JP3058659B2 - Minerals in bioavailable form - Google Patents

Description

The present invention relates to a bioavailable form of mineral,
The present invention relates to a method for administering the mineral to target cells.

Minerals such as zinc, calcium, iron, magnesium, and manganese are contained in certain enzymes and are essential for human, animal and plant life support. In some cases, vitamins promote the incorporation of minerals into enzymes,
Lack of minerals or vitamins suppresses enzyme activity. For example, zinc is included during the synthesis of DNA by DNA polymerase, a zinc-containing enzyme. Nicotinic acid, a vitamin, promotes the incorporation of zinc into the peptide subunit of the DNA polymerase enzyme. A deficiency of either nicotinic acid or zinc in the body reduces tissue DNA polymerase activity, resulting in a lack of growth in both cases.

The principle of drug therapy applies to mineral therapy, the goal of which is to put the right drug in the right tissue at the right concentration for a long enough time to achieve the desired therapeutic effect. If the concentration of the drug is too low, the treatment will not be effective, and if the concentration of the drug is too high, toxicity will result.

Because metals are highly charged molecules, many minerals are poorly absorbed and cannot easily pass through cells, even if available to the serum. For example, the prostate is a zinc-rich male organ, and zinc concentration in semen plasma serves as an indicator of prostate function, as demonstrated in recent studies. Oral administration for supplementation of zinc, e.g., zinc sulfate, zinc chloride or zinc acetate, increases the concentration of zinc in the serum but does not consistently increase the concentration of zinc in the plasma of the semen, Do not improve.

In addition to being difficult to absorb, the consumption of some minerals is unpleasant. For example, supplementation of orally ingested zinc causes nausea, vomiting and diarrhea, and topically applied zinc compounds are astringent and irritating. Zinc oxide, on the other hand, is neutral and can be applied topically, but is not water soluble and is not absorbed into tissues. For example, the acidity of water-soluble zinc salts such as zinc acetate, zinc chloride and zinc sulfate cannot be neutralized with sodium hydrogen carbonate or sodium hydroxide. When sodium bicarbonate is used, since a large number of bases are required to obtain a pH of 7, for example, a molar ratio of 5: 1 with respect to a zinc salt, this compound has a high sodium concentration and also has a high sodium concentration. When used, the neutralized mixture readily precipitates upon standing.

As described above, whether orally ingested, topically applied, or injected into the body, they are easily absorbed into the serum, easily pass through target cells, and become biologically active. There is a need for available forms of minerals and their preferred method of administration. Other objects and features are in part apparent and in part pointed out below. The present invention
The scope of the invention, including the products and methods described below, is set forth in the appended claims.

In the present invention, lysine, arginine and histidine are basic amino acids (positively charged at pH 6) and are used to neutralize the acidity of zinc salts such as zinc acetate, zinc chloride and zinc sulfate. It began with the observation that it could be done. However, experiments do not provide an effective delivery format because this mixture readily precipitates on standing. It has been found that zinc gluconate, unlike zinc acetate, zinc chloride and zinc sulfate, can be neutralized with the basic amino acids described above to provide a stable mixture. Also, unlike zinc acetate, zinc chloride and zinc sulfate, zinc gluconate is neutralized by a base such as sodium hydroxide in the presence of certain non-polar amino acids and certain non-polar non-polar amino acids, It has been found that a stable mixture that is water soluble can be provided.

According to the present invention, neutralized minerals are more readily absorbed and work more effectively at the tissue level in the target organ than the minerals alone. Surprisingly, this is
This is done without the bacterial effects of zinc, which were at least partially attributed to the acidity of the zinc salt. this is,
A new perspective in the field of bacteriology is that the products based on the findings of this subject are new and aged tissues and the eyes, nose and nose, where for example soluble zinc salts were previously not used effectively. It can be used for areas of the tissue that are very sensitive to acid, such as the sensitized vagina.

According to the present invention, for example, by neutralizing the mineral salts of carboxylic acid derivatives of pentoses or hexoses, such as zinc gluconate, zinc glonate, etc. in the presence of amino acids, they are much more readily absorbed than minerals alone and in target organs. , A bioavailable form of a mineral that works effectively at the cellular level. Other minerals that can be administered in such a form include calcium,
There are iron, magnesium and manganese.

Zinc gluconate, like zinc acetate, zinc chloride and zinc sulfate, is acidic as shown in Table 1 below.

Like the other soluble zinc salts described above, zinc gluconate cannot be neutralized with sodium hydroxide without precipitating the mixture. However, the acidity of zinc gluconate is determined by adding amino acids such as alanine, valine, isoleucine, proline, glycine, serine, threonine, asparagine, glutamine, lysine, arginine, histidine, and mixtures thereof, and adjusting the pH to 7.0. Found that it can be neutralized. This adjustment cannot be made with cysteine, tyrosine, aspartic acid or glutamic acid.

Generally, it is preferred that the mineral salts and amino acids be present in substantially equimolar amounts. A preferred therapeutic formulation is a mineral salt such as zinc gluconate: amino acid of about 0.05M: 1.
0M to about 1.0M: 0.05M, preferably about 0.1M: 0.3M to about 0.3M
M: formed from 0.1M, most preferably from about 0.1M: 0.1M to about 0.3M: 0.3M, neutralized to a pH of about 6.0-8.0, preferably about 6.
It is neutralized to a pH of 5-7.5, most preferably 7.0.

Protein general structural formula of commonly found 20 amino acids in is R-C (H) (NH 2) -COOH, most importantly to classify these, the polarity of the R groups Due to: (1) non-polar or hydrophobic R groups, (2) neutral (uncharged) polar R groups, (3) positively charged R groups.
And (4) negatively charged R groups (pH 6.0-7.0, intracellular pH). As shown below, the amino acids suitably used in the present invention differ from this taxon.

There are eight standard amino acids with nonpolar R groups. Five (alanine, leucine, isoleucine, valine and proline) have an aliphatic hydrocarbon R group, two (phenylalanine and tryptophan) have an aromatic ring and one (methionine) has sulfur. As shown in Table 2 below, alanine, valine, isoleucine and proline are preferably used as described herein,
Leucine, phenylalanine, tryptophan and methionine are not preferably used.

There are seven amino acids that have a polar R group without a charge that can hydrogen bond with water. The polarity of serine, threonine and tyrosine is contributed by these hydroxyl groups, the polarity of asparagine and glutamine is contributed by amide groups,
Cysteine is contributed by sulfhydryl groups. Glycine is at the boundary of its group and is often classified as a non-polar amino acid, but its R group is one hydrogen atom, too small to affect highly polar amino and carboxyl groups. Asparagine and glutamine are amides of aspartic acid and glutamic acid, which are readily hydrolyzed by acids or bases to aspartic acid and glutamic acid, respectively. Cysteine and tyrosine have the most polar substituents of this class of amino acids, namely the thiol and phenolic hydroxyl groups, respectively. These groups have a pH
Although slightly ionized at 7.0, it is easier to lose protons by ionizing more easily than the R groups of other amino acids of this class. Of the above amino acids having an uncharged polar R group, as shown in Table 3 below, glycine, serine, threonine, asparagine and glutamine are preferably used here, but cysteine and tyrosine are not preferably used. .

Basic amino acids whose R groups are net positively charged at pH 7.0 all have 6 carbon atoms. This basic amino acid is composed of lysine having an amino group positively charged at position e of the fatty chain, arginine having a positively charged guanidic acid group, and histidine also containing a weakly basic imidazoline action. . Histidine is the only amino acid having an R group pK 'of around 7.0 and having a buffering capacity around pH 7.0. As shown in Table 4 below, all basic amino acids are suitably used in the present invention.

The two amino acids having a negatively charged R group are aspartic acid and glutamic acid, each having a second carboxyl group and are fully ionized and negatively charged at pH 6-7. All of these amino acids are suitably used in the present invention as shown in Table 5 below.

In addition to the standard 20 amino acids, commonly known as proteins, there are synthetic amino acids and other naturally occurring amino acids known to occur in biologically free or linked form. By performing the selection as described above, among these other amino acids, other amino acids suitably used in the present invention can be identified.

In some cases, it may be advantageous to administer the neutralized mineral combined in combination with a vitamin such as, for example, vitamin C, nicotinic acid, etc., depending on the conditions to be treated. For example, when the mixture is considered as a dietary supplement to stimulate growth, nicotinic acid is screened, while when stimulating wound healing, vitamin C is selected. The minerals according to the invention may be, for example, glycerin, carboxymethylcellulose, as a carrier or excipient in water-soluble, emulsion or dried form, optionally in combination with a therapeutic ingredient such as a vitamin or other drug.
It can be used in combination with oils, sweeteners and flavors. Depending on the form to be treated and the target tissue, the mineral is taken orally, applied topically to the external or internal epithelium, or injected.

 Hereinafter, the present invention will be described specifically with reference to Examples.

Example 1 Diaper rash, reddish, hypersensitive from 3 months
Twenty-eight newborns aged 11 months were sprayed twice daily for 3 days with the following formula.

Composition Weight% 1.0% Zinc gluconate 0.3% Lysine 10.0% Glycerin balance Distilled water and HCl recovery to adjust pH to 7.0 was seen in all cases, with 50% of patients showing recovery in 2 days.

Example 2 36 pigs kept on a farm had wet wounds. Some of the flour pigs had ear wounds due to biting and fighting, and some had wire wounds. The wound had previously been treated with a sulfa drug to heal the wound, but remained unhealed.

 The wound was sprayed twice daily for 2 days with the following formulation.

Composition Weight% 5.0% Zinc Gluconate 1.5% Lysine 10.0% Glycerin Rest Within 2 days of distilled water and HCl to adjust pH to 7.0, the ulcers began to heal, bleeding stopped and the condition recovered. The ulcer was no longer noticeable after two weeks. The skin returned within a month.

Example 3 Sensitive skin on the thighs and buttocks of a 6 month old baby and a 2 to 2 1/2 year old child was treated with the following formulation.

The hypersensitivity and redness disappeared completely in 5 days.

Example 4 A diabetic patient with keratinization of the heel and dryness of the foot was prepared in Example 1.
Was sprayed with the same formulation as that used to treat diaper rash. The lotion was used overnight and the regimen continued for one week. One week later, the scales and odor on the feet disappeared, and the skin became soft.

Example 5 Seven patients were asked to spray the inside of a shoe with a formulation containing 5.0% by weight zinc gluconate, 1.5% by weight lysine and the balance water and HCl to adjust the pH to 7.0. did. Before spraying the shoes, swabs were used to verify the large growth of bacteria, and 8 hours later, a small number of growths were verified using a swab. The spray reduced both odor and bacteria in the shoe.

Example 6 A gel containing the following formulation was applied twice daily for 3 days to 3 dogs with pyrogenic spots, scaling, dry skin, hair loss and pathological evidence of common tinea on the skin.

Composition Weight% 2.0% Carboxymethylcellulose 5.0% Zinc gluconate 1.5% Lysine Residue After 5 days of water and HCl to adjust pH to 7.0, redness and scale disappeared, and within two weeks hair growth was restored. One dog has Demodex under the skin
dex) Carried with the mite and treated with this gel for 10 days. This gel inhibited mite growth and restored hair growth.

Example 7 Four dogs had a recurrence of chronic dermatitis during the course of 6-18 months, despite treatment with antibiotics and cortisone. It is caused by dog's skin allergic reaction, but I do not know well.

The following formulation was added to the drinking water of each dog once a day based on 1 ml of solution per 1 kg of body weight.

Each 1 ml solution contained 1 mg zinc gluconate, 4 mg potassium gluconate, 0.5 mg lysine and 2 mg taurine.

After two weeks of this regimen, the dry scale-like skin of the four dogs showed recovery and the hair appeared healthier. After one month, there was no evidence of dermatitis. In hot and dry climatic characteristics, such as the last two months of the follow-up period (June and July 1988), dermatitis is generally increasing, but the three-month follow-up period to date During the course, dermatitis did not recur. None of the dogs exhibited any symptoms such as toxicity, stomach irritation, diarrhea, or vomiting from eating zinc gluconate at a dose determined based on body weight.

Example 8 Between June and July 1988, many dogs suffered feet / paw dryness and inflammation due to dry throat and extreme heat. The following is formulated as a foot ointment or spray to prevent foot / paw burns and dryness caused by extreme conditions.

Composition Weight% 2.0% Carboxymethylcellulose 5.0% Zinc gluconate 1.5% Lysine 1.5% Histidine balance HCl to adjust water and pH to 7.0 Apply this ointment to feet / paw once a day for 2 months did. The dog was examined daily for discomfort. At the end of the two months of treatment, the condition had recovered and protection was achieved.

Example 9 Every day for two weeks, six dogs with halitosis were fed dog biscuits (20 g / day) injected according to the following formula. Also, one of the six dogs has fungal growth on the tongue.

After two weeks, bad breath had disappeared and oral hygiene had improved. The black part of the tongue with fungal growth of one dog was no longer noticeable and the tongue had regained its normal appearance.

Example 10 Six dogs with eye problems were diagnosed and divided into the following groups:

A. 2 with lacrimal sac inflammation B. 3 with subconjunctival hemorrhage and iris inflammation C. 1 with keratitis, ulcerative inflammation and blepharitis The treatment was performed by applying 1 ml of the following eye drops twice daily for 7 days.

The eyes of groups A and B healed after 7 days of treatment,
Group C took 10 days.

Example 11 The following formula having a pH of 7.0 was sprayed on the bleeding gums of two horses and one donkey.

Carboxymethylcellulose is added to adhere the solution to the gum mucosa and to protect against physical damage caused by, for example, hay and dried barley bait. Sweeteners are added to horses because they are a favorite of horses.

The gums of the animals were sprayed twice daily for one week. Bleeding
It stopped and the oral odor was eliminated. Gum pain on touch was reduced. Providing owners with preventive measures once a week
Or it was recommended to spray the gums of this animal twice.

Example 12 Eight patients who had athlete's foot for a few years and were tired of Dr. Shawl products and other osmotic solutions, such as dried saponaria osmotic agents, were subjected to the study. Microscopy and fungal culture of samples taken from patients identified the pathogen as Trichophyton trichome.

Patients were advised to spray feet and shoes twice daily, once in the morning and once in the evening, with the following formula.

* The preparation of zinc ascorbate is described in Example 13 below.

The treatment regimen for athlete's foot had a clear effect after 3 days, eliminating itching on the feet and reducing the smell of the feet. After 5 to 7 days of treatment, the feet were normal.

As a precautionary measure, patients were advised to apply the spray twice a week. During the five-and-a-half months follow-up period, none of the patients had a recurrent athlete's foot.

Example 13 35 g of (2M) ascorbic acid was dissolved in 150 ml of water,
And cooled. The initial pH of the solution was 2. Zinc oxide (1M) 8
g was added and the solution was continuously stirred and kept cool.
After several hours, all the zinc oxide is mixed into the solution and the pH is 4.9.
Went up. This mixture is light yellow in color and is immediately frozen and dried. A bright yellow powder having a molecular weight of 415.61 was obtained in this way. The dried powder was stable, but the solution neutralized to p7 with sodium hydroxide was not.

Example 14 A powdery composition comprising zinc and lysine, which forms a neutral solution when dissolved in water, was prepared as follows.

Dissolve 2M lysine and 1M zinc gluconate in water, pH 7.
A solution with 4 was formed and neutralized to pH 7 with HCl.
After neutralizing the zinc and amino solutions, they were immediately frozen in liquefied nitrogen. Next, the frozen solution was freeze-dried for 24 hours to remove water. Upon drying, it forms a neutral solution (pH 7) when dissolved in water, forming a white powder containing zinc and amino acids.

A comparable formulation is formed with arginine and histidine, but in the case of histidine, the solution has a pH of 5.5 and is therefore neutralized with NaOH.

Example 15 Two patients with vaginitis were treated with 3% zinc gluconate,
Treated once every 1-3 days with a solution containing 1% lysine, 1% carboxymethylcellulose and the balance water and HCl to adjust the pH to 7.0. The tingling sensation subsided 24 hours after treatment, inflammation was reduced, and tenderness and pain were reduced.

Example 16 Three middle-aged female patients were treated with the composition described in Example 3 as a face cream. Each patient was instructed to apply the face cream once or twice daily. Within three weeks, all had a restored skin condition, some wrinkles had disappeared, no hypersensitivity had appeared, and there were no other adverse side effects.

Example 17 A formulation having a pH of 7.1 formed from 0.1 M zinc gluconate dissolved in water with 0.1 M lysine was prepared using Difco Tryptic Soy Pros.
y Broth) (TSB). This resulted in a very slightly turbid solution at pH 6.87. For 50 ml of solution, the pH was raised to 7.2 using about 1.2 ml of 1 M NaOH. This neutralized solution was called ZTSB and sterilized by filtration using a 0.2 μm filter. About 15ml before filter is clogged
ZTSB was filtered. There was no noticeable amount of material on the filter surface and there was very little zinc loss during the sterilization process. Control TSB was similarly sterilized.

Spectrophotometric experiments E. Coil ATCC 25922, Pseudomonas aeruginosa ATCC 2
7853 Staphylococcus aUREUS ATCC 25923 and Streptoco
Four bacterial strains of ccus fecalis ATCC 33186 were used. These bacterial strains are used for quality control evaluation of antibiotic disk susceptibility testing. All four bacterial strains were grown overnight on TSB. 250 μl of each culture
Was placed in a 96-well microtiter plate in Dynatech Immuon IELISA. Each absorbance was measured using an automatic plate reader connected to a microcomputer. Readings at 560, 595, and 650 nm yielded blanks for 250 μl of distilled water. 560nm
Was found to be the most sensitive and was further tested. Also, the sterilized TSB and ZTSB contained negligible absorbance at these wavelengths compared to the blank.

Preliminary Evaluation of ZTSB The sterilized tubes of TSB and ZTSB containing 1.0 mg medium were each inoculated into each of the four bacterial strains and inoculated in air.
Incubated at ° C. Control tubes from both media that were not inoculated were included. After inoculation, each ZTSB tube was slightly hazy. The control TSB tubes were clear, but these ZTSB tubes showed considerable turbidity indicating bacterial growth. These results indicated that bacterial growth was suppressed in ZTSB,
Under incubation, there was a small amount of chemical precipitation. In addition, by storing sterilized ZTSB at 4 ° C for a long time,
There was a slight amount of precipitation.

Spectrophotometric evaluation of bacterial growth in ZTSB Each of the four bacterial strains was grown in TSB at 35 ° C overnight. Tubes of ZTSB, each containing 5.0 ml of liquid medium, and control TSB were added to 10 μl of each of the four bacterial strains.
Was inoculated. Control tubes that were not inoculated were included. 0, 1, 3, 4, 5, 6, 7, 8 at 35 ° C in air
And after 24 hours of incubation, 25
Aliquots of 0 μl and control tubes were placed in the wells of a microtiter plate. The absorbance at 560 nm was measured and a blank of distilled water was used for each reading interval. The results are shown in Table 6 below.

In addition, each was inoculated after 24 hours of incubation.
Separate the contents of TSB and ZTSB into 5% sheep blood medium,
Incubated overnight. There were bacteria that could grow in all incubated tubes except ZTSB Ec and ZTSB ps. Ec and Ps This data, together with the data that there is no visible growth of bacteria in the ZTSB tubes, indicate that ZTSB is E. Coil and Pseudomonas a
This means that it not only inhibited the growth of eruginosa, but also was bactericidal under the incubation conditions.

In view of the above, it will be seen that some objects of the invention have been achieved and other advantageous results have been achieved. While various modifications may be made as described above without departing from the scope of the invention, all that is included in the above description is provided by way of example and is not limited thereto. is not.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁷ identification code FI A61P 17/00 A61P 17/00 (58) Field surveyed (Int.Cl. ⁷ , DB name) A61K 31/19 A61K 31/195 A61K 31/315 A61P 3/12 A61P 15/02 A61P 17/00 CA (STN) MEDLINE (STN)

Claims (9)

(57) [Claims] 1. A bioavailable composition for treating living tissue responsive to the administration of zinc, comprising a zinc salt of a carboxylic acid derivative of pentose or hexose, and alanine. , Valine, isoleucine,
An amino acid selected from the group consisting of proline, glycine, serine, threonine, asparagine, glutamine, lysine, arginine, histidine and mixtures thereof, wherein the zinc salt and the amino acid are in substantially equal molar ratios and
A composition, wherein the composition is present at a concentration of 0.05M to 1.0M and the pH of the composition is in the range of 6 to 8. 2. The zinc salt is a zinc gluconate,
The composition according to claim 1, wherein the concentration of zinc gluconate and amino acid is 0.1M to 0.3M, and the pH of the composition is 6.5 to 7.5. 3. The composition according to claim 2, wherein the pH is substantially 7.0. 4. The composition according to claim 3, wherein said amino acid is lysine. 5. The composition according to claim 3, further comprising a vitamin. 6. The method according to claim 5, wherein said vitamin is niacin.
A composition according to claim 1. 7. The method according to claim 5, wherein said vitamin is vitamin C.
A composition according to claim 1. 8. The composition according to claim 1, wherein the composition is for treating an epithelial disease. 9. The composition according to claim 8, wherein the epithelial disease is selected from the group consisting of diaper rash, vaginitis and dry skin.