INJECTABLE COMPOSITION FOR BONE REGENERATION

Abstract

The present invention relates to an injectable composition for bone regeneration, comprising 1 cc of 6% (w/v) hydrated collagen, 5000 units of thrombin, 0.5 ml of a mixed solution of lidocaine and epinephrine in which the epinephrine amount is 1:100,000 (v/v) on the basis of lidocaine, and acting by being injected into bone marrow. The composition according to the present invention activates undifferentiated cells in bone marrow and also activates the bone regeneration ability in bone marrow through the activation and differentiation of osteoclasts and osteoblasts, and can be a successful treatment method for medication-related osteonecrosis of the jaws (MRONJ) through a myeloid activation treatment method, uses various growth factors for myeloid activation and myeloid activation factors such as cytokines so as to allow for the development of treatment for the fundamental cause of MRONJ through a myeloid activation treatment method, and enables the complete regeneration of jaw bone conditions with respect to aesthetic and function, and thus can be effectively used in the treatment of various diseases caused by bone remodeling failure.

Claims

1. An injectable composition for bone regeneration acting by being injected into the bone marrow, the composition comprising: 1 cc of 6% (w/v) hydrated collagen; 5000 units of thrombin; and 0.5 ml of a mixed solution of lidocaine and epinephrine in which the content of epinephrine is 1:100,000 (v/v) relative to lidocaine.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0027] FIG. 1: a picture of a patient complaining pain, having a fistula in the skin on the mandible discharging pus.

[0028] FIG. 2: a panoramic picture indicating that the radiographic image and the radiopaque image, which show the osteonecrosis of bone marrow in the right mandible, are present in the boundary of osteonecrosis.

[0029] FIG. 3: a picture showing that pus is discharging into the oral cavity.

[0030] FIG. 4: a picture showing removing the alveolar crest and approaching the bone marrow to remove the necrotic bone marrow.

[0031] FIG. 5: a picture filling a therapeutic component for bone marrow activation (OSSCORE LMT collagen scaffold) into the bone marrow while allowing the blood to be smoothly supplied into the bone marrow through cortical perforations in the buccal cortical bone and the lingual cortical bone.

[0032] FIG. 6: a picture showing a suture made such that the bone marrow site and the bone marrow activation scaffold are not exposed using a continuous locking suture and an interrupted suture in combination.

[0033] FIG. 7a: a facial picture 6 months after surgery, showing that the skin fistula in the right mandible disappears.

[0034] FIG. 7b: a picture showing that, according to the doctor's opinion, no pus discharge is present in the oral cavity and that the primary suture has been successfully made at the suture site 6 months after surgery.

[0035] FIG. 7c: a cone beam 3D CT image before surgery and a cone beam 3D CT image 6 months after surgery.

[0036] FIGS. 8a, 8b and 8c: pictures showing the process of treating patients of other cases using the composition according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0037] Hereinafter, the present invention will be described in detail.

[0038] The present invention provides an injectable composition for bone regeneration, comprising hydrated collagen; and a mixed solution of lidocaine, epinephrine and thrombin.

[0039] The thrombin promotes proliferation of osteoblasts while inhibiting apoptosis thereof via activation of protease-activated receptor-1 (PAR-1). The promotion serves as osteoprotegerin (OPG) which inhibits collagen secretion and RANKL using osteoblasts. Thrombin plays a role at the initial stage of bone regeneration, allowing the differentiation of osteoblasts and the inhibition of osteoclasts at the initial stage. When lidocaine-thrombin-collagen, which is a bone marrow activation scaffold, is adequately mixed, pain or inflammation induction at the initial stage is reduced and vascularization is induced, and the vascularization positively stimulates the migration of undifferentiated stem cells.

[0040] Lidocaine is an amide-type local anesthetic synthesized by Swedish chemists Nils

[0041] Lofgren and Bengt Lundqvist in 1943. Lidocaine is slightly inferior in terms of action or duration to tetracaine known as the strongest local anesthetic. However, lidocaine is less toxic than tetracaine and has sufficient efficacy. Thus, lidocaine is a local anesthetic generally safe for use in local anesthesia. It may be used with the addition of epinephrine to prolong its effects as an anesthetic in a small amount and to suppress bleeding by hemostatic action during surgery, by contracting blood vessels around the anesthetized site. It has high fat-soluble protein binding capacity and prolonged duration, which allows good dissolution with rhBMP-2 and collagen proteins, and thus it may also be used as a solvent.

[0042] It may induce the formation into a sustained release capsule through ionic bonding in constituting a sustained-release type scaffold along with the effect of inhibiting initial inflammatory response caused by thrombin. Using lidocaine as a solvent provides various advantages in clinical uses.

[0043] First, it has the effect of significantly reducing the occurrence of pain caused by inflammatory conditions. Second, it has the effect of slowly releasing the drug which is dissolved in a lidocaine solvent.

[0044] In addition, as epinephrine-containing lidocaine is used, it may reduce the amount absorbed into the neighboring tissues during the maximum length of time of one and a half hours in which the drug is released.

[0045] Third, it neutralizes acidic collagen solution, which leads to a change into a hard lump in which the solidity of crystals overall increases. With these three roles and advantages, the function of a scaffold of the LT collagen can be provided.

[0046] When a mixture of thrombin and lidocaine is implanted with the components of the bone marrow activation scaffold of the present invention within the initial 2 hours, hemorrhage in bone marrow is decreased and minimum edema is exhibited, which indicate the bone curing.

[0047] As a need for the sustainable development of bone graft using thrombin has been fulfilled, an injectable bone regeneration composition utilizing the initial process for bony tissue and various bone regeneration capacities of thrombin is useful.

[0048] The injectable composition for bone regeneration according to the present invention as described above is characterized in that the collagen content of the hydrated collagen is 3 to 6% (w/v).

[0049] The injectable composition for bone regeneration according to the present invention as described above is characterized in that the content of lidocaine in the mixed solution is 1 to 3% (w/v).

[0050] The injectable composition for bone regeneration according to the present invention as described above is characterized in that the content of epinephrine in the mixed solution is 1:50,000 to 200,000 (v/v) relative to lidocaine.

[0051] The injectable composition for bone regeneration according to claim 1 of the present invention as described above is characterized in that the content of thrombin in the mixed solution is 1 to 3% (w/v).

[0052] The injectable composition for bone regeneration according to the present invention as described above is characterized in that the ratio of the hydrated collagen and a mixed solution of the lidocaine, epinephrine and thrombin is 1:0.3 to 1.7 (w/w).

[0053] The above-described content ratios are determined based on various experiments and experience of the inventors of the present invention, and are the optimal ratios for achieving the best effect of the present invention.

[0054] The composition according to the present invention, which activates undifferentiated cells in bone marrow and also activates bone regeneration capacity in bone marrow through the activation and differentiation of osteoclasts and osteoblasts, may be a method for successful treatment of medication-related osteonecrosis of the jaw (MRONJ) through a bone marrow activation treatment method, and may develop the treatment of the fundamental causes of MRONJ through a bone marrow activation treatment method using various growth factors for bone marrow activation and bone marrow activation factors such as cytokines and completely regenerate jaw bone conditions aesthetically and functionally. This will be described in detail with the following examples.

Case Patients and Treatment Methods

Case Presentation 1

[0055] A 56-year-old man with multiple myeloma was treated with Actonel, which is a bisphosphonate, as an injection for 3 years to treat cancer and prevent jawbone metastasis. The patient had pain in the right mandible and symptoms of pus discharge along with a fistula in the skin while yellow pus discharged into the oral cavity from a year ago. Thus, the relevant oral and maxillofacial surgery department in the hospital did continuous disinfection and drainage. However, pus discharged continuously and the patient complained pain (see FIG. 1).

[0056] Drainage was performed along with removal of dead bone tissue under five local anesthesias, and treatment was conducted through primary suture. However, skin fistula and pus discharge into the oral cavity continued. According to the classification guidelines of medication-related osteonecrosis of the jaw by the American Association of Oral and Maxillofacial Surgeons, the patient is diagnosed as Stage III. It could be confirmed from the panorama and cone beam CT images that osteonecrosis and osteomyelitis pus remained in the bone marrow (see FIG. 2).

[0057] Also, FIG. 3 shows that pus discharges into the oral cavity.

Treatment Method Using Composition of the Present Invention

[0058] An incision was made on the alveolar crest. A necrotic bone is removed using a round-shaped bur, while letting the buccal cortical bone and the lingual cortical bone remain to the maximum and removing the alveolar crest and approaching the bone marrow, thereby performing removal to the deepest site of the bone marrow as possible. The dead bone tissue in the bone marrow is removed after letting the buccal cortical bone, the lingual cortical bone, and the cortical bone present in the base wall of the mandible or maxilla remain. The cortical perforation is performed such that at least 4 to 5 perforations are made in each of the buccal cortical bone and the lingual cortical bone for each tooth position, allowing the blood to rise to the bone marrow (see FIG. 4).

[0059] In a way of maintaining the buccal cortical bone and the lingual cortical bone, and removing the alveolar crest site and approaching the bone marrow, the bone marrow tissue is removed while approaching the inferior alveolar nerve by completely removing the necrotic bone marrow tissue and protecting the inferior alveolar nerve.

[0060] The composition of the therapeutic agent is as follows: 1.5 ml of a collagen-thrombin-lidocaine complex mixture (OSSCORE LMT collagen scaffold, Lidocaine-Maltodextrin-Thrombin collagen) is made by mixing thrombin (thrombin lyophilized powder 5000 unit—Reyon Pharmaceutical Co., Ltd., pharmaceutical product extracted from bovine plasma, imported from Germany), lidocaine (using 0.5 ml of 1.8 ml containing epinephrine 1:100,000), and 1 cc of 6% hydrated collagen (OSSCORE Denhouse). The mixture is filled by a syringe in the defect site where the bone marrow was removed, and a lidocaine-thrombin (LT) solution is sprayed onto the plug-shaped collagen to fill the whole large volume of the bone marrow (see FIG. 5).

[0061] In other words, through the cortical perforations made in the buccal cortical bone and the lingual cortical bone, a bone marrow activation treatment component (OSSCORE LMT collagen scaffold) was filled in the bone marrow, while allowing the blood to be smoothly supplied to the bone marrow. The absorbent collagen membrane soaked with the lidocaine-thrombin solution was lined around the periosteum on the cortical bone, thereby protecting the bone marrow activation component.

[0062] After filing the bone marrow activation scaffold, the incision site was sutured using a continuous locking suture and an interrupted suture in combination, so that the bone marrow site is not exposed (see FIG. 6). The suture was made using Vicryl 4-0 absorbable suture material and maintained for at least 2 weeks.

[0063] The patient was administered with penicillin antibiotics and clindamycin antibiotics in combination, and the administration was retained for 7 days after surgery. The suture material of the loose portion was removed after 2 weeks or more, and the patient was allowed to take soft foods until the mucous membrane was completely sutured and not to take out his dentures. The patient was examined persistently at 1 month, 3 months, 6 months and 12 months, and the disease has not recurred for 5 years (see FIGS. 7-a, b, c).

[0064] FIG. 7a is a facial picture 6 months after surgery, showing that the skin fistula in the right mandible disappears. FIG. 7b is a picture from which it can be observed that, according to the doctor's opinion, there is no pus discharge into the oral cavity and that the primary suture has been successfully made at the suture site 6 months after surgery.

[0065] Further, FIG. 7c is a cone beam 3D CT image before surgery and a cone beam 3D CT image 6 months after surgery. The success of the surgical procedure was confirmed from the clinical observation and radiological observation. It could be confirmed that the necrotic tissue of the bone marrow was removed, and that the bone marrow and the cortical bone have been perfectly regenerated through the bone marrow activation treatment method.

[0066] The drawings for other patients who underwent similar treatment processes are provided in FIGS. 8a, 8b and 8c. From these examples, the effect of the composition according to the present invention could also be confirmed.