RU2412194C2 - Novel complexonate of derivatives of diphosphonic acids with carbohydrate amines and medical-cosmetic agent based on said complexonate - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention can be used in medical-cosmetic agents used in case of calcium exchange disorder, which accompanies various diseases. The complexonate is characterised by absorption maximum at 275 nm and can be obtained through incubation in aqueous solution of Na+, K+ of a salt of 1-hydroxyethylidene diphosphonic acid with glucosamine.

EFFECT: obtaining a novel complexonate of hydroxyethylidene phosphonic acid with glucosamine.

1 cl, 4 dwg, 7 ex

Description

Technical field

The invention relates to the field of cosmetology and medicine, in particular, to new chemical compounds representing the complexonate derivative of diphosphonic acids with amines of carbohydrates, as well as to various therapeutic and cosmetic products used in case of calcium metabolism disorder, which is accompanied by diseases of various nature.

The problem of regulating calcium metabolism in bone pathology, pathological calcification of soft tissues, oncology, and cardiovascular diseases is relevant, despite the presence of a number of drugs, such as calcitonil, oxydevit, osteikhin, calcitrin, calcium salts, etc.

It is known that some of these drugs exhibit toxicity, others do not have a specificity of action, and therefore the problem of expanding the range of calcium metabolism regulators is in itself an urgent task. One of the common remedies for the treatment of such diseases, as well as for the treatment of neurological diseases and diseases of the musculoskeletal system is the so-called "xidiphone".

State of the art

According to [1], xidiphone has the international nonproprietary name (INN) -ethidronic acid and the chemical name potassium-sodium salt of 1-hydroxy-ethylidene diphosphonic acid. The dosage form of "Xidifon" is a 2% aqueous solution of monopotassium salt of 1-hydroxy-ethylidene diphosphonic acid with the addition of sodium hydroxide.

Xidiphon regulates calcium metabolism: it prevents excessive release of calcium from bones, preventing the development of osteoporosis, prevents pathological calcification of soft tissues, prevents crystal formation, as well as the growth and aggregation of crystals of calcium salts in urine.

Keeping calcium ions in a dissolved state, xidiphone prevents recurring stone formation, eliminating the possibility of the formation of insoluble calcium salts (oxalates, phosphates, etc.), and has a moderate anti-inflammatory effect with interstitial nephritis.

Xidiphon, like other complexones, is able to accelerate the excretion of heavy metals: lead, tin, antimony, strontium, magnesium, silicon, without disturbing the balance of trace elements.

Xidifon has been studied as a tool in the treatment of trigeminal neuralgia [2] and in the treatment of patients with cervical posterior sympathetic syndrome with cervical osteochondrosis [3].

All these properties of the potassium-sodium salt of 1-hydroxyethylidene diphosphonic acid (xidiphon) explain the increased interest in it from researchers in Russia, as evidenced by the large number of patents for a number of drugs and compositions using it.

As a means for regulating calcium metabolism, xidiphone is described in USSR copyright certificate No. 1741801. To increase the stability of the drug and prevent the formation of sparingly soluble trisubstituted salts, a certain ratio of monopotassium salt and sodium hydroxide is proposed (17-25% and 3.5-4.0%, respectively). In addition, a production method is proposed that pursues the same goals and provides for a certain order of draining the components and maintaining the pH of the solution in the range of 5.8-6.5.

In the patent of the Russian Federation No. 2155588, a method for increasing bone mass in fractures is proposed.

In USSR copyright certificate No. 1683757, xidiphone is used to treat facial neuropathy.

In RF patents Nos. 2101015 and 2149824, an external agent and method for treating neurological diseases and diseases of the musculoskeletal system with pain and swelling, which contains 0.5-3.0% xidiphone and 97.0-99.5% of the base. As a basis, ointments, creams, emulsions containing vegetable oils (olive, petroleum jelly, wheat, etc.) are offered.

A treatment method is also proposed, consisting in the fact that the composition is applied to the surface of the skin 1 time per day with an exposure of 1-1.5 hours. In the description of the patent, it is noted that when treating with known application methods using a preparation containing xidiphone, a low therapeutic effect is observed, which is explained by poor penetration of the drug through the skin. It is known that the absorption of xidiphon does not exceed 5%. The use of electrophoretic treatment methods is associated with a number of contraindications (intolerance, cardiovascular disease, oncology, etc.).

According to the authors of RF patent No. 2101015, the composition proposed by them allows to increase the penetration of xidiphone through the skin. Indeed, as follows from [4], the introduction of xidiphone into the composition of an emulsion or gel somewhat increases the effectiveness of its analgesic effect when applied to the burn area. A significant increase in efficiency in this case cannot be expected, because Xidiphon is a highly soluble compound with a low distribution coefficient, and only a small part of it will be adsorbed on the surface of the fat particles of the emulsion, and the bulk of the substance will still remain in solution.

In the patent of the Russian Federation No. 2148881 an external therapeutic and cosmetic product is proposed, including a lipid carrier, an emulsifier, a preservative and a phosphonic complexon.

The following known phosphonic acids are proposed to be used as phosphonic complexones:

- oxymethylene diphosphonic;

- hydroxyethylidene diphosphonic;

- phosphonium formic;

- aminodimethylenediphosphonic;

- ethylenediaminotetramethylene phosphonic;

- hexamethylenediaminetethemethylene phosphonic;

- 4-amino-1-hydroxybutane-1-diphosphonic;

- 6-amino-1-hydroxyhexane-1-diphosphonic;

- 1-hydroxy-2-imidazol-1-yl-ethanediphosphonic, alkaline and ammonium salts of these acids, mixtures of these acids and their salts.

According to the authors, these compounds in the composition have a dual function. Firstly, they are active medicinal additives that regulate the mineral metabolism in the body, which have an anti-infectious effect. Secondly, they have a previously undetected property, namely they are structuring substances that strengthen the emulsion structure of the composition by increasing the effectiveness of the main emulsifiers, which is accompanied by an increase in the homogeneity and thermal stability of the composition and, as a result, an increase in the penetration of active components through the skin. The patent does not provide documentary evidence of previously undetected properties.

According to the authors, due to the good permeability of the patented composition, active additives penetrate the body even at low concentrations, which makes the drug applicable even when small doses of drugs are necessary, for example, in the case of treatment of young children.

In this patent, the hydrophobic phase of the ointment base is considered as a transporting system that promotes better penetration of xidiphon (K, Na salt of HEDPK) through the stratum corneum. However, the percentage of binding of xidiphone to the oil phase is small, because it is a water-soluble, fully ionized compound whose molecule has several negative charges. In the presented formulation, the patent does not contain any components that would either enhance the adsorption of xidiphone on the surface of oil particles (for example, positively charged components), or increase its solubility in the oil phase due to direct binding to xidiphone.

Therapeutic and cosmetic products are patented in RF patents No. 2124881, 2157183, 2189806, 2203033, 2251408.

In RF patent No. 2203033, xidiphone is used in a cosmetic composition to protect the skin from ultraviolet rays.

In RF patent No. 2194517, OEDP magnesium salt is proposed as a decongestant.

Xidiphone is used for various indications:

- for the prevention of complications after surgery on the urinary tract (copyright certificate of the USSR No. 1200903, 1681269, 2238735);

- as an anticonvulsant drug (ed. USSR certificate No. 1607814);

- for the treatment of atopic bronchial asthma (ed. St. USSR No. 1680186);

- for the treatment of acute respiratory viral infections (ed. USSR certificate No. 1745 255);

- for the treatment of Perthes disease (RF patent No. 2083197, 2192842);

- for the treatment of chronic intoxication with salts of heavy metals (RF patent No. 2089192);

- as an anti-infective agent (RF patent No. 2116790).

Numerous patents are known for the formulations of toothpastes and tooth elixirs with xidiphone, which provides a protective and anti-inflammatory effect (USSR Aut. USSR No. 1757522, RF patents No. 2088210, 2112501, 2113842, 2147222, 2253435, 2153322, 2201203).

The problem of increasing the permeability of compounds containing xidifon is noted in a number of the above patents, while one approach to its solution is proposed - the introduction of an oil phase in the formulation. It is known that particles of an oil / water emulsion, obtained by conventional technology and having a size of more than one micron, are mainly retained on the surface layers of the skin without reaching the deeper layers.

Therefore, one cannot expect that a conventional oil / water emulsion can be used as an effective system for transdermal delivery of the active substance. In addition, this path is not universal and cannot be used in cases where an oil phase is not expected. The proposed approach - increasing homogeneity and thermal stability - does not solve the problem of increasing the permeability of the drug.

SUMMARY OF THE INVENTION

The present invention is a universal solution to the problem of permeability, suitable in almost all technical solutions where xidiphone or any other complexon belonging to the class of diphosphonic acids is used.

The problem is solved by the present invention, which consists in creating a new complex of derivatives of diphosphonic acids or their salts with carbohydrate amines, as well as derivatives of carbohydrate amines containing CH ₃ COO - and SO ₃₂ - groups of the following general structure:

where X = H, Na, K

n = 1-6

a, b = 1

, или

, or

m = 2,4

R is an amino carbohydrate radical selected from the group:

- glucosamine, acetylglucosamine, glucosamine sulfate,

- galactosamine, acetylgalactosamine, galactosamine sulfate,

- mannosamine, acetyl mannosamine, mannosamine sulfate,

- fructosamine, acetylfructosamine, fructosamine sulfate.

Another task is to create therapeutic and cosmetic products based on the new complexant "Alantophosphon".

The new Alantophosphon complexonate obtained by the interaction of diphosphonic acid derivatives or its salts with positively charged carbohydrate amines, due to the smaller number of charges in the molecule, has increased permeability through the skin. With a certain ratio of components, all negative charges in the diphosphonic acid molecule are neutralized. It is known that neutral compounds penetrate better through the lipid bilayer of cell membranes than their charged forms [5]. The proposed complex due to good permeability is removed from the surface layers of the skin, which is why it has less irritating ability compared with xidiphone [4].

It should be noted that the second component of the complex - carbohydrate amines are the starting material for the synthesis of cartilage, connective tissue and their appearance contributes to the renewal and restoration of these tissues.

It is known that the pharmacological effect of xidifon (OEDPK salts) is due to their interaction with calcium ions (complexon function). When studying this process, we showed that the formation of a complex between xidiphone and calcium ions is accompanied by the appearance of an absorption maximum at 275 nm (see Fig. 1, curve 1).

Figure 1 - absorption spectrum of the complex of xidifon (2% wt. Or 8 · 10 ^-2 M) with calcium ions (10 ^-4 M CaCl ₂ ): 1 - in water; 2 - in the presence of 0.9% sodium chloride.

It should be noted that this result was obtained for the aqueous phase in the absence of any ionic strength, while biological fluids (blood, lymph) contain a large number of salts. Therefore, the possibility of the formation of a complex of xidiphon with salts of calcium ions in the presence of 0.9% sodium chloride was studied and it was found that under these conditions there is no appearance of a maximum at 275 nm, i.e. the complex is not formed (figure 1, curve 2). This is a logical result, given that the formation of such a complex should be due to electrostatic interaction, which is inhibited in solutions with high ionic strength, and it indicates that the function of xidiphone as a complexon is not achieved under physiological conditions.

Unlike xidiphon, the new complexonate of diphosphonic acid derivatives with carbohydrate amines acts as a complexon of calcium ions even under physiological conditions, which is not obvious and does not follow from known sources of information.

The properties we discovered of new complexonates of diphosphonic acid derivatives with carbohydrate amines, namely: the ability to chelate calcium ions in physiological saline, the ability to renew and restore connective and cartilage tissues, and the decrease in the hydrophilicity of complexonate due to a decrease in charges in the molecule allow their use in medical and cosmetic products for various purposes to obtain relevant technical results. Due to the above properties, new complexonates of diphosphonic acid derivatives with amines of carbohydrates can increase efficiency in physiological environments, simultaneously with the therapeutic and cosmetic effect associated with the regulation of calcium metabolism, ensure tissue repair, increase drug permeability through tissues.

Examples of the preparation of complexonate

The complexonates were prepared according to the following procedure: a diphosphonic acid derivative was incubated at a concentration of 2% and a hydrocarbon amine at a concentration of 0.1 to 15% for 60 minutes at 40 ° C. Next, the optical density of the reaction medium was removed at a wavelength of 275 nm. The proof of the preparation of new complexonates and their properties as complexons is provided by the UV spectra of a mixture of diphosphonic acid derivatives and glucosamine below. It should be noted that neither diphosphonic acid derivatives nor glucosamine in this region (250-300 nm) have a maximum absorption.

Example 1. Incubated 2% solution of Na, K-salt of 1-hydroxyethylidene diphosphonic acid (2% wt. Or 8 · 10 ^-2 M) with glucosamine (2% wt. Or 4.4 · 10 ^-2 M) in water, in the absence of calcium chloride and the UV spectrum was recorded (curve 1 in figure 2). The same components are incubated in the presence of 10 ^-3 M calcium chloride (curve 2 in figure 2).

Figure 2 - absorption spectra of Na, K complexonate salts of 1-hydroxyethylidene diphosphonic acid (2% or 8 · 10 ^-2 M) with glucosamine (2% wt. Or 4.4 · 10 ^-2 M) in the absence (1) and presence calcium chloride (10 ^-3 M) (2). Incubation conditions: 60 min at 40 ° C.

Example 2. Incubated 2% solution of Na, K-salt of 1-hydroxyethylidene diphosphonic acid (2% or 8 · 10 ^-2 M) with glucosamine (12% wt. Or 26.4 · 10 ^-2 M) in water, in the absence of chloride calcium and took the UV spectrum (curve 1 in figure 3). The same components were incubated in the presence of calcium chloride (10 ⁻³ M) (curve 2 in FIG. 3).

As follows from figure 2 and figure 3, the optical density at maximum increased with increasing glucosamine content.

Figure 3 - absorption spectrum of complexonate Na, K salts of 1-hydroxyethylidene diphosphonic acid (2% or 8 · 10 ^-2 M) with glucosamine (12% wt. Or 26.4 · 10 ^-2 M) in a ratio of 1: 6 by weight in the absence of calcium ions (1) and in the presence of 2 · 10 ^-3 M CaCl ₂ (2).

With continued incubation for up to 24 hours, the absorption peak shifted to the long-wavelength region of the spectrum (Fig. 4) and an additional color appeared.

Figure 4 - absorption spectrum of Na, K complexonate salts of 1-hydroxyethylidene diphosphonic acid with glucosamine when incubated for 60 minutes at 40 ° C (1) and for 24 hours at room temperature (2).

At a significantly lower glucosamine concentration, the formation of complexonate, recorded spectrophotometrically, was observed only on the 5th day of incubation.

The optimal ratio of components to obtain complexonate was determined by the optical density at 275 nm. It was found that the highest rate was observed with the ratio of xidiphone: glucosamine 1: 4 (by weight) or 1: 2 (M / M). This suggests that 2 glucosamine molecules bind to 1 xidiphone molecule.

The following examples No. 3-4 are summarized in table.

Example No. Diphosphonic acid derivative Amino carbohydrate N BUT X one

Na, Na, K, K glucosamine one 2

Na, K, K, H glucosamine 2 3

Na, K, K, H mannosamine 3 four

Na, Na, K, K fructosamine four

By varying the conditions of formation, it was found that, unlike xidiphon, which does not form a complex with calcium ions in physiological saline, the new complexonate of diphosphonic acid derivatives with amines of carbohydrates is a complexon of calcium ions not only in the aqueous phase, but also in physiological saline (0.9 % sodium chloride), which is proved experimentally.

It was further established that the resulting complexonate is able to interact with calcium ions. This conclusion was made on the basis that when adding calcium salt to the medium containing complexonate, there was an increase in optical density at a wavelength of 275 nm (Fig. 2, 3 curves 2). In other words, the same effect was observed as when calcium ions were added to xidiphone in the absence of carbohydrate amines.

The formation of an electrically neutral complexonate gives reason to talk about an increase in permeability through the skin, reaching the bloodstream and about the interaction with calcium ions that regulates its metabolism.

On the basis of the new complexonates of diphosphonic acids with amino carbohydrates, various therapeutic and cosmetic products can be created similar to those developed on the basis of xidiphone alone. The following are examples of cosmetic compositions.

Examples of formulations of external cosmetic products using complexonate.

Example 5. Composition: lipid carrier - 4 wt.% (Soybean oil - 4 g), emulsifier - 4.5 wt.% (Mixture of monoglycerides - 2 g, cetyl stearyl alcohol - 1.5 g), thickener - 1 wt.% (cetylhydroxyethyl cellulose - 1 g), moisturizing additive - 5 wt.% (propylene glycol - 5 g), biologically active additive (chondroitin sulfate - 3 wt.%, complexonate salts of 1-hydroxyethylidene diphosphonic acid and glucosamine - 2 wt.%), preservative - 0 wt.%), preservative - 0 , 5 wt.%, Perfume - 0.15%, water up to 100 wt.%.

Example 6. Composition 1: lipid carrier - 4 wt.% (Soybean oil - 4 g), emulsifier - 4.5 wt.% (A mixture of monoglycerides - 2 g, cetylstearyl alcohol - 1.5 g), thickener - 1 wt. % (cetylhydroxyethyl cellulose - 1 g), moisturizing additive - 5 wt.% (propylene glycol - 5 g), biologically active additive (chondroitin sulfate - 3 wt.%, glucosamine complex and 1-hydroxyethylidene diphosphonic acid salt - 2 wt.%, СО ₂ pepper extract - 1 g, rosemary essential oil - 0.1 g), preservative - 0.5 wt.%, Water - up to 100 wt.%.

Example 7. Composition 1: lipid carrier - 2 wt.% (Soybean phospholipids - 2 g), thickener - 2 wt.% (Hydroxyethyl cellulose - 2 g), moisturizing additive - 5 wt.% (Propylene glycol - 5 g), biologically active additive (chondroitin sulfate - 3 wt.%, a complex of glucosamine and salts of 1-hydroxyethylidene diphosphonic acid - 2 wt.%), a preservative - 0.35 wt.%, water - up to 100 wt.%.

LITERATURE

1. Instructions for the medical use of the drug xidifon (reg. No. 001642 / 01-2002).

2. Megdyatov et al. A new chelating agent, xidiphone. Reports of the 2nd All-Union Workshop on the use of complexes in medicine. M. NPO IREA, 1989, p. 32-33.

3. Seleznev A.N. et al. Treatment of patients with posterior cervical sympathetic syndrome with cerebral osteochondrosis by xidiphon. Third All-Union Conference on Chemistry and the Use of Complexons. Abstracts of reports. Chelyabinsk. 1988.

4. Baryshnikova G.I. Development and research of dosage forms of xidiphone. Abstract. diss. for the title of Cand. farm. sciences. M., 1985.

5. Balon K., Riebesehl B.U., Muller B.W. Drug Liposome Partitioning as a Tool for the Prediction of Human Passive Intestinal Absorption. // 1999. Pharm. Res., 16 (6): 882-888.

Claims (1)

The complexonate, characterized by a maximum absorption at 275 nm, obtained by incubation in an aqueous solution of Na +, K + salts of 1-hydroxyethylidene diphosphonic acid with glucosamine.

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