Original Article

Preferential Solvation of Cyclosporin in Aqueous Mixtures of Some Polymeric Cosolvents

Introduction

Cyclosporin (condensed formula C₆₂H₁₁₁N₁₁O₁₂, molar mass 1202.64 g·mol⁻¹, CAS Number: 59865-13-3, PubChem CID 5284373, molecular structure shown in Figure 1), is a lipophilic cyclic polypeptide of 11 amino acids produced by the fungus Beauveria nivea, also known asTolypocladium inflatum, is an immunosuppressant drug which binds with high affinity to an immunophilin termed cyclophilin. The complex cyclosporin-cyclophilin specifically inhibits calcineurin, a calcium- and calmodulin-dependent phosphatase distributed in all cellular compartments. The blockage of calcineurin prevents signal transduction of the nuclear factor of activated T-cells (NF-AT) which impairs gene transcription of interleukin (IL)-4 and CD40 ligand necessary for B-cell activation and those required for T-cell activation including IL-2 and interferon gamma. In this way, cyclosporin inhibits the first phase of T-cell activation leading to a reduced proliferation of T helper lymphocytes. It is also known that cyclosporin inhibits CD4 + CD25 + regulatory T cells, which may obstruct the ability for host immune tolerance.^1-3

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Figure 1.

Molecular structure of cyclosporin

Figure 1.

Molecular structure of cyclosporin

Cyclosporin is used for the prophylaxis of transplant rejection, or in the treatment of graft rejection in patients previously treated with other immunosuppressants. It is also used in severe forms of immune diseases as uveitis, atopic dermatitis, psoriasis, amyotrophic lateral sclerosis, inflammatory bowel disease or rheumatoid arthritis when conventional therapy is ineffective or inappropriate. It is also useful in nephrotic syndrome and in other autoimmune component diseases like aplastic anemia, asthma, Behçet’s syndrome, chronic active hepatitis, multiple sclerosis, myasthenia gravis, polymyositis, and Kawasaki disease.^4-6 Moreover, recently this drug was investigated for the treatment of COVID-19.⁷

From a solid-conglomerate point of view this drug is hydrophobic and the absorption can be affected by first-pass metabolism, mode of administration, formulation, and drug interactions. Its oral bioavailability ranges from 30% to 90% and exhibits a 95% lipoprotein bounding. Cyclosporin acts as a substrate and inhibitor of P-glycoprotein and it is metabolized by the CYP3A enzyme system in the liver, the gastrointestinal tract and kidney. Therefore, when cyclosporin is administered with inhibitors of both CYP3A4 and P-glycoprotein its bioavailability is improved leading to increased cyclosporin concentrations. In patients with normal hepatic function, the average half-life ranges from 16 to 27 hours, but can vary from 10-40 hours.^3,8

Cyclosporin is available in several formulations: as an oral solution (100 mg/mL) or liquid-filled capsules (strength 25-50 and 100 mg); as an ophthalmic emulsion (strength 0.05%) and ophthalmic solution (strength 0.09% and 0.1%), and as a sterile solution (50 mg/mL) that must be diluted in 0.9% sodium chloride or 5% dextrose for intravenous slow infusion. The commercially available oral formulations of cyclosporin differ in their bioavailability, and patients should not be transferred from one to another without appropriate monitoring.³

The dosage and routes of administration depend on the indication. Intravenous route is preferred for kidney transplant reject prophylaxis, for treatment of graft-versus-host disease, acute severe ulcerative colitis, and Kawasaki disease. The oral route is used for other solid organ transplant reject prophylaxis and immune diseases. The ophthalmic route is used only for uveitis and keratoconjunctivitis.^4,5

Adverse effects of cyclosporin are many and involves multiple vital organs. The most common is nephrotoxicity due to intense renal vasoconstriction, which reduces glomerular filtration rate. Hypertension and arrhythmia are also frequent. Metabolic and endocrinological adverse effects include hypertrichosis, hypomagnesaemia, hyperkalemia, dyslipidemia and gynecomastia. As cyclosporin may cause immunosuppression, patients are at increased risk of developing bacterial, viral, fungal, and protozoal infections. To reduce the most important adverse effects, monitoring serum levels of cyclosporin is mandatory. It is also important to check serum creatinine/BUN, serum bilirubin and serum electrolytes.^4,5

Owing the low solubility of cyclosporin in neat water, for improving its apparent solubility several procedures have been proposed in the literature, as follows: solubilization with d-alphatocopheryl-polyethylene-glycol-1000 succinate⁹; solubilization by cosolvency with ethanol, propylene glycol, polyethylene glycol (PEG 400), glycofurol and glycerin, micellization with cremophor, tween 80 and tween 20, and complexation with α-cyclodextrin and hydroxypropyl β-cyclodextrin¹⁰; micellization with sodium cholate/lecithin-mixed micelles;¹¹ complexation with mixed α-cyclodextrin and hydroxypropyl-β-cyclodextrin,¹² liposomes and other heterogeneous systems¹³; self-microemulsifying systems¹⁴; polymeric nanospheres¹⁵; microspheres based on αβ-cyclodextrins polymers¹⁶; microfiber obtained by electrospinning¹⁷; liposomes and other colloidal systems¹⁸; and drug-loaded nanofibers.¹⁹ In particular, dosage forms intended for ophthalmic administration has specially studied.^20-22

Regarding molecular dispersion-solubility studies of cyclosporin in water the investigations by Ismailos et al²³ and Molpeceres et al²⁴ demonstrated some non-common behaviors involving drug solubility diminishing with temperature-arising. More recently, Berton et al reported the cyclosporin solubility in six ionic liquids at 25 and 100 °C;²⁵ whereas, Ha et al reported the solubility of this drug at 25.0 °C in 20 mono-solvents, namely, acetone, acetonitrile, 1-butanol, chloroform, diethylene glycol monoethyl ether (DEGME), dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, ethanol, glycerol, methanol, N-methyl-2-pyrrolidone, 1-propanol, 2-propanol, propylene glycol, PEG 200, PEG 300, PEG 400, tetrahydrofuran, and water, as well as in some aqueous-polymeric cosolvent mixtures.²⁶

As indicated above the physicochemical information about cyclosporin dispersed at molecular level in multi-component solvent systems is not complete as required for optimum liquid pharmaceutical dosage forms design. From practical and theoretical points of view, the drug behavior in binary or ternary cosolvent mixtures is frequently studied for improving substances purification and pharmaceutical preformulation stages.^27-30

Owing the low solubility of cyclosporin in neat water, some binary aqueous cosolvent mixtures, involving the following polymeric cosolvents: DEGME (also known as carbitol and transcutol), PEG 200, PEG 300 and PEG 400 have been studied to increase its solubility.²⁶ It is important to note that DEGME, PEG 200 and PEG 400 are common polymeric cosolvents used for several liquid medicines including injectable products.^31,32 For this reason, the main purposes of this communication were evaluation the effect of mixtures polarity on cyclosporine solubility as well as reporting the preferential solvation of cyclosporin by cosolvents and water in some {polymeric cosolvent + water} mixtures at 298.15 K based on literature solubility values and some thermodynamic properties by means of the inverse Kirkwood-Buff integrals (IKBI).^33-35 The results are expressed in terms of changing the preferential solvation parameter (δx_1,3) of cyclosporin (compound 3) by the respective cosolvent (component 1, i.e. polymeric cosolvent DEGME, PEG 200 or PEG 400) regarding the mixtures composition.

Methods and Computation

Physicochemical properties of cyclosporin dissolutions, involving cosolvency effects and preferential solvation, were calculated as reported earlier in the literature for other organic compounds in similar solvent mixtures as shown below.^36,37 All computations were performed with MS Excel® and Table Curve 2D v.5.01.

Results and Discussion

Effect of polarity on the cyclosporin solubility in aqueous mixtures

Mole fraction solubility of cyclosporin in aqueous binary mixtures of polymeric cosolvents is reported in the research article written by Ha et al.²⁶ Thus, Figure 2 allows the comparison of mole fraction solubilities of this drug in the aqueous mixtures of polymeric cosolvents DEGME, PEG 200 and PEG 400 as function of the Hildebrand solubility parameter of the mixtures free of drug (δ_1 + 2/MPa^1/2) at 298.15 K. It is noteworthy that δ_1 + 2 values were calculated assuming additive behavior as shown in Eq. (1).^27-29 Solubility parameters of DEGME, PEG 200, PEG 400 and water are 22.3, 21.6, 24.3 and 47.8 MPa^1/2, respectively.^38,39

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Figure 2.

Logarithmic mole fraction solubility of cyclosporin as function of the Hildebrand solubility parameter in some aqueous-polymeric cosolvent mixtures at T= 298.15 K. ○: DEGME (1) + water (2); □: PEG 200 (1) + water (2); Δ: PEG 400 (1) + water (2)

Figure 2.

Logarithmic mole fraction solubility of cyclosporin as function of the Hildebrand solubility parameter in some aqueous-polymeric cosolvent mixtures at T= 298.15 K. ○: DEGME (1) + water (2); □: PEG 200 (1) + water (2); Δ: PEG 400 (1) + water (2)

As observed in all cases, the maximum solubility is observed in pure polymeric cosolvents. Moreover, cyclosporin solubility is similar in DEGME and PEG 200 mixtures and lower in aqueous-PEG 400 mixtures.

Table 1 summarizes the apparent Gibbs energies of dissolution at 298.15 K calculated by using Eq. (2).⁴⁰ As observed all ∆_solnG° are positive and diminish with the polymeric cosolvent proportion, regardless the cosolvent that demonstrates the cyclosporin preference by semi-polar media.

Preferential solvation of cyclosporin by mixtures components

The preferential solvation parameters of cyclosporin (identified here as compound 3) by polymeric cosolvent molecules, namely, DEGME, PEG 200 or PEG 400 (identified here as compound 1) molecules in the different {polymeric cosolvent (1) + water (2)} mixtures (δx_1,3), are defined as^33-35:

where

The preferential solvation of cyclosporin (3) in the {polymeric cosolvent (1) + water (2)} mixture depends not only on the interactions of cyclosporin with polymeric solvent (1) and with water (2) but also on the mutual interactions of the two solvents as described by the molar excess Gibbs energy of their mixing in the absence of cyclosporin (3) (

with,

Here, κ_T denotes the isothermal compressibility of the (1 + 2) aqueous-polymeric cosolvent mixtures.

To obtain definitive V_cor values some iteration processes were performed because they depend on the local mole fractions of polymeric cosolvent (1) and water (2) around the cyclosporin (2) molecules in the respective solutions. Thus, these iteration processes were performed by replacing δx_1,3 and V_cor in equations (3), (4) and (7) to recalculate the

Table 2 and Figure 3 shows the apparent Gibbs energies of transfer of cyclosporin (3) from neat water (2) to all aqueous-polymeric cosolvent (1 + 2) mixtures (

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Figure 3.

Gibbs energy of transfer of cyclosporin (3) from neat water (2) to some {polymeric solvent (1) + water (2)} mixtures at T= 298.15 K. ○: DEGME (1) + water (2); □: PEG 200 (1) + water (2); ∆: PEG 400 (1) + water (2)

Figure 3.

Gibbs energy of transfer of cyclosporin (3) from neat water (2) to some {polymeric solvent (1) + water (2)} mixtures at T= 298.15 K. ○: DEGME (1) + water (2); □: PEG 200 (1) + water (2); ∆: PEG 400 (1) + water (2)

It is important to keep in mind that cyclosporin–cyclosporin interactions may be disregarded and thus the cyclosporin (3) molecules are surrounded by polymeric cosolvent (1) and water (2) molecules only. Otherwise, activity coefficients of cyclosporin at each cosolvent mixture composition need to be employed. Another requirement for the application of Eq. (11) is that no crystal solvates are formed by cyclosporin, which means that the conglomerate identity of the cyclosporin solid form at equilibrium with the saturated solutions is independent of the cosolvent mixtures composition.

Obtained

The D values summarized in Table 3 were calculated as the first derivative of Eq. (12) solved in mixtures composition steps of x₁ = 0.05. For the studied aqueous-polymeric cosolvent mixtures, the Q, RT·κ_T,

Figure 4 shows a non-linear variation of cyclosporin δx_1,3 values regarding the polymeric cosolvent-proportion in the solvent mixtures as expressed by the mole fraction of every polymeric cosolvent before solute adding. Initially, the addition of DEGME to neat water as solvent makes negative the δx_1,3 values of cyclosporin in the composition interval of 0.00 < x₁ < 0.12. The maximum negative δx_1,3 value is obtained in the mixture of x₁ = 0.05 with δx_1,3 = –1.28 × 10^–2, being its absolute value slightly higher than 1.0 × 10^–2. As indicated above, δx_1,3 values over 1.0 × 10^–2 are considered as consequence of real preferential solvation effects.^49,50 Otherwise, in the case of aqueous-PEG 200 mixtures a negative δx_1,3 value of –3.3 × 10^–3 is observed which could be a consequence of uncertainties propagation toward IKBI calculations.^49,50 Regarding preferential hydration in observed in the {DEGME (1) + water (2)} cosolvent system, it is probable that the structuring of water molecules by hydrogen-bonding around the methyl and methylene groups of this compound (Figure 1) conducting hydrophobic hydration contributes to lowering of the net δx_1,3 to negative values in these water-rich mixtures.

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Figure 4.

Preferential solvation parameters (δx_1,3) of cyclosporin (3) by polymeric cosolvent in some {polymeric cosolvent (1) + water (2)} mixtures at T= 298.15 K. ○: DEGME (1) + water (2); □: PEG 200 (1) + water (2); ∆: PEG 400 (1) + water (2)

Figure 4.

Preferential solvation parameters (δx_1,3) of cyclosporin (3) by polymeric cosolvent in some {polymeric cosolvent (1) + water (2)} mixtures at T= 298.15 K. ○: DEGME (1) + water (2); □: PEG 200 (1) + water (2); ∆: PEG 400 (1) + water (2)

In the mixtures composition interval of 0.12 < x₁ < 1.00 the local mole fractions of DEGME around cyclosporin molecules are higher than those in the bulk aqueous- DEGME cosolvent mixtures in the absence of this drug. The maximum positive δx_1,3 value is obtained in the mixture of x₁ = 0.25, with δx_1,3 = 6.02 × 10^–2, which is higher than |1.0 × 10^–2|. Hence, it could be considered as a consequence of preferential solvation effects of cyclosporin by DEGME molecules. For PEG 200 and PEG 400 aqueous mixtures δx_1,3 values are positive in almost all the mixtures compositions reaching maximum positive δx_1,3 values in the mixtures of x₁ = 0.50 with δx_1,3 = 8.33 × 10^–2 for PEG 200-aqueous mixtures and x₁ = 0.20 with δx_1,3 = 3.95 × 10^–2 for PEG 400-aqueous mixtures. In these mixtures composition intervals cyclosporin could be acting as a Lewis acid in front of the cosolvent polymeric molecules by means of its hydroxyl and primary amide groups (Figure 1), whose hydrogen atoms would be interacting with the unshared electron pairs of the oxygen atoms of polymeric cosolvent by hydrogen bonding. It is important to keep in mind that polymeric cosolvent exhibit a higher Lewis base behavior compared with water.^42-44

Conclusions

Based on solubility values reported earlier,²⁶ the preferential solvation parameters of cyclosporin in aqueous polymeric cosolvent mixtures were derived by means of the IKBI method at 298.15 K. Thus, this drug in DEGME-aqueous mixtures is preferentially solvated by water in water-rich mixtures but preferentially solvated by DEGME in mixtures of 0.12 < x₁ < 1.00. In this way, it is possible that the preferential hydration in water-rich mixtures is due to hydrophobic hydration around methyl and methylene moieties (Figure 1). Otherwise, in PEG-aqueous mixtures cyclosporin is preferentially solvated by PEG in almost all the mixtures owing the more basic behavior of all these polymeric cosolvents compared with water. However, the specific cyclosporin-cosolvent or cyclosporin-water interactions are not well understood despite the thermodynamic treatment performed here owing the complexity of these ternary mixtures including the high molecular size of this drug.

Acknowledgements

We thank the Department of Pharmacy of the Universidad Nacional de Colombia for for facilitating computational resources.

Competing Interests

No potential conflict of interest was reported by the authors.

Data Availability Statement

All data generated or analyzed during this study are included in this published article.

Ethical Approval

Not applicable.

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