Delivery of proteins routes of administration and absorption enhancement
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DELIVERY OF PROTEINS: ROUTES OF ADMINISTRATION AND ABSORPTION ENHANCEMENT. Parenteral Route of Administration. Intravenous (IV ) Intramuscular (IM ) S ub-cutaneous (SC ) Intraperitoneally ( IP) Intraosseous (IO). Lymphatic System. One way system: to the heart

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Saeb Aliwaini

Parenteral Route of Administration

  • Intravenous (IV)

  • Intramuscular (IM)

  • Sub-cutaneous (SC)

  • Intraperitoneally (IP)

  • Intraosseous (IO)

Saeb Aliwaini

Lymphatic System

  • One way system: to the heart

  • Return of collected excess tissue fluid

  • Return of leaked protein

  • “Lymph” is this fluid

  • Edema results if system blocked or surgically removed

Saeb Aliwaini

  • Lymph capillaries

    • Have one way minivalves allowing excess fluid to enter but not leave

    • Picks up bacteria and viruses as well as proteins, electrolytes and fluid

      (lymph nodes destroy most pathogens)

Saeb Aliwaini

Saeb Aliwaini

The Oral Route of Administration

Preferable way but;

  • protein degradation

    (ii) poor permeability

Saeb Aliwaini

protein degradation

  • Pepsins cleave peptide bonds between two hydrophobic

    amino acids at acidic ph.

    Other endopeptidases ( trypsin, chymo-trypsin, and elastase)

    are active in the GI tract at neutral pH values

    Exopeptidases(carboxypeptidaseA and B)

Saeb Aliwaini


  • High molecular weight molecules do not readily penetrate

    -The oral route of administration for therapeutic proteins is not the best choice till now.

Saeb Aliwaini


  • Oral vaccines:

    only a (small) fraction of the antigen (protein) has to reach lymphocytes and antigen presenting accessory cells located in Peyer’s patches.

    The B-lymphocyte population includes cells that produce secretory IgA antibodies

Saeb Aliwaini

Peyer’s patches

microfold (M) cells

little lysosomal degradation capacity

Goblet cell density is reduced over Peyer’s patches.

This facilitates access to the M cell

To improve antigen delivery via the Peyer’s patches and to enhance the immune

response by using microspheres, liposomes or modified live vectors, such as attenuated bacteria and viruses have been used.

Saeb Aliwaini

Saeb Aliwaini

Alternative Routes of Administration

The nose, lungs, rectum, oral cavity, and skin have been selected as potential sites of application.

Nasal, buccal, rectal, and transdermal routes needs absorption enhancing


-The bioavailability in rats of intratracheally

administered protein solutions with a wide range of molecular weights.

-In humans the drug should be inhaled instead of intratracheallyadminstered

The first pulmonary insulin formulation was

approved by FDA in January 2006

Saeb Aliwaini

  • Uptake of insulin is faster than after a regular SC insulin injection (peak 5–60 minutes versus 60–180 minutes).

  • The fraction of insulin that is absorbed from the lung is estimated to be around 20%

  • These figures demonstrate that insulin absorp-tion via the lung may be a promising route; but the fraction absorbed is small.

Saeb Aliwaini

  • We still look to develop a system that temporarily decreases the absorption barrier resistance with minimum and acceptable safety concerns

  • Suggestions :

    - Absorption Enhancing Effects

Saeb Aliwaini

Mechanism of Absorption Enhancement: Permeation

enhancers in general act by following ways :

1. Increasing the fluidity of the cell membrane

2. Extracting inter and intracellular lipids

3. Disrupting lipid structure e.g., solubilization by

formation of micelles to create aqueous channels

4. Altering cellular proteins

5. Increasing the thermodynamic activity of the


6. Overcoming enzymatic barriers, particularly for

peptide and protein drugs

7. Altering surface mucin rheology

Saeb Aliwaini

Saeb Aliwaini

Sodium glycodeoxycholate acts in the intercellular lipid domain at lower concentrations (2 mM), apparently reducing the amount of polar lipids, whereas disorganizing cell membrane lipids at higher concentrations

Generally, they act reversibly without producing major damage to the mucosa. Bile salts used in permeation enhancement studies include the trihydroxy salts sodium cholate, sodium glycocholate, and sodium taurocholate and the dihydroxy salt sodium deoxycholate, sodium glycodeoxycholate, and sodium taurodeoxycholate.

Saeb Aliwaini

Major issues now

being addressed are reproducibility, effect of pathological conditions on absorption and

safety aspects of chronic use. Interestingly, absorption enhancing effects were shown to be species dependent. Pronounced differences in effect were observed

between rats, rabbits, and humans.

Saeb Aliwaini


Iontophoresisa transdermal electrical current is induced by positioning two electrodes on different places on the skin

Saeb Aliwaini

Saeb Aliwaini

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