Lipid-Based Formulation in Customized Enteric Capsule for Oral GLP-1 Receptor Agonist Peptide Delivery

Objectives of this study

Multiple factors affect oral delivery of therapeutic peptides such as acidic and enzymatic degradation in the upper gastrointestinal tract and poor intestinal permeability.

Several studies report the benefit of lipidbased formulations (LBF) combined with the formation of hydrophobic ion pairs (HIP) to enhance oral bioavailability of peptides.

Therefore, the objectives of this study were to:
• Develop an LBF of glucagon-like peptide-1 (GLP-1) receptor agonist, exenatide (EXE)
• Manufacture an enteric capsule compatible with EXE formulation
• Demonstrate innovative capacities of formulation and customized functional capsules

Methodology of the study

EXE HIP formation and characterization

EXE HIP formation & characterization

Ability of sodium lauryl sulfate (SLS) and sodium docusate (DOC) to form HIPs with EXE was evaluated by measuring unprecipitated EXE using HPLC.

 

Customized enteric capsule manufacturing and characterization

Customized size #0 gelatin/HPMC-AS double layer
capsules were manufactured using patent pending
technology.

The ability of the capsule to protect sensitive APIs
from gastric acid and protease degradation were
evaluated by:

• dissolution using uncoated, acid-sensitive esomeprazole pellets in unsealed capsules
• disintegration with lactose-filled capsules using the Ph. Eur. method for gastro-resistant capsules

Results

EXE HIP formation and characterization

• The highest measured precipitation efficiency was for the molar ratio 1:4 (EXE:DOC)—an expected result, given that EXE exhibits 4 cationic function in an acid medium, and each pairing with one anionic function of the selected counter ion
• This ratio was selected for assessing LBF development
• LogP measurement show higher lipophilicity increase with DOC as counter ion

• Labrafac®MC60 and propylene glycol were selected as the best solvents
• A homogeneous formulation with small particle size upon dispersion was selected to favor intestinal absorption

EXE and EXE:DOC HIP solubility

Formulation characteristics

The LBF prototype was defined as:

• 85% Labrafac®MC60 (glycerol monocaprylocaprate)
• 10% Kolliphor®RH40 (Polyoxyl 40 castor oil)
• 5% propylene glycol
• 6 mg/mL EXE (in native form or HIP)
• 20 mg/mL sodium caprate

The presence of LBF protected EXE from α-chymotripsin-induced proteolysis

• There was rapid degradation of EXE in the presence of chymotrypsin
• The designed LBF provided a protective effect

Customized enteric capsule manufacturing and characterization

• The EMT dissolution test confirmed the capsule’s enteric properties
• No release of encapsulated EMT in acid milieu, followed by rapid and complete EMT release at pH 6.8

Filled capsule enteric properties

Customized size #0 gelatin/HPMC-AS double-dipped capsules filled with EXE:DOC HIP showed:

• No dissolution and retention of enteric properties after 1 hour in HCl 0.1N
• Disintegration within 5 minutes at pH 6.8

Conclusion

This study proposes an innovative and scalable solution to increase oral bioavailability of therapeutic peptides using a combination of lipid-based formulations, hydrophobic ion pairing, permeation enhancer and customized enteric capsules.

The results highlight the capacity to support formulation development, and manufacture a functional capsule that is compatible with fill formulation.

This offers biopharmaceutical companies a novel way to maximize the effectiveness of their therapeutic peptide. If you would like to discuss how we can support you with your drug development journey, please speak with our scientists at Innovaform® Accelerator.

See the full technical brochure on Oral GLP-1 here:

(click the picture to download the brochure)

Source: LONZA technical brochure Oral GLP-1

Read also the following interesting articles by LONZA here:

• Lonza Expands its Capsugel® Capsule Offering to Include Titanium Dioxide-Free White Hard Gelatin Capsules
• In Vivo Evaluation of a Gastro-Resistant Enprotect® Capsule under Postprandial Conditions

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