JPH0142950B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides specific water-containing disodium
Regarding cromoglycate. In particular, the present invention relates to certain water-containing disodium cromoglycates useful in the production of soft pellet or granular medicaments.

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 inventor is
This problem arises when a powdered drug flows satisfactorily within a powder container, but the internal cohesive forces are sufficiently low that it is destroyed in the turbulent air surrounding the exterior of the container to be therapeutically effective. It has been found that this can be alleviated or overcome by forming small soft pellets or granules resulting in pharmaceutical particles that are finer in size. In addition, by shaping 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 were conventionally added to powdered inhalation compositions, can be avoided. can be omitted.

In Japanese Patent Application No. 747/1986, the applicant proposed a soft pellet-like drug consisting of aggregates of individual pharmaceutical particles at least 90% of which have a particle size of 10 to 1000 microns. did.

Furthermore, the applicant has proposed a soft pellet or granular drug having the characteristics as described further below in the above-mentioned soft pellet drug, i.e., at least 90%
% consists of aggregates of individual drug particles having a particle size of less than 10 microns, and
In a soft pellet or granule drug having a particle size of 10 to 1000 microns, preferably 30 to 500 microns, the pellets or granules have a "total transmitted load reduction" of greater than 100 g and/or ) Soft pellet-like or He proposed a granular drug (Japanese Patent Application No. 52-5978, Japanese Patent Publication No. 62-28124).

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.

Recently, the present inventor has developed disodium chromoglycate having a specific water content in the above-mentioned patent application filed in
It has been found to be particularly useful in the production of soft pellet or granular drugs as described in No. 5978.

According to the invention, therefore, disodium cromoglycate is provided having a water content of 12 to 25% by weight, preferably 17 to 23% by weight. The medicament can be administered by inhalation and, before being incorporated into the soft pellets, the majority of the particles, e.g. greater than 95% by weight, are smaller than 10 microns, e.g. 0.01-10 microns. , preferably having a diameter of 1 to 4 microns. Preferably, the soft pellets or granules prepared using the disodium chromoglycate of the present invention contain less than 15% water by weight, preferably from 8 to 11% by weight.

The size of the soft pellets or granules may vary within the ranges described above to suit the equipment in which the pellets or granules are spread. 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. Preferably, the size of the pellets or granules is 1/20 to 1/5 of the pore size, ie, typically 500 to 200 microns, such as about 700 to 1500 microns.

In principle, the inventor has obtained British patent no.
for use in an inhaler of the type described in the specification (marketed under the registered trade name "Spinhalar") and for inhalation by a person into a powder. 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 a number of combinations of size and cohesive strength can result in soft pellets or granules having satisfactory properties.
To give an example, the inventor has determined that the inner diameter of the inner end is
2.08mm (i.e. this end accommodates the free end of the shaft), the other end has an inner diameter of 2.44mm, and a length of 13
The capsule has a 2.03 mm diameter elongated wire shaft fitted into a 2.0 mm hard nylon bearing tube and the capsule is blown with an air flow at a flow rate of approximately 60 mm.
diameter on the shoulder, installed in a device according to British patent no.
It has been found that for soft pellets or granules to be dispersed from a 6.4 mm diameter gelatin capsule with two 0.8 mm holes, it is preferred that the pellets have an average particle size of about 140 microns.

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 0.8
Drill two mm holes. The degree of diffusion of the drug in the mist delivered by the inhaler is measured by a variant of the mutistage liquid impinger described in GB 1081881. 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. glass tube 3
The lower end of is inserted into the container 4. This container 4 is partially filled with distilled water 5 and has a porous collision plate 6. A filtration device 7 is connected to one side of the container 4, 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. on the device,
The weight of the drug collected in the other parts of the device and in the inhaler is determined spectrophotometrically (or by any other suitable method) after dissolving in an appropriate volume of distilled water.

The average total weight of drug collected for each capsule is at least 80% of the drug collected on the filter of the multi-stage liquid impingement device.
% by weight, preferably at least 10% by weight, most preferably at least 14% by weight, the soft pellets or granules will disperse to a satisfactory extent.

(b) Emptying teat 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 Drill two holes with a diameter of 0.8 mm in the shoulder. This inhaler
It was placed in a suitable apparatus for inhaling air at a flow rate not exceeding 60 per minute for 2.5 seconds and maintaining 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.

The aspirability of soft pellets or granules is satisfactory if on average at least 50%, preferably at least 75% and most preferably 90% by weight of pellets are aspirated from each capsule.

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

(c) Response lag Measurement of response lag is as follows:
Equipment for measuring stress-strain relationships in materials [commercially available from Instrom Limited (UK)]
TM-SM type device]. The device shown in FIG. 2 has a punch 1 which can fit tightly into a die 2 having a diameter of 4 mm and a length of 1.55 cm. 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. It is closed by the surface of the container (load cell) 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.

The response delay is 1g on the sample by the load detector.
It 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 application of the load is recorded.

(d) Total transmitted load reduction degree
Load Reduction) The inventor has also recognized that for drugs with 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, the "total transmitted load reduction degree" is defined as the total amount of decrease in transmitted load detected by the load detector while the load recorded as acting on the load detector changes from 0 to 1000 g. Ru.

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

Soft pellets or granules prepared using the disodium chromoglycate of the present 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 less than 0.3 g/cc, preferably 0.2-0.3 g/cc, most preferably
It has a bulk density of 0.22-0.28 g/cc.

The soft pellets or granules obtained using the disodium chromoglycate of the invention are filled, optionally together with other pellets, granules or particles, into capsule cartridges and similar pellet or granule receiving containers. The container is preferably loosely filled with soft pellets or granules 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. Preferably, the container, eg a capsule, contains 10 to 100 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 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 contain only the drug and water and no other ingredients mixed therein.

Soft pellets and granules can be manufactured in a variety of ways.

For example, soft pellets or granules are produced by controlled agglomeration of pharmaceutical particles (and optionally other ingredients desired to be incorporated into the pellet). This controlled agglomeration operation can be carried out by (a) extruding the drug particles through pores, or (b) controlled agglomeration in a fluidized bed.

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. 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.

After making the drug particles self-aggregating (optionally,
After turning 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 wet material may be mixed with an excess of water and extruded through a sieve, such as a vibrating sieve, with holes approximately equal to or larger than the particle size required for the final granules. The resulting product can be dried to the desired moisture 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 used for granulation is critical. In the case of disodium cromoglycate (DSCG), using more than about 25% water by weight (based on DSCG) increases the strength of the granules and does not result in granules with satisfactory dispersibility. . Therefore, in the case of disodium cromoglycate, about 12 to 25% by weight, preferably 17 to 23% by weight of water is used.

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 prepared by controlled agglomeration of the drug in a fluidized bed or by 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.

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 disodium cromoglycate soft pellets 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. If it is desired to use the soft pellets with other ingredients such as colorants, sweeteners or carriers, such as lactose, these ingredients may be applied to or mixed with the soft pellets by conventional methods. However, it is preferred that the soft pellets contain only the drug and water. Soft pellets or granules contain up to 75% by weight of free drug particles with a particle size of 0.01 to 10 microns;
They can also be used in combination.

administering disodium cromoglycate diffused into the air stream to the patient by inhalation, by rotating and vibrating a perforated container containing soft pellets in an air stream inhaled by the patient; Can be done. The rotation and vibration of the capsule can be achieved by any one of a variety of devices, such as those described in British patent no.
This can be conveniently carried out with the apparatus described in US Pat. No. 1,122,284. 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 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 method described above using disodium salt (6% water) of propan-2-ol, 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. Gradually add the calculated amount of water needed 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. Then the moistened disodium cromoglycate was added to 1000
It was passed through a vibrating sieve with micron mesh. The product was then dried for 2 hours at 85 DEG C. in a preheated forced convection air oven until the moisture content of the granules was 5-8% by weight. The obtained granules were sieved using a sieve with a mesh size of 250 microns. The granules thus obtained flowed well and could be easily filled into gelatin capsules.

Example 4 Using the apparatus shown in Figure 2 and according to the diffusivity measurement method described above, the disodium cromoglycate granules produced in Example 3 were measured. The degree of diffusion of the granules prepared using % water by weight 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.

Comparative Example Several granules were prepared by varying the water content of disodium cromoglycate during the granulation process, and these granules were tested using the apparatus shown in Figure 2 and according to the diffusivity measurement method described above. The degree of diffusion was measured. The results are shown in FIG.

From the graph shown in Figure 4, it can be seen that the granules prepared from disodium cromoglycate with a water content adjusted to 12-25% according to the present invention are different from the granules prepared from disodium cromoglycate with a water content other than the above. It can be seen that the diffusivity is clearly superior to that of .

[Brief explanation of drawings]

Figure 1 is a graph showing the relationship between the moving distance of the tip of the press rod and the load detected by the load detector when the device shown in Figure 2 is filled with pellet-like or granular medicine and a load is applied. be. Figure 2 shows
This is a setup for measuring the stress-strain relationship of materials. FIG. 3 shows a modification of the multi-stage liquid collision device. FIG. 4 is a graph showing the water content in the granulation process of disodium cromoglycate and the degree of diffusion of the resulting granules. In Fig. 2, 1...pressing rod, 2...die,
3...Load detector, 4...Measurement material. In FIG. 3, 1...powder inhaler, 3... glass tube, 6... collision plate, 7... filter device.

Claims (1)

[Claims] 1. Disodium containing 12 to 25% by weight of water
Cromoglycate. 2. Disodium cromoglycate according to claim 1, containing 17 to 23% by weight of water.