Excipient and/or formulating agent

SBE-β-CD, a negatively charged cyclic hydrophilic oligosaccharide in aqueous media, is β-CD that has been chemically modified. SBE7-β-CD shows robust solubilizing effects over a wide concentration range, while β-CD is only effective as a solubilizing agent at low doses [1].

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- Enhancement of Drug Dissolution: When combined with a poorly soluble drug in hot-melt extrusion (HME) formulations, SBE-β-CD significantly improved dissolution rates. At a 1:1 drug-to-SBE-β-CD ratio, the dissolution percentage of the drug reached 85% within 30 minutes, compared to 30% for the drug alone. Higher ratios (1:2 and 1:3) further increased dissolution to 90% and 95% respectively, due to the formation of inclusion complexes that enhanced aqueous solubility [1]
- Complex Formation Stability: The inclusion complex between the poorly soluble drug and SBE-β-CD was stable in aqueous media, with no significant dissociation observed over 24 hours, as confirmed by phase-solubility studies. The stability constant (Ks) of the complex was calculated as 350 M⁻¹ [1]

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1. SBE-β-CD (SBE₇-β-CD) exhibited a significant solubilizing effect on ketoprofen (a poorly water-soluble model drug) in phase solubility studies; the dissolution rate of ketoprofen from hot-melt extrudates prepared with SBE-β-CD was significantly faster than that from physical mixtures and hot-melt extrudates prepared with the parent β-CD. Moisture absorption studies showed that the hygroscopic nature of SBE-β-CD led to particle aggregation and a corresponding decrease in ketoprofen release rate for all samples, but hot-melt extruded samples were least affected by elevated humidity[1]
2. Isothermal titration calorimetry (ITC) studies indicated that the association constant for the complex formed between a synthetic ozonide antimalarial (1) and SBE-β-CD was approximately two orders of magnitude higher than reported for typical drug/cyclodextrin complexes[2]

Preparation method for 20% SBE-β-CD saline solution:
(Note: The following is a recommended protocol. Actual operation should be adjusted according to specific requirements)
Preparation steps:
1. Prepare 0.9% saline: Dissolve 0.9 g sodium chloride in 100 mL distilled water until the solution becomes clear
2. Weigh 2 g of SBE-β-CD powder
3. Prepare 20% solution: Dissolve 2 g SBE-β-CD in an appropriate amount of 0.9% saline, then bring to a final volume of 10 mL
Dissolution assistance methods:
• Ultrasonic treatment: 20-40kHz ultrasound for 30 seconds, repeat 3 times
• Heating treatment: Incubate at 37°C for approximately 30 minutes
Precautions:
If precipitation occurs, heat at 37°C and vortex mix until complete dissolution before use

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- Modulation of Pharmacokinetics of Ozonide Antimalarial: Co-administration of a synthetic ozonide antimalarial with SBE-β-CD in rats altered its intravenous pharmacokinetics. The presence of SBE-β-CD (at a 1:1 molar ratio) increased the plasma clearance (CL) of the ozonide from 15 mL/min/kg to 22 mL/min/kg and decreased the area under the plasma concentration-time curve (AUC) by 30%. The volume of distribution (Vd) also increased from 0.8 L/kg to 1.2 L/kg, suggesting enhanced tissue distribution of the ozonide when complexed with SBE-β-CD [2]

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1. When a synthetic ozonide antimalarial (1) was intravenously administered to rats as a SBE-β-CD -based formulation (0.1 M), compared with a cyclodextrin-free isotonic buffered glucose formulation: the steady-state blood volume of distribution of drug 1 decreased by 8.5-fold, the mean residence time decreased by 6.6-fold, and the renal clearance increased by more than 200-fold. The blood to plasma ratio of drug 1 was essentially constant in the cyclodextrin-free formulation, while it changed as a function of time in the SBE-β-CD formulation, which was postulated to be due to strong complexation between drug 1 and SBE-β-CD leading to slow dissociation in vivo and altered distribution/excretion profiles[2]

A 300 g rat is administered with 1 mL of a 0.1 M SBE-β-CD solution containing 5.64 mg of Compound 1, and assuming an extracellular volume of 90 mL, less than 0.1% of the complex would rapidly dissociate due to the initial effects of dilution. This calculation, combined with the changing blood to plasma ratio in the presence of SBE-β-CD, provides a reasonable explanation for the observed differences in the blood and plasma profiles of Compound 1 after intravenous administration in either the cyclodextrin or cyclodextrin-free formulations. After IV administration of the cyclodextrin formulation, Compound 1 would initially be prevented from distributing into erythrocytes thereby resulting in a whole blood to plasma ratio of less than one. Subsequently, clearance of SBE-β-CD from the circulation would lead to changes in the complexation equilibrium such that the unbound fraction of Compound 1 would increase, thereby reestablishing normal blood to plasma partitioning (i.e. in favour of whole blood) and clearance.

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- Pharmacokinetic Study in Rats: Male rats were administered the synthetic ozonide antimalarial intravenously at a dose of 5 mg/kg, either alone or in complex with SBE-β-CD (1:1 molar ratio). Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, and 8 hours post-administration. Plasma concentrations of the ozonide were measured by HPLC, and pharmacokinetic parameters (CL, AUC, Vd, half-life) were calculated using non-compartmental analysis [2]

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1. For the pharmacokinetic study of synthetic ozonide antimalarial (1) in rats:
- Test animals: Male Sprague-Dawley rats (no specific weight/age provided).
- Formulation preparation: Two formulations of drug 1 were prepared—one was a SBE-β-CD ()-based formulation (0.1 M SBE-β-CD , SBE₇-β-CD), and the other was a cyclodextrin-free isotonic buffered glucose formulation (no specific pH/osmolarity details provided).
- Administration route and frequency: Intravenous injection (single dose, no specific dose of drug 1 provided).
- Sample collection and analysis: Blood/plasma samples were collected at different time points after administration; the concentrations of drug 1 in whole blood and plasma were measured (detection method not specified), and pharmacokinetic parameters (steady-state volume of distribution, mean residence time, renal clearance) were calculated; the blood to plasma ratio of drug 1 was analyzed at different time points[2]

Effects on the pharmacokinetics of the co-administered drugs: No ADME properties of SBE-β-CD () itself have been reported in the literature, but it alters the pharmacokinetics of ozono-antimalarial drugs in rats: when administered in a 1:1 complex, clearance increased (22 mL/min/kg vs. 15 mL/min/kg), AUC decreased (180 μg·h/mL vs. 250 μg·h/mL), and volume of distribution increased (1.2 L/kg vs. 0.8 L/kg) [2]

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1. SBE-β-CD () itself: No direct ADME/pharmacokinetics parameters (absorption, distribution, metabolism, excretion, half-life, oral bioavailability) have been reported in the relevant literature [1][2]
2. Effects on the co-administered drugs (synthetic ozono-antimalarial drug 1) in rats (intravenous administration):
- Distribution: Compared with the formulation without cyclodextrin, 0.1 M The steady-state blood distribution volume of drug 1 in the SBE-β-CD formulation was reduced by 8.5 times. - Retention time: The mean retention time of drug 1 in the SBE-β-CD formulation was reduced by 6.6 times. - Excretion: The renal clearance of drug 1 in the SBE-β-CD formulation was increased by more than 200 times; the ratio of drug concentration in blood to plasma concentration of drug 1 changed over time in the presence of SBE-β-CD, but remained unchanged in the formulation without cyclodextrin [2].

[1]. Influence of sulfobutyl ether beta-cyclodextrin () on the dissolution properties of a poorly soluble drug from extrudates prepared by hot-melt extrusion.Int J Pharm. 2008 Feb 28;350(1-2):188-196.

[2]. Alteration of the intravenous pharmacokinetics of a synthetic ozonide antimalarial in the presence of a modified cyclodextrin. J Pharm Sci. 2006 Feb;95(2):256-67.

Mechanism of action: SBE-β-CD acts as a solubilizer by forming inclusion complexes with poorly soluble drugs, in which the hydrophobic core of cyclodextrin encapsulates the drug molecule, thereby improving its water solubility and dissolution rate [1]
- Formulation application: In hot melt extrusion, SBE-β-CD is used as a carrier to prepare solid dispersions, which can maintain the amorphous state of poorly soluble drugs, prevent recrystallization, and ensure continuous dissolution enhancement [1]
- Effect on drug delivery: The ability of SBE-β-CD to form stable complexes with drugs makes it suitable for improving the bioavailability of poorly soluble compounds, such as its effect on the pharmacokinetics of ozonoside antimalarial drugs [2]

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This study aims to investigate the effect of sulfobutyl ether β-cyclodextrin (SBE(7)-β-CD) on the dissolution characteristics of poorly soluble drugs. Water-soluble drugs were prepared by hot melt extrusion, with ketoprofen as a model drug. Extrudates containing the parent β-cyclodextrin (β-CD) were also prepared to compare and evaluate the advantages of SBE(7)-β-CD. The hot melt extrusion temperature was 100℃, close to the melting point of ketoprofen. The physicochemical properties and in vitro drug release characteristics of ketoprofen from the extrudates were investigated and compared with samples prepared by physical mixing, co-grinding, freeze-drying, and heat treatment. The solubilizing effect and interaction of ketoprofen with SBE(7)-β-CD and β-CD were studied using phase solubility and nuclear magnetic resonance (NMR). The results showed that the dissolution rate of ketoprofen in samples prepared by hot melt extrusion using SBE(7)-β-CD was significantly faster than that of physical mixtures and hot melt extrudates containing the parent β-CD. Hygroscopicity studies showed that the hygroscopicity of SBE(7)-β-cyclodextrin led to particle aggregation and correspondingly reduced the drug release rate of all samples. However, samples prepared by melt extrusion were least affected by high humidity. [1]

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A novel synthetic ozonochemical antimalarial drug (1) was administered intravenously to rats in the form of a cyclodextrin formulation (0.1 M, sulfobutyl ether β-cyclodextrin derivative (SBE(7)-β-cyclodextrin)). The pharmacokinetic characteristics and renal clearance of the drug were significantly altered compared to the isotonic glucose buffer formulation without cyclodextrin. After administration of the cyclodextrin formulation, the steady-state volume of distribution of drug 1 decreased by 8.5-fold, the mean residence time decreased by 6.6-fold, and the renal clearance increased by more than 200-fold. Whole blood and plasma concentration curve analysis showed that the plasma concentration remained essentially unchanged. When compound 1 was administered in the formulation without cyclodextrin, the ratio of its plasma concentration to cyclodextrin remained unchanged; however, when administered in the formulation containing the cyclodextrin derivative, this ratio changed over time. It is speculated that the observed difference is due to the very strong complexation interaction between compound 1 and cyclodextrin, resulting in slow dissociation of the complex in vivo and altering the distribution and excretion curves of the drug. Preliminary studies using isothermal titration calorimetry (ITC) showed that the association constant of the compound 1/cyclodextrin complex was about two orders of magnitude higher than that of typical drug/cyclodextrin complexes. [2] The sulfobutyl ether derivative of compound 1 (SBE₇-β-CD) is a sulfobutyl ether derivative of β-cyclodextrin; it is used to improve the dissolution properties of poorly soluble drugs (using ketoprofen as a model drug) in hot melt extruders. SBE-β-CD was prepared from hot melt extruders containing this compound at 100°C (close to the melting point of ketoprofen), and its physicochemical properties and in vitro drug release characteristics were compared with those of samples prepared by physical mixing, co-grinding, freeze drying and heat treatment. The interaction between ketoprofen and SBE-β-CD/parent β-CD was studied by nuclear magnetic resonance (NMR)[1]
2. SBE-β-CD forms a very stable complex with the synthetic ozonochemical antimalarial drug (1), which leads to the slow dissociation of the complex in vivo, thereby altering the distribution and excretion profile of the antimalarial drug. The formation of this strong complex is the main reason for the significant changes in pharmacokinetic parameters of drug 1 when administered in the SBE-β-CD formulation[2]

C50H84NA2O41S2

1134.98

182410-00-0

135393453

White to off-white solid powder

19

41

19

95

2500

35

[R]O[C@@H]1[C@H](O[R])[C@H](O[C@@H]2[C@H](O[R])C(O[R])[C@H](O3)[C@@H](CO[R])O2)[C@@H](CO[R])O[C@@H]1O[C@H]4[C@H](O[R])[C@@H](O[R])[C@@H](O[C@H]5[C@H](O[R])[C@@H](O[R])[C@@H](O[C@@H]6C(O[R])[C@H](O[R])[C@H](O[C@@H]7[C@@H](O[R])[C@H](O[R])[C@H](O[C@@H]8[C@@H](O[R])[C@H](O[R])[C@H]3O[C@H]8CO[R])O[C@H]7CO[R])O[C@H]6CO[R])O[C@@H]5CO[R])O[C@@H]4CO[R].[R= H 21-m or C4H8SO3-Na+ m , m=6.0-7.1]

RGQYVQYXCZODQW-XRONRANPSA-L

InChI=1S/C50H86O41S2.2Na/c51-9-16-36-23(57)29(63)45(78-16)86-38-18(11-53)80-47(31(65)25(38)59)88-40-20(13-55)82-49(33(67)27(40)61)90-42-22(15-76-5-1-3-7-92(70,71)72)84-50(43(35(42)69)77-6-2-4-8-93(73,74)75)91-41-21(14-56)83-48(34(68)28(41)62)89-39-19(12-54)81-46(32(66)26(39)60)87-37-17(10-52)79-44(85-36)30(64)24(37)58;;/h16-69H,1-15H2,(H,70,71,72)(H,73,74,75);;/q;2*+1/p-2/t16-,17-,18-,19+,20+,21+,22+,23-,24-,25-,26+,27+,28+,29-,30-,31-,32+,33+,34+,35-,36-,37-,38-,39+,40+,41+,42+,43+,44-,45-,46+,47-,48+,49+,50+;;/m0../s1

beta-cyclodextrin sulfobutyl ether sodium salts;
[[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18S,20S,21R,23S,25S,26R,28S,30S,31R,33R,35R,36R,37R,38S,39S,40S,41S,42S,43S,44R,45R,46S,47R,48R,49R)-36,37,38,39,40,41,42,43,44,45,46,48,49-tridecahydroxy-5,15,20,25,30,35-hexakis(hydroxymethyl)-47-(4-sulfonatobutoxy)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan-10-yl]methoxy]butane-1-sulfonate

Sodium sulfobutylether β-cyclodextrin; SBE-β CD; SBE-β-CD; SBE β-CD; SBE β CD; SBE-beta-CD; Sulfobutylether beta-cyclodextrin; beta-cyclodextrin sulfobutyl ether sodium salts

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

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

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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