CN111973550B - Nitric oxide in situ hydrogel for treating osteoarthritis - Google Patents
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Abstract
The nitric oxide in-situ hydrogel for treating osteoarthritis comprises a hydrogel matrix and nitric oxide nanobubbles, wherein the nitric oxide nanobubbles are uniformly dispersed in the hydrogel matrix. The hydrogel matrix consists of catechol-terminated polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer, heparin-poloxamer and acidic fibroblast growth factor, wherein the mass ratio of the catechol-terminated polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer to the heparin-poloxamer is 1-5:10, and the molar mass of the acidic fibroblast growth factor and the heparin-poloxamer is equal. The nanometer nitric oxide bubble consists of yolk phospholipid and poloxamer as bubble membrane material and the yolk phospholipid and poloxamer are coated with nitric oxide gas in the weight ratio of 1 to 25, particle size of 500-900 nm and concentration of 1X 10 7 ～5×10 7 And each mL. The nitric oxide in-situ hydrogel is injected into joint cavities and is used for treating osteoarthritis.
Description
Technical Field
The invention relates to an in-situ preparation for treating osteoarthritis, in particular to nitric oxide in-situ hydrogel for treating osteoarthritis.
Background
Osteoarthritis (OA) is a common chronic progressive arthritis, the pathological hallmark of which is degeneration, destruction, and hardening of subchondral bone. Joint margin and subchondral bone reactive hyperplasia, osteophytes, are formed. Osteoarthritis is commonly seen in the elderly, and epidemiological investigation has shown that its incidence in the 55-64 year old population is 40% and in the population over 65 years up to 60%, with the world population being accelerated in ageing and the sports becoming vigorous, the incidence of osteoarthritis also rising year by year. Osteoarthritis is a type of chronic degenerative disease characterized mainly by cartilage degeneration accompanied by inflammation of synovial tissue. The osteoarthritis patients have pain and joint deformation, the serious patients cause limb disability, the life quality of the old is reduced, and the two pains of the flesh and the spirit are brought, so that the osteoarthritis patients have been widely concerned.
The research shows that the nitric oxide has good therapeutic effect on osteoarthritis. Compared with the traditional nonsteroidal anti-inflammatory drug, the nitric oxide donor type nonsteroidal anti-inflammatory drug has less adverse reaction and becomes a main method for treating osteoarthritis by nitric oxide. Nitric oxide donor compounds fall into two categories: non-enzymatic and enzymatic forms. The non-enzymatic nitric oxide donor compound is mostly from nitro compounds, including nitroprusside, organic or inorganic nitrite and nitrate, nitrosamine, nitrogen mustard, hydrazine, etc., and has small dosage and large toxic and side effects. Whereas enzymatic nitric oxide donor compounds (e.g. arginine) require the generation of nitric oxide molecules by decomposition of the compound by biological enzymes in the body, etc. The traditional oral route of administration of nitric oxide-donating non-steroidal anti-inflammatory drugs results in low concentrations of nitric oxide reaching the joint lesion site and is difficult to maintain due to the "first pass effect". Whereas nitric oxide-donor type non-steroidal anti-inflammatory drugs injected in the joint cavity cannot produce nitric oxide due to the lack of degrading enzymes. Therefore, the conventional articular cavity injection of nitric oxide donor type non-steroidal anti-inflammatory drugs does not play a role in inhibiting degeneration of articular cartilage.
The nitric oxide molecules are in the form of a gas, and nitric oxide gas (NO) is slightly soluble in water, and has a solubility of only 5.6X10 in water at 20 DEG C -3 g/L (equivalent to 0.186 mu mol/L) can not be prepared into common administration forms to play a role in treating osteoarthritis.
In situ hydrogels are a class of formulations that can undergo a phase transition immediately at the site of administration after administration in a solution state, and form a non-chemically crosslinked semi-solid hydrogel from a liquid state. The hydrogel agent has good tissue compatibility and long retention time at the administration position; meanwhile, the medicine can be stored, and the medicine is prevented from being influenced by the environment and the like. In-situ hydrogels can be classified into temperature-sensitive, pH-sensitive, ion-sensitive, etc., according to the mechanism of formation. The in-situ hydrogel agent is used as a novel drug dosage form, is widely used in novel drug delivery systems such as slow release, controlled release, pulse release and the like, can be applied to various routes of drug delivery such as skin, eyes, nasal cavities, oral cavities, vagina, rectum and the like, and becomes a research hot spot in the fields of pharmacy and biotechnology.
While in situ hydrogels have a number of advantages in terms of joint cavity administration and local treatment, nitric oxide is a gas, and no research reports have been seen to date that can efficiently carry nitric oxide gas into in situ hydrogels. Thus, the preparation of in situ hydrogels that efficiently carry nitric oxide gas is a limiting bottleneck in the use of nitric oxide to treat osteoarthritis.
Disclosure of Invention
The invention aims to overcome the defects of the prior art (namely, lack of the in-situ hydrogel for efficiently carrying nitric oxide gas), provide the nitric oxide in-situ hydrogel capable of locally acting in the joint cavity, provide the maximum guarantee for guaranteeing the effective concentration of nitric oxide and the curative effect of osteoarthritis, and simultaneously meet the requirements of safety, effectiveness, convenience and economy of clinical treatment.
Through a plurality of experiments, the inventor obtains a nitric oxide in-situ hydrogel which can locally play a role in a joint cavity, wherein the hydrogel comprises a hydrogel matrix and nitric oxide nanobubbles, and the nitric oxide nanobubbles are uniformly dispersed in the hydrogel matrix.
The hydrogel matrix consists of catechol-terminated polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer, heparin-poloxamer and acidic fibroblast growth factor, wherein the mass ratio of the catechol-terminated polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer to the heparin-poloxamer is 1-5:10, and the molar mass of the acidic fibroblast growth factor to the heparin-poloxamer is equal.
The preferable mass ratio of the catechol-terminated polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer, the heparin-poloxamer and the acidic fibroblast growth factor in the hydrogel matrix is 2-3:10, and the molar mass of the acidic fibroblast growth factor is equal to that of the heparin-poloxamer.
The hydrogel matrix is further added with the following components: sugar, electrolyte salt, amino acid, pH buffer and antioxidant.
The nitric oxide nanobubble is composed of a vesicle formed by wrapping nitric oxide gas by taking egg yolk phospholipid and poloxamer as bubble membrane materials, wherein the mass ratio of the egg yolk phospholipid to the poloxamer is 1:25.
The particle size of the nitric oxide nanobubble is 500-900 nm.
The concentration of the nitric oxide nanobubble in the nitric oxide in-situ hydrogel is 1 multiplied by 10 7 ～5×10 7 And each mL.
A method for preparing nitric oxide in-situ hydrogel for treating osteoarthritis, which comprises the following steps:
a: dispersing polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer and heparin-poloxamer in 6 times of water for injection at 8 ℃, placing the mixture in a refrigerator at 4-8 ℃ for overnight, slowly dissolving, adding acidic fibroblast growth factor, and uniformly mixing to form hydrogel matrix solution;
b: mixing yolk phospholipids and poloxamer in a mass ratio of 1:25, dissolving in anhydrous tertiary butanol with a mass of 10 times of that of 65 ℃, slowly cooling to solidify the solution, standing overnight at-10 ℃, freeze-drying to obtain loose freeze-dried powder, transferring into a bottle with a plug, filling nitric oxide gas to saturation, adding into water for injection with a mass of 5 times of that of the freeze-dried powder, and uniformly mixing to form a nitric oxide nanobubble solution;
c: adding the nitric oxide nanobubble solution prepared in the step b into the hydrogel matrix solution prepared in the step a at 10 ℃ until the concentration of the nitric oxide nanobubbles in the hydrogel is 1 multiplied by 10 7 ～5×10 7 Mixing the materials with a small amount of water at a concentration of one mL, and stirring the materials evenly to prepare nitric oxide in-situ hydrogel solution, and preserving the nitric oxide in-situ hydrogel solution in a sealed manner at 10 ℃;
d: exposing the nitric oxide in-situ hydrogel solution prepared in the step c to the environment of 30-37 ℃ to quickly gel to form the nitric oxide in-situ hydrogel.
The hydrogel matrix solution is further added with the following components: sugar, electrolyte salt, amino acid, pH buffer and antioxidant.
The nitric oxide in-situ hydrogel is injected into joint cavities and is used for treating osteoarthritis.
The nitric oxide in-situ hydrogel for treating osteoarthritis has the following advantages: (1) the in-situ hydrogel has the functions of bioadhesion, slow release and long-acting, and has good affinity and biocompatibility on colonic epithelial mucosa; (2) the hydrogel does not use any nitric oxide donor compound, and does not generate adverse reaction and toxic and side effects on organism tissues due to the nitric oxide donor compound; (3) the in-situ hydrogel is convenient to use, is in a hydrogel state immediately after in-situ injection, and meets the requirement of controlled-release long-acting treatment of osteoarthritis; (4) the in-situ hydrogel is convenient to store and transport.
Detailed Description
Hereinafter, specific embodiments of the present invention will be described in detail. It should be noted that the technical features or combinations of technical features described in the following embodiments should not be regarded as being isolated, and they may be combined with each other to achieve a better technical effect.
EXAMPLE 1 preparation of nitric oxide in situ hydrogel
According to the component proportion in table 1, nitric oxide in-situ hydrogel of experimental group is prepared, which comprises the following steps:
a: dispersing polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer and heparin-poloxamer in 6 times of 8 ℃ water for injection, placing the mixture in a refrigerator at 4-8 ℃ for overnight, slowly dissolving, adding acidic fibroblast growth factor with the same molar mass as the heparin-poloxamer, and uniformly mixing to form hydrogel matrix solution;
b: mixing yolk phospholipids and poloxamer in a mass ratio of 1:25, dissolving in anhydrous tertiary butanol with a mass of 10 times of 65 ℃, slowly cooling to solidify the solution, standing overnight at-10 ℃, freeze-drying to obtain loose freeze-dried powder, transferring into a bottle with a plug, filling nitric oxide gas to saturation, adding into water for injection with a mass of 5 times of the freeze-dried powder, and uniformly mixing to form a nitric oxide nano bubble solution;
c: adding the nitric oxide nanobubble solution prepared in the step b into the hydrogel matrix solution prepared in the step a at 10 ℃, adjusting the concentration of the nitric oxide nanobubbles in the hydrogel according to the design of the table 1, mixing the solution with the solution uniformly by shaking to prepare a nitric oxide in-situ hydrogel solution, and preserving the solution in a sealing manner at 10 ℃ to obtain the nitric oxide in-situ hydrogel.
Hydrogels of the control group were prepared according to the component ratios of table 1 with reference to the experimental group. Each experimental group is configured according to the components and proportions within the scope of the claims of the application, and each control group is a component with a missing or component mass percent that is beyond the scope of the claims of the application.
Table 1 composition of hydrogels of experimental and control groups
Note that: "v" represents the concentration and method of the experimental group of example 1; "/" indicates that the term is absent; * Representing that the component is replaced by a component in brackets; KGF-2 represents keratinocyte growth factor-2; NO represents nitric oxide gas; o (O) 2 Represents oxygen; n (N) 2 Representing nitrogen.
Example 2 nitric oxide in situ hydrogel application effects for treatment of osteoarthritis
(1) Model animal establishment
The method is characterized in that a Yunnan small-ear pig is taken as a study object, 20% papain (papain) is injected into the right knee joint of an adult Yunnan small-ear pig, and after 4 weeks, the articular cartilage is degenerated, osteoblast activity and osteophyte are formed, and the modeling success is determined through histological evaluation.
(2) Application effect of nitric oxide in-situ hydrogel in treating osteoarthritis
The adult Yunnan small-ear pig with the successful modeling is selected, the adult Yunnan small-ear pig with the successful modeling is averagely divided into a plurality of groups according to the design of the table 1, 2mL of nitric oxide in-situ hydrogel is injected into the right knee joint cavity, the normal feeding is carried out, the adult Yunnan small-ear pig is sacrificed after 2 months, the pathophysiological condition of the cartilage part is observed through histological staining, and the effect of each group of hydrogel on treating the osteoarthritis is evaluated.
The evaluation results of the groups are shown in Table 2, and the total scores of the application effects of the hydrogels of the groups are given by integrating the evaluation indexes.
TABLE 2 Effect of hydrogels in experimental and control groups on treatment of osteoarthritis
As can be seen from the experimental results in Table 2, the nitric oxide in-situ hydrogel of the experimental group has good therapeutic effect on osteoarthritis, in particular to the cartilage recovery of the osteoarthritis sites of the experimental group 6. Compared with the experimental group, the control group has obviously poorer curative effect on osteoarthritis, and particularly, the control groups 1, 2, 3, 14 and 15 prove that the lack of any component and condition in the technical protection scheme of the invention can obviously influence the cartilage repair effect. The results in Table 2 prove that the nitric oxide in-situ hydrogel provided by the invention can obviously repair cartilage, treat osteoarthritis and has a good application prospect.
The foregoing detailed description is directed to embodiments of the invention which are not intended to limit the scope of the invention, but rather to cover all modifications and variations within the scope of the invention. Further, various modifications, additions and substitutions in other forms and details may be made by those skilled in the art within the scope and spirit of the invention as disclosed in the accompanying claims. Of course, such modifications, additions and substitutions are intended to be included within the scope of the invention as set forth in the accompanying claims.
Claims (7)
1. The nitric oxide in-situ hydrogel for joint cavity injection for treating osteoarthritis is characterized in that: the nitric oxide in-situ hydrogelThe gel comprises a hydrogel matrix and nitric oxide nanobubbles, wherein the nitric oxide nanobubbles are uniformly dispersed in the hydrogel matrix; the hydrogel matrix consists of catechol-terminated polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer, heparin-poloxamer and acidic fibroblast growth factor, wherein the mass ratio of the catechol-terminated polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer to the heparin-poloxamer is 1-5:10, and the molar mass of the acidic fibroblast growth factor to the heparin-poloxamer is equal; the nitric oxide nanobubble is composed of a vesicle formed by wrapping nitric oxide gas by taking egg yolk phospholipid and poloxamer as bubble membrane materials, wherein the mass ratio of the egg yolk phospholipid to the poloxamer is 1:25; the particle size range of the nitric oxide nanobubble is 500-900 nm; the concentration of the nitric oxide nanobubble in the nitric oxide in-situ hydrogel is 1 multiplied by 10 7 ～5×10 7 And each mL.
2. The hydrogel of claim 1, characterized in that: the mass ratio of the catechol end-capped polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer to the heparin-poloxamer in the hydrogel matrix is 2-3:10, and the molar mass of the acidic fibroblast growth factor is equal to that of the heparin-poloxamer.
3. The hydrogel of claim 1, characterized in that: the hydrogel matrix is further added with: sugar, electrolyte salt, amino acid, pH buffer and antioxidant.
4. The hydrogel of claim 1, characterized in that: the particle size of the nitric oxide nanobubble is 700nm.
5. The hydrogel of claim 1, characterized in that: the concentration of the nitric oxide nanobubble in the nitric oxide in-situ hydrogel is 3 multiplied by 10 7 And each mL.
6. A method of preparing the hydrogel of claim 1, comprising: the method comprises the following steps:
a: dispersing catechol-terminated polyoxyethylene-polyoxypropylene-polyoxyethylene copolymer and heparin-poloxamer in 6 times of 8 ℃ water for injection, placing the mixture in a refrigerator at 4-8 ℃ for overnight, slowly dissolving, adding acidic fibroblast growth factor, and uniformly mixing to form hydrogel matrix solution;
b: mixing yolk phospholipids and poloxamer in a mass ratio of 1:25, dissolving in anhydrous tertiary butanol with a mass of 10 times of 65 ℃, slowly cooling to solidify the solution, standing overnight at-10 ℃, freeze-drying to obtain loose freeze-dried powder, transferring into a bottle with a plug, filling nitric oxide gas to saturation, adding into water for injection with a mass of 5 times of the freeze-dried powder, and uniformly mixing to form a nitric oxide nano bubble solution;
c: adding the nitric oxide nanobubble solution prepared in the step b into the hydrogel matrix solution prepared in the step a at 10 ℃ until the concentration of the nitric oxide nanobubbles in the hydrogel is 1 multiplied by 10 7 ～5×10 7 Mixing the materials with a small amount of water at a concentration of one mL, and stirring the materials evenly to prepare nitric oxide in-situ hydrogel solution, and preserving the nitric oxide in-situ hydrogel solution in a sealed manner at 10 ℃;
d: and c, exposing the nitric oxide in-situ hydrogel solution prepared in the step c to the environment of 30-37 ℃ to quickly gel to form the nitric oxide in-situ hydrogel.
7. The method for producing a hydrogel according to claim 6, characterized in that: the hydrogel matrix solution is further added with: sugar, electrolyte salt, amino acid, pH buffer and antioxidant.
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