Editing Polypill

{{Short description|Drug with multiple pharmaceutical ingredients}}

A '''polypill''' or '''single pill combination''' (SPC) is a type of [[combination drug|drug combination]] consisting of a single drug product in pill form (i.e., [[tablet (pharmacy)|tablet]] or [[capsule (pharmacy)|capsule]]) and thus ''combines'' multiple [[medication]]s (that is, more than one [[active ingredient|active pharmaceutical ingredient]]). The prefix "poly" means "multiple", referring to the multiplicity of distinct drugs in a given "pill". In precise [[usage (language)|usage]], a pill is a polypill if it contains at least 4 drugs (meaning that [[combination drug|fixed-dose combinations]] of 2 or 3 drugs are not polypills). An occasional synonym is ''combopill''.  A polypill commonly targets treatment or prevention of [[chronic condition]]s.<ref>{{Cite web | url=https://www.who.int/bulletin/volumes/83/12/news11205/en/index.html | archive-url=https://web.archive.org/web/20131101041741/http://www.who.int/bulletin/volumes/83/12/news11205/en/index.html | url-status=dead | archive-date=November 1, 2013 |title = WHO &#124; Polypill holds promise for people with chronic disease}}</ref>

Polypills may be aimed to be consumed by healthy people as a means of [[preventive medicine]], and/or treating actual pathophysiological condition(s), the former typically involving lower dosages than the latter.  Polypills can reduce the number of [[Tablet (pharmacy)|tablets]] or [[Capsule (pharmacy)|capsules]] (generally [[Oral administration|orally administered]]) that need to be taken, which in turn may facilitate handling and administration of pharmaceuticals as well as alleviate patient pill-burden.  Sometimes the multiple drugs in a given polypill might all be aimed at a single underlying condition (or, group of related conditions), partly because this expands the pool of potential patients for whom a given combination of drugs/dosages might be appropriate (particularly in the case of mass-produced polypills, i.e. FDCs). The term polypill was first coined in the context of [[cardiovascular disease]] prevention,<ref>{{Cite web | url=http://medical-dictionary.thefreedictionary.com/Polypill |title = Polypill}}</ref><ref name="pmid12829553">{{cite journal |vauthors=Wald NJ, Law MR |title=A strategy to reduce cardiovascular disease by more than 80% |journal=BMJ |volume=326 |issue=7404 |page=1419 |date=June 2003 |pmid=12829553 |pmc=162259 |doi=10.1136/bmj.326.7404.1419}}</ref> but has since gained broader acceptance, including now for combinatorial drug products that existed before the term was actually coined (as the bare term without any modifiers is now quite generic).

In addition to the noted fixed-dose types of polypills, polypills can also be custom-made for specific patients through a process called [[pharmacy compounding]]. Physicians in most jurisdictions have wide discretion to prescribe customized drug products containing unique drug-dosage combinations (and/or formulations thereof) specifically for individual patients, which certain pharmacies can then sometimes produce for such patients.

==For treatment or management of disease==

Polypills are a useful therapeutic tool for those afflicted with various diseases/conditions, by consolidating multiple medications into a single product and thereby simplifying medication administration for healthcare personnel as well as alleviating pill-burden for patients.

HIV, mental-health, transplant, and certain other patient groups are known for especially high pill-burdens (whether temporary or indefinite).  Also, elderly patients in particular are likely to require several medications on a daily basis for managing multiple conditions, and they are also particularly susceptible to difficulties remembering or keeping track of their regimen.

===Origin of multi-drug pill usage===

Combinatorial drug products were proposed for ''treating'' diagnosed conditions long before they were proposed for preventive medicine, including "aspolol" (a combination of aspirin and [[atenolol]]) for those diagnosed with cardiovascular disease. Fixed-dose combination (FDC) products today are also common for treating other diseases, such as [[tuberculosis]] and [[HIV/AIDS]].

===Developments in polypill usage for disease therapy===

====Treating cardiovascular disease====
One of the first recommended roles of a polypill was as a means of providing recommended medications to people with heart disease, stroke and other forms of cardiovascular disease. Most cardiovascular disease patients do not receive recommended medications long-term: the proportion of cardiovascular disease patients ''not ''receiving a statin, aspirin and blood pressure lowering medication long-term ranges from about 50% in high income countries to over 90% in low income countries.<ref>{{cite journal |author1=Yusuf S |author2=Islam S |author3=Chow CK |author4=Rangarajan S |author5=Dagenais G |author6=Diaz R | year = 2011 | title = Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE Study): a prospective epidemiological survey | journal = Lancet | volume = 378 | issue = 9798| pages = 1231–43 | pmid = 21872920 | doi=10.1016/S0140-6736(11)61215-4|display-authors=etal}}</ref> In 2001, a World Health Organization and The Wellcome Trust meeting of experts to discuss interventions for non-communicable diseases noted “the use of a single pill could well encourage patients to adhere to treatment as well as seriously reduce the cost of the drugs”<ref>World Health Organization(2002) Secondary prevention of non-communicable disease in low and middleincome countries through community-based and health service interventions. World Health Organization - Wellcome Trust meeting report 1–3 August 2001, Geneva. http://www.who.int/cardiovascular_diseases/media/en/615.pdf</ref> A programme of research was outlined, including stability and bio-availability testing followed by assessment of short-term effects on blood pressure, cholesterol, platelet aggregation, safety and side effects. In 2002, the World Health Organization Annual Report outlined the substantial potential public health impact and cost-effectiveness of scaling up access to combination cardiovascular treatment<ref>World Health Organization(2002) The World Health Report 2002. Reducing risks, promoting healthy life.;WHO, editor. Geneva: WHO. [https://web.archive.org/web/20021202073217/http://www.who.int/whr/2002/en/]</ref> and an editorial in ''The Lancet'' noted that a four component combination pill would reduce cardiovascular risk by about 75% among people with vascular disease.<ref>{{cite journal | author = Yusuf S | year = 2002 | title = Two decades ofprogress in preventing vascular disease | journal = Lancet | volume = 360 | issue = 9326| pages = 2–3 | doi=10.1016/s0140-6736(02)09358-3 | pmid=12114031| s2cid = 33042777 }}</ref>

====Treating diabetes and metabolic syndrome====

Polypills have been proposed for managing [[diabetes]] (and potentially for [[pre-diabetes]]).<ref>{{cite journal |author=Kuehn BM |title="Polypill" could slash diabetes risks |journal=JAMA |volume=296 |issue=4 |pages=377–80 |date=July 2006 |pmid=16868284 |doi=10.1001/jama.296.4.377}}</ref>

[[Diabetes]] - particularly [[Type II diabetes]] - is a major cause of morbidity and mortality. Diabetes also contributes substantially to cardiovascular risk, yet some ingredients appropriate for a cardiovascular polypill may not be advisable for patients with diabetes (such as [[beta-blockers]] and [[thiazide diuretics]]).  A polypill for diabetes could include a [[statin]] (to reduce [[LDL cholesterol]] and for their [[anti-inflammatory]] properties), an [[ACE inhibitor]] (for blood pressure control and to protect the [[kidneys]]), [[aspirin]] (for anti[[platelet]] and anti-inflammatory properties), and [[metformin]] (a medication for diabetes that is also associated with weight loss).

====Role of compounding pharmacy====

As noted, not all polypills are mass-produced fixed-dose (FDC) drug products. Physicians in many countries have wide discretion to prescribe customized drug products containing unique drug-dosage combinations and/or formulations thereof specifically for individual patients, which can then be custom-produced in a [[compounding pharmacy]].  Some kinds or compositions of polypills or similar drug products are more amenable to custom-compounding than others, and most retail pharmacies no longer offer compounding services at all (although hospital pharmacies still commonly compound ''intravenous'' medications). While fewer pharmacists are trained and experienced in the relevant skills anymore, especially regarding oral dosage forms, such compounding pharmacies nevertheless can be found and utilized via mail-order (if not available locally) with sufficient notice and planning. Generally, if a customized drug product is produced for a specific patient in response to a prescription specifying said patient's drug(s)/dosage(s), it is ''not'' subject to regulatory approval (e.g., FDA in the US) but is instead regulated under the practice of pharmacy (governed at the state-level in the US).

Technologies are under development to facilitate production of customized polypills, such as for example by the use of ink-jet printing mechanisms to precisely deposit selected drug substance(s) onto sheets which can then be inserted into capsules (enabling "individualized dosing and automated fabrication of medicines containing multiple drugs," in addition to custom single-drug products).<ref>{{cite journal |pmid=21360709 | doi=10.1002/jps.22526 | volume=100 | issue=8 | title=Inkjet printing of drug substances and use of porous substrates-towards individualized dosing. | date=Aug 2011 | journal=J Pharm Sci | pages=3386–95| last1=Sandler | first1=Niklas | last2=Määttänen | first2=Anni | last3=Ihalainen | first3=Petri | last4=Kronberg | first4=Leif | last5=Meierjohann | first5=Axel | last6=Viitala | first6=Tapani | last7=Peltonen | first7=Jouko }}</ref><ref>{{cite journal|doi=10.1063/1.3524512|title=Electrodeless electrohydrodynamic printing of personalized medicines|journal=Applied Physics Letters|volume=97|issue=23|pages=233501|year=2010|last1=Elele|first1=Ezinwa|last2=Shen|first2=Yueyang|last3=Khusid|first3=Boris|bibcode=2010ApPhL..97w3501E}}</ref><ref>{{cite journal | doi = 10.1002/jps.23165 | volume=101 | issue=7 | title=Electrodeless electrohydrodynamic drop-on-demand encapsulation of drugs into porous polymer films for fabrication of personalized dosage units | journal=Journal of Pharmaceutical Sciences | pages=2523–2533 | pmid=22527973 | date=Jul 2012| last1=Elele | first1=Ezinwa | last2=Shen | first2=Yueyang | last3=Susarla | first3=Ramana | last4=Khusid | first4=Boris | last5=Keyvan | first5=Golshid | last6=Michniak-Kohn | first6=Bozena }}</ref> Similar technology can also be used to print tablets, more directly. Ink-jet or fluid-jet approaches require each drug substance to be dissolved in a liquid solvent, but they can be particularly conducive to custom formulation with various possible excipients (in addition to custom drug/dose selections).

==For preventive medicine==

=== Origin of preventive medicine applications ===
[[Nicholas Wald|Wald]] and [[Malcolm Law|Law]] had first proposed using a combination of well-known and inexpensive medications in one pill for protection against cardiovascular disease.<ref name="pmid12829553"/> They presented a [[statistical model]] which suggested widespread use of such a polypill could reduce mortality due to [[heart disease]] and [[stroke]]s by up to 80%, while the drugs and their respective interactions are already fairly well known and understood due to many years of being prescribed together (via separate pills). They proposed combining six medications already established in treating [[cardiovascular disease]] and associated conditions, providing these in a single pill to people in Western countries aged 55 years or more as a preventive measure (albeit in lower doses than when used for treatment).<ref name="pmid12829553"/>

=== Developments of preventive medicine applications ===

Any physician could currently prescribe all the components of many proposed polypills separately for their patients, whether therapeutically or preventively.  And since the ingredients of many possible polypills are off [[patent]], it can be cheap to commercialize, although FDC products with novel combinations or formulations can sometimes themselves be patented.  Of course, for any FDC product, the potential market for a given combination of drugs/dosages would need to be sufficiently large to justify the clinical trials and other expenses associated with mass-producing a new drug.

=== Producing countries ===
The polypill, drugs to lower blood pressure, is produced<ref>{{cite web |title=بازتاب دستاورد جدید ستاد اجرایی فرمان امام در تولید دارویی برای سکته قلبی و مغزی|url=https://www.isna.ir/news/98060402209/%D8%A8%D8%A7%D8%B2%D8%AA%D8%A7%D8%A8-%D8%AF%D8%B3%D8%AA%D8%A7%D9%88%D8%B1%D8%AF-%D8%AC%D8%AF%DB%8C%D8%AF-%D8%B3%D8%AA%D8%A7%D8%AF-%D8%A7%D8%AC%D8%B1%D8%A7%DB%8C%DB%8C-%D9%81%D8%B1%D9%85%D8%A7%D9%86-%D8%A7%D9%85%D8%A7%D9%85-%D8%AF%D8%B1-%D8%AA%D9%88%D9%84%DB%8C%D8%AF-%D8%AF%D8%A7%D8%B1%D9%88%DB%8C%DB%8C-%D8%A8%D8%B1%D8%A7%DB%8C|website=Isna |access-date=23 August 2019}}</ref><ref>{{cite web |title=تولید داروی پلی پیل و کاهش 50درصدی سکته قلبی و مغزی |url=https://www.farsnews.com/news/13980605000100/%D8%AA%D9%88%D9%84%DB%8C%D8%AF-%D8%AF%D8%A7%D8%B1%D9%88%DB%8C-%D9%BE%D9%84%DB%8C-%D9%BE%DB%8C%D9%84-%D9%88-%DA%A9%D8%A7%D9%87%D8%B4-50%D8%AF%D8%B1%D8%B5%D8%AF%DB%8C-%D8%B3%DA%A9%D8%AA%D9%87-%D9%82%D9%84%D8%A8%DB%8C-%D9%88-%D9%85%D8%BA%D8%B2%DB%8C |website=فارس}}</ref> in [[Iran]] by the support of [[Execution of Imam Khomeini's Order]] was designed 14 years ag and called "PolyIran". According to the study was conducted by doctors from Tehran University, the University of Birmingham in Britain and other institutions and published by The Lancet, it worked quite well in a new study, slashing the rate of heart attacks by more than half among those who regularly took the pills. The pill in the study, which involved the participation of 6,800 rural villagers aged 50 to 75 in Iran, contained a cholesterol-lowering statin, two blood-pressure drugs and a low-dose aspirin.<ref>{{cite news |last1=Gallagher |first1=James |title=Four-in-one pill prevents third of heart problems |url=https://www.bbc.com/news/health-49434337 |access-date=23 August 2019|work=BBC News |date=2019-08-23 }}</ref><ref>{{cite news |last1=McNeil Jr. |first1=Donald G. |title=This Daily Pill Cut Heart Attacks by Half. Why Isn't Everyone Getting It? |url=https://www.nytimes.com/2019/08/22/health/heart-disease-iran-study.html |newspaper=The New York Times |access-date=22 August 2019|date=2019-08-22 }}</ref>

Certain "cardiovascular polypills" are currently available in [[India]] and have been extensively studied there (see [[Polycap]] and [[PolyIran]], for examples). Also, cardiologists in Spain are developing a polypill for secondary cardiovascular prevention.<ref>{{cite journal |vauthors=Sanz G, Fuster V |title=Fixed-dose combination therapy and secondary cardiovascular prevention: rationale, selection of drugs and target population |journal=Nat Clin Pract Cardiovasc Med |volume=6 |issue=2 |pages=101–10 |date=February 2009 |pmid=19104519 |doi=10.1038/ncpcardio1419|s2cid=205339553 }}</ref>

=== Preventive use rationale: Treatment of population risk ===
Some preventive-use advocates propose that everyone over a given age (e.g., 55) should take such medications for preventive health, irrespective of individual risk factor levels. The idea is that most people in western countries are at high overall risk, thus lowering risk factor levels will provide broad benefit. This approach emphasizes the perspective that risk factors are continuous, and rigid dichotomies such as "hypertension" and "no hypertension" may be over-simplified and can be viewed instead as continuums of inter-connected factors.<ref>{{cite journal |vauthors=Law MR, Wald NJ |title=Risk factor thresholds: their existence under scrutiny |journal=BMJ |volume=324 |issue=7353 |pages=1570–6 |date=June 2002 |pmid=12089098 |pmc=1123506 |doi=10.1136/bmj.324.7353.1570}}</ref>

In this paradigm, doctors would in effect be treating population risk rather than individual risk factor thresholds as is current mainstream practice. So, if everyone were given a relevant kind of polypill, the average blood pressure and cholesterol levels in the population would fall, thus reducing overall population risk. Perhaps ironically, this is in a sense going in the ''opposite'' direction from [[personalized medicine]], since mass-produced or fixed-dose-combination polypills are in some tension with the goals of personalized medicine, due to the "fixed" nature of the "dose combinations." Proponents of this population-focused approach contend that the advantages of drug consolidation can outweigh any reduction in personalization of drug and/or dose selection. Also, depending on the demographic distribution and market size, there may be room for some different alternative versions of certain general FDCs to be manufactured with differences in their respective dosages and/or drugs. A widely distributed polypill could contain three blood pressure medications at low dose: a [[diuretic]], such as [[hydrochlorothiazide]], a [[beta-blocker]] such as [[atenolol]], and an [[ACE inhibitor]] such as [[lisinopril]]; and these could be combined with a [[statin]] such as [[simvastatin]], [[aspirin]] at a dose of 75&nbsp;mg, and [[folic acid]], which has been shown to reduce the level of homocysteine in the blood, which is another risk factor for heart disease.

==References==
{{reflist}}

==Selected publications==
*{{cite journal |vauthors=Fuster V, Sanz G |title=A polypill for secondary prevention: time to move from intellectual debate to action |journal=Nat Clin Pract Cardiovasc Med |volume=4 |issue=4 |page=173 |date=April 2007 |pmid=17380163 |doi=10.1038/ncpcardio0858|doi-access=free }}
*{{cite journal |vauthors=Wald NJ, Law MR |title=A strategy to reduce cardiovascular disease by more than 80% |journal=BMJ |volume=326 |issue=7404 |page=1419 |date=June 2003 |pmid=12829553 |pmc=162259 |doi=10.1136/bmj.326.7404.1419}}
*[https://www.theguardian.com/society/2008/sep/29/health.medicalresearch "Tests start on pill that could lengthen millions of lives: Tablet aims to cut heart attack and stroke risk: Four-in-one drug could be sold for just $1 a month" Sarah Boseley, health editor ''The Guardian'', Monday September 29 2008.]
*{{cite journal |vauthors=Xavier D, Pais P, Sigamani A, Pogue J, Afzal R, Yusuf S |title=The need to test the theories behind the Polypill: rationale behind the Indian Polycap Study |journal=Nat Clin Pract Cardiovasc Med |volume=6 |issue=2 |pages=96–7 |date=February 2009 |pmid=19104516 |doi=10.1038/ncpcardio1438}}
*{{cite journal |author=Cannon CP |title=Can the polypill save the world from heart disease? |journal=Lancet |volume=373 |issue=9672 |pages=1313–4 |date=April 2009 |pmid=19339044 |doi=10.1016/S0140-6736(09)60652-8}}
*Gorman, Rachael Moeller. "The Polypill" ''Proto'', Winter 2007

==External links==
* [https://web.archive.org/web/20110320024031/http://protomag.com/assets/the-polypill The Polypill - Proto Magazine - Massachusetts General Hospital]

{{Combined substance use and adulteration}}

[[Category:Combination drugs]]