American Journal of Advanced Drug Delivery Open Access

Keywords

Sjogren disease, Cevimeline hydrochloride, Superdisintigrant, Mouth dissolving tablets, Factorial design

Introduction

The Sjogren’s syndrome is a chronic autoimmune inflammatory disease in which moisture-producing glands are damaged, significantly decreasing the quantity and quality of saliva and tears [1-2]. For the treatment of Sjogren syndrome, the cevimeline hydrochloride capsules are available in market. In this condition, many patients express difficulty in swallowing (dysphasia) tablets and capsules among all age groups, especially in elderly and paediatrics, resulting non-compliance and ineffective therapy [3]. To overcome this problem with the help of recent advances in Novel Drug Delivery System (NDDS) is mouth dissolving tablets that can dissolve or disintegrate in oral cavity, have attracted a great deal of attention [4]. Indeed, the mouthdissolving tablet is an important and attractive alternative to liquid dosage form. Syrups are best for paediatrics but they are bulky and drugs are not as stable in liquid form as compare to solid form like tablets. The major advantage is that can be administered without water, which is suitable for mentally ill patients who cannot access water easily as well as for geriatric and paediatric patients. The other benefits include rapid onset of action, increase bioavailabity and good stability [5-7]. Recently useful dosage forms such as rapidly disintegrating or dissolving tablets, have been developed and applied clinically. When such tablets are placed in the oral cavity, saliva quickly penetrates into the pores to cause rapid tablet disintegration. The objective of this study was to formulate directly compressible tablets of cevimeline Hydrochloride with sufficient mechanical integrity, maximum drug release and acceptable palatability with better mouth feel for the treatment of Sjogren syndrome. As cevimeline Hydrochloride shows peak plasma concentration/half-life at 4-5 hours after oral administration as well as it is tasteless and highly water-soluble drug, so it can be considered good candidate for mouth dissolving tablet [8-9].

Our work aims to develop an antifungal cream based on Ocimum gratissimum essential oil and to evaluate its activity on a few strains of fungi.

Materials and Methods

Materials

Cevimeline Hydrochloride and Crospovidone, Sodium Starch Glycolate, Mannitol, Avicell-102, Magnesium Stearate and Talc were obtained as a gift sample from Aurobindo Research Centre Hyderabad. All other chemicals used were of analytical grade.

Selection of Excipients

The concentration of each excipients was selected as per their maximum potency per dose of each ingredient. By referring the Handbook of pharmaceutical excipients and Inactive Ingredients Guidelines limit are given in (Table 1) [10-12].

Table 1: Selection of excipients based on IIG limit.

Solubility Studies

An excess of cevimeline hydrochloride was added to various solvents such as 10 mL of distilled water, HCL, Phosphate buffer and subjected to ultrasonication for 24 hours at room temperature. The solution was then filtered through Whatman filter and after making suitable dilutions, the amount of drug dissolved in various solvents was analysed spectrophotometrically using UV spectrophotometer (v- 530, Jasco) at lambda max 207 (Table 2).

Table 2: Solubility study in different solvents.

Calibration Curve of Cevimeline HCl (CVEH)

Based on solubility studies water was used for constructing the calibration curve of cevimeline hydrochloride. The absorbance was measured by using U.V-Visible spectrophotometer (Jasco307) at 207 nm (Figure 1) and the graph was plotted (Figure 2). This graph was used for estimation of drug content in the formulated mouth dissolving tablets of cevimeline hydrochloride.

Preparation of Trial Batches of CVEH Mouth Dissolving Tablets

Tablets were prepared by direct compression method and the batch size was kept as 50 tablets. Required amounts of all ingredients were weighed and sifted together through sieve # 60. Then it was transferred into mortar pestle and was mixed together until it has been mixed properly. The powder blend was compressed on compression machine using 4 mm Round shaped punch (Table 3) [13].

Table 3: Preliminary trail batch CVEH tablets.

Evaluation of Prepared CVEH Fast Dissolving Tablets

Weight variation: Twenty tablets were randomly selected from each batch and weighed using a (Electrolab). The mean SD was calculated.

Thickness: Ten tablets from each formulation batch were taken randomly and their thickness was measured with a vernier callipers (Digimatic, Japan) the mean SD values were calculated.

Hardness and friability: Hardness of disintegrating tablets were tested using electrolab digital tablet hardness tester and friability by using roche friability test apparatus [14].

Wetting time: Two folded circular tissue papers were placed in a petri dish of 10 cm diameter, 10 mL of water containing 1% of methyl blue water-soluble dye was added to the petri dish. Tablet was placed in petri dish to measure the time required for water to reach the upper surface of tablet until it becomes completely wetted. This was noted as the wetting time [15].

In-Vitro disintegration time: The process of breakdown of tablet in to smaller particles is called as disintegration. Orally disintegrating tablet was disintegrated due to water uptake by superdisintigrant via capillary action. Test carried out with specification (Electrolab disintegration apparatus- II), distilled water at 37°C ± 2°C as media. The time required to complete disintegration of tablet with no palatable mass left behind in apparatus was measured (Table 4) [16].

Table 4: Evaluation of preliminary trial batches.

In-Vitro drug release study: In-Vitro Drug Release study of CVEH from all formulation batches was performed using USP-II Paddle method, (Electrolab TDD06P), paddle speed at 50 rpm, and the dissolution medium 900 mL of 0.1 N HCL and temperature 370 ± 20 was maintained. Sample (5 mL) were collected at predetermine rate (5, 10, 15, 30, 45, 60 min) and replaced with equal volume of fresh medium (Figure 3). The sample, which is withdrawn at specified time, was filtered through Whatman filter paper and analysed with UV-Visible Spectrophotometer at λ 207 nm. Drug concentration was calculated from a standard calibration plot and expressed as cumulative % drug dissolved (Table 5) [17]

Table 5: % Drug release of preliminary trial batches.

Optimization of Formulation

The batch no A4 was selected for further optimization. The 23 Factorial design along with three replicates was applied to examine the combined effect of two formulation variables for which 13 batches of CVEH tablets were generated (Table 6). The amount of crospovidone and MCC-102 were taken as independent variables while disintegration time (DT), %Friability and wetting ability were taken as dependent variables (Table 7). Based on the preliminary feasibility study, a DOE with factorial design was performed to optimize MCC-102 and crospovidone concentration used in the formulation. The percentage of friability, disintegration time and wetting ability of tablets was identifying as CQA of the formulation composition, the ranges for the response were based on these three factors of the formulations, and it summarizes the study design and acceptance criteria. A constant tablet weight of 150 mg was used by compensating the quantity with Mannitol to achieve targeted weight. The goal of formulation development was to the optimization of MCC-102 and crospovidone concentration and to understand if there was any interaction within the variables using Design-Expert® 11 software (Table 8) [18].

Table 6: Optimization of A4 batch by using factorial design.

Table 7: Absolute values of level of variables.

Table 8: Evaluations of optimization formulation.

Stability Study

The stability studies were carried out as per ICH guidelines on the most acceptable formulation batch D4 among all batches (Figure 4). Batch D4 was packed in aluminium foils. The stability studies were performed at 40 ± 2 °C/75 ± 5 % RH conditions for 1 month. At the end of study, samples were analysed for the physical evaluation and in vitro dissolution etc (Table 9) [19-20].

Table 9: Evaluations of optimized batch (d4) after stability.

Kinetics Release Study for Optimized Formulation D4

The dissolution release data of the optimized formulation D4 was processed into graphs to understand the linear relationship, i.e., kinetic principles (Figures 5-9). The data were processed for regression analysis using MS - Excel statistical functions. The parameters and equations were given in the (Table 10) is indicated that the release kinetics of the drug followed Zero-order kinetics from optimized formulation.

Table 10: ANOVA model response 1: disintigration time.

Results and Discussion

Compatibility Study

FTIR study: FTIR spectra of Cevimeline hydrochloride and mixture of Cevimeline hydrochloride and Excipients were taken and compared (Figure 10 and Figure 11). The result revealed that there was no appearance of any extra peaks and disappearance of existing peaks, which indicated that there was no interaction between drug and polymer used.

DSC study: The supporting evidence for compatibility between drug and excipients was obtained from DSC studies. and thermogram of cevimeline HCL show sharp endothermic peak at 205°C corresponding to the melting point of drug. The optimized formulation of cevimeline hydrochloride with endothermic peak at 205°C. In the DSC, which reflects that there is no interaction between drug and excipients. (Figure 12 and Figure 13)

Based on dissolution data of office of generic drug Q point is 80% release in 1 hr. The first trial of batch no A1 was taken with Cevimeline HCl tablets by using Crospovidone as a disintegrant and mannitol as diluents and tablets compressed by using direct compression method. The disintegration time was observed 15 to 20 seconds and dissolution results resemble with Q point, but the friability was more than 1% and also capping was obtained.

The second trail batch A2 was taken by changing disintegrant as sodium starch glycolate, but the disintegration time get increased up to 50 to 120 second and dissolution results did not match with Q point limit. The third trail of batch A3 was taken by changing disintegrants as croscarmellose cellulose. The trial resulted in increase in disintegration time i.e. 120 to 180 second but dissolution results was found below the Q point limit. The fourth trail A4 was taken similar as to A1 trail but in this trial the combination of diluent Mannitol & MCC-102 was used in the ratio of 9:1. The disintegration results of this batch were good and dissolution time greater than Q point i.e. 10-15.

Factorial Design

In the 23 central composite full factorial design the dependable variables of formulation batches D1 to D13 such as disintegration time in seconds, friability in % and wetting time in seconds showed a wide variation i.e. 8-50 seconds, 0.27-0.83 %, and 9-20 seconds respectively. The obtained data from DOE batches showed that the dependent variables i.e. DT and wetting time were strongly independent on the selected dependant variables. The factorial equations can be used to draw conclusion after considering the magnitude of coefficient and mathematical sign it carries positive or negative. The analysis of variance (ANOVA) was performed to identify insignificant/significant factors (Tables 10-12). The (Figures 8-10) illustrates the surface plot, which denotes the combined effects of independent variables on dependent variables. It was observed that the combine effect of MCC and Crospovidone concentration inversely proportional to DT, friability and wetting time (Figure 14-16).

Table 11: ANOVA model response 2: wetting time.

Table 12: ANOVA model response 3: friability.

Stability Study

The optimized formulations batch D4 stored at 40 ± 2°C/75 ± 5 % was found to be stable. After storage at 40 ± 2°C/75 ± 5 %, no shape deformation in the tablets was found. The cumulative percentage drug release was nearly similar before and after storage. Therefore, it is clear that drug was thermally stable at 40 ± 2°C as well as not affected by high humidity at 75 ± 5%. Considering the in vitro drug release behaviour of optimized formulation of cevimeline Hydrochloride initially and after 1 month, it was found that there was no much more variation in the in vitro drug release behaviour of tablets (Table 13).

Table 13: Release mechanism of optimized formulation.

Conclusion

The objective of this investigation has been achieved by preparing mouth dissolving tablets of cevimeline hydrochloride by using direct compression technology. The results of a 23 factorial design revealed that the concentration of disintegrating agent and super disintegrating agent are significantly affect on the dependant variables. which shows better disintegration, good mechanical strength, and maximum % drug release. It also shows accuracy of dosage form, easy portability and best alternative to liquid dosage form as well as orally administered solid dosage form, i.e. hard gelatine capsules and tablets for paediatric and geriatric patients who suffers from Sjogren syndrome. The optimized batch has shown the potential for commercialization.

Acknowledgement

The authors thank to Aurobindo Research Centre Hyderabad for providing gift samples of Cevimeline Hydrochloride and other excipient and also thank to Sinhgad Institute of Pharmacy, Narhe, and Pune for providing all facilities for project.

Conflict of Interest

All authors declare that they have no conflict of interest.

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