Method for preparing polyelectolyte microparticles containing incapsulated substance and sensitive to environment composition alteration

FIELD: medicine, biochemistry, pharmacy, biotechnology.

SUBSTANCE: invention relates to a method for preparing polyelectrolyte microparticles containing the end substance and showing sensitivity to alteration of the environment composition. Method involves preparing oppositely charged polyelectrolytes on microaggregates containing an encapsulated substance. These polyelectrolyte microparticles can be used both in medicine as systems used in delivery drugs and providing pH-sensitive release of encapsulated substance and in biotechnology as biocatalysts stabilized with respect to unfavorable conditions. Invention provides preparing polyelectrolyte microparticles characterizing by the high content of active substance - up to 90% of microparticles mass. Proposed method is sample and involves lesser amounts of steps.

EFFECT: improved preparing method.

9 cl, 3 tbl, 2 dwg, 61 ex

 

The invention relates to the field of pharmacy, biochemistry and biotechnology, namely the method of producing microparticles sensitive to changes in the composition of the environment and providing a pH-sensitive release of a target substance, preferably intended for the treatment, prevention and diagnosis.

A method of obtaining polyelectrolyte microcapsules by sequential adsorption of oppositely charged polyelectrolytes on soluble microarrays, the subsequent dissolution of the matrix and the inclusion in the obtained hollow microcapsules of active substance [1]. The disadvantage of this method of obtaining a low amount of active ingredient to be included in the polyelectrolyte wall of hollow microcapsules.

The closest in technical essence to the claimed method is a method for polyelectrolyte microcapsules sequential adsorption of oppositely charged polyelectrolytes on the insoluble microarrays enabled active substance [2]. The disadvantage of this method is the difficulty with the inclusion of the active substance in chips, and the use of a large number of stages of the adsorption of polyelectrolytes on the microarrays. In addition, the high efficiency of inclusion of the active substance in microcapsules, in this way naukasana the release of active ingredient from the microcapsules with the composition of the environment, what is important in their application.

Proposed a simpler and less multistage process of obtaining polyelectrolyte microparticles by adsorption of oppositely charged polyelectrolytes on the microarrays, containing the active substance. This polyelectrolyte microparticles are characterized by a high content of active substances - up to 90% by weight of microparticles (depending on conditions for obtaining microparticles and the number of stages of adsorption of polyelectrolytes).

The invention

The object of the invention is a method of obtaining a polyelectrolyte microparticles through a series of stages sequential layer-by-layer adsorption of oppositely charged polyelectrolytes on the insoluble microarrays containing encapsulated substance at pH 3-8 and adding sodium chloride to its concentration in solution 0-2,5 M

In the case of use as the active substance insoluble proteins chips produced by microwarehouse proteins by salting out, or more preferably by the formation of protein-polyelectrolyte complexes of micron size. As proteins can be used, for example, albumin, chymotrypsin and other enzymes, growth hormones, growth factors, antigens, cytokines and other

Protection is released from the microparticles proteins from actions which I proteolytic enzymes is provided by releasing them in the form of a complex with the polyelectrolyte, and by use in obtaining microparticles on one or more stages of sorption as a polyelectrolyte proteinase.

In the case of use as an active substance of water-insoluble substances chips for deposition of polyelectrolytes get thin grinding substances water-insoluble substances, in particular to an average particle size of 1-10 μm or less, or ultraspecialized their suspension with obtaining nanosized particles, in particular of 100-200 nm. For example, as water-insoluble substances can be used steroids, antioxidants, such as quercetin and selenium compounds, antitumor agents, such as methotrexate and paclitaxel, ftivazid, furosemide and other

In the case of use as the active substance oils or liquid hydrophobic substances as microarrays for deposition of polyelectrolytes used emulsions of these substances containing ionic detergent, subjected to ultrastucture. As such substances can be used, for example, oil herbal extracts, tocopherol acetate, carotenoids and other

As polyelectrolytes can be used natural or synthetic polyanion or polycation.

Preferably used as polianionov - textresult is a, chitosanalginate, chitosanalginate, fitosanitarine, dermatosurgery, chondro-ethyl sulfate, alginate, polystyrenesulfonate and anionic protein inhibitors of proteinases (inhibitor from soybean type Bauman-Birk, proteinase inhibitor from duck eggs), and as polycation - chitosan, Protamine, polylysine, poly-L-ornithine, gelatin, polyethylenimine, allylamine and the main proteinase inhibitor (Aprotinin).

The process of Assembly of polyelectrolyte microparticles in strictly defined pH values of the solution allows to obtain microparticles releasing the encapsulated substance in the active state when the desired pH values, the rate of release of the target substances is regulated by the ionic strength of the solution in the Assembly of microparticles, the number of stages of adsorption of polyelectrolytes, by varying the chemical nature of the polyelectrolytes and their molecular masses. By varying the initial size of microaggregates containing the active substance, and the ultrasonic effect on the microparticles is possible to obtain particles from the nano - to micro.

Polyelectrolyte microparticles with encapsulated substance can be stored for 3 years in suspension without aggregation and loss of activity of the encapsulated substance.

Polyelectrolyte microparticles with inkapsulirovanne the substance can be lyophilized from aqueous suspensions. Resuspension after lyophilization polyelectrolyte microparticles retain their original size before drying, and encapsulated them in substance retains its activity.

The use of biocompatible and biodegradable polyelectrolytes upon receipt of the microparticles allows the use of polyelectrolyte microparticles as a drug, providing a pH-sensitive release of encapsulated active substances, for example, if they enter certain areas of the gastrointestinal tract.

Microparticles based on both synthetic and natural polyelectrolytes enabled encapsulated substance can be applied Biocatalysis as bioreactors or in biotechnology, as a container for the active substance.

A method of obtaining a polyelectrolyte microparticles containing encapsulated substance is illustrated by the following examples.

Examples 1-17.

Obtaining freeze-dried polyelectrolyte microparticles based microarrays representing insoluble complexes of proteins with polyanions.

To obtain microarrays insoluble complex protein-polyanion was mixed with 5 ml of protein solution (20 mg/ml) and 5 ml of polyanion (5 mg/ml). Examples 1-17 used polyelectrolytes, pH and NaCl concentration when received and microparticles are shown in table 1. The suspension was stirred 20 min (300 rpm), the precipitate microparticles were separarely and washed twice with a solution without polyelectrolyte.

To the precipitate microparticles insoluble complex protein-polyanion was added 10 ml of a solution of polycation (2.5 mg/ml). The mixture was stirred 20 min, the precipitate was separarely and washed twice with a solution without polyelectrolyte.

The process was repeated to achieve the three stages of adsorption of polyelectrolytes, then the microparticles were suspensively in solution with the same pH and concentration of NaCl and stored in this form at 4-6°C. Studied the effectiveness of the inclusion of proteins in the microparticles in the suspension of microparticles studied the size of the microparticles, the microparticles protein and activity included enzymes.

The samples in examples 3, 6-9 washed three times 1 mm HCl and freeze dried. After drying the samples suspended in 1 mm HCl and studied the size of the microparticles (data given in parentheses in the last column of table 1).

Examples 18-21.

Getting polyelectrolyte microparticles based microarrays representing insoluble complexes of proteins with polycation.

To obtain microarrays insoluble complex protein-polycation was mixed with 5 ml of protein solution (20 mg/ml) and 5 ml of a solution of chitosan with a molecular weight of 22 KD. (5 mg/ml). Examples 18-19 used polyelectrolytes, pH and the concentration is of NaCl in obtaining microparticles are shown in table 1. The suspension was stirred 20 min (300 rpm), the precipitate microparticles were separarely and washed twice with a solution without polyelectrolyte,

To the precipitate microparticles insoluble complex protein-polycation was added 10 ml of polyanion (2.5 mg/ml). The mixture was stirred 20 min, the precipitate was separarely and washed twice with a solution without polyelectrolyte.

The process was repeated to achieve the three stages of adsorption of polyelectrolytes, then the microparticles were suspensively in solution with the same pH and concentration of NaCl and stored in this form at 4-6°C.

Examples 22-29.

The process of obtaining polyelectrolyte microparticles in the suspension of microparticles insoluble complex protein-polyanion was carried out similarly to examples 1-17, using as a protein, insulin, polyanion - DS, polycation - Protamine, until reaching from 1 to 8 stages of sortie polyelectrolytes (table 2, upper part).

Ready microparticles three suspensively in 1 mm HCl, was stored in 1 mm HCl at 4-6°C. in 3 years studied the stability of the microparticles, by analyzing the amount of protein released from the microparticles.

Examples 30-37.

To obtain polyelectrolyte matrices vysosannyh of microaggregates protein to a 5 ml solution of insulin (20 mg/ml) was added 0.15 g of NaCl. The mixture was stirred 1 h

The process of obtaining polyelectrolyte microparticles on vysosannyh microaggregate protein is rowdily similar to examples 18-25, using as polyanion - DS, polycation - Protamine, until reaching from 1 to 8 stages of adsorption of polyelectrolytes (see table 2).

Examples 38-43.

Obtaining freeze-dried polyelectrolyte microparticles based microarrays representing microparticles vysosannyh aggregates of proteins.

The process of obtaining polyelectrolyte microparticles in suspension insoluble complex protein-polyanion was carried out similarly to examples 1-17, using as protein - chymotrypsin, polyanion - extrasolar with a molecular mass of 500 kDa, polycation - chitosan with a molecular mass of 400 kDa to achieve from 1 to 6 stages of adsorption of polyelectrolytes.

Ready microparticles are washed three times pobyvali 1 mm HCl and freeze-dried and stored at 4-6°C. After drying the samples of masochistic suspended in 1 mm HCl and studied the activity chymotrysin.

Getting polyelectrolyte particles treated with ultrasound

Example 44.

10 ml suspension of polyelectrolyte microparticles with chymotrypsin, obtained in example 4 were subjected to treatment with the help of ultrasonic disperser "USDA-A (operating frequency generator 22 kHz) in an ice bath. After 2 min scoring average size of the microparticles was 3±2 μm, the specific activity of chymotrypsin 83±3%.

Example 45.

5 ml of suspension polyelectro litnih microparticles with insulin (average size 5-13 μm), obtained in example 33 were subjected to dubbing in example 44 for 3 minutes, the Average particle size after the scoring was 100-200 nm.

pH sensitive release of encapsulated substances from polyelectrolyte microparticles.

Example 46.

An aliquot of the suspension of polyelectrolyte microparticles with albumin obtained in example 1, was mixed with universal buffer (0.02 M H3PO4, 0.02 M CH3COOH, 0.02 M H3IN3+0.1 M NaOH, pH 3-8) to obtain a final protein concentration of 0.25 mg/ml After 1 hour stirring at shaker (100 rpm), the samples were centrifuged for 5 min at 1000 g and the supernatant was determined by the protein concentration.

The release of protein microparticles defined as the ratio of the protein content in the supernatant and the suspension of microparticles depending on pH, as shown in figure 1 And

Examples 47-50.

The process was carried out according to example 46, using samples of polyelectrolyte microparticles obtained according to examples 2 (insulin), 3 (chymotrypsin), 5 (with trypsin), 7 (Aprotinin). The results are shown in figure 1 A.

Figure 1. The effect of pH on the release of protein from polyelectrolyte microparticles. Curve number corresponds to the number of the example, which received microparticles.

Regulation of the speed of release of the encapsulated substance from polyelectrolyte microparticles variation Chi is La stages of adsorption of polyelectrolytes, the sequence of use of polianionov and polycation at the last stage of sorption upon receipt of the microparticles and the use of polyelectrolyte microparticles as a means of releasing the encapsulated substance.

Examples 51-56.

The release process of the protein was carried out according to example 46, using samples of microparticles with chymotrypsin with different number of stages of adsorption of polyelectrolytes of dextransucrase with a molecular mass of 500 kDa and chitosan with a molecular mass of 400 kDa, obtained according to the examples 38-43. The results are shown in figure 1 B.

Example 57.

The release process of the protein was carried out according to example 46 at pH 7.0, using a sample of microparticles with insulin, obtained according to example 6, using three stages of sorption doctranslate with a molecular mass of 500 kDa and the protease inhibitor is Aprotinin.

The supernatant was chromatographically on column with cephalexim G-50f (19,5×2.0 cm) in universal buffer with pH 7.0 (figure 2). At the exit from the column were analyzed by the protein content and the activity of the protease inhibitor. Detected the presence of active proteinase inhibitor found in high-molecular complex with polyelectrolytes, and insulin is not associated with the polyelectrolytes condition.

Figure 2. Gel chromatography on Sephadex G-50f protein released from the sample obtained in example 6: 1 - D280a 2-D50 (protein by Lowry), 3 - conditional inhibitory units.

Example 58.

The use of polyelectrolyte microparticles as biocatalysts.

Used suspensio microparticles obtained in example 43. An aliquot of the suspension was diluted 100 times, 0.001 M HCl. After 10 min measured the activity of chymotrypsin in suspension using as substrate benzoyl-arginine ethyl ester. The preservation of the specific activity of chymotrypsin was 9%.

An aliquot of the suspension was diluted 100 times in 0.05 M phosphate buffer. After 10 min measured the activity of chymotrypsin in suspension using as substrate benzoyl-arginine ethyl ester. The preservation of the specific activity of chymotrypsin against the enzyme that is taken for microencapsulation, amounted to 19%.

An aliquot of the suspension was mixed with 9 volumes of a solution of 0.025 M NaOH. After 30 seconds clear solution was diluted in 90 volumes of 0.05 M Tris-buffers with a pH of 7.8. After 10 min measured the activity of chymotrypsin, released in the destruction of the microparticles,

suspensions using as substrate benzoyl-arginine ethyl ester.

The preservation of the specific activity of chymotrypsin was 58%.

Getting polyelectrolytic microparticles based microarrays poorly soluble substances.

Example 59.

To obtain microarrays insoluble substance quercetin which has adversely fine grinding in an agate mortar and suspended to a concentration of 2 mg/ml solution of 0.25 M NaCl with a pH of 3.0 for 20 minutes

To obtain polyelectrolyte microparticles was mixed with 5 ml announced the suspension of quercetin and 5 ml of dextransucrase with a molecular mass of 500 kDa (5 mg/ml) in 0.25 M NaCl with a pH of 3.0. The mixture was stirred 30 min (300 rpm), the precipitate was separarely and washed twice with a solution without polyelectrolyte. To the precipitate microparticles were added 10 ml of a solution of chitosan with a molecular mass of 400 kDa (2.5 mg/ml) in 0.25 M NaCl with a pH of 3.0. The mixture was stirred 20 min, the precipitate microparticles were separarely and washed twice with a solution without polyelectrolyte. To the precipitate microparticles were added 10 ml of a solution of dextransucrase (2.5 mg/ml) in 0.25 M NaCl with a pH of 3.0. The mixture was stirred 20 min, the precipitate microparticles were separarely and washed twice with a solution without polyelectrolyte, then polyelectrolyte microparticles were suspensively in solution with 1 mm HCl and stored in this form at 4-6°C. Polyelectrolyte microparticles had an average size of 15±10 μm, the content of quercetin in them amounted to 85±5%.

Example 60.

To obtain microarrays insoluble substances in suspension 15 mg/ml 1,5 diphenyl-3-selenipedium-1.5 in water were subjected to dubbing in example 44 for 5 minutes

To obtain polyelectrolyte microparticles was mixed with 5 ml voiced suspension and 5 ml of a solution of chitosan with a molecular mass of 150 kDa (2 mg/ml) with a pH of 3.0 was mixed and stirred 10 min (300 rpm), the precipitate separer the Wali and twice washed with 0.001 M HCl. To the precipitate microparticles were added 10 ml of a solution of chitosan sulfate with a molecular mass of 150 kDa (2 mg/ml) with a pH of 3.0. The mixture was stirred 10 min, the precipitate microparticles were separarely and washed twice with a solution without polyelectrolyte. This procedure was repeated until 5 stages of adsorption of polyelectrolytes. At the end of the process the precipitate was twice washed, and then polyelectrolyte microparticles were suspensively in solution with 1 mm HCl and stored in this form at 4-6°C. Polyelectrolyte microparticles with 1,5 diphenyl-3-selenipedium-1,5 had an average size of 3±2.5 μm.

10 ml of suspension was separarely and separated supernatant. To the precipitate was added to 10 sunflower oil and stirred (100 rpm). After 7 h was not detected release 1.5 diphenyl-3-selenipedium to 1.5 of the microparticles. In the control of the suspension within 10 min after the addition of sunflower oil were observed complete dissolution suspension microarrays ozvucenoj 1,5 diphenyl-3-selenipedium in 1.5.

Example 61.

A method of obtaining a polyelectrolyte microparticles based microarrays representing the microemulsion oil.

To obtain microarrays were prepared emulsion containing tocopherol 2,5% about. and 0.1 wt%. sodium dodecyl sulfate.

To obtain microparticles emulsion was mixed with a solution of 2 mg/ml of allylamine with a molecular mass of 60 kDa ratio :1 by volume) and subjected to dubbing in example 44 for 1 minutes The resulting suspension was mixed in a 1:1 ratio with a solution of 2 mg/ml polystyrenesulfonate with a molecular mass of 70 kDa and stirred 10 min (300 rpm). The precipitate was separarely using ultra filtration and washed twice with a solution of 0.15 M NaCl with pH 4.0. To the precipitate was sequentially added one volume of polyelectrolyte solutions in 0.15 M NaCl with pH 4.0, incubated 10 min and washed twice with solutions without polyelectrolytes to achieve the five stages of adsorption of polyelectrolytes. Polyelectrolyte microparticles with tocopherol had an average size of 10±5 microns.

1. DE 19902553 A1, 22.02.1999. Polyelectrolythullen auf biologischen Templaten. B01J 13/02.

2. DE 10037707 A1, 2.08.2000. Polyelectrolytkapselnherstellung durch Oberflachenprazipitation. B01J 13/02.

1. A method of obtaining a polyelectrolyte microparticles, characterized by the fact that carry out a series of stages of sequential layer-by-layer adsorption of oppositely charged polyelectrolytes on the microarrays containing encapsulated protein at pH 3-8 and adding sodium chloride to its concentration in solution 0-2,5 M, and as one of the polyelectrolytes on one or several stages of adsorption is the protease inhibitor.

2. The method according to claim 1, characterized in that as the e microarrays are used microparticles insoluble complexes of proteins with polyelectrolytes.

3. The method according to claim 1, characterized in that as microarrays are used microparticles vysosannyh aggregates of proteins.

4. The method according to any one of claims 1 to 3, characterized in that the chips or polyelectrolyte microparticles treated with ultrasound to obtain particles with an average size of 100-200 nm.

5. The method according to claim 1, characterized in that the polyelectrolyte microparticles freeze-dried.

6. A method of obtaining a polyelectrolyte microparticles, characterized by the fact that carry out a series of stages of sequential layer-by-layer adsorption of oppositely charged polyelectrolytes on the insoluble microarrays containing micronized substance is not soluble in water substances at pH 3-8 and adding sodium chloride to its concentration in solution 0-2,5 M

7. The method according to claim 6, characterized in that the chips produced by fine grinding the water-insoluble substance to obtain particles with an average size of 10-20 microns.

8. The method according to claim 6, characterized in that the chips are obtained by ultrasonic treatment of a suspension of water insoluble substances to obtain particles with an average size of 0.5 to 5 microns.

9. A method of obtaining a polyelectrolyte microparticles, characterized by the fact that carry out a series of stages of sequential layer-by-layer adsorption of oppositely ZAR is part of polyelectrolytes on the microarrays, representing the processed ultrasound emulsion of oil or hydrophobic liquids containing ionic detergent, at pH 3-8 and adding sodium chloride to its concentration in solution 0-2,5 M



 

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