be followed by oral or vaginal metronidazole or clindamycin therapy. In the case where the treatment is followed by maintenance therapy, the maintenance therapy may be shorter in duration than conventional maintenance therapy. For example, maintenance therapy may be conducted for a period of 3 months, preferably up to 2 months, e.g., up to 1 month.

[0066] As described herein, in one set of embodiments, maintenance therapy may involve vaginal administration of the combined boric acid I nitroimidazole composition as herein described. For use in maintenance therapy, any of the dosage forms herein described may be administered to the patient with an appropriate adjustment to the dosage regimen, e.g., the frequency and / or duration of administration. In embodiments, the frequency of administration is reduced in any maintenance therapy, for example it may be reduced to 1 to 3 times a week, e.g., twice weekly. The duration of treatment for the purposes of maintenance therapy may be extended, for example it may be extended up to 1 month, up to 2 months, up to 3 months, up to 4 months, up to 5 months or up to 6 months. In some cases, maintenance therapy may extend for 6-12 months or more.

[0067] In a preferred set of embodiments, the therapeutic treatment disclosed herein will not involve any follow-on maintenance therapy.

[0068] For prophylactic treatment, the methods disclosed herein may include applying the composition herein described to the vagina from one to three times a week, for example twice a week. Duration of the prophylactic treatment may extend up to several months, for example up to 6 months, up to 12 months, or up to 18 months.

[0069] As used herein, the terms “treatment” or “treating” refer to a reduction in severity of vaginitis, i.e. regression of the underlying cause of the condition including regression of BV, VVC, and / or Trichomonas. In some embodiments, treatment means a reduction in the frequency of infections. For example, the outcome of the treatment will be a patient that does not suffer from bacterial vaginosis for a period of up to 30 days after administration of the composition herein described. In other embodiments, the outcome of the treatment will be patient that does not suffer from bacterial vaginosis for a period of up to 45 days, preferably up to 60 days after administration of the composition. In some embodiments, treatment includes clinical cure, i.e. elimination of the underlying cause of the condition. Regression of the underlying cause of the condition and clinical cure may be assessed post-treatment using any of the tests described herein in respect of diagnosis. Unless otherwise specified, the terms “treatment” or “treating” as used herein include prophylaxis, i.e., prevention of the occurrence of vaginitis or prevention of its recurrence. In one embodiment, the prophylactic treatment is a maintenance therapy for vaginitis. As used herein, the term “maintenance therapy” refers to the administration of a therapeutic agent following the main treatment for the disease. In one aspect, the main treatment for the patient is treatment of BV. The precise treatment protocol in accordance with the methods herein described will be dependent on factors such as the severity of the condition, dosage of active agents, whether the treatment is therapeutic or prophylactic, etc. In one embodiment, the treatment method is effective in the treatment of BV in a female patient suffering from at least one additional vaginal infection, such as VVC or trichomoniasis. In one embodiment, the treatment is a method for the treatment of mixed vaginitis. As used herein, the term “mixed vaginitis” refers to vaginitis caused by the simultaneous presence of at least two vaginal pathogens that contribute to an abnormal vaginal microbiota.

[0070] The compositions provided herein for treatment are vaginal compositions combining an imidazole therapeutic agent with boric acid in stable compositions which advantageously provide safe, therapeutically effective administration of an imidazole therapeutic agent such as nitroimidazole and boric acid when administered to the vagina. The compositions may have immediate and modified release sustained (or extended) release in which therapeutic agents are released at a predetermined rate over a period of time; controlled release, in which a same amount of the therapeutic agents is released over time; delayed release in which the therapeuticagents are released at a later time than administration; and pulsatile release in which the therapeutic agents are released in a predetermined pattern over a specific time.

[0071] The compositions may be administered in the form of a cream, ointment, foam, or a syringe used to deliver the therapeutic agent to the desired body cavity. The syringe may be provided with an appropriate delivery tube or needle. Further disclosed herein are kits including a composition as herein described and an applicator adapted for delivery of the composition to the vagina. The composition may also be contained within a vaginal ring, tampon, or sponge, for example. In embodiments, the composition is provided in the form of a vaginal suppository. In one embodiment, the composition is provided in the form of a vaginal ovule containing the active agents in a pessary base which includes one or more pharmaceutically acceptable excipients.

[0072] Such administration forms are particularly convenient for self-administration by the patient to the vaginal and / or vulva. Any such device will generally be adapted to deliver one or more doses of the product in a highly uniform manner. Typically, a single unit dose may include from 1 to 10 grams of the composition, preferably from 2 to 7 grams, e.g., from 3 to 5 grams.

[0073] In one embodiment, the composition contains only two therapeutically active agents, i.e., the nitroimidazole or imidazole therapeutic agent and boric acid as herein described. For example, it may include metronidazole and boric acid, or a combination of tinidazole and boric acid, or a combination of miconazole and boric acid.

[0074] In one embodiment, more than two therapeutic active agents are present. For example, the composition may contain two or more active agents. In order to provide a broader spectrum of activity against vaginal infections, for example, it may be advantageous for the composition to additionally include one or more active agents against C. albicans. This is particularly desirable where metronidazole is present since its administration may result in the proliferation of fungal pathogens. An anti-fungal agent active against C. albicans may be an imidazole, such as miconazole or tioconazole. Any such agent may be used in the form of their pharmaceutically acceptable salts. Where miconazole is used it may be employed in the form of the free base or as a salt such as the nitrate salt. Typically, it will be employed in the form of miconazole nitrate.

[0075] Examples of other active agents that may be present in the composition disclosed herein include econazole, ketoconazole, itraconazole, posaconazole, fluconazole, voriconazole, clotrimazole, ciclopirox, tolnaftate, terbinafine, sertaconazole, nystatin, tavaborole, efinaconazole, undecylenic acid, and oxiconazole. Derivatives and pharmaceutically acceptable salts of any of these compounds may be employed. Advantageously, however, the composition may be applied without other antibiotics (whether simultaneously or sequentially).

[0076] Non-limiting example combinations of active agents that may be provided in the compositions for use in the methods disclosed herein include, but are not limited to, metronidazole and boric acid; and tinidazole and boric acid; and miconazole nitrate and boric acid.

[0077] It will be understood that the composition containing the active agent will be administered to the subject in a “therapeutically effective amount”, such as, in an amount that will elicit the biological or medical response of the patient that is being sought by the physician in the treatment of vaginitis as herein described. The “therapeutically effective amount” may depend on factors such as the nature of the particular active agent, the choice of any other actives that may be present, the choice of other non-active components, the severity of the condition, and timing and duration of the treatment, whether the treatment is intended to be therapeutic or prophylactic, etc.

[0078] In the embodiments, the imidazole and the boric acid are co-administered to the patient per vagina. The term “co-administration” is used herein to refer to the delivery of two or more separate chemical entities in vivo. Co-administration refers to the simultaneous delivery of separate agents; to the simultaneous delivery of a mixture of agents; as well as to the delivery of one agent followed by the delivery of a second agent or agents. In all cases, agents that are coadministered are intended to work in conjunction with each other, i.e., these will be present together in the vagina to achieve the desired therapeutic and / or prophylactic effect.

[0079] The nitroimidazole active agent against G. vaginalis may be present in the composition in an amount from 4 to 40 wt%, preferably from 5 to 35 wt.% (based on the total weight of the composition). In one embodiment, the high concentration of the nitroimidazole may be employed, for example a concentration that exceeds the conventionally used in the treatment of vaginal infections, such as BV, or trichomoniasis. Where the nitroimidazole is metronidazole, for example, its concentration may range from 15 to 40 wt.%, preferably from 20 to 35% wt.%, e.g., from 20 to 30 wt.% (based on the total weight of the composition).

[0080] In embodiments, the nitroimidazole is provided in a vaginal suppository and is present in an amount from 100 to 1 ,000 mg, preferably from 150 to 900 mg (per suppository). In embodiments, the nitroimidazole is metronidazole and is present in an amount from 500 to 1 ,000 mg, preferably from 550 to 950 mg, more preferably from 600 to 900 mg, yet more preferably from 600 to 900 mg, yet more preferably from 650 to 850 mg, e.g., from 700 to 800 mg (per suppository). An amount of 750 mg metronidazole per suppository, for example, in an overall convenient small suppository weight of 2,500 mg is particularly preferred for easier insertion. In embodiments, the nitroimidazole is tinidazole and is present in an amount from 100 to 400 mg, preferably from 100 to 300 mg (per suppository).

[0081] In an embodiment, the amount of boric acid present in the composition will be effective to disrupt, remove or detach at least part of the bacterial biofilm from the vaginal mucosa. In one embodiment, it will be effective to eradicate the biofilm. As used herein, the term “bacterial biofilm” means as a community of bacteria which are contained within an extracellular polymeric substance (EPS) matrix produced by the bacteria and attached to the body surface such as the vaginal mucosa. In one embodiment, the boric acid is present in an amount of from 10 to 30 wt.%, preferably from 10 to 25 wt.% (based on the total weight of the composition).

[0082] Specifically in BV, the nitroimidazole therapeutic agent simultaneously eradicates G. vaginalis and other anaerobic pathogens. Where the nitroimidazole (e.g., metronidazole) may cause any secondary Candida infection, such as in VVC, the boric acid may additionally prevent and / or treat this thereby avoiding the need to use a second therapeutic agent (e.g. fluconazole) as treatment for the secondary Candida infection.

[0083] Typical boric acid suppositories deliver a dosage of 300 to 600 mg in either a hydrophilic base containing for example, water, glycerin, polyethylene glycol of varied molecular weights, or a lipophilic base containing for example, triglycerides, fatty acids, ethoxylated fatty alcohols, and waxes. Both types of hydrophilic and lipophilic bases provide a short-term boric acid release profile, where suppositories dissolve within minutes to up several hours after vaginal insertion in a rapid release of the boric acid dosage. While typical boric acid suppositories rapidly dissolve (< 2 hours) from insertion, the modified release formulations described herein may extend boric acid administration for 24 hours.

[0084] In embodiments, boric acid is provided in a vaginal suppository and is present in an amount from 300 to 900 mg, preferably from 350 to 850 mg, more preferably from 400 to 800 mg, yet more preferably from 450 to 750 mg, e.g., from 500 to 700 mg (per suppository). An amount of 600 mg boric acid per suppository (for example, in an overall suppository weight of 2,500 mg) is particularly preferred.

[0085] In embodiments, the imidazole is provided in an amount of from 2 to 10 wt.%, preferably from 4 to 8 wt.% (based on the total weight of the composition). In embodiments, the imidazole is provided in a vaginal suppository and is present in an amount from 100 to 300 mg, preferably from 150 to 250 mg, e.g., 200 mg (per suppository). In embodiments, the imidazole is miconazole nitrate and the miconazole nitrate is used in an amount from 100 to 300 mg, preferably from 150 to 250 mg, e.g. 200 mg (per suppository). In some embodiments, the imidazole is tioconazole, and the tioconazole is used in an amount from 100 to 300 mg, preferably 100 or 300 mg per suppository.

[0086] The total amount of active agent (e.g., the nitroimidazole, boric acid and, where present, the imidazole) may range from 15 to 50 wt.%, preferably from 20 to 45 wt.%, for example from 25 to 40 wt.% (based on the total weight of the composition). Where the nitroimidazole is metronidazole, the total amount of active agent in the composition will generally be higher than when the nitroimidazole is tinidazole. For example, in the case where the nitroimidazole is metronidazole, the total amount of active agent in the composition may in embodiments be in the range from 25 to 50 wt.%. Preferably from 30 to 45 wt.%, for example from 32 to 40 wt.% (based on the total weight of the composition. When the nitroimidazole is tinidazole, the total amount of active agent in the composition may in embodiments be in the range from 22 to 32 wt.% (based on the total weight of the composition).

[0087] Described herein are compositions and methods to safely deliver boric acid at a modified release rate over 24 hours for intravaginal administration in combination with an imidazole therapeutic agent in a single unit composition, providing greater therapeutic action with reduced side effects. In addition, described herein is administration of a composition containing both active agents to provide an enhanced synergistic effect in the treatment vaginitis in an effective manner to reduce (e.g., to prevent) its recurrence.

[0088] Preferred combinations of active agents for use in the compositions and methods are those which demonstrate enhanced (e.g., synergistic) activity against one or more causative agents of vaginitis, e.g., G. vaginalis in the case of BV; C. albicans in the case of VVC, and T. vaginalis in the case of trichomoniasis, relative to the use of any one of the agents alone. Evidence of synergy may include any one of the following: a faster cure; cure time or symptoms improvement (such as improvement in at least one sign or key symptom of BV); and a reduction in the relapse rate of BV (for instance, the rate of reappearance of the infection after cessation of the treatment). In the context of the susceptibility of a microorganism to an antimicrobial agent, synergy may be understood with reference to the definition set out by the European Committee of Antimicrobial Susceptibility Testing (EUCAST) of the European Society of Clinical Microbiology and Infectious Disease (ESCMID) 2000 (see ELICADT Definitive Document E. Def 1.2: Terminology relating to methods for the determination of susceptibility of bacteria to antimicrobial agents. Clin. Microbiol. Infect. 2000:6(9): 503-508: fractional inhibitor concentration (FIC) Index (FICI) < 0.5; synergy.

[0089] In one embodiment, provided herein is a method of treatment of vaginitis in which the method does not include administering to the patient any therapeutic amount of EDTA. In one embodiment, the composition for use in the method of treatment will be substantially free from EDTA, e.g., 0% EDTA.

[0090] In one embodiment, the compositions are provided in the form of a vaginal ovule. The ovule size may have a 2000 - 4000 mg capacity, preferably 2000 - 3000 mg capacity, e.g., 2500 mg capacity. When presented in an ovule, these include a pessary base containing the active agents. In one embodiment, a hydrophilic base or lipophilic base is utilized, while a lipophilic oleaginous (fatty acid based) is preferred.

[0091] In embodiments, provided herein are compositions in which the active agents are present in synergistically effective amounts. In this regard, the weight ratio of nitroimidazole to boric acid will generally be in the range of from 2:1 to 1 :3, preferably from 2:1 to 1 :1.2. Where the nitroimidazole is metronidazole, the weight ratio of metronidazole to boric acid may in embodiment be in the range from 1 :0.5 to 1 :1.5, preferably 1 :0.5 to 1 :1.2. Where the nitroimidazole is Tinidazole, the weight ratio of tinidazole to boric acid may in embodiment be in the range from 1 :1 to 1.3.

[0092] Imidazoles such as nitroimidazole are not readily soluble compounds. Specifically, metronidazole has a melting point of 158 °C to 160 °C and is a poorly water soluble therapeutic agent (10 g / L at 25 °C). Solubility in vegetable oils such as hydrogenated palm kernel oil (HPKO) and coconut oil (CCO) is greater, at 40 g / L at 25 °C. Boric acid is moderately soluble in water at 25 °C due to its polarity, with increased solubility at higher temperatures (3.6-5.7 gm / L). Boric acid is stable under normal temperatures and pressure, but is light sensitive and may discolor upon exposure to ultraviolet light. Compositions for intravaginal should be protected by light by a physical UV blocker allowable for intravaginal compositions (i.e., titanium dioxide or bentonite), or should be commercially packaged to reduce exposure to light.

[0093] Nitroimidazoles, and specifically metronidazole, have been esterified as described in EU Patent No. 0096870. Borate esters are organoboron compounds of boric acid and alcohols which can be readily synthesized. Therefore, esterification of nitroimidazole (-OH) with boric acid is preferentially avoided when combining boric acid and nitroimidazole in a single unit therapeutic composition.

[0094] Described herein are vaginal compositions combining a nitroimidazole or imidazole therapeutic agent with boric acid in stable formulations which advantageously provide safety and therapeutic effectiveness when vaginally co-administered in a single composition. In some aspects, the composition may provide one or more of antimicrobial, anti-biofilm, anti-inflammatory, and analgesic therapies.

[0095] In one embodiment, the composition may be formulated in an anhydrous lipophilic base. For example, the composition may be a imidazole therapeutic agent and boric acid in a vegetable oil-polymer base such as nitroimidazole and boric acid in a vegetable base. In one embodiment,excipients that complement the therapeutic agents are preferred. For example, the vegetable oils may be extracted from oleaginous plants such as palm kernel and coconut oil. HPKO and coconut oil CCO are allowed by the U.S. Food and Drug Administration (FDA) for vaginal applications. In some aspects the compositions may include 20 to 60 wt% vegetable oil including 30-45 wt% vegetable oil; or 40 wt% vegetable oil or any fraction thereof.

[0096] HPKO contains over 80% saturated fatty acids; mainly the short-chain fatty acids, such as lauric (C12) and myristic (C14) acid. It has a slip melting point of 27-29 °C and iodine value of 16-20. As a fatty base, it contains very little water and has low hygroscopicity. CCO is also high in saturated fatty acids. This is particularly useful since nitroimidazoles are hygroscopic. Vegetable oils such as HPKO and CCO are therefore ideal. Further, palm kernel and coconut oil have been reported to have antimicrobial properties (Obitte et ai, J. App. Sci. 2008; 8(10) 1950- 1955; Kusmar et al., Trend Microbiology 2020; 28(9): 753-768)). Palm kernel oil also has high content of polyphenols, a-tocopherol and sterols with predominance of p-sitosterol. |3-sitosterol is known to possess a regulatory role in the immune system (Yapi et ai, J. Food Sol. 2020 Dec 9(1 ):95). Other studies have reported that palm kernel oil with higher amounts of sciadonic acid inhibits the activity of phosphodiesterase (PDE-5, efficiency 80% at 133.7 pg / mL) and lipoxygenase-5 (LOX-5, efficiency 65% at 66.7 g / mL) suggesting enhanced anti-inflammatory effect (Zhou et.al, Molecules. 2019 Sept; 19:24 (18):3401 ). Coconut oil has also been reported to have anti-inflammatory, analgesic, and antipyretic effect using an acute animal model (Intaphaak et al., Pham. Biol. 2010 Feb. 48(2):151 -7).

[0097] In one embodiment, the compositions provided herein for use in the treatment of vaginitis provide use of hydrogenated palm kernel oil and coconut oil present in amounts of 10 - 60%, preferably from 25-45%, e.g., 40%.

[0098] The compositions provided herein for use in the treatment of vaginitis may use polymers rich in hydroxyl (-OH) which can crosslink with boric acid, depending on polymer class, concentration of polymer, and temperature at which boric acid is added to the molten base. The polymers can be present in amounts of 1-10%, preferably 2 - 5%, e.g., 2.5% by weight. Polymers which are capable of forming oleo-gels in vegetable oils are preferable, for example, hydrophobic polymers such as starch, bentonite, ethyl cellulose, or combinations thereof.

[0099] For example, mixtures of low and high melting point fats (where the distinction between low and high melting point is 25 °C, or room temperature) with ethyl cellulose (a hydrophobic polymer) have been shown to form a hydrophobic network when the mixture comes into contact with water (i.e. aqueous vaginal fluids) resulting in sustained release of metronidazole. Ethyl cellulose dissolved in the oily base has a significant influence on the rate of drug release, reducesthe initial drug release and prolongs the sustained release of metronidazole. Metronidazole can be released by diffusion of drug molecules through the fat base, though diffusion decreases with time due to the extended distance that the drug must diffuse through the matrix to the exterior thus retarding its release (Sallam et al., Pharm. Dev. Tecnol. 2015; 20(2) 159-168).

[0100] The compositions described herein may also be formulated as hydrogels. Hydrogels are soft, three-dimensional materials made up of a network of natural and / or synthetic polymers and water. Examples of natural polymers include, for example, hyaluronic acid, chitosan, and alginates among others. Natural polymers also can be advantageous for medical use in terms of biocompatibility, biodegradability, and antibiotic / antifungal complimentary benefits in can provide. The compositions may include 1 % to 5% by wt polymer including 1 .5% to 4% by weight polymer, 3% by weight polymer, or any fraction thereof.

[0101] In some aspects, boric acid may be used to crosslink with large polymer molecules such as chitosan, starch, gelatinized starch, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), and carboxymethyl cellulose and NaCMC. In some aspects, the polymers may cross-link with boric acid. Boric acid forms strong bonds with hydroxyl groups due to the presence of vacant d-orbital in boron, which causes it to rapidly react with various nucleophiles to form complexes. In general, the phenomenon of boric acid crosslinking is related to the high presence of hydroxyl groups (-OH) in polymers.

[0102] Boric acid crosslinking with polymers may improve swelling characteristics, affecting polymeric adhesion properties. Although the exact mechanisms of bio-adhesion are not known, it is generally accepted that it involves initial wetting and swelling of the bio-adhesive polymer. This is followed by interpenetration between polymer chains and the mucosal surface, with subsequent formation of chemical bonds between entangled chains, providing the bio-adhesion phenomenon. The use of hydrogels, including hydrogels with polymers cross-linked with boric acid, in the described therapeutic formulations may provide modified release formulations with bioadhesive properties including sustained release, controlled release, pulsatile release, or delayed release formulations; pH triggered release mechanisms. In some aspects, the use of hydrogels may increase drug loading into the delivery formulation.

[0103] For example, chitosan is a linear polysaccharide that is achieved by deacetylation of chitin, which is the second most plentiful compound in nature after cellulose. The biodegradable units of chitosan are broken down in the human body into amino sugars which are easily absorbed. As a cationic, chitosan’s positive charge is responsible for its antimicrobial activity (Shariatinia, Advan. Collo Inter. Sci. 2019 Jan; 263:131-194). Chitosan-boric acid scaffolds exhibit highly porous and interconnected structures with high swelling capacity and enzymatic degradation indicates goodscaffold stability during four weeks of incubation at pH 6.0 and 7.4 (Dornjak et a!., Polymers 2022; 14(21 ): 4753).

[0104] Ethyl cellulose is another polymer that can be crosslinked with boric acid, with crosslinking between hydroxyl groups of cellulose chains. Boric acid cross-linked ethyl cellulose was found to increase the swelling capacity of un-cross-linked ethyl cellulose by 3X providing a superabsorbent feature to cellulose hydrogel. Moreover, the cross-linked cellulose based hydrogels demonstrated antibacterial activity for gram positive bacteria (S. aureus) (Tanpichai et al., Sci. Rep. 2022 May; 12(1 ) 8912).

[0105] Starch is another polymer that crosslinks with borax. Borax cross-linked starch nanoparticles with improved mechanical properties have been reported. Compared with pure starch film, with boric acid the tensile strength of starch film with 10% starch nanoparticles increased 45%, and the elongation at break percentage of starch film with 5% starch nanoparticles increased 20%. Lu et al., J. Agric. Food Chem. 2019 Mar 13: 67 (10): 2916-2925. Starch is ideal for forming hydrogels. At low temperatures, amylose chains form double helices due to the physical cross-linking of the hydroxyl groups in each side chain, thereby forming a three-dimensional hydrogel network.

[0106] Sodium Bentonite Clay (Bentonite) is another example of a polymer rich in (-OH) hydroxyl groups. Bentonite is widely known for its high swelling characteristics. A typical sodium bentonite clay has the ability to absorb 4-5 times its own weight in water and can swell 5-15 times its dry volume at full-unconfined saturation. The swelling power of bentonite is 24+ ml. When bentonite swells it becomes an adhesive. Bentonite and bentonite hybrid bio-composites were improved with small additions of borax into the matrix. Borate ions dissociate in aqueous solution to provide a better effect on the intercalation of bentonite by imparting new hydrogen bonding sites, diol- complexes, and didiol-crosslinking gels, and modulating release properties in addition to bioadhesion properties due to the complexes formed (Benli, June 2013; J Appl. Polym. Sci. 128 (6) 4172-4189).

[0107] Other polymers such as carboxymethyl cellulose have also been crosslinked with boric acid. For example, boric acid crosslinked carboxymethyl cellulose hydrogels have been developed for pH triggered release formulations of boron and thiamethoxam for agricultural application (Sarkar etal., Polym. Plast. TechnoL and Mater., published online, 2018 May; 82-96).

[0108] In view of the above discussion of boric acid as an agent capable of cross-linking polymers, but without intending in any way to be limited to any proposed mechanism, it is contemplated that boric acid included in the described drug delivery compositions or devices may serve to crosslink subunits within or between polymers included in the delivery device (e.g., suppository). Thus,boric acid in some embodiments serves both as a therapeutically active agent and a structural component of the provided delivery technology.

[0109] The methods and compositions described herein deliver high doses of a water insoluble (non-polar) imidazole therapeutic agent; and polar water-soluble boric acid in a sequential or simultaneous modified release rate over 24 hours in a 2500 mg stable suppository ovule composition. While any release mechanism may be used, in some aspects, the release is a function of combining oleaginous ingredient (excipient) with different polymers and surfactants, at specific concentrations in order to modulate the rate of release. In some aspects, the compositions may include wax additives such as beeswax, ozokerite, and ceresin.

[0110] In the compositions and methods described herein, polymers suspended at specific concentrations modulate the rate of release of an imidazole therapeutic agent and boric acid. In some aspects, the rate of release may be modulated by changing the proportion of low and high melting point oils (fats), the polymers, and the surfactants. A “low” melting point oil is one with a melting point at or below room temperature (RT), which is taken as 25 °C; a “high” melting point oil is one with a melting point higher than this temperature. Selection of oils (fats) based at least in part on their melting point can be important for the current technology because beneficial suppository embodiments are formulated to melt completely at e.g., 37 °C (human body temperature) in the vaginal canal, yet that is a solid at room temperature.

[0111] Though not wishing to be bound by theory, it is postulated that the anhydrous compositions described herein will minimize metronidazole esterification when containing boric acid for the treatment of vaginitis. In another aspect, the disclosure provides a method of modified release over 24 hours of an imidazole therapeutic agent and boric acid.

[0112] Typically, the compositions for use in the methods disclosed herein will take the form of a vaginal suppository, ointment, cream, or foam, more preferably a vaginal suppository. The formulations may include allowable excipients for vaginal use according to the FDA Inactive Ingredient Database Guide.

[0113] In some aspects, the formulations may include one or more of acidulants such as acetic acid, citric acid, lactic acid, phosphoric acid, and nitric acid; alkalinizing agents such astrolamine, sodium hydroxide, and potassium hydroxide; preservative such as benzoic acid, methylparaben, propylparaben, and benzyl alcohol; antioxidants including butylated hydroxyanisole, and butylated hydroxytoluene; humectant glycols including propylene glycol, sorbitol, and glycerin; free fatty acids including myristic acid and stearic acid; fatty alcohols including cetyl alcohol, stearyl alcohol, and cetostearyl alcohol; fatty acid esters including apricot kernel oil PEG-6 esters, cetyl palmitate, glyceryl ricinoleate, and glyceryl laurate; polyethylene glycols includingpolyethylene glycol (PEG) 1000, PEG 3350, PEG 400, PEG 4000; emulsifiers including glyceryl monostearate, glyceryl isostearate, glyceryl dipalmitostearate, polyglyceryl 3 oleate, sorbitan monostearate; hydrogenated vegetable oils including palm kernel oil; hydrogenated coconut oil, and peanut oil; polymers including starch, gelatinized starch, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), methylcellulose (MG), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (NaCMC), Ethyl Cellulose (EC), and Bentonite; emollients including mineral oil, petrolatum, and lanolin; lubricants including zinc stearate; skin protective agents including allantoin, and cholesterol; surfactants including sodium lauryl sulfate, polysorbate 20, polysorbate 80, lecithin, and glyceryl monostearate; ethoxylated polyethylene glycol esters including PEG 6-32 Stearate / glycol stearate, PEG-100 Stearate, PEG-120 glyceryl stearate, PEG-2 Stearate, PEG-5 Oleate, and PEGOXOL 7 Stearate. Other triglyceride esters of the higher saturated fatty acids, along with varying proportions of mono- and / or di-glycerides, and ethoxylated fatty alcohols glycerides can be present in the composition described herein.

[0114] Other components which may be present in the composition disclosed herein, for example synthetic antimicrobials, local anesthetics, anti-inflammatory and / or anti-pruritic agents. For example, local anesthetics may include aptocaine, bupivacaine, butanilicaine, carticaine, cinchocaine, clibucaine, ethyl parapiperidinoacetyl-aminobenzoate, etidocaine, lidocaine (lignocaine), mepivacaine, oxethazaine, prilocaine, pyrrocaine, ropivacaine, tolycaine, vadocaine, benzocaine, pramoxine, and mixtures thereof. The anesthetic may also be used in the form of a salt, optionally in combination with the base form whereby to achieve extended release of the anesthetic. The local anesthetic may be used in an amount of 0.1 to 10 wt.%, preferably 1 to 7 wt.%. In one embodiment, the local anesthetic is lidocaine and may be used in the form of its free base (for example in an amount of 1 to 3 wt.%, such as 1 .5 wt.%) or a salt such as its hydrochloride, for example 1 .5 to 4 wt.%, such as 2% wt.%.

[0115] One or more wound healing or skin protectant agents may also be present in the composition. These may be selected from demulcents, absorbants and emollients and include dimethicone (demulcent), allantoin (absorbant), sucralfate and glycerin (absorbent, demulcent and emollient). Examples of other suitable emollients include cocoa butter, white petrolatum and shark liver oil. Dimethicone has been found to be particularly advantageous in facilitating healing of the vaginal mucosa and is therefore particularly preferred for use in the composition herein described. In order to counter the inflammation and itching associated with vaginitis, it may be beneficial to include anti-inflammatory and / or anti-pruritic agents such as hydrocortisone, hydrocortisone acetate, methylprednisolone aceponate, betamethasone valerate, or the like, or aweal topical steroid and / or plant-derived anti-inflammatory bioactive agent such as bisabolol or chamomile. The composition may also include chlorophyll as a deodorant.

[0116] Methods and compositions described herein may include enzymes used by bacteriophages. It may, for example, be advantageous to include one or more endolysin compounds associated with vaginitis biofilm disruption. Specifically, enzymes used by bacteriophages at the end of their replication cycle degrade the peptidoglycan of the bacterial host from within, resulting in cell lysis and release of progeny virions. Due to the absence of an outer membrane in the Gram-positive bacterial cell wall, endolysins can access the peptidoglycan and destroy these organisms when applied externally (Schemelcher eta / ., Future Microbiol. 2012 Oct; 7(10): 1 147-1171).

[0117] Methods and compositions described herein may include antivirals. It may, for example, be advantageous to include one or more antiviral associated with vaginitis such as acyclovir, valacyclovir, and famciclovir for treatment of herpes and HPV.

[0118] Methods and compositions described herein may include hormones. For example, vaginal estrogen has been found to lower vaginal pH, increase lactobacillus in the epithelium, of the vagina, and decrease colonization of Enterobacteriaceae (Stavridis, Estrogens - Advances in Research and Applications, 2013 Edition).

[0119] Methods and compositions described herein may include pre and probiotics, i.e. lactobacilli spp. It may, for example, be advantageous to modulating the vaginal microbiota, for example, by using probiotics. Probiotics are live microorganisms which confer a health benefit to the host, when administered in suitable amounts (Food Agriculture Organization of the United Nations World Health Organization, 2001 ).

[0120] The Exemplary Embodiments and Examples below are included to demonstrate particular embodiments of the disclosure. Those of ordinary skill in the art should recognize in light of the present disclosure that many changes can be made to the specific embodiments disclosed herein and still obtain a like or similar result without departing from the spirit and scope of the disclosure.First Set of Exemplary Embodiments

[0121] 1. A method of treating vaginitis in a subject in need thereof, the method including administering vaginally to the subject a therapeutically effective amount of a composition including: an imidazole therapeutic agent; and boric acid.

[0122] 2. A method of control release delivery of a high dose of nitroimidazole therapeutic agent or imidazole therapeutic agent and boric acid to a subject which delivery occurs over 24 hours.

[0123] 3. The method of embodiment 2, wherein: the high dose of nitroimidazole or imidazole therapeutic agent is more than 500 mg; or the high dose of nitroimidazole or imidazole therapeutic agent is 750-1000 mg.

[0124] 4. The method of embodiment 2, wherein: the high dose of boric acid is more than 300 mg; or the high dose of boric acid is 600 mg.

[0125] 5. The method of embodiment 2, in which the nitroimidazole or imidazole therapeutic agent and the boric acid are delivered sequentially or simultaneously.

[0126] 6. A method for delivering high dose of nitroimidazole or imidazole and boric in an easy to administer suppository ovule delivering a substantially water-insoluble nitroimidazole or imidazole therapeutic agent; and a water-soluble boric acid, in one physically stable dosage unit, wherein the therapeutic agent and boric acid are delivered sequentially or simultaneously at control release rate over 24 hours.

[0127] 7. A method for controlled release administration of boric acid and an imidazole therapeutic agent, essentially as describe herein.

[0128] 8. The method of any one of embodiments 1 -7, wherein the imidazole therapeutic agent includes one or more of nitroimidazole, metronidazole, tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazol, azaindole, secnidazole, or benznidazole.

[0129] 9. A method for controlling a release rate of one or more therapeutic agents, including administering the one or more therapeutic agents in a composition including: an oleaginous excipient, a polymer, and a surface active agent (surfactant), wherein the rate of release of the one or more therapeutic agents is controlled by using a specific concentration of the oleaginous excipient, the polymer, and / or the surface active agent (surfactant).

[0130] 10. The method of embodiment 9, where the oleaginous excipient includes a vegetable oil.

[0131] 1 1. The method of embodiment 10, where the vegetable oil includes hydrogenated palm kernel oil, coconut oil, or a combination of two or more thereof.

[0132] 12. The method of embodiment 9, wherein the polymer includes a hydrophobic polymer.

[0133] 13. The method of embodiment 12, where the hydrophobic polymer includes ethyl cellulose, starch, bentonite, or a combination of two or more thereof.

[0134] 14. The method of any one of embodiments 10-13, where the polymer is suspended in the vegetable oil, thereby modulating rate of release of the one or more therapeutic agents.

[0135] 15. The method of embodiment 9, where the composition includes: 20 - 60 wt.% vegetable oil; 30 - 45 wt.% vegetable oil; or 40 wt.% vegetable oil.

[0136] 16. The method of embodiment 15, where the composition includes: 1 - 5 wt.% polymer; 1.5 - 4 wt.% polymer; or 3 wt.% polymer.

[0137] 17. The method of embodiment 10, whereby the rate of release of the one or more therapeutic agents is controlled by changing one or more of: the proportion of low to high melting point vegetable oil(s), the polymer(s), and / or the surface active agents (surfactant(s)).

[0138] 18. The method of embodiment 17, whereby the rate of release of the one or more therapeutic agents is controlled by changing one or more of the concentration of: the vegetable oil(s), the polymer(s), and / or the surface active agent(s) (surfactant(s)).

[0139] 19. The method of any one of embodiments 2-18, which is carried out in a subject with bacterial vaginitis in need of treatment thereof, and the method includes administering vaginally to the subject a therapeutically effective amount of a control release composition including a nitroimidazole therapeutic agent or imidazole therapeutic agent and boric acid.

[0140] 20. The method of embodiment 19, wherein the nitroimidazole therapeutic agent is a 5- nitroimidazole or a pharmaceutically acceptable salt thereof.

[0141] 21. The method of embodiment 20, wherein the 5-nitroimidazole is metronidazole or tinidazole.

[0142] 22. The method of any one of the prior embodiments, wherein the nitroimidazole is present in the composition in an amount from 4 to 40 wt.% based on total weight of the composition.

[0143] 23. The method of any one of the prior embodiments, wherein the boric acid is present in the composition in an amount of from 10 to 30 wt.% based on total weight of the composition.

[0144] 24. The method of any one of the prior embodiments, wherein the composition additionally includes an active agent effective against Candida albicans.

[0145] 25. The method of embodiment 24, wherein the active agent effective against Candida albicans is an imidazole or a pharmaceutically acceptable salt thereof.

[0146] 26. The method of embodiment 25, wherein the imidazole is selected from miconazole, tioconazole, and pharmaceutically acceptable salts thereof.

[0147] 27. The method of any one of embodiments 24 to 26, wherein the active agent effective against Candida albicans is present in the composition in an amount of from 2 to 10 wt.% based on total weight of the composition.

[0148] 28. The method of any one of the prior embodiments, wherein the composition additionally includes an active agent effective against Trichomonas vaginalis.

[0149] 29. The method of embodiment 28, wherein the active agent effective against Trichomonas vaginalis is a nitroimidazole or a pharmaceutically acceptable salt thereof.

[0150] 30. The method of embodiment 29, wherein the nitroimidazole is metronidazole or pharmaceutically acceptable salts thereof.

[0151] 31. The method of any one of embodiments 28 to 30, wherein the active agent effective against Trichomonas vaginalis is present in the composition in an amount of from 4 to 40 wt.% based on total weight of the composition.

[0152] 32. The method of any one of the prior embodiments, wherein the boric acid is present in the composition in an amount of from 10 to 30 wt.% based on total weight of the composition.

[0153] 33. The method of any one of the prior embodiments, wherein the composition is substantially free from ethylene diamine tetra acetic acid (EDTA).

[0154] 34. The method of any one of the prior embodiments, wherein the composition is provided in the form of a cream, foam, or a vaginal suppository.

[0155] 35. The method of embodiment 34, wherein the vaginal suppository is a small 2500 mg vaginal ovule including a lipophilic pessary base.

[0156] 36. The method of embodiment 35, wherein the vaginal ovule contains from 500 to 1 ,000 mg of the nitroimidazole or imidazole and from 300 to 900 mg boric acid.

[0157] 37. The method of embodiment 36, wherein the vaginal ovule contains from 750 to 1 ,000 mg metronidazole.

[0158] 38. The method of embodiment 36, wherein the vaginal ovule contains from 100 to 400 mg tinidazole.

[0159] 39. The method of any one of the prior embodiments, which is a method of treating vaginitis by simultaneous local application per vagina of a nitroimidazole therapeutic agent or imidazole therapeutic agent and boric acid in a control release composition that provides therapeutic agent release for up to 24 hours.

[0160] 40. The method of any one of the prior embodiments, which is a method of treating vaginitis by simultaneous local application per vagina of a nitroimidazole or imidazole therapeutic agent and boric acid in a composition that provides control release of the therapeutic agent(s).

[0161] 41 . The method of any one of the preceding embodiments, wherein the patient is a female having recurrent vaginitis, optionally at least one of bacterial vaginosis, vulvovaginal candidiasis, and / or trichomoniasis.

[0162] 42. The method of embodiment 41 , wherein the method prevents recurrence of vaginitis in the patient for a period of: at least 30 days from initiation of the treatment, at least 45 days from initiation of the treatment, or at least 60 days from initiation of the treatment.

[0163] 43. The method of embodiment 42, wherein the method prevents recurrence of bacterial vaginosis in the patient for a period of: at least 30 days from initiation of the treatment, at least 45 days from initiation of the treatment, or at least 60 days from initiation of the treatment.

[0164] 44. The method of embodiment 43, wherein the treatment prevents recurrence of bacterial vaginosis in the patient without the need for conventional antibiotic maintenance therapy.

[0165] 45. The method of any one of the prior embodiments, wherein the patient is a female patient having refractory bacterial vaginosis.

[0166] 46. The method of embodiment 45, wherein the patient is refractory to an FDA-approved treatment for bacterial vaginosis, optionally oral or vaginal treatment with clindamycin or metronidazole.

[0167] 47. The method of any one of the prior embodiments, wherein the method includes administration of the composition for a treatment period of: up to 14 days, up to 10 days, up to 7 days, or 7 days.

[0168] 48. The method of any one of the prior embodiments, wherein the composition is administered once a day.

[0169] 49. The method of any one of the prior embodiments, wherein the composition is provided as a vaginal suppository that contains 750 mg metronidazole and 600 mg boric acid, and wherein the method includes administration of the vaginal suppository once a day for a period of 7 days.

[0170] 50. A composition including a nitroimidazole active agent or imidazole active agent and boric acid for use in a method of treating vaginitis according to any of embodiments 1-49.

[0171] 51. Use of a composition including a nitroimidazole active or an imidazole active agent and boric acid in manufacture of a medicament for use in a method of treating vaginitis according to any one of embodiments 46-49.

[0172] 52. A kit including (i) a composition including a nitroimidazole agent active or an imidazole agent and boric acid, and (ii) an applicator adapted for delivery of the composition of any one of embodiments 50-51 to the vaginal cavity of a human subject for treatment of bacterial vaginosis.

[0173] 53. A control release pharmaceutical composition for vaginal administration, including: at least one imidazole therapeutic agent; boric acid; an oleaginous excipient, a polymer, and a surface active agent (surfactant), wherein the rate of release of the at least one imidazole therapeutic agent and / or the boric acid is controlled by using a specific concentration of the oleaginous excipient, the polymer, and / or the surface active agent (surfactant).

[0174] 54. The control release pharmaceutical composition of embodiment 53, wherein the at least one imidazole therapeutic agent includes one or more of nitroimidazole, metronidazole,tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazol, azanidazole, secnidazole, or benznidazole

[0175] 55. The control release pharmaceutical composition of embodiment 53 or 54, where the oleaginous excipient includes a vegetable oil.

[0176] 56. The control release pharmaceutical composition of embodiment 55, where the vegetable oil includes hydrogenated palm kernel oil, coconut oil, or a combination of two or more thereof.

[0177] 57. The control release pharmaceutical composition of any one of embodiments 53-56, wherein the polymer includes a hydrophobic polymer.

[0178] 58. The control release pharmaceutical composition of embodiment 57, where the hydrophobic polymer includes ethyl cellulose, starch, bentonite, or a combination of two or more thereof.

[0179] 59. The control release pharmaceutical composition of any one of embodiments 53-58, where the polymer(s) is suspended in the oleaginous excipient, thereby modulating rate of release of the imidazole therapeutic agent and / or the boric acid.

[0180] 60. The control release pharmaceutical composition of any one of embodiments 53-59, where the composition includes: 20 - 60 wt.% vegetable oil; 30 - 45 wt.% vegetable oil; or 40 wt.% vegetable oil.

[0181] 61. The control release pharmaceutical composition of any one of embodiments 53-60, where the composition includes: 1 - 5 wt.% polymer; 1.5 - 4 wt.% polymer; or 3 wt.% polymer.

[0182] 62. The control release pharmaceutical composition of any one of embodiments 53-61 , whereby the rate of release of the imidazole therapeutic agent and / or the boric acid is controlled by changing one or more of: the proportion of low and high melting point the vegetable oil(s), the type of polymer(s), and / or the type of surface active agents (surfactant(s)).

[0183] 63. The control release pharmaceutical composition of embodiment 62, whereby the rate of release of the imidazole therapeutic agent and / or the boric acid is controlled by changing one or more of: the concentration of the vegetable oil(s), the concentration of the polymer(s), and / or the concentration of the surface active agent(s) (surfactant(s)).

[0184] 64. The control release pharmaceutical composition of any one of embodiments 53-63, including: hydrogenated palm kernel oil, coconut oil, and ethylcellulose; hydrogenated palm kernel oil, coconut oil, and bentonite; hydrogenated palm kernel oil, coconut oil, bentonite, and ethylcellulose; hydrogenated palm kernel oil, coconut oil, bentonite, ethylcellulose, and polysorbate 80; or hydrogenated palm kernel oil, coconut oil, polysorbate 80, and pre-gelatinized starch.

[0185] 65. The control release pharmaceutical composition of embodiment 64, including: 19.5% hydrogenated palm kernel oil, 19.5% coconut oil, and 7% ethylcellulose; 21.5% hydrogenated palm kernel oil, 21.5% coconut oil, and 3% ethylcellulose; 19.5% hydrogenated palm kernel oil, 19.5% coconut oil, and 7% bentonite; 21.5% hydrogenated palm kernel oil, 21.5% coconut oil, and 3% bentonite; 21% hydrogenated palm kernel oil, 21% coconut oil, 1.5% bentonite, 1.5% ethylcellulose, and 1% polysorbate 80; 21.25% hydrogenated palm kernel oil, 21.25% coconut oil, 1 .5% bentonite, 1 .5% ethylcellulose, and 0.5% polysorbate 80; or 21 .25% hydrogenated palm kernel oil, 21 .25% coconut oil, 0.5% polysorbate 80, and 3% pre-gelatinized starch.

[0186] 66. The control release pharmaceutical composition of embodiment 63 or embodiment 64, including: 30% metronidazole and 24% boric acid.Second Set of Exemplary Embodiments

[0187] 1. A method of treating vaginitis in a subject in need thereof, the method including administering vaginally to the subject a therapeutically effective amount of a composition including: an imidazole therapeutic agent; and boric acid, wherein the imidazole therapeutic agent and the boric acid are administered in a combined formulation.

[0188] 2. The method of embodiment 1 , wherein the imidazole therapeutic agent includes one or more of nitroimidazole, metronidazole, tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazol, azaindole, secnidazole, or benznidazole.

[0189] 3. A method of modified release delivery of a high dose of an imidazole therapeutic agent and boric acid to a subject, wherein the modified release delivery occurs over 24 hours.

[0190] 4. The method of embodiment 3, wherein the modified release delivery is sustained release, controlled release, or delayed release.

[0191] 5. The method of embodiment 3, wherein: the high dose of imidazole therapeutic agent is more than 500 mg; or the high dose of imidazole therapeutic agent is 750-1000 mg.

[0192] 6. The method of embodiment 3, wherein: the high dose of boric acid is more than 300 mg; or the high dose of boric acid is 600 mg.

[0193] 7. The method of embodiment 3, in which the imidazole therapeutic agent and the boric acid are administered together in a suppository ovule, and wherein the imidazole therapeutic agent and the boric acid are released sequentially or simultaneously.

[0194] 8. The method of embodiment 3, wherein the imidazole therapeutic agent includes one or more of nitroimidazole, metronidazole, tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazol, azaindole, secnidazole, or benznidazole.

[0195] 9. A method for delivering high dose of nitroimidazole or imidazole and boric in an easy to administer suppository ovule delivering a substantially water-insoluble nitroimidazole or imidazole therapeutic agent; and a water-soluble boric acid, in one physically stable dosage unit, wherein the therapeutic agent and boric acid are delivered sequentially or simultaneously at a modified release rate over 24 hours.

[0196] 10. The method of embodiment 9, wherein the modified release rate is controlled release.

[0197] 11. The method of embodiment 9, wherein the suppository ovule further includes a polymer, wherein the polymer is cross linked with the boric acid.

[0198] 12. The method of embodiment 11 , wherein the imidazole therapeutic agent includes one or more of nitroimidazole, metronidazole, tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazol, azaindole, secnidazole, or benznidazole.

[0199] 13. A method for controlling a release rate of one or more therapeutic agents, including administering the one or more therapeutic agents in a composition including: an oleaginous excipient, a polymer, and a surfactant, wherein the rate of release of the one or more therapeutic agents is controlled by using a specific concentration of the oleaginous excipient, the polymer, and / or the surfactant.

[0200] 14. The method of embodiment 13, where the oleaginous excipient includes a vegetable oil.

[0201] 15. The method of embodiment 14, where the vegetable oil includes hydrogenated palm kernel oil, coconut oil, or a combination of two or more thereof.

[0202] 16. The method of embodiment 14, where the polymer is suspended in the vegetable oil, thereby modulating rate of release of the one or more therapeutic agents.

[0203] 17. The method of embodiment 13, wherein the polymer includes a hydrophobic polymer.

[0204] 18. The method of embodiment 17, where the hydrophobic polymer includes ethyl cellulose, starch, bentonite, or a combination of two or more thereof.

[0205] 19. The method of embodiment 13, where the composition includes: 20 - 60 wt.% vegetable oil; 30 - 45 wt.% vegetable oil; or 40 wt.% vegetable oil.

[0206] 20. The method of embodiment 13, where the composition includes: 1 - 5 wt.% polymer; 1.5 - 4 wt.% polymer; or 3 wt.% polymer.

[0207] 21. The method of embodiment 13, whereby the rate of release of the one or more therapeutic agents is controlled by changing one or more of: a proportion of low to high melting point vegetable oil(s), the polymer(s), and / or the surfactant(s).

[0208] 22. The method of embodiment 13, whereby the rate of release of the one or more therapeutic agents is controlled by changing one or more of the concentration of: the vegetable oil, the polymer, and / or the surfactant.

[0209] 23. The method of embodiment 13, which is carried out in a subject with bacterial vaginitis in need of treatment thereof, and the method includes administering vaginally to the subject a therapeutically effective amount of a modified release composition including a imidazole therapeutic agent and boric acid.

[0210] 24. The method of embodiment 23, wherein the imidazole therapeutic agent is a 5- nitroimidazole or a pharmaceutically acceptable salt thereof.

[0211] 25. The method of embodiment 24, wherein the 5-nitroimidazole is metronidazole or tinidazole.

[0212] 26. The method of embodiment 23, wherein the imidazole therapeutic agent is present in the composition in an amount from 4 to 40 wt.% based on total weight of the composition.

[0213] 27. The method of embodiment 23, wherein the boric acid is present in the composition in an amount of from 10 to 30 wt.% based on total weight of the composition.

[0214] 28. The method of embodiment 23, wherein the composition additionally includes and active agent effective against Candida albicans.

[0215] 29. The method of embodiment 28, wherein the active agent effective against Candida albicans is an imidazole or a pharmaceutically acceptable salt thereof.

[0216] 30. The method of embodiment 29, wherein the imidazole is selected from miconazole, tioconazole, and pharmaceutically acceptable salts thereof.

[0217] 31. The method of embodiment 30, wherein the imidazole effective against Candida albicans is present in the composition in an amount of from 2 to 10 wt.% based on total weight of the composition.

[0218] 32. The method of embodiment 28, wherein the composition additionally includes an active agent effective against Trichomonas vaginalis.

[0219] 33. The method of embodiment 32, wherein the active agent effective against Trichomonas vaginalis is an imidazole.

[0220] 34. The method of embodiment 33, wherein the imidazole is metronidazole or a pharmaceutically acceptable salt thereof.

[0221] 35. The method of embodiment 32, wherein the active agent effective against Trichomonas vaginalis is present in the composition in an amount of from 4 to 40 wt.% based on total weight of the composition.

[0222] 36. The method of embodiment 23, wherein the boric acid is present in the composition in an amount of from 10 to 30 wt.% based on total weight of the composition.

[0223] 37. The method of embodiment 23, wherein the composition is substantially free from ethylene diamine tetra acetic acid (EDTA).

[0224] 38. The method of embodiment 23, wherein the composition is provided as a cream, foam, or a vaginal suppository.

[0225] 39. The method of embodiment 38, wherein the vaginal suppository is a small 2500 mg vaginal ovule including a lipophilic pessary base.

[0226] 40. The method of embodiment 39, wherein the vaginal ovule contains from 500 to 1 ,000 mg of imidazole and from 300 to 900 mg boric acid.

[0227] 41 . The method of embodiment 39, wherein the vaginal ovule contains from 750 to 1 ,000 mg metronidazole.

[0228] 42. The method of embodiment 39, wherein the vaginal ovule contains from 100 to 400 mg tinidazole.

[0229] 43. The method of embodiment 23, wherein the modified release composition is a controlled release of the imidazole therapeutic agent and the boric acid for up to 24 hours.

[0230]

[0231] 44. The method of embodiment 23, wherein the subject has recurrent vaginitis, optionally at least one of bacterial vaginosis, vulvovaginal candidiasis, and / or trichomoniasis.

[0232] 45. The method of embodiment 44, wherein the method prevents recurrence of vaginitis in the subject for a period of: at least 30 days from initiation of the treatment, at least 45 days from initiation of the treatment, or at least 60 days from initiation of the treatment.

[0233] 46. The method of embodiment 45, wherein the method prevents recurrence of bacterial vaginosis in the subject for a period of: at least 30 days from initiation of the treatment, at least 45 days from initiation of the treatment, or at least 60 days from initiation of the treatment.

[0234] 47. The method of embodiment 46, wherein the treatment prevents recurrence of bacterial vaginosis in the subject without the need for conventional antibiotic maintenance therapy.

[0235] 48. The method of embodiment 23, wherein the method includes administration of the composition for a treatment period of: up to 14 days, up to 10 days, up to 7 days, or 7 days.

[0236] 49. The method of embodiment 23, wherein the composition is administered once a day.

[0237] 50. The method of embodiment 23, wherein the composition is provided as a vaginal suppository that contains 750 mg metronidazole and 600 mg boric acid, and wherein the method includes administration of the vaginal suppository once a day for a period of 7 days.

[0238] 51. A composition including a nitroimidazole active agent or imidazole active agent and boric acid for use in a method of treating vaginitis, according to any one of embodiments 1 -46.

[0239] 52. Use of a composition including a nitroimidazole active imidazole active agent and boric acid in manufacture of a medicament for use in a method of treating vaginitis according to any one of embodiments 1 -49.

[0240] 53. A kit including (i) a composition including an imidazole active agent and boric acid, and (ii) an applicator adapted for delivery of the composition of any one of embodiments 51 -52 to the vaginal cavity of a human subject for treatment of vaginitis.

[0241] 54. A modified release pharmaceutical composition for vaginal administration, including: at least one imidazole therapeutic agent; boric acid; an oleaginous excipient; a polymer; and a surface active agent (surfactant), wherein a rate of release of the at least one imidazole therapeutic agent and / or the boric acid is controlled by using a specific concentration of the oleaginous excipient, the polymer, and / or the surface active agent (surfactant).

[0242] 55. The modified release pharmaceutical composition of embodiment 54, wherein the at least one imidazole therapeutic agent includes one or more of nitroimidazole, metronidazole, tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazol, azanidazole, secnidazole, or benznidazole.

[0243] 56. The modified release pharmaceutical composition of embodiment 55, where the oleaginous excipient includes a vegetable oil.

[0244] 57. The modified release pharmaceutical composition of embodiment 56, where the vegetable oil includes hydrogenated palm kernel oil, coconut oil, or a combination of two or more thereof.

[0245] 58. The modified release pharmaceutical composition of embodiment 54, wherein the polymer includes a hydrophobic polymer.

[0246] 59. The modified release pharmaceutical composition of embodiment 58, where the hydrophobic polymer includes ethyl cellulose, starch, bentonite, or a combination of two or more thereof.

[0247] 60. The modified release pharmaceutical composition of embodiment 54, where the polymer is suspended in the oleaginous excipient, thereby modulating rate of release of the imidazole therapeutic agent and / or the boric acid.

[0248] 61 . The modified release pharmaceutical composition of embodiment 54, where the composition includes: 20 - 60 wt.% vegetable oil; 30 - 45 wt.% vegetable oil; or 40 wt.% vegetable oil.

[0249] 62. The modified release pharmaceutical composition of embodiment 54, where the composition includes: 1 - 5 wt.% polymer; 1.5 - 4 wt.% polymer; or 3 wt.% polymer.

[0250] 63. The modified release pharmaceutical composition of embodiment 54, whereby the rate of release of the imidazole therapeutic agent and / or the boric acid is controlled by changing one or more of: a proportion of low and high melting point of the vegetable oil, the type of polymer, and / or the type of surfactant.

[0251] 64. The modified release pharmaceutical composition of embodiment 63, whereby the rate of release of the imidazole therapeutic agent and / or the boric acid is controlled by changing one or more of: the concentration of the vegetable oil(s), the concentration of the polymer(s), and / or the concentration of the surfactant(s).

[0252] 65. The modified release pharmaceutical composition of embodiment 54, including: hydrogenated palm kernel oil, coconut oil, and ethylcellulose; hydrogenated palm kernel oil, coconut oil, and bentonite; hydrogenated palm kernel oil, coconut oil, bentonite, and ethylcellulose; hydrogenated palm kernel oil, coconut oil, bentonite, ethylcellulose, and polysorbate 80; or hydrogenated palm kernel oil, coconut oil, polysorbate 80, and pre-gelatinized starch.

[0253] 66. The modified release pharmaceutical composition of embodiment 65, including: 19.5% hydrogenated palm kernel oil, 19.5% coconut oil, and 7% ethylcellulose; 21.5% hydrogenated palm kernel oil, 21.5% coconut oil, and 3% ethylcellulose; 19.5% hydrogenated palm kernel oil, 19.5% coconut oil, and 7% bentonite; 21.5% hydrogenated palm kernel oil, 21.5% coconut oil, and 3% bentonite; 21% hydrogenated palm kernel oil, 21 % coconut oil, 1.5% bentonite, 1.5% ethylcellulose, and 1% polysorbate 80; 21.25% hydrogenated palm kernel oil, 21.25% coconut oil, 1 .5% bentonite, 1 .5% ethylcellulose, and 0.5% polysorbate 80; or 21 .25% hydrogenated palm kernel oil, 21 .25% coconut oil, 0.5% polysorbate 80, and 3% pre-gelatinized starch.

[0254] 67. The modified release pharmaceutical composition of embodiment 65, including: 30% metronidazole and 24% boric acid.EXAMPLES

[0255] The following examples provide exemplary compositions for the modified release of vaginally administered therapeutic agents. As shown herein below, the release rate and the amounts of the therapeutic agents released may be modified based on the particular polymers and surfactants used in the manufacture of therapeutic agents for vaginal administration.

[0256] Example 1 : Lipophilic Vegetable Oil / Polymer - Ethyl Cellulose @ 7% / No surfactant

[0257] This example describes making a composition with a high concentration of polymer (ethyl cellulose at 7%). In order to obtain 2500 mg suppositories, 5850 mg of hydrogenated palm kernel oil was combined with 5850 mg of coconut oil in a 250 mL beaker. The combined oils were heated slowly to 65 - 70°C forming a clear liquid. 2100 mg of ethyl cellulose was stirred into the mixture followed by 7200 mg boric acid. Maintaining mixing and temperature conditions, the beaker was covered with aluminum foil to protect it from ultraviolet light. 9000 mg of metronidazole was then added, and the mixture was stirred to obtain a smooth dispersion. While continuing to stir, the mixture was allowed to cool to 55 - 60°C and then placed into 12 chilled molds prior to refrigerating for 24 hours resulting in 12 2500 suppositories of 19.5% hydrogenated palm kernel oil, 19.5% coconut oil, 7% ethyl cellulose, 30% metronidazole; and 24% boric acid.

[0258] The vaginal suppositories were then tested using a Lorderan RC-3 Dissolution Tester (Dover, DE, USA). A 2500 mg vaginal suppository (weight equivalent to 600 mg of boric acid and 750 mg of metronidazole) was transferred to dissolution media @ pH 4.5 of 500 mL of Simulated Vaginal Fluid (SVF) (Hiorth et al., Pharmaceutics 2014 (6); 494-511 ). The temperature of the medium was maintained at 37 ±0.5°C. The medium was centrifuged at 100 rpm for 24 hours. Aliquots were taken at time intervals and metronidazole was analyzed using an L7 USP HPLC column with a 254 nm detector and a 4.6 mm x 15 cm column with a flow rate ~ 1 ml / min (Sigma- Aldrich, Burlington, MA, USA). Boric acid was analyzed by UV spectrophotometry whereby the solution was prepared to cover the range: 0.02 mg / mL to 0.2 mg / mL, and the standards were read at 585 nm to prepare a standard curve with R square has to be NLT 0.995. Samples were diluted with SVF. The dilutions have to be calculated so that the concentrations fall within the range: 0.02 mg / mL to 0.2 mg / mL, UV / VIS spectrophotometer at 585 nm to obtain the concentrations from the standard curve. The dissolution rates (shown as percent released) of boric acid and metronidazole in these suppositories are shown in Table 1 .Table 1. Dissolution Rates in suppositories with a high concentration of Ethyl Cellulose

[0259] As shown in FIG. 9 and Table 1 , a high concentration of ethyl cellulose at 7%), limited the release of both therapeutic agents (approx. 35% of active input), with boric acid release slightly accelerated over 36 hours in comparison to metronidazole.Example 2: Lipophilic Vegetable Oil / Polymer - Ethyl Cellulose @ 3% I No surfactant

[0260] This example describes making a composition with a low concentration of polymer (Ethyl Cellulose at 3%). In order to obtain 2500 mg suppositories, 6450 mg of hydrogenated palm kernel oil was combined with 6450 mg of coconut oil in a 250 mL beaker. The combined oils were heated slowly to 65 - 70°C forming a clear liquid. 900 mg of ethyl cellulose was stirred into the mixture followed by 7200 mg boric acid. Maintaining mixing and temperature conditions, the beaker was covered with aluminum foil to protect it from ultraviolet light. 9000 mg of metronidazole was then added, and the mixture was stirred to obtain a smooth dispersion. While continuing to stir, the mixture was allowed to cool to 55 - 60°C and then placed into 12 chilled molds prior to refrigerating for 24 hours, resulting in twelve suppositories of 21.50% hydrogenated palm kernel oil, 21.50% coconut oil, 3.00% ethyl cellulose, 30.00% metronidazole; and 24.00% boric acid.

[0261] The vaginal suppositories were then tested using a Lorderan RC-3 Dissolution Tester (Dover, DE, USA). A 2500 mg vaginal suppository (weight equivalent to 600 mg of boric acid and 750 mg of metronidazole) was transferred to dissolution media @ pH 4.5 of 500 mL of Simulated Vaginal Fluid (SVF) (Hiorth et al., Pharmaceutics 2014 (6); 494-511 ). The temperature of the medium was maintained at 37 ±0.5°C. The medium was centrifuged at 100 rpm for 24 hours. Aliquots were taken at time intervals and metronidazole was analyzed using an L7 USP HPLC column with a 254 nm detector and a 4.6 mm x 15 cm column with a flow rate ~ 1 ml / min (Sigma- Aldrich, Burlington, MA, USA). Boric acid was analyzed by UV spectrophotometry whereby the solution was prepared to cover the range: 0.02 mg / mL to 0.2 mg / mL, and the standards were read at 585 nm to prepare a standard curve with R square has to be NLT 0.995. Samples were diluted with SVF. The dilutions have to be calculated so that the concentrations fall within the range: 0.02 mg / mL to 0.2 mg / mL, UV / VIS spectrophotometer at 585 nm to obtain the concentrations from the standard curve. The dissolution rates (shown as percent released) of boric acid and metronidazole in vaginal suppositories made with 3% ethyl cellulose is shown in Table 2.Table 2. Dissolution rates in suppositories with a low concentration of ethyl cellulose

[0262] As shown in FIG. 10, beginning at 12 hours, using a lower concentration of polymer (EC@ 3%) increased the release rate of the active ingredients in comparison to the suppositories of Example 1 which used a higher concentration of ethyl cellulose, though in the suppositories made using a lower concentration of polymer, the release of boric acid began to decrease at 24 hours.Example 3: Lipophilic Vegetable Oil / Polymer - Bentonite @ 7% I No Surfactant

[0263] This example describes making a composition with a high concentration of polymer (Bentonite @ 7%). In order to obtain 2500 mg, 5850 mg of hydrogenated palm kernel oil was combined with 5850 mg of coconut oil in a 250 mL beaker. The combined oils were heated slowly to 65-70°C forming a clear liquid. 2100 mg of bentonite was stirred into the mixture followed by 7200 mg boric acid. Maintaining mixing and temperature conditions, the beaker was covered with aluminum foil to protect it from ultraviolet light. 9000 mg of metronidazole was then added, and the mixture was stirred to obtain a smooth dispersion. While continuing to stir, the mixture was allowed to cool to 55 - 60°C and then placed into 12 chilled molds prior to refrigerating for 24 hours, resulting in 12 suppositories of 19.50% hydrogenated palm kernel oil, 19.50% coconut oil, 7.00% bentonite, 30% metronidazole, and 24% boric acid.

[0264] The vaginal suppositories were then tested using a Lorderan RC-3 Dissolution Tester (Dover, DE, USA). A 2500 mg vaginal suppository (weight equivalent to 600 mg of boric acid and 750 mg of metronidazole) was transferred to dissolution media @ pH 4.5 of 500 mL of Simulated Vaginal Fluid (SVF) (Hiorth et al., Pharmaceutics 2014 (6); 494-511 ). The temperature of the medium was maintained at 37 ±0.5°C. The medium was centrifuged at 100 rpm for 24 hours. Aliquots were taken at time intervals and metronidazole was analyzed using an L7 USP HPLC column with a 254 nm detector and a 4.6 mm x 15 cm column with a flow rate ~ 1 ml / min (Sigma- Aldrich, Burlington, MA, USA). Boric acid was analyzed by UV spectrophotometry whereby the solution was prepared to cover the range: 0.02 mg / mL to 0.2 mg / mL, and the standards were read at 585 nm to prepare a standard curve with R square has to be NLT 0.995. Samples were diluted with SVF. The dilutions have to be calculated so that the concentrations fall within therange: 0.02 mg / mL to 0.2 mg / mL, UV / VIS spectrophotometer at 585 nm to obtain the concentrations from the standard curve. The dissolution rates (shown as percent released) of boric acid and metronidazole in suppositories with 7% bentonite are shown in Table 3.Table 3. Dissolution rates in suppositories with a high concentration of bentonite

[0265] As shown in FIG. 1 1 , in vaginal suppositories made with bentonite, there was a limited release of both active agents (approx. 50% BA and 35% MTZ of active input), with boric acid release accelerated over 36 hours.Example 4: Lipophilic Vegetable Oil / Polymer - Bentonite @ 3% I No surfactants

[0266] This example describes making a composition with a low concentration of polymer (Ethyl Cellulose at 3%). In order to obtain 2500 mg suppositories, 6450 mg of hydrogenated palm kernel oil was combined with 6450 mg of coconut oil in a 250 mL beaker. The combined oils were heated slowly to 65-70°C forming a clear liquid. 900 mg of bentonite was stirred into the mixture followed by 7200 mg boric acid. Maintaining mixing and temperature conditions, the beaker was covered with aluminum foil to protect it from ultraviolet light. 9000 mg of metronidazole was then added, and the mixture was stirred to obtain a smooth dispersion. While continuing to stir, the mixture was allowed to cool to 55 - 60°C and then placed into 12 chilled molds prior to refrigerating for 24 hours, resulting in 12 suppositories of 21.50% hydrogenated palm kernel oil, 21.5% coconut oil, 3% bentonite, 30% metronidazole; and 24% boric acid.

[0267] The vaginal suppositories were then tested using a Lorderan RC-3 Dissolution Tester (Dover, DE, USA). A 2500 mg vaginal suppository (weight equivalent to 600 mg of boric acid and 750 mg of metronidazole) was transferred to dissolution media @ pH 4.5 of 500 mL of Simulated Vaginal Fluid (SVF) (Hiorth et al., Pharmaceutics 2014 (6); 494-511 ). The temperature of the medium was maintained at 37 ±0.5°C. The medium was centrifuged at 100 rpm for 24 hours. Aliquots were taken at time intervals and metronidazole was analyzed using an L7 USP HPLC column with a 254 nm detector and a 4.6 mm x 15 cm column with a flow rate ~ 1 ml / min (Sigma- Aldrich, Burlington, MA, USA). Boric acid was analyzed by UV spectrophotometry whereby the solution was prepared to cover the range: 0.02 mg / mL to 0.2 mg / mL, and the standards wereread at 585 nm to prepare a standard curve with R square has to be NLT 0.995. Samples were diluted with SVF. The dilutions have to be calculated so that the concentrations fall within the range: 0.02 mg / mL to 0.2 mg / mL, UV / VIS spectrophotometer at 585 nm to obtain the concentrations from the standard curve. The dissolution rates (shown as percent released) of boric acid and metronidazole in vaginal suppositories made with 3% bentonite are shown in Table 4.Table 4: Dissolution rates in suppositories with a low concentration of bentonite

[0268] As shown in FIG. 12, in a vaginal suppository made with 3% bentonite, the release of both boric acid and metronidazole was limited (approx. 28% BA and 50% MTZ of active input), with boric acid release decreasing at T=18 hrsExample 5: Lipophilic Vegetable Oil / Polymer - Ethyl Cellulose I Bentonite @ 3% + Polysorbate 80 @ 1%

[0269] This example describes making a composition with a low concentration of two polymers (a 50 / 50 blend of Ethyl Cellulose and Bentonite @ 3%) + Polysorbate 80 @ 1 .0%. In order to obtain 2500 mg suppositories, 6300 mg of hydrogenated palm kernel oil was combined with 6300 mg of coconut oil in a 250 mL beaker. The combined oils were heated slowly to 65-70°C forming a clear liquid. 450 mg of bentonite and 450 mg of ethyl cellulose were stirred into the mixture followed by 1200 mg boric acid and 300 mg polysorbate 80. Maintaining mixing and temperature conditions, the beaker was covered with aluminum foil to protect it from ultraviolet light. 9000 mg of metronidazole was then added, and the mixture was stirred to obtain a smooth dispersion. While continuing to stir, the mixture was allowed to cool to 55 - 60°C and then placed into chilled molds prior to refrigerating for 24 hours, resulting in 12 suppositories of 21.00% hydrogenated palm kernel oil, 21.00% coconut oil, 1.50% ethyl cellulose, 1.50% bentonite, 30.00% metronidazole, 4.00% boric acid, and 1 .00% polysorbate 80.

[0270] The vaginal suppositories where then tested using a Lorderan RC-3 Dissolution Tester (Dover, DE, USA). A 2500 mg vaginal suppository (weight equivalent to 600 mg of boric acid and 750 mg of metronidazole) was transferred to dissolution media @ pH 4.5 of 500 mL of SimulatedVaginal Fluid (SVF) (Hiorth et al., Pharmaceutics 2014 (6); 494-511 ). The temperature of the medium was maintained at 37 ±0.5°C. The medium was centrifuged at 100 rpm for 24 hours. Aliquots were taken at time intervals and metronidazole was analyzed using an L7 USP HPLC column with a 254 nm detector and a 4.6 mm x 15 cm column with a flow rate ~ 1 ml / min (Sigma- Aldrich, Burlington, MA, USA). Boric acid was analyzed by UV spectrophotometry whereby the solution was prepared to cover the range: 0.02 mg / mL to 0.2 mg / mL, and the standards were read at 585 nm to prepare a standard curve with R square has to be NLT 0.995. Samples were diluted with SVF. The dilutions have to be calculated so that the concentrations fall within the range: 0.02 mg / mL to 0.2 mg / mL, UV / VIS spectrophotometer at 585 nm to obtain the concentrations from the standard curve. The dissolution rates (shown as percent released) of boric acid and metronidazole in vaginal suppositories made with 3% bentonite, 3% ethyl cellulose, and 1 % polysorbate 80 are shown in Table 5.Table 5. Dissolution rates with 3% bentonite, 3% ethyl cellulose, and 1% polysorbate 80

[0271] As shown in FIG. 13, in the vaginal suppository containing a combined lower polymer concentration (EC / Bent @ 3%) + Polysorbate 80 @ 1%, boric acid release was low (approx. 50% of input) while metronidazole release was improved (approx. 77%). Boric acid release began to de-accelerated at T=6 hrs.Example 6: Lipophilic Vegetable Oil / Polymer - Ethyl Cellulose I Bentonite @ 3% + Polysorbate 80 @ 0.50%

[0272] This example describes making a composition with a low concentration of 2 polymers (a 50 / 50 blend of Ethyl Cellulose and Bentonite @ 3%) + Polysorbate 80 @ 0.5%. In order to obtain 2500 mg suppositories, 6375 mg of hydrogenated palm kernel oil was combined with 6375 mg of coconut oil in a 250 mL beaker. The combined oils were heated slowly to 65 - 70°C forming a clear liquid. 450 mg of bentonite and 450 mg of ethyl cellulose were stirred into the mixture followed by 1200 mg boric acid and 150 mg polysorbate 80. Maintaining mixing and temperature conditions, the beaker was covered with aluminum foil to protect it from ultraviolet light. 750 mg of metronidazole was then added, and the mixture was stirred to obtain a smooth dispersion. While continuing to stir, the mixture was allowed to cool to 55 - 60°C and then placed into 12chilled molds prior to refrigerating for 24 hours, resulting in 12 suppositories of 21.25% hydrogenated palm kernel oil, 21.25% coconut oil, 1.5% ethyl cellulose, 1.5% bentonite, 30.00% metronidazole, 4.00% boric acid, and 0.5% polysorbate 80.

[0273] The vaginal suppositories were then tested using a Lorderan RC-3 Dissolution Tester (Dover, DE, USA). A 2500 mg vaginal suppository (weight equivalent to 600 mg of boric acid and 750 mg of metronidazole) was transferred to dissolution media @ pH 4.5 of 500 mL of Simulated Vaginal Fluid (SVF) (Hiorth et al., Pharmaceutics 2014 (6); 494-511 ). The temperature of the medium was maintained at 37 ±0.5°C. The medium was centrifuged at 100 rpm for 24 hours. Aliquots were taken at time intervals and metronidazole was analyzed using an L7 USP HPLC column with a 254 nm detector and a 4.6 mm x 15 cm column with a flow rate ~ 1 ml / min (Sigma- Aldrich, Burlington, MA, USA). Boric acid was analyzed by UV spectrophotometry whereby the solution was prepared to cover the range: 0.02 mg / mL to 0.2 mg / mL, and the standards were read at 585 nm to prepare a standard curve with R square has to be NLT 0.995. Samples were diluted with SVF. The dilutions have to be calculated so that the concentrations fall within the range: 0.02 mg / mL to 0.2 mg / mL, UV / VIS spectrophotometer at 585 nm to obtain the concentrations from the standard curve. The dissolution rates (shown as percent released) of boric acid and metronidazole in vaginal suppositories made with 3% bentonite, 3% ethyl cellulose, and 0.5% polysorbate 80 are shown in Table 6.

[0274] Table 6. Dissolution rates with 3% bentonite, 3% ethyl cellulose, and 0.5% polysorbate 80

[0275] As shown in FIG. 14 a combined lower polymer concentration (EC / Bent @ 3%) + Polysorbate 80 reduced to @0.50 %, improved release of MTZ (97%) and BA (72%). Boric acid release began to de-accelerate at T=12 hrs.Example 7: Pre-Gelatinized Starch @ 3 + Polysorbate 80 @ 0.50%

[0276] This example describes making a composition with a low concentration of polymer (Pre- Gelatinized Starch @ 3%) + Polysorbate 80 @ 0.5%. In order to obtain 2500 mg suppositories, 6378 mg of hydrogenated palm kernel oil was combined with 6378 mg of coconut oil in a 250 mL beaker. The combined oils were heated slowly to 65 - 70°C forming a clear liquid. 900 mg of pre-gelatinized starch was stirred into the mixture followed by 1200 mg boric acid and 150 mg polysorbate 80. Maintaining mixing and temperature conditions, the beaker was covered with aluminum foil to protect it from ultraviolet light. 9000 mg of metronidazole was then added, and the mixture was stirred to obtain a smooth dispersion. While continuing to stir, the mixture was allowed to cool to 55 - 60°C and then placed into 12 chilled molds prior to refrigerating for 24 hours, resulting in 12 suppositories of 21 .25% hydrogenated palm kernel oil, 21 .25% coconut oil, 1.5% pre-gelatinized starch 3.0%, 30.00% metronidazole, 24.00% boric acid, and 0.5% polysorbate 80.

[0277] The vaginal suppositories where then tested using a Lorderan RC-3 Dissolution Tester (Dover, DE, USA). A 2500 mg vaginal suppository (weight equivalent to 600 mg of boric acid and 750 mg of metronidazole) was transferred to dissolution media @ pH 4.5 of 500 mL of Simulated Vaginal Fluid (SVF) (Hiorth et al., Pharmaceutics 2014 (6); 494-511 ). The temperature of the medium was maintained at 37 ±0.5°C. The medium was centrifuged at 100 rpm for 24 hours. Aliquots were taken at time intervals and metronidazole was analyzed using an L7 USP HPLC column with a 254 nm detector and a 4.6 mm x 15 cm column with a flow rate ~ 1 ml / min (Sigma- Aldrich, Burlington, MA, USA). Boric acid was analyzed by UV spectrophotometry whereby the solution was prepared to cover the range: 0.02 mg / mL to 0.2 mg / mL, and the standards were read at 585 nm to prepare a standard curve with R square has to be NLT 0.995. Samples were diluted with SVF. The dilutions have to be calculated so that the concentrations fall within the range: 0.02 mg / mL to 0.2 mg / mL, UV / VIS spectrophotometer at 585 nm to obtain the concentrations from the standard curve. The dissolution rates (shown as percent released) of boric acid and metronidazole in vaginal suppositories made with 3% pre-gelatinized starch and 0.5% polysorbate 80 are shown in Table 7.Table 7. Dissolution rates with 3% pre-gelatinized and 0.5% polysorbate 80

[0278] As shown in FIG. 15, the use of pre-Gelatinized Starch @ 3% + Polysorbate 80 @0.50%, resulted in moderate release of MTZ (approx. 81%) and BA (approx. 75%) with contemporaneous release at T=24 hrs.

[0279] Table 8 (Summary of release rates of Examples 1 -7) is provide in four parts.Example 8: Tinidazole and Boric Acid Composition in a 2500 mg Suppository Ovule

[0280] This example describes a representative method for making a composition with Tinidazole and Boric Acid, using a low concentration of 2 polymers (in this case a 50 / 50 blend of Ethyl Cellulose and Bentonite @ 3%). In order to obtain 2500 mg suppositories, 9750 mg of hydrogenated palm kernel oil was combined with 9750 mg of coconut oil in a 250 mL beaker. The combined oils were heated slowly to 65-70°C forming a clear liquid. 450 mg of bentonite and 450 mg of ethyl cellulose were stirred into the mixture followed by 7200 mg boric acid. Maintaining mixing and temperature conditions, the beaker was covered with aluminum foil to protect it from ultraviolet light. 400 mg of tinidazole was then added, and the mixture was stirred to obtain a smooth dispersion. While continuing to stir, the mixture was allowed to cool to 55 - 60°C and then placed into a chilled mold prior to refrigerating for 24 hours, resulting in 12 suppositories of 32.50% hydrogenated palm kernel oil, 32.50% coconut oil, 1 .50% bentonite, 1 .50% ethyl cellulose, 8.00% tinidazole, and 24.00% boric acid.Example 9: Miconazole Nitrate and Boric Acid Composition in a 2500 mg Suppository Ovule

[0281] This example describes making a composition with Miconazole Nitrate and Boric Acid and a low concentration of two polymers (a 50 / 50 blend of ethyl cellulose and bentonite @ 3%). In order to obtain 2500 mg, 10050 mg of hydrogenated palm kernel oil was combined with 10050 mg of coconut oil in a 250 mL beaker. The combined oils were heated slowly to 65 - 70°C forming a clear liquid. 450 mg of bentonite and 450 mg of ethyl cellulose were stirred into the mixture followed by 7200 mg boric acid. Maintaining mixing and temperature conditions, the beaker was covered with aluminum foil to protect it from ultraviolet light. 1800 mg of miconazole nitrate was then added, and the mixture was stirred to obtain a smooth dispersion. While continuing to stir, the mixture was allowed to cool to 55 - 60°C and then placed into 12 chilled molds prior to refrigerating for 24 hours, resulting in 12 suppositories of 33.50% hydrogenated palm kernel oil, 33.50% coconut oil, 1.50% bentonite, 1.50% ethyl cellulose, 8.00% miconazole nitrate, and 24.00% boric acid).Example 10: Metronidazole and Boric Acid PEG - Based Hydrophilic Composition in a 2500 mg Suppository Ovule

[0282] This example describes making a composition with of Metronidazole and Boric Acid in a hydrophilic Polyethylene Glycol base with low concentration of polymer (in this case Ethyl Cellulose @3%). To make a 2500 mg vaginal suppository (24.00% PEG 1000, 6.00% PEG 3350.0.50% PEG 5M, 4.00% PEG 400, 3.00% ethyl cellulose, 5.50% distilled water, 30.00% metronidazole, and 24.00% boric acid), 7200 mg PEG 1000 and 1800 mg PEG 3350 were combined and heated slowly to 70-75°C until the materials were melted and clear. 900 mg ethyl cellulose was then stirred into the mixture followed by the slow addition of 7200 mg of boric acid to form a first mixture. In a separate container, 2100 mg PEG 400 and 1650 mg distilled water were combined. 150 mg of PEG-5M was then combined with the 11584 mg PEG 400-distilled water to hydrate the PEG-5M. The hydrated PEG-5M was mixed with the first mixture at 70-75°C for 10-15 minutes. 9000 mg of metronidazole was then added and the mixture was cooled to 55- 60°C, poured into 12 chilled suppository molds and chilled overnight.

[0283] The vaginal ovule produced in this example did not exhibit extended or control release - ovules fully dissolved after 1 hour in a dissolution vessel. The dissolution Study was not completed as the ovule fully dissolved in a short period of time, eliminating the possibility of extended release.Example 11 : Two Therapeutic Active Agents and Boric Acid Composition in a 2500 mg Suppository Ovule

[0284] This example describes making a composition with Metronidazole and Miconazole Nitrate + Boric Acid in a lipophilic base with low concentration of polymer (in this case, Pre-Gelatinized Starch @ 3%). In order to obtain a 2500 mg suppository, 5550 mg of hydrogenated palm kernel oil was combined with 5550 mg of coconut oil in a 250 mL beaker. The combined oils were heated slowly to 65-70°C forming a clear liquid. 900 mg of pre-gelatinized starch was stirred into the mixture followed by 7200 mg boric acid. Maintaining mixing and temperature conditions, the beaker was covered with aluminum foil to protect it from ultraviolet light. 9000 mg of metronidazole and 1800 mg of miconazole nitrate was then added, and the mixture was stirred to obtain a smooth dispersion. While continuing to stir, the mixture was allowed to cool to 55 - 60°C and then placed into a chilled mold prior to refrigerating for 24 hours, resulting in 18.50% hydrogenated palm kernel oil, 18.50% coconut oil, 3.00% pre-gelatinized starch, 30% metronidazole, 6.00% miconazole nitrate, and 24.00% boric acid.Example 12: Vaginal 5 gram Ointment Compositions with 750 mg Metronidazole and 600 mg Boric Acid

[0285] This example describes making a 5 gram ointment with Metronidazole and Boric Acid and a high concentration of polymer (Ethyl Cellulose @ 7% and Bentonite @ 7%).

[0286] The composition includes:

[0287] The coconut oil and hydrogenated palm kernel oil were combined and heated to 65-70°C. The bentonite and ethyl cellulose were then added to the mixture and stirred until the mixture was uniform. Boric acid was then added and combined until the mixture was uniform followed by the addition of the metronidazole to form the first mixture.

[0288] In a separate container, lanolin, glyceryl monolaurate, and propylene glycol were combined and heated to 65-70°C. The two mixtures were combined to form a mixture and cooled to 35°C prior to packaging into a UV protected syringe for vaginal application.Example 13: Vaginal 5 gram Miconazole and Boric Acid Oleo-foam Compositions

[0289] This example describes a representative way to make a composition with a Metronidazole and Boric Acid 5 gram Oleofoam with low concentration of polymer (in this case Ethyl Cellulose @ 2%).

[0290] The composition includes:

[0291] The coconut oil and hydrogenated palm kernel oil are combined and heated to 65-70°C. The ethyl cellulose is then added to the mixture and stirred until the mixture is uniform. Boric acid is then added and combined until the mixture is uniform followed by the addition of the miconazole nitrate to form the first mixture.

[0292] In a separate container, isostearic acid and glyceryl mono stearate are combined and heated to 65-70°C to form a second mixture. The first and second mixtures are then combined and cooled to 50°C and 25% Sodium Lauryl Sulfate solution is added with high-speed mixing. The mixture is then cooled to 32°C, propellant is added and the resulting foam is packaged into a UV protected syringe for in office administration.

[0293] It is expected that the described composition will deliver burst release within 6 hours.Example 14: 750 mg Metronidazole 600 mg Boric Acid Ovule Hardness and Moisture Content

[0294] The ovule compositions from Examples 1 -7 described herein were evaluated for hardness with a Durometer using ASTM D2240 standards. Hardness scores ranged between 30-45 shore A.

[0295] The ovule compositions of Examples 1 -7 and Example 10 described herein were evaluated for moisture content with a Moisture Gravimetric (drying 103-105°C) method ASC- GM005. Moisture readings ranged between 2.50 - 3.4% for lipophilic base examples (Examples 1 -7), and between 6.9 - 8.75% in a hydrophilic base example (Example 10).Example 15: 750 mg Metronidazole 600 mg Boric Acid Ovule Physical and Chemical Stability

[0296] Ovule examples described in Examples 1-7 were found physically and chemically stable at 25°C and 37°C after 1 month of storage. No discoloration was observed. There was some slight distortion of ovules observed at 37°C, which is acceptable and desirable as this is indicative that ovules will dissolve under use conditions (vaginal temperature = 37°C).Example 16: In vitro studies versus planktonic cells of G. vaginalis

[0297] Combinations of boric acid with metronidazole or tinidazole were tested in vitro against planktonic bacteria belonging to the species G. vaginalis (ATCC strain 14018), considered among the likely causal pathogens responsible for bacterial vaginosis. The efficacy of the combinationtreatment was investigated using a checkerboard assay as described by Algburi et al., (Antimicrob. Agents Ch. 61 : e00650-17, 2017).Method:

[0298] G. vaginalis ATCC 14018 was treated with a combination of boric acid with either metronidazole or tinidazole. A 24 h culture of G. vaginalis was diluted to ~106 CFLI / ml. Each agent was diluted two-fold with sBHI (Brain heart infusion +3% horse serum) broth into two separate 96-well non-tissue culture microplates. From each dilution of boric acid, 50 pl was added horizontally over 50 pl of metronidazole 25 or tinidazole. Then, 100 pl of the bacterial suspension (10 CFU / ml) was separately added to each well. The MIC of each combination was determined after 24 h incubation anaerobically at 37 °C. Wells that showed no growth after 24 h incubation were then used in the calculation of fractional inhibitor concentration (FIC) values.

[0299] FIC is defined as the concentration that kills when used in combination with another agent divided by the concentration that has the same effect when used alone (see Hall et al., J. Antimicrob. Chemoth. 11 : 427-33, 1983; and Krogstad et al., Antimicrobial combinations, In: Lorian V (ed). Antibiotics in Laboratory Medicine, 2nd ed. Baltimore, MD: Williams and Wilkins, 1986, 557-78). The FIC index (FIC I) for the combination of two agents is the sum of their individual FIC values. By convention, the FIC values of the most effective combination are used in calculating the FICI.

[0300] The European Committee for Antimicrobial Susceptibility Testing (EUCAST) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) 2000 adopts the following definitions to determine the susceptibility of bacteria to an antimicrobial agent (see EUCAST Definitive Document E. Def 1.2: Terminology relating to methods for the determination of susceptibility of bacteria to antimicrobial agents. Clin. Microbiol. Infect. 2000; 6(9): 503-508):• FICI value < 0.5; synergy• 0.5 < FICI value < 1 ; additive effect• 1 < FICI value < 2; indifferent effect• FICI > 2; antagonistic effectResults:

[0301] Boric acid was found to have a minimal inhibitory concentration (MIC) of 1 .25 pg / ml against G. vaginalis 14018, while the MICs for metronidazole and tinidazole were found to be 6.25 pg / ml, and 1 .5625 pg / ml, respectively.

[0302] Isobolograms were used to compare the MIC values of each therapeutic agent alone to its MIC value in combination with another antimicrobial therapeutic agent. FIG. 1 is an isobologram for the combination treatment of boric acid and metronidazole. FIG. 2 is an isobologram for the combination treatment of boric acid and tinidazole. In the isobolograms, the point on the x axis refers to the MIC value of the first antimicrobial, with the coordinates (0, x), and the point on the y axis represents the MIC value of the second antimicrobial, with the coordinates (y, 0), when the antimicrobials are used alone. The two MIC values are connected by a dashed line. The MIC values of each antimicrobial combination are plotted as dots on the graph. Results are expressed according to the locations of these dots relative to the line that connects the MIC values of the first and second antimicrobials. When the MIC values are located under the line, the combination of the two antimicrobials shows synergy, but when these dots of interaction are above the line, the combination of the two antimicrobials shows antagonism against the tested microorganism. An additive effect is observed when these dots are located on the line. The isobolograms confirm that the combinations of boric acid and either metronidazole (FIG. 1 ) or tinidazole (FIG. 2) are synergistic.

[0303] The differences between the isobolograms and the FICI values with respect to synergy vs. an additive effect is dependent on the conventions of the two different methods and the designation of an additive effect vs. synergy is arbitrary. In effect, isobolograms are a qualitative means of displaying potential synergy, whereas FICI values provide a means of quantifying synergy, and also introduce a means of measuring either an additive effect or indifference. A combination of the isobolograms overlaid with FICI data represents a means of conveying synergy data in the most comprehensive manner. Whilst the combination of boric acid with metronidazole or tinidazole did not display synergy against planktonic cells of G. vaginalis according to the above FICI definitions, the additive effect that was seen is beneficial. It may, for example, decrease the required concentrations of antimicrobials and make it more difficult for the treated pathogens to develop resistance. This is especially true when the compounds have different modes of action as is the case with boric acid and metronidazole or tinidazole (Rybak et al., Drugs 52:390-405, 1996). In addition, the use of a non-conventional antimicrobial compound, either alone or in combination with conventional antibiotics, is not associated with the same level of risk seen with the use of conventional antibiotics alone (i.e., tinidazole or metronidazole) (Algburi et al., Pathog. Dis. 73: ftv018 2015).Example 17: In vitro studies vs. biofilm formation by G. vaginalis

[0304] Combinations of boric acid with metronidazole or tinidazole were tested in vitro in a nonplanktonic, biofilm model for inhibition of biofilm formation by G. vaginalis (ATCC strain 14018). Method:

[0305] Bacterial strain, culture media and growth conditions: From the frozen stock (-80 °C), G. vaginalis ATCC 14018 was inoculated in three culture media and propagated at 37°C for 48 h. Brain-heart infusion (BHI) broth (Difco BD, Franklin, NJ, USA) supplemented with horse serum 3% (JRH Biosciences, KS) was used to maintain microbial growth. Human blood tissue (HBT) agar (Remel, Lenexa, KS, USA) was used to confirm the purity of the frozen stock. The inoculated broth and HBT agar were incubated anaerobically (10% hydrogen, 5% carbon dioxide and 85% nitrogen) using an anaerobic gloves box (Coy Laboratory Products, Inc., Grass Lake, Ml, USA). After the incubation period, the bacterial cells were transferred to BHI broth supplemented with 1% glucose (Fisher Scientific, Waltham, MA, USA) (BHIG), every 24 h twice prior to the initiation of an experiment. In order to provide suitable conditions for G. vaginalis anaerobic growth and to avoid oxidative stress, culture media were pre-incubated in the anaerobic chamber at least overnight before bacterial inoculation.

[0306] Stock solutions of antibacterial agents: Antimicrobials were evaluated for their activity against biofilm-associated G. vaginalis. Metronidazole was purchased from Alfa Aesar (Ward Hill, Massachusetts, USA). Metronidazole was prepared as a stock solution of 10 mg mL‘1in ddH2O. Tinidazole was purchased from TCI America (Portland, OR, USA).

[0307] Tinidazole was prepared as a stock solution of 10 mg / ml in DMSO. Boric acid was purchased from Fisher Chemical (Hampton, NH, USA). A fresh 1 mg mL-1 boric acid solution in BHIG was prepared at the beginning of each experiment within the anaerobic chamber and mixed with BHIG that had been in the anaerobic chamber overnight (to avoid oxidative stress). The stock solutions of antimicrobials were sterilized using syringe filter 0.45 urn and kept in the refrigerator for a maximum of 3 weeks. On the day of the experiment, the stock solutions were diluted in the anaerobic chamber (to avoid oxidative stress) with pre-incubated BHIG broth to avoid changing the concentrations of nutrients of growth media.

[0308] Determination of minimum biofilm inhibitory concentrations (MICs-B): MIC determination was performed according to Sutyak et al., (Antimicrob. Agents Ch 56: 1756-61 , 2012) with minor modifications. Each agent was diluted two-fold with BHIG broth into two separate 96-well nontissue culture microplates. From each dilution of boric acid, 50 pl was added horizontally over 50 pl of metronidazole or tinidazole. The final volume of antimicrobial agents diluted into the broth was 100 pl in each well. The overnight cell culture at 3 ± 2 x 108CFU mL-1 was diluted in BHIGto a final concentration of 5 x 106CFU mL-1. From the diluted bacterial cells, 100 pl was transferred into the wells containing predetermined concentrations of antimicrobials. Sterile sealing tape (Thermo Fisher Scientific, Rochester, NY) was used to prevent evaporation. The 96- well plate was then incubated anaerobically at 37 °C for 48 h. After incubation, the biofilm was stained using 0.1% crystal violet as described by Algburi et al., (Appl Environ Microbiol. 83(3):e02508-16, 2017. doi: 10.1128 / AEM.02508-16).

[0309] Biofilm staining using CV: Biofilm staining using CV was performed as described by Borucki etal., (doi: 10.1128 / AM.69.12.7336-7342.2003) with minor modifications. Briefly, after 25 counting of the non-adherent cells, the biofilm was fixed at 60 °C for 60 minutes in an inverted position in an incubator (New Brunswick Scientific Co., Inc., NJ, USA). To each well, 125 pl of 0.1% CV was added and left at room temperature for 20 minutes. Each well was then rinsed three or four times with 200 pl of ddH2O and left for 15 minutes to dry at room temperature. To solubilize the CV-stained biofilm, 200 pl of 95% ethanol in water was added, and the microplate was incubated at 4°C for 30 minutes. One-hundred-microliter samples of solubilized CV were then transferred to a new flat-bottomed 96-well microplate. The absorbance of each sample was measured using a plate reader at 595 m (model 550; Bio-Rad Laboratories, Hercules, CA, USA). The MIC-B was defined according to Clinical and Laboratory Standards Institute guidance as the lowest concentration of antimicrobial in wells with absorbance A595 equal to or less than 20% of the control's mean absorbance (bacterial growth without antimicrobial addition).

[0310] Checkerboard assay for antimicrobial combinations against pre-formed biofilms of G. vaginalis ATCC 14018: o evaluate the potential effectiveness of the boric acid in combination with metronidazole / tinidazole against biofilm-associated G. vaginalis ATCC 14018 cells, a checkerboard assay was performed as described by Algburi et al., (Pathogens & Dis., 73(5): 12 pages, 2015; doi:10.1093 / femspd / ftv018.) with minor modifications. For biofilm formation, the overnight culture of G. vaginalis ATCC 14018 was diluted to approximately 107 CFU / ml, and 200 pl was transferred to a 96-well tissue culture microplate and incubated anaerobically at 37 °C for 24 to 36 h. Following biofilm formation and removal of non-adherent cells by washing the biofilm twice with BHIG, each antimicrobial w a s diluted 2-fold separately with BHIG broth in two 96-well (deep well) microplates. From each dilution of antimicrobial B, 125 pl was added horizontally over 125 pl of antimicrobial A. From each combination, 200 pl samples were added to the biofilm in sequence, and the microplate was incubated for 24 h at 37°C under anaerobic conditions. The spot plate method was utilized for counting the number of CFU per milliliter and evaluating the bactericidal activity (MBC-B) of each antimicrobial combination against biofilm- associated G. vaginalis ATCC 14018.

[0311] Plate counting method: The number of bacteria that survived was expressed in colonyforming units per milliliter (CFU mL-1 ) and was enumerated using the drop plate method. The methodology was performed as described by Hamilton and Heersink (J. Microbiol. Meth. 44: 121 - 9, 2001) with a minor modification. The washed biofilm was disrupted by vigorous pipetting with 200 L of fresh BHIG broth. Six 10-fold dilutions for each well (from 101-106CFU mL1) were made using pre-incubated fresh BHIG 1 % broth. 20 pL of the cell suspension was then transferred from each dilution and spotted in duplicate on BHI agar plates which were then incubated for 72 h at 37 °C under anaerobic conditions. The number of colonies between 2 and 20 CFU per spot was regarded as a quantifiable number.

[0312] Checkerboard assay, data analysis: Isobolograms were used to analyze the interactions of metronidazole or tinidazole with boric acid. This method is based on the comparison of the MBC-B value of each individual antimicrobial with its MBC-B value when used in combination. Axis(x) represents the MBC-B of tinidazole or metronidazole (A) with the coordinates (0, x), and axis (y) represents boric acid (B) with the coordinates (y, 0). The two points (A) and (B) are connected by a line (Turovskiyeta / ., Probiotics Antimicrob. Proteins 3: 144-9, 201 1). Each MBCs- B value of two combining antimicrobials is represented as a point on the graph. Results are expressed according to locations of MBCs-B points on the line that connects (A) and (B) as follows: when MBCs-B points are located under or above the line, the two combining antimicrobials are synergized or antagonized respectively, against the biofilm-associated G. vaginalis.Statistics:

[0313] Each antimicrobial combination was conducted at least three times in duplicate. The results illustrate the average of three experiments.Results:

[0314] The minimal inhibitory concentration for biofilm is defined as the concentration needed to inhibit 90% of biofilm compared to a positive control (MIC-Bg0). The MIC-B90for boric acid was found to be 0.25% m / v (2.5 pg / ml) against G. vaginalis 14018, while the MIC-B90for both metronidazole and tinidazole was 25 pg / ml. These concentrations are well above the determined MIC concentrations for each compound against planktonic cells, and so the possibility of quorum quenching as a potential mechanism is unlikely.

[0315] Combination treatments for each of metronidazole and tinidazole together with boric acid were effective. Several combinations of boric acid together with the nitroimidazole compounds had fractional inhibitory concentration indices (FICI values) for biofilm inhibition (FICI-B90, using 90% inhibition as the cutoff value) < 0.5, which is indicative of synergy.

[0316] Tables 9 and 10 show the data for the checkboard assay as a whole to show the exact concentrations for the different FICI-Bo values, as well as the percentage of biofilm mass for every combination tested. FIC values were determined from those combinations of antimicrobials that fall below the individual MIC-Bo values (shown underlined in the tables). MIC-B90and FIC90 values were defined as those wells / combinations where the biofilm mass after treatment was <10% of the positive control (these wells are marked with *in the tables). FICI values were calculated as explained above, and the designation synergy vs. additive effect was determined based on the EUCAST definitions as outlined above (i.e., a synergistic effect (SynE) is observed when FICI value < 0.5; an additive effect (AddE) when 0.5 < FICI value 51 ; an indifferent effect (IndE) when 1 < FICI value < 2; and an antagonistic effect (AntE) when FICI value > 2).

[0317] Based on these definitions, there is one combination of metronidazole and boric acid that shows synergy (FICI value < 0.5) and one combination of tinidazole and boric acid that shows synergy. These are well F3 in Table 8 (FICI90 = 0.3125) and well D4 in Table 9 (FICIgo = 0.375), respectively. The other combinations marked with *in Tables 8 and 9 and shown in FIGs. 3 and 4 are indicative of an additive effect (0.5 < FICI value <1). FIGs. 3 and 4 are another representation of this data, with each bar representing a combination marked with *from Tables 8 and 9 and showing the relative biofilm mass as a percentage of the control and the FICI value as calculated from the Tables (calculations not shown).

[0318] As an example, in FIG. 4, the first bar after the control has a FICIgo of 0.375 and is taken from well D4 in Table 9, which has a relative biofilm mass of 1%. The calculations for the FICIgo are (3.125 / 25) +(0.0625 / 0.25). The italicized concentrations are the MIC-B90values for the two antimicrobials on their own (3.125 for tinidazole and 0.0625 for boric acid), and the concentrations in bold are taken from well D4 in Table 9.

[0319] FIGs. 5 and 6 are a further representation of the data. FIG. 5 is an isobologram for the combination treatment of boric acid and metronidazole. FIG. 6 is an isobologram for the combination treatment of boric acid and tinidazole. Calculated FIC values for the combination of boric acid together with metronidazole or tinidazole against biofilm cells of G. vaginalis 14018 are shown in the isobolograms.

[0320] The isobolograms show that the boric acid and nitroimidazole (metronidazole or tinidazole) combinations were synergistic as all FIC values are located under the dashed line. In respect of both boric acid and nitroimidazole (metronidazole or tinidazole) combinations, two of the FIC values shown in the isobolograms indicated synergy (FICI value < 0.5) whilst the other two FIC values indicated an additive effect (0.5 < FICI value < 1 ). As discussed herein, the differencesbetween the isobolograms and the FICI values in respect of synergy vs. additive effect is due to the conventions of the two different methods.

[0321] There are observed differences in synergy comparing the planktonic cells, biofilm inhibition, and biofilm killing. This is not unexpected and results from differences in the variables at play for the different experiments. These variables include influence of the biofilm network and the extracellular polymeric substance matrix, differences in the metabolic state of the cells (mostly stationary and much lower activity in a biofilm), the different growth media used, etc. The biofilm model is considered more relevant to the clinical situation in women. Synergy was reflected by a decrease in G. vaginalis induced biofilm mass and a decrease in the number of viable G. vaginalis ATCC 14018 cells within the biofilm, coupled with lower concentrations of metronidazole / tinidazole and boric acid compared to their use alone.

[0322] Overall, the in vitro synergy studies provide strong evidence for synergy between metronidazole / tinidazole and boric acid in preventing biofilm formation, which is critical not only in preventing initial colonization by G. vaginalis, but most importantly, may reduce the risk of reinfection and recurrence following treatment. As described herein, recurrence is a significant problem in respect of conventional antibiotic regimens, resulting in increased healthcare costs and the risk of negative health outcomes, such as endometriosis or the increased transmission and acquisition of STIs that may be linked to bacterial vaginosis.

[0323] Regarding the efficacy of the combination treatments against preformed biofilms, there is strong evidence for synergy between metronidazole and boric acid, while the tinidazole and boric acid combination has an additive effect. These results show that the tested combinations may be effective in eradicating the biofilms that are a hallmark of bacterial vaginosis.

[0324] The results documented herein clearly show that the combination treatment may be used as an effective primary treatment for bacterial vaginosis, and together with the data on biofilm inhibition, may be effective for the treatment and prevention of recurrent bacterial vaginosis, while also greatly reducing the risk for antibiotic resistance development as compared to single drug antibiotic regimens.

[0325] Table 9 - Biofilm mass as a percentage of an untreated control for combination treatments of metronidazole together with boric acid for the inhibition of biofilm formation by G. vaginalis MG14018. MIC-Bgo concentrations for boric acid and metronidazole alone are underlined.Combinations with FICg0values indicative of additive effect or synergy are marked with *

[0326] Table 10 - Biofilm mass as a percentage of an untreated control for combination treatment tinidazole together with boric acid for the inhibition of biofilm formation by G. vaginalis ATCC 14018. MIC B9Oconcentrations for boric acid and tinidazole alone are underlined. Combinations with FICgo values indicative of additive effect or synergy are marked with *Example 18: Pre-clinical and Clinical Studies

[0327] Pre-clinical repeat dose animal studies (rabbit) are proposed to demonstrate safety. Clinical studies are also proposed to demonstrate the efficacy and safety of boric acid andmetronidazole vaginal ovules in the treatment of recurrent bacterial vaginosis. The drug product will consist of metronidazole (750 mg), boric acid (600 mg) and in a lipophilic pessary base delivering extended or control release of therapeutic agents within the vaginal cavity, designed as a non-irritant with excellent mucosal tolerance. The vaginal ovule will be self-administered via fingertip insertion.

[0328] Efficacy will be tested in an initial proof of concept / tolerability study and a Phase 3 study to demonstrate efficacy via statistical significance vs. placebo formulation. The proposed placebo will consist of an identical ovule with boric acid but without the metronidazole component. The intent of the clinical efficacy program is to demonstrate the efficacy of a 7-day treatment with the drug product in both short-term (30 days) and long-term (60 days) test-of-cure endpoints. The design of the studies will be compliant with the August 2019 Guidance Bacterial Vaginosis: Developing Drugs for Treatment. The addition of a long-term primary efficacy endpoint (day 60) following one initial treatment regimen will be unique to the proposed clinical program.

[0329] Given that the overall concept is to reduce the occurrence of BV at time points beyond day 30, the study populations will be enhanced to enroll only those subjects recently treated for B with occurrence beyond day 30. The proposed clinical efficacy studies will be as follows:One Phase 2 clinical study of 7 days of treatment (one vaginal ovule per day) vs. placebo. Efficacy will be evaluated at days 30, 60, 90 and 120. Primary endpoints will be at day 30 and day 60; days 90 and 120 will be evaluated as secondary endpoints.One Phase 3 randomized, placebo-controlled study with primary endpoints at day 30 and day 60. The study will be designed and powered based upon the results of the Phase 2 study.

[0330] The proposed clinical program is intended to support the approval of a product with efficacy demonstrated out to day 60.Closing Paragraphs

[0331] While the present disclosure describes in detail specific embodiments, it will be understood that the various changes and modifications can be made.

[0332] As will be understood by one of ordinary skill in the art, each embodiment disclosed herein can comprise, consist essentially of or consist of its particular stated element, step, ingredient or component. Thus, the terms “include” or “including” should be interpreted to recite: “comprise, consist of, or consist essentially of.” The transition term “comprise” or “comprises” means has, but is not limited to, and allows for the inclusion of unspecified elements, steps, ingredients, or components, even in major amounts. The transitional phrase “consisting of” excludes any element, step, ingredient, or component not specified. The transition phrase “consistingessentially of” limits the scope of the embodiment to the specified elements, steps, ingredients, or components and to those that do not materially affect the embodiment. A material effect would cause a statistically significant reduction in the effectiveness of treatment of bacterial vaginosis or vaginitis, for instance.

[0333] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. When further clarity is required, the term “about” has the meaning reasonably ascribed to it by a person skilled in the art when used in conjunction with a stated numerical value or range, i.e. denoting somewhat more or somewhat less than the stated value or range, to within a range of ±20% of the stated value; ±19% of the stated value; ±18% of the stated value; ±17% of the stated value; ±16% of the stated value; ±15% of the stated value; ±14% of the stated value; ±13% of the stated value; ±12% of the stated value; ±11 % of the stated value; ±10% of the stated value; ±9% of the stated value; ±8% of the stated value; ±7% of the stated value; ±6% of the stated value; ±5% of the stated value; ±4% of the stated value; ±3% of the stated value; ±2% of the stated value; or ±1% of the stated value.

[0334] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0335] The terms “a,” “an,” “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, orexemplary language e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0336] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0337] Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0338] Furthermore, numerous references have been made to patents, printed publications, journal articles, other written text, and web site content throughout this specification (referenced materials herein). Each of the referenced materials are individually incorporated herein by reference in their entirety for their referenced teaching(s), as of the filing date of the first application in the priority chain in which the specific reference was included. For instance, with regard to chemical compounds, nucleic acid, and amino acids sequences referenced herein that are available in a public database, the information in the database entry is incorporated herein by reference as of the date of an application in the priority chain in which the database identifier for that compound or sequence was first included in the text.

[0339] It is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.

[0340] The particulars shown herein are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of various embodiments of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for the fundamental understanding of the invention, the description taken with the drawings and / or examples making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

[0341] Definitions and explanations used in the present disclosure are meant and intended to be controlling in any future construction unless clearly and unambiguously modified in the example(s) or when the application of the meaning renders any construction meaningless or essentially meaningless. In cases where the construction of the term would render it meaningless or essentially meaningless, the definition should be taken from Webster's Dictionary, 11 th Edition or a dictionary known to those of ordinary skill in the art, such as the Oxford Dictionary of Biochemistry and Molecular Biology, 2ndEdition (Ed. Anthony Smith, Oxford University Press, Oxford, 2006), and / or A Dictionary of Chemistry, 8thEdition (Ed. J. Law & R. Rennie, Oxford University Press, 2020). See also, Green and Sambrook, Molecular Cloning: A Laboratory Manual, 4th Edition (2012); F. M. Ausubel et al. eds., Current Protocols in Molecular Biology, (2003); the series Methods In Enzymology (Academic Press, Inc.); Behlke et aL, Polymerase Chain Reaction: Theory and Technology (2019); Greenfield, ed. Antibodies, A Laboratory Manual, 2nd Edition (2014); and Capes-Davis and R. I. Freshney, eds. Freshney's Culture of Animal Cells 8th Edition (2021 ).

Claims

LISTING OF CLAIMSWe claim:

1. A method of treating vaginitis in a subject in need thereof, the method comprising administering vaginally to the subject a therapeutically effective amount of a composition comprising: an imidazole therapeutic agent; and boric acid, wherein the imidazole therapeutic agent and the boric acid are administered in a combined formulation.

2. The method of claim 1 , wherein the imidazole therapeutic agent comprises one or more of nitroimidazole, metronidazole, tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazol, azaindole, secnidazole, or benznidazole.

3. A method of modified release delivery of a high dose of an imidazole therapeutic agent and boric acid to a subject, wherein the modified release delivery occurs over 24 hours.

4. The method of claim 3, wherein the modified release delivery is sustained release delivery, controlled release delivery, or delayed release delivery.

5. The method of claim 3, wherein: the high dose of imidazole therapeutic agent is more than 500 mg; or the high dose of imidazole therapeutic agent is 750-1000 mg.

6. The method of claim 3, wherein: the high dose of boric acid is more than 300 mg; or the high dose of boric acid is 600 mg.

7. The method of claim 3, in which the imidazole therapeutic agent and the boric acid are administered together in a suppository ovule, and wherein the imidazole therapeutic agent and the boric acid are released sequentially or simultaneously.

8. The method of claim 3, wherein the imidazole therapeutic agent comprises one or more of nitroimidazole, metronidazole, tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazol, azaindole, secnidazole, or benznidazole.

9. A method for delivering high dose of nitroimidazole or imidazole and boric in an easy to administer suppository ovule delivering a substantially water-insoluble nitroimidazole or imidazole therapeutic agent; and a water-soluble boric acid, in one physically stable dosage unit, wherein the therapeutic agent and boric acid are delivered sequentially or simultaneously at a modified release rate over 24 hours.

10. The method of claim 9, wherein the modified release rate is controlled release rate.11 . The method of claim 9, wherein the suppository ovule further comprises a polymer, wherein the polymer is cross linked with the boric acid.

12. The method of claim 11 , wherein the imidazole therapeutic agent comprises one or more of nitroimidazole, metronidazole, tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazol, azaindole, secnidazole, or benznidazole.

13. A method for controlling a release rate of one or more therapeutic agents, comprising administering the one or more therapeutic agents in a composition comprising: an oleaginous excipient, a polymer, and a surfactant, wherein the rate of release of the one or more therapeutic agents is controlled by using a specific concentration of the oleaginous excipient, the polymer, and / or the surfactant.

14. The method of claim 13, where the oleaginous excipient comprises a vegetable oil.

15. The method of claim 14, where the vegetable oil comprises hydrogenated palm kernel oil, coconut oil, or a combination of two or more thereof.

16. The method of claim 14, where the polymer is suspended in the vegetable oil, thereby modulating rate of release of the one or more therapeutic agents.

17. The method of claim 13, wherein the polymer comprises a hydrophobic polymer.

18. The method of claim 17, where the hydrophobic polymer comprises ethyl cellulose, starch, bentonite, or a combination of two or more thereof.

19. The method of claim 13, where the composition comprises:20 - 60 wt.% vegetable oil;30 - 45 wt.% vegetable oil; or40 wt.% vegetable oil.

20. The method of claim 13, where the composition comprises:1 - 5 wt.% polymer;1.5 - 4 wt.% polymer; or3 wt.% polymer.21 . The method of claim 13, whereby the rate of release of the one or more therapeutic agents is controlled by changing one or more of: a proportion of low to high melting point vegetable oil(s), the polymer(s), and / or the surfactant(s).

22. The method of claim 13, whereby the rate of release of the one or more therapeutic agents is controlled by changing one or more of the concentration of: the oleaginous excipient, the polymer, and / or the surfactant.

23. The method of claim 13, which is carried out in a subject with bacterial vaginitis in need of treatment thereof, and the method comprises administering vaginally to the subject a therapeutically effective amount of a modified release composition comprising a imidazole therapeutic agent and boric acid.

24. The method of claim 23, wherein the imidazole therapeutic agent is a 5-nitroimidazole or a pharmaceutically acceptable salt thereof.

25. The method of claim 24, wherein the 5-nitroimidazole is metronidazole or tinidazole.

26. The method of claim 23, wherein the imidazole therapeutic agent is present in the composition in an amount from 4 to 40 wt.% based on total weight of the composition.

27. The method of claim 23, wherein the boric acid is present in the composition in an amount of from 10 to 30 wt.% based on total weight of the composition.

28. The method of claim 23, wherein the composition additionally comprises and active agent effective against Candida albicans.

29. The method of claim 28, wherein the active agent effective against Candida albicans is an imidazole or a pharmaceutically acceptable salt thereof.

30. The method of claim 29, wherein the imidazole is selected from miconazole, tioconazole, and pharmaceutically acceptable salts thereof.

31. The method of claim 30, wherein the imidazole effective against Candida albicans is present in the composition in an amount of from 2 to 10 wt.% based on total weight of the composition.

32. The method of claim 28, wherein the composition additionally comprises an active agent effective against Trichomonas vaginalis.

33. The method of claim 32, wherein the active agent effective against Trichomonas vaginalis is an imidazole.

34. The method of claim 33, wherein the imidazole is metronidazole or a pharmaceutically acceptable salt thereof.

35. The method of claim 32, wherein the active agent effective against Trichomonas vaginalis is present in the composition in an amount of from 4 to 40 wt.% based on total weight of the composition.

36. The method of claim 23, wherein the boric acid is present in the composition in an amount of from 10 to 30 wt.% based on total weight of the composition.

37. The method of claim 23, wherein the composition is substantially free from ethylene diamine tetra acetic acid (EDTA).

38. The method of claim 23, wherein the composition is provided as a cream, foam, or a vaginal suppository.

39. The method of claim 38, wherein the vaginal suppository is a small 2500 mg vaginal ovule comprising a lipophilic pessary base.

40. The method of claim 39, wherein the vaginal ovule contains from 500 to 1 ,000 mg of imidazole and from 300 to 900 mg boric acid.

41. The method of claim 39, wherein the vaginal ovule contains from 750 to 1 ,000 mg metronidazole.

42. The method of claim 39, wherein the vaginal ovule contains from 100 to 400 mg tinidazole.

43. The method of claim 23, wherein the modified release composition is a controlled release of the imidazole therapeutic agent and the boric acid for up to 24 hours.

44. The method of claim 23, wherein the subject has recurrent vaginitis, optionally at least one of bacterial vaginosis, vulvovaginal candidiasis, and / or trichomoniasis.

45. The method of claim 44, wherein the method prevents recurrence of vaginitis in the subject for a period of: at least 30 days from initiation of the treatment, at least 45 days from initiation of the treatment, or at least 60 days from initiation of the treatment.

46. The method of claim 45, wherein the method prevents recurrence of bacterial vaginosis in the subject for a period of: at least 30 days from initiation of the treatment, at least 45 days from initiation of the treatment, or at least 60 days from initiation of the treatment.

47. The method of claim 46, wherein the treatment prevents recurrence of bacterial vaginosis in the subject without the need for conventional antibiotic maintenance therapy.

48. The method of claim 23, wherein the method comprises administration of the composition for a treatment period of: up to 14 days, up to 10 days, up to 7 days, or7 days.

49. The method of claim 23, wherein the composition is administered once a day.

50. The method of claim 23, wherein the composition is provided as a vaginal suppository that contains 750 mg metronidazole and 600 mg boric acid, and wherein the method comprises administration of the vaginal suppository once a day for a period of 7 days.51 . A composition comprising a nitroimidazole active agent or imidazole active agent and boric acid for use in a method of treating vaginitis, according to any one of claims 1 -46.

52. Use of a composition comprising a nitroimidazole active imidazole active agent and boric acid in manufacture of a medicament for use in a method of treating vaginitis according to any one of claims 1-49.

53. A kit comprising (i) a composition comprising an imidazole active agent and boric acid, and (ii) an applicator adapted for delivery of the composition of claim 51 or claim 52 to a vaginal cavity of a human subject for treatment of vaginitis.

54. A modified release pharmaceutical composition for vaginal administration, comprising: at least one imidazole therapeutic agent; boric acid; an oleaginous excipient; a polymer; and a surface active agent (surfactant), wherein a rate of release of the at least one imidazole therapeutic agent and / or the boric acid is controlled by using a specific concentration of the oleaginous excipient, the polymer, and / or the surface active agent (surfactant).

55. The modified release pharmaceutical composition of claim 54, wherein the at least one imidazole therapeutic agent comprises one or more of nitroimidazole, metronidazole, tinidazole, nimorazole, dimetridazole, pretomanid, ornidazole, megazol, azanidazole, secnidazole, or benznidazole.

56. The modified release pharmaceutical composition of claim 55, where the oleaginous excipient comprises a vegetable oil.

57. The modified release pharmaceutical composition of claim 56, where the vegetable oil comprises hydrogenated palm kernel oil, coconut oil, or a combination of two or more thereof.

58. The modified release pharmaceutical composition of claim 54, wherein the polymer comprises a hydrophobic polymer.

59. The modified release pharmaceutical composition of claim 58, where the hydrophobic polymer comprises ethyl cellulose, starch, bentonite, or a combination of two or more thereof.

60. The modified release pharmaceutical composition of claim 54, where the polymer is suspended in the oleaginous excipient, thereby modulating rate of release of the imidazole therapeutic agent and / or the boric acid.61 . The modified release pharmaceutical composition of claim 54, where the composition comprises:20 - 60 wt.% vegetable oil;30 - 45 wt.% vegetable oil; or40 wt.% vegetable oil.

62. The modified release pharmaceutical composition of claim 54, where the composition comprises:1 - 5 wt.% polymer;1.5 - 4 wt.% polymer; or3 wt.% polymer.

63. The modified release pharmaceutical composition of claim 54, whereby the rate of release of the imidazole therapeutic agent and / or the boric acid is controlled by changing one or more of: a proportion of low and high melting point of the oleaginous excipient, the type of polymer, and / or the type of surfactant.

64. The modified release pharmaceutical composition of claim 63, whereby the rate of release of the imidazole therapeutic agent and / or the boric acid is controlled by changing one or more of: the concentration of the vegetable oil(s), the concentration of the polymer(s), and / or the concentration of the surfactant(s).

65. The modified release pharmaceutical composition of claim 54, comprising: hydrogenated palm kernel oil, coconut oil, and ethylcellulose; hydrogenated palm kernel oil, coconut oil, and bentonite; hydrogenated palm kernel oil, coconut oil, bentonite, and ethylcellulose; hydrogenated palm kernel oil, coconut oil, bentonite, ethylcellulose, and polysorbate 80; or hydrogenated palm kernel oil, coconut oil, polysorbate 80, and pre-gelatinized starch.

66. The modified release pharmaceutical composition of claim 65, comprising:19.5% hydrogenated palm kernel oil, 19.5% coconut oil, and 7% ethylcellulose;21.5% hydrogenated palm kernel oil, 21.5% coconut oil, and 3% ethylcellulose;19.5% hydrogenated palm kernel oil, 19.5% coconut oil, and 7% bentonite;21.5% hydrogenated palm kernel oil, 21.5% coconut oil, and 3% bentonite;21% hydrogenated palm kernel oil, 21 % coconut oil, 1 .5% bentonite, 1 .5% ethylcellulose, and 1 % polysorbate 80;21.25% hydrogenated palm kernel oil, 21.25% coconut oil, 1.5% bentonite, 1.5% ethylcellulose, and 0.5% polysorbate 80; or21.25% hydrogenated palm kernel oil, 21.25% coconut oil, 0.5% polysorbate 80, and 3% pre-gelatinized starch.

67. The modified release pharmaceutical composition of claim 65, comprising: 30% metronidazole and 24% boric acid.

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