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HK1121667B - Method of producing drug-containing wax matrix particles, extruder to be used in the method and sustained-release preparation containing cilostazol - Google Patents

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

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Publication number
HK1121667B
HK1121667B HK09101650.0A HK09101650A HK1121667B HK 1121667 B HK1121667 B HK 1121667B HK 09101650 A HK09101650 A HK 09101650A HK 1121667 B HK1121667 B HK 1121667B
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HK
Hong Kong
Prior art keywords
sustained
wax
extruder
drug
cilostazol
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HK09101650.0A
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Chinese (zh)
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HK1121667A1 (en
Inventor
裕三 友平
恭生 山口
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大塚制药株式会社
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Application filed by 大塚制药株式会社 filed Critical 大塚制药株式会社
Priority claimed from PCT/JP2006/325501 external-priority patent/WO2007072908A1/en
Publication of HK1121667A1 publication Critical patent/HK1121667A1/en
Publication of HK1121667B publication Critical patent/HK1121667B/en

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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

Method for producing drug-containing wax matrix particles, extruder used for the method, and sustained-release preparation containing cilostazol
Technical Field
The present invention relates to a method for producing wax-based particles containing a drug. In addition, the invention relates to an extruder (extruder) for the manufacture of wax matrix particles containing a drug.
The invention also relates to a sustained-release preparation containing cilostazol. More specifically, the present invention relates to a sustained-release preparation which comprises wax matrix particles containing cilostazol, has a small difference in cilostazol release or blood concentration change between fasting administration and post-feeding administration, and has an excellent sustained-release property.
Background
As oral sustained-release preparations, single-unit forms such as tablets and multiple-unit forms such as granules are known, and a multiple-unit form preparation having small individual differences in drug release in vivo and in blood concentration distribution is desired. In addition, as sustained release preparations, hydrophilic hydrogel preparations using water-soluble polymers such as Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), and polyethylene oxide (PEO) are suitable, but the above-mentioned hydrophilic hydrogel preparations tend to have a drug release rate susceptible to foods. Further, although the pH-dependent or pH-independent polymer film coating can adjust the solubility of the preparation and is applicable to both tablets and granules, the film coating is not negligibly affected by the difference in acidity in the stomach, and has many problems in terms of the production applicability (coating time, yield, difference between groups) to granules having a small particle size, particularly fine particles having a particle size of 100 μm or less. Further, film-coated preparations of water-insoluble polymers such as Ethyl Cellulose (EC) have a drawback that they are not only hardly applicable to fine particles but also hardly applicable to sustained release of poorly soluble drugs.
It is also known that sustained release can be achieved by using a water-insoluble oleaginous substance as a base matrix, and particles containing the base matrix (hereinafter, also referred to as wax-based particles) are useful as sustained release preparations.
Conventionally, granular formulations having a wax matrix of 1mm or less to granular or tablet formulations having a size of several mm or more have been known, and as a method for producing the same, a melting method, a spraying method, a hot melt spraying method, a kneading extrusion method, and the like can be used. Among the above conventional methods, as a method for producing wax matrix particles having an average particle diameter of 1mm or less, there is known a method (a heating-melting spray method) in which a low-melting substance is heated and melted at a temperature of not less than the melting point, a drug and other additives are added and mixed, and then the mixture is spray-cooled using a large spray cooler (see patent document 1). This hot melt spraying method is suitable for forming spherical matrix particles, but has the following disadvantages: (1) large equipment for spray cooling is necessary; (2) a device for uniformly mixing the raw materials in the heating melting storage tank is required; (3) it is necessary to perform temperature control and the like for piping, pumps and the like required for connecting the storage tank and the spray cooling device. Further, in mass production by the hot melt spray method, a large amount of raw materials must be heated, and the raw materials are inevitably exposed to high temperatures for a long time, so that stability of the drug or additive may be deteriorated by heat. Further, the thermal melt spraying method has the following drawbacks: when the drug dissolved in the molten mixture is likely to precipitate, the drug precipitates and solidifies on the surface of the molten mixture in the tank, or on the surface of the tank wall where the liquid is poured, or on the surface of the tank wall where the liquid is sprayed, such as a liquid transfer tube, a rotary disk, or a nozzle.
Further, patent document 2 discloses a method for producing wax matrix particles using a multi-screw extruder. In the method of patent document 2, the temperature of the discharge from the die (die) is controlled to be not higher than the melting point of the wax (preferably, a low temperature lower than the melting point by 10 to 20 ℃), the discharge is cut into pellets by a high-speed cutter while being cooled and solidified, and then the pellets are pulverized by a roll granulator or the like to obtain wax matrix particles having an average particle diameter of not more than 1 mm. However, even if this method can form the raw material into a matrix form by only one step using a multi-screw extruder, there is a drawback that it is necessary to separately perform a pulverization treatment in order to form particles of 1mm or less, and spherical particles cannot be obtained by the pulverization treatment.
Further, as a method for producing a wax base preparation using an extruder, the following methods are known: a method of cutting the discharge from the extruder with a high-speed cutter to form a circular shape (for example, see patent document 3); a method of forming the discharge from an extruder into a lobed tablet (for example, see patent document 4); a method in which the discharge from the extruder is pulverized by a mill and further cut by a high-speed cutter while cooling with water or air (see, for example, non-patent document 1). However, the method using an extruder has a drawback that, in the same manner as the method of patent document 1, it is necessary to separately perform a pulverization treatment in order to obtain wax matrix particles having an average particle diameter of 1mm or less, and in addition, there is a problem that the shape is not uniform and spherical particles cannot be obtained. Further, a method of melt-mixing raw materials using a twin-screw extruder and conveying the mixture to an atomizer by a pump to spray the mixture has been disclosed (see patent document 5). However, this method requires a pump to perform infusion, and has a drawback that a liquid blockage or the like occurs at the connection portion of the tube due to crystallization of the molten drug, which increases the burden of maintenance of the device and reduces the manufacturing efficiency.
In view of the above-mentioned prior art, it is highly desirable to establish a method capable of producing drug-containing wax matrix particles, particularly drug-containing wax matrix particles having an average particle diameter of 1mm or less, by a simple method without causing liquid clogging due to recrystallization of the molten drug in the steps from melting to spraying.
In addition, the conventional drug-containing wax matrix particles have not only the above-mentioned problems in terms of production but also the drawback of limitation in the drug to be blended, and therefore, have a limited range of clinical applications. Specifically, the present situation is limited to drugs such as theophylline having a high solubility of about 0.6 w/v% in water, since it is important that the wax matrix particles are completely released and absorbed within a limited time period of movement in the digestive tract. Further, it is considered that the wax matrix particles are rapidly disintegrated by digestion in the digestive tract, and thus the difference between the drug release and the change in blood concentration between the fasting administration and the administration after eating is increased. Although the above-mentioned drawbacks can be eliminated by strictly setting the administration time of the preparation, it is necessary for the patient to follow the administration time of the preparation by himself or herself, and it is desired to eliminate the above-mentioned drawbacks from the viewpoint of the preparation characteristics.
On the other hand, cilostazol, which is a poorly soluble drug, is useful as an antiplatelet drug having a peripheral vasodilating action for treating ulcers based on chronic arterial occlusion or improving ischemic symptoms such as acute pain and cold. Patent document 6 discloses a technique for preparing cilostazol as a sustained release preparation, but no technique for preparing cilostazol as a wax matrix particle has been reported. In addition, in order to effectively exhibit a desired drug effect, it is important to release cilostazol in the lower part of the digestive tract, and therefore it is considered effective to contain cilostazol having a particle size of several μm in a sustained release preparation.
Therefore, there is a strong demand for the development of a wax matrix particle comprising cilostazol which has a small difference in cilostazol release or blood concentration change between the fasting administration and the after-meal administration and has an excellent sustained release property.
Patent document 1: patent specification No. 2973751
Patent document 2: patent specification No. 2616252
Patent document 3: japanese unexamined patent publication Hei 10-57450
Patent document 4: japanese patent application laid-open No. Hei 10-511289
Patent document 5: japanese unexamined patent application publication No. 2005-162733
Patent document 6: japanese laid-open patent publication No. 2001-163769
Non-patent document 1: pharmaceutical Extrusion Technology, edited by isaacghibre-sellsie, Charles Martin, DRUGS AND THEPHARMACEUTICAL SCIENCE VOL.133, MARCEL DEKKER, INC, 2003, Chapter 9pages 171-181
Disclosure of Invention
The purpose of the present invention is to provide a method for easily producing drug-containing wax matrix particles, particularly drug-containing wax matrix particles having an average particle diameter of 1mm or less, wherein liquid clogging due to recrystallization of a molten drug does not occur in the steps from melting to spraying. It is another object of the present invention to provide an apparatus for easily producing wax-based particles containing a drug. Further, another object of the present invention is to provide a sustained-release preparation which comprises wax matrix particles containing cilostazol, has a small difference in cilostazol release or blood concentration change between the fasting administration and the after-meal administration, and has an excellent sustained-release property.
The present inventors have made intensive studies to solve the above problems and found that a drug-containing wax matrix in the form of particles can be produced by using an extruder directly equipped with a nozzle capable of discharging a raw material by spraying. That is, the drug and the wax are supplied to the extruder, the temperature of the barrel and the die is set to a temperature equal to or higher than the melting point of the wax, the drug and the wax are sprayed into the air from a nozzle attached to a die portion provided at the tip of the barrel of the extruder while being melted and kneaded, and the drug and the wax are cooled and solidified in the air, whereby a drug-containing wax matrix in a particle form can be produced.
Furthermore, the present inventors have found that a combination of a preparation containing (a) cilostazol crystals and (B) a fatty acid glyceride and/or a polyglycerol fatty acid ester and containing wax matrix particles having an average particle size of 40 to 200 μm has excellent sustained-release cilostazol properties, and that the difference in cilostazol release or blood concentration change between fasting administration and post-ingestion administration is reduced. The present invention has been completed based on the above findings by further repeating improvements.
That is, the present invention provides the following inventions:
item 1 is a method for producing drug-containing wax matrix particles containing at least 1 drug and at least 1 wax, comprising the steps of,
step (i): supplying the at least 1 drug and the at least 1 wax to an extruder, wherein the temperature of a roller and a die in the extruder is set to a temperature higher than the melting point of the wax, and
step (ii): the mixture of the drug and the wax is formed into a particle shape by spraying the mixture into an atmosphere having a temperature lower than the melting point of the wax from a nozzle directly attached to a die portion provided at the tip of the extruder barrel while melt-kneading the drug and the wax in the extruder.
Item 2 is the production method according to item 1, wherein the nozzle is a single-fluid nozzle, a pressurized nozzle, a two-fluid nozzle, or a multi-fluid nozzle.
Item 3 is the production method according to item 1, wherein the extruder is a single-screw extruder, a twin-screw extruder, or a multi-screw extruder having three or more screws.
The production process according to item 4 or 1, wherein the drug-containing wax matrix particles are spherical.
The production method according to item 5 or 4, wherein the average particle diameter of the drug-containing wax matrix particles is 1mm or less.
Item 6 is the production method according to item 1, wherein the drug is at least 1 selected from the group consisting of theophylline, cilostazol, ketoprofen, naproxen, diclofenac, itraconazole, piroxicam, phenytoin, verapamil, probucol, and tolvaptan.
The production method according to item 7 or 1, wherein the wax is at least 1 selected from the group consisting of paraffin wax, microcrystalline wax, ozokerite, japan wax, cacao butter, carnauba wax, beeswax, cetyl alcohol, stearyl alcohol, myristic acid, palmitic acid, stearic acid, fatty acid glyceride, polyglycerin fatty acid ester, glycerin organic acid fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, and hardened oil.
The production method according to item 8 or 1, wherein the drug-containing wax matrix particles contain 0.001 to 90 wt% of the drug and 0.1 to 99.99 wt% of the wax based on the total amount of the particles.
The process according to item 9 or 1, wherein the drug is cilostazol (A), the wax is fatty acid glyceride and/or polyglycerin fatty acid ester (B), and the average particle size of the drug-containing wax matrix particles is 40 to 200. mu.m.
The production method according to item 10 or 9, further comprising a step (iii): (iii) subjecting the particles obtained in the step (ii) to a heat treatment at a temperature of 40 to 55 ℃.
The production method according to item 11 or 10, wherein the step (iii) is a step of attaching an inert powder to the surface of the particles obtained in the step (ii) and then performing a heat treatment at a temperature of 40 to 55 ℃.
Item 12 is an extruder for producing wax matrix particles containing a drug, comprising:
a drum equipped with a temperature control device;
a supply port for supplying at least 1 kind of medicine and at least 1 kind of wax into the drum;
an outlet die section provided on the drum;
an extrusion screw disposed within the barrel for preparing a melt-mixed mixture of the drug and wax and delivering the mixture to the outlet die section;
and a nozzle directly mounted on the outlet die section for spraying the mixture of the melt-kneaded drug and the wax.
The extruder according to item 13 or 12 for producing wax matrix particles containing a drug, further comprising a particle-forming cavity for solidifying the melt-kneaded mixture of the drug and the wax sprayed from the nozzle to form particles.
The sustained-release preparation according to item 14 is characterized by comprising particles containing (A) cilostazol crystals and (B) a fatty acid glyceride and/or a polyglycerol fatty acid ester, wherein the average particle diameter of the particles is 40 to 200 μm.
The sustained-release preparation of item 15 or 14, wherein the cilostazol crystals (A) have an average particle size of 10 μm or less.
The sustained-release preparation according to item 16 or 14, wherein the sustained-release preparation contains 5 to 60 wt% (a) of the cilostazol crystal and 30 to 95 wt% (B) of the fatty acid glyceride and/or the polyglycerol fatty acid ester, based on the total amount of the particles in the sustained-release preparation.
The sustained-release preparation of item 17 or 14, wherein the sustained-release preparation further comprises a water-soluble cellulose derivative.
The sustained-release preparation of item 18 or 17, wherein the water-soluble cellulose derivative is hydroxypropylmethyl cellulose.
The sustained-release preparation according to item 19 or 17, wherein the total amount of the water-soluble cellulose derivative is 1 to 15% by weight based on the total amount of the sustained-release preparation.
The sustained-release preparation according to item 20 or 18, wherein the hydroxypropyl methylcellulose is contained in an amount of 1 to 15% by weight based on the total amount of the sustained-release preparation.
The sustained-release preparation of item 21 or 14, wherein the particles containing the components (A) and (B) are particles obtained by solidifying a molten mixture of the components (A) and (B).
The sustained-release formulation of item 22 to item 14, wherein an inert powder is attached to the surface of the particles.
Item 23 the sustained-release preparation of item 22, wherein the inert powder is at least 1 selected from the group consisting of talc, light silica, titanium oxide, and cellulose-based polymers.
Item 24 is the sustained-release preparation according to item 14, wherein the component (B) is at least 1 selected from the group consisting of glyceryl stearate, polyglyceryl stearate, glyceryl behenate, and polyglyceryl behenate.
The sustained-release preparation of item 25 or 14, wherein the component (B) is at least 1 selected from the group consisting of glyceryl behenate, diglyceryl stearate, and triglycerol hemibehenate.
The sustained-release preparation according to item 26 or 14, which is produced by the following steps (i) and (ii):
step (i): supplying cilostazol (A) and fatty acid glyceride and/or polyglycerin fatty acid ester (B) to an extruder, wherein the temperature of a drum and a die is set to a temperature not lower than the melting point of component (B), and
step (ii): the mixture of the components (a) and (B) melt-kneaded is sprayed and discharged from a nozzle directly attached to a die section provided at the tip of the extruder barrel into an atmosphere having a temperature lower than the melting point of the component (B) while melt-kneading the components (a) and (B) in the extruder, thereby forming the mixture into a particulate form.
Item 27 and the sustained-release preparation of item 26, wherein in the step (i), a water-soluble cellulose derivative (C) is supplied in addition to the components (A) and (B).
The sustained-release preparation according to item 28 or 26, wherein the sustained-release preparation is further produced by subjecting the particles obtained in the step (ii) to a heat treatment at a temperature of 40 to 55 ℃.
The sustained-release preparation according to item 29 or 26, further comprising a step of attaching an inert powder to the surface of the particles obtained in the step (ii) before the heat treatment in the step (iii).
According to the production method and extruder of the present invention, drug-containing wax matrix particles, particularly drug-containing wax matrix particles having an average particle diameter of 1mm or less can be produced without causing clogging of an infusion tube (conduit) or the like due to recrystallization of a molten drug. Further, according to the production method and extruder of the present invention, the drug-containing wax matrix particles can be easily produced by only one step without requiring a step such as pulverization treatment, and therefore, the method and extruder are highly useful from the industrial point of view.
The essential structure of the particles (wax matrix particles) contained in the sustained-release preparation of the present invention is: (1) comprises cilostazol crystals (preferably having an average crystal particle diameter of 10 μm or less), (2) a fatty acid glyceride and/or a polyglycerin fatty acid ester as a wax base, and (3) a wax base is molded into a particle form having an average particle diameter of 40 to 200 μm. By adopting the above structure, the sustained-release preparation of the present invention provides poorly soluble cilostazol of excellent sustained-release properties, and the difference between cilostazol release or blood concentration change between fasting administration and administration after eating is reduced. Therefore, the sustained-release preparation of the present invention can exhibit the pharmacological effects of cilostazol more effectively and is useful as a pharmaceutical preparation.
In addition, the sustained-release preparation of the present invention further contains a water-soluble cellulose derivative, particularly hydroxypropylmethylcellulose, and therefore, it can ensure sustained-release property and has high bioavailability, and therefore, it is extremely useful in clinical practice.
Detailed Description
In the present invention, the drug-containing wax matrix refers to a wax matrix in which a drug is dissolved or dispersed and embedded in a wax which is a continuous phase. In the present invention, the term "sustained release preparation" refers to a preparation which exhibits sustained release of a drug contained therein by oral administration. The present invention will be described in detail below.
1. Method for producing drug-containing wax-based particles
Extruding machine
The manufacturing method of the present invention is carried out using an extruder in which a nozzle is attached to an outlet die portion provided at the front end of a drum.
The embodiment of the extruder (extruder for producing wax matrix particles containing a drug) preferably used in the production method of the present invention will be specifically described.
The extruder was equipped with a temperature control device on the cylinder (cylinder). The temperature control device can heat the wax supplied into the drum to a temperature higher than the melting point. In addition, the temperature control device preferably further has a cooling function. By having the cooling function as described above, the temperature of the raw material in the drum can be controlled more appropriately. Specific examples of the temperature control device include a roller shell that can be heated and/or cooled.
In the barrel of the extruder, a supply port for supplying a raw material is provided on the upstream side thereof, and an outlet die portion for discharging a raw material (melt-kneaded raw material) that has been melt-kneaded is provided on the downstream side thereof.
In the barrel of the extruder, an extrusion screw is disposed for preparing a melt-kneaded raw material from a raw material fed from a supply port and conveying the melt-kneaded raw material to the outlet die section. The number of the extrusion screws is not particularly limited, and may be any of a single screw type, a twin screw type, or a multi-screw type of three or more screws, and a twin screw type is preferable.
The shape of the screw is not particularly limited as long as the screw can prepare a melt-kneaded material from a raw material fed from a supply port and convey the melt-kneaded material. Examples thereof include a conveying screw, a kneading screw, a mixing screw, and a combination thereof.
The extruder is provided with a nozzle at the outlet die part, and the nozzle is configured to spray and discharge the molten kneaded material, which is fed to the outlet die part via the screw, to the outside.
The spray discharge mode of the nozzle is not particularly limited, and may be any of a pressurized nozzle, a two-fluid nozzle, or a multi-fluid nozzle of two or more fluids. The shape of the discharge hole of the nozzle is not limited as long as the molten kneaded material can be discharged by spraying, but a circular shape is a preferred example. When the discharge hole is circular, the inner diameter thereof is, for example, 0.1 to 20mm, preferably 0.2 to 15mm, and more preferably 0.2 to 10 mm.
The extruder is preferably provided with a heating device for heating the spray gas (air used for spraying) supplied to the nozzle.
Further, the extruder is preferably provided with a particle-forming chamber for solidifying the molten kneaded material sprayed from the nozzle to form particles. The particle-forming chamber is not particularly limited as long as it is configured to discharge the molten kneaded material from the discharge hole portion of the nozzle into the particle-forming chamber, and, for example, the particle-forming chamber is configured such that the discharge hole portion of the nozzle is incorporated into the particle-forming chamber. The particle-forming chamber is not particularly limited as long as the molten and kneaded raw materials can be solidified in the chamber to form particles. For example, the particle-forming chamber may have a structure in which the molten kneaded material is sprayed from a nozzle into the atmosphere in the chamber. In addition, a liquid such as liquid nitrogen may be held in the chamber, and the temperature in the chamber may be controlled by the liquid. Further, the cavity for particle formation is provided with a wax matrix particle recovery section for recovering the wax matrix particles formed in the cavity. In addition, the particle-forming chamber is preferably provided with a temperature control device for controlling the temperature of the ambient gas of the molten and kneaded material sprayed into the chamber, and further preferably provided with an exhaust device for exhausting the spray gas introduced into the chamber. In order to recover the wax matrix particles remaining in the exhaust gas, a recovery unit for recovering the wax matrix particles in the exhaust gas may be disposed in the exhaust device.
One preferred embodiment of the extruder is described below with reference to the drawings.
In the extruder shown in FIG. 1, 4 temperature-controllable barrel jackets 1a (numbered 1a-1, 1a-2, 1a-3, and 1a-4 from the upstream side) were provided as temperature control devices on the barrel 1. Further, the drum 1 is provided with a supply port 2 for supplying a raw material on the upstream side and an outlet die portion 3 on the downstream side. A screw 4 is disposed in the barrel 1 for conveying the raw material fed from the supply port 2 to the outlet die section 3 while melting and kneading the raw material. The screw 4 is configured to be driven by a motor 4 a. Further, a nozzle 5 is attached to the outlet die section 3, and the nozzle 5 is provided with a heating device 5a for heating the spray gas and a discharge hole 5b for discharging the molten kneaded material.
Fig. 2 shows an example of an extruder equipped with a particle-forming chamber 6, and the particle-forming chamber 6 is configured such that a molten kneaded material is sprayed from a nozzle into an atmosphere. In fig. 2, for convenience, the sizes of the extruder and the particle forming chamber 6 are shown in a ratio different from the actual ratio. In the extruder of fig. 2, a particle-forming chamber 6 is provided, and a discharge hole 5b of a nozzle 5 is partially assembled therein. In the bottom of the particle-forming chamber 6, a wax-based particle collecting section 6a is provided for collecting wax-based particles that have fallen by gravity and accumulated on the bottom. Further, an exhaust device 7 is provided in the particle forming chamber 6 on the opposite side of the discharge hole 5b of the nozzle 5, and the mist gas introduced into the chamber can be exhausted. Next, the exhaust device 7 is provided with an exhaust fan 7a and a recovery part 7b for recovering the wax matrix particles in the exhaust gas, so that the wax matrix particles remaining in the exhaust gas can be recovered while the gas in the particle formation chamber 6 is exhausted.
Supply of raw materials and melt kneading
In the method of the present invention, a predetermined amount of raw materials is supplied to an extruder, and the raw materials are melt-kneaded. The raw material to be fed to the extruder is a component to be blended in the produced drug-containing wax matrix particles, and specific examples thereof include at least 1 type of drug and at least 1 type of wax. The drug-containing wax matrix particles produced in the present invention may contain other additives in addition to the drug and the wax, and when the additives are contained as described above, the additives are supplied to the extruder together with the drug and the wax as raw materials.
The temperatures of the cylinder and the die at the time of melt-kneading by the extruder are set to a temperature not lower than the melting point of the wax to be blended, preferably 5 to 200 ℃ higher than the melting point of the wax to be blended, and more preferably 10 to 200 ℃ higher than the melting point of the wax to be blended. The set temperature is within a range that does not affect the stability of the drug, wax, and other additives to be added. The set temperature of the drum is set so that the temperature gradually increases from the upstream side (raw material supply port side) to the downstream side (outlet die side), and preferably reaches the temperature at the end of the downstream side.
The residence time of the supplied raw material in the barrel, the rotational speed of the screw, the supply speed of the raw material, and the like can be appropriately set, and the melt-kneaded raw material is formed in the outlet die section of the extruder.
Spray discharge of melt-kneaded product and formation of particles
While melting and kneading the raw materials (the drug, the wax, and the additives added as needed) under the above conditions, the melted and kneaded raw materials are sprayed from a nozzle attached to a die section of the extruder into an atmosphere having a temperature lower than the melting point of the wax and discharged. The discharge rate of the melt-kneaded raw material from the nozzle when it is discharged by spraying into the above-mentioned temperature atmosphere gas is appropriately determined in consideration of the particle diameter of the finally obtained drug-containing wax matrix particles, the viscosity of the melt-kneaded raw material, and the like, and further in accordance with the shape of the nozzle, the hole diameter of the nozzle discharge hole, the amount of air of the spray gas in the case of a two-fluid or higher multi-fluid nozzle, and the like.
Specifically, the discharge rate of the melt-kneaded material from the extruder is usually 0.1 to 1000 kg/hr, preferably 0.5 to 700 kg/hr, and more preferably 1 to 400 kg/hr per 1 discharge hole of the die. By adopting the above discharge rate, drug-containing wax matrix particles having the following particle size range can be produced. When the amount of the spray gas and the nozzle hole diameter are the same, the particle diameter tends to increase as the discharge speed increases, and the particle diameter tends to decrease as the discharge speed decreases. In addition, when the atomizing gas is not used, the particle size tends to be smaller as the discharge rate is higher, and the particle size tends to be larger as the discharge rate is lower.
The temperature of the spray gas used when the molten kneaded material is discharged and sprayed is not particularly limited. For example, when the nozzle is a multi-fluid nozzle of two or more fluids, the temperature of the spray gas is preferably about-10 to +300 ℃ of the melting point of the wax to be mixed, more preferably about-10 to +250 ℃ of the melting point of the wax to be mixed, and still more preferably about ± 0 to +200 ℃ of the melting point of the wax.
The raw materials are discharged under the above conditions into an atmosphere having a temperature lower than the melting point of the wax, and the mixture is cooled in the atmosphere to form spherical particles. The temperature of the atmosphere for discharging the melt-kneaded raw material may be a temperature at which the melt-kneaded raw material is solidified, as long as it is lower than the melting point of the wax, and examples thereof include-196 to 50 ℃, preferably-196 to 40 ℃. The ambient gas at the above temperature may be prepared by a commonly used temperature control device, and may be a gaseous ambient gas produced by using liquid nitrogen. In a preferred embodiment, the molten kneaded material is sprayed and discharged in an atmosphere of a gas lower than the melting point of the wax.
Under the above conditions, the melt-kneaded raw material is discharged into an atmosphere having a temperature lower than the melting point of the wax, and the melt-kneaded raw material is cooled, thereby producing drug-containing wax matrix particles having a predetermined particle size. According to the production method of the present invention, drug-containing wax matrix particles having an average particle diameter of 1.5mm or less, preferably 0.01 to 1.5mm, more preferably 0.02 to 1.0mm, and still more preferably 0.03 to 0.9mm can be produced. In the production method of the present invention, the average particle diameter of the drug-containing wax matrix particles can be appropriately adjusted by appropriately controlling the kind and the blending amount of the raw materials used, the discharge rate of the melt-kneaded raw materials, the amount of the spray air, and the like. The average particle diameter referred to herein is a 50% cumulative diameter, that is, a particle diameter at 50% by volume integrated from 0 μm in a particle size distribution chart, and is a value measured by a particle size distribution measuring instrument using a laser diffraction/scattering method.
When spherical drug-containing wax matrix particles having an average particle diameter in the above-mentioned range are produced by the conventional technique, there is a problem that the molten drug is recrystallized in the inside of the tube, the tube connection part or the atomizer part, and a trouble such as clogging of the tube occurs. The production method of the present invention can solve the above-mentioned problems of the prior art, and is therefore useful as a method for producing spherical drug-containing wax matrix particles having an average particle diameter in the above-mentioned range.
Formation of drug crystals in wax matrix particles
When the drug in the wax matrix particles is not completely crystallized, the drug can have stable release control characteristics by the crystallization of the drug.
Therefore, the drug crystals having a desired crystal particle size can be precipitated in the wax matrix particles by storing the drug-containing wax matrix particles obtained as described above at room temperature or by heat treatment. From the viewpoint of crystallizing out the desired drug in a short time, it is preferable to perform a heat treatment.
Before the heat treatment, a predetermined amount of the inert powder is preferably attached to the surface of the drug-containing wax matrix particles. By attaching the inert powder as described above, aggregation between the wax matrix particles can be prevented, and the production efficiency can be improved. The inert powder is simply mixed with the wax matrix particles to adhere the particles to each other.
The heat treatment conditions are not particularly limited, and are usually at a temperature of room temperature or higher and the melting point of the wax or lower, preferably 40 to 55 ℃, and more preferably 45 to 54 ℃. The heating time varies depending on the heating temperature and the like, and may be usually 1 minute to 24 hours, preferably 5 minutes to 20 hours, and more preferably 10 minutes to 15 hours.
When the drug is cilostazol, it is particularly effective to form crystals of the drug in the above wax matrix particles.
Medicine
The drug used in the production method of the present invention is not particularly limited as long as it is a pharmaceutically acceptable drug and exhibits a pharmacologically active action, and may be any of water-soluble, fat-soluble, and water-insoluble. Examples of the drug include angiotensin 2 receptor Antagonists (ARBs), gastrointestinal drugs, nutritional agents, nutritional oils, opioid analgesics, calcium (Ca) antagonists, remedies for overactive bladder, keratolytics, cardiotonics, muscle relaxants, anti-malignant tumor drugs, antiviral drugs, anti-inflammatory drugs, antibacterial drugs, antianginal drugs, anthelmintics, antidepressants, schizophrenia-treating drugs, antiepileptics, antiarrhythmics, analgesics, antifungal drugs, anticoagulants, antidiabetics, antigout drugs, antihypertensive drugs, antidiarrheal drugs, antimalarials, antimigraine drugs, antimuscarinics, antiparkinsonian drugs, antihistamines, antiobesity drugs, anxiolytics, antiarrhythmics, anti-benign prostatic hypertrophy drugs, stimulants, osteoporosis-treating drugs, steroids, CCR5 receptor antagonists (HIV invasion inhibitors), Lipid regulators, anticonvulsants, erectile dysfunction improving agents, immunosuppressive agents, antiprotozoal agents, antithyroid agents, Cox-2 inhibitors, hypnotic agents, muscle relaxants, sex hormones, sedatives, recognition enhancers (recognition enhancers), dysuria improving agents, beta blockers, essential fatty acids, non-essential fatty acids, protease inhibitors, macrolide antibiotics, diuretics, leukotriene antagonists, and the like. In the present invention, 1 kind of drug may be used alone, or 2 or more kinds may be used in combination arbitrarily.
Specific examples of the drug used in the present invention include Avermectin A (acetretin), albendazole, salbutamol, aminoglutethimide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, beclomethasone, benazepril, benzonatate, betamethasone, bicalutamide, budesonide, bupropion, busulfan, butenafine, calcifediol, calcipotriol, calcitriol, camptothecin, candesartan, capsaicin, carbamazepine, carotene, celecoxib, simvastatin, cetirizine, chlorpheniramine, vitamin D3Cilostazol, cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithromycin, clemastine, clomiphene, clomipramine, clopidogrel, codeine, coenzyme Q10Aminophenoheptene, cyclosporin, danazol, damren, dexchlorpheniramine (dexchlorpheniramine), diclofenac, dicumarol, digoxin, prasterone, dihydroergotamine, dihydrotachysterol, dirithromycin, donepezil, efavirenz, eprosartan, vitamin D2Ergotamine, essential fatty acid supply source, etodolac, etoposide, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, fluconazole, flurbiprofen, fluvastatin, fosphenytoin, fuwhatRotigotine, furazolidone, gabapentin, gemfibrozil, glyburide, glipizide, glyburide, glimepiride, griseofulvin, fluroxyphenanthrol, ibuprofen, irbesartan, irinotecan, isosorbide dinitrate, isotretinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lansoprazole, leflunomide, lisinopril, loperamide, loratadine, lovastatin, L-thyroxine, lutein, lycopene, medroxyprogesterone, mifepristone, mefloquine, megestrol, methadone, methoxsalen, metronidazole, miconazole, midazolam, miglitol, minodill, mitoxantrone, montelukast, naproxen, nalbuphine, nelfinavir, nifedipine, nisoldipine, nilutamide (nilutanide), nitrofurantoin, nizatidine, omeprazole, oxepirekinins (opirox), Estradiol, oxaprozin, paclitaxel, paracasenol, paroxetine, methacetin, pioglitazone, phentolin, pravastatin, prednisolone, probucol, progesterone, pseudoephedrine, pirstine, rabeprazole, raloxifene, rofecoxiexine, repaglinide, rifabutin, rifapentine, rimexolone, ritonavir, rizatriptan, rosiglitazone, saquinavir, sertraline, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tasocicin, besartan (targretin), talzostatin, telmisartan, teniposide, terbinafine, terazosin, tetrahydrocannabinol, tiagardine, tiagabine, tipiranib, piriramate, irinotecan, and other drugs, Tretinoin, troglitazone, trovafloxacin, ubidecarenone, valsartan, venlafaxine, verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolpidem, zopiclone, acarbose, acyclovir, acetylcysteine, chloroacetylcholine, alafloxacin, alendronate, acesulfame, amantadine hydrochloride, amberlotin, amifostine hydrochloride, amiloride hydrochloride, aminocaproic acid, amphotericin B, aprotinin B, fluvastatin, dexamethosine, valtrexone, valsartan, and the likeEnzymes, asparaginase, atenolol, antomorphan, atropine, azithromycin, aztreonam, BCG bacillus calmette-guerin, bacitracin, becaplamine, belladonna, bepridil hydrochloride, bleomycin sulfate, human calcitonin, salmon calcitonin, carboplatin, capecitabine, capreomycin sulfate, cefamandole sodium, cefazolin sodium, cefepime (cefepime dihydrate) hydrochloride, cefixime, cefonicid sodium, cefoperazone, cefotetan disodium, cefotaxime, cefoxitin sodium, ceftizoxime, ceftriaxone, cefuroxime axetil, cephalexin, cefpirome sodium, cholera bacterin, cidula, cisplatin, cladribine, bromcridine, clindamycin and clindamycin derivatives, ciprofloxacin, clodronate disodium, polymyxin E mesylate, polymyxin E sulfate, corticotropin, tetracalcifermoment sodium, cromolyn-degrading, Cytarabine, dalteparin sodium, danaparoc, deferoxamine, dinil interleukin 2, desmopressin, diatrizoate sodium, bicyclovine, didanosine, dirithromycin, dopamine hydrochloride, deoxyribonuclease alpha, doxorammonium chloride, doxorubicin, etidronate disodium, enalaprilat, enkephalin, enoxacin, enoxaparin sodium, ephedrine, epinephrine, erythromycin, esmolol hydrochloride, famciclovir, fludarabine, fluoxetine, foscarnet sodium (foscarnet sodium), ganciclovir, gentamycin, glucagon, glycopyrrolate, homonarrelin, indolovir sulfate, influenza virus vaccine (influeza virus vaccines), ipratropium bromide, ifosfamide, lamivudine, leucovorin calcium, leuprolide acetate, levofloxacin, lincomycin and lincomycin derivatives, lotbrazivir, lotoxin derivatives, lomicrivir, roxacin, Loracarbef, meperidine bromide, mesalazine, urotropin, methotrexate, scopolamine methoate, metformin hydrochloride, metoprolol, mezlocillin sodium, micraconium chloride, nedocromil sodium, neostigmine bromide, neostigmine methosulfate, gabapentin, norfloxacin, octreotide acetate, ofloxacin, sodium olpadronate (olpadronate), oxytocin, disodium pamidronate, pancuronium bromide, paroxetine, mefloxacin, pentamidine (pentamidine isethionate), pentostatin, hexanoneTheobromine, penciclovir, pentagastrin, phentolamine mesylate, phenylalanine, physostigmine salicylate, plague vaccine, piperacillin sodium, polymyxin B sulfate, chlorphosphodine, pramlintide, pregabalin, propafenone, bromamine, pirfenimin bromide, rabies vaccine, risedronate sodium, ribavirin, rimantadine hydrochloride, salmeterol xinafoate, octyl carfate, sotalol (solatol), growth hormone release inhibitor, sparfloxacin, spectinomycin, stavudine, streptokinase, streptozotocin, succinylcholine chloride, tacrine hydrochloride, terbutaline sulfate, thiotepa, ticarcillin, sodium tiludronate, timolol, trandol, trimetrexate (trimetrexate), tolperistomycin (troxetin), troxifloxacin chloride, trevafloxacin chloride, urokinase, trexate, urokinase, urocanine, urokinase, uroclein, bromhexedrine, bromelargyrne, bromhexine, doxorubine, troxib, Vancomycin, valacyclovir, valsartan, vasopressin and vasopressin derivatives, vecuronium bromide, vinblastine, vincristine, vinorelbine, vitamin B12Warfarin sodium, zalcitabine, zanamivir, sotitanium (zoledronate), zidovudine, theophylline, gepasfloxacin, carteolol, procaterol, rebamipide, aripiprazole, tolvaptan, paracetamol, ketoprofen, naproxen, piroxicam, phenytoin, verapamil, pharmaceutically acceptable salts thereof, isomers thereof, derivatives thereof, and the like. In the present invention, 1 kind of the above-mentioned drugs may be used alone, or 2 or more kinds may be used in combination arbitrarily.
Since the wax matrix particles containing the drug can have a sustained-release property, the drug used in the present invention is preferably a drug which must have a sustained-release property. From the above viewpoint, preferable examples of the drug used in the present invention include theophylline, cilostazol, ketoprofen, naproxen, diclofenac, itraconazole, piroxicam, phenytoin, verapamil, probucol, and tolvaptan; more preferred examples include theophylline, cilostazol, probucol and tolvaptan.
In the present invention, even for a drug in which crystallization is likely to occur in a state where the base component (wax) is melted, the drug-containing wax matrix particles can be produced without causing crystallization of the drug. In view of the above-mentioned effects of the present invention, one preferable example of the drug used in the present invention is a drug in which a crystal is easily precipitated in a state where the base component (wax) is melted (for example, a drug having a melting point of about 100 to 200 ℃). Specific examples of the above-mentioned drugs include cilostazol.
The concentration of the drug in the drug-containing wax matrix particles to be produced varies depending on the kind and effect of the drug to be used, sex and age of the subject to be administered, and the like, and examples thereof include 0.001 to 90% by weight, preferably 0.05 to 95% by weight, and more preferably 0.1 to 90% by weight, based on the total amount of the wax matrix particles.
Wax
The wax (wax matrix base material) used in the production method of the present invention is not particularly limited as long as it is a pharmaceutically acceptable wax and is a wax that is solid at room temperature (30 ℃), and may be any of animal-derived, plant-derived, synthetic, or semi-synthetic wax having a melting point of 40 to 120 ℃, preferably 40 to 90 ℃. The melting point was measured according to "14 th edition Japanese pharmacopoeia general test method 14. freezing point measurement method".
Specific examples of the wax include paraffin wax, microcrystalline wax, ozokerite, japan wax, cacao butter, carnauba wax, beeswax, cetyl alcohol, stearyl alcohol, myristic acid, palmitic acid, stearic acid, fatty acid glyceride, polyglycerin fatty acid ester, glycerin organic acid fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, and hardened oil.
The fatty acid glyceride is a monoester, diester, or triester of glycerol and various fatty acids. Examples of the fatty acid constituting the fatty acid glyceride include C6-C22 fatty acids. Examples of the fatty acid include stearic acid, behenic acid, palmitic acid, oleic acid, linoleic acid, linolenic acid, myristic acid, lauric acid, ricinoleic acid, caprylic acid, and capric acid. Specific examples of the fatty acid glyceride include glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl monobehenate, glyceryl dibehenate, glyceryl tribehenate, glyceryl monostearate and the like.
The polyglycerin fatty acid ester is an ester in which 1 or more fatty acids are bonded to a polyglycerin obtained by polymerizing 2 or more glycerols. The polyglycerin fatty acid ester includes a polyglycerin full fatty acid ester in which fatty acids form ester bonds with all hydroxyl groups of polyglycerin, and a polyglycerin half fatty acid ester in which fatty acids form ester bonds with about half of the hydroxyl groups of polyglycerin. The polyglycerin half fatty acid ester is specifically an average value (N) of the number of esterified hydroxyl groups of polyglycerinE) About half of the total number of hydroxyl groups (N) of the unesterified polyglycerin itself or a mixture thereof, and for example, 0.3. ltoreq.NE0.7, preferably 0.35. ltoreq.NEA compound having a/N value in the range of 0.65 or less. For example, triglycerol hemibehenate refers to a compound in which behenic acid forms 2 or 3 ester bonds with triglycerol having 5 hydroxyl groups formed by dehydration condensation of 3 molecules of glycerol, or a mixture thereof, that is, triglycerol behenate (di-or tri-) ester.
The fatty acids constituting the polyglycerin fatty acid ester include C6-C22 fatty acids, and specific examples thereof are the same as those constituting the fatty acid glyceride described above. Specific examples of the polyglycerin fatty acid ester include diglycerin-mono or distearate; diglycerol-mono or dipalmitate; diglycerol-mono or dilaurate; diglycerol-mono or dioleate; diglycerol-mono or dilinoleate; diglycerol-mono or dicaprylate; diglycerol-mono or behenate; triglycerol-mono-, di-, tri-, tetra-, or pentastearate; triglycerol-mono-, di-, tri-, tetra-, or pentapalmitate; triglycerol-mono-, di-, tri-, tetra-or pentalaurate; triglycerol-mono-, di-, tri-, tetra-, or pentaoleate; triglycerol-mono-, di-, tri-, tetra-, or penta-linoleate; triglycerol-mono-, di-, tri-, tetra-or pentaoctanoates; triglycerol-mono-, di-, tri-, tetra-or pentabehenate; tetraglycerol-mono-, di-, tri-, tetra-, penta-, or hexastearate; tetraglycerol-mono, di, tri, tetra, penta or hexapalmitate; tetraglycerol-mono, di, tri, tetra, penta or hexalaurate; tetraglycerol-mono-, di-, tri-, tetra-, penta-, or hexaoleate; tetraglycerol-mono, di, tri, tetra, penta or hexalinoleate; tetraglycerol-mono-, di-, tri-, tetra-, penta-, or hexaoctanoate; tetraglycerol-mono-, di-, tri-, tetra-, penta-, or hexabehenate; pentaglycerol-mono-, di-, tri-, tetra-, penta-, or hexastearate; pentaglycerol-mono-, di-, tri-, tetra-, penta-, or hexastearate; pentaglycerol-mono, di, tri, tetra, penta or hexapalmitate; pentaglycerol-mono, di, tri, tetra, penta or hexalaurate; pentaglycerol-mono, di, tri, tetra, penta or hexaoleate; pentaglycerol-mono, di, tri, tetra, penta or hexalinoleate; pentaglycerol-mono-, di-, tri-, tetra-, penta-, or hexacaprylate; pentaglycerol-mono-, di-, tri-, tetra-, penta-, or hexabehenate; hexaglycerol-mono, di, tri, tetra, penta, hexa or heptastearate; hexaglycerol-mono, di, tri, tetra, penta, hexa or heptapalmitate; hexaglycerol-mono, di, tri, tetra, penta, hexa or heptalaurate; hexaglycerol-mono, di, tri, tetra, penta, hexa or heptaoleate; hexaglycerol-mono, di, tri, tetra, penta, hexa or heptalinoleate; hexaglycerol-mono, di, tri, tetra, penta, hexa or heptacaprylate; hexaglycerol-mono, di, tri, tetra, penta, hexa or heptabehenate; heptaglycerol-mono-, di-, tri-, tetra-, penta-, hexa-, hepta-or octastearate; heptaglycerol-mono, di, tri, tetra, penta, hexa, hepta or octapalmitate; heptaglycerol-mono, di, tri, tetra, penta, hexa, hepta or octalaurate; heptaglycerol-mono-, di-, tri-, tetra-, penta-, hexa-, hepta-or octaoleate; heptaglycerol-mono, di, tri, tetra, penta, hexa, hepta or octalinoleate; heptaglycerol-mono-, di-, tri-, tetra-, penta-, hexa-, hepta-or octa-octanoate; heptaglycerol-mono-, di-, tri-, tetra-, penta-, hexa-, hepta-or octabehenate; decaglycerol-mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, or undecanoate; decaglycerol-mono, di, tri, tetra, penta, hexa, hepta, octa, nona, deca or undecaprate; decaglycerol-mono, di, tri, tetra, penta, hexa, hepta, octa, nona, deca or undecanoate; decaglycerol-mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, or undecanoate; decaglycerol-mono, di, tri, tetra, penta, hexa, hepta, octa, nona, deca or undecalate; decaglycerol-mono, di, tri, tetra, penta, hexa, hepta, octa, nona, deca or undecalate; decaglycerol-mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, or undecamate, and the like. In addition to the above, a polyglycerin fatty acid ester comprising an ester of a polyglycerin and 2 or more fatty acids selected from stearic acid, behenic acid, palmitic acid, oleic acid, linoleic acid, linolenic acid, myristic acid, lauric acid, ricinoleic acid, caprylic acid and capric acid is also included.
The glycerin organic acid fatty acid ester is an ester in which an organic acid and a fatty acid are bonded to glycerin. The fatty acids constituting the organic acid fatty acid esters of glycerin include C6 to C22 fatty acids, and specific examples thereof are the same as those constituting the fatty acid glycerides described above. Specific examples of the glycerin organic acid fatty acid ester include glycerin citric acid fatty acid ester, glycerin acetic acid fatty acid ester, glycerin lactic acid fatty acid ester, glycerin succinic acid fatty acid ester, glycerin fumaric acid fatty acid ester, glycerin tartaric acid fatty acid ester, glycerin diacetyl tartaric acid fatty acid ester, polyglycerin citric acid fatty acid ester, polyglycerin acetic acid fatty acid ester, polyglycerin lactic acid fatty acid ester, polyglycerin succinic acid fatty acid ester, polyglycerin fumaric acid fatty acid ester, polyglycerin tartaric acid fatty acid ester, and polyglycerin diacetyl tartaric acid fatty acid ester.
Examples of the fatty acid constituting the sorbitan fatty acid ester include C6 to C22 fatty acids, and specific examples thereof are the same as those of the fatty acid glyceride constituting the above-mentioned fatty acid ester. Specific examples of the sorbitan fatty acid ester include sorbitan laurate, sorbitan palmitate, sorbitan oleate, and sorbitan stearate.
The fatty acid constituting the propylene glycol ester of fatty acid includes C6-C22 fatty acids, and specific examples thereof are the same as those of the fatty acid constituting the fatty acid glyceride. Specific examples of the propylene glycol fatty acid ester include propylene glycol myristate, propylene glycol stearate, propylene glycol laurate, propylene glycol oleate, and propylene glycol decanoate. In addition to the above, propylene glycol fatty acid esters in which 2 or more fatty acids are bonded in combination may be mentioned.
Specific examples of the hardened oil include castor oil, cottonseed oil, soybean oil, rapeseed oil, and beef tallow.
Among the waxes, preferred are fatty acid glycerides and polyglycerin fatty acid esters.
The wax may be used alone in 1 kind, or may be used in combination of 2 or more kinds.
The concentration of the wax in the drug-containing wax matrix particles to be produced is, for example, 0.1 to 99.99% by weight, preferably 0.5 to 99% by weight, and more preferably 1 to 90% by weight, based on the total amount of the wax matrix particles.
Optional compounding ingredients (additives)
In the production method of the present invention, a suitable amount of a surfactant may be added as a raw material in addition to the above-mentioned drug and wax. Examples of the surfactant include alkyl glucosides, alkyl maltosides, alkyl thioglycosides, glycerol laurel glycol (lauryl macrogol glycerides), polyoxyethylene alkyl ethers, polyoxyethylene alkylphenols, polyethylene glycol fatty acid esters, glycerol polyethylene glycol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene polyoxypropylene alkyl ethers, polyoxyethylene-polyoxypropylene block copolymers, polyoxyethylene glycerol esters, polyoxyethylene sterols (polyethylene sterols), derivatives thereof, polyoxyethylene vegetable oils, polyoxyethylene solidified vegetable oils, Tocopherol Polyethylene Glycol Succinate (TPGS), sugar esters, sugar ethers, sucrose glycerides (sucroglycerides), esters of lower alcohols (C2 to C4) and fatty acids (C8 to C18).
More specific examples of the surfactant include polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, and polyoxyethylene behenyl ether; polyethylene glycol fatty acid esters such as polyethylene glycol laurate, polyethylene glycol stearate, polyethylene glycol oleate, polyethylene glycol palmitate, and polyethylene glycol-fatty acid mono-and diester mixtures; polyethylene glycol fatty acid glycerides such as polyethylene glycol glyceryl laurate, polyethylene glycol glyceryl stearate, and polyethylene glycol glyceryl oleate; polyoxyethylene sterols such as polyoxyethylene phytosterol ester, polyoxyethylene cholesteryl ester, and polyoxyethylene cholestanol ester, and derivatives thereof; polyethylene glycol sorbitan fatty acid esters such as polyethylene glycol sorbitan laurate, polyethylene glycol sorbitan oleate, and polyethylene glycol sorbitan palmitate; polyoxyethylene polyoxypropylene alkyl ethers such as polyoxyethylene polyoxypropylene cetyl ether and polyoxyethylene polyoxypropylene decyltetradecyl ether; polyoxyethylene-polyoxypropylene block copolymers such as POLOXAMERs 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 334, 335, 338, 401, 402, 403, 407, etc., Pluronic (registered trademark) series (BASF), Emkalyx, Lutrol (BASE), supranic, Monolan, pluracane, and Plurodac; sugar esters such as sucrose-mono or di-stearate, sucrose-mono or di-palmitate, sucrose-mono or di-laurate; and esters of lower alcohols (C2-C4) such as ethyl oleate, isopropyl myristate, isopropyl palmitate, ethyl linolenate, and isopropyl linolenate, and fatty acids (C8-C18).
In the production method of the present invention, a suitable amount of a polymer substance such as a water-soluble polymer, a water-insoluble polymer, an enteric polymer, or a gastric polymer that can be melted or dispersed in a wax that is melt-kneaded may be blended in the raw material. Specific examples of the polymer substance include hydroxycellulose, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, ethylcellulose, cellulose acetate, polyvinylpyrrolidone, hydroxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylcellulose sodium, hydroxyethylcellulose, cyclodextrin, a cyclodextrin derivative, an aminoalkyl methacrylate copolymer E, an alkyl methacrylate copolymer RS, a methacrylate copolymer L, a methacrylate copolymer S, carbopol (carbopol polymer), polyvinylacetal diethylamine acetate (polyvinylacetal diethylamine acetate), polyvinyl alcohol, sodium alginate, propylene glycol alginate, gelatin, shellac, and the like.
In addition to the above, examples of additives that can be blended as raw materials include inert powders, ion exchange resins, solubilizers, plasticizers, diluents, sweeteners, lubricants, excipients or fillers, enzyme inhibitors, anti-caking agents, anti-coagulating agents, antifoaming agents, binders, pH adjusters or buffers, chelating agents, coagulants, absorption promoters, binders, flavor-reducing agents, flavors, preservatives, antioxidants, anti-freezing agents, colorants, opacifying agents, coolants, solvents, thickeners, and disintegrating agents. Specific examples of the additives include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactic acid esters of fatty acids, stearyl-2-lactic acid ester (stearyl-2-lactate), stearyl lactate (stearyl lactate), succinic acid monoglyceride (succinylated monoglyceride), mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholic acid, taurocholic acid, glycocholic acid, deoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, phosphatidylethanolamine, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, lysophosphatidylserine, lysophosphatidylethanolamine, lyso, Taurochenodeoxycholic acid, ursodeoxycholic acid, N-methyltaurocholic acid, caproic acid, caprylic acid, capric acid, lauric acid, oleic acid, ricinoleic acid, linoleic acid, linolenic acid, dodecyl sulfate, tetradecyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, sodium caproate, sodium caprylate, sodium laurate, sodium myristate, sodium myristoleate, sodium palmitate, sodium oleate, sodium ricinoleate, sodium linoleate, sodium linolenate, sodium stearate, sodium lauryl sulfate, sodium tetradecyl sulfate, sodium lauryl sarcosinate, sodium Dioctylsulfosuccinate (DOSS), sodium bile acid, sodium cholate, sodium taurocholate, sodium glycolate, sodium deoxycholate, sodium taurodeoxycholate, dodecyl sulfate, glycodeoxycholate, N-methyltaurocholic, caproic acid, caprylic acid, Glycodeoxycholate sodium, ursodeoxycholate sodium, chenodeoxycholate sodium, cardiolipin, polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 600, polyethylene glycol 10000, polyethylene glycol 6000, lactose, white sugar, mannitol, sodium chloride, glucose, calcium carbonate, kaolin, crystalline cellulose, cellulose-based polymers, light silica, silicates, water, ethanol, simple syrup, glucose solution, starch solution, gelatin solution, dextrin, pullulan (pullulan), citric acid, citric anhydride, sodium citrate dihydrate, anhydrous sodium phosphate, anhydrous sodium dihydrogen phosphate, sodium hydrogen phosphate, polysorbate 80, quaternary ammonium salt group, sodium lauryl sulfate, refined talc, stearate, polyethylene glycol, colloidal silicic acid, yellow iron oxide, yellow iron trioxide, beta carotene, titanium oxide, sodium phosphate, sodium alginate, sodium, Food coloring (e.g., food blue No. 1), copper chlorophyll, riboflavin, ascorbic acid, aspartame, hydrangea dulcis folium (hydrangeae dulcis folium), sodium chloride, fructose, saccharin, and powdered sugar.
The optional compounding ingredients may be compounded by supplying the above-mentioned drugs and waxes as raw materials into an extruder, or may be compounded by mixing the above-mentioned components with the formed wax matrix particles.
Wax matrix particles containing a drug
The drug-containing wax base particles produced by the production method of the present invention are used as pharmaceutical preparations. The preparation can be in the form of powder or granule containing wax matrix particles of the medicine, or can be filled into microcapsule, soft capsule, hard capsule, etc. to form capsule.
2. Sustained-release preparation containing cilostazol
Further, the present invention provides a sustained-release preparation comprising the wax matrix particles containing cilostazol. The cilostazol-containing wax base particles contained in the sustained-release preparation can be produced by the above-mentioned production method easily, or by other production methods, and the production method thereof is not particularly limited.
The sustained-release preparation of the present invention contains cilostazol crystals (hereinafter, may be simply referred to as component (a)) as a drug. The average particle size of the cilostazol crystals is not particularly limited, and may be 10 μm or less, preferably 0.1 to 10 μm, and more preferably 0.5 to 8 μm. When cilostazol is a crystal satisfying the above average particle size, it is possible to more stably perform slow release and absorption of cilostazol in the lower part of the digestive tract where water is small.
The crystals of cilostazol having the above average particle size can be produced by allowing the wax matrix particles in which cilostazol is completely dissolved to stand at normal temperature, but the crystals can be produced more rapidly than in the case of standing at normal temperature by subjecting the wax matrix particles in which cilostazol is completely dissolved to a predetermined heat treatment. Specifically, the cilostazol crystals having the above average particle size can be produced in the wax matrix particles by mixing the following component (B) and cilostazol in predetermined amounts, heating the mixture to solidify the resulting molten mixture into particles, and then heating the mixture at a temperature higher than room temperature and lower than the melting point of the component (B), preferably at 40 to 55 ℃, more preferably at 45 to 54 ℃. The heat treatment time is not particularly limited, and is usually 1 minute to 24 hours, preferably 5 minutes to 20 hours, and more preferably 10 minutes to 15 hours.
The average particle diameter of the cilostazol crystal is measured by observation with a polarization microscope. Specifically, measurement was performed by presenting a straight edge having a predetermined size in a visual field of a polarization microscope and observing the size of the crystal.
In the sustained-release preparation of the present invention, the concentration of the component (a) varies depending on the use of the preparation, sex, age of a subject to be administered, and the like, and is, for example, 5 to 60% by weight, preferably 10 to 50% by weight, and more preferably 20 to 45% by weight based on the total amount of the wax matrix particles contained in the preparation.
The sustained-release preparation of the present invention may further contain, in addition to the component (a), a fatty acid glyceride and/or a polyglycerol fatty acid ester (hereinafter, also simply referred to as the component (B)) as a wax (wax matrix base).
The same fatty acid glycerides and polyglycerin fatty acid esters as described above are used.
The component (B) may be used alone in 1 kind, or may be used in combination of 2 or more kinds.
Among the above-mentioned components (B), from the viewpoint of further improving the sustained release property and further reducing the influence of food intake on the release rate of cilostazol, glyceryl behenate, diglyceryl stearate, triglyceryl behenate, triglyceryl hemistearate, and decaglyceryl monostearate are preferable, and glyceryl behenate, diglyceryl stearate, and triglyceryl hemibehenate are more preferable.
In the sustained-release preparation of the present invention, the blending ratio of the components (a) and (B) is not particularly limited, and it is usually 50 to 2000 parts by weight, preferably 70 to 1000 parts by weight, and more preferably 100 to 500 parts by weight of the component (B) per 100 parts by weight of the component (a). By satisfying the above ratio, the sustained release of cilostazol can be more effectively improved, and the release characteristics are less susceptible to the influence of food intake.
In the sustained-release preparation of the present invention, the concentration of the component (B) may be appropriately set according to the blending ratio of the components (a) and (B) and the blending amount of the component (a), and examples thereof include 30 to 95% by weight, preferably 40 to 90% by weight, and more preferably 50 to 80% by weight, based on the total amount of the wax matrix particles contained in the preparation.
The wax matrix particles contained in the sustained-release preparation of the present invention may contain, in addition to the components (a) and (B), (C) a water-soluble cellulose derivative (water-soluble cellulose ether) such as hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, cellulose acetate, polyvinylpyrrolidone, hydroxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose phthalate, or the like. Among them, hydroxypropyl cellulose or hydroxypropyl methylcellulose is preferable, and hydroxypropyl methylcellulose is more preferable. The water-soluble cellulose derivatives can be used alone in 1, or can be combined with 2 or more. By further compounding a water-soluble cellulose derivative as described above, it is possible to ensure sustained release and to achieve high bioavailability. In the sustained-release preparation of the present invention, when the water-soluble cellulose derivative is blended, the amount of the water-soluble cellulose derivative blended is, for example, 1 to 15% by weight, preferably 2 to 12% by weight, and more preferably 2 to 10% by weight, based on the total amount of the wax matrix particles contained in the preparation.
In addition, an appropriate amount of a surfactant may be further blended in the sustained-release preparation of the present invention. The surfactant that can be blended is the same as that in the above item "1. method for producing wax matrix particles containing a drug".
Further, other water-soluble polymers, water-insoluble polymers, enteric polymers, gastric polymers, and other high-molecular substances may be blended in an appropriate amount in the sustained-release preparation of the present invention. The specific examples of the polymer substance are also the same as those in the item "1. method for producing drug-containing wax matrix particles".
In addition to the above-mentioned substances, an inert powder, an ion exchange resin, a solubilizing agent, a plasticizer, a diluent, a sweetener, a lubricant, an excipient or filler, an enzyme inhibitor, an anti-caking agent, an anti-coagulating agent, an antifoaming agent, a binder, a pH adjuster or buffer, a chelating agent, a coagulant, an absorption enhancer, a flavor desensitizer, a flavoring agent, a preservative, an antioxidant, an anti-freezing agent, a coloring agent, an opacifying agent, a coolant, a solvent, a thickener, a disintegrant, and the like may be blended in an appropriate amount in the sustained-release preparation of the present invention. The specific examples of the additives are the same as those in the item "1. method for producing wax matrix particles containing a drug" described above.
The compounding ingredients other than the components (a) and (B) may be contained in the wax matrix particles together with the components (a) and (B), or may be mixed with the wax matrix particles containing the components (a) and (B).
For example, inert powder having no chemical or biological activity in the additive may be contained in a form of being adhered to coat the surface of the wax matrix particles containing the components (a) and (B). The coating of the surfaces of the wax matrix particles with the inert powder described above can function to suppress aggregation between the particles during the heat treatment for crystallizing cilostazol.
Specifically, examples of the inert powder include talc; light silica; titanium oxide; cellulose polymers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, and ethyl cellulose; saccharides such as fructose, saccharin, and powdered sugar. The inert powder can be used alone in 1, in addition to arbitrary combination of 2 or more. The average particle diameter of the inert powder is not particularly limited, but is preferably 10 μm or less, and more preferably 7 to 10 μm. The average particle diameter of the inert powder can be measured by a method generally used for measuring the particle diameter of the powder.
The amount of the inert powder to be deposited is not particularly limited, and examples thereof include an amount of 0.5 to 15 parts by weight, preferably 1 to 10 parts by weight, and more preferably 2 to 10 parts by weight, based on 100 parts by weight of the wax matrix particles containing the components (a) and (B).
The particles contained in the sustained-release preparation of the present invention are preferably particles produced by mixing the above-mentioned component (a), component (B), and other components added as needed in predetermined amounts, heating to obtain a molten mixture, and adjusting the particle size to a predetermined size to solidify the mixture. The particles contained in the sustained-release preparation of the present invention are preferably the above-mentioned component (a), component (B), and if necessary, other components, and examples thereof include particles produced by the method described in the above-mentioned "method for producing drug-containing wax matrix particles" section 1.
The wax matrix particles contained in the sustained-release preparation of the present invention have an average particle diameter of 40 to 200 μm. Preferably 50 to 150 μm, and more preferably 60 to 130 μm. By having the above average particle diameter and containing the components (a) and (B) in combination, a desired sustained release of cilostazol can be achieved and the influence of eating on the release characteristics of cilostazol can be reduced. The average particle diameter referred to herein is a 50% cumulative diameter, that is, a particle diameter at 50% by volume integrated from 0 μm in a particle size distribution chart, and is a value measured by a particle size distribution measuring instrument using a laser diffraction/scattering method.
The wax matrix particles contained in the sustained-release preparation of the present invention have excellent sustained-release properties by having the components (a) and (B) and having the average particle diameter. The sustained release property itself of the particles contained in the sustained release preparation of the present invention is not particularly limited, and for example, when an amount of particles corresponding to 15mg of cilostazol is added to the dissolution test 2 nd method (paddle method) of japanese pharmacopoeia 14 th edition, the dissolution rate after 2 hours is preferably 20% to 35%, the dissolution rate after 6 hours is 40% to 60%, the dissolution rate after 12 hours is 60% to 80%, and the dissolution rate after 18 hours is 60% to 90%, more preferably the dissolution rate after 2 hours is 25% to 35%, the dissolution rate after 6 hours is 45% to 60%, the dissolution rate after 12 hours is 60% to 80%, and the dissolution rate after 18 hours is 65% to 90%.
The sustained-release preparation of the present invention may be in the form of powder or granules containing the wax base particles of the components (a) and (B) as such, or may be in the form of capsules filled in microcapsules, soft capsules, hard capsules, or the like.
The dose of the sustained-release preparation of the present invention can be appropriately set according to the intended medical use, the age or sex of the patient, and the like.
Examples
The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.
Example 1
Using an extruder having the structure shown in fig. 2, wax-based particles were produced. As the extruder, the structure and the operation conditions thereof are as follows.
Extruder type: twin-screw extruder (KEX-25, chestnut iron works)
Screw shape: the shape of the conveying, kneading and mixing parts connected in sequence from the downstream side to the upstream side
A nozzle: two-fluid nozzle
Length of screw part: about 50cm
Rotation speed of screw: 125rpm
Shape and pore diameter of discharge hole of nozzle: a circular shape,0.5mm
Residence time of raw material in drum: about 2 minutes
Set temperature of drum temperature: the roller sleeve 1a-1 is 140 deg.C, the roller sleeve 1a-2 is 150 deg.C, the roller sleeves 1a-3 and 1a-4 are 160 deg.C
Temperature and introduction rate of the mist gas: about 200 ℃ and 25L/min
Discharge rate per 1 discharge hole of the molten kneaded material: 50g/min
Ambient gas in the particle-forming chamber: air, about 30 ℃.
Specifically, 300g of theophylline and 700g of fatty acid glyceride (glyceryl monobehenate; melting point about 75 ℃ C.) were mixed. The wax matrix particles were produced by the extruder having the above-described configuration and conditions while feeding the obtained mixed raw material into the supply port of the extruder at a speed of about 50g/min, and the wax matrix particles were recovered from the wax matrix particle recovery unit of the particle-forming chamber.
The result of observing the obtained wax matrix particles under a microscope is shown in FIG. 3. The obtained wax matrix particles were in the form of spheres, and when the particle size distribution was measured by a laser diffraction particle size distribution analyzer (Tohnichi computer Applications), the 10% cumulative diameter was 37 μm, the 50% cumulative diameter (average particle diameter) was 84 μm, the 90% cumulative diameter was 165 μm, and the 99% cumulative diameter was 219 μm.
In addition, it was confirmed that no troubles such as theophylline precipitation and liquid clogging occurred in the extruder during the production process. In addition, the theophylline content of the resulting wax matrix particles was about 100% relative to theoretical.
Example 2
As raw materials, 300g of theophylline, 10g of ethylcellulose and 690g of fatty acid glyceride (glyceryl monobehenate; melting point about 75 ℃) were mixed, and using the mixed raw materials, wax matrix particles were produced under the same conditions as in example 1 above.
The obtained wax matrix particles were spherical and when the particle size distribution was measured by a laser diffraction particle size distribution meter (applied to Dongri computer), the 10% cumulative diameter was 43 μm, the 50% cumulative diameter (average particle diameter) was 88 μm, the 90% cumulative diameter was 160 μm, and the 99% cumulative diameter was 204 μm.
In addition, it was confirmed that no troubles such as theophylline precipitation and liquid clogging occurred in the extruder during the production process. In addition, the theophylline content of the resulting wax matrix particles was about 100% relative to theoretical.
Example 3
300g of theophylline and 700g of a hardened oil (melting point: about 86 ℃) were mixed as raw materials, and wax matrix particles were produced using the mixed raw materials under the same conditions as in example 1. The obtained wax matrix particles were spherical, and when the particle size distribution was measured by a laser diffraction particle size distribution analyzer (applied to Dongri computer), the 10% cumulative diameter was 48 μm, the 50% cumulative diameter (average particle diameter) was 96 μm, the 90% cumulative diameter was 169 μm, and the 99% cumulative diameter was 221 μm.
In addition, it was confirmed that no troubles such as theophylline precipitation and liquid clogging occurred in the extruder during the production process. In addition, the theophylline content of the resulting wax matrix particles was about 100% relative to theoretical.
Example 4
As raw materials, 1350g of cilostazol, 1710g of diglycerin monostearate (poem J-2081, product of Suiyu vitamin Co., Ltd.), 990g of pentaglycerol monostearate (Sunsoft A-181E, product of Suiyo chemical Co., Ltd.), and 450g of polyvinylpyrrolidone (Kollidon25, Povidone, product of BASF Co., Ltd.) were mixed, and using the obtained mixed raw materials, wax matrix particles were produced under the same conditions as in example 1.
The wax matrix particles obtained were spherical and had a 50% cumulative diameter (average particle diameter) of about 90 μm as measured by a laser diffraction particle size distribution analyzer (applied to Dongri computer). In addition, it was confirmed that problems such as the precipitation of cilostazol or the clogging of liquid in the extruder did not occur in the production process. In addition, the content of cilostazol in the obtained wax matrix particles was 100%.
Example 5
Using an extruder having the structure shown in fig. 2, wax-based particles were produced. As an extruder, the structure and the operating conditions thereof are as follows:
extruder type: twin-screw extruder (KEX-25, chestnut iron works)
Screw shape: the shape of the conveying, kneading and mixing parts connected in sequence from the downstream side to the upstream side
A nozzle: two-fluid nozzle
Length of screw part: about 50cm
Screw rotation speed: 130rpm
Shape and pore diameter of nozzle discharge hole: a circular shape,0.5mm
Residence time of raw material in drum: about 2 minutes
Set temperature of drum temperature: the roller sleeve 1a-1 is 140 deg.C, the roller sleeve 1a-2 is 160 deg.C, the roller sleeve 1a-3 is 165 deg.C, and the roller sleeve 1a-4 is 160 deg.C
Temperature and introduction rate of the mist gas: about 200 ℃ and 25L/min
Discharge rate per 1 discharge hole of the molten kneaded material: 50g/min
Ambient gas in the particle-forming chamber: air, about 30 ℃.
Specifically, 240g of cilostazol of an average particle size of about 20 μm, 348g of diglycerol monostearate (poemJ-2081, physical grinding vitamins) and 12g of triglycerol hemibehenate (TR-HB, physical grinding vitamins) were mixed. The wax matrix particles were produced by the extruder having the above-described configuration and conditions while the obtained mixed raw material was fed into the supply port of the extruder at a rate of about 50g/min, and the wax matrix particles were recovered from the wax matrix particle recovery unit of the particle-forming chamber.
The resulting matrix particles had strong adhesion, but the fluidity was improved by adding and mixing 14.8g of talc, and the mixture passed through a sieve having a mesh size of 355 μm. Then, the whole-sized matrix particles were heat-treated at 50 ℃ for 16 hours.
When the obtained wax matrix particles were observed with an optical microscope, it was confirmed that cilostazol crystals having a particle size of 10 μm or less were formed. The wax matrix particles obtained were spherical and had an average particle diameter (50% cumulative diameter) of 92 μm as measured by a laser diffraction particle size distribution meter (applied to a Toray computer). In addition, it was confirmed that problems such as the precipitation of cilostazol or the clogging of liquid in the extruder did not occur in the production process.
Example 6
As raw materials, 240g of cilostazol having an average particle size of about 20 μm, 336g of diglycerol monostearate (poem J-2081, physically milled vitamin) and 24g of triglycerol hemibehenate (TR-HB, physically milled vitamin) were mixed, and using the obtained mixed raw materials, wax base particles were produced under the same conditions as in example 1.
When the obtained wax matrix particles were observed with an optical microscope, it was confirmed that cilostazol crystals having a particle size of 10 μm or less were formed, and the wax matrix particles were spherical and had an average particle size (50% cumulative diameter) of 93 μm as measured by a laser diffraction particle size distribution analyzer (applied to east-day computer). In addition, it was confirmed that problems such as the precipitation of cilostazol or the clogging of liquid in the extruder did not occur in the production process.
Example 7
As raw materials, 240g of cilostazol having an average particle size of about 20 μm, 324g of diglycerin monostearate (poem J-2081, physically milled vitamin) and 36g of triglycerol hemibehenate (TR-HB, physically milled vitamin) were mixed, and using the obtained mixed raw materials, wax base particles were produced under the same conditions as in example 5.
The obtained wax matrix particles were observed with an optical microscope to confirm that cilostazol crystals having a particle size of 10 μm or less were formed, and the wax matrix particles were spherical and the average particle size (50% cumulative diameter) thereof was 91 μm as measured by a laser diffraction particle size distribution meter (east-day computer). In addition, it was confirmed that problems such as the precipitation of cilostazol or the clogging of liquid in the extruder did not occur in the production process.
Example 8
As raw materials, 240g of cilostazol having an average particle size of about 20 μm, 234g of diglycerol monostearate (poem J-2081, physical research vitamin), 24g of triglycerol hemibehenate (TR-HB, physical research vitamin), and 102g of glycerol behenate (poem B-100, physical research vitamin) were mixed, and using the obtained mixed raw materials, wax matrix particles were produced under the same conditions as in example 5 above.
The obtained wax matrix particles were observed with an optical microscope to confirm that crystals of cilostazol of not more than 10 μm were formed, and the wax matrix particles were spherical and had an average particle diameter (50% cumulative diameter) of 79 μm as measured by a laser diffraction particle size distribution meter (applied to east-day computer). In addition, it was confirmed that problems such as the precipitation of cilostazol or the clogging of liquid in the extruder did not occur in the production process.
Example 9
240g of cilostazol of an average particle size of about 20 μm, 222g of diglycerin monostearate (poem J-2081V, physical research vitamin), 24g of triglycerol hemibehenate (TR-HB, physical research vitamin), 96g of glyceryl behenate (poem B-100, physical research vitamin), and 18g of hydroxypropylmethylcellulose (TC-5E, shin-Etsu chemical) were mixed. Using the obtained mixed raw materials, wax-based particles were produced under the same conditions as in example 5. Wherein the roller temperature 1a-1 is 120 deg.C, 1a-2 is 185 deg.C, 1a-3 is 185 deg.C, and 1a-4 is 185 deg.C; spraying gas at 200 deg.C and 50L/min; the discharge rate of the molten mixture per 1 discharge hole was 118 g/min. 12.6g of talc was added to 314g of the resulting pellets, mixed, and heat-treated at 50 ℃ for 16 hours. Then, the granules were granulated with a sieve having a mesh size of 350. mu.m.
When the obtained wax matrix particles were observed by an optical microscope, it was confirmed that there was no cilostazol crystal having a particle diameter of more than 10 μm. The wax matrix particles obtained were spherical and had an average particle diameter (50% cumulative diameter) of about 77 μm as measured by a laser diffraction particle size distribution meter (applied to Dongri computer). In addition, it was confirmed that no problems such as the precipitation of cilostazol or the clogging of a liquid in the extruder occurred in the production process.
Example 10
240g of cilostazol of an average particle size of about 20 μm, 210g of diglycerin monostearate (poem J-2081V, physical research vitamin), 24g of triglycerol hemibehenate (TR-HB, physical research vitamin), 90g of glyceryl behenate (poem B-100, physical research vitamin), and 36g of hydroxypropylmethylcellulose (TC-5E, shin-Etsu chemical) were mixed. Using the obtained mixed raw materials, wax-based particles were produced under the same conditions as in example 5. Wherein the roller temperature 1a-1 is 120 deg.C, 1a-2 is 185 deg.C, 1a-3 is 185 deg.C, and 1a-4 is 185 deg.C; spraying gas at 200 deg.C for 40L/min; the discharge rate of the molten mixture per 1 discharge hole was 175 g/min. To 353g of the resulting pellets were added 14.1g of talc, mixed, and heat-treated at 50 ℃ for 16 hours. Then, the granules were prepared by sieving with a sieve having a mesh size of 350. mu.m.
The obtained wax matrix particles were observed with an optical microscope to confirm that there was no cilostazol crystal having a particle diameter of more than 10 μm. The wax matrix particles obtained were spherical and had an average particle diameter (50% cumulative diameter) of about 104 μm as measured by a laser diffraction particle size distribution meter (applied to Dongri computer). In addition, it was confirmed that no problems such as the precipitation of cilostazol or the clogging of a liquid in the extruder occurred in the production process.
Example 11
240g of cilostazol of an average particle size of about 20 μm, 198g of diglycerin monostearate (poem J-2081V, physical research vitamin), 24g of triglycerol hemibehenate (TR-HB, physical research vitamin), 84g of glyceryl behenate (poem B-100, physical research vitamin), and 54g of hydroxypropylmethylcellulose (TC-5E, shin-Etsu chemical) were mixed. Using the obtained mixed raw materials, wax-based particles were produced under the same conditions as in example 5. Wherein the roller temperature 1a-1 is 120 deg.C, 1a-2 is 185 deg.C, 1a-3 is 185 deg.C, and 1a-4 is 185 deg.C; spraying gas at 200 deg.C and 50L/min; the discharge rate of the molten mixture per 1 discharge hole was 120 g/min. To 267g of the resulting pellets, 10.7g of talc was added, mixed and heat-treated at 50 ℃ for 16 hours. Then, the granules were prepared by sieving with a sieve having a mesh size of 350. mu.m.
When the obtained wax matrix particles were observed by an optical microscope, it was confirmed that there was no cilostazol crystal having a particle diameter of more than 10 μm. The wax matrix particles obtained were spherical and had an average particle diameter (50% cumulative diameter) of about 93 μm as measured by a laser diffraction particle size distribution meter (applied to Dongri computer). In addition, it was confirmed that problems such as the precipitation of cilostazol or the clogging of liquid in the extruder did not occur in the production process.
Example 12
240g of cilostazol of an average particle size of about 20 μm, 222g of diglycerin monostearate (poem J-2081V, physical research vitamin), 24g of triglycerol hemibehenate (TR-HB, physical research vitamin), and 60g of hydroxypropylmethylcellulose (TC-5E, shin-Etsu chemical) were mixed. Using the obtained mixed raw materials, wax-based particles were produced under the same conditions as in example 5. Wherein the roller temperature 1a-1 is 130 deg.C, 1a-2 is 165 deg.C, 1a-3 is 175 deg.C, and 1a-4 is 170 deg.C; spraying gas at 200 deg.C and 50L/min; the discharge rate of the molten mixture was 140g/min per 1 discharge hole. 12.8g of talc was added to 320g of the resulting pellets, mixed, and heat-treated at 50 ℃ for 16 hours. Then, the granules were prepared by sieving with a sieve having a mesh size of 350. mu.m.
When the obtained wax matrix particles were observed by an optical microscope, it was confirmed that there was no cilostazol crystal having a particle diameter of more than 10 μm. The wax matrix particles obtained were spherical and had an average particle diameter (50% cumulative diameter) of about 98 μm as measured by a laser diffraction particle size distribution meter (applied to Dongri computer). In addition, it was confirmed that problems such as the precipitation of cilostazol or the clogging of liquid in the extruder did not occur in the production process.
Example 13
240g of cilostazol of an average particle size of about 20 μm, 228g of diglycerol monostearate (poem J-2081V, physical research vitamin), 48g of triglycerol hemibehenate (TR-HB, physical research vitamin), 60g of glyceryl behenate (poem B-100, physical research vitamin) and 24g of Carbopol (Carbopol 974P) were mixed. Using the obtained mixed raw materials, wax-based particles were produced under the same conditions as in example 5. Wherein the roller temperature 1a-1 is 120 deg.C, 1a-2 is 185 deg.C, 1a-3 is 185 deg.C, and 1a-4 is 185 deg.C; spraying gas at 200 deg.C and 45L/min; the discharge rate of the molten mixture per 1 discharge hole was 128 g/min. To 384g of the resulting particles, 15.4g of talc was added, mixed, and heat-treated at 50 ℃ for 16 hours. Then, the granules were prepared by sieving with a sieve having a mesh size of 350. mu.m.
When the obtained wax matrix particles were observed by an optical microscope, it was confirmed that there was no cilostazol crystal having a particle diameter of more than 10 μm. The wax matrix particles obtained were spherical and had an average particle diameter (50% cumulative diameter) of about 135 μm as measured by a laser diffraction particle size distribution meter (applied to Dongri computer). In addition, it was confirmed that no problems such as the precipitation of cilostazol or the clogging of a liquid in the extruder occurred in the production process.
Example 14
A capsule was prepared by mixing 260g of the wax base particles obtained in example 13 with 1.0g of light silica (Adsolider 101/YKF), and filling 261mg of the mixture into a hard capsule.
Comparative example 1
A transparent melt was prepared by adding 1350g of cilostazol, 1710g of poem J-2081 (diglycerol monostearate, product of Soken vitamin Co., Ltd.), 990g of Sunsoft A-181E (pentaglycerol monostearate, product of Suzuku Kogyo Co., Ltd.), and 450g of Povidone (Kollidon25, polyvinylpyrrolidone, product of BASF Co., Ltd.) to an airtight stirring tank equipped with a jacket and kneading them while heating to 150 ℃. The molten kneaded mixture was transferred from a storage tank to a rotary disk type spray cooler (diameter: 2.5m) by pressurization. Although about 60cm of piping from the storage tank to the tray was heated to about 150 c by the electric heating tape, cilostazol precipitated in the middle of the piping and blocked the piping, and spraying was impossible. From these results, it was found that the method of comparative example 1 cannot produce wax-based particles even when the same raw material components as in example 4 were used.
Comparative example 2
A melt was prepared under the same conditions as in comparative example above using 1000g of cilostazol, 1800g of poem J-2081 (diglycerol monostearate, product of Soxhlet vitamin), 400g of Povidone (Kollidon25, polyvinylpyrrolidone, product of BASF) and 800g of Sunsoft No.621G (glycerol citrate monostearate, product of Suo chemical Co., Ltd.), and the melt was transferred to a spray cooler and granulated by spray cooling with a rotary plate, whereby a small amount of wax matrix particles were obtained. However, cilostazol crystals were precipitated in the immersion liquid surface, the rotary screw portion and the pipe line in the storage tank. In addition, the content of cilostazol in the obtained wax matrix particles was 45% with respect to the theoretical value.
Test example 1Dissolution test
Cilostazol release characteristics were evaluated using the wax matrix particles of examples 5-8. Specifically, an amount of the wax matrix particles equivalent to 15mg of cilostazol (examples 5 to 8) was used, an elution test was carried out using 900mL of a 1 wt% aqueous solution of polysorbate 80 as an elution solution by the paddle method of the 2 nd method of the elution test method of the japanese pharmacopoeia 14 th edition with the number of paddle rotations set to 75rpm, and the amount of cilostazol eluted from the elution solution was measured over time (measurement of both 257nm and 325 nm), whereby the ratio of cilostazol eluted from the wax matrix particles (elution rate) (%) was determined.
The results are shown in FIG. 4. From these results, it is understood that the wax matrix particles of examples 5 to 8 all exhibited preferable dissolution behavior as sustained-release preparations.
Test example 2Evaluation of pharmacokinetics
An amount equivalent to 100mg of cilostazol of the wax base particles of example 6 or 8 was filled in a gelatin capsule, and 3 beagle dogs 1 of this gelatin capsule were orally administered on an empty stomach or after eating, blood was taken over time, and the concentration of cilostazol in blood was measured. In addition, commercially available Pletal tablets (containing cilostazol, crystalline cellulose, corn starch, carboxymethylcellulose calcium, hydroxypropylmethylcellulose, and magnesium stearate equivalent to 100 mg) (immediate release tablets) were orally administered in the same manner, and blood was collected over time to measure the cilostazol concentration in blood. The resulting comparison of the concentration changes in blood is shown in fig. 5, and in addition, the calculated drug dynamics parameters are shown in table 1.
When the immediate release tablet is administered, the difference between Cmax and AUC between fasting administration and after eating is large, and the effect on food is large. On the other hand, when the wax matrix particles of example 6 or 8 were administered, the difference between Cmax and AUC between fasting administration and post-feeding administration was small, and the particles were not easily affected by food.
[ Table 1]
AUCt: area under the time curve of blood concentration (trapezoidal method)
AUC ∞: to the area under the blood concentration time curve in an infinite time
Cmax: maximum blood concentration
Tmax: time to reach maximum blood concentration
MRTt: average residence time
Test example 3Evaluation of pharmacokinetics
The wax base particles of example 10 or 13, which corresponded to 100mg of cilostazol, were filled in a gelatin capsule, and 1 of this gelatin capsules was orally administered to 3 beagle dogs after eating, and blood was collected over time to measure the concentration of cilostazol in blood. The drug kinetics parameters calculated from the resulting blood cilostazol concentrations are shown in table 2.
From these results, it was confirmed that the wax matrix particles of examples 10 and 13 each exhibited particularly excellent dissolution behavior as a sustained release preparation. From these results, it was found that the dissolution state required for sustained-release preparations can be more effectively achieved by blending hydroxypropyl methylcellulose in addition to cilostazol crystals and fatty acid glyceride and/or polyglycerin fatty acid ester.
[ Table 2]
AUCt: area under the time curve of blood concentration (trapezoidal method)
AUC ∞: to the area under the blood concentration time curve in an infinite time
Cmax: maximum blood concentration
Tmax: time to reach maximum blood concentration
MRTt: average residence time
Drawings
FIG. 1 is a side view, partially omitted, showing an example of an extruder for producing wax matrix particles containing a drug.
FIG. 2 is a side view of an example of an extruder for producing drug-containing wax matrix particles in a state having a cavity for forming the particles.
FIG. 3 shows the result of microscopic observation (photomicrograph) of the wax matrix particles obtained in example 1. The stub lengths shown in the figure represent 200 μm.
FIG. 4 shows the elution characteristics of the wax matrix particles (examples 5 to 8) measured in test example 1.
FIG. 5 shows the change with time in the mean blood cilostazol concentration of the wax matrix particles (examples 6 and 8) and the immediate release tablets measured in test example 2.
Description of the symbols
1 roller
2 supply port
3 outlet die part
4 screw rod
5 spray nozzle
6 particle-forming chamber
7 exhaust device
10 wax base particles discharged from the discharge hole 5b of the nozzle

Claims (14)

1. A sustained-release preparation comprising particles containing (A) cilostazol crystals, (B) a fatty acid glyceride and/or polyglycerin fatty acid ester and (C) hydroxypropylmethylcellulose, the particles having an average particle diameter of 40 to 200 μm,
the particle diameter of the cilostazol crystal (A) is 10 μm or less,
the particles are obtained by solidifying the above-mentioned melt mixture of (A) cilostazol crystals, (B) fatty acid glyceride and/or polyglycerin fatty acid ester, and hydroxypropylmethylcellulose by spraying.
2. The sustained-release preparation according to claim 1, wherein the average particle size of the cilostazol crystal (a) is 10 μm or less.
3. The sustained-release preparation according to claim 1 or 2, which comprises 5 to 60% by weight of (A) the crystalline cilostazol and 30 to 95% by weight of (B) the fatty acid glyceride and/or the polyglycerol fatty acid ester, based on the total amount of the particles in the sustained-release preparation.
4. The sustained-release preparation according to claim 1 or 2, wherein the hydroxypropyl methylcellulose is contained in an amount of 1 to 15 wt.% based on the total amount of the sustained-release preparation.
5. The sustained-release preparation according to claim 1 or 2, wherein an inert powder is attached to the surface of the particles.
6. The sustained-release preparation according to claim 5, wherein the inert powder is at least 1 selected from talc, light silica, titanium oxide, and cellulose-based polymers.
7. The sustained-release preparation according to claim 1 or 2, wherein the component (B) is at least 1 selected from the group consisting of glyceryl stearate, polyglyceryl stearate, glyceryl behenate, and polyglyceryl behenate.
8. The sustained-release preparation according to claim 1 or 2, wherein the component (B) is at least 1 selected from the group consisting of glyceryl behenate, diglyceryl stearate, and triglyceryl behenate.
9. The sustained-release preparation according to claim 1 or 2, which is produced by the following steps (i) and (ii),
step (i): supplying cilostazol (A), fatty acid glyceride and/or polyglycerin fatty acid ester (B) and hydroxypropylmethylcellulose (C) to an extruder, wherein the temperatures of a drum and a die in the extruder are set to a temperature not lower than the melting point of the component (B), and
step (ii): the mixture of the components (a) and (B) melt-kneaded is sprayed and discharged from a nozzle directly attached to a die section provided at the tip of the extruder barrel into an atmosphere having a temperature lower than the melting point of the component (B) while melt-kneading the components (a) and (B) in the extruder, thereby forming the mixture into a particulate form.
10. The sustained-release preparation according to claim 9, which is further produced by a step (iii) of heat-treating the particles obtained in the step (ii) at a temperature of 40 to 55 ℃.
11. The sustained-release preparation according to claim 10, further comprising a step (iii) of attaching an inert powder to the surface of the particles obtained in the step (ii) before the heat treatment.
12. A method for producing the sustained-release preparation according to claim 1 or 2, comprising the steps of:
step (i): supplying cilostazol (A), fatty acid glyceride and/or polyglycerin fatty acid ester (B) and hydroxypropylmethylcellulose (C) to an extruder, wherein the temperatures of a drum and a die in the extruder are set to a temperature not lower than the melting point of the component (B), and
step (ii): the mixture of the components (a) and (B) melt-kneaded is sprayed and discharged from a nozzle directly attached to a die section provided at the tip of the extruder barrel into an atmosphere having a temperature lower than the melting point of the component (B) while melt-kneading the components (a) and (B) in the extruder, thereby forming the mixture into a particulate form.
13. The production method according to claim 12, further comprising the step (iii): (iii) subjecting the particles obtained in the step (ii) to a heat treatment at a temperature of 40 to 55 ℃.
14. The production process according to claim 13, wherein the step (iii) is a step of attaching an inert powder to the surface of the particles obtained in the step (ii) and then performing a heat treatment at a temperature of 40 to 55 ℃.
HK09101650.0A 2005-12-22 2006-12-21 Method of producing drug-containing wax matrix particles, extruder to be used in the method and sustained-release preparation containing cilostazol HK1121667B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
JP2005-370927 2005-12-22
JP2005370927 2005-12-22
JP2006156578 2006-06-05
JP2006-156578 2006-06-05
PCT/JP2006/325501 WO2007072908A1 (en) 2005-12-22 2006-12-21 Method of producing drug-containing wax matrix particles, extruder to be used in the method and sustained-release preparation containing cilostazol

Publications (2)

Publication Number Publication Date
HK1121667A1 HK1121667A1 (en) 2009-04-30
HK1121667B true HK1121667B (en) 2015-08-14

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