JPH0137369B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to hard granules of disodium cromoglycate.

1,3-bis(2-carboxychromone-5-
The disodium salt of propan-2-ol (disodium cromoglycate or cromolyn sodium) is useful in the treatment of various diseases of the gastrointestinal tract in which allergic or immune reactions play a role and in the treatment of asthma. It is a known medical treatment.
For the treatment of these various diseases of the gastrointestinal tract, it is often convenient to have the medicine present, at least initially, in powder form. However, finely powdered disodium cromoglycate flows extremely poorly;
It is extremely difficult to fill capsules with acceptably accurate dosages unless flow aids such as lactose are incorporated. In some situations and for some patients, such flow aids have proven themselves to be allergens.

Furthermore, the use of disodium cromoglycate in finely divided form or in soft pellet or soft granule form allows filling of the drug in a small and easily swallowable form, for example in a quantity sufficient for a conventional capsule. It was discovered that this was not possible. In practice so far only 10 or 20 mg of disodium cromoglycate (mixed with lactose) has been loosely filled into capsules, which are approximately 1/3 full.
It only shows that.

Although many drugs are granulated for use as intermediates in the manufacture of other pharmaceutical compositions, such as tablets, it is common to granulate the drug using binders or other excipients. Furthermore, it is most unusual to fill granulated drugs into capsules.

It is also known to formulate drugs in capsules, which typically include a lubricant or other pharmaceutical flow aid to enable the drug to be filled into the capsule.

The inventors have also discovered that certain particle sizes of disodium cromoglycate are easier to fill into capsules than other particle sizes.

According to the invention, British Standards Institute Test No.1460
Hard granules of disodium cromoglycate are provided having a bulk density of greater than 0.45 g/ml as measured by (1967).

The hard granules of disodium cromoglycate preferably have a bulk density of 0.5 to 0.7 g/ml, more preferably 0.53 to 0.66 g/ml.

The hard granules of disodium cromoglycate preferably contain up to 5% by weight of any other compound, more preferably up to 1% by weight, excluding water. , and most preferably no other compounds.

The hard granules of disodium cromoglycate desirably contain substantially no particles (ie, consist of less than 20% by weight) of particles larger than 250 microns in diameter, and preferably do not contain particles larger than 200 microns in diameter. Preferably, 60% by weight or less consists of particles with a diameter of 60μ or less, more preferably 80μ or less, and most preferably 90μ or less. In certain embodiments of the invention, the hard granules of disodium cromoglycate are substantially free (i.e., consist of no more than 20% by weight) of particles smaller than or equal to 60 microns in diameter and free of particles smaller than or equal to 45 microns in diameter. is preferred.

It is particularly preferred that the hard granules of disodium cromoglycate are substantially free of particles outside the diameter range of 60 to 200 microns. Particle sizes described herein are determined by sieve analysis unless otherwise specified.

The hard granules of disodium cromoglycate described above are made by substantially (i.e., 90% by weight or more) disodium cromoglycate being micronized to a particle size of less than 10 microns (as measured by a Coulter counter) (with the exception that this step may be omitted if desired) and mixed with water to give a concentration of 15 to 35% by weight (more preferably 20 to 30% by weight).
% by weight, most preferably from 21 to 26% by weight, especially 22
passing the mixture through a granulator equipped with a sieve with a mesh size of 4 to 30 openings/inch and drying to a moisture content of 5 to 8% by weight; It can be adjusted by sieving to obtain particles with a desired range of diameters.

The higher the proportion of water added, the higher the proportion of coarse particles (i.e. 250μ and above) will generally be. Therefore, the water addition rate is preferably no more than 2% by weight per minute, based on the initial total weight of disodium cromoglycate, including any water initially present. Addition rate of water is 0.5 to 1.5% by weight per minute
It is more preferable that The addition of water is preferably carried out in such a way that the water is mixed as intimately as possible with the disodium cromoglycate. That is, it is preferable to add water by spraying and stirring during mixing.

Preferably, the granulator used is a vibratory granulator equipped with 20 or 24 mesh sieves. Granulation temperature also ends up influencing particle size distribution, with higher temperatures resulting in a higher proportion of coarse particles. That is, the granulation bed temperature is
The temperature is preferably 50°C or lower, more preferably 40 to 50°C.

Drying is preferably carried out in a preheated forced convection hot air oven or fluidized bed dryer. Drying temperature is 60~
Preferably the temperature is 100°C, more particularly 75 to 75°C.
A temperature of 85°C is desirable.

Sieving to remove particles of diameter greater than the desired maximum dimension and smaller than the desired minimum dimension is preferably accomplished by passing the dry particles through one or more suitable sieves.

The unit dosage form containing the hard granules of the present invention preferably includes the hard granules encapsulated in a suitable membrane, for example a sac, such as a rice paper sac, or preferably a capsule, eg a gelatin capsule. Preference is given to lubricant-free unit preparations, especially hard granules in unit preparations.

When capsules are used, they are preferably free of colored substances.

That is, according to the application example of the present invention, 10% by weight or more,
Preferably, a unit preparation is provided containing at least 50% by weight of hard granules of disodium cromoglycate, 5 to 12% by weight of water, and 35 to 85% by weight of an encapsulating substance such as gelatin. be.

When the unit dosage is a capsule, the capsule is preferably 10 to 100% full, more preferably 20 to 80% full, most preferably 60 to 80% full when loosely filled. preferable.

The hard granules of the invention are useful in the treatment of diseases of the gastrointestinal tract in which allergic reactions play a contributing role, such as milk allergy. For these uses,
Preparations of about 5 to 250 mg of disodium cromoglycate may be used. The LD ₅₀ of disodium cromoglycate in rats is per kg of body weight.
Greater than 1000mg. It has been found that daily doses of 40 to 2000 mg of disodium cromoglycate are effective in the treatment of diseases of the gastrointestinal tract in which allergic or immune reactions play a contributing role. The hard granules of the present invention are also useful in treating nasal allergic conditions such as hay fever, for which doses of about 1 to 10 mg of disodium cromoglycate may be used.

Capsules containing the hard granules of the present invention have a greater density than conventional micronized disodium cromoglycate (bulk density is 0.31-0.35 g/ml). or up to twice the weight of disodium chromoglycate in soft pellet form that can be filled into capsules of a particular size.

The invention will be further illustrated by the following examples, which are given by way of illustration only.

Example 1 2000 g of micronized disodium cromoglycate with a determined moisture content are placed in the bowl of a planetary mixer. A calculated amount of water (approximately 500 g) to bring the moisture content of the disodium cromoglycate within the range of 22 to 24% by weight is then added by spraying, and the sides of the mixer bowl are scratched regularly to ensure even moisture distribution. ensure that The wet disodium cromoglycate is passed through a vibratory granulator equipped with an 8 mesh sieve and then through a 24 mesh sieve. The product is then dried in a preheated forced convection hot air oven at 80° C. for 3 hours until the moisture content of the granules is in the range of 5 to 8% by weight. Then, the fine grains were sieved through a 250μ sieve.
A fraction containing no particles with a diameter larger than 250μ is obtained. (The sieved product is then sieved to 40 μm, optionally using a sieve with an air jet stream.)
particles of smaller diameter may be removed). The resulting hard granules were found to be sufficiently flowable and could be easily filled into gelatin capsules with a bulk density of 0.51-0.52 g/ml. Approximately 250
It has been found that mg of granules can be filled into standard clean No. 0 capsules.

Example 2 30Kg of micronized disodium cromoglycate was analyzed for its moisture content and the moisture content was reduced to 22% w/w in a Hobart mixer.
Spray the required amount of water at a rate of 300ml/min. The wet powder is then passed through an 8 mesh sieve and then a 20 mesh sieve on a vibratory granulator. The granules are then dried at 80° C. to a moisture content of less than 8% w/w and finally passed through a 60 mesh sieve.

Hard granules of disodium cromoglycate in quantities formed by this method range from 0.60 to
It had a bulk density of 0.68 g/ml.

Claims (1)

[Claims] 1. Having a bulk density of greater than 0.45 g/ml as measured by British Standards Institute Test No. 1460 (1967);
Hard granules of disodium cromoglycate. 2. The hard granules according to claim 1, having a bulk density of 0.5 to 0.7 g/ml. 3. The hard granules according to claim 2, having a bulk density of 0.53 to 0.66 g/ml. 4. The hard granules according to claim 1, wherein the total content of other compounds excluding water is 5% by weight or less. 5. The hard granule according to claim 4, which does not contain any other compounds except water. 6. The hard granule according to claim 1, wherein 20% by weight or less of the particles have a diameter of 200μ or more. 7. The hard granule according to claim 1, wherein 60% by weight or less of the particles have a diameter of 60 μm or less. 8. The hard granule according to claim 1, wherein 20% by weight or less of the particles have a diameter of 60 μm or less.