Special Drug Delivery Systems

7/29/2019 Special Drug Delivery Systems

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28/12/2012


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Definition

Types

Mechanism of drug delivery

Applications

Merits

Demerits

Future prospects


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SPECIAL DRUG DELIVERY SYSTEM:

These are various types of drug deliverysystems which incorporate drugs in a dosage form

that releases the medication at a predeterminedsite and rate, over the extended period of timefrom a single application.

R.S.SATOSKAR, 21st ed.


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TYPES OF SPECIAL DRUG DELIVERY

SYSTEM1. Devices for slow, prolonged release of a drug for topical

action- ocusert, progestasert, transdermal patches andiontophoresis.

2. Implants and drug-eluting stents.

3. A device for rapid delivery of anti-convulsantLorazepam to the CNS.

4. Prodrugs.

5. Targeted drug delivery systems.

6. Computerized miniature pumps.


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DEVICES FOR SLOW, PROLONGED

RELEASE OF A DRUG FOR TOPICALAPPLICATION

OCUSERTS: thin elliptical microunits, contain the drug ina reservoir from which the drug is slowly released through amembrane by diffusion at a steady rate.

- Pilocarpine Glaucoma.

- round the clock for 7days.


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Pilo-20 and Pilo-40: release 20g and 40g of

pilocarpine per hour respectively for 7days.

Advantages:

Rapid absorption.

Ease of administration.

Good local tolerance.

Avoids the need for repeated administration

of eye drops.


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Recent trends:

Polymer solution

Phase transition system

Micro adhesive/ biodhesive dosage forms

Collagen shields

Pendolatices

Ocular penetration enhancers


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PROGESTASERT:

An intrauterine contraceptive device

1st hormonal uterine device 1976

Controlled release of minute quantities of progesterone

(38mg) within the uterus for a year


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Uses:

Contraception.

Menorrhagia, dysmenorrhoea.

Contraindications:

Weight gain

Pregnancy, ectopic pregnancy.

Immediately after septic abortion, Postpartum puerperal

sepsis.

PID

Endometrial cancer, cervical cancer.


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Advantages: Prolonged action (1 yr)

Adverse effects and complications:

Expulsion (4%) [ Nulliparous- 3%]

Failure rate of2%.

Bleeding, anemia

PID, Uterine perforation.

Endometriosis, ectopic pregnancy.Withdrawn from the market since 2001.


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Mirena (1990-present):1st marketed in Finland in 1990.

approved by U.S. FDA in 2000.

20 g of levonorgestrel per day.

uses - +endometriosis, DUB.

May be used for 5 yrs.

Products in development:Femilis:a lower-dose (14g levonorgestrel per day) T-frame

IUS, developed by the Belgian companyContrel.

FibroPlant-LNG: a frameless IUS, initially releases 14g oflevonorgestrel per day, and may be used for a period of3 yrs.


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TRANSDERMAL DRUG DELIVERY SYSTEM:

These are devices in the form of adhesive patches ofvarious shapes and sizes (15-20 cm) which deliver thecontained drug at a constant rate into systemic circulation

via the stratum corneum.


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Designed to last for 1-7 days.

The sites of application: chest

abdomen

upper arm lower back

buttock

mastoid region (efficient)

GTN, fentanyl, nicotine and estradiol - India.

Isosorbide dinitrate, hyoscine and clonidine.


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The potential advantages:

Minimize inter individual variations (drug is subjected tolittle hepatic first pass metabolism).

Provide smooth plasma concentration of drug without

fluctuations.

Maintains constant blood levels for of drug longer period

of time.

Decreases gastrointestinal effect that occur due to local

contact with gastric mucosa.

More convenient - improved compliance.


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Disadvantages: Local irritation and erythema, generally mild.

Discontinuation - 2-7% cases.


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Transderm Scop:

Transdermal preparation of scopalamine.

Post auricular area

1.5 mg/2.5cm2

0.5mg/24hr over a period of75hrs.

Transdermal local anaesthetic delivery system: successfully introduced into the clinical practice forproviding topical analgesia.


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Future aspects:

To extend the duration of local anaesthetic action.

Novel delivery system in development-

Polymers

Liposomes

Suspensions.

A mutlivesicular liposomal formation of bupivacaine

(Depo Bupivacaine) is in the advanced stages of clinicaldevelopment.

- Action lasting up to 72 hrs.


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IONTOPHORESIS [Electromotive Drug Administration

(EMDA)]: is a technique using a small electric charge to deliver amedicine or other chemical through the skin.

basically an injection without the needle.

unlike transdermal patches, this method relies on activetransportation within an electric field.

galvanic current


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Galvanic current

Eg. Salicylates


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Uses:

anti-inflammatory medications (physiotherapy) plantar fasciitis, bursitis and some typesof hyperhidrosis

Adverse effect:mild skin irritation transient.

Future aspects:- local anaesthetics

- ocular iontophoresis


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IMPLANTS AND STENT

SUBCUTANEOUS IMPLANTS:

- Drug is deposited in loose subcutaneous tissue, richlysupplied by nerves but is less vascular

- Repository (depot) preparations can be injected forprolonged action

Pellet implantation:

- Drug in the form of solid pellet is introduced with atrochar and cannula.

- Provides sustained release-over weeks and monthsEg: testosterone.


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Sialistic (Nonbiodegradable) and biodegradable

implants:- Crystalline drug is packed in tubules or capsules made of

suitable materials and implanted under skin.

- release drug over months

Norplant: nonbiodegradable hormonal contraceptive

- set of 6 capsules each containing 36 mg levonorgestrel(216mg)

- up to 5yrs


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Dermojet:

- a high velocity jet of drug solution is projected from amicrofine orifice using a gun like implement.

- needle is not used- painless

- suited for mass inoculations

- insulin


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DRUGELUTING STENTS:

Peripheral or coronary stent (a scaffold) placed intonarrowed, diseased peripheral or coronary arteries that

slowly releases a drug to block cell proliferation.

These stents consist of a metallic stent backbone coveredby a polymer, containing a drug (SIROLIMUS OR

PACLITAXEL).

The first successful trials were of sirolimus - eluting stents

Drug is gradually released- 14-30 days


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Expensive.

Indications:- coronary stenting

- improve the diameter of the coronary artery lumen

Risks:

- new clot/thrombosis formation with stents

- Stent occlusion because of thrombosis may occur

during the procedure, in the following days, or later.


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A DEVICE FOR RAPID DELIVERY OF

ANTICONVULSANT LORAZEPAM TO

THE CNS

In Status epilepticus, Lorazepam has been

administered by squirting it intranasally using anatomizingpump.

- reaches the brain rapidly along the perineural pathwaysof olfactory and trigeminal nerves

- bypasses the BBB.

- acts within minutes.


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PRODRUGS

It is an inactive form of drug which gets metabolized in

the body to an active drug, or one or more active metabolite.

Overcome the pharmacokinetic disadvantages of the

useful drug.

More stable

Better bioavailability

Less side and toxicity


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Dopamine Levodopa (BBB - Parkinsonism)

Enalapril Enalaprilat

Esters of antipsychotic phenothiazines likefluphenazine (longer duration of action)

Methenamine prodrug for formaldehyde. It isconverted to formaldehyde and ammonia at acidic urinaryPH (Site specific delivery of drugs)

Altering polarity of ampicillin by esterifying ampicillin

to form talampicillin - improves bioavailability ofampicillin.


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TARGETED DRUG DELIVERY SYSTEM(SMART DRUG DELIVERY)

It is the one, which delivers the drug only to its site of

action and not to the non-target organs or tissues.

produce maximum stability activity and bioavailability.

the goal is to prolong, localize, target and have a protecteddrug interaction with the diseased tissue.


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The advantages:

reduction in the frequency of the dosages taken by thepatient

having a more uniform effect of the drug

reduction of drug side effects

reduced fluctuation in circulating drug levels.

Disadvantages:

High cost.

Reduced ability to adjust the dosages.


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Two kinds of T.D.D-

1. Active T.D.D- such as some antibody medications.2. Passive T.D.D- enhanced permeability and retention

effect.

Types of Targeted drug delivery system:1. Monoclonal antibodies (MAbs)

2. Liposomes

3. Nanoparticles (Nanopharmacology)

4. Polymeric micelles

5. Dendimers


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MONOCLONAL ANTIBODIES (MAbs):These are antibodies produced by a single clone of

lymphocytes or plasma cells and directed against a singleantigenic determinant (epitope).

Georges Kohler and Cesar Milstein in 1975.

Noble Prize for Medicine in 1984 - hybridomatechnology.


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Conventional production of MAbs:

The hybridoma technology:B lymphocytes from spleen of immunized mice are fused

with the murine myeloma cells.

Classified into four fields (depending on cell culturemethods):

1. Robottle cell culture process.

2. Membrane binded cell culture process.

3. Microcarrier cell culture process.

4. Suspended cell culture process.


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The types/sources of MAbs:

1. Murine (rodents) MAbs: shorter life,- induce a human antimouse antibody allergicreactions.

2. Chimeric MAbs: murine MAbs partly humanized by

genetic manipulation (part human part mouseantibody)

3. Humanized MAbs: obtained by recombinant DNAtechnology or by grafting of complimentarity

determining regions (CDRs) of murine MAbs onhuman Ig framework- least antigenic


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Nomenclature of MAbs:Prefix + Target subsystem + Origin subsystem + Suffix.

Suffix- mab.

Origin- depending on sourcezu- human (zumab), xi- chimeric (ximab),

o- murine (omab). Target- specific letters

vi- virus (Palivizumab),ci- circulation (Abciximab),

tu- tumour (Trastuzumab),If no such prefix, then the MAb is generally animmunomodulator (Infliximab).

Prefix- different for each Mab.


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Prefix Target subsystem Source subsystem

Old New Meaning Meaning

Variable

vi (r)ba (c)li (m)fu (ng)ne (r)ki (n)mu (l)o (s)

v (i)b (a)l (i)f (u)n (e)k (i)-s (o)

ViralBacterialLower immunityFungalNervous systemInterleukin as targetMusculoskeletalBone

uoaixizuaxoxizu

HumanMouseRatPrimateChimericHumanizedRat mouse hybridChimeric humanizedhybrid

co (l)me (l)

ma (r)go (t)go (v)pr (o)tu (m)

-t (u)

Colonic tumorMelanoma

Mammary tumorTesticular tumorOvarian tumorProstate tumorMiscellaneous tumor


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Mab Target Indication

Abciximab Alemtuzumab Bevacizumab Cetuximab Daclizumab

Gemtuzumab Palivizumab Rituximab Trastuzumab

Gp II/IIIaCD 52

VEGFEGFRIL-2R

CD 33Fusion proteinCD 20her- 2/neu

AntiplateletB cell CLLColorectal Ca.Colorectal Ca.TR

AMLRSV infectionB cell NHLBreast cancer

VEGF- vascular endothelial growth factor. EGFR- epithelial growth factor receptor. TR- transplant rejection NHL- non-Hodgkins lymphoma. AML- acute myeloid leukemia. RSV respiratory syncytial virus.


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Application of MAbs:

Diagnostic tests- Western blot test, immuno dot blottest, immunohistochemistry, immunofluorescence test,biosensors, microarrays.

Therapeutic treatment

Clinical applications- purification of drugsimaging the target

Autoimmune diseases- rheumatoid arthritis

(infliximab), Crohns disease, ulcerative colitis, acuterejection of kidney transplants and asthma


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Three mechanisms could be responsible for the cancertreatment:

A. MAbs act directly when binding to a cancer specificantigen and induce immunological response tocancer cells. Such as inducing cancer cell apoptosis,

inhibiting growth or interfering with a key function.B. MAbs was modified for delivery of a toxin,

radioisotope, cytokine or other active conjugates.

C. it is also possible to design bispecific antibodies that

can bind with their Fab regions both to target antigenand to a conjugate or effector cell


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Adverse reactions:

Hypersensitivity reactions (rare)

Suppression of physiologic function- may occur

Activation of inflammatory cells

Increased risk of infection and cancer


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LIPOSOMES:

These are concentric, spherical shells of phospholipidsin a watery medium, into which drugs are incorporated.

Produced by sonificaton of aqueous suspension ofphospholipids.

Administered by I.V route.

Most common vehicle currently used for T.D.D

Non toxic, non hemolytic and non immunogenic- evenon repeated injections.


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Drugs administered via liposomes are:

- anti cancer drugs (daunorubicin and doxorubicin).

- anti fungal drugs (amphotericin B)- less nephrotoxic andbetter tolerated.

- antibiotic like gentamicin.

Disadvantage: Biodegradable - immediate uptake andclearance by RE system.

- overcome by adding poly ethylene glycol (PEG).


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NANOPHARMACOLOGY:

The application of nanotechnology to the developmentand/or discovery of methods to deliver drugs.

a nanodrug can be a vector (nanovector) designed todeliver a pharmacological agent (drug).

Nanos = dwarf (Greek word), patuljak (Croatian)

1 nm = 10-9 m

Term nanotechnology was introduced by NorioTaniguchi, 1974.
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Designed to allow controlled (sustained) drug releasefrom matrix

Advantages: high stability, high carrier capacity

can solubilize water insoluble compounds

feasibility of variableroutes of administration, includingoral application and inhalation.

can reduce toxicity of anticancer agents

Passive targeting: enhanced permeability and retentioneffect
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Applications of Nanopharmacology:

Anticancer therapy- paclitaxel, 5- fluorouracil,doxorubicin

Drug and tumor targeting, imaging.

Alzheimers disease

Potentialfor treatment of tuberculosis (TB)

FUTURE of drug delivery
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Type of Nanoparticles Material used Application

1. Polymeric

nanoparticles

Biodegradable polymers Controlled and T.D.D

2. Quantum dots CdSe-CdS core-shell Targeting, imaging agent

3. Nanopores Aerogel, produced by sol-gel chemistry

Controlled release drugcarriers

4. Nanowires or carbon

nanotubes

Metals, semiconductors or

carbon

Gene and DNA delivery

5. Nanoshells coatedwith gold

Dielectric (typically goldsulfide or silica) core or ametal (gold) shell

Tumor targeting

6. Liposomes Phospholipid vesicles Controlled and T.D.D

7. Ceramicnanoparticles

Silica, alumina, titania Drug targeting,Bio-molecules delivery

8. Polymeric micelles Amphiphilic blockcopolymers

Systemic and controlleddelivery of water insoluble drugs


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MICELLES: prepared from certain amphiphilic co-

polymers consisting of both hydrophilic and hydrophobicmonomer units.

can be used to carry drugs that have poor solubility

Limitations- offers little in terms of size control or functionmalleability.

DENDRIMERS: These are also polymer based deliveryvehicles.

have a core that branches out in regular intervals to forma small, spherical and very dense nanocarrier.


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Application of T.D.D:

Cancer treatment

Cardiovascular diseases

Diabetes mellitus

Infectious diseases

Inflammatory diseases

Transplant rejections


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COMPUTERISED MINIATURE PUMPS:

Programmed to release drugs at a definite rate, eithercontinuously as in case of insulin or intermittently in pulsesas in case of GnRH.

May also be provided with glucose sensor devices which

trigger the desired dose of insulin as per body's demand.

Insulin pumps: Portable infusion devices connected to asubcutaneously placed cannula

- provides continuous s.c insulin infusion(CSII)- regular insulin only


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- can be programmed to deliver insulin at a low basal rate

( approx. 1 U/hr) and premeal boluses (4-15 times the basalrate to control post-prandial glycaemia.

- costly, risk of pump failure, site infection

Implantable insulin pumps: Consist of anelectromechanical mechanism which regulates insulindelivery from a percutaneously refillable reservoir.

- mechanical pumps, fluorocarbon propellant and osmotic

pumps are being developed


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References: Essentials of medical pharmacology; KD Tripathi, 6th

edition Principles of pharmacology; HL Sharma, KK Sharma, 2ndedition Review of pharmacology; Gobind Rai Garg, Sparsh Gupta,

4th

edition Pharmacology and pharmacotherapeutics; RS Satoskar,SD Bhandarkar, Nirmala N Rege, 21st edition Goodman and Gilmans The pharmacological basis oftherapeutics; Brunton, Chabner, Knollman, 12th edition Basic and clinical pharmacology; Bertram G. Katzung,Susan B. Masters, Anthony J. Trevor, 11th edition


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