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Method of producing drug-containing wax matrix particles, extruder to be used in the method and sustained-release preparation containing cilostazol

A manufacturing method and technology of sustained-release preparations, which are applied in the field of wax-based particle manufacturing, can solve the problems of drug or additive stability damage, wax-based particle preparation technology, solidification, etc., and achieve high biological availability , effective pharmacological effects, and the effect of ensuring sustained release

Inactive Publication Date: 2009-01-07
OTSUKA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This heating melting spraying method is suitable for forming spherical matrix particle, but there are following disadvantages: (1) must have the large-scale device that is used for spray cooling; ) must carry out temperature control on pipelines, pumps, etc. required to connect storage tanks and spray cooling devices, etc.
Also, a large amount of raw materials must be heat-treated during mass production by the heating melt spray method, and the raw materials are inevitably exposed to high temperatures for a long time, so the stability of drugs or additives may be destroyed by heat
Furthermore, the heating melt spraying method also has the following defects: when the medicine dissolved in the molten mixture is easy to separate out, the surface of the molten mixture in the storage tank or the liquid immersion surface with the storage tank wall, the infusion tube, the rotating disk, the nozzle, etc. Problems caused by drug precipitation and solidification in the sprayed part, etc.
So far, Patent Document 6 discloses the technology of making cilostazol into a sustained-release preparation, but there is no report on the technology of making cilostazol into a formulation as wax matrix particles

Method used

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  • Method of producing drug-containing wax matrix particles, extruder to be used in the method and sustained-release preparation containing cilostazol
  • Method of producing drug-containing wax matrix particles, extruder to be used in the method and sustained-release preparation containing cilostazol
  • Method of producing drug-containing wax matrix particles, extruder to be used in the method and sustained-release preparation containing cilostazol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0152] use figure 2 The extruder of the configuration shown, produces wax matrix particles. As an extruder, the structure and its operating conditions are shown below.

[0153] Extruder type: Twin-screw extruder (KEX-25, manufactured by Kurimoto Iron Works)

[0154] Screw shape: From the downstream side to the upstream side, the shape in which the conveying, kneading, and mixing sections are connected in sequence

[0155] Nozzle: Dual Fluid Nozzle

[0156] Screw part length: Approximately 50cm

[0157] Rotation speed of the screw: 125rpm

[0158] The shape and diameter of the discharge hole of the nozzle: circular, 0.5mm

[0159] The residence time of raw materials in the drum: about 2 minutes

[0160] Drum temperature setting temperature: drum sleeve 1a-1 is 140°C, drum sleeve 1a-2 is 150°C, drum sleeve 1a-3 and 1a-4 are 160°C

[0161] Temperature and introduction speed of spray gas: about 200°C, 25L / min

[0162] Discharge speed per discharge hole of molten kneaded...

Embodiment 2

[0168] As raw materials, 300 g of theophylline, 10 g of ethyl cellulose, and 690 g of fatty acid glyceride (glycerol monobehenate; melting point of about 75° C.) were mixed, and wax was produced under the same conditions as in Example 1 above using the obtained mixed raw material. matrix particles.

[0169] The obtained wax matrix particles were spherical, and when the particle size distribution was measured with a laser diffraction particle size distribution meter (Tohnichi Computer Application), the 10% cumulative diameter was 43 μm, the 50% cumulative diameter (average particle diameter) was 88 μm, and the 90% cumulative diameter was 160 μm, 99% cumulative diameter is 204 μm.

[0170] In addition, it was confirmed that no troubles such as theophylline precipitation in the extruder and liquid clogging occurred during the production process. In addition, the content of theophylline in the obtained wax-based particles was about 100% relative to the theoretical value.

Embodiment 3

[0172] As raw materials, 300 g of theophylline and 700 g of hardened oil (melting point: about 86° C.) were mixed, and using the obtained mixed raw material, wax matrix particles were produced under the same conditions as in Example 1 above.

[0173] The obtained wax matrix particles were spherical, and when the particle size distribution was measured with a laser diffraction particle size distribution meter (Tohnichi Computer Application), the 10% cumulative diameter was 48 μm, the 50% cumulative diameter (average particle diameter) was 96 μm, and the 90% cumulative diameter was 169 μm, 99% cumulative diameter is 221 μm.

[0174] In addition, it was confirmed that no troubles such as theophylline precipitation in the extruder and liquid clogging occurred during the production process. In addition, the content of cilostazol in the obtained wax-based particles was about 100% relative to the theoretical value.

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Abstract

It is intended to provide a method of conveniently producing drug-containing wax matrix particles (in particular, drug-containing wax matrix particles having an average particle diameter of 1 mm or less) through melting and spraying steps without suffering from a jamming failure caused by the recrystallization of the once molten drug. Namely, drug-containing wax matrix particles containing a drug and a wax are produced via the following steps (i) and (ii): (i) the step of feeding the drug and wax as described above into an extruder wherein the temperatures of a barrel (1) and a die have been controlled to a level higher than the melting point of the wax; and (ii) the step of melt-kneading the drug with the wax in the extruder as described above and simultaneously spraying out the melt-kneaded mixture comprising the drug and the wax from a spray nozzle (5), which is attached directly to a die (3) provided at the tip of the barrel (1) in the extruder, into an atmosphere at a temperature lower than the melting point of the wax to thereby form particles.

Description

technical field [0001] The present invention relates to a method for manufacturing wax matrix particles containing medicine. In addition, the present invention relates to an extruder for the manufacture of drug-containing wax-based particles. [0002] The present invention also relates to a sustained-release preparation containing cilostazol. In more detail, the present invention relates to a sustained-release preparation comprising wax-based particles containing cilostazol, which releases cilostazol when administered on an empty stomach and after a meal. Or the difference in blood concentration changes is small, and it has excellent sustained-release properties. Background technique [0003] As oral sustained-release preparations, single-unit types such as tablets and multi-unit types such as granules are known, and a multi-unit type preparation with little inter-individual variation in drug release in vivo and blood concentration distribution is expected. In addition, a...

Claims

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Application Information

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IPC IPC(8): A61J3/06A61K9/14A61K31/4709A61K31/522A61K47/12A61K47/14A61K47/44B01J2/04A61K47/06
CPCB29B7/826B29B7/823B29B7/726B29B7/007B29C48/022B29C48/04B29C48/1472B29C48/397A61K9/1617A61K31/4709
Inventor 友平裕三山口恭生
Owner OTSUKA PHARM CO LTD
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