RU2800117C1 - Artificial nasal secret - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: treatment and prevention of diseases of the upper respiratory tract. Artificial nasal secretion for correction of the microflora of the nasal mucosa contains sodium hyaluronate (powder) 1.0 mg per 1 ml, lysozyme hydrochloride (powder) 2.5 mg per 1 ml, lactoferrin (powder) 5.0 mg per 1 ml, lyophilisate probiotic microorganisms Streptococcus salivarius K12 not less than 10⁷ CFU per 1 ml.

EFFECT: correction of the microflora of the mucous membrane of the nasal cavity and nasopharynx, increase of local immunity of the mucous membrane of the upper respiratory tract.

2 cl, 3 ex

Description

The invention relates to medicine, namely to combined preparations, and can be used to prevent the development of acute and exacerbate chronic infectious-inflammatory, allergic, subatrophic diseases of the upper respiratory tract. The pharmaceutical composition imitates the composition of the natural secret of the nasal cavity of a healthy person and can be enriched with probiotic microorganisms characteristic of normal oropharyngeal and nasopharyngeal microbiocenosis.

The pharmaceutical composition is preferably, but not necessarily, in the form of a nasal spray.

Maintaining the quantitative and species composition of the human microflora is one of the important health factors. Numerous studies by domestic and foreign authors have shown that a person's stay in an environment with altered parameters, exposure to exogenous and endogenous stress factors leads to the development of the so-called colonization resistance disorder syndrome, which manifests itself in a decrease in the body's natural immune defense and an increase in the number of representatives of opportunistic microflora, which can lead to the development of acute inflammatory diseases and exacerbate chronic inflammatory processes.

It is known that the secretion of the mucous membrane of the nasal cavity contains a number of non-specific and specific protective factors that contribute to the neutralization and removal of microorganisms. The former include glycoproteins, lysozyme, lactoferrin, complement, protease inhibitors, secretory glucosidases, interferon (Kunelskaya N.L, Artemyeva-Karelova A.V., 2013; GD Raphael ¹ E.V. Jeney, 1989).

Specific factors are represented by immunoglobulins that play the role of protection against microorganisms. Due to the activity of those and other factors, viruses, toxins are neutralized, bacteria are lysed. (Kunelskaya N.L., Artemyeva-Karelova A.V., 2013).

The microflora of the nasal cavity and paranasal sinuses of a healthy adult is represented by the main types: actinobacteria, firmicutes, proteobacteria. A number of researchers assign a certain role to the type Bacteroidetes. Most of the microorganisms that make up the sinonasal microbiome are in a state of constant direct or indirect syntropy/competition for ecological niches. This competition can be carried out both between commensals and potential pathogens, and to some extent between microbes and the host itself (Lopatin A.S., Azizov I.S., Kozlov R.S. 2021). It is known that some strains of Corynebacterium pseudodiphtheriticum and C. accolens can inhibit the growth of Staphylococcus aureus. (Lopatin A.S., Azizov I.S., Kozlov R.S. 2021) Competitive relations between C. pseudodiphtheriticum and S. aureus- were clearly demonstrated in studies involving humans in altered environmental conditions (Kiryukhina N.V. et al., 2016).

It is widely known that carriage of S. aureus in the nasal cavity is a risk factor for the development of infectious and inflammatory diseases of the skin, soft tissues, bacteremia (von Eiff C., Becker K., Machka K. et al., 2003; Datta R., Huang S.S., 2008), and in most cases autoinfection plays an etiological role in the development of the infectious process (Huang S.S., Platt R., 2003 ; Wertheim H.F., Vos M.C., Ott A. et al., 2004; Wertheim H.F., Melles D.C., Vos M.C. et al., 2005). The currently accepted methods of eradication of opportunistic microflora of the nasal mucosa are mainly associated with the use of antiseptic and antibacterial agents (Wertheim H.F., Melles D.C., Vos M.C. et al., 2005). Thus, the use of the local antibiotic mupirocin in the form of an intranasal ointment is considered the “gold standard” for the treatment of S. aureus bacteria in the nasal cavity (van Rijen M., Bonten M, Wenzel R. et al., 2008; McConeghy K.W., Mikolich D.J., LaPlante K.L., 2009). Nevertheless, such tactics of exposure can lead to dysbiotic shifts in the host organism, changes in drug sensitivity and the formation of aggression factors in representatives of the microflora and, thus, provoke an infectious process (Zaloguev S.N., Viktorov A.N., Startseva N.D. et al., 1980; Ilyin V.K., Volozhin A.I., Vikha G.V., 2005). At the same time, the literature presents data showing that the use of mupirocin as an antibacterial agent can contribute to an increase in antibiotic resistance in strains of Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) (Patel J.B., Gorwitz R.J., Jernigan J.A., 2009; Caffrey A.R., Quilliam B.J., LaPlante K. L., 2010). It is also known that after the use of mupirocin, mucosal recolonization occurs within several months (Doebbeling B.N., Reagan D.R., Pfaller M.A. et al., 1994). These circumstances dictate the search for alternative ways to prevent the formation of carriage and eradication of opportunistic microflora of the nasal cavity and pharynx, in particular with the help of probiotic strains. (Tagg JR, 2004; Burton JP et al., 2006, Kiryukhina NV et al., 2016).

The complex multicomponent composition of the nasal secretion of a healthy person cannot be exactly reproduced artificially. The composition of the proposed drug includes the main agents that provide non-specific immune protection of the nasal mucosa: lysozyme, lactoferrin, hyaluronic acid. This base composition can be enriched with probiotic microorganisms.

All three components proposed for inclusion in the composition of the artificial nasal secret are used in the formulations of various preparations for the oropharynx and nasal cavity.

Lysozyme is an antibacterial agent, an enzyme of the hydrolase class that destroys bacterial cell walls by hydrolysis of peptidoglycan (murein). It is used as a part of tablet preparations for the oral cavity (Lizobakt, Geksaliz) and some sprays for the nasal cavity that are not registered in the territory of the Russian Federation.

Known combined preparation Geksaliz, containing as antimicrobial components - biclotymol 5 mg, lysozyme 5 mg and enoxolone 5 mg. Mistake! Invalid hyperlink object.

Known drug Lizobakt containing as antimicrobial components of lysozyme hydrochloride 20.00 mg, pyridoxine hydrochloride 10.00 mg.https://www.rlsnet.ru/tn_index_id_24402.htm.

Known drug Zyme nasal spray (Crab Sinergy, Italy) containing lysozyme. https://www.emag.bg/sprej-za-nosa-zyme-hipertonichen-raztvor-s-evkalipt-30ml-10/pd/DZ37H3MBM/

Known product for washing the nasal cavity Nasalzyme (H2Ocean, USA), containing lysozyme. https://h2ocean.com/product/nasalzyme-max-natural-sea-salt-nasal-care-2-fl-oz/.

Lactoferrin is a polyfunctional protein from the transferrin family. Lactoferrin is a globular glycoprotein with a molecular weight of about 80 kDa and is widely present in various secretory fluids such as milk, saliva, tears, and nasal secretions. The predominant localization of lactoferrin in the secretions of secretory cells definitely indicates that the main function of this molecule is to protect the entry gate for infection penetrating from the outside. Subsequently, it was found that neutrophil lactoferrin is effectively involved in protecting the body from intestinal infections. The antimicrobial properties of lactoferrin have been well studied in in vitro and in vivo experiments. (I.B. Brodsky, V.M. Bondarenko, 2013)

Lactoferrin is part of a number of preparations for the oropharynx and nasal cavity.

Known drug Sesderma Lactoferrin Spray Nasal (Sesderma, Spain), containing lactoferrin https://www.sesderma.com/gb_en/lactyferrin-defense-spray-nasal-40006215.html.

Known drug Lattoferrina 200 Immuno Spray Nasale (Promopharma, Italy), containing lactoferrin https://www.promopharma.it/it/lattoferrina-200-immuno-spray-naso/.

Known drug Cavisept (Bioshield ltd, Bulgaria) containing lactoferrin https://bioshield-bg.com/en/product/cavisept-spray-for-nose/.

Hyaluronic acid is a non-sulfonated glycosaminoglycan, which is part of the connective, epithelial and nervous tissues. It is one of the main components of the extracellular matrix and is found in many biological fluids. Hyaluronic acid is a natural polymer, present everywhere in the human body, has a lubricating, moisturizing property and the necessary viscosity, which contributes to the creation of a protective film in the nasal cavity due to its high ability to retain moisture, thus providing uniform long-term hydration of the nasal mucosa and protecting the mucous membrane from the effects of adverse environmental factors.

Hyaluronic acid is included in some nasal sprays, providing moisture to the mucous membrane. For example: the drug Olifrin is known, containing in 1 ml: anhydrous glycerol - 62.5 mg, sodium benzoate - 5.0 mg, sodium hyaluronate - 1.9 mg, polysorbate 80 (tween 80) - 1.9 mg, macrogol glycerylhydroxystearate 40 - 0.6 mg, lemon essential oil - 0.6 mg, racemic alpha-tocopherol acetate - 0, 1 mg, water for injection - up to 1 ml. https://olyfrin.ru/en.

It is known that in the natural nasal secretion of a healthy person, protective microflora is found (for example, non-pathogenic staphylococci, streptococci, Neisseria, non-pathogenic corynebacteria), which may have antagonistic activity against opportunistic representatives of the microflora, in particular, S. aureus.

Thus, the artificial nasal secretion can be enriched with strains of probiotic microorganisms. As such a strain, Streptococcus salivarius K12 can be proposed, which is widely used in preparations for the correction of nasopharyngeal and oral microflora (J.P. Burton et al, 2010, Tagg J.R, Hale J.D., Wescombe P.A. 2012). This strain has long been known on the international market and is the most studied probiotic used to correct the microflora of the upper respiratory tract, both in adult and pediatric practice. Streptococcus salivarius K12 is included in the American Type Culture Collection (ATCC BAA 1024) and the German Collection of Microorganisms and Cell Cultures (DSM 13084); the conducted examination showed the absence of a negative effect on the human body. The Food and Drug Administration (FDA) has given the product GRAS (Generally Regarded As Safe) status; GRAS Notice No. GRN 000591, 2016.

The described positive effects of Streptococcus salivarius K12 are characterized by: a decrease in the incidence of acute tonsillopharyngitis in children (Di Pierro F., Colombo M., Giuliani M., et al. 2016, Di Pierro F., Risso P., Poggi E., et al, 2018), a decrease in the incidence of acute otitis media in children (Di Pierro F., Di Pasquale D. , Di Cicco M, 2012), prevention of the development of oral candidiasis (Ishijima S.A., Hayama K., Burton J.P., et al, 2012), etc.

Thus, the known drug "Baktoblis" (MEDICO DOMUS (Serbia), for: BLUESTONE PHARMA), in tablets and powder, containing Streptococcus salivarius K12≥1×10 ⁹ CFU

Of the preparations used as nasal sprays and containing other probiotic microorganisms, the ProbioRinse™ preparation containing Lactococcus lactis W136 is known https://probiorinse.com/

LiviaOne Probiotics Nasal Spray is also known, containing Lactobacillus acidofilus, Lacrobacillus rhamnosus, Streptococcus thermophiles https://store.liviaglobal.com/products/probiotic-nasal-spray-loz

Known Rhinogermina spray containing Streptococcus salivarius 24SMBc, Streptococcus oralis 89a https://www.italy-apteka.ru/goods/rinogermina-spray-nasale-10ml-8816/

The task to be solved by the claimed invention is the creation of a pharmaceutical composition for the treatment and prevention of diseases of the upper respiratory tract, in particular the nasal cavity, nasopharynx and oropharynx, containing a combination of active substances and a probiotic component, exhibiting a synergistic effect in combination with each other, aimed at improving the protective properties of the mucous membrane of the nasal cavity and nasopharynx in relation to aggressive environmental factors, bacterial and viral load.

The technical result is the correction of the microflora of the mucous membrane of the nasal cavity and nasopharynx.

The use of the proposed tool provides an increase in local immunity of the mucous membrane of the upper respiratory tract by increasing the number of protective enzymes, moisturizing, reducing the activity of opportunistic microflora.

The technical result is achieved by the fact that the pharmaceutical composition contains lysozyme, lactoferrin, hyaluronic acid, as well as a lyophilizate of the probiotic strain Streptococcus salivarius K12 - at least 10 ⁷ CFU per 1 ml

In this case, a 0.9% isotonic NaCl solution is used as a pharmaceutically acceptable carrier, the drug can be made in the form of a nasal lavage solution, nasal drops, nasal spray.

The pharmaceutical composition includes the following components:

- hyaluronic acid (sodium hyaluronate, powder) 1.0 mg per 1 ml,

- lysozyme hydrochloride (powder) 2.5 mg per 1 ml

- lactoferrin (powder) 5.0 mg per 1 ml

- lyophilizate of probiotic microorganisms Streptococcus salivarius K12 - not less than 10 ⁷ CFU per 1 ml

Before direct use, sodium hyaluronate in powder form, lactoferrin in powder form, lysozyme in powder form, lyophilisate of probiotic bacteria Streptococcus salivarius K12 are dissolved in NaCl 0.9% in a sterile glass bottle, 15 ml in volume, with a spray or dropper nozzle. The prepared pharmaceutical composition can be used in the form of a spray or nasal drops.

The shelf life of the prepared pharmaceutical composition is 7 days in a refrigerator at a temperature of +4 - +6 C.

The scheme of application of the finished pharmaceutical composition:

2 injections in both halves of the nose 3 r / day from 2 to 4 weeks. Shake the solution thoroughly before use.

The examples included in the present description do not limit the claimed invention and are given only for the purpose of demonstrating the effectiveness of a pharmaceutical composition and a drug based on it for the treatment and prevention of diseases of the upper respiratory tract and confirming the achievement of a technical result. These examples are one of the many experimental data obtained by the inventors, for a pharmaceutical composition and medicinal product that are within the scope of the claims.

Clinical studies of the effectiveness of a medicinal product containing a pharmaceutical composition.

Clinical studies of the drug were carried out on volunteers after signing informed consent.

Clinical example No. 1.

A 27-year-old man with long-term complaints of dryness in the nasal cavity, bleeding of the nasal cavity, difficulty in nasal breathing through the right half of the nose, crusts in the nasal cavity. In the anamnesis - deviated septum of the nose, smoking. From surgical treatment of the curvature of the nasal septum refrains. She has a history of chronic contamination of the nasal cavity with S. aureus, a course of topical application of mupirocin in the form of an ointment with a temporary effect.

Objective status before the use of the drug: with anterior rhinoscopy, a sharp curvature of the nasal septum to the right is determined, the mucous membrane of the nasal cavity with subatrophic changes, abundant crusts in the right half of the nose, contact bleeding of the mucous membrane of the nasal cavity, the inferior turbinates are pasty, nasal breathing is moderately difficult through the right half of the nose.

Bacteriological culture from the nasal cavity is determined by S. aureus 10 ⁶ CFU / ml.

The patient used the pharmaceutical composition in the form of a spray, 2-3 injections in both halves of the nose 3 times a day for 2 weeks. After using the drug, the patient noted a moderate improvement in nasal breathing, a significant decrease in dryness and bleeding of the nasal cavity.

Objective status after the use of the drug: anterior rhinoscopy reveals a sharp curvature of the nasal septum to the right, the mucous membrane of the nasal cavity is pink, there is a crust in the Kisselbach area on the right, the inferior turbinates are pasty, nasal breathing is moderately difficult through the right half of the nose.

During bacteriological culture from the nasal cavity after the use of the drug, the following were determined: S. aureus 10 ³ CFU/ml, Corynebacterium spp. 10 ⁴ CFU/ml, Str. salivarius 10 ³ cfu/ml

2 weeks after the use of the drug, the positive effect of the drug was preserved, with a control culture from the nasal cavity, S. aureus 10 ³ CFU/ml, Corynebacterium spp. 10 ⁴ CFU/ml, Str. salivarius 10 ² CFU/ml, which indicates a possible partial "displacement" of S. aureus by the probiotic strain.

Clinical case #2

A 52-year-old man complains of prolonged expectoration of discharge from the nasopharynx, viscous discharge from the nose of a periodic nature. History - chronic rhinosinusitis with rare exacerbations, chronic catarrhal laryngitis, GERD. Long history of smoking.

MSCT of the paranasal sinuses - chronic bilateral parietal-hyperplastic sinusitis, periapical cysts 1.5; 2.6

Objective status before the use of the drug: with anterior rhinoscopy, an S-shaped curvature of the nasal septum is determined, the mucous membrane of the nasal cavity is pale, abundant viscous mucous secretions are determined in the common nasal passages, the lower nasal conchas are hypertrophied, nasal breathing is difficult.

S. aureus 10 ⁵ CFU/ml, S. epidermidis 10 ³ CFU/ml was determined during bacteriological culture from the nasal cavity before the drug application.

The patient used the pharmaceutical composition in the form of a spray, 2-3 injections in both halves of the nose 3 times a day for 2 weeks.

The patient was also given recommendations on the need for planned surgical treatment and consultation with a dentist.

After using the drug, the patient noted an improvement in nasal breathing, a decrease in viscous discharge from the nasal cavity, and the flow of discharge along the back wall also decreased. Objective status after the use of the drug: with anterior rhinoscopy, an S-shaped curvature of the nasal septum is determined, the mucous membrane of the nasal cavity is pale, scanty mucous secretions are determined in the common nasal passages, the inferior turbinates are hypertrophied, nasal breathing is moderately difficult.

Bacteriological inoculation from the nasal cavity after the use of the drug was determined by S. aureus 10 ³ CFU/ml, S. epidermidis 10 ⁶ CFU/ml.

2 weeks after the use of the drug, the positive effect of the pharmaceutical composition remained, with the control culture from the nasal cavity, S. aureus 10 ² CFU / ml, S. epidermidis 10 ² CFU / ml were determined, which indicates a positive delayed effect of the use of the pharmaceutical composition.

Clinical case #3

A 21-year-old man complains of difficulty in nasal breathing, nasal discharge of a mucous nature. She has a history of chronic tonsillitis with frequent exacerbations, adenoid vegetations of the 1st degree, hay fever, allergy to house dust. Observed by an allergist, courses of topical nasal corticosteroids with little improvement.

Objective status before the use of the drug: with anterior rhinoscopy, the nasal septum is not significantly curved, the mucous membrane of the nasal cavity is pale pink, pasty, abundant mucous discharge in the nasal passages on both sides, the lower nasal conchas are edematous. When viewed with an endoscope in the vault of the nasopharynx, adenoid vegetations of the 1st degree are determined, covered with a cloudy discharge, the mouths of the auditory tubes are contoured.

S. aureus 10 ⁴ CFU/ml, Enterobacter spp. 10 ² cfu/ml.

The patient used the pharmaceutical composition in the form of a spray, 2-3 injections in both halves of the nose 3 times a day for 2 weeks.

After using the drug, the patient noted a moderate improvement in nasal breathing, a significant reduction in mucous secretions. Objective status after the use of the drug: the mucous membrane of the nasal cavity is pale pink, pasty, there is no discharge, the lower turbinates are edematous. When viewed with an endoscope in the vault of the nasopharynx, adenoid vegetations of the 1st degree are determined, there is no discharge, the mouths of the auditory tubes are contoured.

Bacteriological culture from the nasal cavity after the use of the drug was determined by S. aureus 10 ¹ CFU/ml, Str. salivarius 10 ⁴ cfu/ml.

2 weeks after the use of the drug, the positive effect persisted, with a control culture from the nasal cavity, S. aureus 10 ² CFU/ml, S. epidermidis 10 ⁴ CFU/ml, Str. salivarius 10 ³ CFU/ml, which indicates a delayed positive effect of the pharmaceutical composition.

Claims (6)

1. An artificial nasal secret for correcting the microflora of the nasal mucosa, consisting of a combination of active substances, characterized in that it contains - sodium hyaluronate, powder 1.0 mg per 1 ml, - lysozyme hydrochloride, powder 2.5 mg per 1 ml, - lactoferrin, powder 5.0 mg per 1 ml, - lyophilizate of probiotic microorganisms Streptococcus salivarius K12, not less than 10 ⁷ CFU per 1 ml. 2. An artificial nasal secret according to claim 1, characterized in that it is made in the form of a solution for washing the nose, or nasal drops, or a nasal spray.