Linagliptin pharmaceutical composition and preparation method thereof

Abstract

The invention provides a linagliptin tablet which is stable in quality and does not need coating and double-aluminum packaging and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The linagliptin tablet is prepared from 50 parts of medicated pellets, 92 parts of mannitol, 18 parts of pregelatinized starch, 18 parts of corn starch and 2 parts of magnesium stearate, the medicated pellets are prepared from 5 parts of linagliptin, 29-37 parts of mannitol blank pellets, 2-4 parts of shellac and 6-12 parts of kaolin, and the linagliptin tablet is prepared through a fluidized bed bottom spraying technology.

Description

Technical Field

[0001] The invention relates to a linagliptin pharmaceutical composition and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. Background Art

[0002] Diabetes is a group of multi-cause, one of the most important non-communicable chronic diseases threatening global human health. Linagliptin is a potent and selective DPP-4 inhibitor developed by Boehringer Ingelheim, approved for the treatment of type II diabetes. Linagliptin is a xanthine derivative, a white to slightly yellow solid substance, chemical name: 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl-1)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione. The original formulation patent CN101437493B discloses its composition, including linagliptin and diluents mannitol, pregelatinized starch, adhesive copolyvidone, disintegrant corn starch, lubricant magnesium stearate, and tablets are prepared by conventional wet granulation process. The researchers conducted an influencing factor test on the original research and found that the relevant substances of this product increased significantly under high temperature, light and high humidity conditions; the long-term (30℃±2℃ / 65%RH±5%RH) stability test on the original research found that the dissolution rate and dissolution behavior of this product tend to slow down over time, which may have adverse effects on the efficacy of this product. In order to ensure the stability of the product during the shelf life, the original research tablets are packaged in double aluminum, and the moisture content of the finished product is controlled to not exceed 3.5%. It is stored in a closed condition at 25℃, which invisibly increases the packaging, storage and circulation costs of the product.

[0003] Linagliptin belongs to BCS III class, and its maximum single dose (5mg) is relatively small. Although it can be completely dissolved in the physiological pH range of 1.0-6.8, its bioavailability is low, only about 30%. In order to overcome the low bioavailability of linagliptin, patent CN105878219B discloses a linagliptin oral film and preparation method, but the use characteristics of the oral film require that the unpleasant bitter taste of the drug can be completely covered and the taste can be maintained. This is a huge challenge for the oral film. In addition, the film is light, thin and easy to absorb moisture, which requires independent packaging, high requirements for storage and transportation, expensive production line equipment, and dosage consistency is also a challenge.

[0004] Patent CN111407730B discloses a pharmaceutical composition containing linagliptin. The invention dissolves linagliptin together with a binder in anhydrous ethanol heated in a 50°C water bath. The processes of heating, dissolving, granulating and adding the binder must be explosion-proof, which poses a safety hazard.

[0005] Patent CN115227661B discloses a linagliptin tablet and a preparation method thereof, wherein the drug-containing granules are subjected to two dry granulation roller compactions and then directly mixed with magnesium stearate for tableting. The compressibility of the material will be significantly reduced after two roller compactions, and the particle size distribution of the particles will vary greatly, making it difficult to mix magnesium stearate evenly, and there is a risk of tablet splitting during the tableting process; due to the problem of material mixing uniformity, the tablet content is very likely to be uneven.

[0006] CN106236754A discloses a composition containing the active ingredient of linagliptin and a preparation method thereof. Compared with the original patent CN101437493A prescription, only the adhesive is slightly different, but according to the description, the adhesive polyvidone can also be replaced with the copolyvidone used in the original patent, so there is no essential difference in the type of prescription between the two, and the dosage is also overlapping; the patent application sprays the API suspension and the adhesive solution into the fluidized bed for granulation, which has no substantial innovation compared with the original wet granulation, and the existing related substances, dissolution behavior, packaging and storage and other issues have not been solved. CN106137991A has the same problems as above. Summary of the invention

[0007] Purpose of the invention: To improve the inherent physical and chemical properties of the raw material through formulation technology, and to develop a linagliptin composition and preparation method with stable quality of related substances and dissolution and no need for excessive packaging.

[0008] The present invention applies micro-pill preparation technology to prepare linagliptin-containing micro-pills in the form of solution-coating. During the micro-pill preparation process, the applicant was pleasantly surprised to find that adding an appropriate amount of natural high molecular polymer shellac to the coating solution can effectively inhibit the rapid growth of related substances in linagliptin micro-pills and tablets, without the need for subsequent coating and double aluminum packaging, but the dissolution becomes slower. Through a large number of experimental studies, the applicant found that the introduction of kaolin in the prescription of drug-containing micro-pills and the combined use of shellac in a specific ratio can effectively overcome the problem of slow dissolution. In addition, it was unexpectedly found that the introduction of kaolin solved the production problem of easy breakage of micro-pill tablets.

[0009] In order to prevent the rapid growth of drug-related substances, the present invention protects the linagliptin tablet composition on the one hand: A linagliptin tablet composition comprises linagliptin drug-containing micropellets and other excipients, wherein the drug-containing micropellets are prepared from linagliptin, mannitol blank pellet cores, shellac, kaolin and purified water, and the other excipients are composed of mannitol, pregelatinized starch, corn starch and magnesium stearate.

[0010] Furthermore, the drug-containing micropellets are prepared from 5 parts of linagliptin, 29-37 parts of mannitol blank pellet cores, 2-4 parts of shellac, and 58-116 parts of purified water, and the parts are all by mass.

[0011] Furthermore, the drug-containing micropellets are prepared from 5 parts of linagliptin, 33 parts of mannitol blank pellet cores, 3 parts of shellac, 9 parts of kaolin, and 87 parts of purified water.

[0012] The linagliptin tablet composition consists of 50 parts of drug-containing pellets, 92 parts of mannitol, 18 parts of pregelatinized starch, 18 parts of corn starch and 2 parts of magnesium stearate.

[0013] In order to effectively maintain the long-term stability of drug dissolution, it is further stipulated that shellac and kaolin must be used together in the prescription, the ratio of the two in the prescription is 1:3, and the mass proportion of the two in the drug-containing microcapsules is 16%~32%.

[0014] Another aspect of the present invention provides a method for preparing a linagliptin tablet composition, comprising the following steps: Part I: Preparation of drug-containing pellets S1: Preparation of suspension: After dissolving the prescribed amount of shellac in purified water, add the prescribed amount of kaolin and linagliptin, stir while adding, to prepare a suspension containing linagliptin; S2: Drug loading on pellets: Add the prescribed amount of mannitol blank pellets into the fluidized bed and spray the S1 suspension into it to prepare linagliptin-containing pellets.

[0015] Part II: Preparation of Linagliptin Tablets S3: Total mixing: Add the prescribed amount of mannitol, the drug-containing pellets prepared in S2, pregelatinized starch, and corn starch into the hopper mixer in sequence, add magnesium stearate, and continue mixing.

[0016] S4: Tableting: The materials after S4 mixing are tableted. Beneficial Effects

[0017] (1) The technical solution of the present invention adopts a micro-pill drug application process, adds shellac and kaolin to the prescription, prepares the drug-containing micro-pills and then compresses them into tablets with other excipients. The combined use significantly improves the quality stability of linagliptin tablets under high temperature, high humidity and light conditions, and does not require coating and double aluminum packaging; (2) By controlling the dosage ratio of shellac and kaolin in the drug-containing micro-pills, the dissolution stability of linagliptin tablets is further improved; (3) The present invention prepares the drug-containing micro-pills of linagliptin and then compresses them into tablets, which form a multi-unit preparation after disintegration, which is less affected by gastric emptying rate and food category. The drug is evenly dispersed in the gastrointestinal tract, reducing gastrointestinal irritation and individual differences, and is beneficial to drug absorption. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 SEM image of pellets tablets in Example 1 Figure 2 SEM image of pellets tablets of control example 4 DETAILED DESCRIPTION

[0019] In order to better understand the technical solution of the present invention, it is further described below in conjunction with specific embodiments.

[0020] Example 1 Prescription composition:

[0021] Preparation method: S1: Preparation of suspension: Weigh the prescribed amount of shellac and add it into purified water, stirring while adding until it is completely dissolved; then weigh the prescribed amount of kaolin and linagliptin and add them into the shellac solution, stirring evenly until it is suspended.

[0022] S2: Pellets drug application: Add the prescribed amount of blank pellets into the Glatt fluidized bed, use the bottom spraying process, adjust the Wurster column height to 1.5-2.0 cm from the bottom net, set the inlet air temperature to 50-60°C, the inlet air volume to 25-45 cm³ / h, the atomization pressure to 1.5-2.0 bar, and the peristaltic pump speed to 5-8 r / min; when the material temperature rises above 40°C, spray the suspension prepared in S1 into the fluidized bed granulator, and keep the material temperature not lower than 35°C during the granulation process; after the suspension is completely sprayed, continue drying for 5 minutes, stop the machine, and collect the drug-containing pellets; S3: Total mixing: weigh the prescribed amount of mannitol, the drug-containing pellets prepared in S2, pregelatinized starch, and corn starch and add them into the hopper mixer in sequence, set the speed to 15r / min, mix for 10min, add magnesium stearate, and continue mixing for 5min; S4: Tablet pressing: The S3 total mixed material is tableted using a rotary tablet press equipped with an 8mm shallow concave die, with a theoretical tablet weight of 180 mg and an average hardness of not less than 50N.

[0023] Example 2 Prescription composition (the main difference from Example 1 is that the dosage of shellac and kaolin is the lower limit of the protection range, and both account for 16% of the drug-containing pellets):

[0024] Preparation method: Referring to the preparation method in Example 1, 1000 linagliptin tablets were prepared.

[0025] Example 3 Prescription composition (the main difference from Example 1 is that the dosage of shellac and kaolin is the upper limit of the protection range, and both account for 32% of the drug-containing pellets):

[0026] Preparation method: Referring to the preparation method in Example 1, 1000 linagliptin tablets were prepared.

[0027] Comparative Example 1 Prescription composition (refer to original patent CN101437493B):

[0028] Preparation method (refer to the original patent CN101437493B, using wet granulation process, but without coating): S1: Dry mixing: Add mannitol, linagliptin, copovidone, corn starch and pregelatinized starch into the wet granulator in sequence, set the stirring speed to 150 r / min, and dry mix for 3 min; S2: Granulation: set the stirring speed to 180r / min, the chopping speed to 1800r / min, the atomization pressure to 0.2Mpa, the peristaltic pump speed to 35r / min, spray the purified water into the S1 dry mixed material, and the granulation time to 6min; S3: Drying: Add the wet granules obtained in S2 into a fluidized bed dryer, set the air inlet temperature to 50-60°C and the air inlet frequency to 25-35Hz, and dry until the granule moisture is ≤3.0%, then stop drying; S4: Granulation: The granules obtained in S3 are granulated using a 1.0 mm aperture sieve, and the granulator speed is 300 r / min; S5: Total mixing: Add the granules obtained in S4 into the hopper mixer, set the machine speed to 15r / min, mix for 10min, add the prescribed amount of magnesium stearate, continue mixing for 5min, and collect the material; S6: Tableting: The total mixed granules obtained in S5 are tableted using a rotary tablet press with an 8 mm shallow concave die.

[0029] Comparative Example 2 Prescription composition (the amount of shellac is lower than the protection range, shellac: kaolin = 1:5):

[0030] Preparation method: Referring to the preparation method in Example 1, 1000 linagliptin tablets were prepared.

[0031] Comparative Example 3 Prescription composition (the amount of shellac is higher than the protection range, shellac: kaolin = 1:2):

[0032] Preparation method: Referring to the preparation method in Example 1, 1000 linagliptin tablets were prepared.

[0033] Comparative Example 4 Prescription composition (shellac is introduced alone, accounting for 20% of the drug-containing pellets):

[0034] Preparation method: Referring to the preparation method in Example 1, 1000 linagliptin tablets were prepared.

[0035] Comparative Example 5 Prescription composition (the dosage of shellac and kaolin is lower than the protection range, shellac: kaolin = 1:3, and the two account for 12% of the drug-containing pellets):

[0036] Preparation method: Referring to the preparation method in Example 1, 1000 linagliptin tablets were prepared.

[0037] Comparative Example 6 Prescription composition (the dosage of shellac and kaolin is higher than the protection range, shellac: kaolin = 1:3, and the two account for 36% of the drug-containing pellets):

[0038] Preparation method: Referring to the preparation method in Example 1, 1000 linagliptin tablets were prepared.

[0039] Test Example 1 Influencing Factor Test The tablets of Examples 1-3 and Control Examples 1-6 were placed in a high temperature (60°C), high humidity (25°C / 90%RH) and light (4500lx±500lx) test chamber, respectively, and samples were taken on the 10th and 30th days to detect the main degradation impurities A, B and total impurities in the samples.

[0040] The determination was carried out according to the high performance liquid chromatography method (General Rules 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia). The chromatographic conditions were as follows: octadecylsilane bonded silica gel was used as the filler; phosphate buffer (2.0 g of potassium dihydrogen phosphate was taken, dissolved in 1000 mL of water, and the pH value was adjusted to 2.5±0.1 with phosphoric acid) was used as the mobile phase A, and methanol-acetonitrile (55:45) was used as the mobile phase B, and linear gradient elution was performed; the column temperature was 55°C; the flow rate was 1.5 mL / min; the detection wavelength was 225 nm; and the injection volume was 20 μL.

[0041]

[0042]

[0043] The results show that the growth rates of related substances in Examples 1-3 and Comparative Examples 2-6 in which shellac is added to the prescription are significantly better than those in Comparative Example 1 in which the original prescription and wet granulation process are used.

[0044] When the amount of shellac is lower than the lower limit of the protection range, the growth rate of related substances in Control Examples 2 and 5 is faster than that in Examples 1-3 and Control Examples 3, 4, and 6, but is still better than that in the original comparative example 1; the growth rate of related substances in Examples 1-3 and Control Examples 3, 4, and 6 is extremely low, and the total impurity level is lower than 0.1% under the conditions of various influencing factors, indicating that more than a certain amount of shellac is more conducive to the control of linagliptin impurities in the preparation.

[0045] Test Example 2 Dissolution curve test Using 900 mL of 0.1 mol / L hydrochloric acid solution (pH 1.0), acetate buffer (pH 4.5) and phosphate buffer (pH 6.8) as dissolution media and a rotation speed of 50 revolutions per minute, the dissolution rates of the tablets of Examples 1-3 and Control Examples 1-6 were measured at 5, 10, 15, 20 and 30 min, respectively.

[0046]

[0047] The results show that the dissolution of Control Example 1, which refers to the original formulation process, in pH 1.0, pH 4.5 and pH 6.8 media belongs to the FDA "very fast dissolution" (dissolution rate greater than 85% in 15 minutes). Examples 1-3 and Control Examples 2 and 5 also meet this standard. These samples dissolve faster than Control Example 1, with dissolution rates exceeding 90% in 10 minutes. The amount of shellac used in Control Examples 3, 4 and 6 exceeds the protection range, and their dissolution is obviously slow, indicating that there may be a risk of in vivo absorption, so no subsequent dissolution curve stability test will be carried out.

[0048] Test Example 3 Dissolution curve stability test A representative dissolution medium, 0.1 mol / L hydrochloric acid solution (pH 1.0), was selected to test the dissolution of Examples 1-3 and Comparative Examples 1, 2, and 5 under long-term (30°C / 65%RH) conditions for 12 and 24 months, respectively.

[0049]

[0050] The results show that the dissolution curves of Examples 1-3 have good stability; after long-term storage for 24 months, the 15-minute dissolution amount of Control Example 1 has decreased by about 10 points compared with that on day 0; although the dissolution amounts of Control Examples 2 and 5 are higher on day 0, the 15-minute dissolution amounts also decrease by about 10 and 15 points, respectively, after long-term storage for 24 months.

[0051] Test Example 4: Moisture Detection of Finished Product The tablets of Examples 1-3 and Comparative Examples 1-6 were packaged in ordinary aluminum-plastic packaging and placed in a high humidity test box (25°C / 90%RH). Samples were taken on the 15th and 30th days to detect moisture content, and the moisture content was not more than 3.5%.

[0052]

[0053] The results showed that the moisture content of control example 1 exceeded the standard limit after aluminum-plastic packaging, so the original researcher had to coat and double-aluminum package it; the moisture content of control examples 2 and 5 increased significantly during the inspection period, and there may be a risk of exceeding the standard if they are continued to be stored.

[0054] Test Example 5 Observation of the integrity of micropellets Representative Example 1 and Comparative Example 4 were selected for pellet tableting. The pellet samples were scanned by electron microscope to observe the integrity of the pellets. The results are shown in the attached Figure 1 , 2 .

[0055] The results show that after the pellets are compressed, the drug-containing pellet core of Example 1 remains intact, meeting the design expectation. The tablets will form multi-unit drug release after disintegration in the body, which is conducive to in vivo absorption. Although the amount of shellac used in the prescription of Control Example 4 is relatively high, the drug-containing pellet core has been destroyed after the pellets are compressed because no kaolin is introduced.

Claims

1. A linagliptin tablet composition, characterized in that The tablets are composed of linagliptin-containing pellets and other excipients, wherein the linagliptin-containing pellets are composed of linagliptin, mannitol blank pellet cores, shellac, and kaolin; and the tablets are composed of the pellets, mannitol, pregelatinized starch, corn starch, and magnesium stearate.

2. The linagliptin tablet composition according to claim 1, characterized in that The linagliptin-containing micropellets contain 5 parts of linagliptin, 29-37 parts of mannitol blank pellet cores, 2-4 parts of shellac, and 6-12 parts of kaolin, and the parts are all by mass.

3. The linagliptin tablet composition according to claim 1, characterized in that The linagliptin-containing micropellets contain 5 parts of linagliptin, 33 parts of mannitol blank pellet cores, 3 parts of shellac, and 9 parts of kaolin, and the parts are all by mass.

4. The linagliptin tablet composition according to claim 1, characterized in that Linagliptin tablets are composed of 50 parts of drug-containing pellets, 92 parts of mannitol, 18 parts of pregelatinized starch, 18 parts of corn starch, and 2 parts of magnesium stearate, and the parts are all by mass.

5. The linagliptin tablet composition according to claim 1, characterized in that: The mass ratio of shellac to kaolin in the linagliptin-containing micropellets is 1:3, and the mass proportion of the two in the micropellets is 16%~32%.

6. The linagliptin tablet composition according to claim 1, characterized in that: The preparation method is as follows: (1) Preparation of drug-containing pellets: S1: Preparation of suspension: After dissolving the prescribed amount of shellac in purified water, add the prescribed amount of kaolin and linagliptin, and stir while adding to prepare a suspension containing linagliptin; S2: Add the prescribed amount of mannitol blank pellets into the fluidized bed, spray the S1 suspension into it, and prepare linagliptin-containing pellets; (2) Preparation of Linagliptin Tablets: S3: Total mixing: Add the prescribed amount of mannitol, the drug-containing pellets prepared in S2, pregelatinized starch, and corn starch into the hopper mixer in sequence, add magnesium stearate, and continue mixing; S4: Tablet pressing: The mixed material of S4 is tablet pressed.

7. The linagliptin tablet composition according to claim 1, characterized in that: The preparation method is as follows: (1) Preparation of drug-containing pellets: S1: Preparation of suspension: After dissolving the prescribed amount of shellac in purified water, add the prescribed amount of kaolin and linagliptin, and stir while adding to prepare a suspension containing linagliptin; S2: Add the prescribed amount of mannitol blank pellets into the Glatt fluidized bed, and spray the S1 suspension into the fluidized bed using the bottom spray process. Set the air inlet temperature to 50-60°C and the air volume to 25-45 cm 3 / h, the peristaltic pump speed is 5-8r / min, and linagliptin-containing micropellets are prepared; (2) Preparation of Linagliptin Tablets: S3: Total mixing: Add the prescribed amount of mannitol, the drug-containing pellets prepared in S2, pregelatinized starch, and corn starch into the hopper mixer in sequence, set the speed to 15r / min, mix for 10min, add magnesium stearate, and continue mixing for 5min; S4: Tablet pressing: The mixed material of S4 is pressed into tablets with an 8mm shallow concave die, and the average hardness is not less than 50N.

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