Semisolid-filled Capsules of Carvedilol for Improving Dissolution Behaviour

The present investigation was aimed at enhancing the dissolution properties of carvedilol, a poorly water-soluble drug using a combination of solid dispersion and semisolid-filled capsule. The use of lauroyl polyoxyl-6 glycerides as a carrier in a semisolid base to improve the dissolution behaviour of carvedilol was investigated. Solid dispersions containing carvedilol were prepared and percent drug content was assessed. In vitro dissolution studies, Fourier-transform infrared spectroscopy, differential scanning calorimetry and scanning electron microscopy were used to characterize solid dispersions.

Semisolid-filled capsules of carvedilol were prepared using different bases, and their percent drug content and in vitro dissolution behaviour were studied. The optimized solid dispersion containing 3 parts of poloxamer and 0.2 part of Plasdone K90 with respect to 1 part of carvedilol was incorporated into an optimized semisolid base containing 20 parts of lauroyl polyoxyl-6 glycerides with respect to 1 part of carvedilol). The combination of solid dispersions and semisolid-filled capsule produced a significant increase in the rate of release of the drug. The differential scanning calorimetry thermogram of the optimized semisolid formulation did not show carvedilol peak, which suggested that carvedilol had dissolved in the base in the presence of lauroyl polyoxyl-6 glycerides. The dissolution of carvedilol was improved and the lag time of drug release was reduced in the semisolid-filled capsules in which lauroyl polyoxyl-6 glycerides was used as a carrier.

Most of the active pharmaceutical ingredients discovered recently through screening and combinatorial chemistry are poorly water-soluble drugs[1,2]. The therapeutic efficacy of an orally administered drug mainly depends on its solubility, dissolution and absorption[3,4]. One of the major challenges in drug development lies in enhancing the solubility, dissolution and bioavailability of poorly water-soluble drugs[5]. Various approaches that have been used to improve the dissolution behaviour of such drugs involve the use of salt formation[6], self-emulsifying drug delivery systems[7], inclusion complexes[8], co-crystallization[9], solid dispersions (SD)[10] and semisolid matrix filled capsules (SSCs)[11]. SD techniques, of all these approaches, have been used most to enhance the solubility of water-insoluble drugs. SSCs are being used more recently because of several benefits such as reduced weight variations, content uniformity, enhanced stability and improved dissolution of poorly water-soluble drugs[12].

The major disadvantage of the use of a single approach to enhance dissolution is that in emergencies such as heart attacks, myocardial infarctions and asthma, the requirement of dissolution enhancement of a poorly water-soluble drug to achieve therapeutic concentration within a short period might not be achieved[11]. Any delay in achieving therapeutic concentration due to poor dissolution would result in a delayed onset of action and might worsen the emergency situation. Thus increasing the aqueous solubility and dissolution behaviour of the drug is of therapeutic importance. A combination of approaches and material attributes might provide results in terms of dissolution. Selecting a suitable material with the desirable attributes in relation to solubility enhancement is more vital in shaping a drug delivery device. Lauroyl polyoxyl-6 glycerides (LP6G) is a transesterified product of a C12-18 glyceride and polyethylene glycol, with a melting point of about 35-40°[13]. It is an inert, waxy, semisolid material with unique emulsifying properties[14,15]. LP6G is preferred for faster drug release due to its high hydrophilic lipophilic balance (HLB)[16].

Carvedilol (CV) is a non-cardioselective β-blocker used in the treatment of hypertension, congestive cardiac failure and myocardial infarction[17]. If the therapeutic concentration of CV is to be achieved immediately, as in an emergency, the dissolution at the absorption site should be increased within a short period of time. Several approaches have been used to improve the dissolution of CV, such as the use of SD[18], inclusion complexes[19] and nanotubes[20]. Yuvaraja and Khanam developed a SD containing CV using different carriers such as β-cyclodextrin (βCD), hydroxypropyl-β-cyclodextrin (HPβCD), tartaric acid (TA), polyvinyl pyrrolidone K-30 (PVP K-30) and poloxamer-407 (PLX-407). They found that the solubility of CV was increased because of increased wettability and transformation of the crystalline form of the drug to an amorphous form[18]. Zheng et al. successfully improved the dissolution of CV by synthesizing nanotubes[20]. No reports have yet been reported the incorporation of LP6G as a carrier of CV in a semisolid base formulation.

Considering the benefits of a combination of approaches and materials with the required attributes, the present study was carried out to formulate a combination of SD and SSC of CV that contained LP6G. The combined effect of adding LP6G and using SD to improve the solubility and reduce the lag time of dissolution of CV at the absorption site is reported for the first time in the present study. Read the full publication here

Neha Chavan, D. J. Singhavi^*, Shagufta Khan and L. Rathi
Indian J Pharm Sci 2019;81(6):1099-1106

DOI: 10.36468/pharmaceutical-sciences.608