BR102012008322B1 - low-ozone, ozone-depleting aerosol medicinal formulations - Google Patents

Abstract

low-ozone, non-ozone depleting aerosol medicinal formulations. Pressurized metered dose pharmaceutical inhalers are being shown to have a cfc-free and wholly or partially hfa-free composition, thus enabling the manufacture of medical aerosols which do not cause harmful effects to the ozone layer of the atmosphere and have a low or negligible greenhouse effect.

Description

"MEDICAL FORMULATIONS IN AEROSOL THAT DO NOT DEBILITATE THE OZONE LAYER AND WITH LOW GREENHOUSE EFFECT"

FIELD OF THE INVENTION

The present invention relates to the formulation of metered dose inhalers which are free of chlorofluorocarbons (CFCs) and free or partially free of hydrofluoralkanes (HFA) which have a low greenhouse effect, good uniformity of dosage and deposition superior to that some other HFA metered dose inhalers on the market.

TECHNICAL STATUS

Inhalation has become a widely used route for the administration of bronchodilators, steroids and other drugs to the airways of patients suffering from respiratory diseases. One of the pharmacological dosage forms used for this purpose is pressurized metered dose inhalers.

Pressurized metered dose inhalers need a propellant within their formulation in order to produce a fine spray of micronized particles, as the formulation is expelled through the valve stem and the actuator orifice into the patient's oral cavity. Until recently, the most widely used propellants for this purpose had been chlorofluorocarbons (CFCs). However, it has been found that these propellants react with the ozone layer in the atmosphere and contribute to its reduction. This discovery has put enormous pressure on companies that produce and consume these propellants worldwide to reduce their production and consumption. Recently, the FDA and most governments in the world have begun to ban its use even for pressurized metered dose inhalers.

In recent years, the pharmaceutical industries have made great efforts to reformulate their products in formulations that do not affect the ozone layer, mainly with the replacement of CFC by hydrofluoralkanes (HFA). The HFA most widely used for this purpose have been HFA 134a (Norflurane or 1,1,1,2-tetrafluoroethane) and HFA 227ea (1,1,1,2,3,3,3-heptafluoropropane), according to teachings of Purewal et al. (US Patent 5,776,434), Akehurst et al. (US Patent

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6,893,628) and others (Govind et al. US Patent 7,759,328). The active ingredients were formulated in suspension (eg Purewal et al. US Patent 5,776,434, Govind et al. US 7,759,328), in solution (eg US Patent 6045778) and in a combination of active ingredients in suspension and others in solution (for example Patent Application 13024414, filed in 2011). Various formulations with different active ingredients and using different excipients have been intensively studied and taught through patents. However, all these efforts were directed mainly at controlling the ozone layer reduction without significantly reducing the greenhouse effect. This can be easily seen when the ozone depletion potential and greenhouse effect of CFC and HFA are listed as in the Table

1.

Table 1

Propellant Ozone layer reduction potential (considering CFC Atmosphere duration in years ((*) **) GWP (100 years) (**) (considering CO2 as D CFC 11 K *) 45 4,750 CFC 12 K *) 100 10,900 HFA 134a 0 14 1,430 HFA 227ea 0 34.2 3,220

(*) Extracted from http: llwww. hey. gov / Ozone / science / ods / classone. html (US Environmental Protection Agency website) (**) Extracted from http: // www. ipcc. ch / pdf / assessment-report / ar4 / wglVar4-wgl-chapter2.pdf (2007 IPCC Fourth Assessment Report (AR4) Chapter 2, p. 212 and 213)

On the other hand, in relation to pressurized metered dose inhalers, there was only a secondary effort focused on reducing both the destruction of the ozone layer and the greenhouse effect. There was a proposal to replace CFCs using isobutane with up to 10% propane w / w in the formulation, taught by Warnke in EP 0605483. This approach creates pressurized inhalers with no potential for ozone layer destruction and with negligible greenhouse effect, as shown in Table 2.

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Table 2. Environmental impact of hydrofluoralkanes and hydrocarbons

Propellant Ozone layer reduction potential (considering CFC as 1) Atmosphere duration in years GWP (20 years) (**) (considering CO2 as D HFA 134a 0 14 3,830 HFA 227ea 0 34.2 5,310 Propane 0 Month 12 (***) n-Butane 0 Weeks 12 (***) Isobutane 0 Weeks 12 (***) n-pentane 0 Weeks 12 (***)

(***) These substances are not considered greenhouse gases by the

Kyoto Protocol and therefore it is difficult to find the exact global warming potential (GWP). These data are based on a publication on the NASA website http://www.giss.nasa.gov/meetings/pollution2002/d3_edwards.html. However, it is worth mentioning that in a report of intentions by CECED (European Committee of Manufacturers of Household Equipment) the value of hydrocarbons for GWP is 3 (100 years) and is determined by the IPCC (Intergovemamental Panel on Climate Change 10) ; in addition, the US Environmental Protection Agency (EPA) refers to hydrocarbons other than methane as low GWP substances ((http: // www. epa.gov/ozone/defns. htmlttgwp).

However, this patent (EP 0605483) filed in 1992 did not result in the production of any commercial product and did not contain any data related to the uniformity of dosage and fine particle fraction. As Warnke teaches, the formulation of pressurized dose inhalers with hydrocarbons is full of challenges, especially in the case of isobutane. These challenges according to the description of

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Warnke are:

- The relatively low density compared to CFCs, which speeds up sedimentation, tends to make suspensions physically unstable and can cause problems with regard to the uniformity of the amount of drug administered by each actuation.

- A relatively low vapor pressure at room temperature, in the case of isobutane (3.2 bar at 21 ° C according to the USP monograph), tends to decrease the deposition of these MDIs (metered dose inhalers) compared to those formulated CFC (CFC CFC 11 + 12 mixture 30/70, 4.5 bar at 20 ° C (according to the Handbook of Pharmaceutical Excipients 2nd Edition, published by the American Pharmaceutical Association & the Pharmaceutical Press, printed in Britain in 1994) or HFA (norflurane or HFA 134a: 5.7 bar at 20 ° C according to the Handbook of Pharmaceutical Excipients 2nd Edition, published by the American Pharmaceutical Association & the Pharmaceutical Press, printed in Britain in 1994). Deposition is measured in vitro, using devices called impactors. USP (United States Pharmacopeia) allows the use of several types of impactors. The Andersen Cascade Impactor is one of them, and is widely used.

Deposition is measured as the mass of fine particles per drive. These fine particles are those capable of reaching the bronchial lungs when inhaled. Therefore, the greater the mass of fine particles per actuation, the greater the expected effect on the respiratory airways. Increasing the mass of fine particles can also allow for the reduction of the total amount of pharmacologically active component administered to the patient to obtain the same dose of respirable particles, thereby improving therapeutic efficacy by reducing systemic exposure and, therefore, the potential effects adverse.

- The flammability of propellants makes it difficult to stir their mixtures at room temperature.

Although Warnke said he believed he had overcome these difficulties, the suspensions he taught were not subjected to performance tests with metering valves or placed in cans equipped with valves to evaluate their

5/12 performance characteristics. In addition, Warnke teaches only formulations with a single active ingredient, a surfactant and isobutane with a maximum of 10% propane in the formulation. In the present invention, other formulation compositions have been found to make such formulations useful for metered dose pharmaceutical inhalers.

Therefore, although hydrocarbons have been tested as possible substitute propellants for pressurized metered dose inhalers, formulations suitable for obtaining the proper performance characteristics for pressurized metered dose inhalers have yet to be found.

DESCRIPTION OF THE INVENTION

Surprisingly, the inclusion of an alcohol 1 allows the suspension and solution of the formulation in metered dose inhalers that use hydrocarbons as propellants with the same or greater deposition than some formulations with hydrofluoralkanes, ensuring satisfactory dose uniformity.

DETAILED DESCRIPTION OF THE INVENTION

It has surprisingly been found that the addition of an alcohol can lead to substantially more stable suspension formulations based on hydrocarbon propellants, with the uniformity of the appropriate dose and greater deposition than some hydrofluoralkane formulations on the market. Said formulations contain hydrocarbons as the main propellants and can also include a certain proportion of hydrofluoroalkanes. At the same time, the addition of alcohol allows the use of two pressure filling stages, which is much safer, since the first portion to be filled is a concentrate of the active ingredient dissolved or suspended in ethanol or another suitable alcohol, or their mixtures. The addition of alcohol also makes it possible to dissolve some active ingredients, such as ipratropb bromide, fenoterol hydrobromide and others, to obtain solutions formulations of these active ingredients stabilized by the addition of acids.

Although it is not intended to be limited to any particular theory, it is believed that the addition of alcohol to the formulation helps to achieve the previous results because it profoundly alters the dielectric constant of the dispersion medium, modifying the

6/12 flocculation behavior and the size of the floating particles. This change is so profound that even the addition of n-propane in a large proportion alters the flocculation behavior of the suspended particles.

In all preparations the propellants used are hydrocarbons or suitable mixtures of hydrocarbons with hydrofluoroalkanes. Hydrofluoroalkanes can be selected from the group: Norflurane (1,1,1,2-Tetrafluoroethane, also called HFA 134a), HFA 227ea (1,1,1,2,3,3,3-heptafluoropropane) or others known. Hydrocarbons can be selected from the group: Isobutane, propane, n-butane, n-pentane or others known.

In all preparations the alcohol used is one of the group anhydrous ethanol, isopropanol and others. The amount to be used should be between 0.1 to 20% w / w, in the case of formulations that contain at least one active ingredient in suspension and 1 to 30% w / w, in the case of formulations that contain only dissolved active ingredients. If necessary, water can be added.

In all preparations, an adequate amount of a pharmacologically active ingredient is added to obtain the correct dose when the jet is released from the valve metering chamber. The active ingredients may be: Salbutamol, salbutamol sulphate, r-salbutamol and its salts, beclomethasone dipropionate, budesonide, fluticasone propionate, fluticasone fumarate, salmeterol xinafoate, dihydrated formoterol fumarate, phenoterol hydrobromide, phenoterol bromide ciclesonide and other salts and derivatives, as well as other therapeutically active substances suitable for administration via inhalation.

In some preparations, particularly those in which at least one active ingredient is in suspension, suspension stabilizers or surfactants taken from the group are included: Oleic acid, sorbitan trioleate, lecithin, perfluorinated surfactants, polyethylene glycols, poloxamers, polyvinylpyrrolidone or others known. The amount used is from 0.001 to 5% w / w, depending on the active ingredient and the stabilizer used.

In some preparations the active ingredients are in suspension and in others they are dissolved by using the appropriate amount of alcohol or

7/12 alcohol and water.

In these preparations in which the active ingredient is in suspension, it must be micronized so that 100% of the particles remain below 20 μτη and 95% of the particles below 10 μνη.

In some preparations, in particular in the case of formulations that have at least one dissolved pharmacologically active ingredient, a stabilizer such as an acid and / or other antioxidant will be useful. The acids can be taken from the group: Citric acid, tartaric acid, EDTA, hydrochloric acid, sulfuric acid and others known in the art. Antioxidants can be taken from the group: Ascorbic acid, tocopherol, tocopherol acetate, EDTA, its salts and / or derivatives and others known in the art. The inclusion of alcohol increases the solubility of these excipients and allows their introduction if necessary.

All formulation preparations are packaged in cans equipped with a metering valve.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1. Flocculation behavior of various formulations using hydrocarbons as propellants, with and without ethanol, with budesonide as an active ingredient in suspension and with inactive ingredients as shown in Example 1. The image on the left shows the initial condition and the image on the right depicts the formulation image after ten seconds.

Figure 2. Flocculation behavior of various formulations using hydrocarbons as propellants, with and without ethanol, with salbutamol sulfate as active ingredient in suspension, ipratropium bromide monohydrate or beclomethasone dipropionate as dissolved active ingredient and with inactive ingredients as shown in Example 3. The image on the left shows the initial condition and the image on the right depicts the formulation image after ten seconds.

Figure 3. Flocculation behavior of the formulation using a hydrocarbon and hydrofluorocarbon as propellants, with ethanol, with salbutamol sulfate as active ingredient in suspension and with inactive ingredients as shown in Example 4. The image on the left shows the initial condition and the image of

8/12 right depicts the formulation image after ten seconds.

EXAMPLE 1

This example illustrates the flocculation behavior of various formulations using hydrocarbons as propellants, with and without ethanol and with budesonide 5 as a suspended active ingredient.

Composition w / w Ingredient THE B Ç D Budesonide 0.73 0.73 0.65 0.73 Sorbitan trioleate 0.65 1.31 0.64 0.65 Anhydrous ethanol 5 2 Isobutane qs qs 100 qs 100 qs 100 qs 100

The formulations were packed in pressurized glass test tubes and photographed (see Figure 1). Formulations C and D clearly show flocculation without rapid sedimentation. This is advantageous because the floating particles are clustered together, joined by relatively weak electrostatic forces. This is the best way to avoid agglutination, which is the formation of tightly grouped sediments that are very difficult to redisperse. In the photographs presented it is evident that formulations without ethanol do not flocculate and tend to form sediment very quickly at the bottom of the test tubes.

Photographs of formulations A, B, C and D at time zero and after 10 15 seconds are presented in order to observe the presence or absence of flocculation and the formation of a firm sediment in alcohol-free formulations.

Figure 1

EXAMPLE 2

This example illustrates formulations with dissolved active ingredients.

Composition w / w Ingredient THE B

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Ipratropium bromide monohydrate 0.07 Beclomethasone dipropionate - 0.18 Ethanol 10 5 Isobutane qs 100 qs 100

EXAMPLE 3

This example illustrates formulations with dissolved and suspended active ingredients.

Composition as p / p Ingredient THE B Salbutamol Sulfate 0.43 0.43 Ipratropium bromide monohydrate 0.07 Beclomethasone dipropionate —— 0.18 Sorbitan trioleate 1.3 - Lecithin - 0.5 Ethanol 10 5 Isobutane qs 100 qs 100

In both formulations, salbutamol sulfate is in suspension and the other pharmacologically active ingredient is dissolved.

The images reveal an excellent sedimentation behavior without the formation of firm sediments at the bottom of the test tube (see Figure 2).

Figure 2

EXAMPLE 4

This example illustrates the possibility of adding hydrofluoroalkane as an additional ingredient in a formulation.

Ingredient % w / w

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Salbutamol Sulfate 0.18 Sorbitan trioleate 0.30 Ethanol 2.0 HFA 134a 29.4 Isobutane qs 100

The following image illustrates the slow sedimentation behavior of this formulation: (see Figure 3)

EXAMPLE 5

This example illustrates the performance characteristics of a salbutamol sulfate formulation packaged in cans equipped with a valve.

Ingredient mg / actuation Salbutamol Sulfate 0.120 Sorbitan trioleate 0.180 Anhydrous ethanol 0.554 Isobutane qs q 27.7

The ethanolic concentrate was introduced into the cans, the valve was later attached and, finally, the isobutane was introduced under pressure through the valve.

The metered dose inhalers were tested for uniformity of dose administered using a USP / European 10 Pharmacopeia sampling device and the mean percentage range was 87.8% minimum to 104.6% maximum. [The pharmacopoeial requirements indicate that 9 out of 10 jets must be within 75% to 125% and a jet must be within 65% to 135%.]

The mass of fine particles was determined using an Andersen Cascade Impactor and 51.2 jug was measured per actuation.

From the literature (Dellamary LA et al, Pharmaceutical Research Vol. 17, No. 2,

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200, ρ. 168-174), we know that Proventil HFA, currently on the US market, has a mass of fine particles per jet of around 45.1 µg.

As can be seen, this formulation surprisingly reaches a larger mass of fine particles with the same amount of Salbutamol Sulfate per actuation (in both cases 0.120 mg per actuation), although the isobutane vapor pressure (3.2 bar at 21 ° C according to the USP monograph) is much lower than that of Norflurane (propellant used in the formulation of Proventil HFA with a vapor pressure of 5.7 bar at 20 ° C, according to the Handbook of Pharmaceutical Excipients 2nd Edition, published by the American Pharmaceutical Association & the Pharmaceutical Press, printed in Britain in 1994).

EXAMPLE 6

This example illustrates the performance characteristics of another formulation of salbutamol sulfate containing propane and isobutane as propellants packaged in cans equipped with a valve.

Ingredient mg / actuation Salbutamol Sulfate 0.120 Sorbitan trioleate 0.180 Anhydrous ethanol 0.554 Isobutane 18.8 Propane qs q 27.7

The ethanolic concentrate was introduced into the cans, the valve was attached afterwards and, finally, the isobutane was introduced under pressure through the valve.

Pressurized metered dose inhalers were tested for administered dose uniformity using a USP / European Pharmacopeia sampling device and the average percentage range was 83.9% at least and 110.7% at most ( The pharmacopoeial requirements indicate that 9 out of 10 jets must be within 75% to 125% and a jet must be within 65% to 135%).

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The mass of fine particles was determined using an Andersen Cascade Impactor and 61.2 / zg was measured per actuation.

From the literature (Dellamary LA et al, Pharmaceutical Research Vol. 17, No. 2, 200, p. 168-174), we know that Proventil HFA, currently on the US market, 5 has a mass of fine particles per jet around 45.1 jug.

As can be seen, this formulation surprisingly reaches a larger mass of fine particles (about 36% more) with the same amount of salbutamol sulfate per actuation (in both cases 0.120 mg per actuation), although the vapor pressure of mixture 30/70% w / w propane + isobutane used in this formulation (5.1 bar according to the average acceptable values of vapor pressure for propane and isobutane at 21 ° C according to USP), is lower than the norflurane (propellant used in the formulation of Proventil HFA having a vapor pressure of 5.7 bar at 20 ° C according to the Handbook of Pharmaceutical Excipients 2nd Edition, published by the American Pharmaceutical Association & the Pharmaceutical Press, 15 printed in Great Britain in 1994).

Claims (11)

1. Pressurized metered dose pharmaceutical inhalers CHARACTERIZED for including: At least one pharmacologically active ingredient; At least one hydrocarbon propellant; At least one aliphatic alcohol between 0.1% and 30% w / w; At least one surfactant between 0.001% and 5% w / w; A dispensing medium consisting of a can equipped with a measuring valve providing between 20 and 200 µL of the formulation by actuation. 2. Pressurized metered dose pharmaceutical inhaler according to claim 1, characterized by the hydrofluorocarbon propellant containing up to 30% w / w of the contents of said metered dose pressurized pharmaceutical inhaler. A pressurized pharmaceutical inhaler of a metered dose according to claim 1, CHARACTERIZED by said active ingredient being in suspension form. 4. Pressurized pharmaceutical inhaler of metered dose according to claim 1, CHARACTERIZED by said active ingredient being in solution form. A pressurized pharmaceutical inhaler of a metered dose according to claim 1, CHARACTERIZED by said surfactant being sorbitan trioleate. 6. Pressurized pharmaceutical inhaler of metered dose according to claim 1, CARA CTERIZED by said aliphatic alcohol 1 is anhydrous ethanol. 7. Pressurized pharmaceutical dose inhaler according to claim 1, CHARACTERIZED by said inhaler additionally including an antioxidant selected from a group of antioxidants that includes vitamin E and its derivatives, ascorbic acid and its derivatives, EDTA and its salts . 8. Pressurized pharmaceutical dose inhaler according to claim 1, characterized by said inhaler additionally including a 2/2 organic acid or an inorganic acid in a concentration ranging from 0.00001% to 0.1% w / w to improve chemical stability. 9. Pressurized pharmaceutical inhaler of metered dose according to claim 1, CHARACTERIZED by said metering valve to provide 5 50 to 100 pL of the formulation per actuation. A pressurized metered dose pharmaceutical inhaler according to claim 1, CHARACTERIZED that said active ingredient is selected from a group of drugs administered by inhalation including salbutamol, salbutamol sulfate, beclomethasone dipropionate, budesonide, formoterol fumarate, 10 fluticasone propionate, fluticasone fumarate, mometasone furoate, salmeterol xinafoate, ciclesonide, ipratropb bromide, oxitropb bromide and tiotropb bromide. A pressurized metered dose pharmaceutical inhaler according to claim 1, CHARACTERIZED by said propellant being selected from a group of propellants derived from isobutane, butane and isopropyl hydrocarbons.