Prefilled devices for parenteral applications.

Review

Prefilled devices for parenteral applications Expert Review of Medical Devices Downloaded from informahealthcare.com by Nyu Medical Center on 01/14/15 For personal use only.

Expert Rev. Med. Devices 11(2), 205–223 (2014)

Pablo Gurman1,2, Albert Chi1, Tiffany Hood1, Micaela Reina3, Yitzhak Rosen1, Sebastian D’hers3 and Noel Elman*1 1

Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology, 500 Technology Square, NE47-525, Cambridge, MA 02139, USA 2 Department of Materials Science and Engineering, University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 77080, USA 3 Computational Mechanics Center, Department of Mechanical Engineering, Instituto Tecnolo´gico de Buenos Aires (ITBA), Ave. Madero 399, A-1-2, CP 1106, Buenos Aires, Argentina *Author for correspondence: [email protected]

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Current parenteral administration of drugs suffers from several drawbacks including the requirement of healthcare personnel to administer the drug, the risk of needle stick injuries that may result in the transmission of blood borne pathogens, and patient discomfort. Prefilled devices have emerged as powerful tools to improve parenteral administration of drugs. There are a number of clinical conditions including treatment of endocrine diseases, neurological disorders, autoimmune diseases and emergency medicine where prefilled devices have made major improvements to patient care. Prefilled devices have become an important set of tools for the medical practitioner due to their ease of use and safety, cost effectiveness and patient convenience. This review provides a comprehensive summary of existing prefilled devices, their current clinical uses and corresponding regulatory processes. KEYWORDS: acute conditions and chronic diseases • ambulatory • autoinjectors • combination products • drug delivery • emergency medicine • parenteral • pen injectors • prefilled devices • therapeutic applications

This review provides a comprehensive summary of the pharmacological therapies that use prefilled devices as delivery modalities for parenteral applications. A summary of several innovative prefilled devices are described according to target disease. Six major categories of clinical applications are described with their respective examples of therapeutic modalities based on specific uses of prefilled devices, including: endocrine, neurological, pain management, immune disorders, anaphylaxis and emergency medicine. These categories were described where prefilled injectors have made the most impact. Traditional injectors involve two main components: the pharmaceutical drug and delivery mechanism. Pharmacokinetics and pharmacodynamics define the selection of the pharmacological therapy as they determine the safety and efficacy of the treatment. Pharmacokinetics involves biophysical and biochemical parameters associated with absorption, distribution, metabolism and excretion of the pharmaceutical drugs. Pharmacodynamics involves interaction of the drug with receptors that lead to the pharmacological effect. As pharmacodynamics responses are related to the intrinsic properties of the selected pharmaceutical drugs, pharmacokinetics can play an important role by tuning drug formulation, dosage, administration route and duration and periodicity of administration. 10.1586/17434440.2014.882227

Parenteral delivery represents one of the most important administration routes because many conditions requiring this route are acute and often times life-threatening. Parenteral delivery involves the administration through subcutaneous (sc.), intramuscular (im.), intravenous (iv.) and intraosseous (io.) routes, often providing high bioavailability and rapid onset of action, a prerequisite for emergency situations where the parenteral route is the preferred (and sometimes the only alternative) route of rapid administration. The sc. route refers to the introduction of the drug into the tissue lying underneath the dermis and epidermis that constitutes the skin. The sc. route is the preferred route for athome injection, is adapted for short- and longterm therapies and compared with the other parenteral routes, improves the quality of life. The im. route involves the introduction of a drug through the muscular tissue, where the vessels that are supplying the tissue absorb the drug. Because every muscle has different blood supply, the rate of absorption varies according to the site of administration. The im. route has higher absorption rates than the sc. route and could accept more volume, but it is prone to irritation resulting in patient discomfort, and the formation of sterile abscess at the site of injection. The iv. route is the preferred route to achieve rapid therapeutic concentration, but

2014 Informa UK Ltd

ISSN 1743-4440

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Expert Review of Medical Devices Downloaded from informahealthcare.com by Nyu Medical Center on 01/14/15 For personal use only.

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Gurman, Chi, Hood et al.

a cartridge where the drugs are contained. In this manner, there is no need to load the syringe using a vial or ampule. The needle is retractable so it generates less space avoiding the risk of needle injuries. • Autoinjectors: These are devices intended for patient selfadministration and that has either manual or electronic control of activation and dosage. Digital injectors allow control over the injection depth, injection rate and injection time and provide on screen instructions for guidance in correct use. The needle is usually hidden and that is one of the reasons that pen injectors are adopted by needle phobic patients. • Dual chamber syringes: These devices contain two chambers, allowing the incorporation of the active ingredients and solvents separately. This system allows reconstitution and administration on demand as needed.

Figure 1. A needle stick injury with a syringe carrying BCG vaccine produced a granulomatous reaction in the thumb of a healthcare personnel.

requires help from trained healthcare personnel since it involves the access to a superficial vein that will transport the drug to the heart via the superior vena cava, and from there to the aorta to the rest of the body. The io. route constitutes an alternative to the iv. route when peripheral or central vein cannulation is not accessible. The io. route is used for critical ill infants and adults during emergency situations. A key advantage of the io. route over the peripheral veins is its non-collapsible nature, a critical requirement during shock and other critical conditions. The standard injection system was originally designed to overcome the anatomical barriers such as the skin that separates the drug from the site of absorption. Injection systems comprise a syringe made of the following components: a needle, a drug container (barrel) and a piston to pull the drug out from the vial, and push it back through the needle to the site of absorption. The use of injection systems is still not without complications. Issues such as contamination of the needle through reuse and other poor injection practices put patients and health workers at risk of needle-stick injuries with the potential risk of transmitting blood-borne pathogens, as shown in FIGURE 1. Other significant disadvantages of traditional needle and syringe injections are compliance-related issues with patients. Needle phobia and related stress due to pain and bruising associated with this method is a very common reason for discontinuation or avoidance of treatment. The use of prefilled devices has opened up a new era in parenteral delivery for management of a variety of complex diseases for which the delivery route can be enhanced for the medical administrator, the end-user experience as well as the overall cold chain logistics. Prefilled devices can be divided according to the following categories: • Prefilled syringes: In addition to the classical syringe components (barrel, piston, needle, caps), prefilled syringes include 206

Advantages for using prefilled devices for parenteral administrations include: accuracy, sterility, safety, waste minimization, better materials, logistics, ergonomics and affordability. These advantages are summarized as follows: • Accuracy is one of the critical parameters for an effective treatment. Classic syringes must be loaded by the medical practitioner or the patient resulting in potential errors that have higher probability to occur in specific situations such as during emergencies or the use by people not trained in parenteral administration. Prefilled devices, on the other hand, are designed to administer accurate drug doses. This accuracy is achieved by electronic or mechanical control or by prefilling in the correct dosage [1]. • Sterility represents a critical issue in the preservation of pharmaceuticals. Prefilled devices do not need reconstitution or reconstitution takes place inside the device without exposing the drug to the exterior environment, thereby avoiding contamination. • Safety is a critical requirement for the medical practitioner and end-user. For the healthcare personnel, avoiding the need of filling and reconstituting a drug could facilitate their work while making it safer is critical, particularly for the healthcare personnel working in emergency settings where overcrowding of patients could increase the risk of errors during drug reconstitution. Several devices have been developed to address safety issues related to the use of traditional injection systems. Auto-disable syringes are a type of syringe that inactivates itself after a single use, locking the plunger with a metal clip. In another example, a small ring etched in the inner barrel sidewall allows the especially adapted plunger to move only in a unidirectional configuration. The most common cause of syringe handling-based injuries is needlestick injuries in which cases the operators accidentally inject himself/herself incorrectly or by accident. After the US Needle Stick Safety and Prevention Act of 2000, syringe manufacturers were required to design safer syringe systems to avoid needle injuries. Many needle-stick injuries occur during recapping. For this reason, in some safety designs the cap is attached to the syringe via a hinge, making one-handed recapping plausible. In other designs, the device slides over Expert Rev. Med. Devices 11(2), (2014)

Prefilled devices for parenteral applications

Beta cell

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Peripheral tissue (muscle)

Glucose transporter (GLUT2)

Translocation of glucose transporter (GLUT4)

CAP Insulin receptor

Glucose

Cbl

P Glucose

Phosphorylation


ATP-sensitive K+ channel

Glucose

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Glycolysis

X

X X

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Regulation of glucose, lipid and protein metabolism

P

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Gene expression and cell growth

Insulin NovoLog FlexPen HumaLog KwikPen HumaPen Luxura NovoPen Junior Lantus Solo Star

IRS family

PI(3)K P

Grb2, SHP2

Insulin-containing granules

Figure 2. Insulin, which is produced by the pancreatic b-cells exerts is action upon binding to the insulin receptor, a member of the tyrosine kinase family, leading to a downstream cascade of molecular events that results in translocation from the cytoplasm to the cell surface of the GLUT-4 family of glucose transporters responsible for glucose uptake from the blood to tissues such as muscle. Figure created by Velimir Manjulov.

the needle and fully covers the tip, locking securely in place to prevent injuries. • Waste minimization is of critical importance to make the pharmaceutical product cost-effectively. The waste of pharmaceuticals drugs occurs due to poor control of cartridge refilling or inefficient extraction of the drug from the packaging (such as during ampule loading). It is also worth mentioning the considerable amount of drug waste generated in the overfilling of vials by the pharmaceutical industry that could reach up to 25% of the vial volume. Prefilled devices carry the exact amount of drug, thus overall minimizing waste of drugs. • Materials drive innovation in the next generation of devices. Prefilled syringes have increasingly relied on the use of polymers, for example, borosilicate, which resulted in lighter, safer and cheaper devices. Several materials are involved in the fabrication of prefilled devices. Silicone is an important material to allow lubricity for the plunger to move smoothly and without mechanical disruptions. Metals are used for the fabrication of the hypodermic needle. Elastomers are also used in plungers and tip caps. Some formulations using fluoropolymers to coat internal parts of devices were developed informahealthcare.com

to avoid adhesion of proteins to the device that could lead to aggregation. Materials used in barrels include glass or plastic. Examples of plastics used in barrels are cyclo-olefin polymer and cyclo-olefin co-polymer. A fast growing and promising polymeric material for barrels are the crystal zeniths, which provide temperature stability, drain ability, high breakage resistance, high transparency and solvent resistance. Lastly, an important criterion in the selection of materials is the compliance with the USP standards (US Pharmacopeia) to ensure material biocompatibility and prevent any undesired interference between the device and pharmaceutical drugs and between the device and the patient. • Logistics represents one of the drivers in the increased adoption of prefilled devices. Cold chain logistics can be improved as the prefilled devices with lyophilized active pharmaceutical ingredients can typically withstand harsher environmental conditions. Prefilled devices were developed to allow portability, improving patient self-management behavior. In terms of disposability, some pen injectors were designed to be reusable and only required to replace the cartridge when empty, while other pen injectors were designed to be fully disposable as one-time use devices. 207


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Figure 3. The NovoLog FlexPen (Novo Nordisk A/S) for insulin.

• Ergonomics facilitate the use of prefilled devices. When handling a syringe, the thumb plays a critical role since it exerts the force in the plunger to displace a piston. The design of the new generation of pen injectors takes into account the distance between holding the pen in one hand to the thumb extension. In this manner, maximum dose and lowest injection force is achieved making the device effective and user friendly, while taking into account patient anatomy. • Affordability of materials during the manufacturing and packaging processes of prefilled devices plays a key role in the economics of scale. The new barrels for prefilled syringes and injectors are made of polymers, decreasing the manufacturing costs and improving the design versatility of the devices [2]. All these advantages have accelerated the development of the technology at a rapid pace to the extent that prefilled devices represent one of the fastest growing segments in healthcare industry. Current clinical uses of prefilled devices Endocrinology Diabetes

In the USA, 25.6 million people aged 20 years or older are currently diagnosed with diabetes. Diabetes is a chronic disease that results from a resistance to insulin (diabetes type II or non-insulin dependent) or not enough insulin being produced by the b-cells of the islets of Langerhans in the pancreas (diabetes type I or insulin dependent) [3]. The etiology of diabetes remains elusive, but extensive research has provided some evidence on the immunological pathogenesis in the destruction of b-cells as the underlying cause of diabetes type I. In diabetes type II, it is thought that genetic predisposition could lead to resistance to insulin by affecting insulin receptors or the insulin signaling pathway inside cells. This deficiency of insulin prevents the uptake of glucose from the bloodstream to muscles, fat and liver cells to be used as energy. The inability for glucose to be transported 208

to the tissues causes the patient to develop high levels of glucose in the blood, which leads to a metabolic disturbance. This disturbance can cause acute life-threatening conditions, such as diabetic ketoacidosis or hyperglycemic coma. Current treatments for the disease range from regulation of diet and exercise to medication. When all of these treatment paths have failed to control glucose levels in plasma, the injection of insulin becomes the treatment of choice. Transplantation of b-cells is a last resort alternative. FIGURE 2 shows the current understanding of the pathways that produce or are affected by insulin. Patients with diabetes (Type II in particular) suffer from problems in adherence to several types of regimes (food diet, exercise) and precise control over insulin delivery is needed to avoid potential life-threatening episodes of hypoglycemia [4]. Therefore, it becomes critical to create a therapy that facilitates patient adherence to treatment (acceptance, persistence and compliance) to ensure the success of the therapy as a reliable method for insulin administration. Pen injectors achieve both requirements by improving patient adherence to treatment because they are easy to use, self-administrated, generally painless and safe for the patient. The dose could be tailored according to the patient’s glucose levels. Pen injectors for diabetes have adopted to the extent that they are now the gold standard in diabetes management [5,6]. The injection of insulin provides synthetic insulin for patients that lack the capacity to produce their own insulin or for cases in which the amount of insulin being produced is not sufficient enough to fulfill the body insulin requirements. In this way, glucose may be metabolized in the same manner as if natural insulin was present. There are rapid-, intermediate- and long-acting types of insulin, which differ in their half-life time and onset of action. Pen injectors usually contain rapid-acting insulin because the pen injector is intended to rapidly stabilize glucose levels after a meal. Pen injectors can also contain a combination of types of insulin allowing rapid onset of action, followed by steady levels of insulin to maintain a constant level of glucose concentration in plasma during the day. Rapid-acting insulin usually takes about 15 min to start working after injection and continues to work for about 3–5 h. The intermediate-acting insulin starts working in the 1–3 h range after injection and works in the 12–16 h range, while the long-acting insulin starts to work in the 1–2 h range with flat levels and last for 24 h [7]. Two popular insulin autoinjectors on the market today are NovoLog FlexPen (Novo Nordisk A/S, Bagsværd, Denmark) and Humalog KwikPen (Lilly USA, LLC, Indianapolis, IN, USA). Both have versions that inject purely rapid-acting insulin and versions that inject a combination of rapid- and intermediateacting insulin. The NovoLog FlexPen is prefilled with 3 ml of 300 units of NovoLog insulin that can be purely rapid-acting insulin or contains about 70% intermediate-acting insulin and 30% rapid-acting insulin, as shown in FIGURE 3. The pen has a dial Expert Rev. Med. Devices 11(2), (2014)



that allows the patient to adjust the insulin dosage in 1 unit increments from 1 to 60 units of insulin, making the pen injector very easy and safe for patients to use. The Humalog KwikPen is also prefilled with 3 ml of 300 units of Humalog insulin and can inject up to 60 units of insulin in 1 unit increments. The KwikPen can contain purely rapid-acting insulin, 75% intermediate- and 25% rapid-acting or 50% intermediate- and 50% rapid-acting insulin [8]. Insulin pen injectors are chosen by the patient’s doctor based on the ability of the injector to meet the patient’s specific needs. Other pen injectors are sometimes chosen over the commonly used FlexPen and KwikPen due to specific clinical functions. For example, the HumaPen Luxura HD and the NovoPen Junior are often chosen for children because the dosage can be tuned in 0.5 unit increments instead of 1 unit increments. These injectors also have smaller maximum doses: 30 units for the HumaPen Luxura HD and 35 units for the NovoPen Junior. In contrast to the aforementioned autoinjectors, the Novo Pen Junior is refillable [9]. Infertility

About 6 million people between the ages of 15 and 44 in the USA have problems with infertility and about one-third of the infertility cases are women [10]. One common cause associated with infertility in women is associated with ovulation, which is usually due to hormone imbalances. Most treatments involve the administration of luteinizing hormone (LH) and the follicle-stimulating hormone (FSH), which both stimulates ovulation. FSH and LH are produced by the pituitary gland in response to activation of gonadotropinreleasing hormone (GnRH) receptors by GnRH produced in the hypothalamus. FSH promotes development of the ovarian follicles, while LH promotes their maturation that ultimately leads to ovulation [11]. Current treatments for infertility can involve many medications with varying dosage schedules. The dosing is usually administered by the patient; therefore, ease of use for administration is essential for treatment adherence [12]. Prefilled syringes and pen injectors are becoming more prevalent in infertility treatment because they are easier than using vials and syringes for patient self-administration. Patients also find prefilled devices more discreet. This is a vital consideration since patients often need to inject at specific times. Pen injectors for infertility could provide more privacy to the female patients avoiding the need for healthcare personnel to assist in the procedure. Privacy, self-administration and painless are some of the features that make pen injectors an attractive choice to syringesampules for infertility treatment. One of the main prefilled syringes used for infertility is the Gonal-f (EMD Serono, Inc., Rockland, MA, USA). Gonal-f is a prefilled, disposable, multi-dose pen injector device used to subcutaneously administer recombinant follitrophin alpha. Follitrophin alpha is used to supplement FSH [13]. During infertility treatment, Gonal-f is usually administered daily. The Gonal-f pen has a see-through pen body so that the patient can informahealthcare.com

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see how much medication is left in the device. It also has a dial that can be used to vary the dose to be administered. Injection is initiated by a button at the top of the device [14]. Follistim AQ Pen is also commonly used for infertility treatment. Follistim is a pen injector prefilled with follitrophin beta, which is also used to supplement FSH. Follistim has a dial that can be used to adjust the dosage of follitrophin beta [15,16]. Elonva is a newly developed drug that is also starting to be used for the treatment of infertility and is administered in a prefilled syringe. Elonva contains corifollitropin alpha, which was developed using recombinant DNA. Corifollitropin alpha is similar to other FSH supplements but it initiates a prolonged activity of FSH. The prolonged activity of FSH results in weekly injections, increasing patient adherence to treatment [17]. Ganirelix acetate is often used in conjunction with other therapies for infertility and administered in a prefilled syringe (Vetter GmbH). Each standard prefilled syringe is prefilled with 250 mg of Ganirelix acetate per 0.5 ml. Granirelix acetate is used in conjunction with FSH therapy. It is administered daily during the middle-to-late segment of the follicular phase. Granirelix acetate competitively inhibits GnRH receptors. This suppresses premature LH surges, which prevents untimely ovulation during in vitro fertilization [18]. Human growth hormone deficiency

Growth hormone is produced by cells known as somatotropes located in the anterior pituitary gland. Growth hormone binds to growth hormone receptors leading to a number of molecular events including the recruitment of two JAK2 molecules that possess tyrosine kinase activity. This tyrosine kinase activity is responsible for the phosphorylation and activation of both JAK2 molecules, leading to further phosphorylation and activation of other cytoplasmic proteins including STAT, SHC and IRS 1 that will ultimately activate transcription factors resulting in the expression of genes involved in cell proliferation and differentiation, as shown in FIGURE 4 [19]. Human growth hormone therapy is used mainly for the treatment of children who are born small for their gestational age or patients diagnosed with Turner syndrome. Turner syndrome occurs in about 1 out of every 200,000 births and is caused when a female only has one X chromosome instead of two. This causes a variety of symptoms, including short stature. Children born small for their gestational age can be treated with self-administered injections of human growth hormone until near-normal adult height is reached. Injections of human growth hormone for patients with Turner syndrome is also self-administered, so ease of use is essential and prefilled pen injectors are often used [20]. For children receiving injections as well as their parents providing drug administration, a pen injector could provide a more innocuous approach since the syringe needle is not visible, which may result in a less traumatic experience. Parents are more confident and suffer from less stress while administering a parenteral drug with an injector to their children [21]. 209

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GH


STATs Transcription of target genes

JAK2 SHC

MAPK


IRS Metabolism PI 3’K

Growth Proliferation Differentation

Glucose

Figure 4. Growth hormone mechanism of action. Upon binding to the growth hormone receptor, growth hormone promotes a downstream molecular signal cascade involving the JACK family of tyrosine kinases and the STAT family of transcription factors leading to activation of a number of genes involved in metabolic pathways and cell growth and differentiation. Figure created by Velimir Manjulov.

There are a number of prefilled devices currently on the market for the self-administration of synthetic human growth hormone for the treatment of human growth hormone deficiency. One of the main devices on the market is the refillable pen injector, HumatroPen (Eli Lilly and Company, Indianapolis, IN, USA). The HumatroPen is refilled by cartridges of somatropin, which is synthetic human growth hormone. The pen can be used with cartridges of 6, 12 or 24 mg of somatropin that must be reconstituted before they are put into the pen device. An individual sc. injection can be set to 12 different dosage volumes between 0.05 and 0.60 ml using a dial on the pen device. Depending on the cartridge used, a certain volume corresponds to a different concentration of drug being delivered to the patient. The 6 mg cartridge can be administered in 0.1 mg increments, 0.2 mg increments for the 12 mg cartridge and 0.4 mg increments for the 24 mg cartridge [22]. The degree of freedom of dosage available using this pen is particularly useful for human growth hormone administration. This is because the therapeutic dosage can be highly variable across a patient population.

The Genotropin Pen (Pharmacia Corporation, Stockholm, Sweden) is another refillable pen for the administration of somatropin. This pen comes in two different sizes, as shown FIGURE 5. One pen is for 5 mg cartridges of somatropin and the other is for 12 mg cartridges. The cartridges are a two-chamber system with lyophilized drug in one chamber and 2 ml of diluent in the other. After the cartridge is placed into the pen, the two chambers of the cartridge are mixed together when the pen is closed by a screw mechanism. The patient must then continue to move the pen side to side to ensure reconstitution. Once this is complete, a dose between 0.1 and 2.0 mg for the 5 mg pen or between 0.2 and 4.0 mg for the 12 mg pen can then be selected by the patient using the dial [23]. The Nutrospin AQ Pen (Genentech Inc., San Francisco, CA, USA) is another pen used to deliver somatropin. The Nutrospin AQ is similar to the Genotropin Pen since it also has specific versions of the pen for different strength cartridges. The main difference is that the pen comes in 5, 10 and 20 mg of somatropin versions. The 5 mg cartridge can be administered in dosing increments of 0.05 mg up to 1.75 mg, the 10 mg pen can be administered in 0.1 mg increments up to 3.5 mg and the 20 mg pen can be administered in 0.2 mg increments up to 8.0 mg at a time. The doses for this pen are also selected by the trained patient using a dial on the pen [24,25]. Neurological Migraine

Migraine is an incapacitating headache that usually lasts between 4 and 72 h. The headaches are often exacerbated with sensitivity to light and sound, nausea and vomiting. About 28 million people in the USA suffer from migraine. Migraine is considered to be a neurovascular disease that is associated with blood vessel swelling. The exact trigger for the swelling is not well understood, although it has been found that there are increased levels of a metabolite of serotonin, 5-hydroxyindole acetic acid, during a migraine [26]. One form of treatment for migraines is a class of drugs called triptanes. Triptanes are serotonin (5-hydroxytryptamine) agonists that bind to serotonin receptors (5-HT). In particular, triptanes bind to the subfamilies of 5-HT receptors, 5-HT1B 5-HT1D, located in the trigeminovascular system. One type of triptan is sumatriptan, which is the main active ingredient in drugs that have been incorporated into autoinjectors and jet injectors for the treatment of migraine crises. By activating these receptors, sumatriptan induces vasoconstriction through 5HTD1B receptors and inhibition of nociceptive transmission in the central nervous systems through activation of 5-HT1D receptors, as shown in FIGURE 6 [27]. Due to their incapacitating nature, migraine attacks will be greatly benefited from an early self-administration that may quickly prevent or reduce the onset of the migraine crisis, thereby promoting fast Figure 5. Genotropin in a dual chamber prefilled device (Vetter, Inc.). relief. Because an aura precedes a migraine

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1 + 2 + 3 = relief from headache pain and associated symptoms Neuropeptide release Nuclei A Substance P CCRP

1 B B


CORTEX

Sumatriptan (alsuma) 5-HT1B receptors

PAIN Vasoconstriction

THALAMUS

D D Trigeminal ganglion 3 Sumatriptan (alsuma) Decreasing pain signal transmission

2

Sumatriptan (alsuma) 5-HT1D receptors Trigeminal inhibition

Figure 6. 5-Hydroxytryptamine receptors have been identified to play a critical role during migraine attacks. Sumatriptan, a 5-hydroxytryptamine 1D, 1B agonist, suppresses the migraine crisis by modulating the trigeminovascular system. Figure created by Velimir Manjulov.

attack, there is an opportunity for the patient to carry a selfadministered device and use it just before the crisis begins. Hence, injectors containing sumatriptan represent an important therapeutic modality in migraine management [28–31]. The main prefilled device used for the treatment of migraine is the Alsuma autoinjector (Pfizer Inc., New York City, NY, USA) for sc. injection of sumatriptan. Alsuma is a portable disposable single-use autoinjector. It is prefilled with 6 mg/0.5 ml sumatriptan. If the first dose is not effective, a second dose can be administered 1 h after the first dose with a new autoinjector. Alsuma is made for the purpose of self-administration of sumatriptan by the patient when a migraine starts to occur [32]. The autoinjector is particularly useful for administration as it is easy for the patient to use and they can get relief right away because no cartridge or needle must be attached by the patient prior to use. The autoinjector is ready to be used at a moment’s notice. Epilepsy

Epilepsy is a neurological disorder that causes a person to have repeated seizures over time. Seizures occur when a disruption of brain activity affects a person’s attention or behavior. About 2 million people in the USA are affected by epilepsy. Epileptic seizures result in about 55,000 deaths a year, so the quick treatment for the stoppage of convulsions is essential [33–35]. At the informahealthcare.com

molecular level, during a seizure, there is excessive and abnormal excitation of a given population of neurons. During the initiation of a seizure, bursts of action potentials and hypersynchronization of a population of neurons occurs. The seizure can then propagate to other areas of the brain, if there is enough activation to recruit surrounding neurons. A class of drugs called benzodiazepines is often used to stop seizure activity. Benzodiazepines work by binding to GABA A receptors allosterically causing the receptors affinity for GABA to increase. The increased binding of GABA to its receptors causes Cl– channels to open, causing an influx of chloride ions through the membrane of the neuron. This effect hyperpolarizes the cell and inhibits action potentials, resulting in an overall inhibition of neural activity that stops the seizure, as shown in FIGURE 7. Benzodiazepines are usually administered using prefilled syringes intravenously in the ambulance to help stop the convulsions in a pre-hospital setting. Autoinjectors are also starting to be used because errors with the iv. administration in the ambulance settings may occur. In addition, because some epileptic crises are preceded by an aura, there is an opportunity for the patient to prevent or reduce a seizure if the patient can carry a self-administered device. This modality has very important implications for the patient’s quality of life due to the 211

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Multiple sclerosis


GABA A receptor

Multiple sclerosis (MS) is an inflammatory, chronic and progressive disease charSynaptic cleft acterized by damage to the myelin sheath on the axons of nerve cells. The myelin GABA Gaba binding site sheath is a protective coating around the Benzodiazepine binding site (Daizepam) axons nerve cells that allows an electrical ClDiazepam impulse to transmit quickly and efficiently along the axon. Therefore, damage to the myelin sheath causes nerve cell signals to slow down or stop. This disease Clcurrently affects over 350,000 people in the USA and to date there is no cure, although there are several treatment options [40]. The present aim of the first line of medication treatment for MS is to slow down neurodegeneration before excessive Post-synaptic membrane damage occurs. The three main drugs currently used for MS are IFN-b1a, IFN-b1b and glatiramer acetate. Interferons are immunomodulatory drugs that interfere Figure 7. Diazepam, a benzodiazepine, binds allostericallly to the GABA A with T-cell activation through several receptor resulting in increasing Cl– inflow to the neurons leading to cell mechanisms including antigen processing hyperpolarization, preventing the propagation of the epileptic stimuli. and reduction of co-stimulatory molecules Figure created by Velimir Manjulov. (FIGURE 9). The interferon therapy requires emotional impact that an aura episode represents as a pro- patient-administered injections multiple times a week and the glatiramer acetate requires injections once a day. The fredrome of an epileptic seizure. The most commonly used prefilled device treatment of epi- quency of these injections makes the use of autoinjectors favorlepsy during a seizure is iv. administration using a prefilled able. Autoinjectors for MS have been reported by patients as syringe of the benzodiazepine called lorazepam [36]. The main easier to use, less painful, providing greater assurance that the limitation with this treatment is that it is often hard to admin- injection is at the correct depth. All these features become ister iv. when the patient is convulsing, which may result in a essential in a disease that carries a heavy psychological burden considerable amount of time to get the iv. into the patient. for the patient [41]. Lorazepem also has a shorter half-life than other benzodiazeOne of the main prefilled devices used for the treatment of MS pines such as diazepam or midazolam, once it is removed from is the Extavia autoinjector. Extavia is an IFN-b1b treatment and the refrigerator. This makes the lorazepem harder to be can be administered with vial and syringe or with the Extavia autodeployed in ambulatory settings that lack refrigeration [37]. injector. The autoinjector is usually chosen for patients because it A diazepam autoinjector (Meridian Medical Technologies is easier to use and the patient can’t see the needle during the Inc., Columbia, MD, USA), as shown in FIGURE 8, can be used injection. In order to use the autoinjector, a 2.25 ml Extavia preinstead of the traditional iv. administration. The Diazepam filled glass syringe must be placed inside the device. The needle Autoinjector C-IV is a single-use disposable device for the injection depth can then be adjusted by the user with a dial at the administration of 10 mg of diazepam in 2 ml [38]. The autoin- bottom of the syringe. The depth can be set to 12, 10 or 8 mm. jector is administered intramuscularly, rendering it easier to The medication is administered by pushing a button at the top of administer to a convulsing patient. It also has fewer steps the device. After the injection, the syringe can be removed from required of the medical practitioner, enabling faster treatment the autoinjector and be used for the next injection [42]. and improved prognosis, leaving less time for the seizures to The BetaJect autoinjector is similar to the Extravia autoinjeccause damage. tor and is used to administer Betaferon, which is a type of A midazolam autoinjector has also been developed that is IFN-b1b. The BetaJect autoinjector is loaded with a prefilled similar to the diazepam autoinjector. The only difference syringe for doses between 0.25 and 1.0 ml. The needle depth between the devices is that it has a smaller needle. Midazolam is can be adjusted, but only by a trained professional [43]. another type of benzodiazepine that has a rapid onset action, The Rebiject II, RebiSmart and the more recently available which has been shown in studies to be effective for the treat- Rebidose are three prefilled devices also used for the treatment ment of seizures. A midazolam autoinjector is yet to be of MS. All of these devices administer Rebif, which is an approved by the US FDA [39]. IFN-b1a treatment. This is used to treat relapsing MS. 212




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The Rebiject II is an autoinjector that can be loaded with prefilled syringes with 22 or 44 mg of Rebif. The Rebiject II is pre-set to have a needle depth of 10 mm but the patient can adjust the depth if necessary [44]. A new delivery device for Rebif is the RebiSmart. The RebiSmart is currently approved in Europe, but to this date not approved for use in the USA. The RebiSmart is an electronic autoinjector that has an information screen to set personalized injection settings such as dose and needle depth. The device also stores injection history that can be reviewed on the screen. The screen makes this device particularly user friendly. The RebiSmart is filled with prefilled multi-dose cartridges of Rebif and only the needle needs to be changed for each injection. This also makes the device more convenient for patients. The newest Rebidose autoinjector is a single-use, preassembled device that can be configured to administer 22 or 44 mg of Rebif. It was approved by the FDA in early 2013 and entered the US market in April 2013 [45]. Pain management

When a patient suffers from extreme pain, several drugs are available to palliate symptoms. Opioids are among the most effective therapeutic drugs. One of the most widely used opioids is morphine. Morphine interacts with receptors, located at the spinal and supraspinal levels of the supraspinal nociception. Activation of m receptors lead to activation of the heterotrimeric G protein-coupled receptors by dissociation of the a-subunit from the bg-subunit, which results in downstream signaling pathways involving the activation of a number of proteins including the MAPK family, adenylcyclases, phospolipase C and calcium and potassium channels that will ultimately produce the acute physiologic effects of morphine, as shown in FIGURE 10. Tolerance (the need to increase the drug dose to achieve the same efficacy) to morphine can quickly develop in a patient. Initially, morphine can cause analgesia in about 5–20 min and can last for 3–4 h. Once a patient is started on morphine, a higher dosage is required to achieve analgesia. Morphine is usually injected intramuscularly in a sterile hospital setting. When this environment is not available, such as in trauma or combat situations, autoinjectors are often preferred. Because of the addictive properties, tolerance and physical dependence of morphine, a device capable of regulating the precision of a morphine dose could significantly benefit the patient by avoiding possible downstream problems of drug overdose. In addition, the anxiety produced by the expectation of feeling pain could be mitigated by a device that the patient carries with him and is ready for use anytime. A morphine autoinjector (Morphine Autoinjector CII, Meridian Technologies Inc.) was developed for self-administration of morphine for pain management. This autoinjector has a spring-driven injection mechanism, which causes 10 mg of morphine sulfate in 0.7 ml of water of injection to be delivered intramuscularly to the patient [46]. This device was developed for the administration of a fixed dose of morphine by non-medical professionals. informahealthcare.com

Figure 8. The Diazepam Autoinjector C-IV (Meridian Medical Technologies) for treatment of epilepsy.

Immune disorders Rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic and progressive disease that primarily involves inflammation in joints. RA is also a systemic disease that has extra-articular manifestations in other organs. In industrialized countries, 0.5–1.0% of adults are affected by RA [47]. RA thus far has been considered an autoimmune disease, although its etiology is still under investigation. At the molecular level, patients with RA express a number of proinflammatory molecules in the synovial cell membranes of the joints including TNF, a cytokine considered a key regulator of the inflammatory process responsible for the damage of joints and progression of the disease [48]. The current treatments for RA include physical therapy, exercise, medications and sometimes surgery [49]. The first stages of treatment include anti-inflammatory drugs, corticosteroids and non-biological, disease-modifying anti-rheumatic drugs. The final stage of treatment is the use of biologicals that aim to target specific molecules involved in the disease [50]. High compliance of treatment is required to prevent disease progression. Therefore, injectors that are easy to use and less painful are attractive choices for the patient. Several prefilled devices containing TNF inhibitors have been developed for the management of RA. Examples of these are etanercept (ENBREL, co-marketed by Amgen and Pfizer in North America), adalimumab (HUMIRA, Abbott Inc., Abbott 213


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hold down the button until the indictor window on the pen shows that the entire Monocytes dose has been injected [52]. SIMPONI (golimumab) is adminisInterpheron beta mechanism tered by sc. injection monthly and is of action (extravia, betaJect, available in various dosage forms and conrebiject II) centrations: 50 mg/0.5 ml in a single-dose T-cell prefilled SmartJect autoinjector or singledose prefilled syringe, and 100 mg/1 ml Damaged myelin in a single-dose prefilled SmartJect autoinExposed axon jector or single-dose prefilled syringe. Patients may self-inject after approval and proper training. SIMPONI is FDA approved for the treatment of RA in combination with methotrexate, active psoriatic arthritis, ankylosing spondylitis and ulcerative colitis. The SureClick and SmartJect autoinjectors present three common safety feaDamaged nerve tures for patients: safety needle cover, which does not release the needle unless the autoinjector is placed firmly against the injection site (preferably in the front of the thigh), two audible ‘clicks’ that sigHealthy nerve nal beginning and end of the injection and a color indicator to show that patient Figure 9. The anti-inflammatory effects of IFN-b are thought to protect against has received the dose. For activation, the myelin destruction during relapsing-remitting multiple sclerosis. patient must uncap the device and press Figure created by Velimir Manjulov. it onto skin to unlock. Once unlocked, Park, IL, USA) and golimumab (SIMPONI, Centocor Biotech, the patient must activate a button, while keeping it firmly Inc.). The mechanism of action of adalimumab is shown against the skin for a period of time. Inspection window color in FIGURE 11. change ensures successful injection. For disposal, needle autoSince the patients suffering from RA become dependent on matically retracts and cannot be exposed again. others to perform daily activities, a device that can promote self-management behavior would improve patients’ self-confi- Anaphylaxis dence, improving the quality of life. A self-administration Anaphylaxis is a severe, life-threatening allergic reaction with a device of this type allows the patient to continue with their very rapid onset. It occurs when the body is exposed to an normal activities, while avoiding the sense of frustration for not allergen. During anaphylaxis, the body’s immune system is actibeing able to perform a task. vated and tissues release histamine, causing inflammation in the ENBREL (etanercept) is available in three administration airways and other parts of the body, as detailed in FIGURE 12. options including the 50 mg/ml prefilled syringe, 25 mg multi- Therefore, prefilled cartridge devices or syringes are very useful ple use vial and the ENBREL SureClick (50 mg/ml of because treatment must happen quickly [53–55]. ENBREL) single-use autoinjector. ENBREL is FDA approved The primary form of treatment is the injection of epinephto treat RA, psoriatic arthritis, plaque psoriasis and ankylosing rine. The adrenaline interacts with b-adrenergic receptors, causspondylitis. ing smooth muscles to relax. This helps reduce bronchospasms The administration of adalimumab is usually done through and increases coronary blood flow and cardiac output to syringe and vial or the HUMIRA pen device (Abbott Inc.). In increase the blood pressure. a study comparing the two routes of administration, 88% of Prefilled devices were developed to be used for the treatment patients preferred the HUMIRA pen because they found the of anaphylaxis including the EpiPen, TwinJect and the AnaPen. injection less painful, the device easier to use and less time for The EpiPen (Mylan Inc., Canonsburg, PA, USA) is a administration [51]. The HUMIRA pen is a single-use prefilled cartridge-based autoinjector that administers a single dose of disposable pen. The pen can be used by medical professionals 300 mg/0.3 ml of adrenaline for adults. The EpiPen is activated or can be self-administered by patients, once they have been by the pressure between the device and the tissue after the trained. Usually patients need to inject about once a week. The device is forcefully pushed against the skin, as shown pen is activated by a button and the patient must continue to in FIGURE 13. This causes the spring system and the cartridge 214


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The role of morphine in the analgesia pathway Opioids α2 agonists Centrally acting analgesis COX-2-specific inhibitors. Traditional NSAIDS

Pain

NH2

Morphine Opioid μ receptor α


Ascending input

Descending modulation

Local anesthetics Opioids α agonists COX-2-specific inhibitors Local anesthetics

Dorsal root ganglion

Dorsal horn

β

γ

GTP

↓ Adenylate cyclase ↓ Vesicular release

α γ

β

GIRK ↑ Delayed rectifier ↑ Big K ↑ lh ↑ Voltage-gated Ca channel ↓

Peripheral nerve

Local anesthetics COX-2-specific inhibitors Traditional NSAIDS

Trauma

Peripheral nociceptors

Figure 10. The role of morphine in the analgesia pathway. Several pharmacological approaches for pain management have been developed. Opioids such as morphine activate m receptors triggering a signaling pathway that results in cell hyperpolarization. At the spinal level, morphine decrease release of excitatory neurotransmitters from C fibers and decrease excitability of dorsal horn neurons controlling spinal pain processing, while at the central level morphine induces suppression of central pain centers including the amygdala, substantia nigra and periaqueductal grey zone. Figure created by Velimir Manjulov.

with the attached needle to move into the end position and pierce the skin. Once the skin is pierced, the rest of the spring force causes the cartridge of adrenaline to burst and the adrenaline flows into the muscle. The EpiPen has a needle length of 17 mm when injected by an adult. This ensures that the needle goes past the sc. level, into the muscle. This is essential because adrenaline is most effective when it is able to reach the muscle [56]. TwinJect (Sciele Pharma Inc., Atlanta, GA, USA) is a similar cartridge-based autoinjector for the administration of adrenaline. One interesting feature about the TwinJect is that after the initial dose has been given, the autoinjector can be opened up to get a second dose of adrenaline in a prefilled syringe that can be administered to the patient manually. In a study of anaphylaxis, it was shown that about 19% of food-induced anaphylaxis required more than one dose of adrenaline in order for the patient to fully recover. Therefore, the extra dose of adrenaline in the TwinJect can become very useful. Errors, such as using the autoinjector upside down, also can occur during the administration of adrenaline. Another type of autoinjector sometimes used for the administration of adrenaline is the AnaPen (Lincoln Medical Ltd., Salisbury, UK). The AnaPen is a single-use syringe-based autoinjector for adrenaline approved for use in Europe. The AnaPen was originally developed for sc. self-administration of informahealthcare.com

insulin and has been adapted for the administration of adrenaline. The AnaPen requires the user to remove a needle shield and then push a button to activate the device. This can be a problem for anaphylaxis because these extra steps take extra time. Once the device is activated, the needle penetrates the skin about 7 mm in adults. At this depth, the injection is sc. and does not reach the muscle layer. This is good for the original purpose of insulin administration, but limited for adrenaline administration as muscular injections are more effective. The sc. injection means that it takes longer for the adrenaline to peak in the plasma, making it less efficient than the EpiPen and TwinJect. This example shows that although some devices can be converted for different drugs, there are also features of devices that can be very specific for a certain drug. Intravascular access in emergency applications

Emergencies in adults and children involve a number of lifethreatening conditions that exemplify the need for immediate interventions. These interventions require an intravascular access to administrate drugs, restore intravascular volume, deplete an excess of volume or perform an immediate diagnostic test such as measure central venous or arterial pressure. Every year, more than 32 million people enter into emergency rooms requiring intravascular access. A number of clinical entities fall into the category of emergencies including 215

Review


iv. route as drugs administered present a similar onset of action [57,58]. There are a number of techniques to create an intraosseus access including manual needles and intraosseus devices, including the intraosseus infusion system (EZ IO, Vidicare Corporation, Shavano Park, TX, USA), bone injection gun (BIG, TNF TNF receptor PerSys Medical, Houston, TX, USA) and the bone injection device (FAST1, Pyng TNF Medical Corporation, Richmond, BC, Canada). EZIO is a battery-powered infuAdalimumab (HUMIRA AUTOINJECTOR) sion drill, BIG is a manually operated spring-loaded device, while FAST1 is a manually operated system that depends on the operator force to introduce an infusion tube into the sternum, as shown in FIGURE 14. FAST1 is the only device Figure 11. Adalimumab, a monoclonal antibody binds to TNF-a, a cytokine known to play a major role in the inflammatory process avoiding the designed to be inserted in the sternum. interaction with the TNF-a receptor and its activation. Insertions sites for BIG include proximal Figure created by Velimir Manjulov. humerus and tibia and EZIO in addition could be inserted in the distal tibia. cardiovascular diseases, infectious diseases, neurological diseases Additional contraindications for all devices include osteopoand trauma. All these disorders demand an immediate interven- rosis and infections at the site of infection. There are injection tion to keep cardiopulmonary activity at a level that allows devices customized for adults and for children due to the proper oxygenation of tissues. unique nature of the bone anatomy for every age. Specific An impairment of stroke volume or heart rate could depth markers and needle sizes exist for adults and for children threaten cardiac output and thus tissue oxygenation. In designed to reach the bone marrow where the vein sinusoids infectious emergencies such as septic shock, the cardiovascu- are located. In order to penetrate the bone tissue, specialized lar activity remains normal but the capillary network is needles (16–18 gauges) are being manufactured and designed unable to provide the pressure necessary to maintain tissue to prevent blockage of the needle with bone spicules by using a perfusion. In neurological emergencies, the cardiovascular stiletto. The maximum administration rate using the intraosseus activity could be affected by central mechanisms or the respi- route equals to a #21 gauge peripheral cannula. ratory activity could be threatened by disruption of the neural circuits controlling the respiratory function at the CNS. Regulatory considerations for prefilled devices: FDA For all these conditions, ensuring a vascular access is critical The FDA is the federal agency of the USA health and human to maintain intravascular volume and cardiac activity, while services responsible for ensuring that drugs, medical devices, biokeeping tissue perfusion to ensure tissue oxygenation or to logical products, veterinary products and electronic products maintain brain pressure and perfusion at a level that will not emitting radiation are safe and effective. The FDA is divided into threaten critical neural circuits responsible for cardiopulmo- several offices, each of them in charge of the assessment of spenary activity. cific products. The office of drugs and evaluation research There are a number of non-pharmacological and pharmaco- (CDER) supervises the regulation of drugs including new moleclogical approaches to keep the hemodynamic activity steady ular entities and generic versions (copies of new molecular entisuch as the infusion of iv. fluids or blood substitutes and/or ties). The office of devices and radiological health (CDRH) is the use of drugs such as inotropics and diuretics. For both responsible for regulating medical devices and radiation-emitting approaches intravascular access is a prerequisite. When intravas- products. The office of biological research (CBER) supervises biocular accesses are not accessible, the io. route becomes the route logical products such as monoclonal antibodies and vaccines [59]. of choice. Introducing an access throughout the bone is not without Manufacturing & non-clinical testing risk. There are some drawbacks such as the risk of fracture, Good manufacturing practices (GMP) for pharmaceuticals development of osteomyelitis and fat embolism. The io. route or quality system regulation (QS) for finished devices are became an attractive alternative to the iv. route for emergencies required FDA standards for prefilled injectors manufacturbecause the anatomy of the bone vasculature is such that the ing. As long as the drug and device are manufactured as a sinusoids that drain into the venous system do not collapse single entity or co-packaged, both set of regulations (GMP during an emergency. Moreover, the io. route is similar to the and QS) are demanded, whereas if they are manufactured


Cell membrane

216



First exposure to allergen

IgE Native T-cell with egg-specific T-cell receptor

Allergens

Egg allergen

Antigen presenting cell

B-cell producing egg-specific IgE

IgE receptor

Th2 cell Second exposure to allergen Expert Review of Medical Devices Downloaded from informahealthcare.com by Nyu Medical Center on 01/14/15 For personal use only.

Review

Degranulation Egg protein cross-linking IgE on mast cell

Mast cell release of granules containing: -Histamine -Leukotriene -Prostaglandin -Cytokines

Local symptoms -Itching -Swelling -Nausea -Vomiting -Cramping -Diarrhea

Adrenaline (EpiPen®)

Systemic symptoms: -Airway swelling -Hypotension

Figure 12. Anaphylaxis is a severe allergic reaction mediated by IgE in response to an allergenic substance characterized by release of inflammatory mediators such as histamine by mast cells. Massive amounts of histamine promotes blockage of the airways and hypotension, adrenaline works by counteracting these effects by activating b2-adrenergic receptors in the airways producing broncodilatation. In the cardiovascular system, adrenaline activates b1 receptors and a2 receptors producing vasoconstriction and cardiac inotropism, restoring blood pressure to normal levels. Figure created by Velimir Manjulov.

separately each standard apply for each component. Good laboratory practices are FDA standards developed to ensure the uniformity, consistency, reliability, reproducibility, quality and integrity of the data generated during preclinical testing [60,61]. Clinical development

In order to start clinical development, a manufacturer of a prefilled device must submit either an investigational new drug application (IND) or an investigational device exemption (IDE) corresponding whether the prefilled device is considered a device or a drug. An IND or IDE collects the information produced during the laboratory phase of the product development (in vitro/in vivo). Once an IND or an IDE is approved, the manufacturer is authorized to initiate clinical studies. Clinical development involves several phases, including Phase I–IV. Phase I is focused on pharmacokinetics and optimal dose range, carried out in healthy volunteers. Phase II is focused on drug efficacy and safety in patients carrying the disease (200–300). Phase III is focused on comparative studies to study drug efficacy and safety across a large number of patients (2000–3000 patients). Phase IV is focused on post-approval studies and post-marketing surveillance. After Phase III has successfully being tested, a new drug application (NDA) or biological license application (BLA) can be submitted to obtain clearance for commercialization [62]. informahealthcare.com

A NDA or BLA is a premarket requirement that has to be submitted in order to obtain FDA clearance for commercialization. Both NDA and BLA have to be presented by the manufacturer for review to the CDER. In the case of medical devices, the clinical development includes a biocompatibility phase (analog to Phase I in drug clinical trials), a feasibility phase trial (equivalent to Phase II

Figure 13. Application site for an adrenaline autoinjector.

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Figure 14. Adult and pediatric bone injection guns. These devices are used for creating an intraosseus route for immediate administration of drugs or fluids when a vascular access is not accessible during emergencies. Reproduced with permission of PerSys Medical.

drug trials) and a lager trial known as pivotal studies (usually multicenter studies) to assess the safety and effectiveness of the device against the current standard. Finally, medical devices require a premarket notification (510k) or premarket approval (PMA) in order to obtain FDA clearance for commercialization. FDA classification of prefilled devices: combination products

From a regulatory standpoint, there are three classes of prefilled injectors: general injectors intended for use with a wide range of drugs/biological products; injectors intended for use with a certain class/family of drugs or biological products or with a specific product line; injectors intended for use with a specific drug/biological product, for example, prefilled with the drug/ biological product, co-packaged with the drug/biological product or separately distributed but labeled for use together. Prefilled syringes, prefilled devices co-packaged with a specific drug-biologic or those products labeled to be used together are considered combination products. The decision to whether the combination product will be reviewed by the CDER, CDRH or CBER is based on the primary mode of action of the combination product. In most prefilled injectors, the drug determines the therapeutic effect and primary mode of action. Prefilled devices that do not enter into the category of combination products such as injectors designed for general use, are considered medical devices and therefore are reviewed by the CDRH [63,64]. Premarket approval of prefilled devices

For prefilled devices considered drugs or biologics, an NDA or BLA should be submitted to the CDER. An NDA or BLA has to demonstrate that the new product is safe and effective to be commercialized. While a NDA is a requirement for new molecular entities (‘new drugs’), for a copy of 218

an existing drug (‘a generic drug’) an abbreviated NDA process (ANDA) should be submitted. ANDA are less stringent than NDA and usually do not require preclinical or clinical data, although pharmacokinetic equivalence (bioequivalence) with the innovator drug must be submitted. Most of devices classified as class I (low risk, e.g., surgical gloves) and class II (medium risk e.g., endoscopes) require a premarket notification (known as 510k) in order to obtain FDA clearance for commercialization, while class III devices (high risk, e.g., pacemakers) require a PMA. The 510k pathway demands from the manufacturer to demonstrate substantial equivalence with an existing legally marketed US device. On the other hand, PMA is usually demanded for high-risk devices requiring a higher level of evidence (clinical data) to demonstrate the safety and effectiveness of the medical device. Injectors intended for general use with a wide spectrum of drugs/biological products generally are considered as class II medical devices and therefore follow the premarket notification 510k pathway. Likewise, injectors intended for use with a certain class/family of drugs/biological products often follow the 510k pathway. Injectors intended for use with a specific drug/biological product are typically considered combination products. Within this group, there are injectors containing a drug such as prefilled syringes, injectors copackaged with a drug or biologic or injectors separately marketed but with mutually conforming labeling with a drug or biologic. Because for all these combination products the primary mode of actions resides on the drug, a NDA or BLA application should be submitted to the CDER. In the case of co-manufacturing, where a device manufacturer outsources the filling of the device with a drug or biologic and the drug manufacturer submits a NDA or BLA, the device manufacturer could send a device master file that contains confidential information about the device together with a letter of authorization to the drug manufacturer to reference any FDA request regarding the device part to the device master file [65]. Patient education

Prefilled devices are designed to provide a safe and effective method for drug therapy. These devices allow patients to selfadminister a drug using the parenteral route without the need of healthcare personnel. Proper handling and use of prefilled devices is a prerequisite for successful drug therapy. To achieve this task, patients must be informed about several issues including how the device works, drug characteristics (storage conditions) and drug side effects, potential sites of administration, dose and depth and rate of administration. Other relevant information includes aseptic handling and proper disposal of material. These requirements entail a learning curve that will ultimately allow the patient to acquire a self-management behavior, namely administration of the drug safely and efficiently with minimum discomfort. Most of the literature for patient education on prefilled devices utilization originates from device manufacturer’s user guides Expert Rev. Med. Devices 11(2), (2014)



and leaflets. Additionally, some manufacturers also provide training sessions on how to handle their device with assistance of the physician or video training sessions through their websites. User guides contain general and specific information related to a particular device and drug. For example, a common feature of prefilled device leaflets is the safety considerations on how to handle and dispose sharp material. Most user guides describe specific side effects related to the drug contained on the cartridges that the patient must be aware of. Most leaflets also provide schematics including prefilled device parts and how they should be assembled, sites of injection and how to hold the prefilled device correctly to penetrate the skin tissue. Depending on the type of prefilled device, drawings of dials or electronic screenings are given to inform the patient how to set up the correct dose and avoid overdosification or underdosification. The level of device sophistication has important implications for patient education. Devices with electronic components such as memory may not require many steps for the patient to recall as opposed to older nonelectronic devices. Therefore, patient education seems to be related to the type of device being used and its technological features. The importance of education on the use of prefilled devices should be stressed due to the short- and long-term consequences of improper use of these types of devices. For example, a recent survey reported the lack of training in the use of adrenaline autoinjectors for the management of anaphylaxis among teenagers. Anaphylaxis is a life-threatening condition, and failure to properly use an adrenaline autoinjector during an anaphylaxis crisis could put the life of the patient at risk. For other clinical situations involving long-term therapies such as the use of prefilled devices for growth hormone therapy in children, poor compliance with injections does not necessary carry a life-threatening situation, but could have long-term implications in child development. A survey conducted on compliance with growth hormone prefilled devices has revealed that most of the population being interviewed had positive experience with prefilled devices and only a small population was dissatisfied and preferred the use of conventional syringe and vials. Interestingly, this small population claimed dissatisfaction on the training and education on the use of the device. An important aspect of patient education is to consider personal issues such as psychological (beliefs, fears) and lifestyle, that could influence patient compliance to treatment. This issue was described in a survey among teenagers using adrenaline autoinjectors, where the influence of such variables in the use of prefilled adrenaline autoinjectors was observed. Therefore, individualized education rather than educational groups has been suggested as an educational tool to improve patient compliance with treatment. Education might not only be relevant for the patient but for the healthcare personnel as well. In a survey among healthcare informahealthcare.com

Review

workers who teach their patients how to use prefilled devices, 79% of the professionals failed to use the device properly. Even more striking was the finding in another study carried out by Hayman and coworkers in the UK. This study was carried out among 50 medical practitioners, where only one knew how to use an adrenaline autoinjector due to a personal history of anaphylaxis [66–69]. Expert commentary

The recent development of new prefilled delivery systems for parenteral applications has opened an era in management of diseases. These injection systems consist of prefilled syringes and cartridges that have a number of attributes: decrease dosage errors, allow for portability due to their small form factor and ultimately provide better patient compliance. Some of the prefilled injectors include the active pharmaceutical ingredient in lyophilized form to increase stability and shelf-life. Some injectors provide dosage tuning allowing for more personalized treatment on demand. Moreover, prefilled devices can be suitable for emergency applications that require timecritical delivery. Such applications include ambulatory settings in rural areas and hostile environments, such as disaster zones or battlefield conditions. This new generation of prefilled devices has the potential to change disease treatment, expediting operational effectiveness and increasing accessibility for immediate treatment of both chronic and acute conditions. For diabetes management, NovoLog FlexPen and the Humalog KwikPen are two of the most common pen injectors being used. For these devices, different types of insulin are used, though the most common ones are rapid-acting insulins. Gonal-f, an autoinjector containing follitrophin alpha has been commercialized for the treatment of infertility. Migraine, epilepsy, MS and pain have been some of the neurological disorders where autoinjectors have been developed including Alsuma (sumatriptan, for migraine management), diazepam autoinjector (epilepsy), IFN-b1b (MS) and morphine autoinjectors (pain management), respectively. For autoimmune disorders, pen injectors containing adrenaline for the treatment of anaphylactic shock and HUMIRA (adalimumab, a TNF inhibitor) for the treatment of RA and other autoimmune disorders are currently being used by millions of people worldwide. From a regulatory standpoint, prefilled devices are subjected to a number of standards including GMP and QS. Also, draft guidance for Industry has been redacted by FDA to assist manufacturers to comply with technical specifications for pen injectors. FDA regulates prefilled devices differently according to several features such as if the device will be used with a number of drugs or if will be used for a specific drug. One common designation for prefilled devices is known as combination products because they combine a drug and a device in a single product. TABLE 1 provides a summary of prefilled devices for various medical applications. Prefilled injectors have already improved 219

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Table 1. Summary of the key features of commercially available prefilled devices. Drug

Device

Manufacturer

Insulin aspart, rapid acting

NovoLog FlexPen TM injector

NovoNordisk

Insulin Lispro recombinant rapid acting

Humalog KwikPen TM injector

Eli Lilly

Insulin injector (pediatric)

HumaPen Luxura HD

TM

TM

TM

TM

Eli Lilly

TM

US FDA status/ approval pathway

Year of approval

Approved NDA #020986

2000


1996

Approved 510k (injector)

2007

510K #K942159

1995

Insulin (pediatric)

NovoPen refillable autoinjectors

NovoNordisk

Insulin (rDNA origin) (adults) Apidra Lantus

SoloSTAR ClickSTAR

Sanofi-Aventis

NDA #021081/S024 (Lantus Package) NDA Apidra: 021629 NDA Lantus: 021081

Lantus: 2000 Apidra: 2004 Approval Package (cartridge + pen injector) 2007

Follitropin alpha

Gonal-f prefilled disposable multifilled pen injector

EMD Serono-Merck


1997

Follitropin alpha/beta

Folistim AQ injector

Organon (now Merck & Co)

Approved NDA #021211 and NDA #021273 (different strength formulations)

1997

Ganirelix acetate

Ganirelix acetate (prefilled TM syringe)

Vetter/Organon (Merck & Co)


1999

Somatotropin

HumatroPen

Lilly


1987

Pharmacia (now Pfizer)

Genotropin Approved NDA #020280 Genotropin Pen 510k #K954337

Genotropin: 1995 Genotropin mixer: 1995

TM

TM

TM

prefilled pen

TM

TM

Somatotropin (Genotropin)

Genotropin Pen

Somatotropin

Nutropin AQ

Genentech Inc.


1994

Sumatriptan

Alsuma autoinjector

Manufactured by Meridian Medical Technologies (a Pfizer company) (distributed by Pfizer)


2010

Diazepam

Diazepam autoinjector TM C-IV

Meridian Medical Technologies (a Pfizer Company)

Information not available

Midazolam

Midazolam autoinjetor

Meridian Medical Technologies (a Pfizer Company)

Information not available

IFN-b1b

Extavia autoinjector

Novartis

Approved BLA #125290

2009

IFN-b1b (Betaseron)

Betaseron with BetaJect TM autoinjector

Bayer Healthcare


1993

IFN-1a (Rebif)

Rebiject II (autoinjector with prefilled syringe)

Merck Serono-Pfizer (Rebif) Becton Dickenson (Rebiject II)


2002

TM

TM

TM

TM

BLA: Biological license application; NDA: New drug application.

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Table 1. Summary of the key features of commercially available prefilled devices (cont.). Drug

Device

Manufacturer

US FDA status/ approval pathway

IFN-1a (Rebif)

RebiSmart (electronic TM autoinjector)

EMD Serono Canada Inc.

Approved in Europe

Morphine sulfate

Morphine autoinjector TM CII

Meridian Medical Technologies (A Pfizer Company)

Listed on the Orange Book for therapeutic equivalent drugs Application # N019999 autoinjector: Information not available

1990

Etanercept

SureClick

Immunex

BLA #103795

1998

Abbott

BLA #125057

2002

Centocor Biotech

BLA #125289

2009

Meridian Technologies (a Pfizer company)

NDA #19430

1987

Amedra Pharmaceuticals

NDA #020800

2003

AnaPen

FDA Import Refusal Import (originally from UK) unapproved new drug (NDA)

Adalimumab Golimumab

TM

autoinjector

TM

HUMIRA

TM

SmartJect

autoinjector TM

Adrenaline

EpiPen/EpiPen Jr

Adrenaline

TwinJect

Adrenaline

TM

TM

AnaPen

TM

Year of approval

BLA: Biological license application; NDA: New drug application.

the quality of life of millions of people. These devices offer better user experience, higher compliance, portability and cost–effectiveness without the need to go through a dosification step. Therefore, a larger number of prefilled devices will be expected to be adopted for a wide variety of medical applications. The field of prefilled injectors is growing rapidly with an increasing number of improvements being made to improve patient experience. For example, although some of the current prefilled devices utilize mechanical dialing to select the dose, programmable devices with on-board memory are gaining popularity and will occupy a substantial percentage of the prefilled device space. Moreover, backward dialing is now available in some insulin pens to correct misdialed doses. Additional noteworthy features of current prefilled devices include control over needle depth, needle insertion speed and injection speed and injection time. These attributes improve device safety. Disposable devices are an additional advantage for those patients who are reluctant to reuse the same device. Overall, the evolution of prefilled devices has been driven by identifying patient needs and translating those needs into new device designs. Five-year view

The field of prefilled devices will continue to grow and new technologies will bring novel capabilities to existing prefilled devices. In the next 5 years, more devices will adopt electronic systems. The increasing trend toward telemedicine will also impact prefilled injectors. We may be able one day to


see how a doctor sends instructions to the prefilled device to change a dose regime by only connecting the device to a computer via USB port. It is also foreseen that novel materials will bring about lighter devices and new safety systems will provide devices with a higher degree of safety. As the technology of prefilled injectors continues to mature, a number of clinical conditions will adopt prefilled devices to improve compliance for hard-to-treat diseases such as tuberculosis, HIV, epilepsy and arterial hypertension. For this to happen, a clear advantage over oral and parenteral state-ofthe-art treatments must be demonstrated. Finally, due to the growth of the biopharmaceutical industry, an increasing number of biodrugs will adopt prefilled devices. This is because biologicals often require parenteral delivery and the diseases they are targeting usually require high compliance. Furthermore, the development of prefilled devices containing biologicals will probably increase as this will represent an entry barrier for biogeneric manufacturers. Financial & competing interests disclosure

The authors would like to thank V Manjulov for his contribution for illustrations (Figures 2, 4, 6, 7, 8, 10, 11 and 12). This research work was supported by the US Army Research Office via the Institute for Soldier Nanotechnologies (ISN) at MIT (contract: W911NF-07-D-0004). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

221

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Key issues • Prefilled devices are drug delivery devices for parenteral administration (subcutaneous, intramuscular, intravenous and intraosseous routes) that integrate the delivery mechanism with the therapeutic drug. • Prefilled devices can come in the form of: prefilled syringes (syringes with drug already loaded), autoinjectors (for self-administration with a manual or automatic inject) and dual chamber (allows for additional reconstitution of lyophilized or powder drug). • Prefilled device designs have to take into account: accuracy, sterility, safety, waste minimization, materials interactions, logistical concerns, ergonomics and usability and affordability. • Prefilled devices are increasingly being adopted due to their increasingly safe and easy utilization by patients, portability, accuracy of


dose and quick delivery, which lead to increased patient compliance. • Currently, prefilled devices are implemented in clinical therapies for: diabetes, infertility, human growth hormone deficiency, migraine, epilepsy, multiple sclerosis, pain management, rheumatoid arthritis, anaphylaxis and emergency intravascular access. • US FDA regulatory considerations for prefilled devices include: manufacturing and non-clinical/premarket testing, clinical trials, whether the device is a combination product including a drug packaged in the device, patient education and human factors. • Most prefilled devices filled with drugs will be considered ‘combination products’ and subject to additional manufacturing (good manufacturing practices) and quality standards. • Devices can be classified by the FDA as any of three classes: class I (low risk), class II requiring 510k premarket notification and class III (high risk) requiring a premarket approval application. • Among trends in prefilled device designs, some of the most notable include: capabilities for dose adjustment (e.g., dials), exploration of new materials for drug cartridge, adoption of electronic systems to monitor prefilled device deployment and obscuring of the needle.

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Prefilled syringes and usability of ophthalmic viscosurgical devices.

Review of nanostructured devices for thermoelectric applications.

Extractables and leachables considerations for prefilled syringes.

Development of high-throughput glass inkjet devices for pharmaceutical applications.

Oligothiophene semiconductors: synthesis, characterization, and applications for organic devices.

Phase-change devices for simultaneous optical-electrical applications.

Comparison of drug delivery with autoinjector versus manual prefilled syringe and between three different autoinjector devices administered in pig thigh.

Development and examination of a rubric for evaluating point-of-care medical applications for mobile devices.

Developing trends in aptamer-based biosensor devices and their applications.

Clinical applications of adaptive servoventilation devices: part 2.

Medical applications of near-eye display devices: an exploratory study.

Indium phosphide nanowires and their applications in optoelectronic devices.

Electrosurgery: part II. Technology, applications, and safety of electrosurgical devices.

Applications of piezoelectric fluid jetting devices to neuroscience research.

Fluids for parenteral nutrition.

Parenteral clonazepam for catatonia.

Fluids for parenteral nutrition.

Subcutaneously administered methotrexate for rheumatoid arthritis, by prefilled syringes versus prefilled pens: patient preference and comparison of the self-injection experience.

Commercial Smartphone-Based Devices and Smart Applications for Personalized Healthcare Monitoring and Management.

Design Strategies and Applications of Biomaterials and Devices for Hernia Repair.

Applications of direct-to-consumer hearing devices for adults with hearing loss: a review.

Microfluidic Devices for Terahertz Spectroscopy of Live Cells Toward Lab-on-a-Chip Applications.

Paper as a platform for sensing applications and other devices: a review.

Plasmonic ruler on field-effect devices for kinase drug discovery applications.