ORALLY DISINTEGRATING TABLETS: BRIDGING THE DIVIDE FOR COMPLIANCE

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1 ORALLY DISINTEGRATING TABLETS: BRIDGING THE DIVIDE FOR COMPLIANCE Joseph A. Zeleznik Associated Director R&D JRS PHARMA 2981 Route 22; Suite 1 Patterson, NY j.zeleznik@jrspharma.com What Drives the ODT Market? Economic value 2004 Approx $2.4 bn up 20% from molecules account for approximately 86% of the market $3 bn A 25% increase Projected growth Expected to grow at 20% annually More recent information supports this annual growth rate Drivers include: Increased popularity More accessible and improved technologies 1

2 The ODT Market Economic value Patient expectations Recent market studies indicate that more than half of the patient population prefers ODTs to other dosage forms 70% of consumers would ask their doctors for ODTs 70% purchase ODTs, if available >80% prefer ODTs to regular tablets or liquids W.PfisterandT.Gosh,"OrallyDisintegratingTablets:Products,Technologies,andDevelopmentIssues, Pharm.Technol.29(10), (2005). What is an ODT? Solid dosage form, typically as a tablet Exhibits rapids disintegration/dissolution within the oral cavity through rapid hydration Disintegration occurs in the absence of mastication or chewing and without the need for water The disintegrated/dissolved dosage form is then swallowed 2

3 Orally Disintegrating Tablet Defined U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) December 2008 Guidance for Industry: Orally Disintegrating Tablets A solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue. Dosage form characteristics Tablet mass: NMT 500 mg Disintegration time: NMT 30 seconds In vitro using USP disintegration test method <701> Issues Associated with the Guidance Tabletdisintegration Invitrodisintegrationtesting;USPmethod<701> Nodirectinvivocorrelationfortabletdisintegration Invitrodisintegrationrequires900mlwater Oralcavityproducesapproximately10mlsaliva USPdisintegrationtester:basketwithdisks Doesnotadequatelysimulatetonguein work thetablet DoesnotspecificallyaddressODTswith>30sdisintegration Tabletsize Mediumtohighdoseapplications APIdosesinexcessof~250mg ManyODTtechnologiescannotcarrywithoutexceeding500mgtotalmass if atablet intended for use as an ODT weighs more than 500 mg, its ability to perform effectively as an ODT shouldbejustifiedbasedonproductperformance. Globalharmonization Europe theeuropean Pharmacopeia definesorodispersibledosageforms ashavingadisintegration timeof lessthan3min. Nosizerequirementisrecommended/specified 3

4 Dosage Form Selection Considerations Demographic Who is the target? Marketing Color, shape, and size preferences Condition What illness is being treated? Excipient Technology What is available? What is the cost? Dosage form considerations complicate compliance Compliance: a patient's (or doctor's) adherence to a recommended course of treatment. WHY ODT? 4

5 For many, the medicine taking process starts here, be it atablet, caplet, capsule, chewable, sublingual, or some other solid oral dosageform. For some, this is where the problems start as well! Many patients are dysphagic and find ingesting tablets hard to swallow! Factors Related to Compliance Issues Forgetfulness Poor rapport with physician Few symptoms Chronic illness Prescription not collected or not dispensed Purpose of treatment not clear Perceived lack of effect Real or perceived side-effects Instructions for administration not clear Unattractive formulation, such as unpleasant taste Complicated regimen Cost Physical difficulty in complying opening medicine containers, handling small tablets, travel to place of treatment, and dysphagia (issues with swallowing 5

6 Dysphagia Causes Diseases of the nervous system Cerebral palsy Parkinson's disease Throat or neck injuries Diseases of the esophagus Cancer Acid reflux Age Geriatric Pediatric Stroke or head trauma Infection and irritation Birth defects Psychosomatic Perception Perception is everything. After all, what would seem to be an acceptabletabletorcapsuletotheaveragepatient might seem as a unacceptable challenge for many! 6

7 Orally Disintegrating Tablet Advantage Fast, easy, and convenient No water required Tablets can be taken virtually anywhere Discrete administration Broad application Suitable for numerous indications and patient types Improved compliance Why Orally Disintegrating Tablets? Solid dose form for ALL! Old and young alike Overcomes issues with dysphagic patients Unable or difficult to swallow tablets efficiently A real problem with regimens requiring many tablets Chronic pain abatement Benefits for treatment adversely affected by water intake Stress urinary incontinence Sleep disorders, including restless leg syndrome Veterinary applications for companion animals Third-world potable water issues Approximately 17% of the global population has little or no access to suitable drinking water Patient compliance Non compliance is ineffective and costly 7

8 Non-compliance costs us all! When tablet regimens are not adhered to, whether in whole or in part, then there is waste! Waste is costly and drives prices up. It also leads to reduced patient health which costs the insurance companies and the government, increasing the burden on us. The cost of Non-Compliance Place on your tongue and swallow then spit out when nobody is looking. 8

9 The Cost of Non-Compliance A WHO study estimates that only 50% of patients suffering from chronic diseases in developed countries follow treatment recommendations 1 It is estimated that non-compliance with medication adds over US $100 bn to the U.S. health care system annually 2 Approximately 6% of total health care spend Increase hospitalization rates 2 Approximately 11% of hospitalizations due to poor or noncompliance of prescription medicine Over one million people per year in the U.S. 1 Sabaté, E. (ed.): "Adherence to Long term Therapies: Evidence for Action". World Health Organization. Geneva, pp. ISBN [1] National Pharmaceutical Council Approaches to Improving Compliance Make dosage form more acceptable Reduce size Improve shape Change to easier administration Chewable Liquid Suspension Effervescent Breakable Orally disintegrating tablet 9

10 Hot Topic Fast Dissolve/Disintegrating Forms (BUCCAL SYSTEMS) Film Technology Orally Disintegrating Technology Convenient, discrete administration Available ODT Technologies Thin films Sugar floss Compacted tablets Molded Lyophilized Compacted tablets 10

11 Available ODT Technologies Thin films Advantages Rapid disintegration Elegant presentation Packaging Discrete administration Disadvantages API loading Film integrity Manufacturing cost Dispensing Packaging Stability» Physical» Chemical Dispensing issues Thin films Available ODT Technologies Sugar floss Advantages Rapid disintegration Content uniformity Disadvantages API loading Manufacturing complexity Friability Packaging Blisters 11

12 Thin films Sugar floss Available ODT Technologies Molded Advantages Rapid disintegration Content uniformity Unique shapes Marketing Product differentiation Disadvantages API loading Manufacturing complexity Friability Packaging Blisters Thin films Sugar floss Molded Lyophilized Available ODT Technologies Advantages Rapid disintegration Unique shapes Marketing Product differentiation Disadvantages API loading Manufacturing complexity Friability Packaging Blisters Elegance 12

13 Thin films Sugar floss Molded Lyophilized Available ODT Technologies Compacted tablets Advantages API loading Manufacturing ease Standard equipment Simplified development Packaging flexibility Bottles or blisters Cost Disadvantages Disintegration compared to other technologies Thin films Sugar floss Molded Lyophilized Available ODT Technologies Compacted tablets The one thing common to all orally disintegrating tablet products is the relianceon tastemaskingtechnologies 13

14 API Taste Masking Almost always required for orally soluble APIs Most, if not all, APIs possess unpleasant taste Technologies Microencapsulation Chelation Complexation Taste blocking Most result in a bulking-up of API Unwanted mass Additional excipient loading Can add significant cost to API and final dosage form And do not ignore flavor technologies Flavor Considerations Flavors may contribute to, or be a part of, taste masking approach and/or technology choice Flavors may be applied individually or collectively Different flavors are experienced at varying locations within the oral cavity, on the tongue, and into the throat Multiple flavors in combination may be beneficial within the same dosage form Multiple flavors in combination change patient experience when taking medicine Vanilla with orange or mint-mojito Flavors are not universally accepted throughout the globe. Geography can influence flavor choice Cultural differences could affect flavor acceptance Even within the same geography Flavor selection/acceptability can be age related Tastes change with age 14

15 Examples of Existing Excipients and Systems Zydis Cardinal Health $$$$$ Advatab Eurand $$$$ FlashTab Ethypharm $$$ Pharmaburst SPI $$$ Licensing and royalty agreement required Licensing and royalty agreement required Eurand taste masking required Licensing and royalty agreement required Licensing and royalty agreement required Ludiflash BASF $$$ Bulk powder sale F-Melt Fuji $$ Bulk powder sale PROSOLV ODT JRS PHARMA $$ Bulk powder sale Most of these are strongly polyol-based with virtually no insoluble portion with PROSOLVODT&F-Meltastheexceptions. Some Commercial ODT Product Examples Technology Commercial examples API Dose (mg) Excipients Zydis Claritin Reditab Loratidine 10 Citric acid, gelatin, mannitol, flavor Feldene Melt Piroxicam 10, 20 Gelatin, mannitol, aspartame, citric anhydrous Maxalt-MLT Rizatriptan 5, 10 Gelatin, mannitol, aspartame, flavor Pepcid RPD Famotidine 20, 40 Gelatin, mannitol, aspartame Zyprexa Zydis Olanzapine 5, 10, 15, 20 Zoltan ODT Ondansetron 4, 8 Orasolv Remeron Soltab Mirtazepine 15, 30, 45 Durasolv Tempra First Tabs APAP 80, 160 NuLev Hyoscyamine sulfate Zomig ZMT Zolmitriptan 2.5 Gelatin, mannitol, aspartame, methylparaben sodium, proplyparaben sodium Aspartame, gelatin, mannitol, methlyparaben sodium, proplyparaben sodium, flavor Magnesium stearate, mannitol, MCC, polymethacrylate, povidone, sodium bicarbonate, starch, sucrose, flavor Aspartame, CSD, crospovidone, flavor, magnesium stearate, mannitol, MCC Mannitol, MCC, crospovidone, aspartame, sodium bicarbonate, citric acid, CSD, magnesium stearate, flavor 15

16 ODT Matrices as Multi-component Systems Most matrices/technologies are multi-component Many are co-processed during manufacture by suppliers Does this complicate quality/regulatory status? Should it? Almost all contain one or more polyols Mannitol seems the polyol of choice Negative heat of solution Cooling effect during disintegration/dissolution in oral cavity Aids with compliance Some are completely soluble in nature Is this desirable? Does inclusion of insoluble materials offer benefit? Some insoluble material can offset grittiness from taste masking Particularly microencapsulation Aids with compliance ODT Challenges Manufacturers Struggles Rapid Disintegration Taste Masking Smooth/Creamy Mouth feel Packaging (Bottles vs. Blisters) Compliance Low Friability Ease in Manufacture Ease in Use Carrying Capacity This is what we re trying to achieve! 16

17 Summary Guidance is in place U.S. and Europe Remember, it is a guidance Global harmonization is needed in definitions and scope Noncompliance is an issue No demographic category is immune to noncompliance Noncompliance is wasteful & costly Unnecessary hospitalizations can result Taste masking is necessary for most APIs Limiting factor in development & manufacture Increases in API mass results Flavors individually or in combination provide assistance Not all flavors acceptable in every situation Orodispersible dosage forms can improve compliance ODTs provide an economical means of developing and manufacturing desirable dosage forms ODTs offer many benefits over ingestible tablets Fast, easy, discrete administration Overcomes potable water issues as well as indications where water is undesirable ODTs are desirable by most patients polled Offers one of best approaches to securing optimum patient compliance Regardless of demographics 17