Abstract

The aim of this study was to develop and evaluate carvedilol melt-in-mouth tablets incorporating a mucoadhesive polymer to enhance bioavailability and improve patient compliance, particularly for those with difficulty swallowing tablets. Carvedilol is a non-selective ?-blocker, primarily used in the management of hypertension and heart failure. This formulation approach is designed to provide rapid onset of action and ensure a controlled release of the drug at the site of action. The incorporation of mucoadhesive polymers helps to improve the retention time of the tablet in the oral cavity, enhancing absorption and therapeutic efficacy.

Keywords

Introduction

Preparation of granules

Table 1 gives an overview of the percent composition of the granules prepared by wet granulation. PEG?6?stearate was used as a hydrophilic waxy binder in the formulation blend. Wet granulation took place in a planetary mixer (Kenwood, United Kingdom), operated with a planetary action to ensure that all the parts of the mixer were thoroughly active. The granulation process was performed, starting with preliminary trials. Carvedilol, pearlitol SD 200, and polymer were first dry blended for five minutes at 60 rpm. The granulating agent (PEG?6?stearate) was added in small quantities under continuous stirring. The formed wet mass was blended for 10 minutes at 100 rpm and dried at 40°C in a dryer for 120 minutes. Finally, the granules were sieved through 1mm mesh in an oscillating calibrator (Erweka type FGS).

Preparation of tablets

Prior to compression, each formulation of granules was dry blended with CCS (cross carmilose sodium) as superdisintegrants, 1.4% aspartame, and 0.4% magnesium stearate for 15 minutes at 50 rpm. A single?punch tableting machine (Korsch, Lyon France), equipped with flat forced punches with a die diameter of 4 mm, was employed to prepare tablets at the rate of 45 tablets per minute.

Determination of physiochemical parameters Content uniformity, weight variation, thickness, hardness test, and friability

Uniformity of drug content was determined by dissolving the crushed tablets in distilled water and filtered through a 0.45µm filter. The stock solution was diluted with necessary dilutions and was analyzed at 232 nm using a spectrophotometer (Shimazdu 1700 spectrophotometer). A weight variation test was performed by weighing 20 tablets, and weights of the individual tablets were compared with calculated average weights. The thickness of the tablets was measured with a vernier calliper (Microtek, India). Hardness was checked to find the mechanical strength of the tablet. It is also expressed as crushing strength. It is the force required to break the tablet into halves by compression. The crushing strength of the tablet was measured using a Pfizer hardness tester. Friability test was performed to access the effect of friction, shocks, vibration, capping, or breaking (Roche Friabilator). Twenty?five tablets were weighed and placed in the friabilator, which was then operated at 100 rpm. The tablets were dusted and reweighed. The compressed tablets should not lose more than 1% of their weight.^[9,10]

In vitro deaggregation

In vitro disintegration time was checked by apparatus specified in the United States Pharmacopeial Convention (USP) at 50 rpm. Phosphate buffer pH 6.8, 900 mL was used as the disintegration medium; the temperature of this was maintained at 37 ± 2°C and the time taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured in seconds.^[11,12]

In vitro dissolution studies

The formulations were studied for drug dissolution, employing a USP apparatus type II (paddle type) [Electrolab (ETC?11L) tablet dissolution tester] at 50 rpm. Phosphate buffer pH 6.8, 900 mL was used as dissolution medium which was maintained at 37 ± 0.5°C.^[13,14]

In vitro permeation study

In vitro  permeation studies were carried out using the Franz diffusion cell. The medium used for permeation was phosphate buffer pH 7.4 which was maintained at 37 ± 0.5°C. Cellulose acetate membrane was used as a permeation barrier. Samples were collected at predetermined time intervals (0, 5, 10, 15, 20, 30, 40, 50, 60, 90, and 120 minutes). They were analyzed for drug content with an ultraviolet (UV) spectrophotometer at 232 nm. Three trials of each batch were performed and the average percentage drug release with standard deviation was calculated and recorded. The calibration curve for carvedilol, in the phosphate buffer, was linear from 1 to 8 µg/mL (r² = 0.998).^[15,16]

Wetting time

A piece of tissue paper folded twice was placed in a small petridish (internal diameter: 6.5 cm) containing 6 mL of simulated saliva pH (phosphate buffer 6.8). A tablet was put on the paper and the time required for complete wetting of the tablet was measured. The average time for wetting with standard deviation was recorded. Each trial was performed in triplicate.^[17]

Stability studies

Accelerated stability studies were carried out at 30 ± 2°C, 65 ± 5 °RH and 40 ± 2°C, 75 ± 5 °RH for three months. The tablets were evaluated for hardness, variation in weight, friability, loss on drying, disintegration, drug release, and uniformity of content.^[18,19]

F7, and F10 were subjected to dissolution testing and their drug release profiles were found to be comparable; so, they were shortlisted for further stability studies.

Studies

In vitro deaggregation study

Avicel has a good capacity to absorb. Tablets consisting of avicel disintegrate rapidly due to the rapid passage of water into the tablets resulting in the instantaneous rupture of the hydrogen bonds. The ratio of avicel in the tablet formulations was kept almost constant for all the formulations. Avicel accelerates water penetration into the tablets and enables easy swelling of CCS; this reveals the superdisintegrant property of CCS. The ratio of CCS in MMTs is very important because it was reported that disintegration time increased with increase in the level of CCS in the tablets. It was shown that the increase in the level of CCS had a negative effect on the disintegration of the tablets. Higher concentrations of CCS lead to the formation of a viscous gel layer by CCS which might form a thick barrier to the further penetration of the disintegration medium and hinder the disintegration or leakage of tablet contents. Thus, disintegration is retarded to some extent with tablets containing CCS. So, it can be concluded that the use of CCS (cross carmilose sodium) in MMT formulations at a ratio of 2 % gives the desired disintegration time.^[20]

On the other hand, pearlitol SD 200 has good water solubility, and this may leave pores on the tablet matrix after rapid dissolution of it. These pores can accelerate the capillary action that maybe responsible for penetration of the surrounding fluid in the tablet matrix and rapid disintegration thereafter.^[21] The effect of different polymers on disintegration of tablets was optimized. Increasing the HPMC content in MMT formulations from 1.5, 3, and 3.5% ratios increased the disintegration time (P > 0.05). It was shown that increasing the concentration of HPMC caused an increase in the disintegration time of HPMC tablets. When HPMC tablets were exposed to water, HPMC absorbed water rapidly and formed a gelatinous layer on the tablet surface. This resulted in a poorly disintegrated tablet, and erosion became the main pathway for the size reduction of the tablet. When the concentration of the HPMC was less than 10%, the gel was not formed and the tablet could disintegrate easily.

Disintegration time increased with increase in the level of polymers in the tablets of chitosan and Na?CMC. This increase is significant in the formulations prepared with Na?CMC. This indicates that increase in the level of polymer had a negative effect on the disintegration of the tablets. From this result it was expected that at higher polymer ratios, formation of a viscous gel layer by polymers might have formed a thick barrier to the further penetration of the disintegration medium and hindered the disintegration of leakage of tablet contents.

In vitro dissolution study

In particular, pearlitol with a higher solubility might also facilitate the dissolution of solid dosage forms.^[22] When dissolution was performed, within two minutes, chitosan?containing formulations gave the maximum release of drug ^[23]. This can be attributed to the fact that chitosan generously engulfs water when in contact with an aqueous medium and bursts due to the pressure exerted by the capillary action, thereby imparting instantaneous disintegration of the dosage form and resulting in the formation of a uniform dispersion in the surrounding medium which behaves like a true suspension formed inside the body leading to rapid dissolution of the drug. On the other hand, there were no significant findings between polymer content and dissolution rate of drug for the formulations containing HPMC and chitosan.^[24] The tablet prepared with Na?CMC alone showed a correlation that increasing the polymer content of the formulation decreased the dissolution rate of the drug. This can be explained by the fact that a high ratio of polymer content in the formulation increases the diffusional pathway and decreases the water uptake and erosion of the tablets so as to decrease the dissolution of the drug. After evaluation of the tablets, it was found that polymer ratios (0.5–5%) enable preparation of MMTs without changing the basic characteristics of the tablet, especially the disintegration and dissolution profiles.^[25]

CONCLUSION

mucoadhesive polymers at a ratio of 0.5?5?n be used in MMT formulations to provide the necessary time for carvedilol to be absorbed and protect it from the flushing action of saliva. When orally administered, carvedilol is well absorbed and becomes more bioavailable. As a result, MMT administration of carvedilol appears to be a promising alternative to traditional routes of drug administration.

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