CN111920761B - In situ hydrogel for treating chronic muscle and soft tissue soreness - Google Patents

In situ hydrogel for treating chronic muscle and soft tissue soreness Download PDF

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CN111920761B
CN111920761B CN202010815404.1A CN202010815404A CN111920761B CN 111920761 B CN111920761 B CN 111920761B CN 202010815404 A CN202010815404 A CN 202010815404A CN 111920761 B CN111920761 B CN 111920761B
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nitric oxide
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赵子逸
鲁翠涛
赵应征
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The in-situ hydrogel for treating the chronic muscle and soft tissue ache comprises a hydrogel matrix and nitric oxide nano bubbles, wherein the nitric oxide nano bubbles are uniformly dispersed in the hydrogel matrix. The hydrogel matrix consists of polyglutamic acid and sodium alginate, and the mass ratio of the polyglutamic acid to the sodium alginate is 1-3: 1. The nitric oxide nanobubble is composed of a vesicle formed by wrapping nitric oxide gas by a vesicle membrane material of yolk phospholipid and poloxamer, wherein the mass ratio of the yolk phospholipid to the poloxamer is 1: 25, the particle size range is 200-400 nm, and the concentration is 1 × 10 8 ～4×10 8 One per mL. The hydrogel of the invention is locally implanted or injected into the sore area of muscles and soft tissues for treating chronic sore muscles and soft tissues.

Description

In situ hydrogel for treating chronic muscle and soft tissue soreness
Technical Field
The invention relates to a medicinal preparation for treating chronic muscle and soft tissue ache, in particular to an in-situ hydrogel for treating the chronic muscle and soft tissue ache.
Background
Muscle and soft tissue soreness can be caused by sports, infectious diseases, and the like. The physiological tissues involved in muscle and soft tissue soreness include: (1) tissue traction: the muscle is damaged. (2) Muscle spasm: the muscles have a repetitive cramp. (3) Connective tissue: the connective tissue of the muscle is injured (e.g., tendon).
Chronic muscle and soft tissue soreness refers to muscle and soft tissue soreness that lasts more than 3 months. Causes of muscle and soft tissue soreness are: (1) and (3) movement: chronic muscle and soft tissue soreness that occurs hours to about 24 hours after exercise usually lasts for about 1 to 3 days. The cause is not simply a muscle injury, a muscle spasm or an abnormality of the connective tissue, which is generally considered to be the largest cause of chronic muscle and soft tissue soreness. (2) Infectious diseases: such as middle east respiratory syndrome, siberian rickettsia macula fever, legionnaires' disease, pontiaca fever, mumps, malaria, etc., all can have symptoms of continuous high fever at body temperature of more than 40 ℃, repeated chills, chronic muscular and soft tissue ache of the whole body, etc. (3) Other diseases: such as repeated stress injury, uveitis accompanied by Wegner granuloma, beriberi heart disease, etc. also commonly present chronic muscle and soft tissue soreness symptoms.
The main treatment method for the muscle and soft tissue ache is rest and physical treatment, such as massage and hot compress, so as to achieve the effects of promoting blood circulation and dredging channels and collaterals, and be not suitable for excessive activities. Oral administration of vitamin C promotes collagen synthesis in connective tissue, and helps to accelerate the repair of damaged tissue and relieve soreness. However, these methods are slow acting, slow in efficacy and poor in the treatment of chronic muscle and soft tissue soreness.
The research finds that the nitric oxide has good treatment potential in the treatment of chronic muscle and soft tissue ache, but the treatment mechanism is not clear. It is believed that nitric oxide promotes blood circulation by expanding blood vessels, and that sufficient blood flow can effectively carry away lactic acid, relieving muscle fatigue and muscle soreness.
Most of the reported methods for supplementing nitric oxide in vivo have been the use of nitric oxide donor compounds. Nitric oxide donor compounds fall into two classes: non-enzymic and enzymic forms. Most of non-enzymatic nitric oxide donor compounds come from nitro compounds, including nitroprusside, organic or inorganic nitrite and nitrate, nitrosamine, nitrogen mustard, hydrazine and the like, and have small dosage and large toxic and side effects. The enzymatic nitric oxide donor compound (such as arginine) needs to be decomposed by in vivo biological enzymes to produce nitric oxide molecules. The nitric oxide molecules generated by these nitric oxide donor compounds are unable to concentrate at the site of muscle and soft tissue soreness and act, and thus the effect of treating chronic muscle and soft tissue soreness using nitric oxide donor compounds is poor.
The nitric oxide molecule is in gaseous form, and nitric oxide gas (NO) is slightly soluble in water, and has a solubility of only 5.6X 10 in water at 20 deg.C -3 g/L (equivalent to 0.186 mu mol/L), can not be prepared into common dosage forms and has the treatment effect on chronic muscle and soft tissue ache.
In situ gels are formulations that undergo a phase transition at the site of administration immediately after administration in solution, from a liquid state to a non-chemically crosslinked semi-solid gel. The gel has good histocompatibility, and long retention time at administration position; meanwhile, the medicine can be stored and prevented from being influenced by the environment. According to different forming mechanisms, the in-situ gel can be divided into a temperature sensitive type, a pH sensitive type, an ion sensitive type and the like. The in-situ gel is used as a novel drug dosage form and widely applied to novel drug delivery systems such as slow release, controlled release, pulse release and the like, can be applied to multiple ways of drug delivery such as skin, eyes, nasal cavities, oral cavities, vaginas, rectum and the like, and becomes a research hotspot in the fields of pharmaceutics and biotechnology.
Although in situ gels have various advantages in topical treatment, nitric oxide is a gas, and no research report that nitric oxide gas can be efficiently carried in situ gels is available. Therefore, the preparation of in situ gels that efficiently carry nitric oxide gas is a limiting bottleneck in the development of nitric oxide for the treatment of chronic muscle and soft tissue soreness.
Disclosure of Invention
The invention aims to overcome the defects of the prior art (namely, the lack of in-situ gel carrying nitric oxide gas efficiently) and provide the medicine gel with local effect on the sore parts of the chronic muscles and the soft tissues, thereby providing the maximum guarantee for ensuring the treatment effect of the sore parts of the chronic muscles and the soft tissues and meeting the requirements of safety, effectiveness, convenience and economy of clinical treatment.
The inventor finds that polyglutamic acid and nitric oxide molecules can generate mutual synergistic effect in the treatment of chronic muscle and soft tissue ache. The yolk phospholipids and the poloxamer are bubble membrane materials which wrap the nitric oxide gas to form the nitric oxide nano bubbles which can convert the nitric oxide gas into liquid. In addition, both the polyglutamic acid and the sodium alginate have the property of forming in-situ hydrogel, and the compatibility of the polyglutamic acid and the sodium alginate is good. However, no research report is found on how to organically combine the beneficial factors of nitric oxide, polyglutamic acid and sodium alginate to play a synergistic therapeutic effect on the aching pain of the chronic muscles and soft tissues.
Through a large number of experiments, the inventor obtains an in situ hydrogel for treating the chronic muscle and soft tissue ache, which can take effect locally at the ache part of the chronic muscle and soft tissue, wherein the hydrogel comprises a hydrogel matrix and nitric oxide nano bubbles, and the nitric oxide nano bubbles are uniformly dispersed in the hydrogel matrix.
The hydrogel matrix consists of polyglutamic acid and sodium alginate, and the mass ratio of the polyglutamic acid to the sodium alginate is 1-5: 10.
The mass ratio of the polyglutamic acid to the sodium alginate in the hydrogel matrix is 2-3: 10.
The hydrogel matrix is further added with: sugars, electrolyte salts, amino acids, pH buffers and antioxidants.
The nitric oxide nanobubble is composed of a vesicle formed by wrapping nitric oxide gas by a vesicle membrane material of yolk phospholipid and poloxamer, wherein the mass ratio of the yolk phospholipid to the poloxamer is 1: 25.
The particle size range of the nitric oxide nano bubbles is 200-400 nm.
The concentration of the nitric oxide nano bubbles in the in-situ hydrogel is 1 x 10 8 ～4×10 8 one/mL.
The preparation method of the in-situ hydrogel for treating the chronic muscle and soft tissue ache comprises the following steps:
a: dispersing polyglutamic acid and sodium alginate in 9 times of water for injection at 8 ℃, placing the water for injection in a refrigerator at 4-8 ℃ overnight, slowly dissolving the components, and uniformly mixing to form a hydrogel matrix solution;
b: mixing yolk phospholipid and poloxamer at a mass ratio of 1: 25, heating to 65 deg.C, transferring into a heat-insulating pressure-resistant container with a plug, vacuumizing, injecting nitric oxide gas, high-speed oscillating for 3min with a vortex mixer, and homogenizing particle size with a screen with specified aperture under high pressure to obtain 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 the temperature of 10 ℃, and adjusting the final concentration of the nitric oxide nanobubbles to be 1 x 10 8 ～4×10 8 The amount of the active carbon is one/mL,shaking gently and mixing well to obtain in situ hydrogel solution for treating chronic muscle and soft tissue soreness, and sealing and storing at 10 deg.C;
d: and c, exposing the in-situ hydrogel solution for treating the chronic muscle and soft tissue ache, prepared in the step c, to the environment of 30-37 ℃, and quickly gelling to form semisolid hydrogel.
The hydrogel matrix solution prepared above was further added with: sugars, electrolyte salts, amino acids, pH buffers and antioxidants.
The in-situ hydrogel is locally implanted or injected into the sore area of the chronic muscle and soft tissue for treating the chronic muscle and soft tissue pain.
The in-situ hydrogel for treating the chronic muscle and soft tissue ache has the following advantages: (1) the beneficial components of nitric oxide, polyglutamic acid and sodium alginate are organically combined to play a synergistic treatment role in treating the soreness of the muscles and soft tissues; (2) has the long-acting effects of bioadhesion and slow release, and has good affinity and biocompatibility to muscles and soft tissues; (3) no nitric oxide donor compound is used, and adverse reaction and toxic and side effects on body tissues caused by the nitric oxide donor compound are avoided; (4) the medicine is convenient to use, and is in a gel state immediately after being locally implanted or injected to the sore parts of muscles and soft tissues, so that the long-acting treatment aim of the chronic sore muscles and soft tissues is fulfilled.
Detailed Description
Hereinafter, specific embodiments of the present invention will be described in detail. It should be noted that technical features or combinations of technical features described in the following embodiments should not be considered as being isolated, and they may be combined with each other to achieve better technical effects.
EXAMPLE 1 preparation of in situ hydrogel for the treatment of Chronic muscle and soft tissue soreness
Experimental groups preparation of in situ hydrogel: the method is carried out according to the following steps according to the component proportions in the table 1.
a: dispersing polyglutamic acid and sodium alginate in 9 times of water for injection at 8 ℃, placing the water for injection in a refrigerator at 4-8 ℃ overnight, slowly dissolving the components, and uniformly mixing to form a hydrogel matrix solution;
b: mixing yolk phospholipid and poloxamer at a mass ratio of 1: 25, heating to 65 deg.C, transferring into a heat-insulating pressure-resistant container with a plug, vacuumizing, injecting nitric oxide gas, oscillating at high speed for 3min with a vortex mixer, and homogenizing at high pressure with a screen with specified aperture to obtain nitric oxide nanobubble solution;
c: and (3) 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 shown in the table 1, shaking and mixing uniformly to prepare an in-situ hydrogel solution, and sealing and storing the in-situ hydrogel solution at 10 ℃ to obtain the in-situ hydrogel.
Preparation of control in situ hydrogel: the preparation was carried out according to the method of the experimental group, according to the component ratios of table 1. The experimental groups are configured according to the components and the proportion within the protection scope of the claims of the application, and the control groups are the deletion of a certain component or the mass percentage of the component beyond the protection scope of the claims of the application.
TABLE 1 composition of in situ hydrogels for the experimental and control groups
Figure BSA0000216754280000041
Figure BSA0000216754280000051
Note: "/" indicates that the item is not present; * Represents that the component is replaced by the component in brackets; NO represents nitric oxide gas; o is 2 Represents oxygen; n is a radical of 2 Representing nitrogen.
EXAMPLE 2 Effect of in situ hydrogel application for treatment of Chronic muscle and Soft tissue soreness
(1) Establishment of chronic muscle and soft tissue soreness model animal
References [ electrophysiological and histopathological studies of trigger points of chronic myofascial pain in rats [ J ] china journal of sports medicine, 2013, 32 (007): 621-628, SD rat is used as experimental object, adopting the method of beating medial femoral muscle and centrifugal movement to establish chronic muscle and soft tissue ache animal model.
(2) Effect of various groups of hydrogels on treating chronic muscle and soft tissue soreness
Selecting rats successfully modeled after chronic muscle and soft tissue soreness, averagely dividing the rats into a plurality of groups according to the design of table 1, injecting 0.3mL of hydrogel into the femoral medial muscle part, conventionally feeding the rats, observing the model rat behaviours every day, measuring the mechanical foot contraction threshold value by using a Von Frey filament, killing the rats at 14 days, taking tissues of the femoral medial muscle part for histological staining, observing the ultramicro morphology of the femoral medial muscle tissue, and evaluating the effect of each group of hydrogel on the treatment of the chronic muscle and soft tissue soreness.
The evaluation results of the groups are shown in table 2, and the total application effect score of the hydrogel of each group is given by integrating the evaluation indexes.
TABLE 2 Effect of in situ hydrogel for the treatment of chronic muscular and soft tissue soreness of the experimental and control groups
Figure BSA0000216754280000052
Figure BSA0000216754280000061
As can be seen from the experimental results shown in Table 2, the in situ hydrogel of the experimental group has good therapeutic effect on the chronic muscle and soft tissue soreness, and particularly in the experimental group 5, the rat behavioral recovery is basically observed, the mechanical foot-shortening threshold value is reduced to a normal value, and the ultramicro morphology of the medial femoral muscle tissue is close to normal, so that the therapeutic effect on the chronic muscle and soft tissue soreness is proved to be good. Compared with the experimental group, the hydrogel of the control group has obviously poorer treatment effect on the chronic muscle and soft tissue ache, particularly, the hydrogel of the control group 1, 2, 3, 8 and 9 has the characteristics that rats are very scorched, the mechanical foot-contracting threshold value is obviously higher than the normal value, and the ultramicro form of the medial femoral muscle tissue is obviously deformed, which indicates that the in-situ hydrogel of the groups has very poor treatment effect on the chronic muscle and soft tissue ache.
The experimental results in table 2 demonstrate that any component and condition in the technical protection scheme of the present invention are synergistic and indispensable, and that the absence of any component and condition in the technical protection scheme of the present invention has a significant effect on the therapeutic effect of chronic muscle and soft tissue soreness. The in-situ hydrogel organically combines the beneficial factors of nitric oxide, polyglutamic acid and sodium alginate, plays a role in the cooperative treatment of the ache of the chronic muscle and soft tissue, and has good application prospect.
The above detailed description is specific to possible embodiments of the invention, and the embodiments are not intended to limit the scope of the invention, and all equivalent implementations or modifications that do not depart from the scope of the invention should be construed as being included within the scope of the invention. In addition, various modifications, additions and substitutions in form and detail may occur to those skilled in the art within the scope and spirit of the invention as disclosed in the accompanying claims. It is understood that various modifications, additions, substitutions and the like can be made without departing from the spirit of the invention as disclosed in the accompanying claims.

Claims (8)

1. The in-situ hydrogel for treating chronic muscle and soft tissue ache is mainly characterized in that: the hydrogel comprises a hydrogel matrix and nitric oxide nanobubbles, wherein the nitric oxide nanobubbles are uniformly dispersed in the hydrogel matrix, the nitric oxide nanobubbles are formed by wrapping nitric oxide gas by a membrane material which is yolk phospholipid and poloxamer, the mass ratio of the yolk phospholipid to the poloxamer is 1: 25, the hydrogel matrix is formed by polyglutamic acid and sodium alginate, the mass ratio of the polyglutamic acid to the sodium alginate is 1-3: 1, the particle size range of the nitric oxide nanobubbles is 200-400 nm, and the concentration of the nitric oxide nanobubbles in the in-situ hydrogel is 1 × 10 8 ～4×10 8 one/mL.
2. The in situ hydrogel for treating chronic muscle and soft tissue soreness of claim 1, wherein: the mass ratio of the polyglutamic acid to the sodium alginate in the hydrogel matrix is 2: 1.
3. The in situ hydrogel for treating chronic muscle and soft tissue soreness of claim 1, wherein: the hydrogel matrix is further added with: sugar, electrolyte salt, amino acid, pH value buffering agent and one or more of antioxidants.
4. The in situ hydrogel for treating chronic muscle and soft tissue soreness of claim 1, wherein: the average particle size of the nitric oxide nanobubbles is 300nm.
5. The in situ hydrogel for treating chronic muscle and soft tissue soreness of claim 1, wherein: the average concentration of the nitric oxide nano bubbles in the in-situ hydrogel is 2.5 multiplied by 10 8 One per mL.
6. A method of preparing an in situ hydrogel for the treatment of chronic muscle and soft tissue soreness of claim 1, comprising the steps of:
a: dispersing polyglutamic acid and sodium alginate in 9 times of water for injection at 8 ℃, placing the water for injection in a refrigerator at 4-8 ℃ overnight, slowly dissolving, and uniformly mixing to form a hydrogel matrix solution;
b: mixing yolk phospholipid and poloxamer at a mass ratio of 1: 25, heating to 65 deg.C, transferring into a heat-insulating pressure-resistant container with a plug, vacuumizing, injecting nitric oxide gas, high-speed oscillating for 3min with a vortex mixer, and homogenizing particle size with a screen with specified aperture under high pressure to obtain 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 the temperature of 10 ℃, and adjusting the final concentration of the nitric oxide nanobubbles to be 1 x 10 8 ～4×10 8 And (5) shaking gently and mixing uniformly to prepare an in-situ hydrogel solution for treating chronic muscle and soft tissue soreness, and sealing and storing at 10 ℃.
7. The method of preparing an in situ hydrogel for treating chronic muscle and soft tissue soreness of claim 6, wherein: the hydrogel matrix solution is further added with: sugar, electrolyte salt, amino acid, pH value buffering agent and one or more of antioxidants.
8. The in situ hydrogel for treating chronic muscle and soft tissue soreness of claim 1, wherein: the in-situ hydrogel is locally implanted or injected to the parts with chronic muscular and soft tissue soreness, and is used for treating the chronic muscular and soft tissue soreness.
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