CN109010348B - Lacidipine-spironolactone co-amorphous solid dispersion and preparation thereof - Google Patents
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Abstract
The invention belongs to the technical field of medicines, and relates to lacidipine-spironolactone co-amorphous solid dispersion and a preparation method thereof. The invention uses lacidipine and spironolactone which have synergistic pressure reduction effect as carriers, and adopts a solvent volatilization method to prepare the co-amorphous solid dispersion. The lacidipine and the spironolactone are combined according to the molar ratio of 1:1-9, Cu-Kalpha radiation is used, and a powder X-ray diffraction spectrum expressed by a 2 theta angle has no sharp diffraction peak; the peak position and the peak intensity of the co-amorphous solid dispersion in the Fourier infrared spectrum are obviously changed. Compared with lacidipine crystals and spironolactone crystals, the dissolution rate and dissolution rate of lacidipine and spironolactone in the co-amorphous solid dispersion are remarkably improved. The preparation method of the solid dispersion is simple and easy to implement, has good reproducibility, is easy to amplify production, carries out industrial conversion, and has good clinical application prospect.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to lacidipine-spironolactone co-amorphous solid dispersion and a preparation method thereof.
Background
The chemical name of Lacidipine (Lacidipine) is: (E) -4- [2- [3- (1, 1-Dimethylethoxy) -3-oxo-1-propenyl]Phenyl radical]Diethyl (E) -1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylate is a specific, powerful and durable dihydropyridine calcium channel blocker, and is mainly used for selectively blocking calcium channels of vascular smooth muscles, dilating peripheral arteries, reducing peripheral vascular resistance, reducing afterload of heart and lowering blood pressure. Is clinically used as a first-line medicament for treating the hypertension. In terms of physical properties, lacidipine is white or off-white crystalline powder, is unstable when exposed to light, is easily soluble in ethyl acetate, is soluble in acetone, is slightly soluble in methanol and ethanol, and is almost insoluble in water. The melting point is 175-179 ℃. Molecular formula and molar mass are respectively C26H33NO6And 455.54 g/mol. The structural formula is as follows:
spironolactone (Spironolactone) has the chemical name: 17 β -hydroxy-3-oxo-7 α - (acetylsulfanyl) -17 α -pregn-4-ene-21-carboxylic acid- γ -lactone; the (7 alpha, 17 alpha) -7- (acetylmercapto) -17-hydroxy-3-oxopregn-4-ene-21-carboxylic acid gamma-lactone is an artificially synthesized steroid compound, has a structure similar to that of aldosterone, is a competitive inhibitor of aldosterone, has diuretic and antihypertensive effects, is often used as an auxiliary drug for treating hypertension, and is combined with other antihypertensive drugs. In terms of physical properties, spironolactone is a white or off-white fine crystalline powder, and has slight thiol odor. It is very soluble in chloroform, soluble in benzene or ethyl acetate, soluble in ethanol, and insoluble in water. Molecular formula and molar mass are respectively C24H32O5S and 416.57 g/mol. The melting point is 203-209 ℃, and the melting and the decomposition are carried out simultaneously. The structural formula is as follows:
the lacidipine and the spironolactone are two insoluble medicines with pharmacological synergistic effect, the blood pressure is reduced through different action mechanisms respectively, and the antihypertensive medicines with the different action mechanisms are used in a combined manner, so that adverse reactions are reduced, the drug effect is enhanced, and the clinical individualized treatment is realized.
For the long-term treatment of chronic diseases such as hypertension, the oral administration is especially important as a simple, safe and highly patient-compliant administration mode. For BCS class II drugs, the solubility of the drug is the primary factor limiting its dissolution rate, which in turn limits its oral bioavailability. Therefore, the improvement of the solubility of the slightly soluble drug has great significance for improving the oral bioavailability of the slightly soluble drug.
Co-amorphous (Co-amophorus) is a single-phase amorphous binary system with a single glass transition temperature formed by combining a pharmaceutically active ingredient with other small molecular substances (drugs or excipients). The co-amorphous form is in a thermodynamic high-energy state, can improve the physical and chemical properties of the drug such as solubility, dissolution rate, stability and the like, has higher stability than an amorphous monomer, and is a new way for drug research and development.
Through a large amount of researches, after the lacidipine and the spironolactone are prepared into the co-amorphous solid dispersion, the dissolution rates of both the lacidipine and the spironolactone in the co-amorphous solid dispersion are remarkably improved, and the co-amorphous solid dispersion has good high-humidity stability.
Disclosure of Invention
The invention aims to prepare a lacidipine-spironolactone co-amorphous solid dispersion. The co-amorphous solid dispersion has high drug loading, can obviously improve the solubility and in-vitro dissolution rate of two insoluble drugs, and has good high-humidity stability. Meanwhile, the combination of the two medicines with different action mechanisms can generate synergistic pharmacological action, thereby improving the curative effect and being beneficial to the individual treatment in clinic.
The invention provides a lacidipine-spironolactone co-amorphous solid dispersion, which comprises lacidipine and spironolactone, wherein the molar ratio of the lacidipine to the spironolactone is as follows: 3:1 to 1:9, preferably: 1:1 to 1:9, more preferably 1:6 to 1: 9.
Further, the molar ratio of lacidipine and spironolactone can be 3:1, 1:1, 1:3, 1:6,1: 9.
The molar ratio of lacidipine to spironolactone is: at 3:1, 1:1 and 1:3, at 120 minutes, the dissolution rates of lacidipine and spironolactone are respectively 5.1%, 21% and 56%, and the dissolution rates of spironolactone are respectively 46.2%, 57% and 60.4%; and the molar ratio of the lacidipine to the spironolactone is as follows: at 1:6 and 1:9, the dissolution rates of lacidipine and spironolactone were 69% and 63.7%, respectively, and 68.4% and 58.3%, respectively.
At 120 minutes, the lacidipine-spironolactone co-amorphous solid dispersion is in the range of 1:3-1:9, the lacidipine is dissolved out by more than 50%, the spironolactone is dissolved out by more than 50%, and in the range, the lacidipine and the spironolactone are synchronously released, so that a good synergistic effect can be achieved between the lacidipine and the spironolactone.
When the lacidipine-spironolactone co-amorphous solid dispersion is in the range of 1:6-1:9, the lacidipine is dissolved out by more than 60%, the spironolactone is dissolved out by more than 55%, the lacidipine and the spironolactone are both dissolved out optimally, and the synergistic effect is optimal.
Meanwhile, the high-humidity stability test is carried out on the lacidipine-spironolactone co-amorphous solid dispersion, and the result shows that: the molar ratio of lacidipine to spironolactone is: at the ratio of 1:6 and 1:9, after being placed under high humidity conditions (RH 92.5%) for 10 days, the lacidipine dissolution rates are 67.1% and 64.9%, and the spironolactone dissolution rates are 60.9% and 64.7%, respectively. The stability of the 1:6 and 1:9 amorphous solid dispersions was demonstrated to be good under high humidity conditions.
The lacidipine-spironolactone co-amorphous solid dispersion has the following characteristics:
1. powder X-ray diffraction (PXRD)
The PXRD diffraction pattern of the lacidipine-spironolactone co-amorphous solid dispersion is an amorphous diffraction ring without sharp diffraction peaks.
2. Differential Scanning Calorimetry (DSC)
The endothermic melting peak of lacidipine is 185.56 ℃, the endothermic melting peak of spironolactone is 207.32 ℃, and the glass transition temperature of lacidipine-spironolactone amorphous solid dispersion is 92.87 ℃.
3. Fourier infrared spectroscopy (FT-IR)
The lacidipine infrared spectrum characteristic wave number is as follows: 3348.3cm-1The spironolactone infrared spectrum characteristic wave number is as follows: 1691.1cm-1；1768.1cm-1；1674.1cm-1。
Spirolactone 1691cm in a co-amorphous solid dispersion-1The C ═ O peak of thioacetyl group at (A) broadened and shifted to low wavenumber, and lacidipine was 3348.3cm-1the-NH peak at (C) disappeared. Indicating that-NH of lacidipine and O ═ C of the thioacetyl group in spirolactone form intermolecular hydrogen bonds.
Another object of the present invention is to provide a method for preparing lacidipine-spironolactone co-amorphous solid dispersion.
The preparation method of the lacidipine-spironolactone co-amorphous solid dispersion comprises the steps of dissolving lacidipine and spironolactone in an organic solvent to obtain a clear liquid, carrying out reduced pressure rotary evaporation on the solvent at the temperature of 20-60 ℃, and carrying out vacuum drying on residues for 24 hours to obtain the co-amorphous solid dispersion.
The organic solvent is one or more of ethanol, methanol, chloroform or ethyl acetate, preferably ethanol, methanol or a mixed solvent of the two.
The temperature of the decompression rotary evaporation solvent is preferably 30-40 ℃.
The PXRD, DSC and FT-IR spectrums of the co-amorphous solid dispersion disclosed by the invention are different from those of lacidipine crystals and spironolactone crystals reported in the prior patent. Thus, the solid form is a form that is completely different from the raschide and spironolactone forms obtained in the prior art.
The invention has the advantages that the lacidipine and spironolactone are used as effective components, the co-amorphous solid dispersion can be prepared without adding any other carrier, the drug loading is up to 100 percent, and the problems of high cost, easy moisture absorption, large preparation volume, biological safety and the like caused by adding a polymer carrier are avoided. By carrying out in-vitro dissolution experiments on the obtained lacidipine-spironolactone co-amorphous solid dispersion, compared with a physical mixture, the prepared co-amorphous solid dispersion can remarkably improve the in-vitro dissolution of the lacidipine and the spironolactone. The lacidipine-spironolactone (1:6,1:9) co-amorphous solid dispersion has good stability under high humidity conditions. Therefore, the co-amorphous solid dispersion can be further prepared into oral dosage forms such as tablets, hard capsules and the like, and has better clinical application prospect. The preparation method is simple, easy to operate, low in cost, good in economy and easy for industrial production, and has guiding significance for preparing the insoluble drug co-amorphous solid dispersion with other synergistic pharmacological effects.
Drawings
FIG. 1 is a powder X-ray diffraction pattern of a lacidipine drug substance;
FIG. 2 is a powder X-ray diffraction pattern of a spironolactone drug substance;
FIG. 3 is a powder X-ray diffraction pattern of lacidipine-spironolactone co-amorphous solid dispersions at different ratios;
FIG. 4 is a DSC of lacidipine drug substance;
FIG. 5 is a DSC of spironolactone drug substance;
FIG. 6 is a DSC of lacidipine-spironolactone co-amorphous solid dispersions in different ratios;
FIG. 7 is an FT-IR spectrum of a lacidipine drug substance;
FIG. 8 is a FT-IR spectrum of a spironolactone drug substance;
FIG. 9 is FT-IR spectra of lacidipine-spironolactone co-amorphous solid dispersions of varying proportions;
FIG. 10 is a dissolution profile. Respectively represents the dissolution curves of the lacidipine bulk drug, the physical mixture and the lacidipine-spironolactone co-amorphous solid dispersion with different proportions;
FIG. 11 is a dissolution profile. Respectively represents the dissolution curves of spironolactone in the spironolactone bulk drug, physical mixture and lacidipine-spironolactone co-amorphous solid dispersion with different proportions;
FIG. 12 dissolution profile. Respectively represent dissolution curves of the lacidipine in different proportions of the lacidipine-spironolactone co-amorphous solid dispersion after being placed under high-humidity conditions for 10 days.
FIG. 13 dissolution profile. Respectively represent dissolution curves of spironolactone in different proportions of lacidipine-spironolactone co-amorphous solid dispersions after being placed under high-humidity conditions for 10 days.
Detailed Description
The above-mentioned contents of the present invention are further described in detail by the following specific examples, but the present invention is not limited by the examples.
The solid state characterization of the co-amorphous solid dispersion of the present invention is as follows:
1. powder X-ray diffraction
The instrument comprises the following steps: powder X-ray diffractometer (Rigaku corporation, Japan)
Target: Cu-Kalpha radiation
Wavelength:
x-ray tube voltage: 40kV
X-ray tube current: 30mA
Step length: 0.02 degree
Scanning speed: 6 °/min
The results show that: the lacidipine-spironolactone co-amorphous solid dispersion system has an amorphous diffraction ring observed in a diffraction pattern, and has no sharp diffraction peak.
2. Differential Scanning Calorimetry (DSC)
The instrument comprises the following steps: DSC 1 thermal analyzer (Mettler-Toledo, Switzerland)
The range is as follows: 25 to 230 DEG C
Temperature rise rate: 10 ℃/min
The results show that: the endothermic melting peak of lacidipine is 185.56 ℃; the endothermic melting peak of spironolactone is 207.32 ℃; the glass transition temperature of the lacidipine-spironolactone co-amorphous solid dispersion is 92.87 ℃.
3. Fourier infrared spectroscopy (FT-IR)
The instrument comprises the following steps: fourier infrared spectrometer (Switzerland Bruker company)
Absorption wavelength: 400-4000cm-1
The results show that: the results show that: the lacidipine infrared spectrum characteristic wave number is as follows: 3348.3cm-1
The spironolactone infrared spectrum characteristic wave number is as follows: 1691.1cm-1；1768.1cm-1；1674.1cm-1
Spirolactone 1691cm in a co-amorphous solid dispersion-1The C ═ O peak of thioacetyl group at (A) broadened and shifted to low wavenumber, and lacidipine was 3348.3cm-1the-NH peak at (C) disappeared. Indicating that-NH of lacidipine and O ═ C of the thioacetyl group in spirolactone form intermolecular hydrogen bonds.
The effect of different lacidipine to spironolactone ratios on the dissolution of lacidipine and spironolactone:
example 1:
the molar ratio of lacidipine to spironolactone is 3: 1. Weighing 0.5g of lacidipine bulk drug and 0.15g of spironolactone bulk drug, and adding a proper amount of ethanol to dissolve until the mixture is clear. And carrying out reduced pressure rotary evaporation on the solvent at the temperature of 20-60 ℃, and drying the residue for 24 hours in vacuum to obtain the catalyst. The dissolution rate of lacidipine is 5.1% and the dissolution rate of spironolactone is determined according to the dissolution rate determination method as follows: 46.2 percent.
Example 2:
the molar ratio of lacidipine to spironolactone is 1: 1. 0.5g of lacidipine bulk drug and 0.46g of spironolactone bulk drug are weighed, and are dissolved by adding a proper amount of ethanol until the mixture is clear. The preparation process is the same as in example 1. The dissolution rate of lacidipine is 21% and the dissolution rate of spironolactone is determined according to the dissolution rate determination method as follows: 57 percent.
Example 3:
the molar ratio of lacidipine to spironolactone is 1: 3. 0.5g of lacidipine bulk drug and 1.37g of spironolactone bulk drug are weighed, and are dissolved by adding a proper amount of ethanol until the mixture is clear. The preparation process is the same as in example 1. The dissolution rate of the medicine is 56 percent according to the dissolution rate determination method, and the dissolution rate of spironolactone is as follows: 60.4 percent.
Example 4:
the molar ratio of lacidipine to spironolactone is 1: 6. 0.5g of lacidipine bulk drug and 2.74g of spironolactone bulk drug are weighed, and are dissolved by adding a proper amount of ethanol until the mixture is clear. The preparation process is the same as in example 1. The dissolution rate of the medicine is 69 percent according to the dissolution rate determination method, and the dissolution rate of spironolactone is as follows: 68.4 percent.
Example 5:
the molar ratio of lacidipine to spironolactone is 1: 9. Weighing 0.5g of lacidipine bulk drug and 4.1g of spironolactone bulk drug, and adding a proper amount of ethanol to dissolve until the mixture is clear. The preparation process is the same as in example 1. The dissolution rate of the medicine is 63.7 percent according to the dissolution rate determination method, and the dissolution rate of the spironolactone is as follows: 58.3 percent.
Example 6:
high moisture stability: the prepared co-amorphous solid dispersion was placed in a watch glass, left open in an environment of 92.5% relative humidity, and sampled on day 10 to examine the change in dissolution behavior.
The dissolution rate determination method comprises the following steps:
respectively and precisely weighing lacidipine bulk drug, spironolactone bulk drug, lacidipine-spironolactone physical mixture (the molar ratio is 1:6) and the prepared lacidipine-spironolactone co-amorphous solid dispersion (which is equivalent to about 4mg of lacidipine) into a hard capsule shell, and referring to a dissolution determination method (appendix X C second method) in the Chinese pharmacopoeia of 2015 edition, adopting an aqueous solution of 0.07% Tween 80 as a dissolution medium, rotating at 50 revolutions per minute, operating according to the method, taking a subsequent filtrate for determination after 5 min, 10 min, 20min, 30 min, 45 min, 60 min and 120min, and calculating the cumulative dissolution according to an external standard method.
Detection conditions of the high performance liquid chromatography are as follows:
the instrument comprises the following steps: high performance liquid chromatograph (Hitachi Co., Ltd.)
A chromatographic column: thermo Hypersil C18 chromatographic column (250X 4.6mm,5 μm)
Mobile phase: methanol: water 80:20(v/v)
Flow rate: 1.0ml/min
Detection wavelength: 284 nm; 238nm
As shown in the attached drawing 10 and fig. 11, the 120min dissolution rates of the lacidipine bulk drug and the spironolactone bulk drug are respectively 1.2% and 43%, the 120min dissolution rates of the lacidipine and the spironolactone in the physical mixture (1:6) are respectively 6% and 37.6%, and the 120min dissolution rates of the lacidipine and the spironolactone in the lacidipine-spironolactone (3:1, 1:1, 1:3, 1:6,1:9) co-amorphous solid dispersion are respectively 5.1%, 21%, 56%, 69% and 63.7%; the dissolution rates of spironolactone are 46.2%, 57%, 60.4%, 68.4% and 58.3%, respectively. As can be seen from the figure, the dissolution rate and the dissolution rate of the co-amorphous solid dispersion system disclosed by the invention are obviously improved along with the increase of the amount of the spirolactone, and the equilibrium is reached at 1:6, so that 1:6-1:9 is an optimal formula. The dissolution rate of the co-amorphous solid dispersion prepared by the method is high and is higher than that of two bulk drugs and physical mixtures thereof.
As shown in attached figure 12 and figure 13, the lacidipine-spironolactone (1:1, 1:3) co-amorphous solid dispersion has obviously reduced dissolution rate under high-humidity conditions, and the lacidipine-spironolactone (1:6,1:9) co-amorphous solid dispersion has good stability under high-humidity conditions.
Claims (11)
1. The lacidipine-spironolactone co-amorphous solid dispersion is characterized by consisting of lacidipine and spironolactone, wherein the molar ratio of the lacidipine to the spironolactone is 1:1-1: 9.
2. The lacidipine-spirolactone co-amorphous solid dispersion according to claim 1, wherein the molar ratio of lacidipine to spirolactone is from 1:6 to 1: 9.
3. The lacidipine-spirolactone co-amorphous solid dispersion according to claim 1, wherein the molar ratio of lacidipine to spirolactone is 1:6 or 1: 9.
4. A process for the preparation of lacidipine-spironolactone co-amorphous solid dispersions according to any one of claims 1 to 3, wherein lacidipine and spironolactone are dissolved in an organic solvent in a ratio, the solvent is rotary evaporated under reduced pressure, and the residue is dried under vacuum to obtain the co-amorphous solid dispersion.
5. The method of preparing lacidipine-spironolactone co-amorphous solid dispersion as claimed in claim 4, wherein the organic solvent is one or more of ethanol, methanol, chloroform or ethyl acetate.
6. The method of preparing a lacidipine-spironolactone co-amorphous solid dispersion according to claim 4, wherein the organic solvent is ethanol, methanol or a mixed solvent thereof.
7. The method for preparing lacidipine-spironolactone co-amorphous solid dispersion as claimed in claim 4, wherein the temperature of the reduced pressure rotary evaporation is 20 to 60 ℃.
8. The method for preparing lacidipine-spironolactone co-amorphous solid dispersion as claimed in claim 4, wherein the temperature of the reduced pressure rotary evaporation is 30 to 40 ℃.
9. A pharmaceutical composition comprising the lacidipine-spironolactone co-amorphous solid dispersion of any one of claims 1-3.
10. Use of the lacidipine-spironolactone co-amorphous solid dispersion of any one of claims 1 to 3 or the pharmaceutical composition of claim 9 for the preparation of a hypotensive drug.
11. Use of the lacidipine-spironolactone co-amorphous solid dispersion of any one of claims 1 to 3 or the pharmaceutical composition of claim 9 for the manufacture of a medicament for enhancing oral bioavailability.
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