WO2001056581A1 - Powdered preparation for inhalation and powder inhalant containing the same packed - Google Patents

Abstract

A powdered preparation for inhalation which is improved in the efficiency of drug particle delivery to the lungs, is reduced in the amount of a drug packed into a container to be attached to an inhalation instrument, contains oleic acid or sorbitan oleate as an additive and a dinucleotide derivative represented by the formula (I) as an active ingredient, and is useful for the treatment of various lung diseases accompanied by difficulty in discharging a mucous secretion; and a powder inhalant which comprises the powdered preparation and a container, e.g., a capsule, packed therewith. The powdered preparation for inhalation can be produced, for example, by evenly dispersing fine particles of the dinucleotide derivative into a solution of the additive in a solvent, subsequently drying the dispersion in a vacuum, pulverizing the resultant agglomerates of the fine particles, and then vacuum-drying the resultant powder.

Description

 Powder formulation for inhalation and powder inhalant filled with it [Technical field]

 TECHNICAL FIELD The present invention relates to a powder preparation for inhalation containing diduridine 5, tetratetraphosphate tetrasodium salt as an active ingredient, and a powder inhalant filled with the same. More particularly, the present invention comprises an oleic acid or sorbitan oleate for use as a powder inhaler, comprising:

The present invention relates to a powder formulation for inhalation containing a dinucleotide derivative represented by the following formula (chemical name: diperidine 5, tetrasodium tetraphosphate) as an active ingredient, and a powder inhaler filled with the same.

(Background technology)

 The dinucleotide derivative represented by the above formula (I) stimulates P 2 Y 2 receptors present in the lungs and the airways, hydrates mucus secretions retained in the lungs, and promotes removal of mucus secretions It is useful for the treatment of various pulmonary diseases such as cystic fibrosis in which mucus secretions are retained in the lung, chronic bronchiolitis, asthma, bronchiectasis, postoperative aterectase, and cartagena syndrome. It is reported that there is. As a method of administering the compound, an aerosol for inhalation using an aerosol suspension has been proposed (Japanese Patent Application Laid-Open No. 11-670790).

In general, in the treatment of the above-mentioned various pulmonary diseases, high bioavailability can be expected, and there are advantages such as the first-pass effect can be avoided. Often used. Inhalants include nebulizers, aerosols and powder inhalants. Of these, nebulizers are inconvenient due to lack of portability of the inhalation device, and when the amount of drug used is large, the inhalation time is long and the burden on the patient is large. There are disadvantages, such as the necessity to use, and the limited number of doses, which inevitably increases the number of doses. In the case of liquids and suspending agents, a sterilization step is indispensable and the production cost is high, and a special spraying device is often required. Therefore, for example, in the case of sodium bromoglicate / fluticasone propionate as a therapeutic agent for bronchial asthma, a powder inhaler is used in which a finely divided powder is filled into a container such as a capsule and then inhaled using an inhaler. In the case of powder inhalants, it is desirable to use a powder with a small particle size in order to make the micronized drug reach the lungs.On the other hand, the micronization inevitably increases the cohesiveness and adhesion of the drug, A problem arises in that the efficiency of drug delivery to the lungs decreases. Therefore, in order to solve this problem, the fine primary particles are agglomerated by an appropriate method and granulated into secondary particles having a relatively large particle size. Dissociate into particles, lactose with a larger particle size than the drug used is mixed, and the finely divided drug is uniformly adsorbed on the lactose surface to separate the drug and lactose during inhalation. Improving the lung delivery rate by modifying the surface characteristics by attaching them.

 As an inhalant containing the dinucleotide derivative represented by the formula (I) as an active ingredient, only an aerosol suspending agent has been devised, and no powder inhalant has been developed up to now. . As described above, a powder inhalant is most recommended as an inhalant. However, the dinucleotide derivative represented by the formula (I) itself has a high hygroscopicity, and a simple method of pulverization causes agglomeration of powder particles. Are likely to occur, and the rate of drug delivery to the lungs is extremely poor. In addition, due to its high hygroscopicity, the dinucleotide derivative cannot be expected to have a surface modified by the method of attaching ultrafine particles to the surface of drug particles, and the method of agglomeration into secondary particles has poor dissociation and improves lung reach. Can not. Furthermore, the dose of the dinucleotide derivative is relatively larger than that of a usual inhalant, and it is expected that the method using lactose as a dispersant will increase the inhalation amount per dose and make inhalation difficult. Cannot be adopted.

Based on the above, a new method that is different from the conventional method is used to attach to the inhalation device. Development of a powder formulation for inhalation containing the dinucleotide derivative represented by the formula (I) as an active ingredient, which does not increase the amount of drug filled in a container and improves the efficiency of drug particles reaching the lungs Have been. [Disclosure of the Invention]

 The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, by adding a certain additive to the drug powder particles as described below, significantly improved the efficiency of drug powder particles reaching the lungs, In addition, they have found that it is possible to reduce the amount of the preparation per use when using an inhalation device, and have accomplished the present invention.

 That is, the present invention contains oleic acid or sorbitan oleate, and contains as an active ingredient a dinucleotide derivative represented by the formula (I) (chemical name: dipyridine, tetrasodium tetraphosphate). The present invention relates to a powder preparation for inhalation and a powder inhalation agent filled with the preparation.

The powder formulation for inhalation of the present invention comprises a fine powder having a particle size of about 0.5 to 10 / m, which is obtained by using a dinucleotide derivative represented by the formula (I), which is an active ingredient, usually using a milling machine such as a jet mill. And then mixed with oleic acid or sorbitan oleate as an additive. Specifically, for example, oleic acid or sorbitan oleic acid as an additive is contained in an inert solvent such as ethanol and hexane, which is a good solvent for the additive and a poor solvent for the active ingredient. After dissolving the ester, adding the fine powder of the dinucleotide derivative and uniformly dispersing the mixture, the residue is dried under reduced pressure at room temperature to 50 ° C by a conventional method, and dried under reduced pressure at room temperature. The obtained fine powder is appropriately crushed, and then dried under reduced pressure at 50 to 60 ° C by a conventional method to produce the powder. As the powder preparation for inhalation of the present invention, a fine powder having a particle diameter of about 10 / im or less is usually used, and preferably, a particle diameter of about 0.5 to 7.0 m or an average particle diameter of 1 to 10 / im. 5 to 5.0 m. In the additive used in the present invention, the sorbitan oleate refers to various oleic esters of sorbitan such as sonorebitan monooleate and sorbitan triolate. As the additive, oleic acid, sorbitan monoolate or sorbitan trioleate is preferred, and oleic acid is most preferred. The amount of the additive is usually about 0.5 to 5.0% by weight based on the amount of the active ingredient. And it is preferably 0.75 to 3.0%.

 The powder inhalant of the present invention can be produced by filling the above-mentioned powder formulation for inhalation into an appropriate container such as a capsule, a blister or a reservoir. The dosage of the formulation can be increased or decreased as appropriate, but is usually about 2 to 4 mg. For example, when used as a capsule agent, it is possible to use, for example, Japanese Pharmacopoeia No. 2 capsules of hydroxypropylmethylcellulose.

 The dinucleotide derivative represented by the formula (I) used in the method for producing the powder preparation for inhalation and the powder inhalation is a known compound, and can be easily produced by a method described in a literature or a method analogous to the method. (For example, Ί he J ournalof Biological Chemistry,

Vol. 262, No. 25, 12096-: p. 12103 (1987), WO 99Z05 155, JP-T-Hei 11-506790).

 The powder formulation for inhalation of the present invention has excellent inhalation characteristics as described below. First, in the inhalation characteristics test using a cascade impactor, the lung penetration rate (the percentage reaching the lower stage than stage 2) was about 16% for the formulation without additives and about 27% for the secondary granules. %, Whereas the powder formulation for inhalation of the present invention showed an excellent reach of about 35 to 51%. As described above, the powder formulation for inhalation of the present invention has a remarkably improved lung reach rate, is a formulation with good drug use efficiency, and has a small amount of drug to be filled in a container to be attached to an inhalation device. It is a preparation that can reduce

 In the same study, the residual ratio of the drug in the inhalation device was approximately

In comparison with 34%, the powder formulation for inhalation of the present invention is improved to about 12 to 27%. Specifically, for example, a preparation containing 1.0% oleic acid shows extremely excellent properties such as a drug residual ratio of about 12%.

 The powder formulation for inhalation of the present invention is an excellent formulation that is not irritating or extremely weak, and less burdens the patient during inhalation.

Furthermore, the powder preparation for inhalation of the present invention has extremely high stability in storage of the preparation. For example, the preparation containing 1.0% oleic acid did not decrease the lung reach when left at 40 ° C and 75% relative humidity for 2 months. Thus, the powder preparation for inhalation of the present invention is an extremely stable preparation that can be stored for a long time. When the powder formulation for inhalation of the present invention is actually inhaled, the powder formulation for inhalation of the present invention is filled into an appropriate container such as a capsule, a prister, or a reservoir, and the obtained powder formulation for inhalation of the present invention is inhaled. After attaching to the container, make a hole in the container or measure the amount and inhale. The amount of drug used can be determined appropriately according to the type of disease and the condition of the patient, but it is usually possible to use it in adults at about 2 to 4 mg per day, in 1 S1 to several times. it can. As an inhalation device, any device can be used as long as the powder formulation for inhalation of the present invention can be appropriately inhaled. Specifically, Jet Heller (manufactured by Unicia Diex Co., Ltd.) ( Japanese Unexamined Patent Application Publication No. 7-313599, Japanese Unexamined Patent Application Publication No. 11221280), and the like.

 Thus, the powder formulation for inhalation of the present invention and the powder inhalant filled with the same include cystic pulmonary fibrosis, chronic bronchiolitis, bronchiectasis, postoperative aterectase, Cartagener's syndrome, aspiration pneumonia, etc. It is extremely useful for the treatment of various pulmonary diseases accompanied by difficulty in excreting mucus secretions.

[Best mode for carrying out the invention]

 The content of the present invention will be described in more detail in the following examples, comparative examples and test examples. The present invention is not limited to the content. Example 1

 0.5% oleic acid-containing preparation

 After dissolving 10 mg of oleic acid in about 5 g of ethanol and adding about 50 g of hexane, the average particle size is 1.5 to 3.0 μτη using a jet mill. Approximately 20 g of diduridine 5, tetrasodium monotetraphosphate was added to the mixture and uniformly dispersed. The mixture was evaporated to dryness under reduced pressure at 30-40 ° C and dried under reduced pressure at room temperature overnight. The resulting dry powder is averaged with a jet mill at an average particle size of 1.

After crushing to 5 to 3.0 / m (containing 90% or more of particles of 10 m or less), the mixture was dried overnight at 60 ° C under reduced pressure. Example 2 0.75% oleic acid-containing preparation

 It was produced in the same manner as in Example 1 except that 15 Omg of oleic acid was used. Example 3

 1. Formulation containing 0% oleic acid

 The production was carried out in the same manner as in Example 1 except that 20 Omg of oleic acid was used. Example 4

 1.5 Formulation containing 5% oleic acid

 It was produced in the same manner as in Example 1 except that 30 Omg of oleic acid was used. Example 5

 2.0% oleic acid containing preparation

 The production was carried out in the same manner as in Example 1 except that 40 Omg of oleic acid was used. Example 6

 3.0% oleic acid containing preparation

 It was produced in the same manner as in Example 1 except that 60 Omg of oleic acid was used. Example 7

 0.5% sorbitan monoolate-containing preparation

Production was carried out in the same manner as in Example 1, except that 10 Omg of sorbic acid was used instead of 10 Omg of oleic acid. 1. Formulation containing 0% sorbitan monoolate

 Production was carried out in the same manner as in Example 1, except that sorbitan monoolate 20 Omg was used instead of oleic acid 10 Omg. Example 9

 1. Preparation containing 5% sorbitan monoolate

 Production was carried out in the same manner as in Example 1, except that 30 Omg of sorbitan monoolate was used instead of 10 Omg of oleic acid. Example 10

 2.0% sonolebitan monoolate-containing preparation

 Production was carried out in the same manner as in Example 1, except that sorbitan monooleate 40 Omg was used instead of oleic acid 10 Omg. Example 11

 Preparation containing 0.5% sorbitan trioleate

 Production was carried out in the same manner as in Example 1 except that 10 Omg of sorbic acid was used instead of 10 Omg of oleic acid. Example 12

 1.0% sorbitan triolate containing formulation

 Production was carried out in the same manner as in Example 1 except that sorbitan trioleate 20 Omg was used instead of oleic acid 10 Omg. Example 13

 1. Formulation containing 5% sorbitan triolate

Production was carried out in the same manner as in Example 1, except that 30 Omg of sorbitan triolate was used instead of 10 Omg of oleic acid. Example 14 2.0% sonolevitan trioleate containing formulation

 Production was carried out in the same manner as in Example 1, except that 40 Omg of sorbitan triolate was used instead of 10 Omg of oleic acid. Example 15

 3.0% sonolebitan trioleate containing formulation

 Production was carried out in the same manner as in Example 1 except that sorbitan triolate 60 Omg was used instead of oleic acid 10 Omg. Comparative Example 1

Excipient-free formulation

 Diduridine 5, tetrasodium tetraphosphate was produced by pulverizing with a jet mill to an average particle size of 1.5 to 3.0 μτη (containing 90% or more of particles of 10 m or less). Comparative Example 2

 Secondary particle preparation

 Using a jet mill, 120 g of diziridine 5'-tetrasodium tetraphosphate tetrasodium salt, which has been pulverized to 1.5 to 3.0 / zm (containing 90% or more Using a fluidizing and consolidation system (manufactured by Fuji Padal Co., Ltd.), granulation was performed for about 15 minutes to produce a granulated product having a particle size of 0.3 to 0.8 mm. Example 16

Capsules 1

 20 mg of the 0.5% oleic acid-containing preparation obtained in Example 1 was prepared by filling hydroxypropylmethylcellulose into a No. 2 force capsule of Japanese Pharmacopoeia. Example 17

Capsule 2

20 mg of the 0.75% oleic acid-containing preparation obtained in Example 2 was This product was prepared by filling into the Japanese Pharmacopoeia No. 2 force column of pill methyl cell mouth. Example 18

Capsule 3

 The preparation containing 20% of the 1.0% oleic acid-containing preparation obtained in Example 3 was filled in hydroxypropylmethylcell orifice No. 2 force pharmacopoeia of Japan Pharmacopoeia. Example 19

Capsules 4

 The preparation containing 20 mg of the 1.5% oleic acid-containing preparation obtained in Example 4 was prepared by filling hydroxypropylmethylcellulose into a Japanese Pharmacopoeia No. 2 force capsule. Example 20

Capsule 5

 20 mg of the 2.0% oleic acid-containing preparation obtained in Example 5 was prepared by filling hydroxypropylmethylcellulose in a No. 2 force capsule of Japanese Pharmacopoeia. Example 2 1

Capsules 6

 The preparation containing 20% of the 3.0% oleic acid-containing preparation obtained in Example 6 was filled in a hydroxypropylmethylcell orifice No. 2 force capsule of Japanese Pharmacopoeia. Example 22

Capsules 7

 The preparation containing 20 mg of the 0.5% sorbitan monoolate-containing preparation obtained in Example 7 was filled in a hydroxypropylmethylcellulose No. 2 capsule of Japanese Pharmacopoeia. Example 2 3

Capsules 8 The preparation containing 20% of the 1.0% sorbitan monoolate-containing preparation obtained in Example 8 was filled in hydroxypropylmethylcellulose No. 2 capsules of Japanese Pharmacopoeia. Example 2 4

Capsules 9

 A preparation was prepared by filling 2 O mg of the 1.5% sorbitan monoolate-containing preparation obtained in Example 9 into a Japanese Pharmacopoeia No. 2 force cell of Hydroxypropyl Methyl Cell Oral. Example 2 5

Capsules 1 0

 The preparation containing 20% of the 2.0% sorbitan monoolate-containing preparation obtained in Example 10 was filled in a hydroxypropylmethylcellulose No. 2 capsule of Japanese Pharmacopoeia. Example 26

Capsule 1 1

 This was prepared by filling 20 mg of the 0.5% sonolevitan trioleate-containing preparation obtained in Example 11 in a Japanese Pharmacopoeia No. 2 capsule of hydroxypropyl methylcellulose. Example 2 7

Capsule 1 2

 The preparation was prepared by filling 2 mg of the 1.0% sorbitan triolate-containing preparation obtained in Example 12 into 2 capsules of Japanese Pharmacopoeia of hydroxypropylmethylcellulose. Example 2 8

Capsules 1 3 The preparation containing 20% of the 1.5% sorbitan trioleate-containing preparation obtained in Example 13 was filled in a hydroxypropylmethylcellulose Japanese Pharmacopoeia No. 2 capsule. Example 2 9

Capsules 1 4

 The preparation containing 20% of the 2.0% sorbitan trioleate-containing preparation obtained in Example 14 was filled in a hydroxypropylmethylcellulose No. 2 capsule of Japanese Pharmacopoeia. Example 30

Capsules 1 5

 The preparation containing 20% of the 3.0% sorbitan trioleate-containing preparation obtained in Example 15 was filled in a hydroxypropyl methylcellulose No. 2 capsule of Japanese Pharmacopoeia. Comparative Example 3

Capsules 1 6

 20 mg of the additive-free preparation obtained in Comparative Example 1 was prepared by filling hydroxypropylmethylcellulose in Japanese Pharmacopoeia No. 2 capsules. Comparative Example 4

Capsules 1 7

 20 mg of the secondary particle preparation obtained in Comparative Example 2 was prepared by filling hydroxypropyl methylcellulose into a No. 2 force capsule of Japanese Pharmacopoeia. Test example 1

Inhalation characteristics test

Using capsules 1 to 5, 7 to 17 described in Examples 16 to 20 and 22 to 30 and Comparative Examples 3 to 4 each filled with various preparations, cascade as follows: The amount of drug in each part of the impactor was measured. After fixing the above capsule on the capsule base of the inhalation device (jet heller) connected to the cascade drainer device, press the needle button to make a hole in the capsule, and with a suction flow rate of 28.3 ± 0.5 LZ for 5 seconds Aspirated. After aspiration, the capsule was removed from the inhaler and placed in a triangular flask. After repeating the suction operation in the same manner as the five capsules, the inhaler and the cascade impactor were disassembled into individual parts and separately placed in polyethylene plastic bags. Next, add 50 mL of water to the Erlenmeyer flask containing the capsule after suction, and then add 50 to 20 OmL of water to each polyethylene plastic bag containing each part, and then tightly close the mouth of the polyethylene plastic bag. The mixture was shaken for about 1 minute, and washed with water to which the drug deposited on each part was added. After shaking, each washing solution was separately transferred to an Erlenmeyer flask to prepare a sample solution. Separately, after dissolving 5 Omg of dipyridine 5'-tetraphosphate tetrasodium salt in water, further add water to make 10 OmL, collect 1 OmL of this solution, and add water to make 10 OmL. Was used as a standard solution. For each of the prepared sample solutions and standard solutions, the amount of drug in each part was measured using an ultraviolet absorption spectrophotometer based on the absorbance at 262 nm according to the absorbance measurement method (listed in the 13th revision of the Japanese Pharmacopoeia).

 (1) Pulmonary drug arrival rate measurement

The sum of the drug amounts in the parts below Stage 2 was calculated, and the inhalation efficiency was evaluated using the ratio (weight ratio) to the total drug amount as the lung arrival rate. The results are shown in Table 1 below

Ho 1]

(2) Measurement of residual rate of drug in inhalation device

The amount of drug in the main body of the inhaler was calculated, and the ratio (weight ratio) to the total amount of drug was evaluated as the residual ratio in the inhaler. The results are shown in Table 2 below 2]

試験例 2 - 安定性試験

Test Example 2-Stability test

Using the capsule 3 described in Example 18, moisture-proof packaging in a thermo-hygrostat at 40 ° C and a relative humidity of 75% or 25 ° C and a relative humidity of 60%, and left for 2 months, The arrival rate was measured according to the method described in Test Example 1, and the change in the arrival rate was confirmed. Table 3 shows the results. [Table 3]

[Industrial applicability]

 The powder formulation for inhalation of the present invention significantly improves the efficiency of drug powder particles reaching the lungs, improves the efficiency of drug use, and reduces the amount of drug used to fill a container attached to an inhalation device. Can be reduced. Furthermore, the powder formulation for inhalation of the present invention is non-irritating or extremely weak, so that the burden on the patient during inhalation is small, and the stability of the formulation is extremely high, so that long-term storage is possible. According to the present invention, it is possible to provide a powder formulation for inhalation and a powder inhaler which are suitable for treatment of various pulmonary diseases accompanied by difficulty in excreting mucus secretions.

Claims

The scope of the claims 1. A powder preparation for inhalation, comprising oleic acid or sorbitan oleic acid ester, comprising tetrasodium salt of didiridine 5, -tetraphosphate as an active ingredient. 2. The powder preparation for inhalation according to claim 1, which is obtained by mixing tetrasodium salt of dipyridine 5'-tetraphosphate with oleic acid or sorbitan oleate. 3. A powder inhalant filled with the powder formulation for inhalation according to claim 1 or 2.