Photodynamic therapy gel composition for 3D printing and preparation method thereof

Abstract

The present invention discloses a photodynamic therapy gel composition for 3D printing and its preparation method. The gel composition comprises the following components: 0.1-10% by mass of a photosensitizer, 70-97.9% by mass of a temperature-sensitive gelling agent, 1-10% by mass of a coupling agent, and 1-10% by mass of an auxiliary agent. Compared with existing technologies, the present invention has the following advantages: the materials are primarily derived from natural substances, which are friendly to life and health; the preparation process is simple, with no resource waste or waste discharge, and the application environment is safe and controllable; and the temperature-sensitive hot melt characteristics are utilized for 3D printing, making it suitable for a variety of tissue and organ treatments.

Description

Technical Field

[0001] The present invention belongs to the field of photodynamic therapy medicine and pharmacy, and specifically relates to a photodynamic therapy gel composition for 3D printing and a preparation method thereof. Background Art

[0002] Photodynamic therapy (PDT) is a new method for treating tumors, precancerous lesions, proliferative skin diseases, and vascular diseases using photosensitizers and laser activation (Chinese Journal of Laser Medicine, 2007, 16(3):186). By irradiating the lesion with a specific wavelength, the photosensitizer selectively accumulates in the lesion tissue and activates it, triggering a photochemical reaction that destroys the lesion. The photosensitizer transfers energy to the surrounding oxygen, generating highly active singlet oxygen. Singlet oxygen can react with nearby biomacromolecules to produce cytotoxicity and kill the diseased cells. Compared with traditional therapies, PDT has the advantage of being able to accurately and effectively treat the disease with minimal side effects (Chinese Journal of Pharmaceutical Sciences, 1993, 28(4):208).

[0003] Gel is a general term for a macromolecular network system containing two or more components, including a semi-solid jelly containing a liquid and its dry system (dry gel). In modern pharmacy, sustained-release and controlled-release dosage forms based on gels, such as gastric retention controlled-release systems, gel matrix tablets, and topical gels, have been comprehensively studied. Drugs suitable for gel delivery systems can be administered through various routes, including the oral cavity, nasal cavity, ocular mucosa, digestive tract mucosa, vagina, rectum, and skin (Chinese Patent Medicine, 2003, 25(4):328).

[0004] When Shi Xiafei et al. studied photodynamic therapy for rectal cancer (International Journal of Biomedical Engineering, 2017, 40(3):143), they dissolved a photosensitizer in a sodium alginate solution and injected it into the rectal cavity of mice. The tail was lifted to prevent leakage and a calcium chloride solution was quickly injected to form a therapeutic suppository in situ, which caused pain to the treated subjects. Chinese patents CN107812190A, CN101524327A, CN110123738A, CN1823816A, and CN110075101A, etc., inject the drug into a mold to form a suppository. Their shape is limited by the uniform size of the mold and cannot be adapted to the treatment of various tissues and organs. Therefore, traditional drug preparation technology has severely limited the application of photodynamic therapy (PDT) in the treatment of tumors in various organs. It is necessary to introduce new preparation technology to adapt to the progress of medical technology.

[0005] Prior patent 201711106205.8 discloses a photodynamic therapy kit and preparation method for rectal tumor treatment. The kit includes: a 5-aminolevulinic acid (ALA) suppository and a suppository-type LED light source. The 5-aminolevulinic acid suppository is bullet-shaped and contains 20% 5-aminolevulinic acid. The suppository-type LED light source is a small device with a bullet-shaped suppository shape, consisting of a transparent epoxy resin-encapsulated LED unit, a lithium battery, a normally closed magnetic switch, and a constant current drive circuit, along with a matching magnetic ring. However, fatty acid glycerides are actually mixed esters, and their temperature-sensitive phase transition sensitivity is insufficient, affecting 3D printing accuracy.

[0006] Therefore, the application of 3D printing technology in the preparation and molding of photodynamic therapy gel compositions has become a challenge in photodynamic therapy pharmacology. Summary of the Invention

[0007] To solve the above technical problems, the present invention provides a 3D printable photodynamic therapy gel composition and a preparation method thereof.

[0008] The object of the present invention is achieved through the following technical solutions:

[0009] A photodynamic therapy gel composition for 3D printing, the gel composition comprising, in parts by mass:

[0010] Photosensitizer 0.1~10%

[0011] Thermosensitive gel 70~97.9%

[0012] Coupling agent 1~10%

[0013] Additives 1-10%.

[0014] The photosensitizer includes at least one of hematoporphyrin monomethyl ether, sodium hematoporphyrin, Photofrin, Visudyne and Temoporfin.

[0015] The temperature-sensitive gel comprises one or more of beeswax, palm wax, rice bran wax, fatty acid, ceramide, lauroyl diethanolamine and sitosterol.

[0016] The temperature-sensitive gel of the present invention has better printing accuracy than the fatty acid glyceride in the prior art. In the prior art, the fatty acid glyceride is actually a mixed ester, which has insufficient sensitivity in temperature-sensitive phase change and affects the 3D printing accuracy.

[0017] The coupling agent includes one or more of propylene glycol, oleic acid, N-methyl-2-pyrrolidone, Tween, isopropyl myristate, menthol and lauryl alcohol.

[0018] The auxiliary agent includes one or more of tocopherol acetate, vitamin C, vitamin E, tert-butylhydroquinone, butylated hydroxyanisole and propyl gallate.

[0019] The preparation method of the gel composition comprises the following steps:

[0020] The thermosensitive gel is heated to a temperature 0-20°C above the melting point, a photosensitizer, a penetration enhancer and an adjuvant are added, stirred thoroughly to dissolve them, and hot filtered to obtain a photodynamic therapy gel composition for 3D printing.

[0021] The 3D printer is a hot-melt 3D printer with a print head aperture of 0.1 to 1.0 mm.

[0022] The 3D printable photodynamic therapy gel composition 3D printed part can be modeled into a column, tube, tablet, sphere, etc. according to the treatment site, and can be equipped with a controllable protruding tail.

[0023] The application of the photodynamic therapy gel composition for 3D printing in anti-tumor preparations also falls within the scope of protection of the present invention.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] 1) The materials are mainly derived from natural substances, such as natural glycerides, natural waxes, etc., avoiding chemical irritants such as calcium chloride used in traditional technologies, and are friendly and safe to life and health;

[0026] 2) The preparation process is simple, with no waste of resources or waste discharge, and the application environment is safe and controllable;

[0027] 3) The formula uses a thermosensitive gel, which can be applied to hot-melt 3D printing. Utilizing the thermosensitive hot-melt characteristics for 3D printing, it is suitable for the treatment of a variety of tissues and organs, avoiding the limitation of traditional technology that the form of the drug is limited by the mold of uniform size, and adding a manipulable protruding tail to facilitate clinical use. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Other features, objects and advantages of the present invention will become more apparent upon reading the detailed description of non-limiting embodiments with reference to the following drawings:

[0029] Figure 1 The configuration of a 3D-printed photodynamic therapy gel composition is modeled according to the treatment site.

[0030] Figure 2 The photodynamic therapy effect of the 3D printed gel composition applied to tumors, wherein the PDT group is Example 1 and the Blank group is Comparative Example 1. DETAILED DESCRIPTION

[0031] The present invention will be described in detail below with reference to specific embodiments. The following embodiments will help those skilled in the art further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that those skilled in the art may make various changes and modifications, including any combination of the various examples, without departing from the scope of the present invention.

[0032] Example 1

[0033] A 3D-printable photodynamic therapy gel composition and a preparation method thereof. The gel composition is composed of the following components: 1% by mass of hematoporphyrin monomethyl ether (Sigma-Aldrich), 93% by mass of palm wax (melting point 82°C), 3% by mass of propylene glycol, and 3% by mass of tocopheryl acetate.

[0034] The preparation steps are:

[0035] Heat palm wax to a temperature between 87 and 99° C., add hematoporphyrin monomethyl ether, propylene glycol, and tocopherol acetate, stir thoroughly to dissolve them, and filter while hot to obtain a 3D printable photodynamic therapy gel composition.

[0036] The gel composition was 3D printed by Sweetin 3D printer (Wiiboox) to form a photodynamic therapy gel suppository. The printed product (suppository) was modeled based on the rectum and residence characteristics of New Zealand male white rabbits. Figure 1 In the configuration shown, the print head aperture is Φ0.3mm.

[0037] The gel composition printed suppositories were placed in the rectum of New Zealand male white rabbits with tumors inoculated under the rectal mucosa. After 1 hour, the suppositories melted and photodynamic therapy (light source wavelength 630nm, light power 20mW) was performed for 1 hour, and then the tumor inhibition was observed. Figure 2 As shown, 82% of the tumors were effectively inhibited and the tumors were basically eliminated.

[0038] Example 2

[0039] A 3D-printable photodynamic therapy gel composition and a preparation method thereof. The gel composition consists of the following components: 8% by mass of sodium huaporphyrin (Qinglong High-Tech Group), 90% by mass of beeswax (melting point 62-67°C), 1% by mass of N-methyl-2-pyrrolidone, and 1% by mass of vitamin E.

[0040] The preparation steps are:

[0041] Heat beeswax to 70-82°C, add sodium chloroporphyrin, N-methyl-2-pyrrolidone and vitamin E, stir thoroughly to dissolve them, and filter while hot to obtain a 3D printable photodynamic therapy gel composition.

[0042] The gel composition was 3D printed into a photodynamic therapy gel suppository using a Sweetin 3D printer (Wiiboox). The printed material was modeled based on the characteristics of the cervix of inbred mice C57BL / 6J, and the aperture of the print head was Φ0.1 mm.

[0043] The gel composition prints were placed submucosally in the cervix of C57BL / 6J inbred mice inoculated with tumors. After one hour, the prints melted and photodynamic therapy (630nm wavelength, 20mW power) was performed for one hour. Tumor suppression was then observed. Results showed 91% tumor suppression, essentially eliminating the tumors.

[0044] Example 3

[0045] A 3D-printable photodynamic therapy gel composition and a preparation method thereof. The gel composition comprises the following components: 0.1% by mass of Photofrin (Sigma-Aldrich), 79.9% by mass of rice bran wax (melting point 60-85°C), 10% by mass of isopropyl myristate, and 10% by mass of butylated hydroxyanisole.

[0046] The preparation steps are:

[0047] The rice bran wax is heated to 85-100° C., Photofrin, isopropyl myristate and butylated hydroxyanisole are added, stirred thoroughly to dissolve, and filtered while hot to obtain a 3D printable photodynamic therapy gel composition.

[0048] The gel composition was 3D printed using a Sweetin 3D printer (Wiiboox) to form a photodynamic therapy gel suppository. The printed material was modeled based on the vaginal and retention characteristics of inbred mice C57BL / 6J, and the print head aperture was Φ1.0 mm.

[0049] The gel composition was printed onto the rectum of New Zealand male white rabbits inoculated with tumors under the rectal mucosa. One hour later, the suppository melted and photodynamic therapy (630nm wavelength, 20mW power) was performed for one hour. Tumor suppression was then observed. Results showed that 77% of the tumors were effectively suppressed, with virtually no tumors at all.

[0050] Comparative Example 1

[0051] A gel composition and a preparation method thereof. The gel composition consists of the following components: 94% by mass of palm wax (melting point 82° C.), 3% by mass of propylene glycol, and 3% by mass of tocopherol acetate.

[0052] The preparation steps are:

[0053] Heat palm wax to a temperature between 87 and 99° C., add propylene glycol and tocopheryl acetate, stir thoroughly to dissolve them, and filter while hot to obtain a 3D printable photodynamic therapy gel composition.

[0054] The gel composition was 3D printed by a Sweetin 3D printer (Wiiboox). The printed product (suppository) was modeled based on the rectum and residence characteristics of New Zealand male white rabbits. Figure 1 In the configuration shown, the print head aperture is Φ0.3mm.

[0055] The gel composition printed suppositories were placed in the rectum of New Zealand male white rabbits with tumors inoculated under the rectal mucosa. After 1 hour, the suppositories melted and photodynamic therapy (light source wavelength of 630nm, light power of 20mW) was performed for 1 hour, and then the tumor inhibition was observed. Figure 2 As shown, the tumor was not inhibited.

[0056] Comparative Example 2

[0057] The difference between this comparative example and Example 1 is that palm wax is replaced with semi-synthetic fatty acid glyceride. The details are as follows:

[0058] A 3D-printable photodynamic therapy gel composition and a preparation method thereof. The gel composition consists of the following components: 1% by mass of hematoporphyrin monomethyl ether (Sigma-Aldrich), 93% by mass of semi-synthetic fatty acid glyceride (melting point 36°C), 3% by mass of propylene glycol, and 3% by mass of tocopherol acetate.

[0059] The preparation steps are:

[0060] Heat the semi-synthetic fatty acid glyceride to a temperature between 36 and 56° C., add propylene glycol and tocopheryl acetate, stir thoroughly to dissolve them, and filter while hot to obtain a 3D printable photodynamic therapy gel composition.

[0061] The gel composition was 3D printed using a Sweetin 3D printer (Wiiboox) to prepare a photodynamic therapy gel suppository. The results showed that the printing accuracy was poor.

[0062] During the printing process, it was found that the hot-melt extruded material failed to solidify into a solid in time and flowed while printing (the reason is that the semi-synthetic fatty acid glyceride is a mixed ester and does not have a sharp solidification point [Chinese Journal of Pharmaceutical Sciences, 1986, 21(3):157]). Therefore, it was impossible to obtain a shaped printed object, so this example has no practical application value for 3D printing.

[0063] The above describes specific embodiments of the present invention. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art may make various changes or modifications within the scope of the claims, which do not affect the essence of the present invention. The embodiments of this application and the features in the embodiments may be combined with each other in any manner unless there is a conflict.

Claims

1. A photodynamic therapy gel composition for 3D printing, characterized in that: The gel composition comprises, in parts by mass: Photosensitizer 0.1~10% Thermosensitive gel 70~97.9% Coupling agent 1~10% Additives 1-10%; The photosensitizer includes at least one of hematoporphyrin monomethyl ether, sodium hematoporphyrin, Photofrin, Visudyne and Temoporfin; The temperature-sensitive gel comprises one or more of beeswax, palm wax and rice bran wax.

2. The photodynamic therapy gel composition for 3D printing according to claim 1, characterized in that: The coupling agent includes one or more of propylene glycol, oleic acid, N-methyl-2-pyrrolidone, Tween, isopropyl myristate, menthol and lauryl alcohol.

3. The photodynamic therapy gel composition for 3D printing according to claim 1, characterized in that: The auxiliary agent includes one or more of tocopherol acetate, vitamin C, vitamin E, tert-butylhydroquinone, butylated hydroxyanisole and propyl gallate.

4. The photodynamic therapy gel composition for 3D printing according to claim 1, characterized in that: The 3D printable photodynamic therapy gel composition 3D printed parts may have shapes including columns, tubes, tablets, and spheres.

5. The method for preparing a photodynamic therapy gel composition for 3D printing according to any one of claims 1 to 4, wherein: The preparation method of the gel composition comprises the following steps: The thermosensitive gel is heated to a temperature 0-20°C above the melting point, a photosensitizer, a penetration enhancer and an adjuvant are added, stirred thoroughly to dissolve them, and hot filtered to obtain a photodynamic therapy gel composition for 3D printing.

6. The preparation method according to claim 5, characterized in that The 3D printer is a hot-melt 3D printer with a print head aperture of 0.1 to 1.0 mm.

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