Figure 1 shows a schematic diagram of the syringe system in which needle is pre-attached to the syringe barrel at frontend. This configuration is also called a syringe with a staked needle. The syringe barrel or container is called a primary container as it holds the medicine and has direct contact with it. The needle has two open ends and one of it will remain inside the syringe barrel. The needle is made out of metal and comes in different gauges. The needle gauge is defined by its inner bore diameter, outer diameter, and wall thickness. There are other syringe configurations in which needles can be attached at the front end of the syringe manually before the injection. The syringe barrel is filled with the drug fluid or medicine. The rubber stopper is placed inside the syringe barrel at the other end so that fluid will always remain inside the syringe barrel. The fluid will not come out of the needle unless there is an adequate amount of force is applied on the rubber stopper through the plunger rod to move it towards needle end. The plunger rod may be attached to the rubber stopper as shown.
In pharmaceutical industries, medicines are developed to treat certain illnesses. There are several types of delivery systems with which these medicines can be administered into the human or animal body. Injectable medicines are mainly administered with the help of syringes or delivery devices. Syringes or delivery devices are used with needles to inject the medicine or drug into the body.
However, a major challenge is to develop the syringe or delivery device which can be used to deliver the drug under the skin with more comfort and less pain. Injecting the drug under the skin with the help of syringes is mostly dependent upon the fluid properties of the drug. The design of delivery devices or syringes is based on fluid properties of the medicine or drug. It becomes more inconvenient or painful to the patient if the drug or fluid is with high viscosity or semi-solid type which needs high force to inject.
So, it is very important to understand the pressure and force requirement for delivery of highly viscous fluid. Based on the force requirement to deliver the drug, the device designer can design and develop a delivery system which would be used by the patient or user with more comfort and less pain. For the measurement of force, injectable drugs or fluids are classified as Newtonian and non-Newtonian fluids. The information in this paper on a mathematical equation, experiments, and suggestions will help the pharmaceutical industries as a basis to design and develop the syringes or drug delivery devices to deliver highly viscous, semi-solid or visco-elastic type of drug or medicine. The design parameters or functional features of the drug delivery device can be collectively called as design formulation. So, for a drug-device combination product, both the things viz. design and drug formulations are equally important for its safety and efficacy.
The material of construction (MOC) of the syringe barrel could be glass or plastic or metal. There are different types of plastics used for syringe barrel. In all cases, the inner surface of the syringe barrel should be smooth enough so that movement of rubber stopper becomes uniform and with minimum or negligible friction. The inner surface of the syringe barrel can be siliconized to make a smooth or frictionless movement of the rubber stopper inside it.
To administer the dose, the user has to insert the needle under the skin at the injection site of the body and then push the plunger rod forward to dispense the medicine. An adequate amount of force is required to push the plunger rod forward. It becomes uncomfortable and inconvenient to the patient or user if the force required to push the rubber stopper is more.
However, the needle insertion and drug delivery steps can be made automatic with the help of an auto-injector delivery device. To design an auto-injector or prefilled syringe, the designer needs to understand the force or pressure required to dispense the medicine out of the needle.
To administer the medicine with comfort and less pain, it is very important to understand the design parameters or factors of a delivery device as well as fluid properties of drug which affect the force required to push the rubber stopper forward. The force required to inject medicine at a specific flow rate with a specific needle length and the gauge is called syringeability.
Tissue resistance to the needle at the beginning of the needle insertion and frictional force inside syringe and needle barrel also adds to the total force required. The designer can build the mathematical model based on the equation on the right. It will provide indicative value for the force required to dispense the drug out of the needle and help the designer optimize the design attributes of the delivery device.
Design constant also needs to be considered for robustness, safety, and reliability of the device. There are certain constraints on the selection of larger needle sizes and length as pain increases if the needle diameter and length increases.
The force required to push the rubber stopper from its initial position is termed as break out or initiating force and force required to keep the rubber stopper moving is called glide or sustaining force2.
Fluid Types and Experimentation
1. Newtonian Fluid3
Newtonian fluid is the fluid in which viscous stresses are linearly proportional to the local strain rate. In a Newtonian fluid, the relation between the shear stress and the shear strain is linear.
The chart below the mean break out and glide force values for the syringe filled with liquid medicine or drug formulation which has a density of 1.06gm/mL and viscosity around 2cP. The test was conducted at standard speed 50mm/min on a universal testing machine.
The volumetric flow rate or the speed at which liquid medicine needs to be delivered is important when the patient or user desires to have a full dose of a certain amount of medicine in a specified time limit. Generally, every patient wants to have a full dose within a few seconds to avoid pain and inconvenience holding a needle inside the skin. However, while doing the experiments it has been observed that if the delivery speed increases significantly, such as more than 360 mm/min, the force does not get increased in that proportion.
These tests were conducted using a primary container of 1mL long glass prefilled syringe of ISO standard with staked needles of 26 and 27Gauge. The prefilled syringe inner diameter was 6.35mm. As there is a minor difference between two needles in terms of inner bore diameter (0.26 and 0.21mm) and needle extension (15.8 and 12.7mm), break out and glide force values also shows minor differences.
Chart 1 below also shows that the breakout and glide force mean values for other experimentation where it was observed that force to dispense liquid medicine increases significantly if the inner diameter of the primary container increases significantly keeping the viscosity of fluid same. The test was conducted on a universal testing machine with the speed of 50mm/min using the 3mL ISO standard cartridge with inner diameter 9.70mm. The needle size was 31G with 5mm needle extension. The mean breakout and glide force were 10.5 N and 8.7 N respectively.
The experiments were carried out dispensing medicine into the air and not under the skin of the patient. The breakout force graphs show that the volumetric flow somewhat follows the Hagen-Poiseuille equation at the standard delivery speed of 50 mm/min. As mentioned earlier, it is to be noted that the Hagen-Poiseuille equation will provide an indicative value of force required to dispense the drug out of the needle.
There are other factors which also influences the dispensing force. With these practical experimentations, the designer will get actual values of force required to dispense the drug. Based on these values designer can optimize design formulation by choosing the primary container system, the size, and length of the needle, the amount of drug to be delivered, time in which the dose has to be delivered.
The designer also needs to consider the stability or variability of fluid or medicine properties (viscosity and density) over the period of shelf life of the drug and optimize the design formulation accordingly. With these type of experiments and data on breakout and glide force, the designer can build a drug delivery device that will be easy to operate and less painful and more convenient to the patient. This drug delivery device could be pre-filled syringe itself or self-administrable mechanical or electromechanical pen or auto-injector.
Currently, several pharmaceutical sectors have such type of delivery devices for liquid injectable drug delivery. These devices are also available as a standard ready-to-use platform from several device manufacturers.
Challenges come in drug delivery device design when the medicine is non-Newtonian fluid like visco-elastic gel or semi-solid type of formulation.
2. Non-Newtonian Fluid
Non-Newtonian fluid4 is the fluid in which the viscosity is dependent on the shear rate. In non-Newtonian fluid, the relation between the shear stress and the shear rate is different and can even be time-dependent.
Chart 3 below shows the needle gauge versus the amount of semi-solid type drug delivered. Force applied was 55N to deliver visco-elastic semisolid gel medicine with a density of 1.05gm/mL and flow point 2500 Pa and Yield point 1900 Pa when measured using oscillation rheology at a constant angular frequency and variable shear strength at room temperature. The test was conducted at 30 mm/min speed on a universal testing machine. The prefilled syringe inner diameter was 6.35mm. The time between drug delivery start and end without stoppage was 4 seconds. After 4 seconds, there was no continuous drug delivery observed from any needle.
The semi-solid type of medicine is very difficult to deliver from the needles of higher gauges (lesser inner bore diameter). The chart below also shows there is no medicine delivered from 26G and 27G needle even after applying 55N of force on rubber stopper. It shows that lesser the needle gauge higher the weight of drug delivered. The length of the needle is important because, for the shorter length, drug delivery becomes easy.
It has been observed that the fluid coming out of the needle was in the form of a coil. It takes some time to form the fluid into the shape of a coil. The diameter of this coil is in line with the inner bore diameter of the needle.
Chart 3 shows the needle gauge versus force required to dispense the semi-solid type of medicine at 255mm/min. The medicine or drug used was having similar fluid properties which were used for experimentation in the above-mentioned test of Chart 2.
The inner diameter of the syringe barrel was 2.8mm. Speed was derived to deliver a certain amount of medicine in less than 10 seconds. It shows that the average force required to dispense semi-solid type medicine is directly proportional to needle gauge if needle extension, fluid properties, flow rate, and syringe inner diameter remains constant. The higher the needle gauge more would be the dispensing force required. This type of experimentation will help to optimize the design parameters of the drug delivery device.
After doing experiments with several combinations of needle gauges and length of the needle, it has been observed that the force required to dispense the semisolid visco-elastic gel type fluid is largely dependent on below parameters.
- Inner diameter of the syringe barrel
- Length of the needle
- Inner bore diameter of the needle
- Viscosity of the fluid or medicine
The force required to dispense the medicine is directly proportional to inner diameter of the syringe barrel and length of the needle and inversely proportional to inner diameter of the needle.
So, the challenge here is to design prefilled syringe or drug delivery device for delivery of semi-solid viscoelastic gel type of medicine or formulation. Prefilled syringe or delivery device should be easy to use and injection should be less painful to the patient.
While designing the drug delivery device, there are two sub-systems needs to be taken into consideration. One is the primary container system, which directly comes in contact with the drug formulation. The other is the injection, delivery, and needle retraction mechanism. The latter part can be made either manual or automatic. The objective of the primary container system is to hold the drug or medicine in the required conditions and while doing this there should not be any deter-rioting effect of it on the medicine during its shelf life. The objective of injection, delivery and needle retraction mechanism is to deliver the medicine at appropriate depth under the skin in the appropriate time with the appropriate quantity with comfort and convenience.
The force required to dispense the medicine plays a very important role in the usability of the device and comfort of the patient while administering the drug. If the force required and time taken to dispense the medicine is very high then the user feels uncomfortable with the delivery device. It also becomes painful to the user. It is more relevant in semi-solid visco-elastic gel type of medicine or formulation. To make the drug delivery device or prefilled syringe more user-friendly and with less painful to the user, the designer should optimize the delivery device or prefilled syringe design on the below parameters.
- Select the needle gauge and length based on the injection depth, volume to be dispensed and time required to dispense it. For example, if the needle is 21G then insertion pain would be higher as compared to 23G however the time taken to dispense the same amount of medicine would be less. Needle length is based on whether the required injection is subcutaneous or intramuscular. If the medicine is liquid the needle gauge could be much higher, like in the range of 29 to 31G and even more, if the injection is subcutaneous.
- The syringe barrel inner diameter should be as minimum as possible so that the force required to push the rubber stopper forward would be minimum. However, there are some constraints for the minimum inner diameter of the syringe and those are based on the strength and material of plunger rod which is used to push the rubber stopper forward.
- The inner shape of the syringe should be in such a way that the semi-solid fluid can move forward smoothly particularly at the neck part of the syringe where needle and syringe assembly starts. Smooth and well-optimized converging ends will help the medicine to move forward with less friction.
- The flanges or the neck portion of the syringe should withstand the high forces. If the designer builds the pen or an auto-injector device to deliver the drug then the primary container will be held at its neck or flanges.
- The plunger rod design should be in such a way that it can transfer adequate force on the rubber stopper. It should have enough strength to withstand such high force.
- The above five parameters are helpful while designing prefilled syringe for delivery of semi-solid visco-elastic gel type of fluid with manual needle insertion, drug delivery, and needle retraction. For automatic needle insertion and drug delivery of a semi-solid visco-elastic gel type of fluid, the delivery mechanism could be based on spring or gear or gas-driven technology. If the force required pushing rubber stopper forward and time required to dispense the desired dose is high, it is good to evaluate gear or rack and pinion mechanism.
- The applicable ISO6 7 8 standards and regulatory guidance9 10 have to be referred and followed while designing customized prefilled syringe as well as a delivery device. Prefilled syringe or drug delivery device performance standards are well established and the designer has to follow these guidelines and optimize the design parameters accordingly.
The injectable drug delivery by prefilled syringe or delivery device is based on the fluid properties of the medicine. If the fluid is of Newtonian type, then the force required to dispense the medicine is considerably low. The delivery of low viscosity medicine may not become inconvenient to the user or patient. However, if the fluid is of non-Newtonian in nature, there would be a considerable increase in force to dispense the medicine which in turn will increase efforts as well as pain in the delivery of the medicine.
To reduce the discomfort and increase the user-friendliness of the delivery system, it is important to consider the design factors or parameters which plays an important role in designing the delivery device. Device designer can optimize the design by selecting appropriate needle gauge and length, the inner diameter of the syringe barrel (primary container system), time and volume of fluid to be dispensed. This optimized design parameters of the delivery device can be called design formulation. With due consideration of prefilled syringe or drug delivery device design formulation, the designer can build the system that would be more convenient for the user or patient. At the same time, the designer has to consider the applicable ISO standards or regulatory guidance while finalizing the device design parameters.
- Injecting Highly Viscous Drugs, Nov 02, 2014 By Andy Fry, Pharmaceutical Technology, Volume 38, Issue 11
- ISO 11608 – 3 – Pen Injectors for medical use – Finished cartridges – Requirements and test methods
- Panton, Ronald L. (2013). Incompressible Flow (Fourth ed.). Hoboken: John Wiley & Sons. p. 114. ISBN 978-1-118-01343-4.
- Tropea, Cameron; Yarin, Alexander L.; Foss, John F. (2007). Springer handbook of experimental fluid mechanics, Springer. pp. 661, 676. ISBN 978-3-540-25141-5.
- ISO 11040-4 – Prefilled Syringes – Glass barrels for injectables and sterilized subassembled syringes ready for filling
- ISO 11608-1: 2014 Needle-based injection systems for medical use — Requirements and test methods– Part 1: Needle-based injection systems
- ISO 11608-5:2012 Needle-Based Injection Systems for Medical Use-Requirements and Test Methods-Part 5: Automated Functions.
- ISO 14971: 2007; Medical Devices – Application of Risk Management to Medical Devices.
- Design Control Guidance for Medical Device Manufacturers, March 1997
- Applying Human Factors and Usability Engineering to Medical Devices. Guidance for Industry and Food and Drug Administration Staff, February 2016.