Use of proline dipeptides in the preparation of a medicament for treating cisplatin-induced kidney damage

Abstract

This invention discloses the application of propylglycine dipeptide in the preparation of drugs for treating cisplatin-induced kidney injury. In vitro and in vivo experiments demonstrate that propylglycine dipeptide can significantly inhibit cisplatin-induced renal tubular epithelial cell apoptosis, reduce renal oxidative stress, block the IL-6 / GP130 / STAT3 inflammatory signaling axis, downregulate pro-inflammatory cytokines such as IL-6, CSF1, and MCP-1, and reduce immune cell infiltration through a multi-target mechanism, thereby effectively improving cisplatin-induced renal dysfunction and histopathological damage. This invention reveals for the first time a novel pharmaceutical use of propylglycine dipeptide as an adjuvant nephroprotective agent in chemotherapy, providing a safe and efficient intervention strategy for the prevention and treatment of cisplatin-induced kidney injury.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the use of L-Alanyl-L-glutamine (AG) or its pharmaceutically acceptable salts or hydrates in the preparation of a medicament for treating kidney injury caused by the chemotherapy drug cisplatin (CDDP). Background Technology

[0002] Cisplatin is a classic, broad-spectrum, and highly effective anti-tumor chemotherapy drug widely used in the treatment of various solid tumors. However, its clinical application is severely limited, mainly due to its serious dose-dependent toxicities, with nephrotoxicity being the most prominent. Statistics show that approximately 30% of patients receiving cisplatin treatment develop acute kidney injury (AKI), which not only affects patients' quality of life but also limits the successful implementation and efficacy of chemotherapy regimens.

[0003] The pathological mechanism of cisplatin-induced kidney injury is complex, involving multiple pathways such as oxidative stress, inflammatory response, apoptosis, and mitochondrial dysfunction. Specifically, cisplatin accumulates in renal tubular epithelial cells, inducing the generation of large amounts of reactive oxygen species (ROS) by consuming antioxidants such as glutathione (GSH), leading to lipid peroxidation and cell damage. Simultaneously, damaged cells release inflammatory factors, activating immune cell infiltration and inducing an inflammatory cascade and tissue damage. Furthermore, apoptosis of renal tubular epithelial cells is a direct pathological manifestation of cisplatin-induced kidney injury. Although supportive therapies such as hydration and diuresis are used clinically, their effectiveness is limited, and there is currently a lack of highly specific and safe interventional drugs. Therefore, developing novel protective agents that can block the progression of cisplatin-induced kidney injury at multiple targets is of significant clinical importance.

[0004] Alanine-glutamine dipeptide (ALD) is a dipeptide composed of L-alanine and L-glutamine, possessing advantages such as high solubility, good thermal stability, and high bioavailability, and has been widely used in parenteral nutrition support. Studies have shown that ALD can be rapidly broken down into alanine and glutamine in vivo, providing the body with important nitrogen sources and energy substrates. In recent years, its pharmacological activities have been continuously explored, showing multiple effects such as antioxidation, anti-apoptosis, and immunomodulation. While some literature reports that ALD has a protective effect against ischemia-reperfusion liver injury and intestinal mucosal barrier damage, no research or application reports on its systemic protection against cisplatin-induced acute kidney injury have been found to date. Summary of the Invention

[0005] The technical problem to be solved by this invention is to provide a novel use of propylglycine dipeptide in the preparation of drugs for treating cisplatin-induced kidney injury. This invention demonstrates through in vitro and in vivo experiments that propylglycine dipeptide can significantly inhibit cisplatin-induced renal tubular epithelial cell damage, apoptosis, oxidative stress, and inflammatory responses through multiple targets and pathways, thereby providing a new pharmaceutical strategy for the prevention and treatment of chemotherapy-related kidney injury.

[0006] The primary objective of this invention is to provide the use of propionyl dipeptide in the preparation of a medicament for treating cisplatin-induced kidney injury.

[0007] Furthermore, the kidney injury described is acute kidney injury.

[0008] Furthermore, the drug is used to alleviate cisplatin-induced renal function impairment, renal tubular damage, or renal histopathological changes.

[0009] The second objective of this invention is to provide the application of propionylglutamate in the preparation of renal tubular epithelial cell apoptosis inhibitors.

[0010] The third objective of this invention is to provide the application of propionylglutamate in the preparation of renal tissue oxidative stress inhibitors.

[0011] Furthermore, the oxidative stress inhibitor is a malondialdehyde (MDA) generation inhibitor and / or a glutathione (GSH) depletion inhibitor.

[0012] Furthermore, the oxidative stress inhibitor is an activity promoter of superoxide dismutase (SOD), catalase (CAT), or glutathione peroxidase (GPX).

[0013] The fourth objective of this invention is to provide the application of propionylglutamate in the preparation of inhibitors of renal tissue inflammatory response.

[0014] Furthermore, the inflammatory response inhibitor is an inhibitor of the IL-6 / GP130 / STAT3 signaling pathway.

[0015] Furthermore, the inflammatory response inhibitor is an inhibitor of the expression of chemokines CSF1, MCP-1, or RANTES.

[0016] Furthermore, the inflammatory response inhibitor is an inhibitor of immune cell (such as CD68+ macrophages or MPO+ neutrophils) infiltration.

[0017] The fifth objective of this invention is to provide the application of propionylglutamate in the preparation of inhibitors of renal fibrosis.

[0018] Furthermore, the fibrosis inhibitor is a collagen (such as Col1a1, Col3a1) or an inhibitor of the expression of the pro-fibrotic factor TGF-β1.

[0019] The present invention also provides a pharmaceutical composition for the prevention and / or treatment of cisplatin-induced kidney injury.

[0020] Furthermore, the pharmaceutical composition comprises an effective amount of propionyl dipeptide, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.

[0021] Furthermore, the pharmaceutical composition is prepared into any pharmaceutically acceptable dosage form, such as tablets, capsules, granules, injections, lyophilized powder for injection, or oral liquid.

[0022] Compared with the prior art, the advantages of the present invention are as follows: 1. This invention reveals for the first time the significant effect of propionyl-glucopyranoside in treating cisplatin-induced acute kidney injury and systematically elucidates its mechanism of action, opening up a new pharmaceutical application for propionyl-glucopyranoside as an adjuvant renal protectant in chemotherapy.

[0023] 2. This invention confirms that propionyl dipeptide exerts its renal protective effect through multiple mechanisms, including comprehensively inhibiting cell apoptosis, reducing oxidative stress, blocking the IL-6 / GP130 / STAT3 inflammatory signaling axis, and reducing immune cell infiltration.

[0024] 3. Propionibacterium-glutamyl dipeptide is already a marketed parenteral nutrition supplement with a sound safety profile. This invention provides solid experimental evidence for its expanded application in the field of chemotherapy, and is expected to fill the clinical gap in the lack of specific drugs for the prevention and treatment of cisplatin-induced kidney injury, possessing extremely high translational potential and market value. Attached Figure Description

[0025] Figure 1 The results of the assessment of the effect of alanine dipeptide on cisplatin-induced acute kidney injury in mice are shown in the following table: A is the blood urea nitrogen (BUN) level in mouse plasma; B is the creatinine (CRE) level in mouse plasma; C is the H&E staining result of mouse kidney tissue; D is the PAS staining result; E is the renal tubular injury score of the two staining results; F is the KIM1 expression level in kidney tissue; and G is the NGAL expression level in kidney tissue. Figure 2 TUNEL staining images show the inhibition of cisplatin-induced apoptosis in renal cells by propranolol dipeptide. In the images, A is the result at 100 µm field of view, B is the result at 50 µm field of view, and C is the TUNEL staining positive quantitative bar graph. Figure 3 The results show the effects of alanine dipeptide on cisplatin-induced oxidative stress in renal tissue. A represents the MDA content in renal tissue; B represents the SOD content of the antioxidant enzyme; C represents the CAT content; D represents GPX activity; E represents GSH content; F represents PTGS2 mRNA expression level; and G represents ACSL4 mRNA expression level. Figure 4 This study analyzed the mRNA and protein levels of inflammation-related genes in different treatment groups of propylglycine dipeptide. A represents the mRNA level of CSF1; B represents the mRNA level of the inflammatory gene L-6; C represents the mRNA level of the gene HMGA1; D represents the mRNA level of the gene CDK9; E represents the mRNA level of the gene GP130 (IL6ST); F represents the mRNA level of the gene GNBI; G represents the mRNA level of the inflammatory gene TNF-α; H represents the mRNA level of the inflammatory gene IL-1β; I represents the mRNA level of the chemokine MCP-1; and J represents the mRNA level of the chemokine RANTES. Figure 5 To detect the protein levels of IL-6 and CSF1 in kidney tissue homogenate using ELISA, where A represents the protein level of the inflammatory factor IL-6 and B represents the protein level of the colony-stimulating factor CSF1. Figure 6 The images show the staining results of different treatment groups of glutathione reducing the number and infiltration of inflammatory cells in mice. A represents the staining results of CD68+ macrophages, B represents the staining results of MPO+ neutrophils, C represents the bar chart of CD68+ macrophage staining results, and D represents the bar chart of MPO+ neutrophil staining results. Figure 7 The results show the effects of different treatments on protein expression levels of GP130, P-STAT3, STAT3, and the internal reference β-actin. A is a WB protein expression level chart of GP130, P-STAT3, STAT3, and β-actin; B is a bar chart of GP130 protein expression quantification; and C is a bar chart of P-STAT3 / STAT3 protein expression quantification. Figure 8 The results show the experimental effects of alanine dipeptide inhibiting the expression of cisplatin-induced renal fibrosis-related genes. A represents Col1a1 mRNA levels; B represents Col3a1 mRNA levels; C represents TGF-β1 mRNA levels; D represents α-SMA mRNA levels; E represents TGFBR1 mRNA levels; F represents MMP2 mRNA levels; and G represents MMP9 mRNA levels. Figure 9The results of using propranolol dipeptide (PDP) to reduce HK-2 renal tubular epithelial cell damage in vitro are shown below. A represents the survival rate of HK-2 cells after treatment with different concentrations of PDP; B represents the survival rate of HK-2 cells after treatment with different concentrations of cisplatin; C represents the survival rate of HK-2 cells after co-incubation with PDP and cisplatin; D represents the total LDH release capacity of lactate dehydrogenase in HK-2 cells after treatment with 0.1-0.5 mM PDP; E represents the WB protein expression levels of NRF2, HO-1, HMGA1, and the internal control β-actin; F represents the quantitative results of NRF2 protein expression; G represents the quantitative results of HO-1 protein expression; and H represents the quantitative results of HMGA1 protein expression. Figure 10 The results show the in vitro efficacy of propionylglutamate in reducing inflammation levels in RAW264.7 macrophages. Figure A shows the Western blot (WB) protein expression levels of different concentrations of P-STAT3, STAT3, GP130, IL-6R, HMGA1, and the internal control β-actin; Figure B shows the bar chart of P-STAT3 / STAT3 protein expression quantification; Figure C shows the bar chart of GP130 protein expression quantification; Figure D shows the bar chart of IL6R protein expression quantification; and Figure E shows the bar chart of HMGA1 protein expression quantification.

[0026] Compared with the blank group, *P<0.05, **P<0.01, ***P<0.001; compared with the model group, #P<0.05, ##P<0.01, ###P<0.001, ####P<0.001. Detailed Implementation

[0027] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments, but the implementation of the present invention is not limited thereto.

[0028] Example 1: Protective effect of propionylglutamate against cisplatin-induced acute kidney injury in mice.

[0029] 1. Experimental Method: Experimental system: 6-8 week old male C57BL / 6 mice (weighing 20-22g) were purchased from Shanghai Silex Laboratory Animal Co., Ltd. All mice were acclimatized for one week in a standard SPF-grade animal facility with free access to food and water.

[0030] Animal grouping, model establishment, and drug administration: Mice were randomly divided into 6 groups (n=8-10) according to body weight: Normal control group (Control): administered an equal volume of solvent. High-dose glutathione (AG-H) control group: administered only 1500 mg / kg AG. Cisplatin model group (CDDP): intraperitoneal injection of 20 mg / kg cisplatin. Low-dose glutathione (AG-L) group: 500 mg / kg AG + 20 mg / kg cisplatin. High-dose glutathione (AG-H) group: 1500 mg / kg AG + 20 mg / kg cisplatin. Positive control group (Curcumin): 100 mg / kg curcumin + 20 mg / kg cisplatin. Cisplatin and curcumin were dissolved in a carrier containing 10% PEG 400, 10% Tween-80, and 80% physiological saline. AG was dissolved in physiological saline. All drug groups were administered the corresponding drug or solvent orally or by gavage once daily for 10 consecutive days. On day 7 of the experiment, all mice, except for the control group and the high-dose AG control group, were intraperitoneally injected with 20 mg / kg cisplatin. Samples were collected 72 hours after cisplatin injection (i.e., day 10).

[0031] Sample Collection and Processing: Mice were euthanized by anesthesia with sodium pentobarbital overdose. Blood was collected, centrifuged at 2000×g for 20 minutes at 4°C, and plasma was separated and stored at -80°C. Kidneys were quickly removed, weighed, and a portion of the kidney tissue was fixed in 4% paraformaldehyde for histopathological analysis. The remaining tissue was quickly immersed in liquid nitrogen and stored at -80°C.

[0032] Renal function and renal tubular injury marker detection: Plasma biochemical indicators: Blood urea nitrogen (BUN) and creatinine (CRE) levels in plasma were measured according to the kit instructions. Renal tubular injury markers: Total RNA was extracted from renal tissue, and the mRNA expression levels of kidney injury molecule-1 (KIM1) and neutrophil gelatinase-associated lipocalin (NGAL) were detected by real-time quantitative PCR (qRT-PCR). β-Actin was used as an internal control, and the relative expression levels were calculated using the 2^-ΔΔCt^ method.

[0033] Histopathological analysis of kidney tissue: Fixed kidney tissue was dehydrated, embedded in paraffin, and prepared into 3 μm thick sections. Hematoxylin-eosin (H&E) staining and periodic acid-Schiff (PAS) staining were performed. Images were acquired and observed under a light microscope.

[0034] 2. Experimental Results: Experimental results are as follows Figure 1 China A- Figure 1As shown in Figure G. H&E and PAS staining results showed that, compared with the control group, the model group mice exhibited significant renal tubular dilation, epithelial cell vacuolar degeneration, brush border loss, cast formation, and inflammatory cell infiltration in their renal tissue. Compared with the control group, the cisplatin model group mice showed significantly elevated plasma BUN and CRE levels (p<0.0001), and significantly upregulated NGAL and KIM1 mRNA expression in renal tissue (p<0.0001), indicating severe renal function impairment. Compared with the model group, the low- and high-dose propylgludec dipeptide groups showed significant improvement in the above-mentioned renal function indicators (significantly decreased BUN and CRE levels, downregulated KIM1 and NGAL expression), and the renal tissue pathological damage also showed a dose-dependent reduction, with the high-dose group showing particularly significant effects, approaching those of the positive control drug curcumin. These results indicate that propylgludec dipeptide pretreatment has a clear protective effect against cisplatin-induced acute kidney injury.

[0035] Example 2: Effect of propionylglutamate on cisplatin-induced apoptosis in renal tissue cells.

[0036] 1. Experimental Method: Renal tissue cell apoptosis was detected using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) fluorescent staining. Paraffin-embedded kidney tissue sections were dewaxed and rehydrated, then repaired with proteinase K, and incubated at 37°C for 1 hour in the dark using a TUNEL reaction mixture (TDT enzyme: dUTP: buffer = 2:5:50 (v / v)). Cell nuclei were counterstained with DAPI. After mounting, the sections were observed and photographed under a fluorescence microscope. Five high-power fields (200× and 400×) were randomly selected from each section to count the number of TUNEL-positive cells.

[0037] 2. Experimental Results: Experimental results are as follows Figure 2 China A- Figure 2 As shown in Figure C, only a very small number of TUNEL-positive cells were observed in the control group. A large number of TUNEL-positive signals appeared in the renal tubular epithelial cells of the cisplatin model group, indicating a significant increase in apoptosis. After intervention with propylglycine dipeptide, the number of TUNEL-positive cells decreased in a dose-dependent manner. This result indicates that propylglycine dipeptide can effectively inhibit cisplatin-induced apoptosis of renal tubular epithelial cells.

[0038] Example 3: Inhibitory effect of propionylglutamate on cisplatin-induced oxidative stress in renal tissue 1. Experimental Method: Mouse kidney tissue was homogenized, and the following oxidative stress indicators were detected using appropriate kits: Malondialdehyde (MDA) content: determined using the thiobarbituric acid (TBA) method; Superoxide dismutase (SOD) activity: determined using the xanthine oxidase method; Catalase (CAT) content: determined using the ammonium molybdate method; Glutathione peroxidase (GPX) activity: determined using the DTNB method; Glutathione (GSH) content: determined using the microplate method; PTGS2 mRNA expression: the mRNA level of prostaglandin intraperoxidase 2 (PTGS2) in kidney tissue was detected by qRT-PCR.

[0039] 2. Experimental Results: Experimental results are as follows Figure 3 China A- Figure 3 As shown in Figure G. Compared with the control group, the cisplatin model group showed significantly increased MDA content and PTGS2 and ACSL4 mRNA expression in renal tissue (p<0.01), while the activities of antioxidant enzymes SOD and GPX and the content of GSH were significantly decreased (p<0.01), indicating that cisplatin induced severe oxidative stress. After intervention with alanine dipeptide, the above oxidative stress indicators showed a dose-dependent reversal: MDA level significantly decreased, SOD, CAT, GPX activities and GSH content significantly increased, and PTGS2 and ACSL4 expression were significantly inhibited. These results indicate that alanine dipeptide effectively alleviates cisplatin-induced oxidative damage to renal tissue by enhancing antioxidant enzyme activity, restoring glutathione reserves, and inhibiting lipid peroxidation.

[0040] Example 4: Inhibitory effect of propionylglutamate on cisplatin-induced renal tissue inflammation.

[0041] 1. Experimental Method: The mRNA expression of inflammation-related genes GP130, HMGA1, CSF1, CDK9, GNBI, TNF-α, IL-6, IL-1β, MCP-1, and RANTES in renal tissue was detected by real-time quantitative PCR.

[0042] The protein levels of IL-6 and CSF1 in kidney tissue homogenate were detected by ELISA.

[0043] Western blotting was used to detect the protein expression levels of GP130 (IL6ST), total STAT3, and phosphorylated STAT3 (P-STAT3) in kidney tissue.

[0044] (4) Immunohistochemistry (IHC): Detects the infiltration of CD68+ macrophages and MPO+ neutrophils in kidney tissue.

[0045] 2. Experimental Results: Experimental results are as follows Figure 4 China A- Figure 4 As shown in Figure J, compared with the control group, the mRNA levels of inflammation-related genes such as IL6ST, CSF1, CDK9, GNBI, TNF-α, IL-6, IL-1β, MCP-1, and RANTES, as well as the HMGA1 transcription factor, were significantly upregulated in the cisplatin model group (p<0.01). Figure 5 China A- Figure 5 As shown in Figure B, the levels of IL-6 and CSF1 proteins were also significantly increased (p<0.01).

[0046] like Figure 6 Chinese A-like Figure 6 As shown in Figure D, immunohistochemical results revealed a significant increase in the number of CD68+ macrophages and MPO+ neutrophils infiltrating the renal tissue of the model group. After intervention with propylglycine dipeptide, all of the above inflammatory markers were significantly inhibited, STAT3 phosphorylation levels decreased, and immune cell infiltration was reduced. These results indicate that propylglycine dipeptide effectively inhibits the release of downstream inflammatory factors and the infiltration of inflammatory cells by blocking the IL-6 / GP130 / STAT3 signaling axis, thereby alleviating cisplatin-induced renal inflammatory damage.

[0047] At the same time, such as Figure 7 China A- Figure 7 As shown in Figure C, the Western blot results showed that the expression of GP130 protein and the phosphorylation level of STAT3 in the model group were significantly enhanced (p<0.01), indicating that the IL-6 / GP130 / STAT3 inflammatory pathway was abnormally activated.

[0048] Example 5: Effects of propionylglutamate dipeptide on the expression of genes related to cisplatin-induced renal fibrosis.

[0049] 1. Experimental Method: The mRNA expression levels of fibrosis-related genes Col1a1 (type I collagen α1 chain), Col3a1 (type III collagen α1 chain), α-SMA (α-smooth muscle actin), and TGF-β1 (transforming growth factor-β1) in kidney tissue were detected by quantitative real-time PCR.

[0050] 2. Experimental Results: Experimental results are as follows Figure 8 China A- Figure 8 As shown in Figure G, compared with the control group, the mRNA expression of Col1a1, Col3a1, α-SMA, TGF-β1, TGFBR1, MMP2, and MMP9 in the cisplatin model group was significantly upregulated (p<0.01), indicating that the renal tissue had developed a pro-fibrotic phenotype. After intervention with alanine dipeptide, the expression of these fibrosis-related genes was downregulated in a dose-dependent manner. This result indicates that alanine dipeptide can inhibit the cisplatin-induced renal fibrosis process at the transcriptional level.

[0051] Example 6: Effects of propionylglutamate dipeptide on cisplatin-induced renal tubular epithelial cells HK-2 and LPS-induced macrophages RAW264.7 in vitro. 1. Experimental Method: (1) The effects of different concentrations of propionyl dipeptide and cisplatin on the survival rate of two cell types were detected by CCK-8 assay, and the LDH release capacity of propionyl dipeptide on HK-2 cells was detected by lactate dehydrogenase assay.

[0052] (2) Western Blot method was used to detect the protein expression levels of NRF2, HO-1, P-STAT3, STAT3, GP130, IL-6R, HMGA1 and internal reference β-actin in cells.

[0053] 2. Experimental Results: Experimental results are as follows Figure 9 China A- Figure 9 As shown in Figure H, cisplatin treatment significantly downregulated the protein levels of Nrf2 and its downstream target HO-1, while upregulating HMGA1. Notably, the drug propranolol not only restored the expression of Nrf2 and HO-1, but also significantly inhibited cisplatin-induced HMGA1 upregulation (P < 0.05 compared to the cisplatin group). These data indicate that propranolol directly activates the Nrf2 / HO-1 antioxidant pathway and alleviates cisplatin-induced renal tubular epithelial damage in vitro. Figure 10 China A- Figure 10 Western blot analysis showed that LPS stimulation significantly upregulated the protein levels of P-STAT3, IL6ST, and HMGA1. Consistent with our in vivo observations, propylglycine dipeptide treatment significantly inhibited LPS-induced P-STAT3 activation and the expression of inflammatory factors such as IL6ST and HMGA1.

[0054] The foregoing description is not intended to limit the invention, nor is the invention limited to the examples given. Any changes, modifications, additions, or substitutions made by those skilled in the art within the scope of the invention should also be considered within the protection scope of the invention.

Claims

1. Application of propionylglutamate in the preparation of drugs for treating cisplatin-induced kidney injury.

2. The application according to claim 1, characterized in that: The kidney injury described is acute kidney injury.

3. The application according to claim 1, characterized in that: The drug is used to alleviate renal function damage, renal tubular damage, or renal histopathological changes caused by cisplatin.

4. Application of propionylglutamate in the preparation of renal tubular epithelial cell apoptosis inhibitors.

5. Application of propionylglutamate in the preparation of renal tissue oxidative stress inhibitors.

6. The application of propranolol dipeptide in the preparation of inhibitors of renal tissue inflammatory response, characterized in that, The inflammatory response inhibitor is an inhibitor of the IL-6 / GP130 / STAT3 signaling pathway; or the inflammatory response inhibitor is an inhibitor of the expression of chemokines CSF1, MCP-1, or RANTES; or the inflammatory response inhibitor is an inhibitor of CD68+ macrophage or MPO+ neutrophil infiltration.

7. The application of propranolol dipeptide in the preparation of renal fibrosis inhibitors, characterized in that, The fibrosis inhibitor is an inhibitor of collagen or the expression of the pro-fibrotic factor TGF-β1.

8. Use of propionyl dipeptide, or a pharmaceutically acceptable salt or hydrate thereof, in the preparation of a medicament for the treatment of cisplatin-induced kidney injury.

9. A pharmaceutical composition for treating cisplatin-induced kidney injury, characterized in that, It contains an effective amount of propionyl dipeptide, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.

10. The pharmaceutical composition according to claim 9, characterized in that, The pharmaceutical composition is prepared into any pharmaceutically acceptable dosage form, such as tablets, capsules, granules, injections, lyophilized powder for injection, or oral liquid.

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