Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
  • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
  • A61L26/0052—Mixtures of macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
  • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
  • A61L26/0023—Polysaccharides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
  • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
  • A61L26/0028—Polypeptides; Proteins; Degradation products thereof
  • A61L26/0033—Collagen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
  • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
  • A61L26/0028—Polypeptides; Proteins; Degradation products thereof
  • A61L26/0038—Gelatin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
  • A61L26/0061—Use of materials characterised by their function or physical properties
  • A61L26/008—Hydrogels or hydrocolloids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
  • A61L2300/23—Carbohydrates
  • A61L2300/232—Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
  • A61L2300/412—Tissue-regenerating or healing or proliferative agents

Definitions

• Rotator cuff tear repair composition comprising nucleic acid and chitosan
• the present invention relates to a rotator cuff tear repair composition containing nucleic acid and chitosan.
• the rotator cuff converts the vertical shear force of the strong triceps into smooth external shear force and serves as a protective film to prevent the humeral head from coming into contact with the lower shoulder. et al., 2007).
• Rotator cuff injury may be caused by acute trauma, but most of the cases are known to occur without specific trauma in patients.
• Rotator cuff disease is basically a degenerative disease caused by aging but is an external factor. It may be caused by shoulder instability, arthritis of the shoulder blade joint, scapula (osacromiale), scapula collision, condylar collision, posterior condyle and stratification.
• shoulder instability arthritis of the shoulder blade joint
• scapula osteomiale
• scapula collision condylar collision
• posterior condyle posterior condyle and stratification.
• several factors are known to work in combination, such as the internal degeneration of the rotator cuff itself or the effects of inflammatory reactions. When accompanied by minor trauma, rupture of the rotator cuff can lead to serious impairments in daily life and work activities (Cho NS, et al., 2012). .
• Symptoms of rotator cuff injury include pain, muscle atrophy, limitations of joint movement, weakened shoulder joint strength, and external tenderness before shoulder joints. ⁇ When the degree of rupture is severe, the ruptured part is promoted externally. Attempts to raise the arm may cause weakness due to rises or ruptures, which may prevent the arm from holding up and cause the arm to fall or complain of shoulder pain.
• Rotator cuff injury of the shoulder differed in each stage from initial stage 1 to stage 3, and the clinical features and treatment of paragragm. In stage 1, swelling and bleeding of the rotator cuff appear, many in the age group under 25 years old and can be cured by conservative treatment.
• Stage 2 is fibrosis and tendonitis of the rotator cuff, which is common in the 25- to 40-year-old age group. Symptoms recur depending on the amount of activity, which may improve with conservative treatment, but requires severe surgery. Stage 3 is a degenerative osteoporosis and rotator cuff rupture. Many patients are older than 40 years old, and their symptoms continue to deteriorate and require surgery.
• Surgical treatments are widely performed, including endoscopic suture and open sutures. Surgical treatments have the potential for sequelae, such as surgical failure and infection, and may have scars in the triangle. Several months of rehabilitation are required after surgery, and pain may not remain completely after surgery, or the movement of the joint may not be fully recovered (Lee JH, et al., 2011).
• Conservative treatment is a method for relieving inflammation and pain. It can be used for relaxation, analgesic anti-inflammatory drugs, topical steroid injections, physiotherapy, etc., and stretching exercises and functions for soft tissue recovery. Strengthening exercises for parliamentary clothing can be carried out (Jung HJ, et al., 2012). In the case of drug treatment, oral administration or topical application of NSAIDs or topical steroids.
• Injectable methods have been used, but these medications have short-term effects, high recurrence rates, and side effects.
• non-surgical treatments such as physical therapies such as ultrasound thermal therapy and electrotherapy are painful.
• symptom relief such as diminishing symptoms, and could not be a cure for aggressive resolution of the cause.
• the present inventors found the present invention by verifying that the composition containing nucleic acid and chitosan was excellent in relieving pain caused by the rotator cuff tear and repairing the rotator cuff. I could finish it.
• a pharmaceutical composition for the prevention or treatment of a myocardium rupture containing a complex is disclosed, and Korean Patent No. 1536134 discloses a mattress for soft tissue repair including a rotator cuff, but it contains a nucleic acid and a chitosan. There is no description of a composition for rotator cuff tear repair, which is inconsistent with the present invention in its composition.
• the object of the present invention is to provide a rotator cuff tear repair composition containing nucleic acid and chitosan.
• Another object of the present invention is to provide a method for preparing a composition for rotator cuff tear repair, comprising nucleic acid and chitosan.
• the present invention relates to a rotator cuff tear repair composition containing nucleic acid and chitosan.
• the content of the silver nucleic acid based on the total weight of the composition, is 0.1% by weight to 3% by weight have.
• the chitosan silver content is 0.001% by weight based on the total weight of the composition
• the nucleic acid and chitosan may be in a ratio of 1: 1 to 3000: 1 by weight.
• the nucleic acid may be deoxyribonucleic acid (DNA), ribonucleic acid (RNA), or a combination thereof.
• DNA Deoxyribonucleic acid
• the deoxyribonucleic acid is an oligonucleotide
• It can be chosen from polydeoxyribonucleotides.
• the nucleic acid may have a molecular weight of lkDa to 100,000 kDa.
• the nucleic acid is 10 kDa to 10,000 kDa, more preferably 50 kDa to 3,500 kDa.
• the chitosan may have a molecular weight of 3 kDa to l, 000 kDa.
• the composition may contain a water-soluble polymer as an additional component.
• the water-soluble polymers include hyaluronic acid, chondroitin sulfate, glycogen, dextrin, dextran, dextran sulfate, and hydroxypropylmethylcell. Ross (hydroxypropyl
• It may be at least one selected from the group consisting of polyvinyl alcohol, poly vinyl pyrrolidone, polyacrylic acid and carboxylvinylpolymer.
• the composition may be injected through a syringe.
• the composition may be a hydrogel in which a sol-gel transition occurs depending on temperature.
• composition for rotational root rupture repair containing nucleic acid and chitosan is obtained by i) dissolving the nucleic acid in a buffer and dissolving it for 30 minutes to 1 hour while stirring at 40 ° C. to 70 ° C. Manufacturing step; ii) dissolving chitosan in an acid buffer solution to produce a chitosan stock solution; iii) the nucleic acid storage solution of step i) and the chitosan storage solution of step ii) are mixed so that the weight ratio of the nucleic acid and the chitosan is 1: 1 to 3000: 1, and it is within 30 minutes at 40 ° C to 70 ° C. Stirring for a time; and iv) lowering to room temperature while stirring the nucleic acid-chitosan mixture of step iii).
• the buffer solution for use in the preparation of the nucleic acid storage solution includes sodium phosphate dibasic dodeca 7; hydrate (sodium chloride), sodium chloride, magnesium chloride,
• Potassium chloride phosphate buffer saline, or HEPES (N- (2-hydroxyethyl) -piperazine-N'-2-ethanesulfonic acid)
• HEPES N- (2-hydroxyethyl) -piperazine-N'-2-ethanesulfonic acid
• Complete solution preferably sodium phosphate dibasic dodecahydrate, most preferably 5 ⁇ 300mM
• Sodium phosphate dibasic can also use decahydrate, but is not limited thereto.
• Acetic acid hydrochloric acid, ascorbic acid, lactic acid, nitric acid, glutamic acid or formic acid, preferably acetic acid (acetic acid), most preferably 10-300 mM acetic acid, but not limited to this.
• the rotator cuff tear repair composition containing nucleic acid and chitosan may be a temperature sensitive hydrogel in which a sol-gel transition occurs depending on temperature.
• the temperature sensitive hydrogel is a phase transition of a sol gel or a gel sol depending on temperature, and the sol turns into a gel.
• gelation is defined as viscoelasticity, and the molecules remain in the solvent without forming in a three-dimensional net structure with increasing temperature.
• the retention time of the composition can be increased at the rupture site, thereby increasing the tissue repair effect.
• the gelation of the composition slows down the decomposition rate of the composition. The long-term treatment effect can be obtained.
• composition for rotator cuff tear repair comprising the nucleic acid and chitosan
• nucleic acids and chitosan can be 1: 1 to 3000: 1 weight ratio, preferably 10: 1 to 300: 1. More preferably 10: 1 to 100: 1
• the nucleic acid content is 0.1 weight «3 ⁇ 4 to 3% by weight, based on the number of days the composition increased water gun. Preferably from 1% to 2 weight ⁇ 3 ⁇ 4 weight.
• the nucleic acid may have a molecular weight of lOkDa to 100,000kDa, preferably lOkDa to 10,000kDa, and most preferably 50kD to 3,500kDa. If the molecular weight of the nucleic acid is less than lOkDa, it is difficult to control the rate of degradation of the gel.
• the nucleic acid may be deoxyribonucleic acid (DNA), ribonucleic acid (RNA) or a combination thereof.
• the nucleic acid is deoxyribonucleic acid.
• the deoxyribonucleic acid is an oligonucleotide (oligonucleotide),
• the content of the chitosan may be from 0.001% to 0.1% by weight based on the total weight of the composition, preferably 0. 2% to 0.1% by weight.
• the chitosan preferably has a molecular weight of 3 kDa to l, 000 kDa,
• the mixture of nucleic acid and chitosan is mixed so that the weight ratio of nucleic acid and chitosan is 1: 1 to 3000: 1, wherein the content of nucleic acid is 0.1% to 3% by weight based on the total weight of the composition. It is desirable that the content of chitosan be 0.001% by weight to 0.1% by weight based on the total weight of the composition. .
• a composition for rotator cuff tear repair containing the nucleic acid and the chitosan is water soluble.
• the polymer may contain additional components.
• the water-soluble polymer for rotator cuff tear repair including nucleic acid and chitosan
• the water-soluble polymer is soluble or degradable in vivo
• Hyaluronic acid chondroitin sulfate
• Proteins such as collagen, gelatin and their hydrolysates
• Synthetic high molecular weight compounds such as polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, and carboxylvinylpolymer can be used.
• hyaluronic acid is used.
• the rotational root rupture repair composition containing nucleic acid and chitosan containing additional water-soluble polymers may be a mixture of nucleic acid, chitosan and water-soluble polymer in a weight ratio of 13000: 1: 1 to 1-3000. Is 10-1,000: 1: 10-1,000 weight ratio, more preferably: 25-100: 1: 25-100 weight ratio.
• the hyaluronic acid may include a linear or crosslinked form, and may have a molecular weight of 20 kDa to 10,000 kDa, with 500 kDa to 3,000 kDa being preferred, but not limited thereto.
• the rotator cuff repair composition containing nucleic acid and chitosan can suppress fatty degeneration and inflammatory reaction following rotator cuff rupture, and improve the continuity and parallelism of the collagen fibers in the rotator cuff tissue to restore rotator cuff tissue repair effect.
• the present invention relates to a composition for rotator cuff tear repair containing nucleic acid and chitosan. More specifically, a composition for rotator cuff tear repair produced through the combination of nucleic acid and chitosan is produced according to temperature. The effect of tissue repair is higher than that of the existing single composition, and the decomposition rate of the composition is slowed down. The restoration effect was confirmed to persist.
• the rotator cuff tear repair composition of the present invention can be directly injected into the rupture area that needs to be treated. As it increases, the effect of tissue repair can be fully demonstrated, and it is expected that it will be able to obtain an excellent therapeutic effect.
• composition for rotational muscle rupture repair of the present invention is a view showing the physical properties of the composition for rotational muscle rupture repair of the present invention
• Each rotator cuff tear repair composition was prepared and left for 3 days, after which the composition transparency, precipitate formation and layer separation were checked.
• Example 2 shows a sol-gel transition according to the temperature of the rotary root tear rupture repair composition of Example 1 of the present invention.
• FIG. 3 shows a method for measuring the maximum tensile strength when a rotator cuff teared with a rotator cuff tear repair composition of the present invention is ruptured.
• nucleic acid stock was prepared in 190 mM sodium phosphate dibasic dodecahydrate buffer solution and dissolved for at least 30 minutes using a 70 ° C. heat agitator.
• Chitosan stock solutions were prepared using 100 mM acetic acid.
• nucleic acid and chitosan stock solutions were mixed and stirred for 30 minutes in a 70 ° C. heat agitator. Then, the temperature was lowered to room temperature, followed by stirring for 1 hour to prepare a rotator cuff tear repair composition containing nucleic acid and chitosan. At this time, the concentrations of the nucleic acid and the chitosan were mixed so that the concentrations of Table 1 below.
• Example 1-5 3 0.1 30 1
• Example 2 Preparation of a Rotator Cuff Repair Composition Comprising Nucleic Acid, Chitosan and Hyaluronic Acid
• nucleic acid is 190 mM sodium phosphate dibasic.
• Dodeca hydrate It was prepared by dissolving in sodium phosphate dibasic dodecahydrate buffer solution and dissolving for at least 30 minutes using a heat stirrer at 70 ° C.
• the chitosan stock solution was prepared using 100 mM acetic acid.
• the hyaluronic acid has a molecular weight of 1,000 kDa, but may be a molecular weight of 20 kDa to 10,00 () kDa.
• a composition for rotator cuff tear repair was prepared. The same method as in Example 1 and Example 2 was used. [65] [Table 3]
• Example 1 (Example 1-1 to Example 1-5), Example 2 (Example 2-1 to Example)
• Comparative Example 1-13 o O 0 O Referring to Table 4 and FIG. 1, in the case of the compositions for rotational muscle rupture repair of Examples 1 and 2, the viscoelasticity and delamination do not occur after 3 days. It can be seen that, in the case of gel solubility,. 3A gel was formed at 5 ° C., and the formed gel was observed to be sustained.
• Viscoelasticity was not possible due to sediment formation, layer separation or partial mass formation, and it was found that the solubility of the gel dissolved within 5 minutes even if it did not gel or gel at 37.5 0 C.
• nucleic acids such as in the composition of rotator cuff tear repair of Comparative Examples 1-12 and Comparative Examples 1-13, the composition is viscoelastic, but sediment formation and layer separation occur, and the gel at 37.5 0 C It was confirmed that all of them dissolved within 5 minutes after the formation of the stability (see Table 4).
• the composition of the present invention was gelated at the rotator cuff where the composition of the present invention was ruptured. It can be expected that the increased rotator cuff tear effect can be obtained by increasing the therapeutic effect of the damaged rotator cuff site.
• a rheometer was used to check the sol-gel transition.
• the measurement conditions used were PU20, gap 0.5 mm, 0.1 Hz, and 1% stress strain.
• the temperature-sensitive hydrogel has: the characteristic temperature increases .
• the reduction width of G '(elastic) was observed to be moderate, and the G' (viscosity) was increased.
• the composition for rotational root rupture repair of Example 1-1 was less than 36 ° C.
• the right shoulder region was opened, the infraspinatus, one of the rotator cuffs, was wrapped with penrose drain, the skin was sealed, and reared for 4 weeks to chronic rotator cuff tear).
• the composition for rotator cuff tear repair according to the present invention was injected in 0.5 m £ increments. Breeding for weeks or six weeks. Three or six weeks later, histologic examination was performed on the rotator cuff site of each group of animal models. Paraffin invasion confirmed the proximal 0.3 cm site of the muscle-musculotendinous junction.
• composition for rotational rotator cuff repair of the present invention was expected to have excellent biocompatibility and to increase the drug retention at the site of rotator cuff tear, thereby significantly improving the tissue repair effect.
• the degree of ruptured rotator cuff repair was confirmed by histological examination for the continuity and regular parallelism of the collagen fibers in the bone-tendon junction.
• composition for rotational rotator cuff repair of the present invention increased the drug retention of the rotator cuff tear region, thereby improving the continuity and parallelism of collagen fibers, resulting in a tissue repair effect.
• Tensile load was measured to give the maximum tensile force at the time of rupture, with the pattern of rupture being an insertional tear at the connection between the bone and the tendon and an intermediate tear at the midline of the tendon ( in the form of midsubstance tear).
• the type of rupture is distinguished by the strength of the bond, with the midsubstance tear occurring when there is a strong bond in the bone-tendon, and the insertion tear being known when the relative weakness occurs in the bone-tendon. When midsubstance tears appeared, the tissues were judged to have strengthened.
• Pretreatment was performed by adding 10 cycles of repetition under strain.
• the stress-relaxation response was tested at a slope of 5% at 2.5% / s strain rate, waited for 300 seconds, then returned to full load of 1 N, and then quasi-static failure test (quasi)
• a static load-to-failure test was performed at 0.1 mW / s. Load and displacement were recorded at 100 Hz.

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• 2017
  • 2017-01-09 CN CN201780036342.0A patent/CN109310800B/zh active Active
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