USOO6129925A United States Patent (19) 11 Patent Number: 6,129,925 Kido et al. (45) Date of Patent: *Oct. 10, 2000 54 CONTAINER FILLED WITH INFUSION 5,770,233 6/1998 Kido et al. .............................. 424/641 LIQUIDS AND INFUSION PREPARATION FOREIGN PATENT DOCUMENTS 75 Inventors: Takae Kido; Shigeo Ii; Shun-ichi Abe; 0510687 10/1992 European Pat. Off.. Kazumasa Yokoyama, all of Osaka, 58-162515 9/1982 Japan. Japan 58-162517 9/1983 Japan. 61-058560 3/1986 Japan. 73 Assignee: Yoshitomi Pharmaceutical Industries, 62-135421 6/1987 Japan. Ltd., Osaka, Japan OTHER PUBLICATIONS * Notice: This patent issued on a continued pros Derwent Abstract N89-244721, abstracting JP 1-240469, ecution application filed under 37 CFR 1989. 1.53(d), and is subject to the twenty year Chemical Abstracts 99:146124J, 1983. patent term provisions of 35 U.S.C. Chemical Abstracts 69:89709h (1968). 154(a)(2). Primary Examiner S. Mark Clardy Assistant Examiner Kathryne E. Shelborne 21 Appl. No.: 09/032,843 Attorney, Agent, or Firm Sughrue, Mion, Zinn, Macpeak 22 Filed: Mar. 2, 1998 & Seas, PLLC 57 ABSTRACT Related U.S. Application Data An object of the present invention is to provide an infusion 60 Division of application No. 08/437,330, Apr. 21, 1995, Pat. preparation set (a container filled with infusion liquids) No. 5,770,233, which is a continuation-in-part of application useful for preparation of an infusion liquid containing No. PCT/JP93/01521, Oct. 21, 1993. Sugars, amino acids, electrolytes, a fat emulsion and Vita 30 Foreign Application Priority Data mins. The present invention is constituted by the use of a container having two compartments which are separated Oct. 22, 1992 JP Japan .................................... 4-309249 from each other by a separation means, which contains an 51 Int. Cl." .............................. A61K 13/00; A61K 9/66 infusion liquid comprising a fat emulsion, Sugars, fat-Soluble 52 U.S. Cl. .......................... 424/400; 424/422; 424/423; Vitamins and Specified water-Soluble Vitamins in the first 424/455 compartment and an infusion liquid comprising amino acids, 58 Field of Search ..................................... 424/400, 422, electrolytes and other specified water-Soluble Vitamins in the 424/423, 455; 514/937, 943 Second compartment. An infusion preparation containing Sugars, amino acids, electrolytes, a fat emulsion and Vita 56) References Cited mins can be obtained easily and aseptically upon use, by Simply removing a separation means and mixing the infu U.S. PATENT DOCUMENTS Sion liquids included in the first and Second compartments. 4,000,190 12/1976 Mader et al. ........................... 424/127 Further, the components of the infusion liquids included in 5,560,403 10/1996 Balteau et al. .............................. 141/9 each compartment have good Stability. 5,626,880 5/1997 Inoue et al. ... ... 424/489 5,674,527 10/1997 Inoue et al. ............................. 424/450 21 Claims, 3 Drawing Sheets 6,129,925 1 2 CONTAINER FILLED WITH INFUSION tation. In order to prevent the formation of turbidity and LIQUIDS AND INFUSION PREPARATION precipitation, Such an electrolyte infusion liquid is usually adjusted to a low pH value (less than pH 5). When such a CROSS REFERENCE TO RELATED electrolyte infusion liquid is mixed with an amino acid APPLICATIONS infusion liquid, the pH of the mixture increases to the amino acid pH value because of the Strong buffer action of amino This is a continuation-in-part application of PCT Appli acids, thus requiring a large quantity of acidic materials (for cation No. PCT/JP93/01521, filed Oct. 21, 1993. example, hydrochloric acid, acetic acid and the like) to keep This is a divisional of application Ser. No. 08/437,330 the pH value at a low level. However, acidic materials can filed Apr. 21, 1995 now U.S. Pat. No. 5,770,223. be used only in a limited amount because a large quantity of acid Spoils the balance of the infusion components. AS a TECHNICAL FIELD consequence, the pH value of the mixture of electrolyte and This invention relates to infusion preparations which amino acid infusion liquids cannot be lowered to a Satisfac comprise a fat emulsion, Sugars, amino acids, electrolytes tory level, thus resulting in the generation of turbidity and and Vitamins, to a container filled with infusion liquids for 15 precipitation at the time of heat Sterilization of the mixture. use in making Said infusion preparations and infusion liq In addition, when a mixture of an amino acid infusion uids. More specifically, the invention relates to (1) an liquid with a Sugar infusion liquid is Sterilized by heating, infusion preparation comprising a fat emulsion, Sugars and considerable coloring occurs due to the Maillard's reaction. Specific Vitamins, (2) an infusion preparation comprising AS described above, it is difficult to prepare a storable amino acids, electrolytes and other vitamins, (3) a container infusion preparation which contains a Sugar, amino acids, filled with infusion preparations in which the above infusion electrolytes and a fat emulsion, in advance, because mixing preparations (1) and (2) are contained in the respective these different types of infusion liquids or emulsions causes compartments, and (4) an infusion preparation prepared by various problems Such as precipitation, denaturation, color mixing infusion liquids contained in the respective compart ing and the like. Because of these problems, a fat emulsion, mentS. 25 a Sugar infusion liquid, an amino acid infusion liquid and an electrolyte infusion liquid are ordinarily mixed upon use. AS BACKGROUND ART a consequence, an infusion preparation has been desired Intravenous infusion is carried out for the purpose of which contains Sugars, amino acids, electrolytes and a fat Supplying nutrients to maintain a patient's life when oral or emulsion and can be stably Stored. nasal feeding is impossible or insufficient, when the diges Under these circumstances, the present inventors have tion and absorption functions of the patient are in a poor conducted intensive Studies on the development of a prepa State, even if Such a feeding means can be carried out, or ration method of a Stable infusion preparation which con when the passage of food through the digestive tract makes tains Sugars, amino acids, electrolytes and a fat emulsion. the patient's condition or disease more Serious. Examples of They have found that preparations containing the above commercially available infusion preparations include a 35 components in a certain combination can be stably Stored Sugar intravenous infusion which contains reducing Sugars and an infusion preparation containing Sugars, amino acids, and the like, amino acids and the like, an electrolyte infusion electrolytes and a fat emulsion can be easily obtained, upon liquid which contains electrolytes and the like, a fat emul use, without Suffering from precipitation, denaturation, col Sion which contains a plant oil and the like, and a vitamin oring and other problems. More specifically, it has been mixture. These infusion preparations are appropriately 40 found that the above problems can be Solved by putting an Selected depending on the condition of the patient and are infusion liquid containing a fat emulsion and Sugars into the mixed upon use. However, mixing these preparations at the first compartment of a container having two compartments time of their use requires complex handling and, above all which are separated by a separation means, putting an things, raises the problem of microbial contamination. With infusion liquid containing amino acids and electrolytes into the aim of overcoming Such problems, various infusion 45 its Second compartment, Sterilizing Said container, preserv preparations, in which Some of the aforementioned infusion ing it in this State, and mixing the infusion liquids contained liquids are mixed in advance, have been proposed. Infusion in the first compartment and the Second compartment by preparations which contain Sugars, amino acids, electrolytes removing the separation means upon use (cf. JP-A-5- and a fat emulsion, all being essential nutrients to be 50 31151). Supplied, are especially useful from a clinical point of view. It has become common to give various vitamins during However, Since these Sugar infusion liquids, amino acid treatment with total parenteral nutrition (TPN). In this infusion liquids, electrolyte infusion liquids and fat emul instance, vitamins are added to TPN admixture upon clinical Sion are different from one another in terms of the conditions use. In order to further improve the above-described newly for their stable existence, various problems arise when they 55 developed infusion preparation containing Sugars, amino are mixed, and the mixture becomes useleSS in many cases. acids, electrolytes and a fat emulsion, it is desirable to For example, because of its unstable nature, a fat emul develop TPN admixture in a more perfect form containing Sion is apt to form bulky fat particles and to cause phase Vitamins, in advance, thereby Saving the Step of adding Separation (creaming) when mixed with other infusion liq Vitamins upon clinical use. uids. In particular, divalent cations contained in an electro 60 However, Vitamins are usually unstable and a certain lyte infusion liquid cause aggregation and disintegration of combination of Vitamins can cause decomposition of one of fat emulsion particles. the Vitamins or can make the liquid turbid. For example, the In the case of an electrolyte infusion liquid, Since it present inventors have found that the Solution becomes contains calcium and phosphoric acid as essential compo turbid when folic acid is mixed with vitamin C, and that nents to maintain the balance of electrolytes, it is apt to form 65 Vitamin C promotes decomposition of Vitamin B. calcium phosphate by the reaction of calcium with phos Therefore, it is necessary to pay attention to the combination phoric acid and therefore to generate turbidity and precipi use of vitamins. Vitamins are roughly divided into two 6,129,925 3 4 groups: a water-Soluble group and a fat-Soluble group.