JPS6228124B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a soft pellet or granule drug and a method for producing the same.

The present invention relates to an additional invention disclosed in Japanese Patent Application No. 51-747.

British Patent No. 1,122,284 discloses that a shaft which is loosely fitted into a tapered shaped bearing tube rotates into a tubular chamber having a mouthpiece to enable the recipient to inhale air. An insufflator is described for use in administering powdered medicaments by inhalation, having a propeller-shaped device for displacing a powder capsule, optionally mounted thereon. Using the device described above and for example the device described in GB 1331216, the recipient draws air through a device that rotates a powder container provided in the device. The powder within the powder container is fluidized and dispersed into an air stream for inhalation by the recipient.
For optimal dispersion of powdered drugs,
Although this powdered drug must be relatively free-flowing, the final particle size of the drug must be approximately 10 microns or less in order to allow adequate penetration of the drug into the lungs of the recipient. Are known. However, these two requirements are clearly in conflict because such fine powders are not sufficiently free-flowing. The inventors have now discovered that the problem is that the powdered drug flows satisfactorily within the powder container, but the internal cohesive forces are sufficiently small that it breaks down in the turbulent air surrounding the exterior of the container. It has been recognized that this can be alleviated or overcome by forming into soft small pellets or granules resulting in finer drug particles of therapeutically effective size. Furthermore, by molding the drug into soft pellets or granules, it becomes easier to fill the drug into capsules, and the use of coarse diluents such as lactose, which are conventionally added to powdered inhalation compositions, can be avoided. It becomes possible to omit it.

In the original application, the applicant has determined that at least 90% of
We have proposed a soft pellet drug consisting of an aggregate of individual drug particles with a particle size of less than 10 microns and having a particle size of 10 to 1000 microns.

According to the present invention, there is provided a soft pellet-like or granular drug having the characteristics described below in addition to the soft pellet-like drug of the above-mentioned original invention.

According to the invention, therefore, at least 90% consists of aggregates of individual drug particles having a particle size of less than 10 microns;
In a soft pellet or granule drug having a particle size of ~1000 microns, preferably 30-500 microns, the pellets or granules have (a) a "total transmitted load reduction degree" of greater than 100 g and/or (b) Soft pellets or granules characterized by having a product of "total transmitted load reduction" and "response delay" greater than 30 g cm and/or (c) "response delay" of at least 0.3 cm drug is provided.

Soft pellets or granules may be filled into containers, e.g. capsules, using automatic or semi-automatic filling machines and flowed inside the container in devices for dispersing the pellets or granules under the conditions during transport and storage. It is preferred that the particles have an internal cohesive strength such that they do not break up in some cases, but break up outside the container into therapeutically effective particles when expelled from the container.

The medicament in the soft pellets or granules of the present invention is
One can choose from a wide range of powdered medicaments, which can be amorphous or crystalline; and can be made into a powder, for example by grinding; For example, an air jet sieve is used to obtain the size.
The desired size can be achieved by classification on a sieve or sieving or direct crystallization. However, the medicament can be administered by inhalation, and before being incorporated into the soft pellets of the invention, the majority of particles, e.g. greater than 95% by weight, are smaller than 10 microns, e.g. 0.01 ~10 microns, preferably 1~
Preferably, it has a diameter of 4 microns. It is desirable that the individual drug particles be self-cohesive, as is commonly found in hygroscopic materials. Examples of suitable medicaments include medicaments suitable for the inhalation treatment of airborne allergic diseases, e.g.
- Pharmaceutically acceptable salts of bis(2-carboxychromon-5-yloxy)propan-2-ol; 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol;
Pharmaceutically acceptable salts of 7-yloxy)propan-2-ol; sympathomimetic amines such as isobrenaline, efuedrine or isoetaline and salts thereof; antibiotics such as tetracycline;
Includes steroids; enzymes; vitamins; and antihistamines. If desired, a mixture of pharmaceuticals,
For example, 1,3-bis(2-carboxychromone-
Disodium salt of 5-yloxy)propan-2-ol [sodium cromoglycate, disodium cromoglycate
A mixture of cromolycate (commonly known as cromolyn sodium) and isobrenaline may be used.

The pellets or granules of the present invention contain other ingredients,
For example, diluents, colorants and flavoring agents may also be included.
If the pharmaceutical particles are not self-cohesive, for example hygroscopic, it is preferred to add a small proportion of binder to the soft pellets or granules. Suitable binders include gum arabic, gum tragacanth, celluloses such as salts or ethers of carboxymethylcellulose, dextran and sugar solutions.
If the pharmaceutical particles are not easily wettable, it is preferred to add a small proportion of a surfactant to the soft pellets or granules or to use a solvent in preparing the soft pellets or granules. However, it is generally preferred that no binders, surfactants or solvents (other than water) be added to the soft pellets or granules.

If the drug particles are hygroscopic, optionally
A small proportion of water, added to the medicament in the vapor state in the case of pellets or in the liquid state in the case of granules, is usually sufficient to act as a binder. The water content of the drug can be adjusted depending on the physical properties of the particular drug, e.g. in the case of disodium cromoglycate, soft pellets or granules may contain up to 15% by weight, preferably 8-11% by weight. It is preferable that the water content is .

The size of the soft pellets or granules of the present invention is
It can be varied within the ranges mentioned above to suit the equipment in which the pellets or granules are dispersed. For a given device, there is an optimum particle size for optimal flow of soft pellets or granules, which can be determined by simple test methods, e.g. This can be easily determined by measuring the fluidity of pellets or granules. The inventors have also recognized that the optimum dispersibility of soft pellets or granules is related to the size of the pores in the container through which the pellets flow. The size of the pellets or granules is the pore size, i.e. usually 500-
Preferably, the pore size is 2000 microns, for example 1/20 to 1/5 of the pore size of about 700 to 1500 microns.

In principle, the inventor has obtained British patent no.
No. 5,006,000, for use in an inhaler of the type described in the specification (marketed under the trademarked name "Spinhaler"), and which is reduced to a powder when inhaled by a person. Soft pellets or granules from 50 to 250 microns, preferably from 120 to
It was found to have an average particle size of 160 microns, most preferably about 140 microns.

Soft pellets or granules should have a sufficient degree of cohesive strength to be filled into containers, transported and stored; the reason is that apparent destruction of the soft pellets or granules occurs under these conditions. Because it shouldn't happen.

From the foregoing it will be appreciated that soft pellets or granules with satisfactory properties can be obtained from numerous combinations of particle size and cohesion. By way of example, the inventor has determined that the inner end has an inner diameter of 2.08 mm (i.e., this end accommodates the free end of the shaft), the other end has an inner diameter of 2.44 mm;
The capsule has an elongated wire shaft 2.03 mm in diameter fitted into a 13 mm long hard nylon bearing tube and is rotated around the axis of said shaft at a speed of approximately 1800 rpm with an air flow at a flow rate of 60 min. 6.4 mm diameter with two 0.8 mm diameter holes in the shoulder, installed in a device according to British Patent No. 1122284 (marketed under the registered trade name "Spinhaler") for rotating a It has been found that for soft pellets or granules to be dispersed from gelatin capsules, it is preferred that the pellets have an average particle size of about 140 microns. Pellets or granules are disodium
Particularly preferred is a chromoglycate.

Soft pellets or granules satisfy conditions (a) and (b) as determined by the following two tests when placed in a 6.4 mm diameter gelatin capsule containing 20 mg of drug as soft pellets or granules. It is preferable that the

(a) Diffusion test A capsule filled with soft pellets is placed in the capsule holder of a powder inhaler (having the specified dimensions) as described in British Patent No. 1122284 and the shoulder of the capsule has a diameter Drill two 0.8mm holes. The degree of dispersion of the drug in the mist delivered by the inhaler was determined using a multi-stage liquid impingement device as described in British Patent No. 1081881.
(impinger) deformation device. A sectional view of the deforming device of this collision device is shown in FIG.

In FIG. 3, the powder inhaler 1 is inserted into a rubber sleeve 2 and thereby connected to a bent glass tube 3. In FIG. The lower end of the glass tube 3 is inserted into the container 4. This container 4 is
A portion thereof is filled with distilled water 5 and has a porous collision plate 6. On one side of the container 4 there is a filtration device 7.
is connected, and this filtration device is connected via a tube 8 to a vacuum pump. The dimensions of the above device are as follows: a-a 35mm b-b 150mm c-c 19mm dd 30mm ee 55mm f-f 100mm g-g 4mm h-h 38mm i-i 6mm j-j 10mm The inhaler is inserted into the upper horizontal end of the glass tube and the air is allowed to flow down at a rate of 60 per minute for 30 seconds. At least 5 capsules are processed in this way and the results are averaged. By spectrophotometry (or by any other suitable method) after dissolving the weight of the drug collected on the filter device, other parts of said device and in the inhaler in a suitable volume of distilled water. Measure.

The average total weight of drug collected for each capsule is at least 8% by weight, preferably at least 10% by weight, most preferably at least 14% by weight of the drug with respect to that collected on the filter of the multi-stage liquid impingement device. % by weight, the soft pellets or granules disperse satisfactorily.

(b) Emptying test A capsule filled with soft pellets or granules is inserted into the capsule holder of a powder inhaler (having the specified dimensions) as described in GB 1122284, and then the capsule is diameter 0.8 at the shoulder of
Drill two mm holes. This inhaler per minute
It was placed in an apparatus suitable for inhaling air at a flow rate of not more than 60 for 2.5 seconds and holding a flow rate of 60 per minute for at least 2 seconds. The capsule inserted into the inhaler was inhaled four times in the same manner as described above, and then the weight of the pellet remaining in the capsule was measured. The above operation was repeated 20 times and the results were averaged.

On average at least 50% by weight from each capsule,
Preferably at least 75% by weight, most preferably
The suction properties of soft pellets or granules are satisfactory if 90% by weight of pellets are suctioned.

The following tests are also important in determining the properties of the soft pellets or granules of this invention.

(c) Response lag The response lag can be measured using a device for measuring stress-strain relationships in materials [commercially available from Instron Limited (UK)].
TM-SM type device]. Second
The device shown in the figure consists of two dies with a diameter of 4 mm and a length of 1.55 cm.
It has a punch 1 which can be tightly fitted into it. The upper end of this die is open except when a push rod is inserted into the end, and its bottom is a load detector connected to a recorder suitable for recording loads from 1 to 1000 g. device (load cell)
It is closed by the surface of 3. In operation, the material to be tested 4 is carefully filled into the die so as not to form bridging and its surface is level with the top of the die.
The pressure rod is moved from the top of the die into the interior at a constant speed and the pressure transmitted to the load detector is recorded graphically.

Response delay is defined as the distance, expressed in cm, that the tip of the press rod moves downward from the top of the die until the load detector records that a load of 1 g is applied to the sample. be done.

(d) Total transmitted load reduction degree
(Load Reduction) The inventor also found that with the drug of the present invention having a satisfactory degree of diffusivity, the load transmitted to the load detector in the device described in (c) above does not increase uniformly. (See Figure 1). The back track of the curve, ie, the "easing" of the load in g, may be referred to as the "total transmitted load reduction" of the material under test. Therefore, “total transmitted load reduction degree”
was detected by the load detector while the load recorded as acting on the load detector changed from 0 to 1000 g. Defined as the total amount of reduction in transmitted load.

The inventor has recognized that the most useful parameter characterizing the soft pellets or granules of the present invention is the product of "total transmitted load reduction" and "response delay."

The soft pellets or granules of the invention have a lower bulk density than pellets or granules obtained by conventional methods. For example, soft pellets or granules prepared using disodium cromoglycate are smaller than 0.3 g/cc.
Preferably 0.2-0.3 g/cc, most preferably 0.22
It has a bulk density of ~0.28 g/cc.

The soft pellets or granules of the present invention are filled into containers such as capsules and cartridges, optionally in combination with other pellets, granules or particles. The container is preferably loosely filled with the soft pellets or granules of the present invention in an amount of not more than about 80% by volume, preferably not more than about 50% by volume. Of course, the soft pellets or granules should not be compacted in the container. Containers, e.g. 10 to 100 capsules
mg of soft pellets or granules. It is convenient to punch holes in this container during its manufacture (and plug the holes, for example using a plastic lid) and then, after removing the lid, to use it in an inhaler that is not equipped with a piercing device. could be.

If the soft pellets or granules of the invention are used in conjunction with other ingredients such as colorants, sweeteners or carriers, such as lactose, these ingredients can be applied to or mixed with the pellets or granules in a conventional manner. However, it is preferred that the soft pellets or granules of the present invention contain only the drug and water, with no other ingredients mixed therein.

The soft pellets of the present invention can be produced in a variety of ways.

For example, the soft pellets or granules of the present invention provide controlled agglomeration of pharmaceutical particles (and optionally other ingredients desired to be incorporated into the pellet) that are naturally or rendered self-agglomerated. Manufactured by This controlled aggregation operation may include (a) forcing the drug particles through pores, (b) controlling agglomeration in a fluidized bed, or (c) spraying a solution or slurry of the drug particles. This can be done by drying.

In method (a), which is a preferred method, if necessary, the finely divided drug particles, for example having a particle size of 0.01 to 10 microns, are first treated to render the powder particles self-cohesive. For example, if the pharmaceutical particles are hygroscopic, this treatment is carried out by wetting the powder particles by contacting them with water.

If soft pellets are required, the powder particles are contacted with moist air at a temperature of, for example, about 15 DEG to 50 DEG C. The amount of water required to obtain adequate self-cohesive properties can vary depending on the type of drug, but when obtaining soft pellets, the water content of the powder is usually reduced to approximately
It may not be necessary to increase it by more than 15% by weight, for example 5-10% by weight. If the pharmaceutical particles are non-hygroscopic, the necessary self-cohesive properties can be imparted to the powder by the addition or evaporation of a pharmaceutically acceptable binder, such as one selected from those mentioned above. This is done by treating the powder (under carefully controlled conditions) with a liquid that is capable of producing bonding bridges of solid residues that bind the particles, or of creating suitable contact between the particles. It will be appreciated that the type of binder will affect the cohesiveness of pellets or granules formed from treated pharmaceutical particles. If desired, a binder solution may be used with hygroscopic pharmaceuticals to improve the internal cohesiveness of the resulting pellets or granules.

After the pharmaceutical particles are made self-agglomerated (optionally after being rotated for a controlled period of time, for example in a drum or bath), the particles are passed through holes of approximately the same diameter as the desired particle size of the pellet. For example, the pharmaceutical particles are extruded through the pores of a vibrating screen having pores similar to the desired final pellet or granule particle size. The product obtained by passing through this mesh hole is a preformed pellet of drug.

If soft granules are required, the moist material is mixed with an excess of a suitable solvent, e.g. After extrusion through a sieve, the extruded product can be dried to a desired solvent content, eg water content. This product can be dry granulated into the desired product.

If it is desired to incorporate other ingredients, such as a binder, into the soft granules, the formulation of the other ingredients may be
This may be conveniently done by mixing with the medicament before wetting the medicament or by incorporating it into the solvent used for wetting the other ingredients.

The amount of water or other solvent used in granulation can be critical in some cases. For example, in the case of disodium cromoglycate (DSCG),
Using more than about 25% by weight (based on DSCG) water will make the granules too strong to provide granules with satisfactory dispersibility. Therefore, in the case of disodium cromoglycate it is preferred to use about 12 to 25% by weight of water, preferably 17 to 23% by weight.

Drying of the granules is preferably carried out in a preheated forced air circulation oven. The drying temperature is preferably 60 to 100°C, particularly 80 to 100°C.

Soft granules may also be produced by controlled agglomeration of the drug in a fluidized bed or by spray drying a solution or slurry of the drug.

In method (b), the fine particles of the medicament to be formed into pellets or granules are suspended in a gas stream in a fluidized bed apparatus together with any other ingredients desired to be added to the pellets or granules. When forming hygroscopic medicaments into pellets or granules, the moisture content of the solid material can be controlled by varying the humidity of the gas stream passing through the fluidized bed or by spraying the fluidized bed with water. The medicament may be processed in a fluidized bed under conditions and for a period of time sufficient to produce pre-pellets or granules of the desired internal cohesion and particle size.

In method (c), a solution or preferably a slurry of the medicament is spray dried to produce soft granules.
It is preferred to use a slurry of individual drug particles of the desired fine particle size, also containing other ingredients desired to be added to the granules. The solvent in the slurry is preferably a non-solvent or anti-solvent for the drug to ensure that no or very few bonding bridges of the drug are formed between the drug particles during spray drying. If a controlled amount of water is desired to be present in the product, a correspondingly larger amount of water can be included in the solvent in the slurry.

The degree of densification of the treated pharmaceutical powder when subjected to controlled agglomeration will vary depending on the method and powder used in performing the agglomeration. However, the inventor has found that, in principle, suitable preformed pellets are obtained by preparing the powder according to method (a) using a powder of disodium chromoglycate containing about 8-10% by weight of water. It has been found that 150 micron pores can be produced by extrusion through a sieve having pores of about 150 microns.

The preformed pellets produced by any of the foregoing methods may, if desired or required, be tumbled and agitated in accordance with conventional methods until pellets of the desired size, shape and cohesiveness are obtained. be able to. It is preferred that a proportion, for example a majority, of the soft pellets, especially of disodium cromoglycate, be spherical. The tumbling and agitation are conveniently carried out in a tank or drum pelletizer. Processing of the preformed pellets in such a machine is carried out until the majority of the pellets loaded into the machine have a particle size within the desired range. The particle size of the preformed pellets used and the conditions used for their tumbling and stirring may be varied by known methods to obtain soft pellets of the desired particle size. The time the pellets are tumbled is important under certain circumstances to produce effective soft pellets. Tumbling or stirring the pellets usually strengthens the pellets, slightly increasing the particle size and making the pellets more spherical in shape.

As noted above, the final product obtained from the stirring and tumbling process will have a particle size range of approximately the desired average particle size. By classifying this product, for example by sieving, pellets larger than the desired particle size and pellets smaller than the desired particle size can be removed. Pellets larger than the desired particle size and pellets smaller than the desired size can be ground into fine particles and recycled to the agglomeration process if desired.

The final soft pellets or granules may be placed into containers of any suitable shape, such as capsules or cartridges. The soft pellets of the present invention are used as a coloring agent,
If desired to be used in conjunction with other ingredients such as sweeteners or carriers, such as lactose, these ingredients may be applied to or mixed with the soft pellets in a conventional manner. However, it is preferred that the soft pellets of the present invention contain only the drug and water. Soft pellets or granules range from 0.01 to
75 free drug particles with a particle size of 10 microns
It is also possible to use mixtures in amounts up to % by weight.

A perforated container containing the soft pellets of the invention is rotated and vibrated in an air stream inhaled by the patient, thereby inhaling a drug, e.g. disodium cromoglycate, dispersed in the air stream. It can be administered to patients depending on the method. Rotation and vibration of the capsule may be conveniently carried out by any one of a variety of devices, for example the device described in GB 1122284. Disodium cromoglycate is known to be used in the treatment of asthma and subtilis asthma.

As used herein, the term "pellet" refers to aggregates held together by intermolecular forces of attraction (eg Van der Waals attraction) and produced by methods using, for example, water vapor. The pellets are usually spherical. The term "granule" also refers to aggregates in which particles are held together by intermolecular bonding bridges. In the case of soft granules, these bonding bridges are fragile. The bulk of the granules can have any shape. Granules are, for example,
It is prepared by overwetting the medicament with a solvent, such as water, and removing some of the solvent.

Examples of the present invention are shown below. In the examples, all parts and percentages are by weight unless otherwise specified.

Example 1 At least 98% of the powder has a particle size of 10 microns or less and has a mass median diameter
The moisture content of micronized disodium chromoglycate with a diameter of 1-3 microns was determined initially by contacting the powder with 33% air at a relative humidity of 18-24°C in a shallow dish. The value was adjusted from 4 to 6% by weight to about 9.5% by weight.

After the moisture content has reached the desired value, the treated powder (possibly after tumbling in a bath pelletizer) is placed in a Russel vibrating screen operating at a frequency of 1000 cycles per second. Chips were formed on a stainless steel sieve screen with a mesh size of 150 microns. The powder on the sieve screen was forced out of the sieve screen by using a spatula that pressed across the surface of the sieve screen. The particles exiting the vibrating screen as particles having an average particle size of about 150 microns were fed directly to a drum-shaped pelletizer adapted to rotate about a horizontal axis. The pelletizer drum has an internal diameter of approximately 0.3 m and a length of 0.37 m, closed at one end and equipped with a 0.18 m orifice at the other end for loading material into or removing material from the drum. A communicating frusto conical shoulder is provided. The inside of the drum is well polished. 2 Kg of powder from the vibrating sieve was charged into the drum and the drum was then rotated for 15 minutes at a circumferential speed of 0.38 m±0.025 m per second. The soft pellets obtained after this time have an average particle size of 135 microns,
The amount of particles remaining on a sieve with a mesh size of 350 microns is
The amount of particles less than 10% by weight and remaining on the 65 micron mesh sieve was greater than 90% by weight. Moisture content of final soft pellets is 8.5-10.5% by weight
It was hot.

It will be appreciated that these steps, which are carried out after adjusting the moisture content of the initial powder, should be carried out under controlled humidity conditions so as not to significantly alter the moisture content of the powder. . The water used in the above method should be sterile and the air should be Class 100 air.

The soft pellets obtained by the above method are approximately spherical and, when observed under a microscope, are found to have an open and loose structure and a flocculent surface.

up to 90 mg of the above soft pellets, e.g. 40 or
60 mg was placed in a gelatin capsule having two holes of 0.8 mm diameter in the shoulder, and the capsule was then sealed into a gelatin capsule having the construction and dimensions as described above.
1122284. When air is passed through this device at a flow rate of 60 per minute, the soft pellets in the capsules are completely dispersed into the air stream and broken down to form a mist of very fine particles suitable for inhalation. A similar substance was formed.

For comparison, if the original fine powder used to make the soft pellets were tested under similar conditions, only a relatively small amount of powder would diffuse out of the capsule, and the amount of powder dispersed would be changed significantly each time the test was conducted.

1,3-bis(2-carboxychromone-7-
Similar results were obtained when soft pellets were prepared using the Seiki method using disodium salt of propan-2-ol (6% water), isoprenaline sulfate and tetracycline.

Example 2 As a result of measurements made using the apparatus shown in Figure 2, the disodium chromoglycate pellets of Example 1 had a response delay of 0.4 cm or more, a total transmitted load reduction of 900 mg, and a diffusivity of 10%. It turns out that this is all.

Example 3 1000 g of micronized disodium chromoglycate with a given water content was charged into the bowl of a planetary mixer. Then gradually add the amount of water calculated to bring the water content of the disodium cromoglycate to the desired range, and rub the sides of the mixer bowl regularly to evenly distribute the water. I let it happen. The moistened disodium chromoglycate was then passed through a vibrating screen with 1000 micron mesh. This product is then processed into granules with a moisture content of 5 to 8% by weight.
The sample was dried for 2 hours at 85° C. in a preheated forced convection air oven until . The obtained granules are sieved.
Sieved through a 250 micron sieve. The granules thus obtained flowed well and could be easily filled into gelatin capsules.

Example 4 The granules of disodium cromoglycate produced in Example 3 were measured using the apparatus shown in Figure 2 and according to the diffusivity measurement method described above. The degree of diffusion of granules made using ~25% by weight water was greater than 10%. The response delay of these granules was 0.3 cm or more, and the total transmitted load reduction was 100 g or more.

Additional Relationships The original patent (Patent No. 1341866, Japanese Patent Publication No. 61-7408) states that at least 90% of the particles are composed of aggregates of individual drug particles having a particle size of 10 microns or less, and that the particle size is between 10 and 1000 microns. However, the present invention relates to a soft pellet-like drug according to the original invention, and (a) a "total transmitted load reduction degree" of greater than 100 g, and (b) a "total transmitted load reduction degree" of more than 30 g.
g/cm, the product of the “total transmitted load reduction degree” and the response delay degree and (or (c) at least 0.3
In that the invention relates to soft pellets or granules having a response delay of cm, it has an additional relationship to the original invention as stipulated in Article 31, Item 1 of the Patent Law.

[Brief explanation of the drawing]

FIG. 1 shows the relationship between the moving distance of the tip of the pressing rod and the load detected by the pressure-sensitive plate when the device shown in FIG. 2 is filled with the pellet-like or granular drug of the present invention and a load is applied. It is a graph. FIG. 2 shows an apparatus for measuring stress-strain relationships in materials. FIG. 3 shows a modification of the multi-stage liquid collision device. In Fig. 2, 1...pressing rod, 2...die,
3...Pressure sensitive plate, 4...Measurement material. In FIG. 3, 1...powder inhaler, 3...glass tube, 6...collision plate, 7...passing device.

Claims (1)

[Scope of Claims] 1. A soft pellet or granular drug comprising at least 90% of aggregates of individual drug particles having a particle size of less than 10 microns and having a particle size of 10 to 1000 microns, or granules, (a) the total transmitted load reduction degree is greater than 100 g, and (or) (b) the product of the total transmitted load reduction degree and the response delay degree, which is greater than 30 g cm, and (or) (c) A soft pellet or granule drug, characterized in that it has a response delay of at least 0.3 cm. 2. The drug according to claim 1, in which the degree of reduction in total transmitted load is greater than 400 g. 3. The drug according to claim 2, in which the degree of reduction in total transmitted load is greater than 800 g. 4. The drug according to claim 3, in which the degree of reduction in total transmitted load is greater than 1000 g. 5 The product of total transmitted load reduction and response delay is 40g・
The drug according to any one of claims 1 to 4, which is larger than cm. 6 The product of total transmitted load reduction degree and response delay degree is 40~
The drug according to any one of claims 1 to 5, which has a weight of 1000 g·cm. 7. The drug according to any one of claims 1 to 6, which has a response delay of at least 0.4 cm. 8. The drug according to any one of claims 1 to 7, which has a response delay of 0.4 to 0.8 cm. 9. A medicament according to any one of claims 1 to 8, wherein in the diffusivity test, at least 8% by weight of the medicament, by average total weight, is collected on the overloader of the liquid impingement device. 10 In a diffusivity test, at least 10% of the medicinal product, by average total weight, is
10. The agent according to claim 9, wherein % by weight is collected. 11. In a diffusivity test, an average total weight of at least 14
11. The agent according to claim 10, wherein % by weight is collected. 12. The drug according to any one of claims 1 to 11, in which an average of at least 50% by weight of the drug is aspirated from each capsule in an aspiration test. 13. From each capsule an average of at least 75% by weight
13. The drug according to claim 12, wherein the drug is inhaled. 14. A medicament according to claim 13, wherein on average at least 90% by weight of the medicament is aspirated from each capsule. 15. The drug according to any one of claims 1 to 14, wherein the pellets or granules have a diameter of 30 to 500 microns. 16 The average diameter of most pellets or granules is
The drug according to claim 15, which has a particle size of 50 to 250 microns. 17. The drug according to claim 16, which has an average particle diameter of 120 to 160 microns. 18. The drug according to claim 17, which has an average particle diameter of 140 microns. 19. The drug according to any of claims 1 to 18, wherein at least 95% by weight of the drug particles have a diameter of 10 microns or less. 20 At least 95% by weight of the pharmaceutical particles are between 0.01 and 10
A medicament according to claim 19 having a diameter of microns. 21. The medicament of claim 19, wherein at least 95% by weight of the drug particles have a diameter of 1 to 4 microns. 22. The drug according to any one of claims 1 to 21, wherein the individual drug particles are self-aggregating. 23. The drug according to any one of claims 1 to 22, wherein the drug particles are hygroscopic. 24. The drug according to any one of claims 1 to 23, which is an inhalation drug for treating airborne allergic diseases. 25. The drug according to claim 24, wherein the drug for inhalation is a pharmaceutically acceptable salt of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol. 26. The drug according to claim 25, wherein the drug for inhalation is disodium cromoglycate. 27 Claim 26, wherein the medicine for inhalation is disodium cromoglycate and isoprenaline.
Drugs listed in section. 28. A medicament according to claim 26 containing less than 15% by weight of water. 29. The drug according to claim 28, containing from 5 to 10% by weight of water. 30. The drug according to any one of claims 1 to 29, wherein the soft pellets are spherical. 31. The drug according to claims 1 to 30, which contains a coloring agent, a sweetener, or a diluent. 32. The drug according to any one of claims 1 to 31, which is filled into a capsule. 33. The drug according to claim 32, wherein the capsule is loosely filled with less than 80% by volume of the soft pellet or granular drug. 34. The drug according to claim 33, wherein the capsule is loosely filled with less than 50% by volume of the soft pellet or granular drug. 35. The drug according to any one of claims 32 to 34, wherein the capsule contains 10 to 100 mg of the soft pellet or granule drug. 36. The drug according to any of claims 32 to 35, wherein the capsule has pores. 37. The drug according to claim 26, having a bulk density of less than 0.3 g/cc. 38. The drug according to claim 37, having a bulk density of 0.2 to 0.3 g/cc. 39. The drug according to claim 37 or 38, having a bulk density of 0.2 to 0.28 g/cc. 40. Individual drug particles, at least 90% of which have a particle size of less than 10 microns, are (a) agglomerated by extrusion through pores, or (b) agglomerated by fluidization in a fluidized bed, or (c ) agglomerate a solution or slurry of pharmaceutical particles by spray drying; so that at least 90%
A method for producing a soft pellet or granule drug consisting of an aggregate of individual pharmaceutical particles having a particle size smaller than microns and having a particle size of 10 to 1000 microns, wherein the pellets or granules contain (a) 100 g has a greater total transmitted load reduction degree, and (b) a product of the total transmitted load reduction degree and response delay degree that is greater than 30 g cm, and (or) (c) has a response delay degree of at least 0.3 cm. A method for producing a soft pellet-like or granular drug, characterized by: 41 Claim 40, in which a medicament consisting of individual medicament particles is agglomerated by extrusion through pores.
The method described in section. 42 Claim 4, in which a medicament consisting of individual medicament particles is agglomerated by extrusion through a sieve having a mesh approximating the particle size of the desired final pellet.
The method described in Section 1. 43. A method according to any of claims 40 to 42, in which a medicament consisting of individual medicament particles is subjected to an initial treatment to render the particles self-aggregating. 44. The method of claim 43, wherein the medicament is hygroscopic and the initial treatment consists of wetting the powder particles by contacting them with a humid atmosphere. 45. The method of claim 44, wherein the pharmaceutical particles are contacted with a humid atmosphere at a temperature of 15-50°C. 46. A method according to any of claims 40 to 43, wherein the medicament is non-hygroscopic and the self-aggregating properties are imparted by the addition of a pharmaceutically acceptable binder. 47 Fluidizing individual pharmaceutical particles in a fluidized bed;
A method according to claim 40. 48. The method of claim 40, wherein the pharmaceutical solution or slurry is spray-dried. 49. The method according to any one of claims 40 to 48, wherein the obtained product is tumbled and stirred. 50. The method according to claim 49, wherein the tumbling and stirring are carried out in a tank or drum type pelletizer. 51. Mixing individual pharmaceutical particles with excess solvent;
Claim 40: Producing soft granules by extruding the moistened drug through pores that are equal to or larger than the particle size of the final granules and drying the resulting product to the desired final solvent content.
The method described in section. 52. The method of claim 51, wherein the solvent is water. 53. The method of claim 52, wherein the medicament is disodium cromoglycate and the water content of the disodium cromoglycate before drying is from 12 to 25% by weight. 54. The method according to claim 53, wherein the water content of the disodium cromoglycate before drying is 17 to 23% by weight. 55. The method according to any one of claims 50 to 54, wherein the drying temperature is 60 to 100°C. 56 Claim 40, which classifies the product to remove particles larger and smaller than a desired particle size.
56. The method according to any one of Items 55 to 55.