Collagen-containing filling agent and application thereof

Abstract

The invention discloses a filler containing collagen and application thereof, and relates to the field of implants. The filling agent is obtained by compounding a filler and a solvent, the filler contains collagen, the content of the collagen in the filling agent is 10-40 mg / mL, and the osmotic pressure of the filling agent is 200-320 mOsm / kg; the solvent contains monohydrogen phosphate, dihydric phosphate and chlorine salt, salt ions in the chlorine salt are monovalent salt ions, the osmotic pressure of the solvent is 270-430 mOsm / kg, and the concentration of the chlorine salt in the solvent is 6-12 g / L. Calcification can be avoided, and collagen cannot be separated out.

Description

Technical Field

[0001] The present application relates to the field of implants, and in particular to a filler containing collagen and an application thereof. Background Art

[0002] As we age, the loss of collagen and hyaluronic acid in the face accelerates, causing wrinkles and sagging of the facial skin. More and more people are choosing medical cosmetology to tighten their skin and remove wrinkles. Some common projects include photoelectric projects and injection filler projects. Existing injection fillers mainly include hyaluronic acid, collagen, and biodegradable microspheres.

[0003] Since implant fillers need to be injected into the human body, the osmotic pressure usually needs to be controlled to be substantially equal to that of human blood, which is safer. Therefore, when preparing collagen fillers, osmotic pressure regulators are generally added to the collagen stock solution to adjust the osmotic pressure, and the added osmotic pressure regulators cannot affect the properties of collagen. The inventors of the present application tried to add monohydrogen phosphate and dihydrogen phosphate to the collagen stock solution to adjust the osmotic pressure of the implant to be close to that of human plasma, but found in animal experiments that the implants prepared in this way would produce calcification under the skin. Summary of the invention

[0004] The embodiments of the present application provide a filler containing collagen and application thereof, which can prevent calcification and prevent collagen from precipitating.

[0005] This application is implemented as follows: In a first aspect, the present application provides a filler containing collagen, wherein the filler is compounded with a filler and a solvent, wherein the filler contains collagen, the content of collagen in the filler is 10-40 mg / mL, and the osmotic pressure of the filler is 200-320 mOsm / kg; the solvent contains monohydrogen phosphate, dihydrogen phosphate and chloride, the salt ions in the chloride are monovalent salt ions, the osmotic pressure of the solvent is 270-430 mOsm / kg, and the concentration of the chloride in the solvent is 6-12 g / L.

[0006] In one possible embodiment, the chloride salt includes at least one of sodium chloride and potassium chloride.

[0007] In a possible implementation manner, the mass ratio of the sodium chloride to the potassium chloride is 1:30-50.

[0008] In a possible embodiment, the monohydrogen phosphate is sodium monohydrogen phosphate, and the dihydrogen phosphate is potassium dihydrogen phosphate.

[0009] In one possible embodiment, the collagen is animal-derived collagen.

[0010] In a possible embodiment, the filler further includes degradable microspheres.

[0011] In a possible embodiment, the degradable microspheres include degradable aliphatic polyester microspheres.

[0012] In a possible embodiment, the degradable aliphatic polyester is at least one selected from polycaprolactone, poly(L-lactic acid), poly(glycolic acid) and poly(lactic acid-glycolic acid) copolymer.

[0013] In a possible embodiment, the mass concentration of the degradable microspheres in the filler is 5-15%.

[0014] In a second aspect, the present application provides a use of a filler containing collagen as in the first aspect in the preparation of facial filling products, urethral filling products, and orthopedic filling products.

[0015] This application has at least the following beneficial effects: The collagen-containing filler of the present application has a collagen content of 10~40mg / mL, and the osmotic pressure of the solvent is 270~430mOsm / kg. After the filler and the solvent are compounded, the osmotic pressure of the filler can be guaranteed to be close to the osmotic pressure of human plasma. In addition, the solvent with an osmotic pressure of 270~430mOsm / kg contains monohydrogen phosphate, dihydrogen phosphate and chloride salt. The chloride salt can provide a certain osmotic pressure, and the concentration of the chloride salt in the solvent is 6~12g / L. The concentration of monohydrogen phosphate and dihydrogen phosphate can be reduced while ensuring the osmotic pressure of the solvent. Experimental results show that the solvent defined in the present application can make the filler implanted in the body without calcification. Moreover, the solvent defined in the present application will not cause the collagen in the filler to precipitate. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This is a photograph of the experimental animal 4 weeks after the filler of Example 1 of the present application was implanted subcutaneously in the experimental rat; Figure 2 This is a photograph of the experimental animal 4 weeks after the filler of Example 2 of the present application was implanted subcutaneously in the experimental rat; Figure 3 This is a photograph of the experimental animal 4 weeks after the filler of Example 3 of the present application was implanted subcutaneously in the experimental rat; Figure 4 This is a photograph of the experimental animal 4 weeks after the filler of Comparative Example 1 of the present application was implanted subcutaneously. DETAILED DESCRIPTION

[0017] The embodiments of the present application will be described in detail below in conjunction with the examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present application and should not be considered as limiting the scope of the present application. In the examples, if specific conditions are not specified, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0018] Since implant fillers need to be injected into the human body, they usually need to control the osmotic pressure to be basically equal to the osmotic pressure of human blood, which is safer. Therefore, when preparing collagen fillers, osmotic pressure regulators are generally added to the collagen stock solution to adjust the osmotic pressure, and the added osmotic pressure regulators cannot affect the properties of collagen. The inventors of this application tried to add monohydrogen phosphate and dihydrogen phosphate to the collagen stock solution to adjust the osmotic pressure of the implant to be close to the osmotic pressure of human plasma, but found in animal experiments that the implants prepared in this way will produce calcification under the skin. According to the inventors' research, this may be because simple monohydrogen phosphate and dihydrogen phosphate want to adjust the filler to an osmotic pressure close to that of human plasma, and the amount that needs to be added is large, resulting in too high a concentration of phosphate in the filler, which causes calcium enrichment after implantation in the body, thereby leading to calcification.

[0019] In addition, the inventors of the present application also tried to add saline to the implant containing collagen to adjust the osmotic pressure, but found during the experiment that in order to adjust the osmotic pressure of the implant to be close to human plasma, a large volume of saline needs to be added, resulting in a high concentration of NaCl in the implant, thereby causing collagen to precipitate; and if a small volume of saline is added, the concentration of NaCl in the implant is reduced without collagen precipitation, which will cause the osmotic pressure of the implant to be much lower than the osmotic pressure of human blood. Based on this, the present application provides a filler containing collagen and its application.

[0020] The following is a detailed description of a filler containing collagen and its application according to an embodiment of the present application: In a first aspect, an embodiment of the present application provides a filler containing collagen, wherein the filler is compounded with a filler and a solvent, the filler contains collagen and a solvent, the content of collagen in the filler is 10-40 mg / mL, and the osmotic pressure of the filler is 200-320 mOsm / kg; the solvent contains monohydrogen phosphate, dihydrogen phosphate and chloride, the salt ions in the chloride are monovalent salt ions, the osmotic pressure of the solvent is 270-430 mOsm / kg, and the concentration of the chloride in the solvent is 3-8 g / L.

[0021] The filler containing collagen of the present application, the collagen content in the filler is 10~40mg / mL, the osmotic pressure of the solvent is 270~430mOsm / kg, and the filler and the solvent are compounded to ensure that the osmotic pressure of the filler is close to the osmotic pressure of human plasma. Optionally, the collagen is animal-derived collagen. Exemplarily, the osmotic pressure of the filler is 200mOsm / kg, 210mOsm / kg, 220mOsm / kg, 230mOsm / kg, 240mOsm / kg, 250mOsm / kg, 260mOsm / kg, 270mOsm / kg, 280mOsm / kg, 290mOsm / kg, 300mOsm / kg, 310mOsm / kg, 320mOsm / kg, or any value between any two.

[0022] Illustratively, the content of collagen in the filler is any one of 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL and 40 mg / mL, or a value between any two of them.

[0023] Illustratively, the osmotic pressure of the solvent is any one of 270mOsm / kg, 280mOsm / kg, 290mOsm / kg, 300mOsm / kg, 310mOsm / kg, 320mOsm / kg, 330mOsm / kg, 340mOsm / kg, 350mOsm / kg, 360mOsm / kg, 370mOsm / kg, 380mOsm / kg, 390mOsm / kg, 400mOsm / kg, 410mOsm / kg, 420mOsm / kg and 430mOsm / kg, or a value between any two of them.

[0024] In addition, the solvent with an osmotic pressure of 270~430mOsm / kg contains monohydrogen phosphate, dihydrogen phosphate and chloride. Chloride can provide a certain osmotic pressure, and the concentration of chloride in the solvent is 6~12g / L. The concentration of monohydrogen phosphate and dihydrogen phosphate can be reduced while ensuring the osmotic pressure of the solvent. The experimental results show that the solvent defined in this application can make the filler implanted in the body without calcification. Moreover, the solvent defined in this application will not cause the collagen in the filler to precipitate. In addition, the salt ions in the chloride are monovalent salt ions, which can make the ion concentration provided by the chloride salt higher under the same chloride mass, and can provide a higher osmotic pressure, thereby further reducing the overall concentration of monohydrogen phosphate and dihydrogen phosphate, which is more conducive to the filler not producing calcification in the body. Moreover, if the salt ions in the chloride are divalent salt ions (such as calcium ions), the filler can easily cause calcification after being implanted in the body.

[0025] Optionally, the concentration of the chloride salt in the solvent is any one of 6 g / L, 7 g / L, 8 g / L, 9 g / L, 10 g / L, 11 g / L and 12 g / L or a value between any two thereof. In addition, the chloride salt includes at least one of sodium chloride and potassium chloride.

[0026] Optionally, the mass ratio of sodium chloride to potassium chloride is 1:30-50, for example, any one of 1:30, 1:35, 1:40, 1:45 and 1:50 or a value between any two of them.

[0027] Furthermore, the monohydrogen phosphate is sodium monohydrogen phosphate, and the dihydrogen phosphate is potassium dihydrogen phosphate. It should be noted that in other embodiments, the monohydrogen phosphate may also be phosphoric acid; potassium monohydrogen, etc.; and the dihydrogen phosphate is sodium dihydrogen phosphate.

[0028] Furthermore, the filler also includes degradable microspheres. After the filler is implanted into the body, the collagen and degradable microspheres contained in the filler can achieve an immediate filling effect. As time goes by, the collagen is first absorbed by the human body, while the degradable microspheres gradually degrade to stimulate the regeneration of collagen in the body, so that the filling effect lasts.

[0029] Optionally, the degradable microspheres include degradable aliphatic polyester microspheres, and the degradable aliphatic polyester is at least one selected from polycaprolactone, poly(L-lactic acid), polyglycolic acid and poly(lactic acid-glycolic acid copolymer).

[0030] Exemplarily, the mass concentration of the degradable microspheres in the filler is 5-15%, for example, any one of 5%, 7%, 8%, 10%, 12%, 13% and 15%, or a value between any two of them.

[0031] In a second aspect, the present application provides a use of a filler containing collagen as in the first aspect in the preparation of facial filling products, urethral filling products, and orthopedic filling products.

[0032] The filler containing collagen of the present application can play a certain supporting effect and can be used for facial filling, urethral filling and orthopedic filling.

[0033] The collagen-containing filler and its application are further described in detail below with reference to the examples. Example

[0034] The present embodiment provides a filler containing collagen, which is obtained by homogenizing a collagen stock solution and a solvent, and the osmotic pressure of the filler is 298mOsm / kg. The content of collagen in the filler is 30mg / mL, and the solvent contains sodium monohydrogen phosphate, potassium dihydrogen phosphate, sodium chloride, and potassium chloride. Among them, the total concentration of monohydrogen phosphate and dihydrogen phosphate in the solvent is 0.015M, the concentration of sodium chloride is 12g / L, the concentration of potassium chloride is 0.3g / L, and the osmotic pressure of the solvent is 420mOsm / kg. Example

[0035] The present embodiment provides a filler containing collagen, which is obtained by homogenizing a collagen stock solution and a solvent, and the osmotic pressure of the filler is 239mOsm / kg. The content of collagen in the filler is 32mg / mL, and the solvent contains sodium monohydrogen phosphate, potassium dihydrogen phosphate, sodium chloride, and potassium chloride. Among them, the total concentration of monohydrogen phosphate and dihydrogen phosphate in the solvent is 0.012M, the concentration of sodium chloride is 9.5g / L, the concentration of potassium chloride is 0.25g / L, and the osmotic pressure of the solvent is 335mOsm / kg. Example

[0036] The present embodiment provides a filler containing collagen, which is obtained by homogenizing a collagen stock solution and a solvent, and the osmotic pressure of the filler is 203mOsm / kg. The content of collagen in the filler is 32mg / mL, and the solvent contains sodium monohydrogen phosphate, potassium dihydrogen phosphate, sodium chloride, and potassium chloride. Among them, the total concentration of monohydrogen phosphate and dihydrogen phosphate in the solvent is 0.01M, the concentration of sodium chloride is 8g / L, the concentration of potassium chloride is 0.2g / L, and the osmotic pressure of the solvent is 284mOsm / kg.

[0037] Comparative Example 1 This comparative example provides a filler containing collagen, which is obtained by mixing a collagen stock solution with a solvent and then homogenizing it, and the osmotic pressure of the filler is 246mOsm / kg. The content of collagen in the filler is 38.2mg / mL, and the solvent is composed of sodium monohydrogen phosphate and potassium dihydrogen phosphate. Among them, the total ion concentration of monohydrogen phosphate and dihydrogen phosphate in the solvent is 0.15M, and the osmotic pressure of the solvent is 338mOsm / kg.

[0038] Animal experiments (1) Preoperative preparation The experimental rats were fasted for 12 hours before the operation, but not water deprivation. Each experimental rat was randomly numbered and anesthetized with intraperitoneal injection of Zotalitone before the operation.

[0039] (2) Surgical method After successful anesthesia, the experimental rats were fixed on the surgical board, the dorsal hair of the surgical area in the middle of the back (about 5cm×8cm), the surgical area was disinfected with iodine and alcohol, and subcutaneous injection implantation points were made 1-2cm on both sides of the midline of the animal's back spine from top to bottom, and the collagen injections of Examples 1-3 and Comparative Example 1 were implanted into the implantation points respectively. Among them, the implantation dose of the filler at each point was about 0.2mL, and the surgical area was disinfected with iodine.

[0040] (3) Detection method After the experimental rats were raised normally for 4 weeks, they were killed, and their cortices were cut open to expose the subcutaneous injection implantation sites.

[0041] The photos of the subcutaneous implantation points corresponding to Examples 1 to 3 are as follows: Figure 1~Figure 3 As shown, the photo of the subcutaneous implantation point corresponding to Comparative Example 1 is as follows Figure 4 As shown. Figure 1~Figure 3 It can be seen that the subcutaneous implantation point is in a soft state, while Figure 4 The subcutaneous implantation point in the present invention is in a hard calcified state. This shows that the filler containing collagen in the embodiment of the present application (the solvent contains sodium monohydrogen phosphate, potassium dihydrogen phosphate, sodium chloride, and potassium chloride) does not cause calcification, while the filler containing collagen in comparative example 1 (the solvent contains only sodium monohydrogen phosphate and potassium dihydrogen phosphate) causes calcification. Moreover, according to the observation of the inventor of the present application, the fillers in Examples 1 to 3 do not have the phenomenon of collagen precipitation.

[0042] The above description is only a specific embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A filler containing collagen, characterized in that: The filler is compounded by a filler and a solvent, the filler contains collagen, the content of collagen in the filler is 10-40 mg / mL, and the osmotic pressure of the filler is 200-320 mOsm / kg; the solvent contains monohydrogen phosphate, dihydrogen phosphate and chloride, the salt ions in the chloride are monovalent salt ions, the osmotic pressure of the solvent is 270-430 mOsm / kg, and the concentration of the chloride in the solvent is 6-12 g / L.

2. The collagen-containing filler according to claim 1, characterized in that: The chloride salt includes at least one of sodium chloride and potassium chloride.

3. The collagen-containing filler according to claim 1, characterized in that: The mass ratio of the sodium chloride to the potassium chloride is 1:30-50.

4. The collagen-containing filler according to claim 2, characterized in that: The monohydrogen phosphate is sodium monohydrogen phosphate, and the dihydrogen phosphate is potassium dihydrogen phosphate.

5. The collagen-containing filler according to any one of claims 1 to 4, characterized in that: The collagen is animal-derived collagen.

6. The collagen-containing filler according to any one of claims 1 to 4, characterized in that: The filler also includes degradable microspheres.

7. The collagen-containing filler according to claim 6, characterized in that: The degradable microspheres include degradable aliphatic polyester microspheres.

8. The collagen-containing filler according to claim 7, characterized in that: The degradable aliphatic polyester is at least one selected from polycaprolactone, poly(L-lactic acid), poly(glycolic acid) and poly(lactic acid-glycolic acid) copolymer.

9. The collagen-containing filler according to claim 7, characterized in that: The mass concentration of the degradable microspheres in the filler is 5-15%.

10. Use of the filler containing collagen as claimed in any one of claims 1 to 9 in the preparation of facial filling products, urethral filling products and orthopedic filling products.

Images