Transcript drug targetting to lymphatic system

DEPARTMENT OF PHARMACEUTICS

The term “DRUG TARGETTING” implies to the which exists for locallising
a therapeutic agent on the minority of cells that are actually in need of
treatment.
ADVANTAGES:

Achieving the aim of directing the drug with specific sites

Decreasing the dose of drugs

Minimising the adverse effects caused by potent drugs
DRUG TARGETTING TO LYMPHATIC
SYSTEM:

Lymphatic drug targeting refers to targetting of drugs into the
lymphatic system for drug action or for their transportation in the
lymph to specific tissues of interest.

Lymphatics provide the primary route of drug absorption and drug
concentration in lymph is 5-10,000 times higher than in systemic
plasma.
ADVANTAGES:
1.
Avoidance of hepatic first pass metabolism leads to enhanced
bioavailability.
2.
Selective treatment of diseases and infections of Mesentric
lymphatic.
3.
Enhancement of the absorption of large molecules such as Peptides
and particulates.
4.
Inhibition of cancer cell metastasis.
5.
Reduction in local gastrointestinal irritation and toxicity
6.
An overall modulation in rate of drug input, thus providing a
sustained delivery
LYMPH:



Is clear watery fluids that are found in the lymphatic vessels.
Is intermediary between blood in the capillary and tissue.
Lymph is similar in composition to plasma except it contains less
amount of protein, hence lymph contains:
water,lymphocytes,granulocytes.respiratorygases,nuitrent,hormon
es,ions urea. No Erythrocytes and large protein
LYMPH NODE:


Produce lymphocytes
Filterout solid particles
including bacteria.
•TONSILS protects respiratory tract
and GIT from pathogens
•THYMUS produce T-lymphocytes
•LYMPH NODE filter out foreign
material.
•SPLEEN destroys old RBC and
produce antibodies
•BONEMARROW produce Tlymphocytes and B-lymphocytes.
Lymphatics of skin and subcutaneous tissue.

The lymphatics of the skin consists of superficial lymphatic plexus
and deep fluxeslying in a deeper part of the dermis adjacent to
the subcutaneous tissue

The popliteal lymphatics drian the skin and subcutaneous tissue.

Lymph flow is 1ml/hr/100 gm in this region
Lymphatics of skeletal system

Lymphatic capillaries are located between muscle fibers fasica

Muscles have two main drainage systems that is superficial and
deep seated

Lymph flow from skin was higher than from muscle.
VESICLES
INTERCELLULAR JUNCTIONS
LYMPHATIC TARGETING AREAS

Uptake of particulates-Endocytosis by Enterocytes:

Intestinal macrophages by Phagocytosis
Uptake via (1) Regular epithelial cells (2) M cells of the lymphoid
aggregate (3) Persorption and (4) the Paracellular transport

Uptake by Peyer’s patches
 PHYSICOCHEMICAL
PROPERTIES OF THE
DRUG
 ROUTE OF ADMINISTRATION
 DESIGN OF DRUG DELIVERY SYSTEM
PHYSICOCHEMICAL PROPERTIES :
Co-administration of lipid vehicle :
-
Lipids increases the bioavailability of the administered drug by
1.
Decreased gastric emptying rate
2.
Increased solubility and dissolution rate of the drug
3.
Formation of lipoproteins
Lymphatic drug targeting through the oral route:
-Rate of lymph flow in intestine is 500 times less than the blood in portal

vein
-After oral administration ,macromolecules are uptaken by the M cells in
Peyers patches and distribution via the mesenteric lymph towards the
lymph nodes
-Avoidance of first pass metabolism
Lymphatic drug targeting through Parentral route:
-Depend on:

1.volume of injection
2.area of the drug depot formed after injection
3.drug concentration and pH
4.tissue condition at the site of injection affect the rate of diffusion
5.biological factors i.e body movements,disease state,age
-Various parentral routes are:
 subcutaneous administration:
-Lymphotropic delivery system i.e liposomes
-Factors affecting are site of injection and liposomal size
-MW between 1000-16000 are absorbed well
eg:Interferons,interleukins

Intramuscular administration:
-Liposomes have enhanced uptake through this route
-Factors affecting are liposome size and charge
- Mechanism by Endocytosis
Intraperitoneal administration:

-Liposome absorption is not effected by the size
-Nanoparticles of polyhexylcyanoacrylate(543nm),higher levels were
detected in lymph by I.P than I.V
e.g: smaller microparticles of biodegradable polymers

Intrapulmomary administration:
-Transfer of fluorscein isothiocyanate to the intrapulmonary lymph
nodes increased with increasing MW
- Transfer is increased by absorption enhancers like sodium
glycocholate,mixed micelles

Microspheres and nanospheres –Oral & parentral route

Liposomes – parentral route

Chemical modification of drugs(prodrugs)
Useful in treating lymphomas,tumor metastates & inflammatory
conditions of the lymphatics
Eg; glyceride prodrug of Chlorambucil

Pharmaceutical modifications
Passive targeting,actively delivered by physical forces such as magnetic
force or biochemical interactions.
Emulsions:
-order of selective uptake
o/w > w/o > aqueous solution
- Intraperitoneal and intramuscular route
- used for controlled and sustained release
eg:anticancer drug :Lipiodal-pirarubicin emulsions
Liposomes:
- Delivery through i.V route is limited due to drug uptake by
reticuloendothelial system
-
Given by subcutaneous, Intraperitoneal and Intramuscular
administration
-
Proposed as carriers for the delivery of therapeutic and diagnostic
agents to the lymphatic system
- Phagocytosis by macrophagess
Factors influencing lymphatic absorption and lymph node uptake
1.
Influence of liposome size:
E.g:Melphalan encapsulated lipospmes
Shortperiod of sonification-larger liposomes(<250nm)- slow
uptake
Prolonged sonication time-smaller lioposomes(34nm)-10 fold
higher uptake
2.Influence of liposome composition
3.Influence of liposome dose:
Percentage of dose uptaken is independent of injected dose
4.Influence of surface modification:
Surface modification with polyethylene glycol (PEG):
-Steric stabilization can be done with PEG coating of
liposomesurface.
-This liposome would not uptake by macrophages. So PEG coating
have negative effect on lymph node uptake
Surface modification with biotin:
-
The new subcutaneous delivery system comprises of biotin-coated
liposomes, showed greater lymphatic uptake when used in
combination with avidin injection to adjacent site
Surface modification with ligands:
-
Liposomes coated with non-specific human antibodies as ligand
showed greater lymphatic absorption and lymph node uptake
compared to uncoated liposomes at subcutaneous site.
-
Eg: lectin in anticancer drugs, PEG in vaccine delivery
DIFFERENT SURFACE MODIFICATION TECHNIQUES

Fabrication of polymeric micro particles for drug delivery
By soft lithography
By the double emulsion method
By solvent evaporation method
By emulsification-crosslinking method

Covalent conjugation

Encapsulation

Electrostatic surface modifications

Surface coating of particles by nanospray process

Wet chemical method

Surface graft polymerization

Co-electro spinning

Surface modification with layer-by-layer technique
Immunotherapy:
-Antibody–drug conjugates are a type of immunoconjugate with
bifunctional molecules,consisting of a targeting domain (antibody)
that localizes the conjugate to tumors and a therapeutic moiety
(antitumor drug)
Eg:murine monoclonal antibody A7 (Mab A7) against human colorectal
cancer was conjugated to neocarzinostatin (NCS) through a disulfide
bond
Polymer based drug delivery system:
-Nano/microspheres are used to improve lymphatic drug delivery
-Natural polymers :- Dextrans(24),Hyaluronic acid
synthetic polymers :- Poly(lactide-co-glycolide),Poly(L-lactic acid) etc
have been used as drug carriers for targeted lymphatic delivery
Nanoparticles:
- Biodegradable, polymeric nanoparticulate systems have been
developed to enhance the targeting ability to the lymphatic systems or
to improve the drug loading and/or the physicochemical stability of
other colloidal carriers.
Eg: Magnetite-Dextran nanoparticles
Solid lipid nanoparticles used for oral lymphatic delivery
Nanocapsules:
- A nanocapsule is an ultrafine particle with a diameter of less than 1
mm with a surface coating of a polymeric substance
- Consists :- Core vehicle-Soyabean oil,Miglyol(best used)
Polymers-Polylactides,Polyalkylcyanoacrylates
Eg: Panretin loaded nanocapsules
Modified novel nanosystems targeting lymphatic system

-
-

-
Controlled delivery of vaccines:
The controlled release of vaccines in GALT was studied. And it was
found that orally administered biodegradable microspheres targeted
the Peyer’s patches and good control over the release rate was
obtained.
Eg: staphylococal enterotoxin B toxoid
Treatment of inflammation:
The distribution of latex micro spheres in vivo as a potential targeted
system for treatment of inflammation were found in the circulation
and in inflamed tissues and excudates.

Peroral delivery of macromolecules :
-Macromolecules such as peptides and proteins are being used extensively
in therapeutics.
-Colon-specific delivery is preferred because the enzyamatic activity is
low in colon leads to increased peptide absorption
-Targeting to payer’s patches at which macromolecules can be absorbed
even of large MW.
Eg:Cyclosporin

Cancer Therapy:
- Major disadvantages of chemotherapy of cancer is non specific action of
the potent chemotherapeutic agent used.
- Approach is to alter the biopharmaceutical behavior would be the
derivitisation into a latent form with a high molecular weight.
- And to treat tumors involves the use of endogenous proteins, the so-called
biological response modifiers.

Detection of tumour metastasis:
- Lymphatic circulation is one of the major routes of movement for
metastases.
-
Liposomes can be used to detect metastases in lymph nodes
-
Eg:99MTc labelled liposomes for regional lymph node imaging

Treatment of infections:
-
Lymphatic targeting can be used beneficially to treat infections of the
lymphatics and reticuloendothelial system,used for treatment of
parasitic diseases of the liver.
-
Liposomal encapsulated antimonial drugs have been used to treat
leishmaniasis, a parasitic infection that affects the macrophages
 Controlled
and Novel drug delivery by N. K Jain,
169-186.
 Targeted and Controlled drug delivery Novel
carrier systems by S. P Vyas, R. K Khar, 129-137.
 Controlled drug delivery, Fundamentals and
applications by Robinson, Vincet. H. lee, 56.
 www. Wikepedia.com.
 www.lymphedemapeople.com