JPH07114946B2 - Treatment method for sparingly soluble substances - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION a. Field of Industrial Application The present invention uses a high-velocity impact method in which a poorly soluble substance is amorphized or partially amorphous on the surface of various excipient particles. By immobilizing in the state of solidification, and / or by immobilizing the substance in the form of fine particles, the surface area of the substance particles is expanded, and composite particles excellent in dispersibility / solubility are produced. The present invention relates to a method for treating a poorly soluble substance by promoting a dissolution rate.

b. Conventional Technology Hereinafter, an example of a poorly soluble substance will be described as an example of a poorly soluble substance.

Conventionally, various methods have been attempted to increase the dissolution rate for the purpose of improving the bioavailability of poorly soluble drugs.

It is a method of pulverizing the sparingly soluble drug with an impact-type pulverizer such as a hammer mill, a bin mill, and an anomizer to about several hundreds to several tens of microns for the purpose of merely increasing the specific surface area of the drug. As a method of pulverizing the drug into particles having a particle size of several microns or less, an automatic mortar (experiment,
There is a grinding type crusher such as a ball mill and an impact type fine crusher with a classification mechanism.

Further, as one of the pulverizing methods, a method of performing pulverization by mixing with various polymer compounds for a long period of time using an abrasion type pulverizer such as the above-mentioned automatic mortar and ball mill is also performed.

Other than pulverization, a coprecipitate is formed with a hydrophilic polymer, and a poorly soluble drug is dispersed and present at a molecular level between the hydrophilic polymer, and the drug is freeze-dried. There is a method of taking out in an amorphized state.

c. Problems to be Solved by the Invention However, the above method has the following problems.

Not only organic substances and inorganic substances, powders treated by a pulverizer are stagnant or remain in the pulverizer in the form of adhesion and agglomeration due to the nature of the powder itself, and as a result, the recovery rate as a product is not only low. In the case of organic substances, especially pharmaceuticals having a low heat resistant temperature, problems such as heat deterioration occur due to stagnation or remaining in the crusher for a long time, and it is generally impossible to prevent this heat deterioration from being mixed into the product.
Therefore, a big problem occurs in quality control. Further, the finer the obtained product, that is, the powder, the stronger the adhesive force and the cohesive force between the particles, so that they do not exist as primary particles and the specific surface area increases, but the effective surface area for dissolution decreases rather. Not only that, even if it is attempted to disperse / dissolve in a solvent such as water, it becomes difficult to wet the solvent, so that it takes a long time to completely disperse or dissolve it.

On the other hand, the modification of the crystal structure by the freeze-drying method, that is, the amorphization requires a long process in addition to a complicated process and requires a large amount of energy. Furthermore, the product obtained by this method is poor in stability and absorbs moisture when left standing or in the next step of unit operation, resulting in changes in fluidity or changes such as hydrolysis and oxidative decomposition. Was needed.

Further, the method for producing a coprecipitate requires a long time for the process, the energy required for drying is enormous, and the physical composition change such as phase separation occurs as in the freeze-drying method.

In general, mixed pulverization not only improves the fluidity by pulverizing a drug and various polymer compounds for a long time by pulverization type milling, but is also effective at the time of dissolution caused by aggregation of finely pulverized drug. It may be possible to prevent the reduction of the surface area to some extent. Further, in the mixed pulverization, although the particle size obtained is the same as that obtained when the drug is pulverized alone, it is found by analysis such as X-ray diffraction that there is a difference in amorphization,
The amorphous part dissolves relatively easily. In addition, an increase in the dissolution rate of the drug may be observed due to the interaction of the hydrogen bond between the drug and the additive.

In addition, although the research has just begun recently, using a grinding type crusher such as an automatic mortar and a ball mill, the particles used as an excipient having a particle size larger than that of the drug particles are made into core particles. And the drug particles are mixed, and the drug particles are attached on the surface of the core particle to obtain the ordered mixture (Orde
There is also a compounding method that forms a red mixture. Also in this method, the same effect as in the case of the above-mentioned mixed pulverization is obtained. In this case, the more easily the core particles are soluble, the more easily the drug particles are dispersed in the solvent, and the more the surface has affinity for the solvent, the more easily the drug particles are wetted, and as a result, the dissolution tends to be promoted.

However, in the above-mentioned mixing and pulverizing / compositing method using a grinding type pulverizer, the energy per unit time given to each particle of the powder in the state of a mixture is very small, and
Due to the poor dispersion and mixing state of different kinds of powders to be composited, the ratio of particles to be composited is very small in spite of requiring a long milling time. As a result, it takes a very long time to obtain the above effect, so even if it is good at the research and development stage, it is difficult to make a line for the purpose of processing on an industrial production scale. At the same time, it is extremely inefficient. Also. Since the processing time is long, problems such as adhesion to the crusher and heat deterioration occur, and peeled adhered products and heat deteriorated products are mixed in the processed products, and GMP (manufacturing and quality of pharmaceuticals) It becomes a serious problem in management norms).

In addition, in the case of composite particles (ordered mixture) simply by adhesion, a very large problem occurs in actual formulation. That is, the target particle (medicinal drug) is a drug
The purpose is to evenly disperse the particles. Therefore, in the case of using composite particles by simple adhesion, mixing, transportation, supply,
By subjecting each unit operation in various manufacturing processes such as discharge, segregation and segregation of the drug occurs, product quality varies, and the result is that the content of the drug added in a small amount varies depending on each sample. Changes in dosage and release can result in bioavailability (Bioavail
influence). In fact, there is a report that the third additive component caused the drug to be peeled off and replaced from the core particles.

d. Means for Solving the Problems The present invention has been made to solve such problems, and a large mechanical force can be obtained in a short time for each powder fine particle composed of a plurality of components. By using a high-speed air-flow impact type powder surface reformer (Hybridizer Co., Ltd. Nara Machinery Co., Ltd.) that can give energy, drug particles can be transferred onto the surface of the core particles in micron within an extremely short time. By firmly immobilizing in the state of particles of submicron order and / or amorphous state (such treatment is defined as immobilization treatment), the surface area of drug particles can be maximized and the dispersibility, It is intended to provide a method for treating a poorly soluble substance which is excellent in solubility and does not cause separation / segregation of a drug even when subjected to various unit operations in a production process and which constitutes a strong composite powder particle.

That is, the present invention is provided with a poorly soluble substance and a particle serving as a core of the poorly soluble substance, which is subjected to an immobilization treatment to amorphize the poorly soluble substance on the surface of the core particle and a state of fine particles, or any one of them. The above problems were solved by immobilizing in such a state to accelerate the dissolution rate.

Hereinafter, the present invention will be described in detail based on examples.

There are various types of core particles used in the method of the present invention. For example, various celluloses such as crystalline cellulose, hydroxypropyl cellulose, and carboxymethyl cellulose used as an excipient, a disintegrant, etc. in the formulation of drugs. Derivatives, starches such as potato starch, wheat starch and dextrin and their derivatives, natural polymers such as agar and gelatin and their derivatives, and synthetic polymers such as polyvinylpyrrolidone and polyvinyl alcohol, and mixtures thereof It is a mixture.

The size of the nuclear particles is preferably in the range of 0.5 micron to 1 mm. If it is less than 0.5 micron, it easily floats in the air and the impact force is not transmitted to the particles. On the other hand, when the thickness is 1 mm or more, the particles are easily broken by the impact, and the particles having a predetermined quality are not particularly efficient. The shape of the core particles is preferably spherical or ellipsoidal, but may be plate-shaped, needle-shaped or any other unspecified shape. However, it is desirable that the particles have an affinity (particularly hydrophilic) for the solvent.

On the other hand, as an example of drug particles as particles of a poorly soluble substance immobilized on the surface of a core particle, a poorly soluble and crystalline drug such as indomethacin, nifedipine, oxyphenbutazone, clemastine fumarate, and adrenaline can be used. is there.
The size of such drug particles is not particularly limited.

The method of treating a poorly soluble substance in the present invention, that is, a poorly soluble substance is firmly fixed to the surface of the core particle to obtain a dispersibility
A production method for producing composite particles having excellent solubility will be described below by taking a poorly soluble drug as an example.

e. Example 1 A method for producing composite particles according to the present invention will be described in detail by taking a case where potato starch is used as a core particle and indomethacin (an anti-inflammatory analgesic agent) is used as a drug to be immobilized.

FIG. 1 and FIG. 2 show a high-speed air current impact type powder surface reforming apparatus used for carrying out the present invention, in which a dry type and mechanical means are used to change the surface of the powder to another powder. Reform with the body,
This is an apparatus developed for producing a functional composite powder.

In the figure, 1 is a casing of the surface reforming apparatus, 2 is a rear cover, 3 is its front cover, 4 is a rotor which rotates in the casing 1 at a high speed, and 5 has a predetermined interval on the outer periphery of the rotor 4. And a plurality of impact pins radially arranged around, generally of hammer type or blade type. Reference numeral 6 is a rotary shaft that rotatably supports the rotor 4 in the casing 1, and 7 is a collision ring that is provided along the outermost peripheral raceway of the impact pin 5 and has a constant space with respect to it. For this, various types of concave-convex type or circumferential plane type are used. 8 is an opening / closing valve for discharging the reforming powder, which is provided by cutting out a part of the collision ring, 9 is a valve shaft of the opening / closing valve 8, 10 is an actuator for operating the opening / closing valve 8 via the valve shaft 9, and 11 is one end Open to a part of the inner wall of the collision ring 7 and the other end opens near the center of the front cover 3 to form a closed circuit, 12 is a raw material hopper, 13 is a raw material hopper 12 and a circulating circuit 11. Chute for supplying raw material,
14 is a raw material measuring feeder, and 15 is a raw material storage tank. Reference numeral 16 denotes an impact chamber provided between the outer periphery of the rotor 4 and the collision ring 7, and 17 denotes a circulation port to the circulation circuit 11. 18 is a modified powder discharge pipe, 19 is a cyclone, 20 and 21 are rotary valves, 21 is a bag filter, 23 is an air blower, and 24 is various types used when it is necessary to attach child particles to base material particles in advance. Well-known preprocessors such as a mixer and an automatic mortar are shown respectively. The operation of this device is designed so that the timed control device 25 performs an automatic batch operation.

The above device is operated in the following manner.

First, the opening / closing valve 8 for discharging the modified powder is kept closed, and the rotating shaft 6 is driven by a driving means (not shown) to rotate the rotor 4 at an outer peripheral speed of 80 m / sec, for example. At this time, a sudden flow of air is generated along with the rotation of the impact pin 5 on the outer periphery of the rotor 4, and the fan effect based on the centrifugal force of this air flow causes the circulation circuit 11 to circulate from the circulation port 17 opening to the impact chamber 16. A circulation flow of the air flow returning to the center of the rotor 4, that is, a complete self-circulation flow is formed.

Moreover, since the amount of circulating air per unit time generated at this time is remarkably large compared with the total volume of the impact chamber and the circulation system, an enormous number of air flow circulation cycles are formed in a short time.

For this reason, the number of circulations calculated from the total volume of the impact chamber and circulation circuit based on the actually measured circulation air volume is 579 revolutions / minute under the condition of the number of revolutions of the turntable 9385r / m. Here, the outer peripheral speed of the rotor is preferably in the range of 30 m / sec to 150 m / sec. At a speed of 30 m / sec or less, sufficient air flow does not occur in the circulation circuit, and it takes time to process and efficiency is poor.
Also, speeds above 150 m / sec are mechanically impossible.

Next, potato starch particles (dp50 (average particle size) = 60μ
m) and crystal particles of indomethacin (dp50 = 10 μm, hereinafter simply referred to as indomethacin particles) are mixed into the raw material hopper 12 from the weighing feeder 14 in a short time.
This mixed powder enters the impact chamber 16 from the raw material hopper 12 through the chute 13 and is subjected to an instantaneous impact action by a large number of impact pins 5 of the rotor 4 rotating at a high speed, and further impacts the peripheral impact ring 7. To do. At this time, if the rotational speed of the rotor 4 (that is, the outer peripheral speed of the collision pin 5) is set to a high speed that does not destroy the starch particles, only the indomethacin particles are selectively crushed in the impact chamber 16, and at the same time, the indomethacin particles become fine particles. The particles provide a strong compressive action on the surface of the potato starch particles. Then, accompanying the circulation flow of the air flow, it circulates in the circulation circuit 11 and returns to the impact chamber 16 again, and is subjected to the same action again. Thus, by repeatedly receiving the same action, uniform immobilization treatment was performed in a short time (1 to 5 minutes), and thus indomethacin particles could be firmly immobilized on the surface of potato starch particles. The composite particles are manufactured by such a method and process.

After the immobilization work is completed, the on / off valve 8 for discharging the modified powder is moved to the position shown by the chain line and opened to discharge the composite particles. The composite particles are discharged from the impact chamber 16 and the circulation circuit 11 in a short time (several seconds) by the centrifugal force acting on the composite particles and the suction force of the blower 23, and the discharge pipe 18
After being guided through a powder collecting device such as a cyclone 19 and a bag filter 21 through the rotary valve 20,
It is discharged to the outside of the system via 22.

In this example, the treatment amount: potato starch 90 g, indomethacin particles 10 g, treatment condition: rotor peripheral speed 80 m / s, treatment time: 5 min, Example 2 Using the same apparatus as above, potato starch and oxyphenbutazone Composite particles were also produced for the system. In this example, the treatment amount: potato starch 90 g, oxyphenbutazone 10 g, treatment condition: rotor outer peripheral speed 80 m / s, treatment time: 5 min.

3 (a) to 3 (g) are scanning electron microscopes of particles in the potato starch / indomethacin system shown in Example 1 (S.530 Hitachi, Ltd., hereinafter simply referred to as SEM).
Fig. 4 (a) and (b) are photographs of potato starch particles used as core particles, (c) is indomethacin particles of a drug used as an example of a poorly soluble substance, and (d) is the method of the present invention. Immediately after treatment of the produced composite particles, (e) is the composite particles after 7 days of treatment, (f) and (g) are photographs of a physical mixture of potato starch and indomethacin particles. .

FIG. 4 is a diagram showing the dissolution behavior of the drug according to Example 1, where (a) is a simple substance of inodomethacin, (b) is a simple physical mixture of potato starch and indomethacin particles,
(C) is a composite particle produced by the method of the present invention (10
The elution behavior of each month is shown. Further, FIG. 5 is a diagram showing the time-dependent change in drug dissolution behavior from the composite particles, (a) is a sample 4 hours after the immobilization (composite) treatment, and (b) is 7 days. Sample, (c) is 37
It is an elution curve of the sample which passed the day.

The dissolution behavior was measured according to the dissolution test method No. 2 listed in the Japanese Pharmacopoeia (JP X1).

That is, the device used for this test method has an inner diameter of 100 m.
A test liquid container with an inner volume of 1000 ml having a radius sphere of m and a disc with a diameter of 83 mm and a thickness of 3 to 5 mm is divided by parallel strings of 42 mm and 75 mm, and a rotating shaft with a diameter of 10 mm is the center. And a 42 mm chord of a stirring blade is fixed so as to be horizontal on the same plane as the lower end of the rotating shaft, and this is inserted into the test solution in the test solution container. The test solution is agitated by the agitating blades by the rotational movement by the electric motor. In addition, a constant temperature water bath for keeping the test solution at a constant temperature, a spectrophotometer for measuring the drug concentration, and a test solution container and a spectrophotometer are provided between the test solution and the test solution for measuring the drug concentration. And a tube pump unit for sending a part of the test solution back to the test solution after the measurement and sending to the (flow) cell in the spectrophotometer.

In addition, this device is connected to a personal computer,
It is programmed to automatically measure the time course of drug dissolution behavior (dissolution tester model NTR-VS6
(P) Toyama Sangyo Co., Ltd.).

The test solution used in this dissolution test is 0.1N acetate buffer solution of PH 4.7 900
ml, the liquid temperature was 37 ° C, and 20 mg of indomethacin was used for each powder sample. The rotation speed of the paddle (stirring blade) is 200r.
pm. The maximum absorption wavelength of indomethacin is 318-321 nm
The wavelength was 319 nm.

FIG. 6 is a diagram showing changes in the X-ray diffraction pattern in the potato starch / oxyphenbutazone system shown in Example 2, where (a) is oxyphenbutazone alone and (b) is
Is a physical mixture of potato starch and oxyphenbutazone, and (c) is the composite particles produced by the method of the present invention.

Table 1 is a table showing changes with time of the crystallinity of oxyphenbutazone (also referred to as amorphism = 100−crystallinity) of the composite particles shown in Example 2.

From the comparison of the dissolution curves shown in FIG. 4, it is understood that the dissolution rate of the poorly soluble drug can be dramatically accelerated by producing the composite particles by the method of the present invention.

Further, from the SEM photograph of FIG. 3, indomethacin immediately after the treatment (FIG. 3 (d)) was strongly immobilized in an amorphous state on the surface of potato starch, but became amorphous with the passage of time. It can be observed that indomethacin is present as extremely fine particles (submicron particles) on the surface of potato starch due to changes over time (7 days, same figure, (e)) such as partial recrystallization. . This is because when a large amount of mechanical energy is applied to the indomethacin crystal, the indomethacin crystal undergoes plastic deformation due to a mechanochemical phenomenon, and most or part of it becomes amorphous and is firmly immobilized on the surface of potato starch. However, due to the residual energy accumulated in indomethacin over time, it partially recrystallized locally, resulting in extremely fine particles.

It can be confirmed from the elution curve in FIG. 5 that indomethacin was partially amorphized. That is, since a considerable part of indomethacin is amorphized, indomethacin is eluted at a concentration equal to or higher than the saturated solubility (supersaturated state) in the completely crystalline state. However, after 7 days or more
Since no change was observed from the SEM photograph or the elution curve, it is considered that recrystallization was almost completed in 7 days in this system. In any case, the elution rate of the hardly soluble substance could be dramatically improved.

On the other hand, from FIG. 6 and Table 1, it can be seen that, by forming the composite particles by the method of the present invention, the X-ray diffraction peak of oxyphenbutazone is lowered, and thereafter its strength is recovered with time. From the above, it can be seen that the poorly soluble drug has become amorphous due to the mechanochemical phenomenon. 7 for this system
It can be seen that the amorphous portion still exists in the drug even after the lapse of months.

f. Effect of the invention As described above, by using the method of the present invention, by immobilizing the poorly soluble substance on the surface of the core particle by amorphization or fine particle formation by utilizing the mechanochemical phenomenon, It is possible to greatly accelerate the elution rate of the soluble substance, and even after that, even when it is recrystallized and becomes stable, the hardly soluble substance is finely divided and immobilized on the surface of the core particle, It was explained that the dissolution rate could be significantly enhanced by taking the crystalline drug as an example. Also, by immobilizing it on the surface of the core particles, the specific surface area of the sparingly soluble substance itself was maximized, and the problems of dispersibility and wettability were improved. It was explained that the use of particles having hydrophilicity is also a factor in promoting the dissolution rate.

Furthermore, since the method of the present invention can impart strong mechanical energy to a poorly soluble substance, it is always a problem with composite particles based on a simple mixed powder produced by another method. It was also explained that the separation / segregation of poorly soluble substances and the resulting variation in the quality of preparations could be fundamentally improved.

Furthermore, in the method according to the present invention, since the mechanical energy applied to the powder particles is strong, it becomes possible to efficiently produce a large amount of the composite powder in a short time, and also for a long time. The problems of reduction of the recovery rate due to the growth of the adherence of heat-deteriorated products into the product caused by the treatment and the adhesion were also overcome.

In addition, since it is a completely dry process that does not use various solvents at all, the manufacturing cost can be significantly reduced.

As described above, the method of the present invention is not limited to the above-mentioned examples of poorly soluble drugs, that is, speeding up the solubility of not only pharmaceuticals but also all poorly soluble organic and inorganic substances such as pesticides and general chemicals. Applicable to

[Brief description of drawings]

FIG. 1 is a surface of a powder of impact type in a high-speed air flow used for explaining a method for treating a hardly soluble substance according to the present invention (that is, a method for producing composite particles of particles of a hardly soluble substance and core particles). FIG. 2 is a conceptual explanatory view systematically showing the reforming device together with its front and rear devices, FIG. 2 is a side sectional explanatory view of FIG. 1, and FIGS. 3 (a) to 3 (g) are scanning electron microscopes. In the photograph, (a) and (b) are particles of potato starch, (c) is indomethacin particles, (d) is composite particles immediately after treatment,
(E) is composite particles after 7 days of treatment, (f),
(G) is a photograph of just a physical mixture. FIG. 4 is a diagram showing the elution behavior in potato starch + indomethacin system, (a) is indomethacin alone,
(B) is a mere physical mixture, (c) shows the case of composite particles, and FIG. 5 is a diagram showing the time-dependent change in the elution behavior of composite particles (potato starch + indomethacin).
(A) is composite particles 4 hours after the treatment, (b) is 7
(C) is an elution curve for each composite particle after 37 days. FIG. 6 is an X-ray diffraction pattern in the potato starch + oxyphenbutazone system, (a) shows oxyphenbutazone alone, (b) shows a physical mixture, and (c) shows composite particles. . 1 ... Casing, 2 ... Rear cover, 3 ... Front cover, 4 ... Rotor, 5 ... Impact pin, 6 ... Rotating shaft, 7 ... Collision ring, 8 ... Open / close valve, 9 ... Valve shaft, 10 ... Actuator, 11 ... Circulation circuit, 12 ... Raw material hopper, 13 ... Raw material supply chute, 14 ... Raw material metering feeder, 15 ... Raw material storage tank, 16 ... Shock chamber, 17 ... Circulation port, 18 ... Modified powder discharge pipe, 19 ... Cyclone, 21 ... Bag filter, 22,22 ... Rotary valve, 23 ... Fan, 24 ... Preprocessor, 25 …… Time control device.

Claims (3)

[Claims] 1. A sparingly soluble substance and particles serving as nuclei for the sparingly soluble substance are provided, and an immobilization treatment is performed on the core particle to amorphize the sparingly soluble substance on the surface of the core particles and / or fine particles. A method for treating a poorly soluble substance, characterized in that it is immobilized in the state of, and the dissolution rate is accelerated. 2. The method for treating a sparingly soluble substance according to claim 1, wherein the immobilization treatment is carried out by using a surface reforming device for a powder impact type in a high-speed air stream. 3. The method for treating a hardly soluble substance according to claim 1, wherein the immobilization treatment is performed in a state where only particles of the hardly soluble substance are selectively pulverized.