Polymeric Delivery Systems - American Chemical Society

Chapter 20

Drug Release from Triblock Copolymers of Poly(hydroxyalkyl L-glutamine)—Poly(ethylene oxide)—Poly(hydroxyalkyl L-glutamine)

Downloaded by YORK UNIV on October 29, 2012 | http://pubs.acs.org Publication Date: March 5, 1993 | doi: 10.1021/bk-1993-0520.ch020

Chong Su Cho, You Han Bae, and Sung Wan K i m Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, U T 84112

The loading and release behavior of drugs with various aqueous solubilities from potentially biodegradable block copolymer discs were investigated. The block copolymers used were crosslinked poly(hydroxyalkyl L-glutamine)(PHAG)/poly(ethylene oxide)(PEO)/PHAG block copolymers, which were obtained by aminoalcoholysis of poly(γ-benzyl L-glutamate) (PBLG)/PEO/PBLG using various aminoalcohols. The release pattern and rate were influenced by the ratio of the two domains, microstructure morphology, drug solubility, and chemical composition which was determined by alkyl length and degree of aminoalcoholysis. In particular, a combination with low PEO content, low drug solubility, low degree of aminoalcoholysis, and longer alkyl chains led to long term constant release from these matrices. This constant release can be explained by a barrier effect of the continuous PHAG phase. Drug release from biodegradable or bioerodable polymeric matrices has been intensively investigated for the last decade. One major advantage of using a biodegradable system is to eliminate surgical removal of an implanted delivery device after the delivery system is exhausted. Biodegradable materials used for drug delivery include poly(lactide-co-glycolide)s, polyanhydrides, poly(ortho esters), poly(αamino acids), and polyphosphazenes. Besides the good biocompatibility and nontoxic by-products of the matrix degradation, one important factor in designing a biodegradable delivery system is to control the release kinetics. Biodegradable delivery systems can also be used to achieve zero-order release kinetics which would be desirable for a long term delivery of drugs having a narrow therapeutic window. One way to obtain constant releasefroma biodegradable monolithic device is to use a polymeric prodrug, where drug molecules are bound to a biodegradable polymeric backbone. Poly(α-amino acids) is commonly used as a biodegradable via hydrolytically labile bonds, polymeric backbone (1-4). The drug release ratefroma polymeric biodegradable matrix is controlled by several processes, such as penetration of water into the device, hydrolysis of the labile bonds, and diffusion of free drugs out of the device. Zero-order release can be achieved if water penetration or drug diffusion is the rate determining step. Following release, the polymeric backbone would be further degraded. 0097-6156/93/0520-0274$06.00/0 © 1993 American Chemical Society

In Polymeric Delivery Systems; El-Nokaly, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.


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Drug ReleasefromTriblock Copolymers

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Another approach to constant release is surface erosion of bioerodable polymer matrices containing dispersed or dissolved drugs (5, 6). The release of the drugs is governed by the erosion of the polymer at the interface between the device surface and the release media. Constant release can be achieved if the device maintains a constant surface area during erosion. There are few studies on drug release from microphase-separated polymeric matrices (7-10). The factors influencing the drug release pattern and/or the release rate are specific molecular interactions between loaded drugs and polymer microdomains (7), the mode of microdomain structure (8), degradation rate (9,10), and hydrophilicity of involved segments (10). W e synthesized and characterized potentially biodegradable, microphaseseparated block copolymer hydrogels, aiming at a long term implantable drug delivery device. It has been reported that A B A block copolymers, consisting of poly(y-benzyl L - glutamate)(PBLG) as the A block and poly(ethylene oxide)(PEO) as the Β block, showed a microphase-separated structure (77) and that the block copolymer was degraded by proteolytic enzymes both in vitro and in vivo (12,13). The P B L G block was derivatized with varying alkyl groups to yield poly(hydroxyalkyl L glutamine)(PHAG) blocks and then the resulting block copolymers were crosslinked. Hayashi et al.(74) reported that the in vitro degradation, by pronase E , of the poly(hydroxyalkyl L-glutamine-co- γ-methyl L-glutamate) fibers was highly dependent on the swelling of the fibers. Pytela et al.(75) also reported that the degradation, by proteolytic enzymes, of the copolymers of hydroxyethyl L glutamine(HEG) was enhanced by the introduction, or copolymerization, of hydrophobic groups into the poly(hydroxyethyl L-glutamine)(PHEG). The loading and release behaviors of model solutes with varying aqueous solubilities were investigated using our polymer matrices. Experimental C h e m i c a l s a n d Reagents. γ-Benzyl L-glutamate, hydrocortisone (HC), timolol maleate (TM), and verapamil hydrochloride (VP) were purchased from Sigma Chem. Co.(St. Louis, M O ) . 1,8-Octamethylene diamine ( O M D A ) , 3-amino-l-propanol, 5amino-l-pentanol, 6-amino-l-hexanol, and triphosgene were purchased from Aldrich Chem. Co., Inc.(Milwaukee, WI). Ruthenium tetroxide was purchased from Polysciences, Inc.(Warrington, P A ) . Amine-terminated poly(ethylene oxide)(ATPEO, M W : 4 , 000) was obtained from Texaco Chem. Co.(Houston, T X ) . Poly(y-benzyl L-glutamate)(PBLG, M W : 40,000) was obtained from Miles-Yeda L T D . ( Israel). A l l chemicals used were of reagent or spectrometric grade. Tetrahydrofuran, n-hexane, methylene dichloride, dioxane and absolute ethanol were stored with 4 Â molecular sieves and used without further purification. Synthesis of P B L G / P E O / P B L G B l o c k C o p o l y m e r . γ-Benzyl L-glutamate N-carboxyanhydride(BLG-NCA) was prepared by a method described in the literature (76). The method of the block copolymer synthesis was previously reported (77). Briefly, the P B L G / P E O / P B L G block copolymer was obtained by polymerization of B L G - N C A initiated by the amine-terminated P E O in methylene dichloride, at a total concentration of B L G - N C A and A T P E O of 3 % (W/V), at room temperature for 72 hrs. The reaction mixture was poured into a large excess of diethyl ether to precipitate the P B L G / P E O / P B L G copolymer. The resulting copolymer was washed with diethyl ether and then dried in vacuo. The unreacted monomer and A T P E O do not precipitate from a mixture of methylene dichoride and diethyl ether. The reaction scheme is shown i n F i g . 1.


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Preparation of Poly(hydroxyalkyl L-gIutamine)(PHAG)/PEO/PHAG Block Copolymer Hydrogel. The P B L G / P E O / P B L G block copolymer was dissolved i n dioxane (6 W/V %) at 60°C, casted into a membrane and then the solvent was evaporated for 48 hrs. The prepared membrane was immersed in ethanol solution which contained aminoalcohol (containing 25 χ B L G repeat units) and O M D A (0.1 χ B L G repeat units) as the crosslinking agent at 65°C for 7 days. The resulting P H A G / P E O / P H A G copolymer hydrogel membranes were washed with ethanol to remove the unreacted aminoalcohols and O M D A . Poly(hydroxyhexyl L glutamine)(PHHG) homopolymer hydrogel was prepared by a similar method. Elemental analysis of the polymers was performed to determine the degree of aminoalcoholysis of the P B L G homopolymer and P B L G / P E O / P B L G copolymer, using C H N - 6 0 0 elemental analyzer ( L E C O Corp., St. Joseph, MI). Once the degree of polymerization of P B L G is known, one can calculate the degree of aminoalcoholysis from the C, Η, Ν values in the elemental analysis after aminoalcoholysis. The reaction scheme is presented in F i g . 2. H N M R Spectroscopy. U N M R spectra of the P B L G / P E O / P B L G block copolymers were measured in a mixed solvent of C D C I 3 and trifluoroacetic acid (9/l:V/V) to estimate the copolymer compositions and the molecular weights of P B L G blocks, using a I B M NR/200 F T N M R spectrometer. A s the number-average molecular weight (4,000) of P E O is known, one can estimate the number-average molecular weights of the P B L G block and of the copolymer from the copolymer composition calculated from the peak intensities in the spectrum assigned to each polymers (77). 1

l

X-ray Diffraction. X-ray diagrams were obtained to detect crystallinity of the copolymer with Philips Electronic Instruments using Ni-filtered C u K radiation (35 k V , 15 m A ) . a

Differential Scanning Calorimeter (DSC). The glass transition temperature (Tg) and melting temperature (Tm) of the dried samples, which were weighed (10 to 15 mg) and sealed i n stainless steel pans with a rubber O-ring (pan no. : 319-0218), were determined by using D S C (Perkin-Elmer DSC-4) at a heating rate of 20 K/min from 183 Κ to 623 K . H e l i u m was used as sweep gas (24 ml/min.). Swelling. Solvent uptake in water and D M F of P H A G / P E O / P H A G discs were obtained by monitoring solvent absorption periodically at 37°C and were determined when no significant weight change was observed. The equilibrium was reached within one day. Solvent uptake was defined as, Ws/Wp, where W is the absorbed solvent weight and W p is the dried polymer weight. s

Transmission Electron Microscopy (TEM). The block copolymer discs were exposed to the vapor of ruthenium tetroxide(0.5 wt.-% aqueous solution) at room temperature for 12 hrs and then embedded in epoxy resin by a method described in the literature (18). The embedded specimens were microtomed to obtain ultrathin sections of 50 nm thickness. The ultrathin sectioned specimens were again stained before T E M observation. A J E O L transmission electron microscope (Model 100 C X ) was used at an accelerating voltage of 100 k V . Drug Loading. The dried polymer discs (7 m m in diameter and 0.9 m m i n thickness) cut from P H A G / P E O / P H A G copolymer hydrogel membranes were equilibrated in 10 W/V % drug solutions in D M F at 37°C for 24 hrs. After blotting the swollen discs with a paper towel, the discs were vacuum-dried (20-30 m m Hg) at 65°C for at least two days. The weights of dried samples were determined when there


Drug Release from Triblock Copolymers

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Polymeric Delivery Systems - American Chemical Society

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