JP3494321B2 - Dry syrup of theophylline sustained release microcapsules and method for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a dry syrup preparation for theophylline sustained-release microcapsules and a method for producing the same, and more specifically, it is a fine granule that can be taken as a suspension at the time of use and produces little dust during use or preparation. The present invention relates to a dry syrup agent and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION Theophylline is a useful drug commonly used as a symptomatic therapeutic agent for acute and chronic bronchial asthma, but its biological half-life is about 6 hours in adults. Due to their short duration, efforts are underway to develop sustained release theophylline formulations. Several tablets and granules have already been put on the market, and further theophylline sustained-release microcapsules (JP-A-61-109).
No. 711) is also known. However, the microcapsules are weak against external pressure, and in normal wet crushing granulation and dry granulation, the microcapsules are broken and the sustained release property is lost, so granulation was impossible.

On the other hand, there are a wide range of ages for taking sustained-release preparations of theophylline from infants to elderly people, but the currently marketed dosage forms of tablets and granules are difficult to take, especially for young children and the elderly. It was a dosage form. Therefore, it is easy to increase or decrease the prescription amount, it is easy to take it as it is, it can be taken as a suspension at the time of use, and it is a new dosage form that can be taken with foods that infants and old people like such as pudding and ice cream. Development was desired.

[0004]

Means for Solving the Problems The present inventors have used theophylline sustained-release microcapsules and can rapidly take a suspension before use without impairing the sustained-release properties of theophylline sustained-release microcapsules. In addition, as a result of various studies to obtain a dry syrup preparation of theophylline sustained-release microcapsules in the form of fine particles with little dust generation during use or preparation, the present invention has been completed.

That is, the gist of the present invention is to provide a theophylline sustained-release microcapsule, a dry syrup formulation of theophylline sustained-release microcapsule characterized by containing a binder and a surfactant, and theophylline sustained-release microcapsule. A method for producing a dry syrup preparation of theophylline sustained-release microcapsules, which comprises granulating a mixture containing a binder and a surfactant with a fluidized bed granulator.

The present invention will be described in detail below. In the present invention, the theophylline sustained-release microcapsules refer to Pharmasome (trade name; manufactured by Elan Co.) described in JP-A-61-1109711. The binder and the surfactant are not particularly limited as long as they are commonly used.

Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, gum arabic, sodium carboxymethylcellulose, corn starch, xanthan gum, and the like, with preference given to hydroxypropylcellulose, Hydroxypropyl methylcellulose,
Methyl cellulose is particularly preferred, and hydroxypropyl cellulose is particularly preferred.

Examples of the surfactant include sodium lauryl sulfate, glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester and propylene glycol fatty acid ester. Preferred are sodium lauryl sulfate, glycerin fatty acid ester and sorbitan fatty acid ester, and particularly preferred is sodium lauryl sulfate.

The mixing ratio of theophylline sustained-release microcapsules, the binder and the surfactant is appropriately adjusted depending on the amount of theophylline contained in the dry syrup preparation as the final product. For example, in order to obtain a dry syrup containing 20% of theophylline, about 35% of the theophylline sustained-release microcapsules containing about 55% of theophylline (wt%, hereinafter, unless otherwise specified, all wt% are used). Representation), about 2% binder and about 0.2% surfactant.

The dry syrup preparation of the present invention is characterized in that it is granulated using a fluidized bed granulator rather than the conventionally used wet crush granulator or dry granulator.
As a fluidized bed granulator, a fluidized bed granulation coating machine (W
SG-5 type, Okawara Seisakusho Co., Ltd., swirl type fluidized bed granulation coating machine (SFC-5 type, Freund Industrial Co., Ltd.) and the like. For example, in the case of using the former fluidized bed coating machine, under the conditions of the intake temperature of 70 to 80 ° C., the spray pressure of 2.0 kg and the flow rate of 120 g / min, and the latter of the swirling type fluidized bed granulation coating machine. Has an intake air temperature of 70 to 80 ° C., a spray pressure of 2.0 kg,
The flow rate is 60 g / min and the agitator rotation speed is 100.

To obtain the dry syrup preparation of the present invention, there are two methods, depending on whether the surfactant is added at the beginning of the manufacturing process or at the end thereof. Examples of the method of initial addition include a method of spraying a binder onto a mixture containing theophylline sustained-release microcapsules and a surfactant. As a final addition method, a method of spraying the theophylline sustained-release microcapsules with a binder and a surfactant dissolved in the binder can be mentioned.

More specifically, in the former method, theophylline sustained-release microcapsules and a surfactant are mixed in advance, and the binder is sprayed onto the mixture by using the above fluidized bed granulator. There is a method. At this time, the theophylline sustained-release microcapsules and the surfactant are mixed using a rotary mixer, for example, a V-type mixer. Examples of the latter method include a method of spraying theophylline sustained-release microcapsules with a binder and a surfactant dissolved in the binder with a fluidized bed granulator.

The dry syrup preparation of the present invention may be added with one or more kinds of commonly used excipients such as mannitol and sucrose. The excipient is
In the case of the method of adding the surfactant first, the mixture of theophylline sustained-release microcapsules and the surfactant is added together when charging the fluidized bed granulator. In the case where the surfactant is added last, the theophylline sustained-release microcapsules are added together when the fluidized bed granulator is charged.

After granulation as described above, it is preferable to add talc to the dry syrup preparation of the present invention in order to prevent the generation of static electricity. It is also possible to add commonly used flavors and sweeteners.

[0015]

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to the following examples as long as the gist thereof is not exceeded.

Example 1 1.7 kg of theophylline sustained-release microcapsules (Pharmasome) and 0.01 kg of sodium lauryl sulfate were mixed with V
Mix using a type mixer. Separately mannitol 2.6k
g, Avicel RC591NF (Asahi Kasei) 0.25k
g, Carplex (Shionogi Pharmaceutical Co., Ltd.) 0.1 kg, titanium oxide 0.05 kg, Henschel mixer (FM-20
B, Mitsui Miike Manufacturing Co., Ltd.). Both the mixed products are charged into a fluidized bed granulation coating machine (WSG-5).

0.02 kg of sodium saccharin is dissolved in 1.8 kg of purified water, and 0.12 kg of hydroxypropyl cellulose is further dissolved to form a binding solution, and granulation is carried out under the following conditions. After granulation, it is sieved through a 20-mesh sieve, and then about 2% talc and a trace amount of fragrance are added to obtain a product.

[0018]

[Table 1] Granulation conditions: Intake air temperature (° C) 70-80 Spray pressure (kg) 2.0 Flow rate (g / min) 120

Example 2 Mannitol 2.6 kg, Avicel RC591 NF
(Asahi Kasei) 0.25 kg, Carplex (Shionogi Pharmaceutical Co., Ltd.) 0.1 kg, and titanium oxide 0.05 kg are mixed with a Henschel mixer. The mixture and 1.7 kg of theophylline sustained-release microcapsules (Pharmasome) are charged into a fluidized bed granulation coating machine (WSG-5).

0.02 kg of sodium saccharin is dissolved in 1.8 kg of purified water, and 0.12 kg of hydroxypropyl cellulose is further dissolved to form a binding solution, which is granulated under the same conditions as in Example 1. At the end of the granulation, a solution prepared by adding 0.01 kg of sodium lauryl sulfate to a part of the binding solution is sprayed.
After granulation, it is sieved through a 20-mesh sieve, and then about 2% talc and a trace amount of fragrance are added to obtain a product.

FIG. 1 shows the particle size distribution of the dry syrup preparations obtained in Example 1 and Example 2. From FIG. 1, the dry syrup preparation of the present invention sufficiently satisfies the standards for fine granules prescribed by the Japanese Pharmacopoeia, and further, since the amount of fine powder is small, it maintains a preferable particle size distribution with little dust generation during use or preparation. I understand.

Comparative Example 1 1.7 kg of dry granulated theophylline sustained-release microcapsules (Pharmasome) and 0.01 kg of sodium lauryl sulfate were mixed with V
Mix using a type mixer. Separately Mannitol 2.19
kg, Avicel RC591NF (Asahi Kasei) 1.0kg
Are mixed with a Henschel mixer (FM-20B, Mitsui Miike Seisakusho). After mixing both mixtures with a Henschel mixer, they were compression-granulated using a Roller Compactor Mini (Freund Industrial Co., Ltd.) (Roll
5 rpm, Feed 20 rpm, pressure 60 kg / c
m ² ), sizing with a speed mill. After sizing, about 1% talc is added to obtain a product.

Comparative Example 2 1.7 kg of wet-crushed granulated theophylline sustained-release microcapsules (Pharmasome) and 0.01 kg of sodium lauryl sulfate were mixed with V
Mix using a type mixer. Separately, 2.97 kg of sucrose, 0.25 kg of Avicel RC591NF (Asahi Kasei) and 0.05 kg of titanium oxide were added to a Henschel mixer (FM-20.
B, Mitsui Miike Manufacturing Co., Ltd.). Both mixtures are charged into a Henschel mixer, mixed and then granulated with about 10% purified water (1000 rpm × 3 min). After drying, after sieving with a 20-mesh sieve, 0.02 kg of talc is added to obtain a product.

FIG. 2 shows theophylline sustained-release microcapsules (Pharmasome) (⋄), the dry syrup preparation of the present invention obtained in Example 1 (◯), the dry syrup preparation of the present invention obtained in Example 2 (Δ). ), The dry syrup preparation (●) obtained in Comparative Example 1 and the dry syrup preparation (♦) obtained in Comparative Example 2 are shown in the results of dissolution tests. The dissolution test was performed by the paddle method (100 rpm, 37 ± 0.5 ° C.) using 900 ml of the Japanese Pharmacopoeia Disintegration Test Method Second Liquid. In the dry syrup preparations obtained in Comparative Examples 1 and 2, the sustained release property of theophylline sustained-release microcapsules was remarkably lost, but the dry syrup preparations of the present invention obtained in Examples 1 and 2 were treated with theophylline sustained-release preparation. Releasable microcapsules The original sustained release property is maintained.

Test Example Theophylline sustained-release microcapsule dry syrup preparation obtained in Example 1 (equivalent to theophylline 400 mg)
Was orally administered to 12 healthy adult males, and the transition of serum theophylline concentration and pharmacokinetic parameters were examined. Fig. 3 shows the transition of the theophylline concentration in the obtained serum.
The pharmacokinetic parameters are shown in the table below. The theophylline concentration in serum of the dry syrup preparation of the present invention reached the maximum concentration 5 hours after the administration, and showed a favorable transition of the effective blood concentration up to 12 hours.

[0026]

[Table 2] C _max : Maximum blood concentration T _max : Time to reach the maximum blood concentration AUC _0-48 : Area under the Curve from 0 to 48 hours (indicator of the amount of drug in the body) MRT: Mean retention of drug in the body time

[0027]

INDUSTRIAL APPLICABILITY According to the present invention, theophylline sustained-release microcapsules are in the form of fine particles that can be rapidly taken as a suspension without impairing the original sustained-release property of theophylline, and are also released during use or preparation. A dry syrup preparation with less dust can be obtained.

[Brief description of drawings]

FIG. 1 is a diagram showing the particle size distribution of the dry syrup preparations obtained in Examples 1 and 2.

FIG. 2 is a diagram showing the results of a dissolution test of theophylline sustained-release microcapsules and the droy syrup preparations obtained in Example 1, Example 2, Comparative Example 1 and Comparative Example 2.

FIG. 3 is a graph showing changes in serum theophylline concentration of the dry syrup preparation obtained in Example 1.

─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A 61-109711 (JP, A) JP-A 2-72113 (JP, A) JP-A 6-157312 (JP, A) JP-A 6- 116138 (JP, A) Tokuyohei 5-501421 (JP, A) International publication 89/006129 (WO, A1) (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 31/52 A61K 9 / 16 A61K 9/52 A61P 11/08 B01J 2/16

Claims (8)

(57) [Claims] 1. A theophylline sustained-release microcapsule,
A dry syrup preparation of theophylline sustained-release microcapsules, which contains at least one binder of hydroxypropylcellulose, hydroxypropylmethylcellulose or methylcellulose and a surfactant and is obtained by granulation with a fluidized bed granulator. . 2. The dry syrup preparation according to claim 1, wherein the binder is hydroxypropyl cellulose. 3. The dry syrup preparation according to claim 1, which is obtained by previously mixing theophylline sustained-release microcapsules and a surfactant and spraying the mixture with a binder using a fluidized bed granulator. 4. The theophylline sustained-release microcapsules obtained by spraying a binder and a surfactant dissolved in the binder with a fluidized bed granulator.
Dry syrup formulation as described. 5. Theophylline sustained-release microcapsules,
Production of dry syrup preparation of theophylline sustained-release microcapsules, characterized in that a mixture containing at least one binder of hydroxypropylcellulose, hydroxypropylmethylcellulose or methylcellulose and a surfactant is granulated by a fluidized bed granulator. Method. 6. A pre-mixed theophylline sustained-release microcapsule and a surfactant are mixed in advance, and the mixture is sprayed with at least one binder selected from hydroxypropylcellulose, hydroxypropylmethylcellulose or methylcellulose in a fluidized bed granulator. A method for producing a dry syrup preparation of theophylline sustained-release microcapsules, which is characterized. 7. Theophylline sustained-release microcapsules are sprayed with a fluidized bed granulator with at least one binder of hydroxypropylcellulose, hydroxypropylmethylcellulose or methylcellulose and a surfactant dissolved in the binder. A method for producing a dry syrup preparation of theophylline sustained-release microcapsules, which is characterized. 8. The method for producing a dry syrup preparation according to claim 5, wherein the binder is hydroxypropyl cellulose.