TD: Lipid Based Drug Delivery Systems

Question 1

Describe the biopharmaceutics classification system

Answer 1

Question 2

What class of drugs suffer from poor aqueous solubilty?

What does this mean and why is this bad?

Answer 2

• Class II and IV
• Need aqueous solubility to ensure absorption.
• Poor aq. solubility = poor bioavailability therefore need high dose to achieve effect.
• Need to formulate to overcome poor solubility

Question 3

What are ways to improve poor aqueous solubility in terms of formulation?

Answer 3

1. Reduce particle size – increased surface area.
   
   • Increase SA therefore drug into solution faster therefore absorbed faster and more can be absorbed within the same time period.
2. Use hydrophilic polymers within formulation.
   
   • Mix into drug solution and precipitate to create an amorphous drug dispersion.
     
     • Removes strong covalent bonds in drug (crystalline?) which are difficult to break
3. Develop orodispersable tablet
   
   • Zydis from Catalent (later in semester)
4. Formulate as an oil based system.
   
   • Emulsions
   • Develop a lipid-based drug delivery system, or a S(M)EDDS

Question 4

What are LBDDs?

How do they work?

Answer 4

Lipid-based drug delivery systems

• If a drug has poor aqueous solubility often it will have good lipid solubility.
• In this case a mixture of the drug, oils, surfactants and hydrophilic co-solvents (pre-concentrate) which can be encapsulated and delivered as a solid dosage form.
• This pre-concentrate filled capsule is then administered to the patient
• The capsule shell dissolves and ‘pre-concentrate’ mixes with GI fluids.
• This forms an emulsion or a microemulsion.
• Hence self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS).
  
  • Microemulsion - particles in nano range

Question 5

What are LBDDs composed off?

Answer 5

3 comonents: Co-solvent, lipid, surfactant

Only one lipid but can be more than 1 co-solvent or surfactant

Question 6

Describe the lipid used

Answer 6

• Lipids are oils or waxes containing a TGA.
• Oil – natural, vegetable oil.
• The oil is then modified e.g. fractionated, hydrogenated, esterified etc to produce mono-, di- and triglycerides.
• Depending on the number of FA reacting with TG depends on if mono-, di-, tri- etc. Then chain length and properties determines the property of the oil. For example short chain = harder.

Question 7

Describe the property of the surfactant used

Answer 7

• Molecules which contain both hydrophilic and hydrophobic regions (amphipathic).
• Hydrophobic region is usually a long alkyl chain.
• Hydrophilic region can be cationic, anionic or non-ionic.
  
  • Care taken with internal use e.g. cationic and anionic toxic and have some undesirable side effects so non-ionicn preferred
• Used to reduce interfacial tension between oil & water interface.
• HLB of surfactant used (and quantity) influences type of product produced.
• Combinations of surfactants can be used (Type IV LBDDS).

Question 8

Describe the properties of the co-solvent used

Answer 8

•Hydrophilic co-solvent (low molecular weight alcohols, propylene glycol etc).

Question 9

What is used to categorise LBDDs?

What is this?

Answer 9

• Lipid formulation classification system.
• Five classes based on the excipients used within them and the characteristics achieved

Question 10

What are the classes of the LFCS?

Answer 10

Question 11

Advantages and Disdvantages of each LFCS class

Answer 11

Question 12

How do you make an LBDDs?

Answer 12

Simple mixing: of drug with excipents. These processes can also be used when necessary:

• Heat (thermosensitive drugs),
• sonication
• reduction of particle size (where necessary).

Mixture encapsulated.

• Encapsulate drug in solution in soft or hard gelatine capsules.

Formulation process: Formulation of drug in solution needs to be determines prior to encapsulaiton

• Drug plus oil.
• Drug plus surfactant.
• If OK work on ratios of drug:oil:surfactant.
• If not add co-surfactants.
• Still having problems try addition of co-solvents.

Question 13

How do we evaluate LBDDs?

Answer 13

• •Looking for increase in solubility rate
• •Thus bioavailability
• •Also looking for self-emulsification capability

Question 14

Describe looking for increased solubility

Answer 14

• •Drug needs to be soluble in oil:surfactant:co-surfactant:co-solvent mix (at least two of the above components must be used).
• •Visual evaluation of drug mixes with each component of the formulation.
  
  • •Optical microscope – isotropic (same in all directions) clear field.
  • •Polarising filters – nothing visible. If bright light then some crystalline stucture there therefore LBDS not complete

Question 15

Describe looking for increase BA

Answer 15

• Modified dissolution testing (such as dialysis bag method) to evaluate effectiveness of the solubility enhancement of the S(M)EDDS formulation.
• In vivo studies using animals to determine enhancement of absorption from S(M)EDDS formulations.

Question 16

Describe looking for self-emulsification capability.

Answer 16

• Dispersability – no standardised method as yet.
• Particle size analysis using laser light scattering (Mastersizer) for >0.5µm size or dynamic light scattering (Zetamaster) for < 0.5µm size of dispersed S(M)EDDS.
• Viscosity & rheological measurements – is sometimes required to improve the accuracy of particle size measurement (using DLS).
• Zeta potential (measured using the Zetamaster) is a useful indicator or stability of the dispersed sample.
• Conductivity – structure of emulsion (or ME) formed on dispersion.
• Transmission electron microscopy – dry dispersed sample and look at morphological characteristics of disperse phase droplets.
• Trying to avoid precipitation of drug once dispersed in stomach.
• Small angle x-ray scattering – can show degree of order within internal structure of dispersed droplets.

Question 17

Describe the delivery options for LBDDs

Answer 17

Fill lipid solution into gelatine capsules (either hard gelatine or soft gelatine). Where lipid components are solid at room temperature heat to above melting point and fill when molten.

OR

Absorb into inert carrier (MCC, HPMC etc) and convert into a powder. Mix with appropriate excipients and tablet powders.

OR

Use lipid components which are solid at RT. Mill ensuring components remain below their glass transition temperatures. Add additional excipients and tablet powders

OR

If lipid components are solid at RT then melt pelletisation or melt extrusion & spheronisation can be used. These materials would then be filled into capsules.

Question 18

What are Supersaturable S(M)EDDs used for and why?

Answer 18

When a poorly soluble drug is mixed with a material to help increase its solubility a problem can occur. If this material is hydrophillic then when the S(M)EDD comes into contact with the GI fluid and becomes diliuted with GI fluid then hydrophillic components can mix with the aqueous phase causing the drug to precipitate out. This leads to the inital problem of a poorly soluble drug therefore dissolution slow and therefore absorption.

The particles when they precipitate out are very small therefore increased SA therefore dissolution and absorbed faster than if not formulated as S(M)EDD but still slower than if in liquid form.

Supersaturable S(M)EDDs can be used to prevent this occuring and maintain it in the liquid phase. Precipitation inhibitors are added which prevent the precipitation of the drug in an aqueous enviroment e.g. HPMC or PVP

Question 19

How do LBDDS improve BA?

Answer 19

• Dissolve drug in lipid/surfactant mix.
  
  • Removing rate limiting step of dissolution.
  • Presenting the dissolved drug at GI interface.
  • Absorption can begin immediately.
• Formulation in lipids allows use of lymphatic transport mechanisms.
  
  • This can avoid degradation of drug by first pass metabolism.
• Use of excipients which have an inhibitory effect on P-gp efflux and cytochrome P450 3A isozyme biological systems.
  
  • More drug gets into cells

Question 20

Advntages of LBDDs

Answer 20

• Improves BA of poorly soluble API.
• Allows less API per dose.
• Reduced side-effects.
• Reduces cost.
• Reduced environmental impact.
• Less inter-subject variability.
• Effect of fed or fasted state is reduced.

Question 21

Disadvantages of LBDDs

Answer 21

• Difficult to formulate.
• Takes far more time.
• Use of high levels of surfactant can have effects on GI system.
• Type IIIB and IV need additional precipitation inhibitors to prevent drug from recrystallising on dispersion.