Conjugate of hyaluronic acid and novocaine with amphoteric properties

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biochemistry. What is presented is a conjugate of hyaluronic acid and novocaine of a structure as defined in the patent claim containing 20-50% residues of novocaine.

EFFECT: conjugate is water-soluble; it possess the amphoteric properties and contains no side O-acylisourea.

3 tbl, 3 ex

 

The invention relates to new chemical substances, namely, modified hyaluronic acid, which can be used in cosmetic, food industry, pharmacology, veterinary medicine, and the pharmaceutical industry.

Hyaluronic acid (ha) - heteropolysaccharide linear structure, belongs to the class of acidic glycosaminoglycans, is in the connective tissues of animals and humans and consists of units of D-glucuronic acid and N-acetyl-D-glucosamine. Molecular mass Ledger 104-2×106Yes.

On the basis of the civil code produces the following preparations. High-molecular GK (M=106Yes is part of gels "Provisk" (Sweden) and "Healon" (Canada), used in ophthalmic surgery operations cataract extraction, is the active substance in the films "Seprafilm" to prevent adhesive disease of the peritoneum. Low-molecular ha impregnated wipes "Gaplus", intended for the treatment of burn disease. For the treatment of venous ulcers and acne, apply a zinc salt Ledger (medicine "Curiosin" (in the form of a solution or gel), and the drug Cystistat" is intended to repair a damaged mucosa of the urinary bladder in interstitial cystitis. GK is an integral component of cosmetic sham what una, creams and tonics to stimulate hair growth. Patented application of ha in the treatment of herpes, psoriasis, and also for the manufacture of suppositories for various purposes [Peredelkino YOU, V.S. Lukin, Odinokov V.N. Acidic glycosaminoglycans and their chemical modification (review) // Bioorg. chemistry. 2008. T. No. 1. P.5-28].

Hyaluronic acid is a negatively charged polyelectrolyte. Introduction to the structure of Ledger groups with opposite charge gives the ha molecules amphoteric properties, and increase intra - and intermolecular interactions of macromolecules. The group acquires the ability to form hydrogels having hydrophilic properties. The polyampholytes based on the Ledger can be used as carriers for other molecules, such as DNA [S. Asayama, M. Nogawa, Y. Takei, Akaike T., Mamyama A. Synthesis of novel polyampholyte comb-type copolymers consisting of a poly(L-lysine) backbone and hyaluronic acid side chains for a DNA carrier // Bioconjug Chem. 1998. V.9. No. 4. P.476-81].

Among known previously synthesized derivatives of GA amphoteric structure are conjugates Ledger with carbodiimide different structures [K.P. Vercruysse, Prestwich G.D. Hyauronate derivatives in drug delivery // Therapeutic Drug Carrier Systems. 1998. V. 15. No. 5. P.513-555], with isonicotinic acid hydrazide [E.S. Lukin abstract. Diss. on saisc. step. Kida. Sciences. Ufa, 2007. 110 S(www.anrb.ru/ink that thesis. Council)] and hexamethylenediamine were [J. Yeom, Bhang, S., Kim, B-S., Seo M.S., E.J. Hwang, I.H. Cho, J.K. Park, Hahn S.K. Effect of cross-linking reagents for hyluronic acid hydrogel dermal fillers on tissue augmentation and regeneration // Bioconjugate Chem. 2010. V.21, p. 240-247]. Amphoteric properties of these conjugates have not been investigated.

One of the ways to get the Ledger with amphoteric properties is the covalent binding of GC with β-diethylaminoethyl ether of para-aminobenzoic acid (novocaine). Novocaine belongs to the class of local anesthetic drugs. In addition to anesthetic action, novocaine by direct injection into the blood stream will have an overall effect on the body: it reduces the formation of acetylcholine and reduces the sensitivity of peripheral receptors, exerts a blocking effect on the autonomic ganglia, reduces spasms of smooth muscles, the excitability of the heart muscle and motor areas of the cortex [Mashkovsky PPM Medicines. - Kharkov: Torching. 1997. Vol.2. S]. In the body novocaine relatively rapidly hydrolyzed, forming a p-aminobenzoic acid (vitamin Hi) and Diethylaminoethanol (has a moderate vasodilator action), which are themselves pharmacologically-active substances.

Conjugates of glycosaminoglycans (GAGS) (chondroitin-sulfate, heparin and oxidized primary hydroxy-group of hyaluronic acid) with novocaine are known [1-8, see references below]. They were obtained by the reaction of GAG with novocaine in the presence of a condensing reagent water-soluble 1-ethyl-3-[3-(dimethylamino)propyl]to the of bodiimide (CBI) and contained (depending on the ratio of reagents), according to NMR spectroscopic analysis, 33-38% of residues of novocaine (per 100 disaccharide glycosides of links) in a modified chondroitin sulfate, 66-90% - modified heparin, 60% in oxidized Ledger (scheme 1). References 1-8:

1. Peredelkino YOU, Odinokov V.N., V.S. Lukin, Temkina T.V., Khalilov L.M., Dzhemilev sea level Chemical modification of heparin // Bioorg. chemistry. 2006. 32. No. 5. S-529;

2. Peredelkino YU, E.S. Lukin, Odinokov V.N. Acidic glycosaminoglycans and their chemical modification (review) // Bioorg. chemistry. 2008. T. No. 1. P.5-28;

3. Peredelkino YOU, Odinokov V.N., Lukin Y.S., Dzhemilev sea level Conjugation of chondroitin sulfates with amines // Bioorg. chemistry. 2008. T. No. 5. S-710;

4. Peredelkino YOU, Odinokov V.N. Lukin Y.S., Sufijarova RS Parfenova TI, Bashkatov S.A., sibagatullin N.G., Dzhemilev sea level // Pat. Of the Russian Federation No. 2283320. Publ. 10.09.2006. BI No. 25;

5. Peredelkino YOU, Odinokov V.N. Lukin Essenially N.G., Suverov IVAN, Serik E.M., Dzhemilev sea level // Pat. Of the Russian Federation No. 2298406. Publ. 10.05.2007. BI No. 13;

6. Peredelkino YOU, Odinokov V.N., Lukin Y.S., Dzhemilev sea level, Ivanov O.V., Cathalina E.A. // Pat. Of the Russian Federation No. 2318830. Publ. 10.03.2008. BI No. 7;

7. Peredelkino YOU, Cathalina E.A., E.S. Lukin, Odinokov V.N., Dzhemilev sea level // Patent RF №2350625. Publ. 27.03.2009. BI No. 9;

8. Peredelkino YOU, Suverov IVAN, E.S. Lukin, Cathalina E.A., Odinokov V.N., Dzhemilev sea level // Pat. Of the Russian Federation No. 2343932. Publ. 20.01.2009. BI No. 2.

Scheme 1

In addition to residues of novocaine, conjugates of chondroitin sulfates from the umbilical cord of newborns contained 3% O-utilization (products joining the CBI on carboxy-groups), conjugates of heparin-3-10%, compared dermatosurgery from pig skin is 32%.

Closest to the proposed invention is a conjugate Ledger containing, depending on the ratio of reagents, 10-53% of residues of novocaine and 18-36% urednik residues (O-utilization) [E.S. Lukin abstract. Diss. on saisc. step. Kida. Sciences. Ufa, 2007. 110 C. (www.anrb.ru/ink. thesis. Council)] (Fig.1). It was obtained according to scheme 1 and high content of O-utilization practically does not dissolve in water.

The main drawback of the above-mentioned conjugate is the presence in its composition of by-products attach carbodiimide (Fig.1), so that the solubility of the compounds was practically reduced to a minimum.

Fig.1.

The task of the invention is to obtain having amphoteric properties of water-soluble conjugate Ledger with novocaine, not containing by-products. This is achieved as follows. The reaction of GA with novocaine is carried out in the presence of the OED and N-hydroxybenzotriazole (HOBt) as an additive that prevents the formation of side O-utilization. Synthesis of OS the effect in the aquatic environment (pH 4.7-4.8) at room temperature for 30-60 min at a ratio of chemicals VOC:novocaine:t:CBI=1:1-2:0.5-2:0.75-2 and get a water-soluble products with 20-50% of residues of novocaine, not containing O-utilization (scheme 2). It should be noted that, HOBt is used in peptide synthesis and is sometimes used in the carbodiimide synthesis of some derivatives of GA (1-5-fold excess relative to the COOH-group of the substrate) [Kurisawa, M., J.E. Chung, Y.Y. Yang, Gaoa Sh.J., H. Uyama Injectable biodegradable hydrogels composed of hyaluronic acid-tyramine conjugates for drug delivery and tissue engineering // Chem. Commun. 2005. P. 4312-4314; Bulpitt, P., Aeschlimann D. New strategy for chemical modification of hyaluronic acid: preparation of functionalized derivatives and their use in the formation of novel biocompatible hydrogels // J. Biomed. Mater. Res. 1999. V.47. P.152-169; Crescenzi V., Francescangeli, A., A. Taglienti, D. Capitani, L. Mannina Synthesis and partial characterization of hydrogels obtained via glutaraldehyde crosslinked of acetylated chitosan and of hyaluronan derivatives // Biomacromolecules. 2003. V.4. P.1045-1054; Crescenzi V., Francescangeli, A., A. Taglienti New gelatin-based hydrogels via enzymatic net working // Biomacromolecules. 2002. V.3. P.1384-1391].

Scheme 2

All samples conjugates Ledger with 20-50% of residues of novocaine showed properties of polyampholytes [S. Asayama, M. Nogawa, Y. Takei, Akaike T., Maruyama A. // Bioconjug. Chem. 1998. V.9. No. 4. P.476-481.], i.e. measured at 500 nm turbidity their aqueous solutions (concentration 4 mg/ml) was changed by varying the pH from 2 to 11. Maximum absorption of solutions of the samples was observed at pH 2-5 .5 (table 1).

The invention is illustrated by the following examples.

Example 1. 0.1 g (0.25 mmol) of GC, 0.07 g (0.25 mmol) of novocaine, 0.016 g (0.125 mmol) of HOBt are placed in a glass container with a volume of 100 cm3equipped with magnetic what esilkoy. Then add 25 ml of distilled water. All components are mixed at room temperature until complete dissolution. Bring the solution to pH 4.75 with 0.1 M NaOH, was added 0.036 g (0.19 mmol) of water-soluble CBI and intensively stirred the reaction mass over a period of 0.5 h, keeping pH 4.7-4.8 titration with 0.1 M Hcl. Then it was cooled to 0-5°C. the reaction mass is added 0.1 M NaOH (to pH 7), 3-5 ml of saturated NaCl solution and 75 ml of ethyl alcohol. The precipitate centrifuged at 3000 rpm for 2-5 minutes the precipitate is dissolved in 15 ml of 6% NaCl and add 45 ml of ethanol. The newly formed precipitate centrifuged at 3000 rpm for 2-5 min, washed with ethanol and then diethyl ether and dried in vacuum. So get modified GC with novocaine with a degree of substitution of carboxyl groups of the polymer 20 mol%. (scheme 2).

To obtain conjugates with novocaine used a CC with a molecular weight of 40 kDa [Peredelkino YOU, Odinokov V.N., Vakhrusheva B.C., Golikova M.L., Khalilov L.M., Dzhemilev sea level Modification of hyaluronic acid aromatic amino acids // Bioorgan. chemistry. 2005, 31 So. No. 1. S-95]) and higher.

Conversion of the carboxylic groups of ha in amide was determined according to the1H-NMR spectroscopy using the integrated intensity of the characteristic signals about the ones residue novocaine (signal with δ 1.4 ppm (t, J=14.1 and 7.0 H2NCF2CH3)) in relation to the intensity of the signal of the methyl protons acetamide group GK in the field 5 2 ppm as an internal standard. Spectra1H-NMR and13C-NMR were recorded for solutions in D2O spectrometer Bruker AMX-400 (operating frequency for1H-NMR 400 MHz), as the standard used acetone. Spectra in the visible region (500 nm) were obtained using the spectrophotometer Specord M-40. Control the pH of the solutions was performed using a pH meter pH-340".

Amphoteric properties of the conjugate of ha with 20% residual novocaine, depending on the pH (from 2 to 11) was investigated according to the method described in S. Asayama, M. Nogawa, Y. Takei, Akaike T., Maruyama A. // Bioconjug. Chem. 1998. V.9. No. 4. P.476-481. Prepared several sample solutions with a concentration of 4 mg/ml, pH of each solution was brought to a desired value and measured the absorbance (turbidity) at 500 nm. Maximum absorption of solutions of the samples was observed at pH 2-5 .5.

Table 1.
pHA (λ500 nm)pHA (λ500 nm)
20.170270.1170
3 0.16237.50.1168
40.159280.1171
50.141190.1150
5.50.1317100.1121
60.1193110.1102

Example 2. Conjugate GC content of residues of novocaine 35 mol%. is obtained analogously to Example 1, but the ratio of chemicals VOC:novocaine:t:CBI=1:1.5:1.5:1.5.

Table 2.
pHA (λ500 nm)PHA (λ500 nm)
20.211070.1523
3.50.20037.50.1512
4.50.19328 0.1509
50.17349.50.1493
5.50.1738100.1496
60.1702110.1498

Example 3. Conjugate GC content of residues of novocaine 50 mol%. is obtained analogously to Example 1, but the ratio of chemicals VOC:novocaine:t:CBI=1:1:2:2.

Table 3.
pHA (λ500 nm)pHA (λ500 nm)
20.260170.2421
3.50.25457.50.2437
40.25678.50.2408
50.254390.2396
5.5/td> 0.2510100.2398
60.2432110.2379

As can be seen from the results (table 1-3), increasing the degree of substitution of carboxyl groups of the polysaccharide on the remains of novocaine from 20% to 50 mol%. the optical density (turbidity) of solutions of the samples proportionally increases and the maximum value is at pH 2-5 .5. At pH 6-11 absorbance value was almost unchanged.

Water-soluble conjugates Ledger with novocaine, having amphoteric properties, can be used as a biomaterial with reparative-regenerative properties in medicine, a carrier for other molecules (such as acids and bases by nature), as well as in cosmetic products.

Conjugate of hyaluronic acid with novocaine formula

where n=20-50%, m=50-80%,
having amphoteric properties.



 

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