JPH02115030A - Treatment of difficultly soluble substance - Google Patents

Abstract

PURPOSE:To improve the solubility of a difficultly soluble substance by coating the surfaces of core particles fixedly with the difficultly soluble substance in the form of noncrystalline solid and/or fine particle by using a powder surface modifying device. CONSTITUTION:By using a powder surface modifying device of high-speed air stream impulse type capable of imparting a great mechanical energy to the individually particles of the powder, the surfaces of core particles (which consist of cellulose, starch, natural polymers and their derivatives and synthesized polymers and their mixtures used as the shaping and breaking agent of medicament and whose sizes are within the range of 0.5mum-1mm with affinity for solvent) are coated in the form of a fine particle and/or noncrystalline solid in an extremely short time firmly and fixedly with a difficultly soluble substance (such as the medicament particles consisting of indometacin, nifedipine, oxyphenbutazone, etc.), thereby obtaining the difficultly soluble substance constituting hard composite powder particles excellent in dispersibility and solubilit.

Description

[Detailed Description of the Invention] a. Industrial Application Field The present invention is directed to amorphous or partially amorphous amorphous or partially amorphous substances on the surface of various excipient particles using a high-speed air impact method. By immobilizing the substance in the form of particles or by immobilizing the substance in the form of fine particles, the surface area of the substance particles can be expanded, composite particles with excellent dispersibility and solubility can be produced, and the The present invention relates to a method for treating a poorly soluble substance by accelerating its dissolution rate.

b. Prior Art The following describes an example of an H-soluble drug as a poorly soluble substance.

Conventionally, various methods have been attempted to increase the dissolution rate of poorly soluble drugs in order to improve their bioavailability.

This is a method in which a soluble drug is crushed into particles of several hundred to several tens of microns using an impact type crusher such as a hammer mill, bottle mill, or atomizer, for the purpose of simply increasing the specific surface area of the drug. Furthermore, methods for crushing drugs into particle sizes of several microns or less include automatic mortars (for experiments and research), attrition-type crushers such as ball mills, and impact-type pulverizers equipped with a classification mechanism. There is.

In addition, as one of the pulverization methods, there is also a method of mixing and pulverizing various polymer compounds for a long time using a grinding type pulverizer such as the automatic mortar or ball mill described above.

Methods other than pulverization include a method in which a coprecipitate is formed with a woody polymer, and a poorly soluble drug is dispersed and present at the molecular level between the hydrophilic polymers, and a freeze-drying method is used to disperse the drug. There are methods for extracting it in an amorphous state.

C1 Problems to be Solved by the Invention However, the above method had the following problems.

Powder processed by a pulverizer, whether organic or non-IM,
Due to the nature of the powder itself, it stagnates or remains in the grinder in the form of adhesion and agglomeration, resulting in not only a low recovery rate as a product, but also organic substances, especially pharmaceuticals with low heat resistance, for a long time. Problems such as thermal deterioration may occur due to stagnation or remaining in the crusher, and -
It is almost impossible to prevent these heat-degraded substances from entering the product, which causes a big problem in terms of quality control. In addition, the finer the obtained product, the powder, the stronger the adhesive force and cohesive force between particles, so it no longer exists as secondary particles, and although the specific surface area increases, the effective surface area for dissolution decreases. Not only that, but even if an attempt is made to disperse or dissolve it in a solvent such as water, it becomes difficult to wet with the solvent, so it takes a long time to completely disperse or dissolve it.

On the other hand, modifying the crystal structure by freeze-drying, that is, making it amorphous, is a complicated process and requires a long time, as well as a large amount of energy. Furthermore, the products obtained by this method have poor stability and absorb moisture when left standing or during unit operations in the next process, resulting in changes in fluidity or hydrolysis/oxidative decomposition, so they must be properly managed and stored. It had become necessary.

In addition, the method of producing a coprecipitate, like the freeze-drying method, requires a long time for the process, requires considerable energy for drying, and also poses problems such as physical composition changes such as phase separation.

- In mixed pulverization, the drug and various polymer compounds are pulverized for a long time in a grinding type pulverizer, which not only improves the fluidity (but also improves the fluidity caused by the agglomeration of the finely pulverized drug). In some cases, the reduction in effective surface area during melting can be prevented to some extent.

In addition, although the particle size obtained by mixed pulverization is the same as when the drug is pulverized alone, analysis such as X-ray diffraction shows that
It was found that there is a difference in amorphization, and the amorphous portion dissolves relatively easily. Furthermore, an increase in the dissolution rate of the drug may be observed due to hydrogen bonding interactions between the drug and the additive.

Although research has only recently begun, it is possible to use a grinding machine such as an automatic mortar or ball mill to turn particles used for excipients, etc., which have a larger particle size than drug particles, into core particles. and drug particles, and the drug particles are attached to the surface of the core particles to form an ordered mixture + (O
There is also a conjugation method to form rdered m1xture). This method also has the same effect as the above-mentioned mixed pulverization. In this case, the more soluble the core particles are, the easier the drug particles are to be dispersed in the solvent, and the more affinity the surface has for the solvent, the easier the drug particles will be wetted, and as a result, dissolution tends to be promoted.

However, in the above-mentioned mixed grinding/compounding method using a grinding type grinder, the energy given per unit time to each particle of the powder in the state of a mixture is very small (and
Due to the poor dispersion and blending of different types of powders to be composited, the proportion of particles to be composited is very small despite the long grinding time required.As a result, it takes an extremely long time to obtain the above effect. Since it requires time-consuming processing, although it may be fine at the research and development stage, it is difficult and extremely inefficient to create a line for processing on an industrial production scale. In addition, because the processing time is long, problems such as adhesion to the inside of the crusher and thermal deterioration occur, and peeled adhesion and heat-degraded products are mixed into processed products, resulting in GNP (manufacturing of pharmaceutical products). and quality control standards).

In addition, composite particles (ordered mixture) that are simply adhered to each other cause a very big problem in actual formulation. In other words, pharmaceuticals have target particles (medicinal drugs).
The objective is to uniformly disperse the particles, and for this reason, when using composite particles that are simply attached, mixing, transportation, supply, and
Due to each unit repetition in various manufacturing processes such as discharge, separation and segregation of drugs occur, resulting in variations in product quality and the content of drugs added in small amounts varying from sample to sample. Changes occur in drug dosage and release, resulting in changes in bioavailability (Bioa).
availability).

In fact, the release of the drug from the core particle by the third additive component
There are reports that replacement has occurred.

d. Means for Solving the Problems The present invention was made to solve these problems, and it applies a large mechanical force to fine powder particles consisting of multiple components in a short period of time. By using a high-speed airflow impact type powder surface modification device (hybridizer - Nara Kikai Seisaku Seikaku) that can provide energy,
By firmly immobilizing drug particles on the surface of core particles in a micron to submicron order particle state and/or in an amorphous state within an extremely short period of time (such treatment is defined as immobilization treatment). By maximizing the surface area of drug particles, we have created strong composite powder particles with excellent dispersibility and solubility, and which do not cause drug separation or segregation even when subjected to various unit operations in the production process. The present invention provides a method for treating the poorly soluble substances that constitute the composition.

That is, the present invention provides a sparingly soluble substance and a particle serving as a core thereof, and performs an immobilization treatment on the substance to form the sparingly soluble substance on the surface of the core particle in an amorphous state, a fine particle state, or both. The above problem was solved by immobilizing in this state and accelerating the dissolution rate.

Hereinafter, the present invention will be explained in detail with reference to examples.

There are a wide variety of core particles used in the method of the present invention, including various types of cellulose such as crystalline cellulose, hydroxypropyl cellulose, and carboxymethyl cellulose, which are used as excipients and disintegrants in drug formulations. Derivatives, starches such as potato starch, wheat starch, dextrin and their derivatives, natural polymers such as agar and gelatin and their derivatives, synthetic polymers such as polyvinylpyrrolidone and polyvinyl alcohol, and those obtained by mixing them. It is a mixture.

The size of the core particles is from 0.5 microns to 1III11
A range of is suitable. When the particle size is less than 0.5 microns, it easily floats in the air and the impact force is not transmitted to the particles.

In addition, if the particle size exceeds 1 mm, the particles are likely to be destroyed by impact, so it is best to use a certain quality (not efficient), but the shape of the core particle is preferably 4T, spherical or ellipsoid, but plate-shaped, needle-shaped, etc. The particles may have an unspecified shape, but preferably have an affinity (particularly hydrophilicity) for the solvent.

On the other hand, examples of drug particles that are particles of poorly soluble substances immobilized on the surface of core particles include indomethacin, nifedipine, and oxyphenbutacin.

There are poorly soluble and crystalline drugs such as talemastine fumarate and adrenaline. Note that the size of such drug particles is not particularly limited.

The method of treating a poorly soluble substance according to the present invention, that is, the hardly soluble substance is firmly fixed on the surface of the core particle, and the dispersibility and
A manufacturing method for producing composite particles with excellent solubility will be described below, taking a poorly soluble drug as an example.

e. Examples Example 1 The method for producing composite particles according to the present invention will be described in detail using an example in which potato starch is used as the core particle and indomethacin (an anti-inflammatory analgesic drug) is used as the drug to be immobilized.

Figures 1 and 2 show a high-speed airflow impact type powder surface modification device used to carry out the present invention, in which the surface of powder is modified by dry and mechanical means. modified by the body,
This equipment was developed to produce functional composite powder.

In the figure, l is a casing of the surface modification device, 2 is a rear cover, 3 is a front cover, 4 is a rotor that is inside the casing 1 and rotates at high speed, and 5 is a radial pattern placed at a predetermined interval around the outer circumference of the rotor 4. a plurality of impact pins circumferentially disposed around the periphery, which are generally hammer or blade shaped. 6 is a rotating shaft that rotatably supports the rotor 4 in the casing l; 7 is a collision ring disposed along the outermost orbital surface of the impact pin 5 and with a certain space therebetween; For this purpose, various types of concave-convex type or circumferential flat type are used. Reference numeral 8 denotes an on-off valve for discharging reformed powder provided by cutting out a part of the collision ring, 9 is a valve shaft of the on-off valve 8, 10 is an actuator that operates the on-off valve 8 via the valve shaft 9, and 11 is one end. is opened in a part of the inner wall of the collision ring 7, and the other end is opened 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 circulation circuit 11; 14 is a raw material measuring feeder, and 15 is a raw material storage tank. Reference numeral 16 indicates a shock chamber provided between the outer periphery of the rotor 4 and the collision ring 7, and reference numeral 17 indicates a circulation port to the circulation circuit 11. 18 is a modified powder discharge pipe, 19 is a cyclone, 20.21 is a rotary valve, 21 is a bag filter, 23 is an exhaust fan, and 24 is various types used when it is necessary to attach child particles to base material particles in advance. The apparatus shown in FIG. 1 is a mixer, an automatic mortar, and other known preprocessors, and the operation of this apparatus is designed to perform an automatic batch operation using a time control device 25.

The above device is operated as follows.

First, the on-off valve 8 for discharging the modified powder is kept in a closed state, and the rotating shaft 6 is driven by a driving means (not shown) to rotate the rotor 4 at, for example, an outer circumferential speed of 80 m/sec. At this time, as the impact pin 5 on the outer periphery of the rotor 4 rotates, a rapid air flow is generated, and based on the centrifugal force of this air flow (fan effect), the circulation port opening into the impact chamber 16
A circulating flow of airflow from 7 through the circulation circuit 11 and back to the center of the loco 4, that is, a completely self-circulating flow is formed.

Moreover, since the amount of circulating air generated per unit time is significantly larger than the total volume of the shock chamber and circulation system, a large number of airflow circulation cycles are formed in a short period of time.

Based on the actually measured circulating air volume, the number of circulations calculated from the total volume of the shock chamber and circulation circuit is 579 times/min under the condition that the rotary disk rotates at 9385 r/m. Here, the outer peripheral speed of the rotor is 30 m/sec.
A range of 150-/sec is preferred. 30m/sec
If the speed is below, sufficient air flow will not be generated in the circulation circuit, and the processing will take time and be inefficient. Also 150m/se
Speeds higher than c are mechanically impossible.

Next, potato starch particles (dp50 (average particle diameter) =
60 μm) and indomethacin crystal particles (dp50-1
0 μm (hereinafter simply referred to as indomethacin particles) is fed into the raw material hopper 12 from the metering feeder 14 in a short time. This mixed powder passes through the chute 13 from the raw material hopper 12 and enters the impact chamber 16, where it is instantaneously impacted by a large number of impact bins 5 of the rotor 4 rotating at high speed, and further collides with the surrounding impact ring 7. do.

At this time, if the rotational speed of the rotor 4 (i.e., the outer circumferential speed of the collision pin 5) is set to a high limit speed that does not destroy the starch particles, only the indomethacin particles are selectively crushed in the shock chamber 16, and at the same time, the indomethacin particles become fine particles. The particles exert a strong compressive action on the surface of the potato starch particles. Then, along with the circulating air flow, the air circulates through the circulation circuit 11 and returns to the shock chamber 16, where it is subjected to the same action again. By repeating the same action in this manner, uniform immobilization treatment was performed in a short period of time (1 to 5 minutes), and in this way, indomethacin particles were able to be firmly immobilized on the surface of potato starch particles. Composite particles are manufactured using such methods and steps.

After the above 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 shock chamber 16 and circulation circuit 11 in a short time (several seconds) by the centrifugal force acting on themselves and the suction force of the exhaust fan 23, and pass through the discharge pipe 18 into the cyclone 19. After being guided to a powder collecting device such as a bag filter 21, the powder is collected and discharged to the outside of the system via rotary valves 20 and 22.

In this example, processing amount: potato starch 90 g indomethacin particles Log processing conditions: rotor peripheral speed 80 m/s processing time: 5 plows.

Example 2 Using the same apparatus as above, composite particles were also produced for a system of potato starch and oxyphenbutacin. In this example, Treatment I: Potato starch 90g Oxyphenbutacin 10g Treatment conditions: Rotor peripheral speed 80v/S Treatment time = 51n.

Figure 3(a) - (The powder is a scanning electron microscope (S.530■ manufactured by Hitachi, Ltd., hereinafter simply referred to as SEM) of particles in the potato starch/indomethacin system shown in Example 1)
These are photographs, in which (a) and (b) are particles of potato starch used as core particles, (C) are particles of indomethacin, a drug used as an example of a poorly soluble substance, and (d) are particles of indomethacin used as an example of a poorly soluble substance. (e) is the composite particles produced immediately after treatment; (e) is the same composite particles after 7 days; (f); (The barrel is a photograph of a mere physical mixture of potato starch and indomethacin particles.

FIG. 4 is a diagram showing the elution behavior of the drug according to Example 1, in which (a) is indomethacin alone, (b) is a simple physical mixture of potato starch and indomethacin particles, (C
) shows the elution behavior of composite particles produced by the method of the present invention (10 months after preparation). Also, the fifth
The figure shows the change in drug elution behavior from the above composite particles over time; (a) is a sample after 4 hours of immobilization (complexing), (b) is a sample after 7 days, and (C) ) is 37
This is an elution curve of a sample after several days.

Note that the dissolution behavior was measured according to Dissolution Test Method 2 listed in the Japanese Pharmacopoeia (JP Xi).

That is, the device used for this test method has an inner diameter of 100
A test liquid container with an inner volume of 100 (ld) and a disk with a diameter of 8301 m and a thickness of 3 to 51111 mm was prepared using a mackerel with a radius of 42 mm.
diameter 10 on stirring blades separated by parallel chords of M and 75 mm.
The shaft of rotation of m is penetrated through its center, and the 42-
Fix the string horizontally on the same plane as the lower end of the rotating shaft, and insert it into the test liquid in the test liquid container. This test liquid is stirred by a stirring blade by rotational movement by an electric motor. In addition, there is a constant temperature water bath to keep the test solution at a constant temperature, a spectrophotometer to measure the drug concentration, and a part of the test solution that is interposed between the test solution container and the spectrophotometer to measure the drug concentration. a tube pump unit for delivering a portion of the test liquid to a (flow) cell within the spectrophotometer and for returning a portion of the test liquid to the test liquid after measurement.

Note that this device can be connected to a personal computer,
It is programmed to fully automatically measure the change in drug dissolution behavior over time (dissolution tester model: NTR
-VS6 (P) manufactured by Toyama Sangyo ■).

The test solution used in this dissolution test had a pH of 4.7 and 0. 900 ml of IN acetate buffer! The liquid temperature was 37°C. For each powder sample, an amount equivalent to 20 μl of indomethacin was used. Further, the rotation speed of the paddle (stirring R) was 200 rpm. Since the maximum absorption wavelength of indomethacin is between 318 and 321 nm, the measurement was performed at a wavelength of 319 nm.

FIG. 6 is a diagram showing changes in the X-ray diffraction pattern in the potato starch/oxyphenbutacin system shown in Example 2, (a) is oxyphenbutacin alone, (bl
(C) is a mere physical mixture of potato starch and oxyphenbutacin, and (C) is a composite particle produced by the method of the present invention.

Table 1 is a table showing changes over time in the crystallinity (also defined as amorphous degree - 100 - crystallinity degree) of oxyphenbutacin in the composite particles shown in Example 2. .

A comparison of the elution curves in Table 1 and Figure 4 shows that the elution rate of poorly soluble drugs can be dramatically accelerated by producing composite particles using the method of the present invention.

Furthermore, from the SEM photograph in Figure 3, indomethacin immediately after treatment (Figure 3 (d)) was firmly immobilized on the surface of potato starch in an amorphous state, but became amorphous with the passage of time. Due to changes over time such as partial recrystallization of indomethacin (7 days elapsed in the same figure, (e)), it becomes distorted and exists as fine particles (submicron particles) on the surface of potato starch. It can be observed. This is because large mechanical energy is applied to the indomethacin crystals, which causes plastic deformation of the indomethacin crystals due to a mechanochemical phenomenon, causing most or part of the indomethacin crystals to become amorphous and become firmly fixed on the surface of the potato starch. However, over time, the residual energy stored in indomethacin caused it to partially and locally crystallize again, resulting in extremely fine particles.

The fact that indomethacin partially became amorphous can be seen in Figure 5.
This can also be confirmed from the yield curve. That is, since a considerable portion of indomethacin has become amorphous, indomethacin is eluted at a concentration higher than the saturation solubility in a completely crystalline state (supersaturated state). However, if more than 7 days have passed, S[! Since no change was observed in either the M photograph or the elution curve, it is considered that recrystallization of this system was almost completed at 7 days. In any case, the elution rate of poorly soluble substances could be dramatically improved.

On the other hand, from FIG. 6 and Table 1, the X-ray diffraction peak of oxyphenbutacin decreases by forming composite particles using the method of the present invention, and then its intensity recovers over time. It can also be seen that poorly soluble drugs become amorphous due to mechanochemical phenomena. In this system, 7
It can be seen that amorphous portions still exist in the drug even after several months have passed.

f. Effects of the Invention As described above, the method of the present invention makes it possible to immobilize a poorly soluble substance on the surface of a core particle by making it amorphous or finely divided by utilizing a mechanochemical phenomenon. It can greatly accelerate the elution rate of soluble substances, and even if they are subsequently recrystallized and become stable, the poorly soluble substances are finely divided and immobilized on the surface of the core particles. The fact that the dissolution rate could be significantly accelerated was explained using a crystalline drug as an example. In addition, by immobilizing it on the surface of the core particle, the specific surface area of the poorly soluble substance itself can be maximized, improving the problems of dispersibility and wettability.
Furthermore, it was explained that the use of particles that have an affinity for the solvent (particularly hydrophilicity) as the core particles is also a factor in promoting the elution rate.

Furthermore, the method of the present invention can impart strong mechanical energy to poorly soluble substances, which is always a problem with composite particles similar to simple mixed powders produced by other methods. It was also explained that it was possible to fundamentally improve the separation and segregation of poorly soluble substances and the variations in quality of the preparations caused by this.

Furthermore, in the method according to the present invention, since the mechanical energy imparted to the powder particles is strong, it is now possible to efficiently produce a large amount of composite powder in a short time, and it is also possible to produce a large amount of composite powder in a short time. The problems of contamination of the product with heat-degraded products caused by processing and a decrease in recovery rate due to the growth of adhesion have also been overcome.

Additionally, since the process is completely dry and does not use any solvents, manufacturing costs 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, but can speed up the solubility of not only pharmaceuticals but also all kinds of poorly soluble organic and inorganic substances such as agricultural chemicals and general chemicals. Applicable to

[Brief explanation of drawings]

FIG. 1 shows the surface of a powder using a high-speed air flow impact method used to explain the method for treating a poorly soluble substance (that is, the method for producing composite particles of particles of a hardly soluble substance and core particles) according to the present invention. Fig. 2 is a conceptual explanatory diagram systematically showing the reformer together with its front and rear devices;
) to (6) are scanning electron micrographs;
(b) is potato starch particles, (C) is indomethacin particles, (b) is composite particles immediately after treatment, (e) is composite particles 7 days after treatment, (f) and (6) are simple This is a photograph of a physical mixture. Figure 4 is a diagram showing the elution behavior in the potato starch + indomethacin system, where (a) is indomethacin alone, (
b) shows the case of a simple physical mixture, (C) shows the case of composite particles, and FIG. 5 shows the change in elution behavior of the composite particles (potato starch + indomethacin) over time;
(b) shows composite particles 4 hours after treatment, (b) shows 7 days,
(C) is an elution curve of each composite particle after 37 days. FIG. 6 shows the X-ray diffraction pattern of the potato starch + oxyphenbutacin system, where (a) shows oxyphenbutacin alone, et al.) shows a mere 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... On-off valve for discharging homogeneous powder, 9... Valve shaft, 10... Actuator 11... Circulation circuit, 12... Raw material hopper 1
3... Raw material supply chute, 14... Raw material measuring feeder 15... Raw material storage tank, 16... Shock chamber, 17.
...Circulation port, 18...Reformed powder discharge pipe, 19
...Cyclone, 21...Bag filter 2
2.22... Rotary valve, 23... Exhaust fan, 24... Preprocessor-25.
...Timed control device. Figure 4 Figure 2 Figure 5 Shima hr 0

Claims (3)

[Claims] (1) A poorly soluble substance and a particle serving as a core thereof are provided, and this is subjected to an immobilization treatment so that the poorly soluble substance is turned into an amorphous state and/or a fine particle state on the surface of the core particle. A method for treating a poorly soluble substance, which is characterized by immobilizing it with a substance and accelerating its dissolution rate. (2) The method for treating a poorly soluble substance according to claim 1, characterized in that the immobilization treatment is performed using a powder surface modification device of a high-speed airflow impact type. (3) The method for treating a sparingly soluble substance according to claim 1, wherein the immobilization treatment is preferably performed in a state where only particles of the sparsely soluble substance are selectively pulverized.