Lecture 3 Principles of Controlled Drug Delivery

June 17, 2016 | Author: Laeeq R Malik | Category: Types, Instruction manuals
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Lecture 3: PRINCIPLES of CONTROLLED DRUG DELIVERY 

Controlled Drug Delivery versus Sustained Release o Controlled Drug Delivery  Active agent combined with other components to produce delivery system  DDS are usually macroscopic  Involve combinations of active agents with inert polymeric materials  Must include a component that can be engineered to regulate an essential characteristic such as duration of release, rate of release or targeting  Must have a duration of action longer than one day o Sustained Release  Achieved by mixing active agent with excipients to alter agent’s rate of dissolution in GI tract or adsorption from local injection site  Essentially achieved by drug formulation



Biocompatibility o William’s definition: ability of a material to perform with an appropriate host response in a specific application o Modified definitions  Long-term implanted devices: ability of the device to perform intended functions with a desired degree of incorporation in the host, without eliciting any undesirable local or systemic effects in that host  Short-term implantable devices: ability to carry out its intended function with flowing blood, with minimum interaction between the device and blood that adversely affects device performance and without inducing uncontrolled activation of cellular plasma protein cascades  Tissue Engineering Products: biocompatibility of a scaffold or matrix refers to the ability of the device to perform as a substrate that will support appropriate cellular activity, including facilitation of molecular and mechanical signaling systems to optimize tissue regeneration, without eliciting any undesirable effects in those cells or any local or systemic responses in the eventual host



Biocompatible Biomaterials o Biomaterials divided into 4 major classes  POLYMERS - will be focused on  Metals

 Ceramics (including carbons, glass ceramics, glasses)  Natural materials (both plants and animals) o Polymers  Molecular weight  In polymer synthesis, polymer is produced with a distribution of molecular weights  Linear polymers used in biomedical applications generally have a number average molecular weight in the range of 25,000 to 100,000 and weight average molecular weight from 50,000 to 30,000  Increasing molecular weight corresponds to increasing physical properties  Tacticity  Arrangement of substituents around the extended polymer chain  Isotactic – chains located on the same side of zig-zag chain  Syndiotactic – chains have substituents alternating from side to side  Atactic – substituents appear at random on either side of chain  Crystallinity  Polymers either amorphous or semicrystalline, never completely crystalline  Tendency of polymer to crystallize enhanced by small side groups and chain regularity  Mechanical properties  Ultimate mechanical properties of polymers at large deformations important in selecting polymers for biomedical applications  Ultimate strength – stress at or near failure  Fatigue behavior – how a polymer withstands cycles of stress and release  Thermal properties  Tg – temperature at which all long-range segmental polymeric motion ceases  Varies from polymer to polymer  Polymers used below Tg tend to be hard and glassy and below Tg tend to be rubbery Tg always below Tm  Target region for biomedical applications is rubbery plateau region  above Tg where long-range segmental motion is occurring but thermal energy is insufficient to overcome entanglement interactions that inhibit flow Crystalline polymers tend to be tough and ductile 





Chemically cross-linked polymers exhibit modulus versus temperature behavior analogous to that of linear amorphous polymers, until flow regime is approached

Controlled Release Delivery Systems I.

Diffusion Controlled Systems 

Reservoir Systems  Diffusion through planar membranes o Drug release from reservoir into external solution in three steps  Dissolution of drug in polymer  Diffusion of drug across polymer membrane  Dissolution of drug into external phase o Assumptions  No bulk flow (no convection)  No generation/consumption of drug  Drug is dilute within material  Drug release is controlled by thickness and composition of surrounding membrane  Diffusion through cylindrical membranes o Drug must dissolve in polymer before diffusing through cylinder wall o C1 (from equation in lecture slides) most generally equals the solubility of drug in the polymer if the drug concentration in the polymer is very high  Commercially available reservoir systems o Ocusert®  System delivers pilocarpine, a drug that reduces pressure in the eye, used to treat glaucoma  Placed in lower eye lid  Administered medicine for one week  Was not successful due to patient compliance – patients felt more comfortable using the regular drops that placing a foreign object in eye; and pricing – device was five times more expensive than regular drops

Norplant® implants and subsequent insertion

o Norplant®  Consists of 6 silicone rods with 36mg of levonorgestrel dissolved in polymer matrix  Implanted under skin in upper arm  Delivers progestin (hormone) continuously for up to five years  Discontinued due to multiple lawsuits in the USA o Transdermal Systems

Global sales among TDD products



  

Transdermal patches are the primary transdermal technology approved by the FDA  FDA has approved, in 22 years, 35 patch products, spanning 13 molecules  Market approached $1.2 billion in 2001 in the US alone, based on 11 molecules ($2.5 billion in US, European markets, and Japan) Enables steady blood-level profile, thus reducing side effects and sometimes improved efficacy Most common technology is drug-in-adhesive (shown in the figure below) Active systems (iontophoresis, electroporation, sonophoresis, magnetophoresis) and microneedle systems (3M’s MTS, mentioned previously) are also being investigated for delivery of peptides and macromolecules

Classification of Transdermal Drug Delivery Devices

 All marketed with Alza’s D-TRANS® technology – clear patch with up to 20mg per day of drug

Successful Systems    

Estraderm® (estradiol) – Alza NicoDerm® CQ® (nicotine) - Alza Duragesic® (fentanyl) – Alza Testoderm® (testosterone) – Alza

 Transderm-Nitro® (nitroglycerine)- Alza

 Tulobuterol (Asthma patch, Japan)  AVEVA  Gel matrix adhesive technology produces minimal irritation to the stratum corneum  Oversaturation of adhesive polymer with medication induces partial drug crystallization which translates into higher drug concentrations in patch  Asthma patch (tulobuterol) in Japan is an approved patch

AVEVA’s gel matrix adhesive technology with crystal reservoir technology



Matrix Systems  Useful for release of proteins  Drug molecules dissolved or disperse throughout a solid polymer phase with homogeneous dispersion  Materials utilized are biodegradable polymers which slowly dissolve  Rate of polymer degradation/dissolution controls the rate of drug delivery  High surface area-to-volume ratio increases release rate by allowing direct access to the matrix exterior to more particles  Rate of release decreases with time since drug molecules near matrix surface are released first  A model slab has a cumulative release proportional to t  release rate decreases with t o If matrix is formed as a hemisphere, zero-order kinetics can be obtained o Longer diffusion distance for molecules on outside of hemisphere balanced by increase in surface area  Pseudo-state approximation o Drugs loaded as fine solid particles  drug concentration within matrix higher than drug solubility in aqueous solution o Boundary between dissolved and dispersed drug is present which moves from outer surface of matrix to the center as release proceeds o This implies linear concentration gradient from solid/dissolved drug interface to releasing surface o Requires that total concentration is much higher than drug solubility  Commercialized Systems o Salvona - DermaSal®  H2O soluble patch  Ingredients dissolved in a polymer matrix  Matrix disintegrates after adhesion, yet utilizes no adhesives

Cross-section of DermaSal® patch

o Valera – Hydron Implant Technology  Vantas® - long duration LHRH therapy for advanced prostate cancer (Indevas Pharmaceuticals)  Hydron – hydrogel polymers spun into small tubes 1” long and 1/8” diameter  Contains micropores for drug diffusion  Nonbiodegradable  1-year continuous, near zero-order release rates

Vantas® implant (Valera)

II.

Swelling Controlled Systems     

Incorporation of drug within a hydrophilic polymer that swells when in an aqueous environment Drug molecules cannot diffuse out of device without water molecules diffusing in Devices have a semi-permeable membrane that allows water movement into device but prevents salt and drug from diffusing out Drug molecules diffuse out due to the pressure increase brought on by the volumetric increase of the device Example of an elementary osmotic pump - OROS® (Alza)

OROS® - best for water-soluble compounds

OROS® Oral Delivery Technology Variations

 Drugs marketed with this device o Procardia XL®  After incorporation of OROS® technology, drug’s use expanded to treatment of angina and hypertension o Concerta® - once-a-day treatment of Attention Deficit Hyperactivity Disorder (ADHD) o Ditropan XL® - once-a-day treatment of overactive bladder 

Example of osmotic driven system - Duros® Implant Technology  Titanium alloy cylinder  Non-biodegradable  Viadur® (leuprolide)- once-a-year implant for treatment of advanced prostate cancer

Duros® Implant Technology

III.

Biodegradable Systems    





Advantage - Supporting matrix will dissolve after drug release  no residual material remains in tissue Disadvantage – release of large quantities of potentially harmful polymer degradation products into body Materials should  Degrade in a controllable fashion  Degrade into naturally occurring or inert chemicals Bioerosion – physical process of dissolution of a polymer matrix or microsphere, in which a solid material slowly losses mass and eventually disappears  Occurs once constituent polymer molecules become sufficiently small and then dissolve  Two idealized patterns of erosion o Bulk erosion  Polymer disappears uniformly throught the material  Microporous matrix becomes spongy, with water-filled holes becoming larger until matrix is no longer mechanically stable o Surface erosion  Polymer disappears from the surface, so matrix becomes progressively smaller with time  Preferred since drug release from slowly shrinking matrix could be more predictable  Potentially provides constant rate of polymer erosion Biodegradation – decrease in MW of polymer within matrix after placement within biological environment  Biologicals - enzymes  Hydrolytic breakdown – H2O degradation Most commonly used polymers  poly(lactic acid) , poly(glycolic acid) and copolymers o pGA – simplest, aliphatic, linear polyester o pLa – hydrophobic o Properties controlled by MW and copolymerization o Different copolymers degrade at varying rates o No linear relationship between ratio of glycolic acid to lactic acid and physicomechanical properties of the corresponding

copolymers (e.g., 50:50 copolymers degrade more rapidly than either pGA or pLA)  poly(anhydride) o Contain the most hydrolytically unstable polymer linkage o Degrade by surface erosion without need to incorporate excipients into device formulation o To control degradation, hydrophobic polymers can be polymerized via anhydride linkages to prevent or control water penetration into matrix – rate of degradation is adjusted  Aliphatic poly(anhydrides) degrade within days  Aromatic poly(anhydrides) degrade over several years  Possess excellent in vivo biocompatibility  poly(ortho esters) o Alzamer® - 1970s by Alza Corporation o Degradation produces a diol and a lactone, which is converted to γ-hydroxybutyric acid  Process is autocatalytic o A compound such as sodium bicarbonate must be incorporated into polymeric matrix to prevent abrupt degradation and erosion

Bulk erosion

Surface erosion

IV.

Liposomes     

Term introduced by Bangham et al. to describe one or more concentric lipid bilayers incorporating an equal number of aqueous compartments Form spontaneously in aqueous media Size and shape can be varied by changing mixture of phospholipids, degree of saturation of the fatty acid side chains, and conditions of formation Hydrophobic drugs may be loaded into liposome membranes while hydrophilic drugs can be loaded into aqueous core regions Disappear rapidly in blood  t1/2 may be increased by coupling to water-soluble polymers (e.g., PEG)



Commercially available liposome systems  Alza – Stealth® Liposomal Technology o For IV drug delivery o Incorporate PEG coating o Basis for Doxil® (doxorubicin HCl liposome suspension) anticancer agent

Half-life  Amphotericin B of various anticancer agents o Amphocil o AmBiosome – liposomal amphotericin B o ABLC – Amphotericin B lipid complex  Amphotericin B complexed with dimiristoyl phosphatidylcholine and dimiristoyl phosphatidylglycerol  Lesser concentrations of drug achieved in blood but higher in liver, spleen, and lungs  Renal concentration similar  Reduced toxicity and increased action, allowing for administration of higher dosages

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