Elsevier

Journal of Controlled Release

Volume 125, Issue 3, 11 February 2008, Pages 193-209
Journal of Controlled Release

Review
Nano/micro technologies for delivering macromolecular therapeutics using poly(d,l-lactide-co-glycolide) and its derivatives

https://doi.org/10.1016/j.jconrel.2007.09.013Get rights and content

Abstract

Biodegradable nano/microparticles of poly(d,l-lactide-co-glycolide) (PLGA) and PLGA-based polymers are widely explored as carriers for controlled delivery of macromolecular therapeutics such as proteins, peptides, vaccines, genes, antigens, growth factors, etc. These devices are mainly produced by emulsion or double-emulsion technique followed by solvent evaporation or spray drying. Drug encapsulation, particle size, additives added during formulation, molecular weight, ratio of lactide to glycolide moieties in PLGA and surface morphology could influence the release characteristics. Encapsulation efficiency and release rates through nano/microparticle-mediated drug delivery devices can be optimized to improve their therapeutic efficacy. In this review, important findings of the past decade on the encapsulation and release profiles of macromolecular therapeutics from PLGA and PLGA-based nano/microparticles are discussed critically in relation to nature and type of bioactive molecule, carrier polymer and experimental variables that influence the delivery of macromolecular therapeutics. Even though extensive research on biodegradable microparticles containing macromolecular drugs has greatly advanced to the level of production know-how, the effects of critical parameters influencing drug encapsulation are not sufficiently investigated for nano-scaled carriers. The present review attempts to address some important data on nano/microparticle-based delivery systems of PLGA and PLGA-derived polymers with reference to macromolecular drugs.

Introduction

The success of any medical treatment depends not only upon the pharmacokinetic/pharmacodynamic activity of the therapeutic agent, but to a large extent, on its bioavailability at the site of action in the human system [1], [2], [3], [4]. Poly(d,l-lactic-co-glycolide), PLGA and its various derivatives have been the center focus for developing nano/microparticles encapsulating therapeutic drugs in controlled release (CR) applications [5], [6], [7], [8], [9] due to their inherent advantages over the conventional devices that include extended release rates up to days, weeks or months, in addition to their biocompatibility/biodegradability and ease of administration via injection. Macromolecular drugs such as proteins, peptides, genes, vaccines, antigens, human growth factors, etc., are successfully incorporated into PLGA or PLGA-based nano/microparticles [10], [11], [12], [13], [14]. Despite the formulations already available in the market, yet research in this area has advanced greatly due to the advantages of PLGA polymers over other systems.

Literature cites many advantages and drawbacks of PLGA and PLGA-based delivery systems for delivering macromolecular drugs [10], [11]. PLGA has a negative effect on protein stability during the preparation and storage, primarily due to the acid-catalyzed nature of its degradation. Its hydrolysis leads to the accumulation of acidic monomers, lactic and glycolic acids within the drug delivery device, thereby resulting in a significant reduction of pH of the microenvironment and denaturation of the encapsulated proteins [12]. In addition, processing conditions used in the manufacturing of PLGA drug delivery vehicles have detrimental effects on certain protein secondary structures [13]. Even for molecules less sensitive than proteins, PLGA delivery vehicles cannot always meet the market requirements. Further, majority of the PLGA devices rarely exhibit zero-order drug release kinetics, but a characteristic triphasic drug release pattern consisting of a relatively high burst effect at the onset, a lag phase and a final release phase, dictated by polymer erosion [14].

To overcome the problems associated with protein degradation, loading, etc., efforts have been made to modify the properties of PLGA for developing nano/microparticles. PLGA delivery devices for protein encapsulation by complexing proteins with zinc or addition of antacid excipients to buffer have been addressed [15]. Several papers describe the different approaches used for developing blends of PLGA with other polymers or excipients to modify the vehicle properties. Over the past one decade, many papers have been published on PLGA blend formulations with alginate and chitosan [16], pectin [17], poly(propylene fumarate) [18], poloxamers and poloxamines [19], polypyrrole [20], gelatin [21], poly(vinyl alcohol) (PVA) [22], PVA–chitosan–PEG [23] and poly(ortho-esters) [24]. This review addresses the development of newer technologies by utilizing PLGA and PLGA-based polymers as NP or MP systems for delivering macromolecular therapeutics. Important literature of the past one decade is covered and representative findings are discussed.

Section snippets

Poly(d,l-lactide-co-glycolide)

PLGA polymers are commercially available from various vendors. There are four major established suppliers of good manufacturing practice (GMP)-grade PLGA polymers in the market. These include: Purac (Trade name: Purasorb); Absorbable Polymers International, a wholly owned international subsidiary of Durect Corporation (Trade name: Lactel); Alkermes (Trade name: Medisorb); Boehringer Ingelheim (Trade Name: Resomer). Other newer suppliers include Absorbable Polymer Technologies (US) and smaller

Production of drug-loaded nano/microparticles of PLGA

Polymeric NPs and MPs are classified based on their sizes. The MPs range in diameter from 1 to 250 μm, while the size of NPs ranges between 10 and 1000 nm. Emulsion solvent evaporation techniques are the frequently used methods to produce NPs and MPs, wherein a significant amount of poly(vinyl alcohol), PVA, the most abundant stabilizing agent is generally employed; this is difficult to remove from the surface of the produced particles. Surfactant-free NPs and MPs have many advantages like ease

PLGA derivatives with tailored properties

PLGA modification is done to improve its formulation properties like drug stability, drug release profiles, degradation and possibility of drug targeting. This section provides a brief summary of the recent reports on modifications of PLGA that have been attempted in the prior-art. To enhance the desirable properties of PLGA, efforts have been made to modify its structure to increase its hydrophilicity, which in turn, would enhance the protein stability after formulation and this, would

Protein/peptide delivery

Efforts to develop PLGA and PLGA-based formulations for delivering proteins and peptide have intensified in recent years as hundreds of recombinant proteins or peptides are in the pipeline for the US FDA approval. These molecules cannot be readily delivered orally or through skin, since these have short half lives in vivo. Thus, they are mostly administered via intravenous (i.v.) route that require daily injections making it clinically undesirable due to patient discomfort, psychological

Delivery of vaccines and immunomodulatory agents

Vaccine is an antigenic preparation used to establish immunity to a disease, which when administered to humans, provides protection against a disease. On the other hand, immune system is a complex network positive and negative feedback loops that acts by means of the secretion of numerous cytokines. Immunization with ‘naked’ plasmid DNA is recently emerging as a novel and effective vaccination strategy [75]. Controlled delivery of vaccines and immunomodulatory proteins is thus becoming more

Delivery of growth factors

Interferons (IFNs) are the natural proteins produced by the cells of the immune system of most vertebrates in response to challenges by foreign agents such as viruses, bacteria, parasites and tumor cells. Interferons belong to the large class of glycoproteins known as cytokines. Interferons assist the immune response by inhibiting viral replication within other cells of the body. On the other hand, interleukins are a group of cytokines that are expressed by white blood cells. Many efforts have

Gene delivery

Genetic factors affect every human through interaction with the environment. A large number of small nucleotides, nucleic acids, peptides, proteins and DNA have been synthesized for specific therapeutic needs. Gene therapy is a recently introduced method for the treatment or prevention of genetic disorders by correcting the defective genes responsible for disease development based on the delivery of repaired or replacement of incorrect genes. Development of an efficient therapy based on such

Concluding remarks

Creating an effective drug delivery device is more of a complex and time-consuming process, nevertheless tremendous opportunities exist for applications of nano/micro technologies for delivering macromolecular therapeutics through PLGA polymers. This review outlines the research and developmental activities on PLGA and PLGA-based nano/microparticles as drug delivery devices. The widely scattered published reports are not only directed in developing appropriate dosage formulations to produce the

Acknowledgement

The authors gratefully acknowledge the encouragement and support of Reliance Life Sciences Pvt. Ltd.

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