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DELIVERY OF PROTEINS: ROUTES OF ADMINISTRATIONAND ABSORPTION ENHANCEMENT

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Parenteral Route of Administration

• Intravenous (IV)• Intramuscular (IM)• Sub-cutaneous (SC)• Intraperitoneally (IP)• Intraosseous (IO)

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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

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• 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)

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The Oral Route of Administration

Preferable way but;(i) protein degradation(ii) poor permeability

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protein degradation

• Pepsins cleave peptide bonds between two hydrophobicamino acids at acidic ph.

Other endopeptidases ( trypsin, chymo-trypsin, and elastase)are active in the GI tract at neutral pH values

Exopeptidases (carboxypeptidase A and B)

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Permeability

• High molecular weight molecules do not readily penetrate

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

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Exceptions • 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

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

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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 technology

-The bioavailability in rats of intratracheallyadministered protein solutions with a wide range of molecular weights.

-In humans the drug should be inhaled instead of intratracheally adminstered

The first pulmonary insulin formulation wasapproved by FDA in January 2006

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• 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.

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

• Suggestions : - Absorption Enhancing Effects

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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 drug 6. Overcoming enzymatic barriers, particularly for peptide and protein drugs 7. Altering surface mucin rheology

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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.

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Major issues nowbeing addressed are reproducibility, effect of pathological conditions on absorption andsafety aspects of chronic use. Interestingly, absorption enhancing effects were shown to be species dependent. Pronounced differences in effect were observedbetween rats, rabbits, and humans.

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

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