1. Zade PS, Kawtikwar PS, Sakarkar DM. Formulation, evaluation and optimization of fast dissolving tablet containing tizanidine hydrochloride. Inter J Pharm Tech Res. 2009;1:34–42.
2. Ishikawa T, Watanabe Y, Utoquchi N, Matsumoto M. Preparation and evaluation of tablets rapidly disintegrating in saliva containing bitter-taste-masked granules by the compression method. Chem Pharm Bull. 1999;47:1451–4.[PubMed]
3. Omaima SA, Mohammed HA, Nagia MA, Ahmed SZ. Formulation and optimization of mouth dissolve tablets containing rofecoxib solid dispersion. AAPS Pharm Sci Tech. 2006;7:E1–9.[PMC free article][PubMed]
4. Simone S, Peter CS. Fast dispersible ibuprofen tablets. Eur J Pharm Sci. 2002;15:295–305.[PubMed]
5. 5th ed. 1.0. Strasbourg, France: 2005. European Pharmacopoeia 5.0; p. 628.
6. Habib W, Khankari R, Hontz J. Fast-dissolve drug delivery systems. Crit Rev Ther Drug Carrier Syst. 2000;17:61–72.[PubMed]
7. Li Q, Wei WX, Xiaofeng C, Tao H. Evaluation of disintegrating time of rapidly disintegrating tablets by a paddle method. Pharm Dev Tech. 2006;11:295–305.[PubMed]
8. Vikas A, Bhavesh HK, Derek VM, Rajendra KK. Drug delivery: Fast dissolve systems. Encycl Phar Tech. 2007;1:1104–14.
9. Sohi H, Sultana Y, Khar RK. Taste masking technologies in oral pharmaceuticals: Recent developments and approaches. Drug Dev Ind Pharm. 2004;30:429–48.[PubMed]
10. Pondell R. Taste masking with coatings, Coating technology. 1996
11. Zelalem A, Vibha P, Lokesh K, Arvind KB. Trends in pharmaceutical taste masking technologies: A patent review. Recent Pat Drug Deliv Formul. 2009;3:26–39.[PubMed]
12. Freudenberg K, Cramer F, Plieninger H. Inclusion compounds of physiologically active organic compounds. Ger Pat. 1953:895769.
13. Szejtli J, Szente L. Elimination of bitter, disgusting tastes of drugs and foods by cyclodextrins. Eur J Pharm Biopharm. 2005;61:115–25.[PubMed]
14. Fu Y, Yang S, Jeong SH, Kimura S, Park K. Orally fast disintegrating tablets: Developments, technologies, taste-masking and clinical studies. Crit Rev Ther Drug Carrier Syst. 2004;21:433–76.[PubMed]
15. Amidon GL, Lennernas H, Shah VP, Crison JR. Theoritical basis for a biopharmaceutics drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12:413–20.[PubMed]
16. Lindenberg M, Kopp S, Dressman JR. Classification of orally administered drugs on the world health organization model list of essential medicines according to the biopharmaceutical classification system. Eur J Pharm Biopharm. 2004;58:265–278.[PubMed]
17. Sharma S, Gupta GD. Farmulation and charracterization of fast dissolving tablet of promethazine theoclate. Asian J Pharm. 2008;2:70–72.
18. Dario L, Maria GB, Maria CL, Claudio JS. Development of prednisone: Polyethylene glycol 6000 fast release tablets from solid dispersion: Solid state characterization, dissolution behaviour, and formulation parameters. AAPS Pharm Sci Tech. 2007;8:221–228.[PMC free article][PubMed]
19. Singh J, Philip AK, Pathak K. Optimization studies on design and evaluation of orodispersible pediatric formulation of indomethacin. AAPS Pharm Sci Tech. 2008;9:60–6.[PMC free article][PubMed]
20. Marzia C, Francesca M, Giovanna C, Paola M. Fast dissolving tablets of Glyburide based on ternary solid dispersions with PEG 6000 and surfactants. Drug Deliv. 2007;14:247–55.[PubMed]
21. Sussanne B, Margareta D, Bo L, Hans L, Anders P, Marie W, et al. In vitro and In vivo evaluation of new sublingual tablet system for rapid oromucosal absorption using fentanyl citrate as the active substance. Eur J Pharm Sci. 2003;20:327–34.[PubMed]
22. Iman SA, Mona HA. in vitro and in vivo evaluation of a fast disintegrating lyophilized dry emulsion tablet containing Griseofulvin. Eur J Pharm Sci. 2007;32:58–68.[PubMed]
23. Sam C, Jean PR. Formulation and Production of Rapidly Disintegrating tablets By Lyophilization Using Hydrocholorothiazide as a Model Drug. Int J Pharm. 1997;152:215–25.
24. Abdelbary G, Prinderre P, Eouani C, Joachim J, Reynier JP, Piccerelle PH. The Preparation of Orally Disintegrating Tablets Using A Hydrophilic Waxy Binder. Int J Pharm. 2004;278:423–33.[PubMed]
25. Raguia AS, Iman SA, Rehab NS. In vitro and In vivo evaluation of nimesulide lyophilized orally disintegrating tablets. Eur J Pharm Biopharm. 2009;73:162–71.[PubMed]
26. Verley P, Yarwood R. Zydis–a novel fast dissolving dosage form. Manuf Chem. 1990;61:36–7.
27. Jinichi F, Etsuo Y, Yasuo Y, Katsuhide T. Evaluation of rapidly disintegrating tablets containing glycine and carboxymethylcellulose. Inter J Pharm. 2006;310:101–109.[PubMed]
28. Segar H. Drug delivery products and the Zydis fast dissolving dosage. J Pharm Pharmacol. 1998;50:375–83.[PubMed]
29. Corveleyn S, Remon J. Formulation of a lyophilised dry emulsion tablet for the delivery of poorly soluble drugs. Int J Pharm. 1998;166:65–74.
30. Chandrasekhar R, Hassan Z, AlHusban F, Smith A, Mohammed A. The role of formulation excipients in the development of lyophilized fast-disintegrating tablets. Eur J Pharm Biopharm. 2009;72:119–29.[PubMed]
31. Carstensen JT. New York: Wiley Interscience; 1977. Pharmaceutics of Solids and Solid Dosage Forms; pp. 11–5.
32. Van Campen L, Zografi G, Carstensen JT. An approach to the evaluation of hygroscopicity for pharmaceutical solids. Int J Pharm. 1980;5:1–18.
33. Chang RK, Guo X, Burnside BA, Couch RA. Fast-dissolving tablets. Pharm Technol N Am. 2000;24:52–8.
34. Blank RG, Mody DS, Kenny RJ, Aveson MC. Fast dissolving dosage form. US Patent 4,946,684. 1990 Aug 7;
35. Green R, Kearney P. Process for preparing fast dispersing solid dosage form. US Patent 5,976,577. 1999 Nov 2;
36. Lawrence J, Posage G. Bicovex rapidly disintegrating dosage form. US Patent 6,224,905. 1998 Dec 3;
37. Simone S, Peter CS. Fast dispersing ibuprofen tablets. Eur J Pharm Sci. 2002;15:295–305.[PubMed]
38. Katzner L, Jones B, Khattar J, Kosewick J. Blister package and packaged tablet. US Patent 6,155,423. 2000 Dec 5;
39. Jaccard TT, Leyder J. A new galenic form: lyoc. Ann Pharm Fr. 1985;43:123–31.[PubMed]
40. Lafon L. Galenic form for oral administration and its method of preparation by lyophilization of an oil-in-water emulsion. US Patent 4616047. 1986 Oct 7;
41. Gole D, Savall T, fu GL, Dale W, Paul K, Davies JD. Tastemasked resinate and preparation thereof. US Patent application 20050036977. 2005 Feb 17;
42. Iles MC, Atherton AD, Copping NM. Freeze-dried dosage forms and methods for preparing the same. US Patent 5,188,825. 1993 Feb 23;
43. Ford J. The current status of solid dispersion. Pharm Acta Helv. 1986;61:69–88.[PubMed]
44. Dobetti L. Fast melting tablets: Developments and technologies. Pharm Technol Drug Deliv. 2001;(Suppl):44–50.
45. Suresh B, Rajendar KM, Ramesh G, Yamsani MR. Orodispersible tablets: An overview. Asian J Pharm. 2008;2:2–11.
46. Bi Y, Sunada H, Yorinobu Y, Danjo K, Otsuka A, Iida K. Preparation and evaluation of a compressed tablet rapidly disintegrating in the oral cavity. Chem Pharm Bull. 1996;44:2121–7.[PubMed]
47. Watanabe Y, Koizumi K, Zama Y, Kiriyama M, Matsumoto Y, Matsumoto M. New compressed tablet rapidly disintegrating in saliva in the mouth using crystalline cellulose and a disintegrant. Biol Pharm Bull. 1995;18:1308–10.[PubMed]
48. Bi Y, Yorinobu Y, Sunada H. Rapidly disintegrating tablets prepared by wet compression method: Mechanism and optimization. J Pharm Sci. 1999;88:1004–10.[PubMed]
49. Sunada H, Bi Y. Preparation, evaluation and optimization of rapidly disintegrating tablets. Powder Technol. 2002;122:188–98.
50. Di CM. Flashtab and T-Mask Technologies, Paper presented at: Proceedings of the 7th International Glatt Symposium. 1997:1–9.
51. Cousin G, Bruna E, Gendrot E. Rapidly disintegratable multiparticulate tablet, US Patent 5,464, 632. 1995 Nov 7;
Fast-dissolving tablet formulations
Meeting the challenge
Diarrheal disease is the second leading killer of children under the age of five worldwide, responsible for approximately 1.3 million child deaths annually. It results from exposure to rotavirus as well as bacterial pathogens such as cholera, enterotoxigenic E. coli (ETEC), and Shigella, among others. A number of live-attenuated oral vaccines containing multiple bacterial strains are in development, giving hope to those that live in ETEC- and Shigella-endemic countries.
To obtain adequate heat stability, these candidate liquid vaccine formulations must be lyophilized (freeze dried), necessitating their reconstitution at the point of use. In this scenario, because the relevant bacterial strains are often incompatible, multiple vials containing each lyophilized strain would be required alongside a vial for the diluent and a reconstitution syringe to combine them—increasing costs, cold chain space requirements, preparation complexity, and the risk of error.
Novel technology solution
To address the potential challenges and costs associated with the complex production, storage, transport, and reconstituted delivery of these important vaccines, PATH has worked to apply existing fast-dissolving tablet (FDT) technologies to a trivalent candidate ETEC vaccine. Manufactured using a standard lyophilization process, our lead ETEC FDT formulation is stable at 12 months under refrigeration. Ongoing work has also produced an ETEC FDT formulation that is stable at ambient temperatures, with maintained viability for at least 3 months.
There are two potential means of delivering the ETEC vaccine tablets. When placed in the mouth, the small tablet disintegrates instantly in a modest amount of saliva, removing the risk of choking and making it safe for use in young children. The tablets can also be reconstituted in a diluent or buffer without need for a reconstitution syringe and then administered orally using a liquid dropper.
Value-added product presentation
Each tablet can be packaged in unit-dose blisters made from foil or other pharmaceutical-grade material, offering an inexpensive, scalable, and easy-to-use product presentation for live-attenuated vaccines containing single or multiple bacterial strains. Due to less expensive packaging material and an increased throughput achieved by lyophilizing smaller volumes, the tablet vaccines may prove to be less expensive to produce than lyophilized vaccines in glass vials. In addition, the stackable product presentation may minimize product volume and thus the space required for storage and transport, resulting in significant savings from a health system and cold chain capacity perspective.
Veterinary vaccine application
PATH has applied the FDT technology to other vaccines, including a veterinary vaccine that protects against Newcastle disease (ND), one of the biggest threats to poultry and the livelihoods of the rural poor globally. Commissioned by the Global Alliance for Livestock Veterinary Medicines, PATH developed a fast-dissolving ND vaccine tablet to facilitate the immunization of “backyard poultry” in developing countries—with the goal of improving stability, enabling dosing size flexibility, and expanding vaccine coverage and impact in low-resource rural settings. Additional technical collaborators on the work included the Southeast Poultry Research Laboratory of the US Department of Agriculture and the University of Washington.
Our journal article detailing the development of a heat-stable FDT formulation of ND vaccine was published in Veterinary Record and awarded the 2014 William Hunting Award, which is bestowed annually by the British Veterinary Association to a research paper considered to have made the most useful contributions to veterinary science. Read this PATH blog profile to learn more about this exciting achievement »
With our partners, we continue to explore the feasibility of producing ND vaccine tablets using equipment and materials that developing-country manufacturers already have or can easily and inexpensively access. Please contact us for more information on available technology transfers.
Potential drug applications
Oxytocin tablets. Currently, the prevention and treatment of postpartum hemorrhage (PPH) or excessive bleeding after childbirth requires an intramuscular injection or intravenous infusion of oxytocin, a drug that reduces bleeding by causing the uterus to contract. To more easily and effectively prevent and treat PPH in developing countries, where 99 percent of the global burden of maternal mortality resulting from PPH occurs, PATH is working to develop heat-stable, fast-dissolving oxytocin tablets for sublingual delivery.
The easy-to-use, heat-stable tablet format will enable traditional birth attendants and midwives to safely and effectively administer oxytocin with little to no training, expanding access to oxytocin in areas lacking formal health care facilities and reliable power for refrigeration. Its needle- and device-free presentation will also eliminate the risks associated with sharps use and disposal. In addition, the tablet’s compact blister packaging will simplify shipping, storage, and distribution logistics—helping to reduce costs for public health programs.
In collaboration with the South African Medical Research Council, pharmacokinetic evaluations of PATH’s fast-dissolving oxytocin tablet are scheduled to commence in 2016.
Tenofovir tablets. A number of antiretroviral medications exist for the treatment and prevention of HIV infection, including tenofovir, a drug indicated for adults and pediatric patients 2 years old or older. Tenofovir is also indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years or older.
In collaboration with CONRAD, PATH scientists are working to develop an easy-to-use, single-dose, fast-dissolving microbicide tablet formulation of tenofovir for vaginal mucosal delivery. Like oxytocin tablets, an inexpensive needle- and device-free presentation of tenofovir will enable the safe and effective administration of the drug with little to no preparation, training, or instruction. The tablet’s compact packaging will also reduce system costs by easing logistics. Altogether, such product attributes hold promise for increasing access to the drug and maximizing its public health impact in low-resource settings.