In-Vitro Dissolution Study protocol for various Vaginal Dosage Forms

Ananta Choudhury, Madhusmita Kumari*, Biplab Kumar Dey

Faculty of Pharmaceutical Science, Assam Down Town University, Guwahati – 781026, Assam, India.

*Corresponding Author E-mail: madhusmitakumari3@gmail.com

ABSTRACT:

The vaginal mucosa is well recognized as a route for delivering variety of drugs. Considerable number of anti-fertility drugs have been successfully delivered through vaginal and uterine canals. The goal of this review is to summarize the present clinical state of intravaginal medicines and IUDs, with a prime focus on the available in-vitro dissolution study methods and their importance. At present different vaginal drug delivery systems are available in the market and a few are under clinical trial. The accurate estimation drug release profile of any of such dosage form is primarily depends on the standard dissolution study protocol. The vaginal delivery system is an effective site for local and systemic drug delivery, and a range of innovative formulation strategies are being researched for its development. The concept behind the study is mainly lies on the fact that the standard dissolution protocol may vary based on formulation type, its design and its therapeutic goals.

KEYWORDS: Intravaginal drug delivery system, intrauterine drug delivery system, Anatomy and physiology of the vaginal and uterine cavities, Marketed vaginal formulation, In-vitro drug release.

INTRODUCTION:

The creation of modern drug delivery technologies is very costly and time consuming, but it has been attempted using various methods such as individualizing drug therapy, dose titration, therapeutic drug tracking, and proper insertion to increase the safety and efficacy ratio of drugs. Many attempts have been made to administer poorly absorbed medications using various delivery systems and through different possible routes.¹ The vaginal and uterine drug delivery systems well are capable of delivering proteins, peptides, and many other therapeutic drugs such as macromolecules through the mucus-laden environment.^2,3 Literature suggests that the vaginal mucosa are ideal for effective delivery of a range of chemical entities like antifertility, antibacterial and antifungal agents through vagina and uterus.⁴

Intra Vaginal drug delivery system:

Vaginal drug delivery are advantageous due to certain unique characteristics, such as a thick network of blood arteries, a large surface area, and the avoidance of fast pass metabolism, that allow this route to provide a wide range of medications to treat local vaginal infections and other health problems.^5,6 Bio-adhesive formulations find extra edge to deliver the drug through vaginal route due to the availability of vaginal mucosal layer and also improve drug retention time inside the vaginal cavity.^7,8 The principle of controlled-release drug delivery has also been effectively applied to the intra-vaginal administration of a systemic prostaglandin derivative for abortion. Intra-vaginal controlled-release medication delivery systems are a good approach to retain therapeutically active drugs like contraceptive steroids and prostaglandins, for example, in the body.^7,8,9

Intra Uterine Drug Delivery System:

An intrauterine device (IUD) is implanted via the cervix and placed in the uterus to prevent pregnancy. The IUD has a thin rope that hangs down into the upper part of the vaginal canal. Richer identified the first IUD used exclusively for contraception in 1909^10,11 When it comes to preventing pregnancy, the intrauterine system (IUD) is extremely successful, they are long-lasting and are also ideal for use when breastfeeding. It has been successfully used to delivered hormones such as estrogens and progestogen.¹²

Anatomy and Physiology of the Vaginal and Uterine cavities:

Vagina is a slightly S-shaped fibromuscular collapsible tube that extends from the uterus's cervix and is between 6 and 10cm length. The epithelial layer, muscular coat, and tunica adventia are the three layers that make up the vaginal wall.¹³ The vaginal tube is a muscular tube that stretches from the uterus's cervix and is around 6-10cm long. The three layers of vaginal wall are inner mucosal layer, middle muscularis Layer, and Outer Adventitial Layer. During menses and childbirth, the vaginal canal acts as both an entrance and exit to the reproductive tract. The vagina is a collapsed organ with the anterior and posterior walls in contact with each other in a transverse cross sectional view.¹⁴ The vagina expands due to vaginal folds and micro-elevations on the epithelial cell surface, allowing vaginal formulation to be kept in side by increasing the surface area of the vagina, that also improve the rate of absorption of drugs. The spread, retention, absorption, and drug discharge of the formulation in the vaginal canal are all influenced by pH, enzyme activity, and microbiota.¹⁵ During the menstrual cycle, the vaginal epithelial layer travels 200-300Am. The presence of smooth elastic fibers in the muscle layer helps to support vaginal elasticity. This suppleness is aided by the loose connective tissue of the tunica adventia. internal iliac artery, uterus, middle rectal artery, and internal prudential artery are the blood arteries that deliver blood to the vaginal region. Drug administration across the vaginal membrane, like other mucosal drug delivery routes, can take several forms: a) Diffusion through a cell caused by a concentration gradient (trans cellular pathway), b) Vesicular or receptor-mediated transport mechanism, or c) Diffusion between cells via tight connections (intercellular route).^16,17

Table 1: The FDA has licensed IUDs and implants in the United States. ^{18, 19}

Active Ingredient	Proprietary Name	Dosage	Strength	Applicant Holder	Year of Approval
Levonorgestrel	KYLEENA	IUD	19.5MG	BAYER	2016
Levonorgestrel	LILETTA	IUD	52MG	MEDICINES360	2015
Levonorgestrel	SKYLA	IUD	13.5MG	BAYER	2013
Levonorgestrel	MIRENA	IUD	52MG	BAYER	2000
Copper  T	PARAGARD380A	IUD	309MG	COOPERSURGICAL	1984
Etonogestrel	NEXPLANON®	Implant	68MG	ORGANON	2011

Table 2: Presently marketed products for intravaginal and intrauterine drug delivery system: - ^{19, 20, 21}

Therapeutic drug (Brand)	Intended use	Dosage form	Company
Nonoxynol-9 (Advantages ®	Contraceptive	Vaginal gel	Columbia laboratories
Etonogestrol, ethinyl estradiol (Nuva ring ®	Contraceptive	Vaginal gel	Organon
Nonoxynol-9 (Conceptrol®)	Contraceptive	Vaginal gel	Advance Care Product
Progesterone	Infertility, secondary	Vaginal gel	Fleet Laboratories
Miconazole nitrate	Anti-fungal	Cream, suppository, swelling controlled release system	Dermocare laboratories (giy) Pvt. Ltd.
Prostaglandin E2	Cervical ripenig	Crosslinked PEG hydrogel, suppository	Ausun pharmaceutics
Lactobacilli strains	Urogenital tract infections	Bi-layered tablet	AIC global healthcare
Progestin, levonorgestrel, orethindrone acetate	contraceptives	Vaginal ring	Cadila pharmaceuticals LTD (VIibra)
estradiol	Hormone replacement therapy	Vaginal ring	Xeno pharmaceuticals Pvt. Ltd. organon (india) Ltd
Relaxin	Cervical ripenig	Gel	Phoenix Pharmaceutical Relaxin
LHRH	Hormone dependent mammary tumors, fertility control	Suppository	Anomex Comit 50
Leuprolide	Ovulation inducing activity	Solution suppository	Zydus Cadila Healthcare Ltd
Insulin	Diabetis mellitus	Solution, gel	Piramal Healthcare
Estring®	hormone replacement	Vaginal ring	Pharmacia and upjohncomp LLC
Femring®	hormone replacement	Vaginal ring	Millicent
NuvaRing®&generics	contraception	Vaginal ring	Merck and Co.inc
Progering®/Fertiring®	contraception	Vaginal ring	Laboratories Andromacosa in santigo, chile
Annovera®	contraception	Vaginal ring	Therapeutics MD
PEG2 tylose	To ripen the cervix prior to induction of labor	Vaginal gel	Se Tylose
Crinone®	Hormone replacement	Vaginal gel	Allergan
Hydroxyethylcellulose gel	To treat intravaginal warts	Vaginal gel	Hetero Healthcare Ltd
Tylose gel	Ripening and induction of labor	Vaginal gel	SE Tylose
Methylcellulose gel	Regulate pH	Vaginal gel	Unimed technologies Ltd
Pro 2000	HIV	Vaginal gel	Indevus Pharmaceuticals
Monocaprin	HIV, HSV, Chlamydia	Vaginal gel	Hangzhou Sage Chemical Co., Ltd.
WHI-05 ME gel	HIV and spermicidal	Vaginal gel	Alberto-Culver company
Chlorhexidine gluconate	Microbicide	Vaginal gel	Basic Pharma Life Science Pvt. Ltd.
Replens	STDs, HIV	Vaginal gel	Church and Dwight Co., Inc.
2000 carrageenan (PC 213)	Bacterial vaginosis	Vaginal gel	carrageenan manufacturers
Pre pidil®	Preeclampsia, induction of labor	Vaginal gel	Pharmacia And Upjohn
Misoprostol®	Cervical ripening	Vaginal gel	Cipla limited
Povidone iodine gel	Vagina antiseptic	Vaginal gel	Salvavidas Pharmaceutical Pvt. Ltd
Vigilone®	Wound healing	Vaginal gel	Ccs Viglione Limited
Hypol®	Wound healing	Vaginal gel	Felton Grimwade and Bosist،s Pvt. Ltd.
Alginate gel	STD, contraceptive/spermicide	Vaginal gel	Sigma-Aldrich

In-Vitro Drug Release Testing of Different Dosage Form:

In-vitro research methods, which are valuable tools in product creation, quality, and performance testing, are used to evaluate the safety, efficacy, and assurance of novel VDFs. In recent decades, there has been a strong need to develop effective test methods, and many dissolution methods for various types of VDFs have been proposed, both for predicting in-vivo drug release and for quality control.^22,23

Dissolution Test Methods for Vaginal Tablets:

Environmental circumstances at the absorption site, volume and composition of the vaginal fluid, and surface exposure to the dosage form are all important elements to consider when designing dissolution studies for vaginal tablet formulations with effective in-vitro - in-vivo correlation.^24,25 The main goal was to develop a dissolution apparatus that could be utilized to simulate the vaginal environment in an in-vitro setting, which could be done by modifying an apparatus proposed by Setnikar and Fantelli for determining the liquefaction duration of rectal suppositories.²⁶ The pH of the medium was fixed at 4.5 to approximate normal vaginal pH values. Kale et al. demonstrate in his study the complete disintegration followed by release of lactobacilli from vaginal table using newly manufactured dissolution apparatus. He suggested the use of the promising technology for routine quality testing of vaginal formulation.²⁷ However, the authors' conclusion may be correct for the stated purpose, but it may not be applicable in other situations because they used a test medium that allowed lactobacilli to grow, which is not a bio relevant medium, the medium discharge rate was not regulated, and the use of a cellophane membrane to simulate vaginal tissue was questionable.^28,29

The function of an alternative configuration for Baloglu et al. dissolution’s setup was explored using a mucoadhesive vaginal table as a sample. The described in- vitro setup allows for the in-vitro dissolving investigation to be carried out with a little amount of fluid and with a low risk of exposure to agitation and sampling instruments.^30,31 This model was found effective against several vaginal formulation and its became the most bio relevant method too.^32,33

Dissolution Test Methods for Vaginal Suppositories:

Zaveri et al. conducted the dissolving study on TFV loaded suppositories using water medium of drug release ^34,35 Two distinct sets of dissolution tests were carried out at 37°C. The fluid volume was mimic as per normal availability of fluid in the vaginal canal. The findings of this study highlight the importance of properly developing biorelevant in-vitro methods, and it also serves as a useful case study for future research.³⁶

Dissolution Test Methods for Vaginal Gels:

The vertical diffusion cell (VDC) is commonly used to determine how much drug is released from vaginal gel formulations.³⁷ The setup was created to test the release rates of microbicides from vaginal gel formulations. The VDC test method adequately addresses the intravaginal environment after the gel formulation is placed within the donor chamber, and it is expected to yield effective results for vaginal gel formulations utilized for systemic action if sink conditions are maintained properly.^38,39

In addition to hydrogels, a range of non-aqueous gel compositions have recently been proposed. They have enhanced clinical performance, particularly with poorly soluble drugs, which is important in the development of HIV microbicide formulations, and they appear to be a promising formulation platform for coitally autonomous vaginal drug delivery.⁴⁰ Forbes et al. studied maraviroc release in-vitro drug release from silicone elastomer gels and hydroxyethylcellulose (HEC)-based hydrogels in VFS.⁴¹ The authors stated that the HEC gel would appear to be the preferable alternative for clinical development based on in-vitro release results, neglecting the greater rheological and water solubility issues with the gel systems. As a result, Forbes et al., in-vitro test approach is unlikely to be effective in properly predicting intravaginal pharmaceutical release and absorption. Because the data reveal that physiologically meaningful fluid volumes and compositions exist, they are crucial for constructing bio predictive in-vitro models of vaginal gel formulations. Physiological agitation concentrations and vaginal discharge may need to be treated adequately to get physiologically significant results.^42,43 The simulation of sexual intercourse may be required since the presence of semen can substantially alter intravaginal pH values, which can affect drug release from pH responsive gel formulations.⁴⁴

Dissolution Test Methods for Vaginal Films:

Yoo et al. created a "simulated dynamic vaginal system" to characterize in-vitro drug release of their prototype formulations when developing polymeric vaginal film preparations to protect women against sexually transmitted infections. Other research groups, such as Bassi et al.,^45,46, employed the same experimental setup to measure nystatin release from bioadhesive vaginal films in VFS. In-vitro and in-vivo vaginal film release actions were not linked in any of these experiments. The stimulated dynamic vaginal system is a step forward toward a more bio relevant in vitro model when compared to most in vitro models used to assess drug release from vaginal films, but it is similar to many of the models discussed previously.^47,48

The active substance in vaginal ring compositions is distributed gradually over several weeks or months. Due to the lengthy in-vivo release studies, creating bio predictive in-vitro release models for IVRs looks to be more challenging than for other VDFs at first glance. A bio predictive in-vitro study method requires point-to-point in-vivo correlations in order to forecast in-vivo drug availability/absorption over the full planned application range^.49

Current methods for screening drug release from IVRs use almost all types of media used in regular dissolution/drug release testing of other VDFs, ranging from water, aqueous (acetate) buffers, and VFS, to hydro alcoholic combinations, and aqueous media including surfactants. The studies are done with full rings or ring segments, and the fluid volumes utilized range from 5 to 1000ml. This method was found to be predictive of Nuvaring in-vivo results, and as a result, it was accepted as a basis for in vivo bioequivalence waivers based on dissolution profile similarity. Temperature, according to Externbrink et al., should be an effective technique of accelerating drug release from Nuvaring if the release mechanism is not modified, because drug release from reservoir type IVRs is diffusion mediated and follows zero-order kinetics.⁵⁰ Using an accelerated in-vitro release approach, the system could then be utilized to screen essential formulation properties while maintaining in-vivo predictability.⁵¹ Temperature and hydro-organic dissolving media were used successfully to speed up drug release from the two IVRs. Combining the temperature effect with the use of a hydro-organic release medium could help increase medicine release even more. According to the findings of this study, a relationship between real-time and expedited release would be aided if the release procedure under real-time test circumstances is unaffected by test parameter variations.^52,53 The degree of acceleration is influenced by the temperature rise, the properties of the solvent, and the physicochemical features of the delivery mechanism. According to Extern brink et al., the most significant parameter for accelerating drug production is release. To assure the test's quality and safety conclusion, it's vital to confirm the accelerated method's discriminatory capacity with appropriate batches. This section's case studies show that there is no physiologically based bio predictive technique for IVRs.^48,49 Surprisingly, Nuvaring's in-vivo drug release and absorption were strongly predicted by results from a basic QC approach. Additionally, the process was successfully expedited while maintaining in-vivo predictability. As a result, non-biorelevant in-vitro models can predict in-vitro release profiles for polymer-based non-erodible IVRs with diffusion-controlled release mechanisms if the in-vivo solubility of the active ingredients is correctly addressed.⁵⁴

Dissolution Test Methods for Intrauterine Delivery Systems:

IUDs do not have a bio predictive in-vitro test paradigm like IVRs. In vitro release models that are suited for QC of these delivery techniques are likewise scarce.⁵⁵ It's impossible to create a physiologically based in vitro release model because an IUD is implanted in the uterus for several years.⁵⁶ Based on the findings for IVRs, it's possible that predictive in vitro release profiles for diffusion-controlled IUDs constructed of non-eroding polymers might be generated using non-bio relevant in-vitro models if the active ingredients' in vivo solubility is adequately addressed. Furthermore, because these formulations have a significantly longer real-time release time than IVRs, predictive accelerated test procedures would be extremely valuable for both formulation manufacture and quality control.⁵⁷

CONCLUSION:

The continuous development in the field research and technology development provides an ultra-edge in the screening method of modern vaginal drug delivery systems and IUDs. Unlike other in-vitro parameters, in-vitro drug release study is one of the key parameter for vaginal drug delivery system which directly reflect the stability and performance of the product. The specific dissolution study protocol for various conventional vaginal formulations has been explained in the above discussion; however, no specific standard reproducible dissolution study process is still existing for the modern novel vaginal formulations and IUDs. The safe, effective and successful therapies through vaginal and intrauterine delivery system is depends on authentic physiologically validated in-vitro dissolution test methods which is the need of the hour.

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Received on 09.03.2021           Modified on 15.10.2021

Accepted on 29.01.2022         © RJPT All right reserved

Research J. Pharm. and Tech. 2022; 15(7):3295-3300.

DOI: 10.52711/0974-360X.2022.00552