1. DRUG DELIVERY AND TARGETING

2. Drug Delivery and Targeting Systems
It is dosage form or device that serve as drug carrier to deliver the drug into targeted site upon application using suitable rout of administration.
Drug delivery and targeting systems are referred to as:
"controlled release“ "monolithic"
"sustained release" "smart“
"zero-order“ "stealth“
"membrane-controlled“ "reservoir"

3. Terminology of Drug Delivery and Targeting Systems
Prolonged/sustained release:
The delivery system prolongs therapeutic levels of the drug in blood or tissue for an extended period of time.
Zero-order release:
The drug release does not vary with time; thus the delivery system maintains a (relatively) constant effective drug level in the body for prolonged periods.

4. Bio-responsive release:
Variable release:
The delivery system provides drug input at a variable rate, to match, for example, endogenous circadian rhythms, or to mimic natural biorhythms.
Bio-responsive release:
The system modulates drug release in response to a 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.

5. Rate-controlled release:
The system delivers the drug at some pre­determined rate, either systemically or locally, for a specific period of time.
Targeted-drug delivery:
The delivery system achieves site-specific drug delivery independent on site and rout of administration
Temporal-drug delivery:
The control of delivery to produce an effect in a desired time-related manner.

6. Spatial-drug delivery:
The delivery of a drug to a specific region of the body (dependant on both route of administration and drug distribution).
Bioavailability:
The rate and extent at which a drug is taken up into the body.

7. Advantages of controlled-release system
Improve patient compliance.
Use of less total drug.
Fewer local or systemic side effects.
Minimal drug accumulation with long-term dosage.
Fewer problems with potentiation or loss of drug activity with long-term use.

8. Improved treatment efficiency.
More rapid control of the patient's condition.
Less fluctuation in drug-blood level.
Improved bioavailability for some drugs.
Improved ability to provide special effects (e.g., morning relief of arthritis by bedtime dosing).
Reduced cost.

9. RATE-CONTROLLED RELEASE IN DRUG DELIVERY AND TARGETING
There are a number of mechanisms by which drug release rate is controlled:
Diffusion-controlled release mechanisms
Dissolution-controlled release mechanisms
Osmosis-controlled release mechanisms
Mechanical-controlled release mechanisms
Bio-responsive controlled release mechanisms

10. DRUG TARGETING SYSTEMS
Advantages of Drug targeting delivery:
improve Drug safety, minimized toxic side-effects caused by drug action at non-target sites .
improve Drug efficacy, as the drug is concentrated at the site of action rather than being dispersed throughout the body.
improve Patient compliance, as increased safety and efficacy make therapy more acceptable .

11. STRATIGES TO ACHIVE DRUG TARGETING SYSTEMS
local administration of drug with conventional dosage forms.
Targeting the skin by apply the drug as ointment, lotion, or cream.
Direct injection of an anti-inflammatory agent into a joint.
oral delivery, targeting the drug to the small intestine, colon, or gut lymphatics. By using enteric coatings, prodrugs , osmotic pumps, colloidal carriers and hydrogels .

12. By parenteral administration.
are most advanced , delivering drug to specific
targets sites , protect drugs from degradation &
premature elimination.
include the use of carriers as :
Soluble carriers ; as monoclonal antibodies, dextrans , soluble synthetic polymers.
Particulate carriers, such as liposomes, micro- and nano- particles, microspheres.
Target-specific recognition moieties, such as monoclonal antibodies, carbohydrates & lectins .

13. Pharmaceutical carriers

14. DOSAGE FORMS FOR ADVANCED DRUG DELIVERY AND TARGETING
Are available, in a wide range of sizes, from the molecular level to large devices.

15. Molecular
Drugs attached to water-soluble carriers, such as monoclonal antibodies, carbohydrates, lectins and immuno-toxins.
Such systems achieve site-specific drug delivery following parenteral administration.
Release of the attached drug molecules at the target site achieved by enzymatic or hydrolytic cleavage.
Larger complexes include drug conjugates with soluble natural or synthetic polymers.

16. Nano- and Micro-particles
Nanoparticles are solid colloidal particles, generally less than 200 nm.
Such systems include us of drug carrier polymer poly (alkyl- cyanoacrylate)
Nanoparticles used for parenteral drug targeting delivery.

17. Liposomes , vesicular structures based on one or more lipid bilayer(s) encapsulating an aqueous core represent highly versatile carriers.

18. Microparticles are colloidal particles in the, in the size range 0
Microparticles are colloidal particles in the, in the size range µm.
Include use of Synthetic polymers, such as poly (lactide-co-glycolide) as drug carrier.
Include use of Natural polymers, such as albumin, gelatin , starch, used as micro-particulate drug carriers.

19. Macrodevices are widely used in many applications, including:
Parenteral drug delivery: mechanical pumps, implantable devices.
Oral drug delivery: solid dosage forms such as tablets and capsules which incorporate controlled release/ targeting technologies.
Buccal drug delivery: buccal adhesive patches and films.

20. Transdermal drug delivery: transdermal patches, iontophoretic devices.
Nasal drug delivery: nasal sprays and drops.
Pulmonary drug delivery: metered-dose inhalers, dry-powder inhalers, nebulizers.
Vaginal drug delivery: vaginal rings, creams, sponges.
Ophthalmic drug delivery: ophthalmic drops and sprays.

21. Properties of an "ideal" Drug Delivery dosage form
Good Patient acceptability and compliance
Parenteral delivery This is painful for the patient, and requiring the intervention of medical professionals.
The oral route, involves swallowing a tablet, liquid or capsule, thus a much more convenient and attractive route for drug delivery.

22. Transdermal patches are also well accepted by patients and convenient.
Nebulizers, pessaries and suppositories, have more limited patient compliance.
2) Reproducibility
The dosage form should allow accurate and reproducible drug delivery, particularly for drugs with a narrow therapeutic index.

23. 3) Ease of termination
The dosage form should be easily removed either at the end of an application period, or in the case of toxicity.
Transdermal adhesive patches and buccal tablet are easily removed
Non-biodegradable polymeric implants and osmotic pumps must be surgically take back at the end of treatment.

24. 4)Biocompatibility and absence of adverse effects
The drug delivery system should be non-toxic and non-immunogenic .
Dosage forms containing penetration enhancers has a harmful effects on epithelial tissue as well as the increased epithelial permeability may allow the entrance of potentially toxic agents.

25. 5) Large effective area of contact
For drugs absorbed via passive mechanisms, increasing the area of contact of the drug with the absorbing surface will increase the amount absorbed.
The dosage form can influence the size of the area over which the drug is absorped . For example, increasing the size of a transdermal patch increases transdermal bioavailability.

26. 6) Prolonged contact time
Ideally, the dosage form should facilitate a prolonged contact time between the drug and the absorbing surface, thereby facilitating absorption.
Drug delivery to epithelial sites is often limited by a variety of physiological clearance mechanisms at the site of administration as mucociliary clearance and intestinal motility.
Bioadhesive materials (sometimes also termed mucocadhesive) adhere to biological substrates such as mucus or tissue and increase the effective contact time.

27. Properties of an "ideal" route of administration
maximize the amount of drug entering the systemic circulation from the site of administration, the delivery site should possess certain properties:
1. A large surface area
2. Low metabolic activity
3. Long Contact time
4. Adequate blood flow
5. Accessibility
6. Lack of variability
7. Permeability

28. 1) Large surface area A large surface area are facilitates absorption.
Due to the presence of the villi and the microvilli, the available surface area of the small intestine of the gastrointestinal tract is very large, which is important for oral drug delivery.
The surface area of the lungs is broad making this region a promising alternative route to the parenteral and oral routes for systemic drug delivery.

29. 2) Low metabolic activity
Degradative enzymes may deactivate the drug, prior to absorption.
Poor drug bioavailability may thus be expected from an absorption site in which enzyme activity is high, such as the gastrointestinal tract. Furthermore, drugs which are orally absorbed must first pass through the intestinal wall and the liver, prior to reaching the systemic circulation. These" first-pass" effects can result in a significant loss of drug activity.

30. Drug delivery via other routes (nasal, buccal etc
Drug delivery via other routes (nasal, buccal etc.) avoid intestinal first-pass effects, as metabolic activity at these sites is often lower than in the gastrointestinal tract, these routes are highly attractive alternatives for the systemic delivery of enzymatically labile drugs.

31. 3) Contact time
The length of time the drug is in contact with the absorbing tissue will influence the amount of drug which crosses the mucosa.
Materials administered to different sites of the body are removed from the site of administration by a variety of natural clearance mechanisms.

32. For example, intestinal motility moves material in the stomach or small intestine towards the large intestine.
In the buccal cavity, the administered dosage form is washed daily with liters of saliva.
In the nasal cavity and the upper and central lungs, an efficient self­cleansing mechanism referred to as the "mucociliary escalator" is in place to remove any foreign material.
In the eye, materials are diluted by tears and removed via the lachrymal drainage system.

33. 4) Blood supply
Adequate blood flow from the absorption site is required to carry the drug to the site of action post-absorption.

34. 5) Accessibility
Certain absorption sites, for example the alveolar region of the lungs, are not readily accessible and thus may require quite complex delivery devices to ensure the drug reaches the absorption site.
Delivery efficiency to such sites may also therefore be low.
In contrast, other sites, such as the skin, are highly accessible.

35. 6) Lack of variability
Lack of variability is essential to ensure reproducible drug delivery.
This is important principle for the delivery of highly potent drugs with a narrow therapeutic window.
Due to such factors as extremes of pH, enzyme activity, intestinal motility, presence of food/ fluid etc., the gastrointestinal tract can be a highly variable absorption site.

36. Diseases such as the common cold and hay fever are alter the physiological conditions of the nose, contributing to the variability of this site.
The presence of disease can also compromise the reproducibility of drug delivery in the lungs.
Cyclic changes in the female menstrual cycle mean that large fluctuations in vaginal bioavailability.

37. 7) Permeability
A more permeable epithelium obviously facilitates greater absorption.
Some epithelia are relatively more permeable than others.
For example, the skin is an extremely impermeable barrier, whereas the permeability of the lung membranes towards many compounds is much higher than the skin and is also higher than that of the small intestine and other mucosal routes.
The vaginal epithelium is relatively permeable, particularly at certain stages of the menstrual cycle.

38. STRATEGIES TO INCREASE DRUG ABSORPTION
a) Manipulation of the Drug
The physicochemical properties of a drug which influence drug absorption include:
lipid solubility and partition coefficient.
pKa.
molecular weight and volume.
aqueous solubility.
chemical stability.

39. These properties can be manipulated to achieve more favorable absorption characteristics for a drug
For example, various lipidization strategies can be employed to increase the lipophilicity of the drug and thereby increase its membrane-penetrating ability and absorption via transcellular passive diffusion.
The hydrogen-bonding tendency of a drug molecule can be minimized by substitution, esterification or alkylation of existing groups on the molecules, which will decrease the drug's aqueous solubility and favoring partitioning of the drug into lipidic membranes.

40. Drug solubility may be enhanced by the use of amorphous or anhydrous forms, or the use of the corresponding salt form of a lipophilic drug.
Low molecular weight analogues of an active moiety can be developed, to facilitate trans-membrane transport. By prepare derivatives which are substrates of natural transport carriers like peptides.

41. b) Manipulation of the formulation
Various formulation additives may be included in the dosage form in order to maximize drug absorption.
1. Penetration enhancers
Penetration enhancers are substances that facilitate absorption of solutes across biological membranes.

42. 2. Mucoadhesives
Mucoadhesives, which are generally hydrophilic polymers, may be included in a dosage form to increase drug bioavailability.
These agents are believed to act by:
Increasing the contact time of the drug at the absorbing surface.
Increasing the local drug concentration at the site of adhesion/absorption.
Protecting the drug from dilution and possible degradation.

43. 3. Enzyme inhibitors
Enzyme inhibitors in a formulation may help to overcome the enzymatic activity of the epithelial barrier.
The use of protease inhibitors facilitates the absorption of therapeutic peptides and proteins.