A Safety and Tolerability Study of Thin Film Freeze-Dried Tacrolimus for Local Pulmonary Drug Delivery in Human Subjects
Due to the low and erratic bioavailability of oral tacrolimus (TAC), the long-term survival rate following lung transplantation remained low compared to other solid organs. TAC was reformulated and developed as inhaled formulations by thin film freezing (TFF). Previous studies reported that inhaled...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/5/717 |
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| author | Sawittree Sahakijpijarn Moeezullah Beg Stephanie M. Levine Jay I. Peters Robert O. Williams |
| author_facet | Sawittree Sahakijpijarn Moeezullah Beg Stephanie M. Levine Jay I. Peters Robert O. Williams |
| author_sort | Sawittree Sahakijpijarn |
| collection | DOAJ |
| description | Due to the low and erratic bioavailability of oral tacrolimus (TAC), the long-term survival rate following lung transplantation remained low compared to other solid organs. TAC was reformulated and developed as inhaled formulations by thin film freezing (TFF). Previous studies reported that inhaled TAC combined with 50% <i>w/w</i> lactose (LAC) was safe and effective for the treatment of lung transplant rejection in rodent models. In this study, we aimed to investigate the safety and tolerability of TFF TAC-LAC in human subjects. The formulation can be delivered to the lung as colloidal dispersions after reconstitution and as a dry powder. Healthy subjects inhaled TAC-LAC colloidal dispersions at 3 mg TAC/dose via a vibrating mesh nebulizer in the first stage of this study and TAC-LAC dry powder at 3 mg TAC/dose via a single dose dry powder inhaler in the second stage. Our results demonstrated that oral inhalation of TAC-LAC colloidal dispersions and dry powder exhibited low systemic absorption. Additionally, they were well-tolerated with no changes in CBC, liver, kidney, and lung functions. Only mild adverse side effects (e.g., cough, throat irritation, distaste) were observed. In summary, pulmonary delivery of TFF TAC-LAC would be a safe and promising therapy for lung transplant recipients. |
| first_indexed | 2024-03-10T11:25:37Z |
| format | Article |
| id | doaj.art-38e29b57300440c98c3cb6395f112866 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T11:25:37Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-38e29b57300440c98c3cb6395f1128662023-11-21T19:38:48ZengMDPI AGPharmaceutics1999-49232021-05-0113571710.3390/pharmaceutics13050717A Safety and Tolerability Study of Thin Film Freeze-Dried Tacrolimus for Local Pulmonary Drug Delivery in Human SubjectsSawittree Sahakijpijarn0Moeezullah Beg1Stephanie M. Levine2Jay I. Peters3Robert O. Williams4Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USADepartment of Pulmonary and Critical Care, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USADepartment of Pulmonary and Critical Care, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USADepartment of Pulmonary and Critical Care, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USADivision of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USADue to the low and erratic bioavailability of oral tacrolimus (TAC), the long-term survival rate following lung transplantation remained low compared to other solid organs. TAC was reformulated and developed as inhaled formulations by thin film freezing (TFF). Previous studies reported that inhaled TAC combined with 50% <i>w/w</i> lactose (LAC) was safe and effective for the treatment of lung transplant rejection in rodent models. In this study, we aimed to investigate the safety and tolerability of TFF TAC-LAC in human subjects. The formulation can be delivered to the lung as colloidal dispersions after reconstitution and as a dry powder. Healthy subjects inhaled TAC-LAC colloidal dispersions at 3 mg TAC/dose via a vibrating mesh nebulizer in the first stage of this study and TAC-LAC dry powder at 3 mg TAC/dose via a single dose dry powder inhaler in the second stage. Our results demonstrated that oral inhalation of TAC-LAC colloidal dispersions and dry powder exhibited low systemic absorption. Additionally, they were well-tolerated with no changes in CBC, liver, kidney, and lung functions. Only mild adverse side effects (e.g., cough, throat irritation, distaste) were observed. In summary, pulmonary delivery of TFF TAC-LAC would be a safe and promising therapy for lung transplant recipients.https://www.mdpi.com/1999-4923/13/5/717lung transplantationimmunosuppressanttacrolimusthin film freezingdry powder inhalationnebulization |
| spellingShingle | Sawittree Sahakijpijarn Moeezullah Beg Stephanie M. Levine Jay I. Peters Robert O. Williams A Safety and Tolerability Study of Thin Film Freeze-Dried Tacrolimus for Local Pulmonary Drug Delivery in Human Subjects Pharmaceutics lung transplantation immunosuppressant tacrolimus thin film freezing dry powder inhalation nebulization |
| title | A Safety and Tolerability Study of Thin Film Freeze-Dried Tacrolimus for Local Pulmonary Drug Delivery in Human Subjects |
| title_full | A Safety and Tolerability Study of Thin Film Freeze-Dried Tacrolimus for Local Pulmonary Drug Delivery in Human Subjects |
| title_fullStr | A Safety and Tolerability Study of Thin Film Freeze-Dried Tacrolimus for Local Pulmonary Drug Delivery in Human Subjects |
| title_full_unstemmed | A Safety and Tolerability Study of Thin Film Freeze-Dried Tacrolimus for Local Pulmonary Drug Delivery in Human Subjects |
| title_short | A Safety and Tolerability Study of Thin Film Freeze-Dried Tacrolimus for Local Pulmonary Drug Delivery in Human Subjects |
| title_sort | safety and tolerability study of thin film freeze dried tacrolimus for local pulmonary drug delivery in human subjects |
| topic | lung transplantation immunosuppressant tacrolimus thin film freezing dry powder inhalation nebulization |
| url | https://www.mdpi.com/1999-4923/13/5/717 |
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