CA1328809C - Compositions and methods for administering vitamin c - Google Patents
Compositions and methods for administering vitamin cInfo
- Publication number
- CA1328809C CA1328809C CA000563727A CA563727A CA1328809C CA 1328809 C CA1328809 C CA 1328809C CA 000563727 A CA000563727 A CA 000563727A CA 563727 A CA563727 A CA 563727A CA 1328809 C CA1328809 C CA 1328809C
- Authority
- CA
- Canada
- Prior art keywords
- vitamin
- acid
- compound
- ascorbate
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
Abstract
ABSTRACT
A composition useful for administering Vitamin C
to a subject comprises a compound having Vitamin C activity and at least one compound selected from the class consisting of the aldono-lactones and edible salts of L-threonic, L-xylonic and L-lyxonic acids. High Vitamin C
levels in the human body are established by orally administering to a human subject an effective amount of this composition.
A composition useful for administering Vitamin C
to a subject comprises a compound having Vitamin C activity and at least one compound selected from the class consisting of the aldono-lactones and edible salts of L-threonic, L-xylonic and L-lyxonic acids. High Vitamin C
levels in the human body are established by orally administering to a human subject an effective amount of this composition.
Description
~` ' 32QQnq -- 1 -- ., This invention relates to an improved form of Vitamin C.
In another respect, the invention concerns improved methods for establishing Vitamin C levels in the human body.
In yet another respect, the invention pertains to methods for improving the human body tolerance to Vitamin C.
In still another respect, the invention relates to a Vitamin C derivative composition which i5 more effectively absorbed and retained in human and animal bodies.
Prior workers have identified over 300 separate metabolic mechanisms in which Vitamin C is involved in physiologic reactions. These mechanisms range from the antiscorbutic effect first observed by Dr. Robert Lind in 1740 to more recently discovered anti-oxidant free-radical scavenging reactions, to co-reaction with enzymes in the formation of collagen, energy metabolism accentuation in the polynuclear-leucosites and facilitation of iron absorption.
The clinical effects of such metabolic reactions have been widely recognized and reported. For example, the free-radical scavenging effect is believed to enable the body to convert carcinogens to non-toxic derivatives which are eliminated in the urine and, consequently, to ameliorate the effect~ of smoking and exposure of the body to other environmental pollutants. Animal studies have demonstrated that body enzymes convert ascorbates to oxidation products ~ which have demonstrated tumor growth inhibition.
! Consequently, there is little scientific doubt that the establishment and maintenance of effective levels of Vitamin C and its derivatives in the human body yield ~ 30 important health advantages. The presence of Vitamin C in - substantial concentration has been observed in the adrenals, ovarie~, brain, pituitaries, liver spleen, blood cells, blood ~erum, and extra-cellular lung liquids.
Nost animal~ have a liver enzyme which enables them to actually manufacture Vitamin C in situ by conversion of blood sugar into ascorbic acid. However, humans do not have ~ this enzyme. As a consequence, the Vitamin C which is ..
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1 3~8809 ..
In another respect, the invention concerns improved methods for establishing Vitamin C levels in the human body.
In yet another respect, the invention pertains to methods for improving the human body tolerance to Vitamin C.
In still another respect, the invention relates to a Vitamin C derivative composition which i5 more effectively absorbed and retained in human and animal bodies.
Prior workers have identified over 300 separate metabolic mechanisms in which Vitamin C is involved in physiologic reactions. These mechanisms range from the antiscorbutic effect first observed by Dr. Robert Lind in 1740 to more recently discovered anti-oxidant free-radical scavenging reactions, to co-reaction with enzymes in the formation of collagen, energy metabolism accentuation in the polynuclear-leucosites and facilitation of iron absorption.
The clinical effects of such metabolic reactions have been widely recognized and reported. For example, the free-radical scavenging effect is believed to enable the body to convert carcinogens to non-toxic derivatives which are eliminated in the urine and, consequently, to ameliorate the effect~ of smoking and exposure of the body to other environmental pollutants. Animal studies have demonstrated that body enzymes convert ascorbates to oxidation products ~ which have demonstrated tumor growth inhibition.
! Consequently, there is little scientific doubt that the establishment and maintenance of effective levels of Vitamin C and its derivatives in the human body yield ~ 30 important health advantages. The presence of Vitamin C in - substantial concentration has been observed in the adrenals, ovarie~, brain, pituitaries, liver spleen, blood cells, blood ~erum, and extra-cellular lung liquids.
Nost animal~ have a liver enzyme which enables them to actually manufacture Vitamin C in situ by conversion of blood sugar into ascorbic acid. However, humans do not have ~ this enzyme. As a consequence, the Vitamin C which is ..
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1 3~8809 ..
required by the human body for the various metabolic reactions discussed above must be ingested with the human diet.
, Furthermore, the human body does not have the ability to store -~ Vitamin C -- if unmetabolized, it is excreted. Low levels of Vitamin C and its derivatives in the human body produce a variety of undesirable physiological responses and extremely low levels produce extreme responses which may result in death, e.g., from scurvy. Wholly apart from these "normal"
requirements of vitamin C, it i8 important in some therapeutic ~, 10modalities to establish and maintain above-normal Vitamin C
levels in the body. These above-normal concentrations are difficult to establish and maintain because the human body ~ exhibits only a finite tolerance for Vitamin C ascorbic acid - with resultant diarrhea and other side reactions, such as gastric irritation and inflammation if these tolerances are exceeded.
; I have now discovered compositions and methods for ~, improving the establishment and maintenance of high levels of Vitamin C (including its derivatives) in the human body.
Briefly, the composition which I have discovered comprises a compound having Vitamin C activity and at least one compound selected from the class consisting of the aldono-lactones and `;edible salts of L-threonic, L-xylonic and L-lykonic acids.
~A method which I have discovered for establishing '; ~ . : -.;:
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'Vitamin c levels in the human body includes the step of orally administering this composition to a subject.
Another method of the invention comprises thestep of converting L-ascorbic acid to this composition and orally administering this composition to the subject.
According to one aspect of the present invention, there is provided a vitamin composition comprising:
I(a) an effective amount of a compound having Vitamin C activity, selected from the group consisting of dehydroascorbic acid and the edible salts thereof, and L-ascorbic acid and the edible salts thereof; and (b) at least one compound selected from the group -¦consisting of the aldono-lactones of L-threonic acid, L-xylonic acid and L-lyxonic acid and the edible salts of L-;15 threonic acid, L-xylonic acid and L-lyxonic acid, in an amount effective to increase the human body absorption rate of said Vitamin C compound.
~According to another aspect of the present ;invention, there is provided a use of a metabolite to -,20 improve the body absorption rate of a compound having Vitamin C activitywherein the metabolite is selected from the group consisting of the aldono-lactones and edible salts of L-threonic, L-xylonic and L-lyxonic acids.
According to a further aspect of the present invention, there is provided a use of the above-mentioned vitamin composition to establish high Vitamin C levels in the human body.
According to yet another aspect of the present invention, there is provided a use of L-ascorbic acid to establish Vitamin C levels in a subject comprising:
(a) converting the L-ascorbic acid to a composition comprising:
'(i) a compound having Vitamin C activity; and (ii) at least one compound selected from the group consisting of the aldono-lactones and edible salts of L-threonic, L-xylonic and L-lyxonic acids; and .. . .
1 3288~9 - 3a -(b) orally administering said composition to said subject.
According to still another aspect of the present invention, there is provided a use of the above-mentioned vitamin composition to treat arthritis.
As used herein, the term "compound having Vitamin C activity" means Vitamin C (L-ascorbic acid) and any derivative thereof which exhibits antiscorbutic activity.
Such derivatives include, for example, oxidation products such as dehydroascorbic acid and edible salts of ascorbic acid such as, illustratively, calcium, sodium, magnesium, potassium and zinc ascorbates.
The metabolites of ascorbic acid and its derivatives include the aldono-lactones and edible salts of aldonic acids. As will appear, the compositions of the present invention are characterized by the presence of at least one or more of these metabolites corresponding to three specific aldonic acids: L-threonic acid, L-xylonic acid and L-lyxonic acid.
ZO The presence of one or more of these metabolites in the compositions of the invention is both a convenient -~ way of identifying such compositions and is also necessary to achieve the desired result, improvement in Vitamin C
absorption and/or retention. -The component of the compositions of the invention which, as indicated above, has "Vitamin C~ -~i activity" can be L-ascorbic acid or any of its derivatives which have the ability to provide the ascorbic/ascorbate --moiety in physiologic processes, e.g., dehydroascorbic acid, calcium and sodium ascorbate which are most commonly employed in Vitamin C food supplements, as well as a wide variety of other edible (non-toxic in appropriate quantity) -salts such as potassium, sodium, magnesium and zinc ' ascorbate. In general, any ~uch compound which exhibits 35 Vitamin C -'' ~"
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, ......................................................................... ........ .~ ,, activity will suffice.
.~ A suitable method for preparing the compositions of the invention comprises reacting L-a~corbic acid with a non-toxic metal compound, e.g., calcium carbonate, sodium ~ 5 bicarbonate, under oxidizing conditions at an elevated - temperature, e.g., 400c-980c, to convert a substantialproportion of the ascorbic acid to its corresponding salt, ~-¦ e.g., calcium or sodium ascorbate, and drying the reaction mixture to produce a solid product of essentially neutral pH
(e.g., 6.0-7.5). Preferably a slight stoichiometric excess of the metal salt reactant is provided. The resultant product has an iodine ascorbate assay in the range 50-480 mg./500 mg.
sample depending upon process parameters, with the higher activity preferred for practical reasons. Longer heating at oxidizing conditions produces lower iodine ascorbate assays.
¦ The co~position~ of the invention appear useful in administering Vitamin C to patients who have low ascorbic acid tolerance. In particular, patients who have a tendency to form kidney stones are particularly susceptible to ¦ 20 difficulties when ingesting ascorbic acid and its common derivative, calcium ascorbate, which cause elevated urine oxalate levels. There are indications that the compositions of the present invention can be administered without increasing the oxalate level in the urine to the levels encountered when the prior art compositions and methods are especially suitable as a means of establishing and maintaining ~s~ ascorbate body level~ in guch kidney stone-prone subjects.
~ The compo~ition~ of the invention also appear to be i useful in the treatment of inflammatory diseases, such as `:..1 arthritis.
The following examples are presented for purposes ~ -of illustrating the practice of the invention and are not intended as limitations on the scope thereof. ~-~
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^-i 35 To an 80-gallon, steam-heated stainless steel ~ reaction vessel was added 60 lbs. of hot (44C) water. ;-Ascorbic acid-U.S.P., 110.23 lbs., was added in one portion to the hot water. The resulting slurry was mechanically stirred and heated with steam (pressure 15 p.s.i.) until a temperature of 70C was achieved.
To the aqueous slurry of ascorbic acid was added 23 lbs. of calcium carbonate. The incremental addition of the carbonate required 3-4 minutes. The reaction mixture appeared gray in color and much foaming due to the evolution of Co2 was evident. After eight minutes of stirring, most of the foaming had subsided and the reaction mixture appeared red-brown in color. The solution temperature was 80C. Stirring and heating were continued for 15 minutes until the temperature ~ -of the reaction mixture reached 98C where it was maintained for an additional 20 minutes, after which an additional 8.25 lbs. of calcium carbonate was added, with stirring.
- After foaming ceased, the reaction mixture was then pumped to a double-drum steam-heated dryer (surface temperature approximately 250F). The pumping-drying step required 35 minutes. The dried product was light-tan color and the yield was approximately 120 pounds of product.
Optionally, air can be bubbled through the reaction ~ mixture to promote the reaction of the ascorbic acid.
-,~ Assays were performed immediately on 5.00 g. samples ~
dissolved in 500 ml. distilled water. --The material collected during the drying process showed 400 mg. anhydrous calcium ascorbate per 500 mg. by this standard iodine titration technique. The same aqueous solution showed pH 7Ø
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The following example describes clinical tests 1 co~paxing the product of Example 1 (test material with L-ascorbic acid and citric acid (placebo), measuring ~
intracellular ascorbate levels, urinary ascorbate output and -`
urinary oxalate excretion at various times after ingestion of standard doses of the test, L-ascorbic acid and placebo.
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Summary of the Protocol Twelve men, ages 27 to 45, were studied.
All were instructed that they should be on a low Vitamin C diet for one week prior to the study (no citrus products and no large amounts of green leafy vegetables).
Following overnight fast, blood and 24-hour urine samples were taken. White blood cell and 24-hour urinary ascorbate and oxalate levels were determined and correlated with serum ascorbate levels.
~3 10 The 12 men were divided into three groups, and were 'l given the following supplements:
(a) Test Group: 4000 MG* per day of the product Ex. 1.
(b) Ascorbate Group: 3000 MG of L-ascorbic per day.
(c) Citric Acid Group: 3000 MG of citric acid per day.
All 12 continued on a low Vitamin C diet. Blood samples were taken at 0, 4, 8 and 24 hours after morning ingestion of the designated supplements. Urinary 24-hour ascorbate and oxalate levels were determined.
¦ After a wash-out period (varying from two days to several days, due to job situation of participants), the ~ groups were switched to another supplement, as follows:
,~ (a) Test group to citrate group.
(b) Citrate group to ascorbate group.
(c) Ascorbate group to test group.
Supplements were taken at the same leYel (4000 MG
of Ex. 1 product, 3000 MG of L-ascorbic and 3000 MG of citric acid) by all three groups. Blood samples were again drawn at 0, 4, 8 and 24 hours from time of ingestion. A 24-hour urine was also collected by all 12 participants at the end of the ~ period. A~ain, all specimens were analyzed for their 1i respective concentration of ascorbate and oxalate levels.
-~ 35 *4000 MG is equivalent in ascorbate (iodine test) to 3000 MG
ascorbic acid.
, ~ .
.~ 1 32880q AnalYtical Procedures The analytical procedures utilized are described in: Clinical ChemistrY Principles and Technii~ues, j edited by Richard J. Henry, Donald D. cannon and James W. Windelman, Harper and Row, 1974, p. 1393-1398.
Standard Methods of Clinical Chemistry, J.S. Roe, edited by Seligson D. New York, Academic Press, 1961, Vol. 3, p. 35-~` In the quantitation of 24-hour urine oxalate, an aliguot of urine i~ ~haken with an absorbent which selectively bind~ the oxalate. The extracted urine i~ discarded and the oxalate i~ eluted from the absorbent with dilute alkali.
Oxalate i8 oxidized to hydrogen peroxide and carbon ~j dioxide by oxalate oxidase. The hydrogen peroxide react~ with 3 methyl-2-benzothiszolinone hydrazone (NBTH) and -` 3(dimethylamino) benzoic acid (DMAB~ in the presence of 'J peroxidas,e,to yield an indamine dye with a maximum absorbance ~ at 590 NM.
`l The urine oxalate test is furthex described in the -~ 20 following references:
Hodgekinson, A.: Oxalic Acid in Violo~v and ~Q9lin~, Acedemic Press, New York, 1977.
Robertson, W.D.; Rutherford, A.: AsPects of the ~-Analv~is of Oxalate in Urine, Scan J. Uro Nephrol, Suppl. 53, p. 85, 1979. -~
Lamden, N.P.; Chrystow~ki, G.A.: Urinary Oxalat~ -Excretion ~y Main Followin~3 Ascorbine Ac~d Inae~,tion, Prog. Soo. Exp. Biol.
Med. 85:190, 1954.
Co~,t~,llo, J.:
Oxalate Metaboli~m in Hu~,an Biochemistxy ~ and Clinical Patholo~v, edited by G.A.
;~ Rose, W.G. Robert~on and R.W.E. Watts.
Proceedings of an International Meeting ;~ 35 $n London, 1971, pp. 270-273.
~` The results of this clinical study are set forth below:
'.: ' .,,' ,, 1 32ssnq Table 1 Percent Change*
' in Group citrate L-ascorbic Test Serum Ascorbate Level 4th Hour 10 180. 3 264. 8 8th Hour 19.6 91.6 144.2 ~ 24th Hour 5.9 24.6 56.2 J 107th Day 45.3 102.5 White Blood Cell (WBC) Ascorbate Level ~ 4th Hour -40. 5 34.1 38 : 8th Hour -21.2 -21.9 -6.80 24th Hour -6. 3 -5. 3 18.2 157th Day 27. 6 30.5 I 24th Hour Urine Ascorbate % Change 27.7 2760.6 486.3 MG/24 Hour43.65 314.5 252 7th Day Urine Ascorbate % Change 4583 617 MG/24 Hour 459 321 24th Hour Urine Oxalate % Change 7 162 35.9 .~ MG/24 Hour25.9 63.8 41. 6 2S *increase unless otherwise indicated.
The conclusions which were drawn from this study ' are:
Serum Ascorbate Level:
At 4, 8 and 24 hours and 7 days later, test groups had higher serum ascorbate level as compared to both the citrate group and the L-ascorbic group.
~ WBC Ascorbate Level:
"~ Although all 8th hour WBC ascorbate groups showed an average decrease, test group had the smallest percentage 35 decreasQ. Four and 24-hour measurement plus the 7th-day level showed that teæt group was able to maintain the highest white blood cell ascorbate level.
.
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~, 24-Hour WBC Ascorbate:
24-Hour post various loadings of: citrate, ,i L-ascorbic and test produce similar results. Both the citrate group and L-a6corbic group showed a decrease in WBC ascorbate levels. Test group maintained a much higher level compared ~, to baseline.
; 7 Davs Post Loading of L-Ascorbic and Test:
Average percentage change in WBC Ascorbate is still higher in the Test Group than in the L-ascorbic group.
j 10 ~4-Hour Urine Ascorbate Output:
`! Both in average percentage change and in absolute total mean values, the test groups had less ascor~ate output ~ -i than L-ascorbic.
-~ 7 Days - 24-Hour Urinary Ascorbate Output:
- 15 Test groups have less ascorbate output than the citrate and the L-ascorbic groups. -~
i 24-Hour Urinary Oxalate Output:
:,. .
Oxalate output is greatly decreased in the test group as compared to the ascorbic group. This means that while taking test product as a supplement, a person hac less 3 chance of forming oxalate-containing kidney calculi than a 'J, person taking L-ascorbic.
-` 7-DaY 24-Hour Oxalate Out~ut:
~- Prolonged supplementation with test product leads -~ 25 to less excretion of urinary oxalate than supplementation with L-ascorbic.
Example 3 To a 2-litre reaction vessel equipped with an agitator and a thermometer is added 30 ml. distilled water and 440 g. (2.5 moles) L-ascorbic acid. To this stirred slurry, finely divided calcium carbonate is added incrementally at a rate such as to produce a constant evolution of carbon dioxide (reaction byproduct), the reaction temperature being maintained is about 20C. The addition of calcium carbonate i~ suspended after about 25 g. to 37.5 g. have been added ':. .
, ,,, ~'' ,; -- 1 o (representing from about 20% to 30% of that required for complete reaction with the L-ascorbic acid charge).
At this point, the temperature is raised to 80C.
; Further additions of calcium carbonate are begun, the 5 temperature being maintained in the range 60C to about 70C.
l The total quantity of calcium carbonate added is 125 g.
-j (1.25 moles).
The reaction mixture is transferred to a shallow container maintained at a temperature of between 60C and 10 80C, for a period of from 12 to 36 hours, during which time the pH of the mixture rises to a pH range of 6.0-7Ø At this point, the excess water is removed under vacuum.
; The dry products are light tan in color and readily soluble in water, except for unreacted calcium carbonate, to 15 produce neutral solutions.
Example ~
- Clinical studies using the product of Example 3 yield similar re ults to those æet forth in Example 2.
~s~mple 5 The products of Examples 1 and 3 are subjected to qualitative analysis as follows:
After filtering out excess insoluble calcium carbonate, ascorbic acid and calcium ascorbate were separated from the product by chromatography and the residue was 25 eubjected to nuclear magnetic resonance spectroscopy. Likely po~sibilities for the structures of the components detected by spectroscopy were formulated and these authentic compounds were then synthesized. After nmr spectra o~ these authentic compounds were obtained, they were compared to the nmr spectra 30 of the test specimens. A match of the spectra was used to identify the components of the test specimens.
The technique~ employed were lH and 13C nmr. The aldonic acid salts identified are the calcium salts of L-threonic acid, L-xylonic acid and L-lyxonic acid.
' ;
1 3~8~0q Exa~ple 6 The procedures of Example 1 are repeated except that the reactant added to the ascorbic acid is changed to yield correspondingly different salts of ascorbic acid which are edible in reasonable quantity.
' -Reactant Salt sodium bicarbonatesodium ascorbate magnesium carbonatemagnesium ascorbate ', potassium bicarbonatepotassium ascorbate zinc oxide zinc ascorbate j These products contain the aldonic acid salts corresponding ' to those identified in Example 5.
., .
X~nmpl~ 7 Quantitative analysis of the products of Example 1, 4 and 6 is performed. The products have the indicated ~ compositions:
i Wt.
Anhydrous metal ascorbate 80-92 3 Unreacted metal reagent 6-7 y 20 Dehydroascorbic Acid 3-9 Moisture 1.5-4.5 Aldonic Acid Derivatives 5-6 ~ The aldonic acid derivatives include derivatives of the ; indicated acid in the following approximate proportions:
. .. .
. .
Acid (~erivative~ Parts by Weiaht Threonic 8 Xylonic 3 Lyxonic There are indications that one or more of these aldonic acids -.'~, 30 may be partially linked.
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~ 328809 Bxample 8 Animal feeding studies of the product of Example 1 provide similar results to the human studies of Example 2.
: . f Exam~L~ 9 The procedure of Example 1 is repeated except that no metal compound reactant (e.g., calcium carbonate) is added.
-` The ascorbic acid is, however, sub~fected to the same oxidizing, heating, drying steps. The product consists of anhydrous ascorbic acid product, DHA, water and aldo-lactone derivatives of threonic, xylonic and lyxonic acids. This product yields fsimilar physiological results to those described in Example 8.
,1 ~xample ~0 ~, The procedures of Example 2 are repeated except thatf~ 15 the test product i6 synthesized by mixing reagent grade calcium ascorbate with Test A - Threonic Acid (calcium salt) Test B - Xylonic Acid (calcium salt) Test C - Lyxonic Acid (calcium salt) ~ 20 in the fffame weight proportions as the components found in -i Example 7.
The tests of Example 2 are repfefated using these test ~; compound~ and using pure calcium ascorbate as an additional f control.
Thesf~ tests confirm that the physiological activity of the mixed ascorbate-aldonic product is due to the aldonic component and that any one of these aldonic compone~fnts causes the simi}arly improved absorption and retention of the Vitamin C component.
,, .
~`~ 30 Having described my invention in such terms as to ~ enable those ~fkilled in the art to undçrstand and practice it, - ~ and having identi~ied the presently preferred embodiments -thereof, I claim:
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, Furthermore, the human body does not have the ability to store -~ Vitamin C -- if unmetabolized, it is excreted. Low levels of Vitamin C and its derivatives in the human body produce a variety of undesirable physiological responses and extremely low levels produce extreme responses which may result in death, e.g., from scurvy. Wholly apart from these "normal"
requirements of vitamin C, it i8 important in some therapeutic ~, 10modalities to establish and maintain above-normal Vitamin C
levels in the body. These above-normal concentrations are difficult to establish and maintain because the human body ~ exhibits only a finite tolerance for Vitamin C ascorbic acid - with resultant diarrhea and other side reactions, such as gastric irritation and inflammation if these tolerances are exceeded.
; I have now discovered compositions and methods for ~, improving the establishment and maintenance of high levels of Vitamin C (including its derivatives) in the human body.
Briefly, the composition which I have discovered comprises a compound having Vitamin C activity and at least one compound selected from the class consisting of the aldono-lactones and `;edible salts of L-threonic, L-xylonic and L-lykonic acids.
~A method which I have discovered for establishing '; ~ . : -.;:
'' ' :
-. ~ , -', ~,':
-' - ' .
.,, ,,.:
~, . .
~:: -`3 l 328809 .
'Vitamin c levels in the human body includes the step of orally administering this composition to a subject.
Another method of the invention comprises thestep of converting L-ascorbic acid to this composition and orally administering this composition to the subject.
According to one aspect of the present invention, there is provided a vitamin composition comprising:
I(a) an effective amount of a compound having Vitamin C activity, selected from the group consisting of dehydroascorbic acid and the edible salts thereof, and L-ascorbic acid and the edible salts thereof; and (b) at least one compound selected from the group -¦consisting of the aldono-lactones of L-threonic acid, L-xylonic acid and L-lyxonic acid and the edible salts of L-;15 threonic acid, L-xylonic acid and L-lyxonic acid, in an amount effective to increase the human body absorption rate of said Vitamin C compound.
~According to another aspect of the present ;invention, there is provided a use of a metabolite to -,20 improve the body absorption rate of a compound having Vitamin C activitywherein the metabolite is selected from the group consisting of the aldono-lactones and edible salts of L-threonic, L-xylonic and L-lyxonic acids.
According to a further aspect of the present invention, there is provided a use of the above-mentioned vitamin composition to establish high Vitamin C levels in the human body.
According to yet another aspect of the present invention, there is provided a use of L-ascorbic acid to establish Vitamin C levels in a subject comprising:
(a) converting the L-ascorbic acid to a composition comprising:
'(i) a compound having Vitamin C activity; and (ii) at least one compound selected from the group consisting of the aldono-lactones and edible salts of L-threonic, L-xylonic and L-lyxonic acids; and .. . .
1 3288~9 - 3a -(b) orally administering said composition to said subject.
According to still another aspect of the present invention, there is provided a use of the above-mentioned vitamin composition to treat arthritis.
As used herein, the term "compound having Vitamin C activity" means Vitamin C (L-ascorbic acid) and any derivative thereof which exhibits antiscorbutic activity.
Such derivatives include, for example, oxidation products such as dehydroascorbic acid and edible salts of ascorbic acid such as, illustratively, calcium, sodium, magnesium, potassium and zinc ascorbates.
The metabolites of ascorbic acid and its derivatives include the aldono-lactones and edible salts of aldonic acids. As will appear, the compositions of the present invention are characterized by the presence of at least one or more of these metabolites corresponding to three specific aldonic acids: L-threonic acid, L-xylonic acid and L-lyxonic acid.
ZO The presence of one or more of these metabolites in the compositions of the invention is both a convenient -~ way of identifying such compositions and is also necessary to achieve the desired result, improvement in Vitamin C
absorption and/or retention. -The component of the compositions of the invention which, as indicated above, has "Vitamin C~ -~i activity" can be L-ascorbic acid or any of its derivatives which have the ability to provide the ascorbic/ascorbate --moiety in physiologic processes, e.g., dehydroascorbic acid, calcium and sodium ascorbate which are most commonly employed in Vitamin C food supplements, as well as a wide variety of other edible (non-toxic in appropriate quantity) -salts such as potassium, sodium, magnesium and zinc ' ascorbate. In general, any ~uch compound which exhibits 35 Vitamin C -'' ~"
,' ', -.
~, " ~
, ......................................................................... ........ .~ ,, activity will suffice.
.~ A suitable method for preparing the compositions of the invention comprises reacting L-a~corbic acid with a non-toxic metal compound, e.g., calcium carbonate, sodium ~ 5 bicarbonate, under oxidizing conditions at an elevated - temperature, e.g., 400c-980c, to convert a substantialproportion of the ascorbic acid to its corresponding salt, ~-¦ e.g., calcium or sodium ascorbate, and drying the reaction mixture to produce a solid product of essentially neutral pH
(e.g., 6.0-7.5). Preferably a slight stoichiometric excess of the metal salt reactant is provided. The resultant product has an iodine ascorbate assay in the range 50-480 mg./500 mg.
sample depending upon process parameters, with the higher activity preferred for practical reasons. Longer heating at oxidizing conditions produces lower iodine ascorbate assays.
¦ The co~position~ of the invention appear useful in administering Vitamin C to patients who have low ascorbic acid tolerance. In particular, patients who have a tendency to form kidney stones are particularly susceptible to ¦ 20 difficulties when ingesting ascorbic acid and its common derivative, calcium ascorbate, which cause elevated urine oxalate levels. There are indications that the compositions of the present invention can be administered without increasing the oxalate level in the urine to the levels encountered when the prior art compositions and methods are especially suitable as a means of establishing and maintaining ~s~ ascorbate body level~ in guch kidney stone-prone subjects.
~ The compo~ition~ of the invention also appear to be i useful in the treatment of inflammatory diseases, such as `:..1 arthritis.
The following examples are presented for purposes ~ -of illustrating the practice of the invention and are not intended as limitations on the scope thereof. ~-~
~' ,~pl~
^-i 35 To an 80-gallon, steam-heated stainless steel ~ reaction vessel was added 60 lbs. of hot (44C) water. ;-Ascorbic acid-U.S.P., 110.23 lbs., was added in one portion to the hot water. The resulting slurry was mechanically stirred and heated with steam (pressure 15 p.s.i.) until a temperature of 70C was achieved.
To the aqueous slurry of ascorbic acid was added 23 lbs. of calcium carbonate. The incremental addition of the carbonate required 3-4 minutes. The reaction mixture appeared gray in color and much foaming due to the evolution of Co2 was evident. After eight minutes of stirring, most of the foaming had subsided and the reaction mixture appeared red-brown in color. The solution temperature was 80C. Stirring and heating were continued for 15 minutes until the temperature ~ -of the reaction mixture reached 98C where it was maintained for an additional 20 minutes, after which an additional 8.25 lbs. of calcium carbonate was added, with stirring.
- After foaming ceased, the reaction mixture was then pumped to a double-drum steam-heated dryer (surface temperature approximately 250F). The pumping-drying step required 35 minutes. The dried product was light-tan color and the yield was approximately 120 pounds of product.
Optionally, air can be bubbled through the reaction ~ mixture to promote the reaction of the ascorbic acid.
-,~ Assays were performed immediately on 5.00 g. samples ~
dissolved in 500 ml. distilled water. --The material collected during the drying process showed 400 mg. anhydrous calcium ascorbate per 500 mg. by this standard iodine titration technique. The same aqueous solution showed pH 7Ø
, ' ":
E%amD1e 2 ~:
The following example describes clinical tests 1 co~paxing the product of Example 1 (test material with L-ascorbic acid and citric acid (placebo), measuring ~
intracellular ascorbate levels, urinary ascorbate output and -`
urinary oxalate excretion at various times after ingestion of standard doses of the test, L-ascorbic acid and placebo.
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; 1 32880q .~
Summary of the Protocol Twelve men, ages 27 to 45, were studied.
All were instructed that they should be on a low Vitamin C diet for one week prior to the study (no citrus products and no large amounts of green leafy vegetables).
Following overnight fast, blood and 24-hour urine samples were taken. White blood cell and 24-hour urinary ascorbate and oxalate levels were determined and correlated with serum ascorbate levels.
~3 10 The 12 men were divided into three groups, and were 'l given the following supplements:
(a) Test Group: 4000 MG* per day of the product Ex. 1.
(b) Ascorbate Group: 3000 MG of L-ascorbic per day.
(c) Citric Acid Group: 3000 MG of citric acid per day.
All 12 continued on a low Vitamin C diet. Blood samples were taken at 0, 4, 8 and 24 hours after morning ingestion of the designated supplements. Urinary 24-hour ascorbate and oxalate levels were determined.
¦ After a wash-out period (varying from two days to several days, due to job situation of participants), the ~ groups were switched to another supplement, as follows:
,~ (a) Test group to citrate group.
(b) Citrate group to ascorbate group.
(c) Ascorbate group to test group.
Supplements were taken at the same leYel (4000 MG
of Ex. 1 product, 3000 MG of L-ascorbic and 3000 MG of citric acid) by all three groups. Blood samples were again drawn at 0, 4, 8 and 24 hours from time of ingestion. A 24-hour urine was also collected by all 12 participants at the end of the ~ period. A~ain, all specimens were analyzed for their 1i respective concentration of ascorbate and oxalate levels.
-~ 35 *4000 MG is equivalent in ascorbate (iodine test) to 3000 MG
ascorbic acid.
, ~ .
.~ 1 32880q AnalYtical Procedures The analytical procedures utilized are described in: Clinical ChemistrY Principles and Technii~ues, j edited by Richard J. Henry, Donald D. cannon and James W. Windelman, Harper and Row, 1974, p. 1393-1398.
Standard Methods of Clinical Chemistry, J.S. Roe, edited by Seligson D. New York, Academic Press, 1961, Vol. 3, p. 35-~` In the quantitation of 24-hour urine oxalate, an aliguot of urine i~ ~haken with an absorbent which selectively bind~ the oxalate. The extracted urine i~ discarded and the oxalate i~ eluted from the absorbent with dilute alkali.
Oxalate i8 oxidized to hydrogen peroxide and carbon ~j dioxide by oxalate oxidase. The hydrogen peroxide react~ with 3 methyl-2-benzothiszolinone hydrazone (NBTH) and -` 3(dimethylamino) benzoic acid (DMAB~ in the presence of 'J peroxidas,e,to yield an indamine dye with a maximum absorbance ~ at 590 NM.
`l The urine oxalate test is furthex described in the -~ 20 following references:
Hodgekinson, A.: Oxalic Acid in Violo~v and ~Q9lin~, Acedemic Press, New York, 1977.
Robertson, W.D.; Rutherford, A.: AsPects of the ~-Analv~is of Oxalate in Urine, Scan J. Uro Nephrol, Suppl. 53, p. 85, 1979. -~
Lamden, N.P.; Chrystow~ki, G.A.: Urinary Oxalat~ -Excretion ~y Main Followin~3 Ascorbine Ac~d Inae~,tion, Prog. Soo. Exp. Biol.
Med. 85:190, 1954.
Co~,t~,llo, J.:
Oxalate Metaboli~m in Hu~,an Biochemistxy ~ and Clinical Patholo~v, edited by G.A.
;~ Rose, W.G. Robert~on and R.W.E. Watts.
Proceedings of an International Meeting ;~ 35 $n London, 1971, pp. 270-273.
~` The results of this clinical study are set forth below:
'.: ' .,,' ,, 1 32ssnq Table 1 Percent Change*
' in Group citrate L-ascorbic Test Serum Ascorbate Level 4th Hour 10 180. 3 264. 8 8th Hour 19.6 91.6 144.2 ~ 24th Hour 5.9 24.6 56.2 J 107th Day 45.3 102.5 White Blood Cell (WBC) Ascorbate Level ~ 4th Hour -40. 5 34.1 38 : 8th Hour -21.2 -21.9 -6.80 24th Hour -6. 3 -5. 3 18.2 157th Day 27. 6 30.5 I 24th Hour Urine Ascorbate % Change 27.7 2760.6 486.3 MG/24 Hour43.65 314.5 252 7th Day Urine Ascorbate % Change 4583 617 MG/24 Hour 459 321 24th Hour Urine Oxalate % Change 7 162 35.9 .~ MG/24 Hour25.9 63.8 41. 6 2S *increase unless otherwise indicated.
The conclusions which were drawn from this study ' are:
Serum Ascorbate Level:
At 4, 8 and 24 hours and 7 days later, test groups had higher serum ascorbate level as compared to both the citrate group and the L-ascorbic group.
~ WBC Ascorbate Level:
"~ Although all 8th hour WBC ascorbate groups showed an average decrease, test group had the smallest percentage 35 decreasQ. Four and 24-hour measurement plus the 7th-day level showed that teæt group was able to maintain the highest white blood cell ascorbate level.
.
~i .
~, 24-Hour WBC Ascorbate:
24-Hour post various loadings of: citrate, ,i L-ascorbic and test produce similar results. Both the citrate group and L-a6corbic group showed a decrease in WBC ascorbate levels. Test group maintained a much higher level compared ~, to baseline.
; 7 Davs Post Loading of L-Ascorbic and Test:
Average percentage change in WBC Ascorbate is still higher in the Test Group than in the L-ascorbic group.
j 10 ~4-Hour Urine Ascorbate Output:
`! Both in average percentage change and in absolute total mean values, the test groups had less ascor~ate output ~ -i than L-ascorbic.
-~ 7 Days - 24-Hour Urinary Ascorbate Output:
- 15 Test groups have less ascorbate output than the citrate and the L-ascorbic groups. -~
i 24-Hour Urinary Oxalate Output:
:,. .
Oxalate output is greatly decreased in the test group as compared to the ascorbic group. This means that while taking test product as a supplement, a person hac less 3 chance of forming oxalate-containing kidney calculi than a 'J, person taking L-ascorbic.
-` 7-DaY 24-Hour Oxalate Out~ut:
~- Prolonged supplementation with test product leads -~ 25 to less excretion of urinary oxalate than supplementation with L-ascorbic.
Example 3 To a 2-litre reaction vessel equipped with an agitator and a thermometer is added 30 ml. distilled water and 440 g. (2.5 moles) L-ascorbic acid. To this stirred slurry, finely divided calcium carbonate is added incrementally at a rate such as to produce a constant evolution of carbon dioxide (reaction byproduct), the reaction temperature being maintained is about 20C. The addition of calcium carbonate i~ suspended after about 25 g. to 37.5 g. have been added ':. .
, ,,, ~'' ,; -- 1 o (representing from about 20% to 30% of that required for complete reaction with the L-ascorbic acid charge).
At this point, the temperature is raised to 80C.
; Further additions of calcium carbonate are begun, the 5 temperature being maintained in the range 60C to about 70C.
l The total quantity of calcium carbonate added is 125 g.
-j (1.25 moles).
The reaction mixture is transferred to a shallow container maintained at a temperature of between 60C and 10 80C, for a period of from 12 to 36 hours, during which time the pH of the mixture rises to a pH range of 6.0-7Ø At this point, the excess water is removed under vacuum.
; The dry products are light tan in color and readily soluble in water, except for unreacted calcium carbonate, to 15 produce neutral solutions.
Example ~
- Clinical studies using the product of Example 3 yield similar re ults to those æet forth in Example 2.
~s~mple 5 The products of Examples 1 and 3 are subjected to qualitative analysis as follows:
After filtering out excess insoluble calcium carbonate, ascorbic acid and calcium ascorbate were separated from the product by chromatography and the residue was 25 eubjected to nuclear magnetic resonance spectroscopy. Likely po~sibilities for the structures of the components detected by spectroscopy were formulated and these authentic compounds were then synthesized. After nmr spectra o~ these authentic compounds were obtained, they were compared to the nmr spectra 30 of the test specimens. A match of the spectra was used to identify the components of the test specimens.
The technique~ employed were lH and 13C nmr. The aldonic acid salts identified are the calcium salts of L-threonic acid, L-xylonic acid and L-lyxonic acid.
' ;
1 3~8~0q Exa~ple 6 The procedures of Example 1 are repeated except that the reactant added to the ascorbic acid is changed to yield correspondingly different salts of ascorbic acid which are edible in reasonable quantity.
' -Reactant Salt sodium bicarbonatesodium ascorbate magnesium carbonatemagnesium ascorbate ', potassium bicarbonatepotassium ascorbate zinc oxide zinc ascorbate j These products contain the aldonic acid salts corresponding ' to those identified in Example 5.
., .
X~nmpl~ 7 Quantitative analysis of the products of Example 1, 4 and 6 is performed. The products have the indicated ~ compositions:
i Wt.
Anhydrous metal ascorbate 80-92 3 Unreacted metal reagent 6-7 y 20 Dehydroascorbic Acid 3-9 Moisture 1.5-4.5 Aldonic Acid Derivatives 5-6 ~ The aldonic acid derivatives include derivatives of the ; indicated acid in the following approximate proportions:
. .. .
. .
Acid (~erivative~ Parts by Weiaht Threonic 8 Xylonic 3 Lyxonic There are indications that one or more of these aldonic acids -.'~, 30 may be partially linked.
,, .
',:
.-' ~'.
~ 328809 Bxample 8 Animal feeding studies of the product of Example 1 provide similar results to the human studies of Example 2.
: . f Exam~L~ 9 The procedure of Example 1 is repeated except that no metal compound reactant (e.g., calcium carbonate) is added.
-` The ascorbic acid is, however, sub~fected to the same oxidizing, heating, drying steps. The product consists of anhydrous ascorbic acid product, DHA, water and aldo-lactone derivatives of threonic, xylonic and lyxonic acids. This product yields fsimilar physiological results to those described in Example 8.
,1 ~xample ~0 ~, The procedures of Example 2 are repeated except thatf~ 15 the test product i6 synthesized by mixing reagent grade calcium ascorbate with Test A - Threonic Acid (calcium salt) Test B - Xylonic Acid (calcium salt) Test C - Lyxonic Acid (calcium salt) ~ 20 in the fffame weight proportions as the components found in -i Example 7.
The tests of Example 2 are repfefated using these test ~; compound~ and using pure calcium ascorbate as an additional f control.
Thesf~ tests confirm that the physiological activity of the mixed ascorbate-aldonic product is due to the aldonic component and that any one of these aldonic compone~fnts causes the simi}arly improved absorption and retention of the Vitamin C component.
,, .
~`~ 30 Having described my invention in such terms as to ~ enable those ~fkilled in the art to undçrstand and practice it, - ~ and having identi~ied the presently preferred embodiments -thereof, I claim:
~, ~ . -'"``' ~E ' ' :' ':i~ ' -:
'~: ' ` .":
. ~!; . ,, ' ' ~ , . ,' ', j ; ~
Claims (7)
1. A vitamin composition comprising:
(a) an effective amount of a compound having Vitamin C activity, selected from the group consisting of dehydroascorbic acid and the edible salts thereof, and L-ascorbic acid and the edible salts thereof; and (b) at least one compound selected from the group consisting of the aldono-lactones of L-threonic acid, L-xylonic acid and L-lyxonic acid and the edible salts of L-threonic acid, L-xylonic acid and L-lyxonic acid, in an amount effective to increase the human body absorption rate of said Vitamin C compound.
(a) an effective amount of a compound having Vitamin C activity, selected from the group consisting of dehydroascorbic acid and the edible salts thereof, and L-ascorbic acid and the edible salts thereof; and (b) at least one compound selected from the group consisting of the aldono-lactones of L-threonic acid, L-xylonic acid and L-lyxonic acid and the edible salts of L-threonic acid, L-xylonic acid and L-lyxonic acid, in an amount effective to increase the human body absorption rate of said Vitamin C compound.
2. A vitamin composition according to claim 1, wherein the compound having Vitamin C activity is an edible metal salt of L-ascorbic acid.
3. A use of a metabolite to improve the body absorption rate of a compound having Vitamin C activity wherein the metabolite is selected from the group consisting of the aldono-lactones and edible salts of L-threonic, L-xylonic and L-lyxonic acids.
4. A use of the vitamin composition of claim 1 to establish high Vitamin C levels in the human body.
5. A use of L-ascorbic acid to establish Vitamin C levels in a subject comprising:
(a) converting the L-ascorbic acid to a composition comprising:
(i) a compound having Vitamin C activity; and (ii) at least one compound selected from the group consisting of the aldono-lactones and edible salts of L-threonic, L-xylonic and L-lyxonic acids; and (b) orally administering said composition to said subject.
(a) converting the L-ascorbic acid to a composition comprising:
(i) a compound having Vitamin C activity; and (ii) at least one compound selected from the group consisting of the aldono-lactones and edible salts of L-threonic, L-xylonic and L-lyxonic acids; and (b) orally administering said composition to said subject.
6. A use according to claim 5 wherein the compound having Vitamin C activity is an edible metal salt of L-ascorbic acid.
7. A use of the vitamin composition of claim 1 to treat arthritis.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/036,598 US4822816A (en) | 1987-04-10 | 1987-04-10 | Compositions and methods for administering vitamin C |
| US36,598 | 1987-04-10 |
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| Publication Number | Publication Date |
|---|---|
| CA1328809C true CA1328809C (en) | 1994-04-26 |
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ID=21889504
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|---|---|---|---|
| CA000563727A Expired - Lifetime CA1328809C (en) | 1987-04-10 | 1988-04-08 | Compositions and methods for administering vitamin c |
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| CA (1) | CA1328809C (en) |
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| ATE123306T1 (en) * | 1989-05-19 | 1995-06-15 | Hayashibara Biochem Lab | ALPHA-GLYCOSYL-L-ASCORBIC ACID AND THEREOF PREPARATION AND USES. |
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| US3459863A (en) * | 1966-10-14 | 1969-08-05 | Merck & Co Inc | Color-stable ascorbic acid tablet |
| ES362615A1 (en) * | 1968-01-18 | 1970-11-01 | Takeda Chemical Industries Ltd | Method for preventing coloring of vitamin c |
-
1987
- 1987-04-10 US US07/036,598 patent/US4822816A/en not_active Expired - Lifetime
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