Chapter 9
Amino Acid Derived Polymers for Use in Controlled Delivery Systems of Peptides 1
Downloaded by UNIV OF NEW SOUTH WALES on February 1, 2016 | http://pubs.acs.org Publication Date: August 1, 1997 | doi: 10.1021/bk-1997-0675.ch009
S. Brocchini, D. M . Schachter, and J. Kohn
Department of Chemistry, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903
A family of synthetic, tyrosine-derived polyarylates is being studied as a new polymeric matrix system for the controlled release of peptides. The polyarylates are degradable amorphous materials whose backbone structure contains amide bonds. Using the cyclic heptapeptide contained in the platelet integrin glycoprotein IIb/IIIa blocking formulation INTEGRILIN™ as a model, the effect of the polymer structure on peptide miscibility within the polymeric matrix and its effect on the release behavior was investigated. A new co-precipitation technique provided polyarylate-peptide blends that were compression molded without decomposition, deactivation, or detectable aggregation of the peptide. Transparent, pliable compression molded films with high peptide loadings of up to 50% (w/w) were fabricated in this way. In spite of such high loadings, the model peptide was not released from these films over a 30 day exposure to physiological buffer solution at 37 °C. Only when poly(ethylene glycol) (PEG) was added to the formulation was the model peptide released. Release rate was a function of polyarylate structure and the amount and molecular weight of PEG used in the blends. This provided an effective means to modulate the release rate.
The clinical effectiveness of peptide drugs is characterized by contrasting pharmacological properties. While a peptide can be highly efficacious in terms of selectivity and potency, adequate dosing by conventional dosage forms tends to be impaired due to low bioavailability and short half life (7). To circumvent these limitations, peptides usually require the custom design of an advanced peptide drug delivery system. Such a delivery system is broadly defined as being either a targeted or a controlled release system. A targeted delivery system directs a drug to a desired biological target. The premise of targeted drug delivery is that the therapeutic index of a drug can be improved when the drug accumu1
Corresponding author
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© 1997 American Chemical Society
In Therapeutic Protein and Peptide Formulation and Delivery; Shahrokh, Zahra, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1997.
9.
BROCCHINI E T A L .
Polymer Use in Controlled Delivery Systems
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lates selectively in specific tissues, organs, or cell types. In contrast, a controlled release delivery system is designed to release a drug in a predetermined, predictable, and reproducible fashion without directing the drug to a specific biological target. Controlled release systems encompass a wide range of possible configurations for delivering a therapeutic agent. For example, the use of a mechanical infusion pump is one method to control dosing, however to minimize complications and possible discomfort to the patient, other methods of controlled release may be preferable (2). Downloaded by UNIV OF NEW SOUTH WALES on February 1, 2016 | http://pubs.acs.org Publication Date: August 1, 1997 | doi: 10.1021/bk-1997-0675.ch009
Notably, transdermal and implantable polymeric delivery systems have been developed and several are marketed. Implantable polymeric controlled release systems offer the advantage that patient compliance is guaranteed and that the dosing process is almost imperceptible to the patient.
A commonly used classification scheme based on the
physical design of such implantable devices differentiates between matrix and reservoir systems.
A matrix system consists of a drug dispersed within a polymer, while a
reservoir system consists of a separate drug phase physically confined within a surrounding polymeric phase or membrane. The use of a degradable (resorbable) polymer would be advantageous in the design of an implantable polymeric controlled release system since the need to retrieve the device after release of the peptide is eliminated. However, the choice of an optimally suitable polymeric matrix for the formulation of implantable peptide release systems is not an easy task. Release of the peptide from a polymeric matrix system is controlled by a combination of drug diffusion through the matrix, imbibation of water into the matrix, chemical degradation of the polymer, physical erosion of the matrix system, and the stability of the peptide within the polymeric matrix. Optimizing this array of parameters for an implantable device designed to deliver a specific peptide is both a scientific and technological challenge. Available
Polymers
Several implantable degradable controlled release systems for peptides have been studied using poly(lactic acid) (PLA), poly(glycolic acid) ( P G A ) or copolymers thereof (1,3). The main advantage of these polymers is their extensive prior history of clinical use and their general acceptance by scientists and regulatory agencies alike as biocompatible and safe materials. However, these polymers are characterized by relatively high equilibrium water contents which can surpass 20% (by weight). The incorporation of water soluble peptides into the polymeric matrix tends to increase water uptake even further and can lead to substantial swelling accompanied by irregular release profiles. A number of alternative degradable polymers are available, including polycaprolactone
(4),
poly(hydroxy butyrate) (5,6),
poly(ortho esters)
(7-10),
polyphosphazenes (77), polyanhydrides (12,13). Synthetic poly(amino acids) (7,7479) as well as natural biopolymers such as proteins (e.g., gelatin, collagen, albumin) (20) and polysaccharides (e.g., dextran, chitosan, starch, cellulose derivatives) (27)) have also been considered as matrix materials in the design of controlled release systems.
In Therapeutic Protein and Peptide Formulation and Delivery; Shahrokh, Zahra, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1997.
T H E R A P E U T I C PROTEIN AND PEPTIDE F O R M U L A T I O N AND D E L I V E R Y
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One of the severe limitations in the design of controlled release systems for peptides and proteins is the observation that these moieties tend to lose their biological activity upon storage within the polymeric matrix. Based on the hypothesis that "protein like" materials may stabilize the peptide drugs dispersed therein, it has been implied that such "protein-like" matrices may be particularly useful for the design of release systems for peptides and proteins. Although poly(amino acids) share many of the structural features of peptides, such materials have been of little practical use because they are Downloaded by UNIV OF NEW SOUTH WALES on February 1, 2016 | http://pubs.acs.org Publication Date: August 1, 1997 | doi: 10.1021/bk-1997-0675.ch009
relatively non-processible, decompose in the molten state, and swell in moist environments. These limitations have been largely overcome in a recently developed class of amino acid derived polymers known as pseudo-poly(amino acids). Pseudopoly(amino acids) are derived from α-amino acids but contain non-amide bonds (e.g., carbonate or ester linkages) in their backbone (22,23). A wide range of different pseudo-poly(amino acids) has been prepared (22). O f particular interest for the design of peptide drug delivery systems are the tyrosine-derived polyarylates 3 (Figure 1) (24). These materials are copolymers of a tyrosine-derived dipeptide 1 and a diacid 2. This family of polyarylates is being used (i) to explore possible correlations between systematic changes in polymer structure and the peptide polymer interactions, and (ii) to design novel controlled release systems for selected peptides. Tyrosine-Derived Polyarylates Tyrosine-derived polyarylates 3 are amorphous materials which are prepared by the polymerization (Figure 1 ) of one of four alkyl esters of desaminotyrosyl-tyrosyl dipeptide 1 and one of four aliphatic acyclic diacids 2 to give a family of 16 polymers (Table I). In effect each polyarylate is systematically homologated by the addition of methylene groups to either the pendent chain or polymer backbone. Varying the number of methylene groups in this manner produces small changes in polymer structure resulting in incremental changes in most polymer properties. While thermomechanical properties, surface hydrophobicity, and miscibility with drugs and peptides differ dramatically among individual polyarylates, all members of this family are similar in regard to processibility, rate and mechanism of degradation, and biocompatibility. Thus, it is possible to select specific polyarylates to match closely the requirements for the release of a given peptide, or one can use a range of polyarylates as model polymers to study the correlations between polymer structure and the observed release profiles. General Considerations.
The polyarylate backbone contains peptide-like amide
bonds. The hydrogen bond donating and accepting sites associated with the amide bonds present in all polyarylates can be expected to increase the solubility of peptides within the polymer matrix while inhibiting peptide aggregation. Although the polyarylates possess a number of hydrophilic and possible peptide solubilizing sites, films and pins fabricated from polyarylates absorb very little water (
