1. Can Novel Delivery Systems Deter Rx Drug Abuse?
Robert Bianchi
Prescription Drug Research Center – Bradenton FL
Atlanta GA – April 18, 2017

2. DISCLAIMER
Robert Bianchi has disclosed no relevant, real or apparent personal or professional financial relationships with proprietary entities that produce health care goods and services.

3. Learning Objectives
Government and industry response to the Rx drug abuse epidemic
FDA Guidance to Industry
In vitro testing to evaluate abuse-deterrent opioids
Success of ADF?

4. Current Situation
CDC has declared Rx abuse as an epidemic. More Americans abuse Rx than cocaine, heroin, inhalants & hallucinogens COMBINED
In 2013 approximately 43,982 overdose deaths occurred, one death every 12 min*
Of these deaths, 22,767 (51.7%) were attributed to Rx drug abuse – 16,235 were attributed to opioids – 6,973 were attributed to benzodiazepines*
*CDC Centers for Disease Control and Prevention. National Vital Statistics System mortality data. (2015)

5. Insatiable Appetite
Rx abuse is the fastest growing drug problem in the United States (4.6% of world population)
US consumes 80% of the worlds supply of pain killers
99% of the global hydrocodone supply
Congressional testimony by the American Society of Interventional Pain Physicians May 2011

6. What caused this phenomenon?
Prescription drugs are more available due to the development of new products and increased prescriptions
Prescription drugs do not fall under the clandestine cloud of illegal drugs such as heroin, ecstasy or methamphetamine
Rx drugs are safe - FDA approved & Dr. prescribed
Friends and family use & supply
Drugs are frequently obtained free of cost

7. Contributing Causes Doctor Shopping Over prescribing
Stolen or forged prescriptions
Pharmacy thefts
Internet pharmacies
Pain clinics

8. Pain Clinic aka Pill Mill

9. Pill Mill seizure

10. Government Response Increased monitoring & investigations of
Manufactures, Distributors, Pharmacies, Doctors
Prescription Drug Monitoring Programs
DEA “Take Back Program” 447 tons of Rx medications May 2016
Educational programs and publications for prescribers and patients
Requires sponsors to develop Risk Evaluation Mitigation Strategy (REMS)

11. Government Response
FDA issued guidance to industry in April 2015, describing how to demonstrate if an opioid formulation contains abuse deterrent properties.
April 2013 FDA allows labeling concession to Purdue for reformulated OxyContin (physical or chemical properties that deter IV and nasal abuse). Original formulation available reformulated OxyContin
FDA issued draft guidance for generics 3/2016
Encouragement to develop Abuse Deterrent Formulations (ADF)

12. FDA GUIDANCE
The Guidance describes four categories of recommended studies for supporting and evaluating claims of abuse-deterrence:
Premarket studies:
Laboratory Manipulation and Extraction Studies (Category 1)
Pharmacokinetic Studies (Category 2)
Clinical Abuse Potential Studies (Category 3)
-Post marketing Studies (Category 4)

13. ABUSE DETERRENT OPTIONS
Physical/Chemical barriers – Physical barriers can prevent chewing, crushing, cutting, grating, or grinding. Chemical barriers can resist extraction of the opioid using common solvents like water, alcohol, or other organic solvents (OxyContin).
Agonist/Antagonist combinations – An opioid antagonist can be added to interfere with, reduce, or defeat the euphoria associated with abuse. The antagonist can be sequestered and released only upon manipulation of the product (Embeda).

14. ABUSE DETERRENT OPTIONS
3. Aversion – Substances can be combined to produce an unpleasant effect if the dosage form is manipulated prior to ingestion or a higher dosage than directed is used. (Oxecta oxycodone/niacin)
4. Prodrug – A prodrug that lacks opioid activity until transformed in the gastrointestinal tract. Can be unattractive for intravenous injection or intranasal routes of abuse (e.g. Vyvanse amphetamine).

15. Industry Response Develop consortium to explore options and advise FDA
Develop formulations that deter abuse
Educate prescribers and patients
Conduct research to develop new pain medications and new delivery systems

16. OXYCODONE HCL ADF DOSAGE FORM
OxyContin – Purdue 2010 &13
10, 20, 40, 60, 80 mg 9, 13.5, 18, 27, 36 mg
Resistant to crushing Resistant to crushing and extraction PEO snorting & IV
Xtampa ER –Collegium 2016

17. OXYCODONE HCL ADF DOSAGE FORM
Troxyca ER – Pfizer 2016 Targiniq ER – Purdue 2014
10, 29, 30, 40, 60, 80 mg 10, 20, 40 mg naltrexone HCL + naloxone

18. HYDROCODONE ADF BITARTRATE DOSAGE FORMS
Hysingla ER – Purdue 2014
Vantrela ER – Teva 2017
No image available - capsule shaped tablet in various colors
20, 30, 40, 60, 80, 100 mg Resistant to crushing & extraction
15, 30, 45, 60, 90 mg
Resistant to extraction

19. MORPHINE SULFATE ADF DOSAGE FORM
Morphabond -2015
Inspirion
Embeda – Pfizer 09/2014
Arymo - Egalet 2016
15, 30 & 60 mg
15, 30, 60, 100 mg
Resistant to crushing and extraction
10, 20, 30, 40, 60, 80 mg + naltrexone HCL
Resistant to crushing and extraction

20. Laboratory Manipulation and Extraction Studies
Evaluate various simple and sophisticated mechanical and chemical ways a drug can be manipulated.
(1) Defeating or compromising the controlled release of
an opioid from extended-release formulations – PSR tools, pre-treatment (heat, freezing, microwave)
(2) Preparing an IR or ER formulation for alternative
routes of administration - extraction solvents
(3) Separating the opioid antagonist, if present, from the opioid
agonist, thus compromising the product’s abuse-deterrent
properties.

21. Coffee mills used to grind tablets
Shown lids have been used for approx 15 runs each
Examples on broken blades from two mills
Photos by permission, Egalet, Copenhagen DK, 2010.

22. Laboratory Manipulation and Extraction Studies
For a product with potential for snorting, the particle size distribution should be established, using various tools – crush, cut, grate, mill.
For a product with potential for snorting, the particle size distribution should be established.
Photo by permission, National Medical Services Laboratories (NMS) 2014

23. SMOKING ABUSE
For a product with potential for smoking, the vaporization temperature and degradation temperature of the opioid in salt and base form should be determined.

24. INTRAVENOUS ABUSE
For a product with potential for intravenous injection, the opioid concentration in a small injection volume and the viscosity (syringeability and injectability) of the injection fluid should be determined.

25. Photos by permission, Egalet, Copenhagen DK, 2010.
INJECTABILITY
Photos by permission, Egalet, Copenhagen DK, 2010.

26. SYRINGABILITY
Photo by permission, National Medical Services Laboratories (NMS) 2014

27. DOSE DUMPING
The ingestion of alcoholic beverages with extended release opioids poses serious safety concerns i.e. uncontrolled immediate release of drug.
The FDA now recommends in vitro drug release studies to determine if alcohol causes enhanced release of opioid using varying concentrations of alcohol – 10, 20, 40, 60, 80, 100%

28. Reformulated OxyContin (2010) first ADF
OUTCOMES
Reformulated OxyContin (2010) first ADF
Australian participants (N=522) rated reformulated oxycodone as more difficult to prepare and inject and less pleasant to use compared to the original formulation.
Reformulated oxycodone was primarily swallowed (15%), with low levels of recent successful injection (6%), chewing (2%), drinking/dissolving (1%), and smoking (<1%)
Int J Drug Policy Dec;26(12): doi: /j.drugpo Epub 2015 Jun 7.

29. OUTCOMES
Significant reduction, past-month abuse (N = 10,784) after its introduction, from 45% in January to June 2009 to 26.0% in July to December 2012, apparently owing to a migration to other opioids, particularly heroin - Cicero
JAMA Psychiatry May;72(5): doi: /jamapsychiatry
There was a 41% general reduction in observed abuse potential in opioid dependent patients (N=140,496) for the reformulated product compared to the original- Omidian A
J Develop Drugs 4:141. doi: /

30. OUTCOMES
The selection of OxyContin as a primary drug of abuse decreased from 35.6% of respondents (N=2,566) before the release of the abuse-deterrent formulation to just 12.8% 21 months later, Cicero.
N Engl J Med 2012; 367: July 12, 2012DOI: /NEJMc

31. SUMMARY
ADF not a panacea – positive results demonstrated for OxyContin
Unintended consequence of migrating to other opioids (Opana ER), primarily heroin
No product has addressed multiple pill abuse & no product is abuse proof
The reformulation of OxyContin represents one of the largest disruptions to date to the supply of abusable opioids.
More formulations in the pipe line

32. Thank you Robert P. Bianchi
President and Chief of Scientific and Technical affairs Prescription Drug Research Center Penguin Drive
Bradenton FL 34212
– Cell