avinash kodoori mpharm (pharmceutics) ii semester department of pharmaceutics uniiversity college of...

Avinash KodooriMpharm(Pharmceutics)II semesterDepartment of PharmaceuticsUniiversity College of Pharmaceutical SciencesKakatiya UniversityWarangal

1. Role of the lymphatic system2. Organisation of Lymphatic system3. Formation of Lymph4. Fat absorption5. Advantages of intestinal lymphatic drug

transport6. Enhancing Lymphatic Transport

a) Prodrug approachesb) Formulation approaches

7. Conclusion

Fluid recovery:

Fluid continually filters from our blood capillaries into the tissue spaces.

Proteins “leak” into the interstitial fluid

The blood capillaries reabsorb most of it

Each day, they lose an excess of 2 to 4 L of water and one-quarter to one-half of the plasma protein.

The lymphatic system absorbs this excess fluid and returns it to the bloodstream by way of the lymphatic vessels.

Drainage system of the body

Immunity:

As the lymphatic system recovers excess tissue fluid, it also picks up foreign cells and chemicals from the tissues.

On its way back to the bloodstream, the fluid passes through lymph nodes, where immune cells stand guard against foreign matter. When they detect it, they activate a protective immune response.

Lymphocytes

Lipid absorption:

In the small intestine, special lymphatic vessels called lacteals absorb dietary lipids that are not absorbed by the blood capillaries

Lymphatic capillaries

Lymphatic vessels

Lymph nodes

Collecting ducts

Lymphatic capillaries:

slightly larger than blood vessels

Have a unique one way structure that permits interstitial fluid to flow into them but not out

Lymph nodes:

Lymph nodes are small encapsulated organs located along the pathway of lymphatic vessels

1 mm to 1 to 2 cm in diameter

widely distributed throughout the body, with large concentrations occurring in the areas of convergence of lymph vessels.

Afferent lymphatic vessels carry lymph into the nodes where waste products and some of the fluid are filtered out

Efferent lymphatic vessels carry lymph out of the node to continue its return to the circulatory system

Lymphocytes, which are specialized white blood cells located within the lymph node, kill pathogens that may be present.

Lymph nodes also trap cancer cells and slow the spread of the cancer until they are overwhelmed by it.

Functions of a lymph node:

1)filter the lymph

2)assist bone marrow and the thymus in the production and maturation of lymphocytes

3)assist in getting an immune response going

Lacteals: Specialised lymphatic

capillary

Present in the villi of

the small intestine.

It absorbs dietary fats

Fenestrated blood capillaries 20-100 nm

RBC 6-8μm = 6000-8000 nm

Lymphatic capillaries 50-500 nm upto 1000 nm

1) Emulsification by lecithin and bile acids

2) Fat hydrolysis by lipases to leave mono glycerides

3) Micelle formation by aid of bile acids

4) Chylomicron formation in enterocytes

5) Uptake of Chylomicrons into lymph

Briefly, lipids are hydrolysed in the stomach and small intestine to the corresponding 2-monoglyceride (MG) and fatty acid (FA)

They are absorbed into the enterocyte, re-esterified into triglyceride (TG) and ‘packaged’ into intestinal lipoproteins., chylomicrons and very low density lipoproteins (VLDL),

Avoidance of hepatic first pass metabolism. Increased bioavailability Selective treatment of diseases and

infections of the mesentric lymphatic. Enhancement of absorption of large

molecules such as peptides and particulates. Targeting Inhibition of cancer cell

metastasis. Sustained drug action Transport of poorly water soluble and

highly lipophilic drug candidates

Avoidance of hepatic first pass metabolism

First Pass Effect

Selective treatment of diseases and infections of the mesentric lymphatic

Elephantiasis occurs in the presence of

microscopic,thread-like parasitic worms of

Wuchereria bancrofti, Brugia malayi, and B. timori

The adult worms live in the human lymphatic system.

Obstruction of the lymphatic vessels leads to swelling in the lower torso, typically in the legs and genitals.

Lymph and Cancer metastasis

T N M

TNM Classification of Malignant Tumours (TNM)

T N M

size or direct extent of the primary tumor

degree of spread to regional lymph nodes

presence of metastasis

0-4 0-3 0-1

Sustained drug action

Blood flow : Lymph flow

500:1

A log octanol/water partition coefficient i.e,

Log P> 5

Soluibilty in lipids

atleast 50 mg/ml

33.5%2.3%

Methods to improve lymphatic transport

◦ Prodrug approaches

◦ Formulation approaches

Prodrug approaches

The molecular and physico-chemical features of candidate compounds for lymphatic transport are restrictive due to the requirement for high lipophilicity.

Therefore, the design of lipophilic prodrugs is a logical approach for the enhancement of lymphatic transport.

Simple ester/ether prodrugs

The fat soluble vitamins (A, D, E and K) are poorly water soluble and rely on transport via the intestinal lymphatics for absorption

The major problems associated with their

formulations1) low absorption and 2) chemical instability.

Aliphatic esters have been synthesised to improve stability and to enhance absorption and lymphatic transport

Simple ester/ether prodrugs ...Epitiostanol – anti mammary tumour agent

Problems -High first pass metabolism Hence given I/M

Mepitiostane; a 17-methoxy cyclopentane ether derivative• Effective orally• Improved lymphatic transport and bioavailability

Glyceride prodrugs

integrate the prodrug into a biochemical pathway associated with lipid processing.

Integration into a metabolic path way effects immobilisation of the molecule within the lipid digestion/absorption cascade thereby circumventing the absorption sink provided by the portal blood.

L-Dopa diglyceride

L-Dopa – oral bioavailability low- Significant first pass effect- only 0.2 % via lymph

L- Dopa diglyceride- 20 % via lymph

The rationale for the prodrug is that the fatty acids in the l- and 3-positions are cleaved during lipid digestion leaving the 2-substituted L- Dopa derivative, as a 2 - monoglyceride mimic, which is absorbed and incorporated into the TG resynthesis pathway.

Chlorambucil (3.4% via lymph)

a)treatment for Hodgkins & lymphomab)Significant oral bioavailability

Chlorambucil diglyceride – (26% via lymph)◦ Used to target lymph

Formulation approaches

Co administered lipid stimulates lipid turnover; thereby increasing the lipoprotein-based lipid sink into which drugs partition

Also by

1. Increased solubilisation in Intestine2. Reducing gastric emptying3. Incresase mucosal permeability

Degree of unsaturation of administered lipid

The degree of fatty acid unsaturation have large effect on the rate of absorption and partitioning of lipids between portal blood and intestinal lymph.

lipids with increasing degrees of unsaturation appear to produce larger size lymph lipoproteins and preferentially promote lymphatic lipid transport.

Example:Lymphatic transport of testosterone undecanoate

In mono unsaturated lipid vehicle=1 X In poly unsaturated lipid vehicle =2 X

Fatty acid chain length of administered lipid

fatty acids with chain lengths of 14 and above are absorbed directly into the thoracic lymph,

shorter chain lipids are absorbed directly into the blood.

Lymphatic transport of exogenously administered increased in linear fashion after co-administration with triglycerides of increasing fatty acid chain length.

  Vitamin D3

3 times More efficiently absorbed with peanut oil (C18 oleic acid) than with Miglyol (C8-C10 fatty acids)

Class of administered lipid (Structure)

Long chain fatty acid are more efficient than corresponding triglycerides

Shorter lag time Improved lymphatic transport

Because synthesis of chylo microns from Fatty acid is faster when compared to tri glycerides

2-fold increase in transport of DDT from C18 fatty acid when compared to corresponding triglyceride

Transport of orally administered drugs to the systemic circulation via the intestinal lymph may provide a number of delivery advantages including avoidance of first pass hepatic metabolism and site specific delivery to the lymphatics

Lymphatic drug transport should be considered as a possible mechanism for very lipophilic drugs.

Further the ability to target anti-infectives anti viral , immuno modulatory and anticancer agents specifically to the lymph holds considerable promise for the improved treatment of immune diseases including HIV and Cancer

Harper’s Illustrated Biochemistry, 26th edition,by Robert K. Murray

Principles of Anatomy and Physiology, 11th edition, by Tortora.

Essentials of medicinal physiology ,by K Sembulingam.

Saladin: Anatomy & Physiology: The Unity of Form and Function, Third Edition

Textbook of Medical Physiology by Guyton

Chistopher J.H Porter, William N. Charman Intestinal lymphatic drug transport :an update Advanced drug delivery reviews 50(2001) .

Chistopher J.H Porter, William N. Charman Uptake of drugs into the Intestinal lymphatics after oral administration Advanced drug delivery reviews 25(1997)

http://faculty.stcc.edu/AandP/AP/AP2pages/Units21to23/immune/lymph1.htm