INTRODUCTION:

Despite the tremendous advances in drug delivery, oral drug delivery remains the most preferred route for drug administration, since they are regarded as the safest, cheapest, and the most cost-effective drug delivery technique with higher patient compliance^1,2.

Commonly, oral dosage forms are classified into two main groups, solid and liquid dosage forms. The former is the most popular and widely spread because of its simple, quick, and cost-effective³.

Unfortunately, the major limitation of the solid dosage forms are represented by difficulty in swallowing such dosage forms especially in the pediatric and geriatric population, in addition to patient suffering from nausea and vomiting, psychiatric, bedridden and traveling people who cannot easily access to water^4-6.

Although many tablet dosage forms had been introduced to overcome swallowing difficulties in which drugs are administrated to the oral cavity without the need of chewing or prior dispersion or dissolution in water to produce a systemic effect, they possess many restrictions, like the requirements of certain properties of the drug for absorption via the mucosa of the oral cavity, not suitable for high doses, irritating and/or bitter taste or odor medications, in addition to the special packaging requirement for ODTs due to its hygroscopic and friable nature^7-9.

Therefore, liquid dosage forms are considered a suitable alternative to solid medications. However, there are many complications accompanied formulation of a drug as a liquid dosage form, like solubility, stability, taste, and volume limitation, moreover, it is considered bulky with the higher possibility of dose wastage and dose dumping¹⁰.

For this reason, oral jelly was formulated to overcome all the previously mentioned obstacles. Oral jelly can be defined as “transparent or translucent non-greasy, semisolid preparations meant for external as well as the internal application”. These are designed to dissolve quickly improving that drug bioavailability and clinical effect via enhancing the dissolution and the absorption of the active ingredient. Furthermore, the greater viscosity of the oral medicated jelly contributes to its optimal taste masking effect that is swallowed easily without the need of water compared to solid dosage forms, making them more attractive among a wide range of populations^1,11,12.

Valsartan is an antihypertensive drug that belongs to the group of angiotensin receptor blockers (ARB) mainly used in the management of hypertension, heart failure and to reduce cardiovascular mortality in patients with left ventricular dysfunction after myocardial infarction. It is available only in the form of tablets and capsules (40, 80, 160mg), with a bioavailability of about 25% and a half-life is 6-9 h^13,14. Therefore, it is critical to developing a good taste masking, easily swallowed dosage form of the drug that is suitable for a patient suffering from swallowing difficulty, especially the pediatric and geriatric population, as well as it may possess a greater bioavailability than the readily available dosage form.

The objective of the recent study is to formulate, evaluate and optimize an oral jelly containing valsartan using a different gelling agent in an attempt to formulate a new easily swallowed dosage form with improved palatability and bioavailability that is suitable for dysphagic children.

MATERIALS AND METHODS:

Materials:

Gelatin (Garland chemical company, U.K.), valsartan (Provizer pharma, India), xanthan gum (Himedia, India), sucrose, methylparaben, and propylparaben (Samara, Iraq), propylene glycol, and sodium alginate (J. T Baker, China). All other used reagents, solutions, and chemicals were of analytical grade.

Preparation of valsartan oral jelly:

To prepare six formulas of the oral jelly containing valsartan, three different gelling agents (xanthan gum, sodium alginate, and gelatin) were used in different concentrations as shown in table (1).

The preparation of valsartan oral jelly using xanthan gum or gelatin as a gelling agent was performed by the dispersion of the gelling agent in a certain amount of distilled water (D.W) containing the required amounts of methyl and propylparaben as preservatives maintained at 95ºC for 30 min using a magnetic stirrer. The next step involved the addition of sucrose syrup (85%) to the previously prepared gum dispersion with continuous stirring at 80-85ºC. After that, the temperature was maintained at 50-65ºC followed by the addition of the drug which was previously dissolved in propylene glycol (PG). Finally, coloring along with the flavoring agent was added subsequently with stirring for a further 30 min after adjusting the weight of the prepared jelly to 100gm by D.W. The prepared valsartan jelly solution was poured and packed in polyethylene mold with an air-tight seal and allowed to cool at room temperature in a dry place.

On the other hand, to prepare oral jelly using sodium alginate, the gelling agent was dissolved slowly in a mixture of sucrose syrup and D.W; containing the required amount of the preservatives; which was kept at 95ºC for 30 min using a high-speed mixer to facilitate the dispersion of the polymer and preventing clumping, further steps are performed like the previously mentioned procedure to prepare the valsartan oral jelly ¹⁵.

Evaluation of valsartan oral jelly:

Physical appearance:

The prepared valsartan oral jelly was visually inspected for clarity, color, consistency, and texture. The texture of the prepared jelly in terms of stickiness and grittiness was evaluated by rubbing the jelly mildly between two fingers¹⁶.

The determination of pH:

The pH was measured in triplicate for 1% aqueous solution of the prepared oral jelly under a constant temperature by using a calibrated digital pH meter (OHAUS, USA)¹⁷.

Rheological study:

The viscosity of valsartan oral jelly was measured using Brookfield viscometer DVE- USA by using spindle 64 at 5 and 10 RPM. It was evaluated for the fixed time (30 sec) at (37ºC±0.5ºC)¹⁸. The measurements were performed in triplicate and the average value ± SD was determined.

Syneresis:

It is the contraction of the gel upon storage and separation of water from the gel. It is more obvious in the gels where a lower concentration of gelling agent is employed. All the prepared formulas were detected for signs of syneresis after 24 h of preparation at room temperature (25ºC±1ºC) and 8ºC±1ºC^19.20.

Evaluation of the taste masking effect:

To evaluate the taste masking efficacy, the prepared valsartan oral jellies were placed in (50ml) beaker, followed by the addition of (5ml) of phosphate buffer pH 6.8 (to simulate the salivary volume and pH) at 37± 0.5ºC, and allowed to stand for (60 sec) and (120 sec), respectively. The solution was then filtered and analyzed by T 80 UV-visible spectrophotometer (PG Instruments, UK) at 250nm for valsartan content, this was done in triplicate and the results were expressed in mean value± SD^21,22.

Content uniformity study:

Ten oral jellies were selected randomly and were dissolved individually in (50ml) phosphate buffer pH 6.8, which was further diluted to measure the absorbance at 250nm using T 80 UV-visible spectrophotometer (PG Instruments, UK). The content of each oral jelly was calculated and then compared to the average value¹⁷. This was performed three times and the average value was calculated and expressed as mean ±SD.

In-vitro drug release:

The in-vitro dissolution study of valsartan from the prepared oral jelly was performed in triplicate in (900 ml) of phosphate buffer pH 6.8 at 37±0.5ºC using USP type II dissolution apparatus (Copley, UK) at 50 rpm. A sample of (5ml) was periodically withdrawn at (10 min) interval for 2 h, which was suitably diluted and analyzed using T 80 UV-visible spectrophotometer (PG Instruments, UK) at ƛmax 250 nm to calculate the % drug release²³. The percent of drug released in 30 min (% D_30min)was determined in three experiments and expressed as an average value ± SD.

Infrared Spectral Analysis:

The compatibility between valsartan, gelling agent, and sucrose used in the preparation of the oral jelly optimum formula (F6) was determined by FT-IR spectrophotometer (Shimadzu 8300, Japan) using the KBr disc technique at the range of 4000–400cm^-1, The absorption maxima in the spectra were obtained and compared, to detect any shifting or presence of additional peaks corresponding to the functional groups²⁴.

Stability study:

The optimum formula of the prepared jelly was evaluated for its physical appearance, viscosity, pH, and syneresis in addition to the taste masking, drug content, and release. The formula samples were kept at two temperatures 2-8ºC and 25ºC ± 5 and checked after 1 and 3 months²⁵.

Statistical analysis:

All the data were statistically analyzed using (ANOVA) single factor to assess and compare the significance of the results, where (P<0.05) considered to be significant.

RESULTS AND DISCUSSIONS:

Physical appearance determination:

All the formulated oral jellies were found to have an acceptable texture and appearance represented by a clear reddish pink color with a thick jelly-like consistency except for the formulas F3 and F5 containing 2% sodium alginate and 3% gelatin respectively having a slightly thick appearance, which might be caused by the lower concentration of these polymers comparing to F4 and F6 correspondingly (Table 2), results that are in consistent with the rheological data in the further investigation.

The pH study:

Table 3 clearly represented the results of the pH measurement of the prepared oral valsartan jellies formulated using different types and concentrations of gelling agents and all the results were ranging from (6.72 - 7.25) which was within the acceptable range of oral cavity. For F1 and F2 oral jelly formulas containing 1% and 1.5% xanthan gum, there is a significant (p < 0.05) reduction in the pH value upon increasing xanthan gum concentration which might be attributed to the glucuronic acid and pyruvic acid moieties in its structure ²⁶. On the other hand, a slight increment in the pH results was noticed upon increasing the concentration of sod. alg. (from 2-4% in F3 and F4), an effect which could be explained due to the anionic nature of sodium alginate which is composed of both guluronic and mannuronic acid units with pKa values of (3.38 and 3.65) respectively, where they will be ionized at pH above their pKa. While no significant change in the pH was observed upon increasing the gelatin concentration from 3-6% in F5 and F6 which can be clarified due to the amphoteric polypeptide nature of this polymer which contains both positive and negative charges^27,28.

Table 2: Physical characteristics of the formulated valsartan oral jellies

Physical Properties	Formulas
Physical Properties	F1	F2	F3	F4	F5	F6
Clarity	Transparent	Transparent	Transparent	Transparent	Transparent	Transparent
Colour	Light pink	Light pink	Light pink	Light pink	Light pink	Light pink
Consistency	Thick	Thick	Slightly thick	Thick	Slightly thick	Thick
Stickiness	Slightly Sticky	Slightly Sticky	Slightly Sticky	Slightly Sticky	Slightly Sticky	Slightly Sticky
Grittiness	Non-gritty	Non-gritty	Non-gritty	Non-gritty	Non gritty	Non gritty

Table 3: The pH determination of the formulated valsartan oral jellies

Formulas	pH value ± SD
F1	7.02 ± 0.62
F2	6.84 ± 0.94
F3	6.72 ± 1.08
F4	6.99 ± 1.03
F5	7.24 ± 0.6
F6	7.25 ± 0.47

^*Results are expressed as mean ± SD, n = 3

Rheological behavior and Syneresis:

The viscosity results of the prepared oral jelly at 5 and 10 rpm are shown in figure 1. The measured values of the viscosities support the visual investigation of the consistency by showing significant increments in its value resulting from increasing the concentration of each gelling agent¹⁶. Furthermore, an obvious significant reduction (p < 0.05) in the viscosity was observed by increasing the rpm for each formula due to the pseudoplastic behavior of xanthan gum, sodium alginate, and gelatin^27,29,30.

Additionally, syneresis or de-swelling is usually occurred due to the release of liquid from the contracted gel due to reduced quality and low concentration of gelling agent³¹. None of the prepared valsartan oral jellies showed syneresis neither in the refrigerator nor at room temperature, which agreed with the consistency and the viscosity data of the prepared oral jellies that are determined previously.

Fig. 1: The rheological data of valsartan oral jellies expressed in centipoise (cps) prepared with a different gelling agent that is measured at 37ºC ± 0.5ºC (Results are expressed as mean ± SD, n = 3)

The analysis of taste masking effect:

The results of taste masking showed a non-significant release of the drug after 1 and 2 minutes except for F5 containing (3% gelatin), this could result from the lower viscosity of the prepared jelly that is related to the low polymer concentration, in addition to the low melting temperature (T_m) of gelatin which gives that polymer its unique organoleptic property and flavor release, an effect which might be reduced by increasing the polymer concentration to )6% ) in the prepared jelly of F6 that increases both the viscosity and the T_m of the polymer which gives an acceptable taste masking effect within the first 2 min as shown in figure 2³².

Fig. 2: Taste masking effect of the prepared valsartan oral jellies in 6.8 phosphate buffer measured at 37 ºC ± 0.5 ºC (Results are expressed as mean ± SD, n =3)

Content uniformity and in-vitro drug release:

The results indicated that all the valsartan oral jellies were prepared properly with an accepted content uniformity. In addition, the values of % D_30min demonstrated a significant reduction in drug release upon increasing the concentration of the gelling agent in the formulas (F1-F4) containing 1-1.5% of xanthan gum in F1-F2 and 2-4% sodium alginate in F3-F4 respectively, the results can be explained by the hydrophilic nature of the polymers which swells and coalesces causing the formation of a continuous viscoelastic matrix that fills the interstices leading to retard further penetration of the dissolution medium and hence delaying drug release from jelly matrix³³. Furthermore, a significant slower release (p < 0.05) of valsartan from the jellies prepared using xanthan gum as a gelling agent in both F1 and F2 comparing to the release of the drug from the jellies formulated using sodium alginate were observed in table 4 and figure 3, this could result from the higher swelling index and lower erosion rate of xanthan gum compared to sod. alg.^34,35

Finally, the higher %D_30minupon using gelatin to formulate the oral jellies F5-F6 comparing to other formulas prepared by xanthan gum and sodium alginate resulted from the unique characteristic of the gelatin being highly soluble in hot water in addition to the low melting temperature of this polymer providing faster drug release³². Although a non-significant difference was observed between F5 and F6 in %D_30min,F6 valsartan oral jelly containing 6% gelatin was selected as the optimum formula giving better taste masking property than F5, with a good physical & rheological properties and accepted pH value.

Fig. 3: In vitro dissolution profile of the prepared valsartan oral jellies in 6.8 phosphate buffer measured at 37 ºC ± 0.5 ºC (Results are expressed as mean ± SD, n = 3)

Fourier transform infrared spectroscopy (FT-IR) results:

The measured FT-IR spectra of pure valsartan, gelatin, and sucrose, in addition to their mixtures, are shown in figures 5 (A, B). In both figures, valsartan showed the characteristic peaks at 3412 cm^-1 indicating the presence of N-H and O-H stretching, with the peak at 2964 cm^-1 resulted from aliphatic C-H stretching. Furthermore, the peak at 1732cm^-1 representing the carboxylic acid C=O stretching, whereas the C=N stretching caused the peak at 1604 cm^-1. In addition, the presence of the bands in the region 1206-1035 cm^-1 was due to the C-N stretching of the tetrazole ring (CN4). These peaks show no significant shifting in figures 5-A and 5-B indicating the absence of any interactions between the drug and other components of the optimum valsartan oral jelly (F6). Although, a broader and higher intensity were shown in the peak at the region of 3400 cm^-1 in both figures, which might be due to O-H stretching of the polysaccharides i.e. gelatin and sucrose^7,36.

(A)

(B)

Fig. 5: FT-IR spectrum of A- Valsartan, gelatin and their mixtures, B- Valsartan sucrose and their mixtures

Stability data:

The results of the physical properties and pH evaluation of the selected valsartan oral jelly (F6) showed no significant difference upon storage for one and three months at 2-8ºC and 25ºC±5. Furthermore, no changes were observed in the syneresis, viscosity, or taste masking after storing in the same conditions. Moreover, no significant alteration in the in-vitro release and content uniformity data of the selected formula (F6) was observed. These data collectively indicating the proper formulation of the selected oral jelly formula which retained its properties after storing at refrigerator and room temperature.

CONCLUSION:

This study presented a new easily swallowed valsartan oral jelly by using 6% gelatin as a gelling agent which can be used as a good alternative for the readily available dosage form of valsartan with good taste masking property that is suitable for a patient suffering from dysphagia, improving by that patient compliance, in addition to the possible improvement of the valsartan bioavailability by introducing the drug is readily dissolved in the oral jelly.

ACKNOWLEDGMENTS:

The authors would like to express their thanks and appreciation Al-Mustansiriyah University, College of Pharmacy, Baghdad, Iraq (www.uomustansiriyah.edu.iq) for presenting and facilitating this work.

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Received on 21.02.2021 Modified on 11.04.2021

Research J. Pharm.and Tech 2022; 15(2):723-728.

DOI: 10.52711/0974-360X.2022.00120

Ingredients	Quantity (%w/w)
Ingredients	F1	F2	F3	F4	F5	F6
Valsartan	0.4%	0.4%	0.4%	0.4%	0.4%	0.4%
Xanthan gum	1%	1.5%	-	-	-	-
Sodium alginate	-	-	2%	4%	-	-
Gelatin	-	-	-	-	3%	6%
PG	3%	3%	3%	3%	3%	3%
Sucrose syrup	60%	60%	60%	60%	60%	60%
Red iron oxide	0.1%	0.1%	0.1%	0.1%	0.1%	0.1%
Strawberry flavour	0.1%	0.1%	0.1%	0.1%	0.1%	0.1%
Methyl paraben	0.03%	0.03%	0.03%	0.03%	0.03%	0.03%
Propyl paraben	0.01%	0.01%	0.01%	0.01%	0.01%	0.01%
D.W	Up to 100 gm	Up to 100 gm	Up to 100 gm	Up to 100 gm	Up to 100 gm	Up to 100 gm