Design and evaluation of solid self-nanoemulsifying drug delivery systems of cyclosporine developed with a superior adsorbent base

Abstract

Cyclosporine (CYC) is a drug that belongs to the BCS class II category. This study was designed to develop novel solid self-nanoemulsifying drug delivery systems (S-SNEDDS) for cyclosporine (CYC), using chitosan–EDTA microparticles. Such microparticles are known to exhibit superior adsorbent characteristics and were prepared by two different methods viz. spray drying (SD-CHEM) and solvent evaporation (SE-CHEM). Capmul® GMS-50K, Labrafac, and PEG 400 were chosen as the oil, surfactant, and co-surfactant, respectively. The cyclosporine liquid self-nanoemulsifying drug delivery system (CYC-L-SNEDDS) was developed with an optimal oil to S_mix (surfactant:co-surfactant) ratio of 40:60, determined through a pseudo ternary phase diagram. The novel S-SNEDDS were developed by adsorbing CYC-L-SNEDDS onto the chitosan–EDTA microparticles, resulting in CYC-SD-S-SNEDDS and CYC-SE-S-SNEDDS. Both formulations exhibited favorable drug loading, with 81.184 ± 4.191% for CYC-SD-S-SNEDDS and 56.426 ± 5.471% for CYC-SE-S-SNEDDS. XRD and DSC confirmed drug amorphization, while SEM revealed a smooth, well-distributed adsorbate on the adsorbent surfaces, with particle sizes of 5–8 μm for CYC-SD-S-SNEDDS and 10–12 μm for CYC-SE-S-SNEDDS. When tested for stability, the developed formulations exhibited excellent physical and thermodynamic stability. The globule size for CYC-SD-S-SNEDDS was 138.7 ± 4.14 nm, with a PDI of 0.613 ± 0.004, while CYC-SE-S-SNEDDS had a globule size of 166.9 ± 4.04 nm and a PDI of 0.579 ± 0.003. The results of in vitro dissolution studies revealed that there was a fourfold increase in drug dissolution for CYC-SD-S-SNEDDS (80.03%) and CYC-SE-S-SNEDDS (72.26%) when compared to the pure cyclosporine (19.8%). A similar pattern was observed in ex vivo permeation studies where CYC-SD-S-SNEDDS showed 39.34% release and CYC-SE-S-SNEDDS exhibited 28.31% release as compared to CYC-L-SNEDDS (41.46%). Furthermore, CYC-SD-S-SNEDDS outperformed CYC-SE-S-SNEDDS, indicating the superiority of microparticles developed by the spray drying method (SD-CHEM) as adsorbents for solidification. These findings suggest enhanced dissolution and permeation for cyclosporine in S-SNEDDS.

Introduction

Cyclosporine (CYC) was first isolated by Sandoz from the crude extracts of Tolypocladium inflatum gams fungus.1 It is an oligopeptide with 11 amino acids and has a molecular weight of 1202 Da. CYC has immunomodulatory properties and prevents allograft rejection after organ transplants and increases the survival of such patients in the initial and long run. It is also used in autoimmune and inflammatory disorders.2 CYC is a calcineurin inhibitor and selectively suppresses different T-lymphocytes’ functions especially the generation of interleukin-2.3 CYC forms a cyclosporine–cyclophilin complex after binding to cyclophilin and by inhibiting calcineurin phosphatase and T-cell activation, it suppresses immunity.4

CYC is a BCS (biopharmaceutical classification system) class II drug with low hydrophilicity (slightly soluble in water, 0.04 mg g−1)5 and high lipophilicity.6 The extent of bioavailability is significantly influenced by the solubility of the drug in the gastrointestinal tract7 (GIT). When taken orally, it has high variability in bioavailability from 20 to 60%.8 The high difference in interpersonal variation in pharmacokinetic parameters is because CYC distribution gets affected by factors like population, age, nutrients, gender, and administration with other medications.9 Sandimmune® and Neoral® are the two products commercially available for the oral delivery of this medication. They have been incorporated into a self-nanoemulsifying drug delivery system (SNEDDS) known as a “microemulsion”, utilizing either soft or hard capsules. The primary distinction between these two formulations lies in the distribution of particle sizes. The globule sizes in Sandimmune® vary from a few nanometres to several micrometres, whereas Neoral® exhibits a more uniform sized system with globule sizes ranging from 100 to 250 nm.10

SNEDDS exhibit a substantial capability to enhance the oral bioavailability and biological effectiveness of drugs that exhibit poor water solubility.11,12 In addressing the challenge of enzymatic degradation in the gastrointestinal tract during the oral delivery of biomolecules (proteins and peptides), lipid-based systems like SNEDDS have demonstrated efficacy.13 SNEDDS present numerous challenges and difficulties, including physical and chemical instability issues. The liquid form of SNEDDS (L-SNEDDS) presents several challenges, including limitations on manufacturing dosage, limited options for dosage forms, low drug loading capacity, and complex challenges in handling and storage.14,15 The most common technique for encapsulating liquid or semi-solid lipid-based formulations intended for oral administration is filling in capsules. This method is suitable for highly potent drugs and enables a moderately high drug loading, constrained by both the fill weight and the drug’s solubility.16 Nevertheless, capsule technologies come with specific drawbacks, mainly when co-solvents are involved; it is essential to consider the interaction between the shell and the filling. Such factors contribute to a slower manufacturing process and higher costs than other solid dosage forms such as tablets.17

Due to these limitations, researchers and formulators consistently explore diverse methods to solidify the L-SNEDDS, facilitating a solid product’s rapid and straightforward development with the desired properties.18 Solid self-nanoemulsifying drug delivery systems (S-SNEDDS) are established and recognized formulation systems. Common adsorbents are polyvinyl alcohol, sodium CMC, dextrin, β-cyclodextrin, lactose, mannitol, HP-β-CD, maltodextrin, PVP K-30, Aerosil-200, Avicel PH102, Syloid XDP 3150, Neusilin US2, Syloid 244FP and magnesium stearate.19 Some of the common SNEDDS (hard and soft capsules) available in the market are Gengraf® (cyclosporine, AbbVie Inc.), Lipirex® (atorvastatin, Highnoon Laboratories Ltd), Convulex® (sodium valproate, Gerot Lannach UK Limited), Norvir® (ritonavir, AbbVie Inc.), Rocaltrol® (calcitriol, Aphena Pharma Solutions), Sandimmune® (cyclosporine, Novartis Pharmaceuticals Corporation), Neoral® (cyclosporine, Novartis Pharmaceuticals Corporation), Vesanoid® (tretinoin, Roche Laboratories Inc.), Accutane® (isotretinoin, Roche Laboratories Inc.), and Agenerase® (amprenavir, GlaxoSmithKline).

S-SNEDDS provide numerous benefits, including an enhanced surface area (resulting in high solubility and bioavailability), robustness, high stability, scalability, ease of handling, high drug loading, improved flowability, reduced drug precipitation, and cost-effective production20,21 as compared to L-SNEDDS. Therefore, the present research focused on developing an S-SNEDDS of the CYC (with the adsorption technique using superior microparticles developed by spray drying and solvent evaporation) having high solid form characteristics and similar dissolution and permeation profiles of reconstituted nanoemulsions from the S-SNEDDS as compared to L-SNEDDS. This approach will offer a stable S-SNEDDS of CYC that delivers comparable dissolution and permeation profiles to those of L-SNEDDS, but without the limitations associated with the liquid form.

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Materials

Cyclosporine was a gift sample from Panacea Biotec (New Delhi, India) with >95.6% purity. Capmul® GMS-50K (glyceryl monostearate), Caprol® ET (hexaglycerol octasterate), Captex® 200 (propylene glycol dicaprylate), and Captex® 300 (glyceryl tricaprylate/tricaprate) were gift samples from Abitech (USA). Labrafac™ PG (propylene glycol dicaprylocaprate) from Gattefossé (Canada) was also received as a gift sample. Polyethylene glycol 400 (PEG 400) was procured from TCI (India). Propylene glycol and ethylene diamine tetra acetic acid disodium (EDTA disodium) were obtained from CDH (New Delhi, India). Chitosan with 90% deacetylation (DA) was acquired from Marine Hydrocolloids (Kerala, India). Cremophor® RH-40 (polyoxyl 40 hydrogenated castor oil) was procured from HiMedia (Mumbai, India). Lipoxol 300 (PEG 300) was obtained from Sasol Chemicals (Texas, USA). Apart from those specifically mentioned, analytical-grade chemicals were used for the study. They were used as received.

Mohit Kumar, Pooja A. Chawla, Abdul Faruka and Viney Chawlab, Design and evaluation of solid self-nanoemulsifying drug delivery systems of cyclosporine developed with a superior adsorbent base, Received 9th July 2024 , Accepted 26th November 2024, First published on 11th December 2024, DOI: 10.1039/D4PM00198B (Paper) RSC Pharm., 2025, Advance Article

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