Application of alpha-pyrone compound in preparation of antithrombotic drugs

Abstract

The invention relates to application of alpha-pyrone compounds in preparation of antithrombotic drugs, and belongs to the technical field of biological medicines. The alpha-pyrone compound separated from deep-sea fungus fermentation liquor is applied to the field of prevention and treatment of thrombotic diseases for the first time. After detection, it is found that the compounds 6-((2S, 3S)-2, 3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one and 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one can significantly increase the red blood volume of zebra fish and relieve tail thrombus, and have the ability to resist thrombus, and the compounds 6-((2S, 3S)-2, 3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one and 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one have the ability to resist thrombus; further detection shows that the 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one can improve the blood flow velocity of a thrombus area and inhibit platelet aggregation, and is low in action concentration, so that the 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one is small in toxic and side effects, has the potential of developing novel antithrombotic drugs, health-care foods and functional foods, and is wide in market application prospect.

Description

Technical Field

[0001] This invention relates to the application of α-pyranone compounds in the preparation of antithrombotic drugs, and belongs to the field of biomedical technology. Background Technology

[0002] Thrombosis is a pathological condition caused by damage to the blood vessel wall, changes in blood composition, and alterations in blood rheology, leading to abnormal coagulation of blood within the vessel to form a solid mass, which then obstructs the blood vessel and affects normal blood circulation. Clinically, it mainly manifests as local ischemia, congestion, pain, and functional impairment, and in severe cases, complications such as organ failure or embolism may occur. Clinically, thrombi can be classified according to their location of formation into arterial thrombosis, venous thrombosis, atrioventricular thrombosis, and microvascular thrombosis. Currently, thrombosis can be treated with surgical or pharmacological intervention. However, surgery carries significant risks, including intraoperative / postoperative complications such as bleeding, vascular injury, thrombus detachment and embolism, infection, pain, and poor wound healing. Therefore, thrombolytic, anticoagulant, and antiplatelet drugs are commonly used clinically for treatment. However, these drugs all carry the risk of bleeding, may be accompanied by adverse reactions such as gastrointestinal discomfort and liver and kidney damage, and long-term use can easily lead to drug resistance. Therefore, the development of antithrombotic active compounds with low side effects and significant efficacy is of great significance for the development of new antithrombotic drugs, improving clinical efficacy, and reducing medication risks.

[0003] For example, Chinese patent document CN114591282A (application number 202210181677.4) discloses a method for preparing α from *Cymbidium ensifolium*. The method for using α-pyranone compounds employed the KLF2 screening model and KLF2-COS7 cells as the experimental subject. The results showed that α-pyranone compounds significantly upregulated KLF2 expression and have potential in the preparation of drugs for treating cardiovascular diseases or anti-inflammatory purposes.

[0004] Zebrafish, as a novel model organism, possesses characteristics such as rapid development, high reproductive capacity, transparent embryos, and ease of gene editing, making it widely used in drug screening and efficacy evaluation research. Importantly, as small vertebrates, zebrafish exhibit coagulation systems and coagulation factor functions highly similar to humans. Physiological processes during thrombosis, such as platelet aggregation and fibrin network construction, are also highly consistent with those in humans, effectively mimicking the pathological characteristics of human thrombotic diseases and providing a reliable experimental model for the study of thrombosis-related diseases. Aspirin, a classic clinical antiplatelet drug, has been widely proven to exert a clear antithrombotic effect in zebrafish thrombosis models and is often used as a positive control drug in this model.

[0005] α-Pyranone compounds are often considered important "dominant structures" in medicinal chemistry due to their simple skeletons and abundant modifiable sites. Precise structural modification can achieve targeted regulation of biological activity, providing a solid foundation for the development of highly effective and low-toxicity innovative drugs. The core structures of these compounds are widely found in various active candidate molecules with antibacterial, antiviral, and antitumor properties. However, the role of the α-pyranone compounds involved in this invention in the field of antithrombosis has not yet been studied. Summary of the Invention

[0006] To address the shortcomings of the prior art, this invention provides the application of α-pyranone compounds in the preparation of antithrombotic drugs.

[0007] The technical solution of the present invention is as follows: The use of α-pyranone compounds in the preparation of antithrombotic drugs, wherein the compounds are 6-((2S, 3S)-2,3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one and / or 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one; The structural formula of compound 6-((2S, 3S)-2, 3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one is shown in Formula I: Formula I; The structural formula of compound 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one is shown in Formula II: Formula II.

[0008] According to a preferred embodiment of the present invention, the compound is 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one.

[0009] According to a preferred embodiment of the present invention, the compound can increase venous return, improve blood flow velocity, inhibit platelet aggregation, and reduce thrombosis.

[0010] An antithrombotic drug comprising an effective amount of the compound 6-((2S, 3S)-2,3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one and / or 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one.

[0011] According to a preferred embodiment of the present invention, the antithrombotic drug comprises an effective amount of 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one.

[0012] According to a preferred embodiment of the present invention, the antithrombotic drug comprises one or more pharmaceutically acceptable carriers or excipients.

[0013] More preferably, the excipient is at least one of a sustained-release agent, excipient, filler, binder, wetting agent, disintegrant, absorption promoter, surfactant, or lubricant.

[0014] According to a preferred embodiment of the present invention, the antithrombotic drug can increase venous return, improve blood flow velocity, inhibit platelet aggregation, and reduce thrombosis.

[0015] According to a preferred embodiment of the present invention, the dosage form of the antithrombotic drug is tablets, pills, capsules, oral liquids, or injections.

[0016] Beneficial effects: This invention is the first to apply α-pyranone compounds isolated from deep-sea fungal fermentation broth to the prevention and treatment of thrombotic diseases. Testing revealed that compounds 6-((2S,3S)-2,3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one and 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one significantly increased venous return in zebrafish and reduced tail thrombosis, exhibiting antithrombotic capabilities. Among these, 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one showed the best effect. Further testing revealed that 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one improved blood flow velocity in the thrombus area, inhibited platelet aggregation, and, due to its low concentration, exhibited minimal toxicity and side effects. It possesses the potential to develop novel antithrombotic drugs, health foods, and functional foods, with broad market application prospects. Attached Figure Description

[0017] Figure 1 Images of stained red blood cells in the tail veins of zebrafish from each group; The area indicated by the yellow dashed circle is the statistical area of ​​erythrocyte staining in the zebrafish tail vein, with a scale bar of 200 μm. Figure 2 A bar chart showing the statistical area of ​​erythrocyte staining in the tail vein of zebrafish in each group; Wherein, #### indicates p < 0.0001 compared with the blank control group, and **** indicates p < 0.0001 compared with the thrombosis model group; Figure 3 Images of stained red blood cells from the hearts of zebrafish in each group; The area indicated by the yellow dashed circle is the statistical area of ​​the stained area of ​​red blood cells in the zebrafish heart, with a scale bar of 200 μm; Figure 4 A bar chart showing the statistical analysis of the erythrocyte staining area in the hearts of zebrafish in each group; Wherein, #### indicates p < 0.0001 compared with the blank control group, ** indicates p < 0.01 compared with the thrombosis model group, *** indicates p < 0.001 compared with the thrombosis model group, and **** indicates p < 0.0001 compared with the thrombosis model group; Figure 5 The graph shows the mortality rate of zebrafish after treatment with different concentrations of 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one as a function of concentration. Figure 6 Hemodynamic diagrams of the tail veins of zebrafish in each group; Figure 7 A bar chart showing the blood flow velocity in the tail vein of each group of zebrafish. Wherein, #### indicates p < 0.0001 compared with the blank control group, ** indicates p < 0.01 compared with the thrombosis model group, and **** indicates p < 0.0001 compared with the thrombosis model group; Figure 8 Images of circulating platelets in the tails of zebrafish from each group were collected. Figure 9 A histogram showing the number of platelets circulating in the tail of zebrafish in each group; Wherein, #### indicates p < 0.0001 compared with the blank control group, * indicates p < 0.05 compared with the thrombosis model group, and ** indicates p < 0.01 compared with the thrombosis model group. Detailed Implementation

[0018] The technical solution of the present invention will be further described below with reference to the embodiments and the accompanying drawings, but the scope of protection of the present invention is not limited thereto.

[0019] Unless otherwise specified in the examples, the procedures were performed under standard conditions; reagents or instruments used without a specified manufacturer were all commercially available products.

[0020] In the following examples, the compounds 6-((2S, 3S)-2,3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one (structure shown in Formula I), 6-((2R, 3S)-2,3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one (structure shown in Formula III), 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one (structure shown in Formula II), pestalotiopyrone G (structure shown in Formula IV), and 6-pentyl-4-methoxy-2H-pyran-2-one (structure shown in Formula V) are all derived from the fermentation products of marine fungi and can be chemically synthesized or bio-fermented using existing methods. Specifically, 6-((2S, 3S)-2,3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one and 6-((2R, 3S)-2,3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one are derived from the fermentation products of marine fungi and can be chemically synthesized or bio-fermented using existing methods. (3S)-2,3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one can be obtained according to the literature: "Xu Rui, Xu Xinyan, Xu Hui, et al. Marine fungi TrichodermaStudy on secondary metabolites of sp. MDCW-16[J]. Chinese Journal of Antibiotics, 2025, 50(04):462-469.DOI:10.13461 / j.cnki.cja.007881”. 6-Ethyl-4-methoxy-3-methyl-2H-pyran-2-one, pestalotiopyrone G and 6-pentyl-4-methoxy-2H-pyran-2-one can be prepared according to the literature: “Feng T, Wu R, Wang Y, Wang P, Zhou L, Wang C, Kong F. Proangiogenic Azaphilones from the Marine-Derived Fungus Neopestalotiopsis sp. HN-1-6. Marine Drugs. 2024; 22(6):241. https: / / doi.org / 10.3390 / md22060241”Preparation (wherein, the compound 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one is named pestalotiopyrone C in the article, and is named by structure in this patent, the structure of which is shown in Formula II), the public can obtain the relevant biological materials from the applicant; Formula III; Formula IV; Formula V.

[0021] In the following examples, the embryo culture water used consisted of: 0.4 mmol / L CaCl2, 5 mmol / L NaCl, 0.16 mmol / L MgSO4 and 0.17 mmol / L KCl, prepared with deionized water; The modified embryo culture medium consisted of 0.33 mmol / L CaCl2, 5 mmol / L NaCl, 0.33 mmol / L MgSO4, and 0.17 mmol / L KCl, prepared with deionized water.

[0022] Example 1 Comparative analysis of the antithrombotic activity of five α-pyranone compounds Zebrafish sample pretreatment: The zebrafish used in this patent follow a standardized rearing process. Male and female individuals are raised separately in a constant-temperature circulating water system at 28±0.5℃, using a 14-hour light / 10-hour dark cycle for controlled light management. They are fed brine shrimp and paramecium twice daily. Before the experiment, mature and healthy zebrafish are selected and placed in a spawning tank at a female:male ratio of 1:1. The partition is removed before the lights are turned on the following day, and light stimulation induces ovulation. Embryos are collected 2 hours later. After washing, the embryos are transferred to a modified embryo culture medium containing 0.5 mg / L methylene blue and placed in a constant-temperature, light-controlled incubator at 28±0.5℃. Dead embryos are removed after 6 hpf (hours post-fertilization), and phenylthionine solution is added to a final concentration of 0.03 mg / mL to inhibit melanin synthesis. The culture medium is changed every 24 hours, and dead individuals are removed to ensure a stable embryonic development environment.

[0023] Experimental methods In this embodiment, wild-type AB strain zebrafish were used as experimental animals. The experimental groups included a blank control group, a thrombosis model group, a positive control group, and a 20 µmol / L compound treatment group (6-((2S, 3S)-2, 3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one, 6-((2R, 3S)-2, 3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one, 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one, pestalotiopyrone G, and 6-pentyl-4-methoxy-2H-pyran-2-one, five compound treatment groups). Ten zebrafish were placed in each well of a 24-well plate, and three biological replicates were set for each group. In this study, 2 mL of embryo culture water was added to the blank control group and the thrombosis model group, 2 mL of embryo culture water containing 124.9 μmol / L aspirin was added to the positive control group, and 2 mL of embryo culture water containing 20 μmol / L of the compound treatment group was added to the compound treatment group. All zebrafish were placed in a constant temperature incubator at 28±0.5℃. After 6 h of culture, except for the blank control group, the other groups were replaced with embryo culture water containing 80 μmol / L arachidonic acid and cultured for another 1.5 h at 28±0.5℃ to induce thrombosis. After treatment, the solution was discarded, and the zebrafish were stained with o-anisidine staining solution in a dark environment for 10 min. They were washed three times with embryo culture water, fixed with 4% paraformaldehyde, and then placed on their sides on slides coated with methylcellulose. Ten zebrafish were randomly selected from each group. Images of the tail and heart were taken using a Zeiss microscope. The erythrocyte staining area in the tail and heart was measured using Image-Pro Plus software, and statistical analysis was performed using GraphPad Prism v.8.3.0 software.

[0024] Among them, zebrafish tail vein erythrocyte staining images are as follows: Figure 1As shown, the statistical analysis of the erythrocyte staining area in the tail vein is as follows: Figure 2 As shown, the image of stained red blood cells in the heart is as follows. Figure 3 As shown, the statistical analysis of the stained area of ​​cardiac erythrocytes is as follows: Figure 4 As shown, the results indicate that arachidonic acid can induce the establishment of a zebrafish thrombosis model. Successful induction of the thrombosis model is manifested by two indicators: a significant increase in the staining area of ​​erythrocytes in the zebrafish tail and a significant decrease in the staining area of ​​erythrocytes in the heart. The increase in the staining area of ​​erythrocytes in the zebrafish tail is a direct manifestation of thrombosis, but the results are usually unstable. In the experiment, it is necessary to combine the staining results of erythrocytes in the heart to determine whether the compound has antithrombotic activity. After treatment with five α-pyranone compounds, the thrombus area in the tail of zebrafish was significantly reduced in the groups treated with compounds 6-((2S,3S)-2,3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one and 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one, and the erythrocyte staining area in the heart was increased to varying degrees. The statistical results were significant, indicating that the two α-pyranone compounds can significantly increase the venous return of zebrafish and reduce tail thrombus, and have obvious antithrombotic activity. Among them, 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one had the best antithrombotic activity. While treatment with compounds 6-((2R, 3S)-2,3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one, pestalotiopyrone G, and 6-pentyl-4-methoxy-2H-pyran-2-one significantly reduced the staining area of ​​erythrocytes in the zebrafish tail, it did not significantly increase the staining area of ​​erythrocytes in the heart, indicating that these three α-pyranone compounds do not have antithrombotic activity.

[0025] Example 2 Safety dose assessment of compound 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one in zebrafish This embodiment uses wild-type AB strain zebrafish as experimental animals, and the zebrafish sample pretreatment method is the same as in Embodiment 1.

[0026] On the second day after zebrafish fertilization, normally developing AB strain zebrafish juveniles were selected under a microscope. Embryo culture water containing 0, 40, 80, 120, 160, 200, 240, 280, 320, 360, and 400 μmol / L of 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one was prepared for culturing the zebrafish. 2 mL of the solution was added to each well of a 24-well plate, with 10 juveniles placed in each well. Three biological replicates were established for each concentration. The plates were incubated at 28±0.5℃, with the solution changed every 24 hours. The zebrafish juveniles were cultured until the sixth day after fertilization. The number of deaths and deformities were observed and recorded daily. The cumulative mortality over 4 days was calculated, and the lethality rate was determined. A mortality curve was plotted with the concentration of 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one on the x-axis and the lethality rate on the y-axis. The 1% lethal concentration (LC1) was calculated as the maximum safe dose of 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one.

[0027] The results are as follows Figure 5 As shown, no significant teratogenicity or mortality was observed when the concentration of 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one was in the range of 0-160 µmol / L. When the treatment concentration was gradually increased from 200 µmol / L to 400 µmol / L, the mortality rate of zebrafish juveniles increased sharply from 6.67% to 100%. The 1% lethal concentration (LC1) of 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one for zebrafish was calculated to be 174.6 μmol / L using nonlinear regression fitting, and the median lethal concentration (LC50) for zebrafish was... 50 The concentration was 280 μmol / L. Based on this result, the antithrombotic effect of 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one was further evaluated using three doses of 5 µmol / L, 10 µmol / L, and 20 µmol / L.

[0028] Example 3 6-Ethyl-4-methoxy-3-methyl-2H-pyran-2-one improves blood flow velocity in zebrafish. This embodiment uses wild-type AB strain zebrafish as experimental animals, and the zebrafish sample pretreatment method is the same as in Embodiment 1.

[0029] The experimental groups included a blank control group, a thrombosis model group, a positive control group, and treatment groups with compound 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one (concentrations of 5, 10, and 20 µmol / L, respectively). Ten zebrafish were placed in each well of a 24-well plate, with three biological replicates per group. The blank control group and the thrombosis model group were supplemented with 2 mL of embryo culture water, the positive control group was supplemented with 2 mL of embryo culture water containing 124.9 μmol / L aspirin, and the 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one treatment groups were supplemented with 2 mL of embryo culture water containing 5, 10, or 20 µmol / L 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one. All zebrafish were placed in an incubator at 28±0.5℃. After 6 h of culture, except for the blank control group, all other groups were replaced with embryo culture water containing 80 μmol / L arachidonic acid and placed in a constant temperature incubator at 28±0.5℃ for another 1.5 h to induce thrombus formation. After treatment, 10 zebrafish were randomly selected from each group, anesthetized, and placed on a glass slide coated with methylcellulose. The tail vein blood flow video was acquired for 15 s using the Zebralab blood flow system. The video sequence was analyzed using ZebraBlood software to perform hemodynamic analysis and generate blood flow velocity. The obtained data were statistically analyzed using GraphPad Prism v.8.3.0 software.

[0030] The hemodynamics and blood flow velocity statistics of the zebrafish tail vein are as follows: Figure 6 , Figure 7 As shown, compared with the blank control group, the blood flow velocity of zebrafish in the thrombosis model group was significantly reduced, indicating abnormal hemodynamics in the thrombotic region of the zebrafish. Compared with the thrombosis model group, the blood flow velocity of zebrafish treated with different concentrations of compound 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one was significantly increased in a concentration-dependent manner. The effects of 10 and 20 μmol / L concentrations of compound 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one were consistent with those of the positive control group of the clinical drug aspirin, but the effective concentration was much lower than that of aspirin (124.9 μmol / L). These results indicate that compound 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one can improve the blood flow in the thrombotic region.

[0031] Example 4 6-Ethyl-4-methoxy-3-methyl-2H-pyran-2-one inhibits platelet aggregation in zebrafish. This embodiment adopts Tg(CD41:EGFP) The zebrafish strains were used as experimental animals, and the zebrafish sample pretreatment method was the same as in Example 1.

[0032] The experimental grouping and culture methods were the same as in Example 3. After the treatment, 10 zebrafish were randomly selected from each group and fixed on their sides on a glass slide coated with methylcellulose. A 15-second dynamic video of circulating platelets was collected using a fluorescence inverted microscope, and the number of circulating platelets passing through the tail during this period was counted. The obtained data were statistically analyzed using GraphPad Prismv.8.3.0 software.

[0033] Images of circulating platelets in the zebrafish tail and platelet count statistics are as follows: Figure 8 , Figure 9 As shown, compared with the blank control group, significant platelet aggregation was observed in the tail vessels of zebrafish in the thrombosis model group, and the number of circulating platelets was significantly reduced. Compared with the thrombosis model group, platelet aggregation in the tail vessels of zebrafish treated with different concentrations of the compound 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one was significantly alleviated, and the number of circulating platelets was significantly increased. The effect of this increase was consistent with that of the positive control group of the clinical drug aspirin, and the effective concentration was much lower than that of aspirin (124.9 μmol / L). The above results indicate that the compound 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one can inhibit platelet aggregation.

Claims

1. The application of α-pyranone compounds in the preparation of antithrombotic drugs, characterized in that, The compound is 6-((2S,3S)-2,3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one and / or 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one; The structural formula of compound 6-((2S, 3S)-2, 3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one is shown in Formula I: Formula I; The structural formula of compound 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one is shown in Formula II: Formula II.

2. The application as described in claim 1, characterized in that, The compound is 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one.

3. The application as described in claim 1, characterized in that, The compound can increase venous return, improve blood flow velocity, inhibit platelet aggregation, and reduce thrombosis.

4. An antithrombotic drug, characterized in that, The effective amount of the compound 6-((2S, 3S)-2,3-dihydroxy-2-butyl)-3-methyl-2H-pyran-2-one and / or 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one.

5. The drug as described in claim 4, characterized in that, The compound containing an effective amount of 6-ethyl-4-methoxy-3-methyl-2H-pyran-2-one.

6. The drug as described in claim 4, characterized in that, It contains one or more pharmaceutically acceptable carriers or excipients.

7. The drug as described in claim 6, characterized in that, The excipient is at least one of the following: sustained-release agent, excipient, filler, binder, wetting agent, disintegrant, absorption promoter, surfactant, or lubricant.

8. The drug as described in claim 4, characterized in that, It can increase the amount of blood returning to the heart, improve blood flow velocity, inhibit platelet aggregation, and reduce thrombosis.

9. The drug as described in claim 4, characterized in that, The drug dosage forms are tablets, pills, capsules, oral liquids, or injections.

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