Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
  • A61K9/0029—Parenteral nutrition; Parenteral nutrition compositions as drug carriers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/127—Liposomes

Definitions

• This invention relates to a method for pro- viding nutrition intravenously using a physiologically compatible, nutritionally effective liquid dispersion of ligosomes which optionally encapsulate a nutrient composition.
• a common approach to this problem is to maxi ⁇ mize the caloric content per unit volume of the intra ⁇ venous fluid, thereby permitting more calories to be introduced using less fluid.
• Increasing nutrient con ⁇ centration in this fashion can be greatly restricted by limits on the permissible osmolality of the intravenous fluid.
• Increases in the nutrient concentration of the fluid are associated with a concomitant increase in- the fluid's osmolality, until a point is reached where additional increases in concentration (and osmolality) make introducing the fluid via conventional intravenous hookups impractical.
• P-900 on the other hand, can be given periph ⁇ erally but its caloric content is only 350 cals/liter, as opposed to 1150 cals/liter for C-1800.
• the caloric needs of a hospitalized patient vary considerably, but requirements in excess of 3000 cals/day are not unusu ⁇ al, and some patients may require as many as 5-6,000 cals/day.
• P-900 by itself cannot prevent weight loss in such patients, even when supplemented with intrali- pids.
• I is yet another object of the present invention to provide a hyperalimentation method which maximizes the uptake _in vivo of .nutrient values contained in the intravenous fluid.
• an intravenous alimentation method comprising the step of introducing into the bloodstream of a mammal a hyperalimentation fluid comprising a phy ⁇ siologically compatible carrier having dispersed therein a nutritionally effective amount of nutrient- containing vesicles, each vesicle comprising a bilayer membrane.
• the vesicles in the hyperalimentation fluid are comprised of lipid material sufficient to satisfy a substantial portion of the mammal' s intravenous caloric requirements.
• the vesicles encapsulate a nutrient solution suitable as an intravenous caloric source for the mammal.
• liposomes refers to a vesicle bounded by a bilayer lipid membrane, as set out in greater detail below.
• liposomes are used as vehicles for delivering the nutrient fraction, via the bloodstream, to targeted organs within the ; body.
• the liposomes are vesicles, generally spherically shaped, formed from one or several con ⁇ centric layers (lamellae) of lipid molecules, i.e., compounds having a lipophobic hydrophilic moiety and a lipophili ⁇ hydrophobic moiety.
• the lamellae of a water-soluble liposome are formed of at least one bi o- lecular lipid layer (which lipid can be ' represented hereinafter by the formula XY, wherein X is the hydrophilic moiety and Y is the hydrophobic moiety) , the molecules of this layer being so oriented that the hydrophilic functions thereof stay in contact with the aqueous phase. Since the ' liposomes lamellae arc separated from each other by a water film, they have a wall-like structure which can be schematically repre- sented, in section, by a series of molecular composites XY—YX stacked together in the plane of the paper.
• the size of the liposome vesicles is variable and depends in part on the method used for their manu ⁇ facture. In general, they range in diameter between about 25 and 3,000 run, and the lipid film constituting the liposome wall is about 3 to 10 nm thick.
• a lipo ⁇ some in this range may have a monolamellar envelope, that is, a monolayer of the following molecular asso ⁇ ciation:
• a given liposome may comprise hundreds of layers, each with the structure of . the above-depicted monolayer.
• MLV's multilamellar vesicles
• MLV's Liposomes in which most of the constituent lipid participates in a plurality of internal lamellae are commonly termed “multilamellar vesicles” (MLV's), and can be prepared, for example, using the method of Bangham et al. , J. MOL. BIOL. 13: 238-52 (1965), the contents of which are incorporated herein by reference. MLV's generally range in size from about 0.2 to about 2 microns.
• Single-compartment liposomes characterized by a large surface-to-encapsulated-volume ratio can be prepared, for example, by sonication of multilamellar liposomes as described by Gregoriadis, "Liposomes,” in DRUG CARRIERS IN BIOLOGY AND MEDICINE, 287-341 (G. Gregoriadis ed. 1979) , the contents of which are incor- porated herein by reference.
• Such liposomes sometimes called “sonicated unilamellar vesicles” in the art, are herein designated “small unilamellar vesicles” (SUV's) , in recognition of the fact that they can be prepared by other known methods than sonication, for example, by passing MLV's through a French press or by the ethanol injection of lipid in an aqueous phase.
• SUV's small unilamellar vesicles
• a third category of liposomes includes vesicles produced by the "reverse-phase evaporation method" described by Szoka, Jr., and Papahadjopoulos,
• liposomes differ in terms of their ability to entrap aqueous material, their respective aqueous space-to-lipid ratios, and their relative affinities for specific targets _in vivo. In general,- the larger a liposome, and the fewer layers it has, the more liquid it can encompass.
• liposomes are potentially useful as biodegradable, relatively non-toxic vehicles for admi ⁇ yakring a pharmaceutically active agent to a living organism without the risk of prematurely degrading the agent as might occur, for example, in the gastroin ⁇ testinal tract. See, generally, Gregoriadis, supra. But liposomes have never been used, to ap ⁇ plicant's knowledge, for the delivery of nutrition during intravenous feeding.
• the delivery of nutrients intra- venously via a dispersion of liposomes in an appropriate carrier medium permits a reduction in the number of par ⁇ ticles in the intravenous fluid medium relative to the number of particles that would otherwise be present if a nutrient-containing solution were mixed, unencap- sulated, into the carrier, as in the prior art.
• the osmolality of a fluid is a func ⁇ tion of the number of distinct particles contained therein, the reduction in particle number which is. effected by encapsulating ' the nutrient solution "shields" the actual number of solute (nutrient) mole ⁇ cules introduced into a peripheral vein with each volume unit of intravenous fluid medium.
• the nutrient solution "shields" the actual number of solute (nutrient) mole ⁇ cules introduced into a peripheral vein with each volume unit of intravenous fluid medium.
• Actual measurements of liposome dispersions in aqueous glucose solution substantiate calculations which, based on cer ⁇ tain assumptions concerning liposome size and total liposome volume'in solution, demonstrate that liposomes dispersed -in a solution account for only a small frac ⁇ tion of the solution's osmolality.
• the present invention allows one to employ an encapsulated nutrient solution having a higher actual osmolality (thus increasing the caloric content per volume of the intra ⁇ venous fluid) while avoiding the problems associated in the prior art with using a high osmolality alimentation solution like C-1800.
• it is possible, in accordance with the present invention to overcome -9- the drawback of excessively high osmolality in hypera ⁇ limentation fluids by encapsulating the nutrient and, thereby, keeping the effective osmolality of the hyperalimentation fluid comparatively lower.
• liposomes When injected intravenously, liposomes generally show a pronounced preference for cells comprising the reticuloendothelial system (RES) , particularly in the liver and the spleen.
• RES reticuloendothelial system
• HISTOLOGY 146-53 L. Weiss & R. Greep eds. 1977
• the aforementioned preference has generally been regarded as a major disadvantage, since sequestration of drug-encapsulating liposomes within the organs of the RES restricts the therapeutic availability of the encapsulated drug to target sites in other organs.
• liposomes are used which are known to be taken up preferentially by RES cells and broken down intracellularly by lysoso- mal enzymes, thereby concentrating the encapsulated contents of the liposomes in the RES.
• RES cells are particularly capable of converting high molecular weight molecules, such as oligosaccharides, into si p- ler constituents . which can be catabolized by other cells, the targeting of the RES in accordance with one embodiment of the present invention permits the use of larger molecules as an energy source in the encap ⁇ sulated nutrient solution.
• a nutrient fraction comprising, for example, a higher saccharide like maltotetrose or maltohexose, as the high molecular weight energy-providing species can be concentrated in the RES and there broken down into glucose, which is then distributed by the RES through the bloodstream to provide needed calories to the rest of the body.
• the present invention provides for the use of larger mole ⁇ cules that are less likely to leak out of the liposomes after encapsulation.
• a lower molecular weight nutrient such as a onosaccharide or an amino acid, can also be utilized in accordance with the present invention. since they are generally usable by cells _in vivo with ⁇ out being broken down enzymatically, i.e., liposomes encapsulating a nutrient solution which contained a lower molecular weight nutrient would not have to be targeted for the RES.
• the liposomes be stable in the carrier medium; once in the blood, the liposomes would become unstable, by virtue of the osmolality differential, enzymatic action, and/or lipid exchange. For example, if a liter of a 14 weight-percent
• glucose solution (wt.%) glucose solution (about 900 raosmoles) were encapsulated by a method assuring a 50% entrapment rate, 70 grams of glucose would be contained in the liposomes. Because of its relatively high osmolality, a 14 wt.% solution is the approximate maximum glucose concentration that can be encapsulated in liposomes which are stable in liquids of like osmolality. But because there is a marked difference between the osmo ⁇ lality of the encapsulated solution and blood serum, these liposomes will become un'stable upon introduction into the bloodstream.
• liposomes encapsulating, for example, a maltotetrose solution as previously described can deliver more calories and yet remain intact (that is, will not swell under osmotic pressure and burst) when dispersed in a conventional intravenous alimentation fluid like P-900 (approximately 900 mosmoles) prior to being introduced into the bloodstream, where the osmo ⁇ lality is in the range of 300 mosmoles.
• a nutrient solution having an osmolality substantially lower than 300 mosmoles can be prepared for encap ⁇ sulation in liposomes, following the present invention.
• oligosac ⁇ harides having a molecular weight of less than ' about 5,000 may be used.
• An intravenous alimentation fluid of enhanced stability is thus obtained with the present invention.
• Derivative compounds for -example, ionized derivatives and/or phosphotized derivatives, can also be used as nutrients.
• various methods are known for preparing liposomes for use in accordance with the present ' invention.
• Several suitable encap- sulation techniques are described by Schneider in U.S. Patent No. 4,224,179, the contents of ⁇ which are incor- porated herein by reference.
• a preferred technique is the "reverse phase evaporation” (REV) method described by Szoka, Jr., and Papahadjopoulos, "Procedure for Preparation of Liposomes with Large Internal Aqueous Space and High Capture by Reverse-Phase Evaporation," PROC. NATL. ACAD.
• REV reverse phase evaporation
• liposomes in the size range between about 0.2 and about 0.8 microns are generally preferred in the present inven ⁇ tion.
• Suitable higher molecular weight constituents include oligosaccharides and polypeptides obtained from starch and proteinaceous material, respectively, by acidic or enzymatic hydrolysis.
• starch or protein can be hydrolyzed and the resulting cleavage products then isolated according to molecular weight via column chromatogr phy, as described byPazur, "Oligosaccharides,” _in THE CARBOHYDRATES (Vol. 2-A) 61-129 (W. Pigman & 0. Horton eds.
• a starch-hydrolysis product which may be used in accordance with the present invention is obtainable by removing components having a molecular weight greater than about 5,000, for example, by paper filtration and Sephadex column fractionation, from a product available commercially as "dextrin. Type III" from Sigma, Inc., (St. Louis, MO).
• the final mixture of oligosaccharides contains compounds having a molecu ⁇ lar weight of less than about 5,000 and less than one percent glucose.
• the breakdown products of other polysaccharides are also suitable.
• the caloric requirements of an intravenously- ⁇ *d subject are met, either in whole or substantial part, using the liposomes themselves as nutrients.
• a hyperalimentation fluid comprising a dispersion of liposomes which encapsulate little or no solution, i.e., which are essentially "empty" can be - - used. While such "low-entrapment" liposomes contain little or no nutrient solution per se, they do comprise phospholipids that can be metabolized to provide calories when the liposomes are phago ⁇ ytized by target cells _in vivo.
• Alimentation via intravenous delivery of a dispersion of low-entrapment liposomes provides significant advan ⁇ tages over conventional intravenous feeding techniques as described above.
• a polar lipid com ⁇ pound which characteristically is charged can be incor ⁇ porated into the vesicular membrane.
• phosphot- idylcholine and/or phosphotidic acid could be added, with or without cholesterol, to the liposome-forming mixture.
• a sufficient amount of the compound would be included such that all the liposomes in dispersion carry a surface charge, which charge tends to- keep the liposomes apart in dispersion and, thereby, counteracts any tendency for liposomes to aggregate and fuse.
• lipids in conventional intravenous fat emulsions exchange with blood plasma lipoproteins in vivo.
• the lipid material contained in a liposomal -15- dispersion delivered intravenously in accordance with the present invention can both be exchanged with blood plasma lipoproteins and taken up and used by the RES.
• the extent to which the liposomes undergo exchange with lipoproteins, rather than phagocytization by the RES, is influenced byliposome composition. For example, incorporating cholesterol into the liposomes can stabilize them against the action of blood enzymes, thereby inhibiting exchange with lipoproteins in blood plasma.
• Liposome size also influences exchange, since smaller vesicles are taken up more slowly by the RES and, hence, remain in the bloodstream longer. Accordingly, smaller liposomes in the size range bet ⁇ ween about 0.08 and about 0.2 microns, such as those produced by the modified REV method of Frokjaer et al,
• a nutrient solution as described above is encapsulated in liposo ⁇ mes, the -liposomes are dispersed in a sterile, phy ⁇ siologically compatible carrier, and the fluid is then introduced into a suitable vein via a conventional intravenous hookup.
• the smaller liposomes (generally, less than 1 micron in size) used in the present inven ⁇ tion avoid the nonspecific symptoms of liposome toxi- city commonly attributed to the blockage of capillaries liposomes which exceed 1 micron in size.
• liposomes in the hyperalimentation fluid would be expected to vary somewhat from subject to subject, dosages of approxima ⁇ tely 60-120 grams of liposomes per day fall within a reasonable clinical range. However, if a vesicle com- ponent associated with toxicity, such as stearylamine, is incorporated into the liposomes, a smaller dosage is indicated. Generally, saturated and unsaturated phospholipids can be used to form the- liposomes, so long as the resultant vesicles display an adequate retention of any encapsulated material.
• Exemplary lipid materials suitable for use in the present inven ⁇ tion include phosphotidylcholine, phosphotidi ⁇ acid, cholesterol, phosphotidylethanolamine, phosphotidyl- serine, phosphotidylglycerol, sphingomyelin, di yrisi- tylphosphotidylcholine, dipalmitoylphosphotidyl- choline, dipalmitoylphosphotidyl glycerol, distearoyl- phosphotidylcholine, hydrogenated phosphotidylcholine, and phosphotidylinositol.
• Mixtures of phosphotidylcho ⁇ line -with other components, such as cholesterol or Vitamin ⁇ are also suitable.
• composition of a hyperalimentation fluid employed in the method of the present invention would vary, depending on the amount of lipid used and the percent entrapment achieved. For example, if 25% of the final fluid volume were taken up by liposomes which contained 66 icromole of phosphotidylcholine per ml of aqueous phase and which encapsulated (at a 50% entrapment) a nutrient solution containing 25% by weight of a particular oligosaccharide, then a liter of fluid would contain approximately 62 grams of the oligosaccharide and 20 grams of lipid material. The caloric content of the liposome-based fraction of the fluid would be about 362 calories.
• the remaining 75% of the fluid's total volume could be made of, for example, equivolumes of a 10% glucose solution and a 9% amino acid solution.
• the inclusion of electrolytes would be optional, although magnesium and calcium would not be preferred, since their presence would enhance fusion of liposomes in dispersion.
• the total caloric content of the hyperalimentation fluid would be about 607 calories per liter. '
• the liposome concentration could be" adjusted so that liposomes accounted for 50% of the hyperalimentation fluid's volume. If a 50% entrapment of the oligosaccharide-containing solution is assumed, then (with the same liposome preparation as in the previous example) approximately 125 grams of oligosaccharide would be encapsulated in liposomes comprising 40 grams of lipid.
• the caloric content of the liposome-based fraction would be from 725 calories, that of the remaining fluid about 143, and the total caloric content would be 868 calories.

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