November 20, 2017History of Medicine
Photo credit: Slashme at the English language Wikipedia, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=21895660
Pills date back to roughly 1500 BCE. They were presumably invented so that measured amounts of a medicinal substance could be delivered to a patient. A long time ago, around 4,000 years or so, medicines were generally liquid preparations. An inscription on an Assyrian clay tablet instructs the user to pulverize various seeds, plant resins and leaves together--then dissolve them in beer. Pills are first referenced in ancient Egyptian. One famous set of papyruses is filled with medical remedies, including pills made from bread dough, honey or grease. Medicinal plants would be reduced to powders, and other active ingredients, and would then be mixed with these substances--then little balls, or pills, would be formed with the fingers. Early ingredients of pills included saffron, myrrh, cinnamon, tree resins and many other botanicals. Pills came in various sizes as well as flat and round, and other assorted shapes. As far back as 500 BCE, some were even trademarked with special indentations in the pills.
Hippocrates, knew about the curative powers of willow bark. And in ancient Greece, the round balls or other shapes were called katapotia (meaning "something to be swallowed"). It was the Roman scholar Pliny (23-79 CE--who first coined the word "pilula."
Some early pills still exist in museums, such as a famous one dating from 500 BCE. that was known as Terra Sigillata--consisting of clay from a particular island that was mixed with goat's blood then shaped into pills. Terra Sigillata was supposedly good for practically every ailment, including dysentery, ulcers and gonorrhea. A pill was originally defined as a small, round, solid pharmaceutical oral dosage form of medication. The oldest known pills were made of the zinc carbonates hydrozincite and smithsonite. The pills were used for sore eyes, and were found aboard a Roman ship Relitto del Pozzino which wrecked in 140 BCE. Today, pills include tablets, capsules, and variants thereof like caplets ? essentially any solid form of medication, colloquially falls into the pill category. There are pieces of ancient Roman pill-making equipment, such as a carved stone in the British Museum. The stone has long flat grooves into which the pill maker would press clay or other substances to make long, snaky strings. Then the pill maker would pry the strings out and cut them into discs to form pills--much the way one cuts dough for cookies.
During the Middle medieval times, people would coat their pills with slimy plant substances and other materials so they were easier to swallow and tasted less bitter. Some pills were rolled in spices, and later pills began to be coated with gold and silver. Silver, unfortunately, rendered the pills pretty inert, since they'd pass right through the digestive tract without releasing any of their medicinal compounds. Gilding of pills, continued well into the 19th century. Medicines in pill form were popular in 17th century England and thereafter. Pill manufacturers were granted special patent rights from the king for their top-secret formulas. One famous patented product from the 18th century: "Hooper's Female Pills," which were guaranteed to contain "the best purging and anti-hysterik ingredients." And pills, of course, made their way over to the still-new United States--which had its own set of patent-protected preparations, courtesy of the U.S. Patent office--including Chase's Kidney-Liver Pills, Cheeseman's Female Regulating Pills and Williams' Pink Pills for Pale People.
The old-fashioned, roll-and-cut kinds of pills had a drawback: Their preparation required moisture. Early researchers, (doctors) were learning that this moisture could de-activate the drugs contained. In the 1800s, innovators began sugar-coating and gelatin-coating pills. At this time gelatin capsules were invented, as well as the ability to compress tablets. In 1843, English scientist, William Brockedon invented a different pill form. Powder was placed in a tube and then compressed with a mallet, until it solidified. Eventually, this invention became popular. Holloway's Pills were perhaps the most famous of the patent medicines, and were popular enough to make Thomas Holloway a wealthy man. Testimonials to the value of the pills can be found at this time, in newspapers all over the British Empire, including Indian, Australia and the North American colonies. The range of diseases the pills claimed to cure is astonishing. Along with Holloway's Ointment, Holloway's Pills could treat almost anything. Analysis of the pills showed that they contained aloe, myrrh, and saffron. While probably not harmful, these pills would be unlikely to have the claimed affects. The Holloway advertising changed from time to time, listing a variety of dangers that the pills could prevent. An example, for "Children's Complaints":
"It is not generally known, but such is the fact that children require medicine oftener than their parents. Three-fourths of the children die before they attain the age of eight years. Let their
mothers, then, be wise, and give to their children small doses of these invaluable pills once or twice every week... The gross humors that are constantly floating about in the blood of children, the forerunners of so many complaints, will thus be expelled, and the lives of thousands saved and preserved to their parents."
Pills have always been difficult to swallow and efforts long have been made to make them go down easier. In medieval 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. In the 1800s sugar-coating and gelatin-coating was invented, as were gelatin capsules. 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 use of an adhesive. 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 segregate during manufacturing operations due to different densities, which can result in tablets with poor drug or active pharmaceutical ingredient (API) content uniformity but granulation should prevent this. Content uniformity ensures that the same API dose is delivered with each tablet. Some APIs may be tableted as pure substances, but this is rarely the case; most formulations include excipients. Normally, a pharmacologically inactive ingredient (excipient) termed a binder is added to help hold the tablet together and give it strength. A wide variety of binders may be used, some common ones including lactose, dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose, povidone polyvinylpyrrolidone and modified cellulose (for example hydroxypropyl methylcellulose and hydroxyethylcellulose).
Often, an ingredient is also needed to act as a disintegrant to aid tablet dispersion once swallowed, releasing the API for absorption. Some binders, such as starch and cellulose, are also excellent disintegrants. Tablets are simple and convenient to use. They provide an accurately measured dosage of the active ingredient in a convenient portable package, and can be designed to protect unstable medications or disguise unpalatable ingredients. Colored coatings, embossed markings and printing can be used to aid tablet recognition. Manufacturing processes and techniques can provide tablets with special properties, for example, sustained release or fast dissolving formulations. Some drugs may be unsuitable for administration by the oral route. For example, protein drugs such as insulin may be denatured by stomach acids. Such drugs cannot be made into tablets. Some drugs may be deactivated by the liver when they are carried there from the gastrointestinal tract by the hepatic portal vein (the first pass effect), making them unsuitable for oral use. Drugs which can be taken sublingually are absorbed through the oral mucosa, so that they bypass the liver and are less susceptible to the first pass effect. The oral bioavailability of some drugs may be low due to poor absorption from the gastrointestinal tract. Such drugs may need to be given in very high doses or by injection. For drugs that need to have rapid onset, or that have severe side effects, the oral route may not be suitable. For example, salbutamol, used to treat problems in the respiratory system, can have effects on the heart and circulation if taken orally; these effects are greatly reduced by inhaling smaller doses direct to the required site of action. A proportion of the population have difficulties swallowing tablets either because they just don't like taking them or because their medical condition makes it difficult for them (dysphagia, vomiting). In such instances it may be better to consider alternative dosage form or administration route.
Tablets can be made in virtually any shape, although 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 thickness is determined by the amount of tablet material and the position of the punches in relation to each other during compression. Once this is done, we can measure the corresponding pressure applied during compression. The shorter the distance between the punches, thickness, the greater the pressure applied during compression, and sometimes the harder the tablet. Tablets need to be hard enough that they don't 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 (i) simple failure and erosion tests, and (ii) 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 principle 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 centimeter. Models of tester 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. In the tablet pressing process, the main guideline is to ensure that the appropriate amount of active ingredient is 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 a tablet: wet granulation and dry granulation. Powders that can be mixed well do not require granulation and can be compressed into tablets through direct compression.
Combined oral contraceptive pills were nicknamed "the pill" in the 1960s