28/12/2012

Definition Types Mechanism of drug delivery Applications

Merits
Demerits

Future prospects

SPECIAL DRUG DELIVERY SYSTEM:

These are various types of drug delivery systems which incorporate drugs in a dosage form that releases the medication at a predetermined site and rate, over the extended period of time from a single application.

R.S.SATOSKAR, 21st ed.

TYPES OF SPECIAL DRUG DELIVERY SYSTEM

1. Devices for slow, prolonged release of a drug for topical action- ocusert, progestasert, transdermal patches and iontophoresis. 2. Implants and drug-eluting stents. 3. A device for rapid Lorazepam to the CNS. 4. Prodrugs. 5. Targeted drug delivery systems. 6. Computerized miniature pumps. delivery of anti-convulsant

DEVICES FOR SLOW, PROLONGED RELEASE OF A DRUG FOR TOPICAL APPLICATION

OCUSERTS: thin elliptical microunits, contain the drug in
a reservoir from which the drug is slowly released through a membrane by diffusion at a steady rate. - Pilocarpine Glaucoma.

- round the clock for 7days.

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.

Recent trends: Polymer solution

Phase transition system

Micro adhesive/ biodhesive dosage forms Collagen shields Pendolatices Ocular penetration enhancers

PROGESTASERT:
An intrauterine contraceptive device

1st hormonal uterine device 1976

Controlled release of minute quantities of progesterone (38mg) within the uterus for a year

Uses: Contraception.

Menorrhagia, dysmenorrhoea.
Contraindications: Weight gain Pregnancy, ectopic pregnancy. Immediately after septic abortion, Postpartum puerperal sepsis. PID Endometrial cancer, cervical cancer.

Advantages: Prolonged action (1 yr) Adverse effects and complications:

Expulsion (4%) [ Nulliparous- 3%]

Failure rate of 2%. Bleeding, anemia PID, Uterine perforation. Endometriosis, ectopic pregnancy. Withdrawn from the market since 2001.

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 company Contrel. FibroPlant-LNG: a frameless IUS, initially releases 14g of levonorgestrel per day, and may be used for a period of 3 yrs.

TRANSDERMAL DRUG DELIVERY SYSTEM:

These are devices in the form of adhesive patches of various shapes and sizes (15-20 cm) which deliver the contained drug at a constant rate into systemic circulation via the stratum corneum.

 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.

The potential advantages: Minimize inter individual variations (drug is subjected to little 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.

Disadvantages:

Local irritation and erythema, generally mild.

Discontinuation - 2-7% cases.

Transderm Scop: Transdermal preparation of scopalamine. Post auricular area 1.5 mg/2.5cm2

0.5mg/24hr over a period of 75hrs.

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

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 clinical development. - Action lasting up to 72 hrs.

IONTOPHORESIS [Electromotive Drug Administration (EMDA)]: is a technique using a small electric charge to deliver a medicine or other chemical through the skin. basically an injection without the needle. unlike transdermal patches, this method relies on active transportation within an electric field. galvanic current

Galvanic current Eg. Salicylates

Uses: anti-inflammatory medications (physiotherapy) plantar fasciitis, of hyperhidrosis bursitis and some types

Adverse effect: mild skin irritation transient. Future aspects: - local anaesthetics - ocular iontophoresis

IMPLANTS AND STENT

SUBCUTANEOUS IMPLANTS:

- Drug is deposited in loose subcutaneous tissue, richly supplied by nerves but is less vascular
- Repository (depot) preparations can be injected for prolonged action Pellet implantation: - Drug in the form of solid pellet is introduced with a trochar and cannula. - Provides sustained release-over weeks and months Eg: testosterone.

 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

 Dermojet: - a high velocity jet of drug solution is projected from a microfine orifice using a gun like implement. - needle is not used- painless - suited for mass inoculations - insulin

DRUGELUTING STENTS:
Peripheral or coronary stent (a scaffold) placed into narrowed, diseased peripheral or coronary arteries that slowly releases a drug to block cell proliferation. These stents consist of a metallic stent backbone covered by a polymer, containing a drug (SIROLIMUS OR PACLITAXEL). The first successful trials were of sirolimus - eluting stents

Drug is gradually released- 14-30 days

 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.

A DEVICE FOR RAPID DELIVERY OF ANTICONVULSANT LORAZEPAM TO THE CNS

In Status epilepticus, Lorazepam has been administered by squirting it intranasally using an atomizing pump. - reaches the brain rapidly along the perineural pathways of olfactory and trigeminal nerves

- bypasses the BBB.

- acts within minutes.

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

 Dopamine Levodopa (BBB - Parkinsonism) Enalapril Enalaprilat

Esters of antipsychotic phenothiazines fluphenazine (longer duration of action)

like

Methenamine prodrug for formaldehyde. It is converted to formaldehyde and ammonia at acidic urinary PH (Site specific delivery of drugs) Altering polarity of ampicillin by esterifying ampicillin to form talampicillin - improves bioavailability of ampicillin.

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 protected drug interaction with the diseased tissue.

The advantages: reduction in the frequency of the dosages taken by the patient 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.

Two kinds of T.D.D1. 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

MONOCLONAL ANTIBODIES (MAbs):

These are antibodies produced by a single clone of lymphocytes or plasma cells and directed against a single antigenic determinant (epitope). Georges Kohler and Cesar Milstein in 1975. Noble Prize for Medicine in 1984 - hybridoma technology.

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 culture methods): 1. 2. Robottle cell culture process. Membrane binded cell culture process.

3.
4.

Microcarrier cell culture process.

Suspended cell culture process.

The types/sources of MAbs: 1. Murine (rodents) MAbs: shorter life, - induce a human antimouse antibody allergic reactions. 2. Chimeric MAbs: murine MAbs partly humanized by genetic manipulation (part human part mouse antibody) 3. Humanized MAbs: obtained by recombinant DNA technology or by grafting of complimentarity determining regions (CDRs) of murine MAbs on human Ig framework - least antigenic

Nomenclature of MAbs:
Prefix + Target subsystem + Origin subsystem + Suffix. Suffix- mab. Origin- depending on source zu- 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 an immunomodulator (Infliximab).
Prefix- different for each Mab.

Prefix

Target subsystem

Source subsystem

Old
vi (r) ba (c) li (m) fu (ng) Variable ne (r) ki (n) mu (l) o (s) co (l) me (l) ma (r) go (t) go (v) pr (o) tu (m)

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

Meaning
Viral Bacterial Lower immunity Fungal Nervous system Interleukin as target Musculoskeletal Bone Colonic tumor Melanoma Mammary tumor Testicular tumor Ovarian tumor Prostate tumor Miscellaneous tumor u o a i xi zu axo xizu

Meaning
Human Mouse Rat Primate Chimeric Humanized Rat mouse hybrid Chimeric humanized hybrid

-t (u)

Mab

Target

Indication

Abciximab Alemtuzumab Bevacizumab Cetuximab Daclizumab Gemtuzumab Palivizumab Rituximab Trastuzumab

Gp II/IIIa CD 52 VEGF EGFR IL-2R CD 33 Fusion protein CD 20 her- 2/neu

Antiplatelet B cell CLL Colorectal Ca. Colorectal Ca. TR AML RSV infection B cell NHL Breast 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.

Application of MAbs: Diagnostic tests- Western blot test, immuno dot blot test, immunohistochemistry, immunofluorescence test, biosensors, microarrays. Therapeutic treatment

Clinical applications- purification of drugs imaging the target

Autoimmune diseasesrheumatoid arthritis (infliximab), Crohns disease, ulcerative colitis, acute rejection of kidney transplants and asthma

Three mechanisms could be responsible for the cancer treatment:

A.

MAbs act directly when binding to a cancer specific antigen and induce immunological response to cancer cells. Such as inducing cancer cell apoptosis, inhibiting growth or interfering with a key function. MAbs was modified for delivery of a toxin, radioisotope, cytokine or other active conjugates.
it is also possible to design bispecific antibodies that can bind with their Fab regions both to target antigen and to a conjugate or effector cell

B.
C.

Adverse reactions: Hypersensitivity reactions (rare) Suppression of physiologic function- may occur Activation of inflammatory cells

Increased risk of infection and cancer

LIPOSOMES:
These are concentric, spherical shells of phospholipids in a watery medium, into which drugs are incorporated. Produced by sonificaton of aqueous suspension of phospholipids.

Administered by I.V route.

Most common vehicle currently used for T.D.D Non toxic, non hemolytic and non immunogenic- even on repeated injections.

 Drugs administered via liposomes are: - anti cancer drugs (daunorubicin and doxorubicin). - anti fungal drugs (amphotericin B)- less nephrotoxic and better tolerated. - antibiotic like gentamicin. Disadvantage: Biodegradable - immediate uptake and clearance by RE system.

- overcome by adding poly ethylene glycol (PEG).

NANOPHARMACOLOGY:
The application of nanotechnology to the development and/or discovery of methods to deliver drugs. a nanodrug can be a vector (nanovector) designed to deliver a pharmacological agent (drug).

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

1 nm

= 10-9 m
was introduced by Norio

Term nanotechnology Taniguchi, 1974.

 Designed to allow controlled (sustained) drug release from matrix

Advantages: high stability, high carrier capacity

can solubilize water insoluble compounds

feasibility of variable routes of administration, including oral application and inhalation.

can reduce toxicity of anticancer agents

Passive targeting: enhanced permeability and retention effect

Applications of Nanopharmacology: Anticancer doxorubicin therapypaclitaxel, 5fluorouracil,

Drug and tumor targeting, imaging. Alzheimers disease Potential for treatment of tuberculosis (TB) FUTURE of drug delivery

Type of Nanoparticles
1. Polymeric nanoparticles 2. Quantum dots

Material used
Biodegradable polymers CdSe-CdS core-shell

Application
Controlled and T.D.D Targeting, imaging agent

3. Nanopores
4. Nanowires or carbon nanotubes 5. Nanoshells coated with gold 6. Liposomes 7. Ceramic nanoparticles 8. Polymeric micelles

Aerogel, produced by solgel chemistry

Metals, semiconductors or carbon Dielectric (typically gold sulfide or silica) core or a metal (gold) shell Phospholipid vesicles Silica, alumina, titania Amphiphilic block copolymers

Controlled release drug carriers

Gene and DNA delivery Tumor targeting

Controlled and T.D.D Drug targeting, Bio-molecules delivery Systemic and controlled delivery of water insoluble drugs

MICELLES: prepared from certain amphiphilic copolymers consisting of both hydrophilic and hydrophobic monomer units. can be used to carry drugs that have poor solubility Limitations- offers little in terms of size control or function malleability.

DENDRIMERS: These are also polymer based delivery

vehicles.

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

Application of T.D.D:
Cancer treatment Cardiovascular diseases Diabetes mellitus

Infectious diseases
Inflammatory diseases Transplant rejections

COMPUTERISED MINIATURE PUMPS:

Programmed to release drugs at a definite rate, either continuously as in case of insulin or intermittently in pulses as 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 a subcutaneously placed cannula - provides continuous s.c insulin infusion(CSII) - regular insulin only

- can be programmed to deliver insulin at a low basal rate ( approx. 1 U/hr) and premeal boluses (4-15 times the basal rate to control post-prandial glycaemia. - costly, risk of pump failure, site infection Implantable insulin pumps: Consist of an electromechanical mechanism which regulates insulin delivery from a percutaneously refillable reservoir. - mechanical pumps, fluorocarbon propellant and osmotic pumps are being developed

References:
Essentials of medical pharmacology; KD Tripathi, 6th edition Principles of pharmacology; HL Sharma, KK Sharma, 2nd edition 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 of therapeutics; Brunton, Chabner, Knollman, 12th edition Basic and clinical pharmacology; Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor, 11th edition

Thank You