Editing Excipient

{{Short description|Substance formulated alongside the active ingredient of a medication or other active substance}}
{{More citations needed|date=January 2009}}
An '''excipient''' is a substance formulated alongside the [[active ingredient]] of a [[medication]]. They may be used to enhance the active ingredient’s therapeutic properties; to facilitate [[drug]] [[Absorption (pharmacology)|absorption]]; to reduce [[viscosity]]; to enhance [[solubility]]; to improve long-term stabilization (preventing [[Denaturation (biochemistry)|denaturation]] and aggregation during the expected [[shelf life]]); or to add bulk to solid formulations that have small amounts of potent active ingredients (in that context, they are often referred to as "bulking agents", "fillers", or "diluents").<ref>{{cite journal | vauthors = Borbás E, Sinkó B, Tsinman O, Tsinman K, Kiserdei É, Démuth B, Balogh A, Bodák B, Domokos A, Dargó G, Balogh GT, Nagy ZK | display-authors = 6 | title = Investigation and Mathematical Description of the Real Driving Force of Passive Transport of Drug Molecules from Supersaturated Solutions | journal = Molecular Pharmaceutics | volume = 13 | issue = 11 | pages = 3816–3826 | date = November 2016 | pmid = 27611057 | doi = 10.1021/acs.molpharmaceut.6b00613 }}</ref><ref>{{cite journal | vauthors = Hsu T, Mitragotri S | title = Delivery of siRNA and other macromolecules into skin and cells using a peptide enhancer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 38 | pages = 15816–21 | date = September 2011 | pmid = 21903933 | pmc = 3179050 | doi = 10.1073/pnas.1016152108 | bibcode = 2011PNAS..10815816H | doi-access = free }}</ref> During the manufacturing process, excipients can improve the handling of active substances and facilitate powder flow. The choice of excipients depends on factors such as the intended [[route of administration]], the [[dosage form]], and compatibility with the active ingredient.

Virtually all marketed drugs contain excipients, and final drug formulations commonly contain more excipient than active ingredient.  Pharmaceutical regulations and standards mandate the identification and safety assessment of all ingredients in drugs, including their chemical decomposition products. Novel excipients can sometimes be patented, or the specific formulation can be kept as a [[trade secret]] to prevent competitors from duplicating it through [[reverse engineering]].{{Citation needed|date=April 2019}}

==Relative versus absolute inactivity==
Though excipients were at one time assumed to be "inactive" ingredients, it is now understood that they can sometimes be "a key determinant of dosage form performance";<ref name="bhatta2006" /> in other words, their effects on [[pharmacodynamics]] and [[pharmacokinetics]], although usually negligible, cannot be ''known'' to be negligible without [[empirical evidence|empirical confirmation]] and sometimes are important. For that reason, in [[basic research]] and [[clinical trial]]s they are sometimes included in the [[scientific control|control substances]] in order to minimize [[confounding]], reflecting that otherwise, the absence of the active ingredient would not be the only variable involved, because absence of excipient cannot always be assumed not to be a variable.<ref name="science">{{cite journal |title=The activities of drug inactive ingredients on biological targets |author=JOSHUA POTTEL |journal=[[Science (journal)|Science]] |date=July 24, 2020 |volume=369 |issue=6502 |pages=403–413 |doi=10.1126/science.aaz9906 |pmid=32703874 |pmc=7960226 |bibcode=2020Sci...369..403P }}</ref> Such studies are called excipient-controlled or [[#Vehicles|vehicle]]-controlled studies.

==Types==

===Adjuvants===
{{main|Immunologic adjuvant}}
Adjuvants are added to vaccines to enhance or modify the immune system response to an immunization. An adjuvant may stimulate the immune system to respond more vigorously to a vaccine, which leads to more robust immunity in the recipient.

===Antiadherents===
Antiadherents reduce the [[adhesion]] between the [[Powder (substance)|powder]] ([[granular material|granules]]) and the [[Tablet press|punch]] faces and thus prevent sticking to tablet punches by offering a [[non-stick surface]]. They are also used to help protect tablets from sticking. The most commonly used is [[magnesium stearate]].

===Binders===
Binders hold the ingredients in a tablet together. Binders ensure that tablets and granules can be formed with required mechanical strength, and give volume to low active dose tablets. Binders are usually:
* [[Saccharide]]s and their derivatives:
** [[Disaccharide]]s: [[sucrose]], [[lactose]];
** [[Polysaccharide]]s and their derivatives: [[starch]]es, [[cellulose]] or modified cellulose such as [[microcrystalline cellulose]] and [[cellulose#Derivatives|cellulose ethers]] such as [[hydroxypropyl cellulose]] (HPC);
** [[Sugar alcohol]]s such as [[xylitol]], [[sorbitol]] or [[maltitol|mannitol]];
* Protein: [[gelatin]];
* Synthetic [[polymer]]s: [[polyvinylpyrrolidone]] (PVP), [[polyethylene glycol]] (PEG)...

Binders are classified according to their application:
*Solution binders are dissolved in a solvent (for example [[water]] or [[ethanol|alcohol]] can be used in wet granulation processes).  Examples include gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose and polyethylene glycol.
*Dry binders are added to the powder blend, either after a wet granulation step, or as part of a direct powder compression (DC) formula.  Examples include cellulose, methyl cellulose, polyvinylpyrrolidone and polyethylene glycol.

===Coatings===
Tablet coatings protect tablet ingredients from deterioration by moisture in the air and make large or unpleasant-tasting tablets easier to swallow. For most coated tablets, a cellulose ether [[Hypromellose|hydroxypropyl methylcellulose]] (HPMC) film coating is used which is free of sugar and potential [[allergen]]s. Occasionally, other coating materials are used, for example synthetic polymers, [[shellac]], corn protein [[zein]] or other polysaccharides. [[Capsule (pharmacy)|Capsules]] are coated with gelatin.

'''[[Enteric coating|Enteric]]s''' control the rate of drug release and determine where the drug will be released in the digestive tract. Materials used for enteric coatings include fatty acids, waxes, shellac, plastics, and plant fibers.

===Colours===
[[Food colouring|Colours]] are added to improve the appearance of a formulation. Colour consistency is important as it allows easy identification of a medication. Furthermore, colours often improve the aesthetic look and feel of medications. Small amounts of colouring agents are easily processed by the body, although rare reactions are known, notably to [[tartrazine]].<ref name=sbm>{{Cite web|url=https://sciencebasedmedicine.org/whats-all-that-other-stuff-in-my-medicine-2/|title=What's all that other stuff in my medicine?|last=Gavura|first=Scott | name-list-style = vanc |date=February 21, 2019|website=Science-Based Medicine|archive-url=https://web.archive.org/web/20190221184000/https://sciencebasedmedicine.org/whats-all-that-other-stuff-in-my-medicine-2/|archive-date=February 21, 2019|access-date=February 21, 2019}}</ref> Commonly, titanium oxide is used as a colouring agent to produce the popular opaque colours along with azo dyes for other colors. By increasing these [[organoleptic]] properties a patient is more likely to adhere to their schedule and therapeutic objectives will also have a better outcome for the patient especially children.

===Disintegrants===
Disintegrants expand and dissolve when wet causing the tablet to break apart in the [[digestive tract]], or in specific segments of the digestion process, releasing the active ingredients for [[Absorption (pharmacokinetics)|absorption]]. They ensure that when the tablet is in contact with [[water]], it rapidly breaks down into smaller fragments, facilitating [[solvation|dissolution]].<ref name=sbm/>

Examples of disintegrants include: 
* Crosslinked polymers: crosslinked [[polyvinylpyrrolidone]] ([[Polyvinylpolypyrrolidone|crospovidone]]), crosslinked sodium [[carboxymethyl cellulose]] ([[croscarmellose sodium]]).
* [[Carboxymethyl cellulose|sodium starch glycolate]], a [[modified starch]]

===Flavours===
[[Flavoring|Flavours]] can be used to mask unpleasant tasting active ingredients and improve the acceptance that the patient will complete a course of medication. Flavourings may be natural (e.g. fruit extract) or artificial.<ref name="whoppt">{{Cite conference|url=http://apps.who.int/prequal/trainingresources/pq_pres/TrainingZA-April07/Excipients.ppt |url-status=live |format=Microsoft PowerPoint |title=Excipients |first=Simon |last=Mills | name-list-style = vanc |date=April 2007 |conference=Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations |conference-url=http://apps.who.int/prequal/trainingresources/Training_courseZA-April07.htm |publisher=[[World Health Organization]] |archive-url=https://web.archive.org/web/20121020184046/http://apps.who.int/prequal/trainingresources/pq_pres/TrainingZA-April07/Excipients.ppt |archive-date=October 20, 2012 }}</ref><ref name=sbm/>

For example, to improve:<ref name="whoppt" />
* a bitter product–[[Mentha|mint]], [[cherry]] or [[anise]] may be used
* a salty product–[[peach]], [[apricot]] or [[liquorice]] may be used
* a sour product–[[raspberry]] or liquorice may be used
* an excessively sweet product–[[vanilla]] may be used

===Glidants===
[[Glidant]]s are used to promote powder flow by reducing interparticle friction and cohesion. These are used in combination with lubricants as they have no ability to reduce wall friction. Examples include [[silica gel]], [[fumed silica]], [[talc]], and [[magnesium carbonate]]. However, some silica gel glidants such as Syloid(R) 244 FP and Syloid(R) XDP are multi-functional and offer several other performance benefits in addition to reducing interparticle friction including moisture resistance, taste, marketing, etc.

===Lubricants===
[[Lubricant]]s 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.<ref name=sbm/>

Common minerals like [[talc]] or [[silica]], and [[fat]]s, e.g. vegetable [[stearin]], [[magnesium stearate]] or [[stearic acid]] are the most frequently used lubricants in tablets or hard gelatin capsules. Lubricants are agents added in small quantities to tablet and capsule formulations to improve certain processing characteristics. While lubricants are often added to improve manufacturability of the drug products, it may also negatively impact the product quality. For example, extended mixing of lubricants during blending may results in delayed dissolution and softer tablets, which is often referred to as "over-lubrication". Therefore, optimizing lubrication time is critical during pharmaceutical development.<ref>{{cite journal | vauthors = Wang J, Wen H, Desai D | title = Lubrication in tablet formulations | journal = European Journal of Pharmaceutics and Biopharmaceutics | volume = 75 | issue = 1 | pages = 1–15 | date = May 2010 | pmid = 20096779 | doi = 10.1016/j.ejpb.2010.01.007 }}</ref><ref>{{Cite journal| vauthors = Wang Y, Osorio JG, Li T, Muzzio FJ |date=2017-12-01|title=Controlled shear system and resonant acoustic mixing: Effects on lubrication and flow properties of pharmaceutical blends|journal=Powder Technology|volume=322|pages=332–339|doi=10.1016/j.powtec.2017.09.028|issn=0032-5910|doi-access=free}}</ref><ref>{{cite journal | vauthors = Morin G, Briens L | title = The effect of lubricants on powder flowability for pharmaceutical application | journal = AAPS PharmSciTech | volume = 14 | issue = 3 | pages = 1158–68 | date = September 2013 | pmid = 23897035 | pmc = 3755167 | doi = 10.1208/s12249-013-0007-5 }}</ref>

There are three roles identified with lubricants as follows:

*True lubricant role:
:To decrease friction at the interface between a tablet’s surface and the die wall during ejection and reduce wear on punches and dies.
*Anti-adherent role:
:Prevent sticking to punch faces or in the case of encapsulation, lubricants.
:Prevent sticking to machine dosators, tamping pins, etc.
*Glidant role:
:Enhance product flow by reducing interparticulate friction.

There are two major types of lubricants:

*Hydrophilic
:Generally poor lubricants, no glidant or anti-adherent properties.
*Hydrophobic
:Most widely used lubricants in use today are of the hydrophobic category. Hydrophobic lubricants are generally good lubricants and are usually effective at relatively low concentrations. Many also have both anti-adherent and glidant properties. For these reasons, hydrophobic lubricants are used much more frequently than hydrophilic compounds. Examples include magnesium stearate.

===Preservatives===
Some typical [[preservatives]] used in pharmaceutical formulations are
* [[Antioxidants]] like [[vitamin A]], [[vitamin E]], [[vitamin C]], [[retinyl palmitate]], and [[selenium]]
* The [[amino acid]]s [[cysteine]] and [[methionine]]
* [[Citric acid]] and [[sodium citrate]]
* Synthetic preservatives like the [[paraben]]s: [[methyl paraben]] and [[propyl paraben]].

===Sorbents===
[[Sorbent]]s are used for tablet/capsule moisture-proofing by limited fluid sorbing (taking up of a liquid or a gas either by [[adsorption]] or by [[absorption (chemistry)|absorption]]) in a dry state. For example, [[desiccant]]s absorb water, [[drying]] out ([[desiccation|desiccating]]) the surrounding materials.

===Sweeteners===
[[Sugar substitute|Sweetener]]s are added to make the ingredients more palatable, especially in chewable tablets such as [[antacid]] or liquids like [[cough syrup]]. [[Sugar]] can be used to mask unpleasant tastes or smells, but artificial sweeteners tend to be preferred, as natural ones tend to cause tooth decay.<ref name=sbm/>

===Vehicles===
In liquid and gel formulations, the bulk excipient that serves as a medium for conveying the active ingredient is usually called the [[wikt:vehicle#Noun|vehicle]]. [[Petroleum jelly|Petrolatum]], [[dimethyl sulfoxide]] and [[mineral oil]] are common vehicles.

== See also ==
*[[Active ingredient]]
*[[Pharmaceutics]]
*[[Pharmacology]]
*[[Placebo]]
*[[Placebo effect]]
*[[Quality system]]

== References ==
{{Reflist
|refs =
<ref name="bhatta2006">{{cite book | first1 = Bhattacharyya | last1 = Lokesh | first2 = Schuber | last2 = Stefan | last3 = Sheehan | first3 = Catherine | last4 = William | first4 = Roger | editor1-last = Katdare | editor1-first = Ashok | name-list-style = vanc | chapter = Excipients: Background/Introduction | editor2-last = Chaubal | editor2-first = Mahesh | title = Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems | publisher = [[CRC Press]] | year = 2006 | isbn = 9781420004137 | oclc = 476062541 }}</ref>
}}

== External links ==
{{Commonscat|Excipients}}
*[https://www.accessdata.fda.gov/scripts/cder/iig/index.Cfm FDA database for Inactive Ingredient Search for Approved Drug Products]
*[https://web.archive.org/web/20140809100407/http://www.ipapharma.org/epharmatimes/Mar2013/#65 Excipient selection for injectable / parenteral formulations]
*[http://ipecamericas.org/ IPEC-Americas]
*[http://excipients.ucsf.bkslab.org/ UCSF-CERSI Excipient Browser]

[[Category:Excipients| ]]
[[Category:Drug manufacturing]]
[[Category:Pharmacy]]