Controlled and SiteSpecific Drug Delivery

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Controlled and Site-Specific Drug Delivery

• Cameron Alexander,
• School of Pharmacy and Biomedical Sciences,
• University of Portsmouth,
• St Michael's Building, White Swan Road,
• Portsmouth, PO1 2DT, UK

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Outline of course

• Introduction

• The need for controlled and site-specific drug
  delivery
  
• Why do we need controlled and site-specific drug
  delivery?
  
• disadvantages of current methods
• advantages of controlled and targeted release

Polymer-based delivery systems

• Polymers in current use
• polymer therapeutics in situ drug release
• Smart or responsive polymers
• pharmaceutical targeting and dynamic release
• Imprinted polymers
• potential new release systems

Future Trends References/Further reading Links
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Why do we need controlled drug delivery?
Reasons

• Medical
• - Optimum dose, at the right time, and in the
  right location

• Industrial
• - Efficient use of expensive ingredients,
  reduction in production costs

• Societal
• - Beneficial to patients, better therapy,
  improved comfort and standard of living

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Why do we need controlled drug delivery?
Case study

• Inositol Monophosphatase and Manic Depression
• Manic depression affects 1 population (500,000
  people in UK)
  
• Inositol Monophosphatase catalyses cleavage of
  phosphate from inositol- 1-phosphate
  
• Loss of phosphate causes cell responses
  overactive in manic depression
  
• Currently treated via lithium ion therapy
  inhibition of Inositol Monophosphatase

• Lithium ion therapy
• Lithium ions extremely toxic (2 mM)
• Very narrow therapeutic window (0.8- 1.2 mM
  optimum
  
• Mode of action by replacing Mg2 in IMPase

A candidate for controlled release?

• New IMPase inhibitors being developed
• Expensive?
• Time taken for clinical acceptability?

• Controlled delivery of lithium ions
• Existing treatment without danger of crossing
  threshold toxicity?

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Why do we need controlled drug delivery?
Disadvantages of current methods

• The drug does not reach the active site
• wasteful, potential toxic responses at other sites

• The drug does not reach the active site in the
  desired concentration
  
• expensive, ineffective at applied dose

Advantages of new methods

• Maintenance of drug levels within a desired
  range
  
• efficient, need for fewer administrations

• Delivery of difficult drugs
• slow release of water-soluble drugs, fast release
  of low-solubility drugs
  

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The need for controlled release
Examples

• Poorly-soluble drugs
• Danazol (pituitary gonadotropin inhibitor)
• Can be solubilised in b-cyclodextrin

• Peptides and proteins
• Proteolysis in vivo, poor bioavailability
• Insulin delivery in diabetes treatment (predicted
  to affect 200million people by 2040!

• Nucleic acids
• Degradation by exo- and endo nucleases barrier
  to gene therapy
  
• Alcoholic Binge Causes Massive Degradation of
  Hepatic Mitochondrial DNA in mice.
  Ethanol-induced mitochondrial DNA depletion was
  prevented by 4-methylpyrazole, an inhibitor of
  ethanol metabolism, and attenuated by melatonin,
  an antioxidant.
• CONCLUSIONS After an alcoholic binge, ethanol
  metabolism causes oxidative stress and hepatic
  mitochondrial DNA degradation in mice.
  Gastroenterology, 117(1)181-90 1999

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What is a polymer and how can they help?
What is a polymer?

• Large molecule composed of a number of sub-units
• Natural e.g. alginates,
• synthetic e.g. poly(HMPA)
• Function governed by number and arrangement of
  constitutional repeat units e.g. A-n,
  -A-B-n, -A-A n-B-B m , --A-A-B-A-B-B-A-

• How are they made?
• Processing of natural products alginates from
  seaweeds, celluloses from plants
  
• Synthesis from chemical feedstocks
  poly(olefins), nylons, poly(esters)

• How can they help?
• Protection of therapeutic compound during passage
  through body, as encapsulant or carrier.
  
• Mediator or activator of controlled release

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Examples of polymers in drug delivery

• Monolithic devices
• films with the drug in a polymer matrix
• Easy to fabricate, typically by simple mixing of
  polymer and drug
  
• Example Eudragit RS100 polymer, mixed with
  sorbitol and Flurbiprofen

• Reservoir devices
• Drug contained by the polymer
• Release is usually diffusion controlled (Fickian)
  i.e. J -D?C where J flux, C component of
  concentration across membrane of defined area,
  and ? is a differential vector operator
• Example PharmazomeTM Theophylline release

• Leachable additives
• Polymer contains drug and a second component
  which is typically hydrophilic and diffuses out,
  rendering the polymer porous thus releasing the
  drug.

• Polymer drug conjugates
• Polymer attached to drug by (covalent)
  sacrificial linker
  
• Example HMPA-doxorubicin (PK1, FCE 28068)
  undergoing clinical trials

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Examples of polymers in drug delivery
Microencapsulation

• Polymer capsules containing active therapeutic
• Natural or synthetic polymers can be used to form
  capsules
  
• Widely adopted in industry fragrance release,
  flavour masking etc

• How are they made?
• Interfacial polycondensation
• polymer forms at boundary of two-phases
• Proteins and cells can be encapsulated
• Controlled gelation in aqueous solution
• E.g. addition of sodium alginate drug in water

• Mode of drug release
• Physical disruption of capsules
• Diffusion through porous capsule membrane
• Example SouthernBiosystems (sucrose acetate
  butyrate) for ocular drug release

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Examples of polymers in drug delivery

• Biodegradable polymers
• Polymer degrades in vivo to release the drug
• Simple release mechanism, but difficult to obtain
  fine control over degradation
  
• Does not invoke an inflammatory or toxic
  response.
  
• Is metabolized in the body after fulfilling its
  purpose, leaving no trace

• Common biodegradable polymers
• Poly(lactide-co-glycolide) (PLGA)
• Poly(hydroxybutyrate-co valerate) (Biopol)

• Synthesis of biodegradable polymers
• Chemical synthesis
• Bacterial biosynthesis (Biopol)

• Examples in use
• Dexon (poly(glycolide)
• Vicryl (PLGA)

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Examples of polymers in drug delivery
Polymers for oral delivery - hydrogels

• Major class of polymer drug delivery vehicles
• Three-dimensional, hydrophilic polymeric
  networks, swollen with water
  
• Cross-linking between polymer chains determines
  swelling and gel flexibility
  
• Natural or synthetic derived very large number
  of hydrogels have been produced
  
• Ionic (acidic, basic) or neutral dependent on
  desired application
  
• Inherently biocompatible strongly hydrated

• How are they made?
• Example 2-hydroxyethylmethacrylate (HEMA)

• Mode of drug release
• Diffusion of drug from gel complex
  mechanistically due to gel microstructure
  
• Active efflux next lecture!

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Examples of polymers in drug delivery
Polymers for oral delivery - mucoadhesives

• 2nd Major class of polymer drug delivery
  vehicles
  
• Similar in design features to hydrogels
  (sub-class)
  
• Ability to localise at mucus membrane via
  adhesive interactions
  
• Contain functional groups for binding to mucosal
  surfaces primarily H-bonding
  
• Pendant chains for intimate contact and
  interdigitation with mucins
  
• Inherently biocompatible strongly hydrated

• How are they made?
• Example Methacrylic acid poly(ethylene oxide)
  mucoadhesives

• Mode of drug release
• Diffusion of drug from gel can be activated by
  pH or hydration change
  
• Active efflux next lecture!

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Examples of polymers in drug delivery
Thermosensitive hydrogels in drug delivery
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Examples of polymers in drug delivery
Polymers for cancer therapy delivery of
therapeutics

• Requirements for intracytoplasmic delivery - 1
• Biocompatible vector
• Ability to carry drug or therapeutic
• Protection against biodegradation/metabolism
  prior to site delivery
  
• Avoidance of rapid liver uptake

• Requirements for intracytoplasmic delivery - 2
• Appropriate cell targeting functionality
• Ability to enter cell by endocytosis
• Ability to exit endosomes and enter cytoplasmic
  compartments
  
• Traffic intracellularly to appropriate organelle
• Deliver drug at target by suitable mechanism

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The Enhanced Permeability and Retention (EPR)
effect

• Schematic diagram showing the fate of long
  circulating polymerdrug.
  
• Top panel shows the selective uptake of the
  polymer
  
• conjugate by the enhanced permeability and
  retention (EPR) effect.
  
• Bottom panel shows the uptake of polymer
  conjugates by endocytosis-release
  
• of drug intracellularly.

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The Enhanced Permeability and Retention (EPR)
effect
Schematic diagram showing a) lysosomotropic b)
intracytoplasmic delivery Lysosomal enzymes (E)
are shown to illustrate the effects of their
presence on polymer-drug conjugates
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References

• Reviews

• Smart polymers and what they could do in
  biotechnology and medicine. Galaev, I.Y.
  Mattiasson, B. TIBTECH. 17, 335-340 (1999).
  
• Hydrogels as mucoadhesive and bioadhesive
  materials a review. Peppas NA, Sahlin JJ.
  Biomaterials (1996) 17 1553-1561

Websites

• http//atom.ecn.purdue.edu/peppamer/research/biop
  oly.html
  
• http//www.searlehealthnet.com/pipeline.html
• http//www.polymers.com/

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Ficks Laws of diffusion
Fick's First Law The flux, J, of a component of
concentration, C, across a membrane of unit area,
in a predefined plane, is proportional to the
concentration differential across that plane such
that
Fick's Second Law The rate of change of concentr
ation in a volume element of a membrane, within
the diffusional field, is proportional to the
rate of change of concentration gradient at that
point in the field, as given by
where t time.
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Polymer collapse in a chiral environment
Variation of polymer LCST in presence of amino
acid
Possible mechanism

• L-Tryptophan interacts with amide groups,
  stabilising polymer in water.
  
• D-tryptophan interaction blocked by bulky
  sec-butyl chains along polymer backbone. Polymer
  destabilised

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Biomolecular recognition systems
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Polymer-based separations

• Smart or responsive polymers
• What is a smart polymer?
• Macromolecule capable of a non-linear response to
  an external stimulus
  
• e.g. temperature, pH, magnetic and electric field
  sensitive systems
  

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Examples of polymers in drug delivery
Polymers for oral delivery - hydrogels

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