Novel 5-aminosalicylic acid intercalated LDHs sustained release preparation and preparation method thereof

Abstract

The invention relates to the technical field of biomedical materials, and discloses a novel 5-aminosalicylic acid intercalated LDHs sustained release preparation and a preparation method thereof, and the novel 5-aminosalicylic acid intercalated LDHs sustained release preparation comprises a sustained release preparation laminate and a 5-aminosalicylic acid object, the sustained release preparation laminate comprises divalent metal ions (M < 2 + >), trivalent metal ions (M < 3 + >) and anions. The method is mild in experimental condition, simple to operate, free of toxic solvents and additives, free of complex synthesis and preparation processes, easy to process and suitable for large-scale production; the prepared 5-aminosalicylic acid intercalated LDHs sustained-release preparation has the characteristics of high drug loading capacity, good stability and remarkable sustained-release effect; the structure, composition and drug release rate of the 5-aminosalicylic acid intercalated LDHs sustained release preparation can be controlled by adjusting the synthesis conditions of the 5-aminosalicylic acid intercalated LDHs sustained release preparation, such as changing the intercalation mode, precipitator type, synthesis temperature and other factors.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedical materials, and in particular to a novel 5-aminosalicylic acid intercalated LDHs sustained-release preparation and a preparation method thereof. Background Art

[0002] Ulcerative colitis is a chronic nonspecific inflammatory bowel disease with unclear causes. Its lesions mainly occur in the mucosa and submucosa of the colon and rectum. It is clinically characterized by diarrhea, bloody stools with mucus, abdominal pain, and tenesmus. It is currently believed that the cause of ulcerative colitis is likely to be the result of the interaction of multiple factors such as oxygen free radical damage, immunological abnormalities, and genetic factors. Due to the easy recurrence of the disease, the disease is not cured, and the treatment effect is poor, the disease has been listed as one of the modern intractable diseases by the World Health Organization. 5-aminosalicylic acid is currently the first-line drug for the treatment of ulcerative colitis in clinical practice, with the characteristics of good efficacy, safety, reliability, and good tolerance. However, since most of the common 5-aminosalicylic acid is absorbed through the upper digestive tract after oral administration, only a small part of the drug can reach the colorectum, the treatment effect is reduced, and the adverse reactions are large. Therefore, it is particularly important to prepare 5-aminosalicylic acid into a sustained-release preparation that can be slowly released in the ileum or colon.

[0003] Layered double hydroxides (LDHs) are layered inorganic materials that can accommodate anions between layers. LDHs have the advantages of good biocompatibility, biodegradability, anion exchange capacity, pH sensitivity and easy surface modification. Based on these advantages, LDHs have become increasingly popular in the biomedical field as nanocarriers for controlled drug release in recent years. Based on the characteristics of LDHs with large specific surface area and adjustable interlayer spacing, efficient loading of drug molecules can be achieved through various methods such as ion exchange, coprecipitation, and physical adsorption. Compared with a single drug, inserting drugs into the interlayer of LDHs has many advantages: LDHs can protect drug molecules from the influence of complex physiological environment, prevent or slow down the degradation and loss of drug efficacy; the hydroxyl groups on the LDHs layer can interact with drug molecules to improve the stability of drug molecules; the surface / space restriction effect of LDHs can reduce the aggregation of drug molecules, so that they can play the best therapeutic effect; the layered structure of LDHs allows poorly soluble drugs to be loaded into LDHs carriers, increasing the solubility of drugs, thereby improving the bioavailability and absorption efficiency of drugs; the positive charge of LDHs is conducive to its binding with negative cell membranes, improving the uptake of LDHs, and promoting the efficiency of cell uptake of drugs; the acid-responsive degradation characteristics of LDHs are not only conducive to the control of drug release rate, but also conducive to the final clearance of LDHs in the body, thereby ensuring biosafety. Therefore, LDHs have attracted extensive attention as drug carriers for sustained targeted drug delivery due to their layered structure, good ion exchange and biocompatibility, and easy preparation in the laboratory. Summary of the invention

[0004] In order to solve the technical problems of the shortcomings of the prior art, the present invention provides a novel 5-aminosalicylic acid intercalated LDHs sustained-release preparation and a preparation method thereof.

[0005] The present invention is implemented by the following technical scheme: a novel 5-aminosalicylic acid intercalated LDHs sustained-release preparation, comprising a sustained-release preparation layer plate and a 5-aminosalicylic acid guest, wherein the sustained-release preparation layer plate comprises a divalent metal ion (M 2+) , trivalent metal ions (M 3+) and interlayer anions.

[0006] As a further improvement of the above scheme, the M 2+ Zn 2+ Mg 2+ 、Ni 2+ , Fe 2+ 、Co 2+ At least one of them, M 3+ For Al 3+ Cr 3+ , Fe 3+、Co 3+ At least one of them has an interlayer anion of CO3 - 、NO3 - OH - At least one of them.

[0007] As a further improvement of the above scheme, the mass percentage of the 5-aminosalicylic acid is 5%-30%.

[0008] As a further improvement of the above scheme, the 5-aminosalicylic acid intercalated LDHs sustained-release preparation is prepared by intercalating 5-aminosalicylic acid between the layers of the sustained-release preparation.

[0009] A method for preparing a novel 5-aminosalicylic acid intercalated LDHs sustained-release preparation comprises the following steps:

[0010] S1. Prepare soluble divalent metal ions (M 2+) and soluble trivalent metal ions (M 3+) A mixed saline solution;

[0011] S2, preparing a precipitant solution and a 5-aminosalicylic acid solution;

[0012] S3. Add the 5-aminosalicylic acid solution to the mixed saline solution, add the precipitant solution during the mixing process, stir and mix to control the pH value of the mixed solution, crystallize, filter, wash and dry the obtained mixed solution to prepare the 5-aminosalicylic acid intercalated LDHs sustained-release preparation.

[0013] As a further improvement of the above scheme, the divalent metal ions (M 2+) and trivalent metal ions (M 3+) The molar ratio is 1-3:1.

[0014] As a further improvement of the above scheme, the precipitant is at least any one of NaOH, NaNO3 and Na2CO3.

[0015] As a further improvement of the above scheme, the reaction conditions of step S3 are: the pH of the stirred mixed solution is 7-9, the reaction temperature is 65-75°C, the obtained mixed solution is crystallized at 64-82°C for 20-28 hours, washed with deionized water to neutrality, and dried at 52-67°C for 6.4-8.5 hours.

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] 1. The experimental conditions of the present invention are mild, the operation is simple, no toxic solvents and additives are required, no complicated synthesis and preparation process is required, the product is easy to handle, and is suitable for large-scale production;

[0018] 2. The 5-aminosalicylic acid intercalated LDHs sustained-release preparation prepared by the present invention has the characteristics of high drug loading, good stability and significant sustained-release effect;

[0019] 3. The present invention can control the structure, composition and drug release rate of the 5-aminosalicylic acid intercalated LDHs sustained-release preparation by adjusting the synthesis conditions of the 5-aminosalicylic acid intercalated LDHs sustained-release preparation, such as changing the intercalation method, the type of precipitant, the synthesis temperature and other factors. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 X-ray powder diffraction (XRD) patterns of 5-aminosalicylic acid intercalated LDHs sustained-release preparations prepared in Examples 3-6 and Control Groups 1 and 2;

[0021] Figure 2 Fourier transform infrared spectra (FT-IR) of 5-aminosalicylic acid intercalated LDHs sustained-release preparations prepared in Examples 3-6 and Control Groups 1 and 2;

[0022] Figure 3 Scanning electron microscope (SEM) photos of 5-aminosalicylic acid intercalated LDHs sustained-release preparations prepared in Examples 3-6 and Control Groups 1 and 2;

[0023] Figure 4 Thermogravimetric (TGA) graphs of 5-aminosalicylic acid intercalated LDHs sustained-release preparations prepared for Examples 3-6 and Control Groups 1 and 2;

[0024] Figure 5 X-ray photoelectron spectroscopy (XPS) diagram of 5-aminosalicylic acid intercalated LDHs sustained-release preparations prepared in Examples 3-6 and Control Groups 1 and 2;

[0025] Figure 6 This is a graph of the cumulative release of the 5-aminosalicylic acid intercalated LDHs sustained-release preparations prepared in Examples 3-6. DETAILED DESCRIPTION

[0026] The present invention is further described below in conjunction with the accompanying drawings and specific implementation methods. It should be noted that, under the premise of no conflict, the various embodiments or technical features described below can be arbitrarily combined to form a new embodiment.

[0027] Embodiment 1:

[0028] A novel 5-aminosalicylic acid intercalated LDHs sustained-release preparation of this embodiment includes a sustained-release preparation layer plate and a 5-aminosalicylic acid (5-ASA) guest, wherein the sustained-release preparation layer plate includes a divalent metal ion (M 2+) , trivalent metal ions (M 3+)and interlayer anions.

[0029] M 2+ Zn 2+ Mg 2+ 、Ni 2+ , Fe 2+ 、Co 2+ At least one of them, M 3+ For Al 3+ Cr 3+ , Fe 3+ 、Co 3+ At least one of them has an interlayer anion of CO3 - 、NO3 - OH - At least one of them.

[0030] The mass percentage of 5-aminosalicylic acid is 5%-30%.

[0031] The 5-aminosalicylic acid intercalated LDHs sustained-release preparation is prepared by intercalating 5-aminosalicylic acid between the layers of the sustained-release preparation.

[0032] Embodiment 2:

[0033] A method for preparing a novel 5-aminosalicylic acid intercalated LDHs sustained-release preparation comprises the following steps:

[0034] S1. Prepare soluble divalent metal ions (M 2+) and soluble trivalent metal ions (M 3+) A mixed saline solution;

[0035] S2, preparing a precipitant solution and a 5-aminosalicylic acid solution;

[0036] S3. Add the 5-aminosalicylic acid solution to the mixed saline solution, add the precipitant solution during the mixing process, stir and mix to control the pH value of the mixed solution, crystallize, filter, wash and dry the obtained mixed solution to prepare the 5-aminosalicylic acid intercalated LDHs sustained-release preparation.

[0037] Divalent metal ions (M 2+) and trivalent metal ions (M 3+) The molar ratio is 1-3:1.

[0038] The precipitant is at least any one of NaOH, NaNO3 and Na2CO3.

[0039] The reaction conditions of step S3 are: the pH of the stirred mixed solution is 7-9, the reaction temperature is 65-75°C, the obtained mixed solution is crystallized at 64-82°C for 20-28 hours, washed with deionized water to neutrality, and dried at 52-67°C for 6.4-8.5 hours.

[0040] Embodiment 3:

[0041] The ion exchange method is used to prepare a 5-aminosalicylic acid intercalated ZnAl-NO3-LDHs sustained-release preparation (A-ZANE), comprising the following steps:

[0042] S1: Dissolve 1.53 g (0.01 mol) of 5-aminosalicylic acid and 2.15 g (0.02 mol) of ZnAl-NO3-LDHs in 30 mL and 100 mL of deionized water, respectively;

[0043] S2: Add 5-aminosalicylic acid solution to ZnAl-NO3-LDHs solution while stirring, and adjust the pH of the mixed solution to 7.5 with 0.5 mol / L NaOH solution, stir at 70°C for 24 hours under N2 atmosphere, and then crystallize for 24 hours;

[0044] S3: Take out the sample after the reaction, filter and wash it with deionized water until it is neutral, place it in a drying oven at 60°C for 8 hours, then take it out, place it in a mortar and grind it into powder to obtain the sample.

[0045] Embodiment 4:

[0046] The 5-aminosalicylic acid intercalated ZnAl-NO3-LDHs sustained-release preparation (A-ZANC) was prepared by chemical coprecipitation method, comprising the following steps:

[0047] S1: Dissolve 12.02 g (0.04 mol) Zn(NO3)2·6H2O and 7.58 g (0.02 mol) Al(NO3)3·9H2O in 40 mL deionized water;

[0048] S2: Dissolve 1.78 g (0.021 mol) of NaNO3 and 1.53 g (0.01 mol) of 5-aminosalicylic acid in 70 mL and 30 mL of deionized water, respectively;

[0049] S3: adding the solution of step S2: dropwise to the solution of step S1: while stirring, adjusting the pH of the mixed solution to 7.5 with 0.5 mol / L NaOH solution, and crystallizing at 70° C. for 24 hours under N2 atmosphere;

[0050] S4: Take out the sample after the reaction, filter and wash it with deionized water until it is neutral, place it in a drying oven at 60°C for 8 hours, then take it out, place it in a mortar and grind it into powder to obtain the sample.

[0051] Embodiment 5:

[0052] The ion exchange method is used to prepare a 5-aminosalicylic acid intercalated ZnAl-CO3-LDHs sustained-release preparation (A-ZACE), comprising the following steps:

[0053] S1: Dissolve 1.53 g (0.01 mol) of 5-aminosalicylic acid and 2.15 g (0.02 mol) of ZnAl-CO3-LDHs in 30 mL and 100 mL of deionized water, respectively;

[0054] S2: Add 5-aminosalicylic acid solution to ZnAl-CO3-LDHs solution while stirring, and adjust the pH of the mixed solution to 7.5 with 0.5 mol / L NaOH solution, stir at 70°C for 24 hours under N2 atmosphere, and then crystallize for 24 hours;

[0055] S3: Take out the sample after the reaction, filter and wash it with deionized water until it is neutral, place it in a drying oven at 60°C for 8 hours, then take it out, place it in a mortar and grind it into powder to obtain the sample.

[0056] Embodiment 6:

[0057] The chemical coprecipitation method is used to prepare a 5-aminosalicylic acid intercalated ZnAl-CO3-LDHs sustained-release preparation (A-ZACC), comprising the following steps:

[0058] S1: Dissolve 12.02 g (0.04 mol) Zn(NO3)2·6H2O and 7.58 g (0.02 mol) Al(NO3)3·9H2O in 40 mL deionized water;

[0059] S2: Dissolve 1.80 g (0.021 mol) of Na2CO3 and 1.53 g (0.01 mol) of 5-aminosalicylic acid in 70 mL and 30 mL of deionized water, respectively;

[0060] S3: Add the solution of step S2 dropwise to the solution of step S1 while stirring, and adjust the pH of the mixed solution to 7.5 with 0.5 mol / L NaOH solution, and crystallize at 70° C. under N2 atmosphere for 24 hours;

[0061] S4: Take out the sample after the reaction, filter and wash it with deionized water until it is neutral, place it in a drying oven at 60°C for 8 hours, then take it out, place it in a mortar and grind it into powder to obtain the sample.

[0062] Control group 1:

[0063] In the 5-aminosalicylic acid intercalated LDHs sustained-release preparation (ZACO3), the layers are composed of divalent metal ions (M 2+ ) and trivalent metal ions (M3+ ) with anions between the layers, including: M 2+ Zn 2+ , M 3+ For Al 3+ , the interlayer anion is CO3 - ;

[0064] The specific steps are as follows: prepare 1.0 mol / L Zn(NO3)2·6H2O solution and 0.5 mol / L Al(NO3)3·9H2O solution, mix the solutions in a nitrogen atmosphere and add them to 0.3 mol / L Na2CO3 solution, and adjust the pH of the mixed solution to 7.5 with 0.5 mol / L NaOH solution, heat at 70°C for 24 hours, and finally wash with deionized water to neutrality, and dry with air at 60°C for 8 hours to obtain ZACO3.

[0065] Control group 2:

[0066] In the 5-aminosalicylic acid intercalated LDHs sustained-release preparation (ZANO3), the layers are composed of divalent metal ions (M 2+ ) and trivalent metal ions (M 3+) Composition, the interlayer contains anions, among which: M 2+ Zn 2+ , M 3+ For Al 3+ , the interlayer anion is NO3 - ;

[0067] The specific steps are as follows: prepare a 1.0 mol / L Zn(NO3)2·6H2O solution and a 0.5 mol / L Al(NO3)3·9H2O solution, mix the solution in a nitrogen atmosphere and add it to a 0.3 mol / L NaNO3 solution, adjust the pH of the mixed solution to 7.5 with a 0.5 mol / L NaOH solution, heat at 70°C for 24 hours, wash with deionized water until neutral, and air dry at 60°C for 8 hours to obtain ZANO3;

[0068] Release experiment of 5-aminosalicylic acid intercalated LDHs sustained-release preparation:

[0069] A certain amount of 5-aminosalicylic acid intercalated LDHs sustained-release preparation was weighed and placed in a conical flask filled with a phosphate buffer solution of pH = 7.4, and continuously shaken at 150 rpm and 37°C. A certain volume of the suspension was taken at a certain time interval, and the supernatant was taken by centrifugation and the concentration of 5-aminosalicylic acid was measured with a spectrophotometer to obtain the corresponding cumulative release rate.

[0070] like Figure 1-5As shown, the 5-aminosalicylic acid intercalated LDHs sustained-release preparations prepared in Examples 3-6 and Control Groups 1 and 2 were characterized by XRD, FT-IR, SEM, TGA, and XPS;

[0071] Wherein, in embodiment 3:

[0072] From the XRD spectrum and SEM photos, it can be seen that the 5-aminosalicylic acid intercalated LDHs sustained-release preparation has a layered morphology structure, and from the interlayer spacing (d003), it can be seen that 5-aminosalicylic acid has been inserted into the LDHs interlayer;

[0073] From the TGA spectrum, it can be seen that the 5-aminosalicylic acid intercalated LDHs sustained-release preparation has better thermal stability;

[0074] FT-IR and XPS spectra further confirmed that 5-aminosalicylic acid interacted with LDHs sheets;

[0075] The sample was analyzed by UV spectrophotometry, and the drug loading of 5-aminosalicylic acid was determined to be 28.57%;

[0076] The cumulative release results of 5-aminosalicylic acid showed that the cumulative release of 5-aminosalicylic acid intercalated LDHs sustained-release preparation was 67.6% within nearly 12 hours, which had a good drug controlled release effect;

[0077] In embodiment 4:

[0078] From the XRD spectrum and SEM photos, it can be seen that the 5-aminosalicylic acid intercalated LDHs sustained-release preparation has a layered morphology structure, and from the interlayer spacing (d003), it can be seen that 5-aminosalicylic acid has been inserted into the LDHs interlayer;

[0079] From the TGA spectrum, it can be seen that the 5-aminosalicylic acid intercalated LDHs sustained-release preparation has better thermal stability;

[0080] FT-IR and XPS spectra further confirmed that 5-aminosalicylic acid interacted with LDHs sheets;

[0081] The sample was analyzed by UV spectrophotometry, and the drug loading of 5-aminosalicylic acid was determined to be 6.90%;

[0082] The cumulative release results of 5-aminosalicylic acid showed that the cumulative release of 5-aminosalicylic acid intercalated LDHs sustained-release preparation was 44.9% within nearly 12 hours, which had a good drug controlled release effect.

[0083] In embodiment 5:

[0084] From the XRD spectrum and SEM photos, it can be seen that the 5-aminosalicylic acid intercalated LDHs sustained-release preparation has a layered morphology structure, and from the interlayer spacing (d003), it can be seen that 5-aminosalicylic acid has been inserted into the LDHs interlayer;

[0085] From the TGA spectrum, it can be seen that the 5-aminosalicylic acid intercalated LDHs sustained-release preparation has better thermal stability;

[0086] FT-IR and XPS spectra further confirmed that 5-aminosalicylic acid interacted with LDHs sheets;

[0087] The sample was analyzed by UV spectrophotometry, and the drug loading of 5-aminosalicylic acid was determined to be 13.85%;

[0088] The cumulative release results of 5-aminosalicylic acid showed that the cumulative release of 5-aminosalicylic acid intercalated LDHs sustained-release preparation was 37.7% within nearly 12 hours, which had a good drug controlled release effect.

[0089] In Example 6:

[0090] From the XRD spectrum and SEM photos, it can be seen that the 5-aminosalicylic acid intercalated LDHs sustained-release preparation has a layered morphology structure, and from the interlayer spacing (d003), it can be seen that 5-aminosalicylic acid has been inserted into the LDHs interlayer;

[0091] From the TGA spectrum, it can be seen that the 5-aminosalicylic acid intercalated LDHs sustained-release preparation has better thermal stability;

[0092] FT-IR and XPS spectra further confirmed that 5-aminosalicylic acid interacted with LDHs sheets;

[0093] The sample was analyzed by UV spectrophotometry, and the drug loading of 5-aminosalicylic acid was determined to be 10.42%;

[0094] The cumulative release results of 5-aminosalicylic acid showed that the cumulative release of 5-aminosalicylic acid intercalated LDHs sustained-release preparation was 18.8% in nearly 12 hours, which had a good drug controlled release effect.

[0095] The experimental conditions of the present invention are mild, the operation is simple, no toxic solvents and additives are required, no complicated synthesis and preparation process is required, the product is easy to handle, and is suitable for large-scale production;

[0096] The 5-aminosalicylic acid intercalated LDHs sustained-release preparation prepared by the present invention has the characteristics of high drug loading, good stability and significant sustained-release effect;

[0097] The present invention can control the structure, composition and drug release rate of the 5-aminosalicylic acid intercalated LDHs sustained-release preparation by adjusting the synthesis conditions of the 5-aminosalicylic acid intercalated LDHs sustained-release preparation, such as changing the intercalation method, the type of precipitant, the synthesis temperature and other factors.

[0098] The above-mentioned embodiments are only preferred embodiments of the present invention and cannot be used to limit the scope of protection of the present invention. Any non-substantial changes and substitutions made by technicians in this field on the basis of the present invention shall fall within the scope of protection required by the present invention.

Claims

1. A novel 5-aminosalicylic acid intercalated LDHs sustained-release preparation, characterized in that: The invention comprises a sustained-release preparation layer plate and a 5-aminosalicylic acid guest, wherein the sustained-release preparation layer plate comprises a divalent metal ion (M 2+) , trivalent metal ions (M 3+) and interlayer anions.

2. A novel 5-aminosalicylic acid intercalated LDHs sustained-release preparation as claimed in claim 1, characterized in that: The M 2+ Zn 2+ Mg 2+ 、Ni 2+ , Fe 2+ 、Co 2+ At least one of them, M 3+ For Al 3+ Cr 3+ , Fe 3+ 、Co 3+ At least one of them has an interlayer anion of CO3 - 、NO3 - OH - At least one of them.

3. A novel 5-aminosalicylic acid intercalated LDHs sustained-release preparation as claimed in claim 1, characterized in that: The mass percentage of the 5-aminosalicylic acid is 5%-30%.

4. A novel 5-aminosalicylic acid intercalated LDHs sustained-release preparation as claimed in claim 1, characterized in that: The 5-aminosalicylic acid intercalated LDHs sustained-release preparation is prepared by intercalating 5-aminosalicylic acid between the layers of the sustained-release preparation.

5. A method for preparing a novel 5-aminosalicylic acid intercalated LDHs sustained-release preparation according to any one of claims 1 to 4, characterized in that: The following steps are involved: S1. Prepare soluble divalent metal ions (M 2+) and soluble trivalent metal ions (M 3+) A mixed saline solution; S2, preparing a precipitant solution and a 5-aminosalicylic acid solution; S3. Add the 5-aminosalicylic acid solution to the mixed saline solution, add the precipitant solution during the mixing process, stir and mix to control the pH value of the mixed solution, crystallize, filter, wash and dry the obtained mixed solution to prepare the 5-aminosalicylic acid intercalated LDHs sustained-release preparation.

6. The method for preparing a novel 5-aminosalicylic acid intercalated LDHs sustained-release preparation as claimed in claim 5, characterized in that: The divalent metal ions (M 2+) and trivalent metal ions (M 3+) The molar ratio is 1-3:

1.

7. The method for preparing a novel 5-aminosalicylic acid intercalated LDHs sustained-release preparation as claimed in claim 5, characterized in that: The precipitant is at least any one of NaOH, NaNO3 and Na2CO3.

8. The method for preparing a novel 5-aminosalicylic acid intercalated LDHs sustained-release preparation as claimed in claim 5, characterized in that: The reaction conditions of step S3 are as follows: the pH of the stirred mixed solution is 7-9, the reaction temperature is 65-75° C., the obtained mixed solution is crystallized at 64-82° C. for 20-28 hours, washed with deionized water to neutrality, and dried with air at 52-67° C. for 6.4-8.5 hours.

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