INTRODUCTION:

Traditionally, the vagina has been used to deliver drugs locally. Because of what is known as the "vaginal first-pass effect," medications can be administered vaginally to the uterus specifically with a lower chance of systemic side effects. The vagina is a complex, ever-changing environment. It observes moisture, pH, and a lot of bacteria. Both internal and external influences might cause it to change¹. Both systemic and local absorption can be accomplished with its help². Pharmacological absorption for systemic application is highly adapted to the vaginal wall. Because it is home to an extensive blood vascular network³. Itching, burning, odor, discharge, and irritation are some of the symptoms of a vaginal infection.

At least once in their lives, most women get vaginitis. The three most common causes of vaginitis are bacterial vaginosis, trichomoniasis, and vulvovaginal candidiasis⁴. A wide variety of bacteria and hosts in the vagina strongly interact to provide the first line of defense against the migration of opportunistic illnesses. In conditions of health, the microbiota maintains eubiosis, a stable balance. Disorders related to the vagina are caused by dysbiosis, a disruption of the microecological equilibrium that permits pathogenic bacteria to multiply⁵.

Bacterial vaginosis:

Bacterial vaginosis is the most common vaginal illness in women who are fertile. Thirty percent of American women who are of reproductive age are afflicted with bacterial vaginosis. Twenty to thirty percent of these women have recurrences after their initial course of therapy⁶. Moreover, BV has been associated with major and costly reproductive and obstetric outcomes, increasing the risk of miscarriage, low birth weight, preterm birth, and pelvic inflammatory disease in women⁷. Atopobium Vaginae and Gardnerella vaginalis are examples of facultative anaerobes that are more prevalent in BV, along with the disappearance of significant lactobacillus species⁸. BV women who engage in regular intercourse are at risk of developing urinary tract infections. Urinary tract infections primarily result from Escherchia coli⁹. In addition to an increased risk of contracting HIV and other sexually transmitted infections (STIs), women with BV are also more likely to experience unfavorable birth outcomes and other gynecologic sequelae¹⁰.

Fig no.1: Bacterial Vaginosis

Epidemiology and risk factors:^11,12

The most frequent cause of vaginal discharge and odor in women is bacterial vaginosis, which affects 29% of all women. The following are risk factors:

· Multiple sex partners

· Douching regularly

· Non use of condoms

· Sex

· Smoking

Mucoadhesive Drug Delivery System:

Mucoadhesion is an issue that designers of medication delivery systems are exploring in these days. The connection of two materials where at least one of the components is the mucosal surface is the standard definition of mucoadhesion. To enable the dosage form to remain at the application or absorption site longer and to provide close contact between the dosage form and the underlying absorbing surface, a mucoadhesive drug delivery system may be developed. In instance, increasing the drug's residence time at a particular site and managing the drug's release from a dosage form can help to stabilize the drug's plasma level and improve bioavailability¹³.

Mechanism of Mucoadhesion¹⁴

Mucoadhesion process is typically split into two stages:

1. Contact stage

2. Consolidation stage

The first step, which is characterized by the formulation spreading and swelling and the start of deep contact with the mucus layer, brings the mucoadhesive and mucous membrane into touch¹⁵.

During the consolidation phase, the mucoadhesive components are activated by moisture. Moisture makes the system more pliable, allowing the mucoadhesive molecules to split apart and create weak hydrogen and van der Waals bonds. The consolidation stage is essentially explained by two theories: the diffusion theory and the dehydration theory¹⁶.

Fig no. 2: Mucoadhesive system

In situ gel:

Liquid formulations known as "in situ gelling systems" take the shape of a solid after being injected into the body or applied topically. For a variety of pharmaceutical and biological applications, they have drawn more and more attention during the past 20 years as an appealing class of responsive drug delivery devices¹⁷ The term "in situ" is derived from Latin and meaning "in its original position or place." Because of its unique future "Sol to Gel" transition feature, it aids in the sustained regulated release of the medication and improves patient compliance and comfort¹⁸.Gel formation is dependent on a number of variables, including pH variations, ions, electrical sensitivity, temperature modulation, ultraviolet irradiation, and the enzyme responsible for the release of the active ingredient¹⁹. Under the brand name Pluronic, the non-ionic, water-soluble triblock copolymers of polyethylene glycol-b-polypropylene and glycol-b-polyethylene glycol are highly sought-after as pharmaceutical excipients. These polymers' amphiphilic nature and surfactant qualities allow them to interact with biological membranes and hydrophobic surfaces²⁰. Hydrogels based on poloxymer 407 show an intriguing reversible thermal property. They are liquid at normal temperature but gel when given at body temperature, which makes them desirable options for pharmaceutical drug delivery systems²¹.

Advantages of in situ gel^22,23,24

· Controlled and sustained release of the drug

· Minimizing the dose frequency and drug toxicity

· Increased bioavailability

· Ease of the drug administration

· Simple formulation and manufacturing so less investment and cost

· Improved patient compliance and comfort

Disadvantages of in situ gel²²

· It requires an elevated level of fluids

· Only small doses can be administered

· The solution form of the drug is more susceptible to degradation

· Due to chemical degradation, there is a chance of instability

· After drug administration, eating and drinking limited for a few hours

Various approaches of in situ gel²⁵

Temperature triggered system:

In these systems, the process and gelation are caused by body warmth alone, without the need for any external heat. These are the systems that are most frequently utilized.

Fig no. 3: Temperature triggered system

pH triggered system:

This method uses pH-sensitive or pH-responsive polymers to create a gel. All pH-sensitive polymers have ionizable functional groups, either acidic or alkaline, that can absorb or release protons in response to pH changes.

Fig no. 4: pH Triggered system

Ion Activated system:

Ionic bond formation: Certain polymers have the ability to generate gels by ionic bond formation with specific ions. One polymer that is commonly utilized in in situ gel systems is gelatin. In these systems, gelatin chains are stabilized through the use of calcium ions, resulting in the formation of a strong gel.

Fig no.5: Ion activated Trigger system

Thermogelling Polymer Systems:

To create hydrogels intended for gynecological treatments, thermoresponsive polymers, both natural and synthetic, are utilized. An 18 w% water solution at 4–5 ◦C transforms into a hydrogel at 32^◦C²⁶. Poloxamer 407 stands out among synthetic formulations; it is made up of hydrophilic poly (ethylene oxide) blocks and a poly (propylene oxide) core block. Pluronic®, Lutrol®, and Synperonic® are other names for Poloxamer, a non-ionic synthetic triblock copolymer²⁷. Notably, a molecule's solubility in water and molecular weight decrease with increasing polyethylene oxide unit concentration. As a result, the hydrophilic-lipophilic balance (HLB) of each kind of poloxamer varies. This is an important consideration when selecting the best poloxamer type for a particular formulation since it shows whether the poloxamer is soluble in water or oil ²⁸.

Method of Preparation^{29,30,31,32,33}

Poloxamer 407 (pluronic F127) was dissolved in water by using “cold method” at 0-4⁰C. HPMC and Sodium alginate were dissolved separately in distilled water using magnetic stirrer, until complete hydration of polymer. Gradually add the above solution to poloxamer solution, Mix and left at 4⁰C for 24hrs.

Probiotics:

The International Scientific Association for Probiotics and Prebiotics released a consensus statement in 2016 that largely adhered to the World Health Organization's definition of probiotics, which is defined as live microorganisms that, when given in sufficient amounts, will benefit the host's health^34,35. The most common type of probiotic strains are Bifidobacterium species, specifically Lactobacillus acidophilus, Lactobacillus casei, and Lactobacillus bulgaricus. These strains have been shown to naturally alter the immune system and generate particular antibacterial compounds, as well as to prevent Escherichia coli from adhering to and invading the intestinal mucosa³⁶.In order to control BV through recolonization of the vaginal microbiota, probiotics containing Lactobacillus are frequently utilized and promoted. These findings were validated by molecular methods, which also made it possible to identify over 20 different Lactobacillus species that are present in healthy vagina. The dominant species representing the Lactobacillus genus were identified as L. crispatus, L. grasseri, and L. iners based on 16S rRNA gene studies of vaginal simples from healthy women³⁷. They can be utilized in place of antibiotics and antimicrobials³⁸. It has been established that certain Lactobacillus species are effective antimicrobials against BV-related bacteria. Both their use in treating BV and preventing BV from returning after receiving antibiotic therapy has been examined³⁹.In order to prevent pathogen invasion and preserve or enhance the microbial balance in the host environment, lactobacillus affects microbial interventions⁴⁰. Certain strains of Lactobacillus can co-aggregate with G. vaginalis and impede or displace strains of G. vaginalis that had attached to vaginal epithelial cells, as several in-vitro tests have shown. Lactobacillus is possible lipase enzyme producer which has been also identified as biological catalyst⁴¹. Coagulation of Lactobacillus acidophilus, Lactobacillus gasseri, and Lactobacillus Jensenii in vitro, obtained from vaginal samples of healthy premenopausal women. L. acidophilus was also found to replace previously adherent strains on vaginal epithelial cells and decrease G. vaginalis adherence⁴².

Role of probiotics in management of BV and Recurrence of BV:

Due to its prolonged activity, non-invasiveness, and ability to bypass the GI tract, vaginal delivery of probiotics has become more popular for the delivery of probiotics when compared to oral delivery of probiotics for vaginal infections⁴³. Women's vaginal microbiome is very important for sustaining the vaginal microbiota. The flora changes, the pH rises, and a rotten fishy stench appears when the vaginal microbiota is disturbed by any BV-related factor⁴⁴.

Probiotic lactobacilli produce H₂O₂, lactic acid, and bacteriocins, which stop the proliferation of BV agents. Different strains of lactobacilli treat BV and RBV and return the normal vaginal flora^45,46. Probiotic lactobacillus species in the vaginal tract create lactic acid, which acts as an immunomodulator. The hydrogen peroxide that lactobacilli produce has antibacterial properties⁴⁷. Probiotics based on lactobacilli release bacteriocins and H₂O₂ as antibacterial agents, stick to vaginal epithelial cells, compete with other bacteria, maintain the pH of the vagina, and colonize the vagina to maintain the normal vaginal flora^48,49.

REFERENCES:

1. Kaur M. Vaginal discharge. International Journal of Advances in Nursing Management. 2020; 8 (3); DOI: 10.5958/2454-2652.2020.00057.8

2. Andrade A. Parente M and Ares G. Screening of mucoadhesive vaginal gel formulations. Brazillian Journal of Pharmaceutical Sciences. 2014; 50 (4); http://dx.doi.org/10.1590/S1984-82502014000400029.

3. Sahoo C. Nayak P. Sarangi D. Sahoo T. Intra Vaginal Drug Delivery System: An Overview. American Journal of Advanced Drug Delivery. 2013.

4. Paladine H and Desai U. Vaginitis Diagnosis and treatment. American Academy of Family Physician. 2018; 97 (5).

5. Zhao Y. Wang T. Chen Z. Ren H. Song P. Zhu Y. Liang S and Tzeng C. Development and evaluation of a thermosensitive in situ gel formulation for intravaginal delivery of lactobacillus gasseri. Pharmaceutics. 2022; 14 (1934); DOI:https://doi.org/10.3390/ pharmaceutics14091934.

6. Webb L. Probiotics for preventing recurrent bacterial vaginosis. Journal of American Academy of PAs. 2021; 34 (2); DOI:10.1097/01.JAA.0000731484.81301.58.

7. Patel G. Patel M. Efficacy of novel acid buffering vaginal tablet of metronidazole for bacterial vaginosis. Research Journal of Pharmaceutical Dosage Forms and Technology. 2009; 1(3).

8. Bradshaw C and Brotman R. Making inroads into improving treatment of bacterial vaginosis-striving for long term cure. BioMed Central. 2015; DOI: 10.1186/s12879-015-1027-4.

9. Permana A. Asri R. Amir M. Himawan A. Arjuna A. Juniarti N. Et. al. Development of thermoresponsive hydrogels with mucoadhesive properties loaded with metronidazole Gel- Flakes for improved Bacterial vaginosis treatment. Pharmaceutics. 2023; 15 (1529); https://doi.org /10.3390/ pharmaceutics15051529.

10. Muzny C. Balkus J. Mitchell C. Sobel J. Workowski K. Marrazzo J and Schwebke J. Diagnosis and Management of Bacterial Vaginosis: Summary of Evidence Reviewed for the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infections Treatment Guidelines. Clinical Infectious Diseases. 2022; https://doi.org/10.1093/cid/ciac021.

11. Brown L. Bacterial vaginosis. GP Pharma update. 2019.

12. Coudray M. Madhivanan P. Bacterial Vaginosis - A Brief Synopsis of the Literature. European Journal of Obstetrics Gynecology and Reproductive Biology. 2021; 245: 143–148. doi:10.1016/j.ejogrb.2019.12.035.

13. Dhutwalia P. Kanwar K et.al. A Review on Mucoadhesive drug delivery systems: A novel approach. International Journal of Pharmaceutical. Chemical and Biological Sciences. 2014; 4(2).

14. Mahajan P. Kaur A. Aggarwal G. Harikumar S. Mucoadhesive drug delivery system: A review. International Journal of Drug Development and Research. 2013; 5(1).

15. Boddupalli B. Mohammed Z. Nath R. Banji D. Mucoadhesive drug delivery system: An overview. Journal of Advanced Pharmaceutical Technology & Research. 2010; 1(4); DOI: 10.4103/0110-5558.76436.

16. Kolawole O. Cook M. In situ gelling drug delivery systems for topical drug delivery. European Journal of Pharmaceutics and Biopharmaceutics. 2023; 184; https://doi.org/10.1016/j.ejpb.2023.01.007.

17. Kurniawansyah I. Rusdiana T. Sopyan I. Arya I. Wahab H and Nurzanah D. Comparative study of in situ gel formulation based on the physico-chemical aspects: Systemic review. Gels. 2023; 9 (645); https:// doi.org/10.3390/gels9080645.

18. Khode P. Dongare P. In situ gel: A review of pharmaceutical and biological evaluation and approaches. Research Journal of Pharmaceutical Dosage Forms and Technology. 2019; 11(3); DOI:10.5958/0975-4377.2019.00037.5.

19. Guven U. Berkman M. Senel B. Yazan Y. Development and in vitro/in vivo evaluation of thermo-sensitive in situ gelling systems for ocular allergy. Brazilian Journal of Pharmaceutical Sciences. 2019; 55:e17511; http://dx.doi.org/10.1590/s2175-97902019000117511

20. Giuliano E. Paolino D. Fresta M and Cosco D. Mucosal applications of poloxamer 407-based hydrogels: An overview. Pharmaceutics. 2018; 10 (159); doi:10.3390/pharmaceutics10030159

21. Mohanty D. Bakshi V. Simharaju N. Haque M. Sahoo C. A review on in situ gel: A novel drug delivery system. International Journal of Pharmaceutical Sciences Review and Research. 2018; 50 (1).

22. Singh A. Kurkure S and Anardi S. Formulation and evaluation of in-situ gelling system for sustained release ophthalmic drug delivery of ciprofloxacin. World Journal of Pharmaceutical Research. 2020; 9(8); DOI: 10.20959/wjpr20208-18075.

23. Konatham M. Gorle M. Pathakala N. Bakshi V. Mamidisetti Y. Chinthakindi P. Jadi R. In situ gel polymer: a review. International Journal of Applied Pharmaceutics. 2020; 13 (1); DOI: http://dx.doi.org/10.22159/ijap.2021v13i1.39504.

24. Dhalkar P. Jagtap S. Jadhav S. Redkar M. Karande B. Formulation and evaluation of in situ gel model naproxen. Asian Journal of Pharmacy and Technology. 2019; 9(3); DOI: 10.5958/2231-5713.2019.00034.5.

25. Jouzdani F. Wolf J. Atyabi F and Schnürch A. In situ gelling and mucoadhesive polymers: why do they need each other ? . Taylor & Francis. 2018; DOI: 10.1080/17425247.2018.1517741.

26. Gosecka M. Gosecki M. Antimicrobial Polymer-Based Hydrogels for the Intravaginal Therapies—Engineering Considerations. Pharmaceutics. 2021; 13 (1393); https://doi.org/ 10.3390/pharmaceutics13091393.

27. Liu Y. Yang F. Feng L. Yang L. Chen L. Wei G. Lu W. In vivo retention of poloxamer-based in situ hydrogels for vaginal application in mouse and rat models. Acta Pharmaceutica Sinica B. 2017; 7 (4); http://dx.doi.org/10.1016/j.apsb.2017.03.003.

28. Carvalho G. Araujo V. Santos B. Araújo J. de Souza M. Duarte J. Chorilli M. Highlights in poloxamer-based drug delivery systems as strategy at local application for vaginal infections. International Journal of Pharmaceutics. 2021; https://doi.org/10.1016/j.ijpharm.2021.120635.

29. Padmasri B. Nagaraju R. Prasanth D. A comprehensive review on in situ gels. International Journal of Applied Pharmaceutics. 2020;12 (6) DOI: http://dx.doi.org/10.22159/ijap.2020v12i6.38918.

30. Nikhar S. Bansode D. Mahadik K. Thermosensitive in situ gel of tinidazole in treatment of bacterial vaginosis: formulation and evaluation. International Journal of Ayurveda and Pharma Research. 2020; 8 (1).

31. Rencber S. Karavana S. Senyigit Z. Erac B. Limoncu M. Baloglu E. Mucoadhesive in situ gel formulation for vaginal delivery of clotrimazole: formulation, preparation, and in vitro/in vivo evaluation. Taylor and Francis. 2016; DOI: 10.3109/10837450.2016.1163385.

32. Swain G. Patel S. Gandhi J. Shah P. Development of Moxifloxacin Hydrochloride loaded in-situ gel for the treatment of periodontitis: In-vitro drug release study and antibacterial activity. Journal of Oral Biology and Craniofacial Research. 2019; https://doi.org/10.1016/j.jobcr.2019.04.001.

33. Mahajan N. Shende S. Dumore N. Nasare L. Development and evaluation of ion induced in situ gelling system of opoid analgesic for nose to brain delivery. Research Journal of Pharmacy and Technology. 2019; 12(10); DOI:10.5958/0974-360X.2019.00817.5.

34. Barrea L. Verde L. Auriemma R. Vetrani C. Cataldi M. Toral E. Pugliese G. Camajan E. Savastano S. Colao A. Muscogiuri G. Probiotics and Prebiotics: Any Role in Menopause Related Diseases?. Springer. 2023; 12; DOI: https://doi.org/10.1007/s13668-023-00462-3.

35. Hossain K. Nahar K. Shokryazdan P. Abdullah N. Hamid K. Jahromi M. Probiotic potential of lactic acid bacterial isolated from cheese, yogurt and poultry faeces. Research Journal of Pharmacy and Technology. 2017; 10 (9); DOI: 10.5958/0974-360X.2017.00530.3.

36. Sugiyartono. Purwanti T. Asega I. Influence of emcompress concentration on the physical properties of tablet containing lactobacillus spp. And guava leaves extract. Asian Journal of Pharmaceutical Research. 2014; 4(4).

37. Ladaycia A. Passirania C and Lepeltier E. Microbiota and Nanoparticles: Description and Interaction. Elsevier. 2021; 169.

38. Chauhan A. Kaur S. Singh R. A review on probiotics and fish farming. Research Journal of Pharmacy and Technology. 2018; 11(11); DOI: 10.5958/0974-360X.2018.00939.3.

39. Balogue E. Karavan S. Senyigit Z. Guner T. Rheological and mechanical properties of poloxamer mixtures as a mucoadhesive gel base. Informa Healthcare. 2010; 16(6) DOI:10.3109/10837450.2010.508074.

40. Abbe C and Mitchell C. Bacterial vaginosis : a review of approaches to treatment and prevention. frontiers in reproductive health. 2023; doi: 10.3389/frph.2023.1100029.

41. Ngyuyen H. Nguyen D. Nguyen T. Biological activites of poly (lactic acid) polymer produced from Lactobacillus rhamnosus PN04. Research Journal of Pharmacy and Technology. 2018; 11(7); DOI:10.5958/0974-360X.2018.00562.0.

42. You S. Ma Y. Yan B. Pei W. Wu Q. Ding C and Haung C. The promotion mechanism of prebiotics for probiotics: A review. Frontiers in Nutrition. 2022; DOI:10.3389/fnut.2022.1000517.

43. Falagas M. Betsi G. & Athanasiou S. Probiotics for the treatment of women with bacterial vaginosis. Clinical Microbiology Infection. 2007; 13 (7);10.1111/j.1469-0691.2007.01688.x

44. Sreeja V. Prajapati J. Probiotic Formulations: Application and Status as Pharmaceuticals-A Review. Probiotics & Antimicrobiology. Proteins. 2013; DOI 10.1007/s12602-013-9126-2.

45. Lehtoranta L. Jaakkola R. Laitila R and Maukonen J. Healthy Vaginal Microbiota and Influence of Probiotics Across the Female Life Span. Frontiers in Microbiology. 2022; doi: 10.3389/fmicb.2022.819958.

46. Yoshikata R. Yamaguchi M. Mase Y. Tatsuyuki Y. Myint K. Ohta H. Evaluation of the efficacy of Lactobacillus containing feminine hygiene products on vaginal microbiome and genitourinary symptoms in pre- and postmenopausal women: A pilot randomized controlled trial. Plos One. 2022; 17(12); https://doi.org/10.1371/journal.pone.0270242.

47. Anh N. Yen T. Vinh D Et. Al. Study on the ability of producing of conjugated linoleic acid of lactobacillus fermemtum A01 isolated from human digestive tract. Research Journal of Pharmacy and Technology. 2021; 14(3); DOI:10.5958/0974-360X.2021.00234.1.

48. Tachedjian G. Aldunate M. Bradshaw C. Cone R. The role of lactic acid production by probiotic Lactobacillus species in vaginal health. Res. Microbiology. 2017; http://dx.doi.org/10.1016/j.resmic.2017.04.001.

49. Palma E. Recine N. Domenici L. Giorgini M. Pierangeli A. Panici P. Long-term Lactobacillus rhamnosus BMX 54 application to restore a balanced vaginal ecosystem: a promising solution against HPV-infection. BMC Infectious Diseases. 2018; 18:13; DOI 10.1186/s12879-017-2938-z.

Received on 22.04.2024 Revised on 02.08.2024

Accepted on 29.10.2024 Published on 10.04.2025

Available online from April 12, 2025

Research J. Pharmacy and Technology. 2025;18(4):1920-1924.

DOI: 10.52711/0974-360X.2025.00274

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