US2695860A - Stabilized pteroyl solutions - Google Patents
Stabilized pteroyl solutions Download PDFInfo
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- US2695860A US2695860A US285090A US28509052A US2695860A US 2695860 A US2695860 A US 2695860A US 285090 A US285090 A US 285090A US 28509052 A US28509052 A US 28509052A US 2695860 A US2695860 A US 2695860A
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- acid
- ethylenediamine tetraacetic
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- pteroyl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S424/00—Drug, bio-affecting and body treating compositions
- Y10S424/06—Chelate
Definitions
- This invention relates to stabilized aqueous solutions containing folic acid or folic acid derivatives stabilized witi an alkali metal salt of ethylenediamine tetraacetic aci It has been difiicult to provide stable solutions containing folic acid or its derivatives for either oral or parenteral administration.
- Folic acid and its derivatives hereafter called pteroyl compounds, are fairly soluble in water provided that they are very pure and that the water is very pure and that the solution is freshly prepared. This lack of stability may in part be due to impurities, as for example, impurities picked up from the filter during sterile filtration at the time of.
- the pteroyl compound is so stabilized that it will remain in solution widiout precipitating over an extended period of time.
- the pH of the solution be alkaline preferably within the range of about 7 to about 10.
- a solution with a pH range of 8 to 9 is most stable and acceptable for injection.
- Commercially pure compounds may be used as the small amounts of impurities which are frequently found associated with pteroyl compounds or introduced when they are prepared 1 for solution no longer are deleterious. 1
- the sodium, potassium or lithium salts of ethylenediamine tetraacetic acid are particularly useful. Normally the sodium salt is used because it is physiologically more acceptable. These salts may be added as such or the ethylt enediamine tetraacetic acid may be added in its acid form and then at least partially neutralized in the solution, or the mono-, di-, trior tetra-alkali metal salts, or mixtures may be used.
- the neutralization of the ethylenediamine tetraacetic acid may be accomplished either by adjustment of the pH or by adding such derivatives of folic acid and other ingredients that the final pH is within the prescribed limits and the acidic characteristics of the ethylenediamine tetraacetic acid are at least partially neutralized by other components in the mixture. Any of the alkali metal salts of ethylenediamine tetraacetic acid may be added, or their mixtures.
- the pH for the respective hydrogens are about 2.3, 5.0, 8.4, and 10.3 so that the degree of replacement of hydrogens by metallic ions can be determined by pH measurement, and being an equilibrium reaction, is independent of the original salt or acid added
- the ethylenediamine tetraacetic acid and its alkali metal salts act in part as a buffer as all of its replaceable hydrogens are not replaced by the alkali metals during the preparation of the solution.
- the ethylenediamine tetraacetic acid is present in at least partially ionized form.
- the quantity of the ethylenediamine tetraacetic acid in part depends upon the quantities of impurities present, the length of time over which stability is required, the pH, and the concentrations of other ingredients. With higher pH solutions, less of the ethylenediamine tetraacetic acid or its salts is needed for stability. It is preferred that fairly pure ingredients be used, but the commercially available pharmaceutical grade pteroyl compounds are adequately stabilized by the addition of from .01 to .5 of ethylenediamine tetraacetic acid.
- folic acid itself but also such folic acid-containing materials as liver injection including both natural and synthetic liver extracts, and their equivalents, pteroylglutamylglutamylglutamate (Teropterin), 4-amino-10- methylpteroylglutamic acid (Amethopterin), 4-aminopteroylglutamic acid (Aminopterin), 4-aminopteroylaspartic acid (Arnino-An-Fol), 9-methylpteroylglutamic acid, 4- amin-9,lO-dimethylpteroylglutamic acid, N -formyltetrahydropteroylglutamic acid, 2,4-dihydroxypteroylglutamic acid, 2-methylaminopteroylglutamic acid, Z-dimethylaminopteroylglutamic acid, 4-methylaminopteroylglutamic acid, 4-dimethyl
- Example 1.-F0lic acid 1.86 parts of folic acid, 0.20 part of 90% distilled phenol and 0.20 part of the tetrasodium solt of ethylenediamine tetraacetic acid were dissolved in water and adjusted to a pH of 7.8 with sodium hydroxide and diluted to 100 volumes. A clear solution was formed which was filled into and sealed in ampoules. The ampoules were autoclaved for 30 minutes at pounds pressure and then stored at room temperature for 14 months. A very slightly hazy solution suitable for parenteral administration remained after the expiration of this time.
- Example 2 Folic acid A preparation similar to that formed in Example 1 was formed except that the pH was adjusted to 8.5 with sodium hydroxide, and found to remain clear and stable under each of the following conditions:
- Example 3.F0lic acid A solution was prepared in accordance with the procedure of Example 2 using the tetrapotassium salt of ethylenediamine tetraacetic acid, and potassium hydroxide for pH adjustment. On stability test, the solution appeared equivalent to that obtained in Example 2.
- Example 4.F0lic acid plus B12 8.4 grams of 88.7% folic acid, milligrams of crystalline vitamin B12 and 40 milligrams of the tetrasodium salt of ethylenediamine tetraacetic acid were added to 400 cc. of water, and the pH was adjusted to 9.0 with sodium hydroxide. The volume was brought up to 500 cc. The solution was sterile filtered and filled into ampoules and vials. The ampoules, after 9 months storage at room temperature in the dark, remained clear, with no loss-of activity.
- Example 5 Pteroyltriglutamate 10 grams of sodium pteroylglutamylglutamylglutamate was dissolved in 900 cc. of water; 2.6 grams of tetrasodium ethylenediamine tetraacetate and 6.5 cc. of phenol were added. The pH was adjusted to 7.8 with sodium hydroxide and the volume was brought up to 1300 cc. This product remained clear and stable for 6 months at room temperature. A control without the tetrasodium ethylenediamine tetraacetate precipitated. Both products precipitated when stored at 3 C. but when reheated to room temperature, the sample containing the ethylenediamine tetraacetic acid redissolved. The product without the ethylenediamine tetraacetic acid did not redissolve.
- Example 6 Liver injection 0.2 gram of the tetrasodium salt of ethylenediamine tetraacetic acid were added to 100 cc. of 15 unit liver injection containing 5 milligrams per cc. of folic acid. The solution remained clear after a year in a dark room at room temperature. Some batches of liver injection required more than 0.2% of the ethylenediamine tetraacetic acid to insure stability.
- Example 7 Liver injection 0.5 gram of the tetrasodium salt of ethylenediamine tetraacetic acid were added to 100 cc. of 15 unit liver injection, United States Pharmacopoeia XIV. A clear stable solution was formed which remained clear at the end of one year, whereas the untreated solution had become hazy. The United States Pharmacopoeia mentions that liver injection may become hazy. It is always desirable that injectable solutions be clear.
- Example 8.4-amin0-10-methylpteroylglutamic acid A solution was prepared by dissolving 0.5 gram of 4- amino-IO-methylpteroylglutamic acid and 0.4 gram of 90% distilled phenol in water. .01% by weight of ethylenediamine tetraacetic acid as the free acid was added, and the pH of the solution adjusted to 8.5 with sodium hydroxide, and the volume to 100 milliliters. The solution was sterile filtered into ampoules, and sealed. The solution remained clear and stable for 9 months at room temperature in daylight.
- concentrations of pteroyl compounds and other preparations containing pteroyl compounds may be prepared in accordance with our invention.
- concentrations and proportions may be varied over an extremely wide range in accordance with the requirements of a particular subject.
- a storage stable aqueous solution comprising from .01 to .5% by weight of an alkali metal salt of ethylenediamine tetraacetic acid and not less than about 0.5% by weight of at least one pteroyl compound, the pH of said solution being between approximately pH 7 and pH 10.
- a storage stable aqueous solution having a pH between about 7 and comprising from .01 to .5% by weight of an alkali metal salt of ethylenediamine tetraacetic acid and not less than about 0.5% by weight of a pteroyl compound selected from the group consisting of folic acid, pteroylglutamylglutamylglutamate, 4-amino-l0- methylpteroylglutamic acid, taminopteroylglutamic acid, 4-aminopteroylaspartic acid, 9-rnethylpteroylglutamic acid, 4-amino-9,lO-dimethylpteroylglutamic acid, N formyltetrahydropteroylglutamic acid, 2,4-dihydroxypteroylglutamic acid, 2-methylaminopteroylglutamic acid, 2-dimethylaminopteroylglutamic acid, 4-methylaminopteroylglutamic acid,
Description
United States Patent fice 2,695,860 Patented Nov. 30, 1954 STABILIZED PTEROYL SOLUTIONS Joseph Francis Weidenheimer and Jens Thuroe Carstensen, Orangeburg, N. Y., assignors to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application April 29, 1952, Serial No. 285,090
12 Claims. (Cl. 167-65) This invention relates to stabilized aqueous solutions containing folic acid or folic acid derivatives stabilized witi an alkali metal salt of ethylenediamine tetraacetic aci It has been difiicult to provide stable solutions containing folic acid or its derivatives for either oral or parenteral administration. Folic acid and its derivatives, hereafter called pteroyl compounds, are fairly soluble in water provided that they are very pure and that the water is very pure and that the solution is freshly prepared. This lack of stability may in part be due to impurities, as for example, impurities picked up from the filter during sterile filtration at the time of. filling the pteroyl compounds into ampoules tends to shorten shelf life. On standing, the pteroyl compounds tend to precipitate out, usually as dark precipitates. Other stabilizing and sequestering agents such as gluconic acid, glutamic acid and the polyphosphate complexes do not stabilize the pteroyl solutions.
For oral administration, if a viscous carrier is used such precipitates do permit administration if the user is not fastidious. It is extremely undesirable to administer such precipitated compounds parenterally. As a result, it has been difficult to prepare pteroyl compounds for parenteral administration. Return rates have been high, and the product has a short shelf life.
We have found that by dissolving from .01 to .5% of an alkali metal salt of ethylenediamine tetraacetic acid in the aqueous solution, the pteroyl compound is so stabilized that it will remain in solution widiout precipitating over an extended period of time. We prefer that the pH of the solution be alkaline preferably within the range of about 7 to about 10. A solution with a pH range of 8 to 9 is most stable and acceptable for injection. Commercially pure compounds may be used as the small amounts of impurities which are frequently found associated with pteroyl compounds or introduced when they are prepared 1 for solution no longer are deleterious. 1
The sodium, potassium or lithium salts of ethylenediamine tetraacetic acid are particularly useful. Normally the sodium salt is used because it is physiologically more acceptable. These salts may be added as such or the ethylt enediamine tetraacetic acid may be added in its acid form and then at least partially neutralized in the solution, or the mono-, di-, trior tetra-alkali metal salts, or mixtures may be used. The neutralization of the ethylenediamine tetraacetic acid may be accomplished either by adjustment of the pH or by adding such derivatives of folic acid and other ingredients that the final pH is within the prescribed limits and the acidic characteristics of the ethylenediamine tetraacetic acid are at least partially neutralized by other components in the mixture. Any of the alkali metal salts of ethylenediamine tetraacetic acid may be added, or their mixtures. With the sodium salt the pH for the respective hydrogens are about 2.3, 5.0, 8.4, and 10.3 so that the degree of replacement of hydrogens by metallic ions can be determined by pH measurement, and being an equilibrium reaction, is independent of the original salt or acid added The ethylenediamine tetraacetic acid and its alkali metal salts act in part as a buffer as all of its replaceable hydrogens are not replaced by the alkali metals during the preparation of the solution. The ethylenediamine tetraacetic acid is present in at least partially ionized form.
The quantity of the ethylenediamine tetraacetic acid in part depends upon the quantities of impurities present, the length of time over which stability is required, the pH, and the concentrations of other ingredients. With higher pH solutions, less of the ethylenediamine tetraacetic acid or its salts is needed for stability. It is preferred that fairly pure ingredients be used, but the commercially available pharmaceutical grade pteroyl compounds are adequately stabilized by the addition of from .01 to .5 of ethylenediamine tetraacetic acid. Among the materials which may be stabilized in accordance with our invention s not only folic acid itself but also such folic acid-containing materials as liver injection including both natural and synthetic liver extracts, and their equivalents, pteroylglutamylglutamylglutamate (Teropterin), 4-amino-10- methylpteroylglutamic acid (Amethopterin), 4-aminopteroylglutamic acid (Aminopterin), 4-aminopteroylaspartic acid (Arnino-An-Fol), 9-methylpteroylglutamic acid, 4- amin-9,lO-dimethylpteroylglutamic acid, N -formyltetrahydropteroylglutamic acid, 2,4-dihydroxypteroylglutamic acid, 2-methylaminopteroylglutamic acid, Z-dimethylaminopteroylglutamic acid, 4-methylaminopteroylglutamic acid, 4-dimethylaminopteroylglutamic acid, and other compounds containing a pteroyl structure. These compounds may be present as their alkali metal salts, depending on the pH of the solution.
Certain specific solutions embodying our invention may be prepared as follows.
Example 1.-F0lic acid 1.86 parts of folic acid, 0.20 part of 90% distilled phenol and 0.20 part of the tetrasodium solt of ethylenediamine tetraacetic acid were dissolved in water and adjusted to a pH of 7.8 with sodium hydroxide and diluted to 100 volumes. A clear solution was formed which was filled into and sealed in ampoules. The ampoules were autoclaved for 30 minutes at pounds pressure and then stored at room temperature for 14 months. A very slightly hazy solution suitable for parenteral administration remained after the expiration of this time.
Example 2.Folic acid A preparation similar to that formed in Example 1 was formed except that the pH was adjusted to 8.5 with sodium hydroxide, and found to remain clear and stable under each of the following conditions:
(a) 7 weeks at 42 C.
(b) 1 year at room temperature in the dark.
1 1(10) 1 year at room temperature when exposed to dayig t.
(d) 1 year at 3 C. in the dark.
Without the salt of ethylenediamine tetraacetic acid, a comparable'preparation precipitated after 7 weeks at 42 C. and precipitated on standing for a year exposed to light.
Example 3.F0lic acid A solution was prepared in accordance with the procedure of Example 2 using the tetrapotassium salt of ethylenediamine tetraacetic acid, and potassium hydroxide for pH adjustment. On stability test, the solution appeared equivalent to that obtained in Example 2.
Example 4.F0lic acid plus B12 8.4 grams of 88.7% folic acid, milligrams of crystalline vitamin B12 and 40 milligrams of the tetrasodium salt of ethylenediamine tetraacetic acid were added to 400 cc. of water, and the pH was adjusted to 9.0 with sodium hydroxide. The volume was brought up to 500 cc. The solution was sterile filtered and filled into ampoules and vials. The ampoules, after 9 months storage at room temperature in the dark, remained clear, with no loss-of activity.
Example 5 .Pteroyltriglutamate 10 grams of sodium pteroylglutamylglutamylglutamate was dissolved in 900 cc. of water; 2.6 grams of tetrasodium ethylenediamine tetraacetate and 6.5 cc. of phenol were added. The pH was adjusted to 7.8 with sodium hydroxide and the volume was brought up to 1300 cc. This product remained clear and stable for 6 months at room temperature. A control without the tetrasodium ethylenediamine tetraacetate precipitated. Both products precipitated when stored at 3 C. but when reheated to room temperature, the sample containing the ethylenediamine tetraacetic acid redissolved. The product without the ethylenediamine tetraacetic acid did not redissolve.
Example 6.-Liver injection 0.2 gram of the tetrasodium salt of ethylenediamine tetraacetic acid were added to 100 cc. of 15 unit liver injection containing 5 milligrams per cc. of folic acid. The solution remained clear after a year in a dark room at room temperature. Some batches of liver injection required more than 0.2% of the ethylenediamine tetraacetic acid to insure stability.
Example 7.-Liver injection 0.5 gram of the tetrasodium salt of ethylenediamine tetraacetic acid were added to 100 cc. of 15 unit liver injection, United States Pharmacopoeia XIV. A clear stable solution was formed which remained clear at the end of one year, whereas the untreated solution had become hazy. The United States Pharmacopoeia mentions that liver injection may become hazy. It is always desirable that injectable solutions be clear.
Example 8.4-amin0-10-methylpteroylglutamic acid A solution was prepared by dissolving 0.5 gram of 4- amino-IO-methylpteroylglutamic acid and 0.4 gram of 90% distilled phenol in water. .01% by weight of ethylenediamine tetraacetic acid as the free acid was added, and the pH of the solution adjusted to 8.5 with sodium hydroxide, and the volume to 100 milliliters. The solution was sterile filtered into ampoules, and sealed. The solution remained clear and stable for 9 months at room temperature in daylight.
Other concentrations of pteroyl compounds and other preparations containing pteroyl compounds may be prepared in accordance with our invention. The concentrations and proportions may be varied over an extremely wide range in accordance with the requirements of a particular subject.
As our invention, we claim:
1. A storage stable aqueous solution comprising from .01 to .5% by weight of an alkali metal salt of ethylenediamine tetraacetic acid and not less than about 0.5% by weight of at least one pteroyl compound, the pH of said solution being between approximately pH 7 and pH 10.
2. A storage stable aqueous solution having a pH between about 7 and comprising from .01 to .5% by weight of an alkali metal salt of ethylenediamine tetraacetic acid and not less than about 0.5% by weight of a pteroyl compound selected from the group consisting of folic acid, pteroylglutamylglutamylglutamate, 4-amino-l0- methylpteroylglutamic acid, taminopteroylglutamic acid, 4-aminopteroylaspartic acid, 9-rnethylpteroylglutamic acid, 4-amino-9,lO-dimethylpteroylglutamic acid, N formyltetrahydropteroylglutamic acid, 2,4-dihydroxypteroylglutamic acid, 2-methylaminopteroylglutamic acid, 2-dimethylaminopteroylglutamic acid, 4-methylaminopteroylglutamic acid, and 4-dimethylaminopteroylglutamic acid.
3. A storage stable aqueous solution having a pH between about 7 and 10, comprising from .01 to .5% by weight of an alkali metal salt of ethylenediamine tetraacetic acid and not less than about 0.5% by weight of folic acid.
4. A storage stable aqueous solution having a pH between about 7 and 10, comprising from .01 to .5% by weight of an alkali metal salt of ethylenediamine tetraacetic acid and not less than about 0.5% by weight of 4-amino-10-methylpteroylglutamic acid.
5. A storage stable aqueous solution having a pH between about 7 and 10, comprising from .01 to .5% by weight of an alkali metal salt of ethylenediamine tetraacetic acid and not less than about 0.5% by weight of 4-aminopteroylglutamic acid.
6. A storage stable aqueous solution having a pH between about 7 and 10, comprising from .01 to .5% by weight of an alkali metal salt of ethylenediamine tetraacetic acid and not less than about 0.5% by weight of 4-aminopteroylaspartic acid.
7. A storage stable aqueous solution having a pH between about 7 and 10, comprising from .01 to .5% by weight of an alkali metal salt of ethylenediamine tetraacetic acid and not less than about 0.5% by weight of N -formyltetrahydropteroylglutamic acid. I
8. A storage stable aqueous solution having a pH between about 7 and 10, comprising from .01 to .5% by weight of a sodium salt of ethylenediamine tetraacetic acid and not less than about 0.5% by weight of folic acid.
9. A storage stable aqueous solution having a pH between about 7 and 10, comprising from .01 to .5% by weight of a sodium salt of ethylenediamine tetraacetic acid and not less than about 0.5% by weight of 4-aminolO-methylpteroylglutamic acid.
10. A storage stable aqueous solution having a pH between about 7 and 10, comprising from .01 to .5% by weight of a sodium salt ofethylenediamine tetraacetic acid and not less than about 0.5% by weight of 4-aminopteroylglutamic acid.
11. A storage stable aqueous solution having a pH between about 7 and 10, comprising from .01 to .5% by weight of a sodium salt of ethylenediamine tetraacetic acid and not less than about 0.5% by weight of 4-aminopteroylaspartic acid.
12. A storage stable aqueous solution having a pH between about 7 and 10, comprising from .01 to .5% by weight of a sodium salt of ethylenediamine tetraacetic acid and not less than about 0.5% by weight of N formyltetrahydropteroylglutamic acid.
References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,193,717 Faust Mar. 12, 1940 2,554,625 McFee May 29, 1951 OTHER REFERENCES Jager, Die Pharm., 1948, vol. 3, No. 12, pgs. 536 to 537. slcheindlin, Am. Jour. Pharm., April 1948, pgs. 103 to 11.
Claims (1)
1. A STORAGE STABLE AQUEOUS SOLUTION COMPRISING FROM .01 TO .5% BY WEIGHT OF AN ALKALI METAL SALT OF ETHYLENEDIAMINE TETRAACETIC ACID AND NOT LESS THAN ABOUT 0.5% BY WEIGHT OF AT LEAST ONE PTEROYL COMPOUND, THE PH OF SAID SOLUTION BEING BETWEEN APPROXIMATELY PH 7 AND PH 10.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US285090A US2695860A (en) | 1952-04-29 | 1952-04-29 | Stabilized pteroyl solutions |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US285090A US2695860A (en) | 1952-04-29 | 1952-04-29 | Stabilized pteroyl solutions |
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| US2695860A true US2695860A (en) | 1954-11-30 |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2731390A (en) * | 1953-02-12 | 1956-01-17 | American Cyanamid Co | Stabilized folic acid and vitamin composition |
| US2804423A (en) * | 1953-10-15 | 1957-08-27 | Sahyun Melville | Iron-vitamin composition |
| US2823167A (en) * | 1955-03-29 | 1958-02-11 | Vitarine Co Inc | Stable vitamin b12-containing solution |
| US4931442A (en) * | 1987-12-07 | 1990-06-05 | Holger Blum | Stabilized aqueous folic acid preparation |
| EP0401895A1 (en) * | 1989-06-06 | 1990-12-12 | Pharmachemie B.V. | Aqueous folinate solution stable at refrigerator temperature, as well as process for its preparation |
| EP0416232A2 (en) * | 1989-08-21 | 1991-03-13 | American Cyanamid Company | Stable injectable pharmaceutical formulation for folic acid and leucovorin salts and method |
| US5173488A (en) * | 1989-08-21 | 1992-12-22 | American Cyanamid Company | Stable injectable pharmaceutical formulation for folic acid and leucovorin salts and method |
| US5223500A (en) * | 1977-02-22 | 1993-06-29 | Bioresearch S.P.A. | Stable pharmaceutical composition of alkaline or alkaline earth 5-methyl tetrahydrofolate |
| EP0667159A2 (en) * | 1994-02-14 | 1995-08-16 | Cerbios-Pharma S.A. | Concentrated injectable solution of alcaline metal salts of reduced folates |
| WO1995026963A1 (en) * | 1994-04-05 | 1995-10-12 | Pharmachemie B.V. | Stable aqueous folinate solution |
| WO2007014644A1 (en) * | 2005-08-01 | 2007-02-08 | Beiersdorf Ag | Stable active-ingredient combinations based on folic acid |
| WO2007014643A1 (en) * | 2005-08-01 | 2007-02-08 | Beiersdorf Ag | Stable active-substance combinations based on folic acid |
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|---|---|---|---|---|
| US2193717A (en) * | 1938-06-09 | 1940-03-12 | Ig Farbenindustrie Ag | Process for preventing the congealing of blood |
| US2554625A (en) * | 1949-11-10 | 1951-05-29 | Gorton Pew Fisheries Company L | Process of canning seafood and resultant product |
-
1952
- 1952-04-29 US US285090A patent/US2695860A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2193717A (en) * | 1938-06-09 | 1940-03-12 | Ig Farbenindustrie Ag | Process for preventing the congealing of blood |
| US2554625A (en) * | 1949-11-10 | 1951-05-29 | Gorton Pew Fisheries Company L | Process of canning seafood and resultant product |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2731390A (en) * | 1953-02-12 | 1956-01-17 | American Cyanamid Co | Stabilized folic acid and vitamin composition |
| US2804423A (en) * | 1953-10-15 | 1957-08-27 | Sahyun Melville | Iron-vitamin composition |
| US2823167A (en) * | 1955-03-29 | 1958-02-11 | Vitarine Co Inc | Stable vitamin b12-containing solution |
| US5223500A (en) * | 1977-02-22 | 1993-06-29 | Bioresearch S.P.A. | Stable pharmaceutical composition of alkaline or alkaline earth 5-methyl tetrahydrofolate |
| US4931442A (en) * | 1987-12-07 | 1990-06-05 | Holger Blum | Stabilized aqueous folic acid preparation |
| EP0401895A1 (en) * | 1989-06-06 | 1990-12-12 | Pharmachemie B.V. | Aqueous folinate solution stable at refrigerator temperature, as well as process for its preparation |
| US5177076A (en) * | 1989-06-06 | 1993-01-05 | Pharmachemie Bv | Aqueous folinate solution stable at refrigerator temperature, as well as process for its preparation |
| US5173488A (en) * | 1989-08-21 | 1992-12-22 | American Cyanamid Company | Stable injectable pharmaceutical formulation for folic acid and leucovorin salts and method |
| AU628211B2 (en) * | 1989-08-21 | 1992-09-10 | Wyeth Holdings Corporation | Stable injectable pharmaceutical formulation for folic acid and leucovorin salts and method |
| EP0416232A3 (en) * | 1989-08-21 | 1992-01-02 | American Cyanamid Company | Stable injectable pharmaceutical formulation for folic acid and leucovorin salts and method |
| EP0416232A2 (en) * | 1989-08-21 | 1991-03-13 | American Cyanamid Company | Stable injectable pharmaceutical formulation for folic acid and leucovorin salts and method |
| EP0667159A2 (en) * | 1994-02-14 | 1995-08-16 | Cerbios-Pharma S.A. | Concentrated injectable solution of alcaline metal salts of reduced folates |
| EP0667159A3 (en) * | 1994-02-14 | 1995-11-29 | Cerbios Pharma Sa | Concentrated injectable solution of alcaline metal salts of reduced folates. |
| US5814635A (en) * | 1994-02-14 | 1998-09-29 | Cerbios-Pharma S.A. | Concentrated injection solution of alkali metal salts of reduced folates |
| WO1995026963A1 (en) * | 1994-04-05 | 1995-10-12 | Pharmachemie B.V. | Stable aqueous folinate solution |
| NL9400530A (en) * | 1994-04-05 | 1995-11-01 | Pharmachemie Bv | Stable aqueous folinate solution. |
| US6613767B1 (en) | 1994-04-05 | 2003-09-02 | Pharmachemie B.V. | Stable aqueous folinate solution |
| WO2007014644A1 (en) * | 2005-08-01 | 2007-02-08 | Beiersdorf Ag | Stable active-ingredient combinations based on folic acid |
| WO2007014643A1 (en) * | 2005-08-01 | 2007-02-08 | Beiersdorf Ag | Stable active-substance combinations based on folic acid |
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