Production process of carbamazepine and loaded dispersant

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a production process of carbamazepine and a loaded dispersant. The preparation method comprises the following steps: firstly, grafting beta-cyclodextrin to a chitosan molecular chain to prepare a loaded dispersant, then under an acidic condition, after amino groups in chitosan molecules in the loaded dispersant are protonized, interacting with carboxylate anions in sodium carboxymethyl cellulose to form nano particles, and finally, loading a carbamazepine drug. The nano particles obtained by the production process contain hydrophobic cavities and have larger specific surface areas, so that the drug loading capacity and the encapsulation efficiency are higher, and the accumulated release rate is also higher, which indicates that the nano particles have good dissolution performance after carrying drugs. In addition, after the methoxy polyethylene glycol is used for further modification, the drug loading capacity and the encapsulation efficiency of the drug-loaded nanoparticles can be improved to a certain extent, so that the dissolution performance of the drug-loaded nanoparticles is further improved.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations, and in particular to a production process and a loading dispersant for carbamazepine. Background Art

[0002] Carbamazepine is virtually insoluble in water and is slowly absorbed orally, resulting in low bioavailability. The bioavailability of carbamazepine is generally limited by its dissolution rate; increasing the dissolution rate significantly improves its bioavailability.

[0003] Common methods for increasing the dissolution rate of macarbazepine include micronization, salt formation, polymer nanoparticle formation, and solid dispersions. Micronization promotes dissolution by increasing the contact area between the drug and the dissolution medium, but the powder has a high specific surface area and may agglomerate, hindering drug dissolution. Forming a suitable salt requires the drug to be weakly acidic or weakly alkaline, which is not applicable to neutral drugs such as carbamazepine. Solid dispersions involve highly dispersing the drug in a molecular, colloidal, microcrystalline, or amorphous state in a suitable carrier material, but generally have low drug loading capacity.

[0004] Polymer nanoparticles have the advantages of being easy to prepare, easy to modify and having good stability. Therefore, they are often used in clinical practice. They are the most studied nanoparticle systems for drug delivery, including nanomicelles, vesicles, nanocapsules and nanospheres. Among them, nanomicelles are formed by self-assembly of amphiphilic polymer molecules in aqueous solution. They have good stability and high drug loading rate, and can also improve the solubility and bioavailability of drugs; nanoparticles are formed by directly encapsulating drugs inside polymers with good biodegradability and biocompatibility. They have good stability, can enhance the activity of drugs and improve their bioavailability. Summary of the Invention

[0005] In order to increase the drug loading and dissolution rate of carbamazepine, and thus improve its bioavailability, the present application provides a production process and a loading dispersant for carbamazepine.

[0006] A loaded dispersant is prepared by a method comprising the following steps: S1: Dissolve β-cyclodextrin in water, add sodium hydroxide solution dropwise, mix well, add p-toluenesulfonyl chloride, react at 0-5°C for 1-3 hours, filter, recrystallize, and vacuum dry to obtain an intermediate powder; S2: Add chitosan to glacial acetic acid aqueous solution, add intermediate powder, evacuate, and react at 100-120° C. under nitrogen protection for 6-12 hours. The product is washed and vacuum-dried to obtain.

[0007] In the above technical solution, in the first aspect, β-cyclodextrin has a unique annular hollow cylindrical structure. The non-polar groups inside its cavity form a hydrophobic environment, while the polyhydroxyl groups on the outside are hydrophilic. This unique structure, with hydrophobicity inside the ring and hydrophilicity outside the ring, can embed insoluble drug molecules into its annular cavity to form inclusion complexes. This inclusion complex can increase the solubility of poorly soluble drugs, making them more easily dissolved and absorbed in the body. Furthermore, the inclusion complex in β-cyclodextrin can reduce the impact of the external environment on the drug, thereby extending the drug's shelf life.

[0008] Secondly, chitosan has good biocompatibility and biodegradability. Grafting β-cyclodextrin onto the chitosan molecular chain can improve the stability and solubility of β-cyclodextrin-encapsulated drugs, thereby extending the shelf life of the drugs and improving the dissolution of the drugs.

[0009] Preferably, in step S1, the molar ratio of β-cyclodextrin to p-toluenesulfonyl chloride is 1:(1-1.2).

[0010] Preferably, in step S2, the deacetylation degree of the chitosan is 80%-95%.

[0011] In the above technical solution, when the deacetylation degree of chitosan is high, the amino content in the chitosan molecule will be relatively increased, and then there will be more groups that can be protonated under weak acid conditions, and more charged groups can be formed, which is conducive to the formation of nanoparticles with negatively charged groups.

[0012] Preferably, in step S2, the mass ratio of chitosan to intermediate powder is 1:(0.5-1).

[0013] A production process of carbamazepine comprises the following steps: The loaded dispersant prepared by the above method is dissolved in acetic acid solution, carbamazepine is added, stirred, the pH is adjusted to 5-6, sodium carboxymethyl cellulose is added, and the mixture is shaken for 12-24 hours. The mixed solution is dialyzed, centrifuged, and dried.

[0014] Using the above technical solution, carbamazepine is a poorly soluble drug and is difficult to be absorbed in the body, so its bioavailability is low. However, the loaded dispersant prepared by the above method contains β-cyclodextrin. The hydrophobic cavity of β-cyclodextrin can enclose carbamazepine in the cavity or adsorb on the surface of the hydrophobic cavity, thereby increasing the drug loading capacity of the loaded dispersant. In addition, under weakly acidic conditions, the amino groups on the surface of the chitosan in the loaded dispersant are protonated, which can electrostatically interact with the carboxylate anions in the sodium carboxymethyl cellulose to form nanoparticles. The large specific surface area of ​​the nanoparticles allows carbamazepine to be loaded on the nanoparticles. Therefore, after the nanoparticles are formed, the drug loading capacity is further increased, and the dispersibility of the drug on the nanoparticles is also better, which is more conducive to drug dissolution and improves bioavailability.

[0015] Preferably, the dialysis time is 4-12 hours.

[0016] In the above technical solution, dialysis treatment can remove unloaded carbamazepine, so the dialysis time should be appropriate. If the dialysis time is too long, the drug loading may be reduced, but if the dialysis time is too short, the encapsulation rate may be reduced, thereby affecting the dissolution and bioavailability of carbamazepine.

[0017] Preferably, the mass ratio of the load dispersant, carbamazepine and sodium carboxymethyl cellulose is 10:(4-8):(2-6).

[0018] Further preferably, the sodium carboxymethyl cellulose is modified by a method comprising the following steps: Dissolve sodium carboxymethyl cellulose in water, add methoxy polyethylene glycol, stir to dissolve, add formaldehyde, react for 3-12 hours, precipitate the product with acetone, filter, and freeze-dry.

[0019] In the above technical solution, methoxy polyethylene glycol has good hydrophilicity. Under the action of formaldehyde, methoxy polyethylene glycol is grafted into the sodium carboxymethyl cellulose molecule. Chitosan in the loading dispersant has a certain hydrophobicity, and β-cyclodextrin also has a hydrophobic cavity. Therefore, the sodium carboxymethyl cellulose modified with methoxy polyethylene glycol has not only a hydrophilic part but also a hydrophobic part, and can self-aggregate in an aqueous solution to form nanomicelles. After drug loading, the drug is encapsulated in the hydrophobic core of the micelle and the hydrophobic cavity of β-cyclodextrin, and the hydrophilic part is exposed to the aqueous phase, which not only further improves the encapsulation efficiency and drug loading capacity of the drug, but also improves the water solubility of the drug, thereby being more conducive to the dissolution of the drug.

[0020] Preferably, the number average molecular weight of the methoxy polyethylene glycol is 1000-6000.

[0021] In the above technical solution, with the increase of the number average molecular weight of methoxypolyethylene glycol, its water solubility decreases and the viscosity becomes large, so when the number average molecular weight of methoxypolyethylene glycol is too high, it is not conducive to the dissolution of the drug; but when the number average molecular weight of methoxypolyethylene glycol is too small, the hydrophilic segment is short, which is not conducive to the formation of nanomicelles.

[0022] Preferably, the mass ratio of the sodium carboxymethyl cellulose, methoxypolyethylene glycol and formaldehyde is 10: (80-150): (2-4).

[0023] The above technical solution of the present application at least includes the following beneficial effects: 1. The present application grafts β-cyclodextrin on chitosan to prepare a loaded dispersant, which not only can embed the poorly soluble drug, but also is conducive to improving the stability and solubility of the inclusion compound, so that the poorly soluble drug is more easily dissolved; 2. The present application forms nanoparticles of the loaded dispersant and sodium carboxymethyl cellulose under weak acid conditions, which improves the drug loading capacity, encapsulation efficiency and stability, and further improves the dissolution rate and bioavailability of the drug; 3. The present application grafts methoxypolyethylene glycol on the molecule of sodium carboxymethyl cellulose to form nanomicelles, which further improves the drug loading capacity and encapsulation efficiency, and further improves the dissolution rate and bioavailability of the drug. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 is the drug loading capacity and encapsulation efficiency of carbamazepine; Figure 2 is the cumulative release curve of carbamazepine. DETAILED DESCRIPTION

[0025] The present application is further described in detail below in combination with examples.

[0026] The raw materials of the examples and comparative examples of the present application are all ordinary commercial products except for special instructions.

[0027] EXAMPLE Example 1 The loaded dispersant of the present example is prepared by a method comprising the following steps: S1: weigh 22.7 g of β-cyclodextrin and dissolve it in 200 mL of distilled water, slowly add 7.5 g of 30% sodium hydroxide aqueous solution by using a rubber dropper, mix uniformly, then add 3.8 g of p-toluenesulfonyl chloride, and react for 1 h in an ice water bath at 0℃, filter the precipitate, recrystallize, and vacuum dry to obtain an intermediate powder; S2: Weigh 10 g of chitosan with a deacetylation degree of 80%, add it to a 1% by volume glacial acetic acid aqueous solution, mix well, add 5 g of the intermediate powder dissolved in DMF solution, evacuate, and reflux in an oil bath at 100°C under nitrogen protection for 12 h. The product is washed with acetone and dried in vacuum to obtain; The production process of carbamazepine in this embodiment comprises the following steps: Weigh 10 g of the loaded dispersant and dissolve it in 0.1 mol / L acetic acid solution. Add 50 mL of ethanol solution containing 4 g of carbamazepine and stir evenly. Adjust the pH to 5. Then add 6 g of sodium carboxymethyl cellulose and shake for 12 h. Transfer the mixture to a dialysis bag, dialyze in distilled water for 4 h, centrifuge, and freeze-dry to obtain drug-loaded particles.

[0028] Example 2 The loaded dispersant of this embodiment is prepared by a method comprising the following steps: S1: Weigh 22.7 g of β-cyclodextrin and dissolve it in 200 mL of distilled water. Slowly add 7.5 g of a 30% sodium hydroxide aqueous solution dropwise using a rubber-tipped dropper. After mixing, add 4.5 g of p-toluenesulfonyl chloride. The mixture is reacted in an ice-water bath at 5°C for 3 h. The precipitate is filtered, recrystallized, and vacuum-dried to obtain an intermediate powder. S2: Weigh 10 g of chitosan with a deacetylation degree of 95%, add it to a 1% by volume aqueous solution of glacial acetic acid, mix well, add a DMF solution containing 10 g of the intermediate powder, evacuate, and reflux in an oil bath at 120°C under nitrogen protection for 6 h. The product is washed with acetone and dried in vacuum to obtain; The production process of carbamazepine in this embodiment comprises the following steps: Weigh 10 g of the loaded dispersant and dissolve it in 0.1 mol / L acetic acid solution. Add 50 mL of ethanol solution containing 8 g of carbamazepine and stir evenly. Adjust the pH to 6. Then add 2 g of sodium carboxymethyl cellulose and shake for 24 h. Transfer the mixture to a dialysis bag, dialyze in distilled water for 12 h, centrifuge, and freeze-dry to obtain drug-loaded particles.

[0029] Example 3 The loaded dispersant of this embodiment is prepared by a method comprising the following steps: S1: Weigh 22.7 g of β-cyclodextrin and dissolve it in 200 mL of distilled water. Slowly add 7.5 g of a 30% sodium hydroxide aqueous solution dropwise using a rubber-tipped pipette. After mixing evenly, add 4 g of p-toluenesulfonyl chloride. React in an ice-water bath at 2°C for 2 h. Filter the precipitate, recrystallize it, and vacuum-dry it to obtain an intermediate powder. S2: Take 10 g of chitosan with 90% deacetylation degree, add to 1% glacial acetic acid aqueous solution, mix uniformly, add DMF solution with 7.5 g of intermediate powder, vacuumize, under nitrogen protection, put in 100℃ oil bath pot, reflux for 8 h, the product is washed with acetone, vacuum dried, and then obtained; The production process of carbamazepine in this embodiment includes the following steps: Take 10 g of dispersant carrier, dissolve in 0.1 mol / L acetic acid solution, add 50 mL of ethanol solution with 7 g of carbamazepine, stir uniformly, adjust pH to 5, then add 4 g of sodium carboxymethyl cellulose, shake for 12 h, transfer the mixed solution into dialysis bag, dialyze in distilled water for 8 h, centrifuge, freeze dry, and then obtain drug-loaded particles.

[0030] Example 4 The dispersant carrier in this embodiment is prepared by the following method: S1: Take 22.7 g of β-cyclodextrin, dissolve in 200 mL of distilled water, slowly add 7.5 g of 30% sodium hydroxide aqueous solution with a dropper, mix uniformly, then add 4 g of p-toluenesulfonyl chloride, react in 2℃ ice water bath for 2 h, filter the precipitate, recrystallize, vacuum dry, and then obtain intermediate powder; S2: Take 10 g of chitosan with 90% deacetylation degree, add to 1% glacial acetic acid aqueous solution, mix uniformly, add DMF solution with 7.5 g of intermediate powder, vacuumize, under nitrogen protection, put in 100℃ oil bath pot, reflux for 8 h, the product is washed with acetone, vacuum dried, and then obtained; The production process of carbamazepine in this embodiment includes the following steps: Take 10 g of dispersant carrier, dissolve in 0.1 mol / L acetic acid solution, add 50 mL of ethanol solution with 7 g of carbamazepine, stir uniformly, adjust pH to 5, then add 4 g of sodium carboxymethyl cellulose, shake for 12 h, transfer the mixed solution into dialysis bag, dialyze in distilled water for 8 h, centrifuge, freeze dry, and then obtain drug-loaded particles.

[0031] In this embodiment, the sodium carboxymethyl cellulose is modified by the following method: Take 1 g of sodium carboxymethyl cellulose, dissolve in 250 mL of distilled water, add 8 g of methoxy polyethylene glycol with a number average molecular weight of 6000, stir and dissolve, add 0.2 g of formaldehyde, react for 3 h, the product is precipitated with acetone, filtered, and freeze dried.

[0032] Example 5 The dispersant carrier in this embodiment is prepared by the following method: S1: Weigh 22.7 g of β-cyclodextrin and dissolve it in 200 mL of distilled water. Slowly add 7.5 g of a 30% sodium hydroxide aqueous solution dropwise using a rubber-tipped pipette. After mixing evenly, add 4 g of p-toluenesulfonyl chloride. React in an ice-water bath at 2°C for 2 h. Filter the precipitate, recrystallize it, and vacuum-dry it to obtain an intermediate powder. S2: Weigh 10 g of chitosan with a deacetylation degree of 90%, add it to a 1% by volume glacial acetic acid aqueous solution, mix well, add 7.5 g of the intermediate powder dissolved in DMF solution, evacuate, and reflux in an oil bath at 100°C under nitrogen protection for 8 h. The product is washed with acetone and dried in vacuum to obtain; The production process of carbamazepine in this embodiment comprises the following steps: Weigh 10 g of the loaded dispersant and dissolve it in 0.1 mol / L acetic acid solution. Add 50 mL of ethanol solution containing 7 g of carbamazepine and stir evenly. Adjust the pH to 5. Then add 4 g of sodium carboxymethyl cellulose and shake for 12 h. Transfer the mixture to a dialysis bag, dialyze in distilled water for 8 h, centrifuge, and freeze-dry to obtain drug-loaded particles.

[0033] In this embodiment, sodium carboxymethyl cellulose is modified by a method comprising the following steps: Weigh 1 g of sodium carboxymethyl cellulose and dissolve it in 250 mL of distilled water. Add 15 g of methoxy polyethylene glycol with a number average molecular weight of 1000 and stir to dissolve. Add 0.4 g of formaldehyde and react for 12 h. Precipitate the product with acetone, filter, and freeze-dry.

[0034] Comparative Example Comparative Example 1 The production process of carbamazepine in this comparative example comprises the following steps: Weigh 16 g of β-cyclodextrin and dissolve it in 200 mL of distilled water. Add 50 mL of ethanol solution containing 4 g of carbamazepine and stir evenly. Transfer the mixture into a dialysis bag, dialyze in distilled water for 4 h, centrifuge, and freeze-dry to obtain drug-loaded particles.

[0035] Performance testing The drug-loaded particles obtained by Examples 1-5 and Comparative Example 1 were added to 50 mL of phosphate buffer with a concentration of 0.1 mol / L and a pH of 5, respectively, and placed in a water bath at 25°C for 72 h. 5 mL of the release solution was taken at regular intervals, and then 5 mL of new phosphate buffer was added. The concentration of carbamazepine was determined by UV, and the drug loading capacity, encapsulation efficiency, and drug release rate were calculated according to the following formula.

[0036] Drug loading = (m0-cV) / (m+m0-cV) × 100%; Encapsulation efficiency = (m0-cV) / m0×100%; Cumulative release rate = (50C n +5 ) / (m0-cV)×100%; Where m0 is the dosage, mg; c is the concentration of carbamazepine in the dialysate, mg / L; m is the mass of the carrier, mg; V is the volume of the dialysate, L; C n and C n-1 is the concentration of carbamazepine in the release solution at the nth and n-1th sampling times, mg / mL, where n is the number of sampling times (n>0).

[0037] Result Analysis from Figure 1 It can be seen that compared with the examples, the drug loading and encapsulation efficiency of the drug-loaded particles obtained in Comparative Example 1 are relatively low, indicating that the formation of nanomicelles improves the drug loading and encapsulation efficiency; it can be seen from the data of Comparative Examples 1-3 that with the increase of the dosage, the drug loading and encapsulation efficiency first increase and then decrease, which may be because when the dosage is large, it exceeds the load of the carrier, resulting in a decrease in the drug loading and the encapsulation efficiency; it can be seen from the data of Comparative Examples 3-5 that after modification with methoxypolyethylene glycol, the encapsulation efficiency increases and the drug loading also increases slightly.

[0038] from Figure 2 As can be seen from the data, compared with Comparative Example 1, the cumulative release rate of the drug-loaded particles obtained in Example 3 and Example 5 is higher, and a higher release rate is achieved in a shorter time, indicating that the drug-loaded particles obtained in Example 3 and Example 5 are easier to dissolve.

[0039] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make non-creative modifications to the present embodiment as needed, but as long as they are within the scope of the claims of the present application, they are protected by the patent law.

Claims

1. A load dispersant, characterized in that It is prepared by a method comprising the following steps: S1: Dissolve β-cyclodextrin in water, add sodium hydroxide solution dropwise, mix well, add p-toluenesulfonyl chloride, react at 0-5°C for 1-3 hours, filter, recrystallize, and vacuum dry to obtain an intermediate powder; S2: Add chitosan to glacial acetic acid aqueous solution, add intermediate powder, evacuate, and react at 100-120° C. under nitrogen protection for 6-12 hours. The product is washed and vacuum-dried to obtain.

2. The load dispersant according to claim 1, characterized in that In step S1, the molar ratio of β-cyclodextrin to p-toluenesulfonyl chloride is 1:(1-1.2).

3. The load dispersant according to claim 1, characterized in that In step S2, the deacetylation degree of the chitosan is 80%-95%.

4. The load dispersant according to claim 1, characterized in that In step S2, the mass ratio of chitosan to intermediate powder is 1:(0.5-1).

5. A production process of carbamazepine, characterized in that: The steps include: The loaded dispersant prepared according to claim 1 is dissolved in acetic acid solution, carbamazepine is added, stirred, the pH is adjusted to 5-6, sodium carboxymethyl cellulose is added, and the mixture is shaken for 12-24 hours. The mixed solution is dialyzed, centrifuged, and dried.

6. The production process of carbamazepine according to claim 5, characterized in that: The dialysis time is 4-12 hours.

7. The production process of carbamazepine according to claim 5, characterized in that: The mass ratio of the load dispersant, carbamazepine and sodium carboxymethyl cellulose is 10:(4-8):(2-6).

8. The production process of carbamazepine according to claim 5, characterized in that: The sodium carboxymethyl cellulose is modified by a method comprising the following steps: Dissolve sodium carboxymethyl cellulose in water, add methoxy polyethylene glycol, stir to dissolve, add formaldehyde, react for 3-12 hours, precipitate the product with acetone, filter, and freeze-dry.

9. The production process of carbamazepine according to claim 8, characterized in that: The number average molecular weight of the methoxy polyethylene glycol is 1000-6000.

10. The production process of carbamazepine according to claim 8, characterized in that: The mass ratio of the sodium carboxymethyl cellulose, methoxy polyethylene glycol and formaldehyde is 10:(80-150):(2-4).

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