PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of aapspharmspringer.comThis journalToc AlertsSubmit OnlineOpen Choice
 
AAPS PharmSciTech. 2003 June; 4(2): 147–156.
Published online 2003 April 30. doi:  10.1208/pt040228
PMCID: PMC2750591

Preparation and characterization of poly(D,L-lactide-co-glycolide) microspheres for controlled release of human growth hormone

Abstract

The purpose of this research was to assess the physicochemical properties of a controlled release formulation of recombinant human growth hormone (rHGH) encapsulated in poly(D,L-lactide-co-glycolide) (PLGA) composite microspheres. rHGH was loaded in poly(acryloyl hydroxyethyl) starch (acHES) microparticles, and then the protein-containing microparticles were encapsulated in the PLGA matrix by a solvent extraction/evaporation method. rHGH-loaded PLGA microspheres were also prepared using mannitol without the starch hydrogel microparticle microspheres for comparison. The detection of secondary structure changes in protein was investigated by using a Fourier Transfer Infrared (FTIR) technique. The composite microspheres were spherical in shape (44.6±2.47 μm), and the PLGA-mannitol microspheres were 39.7±2.50 μm. Drug-loading efficiency varied from 93.2% to 104%. The composite microspheres showed higher overall drug release than the PLGA/mannitol microspheres. FTIR analyses indicated good stability and structural integrity of HGH localized in the microspheres. The PLGA-acHES composite microsphere system could be useful for the controlled delivery of protein drugs.

Keywords: Microspheres, human growth hormone, protein delivery, composite microspheres

Full Text

The Full Text of this article is available as a PDF (440K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
1. Woo BW, Jiang G, Jo YW, DeLuca PP. Preparation and characterization of a composite PLGA and poly(acryloyl hydroxyethyl starch) microsphere system for protein delivery. Pharm Res. 2001;18:1600–1606. doi: 10.1023/A:1013090700443. [PubMed] [Cross Ref]
2. Schrier JA, DeLuca PP. Recombinant human bone morphogenetic protein-2 binding and incorporation in PLGA microsphere delivery. Pharm Dev Technol. 1999;4:611–621. doi: 10.1081/PDT-100101400. [PubMed] [Cross Ref]
3. Okada HY, Heya IT, Ueno H, Ogawa Y, Toguchi H. Pharmacokinetics of once-a-month injectable microspheres of Leuprolide Acetate. Pharm Res. 1991;8:787–791. doi: 10.1023/A:1015818504906. [PubMed] [Cross Ref]
4. Hausberger G, DeLuca PP. Characterization of biodegradable poly (D,L-lactide-co-glycolide)polymers and microspheres. J Pharm Biomed Anal. 1995;13:747–760. doi: 10.1016/0731-7085(95)01276-Q. [PubMed] [Cross Ref]
5. Li X, Zhang Y, Yan R, et al. Influence of process parameters on the protein stability encapsulated in poly-DL-lactide-poly(ethylene glycol) microspheres. J Control Release. 2000;68:41–52. doi: 10.1016/S0168-3659(00)00235-2. [PubMed] [Cross Ref]
6. Sah H. Protein instability toward organic solvent/water emulsification: implications for protein microencapsulation into microspheres. PDA J Pharm Sci Technol. 1999;53:3–10. [PubMed]
7. Johnson O, Cleland JL, Lee HJ, et al. A month-long effect from a single injection of microencapsulated human growth hormone. Nat Med. 1996;2:795–799. doi: 10.1038/nm0796-795. [PubMed] [Cross Ref]
8. Jorgensen JOL. Human growth hormone replacement therapy: pharmacological and clinical aspects. Endocr Rev. 1991;12:189–207. doi: 10.1210/edrv-12-3-189. [PubMed] [Cross Ref]
9. Moller J, Frandsen E, Fisker S, Jorgensen JO, Christiansen JS. Decreased plasma and extracellular volume in growth hormone deficient adults and the acute and prolonged effects of GH administration: a controlled experimental study. Clin Endocrinol. 1996;44:533–539. doi: 10.1046/j.1365-2265.1996.728550.x. [PubMed] [Cross Ref]
10. Fine RN, Kohaut EC, Brown D, Perlman AJ. Growth after recombinant growth hormone treatment in children with chronic renal failure: report of a multicenter randomized double-blind placebo-controlled study. Genentech Cooperative Study Group. J Pediatrics. 1994;124:374–382. doi: 10.1016/S0022-3476(94)70358-2. [PubMed] [Cross Ref]
11. Ranke MB. Growth Hormone therapy in Turner syndrome: analysis of long term results. Horm Res. 1995;44:35–41. [PubMed]
12. Weintroth SE, Parenti DM, Simon GL. Wasting syndrome in AIDS: pathophysiologic mechanisms and therapeutic approaches. Infect Agents Dis. 1995;4:76–94. [PubMed]
13. Cleland JL, Jonson OL, Putney S, Jones AJS. Recombinant human growth hormone poly(lactic-co-glycolic acid) microsphere formulation development. Adv Drug Deliv Rev. 1997;28:71–84. doi: 10.1016/S0169-409X(97)00051-3. [PubMed] [Cross Ref]
14. Wang N, Wu XS. A novel approach to stabilization of protein drugs in poly (lactide-co-glycolide) microspheres using agarose hydrogel. Int J Pharm. 1998;166:1–14. doi: 10.1016/S0378-5173(97)00339-6. [Cross Ref]
15. Pitt CG, Cha Y, Shah SS, Zhu KJ. Blends of PVA and PLGA: control of permeability and degradability of hydrogels by blending. J Control Release. 1992;19:189–200. doi: 10.1016/0168-3659(92)90076-4. [Cross Ref]
16. Huang LK, Mehta RC, Luca PP. Evaluation of a statistical model for the formation of poly(acryloyl hydroxyethyl starch) microspheres. Pharm Res. 1997;14:475–482. doi: 10.1023/A:1012199500072. [PubMed] [Cross Ref]
17. Cleland JL, Jones AJ. Stable formulation of recombinant human growth hormone and interferon-gamma for microencapsulation in biodegradable microspheres. Pharm Res. 1996;13(10):1464–1475. doi: 10.1023/A:1016063109373. [PubMed] [Cross Ref]
18. Shibuya T, Watanade Y, Nalley KA, Fusco A, Salafsky B. The BCA proteind etermination system: an analysis of several buffers, incubation temperature and protein standards. J Tokyo Mid College. 1989;47:677–682.
19. Kang F, Singh J. Effect of additives on the release of a model protein from PLGA microspheres. AAPS Pharm Sci Tech. y2001;2(4) article 30. [PMC free article] [PubMed]
20. Prestrelski SJ, Tedeschi N, Arakawa T, Carpenter JF. Dehydration-induced conformational changes in proteins and their inhibition by stabilizers. Biophys J. 1993;65:661–671. [PubMed]
21. Yang TH, Dong A, Meyer J, Johnson OL, Cleland JL, Carpenter JF. Use of infrared spectroscopy to assess secondary structure of Human Growth Hormone within biodegradable microspheres. J Pharm Sci. 1999;88(2):161–165. doi: 10.1021/js980423n. [PubMed] [Cross Ref]
22. Griebenow K, Klibanov AM. On protein denaturation in aqueous-organic mixtures but not in pure organic solvents. J Am Chem.Soc. 1996;118:11695–11700. doi: 10.1021/ja961869d. [Cross Ref]
23. Griebenow K, Klibanov AM. Can conformational changes be responsible for solvent and excipients effects on the catalytic behavior of subtilisin Carlsberg in organic solvents? Biotechnol Bioeng. 1997;53:351–362. doi: 10.1002/(SICI)1097-0290(19970220)53:4<351::AID-BIT1>3.0.CO;2-M. [PubMed] [Cross Ref]
24. Susi H, Byler DM. Resolution enhanced Fourier transform infrared spectroscopy of enzymes. Methods Enzymol. 1986;130:290–311. [PubMed]
25. Carrasquillo KG, Costantino HR, Cordero RA, Hsu CC, Griebenow K. On the structural preservation of recombinant human growth hormone in a dried film of a synthetic biodegradable polymer. J Pharm Sci. 1999;88(2):166–173. doi: 10.1021/js980272o. [PubMed] [Cross Ref]
26. Costantino HR, Carrasquillo KG, Cordero RA, Mumenthaler M, Hsu CC, Griebenow K. Effect of excipients on the stability and structure of lyophilized recombinant human growth hormone. J Pharm Sci. 1998;87(11):1412–1420. doi: 10.1021/js980069t. [PubMed] [Cross Ref]

Articles from AAPS PharmSciTech are provided here courtesy of American Association of Pharmaceutical Scientists