TR2023016002A1 - PHARMACEUTICAL COMPOSITIONS CONTAINING A STEROID ACTIVE SUBSTANCE SUITABLE FOR INHALATION - Google Patents

Abstract

The present invention relates to a medicament containing fluticasone or a pharmaceutically acceptable derivative thereof as an active ingredient, for sequential or combined use, and to the use of this medicament in the symptomatic and/or prophylactic treatment of respiratory tract diseases.

Description

The present invention relates to a medicament containing fluticasone or a pharmaceutically acceptable derivative thereof as an active ingredient, for sequential or combined use, and to the use of this medicament in the symptomatic and/or prophylactic treatment of respiratory diseases. Respiratory diseases, particularly asthma and chronic obstructive pulmonary disease, have been among the health problems that people have been facing with increasing frequency for many years. Numerous ongoing studies, conducted for a long time to treat and prevent these diseases, which are crucial for individual and therefore public health, have identified their symptoms and proposed various solutions to alleviate or eliminate them. Symptoms such as bronchoconstriction, airway inflammation, and increased mucus secretion are among the symptoms of respiratory disorders, particularly asthma and chronic obstructive pulmonary disease, resulting in wheezing, chest tightness, coughing, and shortness of breath. Asthma is one of the most common respiratory diseases. Allergens, air pollution, respiratory infections, exercise, hyperventilation, emotional stress, weather changes, gastroesophageal reflux, hormonal changes, some foods, additives, and medications can trigger asthma attacks. The causes of asthma are extensively researched, but a definitive conclusion remains. Corticosteroids are one of the most frequently used active ingredient groups, particularly in the treatment of respiratory diseases. Fluticasone, a member of this active ingredient group, is a moderately potent corticosteroid administered by inhalation. Its chemical name is "S-(Fluoromethyl) 6alpha,9-difluoro-1 lbeta,17-dihydroxy-16alpha-methyl-3-oxoandrosta-1,4-diene-17beta-carbothioate," and it was first disclosed in patent number US4335121. The patent application in question describes fluticasone's effectiveness in treating inflammation. Inhalation therapy is a widely preferred treatment method for respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD). This is because the medication reaches its target area directly and quickly, resulting in lower doses achieving the desired effect compared to oral or parenteral administration. Lower doses also have fewer side effects compared to oral or parenteral administration. Drugs administered via inhalation do not enter the bloodstream because they reach the target area directly, minimizing gastrointestinal issues that alter drug efficacy, such as low solubility, low permeability, drug irritation, formation of undesirable metabolites, and reduced bioavailability due to food. Therefore, various inhalation devices have been designed for use in inhaled drug delivery. Inhalation devices are designed based on the substances contained in pharmaceutical formulations containing one or more active ingredients. These pharmaceutical formulations, containing one or more active ingredients, can be in liquid or dry powder form and can also be classified according to whether they contain a propellant. Depending on the pharmaceutical composition and/or device design and/or ease of use, inhalation devices used to deliver medications in liquid form or dry powder form are preferred. In the pharmaceutical formulations included in these metered-dose inhalation devices, a propellant gas is used in addition to the active ingredient or combination of active ingredients. The propellant gas is usually fluorochlorohydrocarbon gases. However, since the understanding that such propellants damage the ozone layer, research has increased on the development of new alternatives. Research conducted to address this need is focusing on delivering pharmacologically effective solutions to the lungs by injecting respirable particles under high pressure. New pharmaceutical compositions prepared in this way eliminate the need for propellant gas. However, ensuring adequate solubility of the active ingredients is a critical parameter in pharmaceutical compositions prepared in this way. Furthermore, these pharmaceutical compositions, which are in liquid form and delivered directly to the lungs, are aimed to maintain a high level of stability. As a result of their development studies in the field of new propellant-free inhalation products, the inventors have succeeded in developing new pharmaceutical compositions that are highly stable and have high therapeutic efficacy. Pharmaceutical compositions containing fluticasone or a pharmaceutically acceptable derivative of the invention are preferably in propellant-free liquid form. In one aspect, the invention discloses pharmaceutical aerosol compositions containing fluticasone or a pharmaceutically acceptable derivative thereof, in solution form and free of propellants. In another aspect, the invention discloses pharmaceutical aerosol compositions containing fluticasone or a pharmaceutically acceptable derivative thereof, in suspension form and free of propellants. As used in the text, the term "fluticasone" includes pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts and the free base form, all esters, polymorphs, crystalline forms and amorphous forms and/or combinations thereof of fluticasone. The term "aerosol" used throughout the text refers to pharmaceutical compositions suitable for inhalation, containing therapeutic amounts of an active ingredient or combination of active ingredients and pharmaceutically acceptable excipients. These pharmaceutical aerosol compositions do not contain propellants. The pharmaceutical aerosol compositions of the invention may be in the form of solutions or suspensions. The pharmaceutical aerosol compositions of the invention that can be administered by inhalation must meet high quality standards. The emergence of a therapeutic effect depends on the homogeneous distribution of the active ingredients in the lungs. The therapeutic active ingredient, along with the liquid pharmaceutical compositions of the invention, can achieve a high therapeutic effect even with very small amounts of the active ingredients. The inhaler device used to administer the drug composition containing fluticasone or a pharmaceutically acceptable derivative according to the invention is a device known by the trade name Respimat® and is disclosed in Figure 6 of Patent No. WO97/12687. An advantage of the inhaler device according to the invention is that it is manufactured with a technology that allows the amount of active ingredient required to achieve a therapeutic effect to be inhaled within a few seconds. In other words, the therapeutic dose can be ingested by the patient within a few seconds, thus providing a rapid therapeutic effect. The device in question sprays a specific volume of the pharmaceutical composition through small nozzles under high pressure to form inhalable aerosols. In such a device, the pharmaceutical solution is converted into an inhalable aerosol by means of a high pressure of up to 500 bar and is then sprayed. The preferred inhalation device within the scope of the invention is an inhaler in which an amount of solution of less than 100 µl, preferably less than 50 µl, more preferably less than 20 µl is sprayed to form an aerosol. In the pharmaceutical compositions of the invention, the inhaler device is sprayed to form an aerosol with an average particle size of less than 20 µm, preferably less than 10 µm. The particle size of the sprayed aerosol in the pharmaceutical compositions of the invention is preferably between 1 and 10 µm. In the methods used for delivering the pharmaceutical aerosol compositions of the invention by inhalation, the pharmaceutical compositions intended to be delivered to the patient may contain the necessary amounts of pharmaceutically acceptable excipients and/or additional substances in addition to the active ingredients. In other words, an inhalable pharmaceutical composition of the invention containing Iluticasone or any pharmaceutically acceptable derivative thereof as an active ingredient may optionally contain at least one pharmaceutically acceptable excipient. Excipients that may be included in the propellant-free inhalable pharmaceutical aerosol compositions of the present invention may be complexing agents, cosolvents, stabilizers, surfactants, antioxidants, preservatives, lubricants, solubility enhancing agents, pH adjusting agents, solvents, or combinations thereof. In one aspect, the present invention discloses an inhalable, propellant-free pharmaceutical composition comprising Iluticasone or a pharmaceutically acceptable derivative thereof as an active ingredient, said composition more particularly comprising: a) Iluticasone or a pharmaceutically acceptable derivative thereof as an active ingredient, b) at least one pharmaceutically acceptable solvent or water-solvent mixture for dissolving the active ingredients, c) at least one other pharmaceutically acceptable excipient. Water, alcohol or a water-alcohol mixture can be used as the solvent in the propellant-free, inhalable pharmaceutical aerosol compositions of the present invention. Water, alcohol or a water-alcohol mixture can be used as the solvent in the propellant-free, inhalable pharmaceutical aerosol compositions of the present invention. In cases where water-alcohol mixtures are used, the alcohol content by volume in the mixture is at least 70%, preferably 70-98%, particularly preferably in the range of 75-98%. The alcohol contained in the pharmaceutical compositions of the invention can be selected from the group consisting of ethanol, propyl alcohol and/or methanol. A particularly preferred alcohol in the pharmaceutical compositions is ethanol. The pharmaceutical aerosol compositions of the invention, which do not contain a propellant, may optionally contain one or more solubility enhancing agents selected from the group consisting of tween-80, poloxamer, polyoxyethylated castor oil, polyethylene glycol and its derivatives, polyvinylpyrrolidone, cyclodextrin, beta cyclodextrin and/or sulfobutylether beta-cyclodextrin. Optionally preferred excipients in the pharmaceutical compositions of the present invention are pharmaceutically acceptable acids used to adjust the pH of the pharmaceutical composition. The propellant-free, inhalable pharmaceutical aerosol compositions of the present invention have a pH between 2 and 7, preferably between 2 and 5. Organic or inorganic acids, preferably hydrochloric acid, citric acid, ascorbic acid, formic acid, fumaric acid, malic acid, tautaric acid, sulfuric acid, or mixtures of one or more of the above, can be used to maintain the pH of the pharmaceutical compositions within these ranges. Preferred cosolvents are other polar groups containing hydroxyl groups, alcohols, especially isopropyl alcohol, and glycols. Other excipients mentioned are substances that do not have active ingredient properties, such as tocopherols, vitamins, provitamins, and surfactants. Preservatives used to prevent contamination by pathogens can be selected from cetyl pyridinium chloride, benzalkonium chloride, benzoic acid, or benzoates, which are also known in the prior art. In the propellant-free, inhalable pharmaceutical aerosol compositions of the present invention, the surfactant can be selected from the group of vegetable oils and organic acids, particularly stearic acid, sorbic acid, oleic acid, saccharin, ascorbic acid, cyclamic acid, and aspartame. However, the propellant-free, inhalable pharmaceutical aerosol compositions of the present invention may contain, in addition to the aforementioned substances, edetic acid (EDTA) or its salts, excipients, sodium edetate, stabilizers, or complexing agents. Edetic acid or its salt contained in said inhalable pharmaceutical aerosol compositions is in the range of 0 mg/100 ml to 120 mg/l 00 ml. The inhalable propellant-free pharmaceutical aerosol composition of the present invention is characterized by Iluticasone or a pharmaceutically acceptable derivative thereof contained in unit dosage form In other words, the inhalable propellant-free pharmaceutical aerosol compositions of the invention contain between 1 µg and 350 µg of Iluticasone or a pharmaceutically acceptable derivative thereof per unit dosage form. In other words, the inhalable propellant-free pharmaceutical aerosol compositions of the invention contain between 1 µg and 300 µg of Iluticasone or a pharmaceutically acceptable derivative thereof per unit dosage form. In other words, the inhalable propellant-free pharmaceutical aerosol compositions of the invention contain between 1 µg and 250 µg of Iluticasone or a pharmaceutically acceptable derivative thereof per unit dosage form. The inhalable propellant-free pharmaceutical aerosol compositions of the invention preferably contain 50 µg of Iluticasone or a pharmaceutically acceptable derivative thereof per unit dosage form. The inhalable propellant-free pharmaceutical aerosol compositions of the invention preferably contain 125 µg of fluticasone or a pharmaceutically acceptable derivative thereof per unit dosage form. The inhalable propellant-free pharmaceutical aerosol compositions of the invention preferably contain 250 µg of fluticasone or a pharmaceutically acceptable derivative thereof per unit dosage form. The unit dosage form referred to throughout the text is a puff dispensed by the device. Therefore, the amounts of active ingredient given throughout the text are those contained in puff pastry. The term "pharmaceutically acceptable derivatives" used throughout the text includes pharmaceutically acceptable solvates, hydrates, organic salts, inorganic salts, esters, free bases, polymorphs, enantiomers or diastereoisomers, racemates, crystalline forms, amorphous forms, and/or combinations thereof. The active substance contained in the propellant-free, inhalable pharmaceutical aerosol compositions according to the present invention is fluticasone and/or pharmaceutically acceptable derivatives thereof. It describes inhalable, propellant-free pharmaceutical aerosol compositions comprising a) fluticasone or a pharmaceutically acceptable derivative thereof as the active substance, b) at least one pharmaceutically acceptable solvent or water-solvent mixture for dissolving the active substances, and c) at least one other pharmaceutically acceptable excipient. It describes inhalable, propellant-free pharmaceutical aerosol compositions containing a) 1 µg - 350 µg of fluticasone or a pharmaceutically acceptable derivative thereof per unit dosage form, b) at least one pharmaceutically acceptable solvent or water-solvent mixture for dissolving the active substances and c) at least one other pharmaceutically acceptable excipient. It describes inhalable, propellant-free pharmaceutical aerosol compositions containing a) 1 µg - 300 µg of fluticasone or a pharmaceutically acceptable derivative thereof per unit dosage form, b) at least one pharmaceutically acceptable solvent or water-solvent mixture for dissolving the active substances and c) at least one other pharmaceutically acceptable excipient. The invention discloses inhalable, propellant-free pharmaceutical aerosol compositions comprising a) 1 µg - 250 µg of Iluticasone or a pharmaceutically acceptable derivative thereof per unit dosage form, b) at least one pharmaceutically acceptable solvent or water-solvent mixture for dissolving the active ingredients, and c) at least one other pharmaceutically acceptable excipient. The propellant-free, inhalable pharmaceutical aerosol compositions of the invention may optionally contain at least one other active ingredient. The active ingredients that can be used in the pharmaceutical compositions of the invention may be selected from long-acting [32- adrenergic agonists (LABA), anticholinergic, corticosteroids, antiallergenics, antihistamines. The active ingredients of the long-acting ß2-adrenergic agonists (LABA) group that may be included in the pharmaceutical compositions of the invention are formoterol, vilanterol, olodaterol, indacaterol, bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, hexoprenaline, procaterol, ibuterol, pirbuterol, tulobuterol, reproterol, salbutamol, salmeterol, sulfonterol, terbutaline or their pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof; in terms of polymorphic structure, they may be in the form of crystals, amorphous or combinations thereof. The anticholinergic active ingredients that may be included in the pharmaceutical compositions of the invention may be in the form of ipratropium, tiotropium, aclidinium, oxitropium, trospium, glycopyrronium, revefenacin, umeclidinium or their pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof; and in terms of polymorphic structure, they may be in the form of crystals, amorphous or combinations thereof. The active ingredients of the corticosteroid group that may be present in the pharmaceutical compositions which are the subject of the invention herein are budesonide, fluticasone, dexamethasone, betamethasone, hydrocortisone, prednisolone, ciclesonide, beclomethasone, mometasone or their pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof; and in terms of polymorphic structure they may be in the form of crystalline, amorphous or combinations thereof. The antiallergenic active ingredients of the pharmaceutical compositions which are the subject of the invention herein are sodium cromoglicate, nedocromil, epinastine or their pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof; and in terms of polymorphic structure they may be in the form of crystalline, amorphous or combinations thereof. The inhalable pharmaceutical aerosol composition described in the invention can be used in a wide range of respiratory diseases, particularly asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis. Accordingly, although respiratory diseases are not limited to these, it is used in the treatment of asthma in all stages, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airways hyperreactivity, bronchiectasis, chronic obstructive pulmonary, respiratory, or lung disease (COPD, COAD, or COLD), including emphysema and chronic bronchitis, pneumoconiosis, aluminosis, anthracosis, asbetosis, calicosis, ptylosis, siderosis, silicosis, tabocosis, and byssnosis. This treatment may be prophylactic or symptomatic. However, the inhalable pharmaceutical aerosol composition of the present invention is used particularly in the symptomatic treatment of allergic asthma and COPD. The inhalable propellant-free pharmaceutical aerosol composition suitable for the present invention is illustrated with the examples below, but the invention is not limited to these examples. EXAMPLE: Aerosol Composition Containing Fluticasone Propionate Amount contained in 1 puff Fluticasone Propionate 100 ug Benzalkonium Chloride 1.15 ug Disodium Edetate 1.15 ug Purified Water k.m. * *Sufficient amount Iluticasone propionate, benzalkonium chloride, Disodium Edetate (EDTA) contained in the pharmaceutical composition above are dissolved with water:alcohol mixture. The resulting solution is filled into the cartridge under appropriate conditions.

Claims (1)

1.