Because of increasing requirements in regards to cycle time and accuracy in almost all areas of production, non-contact dispensing is constantly gaining importance. A good example for this is the attachment of very small electronic parts (SMD parts) onto printed circuit boards and substrates. For this, the part carrier only needs to be positioned in one plane - after that the adhesive can be transferred without contact. The following examples show the advantages of non-contact dispensing:


Non-contact dispensing can be divided in two different methods:


Jet-forming dispensing exists when the flow velocity of a medium at the nozzle exit is high enough that the effects of gravitation and surface tension on the separation of the fluid from the nozzle are of secondary importance. This state is characterized by the  Weber number :


where


The physical border line between drop- and jet-forming is around a Weber-number of 8. At this point the dynamic pressure of the flowing medium exceeds the pressure from the surface tension of the drop, which therefore sticks to the nozzle. This transitional stage can be demonstrated at a water tap by gradually increasing the flow, going from the dropping status until a continuous water jet has formed. The Weber-number in this case is, however, clearly above 8, because of the jet exit conditions of the nozzle.


By using the Weber-number, the theoretical lower limit of the mass flow can be found for the jet-forming conditions. In actual applications, to assure a safe dispensing process, the real Weber-numbers chosen should be between 20 and 50.


For a calculated estimation of the fluid flow velocity in the nozzle, for fluids with Newtonian flow behavior, the formula for capillary fluid flow according to the  Hagen–Poiseuille law  has been proven.


To avoid atomizing of the fluid at the nozzle exit, the fluid flow in the nozzle must be laminar, which is the case as long as the  Reynolds number  (Re) of the nozzle is smaller than the  critical Reynolds-number  of the nozzle:


Reynolds-number of the nozzle:


Critical Reynolds-number of the nozzle:


Thus, the theoretical range of the jet-forming dispension is enclosed at its lower limit by the Weber-number and at its upper limit by the critical Reynolds-number. For practical applications, a high kinetic energy in the fluid jet is not desirable, because the jet probably would burst and spatter tiny droplets around the target point. Jet-forming dispensing systems are therefore usually operated in the area of lower Weber-numbers.


In practice, the calculation of the Weber-number becomes more complicated when fluids with additives are used, which demonstrate a non-Newtonian (i.e. thixotropic) flow behavior and therefore the viscosity during the flow through the nozzle is different.


Dynamic drop dispensing is characterised by separation of a drop from the nozzle exit through a dynamic process, because the static pressure of the liquid medium is insufficient for forming a fluid jet.


A well-known example is  inkjet printing . In this application, the volume of a small dispensing chamber with adjoining nozzle becomes reduced through a short impulse, whereby the ink is ejected through the nozzle. Nozzle chamber, nozzle and ink reservoir are hereby fluidically connected without any valve in between. During the dispensing process, some of the medium is also flowing in the reverse direction (back into the reservoir). The surface tension of the fluid at the nozzle exit prevents air being sucked in and fluid from exiting the nozzle when the dispensing chamber is filled up again. The principle of this process is only useful for low-viscosity fluids and this principle is not applicable with higher fluid pressures.


Ink-jet systems have the following inherent properties:


•	Very small single-drop volumes are achievable (8 picolitres)
•	High dispensing frequencies can be realised (some kHz)
•	Low costs for mass production
•	Only certain low-viscosity media are dispensable (i.e. no volatile media)
•	Principally not leak-proof


For industrial production, the dispensing amounts and the range of viscosity spectra of ink-jet systems for most applications are too small. In these fields of production, specially-designed valves with tappet drives of high dynamic pressure are used instead. These microdispensing systems are characterised by the following properties:


•	Single drop volumes from 10 to 200 nanolitres
•	Dispensing frequencies up to 100 Hz
•	Dispensing accuracy < 1%
•	Media viscosities up to 200 Pa·s (thixotropic)


Mucoadhesion  describes the attractive forces between a biological material and  mucus  or  mucous membrane . [ 1 ]  Mucous membranes adhere to epithelial surfaces such as the gastrointestinal tract (GI-tract), the vagina, the lung, the eye, etc. They are generally  hydrophilic  as they contain many hydrogen macromolecules due to the large amount of water (approximately 95%) within its composition. However, mucin also contains  glycoproteins  that enable the formation of a gel-like substance. [ 1 ]  Understanding the hydrophilic bonding and adhesion mechanisms of mucus to biological material is of utmost importance in order to produce the most efficient applications. For example, in  drug delivery  systems, the mucus layer must be penetrated in order to effectively transport micro- or nanosized drug particles into the body. [ 2 ]   Bioadhesion  is the mechanism by which two biological materials are held together by interfacial forces. The mucoadhesive properties of  polymers  can be evaluated via rheological synergism studies with freshly isolated  mucus , tensile studies and mucosal residence time studies. Results obtained with these in vitro methods show a high correlation with results obtained in humans. [ 3 ] [ 4 ]


Mucoadhesion involves several types of  bonding  mechanisms, and it is the interaction between each process that allows for the adhesive process. The major categories are wetting theory, adsorption theory, diffusion theory, electrostatic theory, and fracture theory. [ 5 ]  Specific processes include mechanical interlocking, electrostatic, diffusion interpenetration, adsorption and fracture processes. [ 6 ]


Wetting theory :  Wetting  is the oldest and most prevalent theory of adhesion. The adhesive components in a liquid solution anchor themselves in irregularities on the substrate and eventually harden, providing sites on which to adhere. [ 6 ]  Surface tension effects restrict the movement of the adhesive along the surface of the substrate, and is related to the thermodynamic work of adhesion by  Dupre's Equation . [ 6 ]  Measuring the affinity of the adhesive for the substrate is performed by determining the contact angle. Contact angles closer to zero indicate a more wettable interaction, and those interactions have a greater spreadability. [ 5 ]


Adsorption theory :  Adsorption  is another widely accepted theory, where adhesion between the substrate and adhesive is due to primary and secondary bonding. [ 5 ]  The primary bonds are due to chemisorption, and result in comparatively long lasting covalent and non-covalent bonds. Among covalent bonds disulfide bonds are likely most important. Thiolated polymers – designated  thiomers  – are mucoadhesive polymers that can form disulfide bonds with cysteine-rich subdomains of mucus glycoproteins. [ 7 ]  Recently several new classes of polymers have been developed that are capable of forming covalent bonds with mucosal surfaces similarly to thiomers. These polymers have acryloyl, methacryloyl, maleimide, boronate and N‐hydroxy (sulfo) succinimide ester groups in their structure. [ 8 ]  Among non-covalent bonds likely ionic interactions such as interactions of mucoadhesive chitosans with the anionically charged mucus  [ 9 ]  and  Hydrogen bonding  are most important. [ 10 ]  The secondary bonds include weak  Van Der Waals  forces, and interactions between  hydrophobic  substructure. [ 11 ]


Diffusion theory : The mechanism for  diffusion  involves polymer and mucin chains from the adhesive penetrating the matrix of the substrate and forming a semipermanent bond. [ 6 ]  As the similarities between the adhesive and the substrate increase, so does the degree of mucoadhesion. [ 5 ]  The bond strength increases with the degree of penetration, increasing the adhesion strength. [ 11 ]  The penetration rate is determined by the  diffusion coefficient , the degree of flexibility of the adsorbate chains,  mobility  and contact time. [ 10 ]  The diffusion mechanism itself is affected by the length of the molecular chains being implanted and cross-linking density, and is driven by a  concentration gradient . [ 5 ]


Electrostatic theory : is an  electrostatic  process involving the transfer of electrons across the interface between the substrate and adhesive. [ 6 ]  The net result is the formation of a double layer of charges that are attracted to each other due to balancing of the Fermi layers, and therefore cause adhesion. [ 10 ]  This theory only works given the assumption that the substrate and adhesive have different electrostatic surface characteristics. [ 11 ]


Fracture theory :  Fracture  theory is the major mechanism by which to determine the  mechanical strength  of a particular mucoadhesive, and describes the force necessary to separate the two materials after mucoadhesion has occurred. [ 10 ]   Ultimate tensile strength  is determined by the separating force and the total surface area of the adhesion, and  failure  generally occurs in one of the surfaces rather than at the interface. [ 5 ]  Since the fracture theory only deals with the separation force, the diffusion and penetration of polymers is not accounted for in this mechanism. [ 5 ]


The mucoadhesive process will differ greatly depending on the surface and properties of the adhesive. However, two general steps of the process have been identified: the contact stage and the consolidation stage. [ 1 ]


The contact stage is the initial  wetting  that occurs between the adhesive and membrane. This can occur mechanically by bringing together the two surfaces, or through the bodily systems, like when particles are deposited in the nasal cavity by inhalation. The principles of initial  adsorption  of small molecule adsorbates can be described by  DLVO theory . [ 1 ]


According to  DLVO theory , particles are held in suspension by a balance of attractive and repulsive forces. This theory can be applied to the adsorption of small molecules like mucoadhesive polymers, on surfaces, like mucus layers. Particles in general experience attractive  van der Waals forces  that promote  coagulation ; in the context of  adsorption , the particle and mucus layers are naturally attracted. The attractive forces between particles increases with decreasing particle size due to increasing surface-area-to-volume ratio. This increases the strength of van der Waals interactions, so smaller particles should be easier to adsorb onto mucous membranes. [ 1 ]


DLVO theory  also explains some of the challenges in establishing contact between particles and mucus layers in mucoadhesion due to their repulsive forces. Surfaces will develop an  electrical double layer  if they are in a solution containing ions, as is the case with many bodily systems, creating electrostatic repulsive forces between the adhesive and surface.  Steric effects  can also hinder particle adsorption to surfaces.  Entropy  or disorder of a system will decrease as polymeric mucoadhesives adsorb to surfaces, which makes establishing contact between the adhesive and membrane more difficult. Adhesives with large surface groups will also experience a decrease in entropy as they approach the surface, creating repulsion. [ 1 ]


The initial adsorption of the molecule adhesive will also depend on the  wetting  between the adhesive and membrane. This can be described using Young's equation:


cos

 (
 θ
 )

 =

 γ

 m
 g

 −

 γ

 b
 m

 γ

 b
 g

 {\displaystyle {\cos(\theta )\;=\;{\frac {\gamma _{mg}\;-\gamma _{bm}\;}{\gamma _{bg}}}}}


where

 γ

 m
 g

 {\displaystyle \gamma _{mg}}

  is the interfacial tension between the membrane and gas or bodily environment,

 γ

 b
 m

 {\displaystyle \gamma _{bm}}

  is the interfacial tension between the bioadhesive and membrane,

 γ

 b
 g

 {\displaystyle \gamma _{bg}}

  is the interfacial tension between the bioadhesive and bodily environment, and

 θ

 {\displaystyle \theta }

  is the contact angle of the bioadhesive on the membrane. The ideal contact angle is 0° meaning the bioadhesive perfectly wets the membrane and good contact is achieved. The interfacial tensions can be measured using common experimental techniques such as a  Wilhelmy plate  or the  Du Noüy ring method  to predict if the adhesive will make good contact with the membrane. [ 11 ]


The consolidation stage of mucoadhesion involves the establishment of adhesive interactions to reinforce strong or prolonged adhesion. When moisture is present, mucoadhesive materials become activated and the system becomes plasticized. [ 10 ]  This stimulus allows the mucoadhesive molecules to separate and break free while proceeding to link up by weak  van der Waals  and  hydrogen bonds . [ 10 ]  Consolidation factors are essential for the surface when exposed to significant dislodging stresses. [ 1 ]  Multiple mucoadhesion theories exist that explain the consolidation stage, the main two which focus on macromolecular interpenetration and dehydration.


The Macromolecular Interpenetration theory, also known as the diffusion theory, states that the mucoadhesive molecules and mucus glycoproteins mutually interact by means of interpenetration of their chains and the forming of secondary semi-permanent adhesive bonds. [ 10 ]  It is necessary that the mucoadhesive device has features or properties that favor both chemical and mechanical interactions for the macromolecular interpenetration theory to take place. [ 10 ]  Molecules that can present mucoadhesive properties are molecules with hydrogen bond building groups, high molecular weight, flexible chains, and surface active properties. [ 10 ]


It is perceived that increase in adhesion force is associated with the degree of penetration of polymer chains. [ 10 ]  Literature states that the degree of penetration required for efficient bioadhesive bonds lies in the range of 0.2-0.5μm. [ 10 ]  The following equation can be used to estimate the degree of penetration of polymer and mucus chains:


l
 =

 (
 t
 ×

 D

 b

 )

 1

 /

 2

 {\displaystyle {l={(t\times D_{b}})^{1/2}}}


with

 t

 {\displaystyle t}

  as contact time and

 D

 b

 {\displaystyle D_{b}}

  as the  diffusion coefficient  of the mucoadhesive material in the mucus. [ 10 ]  Maximum adhesion strength is reached when penetration depth is approximately equal to polymer chain size. [ 10 ]  Properties of mutual  solubility  and structural similarity will improve the mucoadhesive bond. [ 1 ]


The dehydration theory explains why mucoadhesion can arise rapidly. When two gels capable of rapid gelation in an aqueous environment are brought into contact, movement occurs between the two gels until a state of equilibrium is reached. [ 1 ]  Gels associated with a strong affinity for water will have high osmotic pressures and large swelling forces. [ 1 ]  The difference in osmotic pressure when these gels contact mucus gels will draw water into the formulation and quickly dehydrate the mucus gel, forcing intermixing and consolidation until equilibrium results. [ 12 ]


This mixture of formulation and mucus can increase contact time with the mucous membrane, leading to the consolidation of the adhesive bond. [ 12 ]  However, the dehydration theory does not apply to solid formulations or highly hydrated forms. [ 1 ]


Depending on the dosage form and  route of administration , mucoadhesives may be used for either local or systemic  drug delivery . An overview on the mucoadhesive properties of mucoadhesives is provided by Vjera Grabovac and  Andreas Bernkop-Schnürch . [ 13 ]  The  bioavailability  of such drugs is affected by many factors unique to each route of application. In general, mucoadhesives work to increase the contact time at these sites, prolonging the  residence time  and maintaining an effective release rate. These polymeric coatings may be applied to a wide variety of liquid and solid dosages, each specially suited for the route of administration.


Tablets  are small, solid dosages suitable for the use of mucoadhesive coatings. The coating may be formulated to adhere to a specific mucosa, enabling both systemic and targeted local administration. Tablets are generally taken enterally, as the size and stiffness of the form results in poor patient compliance when administered through other routes. [ 10 ]


In general,  patches  consist of three separate layers that contribute and control the release of medicine. The outer impermeable backing layer controls the direction of release and reduces drug loss away from the site of contact. It also protects the other layers and acts as a mechanical support. The middle reservoir layer holds the drug and is tailored to provide the specified dosage. The final inner layer consists of the mucoadhesive, allowing the patch to adhere to the specified mucosa. [ 10 ]


As a liquid or semisolid dosage,  gels  are typically used where a solid form would affect the patient’s comfort. As a trade-off, conventional gels have poor retention rates. This results in unpredictable losses of the drug, as the non-solid dosage is unable to maintain its position at the site of administration. Mucoadhesives increase retention by dynamically increasing the viscosity of the gel after application. This allows the gel to effectively administer the drug at the local site while maintaining the comfort of the patient. [ 10 ]


These dosage forms are commonly used to deliver drugs to the eye and nasal cavity. They often include mucoadhesive polymers to improve retention on dynamic mucosal surfaces. Some advanced eye drop formulations may also turn from a liquid to a gel (so called in situ gelling systems) upon drug administration. For example, gel-forming solutions containing Pluronics could be used to improve the efficiency of eye drops and provide better retention on ocular surfaces. [ 14 ]


With a 0.1-0.7 mm thick mucus layer, the oral cavity serves as an important route of administration for mucoadhesive dosages. Permeation sites can be separated into two groups:  sublingual  and  buccal , in which the former is much more permeable than the latter. However, the sublingual mucosa also produces more  saliva , resulting in relatively low retention rates. Thus, sublingual mucosa is preferable for rapid onset and short duration treatments, while the buccal mucosa is more appropriate for longer dosage and onset times. Because of this dichotomy, the oral cavity is suitable for both local and systemic administration. Some common dosage forms for the oral cavity include gels, ointments, patches, and tablets. Depending on the dosage form, some drug loss can occur due to swallowing of saliva. This can be minimized by layering the side of the dosage facing the oral cavity with an impermeable coating(,) commonly seen in patches. [ 15 ]


With an active surface area of 160 cm 2 , the  nasal cavity  is another noteworthy route of mucoadhesive administration. Due to the sweeping motion of the  cilia  that lines the mucosa, nasal mucus has a quick turnover of 10 to 15 minutes. Because of this, the nasal cavity is most suitable for rapid, local medicinal dosages. Additionally, its close proximity to the  blood–brain barrier  makes it a convenient route for administering specialized drugs to the central nervous system. Gels, solutions, and aerosols are common dosage forms in the nasal cavity. However, recent research into particles and microspheres have shown increased bioavailability over non-solid forms of medicine largely due to the use of mucoadhesives. [ 16 ]


Within the  eye , it is difficult to achieve therapeutic concentrations through systemic administration. Often, other parts of the body will reach toxic levels of the medication before the eye reaches the treatment concentration. Consequently, direct administration through the fibrous tunic is common. This is made difficult due to the numerous defense mechanisms in place, such as  blinking ,  tear production , and the tightness of the  corneal epithelium . Estimates put tear turnover rates at 5 minutes, meaning most conventional drugs are not retained for long periods of time. Mucoadhesives increase retention rates, either by enhancing the viscosity or bonding directly to one of the mucosae surrounding the eye. [ 15 ] [ 17 ]


Intravesical drug administration is the delivery of pharmaceuticals to the urinary bladder through a catheter. [ 18 ]  This route of administration is used for the therapy of bladder cancer and interstitial cystitis. The retention of dosage forms in the bladder is relatively poor, which is related to the need for a periodical urine voiding. Some mucoadhesive materials are able to stick to mucosal lining in the bladder, resist urine wash out effects and provide a sustained drug delivery. [ 19 ] [ 20 ]


Nasal administration , popularly known as  snorting , is a  route of administration  in which  drugs  are  insufflated  through the  nose . It can be a form of either  topical administration  or  systemic administration , as the drugs thus locally delivered can go on to have either purely local or systemic effects. Nasal sprays are locally acting drugs such as  decongestants  for cold and allergy treatment, whose systemic effects are usually minimal. Examples of systemically active drugs available as nasal sprays are  migraine drugs , rescue medications for overdose and seizure emergencies,  hormone treatments ,  nicotine nasal spray , and  nasal vaccines  such as  live attenuated influenza vaccine .


A  nasal septum perforation  is a medical condition in which the  nasal septum , the  bony/cartilaginous  wall dividing the  nasal cavities , develops a hole or fissure. [ 1 ]  Nasal administration may cause nasal septum perforation by gradually injuring and ulcerating the epithelium, causing cartilage exposure and  necrosis . [ 2 ]


Sharing snorting equipment (nasal spray bottles, straws, banknotes, bullets, etc) has been linked to the transmission of  hepatitis C . In one study, the University of Tennessee Medical Center researchers warned that other blood-borne diseases such as  HIV  could be transmitted as well. [ 4 ]


The nasal cavity is covered by a thin mucosa which is well vascularised. [ 5 ]  Therefore, a drug molecule can be transferred quickly across the single epithelial cell layer directly to the systemic blood circulation without first-pass hepatic and intestinal metabolism. The effect is often reached within 5 minutes for  smaller drug molecules . [ 6 ]  Nasal administration can therefore be used as an alternative to oral administration, by crushing or grinding tablets or capsules and snorting or sniffing the resulting powder, providing a rapid onset of effects if a fast effect is desired or if the drug is extensively degraded in the gut or liver. [ 7 ]


Large-molecule drugs can also be delivered directly to the brain by the intranasal route, the only practical means of doing so, following the olfactory and trigeminal nerves  (see section below) , for widespread central distribution throughout the  central nervous system  with little exposure to the blood. [ 8 ] [ 9 ] [ 10 ] [ 11 ]  This delivery method to the brain was functionally demonstrated in humans in 2006, using  insulin , a large  peptide  hormone that acts as a nerve growth factor in the brain. [ 12 ]


Nasal administration is primarily suitable for potent drugs since only a limited volume can be sprayed into the nasal cavity. Drugs for continuous and frequent administration may be less suitable because of the risk of harmful long-term effects on the nasal epithelium. [ 7 ]  Nasal administration has also been associated with a high variability in the amount of drug absorbed. Upper airway infections may increase the variability as may the extent of sensory irritation of the nasal mucosa, differences in the amount of liquid spray that is swallowed and not kept in the nasal cavity and differences in the spray actuation process. [ 13 ]  However, the variability in the amount absorbed after nasal administration should be comparable to that after oral administration. [ 14 ] [ 15 ]


The area of intranasal medication delivery provides a huge opportunity for research – both for specifically developed pharmaceutical drugs designed for intranasal treatment, as well as for investigating off-label uses of commonly available generic medications. Steroids, and a large number of inhalational anaesthetic agents are being used commonly. The recent developments in intranasal drug delivery systems are prodigious.  Peptide drugs  (hormone treatments) are also available as nasal sprays, in this case to avoid drug degradation after oral administration. The peptide analogue  desmopressin  is, for example, available for both nasal and oral administration, for the treatment of  diabetes insipidus . The  bioavailability  of the commercial tablet is 0.1% while that of the nasal spray is 3-5% according to the SPC ( Summary of Product Characteristics ). [ 16 ]  Intranasal  calcitonin , calcitonin-salmon, is used to treat  hypercalcaemia  arising out of malignancy,  Paget's disease of bone , post menopausal and steroid induced  osteoporosis ,  phantom limb pain  and other metabolic bone abnormalities, available as Rockbone, Fortical and Miacalcin Nasal Spray.  GnRH analogues  like nafarelin and busurelin are used for the treatment of anovulatory infertility,  hypogonadotropic hypogonadism ,  delayed puberty  and  cryptorchidism . Other potential drug candidates for nasal administration include anaesthetics, antihistamines (Azelastine),  antiemetics  (particularly metoclopramide and ondansetron) and  sedatives  that all benefit from a fast onset of effect. [ 17 ]  Intranasal  midazolam  is found to be highly effective in acute episodes of seizures in children. Recently, the upper part of the nasal cavity, as high as the  cribriform plate , has been proposed for drug delivery to the brain. This "transcribrial route", published first in 2014, was suggested by the author for drugs to be given for Primary  Meningoencephalitis .  [ 18 ]


Oxytocin  (brand name Syntocinon) nasal spray is used to increase duration and strength of contractions during labour. Intranasal oxytocin is also being actively investigated for many psychiatric conditions including  alcohol withdrawal ,  anorexia nervosa ,  PTSD ,  autism ,  anxiety disorders , pain sensation and  schizophrenia .


List of substances that have higher bioavailability when administered intranasally compared to oral administration.


Insufflation of  cocaine  leads to the longest duration of its effects (60–90 minutes). [ 19 ]  When insufflating cocaine, absorption through the nasal membranes is approximately 30–60%. [ 20 ]


Among the less invasive routes for  ketamine , the intranasal route has the highest bioavailability (45–50%). [ 21 ] [ 22 ]


Snuff  is a type of  smokeless tobacco   product  made from finely ground or pulverized  tobacco  leaves. [ 23 ]  It is  snorted  or "sniffed" (alternatively sometimes written as "snuffed") into the nasal cavity, delivering  nicotine  and a flavored scent to the user (especially if flavoring has been blended with the tobacco). [ 23 ]  Traditionally, it is sniffed or inhaled lightly after a pinch of snuff is either placed onto the back surface of the  hand , held pinched between thumb and index finger, or held by a specially made "snuffing" device.


Snuff trays  and tubes similar to those commonly used for  yopo  were found in the central Peruvian coast dating back to 1200 BC, suggesting that insufflation of  Anadenanthera  beans is a more recent method of use. [ 24 ]  Archaeological evidence of insufflation use within the period 500-1000 AD, in northern Chile, has been reported. [ 25 ]


There is about 20 mL capacity in the adult human  nasal cavity . [ 26 ]  The major part of the approximately 150 cm 2  surface in the human nasal cavity is covered by  respiratory epithelium , across which systemic drug absorption can be achieved. The  olfactory epithelium  is situated in the upper posterior part and covers approximately 10 cm 2  of the human nasal cavity. The nerve cells of the olfactory epithelium project into the  olfactory bulb  of the brain, which provides a direct connection between the brain and the external environment. The transfer of drugs to the brain from the blood circulation is normally hindered by the  blood–brain barrier  (BBB), which is virtually impermeable to  passive diffusion  of all but small, lipophilic substances. However, if drug substances can be transferred along the olfactory nerve cells, they can bypass the BBB and enter the brain directly. [ 10 ] [ 11 ]


The  olfactory transfer  of drugs into the brain is thought to occur by either slow transport inside the olfactory nerve cells to the olfactory bulb or by faster transfer along the perineural space surrounding the olfactory nerve cells into the  cerebrospinal fluid  surrounding the olfactory bulbs and the brain. [ 27 ] [ 28 ]


Olfactory transfer could theoretically be used to deliver drugs that have a required effect in the central nervous system such as those for  Parkinson's  or  Alzheimer's  diseases. Studies have been presented showing that direct transfer of drugs is achievable. [ 28 ] [ 29 ]


Ophthalmic drug administration  is the administration of a drug to the eyes, most typically as an  eye drop  formulation. Topical formulations are used to combat a multitude of diseased states of the eye. These states may include  bacterial infections , eye injury,  glaucoma , and  dry eye . [ 1 ]  However, there are many challenges associated with topical delivery of drugs to the  cornea  of the eye.


Two of the largest challenges faced when using topicals to treat pathological states of the eye include  patient compliance  and ineffective absorbance of drugs into the cornea due to short contact times, solution drainage, tears turnover, and dilution or lacrimation. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]  In fact, researchers in this field of drug delivery agree that less than 7% of drugs delivered to the eye reach and penetrate the corneal barrier, therefore, increasing the frequency of dosing used for topicals. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]  This is one of the fundamental problem associated with using topicals to deliver drugs to the cornea and therefore leads to the increased demand for patient compliance. Together, these two factors drive a need in the field of scientific research and engineering for a way to better deliver drugs to the cornea of the eye while decreasing dosing frequency and demand for patient compliance. Strategies to achieve a prolonged residence time of drug delivery systems on ocular surface include mucoadhesive and in situ gelling polymers and thiolated cyclodextrins (see  thiomers ). [ 8 ]  Besides the logistical problems associated with using topicals, there are also systemic side effects which result from the administration of some drugs used to combat the pathological states of the eye. [ 3 ]  With the increased concentration of drugs in topicals and the frequent application to the eye, a majority of the drug is drained from the eye via nasolacrimal drainage. [ 3 ]  This drainage is thought to be the reason that systemic side effects exist from such administration. [ 2 ] [ 3 ] [ 6 ]


The U.S.  Centers for Disease Control and Prevention  (CDC) claims that there were "about 41 million  contact lens  wearers greater than 18 years old in the United States" in 2018. [ 9 ]  Of all of these wearers, nearly 90% of them wear contact lenses known as 'soft contact lenses' (SCLs). [ 9 ]  Contact lenses are regulated by the United States  Food and Drug Administration  (FDA). [ 10 ]


The main approaches that researchers in this field are using today are: molecular imprinting, supercritical soaking, solvent impregnation, and  nanoparticle  loading. [ 2 ] [ 4 ] [ 5 ] [ 7 ]  Each of these techniques assists by hoping to deliver drugs at a lower, more sustained, rate that does not require a demand for increased patient compliance nor the systemic side effects from  topical drug delivery  systems. However, each of these different types of loading techniques results in contact lenses that all have separate physical and chemical challenges when it comes to the sustained release and penetration of specific drugs at the molecular level in regards to the cornea of the eye.


Molecular imprinting is a process by which polymerization of a polymer around template result in the polymer matrix with embedded templates. [ 2 ] [ 5 ]  After the template is removed, a cavity results with the functionalized monomers within the polymer cavity. This cavity is the idealized position for drug loading since this process can be designed specifically to recruit and hold onto drugs due to chemical specificity. [ 2 ] [ 5 ]  This technique can be better visualized by referring to Figure 3.0. This type of drug loading can be used as a way to create a pH responsive system, which releases drug(s) as the pH of the biological system changes. [ 2 ] [ 5 ]  Some drugs that have been successfully loaded via this method are:  timolol ,  norfloxacin ,  ketotifen ,  polyvinlypyrrolidone , and  hyaluronic acid . [ 5 ] [ 11 ] [ 12 ]  The molecular structures of each of these drugs are shown below in the index of important scientific terminology.


The supercritical soaking method is commonly used in hydrogel-based contact lenses and is the most common of all types of molecular drug loading techniques. Since this technique requires no special equipment or advanced knowledge of polymer-based hydrogels it is the least complex of all loading types. [ 4 ]  In order to load the hydrogel matrix with a certain drug, contact lenses are simply placed in a solution of the drug and the drug diffuses into the matrix. [ 4 ] [ 5 ] [ 7 ]  Since this loading technique is driven solely by the gradient of the drug concentration surrounding the lens relative to the hydrogel matrix, the diffusion rate and amount of drug that is loaded can be controlled solely by the concentration of the drug solution. [ 4 ] [ 7 ]  Since this process allows for specific amounts of a certain drug to be loaded to the hydrogel matrix, this method of loading has become important for patient-specific (personalized) medicine and treatments.


The nanoparticle loading technique includes two major parts. The first part of this process is the creation and conjugation of a specific drug into or onto a nanoparticle or other colloidal particle. [ 5 ]  Next, the nanoparticle is loaded into the hydrogel matrix of the contact lens. [ 5 ]  In this case, before the drug can diffuse out of the hydrogel matrix to reach the cornea, it must also diffuse or be released out of the nanoparticle. [ 5 ]


It is important to recognize the positives and negatives associated with each type of drug loading for using contact lenses as drug delivery devices. In order to seriously address the possibility of clinical translation of these devices, it is important to recognize the physical and chemical barriers. By understanding this better, the mechanism of drug loading and the controlled and sustained release of drugs to a patient's eye can be optimized.


Since contact lenses are used on a part of the body that is important for normal daily functioning (sight) it is critical that scientists take into account the transparency of the lens. [ 5 ]  As larger and more drugs/objects are loaded to a contact lens it begins to physically crowd the space available, making it more difficult for light to penetrate and reach the eye.


Researchers have noted that by using the nanoparticle loading technique, the transparency decreases by nearly 10%. [ 5 ]  Conversely, researchers have confirmed that by using the molecular imprinting and supercritical soaking methods of drug loading, the lens transparency of the contact lenses has stayed at or above the lens transparency of the contact lenses currently approved by the FDA. [ 5 ] [ 12 ]


Oxygen permeability is another important feature of all contact lenses and much be optimized to the largest degree possible when creating drug delivery devices for the eye. The contact lens adheres to the external cornea of the eye which is made up of a layer of cells. [ 13 ]  Cells, being the basic component of living organisms, require sustained and constant access to oxygen in order to survive. The cornea of the eye is not supplied with blood as are most other cells in the body, making this a challenging part of the body to which to deliver drugs. [ 13 ]  Decreasing oxygenation to the eye can result in undesirable side effects. [ 5 ]  Researchers in this field have noted that different types of contact lenses have varying degrees of oxygen permeability. For example, it has been shown that SCLs have limited oxygen permeability while silicon-based contact lenses have much better oxygen permeability. [ 1 ] [ 5 ] [ 12 ] [ 14 ]  Silicon-base contact lenses have also been shown to have some other very important physical parameters. [ 1 ] [ 5 ] [ 12 ] [ 14 ]


Researchers have attempted to make the thickness of the contact lenses in order to increase the drug loading capacity of the contact lens. [ 12 ]  However, for silicon-based lenses this parameter is inversely proportion to oxygen permeability (i.e. as thickness of the contact lens increases the oxygen permeability decreases). [ 12 ]  Moreover, it has been shown that as water content increases in silicon-based lenses, the oxygen permeability decreases, another relationship that is inversely proportional. [ 12 ]  Surprisingly, as SCLs increase with water content the oxygen permeability also increases (a directly proportional relationship). [ 12 ]


In regards to whether silicon-based lenses or SCLs are a better candidate as an ophthalmic drug delivery device is a question that remains unanswered and is not uniformly agreed upon in the scientific community. For example, Ciolino et al. claim that silicon-based contact lenses are better candidates for patients that are long-term contact lens wearer. [ 2 ] [ 3 ]  Conversely, Kim et al. suggest that SCLs are better candidates because they show the possibility to be able to overcome the difficult of oxygen permeability as well as mechanical integrity of the lens. [ 7 ]  Kim et al. have shown that the mechanical strength can be increased for SCLs by incorporating a nanodiamond (ND) infrastructure into contact lens matrix. [ 7 ]


Additionally, many researchers have investigated the implications of loading vitamin E into the contact lens matrix of SCLs. [ 6 ]  Although vitamin E incorporation into the matrix has been shown to slow the release of drugs into the eye and onto cornea (a desirable trait of an ophthalmic delivery system), it has also been shown to decrease oxygen permeability. [ 6 ]  Oxygen permeability continues to be an extremely important factor in the development of these devices and is one of the main reason that much research is beginning to focus on this area of drug delivery.


The amount of water content that a particular contact lens can retain is another extremely important factor that must be taken into account when these devices are designed. Research in this specific area of design suggests that contact lens wearers find it more comfortable to wear lenses that retain water more than those that deter water. [ 5 ] [ 12 ]  For SCLs, as the water content of a lens increases so does the oxygen permeability. [ 12 ]  Conversely, as the water content increases in silicon-based contact lenses, the oxygen permeability decreases. [ 2 ] [ 3 ] [ 12 ]  In reference to SCLs, higher water content in contact lenses allows for easier loading using the supercritical soaking method. [ 3 ] [ 5 ] [ 12 ] [ 15 ]  This could be due to the water acting as a lubricant to some drugs and allowing the drug to be more easily facilitated into the matrix. This would essentially allow for more drug to be loaded into contact lenses of this type. [ 5 ] [ 12 ]  This increase in drug loading capacity is an important advancement and would allow for patients wince it may allow for a longer period of drug release time and would hopefully be more sustained. [ 5 ]


Furthermore, Guzman-Aranguez et al. has shown that when using the molecular imprinting method for loading drugs such as ketotifen and norfloxacin into the contact lens, the water content is not largely impacted. [ 5 ]  Additionally, it has been predicted by Peng et al. by using Fickian release kinetic models that although water content changes once contact lenses are inserted onto the cornea of the eye, this will not pose significant challenges when it comes to the release of rugs from SCLs. [ 16 ]


The most important factor that must be taken into account when designing any type of drug delivery device, and specifically ocular devices, is the release rate of a drug. As discussed previously, the deliver rate and kinetics associated with drugs to the eye can reach levels that are toxic to the eye or could even cause undesirable side effects. The rate of release of a drug is also important because too slow of a release could have no beneficial outcome for the patient and a release that is too quick could result in negative side effects. [ 10 ] [ 14 ] [ 16 ] [ 17 ]  Thus, it is important to balance the factors that govern the release of drugs from contact lenses as potential drug delivery devices. Researchers such as C. Alvarez-Lorenzo have tested (with animal models) and have data which supports that molecularly imprinted contact lenses release drugs in a sustained and long period of time. [ 12 ]  It has also been supported by researchers that the rate of drug release can be controlled by incorporating vitamin E within the hydrogen matrix. [ 6 ]


Over time, it has been reported that many of the same drugs and eye drops used to treat particular eye diseases do, in fact, result in systemic side effects that could possibly be minimized or limited due to a slower, more sustained release of the drug. The systemic side effects of glaucoma medications such as latanoprost increased heart rate resulting in cardiac arrhythmias, bronchoconstriction, and hypotension. [ 16 ] [ 17 ] [ 18 ]   These complications could be life-threatening. Some other drugs that help to reduce the effects of glaucoma in the eye result in vomiting, diarrhea, tachycardia and bronchospasm. [ 15 ] [ 16 ] [ 17 ] [ 18 ]  It has been found that some drugs delivered in the form of eye drops are highly toxic to children since their total body volume and tissue volumes are much lower than that of an adult for which the drugs are intended for use. [ 17 ]  In this case, some parents are not aware of these implications and could use the same drug they would use to help treat their children's bacterial infections in the eye. Moreover, some drugs administered to the eye have been shown to result in cardiac depression and propagation of some disorders such as asthma. [ 16 ] [ 17 ] [ 18 ]  With continued research in this area, it has become known that skin irritation, itching or rash are commonly associated with drugs used to treat ocular bacterial infections. [ 15 ] [ 16 ] [ 17 ] [ 18 ]


There are currently four main ocular disorders that have been heavily investigated and have shown success with using contact lenses as possible devices for molecular drug delivery.


The drug release rate is extremely important in treating many diseased states of the eye, bacterial infections being one of them. Ciprofloxacin and norfloxacin are drugs that are normally used to treat bacterial infections of the eye. It is of utmost importance that these drugs stay in the therapeutic window for an extended period of time in order to be fully effective and kill bacteria. [ 5 ] [ 12 ]  To keep the specific drug in the therapeutic window using eye drops the topical must be applied approximately every 30 minutes in order to be fully effective. [ 5 ] [ 12 ]  Having to apply eye drops every 30 minutes would be nearly impossible for anyone and is not the ideal mechanism by which to deliver such drugs to the eye. Researchers have gathered data to support the idea that silicon-based contact lenses with ciprofloxacin could release the drug in the therapeutic window for approximately one month. [ 5 ]  Ana Guzman-Aranguez et al. also confirmed that the contact lens used also retained important properties such as transparency, oxygen permeability, mechanical strength, and zero-order release pharmacokinetics. [ 5 ]


Many factors can result in corneal injury and cause the deterioration or death of cells that make up the cornea of the eye. [ 5 ] [ 12 ]  The epithelial cells that make up the cornea are important in order for normal vision. These cells play a role in creating a physical environment that can correctly bend light rays to help project images to the retina of the eye. [ 5 ] [ 12 ]  There have been successful human clinical trials with using SCLs infused with epidermal growth factor (EGF) that showed increased rate of healing of the epithelial cell layer of the cornea. [ 5 ]


Glaucoma  is the leading cause of blindness in the world and is a progressive and irreversible disease of the eye. [ 18 ]  A poly(lactic-co-glycolic acid)-based contact lens was shown to release  latanoprost  at a sustained release rate of up to a month in animal models by Ciolino et al. at Harvard Medical School and Massachusetts Institute of Technology. [ 18 ]  Latanoprost is one of the drug interventions used to treat patients with glaucoma, generally in the form of topicals such as  eye drops . [ 18 ]


More than 50% of all contact lens wearers report that they experience  dry eye . [ 5 ]  In order to help combat this issue and be assured that this does not occur in people that will one day be using drug eluting contact lenses, it is important to make sure that this complication is highly investigated. However, these investigations will not only be beneficial for contact lenses as drug delivery devices, but it will also have positive implications on contact lens wearers who use lenses for vision correction and appearance.


Oral administration  is a  route of administration  whereby a substance is taken through the  mouth , swallowed, and then processed via the  digestive system . This is a common route of administration for many medications.


Oral administration can be easier and less painful than other routes of administration, such as injection. However, the onset of action is relatively low, and the effectiveness is reduced if it is not absorbed properly in the  digestive system , or if it is broken down by digestive enzymes before it can reach the bloodstream. Some medications may cause gastrointestinal side effects, such as nausea or vomiting, when taken orally. Oral administration can also only be applied to conscious patients, and patients able to swallow. [ 1 ]


Per os  ( / ˌ p ɜːr ˈ oʊ s / ;  P.O. ) is an adverbial phrase meaning literally from Latin "through the mouth" or "by mouth". The expression is used in medicine to describe a treatment that is taken orally (but not used  in  the mouth  such as, for example,  caries  prophylaxis). [ 2 ]  The abbreviation  P.O.  is often used on  medical prescriptions . [ citation needed ]


Enteral administration includes: [ citation needed ]


Enteral medications come in various forms, including [ 3 ]  oral solid dosage (OSD) forms: [ 4 ]


and oral liquid dosage forms: [ 5 ]


Concomitant ingestion of  water  facilitates in swallowing tablets and capsules. [ 6 ]  If the substance has disagreeable  taste , addition of a  flavor  may facilitate  ingestion . [ 6 ]  Substances that are harmful to the  teeth  are preferably given through a  straw . [ 6 ]


A powder is an assembly of dry particles dispersed in air. If two different powders are mixed perfectly, theoretically, three types of  powder mixtures  can be obtained: the random mixture, the ordered mixture or the interactive mixture.


A  powder  is called  free-flowing  if the particles do not stick together. If particles are  cohesive , they cling to one another to form  aggregates . The significance of cohesion increases with decreasing size of the powder particles; particles smaller than 100  μm  are generally cohesive. [ 1 ] [ 2 ]


A  random mixture  can be obtained if two different free-flowing powders of approximately the same particle size,  density  and  shape  are mixed (see figure A). [ 3 ]  Only primary particles are present in this type of mixture, i.e., the particles are not cohesive and do not cling to one another. The mixing time will determine the quality of the random mixture. However, if powders with particles of different size, density or shape are mixed,  segregation  can occur. [ 4 ]  Segregation will cause separation of the powders as, for example, lighter particles will be prone to travel to the top of the mixture whereas heavier particles are kept at the bottom.


The term  ordered mixture  was first introduced to describe a completely  homogeneous  mixture where the two components adhere to each other to form ordered units. [ 5 ]  However, a completely homogeneous mixture is only achievable in theory and other denotations were introduced later such as adhesive mixture or interactive mixture.


If a free-flowing powder is mixed with a cohesive powder an  interactive mixture  can be obtained. The cohesive particles adhere to the free-flowing particles (now called carrier particles) to form interactive units as shown in figure B. [ 3 ]  An interactive mixture may not contain free aggregates of the cohesive powder, which means that all small particles must be adhered to the larger ones. The difference from an ordered mixture is instead that all carrier particles do not need to be of the same size and a different number of small particles attached to each one. A narrow size range of the carrier particles is preferred to avoid segregation of the interactive units. [ 6 ]  In practice a combination of a random mixture and an interactive mixture may be obtained which consists of carrier particles, aggregates of the small particles and interactive units. [ 7 ]


The formation of interactive mixtures cannot automatically be assumed, especially if smaller carrier particles  [ 8 ]  or a greater proportion of fine particles  [ 9 ] [ 10 ]  are used. If an interactive mixture is to be formed, it is necessary that enough force is exerted by the carrier particles during dry mixing to break up the aggregates formed by the fine particles. Adhesion can then be achieved if the adhesive forces exceed the gravitational forces that otherwise lead to separation of the constituents. [ 3 ]


Interactive mixtures for example can be used in the manufacturing of tablets [ 11 ]  enhancing the dissolution of poorly  soluble   drugs   [ 12 ]  or for  nasal administration . [ 3 ]  One common application is for inhalation therapy, where the concept has been used in the development of alternatives to pressurised metered dose inhalers. [ 13 ]


The  quality by design  initiative (QbD) of the  U.S. Food and Drug Administration  requires a process to be controllable and predictable. Theories and methods to characterize powder mixture have facilitated the implementation of QbD approaches to predict flow properties of powder mixture. For example, QbD approach is shown to be useful for predicting flow performance and finding design space during formulation development. [ 14 ]


Pulmonary drug delivery  is a  route of administration  in which patients use an inhaler to inhale their medications and drugs are absorbed into the bloodstream via the lung mucous membrane. This technique is most commonly used in the treatment of lung diseases, for example,  asthma  and  chronic obstructive pulmonary disease (COPD) . Different types of inhalers include  metered-dose inhalers (MDI) ,  dry powder inhalers (DPI) , soft mist inhalers (SMI) and  nebulizers . The rate and efficacy of pulmonary drug delivery are affected by drug particle properties, breathing patterns and respiratory tract geometry.


Pulmonary drug delivery minimizes systemic side effects and increases bioavailability owing to the localised absorption through the lung. The disadvantages include possible drug irritation to the lung, limited drug  dissolution , relatively high drug  clearance , and the drug effectiveness depends on the inhaler techniques and patients'  compliance . Drug formulation can be challenging since the drug has to bypass the  defence mechanisms in the respiratory tract .  Pharmacokinetics  and  pharmacodynamics  of the drug in elderly patients can also be particularly difficult to predict due to age-related changes in body composition.


Ongoing developments in inhaler device engineering, technology and drug formulations may improve the efficacy and overcome the challenges of pulmonary drug delivery. Recent advancements involve the utilization of the pulmonary route as an entry to  systemic circulation  for treating different diseases, as well as the development of pulmonary drug formulation and  particle engineering technology  to increase the efficacy of pulmonary delivery.


Pulmonary drug delivery is mainly utilized for topical applications in the lungs, such as the use of inhaled  beta-agonists ,  corticosteroids  and  anticholinergic  agents for the treatment of asthma and COPD, the use of inhaled  mucolytics  and  antibiotics  for the treatment of  cystic fibrosis (CT)  and respiratory viral infections, [ 1 ]  and the use of inhaled  prostacyclin   analogs  for the treatment of  pulmonary arterial hypertension (PAH) . [ 2 ]


In addition, this technique is employed for systemic application, for example the use of inhaled  insulin  for  diabetes  management, [ 3 ]  the use of inhaled  loxapine  for treatment of psychiatric disorders.  Vaccines , such as the  measles-rubella vaccines , can also be delivered via inhalation.


Metered-dose inhalers include pressurized metered-dose inhalers (pMDIs) and breath-actuated metered-dose inhalers (BAMDIs). pMDIs are the most commonly used inhalers for treating lung diseases. It requires coordination of patients’ inhalation and inhaler actuation. BAMDIs are triggered by patients’ inspiratory flow instead of hand actuation, solving the coordination issue. [ 4 ]  MDIs with  spacers  have similar effectiveness in drug delivery compared to nebulizers, with additional benefits in convenience and cost-effectiveness. [ 5 ]  The use of MDIs together with spacers, valved holding chambers (VHCs) or masks improve the efficacy of drug delivery into the lungs. [ 6 ]


The solid drug powders in DPIs are released by the force of the patient's inspiratory flow. Turbulent airflow generated inside the inhaler by the inhalation force is associated with the movement of airflow and the resistance inside the inhaler. [ 8 ]  Patients should inhale with adequate inspiratory flow to overcome the resistance of DPIs, leading to drug particle deaggregation for successful pulmonary delivery. [ 9 ]


Soft-mist inhaler aerosolized a fixed dose of liquid drug formulation into inhalable tiny particles through an extremely fine  nozzle  system using the energy generated by the lever-compressed spring, without the use of  propellants . [ 11 ]  The slow and prolonged duration of aerosolization facilitates the patient's coordination between inhaler actuation and inhalation. [ 12 ]


Nebulizer is mainly used in emergencies, or by patients with poor compliance to other handy inhalers. Nebulizer delivers medication into the lungs by converting water-based liquid drug formulations into inhalable droplets mechanically, such as the use of an ultrasonic system, or thermally. [ 14 ]  Major types of nebulizers include vibrating mesh nebulizers (VMN), jet nebulizers (JN) and ultrasonic nebulizers. [ 15 ]


To achieve successful pulmonary drug delivery, a fraction of the inhaled particles should not deposit on the upper respiratory tract since they will be swallowed or expectorated without reaching the lungs, leading to the loss of pharmacological effect or provoking unwanted systemic side effects. Factors affecting the deposition of drug particles in lungs include drug particle properties, breathing patterns and respiratory tract geometry. [ 17 ]


Particle diameter and particle density significantly affect the drug deposition pattern in the respiratory tract, and are the most common considerations for formulation of pulmonary drugs. Drug particles with diameter larger than 5 μm, predominantly deposit on the upper respiratory tract, limiting the amount of drug particles reaching the lung. Moderate-size drug particles with diameter between 2 μm to 5 μm, primarily deposit on the central and small airways. Small drug particles with diameter smaller than 2 μm, predominantly deposit on the alveolar sacs. [ 18 ]  Other factors affecting deposition of drugs include particle electrostatic charge, particle shape and particle volatility. Electrostatic charge of the drug particles enhances deposition due to the formation of electrostatic force on the wall of the respiratory tract. Non-spherical particle shape has a different entry pathway compared to that of the spherical particles, causing a change in deposition pattern. Particle volatility affects particle diameter due to the change of particle diameter during condensation and evaporation. [ 19 ]


Drug particle deposition is associated with mean  residence time  and  tidal volume . An increase in mean residence time or tidal volume enhances drug deposition in lungs, while an increase in air flow decreases the mean residence time, resulting in the decrease of total deposition of drug particles. [ 20 ]


The  bifurcation of trachea  into bronchi with smaller diameter increases turbulent flow, leading to an increase in deposition in the large respiratory tract by impaction. [ 20 ]


Several advantages are associated with the pulmonary route of administration. For respiratory diseases, drug can be delivered directly to the disease site to perform topical relief, thus rapid  onset of action  can be achieved and there is less systemic side effects. [ 21 ]  Less dosage of drug can also achieve similar therapeutic effect compared to other routes of administration. For drugs designed to exert systemic effect through the lung as a drug target, the drug can reach the circulation bypassing poor gastrointestinal absorption and  hepatic first pass metabolism  which improve drug bioavailability. [ 21 ]  The large absorptive surface area, highly permeable membrane with rich blood supply also enable rapid onset of action and increase  bioavailability  of the drug. [ 21 ]


Despite a number of advantages in the pulmonary route compared to other routes of administration, numerous disadvantages are associated with the pulmonary route. As the drug needs to be delivered through the respiratory tract to the lungs, drug formulation can be challenging due to the defense mechanisms which intend to remove or inactivate the exogenous chemicals.  Airway constriction  and  mucus  secretion with  ciliary  movement prevent drugs from reaching the lungs, while  enzymes ,  macrophages  and  surfactant  in the lungs may also inactivate the drugs leading to less drug being absorbed. [ 2 ]  Studies show that only around 20% of drug reaches the lung for each inhalation and drug loss is mainly due to the accumulation in the oropharynx in terms of pMDIs and DPIs and drug retention in the device for nebulisers. [ 2 ]


Some irritating drug particles may also cause local side effects at the respiratory tract, for example inhaled corticosteroid accumulating in the oropharynx can result in  dysphonia  and  oral thrush . Besides, drug dosing may be inaccurate due to the variations of breathing patterns between individuals and the presence of numerous factors affecting the deposition and absorption of drug particles in the lungs. [ 20 ]  In particular, elder patients may not have enough strength to generate sufficient inspiratory flow, resulting in less drug inhalation and hence low drug bioavailability. Finally, inhalers, especially nebulizers, require regular maintenance and cleaning. The inhaler devices are relatively expensive compared to oral tablets, [ 22 ]  which may not be affordable to low income patients.


The effectiveness of drug delivery highly depends on the patient's compliance and proper inhaler technique with no significant error in using the inhalers. Poor compliance may lead to uncontrolled or poorly controlled disease status. [ 23 ]  For instance, a patient may feel recovered and discontinue the treatment, or a patient may forget to take the medication, resulting in suboptimal disease management. Reducing the amount of puffs by combination inhalers delivering two or more drugs in one breath or the use of electronic data loggers can improve compliance. [ 23 ]


Incorrect inhaler techniques, such as poor coordination, no exhalation before inhaling the drug aerosol or not holding breath for a few seconds after inhalation may lead to medication depositing inside the respiratory tract instead of the lungs, resulting in inefficient and inadequate treatment. [ 23 ] [ 24 ]  Practical demonstration instead of verbal instruction, education and rechecking on the inhaler technique after a period of time can reduce error and enhance true compliance.


The use of the pulmonary route as an entry into the systemic circulation is constantly developing due to the additional benefits of bypassing the hepatic first pass metabolism, rapid systemic absorption, higher patients compliance and its non-invasive nature. Potent drugs with the ability to penetrate the lung mucosa into the blood circulation may be available for treating diseases requiring systemic drug delivery. [ 25 ]  The ongoing researches include the use of inhaled  nicotine  for smoking cessation, [ 26 ]  the use of inhaled  levodopa  for the treatment of  Parkinson's disease , [ 27 ]  and the pulmonary delivery of various  biologics . [ 28 ]


In addition to the development of new pulmonary drugs, the drug formulation and particle engineering technology is advancing, such as the use of Ultrasound Mediated Amorphous to Crystalline transition (UMAX) process to micronize drug into inhalable drug particles with better performance, [ 29 ]  the use of drug  nanoparticles  to minimize unwanted drug adverse effects and increase drug bioavailability at the target site, [ 30 ]  and the use of porous drug particles to improve pulmonary delivery efficacy. [ 31 ]


Rectal administration  (colloquially known as  boofing  or  plugging ) uses the  rectum  as a  route of administration  for  medication  and other fluids, which are  absorbed  by the rectum's  blood vessels , [ Note 1 ]  and flow into the body's  circulatory system , which distributes the drug to the body's  organs  and  bodily systems . [ Note 2 ]


A drug that is administered rectally will in general (depending on the drug) have a faster onset, higher  bioavailability , shorter peak, and shorter duration than  oral  administration. [ 1 ] [ 2 ]  Another advantage of administering a drug rectally, is that it tends to produce less  nausea  compared to the oral route and prevents any amount of the drug from being lost due to  emesis  (vomiting). In addition, the rectal route bypasses around two-thirds of the  first-pass metabolism  as the rectum's venous drainage is two-thirds  systemic  ( middle  and  inferior rectal vein ) and one-third  hepatic portal system  ( superior rectal vein ). This means the drug will reach the circulatory system with significantly less alteration and in greater concentrations. [ Note 3 ]


In addition to pharmacological effects, rectal administration has some properties which can be advantageous for the use in medicine. Rectal administration can allow patients to remain in the home setting when the oral route is compromised. Unlike  intravenous  lines, which usually need to be placed in an  inpatient  environment and require special formulation of  sterile  medications, [ 3 ]  a specialized rectal  catheter  can be placed by a clinician, such as a  hospice  nurse or home health nurse, in the home. Many oral forms of medications can be crushed and suspended in water to be given via a rectal  catheter .


The rectal route of administration is useful for patients with any digestive tract motility problem, such as  dysphagia ,  ileus , or  bowel obstruction , that would interfere with the progression of the medication through the tract. This often includes patients  near the end of life  (an estimated 1.65 million people are in  hospice  care in the US each year). [ 4 ]  Because using the rectal route enables a rapid, safe, and lower cost alternative to administration of medications, [ 5 ]  it may also facilitate the care of patients in  long-term care  or  palliative care , or as an alternative to  intravenous  or  subcutaneous  medication delivery in other instances.


Besides its application in medicine, rectal administration is also employed by users of  psychoactive substances . Like in the medical procedure, the psychoactive drug is inserted into the anus, where it gets absorbed by the rectum's  blood vessels .


A study shows that awareness of rectal administration as a possible route of administration varies greatly among users of different drugs. The knowledge of rectal administration is highest among groups of users of  alcohol ,  stimulants  and  opioids , where over 30% of users are aware of it. [ 6 ]


The reasons for rectal administration are largely the same as with medicinal drugs: Bypassing the first-pass effect, fast onset, and a relatively high bioavailability with some drugs. [ 7 ]


Rectal administration is sometimes thought of as a safer alternative to  intravenous injection  of psychoactive substances, [ 8 ]  which carries a significant risk of infections and illnesses like  pulmonary granulomatosis . [ 9 ]


However, rectal administration of psychoactive drugs has risks associated with it also. [ 6 ]  The combination of a brief acting time (compared to oral administration) and an unpredictable absorption-rate can, particularly for new users, result in a risk of  overdoses . Use of shared or  non-sterile  equipment can increase the risk of acquiring  sexually transmitted infections . [ 10 ]  Some psychoactive substances like  substituted amphetamines  can induce a strong  vasoconstriction  in the rectal vasculature and lead to  intestinal ischemia . [ 6 ]


As with illicit psychoactive drugs in general, risks connected to rectal administration stem from the often unknown purity and composition of the drugs. This leads to the user not knowing if and what substances,  by-products  or  cutting agents  are present in their drugs [ 11 ]  before administering them rectally. Possible impurities or falsely marketed substances greatly increase the risk of administering illicit drugs rectally.


Rectal administration of medication may be performed with any of the following:


The  respiratory tract  is the subdivision of the  respiratory system  involved with the process of conducting air to the  alveoli  for the purposes of  gas exchange  in  mammals . [ 1 ]  The respiratory tract is lined with  respiratory epithelium  as respiratory mucosa. [ 2 ]


Air is breathed in through the  nose  to the  nasal cavity , where a layer of  nasal mucosa  acts as a filter and traps pollutants and other harmful substances found in the air. Next, air moves into the  pharynx , a passage that contains the intersection between the  oesophagus  and the  larynx . The opening of the larynx has a special flap of cartilage, the  epiglottis , that opens to allow air to pass through but closes to prevent food from moving into the airway.


From the  larynx , air moves into the  trachea  and down to the intersection known as the  carina  that branches to form the right and left primary (main)  bronchi . Each of these bronchi branches into a  secondary (lobar) bronchus  that branches into  tertiary (segmental) bronchi , that branch into smaller airways called  bronchioles  that eventually connect with tiny specialized structures called  alveoli  that function in  gas exchange .


The  lungs  which are located in the  thoracic cavity , are protected from physical damage by the  rib cage . At the base of the lungs is a sheet of skeletal muscle called the  diaphragm . The diaphragm separates the lungs from the  stomach  and  intestines . The diaphragm is also the main  muscle of respiration  involved in  breathing , and is controlled by the  sympathetic nervous system .


The lungs are encased in a  serous membrane  that folds in on itself to form the  pleurae  – a two-layered protective barrier. The inner  visceral pleura  covers the surface of the lungs, and the outer  parietal pleura  is attached to the inner surface of the thoracic cavity. The pleurae enclose a cavity called the  pleural cavity  that contains  pleural fluid . This fluid is used to decrease the amount of friction that lungs experience during breathing.


The respiratory tract is divided into the  upper airways  and  lower airways . The upper airways or upper respiratory tract includes the  nose  and nasal passages,  paranasal sinuses , the  pharynx , and the portion of the  larynx  above the  vocal folds  (cords). The lower airways or lower respiratory tract includes the portion of the larynx below the vocal folds,  trachea ,  bronchi  and  bronchioles . The lungs can be included in the lower respiratory tract or as separate entity and include the respiratory bronchioles,  alveolar ducts ,  alveolar sacs , and  alveoli . [ 3 ]


The respiratory tract can also be divided into a  conducting zone  and a  respiratory zone , based on the distinction of transporting gases or  exchanging  them.


The conducting zone includes structures outside of the lungs – the  nose ,  pharynx ,  larynx , and  trachea , and structures inside the lungs – the bronchi, bronchioles, and terminal bronchioles. The conduction zone conducts air breathed in that is filtered, warmed, and moistened, into the lungs. It represents the 1st through the 16th division of the respiratory tract. The conducting zone is most of the respiratory tract that conducts gases into and out of the lungs but excludes the respiratory zone that exchanges gases. The conducting zone also functions to offer a low resistance pathway for airflow. It provides a major  defense role  in its filtering abilities.


The respiratory zone includes the respiratory bronchioles, alveolar ducts, and alveoli, and is the site of oxygen and carbon dioxide  exchange  with the blood. The respiratory bronchioles and the alveolar ducts are responsible for 10% of the gas exchange. The alveoli are responsible for the other 90%. The respiratory zone represents the 16th through the 23rd division of the respiratory tract.


From the bronchi, the dividing tubes become progressively smaller with an estimated 20 to 23 divisions before ending at an alveolus. [ 1 ]


The  upper respiratory tract  can refer to the parts of the  respiratory system  lying above the  vocal folds , or above the  cricoid cartilage . [ 4 ] [ 5 ]  The  larynx  is sometimes included in both the upper and lower airways. [ 6 ]  The larynx is also called the voice box and has the associated cartilage that produces sound. The tract consists of the  nasal cavity  and  paranasal sinuses , the  pharynx  ( nasopharynx ,  oropharynx  and  laryngopharynx ) and sometimes includes the larynx.


The  lower respiratory tract  or  lower airway  is derived from the developing  foregut  and consists of the  trachea ,  bronchi  (primary, secondary and tertiary),  bronchioles  (including terminal and respiratory), and  lungs  (including  alveoli ). [ 7 ]  It also sometimes includes the larynx.


The lower respiratory tract is also called the  respiratory tree  or  tracheobronchial tree , to describe the branching structure of airways supplying air to the lungs, and includes the trachea, bronchi and bronchioles. [ 8 ]


At each division point or  generation , one airway branches into two smaller airways. The human respiratory tree may consist on average of 23 generations, while the respiratory tree of the  mouse  has up to 13 generations.  Proximal divisions (those closest to the top of the tree, such as the bronchi) mainly function to transmit air to the lower airways. Later divisions including the respiratory bronchiole, alveolar ducts, and alveoli, are specialized for  gas exchange .


The  trachea  is the largest tube in the respiratory tract and consists of  tracheal rings  of  hyaline cartilage . It branches off into two bronchial tubes, a left and a right main  bronchus . The bronchi branch off into smaller sections inside the lungs, called  bronchioles . These bronchioles give rise to the air sacs in the lungs called the  alveoli . [ 10 ]


The  lungs  are the largest organs in the lower respiratory tract. The lungs are suspended within the  pleural cavity  of the thorax. The  pleurae  are two thin membranes, one cell layer thick, which surround the lungs. The inner ( visceral pleura ) covers the lungs and the outer ( parietal pleura ) lines the inner surface of the chest wall. This membrane secretes a small amount of fluid, allowing the lungs to move freely within the pleural cavity while expanding and contracting during breathing. The lungs are divided into different lobes. The right lung is larger in size than the left, because of the heart's being situated to the left of the midline. The right lung has three lobes – upper, middle, and lower (or superior, middle, and inferior), and the left lung has two – upper and lower (or superior and inferior), plus a small tongue-shaped portion of the upper lobe known as the lingula. Each lobe is further divided up into segments called  bronchopulmonary segments . Each lung has a costal surface, which is adjacent to the ribcage; a diaphragmatic surface, which faces downward toward the diaphragm; and a mediastinal surface, which faces toward the center of the chest, and lies against the heart, great vessels, and the carina where the two mainstem bronchi branch off from the base of the trachea.


The  alveoli  are tiny air sacs in the lungs where gas exchange takes place. The mean number of alveoli in a human lung is 480 million. [ 11 ]  When the diaphragm contracts, a negative pressure is generated in the thorax and air rushes in to fill the cavity. When that happens, these sacs fill with air, making the lung expand. The alveoli are rich with capillaries, called alveolar capillaries. Here the red blood cells absorb oxygen from the air and then carry it back in the form of oxyhaemaglobin, to nourish the cells. The red blood cells also carry carbon dioxide (CO 2 ) away from the cells in the form of  carbaminohemoglobin  and release it into the alveoli through the alveolar capillaries. When the diaphragm relaxes, a positive pressure is generated in the thorax and air rushes out of the alveoli expelling the carbon dioxide.


The respiratory tract is covered in  epithelium , which varies down the tract. There are  glands  and  mucus  produced by  goblet cells  in parts, as well as  smooth muscle ,  elastin  or  cartilage . The epithelium from the nose to the bronchioles is covered in ciliated  pseudostratified columnar epithelium , commonly called  respiratory epithelium . [ 12 ]  The cilia beat in one direction, moving mucus towards the throat where it is swallowed. Moving down the bronchioles, the cells get more cuboidal in shape but are still ciliated.


Glands are abundant in the upper respiratory tract, but there are fewer lower down and they are absent starting at the bronchioles. The same goes for goblet cells, although there are scattered ones in the first bronchioles.


Cartilage is present until the bronchioles. In the trachea, they are C-shaped rings of  hyaline cartilage , whereas in the bronchi the cartilage takes the form of interspersed plates. Smooth muscle starts in the trachea, where it joins the C-shaped rings of cartilage. It continues down the  bronchi  and  bronchioles , which it completely encircles. Instead of hard cartilage, the bronchi and bronchioles are composed of elastic tissue.


The lungs are made up of thirteen different kinds of cells, eleven types of  epithelial  cell and two types of  mesenchymal  cell. [ 13 ]  The epithelial cells form the lining of the tracheal, and bronchial tubes, while the mesenchymal cells line the lungs.


Most of the respiratory tract exists merely as a piping system for air to travel in the lungs, and  alveoli  are the only part of the lung that  exchanges   oxygen  and  carbon dioxide  with the  blood .


Respiration is the  rhythmical process  of  breathing , in which air is drawn into the alveoli of the lungs via  inhalation  and subsequently expelled via  exhalation . When a human being inhales, air travels down the trachea, through the bronchial tubes, and into the lungs.  The entire tract is protected by the rib cage,  spine , and  sternum . In the lungs, oxygen from the inhaled air is transferred into the blood and circulated throughout the body. Carbon dioxide (CO 2 ) is transferred from returning blood back into gaseous form in the lungs and exhaled through the lower respiratory tract and then the upper, to complete the process of  breathing .


Unlike the  trachea  and  bronchi , the upper airway is a collapsible, compliant tube. As such, it has to be able to withstand suction pressures generated by the rhythmic expansion of the  thoracic cavity  that sucks air into the lungs. This is accomplished by the contraction of upper airway muscles during inhalation, such as the  genioglossus  (tongue) and the  hyoid  muscles. In addition to rhythmic innervation from the  respiratory center  in the  medulla oblongata , the  motor neurons  controlling the muscles also receive tonic innervation that sets a baseline level of stiffness and size.


The  diaphragm  is the primary muscle that allows for lung expansion and contraction. Smaller muscles between the ribs, the  external intercostals , assist with this process.


The epithelial lining of the upper respiratory tract is interspersed with  goblet cells  that secrete a protective  mucus . This helps to filter waste, which is eventually either swallowed into the highly acidic stomach environment or expelled via spitting. The epithelium lining the respiratory tract is covered in small hairs called  cilia . These beat rhythmically out from the lungs, moving secreted mucus foreign particles toward the  laryngopharynx  upwards and outwards, in a process called  mucociliary clearance , they prevent mucus accumulation in the lungs.  Macrophages  in the alveoli are part of the immune system which  engulf  and digest any inhaled harmful agents.


Hair in the nostrils plays a protective role, trapping particulate matter such as dust. [ 14 ]  These hairs, called vibrissae, are thicker than body hair and effectively block larger particles from entering the respiratory tract.  They also increase the surface area for particle deposition, improving the nose's ability to filter pathogens.  [ 15 ]  The  cough reflex  expels all irritants within the mucous membrane to the outside. The airways of the lungs contain rings of muscle. When the passageways are irritated by some allergen, these muscles can constrict.


The respiratory tract is a common site for infections.


Upper respiratory tract infections  are probably the most common infections in the world.


The respiratory system is very prone to developing infections in the lungs. Infants and older adults are more likely to develop infections in their lungs because their lungs are not as strong in fighting off these infections. Most of these infections used to be fatal, but with new research and medicine, they are now treatable. With bacterial infections, antibiotics are prescribed, while viral infections are harder to treat but still curable.


The  common cold , and  flu  are the most common causes of an upper respiratory tract infection, which can cause more serious illness that can develop in the lower respiratory
tract.


Pneumonia  is the most common, and frequent  lower respiratory tract infection . This can be either viral, bacterial, or fungal. This infection is very common because pneumonia can be airborne, and when you inhale this infection in the air, the particles enter the lungs and move into the air sacs. This infection quickly develops in the lower part of the lung and fills the lung with fluid, and excess mucus. This causes difficulty in breathing and coughing as the lower respiratory tract tries to get rid of the fluid in the lungs. You can be more prone to developing this infection if you have asthma, flu, heart disease, or cancer [ 16 ]


Bronchitis  is another common infection that takes place in the lower respiratory tract. It is an inflammation of the bronchial tubes. There are two forms of this infection: acute bronchitis, which is treatable and can go away without treatment, or chronic bronchitis, which comes and goes, but will always affect one's lungs. Bronchitis increases the amount of mucus that is natural in your respiratory tract.  Chronic bronchitis is common in smokers, because the tar from smoking accumulates over time, causing the lungs to work harder to repair themselves. [ 17 ]


Tuberculosis  is one of many other infections that occurs in the lower respiratory tract. You can contract this infection from airborne droplets, and if inhaled you are at risk of this disease. This is a bacterial infection that deteriorates the lung tissue resulting in coughing up blood. [ 18 ]  This infection is deadly if not treated.


Some of these  cancers  have environmental causes such as smoking. When a tobacco product is inhaled, the smoke paralyzes the cilia, causing mucus to enter the lungs. Frequent smoking, over time, causes the cilia hairs to die and can no longer filter mucus. Tar from the smoke inhaled enters the lungs, turning the pink-coloured lungs black. The accumulation of this tar could eventually lead to  lung cancer , or  chronic obstructive pulmonary disease . [ 7 ]


Chronic obstructive pulmonary disease  (COPD) is a common lower respiratory disease that can be caused by exposure to harmful chemicals, or prolonged use of tobacco. This disease is chronic and progressive, the damage to the lungs is irreversible and eventually fatal. COPD destroys the alveoli, and lung tissue which makes breathing very difficult, causing  shortness of breath ,  hyperventilation , and raised chest. The decreased number of alveoli causes loss of oxygen supply to the lungs and an increased accumulation of carbon dioxide. There are two types of COPD: primary and secondary. [ citation needed ]  Primary COPD can be found in younger adults. This type of COPD deteriorates the air sacs, and lung mass. Secondary COPD can be found in older adults who smoke or have smoked and have a history of bronchitis.  [ citation needed ]  COPD includes symptoms of  emphysema  and  chronic bronchitis . [ 19 ]


The bronchi are the main passages to the right and left lungs. These airways carry oxygen to the bronchioles inside the lungs.  Inflammation  of the bronchii and bronchioles can cause them to swell up,  which could lead to an  asthma  attack. This results in  wheezing , tightness of the chest, and severe difficulty in breathing. There are different types of asthma that affect the functions of the bronchial tubes. Allergies can also set off an allergic reaction, causing swelling of the bronchial tubes; as a result, the air passage will swell up, or close up completely. [ 20 ]


In general, air is inhaled  through the nose . It can be inhaled through the mouth if it is not possible to breathe through the nose. However, chronic  mouth breathing  can cause a dry mouth and lead to infections. [ 21 ]


Subcutaneous administration  is the insertion of medications beneath the skin either by injection or infusion.


A  subcutaneous injection  is administered as a  bolus  into the  subcutis , the layer of skin directly below the  dermis  and  epidermis , collectively referred to as the  cutis . The instruments are usually a  hypodermic needle  and a  syringe . Subcutaneous injections are highly effective in administering medications such as  insulin ,  morphine ,  diacetylmorphine  and  goserelin . Subcutaneous administration may be  abbreviated  as  SC ,  SQ ,  subcu ,  sub-Q ,  SubQ ,  or  subcut .  Subcut  is the preferred abbreviation to reduce the risk of misunderstanding and potential errors. [ 1 ]


Subcutaneous tissue has few blood vessels and so drugs injected into it are intended for slow, sustained rates of absorption, often with some amount of  depot  effect. Compared with other  routes of administration , it is slower than  intramuscular injections  but still faster than  intradermal injections .  Subcutaneous infusion  (as opposed to subcutaneous injection) is similar but involves a continuous drip from a bag and line, as opposed to injection with a syringe.


A subcutaneous injection is administered into the fatty tissue of the  subcutaneous tissue , located below the  dermis  and  epidermis . [ 2 ]  They are commonly used to administer medications, especially those which cannot be administered by mouth as they would not be absorbed from the  gastrointestinal tract . A subcutaneous injection is absorbed slower than a substance injected  intravenously  or  into a muscle , but faster than a medication administered by mouth. [ 3 ] : 721


Medications commonly administered via subcutaneous injection or infusion include  insulin ,  live vaccines ,  monoclonal antibodies , and  heparin . These medications cannot be administered orally as the molecules are too large to be absorbed in the intestines. [ 4 ]  Subcutaneous injections can also be used when the increased bioavailability and more rapid effects over oral administration are preferred. They are also the easiest form of  parenteral administration  of medication to perform by lay people, and are associated with less adverse effects such as pain or infection than other forms of injection. [ 4 ]


Perhaps the most common medication administered subcutaneously is insulin. While attempts have been made since the 1920s to administer insulin orally, the large size of the molecule has made it difficult to create a formulation with absorption and predictability that comes close to subcutaneous injections of insulin. [ 5 ]  People with  type 1 diabetes  almost all require insulin as part of their treatment regimens, and a smaller proportion of people with  type 2 diabetes  do as well — with tens of millions of prescriptions per year in the United States alone. [ 6 ]


Insulin historically was injected from a vial using a syringe and needle, but may also be administered subcutaneously using devices such as  injector pens  or  insulin pumps . An insulin pump consists of a catheter which is inserted into the subcutaneous tissue, and then secured in place to allow insulin to be administered multiple times through the same injection site. [ 3 ] : 722


Subcutaneous injection may also be used by people to (self-) administer  recreational drugs . This can be referred to as  skin popping . [ 7 ]  In some cases, the administration of illicit drugs in this way is associated with unsafe practices leading to infections and other adverse effects. In rare cases, this results in serious side effects such as  AA amyloidosis . [ 7 ]  Recreational drugs reported to be administered subcutaneously have included  cocaine , [ 8 ]   mephedrone , [ 9 ]  and  amphetamine  derivatives such as  PMMA . [ 10 ]


Contraindications to subcutaneous injections primarily depend on the specific medication being administered. Doses which would require more than 2 mL to be injected at once are not administered subcutaneously. [ 11 ]  Medications which may cause necrosis or otherwise be damaging or irritating to tissues should also not be administered subcutaneously. [ 12 ]  An injection should not be given at a specific site if there is inflammation or skin damage in the area. [ 13 ] : 144


With normal doses of medicine (less than 2 mL in volume), complications or adverse effects are very rare. The most common adverse reactions after subcutaneous injections are administered are termed " injection site reactions ". This term encompasses any combination of redness, swelling, itching, bruising, or other irritation that does not spread beyond the immediate vicinity of the injection. [ 14 ]  Injection site reactions may be minimized if repeated injections are necessary by moving the injection site at least one inch from previous injections, or using a different injection location altogether. [ 14 ]  There may also be specific complications associated with the specific medication being administered.


Due to the frequency of injections required for the administration of insulin products via subcutaneous injection, insulin is associated with the development of  lipohypertrophy  and  lipoatrophy . This can lead to slower or incomplete absorption from the injection site. Rotating the injection site is the primary method of preventing changes in tissue structure from insulin administration. [ 15 ]  Heparin-based anticoagulants injected subcutaneously may cause  hematoma  and bruising around the injection site due to their anticoagulant effect. This includes  heparin  and  low molecular weight heparin  products such as enoxaparin. There is some low certainty evidence that administering the injection more slowly may decrease the pain from heparin injections, but not the risk of or extent of bruising. [ 16 ]  Subcutaneous heparin-based anticoagulation may also lead to necrosis of the surrounding skin or lesions, most commonly when injected in the abdomen. [ 17 ]


Many medications have the potential to cause local lesions or swelling due to the irritating effect the medications have on the skin and subcutaneous tissues. This includes medications such as  apomorphine [ 18 ]  and  hyaluronic acid  injected as a filler, which may cause the area to appear bruised. Hyaluronic acid "bruising" may be treated using injections of  hyaluronidase  enzyme around the location. [ 19 ]


Other common medication-specific side effects include pain, burning or stinging, warmth, rash, flushing, or multiple of these reactions at the injection site, collectively termed "injection site reactions". This is seen with the subcutaneous injection of  triptans  for migraine headache, [ 20 ]   medroxyprogesterone acetate  for contraception, [ 21 ]  as well as many monoclonal antibodies. In most cases, injection site reactions are self-limiting and resolve on their own after a short time without treatment, and do not require the medication to be discontinued. [ 21 ]


The administration of vaccines subcutaneously is also associated with injection site reactions. This includes the  BCG vaccine  which is associated with a specific scar appearance which can be used as evidence of prior vaccination. [ 22 ]  Other subcutaneous vaccines, many of which are live vaccines including the  MMR vaccine  and the  varicella vaccine , which may cause  fever  and rash, as well as a feeling of general  malaise  for a day or two following the vaccination. [ 23 ]


Subcutaneous injections are performed by cleaning the area to be injected followed by an injection, usually at a 45-degree angle to the skin when using a syringe and needle, or at a 90-degree angle (perpendicular) if using an injector pen. The appropriate injection angle is based on the length of needle used, and the depth of the subcutaneous fat in the skin of the specific person. A 90-degree angle is always used for medications such as  heparin . If administered at an angle, the skin and underlying tissue may be pinched upwards prior to injection. The injection is administered slowly, lasting about 10 seconds per milliliter of fluid injected, and the needle may be left in place for 10 seconds following injection to ensure the medicine is fully injected. [ 3 ] : 724


The  gauge  of the needle used can range from 25 gauge to 27 gauge, while the length can vary between  1 ⁄ 2 -inch to  5 ⁄ 8 -inch for injections using a syringe and needle. [ 3 ] : 722   For subcutaneous injections delivered using devices such as  injector pens , the needle used may be as thin as 34 gauge (commonly 30–32 gauge), and as short as 3.5 mm (commonly 3.5 mm to 5 mm). [ 24 ]  Subcutaneous injections can also be delivered via a pump system which uses a cannula inserted under the skin. The specific needle size/length, as well as appropriateness of a device such as a pen or pump, is based on the characteristics of a person's skin layers. [ 3 ] : 722–724


Commonly used injection sites include: [ 3 ] : 723


The choice of specific injection site is based on the medication being administered, with  heparin  almost always being administered in the abdomen, as well as preference. Injections administered frequently or repeatedly should be administered in a different location each time, either within the same general site or a different site, but at least one inch away from recent injections. [ 3 ] : 724


As opposed to intramuscular or intravenous injections, subcutaneous injections can be easily performed by people with minor skill and training required. The injection sites for self-injection of medication are the same as for injection by a healthcare professional, and the skill can be taught to patients using pictures, videos, or models of the subcutaneous tissue for practice. People who are to self-inject medicine subcutaneously should be trained how to evaluate and rotate the injection site if complications or contraindications arise. Self-administration by subcutaneous injection generally does not require disinfection of the skin outside of a hospital setting as the risk of infection is extremely low, but instead it is recommended to ensure that the site and person's hands are simply clean prior to administration. [ 25 ]


Subcutaneous infusion , also known as  interstitial infusion  or  hypodermoclysis , is a form of subcutaneous (under the skin) administration of fluids to the body, often  saline  or glucose solutions. [ 26 ]  It is the infusion counterpart of  subcutaneous injection  with a syringe.


Subcutaneous infusion can be used where a slow rate of fluid uptake is required compared to  intravenous infusion .  Typically, it is limited to 1 mL per minute, although it is possible to increase this by using two sites simultaneously.  The chief advantages of subcutaneous infusion over intravenous infusion is that it is cheap and can be administered by non-medical personnel with minimal supervision.  It is therefore particularly suitable for home care.  The enzyme  hyaluronidase  can be added to the fluid to improve absorption during the infusion. [ 27 ]


Subcutaneous infusion can be speeded up by applying it to multiple sites simultaneously.  The technique was pioneered by  Evan O'Neill Kane  in 1900.  Kane was looking for a technique that was as fast as intravenous infusion but not so risky to use on trauma patients in unhygienic conditions in the field. [ 28 ]


Sublingual  ( abbreviated   SL ), from the  Latin  for "under the  tongue ", refers to the  pharmacological   route of administration  by which substances diffuse into the  blood  through  tissues  under the tongue. [ 1 ]


Many drugs are absorbed through sublingual administration, including  cardiovascular  drugs,  steroids ,  barbiturates ,  benzodiazepines , [ 2 ]   opioid   analgesics ,  THC ,  CBD , some  proteins  and increasingly,  vitamins  and  minerals .


When a  chemical  comes in contact with the  mucous membrane  beneath the tongue, it is absorbed.  Because the  connective tissue  beneath the epithelium contains a profusion of capillaries, the substance then diffuses into them and enters the venous circulation. [ 1 ]   In contrast, substances absorbed in the intestines are subject to  first-pass metabolism  in the liver before entering the general circulation.


Sublingual administration has certain advantages over oral administration.  Being more direct, it is often faster  onset of action , and it ensures that the substance will risk degradation only by salivary enzymes before entering the bloodstream, whereas orally administered drugs must survive passage through the hostile environment of the  gastrointestinal tract , which risks degrading them, by either stomach acid or bile, or by  enzymes  such as  monoamine oxidase  (MAO).  Furthermore, after absorption from the gastrointestinal tract, such drugs must pass to the  liver , where they may be extensively altered; this is known as the  first pass effect  of drug metabolism.  Due to the digestive activity of the stomach and intestines, the oral route is unsuitable for certain substances, such as  salvinorin A .


Pharmaceutical preparations for sublingual administration are manufactured in the form of:


Almost any form of substance may be amenable to sublingual administration if it dissolves easily in saliva.  Powders and aerosols may all take advantage of this method.  However, a number of factors, such as  pH ,  molecular weight , and  lipid solubility , may determine whether the route is practical.  Based on these properties, a suitably soluble drug may diffuse too slowly through the mucosa to be effective.  However, many drugs are much more potent taken sublingually, and it is generally a safer alternative than administration via the nasal mucosa. [ citation needed ]   This method is also extensively used by people administering certain psychoactive drugs.  One drawback, however, is  tooth discoloration  and decay caused by long-term use of this method with acidic or otherwise caustic drugs and fillers.


In addition to  salvinorin A , other psychoactives may also be applied sublingually.   LSD ,  MDMA ,  morphine ,  alprazolam ,  clonazepam ,  diazepam , and many other substances including the psychedelic  tryptamines  and  phenethylamines , and even recreational  cannabis edibles  ( THC ) are all viable candidates for administration via this route. [ citation needed ]   Most often, the drug in question is powdered and placed in the mouth (often directly under the tongue).  If held there long enough, the drug will diffuse into the blood stream, bypassing the GI tract.  This may be a preferred method to simple oral administration, because MAO is known to oxidize many drugs (especially the tryptamines such as  DMT ) and because this route translates the chemical directly to the brain, where most psychoactives act.  The method is limited by excessive salivation washing the chemical down the throat.  Also, many alkaloids have an unpleasant taste which makes them difficult to hold in the mouth.  Tablets of psychoactive pharmaceuticals usually include bitter chemicals such as  denatonium  in order to discourage abuse and also to discourage children from eating them. [ citation needed ]


Allergens  may also be applied under the tongue as a part of  allergen immunotherapy .