KR940000006B1 - Pharmaceutical active compounds compositions - Google Patents

Abstract

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Description

A composition of a therapeutically active compound.

[Brief Description of Drawings]

1 is a histogram of test values showing an increase in the absorption / maintenance rate of aspirin according to the present invention.

2 shows an increase in serum salicylate over time.

3 shows an increase in plasma pyroxycam concentration over time.

4 shows an increase in the absorption / maintenance rate of plasma pyroxycam with time.

Figure 5 shows the increased uptake of ascorbic acid by 3T3 fibroblasts resulting from the inclusion of an aldodon component.

Detailed description of the invention

FIELD OF THE INVENTION The present invention relates to the composition and use of new materials, and more particularly to compositions for improving the effects of certain therapeutically active compounds.

The present invention also relates to methods of making and maintaining such compounds at therapeutically effective levels in the body.

Specifically, the present invention relates to an improved composition of a therapeutically active compound such as antibiotics, vitamins, amino acids, anti-inflammatory agents, analgesics, antipyretics and the like, and to a method of using the same. It is about how to use.

In prophylaxis or drug treatment, it is generally desirable to establish the initial physiologically effective level of a drug or other therapeutically active compound in an animal or human body, and then maintain the effective level for the period necessary to achieve the desired physiological result. .

If absorption or retention (reduction of discharge rate) or both cases improve, they are usually of great physiological and therapeutic benefit. It is also more beneficial if it can reduce or eliminate unnecessary side effects of the therapeutic agent.

In the present invention, it will be described in detail to use the present invention to improve the vitamin-C therapy in order to first illustrate the practice and principles of the present invention to those skilled in the art, but the present invention will be described It is not limited to only those applications.

The prior art has demonstrated more than 300 distinct metabolic mechanisms (mechanisms) in which vitamin-C is involved in physiological responses. These mechanisms began with the scurvy treatment effect first observed by Rover-Trind in 1740, and the extremely recent discovery of free radical capture of antioxidants, enzyme reactions in collagen formation, and in multinuclear leukocytes. Energy range, and to promote the absorption of iron.

The clinical effects of such metabolic reactions are widely recognized and reported. As an example, the free radical capture effect allows the body to convert carcinogens into non-toxic derivatives that are excreted in urine and, as a result, reduce the effects of smoking or other ambient pollutants and exposure to extreme temperatures.

Zoology has demonstrated that enzymes in the body convert ascorbate (ascormate) to oxidation products (proven to inhibit mass growth).

Therefore, there is no scientific doubt about the health benefits of making and maintaining effective levels of vitamin-c and its derivatives in the human body. Significant concentrations of vitamin-c have been observed in the adrenal gland, ovaries, brain, pituitary gland, liver, spleen, blood cells, serum and extracellular waste. Most animals have hepatic enzymes that can produce vitamin-C by converting blood sugar to ascorbic acid, but humans don't carry these enzymes.

As a result, in order to perform various metabolic reactions as described above, the vitamin-C required in the body has no choice but to be consumed by people. In addition, the body does not have the ability to store vitamin-C. If it is not metabolized, vitamin-c can only be excreted. At low levels of vitamin-C and its derivatives in the human body, undesirable physiological reactions occur, and at very low levels there are extreme reactions such as death from scurvy.

Apart from these normal vitamin-C needs, building and maintaining these normal vitamin-C levels in the body is important for therapeutic metabolism.

However, making and maintaining the normal concentration in this way is difficult for the following reasons. That is, because the human body has a limited range of content for vitamin-C because the diarrhea and other side effects resulting from stomach irritation and inflammation occur when the vitamin-C (ascorbic acid) allowance is exceeded.

The inventors have discovered compositions and methods that improve the effect of creating and / or maintaining levels in the body of therapeutically active compounds that are normally excreted from the body without being metabolized via the renal coronary pathway in which organic anions are secreted. . Such therapeutically active compounds have a molecular weight of about 5000 or less, have acidic functional groups, and have a value of pKa ≦ 6 at physiological pH = 7.4.

The composition of the present invention is selected from the therapeutically active compound and L-threonic acid, L-xyronic acid and L-lyxonic acid, non-toxic edible salts of the acids, aldono-lactone and aldono-lactide of the acids. At least one compound.

In a preferred embodiment of the method of the present invention, the method found by the present invention comprises administering a physiologically effective amount of the composition to a human body or an animal body.

According to the method, the first step was to administer the aldon compound in the body to make an effective level in the body, and then to administer the therapeutically active compound.

The inventors have further discovered compositions and methods that improve the production and maintenance of high levels of vitamin-C (including derivatives thereof) in the human body. In short, according to this embodiment of the present invention, the composition I have found is a compound having vitamin C activity, L-threonic acid, L-xyronic acid and L-lyxonic acid, edible salts of the acids, It consists of at least one compound selected from aldono-lactone and aldo-lactide of the acids.

According to another preferred embodiment, the method for achieving vitamin-C levels in the human body comprises administering the composition to a subject.

As used herein, "compound with vitamin C activity" refers to vitamin-C (L-ascorbic acid) and its derivatives that exhibit anti-scurvy activity. By way of example, the derivatives are oxidative products, such as salts of ascorbic anhydride and edible ascorbic acid salts such as calcium, sodium, magnesium, potassium and zinc ascorbate, L-ascorbic acid 2-0-phosphate, L -Esters of vitamin-C with inorganic and organic acids such as ascorbic acid 6-hexadecanoate, L-ascorbic acid monostearate, L-ascorbic acid dipalmitate, and the like.

Metabolites of ascorbic acid and its derivatives include edible salts of aldonic acid, aldono-lactone, aldono-lactide and aldonic acid.

As will be described later, the composition of the present invention is characterized by the presence of one or more of these metabolites corresponding to three particular aldonic acids (L-threonic acid, L-xyronic acid and L-lyxonic acid).

Aldono-lactone has the following structural formula.

The presence of one or more of these metabolites in the compositions of the present invention is convenient for identifying such compositions and is also needed to improve the desired result, namely absorption / maintenance of vitamin-C or other therapeutically active compounds.

Suitable methods for the preparation of the improved vitamin-C compositions of the present invention include L-ascorbic acid in addition to non-toxic metal compounds such as calcium carbonate, soda bicarbonate, and the like. The amount is heated to convert to the corresponding salt, ie calcium or sodium ascorbate, and the reaction mixture is dried to give a solid product with a neutral pH of 6.0-7.5. It is preferred to provide a metal salt reactant which is in stoichiometric excess relative to the reactant of the metal salt. The resulting product has higher activity of ascorbate, and the ascorbic acid iodine assay is in the range of 50-480 mg / 500 mg samples depending on process parameters. Long heating under oxidizing conditions yields lower ascorbic acid iodine sample.

The composition of the present invention is useful when vitamin C is administered to patients with low ascorbic acid resistance.

Patients who tend to form kidney stones are particularly troubled when taking ascorbic acid and its common derivative calcium ascorbate, which cause elevated levels of urea oxalate.

The compositions of the present invention can be administered so that no increase in oxalate (oxalate) levels in the urine occurs upon use of the prior art compositions and methods.

The composition of the present invention is particularly suitable as a means of creating and maintaining an appropriate body level of ascorbate for a subject with a tendency to kidney stones. Vitamin-C compositions of the invention are also useful for the treatment of inflammation, such as arthritis.

The effectiveness of aldon compounds to improve the absorption, solvent resistance and / or retention of vitamin-C compounds is also applicable to improving the properties of therapeutically active compounds having molecular weights of less than about 5000, acidic functionalities and pKa ≦ 6. Can be done. The physiological mechanism of such improvement is that the normal release of non-metabolized therapeutically active compounds from the body via the renal coronary secretion pathway for organic anions is suppressed and the absorption of these components through the cell walls of the tissues of the body is improved.

Aldon compounds obviously offer two effects: improved absorption and suppressed kidney excretion. A general description of the various renal glands can be found in the journal of Pharmacology and Experimental Therapeutics [Vol. 171, p. 103 (1970).

The amount of aldon compound required in the composition of the present invention is a therapeutically effective ratio. The exact ratio will vary to some extent depending on the exact nature of the therapeutically active compound and other factors that can occur to those of ordinary skill in the art. In general, reduced kidney and / or increased body uptake is somewhat improved by very small amounts of aldon compounds.

These features are to be improved by increasing the proportion of aldon compounds, the upper limit of which is set under practical considerations to ensure that the therapeutically active ingredient is too diluted so that an adequate minimum content is not administered. According to the present best information, the ratio of the aldon compound in the composition of the present invention may vary from 1% by weight or less to 24% by weight.

The actual therapeutic effect has been observed in the concentration range of 0.10% by weight of the aldon compound and the present preferred range of the aldon compound is from about 1% to about 7% by weight. The composition of the present invention can be prepared by simply physically mixing the components of the composition.

In the case of vitamin-C, the composition can be prepared in situ according to the techniques described in the practical examples. Non-limiting examples of representative therapeutically active compounds that can be improved according to the present invention include compounds having pKa ≦ 6 and having acidic functional groups such as carboxyl groups, en-diol groups, phenol groups and the like.

Such compounds have a wide variety of structures and pharmaceutical availability.

For example,

A therapeutically active compound of the type described above suitable for use in the practice of the present invention can be readily selected and identified by routine testing by one of ordinary skill in the art. The urine test can be used to determine whether a particular compound is released without metabolism. Moreover, the selection can be confirmed by the smooth muscle test described in Example 14 and the animal studies described in Examples 12 and 13.

The following examples are presented to specifically illustrate the practice of the invention and are not intended to limit the scope thereof.

Example 1

Into an 80 gallon steam heated stainless steel reactor add 60 lbs of hot water at 44 ° C. and 110.23 lbs of ascorbic acid-U.S.P to a portion of the hot water. The resulting slurry is mechanically stirred and heated to pressurized steam (15 psi) to 70 ° C.

231bs of calcium carbonate was added to the liquid ascorbic acid slurry. The addition of carbonate takes 3-4 minutes. The reaction product is gray and the formation of many bubbles is evident due to the generation of CO ₂ . After 8 minutes of stirring most of the foaming disappeared and the reaction mixture became reddish brown. At this time, the liquid temperature is 80 ° C. Stirring and heating are continued for 15 minutes until the temperature of the reaction product is 98 ° C, and additionally 8.251bs of calcium carbonate is added and maintained for 20 minutes while stirring.

After the bubbles settle down, the reaction product is pumped into a dual drum steam-heated dryer (surface temperature is approximately 250 ° C F. This pumping and drying process takes 35 minutes. The dried product is pale yellowish brown and the yield is approximately 1201bs. .

Bubbles may be generated between the reaction mixtures by air to promote the reaction of ascorbic acid. Immediately analyze 5.00 g of sample dissolved in 500 ml of distilled water. The material collected during the drying process showed 400 mg of calcium ascorbic anhydride per 500 mg and pH 7.0 according to the standard temperature titration method.

Example 2

In the following examples, the product of Example 1 (test substance) was dosed with the standard dose of test L-ascorbic acid citric acid (placebo) and at various time points the level of intracellular and serum ascorbate, extracted ascorbic acid urine and It describes a clinical trial comparing L-ascorbic acid and citric acid (placebo), measuring oxalic acid excretion.

Summary of Clinical Trials

The subjects were 12 from 27 to 45 years old. One week before the study, everyone was asked to eat a low-vitamin-C diet (avoid high intake of citrus products and green leafy plants).

After overnight fasting, blood and urine samples were taken 24 hours later. Leukocytes, 24 hour ascorbic acid urine and 24 hour oxalate urine levels were measured and correlated with serum ascorbate levels.

The twelve were divided into three groups, as follows:

a) Test group: Example 1 product of 4000MG * per day

b) ascorbate group: 3000 mg of ascorbic acid per day

c) citric acid group: 3000 mg of citric acid per day

4000 mg * is equivalent to ascorbate: iodine test) for 3000 mg of L-ascorbic acid.

All 12 continued the low vitamin-C meal and blood samples were taken only at 0,4,8 and 24 hours after breakfast of the designated feed. Twenty-four hour ascorbate and oxalate levels of urine were measured. After the washout period (which varies from 2 days to several days due to the participant's work situation), the group was changed to another additional substance as follows:

3) Convert test group to citric acid group

b) conversion of citric acid groups to ascorbate groups

C) converting ascorbate group to test group

Additional materials were taken at the same level (product 4000MG, L-ascorbic acid 3000MG and citric acid 3000MG) in three groups.

Blood samples were taken again at 0, 4, 8 and 24 hours after further ingestion. 24 hour urine was also collected from 12 preclinical subjects at the end of the period. Again all samples were analyzed for their respective concentrations of ascorbate and oxalate levels.

[Method of Analysis]

Analytical methods are described in Clinical Chemistry, Principles and Techniques [Richard J. Henry, Donald D. Cannon, and James W. Wyndelman, Harper and Rowe Press, 1974, p.1393-p.1398] and Standard Method of Clinical Chemistry, (J. S. Rower, Academic Press, 1961. Vol 3 , P.35.

To quantify 24-hour urine oxalate, the surface of urine is shaken with an adsorbent that selectively binds oxalate. The extracted urine is discarded and the oxalate is eluted with an adsorbent diluted with dilute alkali.

Oxalate (oxalate) is eluted with hydrogen peroxide and CO ₂ by oxalate oxidase. Hydrogen peroxide reacts with 3-methyl-2-benzothiozolinone hydrazone (MBTH) and 3 (dimethylamino) benzoic acid (DMAB) in the presence of peroxidase to obtain an indamine dye with maximum absorption at 590 NM.

Urine oxalate tests are described in the following literature.

Oxalic Acid in Viology and Medicine (Hosekinson A., Academic Press, 1977).

Urinary Oxalate Excretion by Main Follow-ing Ascorbine Ingestion [Double You. D. Robertson; G. a. Cristowski, Prog. Soc. Exp. Bil. Med. 85; 190, 1954]

The Effect of Ascorbic Acid on Oxalate Metabolism in Human Bio-chemistry and Clinical Pathology (J. Costello, London International Conference, 1971, P. 270-P. 273].

The results of the clinical trials are as follows.

TABLE I

The results obtained from the clinical trial study are as follows.

Serum Ascorbate Levels:

After 4,8,24 hours and 7 days the test group had high serum ascorbate levels when compared to the citric acid group and the L-ascorbic acid group.

Leukocyte Ascorbate Levels:

The leukocyte asro-bait group after 8 hours in all groups showed a decrease on average, but the test group alone showed the smallest percentage reduction. 4-hour and 24-hour measurements and 7-day levels indicated that the test group could maintain the highest leukocyte levels.

Leukocyte Ascorbate at 24 hours:

Citric acid, L-ascorbic acid and the test group all obtained the same result after 24 hours of ingestion.

In the leukocyte Asro-Bate water, both the citric acid group and the L-ascorbic acid group showed a decrease, but the test group maintained a much higher level than the baseline.

7 days after ingestion of L--ascorbic acid and the test group

The mean percent change in leukocyte ascorbate was significantly higher in the test group than in the L-ascorbic acid group.

24-hour urine ascorbate yield:

The test group produces less ascorbate than the citrate and L-ascorbate groups.

7-24 hour urine ascorbate yield:

The test group produces less ascorbate than the citrate group and the L-ascorbate group.

24-hour urine oxalate yield:

Oxarate output was significantly reduced in the test group compared to the ascorbate group. This fact means that during the additional test product, the test group has less chance to form oxalates with kidney stones than those who take L-ascorbic acid.

7-24 hour oxalate yield:

Increasing the supply of test products results in less excretion of urine oxalate than feeding L-ascorbic acid.

Example 3

30 ml distilled water and 440 g (2.5 moles) L-ascorbic acid are injected into a 2 liter reactor equipped with a stirrer and thermometer.

The calcium carbonate finely pulverized by stirring the slurry is weighed at a rate such that the reaction byproduct CO ₂ can be constantly released, and the reaction temperature is maintained at about 20 ° C.

In addition, 25-37.5 g of calcium carbonate is added to suspend (approximately 20-30% of the amount required to complete the reaction by filling L-ascorbic acid).

At this time, the temperature rises to 80 ° C but is maintained within the range of 60-70 ° C as calcium carbonate is added. The total amount of calcium carbonate added is 125 g (1.25 mo1es).

The reaction mixture is transferred to a shallow vessel maintained at a temperature between 60-80 ° C. for 12-36 hours, during which the pH of the mixture is raised to 6.0-7.0. The excess water at this time is removed in a vacuum.

The dried product is light yellowish brown, soluble in water except neutral calcium carbonate, which is neutral solution.

Example 4

Clinical studies with the product of Example 3 yield the same results as described in Example 2.

Example 5

The products of Examples 1 and 3 are qualitatively analyzed as follows.

Undissolved excess calcium carbonate is filtered off and separated from the product by chromatography, and the residue is subjected to nuclear magnetic resonance (NMR) spectroscopy.

The structure of a likely component is detected by spectroscopic analysis to produce a structure, and the identified compounds are synthesized. NMR spectra of these identified compounds are obtained and compared to the NMR spectra of the test specimens. Use the combination of spectra to identify the components of the test sample.

The technique used is 1H and 13C NMR. Aldonic salts found are calcium salts of L-threonic acid, L-xironic acid and L-lyxonic acid.

Example 6

In this example as well, the method of Example 1 is repeated in addition to changing the reactants added to ascorbic acid to obtain a different amount of nontoxic and edible ascorbic acid in a reasonable amount.

Reaction salt

Sodium bicarbonate-da Ascorbate-da

Magnesium Carbonate Ascorbate

Potassium Bicarbonate Potassium Ascorbate

Zinc Oxide Ascorbate Zinc

These products include the aldonates corresponding to those found in Example 5.

Example 7

The products of Examples 1, 4 and 6 were quantitatively analyzed.

The product has the designated composition.

Aldonic acid derivatives include the following acid derivatives having the following approximate proportions in the residue:

Acid (derivative) weight part

Mount Treon 8

Xyronic acid 2

Lichsonsan 3

One or more of these aldonic acids may be linked to one another or to ascorbate, or ascorbate may be linked thereto.

Example 8

Animal breeding studies with the product in Example 1 show similar results as the studies in the human body of Example 2.

Example 9

The process of Example 2 is repeated except that the test product is synthesized by mixing reagent grade calcium ascorbate with the following materials in the same weight ratio as found in Example 7.

Test A-threonic Acid (Calcium Salt)

Test B-Xyric Acid (Calcium Salt)

Test C-Lixonic Acid (Calcium Salt)

The test of Example 2 was repeated using these test compounds and using pure calcium ascorbate for further control.

The test confirms that the physiological activity of the mixed ascorbate and aldonate products is due to the aldon component, and that either one of these aldon components increases the absorption and retention of the vitamin component.

Example 10

This example describes the practice of absorption / maintenance of aspirin. Sixteen Wistar species 횐 mice (eight males (242-333 mg) and eight females (295-345 mg)) were acclimated for one week before the study began. During this period, rats were fed into a stainless steel cage, which was fed with a Purina (R) Rodent Chow and an arbitrary amount of water. We have a temperature of 700 +/- 2 ℉. A light cycle of 12 to 12 hours of light was maintained at a relative humidity of 60-80%.

Eight rats of four females and four males were randomly divided into two groups and placed in metabolic test cages. Group A contains 54 mg / kg of U.S.P. in 2.0 ml of distilled water. Aspirin is dissolved and fed. In the AM group, 54 mg / kg of U.S.P. was added to 2.0 ml of distilled water by adding 15 mg / kg of calcium threonate (a metabolite of ascorbic acid). Ate aspirin.

Blood samples were analyzed using U.S.P. for serum salicylate analysis. The samples were taken every 1, 2, 3 and 4 hours after aspirin administration. Also, urine was collected when salicylate analysis urine was produced within the same time. To effectively excrete the maximum amount of urine, rats were forced to feed 3 ml more water every 1,2,3,4 hours.

Blood and urine were collected and analyzed by the method of Natleson [Natelson, S. Tchniques of Clinical Chemistry, ed. 3. p. 649, Charles C. Thomas, Pub (1971). The test was completed after 4 hours of collection.

All statistics were calculated using statistical analysis system (SAS Institute, Inc, Box 8000, Cary, NC, 2751l) software. The ANOVA method (measured model repeated) was used to determine the difference in salicylate concentrations between both groups.

Table 1 shows the actual serum salicylate concentrations for each sample of A and AM in both groups. The mean (X), standard deviation (SD), and time for each group are given.

The significance level (P) representing the difference between the two groups with respect to the salicylate concentration in serum at each sampling is shown in the following histograms. FIG. 2 is a diagram of serum silylate after time-lapse for mice in both groups, with bars representing standard deviations. Initial uptake (in the gastrointestinal tract) can be calculated from the straightened curve at the first hour after ingestion.

The data for urine salicylate are not shown in detail but will be discussed below. Since there is no significant difference in serum salicylates due to the sex of the animals, they are not classified as male or female.

TABLE II

The AM group is U.S.P. The data reveals earlier intake and absorption for aspirin. This group has a high intake rate of 11.76 mg / hr while Group A has a low intake rate of 4.40 mg / hr. AM group curves are curves representing two different biphasics representing two processes. The first part of the curve is related to absorption or intake by gastrointestinal pain. Accelerated intake rates can be seen in the AM group compared to the A group, which is evident from the plot of each serum. The second part of the curve is related to distribution to other body parts and output from the kidneys. The difference in the curb at this time (at 2 hours) is due to reduced salicylate release by elongation in group A. This group is declining at this point. It appears to be approaching a stable concentration of salicylate at higher levels than the aspirin group.

The difference between the emission rates of the two groups is important. The reduction rate of plasma concentrations in group A (calculated from peak logarithms) is 1.30 mg / hr, whereas in AM group it is 0.05 mg / hr, which is approximately 26 times greater than in the absence of metabolites.

Urine salicylate assays tend to have a lower amount of salicylate released over time in the AM group compared to the A group. At the first hour after dosing, the urine in group A was generally 9.lmg% and in the AM group 5.0 mg%. This figure is consistent with higher serum levels in the AM group and lower serum levels in the A group.

The results show that the presence of metabolites increases the absorption of aspirin while acting locally on gastric epithelial cells. The metabolites themselves are absorbed to increase the concentration in the blood and have an inhibitory effect on the kidneys. This effect reduces the release of aspirin by the kidney mechanism. Time delays to suppress discharge from the kidneys are expected, which is seen in the second hour drop in the AM group plot.

The rise between 2-3 hours is caused by suppression of excretion in the kidneys and continued absorption.

Improved serum salicylate levels in the AM group are the result of reduced emissions rather than increased uptake.

The absorption rate of the AM group is 2.67 times larger than that of the A group, and the emission rate of the AM group is 26 times smaller than that of the A group. Therefore, reduced kidney excretion is more effective at maintaining serum salicylate levels than increased absorption rate.

Further testing demonstrates that the administration of aldonic acid compounds not only increases the absorption of aspirin but also controls the organic anion transporter tissue in the kidney.

As a result of this fact, aspirin blood levels are maintained for a longer time due to a decrease in the rate of excretion through the secretion process located in the basal tubules of the kidney.

Example 11

180 dogs of various species and ages were fed the product 3X 30 mgs / kg of Example 1. All dogs were suffering from motion disorders.

The effect is measured by the actual symptom change in new clinical numerical measures, in addition to the owners' report on the condition of the dogs. Measurements were taken on day 7 after administration and again 6 weeks thereafter. The last measurements were taken after 6 months or more.

Diagnostic Group:

Many different acute or chronic conditions have been treated.

It has been found that it is difficult to distinguish between the effects of additional administration or other factors in acute diseases with rapidly changing symptoms.

Thus, this study was only studied for conditions with known well-known causes that the symptoms were stable for a long time and the symptoms persisted regardless of administration.

"Funtio laesa" and senile degenerative changes in joint damage, arthrosis, spinal symptoms, hip dysplasia, old discs with secondary permanent changes, supportive tissues and motor tissues with secondary permanent changes such as: Animals with chronic diseases, such as muscle atrophy, which appeared as a result, were selected.

100 dogs were divided according to the above criteria and the species and age were not considered in this report.

TABLE III

This example shows that the product of Example 1 administered cures pain due to chronic deformation in the joints and skeletal tissues that most dogs with the above described types of symptoms have.

Calcium-ascorbate alone or L-ascorbic acid alone does not provide the above treatment.

Example 12

Ten male (375-411gms) Wister species white rats were domesticated seven days before the study began. During this period, the rats were fed Purina (R) Rodent Chow and an arbitrary amount of water and placed in an automatic flush stainless steel cage. We maintained 70 ± 2 ° F, relative humidity 60-80%, and time-to-contrast ratio of 12 hours versus 2 hours.

Mice were randomly divided into 2 groups of 5 animals and placed in Nalgene (R) cages.

For group A, 0.6 mg / kg U.S.P. Pyroxycampi, the AM group, 0.6 mg / kg of U.S.P. added 15 mg / kg of calcium threonate. Pyroxycam was fed.

Plasma samples were taken 4,6,8 and 10 hours after dosing for plasma pyricampam analysis. Selective HPLC was used for pyricampam analysis, and data were analyzed using SAS. ANOVA repeated measurements were used to determine the difference in plasma pyroxycam concentrations between the two groups.

Table IV shows the plasma concentrations for each of the rats in the A and AM groups at each sampling time.

The mean (X) and time for each group was given. 3 is a plot of plasma for the data presented in Table IV.

The initial rise in plasma levels of pyroxycam is much greater in the AM group than in the A group.

At 4 hours in the AM group, the peak pyrixicam plasma levels doubled. This level begins to fall and then coincides with group A at the eighth hour after the six hour point. However, AM plasma levels rise again after 8 hours. This fact indicates that there is an effect of threonate on the level of pyroxycam plasma. The statistical difference does not appear until 10 hours after P. ≦ 0.07. This is strong evidence that the threonate effect occurs.

Table IV

Example 13

Ten male (420-456 gms) Wister species white rats were domesticated seven days before the study began. During this period, the rats were fed Purina® Rodent Chowl and any amount of water and placed in an automatic flush stainless steel cage.

Mice were randomly divided into 2 groups of 5 animals. Rats in group A were fed 1.0 ml of distilled water daily from 3 days before the start of the test.

Rats in the AM group also received 15 mg / kg / ml of calcium threonate daily for 3 days.

The threonate content was adjusted for body weight gain to be administered at 15 mg / kg.

On day 4, rats in group A received 0.6 mg / kg of phyroxicam and the AM group received 0.6 mg / kg of phyroxam and 15 mg / kg of threonate.

Plasma samples were taken every 4, 6, 8 and 10 hours for plasma pyrocampam analysis and selective HPLC was used for the pyrocampam assay, and the data were statistically analyzed by SAS technique. Repeated ANOVA techniques were used to determine the difference in plasma pyroxycam concentrations between the two groups.

Table V shows the concentrations of plasma pyroxicam in which Group A and AM (pretreated metabolites) exist in each rat. The mean (X) for each group at each time point is given and Figure 4 is a plasma plot obtained from the data in Table V.

It can be seen from the plasma diagram that the pretreated AM group has higher pyroxycam plasma levels than the unpretreated group. The AM group had a higher absorption rate and maintained high plasma levels for more than 10 hours. The difference in high plasma levels averages about 60%. This high level is statistically evident at P. <0.05.

Pretreatment with calcium threonate significantly increased the plasma level of Ferixene and maintained for 10 hours.

TABLE V

Example 14

A 25 cm2 T-shaped flask containing 3 T 3 mouse fibroblasts was incubated with 100 mg% (1 mg / ml) calcium L-threonate (pH 7.4) at 37 ° C. for 1 hour.

The control group was incubated with Riner's as a control function.

The culture is transferred again and 1.25 mg% of ascorbic acid is added to each flask (5 μl of 14 C-L ascorbic acid is added and 10.0 mCi / mmol, 0.05 mCi / ml). The pH value was fixed at 7.62 and the flask was kept at 37 ° C. for 20 minutes.

The flask is trypsinized with 0.1 ml trypsin-DETA for 5 minutes after washing with 4 ml HBSS (−). To stop the cell enzymatic reaction, the cells were resuspended in 4 ml of cold HBSS (-) and centrifuged at 1000G for 10 minutes. It is then washed and suspended in 4 ml HBSS (-).

Centrifuge again (10 min at 1000 G) and resuspend in 1.0 ml distilled water for 90 sec.

0.5 ml of each sample is used to measure ¹⁴ C and 0.5 ml is used for protein analysis using the Brad ford method.

¹⁴ C absorbed into the cell resulted in the following results.

Table VI

As a result, the uptake rate of ¹⁴ CL-ascorbic acid in the cells into the flask containing threonate is 1.86 times greater than in the cells containing the control sample. This result is statistically significant and is shown graphically in Figure 5 of the Steent's T-test, alpha = 0.05).

Claims (4)

(a) a therapeutic activity of (i) a molecular weight of 5000 or less, (ii) an acidic functional group, pKa ≤ 6 at a physiological pH = 7.4, and (iii) an unmetabolized, normal release of organic anions via the renal coronary secretion pathway Compounds: and (b) L-threonic acid, L-xylonic acid, L-lyxonic acid (I--Iyxonic acid), edible non-toxic salts from said compounds, said A therapeutic composition consisting of at least one compound selected from aldono-lactone and aldono-lactide from the compounds. (a) an effective amount of a compound having vitamin C activity selected from (i) dihydroascorbic acid (ii) L-ascorbic acid and edible salt therefrom; (b) an aldosterone salt of L-threonic acid, L-xylonic acid and L-lyxone acid and an edible salt of L-threonic acid, L-xylonic acid and L-lyxone acid A vitamin C composition consisting of an effective amount of at least one compound (for an increase in human hop yield of said vitamin C compound). The vitamin C composition according to claim 2, wherein the amount of the aldon compound is effective to increase the absorption rate of the vitamin C compound. 3. A vitamin C composition according to claim 2 wherein the amount of aldon compound is effective to reduce the excretion rate of the vitamin C compound.