Gel for Injection Containing Controlled Degradation Polyester Microspheres

Abstract

The present invention provides a gel for injection containing controlled degradation polyester microspheres. The gel for injection consists of crosslinked sodium hyaluronate gel, non-crosslinked sodium hyaluronate gel, polyester microspheres wrapped with hard fat and a balanced salt solution. The polyester microspheres are separated from water by means of wrapping and hydrophobic effect of the hard fat, and accordingly the present invention solve the problem that polyester materials are prone to degradation in gel. In the meantime, the hard fat has the characteristic of low melting point (melting point being 33° C.-39° C.), after the product is injected into human body, the hard fat is molten and separated under the action of human body temperature, and the wrapped polyester microspheres are released so that the microspheres can be degraded in the human body to achieve controlled degradation.

Claims

1. A gel for injection containing controlled degradation polyester microspheres, comprising crosslinked sodium hyaluronate gel, non-crosslinked sodium hyaluronate gel, polyester microspheres wrapped with hard fat and a balanced salt solution.

2. The gel for injection containing the controlled degradation polyester microspheres of claim 1, wherein the microspheres in the gel for injection remain stable at room temperature with no degradation or micro-degradation when not in use, and after use via subcutaneous injection, the polyester microspheres are released under the action of human body temperature to accelerate degradation of the micro spheres in the body.

3. The gel for injection containing the controlled degradation polyester microspheres of claim 1, wherein when the gel for injection is prepared, the polyester microspheres wrapped with the hard fat are prepared firstly and named as first microspheres, then gel blocks of the crosslinked sodium hyaluronate gel wrapping outsides of the first microspheres are prepared, then the non-crosslinked sodium hyaluronate gel is added to obtain a mixture which is stirred for even dispersion, and the gel for injection is obtained.

4. The gel for injection containing the controlled degradation polyester microspheres of claim 3, wherein preparation steps of the polyester microspheres wrapped with the hard fat comprise: 1) dissolving the hard fat in a solvent to prepare a solution of 0.5%-6%; 2) under stirring, adding the polyester microspheres into the solution to make the microspheres evenly dispersed; and 3) conducting suction filtration to separate the microspheres from the solution, placing the microspheres into a room-temperature bellow for drying, and obtaining the polyester microspheres wrapped with the hard fat.

5. The gel for injection containing the controlled degradation polyester microspheres of claim 1, wherein the hard fat comprises one or more of type 34, type 36 and type 38.

6. The gel for injection containing the controlled degradation polyester microspheres of claim 1, wherein the polyester microspheres comprise one or more of poly-L-lactic acid microspheres, p olycaprolactone microspheres, glycolide-lactide copolymer microspheres and poly(p-dioxanone) microspheres and have a particle size range of 3-65 μm.

7. The gel for injection containing the controlled degradation polyester microspheres of claim 3, characterized in being prepared through the following steps: S1: preparing the polyester microspheres wrapped with the hard fat; S2: dissolving sodium hyaluronate dry powder in purified water, adding a crosslinking agent in the solution, stirring, adding the polyester microspheres wrapped with the hard fat, stirring and reacting for 2-18 h to form the crosslinked sodium hyaluronate gel containing the microspheres; S3: breaking the above crosslinked sodium hyaluronate gel containing the microspheres into small gel blocks of 1-2 cm.sup.3, and soaking and dialyzing the small gel blocks with the balanced salt solution; S4: homogenizing the dialyzed gel with a dispersion machine, adding the non-crosslinked sodium hyaluronate gel, and stirring; and S5: conducting filling and sterilization to obtain a finished product.

8. The gel for injection containing the controlled degradation polyester microspheres of claim 7, wherein feeding amount of the polyester microspheres wrapped with the hard fat accounts for 3%-30% of total mass of a product; and feeding amount of sodium hyaluronate accounts for, by dry powder, 1.2%-2.5% of the total mass of the product; and the balanced salt solution is a sodium chloride solution or phosphate buffered solution with an osmotic pressure of 200-400 mOsmol/L and pH of 6.5-7.5.

9. The gel for injection containing the controlled degradation polyester microspheres of claim 7, wherein the non-crosslinked sodium hyaluronate gel is prepared by dissolving the sodium hyaluronate dry powder in the balanced salt solution.

10. The gel for injection containing the controlled degradation polyester microspheres of claim 1, wherein the gel is capable of improving subcutaneous capacity of human skin and repairing wrinkles, folds, scars and deferring aging of the skin.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0034] FIG. 1 and FIG. 2 are scanning electron microscope comparison diagrams of PLLA microspheres wrapped with hard fat (type 38) and unwrapped PLLA microspheres prepared by embodiment 1 of the present invention; wherein FIG. 1 shows the PLLA microspheres wrapped with hard fat (type 38), and FIG. 2 shows the unwrapped PLLA microspheres.

[0035] FIG. 3 is a degradation curve comparison diagram of the PLLA microspheres of a product prepared by embodiment 1 of the present invention and a control product at 25° C.

[0036] FIG. 4 is a degradation curve diagram of the PLLA microspheres of the product prepared by the embodiment 1 of the present invention at different storage temperatures.

DETAILED DESCRIPTION

[0037] The substantive features and notable progress of the present invention are further clarified by introducing embodiments of the present invention, but the present invention is by no means limited to the embodiments.

Embodiment 1

[0038] S1: PLLA microspheres wrapped with hard fat were prepared: the hard fat of type 38 was dissolved in petroleum ether to prepare a solution of 2%; under stirring, the PLLA microspheres were added into the solution to be evenly dispersed; suction filtration was conducted to separate the microspheres from the solution, the microspheres were placed into a room-temperature bellow to be dried, to obtain the PLLA microspheres wrapped with the hard fat;

[0039] S2: 10.0 g sodium hyaluronate (dry powder) was dissolved in 10 mL purified water, then 120 μL divinyl sulphone, as a crosslinking agent, was added into the solution and stirred for even mixing, then 30.5 g PLLA microspheres wrapped with the hard fat were added, the mixture was evenly stirred and allowed to react for 2-18 h to form crosslinked sodium hyaluronate gel containing the microspheres;

[0040] S3: the above gel was broken into small gel blocks of 1-2 cm.sup.3, and then the small gel blocks were soaked and dialyzed with the balanced salt solution;

[0041] S4: the dialyzed gel was homogenized with a dispersion machine, then the non-crosslinked sodium hyaluronate gel (prepared by dissolving sodium hyaluronate dry powder in the balanced salt solution) accounting for 10% of the mass of the dialyzed gel was added, and the mixture was stirred to be evenly dispersed; and

[0042] S5: filling and sterilization were conducted to obtain a finished product.

[0043] Gel containing PLLA microspheres unwrapped with the hard fat was prepared through the same steps as S2 to S5, serving as a control group.

[0044] FIG. 1 shows the micromorphology of the PLLA microspheres wrapped with the hard fat (type 38), and when compared with the unwrapped microspheres in FIG. 2, it is obvious that a layer of rough hard fat was adhered to the smooth surface of the microspheres after treatment in S1.

[0045] FIG. 3 shows the comparison of degradation rates of the gel containing the PLLA microspheres wrapped with the hard fat (this embodiment) and the gel containing the microspheres unwrapped with the hard fat (the control group) at room temperature (25° C.). By dissociating the gel with hyaluronidase, the PLLA microspheres were extracted from the two groups of gel, and then the intrinsic viscosity of the microspheres was measured through a Ubbelohde viscometer. As can be seen from the figure, at room temperature, the PLLA microspheres in the gel of this embodiment merely underwent a minor reduction in the intrinsic viscosity within 8 weeks, which indicated that there was little PLLA molecular degradation; and the PLLA microspheres in the gel of the control group underwent obvious degradation after preservation for 2 weeks, and degraded to a state of low intrinsic viscosity in the 8th week.

[0046] FIG. 4 shows a degradation curve diagram of the prepared gel preserved at 25° C. for 4 weeks, and then preserved at 37° C. for 12 weeks. As can be seen from the figure, the PLLA microspheres were hardly degraded in the gel within 4 weeks at a room-temperature preservation condition of 25° C.; while when the temperature rose to 37° C., the degradation was obvious, which reflected the controllable degradation characteristic of the PLLA microspheres in the sample.

Embodiment 2

[0047] S1: polycaprolactone (PCL) microspheres wrapped with the hard fat were prepared: hard fat of type 36 was dissolved in trichloromethane to prepare a solution of 6%; under stirring, the PCL microspheres were added into the solution to be evenly dispersed; suction filtration was conducted to separate the microspheres from the solution, the microspheres were placed into a room-temperature bellow to be dried to obtain the PCL microspheres wrapped with the hard fat;

[0048] S2: 10.0 g sodium hyaluronate (dry powder) was dissolved in 100 mL purified water, then 120 μL divinyl sulphone as crosslinking agent was added into the solution to be stirred for even mixing, then 11.4 g PCL microspheres wrapped with the hard fat were added, and the mixture was evenly stirred and allowed to react for 2-18 h to form crosslinked sodium hyaluronate gel containing the microspheres;

[0049] S3: the above gel was broken into small gel blocks of 1-2 cm.sup.3, and then the small gel blocks were soaked and dialyzed with the balanced salt solution;

[0050] S4: the dialyzed gel was homogenized with a dispersion machine, then the non-crosslinked sodium hyaluronate gel (prepared by dissolving sodium hyaluronate dry powder in the balanced salt solution) accounting for 10% of the mass of the dialyzed gel was added, and the mixture was stirred to be evenly dispersed; and

[0051] S5: filling and sterilization were conducted to obtain a finished product.

Embodiment 3

[0052] S1: PLLA microspheres wrapped with the hard fat were prepared: the hard fat of type 37 was dissolved in ether to prepare a solution of 0.5%; under stirring, the PLLA microspheres were added into the solution to be evenly dispersed; suction filtration was conducted to separate the microspheres from the solution, the microspheres were placed into a room-temperature bellow to be dried, to obtain the PLLA microspheres wrapped with the hard fat;

[0053] S2: 10.0 g sodium hyaluronate (dry powder)was dissolved in 100 mL purified water, then 120 μL divinyl sulphone as a crosslinking agent was added into the solution and stirred for even mixing, then 51.0 g PCL microspheres wrapped with the hard fat were added, and the mixture was evenly stirred and allowed to react for 2-18 h to form crosslinked sodium hyaluronate gel containing the microspheres;

[0054] S3: the above gel was broken into small gel blocks of 1-2 cm.sup.3, and then the small gel blocks were soaked and dialyzed with the balanced salt solution;

[0055] S4: the dialyzed gel was homogenized with a dispersion machine, then the non-crosslinked sodium hyaluronate gel (prepared by dissolving sodium hyaluronate dry powder in the balanced salt solution) accounting for 10% of the mass of the dialyzed gel was added, and a mixture was stirred for even dispersion; and

[0056] S5: filling and sterilization were conducted to obtain a finished product.

[0057] Those skilled in the art will easily understood that the above mentioned are only preferable embodiments of the present invention and shall not be used to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.