JP2014221012A - Simulated powder, method for evaluating scattered state of powder, and powder handling facility - Google Patents

Abstract

Simulated powder for evaluating powder scattering state, method for evaluating powder scattering state using the simulated powder, and powder handling facility for evaluating powder scattering state by the evaluation method Offer. 1) A simulated powder comprising microcapsules containing lactose and ATPs, which is a simulated powder used in place of the powder for evaluating the scattering state of the powder. 2) The simulated powder in which the microcapsule has lactose and ATPs as core materials. 3) A powder scattering state evaluation method for evaluating a powder scattering state using a simulated powder, the step of scattering the simulated powder in a space to be evaluated, and a scattering position at a predetermined position in the space A powder scattering state evaluation method, comprising: a step of recovering the simulated powder; and a step of quantitatively or qualitatively analyzing the recovered simulated powder. 4) A powder handling facility having a space for handling powder, wherein the powder scattering state is evaluated by the evaluation method. [Selection figure] None

Description

  The present invention relates to a simulated powder, 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 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 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 is a group consisting of lactose, adenosine 5′-triphosphate (ATP) and derivatives thereof. It is characterized by comprising a microcapsule containing one or more selected compounds.
The microcapsules preferably have lactose and the compound as core materials.
The particle size of the microcapsules is preferably 0.5 μm to 30 μm.

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 microcapsules containing lactose and the compound, the simulated powder in a collected (sampled) single sample can be analyzed by two methods. . The first analysis method is a method for detecting and analyzing the compound contained in the microcapsules 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 blending ratio of lactose contained in the microcapsule and the above compound, the detection sensitivity of the microcapsule is adjusted, and the microcapsule has the same particle density and scattering property as the particles constituting the actual powder. Can be granted.

When the microcapsule is a particle having lactose and the compound as a core substance, the lactose and the compound can be stably held in the microcapsule at a predetermined mixing ratio. For this reason, even when the particles are rubbed during handling of the simulated powder or when the simulated powder is scattered with a strong momentum, separation of lactose and the compound can be suppressed. As a result, since the results obtained by the first analysis method and the results obtained by the second analysis method can be obtained independently and with high accuracy, it is more reliable by referring to both results. High evaluation results can be obtained.
In addition, by adjusting the blending ratio of lactose and the above compound contained in the microcapsule, both the lactose and the above compound are imparted to the microcapsule with the same density and scattering property as the particles constituting the actual powder. However, by constituting the core substance, the blending ratio can be easily adjusted.

  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 powder scattering state evaluation method of the present invention, by using the simulated powder composed of the above-mentioned microcapsules, the simulated powder scattered in the space to be evaluated is detected with moderately high sensitivity, and quantitatively detected. Or it can be analyzed qualitatively. At this time, since the microcapsule contains not only the compound (ATP or a derivative thereof) but also lactose, the concentration of the compound in the simulated powder of the present invention is higher than that of the conventional particles composed only of ATP. Can be reduced. That is, since the concentration of the compound contained in the microcapsule is diluted with lactose, the compound can be detected with 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 microcapsule by the SMEPAC method and the analysis result of the compound constituting the microcapsule.

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.

It is the result of the reference test which shows that ATP melt | dissolved in ethanol is kept stable at room temperature for 3 weeks or more.

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

《Simulated powder》
The simulated powder of the present 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”), and includes lactose and adenosine 5′-3. It consists of microcapsules containing at least one compound selected from the group consisting of phosphoric acid (ATP) and its derivatives.

  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.

<Compound>
The compound contained in the microcapsule 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 type of the compound contained in the microcapsule may be one type or two or more types.

<Microcapsule>
The microcapsule of the present embodiment is a particle composed of a wall film constituting the outer surface (outer shell) and a core substance encapsulated by the wall film.
Lactose and the compound are preferably encapsulated in a microcapsule as a core substance, but either or both of lactose and the compound may be contained in the microcapsule as a material constituting the wall membrane. .

  When lactose and the compound are encapsulated by the wall membrane as the core material of the microcapsule, the form of the lactose and the compound is not particularly limited. For example, lactose particles and particles composed of the compound may be mixed, or may be in a liquid or gel form in which lactose and the compound are dissolved in an appropriate solvent. It may be in a solid state in which the compounds are uniformly mixed.

  The content of lactose with respect to the total weight of the microcapsules 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% by weight or more and less than 100% by weight, more preferably 75% by weight or more and less than 100% by weight, and further preferably 90% by weight or more and less than 100% by weight.

  Materials other than lactose and the above-described compounds constituting the core material of the microcapsule are not particularly limited, and known excipients and the like can be applied, and examples thereof include starch, dextrin, saccharose, glucose and the like.

  The material constituting the wall film of the microcapsule is not particularly limited as long as it does not hinder the qualitative analysis or quantitative analysis of lactose or the compound contained in the microcapsule collected after scattering, and an organic solvent such as an aqueous solvent or alcohol A material that is soluble in a system solvent is preferred. From the viewpoint of easily analyzing lactose or the compound contained in the microcapsule, the material constituting the wall membrane is preferably a water-soluble material. On the other hand, from the viewpoint of facilitating the production of the microcapsules, the material constituting the wall film containing lactose, which is a water-soluble substance, and the compound is a polymer or oil / fat that is hardly soluble or insoluble in water. It is more preferable. The material constituting the wall film of the microcapsule may be one type, or two or more types may be used in combination.

  As the polymer, a polymer compound used in a known microcapsule can be applied. For example, poly fatty acid ester, polyglycolic acid, polyamino acid, polycarbonate, polystyrene, polymethacrylic acid, polyacrylic acid Dextranstearate, ethyl cellulose, acetyl cellulose, nitrocellulose, maleic anhydride copolymer, polyvinyl acetate, polyacrylamide and the like.

  The weight of the wall membrane with respect to the total weight of the microcapsules 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 weight is 1 It is preferably ˜50% by weight, more preferably 1 to 25% by weight, and even more preferably 1 to 10% by weight.

  The thickness of the wall film of the microcapsule may be a thickness having a structural strength capable of stably holding the core substance during scattering, and is usually several tens nm to several μm depending on the type of the wall film material. The thickness may be sufficient.

  The physical properties such as the particle size, shape and density of the microcapsules are preferably close to the actual powder (target powder) such as pharmaceutical powder.

  The particle size of the microcapsules 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 microcapsule is in 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 particle size of the microcapsules constituting the simulated powder was determined by observing a plurality of microcapsules constituting the simulated powder with an electron microscope, and observing the total of the longest diameter (longest diameter) of each microcapsule. The number average diameter divided by the number of capsules or the volume reference average value obtained by a laser scattering particle size distribution measuring device is used.

  The particle size distribution of 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 microcapsule or may be composed of a plurality of types of microcapsules.

The shape of the microcapsule constituting the simulated powder is not particularly limited, and examples thereof include a shape that can be approximated to a sphere, an elliptic rotating body, or various polyhedrons.
The density of the microcapsules 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 lactose constituting the microcapsule and the compound. Specifically, the weight of lactose with respect to the total weight of the microcapsule is preferably 0.1% by weight or more and less than 100% by weight, and usually several tens to 90% by weight.

  The content ratio of the lactose constituting the microcapsule and the compound is not particularly limited as long as it does not inhibit the qualitative analysis or quantitative analysis of the lactose or the compound contained in the microcapsule collected after scattering. In the microcapsule, when the weight of lactose 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.

<Quantification of lactose coexisting with ATP by SMEPAC method>
Here, in the mixed sample of lactose and ATP, if the weight ratio of lactose / ATP is in the range of 1000 to 100,000, the test results for examining that ATP does not affect the lactose quantification by the SMEPAC method will be described below. .
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.

<Method for producing simulated powder>
The production method of the microcapsule constituting the simulated powder of the present embodiment is not particularly limited as long as it can contain lactose and the above compound in the microcapsule. For example, a melt type microcapsule production method, matrix spray coagulation The grain method etc. are mentioned. Specific examples include the methods described in JP-A-6-145046 and JP-B-7-29042.

<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 microcapsules scattered in the evaluation target space is usually suspended 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 the first method, an impinger containing a solvent capable of dissolving the microcapsules may be used as the collector instead of the collector provided with the above-described filter.

<Second method for collecting and analyzing simulated powder>
The simulated powder composed of microcapsules scattered in the evaluation target space is usually suspended 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.

<Stability of ATP in ethanol>
When the wall film of the microcapsule is made of a material that is easily dissolved in ethanol, the microcapsule collected after the scattering can be dissolved in ethanol, and ATP dissolved in the ethanol can be analyzed. As a reference example, FIG. 1 shows a test result confirming that ATP can be accurately quantitatively analyzed by luminescence reaction of luciferase and luciferin even when ethanol in which ATP is dissolved is stored at room temperature for 3 weeks or more.

The horizontal axis in FIG. 1 indicates the number of days that have been stored at room temperature after dissolving ATP in ethanol. The vertical axis | shaft of FIG. 1 shows the relative ratio (fluorescence ratio, unit: Relative Light Unit (RLU)) of the fluorescence intensity emitted from luciferin. The fluorescence ratio on the 0th day of lapse shows the fluorescence ratio when luciferin is caused to emit light using ATP contained in the ethanol immediately after dissolution.
As is clear from FIG. 1, the same fluorescence as that on the 0th day is observed even on the 22nd day. This result shows that ATP is kept stable without being decomposed in ethanol at room temperature.

<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.

  Microcapsules having an average particle diameter of 10 μm were prepared by a conventional method consisting of a wall film made of a water-soluble material and a core substance containing lactose and ATP. The weight ratio of lactose and ATP in the core material was 100: 1.

A predetermined amount of the prepared microcapsules were scattered into a room (within a clean room) having a space volume of about 51 m ³ , and then a part of the microcapsules in the room air was taken into the pure water and collected by the impinger method. Specifically, 0.5 m ³ of room air was fed into 50 ml of pure water placed in a glass container with a dedicated pump and bubbled. The amount of ATP contained in the microcapsules dissolved in the pure water was quantified by a known method (luciferase method) using the aforementioned luciferase.

As a result, it was found that sufficient detection was possible when the weight of ATP contained in the collected room air was 10 ⁻¹ μg to 10 ⁻⁶ μg. This result shows that by using the simulated powder of the present invention, the simulated powder scattered in the space to be evaluated can be detected and quantified with high sensitivity.

  In this example, a plurality of samples in which a known amount of ATP was dissolved in 50 ml of pure water were prepared in advance, and these were measured by the luciferase method described above to determine the relationship between the RLU value indicating the amount of luminescence and the ATP amount. It was. The results are shown in Table 1.

The unit of the RLU value shown in Table 1 is an RLU (Relative Light Unit) representing a relative light emission amount. The ATP content shown in the upper part of Table 1 is converted to the amount of ATP contained in 1 m ³ of recovered indoor air. Among the numerical values shown in the lower part of Table 1,> 9999 indicates that a light emission amount exceeding the light emission amount that can be quantitatively detected by the measuring apparatus is detected. A calibration curve is created from this result, and the amount of ATP contained in the sample and in 1 m ^{3 of} room air can be quantified from the amount of luminescence indicated by ATP in the sample collected by the impinger 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 (6)

A simulated powder used in place of the powder to evaluate the scattering state of the powder,
A simulated powder comprising microcapsules containing lactose and one or more compounds selected from the group consisting of adenosine 5'-triphosphate (ATP) and derivatives thereof.   The simulated powder according to claim 1, wherein the microcapsule has lactose and the compound as core materials.   The simulated powder according to claim 1 or 2, wherein the microcapsule has a particle size of 0.5 to 30 µm. 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 3 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 method for evaluating a powder scattering state according to claim 4, wherein the analysis is performed by detecting a reaction that occurs as a result of coexistence of luciferase, luciferin, and the compound. A powder handling facility with a space for handling powder,
A powder handling facility, wherein the powder scattering state in the space is evaluated by the powder scattering state evaluation method according to claim 5.

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