Comprehensive Review on Pulsatile Drug Delivery System: Hybrid Approaches

Year : 2026 | Volume : 13 | 01 | Page :
    By

    Shradha R. Khopade,

  • Mokshada S. Kashid,

  • Sushma T. Nakhate,

  1. Student, Department of Pharmacy, Genba Sopanrao Moze college of Pharmacy, Wagholi, Pune, Maharashtra, India
  2. Student, Department of Pharmacy, Genba Sopanrao Moze college of Pharmacy, Wagholi, Pune, Maharashtra, India
  3. Assistant Professor, Department of Pharmacy, Genba Sopanrao Moze college of Pharmacy, Wagholi, Pune, Maharashtra, India

Abstract

Pulsatile drug delivery systems (PDDS) represent a groundbreaking approach in pharmaceutical technology, allowing for controlled, targeted, and programmable drug release that aligns with circadian rhythms or caters to time-sensitive therapeutic requirements. Although traditional pulsatile systems have shown considerable clinical promise, their effectiveness is frequently compromised by physiological variations such as gastrointestinal transit times, changes in pH, and enzymatic activity. To tackle these obstacles, hybrid PDDS have been developed by combining two or more release mechanisms—such as time-controlled, stimuli-responsive, or externally triggered within a single framework. These hybrid systems offer improved consistency, flexibility, and accuracy in drug release profiles. This review underlines the basic principles governing PDDS, examines hybridization techniques like time + pH-responsive, enzyme-responsive, multi-stimuli, and device–polymer hybrids, and showcases recent advancements in oral, injectable, transdermal, and wearable systems. Additionally, it addresses the prospects for industrial and clinical application, encompassing areas like oncology, ophthalmology, vaccines, regenerative medicine, and the management of chronic illnesses. Future outlooks highlight the influence of 3D/4D printing, digital therapeutics, and telemedicine in developing personalized hybrid PDDS. Despite facing hurdles in scalability, consistency, and regulatory approval, hybrid PDDS possess transformative potential to enhance precision medicine and next-generation therapeutic approaches.

Keywords: Controlled release, Hybrid drug delivery, Pulsatile drug delivery systems (PDDS), Stimuli-responsive polymers, Time-controlled systems

How to cite this article:
Shradha R. Khopade, Mokshada S. Kashid, Sushma T. Nakhate. Comprehensive Review on Pulsatile Drug Delivery System: Hybrid Approaches. Trends in Drug Delivery. 2025; 13(01):-.
How to cite this URL:
Shradha R. Khopade, Mokshada S. Kashid, Sushma T. Nakhate. Comprehensive Review on Pulsatile Drug Delivery System: Hybrid Approaches. Trends in Drug Delivery. 2025; 13(01):-. Available from: https://journals.stmjournals.com/tdd/article=2025/view=230275


References

1. sawale, A. (2013). A Review on Pulsatile Drug Delivery System. International Research Journal of Pharmacy. https://doi.org/10.7897/2230-8407.04307
2. Ricotti, Leonardo & Cafarelli, Andrea & Iacovacci, Veronica & Vannozzi, Lorenzo & Menciassi, Arianna. (2014). Advanced Micro-Nano-Bio Systems for Future Targeted Therapies. Current Nanoscience. 10.2174/1573413710666141114221246.
3. Mura, S., Nicolas, J., & Couvreur, P. (2013). Stimuli-responsive nanocarriers for drug delivery. Nature materials, 12(11), 991–1003. https://doi.org/10.1038/nmat3776
4. Kikuchi, A., & Okano, T. (2002). Pulsatile drug release control using hydrogels. Advanced drug delivery reviews, 54(1), 53–77. https://doi.org/10.1016/s0169-409x(01)00243-5
5. Patel, Vipul & Soniwala, Moinuddin. (2012). Pulsatile drug delivery system for treatment of various Inflammatory Disorders: A Review. International Journal of Drug Development and Research. 4. 67-87.
6. Khalifa, Al Zahraa; Zyad, Houralaeen; Mohammed, Hoor; Ihsan, Kenda; Alrawi, Leen; Abdullah, Maryam; Akram, Ola. Recent advances in remotely controlled pulsatile drug delivery systems. Journal of Advanced Pharmaceutical Technology & Research 13(2):p 77-82, Apr–Jun 2022. | DOI: 10.4103/japtr.japtr_330_21
7. Jassem, Nizar & k.ali, Samer. (2020). A Novel Pulsatile Drug Delivery Approach -A Laconic Review. International Journal of Pharmaceutical Research. 12. 4606-4613. 10.31838/ijpr/2020.SP2.576.
8. Mattos, B. D., Rojas, O. J., & Magalhães, W. L. E. (2017). Biogenic silica nanoparticles loaded with neem bark extract as green, slow-release biocide. Journal of Cleaner Production, 142, 4206-4213. https://doi.org/10.1016/j.jclepro.2016.11.183
9. Choi, W., & Kohane, D. S. (2024). Hybrid Nanoparticle-Hydrogel Systems for Drug Delivery Depots and Other Biomedical Applications. ACS nano, 18(34), 22780–22792. https://doi.org/10.1021/acsnano.4c06888
10. Kohane DS; Langer R Biotechnology to improve pateints’ medication compliance. Behavioral Health Management 2005, 25 (2), 26–28.
11. Verma, R., & Garg, S. (2001). Current Status of Drug Delivery Technologies and Future Directions.
12. Keraliya R.A., Patel C., Patel P., Keraliya V., Soni T.G., Patel R.C., Patel M.M. Osmotic drug delivery system as a part of modified release dosage form. ISRN Pharm. 2012 doi: 10.5402/2012/528079. 2012.
13. Jain, D., Raturi, R., Jain, V., Bansal, P., & Singh, R. (2011). Recent technologies in pulsatile drug delivery systems. Biomatter, 1(1), 57–65. https://doi.org/10.4161/biom.1.1.17717
14. Patel VP, Desai TR. Pulsatile Drug Delivery System: A Review. PharmaTutor. 2013
15. Gomathi J, Balakrishnan N, Rani D. Pulsatile drug delivery: A strategy for treating chronotherapeutic ailments. Int J Curr Pharm Res. 2023;15(5):59–65.
16. Ravali V, Balaji P. Pulsatile Drug Delivery Systems: A Comprehensive Review. Int J Drug Deliv Technol. 2019;9(2):239–246.
17. HABEEB1, F., & MOHAMMED, S. (2023). A Review on Pulsatile Drug Delivery System. International Journal of Pharmacy Research & Technology (IJPRT), 12(2), 10–23. https://doi.org/10.31838/ijprt/12.02.02
18. Karale, Pradip & Kshirsagar, Diksha & Pande, Vishal. (2015). Pros and cons of pulsatile drug delivery system.
19. Conte U, Colombo P. Pulsincap: A novel pulsatile drug delivery device. Drug Dev Ind Pharm. 1989;15(14–16):2583–2596.
20. Roy, P., & Shahiwala, A. (2009). Multiparticulate formulation approach to pulsatile drug delivery: current perspectives. Journal of controlled release : official journal of the Controlled Release Society, 134(2), 74–80. https://doi.org/10.1016/j.jconrel.2008.11.011
21. Gazzaniga, A., Palugan, L., Foppoli, A., & Sangalli, M. E. (2008). Oral pulsatile delivery systems based on swellable hydrophilic polymers. European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 68(1), 11–18. https://doi.org/10.1016/j.ejpb.2007.05.022
22. Friend, D. R., & Chang, G. W. (1984). A colon-specific drug-delivery system based on drug glycosides and the glycosidases of colonic bacteria. Journal of medicinal chemistry, 27(3), 261–266. https://doi.org/10.1021/jm00369a005
23. Yong Qiu, Kinam Park,Environment-sensitive hydrogels for drug delivery, Advanced Drug Delivery Reviews,Volume 64, Supplement,2012,Pages 49-60,ISSN 0169-409X,https://doi.org/10.1016/j.addr.2012.09.024.
24. O’Neill BE, et al. Pulsatile drug delivery using acoustic radiation force. J Control Release. 2009;133(3):195–200.
25. Kost, J., & Langer, R. (2001). Responsive polymeric delivery systems. Advanced drug delivery reviews, 46(1-3), 125–148. https://doi.org/10.1016/s0169-409x(00)00136-8
26. Shapiro B, et al. External triggering and modulation of drug delivery. Adv Drug Deliv Rev. 2010;62(11):1360–1380.
27. Maroni, A., Zema, L., Cerea, M., & Sangalli, M. E. (2005). Oral pulsatile drug delivery systems. Expert opinion on drug delivery, 2(5), 855–871. https://doi.org/10.1517/17425247.2.5.855
28. Bussemer, T., Otto, I., & Bodmeier, R. (2001). Pulsatile drug-delivery systems. Critical reviews in therapeutic drug carrier systems, 18(5), 433–458.
29. Krishnaiah, Y. S., Veer Raju, P., Dinesh Kumar, B., Bhaskar, P., & Satyanarayana, V. (2001). Development of colon targeted drug delivery systems for mebendazole. Journal of controlled release : official journal of the Controlled Release Society, 77(1-2), 87–95. https://doi.org/10.1016/s0168-3659(01)00461-8
30. Friend, D. R., & Chang, G. W. (1984). A colon-specific drug-delivery system based on drug glycosides and the glycosidases of colonic bacteria. Journal of medicinal chemistry, 27(3), 261–266. https://doi.org/10.1021/jm00369a005
31. Amidon, S., Brown, J. E., & Dave, V. S. (2015). Colon-targeted oral drug delivery systems: design trends and approaches. AAPS PharmSciTech, 16(4), 731–741. https://doi.org/10.1208/s12249-015-0350-9
32. Yang, L., Chu, J. S., & Fix, J. A. (2002). Colon-specific drug delivery: new approaches and in vitro/in vivo evaluation. International journal of pharmaceutics, 235(1-2), 1–15. https://doi.org/10.1016/s0378-5173(02)00004-2
33. Cheng, R., Meng, F., Deng, C., Klok, H. A., & Zhong, Z. (2013). Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery. Biomaterials, 34(14), 3647–3657. https://doi.org/10.1016/j.biomaterials.2013.01.084
34. Colombo P, Bettini R, Peppas NA. Osmotic drug delivery systems: fundamentals and applications. J Control Release. 2000;65(1–2):63–78.
35. Pandita, D. et al. Hybrid PLGA nanoparticles for oral delivery. Adv. Drug Deliv. Rev. (2015).
36. Ghitman, J. et al. Hybrid nanoparticles in smart drug delivery. Mater. Sci. Eng. C (2020)
37. Soares, D.C.F. et al. Polymer-hybrid nanoparticles: Biomedical applications. Eur. J. Pharm. Biopharm. (2020).
38. Operti, M.C. et al. Scale-up challenges of PLGA nanoparticles. Int. J. Pharm. (2021).
39. Sun, W. et al. Stimuli-responsive oral PLGA systems. Polymers (2024).
40. Zhang, L. et al. Oral pulsatile systems: Progress and challenges. J. Control. Release (2023).
41. Gao, W. et al. Nanoparticle–hydrogel hybrid biomaterials. Ann. Biomed. Eng. (2016).
42. Choi, W., Kohane, D. Hybrid Nanoparticle–Hydrogel Systems. Pharmaceutics (2024).
43. Manuel R. Pouso, Bruna L. Melo, Joaquim J. Gonçalves, Ricardo O. Louro, António G. Mendonça, Ilídio J. Correia, Duarte de Melo-Diogo,Injectable and implantable hydrogels for localized delivery of drugs and nanomaterials for cancer chemotherapy: A review,International Journal of Pharmaceutics,Volume 677,2025,125640,ISSN,0378-5173https://doi.org/10.1016/j.ijpharm.2025.125640
44. El-Husseiny, H.M. et al. Stimuli-responsive hydrogels. Mater. Today Bio (2022).
45. Santini, J.T. et al. Microchip-based drug delivery systems. Nat. Biotechnol. (2000).
46. Cao, H. et al. Hydrogel advances in biomedical applications. Signal Transduct. Target Ther. (2021).
47. Duong, H. et al. Smart responsive microneedles for controlled delivery. Polymers (2023).
48. Valentino, O. et al. Smart nanocomposite hydrogels. Gels (2024).
49. Chen, Y. et al. NIR-responsive hydrogel microneedles. Adv. Funct. Mater. (2022).
50. Kim, S. et al. 3D-printed microneedle hybrids. Biomed. Eng. Adv. (2025).
51. Lee, K. et al. Challenges in microneedle-based hybrids. Drug Deliv. Transl. Res. (2023).
52. Kim, J. et al. Bio-integrated wearable systems. Chem. Rev. (2022).
53. Xu, B. et al. Wearable microneedle-based devices. ACS Mater. Au (2024).
54. Cai, L. et al. Hybrid conductive hydrogels in biomedicine. Front. Bioeng. Biotechnol. (2021).
55. Gao, L. et al. Nanostructured wearable electrochemical biosensors. RSC Adv. (2023).
56. W.M. Feng,H.H.Guo,T.Xue,X.Wang,C.W.Tang,B.Ying,G.Cui,Anti-inflammation and anti-fibrosis with PEGylated, apigenin loaded PLGA nanoparticles in chronic pancreatitis disease, RSC Adv. 5 (102) (2015) 83628–83635
57. B. Mandal, H. Bhattacharjee, N. Mittal, H. Sah, P. Balabathula, L.A. Thoma, G.C. Wood, Core–shell-type lipid–polymer hybrid nanoparticles as a drug delivery platform, Nanomedicine 9 (4) (2013) 474–491.
58. Donnelly, R.F.; Larraˇneta, E. Slowly Dissolving Intradermal Microneedles. Nat. Biomed. Eng. 2019, 3, 169–170. [CrossRef] [PubMed]
59. Lee, S.; Fakhraei Lahiji, S.; Jang, J.; Jang, M.; Jung, H. Micro-Pillar Integrated Dissolving Microneedles for Enhanced Transdermal Drug Delivery. Pharmaceutics 2019, 11, 402. [CrossRef] [PubMed]
60. Kim,D.S.; Choi, J.T.; Kim, C.B.; Shin, Y.-R.; Park, P.; Kim, H.; Lee, J.M.; Park, J.H. Microneedle Array Patch (MAP) Consisting of Crosslinked Hyaluronic Acid Nanoparticles for Processability and Sustained Release. Pharm. Res. 2020, 37, 50. [CrossRef]
61. Hadinoto K, Sundaresan A, Cheow WS. Lipid–polymer hybrid nanoparticles as a new generation therapeutic delivery platform: A review. Int J Pharm. 2013.
62. Verma J, et al. Recent patents in polymer–lipid hybrid nanoparticles: industrial trends and implications. Drug Dev Ind Pharm. 2024.
63. Mukherjee A, et al. Lipid–polymer hybrid nanoparticles as a next-generation drug delivery platform: review and clinical possibilities. Int J Nanomedicine. 2019.

64. Parveen S, et al. Lipid–polymer hybrid nanoparticles as potent vehicles for co-delivery and enhanced therapies. Int J Pharm. 2023.
65. Qi Z, et al. Smart Responsive Microneedles for Controlled Drug Delivery. Molecules. 2023;28(21):7411.
66. Rahat I, et al. Polymer–lipid hybrid nanoparticles for phytochemical delivery. Beilstein J Nanotechnol. 2024.
67. Bácskay I, Ujhelyi Z, Fehér P, Arany P. The Evolution of the 3D-Printed Drug Delivery Systems: A Review. Pharmaceutics. 2022;14(7):1312.
68. Olowe M, et al. A Review of 3D-Printing of Microneedles. Pharmaceutics. 2022;14(12):2693.
69. Rajendran A, et al. The Revolution of Digital Therapeutics (DTx) in Healthcare. Open Access Review. 2024.
70. Chiofalo T, et al. Roadmap on Nanomedicine / Translational Frameworks for Nanomedicines. 2020/2024.
71. M.A. et al. A translational framework to DELIVER nanomedicines to the clinic. Nat Rev Mater.2024

Ahead of Print Subscription Review Article
Volume 13
01
Received 06/10/2025
Accepted 27/10/2025
Published 27/10/2025
Publication Time 21 Days
196

Login


My IP

PlumX Metrics