Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Patent
1995-06-30
1997-11-25
Reamer, James H.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
514 54, 514558, A61K 900
Patent
active
056909438
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE93/00915 filed Nov. 2, 1993.
FIELD OF INVENTION
The present invention is directed to the improvement of the physical stability of long-term stored products for parenteral use and especially those products comprising a fatty emulsion packaged in at least partially oxygen permeable containers.
BACKGROUND OF THE INVENTION
It is a considerable problem for manufacturers of products for parenteral administration that the products may deteriorate during the storage period from the packaging to their use in medical applications. This is an especially severe problem when storing chemically and physically complex liquid mixtures with several phases and constituents which to a certain extent are incompatible with each other. Examples of such sensitive products are fat emulsions for parenteral nutrition, which often will comprise further constituents, such as polysaccharides, amino acids, electrolytes and trace elements, with a negative influence both on the chemical and physical stability of the product.
In present technology it is frequently required to remove oxygen from the storage environment to improve the stability for oxygen sensitive products to which category fat emulsions also belong, due to their content of long chain polyunsaturated fatty acids. There are numerous disclosures of how nitrogen and certain rare gases have been employed in inventions having an oxygen depleted atmosphere for the storage of sensitive products. In the American patent U.S. Pat. No. 5,071,667, a method of packaging perishable foodstuffs in containers is disclosed, wherein a jet of preserving gas is directed to the unfilled portions of the containers to expel air before sealing. FR 2406567 discloses a packaging process related to the one described in the American patent, wherein a rare gas is used to conserve the contents of the packages.
It is state of the art when packaging fat emulsions, to fill them in packages made from a partially gas-permeable plastic material such as EVA and thereafter introducing them in an envelope, which is made of an airtight material and removing air with vacuum applying means before supplying nitrogen gas to restore the atmospherical pressure and finally sealing the envelope.
The use of nitrogen gas suffers from a disadvantage in that it is highly soluble in both in the aqueous phase and in the oil phase of a fat emulsion which leads to bubble forming when the packages are warmed up from a storage temperature of about 2.degree.-8.degree. C. to room temperature prior to the use. This is a problem during the administration, especially with infusion pumps, because many pumps alarm when bubbles are detected and the infusion is stopped.
Even if the use of the mentioned substantially oxygen-free atmospheres, optionally together with complementary oxygen scavengers, many times will lead to stored products which comply with the requirements of reducing or avoiding for example chemical oxygen dependent degradation of fats, it is still a considerable problem with a poor physical stability, especially products for total parenteral nutrition containing a fat emulsion.
Some of the most common physical stability problems in stored fat emulsions are creaming, flocculation and coalescence.
Creaming or cream formation is often formed during storage fat emulsion and appears as a cream-like layer on top of the emulsion. The phenomenon is to a certain extent reversible when shaking the container with stored emulsion. Flocculation appears when drops in an emulsion is added to each other and coalescence appears when the drops float together and exchange phospholipids, leading to a break-up of the emulsion. Flocculation and coalescence are irreversible phenomena.
Creaming is a technical problem for manufacturers of preparations for parenteral nutrition containing fatty emulsions and many attempts have been made overcome it, for example by adding stabilizing components, see EP 0 220 152 ( page 2, lines 26 to 34). The creaming phenomenon appears due to reversed sedimentation of the fat
REFERENCES:
patent: 4164109 (1979-08-01), Dubois
patent: 4709819 (1987-12-01), Lattuada et al.
patent: 5071667 (1991-12-01), Grune et al.
Bullock et al., Emulsion Stability in Total Nutrient Admixtures Containing a Pediatric Amino Acid Formulation, Jour. Parent. Enteral. Nutr., vol. 16, No. 1 (1992), pp. 64-68.
Rattenbury et al., Identification of the Cause of Separation (Creaming) of Lipid Emulsions in Intravenous Infusion, Jour. Ped. Gastroent. Nutr., vol. 8, No. 4 (1989), pp. 491-495.
Parry et al., Effect of various nutrient ratios on the emulsion stability of total nutrient admixtures, Am. Jour. Hosp. Pharm., vol. 43, No. 12 (1986), pp. 3017-3022.
Whateley et al., Particle Size Stability of Intralipid and Mixed Total Parenteral Nutrition Mixtures, Jour. Clin. Hosp. Pharm., vol. 9, No. 2 (1984), pp. 113-126.
Mayfield et al., Creaming and Plasma Clearance Rate of Intravenous Fat Emulsion in Critically Ill Patients, Clin. Nutr., vol. 3, No. 2 (1984), pp. 93-97.
Boucheteil Micheline
Bourboulou Yves
Philippon Celine
Tronchet Jean
Pharmacia & Upjohn Aktiebolag
Reamer James H.
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