Composition for treating musculoskeletal disorders comprising leukocyte-rich platelet-rich plasma, thrombin, fibrinogen, and atelocollagen, and preparation method therefor

Abstract

The present invention relates to a composition for treating musculoskeletal disorders, comprising leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen, and a preparation method therefor, wherein the composition, when administered to a patient with a musculoskeletal disorder, improves functions, alleviates pain, reduces the size of ruptured tendons, and induces structural regeneration of the tendons, and thus can be advantageously used as a pharmaceutical composition for preventing or treating musculoskeletal disorders. In addition, the composition of the present invention has an effect of reducing postoperative re-rupture of the rotator cuff after confirming rupture of the rotator cuff and performing suturing.

Description

Composition for treating musculoskeletal diseases comprising leukocyte-rich platelet-rich plasma, thrombin, fibrinogen and atelocollagen, and method for preparing the same

[0001] The present invention relates to a composition for treating musculoskeletal diseases comprising leukocyte-rich platelet-rich plasma, thrombin, fibrinogen and atelocollagen, and a method for producing the same.

[0002] Musculoskeletal disorders are health problems caused by factors such as repetitive movements, improper work posture, excessive use of force, and sports injuries, and are diseases that cause pain or damage to the ligaments, nerves, muscles, bones, tendons, intervertebral discs, and surrounding body tissues of the neck, shoulders, waist, limbs, and arms and legs.

[0003] The types of musculoskeletal disorders are very broad, including tendinopathies such as rotator cuff disease, lateral epicondylitis of the elbow, biceps tendonopathy, plantar fasciitis, and patellar tendonitis, as well as osteoarthritis, herniated discs, and muscle sprains.

[0004] Among these musculoskeletal disorders, rotator cuff tear is a disease in which the four tendons that move the shoulder joint rupture, and it is one of the major diseases that causes pain and functional decline in the shoulder joint. When one or more of the subscapularis, supraspinatus, infraspinatus, or teres minor tendons are damaged, it is called a rotator cuff tear. Most tendon ruptures are due to degenerative changes, but they can also be caused by impingement syndrome or trauma that hits the acromion.

[0005] Treatment of rotator cuff tears generally includes painkillers, physical therapy, and injection therapy (steroids, collagen, platelet-rich plasma, polydeoxyriboneucletide) in cases of partial-thickness tears. However, in cases of partial-thickness tears or full-thickness tears that are not effective with these conservative treatments, arthroscopic rotator cuff repair is indicated.

[0006] Recently, research results have been published on the positive effects of atelocollagen or platelet-rich plasma injection on the sutured rotator cuff after rotator cuff repair. However, the currently commercialized atelocollagen and platelet-rich plasma injections have a disadvantage in that a large amount does not remain at the injection site due to the liquid components, so there is controversy about their effectiveness. Therefore, the inventors of the present invention have devised a method to effectively settle into the tissue by mixing dilute liquid atelocollagen and leukocyte-rich platelet-rich plasma injection, trobin, and fibrinogen and coagulating them to increase the viscosity of the injection solution. By doing so, the high-viscosity mixture can be injected into the space between the tendon and the humerus and into the sutured tendon after rotator cuff repair.

[0007] Against this backdrop, the inventors of the present invention have studied a method for alleviating, improving or treating musculoskeletal diseases, and have completed the present invention by confirming that the administration of a mixture of leukocyte-rich platelet-rich plasma, thrombin, fibrinogen and atelocollagen improves function and pain in patients with musculoskeletal diseases, reduces the size of ruptured tendons and structurally regenerates tendons.

[0008] The purpose of the present invention is to provide a pharmaceutical composition for preventing or treating musculoskeletal diseases, comprising leukocyte-rich platelet-rich plasma, thrombin, fibrinogen and atelocollagen.

[0009] Another object of the present invention is to provide a method for preventing or treating a musculoskeletal disease, comprising administering the pharmaceutical composition to a subject who has developed or is likely to develop a musculoskeletal disease.

[0010] Another object of the present invention is to provide a method for preparing a pharmaceutical composition for preventing or treating musculoskeletal diseases, comprising the step of mixing leukocyte-rich platelet-rich plasma, thrombin, fibrinogen and atelocollagen.

[0011] The advantages and features of the present invention, and the methods for achieving them, will become clearer with reference to the embodiments described in detail below together with the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below and may be implemented in various different forms. These embodiments are provided solely to ensure that the disclosure of the present invention is complete and to fully inform those skilled in the art of the scope of the present invention, and the present invention is defined solely by the scope of the claims.

[0012] The terminology used herein is for the purpose of describing embodiments only and is not intended to limit the present invention. In this specification, the singular also includes the plural unless specifically stated otherwise. As used herein, the terms "comprises" and / or "comprising" do not exclude the presence or addition of one or more other components in addition to the mentioned components. Like reference numerals refer to like components throughout the specification, and "and / or" includes each and any combination of one or more of the mentioned components. Although "first", "second", etc. are used to describe various components, these components are not limited by these terms. These terms are only used to distinguish one component from another. Therefore, it should be understood that a first component mentioned below may also be a second component within the technical spirit of the present invention.

[0013] Unless otherwise defined, all terms (including technical and scientific terms) used herein may be used in their common sense to those skilled in the art to which the present invention pertains. Furthermore, terms defined in commonly used dictionaries are not to be interpreted ideally or excessively unless explicitly and specifically defined otherwise.

[0014] The present invention provides a pharmaceutical composition for preventing or treating musculoskeletal diseases, comprising leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen.

[0015] The leukocyte-rich platelet-rich plasma of the present invention contains 3 to 5 x 10 platelets. 8 / mL may be included.

[0016] The above Leukocyte-Rich Platelet-Rich Plasma (LRPRP) is not particularly limited as long as it is manufactured by a method commonly used in the field, and can be separated using a leukocyte and platelet component collection system, which is a standard and consistent method.

[0017] The above leukocyte-rich platelet-rich plasma (LPP) can be autologous or allogeneic, and refers to plasma with a high platelet content, separated from whole blood by centrifugation, and containing the highest platelet content at the bottom of the plasma. Leukocyte-rich platelet-rich plasma injection can be used for tissue regeneration due to the secretion of growth factors within the platelets.

[0018] Meanwhile, collagen is a light protein that constitutes animal bones, cartilage, teeth, tendons, skin, and fish scales. It exists as a fibrous solid with a complex, transverse structure. Collagen is the most common structural protein found in all mammals, accounting for approximately 30% of their total body weight. There are approximately 20 known types of collagen, with type 1 collagen accounting for the majority.

[0019] Atelocollagen, a type 1 collagen, supplements type 1 collagen, the main component of tendons, aiding tendon healing and reducing inflammation. Atelocollagen with a molecular weight of 1,000 to 20,000 is ideal, but can be used regardless of molecular weight. It facilitates cell adhesion during tissue formation and maintains a physical framework during scaffold manufacturing.

[0020] Atelocollagen removes the telo portion of collagen that causes an immune response, thereby eliminating the element that causes an immune response in the body. It is advantageous for cell attachment during tissue creation and can maintain a physical framework during scaffold manufacturing.

[0021] The composition of the present invention may contain leukocyte-rich platelet-rich plasma, thrombin and fibrinogen, and atelocollagen in a volume ratio of 1:1:0.75 to 1:1:0.5, respectively.

[0022] In one specific embodiment of the present invention, the composition of the present invention can be prepared by including 3 ml of atelocollagen, 4 ml of thrombin and fibrinogen, and 4 ml of leukocyte-rich platelet-rich plasma.

[0023] The composition of the present invention can alleviate re-tear of the rotator cuff that has undergone arthroscopic rotator cuff repair (ARCR).

[0024] After performing arthroscopic rotator cuff repair (ARCR), a composition according to an embodiment of the present invention was administered, and then shoulder joint function (American Shoulder and Elbow Society (ASES) score, the Constant score, the UCLA score, and Shoulder Pain and Disability Index (SPADI)) was checked. In addition, the re-tear rate for the rotator cuff was checked.

[0025] Additionally, the composition of the present invention can reduce pain caused by tendon damage.

[0026] In a specific embodiment of the present invention, when the composition of the present invention was administered, the degree of pain perception on the VAS was significantly improved, and when analyzing the disability scores of the arm, shoulder, and hand, it was confirmed that clinical function was restored through a decrease in the DASH score.

[0027] The Visual Analog Scale (VAS) is a method of assessing pain by giving patients a scale indicating their level of pain and asking them to select the facial expression that best matches their level of pain, or by having a specialist observe the patient's facial expression. This method measures pain by observing a continuous gradation from none, mild, moderate, and severe.

[0028] The Disabilities of the Arm, Shoulder, and Hand (DASH) score assessment is a questionnaire consisting of 38 items in total, including 30 items assessing movement performance, 4 optional work-related questions, and 4 sports and / or artistic activity-related questions. Each item is scored on a 5-point scale (1: no difficulty, 2: some difficulty, 3: moderate difficulty, 4: very difficult, 5: unable to do at all). The DASH is a highly reliable and valid assessment tool used to assess upper limb movement impairment in patients with musculoskeletal disorders.

[0029] The composition of the present invention can regenerate tendon tissue.

[0030] In a specific embodiment of the present invention, when the composition of the present invention was administered, the MRI analysis results showed that the rate of rotator cuff re-rupture was 11.1%, which was significantly lower than 28.3% in the group administered only atelocollagen, indicating that the composition of the present invention is excellent in restoring damaged rotator cuff tissue.

[0031] The musculoskeletal disease of the present invention may be at least one selected from the group consisting of lateral epicondylitis, medial epicondylitis, plantar fasciitis, rotator cuff tendon disease, Achilles tendon disease, patellar tendon disease, tenosynovitis, tendinopathy, tendinitis, tenosynovitis, tendon injury, tendon strain, tendon rupture, tendon tear, tendon avulsion, cruciate ligament injury, ankle ligament injury, collateral ligament injury, ligament rupture, ligament sprain, chondromalacia, osteoarthritis, osteoarthritis, chondrodysplasia, degenerative arthritis, rheumatoid arthritis, osteomalacia, osteitis fibrosa, and aplastic bone disease.

[0032] The above musculoskeletal disorders are health disorders caused by factors such as repetitive movements, inappropriate work postures, excessive use of force, sports injuries, vibrations, and temperatures, and refer to diseases that cause pain or impaired function in the ligaments, nerves, muscles, bones, tendons, intervertebral discs, and surrounding body tissues of the neck, shoulders, waist, and limbs.

[0033] The pharmaceutical composition according to the present invention can be formulated as an injection solution or a gel for local transplantation, and can treat musculoskeletal diseases more quickly and effectively than existing oral therapeutic drugs by directly administering it through the skin rather than orally.

[0034] The injection solution of the present invention may additionally include a sterilized aqueous solution, non-aqueous solvent, suspension, emulsion, lyophilized preparation, etc. that are harmless to the human body. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0035] The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.

[0036] The above pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined according to factors including the type and severity of the individual, age, sex, progression of the disease, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. The composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents. And it can be administered singly or in multiple doses.

[0037] The composition may be administered to mammals such as rats, mice, livestock, and humans via various routes. Any route of administration may be envisaged, including, for example, intramuscular injection or intravenous injection into tendons or ligaments.

[0038] The treatment of the present invention refers to an approach aimed at achieving beneficial or desirable clinical outcomes. For the purposes of the present invention, beneficial or desirable clinical outcomes include, but are not limited to, alleviation of symptoms, reduction in the extent of the disease, stabilization (i.e., non-worsening) of the disease state, delay or reduction in the rate of disease progression, improvement or temporary relief and remission (partial or total) of the disease state, whether detectable or undetectable.

[0039] The above treatment includes not only the treatment required for preventable disorders but also for disorders that have already occurred. Alleviating a disease means reducing the extent of the disease and / or undesirable clinical symptoms, and / or slowing or prolonging the time course of progression, compared to a case without treatment.

[0040] In addition, the present invention provides a method for preventing or treating a musculoskeletal disease, comprising a step of administering the pharmaceutical composition to an affected area of ​​an individual who has developed or is likely to develop a musculoskeletal disease.

[0041] The above musculoskeletal disease is at least one selected from the group consisting of lateral epicondylitis, medial epicondylitis, plantar fasciitis, rotator cuff tendon disease, Achilles tendon disease, patellar tendon disease, tenosynovitis, tendinopathy, tendinitis, tenosynovitis, tendon injury, tendon strain, tendon rupture, tendon tear, tendon avulsion, cruciate ligament injury, ankle ligament injury, collateral ligament injury, ligament rupture, ligament sprain, chondromalacia, osteoarthritis, osteoarthritis, chondrodysplasia, degenerative arthritis, rheumatoid arthritis, osteomalacia, osteitis fibrosa, and aplastic bone disease.

[0042] The above object means all animals, including rats, mice, and livestock, including humans, that can develop or be induced with musculoskeletal diseases.

[0043] Administration of the present invention means introducing the pharmaceutical composition into a subject.

[0044] Prevention of the present invention refers to any action that inhibits or delays the onset of a musculoskeletal disease by administering the pharmaceutical composition.

[0045] The treatment of the present invention refers to all actions that improve or benefit the symptoms of musculoskeletal diseases by administering the pharmaceutical composition.

[0046] In addition, the present invention provides a method for preparing a pharmaceutical composition for preventing or treating musculoskeletal diseases, comprising a step of mixing leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen.

[0047] The above platelet rich plasma (PRP) may be autologous or allogeneic, and refers to plasma with a high platelet content, separated from whole blood using centrifugation, and containing the most platelets at the bottom of the plasma.

[0048] Atelocollagen, a type 1 collagen, supplements type 1 collagen, the main component of tendons, aiding tendon healing and reducing inflammation. Atelocollagen with a molecular weight of 1,000 to 20,000 is ideal, but can be used regardless of molecular weight. It facilitates cell adhesion during tissue formation and maintains a physical framework during scaffold manufacturing.

[0049] Atelocollagen removes the telo portion of collagen that causes an immune response, thereby eliminating the element that causes an immune response in the body. It is advantageous for cell attachment during tissue creation and can maintain a physical framework during scaffold manufacturing.

[0050] The present invention provides a composition for treating musculoskeletal diseases, comprising leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen, and a method for preparing the same. The composition, when administered to a patient with a musculoskeletal disease, improves function and pain, reduces the size of a ruptured tendon, and induces structural regeneration of the tendon, thereby being useful as a pharmaceutical composition for preventing or treating musculoskeletal diseases. In addition, the composition can alleviate re-tear of a rotator cuff that has undergone arthroscopic rotator cuff repair (ARCR).

[0051] Figure 1 is a diagram showing the injection of a mixture of a composition comprising leukocyte-rich platelet-rich plasma, thrombin, fibrinogen, and atelocollagen of the present invention into the tendon-humeral attachment surface and the rotator cuff after rotator cuff repair.

[0052] Figure 2 is a diagram showing the results of MRI analysis before injection of a composition prepared by including leukocyte-rich platelet-rich plasma, thrombin, fibrinogen, and atelocollagen of the present invention into a partial rupture site of the anterior cruciate ligament (case 1).

[0053] Figure 3 is a diagram showing the results of MRI analysis 6 months after injection of a composition prepared by including leukocyte-rich platelet-rich plasma, thrombin, fibrinogen, and atelocollagen of the present invention into the site of partial rupture of the anterior cruciate ligament (case 2).

[0054] Hereinafter, the present invention will be described in more detail through the following examples and experimental examples. However, the scope of the present invention is not limited to the following examples and experimental examples, but includes modifications of technical concepts equivalent thereto.

[0055]

[0056] Manufacturing Example 1. Preparation of materials

[0057] Prepare leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen. Specifically, prepare 4 ml of leukocyte-rich platelet-rich plasma (LRPRP), 4 ml of thrombin and fibrinogen, and 3 ml of atelocollagen in a syringe.

[0058]

[0059] Manufacturing Example 2. Manufacturing of a mixed therapeutic agent of leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen.

[0060] Each of the leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen prepared in the syringe of the above manufacturing example 1 is connected to a connector suitable for the syringe inlet.

[0061] Begin mixing by shooting the WPC into a syringe containing thrombin, fibrinogen, and atelocollagen. Mix by shooting 5 to 10 times.

[0062] The mixed solution is typically about 1.5 cc and shaken well to remove air bubbles. The mixed treatment agent is then connected to a 21-gauge needle.

[0063]

[0064] Comparative Example 1. Preparation of an injection containing only atelocollagen

[0065] Prepare 1 cc of atelocollagen in each 3 cc syringe, and prepare an injection containing only atelocollagen.

[0066]

[0067] Example 1. Analysis of the Visual Analogue Pain Assessment Scale

[0068] The clinical results were evaluated by administering the injections prepared in the above manufacturing examples and comparative examples to damaged musculoskeletal tissues of patients diagnosed with lateral epicondylitis by a specialist.

[0069] More specifically, a total of 40 patients diagnosed with a rupture of the common extensor tendon (CET) of the elbow were randomly assigned to receive a mixed injection of leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen prepared in the above manufacturing example to 20 patients, and an injection containing only atelocollagen prepared in the above comparative example to 20 patients.

[0070] The Visual Analog Scale (VAS) is a method of assessing pain by giving patients a scale indicating their level of pain and asking them to select the facial expression that best matches their level of pain, or by having a physician observe the patient's facial expression. This method measures pain by observing a continuum of perceived pain ranging from none, mild, moderate, and severe.

[0071] The average follow-up period was 13.1 months, and the pain scores of the group administered the mixed injection of the present invention's Leukocyte-Rich Platelet-Rich Plasma (LRPRP), thrombin, fibrinogen, and atelocollagen (preparation example) and the group administered the injection of atelocollagen (comparative example) were compared and analyzed.

[0072]

[0073] Example 2. Analysis of disability scores for the arm, shoulder, and hand.

[0074] The clinical results were evaluated by administering the injections prepared in the above manufacturing examples and comparative examples to damaged musculoskeletal tissues of patients diagnosed with lateral epicondylitis by a specialist.

[0075] More specifically, a total of 40 patients diagnosed with a rupture of the common extensor tendon (CET) of the elbow were randomly assigned to receive a mixed injection of leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen prepared in the above manufacturing example to 20 patients, and an injection containing only atelocollagen prepared in the above comparative example to 20 patients.

[0076] Disabilities of the arm, shoulder, and hand (DASH) scores were analyzed.

[0077] The DASH is a 38-item questionnaire consisting of 30 items assessing motor skills, four optional work-related items, and four sports and / or artistic activities. Each item is scored on a 5-point scale (1: no difficulty, 2: some difficulty, 3: moderate difficulty, 4: very difficult, 5: completely unable). The DASH is a reliable and valid assessment tool that can be used to assess upper limb movement impairments in patients with musculoskeletal disorders.

[0078] The average follow-up period was 13.1 months, and the DASH scores of the group administered the mixed injection of the present invention's Leukocyte-Rich Platelet-Rich Plasma (LRPRP), thrombin, fibrinogen, and atelocollagen (preparation example) and the group administered the injection of atelocollagen (comparative example) were compared and analyzed.

[0079]

[0080] Example 3. Tennis elbow recovery analysis

[0081] The clinical results were evaluated by administering the injections prepared in the above manufacturing examples and comparative examples to damaged musculoskeletal tissues of patients diagnosed with lateral epicondylitis by a specialist.

[0082] More specifically, a total of 40 patients diagnosed with a rupture of the common extensor tendon (CET) of the elbow were randomly assigned to receive a mixed injection of leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen prepared in the above manufacturing example to 20 patients, and an injection containing only atelocollagen prepared in the above comparative example to 20 patients.

[0083] To analyze tennis elbow recovery, the Nirschl score was measured to assess pain relief, and the PRTEE score was measured to assess functional improvement.

[0084] The average follow-up period was 13.1 months, and the Nirschl score and PRTEE score of the group administered the mixed injection of leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen of the present invention (preparation example) and the group administered the injection of atelocollagen (comparative example) were compared and analyzed.

[0085]

[0086] Example 4. Comparative analysis of the size of ruptured tendons in MRI.

[0087] The clinical results were evaluated by administering the injections prepared in the above manufacturing examples and comparative examples to damaged musculoskeletal tissues of patients diagnosed with lateral epicondylitis by a specialist.

[0088] More specifically, a total of 40 patients diagnosed with a rupture of the common extensor tendon (CET) of the elbow were randomly assigned to receive a mixed injection of leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen prepared in the above manufacturing example to 20 patients, and an injection containing only atelocollagen prepared in the above comparative example to 20 patients.

[0089] Magnetic resonance imaging (MRI) analysis was performed 6 months after injection.

[0090]

[0091] Example 5. Clinical evaluation of arthroscopic rotator cuff repair (ARCR)

[0092] 1) Arthroscopic Rotator Cuff Repair (ARCR)

[0093] Arthroscopic rotator cuff repair was performed in the lateral decutibus position under general anesthesia. Among patients who visited our hospital with rotator cuff disease and had a rotator cuff tear greater than 10 mm confirmed by arthroscopy, arthroscopic rotator cuff repair was performed in 91 patients.

[0094] Specifically, systematic exploratory arthroscopy was performed in the glenohumeral joint and subacromial space, and appropriate treatment was administered when necessary. Frayed and torn material from the rotator cuff tear site was removed, and the anteroposterior and medial-lateral dimensions of the tear, the number of affected tendons, and the visual tendon grade were recorded.

[0095]

[0096] 2) A total of 91 patients who underwent arthroscopic rotator cuff repair (ARCR) for rotator cuff tears greater than 10 mm confirmed by arthroscopy were prospectively assigned to two groups: group 1, n=46 injected with a composition of leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen, or group 2, n=45 injected with atelocollagen alone.

[0097] Pain was assessed using a visual analog scale (VAS), and functional outcomes were assessed using the American Shoulder and Elbow Surgeon (ASES) score, the Constant Shoulder score, and range of motion at baseline, 3 months, 6 months, and 12 months.

[0098]

[0099] Example 6. Statistical processing

[0100] All experiments were repeated three times, and the average values ​​were analyzed using Duncan's multiple range test one-way ANOVA in SPSS software (Statistical Package for Social Science, Chicago, IL, USA), and p<0.05 was considered statistically significant.

[0101]

[0102] Experimental Example 1. Confirmation of improvement in function and pain in patients diagnosed with lateral epicondylitis.

[0103] Clinical outcomes were evaluated by administering the injections prepared in the above-mentioned manufacturing examples and comparative examples to damaged musculoskeletal tissues in patients diagnosed with lateral epicondylitis by a specialist. The average follow-up period was 13.1 months.

[0104]

[0105] 1-1. Results of analysis of the visual analog pain assessment scale

[0106] The Visual Analog Scale (VAS) is a method of assessing the degree of pain felt, and is measured based on a continuous change in the pain perceived by patients from none, mild, moderate, and severe.

[0107] The pain scores of the group administered the mixed injection of leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen of the present invention (preparation example) and the group administered the atelocollagen injection (comparative example) were compared and analyzed.

[0108] As a result, it was confirmed that the VAS score of the manufacturing example of the present invention (Leukocyte-Rich Platelet-Rich Plasma (LRPRP), thrombin, fibrinogen, and atelocollagen) decreased from 7.1 to 0.8, and the VAS score of the comparative example (atelocollagen administration group) decreased from 6.8 to 0.8 (p<0.001).

[0109] Through this, the results of analyzing the visual analog assessment scale for pain showed that the pain level of the VAS was significantly improved in both groups.

[0110]

[0111] 1-2. Analysis results of disability scores for arms, shoulders, and hands

[0112] Disabilities of the arm, shoulder, and hand (DASH) scores were analyzed.

[0113] DASH is a highly reliable and valid analysis tool for assessing impairments in upper limb movement in patients with musculoskeletal disorders.

[0114] The DASH scores of the group administered the mixed injection of leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen of the present invention (preparation example) and the group administered the atelocollagen injection (comparative example) were compared and analyzed.

[0115] As a result, it was confirmed that the DASH score of the manufacturing example of the present invention (Leukocyte-Rich Platelet-Rich Plasma (LRPRP), thrombin, fibrinogen, and atelocollagen) decreased from 23.2 to 1.9, and the DASH score of the comparative example (atelocollagen administration group) decreased from 24.0 to 1.7 (p<0.001).

[0116] Through this, the analysis of disability scores of the arm, shoulder, and hand showed that the function was significantly improved through a decrease in the DASH score in both groups (p<0.001).

[0117]

[0118] 1-3. Tennis Elbow Recovery Analysis

[0119] To analyze tennis elbow recovery, the Nirschl score was measured to assess pain relief, and the PRTEE score was measured to assess functional improvement.

[0120] The Nirschl score and PRTEE score of the group administered the leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen of the present invention (preparation example) and the group administered the injection of atelocollagen (PRP) (comparative example) were compared and analyzed.

[0121] As a result, the PRTEE score of the manufacturing example (Leukocyte-Rich Platelet-Rich Plasma (LRPRP), thrombin, fibrinogen, and atelocollagen) decreased from 90.1 to 4.6, and the PRTEE score of the comparative example (atelocollagen administration group) decreased from 91.2 to 4.7 (p<0.001).

[0122] In addition, it was confirmed that the Nirschl score of the manufacturing example of the present invention (Leukocyte-Rich Platelet-Rich Plasma (LRPRP), thrombin, fibrinogen, and atelocollagen) decreased from 6.0 to 1.1, and the Nirschl score of the comparative example (atelocollagen administration group) decreased from 6.2 to 1.0 (p<0.001).

[0123] Through this, the Nirschl score for evaluating pain relief and the PRTEE score for evaluating functional improvement were measured to analyze the recovery of tennis elbow, and the results showed that pain was significantly relieved and function was improved in both groups.

[0124] In addition, the present invention suggests that the combination treatment comprising Leukocyte-Rich Platelet-Rich Plasma (LRPRP), thrombin, fibrinogen, and atelocollagen is effective in alleviating, improving, and treating musculoskeletal disorders.

[0125]

[0126] Experimental Example 2. Confirmation of structural regeneration of ruptured tendons.

[0127] Clinical outcomes were evaluated by administering the injections prepared in the above-mentioned examples and comparative examples to injured musculoskeletal tissues in patients diagnosed with lateral epicondylitis by a specialist (Fig. 1). MRI (magnetic resonance imaging) analysis was performed 6 months after injection.

[0128] As a result, it was confirmed that the size of the ruptured tendon was significantly reduced 6 months after injecting the mixed treatment comprising leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen prepared in the manufacturing example of the present invention (Fig. 2).

[0129] Additionally, the proportion of patients whose ruptured tendon size was reduced was 85% when administered a combination treatment comprising Leukocyte-Rich Platelet-Rich Plasma (LRPRP), thrombin, fibrinogen, and atelocollagen manufactured in the manufacturing example of the present invention. On the other hand, when administered a treatment comprising only atelocollagen manufactured in the comparative example, it was 55% (p<0.05).

[0130]

[0131] Experimental Example 3. Pain Analysis

[0132] After performing arthroscopic rotator cuff repair surgery using the composition prepared from the manufacturing example of the present invention, pain was measured. Specifically, pain was assessed at rest, during movement, and at night using a 10-cm visual analog scale. The average pain score was calculated by averaging the three pain scores. Additionally, the most severe pain score was measured, and the results are shown in Table 1.

[0133] Variables Before treatment 6 months 12 months Pain at rest 3.00±1.50 1.50±1.20 0.00±0.00 Pain on movement 4.80±1.40 2.50±1.70 0.08±0.17 Pain at night 4.50±2.00 2.00±1.80 0.25±0.50 Average pain 4.00±1.60 2.00±1.50 0.11±0.22 Worst pain 5.80±1.60 3.00±2.00 0.25±0.50

[0134]

[0135] As shown in Table 1, after performing arthroscopic rotator cuff repair using the composition of the manufacturing example according to the present invention, all pain measurements gradually decreased, and it was found that the decrease was significantly lower than before the surgery. In particular, it was found that one year after the surgery, pain at rest, pain on movement, pain at night, average pain, and worst pain were either completely absent or significantly reduced by 10 to 20 times compared to before the surgery.

[0136]

[0137] Experimental Example 4. Analysis of Joint Range of Motion

[0138] Range of motion was measured using a protractor, including active forward flexion, abduction, external rotation, and internal rotation. Muscle strength was measured in the supraspinatus, infraspinatus, and subscapularis muscles using an electronic measuring device (CHS, CAS, Republic of Korea), and the results are presented in Table 2.

[0139] Variables Before treatment 6 months 12 months Forward flexion, degrees 130.00±40.00 140.00±1.50 150.00±15.00 Abduction, degrees 135.00±45.00 145.00±18.00 160.00±14.00 External rotation, degrees 42.00±12.00 43.00±11.00 45.00±13.00 Internal rotation, spinal level 10.00±2.50 9.50±2.00 10.00±2.20

[0140]

[0141] As shown in Table 2, forward flexion, abduction, external rotation, and internal rotation did not decrease or worsen compared to before surgery.

[0142]

[0143] Experimental Example 5. Evaluation of shoulder joint function

[0144] The function of the shoulder joint was evaluated using the American Shoulder and Elbow Society (ASES) score, the Constant score, the UCLA score, the Disability of the Shoulder-Hand Score (DASH), and the Shoulder Pain and Disability Index (SPADI), and is shown in Table 3.

[0145] Variables Before treatment 6 months 12 months American Shoulder and Elbow Society score 48.0±18.0 7 2.0±20.0 9 2.0±4.0 Constant score 48.0±9.0 6 6.0±14.0 8 4.0±7.0 UCLA score 16.5±5.0 2 6.0±5.0 3 2.0±3.0 Humerus-Shoulder-Hand Disability score 32.0±10.0 1 8.0±6.0 0.83±1.67 Shoulder Pain and Disability Index 44.0±18.0 2 6.0±18.0 1.69±2.89

[0146]

[0147] As shown in Table 3, it was confirmed that after performing arthroscopic rotator cuff repair using the composition of the manufacturing example according to the present invention, the shoulder joint function (American Shoulder and Elbow Society score (ASES score), Constant score (the Constant score), UCLA score, Disability of Shoulder-Hand Score DASH), and Shoulder Pain and Disability Index (SPADI)) significantly increased.

[0148]

[0149] While the embodiments of the present invention have been described above, the present invention is not limited to the above embodiments, but can be manufactured in various different forms. Those skilled in the art will understand that the present invention can be implemented in other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood to be illustrative in all respects and not restrictive.

Claims

1. A pharmaceutical composition for preventing or treating musculoskeletal diseases, comprising leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen.

2. In paragraph 1, The above leukocyte-rich platelet-rich plasma contains 3 to 5 x 10 platelets. 8 A pharmaceutical composition comprising / mL.

3. In paragraph 1, The composition is a pharmaceutical composition characterized in that it alleviates re-tear of a rotator cuff that has undergone arthroscopic rotator cuff repair (ARCR).

4. In paragraph 1, A pharmaceutical composition characterized in that the above musculoskeletal disease is at least one selected from the group consisting of lateral epicondylitis, medial epicondylitis, plantar fasciitis, rotator cuff tendon disease, Achilles tendon disease, patellar tendon disease, tenosynovitis, tendinopathy, tendinitis, tenosynovitis, tendon injury, tendon strain, tendon rupture, tendon tear, tendon avulsion, cruciate ligament injury, ankle ligament injury, collateral ligament injury, ligament rupture, ligament sprain, chondromalacia, osteoarthritis, osteoarthritis, chondrodysplasia, degenerative arthritis, rheumatoid arthritis, osteomalacia, osteitis fibrosa, and aplastic bone disease.

5. In paragraph 1, A pharmaceutical composition characterized in that the composition is formulated as an injection or a gel for local transplantation.

6. A method for preventing or treating a musculoskeletal disease, comprising administering the pharmaceutical composition of paragraph 1 to an affected area of ​​an individual other than a human who has developed or is likely to develop a musculoskeletal disease.

7. In paragraph 6, A method for preventing or treating a musculoskeletal disease, characterized in that the musculoskeletal disease is at least one selected from the group consisting of lateral epicondylitis, medial epicondylitis, plantar fasciitis, rotator cuff tendon disease, Achilles tendon disease, patellar tendon disease, tenosynovitis, tendinopathy, tendinitis, tenosynovitis, tendon injury, tendon strain, tendon rupture, tendon tear, tendon avulsion, cruciate ligament injury, ankle ligament injury, collateral ligament injury, ligament rupture, ligament sprain, chondromalacia, osteoarthritis, osteoarthritis, chondrodysplasia, degenerative arthritis, rheumatoid arthritis, osteomalacia, osteitis fibrosa, and aplastic bone disease.

8. A method for producing a pharmaceutical composition for preventing or treating musculoskeletal diseases, comprising a step of mixing leukocyte-rich platelet-rich plasma (LRPRP), thrombin, fibrinogen, and atelocollagen.

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