File Name: design and fabrication of oral controlled release drug delivery systems .zip
Novel therapeutic approaches such as nanotechnology and their innovative fabrication methods have opened a new direction in biomedical sciences. Owing to their small particle size and various other characteristics such as capability of encapsulating small molecules as well as biologics, protecting the drugs in biological environments, improving the drug biodistribution, opportunity for providing controlled or stimuli-responsive drug release, enhancement of the targeted and intracellular delivery of therapeutics, flexibility to be combined with diagnostic and imaging agents for theranostic uses, nanotechnology-based formulations are versatile systems for various applications and for better therapeutic outcomes [ 1 ]. This issue has assembled leaders in drug delivery research areas, covering topics on microparticles, microbubbles, nanoparticles, microneedles, organogels, micelles, lipid-based systems, inorganic nanoparticles, laser-generated micropores, and nanoemulsion.
With the rapid development of nanotechnology, the convergence of nanostructures and drug delivery has become a research hotspot in recent years. Due to their unique and superior properties, various nanostructures, especially those fabricated from self-assembly, are able to significantly increase the solubility of poorly soluble drugs, reduce cytotoxicity toward normal tissues, and improve therapeutic efficacy.
Nanostructures have been successfully applied in the delivery of diverse drugs, such as small molecules, peptides, proteins, and nucleic acids. In this paper, the driving forces for the self-assembly of nanostructures are introduced. The strategies of drug delivery by nanostructures are briefly discussed. Furthermore, the emphasis is put on a variety of nanostructures fabricated from various building materials, mainly liposomes, polymers, ceramics, metal, peptides, nucleic acids, and even drugs themselves.
In the past few decades, nanostructures have attracted intensive research interest due to their unique and superior properties as compared with conventional bulk materials. They have been applied in a wide range of fields, such as materials, electronics, sensing, catalysis, environment, and drug delivery.
In drug delivery systems, some of the challenges which need to be faced include bioavailability, in vivo stability, solubility, absorption, sustained and targeted delivery to site of action, therapeutic efficacy, side effects, and fluctuation of drug concentration in plasma [ 1 ]. To surmount these challenges, large quantities of studies have been carried out to explore the fabrication and application of various nanostructures in drug delivery. It is noteworthy that a considerable proportion of nanostructures are obtained via the self-assembly of building blocks.
Based on the properties and structures of building blocks, various kinds of noncovalent interactions play significant roles in the self-assembly processes and contribute to the stability of resultant nanostructures.
The association between drugs and nanocarriers is achieved by either physical encapsulation or chemical conjugation. The fabrication of well-defined nanostructures with distinct properties, especially through self-assembly process, has been an extremely active field in drug delivery. A large variety of nanostructures, including liposomes, polymeric, ceramic, metallic, peptides-based, nucleic acid-based, and drug-based nanostructures, have already emerged and found their applications in the delivery of various drugs, including small molecules, peptides, proteins, and nucleic acids.
In drug delivery system, many nanostructures are formed by self-assembly, which is a force balance process in which well-defined structures or patterns are spontaneously formed from building blocks without human intervention [ 3 ]. Compared with covalent bonds, noncovalent interactions are much weaker, which involve more dispersed variations of electromagnetic interactions between molecules or within a molecule [ 4 ].
However, noncovalent interactions possess the ability to significantly influence the detailed structures of self-assembled nanostructures, separately or synergistically. Among various noncovalent interactions in self-assembly process, hydrophobic effect is the most important. A wide range of building blocks for self-assembly are amphiphilic molecules, including many synthetic building blocks and biomolecules such as proteins and lipids.
Due to the coexistence of polar and nonpolar regions, the self-assembly of amphiphilic molecules can be readily accomplished through microphase separation driven by thermodynamics.
In aqueous solutions, the nonpolar regions of the building blocks will collapse and cluster together to expose the smallest possible hydrophobic area to water while the polar regions attempt to maximize their interaction with water [ 3 ]. Taking amphiphilic diblock copolymers as an example, when the concentration is higher than the critical micelle concentration CMC , the hydrophobic block will assemble into a core, and the hydrophilic block stretches itself in water and thus forms a shell surrounding the hydrophobic core.
Electrostatic interactions, which involve both attractive and repulsive forces between charged atoms, ions, or molecules, also have a strong effect on many self-assembly processes. Cationic polymers can interact with anionic proteins or genes through electrostatic interactions, forming stable nanoparticles in aqueous solutions [ 5 ]. For example, according to Xia et al. Upon reducing the strength of the hydrophobic effect, electrostatic attractions became the important interaction that regulated the binding between the water-soluble conjugated polymer and DNA.
Hydrogen bond is the electrostatic attraction between H atom and a highly electronegative atom nearby, such as N, O, or F. Hydrogen bond attractions can occur both between molecules intermolecular and within different parts of a single molecule intramolecular.
It is very common both in inorganic molecules e. However, due to the lack of hydrogen bond, methotrexate was unable to form any well-defined nanostructures with similar treatment [ 11 ]. In summary, noncovalent interactions play important roles in the formation of nanostructures, separately or synergistically. Good control of physical properties of nanostructures is highly important for their successful utilization in drug delivery. When designing nanostructures for drug delivery, noncovalent interactions should be taken into consideration and be rationally applied in the strategies.
In the former method, drugs are physically incorporated into the internal cavity and stabilized by noncovalent interactions between drugs and nanocarriers, especially hydrophobic effect [ 13 , 14 ]. Many nanostructures such as nanomicelles, nanocapsules, and porous nanoparticles have a net hydrophobicity to stabilize the entrapped drug molecules [ 15 ].
When the nanostructures are disassembled at target sites of action, drugs will be released as a consequence. It is one of the crucial challenges posed by nanostructures on drug delivery. The second method is to attach cargo drugs to the nanocarriers by direct chemical conjugation. In order to have a good control over the triggered release of drugs, the conjugation between nanocarriers and drugs should be cleavable at target sites.
If drugs cannot be cleaved from their nanocarriers in time, their bioactivity and efficacy will be reduced. On the other hand, if drugs tend to be dissociated from their nanocarriers too quickly, they will fail to reach the target sites of action in a significant dose.
Therefore, rational design of the chemical conjugation between a drug and its nanocarrier is of great importance. Apparently, the common strategies mentioned above merely consider drugs as active pharmaceutical compounds which need to be delivered.
However, their properties, such as self-assembly ability and solubility, are ignored. In recent years, there is a growing trend to build well-defined nanostructures with drug molecules as building units. Through this strategy, the distribution and content of drugs in the nanostructures can be accurately controlled. Via rational analysis, design, and fabrication, lots of self-delivering nanostructures with high and fixed drug contents have been created. Detailed illustration and examples will be given in Section 4.
In the past few decades, nanostructures with various shapes and sizes have been fabricated and applied for many drugs. In this section, various nanostructures fabricated by different materials and their applications in drug delivery are illustrated and discussed in detail. Liposomes have been under extensive investigation and have become a common nanocarrier for drug delivery since Nanostructures fabricated with liposome are the first drug delivery system on the nanoscale to make the transition from concept to clinical application and have become a well-established technology platform with considerable clinical acceptance [ 17 ].
Liposomes are small artificial vesicles developed from phospholipids such as phosphatidylglycerol, phosphatidylserine, and phosphatidylcholine [ 18 ]. On the basis of lipid bilayers, liposomes can be classified into unilamellar vesicles UVs and multilamellar vesicles MLVs , as shown in Figure 1. UVs consist of an aqueous core surrounded by a lipid bilayer, separating the inner aqueous core from the outside. As metastable energy configurations, MLVs are composed of various layers of lipid bilayers [ 19 ].
Due to the structures described above, liposomes have the ability to compartmentalize and solubilize both hydrophilic and hydrophobic materials by nature. This unique feature, along with biocompatibility and biodegradability, makes liposomes attractive as drug delivery vehicles.
Particularly, hydrophobic drugs can place themselves inside the bilayer of liposomes and hydrophilic drugs are entrapped within the aqueous core or at the bilayer interface [ 20 ]. Besides, liposomes have the functions to prevent drug degradation, reduce side effects, and target drugs to site of action [ 18 , 21 ].
Hydrophobic drugs such as cyclosporin and paclitaxel are usually formulated in surfactants and organic cosolvents to increase their solubility in water. However, these solubilizers may cause toxicity at the doses needed to deliver the drug.
In contrast, liposomes, which are nontoxic, biocompatible, and biodegradable, can deliver water-insoluble drugs with much less side effects. For example, they have been successfully applied in transdermal drug delivery to enhance skin permeation of drugs with high molecular weight and poor water solubility [ 22 ].
However, the membrane of liposomes is generally thin, fragile, and thus inherently not stable [ 23 ]. Liposomes are also limited by their low encapsulation efficiency, rapid leakage of water-soluble drug in the presence of blood components, and poor storage stability [ 21 , 24 ]. In the past five decades, many important technical breakthroughs, such as remote drug loading, extrusion for homogeneous size, long-circulating PEGylated liposomes stealth liposomes , triggered release liposomes, liposomes containing nucleic acid polymers, ligand-targeted liposomes, and liposomes containing combinations of drugs, have led to numerous clinical trials in the delivery of diverse drugs, such as anticancer, antifungal, and antibiotic drugs, gene medicines, anesthetics, and anti-inflammatory drugs [ 17 ].
In the field of drug delivery, various polymeric nanostructures have been a hot topic of research for a long time. Generally speaking, polymer-based drug nanocarriers can significantly increase the solubility of hydrophobic drugs, reduce their cytotoxicity toward normal tissues, prolong the circulation time of drugs in blood, facilitate the entry of nanoparticles, and improve the utilization efficiency [ 25 ].
It is widely acknowledged that polymers used for drug delivery should be nontoxic and biocompatible. Natural polymers, such as chitosan [ 26 ], dextran [ 27 ], heparin [ 28 ], and hyaluronan [ 29 ], have been well investigated for drug delivery in the past few decades. However, research on using synthetic polymers to build various nanostructures is more prevalent in the field of drug delivery.
Polyesters, polycarbonates, polyamides, polyphosphazenes, and polypeptides are among the most commonly used synthetic polymers [ 5 ]. Owing to a great diversity of polymers, nanostructures of different sizes and morphologies have been obtained.
As mentioned above, amphiphilic molecules are prone to self-assemble into various nanostructures driven by hydrophobic effect. Therefore, amphiphilic polymers containing both hydrophilic and hydrophobic blocks have been extensively studied for use in drug delivery. According to Won et al. Both polymeric micelles and vesicles are the most common and stable morphological structures of amphiphiles in water [ 23 ].
Polymeric micelles are nanostructures with a hydrophilic core and a hydrophilic shell see Figure 2. Generally, hydrophilic drug molecules are encapsulated in the core of nanomicelles.
Meanwhile, polymeric nanovesicles possess bilayer structures with an aqueous interior core, isolating the core from the external medium [ 31 ]. Polymeric vesicles can encapsulate hydrophilic molecules within the aqueous interior and also integrate hydrophobic molecules within the membrane. Therefore, polymeric vesicles have the capability to deliver hydrophilic as well as hydrophobic drugs such as anticancer drugs, genes, and proteins.
However, polymeric nanomicelles and nanovesicles can only be maintained above the critical micelle concentration CMC. Below CMC, they will dissociate into single polymer chains and thus lose the function as drug carriers.
In order to avoid the dissociation of the self-assembled nanostructures, linking the polymers to obtain nanogels which are more stable in different conditions has become a common and effective approach. In recent years, nanogels have drawn increasing attention because of their high loading capacity and good stability [ 5 ]. Hollow polymeric nanocapsules have also been developed by miniemulsion polymerization in the past few decades.
Drugs are confined in the cavities of nanocapsules and surrounded by external polymer membranes [ 32 ]. Nanocapsules are able to improve the oral bioavailability of proteins and peptides, including insulin, elcatonin, and salmon calcitonin [ 32 , 33 ].
Nanocapsules can protect the degradation of drugs, reduce systemic toxicity, provide controlled release, and mask unpleasant taste [ 34 ]. Nevertheless, due to high stability and low permeability of nanocapsules, drugs carried by nanocapsules have trouble both in encapsulation into the capsules after formulation and in the release at target site [ 18 ]. Apart from these nanostructures, dendrimers with three-dimensional, hyperbranched globular nanopolymeric architectures have been the research focus of many scientists these years.
Due to their attractive features like nanoscale size, narrow polydispersity index, excellent control over molecular structures, and availability of multiple functional groups at the periphery and cavities in the interior [ 35 ], dendrimers have been explored to be used in the delivery of different bioactive agents such as drugs [ 36 ], oligonucleotides [ 37 ], enzymes [ 38 ], vaccines [ 39 ], and genes [ 40 ]. Drugs can be either incorporated into the interior or attached on the surface.
Due to their versatility, both hydrophilic and hydrophobic drugs can be associated with dendrimers [ 18 ]. Particularly, recent research has focused on stimulus-sensitive smart nanostructures for drug delivery because it is a superior approach for delivering and releasing drugs to specific site at the desired time.
Many kinds of stimuli, including chemical e.
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This site is operated by a business or businesses owned by Informa PLC and all copyright resides with them. Registered in England and Wales. Number Lisa Brannon-Peppas Nov 01, Controlled drug delivery occurs when a polymer, whether natural or synthetic, is judiciously combined with a drug or other active agent in such a way that the active agent is released from the material in a predesigned manner.
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With the rapid development of nanotechnology, the convergence of nanostructures and drug delivery has become a research hotspot in recent years. Due to their unique and superior properties, various nanostructures, especially those fabricated from self-assembly, are able to significantly increase the solubility of poorly soluble drugs, reduce cytotoxicity toward normal tissues, and improve therapeutic efficacy. Nanostructures have been successfully applied in the delivery of diverse drugs, such as small molecules, peptides, proteins, and nucleic acids. In this paper, the driving forces for the self-assembly of nanostructures are introduced.
Drug delivery is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals.
Scientific rationale for designing controlled drug delivery systems 2. Design and fabrication of Peroral controlled-release delivery systems 3. Design and fabrication of Parenteral drug delivery 4.
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