TD: Oral Modified Release Systems

Question 1

What are modified release tablets?

Answer 1

Modified release tablets - coated or uncoated containing special excipients or which are prepared by special procedures, or both, designed to modify the rate, the place or the time at which the active (s) are released.

Mainly focusing on changing the rate

Question 2

What are Conventional Release Tablets?

What other name is given to these?

Answer 2

uConventional release (or immediate release) dosage forms - dissolution profile depends essentially on the intrinsic properties (See Tablets, Capsules etc from MDM last year and Aulton).

Question 3

Explain the difference in plasma conc vs time for M/R and conventional tablets

What is the advantages of modified release dosage forms to immediate release in terms of plasma levels

Answer 3

• With conventional release the plasma concentration of drug fluctuates between sub and super therapeutic levels frequently and so does not remain in the therapeutic window for prolonged periods. This means that the patient must take their medication frequently in order to maintain drug plasma level. However plasma levels of the drug reach therapeutic levels quickly after admission.

In M/R systems it takes longer after admission for the drug to reach therapeutic levels. However the level of drug in the plasma does not fluctuate and remains in the therapeutic window of the drug for prolonged periods. Therefore the patient only need to take their medication 1-2 times per day.

• Modified release forms allow for a reduced dosage regime, reduced drug amount in the body, allows for the plasma drug levels to stay in therapeutic range for longer, less in toxic range therefore less side effects.
• With immediate release a multiple drugs must be taken to get the plasma levels back to therapeutic range but can often therefore exceed therapeutic range.

Question 4

What are the advantages of M/R dosgae forms compared to Immediate release

Answer 4

Improved Treatment

Improved control over plasma levels of drug, therefore:

• maintenance of therapeutic action overnight;
• reduction in incidence and severity of untoward effects (particularly locally);
• reduction in total amount of drug administered.

Therefore overall Improved compliance

2. Economic Savings

• For pharma companies: cheaper to reformulate an established drug into a M/R system than develop new drugs. Also quicker to do.
• For health services: fewer doses = lower volume purchasing of drugs + improved compliance => fewer noncompliance costs

Question 5

Limitations of M/R therapy

Answer 5

1. Variable physiological factors, e.g. pH, food, etc., may all affect the release.
   
   • If not correct pH e.g. due to Crohns disease in intestine drugs will not be released
2. GI Transit time usually less than 12 hours. This limits time for therapeutic levels to be reached and maintained.
3. Become lodged at some site in GIT due to requirement of swelling of the dosage form
4. Dose size. Dose > 500 mg - dosage form is too bulky to swallow.
5. Dose dumping possible. Large dose may be deposited quickly in GIT due to improper manufacture => overdose.
6. Generally modified release formulations are more costly to produce than conventional dosage forms. (special excipents/ proceedures required)
   
   • Cost disadvantage may be overcome to a certain extent - fewer unit doses of modified release formulation should be required
7. Required drug characteristics.

Question 6

What type of conditions are M/R used for?

Answer 6

Chronic rather than acute

Question 7

What are drug requirements for M/R therpaies?

Answer 7

Half-Life

Exhibit neither very slow nor very fast rates of absorption and excretion. Very slow – means they are inherently sustained release; very fast – require too large a dose.

Half life should be > 2 h, but < 8 h. Too short a half life will require too large a dose. Those with half life more than 8 h do not require modified release systems. Ideally 4-6h.

Absorption

• Absorption should be fast enough such that the release rate controls the concentration of drug in the plasma and not the rate of absorption.
  
  • Quick Absorption after release required
• Absorbed uniformly from the GIT, i.e. not those taken up by active transport in select regions of GIT.
  
  • Must be passive diffusion

Drug solubility:

Drugs should have a degree of both aqueous and lipid solubility. This allows for both dissolution and absorption to occur.

Intermediate aqueous solubility idea. Very poor aqueous solubility then dissolution rate limits absorption. Very highly soluble is difficult to formulate and limits absorption

Relatively small dose of poten drug required. Non-potent drugs require large amounts of drug for same effect.

Good margin of safety:

Therapetutic Window should be large. If therapeutic index is too narrow, then levels may be out with the safe or effective plasma concentrations. In addition If dose dumping occurred then narrow therapeutic index drugs would lead to an overdose.

Drug should be stable in GIT:

Should not undergo degradation due to pH or enzymatic activity.

At any given time point the concentration in the GI fluid is lower than that of an immediate release dosage form.

Question 8

What are the types of M/R system structures available?

What are examples of these?

Answer 8

Two basic types:

• Single-Unit Dosage Forms (SUDFs)
• Multiple-Unit Dosage Forms (MUDFs)

SUDF e.g. Tablet.

MUDF – Dose subdivided into many small dosage units: granules, microcapsules, mini-tablets (2-3 mm diameter), pellets or beads – enclosed in a hard gelatine capsule.

Question 9

Which system is better SUDF or MUDF?

Why is this?

Answer 9

MUDF are more desirable in M/R due to the lessening of risk of drug dumping and evening out of potential fluctuations in drug release.

(If one dosage form fails it does not lead to dosage dumping knew to multiple other dosage forms therefore compensating.)

Question 10

SUDF and MUDF can have 2 types of structures. What are these?

Answer 10

MUDF and SUDF can have two types of Structure:

• Reservoir. The pellet, particle or tablet is coated with varying thickness and composition of polymers.
• Matrix. Drug particles are uniformly dispersed in a polymer. Can be pellet, particle or tablet.

Tablets and Capsules can be either

Question 11

What controlled release mechanisms can M/R tablets undergo?

Answer 11

Most modified release dosage forms rely on dissolution (or erosion) or diffusion of a polymer, or a combination of these, to control drug release.

Question 12

What is the rate limiting step in dissolution/Erosion controlled methods?

What material are used to sustain release?

Answer 12

The rate of drug dissolving (soluble materials) or errosion (soluble material moving away from insoluble material) or both controls the rate of drug release which in turn controls plasma drug concentration levels.

Typically a soluble polymeric material (mucoadhesives), or an insoluble wax, is used to sustain release.

Question 13

Describe the drug release process using a mechanism of erosion/dissolution controled release

Answer 13

On ingestion, GI fluids start to dissolve/erode polymer as this happens water starts to penetrate into device and dissolve drug. Drug molecules then pass out through polymer matrix/coating to enter GIT and can then be absorbed.

Question 14

Images (Flip over)

Matrix Erosion/dissolution

Answer 14

Reservoir dissolution/erosion

Question 15

What polymers are used in diffusion control released mechanisms? Name specific examples

Answer 15

Hydrophobic polymers e.g. ethylcellulose and Eudragit® RS and RL.

Question 16

What problem occurs with diffusion controlled release mechanisms?

Answer 16

Potential problems can occur if the dosage form is so hydrophobic that it does not breakdown so it appears in patient stools. The patient therefore may think it is ineffective. It is necessary for counselling.

For this reason Erosion/ dissolution mechanism is preferred.

Question 17

Describe drug release by a diffusoin controlled release mechanism

Answer 17

Drug release process: On ingestion, GI fluids penetrate into device and dissolve drug. Drug molecules then pass out through polymer matrix/coating to enter GIT and can then be absorbed.

Question 18

Pictures: Matrix - Diffusion

Answer 18

Picture: Reservoir - Diffusion

Question 19

What is the difference between Diffusion and Dissolution/Erosion

Answer 19

With Diffusion the dosage form stays in tact and is not erroded or dissolved so does not shrink compared to D/E dosage forms.

Question 20

What process is used to make Reservoir Modified release systems?

Answer 20

Coating by spray coating or by microencapsulation.

Question 21

What is benefical about formulating reservoir systems

Answer 21

1. Use is made of different thickness and composition of coating to give the desired release rate.
2. Coated pellets can be compressed into rapidly disintegrating tablets (RDTs), or filled into hard geletine capsules. This is good as about 25% of the material can be left uncoated to give a loading dose.
3. Coating provides taste-masking and protection of the GIT from irritation

Question 22

What is negative about formulating Reservoir systems?

How can this risk be reduced?

Answer 22

• Dose dumping highly likely if coating incomplete.
• Risk can be reduced if individual particles/granules are coated instead of whole capsule/tablet.
• In the case of tablets QA/QC must be carried out to ensure compression has not damaged particle coatings.

Question 23

How are Matrix systems made?

Answer 23

Main methods of preparation are:

• Drug and polymer homogenously mixed and co-compressed.
• Congealing: Drug and polymer melted. Mixture is cooled, ground and sieved.
• Microencapsulation.

Question 24

What is preferred Matrix or Reservoir systems and why?

Answer 24

Matrix devices are preferred – simple in design, cheaper than reservoirs and much lower risk of dose dumping due to avoiding the problem of incomplete coating.

Question 25

How do you determine the release mechanism?

Answer 25

Release mechanism can be determined by comparing the data to equations to find the best fit.

Diffusion: Higuchi/ Korsmeyer-Peppas/Power Law

Dissolution/Erosion: Hixson-Crowell cube root law

The line should be linear (R2 > 0.98) to confirm this model

Question 26

Explain how to use the powerlaw to determine if the release system is diffusion

Answer 26

Question 27

What do values of ‘n’ determine and what are examples?

Answer 27

• Case I: diffusion
• Anomalous: Diffusion and Erosion/dissolution
• Case II: Diffusion which is zero order
• Super Case II: Rapid diffusion (RDT)

Question 28

Example graph for Powerlaw

Answer 28

Question 29

Explain how you use the Hixon-Crowell equation to determine if flow rate is dissolution/Erosion

Answer 29

Question 30

Example of Hixon-Crowell graph

Answer 30

Question 31

What is the difference between first and zero order reactions.

Which is preferred and why?

Answer 31

• We would also want to show whether release follows first or zero order kinetics. More often than not we would prefer to obtain zero order kinetics, i.e. drug release rate is independent of drug concentration in GIT and dosage form and time.
• This is useful as it maintains a constant rate of drug release for however long the dosage form is in the GIT => maintains plasma levels more effectively over a prolonged period.
• In first order release the drug release would depend on drug concentration in the GIT and dosage form and so would vary over time.
  
  • Non-zero order (burst) release could be beneficial if a loading dose is required.

Question 32

How do you determine the order of reaction?

Answer 32

• Plot release vs time
• If R2>0.98 then zero if below likely First

Question 33

Why is non-zero order kinetics more likely?

Answer 33

uThis is because drug release is affected by the properties of the rate controlling polymer and overall design of the delivery system as well as the properties of the drug itself. Factors involved here include:

• Drug solubility in GI fluid;
• Dosage form surface area;
• The solubility/erodeability of the polymer and whether or not that varies over time (dissolution/erosion controlled release only);
• The thickness of the polymer coating (reservoir systems only);
• Whether the drug is dispersed homogeneously or heterogeneously in the dosage form – do all drug particles have the same distance to travel to be released from the dosage form (matrix systems only).

Question 34

With dissolution/erosion controlled release you are most likely to get zero order release from a …. device. Why?

Answer 34

Matrix

Reservoir devices will be unlikely to give zero order release in this case as their surface area and thickness of coating will change over time thus causing fluctuations in release rate.

uIt is possible to get zero order release from a matrix if: the drug is homogeneously dispersed in the polymer matrix and the rate of polymer matrix dissolution/erosion is constant and surface only and if the drug is only released on erosion/dissolution of the polymer.

uIf the drug is heterogeneously dispersed then different quantities of drug will be released at different time points.

uIf the matrix dissolves/erodes at inconsistent rates then release will speed up/slow down at different times. If the polymer dissolves in the bulk and not the surface then drug from inside of the device can be released early and cause an initial burst (see diagram on next slide).

uIf some of the drug leaches out of the matrix prematurely (i.e. not due to polymer dissolution/erosion) or is stuck on the outside of the dosage form then you are likely to see an initial burst release.

Question 35

With diffusion mechanism which system is more likely to gain first order kinetics and why?

Answer 35

uIn the case of diffusion controlled release, reservoir systems are more likely to give zero order release than matrix devices.

uThis is because with matrix systems the drug near the centre of the device has much longer to travel in order to be released than the drug near the surface (assuming homogenous dispersion of drug in matrix). Therefore release can tend to be fast initially and then slow down over time.

uWith a diffusion controlled reservoir system, unlike its dissolution/diffusion controlled counterpart, the membrane surface area and thickness should not change that much relatively speaking. Therefore they should not affect release to a great extent and so release should be fairly constant.

Question 36

What is mucoadhesion?

Answer 36

the attachment of a drug carrier system to the mucus layer of a mucosal epithelium (membranes) to maintain intimate contact for extended periods.

Question 37

How is mucoadhesion acheived?

Answer 37

Based on incorporation of mucoadhesives in the formulation e.g. carbopol, poly(acrylic acid), chitosan.

Most polymers are mucoadhesive to some extent, particularly those which hydrate in water (hydrogels).

Question 38

What do mucoadhesives/ hydrogels do?

Answer 38

Used to prolong residence time in GIT, by adhering to GI membrane, and control drug release. Therefore they can prolong duration of drug release and maintain plasma drug levels for prolonged periods.

Question 39

What is the benefit of mucoadhesives and hydogels?

Answer 39

Reduces dosing required therefore improves compliance

Question 40

What are the stages of mucoadhesion?

Answer 40

1. Intimate contact between mucoadhesive and mucus membrane. Must be rapid, i.e. delivery system must wet and swell rapidly on contact with mucosa.
2. Penetration of mucoadhesive into crevices of tissue surface and interpenetration/entanglement of glycoprotein chains (responsible for adhesive and cohesive properties of mucus) of mucus.
3. Formation of secondary chemical bonds between mucus and adhesive – van der Waals, hydrogen bonding and hydrophobic interactions (if anionic/non-ionic); plus electrostatic interactions (if cationic) as mucus is anionic.

Question 41

What polymer-related factors affect mucoadhesion?

Answer 41

i. Molecular weight
ii. Polymer concentration
iii. Flexibility of polymer chains
iv. Spatial conformation - difference in adhesiveness between helical e.g. dextran, and linear conformation e.g. PEG.

Question 42

What Enviromnetal factors affect mucoadhesion?

Answer 42

i. pH - differences in charge density at different pH levels e.g. unmodified chitosan is only soluble (and therefore only adhesive) in acidic conditions as it is a weak base, the opposite is true of poly(acrylic acid) as it is a weak acid.
ii. Initial contact time. Determines the extent of swelling and interpenetration of polymer chains into the mucus.
iii. Degree of swelling. Depends on polymer concentration and presence of water. Determines the extent of chain flexibility and therefore interpenetration with mucus.

Question 43

What are physiologocial factors which affect mucoadhesion?

Answer 43

i. Mucin turnover. Limits the residence time.
ii. Disease states e.g. common cold (nasal cavity), gastric ulcers (GIT) - change physicochemical properties of mucus.

Question 44

What methods are available to measure mucoadhesion?

Answer 44

1. In vitro/ex vivo methods.
   (a) Based on Tensile Strength. Measures force to break adhesive bond e.g. Texture Analyser.
   (b) Based on Shear Strength. Measures force that causes the bioadhesive to slide with respect to the mucus layer in a direction parallel to their plane of contact e.g. Wilhelmy Plate method.
2. In vivo methods. Measurement of residence time at application site or transit times through GIT – using fluorescent markers.

Question 45

MUCOADHESIVE POLYMERS Ideal characteristics:

Answer 45

1. Non-toxic
2. Non-irritant
3. Biodegradable
4. Form strong bonds with mucosa => Adheres quickly
5. High elastic modulus to maintain structure on shearing forces in body
6. Body temperature should not adversely affect viscosity
7. Easy incorporation and controlled release of drug
8. Protect drug against degradation
9. No decomposition on storage
10. Relatively cheap

Question 46

Example of mucoadhesive polymers:

Non-ionic

Anionic

Cationic

Answer 46

• Non - ionic: Hydroxypropyl methylcellulose (HPMC)
• Anionic: Sodium alginate
• Cationic: Chitosan

Question 47

What are delayed release formulations?

Answer 47

• Type of modified release that includes gastro-resistant preparations - intended to resist gastric fluid and release drug in intestinal fluid, i.e. enteric coated systems.
• Not necessarily controlled release.
  
  • Used in concert with controlled release excipients.
  • They are excipents added and only delay release do NOT control it

Question 48

Where do enzyme dependent release preperations work?

What is the advantage of this?

Answer 48

Colon

• Advantageous for drugs which are more soluble/stable at pH in colon (6.4-7).
• Lower protease/peptidase levels than rest of GIT
• Still undergo first pass as enter via hepatic portal vein

Question 49

How do enzyme-depent release work?

Answer 49

Microorganisms in colon produce enzymes which can be used to active prodrugs,

• e.g. Olsalazine (Crohn’s disease) has azo group (-N=N-) which is only cleaved in colon => two molecules of 5-aminosalicylic acid (active form)

Or degrade polymers.

• e.g. Film coating with amylose is degraded by amaylase

Question 51

Where can pH-dependent formulations act?

How do these formulations work?

Answer 51

• Enteric polymers - Eudragits®
• Polymethacrylates: change ratio between methylmethacrylate and methacrylic acid to alter pH solubility.
• This allows for targeted delivery to the small intestine or colon:
  
  • Eudragits L (pH 5.5 - 6.4) - small intesine
  • Eudragits S (pH 7) - colon

This enteric polymer is sprayed onto the surface of the M/R preperation which contains the rate controlling release polymer. Spray coating must be complete to avoid premature release

Question 52

What can pH depenent release be used for?

Answer 52

Suitable for drugs that have to be protected from stomach environment (PPI’s) or stomach needs to be protected from drug (NSAID’s) or if want them to act locally (mebendazole – treat worms).

Question 53

What does enzymatic-release rely on?

Answer 53

Relies upon normal microorganism levels in colon: i.e. suitability affected by disease states or use of certain antibiotics.

Question 54

Describe an osmotic pump and how it differs from other M/R systems

Describe how the drug is released from an osmotic pump

List the factors affecting release and give examples of a polymer used

Answer 54

Describe an osmotic pump and how it differs from other M/R systems:

• They are reservoir type devise which hold the drug in their core. The system is composed of a semi-permeable membrane which is only permeable to water which makes them different to other M/R forms where the polymer is permeable to the drug.

Describe how the drug is released from an osmotic pump

• The drug is released due to water entering the pump, dissolving the drug and increasing osmotic pressure within. This pressure forces the drug out of through a laser drilled orifice in the pump. Alternatively the pump can be designed as a rupture device where pressure builds up inside until the membrane ruptures

List the factors affecting release and give examples of a polymer used

• Osmotic pressure must be consant to have constant drug release
• Drug must be water soluble
• Membrane surface area, thickness and size of orifice
• Permeability to water of polymer used In pump
• Example of polymer used - PVA