Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
2000-01-24
2002-10-08
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S400000, C424S422000, C426S312000, C426S316000, C426S324000, C426S330100, C426S474000
Reexamination Certificate
active
06461633
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a reducing sugar-containing fat emulsion for intravenous injection, such as intravenous hyperalimentation, and more particularly to a high-quality, stable fat emulsion in which the formation of free fatty acids on heat sterilization is minimized despite inclusion of a reducing sugar and which is inhibited against the discoloration due to decomposition of the reducing sugar and to a method for its sterilization.
BACKGROUND ART
Because many patients having undergone a gastro-intestinal surgery cannot be orally fed, the nutritional management for such patients is generally secured by intravenous hyperalimentation through a central vein (IVH). This IVH is very effective in upholding the nutritional status of such patients to accelerate recovery and cure and, therefore, in broad use in the field of surgical therapy.
Meanwhile, said IVH calls for strict control over the procedure and has certain demerits such as the risk of infection and that of metabolic complications such as hyperglycemia. Therefore, the recent trend is toward feeding from a peripheral vein as far as possible even in those patients for whom IVH is contraindicated but whose preoperative nutritional status is good and in whom the degree of surgical invasion is comparatively slight and in those patients in whom the expected duration of impossibility of oral feeding is not too long.
In any event, not only the supply of carbohydrates, amino acids, and electrolytes but also the supply of fat is considered indispensable to the nutritional management of patients. Particularly in the feeding through a peripheral vein, it is essential to use a fat emulsion as part of the energy source so that the caloric requirements may be fulfilled while the elevation of the osmotic pressure of the infusion is prevented as much as possible.
Meanwhile, the ideal dosage form for such hyper-alimentation, etc. is a one-package dosage form containing all the components to be administered in a single package. However, it is known that a sugar and an amino acid undergo a Meillard's reaction to cause browning and that the concurrent presence of a fat emulsion and an electrolyte, particularly a polyvalent cation, results in aggregation of emulsion particles. Therefore, such components cannot be formulated in the same package, and generally it has been attempted to provide a double-packed dosage form containing a reducing sugar and a fat emulsion in one package and amino acids and electrolytes in another package.
However, an aqueous solution of a reducing sugar such as glucose undergoes depression in pH upon sterilization and with time after sterilization and when the solution is mixed with a fat emulsion, this pH depression induces production of free fatty acids due to hydrolysis of the fat and emulsifier. Such free fatty acids are apparently responsible for the adverse reactions associated with administration of a fat emulsion, such as fever and headache, and therefore, occurrence of free fatty acids should be avoided as far as possible. Thus, the production of free fatty acids due to pH depression upon sterilization is a fatal drawback of such a mixed formulation.
To overcome the above disadvantage, research has been undertaken along several lines of approach but invariably no satisfactory results have been obtained. Thus, it has been attempted (as in Japanese Unexamined Patent Publication No. H5-65220) to prevent increase in the concentration of free fatty acids by incorporating L-histidine and/or tris(hydroxy-methyl)aminomethane as a buffer in a reducing sugar-containing fat emulsion but even this method does not provide for complete inhibition of formation of free fatty acids.
It has also been attempted to solve the above problem by adding a phosphate salt to a reducing sugar-containing fat emulsion at a final concentration of 3 mM to 20 mM (Japanese Unexamined Patent Publication No. H7-277989) but since the emulsion particles tend to aggregate particularly after heat sterilization, the method is not suitable for a stable production and supply of an emulsion of high quality.
In addition, a reducing sugar-containing fat emulsion has the disadvantage that the emulsion becomes tinted by decomposition products of the reducing sugar as formed during heat sterilization and during subsequent storage. This disadvantage can be generally obviated by maintaining the pH of the emulsion at a low level but in view of the fact that the emulsion is to be administered in a large dose, the pH of the product is preferably not removed too far from the pH of the circulating blood.
For this reason, the pH of a reducing sugar-containing fat emulsion is conventionally controlled within the range of about 5-7.5 and, separately from this pH adjustment, a coloration inhibitor, such as dithioglycerol or dithiothreitol, is generally incorporated for preventing the above-mentioned coloration associated with the reducing sugar (e.g. Japanese Unexamined Patent Publication No. H5-9112).
However, addition of any component irrelevant to hyperalimentation and so on, such as said coloration inhibitor, is not desirable but preferably avoided. Moreover, this infusion has the drawback that it has a sulfur odor due to the coloration inhibitor. Therefore, the research and development for a reducing sugar-containing fat emulsion which does not contain a coloration inhibitor and yet is free from the discoloration problem arising from decomposition of a reducing sugar and inhibited against production of free fatty acids has been awaited in earnest by the industry.
The object of the present invention is to develop and provide an improved stable reducing sugar-containing fat emulsion and a production technology for the manufacture thereof, long awaited by the industry, the emulsion simulating the physiological pH, being free from or markedly inhibited against the discoloration due to decomposition of the reducing sugar even without the aid of a coloration inhibitor, being inhibited against production of free fatty acids and not undergoing aggregation of emulsion particles which is a disadvantage of the prior art fat emulsion.
To accomplish the above object, the inventors of the present invention explored into a broad range of buffer substances in the first place and discovered that when a certain organic acid or a salt thereof is used within a certain pH range, the enhanced stability of a reducing sugar-containing fat emulsion is neatly insured.
In addition, the inventors of the present invention found that when the pH of a drug system containing a reducing sugar and a fat emulsion (with pH about 5.0-7.5) is temporarily reduced by dissolving carbon dioxide gas therein prior to heat sterilization and, thereafter, the carbon dioxide gas is removed from the drug system, the decomposition of the reducing sugar during heat sterilization and storage is inhibited and, at the same time, the coloration is inhibited even in the absence of a coloration inhibitor to give a satisfactory reducing sugar-containing fat emulsion.
Furthermore, the inventors of the present invention discovered that said removal of carbon dioxide gas from the drug system after sterilization can be quickly achieved through the use of a carbon dioxide gas absorber and that when such carbon dioxide gas absorber is employed, the adverse effect of oxygen on the drug system is also precluded so that the decomposition of the reducing sugar during sterilization and storage is inhibited to prevent not only discoloration of the emulsion but also production of free fatty acids. The present invention has been developed on the basis of the above findings.
DISCLOSURE OF THE INVENTION
The present invention provides a reducing sugar-containing fat emulsion comprising an oil-in-water fat emulsion available upon emulsification of a fat with the aid of an emulsifier, with a water phase containing a reducing sugar and at least one buffer substance selected from among organic acids with acid dissociation exponents in water within the range of 5.0-7.5 and salts thereof and the pH of the emuls
Bandou Aya
Fujimoto Takashi
Hirata Yuki
Ishii Tatsuya
Kawakami Keiichi
Di Nola-Baron Liliana
Otsuka Pharmaceutical Factory Inc.
Page Thurman K.
Sughrue & Mion, PLLC
LandOfFree
Reducing sugar-containing fat emulsion and a method for its... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Reducing sugar-containing fat emulsion and a method for its..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Reducing sugar-containing fat emulsion and a method for its... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2981045