Lec 18- Chronotherapeutic drug delivery

Question 1

The body clock

Answer 1

• 1:00 A.M
  
  • Pregnant women are most likely to go into labor
  • Lymphocytes (white blood cells) are at their peak
• 2:00 A.M
  
  • Growth hormone levels are highest
• 4:00 A.M
  
  • Asthma attacks are most likely
• 6:00 A.M
  
  • Onset of menstration is most likely
  • Plasma insulin is lowest
  • BP and heart rate begin to rise rapidly
• 7:00 A.M
  
  • Symptoms of allergic rhinitis (hayfever) are worst

Question 2

The body clock

Answer 2

• 8:00 A.M
  
  • Calories are burned most readily
  • Risk of heart attack and stroke is highest
  • Symptoms for rheumatoid arthritis are worst
• 10:00 A.M
  
  • GI bleeding is most likely from ulcers
• NOON
  
  • Level of hemoglobin in blood peak
• 1:00 P.M
  
  • Serum ChE PEAKS
• 3:00 P.M
  
  • Grip strength, respiratory rate and reflex sensitivity highest- athletics good time

Question 3

The body clock

Answer 3

• 4:00 P.M
  
  • Body temperature, pulse and blood pressure peak
• 6:00 P.M
  
  • Urinary flow is highest
• 9:00 P.M
  
  • Pain threshold is lowest
• 11:00 P.M
  
  • Skin is most reactive; allergic responses more likely

Question 4

Chronotherapy

Answer 4

• Chronotherapeutics
  
  • Is delivery of drug to the body to the right site (specific part of the GIT, skin, lungs etc), at the right time, at the optimal dose
  • Addresses changes in the body’s circadian rhythms

Question 5

Timed-release products

Delivery during sleep period

Answer 5

• Ischaemic heart disease
  
  • Anti-anginal agents, Anti-Hypertensives, Anti-Arrthymics, Anticoagulants
  • Reduce morning morbidity and mortality
• Asthma
  
  • Bronchodilators- reduce nocturnal symptoms
• Arthritis
  
  • Anti-inflammatory agents- reduce early morning symptoms

Question 6

TimeReleased products

Delivery during sleep period

Answer 6

• Sleep problems
  
  • Hypnotics- reduce early awakening
• Parkinson’s disease
  
  • Antiparkinson agents- to reduce early morning tremors
  • Anticholinergics- reduce nocturnal symptoms
• Pain
  
  • Analgesics- to avoid nighttime awakening
• HIV
  
  • Antivirals- to replace midnight dosing

Question 7

Site-specific (Colonic) delivery

Answer 7

• Inflammatory bowel disease
  
  • Anti-inflammatory agents e.g. in Ulcerative Colitis
• Oral Peptide Delivery
  
  • To avoid degradative eenvironment of upper GIT

Question 8

Timed-release Products

Chronotherapeutic delivery

Answer 8

• Covera-HS (Searle)
  
  • Verapamil 180mg and 240mg
• Mimics the body’s typical 24hr circadian variations in BP and HR
• Single oral dose at bedtime
  
  • Slow release rate at night
  • Peak concentration in early waking hours when BP and HR are maximal

Question 9

Timed-release Products

Covera-HS

Answer 9

• DDS (COER-24, Alza) consists of 2 parts
• Controlled onset
  
  • 4-5 hour delay in a release after bedtime administration
    
    • A layer delayed release within the tablet before you get to the drug
  • 3 hours before awakening, drug release begins
  • Peak effects from about 6 a.m. to noon
• Extended-release
  
  • Slow release portion extends release over 24 hours

Question 10

Timed-release Products

Covera-HS

Delayed release, Slow release

Answer 10

• Delayed release
  
  • Coating layer between the active drug core and an out semi-permeable membrane
  • Water from the GIT enters the tablet, this delay coating is solubilised and released
• Slow release
  
  • Tablet hydration continues, the osmotic layer expands and pushes against the drug layer, releasing drug through precision laser-drilled orifices in the outer membrane at a constate rate
• Advantages are the independence of posture, pH GI motility, and fed or fasting conditions

Question 11

Covera- HS

Answer 11

Question 12

Pulsed-release dosage form

PulsinCap

Answer 12

• Drug help within a hard-shell capsule
  
  • Body is water-soluble
    
    • The drug is held as particles with the shell body
    • Drug sealed in with a hydrogel plug- like a test tube stoppper which swells and cause it to release from the formulation- by making plug thinner you reduce time to release
    • The cap covering plug is water-soluble
  • When the capsule is swallowed
    
    • Cap dissolves
    • Hydrogel plug swells
    • At pre-determined, controlled times
      
      • The swollen plug is eliminated from the device
      • The drug is released as GIT fluids enter the capsule

Question 13

Pulsincap for salbutamol (nocturnal asthma)

Answer 13

Question 14

External control of drug release

Answer 14

• Used where pulses of drug are required to be delivered on demend for targeting applications
• Achieved by
  
  • Magnetic-activated devices: use magnetic field
  • IontophoresisActivated devices: Use electrical current to modulate deffusion of a charged molecule across membrane (e.g. skin)
  • Ultrasound-activated devices: Use ultrasonic energy to trigger delivery from polymer

Question 15

External Control of Drug Release
Magnetic Devices - Mechanism

Answer 15

Question 16

Iontophoresis-activated devices Ionsys

Answer 16

• Iontophoretic fentanyl
  
  • Patient controlled
• Testing and disposal concerns
• A recessed on-demand dosing button and red light
• Press the on-demand button twice with 3 seconds to activate
• A deep at the start and red light remains on throughout the 1-minute dosing interval
• The next dose cannot be initiated until the previous 10-minute delivery cycle is complete. Pressing the button during delivery of a dose will not result in the additional medicinal product being administered

Question 17

Iontophoresis

Answer 17

• A drug with adequate solubility incorporated in a gel form. cationic or neutral therapeutic agents are placed under an anode or anionic therapeutic agents under a cathode.
• When a low voltage and low current density is applied, according to simple electrorepulsion, ions are repelled into and through the skin.
• Cationic drugs are driven into and through the skin by the anode (active electrode), which also extracts anion from the tissue underneath the skin into the anode.
• At the cathode (return electrode) anionic buffer ions are driven into the skin and cations from the tissues are extracted into the cathode.
• It is also possible to include an additionally charged drug in the return electrode to be delivered simultaneously or to use a mixture of drugs in the active electrode to enhance the desired effect or to increase skin permeation, depending on which drugs/molecules are used.
• Positively charged fentanyl molecules within the anode hydrogel reservoir are then repelled from the positively charged anode surface and delivered transdermally into the systemic circulation.