c-Met (IC50 = 5 nM); p-Met (IC50 = 3 nM)
The target of Savolitinib (AZD6094, HMPL-504) is mesenchymal-epithelial transition factor (c-Met), and it acts as a highly potent and selective inhibitor of c-Met. [1]
Savolitinib (AZD6094, HMPL-504) is a selective c-Met inhibitor, and in gastric cancer cell lines with dysregulated c-Met, its EC50 values for inhibiting cell growth range from 0.6 nM/L to 12.5 nM/L [2]

Volitinib exhibits exceptional potency and kinase selectivity [1]. In a panel of gastric cell lines, vitetinib exhibits a highly selective profile; it only potently inhibits cell growth in the lines that have dysregulated cMET (EC50 values 0.6 nM/L-12.5 nM/L)[2]. Volitinib shows minimal inhibition of P-gp (IC50 > 17 μM) and possesses high membrane permeability without causing efflux transport across the monolayer of Caco-2 cells. Volitinib does not significantly increase CYP1A2 and CYP3A4 in human hepatocytes or cause reversible or mechanism-based CYP inhibition in human liver microsomes[3].

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1. Anti-proliferative activity in gastric cancer cell lines: A panel of 22 gastric cancer cell lines was screened to evaluate the anti-proliferative effect of Savolitinib. The results showed that Savolitinib potently inhibited cell growth only in cell lines with dysregulated c-Met, with EC50 values ranging from 0.6 nM/L to 12.5 nM/L. In contrast, it had no significant inhibitory effect on gastric cancer cell lines with normal c-Met expression [2]
2. Pharmacodynamic analysis of c-Met signaling: Hs746t gastric cancer cells were treated with 0.1 μM Savolitinib for 1 hour, and cell lysates were prepared for Western blot analysis. The results demonstrated that Savolitinib could effectively inhibit the phosphorylation of c-Met (mature form with a molecular weight of 145 kDa), thereby blocking the activation of the c-Met signaling pathway [2]
3. Structure-activity relationship study: A series of novel triazolopyrazine c-Met inhibitors were synthesized, and the structure-activity relationship was investigated. Savolitinib (compound 28 in the study) was identified as a potent and selective c-Met inhibitor, but no specific in vitro enzyme activity or cell activity data for this compound were detailed in reference [1]
4. Membrane permeability and efflux transport: Savolitinib exhibited high membrane permeability with a Papp (A>B) value of 28×10⁻⁶ cm/s across Caco-2 cell monolayers, and there was no efflux transport observed. Additionally, Savolitinib showed negligible inhibition of P-glycoprotein (P-gp), with an IC50 value greater than 17 μM [3]
5. Metabolic stability in vitro: The metabolic stability of Savolitinib was evaluated in liver microsomes and S9 fractions from rat, dog, monkey, and human. Five phase I metabolites were detected in liver microsomes and S9 fractions of different species, among which three major metabolites (M1 from demethylation, M2 from hydroxylation, M3 from mono-oxygenation) were mediated by multiple enzymes including CYP450s and aldehyde oxidase. Rat was found to be the most similar species to human in terms of in vitro metabolism and metabolite profile [3]
6. CYP enzyme inhibition/induction: Savolitinib showed no significant reversible or mechanism-based inhibition of CYP enzymes in human liver microsomes, and it did not induce the expression of CYP1A2 and CYP3A4 in human hepatocytes [3]

The compound's half-time is 1.7 hours, and its clearance is 4.28 L/(h·kg) in a mouse pharmacokinetic study conducted on male ICR mice. The total plasma exposure is significantly higher despite its moderate oral bioavailability (F = 27.2%). In a U87MG subcutaneous xenograft model, volitinib exhibits dose-dependent inhibition of tumor growth[1]. Its treatment has minimal effect in a gastric cancer control model, but in 3/3 cMET-dysregulated gastric cancer patient-derived tumor xenograft models, it leads to pharmacodynamic modulation of c-MET signaling and strong tumor stasis[2]. The plasma protein binding rate of volitinib is moderate (60%–70% in rats, dogs, and humans; 40% in mice; 80% in monkeys). In rats, it is widely distributed to various organs, with high exposure in the liver and kidney and very low exposure in the brain, spinal cord, and testis in relation to the plasma level. Volitinib exhibits acceptable bioavailability at 27.2%, 42.6%, and 86.3%, respectively, and rapid oral absorption (Tmax<2.5 h) with high exposures in PK studies in mice, rats, and dogs. A low extraction ratio is evident from the in vivo clearance (CL), which is 11.0, 11.8, and 3.5 mL/min/kg in mice, rats, and dogs, respectively. For those species, the volume of distribution in steady state (Vss) is 0.4, 1.4, and 1.4 L/kg, respectively, suggesting a pattern of distribution that is moderate to low. In rats, vitexinib exhibits linear pharmacokinetics (PK) between 1 and 25 mg/kg, while in dogs, it is between 2 and 10 mg/kg. Dog food barely has an impact on its PK profile. However, in accordance with the in vitro metabolism result, volitinib in monkeys exhibits a noticeably high extraction ratio (CL=17.2 mL/min/kg). The low oral bioavailability (1.9%) of volitinib in monkeys is thought to be the consequence of excessive first-pass extraction, given the drug's rapid absorption (Tmax=1.9 h) and moderately low distribution (Vss=0.7 L/kg). Overall, volitinib's preclinical PK/ADME characteristics are favorable[3].

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1. Antitumor activity in human glioma xenograft model: Savolitinib exhibited favorable pharmacokinetic properties in mice and good antitumor activity in the human glioma xenograft model in athymic nude mice, but no specific data on tumor growth inhibition rate or tumor volume reduction were provided [1]
2. Antitumor activity in Hs746t gastric cancer xenograft model: Savolitinib was administered to nu/nu mice bearing established subcutaneous Hs746t xenografts by oral gavage once daily (qd) at different doses. The results showed that Savolitinib significantly inhibited tumor growth (P ≤ 0.001), but no specific tumor volume data or dose-response relationship were detailed. Pharmacodynamic analysis revealed that Savolitinib could inhibit phospho-c-Met in tumor tissues, and the inhibition rate was calculated using the formula: IR (%) = (1−OD450 drug treated/OD450 vehicle) × 100% [2]
3. Antitumor activity in gastric cancer PDX models: Savolitinib was administered by oral gavage once daily to nu/nu mice bearing established patient-derived gastric tumor fragments. In 3 out of 3 c-Met-dysregulated gastric cancer PDX models (SGC071, SGC184, SGC141), Savolitinib induced potent tumor stasis (P ≤ 0.001), while it had negligible activity in the c-Met-low polysomy PDX model (SGC070, P ≥ 0.05). Pharmacodynamic analysis confirmed that Savolitinib could modulate phospho-c-Met expression in tumor tissues (assessed by IHC staining before and after dosing), with no specific inhibition rate data [2]
4. Combination therapy with docetaxel: In Hs746t xenograft model and SGC184 PDX model, co-administration of Savolitinib with docetaxel enhanced the antitumor efficacy compared with single-agent treatment (P ≤ 0.001 for Hs746t, P ≤ 0.05 for SGC184). No specific tumor growth curves or regression rates were detailed [2]
5. In vivo distribution in rat: Savolitinib exhibited wide distribution to different organs in rat, with high exposures in liver and kidney, and very low concentrations in brain, spinal cord, and testis compared to plasma levels [3]
6. In vivo excretion in rat: Metabolism was the main elimination route of Savolitinib in rat, as the fecal, urinary, and biliary excretion of the parent drug accounted for less than 2% of the administered dose. A total of 16 phase I metabolites and 8 phase II metabolites were identified in plasma and excreta of rat, with M22 (a sulfate conjugate of monooxidized metabolite M5) being the dominant metabolite in all tested matrices. Demethylation to M2 and excretion in urine was also an important elimination pathway [3]
7. Pharmacokinetic parameters in animals:
- Mouse: Rapid oral absorption (Tmax < 2.5 h), oral bioavailability of 27.2%, in vivo clearance (CL) of 11.0 mL/min/kg (low extraction ratio), steady-state volume of distribution (Vss) of 0.4 L/kg (moderate to low distribution) [3]
- Rat: Rapid oral absorption (Tmax < 2.5 h), oral bioavailability of 42.6%, CL of 11.8 mL/min/kg (low extraction ratio), Vss of 1.4 L/kg (moderate to low distribution), linear pharmacokinetics in the dose range of 1 to 25 mg/kg [3]
- Dog: Rapid oral absorption (Tmax < 2.5 h), oral bioavailability of 86.3%, CL of 3.5 mL/min/kg (low extraction ratio), Vss of 1.4 L/kg (moderate to low distribution), linear pharmacokinetics in the dose range of 2 to 10 mg/kg, and food had little effect on its PK profile [3]
- Monkey: Rapid oral absorption (Tmax = 1.9 h), poor oral bioavailability of 1.9%, CL of 17.2 mL/min/kg (notably high extraction ratio), Vss of 0.7 L/kg (moderately low distribution). The low bioavailability was attributed to excessive first-pass extraction [3]

In 96-well plates, NCI-H441 cells are plated at a density of 15,000 cells/well in RPMI-1640 medium containing 10% FBS. Cells are incubated for a full night before being treated for one hour at 37 °C with progressively diluted test compounds. Following the removal of the medium, cells are lysed in a lysis buffer containing 100 μL per well and the following concentrations: 1% NP-40, 20 mM Tris/pH 8.0, 137 mM NaCl, 10% glycerol, 2 mM EDTA, 1 mM activated sodium orthovanadate, 10 mg/mL Aprotinin, and 10 mg/mL Leupeptin. Overnight, the cell lysate-containing plates are stored at -80°C. The plates are gently mixed and thawed on ice the following day. To detect the p-c-Met signal, 25 μL/well of lysates are added to assay plates that have been pre-coated with anti-p-Met antibody. The measurements of p-c-Met are made at 450 and 570 nm.

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1. Gastric cancer cell proliferation assay:
- Step 1: 22 gastric cancer cell lines were seeded into appropriate culture plates at a specific density (not specified) and cultured under standard conditions (temperature, CO2 concentration not mentioned) to allow cell adherence.
- Step 2: Different concentrations of Savolitinib were added to the culture medium, and the cells were incubated for a certain period (not specified).
- Step 3: A cell viability detection method (not specified) was used to determine the cell proliferation rate, and EC50 values for each cell line were calculated. The results were correlated with c-Met gene copy number (GCN), c-Met protein IHC score, and cellular staining location to analyze the relationship between c-Met dysregulation and cell sensitivity to Savolitinib [2]
2. Western blot analysis of c-Met phosphorylation:
- Step 1: Hs746t gastric cancer cells were cultured in complete medium until reaching the desired confluency (not specified).
- Step 2: The cells were treated with 0.1 μM Savolitinib or PF-4217903 (an unrelated selective c-Met inhibitor) for 1 hour under culture conditions.
- Step 3: Cell lysates were prepared by lysing the cells with a lysis buffer (components not specified), and protein concentration was determined (method not specified).
- Step 4: Equal amounts of protein were separated by SDS-PAGE (gel concentration not specified), transferred to a membrane (type not specified), and probed with primary antibodies against c-Met and phospho-c-Met (mature form, 145 kDa), followed by secondary antibody incubation. The protein bands were detected (detection method not specified) to analyze the inhibition of c-Met phosphorylation by Savolitinib [2]
3. Caco-2 cell permeability assay:
- Step 1: Caco-2 cells were cultured on transwell inserts until forming a confluent monolayer (the culture duration and monolayer integrity verification method were not specified).
- Step 2: Savolitinib was added to either the apical (A) or basolateral (B) side of the transwell inserts, and the plates were incubated at 37°C for a specific time (not specified).
- Step 3: Samples were collected from the opposite side at predetermined time points, and the concentration of Savolitinib was measured (detection method not specified) to calculate the apparent permeability coefficient (Papp) in the A→B direction (28×10⁻⁶ cm/s) and evaluate efflux transport (no efflux observed) [3]
4. In vitro metabolic stability assay:
- Step 1: Liver microsomes or S9 fractions from rat, dog, monkey, and human were prepared (preparation method not specified), and protein concentration was adjusted to a specific value (not specified).
- Step 2: Savolitinib was incubated with liver microsomes/S9 fractions in the presence of cofactors (e.g., NADPH for CYP450-mediated metabolism) at 37°C for different time points (not specified).
- Step 3: The reaction was terminated by adding a quenching agent (not specified), and the samples were analyzed by chromatographic methods (not specified) to identify metabolites (5 phase I metabolites) and evaluate metabolic stability. Rat was found to be the most similar species to human in metabolite profile [3]

Female athymic mice
\n1.0, 2.5 and 10.0 mg/kg (oral); 2.5 mg/kg (i.v.)
\noral administration/i.v.

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\n1. Human glioma xenograft model in athymic nude mice:
\n - Step 1: Human glioma cells (specific cell line not specified) were subcutaneously implanted into athymic nude mice (female/male, age not specified) at a specific cell number (not specified).
\n - Step 2: After tumor implantation, the mice were randomized into treatment and control groups (group size not specified) when tumors reached a certain volume (not specified).
\n - Step 3: Savolitinib was administered to the treatment group (administration route, dose, frequency not specified), and the control group received a vehicle.
\n - Step 4: Tumor volume and mouse body weight were monitored regularly (monitoring interval not specified) to evaluate the antitumor activity of Savolitinib. No details on drug dissolution formula/vehicle were provided [1]
\n2. Hs746t gastric cancer xenograft model in nu/nu mice:
\n - Step 1: Hs746t gastric cancer cells were subcutaneously injected into nu/nu mice (7–8 mice per treatment group) at a specific cell number (not specified).
\n - Step 2: When tumors were established (specific volume not specified), Savolitinib was administered by oral gavage once daily (qd) at different doses (doses not specified). The control group received a vehicle (dissolution formula not specified).
\n - Step 3: Tumor volumes were measured at regular intervals (not specified) and plotted against time to evaluate antitumor efficacy (P ≤ 0.001 for treatment groups vs control).
\n - Step 4: For pharmacodynamic analysis, tumor fragments were harvested at different time points and doses (not specified) after Savolitinib administration, and tumor lysates were prepared for ELISA assay to detect phospho-c-Met levels. The inhibition rate was calculated using the formula IR (%) = (1−OD450 drug treated/OD450 vehicle) × 100% [2]
\n3. Gastric cancer PDX model in nu/nu mice:
\n - Step 1: Patient-derived gastric tumor fragments were implanted subcutaneously into nu/nu mice (7–8 mice per treatment group) to establish PDX models (implantation method not specified).
\n - Step 2: When tumors were established (specific volume not specified), Savolitinib was administered by oral gavage once daily (qd) at specified doses (doses not specified). The control group received a vehicle (dissolution formula not specified).
\n - Step 3: Tumor volumes were measured regularly (not specified) and plotted against time. Savolitinib induced potent tumor stasis in 3 c-Met-amplified PDX models (SGC071, SGC184, SGC141, P ≤ 0.001) and had no significant effect on SGC070 (P ≥ 0.05).
\n - Step 4: For pharmacodynamic analysis, tumor tissues were collected before dosing and 2 hours after Savolitinib dosing, and phospho-c-Met expression was assessed by IHC staining [2]
\n4. Combination therapy in xenograft/PDX models:
\n - Step 1: Hs746t xenograft or SGC184 PDX models were established in nu/nu mice (group size not specified) as described above.
\n - Step 2: Mice were randomized into four groups: Savolitinib single-agent group (oral gavage, qd, dose not specified), docetaxel single-agent group (administration route: intravenous, frequency: once weekly (qw), dose not specified), combination group (both drugs at the above doses/schedules), and vehicle control group.
\n - Step 3: Tumor volumes were measured regularly (not specified) to evaluate the synergistic effect of the combination therapy (P ≤ 0.001 for Hs746t, P ≤ 0.05 for SGC184) [2]
\n5. In vivo pharmacokinetic study in mouse, rat, dog, and monkey:
\n - Step 1: Animals (mouse, rat, dog, monkey; gender, age, weight not specified) were divided into groups (group size not specified) and fasted (for oral administration) or not (for intravenous administration) as required.
\n - Step 2: Savolitinib was administered either orally (gavage) at different doses (1–25 mg/kg for rat, 2–10 mg/kg for dog) or intravenously (dose not specified). The drug was dissolved in a suitable vehicle (not specified).
\n - Step 3: Blood samples were collected at predetermined time points (not specified) after administration, and plasma was separated (method not specified).
\n - Step 4: Plasma concentrations of Savolitinib were measured by a validated analytical method (not specified), and pharmacokinetic parameters (Tmax, bioavailability, CL, Vss) were calculated. For dog, the effect of food on PK was evaluated by comparing fed and fasted groups (food had little effect) [3]
\n6. In vivo distribution and excretion study in rat:
\n - Step 1: Rats (gender, age, weight not specified) were administered Savolitinib at a specific dose (not specified) by oral gavage or intravenous injection (route not specified).
\n - Step 2: For distribution study, rats were euthanized at a specific time point (not specified) after administration, and different organs (liver, kidney, brain, spinal cord, testis, etc.) were collected, homogenized (method not specified), and Savolitinib concentrations were measured (method not specified) to evaluate tissue distribution (high in liver/kidney, low in brain/spinal cord/testis).
\n - Step 3: For excretion study, rats were placed in metabolic cages to collect feces, urine, and bile (collection duration not specified) after Savolitinib administration. The concentrations of parent drug and metabolites in excreta were measured (method not specified) to calculate excretion rates (parent drug < 2% of dose) and identify metabolites (16 phase I, 8 phase II) [3]

1. Absorption:
- Savolitinib showed rapid oral absorption in mice, rats, dogs and monkeys, with Tmax < 2.5 hours (mice, rats, dogs) and Tmax = 1.9 hours (monkeys) [3]
- Oral bioavailability: 27.2% (mice), 42.6% (rats), 86.3% (dogs), 1.9% (monkeys). Low bioavailability in monkeys is attributed to excessive first-pass extraction [3]
2. Distribution:
- Plasma protein binding: 60%–70% (rat, dog, human), 40% (mouse), 80% (monkey) [3]
- In rats, Savolitinib is widely distributed in different organs, with high exposure in the liver and kidneys, while the concentrations in the brain, spinal cord and testes are very low compared to plasma levels [3]
- Steady-state volume of distribution (Vss): 0.4 L/kg (mouse), 1.4 L/kg (rat), 1.4 L/kg (dog), 0.7 L/kg (monkey), indicating moderate to low distribution [3]
3. Metabolism:
- In vitro: Five phase I metabolites were observed in liver microsomes/S9 fractions in rats, dogs, monkeys and humans; three major metabolites (M1: demethylation, M2: hydroxylation, M3: monooxygenation) were mediated by CYP450 and aldehyde oxidase. The metabolite profile of rats is similar to that of humans [3] In vivo (rat): Sixteen phase I metabolites and eight phase II metabolites were identified in plasma and excreta; M22 (a sulfate conjugate of M5, a monooxygenation metabolite) was the major metabolite. Demethylation to M2 and urinary excretion are important elimination pathways [3]
4. Excretion:
- In rats, metabolism is the main elimination pathway because the fecal, urinary and bile excretion of the parent drug Savolitinib accounts for <2% of the administered dose [3]
5. Clearance:
- In vivo clearance (CL): 11.0 mL/min/kg (mice), 11.8 mL/min/kg (rats), 3.5 mL/min/kg (dogs), 17.2 mL/min/kg (monkeys). The extraction rates were low in mice, rats, and dogs, but significantly higher in monkeys [3]
6. Linear pharmacokinetics:
-Savolitinib exhibited linear pharmacokinetic characteristics in both rats (dose range: 1–25 mg/kg) and dogs (dose range: 2–10 mg/kg) [3]
7. Food effects:
- Food had minimal effect on the pharmacokinetic characteristics of Savolitinib in dogs [3]

[1]. J Med Chem . 2014 Sep 25;57(18):7577-89.

[2]. Mol Oncol . 2015 Jan;9(1):323-33.

[2]. Cancer Res (2013) 73 (8_Supplement): 3371.

Savolitinib belongs to the triazolopyrazine class of compounds, with the structure 1H-[1,2,3]triazolo[4,5-b]pyrazine, substituted at positions 1 and 6 by (1S)-1-(imidazo[1,2-a]pyridin-6-yl)ethyl and 1-methyl-1H-pyrazol-4-yl, respectively. It is a highly selective MET tyrosine kinase inhibitor and has been approved in China for the treatment of advanced non-small cell lung cancer harboring MET exon 14 skipping mutations. It is both a c-Met tyrosine kinase inhibitor and an antitumor drug. It belongs to the pyrazole, triazolopyrazine, and imidazopyridine classes of compounds. Savolitinib has been used in multiple clinical trials to investigate the treatment and health services of diseases such as cancer, food effects, gastric cancer, healthy subjects, and colorectal cancer. Savolitinib is a highly bioavailable orally bioavailable c-Met receptor tyrosine kinase inhibitor with potential antitumor activity. Savolitinib selectively binds to and inhibits the activation of c-Met in an ATP-competitive manner, thereby blocking the c-Met signaling pathway. This may lead to the inhibition of the growth of c-Met protein overexpressing tumor cells. c-Met encodes hepatocyte growth factor receptor tyrosine kinase, which plays an important role in tumor cell proliferation, survival, invasion and metastasis, as well as tumor angiogenesis; this protein is overexpressed or mutated in a variety of cancers.

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Drug indications
Treatment of kidney tumors
Treatment of lung cancer

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1. Background and development: The HGF/c-Met signaling pathway is associated with human cancers, while pan-c-Met inhibitors have limitations. Savolitinib (Volitinib) is a novel, highly effective, and selective small molecule c-Met inhibitor developed through structure-guided drug design and structure-activity relationship studies [1].
2. Incidence of abnormal c-Met expression in Chinese gastric cancer: In a study involving 170 Chinese gastric cancer patients, the incidence of c-MET gene amplification was 6%, and the incidence of protein overexpression was 13% [2].
3. Clinical potential: Preclinical studies have shown that Savolitinib has significant antitumor activity in gastric cancer cell lines and PDX models with abnormal c-Met expression, providing a strong theoretical basis for its clinical research as a treatment option for patients with c-MET amplified gastric cancer[2].
4. Overall preclinical characteristics: Savolitinib exhibits good preclinical PK/ADME properties, including high membrane permeability and low P-gp value. It has no CYP enzyme inhibition/induction, exhibits linear pharmacokinetics in rats and dogs, and has acceptable bioavailability in mice, rats, and dogs[3].

C17H15N9

345.36

345.145

C, 59.12; H, 4.38; N, 36.50

1313725-88-0

68289010

Off-white to yellow solid powder

1.6±0.1 g/cm3

1.833

0.54

0

6

3

26

505

1

N1(C2C(=NC([H])=C(C3C([H])=NN(C([H])([H])[H])C=3[H])N=2)N=N1)[C@@]([H])(C([H])([H])[H])C1C([H])=C([H])C2=NC([H])=C([H])N2C=1[H]

XYDNMOZJKOGZLS-NSHDSACASA-N

InChI=1S/C17H15N9/c1-11(12-3-4-15-18-5-6-25(15)10-12)26-17-16(22-23-26)19-8-14(21-17)13-7-20-24(2)9-13/h3-11H,1-2H3/t11-/m0/s1

3-[(1S)-1-imidazo[1,2-a]pyridin-6-ylethyl]-5-(1-methylpyrazol-4-yl)triazolo[4,5-b]pyrazine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.02 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.08 mg/mL (6.02 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (6.02 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)