WO2023083850A1

WO2023083850A1 - Medicament for inhalation or breathing, and inhaler or breathing device comprising same

Info

Publication number: WO2023083850A1
Application number: PCT/EP2022/081234
Authority: WO
Inventors: Flemming Licht
Original assignee: Unigroup Aps
Priority date: 2021-11-10
Filing date: 2022-11-09
Publication date: 2023-05-19
Also published as: DK202170549A1; DK202370440A1

Abstract

An ethyl lactate serves as an active agent for use as a medicament for inhalation or breathing. The medicament is useful in the treatment of pulmonary diseases, the prophylactic treatment of pulmonary diseases, and/or the symptomatic treatment of pulmonary diseases.

Description

Medicament for inhalation or breathing, and inhaler or breathing device comprising same

The present invention concerns new medicaments for various treatments of various pulmonary diseases.

In the context of the present invention the term "pulmonary disease"' covers those types of diseases that affect the lungs and other parts of the respiratory system, thus the entire respiratory tract that are involved in breathing. These organs include the nose, throat, larynx, trachea, bronchi, and lungs. Pulmonary diseases may be caused by infection, by smoking tobacco, or by breathing in secondhand tobacco smoke, radon, asbestos, or other forms of air pollution, all of which makes the subject vulnerable to infections and inflammatory conditions. Further pulmonary diseases can i.e. be related to infectious diseases related to bacterial, fungal and yeast infections, and viruses. Patients on mechanical ventilation, long term hospitalized patients, and patients having laryngectomy, or tracheostomy surgeries are as well in high risk of developing pulmonary diseases.

Ethyl lactate is the ethyl ester of lactic acid and has the formula CH₃CH (OH) CO₂CH₂CH₃.

Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 536 reports uses of ethyl lactate as a solvent and in flavoring.

Snyder, R. (ed.) . Ethel Browning's Toxicity and Metabolism of Industrial Solvents. Second Edition. Volume 3 Alcohols and Esters. New York, NY: Elsevier, 1992., p. 348 reports use of ethyl lactate to reduce the alkalinity of cosmetic formulations . Datta R; Hydroxycarboxylic Acids . Kirk-Othmer Encyclopedia of Chemical Technology ( 1999-2015 ) . John Wiley & Sons , Inc . Online Posting Date : December 17 , 2004 reports that ethyl lactate is the active ingredient in many anti-acne preparations , thus used externally .

Ethyl lactate is also known as an ingredient in products for topical treatment of nail fungus .

It is a main aspect of the present invention to provide an alternative medicament for treatment and prevention of symptoms , conditions and diseases in the respiratory tract .

It is a further aspect of the present invention to provide a safe and inexpensive medicament for treatment and prevention of symptoms , conditions and diseases in the respiratory tract .

It is a further aspect of the present invention to provide an inhalable or breathable medicament for treatment and prevention of symptoms , conditions and diseases in the respiratory tract .

The above aspects and further aspects are solved by the present invention by the provision of an ethyl lactate for use as an active agent in a medicament for inhalation or breathing .

Ethyl lactate is generally considered non-toxic by the oral and inhalation route . However the Hazardous Substances Data Bank (HSDB) does report that ethyl lactate is irritating to the rabbit eye and guinea pig skin ( intradermal injections ) , and that it is a central nervous system depressant and lethal to animals in high concentrations , causing respiratory paralysis .

The serious breathing problems in patients suffering from Covid-10 and the long after-effects in many patient s having recovered from Covid-19 however has created an increasing demand for new alternative medicaments for treating symptoms , conditions and diseases in the respiratory tract , and the present invention now proposes ethyl lactate as the active agent of a medicament for inhalation or breathing .

As explained above ethyl lactate is added to many compositions due to its good properties as a solvent and is used in medicaments for topical administration to parts of the skin . However no reports has been found of the use of ethyl lactate as the active agent in a medicament for inhalation or breathing .

During a pandemic with impact on the respiratory tract , such as e . g . the Covid- 19 pandemic and H1N1 pandemic, or during an epidemic with impact on the respiratory tract , such as the infection with avian influenza vira, severe acute respiratory syndrome ( SARS ) , or Middle East Respiratory Syndrome (MERS ) , an acute need arises for medicaments for treating the symptoms , the conditions and/or the diseases , and to help recovered and recovering patients during convalescence . Thus fast manufacturing of huge amounts of helpful medicament s is of the essence . In such sense ethyl lactate is easy and fast to produce in large scale , if not already available , and medical grade ethyl lactate can be produced from low cost , ready available components .

Inhalation of acid vapors and mists can cause nose , throat , and laryngeal burning, and irritation, pain and inflammation, coughing, sneez ing, choking sensation, shortness of breath, hoarseness , laryngeal spasms , upper respiratory tract edema, bronchial constriction, bronchitis , chest pains , as well has headache , and palpitations . Inhalation of high concentrations of acids can result in corrosive burns , necrosis of bronchial epithelium, constriction of the larynx and bronchi , nasospetal perforation, glottal closure , occur, particularly i f exposure is prolonged . Acids can be fatal if inhaled even in moderate concentrations . Advantageously, in the medicament of the present invention the ethyl lactate acts as the act ive agent as a penetration enhancer of the tissue . After inhalation ethyl lactate hydrolyses and transforms into lactic acid and alcohol . The hydrolysis takes places gradually as contact with water becomes possible . Thereby the tissue of the respiratory tract is not subjected to immediate and unsafe high concentrations of acid . In contrast the lactic acid is slowly released from the ethyl lactate during hydrolysis , whereby only microorgani sms and biofilms are attacked, and tissue only subjected to low concentrations of lactic acid . The by-product of the hydrolysis is ethanol , which may contribute to a physical disinfecting of tissue , or simply be exhaled .

So in contrast to conventional medicaments for treatment of diseases in the respiratory tract the intended beneficial action according to the present invention is achieved through physical means , and not by a pharmacological , immunological or metabolic means . The ethyl lactate is immediately absorbed and works by depriving microorganisms , such as bacteria , vira, yeast and fungi existing and growing in the respiratory system of essential survival conditions . Due to the small molecular structure of ethyl lactate , ethyl lactate is easily absorbed into tissue . The low pH level arising from the hydrolysis when ethyl lactate comes in contact with water, kills or inactivates formation of the microorganisms , such as bacteria, vira, yeast and fungi , which then are physically prevented from growth in the respiratory system and thus also instantaneously prevent further biofilm formation . Further the respiratory system is treated and protected from dryness , including but not limited to the pharynx and/or the larynx . The moisturi z ing can be further supported if a hygroscopic acid is added .

So to summari ze : When inhaled ethyl lactate contact s and penetrates the tissue of the respiratory system it comes in contact with body fluid having a water content . Then hydrolysis occurs gradually whereby lactic acid and ethanol are released from the inhaled bolus of ethyl lactate . The effect is a lowering of the pH level in the respiratory system and associated tissue which deprives the microorganisms of vital survivability due to the lack of required essential survival conditions . Beneficial growth conditions for the microorganisms are taken away in a very simple and efficient manner . An example of a beneficial effects is that mucus production, that can block the air passage and form micro-aerophilic or even anaerobic micro-environments and biofilms , as often seen in viral infections , can be reduced substantially or even prevented . Further the respiratory system is treated and protected from dryness .

The ethyl lactate for use as a medicament for inhalation or breathing according to the present invention is thus particularly suited for use in the treatment of pulmonary diseases , or for use in the prophylactic treatment of pulmonary diseases , or for use in the symptomatic treatment of pulmonary diseases , or for the use in said combined treatments of pulmonary diseases .

More particular the medicament consisting of , or including, ethyl lactate according to the present invention may be used in the treatment of symptoms , conditions and/or diseases in the trachea, bronchi , bronchioles , alveoli , pleurae , lungs and pleural cavity, larynx, pharynx, as well as nasal cavities , nostrils and oral cavities .

Such conditions and diseases may be selected from the group including common cold, influenza, pneumonia, pulmonary edema, pulmonary emphysema, Interstitial Lung Disease ( ILD ) , pharyngitis , asthma Respiratory Tract infection, Plureal cavity diseases , CORD , viral infections , yeast and fungi infections , and bacterial infections , including bacterial pneumonia and tuberculosis, acute asthma, emphysema (infant) Respiratory distress syndrome, Chronic inflammation, Cystic Fibrosis, Pneumoconiosis, Radiation induced lung injury, Parenchymal lung disease and Acute respiratory distress syndrome (ARDS) , including Severe acute respiratory syndrome (SARS) , Middle East Respiratory Syndrome (MERS) , Covid-19, H1N1, avian influenza viruses, and other strains, as well as symptoms and conditions associated therewith, including but not limited to dryness, cough and mucus. This list is however not exhaustive.

Pulmonary diseases include asthma, Chronic bronchitis, chronic obstructive pulmonary disease (COPD) , pulmonary fibrosis, pneumonia, Emphysema, and lung cancer. Also called lung disorder and respiratory disease. This list of diseases gives examples and should not be construed as limiting the scope of the present invention of conditions, illnesses, symptoms, diseases, etc. associated with the respiratory tract system for which the present invention can be used.

To better facilitate the absorption by the respiratory tract tissue, the medicament may formulated as a liquid, vapor, mist, gas, aerosol, powder, solution or dispersion, to be inhaled by an inhaler or a breathing device. Within the context of the present invention the term "inhaler or breathing device"' means any device suitable for transferring the medicament to a subject by the subject inhaling or breathing the medicament. Inhaler or breathing devices include the pressurized metered dose inhaler (pMDI) , and the soft mist inhaler (SMI) . Other ways to inhale the medicament can e.g. be using a mask, such as a Hudson mask-like device, or a breath-activated device. Further the inhaler or breathing device and/or formulation including the medicament can be incorporated in devices used for patients having performed laryngectomy or tracheostomy, for example but not limited to, Heat and Moisture Exchangers (HME's) tubes or voice prosthesis, for example but not limited to filters in these. Other examples of inhaler or breathing devices includes but are not limited to E-cigarettes , aerosol devices , atomi zers , and nebuli zers . Devices suited for instilling or otherwise delivering the medicament to the respiratory tract are also contemplated covered within the term " inhaler or breathing device"' . Examples of such alternative devices includes a dropper, a pipette , or a dispenser . The medicament can also be delivered for inhalation or breathing as fine droplets , mist , sprays , powder, and aerosols . The medicament can also be administered by e . g . an intranasal pump dispenser or squeeze bottle .

The ethyl lactate for use as a medicament for inhalation or breathing according to the present invention may advantageously be used in combination with one or more acids selected from the group comprising hypochlorous acid, hydrochloric acid, acetic acid, lactic acid, formic acid, citric acid, gluconic acid, oxalic acid, tartaric acid, ascorbic acid, hydrogen halides and their solutions , nitric acid, phosphoric acid, dichloroacetic acid, trichloroacetic acid, polystyrene sulfonic acid, ethanesulfonic acid, and salicylic acid . This list of acids gives examples and should not be construed as exhaustive .

When an ester is exposed to water it hydrolysis fol lowing the below equation :

Ester + Water < - > Acid + alcohol . whereby acid and alcohol is produced . The addition of just a little amount of acid to the medicament forces the reaction to the left to help avoiding hydrolysis during storage in the event of entry of water to the ester . Thus just a l ittle amount of acid preserves the activity of the ester until hydrolysis upon contact with water from bodily moisture . As an example, as little as less than 0.1 wt% of acid based on the total weight of the composition is believed needed to prevent unintended hydrolysis when the acid is acetic acid or hypochlorous acid.

When ethyl acetate is combined with other acids than acetic acid or hypochlorous acid higher acid concentrations may be preferred, preferably a higher acid concentration than 0.1 wt% based on the total weight of the medicament, such as at least 0.05 wt% of acid based on the total weight of the medicament, or at least 2.50 wt% of acid based on the total weight of the medicament. For most medicaments an acid concentration between 0.1 - 5.0 wt% of the total weight of the medicament would be preferred, however acid concentrations of at least 5.0 wt%, and even at least 10.0 wt% of acid based on the total weight of the medicament can be used. A concentration of 1 - 2 wt% ethyl acetate may suffice.

A preferred pharmaceutical active concentration of ethyl lactate is expected to be between 0.5 - 100 wt% based on the total weight of the medicament, preferably 10 - 100 wt% based on the total weight of the medicament, more preferred 15 - 100 wt% based on the total weight of the medicament, and even more preferred 15 - 99.5 wt% based on the total weight of the medicament .

The rest of the total weight of the medicament may be an alcohol, preferably ethanol.

Water may in some embodiments be present in an amount of less than 10 wt% of the total weight of the medicament, preferably less than 8 wt% of the total weight of the medicament, more preferred less than 5 wt% of the total weight of the medicament. In some embodiments the medicament is free of water . The present invention further relates to an inhaler or breathing device comprising a medicament as described above for inhalation, breathing or aspiration, wherein ethyl lactate is an active ingredient used as a medicament for inhalation or administered during breathing .

An inhaler or breathing device , or parts of such, can e . g . be masks , tracheostomy tubes or other parts of a breathing aid means in connection with a tracheostomy, adaptors for endotracheal tubes , or parts of such devices involved in ventilation, such as filters , pipes , or coupling components .

The invention is also useful in e . g . breathing masks and in connection with voice prosthesis , etc . Such means and devices need to be replaced frequently to avoid biofilm coloni zation and growth on surfaces , which biofilm may cause severe or at least unpleasant conditions in the respiratory system . In particular voice prothesis has a very dominant problem with formation of biofilms , (Bio film Growth Causes Damage to Silicone Voice Prostheses in Patients after Surgical Treatment of Locally Advanced Laryngeal Cancer by Jakub Spalek, Piotr Deptula, Mateus z Ciesluk, Agnieszka Strzelecka, Dawid Lysik, Joanna Mystkowska, Tamara Daniluk, Grzegorz Krol , Stanislaw Gozdz, Robert Bucki , Bonita Durnas and Slawomir Okla . Pathogens 2020 , 9 ( 10 ) , 793 ) .

When the medicament according to the present invention is administered it has a beneficial growth reducing ef fect on the inhaler devices , breathing devices or voice prosthesis in the prevention or at least reducing formation of biofilm on surfaces of said devices , thereby minimi z ing the need for conventional frequent replacement .

The inhaler or breathing devices may in the alternative have a protective coating with the medicament of the present invention . Preferably the medicament for inhalation or breathing according can be applied to at least a surface part of an inhaler or breathing device .

Although the medicament according to the invention is described above as for inhalation or breathing, it is emphasi zed that a combined used including both inhalation and breathing is within the scope of the present invention .

Claims

1. An ethyl lactate as an active agent for use as a medicament for inhalation or breathing.

2. An ethyl lactate for use as a medicament for inhalation or breathing according to claim 1 in the treatment of pulmonary diseases, or the prophylactic treatment of pulmonary diseases, or the symptomatic treatment of pulmonary diseases, or said treatments of pulmonary diseases in combination.

3. An ethyl lactate for use as a medicament for inhalation or breathing according to any of claims 1 or 2 in the treatment of symptoms, conditions and/or diseases in the trachea, bronchi, bronchioles, alveoli, pleurae, lungs, larynx, pharynx, pleural cavity, nasal cavities, nostrils and oral cavities.

4. An ethyl lactate for use as a medicament for inhalation or breathing according to any of claims 1, 2 or 3 in the treatment of common cold, influenza, pneumonia, pulmonary edema, pulmonary emphysema, Interstitial Lung Disease (ILD) , pharyngitis, asthma Respiratory Tract infection, Plureal cavity diseases, CORD, viral infections, yeast and fungi infections, and bacterial infections, including bacterial pneumonia and tuberculosis, bronchitis, bronchiectasis, acute asthma, emphysema (infant) Respiratory distress syndrome, Chronic inflammation, Cystic Fibrosis, Pneumoconiosis, Radiation induced lung injury, dryness, cough, mucus, Parenchymal lung disease and Acute respiratory distress syndrome (ARDS) , including Severe acute respiratory syndrome (SARS) , Middle East Respiratory Syndrome (MERS) , Covid-19, H1N1, avian influenza viruses, and other strains. An ethyl lactate for use as a medicament for inhalation or breathing according to any of the preceding claims 1 - 4 , wherein the medicament is formulated as a liquid, vapor, mist , gas , aerosol , powder, solution or dispersion . An ethyl lactate for use as a medicament for inhalation or breathing according to any of the preceding claims 1 - 5 in combination with one or more acids selected from the group comprising hypochlorous acid, hydrochloric acid, acetic acid, lactic acid, formic acid, citric acid, gluconic acid, oxalic acid, tartaric acid, ascorbic acid, hydrogen halides and their solutions , nitric acid, phosphoric acid, dichloroacetic acid, trichloroacetic acid, polystyrene sulfonic acid, ethanesulfonic acid, and salicylic acid . An ethyl lactate for use as a medicament for inhalation or breathing according to any of the preceding claims 1 - 6 , wherein ethyl lactate is present in the medicament in an amount of 0 . 5 - 100 wt% , preferably 10 - 100 wt% based on the total weight of the medicament , more preferred 15 - 100 wt% based on the total weight of the medicament , and even more preferred 15 - 99 . 5 wt% based on the total weight of the medicament . An ethyl lactate for use as a medicament for inhalation or breathing according to any of claims 6 - 7 , wherein the medicament comprises less than 0 . 1 wt% of acid based on the total weight of the medicament when the acid is acetic acid or hypochlorous acid, or when the acid is not acetic acid or hypochlorous acid the medicament comprises at least 0 . 05 wt% of acid based on the total weight of the medicament , or at least 2 . 50 wt% of acid based on the total weight of the medicament , preferably the acid concentration is between 0 . 1 - 5 . 0 wt% of the total weight of the medicament . An ethyl lactate for use as a medicament for inhalation or breathing according to any of the preceding claims 1 - 8 , wherein water is present in an amount of less than 10 wt% of the total weight of the medicament , preferably less than 8 wt% of the total weight of the medicament , more preferred less than 5 wt% of the total weight of the medicament , optionally the medicament is free of water . An inhaler or breathing device comprising a medicament for inhalation or breathing according to any of the preceding claims 1 - 9 , wherein ethyl lactate is an active ingredient for inhalation or breathing . An inhaler or breathing device according to claim 10 , wherein the medicament for inhalation or breathing according to any of the preceding claims 1 - 9 is applied to at least a surface part of said inhaler or breathing device .