447

Polymers in drug delivery

Omathanu Pillai and Ramesh Panchagnula*
Advances in polymer science have led to the development of considerations in selection and design of polymers for
several novel drug-delivery sytems. A proper consideration of drug-delivery applications.
surface and bulk properties can aid in the designing of
polymers for various drug-delivery applications. Biodegradable Considerations for selection of polymers
polymers find widespread use in drug delivery as they can be The selection and design of a polymer is a challenging task
degraded to non-toxic monomers inside the body. Novel because of the inherent diversity of structures and requires
supramolecular structures based on polyethylene oxide a thorough understanding of the surface and bulk proper-
copolymers and dendrimers are being intensively researched ties of the polymer that can give the desired chemical,
for delivery of genes and macromolecules. Hydrogels that can interfacial, mechanical and biological functions. The
respond to a variety of physical, chemical and biological stimuli choice of polymer, in addition to its physico-chemical
hold enormous potential for design of closed-loop drug- properties, is dependent on the need for extensive bio-
delivery systems. Design and synthesis of novel combinations chemical characterization and specific preclinical tests to
of polymers will expand the scope of new drug-delivery prove its safety. Recently, Angelova and Hunkeler [4••]
systems in the future. have proposed a flow chart for rational selection of
polymers for biomedical applications. Table 1 gives a rep-
Addresses resentative list of polymers that have been investigated for
Department of Pharmaceutics, National Institute of Pharmaceutical drug-delivery applications and can be broadly classified
Education & Research (NIPER), Sector-67, Ph X, into biodegradable and non-biodegradable.
SAS Nagar – 160 062 (Punjab), India
*e-mail: [email protected]
Surface properties such as hydrophilicity, lubricity, smooth-
Current Opinion in Chemical Biology 2001, 5:447–451 ness and surface energy govern the biocompatibility with
1367-5931/01/$ — see front matter tissues and blood, in addition to influencing physical prop-
© 2001 Elsevier Science Ltd. All rights reserved. erties such as durability, permeability and degradability
[4••]. The surface properties also determine the water sorp-
Abbreviations
DDS drug-delivery system
tion capacity of the polymers, which undergo hydrolytic
PGA polyglycolic acid degradation and swelling (hydrogels). On the other hand,
PLA polylactic acid materials for long term use (orthopaedic and dental
PLGA poly(lactic acid-co-glycolic acid) implants) must be water-repellent to avoid degradation or
erosion processes that lead to changes in toughness and loss
Introduction of mechanical strength. Surface properties can be improved
Polymers, the most versatile class of materials, have by chemical, physical and biological means to increase their
changed our day-to-day lives over the past several decades. biocompatibility. Grafting of enzymes, drugs, proteins and
However, the distinction between temporary and perma- antibodies to the polymer surface has led to ‘polymer
nent biomedical applications of polymers was made only therapeutics’ for targeting to organs and cells [5].
30 years ago [1••]. Subsequently, the amalgamation of
polymer science with pharmaceutical sciences led to a Bulk properties that need to be considered for controlled
quantum leap in terms of ‘novelty’ (flexibility in physical delivery systems include molecular weight, adhesion, solubil-
state, shape, size and surface) in design and development ity based on the release mechanism (diffusion- or
of novel drug-delivery systems (DDSs). Polymeric dissolution-controlled), and its site of action. Bioadhesiveness
delivery systems are mainly intended to achieve either a need to be taken into account when DDSs are targeted to
temporal or spatial control of drug delivery [2•]. The intro- mucosal tissues, whereas polymers for ocular devices have to
duction of the first synthetic polymer-based (polyglycolic be aqueous or lipid-soluble in addition to having good film-
acid) DDS led to a heightened interest in the design and forming ability and mechanical stability for good retention [6].
synthesis of novel biodegradable polymers that obviated Structural properties of the matrix, its micromorophology and
the need to remove the DDS, unlike the nondegradable pore size are important with respect to mass transport (of
polymeric systems. Recognizing that intimate contact water) into and (of drug) out of the polymer. For non-
between a delivery system and an epithelial cell layer will biodegradable matrices, drug release in most cases is
improve the residence time as well as the efficacy of the diffusion-controlled and peptide drugs with low permeability
DDS resulted in the design of bioadhesive polymers [3]. can only be released through the pores and channels created
Further advancements in polymer science led to ‘smart’ by the dissolved drug phase [7].
polymeric hydrogel systems that can self-regulate the
delivery of a bioactive agent in response to a specific stim- With regard to biodegradable polymers, it is essential to
ulus. With the availability of a large number of synthetic recognize that degradation is a chemical process, whereas
and natural polymers, this article discusses the various erosion is a physical phenomena dependent on dissolution
448 Next generation therapeutics

Table 1 Table 2

Representative list of polymers used in drug delivery. Factors influencing biodegradation of polymers.

Classification Polymer Chemical structure and composition

Natural polymers Physico-chemical factors (ion exchange, ionic strength, pH)

Protein-based polymers Collagen, albumin, gelatin Physical factors (shape, size, chain defects)
Polysaccharides Agarose, alginate, carrageenan, Morphology (amorphous, semicrystalline, crystalline, microstructure,
hyaluronic acid, dextran, chitosan, residual stress)
cyclodextrins
Mechanism of degradation (enzymatic, hydrolysis, microbial)
Synthetic polymers Molecular-weight distribution
Biodegradable
Processing conditions and sterilization process
Polyesters Poly(lactic acid), poly(glycolic acid),
poly(hydroxy butyrate), poly(ε- Annealing and storage history
caprolactone), poly(β-malic acid), Route of administration and site of action
poly(dioxanones)
Polyanhydrides Poly(sebacic acid), poly(adipic acid),
poly(terphthalic acid) and various
combinations of polymer species either physically mixed
copolymers (polymer blends or interpenetrating networks) or chemi-
Polyamides Poly(imino carbonates), polyamino cally bonded (copolymers) offer tremendous scope as
acids delivery systems. Although selection of polymers is a
Phosphorous-based polymers Polyphosphates, polyphosphonates,
prime concern, especially with regard to compatibility with
polyphosphazenes
the drug, the manufacturing process also needs to be con-
Others Poly(cyano acrylates), polyurethanes, sidered, because the additives used during polymerization
polyortho esters, polydihydropyrans,
polyacetals may degrade the drug. A recent patent describes a method
wherein a protein is first dispersed in a glassy matrix
Non-biodegradable
(whose glass-transition temperature is well above the melt-
Cellulose derivatives Carboxymethyl cellulose, ethyl
cellulose, cellulose acetate, ing point of the polymer) and subsequently is dispersed in
cellulose acetate propionate, the polymer, which then can be fabricated into a DDS of
hydroxypropyl methyl cellulose any desired shape, thereby protecting the protein from the
Silicones Polydimethylsiloxane, colloidal silica harsh manufacturing process [P1].
Acrylic polymers Polymethacrylates, poly(methyl
methacrylate), poly hydro(ethyl- Natural polymers are usually biodegradable and offer excel-
methacrylate)
lent biocompatibility, but suffer from batch to batch
Others Polyvinyl pyrrolidone, ethyl vinyl variation because of difficulties in purification. On the other
acetate, poloxamers, poloxamines hand, synthetic polymers are available in a wide variety of
compositions with readily adjustable properties [4••].

and diffusion process. Depending on the chemical struc- Biodegradable and nondegradable polymers
ture of the polymer backbone, erosion can occur by either A variety of biodegradable polymers have been synthe-
surface or bulk erosion. Surface erosion occurs when the sized to deliver drugs, macromolecules, cells and enzymes.
rate of erosion exceeds the rate of water permeation into The wide acceptability of these polymers can be appreci-
the bulk of the polymer and is desirable because the kinet- ated from the fact that the biodegradability can be
ics of erosion and rate of drug release (zero order) are manipulated by incorporating a variety of labile groups
highly reproducible. Bulk erosion occurs when water mol- such as ester, orthoester, anhydride, carbonate, amide, urea
ecules permeate into the bulk of the matrix at a faster rate and urethane in their backbone [7]. It is pertinent to men-
than erosion, thus exhibiting a complex degradation/ero- tion that Langer’s group [8••] has made significant
sion kinetics. Most of the biodegradable polymers used in contributions in investigating various polymers for drug
drug delivery undergo bulk erosion. However, the use of delivery and characterizing the release of macromolecules
nanoparticle or microparticle formulations possessing from the polymer. Biodegradation can be of enzymatic,
massive surface areas results in bulk- and surface-eroding chemical or microbial origin, and these may operate either
materials that show similar erosion kinetics. Further, the separately or simultaneously and are often influenced by
erosion process can be manipulated by modifying the many other factors (Table 2).
surface area of the DDS or by including hydrophobic
monomer units in the polymer [1••]. Polyester-based polymers are one of the most widely
investigated for drug delivery. Poly(lactic acid) (PLA)
Microstructural design and chemical composition can be poly(glycolic acid) (PGA) and their copolymers poly(lactic
used to adapt the structure–property relationship and tailor acid-co-glycolic acid) (PLGA) are some of the well-defined
improved polymeric matrices. Various polymer architec- biomaterials with regard to design and performance for
tures (linear, branched, star-like comb-like polymer) and drug-delivery applications [2•]. It is possible to modify the
 Polymers in drug delivery Pillai and Panchagnula 449

mechanical, thermal and biological properties of PLA by peroral dosage forms, transdermal films and devices [14•].
altering its stereochemistry. Further biodegradability can Cyclodextrins are potential high-performance carrier mate-
be tuned by changing the proportion of PLA and PGA in rials that have the ability to alter physical, chemical and
the copolymer. Although PLGA represents the ‘gold stan- biological properties of guest (drug) molecules through the
dard’ (exemplified by more than 500 patents) of formation of inclusion complexes both in solution and solid
biodegradable polymers, increased local acidity because of state [15]. The alpha, beta and gamma cyclodextrins are the
degradation can lead to irritation at the site of polymer most common natural cyclodextrins consisting of six, seven
application [1••]. Further, the increased local acidity may and eight D-glucopyranose residues, respectively, linked by
also be detrimental to the stability of protein drugs [9•]. α-1,4 glycosidic bonds into a macrocycle. There has been
an explosion in the number of reports dealing with the
Polyorthoesters have been under development since the practical uses of natural cyclodextrins (more than 16,300
1970s and most research has focused on the synthesis of patents and papers). Around 1500 derivatives of cyclodex-
polymers by addition of polyols to diketene acetals. They trins have been discussed in the literature, which include
are unique among all biodegradable polymers, as mechani- hydrophilic, hydrophobic and ionic derivatives to expand
cal properties can be readily varied by choosing appropriate the physico-chemical properties and inclusion capability of
diols or mixture of diols in their synthesis [10]. A number of natural cyclodextrin as novel drug carriers [16].
applications have been found for polyorthoesters and
crosslinked polyorthoestes such as delivery of 5-flurouracil, Dextrans are being actively investigated for sustained
periodontal delivery systems of tetracycline and pH-sensi- delivery of therapeutic and imaging agents, particularly for
tive polymer systems for insulin delivery. Polyanhydrides injectables and colon-specific DDSs [17]. Polyethylene
are characterized by their fast degradation followed by oxide (PEO) and polyoxypropylene (POP) copolymers are
rapid erosion of material, but at the same time can be one of the most interesting classes used for nanoparticulate
designed to release drugs that last from days to weeks by DDSs. They are commercially available as polaxmers in a
suitable choice of monomers [11]. By varying the monomer range of liquids, pastes and solids. Since their first intro-
ratio of aliphatic (sebacic acid) and aromatic (carboxyphe- duction as non-ionic surfactants in the 1950s, they have
noxypropane) polyanhydrides, polymer-carmustine disks found a wide range of applications in the pharmaceutical
were fabricated for chemotherapy of brain cancer, which and biomedical fields [18]. Soluble block copolymers
was the first US Food and Drug Administration (FDA)- based on PEO–PLA can self-assemble into novel
approved polymer-based chemotherapy DDS [8••]. supramolecular structures and are being investigated for
delivery of anti-cancer agents, proteins and plasmid DNA
Polyaminoacids that have good biocompatibility have been [19•]. They are advantageous in terms of drug targeting
investigated for the delivery of low-molecular-weight com- and safety, and they can mimic biological transport
pounds. However, their widespread use is limited by their systems, lipoproteins or viruses.
antigenic potentials and poor control of release because of
the dependence on enzymes for biodegradation. Poly(imino Polysiloxanes are a unique class of non-deformable poly-
carbonates), which are ‘pseudo’ polyaminoacids, have been mer possessing good low-temperature flexibility, excellent
synthesized from tyrosine dipeptide to overcome the electrical properties, water repellency and remarkable
abovementioned limitations [1••]. biocompatibility, features that are not common with hydro-
carbon polymers [14•]. Because of ease of fabrication and
A relatively new class of biodegradable polymers belong- high permeability, polydimethyl siloxanes (PDMSs) are
ing to polyphosphoesters has a unique backbone consisting useful for water-soluble drugs and steroids for long-acting
of phosphorous atoms attached to either carbon or oxygen. DDSs such as subdermal implants and intravagnial
The uniqueness of this class of polymer lies in the chemi- systems [20].
cal reactivity of phosphorous, which enables a wide range
of sidechains to be attached for manipulating the biodegra- Lectins and lectin-like molecules of plant or microbial ori-
dation rates and the molecular weight of the polymer [7]. gin, as well as biotechnologically generated derivatives of
Polyphosphazenes, another new class of polymers are such molecules, have interesting characteristics to control
being investigated for delivery of proteins [12]. the binding, uptake and intracellular routing of macromol-
ecules as well as colloidal carrier systems [21•]. In contrast
Chitosans are promising natural polymers that show good to other mucoadhesive polymers, lectin binds directly to
absorption-enhancing, controlled release as well as bioad- epithelial cells rather than to the mucus gel layer.
hesive properties. The degree of deacetylation and
derivatization with various sidechains can be a source of Dendrimers belong to a novel and exciting class of highly
manipulation for specific drug-delivery applications [13]. branched three-dimensional polymer in which growth
emanates from a central core molecule such as ammonia,
A variety of non-degradable polymers are used in drug ethylenediamine, polydiamine or benzene tricarboxylic
delivery of which polysaccharide-based and acrylic-based acid chloride [22•]. Compared with traditional linear poly-
polymers have found wide application in the fabrication of mers, dendrimers have much more accurately controlled
450 Next generation therapeutics

Table 3 The glycosylated insulin, which is biologically active, can

be displaced from the concovalin A in proportion to the
Various stimuli used for triggering drug release from
hydrogels. amount of glucose that competes for the same binding
sites [27]. Polymeric systems that can simultaneously
Stimulus Mechanism respond to pH and temperature can be achieved by modi-
fication of polyelectrolyte gels with lower critical solution
pH pH change causes swelling and release of drug
Ionic strength Change in concentration of ions inside the gel temperature (LCST) monomers [28].
causes swelling and release of drug
Chemical Formation of charge-transfer complex cause Recent findings indicate that a hydrogel of polyacrylamide
swelling and release of drug semi-interpenetrating networks can respond to antigen,
Enzyme–substrate Product of enzymatic conversion causes
swelling and release of drug
which could find potential application for delivery of drugs
Magnetic Applied magnetic field causes pore in gel and in response to a specific antigen and has far-reaching
swelling followed by drug release implications in treatment of variety of immunological-
Thermal Change in polymer–polymer and polymer–water based diseases [29•]. Hydrogel systems responsive to
interactions cause swelling and drug release
microbial infection have been designed based on pro-
Electrical Change in charge distribution causes swelling
and drug release teinase specific to a bacteria as a triggering mechanism for
Ultrasound Temperature increase causes release of drug release of antibiotics, and have found application in the
irradiation localized delivery of antibiotics for wound healing [30].
This can overcome the renal and liver toxicity problems
associated with prolonged use of antibiotics, in addition to
structures with a globular shape, a single molecular weight reducing the possibility of emergence of drug resistance.
rather than a distribution of molecular weight and a large An interplay of ‘innovative’ chemistry of coating respon-
number of ‘controllable’ peripheral functionalities [22•]. sive hydrogel microspheres with lipid bilayer resulted in
They are truly nanoscale molecules with sizes ranging emulating the physiological secretory granules that can
from 10–30 Å. and the excitement associated with this release the stored drugs on application of an electropora-
class of polymers is mainly because of their applications as tion pulse, which then allows the fusion of the hydrogel
synthetic vector systems for gene delivery [23]. with the lipid bilayer, releasing the drug by an
Polyaminodiamine (PMAM) is a promising polycationic ion-exchange mechanism [31].
polymer from this class that can form complexes with the
negatively charged nucleic acids; additionally, the surface Conclusions
positive charge can interact and fuse with phospholipids of Polymer science has been the backbone for the develop-
the cell membrane, thereby facilitating the translocation of ment of new DDSs for the past few decades. Future
DNA into cells [23]. A number of other polymeric systems advances in polymer science will be based on modifying
are also under investigation for DNA delivery [24]. the chemical and physical properties of the polymer, a
novel and ‘creative’ combination of copolymers with
‘Smart’ polymers targeting and bioresponsive components that can deliver a
The concept of ‘smart’ polymers originated from the abili- wide variety of bioactive agents. Further, newer fabrication
ty of certain synthetic polymers (hydrogels) to mimic the and manufacturing processes such as molecular imprinting
non-linear response of biopolymers (DNA, proteins etc.) [32], supercritical fluid technology [33] and nanoscale
caused by cooperative interactions between monomers engineering are bound to revolutionize the design, devel-
[25]. Because of their excellent water-absorbing capacity, opment and performance of polymer-based DDSs.
hydrogels resemble natural living tissues more closely than
any other class of synthetic polymeric materials [26]. Both Acknowledgements
the swelling and permeability characteristics of hydrogels Omathanu Pillai is supported by a senior research fellowship from the
Department of Science and Technology, New Delhi, India.
and their ability to undergo structural changes in response
to a variety of physical, chemical and biological stimuli
(Table 3) have given rise to the concept of ‘intelligent’ or References and recommended reading
‘stimuli’-responsive DDSs [27]. Papers of particular interest, published within the annual period of review,
have been highlighted as:
• of special interest
Attempts to develop a truly closed-loop-regulated DDS •• of outstanding interest
have the eventual goal of delivering insulin in response to
1. Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM: Polymeric
blood glucose levels. Typically, these systems have been •• systems for controlled drug release. Chem Rev 1999,
prepared by incorporating glucose oxidase into hydrogel 99:3181-3198.
Various biodegradable polymers that are useful in controlled drug delivery
(cationic, anionic or neutral polymers) during polymeriz- along with their structural features are discussed.
tion, which exhibits glucose-sensitive swelling behaviour 2. Li S, Vert M: Biodegradable polymers: polyesters. In Encyclopaedia
[26]. Another approach exploits the competitive binding of • of Controlled Drug Delivery, Vol 1. Edited by Mathowitz E. New York:
glucose and glycosylated insulin to a fixed number of bind- John Wiley and Sons; 1999:71-93.
Discusses various polyesters with detailed descriptions of synthesis and
ing sites in concovalin A immobilized on sepharose beads. applications of poly(lactic acid), poly(glycolic acid) and their copolymers.
 Polymers in drug delivery Pillai and Panchagnula 451

3. Mathowitz E, Chickering D, Jacob JS: Bioadhesive drug delivery 19. Kuon GS, Okano T: Soluble self-assembled block copolymers for
systems. In Encyclopaedia of Controlled Drug Delivery, Vol 1. Edited • drug delivery. Pharm Res 1999, 16:597-600.
by Mathowitz E. New York: John Wiley and Sons; 1999:9-45. A commentary on the potential of soluble self-assembled block copolymers
to mimic biological transport systems and their use in drug delivery.
4. Angelova N, Hunkeler D: Rationalizing the design of polymeric
•• biomaterials. Trends Biotechnol 1999, 17:409-421. 20. Bodmeir R, Siepmann S: Nondegradable polymers for drug
A comprehensive flow chart and table for rational selection of polymers for delivery. In Encyclopaedia of Controlled Drug Delivery, Vol 1. Edited
various biomedical applications is the hallmark of this paper. The authors by Mathowitz E. New York: John Wiley and Sons; 1999:664-689.
also highlight the design of polymers for future applications.
21. Lehr CM: Lectin-mediated drug delivery. The second generation of
5. Brocchini S, Duncan R: Pendant drugs, release from polymers. In • bioadhesives. J Control Release 2000, 65:19-29.
Encyclopaedia of Controlled Drug Delivery, Vol 2. Edited by Lectins and their interaction with cells demonstrated using CaCo2 and
Mathowitz E. New York: John Wiley and Sons; 1999:786-816. MDCK cells in various colloidal drug-carrier systems.

6. Colthrust MJ, Williams RL, Hiscott PS, Grierson I: Biomaterials used 22. Liu M, Frechet MJ: Designing dendrimers for drug delivery. Pharm
in the posterior segment of the eye. Biomaterials 2000, • Sci Tech Today 1999, 2:393-401.
21:649-665. This review discusses the preparation of dendrimers along with mechanisms
of drug entrapment and potential applications for gene and drug delivery.
7. Mao HQ, Kdaiyala I, Leong KW, Zhao Z, Dang W: Biodegradable
polymers: poly (phosphoester)s. In Encyclopaedia of Controlled 23. Eichman JD, Bielinska AU, Latallo JFK, Baker JR Jr: The use of
Drug Delivery, Vol 1. Edited by Mathowitz E. New York: John Wiley PMAM dendrimers in the efficient transfer of genetic material into
and Sons; 1999:45-60. cells. Pharm Sci Tech Today 2000, 3:232-245.

8. Langer R: Biomaterials in drug delivery and tissue engineering: 24. Madsen SK, Mooney DJ: Delivering DNA with polymer matrices:
•• one laboratory’s experience. Acc Chem Res 2000, 33:94-101. application in tissue engineering and gene therapy. Pharm Sci
This paper deals with the outstanding achievements of Langer’s group in Tech Today 2000, 3:381-384.
polymeric DDSs over the past 20 years. 25. Galaew IY, Mathiasson B: ‘Smart’ polymer and what they could do in
biotechnology and medicine. Trends Biotechnol 1999, 17:335-339.
9. Fu K, Pack DW, Kilbanov AM, Langer R: Visual evidence of acidic
• environment within degrading poly(lactic-co-glycolic acid)(PLGA) 26. Lowman AM, Peppas NA: Hydrogels. In Encyclopaedia of Controlled
microspheres. Pharm Res 2000, 17:100-106. Drug Delivery, Vol 2. Edited by Mathowitz E. New York: John Wiley
pH-sensitive fluorescent dyes were used to determine the intrapolymer acid- and Sons; 1999:397-418.
ity by imaging through confocal microscopy.
27. Kost J, Langer R: Responsive polymeric delivery systems. Adv
10. Heller J, Gurny R: Poly (orthoesters). In Encyclopaedia of Controlled Drug Deliv Rev 1991, 6:19-50.
Drug Delivery, Vol 2. Edited by Mathowitz E. New York: John Wiley
and Sons; 1999:852-874. 28. Ganorkar CR, Liu F, Baudys M, Kim SW: Modulating insulin release
profile from pH/thermosensitive polymeric beads through
11. Gopferich: Biodegradable polymers: polyanhydrides. In polymer molecular weight. J Control Release 1999, 59:287-298.
Encyclopaedia of Controlled Drug Delivery, Vol 1. Edited by
Mathowitz E. New York: John Wiley and Sons; 1999:60-71. 29. Miyoto T, Asami N, Uragami T: A reversibly antigen-responsive
• hydrogel. Nature 1999, 399:766-769.
12. Andrianov AK, Payne LG: Protein release from polyphosphazene Antigen-responsive semi-interpenetrating network hydrogel systems are dis-
matrices. Adv Drug Deliv Rev 1998, 31:185-196. cussed for which the authors have demonstrated that competitive binding of
free antigen triggers a change in gel volume because of breaking of the non-
13. Dodane V, Vilivalam VD: Pharmaceutical applications of chitosan. covalent crosslinks between grafted antigen and polymer network.
Pharm Sci Tech Today 1998, 1:246-253.
30. Tanihara M, Suzuki Y, Nishimura Y, Suzuki K, Kakimarau Y, Fukunishi Y:
14. Kumar MNV, Kumar N: Polymeric controlled drug delivery systems: A novel microbial infection responsive drug release systems.
• perspective issues and opportunities. Drug Dev Ind Pharm 2001, J Pharm Sci 1999, 88:510-514.
27:1-30.
Various copolymers used in hydrogels and in the fabrication of tablets, trans- 31. Kiser PF, Wilson G, Needham D: A synthetic mimic of the secretory
dermal films and devices are discussed. granule for drug delivery. Nature 1998, 394:459-462.

15. Uekama K: Cyclodextrins in drug delivery system. Adv Drug Deliv 32. Allender CJ, RichardsonC, Woodhouse B, Heard CM, Brain KR:
Rev 1999, 36:1-2. Pharmaceutical applications for molecularly imprinted polymers.
Int J Pharm 2000, 195:39-43.
16. Szente L: Highly soluble cyclodextrin derivatives, chemistry,
properties and trends in development. Adv Drug Deliv Rev 1999, 33. Ghaderi R, Artursson P, Carlfors J: A new method for preparing
36:17-28. biodegradable microparticles and entrapment of hydrocortisone
in DL-PLG microparticles using supercritical fluid. Eur J Pharm Sci
17. Mehavar R: Dextrans for targeted and sustained delivery of 2000, 10:1-9.
therapeutic and imaging agents. J Control Release 2000, 69:1-25.
18. Moghimi SM, Hunter AC: Polaxmers and polaxamines in Patent
nanoparticles engineering and experimental medicine. Trends P1. Wang YCJ, Yang B, Jennings RN Jr, Protter AA: Controlled release
Biotechnol 2000, 18:412-420. delivery of peptide or protein. 2001, US patent 6187330.