MXPA00005270A

MXPA00005270A - Soft-pellet drug and process for the preparation thereof

Info

Publication number: MXPA00005270A
Application number: MXPA/A/2000/005270A
Authority: MX
Inventors: Hiromitsu Yoshida; Hideki Ito; Yasuko Soeda
Original assignee: Fujisawa Pharmaceutical Co Ltd
Priority date: 1997-12-03
Filing date: 2000-05-29
Publication date: 2001-07-31

Abstract

A soft-pellet drug suitable for inhalation, which is easily handleable in pharmaceutical preparation, does not give the feeling of irritation to a taker, and permits the control of drug particle size distribution at inhalation. The soft-pellet drug can be prepared by dissolving or suspending a medicinal compound having self-agglomerability in a fluid containing a sugar such as lactose, drying the obtained solution or suspension, pulverising theresidue of the drying, and shaping the obtained powdery mixture into soft pellets having a mean particle diameter of 100&mgr;m to 1 mm by means of tumbling in a drum tumbler or the like.

Description

A MEDICAMENT IN THE FORM OF A SMOOTH PELLA AND PROCESSES FOR ITS PREPARATION TECHNICAL FIELD This invention relates to a drug composition in the form of soft pellets, and more particularly to a drug composition in the form of soft pellets which is easy to handle in a pharmaceutical manufacturing process and easy for patients to inhale.

BACKGROUND OF THE INVENTION The prevention or treatment of a disease (eg, asthma) with an inhalation involves the administration of the drug to the respiratory tract by the nasal or oral route, to achieve a local effect on the bronchi or a systemic effect through pulmonary absorption . It is well known that the inhalation product of the dry powder inhaler is formulated with only a finely micronized drug substance, or a mixed mixture of a finely micronized bulk drug and, for example, a sugar such as lactose, which is filled into one capsule This capsule will be adjusted in an inhalation device to be inhaled by the user. However, the formulated composition manufactured in the above manner can be hardly controlled in the amount of the drug reaching the target site, such as the bronchi or alveoli. Furthermore, in the first case, the finely micronized drug powder is so non-flowable that a variation in the filling for the drug content in the capsule unit is inevitable, because a large portion of the bulk powder tends to adhere to the filling machine and the inhalation device and in the inhalation device, a large amount of undistributed drug remains when administered, due to its adhesive behavior. Thus, there are many types of problematic issues in the formulation of the micronized drug substance. In the latter case, it has been pointed out, for example, that the larger particle diameter of the sugar formulated with the drug substance tends to irritate the pharynx of the patient. With reference to the prior art, the Japanese Patent Kokai Tokkyo Koho S48-18420 (corresponding to UK Patent 1381872) describes an inhalable pharmaceutical composition comprising a simple mixture of a solid drug substance, having an effective particle diameter of 0.01 - 10 microns and a carrier ( an inorganic salt, a saccharide and the like) having an effective particle diameter of 80 ~ 150 microns. Japanese Patent Kokai Tokkyo Koho 552-83920 and United Kingdom Patent 1520247 describe a pellet or soft pellet comprising agglomerates of individual pharmacological particles, at least 90% of which have diameters not greater than 10 microns and having a size of particle of 10 ~ 1000 micrometers and a method for the production of soft pellet. Japanese Patent Kohyo Tokkyo Koho H9-504225 (corresponding to European Patent Laid-open 721332) describes a method for the production of agglomerates of drug particles or pellets, suitable for inhalation. However, these technologies are not completely capable of overcoming the aforementioned drawbacks.

DESCRIPTION OF THE INVENTION Developed in view of the prior art, this invention has as its objective to provide an inhalable pharmaceutical composition that is easy to handle in its manufacturing process, varying little in the administered dose, even if the speed or proportion of inhalation varies, ensuring efficient production of a finely breathable cloud, and capable of efficiently distributing the drug to the target site, such as the bronchi, bronchioles or alveoli. The inventors of this invention conducted much research and found that the aforementioned drawbacks can be clearly overcome with a pharmacological composition in the form of soft pellets prepared, for example, by mixing a pharmacological substance having self-binding properties., with a dissolved sugar suspended and spin the resulting mixture in a dry state. The drug composition in the form of soft pellets of this invention comprises a self-agglomerating drug substance and a sugar. More particularly, the composition comprises agglomerates of particles of a drug substance having self-agglomerating properties and sugar particles. The term "pharmacological substance having self-agglomerating properties" as used throughout this specification means a medicinally active compound such that its bulk substance itself has self-agglomerating properties or that its finely micronized powder has self-regulatory properties. binders. The term "pharmacological composition in the form of soft pellets" is used in this specification to mean a pharmaceutical composition having an average particle diameter of about 100 μm to about 1 mm and does not break under the usual conditions of the processes of handling such as weighing and loading in an inhalation device, but is easily broken or disintegrated to the required particle size within the inhalation device. The inhaler of this invention uses the pharmacological composition in the form of above mentioned soft pellets. The method of manufacturing a pharmacological composition in the form of soft pellets according to the invention comprises dissolving the suspension of a pharmacological substance having self-agglomerating properties in a sugar solution, drying the resulting solution or suspension, micronizing the mixture Dry, and spin the micronized powder mixture. As an alternative, the pharmacological composition in the form of soft pellets of the invention can also be obtained by the micronization of a homogeneous mixture of a pharmacological substance having self-agglomerating properties and a sugar or by mixing a finely micronized powder of the drug substance uniformly with a sugar spin the mixture.

BEST MODALITY TO CARRY OUT THE INVENTION The embodiments of the invention are now described. The pharmacological substance for the pharmacological composition in the form of soft pellets of this invention is a compound having self-binding properties and, as such, includes but is not limited to disodium cromoglycate, tacrolimus (FK-506), budesonide, terbutaline sulfate , isoproterenol sulfate, beclomethasone dipropionate, salbutamol, and compounds that have neurokinin antagonist activity, as described in Kokai Tokkio Patent H4-210996, such as N2 - [(2R) -4-hydroxy-1- [(1-methyl-1H-indol-3-yl) carbonyl] -L-propyl] -N-benzyl-N- methyl-3- (2-naphthyl) -L-alaninamide (hereinafter referred to as Compound A). Compound A is represented by the following chemical formula.

The sugar for this invention includes, but is not limited to glucose, galactose, and fructose, among other monosaccharides, and lactose, sucrose, and maltose, among other disaccharides. Particularly preferred is lactose. The weight ratio of the drug substance to sugar can vary within the range of 100: 1.1 ~ 1: 100, preferably 10: 1 ~ 1:10, and more preferably 5: 1 ~ 1: 5. Depending on the solubility characteristic of the pharmacological substance used, the method of manufacturing the invention of the pharmacological composition in the form of soft pellets, for example, can comprise either dissolving the sugar in water and mixing the solution with a solution of the same. pharmacological substance in methanol or similar, or by dissolving the sugar in water, and dissolving or suspending the pharmacological substance therein, followed by drying the resulting solution or suspension by vacuum drying or the like, micronising it in a grinding machine such as a jet mill up to a particle size no greater than 10 μm, feeding the resulting powder into a rotating drum, and rotating it at a drum speed of 10 rpm ~ 50 rpm for a residence time of the powder of 20 ~ 60 minutes at room temperature. By this rotary method, the particles of the drug substance and the sugar particles together form agglomerates to give a pharmacological composition in the form of soft pellets having a suitable particle diameter. An alternative process comprises mixing a drug substance having a particle diameter of about 100 μm uniformly with a sugar, micronizing the resulting mixture to an average particle diameter of not more than 10 μm, feeding the micronized powder to a rotating drum, and proceeding there in a similar manner as described above to provide the pharmacological composition in the form of soft, objective pellets. A further alternative procedure comprises micronizing the drug substance to a particle diameter no greater than 10 μm, mixing the resulting powder uniformly with a sugar, feeding the resulting mixture to a rotary drum, and proceeding there in a similar manner as described. previously to provide the pharmacological composition in the form of objective soft pellets. The average particle diameter of the thus obtained soft pellet pharmacological composition of the invention falls within the range of about 100 μm to 1 mm, but can be adjusted according to the operating characteristics of the device. inhalation. The preferred average particle diameter is 150 μm ~ 350 μm. The pharmacological composition in the form of soft pellets thus obtained, of the invention, is filled into a cartridge such as a hard capsule which is fitted in an inhalation device for administration. In the case of Compound A having high self-agglomerating properties, it was found that a composition in the form of soft pellets having an average particle diameter of about 100 μm ~ 1 mm, which is easy to handle and has excellent breathable characteristics, it can be obtained even without the aid of a sugar, by the simple procedure of micronizing its bulk substance, and by rotating the resulting fine powder in a rotating drum under the above-mentioned conditions. This product is preferable for patients who are prone to receive irritable responses to large sugar particles.

EXAMPLES The following examples illustrate this invention.

EXAMPLE 1 In 144 g of absolute ethanol, 5 g of Compound A was dissolved. Separately, 5 g of lactose was dissolved in 96 g of water to prepare an aqueous solution of lactose. The two solutions were mixed to give 250 grams of a mixed solution. This mixed solution was dried under vacuum at 40 ° C to give a dry mixture. This dry mixture of Compound A and the lactose was comminuted and sieved through a 850 μm sieve. The finely divided powder of Compound A obtained in this way was fed to a rotating drum which was rotated at the drum speed of 37 rpm at room temperature for 30 minutes. The resulting product was then subjected to size selection to provide a pharmacological composition in the form of soft pellets, comprising Compound A and lactose, and having a mean particle diameter of 180 μm ~ 350 μm. The weight ratio of Compound A to lactose was controlled to be 1: 1.

EXAMPLE 2 A dry batch of Compound A was pulverized and sieved through a 850 μm sieve. The resulting powder, which was exclusively composed of Compound A, was fed to a rotating drum and further processed as in Example 1 to provide a soft pellet drug preparation composed exclusively of Compound A. Pharmacological preparation in the form of soft pellets obtained in this way was filled into a hard capsule and by using an inhalation device its inspiratory characteristics were investigated. The results are shown in Table 1.

Table 1 Inhalation characteristics of pharmacological preparations in the form of soft pellets Inhalation speed: 28.3 liters / minute. Measurement Instrument: Dylec Cascade Impactor (with a glass throat). Inhalation device: E-haler Breathable Fraction: The percentage of the particles of the Compound A smaller than 6.4 μm in diameter in the emitted dose of Compound A (fine particle fraction).

Administered Doses: The percentage of Compound A particles administered, less than 6.4 μm in diameter relative to the content of Compound A (for example mg) (dose of fine particles). The flowability of the pharmacological composition in the form of soft pellets of the invention is shown in Table 2. A powder tester was used for the determination and each index was calculated by the method proposed by Carr. The method of Carr is described in Chemical Engineering, Vol. 18, January, 166-167 (1965).

Table 2 Flow Capacity of the Soft Pellets of the Invention Sample [I] [II] [III] [IV] index index index index Angle of repose 12 12 16 16 Compressibility 0 0 0 17 Spatula angle 12 12 12 17.5 Uniformity 23 25 23 23 Flow index 47 49 51 78.5 Notes: [I]: Lactose JP (Japanese Pharmacopoeia) [II]: A mixture of [I] and [III] [III]: A micronized powder of Compound A [IV]: The soft pellet of the invention (with lactose) . It is apparent from the above data that because the anti-caking properties of Compound A were abated by the addition of lactose, the composition in the form of soft pellets of the invention was definitely increased in the respirable fraction. It is also clear that the flowability of the composition in the form of soft pellets of the invention is definitely superior to that of a simple mixture of Compound A and lactose. While the average particle diameter of the same finely micronized powder of Compound A (containing lactose) as described above before processing into soft pellets was 2.5 μm, the mean particle diameter of the soft pellets was 308 μm (method Measurement: sieving, classification time: 3 minutes). Soft pellets of this size are very easy to handle when weighing and loading the cartridge. Furthermore, as described above, the inspiration characteristic data indicate that the composition in the form of soft pellets of the invention produces a sufficiently fine cloud after administration, which is suitable for inhalation, thus overcoming the disadvantages of the prior art.

EXAMPLE 3 Using the soft pellets composed exclusively of Compound A and the soft pellets composed of Compound A and lactose, a comparison was made in the dose administered by varying the inhalation speed with the cascade impactor. The soft pellets of the invention were prepared by mixing a finely micronized powder of Compound A uniformly with lactose, sieving the mixture, rotating it in a rotating drum, and holding product A to size selection. The soft pellets composed exclusively of Compound A were prepared in the same manner except that the lactose was not added. The results of the measurement are shown in Table 3.

Table 3 Dose Distributed at Variable Inhalation Rate Capsule of 40 mg Capsule of 40 mg of Compound A with lactose only Inhalation Speed 28.3 60 28.3 60 Administered dose 9.5 16.3 11.6 11.1 40 mg of the capsule with lactose: 40 mg of Compound A and 13.3 mg of lactose are contained. Inhalation device: E-haler Inhalation speed: L / min. Administrative dose (the amount of pharmacological particles with diameters less than 5.8 μm in the cloud): mg.

As is obvious from the above data, the pharmaceutical device of this invention, which is the addition of a sugar, releases the amount of drug intake from the usual dependence on the inhalation speed, and ensures dosing with a minimum of variation. Accordingly, a medicament in the form of soft pellets of this invention is designed for a patient irrespective of his age and the severity of the disease.

EXAMPLE 4 1 g of tacrolimus (FK506) was uniformly mixed with 99 g of lactose and the mixture was pulverized and sieved through a 500 μm sieve. The finely micronized powder obtained was fed to a rotating drum which has been rotated at 20 rpm at room temperature for 30 minutes. The product was subjected to size selection to provide a pharmacological composition in the form of soft pellets with a mean particle diameter of 180 μm ~ 600 μm containing tacrolimus and lactose in a weight ratio of 1:99.

Possibility of Industrial Application The pharmacological composition in the form of soft pellets, provided according to this invention, has a low bulk density compared to a simple mixture of the drug substance and the lactose, prepared by conventional technology, so that it can be easily handled in the load inside an inhalation device. In addition, this has the advantage that the pellets are disintegrated in the inhalation device, for example, E-haler (manufactured by Rhone-Poulenc Rorer), up to a range of particle size suitable for inhalation in the dosage. In addition, in the pharmacological composition in the form of soft pellets of the invention, the particle size distribution of the drug on inhalation can be controlled by varying the amount of addition of a sugar to a drug substance. Furthermore, when the proportions of sugar and of the pharmacological substance are varied, pellets can be manufactured that vary in the concentration of the pharmacological substance, but little altered in the specific volume. The consequent advantage, which can not be ignored, is that the specifications of the filling machine and the inhalation device do not need to be modified even if the content of the drug is smaller. Yet another advantage is that even if the drug substance is insoluble in water, the sugar is dissolved in water, so that the drug substance remaining in the device after dosing can be efficiently swept by washing with water. It is also notorious that due to the pharmaceutical ingenuity of the formulation of a sugar with a pharmacological substance, the amount of inhalation of the drug is no longer dependent on the speed of inhalation, so that the medication with a minimum of dose variation can be assured regardless of the age and gender of the patient and the severity of the disease.

Claims

1. A pharmacological composition in the form of soft pellets comprising a pharmacological substance having self-agglomerating properties, and a sugar.

2. The pharmacological composition in the form of soft pellets according to claim 1, wherein the drug substance is a member selected from the group consisting of N2 - [(4R) -4-hydroxy- [(1-methyl-1H-indole) 3-yl) carbonyl] -L-propyl] -N-benzyl-N-methyl-3- (2-naphthyl) -L-alaninamide and tacrolimus.

3. The pharmacological composition in the form of soft pellets according to claim 1 or claim 2, wherein the sugar is lactose.

4. The pharmacological composition in the form of soft pellets according to claim 1 to claim 3, wherein the drug substance and the sugar are formulated in a weight ratio of 100: 1 ~ 1: 100.

5. The pharmacological composition in the form of soft pellets according to claim 1 a. Claim 4, which has an average mean particle size of 100 μm ~ 1 mm.

6. An inhaler using the pharmacological composition in the form of soft pellets according to claim 1 or claim 5.

7. A method for the manufacture of a pharmacological composition in the form of soft pellets, comprising dissolving or suspending a pharmacological substance having self-agglomerating properties, in a solution of a sugar, drying the solution or suspension to give a dry mixture , micronizing the dry mixture, and spinning the finely micronized, resulting powder.

8. A method for the production of a pharmacological composition in the form of soft pellets, comprising rotating a finely divided homogeneous mixture of a pharmacological substance having self-agglomerating properties and a sugar, or a homogeneous mixture of a finely micronized drug substance and a sugar

9. A pharmacological composition in the form of soft pellets, having a mean particle diameter of 100 μm ~ 1 mm which is available after spinning a finely micronized powder of N2 - [(4R) -4-hydroxy- [(1-methyl) -lH-indol-3-yl) carbonyl] -L-propyl] -N-benzyl-N-methyl-3- (2-naphthyl) -L-alaninamide or tacrolimus.

10. An inhaler using the pharmacological composition in the form of soft pellets according to claim 9.

11. A method for the manufacture of a pharmacological composition in soft pellet forms having a mean particle diameter of 100 μm ~ 1 mm comprising the spraying of N2- [(4R) -4-hydroxy- [(1-methyl-) lH-indol-3-yl) carbonyl] -L-propyl] -N-benzyl-N-methyl-3- (2-naphthyl) -L-alaninamide or tacrolimus and spinning the resulting finely micronized powder.