Eletriptan hydrobromide Orodispersible tablets: Design, Development and

In vitro characterization

 

Spandana B, Shashidher B, Dinesh S, Nagaraj B*

University College of Pharmaceutical Sciences, Kakatiya University, Warangal – 506001 Telangana State, India.

 

ABSTRACT:

The main objective of this research work was to formulate and evaluate the orodispersible tablets of eletriptan hydrobromide (EH). EH is a selective 5HT1B/1D receptor agonist used in the treatment of migraine. Formulation of EH in the form of orodispersible tablets (ODT) would facilitates the release of the drug in less time; hence it can be used in acute treatment of migraine. The EH-ODT formulations were prepared with varying concentrations of different supradisintegrants such as crosspovidone, croscarmellose sodium, and sodium starch glycolate by direct compression method. Prepared EH-ODTs were evaluated for physical parameters, drug content, disintegration time, and in vitro drug release. Other parameters such as wetting time, water absorption ratio, and drug-excipient compatibility were also evaluated. Based on the results, formulation F9 was selected as optimized formulation with disintegration time of 18 sec and cumulative percentage drug release of more than 95% in 10 min. The optimized formulations were subjected to short term stability study by storing the formulations at 40± 2ºc/75± 5% RH up to three months. The formulations F9 was found to be stable during the study. Therefore, the results confirm the ODTs of EH could be considered as an alternative for acute treatment of migraine.

 

 

 

INTRODUCTION:

Over a decade, the demand for development of orally disintegrating tablets (ODTs) has enormously increased as it has significant impact on the patient compliance.  Orally disintegrating tablets offer an advantage for populations who have difficulty in swallowing. It has been reported that dysphagia (difficulty in swallowing) is common among all age groups and more specific with pediatric, geriatric population along with institutionalized patients and patients with nausea, vomiting, motion sickness complications, for travelers, busy people, and who do not always have access to water. ODTs with good taste and flavor increase the acceptability of bitter drugs by various groups of population¹.

 

Orodispersible tablet is defined as “A solid dosage form containing active pharmaceutical ingredient which disintegrates rapidly usually within a matter of seconds when placed upon the tongue.” The main criteria for mouth disintegrating (dissolving) tablet is to disintegrate or dissolve rapidly in oral cavity with saliva in 15 to 60 seconds, without need of water, should have pleasant mouth feel, taste masking property and no residue in mouth after administration. Rapid dissolution and achieve increased bioavailability/rapid absorption through pre-gastric absorption of drugs from mouth, pharynx and esophagus as saliva passes down².

 

The most important drug delivery route is undoubtedly the oral route. It offers advantages of convenience of administration and potential manufacturing cost savings. Drugs that are administered orally, solid oral dosage forms in general and tablets in particular represent the preferred class of product. Today drug delivery companies are focusing on solid oral drug delivery systems that offer greater patient compliance and effective dosages^3-6.

 

ODTs are formulated to obtain disintegration time usually less than a minute. While doing so, maintaining a good mechanical strength is a prime challenge. Many ODTs are fragile and there are many chances that such fragile tablet will break during packing, transport or handling by the patients. Tablets based on technologies like Zydis need special type of packaging. It is very natural that increasing the mechanical strength will delay the disintegration time. So effective taste masking of the bitter drugs must be done so that the taste of the drug is not felt in the oral cavity^7,8.

 

Drugs with relatively larger doses are difficult to formulate into ODT e.g. antibiotics like ciprofloxacin with adult dose tablet containing about 500 mg of the drug. The dosage form can accommodate only up to 600 mg of drug. Patients who concurrently take anticholinergic medications may not be the best candidates for MDT. Similarly, patients with Sjögren’s syndrome or dryness of the mouth due to decreased saliva production may not be good candidates for these tablet formulations. These are the disintegrants which are used in low concentration to aid in faster disintegration and to promote rapid break down of oral solid dosage forms to aid dissolution in-vivo. Because they can be a smaller part of the overall formulation and any possible adverse effect on fluidity or compactability would be minimized and provides formulation scientists greater flexibility, particularly in designing direct compression tablets^9,10 (Bhupendra, 2010; Raghavender Rao, 2010).

 

Eletriptan hydrobromide (EH) is well absorbed after oral administration with a mean absolute bioavailability of approximately 50% due first pass hepatic metabolism. One theory suggests that activation of 5-HT1 receptors located on intracranial blood vessels leads to vasoconstriction, which is correlated with the relief of migraine headache. The other hypothesis suggests that activation of 5-HT1 receptors on sensory nerve endings in the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release^11-13.

 

Materials:

Eletriptan Hydrobromide procured from Mylan Laboratories, Hyderabad. Mannitol, Microcrystalline cellulose, Croscarmelose sodium, Crospovidone, SSG, Aspartame, Magnesium stearate, Talc, Vanilla flavor.

 

METHODS:

Solubility studies:

Excess amount of drug was taken into a vial contains 10 ml of 0.1 N HCl and placed on a horizontal shaker for 24 h till equilibrium was achieved. The supernatant was filtered and the filtrate was diluted with respective buffers and estimated by UV visible spectrometer and same procedure repeated with pH 6.8 phosphate buffer and water¹⁴.

 

Preformulation studies:

The quality of tablets once formulated, is generally dictated by the quality of physicochemical properties of blends. Angle of repose, Bulk density, tapped density, compressibility index and Hausner’s ratio tests were conducted¹⁵.

 

Differential Scanning Calorimeter (DSC):

DSCC studies were carried out to find out the presence of any interaction among drug and other excipients like cross povidone, microcrystalline cellulose, mannitol, aspartame. Optimized formulation after 3 months stability studies were subjected to the study 3-10mg of sample to be analyzed was taken in DSC crucibles and scanned in the temperature range of 100-300^oC. The heating rate was 10ºc/min nitrogen served as purged gas and the system was cooled by liquid nitrogen¹⁶.

 

FT-IR Spectroscopy:

The Infrared spectra of EH, physical mixture of drug and excipients were recorded between 400-4000 cm^-1 on FTIR to detect the drug excipient interactions. The IR spectra for the test samples were obtained using KBr disk method using an FTIR spectrometer¹⁷.

 

Preparation of EH orodispersible tablets:

EH-ODTs were prepared using direct compression method as per the composition showed in Table 1. All the required ingredients were passed through #40 mesh to get uniform particles and mixed in increasing order of their weights in a mortar.

 

Table 1: Composition of Eletriptan hydrobromide orodispersible tablets

 

Table 2: Flow properties of Eletriptan hydrobromide granules

 

Table 3: Physico-chemical characteristics of Eletriptan hydrobromide orodispersible tablets

 

 

To this mixture talc and magnesium stearate were added and final mixture was shaken manually for 5-10 minutes in plastic cover. This final powder blend was compressed in to tablets using 16 station rotary tablet compression machine using 6 mm punches¹⁸.

 

Characterization of prepared tablets:

The prepared EH-ODTs were evaluated following tests weight variation, tablet hardness, drug content, tablet thickness, friability, wetting time, water absorption ratio, in vitro dispersion time and in vitro disintegration time¹⁹.

 

In vitro dissolution studies:

Dissolution of the tablet of each batch was carried out using USP XX111dissolution type II apparatus (Electro lab, Hyderabad, India) using paddles at 50rpm. As per the official recommendation of IP900ml of 6.8 PH of phosphate buffer and 0.1N HCl used as dissolution medium and temperature of the Medium was set at 37±0.5^oC. About 5 mL of sample was withdrawn at predetermined time interval of 2, 6, 8 and 10 min, and same volume of fresh medium was replaced. The withdrawn samples were analyzed by an UV spectrophotometer at 225nm against respective blank solution. The drug content was calculated using the equation generated from standard calibration curve. The % cumulative drug release was calculated²⁰.

 

Stability studies:

The optimized EH-ODT formulation was subjected to short term stability study, by storing the formulations at 40±2ºC/75±5% RH up to three months. At predetermined time intervals, the tablets were again analyzed for the hardness, friability, disintegration time, drug content, dispersion time and drug release.

 

RESULTS AND DISCUSSIONS:

Solubility of EH:

EH solubility was low at acidic pH (85.9µg/mL) compared with pH 6.8 buffer (99.5µg/mL) and water (95.9µg/mL).

 

Preformulation studies:

The physical properties like angle of repose for all the formulations was found to be <30º indicating free flowing of the material and cars index values were found to be in the range of 13-15 showing good flow properties. The results are presented in Table 2.

 

Physico-chemical parameters of EH-ODTs:

EH-ODTs were evaluated for physical parameters such as thickness, weight variation, hardness, friability and showed in Table 3. The results of the physical parameters of the formulations were found to be within the limits and comply with the standards. In all the formulations as shown in the table, no tablets were outside the ±10% of mean tablet weight and the tablet thickness of all the formulations were within ±5% standard value. Hardness of the tablets was in the range of 2.8 to 3.2kg/cm². Friability was in the range of 0.5% to 0.6%. Lowest friability was seen for sodium starch glycolate formulation. The maximum drug content among all the formulations was found to be 95.32%. The drug content on an average was found to be 99%. The weight variation was achieving USP limits.

 

Disintegration, wetting and dispersion time of EH-ODTs:

The results of disintegration time, wetting time, water absorption ratio, in vitro dispersion time are showed in Table 4. The disintegration time of F7, F8, F9 with 2, 4 and 6% of crospovidone formulations were observed to be as 30.4±0.6, 26.8±1.1, 18.9±0.4 sec, respectively and is almost better than F1, F2, F3, F4, F5, F6 formulations. From the results of disintegration test, formulation F9 showed the low disintegrating time as18.9±0.4 sec, compared to other ODT formulations. It was observed that in all the formulations disintegration time was decreased with increase in the concentration of superdisintegrant.

 

Table 4: Evaluation parameters of Eletriptan ODT formulations

 

The wetting process was very rapid in almost all formulations. This may be due to the ability of swelling followed by breaking and also capacity of water absorption and cases swelling. It was found to be in the range of 14.5±0.2 sec to 27.2±0.6 sec. The formulations F9, containing 6% of cross povidone have better wetting time comparing with that of crosscaramellose sodium, sodium starch glycolate formulations.

 

Water absorption ratio which is important criteria for understanding the capacity of disintegrants to swell in the presence of little amount of water .it was found to be in the range of 12.4±0.6 to 54.2±2.1%. This shows that all the formulations have good water absorption capacity. The formulations of cross povidone have shown better water absorption ratios.

 

The in vitro dispersion time of formulations F7, F8 and F9 were 35, 27, 15 sec, and better than other formulations. Among all the formulations, cross povidone with 6% (F9) has shown less in vitro dispersion time.

 

In vitro release studies:

The cumulative drug release of EH-ODTs form F1, F2, F3 formulations, containing SSG at a concentration of 2, 4, 5 and 6%, respectively was found to be 53.7, 81.7 and 89.4% (Figure 1). The cumulative drug release for formulations F4, F5, F6 containing CCS at a concentration of 2, 4, 6% respectively was found to be 62.9, 85.9, 92.2% (Figure 2). The cumulative drug release for formulations F7, F8, F9 containing crospovidone at concentration of 2, 4, 6%, respectively was found to be 70.6, 90.2, and 96.9% (Figure 3). Hence, from the in vitro dissolution data, it indicates that the crosspovidone as superdisintegrant containing ODTs found to be best among the three supradisintegrants.

 

Figure 1: In vitro drug release profile of eletriptan from EH-ODTs containing sodium starch glycolate in pH 6.8 phosphate buffer (mean±SD, n=3)

 

Figure 2: In vitro drug release profile of eletriptan from EH-ODTs containing croscarmellose sodium in pH 6.8 phosphate buffer (mean±SD, n=3)

 

Figure 3: In vitro drug release profile of eletriptan from EH-ODTs containing crospovidone in pH 6.8 phosphate buffer (mean±SD, n=3)

 

The cumulative drug release from EH-ODTs also performed in 0.1N HCl. From the results, formulations F1, F2, F3 containing SSG at a concentration of 2%, 4%, 6% respectively was found to be 46.9, 61.7 and 71.5%.

 

Figure 4: Overlay DSC thermograms of  a) pure drug, b) physical mixture of drug with crospovidone, c) formulation F9 and d) formulation F9 after 3 months.

 

 

Figure 5: FTIR spectra of a) pure drug, b) pure drug + crospovidone, c) pure drug + sodium starch glycolate, d) pure drug + cross carmellose sodium and e) optimized formulation F9 mixture

 

The cumulative drug release from formulations F4, F5, F6 containing croscarmellose sodium at a concentration of 2, 4, 6% respectively was found to be 52.3%, 75.8 and 78.1%. The cumulative drug release from formulations F7, F8, F9 containing crospovidone at a concentration of 2%, 4%, 6% respectively was found to be 61.2%, 79.3% and 81.2%. The drug release was highest in formulation F9 containing 6% of crospovidone in 0.1 N HCl.  From the drug release studies in 0.1 N HCl, it was noticed that the release of drug was low when compared to that of in 6.8 pH phosphate buffer at the end of 10 minutes. The possible reason might be low solubility of the drug 0.1N HCl. determine whether there is any change in the optimized formulation during the stability studies.

 

DSC Study results:

The thermal properties of the drug and excipients are the interest; this can help to assess the interaction among different components of the formulation (Figure 4). DSC thermogram of EH showed a sharp endothermic peak at 180ºC corresponding to its melting point. Drug peaks of EH were retained in physical mixture of EH and crospovidone and there is a slight decrease in melting point in the composition of formulation, and after stability studies indicating no potential chemical interaction. In the figure optimized formulation also showing peak at 180^oC and after 3 months stability studies that F9 formulation showing the peak at 173^oC nearby drug peak. From the DSC studies it can be concluding that, there was no significant drug-excipient interaction and also concluded drug and other excipients are compatible with each other.

 

FT-IR studies:

The samples are mixed with dry crystalline KBr in a1: 100ratio and pellets are prepared and spectrums were recorded for each sample within the wave number region 4000-400cm^-1. In the FTIR spectra of pure drug and formulations, it is observed that the peaks of major functional groups of EH, which are present in spectrum of pure drug, are observed (Figure 5). It means that there are no interactions between drug and other ingredients in the physical mixture and drug is compatible with each other.  The pellet compound will exhibit peaks at 726, 804 (=C-H), 1019 (sulfonyl group), 1148(Secondary amine), 1262 (C-N), 1305 (C=C stretching mode), 2171 (C-H stretching mode), 3647-3859 cm^-1.

 

Stability studies of the optimized formulation: 

The formulations F9 was selected on the basis of % drug release profile and disintegration time. During the three months storage conditions, the tablets were analyzed for physico-chemical parameters and in vitro drug release. From the results, the increase in the disintegration time was observed. This may be due to increase in the hardness of the tablets during storage. No significant change was observed in the drug content, % drug release profile of the formulation.

 

CONCLUSION:

Eletriptan hydrobromide orodispersible tablets were successfully prepared and optimized for the treatment of migraine. The ODTs of EH were prepared using direct compression method, using crospovidone, sodium starch glycolate and crosscaramellose sodium as superdisintegrant. The optimal system was identified based on the physical and chemical evaluation parameters. The crospovidone at a concentration of 6% has shown disintegration time of 18 sec and the drug release was found to be more than 95% in 10 min. This formulation F9 has shown good stability for a period of 3months.

 

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Received on 29.10.2019           Modified on 31.01.2020

Accepted on 23.03.2020         © RJPT All right reserved