Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-11-04
2003-12-30
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S484000, C424S489000, C424S500000, C424S501000, C424S502000, C435S091530, C514S002600, C426S103000
Reexamination Certificate
active
06669963
ABSTRACT:
All living organisms require water. Indeed, to a large extent, most creatures are water. One of the few unifying themes in biology is that water accounts for about 75% of an organism's weight. Yet, remarkably, there are a number of creatures which can survive in a dry state after losing almost all of their water. This ability, called anhydrobiosis (“life without water”), is found across all biological kingdoms, including bacteria, fungi, animals and plants, and probably evolved at least two billion years ago. Such anhydrobiotic organisms are able to dry out completely and apparently die, yet they are not dead; they survive, inert and lifeless for indefinite periods in a state of suspended animation, until brought back to life by the presence of water. All these living things have solved the problem of how to preserve biological molecules without refrigeration or freezing.
A clearly defined characteristic which is common to anhydrobiotic organisms, and which is probably crucial to their desiccation tolerance, is their ability to make large amounts of a simple sugar. The most effective is trehalose (&agr;-D-glucopyranosyl &agr;-D-glucopyranoside) but the anhydrobiotic plant Craterostigina plantagineum for example accumulates sucrose rather than trehalose. It is clear that intracellular and extracellular sugars are necessary for the viability of dried cells or organisms. That trehalose alone can be sufficient for anhydrobiosis is confirmed by work in which the disaccharide has been artificially introduced into living cells, allowing them to be dried and rehydrated successfully.
Trehalose derives its stabilising ability from a combination of several properties. Like many other sugars, it can replace structural water by hydrogen-bonding with molecular surfaces. Trehalose is inert and cannot react with other molecules in the dry state. Certain other analogues are also stable and inert but most sugars react with amino groups (the so called Maillard reaction) at temperatures above freezing and destroy the product. When molecules are dried from a sugar solution using the correct procedure, a glass is formed in which molecules become embedded, minimising molecular diffusion and any associated degradation.
Many sugar solutions can behave in two very different ways upon drying. The commonest behaviour is that the sugar crystallises. Molecules in solution with the sugar are not protected when this occurs, since they are excluded from the crystals. The alternative behaviour is that the solution progressively becomes more concentrated until it is so viscous that it forms a solid glass at room temperature. When this happens, the biomolecular product has undergone a smooth change from being in liquid solution at the beginning to being in solid solution in the glass at the end. In this state the molecules of product can be visualised as embedded and tightly immobilised in the glass matrix. This is analogous to the ancient insects which are found embedded in fossil amber in a perfect state of preservation.
Since sugar glass is water soluble, the process is easily reversed in water so that the product smoothly goes back into its native state in liquid solution. These smooth, transitions ensure that there is no product damage during drying. As far as the product is concerned, the transition from liquid solution to solid solution is imperceptible. Because glasses of the best sugars are inert and have a high melting point when dry, the product is also protected on storage, even under hostile conditions.
Parenterally administered drugs are conventionally injected through a hollow metal needle as a solution in water containing buffer salts. Injections may be intradermal, subcutaneous, intramuscular or intravenous. More rarely another route such as intrathecal or intraocular may be appropriate. Drugs have been administered in this traditional way for over 100 years and in spite of the fear, pain and risk of infection associated with injections there has not been any major generally accepted improvement in the process in that time.
The liquid jet injector, which works by firing a very thin stream of liquid directly through the skin under very high pressure, achieved some success in vaccination programs but early models were unreliable. More recent developments such as the Mediject and Bioject devices have found significant niche applications in diabetes their uses and are being extended into other areas. However, a major disadvantage of the present technology is shared both by syringe and needle and by jet injector technology. Many parenteral drugs are unstable in aqueous solution and are manufactured and stored as a more stable freeze-dried cake or as a powder which requires reconstitution with water or buffer just before injection. This extra step demands training in the technique and adds risks in the form of inaccurate dispensing of solvent and therefore of dosage, or the introduction of infection by non-sterile technique. Drugs which are stored as a solution or a suspension (such as insulin) require refrigeration to prevent degradation and have a limited shelf life.
Reconstitution of dry drugs must be done correctly and precisely to ensure correct dosage and any errors in this step can be dangerous and, with highly potent drugs, can even be fatal. Often it is necessary to give more than one drug at a time. This may require multiple painful injections because certain drugs cannot be mixed in the one syringe as there are chemical incompatibilities between the molecules in solution which lead to loss of potency or even the generation of toxic reaction products.
The optimal solution to these problems which has long been a goal of drug formulation scientists is a stable liquid formulation that requires no reconstitution with solvent before injection. Although some minor improvements in aqueous solution stability have been achieved they do not provide the very high levels of drug stability which can be obtained with modern dry formulations using trehalose or similar stabilising excipients. However these latter preparations although extremely stable, even under very hostile environmental conditions, still require reconstitution before injection. They are also only stable so long as they are very dry. The uptake of moisture even in small amounts can render these dry preparations unstable on storage. They are usually stored as two-phase systems in which the drug is in the discontinuous solid chase and the continuous fluid phase is dry air, often under reduced pressure, or dry nitrogen, in a sealed glass vial.
Of the two main problems with existing vaccines for jet injection, instability on storage and the need to reconstitute dried vaccines, the former is solved by a drying process now patented by Quadrant Holdings Cambridge Ltd. using the simple sugar trehalose. Trehalose-dried vaccines can be stored at ambient temperatures of at least 45° C. without detectable deterioration. Most remarkably, even the aluminium hydroxide adjuvant gels are stabilised by trehalose during drying and storage and regain their full hydrated volume and function without clumping or precipitation.
Although the instability problem is addressed by this drying process, the previously described trehalose-dried vaccines were in the form of a solid glass foam and required reconstitution (for example with sterile water or buffer solution) before injection by conventional needle and syringe technology. Dry vaccines can be formulated in powder form and can be delivered through the skin using hypersonic shock waves of gas. Because of limitations of gas velocity and consequent penetrating power, there is some doubt as to whether deep intramuscular injections can be achieved by these means. A more useful formulation would be a ready to use stable liquid which did not require the transport of separate buffer solutions or reconstitution in the field yet which still had the extraordinary stability of trehalose-dried material. Such a vaccine could be formulated in multi-dose containers and delivered conveniently in mass immunisation campaign
Elan Drug Delivery Limited
Low Christopher S. F.
Lukton David
Morrison & Foerster / LLP
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