Targeted drug dellivery system.

transcript

Presented by: Chinchole Pravin Sonu

(M.PHARM 2nd SEM)DEPARTMENT OF PHARMACEUTICS &

QUALITY ASSURANCE

R. C. Patel Institute of Pharmaceutical Education and Research, shirpur.

HOPE U ALL HAVE A BRAIN STORMING HOUR

The Current Drug DeliverySystem Market Size:

$50 billion for 2003,$67 billion for 2006 (projected to grow)

The total pharmaceutical market was $250 billions in 2001.

Definitions

Prolonged/Sustained release: the delivery system prolongs therapeutic blood or tissue levels of the drug for an extended period of time.Zero-Order release: the drug release does not vary with time; thus the delivery system maintains a (relatively) conatat effective drug level in the body for prolonged periods.Variable release: the delivery system provides drug input at a variable rate, to match, for example, endogenous circadian rhythms.Bio-responsive release: the system modulates drug release in response to biological stimulus (e.g. blood glucose levels triggering the release of insulin from a drug delivery device)

Modulated/self-regulated release: the system delivers the necessary amount of drug under the control of the patient.

Rate-controlled release: the system delivers the drug at some pre-determined rate, either systemically or locally, for a specific period of time.

Targeted-drug delivery: the delivery system achieves site specific drug delivery.

Temporal-drug delivery: the control of delivery to produce an effect in a desired time-related manner.

Spatial-drug delivery: the delivery of a drug to a specific region of the body.

WHY…..THE NEED…WHY…..THE NEED…

•Drug safety: Toxic side effects caused by drug action at non target sites are minimized.

•Drug efficacy: as the drug is concentrated at the site of action rather than being dispersed throughout the body.

•Patient compliance: as increased safety and efficacy should make therapy more acceptable and thus improve compliance.

CLASSIFICATION OF DRUG CLASSIFICATION OF DRUG TARGETING SYSTEMTARGETING SYSTEM

Physical

Biological

Chemical

The physical delivery systemsThe physical delivery systems

This class of drug targeting actually started with modifying drug Pharmacokinetics

Provide a way to achieve a sustained, quasiconstant blood/tissue concentration of a drug

Example: Ocusert not only provides controlled release but also targets pilocarpine delivery to the eye from a polymeric device

The biological targeting The biological targeting systemssystems

Use of antibodies is a principle here

Drawbackso The potential modification of the

specificity o The problem of stoichiometry

o enzymatic, timely cleavage of the antibody-drug conjugates

Drug Targeting by Chemical Drug Targeting by Chemical Delivery Systems (CDSs)Delivery Systems (CDSs)

1. Enzymatic physical-chemical-based targeting

2. Site-specific enzyme-activated targeting

3. Receptor-based chemical targeting.

1) Enzymatic 1) Enzymatic physical-chemical-physical-chemical-based targeting based targeting

The target drug (D) is chemically (either directly or indirectly) converted into an inactive analog, which on enzymatic conversion gives target drug.

Synthetic modifications are done

The system formally separates into the target site (s) and the rest of the body (r)

2) Site-specific 2) Site-specific enzyme-activated enzyme-activated

targeting targeting It is based on enzymatic conversions of

the strategically designed CDS only at the site of action

Separation between the desired

pharmacological activity and unwanted toxicity can be achieved

Example: Intraocular pressure (IOP)-reduction by ß-adrenergic blocking agents

FIGURE: Specific enzymes at the target organ activate the CDS to drug (D) only at the site. In the periphery or rest of the body, D is not formed due to the lack of activating enzymes or unfavorable rate processes.

Different size of DF forDifferent size of DF forTargeted DDSTargeted DDS

Different size of DF Different size of DF for Targeted DDS for Targeted DDS

Molecular Monoclonal antibodies, carbohydrates,

lectins and immunotoxins

• Nanoparticles Less than 200 nm Polyalkyl-cyanoacrylate nanoparticles

are used for parenteral drug delivery and targeting

Different size of DF Different size of DF for Targeted DDSfor Targeted DDS

Microparticles Size range 0.2-100 µm Synthetic polymers - poly(lactide-co-

glycolide) Natural polymers- albumin, gelatin and

starch

Macrodevices are used in many applications including:

Parenteral drug delivery: mechanical pumps, implantable devices;

Oral drug delivery: solid dosage form such as tablet and capsules;

Buccal drug delivery: buccal adhesive patches and films;

Different size of DF for Different size of DF for Targeted DDSTargeted DDS

Transdermal drug delivery: transdermal patches, iontophoretic devices;

Nasal drug delivery: nasal spray and drops;

Pulmonary drug delivery: metered dose inhalers, dry powder inhalers and nebulizers;

Vaginal drug delivery: vaginal rings, creams, sponges;

Opthalmic drug delivery: ophthalmic drops and ointments.

Different size of DF for Different size of DF for Targeted DDSTargeted DDS

They are drug vectors, which sequester, transport and deliver drug to its target.

Ideal features:•It should be able to cross anatomical barriers.•It must be recognized specifically and selectively by target cells.•The linkage of the drug and the directing unit should be stable in plasma.•Carrier should be non-toxic, non-immunogenic and biodegradable.

Carriers

Carrier systems used Carrier systems used for targeted drug for targeted drug

deliverydelivery Colloidal carriers

Vesicular systems: Liposomes, Niosomes, Virosomes, Immunoliposomes

Microparticulate systems: Microspheres, Nanoparicles

Cellular carriers: Resealed erythrocytes; serum albumin; antibodies; platelets; leucocytes

Supramolecular delivery systems: Micelles, Liquid crystals, Lipoproteins

CONTD….

Carrier systems used Carrier systems used for targeted drug for targeted drug

deliverydelivery Polymer based systems: Mucoadhesive,

Biodegradable, Bioerodible, Soluble synthetic polymeric carriers

Macromolecular carriers Proteins, glycoproteins, Artificial viral

envelopes (AVE) Glycosylated water soluble polymers Monoclonal antibodies, immunological

fragments, antibody enzyme complex Toxins and immunotoxins Lectins and polysaccharides

CONTD….

CLASSIFICATION OF TARGETED DDSCLASSIFICATION OF TARGETED DDS(MECHANISM WISE)(MECHANISM WISE)

Passive targetingInverse targetingActive targetingDual targetingDouble targetingCombination targeting

Passive targetingPassive targeting

It is a sort of passive process through which it eventually accumulate in the organ compartment of the body.

Here targeting occurs because of the body’s natural response to the physicochemical characteristics of the drug or drug-carrier system.

They are taken up by the RES especially in liver and spleen.

Inverse targetingInverse targeting

Avoid passive uptake of colloidal carriers by RES

How can these be accomplished?

Suppress the function of RES by

Pre-injection of a large amount of blank colloidal carriers or macromolecules of dextran.

Modification of the size, surface charge,

composition, surface rigidity and hydrophilicity of carriers

Active targetingActive targeting

The natural distribution pattern of the drug carrier composites is enhanced so that it approaches particular biosites.

Use of ligands or engineered homing devices

Active targeting approach is further classified into three different levels of targeting: first order targeting, second order targeting and third order targeting.

CONTD….

First order targeting:Restricted distribution of the drug-carrier system to the capillary bed of a predetermined target site, organ or tissue

Second order targetingThe selective delivery of drugs to a specific cell type

e.g. the selective drug delivery to the Kupffer cells in the liver.

Active targetingActive targeting

CONTD….

Third order targetingDrug delivery specifically to the intracellular site of target cells.

An example of third order targeting is the receptor based ligand-mediated entry of a drug complex into a cell by endocytosis.

Active targetingActive targeting CONTD….

Ligand mediated targetingLigand mediated targeting

Targeting components are pilot molecules themselves or anchored by ligands on some delivery vehicle (drug-carrier system)

Generally the carrier systems are colloidal in nature.

They can be specifically functionalized using various biologically relevant molecular ligands including antibodies, polypeptides, oligosaccharides, viral proteins.

Physical targetingPhysical targeting

Some characteristics of the bioenvironment are used either to direct the carrier to a particular location.

The first such approach reported is the temperature sensitive liposomes, which are developed and applied to tumor.

Here the combination is made between spatial control and temporal control of drug delivery. Thus along with providing targeted release it also provides controlled release of the drug

Double targeting

Combination targetingCombination targeting

These targeting systems are equipped with carriers, natural polymers and synthetic polymers of molecular specificity that could provide a direct approach to target site.

Dual targetingDual targeting

This classical approach of the drug targeting employs carrier molecules, which have their own intrinsic antiviral effect thus synergies the antiviral effect of the loaded active drug.

• Rapid clearance of targeted systems specially antibody targeted carriers

• Immune reactions against intravenous administered carrier systems

• Target tissue heterogeneity

• Problems of insufficient localization of targeted systems into tumor cells

• Diffusion and redistribution of released drug leading to no-specific accumulation

Problems associated with targeted Problems associated with targeted delivery systemsdelivery systems

DIFFERENT DOSAGE FORMS DIFFERENT DOSAGE FORMS FOR DRUG TARGETINGFOR DRUG TARGETING

Emulsions Liposomes Polymeric prodrugs Polymeric micelles Needle-free injections Implant systems Solid microparticles Solid nanoparticles pH-sensitive gels

DIFFERENT DOSAGE FORMS DIFFERENT DOSAGE FORMS FOR DRUG TARGETINGFOR DRUG TARGETING

Redox based drug delivery Needle-free injection systems Transdermal Drug Delivery System Opthalmic Erythrocyte-based drug delivery Pulmonary drug targeting Ultrasound to Aid Drug Delivery Magnetically modulated therapeutic systems Smart Polymers and their Bioconjugates

STUDY IN DETAIL

BRAIN TARGETING (CNS)

(a) Invasive Drug Delivery to the Brain (b) p-glycoprotein drug efflux system (c) Lipidization (d) Exploitation of carrier mediated transport systems (e) Exploitation of receptor mediated transcytosis

systems

Contd…..

STUDY IN DETAILCANCER TARGETING(a) Enzyme-Catalyzed Activation of Anticancer

Prodrugs 1) Prodrugs Designed to Increase the Bioavailability of

Antitumor Drugs 2) Prodrugs Designed to Increase the Local Delivery of

Antitumor Drugs

3) Prodrugs Activated by Enzyme Immunoconjugates and by Gene Therapy

i) ADEPT, ii) GDEPT, iii) VDEPTSlide 103 Contd…..

STUDY IN DETAIL

CANCER TARGETING

(b) Nano-therapeutics

(c) Monoclonal antibodies for cancer treatment

CANCER

Contd…..

DIFFERENT DOSAGE FORMS FOR DRUG TARGETING

Emulsion formulations, with a droplet size of 100 to 200nm, usually result in high drug liver uptake on IV injection.

Diverted by : polyoxyethylene surfactants + antibodies

Emulsions

Figure 1: Liposomes - (left) A = aqueous soluble drug encapsulated in aqueous compartment; (centre) B = a hydrophobic drug in the liposome bilayer; (right) C = hydrophilic polyoxyethylene lipids incorporated into liposome

Liposomes

Figure: Immunoliposomes - (left) antibodies (A) attached to the surface of stealth liposomes; (centre) antibodies attached to the distal ends of polyoxyethylene chains in stealth liposomes; (right) antibodies attached to the surface of non-stealth liposomes

Active targeting of liposomes

Polymeric prodrugs

Figure: Polymer drug conjugates

Drug delivery with polymeric prodrugs involves the use of an active substance and possibly a targeting moiety, both linked via spacers to a water-soluble polymeric backbone

It involves the concept of ampiphillic block copolymers

The size of polymeric micelles range from 10 to 100 nm

Drugs are trapped in the core of a micelle Ampiphillic block copolymers such as the Pluronics

self-assemble into polymeric micelles Pluronic micelles solubilising the neuroleptic drug

haloperidol may be targeted to the brain when conjugated to brain specific antibodies

Polymeric micelles

Figure : Polymeric micelles — A = drug solubilised in hydrophobic micelle core; B = drug covalently linked to hydrophobic portion of polymer chain; C = polymeric micelle carrying antibodies attached to hydrophilic portion of polymer molecule

IMPLANTS Clinically, implant systems have been used in

situations where chronic therapy is indicated Parenteral implants may take the form of highly

viscous liquids or semi-solid formulations Implants may be in the form of tiny rods impregnated

with drug substances or a liquid which gels in situ Ethylene vinyl acetate copolymer dexamethasone

intracranial implants achieve high drug levels in the brain

Solid Microparticles

Size 10-160 mm Microparticulate

technology has been evaluated in experimental tumors

Example: Doxorubicin ion exchange resin microparticles are superior to the free drug when administered via the hepatic artery

Solid Nanoparticles Nanoparticles may

be injected intravenously and used to target drugs to particular organs because of their small size.

Example: Stealth nanoparticles

Figure: Stealth nanoparticles: - A = polymer matrix containingdrug, B = polyoxyethylene chains

Solid Nanoparticles

Figure: Nano particles encapsulated within a capsule to resist pH

pH-sensitive gels

pH-sensitive gels Construction Step1: The secretory granules are polymerized with

methacrylic acid. Step2: The polymerized secretory granules are encapsulated

by bilipid layer. Working

Biological mediators like histamine are in collapsed state initially

pH-sensitive gels Release of histamine from such granules is

initiated through the fusion of the granule with the cell membrane exposing the polyanionic internal matrix to the extracellular environment.

The change in the pH and ionic strength results in

ion exchange and swelling of the polyanionic network which in turn causes release of the endogenous mediators.

Needle-free injection systems: by forcing liquid medication through a tiny orifice that is held against the skin. This creates a very fine, high-pressure stream of medication that penetrates the skin, depositing medication in the tissue beneath.

Needle-free injection systems

Transdermal Drug Delivery System

Iontophoresis is a non-invasive method of propelling high concentrations of a charged substance, normally medication or bioactive-agents, transdermally by repulsive electromotive force using a small electrical charge applied to an iontophoretic chamber containing a similarly charged active agent and its vehicle.

Advantage:Non-invasive, painless and it eliminates potential side effects and adverse reactions which can occur with medications delivered orally or by injection.

Iontophoresis

Power supply

Drug solution

Normal

Recovery

Electroporation

Most interesting, however, is the amount of drug delivered through iontophoresis compared with oral meds and injections.

Injection dosages 0.5mg to 4.0mg.

Iontophoresis typically requires 8 - 13ug of drug to bring about the same effect.

So, iontophoresis reduces the dose requirement

Interesting Iontophoresis…………..

OpthalmicVitrasert It is a commercially available sustained release intraocular

device approved for use in patients suffering from cytomegalovirus retinitis.

The device consists of a 6 mg pellet of ganciclovir coated with EVA and PVA

The current device is designed to release ganciclovir at a rate of 2µg/hr

Ultrasound to Aid Drug Delivery

Take a sample of the patient’s blood, infuse it with drugs, then put the blood through a process that makes it release the medication when exposed to ultrasound.

Essentially the blood cells are exposed to an electric field which opens up their pores to allow drugs to penetrate inside the target organ

Ultrasound to Aid Drug Delivery

Power supply

Sonophoresis

Wave generator

reservoir

Backing membra

ne in reservoi

Erythrocyte-based drug delivery Introduction Erythrocytes possess the singular ability to

swell and to become leaky when placed in hypo-osmotic solutions

Extracellular substances can enter the red cell at this stage, after which membrane resealing can be performed using hyper-osmotic solutions

Other methods for drug loading The procedure of encapsulation based on hypotonic

dialysis, isotonic resealing and reannealing

Erythrocyte-based drug deliveryMechanism of drug release

If the encapsulated drug is diffusible it can permeate the erythrocyte membrane and be released slowly into the circulation;

If the drug is not diffusible it may be metabolized by erythrocyte enzymes into diffusible molecules;

If the encapsulated drug is neither diffusible nor metabolized, it remains entrapped in the carrier cells and can be targeted to selective organs or cells by appropriate manipulations of the erythrocyte.

Magnetic Drug Delivery

Traditional drug

Taken at predetermined intervals

Only small percentage of drug reaches desired target

Side effects common

Magnetic drug delivery

Small size allows capillary distribution and uniform perfusion at

specific sites

Reduces chances of side effects

Controllable release rate of drugs

Principle of magnetic targeting In magnetic targeting, a drug or therapeutic

radioisotope is bound to a magnetic compound, injected into a patient’s blood stream, and then stopped with a powerful magnetic field in the target area.

Depending on the type of drug, it is then slowly released from the magnetic carriers or confers a local effect

Materials such as magnetite, iron, nickel, cobalt, neodymium–iron–boron or samarium–cobalt are used

Guided Drug DeliverySolid tumor

Apply magnetic field to concentrate particles

Modulate field to release drug from particles

Inject MPs IV,NMP will circulate through the blood stream

Other options for targeting:1 - Direct injection into tumor site2 - Coating MP with antibodies to target tumor

Reloading Drug Eluting Coatings

Substrate

Polymer Coating

Concentration G

radient

Controlled

Magnetic Field

Drug Molecules

Drug bound to MP carrier

Nanomagnetic layer

Substrate

Polymer Coating

Nanomagnetic layer

trolle

Drug bound to MP carrier

trolle

Particle type ADrug AParticle type BDrug B

Surface Elution on Demand

PROBLEM OF USING MAGNETITE Biodegradability Toxicity Immune System Non-Biocompatibility i..e may enhance immune response

Methoxy poly(ethylene glycol) (mPEG)Microparticles (MP) coated with mPEG•Coating reduces the uptake of nanoparticles into macrophage cells

•Prevents body’s immune system from attacking the drug carriers

•Also increases biocompatibility, resists protein absorption, increases circulation time, and internalization efficiency

SOLUTION……….

Gold Coating • Very compatible with biological molecules• Easy control of composition, size, and geometry• Better stabilization and drug release rate

Poly L Poly L-Lactic Acid (PLLA) Lactic Acid (PLLA)

High biocompatibility Good biodegradable feature Non-toxic products

Smart Polymers and their Bioconjugates

"stimuli-responsive", or "environmentally sensitive" polymers.

Smart polymers may be physically mixed with or chemically conjugated to biomolecules to yield a large family of polymer-biomolecule systems.

Figure: Schematic of the different types of responses of intelligent polymer systems to environmental stimuli.

Curved line is the polymer; hatched rectangle is a surface; circle is hydrogel.

CLASSIFICATION

We want to bring Drugs to the Brain…

…to treat Brain Diseases.

Alzheimer’s Disease

Parkinson’s Disease

Multiple Sclerosis

Stroke

Tumors

There are many good Drugs to treat Brain Diseases…

•Targeting growth factors to the brain (stroke, Parkinson Disease)

•Targeting enzymes to the brain (lysosomal storage diseases like Gaucher, Fabry, etc.)

•Targeting radionuclides and iRNA to the brain (tumors)

•Targeting the neprilysin gene to the brain (Alzheimer Disease)

•Targeting tyrosine hydroxylase gene to the brain (Parkinson Disease)

• 600 km capillaries (BBB)

• 20 m2

• distance between capillaries: 40 m

• every neuron has its own capillary

however, most do not pass the Blood-Brain Barrier and therefore cannot enter

the Brain.

Solution:(A) Invasive Drug Delivery to the Brain?

(A) Invasive (viral) delivery into brain tissue: intracavitary

(A) Invasive Drug Delivery by direct administration in the cerebrospinal fluid:

intrathecal, intraventricular

intrathecal / intraventricular: harmful and inefficient (effective only for leptomeningeal cq intraventricular applications)

BRAINBLOOD

(Blood-Brain Barrier)

Lipophilic drugs

Influx transporters

Efflux transporters

tight junctions

Conventional Drug Delivery to the Brain

Metabolism

Hydrophilic drugs

Lipophilic drugs

Influx transporters

Efflux transporterstight junctions

(B) Pgp inhibitors

Pgp Pgp inhibitors

P-glycoprotein

• Integral efflux membrane protein

• ATP binding cassette (ABC) protein superfamily

– ATP hydrolysis driven active transport out of the cell

• Variety of chemically diverse substrates

– Protects cells against passive transported drugs and toxins

– Reduces bioavailability of drugs (e.g. antidepressants, antipsychotics, immunosuppressants, HIV protease inhibitors)

P-glycoproteinP-glycoprotein• Highly expressed in

– tissues with protective barrier function• Brain (blood-brain barrier)• Liver• Intestine• Kidney• Testis / Placenta

– cancer cells– cells with multidrug resistance

phenotypes

P-glycoproteinP-glycoprotein

• Assumed transport mechanism – binds substrate within membrane– conformational change

due to ligand binding and ATP hydrolysis

– release of substrate into the extracellular fluid

(C) Lipidization

The lipophilicity of a drug may be increased by • Blocking hydrogen bond-forming functional

groups on the drug structure

• Covalently binding the drug to Lipidic moieties, such as long chain fatty acids

• For example, blocking one hydroxyl group on morphine via O-methylation to form codeine increases the BBB permeability to morphine.

Physiologically based strategies

(D) Exploitation of carrier mediated transport systems

• Certain nutrients are taken up into brain by carrier-mediated systems

• If a drug possesses a molecular structure similar to that of a nutrient the “pseudo-nutrient” drug may be transported across the BBB by the appropriate carrier mediated system.

• E.g. L-Dopa crosses BBB via the neutral amino acid carrier system

(E) Exploitation of receptor mediated transcytosis systems

• Design consideration in the development of the effective chimeric peptide includes vector specificity for the brain, vector pharmacokinetics, coupling between vector and drug, and intrinsic receptor affinity for the released drug.

• Anti-transferrin receptor antibodies have been proposed as efficient and selective BBB transport vectors.

Via Transport Systems at the Blood-Brain Barrier:

Receptor-Mediated Drug Delivery to the Brain

transport receptor

carrierprotein

The Trojan Horse Approach

YY Y Y Cell targeting and entry

Intracellular targeting

Biomolecular sensing

Gene/drug delivery

Y Targeting molecules (e.g. an antibody, an DNA, RNA or peptide sequence, a ligand, a thioaptamer), in Boolean combinations for more precise nanoparticle delivery

Biomolecular sensors

CLASSIFICATION STUDY IN DETAIL

• Anti tumor drugs possess limited bioavailibility• Activation is preferred slowly in blood

• Prodrugs should be activated by moderate catalytic efficiency

• Limitation: Due to the reactivity of most antitumor drugs, a limitation of this slow-releasing prodrug concept is that frequently nontumor tissues are also affected.

1) Prodrugs Designed to Increase the Bioavailability of Antitumor Drugs

• In this approach prodrugs are designed to achieve a high local concentration

• Enzyme involved in the prodrug activation must be selectively present in the target organ or the target organ should selectively take up the prodrug.

• Hypoxic environments of solid tumors that can be treated with bioreductive prodrugs.

1) Prodrugs Designed to Increase the Local Delivery of Antitumor Drugs

Antibody-directed enzyme prodrug therapy (ADEPT)

•The approach has been used most extensively to target drugs to tumor cells by employing an enzyme, not normally present in the extracellular fluid or on cell membranes, conjugated to an antitumor antibody which localizes in the tumor via a antibody-antigen interaction.

•The bound enzyme-antibody conjugate ensures that the prodrug is only converted to the cytotoxic parent compound at the tumor site thereby reducing systemic toxicity.

Figure: Principle behind ADEPT approach to drug targeting. Step 1 — injection of antibody enzyme conjugate; step 2 — activation of the prodrug

Gene Directed Enzyme Prodrug Therapy (GDEPT)

• Suicide genes encode for non-mammalian enzymes which can be used to convert a prodrug into a cytotoxic agent.

• Cells which are genetically modified to express such genes essentially commit metabolic suicide on administration of the appropriate prodrug. • Typical suicide genes include herpes simplex thymidine kinase and E.coli cytosine deaminase

GDEPT is a gene-based two-step treatment for cancer

(b) Nano-therapeutics

An Example:The development of Targeted Nano Therapeutics (TNT):

The TNT system attacks cancer in 3 steps.1. The patient receives a simple infusion containing

trillions of bioprobes, each of which is a nanoscale magnetic sphere bound to an antibody,

2. The bioprobes will seek and attach to cancer cells in the bloodstream,

3. The physician will switch on the magnetic field in the region of the cancer. This will cause the bioprobes to heat up to kill the cancer cells within minutes.

Why does it work?

•A tumor or cancerous cell can be destroyed at 43°C. Normal cells can be kept alive at ~49°C.

•When ferri- or ferro-magnetite materials are implanted, heating at alternating magnetic field can kill the cancerous cells.

(c) Monoclonal antibodies for cancer treatment

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THANKS