Analysis of Possible Ingredient and Manufacture Steps of Oral

GLP-1 Receptor Agonists

Zhiyue Lin

Malvern College Chengdu, Chengdu, 610000, China

Keywords: Oral Glucagon-Like Peptide 1 Receptor Agonists, Excipients, Freeze-Drying, Granulation, Tablet Coating.

Abstract: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) is a efficient medicine treating diabetes 2 and the

dosage form are mainly injection. The Rybelsus is the only oral dosage form at current. This paper analyzes

the possible ingredient and pharmaceutical techniques for different steps when putting GLP-1RAs into

manufacture process like the choose the excipients, granulation and coating. The analysis based on the

research on peptide drugs and the assignment regarding the details of Rybelsus. The data involved come from

different studies or journal and the assignment published by Novo Nordisk. This paper also analyzes the

feature the excipient need to have, the possible advantages and different between the freeze drying, dry

granulation and direct compression and sort out the two with greatest possibility to be applied based on the

feature of API, the importance of coating for biologics will be stated, the function and feature of the coating

will be mentioned and a few common example with good quality will be given.

1 INTRODUCTION

Glucagon-like peptide 1 receptor agonists (GLP-

1RAs) are a member of peptide drug which is a

unique medicine used to treat diabetes 2. At present,

the most common dosage form of GLP-1 receptor

agonists is the solution for injection as the first oral

semaglutide discovered by Novo Nordisk has

finished the clinical trial and being qualified to

publish in 2020 (European Medicines Agency, 2020).

The main difficulties that limit the clinical use of

GLP-1 receptor agonists are the extreme short half-

life time of injection (1.5-5 min) in plasma as it can

be break down by dipeptidyl peptides 4 (DDP-4)

rapidly (Hui, 2002).

According to the statistic of a clinical trial that

have been done in Japan with the purpose to sort out

which dosage form, oral or injection, leads to a better

efficacy and acceptance among Japanese diabetes 2

patients. The overall statistic stated that the oral

dosage form would result in a better blood sugar

control and the risk of hypoglycemia. The oral dosage

form has been provide with a better acceptance

among about 1000 patient (Davies, 2017). This

statistic shows the significance of putting forward the

research on oral GLP-1 receptor agonists for diabetes

2 patient.

This paper will analyze the possible ingredients

and pharmaceutical techniques that could apply to

different manufacture steps of GLP-1RAs tablets

based on the current research progress on GLP-1RAs

and the details of approved sample Rybelsus

(semaglutide).

2 LITERATURE REVIEW

Functionally, glucagon-like peptide 1 receptor

agonists imitate the function of GLP-1 that secret in

to hepatic portal system by the intestinal L cell

located in the colon and distal ileum and this type of

hormone can decrease the concentration of glucagon

and concentration of available fatty acid, slow down

the gastric emptying, increase the insulin sensitivity

and the secretion amount (Baguio, 2007, Hinnen,

2017, Prasad-Reddy, 2015). The other effects of

GLP-1 receptor agonists including positive impacts

on weight, blood pressure and the cholesterol level.

Using GLP-1 receptor agonists to treat diabetes 2 has

a relatively low risk of suffering hypoglycemia as the

effect of GLP-1RAs depend on the blood sugar

concentration and the effect is in direct proportion to

blood sugar level. However, the most common side

effects of taking GLP-1 receptor agonists includes

Lin, Z.

Analysis of Possible Ingredient and Manufacture Steps of Oral GLP-1 Receptor Agonists.

DOI: 10.5220/0011205700003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 321-326

ISBN: 978-989-758-595-1

321

nausea, vomit and the discomfort at the site of

injection (Prasad-Reddy, 2015).

At present, GLP-1 receptor agonists includes

exenatide, liraglutide, albiglutide, dulaglutide,

lixisenatide and semaglutide. There are great

different between each agent in the pharmacokinetic,

pharmacodynamic and clinics (Prasad-Reddy, 2015).

The most common dosage form of GLP-1 receptor

agonists is the solution for injection as the first oral

semaglutide discovered by Novo Nordisk has

finished the clinical trial and published in 2020

(European Medicines Agency, 2020). The main

difficulties that limit the clinical use of GLP-1

receptor agonists are the extreme short half-life time

of injection (1.5-5 min) in plasma as it can be break

down by dipeptidyl peptides 4 (DDP-4) rapidly (Hui,

2002).

The techniques can apply to the manufacture of

GLP-1 receptor in different steps.

2.1 The Selection of Excipients

The first oral GLP-1 receptor agonist, semaglutide,

which has shown in Figure 1, has been published by

Novo Nordisk in 2020 (European Medicines Agency,

2020). Before Rybelsus has been published, the GLP-

1 receptor agonists can only be used in injection. In

order to designed it into oral dosage form, the

excipients which contribute to the formulation that

Novo Nordisk have chosen are massive. In this

section, the author will use the example of Rybelsus

to analyze what features the excipients should have

so that they can be used to form an oral GLP-1

receptor agonists tablet.

According to the public assignment report that

published by Novo Nordisk, the excipient used in

Rybelsus are salcaprozate sodium, microcrystalline

cellulose, povidone K90 and magnesium stearate

(European Medicines Agency, 2020).

Figure 1: Structural formula of semaglutide.

Microcrystalline cellulose (MCC) is a pure and

partially depolymerized cellulose with the chemical

formulation (C6H10O5)n. It is widely used in

pharmaceutical industry as a disintegrant, filler,

binder and absorbent. It also act as a dry binder and

filler in direct compression as it could improve the

compatibility and compressibility of the mixture.

Overall it is a comprehensive excipients

(Chaerunisaa, 2019). Povidone K90 stands for the

term “polyvinylpyrrolidone K-90”, a soluble PVP

product with the outstanding solubility in all

conventional solvent and it often act as a binder,

bioavailability enhancer and film formation.

Additionally, the ability of Povidone K90 to form

water-soluble complex with active substance to

improve the rate of release and solubility (Folttmann,

2008).

Magnesium stearate, Mg(C

)

, is a

common chemical compound that participate in

formulation as a lubricant to prevent the tablet stick

on the die whereas it increase the liberation and

disintegrate time by acting as a film formation

(Uzunović, 2007).

Salcaprozate sodium (C₁₅H₂₀NNaO₄) is an

excipients that has been mentioned alone in details in

the public assignment report as a new excipient which

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322

has been added into the formulation to improve the

bioavailability of semaglutide. Basically,

salcaprozate sodium is a sodium salt form of

salcaprozate and it is a powder with the color between

white and almost white, but it worked as an excipient

with polymorphism. As a oral absorption promoter,

the function is to promote the absorption of specific

macromolecules such as insulin. The solubility of

salcaprozate sodium is about 10 mg/ml when the pH

value is between 2-4 but the solubility in the

environment of pH value around 8 is about 300

mg/ml (European Medicines Agency, 2020; Twarog,

2019). The structure is shown in Fig. 2.

Figure 2: Structure of salcaprozate sodium.

In summary, due to the extreme short half-life of

GLP-1 receptor agonists, 3 out of 4 excipients used

have the ability of improving bioavailability and film

formation. Undoubtedly, the general excipients like

filler, disintegrant and binder should be include.

Additionally, the formulation of Rybelsus shows that

most of the excipient should be provided with the

ability to enhance the bioavailability and some

general function.

2.2 Freeze Drying, Granulation and

Direct Compresssion

Both freeze drying and granulation are common in

the manufacture of tablet. However, as a peptide drug

that belong to the biologics, it is more common to

include freeze drying instead of granulation in the

manufacture process due to the similarity between

peptide and protein. Basically, peptide is a short

chain of amino acid that combined by peptide bond,

and the peptide that include over about 50 amino acid

is the big molecule that been named as protein

(Hamley, 2020). The reason of using freeze drying is

that the peptide could denature if it experienced a

high temperature condition so the efficacy of peptide

drug could be reduced (Hamley, 2020). Freeze drying

is a process that dries the peptide drug by place it in

extreme low temperature to turn it into solid state

which is a more stable state because the peptide could

hardly form a chemical reaction such as oxidation

and hydrolysis etc (Rey, 2010).

The process of freeze drying generally involve 3

main steps: 1. Freezing 2. Primary drying or

sublimation of ice 3. Secondary drying of unfrozen

water (Rey, 2010).

In the freezing stage the peptide drug would

usually be put into a condition that the temperature is

about -40°C or even colder for a period of time to

freeze the water completely. The freezing stage is the

most vital part in the whole freeze drying process as

this step would vastly affects the speed on

reconstitution, the duration of freeze drying cycle, the

proper crystallization and the stability of the product.

In the primary drying, the product of last process will

be placed in a vacuum environment and the product

will be heat up to sublimate the ice particles. It is

crucial that the thermal energy has been provided and

the sublimation of ice reach a balance, so the API

could remain active. Some residuary water may

remain in the product, so the goal of secondary drying

is to remove the residuary water but not to dry it

excessively (ensure the appropriate moisture of the

product) (Rey, 2010). Overall, the proper freeze

drying could be a appropriate technique that can

apply to the manufacture of oral GLP-1 receptor

agonists for a few reasons summarised as keeping the

biologics active and ensuring the GLP-1 receptor

agonists would not have adverse reactions. The

drying chamber that participate in the freeze-drying

process has shown in Fig. 3 with its structure (Garcia-

Amezquita, 2016).

Analysis of Possible Ingredient and Manufacture Steps of Oral GLP-1 Receptor Agonists

323

Figure 3: A freeze dryer.

In fact, granulation is a relatively less common

pharmaceutical process that apply to biologics and

peptide drug. However, according to the Novo

Nordisk’s public assignment report, the company

involved the granulation step in the manufacture

process instead of the freeze drying (European

Medicines Agency, 2020), which stated that

granulation can be applied to GLP-1 receptor

agonists as semaglutide falls into the category of

DLP-1 receptor agonists. In the second half part of

this section, the author will analyze the possibility

and appropriateness of different granulation when

applying to the actual production of oral GLP-1

receptor agonists.

The granulation can be divided into 2 types: wet

granulation and dry granulation. Basically, the main

difference is wether the API would be put into a

solvent.

Figure 4: Dry granulation.

Figure 5: Direct compression.

The two main solvent that been used in wet

granulation are aqueous and organic solvent.

However, peptide drug has a low solubility in organic

solvent, the solubility are different from individual

cases. The problem with using aqueous solvent in wet

granulation to manufacture GLP-1 receptor agonists

is the drying step to evaporate the solvent. Generally,

the boiling point of purified water is 100°C, but

most of the peptide and protein will denatured under

such high-temperature condition, so this may be a

risk that the heat cause negative impacts to the API

(GLP-1Ras). As a member of peptide drug family, the

two problem that peptide drug meet when processing

wet granulation would also apply to GLP-1 receptor

(Jenssen, 2008).

Dry granulation is simple and low cost method

and it brings the powder particles together by putting

on a high pressure to the mixture. The general steps

of dry granulation shows in order: grind the API and

excipients to form powders, mix the powder,

compression, screening the product from step 3,

lubricant and disintegrant are added and mixed, final

compression (Jannat, 2016).

Factually, there is two type of compression (step

3) which are slugging process and roller compaction.

The slugging process use tablet press to put on

pressure on the powder particles whereas roller

compaction press the powder to a strip, but these two

steps mainly aimed for the same goal. Even though

the slugging process have the requirement on

compressibility, compression ratio and density of the

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powder (Jannat, 2016), these can be enhanced to

achieve the standard by selecting the appropriate

excipients and design a reasonable formulation. As a

pH and temperature sensitive drug, the whole process

of dry granulation has excluded most of the risky

issue so this may be an possible and ideal technique

that can apply to the manufacture of GLP-1 receptor

agonists in future. The order of the process has shown

in Fig. 4 (Mistry, 2021).

The last technique the author want to mention is

the direct compression (DC), this technique usually

used when then drug is moisture and heat sensitive

(Iqubal, 2014), the later which is the feature that

peptide drugs has been provided with (Garcia-

Amezquita, 2016). In the excipients that Novo

Nordisk used when producing Rybelsus

(semaglutide), microcrystalline cellulose is a material

that has been widely used in the direct compression

stage (Chaerunisaa, 2019), so although the medicine

that can attend direct compression are really limited

as the compressibility and compatibility should be

critically considered, can this technique be applied in

the manufacture of GLP-1 receptor agonists has not

been proved yet. This mostly depend on the

constitution of formulation, which means that the

ingredient powder can form a perfect tablet after

mixed and tablet press, there is no any granulation

included in direct compression (Jannat, 2016).

However, there is still a possibility of involving direct

compression in the manufacture of oral GLP-1

receptor agonists production in future. Each steps of

direct compression are demonstrate in Fig. 5 (Mistry,

2021).

Overall, the freeze drying and dry granulation are

the most appropriate method to manufacture oral

GLP-1 receptor agonists tablet as one is the

traditional and widely accepted manufacture process

for peptide drugs, the latter one is more flexible,

simple and having the advantage of relatively lower

cost if the cost are considered. For the direct

compression, as there is an extreme strict requirement

on the constitution of formulation, the requirement

can be hardly achieved by GLP-1 receptor agonist as

well as other oral medicine.

2.3 Coating

Stomach is a human organ that all oral medicine need

to pass through, the medicine could only reach small

intestine after that. The acidic environment that

between the pH value of 1.5 and 2.5 is mostly

contribute by hydrochloric acid and pepsin, such as

protease which break down proteins are also in the

stomach (Piper,1965). As a member from peptide

family, GLP-1 receptor agonists are also pH sensitive

drugs and it is certain that the drug can easily

denatured and lose the efficacy if the surface does not

covered by any edible anti-acid material.

Tablet coating is a common pharmaceutical

technique with a variety of advantages such as protect

the tablet being broken down by pepsin and provide

a physical and chemical protection to the tablet to

achieve a successful delay release. A polymer-based

film would usually be sprayed on the surface of tablet

after tablet compression or over up the surface of

granules. Additionally, the author could not found

any description on the original taste of the oral GLP-

1 receptor agonists tablet, but the coating could also

be used to enhance the flavor if the taste is not

pleasant (Ankit, 2012).

Take Eudragit as a example, it is a typical sample

of enteric coatings which shows frequently in the

pharmaceutical industry. Eudragit is a poly acrylate

polymers that needs up with different acidic or alkali

end groups, different individuals have their own

solubility in specific ph value as they dissolve by

forming salt with acid/alkali substances. The most

ideal option in Eudragit family seems to be Eudragit

S100, which dissolve under the condition of pH value

greater than 7 and the pH value at the beginning of

the small intestine is about 8, so hopefully the tablet

would break down in the main organ for absorption

and attend a successful delay release (Arruebo,

2020). Additionally, polymer is a chemically inert

compound so the interaction between the coating and

the ingredient could hardly form, which stated that

Eudragit S100 might be a ideal coating material when

manufacturing GLP-1 receptor agonists tablet.

3 CONCLUSIONS

Nowadays, Diabetes has become a common disease

with large group of patient and the age of patient

started to experience a trend of getting younger. In

these cases, the mission of inventing a safer and

effective medicine with a more convenient

administration route become more and more vital and

oral GLP-1 receptor agonist would be an ideal

medicine to put forward the drug therapy for diabetes

2. Manufacturing the GLP-1 receptor agonists into

oral dosage form (tablet) would partially reduce the

inconvenient and the problem with self-injecting

which requires the professional skill. Based on the

approved sample of Rybelsus and the chemical and

biological feature of GLP-1 receptor agonists, the

theoretical analysis shows the possible ingredient and

techniques that may generally apply to most GLP-1

Analysis of Possible Ingredient and Manufacture Steps of Oral GLP-1 Receptor Agonists

325

receptor agonists in key steps when they are put into

manufacture stage. The critical control of variables in

the manufacture process could achieve the best

efficacy of the tablet so that it can be more effective

for diabetes 2 patients. The greatest problem of

putting forward the production of oral tablet is the

short half-life in plasma, however, this problem could

be solved by taking appropriate amount of DDP-4

inhibitor along with GLP-1 receptor agonists but can

not be addressed only by GLP-1RAs.

The analysis may not be specific enough to

theoretically apply to specific peptide drug falls in to

the family because it is based on the general feature

of GLP-1RAs. As Rybelsus is currently the only oral

dosage form, so the excipients sample is relatively

less but still a valuable sample.

ACKNOWLEDGEMENTS

This paper was supported by Pr. Axel Zeitler and Mr.

Wei. this paper would not have been possible without

the academic support provided by Pr. Axel Zeitler

and I would also like to extend my deep gratitude to

Mr. Wei, the teaching assistant who have shown great

understanding to the course and offered a consecutive

help.

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