A relatively new way of administration of therapeutic  peptides  and proteins (such as  cytokines , domain  antibodies ,  Fab fragments  or single chain antibodies)  is sublingual administration.  Peptides and proteins are not stable in the  gastro-intestinal tract , mainly due to degradation by enzymes and pH differences.  As a consequence, most peptides (such as  insulin ,  exenatide ,  vasopressin , etc.) or proteins (such as  interferon ,  EPO  and  interleukins ) have to be administered by injection. Recently, new technologies have allowed sublingual administration of such molecules.  Increased efforts are underway to deliver macromolecules (peptides, proteins and immunotherapies)  by sublingual route, by companies such as  Novo Nordisk ,  Sanofi  and BioLingus. [ 3 ]
Sublingual delivery may be particularly effective for immuno-active medicines, due to the presence of immune-receptor cells close to the sublingual area.


The sublingual route may also be used for  vaccines  against various infectious diseases. Thus, preclinical studies have found that sublingual vaccines can be highly immunogenic and may protect against influenza virus [ 4 ] [ 5 ]
and  Helicobacter pylori , [ 6 ]  but sublingual administration may also be used for vaccines against other infectious diseases. [ citation needed ]


A  suppository  is a  dosage form  used to deliver  medications  by insertion into a  body orifice  (any opening in the body), where it dissolves or melts to exert local or systemic effects. There are three types of suppositories, each to insert into a different sections: rectal suppositories into the  rectum , vaginal suppositories into the  vagina , and urethral suppositories into the  urethra of a male .


Suppositories are ideal for infants, elderly individuals and post-operative patients, who are unable to swallow oral medications, and for individuals experiencing severe nausea and/or vomiting. [ 1 ] [ 2 ] [ 3 ]


Several different ingredients can be used to form the base of a suppository:  cocoa butter  or a similar substitute,  polyethylene glycol ,  hydrogels , and glycerinated  gelatin . The type of material used depends on the type of suppository, the type of drug, and the conditions in which the suppository will be stored. [ 4 ]


In 1991, a study on suppository insertion in  The Lancet  found that the "torpedo" shape helps the device to travel internally, increasing its efficacy. [ 5 ]  The findings of this single study have been challenged as there is insufficient evidence on which to base clinical practice. [ 6 ]  Rectal suppositories are intended for localized or systemic action to relieve pain, constipation, irritation, inflammation, nausea and vomiting, fever, migraines, allergies, and sedation. [ 7 ] [ 8 ]  If they cause inflammation, chronic use of suppositories may cause  rectal stricture , [ 9 ]  but overall this is a safe method of drug delivery. [ 10 ]


Alprostadil  pellets are urethral suppositories used for the treatment of severe  erectile dysfunction (impotence) . They are marketed under the name  Muse  in the United States. [ 11 ]  Its use has diminished since the development of oral impotence medications.


Modified-release dosage  is a mechanism that (in contrast to immediate-release  dosage ) delivers a  drug  with a delay after its  administration  (delayed-release dosage) or for a prolonged period of time (extended-release [ER, XR, XL] dosage) or to a specific target in the body (targeted-release dosage). [ 1 ]


Sustained-release dosage forms  are  dosage forms  designed to  release (liberate) a drug  at a predetermined rate in order to maintain a constant drug concentration for a specific period of time with minimum  side effects . This can be achieved through a variety of formulations, including  liposomes  and drug-polymer conjugates (an example being  hydrogels ). Sustained release's definition is more akin to a "controlled release" rather than "sustained".


Extended-release dosage consists of either sustained-release (SR) or controlled-release (CR) dosage. SR maintains drug release over a sustained period but not at a constant rate. CR maintains drug release over a sustained period at a nearly constant rate. [ 1 ]


Sometimes these and  other terms  are treated as synonyms, but the United States  Food and Drug Administration  has in fact defined most of these as different concepts. [ 1 ]  Sometimes the term "depot tablet" is used, by analogy to the term for an  injection formulation of a drug which releases slowly over time , but this term is not medically or pharmaceutically standard for oral medication.


Modified-release dosage and its variants are mechanisms used in  tablets  (pills) and  capsules  to  dissolve  a  drug  over time in order to be released more slowly and steadily into the bloodstream, while having the advantage of being taken at less frequent intervals than immediate-release (IR) formulations of the same drug. For example, orally administered  extended-release morphine  can enable certain chronic pain patients to take only  1–2  tablets per day, rather than needing to redose every  4–6   hours  as is typical with standard-release morphine tablets.


Most commonly it refers to time-dependent release in oral dose formulations. Timed release has several distinct variants such as sustained release where prolonged release is intended, pulse release, delayed release (e.g. to target different regions of the GI tract) etc. A distinction of controlled release is that it not only prolongs action, but it attempts to maintain drug levels within the  therapeutic window  to avoid potentially hazardous peaks in drug concentration following ingestion or injection and to maximize therapeutic efficiency.


In addition to pills, the mechanism can also apply to capsules and injectable  drug carriers  (that often have an additional release function), forms of controlled release medicines include gels, implants and devices (e.g. the  vaginal ring  and  contraceptive implant ) and  transdermal patches .


Examples for cosmetic, personal care, and food science applications often centre on odour or flavour release.


The release technology scientific and industrial community is represented by the Controlled Release Society (CRS). The CRS is the worldwide society for delivery science and technologies. CRS serves more than 1,600 members from more than 50 countries. Two-thirds of CRS membership is represented by industry and one-third represents academia and government. CRS is affiliated with the  Journal of Controlled Release  and  Drug Delivery and Translational Research  scientific journals.


There is no industry standard for these abbreviations, and confusion and misreading have sometimes caused prescribing errors. [ 2 ]  Clear handwriting is necessary. For some drugs with multiple formulations, putting the meaning in parentheses is advisable.


A few other abbreviations are similar to these (in that they may serve as suffixes) but refer to dose rather than release rate. They include  ES  and  XS  (Extra Strength).


Today, most time-release drugs are formulated so that the  active ingredient  is embedded in a matrix of insoluble substance(s) (various: some  acrylics , even  chitin ; these substances are often  patented ) such that the dissolving drug must find its way out through the holes.


In some SR formulations, the drug dissolves into the matrix, and the matrix physically swells to form a gel, allowing the drug to exit through the gel's outer surface.


Micro-encapsulation  is also regarded as a more complete technology to produce complex dissolution profiles. Through coating an active pharmaceutical ingredient around an inert core and layering it with insoluble substances to form a microsphere, one can obtain more consistent and replicable dissolution rates in a convenient format that can be mixed and matched with other instant release pharmaceutical ingredients into any two piece gelatin  capsule .


There are certain considerations for the formation of sustained-release formulation:


The  biological half-life  of the drug refers to the drug's elimination from the bloodstream which can be caused by metabolism, urine, and other forms of excretion. If the active compound has a long half-life (over 6 hours), it is sustained on its own. If the active compound has a short half-life, it would require a large amount to maintain a prolonged effective dose. In this case, a broad therapeutic window is necessary to avoid toxicity; otherwise, the risk is unwarranted and another mode of administration would be recommended. [ 3 ]  Appropriate half-lives used to apply sustained methods are typically 3–4 hours and a drug dose greater than 0.5 grams is too high. [ 4 ] [ 5 ]


The  therapeutic index  also factors whether a drug can be used as a time release drug. A drug with a thin therapeutic range, or small therapeutic index, will be determined unfit for a sustained release mechanism in partial fear of  dose dumping  which can prove fatal at the conditions mentioned. [ 6 ]  For a drug that is made to be released over time, the objective is to stay within the therapeutic range as long as needed. [ 3 ]


There are many different methods used to obtain a sustained release.


Diffusion systems' rate release is dependent on the rate at which the drug dissolves through a barrier which is usually a type of polymer. Diffusion systems can be broken into two subcategories, reservoir devices and matrix devices. [ 3 ]


Dissolution systems must have the system dissolved slowly in order for the drug to have sustained release properties which can be achieved by using appropriate salts and/or derivatives as well as coating the drug with a dissolving material. [ 3 ]  It is used for drug compounds with high solubility in water. [ 6 ]  When the drug is covered with some slow dissolving coat, it will eventually release the drug. Instead of diffusion, the drug release depends on the solubility and thickness of the coating. Because of this mechanism, the dissolution will be the rate limiting factor for drug release. [ 3 ]  Dissolution systems can be broken down to subcategories called reservoir devices and matrix devices. [ 6 ]


Osmotic controlled-release oral delivery systems (OROS) have the form of a rigid  tablet  with a semi-permeable outer membrane and one or more small  laser drilled  holes in it. As the tablet  passes through the body , water is absorbed through the  semipermeable membrane  via  osmosis , and the resulting  osmotic pressure  is used to push the active  drug  through the opening(s) in the tablet. OROS is a trademarked name owned by  ALZA Corporation , which pioneered the use of osmotic pumps for oral drug delivery. [ 10 ] [ 11 ] [ 12 ]


Osmotic release systems have a number of major advantages over other controlled-release mechanisms. They are significantly less affected by factors such as  pH , food intake,  GI motility , and differing intestinal environments. Using an osmotic pump to deliver drugs has additional inherent advantages regarding control over drug delivery rates. This allows for much more precise drug delivery over an extended period of time, which results in much more predictable  pharmacokinetics . However, osmotic release systems are relatively complicated, somewhat difficult to manufacture, and may cause irritation or even blockage of the GI tract due to prolonged release of irritating drugs from the non-deformable tablet. [ 10 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ] [ 17 ] [ 18 ]


In the ion-exchange method, the resins are cross-linked water-insoluble polymers that contain ionisable functional groups that form a repeating pattern of polymers, creating a polymer chain. [ 3 ] [ 6 ]  The drug is attached to the resin and is released when an appropriate interaction of ions and ion exchange groups occur. The area and length of the drug release and number of cross-link polymers dictate the rate at which the drug is released, determining the SR effect. [ 6 ]


A floating system is a system where it floats on gastric fluids due to low density. The density of the gastric fluids is about 1 g/mL; thus, the drug/tablet administered must have a smaller density. The  buoyancy  will allow the system to float to the top of the stomach and release at a slower rate without worry of excreting it. This system requires that there are enough gastric fluids present as well as food. [ 3 ]  Many types of forms of drugs use this method such as powders, capsules, and tablets. [ 19 ]


Bio-adhesive  systems generally are meant to stick to mucus and can be favorable for mouth based interactions due to high mucus levels in the general area but not as simple for other areas. Magnetic materials can be added to the drug so another magnet can hold it from outside the body to assist in holding the system in place. However, there is low patient compliance with this system. [ 3 ]


The matrix system is the mixture of materials with the drug, which will cause the drug to slow down. However, this system has several subcategories: hydrophobic matrices, lipid matrices, hydrophilic matrices, biodegradable matrices, and mineral matrices. [ 3 ]


Examples of stimuli that may be used to bring about release include pH, enzymes, light, magnetic fields, temperature, ultrasonics, osmosis, cellular traction forces, [ 21 ]  and electronic control of  MEMS [ 22 ]  and  NEMS . [ 23 ]


Spherical hydrogels, in micro-size (50-600 μm diameter) with 3-dimensional cross-linked polymer, can be used as drug carrier to control the release of the drug. These hydrogels are called microgels. They may possess a negative charge as example DC-beads. By ion-exchange mechanism, a large amount of oppositely charged amphiphilic drugs can be loaded inside these microgels. Then, the release of these drugs can be controlled by a specific triggering factor like pH, ionic strength or temperature. [ 24 ]


Some time release formulations do not work properly if split, such as controlled-release tablet coatings, while other formulations such as micro-encapsulation still work if the microcapsules inside are swallowed whole. [ 25 ] [ 26 ]


Among the  health information technology  (HIT) that pharmacists use are medication safety tools to help manage this problem. For example, the ISMP "do not crush" list [ 27 ]  can be entered into the system so that warning stickers can be printed at the point of dispensing, to be stuck on the pill bottle.


Pharmaceutical companies that do not supply a range of half-dose and quarter-dose versions of time-release tablets can make it difficult for patients to be slowly tapered off their drugs.


The earliest SR drugs are associated with a patent in 1938 by Israel Lipowski, who coated pellets which led to coating particles. [ 7 ]  The science of controlled release developed further with more oral sustained-release products in the late 1940s and early 1950s, the development of controlled release of marine anti-foulants in the 1950s, and  controlled release fertilizer  in the 1970s where sustained and controlled delivery of nutrients was achieved following a single application to the soil. Delivery is usually effected by dissolution, degradation, or disintegration of an  excipient  in which the active compound is formulated.  Enteric coating  and other encapsulation technologies can further modify release profiles.


Topical drug delivery  (TDD) is a  route of drug administration  that allows the topical formulation to be delivered across the skin upon application, hence producing a localized effect to treat skin disorders like  eczema . [ 1 ] [ 2 ]  The formulation of topical drugs can be classified into  corticosteroids ,  antibiotics ,  antiseptics , and  anti-fungal . The mechanism of topical delivery includes the  diffusion  and  metabolism  of drugs in the skin. [ 1 ]  Historically, topical route was the first route of medication used to deliver drugs in humans in ancient Egyptian and Babylonian in 3000 BCE. In these ancient cities, topical medications like  ointments  and  potions  were used on the skin. [ 3 ] [ 4 ]  The delivery of topical drugs needs to pass through multiple skin layers and undergo  pharmacokinetics , hence factor like dermal diseases minimize the  bioavailability  of the topical drugs. [ 5 ]  The wide use of topical drugs leads to the advancement in topical drug delivery. These advancements are used to enhance the delivery of topical medications to the skin by using chemical and physical agents. For chemical agents, carriers like  liposomes  and  nanotechnologies  are used to enhance the absorption of topical drugs. [ 4 ] [ 6 ]  On the other hand, physical agents, like  micro-needles  is other approach for enhancement ofabsorption. [ 4 ]  Besides using carriers, other factors such as  pH ,  lipophilicity , and drug molecule size govern the effectiveness of topical formulation. [ 1 ]


In ancient times, human skin was used as a layer for self-expression by painting cosmetic products on it. They used those products as a protection for their skin from the sun and dry environment. [ 3 ]  Later on in 2000 BCE, the Chinese used topical  remedies  that wrap in bandages to treat skin diseases. [ 4 ] [ 3 ]  The contact between these topical remedies and skin deliver its  therapeutic effect  on the skin. The newer development of topical drugs occurred between 130 and 200 AD. This development was made by  Claudius Galenus , a Greek physician. He first loaded the herb medication to Western medicine and formulated it as cream. [ 3 ]  More recently in the 1920s, some observations were made when applying topical skin, such as to determine its  systemic effects . [ 4 ]  In 1938,  Zondek  successfully managed  urogenital  infections after applying  chloroxylenol  on the skin by the use of  disinfectant  in ointment form. After some years, observations were made from various experiments. These experiments led to the development of skin toxicology in the mid-1970s, including symptoms like irritation, skin inflammation, and skin photo-toxicity upon application of topical drugs. After the development of  toxicology , a mathematical model was also created for skin diffusion coefficient formulated by Michaels. This formulation suggests how they related to the aqueous solubility and  partition coefficient  in skin. [ 4 ]


The human body's largest organ is the skin layers, which protects against foreign particles. [ 7 ] [ 8 ]  Human skin contains several layers, including the  subcutaneous layer , the  dermis , the  epidermis , the  stratum corneum , and the  appendages . Each of these layers have an effect on the absorption of topical drug. [ 1 ]  When the topical drug is applied to the skin, it must pass via the  stratum corneum , which is the outermost skin layer. [ 8 ]   Stratum corneum 's function includes prevention of water loss in skin and inhibit the penetration of foreign molecules into the dermal layers. [ 8 ]  Hence, it also prevents the  hydrophilic  molecules to get absorbed into the skin since it is made out of bilayered lipids. [ 9 ]  With this barrier,  stratum corneum  affects the permeability of topical drugs. Another part of the skin is called the  appendages , and it is known as the “shortcut” for topical drug delivery. The shortcut pathway allows the drug molecules to first pass the  stratum corneum  barrier via  hair follicles . [ 5 ]


When drugs are applied to skin topically, the drug molecules will undergo passive  diffusion . This process occurs down the  concentration gradient  when drug molecules move to one area to another region.  Diffusion  is described by a mathematical equation. [ 1 ] [ 4 ]  The drug molecule (J), known as  flux  and it represents the entry of topical drug molecules across the skin  membrane . The skin membrane is the area (A) for the topical drug molecules to travel across. The skin membrane thickness is known as (h) in the expression, and it determines the  diffusion  path length. [ 4 ]  The (C) is the concentration of the diffusing substance across the skin layers and the (D) is the  diffusion coefficient . The expression illustrates the transportation of topical drug molecules across the  stratum corneum  membrane through  diffusion . [ 9 ]


Diffusion expression:


J
 =
 A
 D
 C

 /

 h

 {\displaystyle J=ADC/h}


Upon application of the topical drug on the skin, it will  diffuse  to the outer layer of the skin, known as  stratum corneum . There are three routes possible for the drugs to cross the skin. The first route is through the  appendages . It is known as the "first cut" where the drug molecules will be  partitioned  into the  sweat gland  to bypass the  stratum corneum  barrier. [ 1 ]  If the drug molecules is not transported via the "first cut", it is usually remains in the  stratum corneum's  bilayered lipids, where the drug molecules transport through either the  transcellular  route or  paracellular  route into the deeper area of the skin like subcutaneous layer. For the  paracellular  route, it means that the solutes transport via the junction between the cell. [ 10 ]  When the topical drug molecules transport via the paracellular route, it needs to travel across the  stratum corneum , which is a highly fat region, but between the cells. [ 9 ] [ 1 ]  On the other hand, the topical drug molecules may travel through the  transcellular  route. This route allows molecules to be transported via the cell.  Transcellular  route transports the drug molecule into the bilayered lipid cells found in  stratum corneum . Inside of the bilayered lipids in the  stratum corneum  is a water-soluble environment, and the drug molecules will  diffuse  through these bilayered lipids into deeper area of the skin. [ 1 ] [ 11 ]  During the transportation of the topical drug molecules, it can bind to the  keratin  that exists as one of the skin components in the  stratum corneum . [ 11 ]


The activities of skin  metabolism  are commonly occurring on the skin surface,  appendages , the  stratum corneum , and the  viable epidermis . [ 1 ] [ 5 ]  This process comprises phase one  hydrolysis ,  reduction , and  oxidation , also known as functionalization phase. If phase one is insufficient to metabolize the drugs, phase two  conjugation reaction  occurs. This phase includes  glucuronidation ,  sulfation , and  acetylation .  It is found that phase two activities are lower than phase two in the skin. [ 12 ]  One common example is thearylamine-type hair dye, after it is applied topically, it will undergo  metabolism  in the skin through  enzyme   N-acetyltransferase , thus resulting in a N-acetylated  metabolite . [ 5 ] [ 3 ]  These metabolic  enzymes  cause the loss of topical drug activities, thus reducing its  bioavailability . They may eventually form atoxic compound that reaches to the  systemic circulation  and causes damage to the skin layers. [ 13 ]  The longer the topical drug remains in the skin, the greater amount of it will be metabolized by the underlying enzymes. To reduce such an effect, the topical drug needs to remain on the skin for a shorter period of time. Also, certain amount of topical molecules needs to be applied to the skin and cause metabolic  enzymes  saturation. [ 5 ]


The amount of topical drug molecules being delivered to the skin is affected solely by the  physicochemical  properties of the topical drug. [ 1 ]  The first factor is the weight of the drug molecule. The smaller of the drug  molecular weight  or particle size, the higher rate of its  diffusion  and absorption into the skin. [ 1 ] [ 14 ]  The second factor is the  lipophilicity  of the drug molecules, since the three pathways for absorption are quite  lipophilic . The higher  lipophilicity  of it, the easier of the drug molecules to be absorbed when compared to the  hydrophilic  drug molecules. [ 14 ]  The third parameter is the  pH  level of the skin. The pH of the skin layers are basic, hence basic topical drugs will be absorbed better than acidic topical drugs. [ 14 ]  These factors are vital to determine the permeability of topical drug delivery. [ 3 ] [ 1 ]


Colloidal system  is one of the techniques used for topical drug delivery into the skin and functions as skin permeability enhancers. They are known as carriers and can be classified into  nanoparticles ,  liposomes , and nanoemugel. [ 15 ] [ 6 ] [ 16 ]


Liposomes  contain a bilayer of  phospholipids  in a sphere shape that may exist as one or more than one bilayer of  phospholipids.  With this structure, its function is to trap  hydrophilic  or  lipophilic  drug molecules within the spherical bilayers. [ 4 ]  The  hydrophilic  drug molecule sticks to the  hydrophilic  head since it is  polar  and favours water. On the other hand, the  lipophilic  drug molecules will be entrapped in the  phospholipid  tails of the bilayer due to its  lipophilic  nature. [ 6 ] [ 4 ]  With these mechanisms,  liposomes  will behave like carriers and carry the  lipophilic  or  hydrophilic  drug molecules into the  stratum corneum  and release them into deeper layers of the skin by interacting with the bilayers lipids found in  stratum corneum . [ 15 ]  The Use of  liposome  as carrier enhances the overall permeability of topical drug into the skin to reach the target site. [ 15 ] [ 17 ]  For example, a drug like  amphotericin B , is used to treat fungal infections. [ 18 ]  The drug is loaded into  liposome  and this carrier enhances the penetration of  amphotericin B  into the skin, regardless of its  molecular weight . [ 19 ]


Nanoemulgel is another type of enhancer for delivery of topical drugs into the skin. The formulation process for nanoemulgel is produced by incorporating the nanoemulsion into a  gel  matrix. The  gels  are made out of aqueous bases and it allows for a more rapid release of drugs through dissolution. The use of nanoemulgel enhances patient compliance because the use of gel is less greasy than traditional  cream  or  ointment , hence there is less incident in skin irritation. [ 16 ]  Nanoemulgel increases the topical drug  bioavailability  by inserting the  lipophilic  drug molecules into the oil droplet of the nanoemulgel and it will travel through the skin layers. With its high dissolution rate, the nanoemulgel produces a high  concentration gradient  toward the skin, thus allowing for a rapid uptake of oil droplet into the  stratum corneum . Also, the  surfactant  being incorporated into the nanoemulgel has the ability to penetrate through the bilayer lipid by interrupting the  hydrogen bond  between the lipid in the skin to further enhance its permeability. [ 16 ]  In terms of treatment, the use of nanoemulgel is against cancer cells and useful in skin cancer. [ 16 ]   Also, the formulation of nanoemulgel with  methoxsalen  is used to treat  psoriasis . The carrier enhances both the penetration and accumulation of  methoxsalen  in the skin layers. [ 20 ]


Micro-needle  belongs to the physical enhancer to improve absorption of topical drug molecules into the skin. It is known as ‘poke and patch’ because it uses tiny needles and stick into the skin across the  stratum corneum . [ 6 ] [ 4 ]  These tiny needles ensure that they will not contact the nerve endings or  cutaneous  blood vessels under the skin, hence they can be removed easily from the skin. [ 21 ]  There are several types of micro-needle, the first one is solid micro-needles. The solid micro-needles are used to project into the skin. Once the needles are removed after insertion, the topical drugs are applied to skin. This enhances the ability of drugs to diffuse across the  viable epidermis . The second type is the dissolvable micro-needle. These types of needles are composed of materials that allow them to dissolve after poking into the skin, hence no need to remove the needles after injection. The third type of micro-needle is the swell-able micro-needles, which consist of  hydrogel . [ 22 ]  After poking its needle into the skin, it allows the skin  interstitial fluid  diffuse into the micro-needles, thus it will swell to  diffuse  the drug molecules across the skin. [ 4 ] [ 23 ]  It is found that micro-needles are safe and effective in enhancing skin permeability. [ 24 ]


A  topical medication  is a  medication  that is applied to a particular place on or in the body. Most often topical medication means application to  body surfaces  such as the  skin  or  mucous membranes  to treat ailments via a large range of classes including  creams ,  foams ,  gels ,  lotions , and ointments. [ 1 ]   Many topical medications are epicutaneous, meaning that they are applied directly to the skin. Topical medications may also be  inhalational , such as  asthma medications , or applied to the surface of tissues other than the skin, such as  eye drops  applied to the  conjunctiva , or  ear drops  placed in the ear, or medications applied to the surface of a  tooth . The word  topical  derives from  Greek   τοπικός   topikos , "of a place".


Topical drug delivery is a route of administering  drugs  via the  skin  to provide topical therapeutic effects. As skin is one of the largest and most superficial  organs  in the  human  body,  pharmacists  utilise it to deliver various drugs. This system usually provides a local effect on certain positions of the body. In ancient times, people used  herbs  to put on wounds for relieving the inflammatory effect or as pain relievers. The use of  topical drug  delivery system is much broader now, from  smoking cessation  to beauty purposes. Nowadays, there are numerous  dosage forms  that can be used topically, including  cream ,  ointment ,  lotion ,  patches , dusting powder and much more. [ 2 ]  There are many advantages for this  drug delivery system  – avoiding  first pass metabolism  which can increase its  bioavailability , being convenient and easy to apply to a large area, being easy to terminate the medication and avoiding gastro-intestinal irritations. All these can increase patient compliance. However, there are several disadvantages to this system – causing  skin irritations  and symptoms like  rashes  and  itchiness  may occur. Also, only small  particles  can pass through the skin, which limits the choice of  drugs . Since skin is the main medium of the topical drug delivery system, its conditions determine the rate of skin penetration leading to affecting the  pharmacokinetics  of the  drug . The  temperature ,  pH value , and dryness of the skin need to be considered. There are some novel topical drugs in the market which can utilise the system as much as possible.


This localized system provides topical therapeutic effects via skin,  eyes ,  nose  and  vagina [ 3 ]  to treat  diseases . The most common usage is for local  skin infection  problems. Dermatological products have various  formulations  and range in consistency though the most popular dermal products are semisolid dosage forms [ 4 ]  to provide topical treatment.


Topical drug absorption depends on two major factors – biological and physicochemical properties.


The first factor concerns body structure effects on the  drugs . The degradation of drugs can be affected by the site of applications. Some studies discovered different  Percutaneous  absorption patterns. Apart from the place, age also affects the absorption as the skin structure changes with age. The lowered  collagen  and broadened  blood capillary  networks happen with aging. These features alter the effectiveness of absorption of both hydrophilic and  lipophilic substances  into  stratum  corneum underneath the surface of the skin. [ 5 ]  The skin surface integrity can also affect the permeability of drugs such as the density of  hair follicles ,  sweat glands  or disintegrated by  inflammation  or  dehydration .


The other factor concerns metabolism of medications on skin. When the percutaneous drug is applied on skin, it will be gradually absorbed down the skin. Normally, when the drugs are absorbed, they will be metabolised by various  enzymes  in our body and the amount will be lower. The exact amount delivered to the target action site determines the potency and bioavailability of the drugs. If the  concentration  is too low, the therapeutic effect is impeded; if the concentration is too high, drug toxicity may happen to cause side effects or even do harm to our body. For the  topical drug  delivery way, degradation of drugs in skin is very low compared to  liver . The metabolism of drugs is mainly by metabolic enzyme  cytochrome P450 , and this enzyme is not active in skin. The  CYP450  actively metabolized drugs can then maintain high concentration when being applied on skin. Despite  CYP450  enzyme action, the  partition coefficient  (K) determines the activity of topical drugs. The ability of drug particles to go through the skin layer also affects the absorption of drugs. For transdermal activity, medicines with higher K value are harder to get rid of the  lipid layer of skin cells . The trapped molecules then cannot penetrate into the skin. This reduces the efficacy of the transdermal drugs. The drugs target cells underneath the skin or need to diffuse into  blood capillary  to exert their effect. Meanwhile, the size of particles affects this transdermal process. The smaller the drug molecules, the faster the rate of penetration.  Polarity  of the drugs can affect this diffusion rate too. If the drug shows lower degree of ionization, it is less polar. Therefore, it can have a faster absorption rate.


The definition of the topical  route of administration  sometimes states that both the application location and the  pharmacodynamic  effect thereof is local. [ 6 ]


In other cases,  topical  is defined as applied to a localized area of the body or to the surface of a body part regardless of the location of the effect. [ 7 ] [ 8 ]  By this definition, topical administration also includes  transdermal  application, where the substance is administered onto the skin but is  absorbed  into the body to attain  systemic  distribution. Such medications are generally  hydrophobic  chemicals, such as  steroid hormones . Specific types include  transdermal patches  which have become a popular means of administering some drugs for  birth control ,  hormone replacement therapy , and prevention of  motion sickness . One example of an  antibiotic  that may be applied topically is  chloramphenicol .


If defined strictly as having a local effect, the topical  route of administration  can also include  enteral administration  of medications that are poorly absorbable by the  gastrointestinal tract . One poorly absorbable antibiotic is  vancomycin , which is recommended by mouth as a treatment for severe  Clostridioides difficile  colitis . [ 9 ]


A medication's potency often is changed with its base. For example, some  topical steroids  will be classified one or two strengths higher when moving from cream to ointment. As a rule of thumb, an ointment base is more occlusive and will drive the medication into the skin more rapidly than a solution or cream base. [ 10 ]


The manufacturer of each topical product has total control over the content of the base of a medication. Although containing the same active ingredients, one manufacturer's cream might be more acidic than the next, which could cause skin irritation or change its absorption rate. For example, a vaginal formulation of  miconazole  antifungal cream might irritate the skin less than an athlete's foot formulation of miconazole cream. These variations can, on occasion, result in different  clinical outcomes , even though the active ingredient is the same. No comparative potency labeling exists to ensure equal efficacy between brands of topical steroids (percentage of oil vs water dramatically affect the potency of topical steroid). Studies have confirmed that the potency of some topical steroid products may differ according to manufacturer or brand. An example of this is the case of brand name  Valisone  cream and  Kenalog  cream in clinical studies have demonstrated significantly better vasoconstrictions than some forms of this drug produced by  generic drug  manufacturers. [ 10 ]  However, in a simple base like an ointment, much less variation between manufacturers is common.


In  dermatology , the base of a topical medication is often as important as the medication itself. It is extremely important to receive a medication in the correct base, before applying to the skin. A pharmacist should not substitute an ointment for a cream, or vice versa, as the potency of the medication can change. Some physicians use a thick ointment to replace the waterproof barrier of the inflamed skin in the treatment of eczema, and a cream might not accomplish the same clinical intention.


There are many general classes, with no clear dividing line among similar formulations. As a result, what the manufacturer's marketing department chooses to list on the label of a topical medication might be completely different from what the form would normally be called.


A  cream  is an emulsion of oil and water in approximately equal proportions. It penetrates the  stratum corneum  outer layer of skin wall. Cream is thicker than lotion, and maintains its shape when removed from its container. It tends to be moderate in moisturizing tendency. For topical steroid products, oil-in-water emulsions are common. Creams have a significant risk of causing  immunological sensitization  due to  preservatives  and have a high rate of acceptance by patients. There is a great variation in ingredients, composition, pH, and tolerance among generic brands. [ 11 ]


Topical corticosteroid foams are suitable for treating a range of skin conditions that respond to corticosteroids. These foams are typically simple to apply, which can lead to better patient compliance and, in turn, improve treatment results for those who favor a more convenient and cleaner topical option.  Foam  can be typically seen with topical steroids marketed for the scalp. [ 12 ]


Gels  are thicker than liquids. Gels are often a semisolid  emulsion  and sometimes use alcohol as a solvent for the active ingredient; some gels liquefy at body temperature. Gel tends to be cellulose cut with alcohol or acetone. Gels tend to be self-drying, tend to have greatly variable ingredients between brands, and carry a significant risk of inducing hypersensitivity due to fragrances and preservatives. Gel is useful for hairy areas and body folds. In applying gel one should avoid fissures in the skin, due to the stinging effect of the alcohol base. Gel enjoys a high rate of acceptance due to its cosmetic elegance. [ 11 ]


Lotions  are similar to solution but are thicker and tend to be more  emollient  in nature than the solution. They are usually oil mixed with water, and more often than not have less alcohol than solution. Lotions can be drying if they contain a high amount of alcohol.


An  ointment  is a homogeneous, viscous, semi-solid preparation; most commonly a greasy, thick water-in-oil emulsion (80% oil, 20% water) having a high viscosity, that is intended for external application to the skin or mucous membranes. Ointments have a water number that defines the maximum amount of water that they can contain. They are used as  emollients  or for the application of active ingredients to the skin for protective, therapeutic, or prophylactic purposes and where a degree of occlusion is desired.


Ointments are used topically on a variety of body surfaces. These include the  skin  and the  mucous membranes  of the  eye  (an  eye ointment ),  chest ,  vulva ,  anus , and  nose . An ointment may or may not be medicated.


Ointments are usually very moisturizing, and good for dry skin. They have a low risk of sensitization due to having few ingredients beyond the base oil or fat, and low irritation risk. There is typically little variability between brands of drugs. They are often disliked by patients due to greasiness. [ 11 ]


The vehicle of an ointment is known as the  ointment base . The choice of a base depends upon the clinical indication for the ointment. The different types of ointment bases are:


The medicaments are dispersed in the base and are divided after penetrating the living cells of the skin.


The water number of an ointment is the maximum quantity of water that 100g of a base can contain at 20 °C.


Ointments are formulated using hydrophobic, hydrophilic, or water-emulsifying bases to provide preparations that are immiscible, miscible, or emulsifiable with  skin secretions . They can also be derived from hydrocarbon (fatty), absorption, water-removable, or water-soluble bases.


Evaluation of ointments: [ 13 ]


Properties which affect choice of an ointment base are: [ 13 ]


Methods of preparation of ointments:


Paste  combines three agents – oil, water, and powder. It is an ointment in which a powder is suspended.


Powder [ 14 ]  is either the pure drug by itself (talcum powder), or is made of the drug mixed in a carrier such as  corn starch  or corn cob powder (Zeosorb AF – miconazole powder). Can be used as an inhaled topical ( cocaine  powder used in nasal surgery).


A shake lotion is a mixture that separates into two or three parts over time. Frequently, an oil mixed with a water-based solution needs to be shaken into suspension before use and includes the instructions: "Shake well before use". [ citation needed ]


Medication may be placed in a solid form. Examples are deodorants, antiperspirants, astringents, and hemostatic agents. Some solids melt when they reach body temperature (e.g. rectal suppositories).


Certain contraceptive methods rely on  sponge  as a carrier of liquid medicine.  Lemon juice  embedded in a sponge has been used as a primitive contraception in some cultures.


Cordran tape is an example of a topical steroid applied under  occlusion  by tape. This greatly increases the potency and absorption of the topical steroid and is used to treat inflammatory skin diseases.


A  tincture  is a skin preparation that has a high percentage of alcohol. It would normally be used as a drug vehicle if drying of the area is desired.


Topical solutions can be marketed as drops, rinses, or sprays, are generally of low viscosity, and often use alcohol or water in the base. [ 15 ] [ 16 ] [ 17 ]  These are usually a powder dissolved in alcohol, water, and sometimes oil; although a solution that uses alcohol as a base ingredient, as in topical steroids, can cause drying of the skin. [ 18 ] [ page needed ]  There is significant variability among brands, and some solutions may cause irritation, depending on the preservative(s) and fragrances used in the base.


Some examples of topical solutions are given below:


Transdermal patches  can be a very precise time released method of delivering a drug. Cutting a patch in half might affect the dose delivered. The release of the active component from a transdermal delivery system (patch) may be controlled by diffusion through the adhesive which covers the whole patch, by diffusion through a membrane which may only have adhesive on the patch rim or drug release may be controlled by release from a polymer matrix. Cutting a patch might cause rapid dehydration of the base of the medicine and affect the rate of diffusion.


Some medications are applied as an ointment or gel, and reach the mucous membrane via vaporization. Examples are nasal  topical decongestants  and smelling salt.


Topical drug classification system (TCS) is proposed by the  FDA . It is designed from the  Biopharmaceutics Classification System  (BCS) for oral immediate release solid drug products which is very successful for decades. There are 3 aspects to assess and 4 classes in total. The 3 aspects include qualitative (Q1), quantitative (Q2) and similarity of  in vitro  release (IVR) rate (Q3). [ 21 ]


In the early 1970s, the  Alza Corporation , through their founder  Alejandro Zaffaroni , filed the first US patents describing transdermal delivery systems for  scopolamine ,  nitroglycerin  and  nicotine . [ 22 ]  People found that applying medicines on the body surfaces is beneficial in many aspects. Skin medicines can give faster onset and local effect on our body as the surface cream can bypass first pass metabolism such as hepatic and intestinal metabolism. Apart from the absorption, dermal drugs effectively prevent oral delivery limitations such as  nausea  and  vomiting  and poor appliances due to unpalatable tastes of the drugs . Topical application is an  easy way for patients to tackle skin infections in a painless and non-invasive way. From a patient perspective, applying drugs on skin also provides stable dosage in blood so as to give the optimal  bioavailability  and  therapeutic effects . In case of  overdose  or unwanted side effects, patients can take off or wash out the medicines quickly to eliminate  toxicity  by simply removing the patch to stop the delivery of drugs. [ 23 ]


The site of putting the patches for topical drugs may get irritated and have  rashes  and feel itchy. Hence, some topical drugs including  nicotine patches  for  smoking cessation  are advised to change places for each application to avoid continuous irritation of the skin. Also, since the drug needs to penetrate the skin, some drugs may not be able to pass through the skin. Some drugs are then “wasted” and the bioavailability of the drug will decrease.


Skin penetration is the main challenge for any topical dosage form. The drug needs to penetrate the skin in order to get into the body to apply its function. The drug follows Fick's first law of diffusion. [ 24 ]  One of the most common versions of  Fick's first law of diffusion  is:


For  D  is described by the  Stokes–Einstein equation . The equation is:


Assuming  concentration gradient  is constant for all newly applied topical drugs and the temperature is constant (normal body temperature: 37 °C), the viscosity and radius of the drug determine the flux of diffusion. The higher the  viscosity  or the larger the radius of the drug is, the lower the  diffusion flux  of the drug is. [ 24 ]


There are many factors for drug developers to consider in developing new topical formulations.


The first one is the effect of the drug vehicle. The medium to carry the topical drugs can affect the penetration of the drug  active ingredient  and  efficacy . For example, this carrier can have a cooling, drying, emollient or protective action to suit the required conditions of the application site such as applying  gel  or  lotion  for hairy areas. Meanwhile, scientists need to match the type of preparation with the type of lesions. For example, they need to avoid oily  ointments  for acute weepy  dermatitis . Chemists also need to consider the  irritation  or any  sensitization  potential to ensure that the topical application can be stable during storage and transport to maintain its efficacy. [ 22 ]  Another potential material is nanofiber-based dispersion to improve the adhesion of active ingredients on the skin. [ 2 ]


In order to enhance drug penetration into the skin, scientists have several ways to achieve their purposes by using chemical, biochemical, physical, and  super saturation  enhancement. Advanced Emulgel technology is a breakthrough in painkilling topical drugs. [ citation needed ]  It helps the gel to enter deeply down the skin layer to strengthen the delivery of diclofenac to the point of pain so as to achieve better  therapeutic effects  by modifying the above properties. [ 22 ]


Transdermal drug delivery  techniques include:


A  transdermal patch  is a  medicated   adhesive  patch that is placed on the  skin  to deliver a specific  dose  of medication through the skin and into the  bloodstream . An advantage of a transdermal drug delivery route over other types of medication delivery (such as oral, topical, intravenous, or intramuscular) is that the patch provides a controlled release of the medication into the patient, usually through either a porous membrane covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive. The main disadvantage to transdermal delivery systems stems from the fact that the skin is a very effective barrier; as a result, only medications whose molecules are small enough to penetrate the skin can be delivered by this method. The first commercially available prescription patch was approved by the U.S.  Food and Drug Administration  in December 1979. These patches administered  scopolamine  for  motion sickness . [ 2 ] [ 3 ] [ 4 ] [ 5 ]


In order to overcome restriction from the skin, researchers have developed  microneedle transdermal patches  (MNPs), which consist of an array of  microneedles , which allows a more versatile range of compounds or molecules to be passed through the skin without having to  micronize  the medication beforehand. MNPs offer the advantage of controlled release of medication and simple application without medical professional assistance required. [ 6 ]  With advanced MNPs technology, drug delivery can be specified for local usage, for example skin whitener [ 7 ]  MNPs that are applied to the face. Many types of MNPs have been developed to penetrate tissues other than skin, such as internal tissues of the mouth and digestive tract. These promote faster and more direct delivery of the molecule to the targeted area.


The main components to a transdermal patch are:


Other components include stabilizers (antioxidants), preservatives, etc.


There are five main types of transdermal patches.


The adhesive layer of this system also contains the drug. In this type of patch the adhesive layer not only serves to adhere the various layers together, along with the entire system to the skin, but is also responsible for the releasing of the drug. The adhesive layer is surrounded by a temporary liner and a backing. It is characterized by the inclusion of the drug directly within the skin-contacting adhesive placed onto the epidermis.


The multi-layer drug-in-adhesive patch is similar to the single-layer system; the multi-layer system is different, however, in that it adds another layer of drug-in-adhesive, usually separated by a membrane (but not in all cases). One of the layers is for immediate release of the drug, and the other layer is for controlled release of the drug from the reservoir. This patch also has a temporary liner-layer and a permanent backing. The drug release from this depends on membrane permeability and diffusion of drug molecules.


Unlike the single-layer and multi-layer drug-in-adhesive systems, the reservoir transdermal system has a separate drug layer. The drug layer is a liquid compartment containing a drug solution or suspension separated by the adhesive layer. The drug reservoir is totally encapsulated in a shallow compartment molded from a drug-impermeable metallic plastic laminate, with a rate-controlling membrane made of a polymer like  vinyl acetate  on one surface. [ 24 ]  This patch is also backed by the backing layer. In this type of system the rate of release is zero order. Reservoir patches should not be cut (with the exception of hyoscine hyrdobromide 1.5mg patch according to the  British National Formulary for Children ). [ 24 ] [ 25 ]


The matrix system has a drug layer of a semisolid matrix containing a drug solution or suspension. The adhesive layer in this patch surrounds the drug layer, partially overlaying it. The release rate is determined by the physical properties of the matrix. [ 24 ]  Also known as a monolithic device. Limited research indicates that it may be possible to cut some matrix patches to provide lower doses, provided the cut part not immediately used is stored at cool temperatures. [ 26 ]


In a vapour patch, the adhesive layer not only serves to adhere the various layers together but also to release vapour. Vapour patches release essential oils for up to 6 hours and are mainly used for decongestion. Other vapour patches on the market improve quality of sleep or aid in  smoking cessation .


The microneedle patch (MNPs) is a type of transdermal patch which retains the advantages, but reduces the disadvantages of basic transdermal patches. Embedding as many as 102-104 needles per square centimetre of patch, encapsulated or coated with intended drug, MNPs can easily pass skin tissue known as the  stratum corneum  which is roughly 20 μm in thickness, allowing up to the size of  macromolecule  to pass. [ 6 ]  MNPs were developed mainly because transdermal patch can deliver smaller size or  micronized  molecules such as  nicotine  and  birth control  which easily diffuse and penetrate the skin, but lack in delivering macro or large size molecules. The 100-1000 μm needles spread across the patch, making sure people will not feel any discomfort from the patch. There are two types of needles used in MNPs, the first one is non-water-soluble needles made out of metal, ceramic, or  polymer , and the second one is water-soluble needles made out of  saccharides  or soluble polymers. [ 6 ]


MNPs can also be engineered to deliver molecules into other tissues. Some that as of 2018 have been under development include internal surfaces such as the mouth, vagina, gastrointestinal tract, and vascular wall; and external surfaces such as the skin, eyes, fingernails, anus, and scalp. [ 6 ]


As mentioned earlier, MNPs deliver more efficient delivery compared to topical or oral intake. In drug delivery study, researchers want to gain faster  peak concentrations  (C max ) in MNPs compared to other methods. Study shows that MNPs reach peak concentration as fast as 20 minutes (t max ), while oral intake reaches peak concentration in one hour. Furthermore, the C max  from MNPs is higher up to six times, compared to oral intake. [ 6 ]  Making the delivery fast and the body gets the most concentration of intended drugs. This value is only matched with direct injection, but with skin trauma and people with needle phobia, MNPs might be an alternative to reach roughly the same time and concentration.


In order to get more direct local delivery, MNPs can be used in different tissues other than the skin. [ 27 ]  In  Table 1 , there are at least five internal surfaces that MNPs have been studied for its delivery and four other external surfaces other than the skin.


There are many types of microneedle that are distinguished by the shape and other characteristics. The types include: Dissolvable MNPs, solid non-soluble MNPs, and hollow MNPs. Different MNPs may be chosen depending on the situation and the drug properties.


One of the types of MNPs are water-soluble needles made out of soluble polymers or saccharide. However, dissolvable needles cannot efficiently deliver drugs to the dermal layer. Drug maximum concentration cannot be carried out to the skin, as the needles will dissolve beforehand. Fortunately, researchers have developed a water-insoluble backing layer, making the needle last longer in the human body environment. This design enables efficient delivery of more than 90% of the drug within 5 minutes of application of MNPs to the skin. [ 29 ]


Other than dissolvable MNPs, needles can also be made out of metal or ceramic that will not dissolve in the body environment. These coated drug needles can deliver consistent concentration of drugs without the needles dissolving in the body. This kind of MNPs has better performance, but compared to the soluble MNPs, metal or ceramic MNPs are the older version of MNPs. Even if the patches are small, the metal or ceramic MNPs may cause several waste issues. Recycling the metal and ceramic are very hard, as the quantity is very small to overcome the cost to recycle. That is why researchers try to develop the dissolvable MNPs with similar characteristic and performance of drug delivery in non-soluble MNPs. [ 29 ]


Among all of the MNPs, hollow needles allow a bigger amount of delivery up to 200μL. The mechanism mimics the operation of a hypodermic, but the fabrication is hard and complex. The hollow needles introduce a potential failure if the insertion is improper. That is why, among the others, hollow MNPs are the least popular because of the complex manufacturing and applying process. [ 1 ]


MNPs vaccination might be an alternative from direct injection. Able to deliver bigger molecules than transdermal patch, MNPs can also deliver bioactive molecules with different physical sizes. Meaning that inactive virus or pathogen can be introduced in the body without discomfort or skin irritation from conventional injection. Possibly it can also reduce the cost of storage that usually needs to be transported in a particular temperature and condition. Stated in cdc.gov website,  Mark Prausnitz , co-developer of the microneedle, says "A major advantage of the microneedle patch would be the ease of delivery." The MNPs are small and thin compared to bottles of vial, making it possible to transport in massive quantities in a single trip. [ 33 ]  Medical waste such as syringes and dirty needles are also eliminated, reducing the possibility of pathogen transmission of blood-borne disease in rural areas. [ 7 ]


In a study, measles coated MNPs might be resistant to higher temperature compared to vial transport. Higher temperature resistance is a safe bet in low income countries, where there is no such luxury for refrigeration. Furthermore, the delivery of the vaccine is controlled by the MNPs. Less requiring highly trained medical workers in developing countries to apply the vaccine. However, the study in MNPs measles vaccine is still under development, but opening possibilities in the future for other types of vaccines [ 33 ]


Skin treatment including face whitening agent and dark eye circles serum can also incorporated in MNPs. [ 34 ]  Its localized property enhance skin whitening delivery to the face area. Even a very specific spot like dark eye circles. By measuring the melanin (dark or black pigment found on the skin) index, subjects that are treated with whitening agents coated in MNPs show lower melanin index, compared to the whitening essence (topical) group. The treatment lasts for eight weeks, and the result shows MNPs might be a promising cosmetic vector because MNPs does not introduce skin irritation and can be engineered to localize or specific parts of the body. [ 35 ]


MNPs may cause skin irritation on people with sensitive skin. Majority of studies show that MNPs do not irritate the skin.
Especially for hollow MNPs, the not so stiff needles may cause unnecessary puncture of the skin outer layer, and may cause trauma to the skin and restricting the performance and flow of the drugs to the body. [ 1 ]


Because most of MNPs applications are still under development, it is important to note the long effect of the efficiency of the drug deliveries. Furthermore, more research is needed to get information of what molecule can be delivered using MNPs. Disposal is also an important topic, as the small plastic backing may contribute to water pollution remembering the compact size can be easily carried away by wind and water without proper disposal.


A transdermal patch is classified by the U.S. Food and Drug Administration as a  combination product , consisting of a  medical device  combined with a drug or biological product that the device is designed to deliver. Prior to sale in the United States, any transdermal patch product must apply for and receive approval from the Food and Drug Administration, demonstrating safety and efficacy for its intended use. [ 36 ]


Transdermal  is a  route of administration  wherein active ingredients are delivered across the skin for systemic distribution. Examples include  transdermal patches  used for medicine delivery.
The drug is administered in the form of a patch or ointment that delivers the drug into the circulation for systemic effect.


Although the skin is a large and logical target for drug delivery, its basic functions limit its utility for this purpose.  The skin functions mainly to protect the body from external penetration (by e.g. harmful substances and microorganisms) and to contain all body fluids.


There are two important layers to the human skin: (1) the  epidermis  and (2) the  dermis .  For transdermal delivery, drugs must pass through the two sublayers of the epidermis to reach the microcirculation of the dermis.


The  stratum corneum  is the top layer of the skin and varies in thickness from approximately ten to several hundred micrometres, depending on the region of the body. [ 1 ]  It is composed of layers of dead, flattened keratinocytes surrounded by a lipid matrix, which together act as a brick-and-mortar system that is difficult to penetrate. [ 2 ]


The stratum corneum provides the most significant barrier to diffusion. In fact, the stratum corneum is the barrier to approximately 90% of transdermal drug applications. However, nearly all molecules penetrate it to some minimal degree. [ 3 ]  Below the stratum corneum lies the viable epidermis. This layer is about ten times as thick as the stratum corneum; however, diffusion is much faster here due to the greater degree of hydration in the living cells of the viable epidermis. Below the epidermis lies the dermis, which is approximately one millimeter thick, 100 times the thickness of the stratum corneum. The dermis contains small vessels that distribute drugs into the systemic circulation and to regulate temperature, a system known as the skin's microcirculation. [ 2 ] [ 3 ]


There are two main pathways by which drugs can cross the skin and reach the systemic circulation. The more direct route is known as the transcellular pathway.


By this route, drugs cross the skin by directly passing through both the phospholipids membranes and the cytoplasm of the dead keratinocytes that constitute the stratum corneum.


Although this is the path of shortest distance, the drugs encounter significant resistance to permeation. This resistance is caused because the drugs must cross the lipophilic membrane of each cell, then the hydrophilic cellular contents containing keratin, and then the phospholipid bilayer of the cell one more time. This series of steps is repeated numerous times to traverse the full thickness of the stratum corneum. [ 1 ] [ 2 ]


The other more common pathway through the skin is via the intercellular route. Drugs crossing the skin by this route must pass through the small spaces between the cells of the skin, making the route more tortuous. Although the thickness of the stratum corneum is only about 20 μm, the actual diffusional path of most molecules crossing the skin is on the order of 400 μm. [ 4 ]  The 20-fold increase in the actual path of permeating molecules greatly reduces the rate of drug penetration. [ 3 ]


Recent research has established that the intercellular route can be dramatically enhanced by attending to the physical chemistry of the system solubilizing the active pharmaceutical ingredient, rendering a dramatically more efficient delivery of payload and enabling the delivery of most compounds via this route. [ 5 ] [ 6 ] [ 7 ]


A third pathway to breach the Stratum Corneum layer is via tiny microchannels created by a medical  micro-needling  device of which there are many brands and variants. [ 8 ]  Investigations at the University of Marburg, Germany, using a standard Franz diffusion cell showed that this approach is efficient in enhancing skin penetration ability for lipophilic as well as hydrophilic compounds. [ 9 ]


The micro-needling approach is also seen as 'the  vaccine  of the future'. [ 10 ]  The microneedles can be hollow, solid, coated, dissolving, or hydrogel-forming. [ 11 ]  Some have regulatory approval. [ 11 ]  Microneedle devices/patches can be used to deliver  nanoparticle medicines . [ 12 ]


Devices and formulations for transdermally administered substances include:


An  unguent  is a soothing preparation spread on  wounds ,  burns ,  rashes ,  abrasions  or other topical injuries (i.e. damage to the skin). It is similar to an  ointment , though typically an unguent is oilier and less  viscous . It is usually delivered as a semi-solid paste spread on the skin, and it is often oily in order to suspend the medication or other  active ingredients .


During the  Victorian era , the use of the unguent  macassar oil  on the hair became so popular that  antimacassars  were invented to prevent damage to furniture. [ 1 ]


Various preparations of  mercurochrome  unguent are occasionally used as  adjunct therapy  in the treatment of  furunculosis , and palliative relief of  Kaposi sarcomas , although mercurials should only be used in extreme cases due to high toxicity and severe hypersensitivity or idiosyncratic reactions.


It was also used by the Egyptians to help soothe their skin from the dry heat.


In  intravenous therapy  a  Y-Set ,  T-Set  and  V-Sets  are Y-, T- and V-shaped three-way connector sets made of connecting plastic tubes used for delivering intravenous drugs into the body from multiple fluid sources. As  Y-Sets [ 1 ]  are the most common shaped sets, Y-Set is a name that is sometimes used to represent the family of connector sets (sometimes called Y-tubes). The majority of these infusion sets have a left and right hand line that deliver fluid and drugs (often via a valve) to a short common limb attached to the female fitting on the  intravenous cannulae .


3-way connectors allow for " piggybacking ", that is, putting a second infusion set onto the same line, such as adding a dose of antibiotics to a continuous  volume expander  drip, with the etymology being to refer to the second infusion as "riding on the back" of the first one.


Most 3+ way connectors can be opened to allow an infusion limb and a vertical limb to deliver fluid via a common limb to the female fitting of an IV  cannulae . V-shaped fittings allow multiple limbs to flow directly to the patient with no common space. As different tubes for these infusion sets usually have different flow rates and fluid delivered from different tubes, there is a risk that the common space (dead volume) of Y-Sets and T-Sets fills with high concentration drugs and accidentally gets flushed out at a high flow rate. [ 2 ]


A  drug  is any  chemical substance   other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. [ 1 ]  Consumption of drugs can be via  inhalation ,  injection ,  smoking ,  ingestion ,  absorption  via a  patch  on the skin,  suppository , or  dissolution under the tongue .


In  pharmacology , a drug is a chemical substance, typically of known structure, which, when administered to a living organism, produces a biological effect. [ 2 ]  A  pharmaceutical drug , also called a medication or medicine, is a chemical substance used to  treat , cure,  prevent , or  diagnose  a  disease  or to promote  well-being . [ 3 ]  Traditionally drugs were obtained through extraction from  medicinal plants , but more recently also by  organic synthesis . [ 4 ]  Pharmaceutical drugs may be used for a limited duration, or on a regular basis for  chronic disorders . [ 3 ]


Pharmaceutical drugs are often classified into  drug classes —groups of related drugs that have similar  chemical structures , the same  mechanism of action  (binding to the same  biological target ), a related  mode of action , and that are used to treat the same disease. [ 5 ] [ 6 ]  The  Anatomical Therapeutic Chemical Classification System  (ATC), the most widely used drug classification system, assigns drugs a unique ATC code, which is an alphanumeric code that assigns it to specific drug classes within the ATC system. Another major classification system is the  Biopharmaceutics Classification System . This classifies drugs according to their solubility and permeability or  absorption  properties. [ 7 ]


Psychoactive drugs  are substances that affect the function of the  central nervous system , altering  perception ,  mood  or  consciousness . [ 8 ]  These drugs are divided into different groups such as:  stimulants ,  depressants ,  antidepressants ,  anxiolytics ,  antipsychotics , and  hallucinogens . These psychoactive drugs have been proven useful in treating a wide range of  medical conditions  including  mental disorders  around the world. The most widely used drugs in the world include  caffeine ,  nicotine  and  alcohol , [ 9 ]  which are also considered  recreational drugs , since they are used for pleasure rather than medicinal purposes. [ 10 ]  All drugs can have potential  side effects . [ 11 ]  Abuse of several psychoactive drugs can cause  addiction  or  physical dependence . [ 12 ]  Excessive use of stimulants can promote  stimulant psychosis . Many recreational drugs are  illicit ; international treaties such as the  Single Convention on Narcotic Drugs  exist for the purpose of their  prohibition .


In English, the noun "drug" is thought to originate from Old French " drogue ", possibly deriving from " droge  ( vate )" from Middle Dutch meaning "dry (barrels)", referring to medicinal plants preserved as dry matter in barrels. [ 13 ] [ 14 ]


In the 1990s however, Spanish  lexicographer   Federico Corriente Córdoba  documented the possible origin of the word in {ḥṭr} [ 15 ]  an early romanized form of the  Al-Andalus  language from the northwestern part of the  Iberian peninsula . [ 16 ]  The term could approximately be transcribed as حطروكة or  hatruka . [ 17 ]


The term "drug" has become a  skunked term  with negative connotation, being used as a synonym for  illegal substances  like cocaine or heroin or for drugs used  recreationally . In other contexts the terms "drug" and "medicine" are used interchangeably. [ 18 ]


Drug action is highly specific and their effects may only be detected in certain individuals. For instance, the 10 highest-grossing drugs in the US may help only 4-25% of people. [ 19 ]  Often, the activity of a drug depends on the  genotype  of a patient. For example, Erbitux ( cetuximab ) increases the survival rate of  colorectal cancer  patients if they carry a particular mutation in the  EGFR  gene. [ 19 ]  Some drugs are specifically approved for certain genotypes.  Vemurafenib  is such a case which is used for  melanoma  patients who carry a mutation in the  BRAF  gene. [ 19 ]  The number of people who benefit from a drug determines if drug trials are worth carrying out, given that phase III trials may cost between $100 million and $700 million per drug. This is the motivation behind  personalized medicine , that is, to develop drugs that are adapted to individual patients. [ 19 ]


A  medication  or  medicine  is a  drug  taken to cure or ameliorate any symptoms of an  illness  or medical condition. The use may also be as  preventive medicine  that has future benefits but does not treat any existing or pre-existing diseases or symptoms. Dispensing of medication is often regulated by  governments  into three categories— over-the-counter  medications, which are available in  pharmacies  and supermarkets without special restrictions;  behind-the-counter  medicines, which are dispensed by a  pharmacist  without needing a doctor's prescription, and  prescription only medicines , which must be prescribed by a licensed  medical professional , usually a  physician . [ 20 ]


In the United Kingdom, behind-the-counter medicines are called  pharmacy medicines  which can only be sold in registered pharmacies, by or under the supervision of a pharmacist. These medications are designated by the letter P on the label. [ 21 ]  The range of medicines available without a prescription varies from country to country. Medications are typically produced by  pharmaceutical companies  and are often  patented  to give the developer exclusive rights to produce them. Those that are not patented (or with expired patents) are called  generic drugs  since they can be produced by other companies without restrictions or licenses from the patent holder. [ 22 ]


Pharmaceutical drugs are usually categorised into  drug classes . A group of drugs will share a similar  chemical structure , have the same  mechanism of action  or the same related  mode of action , or target the same illness or related illnesses. [ 5 ] [ 6 ]  The  Anatomical Therapeutic Chemical Classification System  (ATC), the most widely used drug classification system, assigns drugs a unique  ATC code , which is an alphanumeric code that assigns it to specific drug classes within the ATC system. Another major classification system is the  Biopharmaceutics Classification System . This groups drugs according to their solubility and permeability or  absorption  properties. [ 7 ]


Some religions, particularly  ethnic religions , are based completely on the use of certain drugs, known as  entheogens , which are mostly  hallucinogens ,— psychedelics ,  dissociatives , or  deliriants . Some entheogens include  kava  which can act as a  stimulant , a  sedative , a  euphoriant  and an  anesthetic . The roots of the kava plant are used to produce a drink consumed throughout the cultures of the Pacific Ocean.


Some  shamans  from different cultures use entheogens, defined as "generating the divine within," [ 23 ]  to achieve  religious ecstasy . Amazonian shamans use  ayahuasca  (yagé), a hallucinogenic brew, for this purpose.  Mazatec shamans  have a long and continuous tradition of religious use of  Salvia divinorum , a  psychoactive  plant. Its use is to facilitate  visionary states of consciousness  during spiritual healing sessions. [ 24 ]


Silene undulata  is regarded by the  Xhosa people  as a sacred plant and used as an entheogen. Its roots are traditionally used to induce vivid (and according to the Xhosa, prophetic)  lucid dreams  during the initiation process of  shamans , classifying it a naturally occurring  oneirogen  similar to the more well-known dream herb  Calea ternifolia . [ 25 ]


Peyote , a small spineless  cactus , has been a major source of psychedelic  mescaline  and has probably been used by  Native Americans  for at least five thousand years. [ 26 ] [ 27 ]  Most mescaline is now obtained from a few species of columnar cacti in particular from  San Pedro  and not from the vulnerable peyote. [ 28 ]


The  entheogenic use of cannabis  has also been widely practised [ 29 ]  for centuries. [ 30 ]   Rastafari  use  marijuana  (ganja) as a  sacrament  in their  religious ceremonies .


Psychedelic mushrooms ( psilocybin mushrooms ), commonly called  magic mushrooms  or  shrooms  have also long been used as entheogens.


Nootropics , also commonly referred to as "smart drugs", are drugs that are claimed to improve human  cognitive abilities . Nootropics are used to improve memory, concentration, thought, mood, and learning. An increasingly used nootropic among students, also known as a  study drug , is  methylphenidate  branded commonly as  Ritalin  and used for the treatment of  attention deficit hyperactivity disorder  (ADHD) and  narcolepsy . [ 31 ]  At high doses methylphenidate  can become highly addictive . [ 32 ]  Serious addiction can lead to  psychosis ,  anxiety  and heart problems, and the use of this drug is related to a rise in suicides, and overdoses. Evidence for use outside of student settings is limited but suggests that it is commonplace. [ 31 ] [ 32 ]  Intravenous use of methylphenidate can lead to  emphysematous  damage to the lungs, known as  Ritalin lung . [ 33 ]


Other drugs known as  designer drugs  are produced. An early example of what today would be labelled a 'designer drug' was  LSD , which was synthesised from  ergot . [ 34 ]  Other examples include analogs of  performance-enhancing drugs  such as designer  steroids  taken to improve physical capabilities; these are sometimes used (legally or not) for this purpose, often by professional athletes. [ 35 ]  Other designer drugs mimic the effects of psychoactive drugs. Since the late 1990s there has been the identification of many of these synthesised drugs. In Japan and the United Kingdom this has spurred the addition of many designer drugs into a newer class of controlled substances known as a  temporary class drug .


Synthetic cannabinoids  have been produced for a longer period of time and are used in the designer drug  synthetic cannabis .


Recreational drug use  is the use of a drug (legal, controlled, or illegal) with the primary intention of  altering the state of consciousness  through alteration of the central nervous system in order to create positive emotions and feelings. The hallucinogen  LSD  is a psychoactive drug commonly used as a recreational drug. [ 37 ]


Ketamine  is a drug used for  anesthesia , and is also used as a recreational drug, both in powder and liquid form, for its hallucinogenic and  dissociative effects . [ 38 ]


Some national laws  prohibit the use of different recreational drugs; medicinal drugs that have the potential for recreational use are often heavily regulated. However, there are many recreational drugs that are  legal in many jurisdictions  and widely culturally accepted.
 Cannabis  is the most commonly consumed controlled recreational drug in the world (as of 2012). [ 39 ]  Its use in many countries is illegal but is  legally used  in several countries usually with the proviso that it can only be used for personal use. It can be used in the  leaf  form of  marijuana   (grass) , or in the resin form of  hashish . Marijuana is a more mild form of cannabis than hashish.


There may be an age restriction on the consumption and purchase of legal recreational drugs. Some recreational drugs that are legal and accepted in many places include  alcohol ,  tobacco ,  betel nut , and  caffeine  products, and in some areas of the world the legal use of drugs such as  khat  is common. [ 40 ]


There are a number of legal intoxicants commonly called  legal highs  that are used recreationally. The most widely used of these is alcohol.


All drugs have a  route  of  administration , and many can be administered by more than one.


A  bolus  is the administration of a medication, drug or other compound that is given to raise its concentration in blood rapdily to an effective level, regardless of the route of administration


Numerous governmental offices in many countries deal with the control and supervision of drug manufacture and use, and the implementation of various drug laws. The  Single Convention on Narcotic Drugs  is an international  treaty  brought about in 1961 to prohibit the use of narcotics save for those used in  medical research  and treatment. In 1971, a second treaty the  Convention on Psychotropic Substances  had to be introduced to deal with newer recreational psychoactive and psychedelic drugs.


The  legal status of  Salvia divinorum  varies in many countries and even in  states within the United States . Where it is legislated against, the degree of prohibition also varies.


The  Food and Drug Administration  (FDA) in the United States is a  federal agency  responsible for protecting and promoting  public health  through the  regulation  and supervision of  food safety ,  tobacco products ,  dietary supplements ,  prescription  and  over-the-counter   medications ,  vaccines ,  biopharmaceuticals ,  blood transfusions ,  medical devices ,  electromagnetic radiation  emitting devices,  cosmetics ,  animal foods [ 42 ]  and  veterinary drugs .


In India, the  Narcotics Control Bureau  (NCB), an  Indian federal law enforcement  and  intelligence  agency under the  Ministry of Home Affairs , is tasked with combating  drug trafficking  and assisting international use of illegal substances under the provisions of  Narcotic Drugs and Psychotropic Substances Act . [ 43 ]


A  medication  (also called  medicament ,  medicine ,  pharmaceutical drug ,  medicinal product ,  medicinal drug  or simply  drug ) is a  drug  used to  diagnose ,  cure , treat, or  prevent  disease. [ 1 ] [ 2 ]  Drug therapy ( pharmacotherapy ) is an important part of the  medical field  and relies on the science of  pharmacology  for continual advancement and on  pharmacy  for appropriate management.


Drugs are  classified  in many ways. One of the key divisions is by level of  control , which distinguishes  prescription drugs  (those that a pharmacist dispenses only on the  medical prescription ) from  over-the-counter drugs  (those that consumers can order for themselves). Medicines may be classified by mode of action,  route of administration ,  biological system  affected, or  therapeutic effects . The  World Health Organization  keeps a list of  essential medicines .


Drug discovery  and  drug development  are complex and expensive endeavors undertaken by  pharmaceutical companies , academic scientists, and governments. As a result of this complex path from discovery to commercialization, partnering has become a standard practice for advancing drug candidates through development pipelines. Governments generally regulate what drugs can be marketed,  how drugs are marketed , and in some jurisdictions,  drug pricing . Controversies have arisen over drug pricing and disposal of used medications.


Medication is a medicine or a  chemical compound  used to  treat  or  cure  illness. According to  Encyclopædia Britannica , medication is "a substance used in treating a disease or relieving  pain ". [ 3 ]


As defined by the  National Cancer Institute ,  dosage forms  of medication can include  tablets ,  capsules , liquids,  creams , and patches. Medications can be administered in different ways, such as  by mouth , by  infusion into a vein , or by  drops put into the ear  or  eye . A medication that does not contain an  active ingredient  and is used in research studies is called a  placebo . [ 4 ]


In Europe, the term is "medicinal product", and it is defined by EU law as:


In the US, a "drug" is:


Drug use among elderly Americans has been studied; in a group of 2,377 people with an average age of 71 surveyed between 2005 and 2006, 84% took at least one prescription drug, 44% took at least one  over-the-counter  (OTC) drug, and 52% took at least one  dietary supplement ; in a group of 2245 elderly Americans (average age of 71) surveyed over the period 2010 – 2011, those percentages were 88%, 38%, and 64%. [ 7 ]


One of the key classifications is between traditional  small molecule  drugs; usually derived from chemical synthesis and  biological medical products ; which include  recombinant proteins ,  vaccines ,  blood products  used therapeutically (such as  IVIG ),  gene therapy , and  cell therapy  (for instance,  stem cell  therapies). [ citation needed ]


Pharmaceuticals or drugs or medicines are classified into various other groups besides their origin on the basis of pharmacological properties like mode of action and their pharmacological action or activity, [ 8 ]  such as by  chemical properties , mode or  route of administration ,  biological system  affected, or  therapeutic effects . An elaborate and widely used  classification system  is the  Anatomical Therapeutic Chemical Classification System  (ATC system). The  World Health Organization  keeps a list of  essential medicines .


A sampling of classes of medicine includes:


Pharmaceuticals may also be described as "specialty", independent of other classifications, which is an ill-defined class of drugs that might be difficult to administer, require special handling during administration, require patient monitoring during and immediately after administration, have particular regulatory requirements restricting their use, and are generally expensive relative to other drugs. [ 9 ]


Drugs affecting the  central nervous system  include  psychedelics ,  hypnotics ,  anaesthetics ,  antipsychotics ,  eugeroics ,  antidepressants  (including  tricyclic antidepressants ,  monoamine oxidase inhibitors ,  lithium salts , and  selective serotonin reuptake inhibitors  (SSRIs)),  antiemetics ,  anticonvulsants /antiepileptics,  anxiolytics ,  barbiturates , movement disorder (e.g.,  Parkinson's disease ) drugs,  nootropics ,  stimulants  (including  amphetamines ),  benzodiazepines ,  cyclopyrrolones ,  dopamine antagonists ,  antihistamines ,  cholinergics ,  anticholinergics ,  emetics ,  cannabinoids , and  5-HT (serotonin) antagonists .


The main classes of painkillers are  NSAIDs ,  opioids , and local  anesthetics .


For consciousness (anesthetic drugs)


Some anesthetics include  benzodiazepines  and  barbiturates .


The main categories of drugs for  musculoskeletal disorders  are:  NSAIDs  (including  COX-2 selective inhibitors ),  muscle relaxants ,  neuromuscular drugs , and  anticholinesterases .


Antibiotics ,  sympathomimetics ,  antihistamines ,  anticholinergics ,  NSAIDs ,  corticosteroids ,  antiseptics ,  local anesthetics ,  antifungals , and cerumenolytics.


Bronchodilators ,  antitussives ,  mucolytics ,  decongestants , inhaled and systemic  corticosteroids ,  beta2-adrenergic agonists ,  anticholinergics ,  mast cell stabilizers ,  leukotriene antagonists .


Androgens ,  antiandrogens ,  estrogens ,  gonadotropin ,  corticosteroids ,  human growth hormone ,  insulin ,  antidiabetics  ( sulfonylureas ,  biguanides / metformin ,  thiazolidinediones ,  insulin ),  thyroid hormones , antithyroid drugs,  calcitonin ,  diphosphonate ,  vasopressin analogues .


Antifungal ,  alkalinizing agents ,  quinolones ,  antibiotics ,  cholinergics ,  anticholinergics ,  antispasmodics ,  5-alpha reductase inhibitor ,  selective alpha-1 blockers ,  sildenafils ,  fertility medications .


NSAIDs ,  anticholinergics ,  haemostatic drugs ,  antifibrinolytics ,  Hormone Replacement Therapy  (HRT), bone regulators,  beta-receptor agonists ,  follicle stimulating hormone ,  luteinising hormone ,  LHRH ,  gamolenic acid ,  gonadotropin release inhibitor ,  progestogen ,  dopamine agonists ,  oestrogen ,  prostaglandins ,  gonadorelin ,  clomiphene ,  tamoxifen ,  diethylstilbestrol .


Emollients ,  anti-pruritics ,  antifungals ,  antiseptics ,  scabicides ,  pediculicides ,  tar  products,  vitamin A derivatives ,  vitamin D analogues ,  keratolytics ,  abrasives ,  systemic antibiotics ,  topical   antibiotics ,  hormones , desloughing agents, exudate absorbents,  fibrinolytics ,  proteolytics ,  sunscreens ,  antiperspirants ,  corticosteroids , immune modulators.


Antibiotics ,  antifungals ,  antileprotics ,  antituberculous drugs ,  antimalarials ,  anthelmintics ,  amoebicides ,  antivirals ,  antiprotozoals , probiotics, prebiotics,  antitoxins , and antivenoms.


Vaccines ,  immunoglobulins ,  immunosuppressants ,  interferons , and  monoclonal antibodies .


Anti-allergics ,  antihistamines ,  NSAIDs , [ medical citation needed ]   corticosteroids .


Tonics,  electrolytes  and mineral preparations (including iron preparations and  magnesium preparations ),  parenteral nutrition ,  vitamins ,  anti-obesity drugs ,  anabolic drugs , haematopoietic drugs, food product drugs.


Cytotoxic drugs ,  therapeutic antibodies ,  sex hormones ,  aromatase inhibitors , somatostatin inhibitors, recombinant  interleukins ,  G-CSF ,  erythropoietin .


Contrast media .


A euthanaticum is used for  euthanasia  and  physician-assisted suicide . Euthanasia is not permitted by law in many countries, and consequently, medicines will not be licensed for this use in those countries.


A single drug may contain single or multiple  active ingredients .


The administration is the process by which a patient takes medicine. There are three major categories of drug administration:  enteral  (via the  human gastrointestinal tract ),  injection  into the body, and by other routes ( dermal ,  nasal ,  ophthalmic ,  otologic , and  urogenital ). [ 10 ]


Oral administration , the most common form of enteral administration, can be performed using various  dosage forms  including  tablets  or  capsules  and liquid such as syrup or suspension. Other ways to take the medication include  buccally  (placed inside the cheek),  sublingually  (placed underneath the tongue), eye and  ear drops  (dropped into the eye or ear), and transdermally (applied to the skin). [ 11 ]


They can be administered in one dose, as a  bolus . Administration frequencies [ 12 ]  are often abbreviated from Latin, such as  every 8 hours  reading Q8H from  Quaque VIII Hora . The drug frequencies are often expressed as the number of times a drug is used per day (e.g., four times a day). It [ specify ]  may include event-related information (e.g., 1 hour before meals, in the morning, at bedtime), or complimentary to an interval, although equivalent expressions may have different implications (e.g., every 8 hours versus 3 times a day). [ citation needed ]


In the fields of medicine,  biotechnology , and  pharmacology ,  drug discovery  is the process by which new drugs are discovered. [ citation needed ]


Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by  serendipitous  discovery. Later  chemical libraries  of synthetic  small molecules ,  natural products , or  extracts  were screened in intact cells or whole organisms to identify substances that have a desirable therapeutic effect in a process known as  classical pharmacology .  Since  sequencing  of the  human genome  which allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use  high throughput screening  of large compound libraries against isolated  biological targets  which are hypothesized to be  disease-modifying  in a process known as  reverse pharmacology . Hits from these screens are then tested in cells and then in animals for  efficacy . Even more recently, scientists have been able to understand the shape of biological molecules at the atomic level and to use that knowledge to design (see  drug design ) drug candidates. [ citation needed ]


Modern drug discovery involves the identification of screening hits,  medicinal chemistry , and optimization of those hits to increase the  affinity ,  selectivity  (to reduce the potential of side effects), efficacy/ potency ,  metabolic  stability (to increase the  half-life ), and oral  bioavailability . Once a compound that fulfills all of these requirements has been identified, it will begin the process of  drug development  prior to  clinical trials . One or more of these steps may, but not necessarily, involve  computer-aided drug design .


Despite advances in technology and understanding of biological systems, drug discovery is still a lengthy, "expensive, difficult, and inefficient process" with a low rate of new therapeutic discovery. [ 13 ]  In 2010, the research and development cost of each  new molecular entity  (NME) was approximately US$1.8 billion. [ 14 ]  Drug discovery is done by pharmaceutical companies, sometimes with research assistance from universities. The "final product" of drug discovery is a patent on the potential drug. The drug requires very expensive Phase I, II, and III clinical trials, and most of them fail. Small companies have a critical role, often then selling the rights to larger companies that have the resources to run the clinical trials.


Drug discovery is different from Drug Development. Drug Discovery is often considered the process of identifying new medicine. At the same time, Drug development is delivering a new drug molecule into clinical practice. In its broad definition, this encompasses all steps from the basic research process of finding a suitable molecular target to supporting the drug's commercial launch.


Drug development  is the process of bringing a new drug to the market once a  lead compound  has been identified through the process of  drug discovery . It includes pre-clinical research (microorganisms/animals) and  clinical trials  (on humans) and may include the step of obtaining regulatory approval to market the drug. [ 15 ] [ 16 ]


Drug Development Process


Discovery:  The Drug Development process starts with Discovery, a process of identifying a new medicine.


Development:  Chemicals extracted from natural products are used to make pills, capsules, or syrups for oral use. Injections for direct infusion into the blood drops for eyes or ears.


Preclinical research : Drugs go under laboratory or animal testing, to ensure that they can be used on Humans.


Clinical  testing:  The drug is used on people to confirm that it is safe to use.


FDA   Review:  drug is sent to FDA before launching the drug into the market.


FDA post-Market Review:  The drug is reviewed and monitored by FDA for the safety once it is available to the public.


The regulation of drugs varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency. In other jurisdictions, they are regulated at the state level, or at both state and national levels by various bodies, as is the case in Australia.  The role of therapeutic goods regulation is designed mainly to protect the health and safety of the population. Regulation is aimed at ensuring the safety, quality, and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered before they are allowed to be marketed. There is usually some degree of restriction on the availability of certain therapeutic goods depending on their risk to consumers. [ citation needed ]


Depending upon the  jurisdiction , drugs may be divided into  over-the-counter drugs  (OTC) which may be available without special restrictions, and  prescription drugs , which must be  prescribed  by a licensed medical practitioner in accordance with  medical guidelines  due to the risk of adverse effects and  contraindications . The precise distinction between OTC and prescription depends on the legal jurisdiction. A third category, "behind-the-counter" drugs, is implemented in some jurisdictions. These do not require a prescription, but must be kept in the  dispensary , not visible to the public, and be sold only by a pharmacist or  pharmacy technician . Doctors may also prescribe prescription drugs for  off-label use  – purposes which the drugs were not originally approved for by the regulatory agency. The  Classification of Pharmaco-Therapeutic Referrals  helps guide the referral process between pharmacists and doctors.


The  International Narcotics Control Board  of the United Nations imposes a world law of  prohibition  of certain drugs. They publish a lengthy list of chemicals and plants whose trade and consumption (where applicable) are forbidden. OTC drugs are sold without restriction as they are considered safe enough that most people will not hurt themselves accidentally by taking it as instructed. [ 17 ]  Many countries, such as the United Kingdom have a third category of "pharmacy medicines", which can be sold only in registered  pharmacies  by or under the supervision of a pharmacist.


Medical errors  include over-prescription and  polypharmacy , mis-prescription, contraindication and lack of detail in dosage and administration instructions. In 2000 the definition of a prescription error was studied using a  Delphi method  conference; the conference was motivated by ambiguity in what a prescription error is and a need to use a uniform definition in studies. [ 18 ]


In many jurisdictions,  drug prices  are regulated.


In the UK, the Pharmaceutical Price Regulation Scheme is intended to ensure that the  National Health Service  is able to purchase drugs at reasonable prices. The prices are negotiated between the Department of Health, acting with the authority of Northern Ireland and the UK Government, and the representatives of the Pharmaceutical industry brands, the  Association of the British Pharmaceutical Industry  (ABPI). For 2017 this payment percentage set by the PPRS will be 4,75%. [ 19 ]


In Canada, the Patented Medicine Prices Review Board examines drug pricing and determines if a price is excessive or not. In these circumstances, drug manufacturers must submit a proposed price to the appropriate regulatory agency. Furthermore, "the International Therapeutic Class Comparison Test is responsible for comparing the National Average Transaction Price of the patented drug product under review" [ 20 ]  different countries that the prices are being compared to are the following: France, Germany, Italy, Sweden, Switzerland, the United Kingdom, and the United States [ 20 ]


In Brazil, the prices are regulated through legislation under the name of  Medicamento Genérico  ( generic drugs ) since 1999. [ 21 ]


In India, drug prices are regulated by the  National Pharmaceutical Pricing Authority .


In the United States, drug costs are partially unregulated, but instead are the result of negotiations between drug companies and insurance companies. [ 22 ]


High prices have been attributed to monopolies given to manufacturers by the government. [ 23 ]  New drug development costs continue to rise as well. Despite the enormous advances in science and technology, the number of new blockbuster drugs approved by the government per billion dollars spent has halved every 9 years since 1950. [ 24 ]


A blockbuster drug is a drug that generates more than $1 billion in revenue for a pharmaceutical company in a single year. [ 25 ]   Cimetidine  was the first drug ever to reach more than $1 billion a year in sales, thus making it the first blockbuster drug. [ 26 ]


In the pharmaceutical industry, a blockbuster drug is one that achieves acceptance by prescribing physicians as a therapeutic standard for, most commonly, a highly prevalent chronic (rather than acute) condition. Patients often take the medicines for long periods. [ 27 ]


Antibiotics  first arrived on the medical scene in 1932 thanks to  Gerhard Domagk ; [ 28 ]  and were coined the "wonder drugs". The introduction of the  sulfa drugs  led to the mortality rate from  pneumonia  in the U.S. to drop from 0.2% each year to 0.05% ( i.e. ,  1 ⁄ 4  as much) by 1939. [ 29 ]  Antibiotics inhibit the growth or the metabolic activities of bacteria and other microorganisms by a chemical substance of microbial origin.  Penicillin , introduced a few years later, provided a broader spectrum of activity compared to sulfa drugs and reduced side effects.  Streptomycin , found in 1942, proved to be the first drug effective against the cause of  tuberculosis  and also came to be the best known of a long series of important antibiotics. A second generation of antibiotics was introduced in the 1940s:  aureomycin  and  chloramphenicol . Aureomycin was the best known of the second generation. [ citation needed ]