Oral Controlled Delivery Flashcards
Why modified delivery?
• Conventional dosage forms have little control over the delivery of drug
– Release rate is not controlled
– t1/2 and pharmacokinetic (PK) profiles are not controlled
– Plasma concentration up-and-down, and may need repeated dosing
– Inconvenience, poor patient compliance
– Potential risks of toxicity or ineffective, due to large fluctuation in plasma concentration
• An ideal drug delivery system would delivery the drug to the site of action at a desired rate
– Temporal control
• Delivery drug at constant rate, where therapeutic effect is directly linked to steady state plasma conc
• Delivery drug at a ‘rhythm’, where a variable rate of delivery and a series of peaks of plasma concentration are required
– Spatial control – e.g. delivery to the colon, or other sites in the GI tract
Some terminologies
- Controlled release
- Modified release
- Sustained release
- Prolonged release
- Extended release
- Delayed release
- Repeat action
Rationale for modified release systems
• The basic idea is to alter the pharmacokinetic
(PK) profile of a drug using delivery dosage
forms, so that the PK profile is more of a
property of the delivery systems, not solely the
inherent property of the drug molecule itself
Rationale for modified release systems
continued
•If the absorption rate is good, Cp would be dependent upon Cs, which in turn is
dependent on the release rate
•Therefore, Cp-t profile could be altered by controlling the dissolution rate
•If the absorption rate is poor, it will be challenging to design a modified release
dosage form
Exercises regarding Biopharmaceutics Classification Systems (BCS)
Solubility/Permeability BCS Class I - High/High BCS Class II - Low/High BCS Class III - High/Low BCS Class IV - Low/Low
Drugs in which class are most suitable for MR dosage forms?
Class I
In order to improve bioavailability, drugs in which class would benefit the most from formulation approaches to improve dissolution rate?
Class II
Biological factors affecting the product
design and performance
• Absorption rate constant – the minimum need to
be between 0.25 and 0.35 hr-1
• Gastric emptying – normally around 2 hours, but can vary between 5 minutes and 12 hours
• Transit time in small intestine – 3 to 4 hours (but can be 0.5 to 9 hours)
• Colonic transit time – 1 to 72 hours
• pH and enzymes in the GI tract – drug
degradation
Drug properties affecting product
design and performance
- Aqueous solubility – Drugs must be dissolved before absorbed – Many drugs are poorly soluble at major sites of absorption, therefore are poor candidates for sustained release dosage forms
- Partition coefficient logP – Drugs with extremely high logP diffuse through the lipid membrane easily, but are difficult to go any further – Drugs with low logP do not diffuse across membrane easily – A balance is needed
- Drug stability in the physiological environment
- Biological half life – 4 to 6 hours would be ideal; – <2 hours would be very challenging
Duration of action, half life in vivo, and dose consideration
• To maintain a steady state plasma concentration, the zero order release (the sustaining release) rate should be directly
proportional to the elimination rate
• For drugs with short t1/2, the elimination rate is significant, therefore, require substantial
sustaining supply, i.e. large sustaining dose
Drugs not suitable for (or not easily formulated as) sustained release dosage forms
• Half life too short or too long (e.g. if t1/2 < 2 hours)
• Poor margin of safety (narrow therapeutic index)
• Large dose
• Poor solubility and slow dissolution
• Absorption rate too slow (poor absorption)
• Not uniformly absorbed through out the GI
tract. For example drugs that can only be
absorbed at certain parts in the GI tract (e.g.
some drugs absorbed through active transport)
• C-t course differs to that of pharmacological
effects
• Drugs for acute indications
Advantages of sustained release dosage forms
• Reduced dosing frequency
• Improved patient compliance
• Reduced fluctuation in plasma concentration
• Reduced side effects due to high peak concentrations
• Improved action of drug during night time
• Avoiding plasma concentration dropping below the MEC (minimum
effective concentration) and hence improve the therapeutic effects
for many chronic disease including asthma, depression
• Reduction of total amount of drug required for a given period of
treatment
• Reduction in GI irritation caused by ‘dose dumping’, e.g. KCl
• Chronotherapy: release drug when it is needed
• Treatment specific area in the GI tract, e.g. the colon
• Potential cost savings due to better disease management? (but
keep in mind that modified release dosage forms are more
expensive than conventional ones)
Disadvantages of sustained release
dosage forms
• Potential overdosing due to unexpected dose dumping
– failure of technology – Unpredicted changes of physiological conditions
– Intake of certain other medicines or foods
• Not easy to adjust dose regimen
• More expensive per unit dose than
conventional dosage forms
Hydrophilic matrix systems (1)
• Hydrophilic polymers form a gel layer (or viscous layer) when in contact with water
• Tortuosity and ‘microviscosity’ of the gel layer determine
release rate
Hydrophilic matrix systems (2)
- Matrix-forming materials, e.g. – Hydroxylpropyl methylcellulose (HPMC) – Hydroxylpropyl cellulose – Sodium carboxymethyl cellulose – Alginates
- Gel modifiers – e.g. sugars, soluble polymers, soluble salts. These can modify – drug release (often increase) – rates and extent of the hydration process – microenvironment in the gel layer
- Solubilisers and pH modifiers for the drug
Hydrophilic matrix systems
• Advantages
– ‘Simple’
– Excipients are cheap and generally regarded as safe
– High drug load capacity
– No ‘ghost’ matrix, erodible
– Possible to obtain different profiles of release
– Well established technology
Hydrophilic matrix systems
• Disadvantages
– Diffusion is dependent on two diffusion process: water diffuse into the core and drug diffuse through the gel layer
– Erosion makes drug release process complicated
– Formulation must be thoroughly studied with the right materials
chosen
– Scale-up needs to be critically controlled
Insoluble polymer matrix systems
• Less frequently used
• Polymers for a matrix in which drug particles are interspersed
• You can imagine it is something like a sponge
• The polymer matrix remain intact throughout the GI tract
• Drug molecules diffuse out through the various channels
• Diffuse rate depends on:
– Pore size
– Number of pores
– Tortuosity
• Drug release rate decreases over time (non-zero order)
Insoluble polymer matrix systems
• Fast release rate can be achieved
– Polymers with low molecular weight and low viscosity
– Low percentage of polymers in formulation – Incorporation of release modifier (pore former)
Insoluble polymer matrix systems
• Slow release rate can be achieved
– Viscus polymers
– Polymers with high molecular weight
– Polymers with high degree of crosslinking
– High percentage of polymers in formulation
– Incorporation of release modifier
Membrane-controlled systems
• Dosage form covered in a membrane
– monolithic form (one big unit), or
– pellet form (many pellets) – if one fails, not a big problem (better)
• Rate controlling part is the membrane, not the whole matrix
• Solid drug does not diffuse across membrane
• Upon contact with water, water diffuse into the core
• Drug dissolve and diffuse across the membrane
• Release rate is controlled by
– the thickness and the porosity of the membrane
– drug solubility and concentration in the fluid in the GI tract
Osmotic pump systems
• Only water molecules diffuse through the membrane; drug
molecules cannot
• Solid contents dissolve and build up osmotic pressure inside
• Water molecules enter the core due to the difference of
osmotic pressure
• Drug solution pushed out via the orifice, and more solid contents dissolve
Osmotic pump systems - equation
dM/dt = Ak/h (∆pie - ∆p)Cs
where:
– dM/dt is amount of drug delivered per unit of time
– Cs is concentration of the saturated solution
– A is surface area of semipermeable membrane
– k is permeability of membrane
– h is thickness of membrane
– ∆pieis the difference of osmotic pressure (between inside and
outside)
– ∆p is the difference of static pressure (affected by size of orifice)
• Usually the orifice is large enough so that ∆p can be ignored. Therefore,
dM/dt = ∆pie Cs (simplified form)
-As long as there is excess amount of of solid content, ∆pie is constant. Zero order release!
Factors affecting drug release
osmotic pump systems
• Type of semipermeable membranes (different
membranes may have different k)
• Area (A) and thickness (h) of the semipermeable membrane
• Solubility of drug (Cs)
• Osmotic pressure (drug, osmotic agent)
• Size of orifice which affects ∆p
Gastroretention
• To retain drug in the stomach for longer (against stomach emptying)
– Drugs that are intended for local treatment in
stomach
– Drugs that have a narrow absorption window in the
upper GI tract
• Approaches to achieve gastroretention
– Mucoadhesion: mucoadhesive polymers such as chitosan, carbopol
– Floating: gas generating agents or lipid can be used
– Size increasing system (after hydration)
Success is very limited
Delivery of drug to the colon
• Application
– Inflammatory bowel disease, e.g. ulcerative colitis
– Carcinoma of colon
• Approaches
– Colonic bacteria: some polymers can be broken down by the bacteria in the colon. E.g. glassy amylase, or pectin crosslinked with calcium
– pH sensitive polymers – use of the specific pH of the colon
– Transition time in the GI tract
- Commercial name -Adalat retard modified release tablets
- Active ingredient
- Excipient
- Manufacturer
- Adalat retard modified release tablets
- Nifedipine
- Macrogol 4000
- Bayer plc
- Commercial name -Attia 200 Modified Release Capsules
- Active ingredient
- Excipient
- Manufacturer
- Attia 200 Modified Release Capsules
- Dipyridamole
- HPMC
- Dr. Reddy’s Laboratories (UK) Ltd
-Commercial name -Axorid modifiedr elease capsules -Active ingredient -Excipient -Manufacturer
-Axorid modifiedr elease capsules -ketoprofen, omeprazole -Polyacrylate, ammonio methacrylate copolymer type B etc -Meda Pharmaceuticals
- Commercial name -Efracea 40mg Modified Release Hard Capsules
- Active ingredient
- Excipient
- Manufacturer
-Efracea 40mg Modified Release Hard Capsules
-Doxycycline
-Methacrylic acid-ethyl
acrylate copolymer (1:1)
-Galderma (U.K) Ltd
- Commercial name -Laaglyda MR tablets
- Active ingredient
- Excipient
- Manufacturer
- Laaglyda MR tablets
- Gliclazide
- Hypromellose
- Consilient Health Ltd
-Commercial name Fibrazate XL 400 mg Modified Release Tablets -Active ingredient -Excipient -Manufacturer
-Fibrazate XL 400 mg Modified Release Tablets -Bezafibrate -Macrogol 4000 -Sandoz Limited
