SK278930B6 - Anti-asthmatic aerosol preparation - Google Patents

Abstract

This patent describes an aerosol preparation in a form of suspension which is prepared based on mixing of dispersion medium, active substance insoluble in this dispersion medium, surface active substance (substances) and / or dispersion agent (agents) where the compound with a general formula (I) is applied, playing role of dispersion agent, where x, y, v and z are integers, independent of each other, with a value of 6, 7 or 8. This preparation can be prepared in order to be applied per inhalation or with the use of intranasal or external procedure.

Description

The present invention relates to a novel antiasthmatic aerosol formulation in suspension form.

The aerosol formulation of the invention is prepared by mixing the dispersing medium, the active agent in the dispersing medium of the insoluble, the surfactant (s) and / or the dispersing agent (s).

The formulation according to the invention can be used in particular as a pharmaceutical composition for inhalation or intranasally or for external use.

The aerosol formulation of the invention comprises a suspension of a liquid dispersing medium (propellant) and an active agent of a suitable particle size, wherein the active agent is insoluble in the propellant and the suspension is formed using surfactants and / or dispersants.

BACKGROUND OF THE INVENTION

When such formulations are applied, the dispersing medium evaporates and the surfactant (s) and active ingredient (s) dispersed in the gas phase penetrate the application sites (lungs, nasal mucosa, etc.). The surfactants and / or dispersants used must meet the following requirements:

(a) they must be inert against the active substance and the dispersing medium; they should be biodegradable and not toxic; organs and parts of the organism they come into contact with should irritate as little as possible; they should have an acceptable odor and taste.

(b) they should ensure the appropriate degree of dispersion in the carrier gas and, further, the stability of the suspension, characterized by the following parameters: sediment volume, ability to redisperse, amount of particles adhering to valve or bottle walls, particle size distribution,

c) they should not inhibit (rather increase) the dissolution of the active ingredient into body fluids.

The preferred choice and amount of surfactant (s) or dispersant (s) meeting these requirements is a difficult task.

To date, the use of the following surfactants and / or dispersants for the preparation of aerosol formulations in suspension form has been reported in the art: oleyl alcohol, oleic acid and its esters formed with polyhydric alcohols such as sorbitan monooleate (Span-80 ^r ), sorbitan trioleate (Span-85 ^R). ), soya lecithin, etc. (Aerosol Age, April 1985, Canadian Patent No. 1120441).

SUMMARY OF THE INVENTION

The present inventors have now surprisingly found that the use of the compounds of formula (I) very advantageously affects the properties of the formulation, both the hydrophobic environment (suspension use) and the hydrophilic environment (body fluid environment).

On the one hand, the stability characteristics of the formulation (suspension) can be greatly improved, and in some cases the amount of surfactant (s) can be reduced or even eliminated. On the other hand, the active ingredients of the formulations containing the compound of formula (I) as a dispersing agent dissolve in body fluids at a faster rate than from the formulations containing said surfactants and / or dispersing agents.

It is an object of the present invention to provide an antiasthmatic aerosol formulation for administration by inhalation or intranasally or externally comprising an active ingredient in the form of a suspension in a dispersing medium, a surfactant and / or a dispersing agent, characterized in that it contains 0.001 to 20% by weight. % sodium chromoglycolate, 0.01 to 5 wt. compounds of formula (I)

CH ₃ - (CH _{2) x} CH = CH _{(CH2) s} -COO-CH ₂ - (CH ₂₎ -CH = CH- _{(CH2) z} -CH ₃ (I) wherein x, y , the ligand is 6, 7 or 8, 0.01 to 5.0 wt. % of another surfactant selected from the group consisting of oleyl oleate and sorbitan oleate; a dispersing medium selected from the group consisting of haloalkanes and nitrogen.

Preferably, the composition of the present invention comprises a compound of formula (I) wherein x; y; v and z have a value of Ί.

Oleyl oleate as a dispersed agent is a component of emulsion systems in cosmetic and pharmaceutical formulations. Its use in suspension aerosol formulations is not yet known.

Preferred preparations may contain 0.001 to 20% by weight, preferably 0.5 to 10% by weight. of the active ingredient, 0.01 to 5% by weight, preferably 0.3 to 2% by weight, of a compound of formula (I) in which x, y, and v are integers having values of 6.7 to 8.0, 0 to 0 %, Preferably 0.01 to 1 wt. % further surfactant and 66 to 99 wt.%, preferably 85 to 98 wt. dispersing medium.

Large amounts of active ingredients can be employed in the compositions of the invention.

The formulations according to the invention can be used in various application areas, primarily as inhalants, further for nasal and optionally external use.

The following is a list of treatment areas that can be used to administer the compositions of the invention and some representative examples are given. This list is illustrative only and is intended as a guide for those skilled in the art. The compositions of the invention may contain as active ingredients sympathomimetics (e.g., adrenaline, isoprenaline, orciprenaline, terbutaline, salbutamol, phenoterol, rimiterol); anticholinergic bronchodilators (e.g. ipratropin); corticosteroids (e.g. beclomethasone, dipropionate, betamomethazone valerate, triamcinolone acetonide, budesonide); other hormones (e.g., oxytocin, insulin, sex hormones, glucagon) or desmopressin as an antidiabetic agent; vasopressin such as antidiuretic hormone; mucolytics (e.g., N-acetylcysteine, sodium mercaptoethanesulfonate); calcium antagonists (e.g., nifedipine); antibiotics (e.g., carbenicillin, gentamycin); methylxanthines (e.g., theophylline, aminophylline), antihistamines (tripeleamine, chlorpheniramine maleate, diphenylhydramine hydrochloride); antiviral drugs (e.g. Ribamycin); cardiovascular agents (e.g., nitroglycerin); anti-migraine (e.g. ergotamine) and mixtures thereof.

Antiasthmatic formulations according to the invention have been found to be particularly advantageous for inhalation or intranasal administration.

Sodium chromoglycolate may be advantageously used as the active ingredient of the antiasthmatic preparations, and it is preferably used without drying (with a water content of about 9% by weight) for the preparation of the preparations according to the invention. This is surprising since, according to the description of Canadian patent no. 1120441, only the active ingredient with a water content of less than 5% by weight is suitable for the preparation of the aerosol formulation in suspension form of suitable quality.

Bromohexinium chloride may also be used as the active ingredient.

An important aspect is the particle size of the components used. The requirement for aerosol formulations is that the active ingredients used are microcrystalline or micronized, i. have a suitable particle size.

The required particle size depends on the area of application. Generally, the particle size necessary for a given application area is used. Thus, in the case of inhalation formulations, the particle size of 90% should be less than 10 Nm, preferably less than 5 Nm, in the case of nasal formulations, the size of 90% of the particles should be less than 20 µm, while in the case of external formulations use is the particle size determined by the parameters of the spray system.

The active ingredient and the required particle size can be prepared by suitable crystallization or any of the known dusting methods.

The concentration of the active substance (s) is generally in amounts of from 0.001 to 20% by weight, preferably from 0.5 to 10% by weight. % and most preferably from 1 to 5 wt.

Other surfactants and / or dispersants may optionally be used in addition to the compounds of formula (1). Mixtures of oleyl oleate and various sorbitan oleate may be advantageously used. In such a case, the amount of sorbitan oleate (s) constitutes only the proportion necessary to provide the desired properties of the oleyl oleate-free formulation.

The amount of other surfactants and / or dispersants in the formulation is generally from 0 to 5% by weight, preferably from 0.001 to 1% by weight. % and most preferably from 0.01 to 0.1 wt.

Non-toxic compounds which evaporate at room temperature and atmospheric pressure, such as various alkane derivatives, in particular various chlorofluoroalkanes, can be used as the dispersing medium (propellant). A mixture of said propellants with nitrogen may also be used. Thus, for example, monofluorotrichloromethane (propellant 11), difluorodichloromethane (propellant 12), trifluorotrichloroethane (propellant 113) and tetrafluorodichloroethane (propellant 114) may be used. The amount of propellant is generally in an amount of from 66 to 99% by weight, preferably from 85 to 98% by weight.

The formulations of the invention, in particular formulations for nasal or external use, may contain other excipients and carriers, for example a pH-adjusting buffer (e.g. phosphate buffer), antioxidants (ascorbic acid, bisulfites), preservatives (e.g. benzalkonium chloride) and water.

These aerosol formulations can be prepared by known methods, where after mixing all the ingredients the mixture is filled into vials. cold or pressurized (optionally using a combination of the two).

The additives are preferably mixed in the following order: the surfactant (s) and / or dispersant is dissolved in the liquid dispersing medium (optionally pre-cooled), followed by the addition of the active agent (s).

A commonly used stirrer for preparing suspensions at high rpm (at least 1000 rpm) is used for mixing.

The vials must be provided with a dispensing device to allow the application of a suitable dose. For example, it is preferred to adjust the dosage of active ingredient in the case of sodium chromoglycolate to a value of 1 to 5 mg. In clinical trials, the formulation of Example 3 at a dose of 1 mg has shown to have the same effect as a capsule at a conventional dose of 20 mg.

Especially preferred are formulations containing the following amounts of components (in% by weight): sodium chromoglycolate 1 to 2 oleyl oleate 0.3 to 2 sorbitan trioleate 0 to 0.2 propellant (dispersing medium) to 100.

Advantageously, the following mixture (in% by weight) can be used as the carrier gas: propellant 11 55 to 75 propellant 12 10 to 25 propellant 114 114 to 25

The properties of the formulations according to the invention were compared with those of the known formulations as follows.

A. The absorption of the active ingredient from the formulations of the invention and from known formulations was determined in vitro in a Miihlemann-type dialysis apparatus shown in FIG. 1. An explanation of the symbols used in FIG. 1 is as follows:

sample dosing glass tube receptor phase (pH = 7.4, phosphate buffer) thermostat inlet double wall dialysis vessel outlet to thermostat dialysis membrane magnetic stirrer magnetic stirrer device (IKACAG ROT)

As the membrane was used. membrane for dialysis dialysis (HOECHST, Germany). This membrane was pretreated for 17-18 hours in phosphate buffer pH 7.4 prior to measurement.

ml of buffer solution was placed in a measuring device. The temperature of the measuring system was maintained at 37 ° C and the stirrer was operated at 100 rpm.

Each of the different aerosol formulations was evaluated using 3 parallel doses contacted with the membrane. 1 dose represents the amount of formulation released from the vial by releasing the metering valve after shaking the vial; (contains about 1 mg sodium chromoglycolate). The amount of drug was determined by accurately weighing the vial before and after dose release using an analytical balance.

For a specified period of time, samples were taken from the receptor phase of the system and the amount of sodium chromoglycolate transferred from the donor phase was measured using a spectrophotometer.

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

Table 1

Change in concentration of the distributed active ingredient (in% by weight) over time (in hours)

Prfkl time (hours «ny) e. 1 2 3 4 5 6 1 22.8 ± 2 36.613 48316 54.715 58.117 60916 II 15.4 ± 2 27.112 38312 42.014 48.915 48.818 III 3.511.5 10.211 46.812 58314 61916 64018 IV 5.611.5 10,811 42312 46.812 47.815 48516 5 44.912 57.212 58.514 59114 59.915 61815 1 51.612 52.913 70114 73313 74316 74716 3A 32012 50.213 56.414 58.713.5 60.915 62815

(Preparations were prepared according to the examples below.)

It is apparent from the results of the above tests that the active ingredient dissolves to a substantially higher degree from the oleyl oleate-containing formulations (formulations prepared according to Examples 1, 3A and 5) than from the comparative formulations (I to IV), i. j. preparations containing the accelerating effect of oleyoleate.

B. Table 2 summarizes the physical properties characterizing the different preparations (the symbols of the evaluated preparations are identical to the symbols in Table 1). The parameters and symbols to be used in Table 2 are as follows:

- sediment volume (% v / v) VSE

- redispersing ability and number of shaking necessary for redispersion, ie shaking corresponding to 180 ^Q ABR position change

- amount of ASE sediment

- material adhering to the aerosol container (mg) MAB

material adhering to the valve of the aerosol bottle (mg)

- average particle size, particle size distribution (determined using HTAC CP-420)

Table 2

average vfkotf £ Aste / pm related to Pr. VSE ABR OSE MAV MAB count volume 1 2.8 * 34 small 22.3 9:50 3.20 9:41 111 2.8 * 25 small 23.5 7.70 3.3 ' 9.77 IV 2S * 22 I have 22.9 9:32 3.92 10.73 35 2 23.5 720 3:33 7:40 30 »Y« j * 26.2 840 2.70 5:46 3A 18.5 2 itredný 18.2 620 3.13 5.74

The compact sediment is separated from the vial surface but is not dispersed in the liquid.

The following examples serve to illustrate the invention without limiting it in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 Ingredients: % wt. disodium chromoglycolate (water content 9% by weight) 1.7 oleyloleate 1.3 monofluórtrichlórmetán 70.7 difluórdichlórmetán 13.15 tetrafluórdichlóretán 13.15

100.00

The monofluorotrichloromethane is cooled to 10 + 1 ° C. The oleyl oleate is dissolved in cooled monofluorotrichloromethane and disodium chromoglycolate is added in small portions as the active ingredient under continuous stirring (about 1,400 rpm). The mixture is stirred for 45 minutes at about 2800 rpm. The suspension is filled into aerosol bottles under continuous stirring (about 1400 rpm / min.) And cooling. The vials are sealed with suitable metering valves, which are then individually or mixed, under pressure, filled into the vials with two more gases.

Example 2

Composition: wt.

disodium chromoglycolate (water content 9% by weight) 3,3 oleyl oleate0,6 polyoxyethylene sorbitan monooleate0,1 monofluorotrachloromethane67,0 difluorodichloromethane 14,5 tetrafluorodichloroethane14,5

100.00

The monofluorotrichloromethane is cooled to temperature

5 ° C. The cooled monofluórtrichlórmetáne dissolved oleyl oleate and polyoxyethylene sorbitan monooleate. The solution thus obtained is added to a mixture of difluorodichloromethane and tetrafluorodichloroethane cooled to -45 ° C. At this temperature, with stirring, to the mixture is added in portions disodium chromoglycate (about 2500 revolutions / min.). After an additional 20 to 30 minutes of stirring, the suspension is filled into aerosol vials with continuous mixing and cooling, and the vials are sealed with suitable metering valves.

Example 3 Preparation containing the dose Ingredients: LMG (3A) 5 mgl % wt. sodium chromoglycolate 1.7 3.3 oleyloleate 0.66 0.53 sorbitan 0.05 0.05 propellant 11 68.64 69,82 propellant 12 14,475 13.15 propellant 14,475 13.15

The preparation was prepared as described in Example 1

except that sorbitan trioleate dissolves after oleyl oleate is dissolved. Example 4 Ingredients: % wt. brómhexíniumchlorid 2,040 oleyloleate 0,680 sorbitan trioleate 0,170 trifluorotrichloroethane 35,742 difluórdichlórmetén 30,650 tetrafluórdichlóretán 30,650 aroma 0,068

100.00

Trifluorotrioroethane was cooled to 10 + 1 ° C. Oleyoleate and then sorbitan trioleate are dissolved in cooled trifluorotrichloroethane and bromhexinium chloride (about 1500 rpm) is added in small portions with stirring. The mixture was stirred for an additional 50 minutes (about 2500 rpm). The suspension is filled into aerosol bottles under continuous stirring (about 1400

276 RPM) and cooling. The vials are sealed using metering valves and the two other gaseous components, mixed or separated, are filled into the vials under pressure.

Example 5

Composition: wt.

chromoglycate sodný1,7 oleyloleát0,66 injection, injection, 1169.74 1214.45 11414.45 injection,

The preparation is prepared as described in Example 1. Formulations I to IV

The prior art formulations (II to IV) and the comparative formulation (I) were prepared as described in Example 1 except that the sorbitan trioleate was dissolved in cooled monofluorotrichloromethane instead of oleyl oleate. The amounts of the ingredients are given in Table 3.

Table 3______________________________

Amount in% wt.

Name of component I II III IV

chromoglycolate disodrý 1.7 1.7 1.7 1.7 sort itan tri oleate - 0.1 0.5 1.5 mofiofluórtrichlórmetári 70.0 69.9 69.5 68.5 (fifluórdíchlórmetán 14.1514.15 14.1514.15 tetrafhjôrtílchlóretán 14.1514.15 14.15 14.15

PATENT CLAIMS

Claims (2)

An antiasthmatic aerosol formulation for administration by inhalation or intranasally or externally, comprising an active ingredient in the form of a suspension in a dispersing medium, a surfactant and / or a dispersing agent, characterized in that it contains 0.001 to 20% by weight. % sodium chromoglycolate, 0.01 to 5 wt. compounds of formula (I) CH 3 (CH _{2) x} CH = CH _{(CH2) s} -COO-CH ₂ - (CH ₂₎ -CH = CH- _{(CH2) z} -CH ₃ (I) wherein x, y, a chain is 6,7 or 8, 0.01 to 5.0 wt. % further surfactant selected from the group consisting of oleyl oleate and sorbitan oleate; a dispersing medium selected from the group consisting of haloalkanes and nitrogen. Composition according to claim 1, characterized in that it contains a compound of the general formula (I), wherein x, y, v and z have a value of 7.