DEVELOPMENT OF CORTICOSTEROIDS AND CONSIDERATION OF THEIR FORMULATION FOR INHALED DRUG DELIVERY
Historical development of steroids and corticosteroids
Attempts to synthetize steroids have started in 1920s, but steroid chemistry entered its golden age during the 1930s. It all started with discovering of steroid structure of perhydrocyclo-pentanophenantrene by Otto Rosenheim and Harold King in 1932. In 1936 all compounds with sterol like skeleton got the general name “steroids”. By 1937 most of the human steroid hormones had been isolated with their precise structure determined.
In 1936 three groups independently discovered crystalline compound today known as cortisone. Kendal named this substance compound E, while Reichstein in Switzerland decided to call it substance F. This compound was isolated from bovine adrenal glands together with some other similar substances with whom it shared capability of improving muscular strength in adrenalectomised rats and dogs. Kick start of broader synthetization was US entry in Second World War. US army has had incorrect information that Luftwaffe pilots were taking adrenal extracts to improve their resistance to oxygen deprivation, which lead to a greater quest for a large scale production of active adrenal hormone. Even though at that moment Kendal and his team synthetized 6 different steroidal substances, only compound E was intensively studied. These studies lead to historic 37 steps synthesis of compound E from deoxyocholic acid.
All of that lead to first clinical use of compound E, which occurred in summer 1948 by doctor Philip Showalter Hench at the Mayo clinic. First intra muscular injection of compound E was given to a female patient with rheumatoid arthritis. Results were astonishingly fast and great, so much that previously crippled patient on the third day after the injection went on a shopping trip. After few years (1950) compound E was renamed into cortisone, to avoid its confusion with vitamin E.
Kendal and Hench in 1950 shared the Nobel prize for Physiology and Medicine “for research on the structure and biological effects of adrenal cortex hormones” with Tadeus Reichstein from Switzerland.
Chemical structure of steroids and development of structural changes
In 1936 Reichstein was first to demonstrate structure of Substance E or cortisone. The structure he reported was 17?, 21-dihydroxy-4-pregnane-3,11,20-trione. Before synthesis of cortisone, first substance that was successfully synthetized was compound A (11-dehydrocorticosterone) which lacks 17? part of cortisone. Unfortunately, this substance was not biologically active, but it placed bedrock for synthesis of other corticosteroids, and it was also great achievement in the field of organic chemistry. The first attempts of synthetization used 3?-hydroxy-11-ketobisnorcholanate, which has been prepared from deoxyholic acid. It took 36 steps from this substance to create cortison acetate. Many modifications of initial steps took place to achieve larger quantities and easier synthesis. The greatest obstacle was placing an oxygen in C11, because there was no starting material that had oxygen on C11, and no practical method was known for adding it. One developed method was starting with disogenin (from Mexican yam) that was perfused through fresh cow adrenal glands which biochemically added the ? –hydroxyl to C11. There was also method that used a chemical found in hemp as a starting material. Finally, method that had achieved enough cortisone for clinical trial and therapeutic use was developed by Upjohn, and it was microbiological conversion method, which used progesterone as a starting material.
After some time, many side effects of cortisone became evident. This fact motivated chemists to modify cortisone molecule to increase its systemic activity, and to reduce undesirable side effects, as much as possible. Their main principle was attaching functional groups to the various steroid positions. These processes were multistep, for example, synthesis of fluocinonid required 32 stepwise reactions. Chemists haven’t had any guidelines to follow, so most of their work was practically guesswork and intuitive working. This lead to synthesis of dozens of compounds, that were then sent to biology labs for testing. There they were tested on animal models of human diseases, with hope that they might also work in humans. With time they learned which functional groups are beneficial and which are not. For example, changes that prevented metabolic inactivation of the substance would also enhance potency, but they might negatively affect other processes. Most important changes were with the following functional groups.
C-11 Oxygen (O)
Placing the oxygen to the C11 position was previously described. The most common way to do it is with microbiological processes that start with progesterone molecule.
C-11 Hydroxyl group (OH)
Conversion of cortisone to hydrocortisone happens when oxygen is converted to a hydroxyl group. This was harder to achieve because –OH group was in the ? stereochemical position, while the preferred configuration was ?.
C-9 ? Fluorine (F)
While trying to create hydrocortisone with ? configuration, dr. Joseph Fried created an intermediate compound that was unexpectedly active. The substance was 9? Br, 11 ? OH. He changed it from 9? Br to 9? Cl, and then to 9? F that was 10,7 times more potent than cortisone. This substance exhibited more side effects than cortisone, especially sodium retention activity, which lead to edema.
C-1,2 double bond
The process of changing the 1,2 single bond in cortisone into a double bond created steroids today known as prednisone and prednisolone. They have enhanced antirheumatic and antiallergenic activity that is coupled with less side effects. They became drugs of choice for treatment of inflammatory diseases and remain so.
C-9 ? Fluorine and C-1,2 double bond
This combination lead to greater potency and cumulating of effects of both structural changes. They had undesirable mineralcorticoid activity and were not used. However, this combination was used for development of topical corticosteroids.
C-16 ? Hydroxyl (-OH)
This functional group was added to prednisolone which already had C-9 ? F group. This compound was without undesirable sodium retention effects of C-9 ? F. It was later marketed as triamcinolone.
C-16 ? Methyl (CH3)
This functional group increased antiinflammatory activity and elimination of the sodium-retaining effects of the C-9 ? F group. This change was a basis for development of dexamethasone.
C-6 ? Fluorine (F)
Addition of this group created C-6 ? F cortisol which exhibited potency eight times that of cortisol. Further halogenic reactions that were done lead to development of paramethasone and flumethasone.
Pharmacokinetics of inhaled corticosteroids
Even though chemists and doctors continued to develop new formulations of corticosteroids, to this day there was no corticosteroid without side effects. To achieve less side effects different ways of drug delivery were invented. Today, alongside systematic oral and IV use, we have topical and inhaled corticosteroids mainly used in dermatology and respiratory medicine. Especially large patient population needs to use corticosteroids in treatment of asthma and allergic rhinitis, so large part of corticosteroid research is directed towards this field.
Inhaled corticosteroids were first time used around 30 years ago, and to this day they remain drugs of choice for asthma treatment. They are especially good because of their ability to control inflammatory and other asthmatic processes in the lungs without producing high systemic levels of drug and consequently high systemic side effects.
Inhaled corticosteroids that are most widely used today are beclometasone dipropionat, budesonide, and fluticasone monopropionat. Most essential characteristic that corticosteroid compound has to possess is high affinity for the corticosteroid receptor in respiratory mucosa. Three previously mentioned have different affinity, with fluticasone monopropionate having the highest, and beclometasone dipropionate the lowest. These affinities were tested in vitro, however their effects on allergic airway inflammation in a patient didn’t show similar hierarchy. This is because there are other factors influencing clinical response in a patient.
One of those factors is water solubility since it may ease dissolution of the steroid in the mucosal fluid, facilitate dissolution of the steroid in and out of tissues and improve antiinflammatory potency. Highest water solubility has budesonide.
Lipophilicity is practically most important factor from pharmacokinetic standpoint. Similarly, with affinity, fluticasone has the highest lipophilicity.
After inhalation, steroids can reach systemic circulation via the lungs or GIT. Very important factor for minimization of systemic side effects is rapid inactivation by hepatic biotransformation. All of the widely used inhaled corticosteroids have a high first-pass metabolism, with fluticasone having the highest, at around 99%. Term used for this in pharmacology is oral bioavailability; higher the first-pass metabolism is, lower the bioavailability.
Finally, corticosteroid that is going to be used as inhalatory drug has to have prolonged pulmonary residence to maximize the effect. To achieve long pulmonary residence special devices were created during the years. If a good inhaler achieves adequate pulmonary deposition, that will favor pulmonary selectivity, especially with drugs that have high oral bioavailability, because an increased pulmonary drug deposition will allow the same clinical effects being achieved with a reduced daily dose. There are few different devices used today: hydrofluoroalkane-based metered dose inhalers, nebulizers and dry powder inhalers.
Hydrofluoroalkane based metered dose inhaler is a device that delivers a specific amount of medication to the lungs in the form of aerosolized medicine. They consist of three major part: the stainless steel or aluminum canister, the metering valve, and an actuator which allows the patient to operate the device and directs the aerosol into the lungs.