A loratadine immediate-release tablet based on co-micronization technology and a preparation method thereof

Abstract

The application relates to the technical field of pharmaceutical preparations, in particular to a loratadine immediate-release tablet based on a co-micronization technology and a preparation method thereof; a pharmaceutical composition comprises a co-micronization compound, the co-micronization compound comprises loratadine and a co-micronization carrier; the application discloses a loratadine immediate-release tablet based on a co-micronization technology and a preparation method thereof, the dissolution rate and stability of the loratadine are improved by adopting the co-micronization technology and a new type of excipient combination; meanwhile, the prepared loratadine immediate-release tablet also has good in-vitro dissolution performance; the loratadine immediate-release tablet prepared by the application reduces impurity growth in the production and storage processes and obviously improves the stability of the drug; the loratadine immediate-release tablet disclosed by the application does not contain lactose in the prescription, so that the side reaction of lactose intolerance can be effectively avoided.

Description

Technical Field

[0001] This application relates to the technical field of pharmaceutical preparations, and in particular to a loratadine immediate-release tablet based on co-micronization technology and its preparation method. Background Technology

[0002] Loratadine is a long-acting tricyclic antihistamine that competitively inhibits histamine H1 receptors, suppressing histamine-induced allergic symptoms. It has no significant anticholinergic or central nervous system depressant effects. It is used to relieve symptoms associated with allergic rhinitis, as well as chronic urticaria and other allergic skin diseases. It appears as a white or off-white crystalline powder, odorless; readily soluble in methanol, ethanol, or acetone; slightly soluble in 0.1 mol / L hydrochloric acid solution; practically insoluble in water; its molecular formula is C6H2O. 22 H 23 ClN2O2 has the following structure:

[0003]

[0004] Loratadine

[0005] Loratadine is a low-water-soluble drug, classified as BCS Class II. Its oral absorption is limited by the dissolution rate. Studies have found that existing tablets have insufficient dissolution. Due to the aggregation of drug particles in the traditional wet granulation process, dissolution is slow, with a dissolution rate of less than 80% after 30 minutes. At the same time, the traditional granulation process has stability defects. Under high temperature and high humidity conditions, the material is prone to moisture absorption and clumping, which accelerates the chemical degradation reaction of the drug, leading to the decomposition or transformation of the active ingredient into harmful compounds. This may directly affect the efficacy in vivo or pose a significant safety risk to patients.

[0006] In related technologies, solid dispersion technology is used to improve dissolution, but the process is complex and costly. Adding surfactants can improve wettability, but this may introduce irritating excipients.

[0007] In addition, lactose, as a commonly used filler in loratadine tablet prescriptions, may trigger allergies in lactose-intolerant patients, leading to adverse reactions such as vomiting, diarrhea, abdominal pain, and bloating.

[0008] Therefore, there is an urgent need to develop a low-cost, high-stability formulation of loratadine tablets to improve its slow in vitro dissolution, increase the dissolution rate of loratadine tablets, avoid the use of sensitizing excipients such as lactose, and reduce production capacity and drug degradation risk through process optimization, thereby ensuring safe and effective medication. This has become an urgent problem to be solved. Summary of the Invention

[0009] To address the shortcomings of existing technologies, this application provides a loratadine immediate-release tablet based on co-micronization technology and its preparation method. The main objective of this application is to provide a loratadine immediate-release tablet based on co-micronization technology and its preparation method, aiming to improve the stability of loratadine, reduce the increase in impurity content and growth rate caused by drug degradation instability, optimize in vitro dissolution performance, and ensure the safety of medication in lactose-intolerant individuals.

[0010] In a first aspect, this application provides a pharmaceutical composition, which adopts the following technical solution:

[0011] A pharmaceutical composition comprising a comicronized complex, said comicronized complex comprising loratadine and a comicronized carrier.

[0012] Preferably, the mass ratio of loratadine to the co-micronized carrier is 1:(0.7-0.9).

[0013] Preferably, the particle size D50 of the co-micronized composite is ≤6μm.

[0014] Preferably, the particle size D50 of the co-micronized composite is 4-6 μm.

[0015] Preferably, the co-micronized carrier includes colloidal silica, polyvinylpyrrolidone, pregelatinized starch, copolyvinylpyrrolidone, fumed silica, precipitated silica, and... At least one of XDP F.

[0016] Secondly, this application provides a loratadine immediate-release tablet, which adopts the following technical solution:

[0017] A loratadine immediate-release tablet comprising the above-described pharmaceutical composition and pharmaceutically acceptable excipients.

[0018] Preferably, the pharmaceutical composition comprises a comicronized complex, the comicronized complex comprising loratadine and a comicronized carrier.

[0019] Preferably, the pharmaceutically acceptable excipients include fillers, disintegrants, lubricants, stabilizers, pH adjusters, and coating agents.

[0020] Preferably, the filler includes at least one of mannitol and sorbitol.

[0021] Preferably, the disintegrant includes at least one of crospovidone and sodium carboxymethyl starch.

[0022] Preferably, the lubricant includes at least one of glyceryl behenate, magnesium stearate, and talc.

[0023] Preferably, the stabilizer is L-arginine.

[0024] Preferably, the pH adjuster includes at least one of citric acid, calcium phosphate, sodium phosphate, and sodium dihydrogen phosphate.

[0025] Preferably, a pH adjuster is added to maintain the pH of the tablet core microenvironment at 4.5-5.5.

[0026] Preferably, the coating agent includes at least one of hydroxypropyl methylcellulose (HPMC) E5 and polyvinyl alcohol-polyethylene glycol; hydroxypropyl methylcellulose (HPMC) E5 and polyvinyl alcohol-polyethylene glycol are used as the inner and outer layers, respectively.

[0027] Thirdly, this application provides a method for preparing loratadine immediate-release tablets, using the following technical solution:

[0028] A method for preparing loratadine immediate-release tablets, the preparation method comprising the following steps:

[0029] (1) Weigh the raw materials for loratadine immediate-release tablets according to the prescription amount;

[0030] (2) Crush loratadine to a D90 of 40-60 μm; crush the lubricant and pass it through a 20-40 mesh sieve; crush the filler and disintegrant and pass them through a 60-100 mesh sieve respectively.

[0031] (3) Loratadine was mixed with and pulverized with the co-micronized carrier to obtain the co-micronized complex;

[0032] (4) Mix the co-micronized complex with filler, stabilizer and pH adjuster to maintain the pH of the core microenvironment at 4.5-5.5. After adding disintegrant and mixing, add lubricant and mix to obtain a mixture.

[0033] (5) Compress the mixture into tablets;

[0034] (6) Add the coating agent to water to obtain a coating agent solution. Use the coating agent solution to double-coat the mixture after tableting to obtain loratadine immediate-release tablets.

[0035] Since loratadine belongs to BCS Class II and has poor solubility, and the drug particles aggregate more during the granulation process, making it difficult to disperse, the degradation of loratadine mainly stems from the instability of the tablet microenvironment. By adopting the above-mentioned technical solution, this application reduces the aggregation of drug particles to form a hydrophilic surface through a co-micronization process. At the same time, a specific buffer system (i.e., a pH adjuster to maintain the pH of the tablet core microenvironment at 4.5-5.5) is introduced into the formulation, and a double-layer coating process is used. A lactose-free formulation is used to reduce the risk of allergies, thereby enhancing the dissolution capacity of the tablet and improving the stability and safety of the drug.

[0036] This application presents a tablet formulation and preparation process that significantly improves the dissolution rate, stability, and bioavailability of loratadine through co-micronization technology and novel excipient combinations, making it suitable for industrial production.

[0037] Preferably, the pulverizing step in step (3) is as follows: pulverizing is performed using a pulverizer with a pressure of 0.6-1.0 MPa.

[0038] Preferably, the mass ratio of loratadine, filler, disintegrant, lubricant, stabilizer, pH adjuster and coating agent is 1:(5-7):(0.7-1.3):(0.05-0.3):(0.1-0.5):0.5:(0.1-0.5).

[0039] In summary, this application includes at least one of the following beneficial technical effects:

[0040] This application discloses a loratadine immediate-release tablet based on co-micronization technology and its preparation method. By adopting co-micronization technology and novel excipient combination, the dissolution rate and stability of loratadine are improved; at the same time, the prepared loratadine immediate-release tablet also has good in vitro dissolution performance.

[0041] The loratadine immediate-release tablets prepared in this application reduce the growth of impurities during the production and storage process and significantly improve drug stability.

[0042] The loratadine immediate-release tablets disclosed in this application do not contain lactose, which can effectively avoid the side effects of lactose intolerance. Attached Figure Description

[0043] Figure 1 This is a dissolution curve for a 0.1 mol / L hydrochloric acid solution as the dissolution medium.

[0044] Figure 2 This is a dissolution curve for a pH 3.0 phosphate buffer solution. Detailed Implementation

[0045] The technical solutions of this application are further illustrated by specific embodiments below. These specific embodiments do not represent a limitation on the scope of protection of this application. Any non-essential modifications and adjustments made by others based on the concept of this application still fall within the scope of protection of this application.

[0046] All raw materials involved in this application are commercially available products, among which,

[0047] Loratadine, Changzhou Yabang Pharmaceutical Co., Ltd.

[0048] Colloidal silica, Aerosil 200, purchased from Evonik Industries, Germany;

[0049] Cross-linked polyvinylpyrrolidone, XL-10, purchased from Ashland Chemical Company;

[0050] Glyceryl behenate, 888ATO, purchased from Gattefosse SA;

[0051] Citric acid, AR, purchased from Sinopharm Chemical Reagent Co., Ltd.;

[0052] Disodium hydrogen phosphate, AR, purchased from Sinopharm Chemical Reagent Co., Ltd.

[0053] Hydroxypropyl methylcellulose (HPMC) E5 was purchased from Shanghai Calcare Coating Technology Co., Ltd.

[0054] Polyvinyl alcohol-polyethylene glycol, PVA-PEG, purchased from Shanghai Carrefour Coating Technology Co., Ltd.

[0055] The present application will be further described in detail below with reference to embodiments and comparative examples.

[0056] A loratadine immediate-release tablet comprises a comicronized complex, a filler, a disintegrant, a lubricant, a stabilizer, a pH adjuster, and a coating agent.

[0057] In one specific implementation, the comicronized composite comprises loratadine and a comicronized carrier, wherein the mass ratio of loratadine to the comicronized carrier is 1:(0.7-0.9).

[0058] In one specific implementation scheme, the mass ratio of loratadine, filler, disintegrant, lubricant, stabilizer, pH adjuster, and coating agent is 1:(5-7):(0.7-1.3):(0.05-0.3):(0.1-0.5):0.5:(0.1-0.5).

[0059] In one specific implementation, the particle size D50 of the co-micronized composite is ≤6 μm; further, the particle size D50 of the co-micronized composite is 4-6 μm.

[0060] In one specific feasible embodiment, the co-micronized carrier includes colloidal silica, polyvinylpyrrolidone, pregelatinized starch, copolyvinylpyrrolidone, fumed silica, precipitated silica, and... At least one of XDP F; further, the co-micronized carrier is colloidal silica.

[0061] In one specific implementation, the filler includes at least one of mannitol and sorbitol; further, the filler is mannitol.

[0062] In one specific implementation, the disintegrant includes at least one of crospovidone and sodium carboxymethyl starch; further, the disintegrant is crospovidone.

[0063] In one specific implementation, the lubricant includes at least one of glyceryl behenate, magnesium stearate, and talc; more preferably, the lubricant is glyceryl behenate.

[0064] In one specific implementation, the stabilizer is L-arginine.

[0065] In one specific implementation, the pH adjuster comprises a buffer system of citric acid, calcium phosphate, sodium phosphate, and sodium dihydrogen phosphate; further, the pH adjuster is citric acid and sodium dihydrogen phosphate.

[0066] In one specific feasible implementation, a pH adjuster is added to maintain the core microenvironment pH at 4.5-5.5.

[0067] In one specific implementation, the coating agent is at least one of hydroxypropyl methylcellulose (HPMC) E5 and polyvinyl alcohol-polyethylene glycol (PEG); hydroxypropyl methylcellulose (HPMC) E5 is used as the inner coating agent, and polyvinyl alcohol-polyethylene glycol is used as the outer coating agent.

[0068] Specifically, a method for preparing loratadine immediate-release tablets based on co-micronization technology includes the following steps:

[0069] (1) Weigh the raw materials for loratadine immediate-release tablets according to the prescription amount;

[0070] (2) Pretreatment:

[0071] Loratadine was pulverized in an air jet mill to a D90 of 40-60 μm; the lubricant was pulverized and passed through a 20-40 mesh sieve; the filler was pulverized and passed through a 60-100 mesh sieve to remove coarse powder; the disintegrant was pulverized and passed through a 60-100 mesh sieve to remove coarse powder.

[0072] (3) Co-micronization treatment:

[0073] Loratadine raw material (D90 = 40-60 μm) was mixed with comicronized carrier at a ratio of 1:(0.7-0.9), and then fed into an air jet mill at a grinding pressure of 0.6-1.0 MPa to obtain comicronized composite (D50 ≤ 6 μm).

[0074] (4) Mixing:

[0075] Step 1: Mix the co-micronized composite with the filler, stabilizer, and pH adjuster for 10 minutes (using a V-type mixer at 20-30 rpm), and maintain the pH of the core microenvironment at 4.5-5.5.

[0076] Step 2: Add the disintegrant and mix for 2-4 minutes;

[0077] Step 3: Add lubricant and mix for 1-3 minutes to obtain a mixture;

[0078] (5) Tableting:

[0079] The mixture obtained in step (4) (i.e., the mixed powder) is compressed into tablets using a rotary tablet press, with a pressure of 8-12 kN, a tablet weight of 100 mg, and a hardness of 70-90 N.

[0080] (6) Coating:

[0081] The coating agent is dispersed in an aqueous solution to prepare a coating agent solution; the uncoated tablets are placed in a coating pan, and the tablet bed temperature is controlled at 40-50℃, the atomization pressure at 0.2-0.3 MPa, and the spray flow rate at 40-160 g / min for inner and outer layer coating; the total weight gain of the coating is 2-4%, and loratadine immediate-release tablets are obtained.

[0082] Example 1:

[0083] A loratadine immediate-release tablet has the following formulation:

[0084] Table 1. Formulation of Loratadine Immediate-Release Tablets

[0085] Element Weight (g / 10000 tablets) Loratadine 100 colloidal silica 70 Mannitol 630 Cross-linked polyvinylpyrrolidone 80 Glyceryl behenate 5 L-arginine 30 Citric acid 30 Sodium hydrogen phosphate 20 Hydroxypropyl methylcellulose (HPMC) E5 17.5 Polyvinyl alcohol-polyethylene glycol (PVA-PEG) 17.5

[0086] A method for preparing loratadine immediate-release tablets, comprising the following steps:

[0087] (1) Preprocessing:

[0088] Loratadine was pulverized in an air jet mill to a D90 of 50 ± 5 μm; behenicol was pulverized and passed through a 30-mesh sieve; mannitol was pulverized and passed through an 80-mesh sieve to remove coarse powder; crospovidone was pulverized and passed through an 80-mesh sieve to remove coarse powder.

[0089] (2) Co-micronization treatment:

[0090] Loratadine raw material (D90 = 50 ± 5 μm) was mixed with colloidal silica and then fed into an air jet mill at a grinding pressure of 0.8 MPa to obtain a co-micronized composite (D50 = 5 μm).

[0091] (3) Mixing:

[0092] Step 1: Mix the co-micronized complex with mannitol, L-arginine, citric acid, and sodium dihydrogen phosphate for 10 minutes (V-type mixer, 25 rpm) to maintain the pH of the core microenvironment at 5.

[0093] Step 2: Add crospovidone and mix for 3 minutes;

[0094] Step 3: Add glyceryl behenate and mix for 2 minutes to obtain a mixture;

[0095] (4) Tableting:

[0096] The mixture obtained in step (3) (i.e., the mixed powder) is compressed into tablets using a rotary tablet press, with a pressure of 10 kN, a tablet weight of 100 mg, and a hardness of 80 N.

[0097] (5) Coating:

[0098] A double-layer coating technology is used for coating. The inner layer (i.e., the isolation layer) is coated with a coating premix (hydroxypropyl methylcellulose HPMC E5); the outer layer is coated with a coating premix (polyvinyl alcohol-polyethylene glycol PVA-PEG).

[0099] The specific steps are as follows:

[0100] Hydroxypropyl methylcellulose (HPMC) E5 and polyvinyl alcohol-polyethylene glycol were separately dispersed in 157.5g of aqueous solution to prepare coating solutions.

[0101] The tablets were placed in a coating pan, and the tablet bed temperature was controlled at 45℃, the atomization pressure at 0.25 MPa, and the spray flow rate of the coating agent solution at 100 g / min for inner and outer coating. The total weight gain of the coating was 3.5%, and loratadine immediate-release tablets were obtained.

[0102] Example 2:

[0103] The difference from Example 1 is that the formulation of loratadine immediate-release tablets is different.

[0104] In this embodiment, a loratadine immediate-release tablet has the following formulation:

[0105] Table 2. Formulation of Loratadine Immediate-Release Tablets

[0106] Element Weight (g / 10000 tablets) Loratadine 100 colloidal silica 80 Mannitol 600 Cross-linked polyvinylpyrrolidone 100 Glyceryl behenate 5 L-arginine 30 Citric acid 30 Sodium hydrogen phosphate 20 Hydroxypropyl methylcellulose (HPMC) E5 17.5 Polyvinyl alcohol-polyethylene glycol 17.5

[0107] Example 3:

[0108] The difference from Example 1 is that the formulation of loratadine immediate-release tablets is different.

[0109] In this embodiment, a loratadine immediate-release tablet has the following formulation:

[0110] Table 3. Formulation of Loratadine Immediate-Release Tablets

[0111] Element Weight (g / 10000 tablets) Loratadine 100 colloidal silica 90 Mannitol 570 Cross-linked polyvinylpyrrolidone 120 Glyceryl behenate 5 L-arginine 30 Citric acid 30 Sodium hydrogen phosphate 20 Hydroxypropyl methylcellulose (HPMC) E5 17.5 Polyvinyl alcohol-polyethylene glycol 17.5

[0112] Example 4:

[0113] The difference from Example 1 is that the formulation of loratadine immediate-release tablets is different.

[0114] In this embodiment, a loratadine immediate-release tablet has the following formulation:

[0115] Table 4. Formulation of Loratadine Immediate-Release Tablets

[0116] Element Weight (g / 10000 tablets) Loratadine 100 colloidal silica 70 Mannitol 600 Cross-linked polyvinylpyrrolidone 120 Glyceryl behenate 30 L-arginine 10 Citric acid 30 Sodium hydrogen phosphate 20 Hydroxypropyl methylcellulose (HPMC) E5 10 Polyvinyl alcohol-polyethylene glycol 10

[0117] Example 5:

[0118] The difference from Example 1 is that the formulation of loratadine immediate-release tablets is different.

[0119] In this embodiment, a loratadine immediate-release tablet has the following formulation:

[0120] Table 5. Formulation of Loratadine Immediate-Release Tablets

[0121] Element Weight (g / 10000 tablets) Loratadine 100 colloidal silica 90 Mannitol 500 Cross-linked polyvinylpyrrolidone 130 Glyceryl behenate 30 L-arginine 50 Citric acid 30 Sodium hydrogen phosphate 20 Hydroxypropyl methylcellulose (HPMC) E5 25 Polyvinyl alcohol-polyethylene glycol 25

[0122] Example 6:

[0123] The difference from Example 1 is that the formulation of loratadine immediate-release tablets is different.

[0124] In this embodiment, a loratadine immediate-release tablet has the following formulation:

[0125] Table 6. Formulation of Loratadine Immediate-Release Tablets

[0126] Element Weight (g / 10000 tablets) Loratadine 100 colloidal silica 70 Mannitol 680 Cross-linked polyvinylpyrrolidone 70 Glyceryl behenate 10 L-arginine 10 Citric acid 30 Sodium hydrogen phosphate 20 Hydroxypropyl methylcellulose (HPMC) E5 5 Polyvinyl alcohol-polyethylene glycol 5

[0127] Example 7:

[0128] The difference from Example 1 is that the particle size of the comicronized compound is different; in this example, the comicronized compound has a D50 of 4 μm.

[0129] Example 8:

[0130] The difference from Example 1 is that the particle size of the comicronized compound is different; in this example, the comicronized compound has a D50 of 6 μm.

[0131] Example 9:

[0132] The difference from Example 1 is that the pH of the core microenvironment is different; in this example, the pH of the core microenvironment is maintained at 4.5.

[0133] In this embodiment, a loratadine immediate-release tablet has the following formulation:

[0134] Table 7. Formulation of Loratadine Immediate-Release Tablets

[0135] Element Weight (g / 10000 tablets) Loratadine 100 colloidal silica 70 Mannitol 630 Cross-linked polyvinylpyrrolidone 80 Glyceryl behenate 5 L-arginine 30 Citric acid 35 Sodium hydrogen phosphate 15 Hydroxypropyl methylcellulose (HPMC) E5 17.5 Polyvinyl alcohol-polyethylene glycol 17.5

[0136] Example 10:

[0137] The difference from Example 1 is that the pH of the chip core microenvironment is different; in this example, the pH of the chip core microenvironment is maintained at 5.5.

[0138] In this embodiment, a loratadine immediate-release tablet has the following formulation:

[0139] Table 8. Formulation of Loratadine Immediate-Release Tablets

[0140] Element Weight (g / 10000 tablets) Loratadine 100 colloidal silica 70 Mannitol 630 Cross-linked polyvinylpyrrolidone 80 Glyceryl behenate 5 L-arginine 30 Citric acid 20 Sodium hydrogen phosphate 30 Hydroxypropyl methylcellulose (HPMC) E5 17.5 Polyvinyl alcohol-polyethylene glycol 17.5

[0141] Comparative Example 1:

[0142] The difference from Example 1 is that the formulation of loratadine immediate-release tablets is different.

[0143] In this comparative example, one loratadine immediate-release tablet has the following formulation:

[0144] A method for preparing loratadine immediate-release tablets, comprising the following steps:

[0145] Table 9. Formulation of Loratadine Immediate-Release Tablets

[0146] Element Weight (g / 10000 tablets) Loratadine 100 silicon dioxide 70 Mannitol 630 Cross-linked polyvinylpyrrolidone 80 Glyceryl behenate 5 L-arginine 30 Citric acid 30 Sodium hydrogen phosphate 20 Hydroxypropyl methylcellulose (HPMC) E5 17.5 Polyvinyl alcohol-polyethylene glycol 17.5

[0147] (1) Preprocessing:

[0148] Loratadine was pulverized in an air jet mill to a D90 of 50 ± 5 μm; glyceryl behenate was pulverized and passed through a 30-mesh sieve; mannitol was pulverized and passed through an 80-mesh sieve to remove coarse powder; crospovidone was pulverized and passed through an 80-mesh sieve to remove coarse powder.

[0149] (2) Mixing:

[0150] Step 1: Mix loratadine raw material (D90 = 50±5μm) with silica, then mix with mannitol, L-arginine, citric acid, and sodium dihydrogen phosphate for 10 minutes (V-type mixer, 25 rpm), maintaining the pH of the tablet core microenvironment at 5.

[0151] Step 2: Add crospovidone and mix for 3 minutes;

[0152] Step 3: Add glyceryl behenate and mix for 2 minutes to obtain a mixture;

[0153] (3) Tableting:

[0154] The mixture obtained in step (2) (i.e., the mixed powder) is compressed into tablets using a rotary tablet press, with a pressure of 10 kN, a tablet weight of 100 mg, and a hardness of 80 N.

[0155] (3) Coating:

[0156] A double-layer coating technology is used for coating. The inner layer (i.e., the isolation layer) is coated with a coating premix (hydroxypropyl methylcellulose HPMCE5); the outer layer is coated with a coating premix (polyvinyl alcohol-polyethylene glycol PVA-PEG).

[0157] The specific steps are as follows:

[0158] Hydroxypropyl methylcellulose HPMCE5 and polyvinyl alcohol-polyethylene glycol were dispersed in 157.5g of aqueous solution to prepare a coating solution.

[0159] The tablets were placed in a coating pan, and the tablet bed temperature was controlled at 45℃, the atomization pressure at 0.25 MPa, and the spray flow rate of the coating premix at 100 g / min for inner and outer coating. The total weight gain of the coating was 3.5%, and loratadine immediate-release tablets were obtained.

[0160] Comparative Example 2:

[0161] The difference from Example 1 is that the particle size of the comicronized compound is different; in this comparative example, the comicronized compound D50 = 7 μm.

[0162] Comparative Example 3:

[0163] The difference from Example 1 is that the pH of the chip core microenvironment is different.

[0164] In this comparative example, the pH of the chip core microenvironment was maintained at 4.

[0165] A loratadine immediate-release tablet has the following formulation:

[0166] Table 10. Formulation of Loratadine Immediate-Release Tablets

[0167] Element Weight (g / 10000 tablets) Loratadine 100 colloidal silica 70 Mannitol 630 Cross-linked polyvinylpyrrolidone 80 Glyceryl behenate 5 L-arginine 30 Citric acid 40 Sodium hydrogen phosphate 10 Hydroxypropyl methylcellulose (HPMC) E5 17.5 Polyvinyl alcohol-polyethylene glycol 17.5

[0168] Comparative Example 4:

[0169] The difference from Example 1 is that the pH of the chip core microenvironment is different.

[0170] In this comparative example, the pH of the chip core microenvironment was maintained at 6.

[0171] A loratadine immediate-release tablet has the following formulation:

[0172] Table 11. Formulation of Loratadine Immediate-Release Tablets

[0173] Element Weight (g / 10000 tablets) Loratadine 100 colloidal silica 70 Mannitol 630 Cross-linked polyvinylpyrrolidone (PVPP) 80 Glyceryl behenate 5 L-arginine 30 Citric acid 5 Sodium hydrogen phosphate 45 Hydroxypropyl methylcellulose (HPMC) E5 17.5 Polyvinyl alcohol-polyethylene glycol 17.5

[0174] Comparative Example 5:

[0175] The difference from Example 1 is that only a conventional single-layer coating is performed.

[0176] A loratadine immediate-release tablet has the following formulation:

[0177] Table 12. Formulation of Loratadine Immediate-Release Tablets

[0178] Element Weight (g / 10000 tablets) Loratadine 100 colloidal silica 70 Mannitol 630 Cross-linked polyvinylpyrrolidone 80 Glyceryl behenate 5 L-arginine 30 Citric acid 30 Sodium hydrogen phosphate 20 Hydroxypropyl methylcellulose (HPMC) E5 35

[0179] Comparative Example 6:

[0180] The difference from Example 1 is that only a conventional single-layer coating is performed.

[0181] A loratadine immediate-release tablet has the following formulation:

[0182] Table 13. Formulation of Loratadine Immediate-Release Tablets

[0183] Element Weight (g / 10000 tablets) Loratadine 100 colloidal silica 70 Mannitol 630 Cross-linked polyvinylpyrrolidone (PVPP) 80 Glyceryl behenate 5 L-arginine 30 Citric acid 30 Sodium hydrogen phosphate 20 Polyvinyl alcohol-polyethylene glycol 35

[0184] Test example:

[0185] 1. Accelerated stability test for impurity content detection

[0186] The impurity content was determined according to the high performance liquid chromatography (HPLC) method (General Chapter 0512) of the 2020 edition of the Chinese Pharmacopoeia. The above-mentioned examples, comparative examples, and control examples / reference preparations, including Clarityne, were continuously placed under accelerated testing conditions (temperature 40℃±2℃, relative humidity 75%±5%) for 6 months. The results are shown in Table 14. The specific steps are as follows:

[0187] Preparation of the test solution: Take an appropriate amount of the fine powder of this product, add the mobile phase to dissolve loratadine and dilute quantitatively to prepare a solution containing about 0.2 mg per 1 mL, filter, and take the filtrate.

[0188] Preparation of the control solution: Accurately measure 1 mL of the test solution and place it in a 100 mL volumetric flask. Dilute to the mark with the mobile phase and shake well.

[0189] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; phosphate buffer-methanol (20:80) was used as the mobile phase; the detection wavelength was 247 nm; and the injection volume was 20 μL.

[0190] The preparation of phosphate buffer solution involves dissolving 2.28 g of dipotassium hydrogen phosphate in 800 mL of water, adjusting the pH to 6.0 with phosphoric acid, and then adding water to 1000 mL.

[0191] System applicability requirements: The theoretical plate number, calculated based on the loratadine peak, shall not be less than 2000, and the separation between the loratadine peak and adjacent impurity peaks shall meet the requirements.

[0192] Assay: Accurately measure the test solution and the control solution, inject them separately into the liquid chromatograph, and record the chromatograms up to 2.5 times the retention time of the main component peak.

[0193] Table 14 Impurity Content (Unit: %)

[0194]

[0195] The results showed that the total impurity content of Examples 1-10 and the control-reference formulation Clarityne in this application was below 0.3% within 0 days and 6 months under accelerated testing conditions, and the impurity growth rate of Examples 1-3 was slower; while the impurity content of Comparative Examples 1-6 was greater than 0.3% under the same conditions, and the growth rate was faster. Therefore, it can be seen that the loratadine drug composition obtained in this application has lower impurity growth and better stability under high humidity and high temperature conditions, and the loratadine drug composition and its preparation method described in this application can effectively control the impurity content.

[0196] Based on Examples 1, 9, 10, Comparative Example 3, and Comparative Example 4, it can be seen that during the preparation of loratadine immediate-release tablets, the pH of the tablet core microenvironment affects the impurity growth rate of the prepared loratadine immediate-release tablets. Furthermore, when the pH of the tablet core microenvironment is 4.5-5.5, the prepared loratadine immediate-release tablets exhibit lower impurity growth and better stability under high humidity and high temperature conditions.

[0197] As can be seen from Examples 1, 5, and 6, the coating technology affects the impurity growth rate of the prepared loratadine immediate-release tablets during the preparation process. When a double-layer coating technology is used, the prepared loratadine immediate-release tablets have lower impurity growth and better stability under high humidity and high temperature conditions.

[0198] 2. Comparison of light exposure tests

[0199] The impurity content was determined according to the high performance liquid chromatography (HPLC) method (General Chapter 0512) of the 2020 edition of the Chinese Pharmacopoeia. Examples 1-3 and the control example-reference preparation Clarityne were continuously placed under an illuminance of 4500 lux for 30 days, and the impurity content was detected using HPLC. The results are shown in Table 15. The specific detection steps are as follows:

[0200] Preparation of the test solution: Take an appropriate amount of the fine powder of this product, add the mobile phase to dissolve loratadine and dilute quantitatively to prepare a solution containing about 0.2 mg per 1 mL, filter, and take the filtrate.

[0201] Preparation of the control solution: Accurately measure 1 mL of the test solution and place it in a 100 mL volumetric flask. Dilute to the mark with the mobile phase and shake well.

[0202] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; phosphate buffer-methanol (20:80) was used as the mobile phase; the detection wavelength was 247 nm; and the injection volume was 20 μL.

[0203] The preparation of phosphate buffer solution involves dissolving 2.28 g of dipotassium hydrogen phosphate in 800 mL of water, adjusting the pH to 6.0 with phosphoric acid, and then adding water to 1000 mL.

[0204] System applicability requirements: The theoretical plate number, calculated based on the loratadine peak, shall not be less than 2000, and the separation between the loratadine peak and adjacent impurity peaks shall meet the requirements.

[0205] Assay: Accurately measure the test solution and the control solution, inject them separately into the liquid chromatograph, and record the chromatograms up to 2.5 times the retention time of the main component peak.

[0206] Table 15 Impurity Content (%)

[0207]

[0208] The results showed that, under light conditions (4500 lux, 30 days), the impurity content of Examples 1-3 and the control / reference formulation Clarityne was below 0.8% from day 0 to day 30. Furthermore, the impurity growth rate of Examples 1-3 was slower, and the impurity content was below 0.6%. These results demonstrate that the loratadine pharmaceutical composition and its preparation method described in this application can effectively control drug degradation.

[0209] 3. Dissolution curve detection

[0210] (1) Dissolution and release were determined according to the method for determination of dissolution and release in Appendix IV of the 2020 edition of the Chinese Pharmacopoeia (General Rule 0931, Method II, Paddle Method). Examples 1-3, 7, 8, Comparative Example 2, and the control example (reference preparation Clarityne) were used. Dissolution curves were measured in 0.1 mol / L hydrochloric acid solution. The results are shown in Table 16 and... Figure 1 The specific detection steps are as follows: Preparation of 0.1 mol / L hydrochloric acid solution: Take 9 mL of hydrochloric acid and dilute it with purified water to 1000 mL;

[0211] Preparation of dissolution solution: Using 500 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium, add 1 tablet of this product, rotate at 50 rpm, and proceed according to the procedure to obtain the dissolution solution;

[0212] Preparation of the test solution: Take 10 mL of the dissolution solution, filter it, and collect the filtrate.

[0213] Preparation of reference solution: Weigh an appropriate amount of loratadine reference standard accurately, dissolve it in 0.1 mol / L hydrochloric acid solution and dilute quantitatively to prepare a solution containing approximately 20 μg per mL.

[0214] Assay: Take the test solution and the reference solution, and measure the absorbance at a wavelength of 276 nm ± 3 nm according to the ultraviolet-visible spectrophotometry method (General Rule 0401), and calculate the dissolution amount of each tablet.

[0215] Table 16. Dissolution test results for 0.1 mol / L hydrochloric acid solution as the dissolution medium (dissolution rate in %).

[0216]

[0217] (2) Dissolution and release were determined according to the method for determination of dissolution and release in Appendix IV of the 2020 edition of the Chinese Pharmacopoeia (General Rule 0931, Method II, Paddle Method). Examples 1-3, 7, 8, Comparative Example 2, and the control example (reference preparation Clarityne) were used. Dissolution curves were measured in pH 3.0 phosphate buffer medium. The results are shown in Table 17 and... Figure 2 The specific testing steps are as follows: Preparation of pH 3.0 phosphate buffer: Take 6.8g of potassium dihydrogen phosphate, add 900mL of water, adjust the pH to 3.0 with dilute phosphoric acid, and dilute with water to 1000mL;

[0218] Preparation of dissolution solution: Using 500 mL of pH 3.0 phosphate buffer as the dissolution medium, add 1 tablet of this product, rotate at 50 rpm, and proceed according to the procedure to obtain the dissolution solution;

[0219] Preparation of the test solution: Take 10 mL of the dissolution solution, filter it, and collect the filtrate.

[0220] Preparation of reference solution: Weigh an appropriate amount of loratadine reference standard accurately, dissolve it in pH 3.0 phosphate buffer, and dilute quantitatively to prepare a solution containing approximately 20 μg per mL.

[0221] Assay: Take the test solution and the reference solution, and measure the absorbance at a wavelength of 276 nm ± 3 nm according to the ultraviolet-visible spectrophotometry method (General Rule 0401), and calculate the dissolution amount of each tablet.

[0222] Table 17 Dissolution test results for phosphate buffer solution with pH 3.0 dissolution medium (dissolution rate in %)

[0223]

[0224] The results showed that the dissolution curves of Examples 1-3 and Examples 7-8 of this application in two dissolution media, namely 0.1 mol / L hydrochloric acid solution and pH 3.0 phosphate buffer, were similar to those of the control example-reference preparation Clarityne. Therefore, it can be concluded that the loratadine immediate-release tablets prepared in this application have good in vitro dissolution performance and can provide a guarantee for in vivo bioequivalence.

[0225] Based on Examples 1, 7, 8, and Comparative Example 2, it can be seen that during the preparation of loratadine immediate-release tablets, the D50 of the co-micronized complex affects the dissolution performance of the prepared loratadine immediate-release tablets. Furthermore, only when the D50 of the co-micronized complex is ≤6μm can the dissolution performance be significantly improved, while when the D90 is 7μm, the dissolution performance cannot be effectively improved (or the effect is not obvious).

[0226] This application discloses a loratadine immediate-release tablet based on co-micronization technology and its preparation method. Through a co-micronization technology and a novel combination of excipients, a tablet formulation and preparation process that significantly improves the dissolution rate, stability, and bioavailability of loratadine have been developed. This reduces the growth of impurities during the production and storage process and significantly improves drug stability. At the same time, the loratadine immediate-release tablet prepared in this application has good in vitro dissolution performance. The dissolution curves in two typical dissolution media are similar to those of the reference formulation Clarityne, which can provide a guarantee for in vivo bioequivalence.

[0227] The loratadine immediate-release tablets prepared in this application have the following advantages:

[0228] Dissolution performance: The dissolution curves obtained in both dissolution media were similar to those of the reference formulation; when the dissolution medium was 0.1 mol / L hydrochloric acid solution, the dissolution rate was ≥45% at 10 minutes and ≥80% at 30 minutes; when the dissolution medium was pH 3.0 phosphate buffer, the dissolution rate was ≥85% at 15 minutes and ≥95% at 30 minutes.

[0229] Stability: Accelerated test (40℃ / 75%RH, 6 months): Total impurities ≤0.3%; Light exposure test (4500 lux, 30 days): Total impurities ≤0.6%;

[0230] Process advantages: Shorter production cycle (eliminating granulation and drying steps), energy consumption reduced by 40%;

[0231] Safety: The composition is lactose-free, avoiding lactose intolerance side effects.

Claims

1. A loratadine immediate-release tablet, characterized in that: This includes pharmaceutical compositions and pharmaceutically acceptable excipients; The pharmaceutical composition includes a comicronized complex, the comicronized complex including loratadine and a comicronized carrier; The mass ratio of loratadine to the co-micronized carrier is 1:(0.7-0.9). The particle size D50 of the co-micronized composite is ≤6μm; The co-micronized carrier is colloidal silica; The pharmaceutically acceptable excipients include fillers, disintegrants, lubricants, stabilizers, pH adjusters, and coating agents; pH adjusters are added to maintain the pH of the tablet core microenvironment at 4.5-5.5; A double-layer coating is used, with the inner layer coated with hydroxypropyl methylcellulose (HPMC) E5 and the outer layer coated with polyvinyl alcohol (PVA-PEG).

2. The loratadine immediate-release tablet according to claim 1, characterized in that: The particle size D50 of the co-micronized composite is 4-6 μm.

3. The loratadine immediate-release tablet according to claim 1, characterized in that: The filler includes at least one of mannitol and sorbitol; The disintegrant includes at least one of crospovidone and sodium carboxymethyl starch; The lubricant includes at least one of glyceryl behenate, magnesium stearate, and talc. The stabilizer is L-arginine; The pH adjuster includes at least one of citric acid, calcium phosphate, sodium phosphate, and sodium dihydrogen phosphate.

4. A method for preparing loratadine immediate-release tablets according to any one of claims 1-3, characterized in that: The preparation method steps are as follows: (1) Weigh the raw materials for loratadine immediate-release tablets according to the prescription amount; (2) Crush loratadine to a D90 of 40-60 μm; pass the lubricant through a 20-40 mesh sieve; pass the filler and disintegrant through a 60-100 mesh sieve respectively; (3) Loratadine was mixed with and pulverized with a co-micronized carrier to obtain a co-micronized complex; (4) Mix the co-micronized complex with filler, stabilizer, and pH adjuster, add disintegrant and mix, then add lubricant and mix to obtain a mixture; (5) Compress the mixture into tablets; (6) The coating agent is used to double-coat the mixture after tableting to obtain loratadine immediate-release tablets.

5. The preparation method according to claim 4, characterized in that: In step (4), a pH adjuster is added to adjust the pH of the mixture to 4.5-5.5; The mass ratio of loratadine, filler, disintegrant, lubricant, stabilizer, pH adjuster, and coating agent is 1:(5-7):(0.7-1.3):(0.05-0.3):(0.1-0.5):0.5:(0.1-0.5).

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