polymeric drug delivery systems

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Polymeric Drug Delivery Systems ** By Julio San Roman,* Alberto Gallardo, and Belkn Levenfeld

During the last two decades growing interest has been devoted to the subject of drug delivery and the design of new targeting systems based on the use of macromolecular sup- ports ofnatural or synthetic origin. It is recognized that from a therapeutic point of view, in order to derive the optimum benefit for the application of a pharmacon, the drug should be delivered to its specific target site at a rate that would give the optimal therapeutic concentration while reducing any undesirable side effects to a minimum.[’. Polymeric materials are the systems closest to the natural components of the body and, in addition, independently of their origin (natural or synthetic), can be tailored to give the desired physico- chemical properties. Therefore they are often used as sup- ports or components of devices to deliver drugs into the body with efficien~y.[~-~I

When considering the formulation of a drug within a release delivery system, the following parameters have to be considered: L6 , 71

- Pharmacokinetic properties of the drug, including rate of absorption, rate and mechanism of drug elimination, bio- logical half-life, and bioavailability in the human body.

- Pharmacological properties of the drug, i.e., minimum effective therapeutic concentration, influence of drug concentration, and durability of steady-state kinetics.

- Toxicological properties of the drug-release device : minimum toxic concentration and frequency and type of toxicological effect. Drug delivery systems can be conveniently divided into

two large groups related to “controlled drug release systems” and “targeted drug delivery systems”. These categories are based on the relationship between the site of drug release and the site of drug action. In general a “controlled drug delivery device” delivers the drug into the system stream at a predetermined rate, controlled by a physical or physico-chemical response to a particular action.[’. Conse- quently, the site of drug release and that of drug action are

[*I Prof. J. San Roman, Dr. A. Gallardo Instituto de Ciencia y Tecnologia de Polimeros, CSIC Juan de la Cierva 3, E-28006 Madrid (Spain) Dr. B. Levenfeld Dto. Ingenieria, Area de Ciencia de Materiales Escuela Politecnica Superior, Universidad Carlos I11 Madrid (Spain)

[**I The authors wish to thank the CICYT for financial support proviaded through grants Mat-92-0198, Mat-93-0749-C03-01, and FIS-94/0033, which have enabled much of this work to be performed. They are also grateful to Prof. Jose Luis Serrano for the invitation to contribute to this issue.

not the same. In contrast, “targeted delivery systems” are able to release the active pharmacon at or near the site of action. This means that a high local concentration of drug can be achieved without the dissipation of the active component throughout the whole physiological system.[”- 13]

The science of drug delivery and polymeric drugs is highly interdisciplinary and it is necessary to achieve good cooper- ative contributions from organic and macromolecular chemistry, biology, pharmaceutics, pharmacology and medicine, as is indicated in Figure 1. This means that advances in the

BIOMEDICAL

Fig. 1. Interdisciplinary connections in the field of “controlled release” and “drug action”.

design and development of new and more-specific delivery systems will be the result of a close cooperation between researchers specialized in different disciplines. A particularly strong relationship exists between polymer chemistry and drug delivery, since most drug delivery systems depend on polymeric materials.[’. 141

According to the kinetics and mechanism of release of the active components, the delivery systems can be classified in the main categories “solvent controlled”, “diffusion controlled”, and “chemically controlled”.[’* ’’]

The “solvent controlled systems” are based on the prin- ciple of the permeability of polymer matrices after the swelling process in an hydrated medium. The most characteristic systems are hydrogels prepared from biocompatible polymeric systems. The kinetics of swelling and therefore the

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rate of release depend on the hydration of the support matrix, which is constituted by polymeric systems based on hydrophilic polymers crosslinked with tetrafunctional vinyl or acrylic monomersr16. 17] or, alternatively, by biocompatible copolymers of hydrophilic and hydrophobic monomers with the appropriate composition to control the rate of drug release. Poly(viny1 alcohol), carboxymethylcellulose, poly- (hydroxyethylinethacryla te) , and poly(N-vinylpyrrolidone) are examples of hydrophilic systems widely used in the preparation of controlled devices.[”- 19]

The “diffusion controlled systems” are characterized by the use of reservoirs bearing a non-degradable rate-limiting polymeric membrane in the form of microcapsules, hollow fibers, or tubes with sealed ends.[21 In these, the rate of drug release is controlled by the rate of diffusion through the polymeric membrane. Homogeneous and microporous fibers with a good distribution of porosity have been suggested and tested clinically.[20] The main problem of delivery devices of this kind is the danger of overdose by the acciden- tal rupture of the membrane or microporous barrier. Anoth- er possibility is the use of a matrix system in which the active pharmacon is homogeneously distributed. The matrix system can be made from a hydrophilicjhydrophobic polymeric system or even from a biodegradable polymer, the release mechanism being a combination of diffusion and chemically controlled release.[’] The use of hydrophilic non-resorbable matrices has ;I clear limitation in comparison with biodegradable polymers because of the accumulation of the biostable polymer in the body. Accordingly, biostable systems are used mainly for the preparation of transdermal delivery devices, whereas biodegradable polymers are used for the preparation of implantation or internal administra- tion in the form of microcapsules, coated particles, etc.

“Chemically controlled systems” are those in which the rate of drug release is predominantly controlled by the rate of polymer biodegradation. The biodegradable support can consist of natural polymers such as proteins (albumin, gelatin, collagen). polysaccharides (dextran, starch, chitin, chitosan, etc.) or from synthetic polymers, e.g., poly(hydroxyalkanoate)s, poly(anhydride)s, poly(lactame)s, poly(viny1- alcohol), poly(acrylic)s, etc. Independently of its natural or synthetic origin, the polymeric support must be biocompatible, non-toxic. and uon-carcinogenic and the corresponding biodegradation products should be soluble in the physiological fluids, without the induction of an immunological response or allergic or pyrogenic reactions.[”]

One of the most important characteristics of these systems is the possibility of clearance of the supporting matrix, avoiding its accumulation in the tissues and organs. This behavior is controlled by the chemical structure of functional groups along the macromolecular backbone or as lateral substituents which after hydrolysis provide water-soluble compounds. As is indicated in Figure 2, the functional groups selected for their hydrolytical reactivity are anhydride, carbonate, ester, urethane, orthoester and amides. The presence of these bonds in a macromolecular system

-C-NH-

Fig. 2 . Functional groups susceptible to hydrolysis in physiological conditions.

provides an effective way to control the mechanism of biodegradation, the solubility, and the release of the active drug supported by the original matrix. Systems of this kind are in general rather hydrophobic in nature and become hydrophilic and readily hydrosoluble after the hydrolysis of the functional groups mentioned.

Morphologically, there are at least three different arrange- ments of the active drug dispersed in a biodegradable matrix (see Fig. 3). The drug can be homogeneously distributed in

. a .,, , * 4 ..m.:- ; A . LINEAR POLYMERIC CHAINS

B - DEGRADABLE SIDE SEGMENTS

--c

I , C - DEGRADABLE NETWORKS

Fig. 3. Mechanisms of release of drugs D from biodegradable polymeric matrices. R represcnls a protective group.

a polymeric matrix which undergoes solubilization after the hydrolytical degradation of the functional groups along the macromolecular backbone. In this case, the drug is released from the matrix at a rate modulated by the biodegradative activity of the medium, as represented in Figure 3 a. Typical

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examples of this model are biodegradable systems based on poly(a-hydroxyalkanoate)s, e.g., poly(glyco1ic acid) and poly(D,L-lactide) , as well as several poly(anhydride)s.[22 - 241

The drug is introduced into the system before the crosslink- ing or using appropriate solvents which promote the swelling of the crosslinked matrix. The solvent is then removed by evaporation at reduced pressure. In these systems the release of the active drug is produced by diffusion through the network in a swollen state and in addition by the resorption of short segments of the polymeric network after the hydrolytical breaking of the active functional groups.[2s - 271

However, probably one of the most attractive approaches is the synthesis of so-called “polymeric drugs” based on well- known pharmacologically active compounds bound covalently to a macromolecular soluble support. The advantage of systems of this kind over delivery systems based on a diffusion mechanism is mainly that the polymeric drugs may display pharmacological activity by themselves, and in addition act as a true chemical support for the pharmacological agent.“’] Covalently bound conjugates of polymer and drugs allow an enhancement of the therapeutic index of highly toxic pha r rnacon~ . [~~] The major objective of these polymer-drug conjugates is to obtain a local activity of the active drug with minor side effects, offering not only pro- longed pharmacological activity but also the possibility of a more cell-specific uptake or targeting effect.[’* ~ 301

The term “polymer drug” or “polymeric drug” has been widely used for pharmacologically active inacromolecules since the 173rd National Meeting of the American Chemical Society held in 1977.“ 3 , 3 1 1 According to the definition adopted in this meeting and others held more recently,[321 “polymeric drug” means that the polymer itself shows pharmacological activity, although the corresponding monomeric species may or may not be biologically active.

Independently of their origin, the polymeric systems used for the preparation of polymeric drugs or polymer-drug conjugates have to be biocompatible, non-toxic, non-carcinogenic, and, if possible, soluble in the aqueous physiological media. They should not induce an immunological response or allergic or pyrogenic reactions.[’l> 33-351 One important characteristic of these systems is the necessity of clearance from the body in order to avoid its accumulation in the tissues and organs. Fortunately, this can be achieved by means of the complete dissolution of the polymeric matrix after the enzymatic hydrolysis of the functional groups used to bond the pharmacologically active moiety to the polymeric backbone.

Although there are infinite possibilities for designing polymer-drug conjugates, the most widely accepted model is that suggested by Ringsdorf in 1975,[3h. 371 which considers that the covalent binding of low molecular weight pharma- cons to a polymeric system must be by means of organic functional groups that can be degraded in the physiological medium. Profiting from the many possibilities offered by macromolecular chemistry from a synthetic point of view, it is possible to combine properties such as hydrophilic or hy-

drophobic character, hydrolytical reactivity in hydrated media or even specific interactions with enzymes and receptors. As is shown in Figure 4, the theoretical model suggested by Ringsdorf has three main components, which can be incorporated into the macromolecular systems by the copolymerization of the corresponding monomeric components, with the overall composition producing the best therapeutic action.

POLYMER BACKBONE BIOSTABLE OR BIODEGRADABLE

Fig. 4. Components of polymer - drug conjugates according to the model suggested by Ringsdorf [36].

With this aim, in general one component is designed to provide a liposoluble or hydrosoluble system, depending on the site of action of the active drug. This is introduced into the polymeric chain as comonomeric units with a composition and microstructural distribution appropriate to the sol- ubilizing action designed, Monomers such as hydroxy- ethylmethacrylate, N-vinylpyrrolidone, and N,N-dimethyl- acrylamide are used frequently for the preparation of highly hydrophilic and hydrosoluble systems. Such monomers give rise to biocompatible and hydrosoluble polymers and copolymers, which can be cleared from the body by dissolution in the physiological fluids.

The second component is the support of the pharmacological agent. It consists of degradable or non-degradable units incorporated in the polymeric backbone to which a specific drug is covalently attached through one of the hydrolyzable functional groups represented in Figure 2. The drug can be linked directly to the polymer chain or through a spacer group to increase the flexibility and mobility of the side residue, to minimize the steric hindrance of the neighboring groups and therefore to facilitate the pharmacological action and the enzymatic cleavage of the active side residue. In general the spacer groups ai-e oxyethylene segments for hydrophilic systems and hydrocarbon chains for lipophilic systems.

For specific applications a third component can be introduced into the system as a comonomeric targeting element, to improve the overall performance of the polymeric drug.[’] The polymeric backbone may be biodegradable (dextran,

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polylysine, poly(g1utamic acid), poly(ethy1ene glycol), poly(D,L-lactide), poly(anhydride)s) and several addition copolymers. In the case of the use of a biostable polymeric backbone it is necessary that the system becomes hydrosoluble after the hydrolytical cleavage of the side drug residue. This is in general the case for poly(acry1ic ester)s and substituted poly(acrylamide)s, which after the hydrolysis of the ester or amide groups promoted by enzymes such as esteras- es or lipases are transformed into the corresponding sodium salts of polyacrylic or polymethacrylic acids. These compounds are readily soluble in the physiological fluids and therefore cleared from the body through the normal urinary pathway.

Following this model we have studied the synthesis and pharmacological behavior of poly(acry1ic) conjugated systems by the homo- and copolymerization of methacrylate esters and methacrylamides bearing typical analgesic and antipyretic drugs such as salicylic acid, as well as drugs with anti-inflammatory activity, which are used extensively for the treatment of inflammatory processes of traumatologic origin, e.g., rheumatoid arthritis.[381 These are organic compounds derived from substituted phenyl acetic or phenyl propionic acids, which are known as non-steroidic anti- inflammatory agents (NSAIAs) .[393401

We began studying this series in the early 1980s by prepar- ing a methacrylic derivative of salicylic acid. the 2-methacryl- oyloxybenzoic acid (S), and several polymers in different media. The study of the degradation of the acrylic polymers prepared showed an interesting selective effect of the stereo- chemical configuration of the polymeric chains on the release of salicylic acid from the polyacrylic support of high molecular weight.[411 In addition, the pharmacological behavior of this polymeric drug was rather interesting in comparison with the traditional aspirin, and even presented an anti-aggregating activity for human platelets about 25 times that of aspirin.[421 According to this behavior it could be interesting to profit from the properties of the polymeric system for surgical applications. and more recently we have prepared biocompatible hydrophilic copolymer systems by the free radical copolymerization of the methacrylic derivative of salicylic acid and hydroxyethyl methacrylate (H), or N-vinylpyrrolidone (V). Figure 5 shows the chemical structure of the repeating units of the copolymers. The H or V units are the hydrophilic solubilizer components considered in Ringsdorfs model. Systems prepared with 5-20% of S in the swollen state form hydrophilic films with excellent adhesion to porous surfaces. Therefore, they have been used recently as active coating for commercial vascular grafts of small diameter in order to improve the thromboresistance. In vitro and in vivo experiments have shown that the vascular grafts coated with H-S copolymers with an S content between 5 and 20% present excellent adhesion to the wall of the prosthesis with retention under dynamic conditions at normal blood pressures and with lower deposition of platelets on the luminal surface in comparison with the un- coated prosthesis taken as control.[431

Fig. 5. Chemical structure of comonomeric units in S-H and S-V copolymer systems. (S)-2-methacryl- oyloxybenzoic acid, (H)- hydroxy- ethylmethacrylate, (V)- N-vinylpyrrolidone.

In the same way we prepared and studied the behavior of several acrylic derivatives of paracetamol (N-acetyl-4- aminophenol) with oxyalkyl spacer groups of variable length.[44%451 The chemical structure of the repeating units of copolymers with H are represented in Figure 6. The study of

Fig. 6. Chemical structure of polymer-drug conjugates bearing “paracetamol” side residues.

the hydrolysis of H- MOA copolymer systems prepared with up to 10% of MOA in buffered solution at 37°C and pH > 7.0 demonstrated that the biodegradation of these systems releases paraeetamol, but in addition the cleavage of the acetamide side groups is produced simultaneously, giv- ing rise to the formation of the sodium salt of 4-aminophenol. This is in fact the active metabolite of paracetamol in the human body.

In view of this behavior we have prepared recently several polymeric drugs on the basis of hydrophilic copolymers of hydroxyethyl methacrylate with acrylic monomers bearing derivatives of phenyl acetic or propionic acids, using the 4-aminophenoxy group as an active spacer between the poly-

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mer backbone and the side drug residue, in order to enhance the analgesic activity of the corresponding macromolecular system. The chemical structure of the corresponding monomeric methacrylic esters and methacrylamides are shown in Figure7. The synthesis of these monomers has been de- scribed in previous papers.[46- 501

MAM

MA1

OMM

OM1

Fig. 7. Chemical structure of acrylic derivatives of 4-methoxyphenylacetic acid (MAM, OMM) and of Ibuprofen (MAI, OMI).

The biodegradative mechanism activated by enzymes is represented schematically in Figure 8. There are two side bonds susceptible to hydrolysis: the ester and amide, which in addition can be activated by sterases and peptidases in the

I NH . . . . .. ... , . . . . . . . . . t o

e

Fig. 8. Biodegradation mechanism of the polyacrylic derivatives of NSAIAs represented in Figure 7.

physiological medium. As is indicated in the scheme, different ionic residues in the form of sodium salts can be released from the support acrylic matrix, which can be active directly or after a new hydrolytical process in the presence of the appropriate enzymes, to give the active metabolite. Simulta- neously, the sodium salt of the polyacrylic chains becomes hydrosoluble and is readily cleared from the body, via the urinary pathway.

These systems are being studied in vivo after peritoneal injection in mice. It is possible to follow the variation of the concentration in plasma of the active residues with time by high-performance liquid chromatography (HPLC) , as well as to evaluate the analgesic, antipyretic and anti-inflammatory effects following standard tests. The preliminary results obtained seem to be very interesting, and indicate that these systems may be used as a control delivery system with sustained action over periods of time at least ten times longer than the traditional pharmacon used as a control. In addition, the properties of the polymeric formulations and the ability to prepare formulations soluble in water offer the possibility of the treatment of rheumatoid arthritis by direct injection of the appropriate solution into the joints affected, with a sustained effect over long periods of time (weeks or even months). This application is being studied experimen- tally in cooperation with surgeons.

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1991. 192, I03

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