Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1999-12-07
2003-03-04
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S489000, C521S065000
Reexamination Certificate
active
06528067
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to stabilized liquid and solid compositions useful as total nutrient admixtures (TNA), as well as methods for the preparation thereof. Invention compositions are easily reconstituted with water to form multi-component or three-in-one TNA compositions (i.e., containing fat emulsions, dextrose, and amino acids with electrolytes) suitable for parenteral administration of nutrition.
BACKGROUND OF THE INVENTION
Dextrose and amino acids have been the major components of glucose-based parenteral nutrition systems, with an optimal infusion rate of approximately 400 grams of dextrose per day for a 70-kg person. The addition of intravenous fat emulsions has improved patient care by preventing the development of essential fatty acid deficiencies, and by providing a calorically dense product to supplement nonprotein calories. Traditionally, intravenous fat emulsions have been infused separately from the parenteral nutrition solution (see Warshawsky in Nutrition in Clinical Practice 7:187-196 (1992)).
Lipid for intravenous infusion was originally introduced as a 10% isotonic emulsion (Intralipid) which allowed total parenteral nutrition (TPN) to be administered via a peripheral vein, thereby reducing the complications associated with central venous administration. The lipid emulsion also provided a safe and effective method for administering essential fatty acids to patients receiving glucose from TPN.
More recently, the total nutrient admixture (TNA) system was developed, in which a commercial emulsion (such as Intralipid), amino acid solution, glucose, electrolytes, and trace minerals are mixed in one flexible-container for safer and more convenient administration. The mixture is prepared in the hospital pharmacy prior to use, and is desirably administered within 24 hours of preparation (see Warshawski in Nutrition in clinical practice 7:187-196 (1992)). The order of mixing the various components is crucial, due to the inherent instability of the fat emulsion in the presence of electrolytes and amino acids. Most conservative guidelines for prolonged TNA storage are 7 days at 4° C., or up to 24 hours at room temperature. When TNAs are prepared, the dextrose, amino acids and additives should be admixed first, and the fat emulsion should be added last, while the sterility of the system is maintained. Typical TNA formulations are composed of dextrose, triglycerides, amino acids, vitamins, trace elements and electrolytes (such as, for example, sodium and potassium chlorides; calcium, magnesium, sodium and potassium phosphates, and the like).
Commercially available TNA systems include the “All-In-One TPN Mixing System” from KabiVitrum, and the “3-in-1 Admixture System” from Travenol Laboratories. In each of these commercially available products, all components, including the emulsion, should be mixed shortly prior to use. Although these TNA systems represent significant improvements over older methods, some controversy still remains regarding the stability and clinical application of these admixture systems (see Brown, et al., in Journal of Parenteral and Enteral Nutrition 10:650-658 (1986)). Indeed these TNAs have to be used within a very short time after mixing all components.
Currently available total nutrient admixtures, i.e., mixtures which are prepared prior to their administration, have significantly reduced overall hospital costs associated with both preparation and administration, because the preparation and administration of conventional parenteral nutrients is time consuming. For example, the time spent on the preparation of conventional total parenteral nutrition (TPN, i.e., a mode of treatment wherein the fat emulsion is administered separately) ranges from about 13 minutes for each adult formula to about 49 minutes for each pediatric formula.
As health care costs have continued to escalate, practitioners have begun to search for ways to reduce costs, while maintaining quality patient care. For example, in pediatric patients, the cost of preparation and administration of the TNA system is less than half that of the TPN system. The potential savings is even greater with adult patients, who typically require two to three times greater daily volume of parenteral nutrition, as compared with pediatric patients (see, for example, Warshawsky in Nutrition in Clinical Practice 7:187-196 (1992)).
Fat emulsions, which are one component of TNA compositions, are classified as the “oil-in-water” type (as opposed to “water-in-oil” type). An emulsion is a twophase system in which one immiscible liquid (the internal dispersed phase) is dispersed in the form of small droplets throughout another immiscible liquid (the external continuous phase) by means of emulsifying agents or surfactants (e.g., phospholipids). Several commercially available fat emulsions utilize egg phospholipids as surfactants. The emulsifying agents may form a physical barrier, mainly due to electrostatic repulsion at the interface between the tiny droplets of the oil phase, to prevent the dispersed droplets from coalescing and eventually reverting to two continuous undispersed phases. The barrier produced by the emulsifying agent can take the form of a mechanical interfacial film or an electrostatic repulsion or both.
The emulsifying agent which is commonly used to in stabilize fat emulsions for parenteral nutrition is lecithin (which is obtained from natural sources, e.g., egg yolk). Lecithin comprises a mixture of phospholipids, of which phosphatidylcholine is the most abundant. Since pure phospholipid emulsifiers provide only poor stability, certain ionic lipids (such as phosphatidic acid and phosphatidyl serine) are required in order to increase the electrostatic-repulsive properties and enhance the mechanical barrier by forming liquid crystalline gel structures at the oil-water interface (Brown, et al., Journal of Parenteral and Enteral Nutrition 10:650-658 (1986)).
The pH of an emulsion is an important consideration in determining the stability of phospholipid based emulsions. Fat emulsions are generally most stable at their manufactured pH (about 8.0), and any additives which severely alter pH (such as dextrose, a component of TNA compositions) may adversely affect emulsion stability. Dextrose solutions are acidic and can significantly decrease the pH of lipid emulsions, with resultant loss of stability. As the pH decreases (to about 2.5), the emulsifying agent becomes electrically neutral and its desirable repulsive forces are lost.
In addition, one of the mechanisms for destabilization of phospholipid-based emulsions is the hydrolysis of phospholipid, which releases fatty acids and phosphatidic acid into the aqueous phase of the emulsion. This likely causes a decrease in pH, thus causing a decrease in Zeta potential of emulsion droplets, and hence coalescence and phase separation (see Magdassi et al., in
J. Disp. Sci. Techi
. 12:69-82 (1991)).
The addition of electrolytes, e.g., multivalent cations such as calcium ions, can profoundly reduce the surface potential, thereby leading to decreased repulsion between emulsion droplets and ultimately coalescence of the emulsion. Since typical TNA compositions contain several electrolytes, their presence also leads to instability of the emulsion.
Thus, TNA compositions (i.e., compositions containing fat emulsions, dextrose, amino acids and electrolytes) are inherently of limited stability due to the nature of phospholipid-based emulsions. Thus, there clearly exists a need in the art for stable TNA compositions and methods for the preparation thereof.
BRIEF DESCRIPTION OF THE INVENTION
Thus it is an object of this invention to provide a stabilized total nutrient admixture composition for parenteral administration which is stable for long periods of transportation or storage in the form of a dry lyophilized powder.
It is a further object of the present invention to provide stabilized oil-in-water emulsions for parenteral administration. Invention compositions are stabilized by protein(s) (such as human serum albumin), and can
Desai Neil P.
Magdassi Shlomo
Soon-Shiong Patrick
Tao Chunlin
Yang Andrew
American Bioscience, Inc.
Dees Jose′ G.
DeWitty R.
Foley & Lardner
Reiter Stephen E.
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