JPS6010737B2 - Pulmonary direct powder medicine administration device - Google Patents

Description

[Detailed description of the invention] Pharmaceutical inhalation treatments have been known for a long time.

There has been a continuous effort to ensure that a uniform and relatively precise dose is administered to each localized area of the human body. Larger particles tend to settle in the oral cavity or upper throat, while smaller particles, 10 microns or less, have the potential to reach deep into the lungs. The issue is whether the desired dose of the desired drug can be reliably administered to the desired local area and at the desired time. Sometimes the systemic effects of drugs administered to other organs may be of limited benefit or may actually be undesirable. For example, many steroids have systemic effects when administered orally, but local effects when administered into the arm itself. Therefore, in some cases it may be desirable to have a treatment regimen that allows steroids to be administered only to the surface of the lungs. The present invention covers the following discoveries.

That is, if a deceleration chamber is used when releasing the aerosol from a container containing the aerosol, the particles in the aerosol can be mixed with air and suspended in the propellant in a dry, vaporized state. Furthermore, the deceleration chamber is sufficiently large, so that the aerosol container can be placed inside and carried around during storage and transportation. By installing a constriction spray device at the edge of the pond, a powdered medicine administering device aimed at direct delivery to the lungs can be obtained.The volume of the deceleration chamber is approximately the same as the inside of the oral cavity when a human opens his or her mouth. Make it.

The deceleration chamber then reduces the velocity of the dispersed particles in the aerosol as it is released, absorbing the momentum of the aerosol jet before it becomes suspended particles and enters the user's mouth, and also absorbs the momentum of the aerosol propellant. Completely vaporizes the propellant, eliminating the possibility of the propellant reaching the mouth in a liquid state. In addition, this propellant and suspended particles are diluted with air,
Since the loss of particles is uniform and tolerably suppressed, a consistent and uniform dose can be administered at all times. It is also desirable that a large proportion of the drug released be taken by the user, but even more important is that the dose or absorption rate will not be higher or lower each time, but will be known in advance. It is as it is,
Therefore, a known uniform dose can be taken each time the operating button is operated. Significant loss of centage can be tolerated if doses are reliably uniform. With this device, there is a loss of approximately 25-50% of the total drug. Since the deceleration chamber traps most of the medicine that would have been deposited in the user's mouth, only a small amount of the medicine is deposited in the mouth compared to the amount that reaches the lungs and exerts its effect. The device is further provided with a trap device which immerses the metering valve in the propellant and ensures that the metering valve is always submerged in the propellant.

As a result, the weighing chamber is always kept full of propellant without running out. This device is sometimes called a never-depleting trap. Medicinal agents particularly suitable for use with the device are triamcinolone acetonide and N·N-diethyl-4-methyl-1-piverazine carboxamide pamoate (diethylcarbamazine pamoate). Both are effective in treating asthma. It is also desirable to administer small, known doses uniformly and accurately each time so that both of these drugs are absorbed primarily through the lungs rather than through the nose and throat. Physiological effects are increased by administering the drug to the desired local area than by administering the drug systemically due to the potential for concentration. Depending on the medicine, it may be more convenient to take it by inhalation in order to obtain a systemic effect.

Inhalation of penicillin is used because it is much more convenient to administer penicillin than by injection. Various drugs can be absorbed through the lungs if suitable inhalation dispersion devices are available. Inhalation of gases or liquids such as ether is much more common. One dosing device for administering therapeutic agents under pressure is improved as follows.

That is, a valve is provided for discharging the powdered drug suspended in the propellant, and the body part is cylindrical and has a mouthpiece at its outlet, and also for supporting the spray nozzle device. The spray nozzle obtained when opening said valve is discharged into the inlet of a deceleration chamber, which is provided with an aerosol container holder and at the same time its operating button holder.

The deceleration chamber, which is also an expansion chamber, is preferably constructed in a structure capable of completely surrounding and supporting the entire aerosol container, so that it can be stored or transported, but not when used. It is designed to be used after being reassembled into a different structure.

In addition, since this device has a dust-proof cap and sealing means, it prevents dust from entering during storage or transportation, and it can be easily carried in the user's pocket. It is quick and easy to assemble, avoiding dust on the contents.Depending on the type of medicine, it may only be used in emergencies or emergencies, so the device must be completely protected during storage or transportation. It is a significant advantage that the structure can be simply reassembled for easy and rapid dosing when the drug is taken.Other advantages will be apparent to those skilled in the art from the detailed description below. As can be understood, the main point of the aerosol dosing device of the present invention is the deceleration chamber 11, as shown in FIG.

Preferably, this is made of a plastic material such as polyethylene. The deceleration chamber 11 has a cylindrical body 12
This body has a length of approximately 2 inches, an inner diameter of approximately 2 inches, and a wall thickness of approximately 1-5 inches (6 inches).
It is convenient to use inches). At one end of this is a mouthpiece 13, which conveniently has an outer diameter of 21 feet (inches) and a length of 5 lips (inches). This size is suitable for fitting in the user's lips and holding the mouthpiece airtight with the lips. This mouthpiece is joined to the cylindrical body 12 by an overhang 14. It is convenient, but not necessary, for the mouthpiece, overhang and cylindrical body to be integrally molded from a plastic material such as linear polyethylene. However, in this way, manufacturing costs are lower, and the surface to be used is smoother and easier to clean. The mouthpiece cap 15 is designed to fit snugly onto the mouthpiece so that it can be removed and removed, and is designed to prevent dust from entering. The cap 5 can be slid inwardly or outwardly by applying finger pressure. Shiatsu here refers to the fact that the mouthpiece has a cap on it due to friction when handling the Shindan, but by applying pressure with your fingertips you can easily remove the cap or put it back on. . The outer surface of the mouthpiece is a ``concave and convex surface, that is, a surface with bulges, making it easy to grip with finger pressure.The lip of the mouthpiece cap is made in accordance with the usual method to facilitate assembly, as is the case with the edges of other parts. Add slices or give it a little roundness.
Either the mouthpiece or the mouth booth cap.
Small (o-oo 2 inch) ridges reduce friction and facilitate engagement. In this way, by providing small ridges or beads on the frictional engagement part, the natural elasticity of plastic materials such as polyethylene can be utilized, so it is possible to easily adjust the size of the engagement part at the fingertips without incurring any extra expense to increase the precision of the size of the engagement part. A frictional engagement that allows for easy removal is obtained. Similar assembly details are used throughout the rest of the dosing device of the present invention and are conventional in the art of plastic molding.

At the open end of the cylindrical body 12 is an air.

There is a holder 16 for the sol container. This container holder 16 has many roles. The cylindrical body 12 has a flange 17 over the entire surface of the entrance end, and a sleeve 18 that is fitted with iron. For convenience, this sleeve 18 is usually, but not necessarily, long enough to frictionally engage the interior of the cylindrical body, so that it will not slip out with the slightest movement, but will not dislodge the container retainer 16. Make sure that it can be easily removed for removal. Again, although this is not necessary, this sleeve 18 may extend beyond the flange 17 of the container holder so that its elasticity allows for fingertip frictional engagement with the normal precision of the molded part. It is convenient to keep it. Sleeve 1 for holding an aerosol container
9 also extends inwardly from retainer flange 17 and is sized to fit snugly around aerosol container 20 to secure it.

It is also convenient, but not necessary, for the aerosol container to be made of stainless steel or aluminum to contain the high pressure aerosol propellant. The sleeve of the container holder is of sufficient length and size to loosen and hold the complete aerosol container assembly coaxially within the deceleration chamber during storage and transportation of the device, and to facilitate drug administration. At times, the aerosol container 20 can be easily removed. One or more air holes 21 are provided through the retainer flange to allow dilution air to be admitted during use of the device. Three holes, each 3 inches in diameter, will give satisfactory results. Also extending outwardly from the retainer flange 17 is an operating button retainer 22 . The button retainer is hollow and has a closed end opposite the retainer flange, and includes an aerosol operating button 2 therein, as will be explained in more detail below.
There is an insertion opening 23 having a size and shape for inserting and holding the item 4. Since the aerosol operating button needs to be oriented in a specific direction, the shape of the insertion port 23 matches the operating button 24, so that the operating button is held in a relationship facing in a specific direction. As shown in the figure, "The operation button has a cylindrical shape with a flat surface 25 on one side." When inserted so that this flat surface aligns with the insertion opening 26, the aerosol spray will flow coaxially within the deceleration chamber. Again, it is convenient, but not necessarily necessary, that the button holder 22 has a socket 2.
Two operation buttons 3 are provided, one at the corresponding positions on each end of the opposite diameter, so that the operation button 2 can be inserted into either of them, and the other one serves as an additional air intake □. It is a good idea to keep it. The end of the button retainer 22 distal to the retainer flange 17 is located about 5/100 m from the outer cylindrical surface of the button retainer.
One fastening bead 27 is provided with a protrusion of approximately 5'1000 inches. Also integrally attached to the outer surface of the button retainer is a protective sleeve 28 with a light frictional engagement, which is made of plastic and has sufficient elasticity to easily slip over the aforementioned fastening bead. Once you are jealous, you cannot easily get rid of it, so it will remain that way for as long as this device can be used. This protective sleeve is provided with a hole 29 for the button, and when the sleeve is rotated, this opening aligns with the insertion opening 23, allowing the button to be inserted through them. Approximately 900 rotations will prevent dust from entering the entire device during storage and transportation. FIG. 2 shows the storage of parts when the dosing device of the device is being stored and transported.

The aerosol container 2 is located inside the cylindrical body 12 of the deceleration chamber turtle and is held in the container holding sleeve 9.
The aerosol container 2 is closed by a valve device 38 having a ferrule 31 for keeping the skin valve in place, from which an operating button 24 extends.

As shown in FIG. 3, when using the device, the cap 15 is removed, the flange 17 is also removed from the other end of the cylindrical body 12, and the aerosol container 20' is removed from the container retaining sleeve 19.

Further, the protective sleeve 28 is rotated until the button hole 29 is perfectly aligned with the insertion port 23, and then the operating button 24 is inserted through this button hole 29 into one of the insertion ports 23, and the spray outlet 32 is inserted into the cylinder of the deceleration chamber. By coaxially D with the shaped body, the release from the aerosol container is symmetrical with respect to the deceleration chamber. In this way, a configuration is created in which medicine can be administered. In FIG. 3, the aerosol container is shown extending upwardly during medicament administration.

In this case, therefore, the medicament in the propellant 33 is caused to fall by gravity relative to the valve device 30. The operating button 24 has a spray outlet 32 conveniently made by perforating it from the outside in the button, through which a spray orifice 34 communicates, through which the medicament in the propellant is released. .

This spray orifice may be made integrally with the operation button, or a metal spray orifice may be made separately and inlaid with iron. Both of these methods are conventionally used. The spray orifice must have a diameter such that the released medicament conically expands and is dispersed in fine particles as it exits the spray orifice. Approximately 0.375~0.425 fence (0.015~
The 0.018 inch diameter orifice tends to produce a very good spray. The operating button 24 is snugly mounted on the end of a valve stem 35, which extends into the valve body 36 on one hand. There is a metering chamber 37 inside the valve body 3, into which the valve stem 35 is slidably attached.The valve body 36 and the ring 3
There is a metering gasket 38 between the valve stem 35 and the valve stem 35, which serves as a seal to prevent loss of propellant when the collar 39 of the valve stem presses against the metering gasket. It has a dual role of creating an annular seal around the valve spring. Therefore, when the valve stem is pulled down against the valve spring base 81, the four metering ports in the valve stem come out above the metering gasket. The contents of the metering chamber pass through this metering port 41, then through a dowel-oriented valve stem hole 42 extending through the valve stem, into a discharge passage 43 in the operating button 24, and then into the spray orifice 34. There is a filling groove 44 at the inner end of the valve stem 35. This groove also holds a filling gasket 45 separately so that the two cooperate. The fill gasket is held against the lower end of the metering chamber by a stainless steel valve stem washer 46 which is also held against the bottom of the metering chamber by a valve spring 40. In operation, when the valve stem 35 is depressed, it passes through the fill gasket 45 and the fill groove also passes upwardly through the fill gasket. Therefore, the valve stem 35 is sealed from one end of its diameter to the other end with respect to the filling gasket. Thus, in the measuring chamber, the measuring port 41 is connected to the measuring gasket 38.
It is filled and closed at the inner end before exiting above and passing the contents of the metering chamber through the metering port 41, the axial valve stem hole 42, the discharge passage 43 and the spray orifice 34. FIG. 4 shows the operating button 24 in the depressed position and the valve in the position to discharge the spray.

When the operation button 24 is no longer pressed, the valve stem 35 is pushed outward by the valve spring 40.

As a result, the metering port 41 passes through the metering gasket 38 and closes off the discharge from the metering chamber, following which the filling groove 44
The propellant containing the drug passes through the filling gasket 45 and flows through this groove 44 to fill the metering chamber 37 again. The valve body 36 has a valve body flange 47 which covers the end of the aerosol container 20 and is sealed by a container gasket 48.

The ferrule 31 is tightly fitted onto a stainless steel or aluminum aerosol container to secure the bottom of the container to the overall apparatus. The above-described structure for the metering valve is an example, and several other conventional valves may also be used.

It is commercially reasonable for metering valves to release a relatively small amount of charge with each operation, for example about 50 microliters, which is the volume of a small drop of water, so the metering chamber is It is important that it is completely filled before each operation and that no leakage from the metering chamber back into the aerosol container occurs between these operations.

A leakage prevention tank 49 is provided to prevent loss or leakage of this filling. This anti-moat tank 49 is firmly compressed into the flange sleep 50 from the valve body flange 47 due to friction with its cylindrical inner surface. A filling circuit 51 is provided on the outer peripheral surface of the tank 49 between the tank and the flange sleeve 50. This passageway is for recharging the drug-containing propellant in the aerosol container from the body of the container into a leak-proof tank. In order to prevent the leakage prevention tank 49 from coming off due to dropping the aerosol container on the floor during use,
This tank uses ultrasonic seals and is fixed by ultrasonic welding.

The ultrasonic energy is then transmitted through the flange sleeve 50 to the leakage prevention tank 49, but the discontinuity between the two causes reflection and refraction of the energy, causing dissipation of the ultrasonic energy, which is converted into heat. The leakage prevention tank is sealed by molding to the flange sleeve. Such ultrasonic sealing allows for economical and effective assembly of the device. And so sealed, the anti-draining tank will not become misaligned in a way that could damage the aerosol container itself, no matter how the device is used, or even if it is a little rough. Due to the nature of the propellant, when the operating button 24 is pressed down with the aerosol container to the position where it can be dispensed, the contents in the metering chamber 37 are released, and when the operating button 24 is released, a corresponding amount of the new amount is released. is drawn into the metering chamber 37 from the leak-proof tank 49, and the leak-proof tank 49 is refilled through the filling channel 51.

The leak-proof tank 49 can remain filled with the propellant containing the medicament no matter what direction the aerosol container is placed. Thus, the operating button 24
Each operation ensures uniform, precise dosing. By constantly immersing the grooved upper end of the valve stem in the liquid propellant, the finely divided solid drug in the propellant remains more homogeneous and therefore also provides a more even and consistent dosing.

In a system like this device, electric charge is normally generated and the system becomes electrically charged, but the use of a leak-proof tank made of plastic material seems to be effective in neutralizing the electric charge.

When the aerosol container 20 is made of stainless steel, the outer peripheral surface of the propellant filling only has a single potential, but since the propellant also acts as a dielectric, individual drug particles are charged and dispersed. and discharge rate. With a leak-proof tank, these effects of the stainless steel container are at least partially neutralized, thereby reducing or minimizing electrostatic effects and providing a more uniform charge profile. Without leak proof tank 49, the first 55% of doses would have a higher concentration of drug than the last 25% of doses.

Therefore, using a new dosing device may result in a higher than expected dose, whereas using a nearly empty, unused dosing device may result in a lower than expected dose. With the leak-proof tank of the present invention, charge fluctuations are minimized and the user receives a more reliable and uniform dose of medication. Although it is difficult to measure the effect of electric charge inside the aerosol container 20 and the deceleration chamber 11, no matter what theoretical or scientific basis is used to explain the uniformity of the electric charge, the uniformity of the electric charge cannot be explained. Therefore, when the leakage prevention tank of the present invention is used, the dose can be administered more uniformly, and the cross-sectional area of the mouthpiece 13 is less than half of the cross-sectional area of the cylindrical body 12, and the cylindrical shape of the parentheses is The length of the shaped body 12 is less than twice its diameter so that each dose of the drug in the propellant is dispersed into the deceleration chamber and loses the jet velocity imparted during propellant atomization. .

If some of the particles still do not lose their velocity, they collide with the walls of the deceleration chamber 11 and are caught or bounce off, and the user of the device inhales this finely divided medicament through the mouthpiece. A dispersion of this medicament, sometimes mixed with additional diluting air, is formed and aspirated. A large portion of the drug that would otherwise be deposited in the user's mouth and thus absorbed systemically is deposited on the walls of the deceleration chamber 11.

Even though medicines are quite expensive, ``the dose is small, and the loss in the deceleration chamber 11 is about 25 to 50%, so the dose administered to the patient is even and uniform. Compared to the benefits, this amount of loss is quite acceptable.

For most drugs, it is extremely important to be able to administer the desired amount of drug to the user.

Uniformity is important so that the doctor administering the medication will know how to adjust the dosage based on the user's condition. FIG. 5 shows a modified example of the aerosol dosing device of the present invention.

In this example, the container retaining sleeve as shown fits snugly into the container support flange 53.
The bottom of the aerosol container is fitted into this 52. A button holding slide 54 is mounted on the other end of the receptacle 52 so that it can be pressed inward to seal the device and to activate the operating button. is designed to be pulled outward. In addition to the above, devices with the following configurations can also be used.

In other words, the speed reduction chamber is sufficiently large to reduce the speed of the dispersed aerosol powder, and the dose can be adjusted depending on the inhalation speed of the user, or,
A measuring chamber capable of storing approximately 50 microliters of material is provided ~ the energy of the ejected material is completely dissipated in the deceleration chamber,
In some cases, a fine aerosol of the drug, almost like a candle, is administered and inhaled into the lungs. A candle is a suspension of fine solid particles in a gas, such as is normally produced when a fire is burned, and the particle size is within the colloidal range.

In this case, the particle sizes range from the smallest end of the colloidal range to those slightly larger than true colloids, so the definitions for particle sizes overlap here. For the purposes of this invention, the particle size is approximately 0.
．． Good results are obtained with a thickness of 5 to 10 microns.

Larger particles, approximately 10 microns or larger, tend to settle in the user's mouth or throat and are not desirable for inhalation therapy. Rather, they contribute more to the effect of systemic absorption.When using this device, a portion of the drug is deposited in the deceleration chamber 11, so this deceleration chamber must be cleaned from time to time.

In order to properly disperse the powdered medicine in the propellant,
Relatively high pressure propulsion systems are preferred.

Dichlorodifluoromethane (Freon 12
) gives satisfactory results. Stainless steel or aluminum containers are preferred to avoid damage due to breakage under pressures of this magnitude. Glass containers, plastic containers, or glass containers covered with plastic for protection may also be used;
It is used for low pressure applications of ~3.5k9/carp (30-50 pounds/square inch). valve stem 39
Plastic is preferable to metal.

This is because plastic is less likely to stick or stick when powder is packed around it than metal. A small amount of alcohol, about 1-10%, acts as a solvent and ensures valve operation. However, some drugs can ensure lubricant operation in such propellants.
It is clear that the size of the allosol container 20 and the metering chamber 37 will vary depending on the amount of drug in each operation and the number of times the drug is administered to the patient. The following examples illustrate the effective dosing of certain pharmaceutical agents.

Example 1 Preparation of diethylcarbamazine pamoate 2.0 mol (0.005 mol) of the dihydrogen citrate of diethylcarbamazine (N·N-jethyl-4-methyl-1-piverazine carboxamide) was added at room temperature. It slightly dissolved in water.

2.16 moles (0.005 mol) of pamoic acid disodium salt were added. A crystalline precipitate separated immediately, but upon standing at room temperature for 5 hours, the crystal disappeared and was replaced by an amorphous precipitate. Upon standing for an additional 2 days, the amorphous precipitate gradually changed to a crystalline form, which was collected and dried for 2.5 days. This procedure was repeated, except that the sodium pamoate was added as an aqueous solution rather than as a dry powder, resulting in an immediate precipitate of an amorphous solid that slowly crystallized over two days.

The solid was collected and air dried to yield 2.7 m.p. P. =
215-220 pm (decomposition). Calculated value C 67.44
: Day 6.35; N 7.15 Actual value C-66.90
; day 6.26; N 7.05 Example 2 Preparation of diethyl carbamazine bamoate from bamoic acid 15.4 kg (32
．． 4 mol) was added to 17.52 mol of methane in a 100 gallon stainless steel container and the mixture was stirred until it became a solution, if not completely.

1.5k9 of activated carbon and 1.5k9 of diatomaceous earth were added and the mixture was allowed to stand for 1 hour.

The mixture was heated in a diatomaceous oven. The cake was washed twice with methanol three times each time. The furnace liquor and polishing liquor were placed in a 100 gallon glass-lined container, then 21 liters of water was added, followed by the rapid addition of 10.9 liters (130 moles) of concentrated hydrochloric acid.
A bright yellow solid precipitated immediately. The foundation prayer was continued for 11 hours at room temperature. Free pamoic acid was recovered by filtration and purification three times with 20 ml of water. The cake was slurried in approximately 800ml of water for 1 hour, the solids filtered out, and the solids were washed three times with two parts of water and three times with four parts of methanol. The solid was then dried for 2 days at 50-55°C. Crude pamoic acid (11.
8k9) to dimethylformamide 61Z at 85-90
Dissolved at °C. Add 2 pounds of Keioshi and reduce the mixture to 1
``After the child's rope worship, the preheated funnel was used for the furnace. The cake was washed three times with dimethyl formamide. The furnace liquor was added to 70 liters of water in a 50 gallon glass lined container. Further, water was added thereto, and the resulting mixture was incubated for 11' while cooling to below 25°C. The purified pamoic acid was separated in a furnace, pressed and dried, and then washed three times with water and then three times with methanol. The pamoic acid was dried to a constant weight of 10.8k9. 10.1 kg (25.8 moles) of diethylcarbamazine dihydrogen citrate (86% relative to 95% starting monosodium salt) were dissolved in the water and the solution was filtered.

Purified pamoic acid 10 was prepared as described above by dissolving 1.96 kg (49.0 mol) of caustic soda in water IQ0.
．． 0k9 (25.8 mol) was added.

The pamoic acid-caustic soda mixture was stirred for 1 hour, 2 pounds of limestone was added, the heat was continued for 1 hour, and the mixture was clarified by heating. The furnace liquor was placed in a 100 gallon glass lined container and the diethylcarbamazine citrate solution was added as rapidly as possible.

A very thick cream-colored precipitate formed immediately. 40 After adding the water and stirring for 1 hour, the mixture became very thin.

The rope azusa was continued for another hour. The product was collected by washing and washed three times with water. The product is 50-55℃
dried and pulverized twice in a fluid energy mill.
I got a product worth 5k9.

10.8 kg of this jetylcarbamazimbamoate,
65q0 was dissolved in a mixture of 25% dimethyl sulfoxide and 50% methasol.

The cloudy solution was filtered through a diatomaceous filter and the cake was washed three times with methanol. 50 g of furnace liquid and washing liquid. Methanol was added and the solution was cooled to 0°C to 4°C and kept at that temperature overnight. The product was placed in an 8U oven and washed three times with 1.5 methanol. After drying at 45 to 50 q0 and finely pulverizing, diethylcarbamazine pamoate (90% or more has a particle size of 10 microns or less)
8.0 kg of N·N-diethyl-4-methyl-1-piverazine carpoxamide pamoate (equimolar) was obtained.

Example 3 50.5 parts (0.13 moles) of purified pamoic acid was suspended in 400 °C of acetone heated to 50°C, and dihydrogen citrate of diethylcarbamazine was added to the suspension. 53.0 tons (0.27 mol) was added.

The resulting transparent yellow solution was allowed to cool to room temperature and filtered. The furnace liquid was concentrated and dried under vacuum at 75 to 80°C for 16 hours.
102.0 Yukaze bis(N.N-diethyl-4-methyl-1-piverazinecarboxamide) pamoate was obtained as a yellow amorphous powder. Analysis: Calculated value: C 65.62; Sun 7.44:N IO. 6
8C43rd 53N603 (787) Actual value: C 65.
22; Sun 7.79; NIO. 80 Examples 4N・N
-diethyl-4-methyl-1-piverazine carboxamide pamoate through a fluid energy mill from 0.5 to
It was finely ground to 10 microns.

9% by weight of it was in the range of 1-5 microns. 0.75 mg of absolute ethanol was added to 300 milligrams (dry) in a 19" stainless steel container suitably equipped with an aerosol metering spray nozzle. Cooled (-40 oo) difluoromethane was added to the discharge vessel from a pressurized tank.
The container and contents were cooled by the evaporative cooling. A full 15 minutes of dichlorofluoromethane was added. The container was then closed with a metering valve and the metering valve was sealed in place. A metering valve was used to dispense 50 microliters of contents with each valve stroke.

This allows each time i. NON-jethyl-4-methyl-1-piverazinecarboxamide' of product 9 is 65 dichlorofluoromethane and 3.25
Administered with female ethanol. The latter two are vaporizable and exhibit minimal or no biochemical activity when mixed with sufficient amounts of air. Depending on the severity of the asthma attack, calming could be achieved with one or more inhalations.

Inhalation medication is a fast-acting medication and is far more effective than systemic medication. NON-diethyl-4-methyl-1-piverazine carboxamide pamoate is more effective for preventive or long-term treatment than for immediate treatment.

Other drugs are preferable when a significant rapid effect is desired during an asthma attack. This N'N-jethyl-4-methyl-1-piverazinecarpoxamidopamoic acid is approximately 0
．． The equivalent of 5 to 30 females of Jethylcarbamazine 3 times a day
As single doses administered in multiple doses, such doses are affordable to the patient and compatible with treatment needs, providing long-term control of many asthmatic conditions. Since diethylcarbamazine pamoate is administered directly to the lungs, the usual method of administering diethylcarbamazine is to administer it systemically, that is, by swallowing it orally and transporting the drug to the lungs using the L circulatory system. The dosage is usually lower than that of

Example 5 Triamcinolone Acetonide Triamcinolone acetonide was pulverized by a fluid energy mill until 9% by weight became particles with a size of 1 to 5 microns.

19 parts of a stainless steel container was filled with 30 parts of micronized triamcinolone acetonide and 0.244 parts of absolute ethanol, and then cooled and filled with 19.5 parts of dichlorodifluoromethane at -40 qo.
In order to cool the container through vaporization, a slight excess amount was added and vaporized.

The filled container was closed and sealed with a metering valve as described above. Dispersion in the propellant can be further improved by immersing the filled container in an ultrasonic bath and transferring energy from a thermal force transfer device to the contents in the aerosol container. To disperse the triamcinolone acetonide in this device, vibration alone generally produces satisfactory results.

Ultrasound is used when a more uniform dispersion of fine powder is to be ensured. The above elements are mixed, treated with ultrasonic waves, and filled under pressure.

Pressure filling is more complex for small-volume releases, but is now recommended for large-volume releases.
It also saves propellant. The valve needs to be specially designed for pressure filling. Approximately 0.1 of triamcinolone acetonide is released each time the valve operation button is operated.
give p.

Approximately 2 doses of triamcinolone acetonide can be delivered by performing 5 operations 4 times a day, each time.

A part of it stays in the deceleration chamber and a small amount is discharged, so ``1''
A slightly larger amount is taken by the patient per day. Approximately 8 females are required to administer the whole body to one patient. The ability to deliver the drug to a preferred site in small doses is a major benefit of the present invention. The patient needs to be taught how to operate the control buttons.

The drug is thereby released into the deceleration chamber, which, when inhaled by the patient, causes only the inhaled air to impart velocity to the drug particles to be absorbed. The patient inhales the drug and holds it for a few seconds to allow the drug to be absorbed into the surface of the lungs, then exhales. This results in only a small amount of medicament being expelled. Although in the previous examples the propellant was dichlorodifluoromethane, various other chlorofluoroalkanes and various mixtures thereof can be used. Example 6 Preparation of suspension Triamcinolone acetonide fine powder (0.5-5 microns) 400 9 dichlorodifluoromethane 100 Z sorbitan trioleate 6.9
9. Triamcinolone acetonide and sorbitan trioleate were placed in a beaker and dichlorodifluoromethane was added at -40oo.

A suspension was obtained. The resulting mixture was soaked in soni
fy) did. In other words, Planson Sonic Power
Company, Danbury, Connecticut is the model -
Sonifier manufactured as 75
) for 2 minutes at a current input of 9 amps.

To this was added further cooled dichlorodifluoromethane in an amount necessary to bring the total volume to 100%.The resulting mixture was uniformly dispersed and
Sonication) resulted in increased stability. A 19 cc stainless steel container was filled with 15' of the chilled mixture, the valves described above were inserted, and the bracket valves were sealed in place.

When the solution was adjusted and stored as described above and then flooded, triamcinolone continued to be dispersed. A simple shake provided a uniform dose of differential triamcinolone acetonide each time. When the substance was inhaled by an asthmatic patient, satisfactory results were obtained.Example 7 The procedure was carried out as in Example 6 except that sorbitant IJ oleate in Example 6 was replaced with 1.24% absolute ethanol.

The resulting suspension was stable both during filling into containers and during storage after filling. However, before using it, it is recommended to apply vibration to disperse it. The dosing device is capable of delivering a uniform dose every time, from initial operation to end of consumption.

By operating 4 times a day, 5 times each time, the total amount of
The initial plan is to give triamcinolone acetonide from the shelf.

Dosage must be adjusted based on the patient's clinical results.

[Brief explanation of drawings]

FIG. 1 is a pictorial diagram of the powder medicine dosing device of the present invention, showing the assembly structure when administering medicine. FIG. 2 is a partial cross-sectional view of the administration device, showing the structure during storage and transportation. FIG. 3 is also an enlarged cross-sectional view showing the valve being attached to the expansion chamber cover and sometimes to the leakage tank so that the metering valve is constantly immersed in the propellant;
Therefore, it is possible to prevent part of the drug solution from leaking and resulting in uneven dosage. FIG. 4 shows the valve system in a compressed state after dispensing with the valve stem depressed. FIG. 5 shows an alternative configuration in which the operating button fits snugly into the receptacle of the movable container during storage. Blue L...Deceleration chamber" 12...Cylindrical body ~ 13...Mouthpiece, 14...Protrusion part "Kado S...Mouthpiece cap" Wealth 6...Aerosol container holding part, 17... ...Flange, 18, No.9...Sleeve "2Q...Aerosol container also 21...W/air hole, 2
2...Operation button holding part t 2...Insert port, 2F...Operation button, 25...Flat surface (of the operation button),
28...Flat surface (of the insertion opening), 27...The fastening bead is also grave 8...Protective sleeve, 2 saddles...Section part (with button hole) 30...Valve layering, 31...Fitting theory, 32... Spray outlet, 33... Propellant 3 Turtle... Spray orifice, 3S... Valve stem as well 36... Valve body, 37... Metering chamber, 38... Metering gasket, 39... Valve stem color (brim), 40
...Valve spring, 41...Measuring port, 42...Valve stem hole 43...Discharge path, 44...Groove for filling, 5...Gasket for filling, 46... Valve stem washer, 4?...Valve body flange
48... Container gasket t 49... Moat loss prevention tank "50... Flange sleeve 58... Filling passage"
Flea 2...container fitting opening, 53...container support flange 54...button holding slide. ,evening

Claims (1)

[Claims] 1. Powdered medicament suspended in a propellant and having a particle size ranging from 0.5 to 10 microns is administered in uniform doses.
A cylindrical body 12 constitutes the main body of a powder medicine dosing device for administering at low speed in a dry aerosol state suitable for inhalation, which serves as a holding chamber for a cylindrical aerosol container 20 as well as a deceleration chamber 11. , one end of which is connected to the mouthpiece 13 by an overhanging portion 14 between the mouthpiece and the deceleration chamber.
The mouthpiece 13 has a cylindrical shape to fit the human mouth and is coaxial with the cylindrical body 12, and the mouthpiece 13 also has a removable cap 1 to prevent dust.
5, while the other end of the cylindrical body 12 constitutes a removable aerosol container holder 16 capable of closing the deceleration chamber 11 and making it sufficiently airtight; a retainer flange 17 capable of completely sealing the cylindrical body 12 forming the retainer flange, which is effectively coaxial and integral with the retainer flange, and has dimensions suitable for holding the cylindrical aerosol container in frictional engagement; A container holding sleeve 19 is formed, and when an operation button 24 on the aerosol container 20 is inserted into the insertion port 23 and held during aerosol administration, the aerosol is released coaxially with the deceleration chamber, and the aerosol administration is performed. It has an operation button holder 22 that is coaxial with the holder flange 17 and is equipped with a means for closing this part to prevent dust when carrying or storing the dispenser. A cylindrical aerosol container 20 is provided with an operating button 24 that fits snugly into the holding part and a valve for metering the dose, and the container is kept in the cylindrical deceleration chamber 11 when the administration device is carried or stored. 1. A powder medicine dosing device, characterized in that it can be held in a powder medicine dosing device.