A method of obtaining modified chitosan emulsions and products on its basis

 

(57) Abstract:

Described is a method of obtaining modified chitosan emulsion, comprising the stage of preparing an acidic aqueous solution of chitosan, remove nerastvorim particles of chitosan by filtration or sedimentation and carrying out modifications of chitosan and an acidic aqueous solution of chitosan after removal nerastvorim particles of chitosan was dispersed in the presence of hydrophobic surfactants and acetone by stirring at a speed below 1000 rpm, the resulting emulsion modify the anhydride of the organic acid or dichlorohydrin dicarboxylic acids with additional stirring at the same speed, while receiving chitosan emulsion size nanogramme spherical shape is not more than 100 nm. Also described is a method of obtaining chitosan gel and chitosan suspensions using modified chitosan emulsion. The invention makes it possible to obtain chitosan suspension gels and emulsions with the size of nanogranules spherical shape is not more than 100 nm. 3 S. and 6 C.p. f-crystals.

The invention relates to chemical technology, particularly to a method for producing a gel or suspension of chitosan, and can be An way to get the gel on the basis of chitosan, comprising preparing a solution of chitosan in dilute acid, mixing the resulting solution with a hydrophobic substance, stirring the mixture to obtain an emulsion, carrying out the reaction of covalent fixation of chitosan in the composition of the emulsion by introducing into it a bifunctional reagent capable of forming covalent cross-linking between molecules of chitosan with subsequent washing and filtering of the received product (ed. mon. USSR N 827492, IPC 08 In 37/08, publ. 07.05.81 year ). The product of this technology is cross-linked gel based on chitosan, representing rigid resulting granules used in chromatography.

The disadvantage of this technical solution is that obtained in this way hard microgranular gels based on chitosan contain chitosan microspheres of a size not less than 1 μm and are an inappropriate basis for medical or cosmetic preparations, such as ointments or creams, or food, as they do not have sufficient plastic properties and is not absorbed by the body. In addition, the use of technology poisonous organic solvents and bifunctional reagents bearing such active

A method of obtaining derivatives of chitosan in the form of gel for the pharmaceutical industry (patent USSR N 508212. IPC 08 In 37/08, publ. 04.05.76 year). The method includes preparation of chitosan solution, removing nerastvorim particles of chitosan by filtration or centrifugation and carrying out modifications of chitosan allerease agents under alkaline conditions at pH 7.0 and 9.0 with the subsequent laundering of the finished product, which is released in the form of acid, and in this form he used in the industry. As alleluya agents use unsaturated or saturated anhydrides of dicarboxylic acids of different inner structure of the amino groups of chitosan, such as unsaturated anhydride using maleic, itacademy or citraconic anhydride and a saturated amber, acetoxystyrene, mutilatory, diatsetilvinny or diglycolic anhydride. However, as this technology is the end product of the reaction is released in the form of acid, while the chitosan molecules change their charge on the opposite or at least lose their charge, and with it lost many biologically active properties of chitosan as poly-polysaccharide. In addition, ptx2">

The closest technical solution is a modification of chitosan with the aim of obtaining the gel and pH-neutral substance, which is used as alleluya agents anhydrides and halides of dicarboxylic acids (RF patent 2172325, IPC 08 In 37/08, publ.20.08.2001).

The known method includes the preparation of a solution of chitosan in dilute hydrochloric or acetic acid, removing nerastvorim particles of chitosan by filtration or sedimentation and carrying out modifications of chitosan allermuir agent under alkaline conditions at pH 7.0 and 9.0 with the subsequent laundering of the obtained pH-neutral substances, as Alliluyeva agent use dichlorohydrin dicarboxylic acid, the reaction is carried out at a temperature of 18-25oSince before the formation of the gel structure of the product when the weight ratio of dichlorohydrin dicarboxylic acid and chitosan in terms of dry weight of 1: 5-1: 25, and the resulting pH-neutral substance chitosan-based autoclave, or dried by lyophilization, or it is injected organic acids or products of microbiological synthesis, containing organic acid, in a quantity sufficient to get ready gel method gels have relatively low penetration into the subcutaneous layers. The method does not allow to obtain gels with a particle size of chitosan, comparable to the size of the virus, i.e., in the nano-range.

The task to be solved by the invention is the obtaining of modified chitosan emulsions and products on its basis, namely chitosan chitosan gel or suspension ("milk"), highly penetrating.

The problem is solved by providing a method of obtaining modified chitosan emulsion, comprising the stage of preparing an acidic aqueous solution of chitosan, remove nerastvorim particles of chitosan by filtration or sedimentation. Prepared an acidic aqueous solution of chitosan was dispersed in the presence of hydrophobic surfactants and acetone by stirring at a speed below 1000 rpm, the surface-active substances are used polyvinyl alcohol, or polyethylene oxide, or carboxymethylcellulose, or tween 80, or liquid soap, etc. Obtained emulsion before the modification stand at least 2 hours and modify with additional stirring at the same speed. The modification is carried out in a solution of the anhydride of the organic acid (acrylic, said dicarboxylic acid. Use dichlorohydrin succinic or glutaric, or adipic or fumaric and other acids. You get a chitosan emulsion size nanogramme spherical shape is not more than 100 nm.

Modified chitosan emulsion is an intermediate for obtaining as chitosan gel and chitosan suspension ("milk").

The task is also solved by providing a method of obtaining chitosan gel, which is prepared by thermostating the modified chitosan emulsion at a temperature not lower than the 40oWith at least 10 hours, followed by treatment with alkali solution, washing with water until neutral pH, extraction, then stirred in an aqueous medium with addition of acid, permitted for use in cosmetics and Pharmacopoeia (acetic, or citric or succinic and others), you get a chitosan gel with size nanogramme spherical shape is not more than 100 nm, preferably 10 to 30 nm. The grain size determined by electron microscopy or x-ray analysis, or magnitude of light scattering (optical disdrometer).

The task is also solved by providing a method of obtaining chitosan suspension. Chitosan suspension ("molock the bath water, then stirred for at least 3 min at a speed of 8000-12000 rpm the resulting suspension is pasteurized at a temperature not exceeding 80oC for 3-5 hours. You get a chitosan "milk" size nanogramme spherical shape is not more than 100 nm, preferably 10-30 nm.

Summary of the invention the following examples illustrate. In Primero-3 describes the obtaining of modified chitosan emulsion.

Example 1.

Raw materials (chitosan) dissolved in 2% acetic or hydrochloric acid to obtain a 2% solution of chitosan, which is filtered through fabric filters.

To obtain emulsion mixer speed 1000-8000 rpm add 10 liters of acid 2% of chitosan solution, 1 liter of a 5% solution of surfactant (tween 80) and 800 ml of acetone.

The resulting mixture was dispersed by stirring at a speed of about 5000 rpm for 3 minutes. Then it added another 200 ml of surfactant (tween 80) and stirring is continued for another two minutes. Control ready chitosan emulsion is produced out of line. The resulting chitosan emulsion was incubated for 2 hours, then check for the presence of delamination. If separation is not observed, then the emulsion is considered to carry out the modification of the emulsion. In the mixer chitosan emulsion was added 1% solution in acetone anhydride of acrylic acid in 100 ml of the resulting mixture is stirred in a mixer with the same speed for 5 minutes, then placed in a thermostat at t=60oC for 50 hours. Receive chitosan emulsion size nanogramme spherical shape of about 30 nm.

Example 2.

Proceed analogously to example 1, but as surface-active substances are used polyvinyl alcohol, the mixing speed when the dispersion in the mixer is about 7000 rpm, and the modification carried out in a solution of succinic acid anhydride. Receive chitosan emulsion size nanogramme spherical shape of about 10 nm.

Example 3.

Proceed analogously to example 1, but as a surfactant use liquid soap, stirring speed when the dispersion in the mixer is about 3000 rpm, and the modification is carried out in a solution of dichlorohydrin succinic acid. Receive chitosan emulsion size nanogramme spherical shape of about 50 nm.

In examples 4-8 describes the obtaining of chitosan gel.

Example 4.

For gelatin add about 100 ml of 1 M NOH and mixing by hand.

Then chitosan emulsion hurt on a filter and washed with distilled water until the pH of wash water is not made equal to the pH of distilled water. The weight of the washed and wrung modified chitosan emulsion is about 1 kg of the Emulsion is placed in a mixer where add 7 l H2O, alcohol, oil, perfume and stirred for two minutes.

Then in a mixer add 60 ml of acid, permitted for use in cosmetics and Pharmacopoeia, namely acetic acid. The result is a thickened gel-like mass total volume of around 9-10 l, which is stirred at 2000-3000 rpm for 3-5 minutes. Receive chitosan gel with size nanogramme spherical shape of about 30 nm.

Example 5.

Proceed analogously to example 4, but to get the gel using the emulsion according to example 2. Receive chitosan gel with size nanogramme spherical shape of about 10 nm.

Example 6.

Proceed analogously to example 4, but to get the gel using the emulsion according to example 3. Receive chitosan gel with size nanogramme spherical shape of about 50 nm.

Example 7.

Proceed analogously to examples 4-6, but to get the gel as sour is

Proceed analogously to examples 4-6, but to get the gel as acid, permitted for use in cosmetics and Pharmacopoeia, use citric acid.

Example 9. Obtaining chitosan suspension.

To obtain chitosan suspension ("milk") 50 g of the modified chitosan emulsion is placed in a mixer, add 1 l of distilled water, and then stirred for 3-5 min at a speed of 8000-12000 rpm Obtained suspension pasteurized at 70oC for 3-5 hours. Receive chitosan suspension size nanogramme spherical shape of about 10 nm.

Thus the proposed method can be obtained chitosan chitosan gel or "milk" with a particle size comparable with the size of the virus, i.e., in the nano-range, allowing you to effectively penetrate the gel of chitosan in the subcutaneous layer, and dairy products through the mucous membrane of the gastrointestinal tract and transport of biologically active substances. Furthermore, the method allows to increase the yield of the final product, resulting in a savings of expensive raw material.

Obtained according to the claimed method, the products have been thoroughly tested, confirming the implementation of the clinical and experimental lymphology SB RAMS (Novosibirsk) in 1998-1999 was a series of scientific and clinical studies on the comparative effectiveness of applications of chitosan gel Wasn" in the treatment of patients with lymphedema of the lower extremities in a series of conservative methods.

As a result of the studies have shown that

- use applications of chitosan gel in the adjuvant treatment of patients with lymphedema of the lower extremities 2-3 degree allows you to implement a positive clinical effect in 75% of patients;

- use applications of chitosan gel allows a factor of 2 to increase the volume of lymph outflow and a 68% increase in the rate of lymph outflow compared with the traditional conservative treatment, which is accompanied by a pronounced decrease swelling of the extremities.

Department of eye diseases KSMA, M. N. S. Kyrgyz branch Icial SB RAMS tested chitosan gel for the treatment of burns of the cornea.

The experimental part was performed on the model alkali burn in experimental animals. Animals were divided into three groups: 1st group - spontaneous healing; 2nd group - control animals; group 3 - core, with the use of chitosan gel 4 times a day. It was while the ESA tissues, the absence of zones of ischemia, accelerate epithelization of the cornea. Chitosan gel in the early stages of eye trauma accelerates metabolic processes interstitial fluid, positively complements lymphotropic reaction.

Conclusions: chitosan has no toxic effect on the eye tissue; stimulates reparative processes in the cornea and conjuctiva eyes; accelerates the relief of swelling and epithelialization of corneal wounds.

On the basis of the Novosibirsk inter-regional burn center were tested creams containing chitosan gel. The object of the study were patients with thermal burns in size from 1 to 10% and their consequences in age from 15 to 68 years. All the preparation is applied by 94 people. The following results are obtained:

when superficial burns 1st degree (56 people) in the first hours after injury, the application of the cream leads to subsidence or complete disappearance of pain in 3-5 minutes. Healing occurs within 1-2 days;

when superficial burns 1-2-3A degrees (28 people) at the end of epithelization applying cream leads to a rapid discharge of crusts, prevents drying of the young epidermis, helps to reduce discomfort and leads to education is Stanovlenie the integrity of the skin leads to faster removal of crusts, prevents drying of the young epidermis, helps to reduce the discomfort.

In Scientific research Institute of clinical and experimental lymphology SB RAMS (Novosibirsk) and the Kyrgyz branch (Bishkek) works on experimental substantiation and development of methods to accelerate the regeneration processes in the wall of the stomach with stress ulcers by enteral application of chitosan milk (suspension). Animal studies have shown that application of chitosan jelly on the background of antisecretory and anti-acid funds can significantly accelerate the process of regeneration by affecting local mechanisms of immunity and stimulation of epithelialization. The healing time of ulcers compared with conventional methods antiulcer therapy reduced.

Confirmation of the nontoxicity of the products is, for example, the presence of Sanitary-epidemiological conclusions 54.The national Assembly.08.915.T. 000098.01.02 dated January 17, 2002 , certifying that the requirements established in the Technical specifications 9158-003-67981817-02 "Gel chitosan "Lekvar" and the cosmetic formulations of chitosan gels "Lekvar" RC 9158-003-67981817-02/(1-10) comply with state Sanita is mulshi, including the stage of preparing an acidic aqueous solution of chitosan, remove nerastvorim particles of chitosan by filtration or sedimentation and carrying out modifications of chitosan, wherein the acidic aqueous solution of chitosan after removal nerastvorim particles of chitosan was dispersed in the presence of hydrophobic surfactants and acetone by stirring at a speed below 1000 rpm, the resulting emulsion modify the anhydride of the organic acid or dichlorohydrin dicarboxylic acids with additional stirring at the same speed, while receiving chitosan emulsion size nanogramme spherical shape is not more than 100 nm.

2. The method according to p. 1, characterized in that the formed chitosan emulsion before the modification stand at least 2 hours

3. The method according to PP.1 and 2, characterized in that the modification of the use acrylic anhydride, or salicylic acid, or benzoic acid, or succinic acids.

4. The method according to PP.1-3, characterized in that the modification of the use dichlorohydrin succinic or glutaric, or adipic or fumaric acid.

5. The method according to PP.1-4, characterized in that the surface-sports is idle soap.

6. The method according to PP.1-5, characterized in that after modification spend the temperature of the emulsion at temperatures below 40C for at least 10 hours

7. The method of obtaining chitosan gel, including the stage of preparing an acidic aqueous solution of chitosan, remove nerastvorim particles of chitosan by filtration or sedimentation and carrying out modifications of chitosan, wherein the modified chitosan emulsion obtained according to any one of paragraphs.1-6, is treated with alkali solution, washed to neutral pH, wring out and stirred in an aqueous medium with addition of acid, permitted for use in cosmetics and Pharmacopoeia, you get a chitosan gel with size nanogramme spherical shape is not more than 100 nm.

8. The method according to p. 7, characterized in that the acid permitted for use in cosmetics and Pharmacopoeia, the use of acetic or citric or succinic acid.

9. The method of obtaining chitosan suspension, including the stage of preparing an acidic aqueous solution of chitosan, remove nerastvorim particles of chitosan by filtration or sedimentation and carrying out modifications of chitosan, wherein the modified chitosan is 3 min at a speed of 8000-12000 rpm and pasteurized at a temperature not exceeding 80 ° C for 3-5 h, you get a chitosan suspension size nanogramme spherical shape is not more than 100 nm.

 

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