MXPA04001967A - Pharmaceutical compositions in aerosol containing beclomethasone dipropionate. - Google Patents

Abstract

The present invention refers to aerosol formulations for administering drugs in an aqueous solution, more particularly, beclomethasone dipropionate by inhalation. The invention provides novel aerosol formulations comprising (a) Beclomethasone dipropionate, (b) a polar co-solvent, (c) a lubricating agent, and (d) a hydrofluorocarbon (HFC) or hydrofluoroalkane (HFA) propellant. The formulation is characterized in that it is chlorofluorocarbon (CFC) propellant-free, containing beclomethasone dipropionate in the anhydrous form, which is non-solvated or modified in the surface thereof, thereby facilitating the absorption of the active principle by the airways. The invention ensures the uniformity of the doses administered in each shot and promotes the physical stability of the final formulation. The invention is further characterized in that the beclomethasone dipropionate is drug-free and the formula is contained in a suitable aluminium container, which does not have an inner coating. The present invention includes a non-conventional manufacturing method useful for dispensing the components of the formula without requiring freezing or especial environmental conditions, the same being practically, quickly and easily operated as especial cooling fittings are not required, the dispensing action can be adjusted during the process. Said method is more cost effective since an additional energy consumption is not required, and has the same advantages of the conventional filling method under cooling.

Description

PHARMACEUTICAL FORMULATIONS IN AEROSOL, CONTAINING B? CLOMETHASONE DIPROPIONATE FIELD OF THE INVENTION This invention relates to aerosol formulations for the administration of drugs in solution, in particular Beclomethasone Dipropionate by inhalation.

DESCRIPTION OF THE INVENTION Pharmaceutical aerosols are products that are packaged under pressure and contain therapeutically active ingredients that are released with the activation of an appropriate valve. They are designed for topical application on the skin as well as local application on the nose (nasal sprays), mouth (mouth and sublingual sprays) or lungs (inhalation aerosols).

The development of the first metered dose inhaler (MDI) in the middle of the 50's was the greatest advance in the administration of drugs in localized form in the lung, especially for the treatment of broncho-obstructive diseases such as asthma. The propellants used in aerosol formulations have changed in recent years. Originally the chlorofluorocarbon propellants (CFCs) commercially called "Freons", mainly on 11 and 12, were the main propellants from the 1960s to the 1970s. However, CFCs, because of the chlorine contained in their molecule, have been implicated in the degradation of the ozone layer, which protects the earth from UV rays, which cause an increase in the incidence of skin cancer. A reduction and eventual disappearance of CFCs began in 1987 with the agreement to the Montreal protocol of the United Nations. This agreement establishes that the use of propellant CFCs should disappear from the market. Several kinds of propellants have been considered as an alternative to CFCs, among which the gas most similar to CFCs are hydrofluoroalkane propellants (HFAs) or also known as hydrofluorocarbon propellants (HFCs) which do not contain chlorine and do not they affect the ozone layer. Two HFA compounds have been identified as the best candidates for use as DI propellants: 1, 1, 1, 2-tetrafluoroethane also known as "HFA-134a" "P 134a" or commercially under the name "Dymel 134a" (marketed by the company Dupont) or and the propellant 1, 1, 1, 2, 3, 3, 3, -heptafluoro-n-propane also known as "HFA-227a" "P 227 a" or commercially under the name " Dymel 227a "(marketed by the Dupont company). Therefore, the present invention provides a novel aerosol formulation comprising: (a) Beclomethasone Dipropionate, (b) a polar cosolvent, (c) a lubricating agent and (d) a hydrofluorocarbon propellant (WHFC ") or hydrofluoroalkane ("HFA"). Said formulation is characterized by being free of any chlorofluorocarbon propellant ("CFC"); for containing the raw material in its anhydrous form; by containing the non-particulate drug but completely solubilized in said formulation, which facilitates the absorption of the active principle in the respiratory tract, guarantees the uniformity of the doses that are administered in each action and benefits the physical stability of the final formulation; for not mixing beclomethasone dipropionate with any other medication and because said formulation is contained in a suitable aluminum container with a coating on the inside, with the advantage of preventing the interaction of the formulation with said coating, thus favoring the stability of the formulation. the formula, avoiding organoleptic changes and being more economical since the additional cost of the coating process is avoided.

Beclomethasone Dipropionate is Pregna-1, 4-diene-3, 20-dione, (?? ß, 16ß) -9-chloro-11-hydroxy-16-methyl-17, 21, -bis (1-oxopropoxy ) - also known as 9-chloro-ll, 17, 21 - ^ - 7 ???? G ??? - 16β-p? ß ^ 1? Gß9? -1, 4-diene-3, 20-dione, 17, 21 dipropionate; and can be represented by the formula (I).

The compound of the formula (I) is a glucocorticoid known for its anti-inflammatory pharmacological activity and is currently indicated as an adjunct in the treatment of bronchial asthma in mild, moderate or severe therapy, as well as in chronic inflammatory diseases of the airways classified such as COPD (chronic obstructive pulmonary disease), such as chronic bronchitis. It is also used in the medium and long-term treatment of bronchial asthma.

The concentration of the drug in the formulation is in a proportion of 0.06% to 0.4%, preferably 0.2 to 0.4%, for example 0.36%.

The present invention is characterized in that the active principle is in its anhydrous form; not solvated or modified on its surface and because it is fully solubilized in it, which facilitates the absorption of the active principle in the respiratory tract, guarantees the uniformity of the doses that are administered in each action and benefits the physical stability of the final formulation. Therefore, it has been proposed to use a variety of polar cosolvents, for example, alcohols, such as ethyl alcohol or isopropyl alcohol, propylene glycol, polyethylene glycol, glycerol, preferably 2-carbon alcohols, such as ethyl alcohol, are used. to dissolve the active principle and achieve complete solutions. The final formulation may contain from 13% to 99% w / w of ethyl alcohol with respect to the propellant.

The propellant used is taken from the group of hydrofluoroalkane gases (HFAs) or also known as hydrofluorocarbon propellants (HFCs), mainly the propellants of 1 to 4 carbons containing hydrogen. The propellants used for the present invention are 1,1,1,2-tetrafluoroethane (CF3CH2F) also known as "HFA-134a" "P 134a" or commercially under the name "Dymel 134a" (marketed by the company Dupont) ) and the propellant 1, 1, 1, 2, 3, 3, 3-heptafluoro-n-propane (CF3CHFCF3) also known as wHFA-227a "" P 227a "or commercially under the name" Dymel 227a "( Said formulation is characterized by not containing another additional propellant in its formulation or any other excipient that potentializes or modifies its function.The propellant contained in the present invention is in a proportion of 50% to 80% of the total weight of the formulation.

In some formulations it can be found that the valves require a lubricating agent therefor, so that a lubricating agent of the valve such as oleic acid or soy lecithin has been added to the present invention, with oleic acid being preferred. The lubricant can be contained in a proportion of 0.00010% to 0.1%.

The formulations are contained in containers of adequate capacity to contain the formulation and must withstand an internal pressure of 140 to 180 psig at a temperature of approximately 51 ° C. The containers used in the present invention are made of aluminum, with a capacity of 19 to 20 mL, which are characterized mainly by not containing any type of coating inside.

It has recently been observed that aerosol formulations containing HFA propellants tend over time to adhere to the walls of the container in addition to the presence of ethanol in the formulation tends to oxidize the bottle thus degrading the formulation contained therein. In order to prevent the above, the package has been treated with an anodization process. Anodization is a process of electrolytic oxidation where the surface of the aluminum bottle becomes an inert surface, functionally unobserved and with a better physical appearance without losing its shape or capacity. The bottles used in the present invention are characterized by being anodized on their contact surface with the formulation in order to prevent oxidation or adhesion of the formulation thereto.

The measuring valves used for aerosols are multifunctional, capable of opening and closing easily and in addition they are capable of releasing a measured quantity with great accuracy in each operation. The term "measurement valve" describes those valves that are useful for releasing active substances of great pharmacological potency and operate thanks to a chamber capable of releasing a quantity measured in each action, according to the size and capacity of said chamber, with great reproducibility The valves used in the present invention possess a suitable chamber to release an amount ranging from 25 μL to 150 μ ?.

The measuring valves used for aerosols have packages which are mainly made of materials such as nitrile or neoprene, however it has been observed that these materials when used in formulations containing a mixture of hydrofluorocarbon propellants-ethanol show some incompatibility thus affecting the functionality of it. Therefore, in the present invention, packages made of ethylene-propylene-diene monomer material (EPDM) have been used, which present stability in the presence of mixtures of hydrofluorocarbon propellants-ethanol.

The preparation of the aerosols was carried out by an unconventional method, which allows the dosing of the components of the formula without requiring freezing or special environmental conditions. The drug is dissolved in a polar cosolvent, the lubricating agent is incorporated and then it is dosed in measured aliquots of the empty container. Then a valve is placed on top of it which is engargolada under pressure. Then, the bottle is placed in a suitable filling machine and the propellant is filled under pressure by the valve without cooling. Then the bottle is passed to leak tests. This method has the characteristics of being: more practical by not requiring special environmental conditions; easier to operate, since it does not require special additives to cool faster, allows to make propellant adjustments during filling; cheaper by not requiring external energy to cool; more practical and additionally retains its characteristics in terms of reproducibility and standardization of the filling. Thus, the present invention proposes an unconventional filling method that allows a filling without requiring freezing, easier to operate, faster, more economical with the same advantages of the conventional method of filling under cooling.

When administering Beclomethasone Dipropionate by inhalation, the medication goes directly to its action point, which is the respiratory tree, having a powerful anti-inflammatory, antiallergic and antiproliferative action, with a minimum systemic absorption of the inhaled dose. Beclomethasone dipropionate is rapidly absorbed with a half-life of approximately 30 min. The recommended maintenance dose is 500 μg twice a day or 250 μg four times a day. In severe cases the dose can be increased to 500 μg three times a day. In children, inhalation is recommended every 12 hours (500 μg per day).

Thus, the present invention provides a pharmaceutical formulation of Beclomethasone Dipropionate in aerosol which liberates approximately 25 to 300 μg per actuation in dosing bottles containing approximately 160 to 240 doses or measured puffs of the drug per bottle filled with product.

EXAMPLES The following non-limiting examples serve to illustrate the present invention: EXAMPLE 1 1) Micronized Beclomethasone Dipropionate 50.0 mg 2) Ethanol 4.06 mL 3) Oleic acid 1.5 μ 4) 1,1,1,2-tetrafluoroethane 10.44 g Micronized Beclomethasone Dipropionate is dissolved in ethanol, then oleic acid is incorporated. Once the above was finished, it was placed in an anodized aluminum container of 20 mL capacity, to which a 58 μL capacity valve was engargoló. 10.44 g of 1,1,1,2-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The resulting aerosol provides 250 μg of Beclomethasone Dipropionate by actuation of the valve.

EXAMPLE 2 1) Beclomethasone Dipropionate micronized 55.0 mg 2) Ethanol 5.0 mL 3) Oleic acid 1.5 μ 4) 1,1,1,2-tetrafluoroethane 9.66 g Micronized Beclomethasone Dipropionate is dissolved in ethanol, then oleic acid is incorporated. Once the above was finished, it was placed in an anodized aluminum container of 20 mL capacity, to which a 58 μL capacity valve was engargoló. 9.66 g of 1,1,1,2-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The resulting aerosol provides 250 μg of Beclomethasone Dipropionate by actuation of the valve.

EXAMPLE 3 1) Beclomethasone Dipropionate micronized 50.0 mg 2) Ethanol 2.55 mL 3) Oleic acid 1.5 μ 4) 1,1,1,2-tetrafluoroethane 11.65 g Micronized Beclomethasone Dipropionate is dissolved in the ethanol, then the oleic acid is incorporated. Once the above was finished, it was placed in an anodized aluminum container of 20 mL capacity, to which a valve of 58 μ? - capacity was engargoló. 11.65 g of 1,1,1,2-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The resulting aerosol provides 250 μg of Beclomethasone Dipropionate by actuation of the valve.

EXAMPLE 4 1) Beclomethasone Dipropionate micronized 50.0 mg 2) Ethanol 2.55 mL 3) Oleic acid 1.5 μ 4) 1,1,1, 2-tetrafluoroethane 9.58 g Micronized Beclomethasone Dipropionate is dissolved in ethanol, then oleic acid is incorporated. Once the above was finished, it was placed in an anodized aluminum container of 20 mL capacity, to which a 58 μL capacity valve was engargoló. 9.58 g of 1,1,1,2-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The resulting aerosol provides 250 μg of Beclomethasone Dipropionate by actuation of the valve.

EXAMPLE 5 5) Beclomethasone dipropionate micronized 55.0 mg 6) Ethanol 3.06 mL 7) Oleic acid 1.5 μ 8) 1,1,1,2-tetrafluoroethane 11.24 g Micronized Beclomethasone Dipropionate is dissolved in ethanol, then oleic acid is incorporated. Once the above was finished, it was placed in an anodized aluminum container of 20 mL capacity, to which a 58 L capacity valve was engargoló. 11.24 g of 1,1,1,2-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The resulting aerosol provides 250 g of Beclomethasone Dipropionate by actuation of the valve.

Claims (4)

NOVELTY OF THE INVENTION Having described the invention as above, property is claimed as contained in the following: CLAIMS

1. Aerosol formulation comprising: (a) Beclomethasone dipropionate, (b) a polar cosolvent, (c) a lubricating agent and (d) a hydrofluorocarbon or hydrofluoroalkane propellant without addition of any adjuvant thereto, the formulation is characterized as containing the Beclomethasone dipropionate completely solubilized in said formulation.

2. A formulation in accordance with the claim 1, characterized in that the beclomethasone dipropionate in the formulation is in a proportion of 0.06% to 0.4%.

3. A formulation in accordance with the claim 2, characterized in that the beclomethasone dipropionate in the formulation is in a preferred ratio of 0.2% to 0.4%. . A formulation according to claim 2, characterized in that the beclomethasone dipropionate in the formulation is in an even more preferred proportion of 0.36%. A formulation according to claim 1, characterized in that the propellant is 1,1,1,2-tetrafluoroethane. 6. A formulation according to claim 1, characterized in that the propellant is 1,1,1,2,3,3,3-heptafluoro-n-propane. 7. A formulation according to claim 5 and 6, characterized in that the propellant is in a proportion of 50% to 80% with respect to the total weight of the formulation. 8. A formulation according to claim 1 to 7, characterized in that said formulation is free of any chlorofluorocarbon propellant. 9. A formulation according to claim 1, characterized in that the polar cosolvent is in a ratio of 1.0% to 30.0% w / w with respect to the propellant. 10. A formulation in accordance with the claim 9, characterized in that the cosolvent is selected from ethyl alcohol, or isopropyl alcohol, propylene glycol, polyethylene glycol or glycerol. 11. A formulation according to claim 1, characterized in that the formulation contains an alcohol as a solubilizing agent in a range of 13% to 99% w / w with respect to the propellant. 12. A formulation according to claim 1, characterized in that said formulation can contain a lubricant or surfactant in a proportion of 0.00010% to 0.1%. 13. A formulation in accordance with the claim 12, characterized in that the lubricating agent or surfactant can be oleic acid or soy lecithin. 1

4. A formulation- in accordance with the claim 13, characterized in that the lubricating agent or surfactant is preferably oleic acid. SUMMARY OF THE INVENTION This invention relates to aerosol formulations for the administration of drugs in solution, in particular Beclomethasone Dipropionate by inhalation. The invention provides novel aerosol formulations comprising: (a) Beclomethasone Dipropionate, (b) a polar cosolvent, (c) a lubricating agent and (d) a hydrofluorocarbon propellant ("HFC") or hydrofluoroalkane ("HFA") . Said formulation is characterized by being free of any chlorofluorocarbon propellant ("CFC"), - by containing Beclomethasone Dipropionate in its anhydrous form, not solvated or modified on its surface; by containing the drug completely solubilized in said formulation, which facilitates the absorption of the active principle in the respiratory tract, guarantees the uniformity of the doses that are administered in each action and benefits the physical stability of the final formulation; because Beclomethasone Dipropionate is free of other medication and because said formulation is contained in a suitable aluminum container with no coating inside it. The present invention also proposes an unconventional manufacturing method that allows the dosing of the components of the formula without requiring freezing or special environmental conditions, which gives it the advantage of being more practical, easier to operate since it does not require special cooling additives, faster, allows adjustments during the process and more economical by not requiring additional energy consumption, and with the same advantages of the conventional method of filling under cooling.