Stable orlistat composition and preparation method thereof

Abstract

The invention discloses a stable orlistat composition, which comprises orlistat, a filler, a disintegrating agent, a surfactant, a stabilizer and a flow aid, the stabilizer accounts for 2-5% of the total weight of the composition, and the orlistat is sieved and dispersed before being mixed with other components. The composition can still keep stable dissolution of orlistat capsules under the condition of low stabilizer content, and the product quality and curative effect are guaranteed.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a stable orlistat composition and a preparation method thereof. Background Art

[0002] Orlistat is a long-acting and potent specific gastrointestinal lipase inhibitor. It inactivates the enzymes by forming covalent bonds with the active serine sites of gastric lipase in the stomach and pancreatic lipase in the small intestine, thus exerting its therapeutic effect. The inactivated enzymes cannot hydrolyze fats (mainly triglycerides) in food into absorbable free fatty acids and monoacylglycerols. Undigested triglycerides cannot be absorbed by the body, thereby reducing calorie intake and controlling weight. The drug was first launched in the European Union in 1998, and was approved by the U.S. Food and Drug Administration (FDA) in 1999. It was marketed by Roche in Europe and the United States. The product was registered in China in 2000. Currently, the marketed dosage forms include capsules and chewable tablets, with capsules being the main one.

[0003] Patent CN98800369.4 of the original research company Roche discloses a composition containing orlistat, wherein orlistat, stabilizers and pharmaceutical excipients are prepared into granules by conventional wet granulation process or pellets by extrusion spheronization, and the particle size of these particles is controlled within the range of 0.25-2 mm, and then prepared into a suitable oral solid preparation. Among them, the stabilizer is polyvinyl pyrrolidone, lactose or a combination of polyvinyl pyrrolidone and lactose, hydroxypropyl methylcellulose and hydroxypropyl cellulose. The amount of the stabilizer polyvinyl pyrrolidone is required to be at least 5%, and when the stabilizer is a combination of polyvinyl pyrrolidone and lactose, the amount of polyvinyl pyrrolidone is at least 3%.

[0004] Orlistat has a low melting point of about 44°C. When the intermediate conditions of 30°C ± 2°C and 65% ± 5% relative humidity were used for accelerated testing or 25°C ± 2°C and 60% ± 10% relative humidity for long-term testing, it was found that the dissolution or dissolution curve of many batches of original research products decreased during the inspection. At the same time, samples were prepared according to the composition and preparation method of CN98800369.4, and the formulation stability of the obtained samples changed significantly. Although polyvinyl pyrrolidone is used as a stabilizer in this product to promote the quality stability of the product during stability inspection or storage period, the stabilizer is within a specific proportion range of 3%-5%, and the stabilizer cannot effectively guarantee the stability of the dissolution curve during the product stability inspection.

[0005] The inventors surprisingly found that the raw material drug orlistat drug preparation can not only improve the mixing uniformity of the product after screening with a specific aperture screen, but also effectively improve the stability of the product and ensure the product quality even at a lower stabilizer dosage, and the quality is better than the original preparation. According to the bioequivalence study, the product of the present invention is bioequivalent to the original preparation, thereby realizing the present invention. Summary of the invention

[0006] The object of the present invention is to provide a stable orlistat composition, which can maintain stable quality under the condition of low stabilizer content, thereby ensuring the quality and efficacy of the product.

[0007] To achieve the purpose of the present invention, the following embodiments are provided.

[0008] In one embodiment, a stable orlistat composition of the present invention comprises orlistat, a filler, a disintegrant, a surfactant, a stabilizer and a glidant, wherein the stabilizer accounts for 2-5% of the total weight of the composition, and the orlistat is dispersed by sieving before mixing with other components, and the sieving is selected from one of standard sieve dispersion, integrated sieving machine dispersion, and vibration sieving machine dispersion.

[0009] In some embodiments, the orlistat composition of the present invention comprises 50% orlistat, 35-45% filler, 3-4.5% disintegrant, 1-10% surfactant, 2.0-5% stabilizer, and 0.1% glidant in weight percentage.

[0010] Preferably, the orlistat composition of the present invention comprises 50% orlistat, 39-42% filler, 3-4.0% disintegrant, 2.5-2.9% surfactant, 2.0-5% stabilizer, and 0.1% glidant in weight percentage.

[0011] Preferably, the orlistat composition of the present invention is in the form of a capsule.

[0012] Preferably, in the orlistat composition or capsule of the present invention, the filler is selected from one or more of microcrystalline cellulose, lactose and starch.

[0013] Preferably, in the orlistat composition or capsule of the present invention, the disintegrant is selected from sodium starch glycolate and cross-linked polyvinyl pyrrolidone.

[0014] Preferably, in the above-mentioned orlistat composition or capsule of the present invention, the surfactant is selected from sodium lauryl sulfate, polyethylene glycol and polysorbate.

[0015] Preferably, in the orlistat composition or capsule of the present invention, the stabilizer is polyvinyl pyrrolidone, and the glidant is talc.

[0016] Preferably, in the orlistat composition or capsule of the present invention, the sieve is a standard sieve or a screening machine, wherein the sieve aperture of the standard sieve is 60-150 mesh, more preferably 80-120 mesh, and the sieve aperture of the screening machine is 0.4-0.8 mm, more preferably 0.6 mm.

[0017] In another embodiment, the present invention further provides a method for preparing the orlistat composition or capsule of the present invention, comprising the following steps:

[0018] 1) dispersing orlistat by sieving;

[0019] 2) mixing the dispersed orlistat with a filler and a disintegrant to prepare a premix;

[0020] 3) dissolving the stabilizer and sodium lauryl sulfate in water to form a solution, adding the solution to the premix in the previous step by atomization, and performing wet granulation to obtain a suitable soft material;

[0021] 4) Granulate the soft material to obtain wet granules or micropellets with uniform size and full shape, add talcum powder after drying, mix evenly, and put into capsules.

[0022] Preferably, in the orlistat capsules and preparation method of the present invention, the standard sieve has a mesh size of 60-150 mesh, more preferably 80-120 mesh, and the sieve size of the screening and granulation machine is 0.4-0.8 mm, more preferably 0.6 mm.

[0023] Dissolution determination method of orlistat capsules of the present invention:

[0024] The dissolution determination method is the second method (paddle method) of the fourth part of the Chinese Pharmacopoeia 0931 dissolution and release determination method. The drug sample is placed in 900 ml of pH 6.0 phosphate buffer + 1.0% sodium dodecyl sulfate medium. The paddle method is used at 75 rpm. 1.5 ml of medium is taken at 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes respectively. The drug release amount at each time point is determined by high performance liquid chromatography.

[0025] Study on the effect of API dispersion on stability:

[0026] For orlistat preparations, due to the poor dissolution stability of orlistat, it is often necessary to add a sufficient amount of stabilizer polyvinyl pyrrolidone. However, the inventors found that when conducting stability studies, it was found that simply by increasing the amount of stabilizer, the solubility or dissolution curve may still be unstable with a significant decrease.

[0027] At the same time, since polyvinyl pyrrolidone is easy to absorb moisture, excessive dosage will cause degradation risk; and polyvinyl pyrrolidone has a high viscosity. When its dosage is too high, atomization slurrying is not easy to achieve, resulting in uneven preparation, which is not only not conducive to production operation, but also affects product quality. Therefore, it is necessary to reduce the content of the stabilizer polyvinyl pyrrolidone, but reducing polyvinyl pyrrolidone is difficult to maintain the dissolution stability of orlistat. How to solve this contradictory technical problem is also the purpose of the present invention and the technical problem to be solved.

[0028] According to the characteristics of orlistat and the pharmaceutical products containing orlistat, the present invention disperses the orlistat raw material and then mixes it with auxiliary materials to prepare capsules. This concept can effectively improve the stability of the pharmaceutical products containing orlistat. After a large number of experimental studies, the screening and dispersion method of the orlistat raw material is determined, thereby completing the present invention.

[0029] Beneficial effects of the present invention: The present invention can provide a highly stable preparation composition containing orlistat, wherein the preparation components can ensure the quality stability of the product at a lower stabilizer dosage, and the quality does not change significantly during the stability test, and the preparation composition is obtained by adjusting the dispersion pretreatment of the orlistat raw material in the components. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 This is a dissolution curve of the stability process of the orlistat capsules (not sieved) of Comparative Example 1;

[0031] Figure 2 This is the dissolution curve of the stability process of Orlistat Capsules (8% stabilizer) of Comparative Example 2;

[0032] Figure 3 This is the dissolution curve of the stability process of Orlistat Capsules (passing 40 mesh) of Comparative Example 3;

[0033] Figure 4 This is the dissolution curve of the stability process of the orlistat capsule (over 1.0 mm) of Comparative Example 4;

[0034] Figure 5 This is a dissolution curve of the stability process of orlistat capsules (passing 100 mesh) of Example 1;

[0035] Figure 6 This is a dissolution curve of the stability process of orlistat capsules (passing 60 mesh) of Example 2;

[0036] Figure 7 This is a dissolution curve of the stability process of orlistat capsules (passing 150 mesh) of Example 3;

[0037] Figure 8This is a stability dissolution curve of the orlistat capsule (2% stabilizer) of Example 4;

[0038] Fig. 9 This is a dissolution curve of the stability process of orlistat capsules (passing 80 mesh) of Example 5;

[0039] Fig.10 This is a dissolution curve of the stability process of orlistat capsules (passed through 120 mesh) of Example 6;

[0040] Fig.11 This is the dissolution curve of the stability process of orlistat capsules (over 0.4 mm) of Example 7;

[0041] Fig.12 This is the dissolution curve of the stability process of orlistat capsules (over 0.6 mm) of Example 8;

[0042] Fig.13 This is the dissolution curve of the stability process of orlistat capsules (over 0.8 mm) in Example 9. DETAILED DESCRIPTION

[0043] The following examples are merely representative and are used to illustrate and understand the essence of the present invention, but are not intended to limit the scope of the present invention in any way.

[0044] In the following examples, the orlistat raw material was dispersed by different sieving dispersion methods and sieve mesh apertures, and then the preparation products (represented by capsules) were prepared, and the stability changes of the preparation products were investigated under the conditions of 30°C ± 2°C and 65% ± 5% relative humidity for 6 months. The stability of the preparation was evaluated by evaluating the change trend of the dissolution rate or dissolution curve quality index.

[0045] Example 1-6 Orlistat Capsules

[0046] The prescription of orlistat capsules is shown in Table 1, wherein the orlistat raw materials in Example 1, Example 2, Example 3, Example 4, Example 5 and Example 6 are dispersed through standard sieves of 100 mesh, 60 mesh, 150 mesh, 100 mesh, 80 mesh and 120 mesh, respectively. The amount of stabilizer in Example 1 to Example 3, Example 5 and Example 6 is 5%, and the amount of stabilizer in Example 4 is 2%, which is lower than the amount reported in the literature.

[0047] Table 1. Orlistat treatment methods and capsule prescriptions of Examples 1-6

[0048]

[0049] Preparation process:

[0050] 1. Weighing

[0051] Weigh all raw and auxiliary materials according to the prescription and set aside.

[0052] 2. Premix

[0053] After orlistat is sieved, it is mixed with microcrystalline cellulose and sodium starch glycolate in a wet granulator to prepare a premix.

[0054] 3. Making soft materials

[0055] Polyvinyl pyrrolidone and sodium lauryl sulfate are dissolved in water to form a solution, which is then added to the premix by atomization to prepare a soft material.

[0056] 4. Extrusion and rounding

[0057] The soft material is extruded and spheronized by an extruder, thereby producing granules or pellets.

[0058] 5. Drying

[0059] The granules are dried in a multifunctional fluidized bed, and the material temperature is ≤30°C.

[0060] 6. Total Mixing

[0061] Add the dried granules or pellets and talc into a multi-sport mixer to complete the total blend.

[0062] 7. Filling capsules

[0063] Fill capsules according to target particle weight.

[0064] Example 7-9 Orlistat Capsules

[0065] The prescription of orlistat capsules is shown in Table 2, wherein the orlistat raw materials in Examples 7, 8 and 9 are pre-treated by using a screening and granulation machine to pass through 0.4 mm, 0.6 mm and 0.8 mm sieves to prepare capsules.

[0066] Table 2. Orlistat treatment methods and formulations of Examples 7-9

[0067]

[0068] Preparation process: Except for the processing method of the raw material drug, the preparation process is the same as Example 1-6.

[0069] Comparative Examples 1-4

[0070] The raw materials in Comparative Examples 1-2 were not sieved and dispersed, and the preparation method of the patent prescription of CN98800369.4 was referred to; among which Comparative Example 2 had a higher stabilizer ratio, and the raw materials of Orlistat in Comparative Examples 3 and 4 were respectively sieved through a 40-mesh sieve and a 1.0 mm sieving and granulating integrated machine for sample preparation. The prescription list is shown in Table 3.

[0071] Table 3. Orlistat capsule prescriptions of comparative examples 1-4

[0072]

[0073] Preparation process: Except for the processing method of the raw materials in each comparative example, the preparation process is the same as that of the embodiment.

[0074] Effect experiment

[0075] Stability study and dissolution curve determination

[0076] The orlistat capsules of Comparative Examples 1-4 and the orlistat capsules of Examples 1-9 were placed at 30°C ± 2°C and relative humidity 65% ​​± 5% for 6 months to determine the stability changes in quality indicators such as dissolution or dissolution curve. The dissolution curves at 0 days, 3 months, and 6 months were determined, and the dissolution results are shown in Tables 4-6.

[0077] Table 4. Comparative Examples 1-4 Sample Stability Dissolution Results

[0078]

[0079]

[0080] The data in the above table show that, when samples were prepared with reference to the original patent literature, the raw material orlistat was not pre-dispersed or screened through a sieve with a larger aperture (the screening effect was poor), the stability of the prepared product was poor, and the accelerated samples of 3 months and 6 months showed significant changes compared with 0 days, and the F2 factor was not similar to 0 days, and the product quality showed significant changes. At the same time, it can be seen in the comparative example 2 test that even under the condition of a higher proportion of PVP dosage, although the product stability was improved, the stability trend was inferior to the sample prepared by the method of the present invention at a low stable dosage.

[0081] Table 5. Stability dissolution results of samples from Examples 1-6

[0082]

[0083]

[0084] The data in the above table show that after the API orlistat is dispersed by different dispersion methods, the prepared samples are subjected to stability test. Compared with 0 days, the F2 factor of the dissolution curve after accelerated dissolution for 6 months is similar to that of 0 days. The product quality is relatively stable, and the variation range is significantly smaller than that of the samples prepared with reference to the original patent literature. It shows that sieving within a certain mesh aperture range can effectively improve product stability. After the API in Example 4 is well dispersed, even at a lower stabilizer content, the accelerated dissolution of the product for 6 months has a smaller variation range than that of 0 days, the F2 factor similarity is higher, and the stability is greatly improved, indicating that the technical effect of the present invention is more prominent.

[0085] Table 6. Stability dissolution results of samples from Examples 7-9

[0086]

[0087] The results in Table 6 show that the raw material orlistat was screened by a screening and granulation integrated machine with a specific aperture, and the stability of the prepared sample was accelerated by 6 months compared with 0 days, and the F2 factor of the dissolution curve was similar to 0 days, and the product quality was stable. It can be seen that the orlistat preparation composition of the present invention adopts the orlistat raw material to be first dispersed in a sieve with a specific aperture by different screening and dispersion methods and then mixed with its components, which can improve the stability of the orlistat capsule product to varying degrees.

Claims

1. A stable orlistat composition, comprising orlistat, a filler, a disintegrant, a surfactant, a stabilizer and a glidant, wherein the stabilizer accounts for 2-5% of the total weight of the composition, characterized in that: Orlistat is dispersed by sieving before being mixed with other components, and the sieving is selected from one of standard sieve dispersion, integrated sieving machine dispersion, and vibration sieving machine dispersion.

2. The composition according to claim 1, comprising 50% orlistat, 35-45% filler, 3-4.5% disintegrant, 1-10% surfactant, 2.0-5% stabilizer, and 0.1% glidant in weight percentage.

3. The composition of claim 1, comprising 50% orlistat, 39-42% filler, 3-4.0% disintegrant, 2.5-2.9% surfactant, 2.0-5% stabilizer, and 0.1% glidant in weight percentage.

4. The composition according to any one of claims 1 to 3, wherein the filler is selected from one or more of microcrystalline cellulose, lactose and starch.

5. A composition according to any one of claims 1 to 3, wherein the disintegrant is selected from sodium starch glycolate and cross-linked polyvinyl pyrrolidone.

6. A composition as claimed in any one of claims 1 to 3, wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, polyethylene glycol and polysorbate.

7. The composition according to any one of claims 1 to 3, wherein the stabilizer is polyvinyl pyrrolidone and the glidant is talc.

8. The composition according to any one of claims 1 to 3, which is a capsule.

9. The composition according to claim 1, wherein the sieve is a standard sieve or a sieving and granulating machine, the sieve aperture of the standard sieve is 60-150 mesh, preferably 80-120 mesh, and the sieve aperture of the sieving and granulating machine is 0.4-0.8 mm, preferably 0.6 mm.

10. A method for preparing the composition of claims 1-9, comprising the following steps: 1) dispersing orlistat by sieving; 2) mixing the dispersed orlistat with a filler and a disintegrant to prepare a premix; 3) dissolving the stabilizer and sodium lauryl sulfate in water to form a solution, adding the solution to the premix in the previous step by atomization, and performing wet granulation to obtain a suitable soft material; 4) Granulate the soft material to obtain wet granules or micropellets with uniform size and full shape, add talcum powder after drying, mix evenly, and put into capsules.

Images