A pharmaceutical composition of linagliptin and a preparation method thereof

Abstract

The application provides linagliptin tablets with stable quality, without coating and double aluminum packaging and a preparation method, and belongs to the technical field of pharmaceutical preparations. The linagliptin tablet is composed of drug-containing pellets 50 parts, mannitol 92 parts, pregelatinized starch 18 parts, corn starch 18 parts and magnesium stearate 2 parts. The drug-containing pellets are composed of linagliptin 5 parts, mannitol blank pellet core 29-37 parts, shellac 2-4 parts and kaolin 6-12 parts, and are prepared through a fluidized bed bottom spraying process.

Description

Technical Field

[0001] This invention relates to a linagliptin pharmaceutical composition and its preparation method, belonging to the field of pharmaceutical formulation technology. Background Technology

[0002] Diabetes mellitus is a group of multifactorial, non-communicable chronic diseases that pose a significant threat to global human health. Linagliptin, developed by Boehringer Ingelheim, is a potent, selective DPP-4 inhibitor approved for the treatment of type 2 diabetes. Linagliptin is a xanthine derivative, a white to slightly yellow solid substance, chemically named 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, mannitol as a diluent, pregelatinized starch, copovidone as a binder, corn starch as a disintegrant, and magnesium stearate as a lubricant, prepared into tablets using a conventional wet granulation process. Researchers conducted influencing factor tests on the original drug and found that related substances in this product increased significantly under high temperature, light, and high humidity conditions. Long-term stability tests (30℃±2℃ / 65%RH±5%RH) on the original drug revealed that the dissolution rate and dissolution behavior of this product tended to slow down over time, potentially posing a risk to its efficacy. To ensure product stability within its shelf life, the original drug tablets are packaged in double aluminum containers, and the moisture content of the finished product is controlled to not exceed 3.5%, stored under sealed conditions at 25℃, which increases the costs of product packaging, storage, and distribution.

[0003] Linagliptin belongs to the BCS Class III, and its maximum single-dose dose (5 mg) is relatively small. Although it can be completely dissolved within the physiological pH range of 1.0-6.8, its bioavailability is low, only about 30%. To overcome the low bioavailability of linagliptin, patent CN105878219B discloses a linagliptin oral film and its preparation method. However, the characteristics of oral films require complete masking of the unpleasant bitter taste of the drug and maintenance of a pleasant mouthfeel, which is a huge challenge for oral films. In addition, the light, thin and hygroscopic nature of the film requires individual packaging, which places high demands on storage and transportation. The production line equipment is expensive, and dosage consistency is also a challenge.

[0004] Patent CN111407730B discloses a pharmaceutical composition containing linagliptin. This invention dissolves linagliptin together with a binder in anhydrous ethanol heated in a 50°C water bath. The processes of heating and dissolving and adding the binder during granulation require explosion-proof measures, posing a safety hazard.

[0005] Patent CN115227661B discloses a linagliptin tablet and its preparation method, which involves directly mixing the drug-containing granules with magnesium stearate after two dry granulation and roller compression. After the two roller compressions, the compressibility of the material decreases significantly, and the particle size distribution varies considerably, making it difficult to mix the magnesium stearate evenly. This poses a risk of tablet breakage during compression. Furthermore, the problem of uneven material mixing can easily lead to inconsistent tablet content.

[0006] CN106236754A discloses a composition containing the active ingredient linagliptin and its preparation method. Compared with the original patent CN101437493A, only the binder is slightly different. However, according to the specification, the binder povidone can be replaced with the copovidone used in the original patent. Therefore, there is no essential difference in the types of formulations, and the dosages overlap. This patent application sprays the active pharmaceutical ingredient suspension and binder solution into a fluidized bed for granulation. Compared with the original wet granulation method, there is no substantial innovation, and the problems related to related substances, dissolution behavior, packaging, and storage remain unresolved. CN106137991A has the same problems. Summary of the Invention

[0007] Objective of the invention: To improve the inherent physicochemical properties of active pharmaceutical ingredients through formulation technology, and to develop a linagliptin composition and preparation method that is stable in terms of related substances and dissolution and does not require excessive packaging.

[0008] This invention utilizes microcapsule preparation technology to prepare linagliptin-containing microcapsules via solution loading. During the microcapsule preparation process, the applicant unexpectedly discovered that adding an appropriate amount of the natural polymer shellac to the loading solution effectively inhibited the rapid growth of related substances in the linagliptin microcapsules and tablets, eliminating the need for subsequent coating and double aluminum packaging; however, this slowed dissolution. Through extensive experimental research, the applicant found that introducing kaolin into the drug-containing microcapsule formulation, used in combination with shellac in a specific ratio, effectively overcame the problem of slow dissolution. Furthermore, it was unexpectedly discovered that the introduction of kaolin solved the production problem of easy breakage during microcapsule compression.

[0009] To prevent the rapid growth of drug-related substances, this invention protects, in one aspect, the linagliptin tablet composition:

[0010] A linagliptin tablet composition includes linagliptin-containing microcapsules and other excipients, wherein the microcapsules are prepared from linagliptin, mannitol blank core, shellac, kaolin and purified water, and the other excipients are composed of mannitol, pregelatinized starch, corn starch and magnesium stearate.

[0011] Furthermore, the drug-containing microcapsules are prepared from 5 parts of linagliptin, 29-37 parts of mannitol blank capsule core, 2-4 parts of shellac, and 58-116 parts of purified water, all of which are parts by weight.

[0012] Furthermore, the drug-containing microcapsules are prepared from 5 parts linagliptin, 33 parts mannitol blank capsule core, 3 parts shellac, 9 parts kaolin, and 87 parts purified water.

[0013] The linagliptin tablet composition consists of 50 parts drug-containing microcapsules, 92 parts mannitol, 18 parts pregelatinized starch, 18 parts corn starch, and 2 parts magnesium stearate.

[0014] To effectively maintain the long-term stability of drug dissolution, further restrictions are imposed: shellac and kaolin must be used together in the prescription, with a ratio of 1:3, and the two together account for 16% to 32% of the mass of the drug-containing microcapsules.

[0015] Another aspect of this invention protects a method for preparing a linagliptin tablet composition, comprising the following steps:

[0016] Part 1: Preparation of Drug-Containing Microspheres

[0017] S1: Suspension preparation: Dissolve the prescribed amount of shellac in purified water, then add the prescribed amount of kaolin and linagliptin while stirring to prepare a suspension containing linagliptin.

[0018] S2: Microcapsule loading: Add the prescribed amount of mannitol blank microcapsules to the fluidized bed, and spray in the S1 suspension to prepare linagliptin-containing microcapsules.

[0019] Part Two: Preparation of Linagliptin Tablets

[0020] S3: Total Mixing: Add the prescribed amount of mannitol, the drug-containing microcapsules prepared in S2, pregelatinized starch, and corn starch sequentially into the hopper mixer, add magnesium stearate, and continue mixing.

[0021] S4: Tableting: The S4 mixture is then compressed into tablets. Beneficial effects

[0022] (1) The technical solution of the present invention adopts the micro-pellet loading process, adds shellac and kaolin to the prescription, prepares drug-containing micro-pellets, and then compresses them 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 ratio of shellac and kaolin in the drug-containing micro-pellets, the dissolution stability of linagliptin tablets is further improved; (3) The present invention prepares linagliptin drug-containing micro-pellets and then compresses them into tablets. After disintegration, they form a multi-unit formulation, which is less affected by the gastric emptying rate and food type. The drug is evenly dispersed in the gastrointestinal tract, reducing gastrointestinal irritation and individual differences, which is conducive to drug absorption. Attached Figure Description

[0023] Figure 1 Scanning electron microscope image of microgranule compression in Example 1

[0024] Figure 2 Scanning electron microscope image of the microcapsule tablets compared to Example 4 Detailed Implementation

[0025] To better understand the technical solution of the present invention, further explanation is provided below with reference to specific embodiments.

[0026] Example 1: Prescription Composition:

[0027]

[0028] Preparation method:

[0029] S1: Preparation of suspension: Weigh the prescribed amount of shellac and add it to purified water while stirring until completely dissolved; then weigh the prescribed amount of kaolin and linagliptin and add them to the shellac solution, stirring until a suspension is formed.

[0030] S2: Microcapsule loading: Add the prescribed amount of blank capsule cores to the Gratte fluidized bed, using a bottom spray process. Adjust the height of the Wurster column to 1.5~2.0cm from the bottom screen, set the inlet air temperature to 50~60℃, the inlet air volume to 25~45cm³ / h, the atomization pressure to 1.5~2.0bar, and the peristaltic pump speed to 5~8r / min. When the material temperature rises above 40℃, spray the suspension prepared in S1 into the fluidized bed granulator. During the granulation process, maintain the material temperature at no less than 35℃. After all the suspension has been sprayed, continue drying for 5 minutes, stop the machine, and collect the drug-containing microcapsules.

[0031] S3: Total Mixing: Weigh out the prescribed amount of mannitol, the drug-containing microcapsules prepared in S2, pregelatinized starch, and corn starch and add them sequentially into the hopper mixer. Set the speed to 15 r / min and mix for 10 min. Add magnesium stearate and continue mixing for 5 min.

[0032] S4: Tableting: The total mixture of S3 is compressed into tablets using a rotary tablet press with an 8mm shallow concave die. The theoretical tablet weight is 180mg and the average hardness is not less than 50N.

[0033] Example 2: Formulation composition (the main difference from Example 1 is that the amounts of shellac and kaolin are both at the lower limit of the protection range, and the two together account for 16% of the drug-containing microcapsules):

[0034]

[0035] Preparation method: 1000 linagliptin tablets were prepared according to the preparation method in Example 1.

[0036] Example 3: Formulation composition (the main difference from Example 1 is that the amounts of shellac and kaolin are both at the upper limit of the protection range, and the two together account for 32% of the drug-containing microcapsules):

[0037]

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

[0039] Comparative Example 1: Prescription composition (refer to original patent CN101437493B):

[0040]

[0041] Preparation method (referring to the original patent CN101437493B, using a wet granulation process, but without coating):

[0042] S1: Dry mixing: Add mannitol, linagliptin, copovidone, corn starch, and pregelatinized starch to a wet granulator in sequence, set the stirring speed to 150 r / min, and dry mix for 3 min;

[0043] S2: Granulation: Set the stirring speed to 180 r / min, the chopping speed to 1800 r / min, the atomization pressure to 0.2 MPa, and the peristaltic pump speed to 35 r / min. Spray purified water into the dry mixture in S1. Granulation time is 6 min.

[0044] S3: Drying: Add the wet granules obtained in S2 into a fluidized bed dryer, set the inlet air temperature to 50~60℃ and the inlet air frequency to 25~35Hz, and dry until the granule moisture content is ≤3.0%, then stop drying;

[0045] S4: Granulation: The granules obtained in S3 are granulated using a 1.0mm mesh screen at a granulator speed of 300r / min;

[0046] S5: Total Mixing: Add the granules obtained in S4 to the hopper mixer, set the machine speed to 15 r / min, mix for 10 min, add the prescribed amount of magnesium stearate, continue mixing for 5 min, and collect the material;

[0047] S6: Tableting: The total mixed particles obtained in S5 are tableted using a rotary tablet press with an 8mm shallow concave die.

[0048] Comparative Example 2: Formula composition (lac dosage below the protection range, lac:kaolin = 1:5):

[0049]

[0050] Preparation method: 1000 linagliptin tablets were prepared according to the preparation method in Example 1.

[0051] Comparative Example 3: Formula composition (lac dosage exceeds the protection limit, lac:kaolin = 1:2):

[0052]

[0053] Preparation method: 1000 linagliptin tablets were prepared according to the preparation method in Example 1.

[0054] Comparative Example 4: Formula composition (purebran alone, accounting for 20% of the drug-containing microcapsules):

[0055]

[0056] Preparation method: 1000 linagliptin tablets were prepared according to the preparation method in Example 1.

[0057] Comparative Example 5: Formulation composition (the amounts of shellac and kaolin are both below the protection range; the ratio of shellac to kaolin is 1:3, and the two together account for 12% of the drug-containing microcapsules):

[0058]

[0059] Preparation method: 1000 linagliptin tablets were prepared according to the preparation method in Example 1.

[0060] Comparative Example 6: Formula composition (both shellac and kaolin content exceeded the protection range; shellac:kaolin = 1:3; both constituted 36% of the drug-containing microcapsules):

[0061]

[0062] Preparation method: 1000 linagliptin tablets were prepared according to the preparation method in Example 1.

[0063] Experiment Example 1: Influencing Factors Experiment

[0064] Tablets from Examples 1-3 and Control Examples 1-6 were placed in high temperature (60°C), high humidity (25°C / 90%RH), and light (4500lx±500lx) test chambers, respectively. Samples were taken on days 10 and 30 to detect the main degradation impurities A and B and total impurities.

[0065] The determination was performed according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). The chromatographic conditions were as follows: octadecylsilane-bonded silica gel was used as the stationary phase; phosphate buffer (2.0 g potassium dihydrogen phosphate dissolved in 1000 mL of water, pH adjusted to 2.5 ± 0.1 with phosphoric acid) was used as mobile phase A, and methanol-acetonitrile (55:45) was used as mobile phase B for linear gradient elution; the column temperature was 55℃; the flow rate was 1.5 mL / min; the detection wavelength was 225 nm; and the injection volume was 20 μL.

[0066]

[0067]

[0068] The results showed that the related substance growth rate of Examples 1-3 and Control Examples 2-6, which included shellac in their formulations, was significantly better than that of Control Example 1, which used the original formulation and wet granulation process.

[0069] When the amount of shellac was below the lower limit of the protection range, the growth rate of related substances in Control Examples 2 and 5 was faster than that in Examples 1-3 and Control Examples 3, 4, and 6, but still better than that in the original control example 1. The growth rate of related substances in Examples 1-3 and Control Examples 3, 4, and 6 was extremely low, and the total impurity water content was less than 0.1% under various influencing factors, indicating that a certain amount of shellac is more conducive to the control of linagliptin impurities in the formulation.

[0070] Experimental Example 2: Dissolution Curve Detection

[0071] 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 rotating at 50 rpm, the dissolution rates of tablets from Examples 1-3 and Control Examples 1-6 were measured at 5, 10, 15, 20, and 30 min.

[0072]

[0073] The results showed that Control Example 1, which followed the original formulation and process, exhibited FDA "very rapid dissolution" (dissolution rate greater than 85% at 15 min) in media at pH 1.0, pH 4.5, and pH 6.8. Examples 1-3 and Control Examples 2 and 5 also met this standard, and these samples dissolved faster than Control Example 1, with dissolution rates exceeding 90% at 10 min. Control Examples 3, 4, and 6 had shellac dosages exceeding the protection range, and their dissolution was significantly slower, indicating a potential risk of in vivo absorption. Therefore, further dissolution curve stability testing was not conducted.

[0074] Experimental Example 3: Dissolution Curve Stability Test

[0075] A representative dissolution medium, 0.1 mol / L hydrochloric acid solution (pH 1.0), was selected to detect the dissolution of Examples 1-3 and Control Examples 1, 2, and 5 after 12 and 24 months of long-term (30℃ / 65%RH) storage.

[0076]

[0077] The results showed that the dissolution curves of Examples 1-3 were stable. After 24 months of long-term storage, the dissolution amount at 15 min in Control Example 1 decreased by about 10 points compared to day 0. Although the dissolution amounts of Control Examples 2 and 5 were higher on day 0, the dissolution amounts at 15 min also decreased by about 10 and 15 points respectively after 24 months of long-term storage.

[0078] Test Example 4: Finished Product Moisture Detection

[0079] After the tablets of Examples 1-3 and Control Examples 1-6 were packaged in ordinary aluminum-plastic packaging, they were placed in a high humidity test chamber (25℃ / 90%RH) and samples were taken on the 15th and 30th days to test the moisture content. The moisture content should not exceed 3.5%.

[0080]

[0081] The results showed that the moisture content of Control Example 1, which was packaged in aluminum-plastic packaging, exceeded the standard limit, so the original drug had to be coated and double-aluminum packaged. The moisture content of Control Examples 2 and 5 increased significantly during the observation period, and continued storage may pose a risk of exceeding the standard.

[0082] Experimental Example 5: Observation of Microsphere Integrity

[0083] Representative Example 1 and Control Example 4 were selected for microgranulation. The samples after microgranulation were scanned by electron microscopy to observe the integrity of the microgranules. The results are shown in the appendix. Figure 1 , 2 .

[0084] The results showed that after microcapsule compression, the drug-containing core of Example 1 remained intact, achieving the design expectation. After the tablet disintegrated in the body, it formed a multi-unit drug release, which helped the body absorb the drug. Although the amount of shellac in the formulation of Control Example 4 was relatively high, the drug-containing core of the microcapsule was destroyed after compression because no kaolin was introduced.

Claims

1. A linagliptin tablet composition, characterized in that, The tablet is composed of linagliptin-containing microcapsules and other excipients. The linagliptin-containing microcapsules consist of 5 parts linagliptin, 29-37 parts mannitol blank capsule cores, 2-4 parts shellac, and 6-12 parts kaolin. The mass ratio of shellac to kaolin in the microcapsules is 1:3, and the combined mass percentage of the two is 16%-32%. The tablet is composed of 50 parts microcapsules, 92 parts mannitol, 18 parts pregelatinized starch, 18 parts corn starch, and 2 parts magnesium stearate. All parts are by weight. The preparation method is as follows: (1) Preparation of drug-containing microcapsules: S1: Suspension preparation: Dissolve the prescribed amount of shellac in purified water, then add the prescribed amount of kaolin and linagliptin while stirring to prepare a suspension containing linagliptin. S2: Add the prescribed amount of mannitol blank microspheres into a fluidized bed, and spray in the S1 suspension to prepare linagliptin-containing microspheres; (2) Preparation of linagliptin tablets: S3: Total Mixing: Add the prescribed amount of mannitol, the drug-containing microcapsules prepared in S2, pregelatinized starch, and corn starch to the hopper mixer in sequence and mix. Add magnesium stearate and continue mixing. S4: Tableting: Compress the total mixture from S3 into tablets.

2. The linagliptin tablet composition according to claim 1, characterized in that, The linagliptin microcapsules contain 5 parts linagliptin, 33 parts mannitol blank capsule core, 3 parts shellac, and 9 parts kaolin. All the parts mentioned are by weight.

3. The linagliptin tablet composition according to claim 1, characterized in that, The preparation method is as follows: (1) Preparation of drug-containing microcapsules: S1: Suspension preparation: Dissolve the prescribed amount of shellac in purified water, then add the prescribed amount of kaolin and linagliptin while stirring to prepare a suspension containing linagliptin. S2: Add the prescribed amount of mannitol blank microspheres into the Grat fluidized bed, and spray the S1 suspension into it using a bottom spray process. Set the inlet air temperature to 50-60°C, the air volume to 25-45 cm3 / h, and the peristaltic pump speed to 5-8 r / min to prepare linagliptin-containing microspheres. (2) Preparation of linagliptin tablets: S3: Total Mixing: Add the prescribed amount of mannitol, the drug-containing microcapsules prepared in S2, pregelatinized starch, and corn starch to the hopper mixer in sequence, set the speed to 15 r / min, mix for 10 min, add magnesium stearate, and continue mixing for 5 min; S4: Tableting: The material after S3 is mixed together is pressed into tablets using an 8mm shallow concave die, with an average hardness of not less than 50N.

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