How medicines reach their targets: delivery routes, formulations and the peptide problem

Making a medicine is only half the problem. The other half is getting it to the place in the body where it is meant to act, in the right amount and at the right time. For proteins and peptides, that second half is unusually hard, and the reasons say a great deal about how the body handles what enters it.

Drug delivery as a field

Wikipedia's article on drug delivery describes it as the methods and technologies designed to transport pharmaceutical compounds to their target sites. It draws on principles of drug preparation, route of administration, site-specific targeting, metabolism and toxicity, and one of its key aims is to change how a drug is distributed and handled in the body by combining it with excipients, carriers and devices.

Routes and why they matter

Wikipedia's article on the route of administration defines it as the way by which a drug, fluid, poison or other substance is introduced into the body. Routes are usually classified by where the substance is applied, with oral and intravenous administration as common examples. They can also be classified by where the effect is wanted: topical, meaning local; enteral, meaning a system-wide effect delivered through the gastrointestinal tract; or parenteral, meaning a systemic effect delivered by routes other than the gut.

The route matters because each one puts different barriers in the way. A substance swallowed must survive stomach acid and digestive enzymes, cross the lining of the intestine, and pass through the liver before it reaches the general circulation. A substance placed directly into the blood avoids all of that.

Bioavailability, plainly

The idea that ties routes together is bioavailability. Wikipedia's article on bioavailability defines it as the fraction of an administered drug that reaches the systemic circulation. By definition, a drug given intravenously is fully available; by other routes, availability is lower because of incomplete absorption across the intestinal lining and first-pass metabolism. Put simply, it measures how much of what was given actually arrives.

What peptides and proteins are

Wikipedia's article on the peptide describes peptides as short chains of amino acids linked by peptide bonds. A longer chain is a polypeptide, and the article notes that polypeptides with a molecular mass of 10,000 daltons or more are called proteins. The MedlinePlus Genetics page What are proteins and what do they do? explains that proteins are made of hundreds or thousands of amino acids in long chains, and that their sequence determines their shape and function. The peptide article adds that some peptides act in higher organisms as hormones and signalling molecules.

The peptide problem

That chemistry is exactly the difficulty. The digestive system exists to break proteins down into amino acids, and it does not distinguish a protein meal from a protein medicine. A 2021 review in Acta Pharmaceutica Sinica B by Zhu and colleagues sets out the obstacles. Its abstract explains that, owing to poor stability and limited permeability through the gastrointestinal tract and epithelia, therapeutic proteins and peptides are usually given by a parenteral route. It describes a variety of research aimed at overcoming these barriers, including enteric coating, enzyme inhibitors, permeation enhancers, nanoparticles and intestinal microdevices, and notes that some new technologies have been developed under clinical trials and some have even reached the market.

Insulin is the historical example of the problem. Wikipedia's article on insulin as a medication notes that it is typically given by injection under the skin, although some forms may also be given into a vein or muscle. A hormone made of amino acids would be digested like food if it were swallowed, which is why, a century after insulin entered medicine, oral delivery of proteins remains an active research subject rather than a solved one.

Peptide medicines as a class

Despite these difficulties, peptides have become an important class of medicine. A 2021 Perspective in Nature Reviews Drug Discovery by Muttenthaler and colleagues states in its abstract that since the introduction of insulin almost a century ago, more than 80 peptide drugs have reached the market for a wide range of diseases. The authors summarise trends in peptide drug discovery, from early work on human hormones to rational design, peptides derived from nature and advances in molecular biology and peptide chemistry, and they discuss the challenges that still need to be addressed. A 2022 review in Signal Transduction and Targeted Therapy by Wang and colleagues describes how new production, modification and analytical technologies, together with novel design and delivery strategies, have helped to overcome inherent drawbacks of peptides, and discusses both the value and the challenges of future work.

Wikipedia's article on peptide therapeutics adds an important caution. It explains that the presence of a peptide structure in a substance is not enough to determine its effectiveness or safety, and that peptides with unconfirmed safety and efficacy have recently become popular through social media. It states that there is insufficient evidence for the safety or efficacy of most injected peptides in humans, and that many have only been tested on laboratory-grown cells. It also notes that peptides are fragile and are not generally absorbed by skin, although emerging techniques such as nanoemulsions allow some uptake. The distinction between approved medicines studied in clinical trials and unproven substances is one every reader of this literature needs to keep in view.

Emulsions as carriers

One family of carriers studied for delivery is the emulsion. A 2017 review in the Journal of Controlled Release by Singh and colleagues describes nanoemulsions as dispersions of two immiscible liquids, water droplets in oil or oil droplets in water, stabilised by a surfactant. Its abstract notes that these ultrafine dispersions can serve a wide range of functions, including drug delivery, but that understanding of how to develop and manufacture them is still relatively narrow, because conventional ideas of emulsion formation and stability only partly apply at that scale.