Dipyridamole solid dispersion, pharmaceutical preparation and preparation method

Abstract

The invention relates to the technical field of pharmaceutical preparations, and discloses a dipyridamole solid dispersion, a pharmaceutical preparation and a preparation method, the dipyridamole solid dispersion comprises dipyridamole, an enteric material and a plasticizer, and the mass of the enteric material is 65-75% of the total mass of the dipyridamole solid dispersion. The dipyridamole solid dispersion comprises dipyridamole, an enteric-coated material and a plasticizer, dipyridamole is dispersed in the enteric-coated material in an amorphous molecule form, the dissolution rate of dipyridamole in a medium-high pH environment can be remarkably increased, the problem that dipyridamole is difficult to dissolve in an intestinal alkaline environment is effectively solved, and the dipyridamole solid dispersion is suitable for large-scale industrial production. And the oral bioavailability of the dipyridamole is improved. Besides, the dipyridamole solid dispersion and pharmaceutically acceptable auxiliary materials are used as raw materials to prepare the pharmaceutical preparation, so that the pharmaceutical dosage form of the dipyridamole is widened, the oral compliance of the medicine can be improved, and the dipyridamole pharmaceutical preparation is simple, easy to implement, easy to industrially produce and high in application value.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a dipyridamole solid dispersion, a pharmaceutical preparation and a preparation method. BACKGROUND

[0002] Dipyridamole is a BCS class II drug with antithrombotic effect, which is widely used in clinic as an anti-platelet aggregation drug and a coronary artery dilating drug, and is often used for preventing recurrence of myocardial infarction and angina pectoris. Dipyridamole has the characteristics of low solubility and high permeability, and its solubility in water is pH-dependent, that is, it is easily soluble in dilute acid and hardly soluble in alkali. During oral administration, the drug is in a high solubility state in the stomach with low pH, and in a low solubility state in the intestine with high pH, so the oral bioavailability of dipyridamole is low. Moreover, the main oral dosage form of dipyridamole on the market in China is tablet, which is inconvenient for children, the elderly and other people with difficulty in swallowing to use, so it is of great significance to develop a dipyridamole preparation with high bioavailability and good oral compliance. SUMMARY

[0003] Therefore, the present application provides a dipyridamole solid dispersion, a pharmaceutical preparation and a preparation method to solve the problems of low oral bioavailability and poor oral compliance of the existing dipyridamole raw material.

[0004] To solve the above technical problems, the present application adopts the following technical solutions:

[0005] On the one hand, the present application provides a dipyridamole solid dispersion, which is in an amorphous state and comprises dipyridamole, an enteric material and a plasticizer; the mass of the enteric material is 65-75% of the total mass of the dipyridamole solid dispersion.

[0006] Preferably, the mass ratio of the plasticizer to the dipyridamole is 1:0.5-2.5.

[0007] Preferably, the plasticizer comprises one or more of triethyl citrate, glycerol, castor oil, sorbitol, propylene glycol and polyethylene glycol.

[0008] Preferably, the enteric material is polyacrylic acid resin, and the polyacrylic acid resin is Eudragit L 100.

[0009] Preferably, the dipyridamole solid dispersion further comprises a water-soluble material, and the mass ratio of the plasticizer to the water-soluble material is 1:1-2.

[0010] Preferably, the water-soluble material comprises one or more of hydroxypropyl methylcellulose (HPMC-E5), polyvinylpyrrolidone (PVPK60) and hydroxypropyl cellulose (HPC-L).

[0011] In another aspect, the present application also provides a preparation method of the dipyridamole solid dispersion.

[0012] Preferably, the screw rotation speed in the hot melt extrusion process is 15-45 rpm.

[0013] Preferably, the temperature of the hot melt extrusion is 160-170℃.

[0014] The present application also provides a pharmaceutical preparation comprising the dipyridamole solid dispersion and pharmaceutically acceptable excipients, wherein the dipyridamole solid dispersion is the dipyridamole solid dispersion according to any one of the above or prepared by the method according to any one of the above.

[0015] Preferably, the pharmaceutical preparation comprises one or more of suspensions, tablets, capsules, granules, and dripping pills.

[0016] Preferably, the suspension comprises the dipyridamole solid dispersion, a suspending agent, and a flavoring agent, wherein the mass ratio of the dipyridamole solid dispersion to the suspending agent is 1:0.1-0.9, and the mass ratio of the dipyridamole solid dispersion to the flavoring agent is 1:5-5.5.

[0017] Preferably, the suspending agent is a mixture of xanthan gum and pregelatinized starch with a mass ratio of 1:1.25-6.

[0018] Preferably, the flavoring agent comprises one or more of sucrose, glucose, aspartame, and stevioside.

[0019] The embodiments of the present application provide a dipyridamole solid dispersion, a pharmaceutical preparation, and a preparation method.

[0020] The dipyridamole solid dispersion of the present application comprises dipyridamole, an enteric material, and a plasticizer, and by limiting the content of the enteric material, the dipyridamole is dispersed in the enteric material in an amorphous molecular form, which can significantly increase the dissolution of dipyridamole in a medium-high pH environment, effectively solve the problem of poor solubility of dipyridamole in the alkaline environment of the intestinal tract, and improve the oral bioavailability of dipyridamole.

[0021] In addition, the present application uses the dipyridamole solid dispersion and pharmaceutically acceptable excipients as raw materials to prepare the pharmaceutical preparation, which not only broadens the pharmaceutical dosage form of dipyridamole, but also improves the oral compliance of the drug, is simple and easy to implement, easy to industrialize, and has great application value. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0023] Figure 1 The in vitro dissolution curves are for dipyridamole raw material, commercially available dipyridamole tablets, and the dipyridamole solid dispersion of Example 11 (the left side is the curve simulating gastric fluid environment, and the right side is the curve simulating intestinal fluid environment).

[0024] Figure 2 The in vitro dissolution curves of dipyridamole solid dispersions in Examples 1-9 are shown (the left side is the curve simulating gastric fluid environment, and the right side is the curve simulating intestinal fluid environment).

[0025] Figure 3 The in vitro dissolution curves of dipyridamole solid dispersions in Examples 10-15 are shown (the left side is the curve simulating gastric fluid environment, and the right side is the curve simulating intestinal fluid environment).

[0026] Figure 4 X-ray diffraction patterns of dipyridamole raw material, the physical mixture of Comparative Example 1, and the dipyridamole solid dispersion of Example 11;

[0027] Figure 5 Fourier transform infrared spectra of the physical mixture of Comparative Example 1 and the dipyridamole solid dispersion of Example 11;

[0028] Figure 6 DSC curves of dipyridamole active pharmaceutical ingredient and dipyridamole solid dispersion from Example 11;

[0029] Figure 7 The in vitro dissolution curves of the dipyridamole solid dispersion in Example 11 are shown in the long-term experiment (the left side is the curve simulating gastric fluid environment, and the right side is the curve simulating intestinal fluid environment).

[0030] Figure 8 X-ray diffraction (left) and Fourier transform infrared spectrum (right) of the dipyridamole solid dispersion in high-temperature experiment of Example 11;

[0031] Figure 9 The in vitro dissolution curves of the dipyridamole solid dispersion in Example 11 are shown in the high-temperature experiment (the left side is the curve simulating gastric fluid environment, and the right side is the curve simulating intestinal fluid environment).

[0032] Figure 10X-ray diffraction (left) and Fourier transform infrared spectroscopy (right) of the dipyridamole solid dispersion of Example 11 after the high humidity experiment;

[0033] Figure 11 In-vitro dissolution profile (left for simulated gastric fluid environment profile, right for simulated intestinal fluid environment profile) of the dipyridamole solid dispersion of Example 11 after the light experiment;

[0034] Figure 12 X-ray diffraction (left) and Fourier transform infrared spectroscopy (right) of the dipyridamole solid dispersion of Example 11 after the light experiment;

[0035] Figure 13 In-vitro dissolution profile (left for simulated gastric fluid environment profile, right for simulated intestinal fluid environment profile) of the dipyridamole solid dispersion of Example 11 after the light experiment;

[0036] Figure 14 Pharmacokinetic profile of the dry suspension of Example 16, dipyridamole commercial tablet and dipyridamole raw material in rats. DETAILED DESCRIPTION

[0037] The present application will be described in detail below with specific examples, and those skilled in the art can understand that the specific examples below are only for illustrative purposes, and do not limit the scope of the present application in any way. In addition, in the following examples, unless otherwise specified, the reagents and equipment used are commercially available. If the specific processing conditions and processing methods are not explicitly described in the following examples, the conditions and methods known in the art can be used for processing.

[0038] In one aspect of the present application, the present application proposes a dipyridamole solid dispersion, the dipyridamole solid dispersion is in an amorphous state, comprising dipyridamole, an enteric material and a plasticizer; the mass of the enteric material is 65-75% of the total mass of the dipyridamole solid dispersion, and can be specifically 65%, 68%, 70%, 72%, 75%, etc.

[0039] The dipyridamole solid dispersion of the present application is an amorphous solid dispersion. When the content of the enteric material is too low, such as 60%, the dipyridamole solid dispersion will be completely dissolved in an acidic medium, the simulated gastric fluid dissolution is greater than 15%, and the solid dispersion loses enteric property; and when the content of the enteric material is too high, such as 80%, the dipyridamole solid dispersion although the dissolution in the simulated gastric fluid acidic medium meets the requirements, but is released slowly in the simulated intestinal fluid, and the dissolution is less than 70%.

[0040] In some embodiments of the present application, the mass ratio of the plasticizer and the dipyridamole is 1:0.5-2.5, and can be 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, etc.; the plasticizer includes one or more of triethyl citrate, glycerol, castor oil, sorbitol, propylene glycol, and polyethylene glycol. The amorphous solid dispersion is characterized in that the drug and the material are in a high-energy state, i.e., an unstable amorphous state, the drug is easy to release from the carrier material, and the drug is prone to crystallization during storage or when in contact with a dissolution medium. The present application can inhibit the crystallization of the drug and improve the stability of the solid dispersion by adding a plasticizer.

[0041] In some embodiments of the present application, the enteric material is a polyacrylic resin, and the polyacrylic resin is Eudragit L 100. Compared with Eudragit S-100, the solid dispersion prepared by using Eudragit L 100 as the enteric material can achieve a higher dissolution rate in simulated intestinal fluid, the drug release is more sufficient, and the drug release rate is faster.

[0042] In some embodiments of the present application, the dipyridamole solid dispersion further includes a water-soluble material, and the mass ratio of the plasticizer and the water-soluble material is 1:1-2, and can be 1:1, 1:1.5, 1:2, etc. When the content of the water-soluble material is too high, for example, 20%, the dipyridamole solid dispersion will be completely dissolved in an acidic medium, and the enteric property of the solid dispersion is lost.

[0043] In some embodiments of the present application, the water-soluble material includes one or more of hydroxypropyl methyl cellulose (HPMC-E5), polyvinyl pyrrolidone (PVP K60), and hydroxypropyl cellulose (HPC-L). Different types of water-soluble materials have no obvious difference in the final dissolution rate of dipyridamole in simulated intestinal fluid, and different types of water-soluble materials mainly affect the release rate of the drug in simulated intestinal fluid. The release rate of hydroxypropyl methyl cellulose is greater than that of polyvinyl pyrrolidone, which is greater than that of hydroxypropyl cellulose.

[0044] In another aspect of the present application, the present application further provides a preparation method of the dipyridamole solid dispersion described in any one of the above.

[0045] Specifically, the mixing method of the raw materials is not particularly limited, for example, stirring mixing can be used, as long as uniform mixing can be achieved. The present application uses hot melt extrusion to prepare a dipyridamole solid dispersion. The process is simple and convenient for mass production, and can avoid the use of organic solvents. The dipyridamole solid dispersion has good enteric solubility, can maintain an amorphous state in simulated gastric fluid, and can meet the requirements of rapid release and solubilization in simulated intestinal fluid. It should be noted that the hot melt extrusion is performed using a double-screw hot melt extruder.

[0046] In some embodiments of the present application, the screw rotation speed during the hot melt extrusion process is 15-45 rpm, and can be 15 rpm, 20 rpm, 25 rpm, 30 rpm, 35 rpm, 40 rpm, 45 rpm, etc. Experimental studies have found that when the rotation speed is too fast, such as 50 rpm, the extrusion time is short, the mixing is not uniform, and the extrudate is opaque yellow. When the rotation speed is 10-45 rpm, the extrudate is in good condition. When the rotation speed is too slow, such as 10 rpm, the slow rotation speed causes the drug to stay in the extruder for too long, resulting in an opaque brown end product and large product loss. Therefore, the screw rotation speed is limited to 15-45 rpm.

[0047] In some embodiments of the present application, the temperature of the hot melt extrusion is 160-170°C. At this hot melt extrusion temperature, the extruded product is yellow and transparent, and the dipyridamole and the enteric material / water-soluble material form a relatively uniform solid dispersion system. When the extrusion temperature is too low, such as 155°C, the extrudate is opaque, and the dipyridamole cannot reach a molten state, resulting in poor compatibility between the dipyridamole and the enteric material / water-soluble material. When the extrusion temperature is too high, such as 175°C or 185°C, there is a large color difference between the extrudate and the dipyridamole itself, resulting in degradation and destruction of the drug or carrier material.

[0048] In some embodiments of the present application, when the dipyridamole solid dispersion does not include water-soluble materials, the dipyridamole, enteric material, and plasticizer are mixed uniformly, and then the obtained mixture is subjected to hot extrusion. The conditions for hot extrusion are as described above and will not be repeated here.

[0049] In some embodiments of the present application, when the dipyridamole solid dispersion comprises water-soluble materials, the dipyridamole and water-soluble materials are first mixed for primary extrusion to obtain a primary extrudate, and then the primary extrudate and enteric materials, plasticizers are mixed for secondary extrusion. The conditions of the primary and secondary extrusion are the same as the conditions of the hot melt extrusion, which will not be repeated here. Specifically, the mixing of dipyridamole and water-soluble materials for extrusion can improve the dissolution of the drug in the intestine and thus improve the bioavailability, and the mixing of the extrudate and enteric materials for extrusion can improve the precipitation of dipyridamole in the intestine after dissolution in the stomach.

[0050] In another aspect of the present application, the present application also provides a pharmaceutical preparation comprising a dipyridamole solid dispersion and a pharmaceutically acceptable excipient, wherein the dipyridamole solid dispersion is any one of the above-mentioned dipyridamole solid dispersions or the dipyridamole solid dispersion prepared by any one of the above-mentioned methods.

[0051] In some embodiments of the present application, the pharmaceutical preparation comprises one or more of suspensions, tablets, capsules, granules, and dripping pills.

[0052] In some embodiments of the present application, the suspension is a dry suspension, which comprises a dipyridamole solid dispersion, a suspending agent, and a flavoring agent. The mass ratio of the dipyridamole solid dispersion to the suspending agent is 1:0.1-0.9, and specifically can be 1:0.1, 1:0.3, 1:0.5, 1:0.7, 1:0.9, etc. The mass ratio of the dipyridamole solid dispersion to the flavoring agent is 1:5-5.5, and specifically can be 1:5, 1:5.2, 1:5.4, 1:5.5, etc.

[0053] In some embodiments of the present application, the suspending agent is a mixture of xanthan gum and pregelatinized starch with a mass ratio of 1:1.25-6, and the ratio of the two can be 1:1.25, 1:2, 1:4, 1:6, etc. The addition of the suspending agent can improve the stability of the suspension.

[0054] In some embodiments of the present application, the flavoring agent comprises one or more of sucrose, glucose, aspartame, and stevioside. The addition of the appropriate flavoring agent can not only play a role in flavoring and preservation, but also can be used as a preservative at high concentrations.

[0055] In some embodiments of the present application, as the particle size of the dipyridamole solid dispersion decreases, the specific surface area of the solid dispersion increases, the leakage amount of the suspension in simulated gastric juice increases, and the dissolution rate of the solid dispersion in simulated intestinal juice increases, but there is no significant effect on the final dissolution of the drug. Therefore, the particle size of the dipyridamole solid dispersion in the present application is not specially limited, for example, it can be less than 0.075 mm.

[0056] In some embodiments of the present application, the pH value of the suspension obtained after dissolving the suspension in water is 3.5-3.7. Dipyridamole solid dispersion will leak a large amount of drug in a high pH environment, resulting in failure of the dosage form. The pH value of the dispersion medium needs to be adjusted to be acidic to ensure that the structure of the enteric solid dispersion remains relatively stable. In the present application, the suspension can present an acidic environment without the addition of a pH adjuster, and the drug leakage amount can be reduced without the need for additional adjustment of citric acid or the like to maintain relative stability.

[0057] The technical solutions in the present application will be described clearly and completely below in combination with specific embodiments. The embodiments of the present application are only used as examples, and all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0058] Example 1

[0059] The present embodiment provides a dipyridamole solid dispersion, which is composed of 0.5 g of dipyridamole, 1 g of water-soluble material, 1 g of plasticizer, and 7.5 g of enteric material. The water-soluble material is hydroxypropyl methyl cellulose (HPMC E5), the enteric material is Eudragit L-100, and the plasticizer is triethyl citrate (TEC).

[0060] The preparation method of the dipyridamole solid dispersion is as follows:

[0061] (1) Mix dipyridamole and water-soluble material, and perform first extrusion under the condition of 165°C and 30 rpm to obtain a first extrudate;

[0062] (2) Mix the first extrudate, enteric material, and plasticizer, and perform second extrusion under the condition of 165°C and 30 rpm to obtain a dipyridamole solid dispersion.

[0063] Examples 2-9

[0064] Examples 2-9 are basically the same as Example 1, and the only difference is that the type of water-soluble material in the dipyridamole solid dispersion and the amount of each raw material are changed. For details, see Table 1.

[0065] Example 10

[0066] This example provides a dipyridamole solid dispersion, which is composed of 1.0 g dipyridamole, 1.0 g plasticizer and 8.0 g enteric material. The enteric material is Eudragit L-100, and the plasticizer is triethyl citrate.

[0067] The preparation method of the dipyridamole solid dispersion is as follows: mix dipyridamole, enteric material and plasticizer, and extrude at 165°C and 30 rpm to obtain the dipyridamole solid dispersion.

[0068] Examples 11-15

[0069] Examples 11-15 are basically the same as Example 10, and the only difference is that the type of enteric material in the dipyridamole solid dispersion and the amount of each raw material are changed. For details, see Table 1.

[0070] Table 1

[0071]

[0072]

[0073] The in-vitro dissolution of dipyridamole raw material, dipyridamole commercial tablet (Yabao Pharmaceutical Group Co., Ltd.) and dipyridamole solid dispersion of Example 11 was tested. The test method was in accordance with the in-vitro dissolution of enteric preparation in the dissolution and release determination method of the 2020 edition of the Chinese Pharmacopoeia. The in-vitro dissolution was determined. The pH 1.2 hydrochloric acid solution was selected as the simulated gastric juice dissolution medium to simulate the gastric environment, and the pH 6.8 phosphate buffer solution was selected as the simulated intestinal juice dissolution medium to simulate the intestinal environment.

[0074] From Figure 1It can be seen that in the hydrochloric acid solution of pH 1.2, both dipyridamole raw material (API curve in the figure) and dipyridamole commercial tablets (Tablet curve in the figure) show good solubility, and the dissolution reaches more than 95%, which can be considered as complete dissolution, and the dipyridamole commercial tablets are completely disintegrated within 15 min; the dipyridamole solid dispersion of Example 11 (SD curve in the figure) keeps the dissolution within 15% after 2h dissolution, and the drug leakage in the simulated gastric fluid is in an acceptable range. In addition, in the phosphate buffer solution of pH 6.8, the dipyridamole raw material (API curve in the figure) and the dipyridamole commercial tablets (Tablet curve in the figure) are kept in a solid state suspended in the dissolution medium during the 2h dissolution process, and the final dissolution of the dipyridamole raw material is 3.51% and the dissolution of the dipyridamole commercial tablets is 11.14%, both of which are poor dissolution results; the final dissolution of the dipyridamole solid dispersion of Example 11 (SD curve in the figure) is more than 80%, which can complete the targeted drug release in the simulated intestinal environment and improve the in-vitro dissolution and bioavailability of the dipyridamole raw material.

[0075] From Figure 2 The in-vitro dissolution results of the dipyridamole solid dispersions of Examples 1-9 (F1 to F9 curves in the figure) and Figure 3 The in-vitro dissolution results of the dipyridamole solid dispersions of Examples 10-15 (F10 to F15 curves in the figure) show that the water-soluble material can increase the dissolution rate of dipyridamole in the simulated intestinal fluid, but when too much is added, it will increase the leakage of dipyridamole in the simulated gastric fluid, thereby destroying the enteric solubility of the dipyridamole solid dispersion. In addition, the in-vitro dissolution results of the dipyridamole solid dispersions of Examples 10-12 and Examples 13-15 show that compared with Eudragit S-100, the solid dispersion prepared by using Eudragit L-100 as the enteric material is more in line with the requirements of the in-vitro dissolution experiment, can reach a higher dissolution within 2h in the simulated intestinal fluid, the drug release is more sufficient, and the release rate is faster.

[0076] Comparative Example 1

[0077] The physical mixture of dipyridamole and enteric material provided by the present comparative example 1 is composed of 2.0 g of dipyridamole and 7.0 g of enteric material. The enteric material is Eudragit L-100.

[0078] The preparation method of the physical mixture is as follows: mixing dipyridamole and enteric material, and then obtaining the physical mixture.

[0079] The X-ray diffraction determination of dipyridamole raw material, the physical mixture of Comparative Example 1 and the dipyridamole solid dispersion of Example 11 is carried out, and the determination results are as follows: Figure 4The results show that the physical mixture of dipyridamole and enteric material still exists in crystal form, while in the solid dispersion, it exists in amorphous state.

[0080] The Fourier infrared spectrum of the physical mixture of Comparative Example 1 and the dipyridamole solid dispersion of Example 11 was determined, and the results are shown in Figure 3. Figure 5 As can be seen from the figure, the physical mixture of Comparative Example 1 (PM curve in the figure) has a hydroxyl stretching vibration peak at 3269 cm -1 -1, N-H anti-symmetrical and symmetrical stretching vibration peaks at 3367 cm -1 -1 and 3165 cm -1 -1, which are characteristic peaks of dipyridamole. The dipyridamole solid dispersion of Example 11 (SD curve in the figure) has increased transmittance at 3269 cm -1 -1, and the peak shape tends to be flat. The stretching vibration peaks of the solid dispersion all show a blunting phenomenon, especially the N-H anti-symmetrical and symmetrical stretching vibration peaks at 3367 cm -1 -1 and 3165 cm -1 -1 are obviously blunted. The results show that during the hot extrusion process, the interaction between dipyridamole and the enteric material occurs, resulting in a change in the characteristic peaks, and dipyridamole exists in amorphous state in the enteric material.

[0081] In addition, the differential scanning calorimetry (DSC) determination of dipyridamole raw material and the dipyridamole solid dispersion of Example 11 was also carried out, and the results are shown in Figure 4. Figure 6 As can be seen from the figure, the endothermic peak of dipyridamole raw material (API curve in the figure) is at 170°C, while the peak shape of the dipyridamole solid dispersion of Example 11 (SD curve in the figure) changes obviously, and there is no obvious endothermic peak at 170°C. The obvious migration of the endothermic peak indicates that the drug form has changed obviously, i.e., the dipyridamole solid dispersion of the present application exists in amorphous state.

[0082] In addition, the stability of the dipyridamole solid dispersion of Example 11 was also tested, including long-term stability of in-vitro dissolution, high-temperature stability, high-humidity stability and light stability.

[0083] (1) Long-term stability of in-vitro dissolution

[0084] The dipyridamole solid dispersion of Example 11 was subjected to long-term test, and the storage time was 12 months. The samples were taken at 0 month, 3 months, 6 months, 9 months and 12 months, respectively. The storage temperature was 25±2°C, the storage relative humidity was 65±5%, and the whole storage process was in the dark. The samples were subjected to dissolution test. The results are shown in Figure 7 From the figure, it can be seen that the dissolution of the solid dispersion in simulated gastric fluid and simulated intestinal fluid did not change significantly, and the sample had good long-term stability.

[0085] (2) High temperature stability

[0086] The dipyridamole solid dispersion of Example 11 was placed in a constant temperature drying oven at 60°C, and samples were taken at 0 days, 5 days and 10 days, respectively. The samples were subjected to X-ray diffraction, Fourier infrared spectroscopy and in vitro dissolution test. The results are shown in Figure 8 Figure 9 From the figure, it can be seen that the X-ray diffraction pattern and the Fourier infrared spectroscopy related characteristic peaks remained in a passive state, and the whole did not show obvious crystallization phenomenon. The dissolution of the solid dispersion in simulated gastric fluid and simulated intestinal fluid did not change significantly, and the sample had good thermal stability.

[0087] (3) High humidity stability

[0088] The dipyridamole solid dispersion of Example 11 was placed in a constant humidity sealed container, and was placed at 25°C under the condition of relative humidity 75%±5% for 10 days. Samples were taken at 0 days, 5 days and 10 days, respectively. The samples were subjected to X-ray diffraction, Fourier infrared spectroscopy and in vitro dissolution test. The results are shown in Figure 10 Figure 11 From the figure, it can be seen that the X-ray diffraction pattern and the Fourier infrared spectroscopy related characteristic peaks remained in a passive state, and the whole did not show obvious crystallization phenomenon. The dissolution of the solid dispersion in simulated gastric fluid and simulated intestinal fluid did not change significantly, and the sample had good high humidity stability.

[0089] (4) Light stability

[0090] The dipyridamole solid dispersion of Example 11 was placed in a light box or other suitable light device, and was placed under the condition of illumination 4500lx±500lx for 10 days. Samples were taken at 0 days, 5 days and 10 days, respectively. The samples were subjected to X-ray diffraction, Fourier infrared spectroscopy and in vitro dissolution test. The results are shown in Figure 12 Figure 13 From the figure, it can be seen that the X-ray diffraction pattern and the Fourier infrared spectroscopy related characteristic peaks remained in a passive state, and the whole did not show obvious crystallization phenomenon. The dissolution of the solid dispersion in simulated gastric fluid and simulated intestinal fluid did not change significantly, and the sample had good light stability.​​​

[0091] Example 16

[0092] The present application provides a dry suspension comprising dipyridamole solid dispersion, which consists of dipyridamole solid dispersion, suspending agent and flavoring agent. The mass ratio of dipyridamole solid dispersion and suspending agent is 1:0.28, the mass ratio of dipyridamole solid dispersion and flavoring agent is 1:5, the suspending agent is a mixture of xanthan gum and pregelatinized starch with a mass ratio of 1:6, and the flavoring agent is sucrose.

[0093] Example 17

[0094] The present application provides a dry suspension comprising dipyridamole solid dispersion, which consists of dipyridamole solid dispersion, suspending agent and flavoring agent. The mass ratio of dipyridamole solid dispersion and suspending agent is 1:0.28, the mass ratio of dipyridamole solid dispersion and flavoring agent is 1:5.5, the suspending agent is a mixture of xanthan gum and pregelatinized starch with a mass ratio of 1:6, and the flavoring agent is sucrose.

[0095] Example 18

[0096] The present application provides a dry suspension comprising dipyridamole solid dispersion, which consists of dipyridamole solid dispersion, suspending agent and flavoring agent. The mass ratio of dipyridamole solid dispersion and suspending agent is 1:0.9, the mass ratio of dipyridamole solid dispersion and flavoring agent is 1:5, the suspending agent is a mixture of xanthan gum and pregelatinized starch with a mass ratio of 1:6, and the flavoring agent is sucrose.

[0097] Take 30g of the dry suspension of each of Examples 16-18, respectively, add 100mL of water and shake to make it uniformly dispersed, take 50mL of the dispersed suspension with a dry 50mL cylinder with a stopper, shake vigorously for 1min to make the suspension fully mixed and uniform. Record the initial height H0 of the suspension, and record the final height H after standing for 3h, and calculate the sedimentation volume ratio according to the formula: sedimentation volume ratio = H / H0. At the same time, use the Bettersize laser particle size analyzer to determine the particle size of the dipyridamole solid dispersion in the suspension, and the results are shown in Table 2.

[0098] Table 2

[0099] Example 16 Example 17 Example 18 Sedimentation volume ratio 0.93±0.02 0.94±0.02 0.93±0.02 Particle size D 10 (μm)] 13.10±0.30 12.74±0.30 16.37±0.30 Particle size D 50 (μm) 33.01±0.30 31.09±0.30 37.49±0.30 Particle size D 90 (μm)] 90.34±0.30 65.33±0.30 64.70±0.30 Particle size distribution width SPAN 2.339±0.050 1.691±0.050 1.289±0.050

[0100] As can be seen from Table 2, the sedimentation volume ratio of the dry suspension prepared by the present application is greater than 0.90, which meets the relevant requirements of the Chinese Pharmacopoeia for oral suspensions; the particle size D 50about 30 μm; and the dry suspensions of Examples 16-18 were subjected to in vitro dissolution rate determination, the dissolution rate of the suspension in simulated gastric fluid was less than 15%, the dissolution rate in simulated intestinal fluid was greater than 80%, and the corresponding dissolution rate and sedimentation volume ratio could be maintained for seven days after the wet suspension was prepared.

[0101] In addition, the pharmacokinetic processes of the dry suspension of Example 16, the dipyridamole commercial tablet (Yabao Pharmaceutical Group Co., Ltd.) and dipyridamole raw material in rats were investigated by gavage administration.

[0102] The experimental animals were male SD rats with a body weight of about 200 g, and the rats were fasted for 12 h before the experiment. The rats were administered dipyridamole at a standard dose of 10 mg / kg by gavage, wherein the dry suspension was dispersed in water, and the dipyridamole commercial tablet and dipyridamole raw material were dispersed in a suspension medium (the suspension medium was prepared by mixing 25 g of sucrose, 1.2 g of pregelatinized starch and 0.2 g of xanthan gum in water at 60°C, gelatinizing the mixture by heating, and then cooling to room temperature, and then diluting to 100 ml). Blood was taken from the orbital plexus, and blood samples were taken at 15 min, 30 min, 45 min, 60 min, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h and 24 h after administration. After the blood plasma samples were treated, the drug concentration was determined by HPLC-MS / MS method, and the drug concentration was plotted as the vertical coordinate and the time was plotted as the horizontal coordinate to obtain the drug-time curve, as shown in Figure 14 The determination results were processed by DAS software to calculate the pharmacokinetic parameters, and the calculation results are shown in Table 3.

[0103] Table 3

[0104] Pharmacokinetic parameters Commercially available tablets Dry suspensions Drug substance AUC (0-t) (μg / L*h) 445.10±12.77 624.93±81.70 207.90±50.50 AUC (0-∞) (μg / L*h) 481.39±17.40 916.19±151.60 349.14±193.66 C max (μg / L) 84.27±18.48 72.00±17.81 39.51±8.90 T max (h)]]> 0.75±0.00 2.50±1.00 0.30±0.11 t 1 / 2 (h)]]> 6.72±2.12 15.38±4.99 15.49±9.94 F 0-t (%)]] - 140.40 46.71

[0105] As can be seen from Table 3 and Figure 14 the relative bioavailability of the dry suspension to the commercial tablet was 140.40%, the maximum blood drug concentration was lower than that of the commercial tablet, but the blood drug concentration of the dry suspension could be maintained at a relatively stable and high level for a certain period of time, that is, compared with the commercial tablet, the dry suspension of the present application had a certain sustained-release effect, which could avoid the sharp change of blood drug concentration to a certain extent and improve the bioavailability of the drug.

[0106] Although the embodiments of the present application have been shown and described above, it should be understood that the above embodiments are exemplary and should not be construed as limiting the present application, and those skilled in the art can make changes, modifications, replacements and variations to the above embodiments within the scope of the present application.

Claims

1. A dipyridamole solid dispersion, characterized in that, The dipyridamole solid dispersion is in an amorphous state and includes dipyridamole, an enteric-coated material, and a plasticizer; The mass of the enteric-coated material is 65-75% of the total mass of the dipyridamole solid dispersion.

2. The dipyridamole solid dispersion according to claim 1, characterized in that, The mass ratio of the plasticizer to the dipyridamole is 1:0.5-2.5; The plasticizer includes one or more of triethyl citrate, glycerin, castor oil, sorbitol, propylene glycol, and polyethylene glycol.

3. The dipyridamole solid dispersion according to claim 1, characterized in that, The enteric-coated material is polyacrylic acid resin, and the polyacrylic acid resin is Eudragit L 100.

4. The dipyridamole solid dispersion according to any one of claims 1-3, characterized in that, It also includes water-soluble materials, wherein the mass ratio of the plasticizer to the water-soluble materials is 1:1-2; The water-soluble material includes one or more of hydroxypropyl methylcellulose, polyvinylpyrrolidone, and hydroxypropyl cellulose.

5. A method for preparing the dipyridamole solid dispersion according to any one of claims 1-4, characterized in that, The raw materials are mixed and then hot-melt extruded to obtain dipyridamole solid dispersion.

6. The method for preparing the dipyridamole solid dispersion according to claim 5, characterized in that, The screw speed during the hot melt extrusion process is 15-45 rpm; The temperature of the hot melt extrusion is 160-170℃.

7. A pharmaceutical preparation, characterized in that, The invention includes a dipyridamole solid dispersion and pharmaceutically acceptable excipients, wherein the dipyridamole solid dispersion is the dipyridamole solid dispersion according to any one of claims 1-4 or the dipyridamole solid dispersion prepared by the method according to any one of claims 5-6.

8. The pharmaceutical preparation according to claim 7, characterized in that, The pharmaceutical preparations include one or more of the following: suspensions, tablets, capsules, granules, and pellets.

9. The pharmaceutical preparation according to claim 8, characterized in that, The suspension includes dipyridamole solid dispersion, suspending agent and flavoring agent; The mass ratio of the dipyridamole solid dispersion to the suspending agent is 1:0.1-0.9; The mass ratio of the dipyridamole solid dispersion to the flavoring agent is 1:5-5.

5.

10. The pharmaceutical preparation according to claim 9, characterized in that, The suspending agent is a mixture of xanthan gum and pregelatinized starch in a mass ratio of 1:1.25-6; The flavoring agent includes one or more of sucrose, glucose, aspartame, and steviol glycosides.

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