Polyoxyl 60 hydrogenated castor oil free nanosomal formulation of immunosuppressant Tacrolimus: Pharmacokinetics, safety, and tolerability in rodents and humans

Ali, Shoukath M.; Ahmad, Ateeq; Sheikh, Saifuddin; Ahmad, M. S.; Rane, R C; Kale, Prashant; Paithankar, Mahesh; Saptarishi, Dipak; Sehgal, Ashish; Maheshwari, Kirti; Ahmad, Imran

doi:10.1016/j.intimp.2009.12.003

Cited by 22 publications

(10 citation statements)

References 9 publications

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“…Fundamental mechanism of different formulations was to either increase water solubility of tacrolimus, thereby ensuring proper absorption from GI-tract, or to reduce P-gp efflux and CYP-450 mediated metabolism for enhancing oral bioavailability. Here, we have discussed several formulation approaches like SMEDDS,[1314] pro-drug,[15] oily solution,[16] solid dispersions,[17] complexation with cyclodextrins,[18] pH-sensitive microspheres,[19] nanocapsule,[20] micelles,[21] nanosomes,[22] nano-liposomes of dry powder inhaler,[23] and liposomes[24] for delivery of tacrolimus.…”

Section: Tacrolimus Drug Delivery Systemsmentioning

confidence: 99%

Formulation strategies for drug delivery of tacrolimus: An overview

Patel¹,

Patel²,

Panchal

et al. 2012

Int J Pharma Investig

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Tacrolimus (FK 506) is a potent macrolide lactone immunosuppressive agent used for prophylaxis of organ rejection after transplantation and graft-versus-host disease after bone marrow transplantation in patients. Moreover, tacrolimus is a drug of choice in the treatment of atopic dermatitis for decreasing side effects associated with the use of topical corticosteroids. In spite of its success in ensuring graft survival, therapeutic use of tacrolimus is complicated due to its narrow therapeutic index (between 5 and 15 ng/ml). Tacrolimus has a large inter-/intra-patient variability in pharmacokinetics profile and a poor oral bioavailability because of its poor solubility, P-gp efflux, marked pre-systemic metabolism by CYP3A in the enterocytes and liver first pass effect. Several formulation approaches such as oily solution, solid dispersions, complexation with cyclodextrins, liposomes etc., have been investigated to improve oral delivery of FK 506. In this review, we have discussed various formulation approaches that have been undertaken by various researchers to solve the problems related to the drug delivery of tacrolimus.

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Section: Tacrolimus Drug Delivery Systemsmentioning

confidence: 99%

Formulation strategies for drug delivery of tacrolimus: An overview

Patel¹,

Patel²,

Panchal

et al. 2012

Int J Pharma Investig

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show abstract

“…Most of these techniques have been focused on improving the solubility and absorption of tacrolimus from the GI tract or reducing P-gp efflux and CYP-450-mediated metabolism, with limited success. The reported approaches include prodrug (21), cyclodextrin complexes (22), solid dispersions (23,24), liposomes (25), self-microemulsifying drug delivery system (26)(27)(28), nanocapsules (29), micelles (30), nanosomes (31), microspheres (32), and nanoliposomes of dry powder inhaler (33). However, these investigational findings have not effectively translated into human clinical trials except solid dispersions.…”

Section: Introductionmentioning

confidence: 99%

Design, Characterization, and In Vivo Pharmacokinetics of Tacrolimus Proliposomes

et al. 2015

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Abstract. The objective of this study was to develop proliposomal formulation for a poorly bioavailable drug, tacrolimus. Proliposomes were prepared by thin film hydration method using different lipids such as hydrogenated soy phosphatidylcholine (HEPC), soy phosphatidylcholine (SPC), distearyl phosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), and dimyristoylphosphatidylglycerol sodium (DMPG) and cholesterol in various ratios. Proliposomes were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability, and in vivo pharmacokinetics. In vitro drug release was carried out in purified water using USP type II dissolution apparatus. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA) and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague-Dawley (SD) rats. Among the different formulations, proliposomes with drug/DSPC/cholesterol in the ratio of 1:2:0.5 demonstrated the desired particle size and zeta potential. Enhanced drug release was observed with proliposomes compared to pure tacrolimus in purified water after 1 h. Tacrolimus permeability across PAMPA and everted rat intestinal perfusion models was significantly higher with proliposomes. The optimized formulation of proliposomes indicated a significant improvement in the rate and absorption of tacrolimus. Following a single oral administration, a relative bioavailability of 193.33% was achieved compared to pure tacrolimus suspension.

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“…2 9 Furthermore, considering the poor water solubility of tacrolimus (about 1-2 g mL −1 , the marketed intravenous product contains polyoxyl 60 hydrogenated castor oil (HCO-60), which may cause allergic symptoms such as leukocytosis, hyperpyrexia and eruption. 11 Various pharmaceutical strategies such as the development of water soluble tacrolimus derivates, 12 microemulsions, [13][14][15] solid dispersions, 16 17 liposomes, [18][19][20][21] nanosomes, 22 cyclodextrin complexes, 23 24 micelles, 25 microparticles 26 27 and nanoparticulate systems 6 7 28-32 have been described in an effort to overcome the biopharmaceutical limitations of this drug. Some studies have reported the potential use of tacrolimus entrapped into polymeric nanoparticles aiming at a selective drug deposition in inflamed tissues 6 7 as well as to improve the lymphatic targeting efficiency and reduce the drug toxicity.…”

Section: Introductionmentioning

confidence: 99%

Nanoencapsulation of Tacrolimus in Lipid-Core Nanocapsules Showed Similar Immunosuppressive Activity After Oral and Intraperitoneal Administrations

Friedrich¹,

Dimer²,

Guterres³

et al. 2014

j biomed nanotechnol

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Tacrolimus is widely used in the prophylaxis of solid-organ transplant rejection. Several studies have reported that tacrolimus has variable and poor bioavailability after oral administration, apart from adverse effects such as gastrointestinal disorders, hyperglycemia, nephro-and neurotoxicity. The aim of this work was to encapsulate tacrolimus (TAC) in lipid-core nanocapsules (LNC) as an oral strategy to deliver the drug. To validate our hypothesis, the pharmacodynamic effect of TAC-LNC was determined after oral and intraperitoneal (i.p.) administrations to mice. TAC-LNC had z-average diameter of 210 nm (unimodal), and 99.5% of encapsulation efficiency. In vitro sustained release was determined for TAC-LNC fitting an anomalous transport mechanism (n = 0 8). TAC-LNC demonstrated higher immunosuppressive activity after oral and i.p. administrations, when compared to the drug solution. TAC-LNC administered at 6.0 mg kg −1 day −1 showed equivalent percent reduction in lymphocyte when both routes of administration were used. After oral administration, drug nanoencapsulation allows reducing the dose by at least 40%. Furthermore, the nanoencapsulation of TAC in lipid-core nanocapsules showed pharmacodynamic effect similar for the oral and the i.p. routes. In conclusion, the lipid-core nanocapsules were able to improve the TAC deliver across the oral absorption barrier.

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Polyoxyl 60 hydrogenated castor oil free nanosomal formulation of immunosuppressant Tacrolimus: Pharmacokinetics, safety, and tolerability in rodents and humans

Cited by 22 publications

References 9 publications

Formulation strategies for drug delivery of tacrolimus: An overview

Formulation strategies for drug delivery of tacrolimus: An overview

Design, Characterization, and In Vivo Pharmacokinetics of Tacrolimus Proliposomes

Nanoencapsulation of Tacrolimus in Lipid-Core Nanocapsules Showed Similar Immunosuppressive Activity After Oral and Intraperitoneal Administrations

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