Development of Corticosteroids and their Formulation for Inhaled Drug Delivery

Introduction

Steroids are biologically active organic compounds with substantial roles and functions in the cell. Chemically, steroids are known with four rings settled in a specific configuration [1]. They are powerful and effective drugs used in the treatment of various medical conditions.
There are two principal biological functions of steroids in a human cell. First, they act as important components of cell membranes, which alter membrane fluidity, and second, steroids act as signalling molecules [2].

Hundreds of steroids are found in plants, animals, and fungi. Steroid compounds are manufactured in the cell from the sterols lanosterol or cycloartenol, depending on the type of the species.

Cholesterol, estradiol, testosterone, and the anti-inflammatory drug dexamethasone [3] can be given as popular examples of steroids [4]. Corticosteroids, one of the most common steroid groups, have been used effectively in the treatment of arthritis, asthma, autoimmune diseases, skin disorders, and some types of cancer. Anabolic steroids, a different group of steroids, are rarely used in medicine. These compounds can be abused to improve performance in sports such as competitive athletics and weightlifting.

Inflammation is a significant feature of many diseases with apparently unlimited medical applications of steroids. The list includes some skin conditions such as eczema, psoriasis and skin inflammation, arthritis due to pain, swelling and limited joint mobility. Oral steroids can be prescribed for autoimmune diseases such as lupus, Crohn's disease, and multiple sclerosis. Besides, corticosteroids are used in the treatment of many eye diseases and some cancers. They relieve or reduce chemotherapy-related nausea and reduce some allergic reactions, such as those caused by blood transfusions. One of the main ways in which steroids work in the body is to reduce inflammation. This feature is important in conditions such as corticosteroids can be taken as pills or in the form of injections. However, there are other routes of administration as well, including inhaled corticosteroids, steroid creams, and ointments. Besides, the drug can be injected directly into an inflamed joint.

Additionally, steroids are effectively used to manage asthma. By reducing inflammation and controlling the body's immune system, corticosteroids help open the small airways. Steroids can be given with an inhaler as part of routine care to reduce symptoms for asthma and help prevent acute attacks. In an acute attack requiring a hospital visit, steroids are usually administered as intravenous injections.

This essay aims to give detailed information on the development of corticosteroids with an emphasis on their formulation for inhaled drug delivery.

Historical development of steroids

According to the 1920 edition of The Principles and Practice of Medicine [5], the relationship of Addison's disease with the adrenals was not fully understood. However, efforts were given to extract the hormone, and in 1930 a compound could be made ready for clinical trials [6]. Soon, first treatments of Addison's patients with the cortical hormone of the suprarenal gland were reported [7]. Thus it can be said that the first clinical evidence that an extract of animal adrenocortical tissue could be used to treat human adrenal failure, was demonstrated in the 1930s.

As chemical analyses of cortical extracts proceeded, it became clear that there is not one cortical hormone, but that they all are steroids [8]. By the year 1940, it was concluded that there are two categories of steroids: those that lead to a retention of sodium (and thus, fluid) and those that relieve shock and inflammation [9]

The widespread clinical use of intramuscular cortisone started after 1948 first in rheumatoid arthritis and soon later in other rheumatologic conditions. Only after 1950 it was possible to have oral and intra-articular administrations of cortisone and hydrocortisone.

Research continued to produce semi-synthetic cortisone with some success by the year 1952. Six synthetic steroids were introduced for systemic anti-inflammatory therapy during 1954 -1958. By 1960 almost all side-effects of chronic corticosteroid administration were described. Additionally, protocols were developed to withdraw these medications while minimizing symptoms of cortical insufficiency.

Dose adjustment and use of lower doses was an agenda of the researchers those days. Companion use of non-steroidal anti-inflammatory drugs began in the late 1950s first with phenylbutazone. In the 1970s the introduction of methotrexate and other anti-metabolites further delineated the dosages and indications for corticosteroids in the management of rheumatic diseases.[6]

Parallel to the medical use of steroid hormones, soon athletes discovered its use to win games. As a competitive species, the human has tried all kinds of things to be the best. Athletes have used various substances to improve performance since the beginning of civilization. Even before the invention of the steroids, in the 1860s, a group of swimmers in Amsterdam were charged with taking drugs to speed up their races.

After discovering the anabolic effects of steroids, probably the first application of this kind was among soldiers. German soldiers received testosterone during World War II to increase their performance and become successful on the battlefield.

Anabolic steroids are man-made versions of testosterone, a male sex hormone that helps build bigger muscles. The power of these substances in increasing the performance and boosting the muscle muscles led to widespread abuse. Abusers usually consume use extremely high doses. Some even take 100 times the dose legally prescribed by physicians [10].

In the 1940s testosterone began to be widespread in competitive sports, but the dangers of loading up on testosterone were not known in detail. In the 1952 Olympics, the Russian weightlifting and wrestling teams demonstrated a significant success, which was attributed to synthetic testosterone [11].

Scientists worked to formulate better performance-enhancing drugs after the 1950s. In the early days, there was still not enough awareness on the dangers these substances to users. By 1958, an American pharmaceutical company first developed anabolic steroids. With the widespread access and use, the nasty and hazardous side effects became obvious, but by then most athletes had access to the drugs.

From the 1950s into the 1970s, both the tales and facts of performance-enhancing drug use combined to increase actual use. Those athletes, who required bulk and strength to be competitive, like bodybuilders, football players, and shot put throwers, were the first to abuse anabolic-androgenic steroids. During the 1970's, the demand for anabolic-androgenic steroids grew as athletes in speed-dependent sports discovered some of the potential benefits of using anabolic-androgenic steroids.

All these practices were named as "doping", and were against the sports organizations' rules and against the law. In 1964, the International Olympic Committee first published a list of banned drugs and practices for athletes, but they did not ban steroids until 1975.

Chemical structures of steroids and how structural changes were developed

Steroids are organic compounds with a ring structure (Figure 1). The most important natural steroid compounds are bile acids, male and female sex hormones (Figure 2), and adrenal gland cortex hormones. Most of these hormones are found in the cell in trace ratios, while sterols, a kind of steroid compound, are found to be abundant [12].

Sterols are accompanied by a side chain on the main steroid roof [13]. Cholesterol is the most abundant sterol, free or bound in animal tissues. Plants do not contain sterols, but another sterol phytosterol is abundant. Other important steroids are vitamin D and cardiac glycosides.

Issues with side effects that have arisen during the development

Side-effects of the corticosteroids were already defined during the early invention phases of these compounds. Today, there are numerous studies describing the risks and side-effects of using steroids whether used locally [14] or systemic [15].

The known side-effects depend on the dose and how long the substance is taken. Side effects have been reported affecting many body systems, including gastrointestinal, musculoskeletal, eye, metabolic effects, immune system, pregnancy and fertility, psychological effects, and skin. Short-term use can cause weight gain, puffy face, nausea, mood swings, and trouble sleeping. The skin may get thinner. Acne, unusual hair growth, and spikes in blood sugar and blood pressure are expected. Because corticosteroids turn down the immune system, taking them makes the person prone to infections.

Taking high doses of corticosteroids for a long time can cause serious side effects. Using them for more than 3 months can cause brittle bones and osteoporosis. Kids who take them for a long time might grow more slowly.

Anabolic steroids have similar side effects. These steroids can cause bad acne and fluid retention. Long-term use can stop the body from making testosterone. In men, this causes smaller testicles, lower sperm counts, infertility, and breast growth. Women may have male-pattern baldness, facial hair growth, periods that change or stop, and a deeper voice. Teens that use them might stunt their bone growth and height. High doses can lead to extreme mood swings, anger, as well as aggression.

Long-term anabolic use can damage the liver, kidneys, and heart. Severe fluid retention can cause heart swelling and heart failure. These drugs can also raise LDL cholesterol, which can make the person more likely to have heart attacks and strokes [16].

Aspects of formulation for inhaled drug delivery

New and easier ways of drug deliveries are invented every day. This is a fact also for steroids. Inhaled steroids are popular especially for the management of conditions such as asthma and chronic obstructive lung disease (COPD). Inhaled formulations have many advantages including faster effectiveness, fewer side effects, ease of use, tolerability, and lower costs.

Inhaled steroids are the mainstay treatment for controlling asthma. The use of inhaled steroids leads to better asthma control, fewer symptoms and flare-ups, and reduced need for hospitalization.

Inhaled steroids come in three forms: the hydrofluoroalkane inhaler or HFA (formerly called a metered dose inhaler or MDI), dry powder inhaler (DPI), and nebulizer solutions.

With aerosol devices, the typical inspiratory flow rate is around 30 litres per minute, which is a slow and steady breath in for around 4 seconds. The older pMDIs have a low deposition even with an ideal technique, of around 12% [17], although the newer devices have a softer plume and better valve technology, and some have smaller particle size increasing deposition. The Respimat device, although an aerosol inhaler, has a soft mist which increases deposition in the lung.

The DPIs are dry powders and require less coordination. They do, however, require an adequate inhalation as it is an inspiratory flow that releases the medication from the carrier agent. The DPIs require a quick and deep inhalation, which may be problematic in patients with little inspiratory effort, for example, those with severely compromised lung function [18].

Inhalers contain different medicationsbronchodilators or corticosteroids, either singularly or combined. These medications have different durations of onset and action and an inhaled corticosteroid, for example, will not give a noticeable effect. If the person does not get instant relief from the inhaler, then they may take more doses, or conclude that their inhaler doesn't work [19].

Inhaled steroids have few side effects, especially at lower doses. Thrush and hoarseness (rare) may occur. Rinsing the mouth, gargling after using the inhalers, and using a spacer device with metered dose inhalers can help prevent these side effects. Thrush is easily treated with a prescription of antifungal lozenge or rinse.

As a side note, it should be mentioned that many parents have concerns in giving their children "steroids." The public should be informed that inhaled steroids are not the same as anabolic steroids that some athletes take to build muscle or increase performance. These steroids are anti-inflammatory drugs, which constitute the cornerstone of asthma therapy.

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