Dry suspension of bosutinib and preparation method thereof

Abstract

The invention relates to the technical field of medicines, in particular to a dry suspension of medicine bosutinib for treating chronic myeloid leukemia (CML) and a preparation method of the dry suspension. The bosutinib tablet is prepared from the following raw materials in parts by weight: 50 to 100 parts of bosutinib, 10 to 60 parts of cane sugar, 10 to 60 parts of mannitol, 1 to 20 parts of citric acid, 1 to 20 parts of povidone, 1 to 10 parts of sodium carboxymethyl cellulose, 1 to 20 parts of poloxamer, 1 to 20 parts of xanthan gum, 0.1 to 5 parts of silicon dioxide, 0.1 to 0.5 part of stevioside, 0.01 to 0.5 part of iron oxide yellow and 0.01 to 0.5 part of iron oxide red. By optimizing a prescription and a preparation process, the physical stability and the chemical stability of the suspension are improved, the storage life is prolonged, the dry suspension is quickly dispersed in water, the uniformity and the effectiveness of medicine use are ensured, the medicine taking convenience of old people and child patient groups is improved, and the patient compliance is better.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a dry suspension of bosutinib, a drug for treating chronic myeloid leukemia (CML), and its preparation method. Background Technology

[0002] Bosutinib tablets were co-developed by Pfizer and Avillion LLP and were first approved in the United States on September 4, 2012. The currently approved indication is for newly diagnosed adult patients with chronic-phase (CP) Philadelphia chromosome-positive chronic myeloid leukemia (Ph+CML). It is suitable for adult patients with chronic-phase, accelerated-phase (AP), or blast crisis (BP) Ph+CML who are resistant to or intolerant of prior therapy.

[0003] Bosutinib tablets contain bosutinib monohydrate as their active ingredient, marketed under the brand name BOSULIF, and are available in three strengths: 100mg, 400mg, and 500mg. On September 26, 2023, the FDA approved the expansion of bosutinib tablets' indications to include children aged one year and older newly diagnosed with chronic phase Ph+CML and those with Ph+CML who are resistant to or intolerant of prior treatment. New capsule formulations of 50mg and 100mg were also approved, providing a new treatment option for children with leukemia.

[0004] As one of the four TKIs approved by the U.S. Food and Drug Administration and the European Medicines Agency for first-line treatment of CML, it is not currently available in China. Bosutinib tablets (0.1g specification) have been included in the fourth batch of pediatric drugs encouraged for research and development by the National Health Commission, and their efficacy and safety are beyond doubt.

[0005] Bosutinib has poor water solubility, low bioavailability, and is sensitive to temperature and humidity, which limits the stability of its formulations and its clinical efficacy. Therefore, developing a bosutinib formulation with excellent physicochemical properties and high stability is of great significance.

[0006] This invention aims to address the shortcomings of existing bosutinib formulations, such as poor stability, limited administration methods, and inability to safely and effectively provide them to the elderly and children. It provides a bosutinib dry suspension with excellent physical stability, redispersibility, and ease of administration. This invention considers the swallowing ability and taste preferences of young children and optimizes for the reduced saliva production and swallowing function decline in the elderly, offering a superior solution. Summary of the Invention

[0007] The purpose of this invention is to address the shortcomings of existing technologies by proposing a bosutinib dry suspension.

[0008] A bosutinib dry suspension, comprising the following raw materials in parts by weight:

[0009] Bosutinib: 50-100 parts, sucrose: 10-60 parts, mannitol: 10-60 parts, citric acid: 1-20 parts, povidone: 1-20 parts, sodium carboxymethyl cellulose: 1-10 parts, poloxamer: 1-20 parts, xanthan gum: 1-20 parts, silicon dioxide: 0.1-5 parts, steviol glycoside: 0.1-0.5 parts, iron oxide yellow: 0.01-0.5 parts, iron oxide red: 0.01-0.5 parts.

[0010] The preparation method of bosutinib dry suspension includes the following steps:

[0011] Step 1: Accurately weigh each material according to the prescription;

[0012] Step 2: Raw material processing, strictly control the particle size of the materials and sieve them to ensure uniform particle size;

[0013] Step 3: Add bosutinib, povidone, and poloxamer to a three-dimensional motion mixer, set an appropriate mixing speed and time, and mix thoroughly as A;

[0014] Step 4: Add the remaining materials to the three-dimensional motion mixer, set an appropriate mixing speed and time, and mix them together with A;

[0015] Step 5: Dispense the well-mixed material into portions to obtain bosutinib dry suspension.

[0016] The preparation process of the bosutinib dry suspension includes fillers, wetting agents, suspending agents, flavoring agents, and pH adjusters.

[0017] The filler may be one or more of sucrose, mannitol, erythritol, maltitol, and lactose.

[0018] Preferably, the filler is sucrose and mannitol.

[0019] The wetting agent may be one or more of sodium dodecyl sulfate, Tween 80, povidone, and poloxamer.

[0020] Preferably, the wetting agent is poloxamer.

[0021] According to claim 3, the bosutinib dry suspension is characterized in that the suspending agent can be one or more of gum arabic, tragacanth gum, erythrina gum, xanthan gum, sodium alginate, β-cyclodextrin, etc.

[0022] Preferably, the suspending agent is xanthan gum.

[0023] The flavoring agent is one or more of sucralose, aspartame, sodium saccharin, and stevioside.

[0024] Preferably, the flavoring agent is stevioside.

[0025] The pH adjuster is one or more of acetic acid, tartaric acid, citric acid, lactic acid, etc.

[0026] Preferably, the pH adjuster is citric acid.

[0027] Compared with the prior art, the bosutinib dry suspension of the present invention has the following advantages:

[0028] High stability: By optimizing the formulation and preparation process, the physical and chemical stability of the suspension has been improved, and the shelf life has been extended;

[0029] Good dispersibility: Dry suspensions disperse rapidly in water, ensuring the uniformity and effectiveness of drug use;

[0030] Convenience of administration: Improve the convenience of medication administration for elderly and child patients, and improve patient compliance. Detailed Implementation

[0031] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0032] A bosutinib dry suspension, comprising the following raw materials in parts by weight:

[0033] Bosutinib: 50-100 parts, sucrose: 10-60 parts, mannitol: 10-60 parts, citric acid: 1-20 parts, povidone: 1-20 parts, sodium carboxymethyl cellulose: 1-10 parts, poloxamer: 1-20 parts, xanthan gum: 1-20 parts, silicon dioxide: 0.1-5 parts, steviol glycoside: 0.1-0.5 parts, iron oxide yellow: 0.01-0.5 parts, iron oxide red: 0.01-0.5 parts.

[0034] The preparation method of bosutinib dry suspension includes the following steps:

[0035] Step 1: Accurately weigh each material according to the prescription;

[0036] Step 2: Raw material processing, strictly control the particle size of the materials and sieve them to ensure uniform particle size;

[0037] Step 3: Add bosutinib, povidone, and poloxamer to a three-dimensional motion mixer, set an appropriate mixing speed and time, and mix thoroughly as A;

[0038] Step 4: Add the remaining materials to the three-dimensional motion mixer, set an appropriate mixing speed and time, and mix them together with A;

[0039] Step 5: Dispense the well-mixed material into portions to obtain bosutinib dry suspension.

[0040] As a technical optimization of the present invention, the preparation process of bosutinib dry suspension includes fillers, wetting agents, suspending agents, flavoring agents and pH adjusters.

[0041] As a technical optimization of the present invention, the filler can be one or more of sucrose, mannitol, erythritol, maltitol, and lactose.

[0042] As a technical optimization of the present invention, the wetting agent can be one or more of sodium dodecyl sulfate, Tween 80, povidone, and poloxamer.

[0043] As a technical optimization of the present invention, the suspending agent can be one or more of gum arabic, tragacanth gum, erythrina gum, xanthan gum, sodium alginate, β-cyclodextrin, etc.

[0044] As a technical optimization of the present invention, the flavoring agent is one or more of sucralose, aspartame, sodium saccharin and stevioside.

[0045] As a technical optimization of the present invention, the pH adjuster is one or more of acetic acid, tartaric acid, citric acid, lactic acid, etc.

[0046] The specific implementation method is as follows:

[0047] Example 1

[0048] prescription:

[0049]

[0050]

[0051] Preparation process:

[0052] (1) Weigh each material;

[0053] (2) Bosutinib particles were pulverized by air jet milling to D90<15μm, and other materials (which can be pulverized) were processed through an 80-mesh sieve;

[0054] (3) Put the treated bosutinib and other materials into a three-dimensional motion mixer, set the premixing speed to 15 r / min, and the mixing time to 40 min;

[0055] (4) After mixing evenly, the mixture is dispensed to obtain bosutinib dry suspension.

[0056] Example 2

[0057] prescription:

[0058]

[0059]

[0060] Preparation method: Same as the preparation method in Example 1.

[0061] Example 3

[0062] prescription:

[0063] Material Name Prescription dosage / g Bosutinib 103.40 sucrose 38.60 Mannitol 25.00 Polosham 6.00 Xanthan Gum 6.00 Sodium carboxymethyl cellulose 4.00 silicon dioxide 2.00 Povidone 10.00 Citric acid 5.00

[0064] Preparation process: Same as the preparation method in Example 1.

[0065] Example 4

[0066] prescription:

[0067]

[0068]

[0069] Preparation process: Same as the preparation method in Example 1.

[0070] Comparative Example 1

[0071] prescription:

[0072] Material Name Prescription dosage / g Bosutinib 103.40 sucrose 34.60 Mannitol 40.00 Polosham 6.00 Xanthan Gum 4.00 silicon dioxide 2.00 Povidone 10.00

[0073] Preparation process: Same as the preparation method in Example 1.

[0074] Example 5 (Flavor Improvement)

[0075] prescription:

[0076]

[0077]

[0078] Preparation process:

[0079] (1) Pretreatment: Mannitol is sieved and set aside for later use;

[0080] (2) Preparation of drug-containing solution: Mix bosutinib, poloxamer and povidone and dissolve them in a solution prepared with acetic acid;

[0081] (3) Preparation of coating solution: Add polyvinyl alcohol and glycerin to water and stir until clear;

[0082] (4) Granulation: The drug-containing solution obtained in step (2) is used as a binder and added to mannitol for fluidized bed spray granulation;

[0083] (5) Drying and coating: After the obtained granules are dried, the coating solution obtained in step (3) is added to coat them to make drug-coated granules;

[0084] (6) Mixing: The obtained drug-coated granules are mixed evenly with xanthan gum, silicon dioxide, stevioside and pigment to obtain a dry suspension.

[0085] Technical feature verification

[0086] Dispersion time: Place the suspension in a 100ml graduated cylinder, add water, and rotate at a speed of 20r per minute for a certain period of time. The sediment at the bottom of the graduated cylinder can be redispersed evenly. Record the time required for each test sample to be evenly dispersed.

[0087] Sedimentation volume ratio: Take an appropriate amount of this product, add water to prepare a suspension containing approximately 10 mg of bosutinib per ml, take 50 ml of the solution, place it in a stoppered graduated cylinder, seal tightly, shake vigorously for 1 minute, and let stand for 3 hours. It should meet the requirements (Chinese Pharmacopoeia General Chapter 0123). See the table for specific results.

[0088] Comparison data Dispersion time / s Settlement volume ratio taste Example 1 12 0.95 good Example 2 6 0.97 very good Example 3 10 0.95 good Example 4 8 0.91 good Supplementary Examples 8 0.92 very good Comparative Example 15 0.86 Poor

[0089] The results showed that the samples prepared by each formulation in the examples could be well dispersed. Observation of their sedimentation confirmed that when the experimenters combined xanthan gum and sodium carboxymethyl cellulose in a certain proportion, a better suspending effect than that of a single component could be achieved. Adding an appropriate amount of stevioside, sucrose and citric acid to the formulation would increase palatability. The combination of poloxamer and povidone in this product would also ensure that the product has good dispersibility.

[0090] Therefore, the dry suspension in this invention disperses rapidly in water, ensuring the uniformity and effectiveness of drug use. At the same time, the improved taste of this invention can enhance the convenience of medication for elderly and child patients, resulting in better patient compliance.

[0091] Stability test

[0092] The bosutinib dry suspensions prepared in Examples 1 to 5 were placed under accelerated conditions (40°C, 75% relative humidity) for 10 days and 30 days, respectively, and their appearance, content, related substances, and other indicators were tested periodically. The results are shown in the table below.

[0093]

[0094] The results showed that the suspension exhibited good stability after 30 days of accelerated storage. Except for a slight increase in related substances, all other indicators remained largely unchanged and met the requirements. The addition of pH adjusters and pigments significantly reduced the increase in related substances in bosutinib, playing a crucial role in the quality of the product.

[0095] Therefore, it can be concluded from the table above that the present invention improves the physical and chemical stability of the suspension and extends its shelf life by optimizing the formulation and preparation process.

[0096] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only to the claims and their full scope and equivalents.

Claims

1. A bosutinib dry suspension, characterized in that, It consists of the following raw materials in parts by weight: Bosutinib: 50-100 parts, sucrose: 10-60 parts, mannitol: 10-60 parts, citric acid: 1-20 parts, povidone: 1-20 parts, sodium carboxymethyl cellulose: 1-10 parts, poloxamer: 1-20 parts, xanthan gum: 1-20 parts, silicon dioxide: 0.1-5 parts, steviol glycoside: 0.1-0.5 parts, iron oxide yellow: 0.01-0.5 parts, iron oxide red: 0.01-0.5 parts.

2. The method for preparing the bosutinib dry suspension according to claim 1 comprises the following steps, characterized in that, Step 1: Accurately weigh each material according to the prescription; Step 2: Raw material processing, strictly control the particle size of the materials and sieve them to ensure uniform particle size; Step 3: Add bosutinib, povidone, and poloxamer to a three-dimensional motion mixer, set an appropriate mixing speed and time, and mix thoroughly as A; Step 4: Add the remaining materials to the three-dimensional motion mixer, set an appropriate mixing speed and time, and mix them together with A; Step 5: Dispense the well-mixed material into portions to obtain bosutinib dry suspension.

3. The bosutinib dry suspension according to claim 1, characterized in that, The preparation process of the bosutinib dry suspension includes fillers, wetting agents, suspending agents, flavoring agents, and pH adjusters.

4. The bosutinib dry suspension according to claim 3, characterized in that, The filler may be one or more of sucrose, mannitol, erythritol, maltitol, and lactose.

5. A bosutinib dry suspension according to claim 3, characterized in that, The wetting agent may be one or more of sodium dodecyl sulfate, Tween 80, povidone, and poloxamer.

6. A bosutinib dry suspension according to claim 3, characterized in that, The suspending agent may be one or more of gum arabic, tragacanth gum, erythrina gum, xanthan gum, sodium alginate, β-cyclodextrin, etc.

7. The bosutinib dry suspension according to claim 3, characterized in that, The flavoring agent is one or more of sucralose, aspartame, sodium saccharin, and stevioside.

8. A bosutinib dry suspension according to claim 3, characterized in that, The pH adjuster is one or more of acetic acid, tartaric acid, citric acid, lactic acid, etc.

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