Study of surfactant-preservative and protein-preservative interactions in multi-dose injectable formulation
(2023) KLGM15 20231Food Technology and Nutrition (M.Sc.)
- Abstract
- Multidose injectable formulations require a preservative such as phenol to ensure sterility and protection against microbial contamination during clinical use. However, it is known that the interaction between these components and non-ionic surfactants such as polysorbate 80, also found in this type of formulations, present incompatibilities, which can lead to decreases in the efficacy of the product. This incompatibility is linked to a decrease in the cloud point of the surfactant.
The presence of other common components in this type of formulations, such as salt, proteins or non-ionic tonicity adjusting agents are also known to influence this phenomenon.
Furthermore, it’s known that preservatives can lead to increased aggregation in... (More) - Multidose injectable formulations require a preservative such as phenol to ensure sterility and protection against microbial contamination during clinical use. However, it is known that the interaction between these components and non-ionic surfactants such as polysorbate 80, also found in this type of formulations, present incompatibilities, which can lead to decreases in the efficacy of the product. This incompatibility is linked to a decrease in the cloud point of the surfactant.
The presence of other common components in this type of formulations, such as salt, proteins or non-ionic tonicity adjusting agents are also known to influence this phenomenon.
Furthermore, it’s known that preservatives can lead to increased aggregation in protein-based formulations as a consequence of preservative-protein interaction.
In order to study these incompatibilities, different concentration titrations were carried out in which the emergence of the cloud point was monitored by simultaneous measurement of light scattering. In general, these titrations consisted of the addition of phenol to samples containing polysorbate 80, salt, protein and tonicity adjusting agents in varying concentrations.
Additionally, preservative-protein interaction was studied by complementary concentration titrations and sample-specific analysis by small-angle X-ray scattering.
Results obtained in the study indicate that the presence of phenol, at concentrations within the range commonly used in multi-dose injectable formulations, leads to a reduction in the cloud point of polysorbate 80 down to 25ºC. In addition, the presence of other components such as salt, somatropin or mannitol is shown to decrease the phenol concentration required for the appearance of this phenomenon.
Moreover, results suggest that the interaction between somatropin and phenol leads to protein aggregation, which is significantly enhanced by the presence of salt. (Less) - Popular Abstract
- Interactions between components in multi-dose injectable formulations may lead to incompatibilities.
Preservatives are required in this type of formulations to ensure the sterility of the product during clinical use; however, it is known that their interaction with non-ionic surfactants and proteins can cause turbidity and protein aggregation.
But what are the consequences of these defects and how can they be avoided?
These incompatibilities may lead to a decrease in the efficacy of the medicinal product. Nevertheless, these effects occur for specific preservative concentrations. Hence, the need arises for a proper formulation away from concentrations in which the components may present incompatibilities.
This project aims to study in... (More) - Interactions between components in multi-dose injectable formulations may lead to incompatibilities.
Preservatives are required in this type of formulations to ensure the sterility of the product during clinical use; however, it is known that their interaction with non-ionic surfactants and proteins can cause turbidity and protein aggregation.
But what are the consequences of these defects and how can they be avoided?
These incompatibilities may lead to a decrease in the efficacy of the medicinal product. Nevertheless, these effects occur for specific preservative concentrations. Hence, the need arises for a proper formulation away from concentrations in which the components may present incompatibilities.
This project aims to study in detail at what concentrations these defects become significant.
For this purpose, turbidity of samples containing these components is analysed. This characteristic is related to the concept known as cloud point in the case of surfactant, and aggregation in the case of protein.
A simple, accurate way to analyse the turbidity of a sample is by measuring the scattered light from a laser beam.
Thanks to ProbeDrum® equipment, it is possible to simultaneously perform concentration titrations and scattered light measurements with a detection angle of 90° (side scattering). In this way, any change in the turbidity of a sample containing surfactant and/or protein can be determined while small amounts of preservative are continuously added.
The components used for the study are phenol, polysorbate 80 and somatropin, as preservative, non-ionic surfactant and protein, respectively.
In addition, another aim of the project is to analyse the effect of other components also used in this type of formulations, such as salt and non-ionic tonicity adjusting agents, on these incompatibilities.
Results confirm that phenol causes a significant decrease in the cloud point of polysorbate 80 and an increased aggregation of somatropin. These effects appear at concentration ranges that can be used in multi-dose injectable formulations. In addition, the presence of salt and other tonicity agents reduces the amount of preservative required for the emergence of the cloud point of the surfactant.
Moreover, one of the most interesting results of the project shows that the increased aggregation due to preservative-protein interaction is strongly enhanced by the addition of salt from a very specific concentration. These results are supported by a structural analysis performed with CoSAXS beamline at Max IV. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9133430
- author
- Lagares Martín, Javier LU
- supervisor
- organization
- course
- KLGM15 20231
- year
- 2023
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- Phenol, polysorbate 80, cloud point, somatropin, aggregation, titration, light scattering, salt, surfactant, preservative, protein, tonicity adjusting agents, multi-dose injectable formulation, pharmaceutical technology
- language
- English
- id
- 9133430
- date added to LUP
- 2023-08-10 16:20:47
- date last changed
- 2023-08-10 16:20:47
@misc{9133430,
abstract = {{Multidose injectable formulations require a preservative such as phenol to ensure sterility and protection against microbial contamination during clinical use. However, it is known that the interaction between these components and non-ionic surfactants such as polysorbate 80, also found in this type of formulations, present incompatibilities, which can lead to decreases in the efficacy of the product. This incompatibility is linked to a decrease in the cloud point of the surfactant.
The presence of other common components in this type of formulations, such as salt, proteins or non-ionic tonicity adjusting agents are also known to influence this phenomenon.
Furthermore, it’s known that preservatives can lead to increased aggregation in protein-based formulations as a consequence of preservative-protein interaction.
In order to study these incompatibilities, different concentration titrations were carried out in which the emergence of the cloud point was monitored by simultaneous measurement of light scattering. In general, these titrations consisted of the addition of phenol to samples containing polysorbate 80, salt, protein and tonicity adjusting agents in varying concentrations.
Additionally, preservative-protein interaction was studied by complementary concentration titrations and sample-specific analysis by small-angle X-ray scattering.
Results obtained in the study indicate that the presence of phenol, at concentrations within the range commonly used in multi-dose injectable formulations, leads to a reduction in the cloud point of polysorbate 80 down to 25ºC. In addition, the presence of other components such as salt, somatropin or mannitol is shown to decrease the phenol concentration required for the appearance of this phenomenon.
Moreover, results suggest that the interaction between somatropin and phenol leads to protein aggregation, which is significantly enhanced by the presence of salt.}},
author = {{Lagares Martín, Javier}},
language = {{eng}},
note = {{Student Paper}},
title = {{Study of surfactant-preservative and protein-preservative interactions in multi-dose injectable formulation}},
year = {{2023}},
}