JP2000143502A - Inhalant preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an inhalant preparation whose capsule coating film can keep excellent strength even in the case where the water content of the capsule coating film is set at a lower level and whose filled powdery drug can keep its dryness by filling a powdery drug in a specific capsule. SOLUTION: This inhalant preparation is obtained by filling (A) a powdery preparation to be used for an inhalant preparation whose inner powdery drug is administered into the respiratory tract by spray or inhalation in (B) a hard- gelatin capsule formed of hard-gelatin coating film containing a polyethylene glycol(PEG) having an average molecular weight preferably of 150-40,000. The content of PEG in the hard-gelatin coating film changes according to the molecular weight of PEG. It is 1-100 pts.wt. in the case of less than 800 in the average molecular weight, 1-50 pts.wt. in the case of not less than 800 and less than 2,000, 0.5-15 pts.wt. in the case of not less than 2,000 and less than 5,500, 0.2-10 pts.wt. in the case of not less than 5,500 and less than 12,500, and 0.1-5 pts.wt. in the case of not less than 12,500, based on 100 pts.wt. of gelatin.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an inhalation preparation in which a powdered drug is filled in a capsule, wherein a predetermined hole is pierced in the capsule, and the powdered drug is administered into the respiratory tract by injection or inhalation. About.

[0002]

2. Description of the Related Art Conventionally, there has been known an inhalation preparation in which a hard gelatin capsule formed of a hard gelatin film is filled with a powder drug for inhalation.

[0003] This inhalation preparation is administered into the respiratory tract by piercing a predetermined hole in a capsule using a predetermined tool and injecting the medicine inside by a jetting device, or by inhaling using an appropriate tool. . For example, as a device for administering an inhalation preparation into the respiratory tract using this kind of drug, an inhalation device called "Spin Heller" (trademark) is commercially available, and a powder drug filled in a capsule using this inhalation device is used. The method of administration into the respiratory tract is as follows. First, an inhalation preparation filled with a powder drug for inhalation in a capsule is set on this spin spatula, a predetermined hole is pierced in the capsule, and in this state, the spin spatula is held in a mouth and inhaled, thereby being provided inside. The propeller rotates and the capsule rotates with this, and the drug in the capsule is scattered out of the capsule by the centrifugal force from the perforated hole, and the scattered drug is inhaled and administered into the airway. Is done.

[0004]

However, inhalation preparations in which a hard gelatin capsule is filled with a powdered drug may cause various problems depending on the moisture contained in the gelatin film forming the capsule.

That is, for example, when a drug is administered to the lung by inhalation from the mouth, the particle size of the powdered drug affects the degree of reaching the lungs by inhalation. However, since the powdered drug is generally easily absorbed by moisture, a capsule is formed. The moisture in the gelatin film that migrates easily migrates to the powdered drug inside, and the drug inside may agglomerate due to moisture absorption, making it impossible to effectively inhale the drug. In addition, even when aggregation does not occur, the powder medicine may adhere to the inner wall of the capsule due to moisture, and the powder medicine may not satisfactorily scatter outside the capsule. Therefore, in this type of preparation, it is important to keep the powdered medicine inside in a dry state, and it is necessary to keep the water content of the hard gelatin film forming the capsule low.

[0006] However, if the water content in the gelatin film is set low, the film becomes hard and brittle, the cutting edge of the needle does not easily stick into the film when piercing with a needle, and the capsule is damaged when piercing due to the brittleness of the film. There is a possibility that it will be. In this case, if the capsule is broken, not only can the drug not be effectively inhaled, but also the fragments of the capsule may be inhaled, which is extremely dangerous.

The present invention has been made in view of the above circumstances, and it has been found that, in an inhalation preparation in which a powder drug is filled in a capsule, the capsule film becomes brittle even if the water content of the capsule film is set low. Provided is an inhalation preparation which can maintain good strength without any problems, can surely maintain a dry state of a powdered drug filled therein, and can prevent inconvenience caused by breakage of a capsule as much as possible. The purpose is to:

[0008]

Means for Solving the Problems and Embodiments of the Invention As a result of intensive studies conducted by the present inventor to achieve the above object, the capsule membrane to which polyethylene glycol has been added has a reduced water content. The film can maintain good strength without becoming brittle, and the film becomes slightly soft and flexible, and the edge of the needle is easily pierced when pierced with a needle or the like, which is very preferable as a capsule container for inhalation preparations. The present invention has been found to have properties, and the present invention has been completed.

Accordingly, the present invention relates to an inhalation preparation comprising a hard gelatin capsule filled with a powdered drug and administering the powdered drug inside to the respiratory tract by injection or inhalation, wherein the capsule contains hard polyethylene glycol containing polyethylene glycol. It is intended to provide an inhalation preparation characterized by using a capsule formed by a gelatin film.

Hereinafter, the present invention will be described in more detail.
As described above, the inhalation preparation of the present invention is obtained by filling a capsule consisting of a hard gelatin film containing polyethylene glycol (hereinafter sometimes abbreviated as “PEG”) with a powder drug for inhalation.

The polyethylene glycol (PEG) is not particularly limited, but those having an average molecular weight of 150 to 40,000 are preferably used. As such PEG, the following commercially available products can be used.
In addition, polyethylene glycol 1500 described below is polyethylene glycol 300 and polyethylene glycol 15
40 and an equal mixture. Further, the average molecular weight referred to in the present invention is based on a measurement method described in the Japanese Pharmacopoeia or the standard for cosmetic raw materials. Polyethylene glycol 200: average molecular weight 190-2
10 polyethylene glycol 300: average molecular weight 280-3
20 polyethylene glycol 400: average molecular weight 380-4
20 polyethylene glycol 600: average molecular weight 570-6
30 polyethylene glycol 1000: average molecular weight 950
1050 polyethylene glycol 1500: average molecular weight 500 to
600 polyethylene glycol 1540: average molecular weight 1300
-1600 polyethylene glycol 4000: average molecular weight 2600
~ 3800 polyethylene glycol 6000: average molecular weight 7300
-9300 polyethylene glycol 20000: average molecular weight 150
00-25000 polyethylene glycol 35000: average molecular weight 340
00-39000

The mixing ratio of the PEG is appropriately adjusted according to the molecular weight of the PEG to be used, and is not particularly limited.
It is in the range of 5 to 50 parts by weight. In this case, generally PE
As the molecular weight of G increases, a sufficient effect can be obtained with a small amount of addition. Specifically, depending on the molecular weight of PEG, a. When the PEG average molecular weight is less than 800, 1-1
00 parts by weight, especially 3 to 50 parts by weight, further 5 to 30 parts by weight, b. When the average molecular weight of PEG is 800 or more and less than 2000, 1 to 50 parts by weight, particularly 3 to 20 parts by weight, c. When the PEG average molecular weight is 2,000 or more and less than 5,500, 0.5 to 15 parts by weight, particularly 3 to 10 parts by weight, d. When the PEG average molecular weight is 5500 or more and less than 12500, 0.2 to 10 parts by weight, particularly 1 to 7 parts by weight; When the PEG average molecular weight is 12500 or more,
It is preferably 0.1 to 5 parts by weight, particularly preferably 0.3 to 3 parts by weight. If the PEG compounding amount is less than the above range, the film strength at low water content may not be able to be sufficiently improved, whereas if it exceeds the above range, the gelatin solution for obtaining the gelatin film becomes cloudy, The viscosity suddenly decreases and it becomes impossible to mix PEG uniformly,
In some cases, so-called coacervation occurs, making it impossible to form a uniform capsule film.

The capsule used in the inhalation preparation of the present invention is a hard capsule comprising the above-mentioned PEG-containing gelatin film, and can be formed from the above-mentioned PEG-containing gelatin solution by a known immersion method. For example,
After adding purified water to the gelatin and leaving it to stand for a predetermined time, the gelatin is swelled with water.After the gelatin has sufficiently swelled, the gelatin is heated to about 60 ° C. and stirred to dissolve the gelatin uniformly. A gelatin solution is prepared by adding the PEG aqueous solution to adjust the viscosity and defoaming. In this case, the PEG aqueous solution depends on the average molecular weight of PEG,
Usually, it is preferable to prepare an aqueous solution of about 30 to 50% by weight. Then, a PEG-containing hard gelatin capsule may be manufactured from the gelatin solution by a dipping method using a known capsule manufacturing machine.

According to the present invention, a pair of caps and a body which can be fitted and connected to each other by the above-mentioned immersion method are formed, and a hard gelatin capsule in which the cap and the body are connected is filled with a powder drug for inhalation. After filling the powdered drug, a known band seal can be applied to the connection between the cap and the body, if necessary, if necessary. in this case,
A normal gelatin solution can be used as the band seal solution, and is not particularly limited. However, it is preferable to use a gelatin solution containing PEG as the band seal solution. Incidentally, the PEG-containing gelatin band seal solution is preferably the same composition as the PEG-containing gelatin composition forming the cap and the body,
The molecular weight and content of PEG may be different, and may not necessarily be the same composition.

The PEG-containing hard gelatin capsule used in the present invention has a film for preventing the powder medicine for inhalation to be filled into the capsule from absorbing moisture and agglomerating or adhering to the inner wall of the capsule. It is preferable to reduce the water content in the water as much as possible.
It is preferably at most 4% by weight, particularly preferably about 12 to 8% by weight. In this case, according to the PEG-containing hard gelatin capsule, good strength and flexibility can be maintained even at such a low water content, and the disadvantage that the capsule is damaged when piercing the capsule is avoided. Since the coating does not occur and a relatively soft coating is obtained, the cutting edge of the needle for perforation can be easily pierced.

In the present invention, the drug filled in the PEG-containing hard gelatin capsule may be any drug as long as it is a powdered inhalation drug, for example, an agent for allergic diseases such as sodium cromoglycate, beclomethasone propionate and the like. Corticosteroids, bronchodilators such as salbutamol sulfate, bronchoconstriction preventives such as ipratropium bromide, and the like, but are not limited thereto. May be used.

The inhalation preparation of the present invention is a preparation in which a predetermined hole is pierced in, for example, a capsule using an appropriate tool, and the powdered medicine inside is administered to the respiratory tract by injection or inhalation. It is then administered to the nostrils, oral cavity, pharynx, trachea, bronchi, bronchioles, alveoli and the like. In this case, as a tool used for drug administration,
A tool for inhaling a drug by inhalation such as the above-mentioned "Spin Heller" (trademark) is preferably used. May be used. In general, as a tool for inhaling a drug by inhalation, a device in which a circular hole or a slit-shaped hole is formed in a capsule like the above-mentioned "spin heller", but a device in which a capsule is separated into a cap and a body For example, the internal drug may be released from the capsule by other methods.

[0018]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the following examples.

Example 1 Purified water was added to gelatin, and the gelatin was allowed to stand for a predetermined time to absorb and swell the gelatin. After the gelatin was sufficiently swollen, it was heated to 60 ° C. and stirred to dissolve the gelatin uniformly. . Commercially available polyethylene glycol 40
PEG (average molecular weight: 2600-3800) in purified water to prepare a 50% by weight aqueous solution of PEG.
PEG was added so as to be 5 parts by weight with respect to 0 parts by weight, and the mixture was stirred to adjust the viscosity, followed by bleeding according to a conventional method to obtain a gelatin solution.

The gelatin concentration of the obtained gelatin solution was 2
After adjusting to 7% by weight, maintain the solution temperature at about 60 ° C.,
Using a capsule maker, a cap and a body that can be connected to each other are formed by an immersion method.
An EG-containing hard gelatin capsule (No. 2 capsule) was produced.

The water content of the obtained hard gelatin capsule was adjusted under the relative humidity shown in Table 1, and the capsule was set in a commercially available inhaler “Spin Heller” (trademark), and two holes having a diameter of about 1 mm were formed in the capsule. Then, the generation of fragments was examined. The test was performed on 20 capsules, and the number of fragments generated was recorded. Table 1 shows the results. As a control, a similar test was performed on a normal hard gelatin capsule containing no PEG. The results are also shown in Table 1.

[0022]

[Table 1] *:weight%

Example 2 As polyethylene glycol, commercially available polyethylene glycol 400 (average molecular weight: 380 to 420), 1000 (average molecular weight: 950 to 10)
50), 6000 (average molecular weight 7300-9300),
A PEG-containing hard gelatin capsule was prepared in the same manner as in Example 1 except that 20,000 (average molecular weight: 15,000 to 25,000) was used and the compounding ratio of PEG was set to the ratio shown in Table 2. The test was performed. Table 2 shows the results.

[0024]

[Table 2] *: Parts by weight based on 100 parts by weight of gelatin

As shown in Tables 1 and 2, PEG
Has good strength and flexibility even at a low moisture content, and does not generate fragments when piercing the capsule. Therefore, even when the capsule is filled with the powdered drug to produce an inhalation preparation, even if the water content of the capsule film is set to be low, the dry state of the powdered drug filled therein can be reliably maintained. It was confirmed that inconvenience caused by breakage of the capsule can be prevented as much as possible.

Example 3 As shown in Table 3, commercially available polyethylene glycol 4000 was used and the amount of PEG was changed in the range of 0 to 15% by weight based on 100 parts by weight of gelatin. A gelatin aqueous solution was prepared in the same manner as in Example 1, and a 100 μm-thick PE was prepared from the resulting aqueous solution.
A G-containing gelatin film was prepared. The water content of each of the obtained films was adjusted at a relative humidity of 33% RH, and the water content was adjusted to 11.0 to 12.5% by weight.

A needle having a diameter of about 1 mm was pierced into each film to pierce the film, and the load required to make a hole in the film was measured as a resistance value. Table 3 shows the results. PEG as control
Normal gelatin film containing no water (water content 1
(2.5% by weight). The results are also shown in Table 3.

[0028]

[Table 3] *: Parts by weight based on 100 parts by weight of gelatin

As shown in Table 3, the gelatin film containing PEG has moderate softness even with a low moisture content, and can easily pierce the cutting edge of a needle for perforation. Things. Therefore, it was confirmed that the inhalation preparation in which the powdered drug was filled in the hard gelatin capsule formed of this film was excellent in perforation properties and excellent in usability when taking.

[0030]

As described above, according to the inhalation preparation of the present invention, since the capsule formed by the hard gelatin film containing polyethylene glycol is used, even if the water content of the capsule film is set low. It is possible to maintain good strength without making the capsule film brittle, to surely maintain the dry state of the powdered medicine filled therein, and to prevent the occurrence of inconvenience due to breakage of the capsule as much as possible. Can be prevented. In addition, the capsule film of the hard gelatin capsule used in the inhalation preparation of the present invention has a moderate softness despite its low water content, so that when the needle is pierced, the cutting edge of the needle is sharpened. It can be easily pierced and easily pierced, so that the inhalation formulation of the present invention is excellent in usability.

Claims (4)

[Claims] 1. An inhalation preparation in which a hard gelatin capsule is filled with a powdered drug and the powdered drug is administered into the respiratory tract by injection or inhalation, wherein the capsule is formed by a hard gelatin film containing polyethylene glycol. An inhalation preparation characterized by using a prepared capsule. 2. The inhalable preparation according to claim 1, wherein the polyethylene glycol has an average molecular weight of 150 to 40,000. 3. The inhalation preparation according to claim 2, wherein the content of polyethylene glycol in the hard gelatin film is one of the following with respect to 100 parts by weight of gelatin. I. When the average molecular weight of polyethylene glycol is less than 800, 1 to 100 parts by weight. B. 1 to 50 parts by weight when the average molecular weight of polyethylene glycol is 800 or more and less than 2,000. C. 0.5 to 15 parts by weight when the average molecular weight of polyethylene glycol is 2,000 or more and less than 5,500. D. When the average molecular weight of polyethylene glycol is 5500 or more and less than 12,500, 0.2 to 10 parts by weight. E. The average molecular weight of polyethylene glycol is 12500
If more than 0.1 to 5 parts by weight. 4. The hard gelatin film having a water content of 14
The inhalation preparation according to any one of claims 1 to 3, which is not more than weight%.