MOLDABLE ORTHOPEDIC COMPOSITION WITH ANTI-WASHOUT PROPERTY

Abstract

Provided is an orthopedic composition, including: a powder composition including calcium sulfate hemihydrate, β-tricalcium phosphate and hydroxypropyl methylcellulose; and a solvent including glycerol and water. The orthopedic composition exhibits improved washout resistance. A method of manufacturing the orthopedic composition and a bone graft set including the orthopedic composition are further provided.

Claims

1. A moldable orthopedic composition with improved washout resistance, comprising: a powder composition comprising calcium sulfate hemihydrate, β-tricalcium phosphate (β-TCP) and hydroxypropyl methylcellulose; and a solvent comprising glycerol and water.

2. The moldable orthopedic composition of claim 1, wherein the ratio of the calcium sulfate hemihydrate to the β-tricalcium phosphate (β-TCP) is approximately 1:1 (gram/gram).

3. The moldable orthopedic composition of claim 1, wherein the hydroxypropyl methylcellulose has a percent by weight of 1˜6%.

4. The moldable orthopedic composition of claim 1, wherein the hydroxypropyl methylcellulose has a percent by weight of approximately 1˜4%.

5. The moldable orthopedic composition of claim 1, wherein the glycerol has a percent by volume of approximately 70˜99%.

6. The moldable orthopedic composition of claim 1, wherein the glycerol has a percent by volume of approximately 85%.

7. The moldable orthopedic composition of claim 1, wherein the liquid-to-powder ratio of the powder composition to the solvent is approximately 0.35 milliliter/gram.

8. A bone graft set, comprising the moldable orthopedic composition of claim 1, wherein the moldable orthopedic composition is stored in a standalone container.

9. A medical use of the moldable orthopedic composition of claim 1 in treating bone defects.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Embodiments of the present disclosure and their advantages are illustrated by accompanying drawings and described below.

[0021] FIG. 1 shows orthopedic compositions comprising 70% glycerol but comprising hydroxypropyl methylcellulose (HPMC) of different proportions and shows the washout percentage of the orthopedic compositions being immersed in a simulation body fluid for 15 minutes or one hour. The experiment of FIG. 1 uses t-test, the same formula for **P<0.01, and immersion duration of 15 minutes and one hour to evaluate the difference therebetween.

[0022] FIG. 2 shows orthopedic compositions comprising 85% glycerol but comprising hydroxypropyl methylcellulose (HPMC) of different proportions and shows the washout percentage of the orthopedic compositions being immersed in a simulation body fluid for 15 minutes or one hour. The experiment of FIG. 2 uses t-test, the same formula for *P<0.05 or **P<0.01, and immersion duration of 15 minutes and one hour to evaluate the difference therebetween.

[0023] FIG. 3 shows bone graft materials comprising 99% glycerol but comprising hydroxypropyl methylcellulose (HPMC) of different proportions and shows the washout percentage of the bone graft materials being immersed in a simulation body fluid for 15 minutes or one hour. The experiment of FIG. 3 uses t-test and immersion duration of 15 minutes and one hour, only to find no statistical difference therebetween.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0024] The present disclosure is illustrated by preferred embodiments, depicted by drawings, and described below. Experimental data disclosed in the embodiments is intended to facilitate interpretation of technical features of the present disclosure but is not restrictive of implementable aspects of the present disclosure.

[0025] The adverb “approximately” used herein is indicative of errors in material proportions, errors in medicament concentrations, and variations between experimental subjects. Typically, the adverb “approximately” indicates the variety of being greater than or less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%, as appropriate.

[0026] The specific aspects of the expression “orthopedic composition” used herein include, but are not limited to, joint implants, vertebral implants, craniomaxillofacial implants, dental implants, ankle implants and traumatic implants (plates and nails).

[0027] The expressions “injected,” “injection” and “injectability” used herein mean administering such as injecting, infusing, or delivering any composition to the body through transmission by any conveying device.

[0028] It is an objective of the present disclosure to provide a moldable orthopedic composition comprising: a powder composition comprising calcium sulfate hemihydrate (CaSO.sub.4.Math.0.5H.sub.2O), β-tricalcium phosphate (β-TCP) and hydroxypropyl methylcellulose (HPMC), and a solvent comprising glycerol and water.

[0029] In a specific embodiment of the present disclosure, the ratio of the calcium sulfate hemihydrate to the β-tricalcium phosphate (β-TCP) is approximately 1:1 (gram/gram).

[0030] In a specific embodiment of the present disclosure, the hydroxypropyl methylcellulose has a percent by weight of approximately 1˜6%, preferably approximately 1˜4%, and most preferably approximately 2˜4%, of the powder composition. If the percent by weight of the hydroxypropyl methylcellulose is greater than 6%, the orthopedic composition of the present disclosure will be overly sticky and thus too difficult to manipulate and serve as a moldable orthopedic composition.

[0031] In a specific embodiment of the present disclosure, the liquid-to-powder ratio of the powder composition to the solvent is most preferably approximately 0.35 milliliter/gram. In a specific embodiment of the present disclosure, the calcium sulfate hemihydrate has a percent by weight of approximately 47, 47.5, 48, 48.5, 49, 49.5%, preferably approximately 48, 48.5, 49, 49.5%, most preferably approximately 48, 48.5, 49%, of the powder composition. In a specific embodiment of the present disclosure, the β-tricalcium phosphate (β-TCP) has a percent by weight of approximately 47, 47.5, 48, 48.5, 49, 49.5%, preferably approximately 48, 48.5, 49, 49.5%, most preferably approximately 48, 48.5, 49%, of the powder composition. In a specific embodiment of the present disclosure, the hydroxypropyl methylcellulose has a percent by weight of approximately 1, 2, 3, 4, 5, 6%, preferably approximately 1, 2, 3, 4%, most preferably approximately 2, 3, 4%, of the powder composition.

[0032] In a specific embodiment of the present disclosure, the glycerol has a percent by volume of approximately 70˜99%, preferably approximately 85%, of the solvent. If the percent by volume of the glycerol is less than 70%, the orthopedic composition of the present disclosure will be likely to disintegrate, for example, within one day, and thus cannot effectively take shape.

[0033] The orthopedic composition of the present disclosure further includes a dispersing agent for uniformly distributing a powder, suspension stabilizer for maintaining the suspension state of the powder particles, medicament (for example, osteoblastic bone formation/differentiation promotor, neovascularization promotor), nutrient, antimicrobial agent, antibiotic or additive (for example, curing promotor, curing retarder).

[0034] Another objective of the present disclosure is to provide a bone graft set comprising the moldable orthopedic composition stored in a standalone container. The injection orifice of a common conventional bone graft syringe has an inner diameter of 3 mm approximately; thus, the fluidity of the orthopedic composition in the course of injection depends on the particle diameters of the calcium sulfate hemihydrate, β-tricalcium phosphate (β-TCP) and hydroxypropyl methylcellulose. To enable the orthopedic composition of the present disclosure to exhibit preferred fluidity and thereby be easy to be squeezed out, the calcium sulfate hemihydrate of the present disclosure preferably has an average particle diameter of 20˜40 μm, the β-tricalcium phosphate (β-TCP) of the present disclosure preferably has an average particle diameter of 20˜40 μm, and the hydroxypropyl methylcellulose of the present disclosure preferably has an average particle diameter of 100˜200 μm.

[0035] Yet another objective of the present disclosure is to provide a medical use of the moldable orthopedic composition in treating bone defects.

[0036] The present disclosure is illustrated by embodiments and described below. However, the embodiments are not restrictive of the present disclosure. Persons skilled in the art may make slight improvements and modifications in the embodiments without departing from the scope of the present disclosure.

EMBODIMENT

[0037] Orthopedic Composition Manufacturing Method

[0038] The orthopedic composition is prepared according to the proportions shown in Table 1.

TABLE-US-00001 TABLE 1 Orthopedic composition code A B C D E F Powder CaSO.sub.4•0.5H.sub.2O 50 49.5 49 48 50 49.5 (%) β-TCP 50 49.5 49 48 50 49.5 HPMC 0 1 2 4 0 1 Solvent Glycerol 70 70 70 70 85 85 (%) Water 30 30 30 30 15 15 Orthopedic composition code G H I J K L Powder CaSO.sub.4•0.5H.sub.2O 49 48 50 49.5 49 48 (%) β-TCP 49 48 50 49.5 49 48 HPMC 2 4 0 1 2 4 Solvent Glycerol 85 85 99 99 99 99 (%) Water 15 15 1 1 1 1

[0039] The method of manufacturing the orthopedic composition is carried out according to the percent by weight shown in Table 1 and involves mixing the powder of the calcium sulfate hemihydrate (with an average particle diameter of 20˜40 μm), the powder of the β-tricalcium phosphate (β-TCP) (with an average particle diameter of 20˜40 μm) and the powder of the hydroxypropyl methylcellulose (with an average particle diameter of 100˜200 μm), mixing the glycerol and water according to the percent by volume shown in Table 1, adding the glycerol-water mixture to the powders at room temperature, and blending the mixture and powders with a pharmaceutical spoon to form a moldable orthopedic composition with improved washout resistance.

Washout Experiment Method

[0040] The moldable orthopedic composition is placed inside a 304 stainless steel die (with a diameter of 6 millimeters and a height of 3 millimeters) to take on a cylindrical shape and be weighed. Then, the moldable orthopedic composition is immersed centrally in the bottom of a barrel that contains a simulation body fluid. The barrel has a diameter of 20 millimeters and a height of 20 millimeters and is placed in an environment at 37° C. The ratio of the orthopedic composition to the simulation body fluid is specified to be 0.2 gram of bone graft material to 1 milliliter of simulation body fluid. The simulation body fluid is used, because its ionic concentration approximates to that of the human blood plasma [12]. The immersion of the orthopedic composition in the simulation body fluid lasts 15 minutes, one hour or four hours and is followed by the removal of the simulation body fluid and the introduction of 1 milliliter of 99.5% alcohol, and then the orthopedic composition is placed at room temperature for 30 seconds. After that, alcohol is removed, and then both the intact bone graft material proper (a cylinder with a diameter of 6 millimeters) and the disintegrated fragments are placed in an oven operating at 50° C. for three days. Next, the intact bone graft material proper is weighed. The weight of the intact bone graft material proper is subtracted from pre-experiment weight to figure out weight loss. Then, the weight loss is divided by the pre-experiment weight to obtain washout percentage. Therefore, the lower the washout percentage is, the better the washout resistance of the formula is.

Embodiment 1

[0041] The results of immersing the orthopedic composition in the simulation body fluid for 15 minutes are shown in Table 2.

TABLE-US-00002 TABLE 2 Orthopedic composition code A B C D E F Pre-experiment weight 0.194 0.193 0.198 0.194 0.193 0.195 (gram) Weight (gram) after its 0.044 0.129 0.176 0.187 0.051 0.123 immersion in simulation body fluid for 15 minutes Weight loss = 0.151 0.064 0.021 0.007 0.141 0.073 pre-experiment weight − weight (gram) after its immersion in liquid Washout percentage = 77.52% ± 33.39% ± 10.80% ± 3.55% ± 73.35% ± 37.06% ± weight loss ÷ 3.19 4.61 2.85 1.07 2.40 6.75 pre-experiment weight Orthopedic composition code G H I J K L Pre-experiment weight 0.199 0.194 0.193 0.193 0.190 0.198 (gram) Weight (gram) after its 0.172 0.182 0.034 0.044 0.120 0.158 immersion in simulation body fluid for 15 minutes Weight loss = 0.027 0.012 0.160 0.149 0.070 0.040 pre-experiment weight − weight (gram) after its immersion in liquid Washout percentage = 13.76% ± 6.20% ± 82.62% ± 77.33% ± 36.91% ± 20.25% ± weight loss ÷ 7.32 2.77 3.07 4.71 3.38 7.48 pre-experiment weight

[0042] The results of immersing the orthopedic composition in the simulation body fluid for one hour are shown in Table 3.

TABLE-US-00003 TABLE 3 Orthopedic composition code A B C D E F Pre-experiment weight 0.193 0.191 0.192 0.193 0.192 0.197 (gram) Weight (gram) after its 0.044 0.076 0.153 0.18 0.048 0.053 immersion in simulation body fluid for one hour Weight loss = 0.148 0.115 0.038 0.013 0.144 0.144 pre-experiment weight − weight (gram) after its immersion in liquid Washout percentage = 76.98% ± 60.20% ± 19.80% ± 6.96% ± 74.80% ± 73.14% ± weight loss ÷ 1.42 7.19 6.69 3.54 2.43 3.91 pre-experiment weight Orthopedic composition code G H I J K L Pre-experiment weight 0.193 0.196 0.200 0.198 0.195 0.192 (gram) Weight (gram) after its 0.125 0.165 0.044 0.044 0.116 0.157 immersion in simulation body fluid for one hour Weight loss = 0.068 0.031 0.156 0.154 0.079 0.036 pre-experiment weight − weight (gram) after its immersion in liquid Washout percentage = 35.16% ± 15.81% ± 78.24% ± 77.72% ± 40.34% ± 18.55% ± weight loss ÷ 1.26 1.32 2.51 3.81 3.18 6.67 pre-experiment weight

[0043] The data in Table 1 and Table 2 indicates that the introduction of the hydroxypropyl methylcellulose (HPMC) into the orthopedic composition effectively decreases the percentage of the orthopedic composition. Thus, the higher the percentage of the hydroxypropyl methylcellulose is, the greater the washout resistance of the orthopedic composition is. As shown in FIGS. 1, 2, 3, the hydroxypropyl methylcellulose markedly augments long-term washout resistance of the orthopedic composition, especially in the presence of 85% glycerol.

Embodiment 2

[0044] The results of immersing the moldable orthopedic composition in the simulation body fluid for four hours are shown in Table 4.

TABLE-US-00004 TABLE 4 Orthopedic composition code A B C D E F Pre-experiment weight 0.188 0.195 0.188 0.190 0.191 0.192 (gram) Weight (gram) after its 0.036 0.038 0.107 0.132 0.040 0.042 immersion in simulation body fluid for four hours Weight loss = 0.152 0.157469 0.081 0.057 0.151 0.150 pre-experiment weight − weight (gram) after its immersion in liquid Washout percentage = 81.01% ± 80.62% ± 42.99% ± 30.18% ± 79.03% ± 77.91% ± weight loss ÷ 1.88 3.85 2.81 4.94 0.13 1.55 pre-experiment weight Orthopedic composition code G H I J K L Pre-experiment weight 0.198 0.197 0.192 0.186 0.187 0.191 (gram) Weight (gram) after its 0.086 0.119 0.009 0.026 0.068 0.111 immersion in simulation body fluid for one hour Weight loss = 0.111 0.078 0.182 0.160 0.119 0.080 pre-experiment weight − weight (gram) after its immersion in liquid Washout percentage = 56.21% ± 39.5% ± 95.10% ± 85.87% ± 63.49% ± 41.82% ± weight loss ÷ 2.45 2.56 0.87 2.50 6.03 6.22 pre-experiment weight

[0045] As shown in Table 4, even though the duration of washout lasts four hours, the hydroxypropyl methylcellulose enhances the washout resistance of the orthopedic composition effectively, especially in the presence of a low proportion of glycerol.

Embodiment 3

[0046] The numbers of days of preservation of the orthopedic compositions with different constituents are shown in Table 5.

TABLE-US-00005 TABLE 5 Powder CaSO.sub.4•0.5H.sub.2O 50 50 50 50 50 (%) β-TCP 50 50 50 50 50 HPMC 0 0 0 0 0 Liquid Glycerol 100 70 50 30 0 (%) Water 0 30 50 70 100 Number of days of >21 >21 <1 <1 cannot be preservation days days day day mixed and cured Moldable at the end Yes yes no no not of preservation? executable

[0047] As shown in Table 5, when the proportion of glycerol is less than 70%, for example, equal to 50% or 30%, preservation of the orthopedic composition lasts a maximum of 1 day, as the orthopedic composition disintegrates within 1 day and thus is unable to take shape. When the proportion of glycerol is greater than 70%, the orthopedic composition is not only moldable but can also be preserved at normal temperature for at least 21 days.

[0048] The effect of hydroxypropyl methylcellulose of different concentrations on moldability of orthopedic composition is illustrated by Table 6.

TABLE-US-00006 TABLE 6 Powder CaSO.sub.4•0.5H.sub.2O 49 48 47 (%) β-TCP 49 48 47 HPMC 2 4 6 Liquid Glycerol 70 70 70 (%) Water 30 30 30 Operation properties like styrofoam, like clay, like chewing moldable moldable gum, not moldable

[0049] As shown in Table 6, the viscosity of the orthopedic composition increases with the weight percentage of the hydroxypropyl methylcellulose, leading to deterioration of operability. When the concentration of the hydroxypropyl methylcellulose reaches 6%, the orthopedic composition will be as sticky as chewing gum and thus not moldable.

Embodiment 4

[0050] The results of comparison of the orthopedic composition of the present disclosure and a commercially-available orthopedic composition are shown in Table 7.

TABLE-US-00007 TABLE 7 Weight loss = Weight pre-experiment (gram) after weight − Washout its immersion weight (gram) percentage = in water of pH after its weight loss ÷ Substance Pre-experiment 7.4 for 15 immersion in pre-experiment tested weight (gram) minutes liquid weight Orthopedic 5.4 4.7 0.7 12.96% composition (CaSO.sub.4•0.5H.sub.2O 48%, β-TCP 48%, HPMC 4%, glycerol 70%, water 30%) of the present disclosure GeneX ® Bone 8.8 7.5 1.3 14.77% Graft Substitute

[0051] As shown in Table 7, the orthopedic composition of the present disclosure exhibits slightly greater washout resistance than commercially-available GeneX® Bone Graft Substitute. This indicates that the orthopedic composition of the present disclosure has satisfactory washout resistance and moldability.

[0052] Calcium sulfate is widely applicable to bone graft materials and has advantages as follows: satisfactory biocompatibility, not toxic, biosorption, and excellent osteoconduction. However, after being implanted in the human body, calcium sulfate is likely to be washed out by blood and thus cannot stay at a point to be filled, thereby failing to perform repair. Therefore, a moldable orthopedic composition with improved washout resistance according to the present disclosure has advantages as follows: the moldable orthopedic composition essentially comprises calcium sulfate and calcium phosphate composition (tetracalcium phosphate and dicalcium phosphate), which are supplemented with citric acid and hydroxypropyl methylcellulose to achieve an effective washout resistance effect and thereby attain excellent restoration capability.

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