Abstract
Acute diarrhoea in children is a global health problem with an estimated 2 billion episodes each year; an estimated 1.9 million children die from the condition, mostly in developing countries, amounting to 18% of all deaths in children under the age of 5 years. Racecadotril is an antisecretory drug utilized for the treatment of diarrhoea in the form of tablet formulation. Administration of drugs through oral route is the most common and the easiest way to administer a drug. But it is a challenge in children who have not yet learned to swallow tablets.
To overcome this problem, chewable tablets of racecadotril can serve as a better alternative over oral route. In this present research chewable tablets of racecadotril were prepared using taste masked racecadotril-β-cyclodextrin complex by direct compression method and tablets were subjected to physico-chemical parameters.
The result of the present study conclusively demonstrated that complexation of Racecadotril with β-cyclodextrin successfully masked its bitter taste significantly. Optimized formulation F3 shows maximum fastest % cumulative drug release among all formulations at the end of 35 minutes. From the preliminary stability studies at 30±2 °C and 65±5% relative humidity no substantial change observed in the quality of tablet during the storage period. Thus, it is concluded that chewable tablet of racecadotril with rapid dissolution using β-cyclodextrin as a carrier can be possibly formulated in a more palatable patient friendly dosage forms.
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Introduction
Acute diarrhoea in children is a global health problem with an estimated 2 billion episodes each year; an estimated 1.9 million children die from the condition, mostly in developing countries, amounting to 18% of all deaths in children under the age of 5 years
- According to the World Health Organization (WHO), diarrhoea is defined as the passage of three or more loose or liquid stools per day, or more frequently than is normal for the individual
- Acute infectious diarrhoea results from various viral, bacterial, and parasitic infections and is most frequently of infectious origin. Nonetheless, in about 40% of the cases, no causative agent can be detected
- Oral rehydration has been the mainstay of treatment of diarrhea, however it does not reduce the frequency of stools or the number of diarrheal days
- Racecadotril is a more recent addition to the armamentarium for the treatment of acute diarrhea in children[1]. Racecadotril(Fig. No. 1) (acetorphan) is an antisecretory drug and an enkephalinase inhibitor used in the treatment of acute diarrhea. It prevents the degradation of endogenous enkephalins and thus reduces hypersecretion of water and electrolytes into the intestinal lumen without interfering with motility. Chemically it is N-[(R, S)-3-acetylmercapto-2-benzylpropanol]-glycine benzyl ester. It’s molecular formula is C21H23NO4S. It’s molecular weight is 385.48
- Racecadotril is administered by the oral route, is well absorbed from the intestinal tract. This drug has a repetitive dose schedule, short biological half life (3h) and reduced bioavailability (30-40%). Administration of drugs through oral route is the most common and the easiest way to administer a drug. But it is a challenge in children who have not yet learned to swallow tablets. Chewable tablets are the tablets which are required to be broken and chewed in between the teeth before ingestion. These tablets are given to the children who have difficulty in swallowing and to the adults who dislike swallowing
- In this work, it is designed to develop chewable tablets of racecadotril with the following objectives to reduce the first pass hepatic metabolism of drug, to enhance patients compliance particularly in case of pediatric class, to increase the onset of action owing to buccal absorption, to reduce the duration and severity of diarrhoea and the occurrence of future episodes.
Materials and Methods
Materials
Racecadotril was received as gift sample from Saymed labs limited Hyderabad telangana. Lactic acid was obtained from NCL, Pune. β cyclodextrin was obtained from Balagi drug and excipients. Mannitol, Magnesium stearate, Citric acid, Talc, Amaranth colour were obtained from Loba chem. Mumbai. Avicel pH(102), Sodium starch glycolate, Saccharine sodium were purchased from Zim laboratories, Nagpur. Strawberry flavour was obtained from Gujarat flavours PVT. LTD. Mumbai.
Evaluation of Drug
Determination of λ max
10 mg of racecadotril was dissolve in 100 ml of phosphate buffer pH 6.4 to prepare 100 µg/ml solution. Pipette out 1 ml & dilute with 10 ml of phosphate buffer 6.4 (10 µg/ml). Aliquots of 0.2,0.4,0.6,0.8 and 1 ml of stock solution were pipette into 10.0 ml volumetric flask & the volume was made up to 10 ml with phosphate buffer 6.4 to get concentration of 2,4,6,8,and 10µg/ml respectively. All samples was sonicated for 15 min & scanned for UV spectrum in the range 200-400 nm on UV spectrophotometer. λ max was traced [5].
Compatibility study
The compatibility study of the drug and polymers is an essential requirement before formulating as if the drug will react with the polymers or excipients will lead to a reduced shelf life of the product or may cause unwanted effects on the formulation. The incompatibility between the physical mixture of drug and polymers was determined by Fourier-transformed infrared spectroscopy (FT-IR) spectra and differential scanning calorimetry (DSC) thermogram.
Fourier-transformed infrared (FT-IR) study
FTIR transmission spectra were obtained using a fourier transform infrared spectrophotometer (FTIR-8300, Shimadzu Japan.) Samples were prepared in KBr disk by means of hydrostatic press. The scanning range was 500 to 4,000 cm-1 and the resolution was 4 cm-1. The characteristic peaks were recorded.
Differential scanning calorimetry
Melting point of racecadotril was determined by using differential scanning calorimetry (DSC). Thermo gram for drug was obtained using DSC (Mettle Toledo, DSC 822). The drug was sealed in perforated aluminum pans and heated at constant rate of 10ºC/min over the temperature ranges of 30-350ºC.
Preparation of Inclusion complex of Racecadotril-β-cyclodextrin
Inclusion complexes were prepared by kneading complex method in the sequential w/w ratios of 0.5:0.5, 0.5:1, 0.5:1.5, and 0.5:2. Kneading Complex was prepared by using the physical mixture of Racecadotril and β-Cyclodextrin and it was then triturated in a mortar with a small volume of distilled water. The thick slurry was kneaded until mild dryness (~40 minutes). The dried mass was then pulverized and sieved through # 44 [7].
Characterization of Inclusion complex
Drug content determination
Accurately weighed 10 mg of racecadotril in a 10 ml dried volumetric flask & adjust the volume to 10 ml with phosphate buffer 6.4, serving as a standard solution. And 10mg of racecadotril-β-cyclodextrin dissolve in 10 ml of phosphate buffer 6.4, serving as a test solution. Both the solutions were sonicated for 15 min & analyzed at 231 nm using a UV spectrophotometrically.
In Vivo taste evaluation study
In vivo taste evaluation test was carried out by panel of human volunteers. Six healthy human volunteers, of either sex, in the age group 21-25 years were selected for the study. All the volunteers were made aware of the study protocol and written consents from all six volunteers were taken prior to study.
Series solutions of drug and drug polymer complex were dispersed in phosphate buffer of pH 6.4 buffer. Immediately after preparation, each volunteer kept about 1 ml of the dispersion in the mouth for 30 seconds. After expectoration, bitterness level was recorded. A numerical scale was used with the following values: 0 = Tasteless, 1= Slightly bitter, 2 = Moderate bitter, 3 = Bitter, 4 = Strongly bitter. The oral cavity was rinsed with purified water twice to avoid bias. Time interval between testing different samples was 30 min as a referred period. The threshold bitterness value can be calculated [8].
In vitro taste evaluation study
Complex is filled in empty capsule shell then capsules are placed in a jars containing phosphate buffer 6.4 as a dissolution media and rotate at 100 rpm having temperature 37.5°C .Aliquots of sample were removed after 5 min of interval and absorptions were noted for 10 min by UV spectroscopy. For the satisfactory taste masking, the amount of drug dissolved at the end of 10 min should not be more than the threshold bitterness concentration of the drug [7].
Formulation of Chewable tablets
The Chewable tablets of Racecadotril-β-cyclodextrin were prepared by using the Direct compression method. Drug and excipients (avicel pH 102, mannitol, racecadotril) were sifted and blended for ten minutes in poly bag. Flavouring agent and colouring agent was added to the above mixture. Finally the above blend was lubricated with magnesium stearate, talc for two minutes. The powder blend was evaluated for the flow properties. The evaluated blend was compressed into tablets [9]. The compositions of chewable tablet formulation was mentioned in the Table no.1
General appearance
The general appearance of a tablet, its visual identity and over all “elegance” is essential for consumer acceptance. Include in are tablet’s size, shape, colors, presence or absence of an odour, taste, surface texture, physical flaws and consistency and legibility of any identifying marking.
Dimensional analysis
Diameter and thickness of tablets were important for uniformity of tablet size. Thickness and diameter were measured using digital vernier caliper.
Tablet diameter : The shape and dimensions of compressed tablets were determined by the type of tooling during the compression process.
Tablet thickness : Tablet thickness is an important characteristic in reproducing appearance. Three tablets were taken and their thickness was recorded by vernier caliper expressed in mm.
Tablet hardness Hardness of the tablets was determined by monsanto hardness tester and the hardness should be found within the range of 5 to 5.5 kg/cm² for chewable tablet. Three tablets were randomly picked and analyzed for hardness [10].
Weight variation test
I.P. procedure for uniformity of weight was followed, twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was determined from the collective weight. Not more than two of the individual weights deviate from the average weight by more than the percentage specified in IP. The weight variation test would be a satisfactory method of determining the drug content uniformity [11].
Friability
Friability of the tablet determined using Roche friabilator. This device subjects the tablet to the combined effect of abrasion and shock in a plastic chamber revolving at 25 rpm and dropping a tablet at height of 6 inches in each revolution. Preweighted sample of tablets was placed in the friabilator and were subjected to the 100 revolutions. Tablets were dusted using a soft muslin cloth and reweighed [12]. The friability is given by the formula :
F = Initial weight of tablets – Final weight of tablets / Initial weight of tablets × 100
A maximum loss of weight should not be greater than 1.0 percent is acceptable for tablets.
Drug release study
In vitro dissolution study for chewable tablet is carried out by using USP type II apparatus at 100 rpm in 900 ml pH 6.4 phosphate buffers as dissolution media, maintained at 37±0.5°C. 5ml aliquot dissolution medium was withdrawn at specific time intervals and replaced with an equal volume of fresh medium, which was again diluted. This was pre-warmed at 37±0.5°C into dissolution medium after each sampling to maintain sink condition. Finally the absorbance of filtered solution was checked by UV spectrophotometric method at 231nm and concentration of the drug was determined [8, 13].
Drug content
5 tablet randomly were taken from each formulation batch and crushed. Take quantity equivalent to dose i.e 11.11 mg of powder & dissolve in phosphate buffer 6.4. Filtered & absorption taken at 231.40 nm for drug [8].
Content uniformity
Twenty tablet were randomly selected and twenty tablets were crushed using a mortar and pestle and a powder equivalent to 10 mg of Racecadotril was transferred into a 50 ml volumetric flask and the volume was made up with the mobile phase. The sample was sonicated for 10n min and suitably diluted to fit into the calibration curve range. The diluted samples were analyzed UV-visible spectrometer at as wavelength of 231nm [10].
Determination of viable count
Lactobacilli were cultivated overnight on the agar plate in specific conditions for each bacteria at 37.8ºc. Lactobacillus was incubated on plate count agar at 37.8ºc for 2 days that is 48 hour to produce spores. The 48 hour old cultures were then concentrated up to 107 CFU/ml in sterile distilled water [14].
CFU/ml = No. colonies × Dilution factor
Volume of culture plate
CFU = Colony forming unit.
Palatability test
The direct compression process tablets selected for palatability evaluation study, in that one is the reference formulation, and another is the positive control (Placebo for Racecadotril) and one is negative control (Placebo for taste masking agent like β-cyclodextrin and taste enhancers like saccharine sodium and strawberry flavor) also included. Take one tablet (one dose) in to the mouth (Do not swallow the tablet) and wait for 30 seconds. After 30 seconds spit the tablet (Do not wash the mouth), record the feedback in table no. After spitting, wait for 5 minutes and record the feedback.
During this 5 minutes period do not wash the mouth cavity or eat anything. After recording the feedback at the end of 5 minutes thoroughly wash the mouth cavity with water and eat the bread slice and coca powder provided by the study coordinator. Till the entire test formulations are evaluated, the volunteer shall not eat anything other than that provided during the study [15].
Stability studies
The optimized formulation was kept for intermediate term stability study as per ICH guideline. The conditions for stability were 30 ±2°C and relative humidity of 65±5% for one month. All tablets were suitably packed in group of 10 in aluminum foil. At the end of one month the sealed tablet were opened and evaluated [7].
