The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices

doi:10.1016/S0142-9612(00)00115-0

Biomaterials

Volume 21, Issue 23, 1 December 2000, Pages 2475-2490

https://doi.org/10.1016/S0142-9612(00)00115-0 Get rights and content

Abstract

A considerable research has been conducted on drug delivery by biodegradable polymeric devices, following the entry of bioresorbable surgical sutures in the market about two decades ago. Amongst the different classes of biodegradable polymers, the thermoplastic aliphatic poly(esters) like poly(lactide) (PLA), poly(glycolide) (PGA), and especially the copolymer of lactide and glycolide, poly(lactide-co-glycolide) (PLGA) have generated immense interest due to their favorable properties such as good biocompatibility, biodegradability, and mechanical strength. Also, they are easy to formulate into different devices for carrying a variety of drug classes such as vaccines, peptides, proteins, and micromolecules. Also, they have been approved by the Food and Drug Administration (FDA) for drug delivery. This review discusses the various traditional and novel techniques (such as in situ microencapsulation) of preparing various drug loaded PLGA devices, with emphasis on preparing microparticles. Also, certain issues about other related biodegradable polyesters are discussed.

Section snippets

Introduction and historical perspectives of drug delivery by PLGA devices

In order to avoid the inconvenient surgical insertion of large implants, injectable biodegradable and biocompatible polymeric particles (microspheres, microcapsules, nanocapsules, nanospheres) could be employed for controlled-release dosage forms [1]. Microparticles of size less than 250 μm, ideally less than 125 μm are suitable for this purpose [2]. Biodegradable polymers are natural or synthetic in origin and are degraded in vivo, either enzymatically or non-enzymatically or both to produce

Physico-chemical and biological properties of PLGA

The understanding of the physical, chemical, and biological properties of the polymer is helpful, before formulating a controlled drug delivery device. The various properties of the polymer and the encapsulated drug directly influence other factors like the selection of the microencapsulation process, drug release from the polymer device, etc. [1].

The polymer PLA can exist in an optically active stereoregular form (l-PLA) and in an optically inactive racemic form (d,l-PLA) [1], [5], [9]. l-PLA

Microparticles

Although, a number of microencapsulation techniques have been developed and reported to date, the choice of the technique depends on the nature of the polymer, the drug, the intended use, and the duration of the therapy [1], [2], [4], [5], [10]. The microencapsulation method employed must include the following requirements [1], [2], [23]:

(i)	The stability and biological activity of the drug should not be adversely affected during the encapsulation process or in the final microsphere product.
(ii)

Conclusion

Administration of drugs using biodegradable PLGA polymers has generated immense interest due to its excellent biocompatibility and biodegradability. Also, they are easy to formulate into drug carrying devices and have been approved by the FDA for drug delivery use. The various biodegradable PLGA devices fabricated from different techniques are versatile in terms of the various classes of drugs encapsulated, the different time period of their release, and the diverse routes of their delivery.

References (191)

J Heller
Controlled release of biologically active compounds from bioerodible polymers
Biomaterials
(1980)
J Heller
Controlled drug release from poly(ortho esters)—a surface eroding polymer
J Control Rel
(1985)
L Brannon-Peppas
Recent advances on the use of biodegradable microparticles and nanoparticles in controlled drug delivery
Int J Pharm
(1995)
J.P Kitchell et al.
Poly(lactic/glycolic acid) biodegradable drug-polymer matrix systems
Methods Enzymol
(1985)
Z Zhao et al.
Controlled delivery of antigens and adjuvants in vaccine development
J Pharm Sci
(1996)
D.M Gilding et al.
Biodegradable polymers for use in surgery. Poly(glycolic)/poly(lactic acid) homo and copolymers
Polymer
(1979)
K Jamshidi et al.
Thermal characterization of polylactides
Polymer
(1988)
R.S Raghuvanshi et al.
Biodegradable delivery system for single step immunization with tetanus toxoid
Int J Pharm
(1993)
M.J Alonso et al.
Biodegradable microspheres as controlled-release tetanus toxoid delivery systems
Vaccine
(1994)
A Kamijo et al.
In vitro release test system of (d,l-lactic-glycolic) acid copolymer microcapsules for sustained release of LHRH agonist (leuprorelin)
J Control Rel
(1996)

H Okada et al.

Persistent suppression of the pituitary-gonadal system in female rats by three-month depot injectable microspheres of leuprorelin acetate

J Pharm Sci

(1996)

S Sharif et al.

Biodegradable microparticles as a delivery system for the allergens of Dermatophagoides pteronyssinus (house dust mite)I. Preparation and characterization of microparticles

Int J Pharm

(1995)

H Sah et al.

Continuous release of proteins from biodegradable microcapsules and in vivo evaluation of their potential as a vaccine adjuvant

J Control Rel

(1995)

H Sah et al.

Effects of H⁺ liberated from hydrolytic cleavage of polyester microcapsules on their permeability and degradability

J Pharm Sci

(1995)

G Crotts et al.

Preparation of porous and nonporous biodegradable polymeric hollow microspheres

J Control Rel

(1995)

H Sah et al.

The influence of biodegradable microcapsule formulations on the controlled release of a protein

J Control Rel

(1994)

S Sharif et al.

A comparison of alternative methods for the determination of the levels of proteins entrapped in poly(lactide-co-glycolide) microparticles

Int J Pharm

(1995)

T Heya et al.

In vitro and in vivo evaluation of thyrotrophin releasing hormone release from copoly(d,l-lactic/glycolic acid) microspheres

J Pharm Sci

(1994)

T Heya et al.

Controlled release of thyrotropin releasing hormone from microspheresevaluation of release profiles and pharmacokinetics after subcutaneous administration

J Pharm Sci

(1994)

W Lu et al.

Protein release from poly(lactic-co-glycolic acid) microspheresprotein stability problems

PDA J Pharm Sci Technol

(1995)

T Kissel et al.

Parenteral protein delivery systems using biodegradable polyesters of ABA block structure, containing hydrophobic poly(lactide-co-glycolide) A blocks and hydrophilic poly(ethylene oxide) B blocks

J Control Rel

(1996)

E Esposito et al.

Production and characterization of biodegradable microparticles for the controlled delivery of proteinase inhibitors

Int J Pharm

(1996)

C Yan et al.

Characterization and morphological analysis of protein-loaded poly(lactide-co-glycolide) microparticles prepared by water-in-oil-in-water emulsion technique

J Control Rel

(1994)

I Soriano et al.

Preparation and evaluation of insulin-loaded poly(d,l-lactide) microspheres using an experimental design

Int J Pharm

(1996)

V Labhasetwar et al.

Sotalol controlled-release systems for arrhythmiasin vitro characterization, in vivo drug disposition, and electrophysiologic effects

J Pharm Sci

(1994)

C Schugens et al.

Effect of the emulsion stability on the morphology and porosity of semicrystalline poly l-lactide microparticles prepared by w/o/w double emulsion-evaporation

J Control Rel

(1994)

N Erden et al.

Factors influencing release of salbutamol sulphate from poly(lactide-co-glycolide) microspheres prepared by water-in-oil-in-water emulsion technique

Int J Pharm

(1996)

T.K Mandal et al.

Preparation of biodegradable microcapsules of zidovudine using solvent evaporationeffect of the modification of aqueous phase

Int J Pharm

(1996)

R Ghaderi et al.

Effect of preparative parameters on the characteristics of poly(d,l-lactide-co-glycolide) microspheres made by the double emulsion method

Int J Pharm

(1996)

S Akhtar et al.

Antisense oligonucleotide delivery to cultured macrophages is improved by incorporation into sustained-release biodegradable polymer microspheres

Int J Pharm

(1997)

M.M El-Baseir et al.

Preparation and subsequent degradation of poly(l-lactic acid) microspheres suitable for aerosolisationa physico-chemical study

Int J Pharm

(1997)

S Takada et al.

Sustained release of a water-soluble GP IIb/IIIa antagonist from copoly(d,l-lactic/glycolic)acid microspheres

Int J Pharm

(1997)

R Edelman et al.

Immunization of rabbits with enterotoxigenic E. coli colonization factor antigen (CFA/I) encapsulated in biodegradable microspheres of poly(lactide-co-glycolide)

Vaccine

(1993)

R Jalil et al.

Biodegradable poly(lactic acid) and poly(lactide-co-glycolide) microcapsulesproblems associated with preparative techniques and release properties

J Microencapsulation

(1990)

T.R Tice et al.

Parenteral drug deliveryinjectables

X.S Wu

Synthesis and properties of biodegradable lactic/glycolic acid polymers

X.S Wu

Preparation, characterization, and drug delivery applications of mucrospheres based on biodegradable lactic/glycolic acid polymers

D.H Lewis

Controlled release of bioactive agents from lactide/glycolide polymers

J Heller

Biodegradable polymers in controlled drug delivery

Crit Rev Therap Drug Carrier System

(1984)

T.R Tice et al.

Biodegradable controlled-release parenteral systems

Pharm Technol

(1984)

R Arshady

Preparation of biodegradable microspheres and microcapsules2. Polylactides and related polyesters

J Control Rel

(1991)

S Cohen et al.

Novel approaches to controlled-release antigen delivery

Int J Technol Assessment Health Care

(1994)

Vert M. The complexity of PLAGA-based drug delivery systems. Proceedings of the International Conference on Advances in...

J.E Eldridge et al.

New advances in vaccine delivery systems

Sem Hematol

(1993)

Tice T, Gilley R, Mason D, Ferrell T, Staas J, Love D, McRae A, Dahlström A, Ling E, Jacob E, Setterstrom J....

C Thies et al.

Biodegradable microspheres for parenteral administration

J.M Brady et al.

Resorption rate, route of elimination and ultrastructure of the implant site of polylactic acid in the abdominal wall of the rat

J Biomed Mater Res

(1973)

J.W Fong

Microencapsulation by solvent evaporation and organic phase separation process

R Wada et al.

Preparation of lactic acid oligomer microspheres containing anti-cancer drug by o/o type solvent evaporation process

Polym Mater Sci Engng

(1988)

M Cavalier et al.

The formation and characterization of hydrocortisone-loaded poly((±)-lactide) microspheres

J Pharm Pharmacol

(1986)

Cited by (1924)

Poly(D,L-lactide-co-glycolide) particles are metabolised by the gut microbiome and elevate short chain fatty acids
2024, Journal of Controlled Release
The production of short chain fatty acids (SCFAs) by the colonic microbiome has numerous benefits for human health, including maintenance of epithelial barrier function, suppression of colitis, and protection against carcinogenesis. Despite the therapeutic potential, there is currently no optimal approach for elevating the colonic microbiome's synthesis of SCFAs. In this study, poly(D,l-lactide-co-glycolide) (PLGA) was investigated for this application, as it was hypothesised that the colonic microbiota would metabolise PLGA to its lactate monomers, which would promote the resident microbiota's synthesis of SCFAs. Two grades of spray dried PLGA, alongside a lactate bolus control, were screened in an advanced model of the human colon, known as the M-SHIME® system. Whilst the high molecular weight (Mw) grade of PLGA was stable in the presence of the microbiota sourced from three healthy humans, the low Mw PLGA (PLGA 2) was found to be metabolised. This microbial degradation led to sustained release of lactate over 48 h and increased concentrations of the SCFAs propionate and butyrate. Further, microbial synthesis of harmful ammonium was significantly reduced compared to untreated controls. Interestingly, both types of PLGA were found to influence the composition of the luminal and mucosal microbiota in a donor-specific manner. An in vitro model of an inflamed colonic epithelium also showed the polymer to affect the expression of pro- and anti-inflammatory markers, such as interleukins 8 and 10. The findings of this study reveal PLGA's sensitivity to enzymatic metabolism in the gut, which could be harnessed for therapeutic elevation of colonic SCFAs.
Miniaturized screening and performance prediction of tailored subcutaneous extended-release formulations for preclinical in vivo studies
2024, European Journal of Pharmaceutical Sciences
Microencapsulation of active pharmaceutical ingredients (APIs) for preparation of long acting injectable (LAI) formulations is an auspicious technique to enable preclinical characterization of a broad variety of APIs, ideally independent of their physicochemical and pharmacokinetic (PK) characteristics. During early API discovery, tunable LAI formulations may enable pharmacological proof-of-concept for the given variety of candidates by tailoring the level of plasma exposure over the duration of various timespans. Although numerous reports on small scale preparation methods for LAIs utilizing copolymers of lactic and glycolic acid (PLGA) and polymers of lactic acid (PLA) highlight their potential, application in formulation screening and use in preclinical in vivo studies is yet very limited. Transfer from downscale formulation preparation to in vivo experiments is hampered in early preclinical API screening by the large number of API candidates with simultaneously very limited available amount in the lower sub-gram scale, lack of formulation stability and deficient tunability of sustained release.
We hereby present a novel comprehensive platform tool for tailored extended-release formulations, aiming to support a variety of preclinical in vivo experiments with ranging required plasma exposure levels and timespans. A novel small-scale spray drying process was successfully implemented by using an air brush based instrument for preparation of PLGA and PLA based formulations. Using Design of Experiments (DoE), required API amount of 250 mg was demonstrated to suffice for identification of dominant polymer characteristics with largest impact on sustained release capability for an individual API. BI-3231, a hydrophilic and weakly acidic small compound with good water solubility and permeability, but low metabolic stability, was used as an exemplary model for one of the many candidates during API discovery. Furthermore, an in vitro to in vivo correlation (IVIVC) of API release rate was established in mice, which enabled the prediction of in vivo plasma concentration plateaus after single subcutaneous injection, using only in vitro dissolution profiles of screened formulations.
By tailoring LAI formulations and their doses for acute and sub-chronic preclinical experiments, we exemplary demonstrate the practical use for BI-3231. Pharmacological proof-of-concept could be enabled whilst circumventing the need of multiple administration as result of extensive hepatic metabolism and simultaneously superseding numerous in vivo experiments for formulation tailoring.
Emerging strategies for nanomedicine in autoimmunity
2024, Advanced Drug Delivery Reviews
Autoimmune disorders have risen to be among the most prevalent chronic diseases across the globe, affecting approximately 5–7% of the population. As autoimmune diseases steadily rise in prevalence, so do the number of potential therapeutic strategies to combat them. In recent years, fundamental research investigating autoimmune pathologies has led to the emergence of several cellular targets that provide new therapeutic opportunities. However, key challenges persist in terms of accessing and specifically combating the dysregulated, self-reactive cells while avoiding systemic immune suppression and other off-target effects. Fortunately, the continued advancement of nanomedicines may provide strategies to address these challenges and bring innovative autoimmunity therapies to the clinic. Through precise engineering and rational design, nanomedicines can possess a variety of physicochemical properties, surface modifications, and cargoes, allowing for specific targeting of therapeutics to pathological cell and organ types. These advances in nanomedicine have been demonstrated in cancer therapies and have the broad potential to advance applications in autoimmunity therapies as well. In this review, we focus on leveraging the power of nanomedicine for prevalent autoimmune disorders throughout the body. We expand on three key areas for the development of autoimmunity therapies – avoiding systemic immunosuppression, balancing interactions with the immune system, and elevating current platforms for delivering complex cargoes – and emphasize how nanomedicine-based strategies can overcome these barriers and enable the development of next-generation, clinically relevant autoimmunity therapies.
Recent advances in drug delivery systems based on natural and synthetic polymes for treating obesity
2024, International Journal of Biological Macromolecules
Obesity stands as a pervasive global public health issue, posing a formidable threat to human well-being as its prevalence continues to surge year by year. Presently, pharmacological treatment remains the favored adjunct strategy for addressing obesity. However, conventional delivery methods suffer from low bioavailability and the potential for side effects, underscoring the pressing need for more efficient and targeted delivery approaches. Recent research has delved extensively into emerging drug delivery systems employing polymers as carriers, with numerous preclinical studies contributing to the growing body of knowledge. This review concentrates on the utilization of natural polymers as drug delivery systems for the treatment of obesity, encompassing recent advancements in both natural and synthetic polymers. The comprehensive exploration includes an analysis of the advantages and disadvantages associated with these polymer carriers. The examination of these characteristics provides valuable insights into potential future developments in the field of drug delivery for obesity treatment.
Smart biodegradable hydrogels: Drug-delivery platforms for treatment of chronic ophthalmic diseases affecting the back of the eye
2024, International Journal of Pharmaceutics
This paper aims to develop smart hydrogels based on functionalized hyaluronic acid (HA) and PLGA-PEG-PLGA (PLGA, poly-(DL-lactic-co-glycolic acid); PEG, polyethylene glycol) for use as intraocular drug-delivery platforms. Anti-inflammatory agent dexamethasone-phosphate (0.2 % w/v) was the drug selected to load on the hydrogels. Initially, different ratios of HA-aldehyde (HA-CHO) and thiolated-HA (HA-SH) were assayed, selecting as optimal concentrations 2 and 3 % (w/v), respectively. Optimized HA hydrogel formulations presented fast degradation (8 days) and drug release (91.46 ± 3.80 % in 24 h), thus being suitable for short-term intravitreal treatments. Different technology-based strategies were adopted to accelerate PLGA-PEG-PLGA water solubility, e.g. substituting PEG1500 in synthesis for higher molecular weight PEG3000 or adding cryopreserving substances to the buffer dissolution. PEG1500 was chosen to continue optimization and the final PLGA-PEG-PLGA hydrogels (PPP1500) were dissolved in trehalose or mannitol carbonate buffer. These presented more sustained release (71.77 ± 1.59 % and 73.41 ± 0.83 % in 24 h, respectively) and slower degradation (>14 days). In vitro cytotoxicity studies in the retinal-pigmented epithelial cell line (RPE-1) demonstrated good tolerance (viability values > 90 %). PLGA-PEG-PLGA hydrogels are proposed as suitable candidates for long-term intravitreal treatments. Preliminary wound healing studies with PLGA-PEG-PLGA hydrogels suggested faster proliferation at 8 h than controls.
Advances in hydrogels based cutaneous drug delivery system for management of psoriasis
2024, European Polymer Journal
The complex and chronic nature of psoriasis is responsible for the limited efficacy of current topical drug delivery systems for the management of the disease. The genetic origin of the disease via the activation of Caspase Recruitment Domain Family Member 14 (CARD14), leads to the upregulation of Nuclear Factor Erythroid 2-Related Factor (Nrf2) causing keratinocyte hyperproliferation. The skin thickening due to Matrix Metalloproteinase-19 (MMP-19) and various other skin alterations that can impede the drug absorption, thereby limiting the therapeutic outcomes of the conventional topical formulations. The hydrogels have shown promise in terms of exhibiting a synergistic effect by enhancing the drug permeation through the skin. The stimuli responsive hydrogels release drug at various biological and external stimuli, which are mainly associated with the various type of polymer matrix of the hydrogel materials like hyaluronic acid (HA), chitosan (CS), poly(lactic-co-glycolic acid (PLGA), polyethylene glycol (PEG), Pluronics, Carbopol ®, etc., that are being investigated for their potential in delivering anti-psoriatic drugs. In addition to serving as a basis for the topical system, hydrogels also display functional effects for reducing psoriatic symptoms by moisturizing the skin and increasing the retention time of the formulation. In this review, we aim to highlight the unique properties and recent advancements in polymeric hydrogels and their applications for the management of psoriasis.

View all citing articles on Scopus

View full text

The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices

Abstract

Section snippets

Introduction and historical perspectives of drug delivery by PLGA devices

Physico-chemical and biological properties of PLGA

Microparticles

Conclusion

Biomaterials

J Control Rel

Int J Pharm

Methods Enzymol

J Pharm Sci

Polymer

Polymer

Int J Pharm

Vaccine

J Control Rel

J Pharm Sci

Int J Pharm

J Control Rel

J Pharm Sci

J Control Rel

J Control Rel

Int J Pharm

J Pharm Sci

J Pharm Sci

PDA J Pharm Sci Technol

J Control Rel

Int J Pharm

J Control Rel

Int J Pharm

J Pharm Sci

J Control Rel

Int J Pharm

Int J Pharm

Int J Pharm

Int J Pharm

Int J Pharm

Int J Pharm

Vaccine

Biodegradable poly(lactic acid) and poly(lactide-co-glycolide) microcapsulesproblems associated with preparative techniques and release properties

J Microencapsulation

Parenteral drug deliveryinjectables

Synthesis and properties of biodegradable lactic/glycolic acid polymers

Preparation, characterization, and drug delivery applications of mucrospheres based on biodegradable lactic/glycolic acid polymers

Controlled release of bioactive agents from lactide/glycolide polymers

Biodegradable polymers in controlled drug delivery

Crit Rev Therap Drug Carrier System

Biodegradable controlled-release parenteral systems

Pharm Technol

Preparation of biodegradable microspheres and microcapsules2. Polylactides and related polyesters

J Control Rel

Novel approaches to controlled-release antigen delivery

Int J Technol Assessment Health Care

New advances in vaccine delivery systems

Sem Hematol

Biodegradable microspheres for parenteral administration

Resorption rate, route of elimination and ultrastructure of the implant site of polylactic acid in the abdominal wall of the rat

J Biomed Mater Res

Microencapsulation by solvent evaporation and organic phase separation process

Preparation of lactic acid oligomer microspheres containing anti-cancer drug by o/o type solvent evaporation process

Polym Mater Sci Engng

The formation and characterization of hydrocortisone-loaded poly((±)-lactide) microspheres

J Pharm Pharmacol