CN114533654B - Low-molecular chondroitin sulfate composite hydrogel and preparation method and application thereof - Google Patents
Low-molecular chondroitin sulfate composite hydrogel and preparation method and application thereof Download PDFInfo
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- CN114533654B CN114533654B CN202111639908.3A CN202111639908A CN114533654B CN 114533654 B CN114533654 B CN 114533654B CN 202111639908 A CN202111639908 A CN 202111639908A CN 114533654 B CN114533654 B CN 114533654B
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- chondroitin sulfate
- low molecular
- composite hydrogel
- solution
- molecular chondroitin
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Abstract
The invention discloses a low molecular chondroitin sulfate composite hydrogel and a preparation method and application thereof, and belongs to the technical field of biological medicines. The main body structure of the low molecular chondroitin sulfate composite hydrogel is composite gel formed by low molecular chondroitin sulfate with the average molecular weight of 590-950Da, sodium hyaluronate, glucosamine, a magnesium nutrition enhancer, a thickener, a permeation promoter and a preservative. The invention also provides a preparation method of the composite hydrogel. The composite hydrogel is directly smeared on joint parts when in use, is smeared and massaged to be absorbed, can reduce arthritis symptoms, promote articular cartilage repair, increase bone joint lubrication and the like, and is beneficial to the articular cartilage repair of arthritic patients and the inflammation relief.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a low-molecular chondroitin sulfate composite hydrogel and a preparation method and application thereof.
Background
With the development of society, more people pay attention to exercise, but the amount of exercise is increased, and the damage to bone joints is also increased. Office workers sit for a long time and the joints are stiff and motionless; with age, the self-repairing ability of the joint gradually decreases! Once the knee joint is worn, the invasion of cold is added to induce the onset of arthritis, and the problems of cold sensitivity, pain, stiffness, weakness, swelling, inconvenient movement and the like are caused. The data of the world-guard organization show that the prevalence of arthritis in China has reached 1.2 billions, approaching one tenth, and is gradually younger.
The treatment drugs for early arthritis are: paracetamol, topical analgesic drugs, non-steroidal anti-inflammatory drugs, but these drugs have serious side effects. The macromolecular chondroitin sulfate has the effect of protecting joints, can promote cartilage synthesis, increase the amount of sliding fluid in the joints, and the glucosamine can promote in-vivo synthesis of glycosaminoglycan, stimulate chondrocyte synthesis, remove free radicals and reduce cartilage injury.
At present, the medicine for treating arthritis is mainly oral and injection products, but has the defects of gastric ulcer and inconvenient use in the use process. The product for treating or relieving arthritis is applied in vitro, and the preparation method thereof is less. Patent publication CN111499889a discloses a hydrogel containing chondroitin sulfate magnesium and a preparation method thereof, wherein a mixed solution containing macromolecular hyaluronic acid and macromolecular chondroitin sulfate magnesium is mixed with a crosslinking agent to obtain the hydrogel, an additional crosslinking agent is needed, and the application method is injection, so that secondary injury is caused to a patient. Patent publication CN110548003a discloses a preparation method and application of an external-use chondroitin sulfate nano composition, which uses conventional macromolecular chondroitin sulfate as a main raw material, and adds various grease raw materials to disperse, so that the conventional macromolecular chondroitin sulfate is promoted to permeate through skin, thereby achieving the external-use effect of treating arthritis, but the permeation time is slower, because the conventional chondroitin sulfate used is mainly with the molecular weight of 50-100 kDa, and the higher the molecular weight, the worse the permeation effect. The product using chondroitin sulfate reported at present mainly has conventional large molecular weight, and various grease dressings are needed to be added for solving the permeability, but the permeation effect is still poor, and the preparation method is complex, so that the development of an external medicine for treating arthritis, which has the advantages of faster permeation, simple preparation method and simple use, and the preparation method thereof are necessary.
Disclosure of Invention
The invention aims to solve the technical defects of poor permeation, inconvenient use, poor treatment effect and the like of the existing products in the market, and develops the low-molecular chondroitin sulfate composite hydrogel and the preparation method thereof, which have the advantages of rapid permeation, better treatment effect on arthritis, simple preparation method, no sticky feeling after use, no chapping phenomenon and the effects of moisturizing and nourishing joints.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the low molecular chondroitin sulfate composite hydrogel comprises the following raw materials in parts by mass: 1 to 10 percent of low molecular chondroitin sulfate with the average molecular weight of 590 to 950Da, 0.2 to 0.8 percent of sodium hyaluronate, 1 to 5 percent of glucosamine, 0.5 to 2 percent of magnesium nutrition enhancer, 0.2 to 0.8 percent of thickener, 0.2 to 1.0 percent of penetration enhancer, 0.2 to 1.5 percent of preservative and the balance of water.
As one embodiment of the invention, the low molecular chondroitin sulfate composite hydrogel comprises one or more low molecular chondroitin sulfate with an average molecular weight of 590-950Da.
The active ingredients of the low molecular chondroitin sulfate composite hydrogel are low molecular chondroitin sulfate, sodium hyaluronate, glucosamine and magnesium nutrition enhancer, and the other ingredients are auxiliary materials or matrixes.
As one embodiment of the invention, the low molecular chondroitin sulfate has an average molecular weight of 650-830Da.
As one embodiment of the present invention, the sodium hyaluronate has a molecular weight of 10×10 6 Da to 22×10 6 One or more, preferably 18X 10, da 6 -22×10 6 Da。
As an embodiment of the present invention, the glucosamine includes: one or more of glucosamine hydrochloride and glucosamine sulfate.
As an embodiment of the present invention, the magnesium nutrition enhancer includes: any one or more of magnesium chloride, magnesium gluconate, magnesium hydrogen phosphate, magnesium sulfate, magnesium carbonate and magnesium oxide.
As an embodiment of the present invention, the thickener includes: one or more of carbomer, xanthan gum and sodium carboxymethylcellulose.
As an embodiment of the present invention, a preferred thickener is xanthan gum or sodium carboxymethyl cellulose.
As an embodiment of the present invention, the permeation enhancer includes: one or more of laurocapram, menthol, eucalyptus oil and propylene glycol.
As an embodiment of the present invention, the preservative system comprises: one or more of phenoxyethanol, methylparaben, sorbic acid and sodium sorbate.
The invention also provides a preparation method of the low molecular chondroitin sulfate composite hydrogel, which comprises the following steps:
(1) Weighing the components according to a proportion, adding a proper amount of required water into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at a rotating speed of 100-200r/min and a temperature of 30-50 ℃ and fully dissolving to obtain a phase A solution;
(2) Adding the rest water into another reactor, adding low molecular chondroitin sulfate, permeation promoter, glucosamine, magnesium nutrition enhancer and antiseptic, mechanically stirring at 100-200r/min until the solution is clear to obtain phase B solution;
(3) Adding the B phase solution into the A phase solution while stirring, stirring uniformly at a rotating speed of 100-200r/min, and cooling to 20-25 ℃ to obtain the low molecular chondroitin sulfate composite hydrogel.
The invention also provides a medical article comprising the low molecular chondroitin sulfate composite hydrogel.
The beneficial effects of the invention are as follows:
1) The low molecular chondroitin sulfate composite hydrogel disclosed by the invention adopts low molecular chondroitin sulfate with the average molecular weight of 590-950Da as a main raw material, and has a good permeation effect due to low molecular weight, so that the treatment effect of arthritis is better, the use is more convenient, and the secondary injury to a patient is reduced.
2) The product is added with various kinds of sodium hyaluronate, and the sodium hyaluronate is a large polysaccharide compound which can carry more than 500 times of water, so that the nutrition metabolism of skin can be improved, the skin is smooth, wrinkles are removed, the skin elasticity is increased, and the product can not only preserve moisture, but also promote the joint lubrication.
3) The product is added with magnesium nutrition enhancer, mg 2+ Has obvious effect on inhibiting the inflammation of articular cartilage, has a protective effect on cartilage tissues, and can further promote the absorption of low-molecular chondroitin sulfate and glucosamine.
4) The glucosamine is added into the product, and serves as an important component for cartilage synthesis, and the glucosamine and the chondroitin sulfate can mutually promote the action, and the low-molecular chondroitin sulfate can promote the absorption of the glucosamine, and meanwhile, the glucosamine can promote the absorption of the low-molecular chondroitin sulfate, so that the glucosamine synthesized by cartilage can be supplemented, and the necessary chondroitin sulfate can be provided for the cartilage.
5) Experiments prove that the product has good treatment and alleviation effects on osteoarthritis and good permeation effect.
Detailed Description
In order to facilitate the understanding of the present invention by those skilled in the art, the technical solutions of the present invention will be further described with reference to specific examples, but the following should not be construed as limiting the scope of the present invention as claimed in any way.
The low molecular chondroitin sulfate with the average molecular weight of 500Da and 590-950Da and 1200Da is prepared by cracking macromolecular chondroitin sulfate by referring to a published patent technology CN111741963A of the company. Other active ingredients and usual adjuvants are commercially available.
Example 1
The low molecular chondroitin sulfate composite hydrogel comprises the following raw materials in parts by mass: low molecular chondroitin sulfate 6% having an average molecular weight of 590Da, sodium hyaluronate (22×10) 6 Da) 0.5%, glucosamine hydrochloride 5%, magnesium chloride 1%, xanthan gum 0.5%, laurocapram 0.5%, phenoxyethanol 0.5%, methylparaben 0.1% and the balance water.
The method for preparing the low molecular chondroitin sulfate composite hydrogel can be implemented according to the following steps:
(1) Weighing the components according to the proportion, adding water accounting for 60% of the required water amount into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at the speed of 150r/min and the temperature of 50 ℃ and fully dissolving to obtain a phase A solution;
(2) Adding water with the water content of 40% of the required water content into another reactor, adding low molecular chondroitin sulfate, a permeation promoter, glucosamine hydrochloride, magnesium chloride and a preservative, and mechanically stirring at 150r/min until the solution is clear to obtain a phase B solution;
(3) Slowly adding the B phase solution into the A phase solution while stirring, uniformly stirring at a rotating speed of 150r/min, and cooling to 20 ℃ to obtain the low molecular chondroitin sulfate composite hydrogel.
Example 2
The low molecular chondroitin sulfate composite hydrogel comprises the following raw materials in parts by mass: low molecular chondroitin sulfate having an average molecular weight of 650Da of 6%, sodium hyaluronate (22X 10) 6 Da) 0.5%, glucosamine hydrochloride 5%, magnesium chloride 1%, xanthan gum 0.5%, laurocapram 0.5%, phenoxyethanol 0.5%, methylparaben 0.1% and the balance water.
The method for preparing the low molecular chondroitin sulfate composite hydrogel can be implemented according to the following steps:
(1) Weighing the components according to the proportion, adding water accounting for 60% of the required water amount into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at the speed of 150r/min and the temperature of 50 ℃ and fully dissolving to obtain a phase A solution;
(2) Adding water with the water content of 40% of the required water content into another reactor, adding low molecular chondroitin sulfate, a permeation promoter, glucosamine hydrochloride, magnesium chloride and a preservative, and mechanically stirring at 150r/min until the solution is clear to obtain a phase B solution;
(3) Slowly adding the B phase solution into the A phase solution while stirring, uniformly stirring at a rotating speed of 150r/min, and cooling to 20 ℃ to obtain the low molecular chondroitin sulfate composite hydrogel.
Example 3
The low molecular chondroitin sulfate composite hydrogel comprises the following raw materials in parts by mass: low molecular chondroitin sulfate 6% having an average molecular weight of 720Da, sodium hyaluronate (22×10) 6 Da) 0.5%, glucosamine hydrochloride 5%, magnesium chloride 1%, xanthan gum 0.5%, laurocapram 0.5%, phenoxyethanol 0.5%, methylparaben 0.1% and the balance water.
The method for preparing the low molecular chondroitin sulfate composite hydrogel can be implemented according to the following steps:
(1) Weighing the components according to the proportion, adding water accounting for 60% of the required water amount into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at the speed of 150r/min and the temperature of 50 ℃ and fully dissolving to obtain a phase A solution;
(2) Adding water with the water content of 40% of the required water content into another reactor, adding low molecular chondroitin sulfate, a permeation promoter, glucosamine hydrochloride, magnesium chloride and a preservative, and mechanically stirring at 150r/min until the solution is clear to obtain a phase B solution;
(3) Slowly adding the B phase solution into the A phase solution while stirring, uniformly stirring at a rotating speed of 150r/min, and cooling to 20 ℃ to obtain the low molecular chondroitin sulfate composite hydrogel.
Example 4
The low molecular chondroitin sulfate composite hydrogel comprises the following raw materials in parts by mass: low molecular chondroitin sulfate having an average molecular weight of 830Da 6%, sodium hyaluronate (22X 10) 6 Da) 0.5%, glucosamine hydrochloride 5%, magnesium chloride 1%, xanthan gum 0.5%, laurocapram 0.5%, phenoxyethanol 0.5%, methylparaben 0.1% and the balance water.
The method for preparing the low molecular chondroitin sulfate composite hydrogel can be implemented according to the following steps:
(1) Weighing the components according to the proportion, adding water accounting for 60% of the required water amount into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at the speed of 150r/min and the temperature of 50 ℃ and fully dissolving to obtain a phase A solution;
(2) Adding water with the water content of 40% of the required water content into another reactor, adding low molecular chondroitin sulfate, a permeation promoter, glucosamine hydrochloride, magnesium chloride and a preservative, and mechanically stirring at 150r/min until the solution is clear to obtain a phase B solution;
(3) Slowly adding the B phase solution into the A phase solution while stirring, uniformly stirring at a rotating speed of 150r/min, and cooling to 20 ℃ to obtain the low molecular chondroitin sulfate composite hydrogel.
Example 5
The low molecular chondroitin sulfate composite hydrogel comprises the following raw materials in parts by mass: low molecular chondroitin sulfate having an average molecular weight of 950Da 6%, sodium hyaluronate (22X 10) 6 Da) 0.5%, glucosamine hydrochloride 5%, magnesium chloride 1%, xanthan gum 0.5%, laurocapram 0.5%, phenoxyethanol 0.5%, methylparaben 0.1% and the balance water.
The method for preparing the low molecular chondroitin sulfate composite hydrogel can be implemented according to the following steps:
(1) Weighing the components according to the proportion, adding water accounting for 60% of the required water amount into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at the speed of 150r/min and the temperature of 50 ℃ and fully dissolving to obtain a phase A solution;
(2) Adding water with the water content of 40% of the required water content into another reactor, adding low molecular chondroitin sulfate, a permeation promoter, glucosamine hydrochloride, magnesium chloride and a preservative, and mechanically stirring at 150r/min until the solution is clear to obtain a phase B solution;
(3) Slowly adding the B phase solution into the A phase solution while stirring, uniformly stirring at a rotating speed of 150r/min, and cooling to 20 ℃ to obtain the low molecular chondroitin sulfate composite hydrogel.
Example 6
The low molecular chondroitin sulfate composite hydrogel comprises the following raw materials in parts by mass: low molecular chondroitin sulfate 1% having an average molecular weight of 720Da, sodium hyaluronate (22×10) 6 Da) 0.5%, glucosamine hydrochloride 5%, magnesium chloride 1%, xanthan gum 0.5%, laurocapram 0.5%, phenoxyethanol 0.5%, methylparaben 0.1% and the balance water.
The method for preparing the low molecular chondroitin sulfate composite hydrogel can be implemented according to the following steps:
(1) Weighing the components according to the proportion, adding water accounting for 60% of the required water amount into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at the speed of 150r/min and the temperature of 50 ℃ and fully dissolving to obtain a phase A solution;
(2) In another reactor, water with the water content of 40% is added, low molecular chondroitin sulfate, a permeation promoter, glucosamine hydrochloride, magnesium chloride and a preservative are added, and the solution is mechanically stirred at 150r/min until the solution is clarified, so as to obtain a phase B solution.
(3) Slowly adding the B phase solution into the A phase solution while stirring, uniformly stirring at a rotating speed of 150r/min, and cooling to 20 ℃ to obtain the low molecular chondroitin sulfate composite hydrogel.
Example 7
The low molecular chondroitin sulfate composite hydrogel comprises the following raw materials in parts by mass: low molecular chondroitin sulfate having an average molecular weight of 720Da of 10%, sodium hyaluronate (22×10) 6 Da) 0.5%, glucosamine hydrochloride 5%, magnesium chloride 1%, xanthan gum 0.5%, laurocapram 0.5%, phenoxyethanol 0.5%, methylparaben 0.1% and the balance water.
The method for preparing the low molecular chondroitin sulfate composite hydrogel can be implemented according to the following steps:
(1) Weighing the components according to the proportion, adding water accounting for 60% of the required water amount into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at the speed of 150r/min and the temperature of 50 ℃ and fully dissolving to obtain phase A liquid;
(2) In another reactor, water with the water content of 40% is added, low molecular chondroitin sulfate, a permeation promoter, glucosamine hydrochloride, magnesium chloride and a preservative are added, and the solution is mechanically stirred at 150r/min until the solution is clarified, so as to obtain a phase B solution.
(3) Slowly adding the phase B liquid into the phase A liquid while stirring, uniformly stirring at a rotating speed of 150r/min, and cooling to 20 ℃ to obtain the low-molecular chondroitin sulfate composite hydrogel.
Example 8
The low molecular chondroitin sulfate composite hydrogel comprises the following raw materials in parts by mass: low molecular chondroitin sulfate 6% having an average molecular weight of 720Da, sodium hyaluronate (10×10) 6 Da) 0.5%, glucosamine hydrochloride 5%, magnesium chloride 1%, xanthan gum 0.5%, laurocapram 0.5%, phenoxyethanol 0.5%, methylparaben 0.1% and the balance water.
The method for preparing the low molecular chondroitin sulfate composite hydrogel can be implemented according to the following steps:
(1) Weighing the components according to the proportion, adding water accounting for 60% of the required water amount into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at the speed of 150r/min and the temperature of 50 ℃ and fully dissolving to obtain a phase A solution;
(2) Adding water with the water content of 40% of the required water content into another reactor, adding low molecular chondroitin sulfate, a permeation promoter, glucosamine hydrochloride, magnesium chloride and a preservative, and mechanically stirring at 150r/min until the solution is clear to obtain a phase B solution;
(3) Slowly adding the B phase solution into the A phase solution while stirring, uniformly stirring at a rotating speed of 150r/min, and cooling to 20 ℃ to obtain the low molecular chondroitin sulfate composite hydrogel.
Example 9
The low molecular chondroitin sulfate composite hydrogel comprises the following raw materials in parts by mass: low molecular chondroitin sulfate 6% having an average molecular weight of 720Da, sodium hyaluronate (22×10) 6 Da) 0.5%, glucosamine hydrochloride 1%, magnesium chloride 1%, xanthan gum 0.5%, laurocapram 0.5%, phenoxyethanol 0.5%, methylparaben 0.1% and the balance water.
The method for preparing the low molecular chondroitin sulfate composite hydrogel can be implemented according to the following steps:
(1) Weighing the components according to the proportion, adding water accounting for 60% of the required water amount into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at the speed of 150r/min and the temperature of 50 ℃ and fully dissolving to obtain a phase A solution;
(2) Adding water with the water content of 40% of the required water content into another reactor, adding low molecular chondroitin sulfate, a permeation promoter, glucosamine hydrochloride, magnesium chloride and a preservative, and mechanically stirring at 150r/min until the solution is clear to obtain a phase B solution;
(3) Slowly adding the B phase solution into the A phase solution while stirring, uniformly stirring at a rotating speed of 150r/min, and cooling to 20 ℃ to obtain the low molecular chondroitin sulfate composite hydrogel.
Example 10
The low molecular chondroitin sulfate composite hydrogel comprises the following raw materials in parts by mass: low molecular chondroitin sulfate 6% having an average molecular weight of 720Da, sodium hyaluronate (22×10) 6 Da) 0.5%, glucosamine hydrochloride 3%, magnesium chloride 1%, xanthan gum 0.5%, laurocapram 0.5%, phenoxyethanol 0.5%, methylparaben 0.1% and the balance water.
The method for preparing the low molecular chondroitin sulfate composite hydrogel can be implemented according to the following steps:
(1) Weighing the components according to the proportion, adding water accounting for 60% of the required water amount into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at the speed of 150r/min and the temperature of 50 ℃ and fully dissolving to obtain a phase A solution;
(2) Adding water with the water content of 40% of the required water content into another reactor, adding low molecular chondroitin sulfate, a permeation promoter, glucosamine hydrochloride, magnesium chloride and a preservative, and mechanically stirring at 150r/min until the solution is clear to obtain a phase B solution;
(3) Slowly adding the B phase solution into the A phase solution while stirring, uniformly stirring at a rotating speed of 150r/min, and cooling to 20 ℃ to obtain the low molecular chondroitin sulfate composite hydrogel.
Example 11
The low molecular chondroitin sulfate composite hydrogel comprises the following raw materials in parts by mass: average molecular weight ofLow molecular chondroitin sulfate of 720Da 6%, sodium hyaluronate (22×10) 6 Da) 0.5%, glucosamine hydrochloride 5%, magnesium chloride 0.5%, xanthan gum 0.5%, laurocapram 0.5%, phenoxyethanol 0.5%, methylparaben 0.1%, and water in balance.
The method for preparing the low molecular chondroitin sulfate composite hydrogel can be implemented according to the following steps:
(1) Weighing the components according to a certain proportion, adding water accounting for 60% of the required water amount into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at a rotating speed of 150r/min and a temperature of 50 ℃, and fully dissolving to obtain a phase A solution;
(2) Adding water with the water content of 40% of the required water content into another reactor, adding low molecular chondroitin sulfate, a permeation promoter, glucosamine hydrochloride, magnesium chloride and a preservative, and mechanically stirring at 150r/min until the solution is clear to obtain a phase B solution;
(3) Slowly adding the B phase solution into the A phase solution while stirring, uniformly stirring at a rotating speed of 150r/min, and cooling to 20 ℃ to obtain the low molecular chondroitin sulfate composite hydrogel.
Example 12
The low molecular chondroitin sulfate composite hydrogel comprises the following raw materials in parts by mass: low molecular chondroitin sulfate 6% having an average molecular weight of 720Da, sodium hyaluronate (18×10) 6 Da) 0.5%, glucosamine hydrochloride 5%, magnesium chloride 2%, xanthan gum 0.5%, laurocapram 0.5%, phenoxyethanol 0.5%, methylparaben 0.1% and the balance water.
The method for preparing the low molecular chondroitin sulfate composite hydrogel can be implemented according to the following steps:
(1) Weighing the components according to a certain proportion, adding water accounting for 60% of the required water amount into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at a rotating speed of 150r/min and a temperature of 50 ℃, and fully dissolving to obtain a phase A solution;
(2) In another reactor, water with the water content of 40% is added, low molecular chondroitin sulfate, a permeation promoter, glucosamine hydrochloride, magnesium chloride and a preservative are added, and the solution is mechanically stirred at 150r/min until the solution is clarified, so that a B-phase solution is obtained, and the B-phase solution is stored in a sealed manner.
(3) Slowly adding the B phase solution into the A phase solution while stirring, uniformly stirring at a rotating speed of 150r/min, and cooling to 20 ℃ to obtain the low molecular chondroitin sulfate composite hydrogel.
Example 13
The low molecular chondroitin sulfate composite hydrogel comprises the following raw materials in parts by mass: low molecular chondroitin sulfate 6% having an average molecular weight of 720Da, sodium hyaluronate (22×10) 6 Da) 0.5%, glucosamine hydrochloride 5%, magnesium chloride 1%, carbomer 0.5%, eucalyptus oil 0.5%, phenoxyethanol 0.5%, sodium sorbate 0.1% and the balance water.
The method for preparing the low molecular chondroitin sulfate composite hydrogel can be implemented according to the following steps:
(1) Weighing the components according to a certain proportion, adding water accounting for 60% of the required water amount into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at a rotating speed of 150r/min and a temperature of 50 ℃, and fully dissolving to obtain phase A liquid;
(2) In another reactor, water with 40% of the required water content is added, low molecular chondroitin sulfate, a permeation promoter, glucosamine sulfate, magnesium sulfate and a preservative are added, and the solution is mechanically stirred at 150r/min until the solution is clarified, so that phase B liquid is obtained, and the phase B liquid is stored in a sealed manner.
(3) Slowly adding the phase B liquid into the phase A liquid while stirring, uniformly stirring at a rotating speed of 150r/min, and cooling to 22 ℃ to obtain the low-molecular chondroitin sulfate composite hydrogel.
Example 14
The low molecular chondroitin sulfate composite hydrogel comprises the following raw materials in parts by mass: low molecular chondroitin sulfate 6% having an average molecular weight of 720Da, sodium hyaluronate (22×10) 6 Da) 0.5%, glucosamine hydrochloride 5%, magnesium chloride 1%, sodium carboxymethyl cellulose 0.5%, menthol 0.5%, phenoxyethanol 0.5%, sorbic acid 0.1%, the balance being water.
The method for preparing the low molecular chondroitin sulfate composite hydrogel can be implemented according to the following steps:
(1) Weighing the components according to a certain proportion, adding water accounting for 60% of the required water amount into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at a rotating speed of 150r/min and a temperature of 50 ℃, and fully dissolving to obtain a phase A solution;
(2) Adding water with the water content of 40% of the required water content into another reactor, adding low molecular chondroitin sulfate, a permeation promoter, glucosamine sulfate, magnesium gluconate and a preservative, and mechanically stirring at 150r/min until the solution is clear to obtain a phase B solution;
(3) Slowly adding the B phase solution into the A phase solution while stirring, uniformly stirring at a rotating speed of 150r/min, and cooling to 25 ℃ to obtain the low molecular chondroitin sulfate composite hydrogel.
Example 15
The low molecular chondroitin sulfate composite hydrogel comprises the following raw materials in parts by mass: low molecular chondroitin sulfate 6% having an average molecular weight of 720Da, sodium hyaluronate (22×10) 6 Da) 0.5%, glucosamine hydrochloride 5%, magnesium chloride 1%, xanthan gum 0.5%, propylene glycol 0.5%, sorbic acid 0.5%, methylparaben 0.1% and the balance water.
The method for preparing the low molecular chondroitin sulfate composite hydrogel can be implemented according to the following steps:
(1) Weighing the components according to a certain proportion, adding water accounting for 60% of the required water amount into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at a rotating speed of 150r/min and a temperature of 50 ℃, and fully dissolving to obtain a phase A solution;
(2) Adding water with the water content of 40% of the required water content into another reactor, adding low molecular chondroitin sulfate, a permeation promoter, glucosamine sulfate, magnesium oxide and a preservative, and mechanically stirring at 150r/min until the solution is clear to obtain a phase B solution;
(3) Slowly adding the B phase solution into the A phase solution while stirring, uniformly stirring at a rotating speed of 150r/min, and cooling to 25 ℃ to obtain the low molecular chondroitin sulfate composite hydrogel.
Comparative example 1
The average molecular weight of the low molecular chondroitin sulfate is 1200Da, and the composition, the proportion and the preparation process of the other raw materials are the same as those of the example 3, so that the low molecular chondroitin sulfate composite hydrogel control sample 1 is obtained.
Comparative example 2
The average molecular weight of the low molecular chondroitin sulfate is 500Da, and the composition, the proportion and the preparation process of the other raw materials are the same as those of the example 3, so that the low molecular chondroitin sulfate composite hydrogel control sample 2 is obtained.
In vitro transdermal experiments
Naturally fixing skin of suckling pig on the improved diffusion cell with effective diffusion area of 3.14m 2 The stratum corneum of the skin is made to face upward. 1mL (6% of the low molecular chondroitin sulfate-containing gel) of the low molecular chondroitin sulfate-containing composite hydrogel prepared in example 3, comparative example 1 and comparative example 2 was supplied, respectively, the receiving solution was physiological saline (receiving tank 7 mL), the temperature of the water bath in the receiving chamber was 32.+ -. 0.2 ℃ and the stirring speed was 300r/min. The supply chamber is sealed after adding the liquid medicine, 2mL of the receiving liquid is taken at fixed time at 5min, 30min, 60min, 90min and 120min respectively, and the receiving liquid with the same volume and the same temperature is added after each sampling. The obtained liquid was evaporated, re-dissolved in 1mL of a diluted hydrochloric acid aqueous solution having a pH of 3.5, filtered through a 0.45 μm microporous membrane, and the content of chondroitin sulfate having a low molecular weight was measured by HPLC, and the test results are shown in FIG. 1.
The experimental results show that: the low molecular chondroitin sulfate hydrogel prepared according to the invention is 3.14m 2 The transdermal results on the pigskin show that the product permeates into the skin after 5min of use, the permeation quantity is 160 mug, the permeation quantity increases with the increase of time, and 1100 mug permeates into the deep layer of the skin after 2h, so that the product acts on the joint. Comparison of example 3 with comparative examples 1 and 2 shows that the permeation effect of the 720Da low molecular weight chondroitin sulfate hydrogel is better than that of the 1200Da and 500Da low molecular weight chondroitin sulfate hydrogels, because the high molecular weight itself has a reduced permeation effect, whereas too low molecular weight causes direct absorption of skin, preservation in the skin oil layer, and the amount of permeation through the skin in a short time is reduced, so that the effect of rapid permeation is not achieved.
Rat animal experiment
Rats were fasted for 12 hours prior to anesthesia, and groups were anesthetized with 10% chloral hydrate (3 mL/kg) and 4% papain was injected 1,4,7 days after the start of the experiment. After shaving leg hairs in a region of 1cm around a right knee joint cavity, disinfecting by complexing iodine, and deiodizing by ethanol with the volume fraction of 75%, taking the outer edge of patellar inferior patella tendon as a needle insertion point for inserting a needle in the intercondylar fossa direction, inserting a needle in the intercondylar fossa direction in the injection process to have penetration sense, retracting for 2mm after reaching femoral condyles, injecting 0.15mL of mixed solution (6% papain physiological saline solution: 0.03mol/L of L-cysteine physiological saline solution = 2:1) into the right knee joint cavity, and inducing an osteoarthritis model, and successfully molding on the 14 th day.
Placebo (gel without low molecular chondroitin sulfate) and the drugs of examples 1-15 and the control samples of comparative examples 1-2 were given transdermally once daily for 10 consecutive days after successful molding, respectively. According to the conversion formula of the body surface areas of the human and the animals, the gel dosage of about 0.7cm is used each time. The normal group (normal rats without osteoarthritis induction) and the model group (osteoarthritis-induced rats) were each coated with an equivalent dose of 0.9% sodium chloride solution.
(1) Behavioural assay
The evaluation level of the Lequesne MG knee joint was observed for each group of rats after the end of the treatment (25 days), the specific scores were shown in Table 1 (the lower the score was, the better the score was), and the results were shown in FIG. 2.
TABLE 1 rat Lequesne MG knee score
| Lequesne MG knee score | Score value |
| Local pain stimulus response | |
| Pain-free response | 1 |
| Affected limb contraction | 2 |
| The affected limb contracts and cramps with mild systemic reaction, such as tremor around the body and licking back | 3 |
| Severe contraction of affected limbs, cramps, general tremors, mess, and struggle | 4 |
| Gait of human body | |
| The affected limb has no lameness, runs normally and is forced to step on the ground | 1 |
| Mild lameness when running with ill limbs, powerful pedaling | 2 |
| The affected limb participates in walking, but lameness is obvious | 3 |
| The affected limbs cannot participate in walking, cannot touch the ground and pedal the ground | 4 |
| Joint movement range (straightening 0 degree) | |
| 90 degrees or more | 1 |
| 45-90° | 2 |
| 15-45° | 3 |
| 0-15° | 4 |
| Swelling of joints | |
| No swelling, clear visual signs of osseous | 1 |
| Mild swelling and shallowing of bony marks | 2 |
| Disappearance of bony marks | 3 |
| Maximum total score | 15 |
(2) Biomarker detection
The eyes were collected 5mL and serum CTX II levels were measured using ELISA kit for collagen type II C-terminal peptide (collagen type IIc-telopeptide fragments, CTX II). The C-terminal peptide of type II collagen is the main organic component of cartilage, and CTX II is released into the circulatory system after cartilage degradation, is one of effective indexes for judging the damage degree of osteoarthritis, and can be used as a marker for osteoarthritis diagnosis. The results are shown in FIG. 3.
(3) Pathological section
Normal, model, example 3 rats were sacrificed, 2cm sheared around the knee, the knee removed and the knee skin or excess muscle excised, fixed, decalcified, and paraffin sectioned. The staining was observed for arthritic conditions. The results are shown in FIG. 4.
The test results show that:
lequesne MG demonstrated by real knee joint evaluation: the hydrogel products prepared according to examples 1-15 of the present invention showed good scoring effect relative to the normal group, wherein examples 1-5 each changed the molecular weight of low molecular chondroitin sulfate, and the results showed that the low molecular chondroitin sulfate hydrogel at 590-950Da was effective in joint treatment of rat knee, preferably 720Da, with slight changes in both decrease and increase of molecular weight. Examples 6 and 7 show that the better the therapeutic effect on the knee joint of rats with increasing low molecular chondroitin sulfate content compared to example 3. In example 8, compared with example 3, the molecular weight of the hyaluronic acid was changed, and the high molecular weight hyaluronic acid has a thickening effect, and the gel state of the product was different due to the difference of the molecular weights of the hyaluronic acid (the viscosity of example 8 was relatively low, the fluidity was relatively good), so that the effective residence time of the product at the key part after use was relatively shortened, and the absorption effect of the product was not good as in example 3, but the comparative model set of example 8 was still improved. Example 9, example 10 in combination with example 3 results demonstrate that: the dosage of the glucosamine can promote joint repair of rats, and if the dosage is too low, the repairability is poor; the osmotic effects of the compounds in the examples 11, 12 and 3 are different mainly by changing the content of magnesium chloride, and the magnesium chloride in the example 12 is used in a larger amount, so that the compound absorption of low molecular chondroitin sulfate, glucosamine hydrochloride and the like is promoted, and the therapeutic effect on the knee joint of the rat is better than that of the compound in the example 11; it was found from comparative example 12 and example 3 that the hyaluronic acid of example 12 was relatively smaller in molecular weight, but the magnesium chloride was used in an increased amount, which was substantially equivalent to the effect of treating the knee joint of the rat. Examples 13-15, compared to example 3, show that the carbomer effect is less than that of xanthan gum by changing the thickener type and the penetration enhancer type, because low molecular chondroitin sulfate and magnesium chloride are salts, a large amount of ions are generated, the carbomer has poor ion resistance, so that the effect is weakened due to thinning, and the carboxymethyl cellulose has no such phenomenon, so that the effects of the penetration enhancers eucalyptus oil, menthol and propylene glycol are similar to those of laurocapram, so that the evaluation values are similar. The comparison of the examples and the comparative examples shows that the low molecular chondroitin sulfate hydrogel with the average molecular weight of 590-950Da has better effect of promoting joint repair compared with the chondroitin sulfate hydrogel with the average molecular weight of 500Da or 1200 Da.
The results of the detection by relative CTXII in serum showed that: the higher CTXII index, the more severe arthritis, was shown to be in the normal group at a relative CTXII of 0.5, and thus the rat showed a different degree of improvement in arthritis after the use of the product of the present invention. Examples 1 to 5 each changed the molecular weight of the low molecular chondroitin sulfate, and the low molecular chondroitin sulfate hydrogel at 590-950Da was effective in joint treatment of rat knees, preferably 720Da, with slight changes in both molecular weight reduction and increase.
Examples 6 and 7 and example 3 were improved in therapeutic effect on knee joint of rat as the content increased by changing the content of low molecular chondroitin sulfate, because the more low molecular chondroitin sulfate absorbed by it was, the better the repair of knee joint was and thus the proportion to the content increased, but when the content was too high, absorption saturation was caused, and improvement was not apparent.
Whereas example 8 changed the molecular weight of hyaluronic acid compared with example 3, the gel state change resulted in the product not being able to effectively stay at the critical site after use, resulting in poor absorption of the product and thus an increase in CTXII content compared with example 3.
Example 9, example 10 in combination with example 3 results demonstrate that: the usage amount of the glucosamine can promote joint repair of rats, if the usage amount is too low, the repairability is poor, and if the usage amount is too high, the promotion effect is basically unchanged after the skin reaches absorption saturation.
Examples 11, 12 and 3 have different permeation effects by changing the content of magnesium chloride, and example 12 has a large amount of magnesium chloride, so that it promotes absorption of components such as low molecular chondroitin sulfate and glucosamine hydrochloride, and thus has a good therapeutic effect on rat knee joints.
Examples 13-15 compared with example 3, the change of thickener type and penetration enhancer type showed that the carbomer effect was not as good as that of xanthan gum, because low molecular chondroitin sulfate and magnesium chloride were salts, a large amount of ions were generated, the carbomer was poor in ion resistance and thus weak in effect, whereas the carboxymethyl cellulose was not so much, and the penetration enhancers eucalyptus oil, menthol and propylene glycol were close in effect to laurocapram, and thus the evaluation was close.
The results of joint sections from example 3, normal and model groups were shown by: the cartilage tissue of the bone joint of the normal group of rats has no obvious pathological change, the cartilage surface is smooth, the arrangement of the cartilage cells is regular, the thickness is normal, and the tidal mark is excessively smooth and continuous. The surface of the cartilage of the bone joint of the rat in the model group is damaged and rough, the bone erosion is accompanied, more hypertrophic chondrocytes appear in the deep layer, and the thickness of the cartilage layer is thinned; the tidal level is bumpy. Example 3 the cartilage of the rat bone joint was improved compared with the model group rats, the cartilage surface chondrocyte arrangement was more regular, the cartilage surface was smoother, no bone erosion phenomenon occurred, and the hypertrophic chondrocyte did not appear in the deep layer, which indicates that the low molecular chondroitin sulfate hydrogel has obvious improvement effect on the pathological changes caused by osteoarthritis.
While the invention has been described with reference to the preferred embodiments, it is not limited thereto, and various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (5)
1. The low molecular chondroitin sulfate composite hydrogel is characterized by comprising the following raw materials in parts by mass: 6-10% of low molecular chondroitin sulfate with the average molecular weight of 720Da, 0.5% of sodium hyaluronate, 5% of glucosamine, 1% of magnesium nutrition enhancer, 0.5% of thickener, 0.2-1.0% of penetration enhancer, 0.2-1.5% of preservative and the balance of water;
sodium hyaluronate with molecular weight of 22×10 6 Da；
The thickener is xanthan gum;
the magnesium nutrition enhancer is magnesium chloride;
the glucosamine is glucosamine hydrochloride.
2. The low molecular chondroitin sulfate composite hydrogel of claim 1 wherein the permeation enhancer comprises one or more of laurocapram, menthol, eucalyptus oil and propylene glycol; the preservative comprises one or more of phenoxyethanol, methylparaben, sorbic acid and sodium sorbate.
3. The method for preparing the low molecular chondroitin sulfate composite hydrogel according to any one of claims 1 to 2, which is characterized by comprising the following steps:
(1) Weighing the components according to a proportion, adding a proper amount of required water into a reactor, adding a thickening agent and sodium hyaluronate into the reactor, stirring at a rotating speed of 100-200r/min and a temperature of 30-50 ℃ and fully dissolving to obtain a phase A solution;
(2) Adding the rest water into another reactor, adding low molecular chondroitin sulfate, permeation promoter, glucosamine, magnesium nutrition enhancer and antiseptic, mechanically stirring at 100-200r/min until the solution is clear to obtain phase B solution;
(3) Adding the B phase solution into the A phase solution while stirring, stirring uniformly at a rotating speed of 100-200r/min, and cooling to 20-25 ℃ to obtain the low molecular chondroitin sulfate composite hydrogel.
4. A medical article comprising a low molecular chondroitin sulfate composite hydrogel according to any one of claims 1-2.
5. Use of a low molecular chondroitin sulfate composite hydrogel according to any one of claims 1-2 in the preparation of a medicament for treating arthritis.
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