KR20190141623A - Method for preparing biocompatible hydrogel particle without cross linking agent and hydrogel particle prepared therefrom - Google Patents

Abstract

The present invention relates to a method for preparing a hydrogel by irradiating an electron beam to polysaccharides, and a hydrogel prepared therefrom. Specifically, the present invention relates to a method for preparing a hydrogel in the form of particles, by inducing crosslinking without substantially adding a crosslinking agent to polysaccharides such as hyaluronic acid; and a hydrogel in the form of particles prepared therefrom.

Description

FIELD OF THE INVENTION A method for producing a particulate biocompatible hydrogel without a crosslinking agent, and a particulate hydrogel prepared therefrom {METHOD FOR PREPARING BIOCOMPATIBLE HYDROGEL PARTICLE WITHOUT CROSS LINKING AGENT AND HYDROGEL PARTICLE PREPARED THEREFROM}

The present invention relates to a method for producing a hydrogel by irradiating an electron beam to polysaccharide and a hydrogel prepared therefrom. Specifically, the present invention relates to a method for preparing a hydrogel in the form of particles by inducing crosslinking without substantially adding a crosslinking agent to a polysaccharide such as hyaluronic acid and a hydrogel in the form of particles prepared therefrom.

Hyaluronic acid is a complex negatively charged polysaccharide, a high molecular compound consisting of N-acetylglucosamine and glucuronic acid, and is present in connective tissue, subcutaneous tissue, nerve tissue, or joint synovial fluid in vivo. Hyaluronic acid is extracted from microbial fermentation such as Streptococcus or chicken chalice because of its excellent biocompatibility, and is used as a cosmetic additive, as well as joint cavity injections, anti-adhesion agents, and ophthalmic medicines. In addition, hyaluronic acid gel is widely used as a molding filler which is a tissue repair biomaterial medical device.

On the other hand, as a problem that hyaluronic acid itself can be rapidly released from the body by decomposition by enzymes and free radicals has been reported, various attempts have been made to chemically crosslink to extend the decomposition period in the body.

That is, 1,4-butanediol diglycidyl ether (BDDE) or the like is intended to increase the chemical structural stability of hyaluronic acid to delay the degradation in vivo and maintain the physical retention period. A technique for stabilizing hyaluronic acid by the addition of a crosslinking agent has been developed, among which the maximum retention period of the existing hyaluronic acid crosslinked body and the hyaluronic acid derivative crosslinked body is known to be about 6 months to 24 months.

However, the high viscoelastic hyaluronic acid crosslinked body obtained by simply increasing the amount of crosslinking agent to increase the retention period of hyaluronic acid in vivo may cause inflammatory reaction due to toxicity of the residual crosslinking agent which is decomposed or unreacted in vivo. There is a problem.

As described above, there have been attempts to produce hydrogels by crosslinking polysaccharides such as hyaluronic acid. The prepared hydrogel has the advantage of excellent biocompatibility. Hydrogels (hydrogels) have a three-dimensional network structure in which polymers are cross-linked and have a swelling property of absorbing fluid from the outside. Therefore, it has the property of loading not only biological fluids derived from living tissues, but also therapeutic agents. In addition, since it is softer than other synthetic polymers, it is widely studied in the medical and pharmaceutical fields.

For example, hydrogels with nano- or micro-sizes have good flowability and can absorb or load drugs. In addition, the hydrogel can decompose itself and has the advantage of diversifying the formulation. Such hydrogels can be used as dressings, drug delivery carriers, lenses, cartilage, anti-adhesion agents, medical / non-medical fillers, and the like. In addition, the loading material loaded on the hydrogel is not particularly limited, and may be a fluorescent material, radioisotopes, magnetic resonance imaging or computed tomography contrast agents, ultrasound contrast agents, anticancer agents, anti-inflammatory agents, and the like.

The technical problems of the present invention will be clearly understood by those skilled in the art from the following description.

Specific matters of the embodiments of the present invention are included in the detailed description.

Effects according to embodiments of the present invention are included in the various effects herein.

Advantages and features of the present invention and methods for achieving them will be apparent with reference to the embodiments described below in detail with the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below, but may be implemented in various forms, and only the embodiments are provided to make the disclosure of the present invention complete, and those of ordinary skill in the art to which the present invention pertains. It is provided to fully inform the scope of the invention, and the invention is defined only by the scope of the claims.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In this specification, 'and / or' includes each and all combinations of one or more of the items mentioned. In addition, the singular also includes the plural unless specifically stated in the text.

As used herein, 'comprises' and / or 'comprising' does not exclude the presence or addition of one or more other components in addition to the mentioned components. Numerical ranges shown using 'to' indicate numerical ranges including the values described before and after the lower limit and the upper limit, respectively. "About" or "approximately" means a value or numerical range within 20% of the value or numerical range described thereafter.

In the present specification, the dose unit of the electron beam uses gray (Gy), and may be expressed as energy per weight. In addition, the dose rate unit of the electron beam uses Gy / s, and may be expressed as energy per weight per unit time.

Hereinafter, the present invention will be described in detail.

(A) Production method of hydrogel

Method for producing a hydrogel according to an embodiment of the present invention may include the steps of (a) preparing a polysaccharide aqueous solution, and (b) irradiating electron beam to form hydrogel particles. Each step will be described below.

(a) preparing a polysaccharide aqueous solution

As used herein, the term 'polysaccharide' refers to a molecule in which three or more single sugars form glycosidic bonds. Polysaccharides can be used to mean oligosaccharides. The glycoside bond may comprise α-glycoside and β-glycoside. The polysaccharide may have excellent hydroxyl reactivity because it has a hydroxyl group, an amino group and / or a carboxylic acid group in the molecule.

The polysaccharide is preferably biocompatible and water soluble. Examples of polysaccharides that can be used in the present invention are gelatin, chitosan, collagen, met, dextran, dextransulfate, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, maltodextrin (maltodextrin) ), Fructooligosaccharide, isomaltooligosaccharide, inulin, hyaluronic acid, alginate, glycogen, amylopectin, amylose, sucrose, agarose, galactose, carboxymethyldextran, betaglucan, epichlorohydrin , Hydroxyethylcellulose, carboxymethylcellulose, fucoidan, chondroitin and derivatives thereof. Preferably it may be chitosan, mannan, hyaluronic acid, cyclodextrin, dextran, alginate, fructooligosaccharide, isomaltooligosaccharide, fucoidan or carboxymethyldextran, or derivatives thereof. More preferably hyaluronic acid, dextran or fucoidan, or a derivative thereof.

Such polysaccharides can form hydrogels by intermolecular or intramolecular crosslinking. Crosslinking of the polysaccharide may be carried out by irradiation of electron beams as will be described later, and may proceed without mixing of additional crosslinking agents. That is, the crosslinking agent may increase the viscoelasticity of the crosslinking body, but the residual crosslinking agent that is degraded or unreacted in vivo may cause toxicity and cause an inflammatory response in the body. Therefore, in order to remove such an unreacted crosslinking agent, a crosslinking agent removing process or the like may be required, which may cause inefficiency. On the other hand, according to the manufacturing method according to the present invention has the advantage of crosslinking the polysaccharides only by irradiation of the electron beam.

The concentration of the aqueous polysaccharide solution may be appropriately selected in consideration of the type of polysaccharide and crosslinking reactivity. For example, the concentration of aqueous polysaccharide solution is about 0.1% (w / v), or about 0.5% (w / v), or about 0.7% (w / v), or about 1.0% (w / v), or about 2.0% (w / v), or about 3.0% (w / v), or about 4.0% (w / v), or about 5.0% (w / v), or about 6.0% (w / v), or about 7.0% (w / v), or about 8.0% (w / v), or about 9.0% (w / v), or about 10.0% (w / v), or about 11.0% (w / v), or about 12.0% (w / v), or about 13.0% (w / v), or about 14.0% (w / v), or about 15.0% (w / v), or about 16.0% (w / v), or about 17.0% (w / v), or about 18.0% (w / v), or about 19.0% (w / v), or about 20.0% (w / v), or about 21.0% (w / v), or about 22.0% (w / v), or about 23.0% (w / v), or about 24.0% (w / v), or about 25.0% (w / v), or about 30.0% (w / v), or about 35.0% (w / v), or about 40.0% (w / v), or about 40.0% (w / v), or about 50.0% (w / v).

Where a plurality of numerical values are described herein, it is to be understood that the present specification discloses a numerical range in which any two numerical values are respectively upper and lower limits. For example, the concentration of the aqueous polysaccharide solution is about 0.1% (w / v) to 10.0% (w / v), about 1.0% (w / v) to 15.0% (w / v), or about 5.0% (w / v) to 20.0% (w / v). In addition, where two or more numerical values are described herein, it may be understood that this specification discloses together any numerical value present between the two numerical values. For example, the concentration of the aqueous polysaccharide solution may be about 0.8% (w / v) or about 0.9% (w / v).

The concentration of polysaccharide in the aqueous polysaccharide solution can affect the form of the hydrogel formed by irradiation of electron beams. For example, when the concentration of the aqueous solution is too high, a viscoelastic material having a high crosslinking degree and a viscosity may be formed, and when the concentration of the aqueous solution is too low, a viscoelastic material having a low crosslinking degree and a viscosity may be formed.

The molecular weight of the polysaccharide or its derivatives may be appropriately selected in consideration of the kind of the polysaccharide and the crosslinking reactivity. For example, the molecular weight of the polysaccharide is about 0.1 kDa, or about 0.5 kDa, or about 0.6 kDa, or about 0.7 kDa, or about 0.8 kDa, or about 0.9 kDa, or about 1.0 kDa, or about 1.1 kDa, or about 1.2 kDa, or about 1.3 kDa, or about 1.4 kDa, or about 1.5 kDa, or about 1.6 kDa, or about 1.7 kDa, or about 1.8 kDa, or about 1.9 kDa, or about 2.0 kDa, or about 3.0 kDa, or about 4.0 kDa, or about 5.0 kDa, or about 6.0 kDa, or about 7.0 kDa, or about 8.0 kDa, or about 9.0 kDa, or about 10 kDa, or about 11 kDa, or about 12 kDa, or about 13 kDa, or about 14 kDa, or about 15 kDa Or about 16kDa, or about 17kDa, or about 18kDa, or about 19kDa, or about 20kDa, or about 30kDa, or about 40kDa, or about 50kDa, or about 60kDa, or about 70kDa, or about 80kDa, or about 90kDa, or About 100 kDa, or about 150 kDa, or about 200 kDa, or about 250 kDa, or about 300 kDa, or about 350 kDa, or about 400 kDa, or about 450 kDa, or about 500 kDa, or about 600 kDa, Or about 700 kDa, or about 800 kDa, or about 900 kDa, or about 1,000 kDa, or about 1,200 kDa, or about 1,400 kDa, or about 1,600 kDa, or about 1,800 kDa, or about 2,000 kDa, or about 2,500 kDa, or about 3,000 kDa, or about 3,500 kDa, or about 4,000 kDa, or about 4,500 kDa, or about 5,000 kDa. As mentioned above, the molecular weight of a polysaccharide according to the invention can be understood to disclose together the numerical range between any two values described above as the upper and lower limits, respectively, and / or the numerical value between any two values. .

The pH of the polysaccharide aqueous solution may be appropriately selected in consideration of the type of polysaccharide and crosslinking reactivity. For example, the pH of the aqueous polysaccharide solution is about 0.5, or about 1.0, or about 1.5, or about 2.0, or about 2.5, or about 3.0, or about 3.5, or about 4.0, or about 4.5, or about 5.0, or about 5.5 , Or about 6.0, or about 6.5, or about 7.0, or about 7.5, or about 8.0, or about 8.5, or about 9.0, or about 9.5, or about 10.0, or about 10.5, or about 11.0, or about 11.5, or About 12.0, or about 12.5, or about 13.0, or about 13.5, or about 14.0. As mentioned above, the pH of the aqueous polysaccharide solution according to the invention can be understood to disclose together the numerical range between any two values described above as the upper and lower limits, respectively, and / or the numerical value between any two values. have.

The viscosity of the aqueous polysaccharide solution may be appropriately selected in consideration of the type of polysaccharide and crosslinking reactivity. For example, the viscosity of the aqueous polysaccharide solution is 0.005 Pa.s, or about 0.01 Pa.s, or about 0.02 Pa.s, or about 0.03 Pa.s, or about 0.04 Pa.s, or about 0.05 Pa.s, or about 0.06 Pa.s, or about 0.07 Pa.s, or about 0.08 Pa.s, or about 0.09 Pa.s, or about 0.1 Pa.s, or about 0.2 Pa.s, or about 0.3 Pa.s, or about 0.4 Pa.s, or about 0.5 Pa.s, or about 0.6 Pa.s, or about 0.7 Pa.s, or about 0.8 Pa.s, or about 0.9 Pa.s, or about 1.0 Pa.s. As mentioned above, the viscosity of the aqueous polysaccharide solution according to the present invention can be understood to disclose together the numerical range between any two values described above as the upper and lower limits, respectively, and / or the numerical value between any two values. have.

In some embodiments, the aqueous polysaccharide solution may further include a glycol material such as polyethylene (poly (ethylene glycol), PEG) and / or polyethylene glycol diglycidyl ether (PEPEDE). .

The concentration in the polysaccharide aqueous solution of polyethylene glycol alone, polyethylene glycol diglycidyl ether alone, or a mixture thereof is about 0.1% (w / v), or about 0.5% (w / v), or about 0.7% (w / v). ), Or about 1.0% (w / v), or about 2.0% (w / v), or about 3.0% (w / v), or about 4.0% (w / v), or about 5.0% (w / v ), Or about 6.0% (w / v), or about 7.0% (w / v), or about 8.0% (w / v), or about 9.0% (w / v), or about 10.0% (w / v ), Or about 11.0% (w / v), or about 12.0% (w / v), or about 13.0% (w / v), or about 14.0% (w / v), or about 15.0% (w / v ), Or about 16.0% (w / v), or about 17.0% (w / v), or about 18.0% (w / v), or about 19.0% (w / v), or about 20.0% (w / v ), Or about 21.0% (w / v), or about 22.0% (w / v), or about 23.0% (w / v), or about 24.0% (w / v), or about 25.0% (w / v ), Or about 30.0% (w / v), or about 35.0% (w / v), or about 40.0% (w / v), or about 40.0% (w / v), or about 50.0% (w / v May be). As mentioned above, the concentration of glycols according to the invention can be understood to disclose together the numerical ranges in which any two values described above are the upper and lower limits, respectively, and / or a numerical value between any two values. .

Moreover, in order to promote crosslinking, you may further contain promoters, such as carbon tetrachloride. In addition, a viscosity modifier may be further included to adjust the viscosity. In addition, the polysaccharide aqueous solution may not include a crosslinking agent such as 1,4-butanediol diglycidyl ether (BDDE) conventionally used. Furthermore, the polysaccharide aqueous solution may not include an organic solvent.

(b) irradiating an electron beam

This step may be a step of inducing crosslinking of the aforementioned polysaccharide. That is, the polysaccharide may form a hydrogel by intermolecular or intramolecular crosslinking. For example, covalent bonds present in the polysaccharide may be broken and radicals containing lone pairs of electrons may be formed. Accordingly, crosslinking may occur, but the present invention is not limited to any theory.

The dose of the electron beam, that is, the dose, may be appropriately selected in consideration of the type of polysaccharide and the crosslinking reactivity. For example, the dose of an electron beam is about 0.01 kGy, or about 0.05 kGy, or about 0.1 kGy, or about 0.2 kGy, or about 0.3 kGy, or about 0.4 kGy, or about 0.5 kGy, or about 1.0 kGy, or about 1.5 kGy. Or about 2.0 kGy, or about 2.5 kGy, or about 3.0 kGy, or about 3.5 kGy, or about 4.0 kGy, or about 4.5 kGy, or about 5.0 kGy, or about 5.5 kGy, or about 6.0 kGy, or about 6.5 kGy Or about 7.0 kGy, or about 7.5 kGy, or about 8.0 kGy, or about 8.5 kGy, or about 9.0 kGy, or about 9.5 kGy, or about 10.0 kGy, or about 11.0 kGy, or about 12.0 kGy, or about 13.0 kGy , Or about 14.0kGy, or about 15.0kGy, or about 20.0kGy, or about 25.0kGy, or about 30.0kGy, or about 40.0kGy, or about 50.0kGy, or about 60.0kGy, or about 70.0kGy, or about 80.0kGy , Or about 90.0 kGy, or about 100.0 kGy, or about 150.0 kGy, or about 200.0 kGy, or about 250.0 kGy, or about 300.0 kGy, or about 350.0 kGy, or about 400.0 kGy, or about 450.0 kGy, or about 500.0 kGy Work There. As mentioned above, the dose of an electron beam according to the invention can be understood to disclose together the numerical range between any two values described above as the upper and lower limits, respectively, and / or the numerical value between any two values. .

The irradiation time of the electron beam may be appropriately selected in consideration of the type of polysaccharide and the crosslinking reactivity. For example, the irradiation time of the electron beam may be about 1.0 seconds, or about 2.0 seconds, or about 3.0 seconds, or about 4.0 seconds, or about 5.0 seconds, or about 10.0 seconds, or about 15.0 seconds, or about 20.0 seconds, or about 25.0 Seconds, or about 30.0 seconds, or about 35.0 seconds, or about 40.0 seconds, or about 45.0 seconds, or about 50.0 seconds, or about 55.0 seconds, or about 60.0 seconds, or about 90.0 seconds, or about 120.0 seconds, or about 150.0 Seconds, or about 180.0 seconds, or about 210.0 seconds, or about 240.0 seconds, or about 270.0 seconds, or about 300.0 seconds, or about 360.0 seconds, or about 420.0 seconds, or about 480.0 seconds, or about 540.0 seconds, or about 600 Seconds, or about 11 minutes, or about 12 minutes, or about 13 minutes, or about 14 minutes, or about 15 minutes, or about 16 minutes, or about 17 minutes, or about 18 minutes, or about 19 minutes, or about 20 Minutes, about 30 minutes, or about 40 minutes, or about 50 minutes, or about 60 minutes, or about 70 minutes, or about 80 minutes, or about 90 minutes, or about 100 minutes, or about 110 minutes, or about 120 minutes Or about 150 minutes, Can be about 180 minutes, or about minutes, or about minutes, or about minutes, or about 300 minutes, or about 6 hours, or about 7 hours, or about 8 hours, or about 9 hours, or about 10 hours. As mentioned above, the irradiation time of an electron beam according to the present invention can be understood to disclose together the numerical range between any two values described above as the upper and lower limits, respectively, and / or the numerical value between any two values. have.

In some embodiments, in the irradiation of electron beams for crosslinking of polysaccharides, the irradiation of electron beams may be performed with a resting period in the middle. As a non-limiting example, the irradiation of the electron beam may be started again without irradiating the electron beam for about 10 seconds without irradiating about 20 seconds. This process can be performed multiple times.

The dose rate of an electron beam can be understood as the total dose divided by the irradiation time. The dose rate of the electron beam may be appropriately selected in consideration of the dose and irradiation time. In some embodiments, in the irradiation of electron beams for crosslinking of polysaccharides, the dose rate of the electron beams may be irradiated with a pattern of increasing, decreasing, maintaining, and the like. As a non-limiting example, it is possible to increase the dose rate of the electron beam for a predetermined time, maintain the dose rate of the electron beam for a predetermined time, and then decrease the dose rate of the electron beam for a predetermined time. This process may be performed multiple times.

The polysaccharide aqueous solution may be maintained at a predetermined temperature while the electron beam is irradiated. The temperature may be appropriately selected in consideration of the type of polysaccharide and the crosslinking reactivity. For example, the crosslinking temperature may be about 15 ° C., or about 20 ° C., or about 25 ° C., or about 30 ° C., or about 31 ° C., or about 32 ° C., or about 33 ° C., or about 34 ° C., or about 35 ° C., Or about 36 ° C., or about 37 ° C., or about 38 ° C., or about 39 ° C., or about 40 ° C., or about 41 ° C., or about 42 ° C., or about 43 ° C., or about 44 ° C., or about 45 ° C., Or about 46 ° C, or about 47 ° C, or about 48 ° C, or about 49 ° C, or about 50 ° C, or about 51 ° C, or about 52 ° C, or about 53 ° C, or about 54 ° C, or about 55 ° C, Or about 60 ° C, or about 65 ° C, or about 70 ° C, or about 75 ° C, or about 80 ° C. As mentioned above, the crosslinking temperature according to the present invention may be understood to disclose together the numerical range between any two values described above as the upper and lower limits, respectively, and / or the numerical value between any two values.

In some embodiments, in the irradiation of electron beams for crosslinking of polysaccharides, the temperature may have a pattern of increasing, decreasing, or maintaining. As a non-limiting example, the temperature may be increased for a predetermined time, maintained for a predetermined time, and then decreased for a predetermined time. This process may be performed multiple times.

While the electron beam is irradiated, the polysaccharide aqueous solution may be stirred using a homogenizer or the like. For example, the stirring speed is about 500 rpm, or about 1,000 rpm, or about 1,100 rpm, or about 1,200 rpm, or about 1,300 rpm, or about 1,400 rpm, or about 1,500 rpm, or about 1,600 rpm, or about 1,700 rpm, or About 1,800 rpm, or about 1,900 rpm, or about 2,000 rpm, or about 2,100 rpm, or about 2,200 rpm, or about 2,300 rpm, or about 2,400 rpm, or about 2,500 rpm, about 2,600 rpm, or about 2,700 rpm, or about Or 2,800 rpm, or about 2,900 rpm, or about 3,000 rpm, or about 3,500 rpm, or about 4,000 rpm, or about 4,500 rpm, or about 5,000 rpm, or about 6,000 rpm. As mentioned above, the stirring speed according to the present invention may be understood to disclose together the numerical range between any two values described above as the upper and lower limits, respectively, and / or the numerical value between any two values.

(c) encapsulating the loading body

In some embodiments, a loading body or the like may be mounted on the crosslinked hydrogel. The loading process may be performed by adding a loading body to the particulate hydrogel and then stirring. The stirring speed is not particularly limited, but the stirring speed is 100 rpm, or about 200 rpm, or about 300 rpm, or about 400 rpm, or about 500 rpm, or about 1,000 rpm, or about 1,100 rpm, or about 1,200 rpm, or about 1,300 rpm, or About 1,400 rpm, or about 1,500 rpm, or about 1,600 rpm, or about 1,700 rpm, or about 1,800 rpm, or about 1,900 rpm, or about 2,000 rpm, or about 2,100 rpm, or about 2,200 rpm, or about 2,300 rpm, or About 2,400 rpm, or about 2,500 rpm, about 2,600 rpm, or about 2,700 rpm, or about 2,800 rpm, or about 2,900 rpm, or or about 3,000 rpm, or about 3,500 rpm, or about 4,000 rpm, or about 4,500 rpm, or About 5,000 rpm, or about 6,000 rpm. As mentioned above, the stirring speed according to the present invention may be understood to disclose together the numerical range between any two values described above as the upper and lower limits, respectively, and / or the numerical value between any two values.

The loading body may comprise known ones commonly used in drug delivery systems.

For example, the loading body may comprise a drug. In addition, drugs include antibiotics, anticancer drugs, analgesics, anti-inflammatory drugs, antitussives, expectorants, sedatives, muscle relaxants, antiepileptic drugs, ulcer drugs, antidepressants, anti-allergic drugs, cardiovascular drugs, antiarrhythmic drugs, vasodilators, diuretics, diabetes drugs, anticoagulants, At least one selected from the group consisting of hemostatic agents, anti-nodal agents, hormonal agents, and combinations thereof.

In another example, the loading body may comprise a diagnostic marker. Examples of diagnostic markers include fluorescent substances, radioisotopes, contrast agents and the like. Specifically, the radiolabeled material for computed tomography (CT) may exemplify ^99m Tc, ¹²³ I, ¹²⁵ I, ¹¹¹ In, ⁶⁷ Ga, ¹⁷⁷ Lu, ²⁰¹ Tl, ^117m Sn and the like. Examples of the labeling material for positron emission tomography may include ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F, ³⁸ K, ⁶² Cu, ⁶⁴ Cu, ⁶⁸ Ga, ⁸² Rb, ¹²⁴ I, ⁸⁹ Zr, and the like. In addition, examples of the fluorescent material may include quantum dots such as CdSe, CdS, ZnS, and ZnSe.

Examples of ultrasonic contrast agents include perfluoropropane, perfluorohexane, sulfur hexafluoride, perfluoropentane, decafluorobutane, and the like.

(B) hydrogel

Hydrogels prepared according to the present invention may have a particle form. That is, the hydrogel according to the present invention may have a nano size or a micro size. For example, the average particle size of the hydrogel may be about 10 nm, or about 20 nm, or about 30 nm, or about 40 nm, or about 50 nm, or about 60 nm, or about 70 nm, or about 80 nm, or about 90 nm, or about 100 nm, or About 150 nm, or about 200 nm, or about 250 nm, or about 300 nm, or about 350 nm, or about 400 nm, or about 450 nm, or about 500 nm, or about 550 nm, or about 600 nm, or about 700 nm, or about 800 nm, or about 900 nm Can be. Or the average particle size of the hydrogel is about 10 μm, or about 20 μm, or about 30 μm, or about 40 μm, or about 50 μm, or about 60 μm, or about 70 μm, or about 80 μm, or about 90 μm , Or about 100 μm, or about 150 μm, or about 200 μm, or about 250 μm, or about 300 μm, or about 350 μm, or about 400 μm, or about 450 μm, or about 500 μm, or about 550 μm , Or about 600 μm, or about 650 μm, or about 700 μm, or about 750 μm, or about 800 μm. As mentioned above, the average particle size of a hydrogel according to the present invention is to be understood to disclose together the numerical range between any two values described above with an upper limit and a lower limit, and / or a numerical value between any two values. Can be.

(C) hydrogel composition

Particulate hydrogels according to the present invention may generally comprise a physiologically acceptable carrier fluid, such as an isotonic buffer, particularly preferably a buffered physiological saline solution.

In some embodiments, the hydrogel composition may further include lubricants, wetting agents, emulsifiers, suspending agents, preservatives, pH adjusting agents and / or viscosity adjusting agents, and the like.

The viscosity of the hydrogel composition may be measured at 20 ° C. and 1 Hz with a rheometer. For example, the viscosity of the hydrogel on the particles can be about 0.0001 Pa.s, or about 0.001 Pa.s, or about 0.01 Pa.s, or about 0.1 Pa.s, or about 1.0 Pa.s, or about 2.0 Pa. s, or about 3.0 Pa.s, or about 4.0 Pa.s, or about 5.0 Pa.s, or about 6.0 Pa.s, or about 7.0 Pa.s, or about 8.0 Pa.s, or about 9.0 Pa.s Or about 10.0 Pa.s, or about 11.0 Pa.s, or about 12.0 Pa.s, or about 13.0 Pa.s, or about 14.0 Pa.s, or about 15.0 Pa.s, or about 16.0 Pa.s, Or about 17.0 Pa.s, or about 18.0 Pa.s, or about 19.0 Pa.s, or about 20.0 Pa.s, or about 25.0 Pa.s, or about 30.0 Pa.s, or about 35.0 Pa.s, or About 40.0 Pa.s, or about 45.0 Pa.s, or about 50.0 Pa.s, or about 60.0 Pa.s, or about 70.0 Pa.s, or about 80.0 Pa.s, or about 90.0 Pa.s, or about 100.0 Pa.s, or about 200.0 Pa.s, or about 300.0 Pa.s, or about 400.0 Pa.s, or about 500.0 Pa.s, or about 600.0 Pa.s, or about 700.0 Pa.s, or about 800.0 Pa.s, or about 900.0 Pa.s, May be about 1,000Pa · s, or about 2,000Pa · s, or about 3,000Pa · s. As mentioned above, the viscosity of a hydrogel according to the present invention can be understood to disclose together the numerical range between any two values described above as the upper and lower limits, respectively, and / or the numerical value between any two values. have.

It is to be understood that the present invention discloses a technical spirit including all possible combinations of all the components and factors described above.

Hereinafter, the specific manufacture example of this invention is demonstrated.

To prepare a polysaccharide aqueous solution according to the formulation as shown in Table 1 and to examine the electron beam. As a solvent of the polysaccharide aqueous solution, a separate organic solvent was not added using only sterile water. The electron beam used the direct current | type electron beam accelerator.

Polysaccharide Molecular Weight
(kDa) Aqueous solution concentration
(w / v%) Electron beam dose
(kGy) time
(s) Temperature
(℃) Preparation Example 1 Hyaluronic acid 5.0 0.1 5.0 150 ~ 39 Preparation Example 2 Hyaluronic acid 5.0 1.0 5.0 150 ~ 39 Preparation Example 3 Hyaluronic acid 5.0 5.0 5.0 150 ~ 39 Preparation Example 4 Hyaluronic acid 5.0 15.0 5.0 150 ~ 39 Preparation Example 5 Hyaluronic acid 5.0 20.0 5.0 150 ~ 39 Preparation Example 6 Hyaluronic acid 5.0 0.1 15.0 150 ~ 40 Preparation Example 7 Hyaluronic acid 5.0 1.0 15.0 150 ~ 40 Preparation Example 8 Hyaluronic acid 5.0 5.0 15.0 150 ~ 40 Preparation Example 9 Hyaluronic acid 5.0 15.0 15.0 150 ~ 40 Preparation Example 10 Hyaluronic acid 5.0 20.0 15.0 150 ~ 40 Preparation Example 11 Hyaluronic acid 5.0 0.1 30.0 150 ~ 45 Preparation Example 12 Hyaluronic acid 5.0 1.0 30.0 150 ~ 45 Preparation Example 13 Hyaluronic acid 5.0 5.0 30.0 150 ~ 45 Preparation Example 14 Hyaluronic acid 5.0 15.0 30.0 150 ~ 45 Preparation Example 15 Hyaluronic acid 5.0 20.0 30.0 150 ~ 45 Preparation Example 16 Hyaluronic acid 5.0 0.1 100.0 210 ~ 48 Preparation Example 17 Hyaluronic acid 5.0 1.0 100.0 210 ~ 48 Preparation Example 18 Hyaluronic acid 5.0 5.0 100.0 210 ~ 48 Preparation Example 19 Hyaluronic acid 5.0 15.0 100.0 210 ~ 48 Preparation Example 20 Hyaluronic acid 5.0 20.0 100.0 210 ~ 48 Preparation Example 21 Hyaluronic acid 5.0 0.1 150.0 300 ~ 48 Preparation Example 22 Hyaluronic acid 5.0 1.0 150.0 300 ~ 48 Preparation Example 23 Hyaluronic acid 5.0 8.0 150.0 300 ~ 48 Preparation Example 24 Hyaluronic acid 5.0 15.0 150.0 300 ~ 48 Preparation Example 25 Hyaluronic acid 5.0 20.0 150.0 300 ~ 48

In addition, a polysaccharide aqueous solution was prepared according to the formulation as shown in Table 2 below, and the electron beam was irradiated. As a solvent of the polysaccharide aqueous solution, a separate organic solvent was not added using only sterile water. The electron beam used the direct current | type electron beam accelerator.

Polysaccharide Molecular Weight
(kDa) Aqueous solution concentration
(w / v%) Electron beam dose
(kGy) time
(s) Temperature
(℃) Preparation Example 26 Dextran 7.0 0.1 5.0 90 ~ 38 Preparation Example 27 Dextran 7.0 2.0 5.0 90 ~ 38 Preparation Example 28 Dextran 7.0 15.0 5.0 90 ~ 38 Preparation Example 29 Dextran 7.0 20.0 5.0 150 ~ 38 Preparation Example 30 Dextran 7.0 25.0 5.0 300 ~ 38 Preparation Example 31 Dextran 7.0 0.1 10.0 90 ~ 38 Preparation Example 32 Dextran 7.0 2.0 10.0 90 ~ 38 Preparation Example 33 Dextran 7.0 15.0 10.0 90 ~ 38 Preparation Example 34 Dextran 7.0 20.0 10.0 150 ~ 38 Preparation 35 Dextran 7.0 25.0 10.0 300 ~ 38 Preparation Example 36 Dextran 11.0 0.1 15.0 90 ~ 38 Preparation Example 37 Dextran 11.0 2.0 15.0 90 ~ 38 Preparation Example 38 Dextran 11.0 15.0 15.0 90 ~ 38 Preparation Example 39 Dextran 11.0 20.0 15.0 150 ~ 38 Preparation Example 40 Dextran 11.0 25.0 15.0 300 ~ 38 Preparation Example 41 Dextran 10.0 0.1 25.0 90 ~ 38 Preparation Example 42 Dextran 10.0 2.0 25.0 90 ~ 38 Preparation Example 43 Dextran 10.0 15.0 25.0 90 ~ 38 Preparation Example 44 Dextran 10.0 20.0 25.0 150 ~ 38 Preparation Example 45 Dextran 10.0 25.0 25.0 300 ~ 38

In addition, the polysaccharide aqueous solution was prepared according to the formulation as shown in Table 3 below, and the electron beam was irradiated. As a solvent of the polysaccharide aqueous solution, a separate organic solvent was not added using only sterile water. The electron beam used the direct current | type electron beam accelerator.

Polysaccharide Molecular Weight
(kDa) Aqueous solution concentration
(w / v%) Electron beam dose
(kGy) time
(s) Temperature
(℃) Preparation Example 46 Fucoidan 2.0 7.0 10.0 120 ~ 40 Preparation 47 Fucoidan 2.0 10.0 20.0 120 ~ 40 Preparation Example 48 Fucoidan 2.0 10.0 50.0 120 ~ 40 Preparation 49 Fucoidan 2.0 15.0 50.0 120 ~ 40 Preparation 50 Fucoidan 2.0 25.0 50.0 360 ~ 40

In addition, a polysaccharide aqueous solution was prepared according to the formulation as shown in Table 4 below, and the electron beam was irradiated. As a solvent of the polysaccharide aqueous solution, a separate organic solvent was not added using only sterile water. The electron beam used the direct current | type electron beam accelerator.

Polysaccharide Molecular Weight
(kDa) Aqueous solution concentration
(w / v%) Electron beam dose
(kGy) time
(s) Temperature
(℃) Preparation Example 51 Fructooligosaccharide 10.0 5.0 4.0 30 ~ 40 Preparation Example 52 Fructooligosaccharide 10.0 10.0 7.0 60 ~ 40 Preparation Example 53 Fructooligosaccharide 10.0 10.0 15.0 120 ~ 40 Preparation Example 54 Fructooligosaccharide 10.0 15.0 15.0 120 ~ 40 Preparation Example 55 Fructooligosaccharide 10.0 15.0 21.5 150 ~ 40 Preparation Example 56 Fructooligosaccharide 10.0 20.0 21.5 150 ~ 40 Preparation Example 57 Fructooligosaccharide 10.0 20.0 25.0 180 ~ 40 Preparation 58 Fructooligosaccharide 10.0 20.0 30.5 180 ~ 40 Preparation Example 59 Fructooligosaccharide 10.0 22.0 30.5 180 ~ 40 Preparation Example 60 Fructooligosaccharide 10.0 22.0 50.0 360 ~ 40

In addition, the polysaccharide aqueous solution was prepared according to the formulation as shown in Table 5 below, and the electron beam was irradiated. As a solvent of the polysaccharide aqueous solution, a separate organic solvent was not added using only sterile water. The electron beam used the direct current | type electron beam accelerator.

Polysaccharide Molecular Weight
(kDa) Aqueous solution concentration
(w / v%) Electron beam dose
(kGy) time
(s) Temperature
(℃) Preparation Example 61 Isomaltooligosaccharide 7.0 4.0 7.0 90 ~ 41 Preparation Example 62 Isomaltooligosaccharide 7.0 10.0 7.0 90 ~ 45 Preparation Example 63 Isomaltooligosaccharide 7.0 11.0 7.0 90 ~ 45 Preparation Example 64 Isomaltooligosaccharide 7.0 12.0 7.0 90 ~ 45 Preparation 65 Isomaltooligosaccharide 7.0 15.0 7.0 90 ~ 45 Preparation 66 Isomaltooligosaccharide 7.0 4.0 15.0 180 ~ 41 Preparation Example 67 Isomaltooligosaccharide 7.0 10.0 15.0 180 ~ 45 Preparation Example 67 Isomaltooligosaccharide 7.0 11.0 15.0 180 ~ 45 Preparation Example 69 Isomaltooligosaccharide 7.0 12.0 15.0 180 ~ 45 Preparation 70 Isomaltooligosaccharide 7.0 15.0 15.0 180 ~ 45

Although the above has been described with reference to the embodiments of the present invention, this is merely an example, not to limit the present invention, those skilled in the art to which the present invention belongs without departing from the essential characteristics of the embodiments of the present invention It will be appreciated that various modifications and applications are not possible.

Therefore, the scope of the present invention should be understood to include modifications, equivalents, or substitutes of the technical spirit exemplified above. For example, each component specifically shown in the embodiment of the present invention may be modified. And differences relating to such modifications and applications will have to be construed as being included in the scope of the invention defined in the appended claims.

Claims (1)

A method for producing particles which induce molecular crosslinking by irradiating an electron beam to an aqueous solution of hyaluronic acid, mannan, cyclodextrin, alginate, fructooligosaccharide, isomaltooligosaccharide, fucoidan, chitosan or carboxymethyldextran, or derivatives thereof.