Enhances latent solvents
At present, more than 70% of drugs are limited in their use in entity screening due to their low solubility, which can also lead to unstable drug absorption, low bioavailability, and damage to experimental cells or animals.
1-2]。In order to improve the solubility of poorly soluble drugs, researchers have taken various measures, such as:Ultrasound, heating, adjusting the pH of the solution, changing the particle size of the drug, making the drug in salt form, using surfactants, using co-solvents, etc
Among them,The use of solubilizers, co-solvents and latent solvents has become an indispensable tool to increase the solubility of poorly soluble drugs。But everyone often wonders, solubilization, dissolution, and latent dissolution, the names of these three are the same as "triplets", what is the difference?Don't worry, little m is here to take you a**!
Solubilization refers to the method of adding surfactants to poorly soluble drug solutions to increase their solubility. Among them, the added surfactant is calledSolubilizer。thePrincipleIt is the surfactant that forms micelles in water, so that the poorly soluble drug is encapsulated or adsorbed, thereby increasing the amount of dissolution. Commonly used solubilizers mainly include:PolysorbatesPolyoxyethylene fatty acid estersetc. [6].
Co-solubilization refers to the method of adding a third substance to a poorly soluble drug solution to increase its solubility. Of these, the third substance added is calledCo-solvents, which is generally a low-molecular-weight compound. thePrincipleIt is mainly the formation of water-soluble complexes, associations or complex salts between drugs and small molecule substances. Commonly used co-solvents mainly include:Some organic acids and their sodium salts, amides or amine compoundsetc. [6].
Latent solubility means that when each solvent in the mixed solvent is in a certain proportion, the solubility ratio of the drug is significantly increased in each single solvent. The mixed solvent is calledLatent solvents。thePrincipleIt is the principle of using mixed solvents, according to the principle that different solvents have special affinity for the different structures of drug molecules, so that the drug can reach the maximum solubility at a certain ratio. Commonly used latent solvents mainly include:Ethanol, propylene glycol, glycerinWait.
7]。Table 1Proportion of solvent administration in animal experiments[8].
To put it simply,Solubilizers are some surfactants that have a solubilizing effectCo-solvents are the third substance added to poorly soluble drugs and solvents, which is generally a low-molecular-weight compound. Latent solvents are mixtures of two solvents.
How's that, have you figured it out?
How to choose and use the right latent enhancer?
Select solvents that significantly increase the solubility of the drug without affecting the drug's effectiveness Choose solvents that are less toxic and do not cause damage to the subject.
Choose a solvent that can be stabilized during sterilization or long-term storage (co-solvent can be stored for a long time when the co-solvent is used as a single solvent, but it is recommended to use it in the final solution system).
Whenever possible, choose a solubility that dissolves the poorly soluble drug at a lower concentration.
The optimal concentration can be filtered out when used.
Make sure that the drug dissolves completely or dissolves into a homogeneous suspension when used.
Use the correct order in which you add them.
The correct order of addition: e.g. 10% DMSO + 40% PEG300 + 5% TWEEN 80 + 45% SALINE, where the percentage refers to the proportion of each solvent in the final dissolved system. Assuming that the final dosing system is 200 L, 10X of DMSO stock solution is prepared first, 20 L of DMSO is taken, then 80 L of PEG300, 10 L of Tween 80, and finally 90 L of SALINE is added. Case Analysis
MCE Solubilizer Co-solvent Latent solvent series products are diverse and completeAccording to the incomplete statistics of Xiao M, our solubilizer, co-solvent and latent solvent products have helped publish 260+, with a cumulative impact factor of 2,600+. Among them, there are also a number of studies in other high-scoring journals including Nature, Cell, Cell Res, Cancer Cell, etc. 
Without further ado, let's go straight to the case!
Customer Verification 1
Kazuhiro Koikawa et al. tested the effects of a proline isomerase pin1 inhibitor (pin1i-2, sulfopin) with PD1, paclitaxel (PTX), and anti-CTLA4 (CTLA4) alone and in combination, and found that PIN1I-2 alone inhibited tumor growth, and PD1 + PIN1I-2 combination significantly enhanced the inhibitory effect, CTLA4+ PIN1I-2 There is a slight potentiating inhibitory effect, while Pin1I-2 does not enhance the anti-tumor activity of PTX.
Figure 1Effects of drugs alone or in combination on tumor cells
in vivo：ptx (10mg/kg i.p., weekly) or vehicle (ptx diluted solution; 10% dmso,40% peg300, 5% tween 80, 45% saline
Publications from MCE clients:cell. 2021 sep 2;184(18):4753-4771.e27.
Customer Verification 2
Traumatic colon injury (TCI) is a common disease, and prolonging survival after trauma is an effective way to improve patient outcomes. Bo Cao et al. found that supplementation with specific deficient metabolites may restore intestinal homeostasis and prolong the survival time of TCI rats, and identified four metabolites studied by screening: ASN, LactoSe, IAA, and IPA, and gave four metabolites orally to TCI rats, respectively, and found that ASN and IPA were effective in prolonging the survival time of TCI rats, while Lactose and IAA reduced the survival rate of rats.
Figure 2Schematic diagram of the experimental procedure for four metabolite-treated TCI ratsin vivo：the vehicle was 15%cremophor el(medchemexpress, nj, usa) and 85% sterile water.
Publications from MCE clients:mil med res. 2022 jul 6;9(1):37.
Customer Verification 3
To validate the possible role of the TLR4 signaling pathway in coronavirus-induced fatal infection. Qirui Guo et al. treated mice infected with SARS-CoV-2 and MHV with the TLR4 signaling pathway inhibitor Resatorvid and found that the proportion of aberrant neutrophils in coronavirus-infected mice was significantly reduced after treatment with Restatvid.
Figure 3Flow cytometry analysis of neutrophils in mouse lung, blood, and bone marrowin vivo：the control group mice were givenintraperitoneally 200 μl of corn oil solution which contained 20 μl of dmso
Publications from MCE clients:cell host microbe. 2021 feb 10;29(2):222-235.e4.
Summary
In this issue, Xiao M solves the problem of "insoluble administration" in drug screening. The solubility of poorly soluble drugs can be increased by using solubilizers, co-solvents and latent solvents, and the relevant definitions and how to choose and use them are introduced, and through case analysis, we will have a further understanding of its use
References
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2] goke k, lorenz t, repanas a, et al. novel strategies for the formulation and processing of poorly water-soluble drugs [j]. eur j pharm biopharm, 2018, 126: 40-56.
3] madgulkar a, bandivadekar m, shid t, e al. sugars as solid dispersion carrier to improve solubility and dissolution of the bcs class il drug: clotrimazole [j].drug dev ind pharm, 2016, 42 (1): 28-38.
4] poovi g, damodharan n. lipid nanoparticles: a challenging approach for oral delivery of bcs class- ⅱdrugs [j]. futur j pharm sci, 2018, 4(2): 191-205.
5] choudhary a n, nayal, s. a review: hydrotropy a solubility enhancing technique [j]. pharma innov, 2019.8(4): 1149-1153.
6] he m, et al. molecular dynamics simulation of drug solubilization beh**ior in surfactant and cosolvent injections. pharmaceutics. 2022;14(11):2366.
7] Lin Ruilai. Methods for improving the solubility of poorly soluble drugs[J].China Medical Guide South,2010,8(03):32-33
8] li p, et al. developing early formulations: practice and perspective. int j pharm. 2007;341(1-2):1-19.
9] koikawa k, kibe s, suizu f, et al. targeting pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy. cell. 2021 sep 2;184(18):4753-4771.e27.
10] cao b, zhao ry, li hh, xu xm, cui h, deng h, chen l, wei b. oral administration of asparagine and 3-indolepropionic acid prolongs survival time of rats with traumatic colon injury. mil med res. 2022 jul 6;9(1):37.
11] guo q, zhao y, li j, et al. induction of alarmin s100a8/a9 mediates activation of aberrant neutrophils in the pathogenesis of covid-19. cell host microbe. 2021 feb 10;29(2):222-235.e4.