Ion exchange resin-based paliperidone long-acting oral suspension and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a paliperidone long-acting oral suspension based on ion exchange resin and a preparation method of the paliperidone long-acting oral suspension. The cation exchange resin and the paliperidone are adopted to form a medicine-resin compound, pH responsive release is achieved through ionic bonds, and the effects of low dissociation in gastric juice and slow release in intestinal juice are achieved; meanwhile, a ready-to-use oral suspension is developed for patients with dysphagia, a flavoring agent is added, the taste is improved, compared with controlled release tablets, the compliance of the patients can be improved, the medication convenience can be improved, and the paliperidone long-acting oral suspension preparation has a good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a long-acting oral suspension of paliperidone based on ion exchange resin and its preparation method. Background Technology

[0002] Paliperidone is 9-hydroxyrisperidone, the active metabolite of the atypical antipsychotic risperidone. It is a derivative of benzisoxazole and primarily exerts its antipsychotic effects by blocking serotonin 2A (5-HT2A) and dopamine D2 (DA2) receptors. Currently, most marketed antipsychotic medications are in tablet form, which is insufficient to meet the clinical needs of some patients with swallowing difficulties.

[0003] Existing conventional suspensions do not have a sustained-release effect and require frequent administration. The riluzole sustained-release suspension disclosed in CN111437256A mainly relies on microspheres or liposomes. The microspheres are mainly prepared by spray drying of the drug, but they have problems such as low drug loading and poor stability.

[0004] Based on considerations of medication adherence, this invention provides an oral suspension that is easier to take, especially for the elderly or children, and also makes it easier to adjust the dosage to meet the needs of individual patients. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a long-acting oral suspension of paliperidone based on ion exchange resin and its preparation method.

[0006] The technical solution of the present invention is as follows: a long-acting oral suspension of paliperidone based on ion exchange resin, comprising the following components: paliperidone, sulfonic acid cation exchange resin, thixotropic agent and flavoring agent.

[0007] In some embodiments, the sulfonic acid cation exchange resin is selected from... The mass ratio of IRP69 resin, paliperidone, and sulfonic acid cation exchange resin is 1:3 to 1:4.

[0008] In some embodiments, the thixotropic agent is selected from one or more of xanthan gum, gum arabic, sodium carboxymethyl cellulose, hydroxypropyl cellulose, talc, or silica.

[0009] In some embodiments, the flavoring agent is one or more of acesulfame potassium, aspartame, and sucralose.

[0010] In some embodiments, the paliperidone long-acting oral suspension further includes a pH adjuster, wherein the pH adjuster is citric acid and sodium citrate.

[0011] In some embodiments, the paliperidone long-acting oral suspension comprises, by weight, the following components: 5 parts paliperidone, 15 parts sulfonic acid cation exchange resin, 1.25 parts xanthan gum, 0.25 parts silica, and 1.25 parts acesulfame potassium.

[0012] The present invention also provides a method for preparing the paliperidone long-acting oral suspension, comprising the following steps:

[0013] 1) Complex preparation: The prescribed amount of paliperidone and sulfonic acid cation exchange resin were stirred in a buffer solution, dried under vacuum, and then sieved to obtain the drug-loaded resin;

[0014] 2) Add the prescribed amount of thixotropic agent and flavoring agent, mix and disperse in ultrapure water to obtain the paliperidone long-acting oral suspension.

[0015] In some implementations, the particle size of the drug-loaded resin in step 1) is ≤50μm.

[0016] In some embodiments, the buffer solution in step 1) is a citrate buffer solution with a pH of 3.8 to 4.5, preferably a pH of 4.

[0017] In some implementations, the stirring time in step 1) is 7 hours.

[0018] The beneficial effects of this invention are: 1. Innovative carrier: It uses cation exchange resin (such as...) IRP69 forms a drug-resin complex with paliperidone, achieving pH-responsive release through ionic bonds (low dissociation in gastric juice, sustained release in intestinal juice).

[0019] 2. Dosage form optimization: Develop ready-to-use oral suspensions and add flavoring agents to improve taste.

[0020] 3. Expanded indications: Provide convenient dosage forms for patients with dysphagia (such as Alzheimer's disease with comorbid mental disorders). Detailed Implementation

[0021] The following embodiments are intended to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the invention to the scope of the embodiments described.

[0022] Preparation of drug-resin complex:

[0023] Paliperidone was dynamically adsorbed onto a sulfonic acid-type cation exchange resin in the pH buffer solution shown in the table below. The drug loading in the drug-resin complex was determined, and the results are shown in the table below. The highest drug loading, reaching 30%, was observed in the citrate buffer solution at pH 4.0.

[0024] pH conditions Drug loading % pH 2.0 hydrochloric acid solution 17 pH 3.8 acetate buffer 26 citrate buffer at pH 4.0 30 citrate buffer at pH 5.0 28

[0025] Example 1:

[0026] 1. Complex preparation: 5g paliperidone was mixed with 15g sulfonic acid cation exchange resin. IRP69 resin was stirred in citrate buffer at pH 4.0 for 7 hours, vacuum dried, and then sieved to obtain drug-loaded resin (particle size ≤ 50 μm).

[0027] 2. Add 1.25g xanthan gum, 0.25g silica, and 1.25g acesulfame potassium, mix, and disperse in ultrapure water.

[0028] Example 2:

[0029] 1. Complex preparation: 5g paliperidone and 15g Eudragit RS100 polyacrylic acid resin were stirred in citrate buffer at pH 4.0 for 7 hours, dried under vacuum, and then sieved to obtain the drug-loaded resin (particle size ≤ 50μm).

[0030] 2. Add 1.25g xanthan gum, 0.25g silica, and 1.25g acesulfame potassium, mix, and disperse in ultrapure water.

[0031] Example 3:

[0032] 1. Preparation of the complex: 5g paliperidone and 15g methacrylic acid resin were stirred in citrate buffer at pH 4.0 for 7 hours, dried under vacuum and sieved to obtain the drug-loaded resin (particle size ≤ 50μm).

[0033] 2. Add 1.25g xanthan gum, 0.25g silica, and 1.25g acesulfame potassium, mix, and disperse in ultrapure water.

[0034] Comparative Example 1: Formulation of CN112451483B

[0035] 1. Preparation of drug-containing solution: Dissolve 8g of glacial acetic acid and 0.54g of polysorbate 20 in 1.4g of ultrapure water by stirring. Add 5g of paliperidone and stir thoroughly to dissolve (particle size ≤100μm).

[0036] 2. Add the drug-containing solution dropwise to 450g of ice water (0-3℃) containing 2% polysorbate using a peristaltic pump and injection needle, while simultaneously applying high shear at 13000rpm. Continue stirring for 1h, and after returning to room temperature, add phosphate buffer to adjust the pH to 1.0. Vacuum for 4-5h until the acetic acid concentration is below 3.5g / L.

[0037] Comparative Example 2

[0038] 1. Preparation of the complex: 5g paliperidone and 15g methacrylic acid resin were stirred in citrate buffer at pH 4.0 for 7 hours, dried under vacuum and sieved to obtain the drug-loaded resin (particle size ≤ 50μm).

[0039] 2. Add 5g bentonite, 0.25g polysorbate, and 1.25g acesulfame potassium, mix and disperse in ultrapure water.

[0040] Comparative Example 3

[0041] 1. Preparation of the complex: 5g paliperidone and 15g methacrylic acid resin were stirred in citrate buffer at pH 4.0 for 7 hours, dried under vacuum and sieved to obtain the drug-loaded resin (particle size ≤ 50μm).

[0042] 2. Add 2g of guar gum, 2.5g of microcrystalline cellulose (MCC101), and 1.25g of acesulfame potassium, mix and disperse in ultrapure water.

[0043] Comparative Example 4

[0044] 1. Preparation of the complex: 5g paliperidone and 15g methacrylic acid resin were stirred in citrate buffer at pH 4.0 for 7 hours, dried under vacuum and sieved to obtain the drug-loaded resin (particle size ≤ 50μm).

[0045] 2. Add 0.5g xanthan gum, 0.25g silica, and 1.25g acesulfame potassium, mix, and disperse in ultrapure water.

[0046] Comparative Example 5

[0047] 1. Preparation of the complex: 5g paliperidone and 15g methacrylic acid resin were stirred in citrate buffer at pH 4.0 for 7 hours, dried under vacuum and sieved to obtain the drug-loaded resin (particle size ≤ 50μm).

[0048] 2. Add 1.25g xanthan gum, 1.25g silica, and 1.25g acesulfame potassium, mix, and disperse in ultrapure water.

[0049] Table 1: Detection Results of Each Example

[0050]

[0051]

[0052] Compared with Example 1, the suspension prepared in Example 2 showed significant sedimentation after 24 hours, poor resuspensibility after one week, and low suspension content.

[0053] Compared with Example 1, Comparative Example 2 showed a lower adsorption capacity of bentonite for drugs and a poorer drug loading effect; moreover, it had a noticeable gritty feel, requiring an additional amount of flavoring agent.

[0054] Compared with Example 1, Comparative Example 4 used less xanthan gum, and the resulting suspension showed significant sedimentation after 24 hours, but poor resuspensibility after one week.

[0055] Compared with Example 1, Comparative Example 5 increased the amount of silica, resulting in poorer fluidity of the suspension, which is not conducive to drug administration. Therefore, the preferred dosage of xanthan gum and silica is (0.5% + 0.1%).

[0056] Stability testing was performed on the preferred embodiment, and the results are as follows:

[0057] Table 2: Stability results of each embodiment

[0058]

[0059] Note: No stability testing was performed on Examples 2, 2, 4, and 5.

[0060] The present invention (Example 1) exhibits good redispersibility, good resuspension after one week of storage, and no significant changes in appearance, particle size, and dissolution stability during the stability testing process, with no significant decrease in content.

[0061] The suspension prepared in Example 3 had a large particle size and low content. During the stability testing process, the particle size increased, the content decreased, and the dissolution became slower.

[0062] Comparative Example 1 requires a large amount of acetic acid to be used in its preparation process, which needs to be removed by another process, making the process troublesome and still leaving residues; the acetic acid is highly irritating during the preparation process and poses certain risks to the human body; the prepared drug-containing suspension has a large API particle size; as can be seen from the dissolution rate, the sustained-release effect of the formulation is slightly poor, and the dissolution slows down during the stability process.

[0063] Comparative Example 3 showed significant sedimentation after 3 months of stability, indicating that the composite stabilizer of guar gum and microcrystalline cellulose had a poor effect.

Claims

1. A long-acting oral suspension of paliperidone based on ion exchange resin, comprising the following components: paliperidone, sulfonic acid cation exchange resin, thixotropic agent, and flavoring agent.

2. The paliperidone long-acting oral suspension according to claim 1, characterized in that, The sulfonic acid type cation exchange resin is selected from... The mass ratio of IRP69 resin, paliperidone, and sulfonic acid cation exchange resin is 1:3 to 1:

4.

3. The paliperidone long-acting oral suspension according to claim 1, characterized in that, The thixotropic agent is selected from one or more of xanthan gum, gum arabic, sodium carboxymethyl cellulose, hydroxypropyl cellulose, talc, or silica.

4. The paliperidone long-acting oral suspension according to claim 1, characterized in that, The flavoring agent is one or more of acesulfame potassium, aspartame, and sucralose.

5. The paliperidone long-acting oral suspension according to claim 1, characterized in that, The paliperidone long-acting oral suspension also includes a pH adjuster, wherein the pH adjuster is citric acid and sodium citrate.

6. The paliperidone long-acting oral suspension according to claim 1, characterized in that, The paliperidone long-acting oral suspension comprises the following components by weight: 5 parts paliperidone, 15 parts sulfonic acid cation exchange resin, 1.25 parts xanthan gum, 0.25 parts silica, and 1.25 parts acesulfame potassium.

7. The method for preparing paliperidone long-acting oral suspension according to claim 1, comprising the following steps: 1) Complex preparation: The prescribed amount of paliperidone and sulfonic acid cation exchange resin were stirred in a buffer solution, dried under vacuum, and then sieved to obtain the drug-loaded resin; 2) Add the prescribed amount of thixotropic agent and flavoring agent, mix and disperse in ultrapure water to obtain the paliperidone long-acting oral suspension.

8. The preparation method according to claim 7, characterized in that, The particle size of the drug-loaded resin in step 1) is ≤50μm.

9. The preparation method according to claim 7, characterized in that, The buffer solution in step 1) is a citrate buffer solution with a pH of 3.8 to 4.5, preferably a pH of 4.

10. The preparation method according to claim 7, characterized in that, The stirring time in step 1) is 7 hours.

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