FI104410B - Carrier for producing an inhalation aerosol - Google Patents

Abstract

In order to produce an aerosol, a velvety or velours-like material charged with a powder is brought into an air current.

Description

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Carrier for Inhalation Aerosol Production - Bärare för att producera en inhale-ringsaerosol

The invention relates to a carrier for loading a powdered pharmaceutical preparation for the production of an aerosol inhalation.

Small amounts of fine, preferably micronized powder are used for therapeutic purposes, mainly in the form of aerosols by inhalation to treat respiratory problems such as asthma.

Powders of this type are delivered to the lungs of the patient in amounts usually well below 50 mg in inhaled air. It has been found that the particles of the active substance should have a particle size of less than 10 μ to ensure that they penetrate deep into the lungs. However, this does not exclude the use of some of the larger particles in the formulations, in particular any filler.

If particles of different sizes are used, a significant difference in size is sometimes even desirable, or in any case not harmful; see De-search · Musical Publication 1792207.

Two significant methods have been developed for delivering fine powders to the respiratory tract without the use of propellants.

Another method uses hard gelatine capsules, each containing a dose of the active ingredient and optionally also excipients, while the other removes, using a dosing chamber, a special amount of powder from the storage vessel and mixes it with inhaled air. A large number of devices have been described for both methods, see, for example, DE-A-23469114; EP Application Publication No. 166294.

The present invention now provides a new method of delivering fine powders. In this method, the ease of preparation of the carriers loaded with the active ingredient combines advantageously with the precision of dosing and the ability to produce an aerosol that is suitable for inhalation in a simple manner.

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According to the invention, the velor or silk-like material is loaded with a powder to be dispensed, and the desired amount of powder is blown down from the carrier by means of a gas jet, possibly after mechanical removal, preferably using an air jet of suitable intensity. When used for inhalation, ♦ 5 released powder is mixed with inhaled air, possibly via an inhalation device such as that described, for example, in DE utility model 8908273.

: When the dry powder is applied to the velor material, the movement of the fibers under the scraper causes initial disintegration. In this case, the particles are in a very loose state and are correspondingly less prone to lumping together. When the powder is added by means of a suspension, this initial fracture is achieved by running the powder over the blade so that again the gas jet has to supply only some energy for the fracture. In addition, the previously broken particles 15 represent a large surface area for contact with the gas jet, which in turn has a beneficial effect on decomposition.

: 'The carrier consists of a substantially planar material with a thin fiber surface. The fibers are secured at one end or center to the carrier 20 or to the carrier, with the free end or free ends facing upwards, and the carrier and the fibers generally form angles between 45 ° and 90 °, more particularly 60-90 °. The material on which the fibers are made may be, for example, paper, plastic film or textile fabric; the fibers may be natural or synthetic, pre-; such as cotton, wool, silk, viscose, perlon, nylon or polyacrylic.

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The fibers are up to about 3 mm long, preferably up to about 1 mm long. They should not be too tangled to ensure that the added powder, which is substantially layered between the fibers, can again be blown out relatively easily.

The lower limit for the length of the fibers is about 0.1 mm. In general, the length of the fibers should be such that the desired amount of powder added can be distributed per unit area.

Thus, a carrier material with smaller fibers is suitable for relatively large amounts of powder per unit area, while shorter fibers are useful, or even preferable, for very small amounts of 104410 3 powder per unit area. The amount of powder that can be added per unit area depends mainly on the nature (density) of the powder and its size. However, if the powder is to be administered by inhalation, care must be taken to ensure that excessive compression does not interfere with the dispersion of the powder into the gas or air jet used.

The number of fibers per unit area may vary considerably.

Various commercially available carriers have proven to be suitable (velor 10 film, velvet, Niki). These products also provide an appropriate indication of the appropriate fiber density of other carriers. The fiber density also varies within wide limits.

Fibers having a diameter of 0.002 to 0.05 mm, preferably 0.004 to 0.03 mm are generally used. The velvety support itself may also be attached, for example, by gluing to a rigid layer. It is also possible to attach it to the ab-15 sorbent support.

Correspondingly, the carrier may be, for example, elastic or rigid and rectangular · shaped or circular. Preferably, the carrier is in the form of a ribbon. Here, powder can be charged over its entire surface or in individual areas. In the latter case, the tape can be powder-loaded by means of a template into small individual regions, for example in the form of circular regions of a few millimeters in diameter and clearly separated so that when; the powder is blown from one of these areas so that adjacent areas remain unchanged. 1 25

Thus, the dose can be accurately fixed at each of these small loaded areas

powder.

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If the entire surface of the carrier is coated with powder, the amount of = 30 powder to be blown out can be simply determined by the size of the area exposed to the gas jet during each removal operation and determined, for example, by a trimming mask. However, a mask is not necessary. In fact, it has been found that the amount of powder blown downwardly from a uniformly charged carrier by a gas jet is 1044104. As a result, the amount of powder dispersed can also be controlled by gas jet intensity and nozzle geometry.

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To protect the powder layer, it may be convenient to coat or laminate the * 5 carrier, for example, with a plastic film so that only the portion of the carrier from which the powder is taken is exposed. Particularly in moisture-sensitive powders, aluminum lamination on both sides could be considered. Ultimately, it is also possible to use carriers such as tapes having alternating areas filled with fibers and flat areas.

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In order to load the carrier, it is firstly distributed as evenly as possible with a layer of powder having a thickness of 1-2 mm in the case of highly effective pharmaceutical powders, and with carriers having very short fibers, the layer may be considerably thinner. The powder is pressed onto the tape by means of a doctor blade 15 and the excess powder is wiped off. This treatment is repeated once or several times as necessary with the doctor blade progressively lowered. As a result of the movement of the fibers under the pressure of the doctor blade, the agglomerated areas of the powder are broken.

j 20 If only certain areas of the carrier are to be loaded, the carrier may be covered, for example, by a template, for example a suitably perforated film. If powder is then added as described above, the carrier will be charged only at the points where the holes are located.

The powder may also be added to the carrier in the form of a suspension. In the case of pharmaceutical compositions for inhalation, the dosage of the active ingredient is usually so low that the amount of active ingredient Ί · contained in one drop of suspension is sufficient. One drop of suspension is then added at a desired distance from the next drop. The distance is chosen so that the spot of powder remaining after evaporation of the suspending agent is clearly separated from the adjacent spot. The purpose is to be able to separate the exact amount of powder added from the carrier in only one drop when the powdered active agent is transferred to an inhaled air stream.

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It is particularly satisfactory to load the carrier with a precisely metered amount of powder into a small area using a suspension.

The suspending agents used may be liquid organic compounds (5) to which the powder to be added is not readily soluble and which can be removed as closely as possible.

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Examples of suspending agents of this type selected according to the solubility characteristics of the suspending agent or mixture of suspending agents are e.g. dichloromethane, ethyl acetate, 1,1,1-trichloroethane or gasoline (e.g. 60/95 or 80/110 fraction). As an adjustment, excipients such as lecithin are added to the suspension. The solids content of the suspension is usually between 3 and 30% by weight, preferably between 5 and 25% by weight; the amount of suspension excipients varies between about 0.5 and 3% by weight of the solid.

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The carriers and suspension should be such that the powder particles remain behind the dot where the droplet penetrates the carrier while the suspending agent spreads out and then evaporates. Evaporation may be promoted by reducing the pressure and / or heating.

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Material from the dried droplet of the suspension cannot usually be released and disintegrated - simply by an air jet. However, if the carrier fibers are moved [for example, as the blade is moved over them, the bond between the powder particles is broken again and the powder is "activated". The individual particles, which after being activated, adhere to each other or to the carrier fibers with only a little adhesive force, can then be released by air jet and dispersed, to a large extent, in the lungs.

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Instead of removing the powder from the carrier by means of an air jet, it is possible to remove it by transporting it over the blade or brushing it, immediately before

passage of a breathable air stream through, or during, the carrier and carrying I

thus the powder is inhaled air.

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Apart from the high accuracy of dosing, the addition of a drop of suspension still has the advantage over the addition of a dry powder that the powder is protected against release due to acceleration (shock, vibration).

Activation by running the blade should be performed immediately before the powder is released for inhalation.

Figure 1 schematically illustrates a device according to the invention for adding a drop of suspension. Suspension 1 initially resides in storage vessel 2. From there, it flows through line 3 to solenoid valve 4 and passes through valve surfaces along line 10 5 to storage container 6. In a rest position, piston 7 closes the inlet of line 8, from which suspension is added to carrier 11. 3 to line 5. As the electromagnet pulls the plunger behind, it exposes the opening so that the suspension can reach carrier 11. The suspension is pumped out of the container 6 by means of pump 9 to storage container 2. To ensure that the suspension in storage container 2 is always level between the two vessels there is a connecting line 10 through which the suspension can flow from the storage 5 to the storage 6 when the liquid level is higher than the inlet of this connecting line. The cross-sections of lines 3 and 10 are made so small that the volume of suspension flow flowing through these two lines is less than 20 pi than the volume released by pump 9. The storage tanks 2 and 6 are mixed, which keep the particles continuously suspended. For uniform dispensing, the solenoid valve 4 is controlled by an electronic clock device. Figure 2 illustrates details of a valve.

Example of adding a pharmaceutical composition in suspension:

A suspension of micronized phenoterol (proportion of phenoterol: 10% by weight) in dichloromethane with the addition of lecithin (0.1% by weight) was added to a velvet having a fiber length of 1.2 mm over the base fabric, dropwise about 10 mm, and then dried.

The powder was then activated by passing a blade over it and blown out of the carrier * with a gentle jet of compressed air.

] The inhalable proportion of particles (particle diameter <5.8 µm) was 4141.4% of the delivered dose.

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A relatively small amount of gas, for example 10 cm 3, with or without pressure forced through a 0.5 mm diameter nozzle is sufficient to disperse (blow out) the powder.

The gas jet required for disintegration can be produced in various ways, for example by using a cylinder fitted with a nozzle forcing the air through a spring-loaded piston, or by means of conventional small CO2 containers which can be used to generate pressure. Instead of using a cylinder having a piston, it is also possible to use bellows.

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Figures 3 and 4 schematically show a simple device in which carriers loaded according to the invention can be used. The most important parts are two coils, one receiving the downloaded tape and the other receiving the spent tape.

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The tape is guided past the panel while being guided past the blade to activate the powder. Here, a gas or air jet comes in contact with the strip and carries the powder with it. The shower is usually released when the air is inhaled through the mouthpiece. It is advisable to initiate a stream of gas or air with inhaled air to coordinate the disintegration of the powder with the inhalation of the event.

Figure 3 is a front view of the inhalation device. The carrier tape 12 having powder added to the tape in individual spots at regular intervals 25 is open to the yellow coil 13, and when empty is wound onto the coil 14. A conventionally constructed conveying mechanism is used to rewound the tape during each start up of the device by that a new spot arrives on a flat surface 15. The flat surface 15 is located in the mouthpiece 16 through which the patient inhales. The slot through which the carrier band 12 is guided to the mouth 30 is slightly narrower than the thickness of the carrier band 12. The upper slot 7 is constructed as a blade for activating the powder. The air is directed to the powder spot through a nozzle from a cylinder 17 having a piston which is subjected to a spring pressure on the shaft 18. knob 20. As the patient inhales through mouthpiece 16, he presses knob 20 to ensure that the piston conveys the amount of air contained in the cylinder forward through the nozzle to the powder spot so that the powder is dispersed into the inhalation air.

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Figure 4 is a schematic side view of the device, showing the mouthpiece 16 in vertical section. The nozzle 21 directs the air jet out of the cylinder 17 to the powder spot.

10 In this case, the reels containing the carrier are incorporated in a cassette similar to that used in cassette recorders. Their movement is preferably combined with the movement of the arm 18 such that each time the piston is held under tension, the carrier web moves until the next spot reaches a flat surface 15.

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Instead of a cylinder and a spring, it is also possible to use a bellows or conventional design CO 2 cartridge which releases a few cubic centimeters

B

meters of CO2 each time the device is used to provide the aforementioned gas flow. The CO 2 is then again passed through the nozzle to the powder-coated carrier surface. The volume of gas required to disperse the amount of powder required for therapeutic purposes is generally 3 to 30 cm 3 (under normal conditions).

Nozzles with a mouth shaped to a carrier type are used. In the case of annular powder spots, the nozzle has a small, preferably circular, opening. For larger powder-coated carrier surfaces, a slit or rectangular nozzle may be more suitable. In this case, a larger amount of gas is required to produce the required outflow rate.

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Dosing Accuracy was measured in a series of tests in which either (tests 1,2,3) carrier-1 tape is continuously coated with dry powder, and the tape is accurately | the defined portion was examined in each case, or otherwise a strip with powder coating only at designated locations was used.

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The following surface coatings and relative standard deviations were observed:

Surface Relative

Material_coating standard deviation 5 1. Velor film 6.6 mg / cm2 6.3% 2. Silk 2.2 mg / cm2 6.0% 3. Nicki 5.4 mg / cm2 6.2% 4. Velor film with film individual 10 round flour spots * 2.1 mg / spot 11.2% * When powder was added, the carrier was coated with a perforated film. The holes were 4 mm in diameter and 10-15 mm apart. By improving the input, the standard deviation could be further reduced in the following tests.

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For substantially complete dispersion in powder blowing, relatively. a small amount of gas is sufficient, for example 10 cm3 of air forced through: •: - '- a 0.8 mm diameter nozzle (in the case of powder spots according to test number 4). Excellent decomposition is observed.

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As confirmed by the Andersen impactor using micronized phenoterol, 40% of the expelled dose particles had a particle size range of less than 5.8 µm.

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Claims (9)

10 104410 A carrier for loading an inhalable aerosol into a powdered pharmaceutical preparation, characterized in that it consists of a substantially flat material on which the fibers are arranged in a velvety or velor-like manner and that the powder is incorporated between the fibers. A carrier according to claim 1, characterized in that the fiber has a length of 0.1 to 3 mm. Carrier according to claim 1 or 2, characterized in that the layer on which the fibers are laid is flexible. A carrier according to claim 1 or 2, characterized in that the layer 15 on which the fibers are laid is rigid. 5. A carrier according to claims 1-4, characterized in that the powder is applied uniformly over the entire surface of the carrier. 6. A carrier according to any one of claims 1 to 4, characterized in that the powder is applied only to a sub-region of the carrier, wherein the individual loaded sub-regions of the carrier each contain a single dose of pharmaceutical agent. Carrier according to claims 1 to 6, characterized in that the carrier is provided with a protective film on the powder-containing side or on both sides. Process for producing a carrier according to claims 1 to 7, characterized in that the powder is uniformly distributed on the carrier and incorporated in one or more steps into the fiber layer using a doctor blade. t 30 104410 Process for preparing a carrier according to claims 1-7, characterized in that the powder is added to the velvet and velor carrier in the form of a small amount of suspension, and the suspension agent is evaporated off. 4 * »12 104410