Microparticles, Microspheres, and Microcapsules for Advanced Drug Delivery
Abstract
:1. Introduction
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- choice of dosage form for the desired drug delivery route (peroral tablets, parenteral injections);
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- modified and targeted (even site-specific) drug release and delivery;
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- more expectable pharmacokinetics with reduced intra- or inter-subject variability;
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- more homogenous distribution in the physiological environment;
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- stable fixed-dose combinations of drugs;
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- dose titration and less dose-dumping;
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- patient centricity through better compliance (e.g., patients with dysphagia) and adherence;
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- individual therapy (e.g., for pediatric or geriatric population);
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- improving stability of the medicinal preparations;
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- isolating the constituents to ensure better compatibility;
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- innovative products with a prolonged life cycle through patent protection.
2. Construction and Structure
2.1. Microspheres and Microcapsules
2.1.1. Janus Particles
2.1.2. Patchy Particles
2.2. Liposomes
2.3. Colloidosomes
3. Types and Mechanism of Drug Release
Magnetic Microcapsules
4. Formulation and Manufacturing
4.1. Composition and Excipients
4.2. Processes for the Particle Formation
4.2.1. Coacervation
4.2.2. Air Suspension Method/Fluid-Bed Coating
4.2.3. Extrusion through a Nozzle
4.2.4. Vibrational Jet/Electrostatic Extrusion
4.2.5. Spinning Disk and Cutting Wire
4.2.6. Spray Drying
4.2.7. Supercritical Fluid Precipitation
4.2.8. Freeze-Drying
4.2.9. Microfluidics in Microparticle Fabrication
Microfluidic Droplet Generators (MFDG)
4.2.10. Lithography
5. Characterization
5.1. Morphology
5.1.1. Particle Size Analysis
5.1.2. AFM (Atomic Force Microscopy)
5.1.3. Coulter Counter
5.1.4. Image Analysis
5.2. Physicochemical Properties
Zeta-Potential Analysis
5.3. Physical Properties
5.3.1. Density
5.3.2. Porosity
5.3.3. Microcomputed Tomography
5.3.4. Flowability and Compressibility Studies
5.3.5. Mechanical Test
5.3.6. Swelling
5.3.7. Wetting Property
5.4. Drug Entrapment Efficiency
5.5. Drug Release
5.5.1. In Vitro Dissolution Test for Multiparticulates
5.5.2. Dissolution Test for Inhaled Particles
5.5.3. In Vitro Performance of Intramuscular Injections
5.5.4. In Vitro Dissolution Test for Topical Microsponge Preparations
6. Other Studies
6.1. Spectrometry
6.2. Thermoanalytical Methods
6.3. Biocompatibility
7. Applications in the Therapeutical Practice
7.1. Insulin for Inhalation (Technosphere®)
7.2. Depocyte® (Parenteral Suspension)
7.3. DepoDur™
7.4. Microsponge Delivery System (MDS)
7.5. Microbubbles
8. Summary
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Excipient | Physicochemical Properties | Application and Benefits | Limitations | Ref. |
---|---|---|---|---|
Gelatine | Amphoteric gelatin A (isoelectric point (IEP) pH: 7–9.4 gelatin B (IEP: pH 4.8–5.5) Swells, then dissolves in water | At low pH coacervation with negatively charged polymers, high potential of crosslinking emulsifier, stabilizer (high viscosity), binder Thermoreversible gelling, implantable pulmonary delivery pH-dependent, swelling, dissolution, erosion | Influence of pH and ionic strength on behavior Need for preservation against possible prion (BSE) contamination | [20,21] |
Casein | Hydrophilic, metal binding Insoluble in water at its IEP (pH 4.6) | calcium caseinate –reversible thermal gelation solubility increase (coenzyme Q10) | Anaphylactic reactions | [22] |
Whey protein | Insoluble at its IEP (pH 5.2) | Thermal gelation, encapsulation of oils film formation: gas barrier, good tensile strength | Thermally irreversible gel formation above 70 °C Denatures at higher salt conc. Anaphylactic reactions | [23] |
Albumin | IEP: 4.7 Freely soluble in water negative charge at pH 7.4 | Pulmonary delivery Alginate-albumin | Chemical degradation, denaturation at high salt conc., enzymes, heat | [24] |
Zein | α, β, γ, δ, zein with different Mw amphiphilic character IEP: 6.8 hydrophobic | Oral controlled release matrix and wall | Brittle, rigid wall, complex with a gelling component to plasticize | [25,26] |
Soy protein | Partly soluble in water, depending on the extraction process; IEP 4.5 | Oral controlled release matrix and wall Emulsifier, foaming agent | Sensitivity | [27] |
Gluten | Water-insoluble; IEP:7.5 | Wall material, good elastic, good thermoplastic properties | Gluten sensitivity | [28] |
Bees-wax (Apis mellifera) | mp (melting point): 62–64 °C HLBrequired = 12 | Edible, easy use, smooth surface, hot melt extrusion prolonged release for hydrophilic substances, protection from chemical degradation | Oxidation | [29] |
Carnauba wax (Copernica cerifera) | mp: 78–85 °C HLBrequired = 12 | Good compatibility hot melt extrusion, embedding water soluble components, taste masking | Oxidation | [30,31] |
Paraffin (hard) (mineral) | mp: 50–61 °C | Embedding water soluble components liquid paraffin in the emulsification process | Sensitivity | [32] |
Excipient | Physicochemical Properties | Applications and Benefits | Limitations | Ref. |
---|---|---|---|---|
Chitosan (deacylated chitin) | Soluble in weak acids Mucoadhesive reacts with negatively charged surfaces | Antifungal, antibacterial, reduces LDL (low-density lipoprotein), tissue regenerative, pulmonary delivery Ionotropic gelation, coacervation with anions, modified emulsification | pH dependence (insoluble above pH 6.5) Addition of electrolytes precipitates chitosan in solution, hygroscopic | [33,34,35] |
Sodium hyaluronate | Anionic character, soluble in water, high viscosity at low concentration | In microspheres nasal, vaginal, ophthalmic delivery systems | Very hygroscopic, when heated, emits Na2O | [36,37] |
Starch (wheat, corn, potato, rice, tapioca) | Starch from different origins Differ in particle size and shape Soluble in hot water after a time of gelatinization | Spray drying, extrusion, molecular inclusion, coacervation with proteins, hydrocolloid-forming, release via swelling, diffusion, erosion | Hygroscopic | [38] |
Guar gum | Water soluble, nonionic, galactomannan forms a thixotropic solution, stable at pH 4–10.5 | Controlled-release, colon-targeted release, appetite suppressant, thermoreversible | Needs preservation, borate hinders swelling | [39] |
Locust bean gum (LBG)/carob, ceratonia/ | Nonionic, galactomannan, dispersible in hot water, soluble at higher temperature | Controlled release in combination pseudoplastic, gelling with the addition of borate, solubility not affected by pH or ionic concentration | Low water solubility, hypersensitivity | [40] |
Konjac gum | Water soluble | Elevation of temperature increases gelation, antioxidant properties | Indigestable | [41,42] |
Κ, ι, λ−, Carrageenan | Anionic polymer, ι−Carrageenan: shear thinning thixotropic gel forming | λ−Carrageenan: highest anionic charge, high solubility, but no gelling, κ, ι−Carrageenan: elastic gel is formed with K+, Ca2+, thermoreversible gel forming Release by erosion (physical contact-Scentcaps®), effective against HPV (human papilloma virus) | Acid-catalyzed hydrolyses, especially at higher temperature and pH < 3 Administration of >2 g/kg orally Induces intestinal ulcers, not biodegradable | [43,44] |
Agarose | Soluble in hot water | swelling, Thermoreversible gelation (at ≈37 °C) with hysteresis | Poor biodegradability | [45] |
Sodium alginate | Water soluble, anionic coacervation with ions (Ca2+, Sr2+, Ba2+), polycations (chitosan) or poly-l-lysine disintegrant, binder, viscosity increasing | swelling ability (200–300× of its own weight from water) pH-dependent swelling nontoxic, nonirritant low density (capable of floating in gastric juice) Diffusion, erosion, in situ forming hydrogels | pH dependence (insoluble in acidic medium) heat-sensitivity (hydrolysis) microbial spoilage on storage (depolymerization) | [46] |
Tragacanth | Water soluble arabinogalactan and swellable bassorin components, swells quickly in water | Acid-resistance emulsifier, encapsulation of oils, stabilizer in emulsions | Di/trivalent cations cause drop in viscosity because of precipitation | [47] |
Gum arabic/ Acacia gummi (Ph. Eur.) | Water soluble, clear solution of pH 4.5, protective colloid | Emulsifier, spray-dry encapsulation of flavor and of essential oils, 30% solution has a relatively low viscosity, Newtonian flow permeable coating dietary fiber | Variation dependent on source pH, ionic strength influences viscosity (max at ≈pH 6–7) | [48,49,50] |
Pectin (low or high methoxylated) (apple, citrus peel, beet) | Negatively charged molecule | Gelation depends on the degree of esterification, cation (Ca,Zn) concentration in solution, temperature and pH In situ gelling, sustained delivery, dietary fiber, drug delivery in colorectal carcinoma (5-FU), antiviral activity | Gelling occurs at low pH (<3.5), presence of sugars necessary for gelation of HM pectin | [51,52] |
Excipient | Physicochemical Properties | Applications and Benefits | Limitations | Ref. |
---|---|---|---|---|
Xanthan gum | Soluble in warm and cold water, not affected by pH anionic polyelectrolyte | No gelation at room temp, cryogelation possible, stable viscosity over wide pH range, surface activity, emulsion stabilizer, controlled-release, colon-targeted swelling, diffusion, matrix erosion | Hydrolysis Acceptable daily intake (WHO) 10 mg/kg BW Contains cellulase | [53] |
Gellan gum | Anionic polyelectrolyte soluble in water | Thermoreversible gelation with cations sol-gel transition under physiological conditions bioadhesive nasal administration | Poor biodegragability | [54] |
Dextran | Neutral polymer, solubility depends on degree of polymerization | Colon-targeted delivery, formation of porous particle pulmonary delivery | At parenteral adiminitration: possible platelet adhesiveness | [55,56] |
Pullulan | Neutral polymer underivarized pullulan has high water solubility | Emulsifier sustained-release preparations | Relatively high price | [57,58] |
Excipient | Physicochemical Properties | Applications and Benefits | Limitations | Ref. |
---|---|---|---|---|
Methylcellulose (MC) | Soluble in cold water Tsol-gel: 80 °C amphiphilic | Emulsifier, pseudoplastic solution, pH-independent gel formation above 50 °C, high variety in Mw | Complexation with surface-active components, laxative | [59] |
Carboxymethyl-cellulose sodium (CMC-Na) | Anionic cellulose ether, dispersible in water (forms a colloidal solution) | Injectable thermoreversible gel-forming, mucoadhesive | Microbial instability hygroscopicity | [60,61] |
Hydroxypropyl-cellulose (HPC) | Soluble in cold water, compatible with waxes, oils, Tsol-gel: 55 °C | High surface activity film-forming ability | Incompatible with alkaline substances, substituted phenol derivatives, anionic polymers increase viscosity | [62] |
Hydroxypropyl-methylcellulose (HPMC) | Water soluble, nonionic | Reversible thermal gelation surface activity, emulsion stabilizer, film-forming ability | No complex with metallic salts or ionic organics | [63] |
Ethylcellulose | Water-insoluble, hydrophobic coating | Film forming ability, membrane-controlled diffusion, modified release, floating, gastroretentive systems | Organic solvent residuals | [64] |
Cellulose acetate butyrate | Insoluble in water, soluble in aceton-water blends | Semipermeable coating, extended release formulations, diffusion, matrix erosion | Organic solvent residuals | [65] |
Excipient | Physicochemical Properties | Applications and Benefits | Limitations | Ref. |
---|---|---|---|---|
Poly (lactic acid) (PLA) | Insoluble in water degrades to CO2 and H2O over 12–24 months | Biodegradability, prolonged-release in im or sc injections, implants, oral solid dispersions | Digestive tract influences degradation, parenteral administration is favorable, initial burst release may occur | [64,65] |
Polylactic acid-glycolic acid copolymer (PLGA) | Insoluble in water lactic acid-glycolic acid ratio influences degradation ability to thermoplastic gel forming | Injectable or implantable systems (microparticles, gels) for human and veterinary use, pH-responsive/non-pH-responsive polymer degradation, bone tissue engineering | Degrades into by-products that can induce inflammation | [66,67,68,69] |
Polyacrylic acid (Carbopol) | Neutralization with alkaline chemicals for gelling | Bioadhesive, targeted delivery, intranasal administration with microencapsulation | Neutralization at preparation, preservative needed | [70] |
Polymethacrylates | Soluble in organic solvents, most of them are miscible with water | pH-dependent solubility, permeability gastric or enteric targeted delivery possible | Water insolubility | [71] |
Poly-(N-isopropylacrylamide) | LCST: 35–40 °C | Thermoresponsive | Not biodegradable | [72,73] |
Polyethylene glycols | Liquid or solid grades depending on the Mw, PEG (polyethylene glycol) 1500 freezing point at 37–41 °C | Plasticizer in wall of compressible microcapsules, oral insulin delivery cell delivery in combination | Not biodegradable | [74] |
Fumaryl diketopiperazine (FDKP) | High solubility at pH ≥ 6, no biological activity | Self-assembled highly porous microparticles, Technosphere® carrier | Not biodegradable, excreted via urine | [75] |
Polymer | Active Ingredient | Particle Size | Physicochemical Mechanisms | Ref |
---|---|---|---|---|
Carbohydrate-Carbohydrate | ||||
Chitosan-alginate | Leydig cells | 230–370 µm | Complex coacervation | [77] |
Agarose-alginate (CaCl2) | Sertoli cells | 250 µm | Microfluidics ionic gelation, | [78] |
Gum arabic | Xylitol | 100 µm | double emulsion/coacervation | [79] |
Cellulose acetate butyrate (CAB) | Sulfopropylated dextran microspheres | 40–120 µm | O/W emulsification, solvent evaporation | [65] |
Gelatin + gum arabic | Raspberry anthocyanins | 150 µm | Emulsification, coacervation | [80] |
Maltodextrin + gum arabic | Lavender oil | 10–20 µm | S/O/W emulsification, spray-drying | [50] |
CMC-Na + xanthan gum | Diclofenac sodium | 1000–1500 µm | Emulsification, ionic gelation, Interpenetrating network | [81] |
LBG + PVA | Buflomedil hydrochloride (BH) | 350–750 µm | emulsification, Interpenetrating network | [40] |
Chitosan + pectin | Insulin | 0.24–2 µm | electrostatic self-assembly | [82] |
Carbohydrate-Protein | ||||
Gelatin + gum arabic | Aspartame | 100 µm | Double emulsion/complex coacervation | [83] |
Gelatin + chitosan | Citronella oil | 100 µm | Coacervation | [33] |
whey Protein + maltodextrin | Flaxseed oil | ≈10 µm | emulsification, spray drying | [84] |
Whey protein + alginate | Flaxseed oil | <10 µm | Double layer emulsification spray drying | [85] |
Alginate + gelatin | Whey peptides (antihypertensive activity | 1000 µm | Dripping, coacervation | [86] |
Alginate + zein | Bifidobacterium bifidum | 1200–1700 µm | Extrusion coacervation shell-core | [87] |
Chitosan-zein | Oral gene delivery | 10 µm | Zein-sodium tripolyphosphate W/O emulsion | [88] |
Poly-l-lysine | Poly (methyl vinyl ether-alt-maleic anhydride) (PMM0) | 400 µm | prilling, coacervation | [89] |
Poly (l-ornithine) + alginate + PLA, PLGA | Superoxide dismutase, ketoprofen | 500 µm | W/O/W, O/W, solvent evaporation | [90] |
Poly (l-ornithine) + ursodeoxycholic acid, Polystyrene sulfonate, polyallilamine | Pancreatic ß-cells | 700 µm | Complex coacervation, vibrational jet | [91] |
Poly (ethylene glycol) (PEG)-anthracene alginate | Coomassie blue | no data | Coacervation | [92] |
Vinyl-sulfone terminated PEG + alginate | Human foreskin fibroblast | 550 µm | Simple coacervation | [93] |
Alginate + Poly-ε-caprolactone | Theophylline | 800 µm | Complex coacervation | [94] |
Polypropylene + PMMA + ethylcellulose | Verapamil | 150–200 µm | O/W solvent evaporation | [95] |
PLGA-alginate | Rifampicin | 15–50 µm | Microfluidics | [96] |
Method | Typical Initial Form of the Core | Approximate Size (µm) | Structure | Final State | ||
---|---|---|---|---|---|---|
Matrix | Core/Shell | |||||
Chemical | Interfacial polymerization | In emulsion or suspension | 0.1–500 | X | wet (slurry), can be dried | |
In situ polymerization | In emulsion or suspension | 1–1000 | X | wet (slurry), can be dried | ||
Physicochemical | left | In emulsion or suspension | 2–5000 | X | X | wet, can be dried |
Dripping- (Vibrating nozzle-single; multiple) | Droplet formulation/extrusion; coextrusion | 10–5000 | X | X | wet, can be dried | |
Solvent evaporation | In emulsion or suspension | 0.1–5000 | X | X | wet, can be dried | |
Spray drying (from solution) | Droplet formulation/spraying | 1–100 | X | dry | ||
Spray chilling | Droplet formulation/spraying | 1–100 | X | X | dry | |
Fluid bed coating/drum coating | Solid core particle | 100–5000 | X | dry |
Type | Dosage Form | Key Excipient | Drug | Indication | Product Example |
---|---|---|---|---|---|
Micropellets | Peroral pellets in capsule | HPC | Lansoprazole | Proton pump inhibitor | Lansoprazole® |
Enteric-coated microgranules | Delayed-release orally disintegrating tablets | Methacrylic acid, polyacrylate | Lansoprazole | Proton pump inhibitor | Prevacid® SoluTab™ |
Coated pellets | Compressing pellets into an extended release tablet | HPC, EC | Metoprolol succinate | Cardioselective beta blockers | Betaloc® ZOK |
Microtablets | Peroral minitablets in capsule | Methacrylic acid-ethyl acrylate, MCC | Lipase, amylase, | Enzyme supply | Pangrol® |
Dry powder (Technospheres®) | inhalation | Fumaryl diketopiperazine | Insulin | Diabetes | AfrezzaTM |
Microspheres | Im suspension injection | Poly-d, l-lactid-co-glycolide | Risperidone | Schizophrenia | Risperdal® consta |
Microspheres | Powder for injection | Poly-d, l-lactide-co-glycolide | Bromocriptine | Acromegaly, parkinsonism | Parlodel® LAR |
Microspheres | Powder and solvent for suspension and injection | Poly-d, l-lactide-co-glycolide | Octreotide | Acromegaly pancreatic tumors | Sandostatin LAR® |
Microspheres | Prolonged-release suspension for injection | Poly-d, l-lactide-co-glycolide | Exenatide | Diabetes type 2 | Bydureon® |
Lyophilized microspheres | Suspension depot injection | Poly-d, l-lactid-co-glycolide | Leuprolide acetate | Endometriosis | Lupron® depot |
Liposomes | Liposome inhalation suspension | Cholesterol, dipalmitoylphosphatidylcholine | Amikacin | Antibacterial | Arikayce® |
Liposomes (DepoFoam™) | Powder for suspension for injection | Cholesterol, DOPC, DPPG | Cytarabine | Neoplastic meningitis | Depocyte® |
Liposomes (DepoFoam™) | Powder for suspension for injection | Cholesterol, DOPC, DPPG, tricaprylin, triolein | Morphine | Epidural analgesia | DepoDur® |
Microbubbles | Intravenous injection | Albumin | Perflutren | Ultrasound contrast agent | Albunex® |
Microbubbles | Intravenous injection | PEG 4000, DSPC, DPPG-Na, palmitic acid | Sulfur hexafluoride | Ultrasound contrast agent | Lumason/SonoVue® |
Microbubbles | Intravenous injection | DPPA, DPPC, MPEG5000 DPPE | Perflutren | Ultrasound contrast agent | Definity® |
Microsponge | Topical gel | Methyl methacrylate/glycol dimethacrylate crosspolymer | Tretinoin | Acne vulgaris | Retin A® micro gel |
Microsponge | Topical cream | Methyl methacrylate glycol dimethacrylate crosspolymer, dimethicone. | 5-fluorouracil | Multiple acne/solar keratoses | Carac® cream 0.5% |
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Lengyel, M.; Kállai-Szabó, N.; Antal, V.; Laki, A.J.; Antal, I. Microparticles, Microspheres, and Microcapsules for Advanced Drug Delivery. Sci. Pharm. 2019, 87, 20. https://doi.org/10.3390/scipharm87030020
Lengyel M, Kállai-Szabó N, Antal V, Laki AJ, Antal I. Microparticles, Microspheres, and Microcapsules for Advanced Drug Delivery. Scientia Pharmaceutica. 2019; 87(3):20. https://doi.org/10.3390/scipharm87030020
Chicago/Turabian StyleLengyel, Miléna, Nikolett Kállai-Szabó, Vince Antal, András József Laki, and István Antal. 2019. "Microparticles, Microspheres, and Microcapsules for Advanced Drug Delivery" Scientia Pharmaceutica 87, no. 3: 20. https://doi.org/10.3390/scipharm87030020