Lec 11- MR intro

Question 1

Modified- release systems

Runnign order for lecture series

Answer 1

• Pharmaceutical market and drug delivery systems development
• Rationale for Modified Release products
• Role of polymers
• Design options and mechanism
  
  • Zero order, First-order, root t
• Types of MR products
  
  • Reservoir, matrix, swelling, osmotic
  • Timed release, rapidly dissolving products
• Problem solving

Question 2

Modified-release Systems (MR) &
Nomenclature

Answer 2

• Controlled release systems (CR)
• Extended Release (ER) or (XL) or Sustained release systems (zero order release profile)
  
  • Long-acting systems (LA)
  • Slow or sustained release systems (SR)
  • Slow acting systems (SA)
• Delayed release DR e.g. Enteric Coated (EC)
  
  • No release for a small period of time before immediate release profile (rapid increase in concentration)
• Therapeutic delivery systems (TDS)
  
  • Transdermal Therapeutic Systems (TTS)
• Rapid Action
  
  • Fast dissolving preparations e.g. ODTs (Zydis®)
  • Limit time for drug disintegration (must disintegrate within 30) dissolution then occurs faster
  • Even faster for buccal absorption’s (avoid 1st pass metabolism)

Question 3

Global Pharmaceutical Market

Answer 3

• Global pharmaceutical market
  
  • $837 billion
• Pharmaceutical growth worldwide was driven by
  
  • Increased longevity of populations
  • Rising wealth
  • Innovative new products
  • New applications for existing products

Question 4

Global Drug Delivery Market

Answer 4

• The global drug delivery market
  
  • $26bn in 2000 to approximately $60bn in 2006
• Global oral drug delivery market to be $37bn in 2006, and forecasts growth to $50bn by the end of 2010

Question 5

Reasons for Drug Delivery Systems Development

Answer 5

• Enhance efficacy and tolerance and increase compliance - PATIENT BENEFIT
• Key drivers of innovation
  
  • Poor solubility
  • Poor efficacy
  • Frequent dosing regimens of current drugs
• Broaden a product line
  
  • Extend patent life
  • Revenues fall by ~70% when patent expires
• Delivery for biotherapeutics

Question 6

Drug Delivery Systems Development

Answer 6

• Modified -release strategies may be required for delivery of novel proteins, peptides, DNA, vaccines
  
  • Only 40% of projects involving DDS are focused on novel compounds

Question 7

The Drug Development Process

Answer 7

Question 8

Drug Development of NCEs is Costly

Answer 8

• Average cost of developing NCE is now estimated to be as much as $800 million and are associated with high attrition rates
• Costs vary from around $500 million to $2,000 million depending on the therapy or the developing firm
• Alternative drug delivery systems can be developed at less than 10% of this cost
  
  • Much smaller risk of failure

Question 9

Formulation Development

Answer 9

• Lab scale= 5g
• Piolet= Kg’s
• Commercial= tons

Question 10

Limitations of Conventional Systems
1- Adverse Pharmacokinetics

Answer 10

• Many barriers between site of delivery and site of action
  
  • Frequent dose; 1^st pass metabolism; Harsh acidic condition;
    
    • Fraction of dose reaching site may be small due to
      
      • Poor absorption
      • Metabolism
      • Excretion
• High First-pass metabolism
  
  • Still usually inappropriate for controlled release by oral route
    
    • May be avoided by alternative route - e.g. nasal, transdermal

Question 11

Limitations of Conventional Systems
2- Duration of Action

Answer 11

• Dosage Interval
  
  • Short Half-life- frequent dosing is required
  • Variable half-life

Question 12

Limitations of Conventional Systems
3- Therapeutic concentration

Answer 12

Question 13

Drug Plasma Level with Conventional Multiple Dosing vs. Modified Release

Answer 13

Question 14

Limitations of Conventional Systems
4- Drug burden

Answer 14

• Conventional system may require high drug levels
• MR can reduce the drug burden
  
  • Less drug used in MR
    
    • Deliver locally to site of action
    • Largely retain drug at site
  • Contraceptive Progesterone
    
    • Delivered systemically 10 - 100 mg/d
    • Progestasert IUD 10 - 100 µg/d

Question 15

E.g. of Commercial Drug Delivery Systems based Products

Answer 15

• Reduction in frequency of treatment
  
  • Diclofenac – Voltarol Retard
• Improving bioavailability
  
  • Ciclosporin – Neoral microemulsion
• Fast Action
  
  • Diclofenac – Voltarol Rapid; Paracetamol - Actifast
• New delivery route
  
  • GTN – transdermal; Insulin – inhalation
• Pain-free delivery
  
  • Powderject, Bioject systems
• Taste-masking
  
  • Paediatric Formulations

Question 16

Modified-release Systems
Rationale

1) dosage
2) Compliance

Answer 16

1. Dosage
   
   • Controlled for fixed periods of time
   • Rate and duration specified
   • Reduced dosage compared to conventional systems
   • Increased efficiency
2. Compliance
   
   • Reduced dosage frequency
     
     • Especially when asymptomatic, elderly

Question 17

Modified-release Systems
Rationale

3) Commercial 4) Variety

Answer 17

3) Commercial

• Savenges due to better disease management
• Adding value to generics
• Market expansion
• Creating new markets
  
  • Novel therapies requiring specialised delivery

4) Variety

• Local delivery- Ocusert- pilocarpine
• Systemic delivery- glyceryl trinitrate
• Patient use- Nicotine patches
• Physician use

Question 18

Potential Limitations of modified systems

Answer 18

• General limitations
  
  • Oral products are subject to physiological variation
    
    • Limited duration (12 hour transit)
    • Entrapment in tract
  • Increase requirement for excipients
    
    • If biodegradable, need to consider the toxicity of by-products
  • Can be expensive
    
    • Materials
    • Fabrication process
  • A surgical operation may be required for implants
  • Difficulty in shutting off release if required

Question 19

Potential Limitations of modified systems

Answer 19

• Although the overall burden may be decreased
  
  • each unit may contain high drug levels
  • Potential for leads leading to inadequate control of toxicity
• Construction on the suitability of drug candidates
  
  • E.g. metabolic enhancement
  • conventional bolus delivery can saturate the metabolic enzyme system
  • Low, continuous levels of the drug may not saturate metabolic enzymes
    
    • Therefore more extensive metabolism can occur and can result in reduced bioavailability