CN106913561B

CN106913561B - Application of taurine-chelated calcium in preparation of percutaneous absorption preparation

Info

Publication number: CN106913561B
Application number: CN201511000848.5A
Authority: CN
Inventors: 侯玉庆; 刘彦宏; 陶几中; 马丹; 徐健梅; 侯天歌
Original assignee: Beijing Runing Chuangzhi Biotechnology Research And Development Center LP
Current assignee: Beijing Dairy Innovation Biotechnology Co ltd
Priority date: 2015-12-25
Filing date: 2015-12-25
Publication date: 2020-12-15
Anticipated expiration: 2035-12-25
Also published as: CN106913561A; CN112516123B; CN112516123A; CN112472717A; CN112472717B; CN112353789B; CN112353789A

Abstract

The invention relates to the application of taurine-chelated calcium in preparing percutaneous absorption preparation, wherein the percutaneous absorption calcium supplementing mode can supplement the physiologically active ionic calcium needed by human body to the greatest extent, especially the percutaneous absorption calcium supplementing mode can directly and rapidly realize calcium supplement to the epidermal system without blood circulation system, thus solving the problem that the orally-taken supplemented calcium is firstly used for bone formation and becomes non-physiologically active combined calcium to cause insufficient ionic calcium with physiological activity, and simultaneously, the taurine has the function of regulating the concentration of calcium ions inside and outside the cells of the human body, namely, the taurine inhibits the concentration of calcium ions at high concentration and promotes at low concentration, and the problems of regulating the calcium deficiency and calcium excess in the skin cells, and is an important regulation mode of calcium ion balance inside and outside the cells, and the function of the taurine-chelated calcium capable of being absorbed through skin can be used for external pharmaceutical preparation, Preparing medical health materials, topical health product preparation, and cosmetics.

Description

Application of taurine-chelated calcium in preparation of percutaneous absorption preparation

Technical Field

The invention relates to taurine chelated calcium for percutaneous absorption and treatment of skin diseases or systemic calcium supplement, which has excellent percutaneous absorption effect, can rapidly and percutaneously supplement calcium ions and taurine required by skin, and has the functions of regulating the concentration of calcium ions inside and outside epidermal cells of organisms and repairing skin barrier function. Meanwhile, the stability of the amino acid in aqueous solution is far better than that of amino acids of other proteins, so that the amino acid is more suitable for preparing aqueous external preparations, such as smearing preparation, cream, liniment, spray, gel and the like. It is especially suitable for preparing into pharmaceutical external preparation, medical health preparation, health product external preparation, and cosmetic, and can be used for treating various skin diseases caused by skin calcium deficiency, repairing skin barrier after damage, and daily caring and maintaining skin.

Background

There are two existing states of calcium in the human body, namely, ionic calcium and bound calcium. The combined calcium mainly exists in bones and teeth to form a human body bracket to maintain normal activities, and the calcium has no physiological activity; ionic calcium is physiologically active calcium, is essential for maintaining normal physiological activities of human cells, and is mainly present in blood, extracellular fluid, cells, skin and other soft tissue structures.

The human skin system calcium deficiency phenomenon is ubiquitous and relatively serious, various skin diseases can be caused by the human skin calcium deficiency, the skin barrier effect is poor, the human skin is susceptible to inflammation, is easy to damage, has long healing period after damage, is dry and sensitive, has imbalance of water and oil balance, accelerates skin aging, has weak environmental tolerance and other various skin problems, and particularly, various poor skin states can be caused easily when the facial skin is in a naked state and is influenced by adverse environments such as strong ultraviolet rays, pollution, radiation and the like. The long-term calcium deficiency of the human skin system is mainly caused by the following two factors:

1. human calcium supplemented orally is preferentially used for the requirement of bound calcium having no physiological activity, such as bones and teeth.

Calcium in a human body is in a dynamic loss state for a long time, and at present, two ways of calcium supplement are provided for the human body, one way is to supplement the calcium by an oral way, and various calcium supplement preparations are mainly oral calcium tablets and oral liquid; one is to supplement calcium by intravenous injection, but the method of intravenous injection has great danger and needs to be carried out by a professional physician, so the current common calcium intake method is only oral calcium supplement.

When a human body is in a state of calcium deficiency, the orally supplemented calcium preparation is preferentially used for supplementing combined calcium required by bones, teeth and the like, and at the moment, the supplemented calcium loses physiological activity and can not be supplemented or can only be supplemented with ionized calcium in a very small amount, but the physiological activity for regulating the organism is insufficient, so that the calcium ion is transported to the epidermis layer through blood circulation to keep the balanced steady state of the calcium ion of the epidermis layer under the condition of calcium deficiency of the human body is very difficult.

Oral calcium preparations are difficult to absorb, have low absorption rate and are complicated by a large number of factors, which are mainly caused by the complex environment of the gastrointestinal tract. The oral supplementary calcium agent is digested and absorbed through gastrointestinal tracts, the stomach environment belongs to a strong acid environment, the pH value changes from 0.8 to 3.6, the small intestine environment belongs to weak alkalinity, the pH value changes from 7.2 to 8.0, the change of the acid-base environment is unfavorable for the absorption of calcium ions, for example, the calcium ions are easy to form a gelatinous calcium hydroxide precipitate in an alkaline intestinal tract environment, so that the calcium ions are difficult to be absorbed by a human body, and meanwhile, the gelatinous matter can be adhered to the intestinal wall to further influence the absorption of other nutrient elements. In particular, oral administration of calcium is susceptible to contamination by anions in the gastrointestinal tract to generate insoluble calcium, which greatly reduces the absorption rate of calcium ions, and for example, phytic acid, oxalic acid, alkaline phosphate, fat, uronic acid residues in dietary fibers, nucleotides, uric acid, and the like contained in ingested food can react with calcium ions to generate insoluble or poorly soluble calcium oxalate, calcium phytate, alkaline calcium phosphate, calcium urate, and the like, which not only interferes with the absorption of calcium ions, but also causes calcium to precipitate in tissues as calcifications, and continuously deposit in organs to form calculi, thus affecting the health of the body.

2. The human epidermal system has no blood circulation system, and the calcium ions with physiological activity are difficult to transport

The human body mainly conveys absorbed nutrient substances to all parts of each system of the human body through a blood circulation system, but a blood system does not exist in an epidermal system, the nutrient substances are mainly conveyed through tissue fluid, but the conveying amount and the conveying efficiency are very low, meanwhile, because the oral calcium ions are preferentially used for combining the requirement of calcium, the required ionized calcium is difficult to supplement to the epidermal system through oral administration, the ionized calcium with physiological activity is very important for maintaining the steady state and the health of the epidermal system of the human body, the epidermal system of the human body is the first defense line of the organism for resisting dehydration, injury, infection and bacteria, the normal ionized calcium concentration is the most main factor for maintaining the stability and the repair of the epidermal barrier system of the epidermal system of the human body after damage, and the epidermal barrier can be damaged when the calcium ions are deficient or disordered, thereby causing various skin problems and even pathological changes, maintaining normal calcium ion concentration in the epidermal system is very important for the epidermal barrier to remain stable or repair after damage. Therefore, it is very important to directly supplement physiologically active ionized calcium which is easily absorbed through the skin, especially to maintain the calcium balance of the epidermal system.

3. At present, the market lacks of external targeted calcium supplement

At present, various calcium supplements in the market are oral preparations, including various calcium tablets and oral liquids, which are mainly developed aiming at a special digestive system of the gastrointestinal tract, the pH value of the gastrointestinal tract is between 0.8 and 3.6, the calcium supplements belong to a strong acid environment, calcium ions are polluted by various bacteria, organic acids and anions, and become insoluble substances which are not absorbed by a human body, the normal pH value range of the human epidermis is between 5.2 and 6.5, and the calcium supplements belong to a weak acid environment, so the oral calcium generally used for the digestive absorption of the gastrointestinal tract is difficult to be absorbed by the skin. Meanwhile, inorganic calcium and ionic organic calcium such as calcium chloride, calcium carbonate, calcium lactate, calcium propionate, calcium citrate, calcium gluconate and the like are generally selected for oral calcium preparations, all of the calcium preparations are in an ionic state, and some calcium salts have the problem of poor solubility, so in the field of percutaneous absorption, insoluble compounds and ionic compounds are very difficult to absorb.

Meanwhile, no scholars are available to research the problem of percutaneous absorption of calcium, so that research on calcium supplement agents beneficial to percutaneous absorption is very necessary and is a very innovative research subject, the mode of percutaneous absorption of calcium supplement can realize direct supplement of ionic calcium with physiological activity to a body, particularly, targeted calcium supplement to an epidermal system without a blood circulation system can be realized preferentially, the absorption efficiency is high, the influence of special and complex environments of the gastrointestinal tract is avoided, and the problem of low absorption utilization rate caused by the fact that calcium ions are easily polluted by anions can be solved.

Disclosure of Invention

In view of the above problems of the oral calcium supplement method, especially the difficulties faced by preferentially supplementing physiologically active ionized calcium required by human epidermis and other soft tissue systems, the present invention provides a new calcium supplement method, which uses taurine chelated calcium easy to be absorbed through skin as a calcium supplement agent, directly performs targeted calcium supplement to other soft tissue such as human epidermis system and blood through the percutaneous absorption method, and solves the problem of difficult calcium supplement to the skin epidermis system and other soft tissue systems.

The invention aims to provide a novel calcium supplement mode by a percutaneous absorption way, which is used for supplementing calcium required by a human body, in particular to preferentially supplement physiologically active ionic calcium required by the human body for maintaining normal physiological activities and supplement calcium required by an organism epidermal system without blood circulation in time, and increase the reserve of calcium content in the organism epidermal system.

The invention also aims to research and select one or more calcium-containing compounds with better percutaneous absorption performance so as to improve the percutaneous absorption effect of calcium and achieve better calcium supplement effect.

Generally, the calcium-containing compound includes ionic compounds and coordination compounds, most of which belong to insoluble substances, such as calcium hydroxide, calcium carbonate, calcium oxalate and the like, and the calcium in the ionic calcium-containing compound exists in the form of calcium ions after being dissolved, but because the percutaneous absorption mainly absorbs substances through the endocytosis of cell membranes, the lipid structure of the cell membranes has selectivity on the absorbed substances, similar to the principle of similar compatibility, the ionic substances are generally difficult to realize the percutaneous administration, and only fat-soluble substances or amphiphilic substances which can be dissolved in water and can also be dissolved in lipid solvents can realize the good effect of percutaneous absorption, but another condition which these substances must satisfy is that the molecular weight is suitable and cannot be overlarge. The coordination compound belongs to a non-ionic compound, calcium dissolved in the coordination compound exists in a non-ionic form, and the percutaneous absorption effect of the coordination compound is better than that of an ionic compound.

In the calcium-containing coordination compound, amino acid chelated calcium has better percutaneous absorption effect compared with other calcium-containing compounds, which is probably caused by amino and carboxyl contained in amino acid, wherein, nitrogen-containing amino and lecithin in skin are similar in composition, and carboxyl contained in the amino acid belongs to hydrophilic group, thus the amino acid has certain amphiphilic property, calcium ion is used as central ion to be chelated with amino acid in molecular state through coordination bond, the problem that ionic calcium is difficult to absorb is solved, the absorption effect of the amino acid chelated calcium can be enhanced by virtue of amino acid channel during percutaneous absorption, and the molecular weight is smaller, thereby meeting the requirement of percutaneous absorption on selectivity of substances and improving the percutaneous absorption and utilization effect of calcium.

The experimental researchers of the invention find that taurine is more suitable for preparing the calcium chelate capable of being absorbed through skin among various amino acids, is particularly favorable for supplementing calcium required by a skin system, is also necessary for supplementing taurine to human skin, and no study exists at present for researching that the taurine-chelated calcium is used for supplementing calcium to the skin.

The taurine-chelated calcium can be used for percutaneous calcium supplement, which is mainly caused by the following reasons:

1. bidirectional regulation effect of taurine on calcium ions

Among the biological effects, the most critical is the inhibitory effect. The biological inhibitive property is characterized by maintaining the stability of the system, regulating the biological process of the organism deviating from the steady state, and showing the protection or orderly repair of the injury caused by the deviation from the steady state. It can be said that inhibitory effects encompass regulatory, maintenance, stability and protective effects.

Biological inhibition is an important factor for realizing biological regulation and control, and the normal state of the organism is in a negative feedback regulation state, or the normal state of the organism is in a stable state. For example, cardiovascular activity in the brain centrally controls the activity of the heart and blood vessels through the sympathetic and vagus nerves, maintaining arterial blood pressure at a certain level. For example, many endocrine cells are also regulated by various negative feedback mechanisms to maintain their activities at a certain level.

In the negative feedback regulation mechanism, the system is maintained at a certain level stably, and the system can also be regarded as being maintained at a certain "set point", so that the negative feedback regulation is that the system is stable and close to the original "set point" after being disturbed. The key of the system with a negative feedback regulation mechanism is that the system has a function of inhibiting system deviation, so that the inhibiting function becomes an important factor of the system with negative feedback regulation. Biological inhibition of biological systems is also an important factor in achieving biological regulation and control.

Research experiments of in vivo and in vitro cells of a large number of scholars show that taurine has a regulating effect on the concentration distribution of calcium ions, can maintain the stability of the concentration of the calcium ions, has an obvious regulating effect on a plurality of physiological and pathological phenomena of cells depending on the calcium ions, can inhibit the overload of the calcium ions in the cells caused by various reasons, and protects the cells. It can increase the amount and speed of calcium ion transported by high affinity calcium ion transport system, promote the internal flow of calcium ion at low calcium ion, reduce the internal flow of calcium ion at high calcium ion and increase the affinity of calcium ion with cell, so as to reduce the level of free calcium ion, antagonize the cell protection effect of calcium ion overload, and regulate the calcium ion in cell in stable state. The method is beneficial to the formation and the stabilization of the concentration gradient of calcium ions of the epidermis layer of the skin, ensures the normal formation of the barrier system of the epidermis of the skin and avoids various skin diseases caused by calcium deficiency and excessive calcium.

2. Effect of taurine structural Properties on transdermal absorption

Taurine is a natural substance with amphiphilic property, and both the positively charged amino group and the negatively charged sulfonic acid group in the structure are hydrophilic groups, and the lipophilic hydrophobic group is the hydrocarbon chain. Taurine is used as a natural amphiphilic substance, has similar structural properties with the cell membrane lipid of the skin, generates excellent affinity performance with skin cells according to the principle of 'similar intermiscibility' between similar substances, and can improve the combination of ions on the cell membrane and water by amino and sulfonic groups in molecules so as to ensure that the molecules are quickly absorbed through skin; secondly, the amphiphilic structure of taurine can greatly reduce the surface tension and the reaction activation energy of the solution in the biochemical reaction of an organism, thereby greatly improving the reaction activity, even changing the surface composition and the structure of reactants, having the functions of stabilizing and protecting cell membranes consisting of lipids and maintaining the permeability of the membranes; in addition, taurine, as a natural amphiphilic substance, can improve the biochemical and biomechanical environment of cells and cell membranes, thereby promoting the biochemical reaction of organisms.

3. Lack of taurine in human skin

Human skin is also deficient in taurine, and a certain amount of taurine is contained in human body, and can be synthesized by itself mainly through food intake, but the amount is small because cysteine is required for the synthesis of taurine in human body as a raw material, and cysteine is small in human body and the activity of enzyme necessary for the synthesis of taurine is low. Taurine is distributed in humans mainly in highly excitable tissues such as the nervous system, muscle tissue and lymph and platelets. Although it is distributed differently in various tissues of the body, taurine is not isolated in blood, immune, reproductive, skin, and visual functions.

At present, the taurine is basically taken by human body in an oral way and then is mainly transported to all organs of the whole body through a blood circulation system, but the skin system does not have the blood circulation system, so the taurine taken by oral administration is very little in quantity transported to the skin system, particularly, the content of the taurine in food is low, and the insufficient intake causes the insufficient content of the taurine in skin cells, so the taurine is very necessary to be directly supplemented to the skin after percutaneous absorption.

4. Taurine non-protein amino acid

Taurine is a non-protein amino acid, which is not involved in protein synthesis after being absorbed by the body, and can effectively maintain the content of taurine in each cell tissue of the skin, thereby playing a role in regulation.

5. Other physiological Properties of taurine

1) Regulating effect of taurine on body immunity

Taurine has important influence on the immune function of the organism. Taurine participates in maintaining the immune function of the organism and can play a role in regulating the normal play of the immune function. The concrete expression is as follows: no antigenicity; immunoglobulin levels can be restored and increased to enhance immune function; has immunosuppressive effect, and can reduce toxicity of endothelial cells caused by interleukin; taurine is effective in inhibiting inflammatory factors in tissues; can promote the secretion of gamma-interferon of atopic dermatitis patients, increase the ratio of Th1/Th2, and regulate the imbalance of Th1/Th2, thereby treating atopic dermatitis; can improve the function of red blood cells in removing immune complexes in blood, thereby enhancing the immunoregulation function of the red blood cells.

2) Regulation of growth by taurine

Although taurine is not a growth factor, taurine can play a role in regulating and controlling similar growth factors, for example, taurine can promote cell proliferation and differentiation, regulate growth hormone and promote the growth and development of organisms; has protective effect on injury, and can promote orderly repair of injury, including regeneration of damaged neuron, photochemical injury of retina, and repair and regeneration of other tissues. Taurine is therefore referred to as a non-specific growth factor, or a regulatory growth factor.

3) Taurine has obvious regulation and control function on the expression of important active components such as growth factors, cell factors, genes and the like

4) Antioxidant property

As antioxidant substance, it can prevent oxygen free radical peroxidation process and protect nerve cell membrane integrity.

The researchers of the invention find that the students research the calcium regulation effect of taurine and the students research the importance of calcium on skin, but at present, the researchers do not find that the students research the percutaneous absorption effect of the taurine chelated calcium and directly supplement calcium and taurine to skin in a percutaneous administration mode to achieve the regulation effect, and the taurine chelated calcium is dissociated into taurinate and calcium ions after being absorbed percutaneously, so that the taurine and calcium ions can be simultaneously supplemented to the body, particularly, the taurine and ionic calcium required by a skin system can be preferentially and effectively supplemented, and the utilization rate of the skin system on taurine is improved, which is very important and necessary.

The present inventors have also found that calcium taurine chelate is used for percutaneous absorption as compared with other calcium amino acid chelates, and that it has very excellent stability in an aqueous solution. The general amino acid chelated calcium has poor long-term stability at normal temperature, particularly has stability in an aqueous solution system of about several months to half a year, and is not suitable for preparing water-containing preparations such as external smearing agents, sprays, liniments, emulsions, gels and the like, while the taurine chelated calcium has excellent long-term stability at the high temperature of 50 ℃, the normal temperature and the constant temperature, so the taurine chelated calcium is more suitable for preparing different types of external preparations.

The source of the central ionized calcium of the taurine chelated calcium which can be used for percutaneous absorption in the invention can be inorganic calcium salt such as calcium chloride, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium silicate and the like, can also be non-chelated organic calcium salt such as calcium lactate, calcium propionate, calcium citrate, calcium gluconate and the like, can also be calcium oxide and calcium hydroxide, preferably calcium chloride, calcium carbonate, calcium lactate, calcium propionate, calcium citrate, calcium oxide and calcium hydroxide, can be calcium from mineral substances, and can also be biological sources such as bones of animals and the like.

The taurine-chelated calcium for percutaneous absorption in the invention is characterized in that the chelating ratio of the chelating agent (ligand) taurine to the central ionized calcium is 1: 1-4: 1, preferably the chelating ratio of taurine to calcium ions is 1:1 and 2:1, and more preferably 2: 1. The chelating ratio is related to the feeding proportioning mode of different taurine, the taurine chelated calcium structure with the chelating ratio of 1:1 and 2:1 of the taurine and calcium ions is relatively stable, the molecular weight is relatively small, and the taurine chelated calcium structure is easier to be absorbed through skin, which is probably caused by different influences of different amounts of taurine in the taurine chelated calcium molecules on the membrane structure.

One of the characteristics of the taurine-chelated calcium for percutaneous absorption of the invention is that in a special percutaneous absorption and utilization mode, the taurine-chelated calcium can be dissociated into ion-type calcium and taurine with physiological activity under the action of cell sap after being absorbed into cells in a molecular state, the ion-type calcium can enter a calcium reservoir in the cells for storage or enter a body circulation system through a related calcium channel for utilization, and the taurine can be reused by the body according to the body requirements, so that the taurine-chelated calcium not only can solve the problem of percutaneous absorption of calcium, but also can enhance the utilization efficiency after absorption.

One of the purposes of the taurine chelated calcium for percutaneous absorption in the invention is to improve the absorption utilization rate and solve the problems of difficult absorption, easy influence of gastrointestinal tract environment, easy formation of insoluble calcium salt or compound due to the easy pollution of calcium ions by anions, easy influence of physiological factors such as age and the like, liver first-pass effect, gastrointestinal inactivation, large difference of individual drug use and the like in the traditional oral calcium supplement, and low absorption utilization rate.

The invention is characterized in that the defect of common inorganic calcium, organic calcium and the like on percutaneous absorption is overcome. Inorganic calcium and organic calcium are ionic compounds, and in a dissolved state, calcium exists in an ionic state and is difficult to be absorbed through skin, while taurine and calcium existing in a chelate state in an integrated state in the dissolved state can be absorbed in an integrated form.

One of the characteristics of the invention is to solve the problem that the calcium required by the epidermal layer of the blood circulatory system is difficult to be supplemented by the traditional oral calcium supplementing way. Generally, calcium preparations ingested orally are preferentially used to supplement bound calcium required for bones and teeth, and particularly, it is difficult to supplement ionized calcium required for soft tissues such as the skin epidermal system orally when calcium is deficient in a human body. The taurine-chelated calcium has the characteristic that the taurine and calcium ions can be dissociated again under the action of cell sap and are utilized respectively, and meanwhile, the research of experimenters finds that the taurine-chelated calcium has small molecular weight, and the lipoid structure in amino acid is particularly suitable for percutaneous collection, thereby achieving the effect of targeted calcium supplement to a skin epidermal system and solving the problem of calcium deficiency of an epidermal layer.

One of the characteristics of the invention is that calcium required by the epidermal system can be supplemented in a percutaneous absorption mode, and meanwhile, the storage of the calcium content in the 'calcium reservoir' in cells of the epidermal system and other soft tissue systems can be preferentially increased, the calcium storage amount of the 'calcium reservoir' in the cells is increased, and when the calcium ion flow of the epidermal layer loses, the calcium in the calcium reservoir can be released, thereby being beneficial to relieving the calcium ion loss in the epidermal layer.

One of the characteristics of the invention is that the combined calcium required by the human body, namely the non-physiological active calcium, can be supplemented in a percutaneous absorption mode. When the calcium absorbed through the skin enters the blood circulation system, the calcium can be utilized by the body to supplement bones, teeth and the like to form combined calcium.

Another objective of the invention is to study the penetration-promoting effect of the penetration enhancer on the calcium taurate. For the effective components of the medicine for percutaneous absorption, besides whether the characteristics of the medicine are suitable for percutaneous absorption or not, the medicine can be promoted to be absorbed by adding a penetration enhancer, so that the effective absorption rate of the medicine is improved, and the permeability of the effective components of the medicine is increased mainly by changing the microstructure of a skin barrier, reducing the compactness among epidermal cells and enhancing the solubility of the medicine. The penetration enhancer for the taurine chelated calcium mainly comprises the following types: surfactants such as tween, polyoxyethylene alkylphenol, dodecyltrimethyl ammonium bromide, sodium dodecylsulfonate and the like; organic solvents such as ethanol, dimethyl sulfoxide, isopropyl myristate, etc.; organic acids and fatty alcohols such as oleic acid, linoleic acid, lauryl alcohol, etc.; essential oils and terpene compounds such as menthol, various plant essential oils and essential oils, camphor, limonene, cineole, etc.; azone (Azone) and its homologs such as laurocapram and the like; polymers such as block copolymers of polyethylene glycol and polydimethylsiloxane, and the like; water-absorbing and moisture-retaining agents such as cutin humectant urea and pyrrolidone derivatives; polyhydric alcohols such as propylene glycol, pentanediol, glycerol, butanediol and other short-chain alcohols with 2-8 carbon atoms in the structure; other amino acids and polysaccharides such as glutamic acid, lysine, leucine, proline, trehalose, hyaluronic acid, etc., and taurine itself can also be used as a penetration enhancer for taurine chelated calcium, and one or more of the above-mentioned various penetration enhancers can be selected as a penetration enhancer for taurine chelated calcium. When the taurine-chelated calcium is used for percutaneous absorption, the total addition amount of the penetration enhancer is less than 65% by mass, preferably less than 40% by mass, more preferably less than 30% by mass, and even more preferably less than 15% by mass of the pharmaceutical preparation.

Another object of the present invention is to provide a skin care product containing taurine-chelated calcium, wherein the penetration enhancer is selected from essential oils and terpene compounds such as menthol, various plant essential oils and essential oils, camphor, limonene, cineole, etc., which do not irritate the skin, do not destroy the epidermal barrier system of the skin, and are superior in safety; azone (Azone) and its homologs such as laurocapram and the like; polymers such as block copolymers of polyethylene glycol and polydimethylsiloxane, and the like; water-absorbing and moisture-retaining agents such as cutin humectant urea and pyrrolidone derivatives; polyhydric alcohols such as propylene glycol, pentanediol, glycerol, butanediol and other short-chain alcohols with 2-8 carbon atoms in the structure; other taurine and polysaccharides such as glutamic acid, lysine, leucine, proline, taurine, trehalose, hyaluronic acid, etc. can be used as penetration promoting system for cosmetic. The penetration enhancer for cosmetics containing the taurine-chelated calcium has the effect of promoting the absorption of the taurine-chelated calcium, and can be used as a nutrient substance of skin such as various amino acids and various plant essential oils, or can be used as a humectant of skin such as polysaccharide substances and polyalcohol substances such as trehalose and hyaluronic acid. Wherein the total addition amount of the penetration enhancer accounts for less than 65% of the product by mass, preferably less than 40%, more preferably less than 30%, and still more preferably less than 15%.

Another feature of the present invention is that the taurine chelated calcium is added in an amount ranging from less than 60% by weight, preferably less than 40% by weight, more preferably less than 20% by weight, and even more preferably less than 10% by weight, when used in various external preparation products.

The taurine-chelated calcium can be prepared into different external preparations, such as spray, cream, emplastrum, liniment, gel and the like.

The invention is characterized in that the external pharmaceutical preparation containing taurine chelated calcium can be prepared, and the skin diseases caused by the deficiency or disorder of calcium can be treated by a transdermal administration mode.

The invention is characterized in that the preparation can be used for preparing external medical and health preparations containing taurine chelated calcium.

The invention is characterized in that the external preparation of the medical appliance containing taurine chelated calcium can be prepared.

The invention has the characteristics that the cosmetic containing taurine chelated calcium can be prepared into spray, aqueous emulsion, cream, sticking film and the like so as to accelerate epidermis repair, enhance the epidermis barrier function and improve skin texture, dryness, wrinkles, elasticity, sensitivity and other skin problems.

The invention is characterized in that the health product external preparation containing taurine chelated calcium can be prepared.

The taurine chelated calcium for percutaneous absorption in the invention is added in an amount of less than 60 wt%, preferably less than 40 wt%, more preferably less than 20 wt%, and even more preferably less than 10 wt% in the external transdermal preparation product.

The invention relates to a percutaneous absorption calcium supplementing mode which can supplement ionic calcium with physiological activity required by a human body to the greatest extent, in particular to a percutaneous absorption calcium supplementing mode which can directly and quickly supplement calcium to an epidermal system without a blood circulation system, solves the problem that the calcium supplemented by oral administration is firstly used for bone formation and becomes non-physiologically active combined calcium so as to cause the ionic calcium with physiological activity to be insufficient, simultaneously taurine has the function of regulating the concentration of calcium ions inside and outside cells of the human body, namely the calcium ion concentration is inhibited at high concentration, the promotion is carried out at low concentration, the problems of calcium deficiency and calcium excess in the skin cells can be regulated, and the percutaneous absorption calcium chelating function of the taurine can be used for external medicinal preparations, medical health materials, external health care product preparations, oral administration calcium supplementing calcium and regulating calcium deficiency inside and outside cells And (4) preparing the cosmetics.

Detailed Description

The present inventors have enumerated the following embodiments in order to enhance understanding of the present invention.

Example 1

1. Preparing taurine chelated calcium: in the experiment, taurine is used as a ligand, and one of calcium chloride, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium silicate, calcium lactate, calcium propionate, calcium citrate and calcium gluconate is arbitrarily selected as a calcium source for providing central ion calcium to prepare the amino acid chelated calcium for further experimental research, which specifically comprises the following steps:

1) weighing 45 g of taurine, dissolving the taurine in 150ml of deionized water in a three-neck flask, heating the taurine in water bath to 80 ℃ and keeping the temperature constant until the glutamic acid is completely dissolved;

2) weighing 20g of calcium lactate, completely dissolving in enough water, and adjusting the pH value to 7.8;

3) gradually adding the calcium lactate solution prepared in the step 2) into the taurine solution in the step 1) dropwise, adding the calcium lactate solution while stirring gently, and keeping a constant temperature state in the stirring process;

4) after the calcium lactate solution is added, the reaction is carried out for about 60min, and the reaction is finished;

5) filtering to remove impurities, and directly using the filtrate or evaporating the filtrate until taurine chelated calcium is separated out, drying and crushing for later use;

2. qualitative detection of taurine-chelated calcium

Since calcium in the aqueous solution of taurine-chelated calcium does not exist in an ionic form, whether amino acid-chelated calcium is generated or not can be determined by detecting whether free calcium ions and free amino acid radicals exist in the obtained substance after the reaction, and the generation of amino acid-chelated calcium can be qualitatively detected. The experiment mainly determines whether to generate the taurine chelated calcium by comparing the change before and after the reaction through the color reaction of the dithiohydrazone reagent and free metal calcium ions or the color reaction of the ninhydrin reagent and the taurine sulfonic acid radical. The specific experiment is as follows:

reagent for experimental qualitative detection: a dithiohydrazone reagent, a ninhydrin reagent and sodium sulfide.

Purification of taurine chelated calcium: the experiment mainly eliminates the influence of unreacted calcium ions and taurine in the prepared taurine chelated calcium product.

Removing free calcium ions: weighing a small amount of the prepared sample of the taurine-chelated calcium, adding a proper amount of absolute ethyl alcohol, fully stirring, standing for a period of time for precipitation, filtering, adding a few drops of the dithizone reagent into a small amount of filtrate, observing whether the filtrate changes color, continuously washing and purifying the taurine-chelated calcium according to the method if the filtrate changes color until the filtrate does not change color after the dithizone reagent is added, so as to ensure that metal calcium ions are completely removed;

removing free taurine: dissolving a little of taurine chelated calcium from which free calcium ions are removed in water, adding a few drops of ninhydrin reagent, heating until the solution boils, if the color of the solution changes to bluish purple, then the free taurine still exists in the sample, and continuing to purify by using absolute ethyl alcohol as a purifying agent until the color of the heated solution does not change to bluish purple, so as to ensure that the free taurine is completely removed.

Qualitative detection of taurine-chelated calcium: the experiment mainly determines that the reaction product is taurine chelated calcium.

Dissolving the taurine chelated calcium sample purified in the step 1) in water, and numbering three parts of solution as No. 1, No. 2 and No. 3 samples, wherein the No. 1 solution is added with a quantitative dithiohydrazone reagent, the color of the solution is unchanged, and the sample does not contain free calcium ions; adding a few drops of ninhydrin reagent into sample No. 2, heating until the solution boils for 3min, wherein the color of the solution is unchanged, which indicates that the sample does not contain free taurine; adding excessive sodium sulfide into a No. 3 sample, stirring uniformly, standing for a period of time to generate white precipitate, which indicates that calcium ions in a chelated state are replaced by the sulfur ions to generate more stable metal sulfide calcium sulfide, standing for a period of time to perform precipitation filtration to obtain filtrate, adding a few drops of ninhydrin reagent into the filtrate, heating until the solution boils for 3min, wherein the color of the solution is changed into bluish purple, which indicates that free taurine exists, and the result is that the calcium ions in the product taurine chelated calcium are captured by the sulfur ions and then replaced by the free taurine, so that the product prepared in the step 1 is the taurine chelated calcium.

Example 2

The experiment takes taurine as a ligand, and one of calcium chloride, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium silicate, calcium lactate, calcium propionate, calcium citrate and calcium gluconate is arbitrarily selected as a calcium source for providing central ionized calcium, so as to prepare the taurine chelated calcium with different chelating ratios.

Preparing taurine as chelating ratio: taurine chelated calcium = 2:1

1) Weighing 45 g of taurine, dissolving the taurine in 150ml of deionized water in a three-neck flask, heating the mixture in a water bath to 80 ℃, and keeping the temperature constant until the taurine is completely dissolved;

2. preparing taurine as chelating ratio: taurine chelated calcium of calcium = 1:1

1) Weighing 40g of calcium lactate into a reactor, completely dissolving the calcium lactate into sufficient water, adjusting the pH value to 7.8, heating the calcium lactate in a constant-temperature water bath to 80 ℃, and keeping the temperature constant;

2) weighing 40g of taurine, completely dissolving the taurine in 150ml of deionized water, and heating the solution to 80 ℃ in water bath;

3) gradually dropwise adding the taurine solution prepared in the step 2) into the calcium lactate solution in the step 1), stirring while adding the calcium lactate solution, and keeping a constant temperature state in the stirring process;

4) after the taurine solution is added, the reaction is continued for 60min, and the reaction is finished;

example 3

And (3) investigating the stability of the taurine-chelated calcium aqueous solution: in this experiment, the taurine-chelated calcium prepared in example 1 was used as a raw material, and the glutamic acid-chelated calcium was selected as a comparison target, and the stability of the aqueous solution of the taurine-chelated calcium and other amino acid-chelated calcium was compared, and a preservative was added to the prepared aqueous solution, and the experimental results are as follows:

TABLE, stability of aqueous solutions of taurine chelated calcium-glutamic acid chelated calcium under different conditions

From the above test results it can be seen that: the stability of the aqueous solution of the taurine chelated calcium is superior to that of the glutamic acid chelated calcium, and the stability is very necessary for external liquid preparations, which indicates that the aqueous solution of the taurine chelated calcium is more suitable for preparing external water preparations, such as sprays, gels, paints, liniments and the like.

Example 4

The experiment compares the percutaneous absorption effects of taurine chelated calcium and other amino acid calcium, inorganic calcium and organic acid calcium, the in vitro mouse skin is used in the experiment, the used receiving solution is 0.9 percent sodium chloride water solution, and the experiment time is 10 hours. The method comprises the following steps of preparing solutions with the same concentration from the taurine chelated calcium selected in the test as the taurine chelated calcium prepared in example 1, the inorganic calcium as the calcium chloride and the organic acid calcium as the calcium gluconate, taking a round specification that the effective test area of the mouse skin is the diameter d =1.5cm, uniformly coating three solutions with the same volume on the surface of the mouse skin, and testing and comparing the percutaneous absorption effects of the taurine chelated calcium, the glutamic acid chelated calcium, the calcium chloride and the calcium gluconate by using a franz diffusion cell transdermal tester, wherein the specific test results are shown in the following table 1:

TABLE 1 cumulative transdermal dose of three calcium agents for 10h

Comparing the percutaneous absorption effects of the taurine chelated calcium, the glutamic acid chelated calcium, the inorganic calcium chloride and the calcium gluconate aqueous solution, the fact that the taurine chelated calcium has good percutaneous absorption performance compared with other calcium preparations is demonstrated, particularly, the percutaneous absorption amount of the taurine chelated calcium is larger than that of the glutamic acid chelated calcium and far larger than that of the calcium chloride and the calcium gluconate at the initial stage, and the total absorption amount in 6 hours is also higher than that of the glutamic acid chelated calcium and far higher than that of the calcium chloride and the calcium gluconate.

Example 5

In the experiment, the taurine-chelated calcium prepared in example 1 is used as a test sample, and the influence of the taurine-chelated calcium solutions with different concentrations on the transdermal effect is compared. In the test, the split mouse skin is used, the receiving solution is 0.9% sodium chloride aqueous solution, and the test time is 6 h. Preparing solutions with different mass concentrations from the taurine-chelated calcium, uniformly coating the solution with the same volume and different concentrations of the taurine-chelated calcium on the surface of the mouse skin in a round specification with the diameter d =1.5cm, testing and comparing by using a franz diffusion cell transdermal tester, and obtaining specific results as shown in the following table 2:

TABLE 2 transdermal effect of different concentrations of calcium taurine chelate

As can be seen from the above table, comparing the percutaneous absorption performance at 0.5%, 1%, 1.5%, 2% concentration of the taurine-chelated calcium, the percutaneous absorption performance of the taurine-chelated calcium is related to its concentration, and when the concentration of the taurine-chelated calcium is increased, the percutaneous absorption performance is increased, and particularly, the percutaneous absorption effect at the initial stage can be increased, and within the initial 1h, the percutaneous absorption amount of the taurine-chelated calcium at the concentration of 2% is about 9 times that at the concentration of 0.5%, and about 4 times that at the concentration of 1%, which is very important for the application thereof in cosmetics. Meanwhile, the absorption rate in 6h at the concentration of 2% reaches 75%, which is much higher than 37% at the concentration of 0.5%, and the total absorption amount in 6h at the concentration of 2% is 10 times or more of 0.5%.

Example 6

Influence of pH on the percutaneous absorption effect of taurine-chelated calcium: in the experiment, the taurine-chelated calcium prepared in example 1 is used as a test sample, and the percutaneous absorption effect of the taurine-chelated calcium in different pH value system environments is compared, and the specific experiment is as follows: in the test, the pH value of the taurine-chelated calcium solution simulates the change range of the pH value of human skin, and the percutaneous absorption effect of the taurine-chelated calcium is tested when the pH values are respectively 5.5, 7.0 and 8.5, wherein the testing method of the transdermal performance is the same as that in the previous embodiment, the testing time is 6h, and the testing results are shown in the following table:

TABLE, Effect of different pH values on the transdermal Effect of taurine-chelated calcium

From the above test results, different pH environments have certain influence on the transdermal effect of calcium taurate, and the transdermal effect of calcium glutamate chelate is slightly better at pH 5.5 and 8.5 than at pH 7.0.

Example 7

In this experiment, the taurine-chelated calcium with different chelating ratios prepared in example 3 are used as test samples, the transdermal effect of the taurine-chelated calcium with different chelating ratios is compared, the transdermal test method is the same as that in the previous examples, the test time is 6h, and the test results are shown in the following table:

influence of surface-chelating ratio on transdermal effect of taurine-chelated calcium

From the above experimental results, it can be seen that the transdermal effect of taurine chelated calcium is better than 1:1 when the chelating ratio of taurine chelated calcium is 2: 1.

Example 8

Effect of calcium taurine chelate on the proliferation effect of isolated keratinocytes: in this experiment, the effect of the calcium taurine chelate on the recovery of the skin barrier effect was demonstrated by examining the effect of the calcium taurine chelate on the proliferation of isolated keratinocytes using the calcium taurine chelate prepared in example 1 as a test sample. In the test, mice are moved outwards to carry out an epidermal barrier repair test, taurine chelated calcium solution with certain concentration is used for treatment, a blank control group is additionally arranged for carrying out a parallel comparison test, epidermal keratinocytes are tracked by an immunofluorescence method, and the change condition of the keratinocytes in the proliferation process in the reconstructed epidermis after 24 hours is investigated. The change conditions of certain concentrations of taurine chelated calcium, glutamic acid chelated calcium, calcium chloride and calcium gluconate on keratinocytes in the proliferation process in the epidermis reconstruction process are observed and compared in the experiment, so that the proliferation effect of the taurine chelated calcium on keratinocytes in the epidermis barrier repair process is shown, and the specific results are shown in the following table:

proliferation effect of different calcium agents on keratinocytes in epidermal barrier repair process within 24h

Group name	Blank group	Taurine chelated calcium	Glutamic acid chelated calcium	Calcium chloride	Calcium gluconate
						Keratinocyte growth rate/%)	1.5	27.6	17.1	9.3	13.7

From the above test results, it can be seen that the influence of calcium taurine chelate on the proliferation of keratinocytes is the greatest, which can indicate that the recovery performance of calcium taurine chelate on the barrier function of skin epidermis is better than that of the group without calcium taurine chelate and other calcium amino acid chelates and non-calcium amino acid chelates.

Example 9

This experiment is with the taurine chelate calcium prepared in embodiment 1 as test sample, through designing blank group, the experiment of comparison control group, the influence of taurine chelate calcium to epidermis cuticle barrier recovery effect has been investigated, the influence of taurine chelate calcium to epidermis barrier recovery has been known directly perceivedly, carry out epidermis barrier repair experiment through mouse migrant skin in the experiment, use taurine chelate calcium spray to carry out 3 times/day's processing to the epidermis, carry out Trichrom-Masson dyeing to the epidermis layer in the experimentation, observe its epidermis thickness's the situation of change, the experimental result is shown below the table:

restoration of epidermal keratin layers by different calcium agents within 6 days

Group name	Blank group	Taurine chelated calcium	Glutamic acid chelated calcium	Calcium chloride	Calcium gluconate
						Change in thickness of horny layer/%)	0.9	24.7	17.1	7.5	9.3

The experimental results show that after the taurine chelated calcium is used for 6 days, the thickness of the epidermal layer of the skin is obviously increased and is superior to that of a blank group without the taurine chelated calcium and a control group without other calcium agents, and the taurine chelated calcium plays a better role in the epidermal barrier repair process.

Example 10

In the experiment, the taurine chelated calcium, the glutamic acid chelated calcium, the calcium chloride and the calcium gluconate prepared in the example 1 are respectively used as raw materials, aqueous solutions of the glutamic acid chelated calcium, the calcium chloride and the calcium gluconate with certain concentrations are respectively prepared, physical damage is carried out on human skin, the prepared calcium agents are respectively used for smearing, comparison with blank samples is carried out, the repairing effect of different calcium agents on damaged skin is investigated, and the specific test method is as follows:

human epidermis disruption test: the inner side of the forearm of a healthy human body is taken as a test part, the adhesive tape is used for physically and repeatedly tearing for 15 times to cause damage to the epidermis of the skin, the test components are divided into four groups which are respectively a blank group, a taurine chelated calcium group, a glutamic acid chelated calcium group, a calcium chloride group and a calcium gluconate group to carry out the epidermis damage recovery test, and the specific test results are as follows:

the experimental results show that the repairing effect of the calcium-containing test group on the damaged skin is superior to that of the blank group, the repairing effect of the calcium-containing group sample on the damaged skin is that the taurine chelated calcium is optimal, the glutamic acid chelated calcium is inferior, and the calcium gluconate is slightly superior to the calcium chloride.

Example 11

Spray containing only the taurine-chelated calcium prepared in example 1 was prepared from the raw material, and volunteer tests were performed, wherein blank groups (pure water), control groups, and test groups were set in the tests to examine the skin improvement and regulation effects of the taurine-chelated calcium, and the results were compared with other calcium amino acid salts (calcium glutamate in the tests), inorganic calcium salts, and organic calcium salts. The test part is the face, the test time is two weeks, 40 tested volunteers are totally tested, 20 of the tested volunteers are dry sensitive skin, 20 of the tested volunteers are oily skin, other treatment modes are not carried out during the test period, and other skin care products are forbidden. The VISIA tester is adopted to test the change conditions of the facial skin of a subject, including the change of the water content of the skin, the elasticity value, the sebum amount, the change of the pH value of the face, the growth change of facial bacteria, the skin glossiness, the tightening effect, the pore change, the anti-allergy effect, the adaptability of different types of skin and the like, and the repairing and regulating effect of the calcium glutamate chelate on the facial skin is comprehensively evaluated. The VISIA tester and SOFT5.5 skin property test are as follows:

1) moisture content: the moisture value of the skin can be used for measuring the dryness degree of the skin and is one of important indexes for reflecting the barrier function of the skin; the higher the moisture test value is, the better the water replenishing effect is;

2) sebum: the skin oil secretion capacity is shown, and the higher the test result value is, the higher the oil content is shown;

3) elasticity: the higher the test result value, the better the skin elasticity is;

4) pH value: the low PH of oily skin is generally due to the fact that the secreted oil contains free fatty acids;

5) wrinkling: the dry lines, fine lines, static lines and other conditions of the face are reflected, and the wrinkles generally have close relation with the reduction of the skin elasticity;

6) texture: reflecting the smoothness and plumpness of the skin, the smaller the difference between the peak and the valley of the healthy stratum corneum is, the better the plumpness of the skin is, and the stronger the water locking and moisturizing capacities of the stratum corneum are;

7) purpurin: one of detection items concerned by oily skin has important significance for controlling skin inflammation and oil control effect, mainly detects metabolites of various bacteria at the hair follicle opening, such as propionibacterium acnes, malassezia and the like, and the lower the detection result is, the fewer the bacteria at the hair follicle opening are, and the bacteriostatic effect of the product is obvious;

dry skin application test effects: the results of an effect comparison test were performed by randomly dividing 20 volunteers of dry skin type into 4 groups of 5 persons each, namely a blank group, a taurine chelated calcium group, a glutamic acid chelated calcium group, a calcium chloride group, and a calcium gluconate group, and the results of the test are shown in the following table:

repairing effect of different calcium agents on dry skin

The application test effect of the oily skin is as follows: 20 volunteers with oily skin types were randomly divided into 4 groups of 5 persons each, namely a blank group, a taurine chelated calcium group, a glutamic acid chelated calcium group, a calcium chloride group and a calcium gluconate group, and effect comparison tests were performed, and the experimental results are shown in the following table:

repairing effect of different calcium agents on oily skin

From the above test results, it can be seen that, compared with the blank group, the calcium-containing group is superior to the blank group in skin repair effect, and among the three test groups of different calcium agents, the calcium-glutamate chelate group is significantly superior to the calcium chloride group and the calcium gluconate group, and is suitable for both oily and dry skin.

Example 12

The experiment takes a mouse as an experimental object and is divided into two groups, wherein one group is orally fed with the taurine chelated calcium prepared in the example 1, the other group is used for supplementing the taurine chelated calcium to the skin in a transdermal administration mode, and the atomic absorption spectrophotometry is adopted to respectively test and compare the calcium content in an epidermal system of the two calcium supplementing ways in different time periods.

Influence of different calcium supplement modes on calcium content change in epidermis

From the test results, the oral calcium supplement mode is difficult to supplement calcium in the epidermis, and the transdermal administration mode can quickly and effectively improve the calcium content in the epidermis and solve the problem of calcium deficiency of the epidermis system.

While the foregoing is directed to embodiments of the present invention, and the various embodiments of the invention may be embodied or carried out, it will be apparent to those skilled in the art that various changes and modifications may be made without departing from the principles of the invention, and it is intended that such changes and modifications be considered as within the scope of the invention.

Claims

1. The taurine-chelated calcium for preparing the percutaneous absorption preparation is characterized in that calcium ions are chelate central ions, taurine is a chelate, and the chelating ratio of taurine to calcium ions in the amino acid-chelated calcium is 1: 1-4: 1.

2. The taurine-chelated calcium for use in preparing a transdermal absorption preparation according to claim 1, wherein the molecular weight of the taurine-chelated calcium is in the range of 100 to 1500.

3. The taurine chelated calcium for use in preparing a percutaneous absorption preparation according to claim 2, wherein the molecular weight of the taurine chelated calcium is in the range of 100 to 800.

4. The taurine chelated calcium for use in preparing a percutaneous absorption preparation according to claim 3, wherein the molecular weight of the taurine chelated calcium is in the range of 100 to 650.

5. The taurine chelated calcium for use in preparing a percutaneous absorption preparation according to claim 1, wherein the chelation ratio of taurine to calcium ion is 1:1 and 2: 1.

6. The taurine-chelated calcium for use in preparing a percutaneous absorption preparation according to claim 5, wherein the chelation ratio of taurine to calcium ion is 2: 1.

7. A percutaneous absorption preparation, characterized in that the preparation active ingredient is taurine chelated calcium as described in any one of claims 1-6, the weight percentage content is less than 60%, and the transdermal absorption preparation contains penetration enhancer with mass percentage less than 65%, and the percutaneous absorption preparation does not contain vitamin D.

8. The transdermal formulation of claim 7, wherein the taurine chelated calcium is added in an amount ranging from less than 60% by weight.

9. The transdermal formulation of claim 8, wherein the taurine chelated calcium is added in an amount ranging from less than 30% by weight.

10. The transdermal formulation of claim 9, wherein the taurine chelated calcium is added in an amount ranging from less than 10% by weight.

11. The percutaneous absorption preparation as claimed in claim 7, wherein the penetration enhancer comprises one or more of surfactants, organic acids and fatty alcohols, terpene compounds, azone, polyhydric alcohols, and amino acids.

12. The percutaneous absorption preparation according to claim 11, wherein the amino acid transdermal enhancer is one or more of glutamic acid, lysine, leucine, proline and taurine.

13. The percutaneous absorption preparation according to claim 11, wherein the polyhydric alcohol-based penetration enhancer is one or more of short-chain alcohols having 2 to 8 carbon atoms in the structure.

14. Use of the transdermal absorption preparation according to any one of claims 7 to 13 for the preparation of a pharmaceutical preparation for the treatment or prevention of diseases caused by calcium deficiency and disorders of the skin, wherein the diseases caused by calcium deficiency and disorders of the skin are skin barrier damage, acne, skin disorders with dyschromatosis, skin disorders with dystrophism, allergic skin diseases, skin vascular diseases, skin vasculitis diseases, erythematous skin diseases.