Redox responsive drug delivery systems rely on the natural reduction-oxidation reactions that occur in the body and the availability of reducing or oxidative-agents in the extracellular and intracellular space. [ 2 ]  In redox-stimulated responses, drug carriers enter the intracellular space through endocytosis and are destabilized by intracellular concentrations of reducing agents, leading to their disassembly and the delivery of the therapeutic intracellularly. [ 2 ]  For example, the use of redox stimulated drug delivery is primarily attributed to the high intracellular concentration of glutathione (GSH) as compared to the much lower extracellular concentration of GSH. [ 6 ]  GSH acts as a reducing agent in redox reactions, allowing it to cleave bonds like disulfide bonds. The increased level of GSH in tumor cells combined with its ability to cleave disulfide bonds has led to the development of drug delivery systems, such as polymeric micelles, synthesized with disulfide bonds that are subsequently cleaved by intracellular GSH, which cause the breakdown of the micelle and the intracellular release of the encapsulated therapeutic. [ 5 ]


Gradient responsive drug delivery systems are stimulated to deliver therapeutics through contact with an endogenous chemical gradient. When the system comes into contact with its specific chemical gradient, increased concentration of the chemical can lead to the conformational change or degradation of a drug carrier to allow drug release. [ citation needed ]  Gradient responsive systems also include gradients created by pH or redox reactants.


pH-responsive drug delivery systems are very popular subjects of research for their variability in application. Deviations from physiological pH occur in numerous disease states including infection, inflammation, and cancer, which makes this stimulus one of the most widely researched in the field of endogenous chemically responsive drug delivery systems. [ 3 ]  Applications of pH-responsive drug delivery systems include the synthesis of pH-responsive polymers into carriers like hydrogels, micelles, and micro- and nanovesicles. [ 3 ]  pH-responsive polymers can be selected for certain applications based on characteristics like the drug concentration, number of ionizable groups, and the type of carrier being used. Examples of widely used pH-responsive polymers include but are not limited to: poly(acrylamide), poly(acrylic acid), and poly(methacrylic acid) [ 3 ]


Redox-responsive drug delivery systems are also widely studied for a variety of applications, in particular their use in targeting cancer due to the increased levels of GSH in cancerous cells. Redox-responsive drug delivery systems are also used in the delivery of DNA and siRNA for gene therapy. [ 2 ]  Redox-responsive drug carriers are primarily synthesized as micelles or polymersomes and are highly stable because they contain a high amount of cross-linking [ 2 ]


Gradient-responsive drug delivery systems do not have a substantial body of research as of yet. The primary applications of gradient-responsive drug delivery systems are usually referenced as pH or redox gradients, as opposed to the gradients of other hormones or factors found naturally in the body. Aside from pH and redox gradients, there are no published works on gradient-responsive drug delivery systems.


There are many limitations that exist within the field of endogenous chemically responsive drug delivery systems that prevent many of these products from approved to be used in a clinical setting. One of the primary challenges of endogenous chemically responsive drug delivery is the inability to address or overcome patient heterogeneity. Patient heterogeneity describes the naturally-occurring difference between patient biology, such as differences in tumor pH for the same cancer and blood concentrations of redox reagents. [ 1 ]  The targeting of many chemical properties in pathological tissues is also restricted by a small range of fluctuation of the chemical property, which prevents researchers from being able to safely and specifically target that diseased tissue and stimulus due to small windows of sensitivity that have yet to be optimized. [ 5 ] [ 13 ]
Other important limitations to consider include the formulation of the drug carrier, which can affect the clearance rate and biodistribution of the drug carrier and decrease therapeutic efficacy due to size, shape, or effective penetration of the tissue by the drug carrier. [ 5 ] [ 13 ]  Biocompatibility and toxicity of the drug carrier formulation also poses a significant challenge to the development of the field, so future studies need to be conducted using inherently biocompatible materials to ensure feasibility and safety of these proposed delivery systems. Finally, cost of production and the scalability of the creation of stimuli responsive drug delivery systems remains an enormous barrier between the development and clinical use of these delivery systems.


Stretch-triggered drug delivery  is a method of controlled  drug delivery  stimulated by mechanical forces. The most commonly used materials for stretch-triggered autonomous drug release systems are  hydrogels  and  elastomers . [ 1 ]


This method of drug delivery falls in the category of  stimuli-responsive drug delivery systems  which include  pH ,  temperature , and  redox -responsive systems. Mechanical forces occur naturally throughout the human body therefore, stretch-triggered drug delivery systems may be used to autonomously deliver medications to the body when needed. The use of autonomous drug release systems reduces outcomes such as delays in receiving treatment and inaccurate dosages. [ 1 ]  Autonomous drug release systems induced by stretch apply to drugs such as  antimicrobial agents , cardiovascular medication, and  anticancer drugs . [ 1 ]   Theranostic agents  are also applicable to this drug delivery system, allowing for simultaneous treatment and diagnosis of diseases. [ 2 ]


Compression ,  tension , and  shear  are the three main types of mechanical stimuli. [ 3 ] [ 4 ]  Compression force is when an object experiences forces from two sides, going in opposite directions, causing it to become compacted. Tensile force is when an object experiences forces from two sides, pointing in opposite directions, causing it to stretch. Shear forces are when an object experiences forces that are parallel and are going in opposite directions.  Ultrasound  and  magnetic fields  are also examples of mechanical forces. [ 5 ]  Depending on the mechanical stimuli, a different material may improve the desired results. [ 2 ]  The human body is exposed to mechanical forces on or within  bones, organs, joints, blood vessels, and cartilage. [ 1 ] [ 5 ]


There are naturally occurring mechanical forces in the human body such as increased stress within blood vessels due to  atherosclerotic plaque . [ 4 ]  The naturally occurring mechanical forces in the body enable the self-administration of medications. [ 3 ]  Motion-triggered drug delivery of anticancer therapy is achievable through the natural forces generated by organ movements. [ 7 ]  Research has been conducted on contact lenses that are pre-loaded with  glaucoma medication  that is released by the stretch of the contact lens during natural eye movements. [ 6 ]  The movement of joints has been used to trigger the release of  antibacterial drugs  into the body. [ 5 ]


Stretch-triggered drug delivery has a variety of applications. Intracellular  transfection  can be achieved through drug-delivery systems that are responsive to mechanical stimuli. [ 3 ]  Drug release can be controlled by triggers due to forces experienced by the body from daily motions. [ 4 ]  Mechanical triggers have been applied to polymers to release 2-furylcarbonil derivatives which then trigger the release of molecular cargo. [ 8 ]  An application of stretch-triggered drug delivery systems is the delivery of chemotherapy triggered by  esophageal  stent expansion. [ 4 ]  Also, the incorporation of several drugs into stretch-triggered autonomous drug release systems is a possibility, allowing drugs to be released by the same or different signals. [ 1 ]  Stretch-triggered drug delivery is also applied to nanoparticle-loaded stretchable  elastomers  that release drugs due to their expanded surface area. [ 7 ]  Stretch-triggered drug delivery has been applied to the cardiovascular system through the use of drug-loaded hydrogels that lead to increased  vascularization . [ 5 ]  A research study demonstrated that  quinine -loaded hydrogels resulted in restricted growth of bacteria as a result of exposure to stretching. [ 9 ]


Due to the limited research on mechanical force-responsive drug delivery systems, the effects of mechanical forces on cells remain unclear. [ 10 ]  Current research on stretch-triggered drug delivery systems mostly involves  in vitro  studies, therefore, extensive  in-vivo  studies are required to further improve knowledge in this subject. [ 10 ] [ 4 ]  A limitation of current technology is the release of drugs in the absence of tensile triggers and a limit of loading agents. [ 4 ]   Transdermal  drug delivery systems may include stretch-triggered technology but these devices are typically used for long-term administration, making drug reloading a topic of concern. [ 11 ]  Issues of environmental impact are also a concern when it comes to transdermal drug delivery due to the material's lack of ability to biodegrade and associated electronic waste. [ 11 ]  An area of interest regarding drug delivery devices that use naturally occurring triggers is the variability of  physiological  parameters between people. [ 11 ]  This makes it difficult to set a standard of what will trigger this technology.


In  chemistry , a  suspension  is a  heterogeneous mixture  of a  fluid  that contains  solid   particles  sufficiently large for  sedimentation . The particles may be  visible  to the  naked eye , usually must be larger than one  micrometer , and will eventually  settle , although the  mixture  is only classified as a suspension when and while the particles have not settled out.


A suspension is a heterogeneous mixture in which the  solid  particles do not  dissolve , but get suspended throughout the bulk of the  solvent , left floating around freely in the medium. [ 1 ]  The internal phase (solid) is dispersed throughout the external phase (fluid) through mechanical  agitation , with the use of certain  excipients  or suspending agents.


An example of a suspension would be sand in water. The suspended particles are visible under a  microscope  and will settle over time if left undisturbed. This distinguishes a suspension from a  colloid , in which the  colloid  particles are smaller and do not settle. [ 2 ]  Colloids and suspensions are different from  solution , in which the dissolved substance (solute) does not exist as a solid, and solvent and solute are homogeneously mixed.


A suspension of liquid droplets or fine solid particles in a gas is called an  aerosol . In the  atmosphere , the suspended particles are called  particulates  and consist of fine dust and  soot  particles,  sea salt ,  biogenic  and  volcanogenic   sulfates ,  nitrates , and  cloud  droplets.


Suspensions are classified on the basis of the  dispersed phase  and the  dispersion medium , where the former is essentially solid while the latter may either be a solid, a liquid, or a gas.


In modern chemical process industries,  high-shear mixing technology  has been used to create many novel suspensions.


Suspensions are unstable from a thermodynamic point of view but can be kinetically stable over a longer period of time, which in turn can determine a suspension's shelf life. This time span needs to be measured in order to provide accurate information to the consumer and ensure the best product quality.


"Dispersion stability refers to the ability of a dispersion to resist change in its properties over time." [ 3 ]


Dispersion  of solid particles in a liquid.


Note : Definition based on that in ref. [ 4 ] [ 5 ]


Multiple light scattering coupled with vertical scanning is the most widely used technique to monitor the dispersion state of a product, hence identifying and quantifying  destabilization  phenomena. [ 6 ] [ 7 ] [ 8 ] [ 9 ]  It works on concentrated dispersions without dilution. When light is sent through the sample, it is back scattered by the particles. The backscattering intensity is directly proportional to the size and volume fraction of the dispersed phase. Therefore, local changes in concentration ( sedimentation ) and global changes in size ( flocculation ,  aggregation ) are detected and monitored. Of primary importance in the analysis of stability in particle suspensions is the value of the  zeta potential  exhibited by suspended solids. This parameter indicates the magnitude of interparticle electrostatic repulsion and is commonly analyzed to determine how the use of  adsorbates  and pH modification affect particle repulsion and suspension stabilization or destabilization.


The kinetic process of destabilisation can be rather long (up to several months or even years for some products) and it is often required for the formulator to use further accelerating methods in order to reach reasonable development time for new product design. Thermal methods are the most commonly used and consists in increasing temperature to accelerate destabilisation (below critical temperatures of phase and degradation). Temperature affects not only the viscosity, but also interfacial tension in the case of non-ionic surfactants or more generally interactions forces inside the system. Storing a dispersion at high temperatures enables simulation of real life conditions for a product (e.g. tube of sunscreen cream in a car in the summer), but also to accelerate destabilisation processes up to 200 times including vibration,  centrifugation  and agitation are sometimes used. They subject the product to different forces that pushes the particles / film drainage. However, some emulsions would never coalesce in normal gravity, while they do under artificial gravity. [ 10 ]  Moreover, segregation of different populations of particles have been highlighted when using centrifugation and vibration. [ 11 ]


Common examples of suspensions include:


A  syrette  is a single-use device for injecting liquid through a needle. It is similar to a  syringe  except that it has a sealed  squeeze tube  instead of a rigid tube and  piston . It was developed by the  pharmaceutical manufacturer  E.R. Squibb & Sons (eventually merged into the current day  Bristol-Myers Squibb ) just prior to World War II (WWII). [ 1 ]


In WWII, the  morphine  syrette was included in first aid kits. It had a wire loop with a guard at the end of a hollow needle that was used to break a seal where the needle was attached to the tube. The wire loop was then removed and the needle was inserted under the skin at a shallow angle and the tube slowly squeezed from the sealed end (see  subcutaneous injection ). [ 2 ]  After injection the used tube was often pinned to the receiving soldier's collar to inform others of the dose administered. [ 1 ]


The syrette was adopted for use by the  United States Army  in 1940. [ 1 ]  The US military also distributed  atropine  in syrettes. [ citation needed ]  Chemical treatment was subsequently distributed in  autoinjector  form. [ citation needed ]


A  syringe  is a simple  reciprocating pump  consisting of a  plunger  (though in modern syringes, it is actually a  piston ) that fits tightly within a cylindrical tube called a barrel. The plunger can be linearly pulled and pushed along the inside of the tube, allowing the syringe to take in and expel liquid or gas through a discharge  orifice  at the front (open) end of the tube.  The open end of the syringe may be fitted with a  hypodermic needle , a  nozzle  or  tubing  to direct the flow into and out of the barrel.  Syringes are frequently used in  clinical medicine  to administer  injections , infuse  intravenous therapy  into the bloodstream, apply compounds such as  glue  or  lubricant , and draw/measure liquids. There are also  prefilled syringes  (disposable syringes marketed with liquid inside).


The word "syringe" is derived from the  Greek  σῦριγξ ( syrinx , meaning "Pan flute", "tube").


Medical syringes include disposable and  safety syringes , injection pens, needleless injectors, insulin pumps, and specialty needles. [ 2 ]  Hypodermic syringes are used with  hypodermic needles  to  inject  liquid or gases into body tissues, or to remove from the body. Injecting of air into a  blood vessel  is hazardous, as it may cause an  air embolism ; preventing embolisms by removing air from the syringe is one of the reasons for the familiar image of holding a hypodermic syringe pointing upward, tapping it, and expelling a small amount of liquid before an injection into the  bloodstream .


The  barrel  of a syringe is made of plastic or glass, usually has graduated marks indicating the volume of fluid in the syringe, and is nearly always transparent. Glass syringes may be  sterilized  in an  autoclave . Plastic syringes can be constructed as either two-part or three-part designs. A three-part syringe contains a plastic plunger/ piston  with a rubber tip to create a seal between the piston and the barrel, where a two-part syringe is manufactured to create a perfect fit between the plastic plunger and the barrel to create the seal without the need for a separate synthetic rubber piston. Two-part syringes have been traditionally used in  European countries  to prevent introduction of additional materials such as silicone oil needed for lubricating three-part plungers. [ 3 ]  Most modern medical syringes are plastic because they are cheap enough to dispose of after being used only once, reducing the risk of spreading  blood-borne diseases . Reuse of needles and syringes has caused spread of diseases, especially  HIV  and  hepatitis , among intravenous drug users. Syringes are also commonly reused by diabetics, as they can go through several in a day with multiple daily insulin injections, which becomes an affordability issue for many. Even though the syringe and needle are only used by a single person, this practice is still unsafe as it can introduce bacteria from the skin into the bloodstream and cause serious and sometimes lethal infections. [ 4 ]  In medical settings, single-use needles and syringes effectively reduce the risk of cross-contamination. [ 5 ]


Medical syringes are sometimes used without a needle for orally administering liquid medicines to young children or animals, or milk to small young animals, because the dose can be measured accurately and it is easier to squirt the medicine into the subject's mouth instead of coaxing the subject to drink out of a measuring spoon.


Syringes come with a number of designs for the area in which the blade locks to the syringe body. Perhaps the most well known of these is the  Luer lock , which simply twists the two together.


Bodies featuring a small, plain connection are known as slip tips and are useful for when the syringe is being connected to something not featuring a screw lock mechanism.


Similar to this is the catheter tip, which is essentially a slip tip but longer and tapered, making it good for pushing into things where there the plastic taper can form a tight seal. These can also be used for rinsing out wounds or large abscesses in veterinary use.


There is also an eccentric tip, where the nozzle at the end of the syringe is not in the centre of the syringe but at the side. This causes the blade attached to the syringe to lie almost in line with the walls of the syringe itself and they are used when the blade needs to get very close to parallel with the skin (when injecting into a surface vein or artery for example).


Syringes for  insulin  users are designed for standard U-100 insulin.  The dilution of insulin is such that 1 mL of insulin fluid has 100 standard "units" of insulin. [ 6 ]   A typical insulin vial may contain 10 mL, for 1000 units.


Insulin syringes are made specifically for a patient to inject themselves, and have features to assist this purpose when compared to a syringe for use by a healthcare professional:


U-100 syringe sizes and markings


There are needle syringes designed to reload from a built-in tank (container) after each injection, so they can make several or many injections on a filling. These are not used much in human medicine because of the risk of cross-infection via the needle. An exception is the personal  insulin   autoinjector  used by  diabetic  patients and in dual-chambered syringe designs intended to deliver a prefilled saline flush solution after the medication. [ 21 ]


Venom extraction syringes are different from standard syringes, because they usually do not puncture the wound. The most common types have a plastic nozzle which is placed over the affected area, and then the syringe piston is pulled back, creating a vacuum that allegedly sucks out the venom. Attempts to treat snakebites in this way are specifically advised against, as they are ineffective and can cause additional injury. [ 22 ]


Syringes of this type are sometimes used for extracting  human botfly  larvae from the skin. [ 23 ]


An oral syringe is a  measuring instrument  used to accurately measure doses of liquid  medication , expressed in  millilitres  (mL).  They do not have threaded tips, because no needle or other device needs to be screwed onto them.  The contents are simply squirted or sucked from the syringe directly into the mouth of the person or animal.


Oral syringes are available in various sizes, from 1–10 mL and larger. An oral syringe is typically purple in colour to distinguish it from a standard injection syringe with a luer tip. [ 24 ]  The sizes most commonly used are 1 mL, 2.5 mL, 3 mL, 5 mL and 10 mL. [ 25 ]


A dental syringe is used by  dentists  for the injection of an  anesthetic . [ 26 ]  It consists of a  breech-loading  syringe fitted with a sealed cartridge containing an anesthetic solution.


In 1928,  Bayer  Dental developed, coined and produced a sealed cartridge system under the registered trademark Carpule ® . The current trademark owner is  Kulzer Dental   GmbH .


The carpules have long been reserved for  anesthetic  products for dental use. It is practically a bottomless flask. The latter is replaced by an  elastomer  plug that can slide in the body of the cartridge. This plug will be pushed by the plunger of the syringe. The neck is closed with a rubber cap. The dentist places the cartridge directly into a  stainless steel  syringe, with a double-pointed (single-use) needle. The tip placed on the cartridge side punctures the capsule and the piston will push the product. There is therefore no contact between the product and the ambient air during use.


The ancillary tool (generally part of a  dental engine ) used to supply water, compressed air or mist (formed by combination of water and compressed air) to the oral cavity for the purpose of irrigation (cleaning debris away from the area the dentist is working on), is also referred to as a dental syringe or a dental irrigation nozzle.


A 3-way syringe/nozzle has separate internal channels supplying air, water or a mist created by combining the pressurized air with the waterflow. The syringe tip can be separated from the main body and replaced when necessary.


In the UK and Ireland, manually operated hand syringes are used to inject  lidocaine  into patients' gums. [ 27 ] [ 28 ] [ 26 ]


A dose-sparing syringe is one which minimises the amount of liquid remaining in the barrel after the plunger has been depressed. These syringes feature a combined needle and syringe, and a protrusion on the face of the plunger to expel liquid from the needle hub. Such syringes were particularly popular during the  COVID-19 pandemic  as vaccines were in short supply. [ 29 ]


In some jurisdictions, the sale or possession of hypodermic syringes may be controlled or prohibited without a prescription, [ 30 ]  due to its potential use with illegal  intravenous drugs . [ 31 ]


The syringe has many non-medical applications.


Medical-grade  disposable hypodermic syringes are often used in research laboratories for convenience and low cost. Another application is to use the needle tip to add liquids to very confined spaces, such as washing out some scientific apparatus. They are often used for measuring and transferring solvents and reagents where a high precision is not required.  Alternatively, microliter syringes can be used to measure and dose chemicals very precisely by using a small diameter capillary as the syringe barrel.


The  polyethylene  construction of these disposable syringes usually makes them rather chemically resistant. There is, however, a risk of the contents of the syringes leaching plasticizers from the syringe material. Non-disposable glass syringes may be preferred where this is a problem. Glass syringes may also be preferred where a very high degree of precision is important (i.e.  quantitative chemical analysis ), because their  engineering tolerances  are lower and the plungers move more smoothly. In these applications, the transfer of  pathogens  is usually not an issue.


Used with a long needle or  cannula , syringes are also useful for transferring fluids through rubber  septa  when atmospheric  oxygen  or  moisture  are being excluded. Examples include the transfer of air-sensitive or  pyrophoric  reagents such as  phenylmagnesium bromide  and  n -butyllithium  respectively. Glass syringes are also used to inject small samples for  gas chromatography  (1 μl) and  mass spectrometry  (10 μl). Syringe drivers may be used with the syringe as well.


Some  culinary  uses of syringes are injecting liquids (such as  gravy ) into other foods, or for the manufacture of some  candies .


Syringes may also be used when  cooking  meat to enhance flavor and texture by injecting juices inside the meat, and in  baking  to inject filling inside a  pastry . It is common for these syringes to be made of stainless steel components, including the barrel. Such facilitates easy disassembly and cleaning.


Syringes are used to refill  ink cartridges  with  ink  in  fountain pens .


Common workshop applications include injecting  glue  into tight spots to repair joints where disassembly is impractical or impossible; and injecting lubricants onto working surfaces without spilling.


Sometimes a large hypodermic syringe is used without a needle for very small baby  mammals  to  suckle  from in artificial rearing.


Historically, large pumps that use reciprocating motion to pump water were referred to as syringes.  Pumps of this type were used as early  firefighting  equipment.


There are fountain syringes where the liquid is in a bag or can and goes to the nozzle via a pipe. In earlier times,  clyster  syringes were used for that purpose.


Loose  snus  is often applied using modified syringes. The nozzle is removed so the opening is the width of the chamber. The snus can be packed tightly into the chamber and plunged into the upper lip. Syringes, called portioners, are also manufactured for this particular purpose.


A  tablet  (also known as a  pill ) is a  pharmaceutical  oral dosage form ( oral solid dosage , or OSD) or solid unit dosage form. Tablets may be defined as the solid unit dosage form of medication with suitable  excipients . It comprises a mixture of active substances and excipients, usually in  powder  form, that are pressed or compacted into a solid dose. The main advantages of tablets are that they ensure a consistent dose of medicine that is easy to consume.


Tablets are prepared either by moulding or by  compression .  The excipients can include  diluents ,  binders  or granulating agents,  glidants  (flow aids) and  lubricants  to ensure efficient tabletting;  disintegrants  to promote tablet break-up in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets visually attractive or aid in visual identification of an unknown tablet. A polymer coating is often applied to make the tablet smoother and easier to swallow, to control the release rate of the active ingredient, to make it more resistant to the environment (extending its shelf life), or to enhance the tablet's appearance.


Medicinal tablets were originally made in the shape of a disk of whatever colour their components determined, but are now made in many shapes and colours to help distinguish different medicines. Tablets are often imprinted with symbols, letters, and numbers, which allow them to be identified, or a groove to allow splitting by hand. Sizes of tablets to be swallowed range from a few millimetres to about a centimetre.


The compressed tablet is the most commonly seen  dosage form  in use today. About two-thirds of all  prescriptions  are dispensed as solid dosage forms, and half of these are compressed tablets. A tablet can be formulated to deliver an accurate dosage to a specific site in the body; it is usually taken orally, but can be administered  sublingually ,  buccally ,  rectally  or  intravaginally . The tablet is just one of the many forms that an oral drug can take such as  syrups ,  elixirs ,  suspensions , and  emulsions .


Pills are thought to date back to around 1500 BC. [ 1 ]  Earlier medical recipes, such as those from 4000 BC, were for liquid preparations rather than solids. [ 1 ]  The first references to pills were found on papyruses in ancient Egypt and contained bread dough, honey, or grease. Medicinal ingredients, such as plant powders or spices, were mixed in and formed by hand to make little balls, or pills.
In ancient Greece, such medicines were known as  katapotia  ("something to be swallowed"), and the Roman scholar Pliny, who lived from 23 to 79 AD, first gave a name to what we now call pills, calling them  pilula . [ 1 ]


Pills have always been difficult to swallow, and efforts have been made to make them go down easier. In mediaeval times, people coated pills with slippery plant substances. Another approach, used as recently as the 19th century, was to gild them in gold and silver, although this often meant that they would pass through the digestive tract with no effect. [ 1 ]  In the 1800s, sugar coating and gelatin coating were invented, as were  gelatin capsules . [ 1 ]


In 1843, the British painter and inventor  William Brockedon  was granted a patent for a machine capable of "Shaping Pills, Lozenges, and Black Lead by Pressure in Dies". The device was capable of compressing powder into a tablet without the use of an adhesive. [ 2 ]


A pill was originally defined as a small, round, solid pharmaceutical  oral   dosage form  of medication.  The word's etymology  reflects the historical concepts of grinding the ingredients with a  mortar and pestle  and rolling the resultant paste or dough into lumps to be dried. Today, in its strict sense, the word  pill  still refers specifically to tablets (including caplets) rather than  capsules  (which were invented much later), but because a simple  hypernym  is needed to intuitively cover all such oral dosage forms, the broad sense of the word  pill  is also widely used and includes both tablets and capsules — colloquially, any solid oral form of medication falls into the "pill" category (see  pill § Usage notes ).


An early example of a pill comes from ancient Rome. They were made of zinc carbonates,  hydrozincite  and  smithsonite . The pills were used for sore eyes and were found aboard a Roman ship that wrecked in 140 BC. However, these tablets were meant to be pressed on the eyes, not swallowed. [ 3 ] [ 4 ]


A caplet is a smooth, coated, oval-shaped medicinal tablet in the general shape of a  capsule . Many caplets have an indentation running down the middle, so they may be split in half more easily. [ 5 ]  Consumers have viewed capsules as the most effective way to take medication ever since they first appeared. For this reason, producers of drugs such as  OTC  analgesics wanting to emphasize the strength of their product developed the "caplet", a  portmanteau [ 6 ]  of  capsule-shaped tablet , [ 7 ] [ 8 ]  in order to tie this positive association to more efficiently produced tablet pills as well as being an easier-to-swallow shape than the usual disk-shaped tablet.


An  orally disintegrating tablet  or orodispersible tablet (ODT), is a drug  dosage form  available for a limited range of over-the-counter (OTC) and  prescription  medications.


In the tablet-pressing process, it is important that all ingredients be fairly dry, powdered or granular, somewhat uniform in particle size, and freely flowing. Mixed particle sized powders may separate during the manufacturing process due to differing particle densities. This can result in tablets with non-uniform concentrations of drug or active pharmaceutical ingredient (API), resulting in uneven dosage between tablets, but  granulation  should prevent this.


Some APIs may be compressed into tablets as pure substances, but this is rarely the case; most formulations include pharmacologically inactive ingredients ( excipients ):


Tablets can be made in virtually any shape, although the requirements of patients and tableting machines mean that most are round, oval, or capsule-shaped. More unusual shapes have been manufactured, but patients find these harder to swallow, and they are more vulnerable to chipping or manufacturing problems.


Tablet diameter and shape are determined by the machine tooling used to produce them; a die plus an upper and a lower punch are required. This is called a station of tooling. The amount of tablet material and the placement of the punches in relation to one another during compression determine the thickness. Once this is done, we can measure the corresponding pressure applied during compression. The shorter the distance between the punches, the greater the pressure applied during compression, and sometimes the harder the tablet. Tablets need to be hard enough that they do not break up in the bottle, yet friable enough that they disintegrate in the gastric tract.


Tablets need to be strong enough to resist the stresses of packaging, shipping, and handling by the pharmacist and patient.  The mechanical strength of tablets is assessed using a combination of simple failure and erosion tests, and more sophisticated engineering tests. The simpler tests are often used for quality control purposes, whereas the more complex tests are used during the design of the formulation and manufacturing process in the research and development phase.  Standards for tablet properties are published in the various international pharmacopeias (USP/NF, EP, JP, etc.).  The hardness of tablets is the principal measure of mechanical strength.  Hardness is tested using a  tablet hardness tester .  The units for hardness have evolved since the 1930s but are commonly measured in kilograms per square centimetre. Models of testers include the Monsanto (or Stokes) Hardness Tester from 1930, the Pfizer Hardness Tester from 1950, the Strong Cob Hardness Tester and the Heberlain (or Schleeniger) Hardness Tester.


Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall, as well as between granules, which helps in uniform filling of the die.


Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are the most frequently used lubricants in tablets or hard gelatin capsules. [ 9 ]


In the tablet pressing process, the appropriate amount of active ingredient must be in each tablet.  Hence, all the ingredients should be well mixed. If a sufficiently homogenous mix of the components cannot be obtained with simple blending processes, the ingredients must be granulated prior to compression to assure an even distribution of the active compound in the final tablet. Two basic techniques are used to granulate powders for compression into tablets: wet granulation and dry granulation.  Powders that can be mixed well do not require granulation and can be compressed into tablets through direct compression ("DC"). Direct compression is desirable as it is quicker. There is less processing, equipment, labor, and energy consumption. However, DC is difficult when a formulation has a high content of poorly compressible active ingredients.


Wet granulation is a process of using a liquid binder to lightly agglomerate the powder mixture.  The amount of liquid has to be properly controlled, as over-wetting will cause the granules to be too hard and under-wetting will cause them to be too soft and friable. Aqueous solutions have the advantage of being safer to deal with than solvent-based systems but may not be suitable for drugs which are degraded by hydrolysis.


Low shear wet granulation processes use very simple mixing equipment, and can take a considerable time to achieve a uniformly mixed state.  High shear wet granulation processes use equipment that mixes the powder and liquid at a very fast rate, and thus speeds up the manufacturing process. Fluid bed granulation is a multiple-step wet granulation process performed in the same vessel to pre-heat, granulate, and dry the powders.  It is used because it allows close control of the granulation process.


Dry granulation processes create granules by light compaction of the powder blend under low pressures. The compacts so-formed are broken up gently to produce granules (agglomerates). This process is often used when the product to be granulated is sensitive to moisture and heat. Dry granulation can be conducted on a tablet press using slugging tooling or on a roll press called a roller compactor. Dry granulation equipment offers a wide range of pressures to attain proper densification and granule formation. Dry granulation is simpler than wet granulation, therefore the cost is reduced. However, dry granulation often produces a higher percentage of fine granules, which can compromise the quality or create yield problems for the tablet. Dry granulation requires drugs or excipients with cohesive properties, and a 'dry binder' may need to be added to the formulation to facilitate the formation of granules.


Hot melt extrusion is utilized in pharmaceutical solid oral dose processing to enable delivery of drugs with poor solubility and  bioavailability . Hot melt extrusion has been shown to molecularly disperse poorly soluble drugs in a polymer carrier increasing dissolution rates and bioavailability. The process involves the application of heat, pressure and agitation to mix materials together and 'extrude' them through a die. Twin-screw high shear extruders blend materials and simultaneously break up particles. The extruded particles can then be blended and compressed into tablets or filled into capsules. [ 10 ]


After granulation, a final lubrication step is used to ensure that the tableting blend does not stick to the equipment during the tableting process.  This usually involves low shear blending of the granules with a powdered lubricant, such as  magnesium stearate  or  stearic acid .


Whatever process is used to make the tableting blend, the process of making a tablet by powder compaction is very similar.  First, the powder is filled into the die from above.  The mass of powder is determined by the position of the lower punch in the die, the cross-sectional area of the die, and the powder density.  At this stage, adjustments to the tablet weight are normally made by repositioning the lower punch.  After die filling, the upper punch is lowered into the die and the powder is uniaxially compressed to a porosity of between 5 and 20%.  The compression can take place in one or two stages (main compression, and, sometimes, pre-compression or tamping) and for commercial production occurs very fast (500–50  mg  per tablet). Finally, the upper punch is pulled up and out of the die (decompression), and the tablet is ejected from the die by lifting the lower punch until its upper surface is flush with the top face of the die.  This process is repeated for each tablet.


Common problems encountered during tablet manufacturing operations include:


Consequently, permanent consistency checks are required during the manufacturing process. [ 11 ]


Tablet formulations are designed and tested using a laboratory machine called a Tablet Compaction Simulator or Powder Compaction Simulator. This is a computer controlled device that can measure the punch positions, punch pressures, friction forces, die wall pressures, and sometimes the tablet internal temperature during the compaction event. Numerous experiments with small quantities of different mixtures can be performed to optimise a formulation. Mathematically corrected punch motions can be programmed to simulate any type and model of production tablet press. Initial quantities of active pharmaceutical ingredients are very expensive to produce, and using a Compaction Simulator reduces the amount of powder required for product development.


Tablet presses , also called tableting machines, range from small, inexpensive bench-top models that make one tablet at a time (single-station presses), with only around a half-ton pressure, to large, computerized, industrial models (multi-station rotary presses) that can make hundreds of thousands to millions of tablets an hour with much greater pressure. The tablet press is an essential piece of machinery for any pharmaceutical and nutraceutical manufacturer. Tablet presses must allow the operator to adjust the position of the lower and upper punches accurately, so that the tablet weight, thickness and density/hardness can each be controlled. This is achieved using a series of cams, rollers, or tracks that act on the tablet tooling (punches).  Mechanical systems are also incorporated for die filling, and for ejecting and removing the tablets from the press after compression.  Pharmaceutical tablet presses are required to be easy to clean and quick to reconfigure with different tooling, because they are usually used to manufacture many different products.
There are two main standards of tablet tooling used in pharmaceutical industry: American standard TSM and European standard EU. TSM and EU configurations are similar to each other but cannot be interchanged. [ 12 ]


Modern tablet presses reach output volumes of up to 1,700,000 tablets per hour. These huge volumes require frequent in-process quality control for the tablet weight, thickness and hardness. Due to efforts to reduce rejects rates and machine down-time, automated tablet testing devices are used on-line with the tablet press or off-line in the IPC-labs.


Many tablets today are coated after being pressed. Although sugar-coating was popular in the past, the process has many drawbacks. Modern tablet coatings [ 13 ]  are  polymer  and  polysaccharide  based, with  plasticizers  and  pigments  included. Tablet coatings must be stable and strong enough to survive the handling of the tablet, must not make tablets stick together during the coating process, and must follow the fine contours of embossed characters or logos on tablets. Coatings are necessary for tablets that have an unpleasant taste, and a smoother finish makes large tablets easier to swallow. Tablet coatings are also useful to extend the shelf-life of components that are sensitive to moisture or oxidation. Special coatings (for example with pearlescent effects) can enhance brand recognition.


If the active ingredient of a tablet is sensitive to acid, or is irritant to the stomach lining, an  enteric coating  can be used, which is resistant to  stomach  acid, and dissolves in the less acidic area of the intestines. Enteric coatings are also used for medicines that can be negatively affected by taking a long time to reach the  small intestine , where they are absorbed. Coatings are often chosen to  control the rate of dissolution  of the drug in the gastrointestinal tract. Some drugs are absorbed better in certain parts of the digestive system. If this part is the stomach, a coating is selected that dissolves quickly and easily in acid. If the rate of absorption is best in the large intestine or colon, a coating is used that is acid resistant and dissolves slowly to ensure that the tablet reaches that point before dispersing. To measure the disintegration time of the tablet coating and the tablet core, automatic disintegration testers are used which are able to determine the complete disintegration process of a tablet by measuring the rest height of the thickness with every upward stroke of the disintegration tester basket.


There are two types of coating machines used in the pharmaceutical industry: coating pans and automatic coaters. [ 14 ]  Coating pans are used mostly to sugar coat pellets. Automatic coaters are used for all kinds of coatings; they can be equipped with a remote control panel, a dehumidifier, and dust collectors. An explosion-proof design is required for applying coatings that contain alcohol.


It is sometimes necessary to split tablets into halves or quarters. Tablets are easier to break accurately if scored, but there are devices called  pill-splitters  which cut unscored and scored tablets. Tablets with special coatings (for example, enteric coatings or  controlled-release  coatings) should not be broken before use, as this exposes the tablet core to the digestive juices, circumventing the intended delayed-release effect.


Target-controlled infusion  ( TCI ) automates the dosing of intravenous drugs during surgery.  After the  anesthetist  sets the desired parameters in a computer and presses the start button, the system controls the  infusion pump , while being monitored by the anesthetist. [ 1 ]   TCI is as safe and effective as manually controlled infusion. [ 2 ] [ 3 ]


TCI can be sub-classified according to the  target . The suffix 'e' as in  TCIe  indicates that the target is the effect site, in most cases, the central nervous system or brain. Alternatively, the suffix 'p' denotes plasma, indicating that the device implementing the TCI model is to target the blood plasma. There are important differences in relation to the time taken for  effect site equilibration . Studies have demonstrated the clinical safety of the effect-site target model. [ 4 ]


Popular TCI models exist for  Propofol  and the synthetic opioid  Remifentanil . The models are based on  pharmacokinetic  studies and use software embedded in the  infusion device . For  propofol  the Marsh and Schnider models are available and the Minto model is commonly used for  remifentanil . In 2017, a project to emulate the TCI models in the  python  language was published on  GitHub .


TCI has been used in clinical settings since 1996, initially with  propofol . [ 5 ]


Thin-film drug delivery  uses a  dissolving film  or  oral drug strip  to administer  drugs  via absorption in the mouth ( buccally  or  sublingually ) and/or via the small intestines ( enterically ).  A film is prepared using  hydrophilic  polymers that rapidly dissolves on the tongue or buccal cavity,  delivering  the drug to the  systemic circulation  via  dissolution  when contact with  liquid  is made.


Thin-film drug delivery has emerged as an advanced alternative to the traditional  tablets ,  capsules  and liquids often associated with  prescription  and  OTC  medications.  Similar in size, shape and thickness to a  postage stamp , thin-film strips are typically designed for  oral administration , with the user placing the strip on or under the tongue (sublingual) or along the inside of the cheek (buccal). These drug delivery options allow the medication to bypass the first pass metabolism thereby making the medication more bioavailable. [ citation needed ]  As the strip dissolves, the drug can enter the blood stream enterically, buccally or sublingually. Evaluating the systemic  transmucosal  drug delivery, the  buccal mucosa  is the preferred region as compared to the sublingual mucosa.


Different buccal delivery products have been marketed or are proposed for certain diseases like  trigeminal neuralgia ,  Ménière's disease ,  diabetes , and  addiction . [ citation needed ]   There are many commercial non-drug product to use thin films like Mr. Mint and  Listerine PocketPaks   breath freshening strips . Since then, thin-film products for other breath fresheners, as well as a number of cold, flu, anti-snoring and gastrointestinal medications, have entered the marketplace. There are currently [ when? ]  several projects in development that will deliver prescription drugs using the thin-film  dosage form . [ 1 ]


Formulation of oral drug strips involves the application of both aesthetic and performance characteristics such as strip-forming polymers,  plasticizers , active pharmaceutical ingredient, sweetening agents,  saliva  stimulating agent, flavoring agents, coloring agents, stabilizing and thickening agents. From the regulatory perspectives, all  excipients  used in the formulation of oral drug strips should be approved for use in oral pharmaceutical  dosage  forms.


The polymer employed should be non-toxic, non-irritant and devoid of leachable impurities. It should have good wetting and spreadability property. The polymer should exhibit sufficient peel, shear and tensile strengths. The polymer should be readily available and should not be very expensive. Film obtained should be tough enough so that there won't be any damage while handling or during transportation. Combination of  microcrystalline   cellulose  and  maltodextrin  has been used to formulate Oral Strips of piroxicam made by hot melt extrusion technique.  Pullulan  has been the most widely used film former (used in Listerine PocketPak, Benadryl, etc.)


Plasticizer is a vital ingredient of the OS formulation. It helps to improve the flexibility and reduces the brittleness of the strip. Plasticizer significantly improves the strip properties by reducing the glass transition temperature of the polymer.  Glycerol ,  Propylene glycol , low molecular weight  polyethylene glycols ,  phthalate  derivatives like  dimethyl ,  diethyl  and  dibutyl phthalate ,  Citrate  derivatives such as tributyl, triethyl, acetyl citrate,  triacetin  and  castor oil  are some of the commonly used plasticizer excipients.


Since the size of the dosage form has limitation, high-dose molecules are difficult to be incorporated in OS. Generally 5%w/w to 30%w/w of active pharmaceutical ingredients can be incorporated in the oral strip. [ 2 ]


An important aspect of thin film drug technology is its taste and color. The sweet taste in formulation is more important in case of  pediatric  population. Natural sweeteners as well as artificial sweeteners are used to improve the flavor of the mouth dissolving formulations for the flavors changes from individual to individual. Pigments such as titanium dioxide is  incorporated for coloring.


The stabilizing and thickening agents are employed to improve the  viscosity  and consistency of dispersion or solution of the strip preparation solution or suspension before casting. Drug content uniformity is a requirement for all dosage forms, particularly those containing low dose highly potent drugs. To uniquely meet this requirement, thin film formulations contain uniform dispersions of drug throughout the whole manufacturing process. [ 3 ]   Since this criterion is essential for the quality of the thin film and final pharmaceutical dosage form, the use of Laser Scanning Confocal Microscopy (LSCM) was recommended to follow the manufacturing process. [ 4 ]


An increasing number of film-based therapeutics are in development, including:


Other molecules like sildenafil citrate, tadalafil, methylcobalamin and vitamin D 3  are also developed by IntelGenx Zim Laboratories Ltd.


Thiolated  polymers  – designated  thiomers  – are functional  polymers  used in  biotechnology  product development with the intention to prolong mucosal drug residence time and to enhance absorption of  drugs . The name thiomer was coined by  Andreas Bernkop-Schnürch  in 2000. [ 1 ]  Thiomers have  thiol  bearing  side chains . [ 2 ] [ 3 ]  Sulfhydryl ligands of low molecular mass are  covalently  bound to a polymeric backbone consisting of mainly  biodegradable  polymers, such as  chitosan , [ 4 ] [ 5 ]   hyaluronic acid , [ 6 ]   cellulose  derivatives, [ 7 ]   pullulan , [ 8 ] [ 9 ]   starch , [ 10 ]   gelatin , [ 11 ]   polyacrylates , [ 12 ]   cyclodextrins , [ 13 ] [ 14 ]  or  silicones . [ 15 ]


Thiomers exhibit properties potentially useful for  non-invasive  drug delivery via oral, ocular, nasal, vesical,  buccal  and vaginal routes. Thiomers show also potential in the field of  tissue engineering  and  regenerative medicine . Various thiomers such as thiolated chitosan [ 16 ]  and thiolated hyaluronic acid [ 17 ]  are commercialy available as scaffold materials. Thiomers can be directly compressed to tablets or given as solutions. [ 18 ] [ 19 ]   In 2012, a second generation of thiomers – called "preactivated" or "S-protected" thiomers – were introduced. [ 20 ]


In contrast to thiomers of the first generation, preactivated thiomers are stable towards  oxidation  and display comparatively higher  mucoadhesive  and  permeation enhancing  properties. [ 21 ]  Approved thiomer products for human use are for example eyedrops for treatment of  dry eye syndrome  or adhesive gels for treatment of nickel allergy. [ 22 ]


Thiomers are capable of forming disulfide bonds with cysteine substructures of the mucus gel layer covering mucosal membranes. Because of this property they exhibit up to 100-fold higher mucoadhesive properties in comparison to the corresponding unthiolated polymers. [ 23 ] [ 24 ] [ 25 ]  Because of their mucoadhesive properties, thiolated polymers are an effective tool in the treatment of diseases such as dry eye, dry mouth, and dry vagina syndrome where dry mucosal surfaces are involved. [ 26 ] [ 27 ] [ 28 ]


Various polymers such as  poloxamers  exhibit in situ gelling properties. Because of these properties they can be administered as liquid formulations forming stable gels once having reached their site of application. An unintended rapid elimination or outflow of the formulation from mucosal membranes such as the ocular, nasal or vaginal mucosa can therefore be avoided. Thiolated polymers are capable of providing a comparatively more pronounced increase in viscosity after application, as an extensive crosslinking process by the formation of disulfide bonds between the polymer chains due to oxidation takes place. This effect was first described in 1999 by Bernkop-Schnürch et al. [ 29 ]  for polymeric excipients. In case of thiolated chitosan, for instance, a more than 10,000-fold increase in viscosity within a few minutes was shown. [ 30 ]  These high in situ gelling properties can also be used for numerous further reasons such as for parenteral formulations, [ 31 ]  as coating material [ 32 ]  or for food additives [ 33 ]


Due to a sustained drug release, a prolonged therapeutic level of drugs exhibiting a short elimination  half-life  can be maintained. Consequently the frequency of dosing can be reduced contributing to an improved compliance. The release of drugs out of polymeric carrier systems can be controlled by a simple diffusion process. So far the efficacy of such delivery systems, however, was limited by a too rapid disintegration and/or erosion of the polymeric network. [ 34 ]  By using thiolated polymers this essential shortcoming can be overcome. Because of the formation of inter- and intrachain disulfide bonds during the swelling process, the stability of the polymeric drug carrier matrix is strongly improved. Hence, a controlled drug release for numerous hours is guaranteed. There are numerous drug delivery systems making use of this technology. [ 35 ] [ 36 ] [ 37 ] [ 38 ] [ 39 ] [ 40 ]


Due to the binding of metal ions being essential for various enzymes to maintain their enzymatic activity, thiomers are potent reversible enzyme inhibitors. Many non-invasively administered drugs such as therapeutic peptides or nucleic acids are degraded on the mucosa by membrane bound enzymes, strongly reducing their bioavailability. In case of oral administration, this ‘enzymatic barrier’ is even more pronounced as an additional degradation caused by luminally secreted enzymes takes place. Because of their capability to bind zinc ions via thiol groups, thiomers are potent inhibitors of most membrane bound and secreted zinc-dependent enzymes. Due to this enzyme inhibitory effect, thiolated polymers can significantly improve the bioavailability of non-invasively administered drugs [ 41 ] [ 42 ] [ 43 ]


In vitro , thiomers were shown to have antimicrobial activity towards Gram-positive bacteria. [ 44 ] [ 45 ]  In particular, N-acyl thiolated chitosans show great potential as highly efficient, biocompatible and cost-effective antimicrobial compounds. [ 46 ]  Metabolism and mechanistic studies are under way to optimize these thiomers for clinical applications. Because of their antimicrobial activity, thiolated polymers are also used as coatings that avoid bacterial adhesion. [ 47 ]


Thiomers are able to reversibly open tight junctions. The responsible mechanism seems to be based on the inhibition of protein tyrosine phosphatase being involved in the closing process of tight junctions. [ 48 ]  Due to thiolation the permeation enhancing effect of polymers such as  polyacrylic acid  or chitosan can be up to 10-fold improved. [ 49 ] [ 50 ] [ 51 ]  In comparison to most low molecular weight permeation enhancers, thiolated polymers offer the advantage of not being absorbed from the mucosal membrane. Hence, their permeation enhancing effect can be maintained for a comparatively longer period of time and systemic toxic side effects of the auxiliary agent can be excluded.


Thiomers are able to reversibly inhibit efflux pumps. Because of this property the mucosal uptake of various efflux pump substrates such as anticancer drugs, antimycotic drugs and antiinflammatory drugs can be tremendously improved. [ 52 ] [ 53 ] [ 54 ]  The postulated mechanism of efflux pump inhibition is based on an interaction of thiolated polymers with the channel forming transmembrane domain of various efflux pumps such as P-gp and multidrug resistance proteins (MRPs). P-gp, for instance, exhibits 12 transmembrane regions forming a channel through which substrates are transported outside of the cell. Two of these transmembrane domains – namely 2 and 11 – exhibit on position 137 and 956, respectively, a cysteine subunit. Thiomers seem to enter in the channel of P-gp and likely form subsequently one or two disulfide bonds with one or both cysteine subunits located within the channel. Due to this covalent interaction the allosteric change of the transporter being essential to move drugs outside of the cell might be blocked. [ 55 ] [ 56 ]


Thiomers have the ability to form complexes with different metal ions, especially divalent metal ions, due to their thiol groups. Thiolated chitosans, for instance, were shown to effectively absorb nickel ions. [ 57 ] [ 58 ]


As thiolated polymers exhibit biocompatibility, cellular mimicking properties and efficiently support proliferation and differentiation of various cell types, they are used as scaffolds for tissue engineering. [ 59 ] [ 60 ] [ 61 ] [ 62 ]  Furthermore thiolated polymers such as thiolated hyaluronic acid [ 63 ]  and thiolated chitosan [ 64 ]  were shown to exhibit wound healing properties.


A  throat lozenge  (also known as a  cough drop ,  sore throat sweet ,  troche ,  cachou ,  pastille  or  cough sweet ) is a small, typically medicated tablet intended to be dissolved slowly in the mouth to temporarily stop coughs, lubricate, and soothe irritated tissues of the  throat  (usually due to a  sore throat  or  strep throat ), possibly from the  common cold  or  influenza . Cough tablets have taken the name  lozenge , based on their original shape, a diamond.


Lozenges may contain  benzocaine , an  anaesthetic , or  eucalyptus oil .  Non-menthol throat lozenges generally use either  zinc gluconate glycine  or  pectin  as an  oral demulcent . Several brands of throat lozenges contain  dextromethorphan .


Other varieties such as  Halls  contain  menthol ,  peppermint oil  and/or  spearmint  as their  active ingredient (s).  Honey  lozenges are also available.


The purpose of the throat lozenge is to calm the irritation that may be felt in the throat while swallowing, breathing, or even drinking certain fluids. However, one study found that excessive use of menthol cough drops can prolong coughs rather than relieve them. [ 1 ]


Candies to soothe the throat date back to 1000 BC in  Egypt 's  Twentieth Dynasty , when they were made from honey flavored with  citrus , herbs, and spices. [ citation needed ]  In the 19th century, physicians discovered  morphine  and  heroin , which suppress coughing at its source—the brain.  Popular formulations of that era included  Smith Brothers  Cough Drops, first advertised in 1852, and  Luden's , created in 1879. Concern over the risk of  opioid dependence  led to the development of alternative medications. [ 2 ]


A  tincture  is typically an  extract  of plant or animal material  dissolved  in  ethanol  (ethyl alcohol).  Solvent  concentrations of 25–60% are common, but may run as high as 90%. [ 1 ]  In  chemistry , a tincture is a  solution  that has ethanol as its solvent. In  herbal medicine , alcoholic tinctures are made with various ethanol concentrations, which should be at least 20% alcohol for preservation purposes. [ 1 ] [ 2 ]


Other solvents for producing tinctures include  vinegar ,  glycerol  (also called glycerine),  diethyl ether  and  propylene glycol , not all of which can be used for internal consumption. Ethanol has the advantage of being an excellent solvent for both acidic and basic (alkaline) constituents. A tincture using glycerine is called a  glycerite . Glycerine is generally a poorer solvent than ethanol. Vinegar, being acidic, is a better solvent for obtaining alkaloids but a poorer solvent for acidic components. For individuals who choose not to ingest alcohol, non-alcoholic extracts offer an alternative for preparations meant to be taken internally.


Low  volatility  substances such as  iodine  and  mercurochrome  can also be turned into tinctures.


Tinctures are often made of a combination of  ethyl alcohol  and water as solvents, each dissolving constituents the other is unable to, or weaker at. Varying their proportions can also produce different levels of constituents in the final extraction. As an  antimicrobial , alcohol also acts as a preservative.


A downside of using alcohol as a solvent is that ethanol has a tendency to  denature  some organic compounds, reducing or destroying their effectiveness. This tendency can also have undesirable effects when extracting botanical constituents, such as  polysaccharides . Certain other constituents, common among them  proteins , can become irreversibly denatured, or "pickled" by the alcohol. Alcohol can also have damaging effects on some aromatic compounds.


Ether and  propylene glycol  based tinctures are not suitable for internal consumption, although they are used in preparations for external use, such as personal care creams and  ointments .


Some examples that were formerly common in medicine [ 3 ]  include:


Examples of spirits include:


Toothpaste  is a paste or gel  dentifrice  used with a  toothbrush  to clean and maintain the aesthetics and health of  teeth . Toothpaste is used to promote  oral hygiene : it is an abrasive that aids in removing  dental plaque  and food from the teeth, assists in suppressing  halitosis , and delivers  active ingredients  (most commonly  fluoride ) to help prevent tooth decay ( dental caries ) and gum disease ( gingivitis ). [ 1 ]  Owing to differences in composition and fluoride content, not all toothpastes are equally effective in maintaining oral health. The decline of  tooth decay  during the 20th century has been attributed to the introduction and regular use of fluoride-containing toothpastes worldwide. [ 2 ] [ 3 ]  Large amounts of swallowed toothpaste can be poisonous. [ 4 ]  Common colors for toothpaste include white (sometimes with colored stripes or green tint) and blue.


Since 5000 BCE, the  Egyptians  made a tooth powder, which consisted of powdered ashes of ox hooves, myrrh, powdered and burnt eggshells, and  pumice . The  Greeks , and then the  Romans , improved the recipes by adding abrasives such as crushed bones and oyster shells. [ 5 ]  In the 9th century, Iraqi musician and fashion designer  Ziryab  invented a type of toothpaste, which he popularized throughout  Islamic Spain . The exact ingredients of this toothpaste are unknown, but it was reported to have been both "functional and pleasant to taste". [ 6 ]  It is not known whether these early toothpastes were used alone, were to be rubbed onto the teeth with rags, or were to be used with early toothbrushes, such as  neem-tree  twigs and  miswak . During Japan's  Edo period , inventor  Hiraga Gennai's   Hika rakuyo  (1769) contained advertisements for  Sosekiko , a "toothpaste in a box." [ 7 ]  Toothpastes or powders came into general use in the 19th century.


Toothpastes are generally useful to maintain dental health. Toothpastes containing fluoride are effective at preventing tooth decay. [ 2 ] [ 8 ] [ 9 ]  Toothpastes may also help to control and remove plaque build-up, promoting healthy gums. A 2016 systematic review indicated that using toothpaste when brushing the teeth does not necessarily impact the level of plaque removal. [ 10 ]  However, the active ingredients in toothpastes are able to prevent dental diseases with regular use. [ 11 ]


Toothpastes are derived from a variety of components, the three main ones being abrasives, fluoride, and detergent.


Abrasives constitute 8-20% of a typical toothpaste. [ 11 ]  These insoluble particles are designed to help remove plaque from the teeth. [ 12 ]  The removal of plaque inhibits the accumulation of tartar ( calculus ) helping to minimize the risk of gum disease. [ 13 ]  Representative abrasives include particles of  aluminum hydroxide  (Al(OH) 3 ),  calcium carbonate  (CaCO 3 ),  magnesium carbonate  (MgCO 3 ),  sodium bicarbonate , various  calcium hydrogen phosphates , various  silicas  and  zeolites , and  hydroxyapatite  (Ca 5 (PO 4 ) 3 OH).


After the  Microbead-Free Waters Act of 2015 , the use of  microbeads  in toothpaste has been discontinued in the US, [ 14 ]  however since 2015 the industry has shifted toward instead using  FDA -approved "rinse-off"  metallized-plastic   glitter  as their primary  abrasive agent . [ 15 ] [ 16 ] [ 17 ]  Some brands contain powdered white  mica , which acts as a mild abrasive, and also adds a cosmetic glittery shimmer to the paste. The polishing of teeth removes stains from tooth surfaces, but has not been shown to improve dental health over and above the effects of the removal of  plaque  and Calculus. [ 18 ]


Abrasives, like the dental polishing agents used in dentists' offices, also cause a small amount of enamel erosion which is termed "polishing" action. The abrasive effect of toothpaste is indicated by its  RDA  value. Toothpastes with RDA values above 250 are potentially damaging to the surfaces of teeth. The  American National Standards Institute  and  American Dental Association  considers toothpastes with an RDA below 250 to be safe and effective for a lifetime of use. [ 19 ]


Fluoride  in various forms is the most popular and effective active ingredient in toothpaste to prevent cavities. [ 12 ]  Fluoride is present in small amounts in plants, animals, and  some natural water sources . The additional fluoride in toothpaste has beneficial effects on the formation of dental enamel and bones.  Sodium fluoride  (NaF) is the most common source of fluoride, but  stannous fluoride  (SnF 2 ), and  sodium monofluorophosphate  (Na 2 PO 3 F) are also used. [ 12 ]   At similar fluoride concentrations, toothpastes containing stannous fluoride have been shown to be more effective than toothpastes containing sodium fluoride for reducing the incidence of dental caries and  dental erosion , [ 20 ] [ 21 ] [ 22 ] [ 23 ] [ 24 ]  as well as reducing  gingivitis . [ 25 ] [ 26 ] [ 27 ] [ 28 ] [ 29 ]  Some stannous fluoride-containing toothpastes also contain ingredients that allow for better stain and calculus removal. [ 30 ]  A systematic review revealed stabilised stannous fluoride-containing toothpastes had a positive effect on the reduction of plaque, gingivitis and staining, with a significant reduction in  calculus  and halitosis compared to other toothpastes. [ 31 ]  Furthermore, numerous clinical trials have shown gluconate chelated stannous fluoride toothpastes possess superior protection against dental erosion and  dentine hypersensitivity  compared to other fluoride-containing and fluoride-free toothpastes. [ 32 ]


Much of the toothpaste sold in the United States has 1,000 to 1,100 parts per million fluoride. In European countries, such as the UK or Greece, the fluoride content is often higher; a sodium fluoride content of 0.312% w/w (1,450  ppm  fluoride) or stannous fluoride content of 0.454% w/w (1,100 ppm fluoride) is common. All of these concentrations are likely to prevent  tooth decay , according to a 2019  Cochrane review . [ 9 ]  Concentrations below 1,000 ppm are not likely to be preventive, and the preventive effect increases with concentration. [ 9 ]  Clinical trials support the use of high fluoride (5,000 ppm fluoride) dentifrices, for prevention of root caries in elderly adults by reducing the amount of plaque accumulated, decreasing the number of  mutans streptococci  and  lactobacilli  and possibly promoting calcium fluoride deposits to a higher degree than after the use of traditional fluoride containing dentifrices. [ 9 ]


Many, although not all, toothpastes contain  sodium lauryl sulfate (SLS)  or related  surfactants  (detergents). SLS is found in many other personal care products as well, such as  shampoo , and is mainly a  foaming agent , which enables uniform distribution of toothpaste, improving its cleansing power. [ 18 ]


Triclosan , an antibacterial agent, is a common toothpaste ingredient in the United Kingdom. Triclosan or  zinc chloride  prevent gingivitis and, according to the American Dental Association, helps reduce  tartar  and  bad breath . [ 1 ] [ 33 ]  A 2006 review of clinical research concluded there was evidence for the effectiveness of 0.30% triclosan in reducing plaque and gingivitis. [ 34 ]   Another Cochrane review in 2013 has found that triclosan achieved a 22% reduction in plaque, and in gingivitis, a 48% reduction in  bleeding gums . However, there was insufficient evidence to show a difference in fighting  periodontitis  and there was no evidence either of any harmful effects associated with the use of triclosan toothpastes for more than 3 years. The evidence relating to plaque and gingivitis was considered to be of moderate quality while for periodontitis was low quality. [ 35 ]  Recently, triclosan has been removed as an ingredient from well-known toothpaste formulations. This may be attributed to concerns about adverse effects associated with triclosan exposure. Triclosan use in cosmetics has been positively correlated with triclosan levels in human tissues, plasma and breast milk, and is considered to have potential neurotoxic effects. [ 36 ]  Long-term studies are needed to substantiate these concerns.


Chlorhexidine  is another antimicrobial agent used in toothpastes; however, it is more commonly added in  mouthwash  products. [ 37 ]   Sodium laureth sulfate , a foaming agent, is a common toothpaste ingredient that also possesses some antimicrobial activities. [ 38 ]  There are also many commercial products available in the market containing different  essential oils ,  herbal  ingredients (e.g.  chamomile ,  neem ,  chitosan ,  Aloe vera ), and natural or plant extracts (e.g.  hinokitiol ). [ 39 ]  These ingredients are claimed by the manufacturers to fight plaque, bad breath and prevent  gum disease . A 2020 systematic metareview found that herbal toothpastes are as effective as non-herbal toothpastes in reducing dental plaque at shorter period of follow-up (4 weeks). [ 40 ]  However, this evidence comes from low-quality studies.


The stannous ( tin ) ion, commonly added to toothpastes as stannous fluoride or  stannous chloride , has been shown to have antibacterial effects in the mouth. Research has shown that stannous fluoride-containing toothpaste inhibits extracellular polysaccharide ( EPS ) production in a multispecies  biofilm  greater than sodium fluoride-containing toothpaste. [ 41 ]  This is thought to contribute to a reduction in plaque and gingivitis when using stannous fluoride-containing toothpastes when compared to other toothpastes, and has been evidenced through numerous clinical trials. [ 25 ] [ 26 ] [ 27 ] [ 28 ] [ 29 ]  In addition to its antibacterial properties, stabilised stannous fluoride toothpastes have been shown to protect against dental erosion and dentine hypersensitivity, making it a multifunctional component in toothpaste formulations. [ 32 ]


Toothpaste comes in a variety of  colors  and  flavors , intended to encourage use of the product. The three most common flavorants are  peppermint ,  spearmint , and  wintergreen . Toothpaste flavored with peppermint-anise oil is popular in the Mediterranean region. These flavors are provided by the respective oils, e.g. peppermint oil. [ 18 ]  More exotic flavors include Anethole  anise ,  apricot ,  bubblegum ,  cinnamon ,  fennel ,  lavender ,  neem ,  ginger ,  vanilla ,  lemon ,  orange , and  pine . Alternatively, unflavored toothpastes exist.


Chemical repair ( remineralization ) of early tooth decay is promoted naturally by  saliva . [ 42 ]  However, this process can be enhanced by various remineralisation agents. [ 43 ]  Fluoride promotes remineralization, but is limited by bioavailable calcium. [ 44 ]  Casein phosphopeptide stabilised amorphous calcium phosphate (CPP-ACP) is a toothpaste ingredient containing bioavailable calcium that has been widely researched to be the most clinically effective remineralization agent that enhances the action of saliva and fluoride. [ 45 ] [ 46 ] [ 47 ] [ 48 ]  Peptide-based systems, hydroxyapatite nanocrystals and a variety of  calcium phosphates  have been advocated as remineralization agents; however, more clinical evidence is required to substantiate their effectiveness. [ 48 ]


Agents are added to suppress the tendency of toothpaste to dry into a powder. Included are various sugar alcohols, such as  glycerol ,  sorbitol , or  xylitol , or related derivatives, such as  1,2-propylene glycol  and  polyethyleneglycol . [ 49 ]   Strontium chloride  or  potassium nitrate  is included in some toothpastes to reduce sensitivity. Two systemic meta-analysis reviews reported that  arginine , and  calcium sodium phosphosilicate – CSPS containing toothpastes are also effective in alleviating dentinal hypersensitivity respectively. [ 50 ] [ 51 ]  Another randomized clinical trial found superior effects when both formulas were combined. [ 52 ]


Sodium polyphosphate is added to minimize the formation of tartar. [ citation needed ]


Chlorohexidine mouthwash has been popular for its positive effect on controlling plaque and gingivitis, [ 53 ]  however, a systemic review studied the effects of Chlorhexidine toothpastes and found insufficient evidence to support its use, tooth surface discoloration was observed as a side effect upon using it, which is considered a negative side effect that can affect patients' compliance. [ 54 ]


Sodium hydroxide , also known as lye or caustic soda, is listed as an inactive ingredient in some toothpaste, for example Colgate Total.


A systematic review reported two out of ten studies by the same authors on the same population showed toothpastes with xylitol as an ingredient were more effective at preventing dental caries in permanent teeth of children than toothpastes containing fluoride alone. Furthermore, xylitol has not been found to cause any harmful effects. However, further investigation into the efficacy of toothpastes containing xylitol is required as the currently available studies are of low quality and high risk of bias. [ 55 ]


Fluoride-containing toothpaste can be acutely toxic if swallowed in large amounts, [ 56 ] [ 57 ]  but instances are exceedingly rare and result from prolonged and excessive use of toothpaste (i.e. several tubes per week). [ 58 ]  Approximately 15 mg/kg body weight is the acute lethal dose, even though as small amount as 5 mg/kg may be fatal to some children. [ 59 ]


The risk of using fluoride is low enough that the use of full-strength toothpaste (1350–1500 ppm fluoride) is advised for all ages. However, smaller volumes are used for young children, for example, a smear of toothpaste until three years old. [ 57 ]  A major concern of  dental fluorosis  is for children under 12 months ingesting excessive fluoride through toothpaste. Nausea and vomiting are also problems which might arise with topical fluoride ingestion. [ 59 ]


The inclusion of sweet-tasting but toxic  diethylene glycol  in Chinese-made toothpaste led to a recall in 2007 involving multiple toothpaste brands in several nations. [ 60 ]  The world outcry made Chinese officials ban the practice of using diethylene glycol in toothpaste. [ 61 ]


Reports have suggested triclosan, an active ingredient in many kinds of toothpastes, can combine with  chlorine  in tap water to form  chloroform . [ 62 ]  An animal study revealed the chemical might modify hormone regulation, and many other lab researches proved bacteria might be able to develop resistance to triclosan in a way which can help them to resist antibiotics also. [ 63 ]


PEG  is a common ingredient in some of the formulas of toothpastes; it is a hydrophilic  polymer  that acts as a  dispersant  in toothpastes. Also, it is used in many cosmetic and pharmaceutical formulas, for example: ointments, osmotic  laxatives , some of the  nonsteroidal anti-inflammatory drugs , other medications and household products. [ 64 ]   However, 37 cases of PEG  hypersensitivity  (delayed and immediate) to PEG-containing substances have been reported since 1977, [ 65 ]  suggesting that they have unrecognized allergenic potential. [ 65 ]


With the exception of toothpaste intended to be used on pets such as dogs and cats, and toothpaste used by  astronauts , most toothpaste is not intended to be swallowed, and doing so may cause  nausea  or  diarrhea . Tartar fighting toothpastes have been debated. [ 66 ]   Sodium lauryl sulfate (SLS) has been proposed to increase the frequency of  mouth ulcers  in some people, as it can dry out the protective layer of oral tissues, causing the underlying tissues to become damaged. [ 67 ]  In studies conducted by the university of Oslo on  recurrent aphthous ulcers , it was found that SLS has a denaturing effect on the oral  mucin  layer, with high affinity for proteins, thereby increasing epithelial permeability. [ 68 ]  In a double-blind cross-over study, a significantly higher frequency of  aphthous ulcers  was demonstrated when patients brushed with an SLS-containing versus a detergent-free toothpaste. Also patients with  Oral Lichen Planus  who avoided SLS-containing toothpaste benefited. [ 69 ] [ 70 ]


After using toothpaste,  orange juice  and other fruit juices are known to have an unpleasant taste if consumed shortly afterwards.  Sodium lauryl sulfate , used as a surfactant in toothpaste, alters taste perception. It can break down  phospholipids  that inhibit taste receptors for sweetness, giving food a bitter taste. In contrast, apples are known to taste more pleasant after using toothpaste. [ 71 ]  Distinguishing between the hypotheses that the bitter taste of orange juice results from stannous fluoride or from sodium lauryl sulfate is still an unresolved issue and it is thought that the  menthol  added for flavor may also take part in the alteration of taste perception when binding to lingual  cold receptors . [ citation needed ]


Many toothpastes make whitening claims. Abrasion is the principal way that toothpaste removes stains, and toothpastes that are not marketed as whitening can still remove stains by abrasion. [ 72 ]  Some of these toothpastes contain peroxide, the same ingredient found in tooth bleaching gels. Whitening toothpaste cannot alter the natural color of teeth or reverse discoloration by penetrating surface stains or decay. To remove surface stains, whitening toothpaste may include abrasives to gently polish the teeth or additives such as  sodium tripolyphosphate  to break down or dissolve stains. When used twice a day, whitening toothpaste typically takes two to four weeks to make teeth appear whiter. Whitening toothpaste is generally safe for daily use, but excessive use might damage tooth enamel. [ 73 ]  A recent systematic review in 2017 concluded that nearly all dentifrices that are specifically formulated for tooth whitening were shown to have a beneficial effect in reducing extrinsic stains, irrespective of whether or not a chemical discoloration agent was added. [ 74 ]  However, the whitening process can permanently reduce the strength of the teeth, as the process scrapes away a protective outer layer of enamel. [ 75 ]


Herbal toothpastes are marketed to consumers who wish to avoid some of the artificial ingredients commonly found in regular toothpastes. The ingredients found in so-called natural toothpastes vary widely but often include  baking soda ,  aloe ,  eucalyptus oil ,  myrrh ,  camomile ,  calendula , neem,  toothbrush tree , plant extract (strawberry extract), and essential oils. Many herbal toothpastes do not contain fluoride or  sodium lauryl sulfate . [ 40 ]


A 2020 meta-analysis showed some evidence for the efficacy of herbal toothpaste, albeit from poor quality studies. [ 40 ]  According to a study by the  Delhi Institute of Pharmaceutical Sciences and Research , many of the herbal toothpastes being sold in India were adulterated with  nicotine . [ 76 ]


Charcoal  has also been incorporated in toothpaste formulas; however, there is no evidence to determine its safety and effectiveness, and the American Dental Association does not recommend its use. [ 72 ]


In the United States toothpaste is regulated by the U.S.  Food and Drug Administration  as a  cosmetic , except for ingredients with a medical purpose, such as fluoride, which are regulated as  drugs . [ 77 ]  Drugs require scientific studies and FDA approval in order to be legally marketed in the United States, but cosmetic ingredients do not require pre-approval, except for color additives. The FDA does have labelling and requirements and bans certain ingredients. [ 78 ]


Striped toothpaste was invented by Leonard Marraffino in 1955. The patent (US patent  2,789,731 , issued 1957) was subsequently sold to  Unilever , which marketed the novelty under the Stripe brand-name in the early 1960s. This was followed by the introduction of the Signal brand in Europe in 1965 (UK patent 813,514). Although Stripe was initially very successful, it never again achieved the 8% market share that it cornered during its second year.


Marraffino's design, which remains in use for single-color stripes, is simple. The main material, usually white, sits at the crimp end of the toothpaste tube and makes up most of its bulk. A thin pipe, through which that carrier material will flow, descends from the nozzle to it. The stripe-material (this was red in Stripe) fills the gap between the carrier material and the top of the tube. The two materials are not in separate compartments, but they are sufficiently  viscous  that they will not mix. When pressure is applied to the toothpaste tube, the main material squeezes down the thin pipe to the nozzle. Simultaneously, the pressure applied to the main material causes pressure to be forwarded to the stripe material, which thereby issues out through small holes (in the side of the pipe) onto the main carrier material as it is passing those holes.


In 1990, Colgate-Palmolive was granted a patent (USPTO  4,969,767 ) for two differently colored stripes. In this scheme, the inner pipe has a cone-shaped plastic guard around it, and about halfway up its length. Between the guard and the nozzle-end of the tube is a space for the material for one color, which issues out of holes in the pipe. On the other side of the guard is space for second stripe-material, which has its own set of holes.


In 2016,  Colgate -Palmolive was granted a patent (USPTO  U.S. patent 20,160,228,347 ) for suitable sorts of differently colored toothpastes to be filled directly into tubes to produce a striped mix without any separate compartments. This required adjustment of the different components' behavior ( rheology ) so that stripes are produced when the tube is squeezed. [ 79 ]


Striped toothpaste should not be confused with layered toothpaste. Layered toothpaste requires a multi-chamber design (e.g. USPTO  5,020,694 ), in which two or three layers extrude out of the nozzle. This scheme, like that of pump dispensers (USPTO  4,461,403 ), is more complicated (and thus, more expensive to manufacture) than either the Marraffino design or the Colgate designs.


The iconic depiction of a wave-shaped blob of toothpaste sitting on a toothbrush is called a "nurdle". [ 80 ]


Tooth powders for use with toothbrushes came into general use in the 19th century in Britain. Most were homemade, with chalk, pulverized brick, or salt as ingredients. An 1866 Home Encyclopedia recommended pulverized charcoal, and cautioned that many patented tooth powders that were commercially marketed did more harm than good.


Arm & Hammer  marketed a baking soda-based toothpowder in the United States until approximately 2000, and  Colgate  currently markets toothpowder in India and other countries.


An 18th-century American and British toothpaste recipe called for burned bread. Another formula around this time called for  dragon's blood  (a resin), cinnamon, and burned  alum . [ citation needed ]


In 1873 the Colgate company began the mass production of aromatic toothpaste in jars. [ 81 ]


By 1900, a paste made of  hydrogen peroxide  and  baking soda  was recommended for use with toothbrushes. Pre-mixed toothpastes were first marketed in the 19th century, but did not surpass the popularity of tooth-powder until  World War I .


Together with  Willoughby D. Miller ,  Newell Sill Jenkins  developed the first toothpaste containing  disinfectants , branded as  Kolynos . [ 82 ]  The name is a combination of two Greek words, meaning "beautifier" and "disease preventer". [ 83 ]  Numerous attempts to produce the toothpaste by pharmacists in Europe proved uneconomic. After returning to the US, he continued experimenting with  Harry Ward Foote  (1875–1942), professor of chemistry at  Sheffield Chemical Laboratory  of  Yale University . [ 84 ]  After 17 years of development of Kolynos and clinical trials, Jenkins retired and transferred the production and distribution to his son  Leonard A. Jenkins , who brought the first toothpaste tubes on the market on April 13, 1908. Within a few years the company expanded in North America, Latin America, Europe and the Far East. A branch operation opened in London in 1909. In 1937, Kolynos was produced in 22 countries and sold in 88 countries. Kolynos has been sold mainly in South America and in Hungary. Colgate-Palmolive took over the production of  American Home Products  in 1995 at a cost of one billion US dollars. [ 85 ]


Fluoride  was first added to toothpastes in the 1890s. Tanagra, containing  calcium fluoride  as the active ingredient, was sold by  Karl F. Toellner Company , of  Bremen , Germany, based upon the early work of chemist  Albert Deninger . [ 86 ]  An analogous invention by  Roy Cross , of  Kansas City, Missouri , was initially criticized by the American Dental Association (ADA) in 1937. Fluoride toothpastes developed in the 1950s received the ADA's approval. To develop the first ADA-approved fluoride toothpaste,  Procter & Gamble  started a research program in the early 1940s. In 1950, Procter & Gamble developed a joint research project team headed by  Joseph C. Muhler  at  Indiana University  to study new toothpaste with fluoride. In 1955, Procter & Gamble's  Crest  launched its first  clinically proven  fluoride-containing toothpaste. On August 1, 1960, the ADA reported that "Crest has been shown to be an effective anticavity (decay preventative) dentifrice that can be of significant value when used in a conscientiously applied program of oral hygiene and regular professional care."


In 1980, the Japanese company, Sangi Co., Ltd., launched APADENT, the world's first remineralizing toothpaste to use a nano-form of hydroxyapatite, the main component of tooth enamel, rather than fluoride, to remineralize areas of mineral loss below the surface of tooth enamel (incipient caries lesions). After many years of laboratory experiments and field trials, [ 87 ]  its hydroxyapatite ingredient was approved as an active anti-caries agent by the Japanese Ministry of Health in 1993, and given the name Medical Hydroxyapatite to distinguish it from other forms of hydroxyapatite used in toothpaste, such as dental abrasives.


In 2006,  BioRepair  appeared in Europe with the first European toothpaste containing synthetic  hydroxylapatite  as an alternative to fluoride for the remineralization and reparation of  tooth enamel . The "biomimetic hydroxylapatite" is intended to protect the teeth by creating a new layer of synthetic enamel around the tooth instead of hardening the existing layer with fluoride that chemically changes it into  fluorapatite . [ 88 ]


Toothpaste is usually dispensed via a collapsible tube or with a more rigid pump. Several traditional and innovative designs have been developed. [ 89 ]   The dispenser must be matched to the flow properties of the toothpaste. [ 90 ]


In 1880, Doctor  Washington Sheffield  of  New London, CT  manufactured toothpaste into a collapsible tube,  Dr. Sheffield's Creme Dentifrice . He had the idea after his son traveled to Paris and saw painters using paint from tubes. In  York  in 1896, Colgate-Palmolive Dental Cream was packaged in collapsible tubes imitating Sheffield. The original collapsible toothpaste tubes were made of  lead . [ 91 ] [ 92 ]


Topical cream formulation  is an  emulsion  semisolid dosage form that is used for skin external application. Most of the topical cream formulations contain more than 20 per cent of water and  volatiles  and/or less than 50 per cent of  hydrocarbons ,  waxes , or  polyethylene glycols  as the vehicle for external skin application. [ 1 ]  In a topical cream formulation, ingredients are dissolved or dispersed in either a  water-in-oil (W/O) emulsion  or an  oil-in-water (O/W) emulsion . [ 2 ]  The topical cream formulation has a higher content of oily substance than  gel , but a lower content of oily ingredient than  ointment . Therefore, the viscosity of topical cream formulation lies between  gel  and  ointment . [ 1 ]  The  pharmacological effect  of the topical cream formulation is confined to the skin surface or within the skin. [ 3 ]  Topical cream formulation penetrates through the skin by transcellular route, intercellular route, or trans-appendageal route. [ 4 ]  Topical cream formulation is used for a wide range of diseases and conditions, including  atopic dermatitis  (eczema),  psoriasis ,  skin infection ,  acne , and  wart . [ 5 ]   Excipients  found in a topical cream formulation include  thickeners ,  emulsifying agents ,  preservatives ,  antioxidants , and  buffer agents . [ 6 ] [ 7 ]  Steps required to manufacture a topical cream formulation include excipient dissolution, phase mixing, introduction of  active substances , and  homogenization  of the product mixture. [ 2 ] [ 8 ]


Human skin can be divided, from outside to inside, into the  stratum corneum , viable  epidermis ,  dermis , and underlying  hypodermis . [ 9 ]


The  stratum corneum  is typically 10–20 μm thick and consists of extracellular lipid-surrounded  corneocytes . The lipophilic environment of the stratum corneum can serve as a reservoir for certain highly lipophilic molecules.  Keratin  found in the stratum corneum may provide great affinity with certain drugs. Both of these interactions can play a role in drug accumulation in the stratum corneum and the local drug action on skin disease. [ 4 ]


Below the stratum corneum is the viable  epidermis . The viable epidermis is usually 50–100 μm thick. It includes immunologically sensitive cells (e.g.  Langerhans cells ), and metabolically active cells (e.g.  keratinocytes ,  melanocytes ,  merkel cells ). Melanocytes are involved in  melanoma   pathogenesis . As a result, drugs treating melanoma need to be administered to the lower epidermis.


The  dermis  lies next to the epidermis. It is a 1–2 mm layer mainly composed of  fibroblasts  and  immune cells  (e.g. dermal  dendritic cells ,  macrophages ,  T cells ,  mast cells ) in a  collagen  and  elastic fiber  extracellular matrix. [ 5 ]  These immune cells play important roles in  parasitic infections ,  psoriasis  induction,  tumor progression , dermal inflammation,  angiogenesis ,  wound healing ,  tissue remodeling ,  skin sensitization , and tolerance. [ 10 ]  Therefore, the regional accumulation of drugs in the dermis is necessary for the prevention and treatment of these local skin diseases.


The  hair follicle  is an  invagination  of epidermis cells deep into the dermis. The follicular route is critical in the topical delivery of particle-based formulations and hydrophilic, high-molecular-weight drugs. The follicular route provides benefits such as deeper  penetration , prolonged residence duration, faster entry into the skin, and site-specific targeting. [ 11 ]


Beneath these layers lies the  hypodermis , which is composed of  adipose tissue ,  fascia , as well as larger lymphatic and blood vessels. For joint and muscle disease treatment, topically applied drugs such as  non-steroidal anti-inflammatory drugs  (NSAIDs) can penetrate the  subcutaneous tissue  or even deeper tissues in the hypodermis. [ 12 ]  Drugs are primarily delivered into the underlying muscle by direct penetration without prior entry into the systemic circulation to prevent unintended side effects.


In general, there are three possible routes for drug administration into or across the skin. The first one is the  transcellular  route, where the drugs are required to pass through both lipid matrix and dead  corneocytes  of the  stratum corneum . The second one is the intercellular route, where the drugs only have to pass through lipid domains between  corneocytes . The third one is the trans-appendageal route, where the drugs are transported by  hair follicles ,  sebaceous glands , or  sweat glands . [ 4 ]


The most common route for drug delivery into the skin is the intercellular route. Multiple steps are involved. [ 13 ]


Excipient  has a significant impact on the final product performance, manufacturability, and stability. Therefore, the selection of excipients has to be carefully considered during topical cream formulation design.


In topical cream formulations, oily compounds act as active substance carriers. They also serve as skin penetration enhancers and  consistency  or  viscosity  modifiers. The oily excipients may influence cream viscosity, drug  solubility , physical stability, drug release performance, and transport into the skin. Oily compounds commonly used in cream formulations include saturated and unsaturated  fatty acids /fatty acid  esters ,  hydrocarbons , and  polyols .


Topical cream formulations consist of the oily phase and water phase. As the two phases are immiscible, in the absence of thickeners and emulsifying agents, molecules in the topical cream formulation will form droplets. Rapid aggregation of droplets within each phase will eventually lead to  phase separation . Physical stability is determined by the mitigation ability to these physical instability phenomena.


Thickeners  increase cream viscosity and thus reduce dispersed droplets' mobility. They hinder the separation of phases, thereby increases the physical stability of the cream. For example, the inclusion of  methylcellulose  and  paraffin  reduces dispersed droplets' mobility in an oil-in-water emulsion and water-in-oil emulsion respectively.


Emulsifying agents  can reduce the  interfacial tension  between the two phases, thus retards phase separation. Ionic  surfactants  are used in oil-in-water emulsions, whereas nonionic surfactants are used in both oil-in-water and water-in-oil formulations. [ 6 ]


Oils and fats used in topical cream formulations are susceptible to  oxidation  by atmospheric oxygen or microorganism action. The stability against oxidation can be enhanced by the introduction of  antioxidants . The selection of antioxidants and their concentration can only be determined by testing their effectiveness on the final product, according to pharmacopoeial information. The efficiency of antioxidants depends on their compatibility with other excipients and oil/water  partition coefficient .


Oxidations from microbiological source influence the physicochemical properties of the emulsion, resulting in color and odor changes, fat and oil  hydrolysis , pH changes in the aqueous phase, or phase separation of the cream. Oil-in-water creams are more susceptible to microbial contamination. Therefore,  preservatives  are included to prevent any microorganism growth. Preservatives suitable for topical cream formulations must present a broad spectrum of bactericidal activity, low  logP , compatibility with other excipients, stability, and effectiveness over a wide range of pH and temperatures.


By buffering any potential pH change,  buffer agents  can provide chemical stability and ensure the physical compatibility of the topical cream formulation. They ensure that the formulation can deliver the correct amount of drug to the therapeutic application site, is free from microbial contamination, and physically unchanged since the manufacturing day. Nonetheless, buffer agents need to be carefully added to avoid undesirable effects on physical stability. For example, buffer agents may influence the  rheological  behavior. [ 15 ]


During the production of the topical cream formulation, the first step is to dissolve excipients in the phase in which they are soluble. The initial mixing temperature of both phases should be high enough to ensure intimate liquid mixing and avoid premature solidification of the oily phase by the colder water. The aqueous phase should be warmed to a temperature slightly higher than the oily phase.