CN108883190B - Amorphizing agent, amorphous composition containing amorphizing agent, and use thereof - Google Patents
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Abstract
The purpose of the present invention is to provide a technique for amorphizing a compound represented by the general formula (1) and/or a salt thereof. The purpose of the present invention is to provide an amorphizing agent for a compound represented by the general formula (1) and/or a salt thereof, which is composed of one or more kinds selected from the group consisting of a water-soluble polymer and an acid.
Description
Technical Field
The present invention relates to an amorphizing agent for a compound represented by the following general formula (1) and/or a salt thereof, an amorphous composition containing the amorphizing agent, and use thereof.
[ chemical formula 1]
Background
It is known that a compound represented by the general formula (1) such as luliconazole or lanoconazole has high crystallinity and excellent antifungal activity, but on the other hand, it has high crystallization property and is characterized by being difficult to handle in the production process. Further, since the stability is also poor in light stability, if it takes too much time in the production or formulation process, the production amount of the like may increase (for example, see patent documents 1 to 2). Further, these patent documents disclose that the migration into the living body is suppressed even when crystallization is carried out in the preparation, and that the development of a means for suppressing crystallization is also a technical problem in the preparation of the compound represented by the general formula (1). Further, these patent documents disclose that an α -hydroxy acid such as lactic acid suppresses the instantaneous crystallinity of the compound represented by the general formula (1), but the mechanism of this suppression of the instantaneous crystallinity is not disclosed at all.
As a technique for suppressing such crystallization, for example, a technique of forming a liquid viscous film by using a plasticizer such as polyoxyethylene polyoxypropylene in an excessive amount is known (for example, see patent document 3), however, this technique has the following disadvantages: the mass of the compound represented by the general formula (1) that can be contained in the film is limited.
It is known that the solubility, particularly the dissolution rate, can be improved in general by amorphization. Therefore, amorphization is an important technique for injection preparations and the like (for example, see patent document 4).
On the other hand, although a monoclinic system is known for the compound represented by the general formula (1), it is not known at all for an amorphous solid.
That is, in order to improve the availability of the compound represented by the general formula (1) and/or a salt thereof, development of an amorphization technique of the compound represented by the general formula (1) and/or a salt thereof is desired.
Documents of the prior art
Patent document
Patent document 1: WO2007/102241
Patent document 2: WO2007/102243
Patent document 3: WO2003/105841
Patent document 4: japanese patent laid-open No. 2006-312598
Disclosure of Invention
Technical problem to be solved by the invention
The present invention has been made under such circumstances, and an object of the present invention is to improve the usability of the compound represented by the general formula (1) and/or a salt thereof, and to improve the amorphization technique of the compound represented by the general formula (1) and/or a salt thereof.
Means for solving the problems
In view of the above circumstances, the present inventors have made extensive studies to find a technique for amorphizing a compound represented by the general formula (1) and/or a salt thereof in order to improve the usability of the compound represented by the general formula (1) and/or the salt thereof. As a result, they have found that the amorphization can be carried out by using one or more kinds selected from water-soluble polymers and acids as an amorphizing agent, and have completed the present invention. Namely, the present invention is as follows.
[1] An amorphizing agent which contains one or more selected from a water-soluble polymer and an acid and is a compound represented by the following general formula (1) and/or a salt thereof.
[ chemical formula 2]
General formula (1)
In the formula, R1And R2Each independently represents a hydrogen atom or a halogen atom.
[2] The amorphizing agent according to [1], wherein,
the water-soluble polymer is a vinyl water-soluble polymer or a cellulose water-soluble polymer.
[3] The amorphizing agent according to [2], wherein,
the vinyl water-soluble polymer is polyvinylpyrrolidone or carboxyvinyl polymer.
[4] The amorphizing agent according to [2], wherein,
the cellulose water-soluble polymer is hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, methylcellulose or ethylcellulose.
[5] The amorphizing agent according to any one of [1] to [4], wherein,
the acid is an organic acid.
[6] The amorphizing agent according to any one of [1] to [5], which comprises a water-soluble polymer and an acid.
[7] The amorphizing agent according to any one of [1] to [6], wherein,
the compound shown in the general formula (1) is luliconazole or lanoconazole,
[ chemical formula 3]
Luliconazole
[ chemical formula 4]
Lanoconazole.
[8] A method for amorphizing a compound represented by the general formula (1) and/or a salt thereof, which comprises:
and (2) uniformly mixing the compound represented by the general formula (1) and/or a salt thereof with the amorphizing agent described in any one of [1] to [7] in an amount of 0.05 to 10 times the mass of the compound and/or the salt thereof, and solidifying the mixture.
[9] An amorphous composition comprising a compound represented by the general formula (1) and/or a salt thereof, and an amorphizing agent described in any one of [1] to [7] in an amount of 0.05 to 10 times the mass of the compound and/or the salt thereof.
[10] A process for producing a pharmaceutical composition containing a compound represented by the general formula (1) and/or a salt thereof, which comprises:
a step of using the amorphous composition according to [9] as an intermediate product and dissolving the intermediate product.
[11] A composition comprising a compound represented by the general formula (1) and/or a salt thereof, and an amorphizing agent described in any one of [1] to [7] in an amount of 0.05 to 10 times the mass of the compound and/or the salt thereof.
[12] The composition according to [11], which further contains a solvent to be volatilized.
[13] The composition according to [11] or [12], which is a medicament.
ADVANTAGEOUS EFFECTS OF INVENTION
The present invention can provide a technique for amorphizing a compound represented by the general formula (1) and/or a salt thereof.
Drawings
FIG. 1 is a photograph (a photograph in place of a drawing) showing a process of forming a coating film from the composition of example 1. LLCZ stands for luliconazole, PVP stands for polyvinylpyrrolidone. Fig. 1A is a photograph immediately after dropping, fig. 1B is a photograph after 4 hours of dropping, fig. 1C is a photograph after 1 day of dropping, and fig. 1D is a photograph after 4 days of dropping. In fig. 1A to 1D, the left side shows a sample containing no amorphizing agent (luliconazole solution), and the right side shows a sample containing an amorphizing agent (luliconazole + polyvinylpyrrolidone solution). In fig. 1A to 1D, the upper part shows an observation image of an optical microscope, and the lower part shows an observation image of a polarization microscope.
FIG. 2 is a photograph (photograph in place of the drawing) showing a process of forming a coating film from the composition of example 2. The photograph is a photograph after 0.5 minute of dropping. The lead line indicates the beginning of the appearance of micelles.
FIG. 3 is a photograph (photograph in place of the drawing) showing a process of forming a coating film from the composition of example 2. The photograph is a photograph after dropping for 1 minute. This indicates a structure in which micelles are dispersed.
FIG. 4 is a photograph (photograph in place of the drawing) showing a process of forming a coating film from the composition of example 2. The photograph is taken 3 minutes after dropping. This indicates a coating film in which the amorphous form of the micelle structure is dispersed in the amorphous form of the continuous phase.
Detailed Description
(1) The amorphizing agent of the present invention
The amorphizing agent of the present invention is an amorphizing agent of a compound represented by the general formula (1) and/or a salt thereof, and the amorphizing agent contains one or more selected from the group consisting of a water-soluble polymer and an acid.
Examples of the water-soluble polymer include vinyl water-soluble polymers such as polyvinyl alcohol, polyvinyl pyrrolidone and carboxyvinyl polymers, cellulose water-soluble polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose terephthalate, hydroxyethyl methylcellulose and ethyl cellulose, and polysaccharide water-soluble polymers such as gum arabic, tragacanth gum and xanthan gum. Among them, preferable examples include a vinyl-based water-soluble polymer and a cellulose-based water-soluble polymer. The vinyl polymer preferably includes polyvinylpyrrolidone or a carboxyvinyl polymer, and the cellulose-based water-soluble polymer preferably includes hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl methyl cellulose, or ethyl cellulose. One or two or more kinds of water-soluble polymers may be used.
Preferred examples of the acid include organic acids and inorganic acids, and the organic acids include hydroxy acids such as citric acid, lactic acid and gluconic acid, dibasic acids such as oxalic acid, tartaric acid and adipic acid, carboxylic acids such as formic acid and acetic acid, and particularly preferred are hydroxy acids and dibasic acids. Among them, lactic acid is preferable as the hydroxy acid, and tartaric acid is particularly preferable as the dibasic acid. The inorganic acid is preferably mineral acid or the like. As the acid, one or two or more kinds may be used.
The water-soluble polymer and the acid may be used alone or in combination of two or more. A preferable embodiment is a method of using a water-soluble polymer and an acid in combination.
The amount of the amorphizing agent used in the present invention is preferably 0.05 to 10 times, more preferably 0.5 to 5 times, and still more preferably 0.7 to 3 times the total mass of the compound represented by the general formula (1) and/or the salt thereof. This is because when the equivalent is too small, the amorphization may not be sufficiently performed, and when it is too large, the dosage form is limited. When the water-soluble polymer and the acid are used in combination, the mass ratio of the water-soluble polymer to the acid is preferably 1 to 15% by mass, more preferably 4 to 10% by mass.
As the amorphizing agent of the present invention, when luliconazole is used as the compound represented by the general formula (1), a combination of lactic acid and polyvinylpyrrolidone is preferable as the amorphizing agent, and when lanoconazole is used, a combination of hydroxypropylcellulose, tartaric acid and lactic acid is preferable.
(2) A compound represented by the general formula (1) and/or a salt thereof
The target compound of the amorphizing agent of the present invention is represented by the general formula (1).
In the general formula (1), R1And R2The group represented is a hydrogen atom or a halogen atom, and preferable examples of the halogen atom include a chlorine atom, a bromine atom, a fluorine atom, an iodine atom and the like. Particularly preferred is a hydrogen atom or a chlorine atom.
Among the compounds represented by the general formula (1) and/or salts thereof, luliconazole (R) is particularly preferable1＝R2Cl; (R) - (-) - (E) - [4- (2, 4-dichlorophenyl) -1, 3-dithiolan-2-ylidene]-1-imidazoleacetonitrile) and lanoconazole (R)1＝Cl、R2H; 4- (2-chlorophenyl)) -1, 3-dithiolan-2-ylidene-1-imidazolylacetonitrile), luliconazole is particularly preferred.
Such a compound can be synthesized, for example, according to the method described in Japanese patent laid-open No. Sho 60-218387. Specifically, it can be synthesized by the method described in the following formula. That is, as shown below, 1-cyanomethylimidazole is reacted with carbon disulfide to obtain a compound of formula (III), and the compound is reacted with a compound of general formula (II) having a leaving group to obtain a compound represented by formula (I). Preferred examples of the leaving group are a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, a halogen atom and the like. In the following formula, R and X represent a hydrogen atom or a halogen atom.
[ chemical formula 5]
In the formula, Y, Y' represents a leaving group, and M represents an alkali metal.
The compound represented by the general formula (1) which is the object of the amorphizing agent of the present invention may be used together with sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, and the like as a physiologically acceptable salt. In this case, the salt is a salt which can be stably present in the presence of the amorphizing agent.
(3) Amorphous compositions of the invention
The amorphous composition of the present invention is essentially composed of the amorphizing agent of the present invention and the compound represented by the general formula (1) and/or a salt thereof. The amorphous composition of the invention can be obtained by: the compound represented by the general formula (1) and/or a salt thereof and an amorphizing agent in an amount of 0.05 to 10 times the mass of the compound and/or the salt thereof are uniformly mixed, and the solvent is volatilized to solidify the compound and/or the salt thereof. The composition of the present invention is obtained by uniformly mixing a compound represented by the general formula (1) and/or a salt thereof with an amorphizing agent in an amount of 0.05 to 10 times the mass of the compound and/or the salt thereof. The composition of the present invention may contain a solvent in addition to the compound represented by the general formula (1) and/or a salt thereof and the amorphizing agent. Since the compound represented by the general formula (1) and/or a salt thereof has an antifungal effect, the composition of the present invention may be a pharmaceutical composition, preferably an antifungal pharmaceutical composition, more preferably an antifungal pharmaceutical composition for nail use. Furthermore, the composition of the present invention may also be a composition for the preparation of a medicament, i.e. an intermediate product for the preparation of a medicament.
Since the compound represented by the general formula (1) and/or a salt thereof has an antifungal effect, the composition of the present invention may be a pharmaceutical composition, preferably an antifungal pharmaceutical composition, more preferably an antifungal pharmaceutical composition for nail use.
The dosage form of the pharmaceutical composition is preferably a film-coated dosage form. The mode of use may be suitably selected in consideration of the body weight, age, sex, symptoms, etc. of a patient, and in the case of an adult, usually, the compound represented by the general formula (1) and/or a salt thereof is preferably administered in an amount of 0.01 to 1g per day. In addition, the amount of the compound represented by the general formula (1) and/or a salt thereof which is generally used for diseases caused by fungi can be referred to.
For example, an appropriate amount is applied to the disease site once or several times a day, and such treatment is preferably performed on consecutive days.
Such compositions may contain, in addition to the essential ingredients, optional ingredients used in pharmaceutical compositions and the like. Examples of such optional components include excipients, dispersants, flavoring agents, coloring agents, and surfactants. The proportion of optional ingredients in the composition of the present invention is not limited as long as the amorphous state is maintained, and generally, the upper limit thereof is preferably 50% by mass relative to the amorphous composition as a whole. That is, such a composition may contain an amorphizing agent and 50 to 100% by mass of the compound represented by the above general formula (1) and/or a salt thereof with respect to the entire amorphous composition. The mixing ratio of the amorphizing agent and the compound represented by the general formula (1) and/or a salt thereof is the same as the mixing ratio described in the above-mentioned "(1) amorphizing agent of the present invention".
The present invention also relates to a method for amorphizing a compound represented by the general formula (1) and/or a salt thereof by using the amorphizing agent of the present invention. The amorphization method comprises the following steps: a compound represented by the general formula (1) and/or a salt thereof and an amorphizing agent in an amount of 0.05 to 10 times the mass of the compound and/or the salt thereof are uniformly mixed and cured. The method of uniformly mixing the compound represented by the general formula (1) and/or a salt thereof with the amorphizing agent is, for example, a method of dissolving the compound represented by the general formula (1) and/or a salt thereof in a solvent, adding the amorphizing agent, and mixing. As a method of curing, for example, it can be performed by storing at room temperature after mixing and removing the solvent.
The present invention also relates to a method for producing a pharmaceutical composition containing a compound represented by the general formula (1) and/or a salt thereof, which comprises a step of using an amorphous composition as an intermediate product and dissolving the intermediate product.
The amorphous composition of the present invention provides a stable intermediate product that is easily soluble as an intermediate product. By using such an intermediate product, a method for producing a pharmaceutical composition containing a compound represented by the general formula (1) and/or a salt thereof, in which the formation of the analog is less, can be provided.
Furthermore, the amorphous composition of the present invention, in medicine, can be used as a final coating film for products, an intermediate product for product manufacture.
The amorphous composition of the present invention is an intermediate product (also referred to as "production intermediate" or "intermediate product") for obtaining a pharmaceutical composition containing a compound represented by the general formula (1) and/or a salt thereof stably. By using such an intermediate product, the production of the analog during the production of the pharmaceutical composition can be suppressed to a low level.
The amorphous composition of the present invention may be a film-coated preparation as a product or a film formed when a pharmaceutical composition is finally administered to a target site, and this amorphization can improve the permeability of the compound represented by the general formula (1) and/or a salt thereof to the skin and can maintain a high tissue concentration for a long period of time. This is because amorphous acts as a reservoir. As for the amorphization of such a thin film as a final formulation, the present invention is directed as long as the film has the characteristics of an amorphous film.
The coating film as a final product can be used for forming a coating film of an active ingredient on a carrier such as a pellet, for example, a coating film of a pharmaceutical composition formed on the skin or nail. The coating film of the amorphous composition can improve the bioavailability of the compound represented by the general formula (1) and/or a salt thereof as an active ingredient. This is due to the reservoir effect described above.
Examples
Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples as long as the gist thereof is not exceeded.
< example 1>
An ethanol solution containing 1 mass% of luliconazole and 0.1 mass% of polyvinylpyrrolidone were prepared, and dropped on a slide glass, and the properties thereof were observed under a microscope immediately after dropping, after storage at room temperature for 4 hours after dropping, after storage at room temperature for 1 day after dropping, and after storage at room temperature for 4 days after dropping, respectively. Microscopic observation was performed by a general optical microscope and a polarization microscope. The results are shown in FIG. 1. From this, it is found that a difference in crystallization is observed in the amorphizing agent of the present invention, and polyvinylpyrrolidone is known to function as an amorphizing agent. As described above, even when crystals and amorphousness are present in a mixed state, the effect of the amorphizing agent of the present invention can be judged by the fact that only a substance which should be originally in a crystalline state can coexist with (an amorphous structure is formed) an amorphizing agent of the present invention.
< example 2>
For pharmaceutical composition 1 having the following formulation, a capsule preparation was prepared by the following procedure.
[ Table 1]
The luliconazole is mixed with ethanol, heated and stirred at 70 ℃ to be dissolved, then lactic acid and polyvinylpyrrolidone are added, heated and stirred at 70 ℃, after the dissolution is confirmed, the remaining solvent component is added to be diluted, the mixture is stirred and dissolved, after the dissolution is confirmed, the mixture is stirred and cooled to room temperature, and the pharmaceutical composition 1 is obtained.
< Process for Forming coating film of pharmaceutical composition 1 produced >
1mL of the pharmaceutical composition 1 was taken into a tube, 100. mu.L of a solution obtained by dissolving 10mg of neutral red in 200. mu.L of methanol was added to the tube, and after sufficiently stirring, it was dropped on a slide glass, and the solvent evaporation and the film formation process were observed by a microscope (400 times) at room temperature. The observation process is shown in FIGS. 2-4. Micelle-like structures begin to appear in the homogeneous phase (fig. 2), such micelle structures increase (fig. 3), and amorphous films with micelle-like structures uniformly dispersed in the continuous phase-like structure (fig. 4). This proves the effect of amorphization of polyvinylpyrrolidone and lactic acid as the amorphizing agents of the present invention.
< example 3>
The following formulations of pharmaceutical compositions 2 and 3 (capsule preparations) shown in table 2 were prepared according to the procedure shown in example 2. Further, according to the method described in example 2, the film formation process was observed by a microscope (400 times). In the pharmaceutical compositions 2 and 3, similarly to the pharmaceutical composition 1, an amorphous film in which micelle-like structures are uniformly dispersed in a continuous phase-like structure was observed, and an amorphizing effect was confirmed.
[ Table 2]
Industrial applicability
The invention can be applied to medicines and medicine manufacturing.
Claims (7)
1. Use of polyvinylpyrrolidone as an amorphizing agent for a coating film preparation of luliconazole and/or a salt thereof.
2. The use according to claim 1, wherein,
the amorphizing agent also contains lactic acid.
3. A method for amorphizing luliconazole and/or a salt thereof, comprising:
a step of uniformly mixing luliconazole and/or a salt thereof with the amorphizing agent according to claim 1 or 2 in an amount of 0.05 to 10 times the mass of luliconazole and/or a salt thereof, and solidifying the mixture.
4. An amorphous composition comprising luliconazole and/or a salt thereof, and the amorphizing agent according to claim 1 or 2 in an amount of 0.05 to 10 times by mass of the luliconazole and/or the salt thereof.
5. A method for preparing a pharmaceutical composition containing luliconazole and/or a salt thereof, which comprises:
a step of using the amorphous composition according to claim 4 as an intermediate product and dissolving the intermediate product.
6. The composition of claim 4, further comprising a solvent to be volatilized.
7. The composition of claim 4 or 6, which is a medicament.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2016071569 | 2016-03-31 | ||
| JP2016-071569 | 2016-03-31 | ||
| PCT/JP2017/012578 WO2017170509A1 (en) | 2016-03-31 | 2017-03-28 | Amorphizing agent, amorphous composition comprising amorphizing agent and utilization thereof |
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| Publication Number | Publication Date |
|---|---|
| CN108883190A CN108883190A (en) | 2018-11-23 |
| CN108883190B true CN108883190B (en) | 2022-07-01 |
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| JP (1) | JP7021827B2 (en) |
| KR (1) | KR102359641B1 (en) |
| CN (1) | CN108883190B (en) |
| AU (1) | AU2017244688B2 (en) |
| MY (1) | MY197992A (en) |
| PH (1) | PH12018502095A1 (en) |
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| WO (1) | WO2017170509A1 (en) |
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| JP2017181387A (en) * | 2016-03-31 | 2017-10-05 | 株式会社ポーラファルマ | Evaluation method of film formed by pharmaceutical composition |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007102241A1 (en) * | 2006-03-08 | 2007-09-13 | Nihon Nohyaku Co., Ltd. | External pharmaceutical composition |
| WO2007102243A1 (en) * | 2006-03-08 | 2007-09-13 | Nihon Nohyaku Co., Ltd. | External pharmaceutical composition |
| CN102387785A (en) * | 2009-04-09 | 2012-03-21 | 宝丽制药股份有限公司 | Antimycotic pharmaceutical composition |
| CN103732216A (en) * | 2011-08-16 | 2014-04-16 | 默沙东公司 | Use of inorganic matrix and organic polymer combinations for preparing stable amorphous dispersions |
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| JP3959205B2 (en) * | 1999-08-04 | 2007-08-15 | ポーラ化成工業株式会社 | Surface-treated powder and external preparation for skin containing the same |
| EP1537868B1 (en) | 2002-06-18 | 2011-08-24 | Pola Pharma Inc. | Antifungal medicinal compositions |
| JP2006312598A (en) | 2005-05-09 | 2006-11-16 | Pola Chem Ind Inc | Medicinal composition |
| JP4999412B2 (en) * | 2006-09-20 | 2012-08-15 | ポーラ化成工業株式会社 | Fine particle powder and method for producing the same |
| CN101808638B (en) * | 2007-09-05 | 2012-07-25 | 宝丽制药股份有限公司 | Antifungal composition |
| JP5662495B2 (en) * | 2013-02-08 | 2015-01-28 | 株式会社ポーラファルマ | Pharmaceutical composition in solubilizer form |
| JP6503626B2 (en) * | 2013-03-28 | 2019-04-24 | 大正製薬株式会社 | Pharmaceutical composition |
| JP5587488B1 (en) * | 2013-12-12 | 2014-09-10 | 株式会社ポーラファルマ | Evaluation method and index substance of preparation containing luliconazole |
-
2017
- 2017-03-28 JP JP2017062515A patent/JP7021827B2/en active Active
- 2017-03-28 AU AU2017244688A patent/AU2017244688B2/en active Active
- 2017-03-28 SG SG11201808660UA patent/SG11201808660UA/en unknown
- 2017-03-28 CN CN201780021615.4A patent/CN108883190B/en active Active
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- 2017-03-28 KR KR1020187031311A patent/KR102359641B1/en active IP Right Grant
- 2017-03-28 WO PCT/JP2017/012578 patent/WO2017170509A1/en active Application Filing
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- 2018-09-28 PH PH12018502095A patent/PH12018502095A1/en unknown
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| WO2007102241A1 (en) * | 2006-03-08 | 2007-09-13 | Nihon Nohyaku Co., Ltd. | External pharmaceutical composition |
| WO2007102243A1 (en) * | 2006-03-08 | 2007-09-13 | Nihon Nohyaku Co., Ltd. | External pharmaceutical composition |
| CN102387785A (en) * | 2009-04-09 | 2012-03-21 | 宝丽制药股份有限公司 | Antimycotic pharmaceutical composition |
| CN103732216A (en) * | 2011-08-16 | 2014-04-16 | 默沙东公司 | Use of inorganic matrix and organic polymer combinations for preparing stable amorphous dispersions |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20180126058A (en) | 2018-11-26 |
| CN108883190A (en) | 2018-11-23 |
| KR102359641B1 (en) | 2022-02-08 |
| JP2017186317A (en) | 2017-10-12 |
| SG11201808660UA (en) | 2018-11-29 |
| AU2017244688B2 (en) | 2022-11-10 |
| JP7021827B2 (en) | 2022-02-17 |
| WO2017170509A1 (en) | 2017-10-05 |
| MY197992A (en) | 2023-07-25 |
| PH12018502095A1 (en) | 2019-07-15 |
| AU2017244688A1 (en) | 2018-11-22 |
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