United States Patent
`Ramsay et a1.
`
`[i9]
`
`[54] HIGH CALORIE SOLUTIONS OF LOW
`MOLECULAR WEIGHT GLUCOSE
`POLYMER MIXTURES USEFUL FOR
`INTRAVENOUS ADMINISTRATION
`
`[75]
`
`Inventors: Anne B. Ramsay, Ingleside, 111.;
`Delbert R. Luebke, Kenosha, Wis.;
`David T. Guzek, Wildwood, 111.;
`Chia-Lung Hsieh; Robert Roteman,
`both of Waukegan, 111.; William D.
`Leathem, Lindenhurst, Ill.
`
`[73] Assignee: Abbott Laboratories, North Chicago,
`Ill.
`
`[21] Appl. No.: 853,366 ‘
`
`‘
`Nov. 21, 1977
`[22] Filed:
`[51]
`Int. C1.2 ...................... A61K 31/715; C07H 1/00;
`C08B 37/00
`[52] U.S. C1. .................................... 424/180; 424/177;
`536/ 1; 536/4
`[58] Field of Search ........................ 424/180; 536/1, 4
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,928,135
`4,021,543
`
`12/1975 Milner .................................. 424/180
`5/1977 McKay ................................ 424/ 180
`
`[11]
`
`[45]
`
`4,182,756
`
`Jan. 8, 1980
`
`OTHER PUBLICATIONS
`
`Berlyne, et al., “The Lancet”, Apr., 1969, pp. 689—692.
`Bott et al., “The Pharmaceutical Journal”, May, 1970,
`pp. 533—584.
`
`Primary Examiner—Johnnie R. Brown
`Attorney, Agent, or Firm—Robert L. Niblack; Aaron L.
`Hardt
`
`[57]
`
`ABSTRACT
`
`High calorie solutions of low molecular weight glucose
`polymer mixtures useful for intravenous administration,
`preferably via a peripheral vein, are disclosed. Methods
`of preparing the solutions and their preferred rate of
`infusion at less than 5 mg./min./kg. of patient body
`weight are also disclosed. The solutions can be isotonic
`to human blood at 20—50% W/V as the glucose poly-
`mer mixtures have an average degree of polymerization
`ranging from 4 to 10. At the preferred rate of infusion
`high utilization of the glucose polymers infused occurs
`in human patients, including diabetics. The utilization
`can be further enhanced by concomitant injections of
`insulin. The solutions can be administered concomi-
`tantly with amino acids, lipid emulsions, vitamins and
`electrolytes.
`'
`
`46 Claims, No Drawings
`
`

`

`1
`
`4,182,756
`
`HIGH CALORIE SOLUTIONS OF LOW
`MOLECULAR WEIGHT GLUCOSE POLYMER
`MIXTURES USEFUL FOR INTRAVENOUS
`ADMINISTRATION
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates to high calorie solutions
`for intravenous administration to human patients and
`methods of administering such solutions. More particu-
`larly, the present invention relates to solutions compris-
`ing glucose polymer mixtures‘of low molecular weight
`which can be infused into and utilized by human pa-
`tients in relatively high concentrations without requir-
`ing use of a central vein. The present invention further
`relates to methods of preparing the high calorie solu-
`tions and preferred rates of their infusion. Still further,
`the invention relates to the utilization of the solutions by
`diabetic human patients.
`.
`Major nutritional problems are seen in many human
`patients who for one reason or another cannot obtain an
`adequate supply of calories by mouth. The problems are
`particularly acute in unconscious patients, surgical pa-
`tients who have lost a large amount of weight preopera-
`tively, and in patients in protracted convalescence for
`such diseases as bowel obstruction, peritonitis, or intes-
`tinal fistulae.
`
`Because the patient requires energy to maintain life
`and must constantly synthesize protein tissue, it is essen-
`tial that the patient’s calorie and protein intake be main-
`tained at least at minimum levels. In the absence of any
`exogenous source of nutrition, the patient will obtain
`needed calories by catabolism of endogenous fat stores
`and protein tissues. This can lead to death by starvation,
`lack of resistance to infection, respiratory muscle fail-
`ure, or cardiac muscle failure. Accordingly, the intrave-
`nous administration of nutrients to the patient can be
`life-saving.
`Conventionally, aqueous solutions of glucose or fruc-
`tose have been infused into patients intravenously to
`provide exogenous calories. Because of the osmotic
`relationship between human plasma and blood corpus-
`cles, an important consideration of any solution paren-
`terally administered to a patient is that it can cause
`damage to the patient’s corpuscles if it is not substan-
`tially isotonic to human blood. If the patient’s plasma
`becomes strongly hypertonic, the corpuscles shrivel. If
`it becomes strongly hypotonic, the corpuscles swell and
`may burst. Accordingly, the aqueous solutions of glu-
`cose or fructose most commonly intravenously infused
`into a patient are such isotonic 5% W/V solutions.
`One liter of 5% W/V glucose solution provides 50
`grams of glucose per each 1000 ml. of solution. Each
`gram of glucose provides 3.4 calories and, therefore,
`one liter of a 5% W/V glucose solution provides 170
`calories per each 1000 ml. of solution. Generally, adult
`patients require a total of 2,000—5,000 calories per day.
`To satisfy that need, a patient would have to receive
`from 12—35 liters of 5% W/V glucose solution per day.
`Clearly, such an infusion of 12—35,000 m1. of water
`would grossly over-hydrate the patient.
`Alternatively, hypertonic glucose or fructose 10 to
`20% W/V solutions can and have been intravenously
`injected in order to provide the patient more calories.
`However, their infusion for extended periods of time is
`limited by the inability of the patient’s peripheral veins
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`to handle such hypertonic solutions without serious
`venous thrombosis or thrombophlebitis resulting.
`It is well known thatv25—50% W/V solutions of glu-
`cose or invert sugar have been intravenously adminis-
`tered to patients via a cannula inserted into the vena
`cava. While this technique provides a means by which
`the patient may intravenously receive high calorie solu-
`tions, it is not totally satisfactory in that insertion of the
`cannula is a surgical procedure not generally performed
`by a nurse, or many surgeons, and the dangerous possi-
`bility of septicemia or serious thrombosis in the vena
`cava, as Well as potential damage of the heart and large
`vessels by the catheter tip.
`U.S. Pat. No. 3,067,098 granted Dec. 4, 1962 to W.
`Pool and entitled “Intravenous Nourishment of Pa-
`tients” discloses a high calorie solution that could be
`administered into a peripheral vein by virtue of a small
`amount of an anti-inflammatory steroid hormone such
`as hydrocortisone, cortisone, prednisolone, or predni-
`sone included in the solution. The technique disclosed
`by Pool has not been widely practiced, however, be-
`cause of the undesirable amounts of steriods that would
`be administered with prolonged usage.
`U.S. Pat. No. 3,793,461 granted Feb. 19, 1974 to S.
`Yuen and entitled “Intravenous Administration of Mal—
`
`,tose to Diabetics” discloses that glucose polymers of
`D.P.=2 (maltose) can be intravenously administered
`via a peripheral vein of a patient and that the maltose
`administered is utilized by human patients by a mecha-
`nism unknown to Yuen. The Yuen patent supports the
`findings of the present invention that glucose polymers
`can be utilized when intravenously administered into
`human patients. However, the use of maltose for intra-
`venous therapy is somewhat limited by the fact that
`isotonic solutions of maltose supply only twice the calo—
`ries of isotonic solutions of glucose and the relatively
`high cost of sufficiently pure maltose for intravenous
`administration.
`
`U.S. Pat. No. 3,928,135 granted Dec. 23, 1975 to J.
`Milner and entitled “Process for the Production of Glu-
`cose Polymers” discloses that glucose polymer mixtures
`consisting of 3% glucose and glucose polymers of DR
`2—10 can be administered intravenously. Milner further
`discloses an oral glucose polymer mixture which has a
`significant proportion of its molecules of a DP. greater
`than 10.
`
`An article by D. Bott, et al. at pp. 583—84 of The
`Pharmaceutical Journal of May 30, 1970 reported the
`consideration of a glucose polymer mixture, CALO-
`REEN, for possible intravenous use. CALOREEN,
`which is an orally administered glucose polymer mix-
`ture, is reported to consist of 3% glucose, 7% maltose,
`5% maltotriose and 85% polysaccharides having mole-
`cules of four to fifteen glucose units (A.D.P.=5) at p.
`620 of an article by G. Berlynne, et a1. entitled “A Solu-
`ble Glucose Polymer for Use in Renal Failure and Calo-
`rie Deprivation States”.
`Accordingly, it is clear that a nontoxic metabolizable
`high calorie solution that can be infused into a patient
`via a peripheral vein without causing venous thrombo-
`sis, thrombophlebitis, or other undesired side effects is
`needed.
`
`SUMMARY OF THE INVENTION
`
`Therefore, it is the primary object of this invention to
`provide a high calorie solution suitable for administra-
`tion into a peripheral vein of a human patient. Prefera-
`bly, the solution will provide substantially more calories
`
`

`

`3
`intravenous solutions per ml. of
`
`4,182,756
`
`than conventional
`water administered.
`
`As already discussed, the most limiting factor in intra-
`venous therapy is the inability of the patient’s peripheral
`veins to handle fluids with high osmotic pressure. Os-
`mosis is the passage of water through a semipermeable
`membrane due to differences in the number of mole-
`cules of dissolved substances on the two sides of the
`membrane. Osmotic pressure is directly proportional to
`the number of molecules in solution, without regard to
`the weight of the molecules.
`Thus, if all the molecules of a 5% W/V glucose solu-
`tion were individually replaced by glucose polymer
`molecules containing two glucose units (maltose), the
`osmotic pressure of the solution would remain the same,
`even though the weight of each molecule would have
`been doubled. Such a maltose solution would, therefore,
`constitute 100 grams/1000 ml., which is a 10% W/V
`solution. Further, each molecule would provide two
`glucose units, so that if the human body can utilize
`intravenously administered maltose, such a maltose
`solution would provide twice as many calories as the
`5% WW glucose solution.
`Similarly, replacing the molecules of a 5% W/V
`glucose solution with maltotriose molecules would cre-
`ate a 15% W/V solution providing three times as many
`calories, while maltotetraose would create a 20% W/V
`solution providing four times as many calories. Thus, it
`will be seen that a solution containing X grams/ 1000 ml.
`of glucose will be isotonic with a solution containing X
`grams times the degree of polymerization (D.P.) of a
`glucose polymer/1000 ml. and further that the glucose
`polymer solution can provide increased calories of an
`amount equal to its D.P. times the number of calories
`provided by the glucose solution.
`Likewise,
`if 20% of the molecules of a 5% WW
`glucose solution were individually replaced by glucose
`polymer molecules containing two glucose units, an-
`other 20% by glucose polymer molecules containing
`three glucose units, a third 20% by glucose polymer
`molecules containing four glucose units and a fourth
`20% by glucose polymer molecules containing five
`glucose units, the osmotic pressure of the resulting glu-
`cose polymer mixture solution would remain the same.
`However, the weight of the molecules in the solution
`will have tripled; i.e., 20% same plus 20% doubled plus
`20% tripled plus 20% quadrupled plus 20% quintupled
`equals 300% increase. The average degree of polymeri-
`zation (A.D.P.) of such a glucose polymer mixture re-
`fers to the average number of glucose units per mole-
`cule of the mixture. The average degree of polymeriza-
`tion for the above—described glucose polymer mixture is
`readily calculable as 3.
`For the reasons already explained, it will be clear that
`a maltotriose (D.P.=3) solution isotonic with the
`above-described glucose polymer mixture (A.D.P.:3)
`solution would also have a weight triple that of an iso-
`tonic glucose solution. Thus, it will be seen that glucose
`polymers and glucose polymer mixtures of equal DP.
`and A.D.P. are isotonic at the same weights and will
`provide equal amounts of calories if they are equally
`utilized by the human body.
`Accordingly, there is provided by the present inven-
`tion novel low molecular weight glucose polymer mix-
`tures which can be used to prepare substantially clear,
`nonpyrogenic, stable and sterile high calorie solutions
`suitable for administration to human patients, including
`diabetics, via a peripheral vein. The solutions can be
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`4
`isotonic to human blood at 20—50% W/V as the glucose
`polymer mixtures can have an average degree of poly-
`merization ranging from 4 to 10. The high calorie solu-
`tions are suitable, for admixture with amino acids, lipid
`emulsions, vitamins and electrolytes.
`Maximum utilization of the glucose polymer mixtures
`has been found to occur at rates of infusion less than 5
`mg./min./l<g. of patient body weight. Utilization of the
`glucose polymer mixtures is enhanced by concomitant
`subcutaneous injections of insulin for both diabetic and
`nondiabetic patients.
`Preferred methods of preparing the glucose polymer
`are by either solvent extraction or molecular membrane
`filtration of certain commercially available dried corn
`starch hydrolysates or their equivalents.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Mixtures of glucose polymers can be prepared by the
`hydrolysis of starch. Starch consists of at least two
`known fractions, amylose and amylopectin, that consist
`of chains of glucose units. It is well known in the art of
`starch hydrolysis that the linkages between the glucose
`units are susceptible to both acid and enzyme hydrolysis
`and both are routinely employed in the industrial prepa-
`ration of starch hydrolysates. Because the properties of
`a starch hydrolysate are dictated by the method of its
`hydrolysis, starch hydrolysates are characterized as
`acid treatment, enzyme treatment, and acid-enzyme
`treatment hydrolysates. It
`is well known that such
`starch hydrolysates are useful orally as foods because of
`their sugar content, while U.S. Pat. No. 4,021,543
`granted May 3, 1977 to G. McKay discloses their use as
`a taste disguising agent.
`U.S. Pat. No. 3,663,369 granted May 16, 1972 to A.
`Morehouse, et a1. and entitled “Hydrolysis of Starch"
`contains an extensive review of the art of starch hydro-
`lysis and the teachings of that patent,
`including the
`novel starch hydrolysate products and processes taught
`therein, are hereby incorporated into this application by
`this reference to that patent. The teachings of U.S. Pat.
`No. 3,560,343 granted Feb. 2, 1971 to F. Armbruster, et
`al. and entitled “Low D.E. Starch Conversion Prod-
`ucts” are also incorporated into this application by this
`reference thereto. While the starch hydrolysates taught
`by both U.S. Pat. Nos. 3,663,369 and 3,560,343 are in-
`tended for oral use, when further fractionated and re-
`fined, they serve as excellent raw materials for the sub-
`stantially clear, nonpyrogenic, stable and sterile intrave-
`nous solutions of this invention.
`It will be well understood that starch hydrolysates
`contain a heterogeneous mixture of glucose and poly-
`glucose molecules having a wide range of numbers of
`glucose units per molecule. In this application, the term
`“glucose polymer” will be used to mean only polyglu-
`cose molecules, while the term “glucose polymer mix-
`ture” will be used to describe a mixture wherein glucose
`may also be present.
`According to the present invention, it has been found
`that a glucose polymer mixture having at least 99% of
`its molecules less than 26 glucose units, at least 85% of
`its molecules less than 11 glucose units and at least 20%
`of its molecules less than 4 glucose units can be utilized
`by a human patient when intravenously administered
`via a peripheral vein of the patient. Surprisingly, it has
`been found that maximum utilization of the glucose
`polymers occurs at
`infusion rates of
`5 or
`less
`mg./min./kg. of the patient’s body weight and that total
`
`
`
`

`

`5
`utilization ofthe mixture may occur at infusion ratesof
`2.0 to 3.0 mg./min./kg. of the patient’s body weight.
`Higher rates of infusion apparently exceed the rate at
`which the material can be metabolized, as polymeric
`material appears in the urine of the patient at such rates.
`Further, it has been found that the utilization of glucose
`polymers and glucose polymer mixtures is enhanced by
`concomitant injections of insulin, .in contradiction of the
`findings of the Yuen patent.
`As explained in the above-referenced patents of
`Morehouse, et al. and Armbruster, et al., hazing is a
`serious problem in low dextrose equivalent starch hy-
`drolysates due to retrogradation or reassociation of the
`molecules of higher D.P. with other molecules of
`higher D.P. to form large relatively insoluble aggre-
`gates. It will be realized that the presence of such aggre-
`gates in a solution to be intravenously administered
`must be minimized. Therefore, the glucose polymer
`mixtures in the solutions of the present invention are
`selected for their ability to remain stable and provide a
`substantially haze-free or clear solution.
`A further important consideration of a solution to be
`intravenously administered is the requirement that it be
`free of fever causing materials called pyrogens, particu-
`larly heat-stable polysaccharides, which cannot be re-
`moved by autoclaving. The glucose polymer mixtures
`of this invention have such pyrogens removed by filtra-
`tion techniques during the final preparation of the solu-
`tion.
`Still another important consideration of the suitability
`of a glucose polymer mixture for inclusion'1n the high
`calorie intravenous solutions 'of this invention is the
`ability of the mixture to remain stable during steam
`sterilization or autoclaving. If the mixture would sub-
`stantially retrograde during autoclaving, the aggregates
`so formed and evidenced by hazing of the solution
`would render the solution totally unusable for intrave-
`nous administrationa To the contrary,
`if the mixture
`would degrade, the number of molecules of lower D.P.
`could increase to the point that the average degree of
`polymerization wouldbe reduced, thereby reducing the
`number of calories obtainable from an isotonic solution
`of the mixture.
`Likewise, the stability of the glucose polymer mix-
`ture selected for the solutions for intravenous adminis-
`
`_
`
`tration of the present invention is critical to the admix-
`ture therewith of additional nutrients such as 35—10%
`W/V amino acids, 5—20% W/V lipid emulsions, vita-
`mins and electrolytes. Preferably, the solutions of the
`present invention can be so mixed and stored in-a suit-
`able container prior to the administration thereof. It will
`' be obvious to those skilled in the art that such nutrients
`
`can also be concomitantly administered to the patient
`from another container or solution.
`the
`Generally, with respect
`to glucose polymers,
`term “low molecular weight” is understood to include
`molecules of D.P. = 1—14, while the term “intermediate
`molecular weight” is understood to include molecules
`of D.P. = 15—25, and the term “high molecular weight”
`is understood to include all" molecules greater than
`D.P.=26. The average degree of polymerization of the
`glucose polymer mixtures selected for the high calorie
`solutions 'of the present invention is from 4 to 10. Thus,
`it will be apparent that the mixtures have an average
`low molecular weight.
`-
`The importance of infusing solutions isotonic with
`human blood has already been explained hereinabove.
`Based on that explanation,
`it 'will be apparent that a
`
`4,182,756
`
`6
`glucose polymer mixture having an A.D.P. of 4 will be
`isotonic with blood in a 20% W/V solution, while a
`glucose polymer mixture having an A.D.P. of 10 will be
`isotonic with bloOd in a 50% W/V solution. While it is
`true that the primary object of this invention is to pro-
`vide high calorie solutions for intravenous infusion via a
`peripheral vein,
`it will readily be obvious to those
`skilled in the art that the novel solutions of this inven-
`tion can be used in nonisotonic solutions, if desired, e.g.,
`10
`in a vena cava infusion.
`When the novel solutions of this invention were in-
`
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`jected into human patients, it was found that they are
`utilized by means other than the glucose/insulin route.
`Laboratory evidence indicates that phosphorylase A
`may be important in the metabolism of glucose poly-
`mers, along with other unknown and unidentified en-
`zyme systems. This fact indicates that the glucose poly-
`mer mixtures of this invention will be utilized by human
`diabetic patients.
`
`EXAMPLE 1
`
`A human patient received a continuous injection via
`a peripheral vein of a substantially clear, nonpyrogenic,
`stable and sterile solution isotonic to human blood and
`
`comprising a glucose polymer mixture having an aver-
`age degree of polymerization of 5 and at least 99% of its
`molecules less than 26 glucose units, at least 85% of its
`molecules less than 11 glucose units, and at least 20% of
`its molecules. less than 4 glucose units. The described
`isotonic solution was infused at a rate of 2.5 mg. of
`glucose polymer/min./kg. of the patient’s body weight
`for 3 hours. Urine samples were collected every 30
`minutes. After 6 hours, only 7% of the infused glucose
`polymer mixture had appeared in the urine, indicating
`that 93% of the mixture had been retained for utilization
`by the patient’s body.
`EXAMPLE 2
`
`A second human patient received an identical infu-
`sion as that administered in Example 1. After 6 hours,
`only 2% of the infused glucose polymer mixture had
`appeared in the urine, indicating that 98% of the mix-
`ture had been retained for utilization by the patient’s
`body.
`
`EXAMPLE 3
`
`A third human patient received an infusion identical
`to that administered in Example 1, except that it was
`50.
`infused at a rate of 5.0 mg. of glucose polymer mixture/-
`min/kg. of the patient’s body weight. After 6 hours,
`67% of the infused glucose polymer mixture had ap-
`peared in the urine.
`
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`EXAMPLE 4
`
`A fourth human patient received an infusion identical
`to that administered in Example 3. After 6 hours, 59%
`of the infused glucose polymer mixture had appeared in
`the urine.
`
`EXAMPLE 5
`
`Five human patients received an infusion of maltose
`in a peripheral vein for 12 hours continuously at a rate
`of 2.5 mg. of maltose/min./kg. of patient body weight.
`Urine samples were taken from the patients every 30
`minutes. After 18 hours, from 14 to 20% of the maltose
`had appeared in the patient’s urine.
`
`

`

`7
`
`EXAMPLE 6
`
`4,182,756
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`Four human patients received an infusion of maltose
`identical to that administered in Example 5, except that
`each patient also received a concomitant subcutaneous 5
`injection of 15—16 units of insulin. After 18 hours, from
`1 to 7% of the infused maltose had appeared in the
`patient’s urine, thereby indicating enhanced utilization
`of the maltose because of the insulin injection.
`EXAMPLE 7
`
`10
`
`Six human patients received an infusion of maltose
`identical to that of Example 5, except that the rate of
`infusion was 5.0 mg. of maltose/min./kg. of patient
`body weight. After 18 hours, from 40 to 48% of the 15
`infused maltose had appeared in the patient’s urine.
`EXAMPLE 8
`
`25
`
`Four human patients received an infusion of maltose
`identical to that of Example 7, except that each patient 20
`also received a concomitant subcutaneous injection of
`24—30 units of insulin. After 18 hours, from 21 to 39% of
`the maltose had appeared in the patient’s urine, thereby
`indicating enhanced utilization of the maltose because
`of the insulin injection.
`Preferred solutions of the present invention are fur-
`ther characterized as comprising 20—30% W/V of a
`glucose polymer mixture having an average degree of
`polymerization between 4 and 6,
`less than 1% of its
`molecules greater than 25 glucose units, 4 to 10% of its 30
`molecules between 11 and 25 glucose units,
`1 to 3% of
`its molecules 10 glucose units, 3 to 5% of its molecules
`9 glucose units, 5 to 8% of its molecules 8 glucose units,
`14 to 17% of its molecules 7 glucose units, 16 to 18% of
`its molecules 6 glucose units, 8 to 9% of its molecules 5 35
`glucose units, 10 to 13% of its molecules 4 glucose units,
`13 to 17% of its molecules 3 glucose units, 8 to 13% of
`its molecules 2 glucose units, and 1 to 3% of its mole-
`cules 1 glucose unit. They have been prepared as illus-
`trated in the following examples.
`EXAMPLE 9
`
`4O
`
`A starch hydrolysate having a dextrose equivalent of
`10—13 and consisting of 1% glucose, 4% maltose, 5%
`maltotetraose, 4% maltopentaose and 82% molecules of 45
`six or more glucose units was subjected to reverse os-
`mosis according to the teachings of US. Pat. No.
`3,756,853 granted to G. Meyer on Sept. 4, 1973 and
`entitled “Process for the Production of Nonhazing
`Starch Conversion Syrups,” which teachings are incor-
`porated herein by this reference thereto. After fraction-
`ating the solution through a 1000 molecular weight
`cut-off and a 600 molecular weight cut~off membrane,
`the resulting glucose polymer mixture was found to
`comprise 2.6% glucose, 8.8% maltose, 12.6% maltotri-
`ose, 10.0% maltotetraose, 8.0% maltopentaose, 17.4%
`maltohexaose, 18.1% maltoseptaose, 8.9% maltooc-
`taose, 5.1% maltononaose, 2.8% maltodecaose, and
`5.7% 11—13 glucose units.
`EXAMPLE 10
`
`50
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`A starch hydrolysate having a dextrose equivalent of
`10—13 and consisting of 1% glucose, 4% maltose, 5%
`maltotriose, 4% maltotetraose, 4% maltopentaose and
`82% molecules of six or more glucose units was dis- 65
`solved in distilled water. That solution was then added
`to Ethanol 3A, 200 proof with agitation. (The preferred
`alcohol concentration is 70—95%). After 30 minutes
`
`8
`agitation, a diatomaceous earth filter aid was added.
`Agitation was continued for 30 more minutes and then
`stopped allowing the solids to separate. The supernatant
`liquid was decanted, filtered and transferred to a con-
`centrator. This procedure was repeated 24 times. The
`filtered supernatant solutions were combined and con-
`centrated to remove the ethanol. An aqueous solution of
`the concentrated supernatant was treated with acti—
`vated carbon and then passed through two ion ex-
`change resin columns. The effiuent solution was spray
`dried to produce a dry product.
`EXAMPLE 11
`
`The procedure of Example 10 is followed beginning
`with a starch hydrolysate having a dextrose equivalent
`of 16—20 and consisting of 1% glucose, 7% maltose, 9%
`maltotriose, 6% maltotetraose, 6% maltopentaose and
`71% molecules of six or more glucose units.
`EXAMPLE 12
`
`The procedure of Example 10 is followed beginning
`with a starch hydrolysate having a dextrose equivalent
`of 13—17 and consisting of 1% glucose, 3% maltose, 8%
`maltotriose, 6% maltotetraose and 82% molecules of
`five or more glucose units.
`EXAMPLE 13
`
`The procedure of Example 10 is followed beginning
`with a starch hydrolysate having a dextrose equivalent
`of 18-22 and consisting of 1% glucose, 6%. maltose, 8%
`maltotriose, and 78% molecules of five or more glucose
`units.
`
`EXAMPLE 14
`
`US. Pat. No. 3,668,007 granted to C. Egger, et al. on
`June 6, 1972 and entitled “Syrup Fractionation Pro-
`cess” teaches the fractionation of starch hydrolysates by
`both ultrafiltration and reverse osmosis. The teachings
`thereof are incorporated herein by this
`reference
`thereto. If the teachings of US. Pat. No. 3,668,007 are
`employed in Example 9, substantially identical results
`will be obtained.
`
`EXAMPLE 15
`
`When a dry glucose polymer mixture product ob-
`tained from the procedure of Example 10 was added to
`distilled water in amounts producing a 25% W/V solu-
`tion and subjected to steam sterilization or autoclaving,
`chemical testing of the resulting solution showed that it
`had an average degree of polymerization of substan-
`tially 5, was visually clear when viewed in a light box,
`had a color between 40 and 50 APHA units, had a pH
`of substantially 4.2 and a glucose polymer mixture dis-
`tribution of 2.0% glucose, 8.4% maltose, 13.4% malto—
`triose,
`10.5% maltotetraose,
`8.7% maltopentaose,
`17.3% maltohexaose, 16.4% maltoseptaose, 7.4% mal-
`tooctaose, 4.2% maltononaose, 2.8% maltodecaose,
`8.8% 11—25 glucose units and 0.7% glucose units
`greater than 25. The solutions were determined to be
`stable even during steam sterilization.
`EXAMPLE 16
`
`When another dry glucose polymer mixture product
`obtained from the procedure of Example 10 was added
`to distilled water in amounts producing a 25% WW
`solution and subjected to steam sterilization, chemical
`testing of the resulting solution showed that it had an
`average degree of polymerization of substantially 5, was
`
`
`
`
`
`

`

`4,182,756
`
`9
`visually clear when viewed in a light box, had a color
`between 40 and 50 APHA units, had a pH of substan—
`tially 4.2 and a glucose polymer mixture distribution of
`3.0% glucose, 12.3% maltose, 16.8% maltotriose,
`12.2% maltotetraose, 8.5% maltopentaose, 16.6% mal-
`tohexaose, 14.5% maltoseptaose, 5.9% maltooctaose,
`3.2% maltononaose, 1.9% maltononaose, 4.5% 11—25
`glucose units and 0.7% glucose units greater than 25.
`The solutions were determined to be stable even during
`steam sterilization.
`That which we claim is:
`
`l. A substantially clear, nonpyrogenic, stable and
`sterile solution for intravenous administration to human
`
`patients, said solution comprising at least 20% W/V of
`a glucose polymer mixture having an average degree of
`polymerization of at least 4 and at least 99% of its mole-
`cules less than 26 glucose units, at least 85% of its mole-
`cules less than 11 glucose units, and at least 20% of its
`molecules less than 4 glucose units.
`2. The solution defined in claim 1, wherein said solu-
`tion comprises from 20 to 50% W/V of said glucose
`polymer mixture.
`3. The solution defined in 'claim 2, wherein said solu-
`tion is isotonic to human blood.
`4. The solution defined in claim 3 wherein said glu-
`cose polymer mixture has an average degree of poly-
`merization between 4 and 10.
`5. The solution defined in claim 1, wherein said glu-
`cose polymer mixture has an average degree of poly-
`merization between 4 and 10.
`6. The solution defined in claim 1, wherein said solu-
`tion comprises from 20—30% W/V of a glucose polymer
`mixture having an average degree of polymerization
`between 4 and 6, less than 1% of its molecules greater
`than 25 glucose units, 4 to 10% of its molecules between
`11 and 25 glucose units,
`1 to 3% of its molecules 10
`glucose units, 3 to 5% of its molecules 9 glucose units,
`5 to 8% of its molecules 8 glucose units, 14 to 17% of its
`molecules 7 glucose units, 16 to 18% of its molecules 6
`glucose units, 8 to 9% of its molecules 5 glucose units,
`10 to 13% of its molecules 4 glucose units, 13 to 17% of
`its molecules 3 glucose units, 8 to 13% of its molecules
`2 glucose units, and l to 3% of its molecules 1 glucose
`unit.
`7. A method of providing calories to a human patient
`comprising infusing into a peripheral vein of said patient
`a clear, nonpyrogenic, stable and sterile solution includ-
`ing at least 20% W/V of a glucose polymer mixture
`having an average degree of polymerization of at least 4
`and at least 99% of its molecules less than 26 glucose
`units, at least 85% of its molecules less than 11 glucose
`units, and at least 20% of its molecules less than 4 glu-
`cose units.
`
`8. The method of providing calories defined in claim
`7 wherein said solution comprises from 20 to 50% W/V
`of said glucose polymer mixture.
`9. The method‘ of providing calories defined in claim
`8, wherein said solution is isotonic to human blood.
`10. The method of providing calories defined in claim
`9, wherein said glucose polymer mixture has an average
`degree of polymerization between 4 and 10.
`11. The method of providing calories defined in claim
`7, wherein said glucose polymer mixture has an average
`degree of polymerization between 4 and 10.
`12. The method of providing calories defined in claim
`7, wherein said solution comprises from 20—30% W/V
`of a glucose polymer mixture having an average degree
`of polymerization between 4 and 6, less than 1% of its
`
`10
`molecules greater than 25 glucose units, 4 to 10% of its
`molecules between 11 and 25 glucose units,
`1 to 3% of
`its molecules 10 glucose units, 3 to 5% of its molecules
`9 glucose units, 5 to 8% of its molecules 8 glucose units,
`14 to 17% of its molecules 7 glucose units, 16 to 18% of
`its molecules 6 glucose units, 8 to 9% of its molecules 5
`glucose units, 10 to 13% of its molecules 4 glucose units,
`13 to 17% of its molecules 3 glucose units, 8 to 13% of
`its molecules 2 glucose units, and 1 to 3% of its mole-
`cules 1 glucose unit.
`13. A method of providing calories to a diabetic
`human patient without increasing said patient’s blood
`glucose level comprising infusing into a peripheral vein
`of said diabetic patient a clear, nonpyrogenic, stable and
`sterile solution including at least 20% W/V ofa glucose
`polymer mixture having an average degree of polymeri-
`zation of at least 4 and at least 99% of its molecules less
`than 26 glucose units, at least 85% of its molecules less
`than 11 glucose units, and at lea