PHC 554

Pharmaceutical Material and

Product Characterization

PBL 4:
LIRAGLUTIDE
As Oral Consumption
D2: Group 3
Siti Amalia binti Mohd Azam Salimi Amni binti Adnan Siti Norbaya binti Abdul Rahim
(2017421298) (2017421374) (2017421008)

Siti Norfitriah binti Mohd Salleh Wan Atiqah binti Wan Mohd Azmi
(2017443432) (2017443366)
Contents
• Introduction of Liraglutide

• Limitations of Peptide and Liraglutide

• Strategies to Improve Oral Delivery of Liraglutide

• Proposed Oral Dosage Form for Liraglutide

Introduction
 Liraglutide

Liraglutide is a long-acting, fatty acylated glucagon-like peptide-1 (GLP-1) analog

Liraglutide is indicated in combination with diet and exercise to improve glycemic control in patients
(10 years and older) with type 2 diabetes mellitus
 Physicochemical properties of liraglutide
Physicochemical properties
Molecular formula
Molecular formula
Molecular weight
Molecular weight
Color
Color
Solubility
Solubility
3751 g/mol
3751 g/mol
White to almost white powder
White to almost white powder
• Freely soluble in aqueous base solutions
• Freely soluble in aqueous base solutions
(>270mg/mL)
• (>270mg/mL)
Solubility in water decreases below pH 7
•• Solubility
Lowest at inpHwater decreases below
4-5 (approximately pH 7
0.05mg/mL)
•• Lowest
Increasesat marginally
pH 4-5 (approximately 0.05mg/mL)
at pH 2.5 where it is very
• Increases marginally
slightly soluble at pH 2.5 where it is very
• slightly
Soluble soluble
in methanol (68 mg/mL)
•• Soluble in methanol
Very slightly (68ethanol
soluble in mg/mL)(1.1 mg/mL)
• Very slightly soluble in ethanol (1.1 mg/mL)

pH 9.3 (1 mg/mL aqueous solution of drug substance)

pH 9.3 (1 mg/mL aqueous solution of drug substance)

Nordisk N, Leginus IJ. CHEMISTRY REVIEW NDA 206321 SaxendaTM (Liraglutide [rDNA origin] Injection)
For the Division of Metabolism and Endocrinology Products CHEMISTRY REVIEW #1.
LIMITATIONS of
PEPTIDE and
LIRAGLUTIDE
Limitation to the Use of Peptides
as Therapeutics
 Low oral bioavailability and shorter half-life

 Poor specific bio-distribution due to high conformational

flexibility,

 Eventual risk of immunogenic effects as most peptide and protein

drugs appear immunogenic

 High production costs of synthetic peptides than small molecules

of the same molecular weight of 5000D by more than 10-fold

 Therapeutic peptides and proteins also tend to undergo

denaturation, aggregation, and adsorption which limit their active
concentration and proper function in vivo
Limitation to the Use of Liraglutide
as Therapeutics
Glucagonlike peptide-1 (GLP-1)
o The half-life of GLP-1 is very short
approximately 2 minutes due to its
rapid degradation by the enzyme
dipeptidyl-peptidase-4 (DDP-4)
o Limited clinical experience with its
use
o acts only when plasma glucose
levels are high and are excreted by
renal clearance
Liraglutide
o High incidence of gastrointestinal
adverse effect
o Possible interference with
pharmacokinetics of orally
administered drugs because of the
delay in gastric emptying
o Lack of long-term efficacy and
safety data
WAYS to IMPROVE ORAL
DELIVERY of
LIRAGLUTIDE
CONVENTIONAL approaches
1. Enzyme inhibitor
• Protease inhibitor
• Prevent cleavage of peptides drug in GIT
• Eg; aprotinin, camostat mesylate, chromostatin

2. Permeation enhancer
• Intestinal mucosa is a complex structure
• Enhance permeability across the mucosal walls
• Reversibly open up the tight junction
• Eg; chitosan, thiolated polymer, surfactant
• Drawback
 dissolve bio-membrane leads to local inflammation
3. Mucoadhesive polymer
• Adhere to mucosal membrane of GIT
• Increases drug concentration gradient and resident time (reduce Cl)
• Avoid mucociliary clearance system, high bioavailability
• Formulated with enzyme inhibitor (better absorption)
• Eg; thiolated polymer, chitosan, alginate

4. Emulsion
• Decrease degradation and increase permeation
• Physiochemically unstable (immiscible liquids)
• How to overcome?
 dry emulsion preparation
NOVEL approaches
1. Nano Carrier
• Drug to be delivered is encapsulated in the carrier and delivered to target area
• 2 types: polymer nanoparticle(NP) and solid-lipid NP
• Surface characteristic plays crucial role in crossing mucosal layer
 +vely charged NP produces strong mucosal adhesion to –vely mucin glycoside
 longer residence time in epithelial cell and increase intake
• Size of NP determine the uptake by M cell (preferred 20-100 nm, up to 500 nm) and
enterocytes (< 50 nm)
2. Microsphere
• Particle size ranging between 1-50 microns
• Prepared using synthetic or natural polymer (eg: polysaccharide chitosan)
• Protect proteins/peptides from enzymatic hydrolysis and acidic pH
• Control drug release at specific site through pH-sensitive polymer

3. Liposomes
• Can incorporate both hydrophilic and hydrophobic drug
• Encapsulates protein/peptide drugs in lipid core
• Attachment with Ab on the surface improve target specificity
• Advantages:
• Prevent degradation by oxidation/deamination
• Avoid first pass metabolism (taken up by lymphatic system to systemic circulation)
4. Modifying Peptide Structures
 Biotynilation
• Peptide surface modification by biotin (Vitamin H)
• actively pass through the intestine membrane via sodium-dependent multivitamin transport
• Enhance absorption
• E.g : Lys26,34–biotin–GLP-1 proved oral hypoglycemic efficacy approximately 9 folds compared
to the native GLP-1

 PEGylation
• Attaching polyethylene glycol (PEG) covalently to peptide
• preventing recognition and degradation by proteolytic enzymes, enhancing the stability,
potency of proteins and peptides
• PEG on biotinylated GLP-1 proves better in enhancing absorption and enzyme resistance than
just biotinylation
 Lipidization
• Why need to increase lipophilicity ?
• Enhance oral bioavailability, protect from enzymatic degradation, increase absorption and stability
• The peptide will solubilize albumin or serum lipoprotein
• Enhance stability and circulatory half-life.
• E.g: The attachment of 1,3-dipalmitoylglycerol to insulin by an ester bond improves the intestinal
penetration and stability against enzymatic degradation.

 Unnatural Amino Acid

• The substitution of natural amino acids with unnatural amino acid
• More resistant to enzymatic degradation
• Eg: replacement of ala2 with D-ala2 was proved to improve drug stability, prolong half-life and
increase activity
5. Cell penetrating peptides (CPP)
• Improve the delivery of proteins and peptides over the plasma membrane
• Classified based on the origin of peptide or physicochemical properties
• Origin of peptide: synthetic, chimeric, protein-derived
• Physicochemical properties: cationic, amphipatic, hydrophobic
• Eg: Amphipathic CPP (penetratin) was proved that physically blending penetratin with insulin
could be successful way for oral delivery of insulin under harsh intestinal environment
• Limitation: could degrade by extracellular and intracellular enzymes because of chemical
instability
• Improves by alteration of the amino acid stereochemistry that might reduce the cell-
penetrating of CPP and/or its ability to act as a delivery vector.
PROPOSED ORAL
DOSAGE FORM
 Liraglutide NANOCAPSULES
Coating Components

Binding mechanism of capsules’ coating between the sodium alginate, calcium,

and chitosan around the liraglutide.

Shamekhi F, Tamjid E, Khajeh K. Development of chitosan coated calcium-alginate nanocapsules for oral delivery of liraglutide to diabetic patients. Int
J Biol Macromol [Internet]. 2018 Dec 1 [cited 2020 Dec 30];120(Pt A):460–7. Available from: https://pubmed.ncbi.nlm.nih.gov/30125628/
Advantages of Nanocapsules

• Increase drug-loading efficiency, while reduce the

polymeric matrix content of nanoparticles.

• Avoiding the degradation or burst release induced by

pH, temperature, enzymes and other factors.

• Able to interact with targeted biomolecules, thus

enabling for targeting drug delivery .

• Higher safety and efficacy.

• Improved patient compliance.

References
• Cao S jun, Xu S, Wang H ming, Ling Y, Dong J, Xia R dong, et al. Nanoparticles: Oral Delivery for Protein and Pe
ptide Drugs [Internet]. Vol. 20, AAPS PharmSciTech. Springer New York LLC; 2019 [cited 2020 Dec 23]. p. 1–11.
Available from: https://link.springer.com/article/10.1208/s12249-019-1325-z
• Deng S, Gigliobianco MR, Censi R, Di Martino P. Polymeric nanocapsules as nanotechnological alternative for dru
g delivery system: Current status, challenges and opportunities. Nanomaterials. 2020;10(5).
• Francisca Araújo, M.Sc., Pedro Fonte, M.Sc., [...], and Bruno Sarmento, P. D. (2012). Oral Delivery of Glucagon-Li
ke Peptide-1 and Analogs: Alternatives for Diabetes Control? Journal of Diabetes Science and Tehcnology. Retrie
ved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570891/
• Gupta S, Jain A, Chakraborty M, Sahni JK, Ali J, Dang S. Oral delivery of therapeutic proteins and peptides: a revi
ew on recent developments. Drug Deliv [Internet]. 2013 Aug 20 [cited 2020 Dec 23];20(6):237–46. Available from:
http://www.tandfonline.com/doi/full/10.3109/10717544.2013.819611
• Haggag, Y. A. (2018). Peptides as Drug Candidates: Limitations and Recent Development Perspectives. Biomedic
al Journal of Scientific & Technical Research, 8(4), 6659–6662. https://doi.org/10.26717/bjstr.2018.08.001694/10.
1016/j.jsps.2014.06.004
• Homayun B, Lin X, Choi HJ. Challenges and recent progress in oral drug delivery systems for
biopharmaceuticals. Pharmaceutics. 2019;11(3)
• Mayer C. Nanocapsules as drug delivery systems. Int J Artif Organs [Internet]. 2005 [cited 2020 Dec
30];28(11):1163–71. Available from: https://pubmed.ncbi.nlm.nih.gov/16353123/
• Mikhail, N. E. (2010). Is liraglutide a useful addition to diabetes therapy? Endocrine Practice, 16(6), 1028–1037.
https://doi.org/10.4158/EP10076.RA
• Muheem A, Shakeel F, Jahangir MA, Anwar M, Mallick N, Jain GK, et al. A review on the strategies for oral
delivery of proteins and peptides and their clinical perspectives. Saudi Pharm J [Internet]. 2016;24(4):413–28.
Available from: http://dx.doi.org
• Nordisk N, Leginus IJ. CHEMISTRY REVIEW NDA 206321 SaxendaTM (Liraglutide [rDNA origin] Injection) For
the Division of Metabolism and Endocrinology Products CHEMISTRY REVIEW #1.
• Shamekhi F, Tamjid E, Khajeh K. Development of chitosan coated calcium-alginate nanocapsules for oral
delivery of liraglutide to diabetic patients. Int J Biol Macromol [Internet]. 2018 Dec 1 [cited 2020 Dec 30];120(Pt
A):460–7. Available from: https://pubmed.ncbi.nlm.nih.gov/30125628/