Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-08-01
2003-09-23
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S484000, C424S422000, C424S423000, C514S772100
Reexamination Certificate
active
06623765
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compositions and a method for making microemulsion delivery systems for water insoluble or sparingly soluble drugs.
BACKGROUND OF THE INVENTION
Dissolving water insoluble agents into aqueous solutions appropriate for human use (e.g., oral, topical application, intravenous injection, intramuscular injection, subcutaneous injection) represents a major technological hurdle for pharmaceutical delivery systems. Previous attempts have resulted in a number of serious side effects caused not by the drugs, but by the carrier agents used to dissolve the drug. These complications include significant hypotension during intravenous injection (e.g., amiodarone), painful injection with subsequent phlebitis (e.g., valium), anaphylaxis (e.g., propofol in Cremaphor), postoperative infections (e.g., propofol in Intralipid), and others. Clearly, an approach aimed at improving the solubilization of these drugs and avoiding the complications of solubilizing agents would enhance the quality of health care to patients. For many drugs, a major technological barrier for their routine clinical use is very poor solubility in the aqueous phase. For such drugs, oil/water macroemulsions have been commonly used in the pharmaceutical industry to “dissolve” a drug to its desired concentration. For example, the anesthetic propofol is supplied to the health care industry as Baxter PPI propofol (Gensia Sicor, Inc.) or Diprivan (AstraZeneca Pharmaceuticals, Inc.), as a macroemulsion of propofol in soybean oil (100 mg/mL), glycerol (22.5 mg/mL), egg lecithin (12 mg/mL), and disodium edetate (0.005%) or metabisulfite; with sodium hydroxide to adjust pH to 7.0-8.5. However, the stability of such macroemulsions is relatively poor, and the oil and water components separate into distinct phases over time. In addition, the droplet size of the macroemulsion increases with time. Macroemulsions are defined as formed by high shear mixing and normally having particles of 1 micron to 10 microns in size.
In contrast to macroemulsion systems, microemulsion systems consisting of oil, water, and appropriate emulsifiers can form spontaneously and are therefore thermodynamically stable. For this reason, microemulsion systems theoretically have an infinite shelf life under normal conditions in contrast to the limited life of macroemulsions (e.g., two years for Baxter PPI propofol). In addition, the size of the droplets in such microemulsions remains constant and ranges from 100-1000 angstroms (10-100 nm), and has very low oil/water interfacial tension. Because the droplet size is less than 25% of the wavelength of visible light, microemulsions are transparent. Three distinct microemulsion solubilization systems that can be used for drugs are as follows:
1. oil in water microemulsions wherein oil droplets are dispersed in the continuous aqueous phase;
2. water in oil microemulsions wherein water droplets are dispersed in the continuous oil phase;
3. bi-continuous microemulsions wherein microdomains of oil and water are interdispersed within the system. In all three types of microemulsions, the interface is stabilized by an appropriate combination of surfactants and/or co-surfactants.
It can be seen from the above description that there is a real and continuing need for the development of new and effective drug delivery systems for water insoluble or sparingly soluble drugs. One such approach might be pharmaceutical microemulsions. However, one must choose materials that are biocompatible, non-toxic, clinically acceptable, and use emulsifiers in an appropriate concentration range, and form stable microemulsions. This invention has as its objective the formation of safe and effective pharmaceutical microemulsion delivery systems.
The delivery system described herein has been found particularly useful for propofol, but is not exclusively limited thereto. It is presented here as an example of a state of the art drug, normally poorly soluble in its present delivery form, but when properly delivered in a pharmaceutical microemulsion carrier, the current problems can be solved. Such current problems in the case of propofol stem directly from its poor solubility in water. These include significant pain during injection, and post-operative infections in some patients who, for example, receive a macroemulsion of propofol for surgery or sedation.
In an attempt to lower health care costs, there has been an explosive growth in the number of surgical procedures being done on an outpatient basis in the United States. In the outpatient setting, the use of short acting anesthetics allows for prompt emergence from anesthesia and provides expeditious discharge of patients to their home. Propofol (2,6-diisopropylphenol, molecular weight 178.27) is an organic liquid similar to oil, has very little solubility in the aqueous phase (octanol/water partition coefficient 6761:1 at a pH 6.0-8.5), and is a short-acting intravenous anesthetic that meets the criteria of rapid anesthetic emergence with minimal side effects. Currently, propofol is supplied as a macroemulsion, an opaque dispersion using biocompatible emulsifiers such as phospholipids, cholesterol, and others. In addition, a number of other drawbacks cause significant limitations and risk to some patients.
Most of the disadvantages of propofol relate to its commercial formulation and physical properties. That is, propofol is a liquid at room temperature and is extremely insoluble in water. The inherent lipophilicity of propofol makes dissolution in saline or phosphate buffer problematic. In the early 1980's, Cremaphor was used as a solvent, but subsequently abandoned because of its propensity to cause life threatening anaphylactic reactions. Since that time, propofol is suspended in a macroemulsion consisting of 10% Intralipid, a milky white solution of soybean oil and other additives as specified previously. The current commercial formulation of propofol has several major disadvantages. First, use of propofol in Intralipid has been implicated as the causative agent contributing to several cases of postoperative infection in human patients as detailed by the Center for Disease Control and Prevention. The cause of the infections and death was attributed to extrinsically contaminated Diprivan (i.e., propofol in Intralipid) used as an anesthetic during the surgical procedures. To address the propensity of bacterial growth, manufacturers added the preservatives EDTA (0.05 mg/ml) to Diprivan and sodium metabisulfite (0.25 mg/ml) to Baxter PPI propofol. Unfortunately, both of these preservatives may potentially cause adverse reactions in humans. Whereas sodium metabisulfite may cause allergic-type reactions in susceptible patients, the chelating properties of EDTA were of concern to the FDA because of their effects on cardiac conduction and renal function. Thus, use of a solvent that does not support bacterial growth would significantly enhance the therapeutic safety of propofol not only by preventing intravenous injection of microbes, but also by obviating the need for preservatives and possible adverse effects of these agents.
Second, the cost of Intralipid substantially adds to the expense of manufacturing a propofol macroemulsion. This vehicle is produced by Clinitec, licensed to the pharmaceutical corporations for the purpose of solubilizing propofol, and constitutes a major fraction of the cost of producing Diprivan (propofol in 10% Intralipid).
A third major disadvantage of the current preparation of propofol relates to its free, aqueous concentrations. Propofol is a phenol derivative (2,6-diisopropylphenol) and causes pain on injection. This effect is the single greatest complaint of anesthesiologists and patients regarding propofol and may on occasion necessitate discontinuation of the drug for sedative purposes. Most authorities believe that the stinging relates to the concentration of propofol in free, aqueous solution.
A solvent that completely emulsifies or partitions propofol into the non-aqueous phase would preclude (or markedly reduce) st
Dennis Donn M.
Gravenstein Nikolaus
Modell Jerome H.
Morey Timothy E.
Shah Dinesh
Brinks Hofer Gilson & Lione
Di Nola-Baron Liliana
Page Thurman K.
University of Florida Research Foundation Incorporated
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