CN109503415A - A kind of tranilast co-crystal thereof, preparation method and application - Google Patents
A kind of tranilast co-crystal thereof, preparation method and application Download PDFInfo
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- CN109503415A CN109503415A CN201811618543.4A CN201811618543A CN109503415A CN 109503415 A CN109503415 A CN 109503415A CN 201811618543 A CN201811618543 A CN 201811618543A CN 109503415 A CN109503415 A CN 109503415A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/02—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of urea, its salts, complexes or addition compounds
- C07C273/14—Separation; Purification; Stabilisation; Use of additives
- C07C273/16—Separation; Purification
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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Abstract
The invention discloses a kind of tranilast co-crystal thereofs, preparation method and application.The general formula of the co-crystal thereof is as shown in Equation 1.The co-crystal thereof is tranilast and amides compound (R1‑CONH2) formed co-crystal thereof.For the co-crystal thereof compared with tranilast original shape medicine, photostability is higher, and solubility improves, and has higher oral administration biaavailability.In addition, the original anti-fibrosis effect of tranilast can be improved in tranilast benzamide co-crystal thereof.The co-crystal thereof preparation method is simple, is suitble to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical fields, are related to a kind of new tranilast co-crystal thereof.The invention further relates to the cocrystallization
The preparation method and application of body.
Background technique
Entitled N- (3 ', the 4 '-dimethoxycinnamoyl) anthranilic acid of tranilast (Tranilast, TL) chemistry, nineteen eighty-two by
Kissei pharmaceutical industries Co., Ltd. (Japan) research and development listing, is a kind of allergy preparations, chemical structural formula such as 2 institute of formula
Show.
The mechanism of action of tranilast is to inhibit mast cell and basocyte release chemical mediator, prevents cell cracking de-
Particle, so that the Anaphylactic mediators such as histamine, serotonin be inhibited to discharge.Clinically mainly prevent and treat allergic rhinitis, allergy
Property asthma, atopic dermatitis and nettle rash etc..Commercial dosage forms mainly have the oral preparations such as tablet, capsule and percutaneous preparation." in
State's pharmacopeia " the 2010 editions tablets and capsule preparations for having included tranilast, Japan has produced treatment allergic conjunctivitis now
External application eye drops.Tranilast convenient oral, significant in efficacy, side effect is relatively small, occupies certain market share.
Tranilast has good therapeutic effect, but its solubility is smaller, and solubility is about 14.5 μ g/mL in water,
Solubility in pH 1.2HCl solution is 0.7 μ g/mL, causes the daily dosage of tranilast larger, is 300mg/ days.It removes
There is the cinnamamide group to photo-labile except this, in tranilast structure, is transformed into syn-isomerism when being exposed to light
Body and dimeric forms, so as to cause bioavilability reduction.
Currently, some researchers attempt to improve the dissolubility and photo-labile of tranilast, and achieve one
A little achievements.Kawabata etc. prepares the solid dispersions of tranilast, and solubility and photostability are superior to tranilast
Raw material itself (European Journal of Pharmaceutical Sciences.2010,39:256-262).Hori etc.
Ultraviolet absorber is added to and is used to improve photostability in tranilast gelling agent, is also produced a desired effect
(Chemical&Pharmaceutical Bulletin.1999,47:1713-1716)。
In recent years, the research of polymorph in pharmaceuticals and pharmaceutical co-crystals is grown rapidly both at home and abroad, from 2009, continuous 4 years
Chinese crystal form medicament research and development technology scientific seminar is held, is laid a good foundation for the development of crystal form drug at home.Crystal form drug
As a cross discipline, to pharmaceutical properties are improved, there is important research significance in terms of improving drug bioavailability, have
Broad application prospect.
Eutectic refers to active pharmaceutical ingredient (active pharmaceutical ingredient, API) and one or more
A eutectic ligand (cocrystalformer, CCF) is made by non-covalent bonds such as hydrogen bond, model ylid bloom action power, pi-pi accumulation, halogen keys
With the multi-component material of the fixation stoichiometric ratio connected into.
By forming API co-crystal thereof, the more preferable property of specific API may may be implemented.The co-crystal thereof of API is
The distinct chemical composition that API and eutectic ligand are formed, and when with the property of API and eutectic ligand individually compared with when, one
As have different crystallization and spectral property.Other than other technologies, crystal form and spectral property usually pass through X-ray powder
Last diffraction (XRPD) and single crystal X diffraction crystallography measure.Co-crystal thereof generally also shows different thermal behaviors.Thermal behavior passes through
The technology as capillary melting point, thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC) measures in the lab.As
Crystal form, co-crystal thereof can have more favorable solid form, physics, chemistry, drug and/or pharmacological property.
In crystal form preparation process, using different methods or changes preparation condition, different crystal forms may be obtained
State.The preparation method of polymorph in pharmaceuticals and eutectic has very much, such as solvent method, coprecipitation, suspension method, sublimed method, fusion method
And ball-milling method etc..
Summary of the invention
It is an object of the invention to provide a kind of tranilast co-crystal thereofs, preparation method and application.The invention proposes
Tranilast is prepared into pharmaceutical co-crystals to improve tranilast dissolubility and/or photostability by a kind of new method.When
When compared with tranilast prototype medicine, new tranilast co-crystal thereof of the invention has other beneficial properties as molten in what is improved
Xie Du, improved dissolution rate and/or increased bioavilability.
In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical scheme: a kind of tranilast co-crystal thereof, this is total
The general formula of crystalline solid is as shown in Equation 1；
Wherein-R1For one kind of phenyl, 2- piperidyl, 2- methyl -3- pyridyl group.
The co-crystal thereof is tranilast and amides compound (R1-CONH2) formed co-crystal thereof；The co-crystal thereof
Selected from tranilast benzamide co-crystal thereof, tranilast 2- piperidine formamide or tranilast 2- methylnicotinamide cocrystallization
Body.
The preparation method of tranilast co-crystal thereof above-mentioned, including the following steps:
(1) tranilast of weighed equimolar ratio and amides compound R1-CONH2, it is placed in test tube；
(2) it pipettes in organic solvent to test tube, sealing of jumping a queue, is ultrasonically treated: frequency 40KHz, 30 DEG C of temperature, the time
30min；
(3) it is placed in again and stirs 12h-18h under room temperature；
(4) suspension is filtered, filter cake partial vacuum is dry, obtains tranilast co-crystal thereof powder；
(5) filtrate is placed in volatile organic solvent culture monocrystalline at room temperature, until obtaining colorless and transparent column crystal；
(6) it is measured using single crystal X-ray diffraction instrument.
Amides compound R1-CONH2Selected from benzamide, 2- piperidine formamide or 2- methylnicotinamide, preferably benzoyl
Amine.The organic solvent is acetone, methanol or ethyl alcohol, preferably acetone.
Wherein, a kind of tranilast benzamide co-crystal thereof, have selected from 11.24,12.64,13.06,16.26,
18.65, the powder X-ray diffraction pattern at least three peaks of 21.01,22.51 ° of 2 θ ± 0.2 °, 2 θ；Or have and the basic class of Fig. 1
As powder X-ray diffraction pattern.
A kind of tranilast 2- piperidine formamide co-crystal thereof, have selected from 8.70,8.94,14.75,22.67,23.00,
28.16, the powder X-ray diffraction pattern at least three peaks of 28.46 ° of 22 θ of θ ± 0.2 °；Or with the powder substantially similar with Fig. 2
Last X-ray diffraction pattern.
A kind of tranilast 2- methylnicotinamide co-crystal thereof, have selected from 9.87,16.01,18.37,20.91,
The powder X-ray diffraction pattern at least three peaks of 26.17 ° of 22 θ of θ ± 0.2 °；Or it is penetrated with the powder X-ray substantially similar with Fig. 3
Ray diffraction diagram case.
The present invention also provides tranilast co-crystal thereofs to have the photostability improved and dissolubility and biology benefit in preparation
Application in the tranilast drug of expenditure.
In addition, the present invention also provides tranilast co-crystal thereofs in terms of improving tranilast bulk pharmaceutical chemicals anti-fibrosis effect
Application.
Compared with the existing technology, beneficial effects of the present invention: the invention discloses a kind of new tranilast co-crystal thereofs
Synthetic method and application.The co-crystal thereof is tranilast and amides compound (R1-CONH2) formed co-crystal thereof.It should
For co-crystal thereof compared with tranilast original shape medicine, photostability is higher, and solubility improves, and has higher oral bio benefit
Expenditure.In addition, the original anti-fibrosis effect of tranilast can be improved in tranilast benzamide co-crystal thereof.The cocrystallization
Preparation is simple, is suitble to industrialized production.
Detailed description of the invention
Fig. 1 is that the XRPD of tranilast benzamide co-crystal thereof schemes；
Fig. 2 is that the XRPD of tranilast 2- piperidine formamide co-crystal thereof schemes；
Fig. 3 is that the XRPD of tranilast 2- methylnicotinamide co-crystal thereof schemes；
Fig. 4 is tranilast bulk pharmaceutical chemicals, tranilast benzamide co-crystal thereof, tranilast 2- piperidine formamide and song
Ni Site 2- methylnicotinamide co-crystal thereof is added separately to the solubility curve figure in 1.2 hydrochloric acid solution of pH；
Fig. 5 is tranilast bulk pharmaceutical chemicals, tranilast benzamide co-crystal thereof, tranilast 2- piperidine formamide and song
Ni Site 2- methylnicotinamide co-crystal thereof is added separately to the solubility curve figure in 4.5 acetate buffer of pH；
Fig. 6 is tranilast bulk pharmaceutical chemicals, tranilast benzamide co-crystal thereof, tranilast 2- piperidine formamide and song
Ni Site 2- methylnicotinamide co-crystal thereof is added separately to the solubility curve figure in 6.8 phosphate buffer solution of pH；
Fig. 7 is tranilast bulk pharmaceutical chemicals, tranilast benzamide co-crystal thereof, tranilast 2- piperidine formamide and song
Ni Site 2- methylnicotinamide co-crystal thereof is added separately to the solubility curve figure in purified water；
Fig. 8 is to dissolve tranilast benzamide co-crystal thereof when in the solution, tranilast 2- piperidine formamide and song
The photostability schematic diagram of Ni Site 2- methylnicotinamide co-crystal thereof；
Fig. 9 is the blood concentration-time curve graph of vivo biodistribution availability research；
Figure 10 is the rat urine albumen amount figure of ADR kidney fibrosis rat model；
Figure 11 is renal interstitial fibrosis appraisal result；
Figure 12 is glomerulosclerosis index score result.
Specific embodiment
Illustrate the present invention below by embodiment, these embodiments are not meant to limitation of the present invention.
1 tranilast benzamide co-crystal thereof of embodiment
The preparation of 1.1 tranilast benzamide co-crystal thereofs
Weighed 327mg tranilast and 121mg urea, are placed in test tube with equimolar ratio, pipette 3mL
In acetone solvent to test tube, sealing of jumping a queue is ultrasonically treated (frequency 40KHz, 30 DEG C of temperature) 30min.
It is placed in again and stirs 15h under room temperature.Suspension is filtered, the dry 12h of filter cake partial vacuum obtains tranilast benzene
The powder of formamide co-crystal thereof.Filtrate is placed in solvent flashing culture monocrystalline at room temperature, and colorless and transparent column crystal is obtained after 1 day
Body.It is measured using single crystal X-ray diffraction instrument.
The XRPD of 1.2 tranilast benzamide co-crystal thereofs is characterized
The XRPD figure of tranilast benzamide co-crystal thereof is as shown in Figure 1.With tranilast bulk pharmaceutical chemicals and benzamide
Comparison, characteristic peak occur apparent change, can prove cenotype generation.The tranilast benzene simulated with Mercury software
Formamide co-crystal thereof figure is consistent with measured drawing, it was demonstrated that the eutectic purity of preparation is higher.
1 diffractive features peak position of table, d value and peak intensity
Diffractive features peak position, d value and peak intensity are listed in table 1.Except through scheming with Fig. 1 substantially similar XRPD
Case, the entire list at peak or its subset can be enough to characterize co-crystal thereof.For example, tranilast benzamide of the invention is tied altogether
Crystal may be characterized as having selected from 11.24,12.64,13.06,16.26,18.65,21.01,22.51 ° of 2 θ ± 0.2 °, 2 θ extremely
The powder X-ray diffraction pattern at few three peaks.
2 tranilast 2- piperidine formamide co-crystal thereof of embodiment
The preparation of 2.1 tranilast 2- piperidine formamide co-crystal thereofs
Experimental procedure is similar to tranilast benzamide co-crystal thereof, and 128mg 2- piperidine formamide is substituted benzoyl
Amine.
The XRPD of 2.2 tranilast 2- piperidine formamide co-crystal thereofs is characterized
The XRPD figure of tranilast 2- piperidine formamide co-crystal thereof is as shown in Figure 2.With tranilast bulk pharmaceutical chemicals and 2- piperazine
The comparison of pyridine formamide, characteristic peak occur apparent change, can prove cenotype generation.The song simulated with Mercury software
Ni Site 2- piperidine formamide co-crystal thereof figure is consistent with measured drawing, it was demonstrated that the co-crystal thereof purity of preparation is higher.
2 diffractive features peak position of table, d value and peak intensity
Diffractive features peak position, d value and peak intensity are listed in table 2.Except through scheming with Fig. 2 substantially similar XRPD
Case, the entire list at peak or its subset can be enough to characterize co-crystal thereof.For example, tranilast 2- piperidine formamide of the invention
Co-crystal thereof, which may be characterized as having, is selected from 8.70,8.94,14.75,22.67,23.00,28.16,28.46 ° of 2 θ ± 0.2 °, 2 θ's
The powder X-ray diffraction pattern at least three peaks.
3 tranilast 2- methylnicotinamide co-crystal thereof of embodiment
The preparation of 3.1 tranilast 2- methylnicotinamide co-crystal thereofs
Experimental procedure is similar to tranilast benzamide co-crystal thereof, and 136mg 2- methylnicotinamide is substituted benzoyl
Amine.
The XRPD of 3.2 tranilast 2- methylnicotinamide co-crystal thereofs is characterized
The XRPD figure of tranilast 2- methylnicotinamide co-crystal thereof is as shown in Figure 3.With tranilast bulk pharmaceutical chemicals and 2- first
The comparison of base niacinamide, characteristic peak occur apparent change, can prove cenotype generation.The song simulated with Mercury software
Ni Site 2- methylnicotinamide co-crystal thereof figure is consistent with measured drawing, it was demonstrated that the co-crystal thereof purity of preparation is higher.
3 diffractive features peak position of table, d value and peak intensity
Diffractive features peak position, d value and peak intensity are listed in table 3.Except through scheming with Fig. 3 substantially similar XRPD
Case, the entire list at peak or its subset can be enough to characterize co-crystal thereof.For example, tranilast 2- methylnicotinamide of the invention
Co-crystal thereof may be characterized as at least three peaks selected from 9.87,16.01,18.37,20.91,26.17 ° of 2 θ ± 0.2 °, 2 θ
Powder X-ray diffraction pattern.
The research of 4 powder solubility of embodiment
Weighed tranilast bulk pharmaceutical chemicals respectively, tranilast benzamide co-crystal thereof, tranilast 2- piperidine formamide
1.2 hydrochloric acid solution of 50mL pH, 4.5 acetate of pH are added separately to tranilast 2- methylnicotinamide co-crystal thereof 50mg
In buffer, 6.8 phosphate buffer solution of pH and purified water, stirred in 37 DEG C of water-baths with the rate of 100rpm, every 5,
15,30,45,60,90,120min samplings are diluted to proper volume, use purple after sample is by 0.45 μm of nylon filter filtering
Outer spectrophotometer detection.Shown in result of study such as Fig. 4 (pH 1.2), Fig. 5 (pH 4.5), Fig. 6 (pH 6.8) and Fig. 7 (water).
As seen from the figure in four kinds of dissolution mediums, the maxima solubility and rate of dissolution of tranilast co-crystal thereof are compared
Tranilast bulk pharmaceutical chemicals have a degree of improvement, wherein tranilast benzamide co-crystal thereof solubility and dissolution rate
Improve maximum.In 6.8 phosphate buffer of pH, tranilast benzamide co-crystal thereof, which reaches dissolution in 45min, is put down
Platform；In 1.2 hydrochloric acid of pH, 4.5 acetate buffer of pH and water, tranilast is crystallized almost without dissolution, and bent Buddhist nun is made
After taking charge of special benzamide co-crystal thereof, two hours dissolution rates are respectively increased to 41%, 66% and 55%.
5 solid-state study on light stability of embodiment
It is well known that pure crystallization tranilast is that light is stable in solid form, therefore, studied to determine bent Buddhist nun
Take charge of special benzamide co-crystal thereof, the solid-state of tranilast 2- piperidine formamide and tranilast 2- methylnicotinamide co-crystal thereof
Photostability, and compare the solid-state photostability of itself and pure crystallization tranilast.It is respectively that pure crystallization tranilast and three is total
Crystal form weighs and is dispersed in the bottom surface of transparent glass bottle.Bottle is put into the fast light cabinet of Vindon science, and
It is irradiated with UV light, it is klux=18.2Lux/ hours average, average value=2.55 watt UV/minute, temperature=31.0-32.0 DEG C.
Remaining tranilast percentage was measured using HPLC at 3,24 and 48 hours in each sample.Chromatographic condition is as follows: efficiently
Liquid chromatogram (LC-20A, Shimadzu, Japan), is equipped with diode array detector, detects under the wavelength of 333nm.With
Inertsil ODS-3C18 (5m × 4.6mm × 150mm) is chromatographic column.Mobile phase is methanol: 0.3% formic acid (75:25), stream
Fast 1.0mL/min, sample volume are 10 μ l；
The results are shown in Table 4 for this research.From table 4, it can be seen that co-crystal thereof is whole under these conditions in solid-state
It is that light is stable, without any photodegradative instruction.Studies have shown that tranilast benzamide co-crystal thereof, tranilast 2-
Piperidine formamide and tranilast 2- methylnicotinamide co-crystal thereof all have in solid-state similar with pure crystallization tranilast
Photostability.
4 solid-state photostability of table
6 solution study on light stability of embodiment
Once being dissolved in solution, crystallization tranilast is that optics is unstable.This research and probe when dissolution in the solution
When tranilast benzamide co-crystal thereof, tranilast 2- piperidine formamide and tranilast 2- methylnicotinamide co-crystal thereof
Photostability, and compare these co-crystal thereofs and crystallize tranilast solution photostability.Crystallize tranilast and three
The sample of co-crystal thereof is respectively weighed in transparent vial, and each sample is dissolved in DMSO (200 μ l), methanol (600 μ l)
In water (600 μ l).Bottle is put into the fast light cabinet of Vindon science, and is irradiated with UV light, average klux=18.2Lux/
Hour, average value=2.55 watt UV/minute, temperature=31.0-32.0 DEG C.It is surveyed respectively at 2,12,24,48,72,96h samplings
Remaining tranilast percentage in fixed each sample.The result of the research is as shown in Figure 8.
From figure 8, it is seen that tranilast co-crystal thereof form has in the solution compared with the tranilast of pure crystallization
Higher photostability, wherein tranilast benzamide co-crystal thereof photostability is best, and 2.5% is only degraded after 96h.
The research of 7 vivo biodistribution availability of embodiment
The solubility for improving drug can be effectively improved its oral administration biaavailability.Since tranilast solubility is lower,
Bioavilability is relatively low.By the studies above result it is found that the tranilast of relatively pure crystallization, the dissolution of tranilast crystalline solid
Degree significantly improves, and therefore, after co-crystal thereof is made in tranilast, bioavilability should also increase.Carry out pharmacokinetics
Experiment is to verify effect of the tranilast co-crystal thereof in terms of improving bioavilability.Specific embodiment is as follows.
Tranilast, tranilast benzamide co-crystal thereof, tranilast 2- piperidine formamide and Qu Nisi will be crystallized
Special 2- methylnicotinamide co-crystal thereof physiological saline solution.Rat is divided into 4 groups, and every group 6, fasting 12 hours before testing (but
Can't help water), drug, dosage 10mg/kg are given in stomach-filling.And upon administration 0.5,1,2,4,8,12 and rat eye socket is quiet for 24 hours
Arteries and veins takes blood, and separation serum measures drug concentration therein.
Experiment gained pharmacokinetic parameters are as shown in table 5, and blood concentration-time curve is as shown in Figure 9:
5 pharmacokinetic parameters of table
By table 5 and Fig. 9 it is found that relatively pure crystallization tranilast, it is dense that tranilast co-crystal thereof can reach higher blood medicine
It spends and the long period can be maintained, and peak time (Tmax) is earlier, work faster predictive of tranilast co-crystal thereof.Thus may be used
See, co-crystal thereof, which is made, in tranilast can effectively improve its oral administration biaavailability.
Embodiment 8
Tranilast can treat asthma and atopic dermatitis.It has been found that tranilast energy in research in the past 10 years
Diabetogenous nephrosis fibrosis is reduced, to delay and/or prevent renal insufficiency.Therefore, tranilast co-crystal thereof is investigated in anti-fibre
Effect in terms of dimensionization.Specific implementation method is as follows.
1, ADR kidney fibrosis rat model is established
After being anaesthetized under 10% chloraldurate of rat (300mg/kg) peritonaeum, takes prone position and four limbs are fixed, conventional preserved skin disappears
Poison, back center is other to open right 0.5cm notch, is about 2cm, successively cuts off skin, muscle, fascia, the right kidney of exposure, removing fat
Capsule, haemostatic clamp clamps the arteria renalis, ureter, and ligatures, and extracts right side kidney, closes abdominal cavity, layering suture.Postoperative muscle injection
Benzylpenicillin sodium salt (80,000 units/kg), prevention of postoperative infection, for three days on end, and postoperative the l weeks tail vein injection ADR5mg/kg, postoperative the
It presses 3mg/kg repeat administration 1 time within 2 weeks, it is formal to test the preliminary experiment that moves ahead, if Pathological shows that glomerular mesangium territorial matrix increases,
The contracting of renal tubule ginger, interstitial fibrosis then prompt modeling success.
2, rat grouping and administration
ADR kidney fibrosis rat is divided into normal group, sham-operation group, model group, tranilast group and tranilast benzoyl
Amine co-crystal thereof group, every group 6.The raising of normal rats normal condition, not modeling give physiological saline intraperitoneal injection；Artificial hand
After art group rat cuts off right kidney, ADR is not injected, gives physiological saline intraperitoneal injection；Model group is by giving physiology after upper method modeling
Salt water intraperitoneal injection；Tranilast group and tranilast benzamide co-crystal thereof group rat give bent Buddhist nun by after upper method modeling
The special group of department and tranilast benzamide co-crystal thereof normal saline solution (10mg/kg.d) intraperitoneal injection.Successive administration 8
Rat is put to death after week, each group rat puts to death first 1 day and collects twenty-four-hour urine amount with metabolic cage.With 10% chloraldurate when putting to death rat
After being anaesthetized under (300mg/kg) peritonaeum, left kidney is extractd after abdominal aorta blood sampling 3-5mL and is put into liquid after physiological saline cleans blood
Nitrogen saves detection index of correlation.
3, rat urine albumen amount measures
Rat protein urine content is as shown in Figure 10, normally group a small amount of Urine proteins discharge visible with rats in sham-operated group, and two
Group comparing difference is not statistically significant (P > 0.05)；The discharge of model group rats Urine proteins significantly increases, poor compared with sham-operation group
Different statistically significant (P < 0.01)；Tranilast group and co-crystal thereof group rat Urine proteins, which are discharged, is less than model group, difference
Statistically significant (P < 0.01)；The rat for giving tranilast benzamide co-crystal thereof is more significant, and urine albumen amount is down to
40mg/d is hereinafter, opposite tranilast group difference has statistical significance (P < 0.01).
4, renal pathology changes
General histological observation is dyed to each group renal tissues of rats HE.Model group HE dyes visible glomerular mesangium area and increases
Width, sacculus wall thickening and adhosion, glomerulus are in local stove segment hardening, the contracting of tubule stove shape ginger, the visible inflammatory cell of surrounding
Infiltration；Msasno dyes the visible fibrosis of renal interstitial, though tranilast group and the visible model group of co-crystal thereof group renal tissues of rats
Above-mentioned change, but lesser extent.
Pathological lesion of renal tubulointerstitium in SD evaluation method: being 1-4 points according to kidney region fibrosis proportion score value, 0 point is
Normally (i.e. no tubular ectasia, atrophy, cast, necrosis or tubule are scorching)；1 point is kidney region fibrosis area less than 25%, 2
It is divided into 25%-49%, 3 points are 50%-75%, and 4 points is more than 75%.
Renal interstitial fibrosis appraisal result is as shown in figure 11, and compared with sham-operation group, model group renal tubular interstitium is fine
Dimensionization scoring is significant to be increased, and difference is statistically significant (P < 0.01)；Compared with model group, tranilast group and co-crystal thereof group
Renal interstitial fibrosis scoring decline, difference is statistically significant (P < 0.01), and compared with tranilast group, tranilast
Co-crystal thereof group renal interstitial fibrosis scores lower (P < 0.01).
Glomerulosclerosis index (GSI) is calculated using the semiquantitative method of Raij.Glomerulosclerosis shows as capillary lumen
It collapses and/or hyalinization, every sample slice light microscopic (10 × 40) randomly selects 10 visuals field, calculate separately scoring, make even
Mean value, the GSI as the sample.Method particularly includes: every slice at least observes 30 complete glomerulus, according to shared by hardening stove
Glomerulus ratio divides 0-3 grades.It without lesion or lesion area is lesion area 52%-50% less than 52%, 1 grade that 0 grade, which is glomerulus,
2 grades are lesion area 51%-75%, and 3 grades are greater than 76% for lesion area.Calculating GSI=[(1 × n1+2 × n2+3 × n3)/it is every
Piece glomerulus sum] × 100% (n1 be l grade of the glomerulus number of scoring, and 2n is the glomerulus number of 2 grades of scoring, and n3 is 3 grades
Glomerulus number).
Glomerulosclerosis index score result is as shown in figure 12, compared with sham-operation group, model group, tranilast group and altogether
Crystalline solid group Progression of Glomerulosclerosis index significantly increases, and difference is statistically significant (P < 0.01), but tranilast group and mould
Type group compares, and glomerulosclerosis index is substantially reduced (P < 0.01)；Tranilast co-crystal thereof group is compared with tranilast group, kidney
Bead hardenability value is lower (P < 0.01).
The above is only a preferred embodiment of the present invention, it should be pointed out that: for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of tranilast co-crystal thereof, which is characterized in that the general formula of the co-crystal thereof is as shown in Equation 1；
Wherein-R1For one kind of phenyl, 2- piperidyl, 2- methyl -3- pyridyl group.
2. tranilast co-crystal thereof according to claim 1, which is characterized in that the co-crystal thereof be tranilast with
Amides compound (R1-CONH2) formed co-crystal thereof；The co-crystal thereof is selected from tranilast benzamide co-crystal thereof, bent
Ni Site 2- piperidine formamide or tranilast 2- methylnicotinamide co-crystal thereof.
3. the preparation method of tranilast co-crystal thereof of any of claims 1 or 2, characterized in that it comprises the following steps:
(1) tranilast of weighed equimolar ratio and amides compound R1-CONH2, it is placed in test tube；
(2) it pipettes in organic solvent to test tube, sealing of jumping a queue, is ultrasonically treated: frequency 40KHz, 30 DEG C of temperature, time 30min；
(3) it is placed in again and stirs 12h-18h under room temperature；
(4) suspension is filtered, filter cake partial vacuum is dry, obtains tranilast co-crystal thereof powder；
(5) filtrate is placed in volatile organic solvent culture monocrystalline at room temperature, until obtaining colorless and transparent column crystal；
(6) it is measured using single crystal X-ray diffraction instrument.
4. preparation method according to claim 3, which is characterized in that amides compound R1-CONH2Selected from benzamide,
2- piperidine formamide or 2- methylnicotinamide, preferably benzamide.
5. preparation method according to claim 3, which is characterized in that organic solvent is acetone, methanol or ethyl alcohol, preferably third
Ketone.
6. a kind of tranilast benzamide co-crystal thereof, which is characterized in that have selected from 11.24,12.64,13.06,
16.26, the powder X-ray diffraction pattern at least three peaks of 18.65,21.01,22.51 ° of 2 θ ± 0.2 °, 2 θ；Or have and Fig. 1
Substantially similar powder X-ray diffraction pattern.
7. a kind of tranilast 2- piperidine formamide co-crystal thereof, which is characterized in that have selected from 8.70,8.94,14.75,
22.67, the powder X-ray diffraction pattern at least three peaks of 23.00,28.16,28.46 ° of 2 θ ± 0.2 °, 2 θ；Or have and Fig. 2
Substantially similar powder X-ray diffraction pattern.
8. a kind of tranilast 2- methylnicotinamide co-crystal thereof, which is characterized in that have selected from 9.87,16.01,18.37,
20.91, the powder X-ray diffraction pattern at least three peaks of 26.17 ° of 22 θ of θ ± 0.2 °；Or with the powder substantially similar with Fig. 3
Last X-ray diffraction pattern.
9. tranilast co-crystal thereof described in claim 1 has the photostability improved and dissolubility and biology benefit in preparation
Application in the tranilast drug of expenditure.
10. tranilast co-crystal thereof described in claim 1 is in terms of improving tranilast bulk pharmaceutical chemicals anti-fibrosis effect
Using.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1946753A1 (en) * | 2005-10-21 | 2008-07-23 | Medrx Co., Ltd. | Preparation for external application comprising salt of mast cell degranulation inhibitor having carboxyl group with organic amine |
| CN104379130A (en) * | 2012-03-30 | 2015-02-25 | 诺弗米克斯有限公司 | Tranilast compositions and cocrystals |
-
2018
- 2018-12-28 CN CN201811618543.4A patent/CN109503415A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1946753A1 (en) * | 2005-10-21 | 2008-07-23 | Medrx Co., Ltd. | Preparation for external application comprising salt of mast cell degranulation inhibitor having carboxyl group with organic amine |
| CN104379130A (en) * | 2012-03-30 | 2015-02-25 | 诺弗米克斯有限公司 | Tranilast compositions and cocrystals |
Non-Patent Citations (2)
| Title |
|---|
| NA GENG 等: "Approach of Cocrystallization to Improve the Solubility and Photostability of Tranilast", 《CRYSTAL GROWTH & DESIGN》 * |
| 耿娜: "阿戈美拉汀多晶型和曲尼司特共晶的研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
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Application publication date: 20190322 |