RO113610B1 - Aerosol composition - Google Patents

Description

The present invention relates to an aerosol composition used in medical treatment.

A nasal aerosol composition is known, which consists of a mixture of volatile oils consisting of, 55% 1.8 cineole, 20% menthol, 15% anetole, 6% thymol, 4% caracol.

The invention relates to an aerosol composition, which consists of □, □ 01 to 20% of an active agent 0.01 to 5% dispersing agent having the formula CH ₃ - (CH ₂ ) _x -CH = CH - (CH ₂ ) _y C00-CH ₂ - (CH ₂ ] _y -CH = CH- (CH ₂ ) _z -CH ₃ (I), where x, y, v and z are integers having values 6, 7 or 8 to 5% surface active agent; 66 to 99% dispersion medium, the percentages being expressed by weight; preferably containing 0.5 to 10% active agent, the percentages being expressed by weight; preferably containing 0, 3 to 2% dispersion agent of formula I, the percentages being expressed by weight; preferably contains 0.01 to 1% surface active agent, the percentages being expressed by weight; preferably contains 85 to 98% average dispersion, the percentages being expressed by weight; the dispersing agent of formula (I) is oleyl oleate; the active agent is an anti-asthmatic active agent, preferably single cromoglycate sodium chloride, bromhexine active agent.

The present invention relates to a new suspension-spray composition.

The composition, according to the present invention, can be used in particular, as a pharmaceutical composition for inhalation, intranasally or externally.

The aerosol composition, according to the present invention, contains the suspension of the liquid dispersing medium ("propellant") and the corresponding granulating active agent, wherein the active agent is insoluble in the propellant and the suspension is formed by the use of surfactants and / or agents. dispersion.

When the compositions are used, the dispersion medium is evaporated and the surfactant (s) and the active agent (s) are distributed into vapors entering the application sites (lungs, nasal micoderma, etc.).

Surfactants and / or dispersing agents, to be used, must meet the following requirements:

a] must be inert to the active agent and the dispersing agent; they must be biologically degradable and non-toxic; they will irritate the parts and contact organs of the body to the smallest extent possible, they will also have a proper smell and taste;

b] must have an adequate degree of dispersion in the "propellant gas", also stability for the suspension (characterized by the following characteristics: volume of deposition, capacity of redispersion, amount of material, adhering to the valve or the walls of the cylinder, distribution) of granulation];

c] must not inhibit (but rather improve] the dissolution of the active agent in the body fluids.

Choosing the right type and amount of surfactant (s) and / or dispersing agent (s), which meet the above requirements, is quite a difficult task.

The foregoing material recommends the use of the following surfactants and / or dispersing agents for the preparation of suspended aerosol compositions:

Oleyl alcohol, oleyl acid and its esters formed with polyvalent alcohols such as sorbitan monooleate (Span-80 ^R ), sorbitan trioleate (Span-85 ^R ), soy lecithin, etc.

It has now been surprisingly found that the use of compounds of general formula I influences the properties of the composition in the most advantageous manner, both in a hydrophobic environment (in the suspension used) and in a hydrophilic environment (in the body fluids).

On the one hand, the properties that characterize the stability of the composition (suspension) can thus be significantly improved so that in

In certain cases the amount of surfactant (s) in the composition may be reduced or even eliminated. On the other hand, the active agents are dissolved in the body fluids by the compositions containing a compound of general formula I, as a dispersing agent at a higher rate than the compositions containing the surfactants and / or known dispersing agents, above. - mention. Accordingly, the present invention is an aerosol composition in suspended form obtained by mixing a dispersing medium, an active agent insoluble in the dispersing medium, a surfactant (s) and / or a surfactant (s). dispersion, wherein a compound of general formula I:

CH ₃ - (CH ₂ ) _x -CH = CH- (CH ₂ ) _y -COO-CH ₂ - (CH ₂ ) _v -CH = CH- (CH ₂ ) _z -CH ₃ (I) is used as an agent dispersion, in which x, y, v and z are integers with a value of 6, 7 or 8.

Among the different structural isomers of compounds of general formula I, cis, cis derivatives can best be used. 20

Of the compounds of general formula I, the use of oleyl oleate has been shown to be particularly advantageous (x, y, v and z each having value 7).

Oleyl oil as a dispersing agent is a component of emulsion systems for use as cosmetics and pharmaceutical compositions. Their use in aerosols, in suspended form, has not been well known until now. 30

Advantageous compositions may contain 0.001 to 20% by weight, preferably 0.5 to 10% by weight of an active agent, 0.01 to 5% by mass, preferably 0.3 to 2% by mass. a compound of 35 general formula I, in which x, y, are integers having the value 6.7 or 8, O at 5.0% by mass, preferably 0.01 at 1% by mass from another surfactant and 66 to 99% by mass, preferably 40, 85 to 98% by mass from a dispersion medium.

In the compositions, according to the present invention, a wide variety of active agents can be used. 45

The compositions according to the present invention can be used in a wide range of effects, first of all for inhalation, also for nasal use and, possibly, for external use. 50 in the following is given a list of domains of effect, in which, the compositions according to the present invention, can be used, and in which, are given some representative of them. This list is for illustrative purposes only and serves as a guide for a subject matter specialist. Thus, the compositions according to the present invention may contain as sympathomimetic active agents (for example, adrenaline, isoprenaline, orciprenaline, terbutaline, salbutamol, phenoterol, rimiterol); anticholinergic bronchial dilators (for example, ipratropinum); corticosteroids (for example, heclometasone dipropionate, beta-metasone valerate, triamcinolone acetanide, budesonide); other hormones (for example, oxytocin, insulin, sex hormones, glucagon) or desmopressin like, antidiabetic; vasopressin ca, antidiuretic hormones; mucolytics (for example, N-acetyl cysteine, sodium mercaptoethanesulfonate; calcium, for example, nifedipine antagonists; antibiotics (for example, carbenicillin, gentamicin); methyl xanthins (for example, theophylline, aminophylline); chlorofeniramine melea, diphenylhydramine hydrochloride); antiviral agents (for example, ribamycin); cardiovascular agents (for example, nitroglycerin); anti-migraine agents (for example, ergotamine); and mixtures thereof.

The application of anti-asthmatic compositions according to the present invention for inhalation or intranasal use has been found to be particularly preferred.

Sodium chromoglycate can be used very advantageously as an active agent of anti-asthmatic compositions, wherein this agent can preferably be used without drying (with a water content of about 9% by mass) for the preparation of compositions according to the invention. girl.

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This is surprising because, according to a Canadian Patent, only one active agent, with a water content of less than 5% by mass, is suitable for the preparation of aerosol compositions in suspended form of suitable quality.

As an active agent, bromhexinium chloride may also be used preferably. The granulation of the active agents used is an important aspect.

Regarding the aerosol compositions it is a requirement that their active agent be microcrystalline or micronized, that is, of the appropriate granulation. The required granulation depends on the scope. In general, the granulation required for the given scope is determined. Thus, in the case of application compositions, for inhalation, the 90% particle size should be less than 10 μΐη, preferably less than 5 μτη, in the case of compositions for nasal use, the 90% particle size will be less than 20 μίτι, while, for compositions for external use, the particle size is determined by the characteristics of the spray nozzle system.

The active agent with the required granulation can be prepared by appropriate crystallization or any other spray method.

The concentration of the active agent (s) is generally from 0.001 to 20% by mass, preferably from 0.5 to 10% by mass, and especially from 1 to 5% by mass, with the exception of compounds with general formula I, possibly other surfactants and / or dispersing agents may also be used. Preferably, mixtures of oleyl oleate and different sorbitan oils can be used. In this case, the amount of sorbitan oleate (oleate) represents only a fraction of that required, to confer the desired properties, of a composition without oleyl oleate. The amount of other surfactants and / or dispersing agents in the composition generally reaches 0 to 5% by mass, preferably 0.001 to 1% by mass and in particular 0.01 to 0.1% by mass. As a dispersion medium, non-toxic compounds, ("propellant") volatile at room temperature and atmospheric pressure, different alloy derivatives, in particular different chlorofluorocarbons, can be used. Likewise, a mixture of the mentioned propellants and nitrogen may be applied. Thus, for example, monofluortriclormethane (propellant gas 11), difluordicloromethane (propellant gas 12), trifluortricloroethane (propellant gas 113) and tetrafluordiclorethane (propellant gas 114) can be used. The amount of propellant gas generally reaches 66 to 99% by mass, preferably 85 to 98% by mass.

The compositions according to the present invention, especially those for nasal or external application, may also contain additional agents and support materials, for example, a buffer to match the pH value (for example, a phosphate buffer), antioxidants. (ascorbic acid, bisulphites, preservative, for example, benzalkonium chloride) and water. The aerosol compositions can be prepared by known methods, for example, after mixing the ingredients, the mixture to be introduced into vials by the so-called "cold" method or under pressure (possibly using a combination of the two methods).

The ingredients are advantageously mixed in the following sequence: the surfactant (s) and / or the dispersing agent (s) are dissolved in the dispersed (possibly prereconded) liquid medium, followed by addition to the active agent (s).

For mixing, a stirrer usually used for the preparation of suspensions is used with a greater revolution per minute (at least 1 □□□ revolutions / min).

The vials should be equipped with a dosing apparatus, which will determine the appropriate dose. For example, the dose of the active agent in the case of sodium chromoglycate may preferably be set at a level of 1 to 5 mg. In clinical trials, the composition of Example 3 at a dose of 1 mg shows the same effect as a capsule with the usual dose of 20 mg.

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8

Preparations containing the following amount of ingredients (given as% by mass) were found to be particularly preferred:

- sodium chromoglycate ..................... 1 to 2%

- oleyl oil ........................... 0.3 to 2%

- sorbitan trioleate ......... ............. □ at 0.2%

- propellant gas (dispersion medium) ........ up to 100%

As mixtures of propellant gases of the following composition (given in% by mass), they can be used, preferably:

-Gas propellant 11 .......

- gas propelling 12 .......

-Gas propellant 1141 .....

The properties of the compositions, according to the present invention, are compared with those of compositions known as follows:

A) The absorption of the active agent from the compositions, according to the present invention, 20 and from known compositions, respectively is determined in vitro with a dialysis apparatus, of the type Mbhlemann of fig.1. The explanation of the symbols used in fig.1 is as follows: 25

1, introduction of the sample;

2, glass tube;

3, reception phase (pH = 7.4; phosphate buffer);

4, from thermostat; 30

5, double-walled dialysis vessel;

6, the thermostat;

7, dialysis membrane;

8, magnetic stirrer; 35

9, device for magnetic stirrer (IKAMAG RCT).

As a membrane, a so-called kidney dialysis membrane is used. The membrane is pretreated for 17-40 18 hours in a phosphate buffer having ........ 55 to 75% ........ 10 to 25% ......... □ to 25% pH of 7.4 before measurements.

For the determination, 50 ml buffer solution is introduced into the apparatus. The temperature of the measuring system is maintained at 37 ° C, the stirrer is operated with 100 revolutions / min.

Each of the different aerosol compositions is investigated using 3 parallel "doses" made in contact with the membrane. (1 "dose" refers to the amount of composition removed from the vial by actuating the dosing valve once, after shaking the vial; contains about 1 mg of sodium chromoglycate). The amount of the active agent is determined by accurately weighing the vial, before and after taking the dose, using an analytical balance.

From the given periods of time, samples are taken from the receiving phase of the system and the amount of sodium chromoglycate from the donor phase is measured using a spectrophotometer. The results of the analytical measurements are given in table 1:

Table 1

Change of the concentration of the active agent diffused [in% by mass] with respect to time (hours)

Example no. 1 2 3 4 5 6 I 22.6 ± 2 36.6 ± 3 48.3 + 6 54.7 ± 5 58.1 ± 7 6D, 9 ± 6 II 15.4 ± 2 27.1 ± 2 36.3 ± 2 42.9 ± 4 46.9 ± 5 48.8 ± 6

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10. Table 1 [continued] ·

III 3.5 ± 1.5 10.2 + 1 46.8 ± 2 58.3 ± 4 61.9 + 6 64.0 ± 6 IV 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 I 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

(compositions are prepared according to examples and given). It can be seen from the results of the above test that the active agent dissolves at a substantially higher rate, from oil-containing oil compositions (compositions prepared according to Examples 1,3A and 15 5), than from comparative compositions I to IV (ie compositions containing oleyl oleate have a faster effect).

B) the physical properties that characterize the different compositions are given in table 2 (the symbols of the examined compositions are identical to those of table 1). The investigated parameters and their symbols used in table 2 are the following:

- volume of deposit (% vol / vol) VSE

- redispersing capacity (and the number of stirring required for the redispersing; stirring refers to a 180 ° change in position) ABR

- PSE sediment quantity

- material adhering to the vial with aerosol (mg) MAB

- material adhering to the aerosol vial (mg) MAV

- average granulation, granulation distribution (determined using a HIAC CP-420 type device)

Table 2

Average granulation [I] based on

Example VSE ABR PSE MAV MAB no. You. I 2.93 30 ^xl little bit 22.3 9.50 3.20 9.41 III 2.6 2.5 ^X) little bit 23.6 7.70 3.38 9.77 IV 2.5 22 ^x) little bit 22.9 9.32 3.92 10.73 5 35 2 picked up 23.5 7.20 3.33 7.40 1 30 3 picked up 26.2 6.40 2.70 5.46 3A 18.5 2 environment 16.2 6.20 3.13 5.74

^xl The compact sediment is separated from the surface of the vial, but is dispersed in the liquid.

The present invention is further illustrated by the following non-limiting examples:

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Example 1

Composition% by mass

-chromoglycate disodium (with a water content of 9% by mass ..................... 1.7

- oleyl oil. ................................... 1.3

-monofluortriclormetan ........... 70,7

-difluordichloromethane ............. 13.15

-tetrafluordychloride. . . . ' 13.15

100.00

The monofluortriclormethane is cooled to a temperature of 10 ± 1 ° C.

□ The oleyl alloy is dissolved in the cooled monofluortriclormethane and small portions of disodium chromoglycate as active agent are added to the mixture with continuous stirring 20 (at about 1400 revolutions / min). The mixture is stirred for 45 minutes at about 2800 revolutions / min. The suspension, thus obtained, is introduced into aerosol vials, with continuous stirring, at about 1400 revolutions / min) and cooled. The vials are closed using the appropriate dosing valves, then the two gas components are mixed or inserted separately, under pressure, into vials through the valve.

Example 2.

Composition% by mass

-chromoglycate disodium (with a water content of 9% by mass) 3.3

-Oilyl oil6,6

-polyoxyethylensorbitan 0.1 monofluortriclormethane in 67.0

-fluorofluorochloride 14.5

-tetrafluordychloride 14.5

100.00

The mono-fluorochloromethane is cooled to a temperature of 5 ± 1 ° C.

□ The oleyl leate and then the polyoxyethylensorbitan monooleate are dissolved in the cooled monofluortriclormethane. The solution thus obtained is added to the mixture of di- 40 fluordichloroethane and tetrafluordichloroethane cooled to -45 ° C. At this temperature, the disodium chromoglycate, as active agent, is added in portions to the mixture with continuous stirring at about 2500 revolutions / min. After a stirring period of 20 to 30 minutes, the suspension is introduced into aerosol vials, with continuous stirring and cooled. The vials are closed using the appropriate dosing valves.

Example 3.

Composition containing a dose of

Composition 1 mg (3A) % by mass 5 mg (3B) -Chromoglycate of sodium ........ ............... ................ 1.7 .............. 3.3 - oleyl oil .................... ............. ................ 0.66 .............. 0.53 -sorbitan trioleate ........... 0.05 ................ ............. .............. 0.05 - Propellant gas 11 ............. 68.64 .............. ............. ............ 69.82 - propellant gas in 2 ............ 14.475 .............. ........... ............ 13.15 - Propellant gas 114 ......... 14.475 .............. ........... ............ 13.15

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The composition is prepared according to the procedure described in Example 1, with the exception that the sorbitan trioleate dissolves after dissolving the oleyl oleate.

Example 4

Composition% by mass

- bromhexinium chloride. . . 2,040

-Oloyl oil 0.680

-sorbitan trioleate .............. □, 170

-trifluortriclorethane ............... 35,742

-difluordiclomethane in .............. 30,650

-tetrafluordychloride ............. 30,650

- flavor 0.068

100.00

The trifluortriclorethane is cooled to 15 ± 10 ° C. The oleyl oleate and then the sorbitan trioleate are dissolved in the cooled trifluortriclorethane and small amounts of bromhexinium chloride are added to the mixture with continuous stirring, at about 20 1500 revolutions / min. The mixture is stirred for 50 minutes at about 1500 revs / min. The suspension, thus obtained, is introduced into aerosol vials with continuous stirring at about 1400 revolutions / min and cooled. The vials are closed, using the appropriate dosing valves and both gas components are mixed or inserted separately, under pressure into the vials through the valve.

Example 5

Composition% by mass

- sodium chromoglycate 1.7

-Oloyl oil 0.66

-pulsing gas 11 69.74

- propelling gas 12 14.45

- propelling gas 114 14.45

The composition is prepared according to the process described in Example 1.

Compositions I to IV

Compositions according to the above method (II to IV) and a comparative composition I are prepared according to the procedure described in example 1, with the exception that the sorbitan trioleate is dissolved in the cooled monofluortriclormethane instead of the oleyl oleate. The quantities of components are given in table 3:

Table 3

Name of ingredients Quantity in% by mass 0 I II III IV Disodium chromoglycate 1.7 1.7 1.7 1.7 Sorbitan trioleate - □ 1 0.5 1.5 Monofluortriclormet-in 70.0 69.9 69.5 68.5 □ ifluordiclor methane 14,15 14,15 14,15 14,15 T etrafluoro-dichloroethane 14,15 14,15 14,15 14,15

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Claims (8)

claims 1. Aerosol composition, characterized in that it comprises 0.001 to 20% of an active agent, 0.01 to 5% dispersion agent having the formula: CH ₃ - (CH ₂ ) _x -CH = CH- ( CH ₂ ) _y -C00CH ₂ - (CH ₂ VCH = CH- (CH _a ] _z -CH ₃ [I], where x, y, v and z are integers having values 6, 7 or 8, up to 5 % surface active agent, 66 to 99% dispersion medium, the percentages being expressed by weight. An aerosol composition according to claim 1, characterized in that it preferably contains 0.5 to 10% of the active agent, the percentages being expressed by weight. An aerosol composition according to claim 1, characterized in that it preferably contains 0.3 to 2% dispersion agent of formula I, the percentages being expressed by weight. An aerosol composition according to claim 1, characterized in that it preferably contains 0.01 to 1% surface active agent, the percentages being expressed by weight. 5. Aerosol composition according to claim 1, characterized in that it preferably contains 85 to 98% dispersion medium, the percentages being expressed by weight. An aerosol composition according to claim 1, characterized in that the dispersing agent of formula I is oleyl oleate. An aerosol composition according to claim 1, characterized in that the active agent is an anti-asthmatic active agent, preferably sodium chromoglycate. 8. The aerosol composition according to claim 1, characterized in that the active agent is bromhexin chloride.