Controlled and Site-Specific Drug Delivery PDF

Controlled and Site-Specific Drug Delivery  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...

Controlled and Site-Specific Drug Delivery  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 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  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?  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  The need for controlled release Examples Poorly-soluble drugs - Danazol (pituitary gonadotropin inhibitor) - Can be solubilised in β-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  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  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  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  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)  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!  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! Examples of polymers in drug delivery Thermosensitive hydrogels in drug delivery  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 The Enhanced Permeability and Retention (EPR) effect Schematic diagram showing the fate of long circulating polymer–drug. 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. 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  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/biopoly.html http://www.searlehealthnet.com/pipeline.html http://www.polymers.com/  Fick’s 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 concentration 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.  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 Biomolecular recognition systems  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  Examples of polymers in drug delivery Polymers for oral delivery - hydrogels ds - ds - ds ds - ds ds - ds