CN110357812A - The eutectic compound being made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor - Google Patents
The eutectic compound being made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor Download PDFInfo
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Abstract
The present invention provides a kind of eutectic compound being made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor and containing the composition of the eutectic compound, it is characterized in that, lipase inhibitor of the present invention is selected from orlistat and west for one of Li Sita；And the hydroxy-3-methylglutaryl CoA reductase inhibitor is selected from one of Atorvastatin, Rosuvastatin, Simvastatin, Fluvastatin, Pravastatin, Lovastatin and Pitavastatin or its pharmaceutically acceptable salt.The antibacterial action that eutectic compound of the present invention can generate collaboration simultaneously is acted on the inhibition histamine release cooperateed with, so as to improve the effect and economic feature that bacterium infection causes anaphylactia patient treatment.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to it is a kind of by lipase inhibitor and hydroxyl first glutaryl coenzyme A also
The eutectic compound that reductase inhibitor is constituted and the composition containing the compound.
Background technique
Allergy is also referred to as allergic reaction.It is body by antigenicity substance (such as bacterium, virus, helminth, pollen
Deng) stimulation after caused tissue damage or physiological dysfunction.Belong to abnormal or Focal immune response.It is usually said
Allergic reaction refer to I type allergic reaction, i.e. type Ⅰ hypersensitivity reaction.Its mechanism is production after anaphylactogen enters in allergy sufferers body
The antibody of raw specificity, the latter are incorporated in the surface of mast cell, make body in sensitization, when secondary contact allergy original, fertilizer
Maxicell degranulation, and a variety of chemical mediators are discharged, such as serotonin, slow reacting substance, histamine, leukotriene.These media
The pathological change or symptom of initiation are referred to as the speed hair phase of type Ⅰ hypersensitivity reaction.
The release of inhibition histamine is one of the main mechanism of a variety of Claritins.
As previously mentioned, bacterium stimulation is one of the reason of leading to allergy, at the same have inhibit histamine release effect and
The drug of antibacterial action will bring beneficial effect for improving the therapeutic effect of the patient of bacterium cause allergy, especially
The economic feature of its treatment can be improved.
It is clinical using Atorvastatin as hydroxyl first glutaryl coenzyme A (HMG-CoA) reductase inhibitor class drug of representative
Upper common regulating plasma lipid medicine, the antibacterial activity of such drug appears in the newspapers announcement repeatly in recent years.JerwoodS et al. researches show that
(JAntimicrobChemother.2008Feb；61 (2): 362-4), Simvastatin and Fluvastatin all have certain antibacterial
Effect, wherein the former is respectively 29.2 and 74.9mg/L to the average MIC of MSSA and MRSA, and in contrast, Fluvastatin
Antibacterial action be substantially less than Simvastatin.WelshAM et al. reports (Pathology.2009；41 (7): 689-91) claim atropic
Cutting down statin and Rosuvastatin also has antibacterial action, but is all remarkably higher than it to the MIC value of MRSA and MSSA and is used to adjust blood
Typical blood concentration when rouge.MasadehM(AnnClinMicrobiolAntimicrob.2012May7；11:13) et al.
Report the antibacterial action of Atorvastatin, Simvastatin and Rosuvastatin, but its MIC value it is equal > 100mg/L, and antibacterial
Mechanism of action is unrelated with hydroxyl first glutaryl coenzyme A.
The research of KrauthMT et al. confirms (Allergy.2006Mar；61 (3): 281-8.), Atorvastatin with
Cerivastatin can inhibit the histamine release of people's mast cell of anti-IgE induction.
It is two kinds of lipase inhibitor class loss of weight drugs that Li Sita (cetilistat) is replaced in orlistat and west, due to fat
Enzyme has expression in various bacteria and regulates and controls the growth and function of bacterium, therefore orlistat may also have centainly
Antibacterial action, the present inventor also demonstrate this point in laboratory works.
The present inventor is in laboratory work it has also been found that orlistat and west for Li Sita also there is the histamine of moderate to inhibit
Act on
Another early-stage study of the present inventor finds, including orlistat and west for Li Sita including lipase inhibit
The hydroxy-3-methylglutaryl CoA reductase inhibitors such as agent and Atorvastatin can generate in the molar ratio range of 1:10~10:1
The bacteriostasis and antihistamine release action of collaboration.However, since the oral rear bioavilability of orlistat is extremely low, Er Qierong
Solution property is very poor, causes its bacteriostasis and antihistamine release action to be only limitted in alimentary canal, to greatly limit its application.
Pharmaceutical co-crystals refer to active pharmaceutical ingredient (activepharmaceulicalingredient, API) and eutectic
Formation (cocrystalformer, CCF) acts on, under Van der Waals force or other non-covalent bond effects in hydrogen bond, pi-pi accumulation,
With the crystal that fixed stoichiometric ratio is combined into, wherein the pure state of API and CCF is solid at room temperature, and API is point
It is sub or ionic.CCF is physiologically acceptable acid, alkali, non-ionic compound, can be auxiliary material, vitamin, minerals,
Amino acid and food additives etc..Some API molecules can also make CCF, two kinds of general indications of API in this kind of eutectic
It is similar either to play the role of synergy, and the stoichiometric ratio of the effective concentration relationship of the two and two components in eutectic
It is similar, so eutectic also provides a kind of new paragon for preparing compound medicine.In addition, eutectic can also improve the solubility of former API
With multiple physical signs such as bioavilability.
Temporary fat-free enzyme inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor form eutectic and produce in currently available technology
The bacteriostasis of raw collaboration and the technical teaching of antihistamine effect.
Summary of the invention
The purpose of the present invention is to provide one kind by lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor structure
At eutectic compound and contain the composition of the eutectic compound.The eutectic compound can generate the antibacterial of collaboration
Effect and antihistamine effect.
To achieve the goals above, present invention firstly provides one kind by lipase inhibitor and hydroxyl first glutaryl coenzyme A
The eutectic compound that reductase inhibitor is constituted, which is characterized in that the lipase inhibitor is to replace selected from orlistat with west
One of Li Sita, the hydroxy-3-methylglutaryl CoA reductase inhibitor be selected from Atorvastatin, Rosuvastatin,
One of Simvastatin, Fluvastatin, Pravastatin, Lovastatin and Pitavastatin or its pharmaceutically acceptable salt.
On the one hand preferred, lipase inhibitor and hydroxyl first glutaryl coenzyme A reductase in eutectic compound of the present invention
The molar ratio of enzyme inhibitor is between 0.329:1~3.097:1.
It is furthermore preferred that eutectic compound of the present invention is selected from one of eutectic compound as described below:
The eutectic compound that orlistat and Atorvastatin are constituted with the molar ratio of 2.858:1,
The eutectic compound that orlistat and Rosuvastatin are constituted with the molar ratio of 1.932:1,
The eutectic compound that orlistat and Simvastatin are constituted with the molar ratio of 0.980:1,
The eutectic compound that orlistat and Pitavastatin are constituted with the molar ratio of 0.492:1,
The eutectic compound that west is constituted for Li Sita and Lovastatin with the molar ratio of 0.329:1,
The eutectic compound that west is constituted for Li Sita and Fluvastatin with the molar ratio of 3.097:1,
The eutectic compound that west is constituted for Li Sita and Pravastatin with the molar ratio of 2.059:1.
It is further preferred that eutectic compound of the present invention is selected from one of eutectic compound as described below:
Orlistat and Atorvastatin are constituted with the molar ratio of 2.858:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder slightly figure has the eutectic compound of maximum characteristic absorption peak at 34.6 °,
Orlistat and Rosuvastatin are constituted with the molar ratio of 1.932:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder slightly figure has the eutectic compound of maximum characteristic absorption peak at 29.1 °,
Orlistat and Simvastatin are constituted with the molar ratio of 0.980:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction
Ray powder slightly figure has the eutectic compound of maximum characteristic absorption peak at 17.8 °,
Orlistat and Pitavastatin are constituted with the molar ratio of 0.492:1, and the X- indicated with the 2 θ ± 0.2 ° angles of diffraction
Ray powder slightly figure has the eutectic compound of maximum characteristic absorption peak at 29.2 °,
West is constituted for Li Sita and Lovastatin with the molar ratio of 0.329:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder slightly figure has the eutectic compound of maximum characteristic absorption peak at 7.9 °,
West is constituted for Li Sita and Fluvastatin with the molar ratio of 3.097:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder slightly figure has the eutectic compound of maximum characteristic absorption peak at 18.5 °,
West is constituted for Li Sita and Pravastatin with the molar ratio of 2.059:1, and indicated with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder slightly figure has the eutectic compound of maximum characteristic absorption peak at 13.9 °.
Most preferably, eutectic compound of the present invention is selected from one of eutectic compound as described below:
Orlistat and Atorvastatin are constituted with the molar ratio of 2.858:1, and X-ray powder diffraction figure such as Fig. 1 institute
The eutectic compound shown,
Orlistat and Rosuvastatin are constituted with the molar ratio of 1.932:1, and X-ray powder diffraction figure such as Fig. 2 institute
The eutectic compound shown,
Orlistat and Simvastatin are constituted with the molar ratio of 0.980:1, and X-ray powder diffraction figure is as shown in Figure 3
Eutectic compound,
Orlistat and Pitavastatin are constituted with the molar ratio of 0.492:1, and X-ray powder diffraction figure is as shown in Figure 4
Eutectic compound,
West is constituted for Li Sita and Lovastatin with the molar ratio of 0.329:1, and X-ray powder diffraction figure such as Fig. 5 institute
The eutectic compound shown,
West is constituted for Li Sita and Fluvastatin with the molar ratio of 3.097:1, and X-ray powder diffraction figure such as Fig. 6 institute
The eutectic compound shown,
West is constituted for Li Sita and Pravastatin with the molar ratio of 2.059:1, and X-ray powder diffraction figure such as Fig. 7 institute
The eutectic compound shown.
Another aspect of the present invention provides the composition containing eutectic compound as previously described.
Preferably, composition of the present invention can be made into the pharmaceutical preparation of oral or injection administration.
It is further preferred that oral drug preparation of the present invention is selected from one of capsule, tablet and granule.
Another aspect of the present invention provide foregoing eutectic compound preparation for treat bacterial infection and/or
Purposes in the drug of anaphylactia.
Preferably, bacterial infection of the present invention be by selected from actinomyces viscosus, bacteroides fragilis, brevibacterium epidermidis,
Infection caused by one of clostridium difficile, clostridium tetani, paratyphosus A bacillus.
Eutectic compound of the present invention can generate antibacterial action and the antihistamine release action of collaboration simultaneously.
Figure of description explanation
Fig. 1 is the X-ray powder diffraction figure of 1 gained eutectic compound of embodiment,
Fig. 2 is the X-ray powder diffraction figure of 2 gained eutectic compound of embodiment,
Fig. 3 is the X-ray powder diffraction figure of 3 gained eutectic compound of embodiment,
Fig. 4 is the X-ray powder diffraction figure of 4 gained eutectic compound of embodiment,
Fig. 5 is the X-ray powder diffraction figure of 5 gained eutectic compound of embodiment,
Fig. 6 is the X-ray powder diffraction figure of 6 gained eutectic compound of embodiment,
Fig. 7 is the X-ray powder diffraction figure of 7 gained eutectic compound of embodiment,
Specific embodiment
Below with reference to the embodiment of the present invention, clear, complete description 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 implementation in the present invention
Example, every other embodiment obtained by those of ordinary skill in the art without making creative efforts belong to
The scope of protection of the invention.
The present invention indicates being total to for the two with hydroxy-3-methylglutaryl CoA reductase inhibitor with " " connection lipase inhibitor
Brilliant compound.
Molar ratio of the present invention is lipase inhibitor and HMG-CoA reductase in eutectic compound
The molar ratio of inhibitor.
The preparation of 1 eutectic compound
Present invention polishing with reference to disclosed by ScottC.McKellar et al. (CrystalGrowth&Design2014,
14,5,2422~2430) eutectic compound of the present invention has been prepared.
Specifically, the lipase inhibitor of certain mol proportion and hydroxy-3-methylglutaryl CoA reductase inhibitor is taken to be placed in ball
In grinding machine, ground 15~60 minutes with the frequency of 30~60Hz at room temperature.It is melted away from≤2 DEG C using product as standard, to ball milling
Unit frequency is optimized and is screened with milling time.
The structural identification and characterization of 2 eutectic compounds
The Preliminary detection of determination and purity that 2.1 eutectics are formed
If the product melting range of grinding is lower than 2 DEG C, then it is assumed that have formed single eutectic compound.
The measurement of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor molar ratio in 2.2 eutectic compounds
The present invention uses1H-NMR (500Hz, CD3Cl lipase inhibitor and hydroxyl first glutaryl in eutectic compound) are measured
The molar ratio of CoA-reductase inhibitors, specifically, by calculating various eutectic compounds1Specific suction in H-NMR map
Receive ratio (r) calculating molar ratio (R) that the corresponding peak area (X) in peak accounts for total peak area (Y).
Table 2 utilizes1H-NMR, which calculates lipase inhibitor and HMG-CoA reductase in each eutectic compound, to be pressed down
The method of preparation molar ratio
1.3X- ray powder diffraction
Use Rigaku Co., Ltd. X-ray powder diffraction instrument MiniFlex II, concrete operations parameter such as table 3.
3 X-ray powder diffraction instrument operating parameter of table
| Instrument model | RigakuMinfiFlexⅡ | Emit target | CuKα(1.5405A) |
| Scanning speed | 8°/min | Scanning step | 0.02° |
The preparation of 1. orlistat Atorvastatin eutectic compound of embodiment
Orlistat 148.719g and Atorvastatin 55.864g are taken, is sufficiently mixed and is placed in planetary ball mill,
55min is ground under the revolving speed of 350r/min, collects product, obtains 192.915g micro white powder, and fusing point is 73.3~75.3 DEG C.
With 192.306g white crystals type powder is obtained after ethyl alcohol recrystallization, fusing point is 73.4~74.3 DEG C, and R value is that 2.858, X- is penetrated
Line powder diagram is as shown in Figure 1.
The preparation of 2. orlistat Rosuvastatin eutectic compound of embodiment
Orlistat 132.195g and Rosuvastatin 64.205g are taken, is sufficiently mixed and is placed in planetary ball mill,
35min is ground under the revolving speed of 350r/min, collects product, obtains 178.411g micro white powder, and fusing point is 160.0~162.0
℃.With 177.975g white crystals type powder is obtained after acetone recrystallization, fusing point is 162.9~163.9 DEG C, and R value is 1.932,
X-ray powder diffraction figure is as shown in Figure 2.
The preparation of 3. orlistat Simvastatin eutectic compound of embodiment
Orlistat 99.146g and Simvastatin 83.714g are taken, is sufficiently mixed and is placed in planetary ball mill, in 400r/
60min is ground under the revolving speed of min, collects product, obtains 177.698g micro white powder, and fusing point is 180.5~182.5 DEG C.Use first
177.252g white crystals type powder is obtained after alcohol recrystallization, fusing point is 180.4~181.4 DEG C, and R value is 0.980, X-ray
Powder diagram is as shown in Figure 3.
The preparation of 4. orlistat Pitavastatin eutectic compound of embodiment
Orlistat 66.097g and Pitavastatin 112.389g are taken, is sufficiently mixed and is placed in planetary ball mill,
45min is ground under the revolving speed of 250r/min, collects product, obtains 177.852g micro white powder, and fusing point is 43.6~45.5 DEG C.
With 176.965g white crystals type powder is obtained after recrystallized from acetonitrile, fusing point is 111.1~112.0 DEG C, and R value is 0.492, X-
Ray powder diffraction pattern is as shown in Figure 4.
Replace the preparation of Li Sita Lovastatin eutectic compound in 5. west of embodiment
It takes west to take charge of his 40.129g and Lovastatin 121.392g for benefit, is sufficiently mixed and is placed in planetary ball mill,
30min is ground under the revolving speed of 250r/min, collects product, obtains 158.073g micro white powder, and fusing point is 126.3~128.3
℃.With 157.307g white crystals type powder is obtained after re-crystallizing in ethyl acetate, fusing point is 127.9~128.8 DEG C, and R value is
0.329, X-ray powder diffraction figure is as shown in Figure 5.
Replace the preparation of Li Sita Fluvastatin eutectic compound in 6. west of embodiment
It takes west to take charge of his 120.477g and Fluvastatin 41.147g for benefit, is sufficiently mixed and is placed in planetary ball mill,
55min is ground under the revolving speed of 350r/min, collects product, obtains 159.271g micro white powder, and fusing point is 114.3~116.1
℃.With 158.954g white crystals type powder is obtained after recrystallisation from isopropanol, fusing point is 114.1~115.1 DEG C, and R value is 3.097,
Its X-ray powder diffraction figure is as shown in Figure 6.
Replace the preparation of Li Sita Pravastatin eutectic compound in 7. west of embodiment
It takes west to take charge of his 107.091g and Pravastatin 59.535g for benefit, is sufficiently mixed and is placed in planetary ball mill,
40min is ground under the revolving speed of 250r/min, collects product, obtains 157.108g micro white powder, and fusing point is 144.2~146.1
℃.With 156.963g white crystals type powder is obtained after ethyl alcohol recrystallization, fusing point is 142.5~143.5 DEG C, and R value is 2.059,
X-ray powder diffraction figure is as shown in Figure 7.
1 lipase inhibitor of test example, hydroxy-3-methylglutaryl CoA reductase inhibitor and lipase inhibitor hydroxyl first penta
The antibacterial action of two acyl coenzyme A reductase inhibitor eutectic compounds
Measure lipase inhibitor, hydroxy-3-methylglutaryl CoA reductase inhibitor and fat respectively using filter paper enzyme
Bacteriostatic activity of the enzyme inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor eutectic compound to various bacteria.Specifically,
Prepared bacterial suspension (1 × 10 is drawn with liquid-transfering gun5Preparation method :/mL will be trained for examination strain in slant tube
It supports and is activated [37 ± 1 DEG C, 3 days] on base, recycle oese to beat easily a small amount of lawn from inclined-plane, be respectively added to hold
In the conical flask for having 50mL sterile saline), it is uniformly applied to agar plate surface after cooling, plate containing bacterium is made.It takes
Sterilizing filter paper piece is let off in the tested material methanol solution of 6 kinds of concentration gradients respectively and impregnates 1h, the 6mm circular filter paper that will be impregnated
Piece is attached on the above-mentioned plate containing bacterium made, and it is tested that each culture dish (diameter 90mm) sticks 3 dipped same mass concentrations
The filter paper (filter paper is spaced identical as far as possible) of object methanol solution, using 50% methanol solution as blank control.Processed
Plate containing bacterium, which is placed in 37 DEG C of insulating boxs, to be cultivated for 24 hours, measures colony diameter using crossing method, and according to following formula meter
It calculates inhibiting rate (IR).
It is mapped with logarithm of the inhibiting rate (IR) to free drug concentration (μM), and carries out linear regression with Excel, according to
Regression equation extrapolates the concentration for generating lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor when fa inhibits, point
It Wei not ICfa(A)With ICfa(B)Value.For eutectic compound, then with inhibiting rate (IR) to the dense of eutectic compound lipase inhibitor
Logarithm (log (the c)) mapping of (μM) is spent, and carries out linear regression with Excel, when extrapolating fa inhibition according to regression equation
The concentration of lipase inhibitor in eutectic compound, i.e. ICfa(mixA), further according to R value, it is multiple to extrapolate eutectic when fa inhibits
Close the concentration of hydroxy-3-methylglutaryl CoA reductase inhibitor in object, i.e. ICfa(mixB)。
The eutectic compound index (CI) generated when fa inhibits is calculated according to the following formula
It when CI < 1, as acts synergistically, CI value is smaller, acts synergistically stronger.
As a result as shown in table 4~9.
Association of the 4 lipase inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor eutectic compound of table to actinomyces viscosus
Same bacteriostasis
Note:
aMaximum concentration refers to the minimum concentration of tested material when inhibiting rate enters plateau, for eutectic compound, institute
State the maximum concentration that maximum concentration refers to lipase inhibitor in eutectic compound.
bThe slope and intercept represent the slope and intercept of IR-log (c) equation of linear regression.
cFor eutectic compound, ICfaRepresent ICfa(mixA).
The definition of 5~table of table, 10 gauge outfit is identical as table 4.
5 lipase inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor of table is to the antibacterial work of the collaboration of bacteroides fragilis
With
6 lipase inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor of table is to the antibacterial work of the collaboration of brevibacterium epidermidis
With
Collaboration bacteriostasis of the 7 lipase inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor of table to clostridium difficile
8 lipase inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor of table is to the antibacterial work of the collaboration of clostridium tetani
With
Collaboration of the 9 lipase inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor of table to paratyphosus A bacillus
Bacteriostasis
2 lipase inhibitor of test example, hydroxy-3-methylglutaryl CoA reductase inhibitor and two kinds of eutectic compound inhibit
The effect of histamine release
Logarithmic growth phase, RBL-2H3 cell are collected, and its concentration is adjusted to 8 × 104/ mL is uniformly inoculated in 96 holes
In plate, every 200 μ L cell suspension of hole, in 37 DEG C, 5%CO2, saturated humidity incubator in cultivate for 24 hours, discard culture medium,
Every hole adds 200 μ L tested material (lipase inhibitors, hydroxyl first penta after the Tween 80 (being scattered in PBS) of 200mg/mL is added
Two acyl coenzyme A reductase inhibitors, lipase inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor are scattered in PBS),
Reagent controls group is set simultaneously, and 200 μ LPBS, 37 DEG C of incubation 30min are added in every hole.It is incubated for after terminating, takes out cell conditioned medium 100
μ L is placed in test fluorescent plate (extra supernatant freezes in -20 DEG C of refrigerators, spare), 50 μ L of each hole addition of test board,
After 0.4mol/LNaOH, 0.1% o-phthalaldehyde-methanol solution, 10 μ L is added immediately, mixes, is placed at room temperature for 10min, is added
50 μ L, 0.5mol/LHCl terminate reaction, detect A value (incident wavelength 360nm, launch wavelength 450nm) with microplate reader immediately, institute
There is tested material group to be calculated as ASupernatant, solvent control group is calculated as ABackground。
Remaining cell is cracked with 0.5% Triton100-PBS solution in 96 orifice plates, after 37 DEG C of incubation 30min, is taken thin
100 μ L of cellular lysate liquid is placed in test fluorescent plate (extra lysate freezes in -20 DEG C of refrigerators, spare), each hole of test board
After 50 μ L, 0.4mol/LNaOH is added, 0.1% o-phthalaldehyde-methanol solution, 10 μ L is added immediately, mixes, is placed at room temperature for
10min is added 50 μ L, 0.5mol/LHCl and terminates reaction, detects A value (incident wavelength with microplate reader immediately after mixing
360nm, launch wavelength 450nm), with A above-mentionedSupernatantThe sum of value is calculated as ASupernatant+cracking, the group of each tested material is calculated further according to following formula
Amine release rateT:
Histamine release rateT(%)=(ASupernatant-ABackground)/(ASupernatant+cracking-ABackground)×100
Above-mentioned test is repeated only with Tween 80, obtains the histamine release rate of Tween 80P, calculated further according to following formula various tested
The inhibiting rate IR for the histamine release that object induces Tween 80.
IR (%)=(1- histamine release rateT/ histamine release rateP)×100
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 for generating lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor when fa inhibits, respectively
ICfa(A)With ICfa(B)Value.For eutectic compound, then with inhibiting rate (IR) in eutectic compound lipase inhibitor it is dense
Logarithm (log (the c)) mapping of (μM) is spent, and carries out linear regression with Excel, when extrapolating fa inhibition according to regression equation
The concentration of lipase inhibitor in eutectic compound, i.e. ICfa(mixA), further according to the ratio of the amount of substance in eutectic compound, push away
Calculate the concentration of hydroxy-3-methylglutaryl CoA reductase inhibitor in eutectic compound when fa inhibits, i.e. ICfa(mixB)。
The eutectic compound index (CI) generated when fa inhibits is calculated according to the following formula
It when CI < 1, as acts synergistically, CI value is smaller, acts synergistically stronger.
The results are shown in Table 10.
Table 10
It is compound that embodiment 8 contains the eutectic being made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor
The preparation of the oral solid formulation of object
Prescription (1000 unit dose)
Preparation method
50g eutectic compound and recipe quantity auxiliary material are taken, is sieved with 100 mesh sieve.Take eutectic compound, lactose, microcrystalline cellulose,
Crospovidone is mixed well with starch；The hydroxypropyl methylcellulose for taking recipe quantity, be configured to be according to hydroxypropyl methylcellulose meter concentration
The softwood processed into above-mentioned mixed material is added with newborn acid for adjusting pH to 3.0~4.0 in 10% solution, is pelletized with 16 meshes, and 80
DEG C dry 3~4h.With 16 mesh sieves, it is added the superfine silica gel powder of recipe quantity and magnesium stearate mixes mixing, filling capsule, i.e.,
Obtain capsule；
50g eutectic compound and recipe quantity auxiliary material are taken, is sieved with 100 mesh sieve.Take eutectic compound, lactose, microcrystalline cellulose,
Crospovidone is mixed well with starch；The hydroxypropyl methylcellulose for taking recipe quantity, be configured to be according to hydroxypropyl methylcellulose meter concentration
The softwood processed into above-mentioned mixed material is added with newborn acid for adjusting pH to 3.0~4.0 in 10% solution, is pelletized with 16 meshes, and 80
DEG C dry 3~4h.With 16 mesh sieves, be added the superfine silica gel powder of recipe quantity and magnesium stearate mix mixing, packing to get
Granula；
50g eutectic compound and recipe quantity auxiliary material are taken, is sieved with 100 mesh sieve.Take eutectic compound, lactose, microcrystalline cellulose,
Crospovidone is mixed well with starch；The hydroxypropyl methylcellulose for taking recipe quantity, be configured to be according to hydroxypropyl methylcellulose meter concentration
The softwood processed into above-mentioned mixed material is added with newborn acid for adjusting pH to 3.0~4.0 in 10% solution, is pelletized with 16 meshes, and 80
DEG C dry 3~4h.With 16 mesh sieves, the superfine silica gel powder of recipe quantity is added and magnesium stearate mixes mixing, tabletting both obtains piece
Agent.
Injection of the embodiment 9 containing lipase inhibitor hydroxy-3-methylglutaryl CoA reductase inhibitor eutectic compound
The preparation of liquid
Prescription (100)
| Prescription number | Eutectic compound source | Other auxiliary materials |
| 1. | Embodiment 1 | Sodium citrate 0.3g, 0.5mol/L citric acid, water for injection |
| 2. | Embodiment 2 | Sodium citrate 0.3g, 0.5mol/L citric acid, water for injection |
| 3. | Embodiment 3 | Sodium citrate 0.3g, 0.5mol/L citric acid, water for injection |
| 4. | Embodiment 4 | Sodium citrate 0.3g, 0.5mol/L citric acid, water for injection |
| 5. | Embodiment 5 | Sodium citrate 0.3g, 0.5mol/L citric acid, water for injection |
| 6. | Embodiment 6 | Sodium citrate 0.3g, 0.5mol/L citric acid, water for injection |
| 7. | Embodiment 7 | Sodium citrate 0.3g, 0.5mol/L citric acid, water for injection |
Preparation method
1.5g eutectic compound, recipe quantity sodium citrate are taken, with 0.5mol/L citric acid after adding water for injection 100mL to dissolve
Adjust pH to 5.0 or so.Sterilizing, filtering, packing to get.
Claims (10)
1. the eutectic compound being made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor, which is characterized in that
The lipase inhibitor is selected from orlistat and west for one of Li Sita, and the hydroxyl first glutaryl coenzyme A is also
Reductase inhibitor be selected from Atorvastatin, Rosuvastatin, Simvastatin, Fluvastatin, Pravastatin, Lovastatin with
Cut down one of statin or its pharmaceutically acceptable salt.
2. eutectic compound according to claim 1, which is characterized in that lipase inhibitor and hydroxyl first in the eutectic compound
The molar ratio of glutaryl CoA reductase inhibitor is between 0.329:1~3.097:1.
3. eutectic compound according to claim 2, which is characterized in that the eutectic compound is selected from eutectic as described below
One of compound:
The eutectic compound that orlistat and Atorvastatin are constituted with the molar ratio of 2.858:1,
The eutectic compound that orlistat and Rosuvastatin are constituted with the molar ratio of 1.932:1,
The eutectic compound that orlistat and Simvastatin are constituted with the molar ratio of 0.980:1,
The eutectic compound that orlistat and Pitavastatin are constituted with the molar ratio of 0.492:1,
The eutectic compound that west is constituted for Li Sita and Lovastatin with the molar ratio of 0.329:1,
The eutectic compound that west is constituted for Li Sita and Fluvastatin with the molar ratio of 3.097:1,
The eutectic compound that west is constituted for Li Sita and Pravastatin with the molar ratio of 2.059:1.
4. eutectic compound according to claim 3, which is characterized in that the eutectic compound is selected from eutectic as described below
One of compound:
Orlistat and Atorvastatin are constituted with the molar ratio of 2.858:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate
Line powder slightly figure has the eutectic compound of maximum characteristic absorption peak at 34.6 °,
Orlistat and Rosuvastatin are constituted with the molar ratio of 1.932:1, and are penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate
Line powder slightly figure has the eutectic compound of maximum characteristic absorption peak at 29.1 °,
Orlistat and Simvastatin are constituted with the molar ratio of 0.980:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction
Powder slightly figure has the eutectic compound of maximum characteristic absorption peak at 17.8 °,
Orlistat and Pitavastatin are constituted with the molar ratio of 0.492:1, and the X-ray indicated with the 2 θ ± 0.2 ° angles of diffraction
Powder slightly figure has the eutectic compound of maximum characteristic absorption peak at 29.2 °,
West is constituted for Li Sita and Lovastatin with the molar ratio of 0.329:1, and is penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate
Line powder slightly figure has the eutectic compound of maximum characteristic absorption peak at 7.9 °,
West is constituted for Li Sita and Fluvastatin with the molar ratio of 3.097:1, and is penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate
Line powder slightly figure has the eutectic compound of maximum characteristic absorption peak at 18.5 °,
West is constituted for Li Sita and Pravastatin with the molar ratio of 2.059:1, and is penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate
Line powder slightly figure has the eutectic compound of maximum characteristic absorption peak at 13.9 °.
5. eutectic compound according to claim 4, which is characterized in that the eutectic compound is selected from eutectic as described below
One of compound:
Orlistat and Atorvastatin are constituted with the molar ratio of 2.858:1, and X-ray powder diffraction figure is as shown in Figure 1
Eutectic compound,
Orlistat and Rosuvastatin are constituted with the molar ratio of 1.932:1, and X-ray powder diffraction figure is as shown in Figure 2
Eutectic compound,
Orlistat and Simvastatin are constituted with the molar ratio of 0.980:1, and X-ray powder diffraction figure is as shown in Figure 3 is total to
Brilliant compound,
Orlistat and Pitavastatin are constituted with the molar ratio of 0.492:1, and X-ray powder diffraction figure is as shown in Figure 4 is total to
Brilliant compound,
West is constituted for Li Sita and Lovastatin with the molar ratio of 0.329:1, and X-ray powder diffraction figure is as shown in Figure 5
Eutectic compound,
West is constituted for Li Sita and Fluvastatin with the molar ratio of 3.097:1, and X-ray powder diffraction figure is as shown in FIG. 6
Eutectic compound,
West is constituted for Li Sita and Pravastatin with the molar ratio of 2.059:1, and X-ray powder diffraction figure is as shown in Figure 7
Eutectic compound.
6. the composition containing eutectic compound according to claim 1~any one of 5.
7. composition according to claim 6, which is characterized in that the composition can be made into the drug of oral or injection administration
Preparation.
8. composition according to claim 7, which is characterized in that the oral drug preparation be selected from capsule, tablet with
One of granula.
9. eutectic compound according to claim 1~any one of 5 or the group according to any one of claim 6~8
It closes object and is preparing the purposes in the drug for treating bacterial infection and/or anaphylactia.
10. purposes according to claim 9, it is characterised in that the bacterial infection is by quasi- selected from actinomyces viscosus, fragility
Infection caused by one of bacillus, brevibacterium epidermidis, clostridium difficile, clostridium tetani, paratyphosus A bacillus.
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| CN110812363A (en) * | 2019-11-16 | 2020-02-21 | 中山万汉制药有限公司 | Composition containing trisubstituted phosphine oxide and oxetanone derivative and use thereof |
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| WO2008143491A1 (en) * | 2007-05-21 | 2008-11-27 | Espinosa Abdala Leopoldo De Je | Pharmaceutical compositions combining a hydrogenated lipstatin derived agent and a hmg-coa reductase inhibiting agent |
| CN101756990A (en) * | 2008-11-10 | 2010-06-30 | 鲁南制药集团股份有限公司 | Medical composition for losing weight or treating hyperlipidemia |
| CN109276719A (en) * | 2018-11-01 | 2019-01-29 | 中山万汉制药有限公司 | Composition containing orlistat nanoparticle and kinases inhibitor |
-
2019
- 2019-08-03 CN CN201910714045.8A patent/CN110357812A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008143491A1 (en) * | 2007-05-21 | 2008-11-27 | Espinosa Abdala Leopoldo De Je | Pharmaceutical compositions combining a hydrogenated lipstatin derived agent and a hmg-coa reductase inhibiting agent |
| CN101756990A (en) * | 2008-11-10 | 2010-06-30 | 鲁南制药集团股份有限公司 | Medical composition for losing weight or treating hyperlipidemia |
| CN109276719A (en) * | 2018-11-01 | 2019-01-29 | 中山万汉制药有限公司 | Composition containing orlistat nanoparticle and kinases inhibitor |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110812363A (en) * | 2019-11-16 | 2020-02-21 | 中山万汉制药有限公司 | Composition containing trisubstituted phosphine oxide and oxetanone derivative and use thereof |
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Application publication date: 20191022 |
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