In situ forming parenteral drug delivery systems: an overview

Packhaeuser, C.B; Schnieders, J; Oster, C.G; Kissel, T

doi:10.1016/j.ejpb.2004.03.003

Cited by 413Advanced Drug Delivery SystemsHydrogels: synthesis, properties, applicationsIntramuscular injections and effects

In situ forming parenteral drug delivery systems: an overview

Packhaeuser, C.B, Schnieders, J, Oster, C.G, Kissel, T·2004·European Journal of Pharmaceutics and Biopharmaceutics

DOI 10.1016/j.ejpb.2004.03.003

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Abstract

Biodegradable injectable in situ forming drug delivery systems represent an attractive alternative to microspheres and implants as parenteral depot systems. Their importance will grow as numerous proteins will lose their patent protection in the near future. These devices may offer attractive opportunities for protein delivery and could possibly extend the patent life of protein drugs. The controlled release of bioactive macromolecules via (semi-) solid in situ forming systems has a number of advantages, such as ease of administration, less complicated fabrication, and less stressful manufacturing conditions for sensitive drug molecules. For these reasons, a number of polymeric drug delivery systems with the ability to form a drug reservoir at the injection site are under investigation. Here, we review various strategies used for the preparation of in situ forming parenteral drug depots and their potential benefits/draw-backs, especially with regard to the delivery of protein drug candidates.

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In vivo, block polymer nanomicelles are less likely to be recognized as foreign entities by immune cells, and their hydrophilic shell aids in evading the reticuloendothelial system, thus reducing the exclusion from bloodstream.
“In vivo, block polymer nanomicelles are less likely to be recognized as foreign entities by immune cells, and their hydrophilic shell aids in evading the reticuloendothelial system, thus reducing the exclusion from bloodstream [105].”
From From design to Deployment: The innovative role of nanomicelles in targeted ophthalmic therapeutics (2025) · cites this paper as [105]

The sequence of the human genome
Venter, J. C., Adams, M. D., Myers, E. W., Li, P. W., Mural, R. J., Sutton, G. G., Smith, H. O., Yandell, M., Evans, C. A., Holt, R. A., et al. (2001) · Science · doi:10.1126/science.1058040 · Cited by 13,909 · see citing works
Biodegradable block copolymers as injectable drug-delivery systems
Jeong, B., Bae, Y. H., Lee, D. S., & Kim, S. W. (1997) · Nature · doi:10.1038/42218 · Cited by 1,999 · see citing works
Novel injectable neutral solutions of chitosan form biodegradable gels in situ
Chenite, A., Chaput, C., Wang, D., Combes, C., Buschmann, M. D., Hoemann, C. D., Leroux, J., Atkinson, B. L., Binette, F., & Selmani, A. (2000) · Biomaterials · doi:10.1016/s0142-9612(00)00116-2 · Cited by 1,410 · see citing works
Bioerodible hydrogels based on photopolymerized poly(ethylene glycol)-co-poly(.alpha.-hydroxy acid) diacrylate macromers
Sawhney, A. S., Pathak, C. P., & Hubbell, J. A. (1993) · Macromolecules · doi:10.1021/ma00056a005 · Cited by 969 · see citing works
Thermoreversible Gelation of PEG−PLGA−PEG Triblock Copolymer Aqueous Solutions
Jeong, B., Bae, Y. H., & Kim, S. W. (1999) · Macromolecules · doi:10.1021/ma9908999 · Cited by 618 · see citing works
Biodegradable block copolymers for delivery of proteins and water-insoluble drugs
Zentner, G. M., Rathi, R. C., Shih, C., McRea, J. C., Seo, M.-H., Oh, H., Rhee, B.-O., Mestecky, J. F., Moldoveanu, Z., Morgan, M. E., et al. (2001) · Journal of Controlled Release · doi:10.1016/s0168-3659(01)00276-0 · Cited by 587 · see citing works
Thiolated polymers—thiomers: synthesis and in vitro evaluation of chitosan–2-iminothiolane conjugates
Bernkop‐Schnürch, A. (2003) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(03)00271-0 · Cited by 429 · see citing works
Synthesis and Characterization of Injectable Poly(N-isopropylacrylamide)-Based Hydrogels That Support Tissue Formation in Vitro
Stile, R. A., Burghardt, W. R., & Healy, K. E. (1999) · Macromolecules · doi:10.1021/ma990130w · Cited by 363 · see citing works
Influence of stabilizing agents and preparative variables on the formation of poly(d,l-lactic acid) nanoparticles by an emulsification-diffusion technique
Quintanar‐Guerrero, D., Fessi, H., Allémann, É., & Doelker, É. (1996) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(96)04697-2 · Cited by 311 · see citing works
A novel in situ-forming ophthalmic drug delivery system from alginates undergoing gelation in the eye
Cohen, S., Löbel, E., Trevgoda, A., et al. (1997) · Journal of Controlled Release · doi:10.1016/s0168-3659(96)01523-4 · Cited by 298 · see citing works
New biodegradable polymers for injectable drug delivery systems
Jeong, B., Choi, Y. K., Bae, Y. H., Zentner, G. M., & Kim, S. W. (1999) · Journal of Controlled Release · doi:10.1016/s0168-3659(99)00061-9 · Cited by 285 · see citing works
Cytotoxicity of Solid Lipid Nanoparticles as a Function of the Lipid Matrix and the Surfactant
Müller, R. H., Rühl, D., Runge, S., Schulze‐Forster, K., & Mehnert, W. (1997) · Pharmaceutical Research · doi:10.1023/a:1012043315093 · Cited by 265 · see citing works
Phase inversion dynamics of PLGA solutions related to drug delivery
Graham, P. D., Brodbeck, K. J., & McHugh, A. J. (1999) · Journal of Controlled Release · doi:10.1016/s0168-3659(98)00158-8 · Cited by 222 · see citing works
Effect of sodium chloride on the gelation temperature, gel strength and bioadhesive force of poloxamer gels containing diclofenac sodium
Yong, C. S., Choi, J. S., Quan, Q.-Z., et al. (2001) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(01)00809-2 · Cited by 221 · see citing works
Interstitial taxol delivered from a biodegradable polymer implant against experimental malignant glioma.
Walter, K. A., Cahan, M. A., Gur, A., Tyler, B., Hilton, J., Colvin, O. M., Burger, P. C., Domb, A. J., & Brem, H. (1994) · PubMed · Cited by 211 · see citing works
Eligard: leuprolide acetate in a novel sustained-release delivery system
Sartor, O. A. (2003) · Urology · doi:10.1016/s0090-4295(02)02396-8 · Cited by 184 · see citing works
Phase inversion dynamics of PLGA solutions related to drug delivery
Brodbeck, K. J., DesNoyer, J. R., & McHugh, A. J. (1999) · Journal of Controlled Release · doi:10.1016/s0168-3659(99)00159-5 · Cited by 175 · see citing works
Long‐term therapy with long‐acting octreotide (Sandostatin‐LAR®) for the management of acromegaly
Davies, P. H. O., Stewart, S. E., Lancranjan, I., Sheppard, M. C., & Stewart, P. M. (1998) · Clinical Endocrinology · doi:10.1046/j.1365-2265.1998.00389.x · Cited by 137 · see citing works
Ricinoleic acid-based biopolymers
Teomim, D., Nyska, A., & Domb, A. J. (1999) · Journal of Biomedical Materials Research · doi:10.1002/(sici)1097-4636(19990605)45:3 · Cited by 135 · see citing works
A hydrogel prepared by in situ cross-linking of a thiol-containing poly(ethylene glycol)-based copolymer: a new biomaterial for protein drug delivery
Qiu, B., Stefanos, S., Ma, J., Lalloo, A., Perry, B. A., Leibowitz, M. J., Sinko, P. J., & Stein, S. (2002) · Biomaterials · doi:10.1016/s0142-9612(02)00227-2 · Cited by 132 · see citing works
Controlled release of drugs from injectable in situ formed biodegradable PLGA microspheres: effect of various formulation variables
Jain, R. A. (2000) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/s0939-6411(00)00062-x · Cited by 130 · see citing works
Liposomes Dispersed Within a Thermosensitive Gel: A New Dosage Form for Ocular Delivery of Oligonucleotides
Bochot, A., Fattal, E., Gulik, A., et al. (1998) · Pharmaceutical Research · doi:10.1023/a:1011989202488 · Cited by 121 · see citing works
One-month release injectable microcapsules of a luteinizing hormone-releasing hormone agonist (leuprolide acetate) for treating experimental endometriosis in rats.
Okada, H., Heya, T., Ogawa, Y., & Shimamoto, T. (1988) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)24466-4 · Cited by 116 · see citing works
Controlled release of an osteogenic peptide from injectable biodegradable polymeric composites
Hedberg, E. L., Tang, A., Crowther, R. S., Carney, D. H., & Mikos, A. G. (2002) · Journal of Controlled Release · doi:10.1016/s0168-3659(02)00261-4 · Cited by 108 · see citing works
Myotoxicity studies of injectable biodegradable in-situ forming drug delivery systems
Kranz, H. (2001) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(00)00568-8 · Cited by 96 · see citing works
Sustained suppression of pituitary‐gonadal axis with an injectable, in situ forming implant of leuprolide acetate
Ravivarapu, H. B., Moyer, K. L., & Dunn, R. L. (2000) · Journal of Pharmaceutical Sciences · doi:10.1002/(sici)1520-6017(200006)89:6 · Cited by 94 · see citing works
Development of a Polymeric Surgical Paste Formulation for Taxol
Winternitz, C. I., Jackson, J. K., Oktaba, A. M., & Burt, H. M. (1996) · Pharmaceutical Research · doi:10.1023/a:1016032207246 · Cited by 91 · see citing works
A Clinical Study Of 22.5 mg. La-2550: A New Subcutaneous Depot Delivery System For Leuprolide Acetate For The Treatment Of Prostate Cancer
Chu, F. M., Jayson, M., DINEEN, M. K., et al. (2002) · The Journal of Urology · doi:10.1016/s0022-5347(05)64625-3 · Cited by 89 · see citing works
Parameters affecting the efficacy of a sustained release polymeric implant of leuprolide
Ravivarapu, H. B., Moyer, K. L., & Dunn, R. L. (2000) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(99)00371-3 · Cited by 86 · see citing works
Improvement in the in Situ Gelling Properties of Deacetylated Gellan Gum by the Immobilization of Thiol Groups
Krauland, A. H., Leitner, V. M., & Bernkop‐Schnürch, A. (2003) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.10371 · Cited by 84 · see citing works
Synthesis and Erosion Studies of Self-Catalyzed Poly(ortho ester)s
Ng, S., Vandamme, T., Taylor, M. S., & Heller, J. (1997) · Macromolecules · doi:10.1021/ma9610626 · Cited by 82 · see citing works
Sustained activity and release of leuprolide acetate from an in situ forming polymeric implant
Ravivarapu, H. B., Moyer, K. L., & Dunn, R. L. (2000) · AAPS PharmSciTech · doi:10.1208/pt010101 · Cited by 80 · see citing works
Sustained delivery of human growth hormone from a novel gel system: SABERTM
Okumu, F. W., Dao, L. N., Fielder, P. J., et al. (2002) · Biomaterials · doi:10.1016/s0142-9612(02)00174-6 · Cited by 78 · see citing works
Poloxamer 407-mediated alterations in the activities of enzymes regulating lipid metabolism in rats.
Wasan, K. M., Subramanian, R., Kwong, M., Goldberg, I. J., Wright, T., & Johnston, T. P. (2003) · PubMed · Cited by 73 · see citing works
Design of Amine-Modified Graft Polyesters for Effective Gene Delivery Using DNA-Loaded Nanoparticles
Oster, C. G., Wittmar, M., Unger, F. T., et al. (2004) · Pharmaceutical Research · doi:10.1023/b:pham.0000029279.50733.55 · Cited by 72 · see citing works
Self-citation
Development of an injectable, in situ crosslinkable, degradable polymeric carrier for osteogenic cell populations. Part 2. Viability of encapsulated marrow stromal osteoblasts cultured on crosslinking poly(propylene fumarate)
Payne, R. G., McGonigle, J. S., Yaszemski, M. J., et al. (2002) · Biomaterials · doi:10.1016/s0142-9612(02)00185-0 · Cited by 62 · see citing works
Release of taxol from poly(ϵ-caprolactone) pastes: effect of water-soluble additives
Dordunoo, S. K., Oktaba, A. M., Hunter, W. L., Min, W., Cruz, T. F., & Burt, H. M. (1997) · Journal of Controlled Release · doi:10.1016/s0168-3659(96)01510-6 · Cited by 61 · see citing works
Controlled delivery of drugs from a novel injectable in situ formed biodegradable PLGA microsphere system
Jain, C. T. R. R. A. (2000) · Journal of Microencapsulation · doi:10.1080/026520400288319 · Cited by 59 · see citing works
Structure formation in injectable poly(lactide–co-glycolide) depots
Wang, L., Kleiner, L. W., & Venkatraman, S. S. (2003) · Journal of Controlled Release · doi:10.1016/s0168-3659(03)00198-6 · Cited by 55 · see citing works
Development of biodegradable polymeric paste formulations for taxol: An in vitro and in vivo study
Zhang, X., Jackson, J. K., Wong, W., Min, W., Cruz, T. F., Hunter, W. L., & Burt, H. M. (1996) · International Journal of Pharmaceutics · doi:10.1016/0378-5173(96)04521-8 · Cited by 54 · see citing works
Pain-temperature relation in the application of local anaesthesia
Alonso, P. E., de Torres, L. Á. P., & Rioja, L. F. (1993) · British Journal of Plastic Surgery · doi:10.1016/0007-1226(93)90070-r · Cited by 47 · see citing works
Purity and stability assessment of a semi-solid poly(ortho ester) used in drug delivery systems
Merkli, A., Heller, J., Tabatabay, C., et al. (1996) · Biomaterials · doi:10.1016/0142-9612(96)83285-6 · Cited by 38 · see citing works
Development of poly(ortho esters) and their application for bovine serum albumin and bupivacaine delivery
Heller, J., Barr, J., Ng, S., et al. (2002) · Journal of Controlled Release · doi:10.1016/s0168-3659(01)00482-5 · Cited by 37 · see citing works
Endocrinology: Subcutaneous goserelin versus intranasal buserelin for pituitary down-regulation in patients undergoing IVF: a randomized comparative study
Tapanainen, J. S., Hovatta, O., Juntunen, K., Martikainen, H. K., Ratsula, K., Tulppala, M., & Tuomivaara, L. (1993) · Human Reproduction · doi:10.1093/oxfordjournals.humrep.a137980 · Cited by 34 · see citing works
Development and applications of injectable poly(ortho esters) for pain control and periodontal treatment
Heller, J., Barr, J., Ng, S. Y., Shen, H.-R., Schwach-Abdellaoui, K., Gurny, R., Vivien-Castioni, N., Loup, P. J., Baehni, P., & Mombelli, A. (2002) · Biomaterials · doi:10.1016/s0142-9612(02)00180-1 · Cited by 33 · see citing works
Semisolid, Self-Catalyzed Poly(Ortho Ester)s As Controlled-Release Systems: Protein Release and Protein Stability Issues
van de Weert, M., van Steenbergen, M. J., Cleland, J. L., et al. (2002) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.10109 · Cited by 28 · see citing works
Biotolerance of a semisolid hydrophobic biodegradable poly(ortho ester) for controlled drug delivery
Bernatchez, S. F., Merkli, A., Tabatabay, C., Gurny, R., Zhao, Q., Anderson, J., & Heller, J. (1993) · Journal of Biomedical Materials Research · doi:10.1002/jbm.820270515 · Cited by 28 · see citing works
Controlled delivery of metoclopramide using an injectable semi-solid poly(ortho ester) for veterinary application
Schwach‐Abdellaoui, K., Moreau, M., Schneider, M., et al. (2002) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(02)00314-9 · Cited by 27 · see citing works
The Atrigel Drug Delivery System
Dunn, R. (2002) · CRC Press eBooks · doi:10.1201/9780203910337-57 · Cited by 22 · see citing works
Sustained activity and release of leuprolide acetate from an in situ forming polymeric implant
Ravivarapu, H. B., Moyer, K. L., & Dunn, R. L. (2000) · AAPS PharmSciTech · doi:10.1007/bf02830516 · Cited by 21 · see citing works
A novel drug delivery system for recombinant human growth hormone with photopolymerized hydrogels
Annavajjula, D., Yim, K. S., Rowe, S. C., et al. (2001) · Infoscience (Ecole Polytechnique Fédérale de Lausanne) · Cited by 2 · see citing works

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“In vivo, block polymer nano-micelles are less likely to be recognized as foreign entities by immune cells, and their hydrophilic shell aids in evading the reticuloendothelial system, thus reducing the exclusion from bloodstream [105].”

Authors: Packhaeuser, C. B., Schnieders, J., Oster, C. G., & Kissel, T.
Affiliations: Philipps University of Marburg (DE)
Corresponding author: Kissel, T
Venue: European Journal of Pharmaceutics and Biopharmaceutics
Publisher: Elsevier BV
Published: 2004-09
Volume: 58
Issue: 2
Pages: 445-455
ISSN: 0939-6411 (ISSN-L)
DOI: 10.1016/j.ejpb.2004.03.003
OpenAlex: W2052306144
Cited by: 413
References: 51
Citations by year: 2026: 10 · 2025: 11 · 2024: 17 · 2023: 10 · 2022: 11 · 2021: 20 · 2020: 15 · 2019: 17 · 2018: 9 · 2017: 21 · 2016: 19 · 2015: 24 · 2014: 25 · 2013: 23 · 2012: 27
FWCI: 1.51
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: European Journal of Pharmaceutics and Biopharmaceutics (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
Health Sciences › Medicine › Emergency Medicine › Intramuscular injections and effects
Keywords: parenteral drug delivery, protein drug delivery, controlled release, polymeric drug delivery, drug reservoir
MeSH terms: Animals, Biodegradation, Environmental, Delayed-Action Preparations, Gels, Humans, Injections, Ointments, Polymers, Proteins, Drug Delivery Systems

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In situ forming parenteral drug delivery systems: an overview

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