JP2014222164A - Simulated powder, method for producing simulated powder, method for evaluating scattered state of powder, and powder handling facility - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide simulated powder for evaluating a scattered state of powder, a method for producing the simulated powder, a method for evaluating a scattered state of powder using the simulated powder, and a powder handling facility which evaluates a scattered state of powder by the evaluation method.SOLUTION: There are provided: 1) simulated powder which consists of composite particles in which one or more compound selected from the group consisting of ATP and a derivative thereof are attached to core particles containing lactose; 2) a method for producing simulated powder in which base particles which consists of core particles containing lactose are allowed to collide child particles which consist of one or more compounds selected from the group consisting of ATP and a derivative thereof in high-speed air flow to obtain composite particles in which the surface of the base particles is coated with child particles; and 3) a method for evaluating a scattered state of powder which has: a step of scattering the simulated powder in the space of an evaluation target; a step of recovering the simulated powder scattered to prescribed positions in the space; and a step of analyzing the recovered simulated powder quantitatively or qualitatively.

Description

  The present invention relates to a simulated powder, a simulated powder manufacturing method, a powder scattering state evaluation method, and a powder handling facility. More specifically, the present invention relates to a simulated powder used for evaluating the scattering state of a powder in a powder handling facility such as a manufacturing facility or a research and development facility for a powder that affects the human body, such as a highly pharmacologically active drug. The present invention relates to a body, a method for manufacturing the simulated powder, a method for evaluating the powder scattering state using the simulated powder, and a powder handling facility for evaluating the powder scattering state by the evaluation method.

A highly pharmacologically active drug is a drug that has a strong medicinal effect on the human body in a small amount, typified by anticancer drugs and hormone drugs. For example, there are highly pharmacologically active pharmaceuticals that bring some physiological activity to the human body at an air concentration of 1 μg / m ³ or less. In such drug handling facilities, the prevention of scattering of pharmaceutical powders in manufacturing equipment and equipment (pharmaceutical powders) from the viewpoints of product quality control (preventing contamination), preventing health hazards to workers, and preventing environmental pollution. (Containment of body) measures are important. In general, work is performed in a physically enclosed containment device such as an isolator. However, there are demands for cost reduction and flexible production systems for pharmaceutical manufacturing, and there is a high need for handling pharmaceutical powders in semi-open facilities (semi-enclosed facilities) such as clean booths.

  In the field of manufacturing and R & D, it is indispensable to know the powder powder dispersibility and measure and analyze the containment condition in the field environment. And when pharmaceutical powder is scattered in the field environment, and when evaluating the containment (evaluation of the scattering state of the pharmaceutical powder), using a drug with high pharmacological activity itself, adhesion to the skin, aspiration, etc. There is a concern that it will adversely affect workers. For this reason, the scattered state is often evaluated using a highly safe simulated powder instead of using the pharmaceutical powder.

  In Non-Patent Document 1, the SMEPAC method (The Standardized Measurement of Equipment Particulate Airborne Concentration method) using lactose powder as a simulated powder is recommended. The lactose used here is a substance used as a pharmaceutical excipient, is harmless to the human body, easily dissolved in water, and has a good stability, and is widely used. However, in order to quantitatively analyze the lactose powder dispersed in the facility to be measured, an expensive and large-scale apparatus and complicated work are required. Specifically, the lactose powder scattered in the measurement target facility is sampled by a filter or wiping, transported to the analysis facility, and analyzed and evaluated by a device such as a high performance liquid chromatograph or ion chromatograph. Things have been done. For this reason, it often takes about several days to a week to obtain the result, and it is difficult to perform the evaluation in a short time in the facility to be measured.

  Patent Document 1 discloses an invention in which adenosine 5'-triphosphate (ATP) powder having a specific particle size is used as a simulated powder in evaluating the scattering state of a powder. In this invention, a sampling sheet is installed in the facility to be measured, the ATP powder is scattered, and the ATP powder adhering to the sheet is quantitatively analyzed. Since quantitative analysis of ATP powder can be performed using a detection device that can be brought into the field, an evaluation result can be obtained on the spot. By using ATP powder that can be quantified with high sensitivity with a simple apparatus as a simulated powder, the labor and time required for quantitative measurement are being improved.

ISPE (The International Society for Pharmaceutical Engineering Inc.) Good Practice Guide Guidelines for evaluating the containment performance of pharmaceutical equipment, edited by SMEPAC Committee, ISBN 1-931879-51-6

JP 2010-276468 A

The detection method of ATP powder used in Patent Document 1 described above is extremely sensitive, and for example, ATP existing in units of femtomolar concentration in a sample can be detected.
However, if the sensitivity is so high, when the second measurement is performed after the first measurement, only a very small amount of the first ATP powder remains will affect the second measurement. Such problems may occur. In addition, there is a problem that it cannot be compared with the measurement result of the existing standard method SMEPAC method, and preparing ATP powders that match the particle size and particle density of various powders that are actually used in the field environment. There is also a problem that is difficult.

In view of the circumstances described above, the present invention is based on the SMEPAC method, which is a conventional standard method, for simulating a powder instead of a highly pharmacologically active pharmaceutical powder or the like in a facility to be evaluated and evaluating the scattering state. Can be carried out simultaneously, and a method for evaluating the scattering state of the simulated powder (powder) by a simple measurement method with high detection sensitivity is provided.
It is another object of the present invention to provide a simulated powder used in the evaluation method, a manufacturing method of the simulated powder, and a powder handling facility that evaluates the scattering state of the powder by the evaluation method.

In order to achieve the above object, the present invention provides the following means.
The simulated powder of the present invention is a simulated powder used in place of the powder to evaluate the scattering state of the powder, and the core particles containing lactose are mixed with adenosine 5′-triphosphate (ATP) and It is characterized by comprising composite particles to which one or more compounds selected from the group consisting of the derivatives are attached.
The composite particles are preferably formed by coating the surface of the mother particles made of the core particles with the child particles made of the compound.
It is preferable that the composite particle is formed by the mother particle and the child particle colliding in a high-speed air stream, and the child particle is coated on the surface of the mother particle.
The composite particles preferably have a particle size of 0.5 μm to 30 μm.

  The method for producing a simulated powder according to the present invention is a method for producing a simulated powder used in place of the powder to evaluate the scattering state of the powder, wherein the mother particle composed of core particles containing lactose, and adenosine The surface of the mother particle was coated with the child particles by colliding with a child particle made of one or more compounds selected from the group consisting of 5′-triphosphate (ATP) and derivatives thereof in a high-speed air stream. The simulated powder comprising composite particles is obtained.

The powder scattering state evaluation method of the present invention is a powder scattering state evaluation method for evaluating the scattering state of the powder by using a simulated powder instead of the powder, and the simulated powder in the space to be evaluated. A step of scattering the body, a step of recovering the simulated powder scattered at a predetermined position in the space, and a step of quantitatively or qualitatively analyzing the recovered simulated powder. .
The analysis is preferably carried out by detecting a reaction resulting from the coexistence of luciferase, luciferin and the compound.

  The powder handling facility of the present invention is a powder handling facility having a space for handling powder, wherein the powder scattering state in the space is evaluated by the powder scattering state evaluation method. To do.

  According to the simulated powder of the present invention, it is possible to detect the scattering state with high sensitivity and to analyze quantitatively or qualitatively by scattering in the space to be evaluated instead of the powder of a highly pharmacologically active drug or the like. Can do. At this time, since the particles constituting the simulated powder of the present invention are composite particles, the simulated powder in the collected (sampled) single sample can be analyzed by two methods. The first analysis method is a method for detecting and analyzing the compound constituting the composite particle with high sensitivity, and the second quantitative method is a method for analyzing by the conventional SMEPAC method. By analyzing with these two methods, highly reliable results can be obtained. In addition, the first analysis method can be carried out with high sensitivity using a simple device that can be brought into the field. Therefore, the scattering and / or containment of the simulated powder (powder) can be evaluated quickly at the measurement site. can do.

  By adjusting the compounding ratio of the core particles constituting the composite particles and the compound, the detection sensitivity of the composite particles is adjusted, and the composite particles have a particle density equivalent to the particles constituting the actual powder. And scattering properties can be imparted.

  When the composite particle is a particle formed by adhering the child particle composed of the compound to the surface of the mother particle composed of the core particle, by adjusting the blending ratio of the mother particle and the child particle, It is possible to easily impart the same density and scattering properties as the particles constituting the powder.

  When the composite particle is a particle in which the mother particle and the child particle collide in a high-speed air current, and the child particle is coated on the surface of the mother particle, the child particle is firmly bonded to the surface of the mother particle. The composite particles are hardly decomposed into mother particles and child particles during scattering. Furthermore, since the ratio between the mother particles and the child particles in each composite particle constituting the simulated powder is almost uniform, the scattering state of the simulated powder can be examined more accurately.

  When the particle size of the simulated powder is 0.5 μm to 30 μm, it is easy to give the simulated powder a particle size distribution and density close to those of actual powders such as highly pharmacologically active pharmaceuticals. Evaluation becomes possible.

  According to the method for producing the simulated powder of the present invention, the surface of the mother particles containing lactose can be coated relatively uniformly with the child particles made of the compound. In the composite particles obtained as a result, the mother particles and the child particles are relatively strongly bonded (attached), so that the composite particles can be prevented from being decomposed into the mother particles and the child particles during the scattering. By scattering the composite particles as a simulated powder, highly reliable data can be obtained regarding the scattering properties.

  According to the powder scattering state evaluation method of the present invention, by using the simulated powder composed of the composite particles described above, the simulated powder dispersed in the space to be evaluated is detected with a reasonably high sensitivity and quantified. Or qualitatively. At this time, since lactose functions as a carrier of the compound (ATP or a derivative thereof) in the composite particle, the concentration of the compound in the simulated powder of the present invention is higher than that of the conventional particle composed of only ATP. Can be reduced. That is, since the concentration of the compound in the composite particle is diluted with lactose, the compound can be detected with an appropriate sensitivity. As a result, in the powder scattering state evaluation method of the present invention, the excessively high detection sensitivity of ATP particles is hardly a problem as in the conventional method, and the evaluation result of the powder scattering state can be obtained quickly. Is possible. In addition, more reliable data can be obtained by mutually referring to the result of analyzing the lactose constituting the composite particle by the SMEPAC method and the analysis result of the compound constituting the composite particle.

In addition, when analyzing the recovered simulated powder quantitatively or qualitatively, by detecting the reaction that occurs as a result of the coexistence of luciferase, luciferin and the above compound, it can be easily analyzed in the field, in the space The scattering state of the powder can be evaluated.
In addition, in the space provided by the powder handling facility, by confirming the scattering state and containment state when the powder is scattered, it is confirmed that the specified standard is satisfied, and the powder handling facility handles the powder. It can be determined whether or not it is suitable.

  Hereinafter, the present invention will be described based on preferred embodiments.

《Simulated powder》
The simulated powder of this embodiment is a simulated powder used in place of the target powder in order to evaluate the scattering state of the powder (hereinafter referred to as “target powder”). It consists of composite particles to which one or more compounds selected from the group consisting of adenosine 5′-triphosphate (ATP) and its derivatives are attached.

  The simulated powder is, for example, a target powder having a high pharmacological activity, such as a pharmaceutical manufacturing facility or a research and development facility. It is used for the purpose of evaluating the scattering state. Further, the present invention is not limited to powders of highly pharmacologically active pharmaceuticals, and can be applied to evaluate the scattering state of all target powders.

<Nuclear particles>
The content of lactose with respect to the total weight of the core particles is not particularly limited, but from the viewpoint that it is easy to make the simulated powder similar to the scattering property of a general pharmaceutical powder (target powder), the content is It is preferably 50 to 100% by weight, more preferably 75 to 100% by weight, and still more preferably 90 to 100% by weight.

  Materials other than lactose constituting the core particles are not particularly limited, and known excipients can be applied, and examples thereof include starch, dextrin, saccharose, glucose and the like.

  The particle size of the core particles constituting the simulated powder is not particularly limited, but is preferably 0.01 μm to 500 μm, more preferably 0.1 μm to 100 μm, and still more preferably 0.5 μm to 30 μm. When the particle size of the core particles is within the above range, the scattering state of the target powder can be more accurately evaluated by imitating the particle size of the target powder used in a general pharmaceutical manufacturing facility or the like. . The particle size shown here may be a primary particle size or a secondary particle size.

  The physical properties such as the particle size, shape and density of the core particles are preferably close to those of actual powders such as pharmaceutical powders. The physical properties of the core particles are preferably equivalent to the physical properties of the particles constituting the lactose powder used in the conventional SMEPAC method. Therefore, conventional lactose particles may be used as the core particles in the present embodiment.

<Compound>
The compound attached to the core particle containing lactose is one or more compounds selected from the group consisting of adenosine 5′-triphosphate (ATP) and derivatives thereof.
ATP is a nucleotide that is used in biochemical reactions of living organisms, and is a compound that has little substantial harm even if a small amount of ATP is sucked or attached to an operator.
Examples of ATP derivatives include ADP, AMP, and cAMP. In ADP, among the three phosphate groups linked to the 5 ′ position of ribose constituting the ATP molecule via a phosphate ester bond, the phosphate group at the γ position furthest from ribose was replaced with a hydrogen atom. It is adenosine 5′-diphosphate, AMP is adenosine 5′-monophosphate in which two phosphate groups at γ-position and β-position are substituted with hydrogen atoms, and cAMP is ribose constituting the ATP molecule. Is a cyclic adenosine monophosphate in which the 5′-position and the 3′-position are cyclically linked by one phosphate group. These ATP derivatives can be detected with high sensitivity similarly to ATP by the bioluminescence method described later.

  One or more compounds selected from the group consisting of ATP and its derivatives are not limited to purified pure ATP and ATPs, but include salts and hydrates of ATP and ATPs. An example is ATP disodium salt trihydrate.

  The kind of the compound attached to the core particle containing lactose may be one kind or two or more kinds.

<Composite particle>
The form of the compound attached to the core particle constituting the composite particle is not particularly limited, and may be a form in which the particle (child particle) of the compound is attached to the core particle (mother particle). May be in a form in which a layer is formed on the surface of the core particle and uniformly coated, or a part or all of the compound is included in the core particle.

  The particle size of the composite particles is not particularly limited, but is preferably 0.01 μm to 500 μm, more preferably 0.1 μm to 100 μm, and still more preferably 0.5 μm to 30 μm. When the particle size of the composite particles is within the above range, it is possible to more accurately evaluate the scattering state of the target powder by imitating the particle size of the target powder used in a general pharmaceutical manufacturing facility or the like. it can. The particle size shown here may be a primary particle size or a secondary particle size.

  The particle diameter of the composite particles constituting the simulated powder is a volume-based average diameter obtained by a laser scattering particle size distribution measuring apparatus. In addition, the particle diameter of the above-mentioned core particle can be obtained by the same method.

  The particle size distribution of the composite particles constituting the simulated powder is not particularly limited, and may be appropriately adjusted according to the particle size distribution of the actual target powder. For example, the particle size distribution of the simulated powder can be adjusted by classification. By classifying the simulated powder having a wide particle size distribution width, the particle size distribution width may be narrowed. Conversely, a plurality of simulated powders having a narrow particle size distribution width may be mixed to prepare a simulated powder having a wide particle size distribution width.

  The simulated powder may be composed of only one type of composite particle or may be composed of a plurality of types of composite particles.

The shape of the composite particles constituting the simulated powder is not particularly limited, and examples thereof include shapes that can approximate various polyhedrons, spheres, or elliptical rotators.
The density of the composite particles constituting the simulated powder is not particularly limited, and may be appropriately adjusted so as to be approximately the same as the density of the actual target powder.

  The scattering property of the simulated powder is greatly influenced by the density of the particles. For this reason, it is necessary to make the density of the simulated powder close to the actual target powder. From this viewpoint, it is preferable to adjust the blending ratio of the core particles constituting the composite particles and the compound attached to the core particles. Specifically, the weight of the core particles with respect to the total weight of the composite particles is preferably 70 to 99.999% by weight, more preferably 97 to 99.999% by weight, and still more preferably 99 to 99.99% by weight.

  The mixing ratio of the lactose particles constituting the composite particles and the compound is not particularly limited as long as it does not inhibit the determination of lactose or the compound. In the composite particles, when the weight of the lactose particles is 100 parts by weight, the weight of the compound is preferably 0.001 to 1 part by weight. Within this range, lactose and the compound can be quantitatively analyzed with high accuracy without interfering with each other.

<Method for producing simulated powder>
The method for producing the simulated powder of the present embodiment differs in the method that can be selected depending on the form of the composite particles. Below, the 1st compounding method and the 2nd compounding method are explained, respectively.

<First composite method>
The first composite method is a method for producing composite particles, in which the compound forms a layer (coating layer) on the surface of the core particles, or the compound is impregnated inside the core particles. First, a solution in which the compound is dissolved at a predetermined concentration is prepared, and the solution is uniformly applied to the surface of the core particles. A coating method is not particularly limited, and a known method of mixing particles and the solution can be applied. Next, the target composite particles can be obtained by removing the solvent of the solution applied to the core particles and leaving the compound as the solute of the solution on the surface of the core particles. At this time, by impregnating the inside of the core particles with the solution, the compound can also be arranged inside the core particles. Examples of apparatuses that apply the solution and remove the solvent include a pan coating apparatus, a rolling coating apparatus, and a fluidized bed coating apparatus. By using these apparatuses, the surface of the core particle can be uniformly coated (coated).

<Second composite method>
The second compounding method is a method for producing compounded particles in which particles (child particles) of the compound are attached to core particles (mother particles). In this production method, it is preferable to perform a treatment that allows the child particles to adhere (adhere) relatively strongly to the surface of the mother particles.

  If the child particles and the mother particles are weakly attached, it simply becomes a mixed state of the child particles and the mother particles. When such a mixture is scattered in the space to be evaluated, the scattered particles are decomposed without maintaining the state of the composite particles, and the ratio (possibility) that the child particles and the mother particles scatter independently. Get higher. Since the child particles and the mother particles scattered separately in this way exhibit different scattering properties, the scattering properties of the target powder and the scattering properties of the composite particles that simulate the scattering properties of the target powder are different. There is.

  As a method for producing composite particles in a state where the child particles and the mother particles are relatively weakly adhered, a mixing method in which the child particles and the mother particles are mixed while being stirred by a mill, a mixing method by a fluidized bed method, a high-speed compression / Examples include a mixing method using a shear type mixer. In these mixing methods, even if composite particles in which the child particles and the mother particles are strongly adhered are obtained by appropriately setting the mixing conditions, the weight ratio of the child particles to the mother particles in each composite particle is different. There is a high possibility of becoming uniform composite particles. When such non-uniform composite particles are used as a simulated powder, it is possible to obtain qualitative analysis and evaluation results, but it is difficult to obtain quantitatively accurate evaluation results.

  In the present embodiment, it is preferable to apply a dry particle compositing technique that allows the child particles to adhere relatively strongly to the surface of the mother particles. According to this technology, mother particles and child particles dispersed in a high-speed air current collide with each other, and the mother particles and child particles are fixed (fixed) in a dry manner mainly by the impact force at the time of collision. All or at least part of the surface of the particles can be coated. In other words, this method can be said to be a method in which the surface of the mother particle is surface-modified with the child particles and combined.

  If the dry particle composite technology is used, a film made of child particles can be formed on the surface of the mother particle by appropriately adjusting the conditions at the time of collision. During the film formation, the shape of the child particles before the collision can be maintained, or the shape of the child particles can be deformed by the collision energy. Basically, the shape and particle diameter of the mother particles before the collision can be maintained even after the collision (after compounding).

  In the formation of composite particles by dry particle composite technology, the chamber in which the mother particles collide with the child particles is cooled, and the interior of the chamber is made an inert gas atmosphere such as nitrogen gas or argon gas to constitute the child particles. Thermal decomposition and oxidative decomposition of the compound can be suppressed, and the detection sensitivity of the composite particles can be prevented from being impaired. Such a compounding method can be performed with a known commercial apparatus.

<Method for evaluating powder scattering state>
The powder scattering state evaluation method of the present embodiment is a powder scattering state evaluation method for evaluating the scattering state of a target powder using a simulated powder instead of the target powder, and in the evaluation target space. A step of scattering the simulated powder (powder scattering step), a step of collecting the simulated powder scattered at a predetermined position in the space (collection step), and a step of quantitatively or qualitatively analyzing the collected simulated powder (Analysis step).
The powder scattering state evaluation method of the present embodiment may include steps other than the powder scattering step, the recovery step, and the analysis step, for example, a step (evaluation step) for evaluating the scattering state of the simulated powder. Good. A known method can be applied to this evaluation step.

  The method of scattering the simulated powder in the powder scattering step is not particularly limited. For example, the method of scattering the simulated powder by putting the simulated powder in a rotary drum and rotating it, discharging the simulated powder from the hopper, A known method such as a method of blowing air blow can be applied. The method for scattering the simulated powder may be appropriately selected according to the size and form of the space to be evaluated.

  Below, two methods are concretely demonstrated about a collection | recovery step and an analysis step.

<First method to collect and analyze simulated powder>
The simulated powder composed of the composite particles scattered in the evaluation target space usually floats in the evaluation target space for several minutes to several hours. The air (gas) in the space can be guided to a collector equipped with a filter, and the simulated powder floating in the space can be collected by this filter. The collected simulated powder can be dissolved in the cleaning liquid by washing the filter with purified water, alcohol, or the like after the collection. Quantitatively or qualitatively analyze the simulated powder floating at the collection position by quantifying or detecting the amount or presence of the compound such as ATP contained in the cleaning solution by a known method. Can do. Furthermore, since the amount of lactose having a positive correlation with the above compound such as ATP is dissolved in the washing solution, if the amount of lactose in the washing solution is quantified by SMEPAC method or liquid chromatography (HPLC) according thereto, A more reliable result is obtained.

  As the collector used in this first method, an impinger containing a solvent capable of dissolving the composite particles may be used as the collector instead of the collector provided with the above-mentioned filter. .

<Second method for collecting and analyzing simulated powder>
The simulated powder composed of the composite particles scattered in the evaluation target space usually floats in the evaluation target space for several minutes to several hours. After waiting for this simulated powder to fall, the simulated powder adhering to the ground or wall constituting the space to be evaluated or a desk or the like installed in the space is quantified. In this case, a sampling sheet is set in advance on the wall of the space to be evaluated, the simulated powder falling on the sheet is collected, and a solution in which this simulated powder is dissolved in an appropriate solvent is prepared. The simulated powder falling to the collection position can be quantitatively or qualitatively analyzed by quantitatively or qualitatively analyzing the compound such as ATP in the solution by a known method. Furthermore, since the amount of lactose having a positive correlation with the amount of the compound such as ATP is dissolved in the solution, if the amount of lactose in the solution is quantified by the SMEPAC method or a liquid chromatography equivalent thereto, In addition, more reliable results can be obtained.

  By analyzing the detected simulated powder quantitatively or qualitatively, the scattered state of the simulated powder in the space to be evaluated can be evaluated. Assuming that the scattering characteristics of the actual target powder handled in the evaluation target space are similar to the scattering characteristics of the simulated powder, know the scattering condition of the actual target powder from the scattering state of the simulated powder. The scattering state can be evaluated.

  In addition, the powder scattering state evaluation method of the present embodiment evaluates whether the simulated particles are diffusing (leaking out) in the space (second space) adjacent to the evaluation target space (first space). May be. The collector or the sampling sheet is installed in the first space and the second space, the amount or presence of the simulated powder in the first space and the second space is monitored, and the simulated powder detected in the second space It can be evaluated whether the amount of the body is within the assumed range. If the simulated powder is not detected in the second space or if the detected amount is lower than a predetermined value, it can be determined that the containment property of the simulated powder in the first space is good.

<Method for quantifying the compound such as ATP>
A method for quantifying the compound such as ATP in the analysis sample is not particularly limited, and a known method can be applied. For example, a method using luciferase described in Patent Document 1 can be mentioned. Luciferase is a general term for enzymes that catalyze a chemical reaction (luminescence reaction) in which luciferin, which is a luminescent substance, emits light using the above-described compound such as ATP in an analysis sample. In general, the amount of luminescence shows a positive correlation with the amount of the compound in the analytical sample. By preparing a calibration curve in advance, mixing the luciferase and the analysis sample, and measuring the amount of luminescence, the amount of the compound in the analysis sample can be accurately measured.

  Usually, a metal ion such as magnesium ion is required as a cofactor for luciferase to catalyze a luminescence reaction. For this reason, it is preferable to mix luciferase, a metal ion, and luciferin with an analysis sample. In addition, depending on the type of luciferase, only ATP may be used as a substrate, and the aforementioned ATP derivative cannot be used as a substrate. In this case, it is preferable to perform a process of converting the derivative in the analysis sample into ATP. This conversion process may be performed by a known method, for example, a method disclosed in JP-A-9-234099.

When quantifying ATP in an analysis sample, if the detection sensitivity of ATP is too high, the analysis sample may be quantified after the ATP concentration is lowered by diluting with an appropriate solvent. Examples of the dilution ratio include 10 ⁴ to 10 ⁷ times.

<Powder handling facility>
The powder handling facility according to the present embodiment is a powder handling facility having a space for handling powder, and the powder handling state in which the powder scattering state in the space is evaluated by the above-described powder scattering state evaluation method. It is a facility. The size of the space provided in this facility (the size of the facility) is not particularly limited. Examples of the powder handling facility include a powder handling room, a powder handling booth, a clean booth, a glove box, and a powder storage room in a pharmaceutical manufacturing factory.

An acceptable exposure control amount (OEL: Occupational Exposure Limits) of a pharmaceutical having particularly high pharmacological activity is generally set to 1 μg / m ³ or less. The method for evaluating the scattered state of the simulated powder according to the present embodiment can be applied to the evaluation of facilities (apparatus, equipment) for such highly pharmacologically active pharmaceutical products.

[Test Example 1]
<Preparation of simulated powder 1>
A stirrer (Nara) comprising powder (100 g) composed of lactose hydrate (CAS number: 64044-51-5) and powder (0.1 g) composed of ATP (CAS number: 56-65-5). A simulated powder 1 made of composite particles in which the child particles made of ATP were relatively weakly adhered to the surface of the mother particles made of lactose was obtained by mixing using a machine manufacturer, model name: OM Dither).
The lactose particles used here have a particle size of about 0.5 μm to 30 μm and a specific gravity of about 1.5. The ATP particles used here have a particle size of about 100 nm to 100 μm and a specific gravity of about 1.

<Detection of simulated powder 1>
The simulated powder 1 was scattered almost uniformly in the test space, and samples 1 to 5 were collected in which the simulated powder was collected at five different points in the test space. The amount of ATP contained in these samples was quantified by a known method using a luciferin-luciferase reaction. As a result, as shown in Table 1, although the simulated powder 1 is scattered almost uniformly in the test space, the amount of ATP varies greatly depending on each point. This is because the amount of ATP adhering to the surface of each composite particle constituting the simulated powder 1 is different, or part of the composite particle is decomposed into mother particles and child particles during scattering. It is considered that. Therefore, it is possible to qualitatively examine the state of scattering of the target powder in the evaluation target space using the simulated powder 1 (check the presence or absence of the target powder), but quantitatively determine the scattering state. It turns out that it is difficult to investigate.

  The unit of each numerical value shown in Table 1 is RLU (Relative Light Unit). Control in Table 1 is the amount of luminescence when a sample in which 100 parts by weight of lactose and 0.01 parts by weight of ATP are uniformly mixed is measured in the same manner.

[Test Example 2]
<Preparation of simulated powder 2>
It consists of composite particles in which ATP, which is a child particle, is relatively strongly fixed to the surface of lactose particles, which are mother particles, by a dry particle compounding method in which lactose powder and ATP powder are made to collide with each other in a high-speed air stream. Simulated powder 2 was obtained. The volume average diameter of the simulated powder 2 was about 6 μm.

  For the preparation of the simulated powder 2, the same lactose powder and ATP powder as used in Test Example 1 were used, and a dry particle compounding device (manufactured by Nara Machinery Co., Ltd., model name: hybridizer type 1) was used. Then, the collision chamber temperature was set to 40 to 70 ° C., the atmospheric gas in the chamber was changed to general indoor air, and the composite was performed under the condition of the rotor rotation speed of 8000 rpm.

<Detection of simulated powder 2>
As in the case of the simulated powder 1, the simulated powder 2 was scattered almost uniformly in the test space, and Samples 1 to 5 were obtained in which the simulated powder was collected at five different points in the test space. The amount of ATP contained in these samples was quantified by a known method using a luciferin-luciferase reaction. As shown in Table 1, the amount of ATP detected at each point in the test space was almost equal. This result is consistent with the simulation powder 2 being scattered almost uniformly in the test space. That is, by simulating the simulated powder 2 in the evaluation space and detecting the amount of ATP at a predetermined position, not only qualitatively examining the scattering state of the simulated powder in the evaluation space, but also quantitatively determining the scattering state. It can be seen that it can be evaluated accurately.

<Quantification of lactose coexisting with ATP by SMEPAC method>
Three types of aqueous solutions A1, A2, and A3 in which ATP is added to an aqueous solution having a lactose concentration of 1 μg / L so that the final weight ratio of ATP to lactose is 0.1%, 0.01%, and 0.001%. Was prepared. When the lactose concentrations of these aqueous solutions A1 to A3 were measured by HPLC according to the SMEPAC method, it was confirmed that any aqueous solution contained lactose at a concentration of 1 μg / L.
Similarly, three types of aqueous solutions B1, in which ATP is added to an aqueous solution having a lactose concentration of 5 μg / L, so that the final weight ratio of ATP to lactose is 0.1%, 0.01%, and 0.001%, B2 and B3 were prepared. When the lactose concentrations of these aqueous solutions B1 to B3 were measured by HPLC according to the SMEPAC method, it was confirmed that all the aqueous solutions contained lactose at a concentration of 5 μg / L.
From these results, it is clear that in a mixed sample of lactose and ATP, if the weight ratio of lactose / ATP is in the range of 1000 to 100,000, ATP does not affect lactose quantification by the SMEPAC method.

  The configurations and combinations thereof in the embodiments described above are examples, and the addition, omission, replacement, and other modifications of the configurations can be made without departing from the spirit of the present invention.

Claims (8)

A simulated powder used in place of the powder to evaluate the scattering state of the powder,
A simulated powder comprising composite particles in which at least one compound selected from the group consisting of adenosine 5′-triphosphate (ATP) and derivatives thereof is attached to core particles containing lactose.   2. The simulated powder according to claim 1, wherein the composite particles are obtained by attaching child particles made of the compound to surfaces of mother particles made of the core particles.   3. The simulated powder according to claim 2, wherein the composite particles are such that the mother particles and the child particles collide with each other in a high-speed air stream, and the child particles are coated on the surface of the mother particles.   4. The simulated powder according to claim 1, wherein the composite particles have a particle size of 0.5 μm to 30 μm. A method for producing a simulated powder used in place of the powder in order to evaluate the scattering state of the powder,
By causing a mother particle composed of core particles containing lactose and a child particle composed of one or more compounds selected from the group consisting of adenosine 5′-triphosphate (ATP) and derivatives thereof in a high-speed air stream, A method for producing a simulated powder comprising obtaining the simulated powder comprising composite particles in which the surface of the mother particle is coated with the child particles. A powder scattering state evaluation method for evaluating the scattering state of the powder using simulated powder instead of powder,
Scattering the simulated powder according to any one of claims 1 to 4 in a space to be evaluated;
Collecting the simulated powder scattered in a predetermined position of the space;
And a step of quantitatively or qualitatively analyzing the collected simulated powder.   The powder scattering state evaluation method according to claim 6, wherein the analysis is performed by detecting a reaction resulting from the coexistence of luciferase, luciferin and the compound. A powder handling facility with a space for handling powder,
A powder handling facility characterized in that the powder scattering state in the space is evaluated by the powder scattering state evaluation method according to claim 6.