CN109157660A - Composition containing kinases inhibitor and silaenafil - Google Patents
Composition containing kinases inhibitor and silaenafil Download PDFInfo
- Publication number
- CN109157660A CN109157660A CN201811273123.7A CN201811273123A CN109157660A CN 109157660 A CN109157660 A CN 109157660A CN 201811273123 A CN201811273123 A CN 201811273123A CN 109157660 A CN109157660 A CN 109157660A
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- CN
- China
- Prior art keywords
- kinases inhibitor
- silaenafil
- acceptable salt
- inhibitor
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
Present invention firstly provides a kind of composition containing kinases inhibitor and silaenafil or its pharmaceutically acceptable salt, it is characterized in that, the kinases inhibitor is selected from nilotinib, training azoles pa Buddhist nun, Afatinib, bosutinib, gram azoles for one of Buddhist nun, pazopanib and Rui Gefeini or the solvate of its pharmaceutically acceptable salt or solvate or pharmaceutically acceptable salt, and the molar ratio of silaenafil and the kinases inhibitor is in (0.01~100): between 1.Extracorporeal bacteria inhibitor test discovery, silaenafil of the present invention is with the combination of kinases inhibitor in (0.01~100): can the various bacterias such as acinetobacter haemolyticus be generated with the bacteriostasis (generating drug combination index CI < 1 when 30% inhibition produces) cooperateed in 1 molar ratio.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to the composition containing kinases inhibitor and silaenafil.
Background technique
Infectious diseases is the major class disease caused by the microorganism infections such as bacterium, helminth, fungi or virus, can be passed through
Various approach are directly or indirectly propagated between human body.It is posted including antibiotic, antiviral agent, antifungal with anti-although having at present
A variety of anti-infectives such as infested medicine can be used for the treatment of infectious diseases, cause a disease in this disease still global range or lethal
One of the main reason for.2010, there are about 15,000,000 to die of infectious diseases in the whole world.
First kinases inhibitor Imatinib listing in 2001 is used for the treatment of leukaemia, thus the tumor target pulled open
To the prelude for the treatment of.To in October, 2018, FDA has had been approved by more than ten kinases inhibitors controlling for kinds cancer
It treats.In recent years, application of the kinases inhibitors such as Imatinib in infectious diseases is more and more concerned, such as Sarah
A.Stanley et al. is according to the report, Imatinib can inhibit big by the process for blocking mycobacterium to enter rat macrophage
The duplication of tubercle bacillus in mouse model.In the prior art without other kinases inhibitors to infectious diseases therapeutic effect
Data.The present inventor determines multiple protein kinase inhibitor to the antibacterial activity of various bacteriums in early-stage study, but big
Part antibacterial activity does not reach IC50.
Silaenafil (its medicinal citrate) is clinically one of common male erectile dysfunction therapeutic agent,
Action target spot phosphodiesterase exists in the bacterium of part, and regulates and controls the normal function of bacterium, but temporary nothing in the prior art
The phosphodiesterase inhibitors such as silaenafil combine the technical teaching for generating synergetic antibacterial effect with kinases inhibitor.
Summary of the invention
The purpose of the present invention is to provide a kind of composition containing kinases inhibitor and silaenafil, the composition
Antibacterial action with collaboration.
To achieve the goals above, present invention firstly provides one kind containing kinases inhibitor and silaenafil or its
The composition of pharmaceutically acceptable salt, which is characterized in that the kinases inhibitor is selected from nilotinib
(nilotinib), training azoles pa Buddhist nun (pazopanib), Afatinib (afatinib), bosutinib (bosutinib), a gram azoles replace
One of Buddhist nun (crizotinib), pazopanib (axitinib) and Rui Gefeini (regorafenib) or its pharmaceutically may be used
The salt or solvate of receiving or the solvate of pharmaceutically acceptable salt, and silaenafil and the protein kinase inhibit
The molar ratio of agent is in (0.01~100): between 1.
Preferably, silaenafil of the present invention or its pharmaceutically acceptable salt are sildenafil citrates.
Preferably, kinases inhibitor of the present invention is hydrochloric acid nilotinib monohydrate.
Preferably, kinases inhibitor of the present invention is hydrochloric acid training azoles pa Buddhist nun.
Preferably, kinases inhibitor of the present invention is two maleic acid Afatinibs.
Preferably, kinases inhibitor of the present invention is bosutinib monohydrate.
Preferably, kinases inhibitor of the present invention is gram azoles for Buddhist nun.
Preferably, kinases inhibitor of the present invention is pazopanib.
Preferably, kinases inhibitor of the present invention is Rui Gefeini monohydrate.
Invention further provides the oral solid formulation for containing composition as previously described, dosage form is selected from particle
One of agent, capsule and tablet.
Preferably, the oral solid formulation further contains diluent and lubricant, wherein dilution of the present invention
Agent is preferably pregelatinized starch, starch, dextrin, sucrose, microcrystalline cellulose, sorbierite, mannitol, lactose, calcium sulfate, phosphoric acid hydrogen
One of calcium and calcium phosphate；Lubricant of the present invention is preferably sodium stearyl fumarate, stearic acid, magnesium stearate, tristearin
Sour calcium, paraffin oil, paraffin, glycerin monostearate, monopalmitin, sodium acetate, sodium chloride, DL-leucine, laruyl alcohol
One of sodium sulphate, magnesium laurylsulfate, polyethylene glycol, polyoxyl 40 stearate and Brij30.
Oral solid formulation of the present invention can be used method well known to those of ordinary skill in the art and be prepared,
The method that specific method can refer to but be not limited in " pharmacy " (the 8th edition) that Fang Liang is edited, People's Health Publisher publishes.This
The preparation method of the invention granule be by silaenafil, kinases inhibitor, diluent, mix lubricant to get
To the granule comprising kinases inhibitor and silaenafil.
The preparation method of capsule of the present invention is by silaenafil or its pharmaceutically acceptable salt, protein kinase
After inhibitor, diluent, mix lubricant, filling capsule is to get to including kinases inhibitor and silaenafil or its medicine
The capsule of acceptable salt on.
The preparation method of tablet of the present invention is to press down silaenafil or its pharmaceutically acceptable salt, protein kinase
After preparation, diluent, mix lubricant, tabletting is carried out to get to including kinases inhibitor and silaenafil or its pharmacy
The tablet of upper acceptable salt.
Kinases inhibitor in oral solid formulation of the present invention and silaenafil or its is pharmaceutically acceptable
Salt content and the dosage that is thus related to can be carried out by pharmacological testing well known to those of ordinary skill in the art
Screening and optimization, the present invention is to this without specifically limited.
Supplementary product consumption in oral solid formulation of the present invention can be by well known to those of ordinary skill in the art
Formulation method is screened and is optimized, and the present invention is to this without specifically limited.
Extracorporeal bacteria inhibitor test discovery, the combination of sildenafil citrate and kinases inhibitor of the present invention exist
(0.01~100): can be curved to acinetobacter haemolyticus, aerococcus viridans, Bacteroides merdae, bacteroides vulgatus, mucous membrane in 1 molar ratio
Curved bar bacterium, produces indoles Chryseobacterium sp, clostridium histolyticum, propionic acid bar bacterium, ulcer am, cloaca intestines bar at Cedecea lapagei
Bacterium, fusobacterium necrogenes, haemophilus paraphrophilus, Lactobacillus Jensenii, leptotrichia buccalis, Neisseria cinerea coccus, is detested at escherichia coli
The bacteriostasis that oxygen peptostreptococcus, porphyromonas gingivalis, the various bacteria in proteus vulgaris generate collaboration (generates
Drug combination index CI < 1 when 30% inhibiting rate).
Specific embodiment
Below with reference to the embodiment of the present invention, description that is clear, finishing is carried out to technical solution of the present invention, it is clear that retouched
The embodiment stated is only a part of the embodiments of the present invention, instead of all the embodiments.Based on the embodiments of the present invention,
Every other embodiment obtained by those of ordinary skill in the art without making creative efforts, belongs to this hair
The range of bright protection.
The bacteriostasis that 1 sildenafil citrate of test example is combined with protein kinase kinase inhibitor
Measured respectively using filter paper enzyme sildenafil citrate, kinases inhibitor and sildenafil citrate with
Bacteriostatic activity of the combined system of kinases inhibitor to various bacteria.Specifically, being drawn with liquid-transfering gun prepared
Bacterial suspension (1 × 105/ mL, preparation method: will be activated on slant tube culture medium for examination strain [37 ± 1 DEG C, 3
It], it recycles oese to beat easily a small amount of lawn from inclined-plane, is respectively added to be contained with the conical flask of 50mL sterile saline
In), it is uniformly applied to agar plate surface after cooling, plate containing bacterium is made.Sterilizing filter paper piece is taken, lets off 6 kinds of concentration respectively
1h is impregnated in the tested material methanol solution of gradient, the 6mm circular filter paper piece impregnated is attached on the above-mentioned plate containing bacterium made,
Each culture dish (diameter 90mm) sticks the filter papers of 3 dipped same mass concentration tested material methanol solutions, and (filter paper is most
Amount interval is identical), using 50% methanol solution as blank control.Processed plate containing bacterium is placed in 37 DEG C of insulating boxs and is cultivated
For 24 hours, colony diameter is measured using crossing method, and calculates inhibiting rate (IR) according to following formula.
It is mapped with logarithm of the inhibiting rate (IR) to drug concentration (μM), and carries out linear regression with Excel, according to recurrence
Equation extrapolates the concentration of sildenafil citrate and kinases inhibitor when generating 30% inhibition, respectively IC30(A)With
IC30(B)Value.For drug combination, then with inhibiting rate (IR) to the logarithm of the concentration (μM) of sildenafil citrate in drug combination
It is worth (log (c)) mapping, and carries out linear regression with Excel, when extrapolates 30% inhibition according to regression equation in combined system
Sildenafil citrate concentration, i.e. IC30(mixA), further according to sildenafil citrate in combined system and kinases inhibitor
Molar ratio, when extrapolating 30% inhibition in combined system kinases inhibitor concentration, i.e. IC30(mixB)。
Calculating sildenafil citrate according to the following formula and combining with protein kinase enzyme inhibitor inhibits the joint of various bacteriums to use
Medicine index CI.
As CI < 1, synergistic effect is indicated, and the smaller representative synergistic effect of CI is stronger.The results are shown in Table 1.
Table 1
As it can be seen from table 1 although sildenafil citrate and kinases inhibitor of the present invention are individually
When medication 50% is not crossed to the maximal percentage inhibition of each bacterium, but highest is greatly improved with different mol ratio combinations and is inhibited
Rate, and the inhibiting effect of collaboration can be generated in 30% inhibiting rate in part molar ratio range.
Under 30% depression effect, the combined system of sildenafil citrate and kinases inhibitor produces various bacteriums
The molar ratio (sildenafil citrate/kinases inhibitor) of raw collaboration bacteriostasis is as shown in table 2 below.
Table 2
Embodiment 1 includes the capsule of sildenafil citrate and hydrochloric acid nilotinib monohydrate (molar ratio 0.01:1)
The preparation of agent
Prescription (g)
Preparation method
Sildenafil citrate, hydrochloric acid nilotinib monohydrate, sorbierite and the sodium stearyl fumarate for taking recipe quantity, fill
Divide mixing, filling capsule, packing.
Embodiment 2 includes the preparation of the tablet of sildenafil citrate and hydrochloric acid training azoles pa Buddhist nun (molar ratio 0.5:1)
Prescription (g)
Preparation method
Sildenafil citrate, hydrochloric acid training the azoles pa Buddhist nun, microcrystalline cellulose, magnesium stearate for taking recipe quantity, are sufficiently mixed, press
Piece.
Embodiment 3 includes the system of the granule of sildenafil citrate and two maleic acid Afatinibs (molar ratio 1:1)
It is standby
Prescription (g)
Preparation method
Sildenafil citrate, the two maleic acid Afatinibs, microcrystalline cellulose, sodium stearyl fumarate for taking recipe quantity, fill
Divide mixing, packing.
Embodiment 4 includes the system of the capsule of sildenafil citrate and bosutinib monohydrate (molar ratio 50:1)
It is standby
Prescription (g)
Preparation method
The sildenafil citrate, bosutinib monohydrate, pregelatinized starch, glycerin monostearate of recipe quantity are taken,
It is sufficiently mixed, filling capsule, dispenses.
Embodiment 5 includes the preparation of sildenafil citrate and gram azoles for the tablet of Buddhist nun (molar ratio 100:1)
Prescription (g)
Preparation method
It takes sildenafil citrate, gram azoles of recipe quantity for Buddhist nun, mannitol, sldium lauryl sulfate, is sufficiently mixed, tabletting.
Embodiment 6 includes the preparation of sildenafil citrate and the granule of pazopanib (molar ratio 0.01:1)
Prescription (g)
Preparation method
Sildenafil citrate, pazopanib, pregelatinized starch, the sodium stearyl fumarate for taking recipe quantity, are sufficiently mixed, point
Dress.
Embodiment 7 includes the capsule of sildenafil citrate and Rui Gefeini monohydrate (molar ratio 100:1)
Preparation
Prescription (g)
Preparation method
The sildenafil citrate, Rui Gefeini monohydrate, microcrystalline cellulose, sodium stearyl fumarate for taking recipe quantity, fill
Divide mixing, filling capsule, packing.
Claims (10)
1. a kind of composition containing kinases inhibitor and silaenafil or its pharmaceutically acceptable salt, feature exist
In, the kinases inhibitor be selected from nilotinib, training azoles pa Buddhist nun, Afatinib, bosutinib, gram azoles for Buddhist nun, Ah
Former times is molten for one of Buddhist nun and Rui Gefeini or its pharmaceutically acceptable salt or solvate or pharmaceutically acceptable salt
Agent compound, and the molar ratio of silaenafil and the kinases inhibitor is in (0.01~100): between 1.
2. composition according to claim 1, which is characterized in that the silaenafil or its pharmaceutically acceptable salt are citrons
Sour silaenafil.
3. composition according to claim 1, which is characterized in that the kinases inhibitor is that hydrochloric acid nilotinib one is hydrated
Object.
4. composition according to claim 1, which is characterized in that the kinases inhibitor is hydrochloric acid training azoles pa Buddhist nun.
5. composition according to claim 1, which is characterized in that the kinases inhibitor is two maleic acid Afatinibs.
6. composition according to claim 1, which is characterized in that the kinases inhibitor is bosutinib monohydrate.
7. composition according to claim 1, which is characterized in that the kinases inhibitor is gram azoles for Buddhist nun.
8. composition according to claim 1, which is characterized in that the kinases inhibitor is pazopanib.
9. composition according to claim 1, which is characterized in that the kinases inhibitor is Rui Gefeini monohydrate.
10. the oral solid formulation containing the composition of any one according to claim 1~9, which is characterized in that its dosage form is
Selected from one of granule, capsule and tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811273123.7A CN109157660A (en) | 2018-10-28 | 2018-10-28 | Composition containing kinases inhibitor and silaenafil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811273123.7A CN109157660A (en) | 2018-10-28 | 2018-10-28 | Composition containing kinases inhibitor and silaenafil |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109157660A true CN109157660A (en) | 2019-01-08 |
Family
ID=64875554
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811273123.7A Pending CN109157660A (en) | 2018-10-28 | 2018-10-28 | Composition containing kinases inhibitor and silaenafil |
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| Country | Link |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102770426A (en) * | 2010-02-05 | 2012-11-07 | Irm责任有限公司 | Compounds and compositions as protein kinase inhibitors |
| CN105073115A (en) * | 2013-03-14 | 2015-11-18 | 药品循环有限责任公司 | Combinations of Bruton's tyrosine kinase inhibitors and CYP3A4 inhibitors |
-
2018
- 2018-10-28 CN CN201811273123.7A patent/CN109157660A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102770426A (en) * | 2010-02-05 | 2012-11-07 | Irm责任有限公司 | Compounds and compositions as protein kinase inhibitors |
| CN105073115A (en) * | 2013-03-14 | 2015-11-18 | 药品循环有限责任公司 | Combinations of Bruton's tyrosine kinase inhibitors and CYP3A4 inhibitors |
Non-Patent Citations (5)
| Title |
|---|
| 喻友军等主编: "《实用传染科医师处方手册》", 30 September 2004 * |
| 张瑾: "植物源杀菌剂的复配及其微乳液的制备", 《中国优秀硕士学位论文全文数据库（工程科技I辑）》 * |
| 滕菲等: "***性红斑狼疮相关肺动脉高压的发病机制及治疗研究进展", 《中华医学杂志》 * |
| 申世立: "吡唑衍生物合成、生物活性及罗丹明B类pH荧光探针", 《中国博士学位论文全文数据库（工程科技I辑）》 * |
| 肖晴等: "卡博替尼阻断小鼠体内产单核细胞李斯特菌感染的实验研究", 《南方医科大学学报》 * |
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| PB01 | Publication | ||
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Application publication date: 20190108 |