FI67663B - FREQUENCY REFRIGERATION FOR USE OF DIAGRAMS OF DYNATRIUM CHROMOGLYCLE GRANULATORS - Google Patents

Description

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Talent r.cddelat (51) Kv.lk. * / Int.ci.4 A 61 K 9/16, 9/72 SUOMI_FINLAND (21) Patent application— Patentansökning 770070 (22) Application date - Ansöknlngsdag 11.01.77 (23) Starting date - Giltighetsdag 11.01.77 (41) Has become public - Blivit offentlig 24.07 * 77

National Board of Patents and Registration ...... ..... ,,. „.

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Patent and registration authorities Ansökan utlagd och utl.skriften publicerad 31 * 01 .85 (32) (33) (31) Privilege requested — Begärd priority 23.01.76 23.OI.76 England and England (GB) 2606/76, 2608 / 76 (71) Fisons Limited, 9 Grosvenor Street, London, England-England (GB) (72) John Howard Bell, Loughborough, Leicestershire, England-England (GB) (7 * 0 Leitz Inger Ltd (5 ^) Method for inhalation for the preparation of soft disodium cromoglycate granules - Förfarande för framstä11 Ning av inhalerbara mjuka di nat ri umkromog1ykatg ranu1ater

The present invention relates to a process for the preparation of inhalable soft disodium cromoglycate granules.

Our English Patent 1,122,284 discloses an inhaler for inhaling powdered medicaments; the device comprises a propeller-like device with a powder capsule mounted so as to rotate inside the tubular housing by means of a shaft detached from the tapered bearing tube, said housing having a mouthpiece allowing the user to inhale air through the device. When using this device and other devices, for example the device described in British Patent Publication No. 1,331,216, the user inhales air through the device, which causes the powder container installed inside the device to rotate. The powder inside the container fluidizes and distributes into the air stream that the user inhales. In order to have the best possible distribution, it has been found that the powdered drug particles should be relatively free-flowing and yet have a final particle size of less than 10 microns to ensure adequate penetration of the drug into the user's lungs. These two 67663 mat requirements are prima facie contradictory because such fine powders are not sufficiently free flowing. We have now found that this problem can be reduced or avoided by forming a powdered medicament into small soft spheres or granules which fluidize satisfactorily inside the container but still have such low internal cohesiveness that they disintegrate into a therapeutically efficient airflow around the outside of the container -kehiukkasiksi. Formulation of the drug into soft spheres or granules also aids in filling the drug into capsules, allowing diluents such as coarse lactose previously added to the powdered inhalable compositions to be omitted from the mixture.

The present invention thus provides a process for the preparation of inhalable soft disodium cromoglycate granules having a grain diameter of 10 to 1000 and having: (i) a "total transmitted load reduction" greater than 100 g, and / or (ii) a "total transmitted load reduction" and "reaction a "delay time" of more than 30 g / cm, and / or (iii) a "response time" of 0,3 cm or more, by mixing disodium glycate granules with at least 90% of the diameter less than 10 μm with water and passing the moistened granules through a hole equal to or larger than the final grain size and then drying the resulting material to a final water content of 8-11% by weight, characterized in that the amount of water added to the disodium cromoglycate is such that the water content of the wetted granular material is 12 to 25% by weight.

The internal cohesiveness of the manufactured soft granule is best such that the granule remains intact when filled into a container, such as a capsule, using automatic drives under transport and storage conditions and fluidizing inside the container in the device from which the granules are to be dispensed, and still disintegrating outside when leaving the tank.

The disodium cromoglycate granules may be in amorphous or crystalline form and reduced, for example by grinding, and, if necessary, sorted or screened, for example in an air-jet screen, to obtain a suitable size, or may be made to the desired size by direct crystallization. However, it is recommended that said granules contain a considerable amount, for example more than 95% by weight, of particles with a diameter of less than 10 μm, for example 0.01 to 10 μm, most preferably 1 to 4 μm, before they are combined with the soft granules.

Disodium cromoglycate comprises pharmaceutically acceptable salts of 1,3-bis (2-carboxychromon-5-yloxy) propan-2-ol. It is hygroscopic and a small amount of water is added. The moisture content of the substance is adjusted as mentioned to 8-11% by weight.

The size of the soft granules can be varied within the range given above to suit the equipment from which they are to be distributed. For a given device, there is an optimum size for the granules for optimum fluidization of the soft granules, which can be easily determined by simple experiments, for example by determining the fluidization of very strong granules for use in the intended device. It has also been found that the best possible distribution of the soft granules depends on the size of the hole in the container through which the granules are to be passed. The size of the granules is preferably 1/20 to 1/5 x the diameter of the hole, which is usually 500 to 2000, for example about 700 to 1500.

Generally preferred soft granules that can be used in human inhalation-powered blowing devices of the type described in British Patent 1,122,284 (commercially available under the trademark "Spinhaler") have an average size of between 50 and 250, preferably between 120 and 160 and most preferably the average size is about 140 microns.

From the above, it will be appreciated that soft granules with satisfactory properties can be obtained from combinations of size and cohesiveness. For example, we have found that the average size of the granules is preferably about 140 μm for soft granules to be divided from a 6.4 mm diameter gelatin capsule with two 0.8 mm diameter holes in its shoulder mounted on a British patent 1,122,284. a device (commercially available under the registered trade mark "Spinhaler") with a shaft made of drawn wire 4 67663 with a diameter of 2,03 mm and mounted on a hard nylon bearing tube with a length of 13 mm and an inside diameter of 2 mm .08 mm at its inner end (i.e., the end at which the free end of the shaft is located) and 2.44 mm at the other end, and in which the shaft rotates about its axis at a speed of about 1800 rpm. under the effect of air flow, 'at a flow rate of 60 liters per minute. It is especially recommended that the spheres or granules be made of disodium cromoglycate.

The soft spheres or granules are preferably such that, when placed in 6.4 mm diameter gelatin capsules containing 20 mg of drug in the form of soft spheres or granules, they meet the requirements of tests (a) and (b) below: (a) Dispensing test The filled capsules are placed into a capsule holder of a powder blowing device according to British Patent Publication No. 1,122,284 (dimensions shown above) and are punctured so as to obtain two holes with a diameter of 0.8 mm in the shoulder of the capsule. The distribution of the drug in the cloud formed by the blowing device is determined using a modified modification of the multi-stage liquid jet device described in British Patent Publication 1,081,881. The modified impactor is illustrated in Figure 3, which shows a cross-section of the impactor.

In Fig. 3, the powder blowing device 1 is located in a rubber sleeve 2 which connects it to a bent glass tube 3. The lower end of the glass tube 3 is inserted into a tank 4 partially filled with distilled water and a porous impact plate 6. A filter unit 7 is connected to one side of the tank. through line 8 to the vacuum pump. The dimensions of the device are as follows: a - a 35 mm b - b 150 mm c - c 19 mm d - d 30 mm e - e 55 mm f - f 100 mm g - g 4 mm h - h 38 mm i - i 6 mm j - j 10 mm 67663

The blower is placed inside the upper, horizontal end of the glass tube and air is sucked through at 60 liters per minute for 30 seconds. At least five capsules are treated in this way and the results are averaged. The weight of drug accumulated on the filter, in the rest of the apparatus and in the blower is determined spectrophotometrically after dissolving in an appropriate volume of distilled water (or by some other suitable method).

The soft spheres or granules are satisfactorily distributed if the filters of the liquid jet device are found to have an average total value of at least 8, preferably at least 10 and most preferably at least 14% by weight of the drug in each capsule.

(b) Emptying test The filled capsules are placed in the capsule holder of a powder blowing device according to British Patent Publication No. 1,122,284 (the dimensions of which are given above) and punctured so that two holes with a diameter of 0.8 mm are formed in the shoulder of the capsule. The blower is placed in a device that can suck air through it for 2.5 seconds, at which time the air flow rate does not at any time exceed 60 liters per minute, and the flow rate is maintained at 60 liters per minute for at least 2 seconds. The capsule mounted on the blower is subjected to the four suction described above and the weight of the substance remaining in the capsule is determined. Said treatment is repeated 20 times and the average results are determined.

Soft spheres or granules are well emptied if an average of at least 50% by weight, preferably at least 75% and most preferably at least 90% by weight of the substance has been emptied from each capsule.

The following experiments are also important in determining the spheres or granules of the invention: (c) Reaction delay

The response delay can be measured with a device (available as TM-SM,

Inston Limited, Coronation Road, High Wycombe, Buckinghamshire, England) to measure the stress / stress properties of substances. This device is illustrated in Figure 2. It comprises a punch 1, 67663 which fits snugly on a mating 2 having a diameter of 4 mm and a length of 1.55 cm. The counterpart is open at its upper end except when the punch is inserted into this head. Its lower end is enclosed by the surface of a load cell 3 connected to a plotter that stores loads of 1 to 1000 g. When using the device, the test substance 4 is carefully filled into the counterpart in such a way as to avoid the formation of a bridge, and the surface is leveled to the level of the upper part of the counterpart.

The punch is moved at a constant speed to the counterpart from above, and the load transferred to the load cell is recorded graphically. The reaction delay is defined as the distance in cm that the tip of the punch passes below the top of the counterpart before the load cell registers a 1 g reaction.

(d) Total reduction in transmitted load

With the drugs according to the invention, which disperse well, it has also been found that in the device described in (c) above, the load transmitted to the load cell does not increase evenly (see, for example, Figure 1). The reversal of the curve or the "relief" of the load in grams can be termed the "total reduction in load transmitted" by the test substance. The "total reduction in transmitted load" can thus be defined as the sum of the transmitted load reductions detected by the load cell as the load stored to act on the cell increases from zero to 1000 grams.

We have found that in the definition of the spheres or granules of the invention, the most useful parameter is the product of the "total reduction in transmitted load" and the "response delay".

The spheres and granules of the invention have a lower bulk density than granules or spheres made by conventional techniques.

The bulk density of the soft spheres and granules of disodium cromoglycate is thus less than 0.3 g / cm, preferably 0.2 to 0.3 g / cm and most preferably 0.22 to 0.28 g / cm 3.

The invention also provides a capsule, cartridge or similar container containing the soft spheres or granules of the invention, optionally in combination with other spheres, granules or particles. The container is preferably loosely filled with less than about 80% by volume, most preferably less than 50% by volume of the soft spheres or granules of the invention. Naturally, soft spheres or granules should not be sealed in a container. The container, for example a capsule, contains 10 to 100 mg of soft spheres or granules as recommended. It is expedient to pierce (and coat, for example with a plastic cap) the container during its manufacture and then, after removing the cap, to use it in an inhaler with no piercing mechanism.

When it is desired to use other ingredients, such as colorants, sweeteners or carriers, such as lactose, with the spheres or granules of the invention, these other ingredients may be placed in or mixed with the spheres or granules using conventional techniques. The soft spheres and granules of the invention preferably contain only drug and water and should not be mixed in the hands of any other ingredients.

The soft spheres or granules of the invention can be prepared by several methods.

According to the invention, there is thus provided a method of making the soft spheres or granules of the invention, which agglomerates in a controlled manner drug particles (optionally in admixture with any other ingredient desired to be added to the spheres) which are either inherently self-assembling or made as such. This controlled agglomeration can be performed by (a) extruding the drug particles through the orifice, (b) agglomerating in a controlled manner in a fluidized bed, or (c) spray-drying the drug solution or slurry.

In method (a), which is considered to be the best method, a fine-grained drug, for example a drug having an average particle size of 0.01 to 10 microns, can be initially treated, if necessary, so that the powder particles become self-accumulating. When the drug is hygroscopic, the treatment can be performed by exposing the powder particles to water.

When soft spheres are required, the powder particles can be placed in contact with the atmosphere, for example at a temperature of about 15 to 50 ° C. Although the amount of water required to provide adequate self-accumulation properties may vary from drug to drug, it is generally not necessary to increase the water content of the powder above about 15% by weight, for example 5-10% is sufficient when soft spheres are desired.

When the drug is not hygroscopic, the necessary self-accumulating properties can be provided by adding a pharmaceutically acceptable binder, for example selected from the above binders, or by treating the powder with a liquid (under carefully controlled conditions) which can evaporate to form bridges of solid residue or particles well enough in contact with each other. It is to be understood that the quality of the binder may affect the stability of the spheres or granules formed from the treated drug. If desired, a binder solution may be used in the khn of the hygroscopic drug to improve the internal cohesiveness of the resulting sphere or granule. After the particles have been made self-assembling, they are passed (optionally after being rotated in a drum or pan for a certain time, for example) through an opening of approximately the same size as the desired spheres or granules, for example forced into a vibrating screen with openings. the same size as the desired balls or granules size ready, through the openings. By passing through these openings, shaped spheres of drug are obtained.

When it is desired to obtain soft granules, the powder particles may be mixed with an excess of a suitable solvent, for example water, and passed the wetted material through an opening, for example through a sieve such as a vibrating screen, approximately equal to or larger than the desired finished granule size. The resulting screened material is then dried to the desired final concentration of solvent, e.g., water. The substance can then be granulated dry to give the desired product.

If desired, another ingredient, for example a binder, may be added to the soft granules. This other ingredient may conveniently be either mixed with the drug prior to wetting or added to the solvent used to moisten the drug.

The amount of water or other solvent used in the granulation can be critical in some circumstances. Thus, we have found that when water in excess of about 25% by weight (based on dry DSCG) is used with disodium chromoglycate (DSCG), the granules become too strong and do not have satisfactory dispersing properties. Therefore, it is recommended to use about 12 to 25 and preferably 17 to 23% by weight of water in the granulation of disodium cromoglycate.

Drying is best performed in a preheated forced circulation hot air oven. The drying temperature is preferably 60 to 100 ° C and especially 80 to 90 ° C.

Soft granules can also be prepared by agglomerating the drug in a controlled manner in a fluidized bed or by spray-drying the drug solution or slurry.

In method (b), the finely divided drug particles formed into spheres or granules may be suspended together with any other ingredient to be added to the spheres or granules in a gas stream in a fluidized bed apparatus. When the balls or granules are made into a hygroscopic substance, the water content of the solid can be adjusted by changing the humidity of the gas stream passing through the fluidized bed or by spraying water into the bed. The drug can be treated in a fluidized bed for a time and under conditions sufficient to provide balloons or granules of the desired internal cohesiveness and size.

In method (c), the drug solution or, preferably, the slurry may be spray-dried to a soft granule. It is recommended to use a slurry of discrete drug particles having the desired small particle size, which also contains all the other ingredients that are desired to be added to the granules. It is recommended that the slurry liquid does not dissolve the drug or dissolves only poorly, so that no or too many bridges of drug are formed between the drug particles during spray drying. When a certain amount of water is desired in the product, a correspondingly larger amount of water can be added to the slurry liquid.

The amount of compaction of the treated powder during controlled agglomeration depends on the method and powder used in the agglomeration. As a guide, however, we have found that suitable spheres can be formed by method (a) from a powdered disodium cromoglycate containing about 8-10% by weight of water by forcing the powder through a sieve with apertures of about 150 microns.

Spheres prepared by any of the above methods may, if desired or necessary, be milled or mixed using conventional methods until the desired size, shape and cohesiveness of the spheres are obtained. Some, for example most, of the soft spheres, and in particular the soft spheres made of disodium cromoglycate, are preferably approximately round. The milling and mixing are conveniently performed in a pan or drum type pelletizing machine. The balloons are processed in such machines until most of the balls in the cartridge are in the desired size range. The size of the spheres used and the conditions used for mixing and crushing them can be changed in a known manner so as to obtain a finished soft sphere of the desired size. In some circumstances, the ball milling time is an important utility for making soft balls. The effect of crushing and mixing the balls usually strengthens them and slightly increases their size and makes them more spherical in shape.

As mentioned above, the finished product obtained from the mixing or milling step has a size range approximately equal to the desired average size. The product can be sorted, for example by screening, to remove oversized and undersized material. If desired, the oversized and undersized material can be broken down into very fine particles and recycled back to the agglomeration step.

The finished soft spheres or granules can be placed in any suitable container shape, such as a capsule or cartridge. When it is desired to use the spheres or granules of the invention in combination with ingredients such as colorants, sweeteners or carriers such as lactose, these other ingredients may be added or mixed into the spheres or granules using conventional means. The soft spheres or granules of the invention preferably contain only drug and water. Up to 75% by weight of free drug particles with a diameter of 0.01 to 10 microns can also be used as a mixture with soft spheres or granules.

11 67663

The invention also provides a method of administering a drug, e.g., disodium cromoglycate, to a patient by inhalation, the drug being dispersed in an air stream characterized by rotating and vibrating the ruptured container containing the soft spheres or granules of the invention. Rotation and vibration can conveniently be provided by any suitable device, for example the device according to British Patent Publication 1,122,284. Disodium cromoglycate is known to be used in the treatment of asthma and nasal catarrh.

In this specification, the term "sphere" refers to an agglomerate held together by the forces within the particles (e.g., Van der Waal) and is typically prepared by a process using steam. The spheres are generally spherical in shape. The term "granule" is used to mean an agglomerate held together by bridges within particles. In the case of soft grain, these bridges are brittle. The granules can be of almost any shape. The granules are typically prepared by overwetting the drug as a solvent, for example with water, and then removing some of the solvent.

The invention is illustrated by the following examples in which all parts and percentages are by weight unless otherwise indicated.

Example 1 1000 g of atomized disodium cromoglycate having a certain water content was placed in a plate of a planetary mixer. A calculated amount of water was then gradually added to raise the moisture content of disodium cromoglycate to the desired range, and the sides of the mixing dish were regularly scraped after even distribution of moisture through a full sieve with an orifice size of 1000 microns.

The product was then dried in a preheated forced circulation hot air oven at 85 ° C for 2 hours until the moisture content of the granules was between 5-8% by weight. The granules 12,676,63 were then screened through a 250 micron sieve. The obtained granules were found to flow well and could be easily filled into gelatin capsules. When the dispersions were tested as described above, 13 to 17% by weight of water was obtained in the granulation steps. The "response delay" of these particles was 0.3 to 0.65 cm and the product of the "response delay" and the "total reduction in transmitted load" was 70 to 900 cm / g.

Example 2

Using the apparatus shown in Figure 2, the disodium cromoglycate granules prepared according to Example 1, and the previously described partitioning test, for granules prepared using 10 to 25% by weight of water in the granulation step, a distribution of more than 10% was obtained. The reaction delay of these granules was more than 0.64 cm and the total reduction of the transmitted load was more than 677 g.

Example 3

Several hard gelatin capsules were filled with 50 mg of the particles prepared according to Example 1 but using different amounts of water. Prior to filling the capsule, the particles were screened with a sieve with aperture sizes of 150 microns. The results obtained are shown below, which show that the product according to the invention gives about twice the amount of fine particles in the dispersion test compared to the material which does not fall within the scope of the invention.

Reaction delay x

Total __Content__cm__Small_Dispersion (i) 27 0.15 0.84, 4.50, 0.80 6.8 0.17 0.20 (ii) 23 0 of the "Reaction-Transmitted Load-Product Moisture Delay" particle 50 80, 538, 273 12.8 0.50 0.59 0.35 0.31

Claims (1)

A process for preparing inhalable soft disodium cromoglycate granules having a particle diameter of 10 to 1000 μm and having: (i) a "total mediated load reduction" greater than 100 g, and / or (ii) a "total mediated load reduction" and "reacting" a "delay time" of more than 30 g / cm, and / or (iii) a "response delay" of at least 0,3 cm, by mixing disodium glycate granules of which at least 90% have a diameter of less than 10 μm with water and passing the wetted granules through a hole; through a size equal to or greater than the final granule size and then drying the resulting material to a final water content of 8-11% by weight, characterized in that an amount of water is added to the disodium cromoglycate such that the wetted granular water content is 12-25% by weight -%.