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Pharmaceutical Research

, Volume 32, Issue 7, pp 2180–2191 | Cite as

Long-Acting Injectable Hormonal Dosage Forms for Contraception

  • Linfeng Wu
  • Dileep R. Janagam
  • Timothy D. Mandrell
  • James R. Johnson
  • Tao L. Lowe
Expert Review

Abstract

Although great efforts have been made to develop long-acting injectable hormonal contraceptives for more than four decades, few long-acting injectable contraceptives have reached the pharmaceutical market or even entered clinical trials. On the other hand, in clinical practice there is an urgent need for injectable long-acting reversible contraceptives which can provide contraceptive protection for more than 3 months after one single injection. Availability of such products will offer great flexibility to women and resolve certain continuation issues currently occurring in clinics. Herein, we reviewed the strategies exploited in the past to develop injectable hormonal contraceptive dosages including drug microcrystal suspensions, drug-loaded microsphere suspensions and in situ forming depot systems for long-term contraception and discussed the potential solutions for remaining issues met in the previous development.

KEY WORDS

contraception in situ forming depot systems microcrystals microspheres steroidal progestogens 

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

We thank our former graduates Dr. Zhi-Hui Gao, Dr. Shilpa Thosar and Dr. Yichun Sun, our former research associate Dr. Wen Qu, and our collaborators William R. Crowley, James F. Reger, Catharine J. Wheaton, Donald Neiffer, Bill Lasley, and Gary Anderson for their efforts in our studies on in situ forming depots for contraception at UTHSC. We also thank Dr. Wen Qu for his discussion and comments on the manuscript.

REFERENCES

  1. 1.
    Newton J. Classification and comparison of oral contraceptives containing new generation progestogens. Hum Reprod Update. 1995;1(3):231–63.CrossRefPubMedGoogle Scholar
  2. 2.
    Garza-Flores J, Hall PE, Perez-Palacios G. Long-acting hormonal contraceptives for women. J Steroid Biochem Mol Biol. 1991;40(4–6):697–704.CrossRefPubMedGoogle Scholar
  3. 3.
    Singh M, Saxena BB, Singh R, Kaplan J, Ledger WJ. Contraceptive efficacy of norethindrone encapsulated in injectable biodegradable polydl-lactide-co-glycolide microspheres (NET-90): phase III clinical study. Adv Contracept. 1997;13:1–11.CrossRefPubMedGoogle Scholar
  4. 4.
    Kulier R, Helmerhorst FM, Maitra N, Gülmezoglu AM. Effectiveness and acceptability of progestogens in combined oral contraceptives–a systematic review. Reprod Health. 2004;1:1.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kulier R et al. Effectiveness and acceptability of progestogens in combined oral contraceptives–a systematic review. Reprod Health. 2004;1(1):1.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Rosendaal F, Helmerhorst F, Vandenbroucke J. Female hormones and thrombosis. Arterioscler Thromb Vasc Biol. 2002;22(2):201–10.CrossRefPubMedGoogle Scholar
  7. 7.
    Sitruk-Ware R, Nath A, Mishell DR, Jr. Contraception technology: past, present and future. Contraception. 2012.Google Scholar
  8. 8.
    Sitruk-Ware R. Reprint of pharmacological profile of progestins. Maturitas. 2008;61(1):151–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Zhang Y, Li C-X, Ning M-Y, Duan X-Y, Liu Y. Preparation and evaluation of intravaginal ring containing drospirenone. Adv Pharm Sci. 2013;2013:11.Google Scholar
  10. 10.
    Zhang Y et al. Preparation and evaluation of intravaginal ring containing drospirenone. Adv Pharm Sci. 2013;2013:11.Google Scholar
  11. 11.
    Rajesh N, Rowan S. Female contraception: present and future perspectives. Curr Womens Health Rev. 2009;5(3):167–75.CrossRefGoogle Scholar
  12. 12.
    Potts DM, Siemens AJ. Where next with long-acting steroids? IPPF Med Bull. 1984;18(3):2–3.PubMedGoogle Scholar
  13. 13.
    Delvadia D. Reversible long-acting contraceptives. J Am Osteopath Assoc. 1997;97(8 SUPPL. 1):S8–S12.Google Scholar
  14. 14.
    Rosenberg MJ, Waugh MS. Oral contraceptive discontinuation: a prospective evaluation of frequency and reasons. Am J Obstet Gynecol. 1998;179(3):577–82.CrossRefPubMedGoogle Scholar
  15. 15.
    Ruminjo JK, Sekadde-Kigondu CB, Karanja JG, Rivera R, Nasution M, Nutley T. Comparative acceptability of combined and progestin-only injectable contraceptives in Kenya. Contraception. 2005;72:138–45.CrossRefPubMedGoogle Scholar
  16. 16.
    Ruminjo JK et al. Comparative acceptability of combined and progestin-only injectable contraceptives in Kenya. Contraception. 2005;72(2):138–45.CrossRefPubMedGoogle Scholar
  17. 17.
    Chue P. Risperidone long-acting injection. Expert Rev Neurother. 2003;3(4):435–46.CrossRefPubMedGoogle Scholar
  18. 18.
    Packhaeuser CB, Schnieders J, Oster CG, Kissel T. In situ forming parenteral drug delivery systems: an overview. Eur J Pharm Biopharm. 2004;58:445–55.CrossRefPubMedGoogle Scholar
  19. 19.
    Beck LR, Pope VZ, Tice TR, Gilley RM. Long-acting injectable microsphere formulation for the parenteral administration of levonorgestrel. Adv Contracept. 1985;1:119–29.CrossRefPubMedGoogle Scholar
  20. 20.
    Wang SH, Zhang LC, Lin F, Sa XY, Zuo JB, Shao QX, et al. Controlled release of levonorgestrel from biodegradable poly(D, L-lactide-co-glycolide) microspheres: in vitro and in vivo studies. Int J Pharm. 2005;301:217–25.CrossRefPubMedGoogle Scholar
  21. 21.
    Dhanaraju MD, RajKannan R, Selvaraj D, Jayakumar R, Vamsadhara C. Biodegradation and biocompatibility of contraceptive-steroid-loaded poly (dl-lactide-co-glycolide) injectable microspheres: in vitro and in vivo study. Contraception. 2006;74:148–56.CrossRefPubMedGoogle Scholar
  22. 22.
    Sun Y, Wang J, Zhang X, Zhang Z, Zheng Y, Chen D, et al. Synchronic release of two hormonal contraceptives for about one month from the PLGA microspheres: in vitro and in vivo studies. J Control Release. 2008;129:192–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Machado SR, Lunardi LO, Tristao AP, Marchetti JM. Preparation and characterization of D, L-PLA loaded 17-beta-Estradiol valerate by emulsion/evaporation methods. J Microencapsul. 2009;26:202–13.CrossRefPubMedGoogle Scholar
  24. 24.
    Machado SR et al. Preparation and characterization of D, L-PLA loaded 17-beta-Estradiol valerate by emulsion/evaporation methods. J Microencapsul. 2009;26(3):202–13.CrossRefPubMedGoogle Scholar
  25. 25.
    Trantolo D, Hsu Y-Y, Gresser J, Wise D, Moo-Young A. Biodegradable systems for long-acting nesterone. In: Wise D, editor. Handbook of pharmaceutical controlled release technology. New York: Marcel Dekker, Inc.; 2000.Google Scholar
  26. 26.
    Trantolo D et al. Biodegradable systems for long-acting nesterone. In: Wise D, editor. Handbook of pharmaceutical controlled release technology. New York: Marcel Dekker, Inc; 2000.Google Scholar
  27. 27.
    Rivera R, Alvarado G, Aldaba CFS, Hernandez A. Norethisterone contraceptive microspheres. J Steroid Biochemistry. 1987;27:1003–7.CrossRefGoogle Scholar
  28. 28.
    Grubb GS, Welch JD, Cole L, Goldsmith A, Rivera R. A comparative evaluation of the safety and contraceptive effectiveness of 65 mg and 100 mg of 90-day norethindrone (NET) injectable microspheres: a multicenter study. Fertil Steril. 1989;51:803–10.PubMedGoogle Scholar
  29. 29.
    Grubb GS et al. A comparative evaluation of the safety and contraceptive effectiveness of 65 mg and 100 mg of 90-day norethindrone (NET) injectable microspheres: a multicenter study. Fertil Steril. 1989;51(5):803–10.PubMedGoogle Scholar
  30. 30.
    Kempe S, Mäder K. In situ forming implants—an attractive formulation principle for parenteral depot formulations. J Control Release. 2012;161(2):668–79.CrossRefPubMedGoogle Scholar
  31. 31.
    Junkmann K. Long-acting steroids in reproduction. Recent Prog Horm Res. 1957;13:389–419.PubMedGoogle Scholar
  32. 32.
    Shearman RP. The development of depot contraceptives. J Steroid Biochemistry. 1975;6(6):899–902.CrossRefGoogle Scholar
  33. 33.
  34. 34.
  35. 35.
    Peralta O. Injectable hormonal contraceptives: an overview. Gynaecol Forum. 2000;5(1):p. http://www.medforum.nl/gynfo/leading_article1.asp.
  36. 36.
    Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIHCD), A Phase I Study to Evaluate the Pharmacokinetic and Pharmacodynamic Profile of a Single Injection of Levonorgestel Butanoate for Female Contraception. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US), 2014 May 12 [cited 2014 Sep 7]. (Available from: http://clinicaltrials.gov/show/NCT02173808 NLM Identifier: NCT02173808.).
  37. 37.
  38. 38.
  39. 39.
    Okada H. One- and three-month release injectable microspheres of the LH-RH superagonist leuprorelin acetate. Adv Drug Deliv Rev. 1997;28(1):43–70.CrossRefPubMedGoogle Scholar
  40. 40.
    Putney SD, Burke PA. Improving protein therapeutics with sustained-release formulations. Nat Biotechnol. 1998;16:153.CrossRefPubMedGoogle Scholar
  41. 41.
    Freiberg S, Zhu XX. Polymer microspheres for controlled drug release. Int J Pharm. 2004;282:1–18.CrossRefPubMedGoogle Scholar
  42. 42.
    Freiberg S, Zhu XX. Polymer microspheres for controlled drug release. Int J Pharm. 2004;282(1–2):1–18.CrossRefPubMedGoogle Scholar
  43. 43.
    Clarck SL, Crowley AJ, Schmidt PG, Donoghue AR, Piché CA. Long-term delivery of ivermectin by use of poly(D, L-lactic-co-glycolic)acid microparticles in dogs. Am J Vet Res. 2004;65:752–7.CrossRefGoogle Scholar
  44. 44.
    Berkland C, Kim K, Pack DW. PLG microsphere size controls drug release rate through several competing factors. Pharm Res. 2003;20:1055–62.CrossRefPubMedGoogle Scholar
  45. 45.
    Berkland C, Kim K, Pack DW. PLG microsphere size controls drug release rate through several competing factors. Pharm Res. 2003;20(7):1055–62.CrossRefPubMedGoogle Scholar
  46. 46.
    Berkland C, King M, Cox A, Kim K, Pack DW. Precise control of PLG microsphere size provides enhanced control of drug release rate. J Control Release. 2002;82:137–47.CrossRefPubMedGoogle Scholar
  47. 47.
    Berkland C et al. Precise control of PLG microsphere size provides enhanced control of drug release rate. J Control Release. 2002;82(1):137–47.CrossRefPubMedGoogle Scholar
  48. 48.
    Buntner B, Nowak M, Kasperczyk J, Ryba M, Grieb P, Walski M, et al. The application of microspheres from the copolymers of lactide and ε-caprolactone to the controlled release of steroids. J Control Release. 1998;56:159–67.CrossRefPubMedGoogle Scholar
  49. 49.
    Buntner B et al. The application of microspheres from the copolymers of lactide and ε-caprolactone to the controlled release of steroids. J Control Release. 1998;56(1–3):159–67.CrossRefPubMedGoogle Scholar
  50. 50.
    Tice TR, Gilley RM. Preparation of injectable controlled-release microcapsules by a solvent-evaporation process. J Control Release. 1985;2:343–52.CrossRefGoogle Scholar
  51. 51.
    Dhanaraju MD, Jayakumar R, Vamsadhara C. Influence of manufacturing parameters on development of contraceptive steroid loaded injectable microspheres. Chem Pharm Bull. 2004;52:976–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Song CX, Sun HF, Feng XD. Microspheres of biodegradable block copolymer for long-acting controlled delivery of contraceptives. Polym J. 1987;19:485–91.CrossRefGoogle Scholar
  53. 53.
    Gu ZW, Ye WP, Yang JY, Li YX, Chen XL, Zhong GW, et al. Biodegradable block copolymer matrices for long-acting contraceptives with constant release. J Control Release. 1992;22:3–14.CrossRefGoogle Scholar
  54. 54.
    Gu ZW et al. Biodegradable block copolymer matrices for long-acting contraceptives with constant release. J Control Release. 1992;22(1):3–14.CrossRefGoogle Scholar
  55. 55.
    Dhanaraju MD, Gopinath D, Ahmed MR, Jayakumar R, Vamsadhara C. Characterization of polymeric poly(ε-caprolactone) injectable implant delivery system for the controlled delivery of contraceptive steroids. J Biomed Mater Res A. 2006;76:63–72.CrossRefPubMedGoogle Scholar
  56. 56.
    Dhanaraju MD et al. Characterization of polymeric poly(ε-caprolactone) injectable implant delivery system for the controlled delivery of contraceptive steroids. J Biomed Mater Res A. 2006;76(1):63–72.CrossRefPubMedGoogle Scholar
  57. 57.
    Latha MS, Lal AV, Kumary TV, Sreekumar R, Jayakrishnan A. Progesterone release from glutaraldehyde cross-linked casein microspheres: in vitro studies and in vivo response in rabbits. Contraception. 2000;61:329–34.CrossRefPubMedGoogle Scholar
  58. 58.
    Latha MS et al. Progesterone release from glutaraldehyde cross-linked casein microspheres: in vitro studies and in vivo response in rabbits. Contraception. 2000;61(5):329–34.CrossRefPubMedGoogle Scholar
  59. 59.
    Puthli S, Vavia P. Gamma irradiated micro system for long-term parenteral contraception: an alternative to synthetic polymers. Eur J Pharm Sci. 2008;35(4):307–17.CrossRefPubMedGoogle Scholar
  60. 60.
    Jameela SR et al. Progesterone-loaded chitosan microspheres: a long acting biodegradable controlled delivery system. J Control Release. 1998;52(1–2):17–24.CrossRefPubMedGoogle Scholar
  61. 61.
    Lu B, Guo RL, Liu C. Studies on an injection of microencapsulated levonorgestrel. In: Whateley TL, editor. Microencapsulation of drugs. UK: Harwood Academic Publishers; 1992. p. 103–21.Google Scholar
  62. 62.
    Lu B, Wang Z, Yang H. Long-acting delivery microspheres of levo-norgestrolpoly (3-hydroxybutyrate): their preparation, characterization and contraceptive tests on mice. J Microencapsul. 2001;18:55–64.CrossRefPubMedGoogle Scholar
  63. 63.
    Zhong-wei G, Wei-ping Y, Ji-yuan Y, You-xin L, Xian-li C, Ge-wen Z, et al. Biodegradable block copolymer matrices for long-acting contraceptives with constant release. J Control Release. 1992;22:3–14.CrossRefGoogle Scholar
  64. 64.
    Zhong-wei G et al. Biodegradable block copolymer matrices for long-acting contraceptives with constant release. J Control Release. 1992;22(1):3–14.CrossRefGoogle Scholar
  65. 65.
    Schindler A, et al. Biodegradable polymers for sustained drug delivery. In Contemporary topics in polymer science. Springer; 1977. p. 251–289.Google Scholar
  66. 66.
    Pitt CG et al. Sustained drug delivery systems. I. The permeability of poly (ϵ‐caprolactone), poly (DL‐lactic acid), and their copolymers. J Biomed Mater Res. 1979;13(3):497–507.CrossRefPubMedGoogle Scholar
  67. 67.
    Li YX, Feng XD. Biodegradable polymeric matrix for long‐acting and zero‐order release drug delivery systems. In: Makromolekulare Chemie. Macromolecular Symposia. 1990. Wiley Online Library.Google Scholar
  68. 68.
    Beck LR, Pope VZ. Long-acting injectable norethisterone contraceptive system: review of clinical studies. Res Front Fertil Regul RFFR / PARFR. 1984;3(2):1–10.Google Scholar
  69. 69.
    Beck LR, Ramos RA, Flowers Jr CE. Clinical evaluation of injectable biodegradable contraceptive system. Am J Obstet Gynecol. 1981;140(7):799–806.PubMedGoogle Scholar
  70. 70.
    Beck LR, Cowsar D. Biodegradable microsphere contraceptive system. Acta Eur Fertil. 1980;11(2):139–50.PubMedGoogle Scholar
  71. 71.
    Huang X, Chestang BL, Brazel CS. Minimization of initial burst in poly(vinyl alcohol) hydrogels by surface extraction and surface-preferential crosslinking. Int J Pharm. 2002;248:183–92.CrossRefPubMedGoogle Scholar
  72. 72.
    Wu L, Brazel CS. Modifying the release of proxyphylline from PVA hydrogels using surface crosslinking. Int J Pharm. 2008;349:144–51.CrossRefPubMedGoogle Scholar
  73. 73.
    Wu L, Brazel CS. Modifying the release of proxyphylline from PVA hydrogels using surface crosslinking. Int J Pharm. 2008;349(1–2):144–51.CrossRefPubMedGoogle Scholar
  74. 74.
    Wu J, Kong T, Yeung KWK, Shum HC, Cheung KMC, Wang L, et al. Fabrication and characterization of monodisperse PLGA-alginate core-shell microspheres with monodisperse size and homogeneous shells for controlled drug release. Acta Biomater. 2013;9:7410–9.CrossRefPubMedGoogle Scholar
  75. 75.
    Cong H, Beck LR. Preparation and pharmacokinetic evaluation of a modified long-acting injectable norethisterone microsphere. Adv Contracept. 1991;7:251–6.CrossRefPubMedGoogle Scholar
  76. 76.
    Meyer RF, Rogers WB, McClendon MT, Crocker JC. Producing monodisperse drug-loaded polymer microspheres via cross-flow membrane emulsification: the effects of polymers and surfactants. Langmuir. 2010;26:14479–87.CrossRefPubMedGoogle Scholar
  77. 77.
    Meyer RF et al. Producing monodisperse drug-loaded polymer microspheres via cross-flow membrane emulsification: the effects of polymers and surfactants. Langmuir. 2010;26(18):14479–87.CrossRefPubMedGoogle Scholar
  78. 78.
    Akamatsu K et al. Preparation of monodisperse chitosan microcapsules with hollow structures using the spg membrane emulsification technique. Langmuir. 2010;26(18):14854–60.CrossRefPubMedGoogle Scholar
  79. 79.
    Zhao Y et al. Facile preparation of fluorescence-encoded microspheres based on microfluidic system. J Colloid Interface Sci. 2010;352(2):337–42.CrossRefPubMedGoogle Scholar
  80. 80.
    Sugiura S, Nakajima M, Seki M. Preparation of monodispersed polymeric microspheres over 50 μm employing microchannel emulsification. Ind Eng Chem Res. 2002;41(16):4043–7.CrossRefGoogle Scholar
  81. 81.
    Freitas S, Merkle HP, Gander B. Microencapsulation by solvent extraction/evaporation: reviewing the state of the art of microsphere preparation process technology. J Control Release. 2005;102(2):313–32.CrossRefPubMedGoogle Scholar
  82. 82.
    Berkland C, Kim K, Pack DW. Fabrication of PLG microspheres with precisely controlled and monodisperse size distributions. J Control Release. 2001;73:59–74.CrossRefPubMedGoogle Scholar
  83. 83.
    Berkland C, Kim K, Pack DW. Fabrication of PLG microspheres with precisely controlled and monodisperse size distributions. J Control Release. 2001;73(1):59–74.CrossRefPubMedGoogle Scholar
  84. 84.
    Cardot JM, Davit BM. In vitro-in vivo correlations: tricks and traps. AAPS J. 2012;14(3):491–9.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Pollauf EJ, Kim KK, Pack DW. Small-molecule release from poly(D, L-lactide)/poly(D, L-lactide-co- glycolide) composite microparticles. J Pharm Sci. 2005;94:2013–22.CrossRefPubMedGoogle Scholar
  86. 86.
    Pollauf EJ, Kim KK, Pack DW. Small-molecule release from poly(D, L-lactide)/poly(D, L-lactide-co- glycolide) composite microparticles. J Pharm Sci. 2005;94(9):2013–22.CrossRefPubMedGoogle Scholar
  87. 87.
    Dunn RL, Yewey GL, Fujita SM, Josephs KR, Whitman SL, Southard GL, et al. Sustained release of cisplatin in dogs from an injectable implant delivery system. J Bioact Compat Polym. 1996;11:286–300.Google Scholar
  88. 88.
    Eliaz RE, Wallach D, Kost J. Delivery of soluble tumor necrosis factor receptor from in-situ forming PLGA implants: in-vivo. Pharm Res. 2000;17:1546–50.CrossRefPubMedGoogle Scholar
  89. 89.
    Johansson AK, Linse P, Piculell L, Engström S. Phase behavior of the quaternary poly(DL-lactide-co-glycolide)/monoolein/1-methyl-2-pyrrolidinone/water system: an experimental and theoretical study. J Phys Chem B. 2001;105:12157–64.CrossRefGoogle Scholar
  90. 90.
    Johansson AK et al. Phase behavior of the quaternary poly(DL-lactide-co-glycolide)/monoolein/1-methyl-2-pyrrolidinone/water system: an experimental and theoretical study. J Phys Chem B. 2001;105(48):12157–64.CrossRefGoogle Scholar
  91. 91.
    Dong S et al. An in situ-forming, solid lipid/PLGA hybrid implant for long-acting antipsychotics. Soft Matter. 2011;7(12):5873–8.CrossRefGoogle Scholar
  92. 92.
    Başaran B, Bozkir A. Thermosensitive and pH induced in situ ophthalmic gelling system for ciprofloxacin hydrochloride: hydroxypropyl-β-cyclodextrin complex. Acta Pol Pharm Drug Res. 2012;69:1137–47.Google Scholar
  93. 93.
    Gupta SK, Singhvi IJ. Sustained ophthalmic delivery of moxifloxacin hydrochloride from an pH triggered in situ gelling system. Res J Pharm Technol. 2012;5:1538–42.Google Scholar
  94. 94.
    Royals MA, Fujita SM, Yewey GL, Rodriguez J, Schultheiss PC, Dunn RL. Biocompatibility of a biodegradable in situ forming implant system in rhesus monkeys. J Biomed Mater Res. 1999;45:231–9.CrossRefPubMedGoogle Scholar
  95. 95.
    Royals MA et al. Biocompatibility of a biodegradable in situ forming implant system in rhesus monkeys. J Biomed Mater Res. 1999;45(3):231–9.CrossRefPubMedGoogle Scholar
  96. 96.
    Astaneh R et al. Effects of ethyl benzoate on performance, morphology, and erosion of PLGA implants formed in situ. Adv Polym Technol. 2008;27(1):17–26.CrossRefGoogle Scholar
  97. 97.
    Pandya TP, Modasiya MK, Patel VM. Sustained ophthalmic delivery of ciprofloxacin hydrochloride from an ion-activated in situ gelling system. Der Pharm Lett. 2011;3:404–10.Google Scholar
  98. 98.
    Dunn RL, English JP, Cowsar DR, Vanderbilt DP. Biodegradable in situ forming implants and methods of producing the same. In: USA, editor. USA Patent 4,938,763. USA Patent 4,938,7631990.Google Scholar
  99. 99.
    Dunn RL, English JP, Cowsar DR, Vanderbilt DP. Biodegradable in situ forming implants and methods of producing the same. In: USA Patent 4,938,763, USA, Editor. 1990: USA Patent 4,938,763.Google Scholar
  100. 100.
    Parent M et al. Plga in situ implants formed by phase inversion: critical physicochemical parameters to modulate drug release. J Control Release. 2013;172(1):292–304.CrossRefPubMedGoogle Scholar
  101. 101.
    Thosar SS. Controlled release of a contraceptive steroid from biodegradable and injectable formulations: in vitro and in vivo evaluations. The University of Tennessee Health Science Center, Thesis. 1997.Google Scholar
  102. 102.
    Thosar SS, Shukla AJ, Crowley WR, Johnson JR. Evaluation of the effects of varying formulation factors on the in vitro release of levonorgestrel from a biodegradable injectable drug delivery system. Pharm Res. 1996;13S–298.Google Scholar
  103. 103.
    Gao Z, Shukla AJ, Johnson JR, Crowley WR. Controlled release of a contraceptive steroid from biodegradable and injectable gel formulations: in vitro evaluation. Pharm Res. 1995;12:857–63.CrossRefPubMedGoogle Scholar
  104. 104.
    Tell L, Shukla A, Munson L, Thosar S, Kass P, Stanton R, et al. A comparison of the effects of slow release, injectable levonorgestrel and depot medroxyprogesterone acetate on egg production in Japanese quail (Coturnix coturnix japonica). J Avian Med Surg. 1999;13:23–31.Google Scholar
  105. 105.
    Tell L et al. A comparison of the effects of slow release, injectable levonorgestrel and depot medroxyprogesterone acetate on egg production in Japanese quail (Coturnix coturnix japonica). J Avian Med Surg. 1999;13(1):23–31.Google Scholar
  106. 106.
    Looper S et al. Efficacy of levonorgestrel when administered as an irradiated, slow-release injectable matrix for feline contraception. Zoo Biol. 2001;20(5):407–21.CrossRefGoogle Scholar
  107. 107.
    Wheaton CJ et al. The use of long acting subcutaneous levonorgestrel (LNG) gel depot as an effective contraceptive option for cotton-top tamarins (Saguinus oedipus). Zoo Biol. 2011;30(5):498–522.CrossRefPubMedGoogle Scholar
  108. 108.
    Yewey GL, Krinick NL, Dunn RL, Radomsky ML, Brouwer G, Tipton AJ. Liquid delivery compositions. In: US Patent 5780044, U. Patent, Editor. USA; 1998.Google Scholar
  109. 109.
    Chen S, Singh J. In vitro release of levonorgestrel from phase sensitive and thermosensitive smart polymer delivery systems. Pharm Dev Technol. 2005;10(2):319–25.CrossRefPubMedGoogle Scholar
  110. 110.
    Brodbeck KJG-D, Ann T, Shen TT-I. Gel composition and methods. In: US Patent 6130200, U. patent, Editor. USA; 2000.Google Scholar
  111. 111.
    Bowers R. Longer-acting method that is injectable probed. Contracept Technol Updat. 2013;34(3):28–9.Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Linfeng Wu
    • 1
  • Dileep R. Janagam
    • 1
  • Timothy D. Mandrell
    • 2
  • James R. Johnson
    • 1
  • Tao L. Lowe
    • 1
  1. 1.Department of Pharmaceutical SciencesUniversity of Tennessee Health Science CenterMemphisUSA
  2. 2.Department of Comparative MedicineUniversity of Tennessee Health Science CenterMemphisUSA

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