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Science Sub-Journal: A new model can predict the injectability of microparticle formulations

2020-09-30
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Particulate preparation refers to a solid, liquid, semi-solid or gaseous pharmaceutical preparation composed of particles with a certain particle size (micron or nanometer) made by a certain dispersion and embedding technology with a suitable carrier (generally a biodegradable material) It has excellent properties such as improving the stability of the drug, reducing adverse drug reactions, delaying drug release, and improving drug targeting. With the development of modern preparation technology, microparticle carrier preparations have gradually been used clinically, and their administration methods include external use, oral administration and injection. External and oral microparticles will generally facilitate the permeability of the drug to the skin and mucous membranes. Microparticle preparations for injection generally have sustained release, controlled release or targeting effects. Pharmaceutical formulations with targeting effects are usually called targeting preparation.


Injectability is a major factor in the success of microparticle preparations for injection, but few people pay attention to improving drug delivery techniques. The particle size ranges from 1 to 1,000 microns. Hypodermic needles are the easiest injection option, but they can present challenges for particle-based drug delivery because they can block or leave particles in the syringe after the injection is complete.

Science Sub-Journal: A new model can predict the injectability of microparticle formulations
The formation of particulate blockages is the main obstacle to the use of particulate biopharmaceuticals. Source: Massachusetts Institute of Technology

Recently, researchers from the Massachusetts Institute of Technology have developed a computational model that can help improve the injectability of injectable particulate preparations and prevent clogging. The model can analyze various factors, including the size and shape of the particles, to determine the best design for injectability. The study was recently published in “Science Advances”. Using this model, the percentage of particles that researchers were able to successfully inject increased sixfold. Researchers now hope to use this model to develop and test microparticles that can be used to deliver cancer immunotherapy drugs and other potential applications.

Recently, researchers from the Massachusetts Institute of Technology have developed a computational model that can help improve the injectability of injectable particulate preparations and prevent clogging.

Numerical model of clogging of hypodermic needle

Numerical model of clogging of hypodermic needle
Numerical model of clogging of hypodermic needle  Source: Science Advances

In order to understand the influence of design parameters (ie particle size, shape, concentration, distribution, needle gauge and solution viscosity) on the injectability from a digital point of view, a 3ml model syringe containing 2ml of chloroform was calculated and simulated. These simulations show that in the syringe body (syringe), the maximum flow rate reaches 5.7 mm/s, the flow rate at the tip of the syringe is increased by nearly 12 times (70.5 mm/s) in the 18G needle, and the flow rate is increased by nearly 110 in the 21G needle. Times (627 mm/s). The resulting pressure profile also shows that the highest pressure on the syringe wall and plunger is equal to 89 kPa. The pressure gradient generated at the injection port (plunger) is the driving force for the flow in the entire injection needle system, causing the parabolic velocity curve to reach the maximum at the center line. The gauge pressure drops from the highest value at the plunger (89 kPa) to zero at the outlet of the needle valve to atmosphere.


When water is used as the injection solution, the weight of the particles overcomes the lateral resistance, and the entire particle cluster settles, resulting in zero injectability. Within the scope of the study, viscosity has been found to have a significant impact on the injectability. Compared with water, the injection of low-viscosity solution [1% methylcellulose (MC), μ = 0.37 Pa·s, with an inlet velocity of 2.88 mm/s] significantly enhanced particle transport compared with water, at 18G and 21G The flow rate in the needle is increased by nearly 50% and 40%, respectively.


Researchers evaluated the influence of other parameters (ie particle concentration, shape and size) on injectability in the context of the model. The increase in particle concentration in the solution reduced the injectability of the two needles (18G and 21G), and the decrease in injectability of the small needle was twice that of the large needle. At the same time, the study found that only after a certain concentration threshold (that is, from 500 to 800 particles per injection), increasing the particle concentration is effective. The injectability of the solution loaded with 250 and 500 particles is almost the same, and the injectability of the solution loaded with 800 and 1000 particles is also almost the same.

Experimental study on the influence of different parameters on injectability

Experimental study on the influence of different parameters on injectability
Experimental study on the influence of different parameters on injectability  Source: Science Advances

Researchers observed the influence on injectability by analyzing viscosity, needle gauge, particle shape, particle size and particle concentration. A similar trend was observed for the effect of needle size, so reducing needle size would reduce injectability. It was also observed that there was no statistically significant effect of increasing particle concentration within the range studied. As predicted by the simulation, the particle shape has no significant effect on the injectability, and these trends are consistent between the two syringe sizes.


Next, the researchers used ANOVA based on a general linear model to determine the relative importance of each design factor to injectability. Viscosity is the most important parameter based on DOE1, with a contribution rate of up to 90% (P<0.0001). By excluding viscosity as a variable and using a narrower needle in DOE2, particle size and needle gauge became the two main design factors (P<0.05), while the influence of particle concentration and shape was negligible.

Design and optimize syringe geometry to improve injectability  Source: Science Advances

Researchers are trying to use their understanding of the injectability of microparticles to design and test custom syringe designs optimized for enhanced microparticle injectability. In the detailed design steps, the researchers modified the typical geometry of the syringe and adopted a nozzle-shaped geometry at the tip of the syringe. The design is based on two interconnected nozzle geometries to increase the velocity at each nozzle exit of the entire syringe tip. It was found that two design parameters had a significant impact on the transmission of particles: the inclination θ of the syringe wall and the distance L between the syringe barrel and the syringe outlet. Compared with a similar 3 ml BD syringe in the control group, the optimized syringe design provides a statistically significant improvement in particle injectability. Custom syringes increase the average injection capacity by 10% to 36%. Compared with commercial syringes, the injection capacity of larger particles has been greatly improved.


The injection angle, flow rate, and syringe position are all critical in subcutaneous injection, so injecting particles in the body may be more challenging. In order to test the optimized syringe design, the researchers conducted in vivo injectability experiments in five animal models, and evaluated different injection strategies based on the numerical results, including modifying the initial distribution of particles before injection. The injection technology based on the combination of optimized syringe design and improved particle distribution can provide the best results and significantly improve the injectability of PLGA1 and PLGA2.

Results discussion

The researchers developed a multi-physics finite element model that couples the CFD model of the injected solution with the transportation of solid particles. Using the model, they studied important design parameters that affect the ability of particle injection and conducted experiments to verify these design parameters. The impact and significance on injectability. Based on numerical values and experimental results, the researchers proposed a model to predict the chance of successful injection using a hypodermic injection device.


The results of the study further indicate that the particle size will play a major role in determining the injectability. Compared with a lower concentration of large particles, injecting a large number of small particles will reduce the risk of needle clogging. And as long as the maximum size of the particles is maintained, various forms can basically provide comparable injectability. Within the parameters studied, it was found that solution viscosity was the main statistical factor, followed by particle size and needle size. Increasing the viscosity within the recommended range would increase the injectability, and the increase in particle size and the decrease in needle size would usually Reduce injectability. The study also found that some deviation between the concentrated particles and the plunger in the centerline of the syringe can improve the injectability. All in all, researchers studying drug delivery microparticles only need to input these parameters into the model to predict the injectability of their microparticles, thus saving them time to build different versions of microparticles and conduct experimental tests. The design framework of experimental understanding helps to manufacture cost-effective tailor-made syringes to achieve high injectability. Researchers are currently designing an optimized system for the delivery of cancer immunotherapy drugs, which can help stimulate the immune response that destroys tumor cells. Researchers believe that these types of particles can also be used to deliver various vaccines or drugs, including small molecule drugs. And biological agents.


This research has successfully promoted the development of microparticle formulations. Medicilon has rich R&D experience in sustained and controlled release formulations, microparticle formulations, and protein and peptide pharmaceutical formulations, and many mature products have been handed over to customers. Medicilon’s formulation research and development team is a team that has successfully cooperated with well-known large and medium-sized companies at home and abroad. It provides one-stop and systematic formulation research and development services covering innovative drugs and generic drugs to meet the needs of customers at different stages of research and development. Medicilon not only has outstanding performance in the development and research of traditional dosage forms, but also has a professional technology platform for insoluble innovative drugs and a professional high-end formulation technology platform, such as inhaled drug delivery, ophthalmic drug delivery, transdermal drug delivery, Platforms for slow and controlled release drug delivery and new particle system drug delivery. Medicilon will continue to pay attention to the progress of this research, hoping to help the development of microparticle drug delivery systems.

About Medicilon

Medicilon (stock code: 688202) was established in 2004 and is headquartered in Shanghai. It is committed to providing a full range of preclinical new drug research services for global pharmaceutical companies, research institutions and scientific researchers. Medicilon’s one-stop comprehensive service helps customers accelerate the development of new drugs with strong project management and more efficient and cost-effective R&D services. The services cover the entire process of pre-clinical new drug research in medicine, including drug discovery, pharmaceutical research and clinical trials. Pre-research. Medicilon grows together with high-quality customers at home and abroad, and provides new drug research and development services to more than 700 customers around the world. Medicilon will continue to base itself on a global perspective, focus on innovation in China, and contribute to human health!

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