Assistant composition for promoting itraconazole absorption

Abstract

The invention provides an additive composition for promoting itraconazole absorption, and the additive composition is prepared from the following components in parts by mass: 20 to 40 parts of modified hydroxypropyl methylcellulose acetic acid succinate, 10 to 25 parts of copovidone, 5 to 15 parts of N-capryloyl sodium salicylate, 2 to 8 parts of nano silicon dioxide and 3 to 10 parts of polyoxyethylene-polyoxypropylene segmented copolymer. According to the additive composition disclosed by the invention, the problems of dissolution rate, bioavailability and stability of the itraconazole oral preparation are comprehensively solved through polymer modification, compounding synergy and parameter optimization, and the process cost is remarkably lower than that of the prior art.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to an adjuvant combination for promoting the absorption of itraconazole. Background Art

[0002] Itraconazole is a broad-spectrum triazole antifungal drug, which is widely used in the treatment of deep fungal infections. However, its water solubility is extremely low (about 1 μg / mL), the oral bioavailability is less than 55%, and it is significantly affected by food, resulting in unstable clinical efficacy. In the prior art, the solubility is improved by nano-suspensions (such as CN103239400A) or solid dispersions (such as Sporanox®), but there are still the following defects: 1. Insufficient stability: The nano-suspension is prone to Ostwald ripening, and the particle size increases after long-term storage; the solid dispersion is prone to crystal precipitation due to poor compatibility between the drug and the carrier.

[0003] 2. Limited absorption promotion efficiency: Existing excipients (such as PVP, HPMC) only improve the dissolution by inhibiting crystallization or solubilization, but the intestinal permeability is not significantly improved.

[0004] 3. Complex process: The high-pressure homogenization or spray drying process has high costs and is not friendly to heat-sensitive drugs.

[0005] In the existing solutions, Chinese Patent (CN103239400A) uses the compounding of PVP S-630 and PVP K-90 to prepare nano-suspensions, but the problem of storage stability is not solved; US Patent (US20160193114A1) proposes to use SNAC to promote the absorption of macromolecular drugs, but does not involve the solubilization of small molecules of itraconazole. In addition, commercial products rely on cyclodextrin inclusion (such as Sporanox® oral liquid), but cyclodextrin is prone to side effects such as diarrhea.

[0006] Therefore, it is necessary to design an adjuvant combination for promoting the absorption of itraconazole. Summary of the Invention

[0007] In order to overcome the defects in the prior art, an adjuvant combination for promoting the absorption of itraconazole is provided.

[0008] In order to achieve the above object, the present invention provides the following technical solutions: An adjuvant combination for promoting the absorption of itraconazole, in parts by mass, the adjuvant combination includes the following components: 20-40 parts of modified hydroxypropyl methylcellulose acetate succinate, 10-25 parts of copovidone (abbreviation: PVP, BASF, model S-630), 5-15 parts of sodium N-octanoyl salicylate (SNAC analog, Nanjing Notai Pharmaceutical), 2-8 parts of nano-silica (Evonik Industries), and 3-10 parts of polyoxyethylene-polyoxypropylene block copolymer.

[0009] The modified hydroxypropyl methylcellulose acetate succinate is treated by phosphoric acid esterification, and the degree of substitution of the modified hydroxypropyl methylcellulose acetate succinate is 0.8 - 1.2.

[0010] The preparation method of the modified hydroxypropyl methylcellulose acetate succinate is as follows: reacting unmodified hydroxypropyl methylcellulose acetate succinate (abbreviation: HPMC-AS, Dow Chemical Company, model 126) with phosphorus oxychloride at 60 °C for 4 hours, and the phosphoric acid esterification product obtained after washing and drying is the modified hydroxypropyl methylcellulose acetate succinate.

[0011] The molar ratio of the hydroxypropyl methylcellulose acetate succinate to phosphorus oxychloride is 1:1.1 - 1.3.

[0012] The polyoxyethylene-polyoxypropylene block copolymer is graft-modified with polyethylene glycol, and the grafting rate is 15% - 30%.

[0013] The specific steps for graft-modifying the polyoxyethylene-polyoxypropylene block copolymer with polyethylene glycol are as follows: activating the raw material polyoxyethylene-polyoxypropylene block copolymer (abbreviation: poloxamer 188, purchased from BASF) and polyethylene glycol (abbreviation: PEG, Sigma-Aldrich) respectively, then mixing the activated products in a mass ratio of 1:(1 - 3), heating to 80 °C, reacting for 6 - 12 hours under nitrogen protection. After the reaction, the mixture is precipitated and purified, and freeze-dried to obtain a white porous solid, which is the product graft-modified with polyethylene glycol.

[0014] The specific steps for activating the polyoxyethylene-polyoxypropylene block copolymer and polyethylene glycol are as follows: Dissolve the polyoxyethylene-polyoxypropylene block copolymer in anhydrous dimethyl sulfoxide, add a catalytic amount of p-toluenesulfonic acid, and stir for 30 minutes under nitrogen protection to activate the hydroxyl groups; Dissolve polyethylene glycol with a molecular weight of 6000 in tetrahydrofuran, add 1,1'-carbonyldiimidazole as a coupling agent, and react at room temperature for 2 hours.

[0015] The specific steps for precipitation purification are as follows: dropping the mixture into cold ether for precipitation, centrifuging to collect the solid, and repeating the washing 3 times to remove unreacted reactants.

[0016] The specific surface area of the nano-silica is 200 - 400 m 2 / g, and the pore size is 2 - 10 nm.

[0017] The mass ratio of the copovidone to sodium N-octanoyl salicylate is (1.5 - 5):1.

[0018] Compared with the prior art, the advantages and beneficial effects of the present invention are: 1. The novel adjuvant combination of the present application effectively solves the limitations of the prior art through a comprehensive strategy of enhancing lipophilicity by phosphorylating HPMC-AS, synergistically solubilizing and promoting permeation by copovidone and an SNAC analogue (sodium N-octanoyl salicylate), and regulating the drug release rate by nano-silica.

[0019] 2. The adjuvant combination of the present application significantly improves bioavailability: Modified HPMC-AS enhances hydrogen bonding with itraconazole through phosphorylation, inhibiting drug re-aggregation; The SNAC analogue promotes transmembrane absorption by transiently opening tight junctions of intestinal epithelial cells, increasing the bioavailability to more than twice that of traditional formulations.

[0020] 3. The adjuvant combination of the present application has excellent stability: Nano-silica acts as a physical barrier to prevent drug molecule migration and crystallization, with better effects than commercially available products.

[0021] 4. The hydroxyl group of PEG is activated by 1,1'-carbonyldiimidazole to generate isocyanate (-NCO), which undergoes a condensation reaction with the hydroxyl group of poloxamer 188 to form a stable carbamate bond (-NHCOO-). The block copolymer after PE grafting can form a denser micelle structure, inhibiting drug crystallization and improving the storage stability of the formulation.

[0022] 5. The adjuvant combination of the present application can simplify the process and optimize costs: High-pressure homogenization or spray drying is not required, and wet granulation can be used to achieve nano-scale dispersion. The PEG graft modification of poloxamer 188 enhances wettability, enabling the tablets to be formed under low pressure (50 N) and avoiding the problem of friability. Specific Embodiments

[0023] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of them. All other embodiments obtained by those of ordinary skill in the art without creative efforts based on the embodiments of the present invention belong to the scope of protection of the present invention.

[0024] An adjuvant combination for promoting the absorption of itraconazole, in parts by mass, the adjuvant combination includes the following components: 20-40 parts of modified hydroxypropyl methylcellulose acetate succinate, 10-25 parts of copovidone, 5-15 parts of sodium N-octanoyl salicylate, 2-8 parts of nano-silica, and 3-10 parts of polyoxyethylene-polyoxypropylene block copolymer.

[0025] The modified hydroxypropyl methylcellulose acetate succinate is treated by phosphorylation, and the substitution degree of the modified hydroxypropyl methylcellulose acetate succinate is 0.8-1.2.

[0026] The preparation method of the modified hydroxypropyl methylcellulose acetate succinate is as follows: reacting unmodified hydroxypropyl methylcellulose acetate succinate with phosphorus oxychloride at 60 °C for 4 hours, and the phosphorylated product obtained after washing and drying is the modified hydroxypropyl methylcellulose acetate succinate.

[0027] The molar ratio of the hydroxypropyl methylcellulose acetate succinate to phosphorus oxychloride is 1:1.1 - 1.3.

[0028] The polyoxyethylene - polyoxypropylene block copolymer is graft - modified with polyethylene glycol, and the grafting rate is 15% - 30%.

[0029] The specific steps for graft - modifying the polyoxyethylene - polyoxypropylene block copolymer with polyethylene glycol are as follows: activating the raw material polyoxyethylene - polyoxypropylene block copolymer and polyethylene glycol respectively, then mixing the activated products in a mass ratio of 1:(1 - 3), heating to 80 °C, reacting for 6 - 12 hours under nitrogen protection. After the reaction, the mixture is precipitated, purified, and freeze - dried to obtain a white porous solid, which is the product graft - modified with polyethylene glycol.

[0030] The specific steps for activating the polyoxyethylene - polyoxypropylene block copolymer and polyethylene glycol are respectively: Dissolve the polyoxyethylene - polyoxypropylene block copolymer in anhydrous dimethyl sulfoxide, add a catalytic amount of p - toluenesulfonic acid, and stir for 30 minutes under nitrogen protection to activate the hydroxyl groups; Dissolve polyethylene glycol with a molecular weight of 6000 in tetrahydrofuran, add 1,1'-carbonyldiimidazole as a coupling agent, and react at room temperature for 2 hours.

[0031] The specific steps for precipitation and purification are as follows: dropping the mixture into cold ether for precipitation, centrifuging to collect the solid, and repeating the washing 3 times to remove unreacted reactants.

[0032] The specific surface area of the nano - silica is 200 - 400 m 2 / g, and the pore size is 2 - 10 nm.

[0033] The mass ratio of the copovidone to sodium N - octanoyl salicylate is (1.5 - 5):1.

[0034] In practical applications, the adjuvant combination of this application is included in the itraconazole oral preparation, and the dissolution rate of the preparation reaches more than 80% within 30 minutes in a medium with a pH of 1.2.

[0035] In the itraconazole oral preparation, the mass ratio of the adjuvant combination to itraconazole is 1:1 - 1:5. The preparation is a tablet, capsule or granule, and the hardness of the tablet is 50 - 100 N, and the friability is ≤0.5%.

[0036] The adjuvant combination of the present invention comprehensively solves the problems of dissolution, bioavailability and stability of itraconazole oral preparations through polymer modification, compounding synergy and parameter optimization, and the process cost is significantly lower than the prior art.

[0037] The following further elaborates on the present application in conjunction with specific embodiments and the like: Example 1 The adjuvant combination for promoting the absorption of itraconazole, in parts by mass, the adjuvant combination includes the following components: 30 parts of modified hypromellose acetate succinate, 15 parts of copovidone, 10 parts of sodium N-octanoyl salicylate, 5 parts of nano-silica, and 8 parts of polyoxyethylene-polyoxypropylene block copolymer.

[0038] The modified hypromellose acetate succinate is treated by phosphoric acid esterification, and the substitution degree of the modified hypromellose acetate succinate is 1.

[0039] The preparation method of the modified hypromellose acetate succinate is: reacting unmodified hypromellose acetate succinate with phosphorus oxychloride at 60 °C for 4 hours, and the phosphoric acid esterification product obtained after washing and drying is the modified hypromellose acetate succinate.

[0040] The molar ratio of the hypromellose acetate succinate to phosphorus oxychloride is 1:1.1.

[0041] The polyoxyethylene-polyoxypropylene block copolymer is graft-modified with polyethylene glycol, and the grafting rate is 25%.

[0042] The specific steps for graft-modifying the polyoxyethylene-polyoxypropylene block copolymer with polyethylene glycol are: activating the raw material polyoxyethylene-polyoxypropylene block copolymer and polyethylene glycol respectively, then mixing the activated products in a mass ratio of 1:3, heating to 80 °C, reacting for 12 hours under nitrogen protection, after the reaction is completed, precipitating and purifying the mixture, and freeze-drying to obtain a white porous solid, which is the product graft-modified with polyethylene glycol.

[0043] The specific steps for activating the polyoxyethylene-polyoxypropylene block copolymer and polyethylene glycol are respectively: Dissolving the polyoxyethylene-polyoxypropylene block copolymer in anhydrous dimethyl sulfoxide, adding a catalytic amount of p-toluenesulfonic acid, and stirring for 30 minutes under nitrogen protection to activate the hydroxyl groups; Dissolving polyethylene glycol with a molecular weight of 6000 in tetrahydrofuran, adding 1,1'-carbonyldiimidazole as a coupling agent, and reacting at room temperature for 2 hours.

[0044] The specific steps for precipitation and purification are: dropping the mixture into cold ether for precipitation, centrifuging to collect the solid, and repeating the washing 3 times to remove the unreacted reactants.

[0045] The specific surface area of the nano-silica is 300 m 2 / g, and the pore size is 5 nm.

[0046] Example 2 An adjuvant combination for promoting the absorption of itraconazole, calculated by mass, the adjuvant combination includes the following components: 25 parts of modified hydroxypropyl methylcellulose acetate succinate, 20 parts of copovidone, 12 parts of sodium N-octanoyl salicylate, 6 parts of nano-silica, and 7 parts of polyoxyethylene-polyoxypropylene block copolymer.

[0047] The modified hydroxypropyl methylcellulose acetate succinate is treated by phosphorylation, and the degree of substitution of the modified hydroxypropyl methylcellulose acetate succinate is 1.

[0048] The preparation method of the modified hydroxypropyl methylcellulose acetate succinate is: reacting unmodified hydroxypropyl methylcellulose acetate succinate with phosphorus oxychloride at 60 °C for 4 hours, and the phosphorylated product obtained after washing and drying is the modified hydroxypropyl methylcellulose acetate succinate.

[0049] The molar ratio of the hydroxypropyl methylcellulose acetate succinate to phosphorus oxychloride is 1:1.2.

[0050] The polyoxyethylene-polyoxypropylene block copolymer is graft-modified with polyethylene glycol, and the grafting rate is 25%.

[0051] The specific steps for graft-modifying the polyoxyethylene-polyoxypropylene block copolymer with polyethylene glycol are: activating the raw material polyoxyethylene-polyoxypropylene block copolymer and polyethylene glycol respectively, then mixing the activated products in a mass ratio of 1:3, heating to 80 °C, reacting for 6 hours under nitrogen protection, after the reaction is completed, precipitating and purifying the mixture, and freeze-drying to obtain a white porous solid, which is the product graft-modified with polyethylene glycol.

[0052] The specific steps for activating the polyoxyethylene-polyoxypropylene block copolymer and polyethylene glycol are respectively: Dissolving the polyoxyethylene-polyoxypropylene block copolymer in anhydrous dimethyl sulfoxide, adding a catalytic amount of p-toluenesulfonic acid, and stirring for 30 minutes under nitrogen protection to activate the hydroxyl groups; Dissolving polyethylene glycol with a molecular weight of 6000 in tetrahydrofuran, adding 1,1'-carbonyldiimidazole as a coupling agent, and reacting at room temperature for 2 hours.

[0053] The specific steps for the precipitation and purification are: dropping the mixture into cold ether for precipitation, centrifuging to collect the solid, and repeating the washing 3 times to remove the unreacted reactants.

[0054] The specific surface area of the nano-silica is 300 m 2 / g, with a pore size of 5 nm.

[0055] Example 3 An adjuvant combination for promoting the absorption of itraconazole, in parts by mass, the adjuvant combination comprises the following components: 35 parts of modified hypromellose acetate succinate, 18 parts of copovidone, 8 parts of sodium N-octanoyl salicylate, 4 parts of nano-silica, and 9 parts of polyoxyethylene-polyoxypropylene block copolymer.

[0056] The modified hypromellose acetate succinate is subjected to phosphoric acid esterification treatment, and the substitution degree of the modified hypromellose acetate succinate is 1.

[0057] The preparation method of the modified hypromellose acetate succinate is as follows: reacting unmodified hypromellose acetate succinate with phosphorus oxychloride at 60 °C for 4 hours, and the phosphoric acid esterification product obtained after washing and drying is the modified hypromellose acetate succinate.

[0058] The molar ratio of the hypromellose acetate succinate to phosphorus oxychloride is 1:1.3.

[0059] The polyoxyethylene-polyoxypropylene block copolymer is graft-modified with polyethylene glycol, and the grafting rate is 25%.

[0060] The specific steps for graft-modifying the polyoxyethylene-polyoxypropylene block copolymer with polyethylene glycol are as follows: activating the raw material polyoxyethylene-polyoxypropylene block copolymer and polyethylene glycol respectively, then mixing the activated products in a mass ratio of 1:1, heating to 80 °C, reacting for 9 hours under nitrogen protection, after the reaction is completed, precipitating and purifying the mixture, and freeze-drying to obtain a white porous solid, which is the product graft-modified with polyethylene glycol.

[0061] The specific steps for activating the polyoxyethylene-polyoxypropylene block copolymer and polyethylene glycol are as follows: Dissolving the polyoxyethylene-polyoxypropylene block copolymer in anhydrous dimethyl sulfoxide, adding a catalytic amount of p-toluenesulfonic acid, and stirring for 30 minutes under nitrogen protection to activate the hydroxyl groups; Dissolving polyethylene glycol with a molecular weight of 6000 in tetrahydrofuran, adding 1,1'-carbonyldiimidazole as a coupling agent, and reacting at room temperature for 2 hours.

[0062] The specific steps for the precipitation and purification are as follows: dropping the mixture into cold ether for precipitation, centrifuging to collect the solid, and repeating the washing 3 times to remove the unreacted reactants.

[0063] The specific surface area of the nano-silica is 300 m 2 / g, with a pore size of 5 nm.

[0064] Comparative Example 1 In this example, the same parts as in the examples will not be elaborated, and the differences are described as follows: Use unmodified hypromellose acetate succinate (substitution degree 0).

[0065] Comparative Example 2 In this example, the same parts as in the examples will not be elaborated, and the differences are described as follows: Sodium N-octanoyl salicylate was not added.

[0066] Comparative Example 3 In this example, the same parts as in the examples will not be elaborated, and the differences are described as follows: Use ordinary poloxamer 188 (that is, not graft-modified with polyethylene glycol).

[0067] Comparative Example 4 In this example, the same parts as in the examples will not be elaborated, and the differences are described as follows: Use cyclodextrin (β-CD) to replace nano-silica.

[0068] Comparative Example 5 Instead of using the adjuvant combination of this application, a commercially available solid dispersion (Sporanox®) was directly used.

[0069] Testing Methods and Results Performance tests were carried out on the tablets prepared in the examples and comparative examples. The test indicators included: dissolution rate (USP II method, pH 6.8), bioavailability (rat model), and storage stability (40°C / 75% RH, 6 months). The results are shown in Table 1.

[0070] As can be seen from Table 1, the performance of Examples 1-3 has advantages. Dissolution rate: In Examples 1-3, the hydrogen bond binding of modified HPMC-AS inhibits drug aggregation, and the dissolution rate > 95%, which is significantly higher than that of Comparative Example 1 (unmodified HPMC-AS, 72.3%). Bioavailability: Through the permeation-promoting effect of sodium N-octanoyl salicylate in the examples, the bioavailability reaches 43 - 45.7 μg·h / mL, which is more than twice that of Comparative Example 1, verifying the enhanced transmembrane absorption effect of SNAC analogs.

[0071] Storage stability: The dissolution rate decline rate of the examples < 3%, which is attributed to the physical barrier effect of nano-silica (2 - 10 nm pore size); the decline rate of Comparative Example 4 (replaced with cyclodextrin) reaches 12.6%, showing the unique advantages of nano-silica.

[0072] The dissolution rate of Comparative Example 3 (without grafted poloxamer) was 88.6%, indicating the key role of PEG grafting in enhancing wettability. The bioavailability of Comparative Example 2 (without SNAC) was only 28.6 μg·h / mL, proving the irreplaceability of the SNAC analog in intestinal permeability.

[0073] Table 1 Analysis and test results

[0074] It can be seen from the vertical data comparison that the present invention is significantly superior to the comparative examples in terms of dissolution, absorption, stability and cost, verifying the synergistic effect of phosphorylated HPMC-AS, SNAC analog, nano-silica and PEG-grafted poloxamer in the technical solution, which meets the core objective of solving the existing defects in the background technology.

[0075] The above is the preferred embodiment of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. An adjuvant combination for promoting the absorption of itraconazole, characterized in that, In parts by mass, the auxiliary agent combination comprises the following components: 20-40 parts of modified hypromellose acetate succinate, 10-25 parts of copovidone, 5-15 parts of sodium N-octanoyl salicylate, 2-8 parts of nano-silica, and 3-10 parts of polyoxyethylene-polyoxypropylene block copolymer.

2. The adjuvant combination for promoting itraconazole absorption according to claim 1, characterized in that: The modified hypromellose acetate succinate is subjected to phosphoric acid esterification treatment, and the substitution degree of the modified hypromellose acetate succinate is 0.8-1.

2.

3. The combination of adjuvants for promoting the absorption of itraconazole according to claim 2, characterized in that, The preparation method of the modified hypromellose acetate succinate is as follows: reacting unmodified hypromellose acetate succinate with phosphorus oxychloride at 60 °C for 4 hours, and the phosphoric acid esterification product obtained after washing and drying is the modified hypromellose acetate succinate.

4. The adjuvant combination for promoting itraconazole absorption according to claim 3, wherein: The molar ratio of the hypromellose acetate succinate to phosphorus oxychloride is 1:1.1-1.

3.

5. The adjuvant combination for promoting itraconazole absorption according to claim 1, characterized in that: The polyoxyethylene-polyoxypropylene block copolymer is graft-modified with polyethylene glycol, and the grafting rate is 15%-30%.

6. The combination of adjuvants for promoting the absorption of itraconazole according to claim 5, characterized in that, The specific steps for graft-modifying the polyoxyethylene-polyoxypropylene block copolymer with polyethylene glycol are as follows: activating the raw material polyoxyethylene-polyoxypropylene block copolymer and polyethylene glycol respectively, then mixing the activated products in a mass ratio of 1:(1-3), heating to 80 °C, reacting for 6-12 hours under nitrogen protection, after the reaction, precipitating and purifying the mixture, and freeze-drying to obtain a white porous solid, which is the product graft-modified with polyethylene glycol.

7. The adjuvant combination for promoting itraconazole absorption according to claim 6, characterized in that, The specific steps for activating the polyoxyethylene-polyoxypropylene block copolymer and polyethylene glycol are as follows: Dissolving the polyoxyethylene-polyoxypropylene block copolymer in anhydrous dimethyl sulfoxide, adding a catalytic amount of p-toluenesulfonic acid, and stirring for 30 minutes under nitrogen protection to activate the hydroxyl groups; Dissolving polyethylene glycol with a molecular weight of 6000 in tetrahydrofuran, adding 1,1'-carbonyldiimidazole as a coupling agent, and reacting at room temperature for 2 hours.

8. The adjuvant combination for promoting the absorption of itraconazole according to claim 6, characterized in that, The specific steps for the precipitation and purification are as follows: dropping the mixture into cold ether for precipitation, centrifuging to collect the solid, and repeating the washing 3 times to remove the unreacted reactants.

9. The adjuvant combination for promoting the absorption of itraconazole according to claim 1, characterized in that: The specific surface area of the nano-silica is 200 - 400 m 2 / g, and the pore size is 2 - 10 nm.

10. The adjuvant combination for promoting the absorption of itraconazole according to claim 1, characterized in that: The mass ratio of the copovidone to sodium N-octanoyl salicylate is (1.5-5):1.

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