CN113069453B - Co-amorphous material containing nimodipine and irbesartan, preparation method and application thereof - Google Patents
Co-amorphous material containing nimodipine and irbesartan, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a co-amorphous substance containing nimodipine and irbesartan, a preparation method and application thereof. The co-amorphous comprises nimodipine and irbesartan. The nimodipine and irbesartan in the amorphous substance exist in an amorphous form, so that the solubility and dissolution speed of two indissolvable drugs can be improved simultaneously, and the two indissolvable drugs can be synchronously released in the same proportion, so that the synergistic administration is realized, and the nimodipine and irbesartan show good stability under high-humidity conditions. The amorphous substance is prepared from pure medicines, does not need to add carriers which are used for solid dispersion, has the drug loading up to 100%, solves the problems of high hygroscopicity, low drug loading, oral safety and the like caused by introducing polymer carriers, reduces the process difficulty of further preparing the amorphous substance into dosage forms such as tablets, capsules and the like, is easy to realize, has low cost, is easy to amplify and produce, and provides guidance for solubilization technology of other insoluble medicines.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a co-amorphous substance containing nimodipine and irbesartan, a preparation method and application thereof.
Background
Hypertension is a common chronic disease, is one of the main chronic diseases in China at present, the disease rate of the hypertension in China is up to 23.2 percent according to epidemiological investigation, the number of patients exceeds 2.5 hundred million, and the disease rate of the disease is in a year-by-year increasing trend in the global scope along with the continuous improvement of living standard. In addition, hypertension is often accompanied by complications such as heart disease, dosage form cerebrovascular disease, kidney disease, etc. Wherein, the acute cerebrovascular disease is rapid in onset, critical in symptoms and high in incidence rate up to 36%, is a dangerous complication of primary hypertension, and seriously threatens the life safety of patients.
Nimodipine (Nimodipine), chemical name: (±) -4- (3-nitrophenyl) -2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid methoxyethyl ester isopropyl ester is a dihydropyridine calcium channel blocker which has the effect similar to nifedipine but the efficacy weaker than nifedipine, and the chemical structural formula is shown as follows. Nimodipine is a calcium antagonist acting on cerebral vascular smooth muscle selectively, acts on cerebral vascular smooth muscle, dilates cerebral blood vessels, increases cerebral blood flow, can effectively prevent or reverse ischemic damage of brain tissue caused by cerebral vasospasm caused by subarachnoid hemorrhage of experimental dogs, and has the functions of protecting and promoting memory and promoting intelligence recovery.
Irbesartan (Irbesartan), chemical name: 2-butyl-3- [4- [2- (1H-tetrazol-5-yl) phenyl ] benzyl ] -1, 3-diazaspiro- [4.4] non-1-en-4-one, which is an angiotensin II receptor antagonist, inhibits vasoconstriction and release of aldosterone by selectively blocking the binding of angiotensin II to the AT1 receptor, resulting in a hypotensive effect, having the chemical formula shown below.
At present, the treatment of hypertension complicated with acute cerebrovascular diseases mainly depends on the synergistic effect of peripheral antihypertensive drugs and central antihypertensive drugs. It has been reported that angiotensin II receptor blockers such as irbesartan combined nimodipine can effectively relieve symptoms of hypertension complicated with acute cerebrovascular diseases, reduce incidence rate of subarachnoid hemorrhage, and have neuron protection effect.
From the characteristics of chronic diseases of hypertension complicated with acute cerebrovascular diseases and the corresponding administration frequency of therapeutic drugs, oral administration is the optimal administration route, and has the advantages of convenience, safety, good patient compliance and the like. However, irbesartan and nimodipine both belong to BCS class II drugs, have poor water solubility, lower solubility and dissolution rate, and thus lower oral bioavailability, so it is necessary to develop a compound formulation containing nimodipine and irbesartan, and capable of effectively improving the solubility of two poorly soluble drugs and intestinal barrier permeability.
Co-amorphous (Coamorphus) is a single phase amorphous binary system with a single glass transition temperature formed by combining a pharmaceutically active ingredient with other small molecule substances (drugs or excipients). The co-amorphous solid dispersion has the advantages of the traditional amorphous solid dispersion, namely, the system is in a thermodynamic high-energy state, can improve the physical and chemical properties of the medicine such as solubility, dissolution rate and the like, and has higher stability than an amorphous monomer; in addition, the method can overcome the defects of the traditional amorphous solid dispersion, namely, a high polymer carrier is not used, so that the drug loading capacity is improved, and the thermodynamic instability caused by hygroscopicity is improved, thereby being a solubilization technology with good prospect.
The physicochemical properties of the co-amorphous material and the ease of preparing the co-amorphous material are greatly affected by the crystal form, crystallization rate, pharmacokinetic properties of the drug substance and drug (or adjuvant) compatibility of the drug substance, for example, the co-amorphous material may be formed during the preparation process, or only physical mixtures or co-crystals may be formed, and the products obtained from different combinations have unpredictability, so that a large amount of screening work is required to develop an ideal co-amorphous preparation. Through earlier work, the inventor finds that the co-amorphous form prepared by nimodipine and irbesartan can obviously improve the dissolution rate and the dissolution speed of nimodipine and irbesartan at the same time, can realize the synchronous release of two medicaments with pharmacological synergistic effect, improves the intestinal permeability of the two medicaments, and has good physical stability.
Disclosure of Invention
The invention aims to provide a co-amorphous substance containing nimodipine and irbesartan, a preparation method and application thereof. The amorphous substance can obviously improve the solubility and in-vitro dissolution rate of two insoluble drugs, can realize the synchronous release of the two drugs with pharmacological synergistic effect, improves the intestinal permeability of the two drugs, and has good physical stability.
The specific technical scheme of the invention is as follows:
1. a co-amorphous form comprising nimodipine and irbesartan, wherein the co-amorphous form comprises nimodipine and irbesartan.
2. The co-amorphous form according to item 1, wherein the co-amorphous form consists of nimodipine and irbesartan.
3. The co-amorphous according to item 1 or 2, wherein in the co-amorphous, the molar ratio of nimodipine to irbesartan is 1:0.5-4, preferably 1:1-4, further preferably 1:3-4.
4. The co-amorphous material according to any one of claims 1 to 3, wherein the glass transition temperature of the amorphous material is 11 to 73 ℃.
5. The co-amorphous material according to any one of items 1 to 4, wherein the amorphous material has no sharp diffraction peak in an X-ray powder diffraction spectrum expressed in 2Θ using Cu-kα radiation.
6. The co-amorphous material according to any one of claims 1 to 5, wherein the amorphous material is prepared by using a melt quenching method.
7. The co-amorphous material according to item 6, wherein the melt quenching method comprises the steps of:
mixing nimodipine and irbesartan, and then heating and melting to obtain a melt;
the resulting melt was rapidly cooled to give the amorphous form.
8. The co-amorphous material according to item 7, wherein the heating temperature is 150-210 ℃.
9. The co-amorphous material according to item 7 or 8, wherein the cooling time is 1 to 10s.
10. The co-amorphous material according to any one of items 1 to 5, wherein the amorphous material is produced by a freeze-milling method.
11. The co-amorphous material according to item 10, wherein the freeze-milling method comprises the steps of:
mixing the nimodipine and the irbesartan followed by freeze-milling to obtain the co-amorphous.
12. The co-amorphous material according to item 11, wherein the milling time is 10 to 60 minutes.
13. The co-amorphous material according to item 11 or 12, wherein the milling speed is 500-2000rpm.
14. A process for preparing a co-amorphous comprising nimodipine and irbesartan, said process being a melt quenching process, preferably said melt quenching process comprising the steps of:
mixing nimodipine and irbesartan, and then heating and melting to obtain a melt;
the resulting melt was rapidly cooled to give the amorphous form.
15. The method of item 14, wherein the heating temperature is 150-210 ℃.
16. The method according to item 14 or 15, wherein the cooling time is 1-10s.
17. A process for the preparation of a co-amorphous comprising nimodipine and irbesartan, said process being a freeze-milling process, preferably said freeze-milling process comprising the steps of:
mixing the nimodipine and the irbesartan followed by freeze-milling to obtain the co-amorphous.
18. The method according to item 17, wherein the milling time is 10 to 60 minutes.
19. The method according to item 17 or 18, wherein the milling speed is 500-2000rpm.
20. The process according to any one of claims 14-19, wherein the molar ratio of nimodipine to irbesartan is 1:0.5-4, preferably 1:1-4, further preferably 1:3-4.
21. The method of any one of claims 14-20, wherein the amorphous material has a glass transition temperature of 11-73 ℃.
22. The method of any of claims 14-21, wherein the amorphous material has no sharp diffraction peaks in the X-ray powder diffraction spectrum expressed in 2Θ using Cu-kα radiation.
23. A pharmaceutical composition comprising the amorphous form of any one of claims 1-13 or the amorphous form prepared by the method of any one of claims 14-22.
24. A pharmaceutical formulation comprising the amorphous material of any one of claims 1-13 or the amorphous material prepared by the method of any one of claims 14-22, and pharmaceutically acceptable excipients and/or carriers.
25. The pharmaceutical formulation of item 24 in the form of a tablet or capsule.
26. Use of the amorphous material of any one of claims 1-13 or the amorphous material prepared by the method of any one of claims 14-22 in the preparation of a medicament for treating hypotension.
ADVANTAGEOUS EFFECTS OF INVENTION
The nimodipine and irbesartan in the amorphous substance exist in an amorphous form, so that the solubility and dissolution speed of two indissolvable drugs can be improved simultaneously, and the nimodipine and irbesartan can be released synchronously in the same proportion, thereby realizing synergistic administration and displaying good stability under high humidity conditions. The amorphous substance is prepared from pure medicines, does not need to add carriers which are used for solid dispersion, has the drug loading up to 100%, solves the problems of high hygroscopicity, low drug loading, oral safety and the like caused by introducing polymer carriers, reduces the process difficulty of further preparing the amorphous substance into dosage forms such as tablets, capsules and the like, is easy to realize, has low cost, is easy to amplify and produce, and provides guidance for solubilization technology of other insoluble medicines.
Drawings
Fig. 1 is a powder X-ray diffraction pattern of different substances of experimental example 1, wherein fig. 1-1 is a powder X-ray diffraction pattern of nimodipine bulk drug, fig. 1-2 is a powder X-ray diffraction pattern of irbesartan bulk drug, fig. 1-3 is a powder X-ray diffraction pattern of co-amorphous obtained in examples 1-5, and fig. 1-4 is a powder X-ray diffraction pattern of co-amorphous obtained in examples 6-10.
Fig. 2 is a DSC diagram of different substances in experimental example 2, wherein fig. 2-1 is a DSC diagram of nimodipine drug substance, fig. 2-2 is a DSC diagram of irbesartan drug substance, fig. 2-3 is a DSC diagram of co-amorphous obtained in examples 1-5, and fig. 2-4 is a DSC diagram of co-amorphous obtained in examples 6-10.
Fig. 3 is an FT-IR spectrum of different substances in experimental example 3, in which fig. 3-1 is an FT-IR spectrum of nimodipine drug substance, fig. 3-2 is an FT-IR spectrum of irbesartan drug substance, and fig. 3-3 is an FT-IR spectrum of a mixture obtained by physically mixing the co-amorphous substance obtained in example 1-5 and the drug substance of nimodipine and irbesartan at a molar ratio of 1:3.
Fig. 4 is a graph showing dissolution of different substances in experimental example 4, fig. 4-1 is a graph showing dissolution of nimodipine in the bulk drug of nimodipine and the co-amorphous substance prepared in examples 1-5, and fig. 4-2 is a graph showing dissolution of irbesartan in the bulk drug of irbesartan and the co-amorphous substance prepared in examples 1-5.
Fig. 5 is a graph showing the intrinsic dissolution rates of different substances in experimental example 5, wherein fig. 5-1 is a graph showing the intrinsic dissolution rates of nimodipine in the bulk drug of nimodipine and the co-amorphous substance prepared in examples 1-5, and fig. 5-2 is a graph showing the intrinsic dissolution rates of irbesartan in the bulk drug of irbesartan and the co-amorphous substance prepared in examples 1-5.
FIG. 6 is a DSC of the stability test in Experimental example 6, wherein FIG. 6-1 is a DSC of the co-amorphous prepared in examples 1-5, and FIG. 6-2 is a DSC of the co-amorphous prepared in examples 6-10.
Fig. 7 is a graph showing apparent permeability coefficients of the drug substance, the solution, and the nimodipine-irbesartan co-amorphous material in experimental example 7, fig. 7-1 is a graph showing apparent permeability coefficients of nimodipine in the drug substance, the solution, and the nimodipine-irbesartan co-amorphous material, and fig. 7-2 is a graph showing apparent permeability coefficients of irbesartan in the drug substance, the solution, and the nimodipine-irbesartan co-amorphous material.
Detailed Description
The present invention will now be described in detail with reference to the embodiments thereof as illustrated in the accompanying drawings, wherein like numerals refer to like features throughout. While specific embodiments of the invention are shown in the drawings, it should be understood that the invention may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
It should be noted that certain terms are used throughout the description and claims to refer to particular components. Those of skill in the art will understand that a person may refer to the same component by different names. The specification and claims do not identify differences in terms of components, but rather differences in terms of the functionality of the components. As referred to throughout the specification and claims, the terms "include" or "comprising" are used in an open-ended fashion, and thus should be interpreted to mean "include, but not limited to. The description hereinafter sets forth a preferred embodiment for practicing the invention, but is not intended to limit the scope of the invention, as the description proceeds with reference to the general principles of the description. The scope of the invention is defined by the appended claims.
The present invention provides a co-amorphous form comprising nimodipine and irbesartan, wherein the co-amorphous form comprises nimodipine and irbesartan.
The nimodipine and irbesartan in the co-amorphous substance exist in an amorphous form, so that the solubility and dissolution rate of two indissolvable drugs can be improved.
In one embodiment, the co-amorphous consists of nimodipine and irbesartan.
In one embodiment, in the co-amorphous form, the molar ratio of the nimodipine and the irbesartan (n Nimodipine ：n Irbesartan ) From 1:0.5 to 4, preferably from 1:1 to 4, more preferably from 1:3 to 4, most preferably 1:3.
For example, in the co-amorphous form, the molar ratio (n Nimodipine ：n Irbesartan ) Can be used for1:0.5, 1:1, 1:2, 1:3, 1:4.
When the molar ratio of nimodipine to irbesartan is within the above-described range, the equilibrium solubility of nimodipine and irbesartan (in amorphous form) in water is improved, while the equilibrium solubility of nimodipine and irbesartan (in crystalline form) as a drug substance in water is lower, indicating that co-amorphous forms containing nimodipine and irbesartan can improve the solubility of nimodipine and irbesartan.
In one embodiment, the amorphous material has a glass transition temperature of 11-73 ℃.
For example, the glass transition temperature may be 11 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 73 ℃.
In one embodiment, the amorphous material uses Cu-kα radiation and the X-ray powder diffraction spectrum expressed in 2θ has no sharp diffraction peaks.
In one embodiment, the amorphous material is prepared by employing a melt quenching process.
Preferably, the melt quenching method includes the steps of:
mixing nimodipine and irbesartan, and then heating and melting to obtain a melt;
the resulting melt was rapidly cooled to give the amorphous form.
In one embodiment, the heating temperature is 150-210 ℃, e.g., the heating temperature may be 150 ℃, 160 ℃, 170 ℃, 180 ℃, 190 ℃, 200 ℃, 210 ℃, etc.
In one embodiment, the cooling time is 1-10s, for example, the cooling time may be 1s, 2s, 3s, 4s, 5s, 6s, 7s, 8s, 9s, 10s, etc.
In one embodiment, the amorphous material is obtained by employing a freeze-milling process, preferably comprising the steps of:
mixing the nimodipine and the irbesartan followed by freeze-milling to obtain the co-amorphous.
For example, the amorphous material can be obtained by mixing nimodipine and irbesartan, then placing the mixture in a freeze-grinding device, and adding grinding beads for freeze-grinding.
In one embodiment, the milling time is 10-60 minutes, e.g., the milling time may be 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, etc.
In one embodiment, the milling speed is 500-2000rpm, for example, the milling speed may be 500rpm, 1000rpm, 1500rpm, 2000rpm, or the like.
The crystalline forms of nimodipine and irbesartan in the amorphous form according to the present invention are both present in amorphous form, which are different from the crystalline forms of nimodipine and irbesartan reported in the prior art, i.e. the amorphous form is different from the mixture of nimodipine and irbesartan in the prior art.
The amorphous substances (amorphous nimodipine and irbesartan) disclosed by the invention have the advantages that the dissolution rates of nimodipine and irbesartan are improved, the two drugs have good synchronous release characteristics, and the two drugs have optimal synergistic effect.
When the amorphous substance disclosed by the invention is used for experiments by using Caco-2 cells as a model, the apparent permeability parameters of nimodipine and irbesartan are higher, so that the co-amorphous substance can be proved to provide intestinal permeability of two medicines.
In addition, the co-amorphous material of the present invention has good physical stability under high humidity conditions.
The present invention provides a process for preparing a co-amorphous form comprising nimodipine and irbesartan, said process being a melt quenching process, preferably comprising the steps of:
mixing nimodipine and irbesartan, and then heating and melting to obtain a melt;
the resulting melt was rapidly cooled to give the amorphous form.
The present invention provides a process for the preparation of a co-amorphous form comprising nimodipine and irbesartan, said process being a freeze-milling process, preferably said freeze-milling process comprising the steps of:
mixing the nimodipine and the irbesartan followed by freeze-milling to obtain the co-amorphous.
The method (a melt quenching method and a freeze grinding method) uses pure medicine to prepare the co-amorphous substance, does not need to add carriers which are used for solid dispersion, has the medicine carrying capacity up to 100%, solves the problems of high hygroscopicity, low medicine carrying capacity, oral safety and the like caused by introducing a polymer carrier, reduces the process difficulty for further preparing the preparation formulations such as tablets, capsules and the like, is easy to realize, has low cost, is easy to amplify production, and provides guidance for the solubilization technology of other insoluble medicines.
The invention provides a pharmaceutical composition which comprises the amorphous substance or the amorphous substance prepared by the method.
The invention provides a pharmaceutical preparation which comprises the amorphous substance or the amorphous substance prepared by the method and pharmaceutically acceptable auxiliary materials and/or carriers.
The pharmaceutically acceptable excipients and/or carriers are those known to those skilled in the art, and may be lactose, microcrystalline cellulose, starch, etc.
In one embodiment, the dosage form of the pharmaceutical formulation may be a tablet, capsule, or the like.
The invention provides application of the amorphous substance or the amorphous substance prepared by the method in preparation of antihypertensive drugs.
Examples
The materials used in the test and the test methods are described generally and/or specifically in the examples which follow,% represents wt%, i.e. weight percent, unless otherwise specified. The reagents or instruments used are not noted to the manufacturer and are all conventional reagent products available commercially, wherein nimodipine is purchased from filial deep chemical industry company, and irbesartan is purchased from the chemical industry company, marmor.
Example 1
The molar ratio of nimodipine to irbesartan is 2:1.
Weighing 0.60g of nimodipine crude drug and 0.31g of irbesartan crude drug, uniformly mixing, placing the mixture in an aluminum weighing tray, placing the weighing tray on a heating table (STC 803-II constant temperature heating table, electric heating technology Co., salt city, gemmer Co., ltd.) and heating at 175 ℃, continuously stirring until the mixture is uniform in the process, rapidly cooling, and cooling for 2s to obtain the nimodipine-irbesartan co-amorphous substance.
Example 2
The molar ratio of nimodipine to irbesartan is 1:1.
Weighing 0.50g of nimodipine bulk drug and 0.51g of irbesartan bulk drug, uniformly mixing, placing into an aluminum weighing tray, heating at 210 ℃, continuously stirring until uniform in the process, rapidly cooling for 5s, and obtaining the nimodipine-irbesartan co-amorphous substance.
Example 3
The molar ratio of nimodipine to irbesartan is 1:2.
Weighing 0.30g of nimodipine crude drug and 0.61g of irbesartan crude drug, uniformly mixing, placing in an aluminum weighing tray, heating at 180 ℃, continuously stirring until uniform, rapidly cooling for 10s, and obtaining the nimodipine-irbesartan co-amorphous substance.
Example 4
The molar ratio of nimodipine to irbesartan is 1:3.
0.20g of nimodipine crude drug and 0.61g of irbesartan crude drug are weighed, evenly mixed and placed in an aluminum weighing disc, and the preparation process is the same as in example 1.
Example 5
The molar ratio of nimodipine to irbesartan is 1:4.
0.20g of nimodipine crude drug and 0.81g of irbesartan crude drug are weighed, evenly mixed and placed in an aluminum weighing disc, and the preparation process is the same as in example 1.
Example 6
The molar ratio of nimodipine to irbesartan is 2:1.
150mg of nimodipine drug substance and 76.8mg of irbesartan drug substance are weighed, evenly mixed, placed in a freeze-grinding device (LyserPro program type frozen tissue breaker, monatin biotechnology Co., ltd.) and added with a steel grinding bead (Shandong Taishan Steel ball Co., ltd.) with the diameter of 7mm, and ground for 10min at the grinding speed of 2000rpm, thus obtaining nimodipine irbesartan co-amorphous substance.
Example 7
The molar ratio of nimodipine to irbesartan is 1:1.
Weighing 110mg of nimodipine crude drug and 112.6mg of irbesartan crude drug, uniformly mixing, placing in a freeze-grinding device, adding grinding beads, and grinding for 60min at a grinding speed of 1500rpm to obtain the nimodipine irbesartan co-amorphous substance.
Example 8
The molar ratio of nimodipine to irbesartan is 1:2.
75mg of nimodipine drug substance and 153.6mg of irbesartan drug substance are weighed, evenly mixed and placed in a freeze-grinding device, and the preparation process is the same as in example 6.
Example 9
The molar ratio of nimodipine to irbesartan is 1:3.
50mg of nimodipine drug substance and 153.6mg of irbesartan drug substance are weighed, evenly mixed and placed in a freeze-grinding device, and the preparation process is the same as in example 6.
Example 10
The molar ratio of nimodipine to irbesartan is 1:4.
50mg of nimodipine drug substance and 204.8mg of irbesartan drug substance are weighed, evenly mixed and placed in a freeze-grinding device, and the preparation process is the same as in example 6.
Table 1 shows the amounts of the components used in the examples
| Nimodipine and irbesartan molar ratio | Nimodipine dosage | Dosage of irbesartan | Method | |
| Example 1 | 2:1 | 0.60g | 0.31g | Melt quenching method |
| Example 2 | 1:1 | 0.50g | 0.51g | Melt quenching method |
| Example 3 | 1:2 | 0.30g | 0.61g | Melt quenching method |
| Example 4 | 1:3 | 0.20g | 0.61g | Melt quenching method |
| Example 5 | 1:4 | 0.20g | 0.81g | Melt quenching method |
| Example 6 | 2:1 | 150mg | 76.8mg | Freezing and grinding method |
| Example 7 | 1:1 | 110mg | 112.6mg | Freezing and grinding method |
| Example 8 | 1:2 | 75mg | 153.6mg | Freezing and grinding method |
| Example 9 | 1:3 | 50mg | 153.6mg | Freezing and grinding method |
| Example 10 | 1:4 | 50mg | 204.8mg | Freezing and grinding method |
Experimental example 1 characterization of powder X-ray diffraction
The conditions for powder X-ray diffraction were as follows:
instrument: powder X-ray diffractometer (Rigaku corporation of Japan)
And (3) target: cu-K alpha radiation
Wavelength:
x-ray tube voltage: 40kV (kilovolt)
X-ray light pipe current: 30mA
Step size: 0.02 degree
Scanning speed: 5 DEG/min
The co-amorphous material obtained in examples 1 to 10 and the crude drugs of nimodipine and irbesartan were scanned using the above-described conditions of powder X-ray diffraction, the diffraction patterns of which are shown in fig. 1-1 to 1-4, respectively, wherein fig. 1-1 is the powder X-ray diffraction pattern of the crude drug of nimodipine, fig. 1-2 is the powder X-ray diffraction pattern of the crude drug of irbesartan, fig. 1-3 is the powder X-ray diffraction pattern of the co-amorphous material obtained in examples 1-5, and fig. 1-4 is the powder X-ray diffraction pattern of the co-amorphous material obtained in examples 6-10.
As can be seen from fig. 1-1 to fig. 1-4, both nimodipine and irbesartan are in crystalline form, and the co-amorphous material obtained in the examples has no sharp diffraction peak, which indicates that the co-amorphous material is different from the nimodipine and irbesartan in form.
Experimental example 2 Differential Scanning Calorimetry (DSC)
Differential Scanning Calorimetry (DSC) instrument: DSC 250 thermal analyzer (company TA USA)
The range is as follows: 0-200 DEG C
Rate of temperature rise: 15 ℃/min
The co-amorphous material obtained in examples 1 to 10 and the crude drugs of nimodipine and irbesartan were analyzed by differential scanning calorimetry as described above, and the DSC charts thereof are shown in fig. 2-1 to 2-4, respectively, wherein fig. 2-1 is a DSC chart of the crude drug of nimodipine, fig. 2-2 is a DSC chart of the crude drug of irbesartan, fig. 2-3 is a DSC chart of the co-amorphous material obtained in examples 1 to 5, and fig. 2-4 is a DSC chart of the co-amorphous material obtained in examples 6 to 10.
As can be seen from fig. 2-1 to 2-4, the endothermic melting peak of nimodipine drug substance is 125.3 ℃, the endothermic melting peak of irbesartan drug substance is 181.6 ℃, and the endothermic melting peak of co-amorphous prepared in the examples is around 11-73 ℃, for example, when the molar ratio is 1:3, the glass transition temperature of the nimodipine-irbesartan co-amorphous is 55.56 ℃, which indicates that the co-amorphous system of the invention has only a single-phase system with one glass transition temperature.
Experimental example 3 Fourier transform Infrared Spectroscopy (FT-IR)
Instrument: fourier transform leaf infrared spectrometer (Bruker company Switzerland)
Measurement wavelength: 400-4000cm -1
The co-amorphous material obtained in examples 1 to 10, the bulk drug of nimodipine and irbesartan and the mixture obtained by physically mixing nimodipine and irbesartan in a molar ratio of 1:3 were analyzed by fourier transform infrared spectroscopy, the spectra of which are shown in fig. 3-1, fig. 3-2 and fig. 3-3, respectively, wherein fig. 3-1 is the FT-IR spectrum of nimodipine bulk drug, fig. 3-2 is the FT-IR spectrum of irbesartan bulk drug, and fig. 3-3 is the FT-IR spectrum of the co-amorphous material prepared in examples 1 to 5 and the mixture obtained by physically mixing nimodipine and irbesartan in a molar ratio of 1:3.
As can be seen from the figure, in the co-amorphous form, 1732.7cm of irbesartan -1 The ester carbonyl group at the position moves to low wave number and is obviously widened, and nimodipine is 3299.6cm -1 the-NH peak at it disappeared. Indicating that the carbonyl groups in-NH and irbesartan of nimodipine form intermolecular hydrogen bonds.
Experimental example 4 dissolution measurement
The nimodipine drug substance, irbesartan drug substance, a nimodipine-irbesartan physical mixture (molar ratio 1:3) and the nimodipine-irbesartan total amorphous prepared in examples 1-5 were precisely weighed respectively, about 120mg was referenced to the 2020 edition of chinese pharmacopoeia dissolution test (annex XC second method), water was the dissolution medium, the rotation speed was 100 revolutions per minute, according to the law, 5mL was sampled and 5mL of fresh medium was supplemented at 5, 10, 20, 30, 45, 60min, the sample was filtered through a 0.22 μm filter membrane, and the appropriate amount of the filtrate was measured, the measurement method was performed by high performance liquid chromatography, and the cumulative dissolution was calculated, the result curves were as shown in fig. 4-1 and fig. 4-2, wherein fig. 4-1 is a schematic diagram of the dissolution curve of nimodipine in the nimodipine drug substance and the total amorphous prepared in examples 1-5, and fig. 4-2 is a schematic diagram of the dissolution curve of nimodipine in the total amorphous prepared in examples 1-5.
Wherein, the chromatographic conditions of the high performance liquid chromatography are as follows:
instrument: high performance liquid chromatograph (Hitachi Co., ltd.)
Chromatographic column: akzo Nobel C18 column (250X 4.6mm,5 μm)
Mobile phase: acetonitrile: water=80:20 (v/v)
Flow rate: 1.0mL/min
Detection wavelength: 235nm
As can be seen from fig. 4-1 to 4-2, when nimodipine and irbesartan are dissolved at 1% and 9.39% for 60min, respectively, and nimodipine and irbesartan are dissolved at 7% and 28.5% for 60min in a physical mixture (molar ratio of 1:3), respectively, and when nimodipine and irbesartan are dissolved at 2:1, 1:1, 1:2, 1:3 and 1:4 (i.e., corresponding to the co-amorphous materials prepared in examples 1 to 5), respectively, the cumulative dissolution rate of nimodipine is 3.5%, 23.8%, 39.9%, 69.7% and 78.0%, respectively, and irbesartan is dissolved at 42.5%, 40.2%, 45.8%, 66.1% and 73.9%, respectively, indicating that in the co-amorphous materials, as the molar ratio of nimodipine to irbesartan is increased, the dissolution rate is significantly improved, and when nimodipine and irbesartan is dissolved at 1:3 and 1:4, respectively, and the dissolution rate is significantly higher than that in the co-amorphous materials is the physical mixture
Experimental example 5 measurement of intrinsic dissolution Rate
Each sample was crushed, sieved through a 80 mesh sieve (standard sieve), nimodipine drug substance, irbesartan drug substance and nimodipine-irbesartan total amorphous prepared in examples 1 to 5 were precisely weighed about 120mg, and a rotating disc containing the sample was placed in a micro tablet press (RSC-1050, zhejiang yu xin hydraulic tool mill) and compressed for 1min at a pressure of 200bar to obtain a sample sheet. Referring to the method for measuring the dissolution rate of the 2020 edition of Chinese pharmacopoeia (the second method of the annex XC), water is taken as a dissolution medium, the rotation speed is 100 revolutions per minute, the method is operated, the subsequent filtrate is measured at 5, 10, 20 and 30 minutes, the measuring method adopts high performance liquid chromatography to measure, the accumulated dissolution rate is calculated, and the result is shown in figures 5-1 to 5-2.
It can be seen from fig. 5-1 to 5-2 that when the molar ratio of nimodipine to irbesartan is 1:3, the intrinsic dissolution rates (intrinsic dissolution rate) of nimodipine and irbesartan are 0.400mg/cm, respectively 2 Per minute and 1.132mg/cm 2 The ratio of the two is about 1:3, namely, at the ratio, the two medicines can be considered to have good synchronous release characteristics and have higher dissolution rate, so that nimodipine and irbesartan have optimal synergistic effect.
Experimental example 6 stability test
The stability test was performed on the co-amorphous material prepared in example 1-10, i.e., the sample obtained in example 1-10 was left to stand at room temperature under a condition of 75% relative humidity (saturated sodium chloride solution) for 10 days, and the results are shown in FIGS. 6-1 to 6-2, wherein FIG. 6-1 is a DSC chart of the co-amorphous material prepared in example 1-5, and FIG. 6-2 is a DSC chart of the co-amorphous material prepared in example 6-10.
As can be seen from FIGS. 6-1 and 6-2, when the molar ratio of nimodipine to irbesartan is 1:1-4, after 20 days of standing under high humidity conditions (RH 75%), no endothermic peak representing recrystallization appears in DSC curves, and the physical stability of the 1:1-4 amorphous is good under high humidity conditions.
Experimental example 7 determination of apparent permeability coefficient
The membrane permeabilities of nimodipine and irbesartan were evaluated using Caco-2 cells (beijing synergetic cell bank) as a model. Test on testPrior to assay, the Caco-2 cell layer was gently washed 3 times with HBSS solution, followed by addition of fresh HBSS solution and incubation in incubator for 30min. After the incubation, the HBSS solution was discarded. Quantitative samples to be tested (a crude suspension of nimodipine and irbesartan drug substance (the drug substance is dispersed in water), a solution of nimodipine and irbesartan (the drug substance is dissolved in dimethyl sulfoxide first, and then a certain amount of the organic solution is taken and added into water to make the final concentration of the final samples the same) and the co-amorphous material with the molar ratio of nimodipine to irbesartan of 1:3 prepared in example 4) are added to the top side of the cell layer, and 1.5mL of HBSS solution is added to the base side of the cell layer. Will be
The plates were incubated in an incubator at 37℃for 1h, after which 300. Mu.L was sampled on the receiving side. Measuring the concentration of nimodipine and irbesartan in the sample by high performance liquid chromatography (chromatographic conditions of chromatographic conditions and dissolution) and calculating apparent permeability coefficients of the drugs according to formula (1),
P app ＝(dQ/dt)/(C 0 ×A) (1)
wherein Q is the transmission amount, C 0 For initial concentration, a is the permeate area. The results are shown in fig. 7-1 to 7-2, wherein fig. 7-1 is a graph of apparent permeability coefficients of nimodipine in the bulk drug, the solution and the nimodipine-irbesartan co-amorphous substance, and fig. 7-2 is a graph of apparent permeability coefficients of irbesartan in the bulk drug, the solution and the nimodipine-irbesartan co-amorphous substance.
From figures 7-1 to 7-2, it can be seen that when the molar ratio of nimodipine to irbesartan is 1:3, the apparent permeability coefficient of nimodipine is 0.0042cm/min, the apparent permeability coefficient of irbesartan is 0.0072cm/min, and the apparent permeability coefficients of nimodipine and irbesartan crystalline bulk drug are 0.0001cm/min and 0.0023cm/min, respectively, which indicates that the co-amorphous material of the invention can significantly improve intestinal permeability of nimodipine and irbesartan.
Experimental example 8 determination of solubility
The solubility of nimodipine bulk drug, irbesartan bulk drug and the nimodipine-irbesartan co-amorphous prepared in examples 1-5 were measured, wherein when the molar ratio of nimodipine to irbesartan in the co-amorphous prepared in examples 1-5 was 2:1, 1:1, 1:2, 1:3 and 1:4, the equilibrium solubility of nimodipine in water was 3.2 μg/mL, 6.1 μg/mL, 8.1 μg/mL, 10.3 μg/mL and 13.7 μg/mL, respectively, and the equilibrium solubility of irbesartan in water was 83.2 μg/mL, 86.1 μg/mL, 97.1 μg/mL, 103.3 μg/mL and 103.7 μg/mL, respectively, whereas the equilibrium solubility of nimodipine crystalline bulk drug and irbesartan crystalline bulk drug in water was 1.6 μg/mL and 16.2 μg/mL, respectively, both of the present invention can be seen to improve the solubility of the co-amorphous drug.
In conclusion, compared with the crystal bulk drugs of nimodipine and irbesartan, the co-amorphous substance disclosed by the invention improves the solubility, dissolution rate, intestinal cell permeability and physical stability of the system of the two drugs, and realizes synchronous release. The preparation method of the co-amorphous substance provided by the invention has high feasibility, is easy to amplify, and has good clinical application prospect.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the invention in any way, and any person skilled in the art may make modifications or alterations to the disclosed technical content to the equivalent embodiments. However, any simple modification, equivalent variation and variation of the above embodiments according to the technical substance of the present invention still fall within the protection scope of the technical solution of the present invention.
Claims (24)
1. A co-amorphous form comprising nimodipine and irbesartan, wherein the co-amorphous form comprises nimodipine and irbesartan;
in the co-amorphous form, the molar ratio of nimodipine to irbesartan is 1:3-4;
the glass transition temperature of the co-amorphous material is 11-73 ℃.
2. The co-amorphous form according to claim 1, wherein the co-amorphous form consists of nimodipine and irbesartan.
3. The co-amorphous material according to claim 1, wherein the co-amorphous material has no sharp diffraction peak in X-ray powder diffraction spectrum expressed in 2Θ using Cu-kα radiation.
4. A co-amorphous form according to any one of claims 1-3, wherein the co-amorphous form is prepared by employing a melt quenching process.
5. The co-amorphous form according to claim 4, wherein the melt quenching process comprises the steps of:
mixing nimodipine and irbesartan, and then heating and melting to obtain a melt;
the resulting melt was rapidly cooled to give the co-amorphous.
6. The co-amorphous form according to claim 5, wherein the heating temperature is 150-210 ℃.
7. The co-amorphous material according to claim 5, wherein the cooling time is 1-10s.
8. A co-amorphous material according to any one of claims 1-3, wherein the co-amorphous material is prepared by employing a freeze-milling process.
9. The co-amorphous mass of claim 8, wherein the freeze-milling process comprises the steps of:
mixing the nimodipine and the irbesartan followed by freeze-milling to obtain the co-amorphous.
10. The co-amorphous material according to claim 9, wherein the milling time is 10-60min.
11. The co-amorphous material according to claim 9, wherein the milling speed is 500-2000rpm.
12. A process for preparing a co-amorphous comprising nimodipine and irbesartan, said process being a melt quenching process, said co-amorphous comprising nimodipine and irbesartan;
in the co-amorphous form, the molar ratio of nimodipine to irbesartan is 1:3-4;
the glass transition temperature of the co-amorphous material is 11-73 ℃.
13. The method of claim 12, wherein the melt quenching method comprises the steps of:
mixing nimodipine and irbesartan, and then heating and melting to obtain a melt;
the resulting melt was rapidly cooled to give the co-amorphous.
14. The method of claim 13, wherein the heating temperature is 150-210 ℃.
15. The method of claim 13, wherein the cooling time is 1-10s.
16. A process for preparing a co-amorphous comprising nimodipine and irbesartan, said process being a freeze-milling process, said co-amorphous comprising nimodipine and irbesartan;
in the co-amorphous form, the molar ratio of nimodipine to irbesartan is 1:3-4;
the glass transition temperature of the co-amorphous material is 11-73 ℃.
17. The method of claim 16, wherein the freeze-milling method comprises the steps of:
mixing the nimodipine and the irbesartan followed by freeze-milling to obtain the co-amorphous.
18. The method of claim 17, wherein the milling time is 10-60 minutes.
19. The method of claim 17, wherein the milling speed is 500-2000rpm.
20. The method of any of claims 12-19, wherein the co-amorphous material has no sharp diffraction peaks in the X-ray powder diffraction spectrum expressed in 2Θ using Cu-ka radiation.
21. A pharmaceutical composition comprising the co-amorphous form of any one of claims 1-11 or prepared by the process of any one of claims 12-20.
22. A pharmaceutical formulation comprising a co-amorphous form according to any one of claims 1 to 11 or prepared by a process according to any one of claims 12 to 20 together with pharmaceutically acceptable excipients and/or carriers.
23. The pharmaceutical formulation of claim 22, in the form of a tablet or capsule.
24. Use of a co-amorphous form according to any one of claims 1 to 11 or prepared by a process according to any one of claims 12 to 20 in the manufacture of a medicament for the treatment of hypertension.
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| CN103497178A (en) * | 2013-09-27 | 2014-01-08 | 中国药科大学 | Irbesartan and repaglinide co-amorphous substance |
| CN105646353A (en) * | 2016-03-02 | 2016-06-08 | 中国药科大学 | Celecoxib and irbesartan coamorphous substance |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103497178A (en) * | 2013-09-27 | 2014-01-08 | 中国药科大学 | Irbesartan and repaglinide co-amorphous substance |
| CN105646353A (en) * | 2016-03-02 | 2016-06-08 | 中国药科大学 | Celecoxib and irbesartan coamorphous substance |
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