Elsevier

Journal of Controlled Release

Volume 225, 10 March 2016, Pages 269-282
Journal of Controlled Release

Review article
Reformulating cyclosporine A (CsA): More than just a life cycle management strategy

https://doi.org/10.1016/j.jconrel.2016.01.056Get rights and content

Abstract

Cyclosporine A (CsA) is a well-known immunosuppressive agent that gained considerable importance in transplant medicine in the late 1970s due to its selective and reversible inhibition of T-lymphocytes. While CsA has been widely used to prevent graft rejection in patients undergoing organ transplant it was also used to treat several systemic and local autoimmune disorders. Currently, the neuro- and cardio-protective effects of CsA (CiCloMulsion®; NeuroSTAT®) are being tested in phase II and III trials respectively and NeuroSTAT® received orphan drug status from US FDA and Europe in 2010. The reformulation strategies focused on developing Cremophor® EL free formulations and address variable bioavailability and toxicity issues of CsA. This review is an attempt to highlight the progress made so far and the room available for further improvements to realize the maximum benefits of CsA.

Introduction

Cyclosporine A (CsA) is a well-known immunosuppressive agent that has played a very important role in transplant medicine since the late 1970s. At that time, the fact that it was found to produce selective and reversible inhibition of T-lymphocytes while causing low cytotoxicity won worldwide recognition of CsA as a promising agent in immune therapy. This compound was first isolated from the fungal extract of Tolypocladium inflatum in 1973 but its immunosuppressive activity was discovered later by Borel in 1976. After promising outcomes regarding graft survival after renal transplantation, CsA obtained the US FDA's clinical approval in 1983 for use in prevention of allograft rejection in transplantation. In 1987, the immunosuppressant was registered for the treatment of several autoimmune disorders, and it was in 2003 that the agency approved its use for dry eye disease [1]. Over the years, animal studies and clinical trials have revealed the effectiveness of CsA in other pathologies, such as T-cell large granular lymphocyte leukemia [2], traumatic brain injury (TBI) [3] or ischemic heart disease [4], among others. However, FDA approval has not yet been given for these diseases.

Different CsA formulations are currently available on the market, but there is still a need for improvement. Nowadays, the use of CsA has been limited owing to the related side effects, not only caused by the agent itself but also by the excipients present in the formulations (e.g. high quantities of organic solvents and surfactants). It is also worth mentioning that its unpredictable pharmacokinetics and its narrow therapeutic window are still concerns. In order to overcome these limitations, many promising drug delivery system alternatives based on particulate carriers are now being investigated [5], [6], [7], [8]. The scientific efforts devoted to reformulating CsA have been oriented to improve the drug absorption and to modify its tissue distribution. The final goal is to achieve a better pharmacokinetic profile and controlled drug release, thus increasing its therapeutic range, while avoiding the use of Cremophor® as a vehicle, thereby diminishing the number of related side effects.

In this review, innovative CsA delivery systems developed during recent years are summarized, specifically focusing on those consisting on nano- and micro-carriers. The different sections cover (i) the drug background, (ii) the pharmaceutical and clinical aspects that make CsA a challenging drug to formulate, (iii) the critical points to consider for suitable delivery systems depending on the routes of administration, (iv) and current experimental findings and their contribution to the pharmaceutical field.

CsA (C62H111N11O12) occurs as a white power with a melting point of 148–151 °C, which is barely soluble in water and n-hexane, but highly soluble in other organic solvents and lipids [9]. It has a partition coefficient value (log P) of 2.92 [10]. This lipophilic compound is a neutral cyclic polypeptide consisting of 11 aminoacid residues with a molecular weight of 1202.61 Da (Fig. 1). The aminoacids present in the molecule are: (4R)-4-[(E)-2-butenyl]-4-methyl-L-threonine (MeBmt) at position 1, unknown until the isolation of CsA, l-aminobutyric acid (Abu) at position 2, sarcosine (Sar) at position 3, methyl-leucine (MeLeu) at positions 4, 6, 9 and 10, l-valine (Val) at position 5, l-alanine (Ala) at position 7, d-alanine (d-Ala) at position 8 and methylvaline (MeVal) at position 11. The aminoacids at positions 1, 3, 4, 6, 9, 10 and 11 are N-methylated at the amide nitrogens and are responsible for the highly lipophilic nature of the molecule. The methylamide between residues 9 and 10 is located in the cis configuration and the other remaining fractions are in the trans form. On the other hand, the amide groups at positions 2, 5, 7 and 8 produce four intramolecular hydrogen bonds with the carbonyl groups of residues 5, 2, 11 and 6, respectively, ensuring high rigidity in the structure. Finally, the unsaturated chain at position 1 and the aminoacids at position 2, 3 and 11 are responsible for immunosuppressive activity [11].

The immunosuppressive activity of CsA is attributed to the formation of a complex resulting from the high affinity of the drug with immunophilins, mainly one called cyclophilin A (a cytoplasmic receptor protein of the targeted cells). The CsA-cyclophilin complex formed binds to calcineurin causing the inhibition of its phosphatase activity. Calcineurin is the protein responsible for regulating the nuclear translocation and activation of the nuclear factor of activated T-cells (NFAT) transcription factors. The prevention of the dephosphorylation of NFAT stimulated by the cytosolic calcium hinders their penetration to the core. As a consequence, the transcription of important cytokine genes, including those of IL-2, IL-4, TNF-α and INF-γ, is blocked. Therefore, the proliferation and activation of T-lymphocytes (T-helper and T-cytotoxic cells) are inhibited, the cells do not respond to specific antigen stimulation and thus, the immune system is weakened [12], [13].

Furthermore, CsA also binds to cyclophilin D, a protein located in the mitochondria, leading to the blockage of the mitochondrial permeability transition pore (mPTP) and the prevention of mitochondrial mega-pore formation. This mechanism may be involved in the cardio- and neuro-protective effects attributed to CsA [3], [14].

CsA is considered a highly variable drug and its efficacy depends greatly on the patient population. Several factors strongly influence CsA disposition through the body and lead to a high intra- and inter-individual variability in the pharmacokinetic parameters. These factors include age, gender, genetics, pathology, diet, dosing time after transplantation, and concomitant administration with other drugs, among others [15].

There are two main routes for CsA administration, intravenous and oral. Although oral administration is preferred, the bioavailability of this lipophilic substance is low and highly variable, ranging from 8 to 60%, with the maximum drug concentration achieved 1 to 8 h after the administration [15], [16], [17].

Once in the bloodstream, CsA is widely distributed throughout the body as a result of its lipophilic nature. Its apparent volume of distribution ranges from 2.9 to 4.7 L/kg in humans. From the dose absorbed found in whole blood, CsA is distributed as follows: erythrocytes (58%), plasma (33%), granulocytes (4%) and lymphocytes (5%). In plasma, most of the drug is bound to proteins, mainly to lipoproteins. CsA reaches higher concentrations in lymphoid tissues, such as thymus, spleen, lymph nodes, and bone marrow, rather than in blood. Also, the drug accumulates in lipid-containing tissues, like liver, pancreas, adrenal glands, and adipose tissue, while it barely penetrates into the central nervous system [15].

CsA is largely metabolized in the liver by the oxidation produced by the cytochrome P450 system, specifically by the CYP3A4. Also, the gut wall and the kidney are involved in the drug biotransformation, but to a lesser extent. The cyclic structure of this molecule makes it resistant to metabolization, nevertheless oxidation and demethylation of the side chains lead to the formation of at least 30 metabolites in bile, feces, blood and urine of different species. Some of these metabolites boost the immunosuppressant activity of CsA while others induce toxic effects [17].

Biliary excretion is the main pathway of CsA elimination, which is mostly excreted as metabolites, and only 1% as intact drug. Less important, but also implicated in the drug elimination, is the renal route; approximately 6% of the dose is eliminated in urine. The clearance is approximately 0.35 L/h per kg and the elimination half-life of the drug can vary significantly among patients from mean values of 6.4 h in heart transplantation patients to 20.4 h in patients with hepatic dysfunctions [16].

The most important clinical indication of CsA is the prophylaxis of rejection of several transplanted organs, such as kidneys, liver, heart, lung, small bowel, cornea or skin. Moreover, it has been indicated in bone marrow transplantation and graft-versus-host disease. The success of CsA in the transplantation field arises from its selective immunosuppressive effect that allowed it to significantly decrease the rejection rate in the 1980s, and to prolong patient and allograft survival [18]. Due to its successful outcomes in transplantation, the therapeutic application of CsA was extended to the treatment of various autoimmune disorders (Fig. 2). These include severe rheumatoid arthritis, psoriasis, nephrotic syndrome, severe atopic dermatitis, and uveitis, when patients do not respond adequately to conventional therapy [19]. CsA is also used for the treatment of various ocular disorders with evidence of inflammation, like dry eye disease, posterior blepharitis, vernal and atopic keratoconjunctivitis, among others [1]. CsA's therapeutic activity in treating ulcerative colitis has also been reported [20]. For some physicians, this is the preferred immunosuppressant used as rescue therapy in patients with acute colitis that do not respond to the intravenous steroid treatment, the main reason being that therapeutic levels of CsA can be rapidly reached [21]. Moreover, CsA therapy has been effective in T-cell large granular lymphocyte leukemia and well tolerated regardless of the patient population [2], [22]. In the last decade, CsA has attracted special attention as a cardio- and neuro-protective agent. Preliminary data from preclinical studies and early stage clinical trials have demonstrated the beneficial properties of CsA in TBI, stroke and other neuronal conditions [3], [4]. Its ability to protect neuronal cells and the mitochondria in the cardiac tissue damaged during a heart attack makes CsA a potential candidate for addressing neurological and cardiovascular disorders (Fig. 2). Phase II/III clinical trials are in progress to test CsA's efficacy in the treatment of these disorders and thus, contribute to the limited existing regimens for these purposes. However, there is some concern about the effective dose-toxicity relation since high doses and chronic administration are needed to evoke the cardio- and neuro-protective effect.

Additionally, CsA has exhibited promising results in the treatment of pathologies such as asthma, primary biliary cirrhosis, myasthenia gravis, and insulin-dependent diabetes mellitus, among others [1]. However, more scientific studies are needed for CsA to become part of the established regimens in clinical practice.

The dosing regimen and duration of CsA therapy greatly depends on the patient's individual condition. The treatment period may last months or years, or may become a lifelong therapy. The therapy is conditioned by the clinical response of the patient and his/her tolerability.

For transplantation, the common dose used is 10–15 mg/kg/day of CsA orally within the 12 h prior to the surgery, and is maintained for the first 2 weeks post-transplantation. After this period, this dose is gradually reduced to a maintenance dose of 2–6 mg/kg/day. When the intravenous route is required, the dose is reduced to the third part of the oral dose [23]. Generally, the blood drug concentration is monitored at two hours post dosing (C-2) and the dose is adjusted during the treatment to achieve the desired therapeutic range for an individual patient. The therapeutic CsA C-2 levels can vary from 1000 to 1700 ng/mL during the three first months, depending on the transplanted organ, and followed by a progressive reduction to 600–800 ng/mL [24].

For the treatment of autoimmune diseases, the doses usually employed are lower, starting from 2.5 mg/kg/day of CsA and increasing gradually up to 5 mg/kg/day, if significant clinical enhancement is not observed and the therapy has been well-tolerated. In some cases, discontinuation of the CsA treatment leads to relapse of the pathology [25].

Nephrotoxicity is the major concern in patients exposed to CsA therapy. The acute nephrotoxicity is characterized by a reduction of the glomerular filtration rate along with an increase in serum biochemical parameters, such as urea and creatinine. Nevertheless, if the levels of these parameters are carefully monitored in the initial stage of the treatment, the impairment of the renal function can be avoided, since they usually respond to a dose reduction. Inadequate dose adjustment can lead to chronic nephrotoxicity, also related to long-term CsA treatment. In this case, structural damage of the kidney arises and becomes progressive and irreversible, occurring as an interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, and glomerulosclerosis [26]. The renal tubular injury is associated with metabolic disorders, including wasting of magnesium, calcium and phosphate as well as distal tubular acidosis, and impaired renal potassium excretion [27]. In turn, the magnesium loss may cause muscle cramps, weakness, paresthesia and sometimes convulsions. Additionally, hypertension is one of the most common pathologies that appear at the initial stage of CsA treatment and is also related to electrolyte imbalance. Presumably, CsA's mechanism of action is also related to its side effects since the inhibition of the calcineurin-NFAT pathway produced by this molecule is not specific to immune cells. However, other factors have been studied as responsible for renal CsA susceptibility such as the variability in P-glycoprotein and CYP3A4/5 expression or activity, aged kidneys, salt depletion, concomitant medication, and genetic polymorphisms in genes like TGF-β and angiotensin converting enzyme [28].

Other adverse effects that have been reported for CsA therapy include hepatotoxicity, hirsutism, gingival hyperplasia, lymphoproliferative malignancy, etc. [29].

So far, CsA is available for oral, intravenous and ophthalmic administration (Table 1).

The first CsA formulation on the market was Sandimmune®, supplied as an oral solution or soft gelatin capsules and also as a concentrate solution for intravenous infusion.

Sandimmune® (oral dosage forms) consists of a conventional oil-based formulation containing corn oil, a large amount of ethanol, and inter-esterified corn oil. From this emulsion, CsA absorption is dependent on the presence of bile salts in gastrointestinal environment and its digestion by pancreatic enzymes. As a consequence, the bioavailability of CsA from this formulation has been reported to be low and very variable [30], leading to an erratic relationship between oral dose and total exposure of the compound. Years later Sandimmune Neoral® (hereafter referred as Neoral®) was introduced to the market in order to reach a better pharmacokinetic profile. This is a reformulated product consisting of a preconcentrate microemulsion containing DL-α-tocopherol, ethanol in high proportion, propylene glycol, corn glycerides and Cremophor® RH 40. Unlike the conventional Sandimmune® that forms oil droplets in the micrometric size, the more recent formulation can form homogeneous emulsion droplets of approximately 30 nm immediately after its contact with gastrointestinal fluids, promoting CsA absorption. In this regard, Neoral® has been shown to be less bile-dependent and provide superior and more reproducible bioavailability of CsA, which has been attributed to the micellar solubilization effect and the reduced particle size [31], [32]. Despite the better performance in pharmacokinetics for the microemulsion, there is no evidence that Neoral® reduces the risk of side effects arising from Sandimmune® therapy. In addition, achieving sustained constant levels of the drug in blood within the therapeutic window is still a concern, and therefore costly and unpleasant drug monitoring is required [33]. There are other CsA formulations in the market for oral administration, Gengraf®, Deximune® and Panimun Bioral™ as well as several generic formulations; however, they are not bioequivalent [34]. Switching to a different CsA formulation requires supervision of the physicians, and the drug levels must be carefully monitored during the first weeks.

Sandimmune® concentrate for the intravenous route consists of Cremophor® EL and ethanol. It should be diluted in saline solution or 5% glucose before administration. Due to the risk of anaphylactic reactions caused by Cremophor® EL, its use is limited to those cases in which the oral route is not well-tolerated or there are gastrointestinal disorders that threaten drug absorption. Recently, two intravenous CsA formulations have been developed, named CicloMulsion® and NeuroSTAT®, the first one for the treatment of heart reperfusion injury following stenting in patients with myocardial infarction, and the second one for the treatment of severe TBI. Both of them consist of Cremophor® free formulations, ready-to-use, which contain physiological fats and phospholipids, characteristics that make them advantageous over the existing marketed formulations. Hence, clinical trials are ongoing in order to obtain the marketing authorization. NeuroSTAT® received orphan drug status from US FDA and Europe in 2010 [35], [36].

CsA is also available as an ophthalmic emulsion (Restasis®) containing castor oil, glycerin, polysorbate 80 and carbomer copolymer type A.

Furthermore, another two CsA formulations, specifically for veterinary use, are currently commercialized (Table 1). One is Atopica®, an oral formulation indicated in atopic dermatitis; and the other one is Optimmune®, which consists of an ophthalmic ointment based on white petrolatum, used in dogs for the management of keratoconjunctivitis sicca or chronic superficial keratitis.

Section snippets

Limitations of CsA

Although CsA is available in the market in different dosage forms for different applications and administration routes, its use has been limited owing to certain side effects, which are not only associated with the drug but also with the components used for their preparation. Fig. 3 summarizes some of the pharmaceutical and clinical problems related to CsA, which are explained in more detail in the following sections.

Suitable CsA delivery systems: pharmaceutical and clinical considerations

Several strategies have been investigated to reduce CsA-related side effects. Among these, the co-administration of antioxidants that might induce protective effects against renal injury [38], or the combination with other immunosuppressants in order to minimize CsA dose [19] are the most promising. However, no reliable evidence ensuring patient safety has been demonstrated. Besides, these patients are usually polymedicated so the inclusion of more actives that can interact with the standard

Current trends toward the development of novel CsA delivery systems

The present section aims to give an overview of the current state of the art of drug delivery systems for CsA delivery through novel lipid and polymeric drug delivery systems, providing examples of successful outcomes.

Conclusions and future perspectives

Developing novel drug delivery systems for CsA administration remains a challenge. The balance between efficacy and safety in CsA therapy has not been resolved yet and therefore, the costly and unpleasant monitoring for patients is still required. The scientific community has made an enormous effort to improve the available CsA formulations. The major concerns still remain its variable pharmacokinetics and the excipients used in the formulation of this drug. It is obvious that there is

Acknowledgments

This work has been carried out in the framework of the COST Action TD1004. M. Guada is grateful to “Asociación de Amigos de la Universidad de Navarra” for the fellowship grant. A. Beloqui is a postdoctoral researcher from the Belgian Fonds National de la Recherche Scientifique (F.R.S. — FNRS).

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