Iguratimod solid preparation and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an Iguratimod solid preparation and a preparation method thereof. The invention provides an iguratimod solid preparation. The iguratimod solid preparation comprises iguratimod particles, a disintegrating agent and a lubricating agent. The preparation method of the iguratimod solid preparation comprises the following steps: adding a surfactant and an adhesive into an aqueous solution in which an alkaline reagent is dissolved, and adding an active component iguratimod after dissolving to obtain a medicine-containing alkaline solution; and adding the medicine-containing alkaline solution into the filler, uniformly mixing, performing wet granulation, drying, finishing granules, uniformly mixing with the disintegrating agent and the lubricant, and preparing the uniformly mixed material into the solid preparation. By controlling the prescription and the preparation process, the iguratimod solid preparation with good dissolution rate and stability is obtained, micronization treatment does not need to be performed on the iguratimod raw material, and various problems of environment, safety, loss, equipment requirements and the like caused by the raw material micronization process are avoided.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an iguratimod solid preparation and a preparation method thereof. Background Art

[0002] Rheumatoid arthritis (RA) is an autoimmune disease with symmetrical, progressive, erosive polyarthritis as the main clinical manifestation. The pathological changes are joint synovitis and pannus formation. The disease invades the articular cartilage, subchondral bone and surrounding soft tissue, causing destruction of articular cartilage, bone and joint capsule. The disease progresses progressively, eventually leading to joint deformity, physical disability, loss of function, and reduced quality of life of patients. At present, RA treatment drugs mainly include non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). The main function of NSAIDS is to relieve joint pain, swelling and improve joint function in RA patients, but it does not change the progression of the disease or prevent joint destruction. Its serious adverse reactions to the gastrointestinal tract limit its use. Compared with NSAIDs, DMARDs have a slower onset of action, more adverse reactions, and the efficacy will decrease with the extension of medication time, but it can prevent the progression of the disease and prevent joint destruction.

[0003] Ailamod, chemically named N-[3-(formamido)-4-oxy-6-phenoxy-4H-1-benzopyran-7-yl]-methanesulfonamide, is a new type of disease-modifying anti-arthritis drug that can not only selectively inhibit cyclooxygenase-2 (COX-2), but also regulate T-cells, has autoimmune regulatory effects, and has better efficacy and fewer side effects than existing therapies. However, Ailamod has extremely poor water solubility, is insoluble in water, acid, and commonly used organic solvents such as methanol and ethanol, and is slightly soluble in acetonitrile and acetone. Therefore, when preparing solid preparations such as ordinary tablets, orally disintegrating tablets or capsules, they need to be crushed to a certain fineness or in the form of solid dispersions to ensure that the solid preparation can be rapidly dissolved after oral administration, and to ensure absorption rate and bioavailability.

[0004] At present, the pulverization of poorly soluble drugs is basically carried out by mechanical pulverization or airflow pulverization. Chinese patent CN117462497A discloses a method for preparing Aguratimod tablets: the Aguratimod raw material is subjected to airflow pulverization for micronization treatment, and the particle size D90 is 10 to 50 microns, and then the micronized raw material is subjected to a granulation process to prepare tablets. However, the Aguratimod raw material is a white or off-white crystalline powder, lacks brittleness, and is cotton-like after micronization, has high static electricity and poor fluidity. Therefore, the above-mentioned micronization treatment method has the defects of high dust, environmental pollution and high loss. In addition, when the pulverization treatment is carried out, it is very easy for the operator to inhale the raw material powder, and long-term inhalation may cause adverse reactions or even more serious consequences. Chinese patent CN1531925A discloses a micronization method of mechanical grinding with water, and the particle size after pulverization treatment is less than 74 microns. The pulverization treatment of this method can effectively improve the problems of high dust and high static electricity, but the particle size of the raw material treated by mechanical pulverization is still large, and the improvement effect on the dissolution characteristics of solid preparations is not ideal. In addition, grinding with water requires the use of special equipment such as colloid mills or ball mills, which has high requirements for production equipment and is not conducive to commercial production. Chinese patent CN1931159A discloses a method for micronizing Ailamod, in which the Ailamod raw material is added to dimethylformamide to dissolve it, and then slowly dripped into water, and stirred rapidly while dripping, and Ailamod is immediately precipitated and dispersed in the water. Filter and stir and wash three times with distilled water, filter and separate the solid, and dry to obtain the raw material particle size of the obtained micropowder in 1 to 10 microns. This method effectively controls the raw material particle size, but the organic reagent dimethylformamide used in the process is a high flash point flammable liquid, which has a large production safety hazard.

[0005] Therefore, there is an urgent need to develop a method for preparing a solid preparation of elamod that can overcome the defects of the above-mentioned treatment methods and ensure excellent various quality indicators. Summary of the invention

[0006] In view of this, the present invention provides an iguratimod solid preparation and a preparation method thereof. In the iguratimod solid preparation, the iguratimod active ingredient is firstly dissolved and granulated in an alkaline solution, and then a disintegrant is added, thereby ensuring that the obtained iguratimod solid preparation has good and stable solubility.

[0007] To solve the above technical problems, the first aspect of the present invention provides an iguratimod solid preparation, comprising iguratimod granules, a disintegrant and a lubricant. According to the mass percentage of the solid preparation, the iguratimod granules comprise: 5% to 25% iguratimod, 0.03% to 0.25% surfactant, 4.0% to 15.0% alkaline agent, 65% to 75% filler and 2.0% to 4.0% binder, 2.0% to 5.0% disintegrant and 0.8% to 1.2% lubricant.

[0008] Since Iguratimod is a poorly water-soluble drug, its solid preparations such as tablets or capsules have low solubility. After a large number of experiments, the inventors found that the solubility of Iguratimod raw materials has a certain dependence on pH, and alkaline conditions are more conducive to its dissolution. Therefore, the Iguratimod solid preparation provided by the present invention does not use an acidic reagent, and does not need to be crushed in advance. It only needs to dissolve the active ingredient of Iguratimod in an alkaline solution, granulate, and then combine it with a specific preparation process to obtain an Iguratimod solid preparation with good solubility.

[0009] In combination with the first aspect, the above-mentioned solid preparation of iguratimod includes iguratimod granules, a disintegrant and a lubricant in terms of mass percentage. In terms of mass percentage of the solid preparation, the iguratimod granules include: 12.5% ​​to 17% iguratimod, 0.05% to 0.15% surfactant, 4.2% to 12.5% ​​alkaline agent, 65% to 75% filler and 2.0% to 4.0% binder, 2.0% to 5.0% disintegrant, and 1.0% to 1.1% lubricant.

[0010] Preferably, the above-mentioned iguratimod solid preparation comprises iguratimod granules, a disintegrant and a lubricant in terms of mass percentage. In terms of mass percentage of the solid preparation, the iguratimod granules comprise: 15.6% of active ingredient iguratimod, 0.19% of surfactant, 12.5% ​​of alkaline agent, 65% of filler and 2.5% of binder, 3.2% of the disintegrant and 1.0% of lubricant.

[0011] In conjunction with the first aspect, the surfactant refers to an amphiphilic agent that can increase the solubility of the poorly soluble drug iguratimod. The surfactant used should be a pharmaceutically acceptable agent that is compatible with iguratimod. The compatibility means that they can coexist without adverse effects. The surfactant in the present invention can be selected from one or more of sodium dodecyl sulfate, magnesium dodecyl sulfate, polysorbate and poloxamer.

[0012] Preferably, the surfactant is sodium lauryl sulfate, magnesium lauryl sulfate or polysorbate 80.

[0013] In combination with the first aspect, the alkaline agent is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, disodium hydrogen phosphate, sodium citrate, sodium tartrate, sodium malate and sodium acetate.

[0014] Preferably, the mass ratio of the alkaline agent to the active ingredient iguratimod is 0.3-0.8:1.

[0015] In combination with the first aspect, the filler is selected from one or more of lactose, microcrystalline cellulose, pregelatinized starch, starch, mannitol, sucrose and maltitol.

[0016] In combination with the first aspect, the binder is selected from one or more of hydroxypropyl methylcellulose, povidone and hydroxypropyl cellulose.

[0017] In combination with the first aspect, the disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose and calcium carboxymethyl cellulose, and the lubricant is selected from one or more of colloidal silicon dioxide, sodium stearyl fumarate, talc, magnesium stearate and calcium stearate.

[0018] In combination with the first aspect, the solid preparation is a capsule or a tablet, and may also be an orally disintegrating tablet or a granule.

[0019] The second aspect of the present invention provides a method for preparing the above-mentioned solid preparation of iguratimod, comprising the following steps: adding a surfactant and a binder to an aqueous solution containing an alkaline agent according to a prescription ratio, adding the active ingredient iguratimod after dissolution to obtain a drug-containing alkaline liquid; adding the drug-containing alkaline liquid to a filler, mixing well and then wet granulating, drying the wet granules obtained by the wet granulation, granulating them well and then mixing them evenly with a disintegrant and a lubricant, and preparing the mixture into a solid preparation.

[0020] The preparation method of the solid preparation of iguratimod provided by the present invention controls the adding time of the disintegrant and adds the disintegrant after the whole granules are dried to ensure the maintenance of the local alkaline environment, thereby slowing down the disintegration speed of the granules, facilitating the dissolution and release of iguratimod, achieving a significant improvement in the dissolution rate of iguratimod and increasing the bioavailability.

[0021] In combination with the second aspect, in the aqueous solution containing the alkaline agent, the amount of solvent water is 10% to 80% of the amount of all dry materials, wherein the dry materials are the sum of other raw materials and auxiliary materials except the solvent.

[0022] Preferably, in the aqueous solution containing the alkaline agent, the amount of solvent water is 20% to 60% of the amount of all dry materials.

[0023] The beneficial effects obtained by the present invention are as follows: the present invention directly dissolves the raw material of Aguratimod in an alkaline solution containing a surfactant, and the raw material of Aguratimod can be more evenly converted into a solid form during the drying process of the wet granulation process. The method does not need to use a complicated and cumbersome crushing process in advance to control the particle size of the raw material of Aguratimod, nor does it need to use an organic solvent with high safety hazards, thereby avoiding various problems such as environment, safety, loss, and equipment requirements caused by the raw material micronization process, and the preparation process is simple and feasible. At the same time, the Aguratimod granules do not have an internal disintegrant, and their dissolution behavior is mainly a dissolution phenomenon, which is mainly due to the local high pH environment brought by the alkaline reagent, ensuring that the obtained solid preparation has good solubility. DETAILED DESCRIPTION

[0024] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0025] The existing preparation methods of iguratimod solid preparations mainly control the particle size of iguratimod raw materials by mechanical pulverization or air flow pulverization, but these methods often have the defects of environmental pollution, high loss, high equipment requirements, high static electricity, or the need to use organic reagents with high safety hazards. In view of this, the present invention provides a preparation method of iguratimod solid preparations, which is simple to operate, has less pollution from the reagents used, does not have the aforementioned safety hazards, and does not require the raw materials to be pulverized in advance to achieve particle size control. The iguratimod solid preparation prepared by the method has good solubility, content uniformity and stability.

[0026] The following specific examples are used to illustrate the preparation method of the solid preparation of Aguratimod. In addition, in the following examples, the experimental methods without special conditions are all implemented according to conventional methods, or according to the conditions recommended by the equipment manufacturer. The dosage form specifications of the solid preparation of Aguratimod provided by the present invention are based on the content of Aguratimod, and each unit dose contains 25 mg of Aguratimod (i.e., each tablet contains 25 mg of Aguratimod). In the following examples and comparative examples, the mass percentages of Aguratimod, surfactant and solvent are all the mass percentages of dry materials in wet granulation. Wherein, the amount of solvent used includes water in the alkaline reagent solution.

[0027] Example 1 of the present invention and Comparative Examples 1-2 both provide a prescription of an iguratimod tablet (25 mg / tablet) and a preparation process thereof, as shown in Table 1. The difference between Comparative Example 1 and Example 1 is that a disintegrant is added as an internal excipient, and the remaining components and steps are the same; the difference between Comparative Example 2 and Example 1 is that the prescription does not contain an alkaline agent (only water is used without using an alkaline solution), and iguratimod is pre-crushed by an airflow mill and passed through a 100-mesh sieve before use.

[0028] Table 1

[0029]

[0030] Examples 2 to 3 of the present invention and Comparative Example 3 both provide a prescription of an iguratimod tablet (25 mg / tablet) and a preparation process thereof, as shown in Table 2. The difference between Comparative Example 3 and Example 2 is that the prescription contains an acidic reagent, and the regional components and steps are the same as those of Example 2.

[0031] Table 2

[0032]

[0033] Example 4 of the present invention and Comparative Examples 4-5 all provide a prescription of an iguratimod tablet (25 mg / tablet) and a preparation process thereof, as shown in Table 3. The difference between Comparative Examples 4 and 5 and Example 4 is that different amounts of disintegrant, crosslinked sodium carboxymethyl cellulose, are added as internal and external excipients, respectively, but the total amount added is still the same as that of Example 4.

[0034] Table 3

[0035]

[0036]

[0037] Examples 5 to 6 of the present invention all provide a prescription of an iguratimod tablet (25 mg / tablet) and a preparation process thereof, as shown in Table 4.

[0038] Table 4

[0039]

[0040]

[0041] Examples 7 to 8 of the present invention all provide a prescription of an Aguratimod capsule (25 mg / tablet) and its preparation process, as shown in Table 5.

[0042] Table 5

[0043]

[0044]

[0045] Test Example 1

[0046] The dissolution test of the Ailamod tablets or Ailamod capsules prepared in Examples 1 to 8 and Comparative Examples 1 to 5 was performed respectively, and the specific method was as follows: the product was weighed, and according to the dissolution determination method (Chinese Pharmacopoeia 2020 Edition Four General Rules 0931 Second Method), 900 mL of phosphate buffer (pH 7.8) was used as the dissolution medium, and the speed was set to 50 revolutions per minute, and the operation was carried out in accordance with the law. At 15 min, 30 min and 45 min, 30 mL of the solution was filtered, and 5 mL of the subsequent filtrate was accurately measured and placed in a 25 mL measuring bottle as a sample solution, and a control solution was prepared at the same time. According to the ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2020 Edition Four General Rules 0401), the absorbance was measured at a wavelength of 257 nm, and the dissolution amount of each tablet was calculated. The results are shown in Table 6.

[0047] Table 6

[0048]

[0049]

[0050] As shown in Table 6, the drug dissolution rate and solubility of the solid preparation of Aguratimod prepared according to the prescription and process of Examples 1 to 8 are significantly better than those of the solid preparation of Aguratimod prepared according to the prescription and process of Comparative Example 2 (the Aguratimod raw material used is subjected to micronization treatment) and can be completely released. It shows that the preparation method of the solid preparation of Aguratimod provided by the present invention does not need to pre-micronize the raw material Aguratimod, and a solid preparation with good dissolution rate and solubility can be obtained directly using the Aguratimod raw material without any treatment, and the preparation method is simple and feasible, and effectively improves the solubility of the poorly soluble drug Aguratimod. It can be seen from Comparative Examples 1 and Comparative Examples 4 to 5 that when the disintegrant is added completely or partially as an internal excipient, the dissolution rate and dissolution rate of the prepared solid preparation of Aguratimod are significantly lower than those of other embodiments in which all external disintegrants are added. It can be seen from Comparative Example 3 that during the preparation process, if an additional acidic reagent such as anhydrous citric acid is added to adjust the pH value of the solution to neutral, the dissolution rate and solubility of the obtained iguratimod solid preparation are also significantly lower than those in other examples.

[0051] Test Example 2

[0052] The content uniformity experiment was carried out on the Ailamod tablets prepared in Examples 1 to 6 and Comparative Examples 1 to 2, respectively. According to the content uniformity test method (Chinese Pharmacopoeia 2020 Edition Four General Rules 0941), the content of each tablet was determined, and the content uniformity was calculated. Content determination method: Take an appropriate amount of sample, dissolve it with ultrasonic shaking of the mobile phase, and make a solution containing an appropriate amount of Ailamod in each 1mL mobile phase as a test solution, and prepare a control solution. According to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Four General Rules 0512), octadecyl silicon bonded silica gel was used as a filler, diammonium phosphate solution-acetonitrile (60:40) was used as the mobile phase, and the absorbance was measured and calculated at a wavelength of 257nm. The results are shown in Table 7.

[0053] Table 7

[0054]

[0055]

[0056] As shown in Table 7, the content and content uniformity of the iguratimod tablets prepared in Comparative Examples 1 to 2 and Examples 1 to 6 can meet the requirements of the pharmacopoeia, indicating that the preparation process provided by the present invention has good feasibility.

[0057] Test Example 3

[0058] The iguratimod tablets prepared in Examples 1 to 5 and Comparative Examples 1 to 3 were subjected to an accelerated stability test. The specific method was as follows: the test samples were placed in high-density polyethylene plastic bottles, sealed, and placed in an accelerated inspection box. After an accelerated test for 3 months at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%, the stability of the relevant items was measured.

[0059] Among them, the method for determining the content of related substances is: take an appropriate amount of sample, ultrasonically shake the mobile phase to dissolve it, and prepare a solution containing an appropriate amount of elamod per milliliter as the test solution, and prepare a control solution. According to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512), octadecyl silicon bonded silica gel is used as a filler, and ammonium dihydrogen phosphate solution-acetonitrile (60:40) is used as the mobile phase. The absorbance is measured and calculated at a wavelength of 257nm. The results are shown in Table 8.

[0060] Table 8

[0061]

[0062]

[0063] As can be seen from Table 8, compared with the corresponding examples, after the accelerated test, the dissolution of comparative examples 1 to 3 decreased significantly. Although the solubility, content and related substances of comparative examples 1 to 2 changed slightly, the solubility was significantly lower than that of the examples. The content, solubility and related substances of examples 1 to 5 after 3 months of acceleration were basically consistent with the level at 0 days, indicating that the prescription and preparation process provided by the present invention can prepare a solid preparation of iguratimod with good stability.

[0064] What is described above is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A solid preparation of iguratimod, characterized in that: The invention comprises iguratimod granules, a disintegrant and a lubricant. According to the mass percentage of the solid preparation, the iguratimod granules comprise: 5% to 25% iguratimod, 0.03% to 0.25% of a surfactant, 4.0% to 15.0% of an alkaline agent, 65% to 75% of a filler and 2.0% to 4.0% of a binder, 2.0% to 5.0% of a disintegrant and 0.8% to 1.2% of a lubricant.

2. The iguratimod solid preparation according to claim 1, characterized in that The invention comprises iguratimod granules, a disintegrant and a lubricant. According to the mass percentage of the solid preparation, the iguratimod granules comprise: 12.5% ​​to 17% iguratimod, 0.05% to 0.15% of a surfactant, 4.2% to 12.5% ​​of an alkaline agent, 65% to 75% of a filler and 2.0% to 4.0% of a binder, 2.0% to 5.0% of a disintegrant and 1.0% to 1.1% of a lubricant.

3. The iguratimod solid preparation according to claim 1 or 2, characterized in that The surfactant is selected from one or more of sodium lauryl sulfate, magnesium lauryl sulfate, polysorbate and poloxamer.

4. The iguratimod solid preparation according to claim 1 or 2, characterized in that The alkaline agent is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, disodium hydrogen phosphate, sodium citrate, sodium tartrate, sodium malate and sodium acetate.

5. The iguratimod solid preparation according to claim 1 or 2, characterized in that The filler is selected from one or more of lactose, microcrystalline cellulose, pregelatinized starch, starch, mannitol, sucrose and maltitol.

6. The iguratimod solid preparation according to claim 1 or 2, characterized in that The binder is selected from one or more of hydroxypropyl methylcellulose, povidone and hydroxypropyl cellulose.

7. The iguratimod solid preparation according to claim 1 or 2, characterized in that The disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose and calcium carboxymethyl cellulose, and the lubricant is selected from one or more of colloidal silicon dioxide, sodium stearate fumarate, talc, magnesium stearate and calcium stearate.

8. The iguratimod solid preparation according to claim 1 or 2, characterized in that The solid preparation is a capsule or a tablet.

9. A method for preparing the solid preparation of iguratimod according to any one of claims 1 to 8, characterized in that the steps include: According to the prescription ratio, a surfactant and a binder are added to an aqueous solution containing an alkaline agent, and after the solution is dissolved, an active ingredient iguratimod is added to obtain a drug-containing alkaline solution; The drug-containing alkaline liquid is added to the filler, mixed and then wet granulated. The wet granules obtained by the wet granulation are dried and granulated, and then mixed with a disintegrant and a lubricant to prepare a solid preparation.

10. The method for preparing the iguratimod solid preparation according to claim 9, characterized in that: In the aqueous solution containing the alkaline reagent, the amount of solvent water is 10% to 80% of the amount of all dry materials.

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