A bosutinib dry suspension and a method of preparing the same
Patent Information
- Application Number
- CN202611450456.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-09-17
- Publication Date
- 2026-10-30
AI Technical Summary
而博舒替尼生物利用度低，且对温度和湿度敏感，稳定性和再分散性相对较差，这些因素限制了其作为干混悬剂的稳定性和应用效果
[0016]本发明提供了一种博舒替尼干混悬剂，包括以下重量份的原料：博舒替尼4~7份、蔗糖32~55份、乳糖38~58份、助悬剂1~2.5份、环糊精2~5份、羟丙甲纤维素0.5~3份、胶态二氧化硅1~3份、泊洛沙姆0.2~0.5份、香精0.2~2.5份和氧化铁红0.01~0.04份；所述助悬剂包括黄原胶、海藻酸钠和微晶纤维素羧甲纤维素钠共处理物，所述黄原胶、海藻酸钠和微晶纤维素羧甲纤维素钠共处理物的质量之比为（1.5~2）：（1~1.2）：（0.5~1）。本发明利用蔗糖作为填充剂；乳糖作为助流剂，改善博舒替尼干混悬剂的粉末流动性。本发明以黄原胶、海藻酸钠和微晶纤维素羧甲纤维素钠共处理物作为助悬剂，黄原胶的分子链呈刚性螺旋的棒状结构，具有高度的各向异性，能赋予博舒替尼干混悬剂体系良好的假塑性（摇变稀，静置变稠）；而海藻酸钠的分子链为柔性的无规线团，易于伸展和缠结；当博舒替尼干混悬剂复溶时，柔性的海藻酸钠长链可以缠绕在刚性的黄原胶螺旋棒上，形成一个互穿聚合物网络，这种结构大大增加了体系内的物理交联点，使得整个混合体系的机械强度和结构完整性远超单一组分；本发明添加了微晶纤维素羧甲纤维素钠共处理物，当博舒替尼干混悬剂复溶时，羧甲纤维素钠溶解，共处理物颗粒崩解，释放出大量细小的微晶纤维素粒子，这些微晶纤维素粒子与溶解的羧甲纤维素钠分子链、黄原胶和海藻酸钠形成的互穿聚合物网络共同构建了一个三维的胶体网状结构，提高博舒替尼干混悬剂复溶后体系的稳定性；故同时使用黄原胶、海藻酸钠和微晶纤维素羧甲纤维素钠共处理物不仅能够在博舒替尼干混悬剂复溶后增加体系的粘度以降低微粒的沉降速度，还能够阻碍微粒合并和絮凝，使复溶后的体系更稳定。本发明添加环糊精，利用环糊精的空腔包裹药物，通过“排挤”腔内的不稳定水分子来获得热力学稳定，并利用自身亲水的外壳使药物更易溶出；然而，这种包合是动态平衡的，药物分子可以进出空腔；本发明通过添加羟丙甲纤维素，能够在博舒替尼干混悬剂复溶时吸附在药物微粒的表面，形成一层亲水性的高分子膜；因此，本发明利用羟丙甲纤维素和环糊精配合使用，能够显著提高博舒替尼的溶出效果。本发明添加了胶态二氧化硅，使博舒替尼干混悬剂复溶后分散于液相中，辅助维持颗粒悬浮。本发明添加了泊洛沙姆，提高疏水性药物博舒替尼的润湿性。实施例结果显示，采用本发明提供的博舒替尼干混悬剂具有良好的溶出效果，复溶后的体系具有优异的分散稳定性。
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a bosutinib dry suspension and its preparation method. Background Technology
[0002] Bosutinib, as a tyrosine kinase inhibitor, can be used to treat Philadelphia chromosome-positive chronic myeloid leukemia. Currently, the main dosage form of bosutinib on the market is tablets, which are not suitable for patients with swallowing difficulties (such as children and elderly patients). Oral dry suspension is a special dosage form that combines the advantages of solid and liquid formulations. It is administered by shaking with water before taking, resulting in a smooth and non-jamming-prone delivery. It can even be administered through a nasogastric tube, which can solve the medication problem for patients who cannot swallow tablets.
[0003] Dry suspensions require drugs to have low solubility in water. Bosutinib has poor water solubility, making it a potential candidate for dry suspension formulation. However, dry suspensions also need to meet the requirements of "stable suspension, uniform dispersion, suitable taste, and no impact on drug absorption." Bosutinib, however, has low bioavailability, is sensitive to temperature and humidity, and exhibits relatively poor stability and redispersibility. These factors limit its stability and efficacy as a dry suspension.
[0004] Therefore, there is an urgent need to provide a bosutinib dry suspension with good resolution and dissolution effect and high system stability after resolution. Summary of the Invention
[0005] The purpose of this invention is to provide a bosutinib dry suspension with good reconstitution and high system stability after reconstitution, and its preparation method.
[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a bosutinib dry suspension, comprising the following raw materials in parts by weight: 4-7 parts bosutinib, 32-55 parts sucrose, 38-58 parts lactose, 1-2.5 parts suspending agent, 2-5 parts cyclodextrin, 0.5-3 parts hydroxypropyl methylcellulose, 1-3 parts colloidal silica, 0.2-0.5 parts poloxamer, 0.2-2.5 parts flavoring, and 0.01-0.04 parts iron oxide red; The suspending agent comprises a co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose, wherein the mass ratio of the co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose is (1.5~2):(1~1.2):(0.5~1).
[0007] Preferably, the raw materials include the following parts by weight: 4.17-6.17 parts bosutinib, 32.4-52.4 parts sucrose, 38-58 parts lactose, 1.25-2.25 parts suspending agent, 2-5 parts cyclodextrin, 0.5-3 parts hydroxypropyl methylcellulose, 1-3 parts colloidal silica, 0.2-0.5 parts poloxamer, 0.2-2.5 parts flavoring, and 0.01-0.04 parts iron oxide red; The suspending agent comprises a co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose, wherein the mass ratio of the co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose is (1.5~1.8):(1~1.1):(0.5~0.8).
[0008] Preferably, the raw materials include the following parts by weight: 5.17-6.17 parts bosutinib, 42.4-52.4 parts sucrose, 48-58 parts lactose, 1.25-2 parts suspending agent, 3-5 parts cyclodextrin, 0.655-2.5 parts hydroxypropyl methylcellulose, 2-3 parts colloidal silica, 0.3-0.5 parts poloxamer, 0.5-2.5 parts flavoring, and 0.025-0.04 parts iron oxide red; The suspending agent comprises a co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose, wherein the mass ratio of the co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose is (1.5~1.8):(1~1.1):(0.5~0.8).
[0009] Preferably, the raw materials include the following parts by weight: 5.17 parts bosutinib, 42.4 parts sucrose, 48 parts lactose, 1.25 parts suspending agent, 3 parts cyclodextrin, 0.655 parts hydroxypropyl methylcellulose, 2 parts colloidal silica, 0.3 parts poloxamer, 0.5 parts flavoring, and 0.025 parts iron oxide red; The suspending agent comprises a co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose, wherein the mass ratio of the co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose is 1.5:1:0.5.
[0010] Preferably, the viscosity of the hydroxypropyl methylcellulose is 2600~5600 cp.
[0011] Preferably, the viscosity of the microcrystalline cellulose sodium carboxymethyl cellulose co-treated product is 39~118 mpa·s.
[0012] Preferably, the particle size of the colloidal silica is 10~500nm.
[0013] This invention also provides a method for preparing the bosutinib dry suspension described in the above technical solution, comprising: Bosutinib and lactose were premixed to obtain a premix; Sucrose, xanthan gum, sodium alginate, sodium carboxymethyl cellulose co-treated product, colloidal silica, cyclodextrin, hydroxypropyl methylcellulose, poloxamer, flavoring, and iron oxide red are mixed with the premix to obtain bosutinib dry suspension.
[0014] Preferably, the particle size of the bosutinib, lactose, sucrose, sodium alginate, cyclodextrin, hydroxypropyl methylcellulose, poloxamer, flavoring, and iron oxide red is independently D90 ≤ 35 μm.
[0015] Preferably, the premixing speed is 5~15 r / min and the premixing time is 5~20 min; the mixing speed is 5~15 r / min and the mixing time is 5~15 min.
[0016] This invention provides a bosutinib dry suspension comprising the following raw materials in parts by weight: 4-7 parts bosutinib, 32-55 parts sucrose, 38-58 parts lactose, 1-2.5 parts suspending agent, 2-5 parts cyclodextrin, 0.5-3 parts hydroxypropyl methylcellulose, 1-3 parts colloidal silica, 0.2-0.5 parts poloxamer, 0.2-2.5 parts flavoring, and 0.01-0.04 parts iron oxide red. The suspending agent comprises a co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose from microcrystalline cellulose, wherein the mass ratio of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose from microcrystalline cellulose is (1.5-2):(1-1.2):(0.5-1). This invention utilizes sucrose as a filler and lactose as a flow aid to improve the powder flowability of the bosutinib dry suspension. This invention uses a co-treated compound of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose as a suspending agent. Xanthan gum has a rigid helical rod-like molecular chain with high anisotropy, which imparts good pseudoplasticity (thinning upon shaking, thickening upon standing) to the bosutinib dry suspension system. Sodium alginate, on the other hand, has flexible random coils that easily stretch and entangle. When the bosutinib dry suspension is reconstituted, the flexible sodium alginate chains can wrap around the rigid xanthan gum helical rods, forming an interpenetrating polymer network. This structure greatly increases the physical cross-linking points within the system, making the mechanical strength and structural integrity of the entire mixture far exceed that of a single component. This invention also incorporates microcrystalline fibers. When bosutinib dry suspension is reconstituted, the sodium carboxymethyl cellulose co-treatment compound dissolves, causing the co-treatment particles to disintegrate and release a large number of fine microcrystalline cellulose particles. These microcrystalline cellulose particles, together with the dissolved sodium carboxymethyl cellulose molecular chains, xanthan gum, and sodium alginate forming an interpenetrating polymer network, construct a three-dimensional colloidal network structure, improving the stability of the system after bosutinib dry suspension reconstitution. Therefore, the simultaneous use of xanthan gum, sodium alginate, and microcrystalline cellulose sodium carboxymethyl cellulose co-treatment compound not only increases the viscosity of the system after bosutinib dry suspension reconstitution to reduce the sedimentation rate of particles, but also inhibits particle aggregation and flocculation, making the reconstituted system more stable. This invention incorporates cyclodextrin, utilizing its cavities to encapsulate the drug and achieve thermodynamic stability by "displacing" unstable water molecules within the cavity. Its hydrophilic shell also facilitates drug dissolution. However, this inclusion is in dynamic equilibrium, allowing drug molecules to enter and exit the cavity. The invention also incorporates hydroxypropyl methylcellulose, which adsorbs onto the surface of drug particles during the reconstitution of bosutinib dry suspension, forming a hydrophilic polymer film. Therefore, the combined use of hydroxypropyl methylcellulose and cyclodextrin significantly improves the dissolution of bosutinib. Colloidal silica is added to disperse the bosutinib dry suspension in the liquid phase after reconstitution, aiding in maintaining particle suspension. Poloxamer is added to improve the wettability of the hydrophobic drug bosutinib.The results of the examples show that the bosutinib dry suspension provided by the present invention has a good dissolution effect, and the reconstituted system has excellent dispersion stability. Detailed Implementation
[0017] This invention provides a bosutinib dry suspension, comprising the following raw materials in parts by weight: 4-7 parts bosutinib, 32-55 parts sucrose, 38-58 parts lactose, 1-2.5 parts suspending agent, 2-5 parts cyclodextrin, 0.5-3 parts hydroxypropyl methylcellulose, 1-3 parts colloidal silica, 0.2-0.5 parts poloxamer, 0.2-2.5 parts flavoring, and 0.01-0.04 parts iron oxide red; The suspending agent comprises a co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose, wherein the mass ratio of the co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose is (1.5~2):(1~1.2):(0.5~1).
[0018] Unless otherwise specified, the raw materials used in this invention can be any commercially available products well known to those skilled in the art.
[0019] The bosutinib dry suspension provided by this invention comprises 4 to 7 parts by weight of bosutinib. As an embodiment of this invention, the weight of bosutinib can be 4.17 parts, 5 parts, 5.17 parts, 6 parts, 6.17 parts, 6.5 parts, or 7 parts. This invention utilizes bosutinib as the pharmaceutical component of the bosutinib dry suspension. This invention does not specifically limit the source of the bosutinib; any conventional commercially available product can be used.
[0020] Based on a bosutinib weight ratio of 4-7 parts, the bosutinib dry suspension provided by this invention comprises 32-55 parts sucrose. As an embodiment of this invention, the weight ratio of the sucrose can be 32.4 parts, 33 parts, 34 parts, 35 parts, 36 parts, 37 parts, 38 parts, 39 parts, 40 parts, 4.24 parts, 43 parts, 44 parts, 45 parts, 46 parts, 47 parts, 48 parts, 49 parts, or 50 parts. In this invention, the sucrose serves as a filler.
[0021] Based on a weight percentage of 4-7 parts of bosutinib, the bosutinib dry suspension provided by this invention comprises 38-58 parts of lactose. As an embodiment of this invention, the weight percentage of lactose can be 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, or 58 parts. This invention utilizes lactose as a flow aid to improve the powder flowability of the bosutinib dry suspension. In embodiments of this invention, the lactose can be SuperTab 24AN. This invention does not have a specific limitation on the source of the lactose; any conventional commercially available product can be used.
[0022] Based on a weight ratio of 4-7 parts of bosutinib, the bosutinib dry suspension provided by this invention includes 1-2.5 parts of a suspending agent. As an embodiment of this invention, the weight ratio of the suspending agent can be 1 part, 1.1 parts, 1.15 parts, 1.2 parts, 1.25 parts, 1.3 parts, 1.35 parts, 1.4 parts, 1.45 parts, 1.5 parts, 1.55 parts, 1.6 parts, 1.65 parts, 1.7 parts, 1.75 parts, 1.8 parts, 1.85 parts, 1.9 parts, 1.95 parts, 2 parts, 2.15 parts, 2.25 parts, or 2.5 parts.
[0023] In this invention, the suspending agent comprises a co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose (CCMC). In this invention, the viscosity of the co-treated product of microcrystalline cellulose (CCMC) is preferably 39-118 mPa·s, more preferably 50-100 mPa·s. This invention uses a co-treated product of xanthan gum, sodium alginate, and microcrystalline cellulose (CCMC) as the suspending agent. Xanthan gum has a rigid helical rod-like molecular chain with high anisotropy, which imparts good pseudoplasticity (thinning upon shaking, thickening upon standing) to the bosutinib dry suspension system. Sodium alginate, on the other hand, has flexible random coils that are easy to stretch and entangle. When the bosutinib dry suspension is reconstituted, the flexible sodium alginate chains can wrap around the rigid xanthan gum helical rods, forming an interpenetrating polymer network. This structure greatly increases the physical cross-linking points within the system, making the mechanical strength and structural integrity of the entire mixture far exceed that of a single component. This invention adds microcrystalline... The sodium carboxymethyl cellulose co-treated compound, when reconstituted with bosutinib dry suspension, causes the sodium carboxymethyl cellulose to dissolve, and the co-treated compound particles to disintegrate, releasing a large number of fine microcrystalline cellulose particles. These microcrystalline cellulose particles, together with the dissolved sodium carboxymethyl cellulose molecular chains, xanthan gum, and sodium alginate forming an interpenetrating polymer network, construct a three-dimensional colloidal network structure, improving the stability of bosutinib dry suspension. Therefore, the simultaneous use of xanthan gum, sodium alginate, and the sodium carboxymethyl cellulose co-treated compound not only increases the viscosity of the system after reconstitution of bosutinib dry suspension to reduce the sedimentation rate of particles, but also inhibits particle aggregation and flocculation, making the reconstituted system more stable. In the embodiments of the present invention, the sodium carboxymethyl cellulose co-treated compound can be TOMOLLOSE® TM591 or TOMOLLOSE® TM611, and can be sourced from Zhuhai Dongchen Pharmaceutical Co., Ltd.
[0024] In this invention, the mass ratio of the co-treated xanthan gum, sodium alginate, and sodium carboxymethyl cellulose is (1.5~2):(1~1.2):(0.5~1), preferably (1.5~1.8):(1~1.1):(0.5~0.8), more preferably (1.5~1.8):(1~1.1):(0.5~0.8), and even more preferably 1.5:1:0.5. By controlling the mass ratio of the co-treated xanthan gum, sodium alginate, and sodium carboxymethyl cellulose within the above range, this invention enables the system obtained after reconstitution of bosutinib dry suspension to exhibit excellent stability.
[0025] Based on a weight percentage of 4-7 parts of bosutinib, the bosutinib dry suspension provided by this invention comprises 2-5 parts of cyclodextrin. As an embodiment of this invention, the weight percentage of the cyclodextrin can be 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, or 5 parts. This invention utilizes the cavity of cyclodextrin to encapsulate the drug, achieving thermodynamic stability by "displacing" unstable water molecules within the cavity, and utilizing its hydrophilic shell to facilitate drug dissolution.
[0026] Based on a bosutinib weight ratio of 4-7 parts, the bosutinib dry suspension provided by this invention includes 0.5-3 parts of hydroxypropyl methylcellulose. As an embodiment of this invention, the weight ratio of the hydroxypropyl methylcellulose can be 0.5 parts, 0.6 parts, 0.655 parts, 0.7 parts, 0.75 parts, 0.8 parts, 0.9 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, or 3 parts.
[0027] In this invention, the viscosity of the hydroxypropyl methylcellulose is preferably 2600-5600 cp. In embodiments of this invention, the hydroxypropyl methylcellulose may be sourced from Merck. Using hydroxypropyl methylcellulose of the above viscosity allows for its use in combination with cyclodextrin, improving the dissolution effect of bosutinib and thus enhancing its bioavailability.
[0028] The bosutinib dry suspension provided by this invention comprises 1-3 parts colloidal silica, based on a weight ratio of 4-7 parts of bosutinib. As an embodiment of this invention, the weight ratio of the colloidal silica can be 1 part, 1.5 parts, 2 parts, 2.5 parts, or 3 parts. In this invention, the particle size of the colloidal silica is preferably 10-500 nm. As an embodiment of this invention, the particle size of the colloidal silica can be 10 nm, 50 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, or 500 nm. This invention adds colloidal silica to disperse the bosutinib dry suspension in the liquid phase after reconstitution, helping to maintain the suspension of drug particles. This invention does not have a specific limitation on the source of the colloidal silica; conventional commercially available products can be used. In an embodiment of this invention, the colloidal silica can be sourced from Hubei Huifu Nanomaterials Co., Ltd.
[0029] Based on a weight percentage of 4-7 parts of bosutinib, the bosutinib dry suspension provided by this invention includes 0.2-0.5 parts of poloxamer. As an embodiment of this invention, the weight percentage of poloxamer can be 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, or 0.5 parts. This invention adds poloxamer to improve the wettability of the hydrophobic drug bosutinib.
[0030] Based on a weight percentage of 4-7 parts of bosutinib, the bosutinib dry suspension provided by this invention includes 0.2-2.5 parts of flavoring. As an embodiment of this invention, the weight percentage of the flavoring can be 0.2 parts, 1 part, 1.25 parts, 1.5 parts, 2 parts, 2.25 parts, or 2.5 parts. In this invention, the flavoring is preferably strawberry flavoring. This invention adds flavoring as a taste-correcting agent, which, after reconstitution with water, masks the unpleasant odor and bitterness of the drug.
[0031] Based on a bosutinib weight ratio of 4-7 parts, the bosutinib dry suspension provided by this invention includes 0.01-0.04 parts of iron oxide red. As an embodiment of this invention, the weight ratio of the iron oxide red can be 0.01, 0.02, 0.03, or 0.04 parts. This invention adds iron oxide red as a colorant, imparting a red appearance to the dry powder or the reconstituted liquid.
[0032] This invention also provides a method for preparing the bosutinib dry suspension described in the above technical solution, comprising: Bosutinib and lactose were premixed to obtain a premix; Sucrose, xanthan gum, sodium alginate, sodium carboxymethyl cellulose co-treated product, colloidal silica, cyclodextrin, hydroxypropyl methylcellulose, poloxamer, flavoring, and iron oxide red are mixed with the premix to obtain bosutinib dry suspension.
[0033] This invention involves premixing bosutinib and lactose to obtain a premix.
[0034] Preferably, before premixing bosutinib and lactose, the present invention screens bosutinib, lactose, sucrose, sodium alginate, cyclodextrin, hydroxypropyl methylcellulose, poloxamer, flavoring and iron oxide red, and the particle size of each raw material is independently D90≤35μm.
[0035] In this invention, the preferred premixing speed is 5-15 r / min, and the preferred premixing time is 5-20 min. As an embodiment of this invention, the premixing speed can be 5 r / min, 6 r / min, 7 r / min, 8 r / min, 9 r / min, 10 r / min, 11 r / min, 12 r / min, 13 r / min, 14 r / min, or 15 r / min; and the premixing time can be 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, 16 min, 17 min, 18 min, 19 min, or 20 min. This invention, by premixing bosutinib and lactose, facilitates the thorough dispersion of bosutinib when mixed with other ingredients.
[0036] After obtaining the premix, the present invention mixes sucrose, xanthan gum, sodium alginate, sodium carboxymethyl cellulose co-treated product, colloidal silica, cyclodextrin, hydroxypropyl methylcellulose, poloxamer, flavoring and iron oxide red with the premix to obtain bosutinib dry suspension.
[0037] In this invention, the mixing speed is preferably 5-15 r / min, and the mixing time is preferably 5-15 min. As an embodiment of this invention, the mixing speed can be 5 r / min, 6 r / min, 7 r / min, 8 r / min, 9 r / min, 10 r / min, 11 r / min, 12 r / min, 13 r / min, 14 r / min, or 15 r / min; and the mixing time can be 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min, or 15 min. This invention, through mixing, enables the components to be mixed uniformly.
[0038] The present invention preferably involves packaging the mixed materials separately to obtain bosutinib dry suspension.
[0039] The preparation method provided by this invention is simple and can produce a bosutinib dry suspension with uniform particle size distribution and excellent dispersibility after reconstitution.
[0040] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.
[0041] Example 1 A bosutinib dry suspension is composed of the following raw materials in parts by weight: 5.17 parts bosutinib, 42.4 parts sucrose, 48 parts lactose (SuperTab 24AN), 1.25 parts suspending agent, 3 parts cyclodextrin, 0.655 parts hydroxypropyl methylcellulose, 2 parts colloidal silica, 0.3 parts poloxamer, 0.5 parts strawberry flavoring, and 0.025 parts iron oxide red; The suspending agent is a co-processed compound of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose (TOMOLLOSE® TM591), and the mass ratio of the co-processed compound of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose is 1.5:1:0.5.
[0042] The preparation method of the bosutinib dry suspension is as follows: Bosutinib, lactose, sucrose, sodium alginate, cyclodextrin, hydroxypropyl methylcellulose, poloxamer, strawberry flavoring, and iron oxide red were sieved to ensure that the particle size D90 of each raw material was ≤35μm. Bosutinib and lactose were then added to a three-dimensional motion mixer and premixed at 15r / min for 15min to obtain a premix. Sucrose, xanthan gum, sodium alginate, sodium carboxymethyl cellulose co-processed product, colloidal silica, cyclodextrin, hydroxypropyl methylcellulose, poloxamer, flavoring, and iron oxide red were added into a three-dimensional motion mixer and mixed at 15 r / min for 10 min. The uniformly mixed material was then packaged to obtain bosutinib dry suspension.
[0043] The test results of the bosutinib dry suspension prepared in this embodiment are shown in Table 1: Table 1. Test results of the bosutinib dry suspension prepared in Example 1
[0044] Dissolution curves of the bosutinib dry suspension prepared in this embodiment were determined using four media. The dissolution media were pH 1.0 hydrochloric acid solution, pH 6.8 phosphate buffer solution, water, and pH 4.5 acetate buffer solution. The dissolution method was paddle dispensing at 50 rpm, 900 mL, and 37°C. The sample was added as a suspension. The dissolution test results for pH 1.0 hydrochloric acid solution, pH 4.5 acetate buffer solution, pH 6.8 phosphate buffer solution, and water are shown in Tables 2-5, respectively.
[0045] Table 2 Dissolution curves - pH 1.0 hydrochloric acid solution
[0046] As shown in Table 2, the cumulative dissolution rate of bosutinib dry suspension in hydrochloric acid solution at pH 1.0 is >94% within 5 minutes, indicating very rapid dissolution and good intra-batch homogeneity.
[0047] Table 3 Dissolution curves - pH 4.5 acetate buffer
[0048] As shown in Table 3, the cumulative dissolution rate of bosutinib dry suspension in acetate medium at pH 4.5 is >85% after 30 minutes, indicating complete dissolution, rapid dissolution, and good intra-batch homogeneity.
[0049] Table 4 Dissolution curves - pH 6.8 phosphate buffer
[0050] As shown in Table 4, the cumulative dissolution rate of bosutinib dry suspension in pH 6.8 phosphate buffer medium was 7.2% after 120 min, which is a relatively small amount of dissolution.
[0051] Table 5 Dissolution curves - Aqueous medium
[0052] As shown in Table 5, the cumulative dissolution rate of bosutinib dry suspension in aqueous medium after 120 min is 3.9%, which is less than 5%, indicating almost no dissolution.
[0053] Example 2 A bosutinib dry suspension is composed of the following raw materials in parts by weight: 5.17 parts bosutinib, 47.4 parts sucrose, 43 parts lactose, 1.35 parts suspending agent, 3 parts cyclodextrin, 0.555 parts hydroxypropyl methylcellulose, 2 parts colloidal silica, 0.4 parts poloxamer, 0.5 parts strawberry flavoring, and 0.035 parts iron oxide red; The suspending agent is a co-processed compound of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose (TOMOLLOSE® TM611), and the mass ratio of the co-processed compound of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose is 1.5:1:0.5.
[0054] The preparation method of the bosutinib dry suspension: Bosutinib, lactose, sucrose, sodium alginate, cyclodextrin, hydroxypropyl methylcellulose, poloxamer, strawberry flavoring, and iron oxide red were sieved to ensure that the particle size D90 of each raw material was ≤35μm. Bosutinib and lactose were then added to a three-dimensional motion mixer and premixed at 10r / min for 10min to obtain a premix. Sucrose, xanthan gum, sodium alginate, sodium carboxymethyl cellulose co-processed product, colloidal silica, cyclodextrin, hydroxypropyl methylcellulose, poloxamer, flavoring, and iron oxide red were added into a three-dimensional motion mixer and mixed at 10 r / min for 8 min. The uniformly mixed material was then packaged to obtain bosutinib dry suspension.
[0055] The test results of the bosutinib dry suspension prepared in this embodiment are shown in Table 6: Table 6 Test results of the bosutinib dry suspension prepared in Example 2
[0056] Dissolution curves of the bosutinib dry suspension prepared in this embodiment were determined using four media. The dissolution media were pH 1.0 hydrochloric acid solution, pH 6.8 phosphate buffer solution, water, and pH 4.5 acetate buffer solution. The dissolution method was a paddle method at 50 rpm, 900 mL, and 37°C. The sample was added as a suspension. The dissolution test results for pH 1.0 hydrochloric acid solution, pH 4.5 acetate buffer solution, pH 6.8 phosphate buffer solution, and water are shown in Tables 7-10, respectively.
[0057] Table 7 Dissolution curves - pH 1.0 hydrochloric acid solution
[0058] As shown in Table 7, the cumulative dissolution rate of bosutinib dry suspension in hydrochloric acid solution at pH 1.0 is >95% within 5 minutes, indicating very rapid dissolution and good intra-batch homogeneity.
[0059] Table 8 Dissolution curves - pH 4.5 acetate buffer
[0060] As shown in Table 8, the cumulative dissolution rate of bosutinib dry suspension in acetate medium at pH 4.5 is >85% after 30 minutes, indicating complete dissolution, rapid dissolution, and good intra-batch homogeneity.
[0061] Table 9 Dissolution curves - pH 6.8 phosphate buffer
[0062] As shown in Table 9, the cumulative dissolution rate of bosutinib dry suspension in pH 6.8 phosphate buffer medium was 6.9% after 120 min, which is a relatively small amount of dissolution.
[0063] Table 10 Dissolution curves - Aqueous medium
[0064] As shown in Table 10, the cumulative dissolution rate of bosutinib dry suspension in aqueous medium after 120 min is 3.9%, which is less than 5%, indicating almost no dissolution.
[0065] Comparative Example 1 A bosutinib dry suspension is composed of the following raw materials in parts by weight: 5.17 parts bosutinib, 73.25 parts sucrose, 10 parts xanthan gum, 5 parts hydroxypropyl methylcellulose, 4 parts sodium citrate, 2 parts colloidal silica, 0.5 parts strawberry flavoring, and 0.08 parts iron oxide red.
[0066] The preparation method of the bosutinib dry suspension is as follows: Bosutinib, sucrose, and sodium citrate were sieved separately to ensure that the D90 of the pulverized bosutinib was ≤35μm, the pulverized sucrose was sieved through an 80-mesh sieve, and the pulverized sodium citrate was sieved through an 80-mesh sieve. Bosutinib and sucrose were then put into a three-dimensional motion mixer and premixed at a speed of 10r / min for 15min to obtain a premix. Take colloidal silica, pass it through a 50-mesh sieve, and add it to a three-dimensional motion mixer and mix for 5 minutes. Then add strawberry flavoring, xanthan gum, hydroxypropyl methylcellulose, and sodium citrate and mix for 3 minutes. Finally, add iron oxide red and mix for 3 minutes. Dispense the well-mixed material into individual containers to obtain bosutinib dry suspension.
[0067] Table 11 Test results of bosutinib dry suspension prepared in Comparative Example 1
[0068] Table 12 Test results of the mixing uniformity of the bosutinib dry suspension prepared in Comparative Example 1
[0069] As shown in Tables 11 and 12, the uniformity RSD of the bosutinib dry suspension prepared in Comparative Example 1 is <2%, indicating good uniformity. This batch, however, exhibits poor flowability and an unacceptable sedimentation volume ratio.
[0070] Comparative Example 2 A bosutinib dry suspension is composed of the following raw materials in parts by weight: 5.17 parts bosutinib, 48.00 parts lactose, 42.40 parts sucrose, 1.25 parts xanthan gum, 0.62 parts hydroxypropyl methylcellulose, 2 parts colloidal silica, 0.5 parts strawberry flavoring, and 0.08 parts iron oxide red.
[0071] The preparation method of the bosutinib dry suspension adopts the following two mixing methods: Method 1: Weighing and pretreatment: Weigh according to the prescription amount. Pulverize bosutinib (D90≤20μm) and pulverize sucrose, then pass through an 80-mesh sieve. Premix: Take bosutinib and lactose and mix them through a 50-mesh sieve for 5 minutes to obtain premix powder 1; Intermediate mixing: Take a portion of sucrose, iron oxide red, and hydroxypropyl methylcellulose and sieve and mix them; then take the remaining sucrose, xanthan gum, and strawberry flavoring and sieve and mix them to obtain premix powder 2; mix premix powder 1 and premix powder 2 for 15 minutes to obtain mixed powder; Total mixing: Take a portion of the powder and mix it with colloidal silica through a sieve, then mix it with the remaining powder for 5 minutes.
[0072] Method 2: Wet granulation process Weighing and pretreatment: Weigh according to the prescription amount. Pulverize bosutinib (D90≤35μm) and pulverize sucrose, then pass through an 80-mesh sieve. Adhesive solution: Weigh purified water and hydroxypropyl methylcellulose, stir and dissolve to obtain adhesive; Premix: Sift together lactose and bosutinib to obtain premixed powder. Mix the premixed powder with sucrose and xanthan gum in a multi-functional food processor for 2 minutes to obtain powder mix. Granulation: Add binder to the powder mixture and granulate for 40 seconds; Drying: Electric hot air drying oven at 50℃; Granulation: 24 mesh sieve; Medium mixing: After granulation, the particles are sieved and mixed with colloidal silica for 3 minutes; General mixing: Add strawberry flavoring and red iron oxide, sieve and mix for 5 minutes.
[0073] The prescription results are shown in Table 13.
[0074] Table 13 Results of Formulation Testing for Preparation Process – Flowability, Sedimentation Volume Ratio
[0075] Table 14 Results of Mixing Uniformity Assessment During Preparation Process
[0076] The results in Tables 13 and 14 show that the RSD of the mixing uniformity of both batches is <2%, indicating good uniformity. The wet granulation process produces a product with poor dispersibility.
[0077] Comparative Example 3 A bosutinib dry suspension is composed of the following raw materials in parts by weight: 5.17 parts bosutinib, 42.4 parts sucrose, 48 parts lactose (SuperTab 24AN), 1.25 parts suspending agent, 3 parts cyclodextrin, 0.655 parts hydroxypropyl methylcellulose, 2 parts colloidal silica, 0.3 parts poloxamer, 0.5 parts strawberry flavoring, and 0.025 parts iron oxide red; The suspending agent is xanthan gum and sodium alginate, and the mass ratio of xanthan gum to sodium alginate is 1.5:1.
[0078] The preparation method of the bosutinib dry suspension differs from that of Example 1 in that no microcrystalline cellulose sodium carboxymethyl cellulose co-treatment product is added; the remaining steps are the same as in Example 1.
[0079] Comparative Example 4 A bosutinib dry suspension is composed of the following raw materials in parts by weight: 5.17 parts bosutinib, 42.4 parts sucrose, 48 parts lactose (SuperTab 24AN), 1.25 parts suspending agent, 3 parts cyclodextrin, 0.655 parts hydroxypropyl methylcellulose, 2 parts colloidal silica, 0.3 parts poloxamer, 0.5 parts strawberry flavoring, and 0.025 parts iron oxide red; The suspending agent is a co-treated product of sodium alginate and sodium carboxymethyl cellulose (TOMOLLOSE®™ 591), with a mass ratio of sodium alginate to sodium carboxymethyl cellulose in the form of 1:0.5.
[0080] The preparation method of the bosutinib dry suspension differs from that of Example 1 in that xanthan gum is not added, while the remaining steps are the same as in Example 1.
[0081] Comparative Example 5 A bosutinib dry suspension is composed of the following raw materials in parts by weight: 5.17 parts bosutinib, 42.4 parts sucrose, 48 parts lactose (SuperTab 24AN), 1.25 parts suspending agent, 3 parts cyclodextrin, 0.655 parts hydroxypropyl methylcellulose, 2 parts colloidal silica, 0.3 parts poloxamer, 0.5 parts strawberry flavoring, and 0.025 parts iron oxide red; The suspending agent is a co-treated product of xanthan gum and sodium carboxymethyl cellulose (TOMOLLOSE®™ 591), with a mass ratio of xanthan gum to sodium carboxymethyl cellulose in the form of 1.5:0.5.
[0082] The preparation method of the bosutinib dry suspension differs from that of Example 1 in that sodium alginate is not added, while the remaining steps are the same as in Example 1.
[0083] The test results of the bosutinib dry suspensions prepared in Comparative Examples 3-5 are shown in Table 15.
[0084] Table 15 Dissolution curves of bosutinib dry suspensions prepared in Comparative Examples 3-5 - pH 1.0 hydrochloric acid solution test results
[0085] The results above show that when only two of the xanthan gum, sodium alginate, and sodium carboxymethyl cellulose co-treatment compounds are added, the stability and dissolution effect of the resulting bosutinib dry suspension are significantly lower than those of the bosutinib dry suspension prepared in Example 1. This is because the synergistic effect among xanthan gum, sodium alginate, and sodium carboxymethyl cellulose improves the stability and dissolution effect of the bosutinib dry suspension.
[0086] Comparative Example 6 A bosutinib dry suspension is composed of the following raw materials in parts by weight: 5.17 parts bosutinib, 42.4 parts sucrose, 48 parts lactose, 1.25 parts suspending agent, 3 parts cyclodextrin, 2 parts colloidal silica, 0.3 parts poloxamer, 0.5 parts strawberry flavoring and 0.025 parts iron oxide red; The suspending agent is a co-processed compound of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose (TOMOLLOSE® TM591), and the mass ratio of the co-processed compound of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose is 1.5:1:0.5.
[0087] The preparation method of the bosutinib dry suspension differs from that of the example in that hydroxypropyl methylcellulose is not added, while the remaining steps are the same as in Example 1.
[0088] The test results of the bosutinib dry suspension prepared in this comparative example are shown in Table 16.
[0089] Table 16 Dissolution curves of bosutinib dry suspension prepared in Comparative Example 6 - pH 1.0 hydrochloric acid solution test results
[0090] The results above show that the stability and dissolution of the bosutinib dry suspension obtained without the addition of hydroxypropyl methylcellulose are higher than those of Comparative Example 5, but lower than those of the bosutinib dry suspension prepared in Example 1. This is because the ability of cyclodextrin to improve the stability and dissolution of the bosutinib dry suspension is limited when used alone; it needs to be used in combination with hydroxypropyl methylcellulose to fully improve the stability and dissolution of the bosutinib dry suspension.
[0091] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A bosutinib dry suspension, characterized in that, The ingredients include the following parts by weight: 4-7 parts bosutinib, 32-55 parts sucrose, 38-58 parts lactose, 1-2.5 parts suspending agent, 2-5 parts cyclodextrin, 0.5-3 parts hydroxypropyl methylcellulose, 1-3 parts colloidal silica, 0.2-0.5 parts poloxamer, 0.2-2.5 parts flavoring, and 0.01-0.04 parts iron oxide red; The suspending agent comprises a co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose, wherein the mass ratio of the co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose is (1.5~2):(1~1.2):(0.5~1).
2. The bosutinib dry suspension according to claim 1, characterized in that, The ingredients include the following parts by weight: 4.17-6.17 parts bosutinib, 32.4-52.4 parts sucrose, 38-58 parts lactose, 1.25-2.25 parts suspending agent, 2-5 parts cyclodextrin, 0.5-3 parts hydroxypropyl methylcellulose, 1-3 parts colloidal silica, 0.2-0.5 parts poloxamer, 0.2-2.5 parts flavoring, and 0.01-0.04 parts iron oxide red; The suspending agent comprises a co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose, wherein the mass ratio of the co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose is (1.5~1.8):(1~1.1):(0.5~0.8).
3. The bosutinib dry suspension according to claim 1, characterized in that, The ingredients include the following parts by weight: 5.17-6.17 parts bosutinib, 42.4-52.4 parts sucrose, 48-58 parts lactose, 1.25-2 parts suspending agent, 3-5 parts cyclodextrin, 0.655-2.5 parts hydroxypropyl methylcellulose, 2-3 parts colloidal silica, 0.3-0.5 parts poloxamer, 0.5-2.5 parts flavoring, and 0.025-0.04 parts iron oxide red; The suspending agent comprises a co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose, wherein the mass ratio of the co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose is (1.5~1.8):(1~1.1):(0.5~0.8).
4. The bosutinib dry suspension according to claim 1, characterized in that, The ingredients include the following parts by weight: 5.17 parts bosutinib, 42.4 parts sucrose, 48 parts lactose, 1.25 parts suspending agent, 3 parts cyclodextrin, 0.655 parts hydroxypropyl methylcellulose, 2 parts colloidal silica, 0.3 parts poloxamer, 0.5 parts flavoring and 0.025 parts iron oxide red; The suspending agent comprises a co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose, wherein the mass ratio of the co-treated product of xanthan gum, sodium alginate, and sodium carboxymethyl cellulose is 1.5:1:0.
5.
5. The bosutinib dry suspension according to any one of claims 1 to 4, characterized in that, The viscosity of the hydroxypropyl methylcellulose is 2600~5600cp.
6. The bosutinib dry suspension according to any one of claims 1 to 4, characterized in that, The viscosity of the microcrystalline cellulose sodium carboxymethyl cellulose co-treated product is 39~118 mpa·s.
7. The bosutinib dry suspension according to any one of claims 1 to 4, characterized in that, The colloidal silica has a particle size of 10~500nm.
8. The method for preparing the bosutinib dry suspension according to any one of claims 1 to 7, characterized in that, include: Bosutinib and lactose were premixed to obtain a premix; Sucrose, xanthan gum, sodium alginate, sodium carboxymethyl cellulose co-treated product, colloidal silica, cyclodextrin, hydroxypropyl methylcellulose, poloxamer, flavoring, and iron oxide red are mixed with the premix to obtain bosutinib dry suspension.
9. The preparation method according to claim 8, characterized in that, The particle size of the bosutinib, lactose, sucrose, sodium alginate, cyclodextrin, hydroxypropyl methylcellulose, poloxamer, flavoring, and iron oxide red is independently D90 ≤ 35 μm.
10. The preparation method according to claim 8, characterized in that, The premixing speed is 5~15 r / min, and the premixing time is 5~20 min; the mixing speed is 5~15 r / min, and the mixing time is 5~15 min.