Targeted Modification of Physical-Chemical Properties of Drugs as a Universal Way to Transform “Old” Drugs into “New” Drugs

Abstract

Historically, the bulk of known drugs was created for resorptive action. Therefore, the mechanism of action of drugs was attributed to the specific action of the main ingredients once they were absorbed into the bloodstream. In recent years, it has been found that the mechanism of local action of drugs is determined not only by the specific activity of their main ingredients but also by the nonspecific activity of the excipients and formulation ingredients included in the ready-to-use drug: tablet, injectable solution, aerosol, etc. In this regard, there is an opportunity to repurpose drugs by purposefully changing their quality by changing the physical, chemical, and physical-chemical properties of the finished products. As an example, two new groups of drugs intended for local application to dissolve dense pus and discolor blood stains, namely, piolytics and drugs that bleach bruises, have been created. It is shown that the advantage and at the same time the limitation of the upgraded preparations is their local application, as their peculiarity is the realization of the physical-chemical principle of the drug action in local interaction with the selected part of the patient’s organism.

1. Introduction

Traditional ways of searching for and developing new drugs require large financial, time, and human costs. It is reported that with traditional research design, it would take more than 12 years and $800 million to create a new drug and conduct the entire set of preclinical studies [1, 2]. However, even these costs do not guarantee success, since all traditional drugs have toxicity. Therefore, all drug candidates are traditionally tested for general (resorptive) toxicity. However, no amount of testing can completely eliminate drug toxicity. Therefore, it is no coincidence that most of today’s projects aimed at finding and developing new drugs designed for resorptive action are doomed to fail, as they have in the past. In particular, specialists know that under the traditional scheme of search and development of new drugs out of several thousand substances that participated in trials at the beginning of the complex of these trials, only 1–2 substances can survive all trials more or less successfully and obtain the status of a drug [3]. All other substances will be rejected and forgotten.

That is why it is very important to choose the right design for the search and development of new drugs at the very beginning of this journey in order to reduce the risk of a pharmacological project, the financial and human costs, and to win in time. One very profitable decision these days may be the decision to develop a new drug intended not for general (resorptive) but for local application [4, 5]. The essence of this innovation lies in the fact that in order to reduce financial, human, and time costs when searching for and developing new drugs, it is proposed to abandon the idea of discovering absolutely new chemical compounds intended for resorptive action and to aim at modernizing the formulation of “old” (known) drugs by turning them from resorptive drugs into drugs of local action when applied locally. In other words, it is proposed to create new drugs by purposeful changes in the formulation of known drugs providing them with a new mechanism of local action when applied locally. It has been shown that the transformation of drugs known for their general action into drugs with a new mechanism of local action provides a change in their quality indicators and especially in their physicochemical properties [6, 7].

The author’s experience in using this design for the search and development of new drugs showed the high promise and competitive benefit of the proposed research design compared to the conventional design. It was also confirmed that artificial imparting of quite certain physicochemical properties to ready-made drugs and/or artificial provision of certain physicochemical factors of their local interaction during local application can provide the required mechanism of local drug action and become an alternative to traditional performers of this role in pharmacology, namely, original chemical compounds (substances) with specific pharmacological activity inherent in each of them.

2. Methods

The study is based on Russian research, as there are no similar studies in other countries. The contents of the following materials were included in the analysis:

1. “Development of a remedy for bleaching the skin of the face with black eyes”—report on the implementation of the State Innovation Support Fund grant N 24398 (under the application N C1-19369) (Moscow, Russia).

2. Financial support of research work on the implementation of grant N 24398 from 2016 to 2018. Proceedings of the Institute of Thermology (Izhevsk, Russia).

3. Annual Reports on scientific and inventive work of the Institute of Thermology (Izhevsk, Russia) and the Department of General and Clinical Pharmacology of Izhevsk State Medical Academy in the period from 2016 to 2022 (Izhevsk, Russia);

4. Descriptions of inventions created with the participation of Alexander Urakov and devoted to the development of new drugs from “old” drugs in the period from 2012 to 2022 (Federal Institute of Industrial Property, Moscow, Russia).

5. Official website of the Federal Institute of Industrial Property www1.fips.ru, section “Patent fees” (Moscow, Russia).

3. Results

The first announcement that new materials can be created from old materials by changing their physical and chemical properties was made at the 3rd International Conference on Competitive Materials and Technology Processes (IC-CMTP3) (6–10 October 2014, Miskolc-Lillafüred, Hungary) [4]. Several examples of creating new drugs created from “old”, that is, known drugs by purposeful modification of their physical and chemical properties were shown as evidence of the real possibility of this direction. Thus, there was an example of creating a “floating tablet” due to the fact that the well-known tablet, which is an artificial stone, is made porous, consisting of individual isolated cavities filled with air, and the specific gravity of the tablet is less than 1 g/cm³ (RU 2254121). It has been clearly demonstrated that the specific gravity and strength values of conventional drug tablets are similar to pieces of chalk, natural stone, river pebbles, and even concrete since the tablets are produced from dry powders by pressing them without maintaining isolated cavities filled with air. Therefore, when taken orally, regular pills sink in gastric juice, sink quickly to the very bottom of the stomach and remain at the bottom, no matter how much water the patient drank before, during, or after taking the pills. Moreover, “sinking” pills are very salty and acidic, so they have a local irritating effect on the mucous membrane of the stomach in the area of their contact with it. That is why all the pills cause erosive damage to the mucous membrane of the stomach and gastric ulcers precisely in the pyloric region. At the same time, a floating tablet is lighter and floats on the surface of the gastric juice, not in contact with the pyloric mucosa. Moreover, it has been shown that taking water and raising the liquid level in the stomach cavity causes the floating tablet to move along with the liquid level. Therefore, the floating tablet cannot have a local irritant and ulcerogenic effect on the mucous membrane of the pyloric region of the stomach. The higher the level of liquid in the stomach cavity rises, the higher the floating pill rises.

In addition, it has been convincingly shown that increasing the temperature, alkaline activity, and gas content of conventional drugs can turn them into new drugs, for example—into solvent drugs for thick and dry biological masses (pus, blood clots, blood stains, mucus, sputum, sulfur plugs, etc.). It has been reported that almost any drug can be turned into a solvent for thick pus and blood stains if sodium bicarbonate, hydrogen peroxide, and/or carbon dioxide under increased pressure are additionally introduced into the drug formulation and the drug is heated to a temperature of 37–45°C. In particular, it has been reported that such drug solutions acquire the physicochemical properties of alkaline carbonated drinking beverages.

However, drugs differ from the known carbonated drinking beverages in that they have hydrogen peroxide in their composition. The fact is that the addition of hydrogen peroxide to such solutions further changes their physicochemical properties, especially during local interaction with biological tissues containing the enzyme catalase, which decomposes hydrogen peroxide into oxygen gas and water very quickly. Therefore, warm alkaline solutions of hydrogen peroxide in local interaction with thick pus, mucus, sputum, blood, feces, meconium, sulfur plugs, and other biological objects containing catalase enzyme immediately “explode” them due to cold boiling process. As a result, the above biological objects turn into a soft oxygen foam of white color, because at the same time, oxygen decolorization of hemoglobin and its colored metabolites occurs.

On this basis, it was concluded that by giving drugs physical and chemical properties such as hyperthermia, alkalinity, increased gas content under increased pressure, and the ability to release molecular oxygen under the influence of catalase can provide drugs with the ability to bleach blood spots, bruises, and hematomas, as well as dissolve thick pus and thick sulfur plugs.

Finally, based on the results obtained, it was concluded that a new direction in pharmacology and materials science was discovered, namely, physicochemical pharmacology and physicochemical materials science.

A few years after the first official communication, the assumption was realized in Russia with the help of the State Fund for Innovation Support. This fund provided a grant for the development of the first drug to bleach the skin in the area of the black eye. The first drug, a skin-bleaching agent in the area of a black eye, was successfully developed by the team of the Institute of Thermology (Izhevsk, Russia) in the period from 2016 to 2018. Analysis of the reports of the Institute of Thermology showed that it took 2 years to find and develop a new drug, a skin-bleaching agent for the bruise area, at a cost of $27,132. It is important to emphasize that 10 qualified physicians participated in the development. One of them was a doctor of medicine, a professor in the field of pharmacology, and four doctors had Ph.D. degrees. In addition, five students helped the team to carry out the research on their own initiative, that is, free of charge.

At the same time, in Russia, a group of specialists and students conducted laboratory screening of several dozens of known drugs and some physical, chemical, and physicochemical factors of local interaction between 2015 and 2022. The results obtained made it possible to establish that such “old” drugs as hydrogen peroxide and sodium bicarbonate have weak dissolving and bleaching activity, and such physical–chemical factors of local interaction such as hyperthermia, alkalinity and hypergazing, and increase and accelerate their bleaching and pyolytic action several times.

In addition, this research team conducted several series of experiments on the nonspecific pharmacological activity of warm alkaline hydrogen peroxide solutions when injected into the skin in the area of bruises in awake piglets, by cutaneous and intradermal injection in the area of artificial bruises created in isolated pig skin segments and in models of blood spots on dressing materials. In parallel, laboratory studies were conducted on the transformation of thick pus, mucus, sputum, and meconium into fluffy oxygenated foam under laboratory conditions with the corresponding isolated biological objects of patients, as well as in experiments on rabbits and isolated rabbit lungs. The results confirmed the correctness of the assumption that it is possible to create new drugs from old drugs by artificially and purposefully changing their physical and chemical properties such as temperature, acidity (alkalinity), osmotic, explosive, and oxygen-releasing activity. Examples are new drugs-bleaching stains, traces of blood, bruises, and hematomas, as well as new medical technologies of skin whitening in the area of bruises, developed in Russia on the basis of physical–chemical pharmacology (RU 2539380, RU2589682, RU 2573382, RU 2653465, RU 2647371, RU 2639485, RU 2586278, RU 2582215, RU 2577510, RU 2600504, RU 2634268, RU 2631593, RU 2631592, RU 2641386, RU 2639283, RU 2679334) [5, 7].

Another example of the successful use of the basics of physicochemical pharmacology to transform “old” drugs into new drugs is the development of new aerosols for inhalations and new solutions for intrapulmonary injections based on the original warm alkaline hydrogen peroxide solutions, which provide urgent recanalization of the airways and oxygen saturation of blood through the lungs due to oxygen foaming of thick mucus, sputum, and pus inside the airways during respiratory obstruction caused by COVID-19 (RU Patent No. 2742505, RU Patent No. 2735502, RU Application No. 2021102618, RU Application No. 2021114105) [8].

4. Discussion

In the period from 2012 to 2022, the foundations of physical-chemical pharmacology, pharmacy, and materials science were laid [5, 8]. The essence of the new direction is that new drugs, or rather drugs with a new mechanism of local action, can be created from well-known and proven drugs (that is, old drugs) by purposefully changing their physical-chemical properties. It is reported that a targeted change in the physical-chemical properties of finished drugs (tablets, solutions, aerosols, etc.) allows you to radically change the local mechanism of action of traditional drugs (chemical compounds) with local interaction inside the stomach (with enteral administration), inside blood vessels (with intravenous injections), inside the skin (with intradermal injections), on the surface of the skin and mucous membranes (with applications), as well as inside sulfur plugs, purulent masses, blood clots, thick masses of mucus, sputum, meconium, and other biological masses. It has been convincingly shown that the mechanism of local action of drugs with local application is determined not only by the specific activity of their main ingredients but also by the nonspecific activity of auxiliary and formative ingredients included in the composition of drugs, as well as the physical-chemical properties of finished drugs. That is why for the development of new drugs intended for topical use, “old” drugs can be used, but with artificially altered physical-chemical properties. The new mechanism of local action of “old” drugs can be adjusted by changing the mechanical, physical, chemical, and physical–chemical properties of drugs in specific dosage forms, that is, by changing the quality of tablets, solutions, ointments, creams, aerosols, etc.

It is paradoxical, but the results obtained convince us of the prospects of searching for drugs with new mechanisms of local action among the “old” drugs by purposefully changing their quality (from the standpoint of traditional ideas about the quality of drugs).

Indeed, using the example of ordinary tablets, it was shown that they sink to the bottom of the stomach and move inside its cavity under the influence of gravity in the same way as river sand, pieces of chalk, clay, gravel, and pebbles [9]. It turned out that the specific gravity of all modern tablets exceeds 1 g/cm³, and, therefore, all tablets sink in gastric juice, water, and milk. It has been shown that in the vertical position of the patient’s torso, all tablets fall into the pyloric part of the stomach despite the added liquid. At the same time, it was found that all tablets have an aggressive effect on the gastric mucosa since they corrode the stomach wall and can lead to the formation of ulcers. At the same time, a decrease in the specific gravity of tablets of less than 1 g/cm³ due to the creation of isolated cavities in them by the type of solid or thick foam makes it possible to radically change the intra-stomach pharmacokinetics and pharmacodynamics of tablet drugs.

Further studies have shown that tablets, which are considered high-quality today, cannot be considered such in comparison with natural food lumps that a person swallows with high-quality chewing of food [9]. It is reported that not only the specific gravity of the tablets but also the shape of the tablets distinguish them from natural food lumps. This approach is recommended for the future adjustment of modern standards of quality control of tablets. It was reported that the manufacturing of tablets by pressing dry powders up to their transformation into artificial stones in the form of a round disk is a pharmaceutical mistake since the disc-shaped shape of tablets with the properties of stones is incompatible with the specifics of the human digestive system. In addition, it was reported that the sizes of modern tablets, which are considered high-quality, do not correspond to the sizes of natural food lumps. It has been shown that high–quality tablets from different manufacturers can differ in height by 3 times, and in volume by 10 times. It was also reported that the natural food lump has the shape of an olive with the largest diameter of up to 1 cm and a maximum length of 2 cm. At the same time, food lumps have an average elasticity, a hardness value of about zero, food lumps are porous and have a specific gravity of less than 1 g/cm³, and are also devoid of aggressive osmotic action on the mucous membranes of the mouth and stomach. At the same time, modern tablets considered to be of high quality may differ from each other in terms of their hardness by 500 times, since the hardness of the tablets is not controlled [9].

Therefore, it was not by chance that it was stated that the human stomach is not adapted to the introduction of such pills into it (and in fact—artificial stones), since a person is not a bird. Based on these data, it was proposed to modernize the quality standard of tablets, since to increase their safety there is no alternative to their similarity to natural human food lumps in shape, size, and physical-chemical properties. In particular, tablets–analogs of natural food lumps were developed (RU 2533840).

In parallel with the studies of the physical-chemical properties of tablets, the physical-chemical properties of solutions of drugs intended for injection and considered to be of high quality (from the standpoint of drug quality standards) were carried out. It was reported that most of the modern high-quality drug solutions have acidic activity, that is, a pH value of less than 7.0. At the same time, blood and most human tissues have alkaline activity with a pH value of 7.4 [4, 5]. Therefore, some solutions of drugs, which are considered to be of high quality today, can have a local irritating effect and even post-injection necrosis and abscesses at the sites of intramuscular and intravenous injections [10].

In this regard, it was proposed to modernize the pharmacopeia requirements for drug solutions intended for injection. In particular, it was proposed to replace the traditional division of medicinal solutions by the magnitude of their acid (alkaline) activity from pH 7.0 (that is, acidic and alkaline drugs) with a more physiological division of drugs into groups compared to pH 7.4, namely, acidifying and alkalizing drugs (RU 2219958, RU 2221248). The fact is that the acidic activity of drug solutions coagulates proteins and protein-lipid complexes, and also has a local irritant effect on tissues, causing local aseptic inflammation in the injection and/or application sites (for example, when injecting drug solutions into the conjunctival cavity). On the other hand, the alkaline activity of drug solutions liquefies colloidal tissues and can saponify protein and protein-lipid complexes. Therefore, drug’s alkaline activity optimizes the rheological properties of blood after local interaction of drug solutions with blood inside veins and vascular catheters, preventing clogging. Additionally, it is reported that alkaline activity of drug solutions promotes liquefaction and dissolution of thick mucus, sputum, pus, and blood clots, especially when local temperature increases, namely, when heating solutions to +37 − +45°C [5, 8].

In addition to this, the great importance of the temperature of drug solutions has been shown. The fact is that temperature according to the Arrhenius and Van Goff law is of great importance for the intensity of all metabolic and vital processes at all levels of organization of living systems, including protein molecules. At the same time, there are reports that modern standards of treatment do not take into account the temperature of drugs when they are administered to patients. Because of this, drugs are not heated to human body temperature and most often the drugs are at room temperature, that is, about +24°C [5, 8]. Therefore, during local interactions, cold drugs cool the tissues in the area of local interactions. Thus, the drugs cause formation of a zone of local hypothermia. In its turn, local hypothermia compacts biological tissues and slows down the rate of biochemical processes in them. In particular, it was reported that temperature decrease from +37 to +24°C significantly slows down the process of blood clotting inside the vascular catheters and blood vessels, which reduces the risk of vein and vascular catheter thrombosis formation, especially during infusion of infusion fluids. In addition, during intravenous injections, cold drug solutions cool the veins, the localization of which can be detected using a thermal imaging device by appropriate zones of local hypothermia in the area of vein projection. This role of cold solutions during intravenous injections was the basis of a new method of infrared imaging of subcutaneous veins (RU 2389429).

On the other hand, it is reported that another very important physicochemical property of drug solutions is their osmotic activity. For a long time, ready-to-inject drug solutions were thought to be of impeccable quality and to be isotonic. However, studies conducted in recent years have shown that the drug quality standard includes control of the concentration value of drug ingredients, but does not include control of osmotic activity and local irritant effect of drug solutions on tissues at injection sites [11]. In this regard, any drug in a particular series (or batch) with a particular manufacturer may sooner or later have excessive hypertonic and/or acidic activity.

Using the example of nonsteroidal anti-inflammatory drugs (NSAIDs), it was shown that some of these drugs have a local irritant effect due to the high concentration of ingredients and hypertonic activity [11]. In laboratory conditions, using an osmometer, it was found that a solution of 50% sodium metamizole has an osmotic activity of 4638 ± 12.5 mosmol/l of water, that is, it is a hypertonic solution. In experimental and clinical conditions, it was shown that intramuscular and subcutaneous injections of a solution of 50% metamizole sodium caused aseptic inflammation, necrosis, and abscess. However, preliminary dilution of a 50% metamizole sodium solution with water by 10 times completely prevented the development of postinjection necrosis and abscess during subcutaneous and intramuscular injections. At the same time, the effectiveness of the protective action of water was explained by its physicochemical role in reducing the concentration of ingredients and the hypertonic activity of the diluted sodium metamizole solution.

These reports convince us that one of the causes of acute post-injection local complication, which is manifested by aseptic inflammation, necrosis, and abscess of tissues at the injection sites of drugs, may be an excessively strong dehydrating effect of drugs on tissue cells due to their hypertensive activity. The dehydrating effect is exerted by an excessively large hyperosmotic activity (hypertonic activity) of drugs, which is created by a large concentration of dissolved ingredients. It has been shown that medicinal solutions containing ingredients in the range of 1–10% are isotonic, either weak hypotonic or weak hypertonic solutions. Such solutions have moderate postinjection safety. Drug solutions containing ingredients in the range of 10–76% are strong hypertonic solutions and have an excessively strong dehydrating effect on cells with local interaction. In this regard, solutions with a total concentration of ingredients of more than 10% are excessively hypertensive and have excessively low postinjection safety, since their injections cause excessive dehydration of cells, necrosis, and abscess [12].

Based on the results, it was concluded that traditional drug quality control requirements are responsible for the fact that some drug solutions, now considered to be of high quality, may have excessive hypertonic activity. In turn, hypertonic drug activity may cause local irritation, aseptic postinjection necrosis, and injection site abscesses. In this regard, ignoring the actual values of osmotic and acidic activity of drugs in the drug form “solution for injection” during injection reduces postinjection drug safety. Therefore, in order to improve postinjection drug safety, it is proposed to monitor the osmotic and acidic activity and the local irritant effect of drugs on the tissues at the injection sites. At the same time, it is reported that postinjection necrosis and abscess in the place of subcutaneous injection of hypertonic solution of almost any drug can be prevented by immediate injection of water for injection (not later than 5–6 minutes after the injection) under control of the dynamics of local skin temperature in the injection site using a thermal imager (RU 2326662, RU 2304769, RU 2396562).

Consequently, convincing evidence has been obtained that eliminating the hypertonic activity of highly concentrated drug solutions by diluting them 2–10 times with water increases the safety of drug injections. Therefore, there are grounds for including this recommendation in the instructions for medical use of highly concentrated drug solutions.

5. Conclusion

Thus, in 2014, an affordable way was proposed to transform “old” quality drugs into new drugs by purposefully changing their quality by artificially changing the physical, chemical, and physicochemical properties of finished drugs: tablets, injectable solutions, aerosols, etc. From the point of view of traditional ideas, the newly created drugs in this way may seem to be spoiled or defective. However, this is not the case. Simply known (old) drugs were traditionally developed mainly for the general (resorptive) mechanism of action. Therefore, the “old” drugs have outdated requirements for their quality. Pharmaceutical and pharmacological progress is impossible without revising the pharmacopeia and traditional drug quality control standards, because “old” drug quality standards preclude their qualitative modernization. It is shown that the advantage and at the same time the limitation of modernized drugs is their local application since their peculiarity is the implementation of the physicochemical principle of drug action in local interaction with a selected part of the patient’s (or animal’s) body.

Acknowledgments

We express gratitude to Professor László A Gömze for his constant support and assistance in the formation of physicochemical materials science.

Conflict of interest

The authors declare no conflict of interest.