Pharmaceutics 5

Rassoul DinarvandProfessor of Pharmaceutics

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Drug levels in the blood with (a) traditional drug dosing and (b) controlled-delivery dosing

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Chemical engineering◦ Less soluble melts◦ Prodrugs◦ Targeting linkages (MAB)◦ Pegylation

Pharmaceutical engineering◦ Oil vehicles◦ Liposomes◦ Polymeric delivery◦ Cell based drug delivery

Particle engineering◦ Solid lipid particles◦ Dendrimers

Mechanical engineering◦ Mechanical pumps

• 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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• Matrix (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

• Polymer drug conjugates

- Polymer attached to drug by (covalent) sacrificial linker

- Example: Paclitaxel-albumin conjugate in the market

Docetaxel-albumin conjugate under investigation

• Reservoir devices

- Drug contained by the polymer

- Release is usually diffusion controlled (Fickian) i.e. J = -DC where J =flux, C =

component of concentration across membrane of defined area, and is a differential vector operator

- Example: PharmazomeTM Theophylline release

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• 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

• Examples in use

- Resomer (PLGA)

- Vicryl (PLGA)

• Common biodegradable polymers

- Poly(lactide-co-glycolide) (PLGA)

- Poly(hydroxybutyrate-co valerate) (Biopol)

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Hydrogels• 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

O

OOH

O

O

O

O

HEMA EGDMA>95 parts <5 parts

polymeriseO

O

OH

O

O

O

O O

O

HO[] [

]

[] [

]

Monomer (water-soluble) Cross-linker Hydrogel

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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

O

OH

O

O

O

Methacrylic acid(MAA)

Poly(ethyleneglycol)dimethacrylatePEGDMA

polymeriseO

HO

O

O

O

O O

OH

[] [

]

[] [

]Adhesivegroups

O

[]

n

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Controlled release implies controlled release of drugs from polymer drug delivery systems (DDS)

Type of polymer◦ Non-degradable / Degradable

Type of Design

Reservoir Matrix

Release mechanisms◦ Diffusion / polymer degradation / combination

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Drug delivery from a typical matrix drug delivery system

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Drug delivery from a typical reservoir drug delivery system

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Drug delivery from (a) reservoir and (b) matrix swelling-controlled release systems

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Drug delivery from environmentally sensitive release systems.

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Molecular gates for the delivery of insulin triggered by the presence of glucose in the bloodstream

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Drug delivery from (a) bulk-eroding and (b) surface-eroding biodegradable systems

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Polymer Non-degradable Degradable

Design Reservoir Matrix Reservoir Matrix

Release √√√ √√√ √√ √√

Removal √ √

Rupture √ √

Low Mw √ √ √ √

High Mw √ √ √Duration 5 years 5 years 1-2 years Months

Examples Norplant® Jadelle® CapronorTM Microspheres

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Jadelle

Own work

Norplant

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Particulate systems◦ Nanoparticles

Nanocapsules Nanospheres

◦ Microparticles Microspheres Microcapsules

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Films Membranes Fibers Rods Beads Discs Cylinders

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Simultaneous drug loading and polymerisation/device fabrication

Drug loading after device fabrication◦ Drug uptake by polymeric device when immersed in

drug saturated solution◦ Mechanical drug loading

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DiffusionConcentration gradient in polymeric matrix

Chemical reactionPolymer biodegradation

Solvent effectRelease of soluble drugs in hydrogels

Mechanical releaseDrug release from mechanical devices such as

pumps

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Implants Injectables Transdermal Oral Nasal Ophthalmic Vaginal

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Solid tumor

Apply magnetic field to concentrate particles

Modulate field to release drug from particles

Inject NPs IV,NP will circulate through the blood stream

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