Introduction to Controlled Drug Deliveryمعینی صدیق محمد

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Classical drug delivery

For most of the pharmaceutical industries existence, drug delivery induced simple, fast-acting responses via oral or injection delivery routes

Problems associated with this approach1. Reduced potencies because of partial degradation2. Toxic levels of administration3. Increase costs associated with excess dosing

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Why control drug delivery?

Goal of more sophisticated drug delivery techniques

1. Deploy to a target site to limit side effects

2. Maintain a therapeutic drug level for prolonged periods of time

3. Predictable controllable release rates

4. Reduce dosing frequent and increase patient compliance

Toxicity level

Injection

Controlled release

Therapeutic Level

Time

As the cost and complexity of individual drug molecules has risen the problems with the classical delivery strategies over

took their benefits.

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• Long delivery

• Place of delivery

• Delivery at the required time

• New patents and exclusive renewals period production

• Delivery of specific active ingredients (peptides and proteins)

• Eliminating the peaks and valleys of blood concentration and reduced side effects

Characteristics and Benefits

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

• Use Oily solvents

• Use sparingly soluble salts drug

• Use of pretreatment drugs (Prodrugs)

• Use of non-polymeric carriers (liposomes)

• Use mechanical drug delivery systems (pumps, drug delivery)

• Drug molecules bind to specific molecules (monoclonal antibodies, special proteins, PEG)

• The use of polymeric carriers

Methods of delivery:

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Use Fick’s law to design drug release

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Rate control

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Polymers in drug delivery

• Matrix (Monolithic) devices- films with the drug in a polymer matrix

- Easy to fabricate, typically by simple mixing of polymer and drug

• 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

• Polymer drug conjugates- Polymer attached to drug by (covalent) sacrificial linker

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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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Controlled Release Systems

Entrapment or Encapsulation• During the 1970, scientists first began to encapsulate and

entrap drugs within polymers

• Encapsulation involves surrounding drug molecules with a solid polymer shell

• Entrapment involves the suspension of drug molecules within a polymer matrix.

drugpolymer

DrugPolymer

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Drug release by diffusion• Early encapsulation and entrapment systems released

the drug from within the polymer via molecular diffusion

– When the polymer absorbs water it swells in size different

– Swelling created voids throughout the interior polymer

– Smaller molecule drugs can escape via the voids at a known rate controlled by molecular diffusion (a function of temperature and drug size)

Addwater

Addtime

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Drug release by erosion• Modern delivery systems employ biodegradable

polymers– When the polymer is exposed to water hydrolysis occurs– Hydrolysis degrades the large polymers into smaller

biocompatible compounds

– Bulk erosion process – Surface erosion process

mermer

Polymer

mermer mermer mermer mermer mermer mermer mermer mermer

Water attacks bond

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Bulk erosion:– These small compound diffuse out of the matrix through the

voids caused by swelling

– Loss of the small compounds accelerates the formation of voids thus the exit of drug molecules

– Polymers containing ester, ether, and amide groups, such as poly(lactic acid) (PLA), poly(glycolic acid), poly(ε-caprolactone), polyamide, proteins, and cellulose (and its derivatives), generally exhibit this type of erosion.

Addwater

Addtime

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Surface erosion:

– hydrolysis mainly occurs in the region near the surface, whereas the bulk material is only slightly or not at all hydrolyzed. As the surface is eroded and removed.

– Polymers such as poly(ortho ester)s (POEs), PAHs, and some polycarbonates tend to undergo surface erosion.

Addwater

Addtime

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How is entrapment or encapsulation obtained?

The physical entrapment and encapsulation of drugs within a polymer is complete via one of five techniques

1. Wurster

2. Coacervation

3. Spray drying (or precipitation)

4. Coextrustion

5. Self-assembly methods

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Wurster processing (1949)

• The Wurstur process is essentially a coating process applied after a drug core is formed.

• The polymer shell is applied via spraying while the drug cores (liquid or solid) is suspended and recirculated in a gas stream.

Gas

DrugPolymer

Gas

DrugPolymer

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Coacervation Technique• STEP #1:

– Polymer dissolved in a solvent (or oil)– Drug dissolved in water

• STEP #2:– 2 liquids are rapidly mixed – water droplets form within the solvent

• STEP # 3:– Emulsion from step #2 is mixed rapidly with fresh water – Oil droplets within the fresh water phase – Oil droplets contain original dispersed water/drug phase – Oil diffuses into the fresh water phase precipitating the

polymer & entrapping the drug

Drug/H

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Polym

er/Oil

H20

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Supercritical fluid precipitationSolvent-polymer

solution from pump

CO2 from pump Heat exchanger

Flow stra ightener

Nozzle

Nozzle contraction

Precipita te

0.2µm filter

Back pressure regula tor

Gas outle tPoly(l-lactide) ~1-m diameter

particles formed by PCA processing

Normal operating

conditions:8.5-MPa,

35°C

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Co-extrusion processing

• These concentric cylinders then breakup into individual packets either driven by air flow, electrostatic or mechanical vibration

Syringe pump

HV supply

Neg.

Drug

Polymer

• There are numerous co-extrusion processes but they all share one feature – the polymer shell is flowed concentrically around a pipe containing the drug formulation

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Self-assembling delivery systems

The next advance was to construct materials/polymers that would self assemble with drugs to create

controlled drug delivery vehicles

• Self assembly is typically approach via one of two methods:1. Using a molecule that has a hydrophilic head

and hydrophobic tail to form a shell, or2. Electrostatic interaction to entrap drug

molecules

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Micelles & Bilayers• Entrapment by micelle or bilayer

formation can be obtained using lipids, surfactants and block copolymers

Polar Head Group(hydrophilic)

Fatty Tail(hydrophobic)

Bilayer

monlayer

micelle

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Hydrogels(e.g. polyacrylic acids)

• Cross-linked, hydrophilic, 3-D polymer networks that are highly permeable• Do not swell in the presence of water unless activated• Swelling activate by pH, temperature, electric field• Drug release happens via void generated & diffusion (diffusion rate is regulated by cross-linking

ratio)

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Add water+

activator

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Properties and Structures of Hydrogels

Rs = (Ws-Wd) / Wd

Rs = swelling ratio

Ws = weight of swollen hydrogels

Wd = weight of dried hydrogels

Swelling property is influenced by:•type and composition of monomers•other environmental factors such as :

temperature, pH, ionic strength•cross-linking

Cross-linking and/or copolymerization with hydrophobic comonomers density↑, mechanical strength↑, swelling property↓

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Implantable pumpsThe pumps usually use polymer swelling to drive

drug formulations out of a reservoir

Polymer Drug/H20

Drug/H20

Water

Drug/H20

Water

Swell26

Alza – Duros pump

http://www.alza.com/alza/duros 27