HU211496A9 - Aerosol composition and a process for preparing same - Google Patents

Description

The present invention relates to a novel suspension aerosol formulation and a process for its preparation.

The process of the present invention is carried out by combining a dispersion medium, a drug insoluble in the dispersion medium, surfactant (s) and / or dispersant (s).

The composition of the invention may be used primarily as an inhalation, intranasal or topically applied pharmaceutical composition.

The aerosol formulation of the present invention comprises a suspension of the liquid dispersion medium ("propellant") and the active ingredient of appropriate particle size, wherein the active ingredient is insoluble in the propellant and is formulated with surfactants and / or dispersants.

As the formulations are used, the dispersion medium is evaporated and the surfactant (s) and active ingredient (s) dispersed in the vapor are delivered to the site of application (lungs, mucous membranes, etc.).

The surfactants and / or dispersants to be used must meet the following requirements:

(a) be inert to the active substance and the dispersion medium; be biodegradable and non-toxic; irritation of the parts of the body and organs coming into contact with them as little as possible; in addition, they must have a suitable smell and taste;

(b) ensure that the active ingredient is sufficiently dispersed in the propellant and that the suspension is stable (characterized by the following properties: sediment, redispersibility, amount of material adhered to the valve or cylinder wall, particle size distribution);

(c) do not inhibit (rather assist) the dissolution of the active substance in body fluids.

Choosing the right type and amount of surfactant (s) and / or dispersant (s) to meet the above requirements is a rather difficult task.

Specifically, the literature teaches the use of the following surfactants and / or dispersants in the preparation of suspension aerosol formulations; oleyl alcohol, oleic acid and esters of the latter with polyhydric alcohols such as sorbitan monooleate (Span-80 ^R ), sorbitan trioleate (Span-85 ^R ), soybean lecithin and the like. (Aerosol Age, August 1985; Canadian Patent No. 1,120,441).

Surprisingly, it has been found that the use of the compounds of formula I has a very beneficial effect on the properties of the composition, both in the hydrophobic medium (suspension used) and in the hydrophilic medium (body fluids).

On the one hand, the stability characteristics of the formulation (suspension) can thus be significantly improved, and in some cases the amount of surfactant (s) in the formulation may be reduced or even eliminated. On the other hand, the formulations of the formulations containing a compound of formula I as dispersants are more rapidly soluble in body fluids than formulations containing the above known surfactant (s) and / or dispersant (s).

According to the present invention, aerosol suspension formulations are prepared by mixing a dispersion medium, a drug insoluble in the dispersion medium and at least one surfactant and / or dispersant, wherein the at least one surfactant and / or dispersant is a compound of formula (I):

CH ₃ - (CH ₂ ) _x -CH = CH- (CH ₂ ) _y -COO-CH ₂ - (CH ₂ ) _v CH = CH- (CH ₂ ) ₁ , -CH ₃ (I) where x, y, v and z are integers 6, 7 or 8.

Of the various structural isomers of the compounds of formula (I), cis, cis derivatives are most preferred.

Among the compounds of formula I, in particular, the use of oleyl oleate has been found to be favorable (where x, y, v and z are 7).

As a dispersant, oleyl oleate is a component of emulsion systems for cosmetic and medical use. However, its use in suspension aerosols has not been known so far.

Preferred compositions are from 0.001% to 20% by weight, preferably from 0.5% to 10% by weight, of the active ingredient, from 0.01% to 5% by weight, preferably from 0.3% to 2% by weight of the compound of formula I, wherein x, y, v and z An integer of 6, 7 or 8 may contain from 0 to 5.0% by weight, preferably from 0.01 to 1% by weight, of another surfactant and from 66 to 99%, preferably from 85 to 98%, by weight of the dispersion medium.

A wide variety of active ingredients can be used in the compositions of the invention.

The compositions of the invention may be used in a wide range of activities, primarily as inhalation, nasal and possibly topical formulations.

The following are the areas of action in which the compositions of the present invention may be used, and some of the active ingredients of each of these fields of action are listed. This list is for guidance only and is intended as a guide for the practitioner. Thus, the compositions of the invention may contain sympathomimetics (e.g., adrenaline, isoprenaline, orciprenaline, terbutaline, salbutamol, phenoterol, rimiterol) as active ingredients; anticholinergic bronchodilators (e.g., ipratropin); corticosteroids (e.g., heclomethasone dipropionate, triamcinolone acetonide, budesonide); other hormone (e.g., oxytocin, insulin, sexual forehead, glucagon) or desmopressin as antidiabetic; vasopressin as an antidiuretic hormone; mucolytic (e.g. N-acetyl cysteine, sodium mercaptoethanesulfonate); calcium antagonists (e.g., nifedipine); antibiotics (e.g. carbenicillin, gentamicin); methylxanthines (e.g., theophylline, aminophylline); antihistamines (tripelenamine, chlorpheniramine maleate, diphenylhydramine hydrochloride); antiviral agents (e.g., Ribamycin); a cardiovascular construct (e.g., nitroglycerin); anti-migraine agents (e.g., ergotamine); and a mixture of the active ingredients listed.

Particularly preferred have been the inhaled or nasal application of the anti-asthma compositions of the present invention.

Sodium chromoglycate, which is conveniently used without drying (at a water content of about 9%), for the preparation of the compositions of the invention, is very advantageously used as an active ingredient in anti-asthma compositions. This is surprising, given that no. According to the Canadian patent, only the active ingredient containing less than 5% water is suitable for the preparation of aerosol suspension formulations of suitable quality.

Bromohexinium chloride may also be advantageously used as an active ingredient.

An important consideration is the particle size of the active ingredients used. Aerosol formulations require that the active ingredient be microcrystalline or micronized, that is to say of a suitable particle size.

The required particle size depends on the field of application. Generally, the desired particle size is used for the particular application. Thus, for inhalation formulations, 90% of the particles should have a size of less than 10 micrometers, preferably less than 5 micrometers. For nasal formulations, 90% of the particles should be less than 20 micrometres in size. For externally applied formulations, the particle size is determined by the system characteristics of the nozzle.

The active ingredient of the required particle size may be prepared by suitable crystallization or any known comminution method.

The concentration of active ingredient (s) in the composition is generally from 0.001 to 20% by weight, preferably from 0.5 to 10% by weight, particularly preferably from 1 to 5% by weight.

In addition to the compounds of formula (I), additional surfactants and / or dispersants may be optionally used. Mixtures of oleyl oleate and various sorbitan oleate are preferred. In this case, the amount of sorbitan oleate (s) is only a fraction of the amount that would be required without the oleyl oleate to provide the desired properties of the formulation.

The amount of additional surfactants and / or dispersants in the composition is generally from 0 to 5%, preferably from 0.001 to 1%, particularly preferably from 0.01 to 0.1%.

As the dispersion medium ("propellant"), non-toxic substances, various alkane derivatives, in particular various chlorofluoroalkanes, which are readily evaporated at room temperature and at atmospheric pressure are used. A mixture of said propellants and nitrogen may also be used. Thus, for example, monofluorotrichloromethane (propellant 11), difluorodichloromethane (propellant 12), trifluorotrichloroethane (propellant 113) and tetrafluorodichloroethane (propellant 114) can be used. The amount of propellant gas is generally 66-99% by weight, preferably 85-98% by weight.

The compositions of the present invention, particularly those for nasal or topical administration, may also contain other adjuvants and carriers, such as pH adjusting buffers (such as phosphate buffer), antioxidants (ascorbic acid, bisulfites), preservatives (e.g. benzalkonium chloride) and water.

Aerosol formulations can be prepared by methods known per se, i.e., after mixing the ingredients, the mixture is filled into bottles by the so-called "cold" method or under pressure (or a combination of the two methods may be used).

Preferably, the ingredients are mixed in the following order: the surfactant (s) and / or dispersant (s) are dissolved in the (optionally pre-cooled) liquid dispersion medium and the active ingredient (s) is then added.

For mixing, a mixer conventionally used in the preparation of suspensions is used at a higher speed (at least 1000 rpm).

The bottles must be fitted with a metering device that provides the correct dose. For example, in the case of sodium chromoglycate, the dosage of the active ingredient may preferably be adjusted to 1 to 5 mg. In clinical trials, a dose of 1 mg of the composition of Example 3 provided the same effect as a standard capsule containing 20 mg of the active ingredient.

Compositions containing the following amounts of ingredients (% by weight) have been found to be particularly advantageous:

sodium chromoglycate 1-2 oleyl oleate 0.3-2 sorbitan trioleate 0-0.2 propellant (dispersion medium) gives 100

Preferably the following gas mixtures are used as propellant mixtures: propellant 11 55-75 propellant 12 10-25 propellant 114 10-25

The properties of the formulations of the present invention were compared with known formulations as follows.

A) The in vitro absorption of the drug from the formulations of the present invention and known formulations was determined using the Mühlemann dialysis apparatus shown in Figure 1. The symbols in Figure 1 have the following meaning:

Sample Addition Glass Tube Receptor Phase (pH 7.4; Phosphate Buffer) Thermostatic Conducting Heat Transfer Medium Double Wall Dialysis Vessel to Thermostat Conducting Heat Transfer Medium Dialysis Membrane Magnetic Mixing Magnetic Mixer (IKAMAG RCT).

A so-called kidney dialysis membrane (manufactured by Hoechst, Germany) was used per membrane. Prior to the measurements, the membrane was pretreated for 17-18 hours in phosphate buffer pH 7.4.

For the measurement, 50 ml of buffer solution was added to the apparatus. The temperature of the measuring system was maintained at 37 ° C and the stirrer was operated at 100 rpm.

For each of the different aerosol formulations, 3 parallel "doses" were contacted with the membrane. (One dose of the preparation it

A9 is the amount released from the shaken bottle by actuating the dosing valve once, containing about 1 mg of sodium chromoglycate.) The amount of active ingredient was determined by accurately weighing the bottle before and after the dose on an analytical balance. .

At regular intervals, a sample of the receptor phase of the system was taken and the amount of sodium cromoglycate transferred from the donor phase to the receptor phase was measured spectrophotometrically.

The results of the analytical measurements are shown in Table 1.

Table 1

Variation (t%) in diffused drug concentration over time (hour)

Example number Time, clock 1 2 3 4 5 6 I 22.6 ± 2 36.6 ± 3 48.3 ± 6 54.7 ± 5 58.1 ± 7 60.9 ± 6 11 15.4 ± 2 27.1 ± 2 36.3 ± 2 42.9 ± 4 46.9 ± 5 48.8 ± 6 III 3.5 ± 1.5 10.2 ± 1 46.8 ± 2 58.3 ± 4 61.9 ± 6 64.0 ± 6 ARC 5.6 ± 1.5 10.8 ± 1 42.3 ± 2 46.8 ± 2 47.8 ± 5 48.5 ± 6 5 44.9 ± 2 57.2 ± 2 58.5 ± 4 59.1 ± 4 59.9 ± 5 61.6 ± 5 1 51.6 ± 2 62.9 ± 3 70.1 ± 4 73.3 ± 3 74.3 ± 6 74.7 ± 6 3A 32.0 ± 2 50.2 ± 3 56.4 ± 4 58.7 ± 3.5 60.9 ± 5 62.8 ± 5

(The formulations were prepared as in the example given.) The above test results show that the active ingredient is dissolved much faster from the formulations containing oleyl oleate (formulations prepared in Examples 1, 3A and 5) than ARC. comparative formulation (i.e. formulations containing oleyl oleate are more effective).

B) Table 2 summarizes the typical physical properties of the different formulations (the numbering of the tested formulations is the same as that used in Table 1). The parameters tested and their designation in Table 2 are as follows:

- sediment volume (% vol) UTF

- redispersibility (and the number of shakes needed for this; shaking means a 180 change in position)

- amount of sediment UM

- substance (mg) APA adhered to aerosol can

- secretly adhered substance (mg) in aerosol dispenser

- average particle size, particle size distribution (measured on HLAC CP-420).

Table 2

Example number UTF PSP uM UPS FATHER Average particle size (micrometer) song | volume Based on I 2.9 ^30x few 22.3 9.50 3.20 9.41 111 2.6 ^25x few 23.6 7.70 3.38 9.77 ARC 2.5 ^22x few 22.9 9.32 3.92 10.73 5 35 2 many 23.5 7.20 3.33 7.40 1 30 3 many 26.2 6.40 2.70 5.46 3A 18.5 2 medium 16.2 6.20 3.13 5.74

^X The solid sediment separates from the surface of the bottle but is not dispersed in the liquid.

The invention is illustrated by the following Examples, which are not intended to limit the invention in any way.

Example 1

Ingredients: t% disodium chromoglycate (water content 9% by weight) 1.7 55 oleyl oleate 1.3 monofluorofluorotrichloromethane 70.7 difluoro-dichloromethane 13.15 tetrafluoro-dichloroethane 13.15 100.00 60

The monofluorotrichloromethane was cooled to 10 ± 1 ° C. The oleyl oleate is dissolved therein and the disodium chromoglycate active ingredient is added in small portions under constant stirring (about 1400 rpm). The mixture was stirred for 45 minutes (about 2800 rpm). The resulting suspension was filled into aerosol cans with continuous stirring (1400 rpm) and cooling. The bottles are sealed with a suitable metering valve, and the two additional gas components, either as a mixture or separately, are filled into the bottles under pressure through the valve.

HU 211 496 A9

Example 2

Composition:% disodium chromoglycate (water content 91%) 3.3 oleyl oleate 0.6 polyoxyethylene> sorbitan monooleate 0.1 monofluorotrichloromethane 67.0 difluorodichloromethane 14.5 tetrafluoride dichloroethane 14.5

The monofluorotrichloromethane was cooled to 5 ± 1 ° C. Dissolve the oleyl oleate in it and then the polyoxyethylene sorbitan monooleate. The resulting solution was added to a cooled mixture of difluorodichloromethane and tetrafluorodichloroethane to -45 ° C. At this temperature, disodium chromoglycate is added in portions under constant stirring (about 2500 rpm). The suspension is stirred for an additional 2030 minutes, then filled with aerosol cans under constant stirring and cooling and sealed using suitable dispensing valves.

Example 3 Preparation of mg (3A) 5 mg (3B)

Ingredients: t% Sodium cromoglycate 1.7 3.3 oleyl oleate 0.66 0.53 sorbitan trioleate 0.05 0.05 propellant gas 11 68.64 69.82 propellant 12 14.475 13.15 propellant gas 114 14.475 13.15 The preparation is given in Table 1. The procedure is as described in Example 1b except that sorbitan trioleate is a after dissolving the oleyl oleate.

Example 4

Ingredients: t% bromine chloride hexinium 2,040 oleyl oleate 0.680 sorbitan trioleate 0,170 trifluoro-trichloroethane 35.742 difluoro-dichloromethane 30.650 tetrafluorodichloroethane 30.650 aroma 0,068 100.00

Trifluoro-trichloroethane was cooled to 10 ± 1 ° C. The cooled trifluoro-trichloroethane is dissolved in the oleyl oleate and the sorbitan trioleate, and bromo-hexinium chloride is added in small portions with constant stirring (about 1500 rpm). The mixture was stirred for 50 minutes (about 2500 rpm). The resulting suspension was filled into aerosol cans with continuous stirring (about 1400 rpm) and cooling. The bottles are sealed using the appropriate metering valves and the two additional gas components, either as a mixture or separately, are filled into the cylinders under pressure through the valve.

Example 5

Composition t% sodium chromoglycate 1.7

oleyl oleate 0.66 propellant gas 11 69.74 propellant 12 14.45 propellant gas 114 14.45

The composition was prepared according to the procedure described in Example 1.

I-IV. preparation

The prior art formulations (II-IV) and a comparative formulation (I) were prepared according to the procedure described in Example 1, except that sorbitan trioleate was dissolved in cooled monofluorotrichloromethane instead of oleyl oleate. The amount of ingredients is given in Table 3.

Table 3

Ingredient name Quantity, t% I II. III. ARC. dintárium cromoglycate 1.7 1.7 1.7 1.7 sorbitan trioleate - 0.1 0.5 1.5 mono-fluoro trichloromethane 70.0 69.9 69.5 68.5 difluoro-dichloromethane 14.15 14.15 14.15 14,15, tetrafluoro-dichloroethane 14.15 14.15 14.15 14.15

PATENT CLAIMS

Claims (16)

A process for preparing a suspension aerosol composition comprising mixing a dispersion medium, an active ingredient insoluble in the dispersion medium and at least one surfactant and / or dispersant, wherein the at least one surfactant and / or dispersant is a compound of formula I CH ₃ - (CH _{2) x} -CH = CH- (CH _{2) y} -COOCH ₂ - (CH _{2) v} -CH = CH- (CH _{2) z} -CH ₃ (I) wherein X, Y, and V Z is an integer of 6, 7 or 8. Process according to claim 1, characterized in that the compound of the formula I, wherein X, Y, V and Z are as defined in claim 1, is 0.01-5% by weight, preferably 0.3-21%. %. The process according to claim 1 or 2, wherein the compound of formula (I) is oleyl oleate, wherein X, Y, V and Z are 7. 4. Process according to any one of claims 1 to 4, characterized in that 0.001 to 20% by weight, preferably 0.5 to 10% by weight, of the active compound, 0.1 to 5%, preferably 0.3 to 2% by weight of the compound of formula (I), Y, V and Z are other surfactants as defined in claim 1, 0-5.01%, preferably 0.01-11%, and 66-99%, preferably 85981%, of the dispersion medium. 5. Process according to any one of claims 1 to 3, characterized in that an anti-asthmatic agent, preferably sodium chromoglycate, is used. 6. Process according to any one of claims 1 to 3, characterized in that the active ingredient is bromohexinium chloride. HU 211 496 A9 7. A process for preparing an aerosol composition as set forth in claims 1-5. as described in any one of Examples. An aerosol formulation, wherein the aerosol formulation of any one of claims 1-7. A process according to any one of claims 1 to 4. An aerosol composition comprising a dispersion medium, an active ingredient insoluble in the dispersion medium and at least one surfactant and / or dispersant, characterized in that the at least one surfactant and / or dispersant is a compound of formula I CH ₃ - (CH _{2) x} CH = CH _{(CH2) Y is} -COOCH ₂ - (CH ₂₎ v CH = CH (CH _{2) z} -CH ₃ (I) wherein X, Y, and V Z is an integer of 6, 7 or 8. 10. A composition according to claim 9, wherein the compound of formula I wherein X, Y, V and Z are as defined in claim 1 is 0.01-5% by weight, preferably 0.3-2%. t%. 11. A composition according to any one of claims 1 to 3, wherein the compound of formula (I) is oleyl oleate, wherein X, Y, V and Z are 7. 12. A 8-11. Composition according to any one of Claims 1 to 3, characterized in that 0.001 to 20% by weight, preferably 0.5 to 101% by weight, of the active ingredient, 0.01 to 5%, preferably 0.3 to 2% by weight, of the compound of the formula I Y, V and Z are as defined in claim 1 containing from 0 to 5.0%, preferably from 0.01 to 1% by weight of other surfactants and from 66 to 99%, preferably from 85 to 98%, by weight of the dispersion medium. 13. A 8-12. Composition according to any one of claims 1 to 3, characterized in that it contains an antistatic agent, preferably sodium chromoglycate. 14. A 8-12. Composition according to any one of claims 1 to 3, characterized in that it contains bromhexinium chloride as an active ingredient. An aerosol formulation as claimed in any of claims 1-5. as described in any one of Examples. An aerosol container, characterized in that a 8-15. A composition according to any one of claims 1 to 4.