CN118436652A - Roflumilast pharmaceutical preparation and application thereof - Google Patents
Roflumilast pharmaceutical preparation and application thereof Download PDFInfo
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- CN118436652A CN118436652A CN202410470892.5A CN202410470892A CN118436652A CN 118436652 A CN118436652 A CN 118436652A CN 202410470892 A CN202410470892 A CN 202410470892A CN 118436652 A CN118436652 A CN 118436652A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
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Abstract
The invention relates to the technical field of medicines, and particularly discloses a roflumilast pharmaceutical preparation and application thereof. The components of Luo Shasi his pharmaceutical formulation include roflumilast. The invention provides a new application of a roflumilast pharmaceutical preparation, which provides a new candidate compound for preventing and treating peritoneal failure caused by peritoneal dialysis related peritoneal injury, and the roflumilast pharmaceutical preparation can improve the peritoneal ultrafiltration function and the substance transport state and improve the local metabolic disorder of peritoneal tissues. The roflumilast pharmaceutical preparation has the advantages of good safety and no hepatotoxicity and nephrotoxicity.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a roflumilast pharmaceutical preparation and application thereof.
Background
End-stage renal disease (End-STAGE RENAL DISEASE, ESRD) is the End stage of various chronic renal diseases, with progressively increasing global morbidity, and poor prognosis, high cost, and many complications, have become a global public health problem that places a significant economic burden. Peritoneal dialysis (abbreviated as peritoneal dialysis, peritoneal dialysis, PD) is one of the major routes of kidney replacement therapy (RENAL REPLACEMENT THERAPY, RRT) treatment and is the primary means of treatment for ESRD patients. Peritoneal dialysis is a dialysis mode for carrying out transmembrane transport of solutes and water by using the peritoneal membrane of a human body as a semipermeable membrane, and has the advantages of home implementation, relatively low treatment cost, better protection of residual kidney functions and the like.
Peritoneal damage is an important factor affecting the survival rate of peritoneal dialysis patients and the survival rate of the technique. Peritoneal inflammation, significant neovascularization of the peritoneal blood vessels, and peritoneal fibrosis are the pathological changes of peritoneal lesions that are prevalent during the course of peritoneal dialysis treatment. Early PD treatment, no significant changes in peritoneal function or peritoneal structure. The long-term exposure to the high-sugar dialysate can cause the conditions of metabolic disorders such as sugar metabolism, amino acid metabolism, fat metabolism and the like of the inherent cells of the peritoneum such as the peritoneal mesothelium cells, macrophages and the like, and further can cause the production of various pro-inflammatory factors and angiogenic mediators, so that the peritoneal membrane chronic non-bacterial inflammatory reaction, the peritoneal mesothelium epithelial-mesenchymal transdifferentiation, the cell shedding, the extracellular matrix accumulation and the angiogenesis are caused, and the peritoneal dysfunction and the ultrafiltration failure are caused. Stimulation of the high-sugar peritoneal dialysis solution to peritoneal surface tissues and mesothelial cells gradually increases the peritoneal mass transport of PD patients, gradually weakens the ultrafiltration function, increases the peritoneal permeability, gradually causes insufficient dialysis, can not effectively remove metabolic wastes and the like, and finally forces the PD patients to withdraw from the PD treatment. It can be seen that the improvement of the metabolic disorder of the peritoneal tissue plays an important role in the protection of the peritoneal function and the improvement of the peritoneal structure.
Hypoxia is a common feature of chronic inflammatory processes, with hypoxia-inducible factors (Hypoxia-inducible factor, HIF) being key regulators of regulating chronic inflammatory processes. Hypoxia inducible factor prolyl hydroxylase inhibitors (Hypoxia-inducible factor prolyl hydroxylases inhibitor, HIF-PHI) can reversibly inhibit degradation of HIF, induce stabilization and transcription of HIF. Studies have shown that HIF-PHI can function to protect the kidney from inflammation and development of anemia in a mouse model of renal ischemia reperfusion injury. Luo Shasi he (Roxadustat, FG 4592) is a HIF-PHI drug approved by the drug administration in China for treating chronic kidney disease and end-stage renal disease-related anemia, and researches show that roflumilast can improve heart lipid metabolism and further improve heart injury of lipopolysaccharide-induced shock mouse model. Roflumilast is a common drug for patients with PD complicated with anemia.
However, no research has been carried out to show that roflumilast has the effect of preventing peritoneal damage associated with peritoneal dialysis. And no effective medicine is used for delaying peritoneal failure in clinic. Therefore, there is a need to develop a pharmaceutical preparation of roflumilast and its use in order to ameliorate peritoneal damage associated with peritoneal dialysis.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the prior art described above. Therefore, the invention provides a roflumilast pharmaceutical preparation and application thereof, thereby improving peritoneal damage related to peritoneal dialysis.
A first aspect of the invention provides a pharmaceutical formulation of roflumilast.
Specifically, the Luo Shasi components of his pharmaceutical formulation include Luo Shasi he (FG 4592).
Preferably, luo Shasi is used at a concentration of 0.5-1.5 mg/kg.
Further preferably, luo Shasi is used at a concentration of 0.8 to 1.2mg/kg.
Still more preferably, said Luo Shasi is used at a concentration of 1mg/kg.
Preferably, the Luo Shasi consecutive days of application are 25-35 days.
Further preferably, the Luo Shasi consecutive days of application is 25 to 30 days.
Still more preferably, the Luo Shasi consecutive days of application is 28 days.
In a second aspect, the invention provides the use of a pharmaceutical formulation of roflumilast for the manufacture of a medicament for the treatment of peritoneal disorders.
In a third aspect, the invention provides the use of a roflumilast pharmaceutical formulation in the manufacture of a medicament for improving peritoneal function.
Preferably, the peritoneal function comprises a peritoneal ultrafiltration function.
In a fourth aspect, the invention provides the use of a pharmaceutical formulation of roflumilast for the manufacture of a medicament for improving the state of substance transport in the peritoneum.
Preferably, the substance includes at least one of glucose, creatinine, albumin.
In a fifth aspect, the invention provides the use of a pharmaceutical formulation of roflumilast for the preparation of a medicament for ameliorating a localized metabolic disorder of the peritoneum.
Preferably, the metabolism comprises at least one of pyrimidine metabolism, carbon metabolism, phenylalanine anabolism, tyrosine anabolism, tryptophan anabolism.
Compared with the prior art, the invention has the following beneficial effects:
The invention provides a new application of a roflumilast pharmaceutical preparation, which provides a new candidate compound for preventing and treating peritoneal failure caused by peritoneal dialysis related peritoneal injury, and the roflumilast pharmaceutical preparation can improve the peritoneal ultrafiltration function and the substance transport state and improve the local metabolic disorder of peritoneal tissues. The roflumilast pharmaceutical preparation has the advantages of good safety and no hepatotoxicity and nephrotoxicity.
Drawings
FIG. 1 is a diagram showing the peritoneal function results and analysis of PD rats;
FIG. 2 is a graph showing the results and analysis of the status of PD rat peritoneal regional metabolic disorder.
Detailed Description
In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples will be presented. It should be noted that the following examples do not limit the scope of the invention.
The starting materials, reagents or apparatus used in the following examples are all available from conventional commercial sources or may be obtained by methods known in the art unless otherwise specified.
Example 1
A roflumilast pharmaceutical preparation.
The effective concentration of Luo Shasi He (FG 4592) in the prepared roflumilast pharmaceutical preparation is 1mg/kg.
Example 2
Use of Luo Shasi pharmaceutical formulations for the preparation of a medicament for improving the peritoneal ultrafiltration function and the substance transport state.
(1) Experimental materials
The roflumilast used in the invention is purchased from Selleck company, 50mg/mL mother liquor is prepared by using DMSO and is packaged and stored in a refrigerator at-80 ℃, and the SD rat is purchased from medical laboratory animal center in Guangdong province.
(2) Experimental method
An animal model of PD rat peritoneal injury is constructed by adopting a method of injecting 4.25% peritoneal dialysis solution into the peritoneal cavity daily for 4 weeks at a dose of 100mL/kg, 18 male SPF-grade SD rats of 6 weeks old are selected, and the PD peritoneal dialysis peritoneal injury model is constructed when the rats weight reaches 180-200 g.
The experiments were grouped into a normal control group, a PD group, and a PD+ example 1 roflumilast drug formulation group, 6 rats per group, luo Shasi at a dose of 1mg/kg, were weighed daily, calculated as Luo Shasi his weight and dissolved in 4.25% peritoneal dialysis solution. Rats were examined by killing after evaluation of peritoneal glucose transport and solute permeation functions by peritoneal equilibrium experiments on day 28 of intraperitoneal injection, and blood and peritoneal fluid were collected. The blood was allowed to stand at room temperature for 30min, centrifuged at 3000r/min for 15min at room temperature, and the supernatant was taken out in a fresh 1.5mL EP tube and stored at-80℃for detection. Centrifuging the peritoneal dialysis solution at 3000r/min for 15min, and collecting supernatant, and storing at-80deg.C for detection.
The peritoneal permeability function of the rats was analyzed, the peritoneal permeability function was evaluated using 4h PET, and initially, 4.25% peritoneal dialysis solution was collected for measuring the glucose concentration in the D0 dialysis solution, while 4.25% peritoneal dialysis solution was intraperitoneally injected at a dose of 100mL/kg, and after 4h, rats were anesthetized with 3% sodium pentobarbital (0.01 mL/kg intraperitoneally injected), and the intraperitoneal permeate of the rats was collected, and blood was collected. The concentration of glucose, creatinine, albumin in the permeate and blood was measured using a fully automatic biochemical analyzer, and peritoneal functions were assessed by glucose transport (permeate glucose concentration/initial glucose concentration, D/D0 glucose), creatinine permeability (permeate creatinine/serum creatinine, D/P CREATININE) and albumin permeability (permeate albumin/serum albumin. D/P Alb).
(3) Experimental results
The results showed that the peritoneal ultrafiltration was significantly reduced in the PD group compared to the normal control group, whereas roflumilast was treated at a therapeutic dose of 1mg/kg for 28 days to significantly restore the peritoneal ultrafiltration in the PD rats (as shown in FIG. 1A, for the net peritoneal ultrafiltration in the PD rats of the different groups). Meanwhile, the transport of PD rat peritoneum to peritoneal glucose is increased, the permeation of creatinine and albumin is increased, the PD rat peritoneum function is indicated to be in a higher substance transport state, the transport of PD rat peritoneum to peritoneal glucose can be reduced by using roxat, the permeation of creatinine and albumin is reduced, and the high transport state of PD rat peritoneum is improved (as shown in figure 1B, the permeation of albumin of different groups of rat peritoneum tissues, figure 1C, the permeation of creatinine of different groups of rat peritoneum tissues, and figure 1D, the transport of the peritoneal tissue of different groups of rat peritoneum to peritoneal glucose) is improved, wherein P is less than 0.05 and P is less than 0.01. The decrease in peritoneal ultrafiltration volume and the high transport state of the peritoneum are indicative of a decrease in peritoneal function, whereas the use of the roflumilast pharmaceutical formulation of example 1 improves peritoneal function in PD rats, in particular, peritoneal ultrafiltration function and substance transport state.
Example 3
Use of Luo Shasi pharmaceutical formulations for the preparation of a medicament for the amelioration of a localized metabolic disorder of the peritoneum.
(1) Experimental materials
The biological and chemical materials used in the present invention were the same as in example 2.
(2) Experimental method
Animal model establishment and dosing method reference is made to example 2. On day 28 of intraperitoneal injection, rats were anesthetized with isoflurane, and the visceral peritoneal tissue was collected and stored at-80 ℃ for subsequent metabonomic examination.
Non-targeted metabonomics detection is carried out on each group of peritoneal tissues by adopting a gas chromatography mass spectrometry (GC-MS) method, and the total difference of metabolic profiles among each group is distinguished by adopting an orthogonal partial least squares analysis (OPLS-DA). Screening inter-group differential metabolites by adopting a method combining multidimensional analysis and single-dimensional analysis, wherein the screening standard is that the variable weight value of the first main component of an OPLS-DA model is more than 1, the p value of T test is less than 0.05, and hierarchical clustering is carried out on the expression quantity of the screened metabolites. Metabolic pathway enrichment analysis was performed on differential metabolites based on KEGG database.
(3) Experimental results
From the OPLS-DA result graph, PD group peritoneal tissues are completely separated from normal control group peritoneal tissues (as shown in A of figure 2: control group and PD group peritoneal tissue metabolomics OPLS-DA graph), meanwhile FG4592 treatment group peritoneal tissues are also completely separated from PD group peritoneal tissues (as shown in B of figure 2: PD group and FG4592 group peritoneal tissue metabolomics OPLS-DA graph), and the model distinguishing effect is better. Analysis of the significantly altered metabolites of group PD and FG4592 showed that the carbamate, ornithine, shikimic acid, succinic acid, D-xylose, galactitol, N-acetyl-5-hydroxytryptic were significantly reduced in equal metabolite abundance in peritoneal tissue of FG4592 relative to group PD (as shown in figure 2 for C: the significantly differentially expressed metabolites of peritoneal tissue of group PD and FG 4592). Pathway enrichment analysis of these significantly altered metabolites revealed that FG4592 was able to ameliorate rat peritoneal tissue metabolic abnormalities (e.g., significantly different metabolic pathways in PD and FG4592 peritoneal tissues in FIG. 2) by modulating the metabolic pathways of pyrimidine metabolism, carbon metabolism, phenylalanine tyrosine and tryptophan anabolism, etc. in the peritoneal tissue induced by the high sugar peritoneal dialysis fluid. These results indicate that FG4592 can ameliorate high sugar peritoneal dialysis solution induced peritoneal metabolic disorders in rats.
The foregoing describes in detail preferred embodiments of the present invention. It should be understood that numerous modifications and variations can be made in accordance with the concepts of the invention by one of ordinary skill in the art without undue burden. Therefore, any modification, equivalent replacement, improvement or the like of the prior art through logic analysis, reasoning or limited experiments according to the present invention will be within the scope of protection defined by the claims.
Claims (10)
1. A pharmaceutical formulation of roflumilast, wherein the components of the Luo Shasi pharmaceutical formulation comprise roflumilast.
2. A roflumilast pharmaceutical formulation according to claim 1, wherein Luo Shasi is applied at a concentration of 0.5-1.5 mg/kg.
3. A roflumilast pharmaceutical formulation according to claim 1, wherein Luo Shasi his days of continuous use is 25-35 days.
4. Use of a roflumilast pharmaceutical formulation according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of peritoneal disorders.
5. Use of a roflumilast pharmaceutical formulation according to any one of claims 1 to 3 for the preparation of a medicament for improving peritoneal function.
6. The use according to claim 5, wherein the peritoneal function comprises a peritoneal ultrafiltration function.
7. Use of a roflumilast pharmaceutical formulation according to any one of claims 1 to 3 for the preparation of a medicament for improving the state of peritoneal mass transport.
8. The use according to claim 7, wherein the substance comprises at least one of glucose, creatinine, albumin.
9. Use of a roflumilast pharmaceutical formulation according to any one of claims 1 to 3 for the preparation of a medicament for ameliorating a localized metabolic disorder of the peritoneum.
10. The use according to claim 9, wherein the metabolism comprises at least one of pyrimidine metabolism, carbon metabolism, phenylalanine anabolism, tyrosine anabolism, tryptophan anabolism.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160120859A1 (en) * | 2013-06-06 | 2016-05-05 | Fibrogen, Inc. | Pharmaceutical formulations of a hif hydroxylase inhibitor |
CN113855638A (en) * | 2021-10-28 | 2021-12-31 | 北京福元医药股份有限公司 | Rosemastat pharmaceutical preparation |
CN117122603A (en) * | 2023-09-07 | 2023-11-28 | 南方医科大学顺德医院(佛山市顺德区第一人民医院) | Pharmaceutical preparation and application thereof |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US20160120859A1 (en) * | 2013-06-06 | 2016-05-05 | Fibrogen, Inc. | Pharmaceutical formulations of a hif hydroxylase inhibitor |
CN113855638A (en) * | 2021-10-28 | 2021-12-31 | 北京福元医药股份有限公司 | Rosemastat pharmaceutical preparation |
CN117122603A (en) * | 2023-09-07 | 2023-11-28 | 南方医科大学顺德医院(佛山市顺德区第一人民医院) | Pharmaceutical preparation and application thereof |
Non-Patent Citations (1)
Title |
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LINGYUN WANG,等: "Investigating the therapeutic effects and mechanisms of Roxadustat on peritoneal fibrosis Based on the TGF-β/Smad pathway", BIOCHEM BIOPHYS RES COMMUN., vol. 693, no. 22, 22 January 2024 (2024-01-22), pages 2 - 2 * |
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