CONSIDERATION OF THE END USER AND THE LIMITATIONS DURING THE ORAL ADMINISTRATION DRUG DESIGN: CHALLENGE IN DIFFERENT AGE GROUPS

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1 CONSIDERATION OF THE END USER AND THE LIMITATIONS DURING THE ORAL ADMINISTRATION DRUG DESIGN: CHALLENGE IN DIFFERENT AGE GROUPS Adriana Quiroga Technical Manager Colorcon Latin South America 0

2 Summary General considerations when developing a ODS Safety and compliance FDA Approaches- Patients preference Shape, size and appearance- Survey Swallowability in vivo : How shape and Coating can make the difference Pediatrics considerations: Industry survey Conclusions 1

3 In Vivo In Vitro Considerations In-vivo Considerations In-vitro vitroassessment of Performance Gradient ph & absorption In-vivo performance Fed vs. fasted (mechanical stress) ph effect Physical appearance & size restriction Identify & Swallow (coating, color, shape) Release modulation or Bioequivalence Matching the desired profiles Appearance Removing potential confusion from customers Physico-mechanical properties Robust dosage for handling by supply chain & patient Drug release performance Disintegration & dissolution behavior Different media - resembling invivoconditions vs. pharmacopeial Quality control vs. developing similar in-vivo performance

4 Disturbing Facts. Medication errors cause 7,000 deaths each year (FDA) At least 1.5 million Americans are sickened, injured or killed each year by errors in prescribing, dispensing and taking medications (Washington Post) Treating the related injuries cost an estimated $3.5 billion a year ( Washington Post)

5 Patient Compliance Pharmaceutical Market Fails to Capture $188B U.S. Revenue and $564B Global Revenue Annually Due to Medication Non-Adherence 80% of Pharmaceutical Executives surveyed, felt that adherence was a HIGH or VERY HIGH priority for their company Reference: Estimated Annual Pharmaceutical Revenue Loss Due to Medication Non-Adherence, Capgemini Consulting (2012)

6 FDA Recalls

7 Regulatory Concerns Guidance Different strengths same look potential overdose IR & ER same look potential dosing errors Metformin - IR Metformin - ER Size - choking or lodging in the throat or gastrointestinal tract Tablet scores - possible efficacy concerns

8 Regulatory Concerns Guidance Friable tablets - difficult to remove intact from a blister pack or excessive dust in bottle

9 Summary so far. Safety of drug products is a big concern Regulatory organizations developing guidance to help the industry Design consideration when developing a formulation Choice of technology Physical attributes Use simple formulations & remove sources of error and variability Easy to troubleshoot

10 Technology Attributes Predictable / reproducible / low risk Broad applicability (dose/ solubility /chemistry) Rapid development timescale Cost not prohibitive No regulatory concerns (delays )/ low risk Know-how experience Patient friendly! No one technology has all the answers!

11 Identification & Branding Formulation: Hydrochlorothiazide, HPMC K100LV CR (30%), lactose 100 % Dissolved Round Caplet Pentagon Flat Effect of Shape Equivalent SA/V ratio Time(hrs)

12 Identification & Branding % Metformin HCl Released Uncoated Dumbbell Dumbbell-Opadry II 32K Dumbbell-Opadry II 85F9 Dumbbell-Opadry AMB Time (h) Color film coating and shape for better identification for health care providers and patients No effect on release profiles All trademarks, except where noted, are property of BPSI Holdings LLC

13 CONSUMER PREFERENCE SURVEY A PILOT STUDY

14 Consumer Preference Survey Objectives Pilot study to identify appearance specifications for handling & swallowing of tablets by patients Participants Age, Gender, Region and Dosing Regiment Tablet Attributes Size: 150, 300, 450, 600, 750, and 900mg Dimension: constant weight but tablet thickness was modified Shape: 8 different shapes tested Shade: light, medium, dark Finish: matte, semi-gloss, high-gloss

15 General Information 254 participants General population: US and UK 54% 46% Gender 25% 32% Female Male 43% Age

16 General Information Daily Weekly Monthly Other As needed How often do you take a tablet or capsule? How many tablets or capsules did you take in the allotted time?

17 General Information What is your preferred dosage form? 5% 20% 75% Tablet or Capsule Liquid No Preference Most of participants preferred tablet/capsule to liquid

18 Tablet Size Preference Which tablets do you think would be easiest to handle and swallow? 150mg 300mg 450mg 600mg 750mg 900mg 17

19 Ease of Handling and Swallowing For all shapes, 300mg was the most preferred size Consumer Preference Related to Tablet Size Least preferred 5.6 Mean Ranking Most preferred Tablet Weight (mg) ONE large tablet once a day preferred to 2 smaller tablets at different times of the day

20 Ease of Handling and Swallowing Top View Side View Oval Round Tablet Dimension Title med thick thin

21 Tablet Shape Which tablets do you think would be easiest to handle and swallow? Caplet Oval Shield Half Moon Kidney Triangle Square Double Arrow 20

22 Ease of Handling and Swallowing 7.0 Consumer Preference Related to Tablet Shape 6.0 Mean Ranking caplet double arrow half moon kidney oval shield square triangle Oval and caplet shapes were the most preferred and were common to the participants

23 Ease of Handling and Swallowing Uncoated Matte Semi gloss Comments: Gloss glossy tablets are easier to swallow caplet shape is easier to swallow 3.5 Consumer Preference on Tablet Gloss Mean Ranking Most preferred coat gloss hgloss uncoated

24 Ease of Handling and Swallowing What are the most important attributes for handling and swallowing a tablet? Mean Ranking color dim gloss shade shape size Tablet size is the most important attribute

25 Ease of Handling and Swallowing What are the most important attributes to make a tablet memorable or distinctive? Mean Ranking color dim gloss shade shape size On the other hand, COLORof the tablet became the most important attribute to make a tablet memorable

26 Preference of Consumers (US and UK) Shape Prefer Oval and Caplet; Triangle and Shield most distinctive Dimension Prefer medium thickness Shade Differs by Gender, Region, and Age Size Prefer 300 mg for all shapes Gloss Prefer high gloss; least prefer matte and uncoated tablets

27 Consumer Preference Study

28 Swallowability in vivo Case Study 11/7/

29 Clinical Measurement of Esophageal Transit (Swallowability): Using Gamma Scintigraphy Capsules vs. caplets; uncoated vs. coated caplets and oval tablets 48 volunteers, split into two groups Dosage forms were radio-labeled with 99Tc and taken with 30 ml water Dynamic scanning was conducted for 10 min Images were taken every 0.5 sec for the first 30 sec and every 15 sec thereafter 30 sec static image was taken at 30 min post-dose to confirm formulation was in the stomach Angle 80 º

30 Oral Dosage Forms Studied Soft Gelatin Capsule Caplet Hard Gelatin Capsule Oval Tablet Hard gelatin capsule: White, opaque, size 0 filled with poloxamer 188 Soft gelatin capsule: Commercially available cod liver oil capsules Caplet: placebo Oval tablet: placebo All dosage forms weighed ~ 1,000 mg Oval tablets and caplets were either uncoated or coated with one of three clear film coatings (Opadry, complete film coating system, Opadry II, high performance film coating system, or Opaglos 2, high gloss film coating system)

31 Scintigraphic Analysis The total dynamic scan was used to present an overview of the transit time. Specific areas were noted to show the mouth, esophagus and stomach. The esophagus was further divided into 3 regions of interest -each representing one third of the esophagus. This was used for further analysis of the dynamic scan. Time Median transit time and the incidence of slow transit ( 15 sec) across available subjects were determined.

32 Tablets stuck approx 10 minutes Esophageal Transit Time (sec) Individual Subject Data Coated and Uncoated Oval Tablets Uncoated Opadry Complete Film Coating System Opadry 85 series Opaglos 2 High Gloss Film Coating System Volunteer Number

33 Improvement of Tablet Swallowability Through Film Coating Overall film coated tablets show improved swallowability over uncoated tablets Only uncoated tablets actually stuck in subject s esophageal tracts Improvement to swallowability can improve patient compliance Improved transit time can decrease potential for bitter API taste Certain actives can cause esophageal burns, improved swallowability very important in this case

34 Pediatrics Considerations 11/7/

35 Industry Survey on Development Strategy for Pediatric Dosage Forms Short telephone survey by Dr Jenny Walsh and Colorcon. Eleven global pharmaceutical companies in Europe, USA and India Key subject areas: Platform technologies Modified release (MR) Selection and use of excipients, including colors Palatability

36 Pediatric Dosage Forms Formulator Preference Platform Technologies Currently Used for Pediatric Dosage Forms Solid Oral Dosage Forms Liquid/Other Dosage Forms 35

37 Platform Technologies for Pediatric Products All participants were developing solid oral dosage forms for children Where possible, one dosage form developed to cover whole proposed pediatric patient age range BUT, dosage form selection depended upon age Oral Dosage Form Tablets & Capsules ODTs & FDTs Multi-particulates Dispersible tablets Powder for dispersion Oral liquids Paediatric drops Reported Appropriate Age Range Older children 6/7 years or above (depends on size) From 2 years Young children Weaned infants Babies Young children

38 Key Findings from the Survey Solid dose used widely and based on adult dosage form Low risk approach for the formulator MR is not a priority MR is high risk due to lack of understanding of pediatric pharmacokinetics and pharmacodynamics. Evidence that excipients have already been use in pediatric products Greatest need is for taste-masking Improves patient compliance

39 Approaches to Taste-masking from Survey Results % Respondents Flavours Sweeteners Barriers (coating API) Barriers (coating granules) Taste masking methods Lipidics Complexation Ion exchange resins

40 Technology Selection Tablets and Mini-Tablets Uses standard equipment and standard excipients Applicable to most age groups Granules Either: manufactured granules with a taste-mask coating; Or, pure API particles coated with a taste-mask coating. Standard and specialized equipment can be used Applicable to a wide age range

41 Technology Selection Pellets and Spheres Drug layered non-pareils or extrusion spheronised pellets Specialized equipment required. Larger particle size is not suitable for all age groups. ODT or Dispersible Tablets Specialist Excipients API still needs to be taste-masked Film Strips Specialist Equipment and Experience API still needs to be taste-masked

42 Summary Risk assessment & management through Sound science based formulation Quality & consistency of raw materials used in the formulation Patient in mind Patients perceptions Shape Swallowing Size Remove potential medication error Range of ages Pediatrics as an important topic Increase patient compliance Combine best technology with best results Delight patients, insurers & drug manufacturers

43 Q&A 42