CZ308595B6 - A process for preparing a physically crosslinked hydrogel with at least one solubilized hydrophobic compound - Google Patents

Abstract

A process for preparing a physically crosslinked hydrogel with at least one solubilized hydrophobic compound, in which a solution for gelation is prepared in a reaction vessel by dissolving at least one polymer in an electrically charged powder form and at least one ionic surfactant in powder form with an opposite electric charge in water; during and / or after it is prepared, at least one hydrophobic compound is added, which is / are solubilized/solubilized into the inner hydrophobic part of the micelles of the dissolved ionic surfactant(s), which are before and / or during this and / or then binds to the polymer chain of the dissolved polymer(s), followed by gelation of this solution to form a physically crosslinked hydrogel with the solubilized hydrophobic compound/compounds.

Description

A process for preparing a physically crosslinked hydrogel with at least one solubilized hydrophobic compound

Field of technology

The invention relates to a process for the preparation of a physically crosslinked hydrogel with at least one solubilized hydrophobic compound.

Prior art

Hydrogels are physically (e.g., ionic bonds or strong dipoles of the side groups of macromolecules) or chemically crosslinked macromolecular substances with a strong affinity for water, which typically contain 90 to 99% by weight in their structure. Physically crosslinked hydrogels then have worse mechanical-strength characteristics compared to chemically crosslinked hydrogels, but at the same time they have a much higher potential for biocompatibility and retain the biodegradability of the starting polymeric component. This allows their use, eg as a so-called "wet wound cover", where the hydrogel is easily absorbed and eventually releases the active compound (s) stored in its structure. However, the preparation of these physically crosslinked hydrogels with the active compound (s) is complicated by the fact that most of the active compounds in question have a hydrophobic character, which considerably complicates their incorporation into the structure of the hydrophilic hydrogel.

Currently, two methods are known for embedding hydrophobic compounds in a hydrogel structure. The first is the dispersion of micelles of the ionic surfactant (s) in a hydrogel matrix, wherein the hydrophobic compound (s) bind / bind to the hydrophobic portions of these micelles, and the second is to modify the properties of the starting polymer to bind the hydrophobic compound (s) to each other. . A more used method is the use of an ionic surfactant, which is simpler and faster and leads to the formation of a hydrogel with suitable hydrophilic properties for the intended use. This process then consists in the separate preparation of aqueous solutions of the individual components of the hydrogel-polymer and the ionic surfactant, the hydrophobic compound being previously solubilized in the ionic surfactant solution. After mixing these solutions, spontaneous gelation and hydrogel formation with the solubilized hydrophobic compound occurs.

The disadvantage of this is the time consuming preparation of individual aqueous solutions (up to 48 hours), which is mainly due to the reluctance of polymers (especially highly concentrated and high molecular weight) to dissolve in water, limited dissolution of hydrophobic compounds in aqueous ionic surfactant solution and the need subsequent dispersing of the ionic surfactant micelles in the gelling solution. Another disadvantage is the need to prepare the two solutions separately, usually in addition under sterile conditions, where, for example, a very viscous polymer solution has a reduced molecular weight during sterilization, which has a negative effect on the stiffness of the resulting hydrogel.

The object of the invention is to propose a process for the preparation of a physically crosslinked hydrogel with at least one solubilized hydrophobic compound, which would obviate the disadvantages of the prior art by making its preparation easier, faster and thus more economically advantageous.

The essence of the invention

The object of the invention is achieved by a process for preparing a physically crosslinked hydrogel with at least one solubilized hydrophobic compound, the principle of which is that by dissolving at least one polymer in electrically charged powder form and at least one ionic surfactant in powder form with opposite electrical charge in water, in the reaction vessel

- 1 CZ 308595 B6 a solution for gelation is prepared, at least one hydrophobic compound being added to it during and / or after its preparation. This compound (s) is / are solubilized into the inner hydrophobic part of the micelles of the dissolved ionic surfactant (s), which binds to the polymer chain of the dissolved polymer (s) before and / or after and / or after. Subsequent gelation thus forms a physically crosslinked hydrogel with the solubilized hydrophobic compound (s).

This procedure significantly reduces the time required to prepare the hydrogel (up to a quarter of the original time), as the lengthy preparation of the polymer solution (s) is eliminated, as well as the time required to dissolve the hydrophobic substances in the ionic surfactant solution. In addition, in the case of the use of sterile materials, the need for sterilization is eliminated, or it is necessary to sterilize only one solution in one reaction vessel, or only its non-sterile component (s) before adding to it. In addition, the simultaneous dissolution of the components of the gelation solution allows to solubilize more hydrophobic compound (s) or polymeric fillers into the hydrogel than the process based on separate preparation of individual solutions, which is limited by the solubilizing capacity of the ionic surfactant under given conditions and the amount of solubilized compound. of the compounds depends on its / their solubility in the prepared solution.

At least one hydrophobic compound in powder form or a solution of this compound in a volatile organic solvent from the group consisting of ketone, alcohol, chlorinated hydrocarbon, ether is placed in the reaction vessel and subsequently evaporated, the hydrophobic compound (s) deposited on the inner surface of the reaction vessel, at least one hydrophilic organic polymer in powder form with electric charge from the group of polyamino acid hydrochloride, polyethyleneimine hydrochloride, poly (diallyldimethylammonium chloride), poly (N-isopropylacrylamide) hydrochloride, poly (allylamine) hydrochloride, cationic cellulose, chitosan and its positively charged derivatives, sodium hyaluronan , alginate, carboxymethylcellulose, sodium polystyrene sulfonate, or chondroitin sulfate and at least one ionic surfactant of surfactant character in powder form with the opposite electric charge. To interact with negatively charged polymers, a positively charged ionic surfactant from the group consisting of cetyltrimethylammonium bromide, dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, hexadecyltrimethylammonium bromide, [1 (ethoxycarbonyl) pentadecylbromethylamethylametamethylamethylammonium uses a negatively charged ionic surfactant from the group of sodium / potassium dodecyl sulfate, sodium / potassium tetradecyl sulfate, sodium / potassium p-dodecylbenzenesulfonate.

The molar ratio of the electrically charged groups of ionic surfactant (s) and, conversely, the electrically charged groups of polymer (s) in the gelling solution is 0.05 to 50 and the concentration of ionic surfactant (s) is 8 TO ^-4 to 0.6 mol dm ^{- 3} .

The hydrophilic organic polymer (s) and ionic surfactant are dissolved in water or an aqueous solution of at least one electrolyte to prepare a gelation solution in the reaction vessel, wherein the hydrophobic compound (s) is solubilized into the inner hydrophobic portion of the dissolved ionic surfactant micelles. active substance (s) which physically binds before and / or during and / or after the polymer chain of the dissolved polymer (s), the subsequent spontaneous gelation of this solution in its aqueous medium forming a physically crosslinked hydrogel with a solubilized hydrophobic compound (s).

For the intended use of the hydrogel formed by the process according to the invention in medicine, it is required that the starting polymer used be biocompatible and, if appropriate, biodegradable.

For a faster gelation, it is advantageous if the gelation solution further contains monovalent and / or divalent and / or trivalent and / or tetravalent ions, and its total ionic strength is 10 ^-3 to 1 mol dm ^-3 .

-2 CZ 308595 B6

If desired, the gelling solution may further contain at least one proteinaceous substance which does not participate in the gelation and is enclosed in the structure of the hydrogel formed during it. Such a substance is, for example, oligomer (s), neutral polymer (s), polymer (s) with the opposite charge to the starting polymer (s), enzyme (s), etc. This substance (s) is released from its structure upon degradation of the hydrogel and acts at the site of release, when, for example, they complement or promote the action of the hydrophobic compound (s).

Examples of embodiments of the invention

In a process for the preparation of a physically crosslinked hydrogel with at least one solubilized hydrophobic compound, the process according to the invention dissolves at least one polymer in powder form with positive or negative electric charge and at least one ionic surfactant in powder form with opposite electric charge in water in one reaction vessel. , prepares a solution for gelation. During and / or after preparation of this solution, at least one hydrophobic compound is added to it, e.g. in the form of a solution or in solid form, which solubilizes / solubilizes into the inner hydrophobic part of the micelles of the dissolved ionic surfactant (s). , wherein said ionic surfactant (s) binds to the polymer chain of the dissolved polymer (s) before and / or during and / or after. Subsequent spontaneous gelation of this solution then forms a physically crosslinked hydrogel with the solubilized hydrophobic compound (s). Any free solution over the hydrogel is then discarded or otherwise removed.

The hydrophobic compound is used in the solid state - for example in the form of a powder (see Example 1) or in the form of a solution, in an amount according to its desired final concentration in the hydrogel. The maximum amount of hydrophobic / hydrophobic compound (s) that can be solubilized into the gel matrix is given by the solubilizing capacity of the ionic surfactant (s) used under the given conditions in the given environment without the presence of the polymer.

In a preferred embodiment, a solution of at least one hydrophobic compound in a volatile organic solvent, e.g., ketone, alcohol, chlorinated hydrocarbon, ether, etc., is placed in the reaction vessel prior to forming the gelation solution, which is then evaporated (e.g., under reduced pressure). During its evaporation, the hydrophobic compound (s) dissolved therein is recrystallized on the inner surface of the reaction vessel, from where the ionic surfactants are solubilized into the inner hydrophobic part of the micelles of the ionic surfactant during the subsequent formation of the gelation solution and / or after its formation and / or during gelation. substances (see Example 2) contained in the gelling solution. The solubilization is aided by the large specific surface area of the hydrophobic compound (s). This procedure is particularly suitable for dosing low amounts of hydrophobic compounds which are unattainable on standard analytical balances, e.g. highly active pharmacologically active substances, or for compounds which are strongly hydrophobic.

By these methods, hydrogels can be prepared with at least one hydrophobic compound soluble under the given conditions in one of the ionic surfactants used. These are preferably, in particular, pharmacologically active substances or drugs - eg tocopherol, doxorubicin, paclitaxel, menadione, quinine, diclofenac, or any other hydrophobic substances, incl. dyes - eg Sudan Red G, Oil Red O, perylene, diphenylhexatriene, Nile Red, Oregon Green, Rhodamine 6G, and hydrophobic liquids - eg chloroform, etc.

Along with the hydrophobic compound (s), at least one hydrophilic compound can also be incorporated into the hydrogel, if necessary, which, for example, complements or promotes the action of the hydrophobic compound (s) used and / or improves one of the hydrogel parameters.

Any positively or negatively charged organic polymer-synthetic or natural can be used as the starting polymer, which is preferably biocompatible and possibly also biodegradable due to the intended use of the hydrogel in medicine, and in which the interaction with the oppositely charged

-3GB 308595 B6 The ionic surfactant (s) form a gel. In general, these are either polyanions - eg acids (eg carboxylic, sulfonic, etc.), resp. their salts which, under the given conditions, temperature, ionic strength and pH, carry a negative charge (eg sodium hyaluronate, sodium polystyrenesulphonate, alginate, carboxymethylcellulose, chondroitin sulphate), or polycations - eg polymers which contain amino and / or imino groups and and / or amide groups and / or quaternary ammonium groups, and are, for example, in the form of the hydrochloride and / or the corresponding hydrochloride salts which, under given conditions - temperature, ionic strength and pH, carry a positive charge (e.g. polyamino acids at pH according to their isoelectric point). , polyethyleneimine, poly (diallyldimethylammonium chloride), polyisopropylacrylamide), poly (allylamine) hydrochloride, cationic cellulose, chitosan and its positively charged derivatives.

In addition to the polymers themselves, it is of course possible to use several types of suitable polymers at once, incl. copolymers of positively and negatively charged monomers, provided that one of the molar charges predominates and the polymer is not neutral.

The polymer (s) is / are used in the process for preparing the hydrogel according to the invention in the solid state, so-called powder form.

The ionic surfactant can then be any micelic micelle-forming surfactant. When a positively charged ionic surfactant is used to interact with negatively charged polymers (polyanions) (e.g., alkylammonium bromide - cetyltrimethylammonium bromide, dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, hexadecyltrimethylammonium bromidyl] carbonamide, [1 p-toluenesulfonate, etc.), and a negatively charged ionic surfactant (e.g., sodium / potassium alkylsulfate, sodium / potassium tetradecyl sulfate, or sodium / potassium p-dodecylbenzenesulfonate arylsulfonate) is used to interact with positively charged polymers (polycations). etc.). Ionogenic surfactants can be mixed with each other in any ratio, provided that they carry the same charge. The ionic surfactant (s) is used in a total concentration of 8TO ^-4 to 0.6 mol dm ^-3 . The total concentration of the ionic surfactant (s) must be higher than its / their aggregation concentration under the given conditions in the solution of the given composition, as it must be able to form micelles and micelle-like structures which carry a charge on the surface and hydrophobic in their middle part. strings. The temperature range at which the ionic surfactant (s) interacts is bottom-bounded by the Kraft temperature (specific for the ionic surfactant) and the upper boiling point of the aqueous environment under the conditions.

The ionic surfactant (s) is also used in the process for preparing the hydrogel according to the invention in solid form, in powder form. The ratio of the amount of polymer (s) to the amount of ionic surfactant (s) then depends on the ratio of their opposite charges, the experimentally verified suitable values being the molar ratio of electrically charged groups of ionic surfactant (s) to oppositely electrically charged polymer (s) groups in the gelling solution. 0.05 to 50.

Gelation and hydrogel formation are supported and accelerated by the possible presence of electrolyte. In a preferred variant, monovalent and / or divalent and / or trivalent and / or tetravalent ions are used, which are added to the gelling solution, for example in the form of an aqueous solution, so that the total ionic strength of the gelling solution is 10 ^-3 to 1. mol dm ^-3 . A suitable electrolyte is, for example, aqueous sodium chloride solution.

The hydrogel prepared by the process of the invention may contain, in addition to the basic components - starting polymer (s), ionic surfactant (s), hydrophobic compound (s) and optionally electrolyte, other components which do not directly participate in hydrogel formation, such as protein compound (s). nature - polymers and oligomers, neutral polymer / polymers, polymer / polymers with opposite charge than the starting one

-4CZ 308595 B6 polymer (s), etc. These components are then held sterically in the formed hydrogel, protected and maintained in a native, biologically and chemically active form (e.g. enzymes), and are released from the hydrogel upon degradation and act in place. release.

The process for preparing a physically crosslinked hydrogel with at least one solubilized hydrophobic compound according to the invention comprises the following steps: placing the hydrophobic compound (s) in solid or liquid state, positively or negatively charged polymer (s) and oppositely charged ionic surfactant substances / substances in the solid state, resp. in the form of a powder, and water and / or an aqueous solution of the electrolyte (s) to the reaction vessel, the order of addition of the individual components not being important. In case the hydrophobic compound (s) is applied to the walls of the reaction vessel by recrystallization from a volatile organic solvent, the other components of the gelling solution are added to the reaction vessel only subsequently. The resulting solution is allowed to stand, preferably on a shaker, until spontaneous gelation and the formation of a compact hydrogel.

Any free solution over the hydrogel is then decanted or otherwise removed.

Below are two specific examples of the preparation of a physically crosslinked hydrogel with one solubilized hydrophobic compound of the invention. One skilled in the art will appreciate that in addition to the specific substances listed in these examples, the hydrogel may be formed in the same manner using other substances, such as those listed above, with the same or similar properties, or a combination thereof. 10 ^-7 to 10 ^-5 mol · dm ^-3 (here with respect to the spectrophotometric determination), the concentration of the ionic surfactant may be, depending on the concentration of the hydrophobic compound, in the range of 5 10 ² to 0.2 mol dm ^-3 (in the case of using a solution of a volatile organic solvent, the concentration of the hydrophobic compound in a volatile organic solvent of 10 ^-6 to 5 KUmoldnT ³⁾ and the concentration of the polymer can be depending on the concentration of ionic surfactant in the range of 0.5 to 2 wt%.

Example 1

The model hydrophobic dye Sudan Red G (1- (2-methoxyphenylazo) -2-naphthol) was placed in powder form in a 10 ml reaction vessel in such an amount that the final concentration after the addition of the electrolyte was 5 · 10 “ ⁶ mol dm ^-3 .

Sodium hyaluronate (mean M _w = 1.7 MDa) in powder form and cetyltrimethylammonium bromide (CTAB) in powder form were then added to it in such an amount that the final concentration of sodium hyaluronate after the addition of the electrolyte was 2% by weight. final concentration of cetyltrimethylammonium bromide 0.2 mol dm ^-3 . To the mixture thus formed was added 6 ml of 0.15 mol dm ^-3 sodium chloride (NaCl) solution.

The reaction vessel was sealed and allowed to stand at room temperature until the next day, during which time spontaneous gelation occurred, which was further accelerated by continuous shaking. The hydrogel formed separated in the lower part of the reaction vessel and a free solution remained above it, their ratio being about 1: 3. After completion of the gelation, this free solution was separated by decantation.

0.5 g of the hydrogel was then dissolved in 5 ml of hydrochloric acid (HCl) pH 1.3 and the concentration of sudan red G was determined spectrophotometrically in 15 ml of the solution thus formed after 15 minutes of degradation. 10 ^-6 mol dm ^-3 . It follows that the solubilization efficiency was 74%, which is comparable to the previously used process with separate preparation of a solution of polymer and ionic surfactant, which is approximately 79% using the same substances and concentrations.

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Example 2

A solution of a model hydrophobic dye - Sudan red G (1- (2-methoxyphenylazo) -2-naphthol) in acetone at a concentration of 10 ^-4 moldm · ³ was placed in a 10 ml reaction vessel, in such an amount that the resulting concentration of Sudan red G after the addition of electrolyte was 5 · 10 ^-6 mol dm ^-3 . Subsequent to evaporating the acetone under reduced pressure, Sudan red G was recrystallized on the inner surface of the reaction vessel.

Then, sodium hyaluronate (mean M _w = 1.7 MDa) in powder form and cetyltrimethylammonium bromide (CTAB) in powder form were added to the reaction vessel in such an amount that the final concentration of sodium hyaluronate after the addition of the electrolyte was 2% by weight. , and the final concentration of cetyltrimethylammonium bromide 0.2 mol dm ^-3 . To the mixture thus formed was further added 6 ml of a 0.15 mol dm ^-3 sodium chloride (NaCl) solution.

The reaction vessel was sealed and allowed to stand at room temperature until the next day, during which time spontaneous gelation occurred, which was further accelerated by continuous shaking. The hydrogel formed separated in the lower part of the reaction vessel and a free solution remained above it, their ratio being about 1: 3. After completion of the gelation, this free solution was separated by decantation.

0.5 g of the hydrogel was then dissolved in 5 ml of hydrochloric acid (HCl) pH 1.3 and the concentration of sudan red G was determined spectrophotometrically after 15 minutes in 3 ml of the solution thus formed. ^-6 mol dm ^-3 . It follows that the solubilization efficiency was 78%, which is comparable to the previously used process with separate preparation of a solution of a polymer and an ionic surfactant, which is approximately 79% using the same substances and concentrations.

The hydrogel prepared by the process of the invention is, depending on the choice of starting materials and the particular mechanical operations involved in its preparation, either in the form of a compact gel layer and / or in the form of a system of gel-like particles of various sizes. Its properties are the same in all variants.

The hydrogels prepared by the process according to the invention can, if necessary, be (repeatedly) dehydrated and then rehydrated, optionally (repeatedly) frozen and then thawed without changing its properties.

The process for preparing a physically crosslinked hydrogel according to the invention significantly reduces the time required to prepare the hydrogel (up to a quarter of the original time), as the lengthy preparation of the polymer solution (s) is eliminated and the time required to dissolve hydrophobic substances in the ionic surfactant solution is eliminated. In addition, in the case of the use of sterile materials (polymer (s) and ionic surfactant (s) in powder form as well as some contemplated hydrophobic compounds are supplied sterilized as standard), there is no need for sterilization, and if sterilization is still necessary, only one solution is sterilized per reaction. container, or only its non-sterile component (s) before being added to it.

In addition, this process can be used in a much larger range of concentrations, as the simultaneous dissolution of the gelation solution components allows solubilization of more hydrophobic compound (s) or polymeric fillers into the hydrogel than the process based on separate preparation of individual solutions, which is limited by the solubilizing capacity of the ionic surfactant under the given conditions and the amount of solubilized compound (s) depends on its / their solubility in the prepared solution.

Claims (1)

PATENT CLAIMS A process for preparing a physically crosslinked hydrogel with at least one solubilized hydrophobic compound, characterized in that at least one hydrophobic compound in powder form or a solution of this hydrophobic compound in a volatile organic solvent from the group consisting of ketone, alcohol, chlorinated hydrocarbon, ether is placed in a reaction vessel. which is subsequently evaporated and the hydrophobic compound (s) are deposited on the inner surface of the reaction vessel, at least one hydrophilic organic polymer in powder form with electric charge from the group polyamino acid hydrochloride, polyethyleneimine hydrochloride, poly (diallyldimethylammonium chloride), poly (A-isopropylacrylamide) hydrochloride , poly (allylamine) hydrochloride, cationic cellulose, chitosan and its positively charged derivatives, sodium hyaluronate, alginate, carboxymethylcellulose, sodium polystyrenesulfonate, or chondroitin sulfate and at least one surfactant ionic surfactant in powder form with opposite electric charge, wherein p The interaction with negatively charged polymers uses a positively charged ionic surfactant from the group consisting of cetyltrimethylammonium bromide, dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, hexadecyltrimethylammonium bromide, [1 (ethoxycarbonyl) hexadecylbromethylamethylammonium s) uses a negatively charged ionic surfactant from the group of sodium / potassium dodecyl sulphate, sodium / potassium tetradecyl sulphate, sodium / potassium p-dodecylbenzenesulphonate, the total concentration of ionic surfactant (s) in the gelling solution being 8TO ^-4 to 0,6 mol dm ^-3 and the molar ratio of electrically charged groups of ionic surfactant (s) of surfactant and oppositely electrically charged groups of hydrophilic organic polymer (s) in solution for gelation is 0.05 to 50, the hydrophilic organic polymer (s) and ionic surfactant is dissolved in water or in an aqueous solution of at least one electrolyte, thereby preparing a gelling solution in the reaction vessel, wherein the hydrophobic compound (s) is solubilized into the inner hydrophobic portion of the micelles of the dissolved ionic surfactant (s) previously and / or during and / or thereafter physically binds to the polymer chain of the dissolved polymer (s), the subsequent spontaneous gelation of this solution in its aqueous medium forming a physically crosslinked hydrogel with the solubilized hydrophobic compound (s).