Phenolic compounds  and  monoterpenes  include  essential oil  constituents that have some antibacterial properties, [ 45 ] [ 73 ]  such as  eucalyptol , [ 14 ]   eugenol , [ 45 ]   hinokitiol , [ 74 ]   menthol , [ 75 ]   phenol , [ 45 ]  or  thymol . [ 45 ]
 Essential oils  are oils which have been extracted from plants. Mouthwashes based on  essential oils  could be more effective than traditional mouthcare as  anti-gingival  treatments. [ 73 ] [ 76 ]  They have been found effective in  reducing halitosis , and are being used in several commercial mouthwashes.


Anti-cavity mouthwashes contain  fluoride  compounds (such as  sodium fluoride ,  stannous fluoride , or  sodium monofluorophosphate ) to protect against  tooth decay . [ 77 ] [ 78 ]  Fluoride-containing mouthwashes are used as prevention for dental caries for individuals who are considered at higher risk for tooth decay, whether due to xerostomia related to salivary dysfunction or side effects of medication, to not drinking fluoridated water, or to being physically unable to care for their oral needs (brushing and flossing), and as treatment for those with dentinal hypersensitivity, gingival recession/ root exposure.


Flavoring agents  include sweeteners such as  sorbitol ,  sucralose ,  sodium saccharin , and  xylitol , which stimulate salivary function due to their sweetness and taste and helps restore the mouth to a neutral level of acidity. [ 2 ]


Xylitol rinses double as a bacterial inhibitor, [ 79 ]  and have been used as substitute for alcohol to avoid dryness of mouth associated with alcohol. [ 2 ]


Hydrogen peroxide  can be used as an oxidizing mouthwash (e.g. Peroxyl, 1.5%). [ 59 ] [ 80 ]  It kills anaerobic bacteria, and also has a mechanical cleansing action when it froths as it comes into contact with debris in mouth. [ 59 ]  It is often used in the short term to treat  acute necrotising ulcerative gingivitis . [ 59 ]  Side effects can occur with prolonged use, including  hypertrophy  of the  lingual papillae . [ 59 ]


Enzymes  and non-enzymatic proteins, such as  lactoperoxidase ,  lysozyme , and  lactoferrin , have been used in mouthwashes (e.g.,  Biotene ) to reduce levels of oral bacteria, and, hence, of the acids produced by these bacteria. [ 81 ]


Oral  lidocaine  is useful for the treatment of  mucositis  symptoms ( inflammation  of  mucous membranes ) induced by radiation or chemotherapy. [ 82 ]  There is evidence that lidocaine anesthetic mouthwash has the potential to be systemically absorbed, when it was tested in patients with oral mucositis who underwent a bone marrow transplant. [ 83 ]


Methyl salicylate  functions as an antiseptic, antiinflammatory, and analgesic agent, a flavoring, and a fragrance. [ 49 ]  Methyl salicylate has some anti-plaque action, but less than chlorhexidine. [ 53 ]  Methyl salicylate does not stain teeth. [ 53 ]


Nystatin  suspension is an  antifungal  ingredient used for the treatment of  oral candidiasis . [ 84 ]


A randomized clinical trial found promising results in controlling and reducing  dentine hypersensitivity  when potassium oxalate mouthwash was used in conjugation with toothbrushing. [ 85 ]


A 2005 study found that gargling three times a day with simple water or with a  povidone-iodine  solution was effective in preventing  upper respiratory infection  and decreasing the severity of symptoms if contracted. [ 86 ]  Other sources attribute the benefit to a simple placebo effect. [ 87 ]


PVP-I in general covers "a wider virucidal spectrum, covering both enveloped and nonenveloped viruses, than the other commercially available antiseptics", [ 88 ]  which also includes the novel  SARS-CoV-2  virus. [ 89 ] [ 90 ] [ 91 ]


Sanguinarine -containing mouthwashes are marketed as anti-plaque and anti-malodor treatments. [ 53 ]  Sanguinarine is a toxic alkaloid herbal extract, obtained from plants such as  Sanguinaria canadensis  (bloodroot),  Argemone mexicana  (Mexican prickly poppy), and others. [ 53 ]  However, its use is strongly associated with the development of  leukoplakia  (a white patch in the mouth), usually in the buccal sulcus. [ 53 ] [ 92 ]  This type of leukoplakia has been termed "sanguinaria-associated keratosis", and more than 80% of people with leukoplakia in the  vestibule of the mouth  have used this substance. Upon stopping contact with the causative substance, the lesions may persist for years. Although this type of leukoplakia may show  dysplasia , the potential for  malignant  transformation is unknown. [ 93 ]  Ironically, elements within the complementary and alternative medicine industry promote the use of sanguinaria as a therapy for cancer.


Sodium bicarbonate  is sometimes combined with salt to make a simple homemade mouthwash, indicated for any of the reasons that a saltwater mouthwash might be used. Pre-mixed mouthwashes of 1% sodium bicarbonate and 1.5% sodium chloride in  aqueous solution  are marketed, although pharmacists will easily be able to produce such a formulation from the base ingredients when required. Sodium bicarbonate mouthwash is sometimes used to remove viscous saliva and to aid visualization of the oral tissues during examination of the mouth. [ 51 ] : 4


Saline has a mechanical cleansing action and an antiseptic action, as it is a  hypertonic  solution in relation to bacteria, which undergo  lysis . The heat of the solution produces a therapeutic increase in blood flow ( hyperemia ) [ 59 ]  to the surgical site, promoting healing. [ 1 ]  Hot saltwater mouthwashes also encourage the draining of  pus  from  dental abscesses . [ 94 ]  In contrast, if heat is applied on the side of the face (e.g., hot water bottle) rather than inside the mouth, it may cause a dental abscess to drain extra-orally, which is later associated with an area of  fibrosis  on the face  (see:  Cutaneous sinus of dental origin ) . [ 95 ]


Saltwater mouthwashes are also routinely used after oral surgery, to keep food debris out of healing wounds and to prevent infection. Some oral surgeons consider saltwater mouthwashes the mainstay of wound cleanliness after surgery. [ 95 ]  In dental extractions, hot saltwater mouthbaths should start about 24 hours after a dental extraction. [ 95 ]  The term  mouth bath  implies that the liquid is passively held in the mouth, rather than vigorously swilled around (which could dislodge a blood clot). Once the blood clot has stabilized, the mouthwash can be used more vigorously. [ 95 ]  These mouthwashes tend to be advised for use about 6 times per day, especially after meals (to remove food from the socket). [ 95 ]


Sodium lauryl sulfate  (SLS) is used as a foaming agent in many oral hygiene products, including many mouthwashes. Some may suggest that it is probably advisable to use mouthwash at least an hour after brushing with toothpaste when the toothpaste contains SLS, since the anionic compounds in the SLS  toothpaste  can deactivate cationic agents present in the mouthwash. [ 96 ]


Sucralfate  is a mucosal coating agent, composed of an aluminum salt of sulfated  sucrose . [ 97 ]  It is not recommended for use in the prevention of  oral mucositis  in head and neck cancer patients receiving  radiotherapy  or  chemoradiation , due to a lack of efficacy found in a well-designed,  randomized controlled trial . [ 97 ]


Tetracycline  is an antibiotic which may sometimes be used as a mouthwash in adults (it causes red staining of teeth in children). It is sometimes use for herpetiforme ulceration (an uncommon type of aphthous stomatitis), but prolonged use may lead to oral candidiasis, as the fungal population of the mouth overgrows in the absence of enough competing bacteria. [ 51 ] : 209   Similarly, minocycline mouthwashes of 0.5% concentrations can relieve symptoms of  recurrent aphthous stomatitis . [ 98 ]   Erythromycin  is similar. [ 24 ]


A 4.8%  tranexamic acid  solution is sometimes used as an  antifibrinolytic  mouthwash to prevent bleeding during and after oral surgery in persons with  coagulopathies  (clotting disorders) or who are taking  anticoagulants  (blood thinners such as  warfarin ). [ 99 ] : 473


Triclosan  is a non-ionic chlorinate bisphenol antiseptic found in some mouthwashes. [ 100 ]  When used in mouthwash (e.g. 0.03%), there is moderate substantivity, broad spectrum anti-bacterial action, some anti-fungal action, and significant anti-plaque effect, especially when combined with a  copolymer  or  zinc citrate . [ 53 ]  Triclosan does not cause staining of the teeth. [ 53 ]  The safety of triclosan has been questioned. [ 101 ]


Astringents  like zinc chloride provide a pleasant-tasting sensation and shrink tissues. [ 102 ]   Zinc , when used in combination with other antiseptic agents, can limit the buildup of  tartar . [ 103 ]


A  Murphy drip  is a  rectal infusion  apparatus to administer the medical procedure of  proctoclysis , also known as rectoclysis. [ 2 ] [ 3 ]  During the procedure, an end of the Murphy drip is inserted into the  rectum  and large quantities of liquid are infused into the rectum drop by drop. [ 4 ]  Prior to fluids or medicines being given  intravenously , the Murphy drip and  hypodermoclysis  were the prime routes to administer fluids such as for  replacement  when patients could not be fed by mouth. [ 5 ]  American surgeon  John Benjamin Murphy  introduced the drip method of  saline  infusion per rectum in the treatment of  peritonitis . [ 6 ]


The Murphy drip was invented by  Wisconsin  surgeon  John Benjamin Murphy , for the purpose of administering a proctoclysis for  hydration  and replenishment of  electrolytes , via a  sodium  and  calcium chloride  solution. This would be used when administration by mouth was not possible because of the condition of the patient. [ 7 ]  The Murphy drip was described in the April 1909 issue of the  Journal of the American Medical Association . [ 8 ]  By as early as July 1928, the Murphy drip was considered an auxiliary method of injection behind  intravenous therapy  and  subcutaneous injection , the two principal methods of  injection  at that time. [ 9 ]


The Murphy drip can be used for administering drugs by this route and the apparatus is also used in conjunction with a  catheter  for  bladder  irrigation.
The term can even be applied to apparatus used to administer fluids intravenously. [ 10 ]


A curious anecdote involving the Murphy drip is related by  Walter Lord  in his book on the  Battle of Midway . On 4 June 1942 Pharmacist's Mate Edwin Miller was stationed on Sand Island (part of the  Midway Atoll ) and was making ready for the expected Japanese attack. Miller prepared undrinkably strong coffee which, he claimed, was to be used in an "old fashioned" treatment for  shock  – administration of  strong coffee through the rectum  via a Murphy drip. When the attack got underway, Miller was joined by his commanding officer and doctor in charge, Lieutenant Commander A. E. Ady, who did not appear to know the medical purpose of the coffee and asked for some to be poured. Miller thought that it would be amusing to let his commander drink it, but made the mistake of also drinking some himself. Dr. Ady continued to tell jokes throughout the attack. Miller, however, paid for his practical joke and was sick. [ 11 ]


A description of a Murphy drip set-up is contained in the 1932  Kansas Supreme Court  legal case  Ratliffe v. Wesley Hospital and Nurses' Training School: [ 12 ]


On February 14, 1929, "Dr. Horn directed the nurse to use the proctoclysis, known as the “Murphy drip.” While the operation was in progress a student nurse in the employ of the hospital prepared the room for the return of the appellant. The proctoclysis set was a part of the equipment of the hospital and was assembled and placed at or near the foot of the bed by the student nurse. The proctoclysis set consists of a standard which is an iron pole setting on a tripod containing hooks at intervals, and on these hooks by means of a chain, tape, string, or piece of gauze is hung a can containing hot water and soda solution. From this can a tube extends which is inserted in the rectum of the patient to whom the proctoclysis is administered. It was necessary to keep the solution hot in order that it would have a body temperature after dropping through the tube and entering the body. ... It was not unusual for the vessel holding the water to be fastened to the standard by gauze, string, or other bandage, although a part of the vessels were equipped with chains." [ 12 ]


A  nanocell  is a  drug delivery  platform consisting of a polymer-bound chemotherapeutic drug combined with a lipid-bound anti-angiogenesis drug. Nanocells are currently being developed in the lab of Shiladitya Sengupta of  MIT .


Angiogenesis , or the formation of new  blood vessels , plays a major role in the development of a  tumor .  After a tumor has grown to about the size of a cubic millimeter, its core becomes  hypoxic , and it begins to release growth factors to recruit new blood vessels that will supply it with oxygen.  Inhibiting angiogenesis has been investigated as a means of preventing tumor growth but has not proven to be fully successful, for tumor cells cut off from the blood supply can eventually develop “reactive resistance” to hypoxia.  These resistant cancer cells could be killed by  chemotherapeutic  drugs, but once the vasculature to the tumor has been cut off, there is no way for chemotherapy to be delivered.  Nanotechnology offers a way to deliver chemotherapeutic drugs and anti-angiogenic drugs in the same vehicle so that as the blood supply is shut off, chemotherapy is present to prevent any hypoxia-resistant cells from proliferating.


Labs at MIT are in the process of developing nanocells capable of delivering both types of drugs.  Each nanocell is between 120 and 200 _m in diameter and can be thought of as “a balloon within a balloon.”  Inside each nanocell is a chemotherapeutic drug covalently bound to a polymer, and on the surface of each cell is a lipid coat containing an anti-angiogenic drug.  The technology makes use of the fact that a tumor's blood vessels have pores 600 _m in diameter and are much leakier than normal blood vessels, which have pores only around 50 _m in diameter.  The nanocells circulate in the blood, and because of their size, they leak out of blood vessels only in tumors.  Once there, the nanocells are degraded by enzymes produced by the tumor.  Work remains to be done to win clinical approval for the technology, but results from Sengupta's lab indicate that the nanocells are more effective and less toxic than traditional chemotherapy.


Nanoneedles  may be conical or tubular needles in the  nanometre  size range, made from silicon or boron-nitride with a central bore of sufficient size to allow the passage of large molecules, or solid needles useful in  Raman spectroscopy ,  light emitting diodes  (LED) and  laser diodes .


In 2005 the Research Institute for Cell Engineering at Japan's  National Institute of Advanced Industrial Science and Technology  (AIST) and  Tokyo University of Agriculture and Technology  used nanoneedles controlled by an  atomic force microscope  (AFM) to penetrate the nucleus of living cells and insert molecules of nucleic acid, proteins or possibly to carry out cell surgery. The technique can accurately establish the position of the needle by monitoring the force exerted. Cells to be used for tracking, diagnosing, and treatment of illness may be removed from the body and replaced after being injected. The 100  nm  diameter needles were cut from silicon AFM tips using focused  ion beam etching . [ 1 ]


In 2009, researchers at the  University of Illinois  produced a 50 nm diameter boron-nitride nanoneedle with a thin coating of gold, suitable for biophysical research. Its diameter allows easy penetration of cell walls in order to deliver organic matter or fluorescent  quantum dots  into the cytoplasm or the nucleus. It may also be used as electrochemical probe or optical  biosensor  in a cellular environment. [ 2 ]


The  University of California, Berkeley  in 2008 produced  gallium arsenide  (GaAs) nanoneedles which emit extremely bright light, though  not yet lasers , when  optically pumped . With a length of 3-4 micrometres, they taper to tips of 2-5 nm across. In addition to  optoelectronic  devices, the needles will be useful in atomic force microscopy (AFM), and can be easily grown in arrays. Such AFM arrays, besides producing near-atomic resolution images of surfaces, could lead to new forms of data storage by direct manipulation of atoms. The needles may also find a use in tip-enhanced Raman spectroscopy, a process in which molecular energy levels are measured by comparing the frequency of incident light with that of outgoing light. A sharp needle tip allows for a more precise examination of the sample, down perhaps to that of single molecules. [ 3 ]


Research at the department of NanoMedicine and Biomedical Engineering at the  University of Texas  in 2010 created a new type of nanoneedle using silicon. A solution of  hydrogen peroxide  produces porous needles - their porosity is controlled along their length by altering the concentration of peroxide over time. The coloured porous needles are constructed to biodegrade over a predictable period, and have a surface area 120 times that of equivalent solid wires, making them useful as drug-delivery vehicles. Since porous silicon does not harm cells, the needles may also be used to tag cells and monitor chemical reactions. [ 4 ]


A note of caution was sounded by Martin A. Philbert, professor of  toxicology  at the  University of Michigan, Ann Arbor .  "The ability to manipulate nanometer-scale materials at the molecular level holds the promise of conferring specificity of cellular delivery and the reduction of collateral nuisance injury to neighboring cells. In the context of environmental health, the scientific community will have to pay close attention to those physicochemical properties of engineered nanomaterials that defeat or circumvent normal cellular processes and lend themselves to indiscriminate penetration of biological barriers, tissues, and cellular systems."   [ 5 ]


Nanoparticle drug delivery  systems are engineered technologies that use  nanoparticles  for the targeted delivery and controlled release of therapeutic agents. The modern form of a  drug delivery  system should minimize side-effects and reduce both dosage and dosage frequency. Recently, nanoparticles have aroused attention due to their potential application for effective drug delivery. [ 1 ]


Nanomaterials  exhibit different chemical and physical properties or biological effects compared to larger-scale counterparts that can be beneficial for drug delivery systems. Some important advantages of nanoparticles are their high surface-area-to-volume ratio, chemical and geometric tunability, and their ability to interact with biomolecules to facilitate uptake across the  cell membrane . The large surface area also has a large affinity for drugs and small molecules, like ligands or antibodies, for targeting and controlled release purposes.


Nanoparticles refer to a large family of materials both organic and inorganic. Each material has uniquely tunable properties and thus can be selectively designed for specific applications. Despite the many advantages of nanoparticles, there are also many challenges, including but not exclusive to:  nanotoxicity , biodistribution and accumulation, and the clearance of nanoparticles by human body.


The  National Institute of Biomedical Imaging and Bioengineering  has issued the following prospects for future research in nanoparticle drug delivery systems:


The development of new drug systems is time-consuming; it takes approximately seven years to complete fundamental research and development before advancing to preclinical animal studies. [ 3 ]


Nanoparticle drug delivery focuses on maximizing drug efficacy and minimizing cytotoxicity. Fine-tuning nanoparticle properties for effective drug delivery involves addressing the following factors.
The surface-area-to-volume ratio of nanoparticles can be altered to allow for more ligand binding to the surface. [ 4 ]  Increasing ligand binding efficiency can decrease dosage and minimize nanoparticle toxicity. Minimizing dosage or dosage frequency also lowers the mass of nanoparticle per mass of drug, thus achieving greater efficiency. [ 5 ]


Surface functionalization of nanoparticles is another important design aspect and is often accomplished by  bioconjugation  or passive adsorption of molecules onto the nanoparticle surface. By functionalizing nanoparticle surfaces with ligands that enhance drug binding, suppress immune response, or provide targeting/controlled release capabilities, both a greater efficacy and lower toxicity are achieved. Efficacy is increased as more drug is delivered to the target site, and toxic side effects are lowered by minimizing the total level of drug in the body.


The composition of the nanoparticle can be chosen according to the target environment or desired effect. For example,  liposome-based nanoparticles  can be biologically degraded after delivery, [ 6 ]  thus minimizing the risk of accumulation and toxicity after the therapeutic cargo has been released.


Metal nanoparticles, such as gold nanoparticles, have optical qualities(also described in  nanomaterials ) that allow for less invasive imaging techniques. [ 7 ]  Furthermore, the photothermal response of nanoparticles to optical stimulation can be directly utilized for tumor therapy.


Current nanoparticle drug delivery systems can be cataloged based on their platform composition into several groups: polymeric nanoparticles, inorganic nanoparticles, viral nanoparticles, lipid-based nanoparticles, and nanoparticle albumin-bound (nab) technology. Each family has its unique characteristics.


Polymeric nanoparticles are synthetic polymers with a size ranging from 10 to 100 nm. Common synthetic polymeric nanoparticles include polyacrylamide, [ 8 ]  polyacrylate, [ 9 ]  and chitosan. [ 10 ]  Drug molecules can be incorporated either during or after polymerization. Depending on the polymerization chemistry, the drug can be covalently bonded, encapsulated in a hydrophobic core, or conjugated electrostatically. [ 9 ] [ 11 ]  Common synthetic strategies for polymeric nanoparticles include microfluidic approaches, [ 12 ]  electrodropping, [ 13 ]  high pressure homogenization, and emulsion-based interfacial polymerization. [ 14 ]
Polymer  biodegradability  is an important aspect to consider when choosing the appropriate nanoparticle chemistry. Nanocarriers composed of biodegradable polymers undergo hydrolysis in the body, producing biocompatible small molecules such as lactic acid and glycolic acid. [ 15 ]
Polymeric nanoparticles can be created via self assembly or other methods such as particle replication in nonwetting templates (PRINT) which allows customization of composition, size, and shape of the nanoparticle using tiny molds. [ 16 ]


Dendrimers  are unique hyper-branched synthetic polymers with monodispersed size, well-defined structure, and a highly functionalized terminal surface. They are typically composed of synthetic or natural amino acid, nucleic acids, and carbohydrates. Therapeutics can be loaded with relative ease onto the interior of the dendrimers or the terminal surface of the branches via electrostatic interaction, hydrophobic interactions, hydrogen bonds, chemical linkages, or covalent conjugation. [ 17 ] [ 18 ] [ 16 ]  Drug-dendrimer conjugation can elongate the half-life of drugs. Currently, dendrimer use in biological systems is limited due to dendrimer toxicity [ 19 ]  and limitations in their synthesis methods. [ 20 ]  Dendrimers are also confined within a narrow size range (<15 nm) and current synthesis methods are subject to low yield. The surface groups will reach the de Gennes dense packing limit at high generation level, which seals the interior from the bulk solution – this can be useful for encapsulation of hydrophobic, poorly soluble drug molecules. The seal can be tuned by intramolecular interactions between adjacent surface groups, which can be varied by the condition of the solution, such as pH, polarity, and temperature, a property which can be utilized to tailor encapsulation and controlled release properties. [ 21 ]


Inorganic nanoparticles have emerged as highly valuable functional building blocks for drug delivery systems due to their well-defined and highly tunable properties such as size, shape, and surface functionalization. Inorganic nanoparticles have been largely adopted to biological and medical applications ranging from imaging and diagnoses to drug delivery. [ 22 ]  Inorganic nanoparticles are usually composed of inert metals such as gold and titanium that form nanospheres, however, iron oxide nanoparticles have also become an option.


Quantum dots  (QDs), or inorganic semiconductor nanocrystals, have also emerged as valuable tools in the field of bionanotechnology because of their unique size-dependent optical properties and versatile surface chemistry. Their diameters (2 - 10 nm) are on the order of the exciton Bohr radius, resulting in quantum confinement effects analogous to the " particle-in-a-box " model. As a result, optical and electronic properties of quantum dots vary with their size: nanocrystals of larger sizes will emit lower energy light upon fluorescence excitation. [ 23 ]


Surface engineering of QDs is crucial for creating nanoparticle–biomolecule hybrids capable of participating in biological processes. Manipulation of nanocrystal core composition, size, and structure changes QD photo-physical properties Designing coating materials which encapsulate the QD core in an organic shell make nanocrystals biocompatible, and QDs can be further decorated with biomolecules to enable more specific interaction with biological targets. The design of inorganic nanocrystal core coupled with biologically compatible organic shell and surface ligands can combine useful properties of both materials, i.e. optical properties of the QDs and biological functions of ligands attached. [ 24 ]


While application of inorganic nanoparticles in bionanotechnology shows encouraging advancements from a materials science perspective, the use of such materials in vivo is limited by issues related with toxicity, biodistribution and  bioaccumulation . Because metal inorganic nanoparticle systems degrade into their constituent metal atoms, challenges may arise from the interactions of these materials with biosystems, and a considerable amount of the particles may remain in the body after treatment, leading to buildup of metal particles potentially resulting in toxicity. [ 25 ]


Recently, however, some studies have shown that certain nanoparticle environmental toxicity effects aren't apparent until nanoparticles undergo transformations to release free metal ions. Under aerobic and anaerobic conditions, it was found that copper, silver, and titanium nanoparticles released low or insignificant levels of metal ions. This is evidence that copper, silver, and titanium NP are slow to release metal ions, and may therefore appear at low levels in the environment. [ 26 ]  Additionally, nanoshell coatings significantly protect against degradation in the cellular environment and also reduce QDs toxicity by reducing metal ion leakage from the core. [ 23 ]


Organic nanocrystals consist of pure drugs and surface active agents required for stabilization. They are defined as carrier-free submicron colloidal drug delivery systems with a mean particle size in the nanometer range. The primary importance of the formulation of drugs into nanocrystals is the increase in particle surface area in contact with the dissolution medium, therefore increasing bioavailability. A number of drug products formulated in this way are on the market. [ 27 ]


One of the issues faced by drug delivery is the solubility of the drug in the body; around
40% of newly detected chemicals found in drug discovery are poorly soluble in water. [ 28 ]  This low solubility affects the bioavailability of the drug, meaning the rate at which the drug reaches the circulatory system and thus the target site. Low bioavailability is most commonly seen in oral administration, which is the preferred choice for drug administration due to its convenience, low costs, and good patient practice. [ 28 ]  A measure to improve poor bioavailability is to inject the drugs in a solvent mixture with a solubilizing agent. [ 29 ]  However, results show this solution is ineffective, with the solubilizing agent demonstrating side-effects and/or toxicity.
Nanocrystals used for drug delivery can increase saturation solubility and dispersion velocity. Generally, saturation solubility is thought to be a function of temperature, but it is also based on other factors, such as crystalline structure and particle size, in regards to nanocrystals. The Ostwald-Freundlich equation below shows this relationship:


l
 o
 g
 (

 C

 s

 C

 α

 )
 =

 2
 σ
 V

 2.303
 R
 T
 ρ
 r

 {\displaystyle log({\frac {C_{s}}{C_{\alpha }}})={\frac {2\sigma V}{2.303RT\rho r}}}


Where  C s  is the saturation solubility of the nanocrystal,  C 𝛼  is the solubility of the drug at a non-nano scale,  σ  is the interfacial tension of the substance,  V  is the molar volume of the particle,  R  is the gas constant,  T  is the absolute temperature,  𝜌  is the density of the solid, and  r  is the radius. [ 28 ]  The advantage of nanocrystals is that they can improve oral adsorption, bioavailability, action onset and reduces intersubject variability.
Consequently, nanocrystals are now being produced and are on the market for a variety of purposes ranging from antidepressants to appetite stimulants. Nanocrystals can be produced using two different ways: the top-down method or the bottom-up method. Bottom-up technologies are also known as nanoprecipitation. This technique involves dissolving a drug in a suitable solvent and then precipitating it with a non-solvent. On the other hand, top-down technologies use force to reduce the size of a particle to nanometers, usually done by milling a drug. Top-down methods are preferred when working with poorly soluble drugs.


A disadvantage of using nanocrystals for drug delivery is nanocrystal stability. Instability problems of nanocrystalline structures derive from thermodynamic processes such as particle aggregation, amorphization, and bulk crystallization. Particles at the nanoscopic scale feature a relative excess of Gibbs free energy, due to their higher surface area to volume ratio. To reduce this excess energy, it is generally favorable for aggregation to occur. Thus, individual nanocrystals are relatively unstable by themselves and will generally aggregate. This is particularly problematic in top-down production of nanocrystals. Methods such as high-pressure homogenization and bead milling, tend to increase instabilities by increasing surface areas; to compensate, or as a response to high pressure, individual particles may aggregate or turn amorphous in structure. [ 30 ]  Such methods can also lead to the reprecipitation of the drug by surpassing the solubility beyond the saturation point (Ostwald ripening). [ 31 ]
One method to overcome aggregation and retain or increase nanocrystal stability is by use of stabilizer molecules. These molecules, which interact with the surface of the nanocrystals and prevent aggregation via ionic repulsion or steric barriers between the individual nanocrystals, include surfactants and are generally useful for stabilizing suspensions of nanocrystals. [ 30 ]  Concentrations of surfactants that are too high, however, may inhibit nanocrystal stability and enhance crystal growth or aggregation. It has been shown that certain surfactants, upon reaching a critical concentration, begin to self-assemble into micelles, which then compete with nanocrystal surfaces for other surfactant molecules. With fewer surface molecules interacting with the nanocrystal surface, crystal growth and aggregation is reported to occur at increased amounts. [ 32 ]  Use of surfactant at optimal concentrations reportedly allows for higher stability, larger drug capacity as a carrier, and sustained drug release. [ 30 ]  In a study using PEG as a stabilizer was found that nanocrystals treated with PEG enhanced accumulation at tumor sites and had greater blood circulation, than those not treated with PEG. [ 33 ]
Amorphization can occur in top-down methods of production. With different intramolecular arrangements, amorphization of nanocrystals leads to different thermodynamic and kinetic properties that affect drug delivery and kinetics. Transition to amorphous structures is reported to occur through production practices such as spray drying, lyophilization, and mechanical mechanisms, such as milling. [ 30 ]  This amorphization has been reportedly observed with or without the presence of stabilizer in a dry milling process. Using a wet milling process with surfactant, however significantly reduced amorphization, suggesting that solvent, in this case water, and surfactant could inhibit amorphization for some top-down production methods that otherwise reportedly facilitate amorphization. [ 34 ]


Liposomes  are spherical vesicles composed of synthetic or natural phospholipids that self-assemble in aqueous solution in sizes ranging from tens of nanometers to micrometers. [ 16 ]  The resulting vesicle, which has an aqueous core surrounded by a hydrophobic membrane, can be loaded with a wide variety of hydrophobic or hydrophilic molecules for therapeutic purposes.


Liposomes are typically synthesized with naturally occurring phospholipids, mainly  phosphatidylcholine .  Cholesterol  is often included in the formulation to adjust the rigidity of the membrane and to increase stability. The molecular cargo is loaded through liposome formation in aqueous solution, solvent exchange mechanisms, or pH gradients methods. [ 35 ]  Various molecules can also be chemically conjugated to the surface of the liposome to alter recognition properties. One typical modification is conjugating polyethyleneglycol (PEG) to the vesicle surface. The hydrophilic polymer prevents recognition by macrophages and decreases clearance. The size, surface charge, and bilayer fluidity also alter liposome delivery kinetics. [ 36 ]
Liposomes diffuse from the bloodstream into the interstitial space near the target site. As the cell membrane itself is composed of phospholipids, liposomes can directly fuse with the membrane and release the cargo into the cytosol, or may enter the cell through phagocytosis or other active transport pathways.
Liposomal delivery has various advantages. Liposomes increase the solubility, stability, and uptake of drug molecules. Peptides, polymers, and other molecules can be conjugated to the surface of a liposome for targeted delivery. Conjugating various ligands can facilitate binding to target cells based on the receptor-ligand interaction. Altering vesicle size and surface chemistry can also be tuned to increase circulation time.
Various FDA-approved liposomal drugs are in clinical use in the US. The anthracycline drug doxorubicin is delivered with phospholipid-cholesterol liposomes to treat AIDS-related Kaposi sarcoma and multiple myeloma with high efficacy and low toxicity. [ 37 ]  Many others are undergoing clinical trials, and liposomal drug delivery remains an active field of research today, with potential applications including nucleic acid therapy, brain targeting, and tumor therapy. [ 38 ] [ 39 ]


Viruses can be used to deliver genes for genetic engineering or gene therapy. Commonly used viruses include adenoviruses, retroviruses, and various bacteriophages. The surface of the viral particle can also be modified with ligands to increase targeting capabilities. While viral vectors can be used to great efficacy, one concern is that may cause off-target effects due to its natural tropism. This usually requires replacing the proteins causing virus-cell interactions with chimeric proteins. [ 40 ]
In addition to using viruses, drug molecules can also be encapsulated in protein particles derived from the viral capsid, or virus-like particles (VLPs). VLPs are easier to manufacture than viruses, and their structural uniformity allows VLPs to be produced precisely in large amounts. VLPs also have easy-to-modify surfaces, allowing the possibility for targeted delivery. There are various methods of packaging the molecule into the capsid; most take advantage of the capsid's ability to self-assemble. One strategy is to alter the pH gradient outside the capsid to create pores on the capsid surface and trap the desired molecule. Other methods use aggregators such as leucine zippers or polymer-DNA amphiphiles to induce capsid formation and capture drug molecules. It is also possible to chemically conjugate of drugs directly onto the reactive sites on the capsid surface, often involving the formation of amide bonds.
After being introduced to the organism, VLPs often have broad tissue distribution, rapid clearance, and are generally non-toxic. It may, however, like viruses, invoke an immune response, so immune-masking agents may be necessary. [ 41 ]


Nanoparticle albumin-bound technology utilizes the protein albumin as a carrier for hydrophobic chemotherapy drugs through noncovalent binding. Because albumin is already a natural carrier of hydrophobic particles and is able to transcytose molecules bound to itself, albumin composed nanoparticles have become an effective strategy for the treatment of many diseases in clinical research.


An ideal drug delivery system should have effective targeting and controlled release. The two main targeting strategies are passive targeting and active targeting. Passive targeting depends on the fact that tumors have abnormally structured blood vessels that favor accumulation of relatively large macromolecules and nanoparticles. This so-called  enhanced permeability and retention effect  (EPR) [ 42 ]  allows the drug-carrier be transported specifically to the tumor cells. Active targeting is, as the name suggests, much more specific and is achieved by taking advantage of receptor-ligand interactions at the surface of the cell membrane. [ 43 ]  Controlled drug release systems can be achieved through several methods. Rate-programmed drug delivery systems are tuned to the diffusivity of active agents across the membrane. [ 44 ]  Another delivery-release mechanism is activation-modulated drug delivery, where the release is triggered by environmental stimuli. The stimuli can be external, such as the introduction of a chemical activators or activation by light or electromagnetic fields, or biological - such as pH, temperature, and osmotic pressure which can vary widely throughout the body. [ 45 ] [ 46 ] [ 47 ]


For polymeric nanoparticles, the induction of stimuli-responsiveness has usually relied heavily upon well-known polymers that possess an inherent stimuli-responsiveness. Certain polymers that can undergo reversible phase transitions due to changes in temperature or pH have aroused interest. [ 48 ]
Arguably the most utilized polymer for activation-modulated delivery is the thermo-responsive polymer poly(N-isopropylacrylamide). It is readily soluble in water at room temperature but precipitates reversibly from when the temperature is raised above its lower critical solution temperature (LCST), changing from an extended chain conformation to a collapsed chain. [ 49 ]  This feature presents a way to change the hydrophilicity of a polymer via temperature.
Efforts also focus on dual stimuli-responsive drug delivery systems, which can be harnessed to control the release of the encapsulated drug. For example, the triblock copolymer of poly(ethylene glycol)-b-poly(3-aminopropyl-methacrylamide)-b-poly(N-isopropylacrylamide) (PEG-b-PAPMA-b-PNIPAm) can self-assemble to form micelles, possessing a core–shell–corona architecture above the lower critical solution temperature. It is also pH responsive. Therefore, drug release can be tuned by changing either temperature or pH conditions. [ 50 ]


Drug delivery strategies of inorganic nanoparticles are dependent on material properties. The active targeting of inorganic nanoparticle drug carriers is often achieved by surface functionalization with specific ligands of nanoparticles. For example, the inorganic multifunctional nanovehicle (5-FU/Fe3O4/αZrP@CHI-FA-R6G) is able to accomplish tumor optical imaging and therapy simultaneously. [ 51 ]  It can be directed to the location of cancer cells with sustained release behavior.
Studies have also been done on gold nanoparticle responses to local near-infrared (NIR) light as a stimuli for drug release. In one study, gold nanoparticles functionalized with double-stranded DNA encapsulated with drug molecules, were irradiated with NIR light. The particles generated heat and denatured the double-stranded DNA, which triggered the release of drugs at the target site. [ 52 ]
Studies also suggest that a porous structure is beneficial to attain a sustained or pulsatile release. Porous inorganic materials demonstrate high mechanical and chemical stability within a range of physiological conditions. [ 53 ]  The well-defined surface properties, such as high pore volume, narrow pore diameter distribution, and high surface area allow the entrapment of drugs, proteins and other biogenic molecules with predictable and reproducible release patterns. [ 54 ] [ 55 ]


Some of the same properties that make nanoparticles efficient drug carriers also contribute to their toxicity. For example, gold nanoparticles are known to interact with proteins through surface adsorption, forming a  protein corona , which can be utilized for cargo loading and immune shielding. However, this protein-adsorption property can also disrupt normal protein function that is essential for homeostasis, especially when the protein contains exposed sulfur groups. [ 56 ]  The photothermal effect, which can be induced to kill tumor cells, may also create reactive oxygen species that impose oxidative stress on surrounding healthy cells. Gold nanoparticles of sizes below 4-5 nm fit in DNA grooves which can interfere with transcription, gene regulation, replication, and other processes that rely on DNA-protein binding. Lack of  biodegradability  for some nanoparticle chemistries can lead to accumulation in certain tissues, thus interfering with a wide range of biological processes. [ 57 ]  Currently, there is no regulatory framework in the United States for testing nanoparticles for their general impact on health and on the environment. [ 58 ]


Nasal sprays  are used to deliver medications  locally  in the  nasal cavities  or  systemically . They are used locally for conditions such as  nasal congestion  and  allergic rhinitis . In some situations, the  nasal delivery route  is preferred for systemic therapy because it provides an agreeable alternative to injection or pills. Substances can be assimilated extremely quickly and directly through the nose. [ 1 ] [ unreliable medical source? ]  Many pharmaceutical drugs exist as nasal sprays for systemic administration (e.g.  sedative -analgesics, treatments for  migraine ,  osteoporosis  and  nausea ). Other applications include  hormone replacement therapy , treatment of  Alzheimer's disease  and  Parkinson's disease . Nasal sprays are seen as a more efficient way of transporting drugs with potential use in crossing the blood–brain barrier.


Antihistamines  work by competing for receptor sites to block the function of histamine, thereby reducing the inflammatory effect. Antihistamine nasal sprays include:


Corticosteroid  nasal sprays can be used to relieve the symptoms of  sinusitis ,  hay fever , allergic rhinitis and non-allergic (perennial) rhinitis. They can reduce inflammation and histamine production in the nasal passages, and have been shown to relieve  nasal congestion ,  runny nose , itchy nose and  sneezing . [ 2 ]  Side effects may include  headaches ,  nausea  and  nose bleeds . [ citation needed ]  Corticosteroid nasal sprays include:


Saline  sprays are typically non medicated. A mist of  saline solution  containing  sodium chloride  is delivered to help moisturize dry or irritated nostrils. This is a form of  nasal irrigation . They can also relieve nasal congestion and remove airborne irritants such as pollen and dust thereby providing sinus allergy relief.


Three types of nasal sprays preparations of sodium chloride are available including hypertonic (3% sodium chloride or  sea water ), isotonic (0.9% sodium chloride) and hypotonic (0.65% sodium chloride). Isotonic solutions have the same salt concentration as the human body, whereas hypertonic solutions have a higher salt content and hypotonic solutions have a lower salt content. Isotonic saline nasal sprays are commonly used in infants and children to wash out the thick  mucus  from the nose in case of  allergic rhinitis . Hypertonic solutions may be more useful at drawing moisture from the  mucous membrane  and relieving nasal congestion.


Natural nasal sprays that include chemical complexes derived from plant sources such as  ginger ,  capsaicin  and  tea-tree oil  are also available. There is however no trial-verified evidence that they have a measurable effect on symptoms.


Decongestant  nasal sprays are available  over-the-counter  in many countries. They work to very quickly open up nasal passages by constricting blood vessels in the lining of the nose. Prolonged use of these types of sprays can damage the delicate mucous membranes in the nose. This causes increased inflammation, an effect known as  rhinitis medicamentosa  or the  rebound effect . Decongestant nasal sprays are advised for short-term use only, preferably 5 to 7 days at maximum. Some doctors advise to use them 3 days at maximum. A recent clinical trial has shown that a corticosteroid nasal spray may be useful in reversing this condition. [ 3 ]  Topical nasal decongestants include:


Combination use of two medications as nasal spray preparation has been frequently prescribed by doctors. [ medical citation needed ]


List of some combination nasal sprays:


In some countries, Dymista is marketed by  Viatris  after Upjohn merged with Mylan to create Viatris. [ 5 ] [ 6 ]


In 2022, the combination azelastine/fluticasone was the 299th most commonly prescribed medication in the United States, with more than 300,000 prescriptions. [ 7 ] [ 8 ]


A  nasal vaccine  is a  vaccine  administered through the nose that stimulates an immune response without an injection. It induces immunity through the  inner surface of the nose , a surface that naturally comes in contact with many  airborne microbes . [ 1 ]  Nasal vaccines are emerging as an alternative to injectable vaccines because they do not use needles and can be introduced through the mucosal route. Nasal vaccines can be delivered through nasal sprays to prevent respiratory infections, such as  influenza .


Nasal inoculation dates as far back as the 17th century in China during the  Kangxi Emperor ’s reign. Documentation during this period indicates that the Kangxi Emperor vaccinated his family, army, and others for mild smallpox. Manuals detailing vaccination techniques at the time all focused on sending smallpox up the nose of the individual being vaccinated. Although other vaccination techniques were developed using an infected individual’s scabs, a common method was to place a cotton swab with the fluid from an infected person’s pustule up the nose. [ 2 ]


Following smallpox, influenza became a prominent focus for nasal vaccine development. The first  live attenuated influenza vaccine (LAIV)  in the form of a nasal spray was created in Russia by the  Institute of Experimental Medicine  in 1987. This nasal vaccine development was based on the Russian backbone of LAIV while nasal vaccines since then have been based on other LAIV backbones. [ 3 ]  The first nasal influenza vaccine was released in the United States in 2001 but was taken off the market due to toxicity concerns.  FluMist , one of the most prominent nasal LAIVs, was released in 2003 as nasal LAIVs continued developing. [ 4 ]


Anthrax  attacks at the beginning of the 21st century caused a demand for nasal vaccine development. As anthrax is an airborne substance that can be inhaled, a nasal vaccine has the potential to be used to protect individuals from the effects it can have on the respiratory system. [ 5 ]  Following the  September 11, 2001 terrorist attacks  in the United States, several individuals at news stations and U.S. senators died after being sent letters with anthrax as an act of bioterrorism. [ 6 ]  Nasal vaccine research and development against anthrax was encouraged by the U.S. government in an effort to vaccinate troops. [ 5 ] [ 7 ]   BioThrax , the current anthrax vaccine that is licensed and administered in the United States, requires up to five intramuscular injections and annual boosters; research within the past decade has developed an alternative nasal vaccine that follows the path of infection for anthrax and induces both humoral and cellular immune responses. [ 5 ]


The  global COVID-19 pandemic  led to a rise in nasal vaccines against coronavirus. International efforts for vaccine development occurred as countries such as  India ,  Iran ,  Russia , and  China  created nasal COVID-19 vaccines. [ citation needed ]


Nasal vaccines are a subsection of mucosal immunization as they use a mucosal route for vaccine delivery. As many pathogens can enter the body through the nose, nasal vaccines take advantage of this mechanism to deliver the vaccine. The nose has multiple lines of defense to prevent pathogens from entering further into the body. Nasal hairs are the first defense as they are at the entrance of the nose and prevent large particles from entering. The mucus layer in the nasal cavity can trap smaller particles that get past the nose hairs. [ 8 ]  The nasal cavity has a large vascularization network so particles can go through the epithelial layer and directly enter the bloodstream. [ 9 ]  Intruding particles will interact with the mucosal immune system if they reach the nasal mucosa. The mucosal immune system is composed of lymphoid tissue, B cells, T cells, and antigen-presenting cells. These different types of cells work together to identify intruding particles and trigger an immune response. [ 8 ]  Nasal vaccines must overcome these barriers and get clearance to deliver the viral antigen to patients. [ 4 ]  Nasal vaccines must overcome these barriers and get clearance to deliver the viral antigen to patients. [ 10 ]


Nasal vaccines can come in different forms such as solutions (liquids), powders, gels, and solid inserts. The most prevalent type of nasal vaccine in research and clinical application is solutions due to its ease of use. Although solutions are usually pipetted into test subjects’ nostrils when conducting animal trials for nasal vaccines, nasal sprays are considered the most practical approach for mass human vaccination using nasal vaccines. [ 8 ]  A nasal spray is able to bypass the initial layers of the nasal mucosa and deliver the vaccine particles directly to the mucoadhesive layer. [ 11 ]  The antigen in the nasal vaccine can then trigger an immune response and prevent infection due to nasal vaccines’ accessibility to the immune system. [ 12 ] [ 13 ]


Nasal sprays are commonly used for delivering drugs in addition to vaccines. Decongestant drugs are often directly delivered to the nose through nasal sprays. Cold and allergy medication can be administered using nasal sprays for local delivery by bypassing nasal hairs and being introduced to the nasal cavity. Intranasal administration can have less drug degradation compared to oral administration because of direct particle delivery. Peptide drugs used for hormone treatments can be delivered nasally through nasal sprays instead of orally to retain particle integrity. Nasal sprays can also be used to deliver diabetes treatment, steroids, and intranasal oxytocin to induce labor. Nasal administration is also used to deliver anesthetics and sedatives due to direct access to the mucosal immune system and bloodstream. [ 14 ]


The  olfactory epithelium  makes up approximately 7% of the surface area of the nasal cavity and is connected to the olfactory bulb in the brain. Drugs and vaccines can be delivered to the brain past the  blood-brain barrier  through olfactory nerve cells. [ 14 ]


Compared to injectable vaccines, nasal vaccines can be advantageous because they are safe, painless, and easy to use. Nasal vaccines do not require a needle, which eliminates pain from needlestick injuries and safety concerns due to cross-contamination and needle disposal. Some studies also show that intranasal vaccines can generate cross-reactive antibodies that could lead to cross-protection. [ 8 ]


The live attenuated influenza vaccine (LAIV) in the form of a nasal spray was one of the first nasal vaccines released on the market. Nasal spray LAIVs have been used since the late 1980s as an alternative to the injectable influenza vaccine. [ 3 ]  Nasal influenza vaccines have become popular as they reduce the risk of intramuscular injuries from administration and are painless. They can also be given more easily to patients because they do not require a needle.


The most prominent nasal LAIV is FluMist, which was released in 2003. [ 4 ]  FluMist, officially known as FluMist Quadrivalent in the United States and Fluenz in Europe, is known to be the only flu vaccine on the market that does not use a needle. [ 15 ]  All nasal LAIVs for recent flu seasons (2022-2023) are considered quadrivalents because “they are designed to protect against four types of flu viruses: an influenza A(H1N1) virus, an influenza A(H3N2) virus and two influenza B viruses.” [ 16 ]  Although injectable and nasal LAIVs are presented as options for yearly vaccination against influenza, FluMist was pulled off of the United States market from 2016 to 2018 due to its inefficiency against a common influenza strain in children. Since then, FluMist has been reformulated and has re-entered the market. [ 17 ]


The active ingredients in nasal LAIVs are grown in fertilized chicken eggs. The practice of growing viruses in chicken eggs is common in vaccine production because these viruses need to be grown inside cells. [ 18 ]  Virus fluid from the incubated chicken eggs is extracted and killed for the viral antigen to be purified for LAIV production. [ 19 ]  Similar to other vaccines, nasal LAIVs contain ingredients in addition to the viral antigen. Stabilizers such as gelatine, arginine hydrochloride, monosodium glutamate, and sucrose are commonly used in vaccines to assure the vaccines are still effective during and after production, transportation, and storage as well as delivery. [ 20 ] [ 21 ]  Stabilizers are especially important for nasal vaccines as proteases and amino-peptidase in the mucosal membrane can degrade proteins and peptides in vaccines. [ 4 ]  Research continues to improve nasal LAIVs as influenza affects nearly 9 million people. [ 22 ]  As influenza changes slightly each year, continuous research on new strains can improve vaccine efficiency. Research on nasal vaccine development for nontypeable  Haemophilus influenzae  shows that the vaccine binding to surface proteins prevented biofilm formation. As a result, this vaccine can have the potential to treat ear infections caused by biofilm from influenza infection. [ 23 ]  New components like α-galactosylceramide (α-GalCer) are also being researched to be used as nasal vaccines against influenza. Since α-GalCer induced immune responses when immunized with a replication-deficient live adenovirus, there is evidence that nasal LAIVs can be co-immunized with other treatments against influenza. [ 24 ]


Prior to the 2020 global COVID-19 pandemic, animal studies in 2004 on African green monkeys tested a SARS-associated coronavirus (SARS-CoV) vaccine and showed that these monkeys did not emit the virus from their upper respiratory tract after being infected. [ 25 ]  Since then, several intranasal COVID-19 vaccines have been developed with the onset of the COVID-19 pandemic.  inCOVACC ,  Razi Cov Pars ,  Sputnik , and  Convidicia  are nasal COVID-19 vaccines that were developed throughout the world to improve vaccine availability and reduce the spread of COVID-19.  [ citation needed ]


In August 2020, during the  COVID-19 pandemic , studies in mice and monkeys demonstrated that protection from the  new coronavirus  might be obtained through the nasal route. Another study postulated that if a  COVID-19 vaccine  could be given by a spray in the nose, people might be able to vaccinate themselves. [ 26 ]  Research about the main characteristics of nasal spray vaccines that can affect the efficiency of vaccine delivery for COVID-19 indicates that the spray cone angle can impact the delivery efficiency; droplet initial velocity and composition did not have as much of an impact on nasal vaccine efficiency as the spray cone angle. [ 27 ]


India and China approved  inCOVACC  and  Convidecia , respectively, to be used as boosters for those who have already received at least two COVID-19 vaccine doses. [ 28 ]  Although nasal COVID-19 vaccine research continues in the United States, lack of government funding could prevent this research from moving on to human trials to get approval for public administration. [ 29 ]  Privately funded research for nasal COVID-19 vaccines is starting to reach clinical trials; a nasal COVID-19 vaccine by Blue Lake Biotechnology has started its Phase 1 clinical trials as of late February 2023. Scientists speculate that nasal vaccines might have an advantage over other types of vaccines because they provide immune defense at the site of administration. [ 30 ]


Species other than humans use nasal vaccines to prevent diseases. Intranasal vaccines are used on dogs for  Bordetella bronchiseptica  to prevent  infectious tracheobronchitis  (ITB). ITB, commonly known as kennel cough, typically spreads in highly populated environments such as kennels and dog shelters. Consistent vaccination against ITB using an intranasal vaccine can create an immune response to protect the vaccinated dog. Consistent vaccination against ITB using an intranasal vaccine can create an immune response to protect the vaccinated dog. [ 31 ]


Cattle receive nasal vaccines against diseases such as  bovine herpesvirus 1 , parainfluenza type 3, and bovine rhinotracheitis virus. [ 32 ] [ 33 ]  As all three of these viruses are related to respiratory infection, using an intranasal route can bring the vaccine directly to the respiratory system.


Recent discoveries indicate that rainbow trout have a previously unknown lymphoid structure in their nasal cavity. This structure allows them to have fast innate and adaptive responses to nasal vaccines. [ 34 ]


Current research is exploring new technologies and developments to improve nasal vaccine delivery methods. Particle size and characteristics have become a focus of research as smaller particles can travel more easily to reach the epithelial layer of the nasal cavity compared to larger particles.  Nanoparticles  and nanosystems are being researched to optimize nasal delivery. Coated nanoparticles are an area of focus due to their properties to induce immune effects. Glycol chitosan-coated nanoparticles induced more of an immune response compared to the other types of nanoparticles. [ 35 ]  Nanocarriers designed based on the characteristics of the nasal epithelium can be used to deliver nasal vaccines and can therefore make nasal vaccination more accessible. [ 36 ]  Polymeric nanosystems are also being developed to deliver vaccines to target sites while preventing them from degrading; current research is focused on understanding the material and physical properties of biodegradable materials to be used in nanosystems to improve vaccine efficacy. [ 37 ]  Research on the movement of nasal vaccine particles is focused on developing more effective ways for these vaccines to enter the body. An animal study on mice tested how a nasal vaccine can bypass issues with entry into the nasal epithelium by taking advantage of ciliary movement. The results indicated that tubulin tyrosine ligase-like family member 1 (Ttll1) knockout mice had higher levels of the vaccine antigen compared to the hetero mice. [ 38 ]


In  medicine , a  nebulizer  ( American English ) [ 1 ]  or  nebuliser  ( British English ) [ 2 ]  is a  drug delivery device  used to administer medication in the form of a mist inhaled into the lungs. Nebulizers are commonly used for the treatment of  asthma ,  cystic fibrosis ,  COPD  and other  respiratory diseases  or disorders. They use  oxygen ,  compressed air  or  ultrasonic  power to break up solutions and suspensions into small  aerosol  droplets that are inhaled from the mouthpiece of the device. An aerosol is a mixture of gas and solid or liquid particles.


Various asthma guidelines, such as the Global Initiative for Asthma Guidelines [GINA], the British Guidelines on the management of Asthma, The Canadian Pediatric Asthma Consensus Guidelines, and United States Guidelines for Diagnosis and Treatment of Asthma each recommend  metered dose inhalers  in place of nebulizer-delivered therapies. [ 3 ]
The European Respiratory Society acknowledge that although nebulizers are used in hospitals and at home they suggest much of this use may not be evidence-based. [ 4 ]


Recent evidence shows that nebulizers are no more effective than  metered-dose inhalers  (MDIs) with spacers. [ 5 ]   An MDI with a spacer may offer advantages to children who have acute asthma. [ 3 ] [ 6 ] [ 5 ]  Those findings refer specifically to the treatment of asthma and not to the efficacy of nebulisers generally, as for COPD for example. [ 5 ]  For COPD, especially when assessing exacerbations or lung attacks, there is no evidence to indicate that MDI (with a spacer) delivered medicine is more effective than administration of the same medicine with a nebulizer. [ 7 ]


The  European Respiratory Society  highlighted a risk relating to droplet size reproducibility caused by selling nebulizer devices separately from nebulized solution. They found this practice could vary droplet size 10-fold or more by changing from an inefficient nebulizer system to a highly efficient one. [ 4 ] [ 5 ]
Two advantages attributed to nebulizers, compared to MDIs with spacers (inhalers), are their ability to deliver larger dosages at a faster rate, especially in acute asthma; however, recent data suggests actual lung deposition rates are the same. In addition, another trial found that a MDI (with spacer) had a lower required dose for clinical result compared to a nebulizer. [ 3 ]


Beyond use in chronic lung disease, nebulizers may also be used to treat acute issues like the inhalation of toxic substances. One such example is the treatment of inhalation of toxic  hydrofluoric acid  (HF) vapors. [ 8 ]   Calcium gluconate  is a first-line treatment for HF exposure to the skin. By using a nebulizer, calcium gluconate is delivered to the lungs as an aerosol to counteract the toxicity of inhaled HF vapors.


The lung deposition characteristics and efficacy of an aerosol depend largely on the particle or droplet size. Generally, the smaller the particle the greater its chance of peripheral penetration and retention. However, for very fine particles below 0.5 μm in diameter there is a chance of avoiding deposition altogether and being exhaled. In 1966 the Task Group on Lung Dynamics, concerned mainly with the hazards of inhalation of environmental toxins, proposed a model for deposition of particles in the lung. This suggested that particles of more than 10 μm in diameter are most likely to deposit in the mouth and throat, for those of 5–10 μm diameter a transition from mouth to airway deposition occurs, and particles smaller than 5 μm in diameter deposit more frequently in the lower airways and are appropriate for pharmaceutical aerosols. [ 9 ]
Nebulizing processes have been modeled using  computational fluid dynamics . [ 10 ]


The most commonly used nebulizers are jet nebulizers, which are also called "atomizers". [ 11 ]  Jet nebulizers are connected by tubing to a supply of compressed gas, usually  compressed air  or  oxygen  to flow at high velocity through a liquid medicine to turn it into an  aerosol  that is inhaled by the patient. Currently there seems to be a tendency among physicians to prefer prescription of a  pressurized Metered Dose Inhaler  (pMDI) for their patients, instead of a jet nebulizer that generates a lot more noise (often 60 dB during use) and is less portable due to a greater weight. However, jet nebulizers are commonly used in hospitals for patients who have difficulty using inhalers, such as in serious cases of respiratory disease, or severe asthma attacks. [ 12 ]  The main advantage of the jet nebulizer is related to its low operational cost. If the patient needs to inhale medicine on a daily basis the use of a pMDI can be rather expensive. Today several manufacturers have also managed to lower the weight of the jet nebulizer to just over half a kilogram (just under one and a half pounds), and therefore started to label it as a portable device. Compared to all the competing inhalers and nebulizers, the noise and heavy weight is still the biggest draw back of the jet nebulizer. [ 13 ]


The medical company  Boehringer Ingelheim  also invented a device named  Respimat  Soft Mist Inhaler in 1997. This new technology provides a metered dose to the user, as the liquid bottom of the inhaler is rotated clockwise 180 degrees by hand, adding a buildup tension into a spring around the flexible liquid container. When the user activates the bottom of the inhaler, the energy from the spring is released and imposes pressure on the flexible liquid container, causing liquid to spray out of 2 nozzles, thus forming a soft mist to be inhaled. The device features no gas propellant and no need for battery/power to operate. The average droplet size in the mist was measured to 5.8 micrometers, which could indicate some potential efficiency problems for the inhaled medicine to reach the lungs. Subsequent trials have proven this was not the case. Due to the very low velocity of the mist, the Soft Mist Inhaler in fact has a higher efficiency compared to a conventional pMDI. [ 14 ]  In 2000, arguments were launched towards the European Respiratory Society (ERS) to clarify/expand their definition of a nebulizer, as the new Soft Mist Inhaler in technical terms both could be classified as a "hand driven nebulizer" and a "hand driven pMDI". [ 15 ]


Ultrasonic wave nebulizers were invented in 1965 [ 16 ]  as a new type of portable nebulizer. The technology inside an ultrasonic wave nebulizer is to have an  electronic oscillator  generate a high frequency  ultrasonic wave , which causes the mechanical vibration of a  piezoelectric  element. This vibrating element is in contact with a liquid reservoir and its high frequency vibration is sufficient to produce a vapor mist [ 17 ]  via  ultrasonic atomization . As they create aerosols from ultrasonic vibration instead of using a heavy air compressor, they only have a weight around 170 grams (6.0 oz). Another advantage is that the ultrasonic vibration is almost silent. Examples of these more modern type of nebulizers are:  Omron  NE-U17 and Beurer Nebulizer IH30. [ 18 ]


A new significant innovation was made in the nebulizer market around 2005, with creation of the ultrasonic Vibrating Mesh Technology (VMT). With this technology a mesh/membrane with 1000–7000 laser drilled holes vibrates at the top of the liquid reservoir, and thereby pressures out a mist of very fine droplets through the holes. This technology is more efficient than having a vibrating piezoelectric element at the bottom of the liquid reservoir, and thereby shorter treatment times are also achieved. The old problems found with the ultrasonic wave nebulizer, having too much liquid waste and undesired heating of the medical liquid, have also been solved by the new vibrating mesh nebulizers. Available VMT nebulizers include: Pari eFlow, [ 19 ]   Respironics  i-Neb, [ 20 ]  Beurer Nebulizer IH50, [ 21 ]  and Aerogen Aeroneb. [ 22 ]  As the price of the ultrasonic VMT nebulizers is higher than models using previous technologies, most manufacturers continue to also sell the classic jet nebulizers. [ 23 ]


Nebulizers accept their medicine in the form of a liquid solution, which is often loaded into the device upon use.  Corticosteroids  and  bronchodilators  such as  salbutamol  ( albuterol   USAN ) are often used, and sometimes in combination with  ipratropium . The reason these pharmaceuticals are inhaled instead of ingested is in order to target their effect to the  respiratory tract , which speeds onset of action of the medicine and reduces side effects, compared to other alternative intake routes. [ 12 ]


Usually, the aerosolized medicine is inhaled through a tube-like mouthpiece, similar to that of an  inhaler . The mouthpiece, however, is sometimes replaced with a face mask, similar to that used for inhaled  anesthesia , for ease of use with young children or the elderly. Pediatric masks are often shaped like animals such as fish, dogs or dragons to make children less resistant to nebulizer treatments. Many nebulizer manufacturers also offer pacifier attachments for infants and toddlers. But mouthpieces are preferable if patients are able to use them since face-masks result in reduced lung delivery because of aerosol losses in the nose. [ 11 ]


After use with corticosteroid, it is theoretically possible for patients to develop a  yeast infection  in the mouth ( thrush ) or hoarseness of voice ( dysphonia ), although these conditions are clinically very rare. To avoid these adverse effects, some clinicians suggest that the person who used the nebulizer should rinse his or her mouth. This is not true for bronchodilators; however, patients may still wish to rinse their mouths due to the unpleasant taste of some bronchodilating drugs.


The first "powered" or pressurized inhaler was invented in France by Sales-Girons in 1858. [ 24 ]  This device used pressure to atomize the liquid medication. The pump handle is operated like a bicycle pump. When the pump is pulled up, it draws liquid from the reservoir, and upon the force of the user's hand, the liquid is pressurized through an atomizer, to be sprayed out for inhalation near the user's mouth. [ 25 ]


In 1864, the first steam-driven nebulizer was invented in Germany. This inhaler, known as "Siegle's steam spray inhaler", used the  Venturi principle  to atomize liquid medication, and this was the very beginning of nebulizer therapy. The importance of droplet size was not yet understood, so the efficacy of this first device was unfortunately mediocre for many of the medical compounds. The Siegle steam spray inhaler consisted of a spirit burner, which boiled water in the reservoir into steam that could then flow across the top and into a tube suspended in the pharmaceutical solution. The passage of steam drew the medicine into the vapor, and the patient inhaled this vapor through a mouthpiece made of glass. [ 26 ]


The first pneumatic nebulizer fed from an electrically driven gas (air) compressor was invented in the 1930s and called a Pneumostat. With this device, a medical liquid (typically  epinephrine chloride , used as a bronchial muscle relaxant to reverse constriction). [ 28 ]  As an alternative to the expensive electrical nebulizer, many people in the 1930s continued to use the much more simple and cheap hand-driven nebulizer, known as the Parke-Davis Glaseptic. [ 29 ]


In 1956, a technology competing against the nebulizer was launched by Riker Laboratories ( 3M ), in the form of pressurized  metered-dose inhalers , with Medihaler-iso ( isoprenaline ) and Medihaler-epi ( epinephrine ) as the two first products. [ 30 ]  In these devices, the drug is cold-fill and delivered in exact doses through some special metering valves, driven by a gas propellant technology (i.e.  Freon  or a less environmentally damaging HFA). [ 24 ]


In 1964, a new type of electronic nebulizer was introduced: the "ultrasonic wave nebulizer". [ 31 ]  Today the nebulizing technology is not only used for medical purposes. Ultrasonic wave nebulizers are also used in  humidifiers , to spray out water aerosols to moisten dry air in buildings. [ 17 ]


Some of the first models of  electronic cigarettes  featured an ultrasonic wave nebulizer (having a  piezoelectric  element vibrating and creating high-frequency  ultrasound  waves, to cause vibration and atomization of liquid  nicotine ) in combination with a  vapouriser  (built as a  spray nozzle  with an electric  heating element ). [ 32 ]  The most common type of electronic cigarettes currently sold, however, omit the ultrasonic wave nebulizer, as it was not found to be efficient enough for this kind of device. Instead, the electronic cigarettes now use an electric vaporizer, either in direct contact with the absorbent material in the "impregnated atomizer," or in combination with the nebulization technology related to a "spraying jet atomizer" (in the form of liquid droplets being out-sprayed by a high-speed air stream, that passes through some small venturi injection channels, drilled in a material absorbed with nicotine liquid). [ 33 ]


An  Ommaya reservoir  is an intraventricular  catheter  system that can be used for the aspiration of  cerebrospinal fluid  or for the delivery of drugs (e.g.  chemotherapy ) into the  cerebrospinal fluid . It consists of a  catheter  in one  lateral ventricle  attached to a reservoir implanted under the scalp. It is used to treat brain tumors, leukemia/lymphoma or  leptomeningeal  disease by  intrathecal  drug administration.   In the  palliative care  of terminal cancer, an Ommaya reservoir can be inserted for  intracerebroventricular injection  (ICV) of morphine. [ 1 ]


It was originally invented in 1963 by  Ayub K. Ommaya , a Pakistani-American  neurosurgeon .


In January 2017, researchers at University of Texas Southwestern Medical Centre used an Ommaya reservoir to measure the  intracranial pressure  that is regularly observed in astronauts in  zero-gravity  conditions. [ 2 ] [ 3 ] [ 4 ]


An  orally disintegrating tablet  or  orally dissolving tablet  ( ODT ) is a drug  dosage form  available for a limited range of  over-the-counter  (OTC) and  prescription  medications. ODTs differ from traditional  tablets  in that they are designed to be dissolved on the tongue rather than swallowed whole. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ]  The ODT serves as an alternative dosage form for patients who experience  dysphagia  (difficulty in swallowing) or for where compliance is a known issue and therefore an easier dosage form to take ensures that medication is taken. Common among all age groups, dysphagia is observed in about 35% of the general population, as well as up to 60% of the elderly institutionalized population  [ 12 ] [ 13 ]  and 18-22% of all patients in long-term care facilities
 [ 14 ]  ODTs may have a faster onset of effect than tablets or capsules, and have the convenience of a tablet that can be taken without water. During the last decade, ODTs have become available in a variety of therapeutic markets, both OTC and by prescription.


Tablets designed to dissolve on the buccal (cheek)  mucous membrane  were a precursor to the ODT. This dosage form was intended for drugs that yield low  bioavailability  through the digestive tract but are inconvenient to administer parenterally, such as steroids and narcotic analgesics. [ 15 ]  Absorption through the cheek allows the drug to bypass the digestive tract for rapid systemic distribution. Not all ODTs have buccal absorption and many have similar absorption and bioavailability to standard oral dosage forms with the primary route remaining GI absorption. However, a fast disintegration time and a small tablet weight can enhance absorption in the buccal area. The first ODTs disintegrated through  effervescence  rather than dissolution, and were designed to make taking vitamins more pleasant for children. [ 16 ]  This method was adapted to pharmaceutical use with the invention of microparticles containing a drug, which would be released upon effervescence of the tablet and swallowed by the patient. [ 17 ]  Dissolution became more effective than effervescence through improved manufacturing processes and ingredients (such as the addition of  mannitol  to increase binding and decrease dissolution time). [ 18 ]   Catalent Pharma Solutions  (formerly Scherer DDS) in the U.K., Cima Labs and Fuisz Technologies (whose founder  Richard Fuisz  went on to pioneer orally soluble films, a separate but related dosage form) in the U.S. and  Takeda Pharmaceutical Company  in Japan led the development of ODTs.


The first ODT form of a drug to get approval from the  U.S. Food and Drug Administration  (FDA) was a  Zydis  ODT formation of Claritin ( loratadine ) in December 1996. [ 19 ]  It was followed by a Zydis ODT formulation of Klonopin ( clonazepam ) in December 1997, [ 20 ]  and a Zydis ODT formulation of Maxalt ( rizatriptan ) in June 1998. [ 21 ]  The regulatory condition for meeting the definition of an orally disintegrating tablet is  USP  method 701 for Disintegration. FDA guidance issued in Dec 2008 is that ODT drugs should disintegrate in less than 30 seconds. [ 22 ]  This practice is under review by the FDA as the fast disintegration time of ODTs makes the disintegration test too rigorous for some of the ODT formulations that are commercially available.


The processes used to manufacture orally disintegrating tablets include loose compression tabletting, a process which is not very different than the manufacturing method used for traditional tablets and  lyophilization  processes. In loose compression, ODTs are compressed at much lower forces (4 – 20  kN ) than traditional tablets.  However, since ODTs are compressed at very low forces due to the need for them to be soft enough to disintegrate rapidly in the mouth, issues of material sticking to the  die  walls can be challenging.  Typically, as in most tablet blends, lubricants such as  magnesium stearate  are added to the blend to reduce the amount of material that may stick to the die wall.  Differences may be the use of disintegrating aids, such as  crospovidone , and binding agents that aid in  mouth feel , such as microcrystalline  cellulose .  Primarily, ODTs contain some form of sugar such as  mannitol , which typically serves as the major  diluent  of the ODTs, and is also the primary contributor to the smooth and creamy mouth feel of most ODTs. Lyophilized ODT  formulations may use proprietary technologies but can produce a tablet that has a faster disintegration rate, for example the  Zydis  ODT typically dissolves in the mouth in less than 5 seconds without water and Lyophilized Freeze drying tablets - ODT typically dissolves in the mouth in few seconds depending on the molecules and strength.


ODTs are available in HPDE bottles (Parcopa) or individually sealed in  blister packs  to protect the tablets from damage, moisture, and oxidation.  Because ODTs are soft in nature, the ability to successfully package an ODT in a bottle is difficult. However, CIMA Labs markets their Durasolv ODT as being able to be placed into bottle for commercial sale, while CIMA's Orasolv is marketed for blisters only.   Zydis  ODT tablets manufactured by  Catalent Pharma Solutions  and Lyophilized Freeze drying tablets manufactured by Galien-LPS are delivered in a  blister pack . The differences between the two CIMA products are proprietary, however, the primary difference is expected to be the use of microcrystalline cellulose (MCC), such as Avicel PH101, in the Durasolv product.  MCC serves multiple purposes in an ODT but in the case of CIMA's products, it acts as a binder, increasing the internal strength of the tablet and making it more robust for packaging in bottles.


(Naloxone is included because it deters abuse. Naloxone is poorly absorbed into the body when used by mouth or as an ODT. However, when the pill is crushed and/or filtered and  injected intravenously , naloxone blocks the effects of buprenorphine.)


Ved Parkash et al. note the following advantages of ODTs:


Ved Parkash et al. lists the following disadvantages of ODTs:


An  oxygen concentrator  is a device that concentrates the  oxygen  from a gas supply (typically ambient air) by selectively removing nitrogen to supply an oxygen-enriched product gas stream. They are used industrially, to provide  supplemental oxygen  at high altitudes, and as  medical devices  for  oxygen therapy . [ 1 ]


Oxygen concentrators are used widely for oxygen provision in healthcare applications, especially where liquid or pressurized oxygen is too dangerous or inconvenient, such as in homes or portable clinics, and can also provide an economical source of oxygen in industrial processes, where they are also known as oxygen gas generators or  oxygen generation plants . Two methods in common use are  pressure swing adsorption  and  membrane gas separation .


Pressure swing adsorption (PSA) oxygen concentrators use a  molecular sieve  to adsorb gases and operate on the principle of  rapid pressure swing adsorption  of atmospheric  nitrogen  onto  zeolite  minerals at high pressure.  This type of adsorption system is therefore functionally a nitrogen scrubber, allowing the other atmospheric gases to pass through, leaving oxygen as the primary gas remaining. PSA technology is a reliable and economical technique for small to mid-scale oxygen generation.  Cryogenic separation is more suitable at higher volumes. [ 2 ]


Gas separation across a membrane is a pressure-driven process, where the driving force is the difference in pressure between inlet of raw material and outlet of product. The membrane used in the process is a generally non-porous layer, so there will not be a severe leakage of gas through the membrane. The performance of the membrane depends on permeability and selectivity. Permeability is affected by the penetrant size. Larger gas molecules have a lower diffusion coefficient. The membrane gas separation equipment typically pumps gas into the membrane module and the targeted gases are separated based on difference in diffusivity and solubility. For example, oxygen will be separated from the ambient air and collected at the upstream side, and nitrogen at the downstream side. As of 2016, membrane technology was reported as capable of producing 10 to 25 tonnes of 25 to 40% oxygen per day. [ 3 ]


Home medical oxygen concentrators were invented in the early 1970s, with the manufacturing output of these devices increasing in the late 1970s.  Union Carbide  Corporation and  Bendix Corporation  were both early manufacturers. Before that era, home medical oxygen therapy required the use of heavy high-pressure oxygen cylinders or small cryogenic liquid oxygen systems. Both of these delivery systems required frequent home visits by suppliers to replenish oxygen supplies. In the United States, Medicare switched from fee-for-service payment to a flat monthly rate for home oxygen therapy in the mid-1980s, causing the durable medical equipment (DME) industry to rapidly embrace concentrators as a way to control costs. This reimbursement change dramatically decreased the number of primary high pressure and liquid oxygen delivery systems in use in homes in the United States at that time. Oxygen concentrators became the preferred and most common means of delivering home oxygen. The number of manufacturers entering the oxygen concentrator market increased greatly as a result of this change.  Union Carbide  Corporation invented the  molecular sieve  in the 1950s, which made these devices possible.  It also invented the first cryogenic liquid home medical oxygen systems in the 1960s.


Oxygen concentrators using  pressure swing adsorption  (PSA) technology are used widely for oxygen provision in healthcare applications, especially where liquid or pressurized oxygen is too dangerous or inconvenient, such as in homes or portable clinics. For other purposes, there are also concentrators based on  nitrogen separation membrane  technology.


An oxygen concentrator takes in air and removes nitrogen from it, leaving an oxygen-enriched gas for use by people requiring medical oxygen due to low oxygen levels in their blood. [ 4 ]  Oxygen concentrators provide an economical source of oxygen in industrial processes, where they are also known as oxygen gas generators or  oxygen generation plants .


These oxygen concentrators utilize a  molecular sieve  to adsorb gases and operate on the principle of  rapid pressure swing adsorption  of atmospheric  nitrogen  onto  zeolite  minerals at high pressure.  This type of adsorption system is therefore functionally a nitrogen scrubber, allowing the other atmospheric gases to pass through, leaving oxygen as the primary gas remaining. PSA technology is a reliable and economical technique for small- to mid-scale oxygen generation.  Cryogenic separation is more suitable at higher volumes, and external delivery generally more suitable for small volumes. [ 5 ]


At high pressure, the porous zeolite  adsorbs  large quantities of nitrogen because of its large surface area and chemical characteristics. The oxygen concentrator compresses air and passes it over zeolite, causing the zeolite to adsorb the nitrogen from the air.  It then collects the remaining gas, which is mostly oxygen, and the nitrogen desorbs from the zeolite under the reduced pressure to be vented.


An oxygen concentrator has an air compressor, two cylinders filled with zeolite pellets, a pressure-equalizing reservoir, and some valves and tubes. In the first half-cycle, the first cylinder receives air from the compressor, which lasts about 3 seconds. During that time, the pressure in the first cylinder rises from atmospheric to about 2.5 times normal atmospheric pressure (typically 20 psi/138 kPa gauge, or 2.36 atmospheres absolute) and the zeolite becomes saturated with nitrogen. As the first cylinder reaches near pure oxygen (there are small amounts of argon, CO 2 , water vapour,  radon , and other minor atmospheric components) in the first half-cycle, a valve opens and the oxygen-enriched gas flows to the pressure-equalizing reservoir, which connects to the patient's oxygen hose. At the end of the first half of the cycle, there is another valve position change so that the air from the compressor is directed to the second cylinder. The pressure in the first cylinder drops as the enriched oxygen moves into the reservoir, allowing the nitrogen to be desorbed back into gas. Partway through the second half of the cycle, there is another valve position change to vent the gas in the first cylinder back into the ambient atmosphere, keeping the concentration of oxygen in the pressure-equalizing reservoir from falling below about 90%. The pressure in the hose delivering oxygen from the equalizing reservoir is kept steady by a pressure-reducing valve.


Older units cycled for a period of about 20 seconds and supplied up to 5 litres per minute of 90+% oxygen. Since about 1999, units capable of supplying up to 10 L/min have been available.


Classic oxygen concentrators use two-bed molecular sieves; newer concentrators use multi-bed molecular sieves. The advantage of the multi-bed technology is the increased availability and redundancy, as the 10 L/min molecular sieves are staggered and multiplied on several platforms. With this, over 960 L/min can be produced. The ramp-up time — the elapsed time until a multi-bed concentrator is producing oxygen at >90% concentration — is often less than 2 minutes, much faster than simple two-bed concentrators. This is a big advantage in mobile emergencies. The option to fill standard oxygen cylinders (e.g., 50 L at 200 bar = 10,000 L each) with high-pressure boosters, to ensure automatic failover to previously filled reserve cylinders and to ensure the oxygen supply chain, e.g., in case of power failure, is given with those systems.


In  membrane gas separation , membranes act as a permeable barrier, which different compounds move across at different rates or do not cross at all.


Gas mixtures can be effectively separated by  synthetic membranes  made from polymers such as  polyamide  or  cellulose acetate , or from ceramic materials. [ 6 ]


While polymeric membranes are economical and technologically useful, they are bound by their performance, known as the Robeson limit (permeability must be sacrificed for selectivity and vice versa). [ 7 ]  This limit affects polymeric membrane use for CO 2  separation from flue gas streams, since mass transport becomes limiting and CO 2  separation becomes very expensive due to low permeabilities. Membrane materials have expanded into the realm of  silica ,  zeolites ,  metal-organic frameworks , and  perovskites , due to their strong thermal and chemical resistance as well as high tunability (ability to be modified and functionalized), leading to increased permeability and selectivity.  Membranes  can be used for separating gas mixtures, where they act as a permeable barrier through which different compounds move across at different rates or don't move at all. The membranes can be nanoporous, polymer, etc., and the gas molecules penetrate according to their size,  diffusivity , or solubility.


Gas separation across a membrane is a pressure-driven process, where the driving force is the difference in pressure between inlet of raw material and outlet of product. The membrane used in the process is a generally non-porous layer, so there will not be a severe leakage of gas through the membrane. The performance of the membrane depends on permeability and selectivity. Permeability is affected by the penetrant size. Larger gas molecules have a lower diffusion coefficient. The polymer chain flexibility and free volume in the polymer of the membrane material influence the diffusion coefficient, as the space within the permeable membrane must be large enough for the gas molecules to diffuse across. The solubility is expressed as the ratio of the concentration of the gas in the polymer to the pressure of the gas in contact with it. Permeability is the ability of the membrane to allow the permeating gas to diffuse through the material of the membrane as a consequence of the pressure difference over the membrane, and can be measured in terms of the permeate flow rate, membrane thickness and area, and the pressure difference across the membrane. The selectivity of a membrane is a measure of the ratio of permeability of the relevant gases for the membrane. It can be calculated as the ratio of permeability of two gases in binary separation. [ 3 ]


The membrane gas separation equipment typically pumps gas into the membrane module, and the targeted gases are separated based on difference in diffusivity and solubility. For example, oxygen will be separated from the ambient air and collected at the upstream side and nitrogen at the downstream side. As of 2016, membrane technology was reported as capable of producing 10 to 25 tonnes of 25 to 40% oxygen per day. [ 3 ]


Medical oxygen concentrators are used in hospitals or at home to concentrate oxygen for patients. [ 8 ]  PSA generators provide a cost-efficient source of  oxygen . They are a safer, [ 9 ]  less expensive, [ 10 ]  and more convenient  alternative to tanks of cryogenic oxygen or pressurised cylinders. They can be used in various industries, including medical, pharmaceutical production, water treatment, and glass manufacture.


PSA generators are particularly useful in remote or inaccessible parts of the world or mobile  medical facilities  ( military hospitals , disaster facilities). [ 11 ] [ 12 ]


Since the early 2000s, many companies have produced portable oxygen concentrators. [ 13 ]  Typically, these devices produce the equivalent of one to five liters per minute of continuous oxygen flow and they use some version of pulse flow or "demand flow" to deliver oxygen only when the patient is inhaling. [ 14 ]  They can also provide pulses of oxygen either to provide higher intermittent flows or to reduce power consumption.


Research into oxygen concentration is ongoing, and modern techniques suggest that the amount of adsorbent required by medical oxygen concentrators can be potentially "reduced by a factor of three while offering ~10–20% higher oxygen recovery compared to a typical commercial unit." [ 15 ]


The FAA has approved the use of portable oxygen concentrators on commercial airlines. [ 16 ]  However, users of these devices should check in advance as to whether a particular brand or model is permitted on a particular airline. [ 17 ]  Unlike in commercial airlines, users of aircraft without  cabin pressurization  need oxygen concentrators that are able to deliver enough flowrate even at high altitudes.


Usually, "demand," or pulse-flow, oxygen concentrators are not used by patients while they sleep. There have been problems with the oxygen concentrators not being able to detect when the sleeping patient is inhaling.  Some larger portable oxygen concentrators are designed to operate in a continuous-flow mode in addition to pulse-flow mode. Continuous-flow mode is considered safe for night use when coupled with a  CPAP  machine.


Repurposed medical oxygen concentrators or specialized industrial oxygen concentrators can be made to operate  small   oxyacetylene  or other fuel gas cutting, welding, and  lampworking  torches. [ 18 ]


Oxygen is widely needed for the oxidation of different chemicals for industrial purposes. Previously, these industries purchased oxygen cylinders in large numbers to meet their requirements, but it was very expensive, and oxygen cylinders were not always available in the market.


Oxygen is needed here for the bleaching of paper pulp with the help of the oxidation process to make the paper white.
Moreover, lignin present in the wood is removed by the delignification process, which also needs oxygen.


Huge furnaces are needed to melt the raw materials that combine to form glass. Oxygen flares up the furnace's fire to burn at a higher temperature needed for the production of glass.


Oxygen is needed for the oxidation of different chemicals to form the desired chemical substances. Waste chemical products are burnt down and destroyed in the incinerator with the help of oxygen; thus, the continuous supply of a bulk amount of oxygen is essential, which is possible only by a PSA oxygen generator.


In both clinical and emergency-care situations, oxygen concentrators have the advantage of not being as dangerous as  oxygen cylinders , which can, if ruptured or leaking, greatly increase the combustion rate of fire. As such, oxygen concentrators are particularly advantageous in  military  or  disaster  situations, where oxygen tanks may be dangerous or unfeasible.


Oxygen concentrators are considered sufficiently foolproof to be supplied to individual patients as a prescription item for use in their homes. Typically they are used as an adjunct to  CPAP  treatment of severe  sleep apnea . There also are other medical uses for oxygen concentrators, including  COPD  and other respiratory diseases.


People who depend upon oxygen concentrators for home care may have life-threatening emergencies if the electricity fails during a  natural disaster . [ 19 ]


Industrial processes may use much higher pressures and flows than medical units. To meet that need, another process, called  vacuum swing adsorption  (VSA), has been developed by  Air Products . This process uses a single low-pressure blower and a valve that reverses the flow through the blower so that the regeneration phase occurs under a vacuum. Generators using this process are being marketed to the  aquaculture  industry. Industrial oxygen concentrators are often available in a much wider range of capacities than medical concentrators.


Industrial oxygen concentrators are sometimes referred to as oxygen  generators  within the oxygen and ozone industries to distinguish them from medical oxygen  concentrators . The distinction is used in an attempt to clarify that industrial oxygen concentrators are not  medical devices  approved by the  Food and Drug Administration  (FDA) and they are not suitable for use as bedside medical concentrators. However, applying the oxygen generator nomenclature can lead to confusion. The term oxygen  generator  is a misnomer in that the oxygen is not  generated  as it is with a  chemical oxygen generator , but rather it is concentrated from the air.


Non-medical oxygen concentrators can be used as feed gas to a medical oxygen system, such as the oxygen system in a hospital, though governmental approval is required, such as by the FDA, and additional filtering is generally required.


The  COVID-19 pandemic  increased the demand for oxygen concentrators. During the pandemic  open source  oxygen concentrators were developed, locally manufactured – with prices below imported products – and used, especially during  a COVID-19 pandemic wave in India . [ 20 ] [ 21 ]


An  oxygen mask  is a mask that provides a method to transfer  breathing oxygen gas  from a storage tank to the  lungs . Oxygen masks may cover only the nose and mouth (oral nasal mask) or the entire face (full-face mask). They may be made of  plastic ,  silicone , or  rubber .
In certain circumstances, oxygen may be delivered via a  nasal cannula  instead of a mask.


Medical plastic oxygen masks are used primarily by medical care providers for  oxygen therapy  because they are disposable and so reduce cleaning costs and infection risks. Mask design can determine accuracy of oxygen delivered with many various medical situations requiring treatment with oxygen.


Oxygen is naturally occurring in room air at 21% and higher percentages are often essential in medical treatment. Oxygen in these higher percentages is classified as a drug with too much oxygen being potentially harmful to a patient's health, resulting in oxygen dependence over time, and in extreme circumstances patient blindness. For these reasons oxygen therapy is closely monitored. Masks are light in weight and attached using an elasticated headband or ear loops. They are transparent for allowing the face to be visible for patient assessment by healthcare providers, and reducing a sensation of claustrophobia experienced by some patients when wearing an oxygen mask. The vast majority of patients having an operation will at some stage wear an oxygen mask; they may alternatively wear a nasal cannula but oxygen delivered in this way is less accurate and restricted in concentration.


The global disposable oxygen masks market, according to Altus Market Research, has the potential to grow by US$1.1 billion between 2019 and 2023. The market's growth pace will also pick up speed throughout this time. [ 1 ]