AU2017244688B2 - Amorphizing agent, Amorphous composition comprising Amorphizing agent and utilization thereof - Google Patents
Amorphizing agent, Amorphous composition comprising Amorphizing agent and utilization thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Abstract
The present invention addresses the problem of providing a technique for amorphizing a compound represented by general formula (1) and/or a salt thereof. Provided is an amorphizing agent for a compound represented by general formula (1) and/or a salt thereof, said amorphizing agent comprising one or more members selected from among water-soluble polymers and acids.
Description
Technical Field
[0001]
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 comprising the amorphizing agent, and use thereof
[0002]
R1 R2 /CN
General Formula (1)
(In the formula, R1 and R2 each independently represent a hydrogen atom or a
halogen atom.)
Background Art
[0003]
Compounds represented by General Formula (1) such as luliconazole and
lanoconazole are known to have high crystallinity and excellent antifungal activity.
However, because of their high crystallization and precipitation properties, they
cannot be easily handled during the production process. Those compounds also
have a drawback in stability since they have poor photostability. Therefore, when the process of production or formulation takes a long time, the amount of analogs produced may increase (see, for example, Patent Documents 1 and 2). Moreover, these Patent Documents revealed that instantaneous crystallization occurs during their formulation to inhibit transfer of the compounds into the body, and therefore development of means for suppressing the crystallization has been an issue to be achieved for formulation of compounds represented by General Formula (1). These
Patent Documents also disclose that a-hydroxy acid such as lactic acid suppresses the
instantaneous crystallization of compounds represented by General Formula (1), but
they do not disclose at all by what mechanism the suppression of the instantaneous
crystallization can be achieved.
[0004]
As such a crystallization-suppressing technique, a technique in which an
excess amount of plasticizer such as polyoxyethylene polyoxypropylene is used to
prepare a liquid viscous coating has been known (see, for example, Patent Document
3). However, this technique has a drawback that the mass of the compound
represented by General Formula (1) that can be contained in the coating is limited.
[0005]
It is generally known that solubility, especially the rate of dissolution,
increases by amorphization. Therefore, amorphization has been an important
technique for injections and the like (see, for example, Patent Document 4).
[0006]
On the other hand, regarding compounds represented by General Formula (1),
although their monoclinic crystal system is known, their amorphous solids have not
been known at all.
[0007]
That is, development of an amorphization technique for a compound
represented by General Formula (1) and/or a salt thereof has been demanded for improving usability of the compound represented by General Formula (1) and/or the salt thereof.
Prior Art Documents
[Patent Documents]
[0008]
[Patent Document 1] WO 2007/102241
[Patent Document 2] WO 2007/102243
[Patent Document 3] WO 2003/105841
[Patent Document 4] JP 2006-312598 A
Summary of Invention
Technical Problem
[0009]
The present invention was carried out under such circumstances, and an
object of the present invention is to provide an amorphization technique for a
compound represented by General Formula (1) and/or a salt thereof for improving
usability of the compound represented by General Formula (1) and/or the salt thereof.
Solution to Problem
[0010]
In view of this, the present inventors intensively studied seeking an
amorphization technique for a compound represented by General Formula (1) and/or
a salt thereof in order to improve usability of the compound represented by General
Formula (1) and/or the salt thereof. As a result, the present inventors discovered
that, by using one or more selected from the group consisting of water-soluble
polymers and acids as an amorphizing agent, such amorphization can be achieved, thereby completing the present invention. That is, the present invention is as described below.
[0011]
[1] An amorphizing agent for a compound represented by the following General
Formula (1) and/or a salt thereof, the amorphizing agent comprising one or more
selected from the group consisting of water-soluble polymers and acids:
[0012]
R1 R2 /S CN
General Formula (1)
[0013]
(wherein R 1 and R2 each independently represent a hydrogen atom or a halogen
atom).
[0014]
[2] The amorphizing agent according to [1], wherein the water-soluble polymer is
a water-soluble vinyl polymer or a water-soluble cellulose polymer.
[3] The amorphizing agent according to [2], wherein the water-soluble vinyl
polymer is polyvinyl pyrrolidone or a carboxyvinyl polymer.
[4] The amorphizing agent according to [2], wherein the water-soluble cellulose
polymer is hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl
methylcellulose, methyl cellulose, or ethyl cellulose.
[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], comprising a water- soluble polymer and an acid.
[7] The amorphizing agent according to any one of [1] to [6], wherein the
compound represented by General Formula (1) is luliconazole or lanoconazole:
[0015]
C1 Cl CN
Luliconazole
[0016]
C1 0 ' CN N
S Q lztN
Lanoconazole
[0017]
[8] A method for amorphizing a compound represented by General Formula (1)
and/or a salt thereof, the method comprising; a step of uniformly mixing the
compound represented by General Formula (1) and/or the salt thereof with the
amorphizing agent according to 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 resulting
mixture.
[9] An amorphous composition comprising a compound represented by General
Formula (1) and/or a salt thereof and the amorphizing agent according to 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 method for producing a pharmaceutical composition comprising a compound represented by General Formula (1) and/or a salt thereof, the method comprising; 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 General Formula (1) and/or a salt thereof and the amorphizing agent according to 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], further comprising a solvent to be evaporated.
[13] The composition according to [11] or [12], which is a pharmaceutical composition.
In a first aspect of the present invention, there is provided an amorphizing agent when used for amorphizing luliconazole and/or a salt thereof, the amorphizing agent comprising polyvinyl pyrrolidone. In a second aspect of the present invention, there is provided a method for amorphizing luliconazole and/or a salt thereof, the method comprising; a step of uniformly mixing luliconazole and/or the salt thereof with the amorphizing agent according to the first aspect in an amount of 0.05 to 10 times the mass of luliconazole and/or the salt thereof, and solidifying the resulting mixture. In a third aspect of the present invention, there is provided amorphized luliconazole and/or a salt thereof, produced by the method of the second aspect.
Advantageous Effects of Invention
[0018] By the present invention, an amorphization technique for a compound represented by General Formula (1) and/or a salt thereof can be provided.
Brief Description of the Drawings
[0019]
6a Fig. 1 is a diagram (drawing substitute photographs) illustrating the process of formation of a coating by the composition of Example 1. LLCZ represents luliconazole, and PVP represents polyvinyl pyrrolidone. A of Fig. 1 is a photograph taken immediately after dropping; B of Fig. 1 is a photograph taken four hours after dropping; C of Fig. 1 is a photograph taken one day after dropping; and D of Fig. 1 is a photograph taken four days after dropping. In each of A to D of Fig. 1, a sample containing no amorphizing agent (luliconazole solution) is shown in the left, and a sample containing an amorphizing agent (luliconazole + polyvinyl pyrrolidone solution) is shown in the right. In each of A to D of Fig. 1, the top row shows optical microscopic observation images, and the bottom row shows polarization microscopic observation images.
Fig. 2 is a diagram (drawing substitute photographs) illustrating the process of
formation of a coating by the composition of Example 2. A photograph taken 0.5
minute after dropping is shown. Each leading line shows a micelle that has begun
to appear.
Fig. 3 is a diagram (drawing substitute photographs) illustrating the process of
formation of a coating by the composition of Example 2. A photograph taken 1
minute after dropping is shown. The photograph shows a structure in which
micelles are dispersed.
Fig. 4 is a diagram (drawing substitute photographs) illustrating the process of
formation of a coating by the composition of Example 2. A photograph taken 3
minutes after dropping is shown. The photograph shows a coating in which
amorphous bodies having a micelle-like structure are dispersed among continuous
phase-like amorphous bodies.
Description of Embodiments
[0020]
(1) Amorphizing Agent of Present Invention
The amorphizing agent of the present invention is an amorphizing agent for a
compound represented by General Formula (1) and/or a salt thereof, and comprises
one or more selected from the group consisting of water-soluble polymers and acids.
Preferred examples of the water-soluble polymer include water-soluble vinyl
polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, and carboxyvinyl polymers; water-soluble cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose terephthalate, hydroxyethyl methylcellulose, and ethyl cellulose; and water-soluble polysaccharide polymers such as gum arabic, gum tragacanth, and xanthan gum. Preferred examples among these include water-soluble vinyl polymers and water-soluble cellulose polymers. Preferred examples of the vinyl polymers include polyvinyl pyrrolidone and carboxyvinyl polymers. Preferred examples of the water-soluble cellulose polymers include hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, methyl cellulose, and ethyl cellulose. One or more kinds of water-soluble polymers may be used.
[0021]
Preferred examples of the acid include organic acids and inorganic acids, and
preferred examples of 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; and carboxylic acids such as formic acid and acetic acid. Hydroxy
acids and dibasic acids are especially preferred. Among these, lactic acid is
preferred as a hydroxy acid, and tartaric acid is especially preferred as a dibasic acid.
Preferred examples of the inorganic acids include mineral acid. One or more kinds
of acids may be used.
[0022]
A single kind of water-soluble polymer or acid may be used, or two or more
kinds of water-soluble polymer and/or acid may be used in combination. In a
preferred mode, a water-soluble polymer and an acid are used in combination.
[0023]
The amorphizing agent of the present invention is used, for example,
preferably in an amount of 0.05 to 10 times, more preferably in an amount of 0.5 to 5
times, still more preferably in an amount of 0.7 to 3 times the total mass of the compound represented by General Formula (1) and/or a salt thereof. This is because sufficient amorphization cannot be achieved in some cases where the amount is too small, and limitation in the formulation occurs when the amount is too large.
In cases where a water-soluble polymer and an acid are used in combination, their
mass ratio is set such that the water-soluble polymer is contained in an amount of
preferably 1 to 15% by mass, more preferably 4 to 10% by mass, with respect to the
acid.
[0024]
Regarding the amorphizing agent of the present invention, in cases where
luliconazole is used as the compound represented by General Formula (1), the
amorphizing agent is preferably the combination of lactic acid and polyvinyl
pyrrolidone. In cases where lanoconazole is used, the amorphizing agent is
preferably the combination of hydroxypropyl cellulose, tartaric acid, and lactic acid.
[0025]
(2) Compound Represented by General Formula (1) and/or Salt Thereof
The compound to which the amorphizing agent of the present invention is to
be applied is represented by General Formula (1).
In General Formula (1), each group represented by R, or R2 is a hydrogen
atom or a halogen atom, and preferred examples of the halogen atom include a
chlorine atom, bromine atom, fluorine atom, and iodine atom. A hydrogen atom or
a chlorine atom is especially preferred.
[0026]
Among the compounds represented by General Formula (1) and/or salts
thereof, luliconazole (RI = R2 = Cl; (R)-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan
2-ylidene]-1-imidazolylacetonitrile) and lanoconazole (Ri = Cl, R2 = H; 4-(2
chlorophenyl)-1,3-dithiolan-2-ylidene-1-imidazolylacetonitrile) are especially
preferred. Luliconazole is especially preferred.
These compounds can be synthesized according to, for example, the method
described in JP 60-218387 A. More specifically, the compounds can be synthesized
by the method described in the following formulae. That is, 1
cyanomethylimidazole is reacted with carbon disulfide to obtain a compound (III),
which is then reacted with a compound of General Formula (II)having leaving
groups, to thereby obtain a compound represented by General Formula (I).
Preferred examples of the leaving groups include methanesulfonyloxy,
benzenesulfonyloxy, p-toluenesulfonyloxy, and halogen atoms. In the following
formulae, R and X each represent a halogen atom or a hydrogen atom.
[0027]
CN MS CN N + CS 2 MS \.,N (1N1 (Ill) R X MS C+ R X
MS> N CN> \=N S N N (11) (I)
(In the formulae, Y and Y' represent leaving groups, and M represents an alkali
metal.)
[0028]
The compound represented by General Formula (1) to which the amorphizing
agent of the present invention is to be applied may be used as a physiologically
acceptable salt formed with sulfuric acid, hydrochloric acid, nitric acid, phosphoric
acid, or the like. In such a case, the salt is a salt that can be stably present in the
presence of the amorphizing agent.
[0029]
(3) Amorphous Composition of Present Invention
The amorphous composition of the present invention comprises as essential
constituents 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 present invention can be obtained by uniformly mixing the
compound represented by General Formula (1) and/or a salt thereof with the
amorphizing agent in an amount of 0.05 to 10 times the mass of the compound and/or
the salt thereof, and solidifying the resulting mixture by evaporation of the solvent.
A composition obtained by uniformly mixing a compound represented by 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 is a composition of the
present invention. The composition of the present invention may include a solvent
in addition to the compound represented by General Formula (1) and/or the salt
thereof and the amorphizing agent. Since the compound represented by General
Formula (1) and/or a salt thereof has/have an antifungal effect, the composition of the
present invention may be a pharmaceutical composition. The compound and/or the
salt is/are preferably an antifungal pharmaceutical composition, more preferably an
antifungal pharmaceutical composition for nails. The composition of the present
invention may be a composition for preparation of a pharmaceutical product, that is,
an intermediate product for production of a pharmaceutical product.
Since the compound represented by General Formula (1) and/or a salt thereof
has/have an antifungal effect, the amorphous composition of the present invention
may also be a pharmaceutical composition. The composition is preferably an
antifungal pharmaceutical composition, more preferably an antifungal
pharmaceutical composition for nails.
The formulation of the pharmaceutical composition is preferably a coating
forming formulation. The mode of use may be appropriately selected in consideration of the body weight, age, sex, symptoms, and the like of the patient.
For an adult human, the compound represented by General Formula (I) and/or a salt
thereof is usually preferably administered at 0.01 to 1 g per day. One may also refer
to doses of compounds represented by General Formula (1) and/or salts thereof that
are normally used for diseases caused by fungi.
For example, an appropriate amount of the composition may be applied to an
affected area once or several times per day, and such treatment is preferably carried
out every day.
[0030]
The composition may contain, in addition to the essential components, an
arbitrary component used for a pharmaceutical composition or the like. Preferred
examples of such an arbitrary component include excipients, dispersants, correctives,
coloring agents, and surfactants. The ratio of the arbitrary component in the
composition of the present invention is not limited as long as the amorphous form
can be maintained. The upper limit of the ratio is preferably about 50% by mass
with respect to the total amorphous composition. That is, the composition may
contain the amorphizing agent and the compound represented by General Formula (1)
and/or a salt thereof in an amount of from more than 50% by mass to 100% by mass
with respect to the total amorphous composition. The blend ratio between the
amorphizing agent and the compound represented by General Formula (1) and/or a
salt thereof is the same as the blend ratio described in "(1) Amorphizing Agent of
Present Invention".
[0031]
The present invention also relates to a method for amorphization of a
compound represented by General Formula (1) and/or a salt thereof using the
amorphizing agent of the present invention. The amorphization method of the
present invention comprises a step of uniformly mixing the compound represented by
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, and solidifying the
resulting mixture. Examples of the method of uniformly mixing the compound
represented by General Formula (1) and/or a salt thereof with an amorphizing agent
include a method in which the compound represented by General Formula (1) and/or
the salt thereof is/are dissolved in a solvent, and then the amorphizing agent is added
thereto, followed by mixing the resulting mixture. Examples of the method of
solidification include a method in which the mixture is stored at room temperature,
and then the solvent is removed.
[0032]
The present invention also relates to a method for producing a pharmaceutical
composition comprising a compound represented by General Formula (1) and/or a
salt thereof, the method comprising a step of using the amorphous composition of the
present invention as an intermediate product and dissolving the intermediate product.
The amorphous composition of the present invention provided as the
intermediate product is a readily soluble, stable intermediate product. By the use of
such an intermediate product, a method for producing a pharmaceutical composition
comprising the compound represented by General Formula (1) and/or a salt thereof,
which method hardly causes production of analogs, can be provided.
[0033]
The amorphous composition of the present invention can be used also as a
final coating of a pharmaceutical product, or an intermediate product for production
of a pharmaceutical product.
[0034]
The amorphous composition of the present invention can be an intermediate
product (also referred to as "production intermediate" or "intermediate") for
obtaining a pharmaceutical composition stably comprising a compound represented by General Formula (1) and/or a salt thereof. By the use of such an intermediate product, production of analogs during the production process of a pharmaceutical composition can be reduced.
[0035]
The amorphous composition of the present invention may be a coating
forming preparation as a product, or may be a coating finally generated when a
pharmaceutical composition is administered to a target site. By such amorphization,
penetration of the compound represented by General Formula (1) and/or a salt thereof
into the skin can be improved, and the high concentration in the tissue can be
maintained for a long period. This is because the amorphous has the function as a
reservoir. Such amorphization of a film as a final preparation is also within the
scope of the right of the present invention as long as the film has a property as an
amorphous film.
[0036]
The coating as a final product may be used, for example, as a coating of an
effective component formed on a carrier such as a granule, or may be used as a
coating of a pharmaceutical composition formed on the skin or a nail. With such a
coating of an amorphous composition, bioavailability of the compound represented
by General Formula (1) and/or a salt thereof as an effective component can be
increased. This is due to the reservoir effect described above.
Examples
[0037]
The present invention is described below in more detail by way of Examples,
but the present invention is not limited to these Examples as long as the spirit of the
present invention is not spoiled.
[0038]
<Example 1>
A solution containing 1% by mass luliconazole in ethanol and a solution
containing 1% by mass luliconazole and 0.1% by mass polyvinyl pyrrolidone in
ethanol were prepared, and each solution was dropped onto a slide glass. The
properties of each solution were observed under the microscope immediately after the
dropping, after four hours of storage at room temperature after the dropping, after one
day of storage at room temperature after the dropping, and after four days of storage
at room temperature after the dropping. The microscopic observation was carried
out using both a normal optical microscope and a polarization microscope. The
results are shown in Fig. 1. From the results, it can be seen that the amorphizing
agent of the present invention caused a difference in the crystallization, and that
polyvinyl pyrrolidone acted as an amorphizing agent. Thus, also in cases where
crystals and amorphous bodies coexist, when inclusion of the amorphizing agent of
the present invention caused the coexistence with the amorphous bodies (caused the
appearance of the amorphous structure) while only crystals should be present in the
original state, the amorphizing agent of the present invention is judged to be effective.
[0039]
<Example 2>
With pharmaceutical composition 1 having the following composition, a
coating-forming preparation was produced according to the following procedure.
[0040]
Table 1 Component %by mass Luliconazole 5 N-methyl-2-pyrrolidone 8 Benzyl alcohol 4 Diisopropyl adipate 10 Lactic acid 4 Polyvinyl pyrrolidone 0.5 Ethanol Remainder Total 100
[0041]
Luliconazole and ethanol were combined together, and heated at 70°C with
stirring to allow solubilization. Subsequently, lactic acid and polyvinyl pyrrolidone
were added to the mixture, and the resulting mixture was heated at 70°C with stirring.
After confirmation of solubilization, the remaining solvent components were added
thereto to dilute the mixture, and the resulting dilution was solubilized with stirring.
After confirmation of the solubilization, the liquid was cooled to room temperature
with stirring, to obtain pharmaceutical composition 1.
[0042]
<Coating-forming Process of Pharmaceutical Composition 1 Produced>
Into a tube, 1 mL of pharmaceutical composition 1 was placed, and 100 pL of
a liquid prepared by dissolving 10 mg of neutral red in 200 pL of methanol was
added thereto, followed by stifling the resulting mixture well. Thereafter, the
mixture was dropped onto a slide glass, followed by solvent evaporation and
observation of the coating-forming process under the microscope (x 400) at room
temperature. The observed process is shown in Figs. 2 to 4. Micelle-like
structures began to appear in a uniform phase (Fig. 2), and then the micelle structures
increased (Fig. 3), resulting in appearance of an amorphous film having the micelle
like structures uniformly dispersed in a continuous-phase-like structure (Fig. 4). By
this, an amorphization effect of polyvinyl pyrrolidone and lactic acid as an
amorphizing agent of the present invention could be confirmed.
[0043]
<Example 3>
According to the procedure shown in Example 2, pharmaceutical
compositions 2 and 3 (coating-forming preparations) having the compositions shown
in Table 2 were produced. According to the method described in Example 2, the
coating-forming process was observed under the microscope (x 400). Similarly to pharmaceutical composition 1, pharmaceutical compositions 2 and 3 showed amorphous films in which micelle-like structures are uniformly dispersed in a continuous-phase-like structure. Thus, an amorphization effect could be observed.
[0044]
Table 2 Pharmaceutical composition 2 Pharmaceutical composition 3 Component % by mass Luliconazole 5 5 N-methyl-2-pyrrolidone 8 8 Benzyl alcohol 4 4 Diisopropyl adipate 10 10 Lactic acid 8 6 Polyvinyl pyrrolidone 1 0.5 Ethanol Remainder Remainder Total 100 100
Industrial Applicability
[0045]
The present invention is applicable to pharmaceutical products and
production of pharmaceutical products.
Claims (4)
1. An amorphizing agent when used for amorphizing luliconazole and/or a salt thereof, the amorphizing agent comprising polyvinyl pyrrolidone.
2. The amorphizing agent according to claim 1, comprising polyvinyl pyrrolidone and lactic acid.
3. A method for amorphizing luliconazole and/or a salt thereof, the method comprising; a step of uniformly mixing luliconazole and/or the 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 the salt thereof, and solidifying the resulting mixture.
4. Amorphized luliconazole and/or a salt thereof, produced by the method of claim 3.
Pola Pharma Inc. Nihon Nohyaku Co., Ltd. Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON
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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| AU2017244688A1 AU2017244688A1 (en) | 2018-11-22 |
| AU2017244688B2 true AU2017244688B2 (en) | 2022-11-10 |
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| WO (1) | WO2017170509A1 (en) |
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| WO2007102243A1 (en) * | 2006-03-08 | 2007-09-13 | Nihon Nohyaku Co., Ltd. | External pharmaceutical composition |
| WO2007102241A1 (en) * | 2006-03-08 | 2007-09-13 | Nihon Nohyaku Co., Ltd. | External pharmaceutical composition |
| WO2009031643A1 (en) * | 2007-09-05 | 2009-03-12 | Pola Pharma Inc. | Antifungal composition |
| JP2015114210A (en) * | 2013-12-12 | 2015-06-22 | 株式会社ポーラファルマ | Evaluation method and index substance for formulation containing luliconazole |
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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 |
| WO2003105841A1 (en) | 2002-06-18 | 2003-12-24 | ポーラ化成工業株式会社 | 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 |
| WO2010117089A2 (en) * | 2009-04-09 | 2010-10-14 | Pola Pharma Inc. | Antimycotic pharmaceutical composition |
| US20140206717A1 (en) * | 2011-08-16 | 2014-07-24 | John Higgins | Use of inorganic matrix and organic polymer combinations for preparing stable amorphous dispersions |
| 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 |
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- 2017-03-28 KR KR1020187031311A patent/KR102359641B1/en active IP Right Grant
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007102243A1 (en) * | 2006-03-08 | 2007-09-13 | Nihon Nohyaku Co., Ltd. | External pharmaceutical composition |
| WO2007102241A1 (en) * | 2006-03-08 | 2007-09-13 | Nihon Nohyaku Co., Ltd. | External pharmaceutical composition |
| WO2009031643A1 (en) * | 2007-09-05 | 2009-03-12 | Pola Pharma Inc. | Antifungal composition |
| JP2015114210A (en) * | 2013-12-12 | 2015-06-22 | 株式会社ポーラファルマ | Evaluation method and index substance for formulation containing luliconazole |
Also Published As
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| PH12018502095A1 (en) | 2019-07-15 |
| CN108883190B (en) | 2022-07-01 |
| WO2017170509A1 (en) | 2017-10-05 |
| MY197992A (en) | 2023-07-25 |
| KR102359641B1 (en) | 2022-02-08 |
| AU2017244688A1 (en) | 2018-11-22 |
| JP7021827B2 (en) | 2022-02-17 |
| CN108883190A (en) | 2018-11-23 |
| JP2017186317A (en) | 2017-10-12 |
| KR20180126058A (en) | 2018-11-26 |
| SG11201808660UA (en) | 2018-11-29 |
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