JPH05148185A - Preparation of aerosol composition - Google Patents

Abstract

PURPOSE: To obtain an aerosol compsn. ensuring a considerably increased rate of discharge of an active medicine and considerably improved stability of the suspension by mixing a medium for dispersion with an active medicine insoluble in the medium and a surfactant or a dispersing agent.

CONSTITUTION: The objective aerosol compsn. is obtd. by blending and mixing 0.001-20 wt.%, preferably 0.5-10 wt.% active medicine such as chlorohexyniumbromide with 0.01-5 wt.%, preferably 0.3-2 wt.% surfactant or dispersing agent made of a compd. of the formula (where X, Y, V and Z are 6-8), preferably oleyl oleate, 0-5.0 wt.%, preferably 0.01-1 wt.% other surfactant and 66-99 wt.%, preferably 85-98 wt.% medium for dispersion not dissolving the active medicine, e.g. monofluorotrichloromethane so that a suspended form is imparted.

COPYRIGHT: (C)1993,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel aerosol composition in suspension form and a process for its preparation.

[0002]

BACKGROUND OF THE INVENTION The preparation of an aerosol composition in suspended form involves the step of incorporating a dispersing medium, an active agent insoluble in the dispersing medium, and a surfactant or dispersant.

[0003] This type of aerosol composition can be used mainly as a pharmaceutical composition for inhalation or intranasal or external administration.

[0004]

The aerosol composition of the present invention contains a liquid dispersion medium (a so-called "accelerator") and an active agent of suitable particle size, which is insoluble in the accelerator. , A suspension is formed by using a surfactant or dispersant.

When using this composition, the dispersing medium evaporates and the surfactant and active agent distributed in the vapor penetrate into the application site (lung, nasal mucosa, etc.).

The surfactant or dispersant used must meet the following requirements: (a) It must be inert to the active agent and dispersion medium. Biodegradable and harmless. The degree of irritation to the contact area and body organs should be as small as possible. It has an appropriate odor and taste. (b) The degree of dispersion in the "promoting gas" and the stability of the suspension must be appropriate (precipitation volume, redispersibility, amount of substances adhering to the valve or wall of the container, particle size distribution, etc. Of the characteristics of). (c) Must not interfere with the dissolution of active agents in body fluids
(Rather should be promoted).

Proper selection of the type and amount of surfactant or dispersant that meets the above requirements is a daunting task. The prior art teaches that the following surfactants or dispersants are most preferentially used to produce aerosol compositions in suspension form. That is, oleyl alcohol, oleic acid, and its esters formed with polyhydric alcohols, such as sorbitan monooleate [Span 80: trade name], sorbitan trioleate [span 85: trade name], soya lecithin. And so on [Aerosol Age, August 1985, Canadian Patent No. 1,120,441].

[0008]

The inventors have surprisingly found that the use of the compounds of the general formula (I) described later has led to hydrophobic media (suspension used) and hydrophilic media (body fluids). It was found that each of these) very favorably affects the properties of the composition.

This makes it possible to significantly improve the properties which characterize the stability of the composition (suspension), so that in some cases the amount of surfactant in the composition is reduced, Alternatively, it can even be dispensed with. On the other hand, from the composition containing the compound of the general formula (I) as a dispersant, the active agent is eluted by body fluid at a higher rate than the composition containing the above-mentioned known surfactant or dispersant. ..

The present invention provides a method for producing an aerosol composition in a suspension form, which comprises a step of mixing a dispersion medium, an active agent insoluble in the dispersion medium, and a surfactant or a dispersant. Is represented by the general formula (I)

[Chemical 2] [In the Formula, x, y, v, and z represent the integer of 6-8. ] The manufacturing method of the aerosol composition characterized by using the compound shown by these is provided.

Among the isomers of the compound of the general formula (I) having different structures, the cis-cis derivative can be most preferably used.

Among the compounds of general formula (I), it has proved to be particularly advantageous to use oleyl oleate (where x, y, v and z are each a value of 7).

Oleyl oleate as a dispersant is an emulsion-based component for use in cosmetics and pharmaceutical compositions. The use of this in suspension form in aerosols has not been known to date.

A convenient composition comprises 0.001 to 20% by weight, preferably 0.5 to 10% by weight of active agent, 0.01 to 5% by weight,
Preferably 0.3 to 2% by weight of the compound of general formula (I) [x,
y, v, and z represent an integer of 6 to 8],
0-5.0% by weight, preferably 0.01-1% by weight of other surfactants, and 66-99% by weight, preferably 85-98% by weight
The above-mentioned dispersion medium is contained.

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

The composition of the present invention can be used in a wide variety of therapeutic fields, especially as an inhalant, as well as an intranasal drug, and an external drug.

[0017]

[Examples] The fields of medicinal properties in which the composition of the present invention can be used,
And some typical examples thereof are listed. This list is exemplary only and is provided as a guide for those skilled in the art. The compositions of the invention include sympathomimetic agents such as adrenaline, isoprenaline, orciprenaline,
Terbutaline, salbutamol, fenoterol, rimiterol], anticholinergic bronchodilator [eg ipratropium], corticosteroids [eg beclomethasone, dipropionate, betamethasone valerate,
Triamcinolone acetonide, budesonide (budesonid
e)], other hormonal agents [eg, oxytocin, insulin, sex hormones, glucagon], or desmopressin as an antidiabetic agent, vasopressin as an antidiuretic agent, a mucolytic agent [eg, N-acetylcysteine, mercaptoethanesulfone] Acid sodium], calcium antagonist [nifedipine], antibiotics [eg carbenicillin, gentamicin], methylxanthines [eg theophylline, aminophylline], antihistamines [eg triperenamine, chlorpheniramine maleate,
Diphenhydramine hydrochloride], antiviral agents [eg licamicin (rokitamycin)], cardiovascular agents [eg nitroglycerin], migraine treatment agents [eg ergotamine], and their combinations as active agents .

The asthma therapeutic composition of the present invention has been found to be particularly suitable for use in inhaled or intranasal applications.

Although sodium cromoglycate can be very conveniently used as an active agent in asthma-treating compositions, it is preferably prepared without drying (water content (As about 9% by weight). This means that Canadian Patent No. 1,120,441
According to the specification, it is surprising that active agents having a water content of less than 5% by weight are suitable for producing aerosol compositions in suspension form of suitable quality.

Hexnium bromine chloride can also be preferably used as the activator.

The particle size of the active agent used is an important property. For aerosol compositions, it is a requirement that the active agent be microcrystalline or micronised, ie of suitable particle size.

The required granularity depends on the field of application and it is common to use the granularity required for a given field of application. Thus, for inhalable compositions, 90% of the particles should have a particle size of less than 10 μm, preferably less than 5 μm, and for intranasal compositions 90% of the particles should have a particle size of 20 μm.
For externally administered compositions, the particle size is determined by the characteristics of the spray nozzle device system, although it must be less than m.

The active agent of the required particle size can be prepared by suitable microcrystallization or any known method of micronization.

The concentration of the active agent is generally 0.001-20.
% By weight, preferably 0.5-10% by weight, most preferably 1
~ 5% by weight.

In addition to the compounds of the general formula (I), it is possible to additionally use surfactants or dispersants. A mixture of oleyl oleate and various sorbitan oleates can be preferably used. In this case, the amount of sorbitan oleate will be much less than that required to obtain a composition of the desired properties without oleyl oleate.

The amount of surfactant or dispersant additionally used in the composition is generally 0 to 5.0% by weight, preferably 0.001 to 1% by weight, most preferably 0.01 to 0.1% by weight. ..

As the dispersion medium (“accelerator”), it is possible to use harmless compounds which are volatile at room temperature and atmospheric pressure, that is, various alkane derivatives, especially various chlorofluoroalkanes. Mixtures of the above promoters and nitrogen are also applicable. Thus, for example, monofluorotrichloromethane (promoting gas No. 11), difluorodichloromethane (promoting gas No. 12), trifluorotrichloroethane
(Promoting gas No. 113) and tetrafluorodichloroethane (Promoting gas No. 114) can be used. The amount of accelerating gas is generally 66 to 99% by weight, preferably 85 to 98% by weight.

The compositions of the present invention, especially those used for intranasal or external administration, may be adjuvants or carriers such as pH.
It may further contain a buffer for adjusting the value (for example, phosphate buffer), an antioxidant (ascorbic acid, bisulfite), a preservative (for example, benzalkonium chloride), and water.

Known methods can be used to produce the aerosol composition. That is, after mixing each component,
The container is filled with this mixture using the so-called "low temperature method" or under pressure (resulting in a combination of both).

Conveniently, the components are mixed in the following order. That is, first add a surfactant or dispersant.
It is dissolved in a (optionally precooled) liquid dispersion medium and then the active agent is added.

For the mixing, the stirrers customary for the preparation of suspensions are operated at relatively high rpm (minimum 1,000 rpm).

The container must be provided with a dispensing device to provide the proper dose. For example, when the active drug is sodium cromoglycate, the dose is 1 to 5
Suitably it can be fixed at the mg level. In clinical trials, the composition of Example 3 with a dose of 1 mg proves to have the same efficacy as a conventional dose of 20 mg capsules.

Formulations containing the following amounts of ingredients (shown in weight percent) have been found to be particularly suitable. Sodium cromoglycate 1-2 oleyl oleate 0.3-2 sorbitan trioleate 0-0.2 Accelerating gas (dispersion medium) Less than 100

The mixed promoting gas has the following composition:
Mixtures (shown in weight percent) can also be used with preference. Promotion gas No. 11 55 to 75 Promotion gas No. 12 10 to 25 Promotion gas No. 114 10 to 25

The characteristics of the composition of the present invention are compared with those of the known composition as follows. (A) The absorption of the active agent from the composition of the present invention and the known composition was measured using the Mhlemann type dialysis device shown in FIG. 1, respectively.

As the dialysis membrane, a so-called renal dialysis membrane
(Manufactured by Hoechst, Germany) was used. Prior to measurement, the membrane was pretreated in phosphate buffer pH 7.4 for 17-18 hours.

First, 50 ml of the buffer solution is filled in the measuring device. Keep the temperature of the measuring system at 37 ° C, and stirrer at 100 rpm.
Operate with.

Each of the different aerosol compositions was examined by contacting 3 parallel "dosage units" with the membrane (1 "dosage unit" means that the dispensing valve is actuated once after shaking the container. It is related to the amount of composition released from the container.
Includes sodium cromoglycate). The amount of active agent is measured by precisely weighing the container using an analytical balance before and after the release of one dose unit.

After the elapse of a predetermined time, a sample is taken out from the receiving phase of the device system, and the amount of sodium cromoglycate transferred from the donor phase is measured using a spectrophotometer.

The results of this analytical measurement are shown in Table 1.

(Table 1) Time-dependent change (in units of time) of the concentration (% by weight) of the diffused active agent ──────────────────────── ────────── Example Time Number * 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 II 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 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 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 ───────────── Compositions were made according to the designated example numbers.

From the above test results, the active agent elutes from compositions containing oleyl oleate (compositions according to Examples 1, 3A and 5) at a significantly higher rate than from comparative compositions I-IV. It can be understood that (that is, the composition containing oleyl oleate exerts a faster drug effect).

(B) Table 2 summarizes the physical properties that characterize the various compositions (symbols of the investigated compositions are exactly the same as in Table 1). The measured specifications and their symbols used in Table 2 are as follows. -Precipitation volume (% by volume) VSE-Redispersion capacity (and the number of shakes required for each redispersion: Shake refers to a 180 ° change in position) ABR-Amount of precipitation ASE-Substance attached to aerosol container (mg) MAB-Substance attached to the valve of the aerosol container (mg) MAV-Average particle size, particle size distribution (measured using a device of the type HIAC CP-420)

(Table 2) ─────────────────────────────────── Example VSE ABR ASE MAV MAB Average Particle size (μm) By number By volume ─────────────────────────────────── I 2.9 30 * Small 22.3 9.50 3.20 9.41 III 2.6 25 * Low 23.6 7.70 3.38 9.77 IV 2.5 22 * Low 22.9 9.32 3.92 10.73 5 35 2 High 23.5 7.20 3.33 7.40 1 30 3 High 26.2 6.40 2.70 5.46 3A 18.5 2 Medium 16.2 6.20 3.13 5.74 ────── ───────────────────────────── * A fine precipitate separates from the surface of the container but is not dispersed in the liquid.

Hereinafter, specific non-restrictive experimental examples will be given.
The present invention will be described in more detail.

Experimental Example 1 Composition wt% Disodium cromoglycate (containing 9 wt% water) 1.7 Oleyl oleate 1.3 Monofluorotrichloromethane 70.7 Difluorodichloromethane 13.15 Tetrafluorodichloroethane 13.15 ──────────── ─ 100.00

Monofluorotrichloromethane at 10 ± 1 ° C.
Cool to the temperature of. Oleyl oleate is dissolved in cooled monofluorotrichloromethane, and disodium cromoglycate as the active agent is added to this mixture in small portions with continuous stirring (about 1,400 rpm). Stir the mixture for another 45 minutes (about 2,800 rpm). The suspension obtained is
Fill the aerosol container with continuous stirring (about 1,400 rpm) and cooling. Close the container with an appropriate dispensing valve,
Both remaining gas components are then mixed or separately and charged under pressure through a valve into a container.

Experimental Example 2 Composition% by weight Disodium cromoglycate (containing 9% by weight of water) 3.3 Oleyl oleate 0.6 Polyoxyethylenesorbitan = monooleate 0.1 Monofluorotrichloromethane 67.0 Difluorodichloromethane 14.5 Tetrafluorodichloroethane 14.5 ── ───────── Total 100.00

The monofluorotrichloromethane is cooled to a temperature of 5 ± 1 ° C. First, oleyl oleate and then polyoxyethylene sorbitan monooleate are dissolved in cooled monofluorotrichloromethane. The solution obtained above is added to a mixture of difluorodichloromethane and tetrafluorodichloroethane cooled to -45 ° C. At this temperature, disodium cromoglycate as active agent is added in small portions to the mixture with continuous stirring (about 2,500 rpm). After stirring for a further 20-30 minutes, the suspension obtained is filled into aerosol containers with continuous stirring and cooling and the containers are closed using suitable dispensing valves.

Experimental Example 3 Dosage unit contained in composition 1 mg (3A) 5 mg (3B) Composition weight% Sodium cromoglycate 1.7 3.3 Oleyl oleate 0.66 0.53 Sorbitan trioleate 0.05 0.05 Accelerating gas No. 11 68.64 69.82 Accelerating gas No. 11 No. 12 14.475 13.15 Promoting gas No. 114 14.475 13.15

A composition is prepared according to the method described in Experimental Example 1, except that sorbitan trioleate is dissolved after the dissolution of oleyl oleate.

Experimental Example 4 Composition wt% Hexinium bromine chloride 2.040 Oleyl oleate 0.680 Sorbitan trioleate 0.170 Trifluorotrichloroethane 35.742 Difluorodichloromethane 30.650 Tetrafluorodichloroethane 30.650 Fragrance 0.068 ───────────── Total 100.00

Trifluorotrichloroethane at 10 ± 1 ° C.
Cool to the temperature of. First, oleyl oleate and then sorbitan trioleate are dissolved in cooled trifluorotrichloroethane, and hexinium bromine chloride is added to this mixture in small portions with continuous stirring (about 1,500 rpm). Stir this mixture for an additional 50 minutes (approximately 2,500 rp
m). The resulting suspension is filled into an aerosol container with continuous stirring (about 1,400 rpm) and cooling. The container is closed using a suitable dispensing valve, both remaining gas components are mixed or separately, and the container is filled under pressure through the valve.

Experimental Example 5 Composition wt% Sodium cromoglycate 1.7 Oleyl oleate 0.66 Accelerating gas No. 11 69.74 Accelerating gas No. 12 14.45 Accelerating gas No. 114 14.45

A composition is prepared according to the method described in Experimental Example 1.

Compositions I-IV Compositions according to the prior art (II-IV), and comparative compositions
(I) is prepared according to the method described in Experimental Example 1, except that sorbitan trioleate is added to cooled monofluorotrichloromethane instead of oleyl oleate. The amount of each component is shown in Table 3.

[0057]

[Brief description of drawings]

FIG. 1 is a schematic diagram of a dialysis device used for a comparative test of elution of an active agent from the composition of the present invention and a known composition.

[Explanation of symbols]

1 Addition of sample 2 Glass tube 3 Receptive phase (pH = 7.4, phosphate buffer) 4 From thermostat 5 Double-walled container for dialysis 6 To thermostat 7 Dialysis membrane 8 Magnetic stirrer 9 Magnetic stirrer drive device (IKAMAG) (RCT: product name)

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Rita Barajyu Hungary 1102 Budapest Endo Letutua 6 / A (72) Inventor Volvara Balta Hungary 1118 Budapest Mader Siyu Pachiyu Car Utsua Be / 2 15 (72) Inventor Gizerla Tote Nehje Djarmaty Hungary 2225 Iurloe Kertekarya Utsua 40 / A (72) Inventor Udate Martsishu Hungary 1156 Budapest Hebesi Yuutsua 44 (72) Inventor Andrasyu Saas Hungary 1132 Budapest Victor Fugoatsa

Claims (6)

[Claims] 1. A method for producing an aerosol composition in a suspension form comprising a step of mixing a dispersion medium, an active agent insoluble in the dispersion medium, and a surfactant or a dispersant, wherein the dispersant is: General formula (I) [In the Formula, x, y, v, and z represent the integer of 6-8. ]
A method for producing an aerosol composition, which comprises using the compound represented by 2. A compound of the general formula (I) as defined in claim 1, wherein x, y, v and z are used in an amount of 0.01 to 0.5% by weight, preferably 0.3 to 2% by weight. Item 2. A method for producing an aerosol composition according to Item 1. 3. The method for producing an aerosol composition according to claim 1, wherein oleyl oleate is used as the compound of the general formula (I) in which x, y, v and z are numerical values. 4. 0.001 to 20% by weight, preferably 0.5 to 10% by weight of active agent, 0.01 to 5% by weight, preferably 0.3 to 2
Wt% of compound of general formula (I) [x, y, v, and z
Is as described in claim 1. ], 0-5.0% by weight,
Preferably 0.01 to 1% by weight of other surfactants, and 66
The method for producing an aerosol composition according to any one of claims 1 to 3, wherein the dispersion medium is used in an amount of ˜99 wt%, preferably 85-98 wt%. 5. The method for producing an aerosol composition according to claim 1, wherein an asthma therapeutic active agent, preferably sodium cromoglycate is used. 6. The method for producing an aerosol composition according to claim 1, wherein hexium bromine chloride is used as the active agent.