HK1034669A - Soft-pellet drug and process for the preparation thereof - Google Patents

Description

Soft granular medicine and method for producing same

Technical Field

The present invention relates to a soft granular medicine, and more particularly to an inhalant characterized by a simple preparation process and easy inhalation by the user.

Prior Art

The prevention or treatment of diseases (e.g., asthma) by inhalation of a drug is achieved by administration to the respiratory tract of the nose or mouth, and exerts a local effect on the bronchus or a systemic effect by pulmonary absorption. As for the conventional granular pharmaceutical preparations for inhalation, there are known: a simple mixture of a drug compound which has been simply finely pulverized or a drug compound which has been finely pulverized and a sugar such as lactose is filled in a capsule, and the capsule is put in an inhalation device and then inhaled by a user. However, it has been found that the inhalation preparation produced by this method is not only difficult to control the amount of the drug reaching the bronchial and alveolar regions, but also the former has been pointed out to have: because the particles are fine and have poor flowability, the filling amount difference is large when the capsule is filled; because of its tackiness, it causes many problems in terms of formulation such as adhesion to a filling machine, an inhalation device, and the like, or a large amount of a drug which cannot be sprayed in an inhalation device at the time of inhalation of the drug. And in the latter case, there is a case where the throat of the user is irritated because the sugar particles to be compounded into the prescription together with the medicine are large.

As conventional techniques, for example, there are disclosed: japanese patent application laid-open No. Showa 48-18420 (corresponding to British patent No. 1381872), which is an inhalation composition prepared by simply mixing a solid drug having a practical particle size in the range of 0.01 to 10 μm with a carrier (inorganic salt, saccharide, etc.) having a practical particle size in the range of 80 to 150 μm; japanese patent application laid-open No. Showa No. 52 83920 and British patent No. 1520247 disclose soft particles for inhalation comprising aggregates of an infinite number of drug particles having a particle diameter of at least 90% and 10 μm or less and having a particle diameter of 10 to 1000 μm, and a method for producing the same; further, Japanese patent application No. 9-year 504225 (corresponding to European patent No. 721332) discloses a method for forming a drug aggregate or granules suitable for inhalation administration. These patents are not fully satisfactory for eliminating the above-mentioned problems.

Summary of The Invention

From the above-mentioned viewpoints, the present invention has been made to provide an inhalant which is capable of delivering a drug to an application site of a bronchus, bronchiole or pulmonary alveolus with high efficiency by a simple process in terms of pharmaceutical formulation and by which the drug can be sprayed with high efficiency with little influence on the amount of drug sprayed even when the inhalation speed is changed.

As a result of intensive studies to solve the above problems, the present inventors have found that: the present inventors have found that a soft granular drug can be obtained by mixing a drug compound having self-aggregating ability with a sugar, for example, in a dissolved or suspended state and then finely pulverizing the dried product, and have completed the present invention.

The soft granular drug of the present invention is a drug containing a drug compound having self-aggregating ability and a sugar, and more specifically, is a drug containing an aggregate of drug compound particles having self-aggregating ability and sugar particles. In this specification, the term "drug compound having self-aggregation ability" means that the drug compound itself has self-aggregation ability or that a substance obtained by micronizing the drug compound has self-aggregation ability. The soft granular drug is a drug having an average particle size of about 100 μm to 1mm, which is not broken in ordinary process operations such as weighing and filling into an inhaler, but can be easily broken in size depending on the purpose in the inhaler when administered. The inhalant of the present invention is a substance using the soft granular medicine.

The present invention provides a method for producing a soft granular drug, comprising: dissolving or suspending a drug compound having self-aggregating ability in a solution in which a sugar is dissolved, drying the dissolved solution or suspension, and finely pulverizing the resultant dried substance to rotate the finely pulverized substance. As another method, a soft granular drug of the present invention can be obtained by finely pulverizing a homogeneous mixture of a drug compound having self-agglomerating ability and a sugar, or by uniformly mixing a sugar in the finely pulverized drug compound and then rotating the mixture.

Best mode for carrying out the invention

Embodiments of the present invention are described below. The drug compound used in the soft particulate drug of the present invention is a substance having self-aggregating ability, and examples thereof include: disodium cromoglycate, tacrolimus (FK-506), budesonide, terbutaline sulfate, isoproterenol sulfate, beclomethasone propionate, salbutamol, compounds disclosed in Japanese patent laid-open No. 4-210996 having neurokinin antagonistic action, e.g. N²- [ (4R) -4-hydroxy-1- [ (1-methyl-1H-indol-3-yl) carbonyl]-L-prolyl]-N-benzyl-N-methyl-3- (2-naphthyl) -L-alaninamide (hereinafter referred to as "Compound A"), and the like. Compound a is represented by the following chemical structural formula.

The sugar used in the present invention includes, for example, glucose, galactose and fructose which are monosaccharides, and lactose, sucrose and maltose which are disaccharides. Among them, lactose is preferably used. The ratio of the pharmaceutical compound to the sugar may vary in a weight ratio of 100: 1 to 1: 100, preferably 10: 1 to 1: 10, more preferably 5: 1 to 1: 5.

The method for producing a soft granular drug of the present invention comprises: depending on the dissolution characteristics of the drug compound to be used, for example, a method of dissolving a sugar in water, adding the drug compound dissolved in, for example, ethanol thereto, and mixing; or dissolving sugar in water, adding the drug compound, dissolving or suspending, drying the product by vacuum drying or the like, finely pulverizing the product to 10 μm or less by a pulverizer such as a jet mill, and then, for example, rotating the obtained fine powder in a rotating drum at a drum rotation speed of 10 to 50rpm, a residence time of the fine powder of 20 to 60 minutes, and a room temperature. By the rotation operation, the drug compound particles and the sugar particles are aggregated, and a soft granular drug having an appropriate particle diameter can be obtained. As another production method, a drug compound having a particle size of about 100 μm and a sugar are uniformly mixed, the mixture is pulverized until the average particle size is 10 μm or less, and the resultant fine powder is introduced into a rotating drum, and then the objective soft granular drug can be obtained by the method described above. Alternatively, the drug compound is pulverized until the particle size is 10 μm or less, and the fine powder is uniformly mixed with sugar and introduced into a rotating drum, and then the objective soft granular drug can be obtained by the method described above.

The average particle size of the soft particulate drug of the present invention obtained as described above is in the range of about 100 μm to 1mm, but may be suitably changed in order to adapt the performance of an inhaler. The average particle diameter is preferably 150 to 350. mu.m. The soft granular medicine of the present invention thus obtained is filled into a hard capsule or the like, and then is put into an inhaler for use as an inhalant. On the other hand, compound A has a strong self-aggregating ability, and its original powder is finely pulverized, and under the above conditions, it is found that a soft granular drug having an average particle diameter of about 100 μm to 1mm, which is excellent in spray characteristics and can be obtained by a simple process without using sugar, can be obtained only by rotating in a drum. The formulation is suitable for inhalation administration to patients susceptible to irritation by large particles in sugar.

Examples

Examples of the present invention are explained below.

Example 1

Compound A5g was dissolved in 144g of pure ethanol. Further, 5g of lactose was dissolved in 96g of water to obtain an aqueous lactose solution. Then, the two were mixed to obtain 250g of a mixed solution. The mixed solution was dried under vacuum at 40 ℃ to obtain a dried product. The dried mixture of compound A and lactose thus obtained was pulverized and sieved through a 850 μm sieve. The fine powder of compound A after passing through the sieve was introduced into a rotating drum, rotated at 37rpm for 30 minutes at room temperature, and then classified to obtain a soft granular preparation containing compound A having an average particle size of 180 to 350 μm and lactose. The weight ratio of compound A to lactose was set at this time to 1: 1.

Example 2

After the dry substance of compound a was micronized, the resultant was sieved through a 850 μm sieve, and then the single micronized substance of compound a after sieving was introduced into a rotating drum, a soft granular preparation containing only compound a was obtained in the same manner as in example 1.

The soft granular drug thus obtained was filled in a hard capsule, and the spray characteristics were examined using an inhaler. The results are shown in [ Table 1 ].

[ Table 1]Spray characteristics of soft granular medicaments

Preparation	Containing lactose alone as Compound A
					Content of Compound A	10mg	20mg	10mg	20mg
Discharge amount (%)	63.6	50.6	78.4	62.4
					Inhalable particles (%)	60.6	72.0	39.6	49.9
Effective inhalation dose (%)	38.3(3.83mg)	36.5(7.29mg)	31.0(3.10mg)	30.7(6.14mg)

Suction speed: 28.3L/min.

A measuring device: dylec manufactured a stepped low speed collision sampler (using a glass throat).

An inhalation device: e-haler

Respirable particles (Respirable Fraction): the proportion of compound A having a particle diameter of 6.4 μm or less to the total amount of the ejected material (fine particle component).

Effective inhaled Dose (Delivered Dose): the amount of particles having a particle size of 6.4 μm or less of the compound A to be ejected accounts for the content (for example, 10mg) of the compound A (the dose of the particles).

Further, the results of measuring the flowability of the soft particles of the present invention are shown in [ table 2 ].

The measurement apparatus used a particle detector, and the calculation of each coefficient (Index) was carried out according to the method recommended by Carr. Carr's recommended method is described in "Chemical Engineering, Vol.18, Jan., 166-167 (1965)".

[ Table 2]]Flowability of the Soft particles of the invention

Angle of repose compression, angle of scraping uniformity, flow index

[Ⅰ]Coefficient 120122347

[Ⅱ]Coefficient 120122549

[Ⅲ]Coefficient 160122351

[Ⅳ]Coefficient 21717.52378.5

(Note) the following [ I ]: prescription lactose

[ II ]: mixtures of [ I ] and [ III ]

[ III ]: finely pulverized product of Compound A

[ IV ]: soft granular drug (containing lactose) of the present invention

The above measurement results show that: the soft granular preparation of the present invention has a remarkably increased number of inhalable particles as a result of the self-agglomerating ability of compound a being moderated by the inclusion of lactose. Further, the soft granular medicine of the present invention also has significantly improved flowability as compared with a simple mixture of compound a and lactose. The mean particle size of the fine powder (containing lactose) before the soft particles of Compound A used in the above preparation was 2.5 μm, but the mean particle size of the soft particles obtained in this manner was 308 μm (the measurement method was a sieve method, and the classification time was 3 minutes). The soft granular medicine of this size is very easy to handle in weighing and filling, and from the above results of measurement of the spray characteristics, it is also described that the soft granular medicine of the present invention is sufficiently fine at the time of inhalation, is suitable for inhalation, and solves the conventional problems.

Example 3

The effective dose at the time of comparing the inhalation speed was measured by using soft particles of compound a alone and soft particles containing compound a and lactose, respectively, with a stepwise low-speed collision sampler. The soft granules are produced by uniformly mixing the fine powder of compound a with lactose, sieving, and classifying by turning in a rotary drum. Soft particles of compound a alone were produced in the same manner except that lactose was not contained. The measurement results are shown in Table 3.

[ Table 3 ]]Effective inhaled dose with varying inhalation speed

	Compound A alone in 40mg capsules		Lactose-containing 40mg capsule
					Speed of inhalation	28.3	60	28.3	60
Effective inhaled dose	9.5	16.3	11.6	11.1

Lactose-formulated 40mg capsules: contains compound A40mg and lactose 13.3 mg.

An inhalation device: e-haler

Suction speed: l/min

Effective inhaled dose (amount of drug distributed below 5.8 μm): mg of

From the above measurement results, it can be shown that: by the method of the present invention for preparing a pharmaceutical preparation, the amount of the drug to be inhaled is not dependent on the inhalation rate, and is less affected by the sex, age, and disease degree of the patient, and thus, it is possible to ensure that the amount to be administered varies little. These advantages should be appreciated.

Example 4

1g of tacrolimus (FK506) and 99g of lactose were uniformly mixed, and then pulverized and sieved through a 500 μm sieve. The fine powder after sieving was introduced into a rotary drum, rotated at room temperature at 20rpm for 30 minutes, and then classified to obtain a soft granular preparation containing tacrolimus and lactose having an average particle size of 180 to 600 μm in a weight ratio of 1: 99.

Prospect of industrial application

The soft granular drug obtained by the present invention has a lower bulk density than a simple mixed preparation of a pharmaceutical compound and lactose obtained by a conventional method, and therefore has an advantage that it is easy to handle when filling into an inhaler or the like. In addition, it is also suitable that the particles are thinned and crushed to particles having a size suitable for inhalation in an inhaler such as E-haler (manufactured by Rhone-Poulenc Rorer).

Further, in the soft granular medicine of the present invention, the particle size distribution of the medicine at the time of spraying can be controlled by changing the amount of the sugar to be blended with the medicine compound. In addition, since the change in specific volume is small when the blending ratio between the sugar and the drug compound is changed, and soft granular drugs having different contents of the drug compound can be produced, it is also an important advantage that the operation mode of the filling machine and the inhalation device does not need to be changed even when the amount of the drug compound is small. In addition, even when the drug compound is not soluble in water, the sugar is soluble in water, and therefore the drug compound remaining in the inhaler after use can be removed by washing with water. In the present invention, a sample containing a sugar is used in addition to a drug compound alone, and the method of the present invention for a preparation can ensure that the dose of a drug to be inhaled does not depend on the inhalation rate, is less affected by the sex, age, and disease level of a patient, and thus can ensure that the dose varies little. This advantage should also be taken into account.

Claims (11)

1. A soft granular preparation comprises a medicinal compound having self-aggregating ability and lactose.

2. The soft granular medicament according to claim 1, wherein the drug compound is selected from the group consisting of N²- [ (4R) -4-hydroxy-1- [ (1-methyl-1H-indol-3-yl) carbonyl]-L-prolyl]-N-benzyl-N-methyl-3- (2-naphthyl) -L-alaninamide or tacrolimus.

3. The soft granular medicament according to claim 1 or 2, wherein the sugar is lactose.

4. The soft granular drug according to any one of claims 1 to 3, wherein the ratio of the drug compound to the sugar is in the range of 100: 1 to 1: 100 by weight.

5. The soft granular drug according to any one of claims 1 to 4, which has an average particle diameter of 100 μm to 1 mm.

6. An inhalant comprising the soft granular pharmaceutical preparation according to any one of claims 1 to 5.

7. A method for producing a soft granular drug, characterized by comprising: dissolving or suspending a drug compound having self-aggregating ability in a solution in which a sugar is dissolved, drying the dissolved solution or suspension, and finely pulverizing the resultant dried product to rotate the finely pulverized product.

8. A method for producing a soft granular drug, characterized by comprising: a substance obtained by finely pulverizing a homogeneous mixture of a drug compound having self-agglomerating ability and a sugar, or a substance obtained by uniformly mixing a sugar in the finely pulverized drug compound and rotating the same.

9. Rotation N²- [ (4R) -4-hydroxy-1- [ (1-methyl-1H-indol-3-yl) carbonyl]-L-prolyl]A finely ground substance of (E) -N-benzyl-N-methyl-3- (2-naphthyl) -L-alaninamide or tacrolimus, and a soft granular drug having an average particle size of 100 μm to 1 mm.

10. An inhalant using the soft granular medicine according to claim 9.

11. A process for producing a soft granular drug having an average particle diameter of 100 μm to 1mm, which comprises: will N²-[(4R)-4-hydroxy-1- [ (1-methyl-1H-indol-3-yl) carbonyl]-L-prolyl]-N-benzyl-N-methyl-3- (2-naphthyl) -L-alaninamide or tacrolimus is finely pulverized and the finely pulverized material is swirled.