Orally disintegrating tablet

clonazepam ODT blister pack and tablet

An orally disintegrating tablet or orodispersible tablet (ODT) is a drug dosage form available for a limited amount of over-the-counter (OTC) and prescription medications. ODTs differ from traditional tablets in that they are designed to be dissolved on the tongue rather than swallowed whole.^{[1][2][3][4][5][6][7][8][9][10][11]} The ODT serves as an alternative dosage form for patients who experience dysphagia (difficulty in swallowing) or for where compliance is a known issue and therefore an easier dosage form to take ensures that medication is taken. Common among all age groups, dysphagia is observed in about 35% of the general population, as well as up to 60% of the elderly institutionalized population ^[12][13] and 18-22% of all patients in long-term care facilities ^[14] During the last decade, ODTs have become available in a variety of therapeutic markets, both OTC and by presciption. An additional reason to use an ODTs is the convenience of a tablet that can be taken without water.

History

Tablets designed to dissolve on the buccal (cheek) mucous membrane were a precursor to the ODT. This dosage form was intended for drugs that yield low bioavailability through the digestive tract but are inconvenient to administer parenterally, such as steroids and narcotic analgesics.^[15] Absorption through the cheek allows the drug to bypass the digestive tract for rapid systemic distribution. Not all ODTs have buccal absorption and many have similar absorption and bioavailability to standard oral dosage forms with the primary route remaining GI absorption. However, a fast disintegration time and a small tablet weight can enhance absorption in the buccal area. The first ODTs disintegrated through effervescence rather than dissolution, and were designed to make taking vitamins more pleasant for children.^[16] This method was adapted to pharmaceutical use with the invention of microparticles containing a drug, which would be released upon effervescence of the tablet and swallowed by the patient.^[17] Dissolution became more effective than effervescence through improved manufacturing processes and ingredients (such as the addition of mannitol to increase binding and decrease dissolution time).^[18] Catalent Pharma Solutions (formerly Scherer DDS) in the U.K., Cima Labs in the U.S. and Takeda Pharmaceutical Company in Japan led the development of ODTs.

The first ODT form of a drug to get approval from the U.S. Food and Drug Administration (FDA) was a Zydis ODT formation of Claritin (loratadine) in December 1996.^[19] It was followed by a Zydis ODT formulation of Klonopin (clonazepam) in December 1997,^[20] and a Zydis ODT formulation of Maxalt (rizatriptan) in June 1998.^[21] The regulatory condition for meeting the definition of an orally disintegrating tablet is USP method 701 for Disintegration. FDA guidance issued in Dec 2008 is that ODT drugs should disintegrate in less than 30 seconds.^[22] This practice is under review by the FDA as the fast disintegration time of ODTs makes the Disintegration test too rigorous for some of the ODT formulations that are commercially available.

Manufacturing/packaging

The processes used to manufacture orally disintegrating tablets include loose compression tabletting, a process which is not very different than the manufacturing method used for traditional tables and lyophilization processes. In loose compression, ODTs are compressed at much lower forces (4 – 20 kN) than traditional tablets. However, since ODTs are compressed at very low forces due to the need to them to be soft enough to disintegrate rapidly in the mouth, issues of material sticking to the die walls can be challenging. Typically, as in most tablet blends, lubricants such as magnesium stearate are added to the blend to reduce the amount of material that may stick to the die wall. Differences may be the use of disintegrating aids, such as crospovidone, and binding agents that aid in mouth feel, such as microcrystalline cellulose. Primarily, ODTs contain some form of sugar such as mannitol, which typically serves as the major diluent of the ODTs, and is also the primary contributor to the smooth and creamy mouth feel of most ODTs. Lyophilized ODT formulations may use proprietary technologies but can produce a tablet that has a faster disintegration rate, the Zydis ODT typically dissolves in the mouth in less than 5 seconds without water.

ODTs are available in HPDE bottles (Parcopa) or individually sealed in blister packs to protect the tablets from damage, moisture, and oxidation. Because ODTs are soft in nature, the ability to successfully package an ODT in a bottle is difficult. However, CIMA Labs markets their Durasolv ODT as being able to be placed into bottle for commercial sale, while CIMA's Orasolv is marketed for blisters only. Zydis ODT tablets manufactured by Catalent Pharma Solutions are delivered in a blisterpack. The differences between the two CIMA products are proprietary, however, the primary difference is expected to be the use of microcrystalline cellulose (MCC), such as Avicel PH101, in the Durasolv product. MCC serves multiple purposes in an ODT but in the case of CIMA's products, it acts as a binder, increasing the internal strength of the tablet and making it more robust for packaging in bottles.

ODTs currently or previously available

Product:	Manufactured By/For:	Active ingredient:	Category:	Indication:	Intended Age:
Abilify Discmelt[23]	Otsuka America/Bristol-Myers Squibb	aripiprazole	Atypical antipsychotics	Schizophrenia, Bipolar disorder, adjunct therapy for Major Depressive Disorder[23]	13 years+ for Schizophrenia, 10 years+ for Bipolar disorder, adults for MDD[23]
Alavert Quick Dissolving Tablets	Wyeth	Loratadine	Anti-histamines	Allergy	6 years+
Allegra ODT	Sanofi Aventis	Fexofenadine	Anti-histamines	Allergic rhinitis, Urticaria[1]	6-11 years[1]
Aricept ODT	Eisai Co.	Donepezil	Acetylcholinesterase inhibitors[2]	Alzheimer's disease[2]	adults[2]
Benadryl FastMelt	Pfizer	Diphenhydramine	Anti-histamines	Allergy	6 years+
Calpol Fast Melts	McNeil Healthcare UK	Paracetamol	Analgesics	Pain	6 years+
Clarinex RediTabs	Schering-Plough	Desloratadine	Anti-histamines	Allergy	6 years+
Claritin RediTabs	Schering-Plough	Loratadine	Anti-histamines	Allergy	6 years+
Clonazepam ODT	Par Pharmaceutical	Clonazepam	Benzodiazepines	Anxiety, Panic Disorder, Seizure Disorders[24]	infants+[24]
FazaClo	AzurPharma	Clozapine	Antipsychotics	treatment-resistant Schizophrenia[25]	adults[25]
Fluimucil	Alpex Pharma SA / Zambon Group	N-Acetylcysteine	Mucolitic	Cold and Cough	Group over 16
Jr. Tylenol Meltaways	McNeil Consumer Healthcare	acetaminophen	Analgesics, Anti-pyretics	Pain, Fever	6 years+
Klonopin Wafers[26]	Roche	clonazepam	Benzodiazepines	Panic Disorder, Seizure Disorders[26]	infants+ for seizure disorders, adults for Panic Disorder[26]
Lamictal ODT [2]	Eurand / GlaxoSmithKline	lamotrigine	Anticonvulsant	Bipolar I Disorter, Epilepsy	18+ for bipolar, 2+ for seizure
Loratadine Redidose	Ranbaxy	loratadine	Antihistamines	Allergy	6 years+
Maxalt-MLT	Merck & Co.	Rizatriptan	Triptans/Serotonin agonists	acute Migraine[3]	18 years+[3]
Meloxicam 7.5 & 15 mg Orodispersible Tablets [3]	Alpex Pharma (UK) LTD	Meloxicam	NSAIDs	osteoarthritis,rheumatoid arthritis and ankylosing spondylitis	16 years+
Mirtazapine ODT	Teva Pharmaceuticals	Mirtazapine	Antidepressants	Major Depressive Disorder[4]	adults[4]
Niravam	Schwarz Pharma	Alprazolam	Benzodiazepines	Anxiety, Panic Disorder	Adults 18+[27]
Nurofen Meltlets	Reckitt Benckiser	Ibuprofen	NSAIDs	Pain, Fever, Inflammation	12 years+
Ondansetron ODT	Teva Pharmaceuticals	Ondansetron	Antiemetics	Nausea, Vomiting[5]	4 years+[5]
Orapred ODT	Sciele Pharma	Prednisolone	Corticosteroids	Asthma, severe Allergy, Hemolytic anaemia, Stevens-Johnson syndrome, certain types of Tuberculosis; acute treatment of arthritis, bursitis, COPD, Leukemia, Lupus, Multiple sclerosis, Ulcerative colitis[6]	adults and children weighing over 44lbs/20.1 kg[6]
Parcopa	Schwarz Pharma	Carbidopa/levodopa	DDC inhibitors [carbidopa]	Parkinson's disease[7]	adults[7]
Prevacid SoluTab	Takeda Pharmaceuticals	Lansoprazole	Proton pump inhibitors[8]	Gastro-oesophageal Reflux Disease (GERD), Ulcers[8]	1 year+[8]
Remeron SolTab	Schering-Plough	Mirtazapine	Antidepressants	Major Depressive Disorder[4]	adults[4]
Risperdal M-Tab	Janssen	Risperidone	Atypical antipsychotics	Schizophrenia, Bipolar disorder, Irritability associated with Autistic disorder[9]	13 years+ for Schizophrenia, 10 years+ for Bipolar disorder, 5 years+ for Autism[9]
Striant Buccal	Columbia Laboratories	Testoterone	[[]]	Male Sexual Dysfunction
Suprenza www.alpex.com	Alpex Pharma / Citius	Phentermine	Amphetamine	Weight control	Adults
UNISOM SleepMelts	Eurand / Chattem	Diphenhydramine	Anticholinergic	Nighttime Sleep Aid	Adults and children 12 years+[28]
Zelapar	Valeant Pharmaceuticals Int'l	Selegiline	Monoamine oxidase inhibitors (MAOIs)[10]	adjunct therapy in Parkinson's disease[10]	adults[10]
Zofran ODT	GlaxoSmithKline	Ondansetron	Antiemetics	Nausea, Vomiting[5]	4 years+[5]
Zomig-ZMT	AstraZeneca	Zolmitriptan	Triptans/Serotonin agonists	Migraine[11]	adults[11]
Zyprexa Zydis	Eli Lilly and Company	Olanzapine	Atypical antipsychotics	Bipolar disorder, Schizophrenia[29]	adults [29]

ODTs under development

Product	Manufacturer	Active ingredient	Category	Indication	Intended Age Group
Citalopram ODT[30]	Biovail[30]	Citalopram	SSRIs	Major Depressive Disorder[31]
Metoclopramide Zydis[32]	Salix Pharmaceuticals[32]	Metoclopramide	Dopamine receptor antagonists	short-term therapy for GERD, acute diabetic gastric stasis[32]	adults[32]
Reglan ODT[33]	Schwarz Pharma[33]	Metoclopramide	Dopamine receptor antagonists	short-term therapy for GERD, acute diabetic gastric stasis[33]	adults[33]
Tramadol/Acetaminophen ODT[30]	Biovail[30]	Tramadol/Acetaminophen	Opioid analgesic [Tramadol][34]	Pain[30]	adults[34]
Zolpidem ODT[30]	Biovail[30]	Zolpidem	Nonbenzodiazepine Hypnotics[35]	Sleep disorders[30]	adults[35]

See also

• Phagophobia - fear of swallowing
• Pnigophobia - fear of choking
• Sugar alcohol - a family of chemicals common in ODTs to enhance the mouth feel of the tablet as it disintegrates

References

1. ^ ^{a b c} Allegra Prescribing Information
2. ^ ^{a b c d} Aricept Prescribing Information
3. ^ ^{a b c} Maxalt Prescribing Information
4. ^ ^{a b c d e} Remeron SolTob Prescribing Information
5. ^ ^{a b c d e} Zofran Prescribing Information
6. ^ ^{a b c} Orapred Prescribing Information
7. ^ ^{a b c} Parcopa Prescribing Information
8. ^ ^{a b c d} Prevacid Prescribing Information
9. ^ ^{a b c} Risperdal Prescribing Information
10. ^ ^{a b c d} Zelapar Prescribing Information
11. ^ ^{a b c} Zomig Prescribing Information
12. ^ Sastry, S. et al., Pharm. Sci. & Tech. Today 3: 138-145, 2000.
13. ^ Groher ME, Bukatman MS. The prevalence of swallowing disorders in two teaching hospitals. Dysphagia. 1: 3-6, 1986.
14. ^ Layne KA, Losinski DS, Zenner PM, Ament JA. Using the Fleming index of dysphagia to establish prevalence. Dysphagia. 4: 39-42, 1989.
15. ^ US 5073374, Mccarty, John A., "Fast dissolving buccal tablet", published 1991 
16. ^ US 5223264, Wehling, Fred; Steve Schuehle & Navayanarao Madamala, "Pediatric effervescent dosage form", published 1993 
17. ^ US 5178878, Wehling, Fred; Steve Schuehle & Navayanarao Madamala, "Effervescent dosage form with microparticles", published 1993 
18. ^ US 4946684, Blank, Robert G.; Dhiraj S. Mody & Richard J. Kenny et al., "Fast dissolving dosage forms", published 1990 
19. ^ FDA Drug Details for Claritin RediTabs
20. ^ FDA Drug Details for Klonopin Wafer
21. ^ FDA Drug Details for Maxalt-MLT
22. ^ FDA Guidance for Industry Orally Disintegrating Tablets
23. ^ ^{a b c} Abilify Prescribing Information
24. ^ ^{a b} Clonazepam ODT Prescribing Information
25. ^ ^{a b} FazaClo Prescribing Information
26. ^ ^{a b c} Klonopin Prescribing Information
27. ^ [1]
28. ^ Unisom Drug Facts
29. ^ ^{a b} Zyprexa Prescribing Information
30. ^ ^{a b c d e f g h} Biovail Product Pipeline
31. ^ Citalopram Prescribing Information
32. ^ ^{a b c d} Salix Pharmaceuticals Acquires Patent–Protected Metoclopramide–Zydis
33. ^ ^{a b c d} FDA Drug Approval for Reglan ODT
34. ^ ^{a b} Ultracet Prescribing Information
35. ^ ^{a b} Ambien Prescribing Information