Soft tissue filling composition including particulated acellular dermal matrix

Abstract

A soft tissue filling composition according to one aspect of the present invention has a high collagen content and a low lipid content, and thus has high biocompatibility and moldability without causing allergic reactions and inflammation. In addition, the composition has a high complex viscosity and storage modulus, and thus can perform an excellent supporting function, maintains homogeneous properties, and can be injected with low injection force by using a standard syringe. Accordingly, the soft tissue filling composition according to one aspect of the present invention can be used to restore the volume of defective or recessed soft tissues, for example, breasts, and can be used for alleviating skin curvature, cosmetic fillers, or supplementing moisture sensation.

Description

Soft tissue filling composition containing acellular dermal particles

[0001] The present invention relates to a composition for soft tissue filling comprising acellular dermal particles.

[0002]

[0003] Breast reconstruction is a surgical procedure that restores the damaged area to its pre-mastectomy form following a total mastectomy performed due to reasons such as breast cancer. In the field of soft tissue reconstruction, such as breast reconstruction, there are many cases requiring massive tissue restoration in proportion to the size of the damaged area. Existing methods for tissue reconstruction include the use of autologous tissue or implants.

[0004] In the case of methods using autologous tissue, there are instances where application is impossible depending on the patient's condition, and there is the problem of scarring remaining at the site where the tissue was harvested even after surgery. When using permanent implants, there is a high risk of foreign body reactions, and due to their fixed shape, they have the disadvantage of being difficult to adhere closely to the affected area. In addition to the aforementioned disadvantages, the tissue reconstruction methods mentioned above may also have issues such as low plasticity or deformation of the shape after the procedure.

[0005] As a solution to overcome these problems, particulated acellular dermal matrix is ​​a biological tissue substitute that can be injected by hydrating it to a high concentration in injectable water applicable to the human body. The aforementioned particulated acellular dermal matrix can be used for wound healing or skin regeneration to promote the regeneration of existing tissue and repair defects. However, most commercially available particulated acellular matrix has an average particle diameter of 500 μm or more, so a large-diameter syringe is required when injecting it as a high-concentration putty formulation by hydrating it in injectable water applicable to the human body for tissue repair purposes. In particular, when high concentrations of particulated acellular matrix must be injected, such as in the field of soft tissue reconstruction like breast reconstruction, it may not be easy to inject it using a conventional surgical syringe. In addition, when acellular dermal particles are mixed with other tissue repair biomaterials such as commercially available hyaluronic acid, it is difficult to disperse them homogeneously, and even if they are mixed in a homogeneous state temporarily, phase separation may occur over the long term.

[0006] Accordingly, there is a demand for tissue repair products in the form of putty that possess high biocompatibility and moldability for easy injection and correction, allowing for application regardless of the shape of the defect. Additionally, there is a need for a new soft tissue filling composition that has low injection force, is homogeneously mixed, and ensures dispersion stability.

[0007]

[0008] One aspect is a composition for soft tissue filling comprising acellular dermal particles,

[0009] The average diameter of the above-mentioned acellular dermal particles is 50 to 500 μm;

[0010] The present invention provides a soft tissue filling composition in which the acellular dermal particles are included in an amount of 15 to 20 weight percent within the composition.

[0011] Another aspect is a breast reconstruction composition comprising acellular dermal particles,

[0012] The average diameter of the above-mentioned acellular dermal particles is 50 to 500 μm;

[0013] The present invention provides a breast reconstruction composition in which the above-mentioned acellular dermal particles are included in the composition at a weight of 15 to 20%.

[0014]

[0015] One aspect is a composition for soft tissue filling comprising acellular dermal particles,

[0016] The average diameter of the above-mentioned acellular dermal particles is 50 to 500 μm;

[0017] The present invention provides a soft tissue filling composition in which the above-mentioned acellular dermal particles are included in the composition at a concentration of 15 to 20 weight%.

[0018] The term "acellular dermal matrix (ADM)" refers to a dermal matrix separated from an individual that has been subjected to physical or chemical treatment to remove components such as cells, nucleic acids, or lipids that may cause an immune rejection reaction, while maintaining the specific three-dimensional structure of the dermal matrix and having an extracellular matrix (ECM) as its main component.

[0019] In one embodiment, the acellular dermis may be derived from skin tissue, specifically from skin dermal tissue.

[0020] The above-mentioned individual may be a mammal, specifically a species selected from the group consisting of humans, pigs (porcine), cattle (bovine), and horses (equine). If the above-mentioned individual is human, it may be used as a homologous human tissue graft, and if it is not human, it may be used as a xenologous human tissue graft.

[0021] The term "acellular dermal particles" above refers to acellular dermal particles in a particle structure obtained by crushing acellular dermal

[0022] The above term "acellular dermal particles" may refer to individual acellular dermal particles, or may refer to a mixture of acellular dermal particles having different characteristics, for example, different diameters.

[0023] In one embodiment, the average diameter of the acellular dermal particles may be 50 to 500 μm, 50 to 400 μm, 50 to 300 μm, 100 to 500 μm, 100 to 400 μm, 100 to 300 μm, 150 to 500 μm, 150 to 400 μm, or 150 to 300 μm. When the average diameter of the acellular dermal particles is 50 to 500 μm, the injection force may not become excessively high when injected with a conventional surgical syringe (e.g., 14G), and the acellular dermal particles may be homogeneously distributed within the soft tissue filling composition. However, when the average diameter of the acellular dermal particles is 50 μm or less, the yield of the acellular dermal particles may be excessively reduced. In addition, if the average diameter of the acellular dermal particles exceeds 500 μm, it may be impossible to inject them with a conventional surgical syringe (e.g., 14G), and even if injected, the injection force may be excessively high, making the procedure difficult. Furthermore, when manufactured as a putty formulation, the composition may undergo phase separation, and the properties may not be maintained.

[0024] In addition, in one embodiment, the acellular dermal particles may comprise 60% or more, 75% or more, 80% or more, or 90% or more of the acellular dermal particles included in the soft tissue filling composition, wherein the particles have a diameter of 50 to 500 μm, 50 to 400 μm, 50 to 300 μm, 100 to 500 μm, 100 to 400 μm, 100 to 300 μm, 150 to 500 μm, 150 to 400 μm, or 150 to 300 μm. In addition, the particles having a diameter of 50 to 500 μm, 50 to 400 μm, 50 to 300 μm, 100 to 500 μm, 100 to 400 μm, 100 to 300 μm, 150 to 500 μm, 150 to 400 μm, or 150 to 300 μm may constitute 99% or less, 98% or less, or 95% or less of the acellular dermal particles included in the soft tissue filling composition.

[0025] If the proportion of the acellular dermal particles having a diameter of 50 to 500 μm, 50 to 400 μm, 50 to 300 μm, 100 to 500 μm, 100 to 400 μm, 100 to 300 μm, 150 to 500 μm, 150 to 400 μm, or 150 to 300 μm is less than 60% or exceeds 99%, for example, if the acellular dermal particles with a diameter of less than 50 μm are 40% or more or 1% or less, the yield of the acellular dermal particles may decrease excessively; and if the acellular dermal particles with a diameter exceeding 500 μm are 40% or more, injection with a conventional surgical syringe (e.g., 14G) may be impossible, and even if injected, the injection force may be excessively high, making the procedure difficult, and as a putty formulation During manufacturing, the composition may undergo phase separation, and the properties may not be maintained.

[0026] The term "diameter" above may refer to the diameter of the particle in the case of a spherical particle, or to the length of the semi-major axis measured in a two-dimensional cross-section of the particle visible under a microscope in the case of an elliptical or irregularly shaped particle.

[0027] The above term "average diameter" may be the average obtained by summing the diameters of individual particles having different diameters, volumes, or shapes, etc.

[0028] In one embodiment, the acellular dermal particles may be included in the composition in an amount of 15 to 20 weight%, 15 to 19 weight%, 15 to 18 weight%, 16 to 20 weight%, 16 to 19 weight%, or 16 to 18 weight%. More specifically, the acellular dermal particles may be included in the composition in an amount of more than 15 weight% and less than 20 weight%, more than 15 weight% and less than 19 weight%, more than 15 weight% and less than 18 weight%, more than 16 weight% and less than 20 weight%, more than 16 weight% and less than 19 weight%, or more than 16 weight% and less than 18 weight%.

[0029] If the above-mentioned acellular dermal particles are included in the composition at less than 15% by weight, the storage modulus may decrease, making it difficult to perform a supporting function, and the complex viscosity may become excessively low, causing phase separation or failure to maintain the physical properties when manufactured into a putty formulation. Additionally, if the above-mentioned acellular dermal particles are included in the composition at more than 20% by weight, the viscosity may increase excessively, making it impossible to inject using a conventional surgical syringe (e.g., 14G), and even if injected, the injection force may be excessively high, making the procedure difficult.

[0030] In one embodiment, the storage modulus (G') of the composition may be 1 to 5 kPa, 1 to 4 kPa, 1 to 3 kPa, 2 to 5 kPa, 2 to 4 kPa, 2 to 3 kPa, 3 to 5 kPa, 3 to 4 kPa, or 4 to 5 kPa. The storage modulus may be measured, for example, under conditions of 1% shear strain and 0.1 Hz. If the storage modulus of the composition is less than 1 kPa, it may be difficult to perform a supporting function, and if the storage modulus of the composition is greater than 5 kPa, it may be impossible to inject with a conventional surgical syringe (e.g., 14G), and even if injected, the injection force may be excessively high, making the procedure difficult.

[0031] The term "storage modulus" refers to the component of deformation energy applied to a target material that is accumulated within the material, and corresponds to a numerical representation of the material's elasticity. The higher the storage modulus, the stronger the tendency of a material to return to its original state when force is applied.

[0032] In one embodiment, the complex viscosity of the composition may be 3 to 7 kPa·s, 3 to 6 kPa·s, 3 to 5 kPa·s, 3 to 4 kPa·s, 4 to 7 kPa·s, 4 to 6 kPa·s, 4 to 5 kPa·s, 5 to 7 kPa·s, or 5 to 6 kPa·s. The complex viscosity may be measured, for example, under conditions of 1% shear strain and 0.1 Hz. If the complex viscosity of the composition is less than 3 kPa·s, the properties may not be maintained when manufactured into a putty formulation. Additionally, if the complex viscosity of the composition is 7 If the viscosity exceeds kPa·s, the injection force increases as the viscosity increases excessively, making it impossible to inject with a standard surgical syringe (e.g., 14G), and even if injected, the injection force may be too high to perform the procedure.

[0033] The term "complex viscosity" above refers to a numerical representation of the fluid resistance that occurs when a force is applied to a target substance and its shape changes. The higher the complex viscosity of a substance, the greater the force required for injection.

[0034] In one embodiment, the composition may have an injection force measured with a conventional surgical syringe (e.g., 14G) of 5 to 50 N, 5 to 45 N, 5 to 40 N, 10 to 50 N, 10 to 45 N, 10 to 40 N, 15 to 50 N, 15 to 45 N, or 15 to 40 N. If the injection force of the composition is less than 5 N, the complex viscosity is excessively low, so the properties may not be maintained when manufactured into a putty formulation. Additionally, if the injection force of the composition exceeds 50 N, excessive force is required during the procedure, which may hinder smooth use.

[0035] In one embodiment, the composition may contain collagen in an amount of 30% by weight, 40% by weight, or 45% by weight or more relative to the weight of the acellular dermal particles, and the composition may contain collagen in an amount of 90% by weight, 85% by weight, 83% by weight, or 80% by weight or less. If the composition contains less than 30% by weight of collagen, the tissue repair function of the surgical defect may be reduced.

[0036] In one embodiment, the composition may contain lipids in an amount of 5% by weight or less relative to the weight of the acellular dermal particles, and the composition may contain lipids in an amount of 0.1% by weight, 0.5% by weight, or 1% or more relative to the weight of the acellular dermal particles. If the composition contains lipids in an amount exceeding 5% by weight, decellularization may not be effectively achieved during the manufacturing process of the acellular dermal particles, self-organization such as cell influx after the procedure may be delayed, and inflammation may be induced. Additionally, if the composition contains lipids in an amount less than 0.1% by weight, the manufacturing process time of the acellular dermal particles may increase excessively.

[0037] The above term "lipid" may include all of the following: neutral fats, glycerol, cholesterol, phospholipids, cholesteryl esters, and fatty acids.

[0038] In one embodiment, the composition may further include one or more selected from the group of human-applicable injectable waters consisting of distilled water, saline solution, and buffered aqueous solution. The above-mentioned buffer aqueous solution may be a solution containing one or more from the group consisting of, for example, citric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, acetic acid, diethyl barbituric acid, sodium acetate, TAPS (tris(hydroxymethyl)methylamino)propanesulfonic acid), Bicine (2-bis(2-hydroxyethyl)amino)acetic acid), tris(tris(hydroxymethyl)ammonium methane), Tricine (N-(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)glycine), HEPES (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid), TES (2-[[1,3-dihydroxy-2-(hydroxymethyl)propane-2-yl]amino]methanesulfonic acid) and (piperazine-N,N′-bis(2-ethanesulfonic acid).

[0039] The term "soft tissue" above refers to all unhardened tissues of the body, excluding bone or cartilage. In one embodiment, the soft tissue may be a tissue selected from the group consisting of adipose tissue, muscle tissue, fascia tissue, dry tissue, fibrous tissue, ligament tissue, skin tissue, and joint capsule tissue. Additionally, the soft tissue may be an organ such as a breast, skin, or muscle comprising one or more tissues selected from the group consisting of adipose tissue, muscle tissue, fascia tissue, dry tissue, fibrous tissue, ligament tissue, skin tissue, and joint capsule tissue.

[0040] The term "soft tissue filling composition" refers to a composition capable of treating damage to the defective or depressed area of ​​the soft tissue and restoring the defective or depressed soft tissue to its original volume when the soft tissue is defective or depressed. The soft tissue filling composition can be utilized, for example, to restore the volume of a defective or depressed breast area in mastectomy, lumpectomy, or revision breast augmentation procedure, and can be used for various purposes such as relieving skin irregularities and replenishing moisture. Additionally, the soft tissue filling composition can also be used for the reconstruction of exposed skin tissue, such as in a wound.

[0041] In one embodiment, the composition may be a formulation selected from the group consisting of suspensions, emulsions, gels, pastes, and putties, and specifically may be a putty formulation.

[0042] In one embodiment, the soft tissue filling composition may be used as a filler in addition to being used for tissue repair of a defective area. The term "filler" refers to a supplementary material that is directly injected or inserted into skin tissue to fill in wrinkles or sunken scars, or for cosmetic purposes, and the filler may be administered to the entire body, including the face, neck, and body.

[0043] When the above soft tissue filling composition is used as a filler, it may further include an active pharmaceutical ingredient, for example, a vitamin (e.g., vitamin B, C, or E) or a local anesthetic, lidocaine. If the filler further includes other ingredients, it is important that the amounts mixed allow for maximum effect to be obtained with the minimum amount without side effects, and this can be easily determined by a person skilled in the art.

[0044] A soft tissue filling composition according to one aspect has a high collagen content and a low lipid content, so it does not cause allergic reactions or inflammation while possessing high biocompatibility and moldability. In addition, the composition has high complex viscosity and storage modulus, allowing it to perform excellent support functions, maintain a homogeneous appearance, and maintain low injection force when injected with a conventional surgical syringe (e.g., 14G). Accordingly, the soft tissue filling composition can be utilized to restore the volume of defective or depressed soft tissue, to alleviate skin irregularities, or to replenish moisture.

[0045] In one embodiment, the collagen and lipid content were measured in a soft tissue filling composition (hereinafter referred to as the composition of the preparation example) and a vapor-phase soluble product (Reallo Putty, CG Bio, South Korea, hereinafter referred to as Comparative Example 1), each containing 16, 17, 18, or 19 wt% of acellular dermal particles having an average diameter of 500 μm or less. As a result, the collagen content of the composition of the preparation example was 49.22 wt% relative to the weight of the acellular dermal particles and the lipid content was 2.98 wt% relative to the weight of the acellular dermal particles, whereas the collagen content of Comparative Example 1 was measured to be 28.58 wt% relative to the weight of the acellular dermal particles and the lipid content was 9.40 wt% relative to the weight of the acellular dermal particles, confirming that the composition of the preparation example had a higher collagen content and a lower lipid content compared to Comparative Example 1 (see Experimental Examples 1 and 2).

[0046] In another example, the average diameter of the acellular dermal particles in the composition of the preparation example and Comparative Example 1 was measured. As a result, the average diameter of the acellular dermal particles in the composition of the preparation example was measured to be 196.8 μm, and the average diameter of the acellular dermal particles in Comparative Example 1 was measured to be 752 μm, confirming that the average diameter of the acellular dermal particles in the composition of the preparation example was significantly smaller than that of the acellular dermal particles in Comparative Example 1 (see Experimental Example 3).

[0047] In another example, the storage modulus and complex viscosity of the composition of Preparation Example and the composition of Comparative Example 1 were measured under conditions of a shear strain of 1% and 1 Hz (n=3). As a result, the storage modulus (G') of the soft tissue filling composition of Preparation Example was measured to be an average of 3.08 kPa, and the complex viscosity an average of 4.97 kPa·s. In contrast, Comparative Example 1 was measured to have an average storage modulus of 1.96 kPa and an average complex viscosity of 3.24 kPa·s (see Figs. 7, 8 and Table 2). From this, it was confirmed that the soft tissue filling composition of Preparation Example had a storage modulus approximately 1.57 times higher and a complex viscosity approximately 1.65 times higher than Comparative Example 1 (see Experimental Example 4).

[0048] In another embodiment, the injection force of the soft tissue filling composition was measured while varying the content and average diameter of the acellular dermal particles (n=3). As a result, the injection force from a 14G catheter for soft tissue filling compositions containing 15, 16, 17, 18, 19, and 20 wt% of acellular dermal particles with an average diameter of 500 μm or less, respectively, was measured to be an average of 21.22, 33.64, 34.51, 36.61, 44.25, and 59.65 N, respectively; and the injection force from a 14G catheter for soft tissue filling compositions having an average diameter of acellular dermal particles of 500 to 1,000 μm and a content of 15, 16, 17, 18, 19, and 20 wt%, respectively, was measured to be an average of 20.38, 58.17, 73.21, 90.91, 106.02, and 132.44 N, respectively, so that the average diameter of the acellular dermal particles It was confirmed that when the diameter is 500 to 1,000 μm, the injection force is higher than 50 N, whereas when the average diameter of the acellular dermal particles is 500 μm or less, and when the acellular dermal particles are included in an amount of less than 19 wt%, the injection force is lower than 50 N (see Experimental Example 5).

[0049] In another embodiment, changes in the properties of the soft tissue filling composition were observed while varying the content and average diameter of the acellular dermal particles. As a result, it was confirmed that a soft tissue filling formulation composition containing 15% by weight of acellular dermal particles with an average diameter of 500 to 1000 μm exhibited phase separation and failed to maintain its properties, and a composition containing 15% by weight of acellular dermal particles with an average diameter of 500 μm or less also exhibited phase separation and failed to maintain its properties, resulting in poor moldability. On the other hand, when containing 16% by weight or more of acellular dermal particles, it was confirmed that the properties were maintained homogeneously without phase separation regardless of the average diameter of the acellular dermal particles, and the moldability was also excellent (see Experimental Example 6).

[0050] In another example, the storage modulus and complex viscosity were measured while varying the content of acellular dermal particles (n=3). As a result, the storage modulus of soft tissue filling compositions containing 15, 16, 17, 18, 19, or 20 wt% of acellular dermal particles with an average diameter of 500 μm or less was measured to be an average of 1.65, 2.60, 2.89, 3.08, 3.57, or 4.82 kPa, respectively, and the complex viscosity was measured to be an average of 2.66, 3.07, 3.48, 4.19, 4.22, or 4.63 kPa·s, respectively. From this, it was confirmed that when the acellular dermal particles are included in the composition at more than 15 wt% and less than 20 wt%, the composition can be maintained in a putty form and is easy to inject with a syringe (see Experimental Example 7).

[0051]

[0052] Another aspect is a breast reconstruction composition comprising acellular dermal particles,

[0053] The average diameter of the above-mentioned acellular dermal particles is 50 to 500 μm;

[0054] The present invention provides a breast reconstruction composition in which the acellular dermal particles are included in an amount of 15 to 20 weight% within the composition.

[0055] The above terms "acellular dermis," "acellular dermal particles," "average diameter," etc., are within the aforementioned range.

[0056] The term "breast reconstruction" above refers to restoring the volume of a breast area where the breast is missing or increasing the volume of a sunken breast area where the breast is indented.

[0057] The above breast reconstruction composition may be used as an implant for breast reconstruction surgery. The breast reconstruction surgery may be, for example, a mastectomy, a lumpectomy, or a revision breast augmentation procedure.

[0058] In one embodiment, the breast reconstruction composition may be used together with a breast implant, and the breast reconstruction composition may be implanted into the body in a form that encases part or all of the breast implant.

[0059] A breast reconstruction composition according to a different aspect has a high collagen content and a low lipid content, so it possesses high biocompatibility and moldability without causing allergic reactions or inflammation. In addition, the composition has high complex viscosity and a storage modulus, allowing it to perform excellent support functions, maintain a homogeneous appearance, and maintain low injection force when injected with a conventional surgical syringe (e.g., 14G). Accordingly, the breast reconstruction composition can be used to restore or increase the volume of a defective or sunken breast.

[0060]

[0061] A soft tissue filling composition according to one aspect has a high collagen content and a low lipid content, so it does not cause allergic reactions or inflammation, while possessing high biocompatibility, self-organizing properties, and moldability. In addition, the composition has high complex viscosity and storage modulus, so it can perform excellent support functions, maintain a homogeneous appearance, and maintain low injection force when injected with a conventional surgical syringe (e.g., 14G). Accordingly, the soft tissue filling composition according to one aspect can be used to restore the volume of defective or sunken soft tissue, for example, a defective breast, and can be used for skin contouring, as a cosmetic filler, or for replenishing moisture.

[0062]

[0063] FIG. 1 is a picture of a soft tissue filling composition containing acellular dermal particles. Specifically, it is a picture confirming that the soft tissue filling composition containing acellular dermal particles corresponds to a hydrated putty formulation.

[0064] Figure 2 is a diagram showing the manufacturing process of a soft tissue filling composition containing acellular dermal particles.

[0065] Figure 3 is a figure showing the collagen content relative to the weight of acellular dermal particles in a soft tissue filling composition containing acellular dermal particles and a commercially available putty formulation product (n=3).

[0066] Figure 4 shows the lipid content relative to the weight of the acellular dermal particles in a soft tissue filling composition containing acellular dermal particles and a commercially available putty formulation product (n=3).

[0067] FIGS. 5 and 6 are figures showing the particle size distribution and average diameter of acellular dermal particles in the soft tissue filling composition of the present invention (Preparation Example) and a commercially available putty formulation product (Comparative Example 1), respectively (n=3).

[0068] Figure 7 shows the storage modulus (1% shear strain, 0.1 Hz) of a soft tissue filling composition containing acellular dermal particles and a commercially available putty formulation product (n=3).

[0069] Figure 8 shows the complex viscosity (1% shear strain, 0.1 Hz) of a soft tissue filling composition containing acellular dermal particles and a commercially available putty formulation product (n=3).

[0070] FIG. 9 is a figure showing the injection force (14G) of a soft tissue filling composition according to the diameter and content of acellular dermal particles (n=3).

[0071] FIG. 10 is a figure confirming the characteristics of a soft tissue filling composition containing 15, 16, or 19 weight percent of acellular dermal particles having an average diameter of 500 to 1,000 μm. Specifically, when the acellular dermal particles are included at 15 weight percent, phase separation occurs as can be seen in the part indicated by the arrow in the figure, whereas when they are included at 16 or 19 weight percent, no phase separation is confirmed.

[0072] FIG. 11 is a figure confirming the characteristics of a soft tissue filling composition containing 15, 16, or 19 weight percent of acellular dermal particles with an average diameter of 500 μm or less. Specifically, when the composition contains 15 weight percent of acellular dermal particles, phase separation occurs as can be seen in the part indicated by the arrow in the figure, whereas when the composition contains 16 or 19 weight percent, no phase separation is confirmed.

[0073] FIG. 12 is a figure showing the storage modulus (1% shear strain, 0.1 Hz) of a soft tissue filling composition containing 15, 16, 17, 18, 19, or 20 wt% of acellular dermal particles with an average diameter of 500 μm or less (n=3).

[0074] FIG. 13 is a figure showing the complex viscosity (1% shear strain, 0.1 Hz) of a soft tissue filling composition containing 15, 16, 17, 18, 19, or 20 wt% of acellular dermal particles with an average diameter of 500 μm or less (n=3).

[0075] FIG. 14 is a figure showing the injection force of 1) a soft tissue filling composition containing acellular dermal particles having a lipid content of 10% or more and a particle size exceeding 500 μm (hereinafter, high-fat / high-particle-size composition), 2) a soft tissue filling composition containing acellular dermal particles having a lipid content of less than 5% and a particle size exceeding 500 μm (hereinafter, low-fat / high-particle-size composition), and 3) a soft tissue filling composition containing acellular dermal particles having a lipid content of less than 5% and a particle size of less than 500 μm.

[0076] Figure 15 is a figure evaluating the physical properties of a composition in which the content of acellular dermal particles exceeds 20%. Specifically, in each image, it is a figure confirming that the composition has physical properties similar to a solid formulation rather than a putty formulation, making molding impossible.

[0077]

[0078] The present invention will be explained in more detail below through examples. However, these examples are intended to illustrate the invention and the scope of the invention is not limited to these examples.

[0079]

[0080] Preparation Example - Preparation of a soft tissue filling composition containing acellular dermal particles

[0081] Skin tissue was immersed in an aqueous solution of NaCl and H2O2 and stirred for 24 hours to remove epidermal components from the skin tissue. Subsequently, the skin tissue from which epidermal components had been removed was immersed in an aqueous alcoholic solution such as ethanol (EtOH) or 70% isopropyl alcohol (IPA), and then vigorously shaken to remove surface lipids from the skin tissue. Subsequently, the skin tissue from which surface lipids had been removed was immersed in an aqueous solution of an ionic surfactant such as sodium dodecyl sulfate (SDS) or sodium deoxycholate (SDC), and then vigorously shaken for more than 2 hours to remove cells from the skin tissue.

[0082] Subsequently, the skin tissue was immersed in a buffer solution such as physiological saline or phosphate-buffered saline (PBS) and freeze-dried for at least 16 hours to remove moisture. The dehydrated skin tissue was separated along the grain, cut, and fed into a grinder for pulverization. Afterward, the pulverized tissue was sieved to select particles with a size of 500 μm or less to produce acellular dermal particles.

[0083] A soft tissue filling composition in the form of a putty was prepared by hydrating the manufactured acellular dermal particles to contain 16, 17, 18, or 19 weight%, respectively (Figs. 1 and 2).

[0084]

[0085] Comparative example

[0086] Comparative Example 1. Gas-phase product

[0087] As a comparative example for comparison with the soft tissue filling composition prepared in the above preparation example, a putty formulation product containing acellular dermal particles among currently commercialized products (Reallo Putty, CG Bio, South Korea) was used.

[0088]

[0089] Comparative Example 2. Preparation of a soft tissue filling composition containing 15 or 20 weight% of acellular dermal particles

[0090] Instead of preparing a soft tissue filling composition by hydrating the acellular dermal particles prepared in the above preparation example to contain 16, 17, 18, or 19 weight% each, the method was changed to hydrate the acellular dermal particles to contain 15 or 20 weight% each, thereby preparing a soft tissue filling composition containing 15 or 20 weight% of acellular dermal particles each.

[0091]

[0092] Comparative Example 3. Preparation of a soft tissue filling composition comprising acellular dermal particles having an average particle diameter of 500 to 1,000 μm

[0093] In the above preparation example, instead of selecting particles having an average size of 500 μm or less, the method was changed to selecting acellular dermal particles having a diameter of 500 to 1,000 μm from crushed skin tissue, and a soft tissue filling composition was prepared containing 15, 16, 17, 18, 19, or 20 weight% of acellular dermal particles having a diameter of 500 to 1,000 μm, respectively.

[0094]

[0095] Examples

[0096] Example 1. Measurement of collagen content in a soft tissue filling composition

[0097] The content of collagen, a major component of human skin, was measured in the soft tissue filling composition of the above manufacturing example and the composition of Comparative Example 1.

[0098] Specifically, the soft tissue filling composition of the above preparation example or the composition of Comparative Example 1 was hydrolyzed with papain and 6N HCl for 24 hours. Subsequently, the collagen content was analyzed by measuring the absorbance at 550 nm, which is the wavelength range absorbed by hydroxyproline, a major component of collagen, using a spectrophotometer from Thermo Scientific (n=3).

[0099] As a result, the collagen content in the soft tissue filling composition of the above preparation example was measured to be an average of 49.22% by weight relative to the weight of the acellular dermal particles, and the collagen content of Comparative Example 1 was measured to be an average of 28.58% by weight relative to the weight of the acellular dermal particles. From this, it was confirmed that the soft tissue filling composition of the above preparation example had a collagen content approximately 1.72 times higher than that of Comparative Example 1 (Table 1 and Fig. 3).

[0100]

[0101] Experimental Example 2. Measurement of lipid content of soft tissue filling composition

[0102] The content of lipids, which are components that may cause inflammation upon transplantation, was measured in the soft tissue filling composition of the above manufacturing example and the composition of Comparative Example 1 (n=3).

[0103] Specifically, the composition for soft tissue filling of the above preparation example and Comparative Example 1 were hydrolyzed with lipase for 24 hours, and the lipid content was analyzed by measuring the absorbance at a wavelength of 570 nm, which is absorbed by hydrogen peroxide (H2O2) reacting with a reagent, which is a byproduct generated by oxidizing glycerol, a major component of lipids, using a spectrophotometer from Thermo Scientific.

[0104] As a result, the lipid content in the soft tissue filling composition of the above manufacturing example was measured to be an average of 2.98% by weight relative to the weight of the acellular dermal particles, and the composition of Comparative Example 1 was measured to be an average of 9.40% by weight relative to the weight of the acellular dermal particles.

[0105] From this, it was confirmed that the soft tissue filling composition of the above manufacturing example has a lipid content approximately 0.31 times lower than that of Comparative Example 1 (Table 1 and Fig. 4).

[0106] Preliminary Comparative Example 1 Collagen content (weight%) in acellular dermal particles 49.22 28.58 Lipid content (weight%) in acellular dermal particles 2.98 9.40

[0107]

[0108] Experimental Example 3. Measurement of the diameter of acellular dermal particles in a soft tissue filling composition

[0109] The diameter of the acellular dermal particles in the soft tissue filling composition of the above preparation example and Comparative Example 1 was measured. Specifically, 100 mg each of the soft tissue filling composition of the above preparation example and Comparative Example 1 were separated, diluted in 10 mL of distilled water at a ratio of 1:100, and the diameter of the acellular dermal particles was measured using a particle size analyzer (Beckman Coulter) (n=3).

[0110] As a result, the average diameter of the acellular dermal particles in the soft tissue filling composition of the above preparation example was measured to be 196.8 μm, and the average diameter of the dermal particles in Comparative Example 1 was measured to be 752 μm. From this, it was confirmed that the average diameter of the acellular dermal particles in the soft tissue filling composition of the above preparation example was significantly smaller than that of Comparative Example 1 (Figs. 5 and 6).

[0111]

[0112] Experimental Example 4. Analysis of Rheological Properties of Soft Tissue Filling Composition

[0113] The physical properties of the soft tissue filling composition of the above preparation example and the composition of Comparative Example 1 were measured. Specifically, 1 g each of the soft tissue filling composition of the above preparation example and Comparative Example 1 were separated, and the storage modulus and complex viscosity were measured using an Anton Paar rheometer (1 % shear strain, 0.1 Hz) (n=3).

[0114] As a result, the storage modulus (G') of the soft tissue filling composition of the above preparation example was measured to be an average of 3.08 kPa, and the complex viscosity an average of 4.97 kPa·s. On the other hand, Comparative Example 1 was measured to have a storage modulus of an average of 1.96 kPa and a complex viscosity an average of 3.24 kPa·s (see Figures 7, 8 and Table 2).

[0115] From this, it was confirmed that the soft tissue filling composition of the above manufacturing example has a storage modulus approximately 1.57 times higher and a complex viscosity approximately 1.65 times higher than Comparative Example 1.

[0116] 1% shear strain, 0.1 Hz Manufacturing Preliminary Comparative Example 1 Storage modulus (G') (kPa) 3.08 1.96 Complex viscosity (kPa·s) 4.97 3.24

[0117]

[0118] Experimental Example 5. Confirmation of changes in injection force of soft tissue filling composition according to acellular dermal particle content and average diameter

[0119] In the case of injection force, if it exceeds 50 N, excessive force is required to the extent that an adult finds it difficult to use during the injection process. Accordingly, the change in injection force according to the content or average diameter of acellular dermal particles was confirmed for the soft tissue filling composition of the above manufacturing example, Comparative Example 2, and Comparative Example 3.

[0120] Specifically, a soft tissue filling composition was prepared containing 15, 16, 17, 18, 19, or 20 weight% of acellular dermal particles having an average diameter of 500 μm or less or an average diameter of 500 to 1,000 μm, respectively. Then, a 14G catheter, which has the largest inner diameter and is the easiest to inject among commonly used rigid catheters, was attached to a pre-filled syringe, and the injection force at different concentrations of the syringe contents was measured using a universal testing machine (UTM, ZwickRoell) (n=3).

[0121] As a result, the injection force of a soft tissue filling composition with an average diameter of acellular dermal particles of 500 μm or less and a content of 15, 16, 17, 18, 19, or 20 wt% was measured to be an average of 21.22, 33.64, 34.51, 36.61, 44.25, or 59.65 N, respectively, and the injection force of a soft tissue filling composition with an average diameter of acellular dermal particles of 500 to 1,000 μm and a content of 15, 16, 17, 18, 19, or 20 wt% was measured to be an average of 20.38, 58.17, 73.21, 90.91, 106.02, or 132.44 N, respectively (see Fig. 9 and Table 3).

[0122] From this, it was confirmed that in order to meet the requirement of an injection force of 50 N or less for smooth use, the average diameter of the acellular dermal particles must be 500 μm or less and contained in an amount of less than 20 weight%.

[0123] Acellular Dermal Particle Content (%) 15 16 17 18 19 20 Input (N), Low Particle Size (< 500 μm) 21.2 23 3.6 4 34.5 13 6.6 14 4.2 55 9.6 5 Input (N), High Particle Size (500~1000 μm) 20.3 8 58.1 77 3.2 19 0.9 11 0 6.0 21 32.4

[0124]

[0125] Experimental Example 6. Confirmation of changes in the characteristics of a soft tissue filling composition according to acellular dermal particle content and average diameter

[0126] Changes in the characteristics according to the content or average diameter of acellular dermal particles were confirmed for the soft tissue filling composition of the above preparation example, Comparative Example 2, and Comparative Example 3. Specifically, a soft tissue filling composition was prepared containing 15, 16, or 19 weight% of acellular dermal particles having an average diameter of 500 μm or less, or acellular dermal particles having an average diameter of 500 to 1,000 μm. Afterward, the soft tissue filling composition was injected using a pre-filled syringe, and the characteristics of the composition within the syringe were observed. Then, after dispensing the composition by attaching a 14G catheter, it was confirmed whether it could be molded into a desired shape by hand.

[0127] As a result, in the case of a formulation composition for soft tissue filling containing 15% by weight of acellular dermal particles with an average diameter of 500 to 1,000 μm, it was confirmed that the composition underwent phase separation and did not maintain its appearance, as can be seen in the part indicated by the arrow in Fig. 10. Similarly, in the case of a composition containing 15% by weight of acellular dermal particles with an average diameter of 500 μm or less, it was confirmed that the composition underwent phase separation and did not maintain its appearance, and that moldability was poor, as can be seen in the part indicated by the arrow in Fig. 11. On the other hand, when containing 16% by weight or more of acellular dermal particles, it was confirmed that the appearance was maintained homogeneously and that moldability was also excellent (Figs. 10 and 11).

[0128] From this, it was confirmed that when the average diameter of the acellular dermal particles is 500 μm or less, and the content of the acellular dermal particles exceeds 15 weight%, it can be maintained as a putty formulation and can have excellent moldability.

[0129]

[0130] Experimental Example 7. Confirmation of rheological properties of soft tissue filling compositions according to acellular dermal particle content

[0131] In a composition for soft tissue filling, if the complex viscosity of the composition is less than 3 kPa·s, the properties may not be maintained when manufactured into a putty formulation. In addition, if the complex viscosity of the composition exceeds 7 kPa·s, the injection force increases as the viscosity increases excessively, making it difficult to perform the procedure with a syringe of standard specifications. Accordingly, changes in rheological properties according to the content or average diameter of acellular dermal particles were confirmed for the composition for soft tissue filling of the above manufacturing example and Comparative Example 2.

[0132] Specifically, 1 g each of the soft tissue filling composition of the preparation example or Comparative Example 2 was separated, and the storage modulus and complex viscosity were measured using an Anton Paar rheometer under conditions of a rotational speed of 0.1 Hz and a shear strain of 1% (n=3).

[0133] As a result, the storage modulus of the soft tissue filling compositions containing 15, 16, 17, 18, 19, or 20 wt% of acellular dermal particles with an average diameter of 500 μm or less was measured to be an average of 1.65, 2.60, 2.89, 3.08, 3.57, or 4.82 kPa, respectively, and the complex viscosity was measured to be an average of 2.66, 3.07, 3.48, 4.19, 4.22, or 4.63 kPa·s, respectively (see Figures 12, 13 and Table 4).

[0134] From this, it was confirmed that in a soft tissue filling composition containing acellular dermal particles with an average diameter of 500 μm or less, when the content of the acellular dermal particles exceeds 15% by weight and is less than 20% by weight, it can be maintained in a putty form and is easy to inject with a syringe.

[0135] 1% Shear Strain 0.1 Hz 15% 16% 17% 18% 19% 20% Storage modulus (G') (kPa) 1.65 2.60 2.89 3.08 3.57 4.82 Complex Viscosity (kPa·s) 2.66 3.07 3.48 4.19 4.22 4.63

[0136]

[0137] Experimental Example 8. Evaluation of Injection Power According to Particle Size of Acellular Dermal Particles and Lipid Content in Soft Tissue Filling Composition

[0138] In order to evaluate the injection power according to the particle size of acellular dermal particles and the lipid content in the soft tissue filling composition, 1) a soft tissue filling composition containing high-particle-size acellular dermal particles having a particle size exceeding 500 μm and containing a lipid content of 10% or more (hereinafter, high-fat / high-particle-size composition), 2) a soft tissue filling composition containing high-particle-size acellular dermal particles having a particle size exceeding 500 μm and containing a lipid content of less than 5% (hereinafter, low-fat / high-particle-size composition), and 3) a soft tissue filling composition containing low-particle-size acellular dermal particles having a particle size of less than 500 μm and containing a lipid content of less than 5% (hereinafter, low-fat / low-particle-size composition) were each prepared, and the injection power of the compositions was measured in the same manner as in Experimental Example 5.

[0139] As a result, it was confirmed that in the case of a composition with a high lipid content (more than 10 wt%) (high-fat / high-particle-density composition), a low injection force of 11.65 N can be maintained even when using high-particle-density acellular dermal particles exceeding 500 μm, but when the lipid content is less than 5 wt%, the injection force is very high at 54.99 N when using a composition containing high-particle-density acellular dermal particles (low-fat / high-particle-density composition), making it difficult to perform the procedure with a syringe of standard specifications. On the other hand, it was confirmed that even with a very low lipid content, a composition using low-particle-density acellular dermal particles of 500 μm or less (low-fat / low-particle-density composition) has a low injection force of 17.33 N, similar to the case using high-fat acellular dermal particles (see Fig. 14). From this, it was confirmed that in order to minimize the possibility of inflammation while maintaining a low injection force, it must contain low-particle-density acellular dermal particles of 500 μm or less and a lipid content of less than 5 wt%.

[0140]

[0141] Experimental Example 9. Evaluation of physical properties of the composition according to the content of acellular dermis

[0142] In order to evaluate the physical properties of a composition in cases where the acellular dermis content is excessively high, a composition was prepared in which the content of the acellular dermis particles exceeded 20%, and the moldability of the prepared composition was evaluated.

[0143] As a result, it was confirmed that when the content of acellular dermal particles exceeds 20%, the material has physical properties similar to a solid formulation rather than a putty formulation, making injection and molding impossible (see Fig. 15). From this, it was confirmed that the content of acellular dermal particles in a soft tissue filling composition must be 20% or less.

Claims

1. A composition for soft tissue filling comprising acellular dermal particles, The average diameter of the above-mentioned acellular dermal particles is 50 to 500 μm; A soft tissue filling composition in which the above-mentioned acellular dermal particles are included in the composition at a concentration of 15 to 20 weight%.

2. A composition for soft tissue filling according to claim 1, wherein the average diameter of the acellular dermal particles is 500 μm or less.

3. A soft tissue filling composition according to claim 1, wherein the acellular dermal particles comprise 90% or more particles having a diameter of 50 to 500 μm.

4. A soft tissue filling composition according to claim 1, wherein the acellular dermal particles are included in an amount of more than 15% by weight and less than 20% by weight in the composition.

5. A soft tissue filling composition according to claim 1, wherein the storage modulus (G') of the composition is 1 to 5 kPa.

6. A soft tissue filling composition according to claim 1, wherein the complex viscosity of the composition is 3 to 7 kPa·s.

7. A composition for soft tissue filling according to claim 1, wherein the injection force of the composition is 10 to 50 N.

8. A soft tissue filling composition according to claim 1, wherein the composition comprises at least 30% by weight of collagen relative to the weight of the acellular dermal particles.

9. A soft tissue filling composition according to claim 1, wherein the composition comprises lipids in an amount of 5% by weight or less relative to the weight of the acellular dermal particles.

10. A soft tissue filling composition according to claim 1, wherein the composition further comprises one or more selected from the group consisting of distilled water, saline solution, and a buffer aqueous solution, which are injectable waters applicable to the human body.

11. A soft tissue filling composition according to claim 1, wherein the soft tissue is one or more tissues selected from the group consisting of adipose tissue, muscle tissue, fascia tissue, dry tissue, fibrous tissue, ligament tissue, skin tissue and joint capsule tissue.

12. A soft tissue filling composition according to claim 1, wherein the composition is in the form of a putty.

13. A breast reconstruction composition comprising acellular dermal particles, The average diameter of the above-mentioned acellular dermal particles is 50 to 500 μm; A breast reconstruction composition in which the above-mentioned acellular dermal particles are included in the composition at a concentration of 15 to 20 weight%.

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