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Controlled and SiteSpecific Drug Delivery

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Title: Controlled and SiteSpecific Drug Delivery


1
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

2
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
3
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

4
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?

5
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

6
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

7
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

8
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

9
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

10
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)

11
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!

12
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!

13
Examples of polymers in drug delivery
Thermosensitive hydrogels in drug delivery
14
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

15
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.

16
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
17
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/

18
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.
19
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

20
Biomolecular recognition systems
21
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

22
Examples of polymers in drug delivery
Polymers for oral delivery - hydrogels
  • ds
  • ds
  • ds
  • ds
  • ds
  • ds
  • ds
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