US3234089A - Non-toxic intravenous, high-calorie solution containing glycerol - Google Patents
Non-toxic intravenous, high-calorie solution containing glycerol Download PDFInfo
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- US3234089A US3234089A US188249A US18824962A US3234089A US 3234089 A US3234089 A US 3234089A US 188249 A US188249 A US 188249A US 18824962 A US18824962 A US 18824962A US 3234089 A US3234089 A US 3234089A
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- glycerol
- solution
- ethanol
- intravenous
- glucose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
Definitions
- one of the objects of this invention is the provision of a non-hemolytic, non-toxic, concentrated solution of glycerol, hexose(s) and ethanol which is stable to shipment and storage at the extremes of temperature encountered by our civilian and armed forces medical units.
- Still another object of this invention is the provision of a high-calorie intravenous solution containing a number of energy-yielding metabolizable compounds in such a ratio that a large quantity of total nutrient can be given to a patient over a short period of time without exceeding the bodys ability to metabolize any one of the compounds.
- the object of this invention is the provision of an aqueous solution of the character above described consisting essentially of glucose, fructose, ethanol and glycerol.
- the present invention is predicated upon the discoveries: (1) that ethanol, in concentrations which are easily metabolized and which are non-toxic, will greatly reduce glycerol-induced hemolysis; and (2) that combinations of hexoses and ethanol, again in concentrations which are readily metabolized and which are non-toxic, will abolish glycerol-induced hemolysis. Solutions of the character here contemplated ideally contain suflicient glycerol, glucose, fructose and ethanol to furnish approximately 1,500 calories per liter.
- a preferred solution made according to this invention would contain gm. glycerol, 7.5 gm. glucose, 7.5 gm. fructose, 5.0 gm. ethanol and sufficient distilled water to make 100 ml. of the solution. Such a solution would be found to have a caloric value of approximately 1,500 calories per liter.
- EXAMPLE I 750 gm. of USP 99.5% glycerol, 375 gm. of USP anhydrous glucose, 375 gm. of USP fructose and 250 gm. USP absolute ethanol are dissolved in 2 liters of pyrogenfree distilled water. The solution is diluted to 5.0 liters with pyrogen-free water and mixed well. The solution is filtered through a fine sintered glass filter into clean bottles. The bottles are stoppered, sealed, then autoclaved at 110 C. for .30 minutes.
- EXAMPLE II Sufficient concentrated invert sugar solution to furnish 11.3 kg. of sugar is diluted with pyrogen-free water to ap- "ice proximately 50 liters. 11.7 kg. of USP 96% glycerol are added with sufficient mixing to produce a uniform solution. 67 gm. of Darco G60 are added, the mixture is stirred for 20 minutes, then filtered through eight 8-inch square Diabest E-65 filter pads backed with line-free filter papers. 3.8 kg. of USP absolute ethanol are added, the solution is adjusted to pH 5.0, then made to liters with pyrogen-free water and mixed well. The solution is filtered through a 0.1 Selas candle into 500 ml. bottles. The bottles are evacuated to about 15 inches of mercury, stoppered, sealed, autoclaved at C. for 30 minutes, then spray-cooled.
- EXAMPLE III Sulficient concentrated invert sugar solution to furnish 7.5 kg. of sugar is diluted with pyrogen-free water to ap-' 5.0 kg. of USP 99.5% glycerol.
- proximately 35 liters. are added and the solution is well mixed.
- 45 grams of Darco G-60 are added and the mixture stirred for 30 minutes, then is filtered through six 8-inch square Diabest E-65 filter pads backed with lint-free filter paper.
- 2.5 kg. of USP absolute ethanol are added, the solution is adjusted to pH 5 .0, then made to 50 liters with pyrogen-free water and mixed well.
- the solution is filtered through a 0.1 Selas candle into l-li-ter bottles. The bottles are evacuated to approximately 15 inches of mercury, stoppered, sealed, autoclaved at 110 C. for 30 minutes, then spray-cooled.
- EXAMPLE IV One kg. of USP 99.5% glycerol, 500 gm. USP anhydrous glucose, 500 gm. USP fructose and 500 gm. USP absolute ethanol are dissolved in about 7 liters of pyrogenfree distilled water. The solution is diluted to 10 liters with pyrogen-free distilled water and mixed well. The solution is filtered through a fine sintered glass filter into bottles which are stoppered, sealed and autoclaved at 110 C. for 30 minutes.
- glycerol-induced hemolysis a simple in vitro test is used. Heparin-treated rabbit or human blood is equilibrated for a short period of time with the test solution. This mixture is then rapidly diluted with five or more volumes of normal (isotonic) saline. To determine the degree of hemolysis caused by the test solution the diluted mixture is centrifuged and the amount of hemoglobin in the centrifugate measured. The first three of these operations mimic the conditions occurring in a vein during an intravenous infusion of a glycerol-containing solution. The red blood cells at the site of the infusion are momentraily exposed to a high concentration of glycerol which diffuses into the cells.
- glycerol-induced hemolysis is reportedly due to the rapid influx of water into red blood cells that have been exposed to high concentrations of glycerol, then to plasma low in glycerol. Solutions containing glycerol (or urea) which have been reported in the literature to cause hemolysis in animals when given intravenously cause measurable hemolysis by this in vitro test.
- Dogs have been given 30-consecutive infusions at and above the clinical dosage .of our preferred solution without ill effects or less of weight. Clinical trials in humans with this solution have shown a lack of toxicity and the desired beneficial effects. 7
- the soltuions of the present invention are stable almost indefinitely to temperatures encountered in ;the tropics, and canbe repeatedly frozen'and thawed without. changing their characteristics. or nutrient-value.
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- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
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Description
United States Patent NON-TOXIC INTRAVENOUS, HIGH-CALORIE SOLUTION CONTAINING GLYCEROL Ernest B. McQuarrie, Berkeley, Calif., assignor to Cutter Laboratories, Berkeley, Calif., a corporation of California No Drawing. Filed Apr. 17, 1962, Ser. No. 188,249 2 Claims. (Cl. 167-58) V The invention relates to and in general has for its object the provision of a non-hemolytic, non-toxic, concentrated solution of glycerol, hexose(s) and ethanol which, when given intravenously, will supply a high caloric intake in a small volume. 7
There has long been a need for a product which, when given intravenously, will supply to a patient a large number of calories in a small volume. Numerous intravenous fat emulsions have been devised to meet this need, but to date all have been too toxic for long-term administration. Concentrated glucose and/ or fructose solutions are not satisfactory because of the limited rate of utilization of these hexoses.
More specifically, one of the objects of this invention is the provision of a non-hemolytic, non-toxic, concentrated solution of glycerol, hexose(s) and ethanol which is stable to shipment and storage at the extremes of temperature encountered by our civilian and armed forces medical units.
Still another object of this invention is the provision of a high-calorie intravenous solution containing a number of energy-yielding metabolizable compounds in such a ratio that a large quantity of total nutrient can be given to a patient over a short period of time without exceeding the bodys ability to metabolize any one of the compounds.
More specifically, the object of this invention is the provision of an aqueous solution of the character above described consisting essentially of glucose, fructose, ethanol and glycerol.
The present invention is predicated upon the discoveries: (1) that ethanol, in concentrations which are easily metabolized and which are non-toxic, will greatly reduce glycerol-induced hemolysis; and (2) that combinations of hexoses and ethanol, again in concentrations which are readily metabolized and which are non-toxic, will abolish glycerol-induced hemolysis. Solutions of the character here contemplated ideally contain suflicient glycerol, glucose, fructose and ethanol to furnish approximately 1,500 calories per liter.
Basically a preferred solution made according to this invention would contain gm. glycerol, 7.5 gm. glucose, 7.5 gm. fructose, 5.0 gm. ethanol and sufficient distilled water to make 100 ml. of the solution. Such a solution would be found to have a caloric value of approximately 1,500 calories per liter.
More specifically, satisfactory solutions embodying the objects of my invention may be made up in accordance with the following examples:
EXAMPLE I 750 gm. of USP 99.5% glycerol, 375 gm. of USP anhydrous glucose, 375 gm. of USP fructose and 250 gm. USP absolute ethanol are dissolved in 2 liters of pyrogenfree distilled water. The solution is diluted to 5.0 liters with pyrogen-free water and mixed well. The solution is filtered through a fine sintered glass filter into clean bottles. The bottles are stoppered, sealed, then autoclaved at 110 C. for .30 minutes.
EXAMPLE II Sufficient concentrated invert sugar solution to furnish 11.3 kg. of sugar is diluted with pyrogen-free water to ap- "ice proximately 50 liters. 11.7 kg. of USP 96% glycerol are added with sufficient mixing to produce a uniform solution. 67 gm. of Darco G60 are added, the mixture is stirred for 20 minutes, then filtered through eight 8-inch square Diabest E-65 filter pads backed with line-free filter papers. 3.8 kg. of USP absolute ethanol are added, the solution is adjusted to pH 5.0, then made to liters with pyrogen-free water and mixed well. The solution is filtered through a 0.1 Selas candle into 500 ml. bottles. The bottles are evacuated to about 15 inches of mercury, stoppered, sealed, autoclaved at C. for 30 minutes, then spray-cooled.
EXAMPLE III Sulficient concentrated invert sugar solution to furnish 7.5 kg. of sugar is diluted with pyrogen-free water to ap-' 5.0 kg. of USP 99.5% glycerol.
proximately 35 liters. are added and the solution is well mixed. 45 grams of Darco G-60 are added and the mixture stirred for 30 minutes, then is filtered through six 8-inch square Diabest E-65 filter pads backed with lint-free filter paper. 2.5 kg. of USP absolute ethanol are added, the solution is adjusted to pH 5 .0, then made to 50 liters with pyrogen-free water and mixed well. The solution is filtered through a 0.1 Selas candle into l-li-ter bottles. The bottles are evacuated to approximately 15 inches of mercury, stoppered, sealed, autoclaved at 110 C. for 30 minutes, then spray-cooled.
EXAMPLE IV One kg. of USP 99.5% glycerol, 500 gm. USP anhydrous glucose, 500 gm. USP fructose and 500 gm. USP absolute ethanol are dissolved in about 7 liters of pyrogenfree distilled water. The solution is diluted to 10 liters with pyrogen-free distilled water and mixed well. The solution is filtered through a fine sintered glass filter into bottles which are stoppered, sealed and autoclaved at 110 C. for 30 minutes.
To test for glycerol-induced hemolysis, a simple in vitro test is used. Heparin-treated rabbit or human blood is equilibrated for a short period of time with the test solution. This mixture is then rapidly diluted with five or more volumes of normal (isotonic) saline. To determine the degree of hemolysis caused by the test solution the diluted mixture is centrifuged and the amount of hemoglobin in the centrifugate measured. The first three of these operations mimic the conditions occurring in a vein during an intravenous infusion of a glycerol-containing solution. The red blood cells at the site of the infusion are momentraily exposed to a high concentration of glycerol which diffuses into the cells. As the blood moves along the vein the glycerol solution is rapidly diluted with blood and the glycerol concentration drops. Glycerol-induced hemolysis is reportedly due to the rapid influx of water into red blood cells that have been exposed to high concentrations of glycerol, then to plasma low in glycerol. Solutions containing glycerol (or urea) which have been reported in the literature to cause hemolysis in animals when given intravenously cause measurable hemolysis by this in vitro test.
The following table shows the results from experiments using rabbit blood. In all of these experiments, 0.2 ml. of blood was incubated at room temperature with 0.5 ml. test solution for 30 seconds, then rapidly diluted with 5 ml. of 0.85% sodium chloride solution (isotonic saline). In Experiment No. 1, heparin-treated rabbit blood stored for one week in the refrigerator to make the red cells more fragile was used. In Experiment No. 2 the same blood used in Experiment No. 1 after further aging at room temperature was employed. In Experiment No. 3 heparin-treated rabbit blood stored one day in the refrigerator was used.
AGAINST GLYOEROL-INDUCED IN VITRO HEMOLYSIS OF RABBIT RED BLOOD CELLS Percent Weight by Volume Experiment Percent 'No. HemolySls Glycerol Glucose Fructose Ethanol 10 O U 68 10 0 0 42 5 5 0 5. 4 1O 0 0 5 2. 9 10 5 5 5 0. 8 0 0 (l 70 15 5 0 0 44 15 5 5 0 14 15 7. 5 7. 5 0 2. 7 15 0 0 5 3. 2 15 7. 5 7. 5 5 0.8 8 5 0 0 46 15 7. 5 7. 5 5 2 8 5 0 0 14 15 7. 5 7. 5 5 0. 5
The protective effects of ethanol and ethanol plus hexoses are clearly seen. In Experiments 2 and 3 an 8% glycerol solution in 5% glucose was compared to a solution containing 15% glycerol, 7.5% glucose, 7.5 fructose and 5% ethanol. This 8% glycerol solution was chosen because of the report of Pinter and Zilveramit (Amer. 'J. PhysioL, 198, 895-898, 1961) that intravenous fat emulsions containing these quantities of glycerol and glucose have caused hemolysis in rabbits and humans; As is seen in the table, under the conditions used, the 8% glycerol-5% glucose-solutionwas hemolytic, while the 15% glycerol, 7.5 glucose, 7.5 fructose and 5% ethanol solution showed hardly any effect at all.
Many other in vitro tests have been carried out using both rabbit and human red blood cells. They have all confirmed the protective action .of ethanol and hexoses on glycerol-induced hemolysis. Intravenous infusion studies in dogs, mice, rabbits and humans have confirmed these in vitro tests.
Dogs have been given 30-consecutive infusions at and above the clinical dosage .of our preferred solution without ill effects or less of weight. Clinical trials in humans with this solution have shown a lack of toxicity and the desired beneficial effects. 7
Since my solutions are intended for intravenous infl1- sions, it is understood that appropriate steps must be taken in their preparation to insure that thefin'alprodncts will be" of suitable purity,1will be sterile and will be essentially pyrogen-freei Unlike presently; available? intravenous fat emulsions,
the soltuions of the present invention are stable almost indefinitely to temperatures encountered in ;the tropics, and canbe repeatedly frozen'and thawed without. changing their characteristics. or nutrient-value.
Up to the present time intravenous solu'tionscontaining high concentrations of glycerol :,have been hemolytic in rabbits and men. However,'as above indicated, the in: troduction into solutions of this character :of ethanolin concentrationsywhich are easily metabolized and which are non-toxic greatlyreducesglycerol-induced hemolysis. Furthermore, various combinationsaof hexoses andethanol, likewise .in' concentrations which are readily metabq olizedand whichJarenon-toxic, will avoid glycerol-i111 duced hern olysisu This totally unexpected synergistic.
action is therefore responsible :for an entire new series of high-calorie intravenous solutions extremely valuable for injured-or sick individuals.
I claim: 1. An aqueous solution conta' g in each 1100 cc. there-. of from 2 to=6 grams ethanol; from 8 to 16 grams glycerol; andfrorn 8 to 16 "grams of a carbohydrate selected from the group :consisting; of glucose .and fructose with the weight of=carbohydrate being at least equal to the weight of glycerol.
2..A'method of intravenous fiu'idnutn'tioncomprising infusing into a patienty-a sterile non-pyrogenic solution containing in each. Kcc. thereof, from 2 to 6 grams ethanol, from 8 to 16 :grams glycerol, 'andfrom 8 to .16
grams of a carbohydrateselected from-the group consisting of glucose and fructose, with the weight of carbohydrate, being at least equal to the weightofglycerol.
New & Nonofiicial Remedies,1942-, pages. 418-425. Science News Letter, 621(17), page 265, Oct. 25', 1962. 'U.S.-Dispensatory 25, 1955,. pages 612 and 1737.
FRANKCACCIAPAGLIA, 1R1, Primary Examiner.
Claims (1)
- 2. A METHOD OF INTRAVENOUS FLUID NUTRITION COMPRISING INFUSING INTO A PATIENT A STERILE NON-PYROGENIC SOLUTION CONTAINING IN EACH 100 CC. THEREOF, FROM 2 TO 6 GRAMS ETHANOL, FROM 8 TO 16 GRAMS GLYCEROL, AND FROM 8 TO 16 GRAMS OF A CARBOHYDRATE SELECTED FROM THE GROUP CONSISTING OF GLUCOSE AND FRUCTOSE, WITH THE WEIGHT OF CARBOHYDRATE BEING AT LEAST EQUAL TO THE WEIGHT OF GLYCEROL.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US188249A US3234089A (en) | 1962-04-17 | 1962-04-17 | Non-toxic intravenous, high-calorie solution containing glycerol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US188249A US3234089A (en) | 1962-04-17 | 1962-04-17 | Non-toxic intravenous, high-calorie solution containing glycerol |
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| Publication Number | Publication Date |
|---|---|
| US3234089A true US3234089A (en) | 1966-02-08 |
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| Application Number | Title | Priority Date | Filing Date |
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| US188249A Expired - Lifetime US3234089A (en) | 1962-04-17 | 1962-04-17 | Non-toxic intravenous, high-calorie solution containing glycerol |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1982003987A1 (en) * | 1981-05-15 | 1982-11-25 | Travenol Lab Baxter | Dialysis solution containing clycerol |
| EP0199357A2 (en) * | 1985-04-25 | 1986-10-29 | TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION | Dialytic solution for peritoneal dialysis |
| WO1994025031A1 (en) * | 1993-04-30 | 1994-11-10 | University Of New Mexico | An exercise hydration regimen to enhance exercise endurance and performance |
| US5876763A (en) * | 1998-05-26 | 1999-03-02 | University Of New Mexico | Glycerol enhanced rehydration formulation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2977283A (en) * | 1956-04-30 | 1961-03-28 | Upjohn Co | Therapeutic intravenous fat compositions |
-
1962
- 1962-04-17 US US188249A patent/US3234089A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2977283A (en) * | 1956-04-30 | 1961-03-28 | Upjohn Co | Therapeutic intravenous fat compositions |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1982003987A1 (en) * | 1981-05-15 | 1982-11-25 | Travenol Lab Baxter | Dialysis solution containing clycerol |
| US4574085A (en) * | 1981-05-15 | 1986-03-04 | Baxter Travenol Laboratories, Inc. | Method for using dialysis solution containing glycerol |
| EP0199357A2 (en) * | 1985-04-25 | 1986-10-29 | TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION | Dialytic solution for peritoneal dialysis |
| EP0199357A3 (en) * | 1985-04-25 | 1988-08-10 | Terumo Kabushiki Kaisha Trading As Terumo Corporation | Dialytic solution for peritoneal dialysis |
| WO1994025031A1 (en) * | 1993-04-30 | 1994-11-10 | University Of New Mexico | An exercise hydration regimen to enhance exercise endurance and performance |
| US5403921A (en) * | 1993-04-30 | 1995-04-04 | University Of New Mexico | Exercise hydration regimen to enhance exercise endurance and performance |
| US5876763A (en) * | 1998-05-26 | 1999-03-02 | University Of New Mexico | Glycerol enhanced rehydration formulation |
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