Parenteral Delivery of Peptides and Proteins - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 542

ROCH 2

O

O CH 2 OR

O

O OR OH OH OH OH

RO OH

O

OH
3

OR

RO 3 2

3

2

OH

2

OH

OH OH

ROCH 2 OH OH

OR

3

2

2 3 3

O

2

RO

OR

O

CH 2 OR

OR

O RO

O

6

OR

OR

HO

6

ROCH 2 6

O HO HO

RO OR OH

O OH

OH

RO

CH 2 OR

O

O

CH 2 OR O

Figure 11.4 Structure of -cyclodextrin indicating its hydrophilic zone and hydrophobic
cavity.

In one study, several hydroxypropyl (HP-CDs) and sulfobutylether (SBE-CDs)
cyclodextrins with varying degrees of substitution were investigated for their stabiliz-
ing effect on various P/P drugs such as Clostridium difficile Toxoid A, Yersinia pestis
low-calcium-response V or V antigen (LcrV), and FGF-10 as a function of pH and
temperature. Results showed that CDs can recognize not only the size and shape but
also the chirality of amino acids, and CDs have ability to inhibit thermally induced
aggregation [113,114] . Insulin-HPCD interactions occurring inside microspheres
have been found to be responsible for decreased protein diffusivity in the polymer
matrix and achieve an effective modulation of protein release rate. The extent of this
effect was dependent on the method of microspheres preparation [95] . Buserelin
acetate, a synthetic nonapeptide that is a highly potent agonist of LHRH, has been
used to study the incorporating and protective effects of DM--CD (dimethyl-beta-
cyclodextrin) at various concentrations of peptide [115] . In one study, when CD
was coentrapped in the internal aqueous phase, EPO covalent aggregate formation
was significantly reduced during microparticle preparation by the double emulsion
method [102] . Similar results were obtained after incorporating lysozyme in the mic-
roparticle formation with improved stability [109] .
The use of 2-hydroxypropyl--cyclodextrin (HPCD) and CD as a solubilizing and
stabilizing excipient for many biologically important peptides, such as ovine growth
hormone (O-GH), GHs [116,117] , interleukin-2 (IL-2) [117] , monoclonal antibody
MN12 [118] , aspartame [119] , TNF- [120] , albumin [121] , -globulin [121] , lac-
tate dehydrogenase [122] , and bovine insulin, has also been reported to be very
successful in enhancing protection as well as altering the release pattern favorably
[105,106] .