Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Peroxide or compositions of or releasing gaseous oxygen or...
Reissue Patent
1999-01-21
2004-03-09
Lovering, Richard D. (Department: 1712)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Peroxide or compositions of or releasing gaseous oxygen or...
C206S524300, C424S498000, C428S402200, C514S744000, C514S772000, C514S789000, C514S832000, C514S833000, C514S938000, C516S053000, C516S056000, C516S930000
Reissue Patent
active
RE038459
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to an injectable physiologically acceptable aqueous fluorocarbon emulsion.
BACKGROUND OF THE INVENTION
Certain fluorocarbon emulsions are known in the art, and their use in a number of medical applications has been described.
U.S. Pat. No. 3,911,138 is directed to an artificial blood comprising aqueous emulsions of perfluorocyclocarbons. The upper limit of the emulsion droplet size is given as 100 microns. The disclosure of this patent lacks any mention of sterilization procedures of the storage stability of these emulsions.
U.S. Pat. No. 3,958,014 relates to a process for making injectable emulsions of perfluorocyclocarbons. The preferred emulsion concentrations of perfluorocyclocarbon and lecithin are 25-30% (w/v) and 3/5% (w/v), respectively. Sterilization of the emulsion is performed in a rotating autoclave at 110°-120° C. While the emulsion droplet size is in the range of 0.05-0.25 microns, the emulsion are stable for only two days.
U.S. Pat. No. 3,962,439 is related to emulsions of a group of fluorocarbons. The emulsifying agents are mixtures of phospholipids and fatty acids.
U.S. Pat. No. 3,989,843 discloses preparing fluorocarbon emulsions. Lecithin is not disclosed as being acceptable for use as an emulsifying agent. The emulsions of this patent, which are sterilized while being stirred, separate after being stored for several months.
U.S. Pat. No. 4,423,077 described compositions comprising stable emulsions of fluorocarbons 30-75% (w/v) and an emulsifying phospholipid, such as lecithin, 7-9% (w/v).
U.S. Pat. No. 4,252,827 describes emulsions consisting of F-Decalin and F-Tripropylamine mixtures which are sterilized in a rotary autoclave. When stored for six months at a temperature of 4° C., the mean particle size of these emulsions was substantially unchanged.
U.S. Pat. No. 4,497,892 relates to emulsion compositions containing two perfluoro-compounds, 10-50% (w/v) total, a mixed emulsifying agent which comprises nonionic surfactants, phospholipids and fatty acids. The emulsions of this patent are sterilized in a rotary autoclave. The components are frozen and stored separately. The emulsions must be used within twenty-four hours of thawing and mixing the components.
U.S. Pat. Nos. 4,591,593 and 4,713,459 disclose processes for preparing F-N-methyldecahydroquinoline. An emulsion can be prepared by using lecithin as an emulsifying agent. Thermal sterilization is performed by using a rotary autoclave.
U.S. Pat. Nos. 4,865,836, 4,981,691, and 4,987,154, are directed to methods for making and using fluorocarbon emulsions.
JP 60-166,626 is directed to a process for making stable vascular contrast agent emulsions which contain fluorocarbons that have at least one bromine substitutent, and alpha-tocopherol (Vitamin E).
“Properties of Polyorganosiloxane Surfaces on Glass”, by M. J. Hunter et al., Industrial and Engineering Chemistry, Vol. 39, No. 11 (November 1947), discusses applying an organosilcone film upon a glass surface.
The disclosure of each of the above-identified references is hereby incorporated by reference.
SUMMARY OF THE INVENTION
The present invention relates broadly to a method for preparing an emulsion wherein the quantity of free or unemulsified fluorocarbon is minimized. Without wishing to be bound by any theory or explanation, it is believed that the quantity of free fluorocarbon within an emulsion can be substantially completely eliminated by reducing, if not preventing, any interaction between the emulsion and the interior surface of a storage container. For example, it is believed that pretreating the storage container causes formation of an interior monolayer coating which can prevent such interaction. Should a fluorocarbon emulsion be introduced or injected into a body, the presence of free fluorocarbon is undesirable because free fluorocarbon may cause formation of emboli in the bloodstream.
One aspect of the present invention relates to a sterilized emulsion which can be stored under ambient conditions in sealed infusion bottles for a year or more without significant deterioration, e.g., when stored at about 24° C. the average emulsion droplet size increases to less than about 0.60 micron. Such an emulsion would be partially valuable for emergency use at facilities which are limited or over extended, for example, in disaster relief.
In another aspect, the present invention relates to a process for preparing perfluorocarbon (PFC) emulsions in physiologically compatible saline solutions which can be stored for lengthy periods, e.g., storage for more than about 2 years at a temperature of about 4° C. or at least about 3 months at a temperature of about 24° C. The quality of the emulsion can be improved by pretreating the storage containers, bottles, vials, among others. Typically, greater than about 99.8 wt. % of the PFC emulsified droplets remain in the size range of about 0.2-0.4 micron, when stored for a period longer than about one year at room temperature in a non-oxidizing atmosphere within, for example, sealed bottles.
The emulsions comprise about 10 through about 50% volume/volume (v/v) of at least one liquid perfluorocarbon (PFC), which has a molecular weight in the range of about 460-520, about 1-8% weight/volume (w/v) of at least one emulsifying agent, and the balance comprising a physiologically acceptable saline solution.
A sterilization emulsion, which is prepared by the method described herein, can be stored at ambient temperatures in sealed infusion bottles for at least about one year. The substantially complete elimination of any free fluorocarbon from the present emulsions allows such emulsions to be used safely on demand for medical applications. As a result, the present invention is particularly valuable for medical emergencies, and in situations wherein the availability of hospital equipment is limited.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates broadly to minimizing the presence of free fluorocarbon in an emulsion. By minimizing the presence of free fluorocarbon, the invention can be employed as a process for preparing aqueous perfluorocarbon (PFC) emulsions which can be used in medical applications. By “perfluorocarbon” it is meant a substantially fluorinated fluorocarbon, e.g., this term encompasses completely fluorinated fluorocarbons and hydrogen-containing fluorocarbons. Further, such emulsions are stable over a period of at least one year when stored at room temperature (24° C.), or for at least about 2 years when stored at about 4° C. By “stable” it is meant that the droplet size of the emulsion does not increase significantly, e.g., when stored at about 4° C. the average droplet size of the emulsion remains less than about 0.60 micron. Such emulsion are typically physiologically acceptable to the human body so that these emulsions can be employed for medical purposes.
Physiologically acceptable PFC emulsions have the ability to dissolve large volumes of gases within the human body such as oxygen and carbon dioxide. This ability enables acceptable PFC emulsions to be used for blood substitutes, and in medical treatments which are more effective when supplementary oxygen can be delivered to critical body organs such as the heart, brain, liver, kidneys, among other organs. In view of the world-wide shortage of human blood for use in transfusions, and increasing concern about its freedom from undesirable species, there is a long felt need for an artificial blood which is stable under ambient conditions, and free from infectious agents.
In addition to being effective blood substitutes, the emulsions prepared by the invention are medically useful in coronary angioplasty, cancer radiotherapy and chemotherapy, heart reperfusion, emergency treatment for stroke, among other uses. These emulsions also may be incorporated into a synthetic cerebrospinal fluid composition. For example, the PFC emulsion can be employed in acute stroke therapy by incorporating the emulsion within an oxygenated fluorocarbon-based nutrient emulsion which is administered by ventr
Dettre Robert H.
Raynolds Stuart
Kumar, Esq. Nanda P.B.A.
Lovering Richard D.
McNichol, Esq. William J.
Reed Smith LLP
Thomas Jefferson University
LandOfFree
Emulsion stability does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Emulsion stability, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Emulsion stability will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3238839