Patent Description:
Bleeding is one of the obstacles that make surgery difficult, and stabilizing the bleeding is very important because a lot of blood loss may affect normal body functions. Hemostasis requires the use of a blood clotting agent, gauze, or a blood vessel occlusion device such as a hemostatic clamp. This type of hemostatic material utilizes the property of slowly activating the coagulation factors or narrowing the cut blood vessels. Numerous hemostatic materials have already been developed for soft tissue bleeding applications, but there is a limitation that cannot be applied to bone bleeding. This is because the blood flow hinders the stable formation of blood clots during bone hemorrhage, and the bone tissue itself maintains its structure through this condition. In the past, there have been many hemostatic materials that remain undecomposed in the body because non-biocompatible materials are included therein. As a result of many studies, it was confirmed that a hemostatic material had a negative effect on bone regeneration when components of the bone hemostatic material remained undecomposed.

<CIT> relates to a hemostatic agent and a using method thereof. The hemostatic agent includes reverse micelles having an outer hydrophobic shell of suitable biocompatible hydrophobic components such as alkanes, and hydrophilic positively charged chitosan moieties enclosed within the hydrophobic shell, thereby attenuating or stopping bleeding. However, there is a limitation in that <CIT> does not disclose the application to bone hemostasis and the immediate hemostasis by means of a physical protective film.

<CIT> relates to a novel hemostatic agent including a mussel adhesive protein and a method for manufacturing an absorbent bone hemostatic agent using the same. <CIT> does not disclose the application to bone hemostasis. A lot of ancillary materials such as nanofiber hemostatic dressings, hemostatic sponges and patches are required, and the hemostatic agent is difficult to decompose in vivo, and thus it is highly likely to hinder bone formation. Therefore, there is a need to develop a bone hemostatic agent that is quickly absorbed and decomposed without hindering bone formation and has an immediate hemostatic effect. <CIT> discloses a bioabsorbable composition for bone hemostasis comprising <NUM> to <NUM> parts by weight of poloxamer <NUM>, <NUM> to <NUM> parts by weight of poloxamer <NUM> and <NUM> to <NUM> parts by weight of a polyethyleneglycol-polypropyleneglycol random copolymer.

Therefore, the present invention has been completed with the goal of developing a bone hemostatic agent that has an immediate hemostatic effect and minimally affects bone regeneration.

An object of the present invention is to solve the above-described problems.

An object of the present invention is to provide an absorbent bone hemostatic material composition, which includes a minimal composition harmless to a human body and is quickly absorbed and decomposed in vivo, and thus does not hinder bone regeneration, and an absorbent bone hemostatic material manufacturing method using the same.

Another object of the present invention is to provide an absorbent bone hemostatic material composition having an immediate hemostatic effect and an absorbent bone hemostatic material manufacturing method using the same.

In order to achieve the above-described objects of the present invention and achieve the characteristic effects of the present invention described below, the characteristic construction of the present invention is as follows.

An absorbent bone hemostatic material composition according to the present invention includes <NUM> to <NUM> parts by weight of polyethylene glycol-ran-propylene glycol based on <NUM> to <NUM> parts by weight of poloxamer.

The poloxamer has a weight average molecular weight of <NUM>,<NUM> to <NUM>,<NUM>, and the polyethylene glycol-ran-propylene glycol has a weight average molecular weight of <NUM>,<NUM> to <NUM>,<NUM>, and preferably <NUM>,<NUM> to <NUM>,<NUM>.

The absorbent bone hemostatic material composition may have a hardness of <NUM> to <NUM> HS at a temperature of <NUM> to <NUM>.

The absorbent bone hemostatic material composition may be biodegradable <NUM> to <NUM>% within <NUM> to <NUM> hours in a phosphate buffer solution (PBS) of pH <NUM> to <NUM> under a temperature of <NUM> to <NUM>.

The absorbent bone hemostatic material composition may have a hemostatic time of <NUM> to <NUM> seconds.

The absorbent bone hemostatic material composition may have an adhesive strength of <NUM> to <NUM> N.

The poloxamer may have a melting point of <NUM> to <NUM>.

After the absorbent bone hemostatic material composition is used, a bone mineral density (BMD) may be restored to <NUM> to <NUM>.

An absorbent bone hemostatic material may include the absorbent bone hemostatic material composition according to the present invention.

The absorbent bone hemostatic material may include at least one formulation selected from semi-solid and solid.

The absorbent bone hemostatic material may include a recess at a central portion.

On the other hand, the present invention provides an absorbent bone hemostatic material manufacturing method. Specifically, an absorbent bone hemostatic material manufacturing method including: an adding step of adding <NUM> to <NUM> parts by weight of polyethylene glycol-ran-propylene glycol into a reactor based on <NUM> to <NUM> parts by weight of poloxamer; a heating step of heating the poloxamer and the polyethylene glycol-ran-propylene glycol to <NUM> to <NUM>; a stirring step of stirring the poloxamer and the polyethylene glycol-ran-propylene glycol; and a cooling step of cooling the poloxamer and the polyethylene glycol-ran-propylene glycol by pouring the poloxamer and the polyethylene glycol-ran-propylene glycol into a mold.

The cooling step may be performed for <NUM> to <NUM> minutes at a temperature of -<NUM> to <NUM>.

The poloxamer has a weight average molecular weight of <NUM>,<NUM> to <NUM>,<NUM>, and the polyethylene glycol-ran-propylene glycol has a weight average molecular weight of <NUM>,<NUM> to <NUM>,<NUM>, and preferably, <NUM>,<NUM> to <NUM>,<NUM>.

An absorbent bone hemostatic material composition according to the present invention provides an effect of being quickly absorbed and decomposed in vivo.

An absorbent bone hemostatic material composition according to the present invention provides an immediate hemostatic effect.

An absorbent bone hemostatic material composition according to the present invention has an effect of being easily molded in a desired shape because the hardness thereof changes according to a temperature. Therefore, an effect of increasing adhesion is provided.

An absorbent bone hemostatic material composition according to the present invention includes a minimal material, is harmless to a human body, and is properly mixed to provide an effect that a finished product retains the efficacy of a raw material.

The present invention will be described with reference to specific embodiments and the accompanying drawings. The embodiments will be described in detail in such a manner that the present invention may be carried out by those of ordinary skill in the art. It should be understood that various embodiments of the present invention are different, but need not be mutually exclusive. For example, certain shapes, structures, and features described herein may be implemented in other embodiments without departing from the scope of the present invention in connection with one embodiment. In addition, it should be understood that the locations or arrangement of individual components in the embodiments can be changed without departing from the scope of the present invention. Therefore, the following detailed description is not to be taken in a limiting sense, and the scope of the present invention is to be limited only by the appended claims, if properly explained. In the drawings, similar reference numerals refer to the same or similar functions throughout various aspects.

Hereinafter, embodiments of the present invention will be described with reference to the accompanying drawings, so that those of ordinary skill in the art can easily carry out the present invention.

An absorbent bone hemostatic material composition according to the present invention is a bone hemostatic material for immediate hemostasis. The present invention suggests an absorbent bone hemostatic material composition, which includes a minimal composition harmless to a human body and is quickly absorbed and decomposed in vivo, and thus does not hinder bone regeneration, and an absorbent bone hemostatic material manufacturing method using the same.

In the past, there was a problem that a hemostatic effect of a raw material could not be exhibited <NUM>% in a finished product because the physical properties of the raw material and the physical properties of the finished product were different due to the reaction of each material during mixing. In addition, a lot of unnecessary materials are included so as to increase the hemostatic ability. In many cases, incompatible materials are included. Thus, bone regeneration is hindered. In particular, "BONE WAX" of Ethicon/J&J is applied to a cut surface to provide a physical protective film. However, "BONE WAX" is non-absorbent and remains on the treated region continuously. Therefore, there is a problem that inhibits the induction and growth of normal bone cells.

The absorbent bone hemostatic material composition according to the present invention includes a minimum of a bioabsorbent composition with high biocompatibility, and thus is almost harmless to a human body and quickly absorbed and decomposed. A physical protective film is provided by applying the absorbent bone hemostatic material composition to the bone surface at the time of fracture and bone cutting. Therefore, the absorbent bone hemostatic material composition has an immediate hemostatic effect and does not hinder normal bone regeneration.

The absorbent bone hemostatic material composition according to the present invention includes poloxamer and polyethylene glycol-ran-propylene glycol.

According to the present invention, the polyethylene glycol-ran-propylene glycol is included in an amount of <NUM> to <NUM> parts by weight based on <NUM> to <NUM> parts by weight of the poloxamer.

In addition, according to the present invention, the poloxamer has a weight average molecular weight of <NUM>,<NUM> to <NUM>,<NUM>. When the poloxamer has a weight average molecular weight of less than <NUM>,<NUM> or greater than <NUM>,<NUM>, it may be difficult to obtain the absorbent bone hemostatic material composition of the present invention that has an effect of immediate hemostasis and quick absorption and decomposition.

The polyethylene glycol-ran-propylene glycol has a weight average molecular weight of <NUM>,<NUM> to <NUM>,<NUM>, and preferably <NUM>,<NUM> to <NUM>,<NUM>. When the polyethylene glycol-ran-propylene glycol has a weight average molecular weight of less than <NUM>,<NUM> or greater than <NUM>,<NUM>, it may be difficult to obtain the absorbent bone hemostatic material composition of the present invention that has an effect of immediate hemostasis and quick absorption and decomposition. Therefore, the above-described effect is more preferably provided in the range of <NUM>,<NUM> to <NUM>,<NUM>.

According to the present invention, the polyethylene glycol-ran-propylene glycol is included in an amount of <NUM> to <NUM> parts by weight based on <NUM> to <NUM> parts by weight of the poloxamer. Preferably, the polyethylene glycol-ran-propylene glycol may be included in an amount of <NUM> parts by weight based on <NUM> parts by weight of the poloxamer. When the poloxamer is included in an amount of less than <NUM> parts by weight or greater than <NUM> parts by weight, the absorbent bone hemostatic material composition may not be mixed properly. Due to this, it may be difficult to obtain immediate bone hemostatic performance and satisfactory absorption or decomposition performance. When the polyethylene glycol-ran-propylene glycol is included in an amount of less than <NUM> parts by weight or greater than <NUM> parts by weight, a harmonious absorbent bone hemostatic material composition may not be prepared. Due to this, immediate hemostatic performance and the ability to be absorbed or decomposed in vivo may be reduced.

In addition, the poloxamer and the polyethylene glycol-lan-propylene glycol can be mixed properly. When the poloxamer and the polyethylene glycol-lan-propylene glycol are mixed properly, it is meaningful in that the characteristics of the raw materials can be maintained. Referring to the FT-IR result of <FIG>, it can be confirmed that the absorbent bone hemostatic material composition and the bone hemostatic material according to the present invention are properly mixed with the raw materials, and thus the performance of the composition is equally shown even in the bone hemostatic material.

Referring to <FIG>, the absorbent bone hemostatic material composition according to the present invention may have a hardness of <NUM> to <NUM> HS at a temperature of <NUM> to <NUM>, preferably <NUM> to <NUM> HS at a temperature of <NUM> to <NUM> and <NUM> to <NUM> HS at a temperature of <NUM> to <NUM>. When the hardness is less than <NUM> HS at a temperature of <NUM> to <NUM>, the absorbent bone hemostatic material composition may be so soft that it does not properly adhere to the bone. This may make it difficult to obtain satisfactory immediate hemostatic performance. In addition, when the hardness is greater than <NUM> HS at a temperature of <NUM> to <NUM>, the absorbent bone hemostatic material composition may be so hard that it is difficult to mold the shape as desired. This may make it difficult to properly adhere to the bone and may make it difficult to obtain a satisfactory immediate hemostatic performance effect.

Referring to <FIG> and <FIG>, in the absorbent bone hemostatic material composition according to the present invention, biodegradation may be performed <NUM> to <NUM>% within <NUM> to <NUM> hours in a phosphate buffer solution (PBS) of pH <NUM> to <NUM> under a temperature of <NUM> to <NUM>. Preferably, biodegradation may be performed <NUM>% within <NUM> hours, <NUM>% within <NUM> hours, and more preferably <NUM>% or more within <NUM> hours. When biodegradation is performed for more than <NUM> hours in a phosphate buffer solution (PBS) of pH <NUM> to <NUM> under a temperature of <NUM> to <NUM>, an immune response of an immune system to foreign matters may occur, which may hinder bone formation.

In addition, in the absorbent bone hemostatic material composition according to the present invention, it may take <NUM> to <NUM> seconds for hemostasis. The bone hemostatic material, which is manufactured by including <NUM> to <NUM> parts by weight of the polyethylene glycol-ran-propylene glycol based on <NUM> to <NUM> parts by weight of the poloxamer, is more effective in the immediate hemostatic ability, compared with the conventional bone hemostatic material. The results thereof are shown in <FIG>.

According to the present invention, the absorbent bone hemostatic material composition has an adhesive strength of <NUM> to <NUM> N. When the adhesive strength is less than <NUM> N, it is difficult to obtain a satisfactory immediate hemostatic effect at a bleeding site.

According to the present invention, the poloxamer has a melting point of <NUM> to <NUM>. When the melting point is lower than <NUM>, the bone hemostatic material is liquefied at body temperature, and thus it is difficult to obtain a hemostatic effect. When the melting point is higher than <NUM>, it is necessary to perform a melting process with high heat in a manufacturing process, and thus the molecules of the poloxamer and the polyethylene glycol-lan-propylene glycol may not be arranged properly. Due to this, it may be difficult to obtain the absorbent bone hemostatic material composition having the immediate hemostatic performance and the quick absorption and decomposition performance.

According to the present invention, after using the absorbent bone hemostatic material composition, a bone mineral density (BMD) may be <NUM> to <NUM>, and preferably <NUM>. Referring to <FIG>, photographs comparing the bone formation ability of the absorbent bone hemostatic material composition according to the present invention and a comparative example can be confirmed.

According to the present invention, an absorbent bone hemostatic material includes the absorbent bone hemostatic material composition.

According to the present invention, the absorbent bone hemostatic material includes at least one formulation selected from semi-solid and solid.

In addition, the absorbent bone hemostatic material may include recesses in a central portion. As described above, since the recesses are formed in a line in the central portion, the absorbent bone hemostatic material can be easily removed.

On the other hand, according to the present invention, an absorbent bone hemostatic material manufacturing method using an absorbent bone hemostatic material composition is provided. The absorbent bone hemostatic material manufacturing method according to the present invention includes: an adding step of adding <NUM> to <NUM> parts by weight of polyethylene glycol-ran-propylene glycol into a reactor based on <NUM> to <NUM> parts by weight of poloxamer; a heating step of heating the poloxamer and the polyethylene glycol-ran-propylene glycol to <NUM> to <NUM>; a stirring step of stirring the poloxamer and the polyethylene glycol-ran-propylene glycol; and a cooling step of cooling the poloxamer and the polyethylene glycol-ran-propylene glycol by pouring the poloxamer and the polyethylene glycol-ran-propylene glycol into a mold.

According to the present invention, in the heating step, the poloxamer and the polyethylene glycol-ran-propylene glycol may be preferably melted at a temperature of <NUM>. When the heating temperature is lower than <NUM>, the poloxamer and the polyethylene glycol-lan-propylene glycol may not be stirred properly. Due to this, it is difficult to obtain an absorbent bone hemostatic material composition having an immediate hemostatic effect. When the heating temperature is higher than <NUM>, the molecules of the poloxamer and the polyethylene glycol-lan-propylene glycol may not be arranged properly. Due to this, it may be difficult to obtain an absorbent bone hemostatic material composition having immediate hemostatic performance and quick absorption and decomposition performance.

According to the present invention, the cooling step may be performed at a temperature of -<NUM> to <NUM> for <NUM> to <NUM> minutes. Preferably, the cooling step may be performed at a temperature of <NUM> for <NUM> minutes. When the cooling step is performed at a temperature of lower than -<NUM> or higher than <NUM>, it may be difficult to obtain the absorbent bone hemostatic material composition according to the present invention because the molecules are not arranged properly. In addition, even when the cooling step is performed for less than <NUM> minutes, it may be difficult to obtain the absorbent bone hemostatic material composition having satisfactory immediate hemostasis and quick absorption and decomposition effects.

In addition, according to the present invention, the poloxamer has a weight average molecular weight of <NUM>,<NUM> to <NUM>,<NUM>. When the poloxamer has a weight average molecular weight of less than <NUM>,<NUM> or greater than <NUM>,<NUM>, it may be difficult to obtain the absorbent bone hemostatic material composition of the present invention that has immediate hemostasis and quick absorption and decomposition effects.

According to the present invention, the polyethylene glycol-ran-propylene glycol has a weight average molecular weight of <NUM>,<NUM> to <NUM>,<NUM>, and preferably <NUM>,<NUM> to <NUM>,<NUM>. When the polyethylene glycol-ran-propylene glycol has a weight average molecular weight of less than <NUM>,<NUM> or greater than <NUM>,<NUM>, it may be difficult to obtain the absorbent bone hemostatic material composition of the present invention that has an effect of immediate hemostasis and quick absorption and decomposition. Therefore, the above-described effect is more preferably provided in the range of <NUM>,<NUM> to <NUM>,<NUM>.

Referring to <FIG>, the absorbent bone hemostatic material composition according to the present invention may have a hardness of <NUM> to <NUM> HS at a temperature of <NUM> to <NUM>, preferably <NUM> to <NUM> HS at a temperature of <NUM> to <NUM> and <NUM> to <NUM> HS at a temperature of <NUM> to <NUM>. When the hardness is less than <NUM> HS at a temperature of <NUM> to <NUM>, the absorbent bone hemostatic material composition may be too soft and thus may not be properly bonded to the bone. This may make it difficult to obtain satisfactory immediate hemostatic performance. In addition, when the hardness is greater than <NUM> HS at a temperature of <NUM> to <NUM>, the absorbent bone hemostatic material composition may be so hard that it is difficult to mold the shape as desired. This may make it difficult to properly adhere to the bone and may make it difficult to obtain a satisfactory immediate hemostatic performance effect.

Referring to <FIG> and <FIG>, the absorbent bone hemostatic material composition according to the present invention is biodegradable <NUM> to <NUM>% within <NUM> to <NUM> hours in a phosphate buffer solution (PBS) of pH <NUM> to <NUM> under a temperature of <NUM> to <NUM>. Preferably, the absorbent bone hemostatic material composition is biodegradable <NUM>% within <NUM> hours, <NUM>% within <NUM> hours, and more preferably <NUM>% or more within <NUM> hours. When biodegradation is performed for more than <NUM> hours in a phosphate buffer solution (PBS) of pH <NUM> to <NUM> under a temperature of <NUM> to <NUM>, an immune response of an immune system to foreign matters may occur, which may hinder bone formation. Therefore, it can be confirmed that the case according to the present invention has a preferable biodegradability.

According to the present invention, the adhesive strength of the absorbent bone hemostatic material composition is <NUM> to <NUM> N. When the adhesive strength is less than <NUM> N, it is difficult to obtain a satisfactory immediate hemostatic effect.

Hereinafter, the structure and operation of the present invention will be described in more detail with reference to preferred examples of the present invention. However, these example are shown by way of illustration and should not be construed as limiting the present invention in any way.

Since contents not described herein can be sufficiently technically inferred by those of ordinary skill in the art, descriptions thereof will be omitted.

<NUM> parts by weight of poloxamer and <NUM> parts by weight of polyethylene glycol-ran-propylene glycol were added to a reactor. The added poloxamer and polyethylene glycol-ran-propylene glycol were melted at a temperature of <NUM>. After sufficient stirring, the poloxamer and the polyethylene glycol-ran-propylene glycol were poured into a mold, placed into a cooler, and cooled at a temperature of <NUM> for <NUM> minutes to prepare a solidified absorbent bone hemostatic material (TAB-WAX).

Comparative Example <NUM> was an Ostene hemostatic material from Ceremed/Baxter.

Comparative Example <NUM> was a BONEWAX hemostatic material from Ethicon/J&J.

The absorbent bone hemostatic material of the present invention manufactured in Example <NUM> has to serve as a physical barrier at a treated site for a certain time so as to stop bone bleeding, and gradually melt and disappear from the treated site after a certain time for normal bone healing. For this test, the following experiment was performed.

For the experiment, <NUM> of the absorbent bone hemostatic material composition manufactured in Example <NUM> was precisely weighed in <NUM> of Phosphate buffer solution (PBS) (pH <NUM>) at <NUM> and placed into a conical tube. The absorbent bone hemostatic material composition was taken out from a shaking bath (<NUM>, <NUM> RPM) at a set time, and the amount of the bone hemostatic material that was decomposed and reduced was measured as a weight loss rate. Table <NUM> shows the results of calculating the degree of decomposition according to Equation <NUM> below. In addition, the results thereof are shown in <FIG>.

As described in Table <NUM>, referring to <FIG> and <FIG>, it was confirmed that Example <NUM> (TAB-WAX), which is the absorbent bone hemostatic material according to the present invention, achieved a biodegradability of <NUM>% within <NUM> hours, compared with Comparative Example <NUM> (BONEWAX). On the other hand, Comparative Example <NUM> was not decomposed over time and showed a negative value. Therefore, it can be seen that the sample weight increased after <NUM> hours, and an immune system recognized it as a foreign matter in a human body, causing a reaction such as an inflammatory reaction.

An appropriate amount of the absorbent bone hemostatic material of the present invention manufactured in Example <NUM> should be cut out, kneaded by hand, and then applied to a site to be treated. Therefore, hardness directly related to kneading properties was measured for each temperature, and the results thereof are shown in Table <NUM> and the graph of <FIG>.

As shown in Table <NUM>, it can be expected that, when kneaded by hand, the absorbent bone hemostatic material according to the present invention can be kneaded more conveniently due to the body temperature of the user's hand.

After Example <NUM> and Comparative Example <NUM> were applied to a lesion site, the time taken until hemostasis was measured. The time of hemostasis was evaluated and recorded in seconds from <NUM> seconds to <NUM> seconds through photography and was divided into five sections (section <NUM>: <NUM>-<NUM> seconds [immediate], section <NUM>: <NUM>-<NUM> seconds, section <NUM>: <NUM>-<NUM> seconds, section <NUM>: <NUM>-<NUM> seconds, and section <NUM>: <NUM> seconds or more). This is shown in <FIG>.

When comparing Example <NUM> (TAB-WAX) coated with the sample with Comparative Example <NUM> (BONEWAX), Example <NUM> was <NUM>% and Comparative Example <NUM> was <NUM>%. Therefore, it was confirmed that the absorbent bone hemostatic material according to the present invention had excellent immediate hemostatic performance. There was no subject in which hemostasis was delayed for more than <NUM> seconds, whereas a rate of <NUM>% was confirmed in Comparative Example <NUM>.

Referring to <FIG>, the first-row photograph of autopsy photographs for each group is a photograph immediately shown after skin and periosteum were sequentially incised, and the second-row photograph is a photograph taken against a white background by cutting a rat skull with a size of about <NUM> x <NUM> around a defect.

As a result of visual evaluation, in the case of Example <NUM>, there was no formulation remaining from the third day after surgery, but in the case of Comparative Example <NUM> (BONEWAX), it was confirmed that the formulation remained as it is until <NUM> weeks.

In order to evaluate the degree of bone formation ability (bone healing), a bone mineral density (BMD) and a bone volume ratio (BVR) were measured by analyzing 3D images of a rat skull through microCT.

Claim 1:
An absorbent bone hemostatic material composition comprising <NUM> to <NUM> parts by weight of polyethylene glycol-ran-propylene glycol based on <NUM> to <NUM> parts by weight of poloxamer,
wherein the poloxamer has a weight average molecular weight of <NUM>,<NUM> to <NUM>,<NUM>,
characterized in that the polyethylene glycol-ran-propylene glycol has a weight average molecular weight of <NUM>,<NUM> to <NUM>,<NUM>.