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2022, vol. 79, br. 4, str. 337-344
Prirodni polimeri za vaginalnu mukoadhezivnu primenu sirćeta, korišćenjem dizajna eksperimentalnih metoda
aGuilan University of Medical Sciences, Faculty of Pharmacy, Department of Pharmacognosy, Rasht, Iran
bGuilan University of Medical Sciences, Faculty of Pharmacy, Department of Pharmaceutics, Rasht, Iran
cGuilan University of Medical Sciences, Faculty of Pharmacy, Department of Medicinal Chemistry, Rasht, Iran
dGuilan University of Medical Sciences, Faculty of Pharmacy, Department of Pharmacognosy, Rasht, Iran + Guilan University of Medical Sciences, Faculty of Pharmacy, Department of Pharmaceutics, Rasht, Iran

e-adresaz.hesari@gmail.com
Projekat:
This project has been funded by Guilan University of Medical Sciences under the grant number of 3/132/743.

Ključne reči: sirćetna kiselina; gelovi; polimeri; tragakant; vaginalne kreme, pene i želei; ksantan guma
Sažetak
Uvod/Cilj. Sirće je jedno od glavnih internacionalnih tradicionalnih nutraceutika koje se koristi kao sredstvo za zaštitu vagine, zahvaljujući osobini da održava pH vagine i poseduje antibakterijska svojstva. S obzirom na to da je sirće tečnost, zbog kratkog zadržavanja je teško primenljiv vaginalno. Cilj rada bio je da se od sirćeta dizajnira vaginalni mukoadhezivni gel. Metode. U studiji su kao polimeri koji formiraju prirodni gel korišćeni ksantan guma i tragakant. Efekti ksantan gume i tragakanta na jačinu mukoadhezije i oslobađanje lekova u formulacijama gela optimizovani su korišćenjem faktorijalnog dizajna na 3 nivoa (32). Takođe, istraženo je nekoliko fizičko-hemijskih svojstava formulacije gela, uključujući viskoznost gela, mazivost, slike scanning elektronske mikroskopije lanaca hidrogela i kinetiku oslobađanja lanaca. Rezultati. Utvrđeno je da je tragakant imao statistički značajan uticaj na kontrolu brzine oslobađanja ispuštanja (p = 0,0027), dok su i tragakant i ksantan guma imali značajan uticaj (p = 0,0001 i 0,0017, redom) na svojstva mukoadhezije. Formulacija F7, sa 5% ksantan gume i 1% tragakanta (mukoadhezija = 0,4632 N i stopa oslobađanja = 88,8% tokom 6 h) sa nekim modifikacijama, bila je optimalna. Zaključak. Ksantan guma i tragakant mogu se smatrati odgovarajućim prirodnim polimerima za vaginalnu "isporuku" lekova.

Introduction

The vagina is considered as a drug delivery site to obtain a local as well as systemic pharmacological effect [1][2].

Thanks to the presence of Lactobacilli, the normal pH of the vaginal fluid in healthy women is maintained between 4 and 5.5 [3]. Low pH is one of the natural factors in resistance to the colonization of pyogenic organisms [4]. Lactic acid has been shown to deactivate a wide range of reproductive tract pathogens, including HSV-2 [5], Neisseria gonorrhoeae [6], and uropathogenic Escherichia coli [7]. In addition to direct inactivation of pathogens, vaginal acidity potentiates the slowing and trapping of HIV-1 virions by cervicovaginal mucus [8][9]. Moreover, studies have confirmed the coincidence between the increase in vaginal pH along with bacterial vaginitis and trichomoniasis [10][11].

Conventional vaginal drug delivery systems such as creams, tablets, capsules, pessaries, liquid dosage forms, etc., are associated with some disadvantages including leakage, messiness, and poor retention time (due to vagina self-cleaning action), which requires multiple daily doses and decreases patient compliance [12][13]. In this way, mucoadhesive dosage forms seem to be a promising choice [14]. Among them, gels have received great attention due to their high water content [15] and rheological behavior causing increased vaginal retention time, lubrication, and patient compliance [16][17]. Gels are also easy to manufacture and scale up and are the preferred vaginal drug delivery system among ladies [18][19]. Natural polymers are valuable candidates for mucoadhesive gel formulations due to their proven safety, high biocompatibility [20][21], ability to conjugate with other polymers [22], and eco-friendliness [23].

Xanthan gum and tragacanth are two examples of natural anionic polysaccharide gums that have been widely used in various industries including food, oil-recovery, cosmetics, water-based paints, petroleum, tissue engineering, biomedical, and drug delivery [24][25]. Among several drug delivery systems incorporating these two polymers, mucoadhesive dosage forms are of interest due to their proper mucoadhesion property [26][27][28].

Vinegar called "serkeh" in Persian medicine [29] is produced from fermentable glucose in carbohydrate-rich foods such as grape, apple, fig, rice, etc., through fermentation processes (alcoholic and subsequently acetous fermentation) [30]. Vinegar has a long history and was widely prescribed by physicians of Persian medicine for several therapeutic purposes including oral consumption as an appetizer, digestive, thirst relief, treatment of warm headache, decreasing the bile flow [29][31], and also in hypertension [32]. External dosage forms of vinegar separately or in combination with other medicines have been utilized for treating several illnesses including hemorrhoid, tinnitus, hearing loss, halitosis, gingivitis, mouth ulcers, toothache, intestinal worm infections, fire burning, removal of an attached leech from the pharynx [29][31], and female genital infections [33]. Historically, the use of vinegar against infections dates back to Hippocrates (460-377 BC), who prescribed vinegar for treating sores and ulcers and its oral products in combination with honey named "oxymel" for improvement of persistent cough [34]. Furthermore, there are a few studies about the formulation of dosage forms using vinegar against vaginal infections [35][36]. This liquid nutraceutical has also been studied in current medicine. Different studies show several health benefits of the vinegar such as improving lipid profile and suppressing fat accumulation, reduction of hyperglycemia and improvement of insulin secretion, inhibition of proliferation and induction of apoptosis in human cancer cells, antioxidant properties, exhaustion recovery effects, regulation of blood pressure, and natural disinfectant [30][37].

Nowadays, in many analytical methods, experimental design is used for optimization instead of the traditional one variable-at-a-time (OVAT) approach [38][39]. There are several reasons for the superiority of the design of experiment (DOE) approach over the OVAT approach. DOE yields the best possible formulation, while OVAT may find only suboptimal formulation. In addition, DOE is armed to estimate any synergistic or antagonistic interaction among constituents, whereas OVAT is inept to reveal any possible interaction. In the DOE approach, all response variables are quantitatively governed by a set of input factors (variables); therefore, any change in the optimized formulation for scale-up can be easily incorporated. On the other hand, the OVAT approach is restricted to the suboptimal point, and it is very difficult to modify the optimal points for any possible scale-up. Besides, the DOE approach is highly economistic in terms of resources and time. Factorial design is one of the most popular techniques of DOE. In situations when there are several factors (e.g., 2 or 3 factors), a three-level factorial design is certainly a possible choice by an experimenter who is concerned about curvature in the response function (Montgomery: design and analysis of experiments). The addition of a third-factor level allows the relationship between the response and the design factor to be modeled as a quadratic.

To the best of our knowledge, although there are vinegar douche products in the market, vinegar has not been formulated as a mucoadhesive gel yet. Therefore, in the present study, considering antimicrobial potential and pH modification of vinegar as a natural remedy, a 3-level factorial design was incorporated for the formulation of vinegar vaginal mucoadhesive gel, using tragacanth and xanthan gum natural polymers.

Methods

Materials

Tragacanth and xanthan gum were purchased from Gol Darou Co, Tehran, Iran, and vinegar was obtained from Bidestan co, Qazvin, Iran. Sodium hydroxide of analytical grade was obtained from Merck (Darmstadt, Germany). Dialysis bags with a molecular weight cut-off of 14 kDa were purchased from Sigma (Steinheim, Germany). All gel formulations were prepared with deionized water.

Experimental design

A 2 factor, 3-level (32) full factorial design was utilized for the optimization of vinegar gel using Design Expert 10 software (Stat-Ease Inc., Minneapolis, USA). Amounts (w/w%) of tragacanth and xanthan gum as independent variables were categorized in three (low, intermediate, and high) levels. Mucoadhesion strength and 6 hrs drug release were considered as dependent variables. Each design point was tested three times, while the center point was assessed four times to consider the pure experimental error of the model. Furthermore, two formulations with zero percent of tragacanth or xanthan gum were also investigated. The design matrix and corresponding response values are presented in S1 (Supplementary Information) [40]. The statistical validation was confirmed by ANOVA at a significance level of p < 0.05 [41].

Gel preparation

According to the design matrix, a proper amount of each polymer was mixed with deionized water in a 250 mL beaker. The solution was stirred with a magnetic stirrer at 500 rpm, and vinegar was slowly added to reach the pH of 4 (around the vagina's natural pH). The final volume of each formulation was adjusted to 150 mL.

Viscosity studies

The viscosity of samples was measured using a DV-3 con viscometer (Brookfield, USA). A total of 50 mL of samples were applied to the viscometer container at 37°C (n = 3).

pH measurement

To confirm the compatibility of the prepared formulations for vaginal mucosa, their pH values were measured by a pH meter (Mettler-Toledo GmbH, Switzerland) at room temperature (n = 3).

Gel spreadability

Of each gel formulation, 0.5 g was placed on a circular glass plate with 1 cm diameter, and another glass plate was placed on the gel. A 50 g weight was put on the upper glass for 5 min. The spreading area was calculated using the measurement of the increase in gel diameter (n = 3) [42][43].

Mucoadhesion studies

The mucoadhesion study was performed according to Tasdighi's method [44] with some modifications. As is presented in Figure 1, 0.5 g of each gel formulation (A) was placed between two circle glasses (B) covered with sheep intestinal mucus (C).

Figure 1 Schematic figure of apparatus used for assessment of gel’s mucoadhesion

The bottom glass was fixed in a crystallizer, and the top glass was linked to a balance measuring the required force for detachment of the gel from the mucosal membrane. The test was performed in phosphate buffer medium pH = 4.5 and 37°C.

In vitro release profile

The in vitro release was performed using a 14 kDa Dialysis tubing Cellulose Membrane. The membrane was soaked in distilled water for 24 hrs before the experiment. Five grams of each formulation was packed in a dialysis tube and placed in 200 mL distilled water (receptor medium) at 37°C. Medium was stirred at 100 rpm during the release test, and samples were withdrawn at certain time intervals of 0.5, 1, 2, 4, and 6 hrs. Acetic acid was considered as the main index in vinegar for quantitative analysis. The content of acetic acid in each sample was analyzed with pH metric titration with NaOH 0.005 M to equivalence point pH = 8.2 (Proline B210 pH meter Netherland). The amount of released acetic acid from each sample was calculated.

Release mechanism determination

The release kinetic of formulations F2, F3, F7, F9, and F10 were investigated by fitting the in vitro release data to various mathematical kinetic models. Models included zero order, first order, Higuchi, and Korsmeyer-Peppas [45].

Drug content

One gram of gel was vigorously stirred with 10 mL distilled water, using a sonicator and vortex, resulting in a transparent solution. Then the volume was adjusted to 100 mL, and the acetic acid content was measured using pH metric titration with NaOH as described in the release study (n = 3).

Scanning electron microscopy analysis

Scanning electron microscopy (SEM) evaluations were performed for the characterization of hydrogel polymeric chain micro-morphology.

Polymer chain morphology was investigated by FESEM Sigma VP (Zeiss, Germany) with an accelerating voltage of 10 kV under vacuum conditions. For sample preparation, gels were freeze-dried at -15°C, and dried gels were gold sputter-coated before FESEM.

The study protocol was approved by the research committee of Guilan University of Medical Sciences by the ethics code of IR.GUMS.REC.1396.283.

Results

According to Table 1, gelling agents (polymers) were slowly dispersed in water with a range of 0–5% for both tragacanth and xanthan gum, and the pH was adjusted to 4, using vinegar.

Table 1. Polymer composition and physical properties of formulations F1-F11

Formulation XG (%) TG (%) pH Viscosity (cp) mean ± SD Diameter (cm) mean ± SD Mucoadhesion (N x10-2) Drug content (%) mean ± SD Release rate (%)
F1 2 1 4.01 21,100 ± 1,462.2 3.8 ± 1.3 41.9 95.5 ± 6.2 86.4
F2 2 5 4.09 54,000 ± 2,581.5 3.0 ± 0.5 51.5 92.4 ± 4.4 73.3
F3 3.5 3 4.21 34,000 ± 1,652.4 3.1 ± 0.9 45.2 95.1 ± 8.2 78.3
F4 5 5 4.16 * 2.8 ± 0.4 56.5 89.3 ± 5.7 78.0
F5 5 3 4.19 95,900 ± 4,235.9 3.7 ± 2.0 49.5 94.3 ± 7.0 84.7
F6 3.5 5 4.08 * 2.9 ± 1.3 52.2 88.7 ± 9.3 76.4
F7 5 1 4.14 29,000 ± 1,874.2 3.7 ± 2.8 46.3 91.3 ± 4.6 88.8
F8 3.5 1 4.11 24,700 ± 1,423.5 3.6 ± 1.7 43.3 92.2 ± 11.6 88.2
F9 5 0 4.23 28,600 ± 1,685.6 3.5 ± 1.4 46.0 97.6 ± 9.4 87.3
F10 0 5 4.17 25,100 ± 1,584.5 3.0 ± 2.8 53.8 93.8 ± 6.3 86.4
F11 2 3 4.16 26,400 ± 1,376.1 3.3 ± 1.7 44.3 84.0 ± 8.3 81.4

XG – xanthan; TG – tragacanth; SD – standard deviation.
*Due to very high viscosity, it was not measurable by the apparatus.

The pH of formulations is one of the important parameters for vaginal compatibility. The vaginal pH of healthy women of reproductive age is around 4–5.5, changing during the menstrual cycle. Lactic acid produced by Lactobacilli present in the healthy vagina plays an important role in the control of infection by common pathogens. In our formulations, acetic acid as the index component of vinegar plays such a role.

The results showed that all the formulations were suitable for vaginal application as they could maintain the acidic pH value of the vagina (Table 1).

Viscosity influences other mechanical properties of formulations, such as spreadability and mucoadhesion, which are in direct correlation with patient compliance. The viscosity of each formulation was measured and stated in Table 1. The spreading area of each gel formulation was evaluated by measuring the diameter of the circle, which is formed under the pressure of glass. Spreading values are mentioned in Table 1.

Acceptable content of active pharmaceutical ingredient (API) or its indexes ensures the producer and consumer about receiving the adjusted or necessary dose. Since there is no defined monograph for vaginal vinegar gel in pharmacopeias, the prevalent range of 90–105% was considered acceptable in this study. The drug content of each formulation is presented in Table 1.

Four samples were subjected to SEM, including F9 and F10, which were simply made of xanthan gum and tragacanth, respectively, and F2 with the lowest amount of xanthan gum (2%) and the highest amount of tragacanth (5%), and F7 with the lowest amount of tragacanth (1%) and the highest amount of xanthan gum (5%). Figure 2 shows a homogenous wavy morphology for F9 (Figure 2a) and a relatively smoother morphology for F10 (Figure 2b), while in F2 and F7, a kind of polymeric chain integration is observed (Figure 2c, Figure 2d).

Figure 2 Scanning electron microscopy (SEM) images of hydrogel polymeric chain arrangement in:
a) xanthan gum (5%),
b) trgacanth (5%),
c) xanthan gum (2%) and tragacanth (5%),
d) tragacanth (1%) and xanthan gum (5%)

It seems that formulations containing both polymers show special polymeric interactions due to probable hydrogen or van der Waals bonds.

The acetic acid release profile was evaluated for all formulations in distilled water at 37°C. Release profiles of F2, F7, F9, F10, and F3 (which is the center point of experiment design) are presented in Figure 3.

Figure 3 Release profile of formulations F2, F3, F7, F9, and F10 indicates the cumulative drug release vs. time

Data on formulations are given in Table 1.

Release data for other formulations is accessible in a supplementary file.

According to the release results, F7 showed the highest (88.8%) while F2 showed the lowest (73.3%) release rate among other formulations in 6 hours. Considering F7 and F2 gums composition, they are a combination of both xanthan gum and tragacanth, in which F7 had the highest amount of xanthan gum (5%) with the lowest amount of tragacanth (1%) and F2 had the lowest amount of xanthan gum (2%) with the highest amount of tragacanth (5%).

Data obtained from in vitro release F2, F3, F7, F9, and F10 formulations were fitted to zero order, first order, Higuchi and Korsmeyer-Peppas models [44]. The drug release kinetic data are listed in Table 2, the highest regression coefficient (R2) was considered the best fitted kinetic model for each vinegar gel formulation.

Table 2. Release kinetic parameters for F2, F3, F7, F9, and F10 formulations based on different mathematical models

Formulation Zero order First order Higuchi Korsmeyer-Peppas
K0 R2 K1 R2 KH R2 KK R2
F2 13.709 0.9033 -0.1113 0.9843 13.709 0.9033 0.2954 0.5931
F3 14.309 0.8549 -0.1383 0.9399 14.309 0.8549 0.2921 0.5526
F7 15.229 0.7678 -0.1768 0.9627 15.229 0.7678 0.2941 0.5165
F9 14.027 0.6676 -0.1544 0.8844 14.027 0.6676 0.2865 0.4858
F10 14.126 0.7055 -0.1523 0.9074 14.126 0.7055 0.2875 0.4963

Data on formulations are given in Table 1.

All chosen formulations showed the highest regression coefficient in the first-order model, which confirms that the drug release rate depends on its concentration.

Analysis of variances was used to assess the suitable response surface model and its significance. Table 3 and Table 4 show ANOVA tables for mucoadhesion strength and release rate, respectively.

Table 3. Analysis of variance (ANOVA) table for mucoadhesion strength of the formulations

Source Sum of squares df Mean square F-value p-value
Model 191.9 3 64.0 38.6 4.2 E-05 significant
A: Xanthan gum 35.5 1 35.5 21.4 1.7 E-03
B: Tragacanth 137.0 1 137.0 82.6 1.72 E-05
B2 19.4 1 19.4 11.7 9.1 E-03
Residual 13.3 8 1.6
Lack of fit 4.8 5 0.9 0.4 0.9 not significant
Pure error 8.5 3 2.8
Cor total 205.2 11

Table 4. Analysis of variance (ANOVA) table for release rate of the formulations

Source Sum of squares df Mean square F-value p-value
Model 230.9 2 115.46 9.1 7.0 E-03 significant
A: Xanthan gum 18.0 1 18.0 1.4 0.3
B: Tragacanth 212.9 1 212.9 16.7 2.7 E-03
Residual 114.7 9 12.8
Lack of fit 8.6 6 1.4 0.04 1.0 not significant
Pure error 106.1 3 35.4
Cor total 345.6 11

A p-value lower than 0.05 was used to select significant parameters. As seems in Table 3 and Table 4, the models are significant, and the p-value of the lack of fit implies that it is not significant relative to the pure experimental error and confirms the validity of the models.

Besides, the R-squares value and other statistical parameters of the models are all acceptable. Table 2 S2 (supplementary materials) shows the statistical parameters of the models.

Figure 4 3-Dimensional graph of effect of tragacanth and xanthan gum on a) vinegar in vitro release rate, b) mucoadhesion of gels

A dimensional graph of the effect of tragacanth and xanthan gum on A) vinegar in vitro release rate and B) mucoadhesion of gels is shown in Figure 4.

Discussion

Paying attention to formulations F9 (5% xanthan gum) and F10 (5% tragacanth), it seems that an increase in tragacanth percent leads to decreases in vinegar release rate whilst xanthan gum increases the release rate of vinegar. Although tragacanth's behavior on release control has been observed in other studies [46], xanthan gum's influence on increasing the vinegar release rate is in contrast with former studies [47]. However, most studies have investigated the release of lipophilic API from tragacanth and xanthan gum matrices, while vinegar is a completely hydrophilic API. On the other hand, it's hypothesized that tragacanth can be adsorbed to the oil droplets and therefore possesses a more hydrophobic nature, while xanthan gum just acts through the viscosity increase [47][48]. Therefore, it seems that in this study, tragacanth plays the main role in lowering the release rate, and xanthan gum modulates the rate by decreasing the tragacanth percent in the formulation because in this formulation maximum release of vinegar in 6 hours is desirable.

The release kinetic data is somehow in agreement with results of Salamanca et al. [47] that used xanthan and tragacanth gum in the formulation of a sustained-release tablet and drug release kinetic best fitted with first order and Higuchi models.

According to the models, tragacanth has a significant effect (p-value = 0.0027) on release rate, while xanthan gum has no statistically significant effect (p-value = 0.3). Figure 4a demonstrates the response surface graphically to help visualize the shape of the response surface of release rate. An increase in tragacanth weight (%) leads to a decrease in the release rate. As can be seen, there is no curvature effect of any parameter on the release rate. On the other hand, both tragacanth and xanthan gum, together with the curvature of tragacanth, have a significant effect on the mucoadhesive properties of the formulation. Figure 4b shows the response surface of mucoadhesive strength. Both tragacanth and xanthan gum have a positive effect on mucoadhesive strength.

Conclusion

The main objective of the optimization is to determine the optimum values of the parameters. After rigorous analysis of the selected models and their corresponding parameters, F7 has been selected as the best formulation of the study.

This study demonstrates that xanthan gum and tragacanth can be considered appropriate natural polymers for vaginal drug delivery. A certain combination of these two polymers with specific ratios (F7: 5% xanthan gum and 1% tragacanth) presented high mucoadhesion properties (0.4632 N) and good release characteristics (88.8%) in 6 hrs as a vinegar vaginal natural mucoadhesive gel.

Dodatak

Acknoweldegment

This project has been funded by Guilan University of Medical Sciences under the grant number of 3/132/743.

Conflict of interest

The authors declare that they have no conflict of interest.

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28.Ugoeze KC. Bioadhesive Polymers for Drug Delivery Applications. In: Mittal KL, Bakshi IS, Narang JK, editor(s). Bioadhesives in Drug Delivery. Hoboken, New Jersey: Wiley. 2020; p. 29-56. [Crossref]
29.Aghili Khorasani M. Makhzan al-Advie. Teheran: Iran University of Medical Science & Research Institute for Islamic and Complementary Medicine. 2009.
30.Samad A, Azlan A, Ismail A. Therapeutic Effects of Vinegar: A Review. Curr Opin Food Sci. 2016;8:56-61. [Crossref]
31.Tonekaboni M. Tohfat al Momenin. Tehran: Nashre Shahr. 2008.
32.Heydari M, Dalfardi B, Golzari SE, Habibi H, Zarshenas MM. The Medieval Origins of the Concept of Hypertension. Heart Views. 2014;15(3):96-98.
33.Tansaz M, Meyari A, Naeemi SA, Meybodi RN, Memarzade H, Shirooye P. Recommended Treatment Methods of Iranian Traditional Medicine for Female Genital Tract Infections. Avicenna J Phytomed. 2015;5:88-89.
34.Johnston CS, Gaas CA. Vinegar: Medicinal Uses and Antiglycemic Effect. MedGenMed. 2006;8(2):61.
35.Pavlova SI, Tao L. In Vitro Inhibition of Commercial Douche Products Against Vaginal Microflora. Infect Dis Obstet Gynecol. 2000;8(2):99-104.
36.Martino JL, Vermund SH. Vaginal Douching: Evidence for Risks or Benefits to Women's Health. Epidemiol Rev. 2002;24(2):109-124. [Crossref] [PubMed] [PMC]
37.Ho CW, Lazim AM, Fazry S, Zaki UKHH, Lim SJ. Varieties, Production, Composition and Health Benefits of Vinegars: A Review. Food Chem. 2017;221:1621-1630. [Crossref]
38.Ebrahimi-Najafabadi H, Leardi R, Jalali-Heravi M. Experimental Design in Analytical Chemistry-Part I: Theory. J AOAC Int. 2014;97(1):3-11. [Crossref]
39.Ebrahimi-Najafabadi H, Pasdaran A, Rezaei BR, Bozorgzadeh E. Determination of Toxic Heavy Metals in Rice Samples Using Ultrasound Assisted Emulsification Microextraction Combined with Inductively Coupled Plasma Optical Emission Spectroscopy. Food Chem. 2019;289:26-32. [Crossref]
40.Montgomery DC. Design and Analysis of Experiments. 5th ed. Chichester, UK: John Wiley & Sons. 2001.
41.Soares PA, de Seixas JR, Albuquerque PB, Santos GR, Mourão PA, Barros W. Development and Characterization of a New Hydrogel Based on Galactomannan and C-Carrageenan. Carbohydr Polym. 2015;134:673-679. [Crossref]
42.Dantas MG, Reis SA, Damasceno CM, Rolim LA, Rolim-Neto PJ, Carvalho FO. Development and Evaluation of Stability of a Gel Formulation Containing the Monoterpene Borneol. ScientificWorldJournal. 2016;2016:7394685. [Crossref] [PubMed] [PMC]
43.Deuschle VCKN, Deuschle RAN, Bortoluzzi MR, Athayde ML. Physical Chemistry Evaluation of Stability, Spreadability, in Vitro Antioxidant, and Photo-Protective Capacities of Topical Formulations Containing Calendula officinalis L. Leaf Extract. Braz J Pharm Sci. 2015;51(1):63-75. [Crossref]
44.Tasdighi E, Jafari Azar Z, Mortazavi SA. Development and Invitro Evaluation of a Contraceptive Vagino-Adhesive Propranolol Hydrochloride Gel. Iran J Pharm Res. 2012;11(1):13-26.
45.Nie S, Hsiao WL, Pan W, Yang Z. Thermoreversible Pluronic F127-Based Hydrogel ContaInIng Liposomes for the Controlled Delivery of Paclitaxel: In Vitro Drug Release, Cell Cytotoxicity, and Uptake Studies. Int J Nanomedicine. 2011;6:151-166.
46.Rasul A, Iqbal M, Murtaza G, Waqas MK, Hanif M, Khan SA. Design, Development and In-vitro Evaluation of Metoprolol Tartrate Tablets Containing Xanthan-tragacanth. Acta Pol Pharm. 2010;67(5):517-522.
47.Salamanca CH, Yarce CJ, Moreno RA, Prieto V, Recalde J. Natural Gum-Type Biopolymers as Potential Modified Nonpolar Drug Release Systems. Carbohydr Polym. 2018;189:31-38. [Crossref]
48.Pocan P, Ilhan E, Oztop MH. Characterization of Emulsion Stabilization Properties of Gum Tragacanth, Xanthan Gum and Sucrose Monopalmitate: A Comparative Study. J Food Sci. 2019;84(5):1087-1093. [Crossref]
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O članku

jezik rada: engleski
vrsta rada: originalan članak
DOI: 10.2298/VSP200804121P
primljen: 04.08.2020.
revidiran: 27.09.2020.
prihvaćen: 04.11.2020.
objavljen onlajn: 15.11.2020.
objavljen u SCIndeksu: 12.05.2022.
metod recenzije: dvostruko anoniman
Creative Commons License 4.0

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