KR20190065079A - Pharmaceutical composition for treating rotator cuff tear - Google Patents

Abstract

The present invention relates to: a pharmaceutical composition for treating rotator cuff tear containing a recombinant human growth hormone (rhGH) as an active component; a kit comprising the same; and a method for treating rotator cuff tear.

Description

[0001] PHARMACEUTICAL COMPOSITION FOR TREATING ROTATOR CUFF TEAR [0002]

The present invention relates to a pharmaceutical composition for treating rotator cuff tear, and more particularly, to a pharmaceutical composition for treating rotator cuff tear, which contains recombinant human growth hormone (rhGH) as an active ingredient, A kit comprising the same, and a method of treating a rotator cuff tear.

Rotator cuff tear is characterized by the fact that the four muscles responsible for the stability and rotation of the shoulder (extremities, extremities, wishes and shoulders) and tendons are functioning due to various causes It is a disease that causes it to fall, become stiff or damaged, and severely tear it to pain. The main symptom of rotator cuff tear is pain when moving the affected part, or it starts with showing local tenderness and may lead to complete rupture if it gets worse. Rotator cuff tendon rupture usually occurs as a result of the development of inflammatory reaction due to excessive use of corticosteroids due to exercise or work, and degenerative changes caused by natural aging. In general, tendon damage occurs, and in particular, It is often ruptured.

Various non-surgical treatment methods have been used to treat rotator cuff tear. For example, a method of administering a non-steroidal anti-inflammatory analgesic (NSAID) or a topical application or a steroid injection therapy has been used as a drug therapy, but such a drug treatment has a short-term effect but a high recurrence rate and side effects. In addition, exercise therapy such as stretching to stabilize the range of motion of the passive joints and muscle strengthening exercises to stabilize the shoulder joint, reinforcement of the lubricating action through the hyaluronic acid supplementation of the joint synovial fluid by injection of the arthroscopic injection, In the case of conventional non-surgical treatment methods such as the same physical therapy method, there is a limitation that it can not be a therapeutic method for positively resolving the cause, which is limited to symptom relief such as reduction of pain.

In the treatment of rotator cuff tear, it is common practice to perform surgery such as resection and rotator cuff repair in cases where the above-mentioned non-surgical treatment does not improve or the area of rotator cuff tear becomes large .

However, failure to heal after rotator cuff repair remains one of the most common and well-known complications, and recent studies have reported an unacceptably high healing failure rate, especially in large tear sites . In addition, the rotator cuff tear leads to fatty infiltration of the rotator cuff muscle and fat infiltration is the most important of the anatomical and functional outcomes after rotator cuff repair It is one of the prognostic factors. Unfortunately, it is thought that surgical treatment alone can not stop or restore the progression of fat infiltration.

Insulin-like growth factor-1 (IGF-1), transforming growth factor beta, vascular endothelial growth factor, platelet-derived growth factor and basic fibroblast growth factor (FGF) are known to be involved in the healing process. IGF-1 is an important mediator in all stages of healing, especially inflammation, and stimulates tenoblastic activity, migration, and proliferation during tendon healing, It has been shown that it inhibits the enzymatic degradation of perilesional matrix molecules and directly regulates the tenoblastic function. This action of IGF-1 certainly assists in the tendon healing process. In addition, IGF-1 is known to regenerate skeletal muscle mass through satellite cell activation and is known to be associated with body mass index and visceral fat loss. Based on these properties, it can be assumed that IGF-1 can induce a reduction in fatty infiltration and improvement in muscle atrophy in the case of chronic degenerative rotator cuff tears.

Recombinant human growth hormone (rhGH), on the other hand, has been developed and used to treat patients with growth hormone (GH) deficiency, mainly by increasing the systemic levels of IGF-1 . Considering that circulating growth hormone (GH) and collagen content decrease in older age groups, where rotator cuff tears occur frequently, extrinsic systemic administration of rhGH / IGF-1 promotes collagen synthesis and rotator cuff tear cuff repair, and healing can be stimulated. Furthermore, since IGF-1 mediates loading-induced collagen synthesis, an increase in IGF-1 may improve tendon healing after rotator cuff repair . However, the effect of rhGH / IGF-1 exogenous administration on rotator cuff healing has not been demonstrated.

Under these circumstances, the present inventors have found that systemic administration of recombinant human growth hormone (rhGH) increases the serum IGF-1 concentration and is effective in the treatment of rotator cuff tear, especially after rotator cuff repair . Accordingly, the present inventors have confirmed that the recombinant human growth hormone (rhGH) has better effects in healing after rotator cuff repair by systemically administering the human growth hormone (rhGH) at a specific dose and administration period.

It is an object of the present invention to provide a stable and effective pharmaceutical composition for the treatment of rotator cuff tear, in particular after healing after rotator cuff repair.

It is also an object of the present invention to provide a therapeutic method for effectively treating rotator cuff tear by increasing the concentration of IGF-1 in serum using the above pharmaceutical composition.

.

The present invention provides a pharmaceutical composition for treating rotator cuff tear comprising Recombinant Human Growth Hormone (rhGH).

According to one embodiment of the present invention, the Recombinant Human Growth Hormone (rhGH) may increase the concentration of insulin-like growth factor-1 (IGF-1) in the serum.

According to one embodiment of the present invention, the pharmaceutical composition may contain the recombinant human growth hormone (rhGH) in a dose of 1 mg to 100 mg.

According to one embodiment of the present invention, the pharmaceutical composition may contain the recombinant human growth hormone (rhGH) in a dose of 6 mg to 10 mg.

According to one embodiment of the present invention, the pharmaceutical composition may be administered by systemic administration of the recombinant human growth hormone (rhGH) at a dose of 6 mg / week to 10 mg / week.

According to one embodiment of the present invention, the pharmaceutical composition may be administered by systemic administration of the recombinant human growth hormone (rhGH) at 7 mg / week to 9 mg / week.

According to one embodiment of the present invention, the pharmaceutical composition may be injected for healing after rotator cuff repair.

According to one embodiment of the present invention, the pharmaceutical composition may be a sustained release preparation.

According to one embodiment of the present invention, the pharmaceutical composition may be administered by subcutaneous injection.

The present invention also relates to pharmaceutical compositions comprising Recombinant Human Growth Hormone (rhGH); And instructions for administering the pharmaceutical composition in a systemic manner at a dose of 6 mg / week to 10 mg / week for the treatment of rotator cuff tear.

The present invention also provides a method of treating rotator cuff tear, comprising administering the pharmaceutical composition to a subject other than a human.

The pharmaceutical composition comprising the Recombinant Human Growth Hormone (rhGH) of the present invention is a stable and excellent effect in rotator cuff tear treatment, especially after healing after rotator cuff repair .

In addition, the present invention uses a pharmaceutical composition containing the above recombinant human growth hormone (rhGH) as an active ingredient for rotator cuff tear treatment, thereby increasing the concentration of IGF-1 in serum It has an excellent healing effect, is safe for long-term administration, and has little side effects. In particular, the present invention has the effect of restoring the original function as well as reducing the pain by regenerating the ruptured tendon tissue.

Hereinafter, the present invention will be described in detail in order to facilitate understanding of the present invention. Herein, terms and words used in the present specification and claims should not be construed to be limited to ordinary or dictionary meanings, and the inventor may appropriately define the concept of the term to describe its own invention in the best way. It should be construed as meaning and concept consistent with the technical idea of the present invention.

The present invention provides a pharmaceutical composition for treating rotator cuff tear comprising Recombinant Human Growth Hormone (rhGH).

The recombinant human growth hormone (rhGH) can increase the concentration of insulin-like growth factor-1 (IGF-1) in the serum, thereby improving the therapeutic effect of rotator cuff tear And can exhibit a stable and excellent effect in healing after rotator cuff repair.

As used herein, the term "recombinant human growth hormone " is understood to include all human growth hormones produced, expressed, raised or isolated by recombinant means.

The pharmaceutical composition for treating rotator cuff tear according to an embodiment of the present invention may contain a recombinant human growth hormone (rhGH) at a dose of 1 mg to 100 mg. More specifically, the pharmaceutical composition for treating rotator cuff tear may contain 1 mg to 50 mg, more specifically 6 mg to 10 mg of Recombinant Human Growth Hormone (rhGH).

The pharmaceutical composition for treating rotator cuff tear according to an embodiment of the present invention is administered by systemic administration of the recombinant human growth hormone (rhGH) at a dose of 1 mg / week to 30 mg / week . More specifically, the pharmaceutical composition for treating tarsal rotator cuff tear may be administered by systemically administering the recombinant human growth hormone (rhGH) at a dose of 1 mg / week to 10 mg / week, More specifically, it may be administered in a systemic administration manner at a dose of 6 mg / week to 10 mg / week. More preferably, the pharmaceutical composition for treating tarsal rotator cuff tear can be administered by systemically administering the recombinant human growth hormone (rhGH) at a dose of 7 mg / week to 9 mg / week .

The pharmaceutical composition for treating rotator cuff tear according to an embodiment of the present invention can be introduced to restore rotator cuff tear by non-surgical procedure, and after rotator cuff repair You can put it in for healing.

In addition, the pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not irritate the organism and does not interfere with the biological activity and properties of the administered compound. In the case of oral administration, a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a coloring matter and a perfume can be used. And stabilizers. In case of topical administration, a base, an excipient, a lubricant and a preservative may be used. Formulations of the pharmaceutical compositions of the present invention may be prepared in a variety of ways by mixing with a pharmaceutically acceptable carrier as described above. For example, in the case of an injection, it can be prepared in unit dosage ampoules or in multiple dosage forms. Etc., solutions, suspensions, tablets, pills, capsules, and sustained-release preparations. More preferably, the pharmaceutical composition for treating rotator cuff tear according to one embodiment of the present invention may be a sustained release preparation. In addition, the pharmaceutical composition for treating rotator cuff tear according to an embodiment of the present invention may be prepared by injection and administered by subcutaneous injection.

The present invention also relates to a pharmaceutical composition for treating rotator cuff tearing comprising Recombinant Human Growth Hormone (rhGH); And instructions for administering the pharmaceutical composition in a systemic manner at a dose of 6 mg / week to 10 mg / week for the treatment of rotator cuff tear.

The present invention also provides a method for treating rotator cuff tear, comprising administering the pharmaceutical composition for treatment of rotator cuff tear to a subject other than human.

< Experimental Example  One. Rotator  Clinical trial to confirm healing effect after repair>

1. Subject

Patients aged 40-75 years who had rotator cuff tears with tear size 3-5 cm after arthroscopic repair surgery were included. The tear size was first measured by preoperative magnetic resonance imaging (MRI) and arthroscopically confirmed by using a calibrated probe at the time of surgery.

Exclusion: diabetes (fasting blood glucose ≥126 mg / dL and hemoglobin A1C level ≥6.5%); Malignant tumor; Total bilirubin> 3 mg / dL; Alanine transaminase > 100 units / L; Aspartic acid transaminase > 100 units / L; Alkaline phosphatase > 300 units / L; Serum creatinine> 1.6 mg / dL; Cushing &apos; s syndrome or acromegaly; Record steroid injections or medication 3 months prior to surgery; GH injection or medication within 3 months of operation; Thyroid dysfunction; Oral estrogen therapy; Hypersensitivity to GH; Stiff shoulder before surgery; Systemic inflammatory disease; Acute multiple trauma requiring cardiopulmonary or abdominal surgery; Acute respiratory distress syndrome; Alcoholism or drug addiction surgery within 1 year; Previous surgery on the same shoulder; Severe arthritis (Hamada classification 21, step 3); Workers' compensation status. In addition, patients who underwent repair surgery for upper and lower lateral lesions or intraarticular lesions such as Bankart lesions, patients whose repair was incomplete in the footprint, irreversible tear or total thickness during surgery Of the patients were excluded.

2. Test method

Patients assigned to the treatment group were injected subcutaneously once per week for 12 weeks with sustained rhGH (Eutropin Plus® inj., LG Life Science, Korea). At this time, 4 mg of rhGH 4 mg group and 8 mg of rhGH 8 mg group were injected per week.

The first injection was performed on the 2nd or 3rd postoperative day. Patients then performed self-injection every week on the same day (every 1 week). A total of 12 injections were performed on the treatment group during a 12 week injection period. Patients assigned to the control group did not receive or inject rhGH (untreated group). In addition, during the study period, all patients were severely restricted with estrogen, methylphenidate, anabolic steroid, and systemic corticosteroid treatment. Patients were followed up at 2, 6, 12, and 24 weeks postoperatively. The time allowed was ± 4 days.

Twenty-six rhGH 4mg groups, 24 rhGH 8mg groups and 26 controls were available for final review and were followed up to final evaluation (24 weeks).

3. Evaluation of results

The primary efficacy end point was the healing failure rate and the secondary efficacy end point was fat infiltration, atrophy of the supraspinatus muscle, shoulder ROM, pain VAS, Elbow Surgeons [ASES] score), and serum IGF-1 levels.

Two evaluators interpreted cuff healing, fatty infiltration and atrophy of the supraspinatus muscle separately after surgery and compared them with each other. When the kappa value of the inter-rater agreement was less than 0.6, two evaluators reinterpreted the results. The final kappa value of cuff healing after surgery was 0.71 (p <0.001). When the interpretation of cuff healing was different among the evaluators, it was discussed until a final agreement reached, and the final agreement was used as the analysis.

[ Sugaya Classification Award  Healing failure rate]

Six months after the operation, the cuff healing status of the Sugaya group was examined by MRI examination: type I was thick enough to have homogeneously low strength; type II has a sufficient thickness with a partially high strength region; type III is less than half the thickness without discontinuity; type IV is minor discontinuity; type V is major discontinuity. Tyle IV and type V were defined as healing failure. The ratio of type IV to type V was compared in each group after healing.

[Fatty infiltration]

Fat infiltration was assessed using MRI, Goutallier (Goutallier D, Postel JM, Bernageau J, Lavau L, Voisin MC, Fatty muscle degeneration in cuff ruptures, Pre- and postoperative evaluation by CT scan, Clin Orthop Relat Res 1994: 78-83 J), which is established by the Fuchs (Fuchs B, Weishaupt D, Zanetti M, Hodler J, Gerber C. Fatty degeneration of the muscles of the rotator cuff: assessment by computed tomography versus magnetic resonance imaging. : 599-605).

[ Near-normal  Atrophy of the supraspinatus  muscle)]

The atrophy of the muscular atrophy was measured by Thomazeau (Thomazeau H, Rolland Y, Lucas C, Duval JM, Langlais F. Atrophy of the supraspinatus belly. Assessment by MRI in 55 patients with rotator cuff pathology. Acta Orthop Scand 1996; 67: 264-8. ). &Lt; / RTI &gt; That is, the ratio between the cross-sectional area of the su- paspinatus muscle and the supraspinatus fossa on the scapular Y-view.

[Pain VAS]

Pain VAS (Visual Analogue Scale) was scored preoperatively and at 12 weeks postoperatively.

[Function result score]

Functional outcome scores were assessed using Constant and ASES scores preoperatively and at final follow-up (24 weeks). Changes in shoulder and functional score after surgery were also evaluated.

[serum IGF -1 concentration]

Serum IGF-1 levels were measured at pre-operative and postoperative 6, 12 weeks follow-up and pre-operative IGF-1 levels.

4. Experimental results

(1) Failure rate of healing

In the control group without rhGH, the healing failure rate was 34.6%. On the other hand, the healing failure rate was 30.8% (p = 0.203) in the rhGH 4mg / week administration group and the healing failure rate was 16.7% in the rhGH 8mg / week administration group.

In addition, the results of healing failure rate were similar to those of type IV and type V in the postoperative healing state according to Sugaya classification. In the control group without rhGH, the failure rate of healing was 25.0%. In the rhGH 4mg / week administration group, the healing failure rate was 19.1%. In the rhGH 8mg / week administration group, the healing failure rate was 5.9%.

In other words, the failure rate of healing decreased compared to the control group when rhGH was administered. In particular, the failure rate of healing was significantly reduced in the group administered with rhGH at 8 mg / week.

On the other hand, none of the patients showed any significant side effects associated with rhGH injection, and all patients had no abnormality in vital signs.

(2) fatty infiltration

The fat penetration rate (FI) and Goutallier grade ≥3 values at 6 months postoperatively are shown in Table 1. Fat penetration rate (FI) was assessed according to Goutallier criteria, and Goutallier grade ≥3 indicates the proportion of patients with Goutallier grade ≥ 3. The values in parentheses indicate the standard deviation.

rhGH 4mg / week group rhGH 8mg / week group Control group FI 2.31 (0.74) 2.25 (0.79) 2.50 (0.86) Goutallier grade≥3 23.1% (6/26) 20.8% (5/24) 34.6% (9/26)

As shown in Table 1, when the rhGH was administered, the fat penetration rate (FI) was decreased and the Goutallier grade? 3 was decreased compared with the control group without rhGH.

(3) Pain VAS and function result score

Pain VAS and functional score are shown in Table 2. The values in parentheses indicate the standard deviation.

rhGH 4mg / week group rhGH 8mg / week group Control group Pain VAS Before surgery 52.2 (20.1) 50.3 (21.4) 42.2 (18.9) Three months later 27.4 (17.9) 30.0 (21.0) 32.1 (21.0) Constant score Before surgery 63.4 (15.5) 65.6 (13.3) 67.9 (17.9) 6 months later 76.7 (15.0) 72.5 (18.9) 76.7 (13.5) ASES score Before surgery 76.8 (12.5) 81.4 (17.1) 76.9 (15.8) 6 months later 87.8 (10.8) 90.4 (9.5) 87.8 (9.6)

Referring to Table 2 above, the pain VAS improved after the operation, and the pain VAS decreased more when the rhGH was administered than when the rhGH was not administered.

Constant score and ASES score also improved significantly after the operation, and rhGH treatment improved to the same level or higher compared with the control group without rhGH treatment.

(4) Serum IGF-1 concentration

Serum IGF-1 concentrations were measured and the results are shown in Table 3. The values in parentheses indicate the standard deviation.

rhGH 4mg / week group rhGH 8mg / week group Control group Before surgery (ng / mL) 143.0 (61.7) 162.0 (49.7) 196.8 (276.7) After 6 weeks (ng / mL) 196.8 (72.9) 279.4 (126.0) 186.3 (223.0) After 3 months (ng / mL) 190.5 (77.2) 246.4 (137.9) 173.9 (198.5)

Referring to Table 3, serum IGF-1 concentrations at 6 weeks and 3 months after surgery were higher in the group injected with rhGH than in the control group. In particular, the level of serum IGF-1 was significantly increased in the rhGH 8 mg / week group after rhGH injection as compared with the control group and rhGH 4 mg / week.

Through the present invention, we confirmed a dose-dependent increase in serum IGF-1 levels by rhGH injection. In addition, it was confirmed that the effect of healing of rotator cuffs was improved in the high dose rhGH injection group in which serum IGF-1 level was higher than that of the control group.

In addition, in the present invention, it was confirmed that the degree of muscle atrophy was improved after administration of rhGH at a high dose (8 mg / week) to a patient who underwent arthroscopic treatment of a rotator cuff tear of a large size.

Claims (11)

A pharmaceutical composition for treating rotator cuff tear comprising Recombinant Human Growth Hormone (rhGH).
The method according to claim 1,
Wherein said recombinant human growth hormone (rhGH) increases the concentration of insulin-like growth factor-1 (IGF-1) in the serum.
The method according to claim 1,
Wherein said recombinant human growth hormone (rhGH) is contained at a dose of 1 mg to 100 mg.
The method according to claim 1,
Wherein the recombinant human growth hormone (rhGH) is contained in a dose of 6 mg to 10 mg.
The method according to claim 1,
Wherein the recombinant human growth hormone (rhGH) is administered in a systemic manner at a dose of 6 mg / week to 10 mg / week.
The method according to claim 1,
Wherein the recombinant human growth hormone (rhGH) is administered in a systemic administration of 7 mg / week to 9 mg / week.
The method according to claim 1,
Wherein said pharmaceutical composition is injected for healing after rotator cuff repair.
The method according to claim 1,
The pharmaceutical composition is a sustained-release pharmaceutical composition for the treatment of rotator cuff tear.
The method according to claim 1,
Wherein said pharmaceutical composition is administered by subcutaneous injection.
A pharmaceutical composition comprising Recombinant Human Growth Hormone (rhGH); And
Instructions for administering the pharmaceutical composition in a systemic administration from 6 mg / week to 10 mg / week for the treatment of rotator cuff tear.
10. A method for treating rotator cuff tear, comprising administering the composition of any one of claims 1 to 9 to a subject other than human.