(M1430-03-20) Mini Tablets as a Compliant and Flexible Pediatrics Delivery System

Purpose: Minitablets are a multiple unit dosage form with a size of less than 3.0 mm in diameter with great flexibility to deliver appropriate doses to the pediatric age group. They can be given in different number, according to dosage requirements, with no special prerequisite of formulating age group customized dosage tablets. Minitablets are a friendly drug delivery system for patients having impaired swallowing issues with a polypharmacy therapy. The objective of the study was to develop melatonin (as a model drug) minitablets, by direct compression, for pediatrics to replace conventional size tablets at the same strength of dose.

Methods: Formulation for 3 mg melatonin strength (in each minitablets) consists of 20 % Melatonin (BOC Science), 78.53 % of PEARLITOL^® 200 GT (Mannitol/Roquette) and 1.47 % of magnesium stearate (Roquette). Screened blend of melatonin and PEARLITOL^® 200 GT (sieve no 30) was mixed in TURBULA^® mixer (WAB T2F) at 49 rpm for 5 min. The lubricant, magnesium stearate, was added to the blend and mixed at 49 rpm for 2 min. Approximately, 10 mg of sample blend was taken from three different spots for content uniformity evaluation. The powder mix was compressed using 2.5 mm standard concave punch (Natoli Engineering) single tip using STYL’One Evo compaction simulator (MedelPharm) simulating Korsch XL 400 tablet press. Formulation mix was compressed at four different compression forces (0.65 kN, 1.30 kN, 1.66 kN, and 2.10 kN) at 20 RPM with a target minitablet weight of 15 mg. Breaking force was checked at each compression force using hardness tester. Disintegration of minitablets was tested at 37°C in 800 mL of distilled water using Sotax DT50 disintegration tester. High performance liquid chromatography (HPLC) at a wavelength of 277 nm was used to quantify melatonin uniformity in powder blend and to evaluate its dissolution profile. Conventional marketed regular size melatonin tablet at same strength 3mg/tablet were used as reference for dissolution comparison. To reach within linearity range of HPLC method, three tablets are needed in each vessel. Dissolution of three tablets (9 mg melatonin) was done in each vessel (n=3) of 500 mL distilled water at 37 °C with a paddle speed of 100 rpm. Samples were taken at 5 min, 10 min, 15 min, and 30 min from each vessel and filtered using 0.20 µm nylon filter for melatonin quantification by HPLC.

Results: The flowability of the blend was excellent, with a Hausner ratio of 1.11. The advantage of having excellent flow is indicated by the low weight variation of 2% (10 minitablets average weight was 15.4 ± 0.32 mg, Figure 1). Despite the small diameter die of 2.5 mm, minitablets display weight consistency. The formulation blend displayed 99.5 % content uniformity, evaluated by HPLC, with a standard deviation of 0.45. In comparison, the weight variation in a commercial was higher (weight of three tablets from 902.91 mg to 934.28 mg). Minitablets disintegration time is 2-3 min at all compression forces and approximately 100.0 % dissolution in 30 min (Figure 2) without any disintegrating agent in the formulation. Marketed tablets displayed 115.0 % of dissolution in 30 min.

Conclusion: 1. PEARLITOL^® 200 GT is an excellent filler for direct compression due to its good flowability leading to improved compressibility, prevents capping ensuring it is the perfect choice for tablets of any size. 2. Mannitol being a water-soluble excipient, yet not hygroscopic, increases tablet shelf life. 3. Decreasing 20 times the conventional tablet size, mini tablets are a patient friendly dosage form and offer flexibility in dose adjustment for any age group.

Figure 1: Comparison of minitablet (15mg weight) and regular size tablet (300 mg weight) at the same dose strength of 3 mg of melatonin