Polymers in Biological Systems - American Chemical Society


Recently, polymer chemists have become involved in the development of ... have been applied to biological systems (1-3). ... inert materials can cause...
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Chapter 10

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Polymers in Biological Systems Raphael M. Ottenbrite Department of Chemistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23284

The application of polymers in biological systems has become an important feature of medical care. The most common uses have been for implants and prosthetic devices; however, recent interest has been to use polymers as drugs and drug delivery systems. Polymeric drugs were the first to receive attention, and now the primary interest focuses on new modes of drug administration. Research in this area is highly interdisciplinary and involves not only polymer chemists but health scientists and physicians. Most of the organic matter i n l i v i n g c e l l s consists o f macromolecules; these include not only proteins and nucleic acids but also other polymeric substances such as starch and collagen. Since the macromolecules i n a l l l i v i n g organisms are made from only a r e l a t i v e l y few, simple, building-block molecules, i t appears probable that these basic biomolecules were selected during the course of b i o l o g i c a l evolution f o r t h e i r capacity to serve several functions. Various nucleotides, f o r example, are not only u t i l i z e d as building blocks of nucleic acids by the body but also as coenzymes and as energy-carrying molecules. These primordial molecules may be r e garded as the precursors or ancestors of a l l other biomolecules; they are the f i r s t alphabet of l i v i n g matter. Other macromolecules of l i v i n g organisms evolved from these simple, low-molecular-weight substances which formed an ordered hierarchy of complex mesomeric structures. From t h i s pool of complex macromolecular b i o l o g i c a l systems evolved highly s p e c i f i c polymeric substances that function as membranes for compartmentalization, polynucleic acids for memory and r e p l i c a t i o n , amino acid combinations f o r a variety of proteinaceous f u n c t i o n a l i t i e s , and polysaccharides f o r energy storage, structure, and connective tissue applications. The elucidation of the complexity of both function and structure of these b i o l o g i c a l macromolecules has been a p r i n c i p a l goal of many s c i e n t i s t s . Recently, polymer chemists have become involved i n the development of separation and p u r i f i c a t i o n techniques aimed at the

0097-6156/88/0362-0125S07.50/0 © 1988 American Chemical Society

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i d e n t i f i c a t i o n of the function and structure of these compounds. In addition, polymer chemists have been exploring synthetic methods of preparing both natural and synthetic macromolecular analogs for b i o l o g i c a l use. The evaluation and modification of these materials has l e d to the preparation of an array of polymeric compounds which have been applied to b i o l o g i c a l systems (1-3). This chapter, "Polymers i n B i o l o g i c a l Systems," was chosen to introduce the pertinent research i n t h i s i n t e r d i s c i p l i n a r y f i e l d . The economic impact of polymers i n b i o l o g i c a l systems i s i l l u s t r a t e d i n Table I. The present market i s i n excess of 15 b i l l i o n dollars

Table I. Polymers i n B i o l o g i c a l Systems

Biopolymer

Pharmaceuticals

Billions 1985 1990

0.3

2.5

Agriculture

0.2

1-3

- Hormones - Immuno stimulant s - Pesticides - Nutrients Prosthetic Devices

7.0

12-15

2.5

3.5

General Medical Care

5.0

10-20

Total Market (Billions)

15.0

28-48

- Delivery Systems - Controlled Release

- Contact Lenses - Dental - Joints - Catheters Artificial - Kidney - Heart - Skin

with a projected growth to about 50 b i l l i o n i n the next f i v e years. The topics that w i l l be discussed include: basic studies of prostheti c device implants; biocompatibility of polymers; drug administration

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(by polymeric drugs, polymeric drug c a r r i e r s and polymeric drug delivery devices). The purpose of t h i s chapter i s to give researchers a comprehensive overview of current knowledge, developments, and trends i n t h i s rapidly expanding and exciting f i e l d .

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Polymeric

Implants

Biomaterials used f o r prosthetic devices are defined as substances which are used i n the human body f o r a prolonged period of time without applicable changes i n their properties. Although biomaterials range from strong metals to b r i t t l e ceramics, polymers, with t h e i r wide range of properties including strength and hardness are presently the major source of biomaterials. L i s t e d i n Table I I are some physical properties of polymer materials presently being used. Many devices such as catheters, shunts, cannulae, orthopedic

Table I I . Variable Polymer Properties

Property

Polymer

Use

Hard

Methylmethacrylate

Replacement Parts, Teeth and Bone

Soft

Silicone

Can be Made to Feel Like Human Tissue

Tensile Strength

Kevlar, Polyethylene

Reinforcement of Prosthetics

Transparent

Methylmethacrylate, Polyacetals

Contact Eye Lens

Biodegradable

Poly(Galactic Acid), Orthoester Polymers

Sutures Controlled Drug Delivery

devices, a r t e r i a l grafts, and heart valves have successfully been fabricated and have been successfully implanted through s u r g i c a l means and have functioned for many years (4) . The ultimate goal i n the development of biomaterials i s to implant independently functioning prosthetic organs such as kidneys, lungs, and hearts into a l i v i n g host (5). The r e p l i c a t i o n of l i v i n g tissue, with the a b i l i t y to respond and repair i t s e l f after physical trauma or d e b i l i t a t i n g diseases, i s a major goal of prosthetic research. Presently, one of the greatest problems with s u r g i c a l implants i s the rejection of the foreign biomaterial by the l i v i n g organism (6) . Even the most chemically i n e r t materials can cause blood c l o t t i n g or tissue encapsulation. Furthermore, transplants such as heart valves and a r t e r i a l grafts must be designed to function for more than 30 years. Consequently,

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meticulous research i s continuing for materials or composites that w i l l maximize the desired properties and minimize the undesired side e f f e c t s l i s t e d i n Table I I I .

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Table I I I . C r i t e r i a for Biomaterials

Biopolymer Must Have

Biopolymers Must Not

High Purity

Cause thrombosis

Chemical, physical, and mechanical properties to meet proposed function

Destroy c e l l u l a r

Easy f a b r i c a b i l i t y

Destroy enzymes

High s t a b i l i t y

Deplete e l e c t r o l y t e s

Sterilizability

Cause immune responses

elements

A l t e r plasma protein

Cause cancer Produce toxic and a l l e r g i c reactions

Sutures are the most commonly implanted biomaterials i n humans. Thirty years ago cotton thread, synthetic nylon, polyester f i b e r s , and metal clamps were commonly used for t h i s purpose. These materi a l s and the f i r s t absorbable suture, cat gut, which absorbs i n 40 days, cause s i g n i f i c a n t inflammation of the wound and impede the natural healing process. Consequently, there has been considerable interest i n the development and subsequent application of absorbable sutures composed of biocompatible materials. The two p r i n c i p a l absorbable materials now used are p o l y g l y c o l i c acid provided by American Cyanamide (120 days) and p o l y ( g l y c o l l i c a c i d - c o - l a c t i c acid) by Ethicon Incorporated (Vicryl - 90 days). The application of these two products as sutures i s based on t h e i r a b i l i t y to be readily hydrolyzed i n a physiological environment and the resulting hydrolysis products are readily metabolized without causing any physiological reaction. Continued research i n t h i s area has brought about new products with better degradation properties and biocompatibility (2)· The second most commonly known b i o l o g i c a l implants are contact lenses (8). These were i n i t i a l l y developed from polymethyl(methacrylate) which was found to be compatible with the eye based on the observed tolerance of windshield fragments imbedded i n the eyes of some World War II p i l o t s . The technology to develop contact lenses has evolved over the l a s t 30 years to the point that there are over 40 d i f f e r e n t types of gas permeable hard contact lenses on the market

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with variations i n color, oxygen permeability, shape and patency (Table IV). Soft contact lenses that have been developed for comfort and extended wear represent another large segment of t h i s industry. Permanent intraocular lenses are now being developed for replacement of natural lenses l o s t due to injury, cateracts, and other eye diseases (9). The u t i l i z a t i o n of synthetic or modified natural polymers for prosthetic devices i s s t i l l i n i t s beginning phases. Some of the present applications of t h i s important area of surgical medicine are shown i n Figure 1 (10). B i o l o g i c a l Compatibility of Biopolymers. Tissue and blood compatib i l i t y are essential requirements of any biopolymer introduced into a b i o l o g i c a l system. The a c t i v i t y of a biopolymer i n an organism i s d i r e c t l y related to i t s structure and i t s s o l u b i l i t y i n the tissue or tissue f l u i d s . The biocompatibility of an implanted material or prosthetic device i s a dynamic two-way process that involves the time dependent effects of the host on the material and the e f f e c t s of the material on the host. The implantation of any material whether i t i s a natural polymer or a synthetic material triggers a series of complex b i o l o g i c a l mechanisms which include inflammation chemotaxis and phagocytoses (11). Inflammation i s the host's response to injury or the presence of a foreign material. The i n t e n s i t y and duration of the response i s determined by a variety of b i o l o g i c a l mediators responding to the size and nature of the implant, the trauma due to implantation, and the s i t e of implantation. B i o l o g i c a l systems seem to be much more tolerant of implants that come i n contact with tissue alone rather than with blood. Foreign body reaction within tissues can produce inflammation, tissue encapsulation or cell-change response i n the surrounding tissues. In addition, reactions remote from the s i t e , such as carcinogenic and antileukotactic responses, can occur. Within blood, however, foreign object recognition i s much more sensitive {12). I n i t i a l l y , there i s a rapid adsorption of plasma protein. This may be followed by a number of responses such as p l a t e l e t adhesion and aggregation, thrombin formation, and a f i b r i n ogen activation that could r e s u l t i n blood c l o t formations. Implanted polymers are generally subjected to severe b i o l o g i c a l environments which can cause the polymer to degrade and thus changing the properties of the polymer. More important, these degradation byproducts may be much more sensitive to the surrounding tissue than the polymer i t s e l f . Furthermore, the leaching of small molecules such as monomer, i n i t i a t o r , oligomers, p l a s t i c i z e r s , additives, emulsifiers from implants, and products of hydrolytic or enzymatic reactions on the polymer material can cause serious tissue reactions. These nocuous materials are usually transported by d i f f u s i o n and can cause inflammation, edema, antigenic reactions, and pyrogenicity. Chronic inflammation, l o c a l tissue damage and neurosis can lead to serious infections. Mechanical i r r e g u l a r i t i e s or polymer fragments caused by abrasions have produced fibrous tissue growth as well as tissue encapsulation. In blood, i t i s extremely important to c l a r i f y the influence of adsorbable plasma proteins on an implant; the subsequent p l a t e l e t adhesion and aggregation when designing new nonthrombogenic polymers

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Table

IV. Hard Gas Permeable Lens Materials

Company

A.I.T. BH/HC BH/HC Biocontacts (Canada) Bio Products Corneal Contact Danker Dow Corning Frigitronics Frigitronics Fused Kontact Glasflex Glasflex Neefe Optical Neefe Optical Ocular Technology Ocular Technology Optacryl

Paragon Paragon Paragon Polymer Technology Polymer Technology Rynco Syntex Syntex Toyo Wesley Jessen GBF Bio Medic Polymers Bio Medic Polymers

Name Lens/Material

Medicon Cabcurve GP I I Reviens Oxy-PMMA Alberta (SM38) Me so Silicon Opus I I I Saturn I I S i l 0 Flex Dioxyflex Electrocab Siloxycon 14 Bioflex OTC V OTC VII Optacryl 95 Optacryl 60 Optacryl Κ Paragon 95 Paraperm 0 ParaCab II Boston I Boston I I Rx 56 Polycon I Polycon I I Menicon 0 Airlens BFB 5 Oxycon Oxycon 32 2

2

2

Polymer

Sil/Acry CAB CAB But/Aery Sil/Acry Sil/Acry CAB Silicone N.A. N.A. Sil/Acry Sil/Acry CAB Sil/Acry CAB Sil/Acry Sil/Acry Sil/Acry Sil/Acry Sil/Acry Sil/Acry Sil/Acry CAB Sil/Acry Sil/Acry CAB Sil/Acry Sil/Acry Silicone A l k y l Styrene N.A. Sil/Acry Sil/Acry

Sil/Acry = Silicone/Acrylate; But/Acry = Butyl Acrylate

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10. OTTENBRITE

Polymers in Biological Systems

Figure 1. Applications of synthetic or modified polymers for prosthetic devices.

131

natural

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T H E IMPACT OF CHEMISTRY ON BIOTECHNOLOGY

(12). One of the best known methods of improving blood compatibility i s by modifying the surface of the implant with substances that interfere with thrombin and f i b r i n a c t i v a t i o n . Heparin, heparinoids, and mucopolysaccharides are among the most e f f e c t i v e water soluble polymeric anticoagulants. Heparin i s a naturally occurring sulfated polysaccharide and i s found i n trace amounts i n most mammalian t i s s u e . Heparinoids are biopolymers prepared by the p a r t i a l degradat i o n of natural polysaccharides that are sulfonated; these modified materials exhibit promising anticoagulation properties. Mucopolysaccharides are naturally occurring carbohydrates similar to heparin, but have fewer sulfonate groups and have weaker anticoagulant a c t i v i t y (13 ) . Continual systemic heparinization i s a d i f f i c u l t procedure because of problem with c o n t r o l l i n g the dosage and the p o s s i b i l i t y of i n i t i a t i n g hemorrhaging. A number of years ago, however, i t was found that when a polymeric material was treated with heparin that the r e s u l t i n g surface was much more compatible i n a plasma environment, and that coagulation was decreased. Heparinization has now become a standard method for treating devices that are to be placed in contact with blood. The p r i n c i p l e method of heparin attachment has been by e l e c t r o s t a t i c bonding, but a considerable amount of e f f o r t has been made to covalently bond heparin to polymer surfaces. Heparinization has also been accomplished by adding heparin to the bulk polymer; the heparin then slowly diffuses out of the polymer matrix e f f e c t i n g body compatibility of the polymer device (14). Nonthrombogenic properties have also been exhibited by materials other than the heparin-types. Block polymers of polyurethane (DuPont Co.), polyether polyurethanes (Stanford Research International), polyurethane with s i l i c o n e (Avoco Corp.) and fluorocarbon polymers have a l l shown appreciable a n t i c l o t t i n g a c t i v i t y . A recent unique approach to c o n t r o l l i n g r e j e c t i o n of implants involves the attachment of c l o t - l y s i n g agents such as streptokinase and urokinase to the polymeric material. The theory i s that i f a c l o t does begin to form on the surface of an implant, i t i s immediately lysed by the attached enzyme. Another approach has been to r e p l i c a t e the vascular endothelium which has a macrophase structure composed of hydrophilic and hydrophobic microdomains. Segmented-synthetic polymers of t h i s type have been prepared and are being evaluated with promising results (15) . Various types of p o l y i o n i c complexes prepared by combining polyanions with polycations are also being evaluated for "polymerplatelet" interaction. A l l of these new techniques have produced some interesting results (16). Drug Administration Drugs are generally distributed throughout the body i n the aqueous phase of the blood plasma. Unless they are t o p i c a l l y active, most drugs must f i r s t enter the blood system. They reach the tissues of each organ at a rate determined by the blood flow through that organ and by the rapidity of the passage of the drug molecule across the c a p i l l a r y bed and into the tissue c e l l s of that p a r t i c u l a r organ. Most drugs are retained within the blood plasma due to s o l u b i l i t y or binding to c e l l s and substances such as plasma proteins and do not diffuse freely out of the plasma. Consequently, the amount of drug

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present i n the tissues at the s i t e of a c t i v i t y i s only a small portion of the t o t a l drug present i n the body. The majority of the drug remains i n various f l u i d compartments or i s l o c a l i z e d i n subc e l l u l a r p a r t i c l e s , at macromolecular surfaces, and i n f a t depots by adsorptive or p a r t i t i o n processes. Even with the target t i s s u e , c e l l u l a r fractionation and radioautographic studies reveal that most drug molecules are associated with structures that have nothing to do with the s p e c i f i c drug e f f e c t . Consequently, one of the most d i f f i c u l t problems i n drug admini s t r a t i o n i s getting the agent i n s u f f i c i e n t quantity to the desired s i t e for the required period of time. With conventional delivery systems, such as o r a l or i n j e c t i o n methods, i t i s necessary to administer repeatedly, and the entire body thus becomes infused with the drug. Furthermore, i f drug administration i n t e r v a l i s increased, there w i l l be periods when an i n s u f f i c i e n t amount of the drug i s present, and the disease or i n f e s t a t i o n can reoccur. A l t e r n a t i v e l y , reapplication can lead to a build-up of the agent i n the body to the point where toxic l e v e l s are exceeded, as shown i n Diagram I. Thus the therapeutic u t i l i t y of many drugs i s often l i m i t e d by t h e i r short i n vivo h a l f - l i v e s , lack of s p e c i f i c i t y , acute t o x i c i t y , and undesirable side e f f e c t s . Attention, therefore, has been directed to the development of therapeutic systems for the controlled administration of pharmacol o g i c a l l y active agents that u t i l i z e synthetic polymeric materials as predictable b a r r i e r s for the regulated release and transport of drugs. A number of techniques have been devised to a l l e v i a t e many of the problems inherent with the repeated dosages associated with o r a l and i n j e c t i o n methods. The methods presently being explored include: (a) polymeric drugs - these are polymers that are p h y s i o l o g i c a l l y active either as polymers themselves or are copolymers of active monomers; (b) polymeric drug-carriers - these are polymers that have active drugs covalently attached to the polymer backbone; (c) polymeric prodrugs - these are polymers that have pendent drug molecules that are only active a f t e r being released from the polymer; (d) polymeric drug delivery devices - these involve encapsulation of a drug into a polymer depot from which the drug i s released and i s disseminated by d i f f u s i o n i n vivo. These include osmotic pumps, microcapsules, liposomes and dermal patches. Polymeric Drugs. Polymeric drugs are macromolecules that e l i c i t an efficaceous b i o l o g i c a l a c t i v i t y on t h e i r own. Current developments in the areas of biochemistry and molecular biology have resulted i n the elucidation of the structure and function of many polymer molecules e s s e n t i a l to the o v e r a l l metabolism of l i v i n g organisms. Consequently, there has been s i g n i f i c a n t development i n research regarding the synthesis and the properties of p h y s i o l o g i c a l l y active polymers. It i s now possible to prepare macromolecules with predetermined structures, discrete molecular weights, and with s p e c i f i c functional groups. The major reasons for the development of polymeric drugs are that they exhibit delayed action, prolongation of a c t i v i t y , decreased rate of drug metabolism, and drug excretion. The b i o l o g i c a l a c t i v i t y demonstrated by these polymeric compounds may be the r e s u l t of the polymer i t s e l f , , such as i n the case with polyanions and polycations (16,17) which are made from inactive

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TOXIC L E V E L

E F F E C T I V E DRUG L E V E L

1

2

H-

Ν 3

R E P E A T E D DOSE DELIVERY

TOXIC L E V E L

CONTROLLED RELEASE

E F F E C T I V E DRUG L E V E L

IDEAL CONTROLLED DELIVERY

DIAGRAM 1

4

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monomers or may be the r e s u l t of polymerization or copolymerization of an a c t i v e l y known monomeric drug. Urea formalde-hyde copolymer, for example, known by the trade name "Anafelx", has been used as an a n t i b a c t e r i a l and antifungal agent. Other polymeric drugs currently being used include; poly-N-oxides, which i n h i b i t s i l i c o t i c f i b r o s i s and s i g n i f i c a n t l y increases the s e l f - p u r i f i c a t i o n of the lungs from quartz dust, and copolymers of formaldehyde with sulfapyridine or sulfanilamide which possess antimalarial a c t i v i t y (18). L i s t e d i n Table V are several active polymeric drugs and t h e i r medical a p p l i cations .

Table V.

Medicinal Applications of Some Polymeric Drugs

A n t i b a c t e r i a l agents

Quaternary Ammonium polymers Polyanionic polymers Polypeptides

Antifungal agents

Polyanionic polymers Urea-formaldehyde

A n t i v i r a l agents

Polyanionic polymers Urea-formaldehyde

Antitumor agents

Polyanionic polymers Quaternary Ammonium polymers

Anticoagulants

Polyanionic polymers Heperin Heparinoids

Antisilicosis

Poly-N-oxides

Plasma extenders

Polyvinylprolidones Dextran Gelatin

Hemostatics

Carboxymethylcellulose Polyanions

Many active drug monomers can lose t h e i r a c t i v i t y i n the polymeric form, but others exhibit enhanced a c t i v i t y . It was found, for example, that most amino acids exhibit no a n t i b a c t e r i a l a c t i v i t y i n the monomer form but became very active when polymerized and administered as the cationic s a l t s (Table V I ) . The most notable i s L-lysine, which has no apparent a n t i b a c t e r i a l a c t i v i t y as the monomer but i s very active against E. c o l i and S. aureus as the polyamide. Donaruma (19), who has prepared a large number of polymers and

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Table VI.

A n t i b a c t e r i a l A c t i v i t y of Poly-Basic Amino Acid Polymers

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E. C o l i ug/mL

S. Aureus ug/mL

L-lysine'HCl Di-L-lysine'HCl

450

Poly-L-lysine'HCl

2.5

1

Poly-DL-lysine'HCl

5

3

10

5

10

5

DL-Ornithene'HCl Poly-DL-ornithene"HCl DL-arginine Poly-DL-arginine

copolymers by u t i l i z i n g d i f f e r e n t active drugs as monomers, has concluded that polymerization or copolymerization of drugs can enhance, decrease, or have no e f f e c t on the a c t i v i t y e l i c i t e d by the resultant material. He also found that the incorporation of a drug into a polymer chain could a f f e c t t o x i c i t y . The polymerization of active drug monomers has i n many cases decreased t o x i c i t i e s , but i t has also been shown to enhance or create new t o x i c i t i e s . In evaluating s t r u c t u r e - a c t i v i t y relationships i n polymer drug systems, two of the most important variables that apparently regulate b i o l o g i c a l a c t i v i t y are molecular structure and stereochemical configurations. These two features are manifested i n most polymer systems by molecular weight, copolymer properties, chain c o i l i n g and/or folding, cross l i n k i n g , t a c t i c i t y , and e l e c t r o l y t i c character (20). With drug copolymers i t has been shown that the nature of the nondrug comonomer i s very important and that b i o l o g i c a l a c t i v i t y i s not just related to the drug comonomer alone. I t appears, therefore, that certain properties c h a r a c t e r i s t i c of polymer systems may correlate with b i o l o g i c a l a c t i v i t y . Consequently, there exists a great need for more detailed s t r u c t u r e - r e a c t i v i t y studies of polymeric drugs to serve as a basis to f a c i l i t a t e future drug design. Polymeric drugs have been applied most extensively i n the treatment of cancer. Synthetic polyanions have shown excellent p o t e n t i a l for t h i s pathology. For example, poly(vinyl-sulfonate) i n h i b i t s L1210 leukemia, Krebs 2 carcinoma and E h r l i c h a s c i t e s . Many carboxylic acid polymers e l i c i t antitumor a c t i v i t y but are also very t o x i c . The most widely studied polyanionic polymer i s p o l y ( d i v i n y l ether-co-maleic acid) known as pyran or MVE-2. This polymer has a wide range of b i o l o g i c a l a c t i v i t y including, antitumor, a n t i v i r a l , antifungal and a n t i b a c t e r i a l a c t i v i t i e s . More recently, we have

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developed a polymer, poly(maleic anhydride-alt-cyclohexyl-3,5 dioxepin) which exhibits l i t t l e t o x i c i t y and has produced the f i r s t murine survivors to Lewis lung carcinoma (21). Since nucleic acids and enzymes play such a large role i n the r e p l i c a t i o n of c e l l materials for mitosis, a considerable amount of research has been conducted i n t h i s area to control virus r e p l i c a t i o n . On the molecular l e v e l , analogs of nucleic acids are capable of forming complexes with adenine, cytosine, u r a c i l , thymine, and guanine. Through complexation, these nucleic acid analogs are p o t e n t i a l i n h i b i t o r s o f biosynthesis and require nucleic acids as templates. The polyvinyl analogs of nucleic acids are one of the few polymers that have been tested i n l i v i n g systems to investigate t h e i r b i o e f f e c t s . The most thoroughly investigated polymer i s p o l y [ v i n y l adenine, which has been reported as being e f f e c t i v e against v i r a l leukemia, chemically induced leukemia, and infections caused by other viruses {22). The i n h i b i t i o n of viruses by the complexation of nucleic acids with t h e i r polymer analogs i s apparently virus specific. For example, poly(9-vinyladenine) i n h i b i t s v i r a l r e p l i c a t i o n through the reverse transcriptase step, while poly(9-vinylpurine) i s ineffective. Other antineoplastic polymers include the a z i r i d i n e a l k y l a t i n g funtionalized polymers cyclophosphoramides, mustard type a l k y l a t i n g functionalized polymers, and conjugates of methotrexate, adriamycin and cis-platinum {23). More recently, smaller macromolecules have been found to be active such as muramyl dipeptide (24) and neocarzino-statin conjugated to poly(styrene-co-maleic anhydride) (25). Biopolymeric Drug Carriers or Conjugate Polymeric Drugs. The u t i l i zation of macromolecules to serve as drug c a r r i e r s i s a technology that holds a great potential for drug administration. The p r i n c i p l e reason i s that many drug companies have drugs that are now nearing the end of t h e i r patent protection period. However, by involving these drugs i n new controlled release or delivery methods of administ r a t i o n , new patents can be obtained. Most medications are micromolecular i n size and, as such, are r e l a t i v e l y free to diffuse throughout the b i o l o g i c a l system. Consequently, drugs have been inherently d i f f i c u l t to administer i n a l o c a l i z e d , concentrated mode within the primary target tissues and organs. Since polymers d i f f u s e slowly and are often adsorbed at interfaces, the attachment of pharmaceutical moieties produce a biopolymer with d i s t i n c t pharmacological a c t i v i t y . The main reason for the development of these "polymeric-drug c a r r i e r s " i s to obtain desirable properties such as sustained therapy, slow drug release, prolonged a c t i v i t y , and drug latenation, as well as decreased drug metabolism and excretion (Table VII). A model f o r pharmacologically active polymer-drug c a r r i e r s has been developed by Ringsdorf and others {20), similar to that shown i n Diagram I I . In t h i s schematic representation four d i f f e r e n t groups are attached to a biostable or biodegradable polymer backbone. One group i s the pharmacon or drug, the second i s a spacing group, the t h i r d i s a transport system, and the fourth i s a group to s o l u b i l i z e the entire biopolymer system. The pharmacon i s the agent that e l i c i t s the physiological response i n the l i v i n g system; i t can be attached permanently by a stable bond between the drug and the

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SOLUBLE POLYMER / BACKBONE



SPACER



SPACER

BIODEGRADEABLE LINKAGE TARGETING MOIETY CELL SPECIFIC ENHANCED MEMBRANE INTERACTION MODEL FOR POLYMERIC DRUG CARRIER

DIAGRAM 2

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Characteristics of Polymeric Drug Carriers

Depot effects

Slower d i f f u s i o n of drug Slower absorption of drug Slower elimination of drug Nonadsorbability f o r t o p i c a l application

Pharmokinetic

Sustained release of drug Variable drug metabolism routes

Body d i s t r i b u t i o n

Localization of drug Inhibition of adsorption i n some areas due to molecular weight C e l l - s p e c i f i c interactions and uptake of drug Protein binding

Pharmacological a c t i v i t y

Variable a c t i v i t y from none to an increase Variable t o x i c i t y Incorporation of drug combinations on polymer backbone Reduction of side e f f e c t s such as nausea and i r r i t a t i o n common with large doses of drugs

polymer, or i t can be temporarily attached and removed by hydrolysis or by an enzymatic process. The transport systems f o r these soluble polymer-drug c a r r i e r s can be made s p e c i f i c f o r certain tissue c e l l s by the use of homing or "targeting" devices such as pH-sensitive groups, receptor-active components, i . e . antibody-antigen, or they may be made nonspecific. S o l u b i l i z i n g groups, such as carboxylates, quaternary amines and sulfonates, are added to increase the hydrop h i l i c i t y and s o l u b i l i t y of the whole macromolecular system i n an aqueous media, while large a l k y l groups adjust the hydrophobicity and s o l u b i l i t y i n l i p i d regions. Another important feature i n a polymerdrug c a r r i e r i s to move the pharmacon away from the polymer backbone of other groups so that there i s a minimal s t r u c t u r a l interference with the pharmacological action of the drug. The method of attachment of a drug to the polymer i s dependent upon the ultimate use of the adduct. Further, the chemical reaction conditions f o r the attachment of the drug to the polymer should not adversely a f f e c t the b i o l o g i c a l a c t i v i t y of the drug. Temporary attachment of a pharmacon i s necessary i f the drug i s active only i n the free form. I f the drug i s only active after being cleaved from the polymer chain then i t i s c a l l e d a prodrug. This i s usually the case with agents that function i n t r a c e l l u l a r l y . This form of

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attachment usually involves a hydrolyzable bond such as an anhydride, ester, acetal or orthoester. Permanent attachment of the drug moiety i s generally used when the drug exhibits a c t i v i t y i n the attached form. The pharmacon i s usually attached away from the polymer chain and other pendent groups (Diagram II) by means of a spacer moiety which allows f o r drug-receptor interaction. For example, catecholamines were i n e f f e c t i v e when bonded d i r e c t l y to p o l y a c r y l i c acid but do a f f e c t heart rates and muscle contractions when attached away from the backbone of the macromolecular c a r r i e r . Similarly, isoproterenol was found to e l i c i t a pharmacologic response only when coupled to a polymer by pendant azo groups but not when d i r e c t l y attached to the polymer chain. Drug targeting to a s p e c i f i c b i o l o g i c a l s i t e i s an enormous advantage i n drug delivery since only those s i t e s involved are affected by the drug and not the whole body which can have serious side e f f e c t s . Ideally, a targetable drug c a r r i e r i s captured by the target c e l l to achieve optimum drug delivery while minimizing deposit i o n elsewhere i n the host. Fluid-phase uptake of macromolecules by c e l l s i n general i s a slow process and most administered macromolecules are cleaved from the host before any s i g n i f i c a n t uptake takes place. However, i f the macromolecule contains a moiety that i s compatible with a receptor on a s p e c i f i c c e l l surface then the macromolecule i s held to the c e l l surface and the uptake by that c e l l i s tremendously enhanced. This allows the targeted drug c a r r i e r maximum opportunity f o r s p e c i f i c c e l l capture with minimum deposition elsewhere i n the host. Kopecek and Duncan (26) have successfully developed t h i s type of c e l l s p e c i f i c targeting to hepatocytes, with galactosamine; T-lymphocytes, with anti-T c e l l antibodies; and mouse leukemia c e l l s , with fucosylamine. The ultimate fate o f drugs and drug metabolites i s a major concern for a l l drugs; i f they are not cleared i n a reasonable time, they could promote undesirable side e f f e c t s . Polymeric drug c a r r i e r s are usually nonbiodegradable and because of t h e i r s i z e , they could accumulate i n the host with the p o t e n t i a l of future deleterious e f f e c t s . Consequently, the basic polymeric system used by Kopecek and Duncan i s N-(2-hydroxypropy1) methacrylamide, which was o r i g i n a l l y developed and used as a plasma extender. I t has been established to be nontoxic and well tolerated i n the host as well as being nonimmunogenic. To further enhance the elimination of t h i s macromolecular drug c a r r i e r , Kopecek has cross-linked smaller segments of N-(2-hydroxylpropyl)methacrylamide with b i o l o g i c a l l y hydrolyzable peptides u n t i l the optimum macromolecular size for drug delivery was achieved {2J). After intravenous administration, i n vivo experiments showed that these peptide cross-links are cleaved to produce smaller components that are e a s i l y excreted from the kidneys. The s p e c i f i c i t y of polymer pharmacokinetics i s due largely to t h e i r molecular weight, which hinders t h e i r transport across compartmental b a r r i e r s . However, by c o n t r o l l i n g the molecular weight of the polymeric c a r r i e r i t i s possible to regulate whether the drug passes through the blood-brain b a r r i e r , i s excreted by the kidney, or i s accumulated i n the lymph node, spleen, l i v e r , or other organs. The application of fundamental macromolecular transport theory to b i o polymers and b i o l o g i c a l tissues has been successfully applied to the

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design, fabrication, and p r e d i c t i o n of i n vivo performance of cont r o l l e d drug delivery systems. Consequently, by using only the v a r i a b i l i t y of molecular weight, polymeric drug-carriers have been developed to perform much more s p e c i f i c a l l y than the drug alone. When one considers the many variables such as composition of the polymer chain, structure, p o l y e l e c t r o l y t i c character, and s o l u b i l i t y that can e f f e c t polymer behavior the chemist has a great deal to consider during the development of new polymeric drug c a r r i e r s . The f u l l spectrum of applications for t h i s targeted drug c a r r i e r system has only been implied. The u t i l i z a t i o n of the t o t a l concept, which includes a biocompatible drug-carrier with selective c e l l targeting, controlled-drug release and biodegradability, w i l l provide one of the most potent drug administration systems i n the future. Drug Delivery Devices. Among the f i r s t drug delivery devices used by the pharmaceutical industry involved encapsulation methods. E n t e r i c coated p i l l s were o r i g i n a l l y introduced to r e s i s t the action of gastric f l u i d s . They were designed to disintegrate and dissolve a f t e r passage into the i n t e s t i n e . A major purpose of these coatings was to prevent nausea and vomiting induced by drugs that caused l o c a l gastric i r r i t a t i o n , to achieve a high l o c a l concentration of a drug intended to act i n the intestine or lower bowel region, to produce a delayed drug e f f e c t , or to deliver a drug to the intestine for optimal absorption there. Enteric coatings are usually composed of fats, f a t t y acids, waxes, shellac, or cellulose acetate phthalates that quickly dissolve once ingested o r a l l y . Recently, more complex laminated coatings have been introduced are are referred to as "sustained release" medications (28) (Figure 2). The drug may be applied i n soluble form to the outside polymer layer of a tablet containing a less soluble but porous core. More of the same drug i s trapped inside the core. This i s slowly dissolved by i n t e s t i n a l f l u i d , which gains access through pores i n the polymer core matrix. Another variation of t h i s method involves incorporation of the drug with coatings subject to dissolution at d i f f e r e n t rates, so that the t o t a l drug dose i s released over a long period. Several variables a f f e c t the rate of release of drugs, and these are used i n the development of sustained-release preparations. The size of the tablet and concentration of drug determine the surface area for solution and the rate at which the drug w i l l dissolve. The pore size of the i n e r t matrix, i t s resistance to sloughing, the presence of water-soluble substances i n the matrix, and the i n t r i n s i c s o l u b i l i t y of the drug i n an aqueous medium a l l a f f e c t the release rates. Rose and Nelson and others (29), have developed an implantable osmotic pump for drug d e l i v e r y . This pump consists of three parts; a drug chamber, a s a l t solution chamber, and a water environment or water chamber (Figure 3). The drug and the s a l t chambers are separated from an i n vivo aqueous environment by a semipermeable membrane. The water diffuses into the s a l t area expanding t h i s chamber, which i n turn exerts pressure on the drug-separating latex diaphragm causing the drug to be pushed or "pumped out" of the device through an o r i f i c e at a controlled rate into the b i o l o g i c a l system. Evaluations of t h i s system indicate that similar rates of delivery are encountered f o r i n v i t r o as for rats and mice i n vivo. A d i f f u s i o n controlled drug delivery from a polymer matrix i s

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Artels Rendering

Figure 2. Oral controlled release medications.

Figure 3. Implantable osmotic pump for drug delivery.

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c a l l e d a monolithic system. In t h i s method the drug i s encapsulated as a homogeneous dispersion, or i t i s dissolved throughout a ratec o n t r o l l i n g matrix such as a g e l (Figure 4). The drug diffuses at a given rate to the surface and then escapes into the b i o l o g i c a l environment. This process was f i r s t used for commercial f l e a c o l l a r s such as Shell No Pest S t r i p and Hereon dispensers. These allow the release of pesticides by rate-controlled d i f f u s i o n from the polymer matrix. The membrane reservoir system i s another diffusion-controlled device that involves the dispensing of a drug through a ratecontrolled membrane (Figure 5). Two major purposes can be served by t h i s technique; a long constant intravenous infusion and a prolonged l o c a l release or drug action to tissues i n a s p e c i f i c area. This method avoids many toxic e f f e c t s that could occur i f the drug were introduced into the general c i r c u l a t i o n of the body. For example, Ocursert, an ocular therapeutic system i s a device that delivers pilocarpine, an opthalamic drug for the r e l i e f of glaucoma (30). The device i s placed under the e y e l i d where i t continuously releases drug through rate-controlling membranes (Figure 6). This process obviates the need and complication of eye drops. It has been found that i n s u l i n can be released with near zero order kinetics from implant devices. Glucose sensitive membranes which increase t h e i r permeability i n the presence of glucose are being developed (31). Other microporous membranes, containing amine groups and entrapped glucose oxidase, have been found to a l t e r i n s u l i n permeability i n response to external glucose concentration (32). A cellulose membrane for self-regulated i n s u l i n delivery based on the p r i n c i p l e of competitive and complementary binding behavior of concanavalin A with glucose and glycosylated i n s u l i n i s also being developed. Diabetic rats have been shown to exhibit normal blood sugar for a 30-day period with one p e l l e t . S i m i l a r l y , progesterone has been incorporated into a S i l a s t i c depot which i s then d i r e c t l y inserted into the uterus of rabbits. The subsequent slow release of very small quantities of t h i s hormone affected l o c a l contraceptive action without s i g n i f i c a n t absorption and without suppressed ovulation. Subdermal implants of microcapsules of drugs i n a polymer matrix i s another important device used for drug delivery. O r i g i n a l l y these devices were composed of nondegradable materials such as s i l i c o n rubbers and were subdermally inserted v i a a trocar. A continuous and constant release of a n t i f e r t i l i t y steroids were successfully d e l i v ered for over one year. After the device i s s u r g i c a l l y removed, a rapid return to f e r t i l i t y was observed. The f i r s t implants were i n the form of p e l l e t s and the drug release rates were dependent upon the surface area of the p e l l e t . Subsequently, studies of controlled release from bioerodable polymers such as p o l y ( l a c t i c acid) and p o l y ( g l y c o l i c acid) have been i n v e s t i gated based on the success of these materials as absorbable sutures (Figure 7). The drug i s released as the implant begins to erode or break down. These devices are c a r e f u l l y designed so that a constant rate of release i s obtained. Recently better bioerodable (biodegradable) polymers have been developed such as poly (esters) (33) poly(orthoesters) (34) and poly(anhydrides) (35). The main advantage of these devices over others i s that time related delivery can range

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144 THE IMPACT OF CHEMISTRY ON BIOTECHNOLOGY

LOW LOADED

Figure 4. HIGHLY LOADED

D i f f u s i o n through polymer matrix.

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Figure 5. D i f f u s i o n through polymer membrane.

Figure 6.

Pilocarpine ocusert system

145

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146 THE IMPACT OF CHEMISTRY ON BIOTECHNOLOGY

TIME 0

TIME 2

Figure 7. Biodegradable surface eroding system.

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from a few months to several years and they do not require s u r g i c a l removal. Transdermal drug delivery may well become the preferred method of administration f o r 25% of the prescription medication i n the near future (36). The skin i s a multilayered organ and some years ago i t was thought to be impermeable to chemical i n t r u s i o n . However, the observed e f f e c t s from exposure to toxic substances has lead to the concept of u t i l i z i n g the skin's permeability f o r drug delivery. The f i r s t commercial product was Transderm-Scop which delivers scopolamine transdermally for the prevention of motion sickness (Figure 8). The rate of delivery i s controlled by the d i f f u s i o n properties of scopolamine through a membrane. A s i m i l a r device, Transderm-Nitro, i s used f o r delivery of n i t r o g l y c e r i n f o r heart ailments. Two monolithic systems, Nitro-Dur and N i t r o - d i s c , are also on the market (Table VIII). In these l a t t e r

Table VIII. Transdermal Delivery of N i t r o g l y c e r i n Approved Transdermal Products

Key Pharmaceuticals

Nitroglycerin

Monolith Angina

Searle Pharmaceuticals

Nitroglycerin

Monolith Angina

Ciba-Geigy

Nitroglycerin

Membrane Angina

Ciba-Geigy Sickness

Scopolamine

Membrane Motion

Boehringer-Inglehe im Hypertension

Clonidine

Membrane

systems, the rate of release depends on the concentration differences between the encapsulation matrix and the skin; consequently, the device releases whatever the skin i s capable of transporting. Nitroglycerin, which has a wide therapeutic index, has good skin permeability while scopolamine binds to skin proteins, and these sites need to be saturated before e f f e c t i v e administration occurs. Several new drugs are presently seeking FDA approval f o r transdermal administration (Table IX) . I t i s evident that the u t i l i z a t i o n of transdermal systems w i l l receive considerable attention i n the near future. The p r i n c i p l e reason i s that many pharmaceutical houses have p r o f i t a b l e drugs that are now coming to the end of t h e i r patent protection period. However, by incorporating these drugs into new controlled drug release or delivery methods of administration, patents can be extended without having to repeat many of the costly procedures that are associated with FDA compliancy. Therefore, extended market protection, p r o f i t a b i l i t y , and improved e f f i c a c y are major incentives. The advantage of transdermal delivery i s that drugs can be delivered over a long period of time at a constant rate

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and that administration can be aborted by simply removing the transdermal patch.

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Table IX.

Category

Drugs i n Research and Development

Drug

Hormone

Estradiol E s t r a d i o l esters

Cardiovascular

Isosorbide d i n i t r a t e Timolol Propranolol

Analgesic

Salicylate

Antihistamine

Chlorpheniramine

Cholinergic

Physostigmine

Liposomes were f i r s t used as model biomembranes and are presently being evaluated as drug c a r r i e r s for improved drug therapy. Liposomes are b i l a y e r molecular assemblies of molecules that have long hydrophobic carbon chains with a hydrophilic head (Figure 9) . These b i l a y e r v e s i c l e s are of interest as drug delivery systems since water soluble drugs can be encapsulated i n the central aqueous core, and nonpolar drugs can be situated i n the hydrophobic b i l a y e r area of the liposome. This p o t e n t i a l application received extensive i n i t i a l interest which soon dimmed because of two major drawbacks; f i r s t , these assemblies are not very stable and "leaked" or release encapsulated material very rapidly; and secondly, they are taken up by the liver. Consequently, the drugs were released into t h i s metabolitic a l l y active area and large amounts of l i p i d material (37) were being deposited i n the l i v e r . These d i f f i c u l t i e s stimulated research which solved several pharmaceutical problems such as s t a b i l i t y , s t e r i l i t y , and scale up. Now p r a c t i c a l production of liposome drug formulations f o r human use are available. The liposome appears to be a s p e c i f i c a l l y i d e a l system for drug delivery to the lung. These b i l a y e r systems do not appear to i r r i tate the lung or invoke foreign-body response. Research has shown that guinea pigs after aeresol administration of antihistamine i n a liposome formulation resisted a challenge by histamine. Furthermore, these liposome-encapsulated bronchodiadators produced s i g n i f i c a n t l y lower heart rates (37). Related to t h i s , Sunamoto (38) has e f f e c t i v e l y delivered antibacterials to the alveolar c e l l s by coating the liposome surface with polysaccharides. The polysaccharides not only s t a b i l i z e the liposomes, but target them to the alveolar c e l l s . This liposomal system provides for an e f f e c t i v e treatment of Legionnaire's disease.

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Figure 8. Transdermal therapeutic system.

LIPID BILAYER VESICLE

Figure 9. Liposome.

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Site s p e c i f i c delivery of liposomes i s the present research thrust i n t h i s area. The a b i l i t y to s p e c i f i c a l l y destabilize the l i p i d assembly has l e d to the design of heat-sensitive, l i g h t sensitive and pH-sensitive liposomes while the chemical approach to obtaining s i t e - s p e c i f i c delivery involves the attachment of targeting moieties such monoclonal antibodies, s p e c i f i c carbohydrates, hormones and proteins. The application of polymeric drugs and drug delivery systems should become more popular i n the near future for two reasons. One, they provide f o r a more e f f e c t i v e method of delivering medications; t h i s i s from the viewpoint of time and type of delivery, dosage l e v e l s , and the b i o l o g i c a l demand for the medication. Secondly, new FDA p o l i c i e s with regard to extending the protection period of a drug by improving i t s e f f i c a c y through new administrative modalities w i l l stimulate drug companies to market these systems. The two drug delivery systems that probably have the greatest commercial potential are the transdermal systems f o r external applications and the erodable membranes or "self-destructing" devices that slowly disappear during or subsequent to drug delivery f o r i n t e r n a l application. Other devices w i l l also play an important role but more f o r s p e c i f i c applications.

Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

Anderson, J. M. and S. W. Kim, Eds.; Advances in Drug Delivery Systems; Elsevier: New York, 1986. Tirrell, D., L.G. Donaruma, and A. B. Turer, Eds.; Macromolecules as Drugs and Carriers for Biologically Active Materials; New York Academy of Science Press: New York, 1985. Shalaby, S., A. Hoffman, B. Ratner and T. Horbett, Eds.; Polymers as Biomaterials; Plenum Press: N.Y., 1983. Szycher, M., Ed.; Biocompatible Polymers, Metals and Composites; Technomics Publishing Co.: Lancaster, Pa., 1983. Kambic, E., S. Murabayashi, and Y. Nose. Chem. Eng. News, 1986, 64 (15), p 31-42. Johnson, H.J., S.J. Northrup and Seagraves. J. Biomed. Mater. Res., 1985, 19(5) 489. Stillman, R.M. and Z. Sophie. Arch. Surg., 1985, 120(11) 1281. Refojo, M.F. Curr. Eye Res., 1985, 4(6), 719. McCaffery, and F.W. Lusby. J. Cataract. Refract. Surg., 1986, 12(3), 278. Iwata, H., H. Ameyiya, T. Matsuda, Y. Matsuo, H. Takano, T. Akutsu. Artif. Organs, 1985, 9(3), 299. Jacker, H.J., R. Meter and S. Grutter. Pharmazie, 1985, 40(7), 472. Rosen, J.M.. Ann Plast. Surg., 1986, 16(1), 82. Noishiki, Y. and T. Miyata. J. Biomat. Res., 1986, 20, 337. Jozefowicz, M. and J. Jozefowicz. Asaio J., 1985, 8(4), 218. Toshihiro, A. Oyo Butxuri, 1984, 53, 357. Ottenbrite, R.M., L.G. Donaruma, and O. Vogl, Eds.; Anionic Polymeric Drugs; Wiley-Interscience: New York, 1980. Ottenbrite, R.M. and G.B. Butler. Synthesis and Characterization of Interferon Drugs; Marcel Dekker: New York, 1984.

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