Needle-free injectors

A drug product can only be successful if it is delivered in a timely manner to the site of action in a way that will be amenable to the patient and in a way to ensure product quality. Different routes of administration may be used to achieve either systemic or local delivery of the protein. Devices such as needle-free injectors and nebulizers may be used to deliver the protein and to enhance patient compliance with use of the drug. Both the route of administration and the decision to use a device are optimally determined early in clinical development of the protein so that there is plenty of clinical experience with the final product. Some... 

Selection of the appropriate route of administration and delivery device is critical for the commercial success of a drug product. Although injections are the most efficient delivery method for proteins, they are not always the most suitable from the patient s perspective. Few routes of administration (IV, IM, SC, pulmonary, and topical for local delivery) have been successful to date with protein therapeutics because of the size and complexity of the protein structure. Consideration of the bioavailability via a given route must be made when determining the dose required. Use of a delivery device such as an implantable pump, needle-free injector, or dry-powder inhaler may yield a product with a commercial advantage over a competitor s product. 

Fig. 2 The Intraject device. A prefilled, disposable, needle-free injector. (Courtesy of Aradigm Corporation, Hayward, California, U.S.A.)...

There are instances of older designs of needle-free injectors that, even with a well-characterized molecule such as insulin, show substantial differences between needle-free and needle delivery. However, improvements in the understanding of the aforementioned principles as well as advancements in the design of needle-free injectors have led to the recent reporting of improved clinical data. Table 1 summarizes an incomplete list of drugs for which there exist clinical data from needle-free administration, all of which demonstrated broadly similar performance between the needle-free system and the needle system (not every report provides sufficient data to determine if bioequivalence was demonstrated). 

The needle-free injection field has evolved enormously in recent years. Companies have come and gone, taking with them some technologies. This section summarizes the technologies and the companies behind them that are currently active in the held. A review of some of the more prevalent technologies was published in 2002 while a more comprehensive list of companies that have developed needle-free injectors, for both human and veterinary use, is available at http / / www.cdc.gov/nip / dev/jetinject.htm. 

National Medical Products (NMP) developed a disposable needle-free injector, the J-Tip, powered by a charge of carbon dioxide gas. 

Needle-free injectors have been developed to resolve the issue of pain and fear and hence to improve compliance. There are two types of needle-free injectors fluid and powder. Needle-free powder injectors have been utilized for the delivery of vaccines for hepatitis B, aprostadil for erectile dysfunction, the anesthetic lidocaine, a granulocyte-macrophage colony-stimulating factors tumor vaccine for malignant melanoma, and DNA-coated particles. 

The present summary will cover only those technologies where the drug formulation itself is used to penetrate the skin via its mechanical energy. It will not describe any technology where a needle is used to puncture the skin, even if the needle is not visible to the patient or only the epidermis is punctured, such as mini-needles, microneedles, pen injectors, or autoinjectors. Also excluded are systems that ablate the skin mechanically or otherwise disrupt its chemical or mechanical structure to increase its permeability, such as laser ablation, microdermal ablation, electroporation, or iontophoresis. These are usually referred to as transdermal drug delivery, but can also be described as needle free. 

Establishing clinical bioequivalence to a reference delivery method, usually a needle and syringe or an autoinjector or pen injector is the customary method of demonstrating that these conditions have been successfully met. This requires that the maximum blood plasma concentration of the drug (Cmax) and the total area under the time-concentration curve (AUC), as well as their associated confidence intervals, adequately approximate a reference product. The standard criteria to establish bioequivalence are 70-143% for Cmax and 80-125% for AUC (Fig. 3 for an example of a bioequivalent needle-free delivery). 

Potter, C. Caretek medical device. Management Forum Conference on Needle-Free Injection Systems and Auto-Injectors. Management Forum, London, England, Feb 23, 2004. 

A needle-free powder injector (Powderject) was used to intradermally deliver DNA vaccines in mice. Nanogram quantities of DNA encoding the nucleoprotein gene of influenza A virus coated to gold particles elicited a strong and a nucleoprotein-specific cytotoxic T cell response in the animals, indicating effectiveness of immunization with the DNA vaccine. 

More investigation is needed into transcutaneous delivery. Needle-free systems such as jet injectors , which force liquid or powdered drug though the skin by the means of compressed gas, could be an alternative if discomfort (bruising) is minimised. The microneedle system of delivery also seems very promising. Compared with hypodermic needles, microneedles do not significantly stimulate nerve endings and are thus well tolerated. 

There are different devices conunerciaUy available for needle-free injectirai. Commonly jet injectors produce a high-velocity jet of medicine that penetrate the skin. Medicines and vaccines can be administered either intramuscularly or subcutaneously by means of a narrow, high velocity fluid jet that penetrates the skin. The gas-forced needle-free injection systems are typically made up of three components including an injection device, a disposable needle free syringe and a gas cartridge. 

The injector must be mounted on a micromanipulator. Although many experienced workers use the Singer type, which allows free movement in three planes, a micrometer-driven system such as the Brinkmann MM33 (Laser Laboratory Systems) drives the injection needle into, and out of, the oocyte in a straight line at a preset angle, rather than relying on the manual dexterity of the operator. 

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