CN113952336A - Preparation and effect analysis of nitrendipine-indometacin amorphous coupling system - Google Patents
Preparation and effect analysis of nitrendipine-indometacin amorphous coupling system Download PDFInfo
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Abstract
The invention relates to preparation and effect analysis of an amorphous nitrendipine-indometacin coupling system, wherein nitrendipine-indometacin is used as a dual model drug, the amorphous nitrendipine-indometacin coupling system is prepared by a melting-quenching method, amorphous stabilization in the amorphous coupling system avoids the use of polymers, and the drugs are stabilized by amorphous phases. And analyzing and comparing the physicochemical properties and effects of the obtained amorphous coupling system to obtain the optimal drug ratio of the nitrendipine-indometacin amorphous coupling system of 2: 1. Provides a powerful data basis for the combined medication and new drug development of the nitrendipine-indometacin amorphous coupling system; provides a new research and development direction and powerful technical support for solving the technical problems of low solubility, low bioavailability, preparation of amorphous preparation formula proportion and the like when nitrendipine and indometacin are independently used for clinical treatment, and provides a new scheme for the field of combined medication.
Description
Technical Field
The invention relates to the field of preparations for insoluble drug combination by adopting an amorphous technology, in particular to preparation and effect analysis of an amorphous coupling system of nitrendipine-indometacin.
Background
The low solubility of 40% of the drugs and 75% of the drug candidates already on the market has always been a great challenge in different stages and areas of development of the drugs, and the low solubility and low dissolution rate of the drugs may limit their bioavailability after oral administration. The techniques for improving the dissolution of BCS II drugs are commonly used for preparing water-soluble salts, adding surfactants, preparing inclusion compounds, adopting a solid dispersion technology, adopting a nanotechnology and the like. The bioavailability of BCS class II drugs is low, and most of them are crystalline drugs. The molecular characteristics of the crystal drug show that the crystal drug has a certain sequence in arrangement and structure and has higher lattice energy. The crystal lattice energy of the crystals must be overcome during dissolution and absorption, which severely limits the bioavailability of the drug.
In recent years, research on novel amorphous coupling systems, which are single-phase amorphous coupling systems with a single glass transition temperature obtained by subjecting two or more drugs to a special preparation process, has been receiving attention from pharmaceutical researchers at home and abroad. The system not only has various advantages of single amorphous drug, but also can improve the solubility and dissolution rate of the drug, improve the bioavailability of the drug, and the like. The co-amorphous form of certain drugs has a higher solubility and dissolution rate than the single amorphous drug and also overcomes the generally unstable nature of the single amorphous drug.
The molecular weight of nitrendipine is 360.36, the melting point is 156-167 ℃, and the nitrendipine is yellow crystal or crystalline powder, is odorless and tasteless, and is easy to deteriorate when exposed to light. It is easily dissolved in acetone and chloroform, and is hardly dissolved in methanol and ethanol, and is hardly dissolved in water. Nitrendipine is a second generation dihydropyridine calcium ion channel antagonist, mainly acts on peripheral blood vessels, and causes the expansion of systemic blood vessels such as coronary arteries, renal arterioles and the like by inhibiting the transmembrane calcium ion inflow of vascular smooth muscles and cardiac muscles, and the peripheral resistance is reduced to generate the function of reducing blood pressure. Nitrendipine is suitable for treating various types of hypertension, especially hypertension patients accompanied with hyperlipidemia, hypertension patients accompanied with coronary heart disease and congestive heart failure patients. The preparation of the preparation has certain difficulties due to the extremely low solubility and the low bioavailability.
Indomethacin (Indomethacin) has a molecular weight of 357.79 deg.C, a melting point of 158-162 deg.C, is white or yellowish crystalline powder, is soluble in acetone, slightly soluble in ethanol, diethyl ether and chloroform, and is hardly soluble in water, odorless and tasteless. Indomethacin is one of the strongest PG synthetase inhibitors, has strong inhibition effect on COX-1 and COX-2, can also inhibit phospholipase A2 and phospholipase C, reduce granulocyte migration and lymphocyte proliferation, and has anti-inflammatory effect 10-40 times stronger than that of aspirin. Therefore, the Chinese medicinal composition has obvious anti-inflammatory and antipyretic effects and obvious analgesic effect on inflammatory pain. However, the traditional Chinese medicine composition has many adverse reactions, so the traditional Chinese medicine composition is only used for cases which cannot be tolerated by other medicines or have insignificant curative effect. For acute rheumatic and rheumatoid arthritis, about two thirds of patients can be improved obviously. The medicine has the characteristics of high permeability and low solubility, and is the largest raw material medicine group in the proportion of candidate medicines of the preparation in the current preparation development.
Disclosure of Invention
The invention aims to provide an amorphous nitrendipine-indometacin coupling system, and in order to achieve the aim, the invention provides the following technical scheme so as to solve the problems in the background technology.
The preparation and effect analysis of the nitrendipine-indometacin amorphous coupling system comprises the following steps:
(1) preparation of a single amorphous system: a. weighing nitrendipine and indometacin raw material medicines respectively, placing the nitrendipine and indometacin raw material medicines in preheated crucibles respectively, and carrying out hot melting in a sealed oil bath for 5 min; b. quenching the sealed crucible by using liquid nitrogen; c. drying at 35 deg.C in a dark oven; and d, grinding the dried medicines into powder, respectively sieving the powder by a 120-mesh sieve, and then sealing and storing in dark place.
(2, preparing an amorphous nitrendipine-indometacin coupling system, namely weighing nitrendipine and indometacin raw material medicines according to the mass ratio of 1:1, 1:2 and 2:1, placing the raw material medicines into a preheated crucible, carrying out hot melting in a sealed oil bath for 5min, quenching the sealed crucible by using liquid nitrogen, placing the crucible into a light-proof oven, drying at 35 ℃, grinding the dried medicines into powder, respectively sieving the powder through a 120-mesh sieve, and then carrying out sealed light-proof storage to obtain the three amorphous nitrendipine-indometacin coupling systems (1:1, 2:1 and 1:2) with different ratios.
(3) The effect of the nitrendipine-indometacin amorphous coupling system was analyzed: a.X-ray diffraction experiment confirms that the construction of the nitrendipine-indometacin amorphous coupling system is successful; b. taking a nitrendipine-indometacin amorphous coupling system sample, placing the nitrendipine-indometacin amorphous coupling system sample under a certain condition for 3 months, and measuring the stability of the nitrendipine-indometacin amorphous coupling system sample; c. analyzing the drug shape and the surface property of the nitrendipine-indometacin amorphous coupling system by a scanning electron microscope test; analyzing the change of the Tg value of the nitrendipine-indometacin amorphous coupling system by using a TOPEM (topotecan effect EM) experiment; e. in-vitro solubilization test is used for determining drug content, dissolution rate and solubility change of the nitrendipine-indometacin amorphous coupling system.
Preferably, when the oil bath is heated and melted in the step (1) and the step (2), the temperature point just beginning to melt is taken as the heating temperature, and the samples prepared under the treatment method have no carbonization phenomenon, so that the heating temperatures in the preparation of the medicines in each group are respectively determined as follows: the indometacin bulk drug is 180 ℃; the nitrendipine bulk drug is 185 ℃; the nitrendipine-indometacin co-amorphous coupling system with the mass ratio of 1:1 is 185 ℃; the nitrendipine-indometacin co-amorphous coupling system with the mass ratio of 2:1 is 188 ℃; the mass ratio of the nitrendipine to the indometacin is 1:2, and the amorphous coupling system is 187 ℃.
Preferably, the effect analysis test on the nitrendipine-indometacin amorphous coupling system proves that: the nitrendipine-indometacin amorphous coupling system is more stable than a single amorphous system in the environment with room temperature and relative humidity of 40 percent; the dissolution rate and the solubility are both obviously higher than those of a single amorphous system, and the crystal inhibition effect is obvious.
Preferably, the optimal bulk drug ratio mass ratio of the nitrendipine-indometacin amorphous coupling system is 2:1 through effect analysis of the amorphous coupling system.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention adopts nitrendipine-indometacin as a model drug, prepares the nitrendipine-indometacin amorphous coupling system by adopting a melting-quenching method, and adopts a series of experimental analysis means to analyze and compare the physicochemical properties and the effects of the obtained amorphous coupling system to obtain the optimal bulk drug ratio of the nitrendipine-indometacin amorphous coupling system of 2:1, thereby providing a powerful data basis for the combined medication of the nitrendipine-indometacin amorphous coupling system.
2. By researching the preparation and effect analysis of the amorphous coupling system of nitrendipine and indometacin, the invention provides a new research and development direction and a powerful technical support for solving the technical problems of low bioavailability and difficult medicament preparation due to low solubility of nitrendipine and indometacin when the nitrendipine and the indometacin are independently used for clinical treatment, and provides a new scheme for the field of medicament application.
Drawings
FIG. 1 is a graph showing X-ray diffraction patterns of various samples (in the graph, a is a nitrendipine crystal, b is an indomethacin crystal, c is a physical mixture 1:1 of nitrendipine and indomethacin, d is a nitrendipine single amorphous form, e is an indomethacin single amorphous form, f is a nitrendipine-indomethacin amorphous coupling system 1:1, g is a nitrendipine-indomethacin amorphous coupling system 1:2, and h is a nitrendipine-indomethacin amorphous coupling system 2: 1);
FIG. 2 is a 3-month stability X-ray diffraction pattern for various samples (a is nitrendipine single amorphous form, b is indomethacin single amorphous form, c is nitrendipine-indomethacin amorphous coupling system 1:1, d is nitrendipine-indomethacin amorphous coupling system 1:2, e is nitrendipine-indomethacin amorphous coupling system 2: 1);
FIG. 3 is a graph comparing the results of scanning the structure of each sample by an electron microscope (in the graph, A is a nitrendipine crystal, B is an indomethacin crystal, C is a physical mixture 1:1 of nitrendipine and indomethacin, D is a nitrendipine single amorphous form, E is an indomethacin single amorphous form, F is a nitrendipine-indomethacin amorphous coupling system 1:1, G is a nitrendipine-indomethacin amorphous coupling system 1:2, and H is a nitrendipine-indomethacin amorphous coupling system 2: 1);
FIG. 4 shows the Tg variation results for each amorphous coupling system sample and control;
FIG. 5 shows the result of detecting the content change of nitrendipine in each amorphous coupling system sample;
FIG. 6 shows the results of measuring the content change of indomethacin in each sample of the amorphous coupling system;
FIG. 7 is an elution diagram of nitrendipine in 0.25% SDS aqueous solution in each amorphous coupling system and in control samples;
FIG. 8 is a dissolution chart of indomethacin in 0.1mol/L HCl in each amorphous coupling system and control sample;
FIG. 9 is a graph of the 24 hour solubility of nitrendipine in 0.25% SDS aqueous solution in each amorphous coupling system and in control samples;
FIG. 10 is a graph showing the 24-hour solubility of indomethacin in 0.1mol/L HCl in each of the amorphous coupling systems and the control samples;
fig. 11 is a graph of crystallization inhibition curves of different concentrations of indomethacin on supersaturated solutions of nitrendipine.
Detailed Description
The following examples are given to facilitate a better understanding of the invention, but are not intended to limit the invention thereto. The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified. In the quantitative tests in the following examples, three replicates were set up and the results averaged.
The preparation and effect analysis of the nitrendipine-indometacin amorphous coupling system comprises the following steps:
(1) preparation of a single amorphous system: a. weighing nitrendipine and indometacin raw material medicines respectively, placing the nitrendipine and indometacin raw material medicines in preheated crucibles respectively, and carrying out hot melting in a sealed oil bath for 5 min; b. quenching the sealed crucible by using liquid nitrogen; c. drying at 35 deg.C in a dark oven; and d, grinding the dried medicines into powder, respectively sieving the powder by a 120-mesh sieve, and then sealing and storing in dark place.
Preparation of nitrendipine single amorphous system: weighing 500mg of nitrendipine raw material medicine, placing the nitrendipine raw material medicine into a preheated crucible, heating the nitrendipine raw material medicine to a molten state in an oil bath environment, keeping the molten state for 5min, placing a small crucible into a large crucible filled with liquid nitrogen, rapidly quenching (preventing impurities in the liquid nitrogen from polluting the medicine), and paying attention to the sealing property of the crucible and a pot cover in the process so as to prevent the medicine from contacting with water vapor quenched in the air to cause the medicine to absorb moisture. In addition, nitrendipine is unstable when exposed to light, and should be protected from light during the preparation process. The nitrendipine after melting and quenching is yellow transparent solid, the solid state can exist stably at 20-4 ℃, the sample is stored in a light-proof oven at the temperature of 35 ℃ to dry or reduce the moisture in the sample, then the sample is placed in a mortar to be ground into powder, the powder is sieved by a 120-mesh standard sieve, and the fine powder sieved by the 120-mesh sieve is taken out to be stored in a self-sealing bag in a light-proof dryer in a sealing way for later use.
The preparation process of the indometacin single amorphous system is the same as that of the nitrendipine single amorphous system.
When the oil bath is melted, the temperature point just beginning to melt is taken as the heating temperature, and the samples prepared under the treatment method have no carbonization phenomenon, so that the heating temperatures when preparing each group of medicines are determined as follows: the indometacin bulk drug is 180 ℃; the nitrendipine bulk drug is 185 ℃; the nitrendipine-indometacin co-amorphous coupling system (1:1) with the mass ratio of 1:1 is 185 ℃; the nitrendipine-indometacin co-amorphous coupling system (2:1) with the mass ratio of 2:1 is 188 ℃; the mass ratio of the nitrendipine to the indometacin co-amorphous coupling system (1:2) is 1:2, and the temperature is 187 ℃.
(2 preparing the nitrendipine-indometacin amorphous coupling system, namely weighing nitrendipine and indometacin raw material medicines according to the mass ratio of 1:1, 1:2 and 2:1, placing the nitrendipine and the indometacin raw material medicines into a preheated crucible, heating the crucible to a molten state in an oil bath environment, keeping the molten state for 5min, then placing a small crucible into a large crucible filled with liquid nitrogen for rapid quenching (preventing impurities in the liquid nitrogen from polluting the medicines), paying attention to the sealing property of the crucible and a pot cover in the process so as to prevent the medicines from contacting with water vapor quenched in the air to cause moisture absorption of the medicines, placing the crucible into a light-proof oven for drying at 35 ℃, grinding the dried medicines into powder, respectively sieving the powder through a 120-mesh sieve, sealing and storing the powder in the dark to obtain the nitrendipine-indometacin amorphous coupling system (1:1, 1:2 and 2: 1).
(2) The effect of the nitrendipine-indometacin amorphous coupling system (1:1, 1:2, 2:1) was analyzed:
a.X-ray diffraction experiment confirms that the nitrendipine-indometacin amorphous coupling system is successfully constructed: under the working conditions of a CuK alpha target, a voltage of 40kv, a current of 40mA, a scanning speed of 10 DEG/min and a scanning range of 5-45 DEG, nitrendipine crystal, indomethacin crystal, a physical mixture of nitrendipine and indomethacin 1:1, a nitrendipine single amorphous system, an indomethacin single amorphous system and a nitrendipine-indomethacin amorphous coupling system (1:1, 1:2 and 2:1) are respectively subjected to X-ray diffraction. The results are shown in FIG. 1.
b. Taking a nitrendipine-indometacin amorphous coupling system (1:1, 1:2 and 2:1) sample, standing for 3 months under certain conditions, and determining the stability of the nitrendipine-indometacin amorphous coupling system: the X-ray diffraction of the nitrendipine single amorphous coupling system, the indometacin single amorphous coupling system and the nitrendipine-indometacin amorphous coupling system (1:1, 1:2 and 2:1) is measured after being placed in an environment with the relative humidity of 30% at the temperature of 25 ℃ for 1 month, 3 months, 4 months and 5 months. The results are shown in FIG. 2.
c. The scanning electron microscope test is used for analyzing the drug morphology and the surface property of the nitrendipine-indometacin amorphous coupling system (1:1, 1:2 and 2: 1): the shape and surface properties of the drug are observed by using an SEM (scanning electron microscope), and the structure and the change of each group of the drug are observed by electronically scanning a nitrendipine crystal, an indomethacin crystal, a physical mixture 1:1, a nitrendipine single amorphous system, an indomethacin single amorphous system, a nitrendipine-indomethacin amorphous coupling system (1:1), a nitrendipine-indomethacin amorphous coupling system (1:2) and a nitrendipine-indomethacin amorphous coupling system (2: 1). The results are shown in FIG. 3.
Analysis of changes in glass transition temperature (Tg) values of nitrendipine-indometacin amorphous coupling systems by TOPEM experiments: in the TOPEM experiment, nitrogen gas flow atmosphere is adopted, S is marked on the left side of the sensor, and a sample crucible to be detected is placed; r is marked on the right side, a reference crucible is placed, the scanning speed is 2 ℃/min, the scanning range is 20-150 ℃, and nitrendipine amorphous and indometacin amorphous, nitrendipine-indometacin amorphous (1:1, 1:2, 2:1) DSC tests are carried out. Theoretical T of amorphous drug coupling system can be calculated through Gordon-Taylor equationgThe value, equation is as follows:
Tgab＝(Wa·Tga+K·Wb·Tgb)/(Wa+K·Wb)
Tgabglass transition temperature, W, of the amorphous coupling systemaAnd WbRespectively represents the weight percentage of the drug components a and b in an amorphous coupling system, TgaAnd TgbThe glass transition temperatures of the individual amorphous drug components a and b, respectively.
Where K is a constant, can be obtained by the following formula
K≈ΔCpb/ΔCpa
ΔCpaAnd Δ CpbRespectively represent the heat capacity change values of the single amorphous drug component before and after the change of the glass transition temperature. The change in Tg values for the various samples is shown in FIG. 4.
From fig. 4, it can be seen that the measured values of Tg are all in positive deviation from the theoretical values, indicating that the number and strength of hydrogen bonds between two components in the amorphous coupling system of each ratio of the two mixtures are stronger than the interaction existing in a single component, which is beneficial to the formation of the amorphous coupling system of the drug. Therefore, the strength of drug interaction in an amorphous coupling system can be inferred by comparing the magnitude of the measured Tg value with the theoretical Tg value. In summary, the experimental results can further illustrate that the amorphous coupling system has stronger stability than the amorphous coupling system alone, and provide a new theoretical basis for revealing the stabilization characteristics and formation of the amorphous coupling system.
e. In-vitro solubilization test is used for determining drug content, dissolution rate and solubility change of the nitrendipine-indometacin amorphous coupling system.
Change of drug content: accurately weighing each medicine sample, dissolving and diluting the medicine sample to a scale with methanol in a volumetric flask respectively, fixing the volume, standing for half an hour, performing an n-3 parallel test, measuring the area of the medicine sample by using a high performance liquid chromatograph, and calculating the content. The content results of nitrendipine and indometacin in each amorphous coupling system are shown in fig. 5 and 6 respectively. Through the quenching process, the contents of the two drugs are not obviously reduced, and the chemical stability can be basically kept.
Analysis of dissolution efficiency: weighing various samples in 900ml medium (the medium can be 0.25% SDS water solution, 0.1mol/L HCl), adopting paddle method, at 37 deg.C and 100r/min, taking 5ml through 0.45 micrometer microporous membrane at 5, 10, 15, 30, 45, 60min, taking 20 μ L, injecting into high performance liquid chromatograph, measuring, repeating the same conditions for 3 times, and obtaining the dissolution curve. The results are shown in FIGS. 7 and 8. The results show that the amorphous coupling system (2:1) of nitrendipine and indometacin simultaneously causes the maximum dissolution of the two drugs.
Analysis of change in solubility: adding various samples into a 50ml colorimetric tube, adding 0.25% SDS aqueous solution or 0.1mol/L HCl into the colorimetric tube to 50ml, placing the colorimetric tube in a constant temperature shaker at 37 ℃ for 24 hours at the rotating speed of 100r/min, taking supernate, carrying out sample injection measurement on the supernate through a 0.45-micron filter membrane under the condition of nitrendipine liquid phase, carrying out a parallel test with n being 3, and analyzing the solubility change of the nitrendipine-indometacin amorphous coupling system by comparing with a control group. The results are shown in FIGS. 9 and 10. The results show that the nitrendipine-indomethacin amorphous coupling system (2:1) simultaneously causes the maximum solubility of both drugs.
And (3) analyzing the supersaturated crystal inhibition effect: nitrendipine 45mg was weighed into a 5ml EP tube and dissolved with a minimum amount of methanol. Weighing indomethacin in a ratio of 1:0, 1:1, 1:2, 1:3 and 1:4 respectively, placing the indomethacin in a 5ml EP tube, using a small amount of methanol to assist dissolution, pouring the indomethacin into 900ml of phosphate buffer medium with pH8.0, adopting a paddle method, taking 5ml through a 0.45 micron microporous membrane at the conditions of 37 ℃ and 100r/min for 30, 60, 90, 120, 150, 180, 210 and 240min, taking 20ul of a sample, injecting the sample into a liquid chromatograph, measuring, repeating the same conditions for 3 times to obtain a dissolution curve, and taking the result as a control group. The results are shown in FIG. 11.
The dissolution curves of the nitrendipine single amorphous system, the indomethacin single amorphous system and the nitrendipine-indomethacin amorphous coupling system are measured by the same method and compared with a control group for analysis.
Wherein, the effect analysis test of the nitrendipine-indometacin amorphous coupling system proves that: the nitrendipine-indometacin amorphous coupling system (1:1, 1:2 and 2:1) is more stable than a single amorphous system in an environment with room temperature and relative humidity of 40 percent; the dissolution rate and the solubility are both obviously higher than those of a single amorphous system, and the crystal inhibition effect is obvious.
According to the effect analysis of the amorphous coupling system, the optimal bulk drug ratio mass ratio of the nitrendipine-indometacin amorphous coupling system is 2: 1.
Example one
X-ray diffraction experiments confirm that the nitrendipine-indometacin amorphous coupling system is successfully constructed: under the working conditions of a CuK alpha target, a voltage of 40kv, a current of 40mA, a scanning speed of 10 DEG/min and a scanning range of 5-45 DEG, nitrendipine crystal, indomethacin crystal, a physical mixture of nitrendipine and indomethacin 1:1, a nitrendipine single amorphous system, an indomethacin single amorphous system and a nitrendipine-indomethacin amorphous coupling system (1:1, 1:2 and 2:1) are respectively subjected to X-ray diffraction. The results are shown in FIG. 1: the nitrendipine crystal, the indometacin crystal, the physical mixture of nitrendipine and indometacin 1:1 all have sharp and obvious characteristic crystal peaks, and the characteristic crystal peaks of the nitrendipine single amorphous system, the indometacin single amorphous system and the nitrendipine-indometacin amorphous coupling system (1:1, 1:2 and 2:1) almost completely disappear, so that the amorphous coupling system with the nitrendipine-indometacin ratio after the melting-quenching treatment is more thoroughly amorphous. In conclusion, the amorphous nitrendipine, the amorphous indometacin and the amorphous nitrendipine-indometacin coupling system in each proportion can be preliminarily determined to be successfully constructed.
Example two
The X-ray diffraction results of the amorphous nitrendipine, the amorphous indometacin and the nitrendipine-indometacin co-amorphous coupling system (1:1, 1:2 and 2:1) are measured after being placed in an environment with the temperature of 25 ℃ and the relative humidity of 30 percent for 3 months. The results are shown in FIG. 2: the amorphous coupling system (1:1, 1:2, 2:1) of nitrendipine-indometacin has weaker and smaller diffraction peak than that of single amorphous crystal; therefore, the time for the nitrendipine-indometacin co-amorphous crystallization is prolonged compared with the time for the single amorphous crystallization in the solid state, so the nitrendipine-indometacin co-amorphous is more stable than the single amorphous, and the nitrendipine-indometacin amorphous coupling system (1:2) has the least crystal peaks and is the most stable.
EXAMPLE III
The shape and surface properties of the drug are observed by using an SEM (scanning electron microscope), and the structure and the change of each group of the drug are observed by electronically scanning a nitrendipine crystal, an indomethacin crystal, a physical mixture 1:1, a nitrendipine single amorphous system, an indomethacin single amorphous system, a nitrendipine-indomethacin amorphous coupling system (1:1), a nitrendipine-indomethacin amorphous coupling system (1:2) and a nitrendipine-indomethacin amorphous coupling system (2: 1). The results are shown in FIG. 3: from the graphs A and B, the micro-morphological distribution of the nitrendipine and the indometacin crystal is uniform, and the nitrendipine and the indometacin crystal have obvious lamellar structures; from fig. C, it can be seen that the microscopic morphology of the physical mixture possesses both the distribution of the two drugs and the lamellar structure; it can be seen from fig. D and E that the nitrendipine and indomethacin crystal after the melting-quenching treatment has undergone a large change in morphology, and is in a random state, and the lamellar structure is reduced or even disappears, which is initially presumed to be in an amorphous state. From the graph F, the graph G and the graph H, it can be seen that the forms of the amorphous coupling system after the melting-quenching treatment are changed more obviously in proportion, the lamellar structure almost disappears, the random arrangement sequence is realized, and the change in the microscopic forms can deduce that certain interaction occurs between the two drugs, so that a reliable basis is provided for the successful construction of the novel amorphous coupling system.
Example four
Analyzing the change of the glass transition temperature Tg value of the nitrendipine-indometacin amorphous coupling system by using a TOPEM (topotecan effect) experiment; measurement and analysis were performed by using a temperature-modulated DSC apparatus and a TOPEM experiment. As can be seen from FIG. 4, the measured values of Tg all deviate from the theoretical values, indicating that the number and strength of hydrogen bonds between two components in the amorphous coupling system of each ratio of the two mixtures are stronger than the interaction existing in a single component, which is beneficial to the formation of the amorphous coupling system of the drug. Therefore, the strength of drug interaction in an amorphous coupling system can be inferred by comparing the magnitude of the measured Tg value with the theoretical Tg value. In summary, the experimental results can further illustrate that the amorphous coupling system has stronger stability than the amorphous coupling system alone, and provide a new theoretical basis for revealing the stabilization characteristics and formation of the amorphous coupling system.
EXAMPLE five
Change of drug content: accurately weighing each medicine sample, taking nitrendipine as a reference, wherein the nitrendipine is equivalent to 25mg of nitrendipine, dissolving and diluting the nitrendipine into 50ml volumetric flasks respectively by using methanol until the nitrendipine is scaled, fixing the volume, standing for half an hour, performing an n-3 parallel test, measuring the area of the nitrendipine by using a high performance liquid chromatograph, and calculating the content. The results are shown in fig. 5 and 6: the loss of the content of the nitrendipine in each sample after the melting-quenching treatment is small, so that the construction of the system does not generate large fluctuation on the content of the drug.
EXAMPLE six
Weighing nitrendipine 50mg, various samples (equivalent to nitrendipine 50mg), putting into 900ml of distilled water of 0.25% SDS, adopting a paddle method, taking 5ml through a 0.45 micron microporous membrane at the conditions of 37 ℃ and 100r/min at 5, 10, 15, 30, 45 and 60min, taking 20 mu l, injecting into a high performance liquid chromatograph, measuring, and repeating the same conditions for 3 times to obtain the dissolution curve. The results are shown in FIG. 7: as can be seen from the figure, the dissolution amount of the nitrendipine-indometacin co-amorphous form (1:1, 1:2, 2:1) group is higher than that of the indometacin crystal group and the nitrendipine-indometacin physical mixture (1:1) group within 0-60 min; the highest of the nitrendipine-indometacin amorphous (2:1) group is the nitrendipine-indometacin amorphous coupling system, so that under the condition, the nitrendipine-indometacin amorphous coupling system has obvious solubilization advantages compared with a crystal drug and a single-component drug amorphous.
EXAMPLE seven
Weighing 50mg of indomethacin and various samples (corresponding to 50mg of indomethacin), placing in 900ml of 0.1mol/L HCl, adopting a paddle method, taking 5ml of indomethacin through a 0.45 micron microporous filter membrane at 37 ℃ and 100r/min for 5min, 10 min, 15 min, 30 min, 45 min and 60min, taking 20 mu L of indomethacin, injecting into a high performance liquid chromatograph, measuring, and repeating the same conditions for 3 times to obtain the dissolution curve. The results are shown in FIG. 8: the dissolution amounts of the indomethacin-nitrendipine co-amorphous group (1:1, 1:2, 2:1) and the indomethacin amorphous group are higher than those of the indomethacin crystal group and the indomethacin-nitrendipine physical mixture 1:1 within 0-60 min; wherein the highest concentration of the nitrendipine-indometacin co-amorphous (2:1) group is 19.29 mu g/ml; therefore, under the condition, the novel amorphous coupling system of nitrendipine-indometacin is more advantageous in solubilization.
Example eight
Taking 50mg of nitrendipine, adding various samples (equivalent to 50mg of nitrendipine) into a 50ml colorimetric tube, adding distilled water to 50ml, placing in a constant temperature shaking table at 37 ℃ for 24 hours at the rotating speed of 100r/min, taking supernate, performing sample injection measurement on the supernate through a 0.45-micrometer filter membrane under the condition of nitrendipine liquid phase, performing a parallel test with n being 3, and analyzing the solubility change of the nitrendipine-indometacin amorphous coupling system by comparing with a control group. The results are shown in FIG. 9: the nitrendipine-indometacin amorphous coupling system has obvious proportion solubilization advantage, and the nitrendipine-indometacin amorphous coupling system (2:1) has the highest concentration, so that the nitrendipine-indometacin amorphous coupling system has obvious solubilization advantage and better crystal inhibition effect compared with single-component amorphous coupling system.
Example nine
Taking 50mg of indomethacin and various samples (corresponding to 50mg of indomethacin), adding the indomethacin and various samples into a 50ml colorimetric tube, adding 0.1mol/L HCl into the colorimetric tube to 50ml, placing the indomethacin and various samples in a constant temperature shaking table at 37 ℃ for 24 hours at a rotating speed of 100r/min, taking supernate, performing sample injection measurement on the supernate through a 0.45-micrometer filter membrane under the condition of nitrendipine liquid phase, performing a parallel test with n being 3, and analyzing the solubility change of the nitrendipine-indomethacin amorphous coupling system by comparing with a control group. The results are shown in FIG. 10: compared with 24 hours, the concentrations of the amorphous co-group of nitrendipine and indometacin are all improved, the concentrations of the amorphous co-group of nitrendipine and indometacin are all higher than those of the amorphous single-component, and the concentrations of the amorphous co-group of nitrendipine and indometacin (2:1) are the highest, so that the co-amorphous coupling system has obvious solubilization advantages compared with a single crystal and a physical mixture.
Example ten
Nitrendipine 45mg was weighed into a 5ml EP tube and dissolved with a minimum amount of methanol. Weighing indomethacin in a ratio of 1:0, 1:1, 1:2, 1:3 and 1:4 respectively, placing the indomethacin in a 5ml EP tube, using a small amount of methanol to assist dissolution, pouring the indomethacin into 900ml of phosphate buffer medium with pH8.0, adopting a paddle method, taking 5ml through a 0.45 micron microporous membrane at the conditions of 37 ℃ and 100r/min for 30, 60, 90, 120, 150, 180, 210 and 240min, taking 20ul of a sample, injecting the sample into a liquid chromatograph, measuring, and repeating the same conditions for 3 times to obtain the dissolution curve. The results are shown in FIG. 11: in a liquid state, the concentration of the nitrendipine is higher along with the increase of the concentration of the indometacin, and the concentration of the nitrendipine solution without the indometacin is lowest. It is thus presumed that one drug can inhibit the crystallization of the other drug from the supersaturated state in the supersaturated state, and that one drug can inhibit the crystallization of the other drug in the amorphous coupling system, thereby increasing the stabilization of the amorphous states. Thereby providing powerful data for the combined application of the two medicaments.
Claims (4)
1. The preparation and effect analysis of the nitrendipine-indometacin amorphous coupling system are characterized in that the method comprises the following steps:
(1) preparation of a single amorphous system: a. weighing nitrendipine and indometacin raw material medicines respectively, placing the nitrendipine and indometacin raw material medicines in preheated crucibles respectively, and carrying out hot melting in a sealed oil bath for 5 min; b. quenching the sealed crucible by using liquid nitrogen; c. drying at 35 deg.C in a dark oven; d. grinding the dried medicines into powder, respectively sieving with 120 mesh sieve, sealing, and storing in dark place.
(2, preparing an amorphous nitrendipine-indometacin coupling system, namely weighing nitrendipine and indometacin raw material medicines according to the mass ratio of 1:1, 1:2 and 2:1, placing the raw material medicines into a preheated crucible, carrying out hot melting in a sealed oil bath for 5min, quenching the sealed crucible by using liquid nitrogen, placing the crucible into a light-proof oven, drying at 35 ℃, grinding the dried medicines into powder, respectively sieving the powder through a 120-mesh sieve, and then carrying out sealed light-proof storage to obtain the three amorphous nitrendipine-indometacin coupling systems (1:1, 1:2 and 2:1) with different ratios.
(3) The effect of the nitrendipine-indometacin amorphous coupling system (1:1, 1:2, 2:1) was analyzed: a.X-ray diffraction experiments confirm that the nitrendipine-indometacin amorphous coupling system (1:1, 1:2 and 2:1) is successfully constructed; b. taking a nitrendipine-indometacin amorphous coupling system (1:1, 1:2 and 2:1) sample, standing for 3 months under certain conditions, and determining the stability of the sample; c. analyzing the drug morphology and the surface property of the nitrendipine-indometacin amorphous coupling system (1:1, 1:2 and 2:1) by a scanning electron microscope test; analyzing the change of the Tg value of the nitrendipine-indometacin amorphous coupling system (1:1, 1:2 and 2:1) by using a TOPEM (partial peak area effect) experiment; e. in vitro solubilization assay is used for determining drug content, dissolution rate and solubility change of nitrendipine-indometacin amorphous coupling system (1:1, 1:2 and 2: 1).
2. The method for preparing and analyzing effects of the amorphous coupled system of nitrendipine-indometacin as claimed in claim 1, wherein the heating temperature is the temperature point at which the oil bath just starts to melt when the oil bath is heated and melted in step (1) and step (2), and the samples prepared under the processing method are free from carbonization, so that the heating temperatures for preparing the groups of drugs are determined as follows: the indometacin bulk drug is 180 ℃; the nitrendipine bulk drug is 185 ℃; the nitrendipine-indometacin co-amorphous coupling system (1:1) with the mass ratio of 1:1 is 185 ℃; the nitrendipine-indometacin co-amorphous coupling system (2:1) with the mass ratio of 2:1 is 188 ℃; the mass ratio of the nitrendipine to the indometacin co-amorphous coupling system (1:2) is 1:2, and the temperature is 187 ℃.
3. The preparation and effect analysis of the nitrendipine-indometacin amorphous coupling system according to claim 1, characterized in that the effect analysis experiment on the nitrendipine-indometacin amorphous coupling system (1:1, 1:2, 2:1) proves that: the nitrendipine-indometacin amorphous coupling system (1:1, 1:2 and 2:1) is more stable than a single amorphous system at room temperature and in an environment with the relative humidity of 40 percent; the dissolution rate and the solubility are both higher than those of a single amorphous system, and the crystal inhibitor has obvious crystallization inhibition effect.
4. The preparation and effect analysis of the nitrendipine-indomethacin amorphous coupling system according to claim 1, wherein the optimal bulk drug ratio mass ratio of the nitrendipine-indomethacin amorphous coupling system is 2:1 through the effect analysis of the amorphous coupling system.
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