FREEZE-DRIED COLLAGEN-SPONGE-TYPE COMPOSITION FOR BONE REGENERATION

Abstract

The present invention relates to a collagen sponge-type composition for bone regeneration characterized in that the composition is manufactured by homogenizing a hydrated collagen; and a mixed solution of the lidocaine, epinephrine and thrombin, and then lyophilizing same. 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. Accordingly, the composition according to the present invention may be useful in the treatment of various diseases caused by bone remodeling failure.

Claims

1. A collagen sponge-type composition for bone regeneration characterized in that the composition is manufactured by homogenizing a hydrated collagen; and a mixed solution of the lidocaine, epinephrine and thrombin, and then lyophilizing same.

2. The collagen sponge-type composition for bone regeneration of claim 1, wherein the content of collagen in the hydrated collagen is 3 to 6% (w/v).

3. The collagen sponge-type composition for bone regeneration of claim 1, wherein the content of lidocaine in the mixed solution is 1 to 3% (w/v).

4. The collagen sponge-type composition for bone regeneration of claim 1, wherein the content of epinephrine in the mixed solution is 1: 50,000 to 200,000 (v/v) relative to lidocaine.

5. The collagen sponge-type composition for bone regeneration of claim 1, wherein the content of thrombin in the mixed solution is 1 to 3% (w/v).

6. The collagen sponge-type composition for bone regeneration of claim 1, wherein the ratio of the hydrated collagen and the mixed solution of the lidocaine, epinephrine, and thrombin is 1: 0.3 to 1.7 (w/w).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIGS. 1a-1c are pictures about a lyophilizing process.

[0035] FIGS. 2a-2e are pictures of applying the composition according to the present invention to the right molar region of the upper jaw.

[0036] FIGS. 3a-3j are pictures of applying the composition according to the present invention to the left front tooth region of the upper jaw.

BEST MODE FOR CARRYING OUT THE INVENTION

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

[0038] The present invention provides a collagen sponge-type composition for bone regeneration characterized in that the composition is manufactured by homogenizing a hydrated collagen; and a mixed solution of the lidocaine, epinephrine and thrombin, and then lyophilizing same.

[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 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] When a mixture of thrombin and lidocaine is implanted with the components of the bone marrow activation 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.

[0046] In addition, in view that the necessity for developments of bone graft using thrombin are continuously emerging, the present invention is useful in that it can utilize the initial process for bony tissues and various bone regeneration capacities of thrombin.

[0047] The collagen sponge-type composition for bone regeneration according to the present invention as described above is characterized in that the content of collagen in the hydrated collagen is 3 to 6% (w/v).

[0048] The collagen sponge-type 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).

[0049] The collagen sponge-type 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.

[0050] The collagen sponge-type composition for bone regeneration according to the present invention as described above is characterized in that the content of thrombin in the mixed solution is 1 to 3% (w/v).

[0051] The collagen sponge-type composition for bone regeneration according to the present invention as described above is characterized in that the ratio of the hydrated collagen and the mixed solution of the lidocaine, epinephrine and thrombin is 1: 0.3 to 1.7 (w/w).

[0052] 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.

[0053] Also, the homogenizing and lyophilizing methods of the hydrated collagen and the mixed solution of the lidocaine, epinephrine and thrombin may be used without particular limitation as long as they are widely known in the art to which the present invention belongs. The lyophilizing process is as shown in FIGS. 1a-1c.

[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.

EXAMPLES

Patients and Treatment

Manufacturing Process

[0055] 1.5 ml of a collagen-thrombin-lidocaine complex mixture (OSSCORE LMT collagen scaffold, Lidocaine-Maltodextrin-Thrombin collagen) was made by mixing thrombin (thrombin lyophilized powder 5000 unit—Reyon Phamaceutical 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 complex mixture was filled in a conical mold and lyophilized to produce a collagen sponge-type composition for bone regeneration according to the present invention.

Methods for Using the Composition

[0056] Through the cortical perforations made in the buccal cortical bone and the lingual cortical bone, the composition was filled in the bone marrow, while allowing the blood to be smoothly supplied to the bone marrow. After that, 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. The suture was made using Vicryl 4-0 absorbable suture material and maintained for at least 2 weeks.

[0057] 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.

Pictures of the Treatment Process

[0058] FIGS. 2a-2e are the pictures of applying the composition according to the present invention to the right molar region of the upper jaw, and FIGS. 3a-3j are pictures of applying the composition according to the present invention to the left front tooth region of the upper jaw.

[0059] 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.