Research Article: Comparison of Different Liquid and Semisolid Vehicles Selected for Oral Administration of Pellets and Minitablets with Diazepam: In Vitro Investigation

Date Published: July 31, 2020

Publisher: Springer International Publishing

Author(s): Hanna Kotlowska, Marta Szymanska, Malgorzata Sznitowska.

http://doi.org/10.1208/s12249-020-01761-6

Abstract

The acceptability and palatability of a dosage form are extremely important to improve patient compliance. Mixing oral solid dosage forms with food carriers is often necessary to ease swallowing and provide the taste-masking effect. The present research investigated how a liquid or semisolid carrier influences the disintegration time and drug dissolution rate of pellets and minitablets with diazepam. The disintegration of pellets and minitablets in liquid carriers (water, milk and apple juice) was determined using a texture analyser. Dissolution tests were performed for the dosage forms dispersed in gel vehicles (2% carmellose and 0.5% carbomer gels) or applesauce. The disintegration of minitablets in water and apple juice was fast (1 min), but it slowed to 3 and 5 min in milk and gel vehicles, respectively. The pellets disintegrated in liquid carriers within 3 min. The drug dissolution rate in 0.1 M HCl depended on the gel viscosity in this medium. The preserved high viscosity of a carmellose gel inhibited the dissolution of diazepam. On the other hand, the viscosity of the carbomer gel decreased rapidly, and in effect, the dissolution rate of diazepam from the incorporated pellets or minitablets was comparable to the dissolution from loose pellets or minitablets.

Partial Text

Swallowing difficulties (dysphagia) are becoming more common. Approximately 70–90% of the elderly and 25–45% of children experience swallowing problems (1). The lack of commercially available, age-appropriate medicinal products forces patients and caregivers to manipulate the dosage form, including breaking or crushing the tablets or mixing them with food or drink. All of these actions may reduce clinical efficacy or increase the risk of adverse reactions when the chemical and physical stability or bioavailability is affected (2). Sprinkles are a new medicinal product of multiparticulate solid oral dosage forms dedicated for mixing with soft food or liquids (3).

The sieve analysis demonstrated that all prepared pellets were in the size range of 0.8–1.4 mm, with the main fraction (60%) in the range of 1.0–1.25-mmE, and this fraction, with good size uniformity, was selected for further studies. Moreover, good sphericity was demonstrated in microscopic pictures (Fig. 2), and high sphericity index 0.98 was calculated. The minitablets met the European Pharmacopoeia (9th edition) requirements for mass uniformity with an average mass of 12.1 mg and the maximum percentage deviation from mean value of 2.9%. The obtained dosage forms were characterized by good mechanical strength, which is required for packing into capsules or sachets. The friability was below 0.4%, and the hardness was 12.4 N (± 1.4 N) and 15.5 N (± 0.89 N) for pellets and minitablets, respectively.Fig. 2Stereoscopic microscope image of pellets with the dimensions for calculation the sphericity

The present study showed how the type of a dispersing vehicle influenced the in vitro properties of a dosage form designed for sprinkling. An alternative method for the determination of the disintegration of pellets and minitablets in liquids, which better correlated with conditions in the mouth compared with a pharmacopoeial test, was introduced. The limitation of this method is the applicability only to low viscosity carriers because problems with the endpoint determination occurred for high viscosity gels. The standard dissolution tests performed for pellets and minitablets dispersed in semisolid vehicles demonstrated the validity of these tests during the development of sprinkle formulation. The results showed that the carbomer gel may be an excellent vehicle for the sprinkles due to the pH-dependent viscosity because the stiff gel structure was not preserved in an acidic pH (stomach), and the viscosity of the vehicle did not influence the release of diazepam from pellets and minitablets. Furthermore, the use of a paddle apparatus may be recommended for testing these formulations rather than a basket apparatus because more reliable and reproducible results were obtained.

 

Source:

http://doi.org/10.1208/s12249-020-01761-6

 

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