MXPA04001749A - Pharmaceutical compositions in aerosol containing salbutamol in an aqueous solution, and improved process for packaging pharmaceutical compositions in aerosol. - Google Patents

Abstract

The present invention refers to aerosol formulations for administering drugs, more particularly, salbutamol by inhalation. The invention provides novel aerosol formulations comprising (a) Salbutamol, (b) a polar co-solvent and (c) a hydrofluorocarbon (HFC) or hydrofluoroalkane (HFA) propellant. The formulation is characterized in that it is chlorofluorocarbon (CFC) propellant-free, containing the drug completely solubilized therein, which facilitates 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 salbutamol is drug-free and the formula is contained in a suitable aluminium container, which does not have any inner coating. The present invention includes a non-conventional manufacturing method useful for dispensing the components of the formula without requiring freezing or especial environment al 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 SALBUTAMOL IN SOLUTION; AND IMPROVED PACKAGING PROCEDURE FOR PHARMACEUTICAL FORMULATIONS IN AEROSOL FIELD OF THE INVENTION Pharmaceutical sprays 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 (aerosols for inhalation).

BACKGROUND OF THE INVENTION 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 MDI 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) oy the propellant 1,1,1,2,3,3,3, -heptafluoro-n-propane also known as ¾HFA-227a "" P 227 a "or commercially under the name" Dymel 227a "(marketed by the Dupont company).

SUMMARY OF THE INVENTION Therefore, the present invention provides a novel aerosol formulation comprising: (a) Salbutamol, (b) a polar cosolvent and (c) a hydrofluorocarbon propellant ("HFC") or hydrofluoroalkane ("HFA"). Said formulation is characterized by being free of any chlorofluorocarbon propellant ("CFC"), because it contains the non-particulate drug but is completely solubilized in said formulation, by not mixing salbutamol with any other medication and by being contained in an aluminum container. suitable without any coating in its interior with the advantage of preventing the interaction of the formulation with said coating thus favoring the stability of the formula, avoiding organoleptic changes and being more economical since the additional cost of the coating process is avoided.

DESCRIPTION OF THE INVENTION Salbutamol is 2 (tert-butylamino) -1- [4-hydroxymethyl-a- (terbutylamino) methyl] benzyl alcohol and can be represented by the formula (I).

OH (i) CHCH2NHCCH3 The compound of the formula (I) is known for its pharmacological bronchodilator activity and is currently indicated to prevent and treat bronchial spasm in patients with reversible obstructive airway disease (asthma, bronchitis) and as a preventive of bronchospasm induced by the physical effort. Said activity has been found to be faster when the drug is administered by inhalation.

The concentration of the drug in the formulation is in a proportion of 0.08% to 0.2%, preferably 0.1 to 0.5%, for example 0.14%. Where salbutamol and 1,1,1, 2-tetrafluoroethane are found in a ratio of 0.020: 18 as salbutamol base.

The present invention is characterized in that the active principle is completely solubilized therein, 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 formulation final. Therefore, it has been proposed to use a variety of polar cosolvents, for example, alcohols, such as ethyl alcohol or isopropyl alcohol, propylene glycol, polylene 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 5% to 35% 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 Dupont company) ) and the propellant 1, 1, 1, 2, 3, 3, 3-heptafluoro-n-propane (CF3CHFCF3) also known as "HFA-227a" "P 227a" or commercially under the name "Dymel 227a" (marketed by the Dupont company). Said formulation is characterized by not containing another additional propellant in its formulation or some other excipient that potentializes or modifies its function. The propellant contained in the present invention is in a proportion of 60% to 90% of the total weight of the formulation.

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.

Recently it has 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, able to open and close 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 chamber suitable for releasing an amount ranging from 25 L 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 performed 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 cosolvent and then dosed in aliquots measured in an empty container. Then a valve is placed on top of it and then it is engargolado under pressure. Then, the bottle is placed in a suitable filling machine and the propellant is filled under pressure by the valve without cooling.

Propellant dosing is done without requiring freezing or special environmental conditions. This method is performed with a propellant dosing machine which has: A propellant tank, feed pump and maintenance unit, pressure multiplier and pressure regulator filter (air), stainless steel filter, pressure regulator to the arrival of the dispenser, propellant dispenser dispenser and start buttons (dispensers).

To begin dosing it first, the propellant dosing machine is connected to a compressed air intake which has a pressure ranging from 7 kg / cm2 to 9 kg / cm2 and preferably 8 kg / cm2, immediately The valves of the equipment must be opened in the following order: propellant metering valve, feed pump valve (air maintenance unit), which has a pressure ranging from 5.5 Kg / cm2 to 6.5 Kg / cm2 ', preferably 6.0 u Kg / cm2 (85.35) and it is separated to pressurize the propellant gas into the chamber thereof. Then we proceed to open the multiplier valve, which has a pressure ranging from 20 Kg / cm2 to 22 Kg / cm2 'with a preferred 21 Kg / cm2 (300 psi) and the regulating filter that has a pressure that goes from 6 kg / cm2 to 8.0 Kg / cm2, with a pressure of 7 Kg / cm2 (100 psi) being preferred. Then the valve of the propellant filtration system is opened in which it is at a pressure ranging from 20 Kg / cm2 to 22 Kg / cm2, preferably 21 Kg / cm2 (300 psi). Finally, the final dosing valve is opened at a constant pressure of 21 Kg / cm2 (300 psi) at the inlet and 7 g / cm2 (100 psi) at the propellant outlet to the dosifiers. Once the entire system is pressurized, the machine is ready to adjust the weight of the propellant per bottle.

The desired weight adjustment to be dosed by the machine is done first by adjusting the feeder cylinder, which is driven by a large diameter air piston, which increases the injection pressure of the propellant, and is equipped with a rod that allows the precise adjustment, said rod indicates the position of the piston and the speed of the loading operation of the propellant. Then the stroke length adjustment must be made, adjusting the height of the container according to the height of the bottle to be dosed. At this point it is important to take care of the operation of the air pressure regulator of the feeder cylinder which has as its main function to maintain a control on the injection pressure of the propellant for which a pressure of 3.1635 Kg / cm2 (45 psi) is needed. ) and maintain a stable pressure in line with the dispenser. Finally, the propellant is dosed. Finally, the dosing bottle is leak tested to ensure the absence of propellant leaks.

As you can see from the above, this method is more economical because it does not require a cooling system or electric power for its operation, it is simpler since it does not require freezing systems, more practical since it does not require special environmental conditions, as it allows make propellant adjustments during filling, easy to operate since it does not require special attachments, insurance for personnel that manipulates the equipment 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 administered salbutamol by inhalation produces a rapid pharmacological effect (5 to 15 minutes) that lasts approximately 4 to 6 hours. For the treatment of acute bronchospasm, 1 or 2 puffs of 100 g of salbutamol are administered to relieve symptoms. The basic treatment consists of administering 100 to 200 μg per inhalation every 4 or 5 hours or 3 times a day. The dosage for children consists of administering 100 g 3 or 4 times a day.

Thus, the present invention provides a salbutamol aerosol pharmaceutical formulation that releases approximately 50 to 150 μg per actuation in dosing bottles containing approximately 160 to 240 metered doses or puffs of the drug per vial filled with product.

EXAMPLES The following non-limiting examples serve to illustrate the present invention: EXAMPLE 1 1) Salbutamol base micronized 22.0 mg 2) Ethanol 3.3 mL 3) 1, 1, 1, 2-tetrafluoroethane 11.4 g The micronized salbutamol base is dissolved in ethanol, then placed in an anodized aluminum container of 20 mL capacity to which a valve of 58 μL capacity was engargoló. 11.4 g of 1,1,1,1-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The resulting aerosol provides 100 μg of salbutamol as the base per actuation of the valve.

EXAMPLE 2 1) Salbutamol base micronized 20.0 mg 2) Ethanol 3.0 mL 3) 1, 1, 1, 2-tetrafluoroethane 12.16 g The micronized salbutamol base is dissolved in the ethanol then placed in an anodized aluminum container of 20 mL capacity to which a valve of 58 μL capacity was engargoló. 12.16 g of 1,1,1,1-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The resulting aerosol provides 100 μg of salbutamol as the base per actuation of the valve.

EXAMPLE 3 1) Salbutamol base micronized 20.0 mg 2) Ethanol 1.74 mL 3) 1, 1, 1, 2-tetrafluoroethane 12.66 g The micronized salbutamol base is dissolved in ethanol, then placed in an anodized aluminum container of 20 mL capacity to which a valve of 58 μ? ^ Capacity was engargoló. 12.66 g of 1,1,1,1-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The resulting aerosol provides 100 μg of salbutamol as the base per actuation of the valve.

EXAMPLE 4 1) Salbutamol base micronized 20.0 mg 2) Ethanol 2.60 mL 3) 1, 1, 1, 2-tetrafluoroethane 11.95 g The micronized salbutamol base is dissolved in ethanol, then placed in an anodized aluminum container of 20 mL capacity to which a 58 L capacity valve was engargoló. 11.95 g of 1,1,1,1-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The resulting aerosol provides 100 μg of salbutamol as the base per actuation of the valve.

EXAMPLE 5 1) Salbutamol base micronized 20.0 mg 2) Ethanol 3.54 mL 3) 1, 1, 1, 2-tetrafluoroethane 11.20 g The micronized salbutamol base is dissolved in ethanol, then placed in an anodized aluminum container with a capacity of 20 mL, to which a valve of 58 uL capacity was engargoló. 11.20 g of 1,1,1,1-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The resulting aerosol provides 100 μg of salbutamol as the base per actuation of the valve.

Claims (16)

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

1. An aerosol formulation comprising: (a) Salbutamol, (b) a polar cosolvent and (c) the hydrofluorocarbon or hydrofluoroalkane propellant without addition of any adjuvant thereto, characterized in that the salbutamol is completely solubilized in the formulation.

2. The formulation according to claim 1, characterized in that the concentration of salbutamol in the formulation is in a proportion of 0.08% to 0.2%.

3. The formulation according to claim 1 and 2, characterized by, the salbutamol is preferably 0.1 to 0.5%.

4. The formulation according to claim 1 to 3, characterized in that, the salbutamol is preferably in a proportion of 0.14%.

5. A formulation in accordance with the claim 1, characterized in that the propellant is 1,1,1,2-tetrafluoroethane.

6. A formulation according to claim 1 to 5, characterized in that salbutamol and 1,1,1,2-tetrafluoroethane are present in a proportion of 0.020: 18 as salbutamol base.

7. A formulation according to claim 2, characterized in that the propellant is in a proportion of 60% to 90% with respect to the total weight of the formulation.

8. A formulation according to claim 3, characterized in that said formulation is free of any chlorofluorocarbon propellant.

9. A formulation according to claim 1 to 4, characterized in that said formulation is free of any surfactant agent. 5

10. A formulation in accordance with the claim 5, characterized because salbutamol is found as the only active with some pharmacological activity without mixing it with other medications.

11. A formulation according to claim 10, characterized in that the medicament is completely solubilized therein.

12. A formulation according to claim 15, characterized in that the salbutamol is unsolvated or modified on its surface.

13. A formulation according to claim 12, characterized in that the formulation contains ethanol as a solubilizing agent in a range of 5% to 35% w / w with respect to the propellant.

1 . A formulation according to claim 1 to 13, characterized in that it is contained in an aluminum container of adequate capacity without any coating inside it.

15. A formulation according to all the preceding claims, manufactured by means of an unconventional process of dosing the components thereof which allows the dosing of the components of the formula without requiring freezing or special environmental conditions.

16. A packaging process for aerosol formulations, characterized in that it comprises the following steps: a) connecting a propellant dosing machine to a compressed air outlet at a pressure of 8 Kg / cm2, opening the equipment valves i) the dosing valve of propellant, immediately ii) open the valve of the feed pump (air maintenance unit) at a pressure ranging from 5.5 Kg / cm2 to 6.5 Kg / cm2, preferably 6.0 Kg / cm2 (85.35 psi); c) wait for the propellant gas to pressurize the propellant chamber, d) open the multiplier valve, which must be at a pressure ranging from 20 Kg / cm2 to 22 Kg / cm2, preferably 21 Kg / cm2 (300 psi) and the air regulating filter must be found at a pressure ranging from 6.0 Kg / cm2 to 8.0 Kg / cm2, preferably 7 kg / cm2 (100 psi), e) then, open the valve of the propellant filtration system, which must be found at a pressure ranging from 20 Kg / cm2 to 22 Kg / cm2, preferably 21 Kg / cm2 (300 psi);. f) open the final dosing valve while maintaining a constant pressure of 21 Kg / cm2 (300 psi) at the inlet and 7 kg / cm2 (100 psi) at the propellant outlet to the dosifiers, - until total system pressurization; g) adjust the weight of the propellant per bottle, maintaining the air pressure regulator of the feed cylinder at a constant pressure of 3.1635 Kg / cm2 (45 psi); h) dose the propellant. SUMMARY OF THE INVENTION This invention relates to aerosol formulations for the administration of drugs in solution, in particular salbutamol by inhalation. The invention provides novel aerosol formulations comprising: (a) Salbutamol, (b) a polar cosolvent, and (c) a hydrofluorocarbon propellant (UHFC ") or hydrofluoroalkane (" HFA "). any chlorofluorocarbon propellant ("CFC"), because it contains 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 salbutamol is free of another medication and because it 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 add-ons special cooling, 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.