阅读说明：本技术 一种5-氨基酮戊酸水凝胶组合物及其制备方法及应用 (5-aminolevulinic acid hydrogel composition and preparation method and application thereof ) 是由 闫学海 常蕊 邹千里 邢蕊蕊 徐小洁 于 2019-10-11 设计创作，主要内容包括：本发明涉及一种5-氨基酮戊酸水凝胶组合物,所述水凝胶组合物含有5-氨基酮戊酸与凝胶因子,所述凝胶因子选自蛋白、多糖、共聚物,所述共聚物为PLGA(聚乳酸-羟基乙酸共聚物)、PLGA-PEG(聚乙二醇)-PLGA、PEO(聚氧化乙烯)-PPO(聚苯醚)-PEO中的任意一种或至少两种的混合物。本发明的5-氨基酮戊酸水凝胶组合物生物相容性好,在制备皮肤美容产品、光动力治疗试剂、荧光成像剂等方面具有广阔的应用前景。(The invention relates to a 5-aminolevulinic acid hydrogel composition, which contains 5-aminolevulinic acid and a gelator, wherein the gelator is selected from protein, polysaccharide and copolymer, and the copolymer is any one or a mixture of at least two of PLGA (polylactic acid-glycolic acid copolymer), PLGA-PEG (polyethylene glycol) -PLGA and PEO (polyethylene oxide) -PPO (polyphenylene oxide) -PEO. The 5-aminolevulinic acid hydrogel composition has good biocompatibility and has wide application prospect in the aspects of preparing skin beauty products, photodynamic therapy reagents, fluorescence imaging agents and the like.)

1. A5-aminolevulinic acid hydrogel composition, which comprises 5-aminolevulinic acid and a gelator, wherein the gelator is selected from protein, polysaccharide and copolymer, and the copolymer is any one or a mixture of at least two of PLGA (polylactic acid-glycolic acid copolymer), PLGA-PEG (polyethylene glycol) -PLGA and PEO (polyethylene oxide) -PPO (polyphenylene oxide) -PEO; optionally, the hydrogel composition may or may not contain ingredients other than water.

2. The hydrogel composition of claim 1, wherein the ratio of 5-aminolevulinic acid to gelator is 1-10: 1-10.

3. The hydrogel composition according to claim 1 or 2, wherein the gelator comprises protein, and the protein is any one of silk fibroin, collagen and gelatin or a mixture of at least two of the silk fibroin, the collagen and the gelatin.

4. The 5-aminolevulinic acid hydrogel composition according to claim 2, wherein the 5-aminolevulinic acid is present in an amount of 0.1 to 30% by mass and the protein is present in an amount of 0.1 to 30% by mass.

5. The 5-aminolevulinic acid hydrogel composition according to claim 1, wherein the 5-aminolevulinic acid is contained in an amount of 0.1 to 30% by mass, and the polysaccharide is contained in an amount of 0.1 to 30% by mass.

6. The 5-aminolevulinic acid hydrogel composition according to claim 1, wherein the 5-aminolevulinic acid is present in an amount of 0.1 to 30% by mass and the copolymer is present in an amount of 0.1 to 30% by mass.

7. the method of making a 5-aminolevulinic acid hydrogel composition of claims 1-6, comprising the steps of:

(1) Firstly, weighing required amount of 5-aminolevulinic acid, and dissolving in an aqueous solution;

(2) Mixing the aqueous solution prepared in the step (1) with components capable of forming hydrogel to prepare the 5-aminolevulinic acid hydrogel composition.

8. Use of the 5-aminolevulinic acid hydrogel composition of claims 1-7 for the preparation of a cosmetic product or a medical drug.

9. Use of the 5-aminolevulinic acid hydrogel composition of claims 1-7 for the preparation of a medicament for the treatment of a tumor; preferably, the drug for treating tumor is photodynamic therapy drug.

Technical Field

The invention belongs to the field of biological medicines, and relates to a 5-aminolevulinic acid hydrogel composition, a preparation method thereof and application thereof in skin beauty, fluorescence imaging, photodynamic therapy and the like.

Background

5-aminolevulinic acid is a photodynamic prodrug which can be converted into protoporphyrin under the action of heme enzyme, and the protoporphyrin can absorb light and convert the light energy into fluorescence or active oxygen form to release energy. The 5-aminolevulinic acid has wide application prospect, such as skin beauty, fluorescence imaging and photodynamic cancer treatment. In fluorescence imaging techniques, 5-aminolevulinic acid molecules in biological tissues are converted into protoporphyrins under the action of heme enzymes, and the intensity of fluorescence signals emitted by the protoporphyrins is linearly related to the amount of the protoporphyrins within a certain range. Therefore, the imaging technology can be used for continuously and dynamically monitoring various biological processes in vivo in real time, and has the advantages of convenience, intuition and high sensitivity. In photodynamic therapy, 5-aminolevulinic acid has become widely used in clinical therapy as an FDA approved drug. Compared with the traditional radiotherapy and chemotherapy, the photodynamic therapy has the advantages of less harm to normal cells, simple process, remote controllability and short treatment time due to high selectivity and minimal invasion, thereby greatly reducing the generation of side effects and becoming a powerful technique for treating cancers. In addition, photodynamic therapy techniques can be implemented with only three essential elements: the laser light source, the photosensitive molecule with light conversion performance and the oxygen are adopted. 5-aminolevulinic acid functions as a photosensitive molecule in photodynamic therapy.

5-aminolevulinic acid for fluorescence imaging and photodynamic therapy requires a certain retention time at the lesion site. Since 5-aminolevulinic acid is a water-soluble molecule, the drug diffuses rapidly into the surrounding skin and tissues, and a longer-term sustained administration cannot be achieved, reducing the therapeutic effect. The stability of the aqueous solution of 5-aminolevulinic acid is poor, and the inactivation half-life period of the aqueous solution of 5-aminolevulinic acid is about 15 hours under neutral conditions, so that the storage and the use of the aqueous solution of 5-aminolevulinic acid are greatly influenced. In addition, 5-aminolevulinic acid molecules have a short half-life after intravenous and oral administration, resulting in problems such as low bioavailability. Therefore, it is important to develop a novel 5-aminolevulinic acid dosage form to solve the problem. Based on the above, the invention provides the 5-aminolevulinic acid hydrogel composition which is used for enhancing the stability of the 5-aminolevulinic acid, realizing sustained release administration, improving the treatment effect and reducing the side effect.

Proteins are important components of the organism in nature, and all important parts of the organism require the participation of proteins. The protein is formed by dehydrating and condensing amino acid, can form different secondary structures, and further forms a three-dimensional gel network structure through self-organization and winding under proper conditions. Intermolecular hydrogen bonding, electrostatic and hydrophobic interactions may improve their stability. These gel network structures have shown some advantages in the delivery of drug molecules, which can be used in chemotherapy, phototherapy, immunotherapy.

Polysaccharides are formed by condensation and dehydration of a plurality of monosaccharide molecules, and carbohydrates and derivatives thereof conforming to the concept of high molecular compounds are called polysaccharides and broadly classified into homogeneous polysaccharides and heterogeneous polysaccharides. The polysaccharide has a wide variety of types, is widely distributed and plays an important role, and is rapidly developed as a carrier of chemical drugs and phototherapy drugs at present due to the important role played in drug delivery by the high biocompatibility, low immunogenicity and biodegradability of the polysaccharide.

Besides biomolecules such as proteins and polysaccharides, some copolymers with good biocompatibility, such as PLGA (polylactic-co-glycolic acid), PLGA-PEG (polyethylene glycol) -PLGA, PEO (polyethylene oxide) -PPO (polyphenylene oxide) -PEO, etc., have also been used clinically.

Based on the application of the 5-aminolevulinic acid molecule in fluorescence imaging and photodynamic therapy, the molecule is loaded in hydrogel formed by protein, polysaccharide and copolymer, and the interaction of the hydrogel and the 5-aminolevulinic acid is expected to improve the stability and bioavailability of the 5-aminolevulinic acid, realize the sustained release and transformation of the 5-aminolevulinic acid, and improve the potential in the aspects of skin beautification and diagnosis and treatment.

Disclosure of Invention

The invention aims to provide a 5-aminolevulinic acid hydrogel composition which is used for beauty treatment and biomedicine; the hydrogel composition formed by the invention has the characteristics of good stability, high biological safety and high bioavailability, and can be used for skin beauty, fluorescence imaging, photodynamic therapy and the like.

In order to achieve the purpose, the invention adopts the following technical scheme:

In a first aspect, the present invention provides a 5-aminolevulinic acid hydrogel composition, which comprises 5-aminolevulinic acid and a gelator, wherein the gelator is selected from proteins, polysaccharides and copolymers, and the copolymers are any one or a mixture of at least two of PLGA (polylactic-co-glycolic acid), PLGA-PEG (polyethylene glycol) -PLGA, PEO (polyethylene oxide) -PPO (polyphenylene oxide) -PEO; optionally, the hydrogel composition may or may not contain ingredients other than water.

In a preferred embodiment of the invention, the ratio of the 5-aminolevulinic acid to the gelator is 1-10: 1-10.

In a preferred embodiment of the present invention, the gelator comprises protein, which is any one or a mixture of at least two of silk fibroin, collagen and gelatin. By using the protein as the gelator, the stability of the 5-aminolevulinic acid can be greatly enhanced compared with other gelators, and the technical effect is not possessed by other gelators.

in another preferred embodiment of the present invention, the polysaccharide is any one of trehalose, chitosan, hyaluronic acid or a mixture of at least two thereof.

In a second aspect, the present invention provides the preparation of a hydrogel composition of 5-aminolevulinic acid as described in the first aspect, comprising the steps of:

i. Weighing 5-aminolevulinic acid with required amount, dissolving in water, and preparing into 5-aminolevulinic acid aqueous solution;

mixing the 5-aminolevulinic acid aqueous solution with a gel factor to obtain a hydrogel composition of 5-aminolevulinic acid;

In the 5-aminolevulinic acid hydrogel composition, the mass content of 5-aminolevulinic acid is 0.1-30%, and the mass content of gel factors is 0.1-30%.

In a third aspect, the present invention also provides the use of a 5-aminolevulinic acid hydrogel composition according to the first aspect of the invention; the 5-aminolevulinic acid has wide application in skin cosmetology and disease treatment, and the 5-aminolevulinic acid hydrogel composition can improve the retention of the 5-aminolevulinic acid in local positions and enhance the conversion of the 5-aminolevulinic acid into protoporphyrin, so that the value of the 5-aminolevulinic acid hydrogel composition in skin cosmetology and disease treatment is enhanced, and therefore, the 5-aminolevulinic acid hydrogel composition can be used for preparing cosmetology products and medical drugs.

Compared with the existing 5-aminolevulinic acid injection, the invention has at least the following beneficial effects:

(1) The hydrogel composition taking the protein as the gelator can prolong the stability of the 5-aminolevulinic acid. The inactivation half-life of 5-aminolevulinic acid in aqueous solution is about 15 hours, which greatly affects the preservation and use of 5-aminolevulinic acid aqueous solution. The stability of the 5-aminolevulinic acid can be obviously improved through the interaction of the hydrogel and the 5-aminolevulinic acid, and the inactivation half-life can be prolonged to more than 100 hours. The strategy for improving the stability of the 5-aminolevulinic acid by using the hydrogel with the protein as the gelator is not reported in documents, and is beneficial to the storage and use of the 5-aminolevulinic acid.

(2) The hydrogel composition provided by the invention can prolong the retention time of 5-aminolevulinic acid molecules, and after the hydrogel composition is locally coated, the retention time is prolonged by more than one time;

(3) The 5-aminolevulinic acid hydrogel composition provided by the invention can enhance the conversion of 5-aminolevulinic acid into protoporphyrin, and the amount of protoporphyrin generated by in-situ conversion after local injection is more than doubled compared with an aqueous solution of 5-aminolevulinic acid.

drawings

FIG. 1 is a schematic representation of a 5-aminolevulinic acid hydrogel composition of example 1;

FIG. 2 is an atomic diagram of the 5-aminolevulinic acid hydrogel composition of example 2;

FIG. 3 is a circular dichroism plot of the 5-aminolevulinic acid hydrogel composition of example 3;

FIG. 4 is a photograph of an in vivo fluorescence image of the 5-aminolevulinic acid hydrogel composition of example 4;

FIG. 5 is a rheological profile of the 5-aminolevulinic acid hydrogel composition of example 5;

FIG. 6 is a scanning electron micrograph of a 5-aminolevulinic acid hydrogel composition according to example 6;

FIG. 7 is a transmission diagram of the 5-aminolevulinic acid hydrogel composition of example 7;

FIG. 8 is a graph showing the degradation curve of 5-aminolevulinic acid in the hydrogel composition of example 8, and the degradation curve of 5-aminolevulinic acid in an aqueous solution;

FIG. 9 is a graph showing the degradation curve of 5-aminolevulinic acid in the hydrogel composition of example 9;

FIG. 10 is a graph showing the degradation curve of 5-aminolevulinic acid in the hydrogel composition of example 10;

FIG. 11 is a graph showing the change of fluorescence intensity with time after the hydrogel composition of example 11 was injected in situ into a tumor and the change of fluorescence intensity after the injection of an aqueous solution of 5-aminolevulinic acid.

The present invention is described in further detail below. The following examples are merely illustrative of the present invention and do not represent or limit the scope of the claims, which are defined by the claims.

Detailed Description

The present invention will be described in detail below with reference to examples, but the present invention is not limited to the following examples.