The oral delivery of protein and peptide drugs faces challenges due to enzymatic degradation in the gastrointestinal tract and poor membrane permeability, resulting in very low bioavailability typically less than 1%. Various pharmaceutical approaches can help address these challenges, including chemical modification of the protein or peptide to increase stability and permeability, use of enzyme inhibitors to protect against degradation, penetration enhancers to disrupt the mucosal barrier, and mucoadhesive polymeric systems to prevent presystemic metabolism and target site-specific delivery. While oral delivery of proteins and peptides remains difficult, recent research utilizing these approaches is demonstrating some promising results.

1. Daffodil International University
Why oral bioavailability is more
challenging for biotech product and how
to solve these challenges?

2. ABSTRACT
Protein and Peptide drug delivery system are the Novel drug Delivery System.
Proteins and peptides are the most abundant components of biological cells. They exist
functioning such as enzymes, hormones, structural element and immunoglobulin. The
distinction between peptides and proteins is having a peptide contains less than 20 amino
acids, having a molecular weight less, while a protein possesses 50 or more amino acids and
its molecular weight lies above this value.
The most of pharmaceutical proteins and peptides are absorbed IM, IV and Subcutaneous
route of Absorption, but the oral route is more convenient for absorption of protein as
compared to other.

3.  Protein Protein can be define as high molecular weight mixed polymer of α-amino
acid Joined together with peptide linkage is known as protein.
• Protein is a group of amino acid (Essential amino acid and Non Essential amino
acid).
 Peptide Peptides are short polymers of amino acid (monomers) linked by peptide
bonds is known as peptide.
• The covalent chemical bonds formed between two molecules when the carboxyl
group of one molecule reacts with the amino group of the other molecule.
Department of Pharmaceutics
Introduction

4. STRUCTURE OF PROTEIN

6. Most pharmaceutical proteins and peptides are formulated as solution or
suspensions and delivered by invasive route such as IM, IV, or SC Injections.
These routes have their own Demerits like-
• Poor patient compliance.
• Pain and discomfort associated with these routes.
• Inconvenience to treat the pediatric(শিশুর োগ) patients.
ROUTES OF ABSORPTION

7. The oral route presents a series of advantages towards other drug delivery systems
like
 It is most convenient route of drug administration.
 Avoidance of pain and discomfort associated with injections.
 Higher patient compliance.
Oral route would be preferred to any other route because of its high levels of patient
acceptance and long term compliance, which increases the therapeutic value of the drug.

8. Designing and formulating a polypeptide drug delivery through the gastro intestinal tract has been a
persistent challenge because of their unfavorable physicochemical properties, which includes
 Enzymatic degradation.
 Poor membrane permeability.
 Large molecular size.
 Short plasma half-life.
 High immunogenicity.
 Tendency to undergo denaturation.
 Less bioavailability (less than 1%).
The other routes that have been tried with varying degrees of success are : Oral, Buccal, Intranasal, Pulmonary,
Transdermal and Ocular.
CHALLENGES IN ORAL ROUTE OF ADMINISTRATION

9. The oral administration of protein and peptide drugs faces two potential problems
during their oral absorption :
1. Metabolic degradation of therapeutic proteins and peptides by variety of
proteolytic enzymes.
2. Poor membrane permeability.
Consequently, the absolute oral bioavailability levels of most peptides and proteins are
less than 1%. The challenge here is to improve the oral bioavailability from less than 1% to
at least 30-50%.

10. PHARMACEUTICAL APPROACHES
 Chemical Modification (Prodrug approach)
1. Amino acid modification.
2. Hydro phobization.
 Enzyme (protease) inhibitors.
 Penetration enhancers.
 Formulation vehicles.
 Mucoadhesive polymeric systems.

11. CHEMICAL MODIFICATION
 A chemical modification of protein and peptide drugs improves their enzymatic
stability and membrane permeation. Also it can be used for minimizing the
immunogenicity.
 Prodrug approach includes
 Amino acid modification -Modification of individual amino acids by the substitution of
D- amino acid with the L-amino acid can significantly alter physiological properties of
proteins and peptides. e.g. Desmopressin and Deaminovasopressin.
 Hydrophobization - The Surface modification using the lipophilic moieties. e.g. NOBEX
INSULIN.

12. ENZYME (PROTEASE) INHIBITORS
 The whole GIT and liver tend to metabolize proteins and peptides into smaller
fragments of 2-10 amino acids with the help of variety of proteolytic enzymes.
 So protease inhibitors are co-administered with proteins and peptides to alter
the environment for maximum enzyme stability to suppress proteolytic activity.
They are of 4 major types
1. Aspartic proteases [Pepsin]
2. Cystinyl proteases [Papain]
3. Serinyl proteases [Thrombin]
4. Metallo proteases [Carboxypeptidase]

13. PENETRATION ENHANCERS
 Penetration enhancers are the formulation components that is important to
disrupt the mucosal barrier to improve the permeation of large macromolecular
substances like proteins and peptides.
 Following classes of compounds are commonly used :
1. Surfactants - Polysorbate, SLS
2. Chelating agents - EDTA.
3. Fatty acids - Sodium caprate.
4. Mucoadhesive polymers - Thiomers, cellulose derivatives.
5. Phospholipids - PC.

14. FORMULATION VEHICLES
The oral delivery of therapeutic proteins and peptides can be successfully
achieved by using various carrier systems like:
 Dry emulsions
 Microspheres
 Liposomes
 Nanoparticles

15. MUCOADHESIVE POLYMERIC SYSTEMS
 These systems prevent the Presystemic metabolism of the therapeutic proteins
and peptides.
e.g. Thiomers, polyacrylic acid derivatives and cellulose derivatives.

16. CONCLUSION
Delivering proteins and peptides by the oral route is extremely challenging. The very nature of
digestive system is designed to breakdown these polypeptides into amino acids prior to absorption.
The low bioavailability of drugs remains to be an active area of research. Several sites in the GIT
have been investigated by researchers, but no major breakthrough with broad applicability to
diverse proteins and peptides has been achieved. Considerable progress has been made over past
few years in developing innovative technologies for promoting absorption across GI and numbers of
these approaches are demonstrating potential in clinical studies. Chemical modification and use of
mucoadhesive polymeric system for site-specific drug delivery seen to be promising candidates for
protein and peptide drug delivery.