Abstract: Therapeutic outcomes of vaginal products depend not only on their ability to deliver drugs to or through the vagina but also on acceptability and correct use. Women’s preferences, in turn, may vary according to age and cultural backgrounds. In this work, an anonymous online survey was completed by 2529 Portuguese women to assess their preferences for physical characteristics and mode of application of vaginal products, according to age. Additionally, intention to use and misconceptions about these issues were assessed. The majority of women of all age groups would use vaginal products to treat or prevent diseases, upon medical prescription. Women preferred vaginal products to be odorless and colorless gels, creams and ointments composed by natural origin drugs/excipients and applied by means of an applicator. Although the majority of women would prefer not to insert any product in the vagina, intention to use for self and recommendation to use for others was associated with previous experiences with vaginal products. General concerns and misconceptions related to use of vaginal products were rare. These data may contribute to the development of products that women are more prone to use.
Abstract: Vaginal lubricants are widely used by women to help solve intercourse difficulties or as enhancers, but recent reports raise questions about their safety. Twelve commercially available gel products were tested for pH value, pH buffering capacity, osmolality and cytotoxicity relevant to vaginal delivery. Obtained data were analyzed in light of the recent Advisory Note by the World Health Organization (WHO) for personal lubricants to be concomitantly used with condoms. Results showed that most products do not comply with pH and osmolality recommended standards, thus posing a potential hazard. Four products presented values of osmolality around three-times higher than the maximum acceptable limit of 1200 mOsm/kg. In vitro cell testing further identified substantial cytotoxicity even at 1:100 dilutions for three products, contrasting with no significant effect of up to at least a 1:5 dilution of a Universal Placebo gel. However, no direct correlation between these last results and pH or osmolality was found, thus suggesting that the individual toxicity of specific formulation components plays an important role in the outcome of a particular product. Although further assessment is required, these results highlight potential safety issues related to the formulation of commercially available vaginal lubricants.
Abstract: Microbicides are being actively researched and developed as woman-initiated means to prevent HIV transmission during unprotected coitus. Along with safety and efficacy, assessing and improving compliance is a major area of research in microbicide development. We have developed carrageenan-based semisoft vaginal suppositories and have previously evaluated how physical properties such as firmness, size and shape influence women’s willingness to try them. Firmness has previously been quantified in terms of small-strain storage modulus, G’, however large-strain properties of the gels may also play a role in the firmness perception. In the current study we prepared two sets of suppositories with the same G’ but different elongation properties at four different G’ values (250, 2500, 12,500, 25,000 Pa): For convenience we refer to these as “brittle” and “elastic”, although these terms were never provided to study participants. In the first of two tests conducted to assess preference, women compared pairs of brittle and elastic suppositories and indicated their preference. We observed an interaction, as women preferred brittle suppositories at lower G’ (250, 2500 Pa) and elastic ones at a higher G’ (25,000 Pa). In the second test, women evaluated samples across different G’, rated the ease-of-insertion and willingness-to-try and ranked the samples in order of preference. Brittle suppositories at G’ of 12,500 Pa were most preferred. In vitro studies were also conducted to measure the softening of the suppositories in contact with vaginal simulant fluid (VSF). Release of antiretroviral drug tenofovir in VSF was quantified for the brittle and elastic suppositories at G’ of 12,500 Pa to determine the effect of suppository type on release. The initial rate of release was 20% slower with elastic suppositories as compared to brittle suppositories. Understanding how different physical properties simultaneously affect women’s preferences and pharmacological efficacy in terms of drug release is required for the optimization of highly acceptable and efficacious microbicides.
Abstract: Different non-ionic cellulose ethers (methyl cellulose, MC; hydroxyethyl cellulose, HEC; hydroxypropyl cellulose, HPC; hydroxypropylmethyl cellulose, HPMC) and microcrystalline cellulose (MCC) were investigated as matrix formers for preparation of mini-tablets targeting vaginal drug delivery. Hexyl aminolevulinat hydrochloridum (HAL) was used as a model drug. The mini-tablets were characterized with respect to their mechanical strength, bioadhesion towards cow vaginal tissue in two independent tests (rotating cylinder test, detachment test using texture analyzer), and dissolution rate in two media mimicking the pH levels of fertile, healthy and post-menopausal women (vaginal fluid simulant pH 4.5, phosphate buffer pH 6.8). Mini-tablets with a matrix of either HPMC or HPC were found to possess adequate mechanical strength, superior bioadhesive behavior towards vaginal tissue, and pH independent controlled release of the model drug, suggesting that both systems would be suited for the treatment of women regardless of age, i.e., respective of their vaginal pH levels. Bioadhesive mini-tablets offer a potential for improved residence time in the vaginal cavity targeting contact with mucosal tissue and prolonged release of the drug.
Abstract: New drug candidates increasingly tend to be poorly water soluble. One approach to increase their solubility is to convert the crystalline form of a drug into the amorphous form. Intrinsic dissolution testing is an efficient standard method to determine the intrinsic dissolution rate (IDR) of a drug and to test the potential dissolution advantage of the amorphous form. However, neither the United States Pharmacopeia (USP) nor the European Pharmacopeia (Ph.Eur) state specific limitations for the compression pressure in order to obtain compacts for the IDR determination. In this study, the influence of different compression pressures on the IDR was determined from powder compacts of amorphous (ball-milling) indomethacin (IND), a glass solution of IND and poly(vinylpyrrolidone) (PVP) and crystalline IND. Solid state properties were analyzed with X-ray powder diffraction (XRPD) and the final compacts were visually observed to study the effects of compaction pressure on their surface properties. It was found that there is no significant correlation between IDR and compression pressure for crystalline IND and IND–PVP. This was in line with the observation of similar surface properties of the compacts. However, compression pressure had an impact on the IDR of pure amorphous IND compacts. Above a critical compression pressure, amorphous particles sintered to form a single compact with dissolution properties similar to quench-cooled disc and crystalline IND compacts. In such a case, the apparent dissolution advantage of the amorphous form might be underestimated. It is thus suggested that for a reasonable interpretation of the IDR, surface properties of the different analyzed samples should be investigated and for amorphous samples the IDR should be measured also as a function of the compression pressure used to prepare the solid sample for IDR testing.
Abstract: Hydroxypropyl-β-cyclodextrin (HP-β-CD) is commonly used as a complexation reagent to solubilize compounds with poor aqueous solubility to improve in vivo dosing. However, the degree of solubility enhancement was often limited by the formation of only a 1:1 complex and a lowcomplexation constant (K). Such a limitation can be significantly improved by the formation of 1:2 complexes in some cases. Despite the understanding of the solubility advantage of the formation of the 1:2 complexes, there is no systematic understanding that could drive for the formation of 1:2 complexes. Thus, in most cases, the formation of 1:2 complexes was limited by observation bases. In this study, we pioneer the usages of molecular dynamics (MD) simulation to understand the phenomena of a model drug of celecoxib (CCB) and HP-β-CD. It has been reported that celecoxib (CCB) forms 1:1 complexes with cyclodextrin in solution; however, some data suggest the existence of a 1:2 complex. The simulation results suggest that a transition state of CCB and HP-β-CD may exit at a higher temperature of CCB and HP-β-CD; a model drug, such as celecoxib (CCB), that is known to form 1:1 complexes can achieve a higher degree of complexation (1:2) and obtain much improved solubility when the same amount of cyclodextrin was used and demonstrated in vitro. The simulation results of CCB and HP-β-CD could be a model system that may provide important insights into the inclusion mechanism.