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28SCIENTIFIC SUBSTANTIATION OF THE FORMULATION AND TECHNOLOGY OF A NEW COMPLEX NASAL DRUG COMPOSITION FOR LOCAL TREATMENT OF INFLUENZA AND ACUTE RESPIRATORY VIRAL INFECTIONS
Nefedova L.
Post-graduate student of the Management and Public Adminastration Department, National University of Pharmacy, Kharkiv, Ukraine
Sahaidak-Nikitiuk R Doctor of Pharmaceutical Sciences, Professor, Professor of Management and Public Administration Department, National University of Pharmacy, Kharkiv, Ukraine
Blazheyevskiy M. Doctor of Chemical Sciences, Professor Professor of the Inorganic and physical chemistry department National University of Pharmacy, Kharkiv, Ukraine
Barnatovich S.
PhD in Pharmaceutical Sciences, Associate Professor Associate Professor of the Department of Drug
Technology, Organization and Economics of Pharmacy Luhansk State Medical University, Rubizhne, Ukraine
Abstract
A formulation of the pharmaceutical composition based on 5.0% aminocaproic acid, 0.5% 4-aminobenzoic acid, 0.05% oxymetazoline hydrochloride, and 0.02% decamethoxine for treatment and prevention of acute respiratory viral infections in the form of nasal spray has been suggested and substantiated. A technological process for production of the nasal spray has been developed. It has been determined that quality parameters of the developed nasal drug for 18 months of storage are within the limits indicated in the product specification file.
Keywords: influenza, formulation, technology, nasal spray, shelf life
1. Introduction
Acute respiratory virus infections (ARVIs) caused by influenza viruses, coronaviruses, rhinoviruses, respiratory syncytial viruses, adenoviruses, etc. are the most common groups of infections in human all over the world [1-5].
In most cases, these types of infections affect the mucous of the nose and throat, bronchi, lungs, and sometimes the intestine. ARVIs often cause secondary complications in the ears, throat, nose, lungs, and kidney associated with the activation of opportunistic pathogens living on the mucous membrane and adjacent organs [6-10].
All of this annually causes serious economic and social loss around the world [11, 12]. Thus, counter-measures against these groups of viruses are a very actual task of medicine, and the development of new drugs is an actual task of pharmacy.
At the moment, we have very limited number of active pharmaceutical ingredients (API) to fight the viruses causing ARVIs and influenza in particular, which are developed and successfully used in practical medicine, namely: interferons (a-, P-, y-interferon), inhibitors of membrane protein M2 (amantadine, rimantadine), neuraminidase inhibitors (zanamivir, oseltamivir), and cation-active antiseptics (miramistin, decmetoxin) [13].
Each of the above-mentioned APIs affects different stages of virus life cycle (directly the virus itself or indirectly its binding, copying, assembly, and exit), but all of them have a very restricted action and they do not affect the such negative symptoms like rhinorrhea and nasal blockage.
Therefore, the most optimal way in the development of a drug for prevention and treatment of influenza, ARVIs, and their complications is a combination of APIs with different pharmacological effects that allows for better effectiveness compared to monocompo-nent drugs.
Taking the above-mentioned into consideration, we put forward an assumption that a pharmaceutical composition for prevention and treatment of influenza, ARVIs, and their complications should contain APIs that inactivate viruses and bacteria outside the cell (a cation-acive antiseptic), stop the virus life cycle inside the cell (an antivirus component), and relief the above-mentioned negative symptoms (a decongestant).
The goal of this work is to provide scientific substantiation of the formulation and technology of a new complex nasal drug composition for prevention and treatment of influenza, ARVIs, and their complications in the form of a nasal spray.
2. Planning (methodology) of the research
To achieve the above-mentioned goal we should solve the following tasks:
- Theoretical and experimental substantiation of the pharmaceutical composition in the form of a nasal spray for prevention and treatment of influenza and ARVIs.
- Development of the technology to obtain the pharmaceutical composition.
- Carrying out a complex stability study of the pharmaceutical composition in order to determine its shelf life (at normal storage conditions).
For solving the above-mentioned tasks, we used the requirements of the State Pharmacopoeia of
Ukraine and modern physical and chemical methods of analysis, such as reversed phase high performance liquid chromatography, titration, and pH-metry.
3. Materials and methods
Reagents
For studies, we used Aminocaproic acid (ACA), official reference standard of the State Pharmacopoeia of Ukraine, batch number A0016 and medicine "Aminocaproic acid" in granules (LLC "Zdorov'e", Ukraine, serial number 10317, use before 03/2020); Oxymetazo-line hydrochloride (Om), official reference standard of the State Pharmacopoeia of Ukraine, batch number 00310; Decamethoxine (Dm), official reference standard of the State Pharmacopoeia of Ukraine, series number D0451 and Decamethoxine, pure grade (Institute of Organic Chemistry of the National Academy of Ukraine, Ukraine, serial number C.210917, use before 09/2020); 4-aminobenzoic acid (AA), pure grade (Shanghai Synnad, China, serial number 20170722, use before 07/2020), and aminobenzoic acid official reference standard of the State Pharmacopoeia of Ukraine, batch number A0015; dansyl chloride CAS Number 605-65-2 (Sigma-Aldrich, Germany); sodium tetraborate high grade (Reachem, Russia).
Reverse phase high-performance liquid chro-matography
The analysis was carried out using reversed phase high performance liquid chromatography method on chromatograph Agilent Technologies 1200 Infinity, Agilent Technologies. The method and conditions are described in more detail in [14].
Data analysis was carried out by the regression and statistical methods of analyses with using MS Excel 2010 program by means of Data Analysis add-on according to general pharmacopoeia article Statistical analysis of the results of a chemical experiment [15].
4. Results and discussion
As a result of patent and information search, we paid our attention to the following active pharmaceutical ingredients: decamethoxine (Dm), aminocaproic acid (ACA), 4-aminobenzoic acid (AA), and oxymeta-zoline hydrochloride (Om).
According to scientific data, Dm has a broad spectrum of antimicrobial activity against pathogenic and opportunistic pathogens, including viruses [16].
In our in vitro studies with different test-strains of opportunistic pathogens, Dm in the form of Decasan drug product in comparison with other type cation-active antiseptics, such as 0.05% Chlorhexidine biglu-conate, 0.01% Miramistin, 0.05% bezalkonium chloride, and 0.1% Octenisept, was slightly inferior only to Chlorhexidine bigluconate as for its antimicrobial activity [17].
Moreover, it has been determined that Dm is compatible with different excipients and APIs unlike chlor-hexidine bigluconate, which is incompatible with most excipients and APIs, and its stability depends greatly on the solution pH. At the same time, the results show that the optimal concentration of Dm is 0.02%.
According to scientific data, ACA and AA exhibit antiviral activity against the influenza virus (ACA) and
adenovirus (AA) stopping the life cycle of viruses during their binding, assembling, and exiting the cell [1821].
In our in vitro studies, anti-influenza activity of AA was first detected, and the synergistic effect of AA and ACA was observed, as well as the optimal weight ratio of these APIs, 1:100 (AA/ACA), and their effective concentration in the drug (0.5% for AA, and 5.0% for ACA) were determined [22, 23].
The obtained data demonstrated significant prospects of ACA and AA co-use in the drug composition for etiotropic effect on the influenza virus life cycle inside the mucous cells of the nose and throat.
According to scientific data, Om is an optimal de-congestant and its established effective concentration in the drugs for treatment of rhinorrhea and nasal blockage is 0.05% [24-26].
On the basis of the obtained results, a formulation consisting of 5.0% ACA, 0.5% AA, 0.05% Om, and 0.02% Dm in the form of a nasal spray for prevention and treatment of ARVIs and their negative consequences has been suggested and scientifically substantiated [27].
The second part of our studies refers to the development of the nasal drug technology in the form of a spray. The obtained experimental data demonstrate that the selected APIs (ACA, AA, Om, and Dm) are easily dissolved in water and do not needed any special technological conditions to carried out the process of their dissolution.
Fig. 1 presents a flow chart reflecting the developed technology for obtaining a pharmaceutical composition in the form of a nasal spray for prevention and treatment of ARVIs and influenza.
As seen from Fig.1, the technological process of a nasal spray production consists of seven stages: 1. Preparation of the raw material; 2. Solution preparation; 3. Filtration; 4. Preparation of vials, caps, and valve and spraying device; 5. Dispensing of the solution into containers and their sealing; 6. Labeling and packaging of containers into cartons; 7. Packaging of the finished drug into multipacks.
The third part of our research refers to the study of drug stability for its established shelf life (at normal storage conditions).
The analysis results of nasal drug samples at normal storage conditions (at temperature t=25±2°C and humidity RH=60±5%) are presented in Table 1.
As seen from the data presented in Table 1, the quality parameters of the developed nasal drug for 18 months of storage are within the limits indicated in the product specification file.
5. Conclusions.
The formulation and technology of a new complex nasal drug for prevention and treatment of influenza, ARVIs, and their consequences in the form of a nasal spray have been scientifically substantiated.
The following active pharmaceutical ingredients in nasal spray were theoretically and experimentally substantiated: 5.0% aminocaproic acid, 0.5% 4-amino-benzoic acid, 0.05 % oxymetazoline hydrochloride, and 0.02% decamethoxine.
Fig. 1. Flow chart of the nasal spray production
g n>
OQ
Table 1.
The analysis results of nasal drug samples at normal storage conditions (at temperature t=25±2°C and humidity RH=60±5%)
o £
3
Q)
Quality parameters, requirements, test results*
fi Xj fl o E a> E Description Identification Clarity Color value pH Visible particulate matter Package volume Quantitative content
0» M m Im Clear and Should be clear Should be colorless between 5.5 and 7.0 Should he absent ACA Om Dm AA NaCl
w. colorless solution AC A Om Dm AA 10.0 ml 50.0±5.0 mg/ml 0.50±0.05 mg/ml 0.20±0.02 mg/ml 5.0±0.5 mg/ml 9.0±0.9 mg/ml
Clear and
1 colorless +** + + + clear colorless 6.81±0.05 absent 10.0±0.1 49.8±0.9 0.51±0.01 0.208±0.004 5.2±0.1 9.3±0.3
solution
Clear and
3 colorless solution + + + + clear colorless 6.78±0.05 absent 9.9±0.1 49.6±0.9 0.51±0.01 0.201±0.004 5.1±0.1 9.1±0.3
Clear and
6 colorless solution + + + + clear colorless 6.79±0.05 absent 9.9±0.1 48.5±0.9 0.50±0.01 0.199±0.004 5.2±0.1 9.2±0.3
Clear and
9 colorless solution + + + + clear colorless 6.80±0.05 absent 10.0±0.1 49.1 ±0.9 0.48±0.01 0.198±0.004 5.1±0.1 9.0±0.3
Clear and
12 colorless solution + + + + clear colorless 6.77±0.05 absent 9.9±0.1 48.8±0.9 0.49±0.01 0.199±0.004 5.0±0.1 9.0±0.3
Clear and
18 colorless solution + + + + clear colorless 6.76±0.05 absent 9.9±0.1 48.6±0.9 0.48±0.01 0.196±0.004 5.0±0.1 9.0±0.3
* Note. Repeat count is n=6, acceptance probability is P=95%. ** The "+" sign means that the parameter meets the requirements of the regulatory documentation.
A technology of nasal spray production that consists of the following seven stages has been developed: 1. Preparation of the raw material; 2. Solution preparation; 3. Filtration; 4. Preparation of vials, caps, and valve and spraying device; 5. Dispensing of the concentrate into containers and their sealing; 6. Labeling and packaging of containers into cartons; 7. Packaging of the finished drug into multipacks.
Complex studies were carried out to determine the shelf life of the pharmaceutical composition in the form of a nasal spray (at normal storage conditions), which showed that the quality parameters of the developed nasal composition during 18 months of storage are within the limits laid down in the regulatory documentation.
Conflict of interests
There are no conflicts of interests.
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SELECTION OF excipients AND ANALYSIS OF CRITICAL PARAMETERS OF THE TECHNOLOGICAL PROCESS OF PRODUCTION OF CAPSULES WITH ANTHELMINTIC
ACTIVITY
Semchenko K.
PhD of Pharmacy, Associate Professor of Department of Pharmaceutical Technology of Drugs, NUPh
Vyshnevska L.
Doctor of Pharmacy, Professor, Head of Department of Pharmaceutical Technology of Drugs, NUPh
Abstract
Pharmacotherapy of helminthiasis involves three main stages of treatment: preparatory (desensitization of the body), etiotropic treatment (destruction of the pathogen) and elimination of the consequences and complications of the disease.
After the helminthiasis, the patient needs to restore the normal functioning of the immune system, gastrointestinal tract, metabolism and so on. Therefore, an important task is to develop a drug for this stage of pharmacotherapy of helminthiasis.
Herbal medicines are best suited for the recovery of the patient's body after an invasive disease.
To meet the needs of the population in phytomedicine for the 3rd stage of treatment of helminthiasis of the digestive system, we have proposed a drug based on a complex of extracts of medicinal plants. The composition has anthelmintic, antiparasitic, anti-inflammatory, antibacterial, antiseptic, hepatoprotective, nephroprotective, laxative, antiallergic, antispasmodic, analgesic, sedative activity and can be used to treat helminthiasis of the digestive system.
Keywords: helminthiasis, capsules, technology, plant raw material
Introduction.
Capsules (Latin "Capsula" - literally "case, box") are a solid dosage form with a soft or hard shell, containing a dose of one or more active substances [].
Extensive possibilities of prescribing drugs in the form of capsules have led to an increase in their production and consumption. Thus, abroad, among the dosed drugs of industrial production, capsules take the 3rd place after tablets and ampoules [1, 2].
Capsules show a fairly high level of bioavailabil-ity (on average, the therapeutic effect of the content is manifested in 5-10 min. after administration) and have a number of advantages: good appearance; easiness of usage (easy to swallow); gelatin shell is impermeable to volatile liquids, gases, oxygen (which is very important for the storage of products that are easily oxidized), it is convenient to place in a capsule of dyes and substances that have an unpleasant taste and odor. Also, the capsules are very promising for use in pediatrics and gerontology [1, 3, 4].
As in the technology of tablets, in the production of capsules an important parameter is the flowability of
the capsule mass, which ensures the accuracy of dosing and continuity of the capsule filling machine [3, 4].
It is known that to ensure fluidity the sliding (antifriction) substances are added, and to improve the ejection of the compressed mass from the dosing disks lubricants are introduced to the capsule mass, such as magnesium stearate.
The purpose of this work is the research on the selection of excipients to ensure the proper technological characteristics of the capsule mass.
Materials and methods. The research objects were the concentrate of the dry extract of medicinal plants (tansy flower dry extract, wormwood herb dry extract, centaury herb dry extract, wormwood flower dry extract, buckthorn bark dry extract, elecampane rhizomes with roots dry extract, dandelion herb with roots dry extract, chamomile flowers dry extract, ginger rhizome dry extract, valerian root dry extract), lactose, aerosol, talc, magnesium stearate and the model samples of the capsule mass on their basis.
Studies on determination of the composition and ratio of active ingredients are described earlier [5, 6].
