Taste Masking Orally Disintegrating Tablet Formulations

As appeared in July 2019 Tablets & Capsules Copyright CSC Publishing www.tabletscapsules.com orally disintegrating tablets

Taste masking orally Sreeramaiah Arunkumar, disintegrating tablet formulations Vinay Muley, Michael Baumann, and Rina Chokshi DuPont Nutrition & Biosciences

Orally disintegrating tablets (ODTs) are rising in popularity significant part of the global population—particularly because of their ease of administration and improved patient com- geriatric, pediatric, and psychiatric patients—has diffi- culty swallowing solid oral dosage forms (SODFs). pliance, creating the need for excipients that enable both taste ApproximatelyA 40 to 60 percent of adults living in assist- masking and rapid disintegration. This article describes a method ed-living facilities and nursing homes are reported to for taste masking ODT formulations by coating the active phar- have trouble swallowing [1,2]. And each year, approxi- maceutical ingredient (API) with an aqueous ethylcellulose mately 569,000 children, ages three to seven, also have polymer dispersion combined with different plasticizers. difficulty swallowing [3]. Others who suffer from drug-induced dysphagia or deglutition disorders face sim- ilar difficulties. When developing a new drug product, it is imperative to formulate inclusive, patient-friendly options to enable compliance. Copyright CSC Publishing Figure 1 Preparation of ECD dispersion and coating of paracetamol by fluid-bed processor (FBP)

Mixing (6 hours) Mixing (30 minutes) FBP (top spray) ECD DBS PVA-PEG copolymer

Preparing the dispersion Adding the Coating Curing the API granules in a tray dryer (25 percent solid based pore former the API on EC solids)

Orally disintegrating tablets have most often been used for taste masking oral sus- The ODT is a patient-friendly drug delivery solution tained-release dosage forms [8]. that’s quickly rising in popularity because of its ease of This article describes a study in which researchers administration, accurate dosing, and simple storage demonstrated how to taste mask ODT formulations by requirements. The global ODT market is predicted to coating the API with an ECD polymer prior to tableting. expand at a compound annual growth rate of 11.5 per- This method of taste masking works by physically trap- cent, from $11.4 billion in 2017 to $27 billion by the end ping the porous powder in the thin, hydrophobic ECD of 2025 [4]. matrix backbone, which masks the API’s bitter taste. The Unlike other drug delivery systems and conventional hydrophobicity of ECD can then be reduced by increas- immediate-release solid dosage forms, ODTs disintegrate ing its porosity via a suitable pore former, such as polyvi- in the mouth within 5 to 30 seconds without chewing or nyl alcohol-polyethylene glycol graft copolymer. The requiring water. ODTs are popular with hospitals and coating can also help prevent gastric inactivation and healthcare providers because they yield improved com- hepatic metabolism of the API. pliance, particularly for patients whose swallowing reflex The researchers chose paracetamol as a model API is compromised, which is estimated to be up to 25 per- because of its high bitterness and ease of availability and cent of hospitalized patients [5,6]. handling. For the ECD polymer, they chose DuPont’s ODTs have also been widely supported in the pediat- Aquacoat ECD, which does not contain any plasticizer, ric realm, as the platform combines the administration so it provides formulation flexibility. By varying the sol- flexibility of a solid dosage form with the swallowability ids content of the coating formulation and combining the of a liquid dosage form [7]. ECD with different plasticizers, such as triethyl citrate In addition to disintegration time, an ODT’s organo- (TEC) or dibutyl sebacate (DBS), formulators can opti- leptic properties (taste, aftertaste, and mouthfeel) are crit- mize the tasting masking for the ODT dosage form. ical attributes because they impact patient acceptance Because DBS provides improved film performance, quick and overall medication adherence. Since most APIs are coalescence, and improved taste perception, it is an ideal bitter, sour, metallic, or otherwise unpleasant tasting, the plasticizer for preparing an ECD-based dispersion for API in an ODT must be completely taste masked while taste-masking purposes. the tablet disintegrates, especially since the ODT Coating the API remains in the mouth longer than other SODFs. The researchers first prepared the coating dispersion Taste masking ODTs by blending the ECD with the DBS plasticizer for a mini- In recent decades, the pharmaceutical industry has mum of six hours to ensure homogeneity. A 10 percent invested heavily in new technologies and made great w/w aqueous solution of polyvinyl alcohol-polyethylene strides its ability to mask unpleasant tastes and odors. As glycol graft copolymer (Kollicoat IR) was added to the a result, formulators have a broad range of format options ECD dispersion to function as a pore former, and the dis- and can now develop taste-masked drug products in the persion was stirred for an additional 30 minutes. form of granules, films, tablets, and more. For the coating trials, the researchers chose a parac- One technology that is widely used for taste masking etamol dose that was equivalent to a common clinical is the aqueous ethylcellulose dispersion (ECD). ECD dose. As shown in Figure 1, they prepared the ECD and polymers have been gaining popularity since 1958 but DBS coating dispersion (25 percent of EC solids) in a flu- Copyright CSC Publishing Table 1 Figure 2 Preparation of ECD dispersion Preparation of taste-masked paracetamol ODT tablets Amount Solid Ingredient (grams) (grams) Assumptions

Aquacoat ECD 300 90 25 percent Paracetamol + Blend Alubra PG 100 + Avicel PH 105 + 10 Sucralose + Sift based on EC Pearlitol 160 C + minutes, Strawberry (#60) Plasticizer 22.5 22.5 solids Ac-Di-Sol SD 711 sieve flavor + SiO (#40) 2 Kollicoat IR 10 10 Blend Water 484.17 484.17 (10 minutes) Total coating solution 816.67 816.67 Compress into tablets (12 millimeter)

idized bed processor (ACG Pharma Technologies, GPCG 1.1) using a top-spray technique that applied the Table 2 coating solution onto the paracetamol with optimized Formulation of taste-masked paracetamol tablets coating parameters. To ensure complete coalescence, the researchers cured the resultant granules for approximately 24 hours in a tray dryer with a thermal treatment at S. No. Ingredient Percentage 60°C. The percentage composition of coating solution Paracetamol granules ingredients is listed in Table 1. 1 (30 percent Aquacoat ECD+DBS) 69.15 Formulating the tablets 2 Pearlitol 160 C 20.85 The researchers then used direct compression tech- 3 Avicel PH 105 4.10 niques to formulate the ODT tablets, as shown in Figure 2. The formulation contained the taste-masked parac- 4 Ac-Di-Sol SD-711 3.00 etamol granules, mannitol (Pearlitol 160 C), microcrystal- 5 Silicon dioxide 0.30 line cellulose (Avicel PH-105) as compression aid, and 3 percent w/w croscarmellose sodium (Ac-Di-Sol SD-711) 6 Sucralose, micronized 0.50 as superdisintegrant. All ingredients were passed through 7 Strawberry flavor 0.60 a #40 sieve and mixed in a blender for 10 minutes. The selected lubricant (Alubra PG 100), flavor, sweetener, 8 Alubra PG 100 1.50 and silicon dioxide (SiO ) were then sifted through a #60 2 Total 100 sieve and added to the formulation. The researchers mixed the coated paracetamol and the ODT materials into a uniform blend and compressed the blend into tablets using 12-millimeter round punches. Figure 3 The prepared tablets were evaluated for in-process qual- ity parameters such as friability, hardness, disintegration, Taste-masking efficiency of test ODT formulation and dissolution. The percentage composition of tablet versus commercial formulation ingredients for the formulation is listed in Table 2. Conclusions Marketed paracetamol While preparing taste-masked API granules, the ODT researchers found that coating weight gain up to 25 per- cent w/w ECD-DBS dispersion yielded the most favorable Test results. The formulated tablets provided better sensory paracetamol attributes compared to a commercially available formula- ODT tion, as shown in Figure 3. As Figure 4 shows, the in vitro dissolution profile of the formulated tablet shows complete 0 1 2 3 4 drug release in less than one hour, indicating no specific Taste perception: 0 = bitter; 5 = not bitter sustained barrier to drug release. The weight variation of Copyright CSC Publishing 5. M. F. Brin and D. S. Younger. “Neurologic disorders Figure 4 and aspiration.” Otolaryngolic Clinics of North America. 1988. In vitro dissolution profile of test ODT formulation Vol. 21, pages 691-699. versus commercial formulation 6. K. A. Layne, D. S. Losinski, P. M. Zenner, and J. A. Ament. “Using the Fleming index of dysphagia to estab- lish prevalence.” Dysphagia. 1989. Vol. 4, pages 39-42. 100 7. Felipe L. Lopez, Terry B. Ernest, Catherine Tuleu and Mine Orlu Gul. “Formulation approaches to pediatric 80 oral drug delivery: benefits and limitations of current platforms.” Expert Opinion on Drug Delivery. 2015. Vol. 12, 60 No. 11, pages 1,727-1,740. 8. M. A. Frohoff-Hulsmann, A. Schmitz, and B. C. 40 Lippold, “Aqueous ethyl cellulose dispersions containing API release (%) plasticizers of different water solubility and hydroxypro- 20 Test paracetamol ODT pyl methylcellulose as coating material for diffusion pel- Marketed paracetamol ODT lets. I. Drug release rates from coated pellets.” International 0 0 10 20 30 40 50 Journal of Pharmaceutics. 1999. Vol. 177, No. 1, pages 69-82. Time (minutes) Sreeramaiah Arunkumar is formulation & development scientist, technology & innovation, India; Michael Baumann is global all the tablets was within acceptable limits of pharmaco- strategic marketing manager, immediate release pharmaceutical poeia standards. Overall, the coated particles saw improved flow characteristics and compaction properties. dosage forms; Rina Chokshi is global leader for regional and field When the model tablets were tested for in-process marketing; and Vinay Muley is leader, pharmaceutical excipi- quality control and taste-masking performance, the ents, technology & innovation, India, for DuPont Nutrition & researchers found that both the mouthfeel and disintegra- Biosciences. For questions or comments about this article, please tion time were acceptable to patients. Researchers noted contact Lindsay Torriero, brand & global content leader, DuPont that such characteristics could be improved by optimiz- ing the coating parameters and ODT formulation design. Nutrition & Biosciences ([email protected]). By optimizing the parameters, manufacturers can ensure better product development, including efficient perfor- mance of ODTs with required taste-masking ability. The model formulation shows that, by using ECD in fluidized-bed processor coating, drug product manufactur- ers can provide patient-friendly ODTs with a pleasant mouthfeel and good taste-masking qualities. This has the potential to both increase patient adherence and broaden the possibilities of APIs suitable for ODT formulation. T&C References 1. S. R. Barczi, P.A. Sullivan, and J. Robbins. “How should dysphagia care of older adults differ? Establishing optimal practice patterns.” Seminars in Speech and Language. 2000. Vol. 21, No. 4, pages 347-361. 2. H. Siebens, E. Trupe, A. Siebens, et al. “Correlates and consequences of eating dependency in institutional- ized elderly.” Journal of the American Geriatrics Society. 1986. Vol. 34, No. 3, pages 192-198. 3. L. I. Black, A. Vahratian, and H. J. Hoffman. “Communication disorders and use of intervention ser- vices among children aged 3-17 years: United States, 2012.” NHS Data Brief. 2015. No. 205. Hyattsville, MD: National Center for Health Statistics. 4. “Global market study on orally disintegrating tab- lets: Anti-psychotics drug class segment to record market attractiveness index of 2.4 over the forecast period 2017 – 2025.” Persistence Market Research. August 2017.