MXPA04001748A - Pharmaceutical compositions in aerosol containing sodium chromoglycate. - Google Patents

Abstract

The present invention refers to aerosol formulations for administering drugs, more particularly, sodium chromoglycate by inhalation. The invention provides novel aerosol formulations comprising (a) Sodium chromoglycate, (b) a lubricating agent and (c) a hydrofluorocarbon (HFC) or hydrofluoroalkane (HFA) propellant. The formulation is characterized in that it is chlorofluorocarbon (CFC) propellant-free and the sodium chromoglycate free of other drug; the invention is further characterized in that the formulation is contained in a suitable aluminum container, which does not have an inner coating.

Description

'"' AEROSOL PHARMACEUTICAL FORMULATIONS, CONTAINING SODIUM CHROMOGLYCLEATE" FIELD 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).

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 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 wHFA-227a "" P 227 a "or commercially under the name of wDymel 227a "(marketed by the Dupont company).

SUMMARY OF THE INVENTION Therefore, the present invention provides a novel aerosol formulation comprising: (a) sodium cromoglycate, (b) a lubricating agent and (c) a hydrofluorocarbon propellant ("HFC") or hydrofluoroalkane ( "HFA"). Said formulation is characterized by being free of any chlorofluorocarbon propellant ("CFC"), by not mixing sodium cromoglycate with any other medication and by being contained in a suitable aluminum container without any coating therein. 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 Sodium cromoglycate is the sodium or sodium salt of 5,5 '- [(2-hydroxy-1,3-propanediyl) bis (oxy)] bis [4-oxo-4H-l-benzopyran-2-carboxylic acid ] and can be represented by the formula (I).

(I) The compound of the formula (I) is known to possess anti-allergic pharmacological activity by inhibiting the release of mediators of inflammation by decreasing the hypersensitivity of the bronchial tree and is currently indicated in the prophylactic control of asthma induced by the inhalation of allergen compounds and in the prophylactic treatment of bronchospasm induced by exercise. Said activity has been found to be more selective to the bronchial tree when the drug is administered by inhalation.

Sodium cromoglycate should be used with a specific particle size for its best functionality within the formula and thus facilitate its absorption into the respiratory tract. The particle size can be reduced by conventional techniques such as grinding and / or fragmentation or by micronization, the most used being micronization. For the purposes of the present invention it is preferred that the active principle be in a particle size of less than 15 microns, mainly between 0-10 microns, for example 5 microns.

The concentration of the drug in the formulation is in a proportion from 0.0001% to 10.0%, preferably from 0.1 to 5.0%, for example 3.5%.

The present invention is characterized in that the active ingredient is particulate therein, however a variety of cosolvents can be additionally used in order to give greater solubility to the medicament or increase the stability of the final formulation, thus, for example, water can be used , alcohols, such as ethyl alcohol, or isopropyl alcohol, polyols such as propylene glycol, polyethylene glycol or glycerol, preferably the 2-carbon alcohols are used as is ethyl alcohol, preferably in its anhydrous state. The final formulation can contain 1.0. % at 30.0% w / w of anhydrous ethyl alcohol with respect to the propellant.

Since the formulation contains a high concentration of medicament there may be a tendency to form product agglomerates within the package. In order to prevent the above it is advisable to add a lubricant or surfactant, such as oleic acid, sorbitan monooleate, sorbitan trioleate, soy lecithin, sorbitan monolaurate or sorbitan monostearate, with oleic acid being preferred. The lubricant or surfactant may be contained in a proportion of 0.00001% to 5.0%.

Additionally the formulation may contain other excipients such as preservatives or preservatives, flavoring agents, antioxidants or antiaggregation agents.

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" WP 134 a "or commercially under the name" Dymel 134a "(marketed by 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 "(marketed by the company Dupont). Additionally, combinations of said propellants can be used in order to obtain an adequate solubility or pressure. Said formulation is characterized by not containing any CFC propellant in its formulation or any other propellant or additional excipient that potentializes or modifies its function. The propellant contained in the present invention is present in a proportion of 10% to 99% 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. In the present invention, aluminum, metal alloy containers such as stainless steel, glass or plastic can be used. The containers used in the present invention are preferred with a capacity of up 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 to adhere to the walls of the container over time. Therefore, the container 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. Therefore, the bottles used in the present invention can be 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 an accurately measured quantity in each actuation. 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 40 μL to 150 μL.

The measuring valves used for aerosols have packages which are mainly made of materials such as nitrite or neoprene, however it has been observed that these materials when used in formulations containing HFA propellants or a mixture of HPA-ethanol propellants 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 HFA propellants, or mixtures of HFA-ethanol propellants.

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 suspended in a polar cosolvent and then dosed in aliquots measured in an empty container or dosed as a powder in empty containers, followed by the incorporation of the other excipients that the formulation could contain, mainly the lubricating agent. 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. Optionally the bottle can be placed in an ultrasound bath for a period of 1 to 20 minutes in order to facilitate the dispersion of the drug particles and the excipients in the propellant. Then the bottle is subjected 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 cooling attachments; 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.

After inhalation, approximately 10% of the dose of sodium cromoglycate is absorbed from the respiratory tract; the rest is exhaled or purified by the organism. Since the absorption rate of Sodium chromoglycate in the respiratory tract is less than the rate of elimination, then the absorption of sodium cromolyn will be limited by the frequency of the dosage and half-life of the drug in plasma (1.5 to 2 hours). Therefore, it is recommended to initially administer two inhalations four times a day (every 6 hours) in the morning. A dose may be administered before exposure to the seizure trigger (for example, 15-30 minutes before a sport). The suggested administration regimen is two inhalations at night and two inhalations in the morning (every 12 hours).

Thus, the present invention provides a pharmaceutical formulation of sodium cromoglycate in aerosol that releases approximately 1 to 10 mg per actuation in dosing bottles containing approximately 50 to 150 doses or measured puffs of the drug per vial filled with product.

EXAMPLES The following non-limiting examples serve to illustrate the present invention: EXAMPLE 1 1) Micronized sodium cromoglycate 576.0 mg 2) 1, 1,1, 2-tetrafluoroethane 15.42 g The micronized sodium cromoglycate was dosed in an anodized aluminum container of 20 mL capacity, to which a valve of 100 L capacity was engargoló. 15.42 g of 1,1,1,1-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The resulting aerosol provides 5 mg of sodium cromoglycate per actuation of the valve.

EXAMPLE 2 1) Micronized sodium cromoglycate 576.0 mg 2) Oleic acid 2.5 μL 3) 1,1,1,2-tetrafluoroethane 15.37 g The micronised sodium cromoglycate was dosed in an anodized aluminum container of 20 mL of capacity to which 2.5 μL of oleic acid was added, then a valve of 100 μL capacity was engargoló. 15.37 g of 1,1,1,1-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The resulting aerosol provides 5 mg of sodium cromoglycate per actuation of the valve.

EXAMPLE 3 1) Micronized sodium cromoglycate 565.0 mg 2) 1,1,1,2-tetrafluoroethane 15.43 g The micronized sodium cromoglycate was dosed in an anodized aluminum container of 20 mL capacity, which was fitted with a valve of 100 capacity . 15.43 g of 1,1,1,1-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The flask was then placed in an ultrasound bath for a period of 5 minutes. The resulting aerosol provides 5 mg of sodium cromoglycate per actuation of the valve.

EXAMPLE 4 1) Micronized sodium cromoglycate 565.0 mg 2) Oleic acid 2.0 μL 3) 1,1,1, 2-tetrafluoroethane 15.43 g The micronized sodium cromoglycate was dosed in an anodized aluminum container of 20 L capacity to which 2.0 L of oleic acid was added, then a valve of 100 μL capacity was engargoló. 15.43 g of 1,1,1,1-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The flask was then placed in an ultrasound bath for a period of 5 minutes. The resulting aerosol provides sodium cromoglycate per valve actuation.

EXAMPLE 5 1) Micronized sodium cromoglycate 560.0 mg 2) Oleic acid 2.5 μ! _. 3) 1, 1, 1, 2-tetrafluoroethane 13.55 g The micronised sodium cromoglycate was dosed in an anodized aluminum container of 20 mL of capacity to which 2.5 μL of oleic acid was added, then a valve of 100 μL capacity was engargoló. 13.55 g of 1,1,1,1-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The resulting aerosol provides 5 mg of sodium cromoglycate per actuation of the valve. EXAMPLE 6 1) Micronized sodium cromoglycate 576.0 mg 2) Anhydrous ethyl alcohol 5.0 mL 3) 1, 1, 1, 2-tetrafluoroethane 11.37 g The micronized sodium cromoglycate was suspended in the anhydrous ethyl alcohol, then it was placed in an anodized aluminum container of 20 mL capacity to which a 100 μ ?? valve was engargoló. capacity. 11.37 g of 1, 1, 1, 2-etrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The resulting aerosol provides 5 mg of sodium cromoglycate per actuation of the valve.

EXAMPLE 7 1) Micronized sodium cromoglycate 576.0 mg 2) Anhydrous ethyl alcohol 5.0 mL 3) Oleic acid 2.5 μL 4) 1, 1, 1, 2-tetrafluoroethane 11.37 g The micronized sodium cromoglycate was suspended in the anhydrous ethyl alcohol, the oleic acid was added to this mixture, then it was placed in an anodized aluminum container of 20 mL of capacity, to which a valve of 100 L capacity was engargoló. 11.37 g of 1,1,1,1-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The resulting aerosol provides 5 mg of sodium cromoglycate per actuation of the valve.

EXAMPLE 8 1) Micronized sodium cromoglycate 576.0 mg 2) Anhydrous ethyl alcohol 3.0 mL 3) Oleic acid 2.5 μ? ^ 4) 1,1,1,2-tetrafluoroethane 12.99 g Sodium chromium cromoglycate was suspended in anhydrous ethyl alcohol, and oleic acid was added to this mixture, then it was placed in an anodized aluminum container with a capacity of 20 mL, and a valve of 100 L capacity was engargoló. 12.99 g of 1,1,1,1-tetrafluoroethane (Dymel 134 a) were filled under pressure through the valve. The flask was then placed in an ultrasound bath for a period of 5 minutes. The resulting aerosol provides 5 mg of sodium cromoglycate per actuation of the valve.

Claims (20)

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

1. Aerosol pharmaceutical formulation comprising: (a) Sodium cromoglycate, (b) a lubricant or surfactant and (c) the propellant of idrofluorocarbon or hydrofluoroalkane without addition of any adjuvant thereto, the formulation is characterized as being free of any propellant of chlorofluorocarbon ("CFC"), and for not mixing sodium cromoglycate with any other medication.

2. A formulation according to claim 1, characterized in that the concentration of the sodium cromoglycate in the formulation is in a proportion of 0. 0001% to 10.0%.

3. A formulation in accordance with the claim 1, characterized in that the concentration of sodium cromoglycate in the formulation is in a proportion of 0.1 to 5.0%.

4. A formulation according to claim 1, characterized by the concentration of sodium cromoglycate in the formulation is in a proportion of 3.5

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 5, characterized in that the propellant is 1,1,1,2,3,3,3, - eptafluoro-n-propane.

7. A formulation according to claim 5, characterized in that the propellant is a mixture of the propellants used in claims 2 and 3.

8. A formulation according to claim 5, characterized in that the propellant is in a proportion of 10% to 99% with respect to the total weight of the formulation.

9. A formulation according to claim 1, characterized in that the sodium cromoglycate is used in a particle size of less than 15 microns.

10. A formulation according to claim 9, characterized in that sodium cromoglycate is used in a particle size mainly between 0 and 10 microns.

11. A formulation in accordance with the claim 9, characterized in that sodium cromoglycate is used in a particle size of 5 microns.

12. A formulation according to claim 1, characterized in that said formulation may contain a lubricant or surfactant in a proportion of the 0. 00001% to 5.0%.

13. A formulation according to claim 12, characterized in that the lubricating agent or surfactant can be oleic acid, sorbitan monooleate, sorbitan trioleate, soy lecithin, sorbitan monolaurate or sorbitan monostearate, with oleic acid being preferred.

14. A formulation in accordance with the claim 1, characterized in that the sodium cromoglycate is suspended or solubilized in a polar cosolvent.

15. A formulation according to claim 14, characterized in that the polar cosolvent is present in a ratio of 1.0% to 30.0% w / w with respect to the proponent. 16. A formulation according to claim 15, characterized in that the cosolvent is selected from water, ethyl alcohol, or isopropyl alcohol, polyols such as propylene glycol, polyethylene glycol or glycerol.

16. A formulation according to claim 16, characterized in that the cosolvent is present in the formulation in a proportion of 1.0% to 30% w / W of anhydrous ethyl alcohol with respect to the propellant.

17. A formulation according to claim 1, characterized in that the sodium cromoglycate is not solvated, nor modified on its surface.

18. A formulation according to claim 1 to 17, characterized in that the formulation contains other excipients such as preservatives or preservatives, flavoring agents, antioxidant agents or antiaggregation agents.

19. A formulation according to the preceding claims, characterized by being contained in packages of up to 20 mL capacity, which can be made of aluminum, alloy metals such as stainless steel, glass or plastic without any coating inside.

20. A formulation according to claim 19, characterized in that sodium cromoglycate is the only active with pharmacological activity without mixing thereof with other drugs.