CH621060A5 - Granular medication - Google Patents

Description

The present invention relates to a drug in the form of pellets or granules, in which the grain is brittle, has a diameter of 10 to 1000 p., And preferably from 30 to 500 µm, and comprises an agglomerate of ultimate particles of the drug. which have at least 90%, and preferably for at least 95% by weight, a diameter of less than 10 days, said pellets or granules being further characterized by the fact that they have:

a) a total reduction in transmitted charge (to be defined below) greater than 100 g, preferably greater than 400 g, and better still greater than 800 g, or even greater than 1000 g, and / or b) a product the total reduction in charge transmitted by the response delay (as defined below), greater than 30 g / cm, preferably greater than 40 g / cm and, better still, between 40 and 1000 g / cm, and / or c) a delay in response of at least 0.3 cm, preferably at least 0.4 cm and, better still, between 0.4 and 0.8 cm. The friable tablet, or granule, preferably has an internal cohesion such that it remains intact when a container, for example a capsule, is filled with it, using automatic or semi-automatic filling machines, under conditions of transport and storage, and when fluidized in a container of the device for dispensing the pellets or granules, and it can be divided into particles of a therapeutically effective diameter outside the container when it is dispensed from this latest.

The medicament in the form of pellets or granules of the present invention can be chosen from a wide range of powdered medicaments, it can be in amorphous or crystalline form and it can have been ground and, if necessary, divided by category or sieved, for example on an air jet screen, in order to obtain an appropriate dimension, or else it may have been produced by direct crystallization to the desired dimension. However, it is preferable that the medicament can be administered by inhalation and that it has a large number of particles, for example greater than 95% by weight, with a diameter less than 10 days, for example between 0.01 and 10 n, and preferably between 1 and 4 n, before incorporation into the friable pellets or granules according to the invention. If desired, the individual drug particles are self-agglomerating, as is generally the case with a hygroscopic product. As suitable medicaments, there may be mentioned medicaments suitable for inhalation treatment of allergic disorders of the respiratory tract, such as the pharmaceutically acceptable salts of 1,3-bis- (2-carboxy-chromon-5-yloxy) -propane. -2-ol, the pharmaceutically acceptable salts of 1,3-bis- (2-carboxychromon-7-yloxy) propan-2-ol, the pharmaceutically acceptable salts of 1,3-bis- (2-carboxychromon-7-yloxy ) -propan-2-ol, sympathomimetic amines (for example iso-prenaline, ephedrine, or isoetharine as well as their salts), antibiotics (for example tetracycline), steroids, enzymes, vitamins and antihistamines. If we deduct it, we can use a mixture of drugs, that is to say a drug of the disodium salt of 1,3-bis- (2-carboxychromon-5-yloxy) propan-2-ol (called usually sodium chromoglycate, disodium chromoglycate or sodium chromolyne) and isoprenaline.

The pellets or granules may contain other constituents, for example diluents, colorants and flavorings. When the drug is not self-agglomerating, for example hygroscopic, it may be desirable to incorporate a small amount of a binder into the friable pellets or granules. As suitable binders, mention may in particular be made of gum arabic, gum tragacanth, celluloses, such as the salts and ethers of carboxymethylcellulose, dextrans and sugar solutions. When the medicine is not easily wetted, it

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it may be desirable to incorporate a small amount of surfactant and / or to use a solvent when preparing friable pellets or granules. As a general rule, the licensee prefers not to use a binder, surfactant or solvent (other than water) in friable pellets or granules.

When the drug is hygroscopic, a small amount of water which, if necessary, is added to the drug in the vapor phase for the pellets and in the liquid phase for the granules, is generally sufficient to act as a binder. The moisture content of the product can be adjusted based on the physical properties of the particular product; for example, for the disodium chromoglycate, it is preferable that the friable pellets or granules contain less than 15% by weight of water, and preferably from 8 to 11% by weight of water.

The size of the friable pellets or granules according to the invention can vary within the range indicated above, which is suitable for the devices by means of which they are dispensed. For a given device, there is an optimal dimension of the pellets or granules for the most favorable fluidization, these dimensions being able to be easily determined by simple experiments, for example by appraising the state of fluidization of highly resistant pellets or granules in the device to be used. The licensee has found that the optimal distribution of lozenges or granules depends on the orifice of the container through which this distribution takes place. It is also preferable that the pellets or granules have a dimension of 1/20 to 1/5 of the diameter of the orifice, the latter generally having a diameter of 500 to 2000 | i, for example around 700 to 1500 | i. As a general indication, it is satisfactory that the friable pellets or granules intended for use in insufflators of the type described in British patent No. 1122284 (and sold commercially under the brand Spinhaler), and sprayed by inhalation by the patient, have an average diameter between 50 and 250 d, preferably between 120 and 160 n and, better still, around 140 (i.

Friable pellets or granules must be sufficiently coherent to be introduced into containers, transported and stored, since no appreciable fragmentation of the pellets or granules should occur under these conditions.

It appears from the above that the friable pellets or granules having satisfactory properties can be obtained by a number of permutations of size and cohesion. By way of example, the licensee has found that for friable pellets and granules which must be dispensed by means of a gelatin capsule with a diameter of 6.4 mm having two orifices with a diameter of 0.8 mm in a shoulder, mounted in a Spinhaler apparatus according to British Patent No. 1122284, comprising a drawn metal wire constituting the shaft with a diameter of 2.03 mm journalling in a tubular bearing in hard nylon with a length of 13 mm and having an internal diameter of 2.08 mm at its internal end (that is to say the end housing the free end of the tree) and a diameter of 2.44 mm at its other end, the capsule being animated about its axis of rotation at about 1800 rpm by means of an air jet with a flow rate of 601 / min, it is desirable that the pellets and granules have an average caliber of about 140 n. It is particularly preferable that the pellets or granules are made of disodium chromoglycate.

The friable lozenges or granules are preferably of such a nature that when they are constituted in gelatin capsules of 6.4 mm in diameter, each containing 20 mg of the medicament in the form of lozenges or granules, they satisfy the criteria of the two tests below. -after:

a) Dispersion test

The filled capsules are mounted in the capsule holder of the powder insufflator apparatus (with the specific dimensions mentioned immediately above), in accordance with British Patent No. 1122284, and drilled to present two orifices with a diameter of 0, 8 mm in a shoulder. The dispersion of the drug in the cloud delivered into the insufflator is determined by means of a modified version of the multi-stage liquid impact device described in the British patent N ° 1081881. The modified impact device is illustrated in fig. 3 of the accompanying drawings, which represents a section of said impact device.

Referring to fig. 3, the powder insufflator 1 is placed in the rubber sleeve 2, and it is connected to the bent glass tube 3. The lower end of the glass tube 3 is introduced into a container 4 which is partially filled with water distilled 5 and which comprises a porous impact disc 6. A filter 7 is connected to one side of the container 4 and it is in turn connected to a vacuum pump via a tube 8. The dimensions of the device are data below:

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

4mm h-h

38 mm i-i

6 mm d-d

10 mm

The insufflator is introduced into the upper horizontal end of the glass tube and air passes through it at a rate of 601 / min for 30 s. At least five capsules are treated this way and the results are averaged. The weight of the drug collected on the filter and that which is distributed in the rest of the apparatus and in the insufflator are determined by spectrophotometry after dissolving in an appropriate volume of distilled water (or by any other suitable method).

The friable pellets or granules disperse satisfactorily if there is found on the filter of the impact device a total average, for each capsule, of at least 8% by weight, preferably at least 10% in weight and, better still, at least 14% by weight of the drug.

b) Evacuation test

The filled capsules are mounted on the capsule holder of the powder insufflator (having the dimensions indicated above) of the type described in British Patent No. 1122284 and they are drilled to form two holes of 0.8 mm in diameter on a shoulder of the capsule. The insufflator is placed in a device intended to draw in air therein for 2.5 s, the air flow at no time exceeding 601 / min and being maintained at 601 / min for at least 2 s. The capsule mounted in the insufflator is subjected to four aspirations and the weight of the product remaining in the capsule is determined. The above process is repeated twenty times and the average of the results is determined.

The friable pellets or granules are emptied satisfactorily if an average of at least 50% by weight, preferably at least 75% by weight and, better still, at least 90% by weight of the product has evacuated from each capsule.

The tests below also have a certain importance in the definition of the pellets or granules of the present invention:

c) Response lag

The response offset can be measured using a device (sold by Instron Limited, Coronation Road, High Wycomb, Buckinghamshire, Great Britain, under the model name TM-SM) for the measurement of stress / stress properties materials. This device is illustrated in FIG. 2 of the accompanying drawings and it includes a punch 1 fitted in a die 2 of 4 mm in diameter and 1.55 cm in length. The die is open at the upper end, except when the punch is inserted into

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this end, and it is closed at its lower end by the surface of a load detection cell 3 connected to a recording device intended to record loads ranging from 1 to 1000 g. In operation, the product to be tested 4 is carefully introduced through the matrix so as to avoid any overflow and the surface is at the upper end of the matrix. The punch is moved at a constant speed in the die from the upper end and the load transmitted to the load cell is recorded graphically. The response offset is defined as the distance in centimeters that the end of the punch travels below the upper level of the matrix before recording a response of 1 g on the load cell.

d) Total reduction in transmitted load

It has also been found that with medicaments according to the invention, which disperse satisfactorily, the charge transmitted to the charge detection cell of the device described under c above does not increase steadily (see for example the graph in Fig. 1 where we have plotted the distance D, in centimeters, traveled by the punch and, on the ordinate, the load C from 0 to 1 kg). The descending parts of the curve, or lightening of the load in grams, can be considered as the total reduction in transmitted load of the product tested. Thus, the total reduction in transmitted charge is defined as the sum of the reductions in the charge transmitted and detected by the cell, while the detected charge increases from 0 to 1000 g.

It has been found that the most useful parameter in the definition of the pellets or granules according to the invention resides in the product of the total reduction in charge transmitted by the response shift.

The pellets and granules according to the invention have an apparent density lower than that of the granules or pellets made of disodium chromoglycate have an apparent density less than 0.3 g / cm3, preferably between 0.2 and 0.3 g / cm3 and, better still, between 0.22 and 0.28 g / cm3.

The present invention also provides a capsule, cartridge or similar container, containing friable pellets or granules according to the invention, optionally in combination with other pellets, granules or particles. It is preferable that the container is freely filled to less than about 80% of its volume, preferably to less than 50% of its volume, with the friable pellets or granules according to the invention. Of course, friable pellets or granules should not be packed in the container. It is preferable that the container, i.e. the capsule, contains 10 to 100 mg of friable pellets or granules. It may be convenient to pierce the container (as well as cover it with a plastic cap) during its manufacture, then use it, after removing the cap, in an inhalation device that does not have a mechanism drilling.

When it is desired to use the pellets or granules of the present invention in combination with other ingredients such as colors, sweeteners or carriers such as lactose, these other ingredients can be mixed with the pellets or granules by means of a usual technique. It is preferable that the friable pellets or granules of the invention contain only the drug and water, and that they are not mixed with other ingredients.

The pellets or granules according to the invention can be produced by a number of methods.

According to the invention, a method of manufacturing friable pellets or granules according to the invention consists in subjecting particles of the medicament (optionally in admixture with another ingredient if it is desired to incorporate it into the pellets) and. which are inherently self-agglomerating or which have been made self-agglomerating, to a controlled agglomeration. This controlled agglomeration can be carried out by one of the following processes:

a) by extruding the particles of the medicament through an orifice, b) in a fluidized bed, or c) by spraying a solution or a paste of the medicament.

In the method which is the preferred method, the finely divided drug, for example having an average particle size of between 0.01 and 10 n, can be subjected, if necessary, to an initial treatment to bring the powder particles to be self-agglomerating. Thus, when the drug is hygroscopic in nature, the treatment can be carried out by exposing the powder particles to water. When it is necessary to obtain friable pellets, the powder particles can be subjected to a humid atmosphere, for example at a temperature between 15 and 50 ° C. Although the amount of water necessary to achieve adequate properties self-agglomeration is variable from drug to drug, it is not generally necessary to increase the water content of the powder beyond about 15% by weight, for example from 5 to 10% when we want to make friable pastilles. When the drug is non-hygroscopic, the necessary self-agglomerating properties can be imparted by adding a pharmaceutically acceptable binder, for example one of those mentioned above, or by treating the powder with a liquid ( under carefully controlled conditions), which can be evaporated in order to produce bridges of a solid residue binding the powder particles, or which forms an adequate interparticle contact. It should be noted that the nature of the binder may affect the cohesion of the resulting pellet or granule formed from the treated drug. If desired, a binder solution can be used with a hygroscopic drug to improve the internal cohesion of the resulting pellet or granule. After the particles have been made self-agglomerating, they are passed (possibly after having been rolled, for example in a drum for a determined period) through an orifice having substantially the size of the desired pellet; for example, they can be forced through holes in a vibrating screen which is similar in opening to the final size of the pellet or granule. The product obtained after this passage through an orifice is put in the form of prepastilles of the drug. When it is desired to obtain friable granules, the powder particles can be mixed with an excess of a suitable solvent, for example liquid water, and the moistened substance is passed through an orifice, for example a sieve such as a vibrating sieve, having a dimension substantially equal to or greater than the desired dimension of the final granule, then drying the product thus sieved until the desired final content of solvent, for example water, is obtained. This substance can then be granulated dry to obtain the desired product.

When it is desired to incorporate another ingredient, for example a binder, into the friable granules, one can conveniently either mix the other ingredient with the medicament before its humidification, or incorporate it in the solvent used to humidify the medicament.

The amount of water or other solvent used in the granulation can be critical under certain conditions. Thus, the licensee found that with disodium chromoglycate (DSCG), the implementation of an amount of water greater than 25% by weight (measured relative to dry DSCG) causes the granules to be too resistant and to not have satisfactory dispersion properties. It is therefore preferable to use 12 to 25% by weight, preferably 17 to 23% by weight of water in the granulation of the disodium chromoglycate.

Heating is preferably carried out in a preheated hot air oven with forced current. It is desirable that the drying temperature is between 60 and 100 ° C, and more particularly between 80 and 90 ° C.

The friable granules can also be produced by controlled agglomeration of the drug in a fluidized bed or by dry spraying of a solution or a paste of the drug.

In process b above, the fine particles of the drug to be conformable can be suspended in the form of pellets or granules, together with any ingredient that is desired.

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incorporate into the pellets or granules, in a gas stream from a fluidized bed apparatus. When the hygroscopic substance has to be formed into pellets or granules, the water content of the solid material can be adjusted by varying the humidity of the gas stream passing through the fluidized bed or by spraying water into the bed. The medicament can be treated in the fluidized bed for a time and under conditions sufficient to produce the prepastilles or pre-granules of desired size and internal cohesion.

In method c above, a solution, or preferably a paste, of the medicament can be sprayed to produce a crumbly granule. It is preferable to use a paste of discrete drug particles of desired fine particle size, the paste also containing any other ingredient which it is desirable to incorporate into the granules. The liquid contained in the paste is preferably a non-solvent or a poor solvent for the drug, so that little or no drug bridges form between the particles during spraying. When it is desired to incorporate an amount of water into the product, a higher amount of water can be incorporated into the liquid of the dough.

The degree of compaction of the powder treated during the controlled agglomeration can vary depending on the process and the powder used in the agglomeration. However, by way of indication, the licensee has found that suitable prepastilles can be formed by the process a above from a disodium chromoglycate powder containing from 8 to 10% by weight approximately of water, passing the powder through a sieve having openings of about 150 | i.

If desired, the prepastilles produced by one of the above processes can be subjected, if necessary, to shaking or stirring, using usual methods, until the desired shape is obtained, as well as the desired size and cohesion of the pellets. It is preferable that a certain proportion, for example the majority, of friable pastilles, and in particular friable pastilles of disodium chromoglycate, is substantially spherical. Suitably, the stirring can be carried out on a tablet or drum type tableting machine. The treatment of the prepastilles is carried out in such a machine until the majority of the pellets of the load have a dimension included in the desired range. The size of the prepastilles can be varied as well as the conditions used in their agitation in a manner known per se, in order to obtain the desired final dimension of the friable pellets. In some cases, the period of time during which the pellets are subjected to agitation is important with regard to the production of validly friable passtilles. The effect of the agitation of the passtilles is generally to reinforce the latter and to slightly increase their dimension as well as to make them more spherical.

As indicated above, the final product which results from the stirring stage can be comprised in a certain range of dimensions around a desired average dimension. The product can be calibrated, for example sieving, in order to eliminate products with a higher or lower dimension. The larger or smaller size product can be ground into very fine particles and recycled to the agglomeration stage, if desired.

The resulting friable pellets or granules can be introduced into any suitable form of container, such as a capsule or cartridge. When it is desired to use the pellets or granules according to the invention in combination with other ingredients such as colorings, sweeteners or carriers such as lactose, these other ingredients can be applied or mixed with the pellets or granules by means of usual techniques. It is preferable that the friable pellets or granules of the invention contain only the drug and water. The friable pellets and granules can also be used in mixture with up to 75% by weight of free particles of the drug, having a size of between 0.01 and 10 n.

The term pellet is used to denote an agglomerate which is held in cohesion by interparticle forces (for example Van der Waals forces) and is typically carried out by a process involving water vapor. The pellets are generally spherical in shape. The term granulated is used to designate an agglomerate which is held in cohesion by interparticle bridges. In the case of a friable granule, these bridges are fragile. The granules can be of almost any shape. The granules are typically produced by superhumidifying the drug with a solvent, for example water,

then removing a certain amount of the solvent.

The following examples, given by way of illustration but in no way limitative, will better understand the scope and the interest of the invention.

In these examples, all parts and percentages are given by weight, unless otherwise indicated.

Example 1:

The moisture content of a micronized disodium chromoglycate is adjusted, containing at least 98% of particles less than 10 n and having an average diameter of between 1 and 3 µm, from an initial value of between 4 and 6% by weight, to a value of about 9.5% by weight, by exposing the powder on a tray to an atmosphere of relative humidity of 33%, between 18 and 24 ° C.

When the desired moisture content has been obtained, the treated powder is dropped (after a possible initial stage of rolling in a tableting drum) on a stainless steel sieve of 150 μm opening mounted on a vibrating sieve Russel operating at a frequency of 1000 cycles per second. The powder is passed over the sieve, through the openings of said sieve, using a stainless steel spatula passed over the surface of the sieve. The product resulting from the sieving is in the form of particles having an average particle diameter of approximately 150 μm and it is introduced directly into a pelletizing drum intended to rotate around a horizontal axis. The tableting drum has an internal diameter of approximately 0.3 m and a length of approximately 0.37 m, one end being closed and the other end being provided with a frustoconical shoulder leading to an orifice of 0.18 m by which the product can be loaded or removed from the drum. The interior of the drum has a high degree of polishing. 2 kg of product from the sieve are loaded into the drum and the latter is rotated at a peripheral speed of 0.38 m / s + 0.025 m / s for 15 min. At the end of this period, the friable pellets have an average particle diameter of 135 μm and not more than 10% by weight are retained on a sieve of 350 μm opening and not less than 90% by weight are retained on a sieve with a 63 µ opening The moisture content of the final friable pellets is between 8.5 and 10.5% by weight.

It should be noted that these stages of the process carried out after adjustment of the moisture content of the initial powder must be carried out under controlled humidity conditions so as not to appreciably modify the water content of the powder. The water used in the process must be sterile and the air used in the process must be class 100.

The friable pellets produced by the above process are substantially spherical and have an open and loose structure, with a fluffy surface when viewed under a microscope.

Up to 90 mg, for example 40 to 60 mg, of the above friable lozenges are placed in a gelatin capsule having two orifices of 0.8 mm in diameter drilled in its shoulder, said capsule being mounted in a device such as described in British Patent No. 1122284 and having the detailed structure and the dimensions mentioned above. When air is passed at a rate of 601 / min by this device, it is found that the charge of the capsule is practically entirely distributed in the air stream and dissociated so as to produce a cloud of very fine particles suitable for inhalation.

In contrast, when testing the initial micronized powder from which the capsules were prepared, under identical conditions, little powder is dispersed from the test trial.

Similar results are obtained when subjected to

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process of the example above the disodium salt of 1,3-bis- (2-carboxychromon-7-yloxy) propan-2-ol (at 6% water), isoprenaline sulfate and tetracycline, to obtain friable pellets.

Example 2:

Using the device illustrated in fig. 2 of the accompanying drawings and disodium chromoglycate pellets according to Example 1, a response offset greater than 0.4 cm is obtained, a total reduction in transmitted charge greater than 900 g and a dispersion greater than 10%.

Example 3:

1000 g of micronized disodium chromoglycate with a determined water content are placed in the cage of a planetary mixer. The calculated quantity of water is then gradually added so as to bring the moisture content of the disodium chromoglycate within the desired range, the sides of the mixer cage being regularly scraped to ensure regular distribution of the moisture. The wet disodium chromoglycate is then passed through a vibrating sieve having an opening of 1000 (i). The product is then dried in a hot air oven with forced convection at 85 ° C. for 2 h until the content in moisture of the granules is between 5 and 8% by weight. The granules are then sieved on a sieve of 250 (x. The resulting granules are loose and suitable for easy filling of gelatin capsules.

10 Example 4:

Using the device illustrated in fig. 2 of the accompanying drawings, granules of disodium chromoglycate produced according to Example 3 and the dispersion test described above, dispersions greater than 10% are obtained for granules produced in i5 using 10 to 25% by weight of water in the granulation stage. These granules have response shifts greater than 0.3 cm and a total reduction in transmitted charge greater than 100 g.

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Claims (4)

621,060 CLAIMS 1. Medicament in the form of a tablet, or granule, the tablet or granule being friable, having a diameter of between 10 and 1000 (i and comprising an agglomeration of individual particles of drug having at least 90% a diameter of less than 10 n, characterized in that the tablet, or the granule, has at least one of the properties a, b and c: a) a response offset of at least 0.3 cm, b) a total reduction in transmitted load greater than 100 g, c) a product of the total load reduction transmitted by the response shift greater than 30 g / cm, the response offset being the distance in centimeters traveled by a punch penetrating from top to bottom in a matrix 4 mm in diameter and 1.55 cm in length completely filled with the drug, until a detection cell load which closes the lower opening of the matrix detects a load of 1 g, and the total reduction in transmitted load being the sum of the intermittent load drops detected by said load detection cell while the detected load increases from 0 to 1000 g. 2. Medicament according to claim 1, characterized in that the product of the total reduction in charge transmitted by the response shift is between 40 and 1000 g / cm. 3. A method of manufacturing the medicament according to claim 1, characterized in that the individual particles of medicament are moistened with a solvent, that the humidified product is passed through an orifice of dimension equal to or greater than the dimension necessary granules produced, and then the resulting product is dried to obtain the desired final solvent content. 4. Container containing a medicament according to claim 1, characterized in that it is filled in a movable manner to less than 80% of its volume by the medicament. There has already been described in British Patent No. 1122284 an insufflator which is intended for the administration of powdered medicaments by inhalation and which comprises a helical device carrying a powder capsule capable of rotating in a housing. tubular by means of a freely pivoting shaft in a tapered tubular bearing, the housing comprising a mouthpiece by means of which the patient can inhale air through the insuffiflator. By means of such an apparatus and others, for example that described in British Patent No. 1331216, the patient inhales through the apparatus air which imparts a rotational movement to the container of powder which therein found mounted. The powder contained in the container is fluidized and dispersed in the air stream inhaled by the patient. For optimal distribution, the powdered drug particles should be relatively loose, but should have an ultimate particle size of less than about 10 µm for adequate penetration of the drug into the patient's lungs. At first glance, the two criteria are mutually exclusive, since such fine powders are not sufficiently loose. The licensee has discovered that this disadvantage can be alleviated or overcome by shaping the powdered drug into small, brittle grains which are satisfactorily fluidized but which have an internal cohesion sufficiently weak to break up into finer drug particles d '' a therapeutically effective gauge in the turbulent air current surrounding the outside of the container. The shaping of the drug into small friable grains also promotes the filling of the capsules and makes it possible to remove, in the composition of the composition, diluents, such as coarse lactose, which have hitherto been incorporated into inhaler powders.