Drug carrier for gastrointestinal tumor treatment and preparation method thereof
By using sulfated yeast β-D-glucan, tetrabutyl titanate and calcium alginate fiber in anti-cancer drug carriers, a drug carrier that can tolerate gastric acid erosion and achieve targeted release in the gastrointestinal environment is prepared, which solves the problem that existing anti-cancer drugs are susceptible to gastric acid destruction during oral administration, and improves the bioavailability and safety of the drug.
Patent Information
- Application Number
- CN202510092540.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-21
- Publication Date
- 2025-05-16
AI Technical Summary
Existing anti-cancer chemotherapy drugs are susceptible to gastric acid damage when administered orally, and are difficult to target the release of intestinal tract, resulting in low bioavailability and serious gastrointestinal side effects.
A drug carrier that tolerates gastric acid erosion and targets intestinal release is prepared by adding sulfated yeast β-D-glucan, tetrabutyl titanate and calcium alginate fibers to the dispersion containing the drug, and undergoes specific reaction and treatment steps.
This drug carrier can improve the oral bioavailability of anti-cancer drugs, reduce gastrointestinal side effects, and achieve accurate intestinal release of drugs, and shows obvious advantages in biocompatibility, degradability, stability and preparation costs.
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Figure CN120000799A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of biomedicine and relates to a drug carrier for treating gastrointestinal tumors and a preparation method thereof. Background Art
[0002] In the field of anti-cancer treatment, chemotherapy, as one of the core treatment methods, has played an important role in prolonging patient survival and improving survival rates, but its inherent limitations cannot be ignored. Traditional anti-cancer chemotherapy drugs, such as doxorubicin, cyclosporine and cisplatin, are often limited in their application due to reduced drug activity, poor gastrointestinal absorption or severe gastrointestinal toxicity when directly administered orally. These problems not only reduce the quality of life of patients, but may also lead to interruption or failure of treatment. Therefore, it is particularly important to develop new drug carrier technologies to achieve precise drug delivery.
[0003] In recent years, nano drug carriers designed based on the special microenvironment of cancer (such as low pH or high reducibility) have made significant progress in intravenous administration. Some carriers have been used in clinical practice and have shown good therapeutic effects and safety. However, their application in oral drug systems still faces great challenges. An ideal oral intestinal targeted release carrier should have good biocompatibility, be degradable, stably carry drugs through the gastrointestinal environment, have intestinal specific recognition ability, be easy to prepare, and have controllable costs.
[0004] At present, although there have been some studies on intestinal targeted release, most carriers still find it difficult to meet the above requirements at the same time. Therefore, developing an oral intestinal targeted release carrier to overcome the shortcomings of existing technologies, improve the oral bioavailability of anticancer drugs, reduce gastrointestinal side effects, and achieve precise intestinal release of drugs has important clinical significance and application value. Summary of the invention
[0005] The purpose of the present invention is to treat oral gastrointestinal tumors, which are easily destroyed by gastric acid and difficult to be released in the intestine. To this end, the present invention provides a drug carrier for treating gastrointestinal tumors and a preparation method thereof to solve this need in the field.
[0006] On the one hand, the present invention relates to a method for preparing a drug carrier for treating gastrointestinal tumors, which comprises: adding sulfated yeast β-D-glucan to a dispersion containing a drug, oscillating the reaction for 1 to 6 hours, adding tetrabutyl titanate and continuing the oscillating reaction for 1 to 6 hours, then adding calcium alginate fiber and standing for 12 to 24 hours, and freeze-drying after centrifugation to obtain the drug carrier.
[0007] Furthermore, in the method for preparing a drug carrier for treating gastrointestinal tumors provided by the present invention, the drug is selected from one of 5-fluorouracil, camptothecin, cisplatin, paclitaxel, doxorubicin, cyclosporine, and carmustine.
[0008] Furthermore, in the method for preparing a drug carrier for treating gastrointestinal tumors provided by the present invention, the concentration of the drug in the drug-containing dispersion is 50 to 200 μg / mL.
[0009] Furthermore, in the method for preparing a drug carrier for treating gastrointestinal tumors provided by the present invention, the amount of sulfated yeast β-D-glucan added is 1 to 10% by mass.
[0010] Furthermore, in the method for preparing a drug carrier for treating gastrointestinal tumors provided by the present invention, the amount of tetrabutyl titanate added is 3-5% by mass.
[0011] Furthermore, in the method for preparing a drug carrier for treating gastrointestinal tumors provided by the present invention, the calcium alginate fiber is added in an amount of 10 to 20% by mass.
[0012] Furthermore, in the method for preparing a drug carrier for treating gastrointestinal tumors provided by the present invention, in the drug-containing dispersion, the solvent is anhydrous ethanol.
[0013] Furthermore, in the method for preparing a drug carrier for treating gastrointestinal tumors provided by the present invention, the centrifugation condition is 200-1000 r / min for 1-5 h.
[0014] On the other hand, the present invention relates to a drug carrier for treating gastrointestinal tumors, which is prepared by any of the methods for preparing a drug carrier for treating gastrointestinal tumors.
[0015] On the other hand, the present invention relates to the preparation of the drug carrier for treating gastrointestinal tumors in oral enteric release drugs.
[0016] Compared with the prior art, the present invention has the following beneficial effects or advantages:
[0017] The present invention aims to solve the problem that drugs for oral treatment of gastrointestinal tumors are easily destroyed by gastric acid and difficult to release in the intestine in a targeted manner, and provides a drug carrier for the treatment of gastrointestinal tumors and a method for preparing the same. The method adds sulfated yeast β-D-glucan, tetrabutyl titanate and calcium alginate fiber to a dispersion containing the drug, and after specific reaction and treatment steps, the obtained drug carrier can achieve resistance to gastric acid erosion and targeted intestinal release. This not only improves the oral bioavailability of anticancer drugs, but also significantly reduces gastrointestinal side effects and achieves precise intestinal release of drugs. Compared with the prior art, the technical solution of the present invention shows obvious advantages in biocompatibility, degradability, stability, intestinal-specific recognition ability and preparation cost, and has important clinical significance and application value. BRIEF DESCRIPTION OF THE DRAWINGS
[0018] Figure 1 The release curve of the drug complex in simulated gastric fluid and intestinal fluid, where 0-2h is simulated gastric fluid and 2-10h is simulated intestinal fluid. DETAILED DESCRIPTION
[0019] Below, the technical solution of the present invention is described in conjunction with the embodiments, but the present invention is not limited to the following embodiments. In order to enable those skilled in the art to better understand the technical solution of the present invention and implement it, the present invention is further described below in conjunction with specific embodiments and drawings, but the embodiments are not intended to limit the present invention. The experimental methods and detection methods described in the following embodiments are conventional methods unless otherwise specified; the reagents and materials are available on the market unless otherwise specified; the "%" is mass percentage unless otherwise specified.
[0020] In the following examples, yeast β-D-glucan was purchased from Beijing Solebow Technology Co., Ltd., with a purity of ≥80% and a product number of G9341; calcium alginate fiber was purchased from Shanghai Jianglai Biotechnology Co., Ltd., with a CAS number of 9005-35-0 and a product number of J000273.
[0021] Example 1
[0022] This embodiment provides a method for preparing a drug complex.
[0023] (1) Preparation of Sulfated Yeast β-D-Glucan:
[0024] Place a four-necked flask with a condenser, a stirring device and a temperature measuring device in a salt water ice bath, add pyridine, stir, and cool it to below 0°C, then slowly add chlorosulfonic acid with a constant pressure dropping funnel, and complete the dropwise addition in about 30 minutes. A large amount of light yellow solid appears in the flask, and the esterification agent is obtained. Accurately weigh a certain amount of yeast β-D-glucan and dissolve it in dimethylformamide, stir and suspend it at room temperature, and then add it to the prepared esterification agent. Quickly move the four-necked flask into a hot water bath, stir and react at a constant temperature for a certain period of time, then move it to an ice water bath and cool it to room temperature, pour the reaction solution into ice water, neutralize it with NaOH solution to pH 7.5, add anhydrous ethanol 1:3 (V / V), precipitate a light yellow precipitate, and collect the precipitate by suction. Dissolve the precipitate in water, dialyze it with a dialysis bag for 48 hours, and dialyze it with distilled water for 24 hours. The permeate is freeze-dried to obtain a light yellow powder.
[0025] The sulfate content in the yeast β-D-glucan sulfate in the sulfated yeast β-D-glucan is usually expressed by the degree of substitution (DS). The DS of the sulfated yeast β-D-glucan prepared in this example is 0.32.
[0026] (2) Preparation of drug complexes:
[0027] 5-fluorouracil was dispersed in anhydrous ethanol, and the concentration of 5-fluorouracil was controlled to be 50 μg / mL to obtain a dispersion containing the drug.
[0028] Add 1% of sulfated yeast β-D-glucan to the dispersion containing the drug, and shake at 37°C and 100 rpm for 1 hour; then add 3% of tetrabutyl titanate, and continue shaking at 37°C and 100 rpm for 1 hour; add 10% of calcium alginate fiber and let it stand for 12 hours. After standing, centrifuge at 200 r / min for 5 hours, and freeze-dry to obtain the drug complex.
[0029] Example 2
[0030] This embodiment provides a method for preparing a drug complex.
[0031] (1) Preparation of Sulfated Yeast β-D-Glucan:
[0032] Place a four-necked flask with a condenser, a stirring device and a temperature measuring device in a salt water ice bath, add pyridine, stir, and cool it to below 0°C, then slowly add chlorosulfonic acid with a constant pressure dropping funnel, and complete the dropwise addition in about 30 minutes. A large amount of light yellow solid appears in the flask, and the esterification agent is obtained. Accurately weigh a certain amount of yeast β-D-glucan and dissolve it in dimethylformamide, stir and suspend it at room temperature, and then add it to the prepared esterification agent. Quickly move the four-necked flask into a hot water bath, stir and react at a constant temperature for a certain period of time, then move it to an ice water bath and cool it to room temperature, pour the reaction solution into ice water, neutralize it with NaOH solution to pH 7.5, add anhydrous ethanol 1:3 (V / V), precipitate a light yellow precipitate, and collect the precipitate by suction. Dissolve the precipitate in water, dialyze it with a dialysis bag for 48 hours, and dialyze it with distilled water for 24 hours. The permeate is freeze-dried to obtain a light yellow powder.
[0033] The sulfate content in the yeast β-D-glucan sulfate in the sulfated yeast β-D-glucan is usually expressed by the degree of substitution (DS). The DS of the sulfated yeast β-D-glucan prepared in this example is 0.32.
[0034] (2) Preparation of drug complexes:
[0035] Cisplatin was dispersed in anhydrous ethanol, and the concentration of cisplatin was controlled to be 100 μg / mL to obtain a dispersion containing the drug.
[0036] Add 5% of sulfated yeast β-D-glucan to the drug-containing dispersion, shake and react at 37°C and 100 rpm for 1 hour; then add 4% of tetrabutyl titanate, shake and react at 37°C and 100 rpm for 1 hour; add 15% of calcium alginate fiber and let it stand for 12 hours. After standing, centrifuge at 500 r / min for 3 hours and freeze-dry to obtain the drug complex.
[0037] Example 3
[0038] This embodiment provides a method for preparing a drug complex.
[0039] (1) Preparation of Sulfated Yeast β-D-Glucan:
[0040] Place a four-necked flask with a condenser, a stirring device and a temperature measuring device in a salt water ice bath, add pyridine, stir, and cool it to below 0°C, then slowly add chlorosulfonic acid with a constant pressure dropping funnel, and complete the dropwise addition in about 30 minutes. A large amount of light yellow solid appears in the flask, and the esterification agent is obtained. Accurately weigh a certain amount of yeast β-D-glucan and dissolve it in dimethylformamide, stir and suspend it at room temperature, and then add it to the prepared esterification agent. Quickly move the four-necked flask into a hot water bath, stir and react at a constant temperature for a certain period of time, then move it to an ice water bath and cool it to room temperature, pour the reaction solution into ice water, neutralize it with NaOH solution to pH 7.5, add anhydrous ethanol 1:3 (V / V), precipitate a light yellow precipitate, and collect the precipitate by suction. Dissolve the precipitate in water, dialyze it with a dialysis bag for 48 hours, and dialyze it with distilled water for 24 hours. The permeate is freeze-dried to obtain a light yellow powder.
[0041] The sulfate content in the yeast β-D-glucan sulfate in the sulfated yeast β-D-glucan is usually expressed by the degree of substitution (DS). The DS of the sulfated yeast β-D-glucan prepared in this example is 0.32.
[0042] (2) Preparation of drug complexes:
[0043] Paclitaxel was dispersed in anhydrous ethanol, and the concentration of paclitaxel was controlled to be 200 μg / mL to obtain a dispersion containing the drug.
[0044] Add 5% of sulfated yeast β-D-glucan to the dispersion containing the drug, and shake at 37°C and 100 rpm for 1 hour; then add 4% of tetrabutyl titanate, and continue shaking at 37°C and 100 rpm for 1 hour; add 15% of calcium alginate fiber and let it stand for 12 hours. After standing, centrifuge at 1000 r / min for 1 hour, and freeze-dry to obtain the drug complex.
[0045] Comparative Example 1
[0046] This comparative example is the same as Example 3, except that no calcium alginate fiber is added.
[0047] Comparative Example 2
[0048] This comparative example is the same as Example 3, except that tetrabutyl titanate is not added.
[0049] Test Example 1
[0050] This test example provides the determination of drug loading and encapsulation efficiency of drug complexes.
[0051] The standard curve was obtained by measuring the absorbance of the drug standard solution, and the drug loading and encapsulation efficiency in the drug complex were calculated according to the following formula:
[0052] Drug loading (%) = (mass of loaded drug / mass of drug complex) × 100%;
[0053] Encapsulation efficiency (%) = (mass of loaded drug / total mass of initially added drug) × 100%.
[0054] The test results are shown in Table 1.
[0055] Table 1: Drug loading (%) and encapsulation efficiency (%) in drug complexes
[0056] Drug loading Encapsulation efficiency Example 1 31.7 70.4 Example 2 33.7 78.3 Example 3 36.7 70.6 Comparative Example 1 10.4 38.2 Comparative Example 2 22.6 54.5
[0057] In Examples 1, 2 and 3, with the increase of drug (5-fluorouracil, cisplatin, paclitaxel) concentration and the fine-tuning of preparation conditions, the drug loading and encapsulation efficiency of the drug complex both showed a high level. In particular, in Example 3, when paclitaxel was used as the drug, the drug loading reached 36.7% and the encapsulation efficiency was 70.6%, indicating that the preparation method can effectively load the drug into the complex and maintain a high drug loading and encapsulation efficiency.
[0058] Comparing Comparative Example 1 and Example 3, it can be seen that when calcium alginate fibers are not added, the drug loading and encapsulation efficiency are greatly reduced. The drug loading of Comparative Example 1 is only 10.4%, and the encapsulation efficiency is 38.2%, which shows that calcium alginate fibers play a key role in the preparation of drug complexes. Calcium alginate fibers improve the loading and encapsulation efficiency of drugs by providing additional structural support or drug binding sites. Comparing Comparative Example 2 and Example 3, when tetrabutyl titanate is not added, although the drug loading and encapsulation efficiency also decrease, the decrease is relatively small. The drug loading of Comparative Example 2 is 22.6%, and the encapsulation efficiency is 54.5%, which shows that the addition of tetrabutyl titanate helps to further improve the encapsulation efficiency and loading of drugs.
[0059] Test Example 2
[0060] This test example provides an intestinal delivery release system for a drug complex.
[0061] Place 5 mg of the drug complex in 10 mL of simulated gastric fluid for 2 hours and then centrifuge. Take 200 μL of the supernatant and dilute it to 2 mL with ethanol and measure the absorbance values corresponding to different drug loads. Then transfer the sample to simulated intestinal fluid for release study, and the total release time is 10 hours. Take the supernatant regularly and dilute it with ethanol to measure the absorbance value. At the same time, add an equal amount of the corresponding PBS buffer (the simulated gastric fluid corresponds to a buffer solution with a pH of 2.2, and the simulated intestinal fluid corresponds to a buffer solution with a pH of 7.4). Substitute it into the corresponding standard curve to calculate the drug release. The test results are shown as follows. Figure 1 shown.
[0062] Depend on Figure 1 It can be seen that the present invention adopts the method of first loading the drug with sulfated yeast β-D-glucan, and then curling and wrapping the calcium alginate fiber modified with tetrabutyl titanate, and the obtained drug complex is initially digested by pepsin in the stomach, and the release amount in the stomach for 2 hours is only 8.6-13.2%. After entering the intestine, the enzymes such as trypsin, chymotrypsin, aminopeptidase, dipeptidase, etc. in the intestine fully digest the calcium alginate fiber, making it stretch from curling, causing the drug therein to be fully exposed to the intestine, and the total release amount is as high as more than 80%. The drug complexes provided in Comparative Examples 1 and 2 are not protected by calcium alginate fibers or are not modified with tetrabutyl titanate and are not targeted, and the final cumulative release amount is less than 40%.
[0063] As described above, the present invention can be well implemented. The above embodiments are only descriptions of the preferred implementation modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various changes and improvements made to the technical solutions of the present invention by ordinary technicians in this field should fall within the protection scope determined by the present invention.
Claims
1. A method for preparing a drug carrier for treating gastrointestinal tumors, characterized in that: include: Sulfated yeast β-D-glucan is added to the dispersion containing the drug, and the reaction is shaken for 1 to 6 hours. After adding tetrabutyl titanate, the reaction is continued to shake for 1 to 6 hours. Then, calcium alginate fiber is added and the mixture is allowed to stand for 12 to 24 hours. The mixture is then centrifuged and freeze-dried to obtain the product.
2. The method for preparing a drug carrier for treating gastrointestinal tumors according to claim 1, characterized in that: The drug is selected from one of 5-fluorouracil, camptothecin, cisplatin, paclitaxel, doxorubicin, cyclosporine and carmustine.
3. The method for preparing a drug carrier for treating gastrointestinal tumors according to claim 1, characterized in that: In the drug-containing dispersion, the concentration of the drug is 50 to 200 μg / mL.
4. The method for preparing a drug carrier for treating gastrointestinal tumors according to claim 1, characterized in that: In terms of mass percentage, the added amount of the sulfated yeast β-D-glucan is 1 to 10%.
5. The method for preparing a drug carrier for treating gastrointestinal tumors according to claim 1, characterized in that: In terms of mass percentage, the added amount of tetrabutyl titanate is 3-5%.
6. The method for preparing a drug carrier for treating gastrointestinal tumors according to claim 1, characterized in that: In terms of mass percentage, the added amount of the calcium alginate fiber is 10-20%.
7. The method for preparing a drug carrier for treating gastrointestinal tumors according to claim 1, characterized in that: In the drug-containing dispersion, the solvent is anhydrous ethanol.
8. The method for preparing a drug carrier for treating gastrointestinal tumors according to claim 1, characterized in that: The centrifugal condition is 200-1000 r / min for 1-5 hours.
9. A drug carrier for treating gastrointestinal tumors, characterized in that: The drug carrier is prepared by the method for preparing the drug carrier for treating gastrointestinal tumors according to any one of claims 1 to 8.
10. The preparation of the drug carrier for treating gastrointestinal tumors according to claim 9 in oral enteric release drugs.