JP4406992B2 - Minoxidil preparation manufacturing equipment - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a minoxidil preparation (lotion) production facility, and more specifically to a production facility suitable for producing a minoxidil formulation in which discoloration of the formulation with time is suppressed.
[0002]
[Prior art]
For example, minoxidil preparations used for hair growth agents (those lotions containing minoxidil, propylene glycol, ethanol and purified water to add a predetermined wt% (eg 1 wt% or 2 wt%) minoxidil) It is known to develop and change color.
There have been no proposals based on studies that have been clearly intended for the analysis of color development and discoloration mechanisms of minoxidil preparations and their suppression or improvement.
[0003]
[Problems to be solved by the invention]
The minoxidil formulation as described above is colorless and transparent immediately after the preparation, but after a predetermined time has elapsed from the production, it develops from a colorless and transparent state to a faint yellow color, and gradually changes from light yellow to yellow to purple over time. And discolored. Although there is no particular decrease or degradation in the efficacy of the minoxidil formulation itself due to such color development or discoloration, the appearance may deteriorate and the user may feel anxious about whether the formulation has deteriorated or deteriorated. .
[0004]
According to the researches of the inventors, the minoxidil active substance (white powder) has no cause of color development or discoloration over time. Propylene glycol, ethanol, purified water, etc.) come into contact with containers and piping, so that metal elements such as iron and manganese are eluted and mixed in trace amounts in the formulation, and the absorbance of the formulation at 420 nm increases over time. It became clear that color development and discoloration occurred.
In addition, the inventors of the present invention have disclosed metal elements eluted in the minoxidil active ingredient and the solvent from the production equipment used in the process of storage, delivery and preparation, storage, and delivery of the drug and the minoxidil active ingredient and each solvent. The concentration was examined. As a result, various types of equipment used to manufacture minoxidil preparations from various stored solvents and minoxidil raw materials and fill them into small containers are made of stainless steel and other iron-containing metals (alloys). ) Is used, it is easy to elute and mix iron in minoxidil preparation, and it turns out that the minoxidil preparation develops color and yellows over time if the iron content at the preparation is above the predetermined value did. These color development and yellowing are considered to be due to oxidation of minoxidil by contact with air or the like in the presence of metal elements mainly composed of iron.
[0005]
The inventors have used an iron standard solution and a manganese standard solution to prepare a 1% minoxidil formulation (minoxidil... 1.0 g, propylene glycol. ... 60.5 g, purified water, iron or manganese standard solution (total 100 ml) were prepared, and the change in absorbance at 420 nm with time and the degree of discoloration were examined at room temperature in a light-shielded state.
The absorbance was measured by directly measuring the sample with an ultraviolet-visible spectrophotometer using a quartz cell having a layer length of 1 cm. In this case, 95% ethanol was used for zero adjustment.
As a result, when the iron concentration of the preparation when it is prepared and filled into a light-shielding container (made of black polyethylene terephthalate) exceeds 60 ppb, or the manganese concentration of the preparation exceeds 1 ppb, it is stored at room temperature for 36 months after shading at room temperature. The absorbance at 420 nm exceeded 0.100, and the preparation changed to yellow (a color that may give an uneasiness that the preparation may have deteriorated or deteriorated).
On the other hand, when the iron concentration of the preparation is 60 ppb or less, or when the manganese concentration of the preparation is 1 ppb or less, the absorbance at 420 nm after light-shielded storage at room temperature for 36 months is 0.100 or less. The discoloration state of was only slightly yellow or light yellow.
[0006]
In addition, manganese and chromium, in addition to iron, exist in metals that dissolve and mix in minoxidil preparations. According to experiments, manganese and chromium are used as solvents in the process from preparation to filling in small containers. It was found that the amount of metal dissolved in the preparation is extremely small, and in most cases the concentration of these metals in the preparation is extremely low, so that it hardly causes the color development or discoloration of the minoxidil preparation as described above.
[0007]
The present invention is proposed based on the above-mentioned research results, and the object thereof is a minoxidil preparation in which discoloration of the preparation is suppressed over time, or the progress of discoloration of the preparation over time is extremely slow. It is in providing the manufacturing equipment which can manufacture.
Specifically, a minoxidil preparation that can suppress the iron concentration immediately after preparation to 60 ppb or less and therefore stays at least slightly yellow to light yellow when stored at room temperature for 36 months after preparation at room temperature is produced. An object of the present invention is to provide a manufacturing facility capable of performing the above.
[0008]
[Means for Solving the Problems]
The minoxidil preparation production equipment according to the present invention is configured as follows in order to solve the above-mentioned problems.
That is, the minoxidil preparation production facility according to claim 1 is installed until the preparation is fed to the filling unit 5 in the production facility for producing a minoxidil preparation containing minoxidil, propylene glycol, alcohol and purified water. In addition, the tanks 1 and the pipes 2 in contact with at least propylene glycol are made of a metal containing iron, and a perfluoroalkyl / tetrafluororesin copolymer or an ethylene / tetrafluoride resin copolymer is formed on the inner surface thereof. By fixing a film layer of a fluorine-based synthetic resin composed of coalescence , iron is prevented from eluting and mixing into the minoxidil formulation, and the time-lapse discoloration of the minoxidil formulation is suppressed .
[0009]
The minoxidil preparation manufacturing facility according to claim 2 is characterized in that, in the minoxidil preparation manufacturing facility according to claim 1 , the coating layer is subjected to antistatic treatment.
[0010]
DETAILED DESCRIPTION OF THE INVENTION
Embodiments of the minoxidil preparation production facility according to the present invention will be described in detail below.
FIG. 1 is a schematic view of a piping system showing an embodiment of a minoxidil preparation manufacturing apparatus, FIG. 2 is a partially enlarged sectional view of a tank in contact with propylene glycol in the piping system of FIG. 1, and FIG. It is a partial expanded sectional view of piping which glycol contacts.
[0011]
Reference numeral 10 is a propylene glycol storage tank, 30 is an ethanol storage tank, and 31 is a purified water storage tank.
When the minoxidil preparation is produced, the amount of propylene glycol, ethanol, and purified water is respectively transferred from the storage tanks 10, 30, and 31 through the pipes 20, 40, and 41 by pumps 40a and 41a. While being fed to the preparation preparation tank 11, a predetermined amount of white powdery minoxidil is supplied to the preparation tank 11.
[0012]
For example, when preparing a 1% minoxidil formulation,
Minoxidil ... 1.0g
Propylene glycol: 10.0ml (10.4g)
Ethanol ... 73.7ml (60.05g)
Purified water: 100ml
Each raw material is blended at such a ratio as follows.
When preparing a 2% minoxidil preparation, minoxidil 2.0 g, propylene glycol 20.0 ml (20.8 g), ethanol 73.7 ml (60.05 g), purified water ... Each raw material is blended in such a ratio that the total amount becomes 100 ml.
[0013]
The raw material supplied to the preparation tank 11 at the ratio as described above is sufficiently stirred by a stirring means (not shown) installed in the preparation tank 11 to prepare a minoxidil preparation.
The prepared preparation is sent to the preparation storage tank 12 through the pipe 21 by nitrogen pressure transportation, and is temporarily stored in the storage tank 12. The preparation stored in the storage tank 12 is sent to the filling unit 5 through the pipe 22 by nitrogen pressure transportation.
The formulation fed to the filling unit 5 is filled into a small-sized light-shielding container (not shown) by a certain amount by each filling nozzle 50 made of a fluorine-based synthetic resin (for example, “Teflon”) or ceramic.
[0014]
The tanks 10, 11, 12, 30, and 31 of the piping system constituting the manufacturing equipment of this embodiment and the pipes 20, 21, 22, 40, and 41 are SUS316, SUS304, and others having sufficient thickness in strength. Made of stainless steel.
In the above-described piping system, the tanks 1 such as the storage tank 10, the preparation tank 11 and the preparation storage tank 12 with which the propylene glycol contacts until the preparation reaches the filling section 5, and the pipes 20, 21, As shown in FIGS. 2 and 3, a coating layer a having propylene glycol resistance is fixed on the inner surface of the piping 2 such as 22.
In this embodiment, the coating layer a on the inner surfaces of the tanks 1 and the pipings 2 is obtained by fixing a fluorine-based synthetic resin to a thickness of about 200 to 1000 μm on the inner surface after pretreatment by lining by a coating film melting method. It is.
[0015]
The material of the film layer a in this embodiment may be a fluorine-based synthetic resin, but in order to better prevent iron from leaching from the metal constituting the walls of the tanks 1 and the pipes 2, From the viewpoint of heat resistance, it is preferable to use a perfluoroalkyl / tetrafluoride resin copolymer or an ethylene / tetrafluoride resin copolymer.
Further, since ethanol is used in the preparation as described above, it is desirable that the coating layer a be subjected to an antistatic treatment in order to prevent generation of static electricity inside.
[0016]
In the above-described piping system, the tanks 3 such as the ethanol storage tank 30 and the purified water storage tank 31 that do not come in contact with propylene glycol until the preparation reaches the filling section 5, and the preparation tank 11. The inner surfaces of the pipes 4 such as the connecting pipes 40 and 41 are buffed and pickled. Alternatively, the inner surface may be electrolytically polished after buffing.
[0017]
According to the minoxidil preparation production facility of the above embodiment, fluorine synthetic resin (perfluoroalkyl quaternary 4) is formed on the inner surfaces of the tanks 1 and the pipes 2 in contact with the propylene glycol that is most likely to elute the metal in the raw material of the minoxidil preparation. Since the film layer a made of a fluororesin copolymer) is fixed, it is possible to prevent or remarkably suppress the elution / mixing of iron from the tanks 1 and the pipes 2 into the preparation.
Ethanol and purified water have less metal elution than propylene glycol, but are not completely absent. However, tanks 3 such as ethanol storage tank 30 and purified water storage tank 31 are connected to preparation tank 11. Since the inner surfaces of the pipes 4 such as the pipes 40 and 41 are subjected to acid cleaning or electrolytic polishing after buffing, the smoothness of the inner surfaces is increased, and the contact area between the inner surfaces and ethanol or purified water is reduced. From the tanks 3 and the pipes 4, it is possible to prevent or remarkably suppress the elution of iron into the preparation via ethanol or purified water.
Further, since the coating layer a is subjected to antistatic treatment, static electricity is not generated, and there is no possibility of igniting ethanol in the preparation.
[0018]
Other Embodiments The coating layer a having propylene glycol resistance has a thickness of 1000 to 2500 μm (ground coat on the base metal side) by lining glass (glass lining) on the inner surfaces of the tanks 1 and the pipes 2 after pretreatment. It can be carried out even if it is fixed to about 200 to 500 μm and a cover coat of 800 to 2000 μm on the contact surface side with propylene glycol.
The glass material is preferably glass having corrosion resistance, chemical resistance, impact resistance and abrasion resistance (ordinary physicochemical glass or glass having high corrosion resistance higher than that).
Further, since ethanol is used in the minoxidil preparation as described above, the glass is preferably an antistatic glass.
Antistatic glass is a glass in which the volume resistivity (electric resistance) rate of insulating glass is lowered to a level that can prevent electrostatic charging. For example, platinum fiber having extremely low chemical reactivity is incorporated into the glass structure. Three-dimensionally dispersed and baked, and its volume resistivity is 10 ¹⁰ Ω · cm or less (preferably 10 ⁸ Ω · cm or less).
Since the operations and effects of the manufacturing facility of this embodiment are the same as those of the manufacturing facility of the above-described embodiment, description thereof will be omitted.
[0019]
Test Example The following Ex1 to Ex10 plate-like test pieces (dimensions 20 mm x 45 mm) were prepared, and these test pieces were made of purified water, ethanol, propylene glycol (PG), and 1% minoxidil formulation (minoxidil), respectively. 1.0 g, 10 ml of propylene glycol (10.4 g), 73.7 ml (60.05 g) of ethanol, 100 ml of purified water) for 10 days each (surface area of test piece / amount of immersion liquid = 9 cm ²⁾
/ 15 ml), the elution amount of iron was measured for each, and this is shown in Table 1. The amount of elution of iron was determined by measuring the initial concentration of iron for purified water, ethanol, propylene glycol (PG) and the preparation (“Ex0” in the column of “Test piece” in Table 1 corresponds to this), and soaking for 10 days. The initial concentration is subtracted from the later measured value of iron concentration.
[0020]
Ex1: Buffed surface of SUS304 (used buff: # 320, the same applies hereinafter) Ex2: Acid cleaned after buffing the surface of SUS304 (used acid: 30% nitric acid, between immersions: 3 hours, the same applies hereinafter) Ex3: The surface of SUS316 was buffed. Ex4: The surface of SUS316 was buffed and then acid-washed, washed with water and then electropolished (electrolyte used: phosphoric acid 60%, sulfuric acid 40%, electrolysis conditions: temperature 80-120. Ex 5: Lined with an ethylene / tetrafluoride resin copolymer film layer (film thickness 400 μm) on the surface of SUS304 (coating after pretreatment and in a furnace at 400 ° C. or lower) Ex6: A film layer of ethylene / tetrafluororesin copolymer (film thickness 400μm) is lined on the surface of SUS304, and the film layer is antistatic treated. Ex7: A perfluoroalkyl / tetrafluororesin copolymer film layer (film thickness 400 μm) was lined on the surface of SUS304 (coating after pretreatment and drying in a furnace at 400 ° C. or lower). Ex8: Perfluoroalkyl / tetrafluororesin copolymer film layer (film thickness 400 μm) is lined on the surface of SUS304 and antistatic treatment is applied to the film layer. Ex9: Glass is lined on the surface of SUS304 ( After pretreatment, ground coat: 300 μm, cover coat: 900 μm, fused at a firing temperature of 800 to 900 ° C. Ex10: Antistatic glass on the surface of SUS304 (platinum fiber is dispersed in the glass structure, and its volume after the the resistivity of those below 10 ⁸ Ω · cm) lining (pre-treatment, Grand Court: 300μm, cover coat: That the 00μm, was fused) at a firing temperature 800~900 ℃ [0021]
The methods for measuring the iron concentration of purified water, ethanol, propylene glycol (PG) and minoxidil preparations were as follows.
Measuring method of iron concentration Equipment and instruments used: Polarized Zeeman atomic absorption photometer: Z-8000, manufactured by Hitachi, Ltd.
-Sample cup: Made by Hitachi, Ltd. using the brand name "Teflon".
After soaking in 30% nitric acid for 1 day or more, wash in the order of ultrapure water and ethanol and air dry.
2. Measurement of iron concentration: Standard addition method For each sample, the absorbance is measured by graphite furnace atomic absorption spectrophotometry. Then, as shown in FIG. 4, the horizontal axis represents the metal standard solution addition concentration, the horizontal axis represents the absorbance, and the respective values of the graph are plotted. The regression line obtained from the plot is extended, and the horizontal axis and the origin are plotted. The metal content was determined from the distance. However, the horizontal axis was corrected by blank (diluent) absorbance.
Actually, it was displayed on the display device of the data processing device attached to the device.
3. Measurement condition
(1). INSTRUMENTAL CONDITIONS
LAMP CURRENT (mA) ... 15.0
WAVELENGTH (nm) ... 248.3
SLIT (nm) ... 0.2
CURRIRE GAS ・ ・ ・ ・ ・ ・ ・ ・ ・ 200ml / min
SAMPLE VOLUME ・ ・ ・ ・ ・ ・ ・ ・ 20μl
CUVETTE ・ ・ ・ ・ ・ ・ ・ ・ ・ ・ ・ PYRO-COATED TUBE
(2). TEMPERATURE PROGRAM
No. STAGE TEMPERATURE (℃) TIME
START END (sec)
1 DRY ... 90 180 50
2 DRY ... 180 230 30
3 ASH ・ ・ ・ ・ 1400 1400 30
4 ATOM ・ ・ ・ 2900 2900 10 (CARRIER GAS
: INTERRUPT)
5 CLEAN ... 3000 3000 3
[0022]
[Table 1]
┌──┬───────────────────────────────┐
│Test│ Fe concentration, elution amount (ppb) │
│Kita ├───────┬───────┬───────┬───────┤
│ │ Purified water │ Ethanol │ PG │ Formulation │
│ ├───┬───┼───┬───┼───┬───┼───┬───┤
│ │Measured value │Elution volume │Measured value │Elution volume │Measured value │Elution volume │Measured value │Elution volume│
├──┼───┼───┼───┼───┼───┼───┼───┼───┤
│Ex 0│ 0.1│ − │ 0.0│ − │ 0.9│ − │ 6.6│ − │
│Ex 1│ 1.0│ 0.9│ 0.8│ 0.8│ 17.4│ 16.5│ 39.8│ 33.2│
│Ex 2│ 0.1│ 0.0│ 0.0│ 0.0│ 2.5│ 1.6│ 12.8│ 6.2│
│Ex 3│ 1.0│ 0.9│ 0.5│ 0.5│ 13.6│ 12.7│ 35.7│ 29.1│
│Ex 4│ 0.1│ 0.0│ 0.0│ 0.0│ 2.7│ 1.8│ 14.7│ 8.1│
│Ex 5│ ※ │ ※ │ ※ │ ※ │ 1.0│ 0.1│ 6.6│ 0.0│
│Ex 6│ ※ │ ※ │ ※ │ ※ │ 0.9│ 0.0│ 6.6│ 0.0│
│Ex 7│ ※ │ ※ │ ※ │ ※ │ 0.9│ 0.0│ 6.6│ 0.0│
│Ex 8│ ※ │ ※ │ ※ │ ※ │ 0.9│ 0.0│ 6.6│ 0.0│
│Ex 9│ ※ │ ※ │ ※ │ ※ │ 1.0│ 0.1│ 6.6│ 0.0│
│Ex10│ ※ │ ※ │ ※ │ ※ │ 0.9│ 0.0│ 6.6│ 0.0│
└──┴───┴───┴───┴───┴───┴───┴───┴───┘
Note: * indicates not implemented (because elution could be prevented without coating).
[0023]
According to the results in Table 1, test pieces Ex5 to 8 in which a film layer made of a perfluoroalkyl / tetrafluororesin copolymer or an ethylene / tetrafluoride resin copolymer was fixed on the surface of a stainless steel piece, and The test pieces Ex9 and 10 having a glass lining on the surface of a stainless steel piece have no or very little elution of iron into propylene glycol and a preparation containing it. Therefore, when a film layer made of fluorine-based synthetic resin or glass is fixed on the inner surface of iron or stainless steel tanks or pipes in contact with propylene glycol or a preparation containing the same, a minoxidil preparation having an iron concentration of 60 ppb or less is obtained. The discoloration of the preparation after storage for 36 months at room temperature and after shading can be suppressed to a slight yellow or light yellow level.
In addition, the test pieces Ex2 and 4 obtained by acid cleaning or electropolishing the surface of the stainless steel piece after buffing have no elution of iron into purified water and ethanol, and thus contact with purified water and ethanol in the preparation process of the preparation. When the inner surfaces of stainless steel tanks and piping are buffed and then acid cleaned or electropolished, a minoxidil preparation having an iron concentration of 60 ppb or less can be prepared.
[0024]
【The invention's effect】
According to the minoxidil preparation manufacturing facility according to the first aspect of the present invention, a coating made of a fluorine-based synthetic resin is formed on the inner surfaces of the tanks 1 and the pipes 2 in contact with the propylene glycol that is most likely to elute the metal in the raw materials of the minoxidil preparation. Since the layer a is fixed, it is possible to prevent or remarkably suppress the dissolution and mixing of iron from the tanks 1 and the pipes 2 into the preparation.
Therefore, it is possible to produce a minoxidil preparation in which the progress of discoloration over time is extremely suppressed.
[0025]
According to the minoxidil preparation manufacturing facility according to the invention of claim 2 , since the antistatic treatment is applied to the coating layer a, static electricity is not generated and there is no possibility of igniting ethanol in the preparation.
[Brief description of the drawings]
FIG. 1 is a schematic view of a piping system showing an embodiment of a minoxidil preparation production facility according to the present invention.
FIG. 2 is a partially enlarged cross-sectional view of a tank in contact with propylene glycol in the piping system of FIG.
3 is a partially enlarged cross-sectional view of a pipe in contact with propylene glycol in the pipe system of FIG.
FIG. 4 shows the coordinates used for measuring the absorbance when measuring the iron concentration in the test example.
[Explanation of symbols]
1, 3 Tanks 2, 4 Piping 10, 12, 30, 31 Storage tank 11 Preparation tank 20, 21, 22, 40, 41 Piping 40a, 41a Pump 5 Filling section 50 Filling nozzle

Claims (2)

Tanks 1 and pipes installed in the production facility for producing a minoxidil formulation containing minoxidil, propylene glycol, alcohol and purified water until the formulation is fed to the filling section 5 and at least in contact with propylene glycol with constituting the class 2 with a metal containing iron, to fix the coating layer of a fluorine-based synthetic resin on their inner surfaces made of perfluoroalkyl-tetrafluoride resin copolymer or ethylene tetrafluoride resin copolymer The minoxidil preparation manufacturing equipment which prevents iron from eluting and mixing in the minoxidil preparation and suppresses the discoloration of the minoxidil preparation over time .   The facility for producing minoxidil preparation according to claim 1 or 2, wherein the coating layer made of the fluorine-based synthetic resin is subjected to an antistatic treatment.

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