Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-03-17
2001-02-20
Azpuru, Carlos (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S501000, C424S502000, C428S402210
Reexamination Certificate
active
06190701
ABSTRACT:
BACKGROUND OF THE INVENTION
Vaccines or drugs in solution ready for injection are inherently unstable and need refrigeration. The pharmaceutical industry has traditionally tackled the instability problem by freeze-drying drugs. This is expensive, inconvenient and inherently dangerous, since incorrect reconstitution of dried drugs can result in wrong doses or contaminated solutions. Many attempts have been made over the past 100 years to develop robust, stable, ready-to-inject liquid formulations with pitiful lack of success. Only inherently tough small molecule drugs can survive in aqueous solution with a useful shelf life.
This problem is particularly acute in the vaccine industry. By the year 2005 it is estimated that 3.6 billion doses of vaccine will have to be administered world-wide. It has been stated by the World Health Organization (WHO) that this will not be possible using standard vaccine formats which need to be refrigerated at all times (“Revolutionizing Immunizations.” Jodar L., Aguado T., Lloyd J. and Lambert P-H. Genetic Engineering News Feb. 15, 1998). A “cold chain” of refrigerators is currently in use, which stretches from the vaccine factories to provincial towns in the developing world. The cost of the cold chain for the vaccine industry and for non-governmental health organizations running immunization campaigns is enormous. The WHO has estimated that just the maintenance cost of the cold chain is over $US 200 million annually. In addition, immunization campaigns may reach only those living close to the last link of the cold chain.
Vaccination campaigns require medically trained staff to ensure that the dose is correctly injected and shows no signs of degradation. The need to reconstitute some vaccines, such as measles, yellow fever and BCG, in the field is also a serious concern. This must be done precisely to ensure correct dosage and it also introduces a potential source of contamination, which has frequently led to clinical disasters. In addition, it is often necessary to give more than one vaccine at a session and this may require multiple injections, as particular mixtures or “multivalent” vaccines may not be available due to the chemical incompatibility of some of the components. The WHO has highlighted these problems by actively encouraging research into the next generation of stable vaccines which have no need for refrigeration and which need no reconstitution (“Pre-Filled Monodose Injection Devices: A safety standard for new vaccines, or a revolution in the delivery of immunizations?” Lloyd J. and Aguado M. T. WHO publication May 1998. “General policy issues: injectable solid vaccines: a role in future immunization?” Aguado M. T., Jódar L., Lloyd J., Lambert P. H. WHO publication No A59781.)
An ideal solution to this problem would be completely stable, ready-to-inject formulations. Such stable vaccines could be packed as individual doses in an injecting device itself, or, for mass immunization campaigns, shipped in larger volumes and administered by means of a needle-free jet injector. The transdermal delivery of dry solids by gas jet injection has been described (Sarphie D F, Burkoth T L. Method for providing dense particle compositions for use in transdermal particle delivery. PCT Pub No. WO 9748485 (1996)) and transdermal vaccination with dry DNA vaccines is apparently very effective (“Powderject's Hepatitis B DNA Vaccine First To Successfully Elicit Protective Immune Response In Humans” at http://www.powderject.com/pressreleases.htm (1998)).
The hypersonic shockwave of helium gas that is used to drive these powder injectors has a limited power and cannot deliver its dose of fine particles intra-muscularly. This is because the low-mass particles cannot achieve adequate momentum for deep penetration. While the intradermal delivery of DNA vaccines coated on to colloidal gold particles is adequate for good immunogenicity, the common vaccines, adjuvanted with insoluble aluminum or calcium salts, induce unacceptable skin irritation. They must be given intramuscularly. What is required is a flexible system capable of a range of delivery depths, from intradermal to deep intramuscular, similar to that achievable by existing needle and syringe technology. For mass vaccination campaigns this has been solved by the development of the liquid jet injector capable of accelerating a narrow (~0.15 mm diameter) stream of liquid, using pressures of around 3,000 psi, into a “liquid nail”. This device delivers its dose painlessly through the skin into the deep subcutaneous or muscle tissue by punching a minute hole through the epidermis. The high momentum imparted to the liquid stream ensures deep penetration. To date, the injected drugs and vaccines have been water-based but because of the instability problems discussed above, the range of stable aqueous products accessible to this technology is very limited.
It is now recognized that a wide range of bioactive molecules may be stabilized by drying in sugar glasses (Roser B. “Protection of proteins and the like” UK patent No 2,187,191. Roser B and Colaco C. “Stabilization of biological macro-molecular substances and other organic compounds” PCT Pub No WO 91/18091. Roser B. and Sen S. “New stabilizing glasses”. PCT patent Application no: 9805699.7. 1998). These dry, stabilized actives are unaffected by hostile environments such as high temperatures and ionizing radiation.
The mechanism underlying the remarkable stabilization of molecules by sugars is glass-transformation. As the sugar solution containing an active molecule is dried, it can either crystallize when the solubility limit of the sugar is reached, or can become a supersaturated syrup. The ability of the sugar to resist crystallization is a crucial property of a good stabilizer. Trehalose is good at this (Green J L. & Angel C A. Phase relations and vitrification in saccharide water solutions and the trehalose anomaly J. Phys. Chem. 93 2880-2882 (1989)) but not unique. Further drying progressively solidifies the syrup, which turns into a glass at a low residual water content. Imperceptibly, the active molecules change from liquid solution in the water to solid solution in the dry sugar glass. Chemical diffusion is negligible in a glass and therefore chemical reactions virtually cease. Since denaturation is a chemical change it cannot occur in the glass and the molecules are stabilized. In this form the molecules can remain unchanged providing one other condition is met. This is the second crucial property of a good stabilizer viz. that it is chemically inert and non-reactive. Many glasses fail because they react with the product on storage. Obvious problems occur with reducing sugars, which may form good physical glasses but then their aldehyde groups attack amino groups on the products in a typical Maillard reaction. This is the main reason that many freeze-dried pharmaceuticals require refrigerated storage. Non-reactive sugars give stable products, which require no refrigeration at all.
Biomolecules immobilized in sugar glass are also stable in non-aqueous industrial solvents in which they themselves and the sugar are both insoluble (Cleland J L. and Jones A J S. “Excipient stabilization of polypeptides treated with organic solvents” U.S. Pat. No. 5,589,167. (1994)). Since the sugar glass acts as an impermeable barrier in a non-solvent liquid, the biomolecules in solid solution in the glass are protected both from the chemical reactivity of the solvent and from the environment. Providing the liquid itself is stable, sensitive products in suspended glass particles constitute a stable two phase liquid formulation. Industrial solvents of the kind described by Cleland and Jones (1994) have a limited utility in processing. Substituting a bio-compatible non-aqueous liquid would enable stable liquid formulations of even the most unstable drugs, vaccines and diagnostics to be formulated.
The first generation of stable non-aqueous liquids designed to be used in drug or vaccine delivery (B. J. Roser and S. D. Sen “Stable particle in liquid formu
Garcia De Castro Arcadio
Maki James
Roser Bruce Joseph
Azpuru Carlos
Jacobson Price Holman & Stern PLLC
Peter M. Ronai
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