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