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].

How to prepare 20% SBE-β-CD in Normal Saline? Guidelines (This is our suggested protocol; it should be adjusted to suit your particular requirements; it is merely meant to serve as a guide).
1). A clear 0.9% saline solution can be made by dissolving 0.9 g of NaCl in 100 mL of distilled water.
2). Weigh 2 grams of dry SBE-β-CD.
3). To make 10 mL of a 20% (w/v) solution, dissolve 2 g of SBE-β-CD in 0.9% saline. These might need to be heated (for roughly 30 minutes at 37°C) or sonicated (20–40 kHz, 30 seconds, repeat three times). Before using, dissolve any precipitates that are seen by heating to 37°C and vortexing.

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.

[1]. Influence of sulfobutyl ether beta-cyclodextrin (Captisol) 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.

The aim of this study was to investigate the influence of sulfobutyl ether beta-cyclodextrin (SBE(7)-beta-CD; Captisol on the dissolution properties of a poorly water-soluble drug from extrudates prepared by hot-melt extrusion. Ketoprofen was employed as a model drug. Extrudates containing the parent beta-cyclodextrin (beta-CD) were also produced for comparative evaluation to assess the benefits of SBE(7)-beta-CD. Hot-melt extrudates were produced at 100 degrees C, which was close to the melting point of ketoprofen. The physiochemical properties and the in vitro drug release properties of ketoprofen from extrudates were investigated and compared with samples prepared by physical mixing, co-grinding, freeze-drying and heat-treatment. The solubilizing effects and the interactions of ketoprofen with SBE(7)-beta-CD and beta-CD were investigated using phase solubility and NMR studies, respectively. The dissolution rate of ketoprofen from samples prepared by hot-melt extrusion with SBE(7)-beta-CD was significantly faster than both the physical mixture and the hot-melt extrudates prepared with the parent beta-CD. Moisture absorption studies revealed that the hygroscopic nature of SBE(7)-beta-CD led to particle aggregation and a corresponding decrease in drug release rate for all samples. However, the samples prepared by melt extrusion were least affected by exposure to elevated humidity. [1]

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The pharmacokinetic profile and renal clearance of a novel synthetic ozonide antimalarial (1) was found to be significantly altered when intravenously administered to rats as a cyclodextrin-based formulation (0.1 M Captisol, a sulfobutylether beta-cyclodextrin derivative (SBE(7)-beta-CD)) compared to a cyclodextrin-free isotonic buffered glucose formulation. There was an 8.5-fold decrease in the steady-state blood volume of distribution, a 6.6-fold decrease in the mean residence time and a greater than 200-fold increase in renal clearance of 1 when administered in the cyclodextrin formulation. Analysis of the whole blood and plasma concentration profiles revealed an essentially constant blood to plasma ratio when 1 was administered in the cyclodextrin-free formulation, whereas this ratio changed as a function of time when administered in the presence of the cyclodextrin derivative. It is postulated that the observed differences were due to a very strong complexation interaction between 1 and the cyclodextrin, resulting in a slow dissociation of the complex in vivo, and altered distribution and excretion profiles. Preliminary studies using isothermal titration calorimetry (ITC) indicated that the association constant for the 1/Captisol complex was approximately two orders of magnitude higher than reported for typical drug/cyclodextrin complexes. [2]

C50H84NA2O41S2

1450.372

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; Captisol; 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.)