CN118021812A - Nidaminib targeting compositions - Google Patents

Nidaminib targeting compositions Download PDF

Info

Publication number
CN118021812A
CN118021812A CN202311858812.5A CN202311858812A CN118021812A CN 118021812 A CN118021812 A CN 118021812A CN 202311858812 A CN202311858812 A CN 202311858812A CN 118021812 A CN118021812 A CN 118021812A
Authority
CN
China
Prior art keywords
targeting
tanshinone
agent
therapeutic agent
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202311858812.5A
Other languages
Chinese (zh)
Inventor
贾慧娟
杜海艳
任晓慧
王艳鑫
张加晏
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tianjin Ruichuang Kangtai Biotechnology Co ltd
Beijing Creatron Institute Of Pharmaceutical Research Co ltd
Original Assignee
Tianjin Ruichuang Kangtai Biotechnology Co ltd
Beijing Creatron Institute Of Pharmaceutical Research Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tianjin Ruichuang Kangtai Biotechnology Co ltd, Beijing Creatron Institute Of Pharmaceutical Research Co ltd filed Critical Tianjin Ruichuang Kangtai Biotechnology Co ltd
Priority to CN202311858812.5A priority Critical patent/CN118021812A/en
Publication of CN118021812A publication Critical patent/CN118021812A/en
Pending legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a low first pass metabolism and high-safety Nidaminib targeting composition. The composition comprises the nintedanib or pharmaceutically acceptable salts thereof, a targeting guide agent, other pharmaceutically acceptable auxiliary materials and the like. Compared with the prior art, the Nidamib targeting composition remarkably reduces liver first-pass metabolism of Nidamib, improves lung targeting of Nidamib, reduces clinical medicine dosage of Nidamib, and reduces toxicity of Nidamib to non-target tissues. Improves the treatment effect and medication safety of the medicament and improves the medication compliance of patients.

Description

Nidaminib targeting compositions
Technical Field
The invention relates to the technical field of medicines, in particular to a nilamide targeting composition, a preparation method and application.
Background
Nidamib was developed by Bolin, gendy, and was approved by the FDA for marketing on day 10, 15 of 2014, and has been currently marketed in sixty countries or regions worldwide. Nidamib effectively delays disease progression and reduces acute exacerbation risk by improving lung function in patients with idiopathic pulmonary fibrosis (Idiopathic Pulmonary Fibrosis, IPF) and delaying decline of lung function; in addition, nidamib also delays progression of systemic sclerosis-associated interstitial lung disease (Systemic sclerosis-associated interstitial lung diseases, SSc-ILD) and progression of progressive fibrotic interstitial lung disease (Progressive fibrosing interstitial lung diseases, PF-ILD). In addition, nilamide is also approved in the european union as a therapeutic agent for non-small cell lung cancer.
The first product dosage form marketed by bringen is a soft capsule (trade name: ) The bulk drug of the product on the market is the nintedanib ethanesulfonate. The specifications of the products on the market are 100mg and 150mg; taken twice a day, 1 granule each time, together with food. According to/> In the specification of the soft capsule, the oral absolute bioavailability of the 100mg of the soft capsule of the Nidamib is 4.7 percent, which is equivalent to 6mg of intravenous injection. According to/>Instructions for the soft capsule of nilamide: hepatotoxicity is the most serious toxic side effect of current products of nilotica, and has dose dependency. Second, 75.7% of patients treated with this product had diarrhea (31.6% of placebo). Liver first pass metabolism is a major cause of liver toxicity; clinical high dose administration is a major factor responsible for gastrointestinal toxic side effects (diarrhea, nausea and vomiting, gastrointestinal perforation); according to Brit Jnl Clinical Pharma.2021;87:3690-3698,/>The lung targeting of the Nidamib soft capsule is poor, and myocardial infarction occurs in 2-4% of patients treated by the medicine. In order to solve the problems of low oral bioavailability and serious hepatic first pass metabolism of the Nidamib, pulmonary Pharmacology & therapeutic 63 (2020) 101938 have developed a direct inhalation formulation which can avoid hepatic first pass metabolism. However, the research results show that the lung inflammation is obviously increased compared with oral products after repeated use of the inhalation preparation. The existing therapeutic drugs need to be taken for a long time to delay the disease progression.
In summary, in view of the huge unmet clinical treatment requirements in the field of idiopathic pulmonary fibrosis treatment, the pathogenesis of idiopathic pulmonary fibrosis is multiple and incompletely clear, the existing pipeline products are difficult to prepare aiming at single targets, high uncertainty or early stage exists in the research and development of new generation of therapeutic drugs with safer, good curative effect and high targeting on the basis of marketed drugs, and the urgent need exists.
Modern pharmacological researches show that the traditional Chinese medicine salvia miltiorrhiza has the effects of protecting vascular endothelial cells, improving microcirculation, inhibiting and relieving platelet aggregation, improving the hypoxia tolerance of organisms, inhibiting the generation of collagen fibers, promoting collagen degradation, resisting inflammation and lipid peroxidation, scavenging free radicals and resisting fibrosis, and has a good application prospect in the aspect of preventing and treating tissue and organ fibrosis. And Nidaminib can be used as a small molecular tyrosine kinase inhibitor to simultaneously block relevant signal paths mediated by platelet-derived growth factor receptors, vascular endothelial growth factor receptors and fibroblast growth factor receptors. The two have high complementation and synergy possibility in action mechanism. The two can be combined for treatment or prepared into a compound preparation with fixed dosage, and can realize the regulation, the inhibition and even the reversion of idiopathic pulmonary fibrosis multichannel signals from multiple channels, and the multi-target striking is realized by utilizing the wide pharmacological activity of tanshinone substances or phenolic acid substances, so that the effectiveness of the product is improved. Through the synergistic mechanism of the two, the dosage of the toxicity drug Nidamib can be reduced, and further the hepatotoxicity and the toxic and side effects of the gastrointestinal tract are reduced.
There is no research or report on this aspect in the prior art.
Disclosure of Invention
The invention aims to solve the technical problem of providing a novel treatment method, in particular to a treatment method for lung related diseases by jointly applying Nidamib.
The inventors have unexpectedly found through a great deal of research that the combination of the active ingredients in the nintedanib and the red sage root can significantly change the tissue distribution and the pharmacokinetic characteristics of the combined therapeutic agent, significantly reduce the first pass metabolism of the combined therapeutic agent, reduce the hepatotoxicity and/or the cardiotoxicity and improve the lung targeting of the therapeutic agent.
Therefore, the invention adopts the following technical scheme:
A targeting composition, wherein the targeting composition comprises a targeting agent and a therapeutic agent, wherein the targeting agent is a phenanthrenequinone-based compound.
Preferably, the targeting guide agent is one or more of phenanthrenequinone and p-phenanthrenequinone compounds, and more preferably the phenanthrenequinone compounds.
Specifically, the targeting guide agent is one or more of tanshinone I, tanshinone IIA, tanshinone IIB, cryptotanshinone, tanshinone I, isoptanshinone IIA, isoptanshinone IIB, methyl tanshinone, hydroxy tanshinone IIA, nortanshinone, dehydrotanshinone, 1, 2-dehydrocryptotanshinone, tanshinone (A, B, C), 1, 2-dihydrotanshinone, 15, 16-dihydrotanshinone diol (A, B, C), tanshinone (A, B, C) and derivatives thereof, and can also be derivatives of the phenanthrenequinone compounds, such as sulfonate, anhydride derivatives, hydroxy derivatives and diphenol derivatives.
The targeting guide agent is preferably tanshinone IIA and derivatives, and pharmaceutically acceptable salts, eutectic crystals, hydrates or solvates, particularly preferably one or more of tanshinone IIA and tanshinone IIA sulfonate (such as sodium salt and potassium salt).
The targeting guide agent is preferably a combination of dihydrotanshinone, tanshinone IIA, cryptotanshinone, tanshinone I, tanshinone IIB, hydroxy tanshinone IIA and tanshinone IIA anhydride, and the combination can be obtained by extracting Saviae Miltiorrhizae radix (such as root, stem, leaf, etc.) according to liposoluble component extraction process, further alkaline washing, extracting for multiple times, and removing impurities with macroporous resin.
The phenanthrenequinone compound is shown as a general formula (1):
r1, R2, R3 and R4 are selected from the following groups
Derivatives of phenanthrenequinone compounds are shown in general formula (2) and (3)
R1, R2, R3 and R4 are selected from the following groups
The chemical structure of tanshinone IIA or its sulfonate (such as sodium salt) is shown in formulas (1) and (2):
the chemical structural formula of the cryptotanshinone is shown as a formula (3):
The therapeutic agent in the targeting composition comprises a first therapeutic agent or/and a second therapeutic agent, wherein the first therapeutic agent is one or more of Nidamib, pharmaceutically acceptable salt, hydrate, solvate and eutectic of the Nidamib, and the weight ratio of the targeting guide agent to the first therapeutic agent is 100:1-1:5; preferably 20:1 to 1:2; more preferably from 10:1 to 1:2, or 10:1 to 1:0.6.
The first therapeutic agent in the targeted composition is administered in a daily dose of 10-200mg, preferably 12.5-150mg, more preferably 25-100mg, as Nidamib.
The second therapeutic agent in the targeting composition is selected from the group consisting of one or more of an anti-pulmonary fibrosis drug, a lung cancer therapeutic drug, an oxidative phosphorylation blocker, an anticoagulant, a hormone, an immunomodulator, a bronchodilator, a non-steroidal mineralocorticoid receptor antagonist, an immunosuppressant, an antacid, an anti-infective drug, an antioxidant drug, an antibody drug, an endothelin receptor antagonist, a sodium-glucose cotransporter 2 inhibitor (SGLT-2 inhibitor), an mRNA therapeutic agent, and a dietary supplement.
The antifibrotic is selected from pirfenidone, (a) methyl 1- (2, 3-dichlorobenzyl) -2- (difluoromethyl) -6-morpholino-1H-benzo [ d ] imidazole-4-carboxylate, [1- [ [ (5R) -2- [4- (5-chloropyrimidin-2-yl) piperidin-1-yl ] -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl ] amino ] cyclobutyl ] methanol, 4- [ 6-acetyl-3- [3- (4-acetyl-3-hydroxy-2-propylphenyl) sulfanyl-propoxy ] -2-propylphenoxy ] butanoic acid, 2, 4-difluoro-N- [ 2-methoxy-5- (4-pyridazin-4-ylquinolin-6-yl) pyridin-3-yl ] benzenesulfonamide, 2- [3- [4- (1H-indazol-5-ylamino) quinazolin-2-yl ] phenoxy ] -N-propan-2-yl acetamide, 2- (tert-butylamino) -4- (3-hydroxy-3-propylphenyl) sulfanyl ] -2-propylphenoxy ] butanoic acid, 2, 4-difluoro-N- [ 2-methoxy-5- (4-pyridazin-4-yl) quinolin-6-yl ] benzenesulfonamide, 1- [4- [4- [ 3-methyl-4- [ [ (1R) -1-phenylethoxy ] carbonylamino ] -1, 2-oxazol-5-yl ] phenyl ] cyclopropane-1-carboxylic acid, 2- ((2-ethyl-6- (4- (2- (3-hydroxyazetidin-1-yl) -2-oxoethyl) piperazin-1-yl) -8-methylimidazo [1,2-a ] pyridin-3-yl) (methyl) amino) -4- (4-fluorophenyl) thiazole-5-carbonitrile, 2- (3-pentylphenyl) acetic acid, ivacaine, lu Maka torr and o Mi Lisai.
The lung cancer treatment drug is selected from the group consisting of crizotinib, caboztinib, vandetanib, octreotinib, erlotinib, afatinib, dactinib, aletinib, ceritinib, bunatinib, loratinib, emtrictinib, dabrafenib, trimetinib, vitamin Mo Feini, lartinib, pemetrexed, cisplatin, carboplatin, paclitaxel, docetaxel, vinorelbine, gemcitabine, sotoprazeb, adaglazinb, (3R) -1'- [3- (3, 4-dihydro-2H-1, 5-naphthyridin-1-yl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl ] spiro [ 3H-1-benzofuran-2, 4' -piperidine ] -3-amine, 1- [6- [4- (5-chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3- (1-methylindol-5-yl) -5-methylindol-1H-4-yl ] [3, 3R) -1'- [3- (3, 4-dihydro-2H-1, 5-naphthyridin-1-yl) -1H-pyrazolo [3, 4-5-naphthyridin-1-yl ] [ 3H-pyrazolo-1-5-naphthyridin-yl ] spiro [ 3H-2, 4' -piperidine ] -3-yl ] p-one, 1-fluoro-2, 4-yl ] benzofuranone, 1-yl (3S, 4S) -8- [ 6-amino-5- (2-amino-3-chloropyridin-4-yl) sulfonylpyrazin-2-yl ] -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine, 7- (2-amino-6-fluorophenyl) -1- (4, 6-dicyclohexylpyrimidin-5-yl) -4- [ (2S, 5R) -2, 5-dimethyl-4-prop-2-enylpiperazin-1-yl ] -6-fluoropyrido [2,3-d ] pyrimidin-2-one and 4- (4-acryloylpiperazin-1-yl) -7- (2-amino-3, 4,5, 6-tetrafluorophenyl) -6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carbonitrile.
The antibody therapeutic agent comprises one or a plurality of combinations of pembrolizumab, nivolumab, attitumumab, bevacizumab, ipilimumab, ramucirumab, rituximab, infliximab, adalimumab, pezilimumab, fusion protein etanercept, omab, al Li Xiyou mab, al Li Xiyou mab and eimerizumab.
The anticoagulant comprises one or more of vitamin K, warfarin, dabigatran etexilate, paisa class, rivaroxaban and edoxaban.
The hormone and immunomodulator is selected from one or more of hydrocortisone, prednisone, methotrexate, cyclophosphamide, sirolimus, ticasone, budesonide, azathioprine, tacrolimus, cyclosporine, fuciclosporin, methylprednisolone and dexamethasone.
The anti-infective agents include, but are not limited to, antibacterial agents such as penicillins, pioneers, quinolones, macrolides, lincomycin, gentamicin, tobramycin, polymyxin, aztreonam, levofloxacin, ciprofloxacin, cephalosporins, and azithromycin; antiviral agent such as ribavirin, acyclovir, etc., antipyretic analgesic agent such as, antitussive and expectorant agent such as ambroxol, bromhexine, erdosteine, acetylcysteine.
Such bronchodilators include, but are not limited to, beta-receptor agonists such as terbutaline, formoterol, salmeterol, clenbuterol, terbutaline, salbutamol, and the like; anticholinergic agents such as atropine, anisodamine, scopolamine, procaine, tiotropium bromide, ipratropium bromide, etc.; theophylline drugs such as theophylline and aminophylline.
The sodium-glucose cotransporter-2 inhibitor (SGLT-2) inhibitor includes, but is not limited to, one or more of dapagliflozin (Dapagliflozin), canagliflozin (Canagliflozin), enggliflozin (Empagliflozin), exenatide (Ipragliflozin), lu Gelie flozin (Luseogliflozin), tolagliflozin (Tofogliflozin), elgliflozin (Ertugliflozin), canagliflozin (Janagliflozin), begliflozin (Bexagliflozin), sogliflozin (Sotagliflozin), hengliflozin (Henagliflozin), tergliflozin (Tianagliflozin), reggliflozin (Remogliflozin), anggliflozin (Alligliflozin), reggliflozin (Remogliflozin etabonate), alogliflozin (atigliflozin), rong Gelie flozin ((1R,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-((R)-1-hydroxyethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol)). Preferably dapagliflozin.
The mineralocorticoid receptor blockers (MRA) include, but are not limited to, one or more of spironolactone (Spironolactone), eplerenone (Eplerenone), ai Shali ketone (Esaxerenone), drospirenone (Drospirenone), canrenone (Canrenone), non-nelidanone (Finerenone), A Mo Kuini (Aminolquine), aparilone (Apararenone), 2- [ (3S) -7-fluoro-4 (3-oxo-4H-1, 4-benzoxazine-6-carbonyl) -2, 3-dihydro-1, 4-benzoxazin-3-yl ] -N-methylacetamide (AZD 9977), 4- [ (3S, 3 aS) -3-cyclopentyl-7- (4-hydroxypiperidine-1-carbonyl) -3,3a,4, 5-tetrahydropyrazolo [3,4-f ] quinolin-2-yl ] -2-chlorobenzonitrile (KBP-5074), and 6- (4-phenylcyclohexyl) -5- [ [3- (trifluoromethyl) phenyl ] methyl ] -1H-pyrimidine-2, 4-dione (T335).
The dietary supplement is selected from one or more of quercetin, astragaloside IV and curcumin.
The above substances include one or more of pharmaceutically acceptable salts, esters, co-crystals, complexes, hydrates or solvates thereof, and prodrugs thereof.
Preferably, in the targeted composition, the second therapeutic agent is selected from one or more of non-negliflozin, dapagliflozin, or a pharmaceutically acceptable salt, hydrate, co-crystal, solvate thereof.
Specifically, the targeting guide agent of the targeting composition is tanshinone IIA, the first therapeutic agent is Nidamib, and the second therapeutic agent is a combination of non-nefarnesone and dapagliflozin.
Specifically, the targeting guide agent of the targeting composition is tanshinone IIA sulfonate, preferably tanshinone IIA sodium sulfonate, the first therapeutic agent is nintedanib, and the second therapeutic agent is a combination of non-nefarnesone and dapagliflozin.
The daily dosage of the targeting guide agent in the targeting composition is 6mg-200mg, the daily dosage of the nintedanib is 10mg-200mg, the daily dosage of the non-netidone is 2.5mg-40mg, the daily dosage of the dapagliflozin is 2.5-10mg, preferably the daily dosage of the targeting guide agent is 15mg-150mg, the daily dosage of the nintedanib is 25mg-100mg, the daily dosage of the non-netidone is 5mg-40mg, and the daily dosage of the dapagliflozin is 5-10mg.
In some embodiments, the targeting composition further comprises an adjuvant that is one or more phenolic/acid, phenolic acid compounds. The phenolic acid compounds such as monomers (such as caffeic acid and tanshinol), dimers (such as rosmarinic acid and salvianolic acid D), trimers (such as lithospermic acid and salvianolic acid A), tetramers (such as salvianolic acid B) and oligomers which are formed by condensing salvianolic acid with one or different amounts of caffeic acid or rosmarinic acid can be one or more auxiliary agents.
Specifically, the auxiliary agent contained in the targeting composition is one or more of salvianolic acid, salvianolic acid D, salvianolic acid A and salvianolic acid B.
The weight ratio of the auxiliary agent to the targeting guide agent is 1000:1-3.3: 1, a step of; preferably from 100:1 to 5:1; more preferably 20:1 to 10:1. the targeting composition can be conveniently applied to a user, and can also contain pharmaceutically acceptable auxiliary materials or functional carriers.
The targeting agent is used in the targeting composition concurrently with the therapeutic agent or within 2 hours of the therapeutic agent.
The targeting agent and therapeutic agent in the kit are preferably administered orally.
The kit is administered 1 time daily, or 2 times daily, or 3 times daily, to a subject in need of such treatment.
The targeted composition is used in medicine, for example, in medicine for treating and/or preventing lung diseases, such as pneumonia, asthma, pulmonary tuberculosis, chronic obstructive pneumonia, pulmonary fibrosis, chronic fibrotic interstitial lung disease, systemic sclerosis-related pulmonary interstitial disease, pulmonary arterial hypertension and lung cancer.
Specifically, the invention provides the following technical scheme:
1. A targeting composition or kit, wherein the targeting composition or kit comprises a targeting guide agent and a first therapeutic agent, the first therapeutic agent being one or more selected from the group consisting of nidanib, a pharmaceutically acceptable salt, hydrate, solvate, co-crystal thereof; the targeting guide agent is one or more selected from the group consisting of tanshinone I, tanshinone IIA, tanshinone IIB, cryptotanshinone, tanshinone I, isoptanshinone IIA, isoptanshinone IIB, methyl tanshinol, hydroxy tanshinone IIA, nortanshinone, dehydrotanshinone, 1, 2-didehydrocryptotanshinone, tanshinone (A, B, C), 1, 2-dihydrotanshinone, 15, 16-dihydrotanshinone diol (A, B, C), tanshinone (A, B, C), and derivatives thereof (e.g., sulfonate, anhydride derivatives, hydroxy derivatives, diphenol derivatives); preferably one or more selected from the group consisting of cryptotanshinone, tanshinone IIA, and derivatives (e.g., pharmaceutically acceptable salts, co-crystals, hydrates, or solvates) thereof; more preferably one or more selected from the group consisting of cryptotanshinone, tanshinone IIA sulfonate (e.g., sodium salt, potassium salt), when the targeting guide agent and the first therapeutic agent are in a kit, the targeting guide agent and the first therapeutic agent are each packaged separately, preferably in a manner suitable for oral administration.
2. The targeting composition or kit according to item 1, wherein the targeting guide is a tanshinone component extract, which consists of dihydrotanshinone, tanshinone IIA, cryptotanshinone, tanshinone I, tanshinone IIB, hydroxytanshinone IIA and tanshinone IIA anhydride.
3. The targeting composition or kit according to item 1 or 2, wherein the targeting guide agent to first therapeutic agent weight ratio is from 100:1 to 1:5; preferably 20:1 to 1:2; more preferably from 10:1 to 1:2, or 10:1 to 1:0.6.
4. The targeting composition or kit according to any of the claims 1-3, wherein the daily amount of the first therapeutic agent is 10-200mg in nintedanib; preferably 12.5-100mg; more preferably 25-100mg.
5. The targeting composition or kit according to any one of the claims 1-4, wherein the targeting composition further comprises a second therapeutic agent selected from one or more of the group consisting of anti-pulmonary fibrosis drugs, lung cancer therapeutic drugs, oxidative phosphorylation blockers, anticoagulants, hormones and immunomodulators, bronchodilators, non-steroidal mineralocorticoid receptor antagonists, immunosuppressants, antacids, anti-infective drugs, anti-oxidative drugs, antibody drugs, endothelin receptor antagonists, sodium-glucose cotransporter 2 inhibitors (SGLT-2 inhibitors), mRNA therapeutic agents, dietary supplements, such as one or more of the group consisting of non-nefazidone, dapagliflozin or pharmaceutically acceptable salts, hydrates, co-crystals, solvates thereof; preferably, the second therapeutic agent is a combination of non-nelidamide and dapagliflozin,
Preferably, the targeting agent of the targeting composition is tanshinone IIA, the first therapeutic agent is nidanib, and the second therapeutic agent is a combination of non-nevirapine and dapagliflozin; or the targeting guide agent of the targeting composition is tanshinone IIA sulfonate, preferably tanshinone IIA sodium sulfonate, the first therapeutic agent is Nidamide, and the second therapeutic agent is a combination of non-nefarnesone and dapagliflozin.
6. The targeting composition or kit according to item 5, wherein the daily amount of the targeting guide agent is 6mg to 200mg, the daily amount of the nintedanib is 10mg to 200mg, the daily amount of the non-nelidane is 2.5mg to 40mg, and the daily amount of the dapagliflozin is 2.5mg to 10mg; preferably, the daily dosage of the targeting guide agent is 15mg-150mg, the daily dosage of the nidazole is 25mg-100mg, the daily dosage of the non-netilone is 5mg-40mg, and the daily dosage of the dapagliflozin is 5mg-10 mg.
7. The targeting composition or kit according to any one of the claims 1-6, wherein the targeting composition further comprises an auxiliary agent, which is one or more selected from the group consisting of a monomer, a dimer, a trimer, a tetramer and an oligomer of tanshinol condensed with one or more caffeic acids or rosmarinic acid; preferably one or more selected from the group consisting of salvianic acid, salvianolic acid D, salvianolic acid A, salvianolic acid B and caffeic acid.
8. The targeting composition or kit according to item 7, wherein the weight ratio of auxiliary agent to targeting guide agent is 1000:1 to 3.3:1, a step of; preferably from 100:1 to 5:1; more preferably 20:1 to 10:1.
9. The targeting composition or kit according to any of the claims 1-8, wherein the targeting composition further comprises a pharmaceutically acceptable adjuvant or functional carrier.
10. The kit of any one of claims 1-9, wherein the kit comprises a product specification describing the simultaneous administration of the targeting guide agent and the first therapeutic agent and/or the second therapeutic agent to a subject in need of treatment, or the targeting guide agent is administered within 2 hours prior to the first therapeutic agent and/or the second therapeutic agent, or the product specification describes the administration of the targeting guide agent and the first therapeutic agent 1 time daily, or 2 times daily, or 3 times daily to a subject in need of treatment, and/or the second therapeutic agent, preferably by oral administration.
11. Use of a targeted composition according to any one of claims 1-9 in the manufacture of a medicament for the treatment and/or prophylaxis of pulmonary diseases such as pneumonia, asthma, tuberculosis, chronic obstructive pulmonary disease, pulmonary fibrosis interstitial lung disease, pulmonary arterial hypertension, lung cancer.
Definition:
Targeting guide agent: a substance capable of guiding therapeutic drugs to selectively concentrate at a lesion site, which is often visually referred to as a target site, can be a target tissue, a target organ, or a target cell or a target point in a cell.
Drawings
FIG. 1 shows in vivo PK profiles of oral gavage (NDNB) in rats for different therapeutic agents;
Figures 2A-C show graphs comparing the distribution of heart, liver and lung tissue NDNB of mice orally perfused with NDNB different therapeutic agents, wherein P <0.05 for the treated group compared to the control group at the same time point; * P <0.01, P <0.001;
FIG. 3 shows a graph of HE staining pathology of lung tissue of each group of rats;
FIG. 4 shows a map of the pathological tissue of Masson staining of lung tissue of each group of rats;
Fig. 5 shows comparison of collagen levels in rat lung tissue TypeI, wherein P <0.05, P <0.01, P <0.005, P <0.001 compared to model group; # # P <0.001 compared to control; compared to combination therapy: p <0.05; the ratio of P <0.01, the ratio of the two to the total of the two. P <. 0.001;
Fig. 6 shows a comparison of Hydroxyproline (HYP) levels in rat lung tissue, where: p <0.05, P <0.01, P <0.005, P <0.001 compared to model group; # # P <0.001 compared to control; compared to the combination treatment group, P <0.05; the ratio of P <0.01, the ratio of the two to the total of the two. P <. 0.001;
FIG. 7 shows a comparison of rat lung tissue fibrosis Ashcroft scores;
Fig. 8 shows a comparison of oxidative stress parameters of rat lung tissue, wherein # # # P <0.001 compared to control group; p <0.05 compared to model group; * P <0.01, P <0.001; compared with the combination treatment group, P <0.05; the ratio of P <0.01, the ratio of the two to the total of the two. P <. 0.001;
FIGS. 9A-C show comparison of rat lung tissue inflammatory factors IL-1 beta, IL-6 and TNF-alpha levels, respectively, wherein # # P <0.001 compared to the control group; p <0.05 compared to model group; * P <0.01, P <0.001; compared with the combination treatment group, P <0.05; the ratio of P <0.01, the ratio of the two to the total of the two. P <. 0.001;
fig. 10 shows a rat serum AST level comparison, wherein # # # P <0.001 compared to control group; p <0.01, P <0.001 compared to model group; compared with a combination treatment group, the single drug treatment has the ratio of P <0.05; the ratio of P <0.01, the ratio of the two to the total of the two. P <. 0.001;
Fig. 11 shows a rat serum ALT level comparison, wherein # # # P <0.001 compared to control group; p <0.01, P <0.001 compared to model group; compared with a combination treatment group, the single drug treatment has the ratio of P <0.05; the ratio of P <0.01, the ratio of the two to the total of the two. P <. 0.001;
FIG. 12 shows a comparison of the solubility of tanshinones measured by incubation at 37℃for 6h for comparative example 5 and examples 9-10.
Advantageous technical effects
Compared with the prior art, the composition remarkably reduces liver toxicity caused by liver first pass metabolism of the nilamide, improves lung targeting of the nilamide, reduces clinical dosage of the nilamide, and reduces toxicity of the nilamide to non-target tissues or organs, thereby improving treatment effect, medication safety and medication compliance of patients.
Detailed Description
The present invention will be further described in detail below with reference to specific embodiments and with reference to the accompanying drawings, in order to make the objects, technical solutions and advantages of the present invention more apparent.
The inventor determines the technical scheme of the invention through a large number of experiments, screening and verification in the research process. Examples to illustrate the features and advantages of the present invention, some experiments are provided as illustrative examples, but the present invention is not limited to the examples. The materials and reagents used in the examples were all commercially available products.
Other sources of material information are as follows:
/>
the specific embodiment is as follows:
Examples 1 to 3 and comparative example 1
To eliminate the influence of different prescription compositions on experimental results, 150mg of the product is taken from the marketThe soft capsule of the nintedanib mesylate is 10 granules, the content is poured out, the mixture is uniformly mixed, and the content of the nintedanib is detected by an HPLC method. The chromatographic conditions of the content determination method are as follows:
By external standard method The content of the soft capsule of the ethandibuline comprises the content of the ethandibuline which is 98.92 percent of the marked amount.
The daily maximum dose of the soft capsule of the nintedanib mesylate for people is 300 mg/day, and the soft capsule of the nintedanib mesylate is taken twice. The daily maximum dose of the rats was about 27mg/kg body weight, and the rats were uniformly administered at 30mg/kg body weight.
Weighing appropriate amount of tanshinone IIA (TSN-IIA), adding the above materialsThe content of the soft capsule of the ethandibuline sulfonate and proper amount of oleic acid are respectively and evenly dispersed, and each 1ml of suspension containing the nintedanib (NDNB) (the active ingredient which actually plays a role in treatment is the nintedanib, so no special condition exists, and the content of the free alkali of the active ingredient of the nintedanib is about 7.5mg and the TSN-IIA is about 7.5 mg) is prepared as the prescription of F1;
Weighing appropriate amount of tanshinone IIA (TSN-IIA), adding the above materials Proper amounts of the content of the soft capsule of the nintedanib mesylate and oleic acid are respectively and ultrasonically dispersed uniformly to prepare about 2.5mg of suspension containing the nintedanib and about 1.5mg of suspension containing TSN-IIA per 1ml as F2;
Preparation C of example 7 of reference patent CN105193720B is prepared into a blank auxiliary material (medium chain triglyceride 106.8mg, stearin 51mg and lecithin 1.8 mg) of the capsule of the nintedanib mesylate (specification: 100 mg) and is uniformly mixed to be used as an empty auxiliary prescription; then weighing appropriate amount of tanshinone component extract (total tanshinone contains about 95.1%), adding appropriate amount of oleic acid and air adjuvant, and ultrasonic dispersing at 37deg.C to obtain suspension containing total tanshinone 3.75mg per 1ml as F3.
Weighing and weighingThe content of the soft capsule of ethambutol sulfonate was adjusted to about 7.5mg of each 1ml of ethambutol as a control preparation (Con.) after dilution with oleic acid according to the dilution procedure of the prescription F1.
20 Clean grade Sprague Dawley (SD) male rats, 220-251 g in weight, were purchased from China food and drug verification institute under license number SCXK (Beijing) 2022-0002. The 20 rats were randomly divided into four groups (T1, T2, T3, T4), 5 animals each, fasted for more than 12 hours prior to dosing, were free to drink water, and stopped at 2 hours prior to dosing.
The dosing regimen was as follows:
table 1 oral gavage dosing regimen for examples 1-3 and comparative example 1 rats
The dosage of the NDNB of the rats of the T1-T2 and the T4 groups is 30mg/kg body weight according to Nidani, and the dosage of the NDNB of the rats of the T3 group is 10mg/kg body weight; the administration dose of the T2 and T3 groups TSN-IIA is 30mg/kg body weight and 6mg/kg body weight respectively; the administration dose of the T4 group total tanshinone is 15mg/kg body weight.
The actual gavage volume of each rat was calculated from the actual body weight of each rat, and 1ml of water was fed after gavage until free drinking was resumed 2 hours after administration.
The rats in group T4 were given F3 first, then 0.5ml of the Con. Preparation was given to the stomach at 2 hours, 0.5ml of the Con. Preparation was given to the stomach, and the time at which the blood was taken from the stomach was given to the Con. Preparation at time 0.
After administration, 0.5ml of blood was taken from inner canthus at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 5h, 7h, 9h, 12h, and 24h, with 3% heparin sodium as an anticoagulant. The plasma was separated by centrifugation at 3000rpm for 10 minutes at 4℃and stored in a-20℃refrigerator.
The content of the nilamide in the blood plasma is detected by LC/MS/MS, and the internal standard is ibutenib.
The method for detecting Nidamib (NDNB) in biological samples (plasma and tissue homogenates) is as follows:
Detection was performed using a Waters Xevo TQ-S tandem liquid chromatography-mass spectrometer (LC/MS/MS).
The method has the lowest quantitative limit that: LLOQ=4 ng/mL (10 μl)
Based on the measured plasma concentration data at different time points, pharmacokinetic parameters were calculated using Phoenix winnonlin7.0 to provide parameters such as AUC 0-t、AUC0-∞, cmax, tmax and T 1/2, as well as their mean and standard deviation. The results are shown in the following table, and the PK profile is shown in FIG. 1.
Relative bioavailability (%) = (AUC T×DoseR)/(AUCR×DoseT) ×100%
AUC T: experimental drug (drug in examples) systemic exposure (ng hr/ml);
dose T: experimental drug dosing (mg/kg body weight);
AUC R: reference drug (drug in comparative example) system exposure (ng-hr/ml);
Dose R: reference drug administration dose (mg/kg body weight);
TABLE 2
According to the experimental results, the stomach is separately irrigated with the same NDNB administration dosage as that of the comparative example 1The exposure of NDNB (AUC 0-inf) in plasma of example 1 and example 3 was 9259.6 ± 4836.3ng·hr/ml and 8129.24 ± 2025.9ng·hr/ml, respectively, whereas the exposure of comparative example 1NDNB (AUC 0-inf) was 784.78 ± 605.7ng·hr/ml, the exposure of NDNB in plasma of example 1 and example 3 was significantly increased (P < 0.001), respectively; compared with example 1, the total tanshinone dosage in example 3 is half of the tanshinone IIA dosage in example 1, but the relative bioavailability of the two is basically consistent, and no significant difference (P > 0.05) exists, namely, the tanshinone component extract has the same NDNB exposure as the tanshinone IIA group by half of the dosage, which indicates that other tanshinone substances in the tanshinone component extract (73.1% of tanshinone IIA, 7.8% of cryptotanshinone, 5.6% of tanshinone I, 4.5% of dihydrotanshinone, 3.7% of tanshinone IIB and 0.4% of tanshinone IIA anhydride and 95.1% of total tanshinone) have a synergistic effect with tanshinone IIA.
According to the treatment regimen of example 1 or example 3, NDNB is administered simultaneously with the same mass of tanshinone IIA or with half of the mass of tanshinone ingredient extract, NDNB is expected to be administered at a dose reduced to 1/10 to 1/12 of the original dose; the mass ratio of TSN-IIA to NDNB in example 2 was about 3:5, example 2 compared to comparative example 1, the relative bioavailability of example 2 was 379% of comparative example 1, significantly higher than comparative example 1. According toThe soft capsule of the ethandibuline sulfonate has obvious dose-effect relationship between gastrointestinal dysfunction and liver injury and administration dosage according to one phase 2 clinical test data in a raw research evaluation report CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW (S), and the incidence rate of the gastrointestinal dysfunction is increased from 36.0 percent of 50mg to 74.1 percent of 150mg when the ethandibuline sulfonate is taken for 2 times a day by 50mg or 150mg each time; the rate of increase in liver enzyme index (AST, ALT, GCT) was from 4.7% at 50mg to 19.0% at 150 mg. According to/>The specification of the soft capsule of the ethandibul, the oral administration of the ethandibul capsule of the ethandibul of the 100mg, 65-80% of the administration dose is absorbed by the gastrointestinal tract, and the final oral absolute bioavailability is only 4.69% after the first pass metabolism of the liver. Indicating that liver first pass metabolism is the main factor responsible for liver toxicity. The same systemic exposure as in comparative example 1 was achieved in examples 1-3 using about 1/12 to 1/4 of the dose administered in comparative example 1, with the relative bioavailability calculated from the systemic drug exposure AUC 0-inf of examples 1-3 and comparative example 1 being 1180%, 379% and 1036% for treatment using the protocol of examples 1-3 of the present invention. The total oral dosage is reduced, the total amount of the medicaments exposed to the digestive tract and liver of the first-pass organ after oral administration is obviously reduced, and the liver toxicity and the digestive tract toxic and side effects related to the administration dosage are reduced.
Examples 4-5 and comparative example 2:
The daily dose of the mice was converted to 300mg (the weight of an adult is generally 60kg, and the mice were taken twice) based on the maximum daily dose of the mice, and the daily maximum dose of the mice was 61.5mg/kg of the weight (the weight of an adult was taken twice). The weight of the mice is generally 18 to 25g, and the dosage of the mice is increased to 2.5 mg/mouse in order to avoid that the control group can not absorb too low to reach detection sensitivity. Oleic acid containing 0.3% tpgs was used as solvent to prepare the following formulations, respectively, as con, F4 and F5 formulations in order.
The solubility of the nilamide free base or its different salts in the same solvent is different, and in addition, other excipients are present in the reference formulation, which may have an influence on absorption, and to exclude this effect, the following experiment was carried out using the nilamide free base as active ingredient.
NDNB micronizing free base and tanshinone IIA before use, and sieving with 100 mesh sieve.
Weighing NDNB proper amount of free alkali, adding solvent, and performing ultrasonic treatment to dissolve or disperse uniformly to obtain solution containing NDNB about 10mg per 1ml, which is used as Con.
Weighing NDNB free base and tanshinone IIA in proper amounts, adding solvent, and dissolving by ultrasonic treatment to obtain suspension containing NDNB free base about 10mg and tanshinone IIA about 30mg per 1ml, and shaking before use to obtain F4 prescription;
Weighing NDNB free base, tanshinone IIA, and salvianolic acid component extract, adding solvent, and dissolving by ultrasonic treatment to obtain suspension containing NDNB about 10mg, tanshinone IIA about 30mg, and total salvianolic acid about 100mg per 1ml, shaking before use, and making into F5 prescription;
The detailed prescription composition is as follows:
Table 3NDNB oral lavage tissue distribution prescription (per ml)
SPF-grade Kunming mice, males, body weight 18g-22g,5 weeks old purchased from China food and drug inspection institute, license number: SCXK (Beijing) 2022-0002. 12hr of illumination, 22+ -2deg.C, and RH 55+ -5%x relative humidity. The method comprises the following steps of overnight fasted (freely taking water) for more than 10 hours before the experiment, randomly dividing the mice into three groups, 15 mice in each group, taking 5 mice in each blood point, carrying out gastric lavage administration (0.25 ml/mouse), freely drinking water after 2 hours, killing the dislocation of the neck of the mice after taking blood by taking eyeballs respectively at 0.5 hour, 2 hours and 4 hours, rapidly separating lung, liver and heart tissues of the mice, washing the tissues with normal saline at 4 ℃, sucking the tissue surfaces by using water-absorbing paper, weighing, shearing the tissues, and pressing the tissues (g): normal saline (4 ℃, g) =1: mixing at a mass ratio of 4, homogenizing with a homogenizer, repeatedly freezing and thawing in liquid nitrogen three times, and centrifuging at 13000rpm at 4deg.C for 10 min. Carefully aspirate 150. Mu.L of plasma/tissue homogenate, add 900. Mu.L of methanol as protein precipitant, vortex for 30 seconds, add internal standard solution, vortex for 30 seconds, mix for 30 seconds, after 10 minutes of rest, 4 ℃,13000rpm, centrifuge for 10 minutes, take 20. Mu.L of supernatant and perform content analysis of Nidamib in liver, heart and lung tissues with LC/MS/MS. The results are shown in FIGS. 2A, 2B and 2C.
From the results of the heart tissue detection in each group of mice, compared with the NDNB detection amount in the heart tissue of comparative example 2 (Con.) 2hr, the NDNB detection amount in the heart tissue of example 4 (F4) and example 5 (F5) 2hr was significantly lower than that of comparative example 2 (P < 0.001), and there was no significant difference (P > 0.05) between example 4 and example 5, which indicates that the use of NDNB in combination with TSN-IIA can significantly reduce the distribution of NDNB in the heart tissue of non-target organs, while the salvianolic acid substances contained in example 5 do not affect the distribution of NDNB in the heart tissue. Also examples 4 and 5 had significant differences (P < 0.001) in the amount of NDNB detected in 4hr heart tissue compared to comparative example 2. NDNB is used for treating idiopathic pulmonary fibrosis, and the less the drug exposure in non-target organs/tissues, the less toxic side effects on non-target organs/tissues. See in detail fig. 2A.
From the results of mouse liver tissue NDNB, compared with the NDNB detection amount in the liver tissue of comparative example 2 (con.) for 2hr and 4hr, NDNB detection amounts in the liver tissue of examples 4 and 5 at different time points are significantly lower than those of comparative example 2 (P < 0.001), and the statistical differences (P > 0.05) are not found in the liver tissue of examples 4 and 5 for 2hr and 4hr of NDNB detection amounts, indicating that the salvianolic acid substance contained in example 5 has substantially no influence on the distribution of NDNB in the liver tissue. The lower the drug detection amount of NDNB liver is, the smaller the toxic and side effects of liver are, and meanwhile, after NDNB of the same dosage is orally taken, the higher the effective utilization rate of the drug is. Examples 4 and 5 are both significantly better than comparative example 2, see in detail fig. 2B.
From the results of the detection of mouse lung tissue, the detected amounts of NDNB in the lung tissue at the time points corresponding to the time points of examples 4 and 5 and comparative example 2 were significantly higher than that of comparative example 2, respectively, compared with the detected amounts of NDNB in the lung tissue at the time points of comparative example 2, and the difference was significant (P < 0.001) to indicate that examples 4 and 5 could target NDNB more to the lung of the drug treatment target organ, and the detected amounts of NDNB in the lung tissue of comparative examples 4 and 5 were substantially identical (P > 0.05). As shown in fig. 2C.
In conclusion, compared with comparative example 2, examples 4 and 5 can significantly reduce the drug exposure in liver and heart tissues of non-target organs, inevitably reduce the toxicity of the liver and heart, and simultaneously significantly improve the drug exposure in lung tissues of target organs and the therapeutic effect of the drug.
Examples 6-7 and comparative examples 3-4:
Samples were prepared according to the following recipe:
Non-nelidane (Finerenone, FNRN) is clinically used for the treatment of hypertension, diabetic nephropathy, belonging to aldosterone receptor antagonists, am J nephrol.2021;52 (7) 588-601.Doi:10.1159/000518254 shows a very good anti-fibrotic effect, the clinical maximum daily dose is 40mg/60kg body weight; dapagliflozin (Dapagliflozin, DGLZ) is a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, is clinically used for treating type II diabetes, heart failure and chronic kidney disease, and the research result of BMC Medicine (2022) 20:309https:// doi.org/10.1186/s12916-022-02485-z proves that the dapagliflozin is good in anti-fibrosis effect. The clinical maximum daily dose of dapagliflozin is 10mg/60kg body weight. The doses of the drug administered to rats in terms of non-nefardone and dapagliflozin were 4.13mg/kg body weight and 1.03mg/kg body weight, respectively.
Taking out10 Granules of the soft capsule of the nintedanib ethanesulfonate are extruded, and the content is added with a proper amount of oleic acid for ultrasonic mixing uniformly, and the content is detected by HPLC.
Precisely weighing appropriate amount of micronized non-netilone, and adding certain amountThe suspension of the content of the soft capsule of the nintedanib ethanesulfonate is treated by ultrasonic treatment to ensure that the soft capsule is uniformly dispersed, and the suspension which contains NDNB 7.5.5 mg per 1ml and 1.0mg of the non-nefarnesone is prepared as/>
F6：Nidamib ethane sulfonate soft capsule + FNRN +TSN-IIA, and its preparation method is the same as above, and each 1ml of suspension containing NDNB 7.5.5 mg, 1.0mg of non-nefarnesone and TSN-IIA7.5mg is prepared
F7:The preparation method is the same as above, and a suspension solution containing NDNB 7.5.5 mg per 1ml, 1.0mg of non-nefazidone, 75mg of TSN-IIA-sodium sulfonate (folding sodium salt, calculated by tanshinone IIA sulfonic acid) and DGLZ 0.25.25 mg is prepared;
F8: the preparation method is the same as that, and a suspension solution containing NDNB 7.5.5 mg per 1ml and 0.25mg of DGLZ is prepared;
table 4 oral gavage dosing regimen for rats of examples 6-7 and comparative examples 3-4
The SD male rats are randomly divided into four groups (T1, T2, T3 and T4), 5 animals are fasted for more than 12 hours before administration, and the animals are free to drink water, and the weight of the animals is 210-236 g.
Each group of rats NDNB is dosed at 30mg/kg body weight in terms of Nidamibu, 1ml of each group of rats is respectively perfused with different preparations according to the above table, 1ml of water is supplied after the stomach is perfused, and free drinking water is recovered 2 hours after the administration.
After administration, 0.5ml of blood was taken from the inner canthus at 1h, 1.5h, 2h, 3h, 4h, 5h, 7h, 9h, 12h and 24h, with 3% heparin sodium as anticoagulant. The plasma was separated by centrifugation at 3000rpm for 10min at 4℃and stored in a-80℃refrigerator.
The content of each component in the blood plasma is detected by adopting LC/MS/MS, the internal standard is ibutenib, and according to the blood concentration data of different time points, the pharmacokinetic parameters are calculated by utilizing Phoenix WinNonlin7.0, so as to provide parameters such as Nidamibuteni AUC 0-t、AUC0-∞, cmax, tmax, T 1/2 and the like, and the average value and standard deviation thereof. The results are shown in the following table.
Table 5 examples 6-7 and comparative examples 3-4 rat oral gavage PK parameters (n=5) IB236045
As can be seen from the comparison example 3,With respect to comparative example 1, administration of non-nelidamide was performed simultaneously (administration only/>) Comparative example 3 the oral relative bioavailability of nilotica was 182% of comparative example 1 and the PK parameters were substantially identical to comparative example 1. Example 6 the oral relative bioavailability of comparative example 3 was about 671.0% with the addition of 7.5mg of targeting guide TSN-IIA based on comparative example 3, and the half-life was prolonged from 5.8 hours to 7.7 hours of comparative example 3, affected by the non-nelidamide, and the elimination slowed down as compared to comparative example 3. Example 7 the absorption rate of example 7 was found to be significantly faster than that of example 6 and comparative example 3, with a relative bioavailability of about 1109.6% of comparative example 3, based on the blood concentration of example 7, with the addition of the SGLT-2 inhibitor dapagliflozin, on the basis of example 6, while the targeting guide was replaced with 300mg/kg body weight of TSN-IIA sodium sulfonate. Comparative example 4 was prepared by removing the targeting guide and the non-nelidamide on the basis of example 7, the relative bioavailability of example 7 was about 516% of comparative example 4, and the relative bioavailability of comparative example 4 was about 215% of comparative example 3. From the results of example 7 and comparative example 4, it is evident that the significant change in PK parameters of example 7 is mainly due to the effect of the targeting guide agent sodium tanshinone IIA sulfonate. The introduction of the SGLT-2 inhibitor doubled the relative bioavailability compared to comparative example 3, but was not statistically significantly different.
Example 6 and example 7 both have significant differences (Cmax, AUC0-inf, P < 0.001) compared to comparative example 3; comparative example 4 has a significant difference (p < 0.05) in Cmax compared to comparative example 3, whereas AUC 0→inf has no statistical significance, p >0.05. The results prove that both TSN-IIA and TSN-IIA sodium sulfonate can reduce liver first pass metabolism and improve the exposure of the Nidamib system.
Example 8: synergistic effect of targeting guide agent TSN-IIA
Clean grade healthy SD (Sprague-Dawley) male rats, 8 weeks old, weighing about 250 g+ -20 g, purchased from China food and drug inspection institute (certificate number: SCXK (Beijing) 2022-0002), with ambient temperature of 20+ -2deg.C, 12h day-night alternation, and free water intake. Reference Int J Biochem Cell biol.2008;40 362-382, the most common method for molding pulmonary fibrosis of rats is adopted, namely bleomycin (Bleomycin, BLMC) is injected into the trachea, and the molding of pulmonary fibrosis of rats is carried out by referring to neuropharmacology 2019, vol.9, no.6, 15-20, the combined Chinese and Western medicine journal, 2008,6 (1): 60-67.
BLMC preparation of solution: accurately weighing BLMC, adding sterile physiological saline, dissolving, and clarifying to obtain solution containing BLMC about 6.25mg per 1 ml. TSN-IIA dosing prescription: referring to patent CN105193720B, example 7, preparation C is used for preparing an empty prescription (empty prescription) of the soft capsule of the nintedanib mesylate, a proper amount of micronized TSN-IIA is precisely weighed, a proper amount of oleic acid and empty prescription are added, and ultrasonic treatment at 37 ℃ is carried out to uniformly disperse, so that a suspension with the TSN-IIA content of about 7.5mg per 1ml is prepared for later use.
NDNB prescription for administration: referring to patent CN105193720B, example 7 preparation C is prepared into a Nidamib administration prescription, a proper amount of micronized NDNB is precisely weighed, a proper amount of oleic acid is added, ultrasonic treatment is carried out at 37 ℃ to uniformly disperse, then other auxiliary materials in the preparation C of the embodiment 7 are added, medium chain triglyceride, stearin and lecithin are added, ultrasonic treatment at 37 ℃ is carried out to uniformly disperse, and a suspension containing NDNB 7.5.5 mg per 1ml is prepared for standby.
TSN-iia+ NDNB suspension: precisely weighing appropriate amounts of micronized NDNB free alkali and TSN-IIA, adding oleic acid, ultrasonic dispersing at 37deg.C, adding medium chain triglyceride, stearin and lecithin, and ultrasonic dispersing at 37deg.C to obtain suspension containing about 7.5mg of Nidamib and TSN-IIA in 1 ml.
The above oral formulation should be such that the amount of oleic acid and other fat-soluble excipients (medium chain triglycerides, stearin and lecithin) used in a unit volume of the formulation is kept as consistent as possible.
The control group and BLMC groups were given equal volumes of the mixed solution prepared according to the above preparation method and containing only the air-assist prescription and oleic acid each day.
Treatment groups each group of animals was dosed and modeled as indicated in the following table.
Clean grade healthy male SD rats of 8 weeks old, weighing (250+ -20) g, purchased from China food verification institute (certificate number: SCXK (Beijing) 2022-0002) were selected. At the beginning of the modeling, all rats were randomly divided into a control group (con.), a model group (BLMC), a treatment group 1 (BLMC +tsn-IIA), a treatment group 2 (BLMC + NDNB), and a treatment group 3 (BLMC + NDNB +tsn-IIA), 10 rats per group, with 2 being reserved.
The operation steps of the pulmonary fibrosis model caused by the bleomycin injected into the rat trachea are as follows:
Injecting 10% chloral hydrate (0.3 mL-100 g -1 weight) into abdominal cavity for anesthesia, fixing the rat on the experiment table, fixing the mouth cavity by an opening device, pulling out the tongue, pressing the tongue abdomen by a tongue depressor, rapidly moving the trachea cannula (diameter 2mm, length 4-5 cm) when the animal is inhaling instantly under the direct view of a frontal mirror, calculating the actual injection dose of each rat according to 5mg/kg weight, slowly injecting 0.2-0.3 mL BLMC solution, immediately keeping the animal head and tail downwards, transversely swaying left and right for several times, uniformly distributing the liquid medicine in the lung, recovering the wakefulness, orally irrigating corresponding therapeutic agent or air assist, simultaneously, administering 1mL distilled water, freely drinking after 2h of administration, continuously intervening and treating for 28 days. At the end of the experiment, each rat was anesthetized with 1% sodium pentobarbital, alveolar lavage fluid from each group was collected, lavaged three times, and lavage fluid from each rat was combined for use. After blood is taken from the posterior abdominal aorta of the rat, the rat is sacrificed, after the trachea is cut off, all left lung tissues of the rat are taken out, the lung wet weight (g) is recorded, the lung tissues are transferred into a constant temperature drying oven at 60 ℃, and after 72 hours, the lung tissues are taken out and weighed, and the lung dry weight (g) is recorded. The wet (W, g)/dry (D, g) weight ratio of lung tissue was calculated. The right lung of the rat is quickly taken after the rat is killed, cut into tissues with the thickness of 2.0cm by 2.0cm and the thickness of 0.3cm by a sharp sampling knife, and soaked in a pre-prepared 4% paraformaldehyde solution for more than 24 hours. Washing, dehydrating and transparentizing, waxing, embedding, slicing, spreading and fishing, baking and dewaxing, dyeing, dehydrating, sealing and the like according to the HE dyeing or Masson dyeing flow, and respectively carrying out HE and Masson dyeing on right lung tissues of rats in each group. Performing histopathological observation under an optical microscope, evaluating the inflammation and the pulmonary fibrosis of the lung tissue, and scoring the inflammation degree and the fibrosis degree by adopting an Ashcroft scoring method; ELISA kit detects Type I-collagen and hydroxyproline content in lung tissue; the level of oxidative stress [ Reactive Oxygen Species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) ] of each group of rats was detected using the kit; ELISA kit for determining the contents of tumor necrosis factor (TNF-alpha), interleukin 6 (IL-6) and interleukin 1 beta (IL-1 beta) in the lung tissues of each group of rats. Collecting the blood of abdominal aorta of rat with sterile centrifuge tube, naturally coagulating at room temperature for 20 min, centrifuging at 2-8deg.C for about 20 min (2500 rpm), collecting supernatant, and centrifuging again if precipitate appears during preservation. The above serum was used to detect the content of alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST). Serum and tissue specimen pretreatment, reagent preparation and standard solution preparation and operation steps related to ELISA detection project are strictly carried out according to the instructions attached to each detection kit.
Statistical analysis was performed using SPSS23.0 version, all data were normalized to mean ± standard deviation, comparison between control and model and/or treatment groups using t-test of independent samples, P <0.05 was considered statistically significant; p <0.01 has a significant difference and P <0.001 has a very significant difference. Model group was compared with control group, #p <0.05, #p <0.01, #p <0.001;
Treatment group compared to model group, < P0.05, < P0.01, < P0.001;
the combination therapy is <0.05, <0.01, <0.001, < P compared to the single drug therapy.
(1) The lung wet/dry weight ratios of the rats in each group are shown in the following table:
table 6 lung wet (W, g)/dry weight (D, g) ratio (mean ± SD, n=6) for each group of rats
According to the results, compared with a control group, P <0.001 has a very significant difference, and the lung wet/dry weight ratio of rats in the model group is significantly higher than that of the control group, which indicates that the pulmonary edema of rats in the model group is serious; compared with the control group, the TSN-IIA+ BLMC group and the NDNB + BLMC group have significant difference in P < 0.01; compared with the model group, the TSN-IIA+ BLMC and NDNB + BLMC have significant difference in P < 0.01; intervention with rats BLMC dosed with TSN-IIA or NDNB indicated that pulmonary edema was still present in both groups of rats with TSN-IIA or NDNB alone, but significantly improved compared to the model group; compared with the control group, the TSN-IIA+ NDNB + BLMC has no significant difference, and compared with the model group, the TSN-IIA+ NDNB + BLMC has significant difference, wherein P is less than 0.001. The combined treatment of TSN-IIA and NDNB can obviously improve BLMC-induced pulmonary edema of rats. The P-value of TSN-iia+ NDNB + BLMC group compared with TSN-iia+ BLMC group or NDNB + BLMC group is less than 0.01, which indicates that the difference is significant compared with single drug treatment in combination treatment, and the combination of the two has significant synergistic effect.
(2) Histopathological detection
1) HE staining
Fig. 3 shows a map of HE staining pathology of lung tissue of each group of rats.
2) Masson staining
Fig. 4 shows Masson staining pathology tissue plots for each group of rat lung tissue.
HE staining of lung tissue was divided into three parts according to gray scale, as follows: non-dyeing area: represents alveolar space; deep dyeing area: representing the nuclear area, suggesting the extent of alveolitis; shallow dyeing area: representing fibrous connective tissue within the pulmonary interstitium, suggesting the degree of pulmonary fibrosis.
The Masson-stained pathological section is divided into the following three regions: non-dyeing area: represents alveolar space; deep blue dyeing region: represents fibrous connective tissue; light red dyeing area: representing the nucleus.
According to HE staining results: the control group has normal lung tissue structure, intact alveolar space and no collagen deposition in the interstitium. Group BLMC can see destruction of alveolar structure, inflammatory cell infiltration, widening of alveolar space, increased fibroblast aggregation and collagen matrix deposition in the interstitial areas of the lung, and disturbance of pulmonary parenchyma structure. The treatment groups BLMC +TSN-IIA, BLMC+NDNB and BLMC+TSN-IIA+ NDNB are interfered for 28 days, compared with the model group, inflammatory infiltration is reduced to different degrees, alveolar wall thickening and alveolar interval widening and collagen matrix deposition are improved to different degrees, and the improvement effect of the combined treatment group is obviously better than that of the single-drug treatment group.
According to the Masson staining results, no obvious collagen deposition was seen in the control group; group BLMC can observe a large number of hyperplastic blue fibrils distributed around the alveolar septum, alveolar wall, terminal bronchioles, respiratory bronchioles. The three treatment groups all showed different degrees of improvement or reversal of fibrosis and collagen fiber deposition in the tissues compared with BLMC groups, wherein BLMC +TSN-IIA+ NDNB reversal effect is most obvious, and compared with the control group, the lung tissue structure is clear, the alveolar cavity is complete, and compared with the control group, no obvious change is caused.
Pulmonary fibrosis scoring criteria (Ashcroft scoring criteria):
0 point: normal; 1, the method comprises the following steps: the alveolar walls or bronchial walls are slightly thickened; 2-3: the alveolar wall or the bronchial wall is moderately thickened, but no pulmonary structure is damaged; 4-5 minutes: the fibrous tissue is obviously increased, with obvious lung structure damage, fibrous tissue ropes or small fibrous tissue lumps are formed; 6-7 minutes, severe lung structural damage, large fibrotic areas, honeycomb lung; 8, the following steps: full field fibrous tissue. The lung fibrosis score results are shown in the following table:
(3) Type I-collagen, hydroxyproline content and Ashcroft score in rat lung tissue of each group
ELISA kit was used to determine the Type I-collagen and hydroxyproline content in the lung tissue of each group of rats. The results and graphs are shown in the following tables and FIGS. 5-7.
Table 7 Type I-collagen, hydroxyproline content and Ashcroft score (mean ± SD, n=10) in lung tissue
According to the above results, the expression level of Type I-collagen and Hydroxyproline (HYP) was significantly increased (P < 0.001) in BLMC groups compared with the control group, and significantly decreased (P < 0.005) in the TSN-IIA+ BLMC and NDNB + BLMC treated groups compared with BLMC groups; the TSN-IIA+ NDNB + BLMC group showed significant differences in the expression level of Type I-collagen and Hydroxyproline (HYP) compared to BLMC group (P < 0.001); the TSN-IIA+ BLMC or NDNB + BLMC group has significant difference (P < 0.005) in expression level of Type I-collagen and Hydroxyproline (HYP) compared with the TSN-IIA+ NDNB + BLMC group, which indicates that the TSN-IIA and NDNB combination treatment has significant synergistic effect compared with the single drug treatment. Specifically, rats treated with the combination treatment group TSN-IIA+ NDNB + BLMC were able to recover to normal and were able to cure, whereas the single drug treatment group TSN-IIA+ BLMC or NDNB + BLMC had improved but failed to cure.
According to pathological tissue Masson stained sections are scored according to an Ashcroft scoring standard, the Ashcroft scores of the treatment group are obviously reduced compared with that of a model group, wherein the Ashcroft scores of the TSN-IIA+ BLMC or NDNB + BLMC groups are obviously different from that of the model group (P < 0.005), but the Ashcroft scores of the combination treatment group of the TSN-IIA+ NDNB + BLMC groups are greatly reduced more than that of the single-drug treatment group, and are extremely obviously different from that of the model group (P < 0.001).
(2) Oxidative stress level in rats of each group
The rat lung tissue active oxygen (ROS), malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) of each group are detected by adopting corresponding kits and strictly following the steps specified in the specification, and the detection results are shown in figure 8:
As can be seen from the above experimental results, the ROS and MDA in BLMC groups significantly increased compared to the control group (P < 0.001), while the GSH-Px and SOD in BLMC groups significantly decreased compared to the control group (P < 0.001); the treatment groups all exhibited different degrees of improvement compared to BLMC and were significantly different from BLMC, but the TSN-iia+ NDNB + BLMC group had a more significant synergistic effect compared to the monotherapy group, which was the most significant improvement to the above parameters.
(3) ELISA analysis of IL-1 beta, IL-6, TNF-alpha
Accurately weighing a proper amount of lung tissue according to the weight (g) and volume (ml) ratio of 1:9 adding pre-cooled physiological saline, mechanically homogenizing under ice bath condition, centrifuging at 2500rpm for 10min, and collecting supernatant of the homogenate for the following experiment. The preparation of each test solution was carried out according to the instructions of each test item kit, and the lung tissue homogenates of each group of rats were analyzed strictly according to the operating rule, and the measurement was carried out at 450nm by using an enzyme-labeled instrument, and the results are shown in FIG. 9.
BLMC groups of TNF- α, IL- β and IL-6 were all significantly increased compared to the control group, with significant differences (P < 0.001) from the control group; TNF- α, IL- β and IL-6 were reduced to different extents in rat lung tissue compared to BLMC, either alone or in combination, with the combined TSN-IIA+ NDNB + BLMC being most greatly reduced (P < 0.001) compared to the model group; compared with the combined treatment group, the index of the single-drug treatment group is lower in descending amplitude than that of the combined treatment group, and the obvious difference (P <0.001 or P < 0.01) indicates that the combined treatment effect of the TSN-IIA+ NDNB is obviously superior to that of any single-drug treatment group, and the TSN-IIA+ NDNB and the combined treatment group have a synergistic effect.
(4) AST (AST, ALT) detection in serum
The test solutions were prepared from the serum of each group of rats according to the specifications of the AST and ALT test kits, and the test results were shown in FIGS. 10 to 11, which were performed strictly according to the procedures described in the specification.
Based on the detection results, model group was continuously intervened for 28 days with BLMC, AST significantly increased compared to control group, with significant differences (# # P < 0.001); the single drug treatment group BLMC +tsn-IIA group was continuously intervened for 28 days with a significant decrease in AST compared to the model group, with a significant difference (P < 0.01), the BLMC + NDNB group was slightly increased but not statistically significant (P > 0.05) compared to the model group; the combination treatment group TSN-iia+ NDNB + BLMC group was continuously intervened for 28 days, with a significant decrease in AST compared to the model group, with a significant difference (×p < 0.001). The single drug treatment group has significant difference in AST variation amplitude compared with the combined treatment group, the values of the P are less than 0.001, and the combined treatment group is obviously superior to the single-drug treatment group. As shown in fig. 11.
Similarly, after 28 days of different interventions, ALT levels in the single-drug treatment group were higher than those in the combination treatment group, and the differences were statistically significant (TSN-IIA+ BLMC: P <0.01, NDNB+BLMC: P < 0.001), with the combination treatment group being significantly better than the single-drug treatment group. As shown in fig. 12.
Examples 9 to 10 and comparative example 5
Because tanshinone compounds have strong fat solubility, many solvents or methods for solubilizing insoluble drugs in pharmacy have no effect on tanshinone compounds. Both salvianolic acid and tanshinone belong to the effective components of the underground part of the root of red-rooted salvia, and the existence of salvianolic acid is observed in the F5 preparation process of the embodiment 5 to help to improve the solubility of tanshinone IIA or tanshinone. Therefore, the following experiment is designed to examine whether the salvianolic acid has an effect on the solubility of tanshinones.
Example 9 and comparative example 5:
taking proper amount of tanshinone component extract, adding dimethyl sulfoxide to prepare solution containing tanshinone 10mg per 1ml, and taking the solution as stock solution.
The extract of salvianolic acid component is weighed with proper amount, and is added with phosphate buffer solution (1:5, V/V) with pH of 6.8 to be dissolved into 10mg of salvianolic acid per 1ml of the solution which is used as the salvianolic acid stock solution.
Phosphate buffer with pH of 6.8 is prepared according to the rule of four parts of Chinese pharmacopoeia 2020 edition. And placed in a shaking table at 37℃with an amplitude of 200rpm for 2 hours.
Respectively weighing appropriate amounts of high molecular polymer HPMCAS, PVP-VA64, PVP K30 and Soluplus, HPMC, respectively weighing two parts in parallel, preparing high molecular polymer buffer solution with the concentration of 0.25% by using phosphate buffer solution with the pH of 6.8, and continuously shaking for 30min at 37 ℃. The other part is dissolved and diluted by using a salvianolic acid stock solution to prepare a solution containing 0.25% of high molecular polymer and 1% of salvianolic acid per 1ml, and the solution is continuously shaken for 30min at 37 ℃.25ml of the polymer solution and the mixed solution of the polymer and salvianolic acid were measured, and 0.25ml of the tanshinone stock solution was added to the mixture to prepare comparative example 5 and example 9.
Example 10:
taking a proper amount of the salvianolic acid stock solution, quantitatively diluting with phosphate buffer solution with pH of 6.8 to prepare 1mg of salvianolic acid solution per 1ml, wherein the salvianolic acid solution is used as 0.1% salvianolic acid solution.
Respectively weighing appropriate amounts of high molecular polymers HPMCAS, PVP-VA and Soluplus, respectively dissolving with 0.1% salvianolic acid solution, ultrasonically shaking at 37deg.C for 30min, weighing 25ml of each solution, respectively adding 0.25ml of tanshinone stock solution, ultrasonically dispersing uniformly, shaking with the samples of comparative example 5 and example 9 in a shaking table with air shaking at 37deg.C for 1 hr, 2 hr, 3 hr, 4 hr and 6 hr, respectively, centrifuging at 37deg.C for 12000rpm, collecting supernatant, diluting 5 times, and HPLC analyzing tanshinone content. The solubility of tanshinone substances measured in 6 hours is plotted and compared.
The chromatographic conditions for tanshinone content determination are as follows:
The results are shown in FIG. 12.
Compared with comparative example 5, the solubilization effect of the 1% salvianolic acid-containing solution in example 9 on tanshinones is significantly better than that of comparative example 5, and the solubility of tanshinones in each sample in example 9 is 9.8-85 times of that of comparative example 5 at the same time point. In example 10, the high molecular polymer with good solubilization effect on tanshinone substances in example 9 was selected, and the concentration of salvianolic acid was reduced to 0.1%, which is 5.7 times, 7.3 times and 17.5 times of the solubilities of salvianolic substances in 0.25% HPMCAS+0.1% salvianolic acid, 0.25% PVP-VA64+0.1% salvianolic acid and 0.25% Solupus+0.1% salvianolic acid, respectively, as measured in 6 hours, compared with comparative example 5. Example 10 reduced the amount of auxiliary salvianolic acid by a factor of 10 compared to example 9, and the solubilization effect also decreased with reduced salvianolic acid concentration, but was still significantly higher than that of comparative example 5.
Examples 11 to 13
The daily maximum dose of the soft capsule of the nintedanib mesylate for human is 300 mg/day, and the absolute bioavailability of the soft capsule for oral administration is 4.7%. According to the results of examples 1-3, the administration dose of Nidamib was reduced to 30 mg/day, which was converted to a daily oral dose of about 3mg/kg in rats.
Weighing appropriate amounts of Cryptotanshinone (CTSN) and salvianolic acid (Salvianolic Acid, SVA), adding the above materialsThe content of the soft capsule of the nintedanib mesylate and proper amount of oleic acid are respectively and evenly dispersed by ultrasonic waves, and each 1ml of the soft capsule of the nintedanib mesylate containing (NDNB) (the active ingredient which actually plays a role in treatment is the nintedanib, so no special condition exists and the active ingredient is the amount of the free alkali of the nintedanib), namely about 0.75mg, about 1.5mg containing CTSN and about 150mg containing SVA of suspension is prepared as a NDNB +L-CTSN +SVA prescription;
The NDNB +M-CTSN +SVA prescription is prepared by the same method: about 0.75mg of Nidani-containing (NDNB), about 7.5mg of CTSN, and about 150mg of SVA per 1ml of suspension as a NDNB +M-CTSN +SVA prescription;
respectively weighing appropriate amounts of Cryptotanshinone (CTSN) and salvianolic acid, adding Proper amounts of the content of the soft capsule of the nintedanib mesylate and the oleic acid are respectively added with 1ml of ethanol, and the mixture is evenly dispersed by ultrasound, so that each 1ml of suspension containing 0.75mg of the nintedanib (NDNB), about 15mg of CTSN and about 150mg of salvianolic acid is prepared and is used as a NDNB +H-CTSN +SVA prescription.
15 Clean grade Sprague Dawley (SD) male rats, weighing 250-265 g, were purchased from China food and drug verification institute under license number SCXK (Beijing) 2022-0002. 15 rats were randomly divided into A, B, C groups, each group was fasted for more than 12 hours prior to dosing, were free to drink water, and were stopped 2 hours prior to dosing.
The dosing regimen was as follows:
table 8 examples 11-13 oral gavage dosing regimen for rats
A. The dose of each group of B, C rats NDNB was 3mg/kg body weight as nidanib, and the mass ratio of the targeted guidance agent CTSN to the therapeutic agent NDNB in each of the A, B, C groups was 2:1. 10:1 and 20: the mass ratio of the auxiliary agent SVA to the targeting guide agent in each group of 1, A, B and C is 100 respectively: 1. 20:1 and 10:1. each group of rats was perfused with 1mL of each rat according to the dosing regimen of table 8, and free drinking was resumed for 2 hours after dosing and free feeding was resumed for 4 hours.
After administration, 0.5ml of blood was obtained through inner canthus at 0.5h, 1h, 2h, 3h, 4h, 5h, 7h, 9h, 12h, 16h and 24h, respectively, and 3% heparin sodium was used as an anticoagulant. The plasma was separated by centrifugation at 3000rpm for 10 minutes at 4℃and stored in a-20℃refrigerator for testing.
The method for detecting plasma samples was the same as in comparative example 1 and examples 1-3.
Pharmacokinetic parameters were calculated from the plasma concentration data measured at different time points using Phoenix winnonlin7.0, providing parameters such as AUC 0-t、AUC0-∞, cmax, tmax and T 1/2, as well as their mean and standard deviation, and comparing with comparative example 1.
TABLE 9 pharmacokinetic parameters of examples 11-13
From the results of examples 11-13, it was found that when NDNB was administered at 1/10 of that of comparative example 1, the mass of the targeting guide in the formulations of examples 11-13 was 2, 10 and 20 times that of the therapeutic agent, respectively, the peak Cmax ratios of the nintedanib in the plasma of examples 11-13 and comparative example 1 were 0.94, 1.73 and 1.63, respectively, and the ratios of AUC 0-inf in the plasma were 1.14, 1.56 and 1.42, respectively, and the solubility of the targeting guide cryptotanshinone in the formulations was improved in the presence of the targeting guide and the adjuvant, and that 1/10 of the NDNB dose used in comparative example 1 reached a peak plasma concentration and drug exposure no lower than that of comparative example 1.
While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true scope of the invention.

Claims (11)

1. A targeting composition or kit, characterized in that the targeting composition or kit comprises a targeting guide agent and a first therapeutic agent, the first therapeutic agent being one or more selected from the group consisting of nidanib, pharmaceutically acceptable salts, hydrates, solvates, co-crystals thereof; the targeting guide agent is one or more selected from the group consisting of tanshinone I, tanshinone IIA, tanshinone IIB, cryptotanshinone, tanshinone I, isoptanshinone IIA, isoptanshinone IIB, methyl tanshinol, hydroxy tanshinone IIA, nortanshinone, dehydrotanshinone, 1, 2-didehydrocryptotanshinone, tanshinone (A, B, C), 1, 2-dihydrotanshinone, 15, 16-dihydrotanshinone diol (A, B, C), tanshinone (A, B, C), and derivatives thereof (e.g., sulfonate, anhydride derivatives, hydroxy derivatives, diphenol derivatives); preferably one or more selected from the group consisting of cryptotanshinone, tanshinone IIA, and derivatives (e.g., pharmaceutically acceptable salts, co-crystals, hydrates, or solvates) thereof; more preferably one or more selected from the group consisting of cryptotanshinone, tanshinone IIA sulfonate (e.g., sodium salt, potassium salt), when the targeting guide agent and the first therapeutic agent are in a kit, the targeting guide agent and the first therapeutic agent are each packaged separately, preferably in a manner suitable for oral administration.
2. The targeting composition or kit according to claim 1, wherein the targeting guide is a tanshinone component extract consisting of dihydrotanshinone, tanshinone IIA, cryptotanshinone, tanshinone I, tanshinone IIB, hydroxy tanshinone IIA, and tanshinone IIA anhydride.
3. The targeting composition or kit according to claim 1 or 2, wherein the weight ratio of the targeting guide agent to the first therapeutic agent is between 100:1 and 1:5; preferably 20:1 to 1:2; more preferably from 10:1 to 1:2, or 10:1 to 1:0.6.
4. The targeting composition or kit according to any one of the claims 1-3, wherein the daily amount of the first therapeutic agent is 10-200mg in terms of nilamide; preferably 12.5-100mg; more preferably 25-100mg.
5. The targeting composition or kit according to any one of claims 1-4, further comprising a second therapeutic agent selected from one or more of the group consisting of anti-pulmonary fibrosis drugs, lung cancer therapeutic drugs, oxidative phosphorylation blockers, anticoagulants, hormones and immunomodulators, bronchodilators, non-steroidal salt corticoid receptor antagonists, immunosuppressants, antacids, anti-infective drugs, anti-oxidative drugs, antibodies, endothelin receptor antagonists, sodium-glucose cotransporter 2 inhibitors (SGLT-2 inhibitors), mRNA therapeutic agents, dietary supplements, such as one or more of the group consisting of feonelerenone, dapagliflozin or pharmaceutically acceptable salts, hydrates, co-crystals, solvates thereof; preferably, the second therapeutic agent is a combination of non-nelidamide and dapagliflozin,
Preferably, the targeting agent of the targeting composition is tanshinone IIA, the first therapeutic agent is nidanib, and the second therapeutic agent is a combination of non-nevirapine and dapagliflozin; or the targeting guide agent of the targeting composition is tanshinone IIA sulfonate, preferably tanshinone IIA sodium sulfonate, the first therapeutic agent is Nidamide, and the second therapeutic agent is a combination of non-nefarnesone and dapagliflozin.
6. The targeting composition or kit according to claim 5, wherein the daily amount of the targeting guide agent is 6mg-200mg, the daily amount of the nintedanib is 10mg-200mg, the daily amount of the non-nelidane is 2.5mg-40mg, and the daily amount of the dapagliflozin is 2.5-10mg; preferably, the daily dosage of the targeting guide agent is 15mg-150mg, the daily dosage of the nidazole is 25mg-100mg, the daily dosage of the non-netilone is 5mg-40mg, and the daily dosage of the dapagliflozin is 5mg-10 mg.
7. The targeting composition or kit according to any one of the claims 1-6, further comprising an auxiliary agent, which is one or more selected from the group consisting of a monomer, dimer, trimer, tetramer and oligomer of danshensu condensed with one or more caffeic or rosmarinic acids; preferably one or more selected from the group consisting of salvianic acid, salvianolic acid D, salvianolic acid A, salvianolic acid B and caffeic acid.
8. The targeting composition or kit according to claim 7, wherein the weight ratio of auxiliary agent to targeting guide agent is 1000:1 to 3.3:1, a step of; preferably from 100:1 to 5:1; more preferably 20:1 to 10:1.
9. The targeting composition or kit according to any one of the claims 1-8, wherein the targeting composition further comprises a pharmaceutically acceptable adjuvant or functional carrier.
10. The kit of any one of claims 1-9, wherein the kit comprises a product specification describing the simultaneous administration of the targeting guide agent and the first therapeutic agent and/or the second therapeutic agent to a subject in need of treatment, or the targeting guide agent is administered within 2 hours prior to the first therapeutic agent and/or the second therapeutic agent, or the product specification describes the administration of the targeting guide agent and the first therapeutic agent 1 time daily, or 2 times daily, or 3 times daily to a subject in need of treatment, and/or the second therapeutic agent, preferably by oral administration.
11. Use of a targeted composition according to any one of claims 1-9 in the manufacture of a medicament for the treatment and/or prophylaxis of pulmonary diseases such as pneumonia, asthma, tuberculosis, chronic obstructive pulmonary disease, pulmonary fibrosis interstitial lung disease, systemic sclerosis-associated pulmonary interstitial disease, pulmonary arterial hypertension, lung cancer.
CN202311858812.5A 2023-12-30 2023-12-30 Nidaminib targeting compositions Pending CN118021812A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202311858812.5A CN118021812A (en) 2023-12-30 2023-12-30 Nidaminib targeting compositions

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202311858812.5A CN118021812A (en) 2023-12-30 2023-12-30 Nidaminib targeting compositions

Publications (1)

Publication Number Publication Date
CN118021812A true CN118021812A (en) 2024-05-14

Family

ID=90983083

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202311858812.5A Pending CN118021812A (en) 2023-12-30 2023-12-30 Nidaminib targeting compositions

Country Status (1)

Country Link
CN (1) CN118021812A (en)

Similar Documents

Publication Publication Date Title
US8420624B2 (en) Methods for treating or preventing symptoms of hormonal variations
AU2010315362B2 (en) Coated drug spheroids and uses thereof for eliminating or reducing conditions such as emesis and diarrhea
US20220323531A1 (en) Willow extract and its use in treating a viral infection, allergic reaction, and other medical conditions
JP2008502622A (en) An anticancer composition comprising proline or a derivative thereof and an antitumor antibody
KR20190116416A (en) Compounds and Methods for Treating Primary Bile Cholangitis
EP1986619A2 (en) Use of phosphatases to treat tumors overexpressing n-cor
EP3320901B1 (en) Dimethylaminomicheliolide for use in the treatment of pulmonary fibrosis
ES2383005T3 (en) Medications for glomerular diseases
JP2005537282A (en) Inhibition of angiogenesis by cephalotaxin alkaloids, and derivatives, compositions and methods of use thereof
CA2985379C (en) Micronized pharmaceutical compositions for treatment of angiogenisis conditions
WO2021053651A1 (en) Extract of cocculus hirsutus for treatment of covid-19
CN118021812A (en) Nidaminib targeting compositions
AU2019354771A1 (en) Combination therapy for the treatment of uveal melanoma
CN112438942A (en) Pharmaceutical composition containing alkalizer and its synergist and its application
CN113015527A (en) Platelet count diagnostic method for treating myelofibrosis
WO2009135432A1 (en) The use of salvianolic acid b on anti- thrombus
CN108771662A (en) Purposes of the pterostilbene in the drug for preparing prevention high lithemia nephrosis
AU2016285566A1 (en) Thromboxane receptor antagonists in AERD/asthma
CN103417907A (en) Applications of traditional Chinese medicine composition in preparation of drug used for inhibiting angiogenesis
US20200069675A1 (en) Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain
WO2019232783A1 (en) Cannabidiol composition and use thereof
BRPI0713647A2 (en) pharmaceutical formulations and compositions of a selective cxcr2 or cxcr1 antagonist and methods for its use for the treatment of inflammatory disorders
CN110833551B (en) Use of pyrazolopyrimidine derivatives for the treatment of acute pancreatitis
WO2024109652A1 (en) Use of (-)-epigallocatechin gallate compound
CN107802632B (en) Traditional Chinese medicine effective component composition for treating rheumatic arthritis and rheumatoid arthritis and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination