CN109820828A - Nilotinib liquid-solid compression tablet and preparation method thereof - Google Patents
Nilotinib liquid-solid compression tablet and preparation method thereof Download PDFInfo
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- CN109820828A CN109820828A CN201711179376.3A CN201711179376A CN109820828A CN 109820828 A CN109820828 A CN 109820828A CN 201711179376 A CN201711179376 A CN 201711179376A CN 109820828 A CN109820828 A CN 109820828A
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- nilotinib
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- compression tablet
- solid compression
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Abstract
The invention discloses a kind of nilotinib liquid-solid compression tablets and preparation method thereof.The nilotinib liquid-solid compression tablet contains the nilotinib of effective dose, also contain liquid excipient, carrier material and coating material, the mass ratio of the nilotinib and the liquid excipient is 1:2~1:4, the mass ratio of the liquid excipient and the carrier material is 0.3~0.5, the mass ratio of the carrier material and the coating material is 10:1~30:1, and the liquid excipient is one of glyceride type, double alcohols or pyrrolidinone compounds solvent or a variety of.The present invention effectively increases the dissolution rate and bioavilability of nilotinib, and preparation method is easy, without using special installation, is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of nilotinib liquid-solid compression tablets and preparation method thereof.
Background technique
Nilotinib is a kind of novel targeting therapy for tumor drug, belongs to tyrosine kinase inhibitor, for treatment pair
Chronic granulocytic leukemia (the Chronic Myeloid Leukemia CML) patient of imatinib-resistant, nilotinib pair
Philadelphia chromosome Bcr-Abl has higher affinity and specificity than Imatinib, in June, 2010 by U.S.'s food and medicine
Surveillance Authority's (Food and Drug Administration, FDA) official approval is used for the first-line treatment of CML, in 2009
November in year lists at home, trade name Tasigna, Chinese trade name Da Xina, and the dosage that clinic is recommended is to take orally daily twice,
Each 400mg, relative molecular mass 565.98, CAS registration number are 923288-90-8, and structural formula is as follows:
Nilotinib is a kind of drug of low dissolution hyposmosis, belongs to BCS IV class, 0.2 μ g/ of solubility in water
ml.Liquid consolidates compress technique system for insoluble drug, dissolves or is dispersed in certain non-volatile solvents, then selects suitably
Carrier material and coating material will contain drug solns absorption, the powder with certain fluidity and compressibility be made, for being prepared into
The solid pharmaceutical preparations such as tablet, capsule improve dissolution rate and dissolution rate so as to improve the solubility of drug, and then improve drug
Bioavilability.
Summary of the invention
Technical problem to be solved by the present invention lies in overcome nilotinib low-solubility in the prior art, low-permeability
Defect provides nilotinib liquid-solid compression tablet and preparation method thereof, substantially increases its dissolution rate and bioavilability.
The present invention provides a kind of nilotinib liquid-solid compression tablet, the nilotinib containing effective dose, the Ni Luo is replaced
Buddhist nun's liquid-solid compression tablet also contains liquid excipient, carrier material and coating material, the nilotinib and the liquid excipient
Mass ratio be 1:2~1:4, the mass ratio of the liquid excipient and the carrier material is 0.3~0.5, the carrier material
The mass ratio of material and the coating material is 10:1~30:1, and the liquid excipient is glyceride type, double alcohols or pyrrolidines
One of ketones solvent is a variety of.
Wherein, the mass ratio of the nilotinib and the liquid excipient is preferably 1:3~1:4, is more preferably 1:
3.2；The liquid excipient and the carrier material mass ratio are preferably 0.4~0.5, are more preferably 0.47；The carrier
The mass ratio of material and the coating material preferably 20:1~30:1, is more preferably 23.63.
Wherein, the glyceride type can be conventional for this field, preferably Masine 35-1 (maisine35)；Institute
Stating double alcohols can be conventional for this field, preferably propylene glycol；The pyrrolidinone compounds solvent can be conventional for this field, preferably
For n-methyl-2-pyrrolidone (NMP).
Wherein, the carrier material can be conventional for this field, preferably microcrystalline cellulose, calcium phosphate dibasic anhydrous, silicic acid
One of magnalium and lactose are a variety of, are more preferably aluminum magnesium silicateUS2。
Wherein, the coating material can be conventional for this field, preferably superfine silica gel powder and/or aluminum magnesium silicate, more preferably
For aluminum magnesium silicateUFL2。
Wherein, the nilotinib liquid-solid compression tablet may also include disintegrating agent, and the disintegrating agent can be conventional for this field, compared with
It is goodly one of sodium carboxymethyl starch, croscarmellose sodium and crospovidone (PVPP) or a variety of, more preferably
For crospovidone；The disintegrating agent is routinely accounted for slice weight 3%-5%, preferably 5% by this field.
Wherein, the nilotinib liquid-solid compression tablet may also include lubricant, and the lubricant can be conventional for this field, compared with
It goodly is magnesium stearate；The lubricant is routinely accounted for slice weight 0.5%-1%, preferably 0.5% by this field.
Wherein, one preferred version of nilotinib liquid-solid compression tablet includes nilotinib 100mg, liquid excipient for it
320mg, carrier material 676.0mg, coating material 28.6mg, disintegrating agent 59.5mg, lubricant 6.0mg.
The present invention also provides the preparation methods of aforementioned nilotinib liquid-solid compression tablet comprising following steps:
(1) nilotinib is mixed with the liquid excipient, obtains uniform solution or suspension；
(2) solution described in (1) or suspension are instilled and obtains mixture in the carrier material；
(3) mixture described in (2) is mixed with the coating material, tabletting.
In the step (1), preferably, the nilotinib is completely dissolved or is uniformly dispersed in the liquid excipient
In.
When the nilotinib liquid-solid compression tablet includes disintegrating agent and/or lubricant, preferably, in the step (3)
In, the mixture, the coating material, the disintegrating agent mixing after again with the mix lubricant.
On the basis of common knowledge of the art, above-mentioned each optimum condition, can any combination to get each preferable reality of the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that:
(1) nilotinib liquid-solid compression tablet of the invention improves the dissolution rate of nilotinib, and in 5min, it is dissolved out
Degree is 4 times of ordinary tablet, is 2 times of commercially available capsule, it is 95% that 60min, which accumulates dissolution rate, and ordinary tablet and commercially available capsule 60min
Accumulating dissolution rate is respectively 70%, 85%, from intra-body data as can be seen that effect example 1, Contrast on effect example 1, Contrast on effect
2 Cmax C of examplemax1501,1051,1305ng/mL respectively, AUC0-∞Respectively 12921.1,9039.09,10689.9ngh/
ML, nilotinib liquid-solid compression tablet AUC0-∞21%, 43% has been respectively increased compared to commercially available capsule, ordinary tablet.
(2) preparation method of liquid-solid compression tablet of the present invention is easy, without using special installation, is suitable for industrializing big life
It produces.
Detailed description of the invention
Fig. 1 is dissolution of the nilotinib preparation in pH1.0 of effect example 1, Contrast on effect example 1 and Contrast on effect example 2
Cumulative release result in medium.
Fig. 2 is the nilotinib preparation of effect example 1, Contrast on effect example 1 and Contrast on effect example 2 in the intracorporal medicine of rat
When curve.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
Embodiment 1
The preparation of nilotinib liquid-solid compression tablet
Prescription: nilotinib 100mg, NMP 320mg,US2 640mg,UFL2 32mg,
PVPP 57.8mg, magnesium stearate 5.8mg.
Preparation process:
(1) for the accurate nilotinib for weighing recipe quantity in the NMP of recipe quantity, ultrasound makes complete drug dissolution；
(2) solution instills recipe quantity in (1)In US2, it is uniformly mixed；
(3) recipe quantity is added in (2)UFL2, PVPP add magnesium stearate after being sufficiently mixed uniformly
Direct tablet compressing is after mixing to get nilotinib liquid-solid compression tablet.
Using the hardness of hardness detecting instrument measurement tablet, quality evaluation is as follows:
| Hardness (N) | Friability | Tensile strength (N/mm2) | Whether Ka Chong |
| 60 | < 1 | 2.65 | It is no |
Conclusion: nilotinib liquid-solid compression tablet hardness manufactured in the present embodiment, friability meet the requirements.
Influence of 2~3 liquid excipient type of embodiment to tablet hardness
Liquid excipient selects Masine 35-1 (maisine 35) or propylene glycol, and dosage is the same as embodiment 1.Ni Luo is replaced
Buddhist nun, aluminum magnesium silicateUS2, aluminum magnesium silicateThe dosages such as UFL2, PVPP, magnesium stearate and preparation process
With embodiment 1.Using the hardness of hardness detecting instrument measurement tablet.
Conclusion: liquid excipient is changed to the tablet of maisine35 or the available qualification of propylene glycol, but tablet hardness is small
The tablet prepared when using NMP as liquid excipient selects the liquid of NMP preparation to consolidate compressing powder compressibility more preferably.
Influence of 1~2 liquid excipient type of comparative example to tablet hardness
Liquid excipient selects diethylene glycol monoethyl ether (Transcutol HP) or polyethylene glycol 400 (PEG 400),
Dosage is the same as embodiment 1.Nilotinib, aluminum magnesium silicateUS2, aluminum magnesium silicateUFL2, PVPP, tristearin
The dosages such as sour magnesium and preparation process are the same as embodiment 1.Using the hardness of hardness detecting instrument measurement tablet.
Conclusion: liquid excipient selects diethylene glycol monoethyl ether (Transcutol HP) or polyethylene glycol 400 (PEG
400) when, powder compressibility is poor, and qualified tablet can not be made.
Influence of the 4 liquid excipient dosage of embodiment to tablet hardness
Change the dosage of liquid excipient NMP, nilotinib, aluminum magnesium silicateUS2, aluminum magnesium silicateThe dosages such as UFL2, PVPP, magnesium stearate and preparation process are the same as embodiment 1.Using hardness detecting instrument measurement tablet
Hardness.
Conclusion: due to the presence of liquid excipient in liquid-solid compression tablet, when tabletting, frequently can lead to " liquid extrusion " phenomenon,
Therefore a suitable ratio need to be screened, to guarantee the quality of tablet.In conjunction with the embodiments 1, it is known that the ratio of NMP and US2 is 0.3
When~0.5, the compressibility of powder is good.
Influence of 3~4 liquid excipient dosage of comparative example to tablet hardness
The ratio of the dosage of change liquid excipient NMP, liquid excipient (NMP) and carrier material (US2) is 0 or 2:3,
Nilotinib, aluminum magnesium silicateUS2, aluminum magnesium silicateThe dosages such as UFL2, PVPP, magnesium stearate and system
Standby technique is the same as embodiment 1.Using the hardness of hardness detecting instrument measurement tablet.
| Number | NMP:US2 | US2:UFL2 | PVPP | Magnesium stearate | Highest hardness (N) | Whether Ka Chong |
| Comparative example 3 | 0 | 20:1 | 5% | 0.5% | >100 | It is no |
| Comparative example 4 | 2:3 | 20:1 | 5% | 0.5% | 18 | It is |
Conclusion: in the presence of no liquid excipient, the compressibility of blank auxiliary is good as the result is shown, but works as the ratio of NMP and US2
When example is 2:3, the mobility and compressibility of powder are poor, and the tablet of hardness qualification can not be made.
Influence of 5~6 variety classes coating material of embodiment to tablet hardness
The type of coating material is aluminum magnesium silicateUFL2 or superfine silica gel powder.Nilotinib, NMP, alumina silicate
MagnesiumUS2, aluminum magnesium silicateThe dosages such as UFL2, PVPP, magnesium stearate and preparation process are the same as embodiment 4.
Using the hardness of hardness detecting instrument measurement tablet.
Conclusion: coating material is aluminum magnesium silicateUFL2 or when superfine silica gel powder, powder compressibility is good.
Influence of 7~9 coating material dosage of embodiment to tablet hardness
Change the ratio of carrier material (US2) and coating material (UFL2), nilotinib, NMP, aluminum magnesium silicateThe dosages such as US2, PVPP, magnesium stearate and preparation process are the same as embodiment 1.Using hardness detecting instrument measurement tablet
Hardness.
Conclusion: when NMP:US2 is 1:2, NMP dosage is higher, and the dosage of solvent increases in prescription, can reduce carrier
Dosage, and then reduce slice weight.The experimental results showed that withThe increase of UFL2 dosage, tablet hardness slightly reduce,The addition of UFL2 has larger impact to liquisolid powder mobility.
The dissolution rate and Internal pharmacokinetics of 1 nilotinib liquid-solid compression tablet of effect example are tested
Nilotinib liquid-solid compression tablet prescription is as shown in the table:
Its preparation process is the same as embodiment 1.
Using the hardness of hardness detecting instrument measurement tablet, quality evaluation result is as shown in the table:
| Hardness (N) | Friability | Tensile strength (N/mm2) | Whether Ka Chong |
| 81.8 | < 1 | 4.11 | It is no |
Conclusion: nilotinib liquid-solid compression tablet hardness manufactured in the present embodiment, friability meet the requirements.
Dissolution detection method: 2015 editions the 4th 0,931 first methods of rules of preparations of Chinese Pharmacopoeia are used, with 0.1mol/L
Hydrochloric acid 1000mL is dissolution medium, and revolving speed 75r/min, temperature is (37 ± 0.5) DEG C, respectively in 5,10,15,30,45,60min
Sampling, the detection level in HPLC, and calculate dissolution rate, it is seen that table 1.
Internal pharmacokinetics experimental method:
Rat and Dosing Regimens: 12 male Kunming rats, 200~220g of weight triumphant must be tested purchased from the western Poole in Shanghai
Company of Animals Ltd. is randomly divided into 3 groups, every group 4, distinguishes stomach-filling nilotinib liquid-solid compression tablet, dosage 100mgkg-1。
Blood specimen collection: above-mentioned rat 0.25 after stomach-filling, 0.5,1,2,3,4,6,8,10,12, for 24 hours, tail vein takes blood, point
It Di not be placed in the 1.5mL centrifuge tube containing heparin, 7000rmin-1It is centrifuged 10min, separated plasma is protected in -20 DEG C of refrigerators
It deposits, is spare.
Biology sample detection method: taking the blood plasma of separator well, and the methanol of 3 times of volumes, 10000r/min centrifugation is added
10min takes supernatant using nilotinib content in LC-MS/MS method measurement sample.
Chromatographic condition: chromatographic column: Venusil XBP-PH C18, guard column: Phenomenex C18；Mobile phase is methanol
(containing 0.1% formic acid): water (containing 0.1% formic acid)=50:50；Isocratic elution, flow velocity 0.35ml/mL, 5 μ L of sample volume, column temperature
It is 35 DEG C.
Mass Spectrometry Conditions: triple 3000 electron ion esi ion sources of level four bars mass spectrograph API are used, ESI positive ion electrospray is from side
Formula, more reactive ion monitoring patterns.
Internal pharmacokinetics data can be shown in Table 2 and table 3.
1 nilotinib liquid of Contrast on effect example consolidates dissolution rate and the Internal pharmacokinetics experiment of ordinary tablet
It is as shown in the table that nilotinib liquid consolidates common tablet recipe:
Its preparation process is the same as embodiment 1.
Using the hardness of hardness detecting instrument measurement tablet, quality evaluation result is as shown in the table:
| Hardness (N) | Friability | Tensile strength (N/mm2) | Whether Ka Chong |
| 81.8 | < 1 | 4.11 | It is no |
Conclusion: nilotinib liquid-solid compression tablet hardness manufactured in the present embodiment, friability meet the requirements.
With effect example 1, dissolution data can be shown in Table 1 for its dissolution detection method and Internal pharmacokinetics experimental method,
Internal pharmacokinetics data can be shown in Table 2 and table 3.
The dissolution rate and Internal pharmacokinetics of 2 Da Xina of Contrast on effect example is tested
Commercially available Da Xina is bought, production man is Novartis Pharma Schweiz AG.
With effect example 1, dissolution data can be shown in Table 1 for its dissolution detection method and Internal pharmacokinetics experimental method,
Internal pharmacokinetics data can be shown in Table 2 and table 3.
1 dissolution rate effect data of table
2 plasma drug concentration data of table
3 pharmacokinetic data of table
Dissolution in vitro it is demonstrated experimentally that liquid-solid compression tablet can be improved nilotinib dissolution rate and accumulation dissolution rate,
Nilotinib liquid-solid compression tablet dissolution rate is 4 times that nilotinib liquid consolidates ordinary tablet when 5min, is the 2 of commercially available capsule Da Xina
Times, it is 95% that 60min, which accumulates dissolution rate, and it is respectively 70%, 85% that nilotinib liquid, which consolidates ordinary tablet and commercially available capsule Da Xina,
Rat Internal pharmacokinetics are prepared into tablet it is demonstrated experimentally that consolidating compress technique using liquid, with conventional tablet and commercially available Buddhist nun
Lip river is compared for Buddhist nun's capsule (Da Xina), can significantly improve rat vivo biodistribution availability.Nilotinib liquid-solid compression tablet AUC0-∞Phase
Consolidate ordinary tablet than commercially available capsule Da Xina, nilotinib liquid and is respectively increased 21%, 43%.
Claims (10)
1. a kind of nilotinib liquid-solid compression tablet, the nilotinib containing effective dose, which is characterized in that the nilotinib liquid
Gu compressed tablet also contains liquid excipient, carrier material and coating material, the matter of the nilotinib and the liquid excipient
For amount than being 1:2~1:4, the mass ratio of the liquid excipient and the carrier material is 0.3~0.5, the carrier material with
The mass ratio of the coating material is 10:1~30:1, and the liquid excipient is glyceride type, double alcohols or pyrrolidinone compounds
One of solvent is a variety of.
2. nilotinib liquid-solid compression tablet as described in claim 1, which is characterized in that the nilotinib and the liquid are assigned
The mass ratio of shape agent is 1:3~1:4, preferably 1:3.2；
And/or the liquid excipient and the carrier material mass ratio are 0.4~0.5, preferably 0.47；
And/or the mass ratio of the carrier material and the coating material is 20:1~30:1, preferably 23.63.
3. nilotinib liquid-solid compression tablet as claimed in claim 1 or 2, which is characterized in that the glyceride type solvent is single
Glyceryl linoleate；
And/or double alcohols solvents are propylene glycol；
And/or the pyrrolidinone compounds solvent is n-methyl-2-pyrrolidone；
And/or the carrier material is one of microcrystalline cellulose, calcium phosphate dibasic anhydrous, aluminum magnesium silicate and lactose or a variety of；
And/or the coating material is superfine silica gel powder and/or aluminum magnesium silicate.
4. nilotinib liquid-solid compression tablet as claimed in claim 3, which is characterized in that the carrier material is aluminum magnesium silicateUS2；
And/or the coating material is aluminum magnesium silicateUFL2。
5. nilotinib liquid-solid compression tablet as claimed in claim 1 or 2, which is characterized in that the nilotinib liquid solid pressure contracting
Piece further includes disintegrating agent, and the disintegrating agent is one in sodium carboxymethyl starch, croscarmellose sodium and crospovidone
Kind is a variety of；
The disintegrating agent accounts for the 3%-5% of slice weight, preferably 5%.
6. nilotinib liquid-solid compression tablet as claimed in claim 5, which is characterized in that the disintegrating agent is crospovidone.
7. nilotinib liquid-solid compression tablet as claimed in claim 1 or 2, which is characterized in that the nilotinib liquid solid pressure contracting
Piece further includes lubricant, and the lubricant accounts for the 0.5%-1% of slice weight, preferably 0.5%；The lubricant is preferably hard
Fatty acid magnesium.
8. nilotinib liquid-solid compression tablet as claimed in claim 1 or 2, which is characterized in that the nilotinib liquid solid pressure contracting
Piece includes nilotinib 100mg, liquid excipient 320mg, carrier material 676.0mg, coating material 28.6mg, disintegrating agent
59.5mg, lubricant 6.0mg.
9. a kind of preparation method of nilotinib liquid-solid compression tablet as described in any one of claims 1 to 8, which is characterized in that
It includes the following steps:
(1) nilotinib is mixed with the liquid excipient, obtains uniform solution or suspension；
(2) solution described in (1) or suspension are instilled and obtains mixture in the carrier material；
(3) mixture described in (2) is mixed with the coating material, tabletting.
10. the preparation method of nilotinib liquid-solid compression tablet as claimed in claim 9, which is characterized in that
In the step (1), the nilotinib is completely dissolved or is uniformly dispersed in the liquid excipient；
When the nilotinib liquid-solid compression tablet includes disintegrating agent and/or lubricant, preferably, in the step (3), institute
State mixture, the coating material, the disintegrating agent mixing after again with the mix lubricant.
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| CN201711179376.3A CN109820828A (en) | 2017-11-23 | 2017-11-23 | Nilotinib liquid-solid compression tablet and preparation method thereof |
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| CN201711179376.3A CN109820828A (en) | 2017-11-23 | 2017-11-23 | Nilotinib liquid-solid compression tablet and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111067875A (en) * | 2020-01-16 | 2020-04-28 | 兰州大学 | Albendazole liquid-solid compressed tablet and preparation method thereof |
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| CN104274837A (en) * | 2014-09-18 | 2015-01-14 | 福格森（武汉）生物科技股份有限公司 | Nilotinib oral preparation |
| CN106333931A (en) * | 2016-11-02 | 2017-01-18 | 山东省中医药研究院 | Compound salvia miltiorrhiza liquid-solid compressed tablets and preparation method thereof |
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2017
- 2017-11-23 CN CN201711179376.3A patent/CN109820828A/en active Pending
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| CN104274837A (en) * | 2014-09-18 | 2015-01-14 | 福格森（武汉）生物科技股份有限公司 | Nilotinib oral preparation |
| CN106333931A (en) * | 2016-11-02 | 2017-01-18 | 山东省中医药研究院 | Compound salvia miltiorrhiza liquid-solid compressed tablets and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111067875A (en) * | 2020-01-16 | 2020-04-28 | 兰州大学 | Albendazole liquid-solid compressed tablet and preparation method thereof |
| CN111067875B (en) * | 2020-01-16 | 2021-11-30 | 兰州大学 | Albendazole liquid-solid compressed tablet and preparation method thereof |
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Application publication date: 20190531 |