CN203263805U - Resin container filled with antifungal drug composition - Google Patents
Resin container filled with antifungal drug composition Download PDFInfo
- Publication number
- CN203263805U CN203263805U CN2013201238978U CN201320123897U CN203263805U CN 203263805 U CN203263805 U CN 203263805U CN 2013201238978 U CN2013201238978 U CN 2013201238978U CN 201320123897 U CN201320123897 U CN 201320123897U CN 203263805 U CN203263805 U CN 203263805U
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- Prior art keywords
- pharmaceutical composition
- holding device
- luliconazole
- plastic holding
- quality
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- 0 CCC(CCC1)C[*@@]1C([Zn])=C(NC1)NC1C(C(**)C1)=CC=C1NCC Chemical compound CCC(CCC1)C[*@@]1C([Zn])=C(NC1)NC1C(C(**)C1)=CC=C1NCC 0.000 description 1
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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
Abstract
The utility model provides a drug composition steadily containing the compounds and/or the salt compounds thereof shown by the formula (I), and provides a means for the market (in the formula (I), R1 and R2 in the formula respectively represent the hydrogen atom or halogen atom). The drug composition containing the compounds or the salt compounds thereof shown by the formula (I) is filled and stored in a resin container, wherein the container is colored by Munsell color coordinates in the range of hue (H) of 7.0Y-9.99Y or 7.0YR-9.99YR, the lightness (v) of 1.0-6.0 and the chroma of 0.5-7.5.
Description
Technical field
This utility model relates to plastic holding device and is filled with the plastic holding device of antifungal medicine composition, further specifically, relates to and has filled the pharmaceutical composition that contains antifungal and carried out painted plastic holding device.
Background technology
For medicine, preserving steadily in the long term pharmaceutical composition is important problem.Particularly in the situation that contain have armaticity compound as effective ingredient, guarantee that the stability to light is important problem.As the means of guaranteeing the stability of light, usually have and (for example for example use the shading container, with reference to patent documentation 1) etc. light-shielding structure is set in container, as this light-shielding structure, normally sneak into the light-proofness metal-oxides such as titanium dioxide, zinc oxide in resin.By adopting such structure, ultraviolet, visible light can arrive pharmaceutical composition hardly.Yet, although by adopting the described shading means that are present in container can realize abundant shading, have the situation of the stability of the pharmaceutical composition that can't guarantee internal tank.
Relation about light-proofness metal-oxide and light, various researchs have been carried out in cosmetic field, studies show that light-proofness metal-oxide absorbing light and be excited into the free radical that produces when getting back to ground state after excited state can injured skin, cosmetics (for example, with reference to patent documentation 2 and 3).Yet, do not carry out the research about the stable relation of described free radical and pharmaceutical composition.
On the other hand, the compound shown in known general formula (I) has excellent antifungal activity, particularly R
1And R
2The absolute configuration that is chlorine atom, asymmetric center is remarkable for the luliconazole antifungal activity of (R)-configuration.In addition, as the problem of its stable aspect, also known oriented absolute configuration is for the SE configuration of (S)-configuration and to carrying out isomerization (for example, with reference to patent documentation 4) as pair Z configuration of the geometric isomer of keys part.The inventor etc. confirm: in this isomerization, and key factor only, and can't suppress this isomerization with common shading means.The inventor etc. have found by using the container that forms of layer by two kinds of different colours to prevent above-mentioned isomerized means, but up to now, suppress described isomerization or the unknown with one deck container of the resin material that presents particular color.
[Chemical formula 1]
General formula (I)
(in general formula (I), R
1, R
2Represent independently respectively hydrogen atom or halogen atom.)
On the other hand, in described luliconazole, except the problem of light-proofness, (1) be difficult to be dissolved in solvent, when (2) highly concentrated solution being coated on fingernail etc. surperficial at surperficial crystallization, obstruction absorbs, and (3) have the preferred characteristics such as easy generation stereoisomers, becomes the obstacle of the stable and efficient preparation of exploitation.Particularly about the pharmaceutical preparation of the nail fungi disease more than the amount that requires the medicament that is directed to affected part more than cutaneous fungal infection as object, the instant crystalline problem in dissolubility and when coating be larger problem (for example, with reference to patent documentation 5 and 6), in the selection of solvent, stereospecificity to keep (for example, with reference to patent documentation 3) be larger problem.Under such situation, as having the steric stabilization effect and to the high solvent of the medicament directionality of fingernail, finding to have the N-alkyl-2-Pyrrolidone classes such as METHYLPYRROLIDONE, in this solvent, due to solubility, there is limit in the amount of soluble luliconazole.Therefore, in common preparation system, think that the limit of clear solution preparation is lower than 3 quality %.
high concentrate formulation as luliconazole, in the technology that makes up alkylene carbonates and polyhydric alcohol (for example, with reference to patent documentation 7～9), (for example utilize the preparation of diethylene glycol monoethyl ether, with reference to patent documentation 10) in, can realize containing the clear solution preparation of high concentration luliconazole, but in N-alkyl-ketopyrrolidine system, present situation so far remains the system that can't obtain surpassing 3 quality %, if can realize high concentrate formulation in N-alkyl-ketopyrrolidine is, can utilize it to seek the minimizing of effective ingredient to the premium properties of tissue orientating's property, therefore, expect such technological development.In addition, owing to being above-mentioned high concentrate formulation, therefore, described light-proofness problem becomes larger problem, the means of seeking to address these problems comprehensively.
The prior art document
Patent documentation
Patent documentation 1: Japanese kokai publication hei 10-212234 communique
Patent documentation 2: Japanese kokai publication hei 10-87472 communique
Patent documentation 3: Japanese kokai publication hei 10-77213 communique
Patent documentation 4:WO2007/102242
Patent documentation 5:WO2007/102241
Patent documentation 6:WO2007/102243
Patent documentation 7:WO2010/117091
Patent documentation 8:WO2010/117089
Patent documentation 9:WO2011/24620
Patent documentation 10:WO2010/93992
Summary of the invention
The problem that utility model will solve
This utility model is completed in order to address the above problem, its problem be to be provided at pharmaceutical composition middle and high concentration ground contains above-mentioned general formula (I) even shown in compound and/or its salt and also can stably keep this pharmaceutical composition and be provided in the means in market in the container of one deck resin bed.
Be used for solving the method for problem
The inventor etc. are in view of this situation, seek stably to keep to contain the means of the pharmaceutical composition of compound shown in the above-mentioned general formula (I) of high concentration and/or its salt, after concentrating on studies, found that: undertaken in painted container by pharmaceutical composition being filled in the color shown in specific color coordinates, can realize stabilisation, thereby complete this utility model.In addition, find by the benzyl alcohol combination with N-alkyl-2-Pyrrolidone and specified quantitative, can obtain the high concentration clear solution preparation of N-alkyl-2-Pyrrolidone system, find by said preparation is filled in above-mentionedly in painted container, more stable pharmaceutical composition can be provided.That is, this utility model is as described below.
＜1〉plastic holding device, it is for filling the plastic holding device of content, wherein, this plastic holding device have in the munsell color coordinate tone (H) as 7.0Y～9.99Y or 7.0YR～9.99YR, lightness (V) as 1.0～6.0, chroma (C) carried out painted resin face as the color in 0.5～7.5 scope.
＜2〉according to＜1〉described plastic holding device, wherein, described plastic holding device does not show transmittance in the mensuration of UV, visible light absorbance spectrum.
＜3〉according to＜1〉or＜2〉described plastic holding device, wherein, the material of described plastic holding device is polypropylene or polyethylene.
＜4〉according to＜1 〉～＜3〉the middle described plastic holding device of any one, it is bottle container.
＜5〉according to＜1 〉～＜4〉the middle described plastic holding device of any one, it is used for holding containing the compound shown in following general formula (I) and/or the pharmaceutical composition of its salt,
[Chemical formula 2]
General formula (I)
(in general formula (I), R
1, R
2Represent independently respectively hydrogen atom or halogen atom.)
＜6〉medicine, its be the pharmaceutical composition that will contain the compound shown in following general formula (I) and/or its salt be filled in＜1～＜5 in form in the described plastic holding device of any one,
[chemical formula 3]
General formula (I)
(in general formula (I), R
1, R
2Represent independently respectively hydrogen atom or halogen atom.)
＜7〉according to＜6〉described medicine, wherein, the compound shown in described general formula (I) is luliconazole.
＜8〉according to＜6〉or＜7〉described medicine, wherein, described pharmaceutical composition is the lotion dosage form.
＜9〉according to＜6 〉～＜8〉the middle described medicine of any one, wherein, described pharmaceutical composition contains (1) luliconazole 3～8 quality %, (2) benzyl alcohol 1～3 quality %, (3) METHYLPYRROLIDONE 6～15 quality % and be clear solution.
＜10〉according to＜9〉described medicine, wherein, described pharmaceutical composition also contains the dibasic acid diester of 10～16 quality %.
＜11〉according to＜9〉or＜10〉described medicine, wherein, described pharmaceutical composition also contains the organic acid of 3～6 quality %.
＜12〉according to＜11〉described medicine, wherein, described organic acid is lactic acid.
＜13〉according to＜9 〉～＜12〉the middle described medicine of any one, wherein, described pharmaceutical composition has following physical property:
(1) crystallization not under room temperature, the preservation condition of 3 years.
(2) with respect to the use level of luliconazole, the content of the SE configuration of luliconazole is below 0.5 quality %.
(3) with respect to the use level of luliconazole, the content of the Z configuration of luliconazole is below 0.5 quality %.
(4) under the preservation condition of 40 ℃, 6 months, the growing amount of SE configuration is below 0.2 quality % with respect to the use level of luliconazole.
(5) under the preservation condition of 40 ℃, 6 months, the growing amount of Z configuration is below 0.2 quality % with respect to the use level of luliconazole.
(6) can be on fingernail after just being coated on fingernail crystallization.
＜14〉according to＜11 〉～＜13〉the middle described medicine of any one, wherein, described pharmaceutical composition is made according to as described below:
With the luliconazole moistening, after adding wherein benzyl alcohol and organic acid that it is disperseed, then add wherein remaining composition with the part of METHYLPYRROLIDONE.
＜15〉pharmaceutical composition, it contains (1) luliconazole 3～8 quality %, (2) benzyl alcohol 1～3 quality %, (3) METHYLPYRROLIDONE 6～15 quality %, and be clear solution.
＜16〉according to＜15〉described pharmaceutical composition, it also contains the dibasic acid diester of 10～16 quality %.
＜17〉according to＜15〉or＜16〉described pharmaceutical composition, it also contains the organic acid of 3～6 quality %.
＜18〉according to＜16〉described pharmaceutical composition, wherein, described organic acid is lactic acid.
＜19〉according to＜15 〉～＜18〉the middle described pharmaceutical composition of any one, it has following physical property:
(1) crystallization not under room temperature, the preservation condition of 3 years.
(2) with respect to the use level of luliconazole, the content of the SE configuration of luliconazole is below 0.5 quality %.
(3) with respect to the use level of luliconazole, the content of the Z configuration of luliconazole is below 0.5 quality %.
(4) under the preservation condition of 40 ℃, 6 months, the growing amount of SE configuration is below 0.2 quality % with respect to the use level of luliconazole.
(5) under the preservation condition of 40 ℃, 6 months, the growing amount of Z configuration is below 0.2 quality % with respect to the use level of luliconazole.
(6) can be on fingernail after just being coated on fingernail crystallization.
＜20〉according to＜17 〉～＜19〉the middle described pharmaceutical composition of any one, it is made according to as described below:
With the luliconazole moistening, after adding wherein benzyl alcohol and organic acid that it is disperseed, then add wherein remaining composition with the part of METHYLPYRROLIDONE.
The invention effect
According to this utility model, can to market provide stable and high concentration ground to contain above-mentioned general formula (I) even shown in compound and/or the pharmaceutical composition of its salt also can stably keep the plastic holding device of this pharmaceutical composition in the container of one deck resin bed, this pharmaceutical composition is filled in the medicine in the plastic holding device that can stably keep pharmaceutical composition.
Description of drawings
Fig. 1 illustrates the structure of container that uses in embodiment.1 is the resin wall, and 2 expressions utilize elastomeric pushing structure, the 3 movable bolts of expression.
Symbol description
1 ... the resin wall
2 ... utilize elastomeric pushing structure
3 ... movable bolt
The specific embodiment
＜1〉plastic holding device
Fig. 1 hereinafter with reference to an expression one embodiment is elaborated to plastic holding device of the present utility model.Embodiment shown in Figure 1 be for filling the plastic holding device of content, has resin wall 1, utilizes elastomeric pushing structure 2, movable bolt 3.Can fill content at the internal tank that arranges by resin wall 1.Resin wall 1 by tone (H) in the munsell color coordinate for 7.0Y～9.99Y or 7.0YR～9.99YR, lightness (V) are 1.0～6.0, chroma (C) is that color in 0.5～7.5 scope has been carried out painted.
Plastic holding device of the present utility model is characterised in that, the resin face has carried out painted, with painted as essential element.Describedly be colored as specific color, with being colored as following color as element, in the munsell color coordinate, the tone of described color (H) is 7.0Y～9.99Y or 7.0YR～9.99YR, more preferably 7.3Y～9.8Y or 7.3YR～9.8YR, lightness (V) is 1.0～6.0, more preferably 1.5～5.5, chroma (C) is 0.5～7.5, more preferably 0.5～6.As concrete color, preferred Lycoperdon polymorphum Vitt, green or dark brown, according to the munsell color coordinate, preferred hue is that 7.0Y～8.6Y, lightness are 4.0～6.0, chroma is 0.5～1.0 Lycoperdon polymorphum Vitt, tone is that 9.0Y～9.9Y, lightness are 1.5～2.5, chroma is 6～7.5 green, and tone is that 8YR～9YR, lightness are 1.5～2.0, chroma be 4～5 dark brown.As carrying out above-mentioned painted pigment, if white can be utilized titanium dioxide, zinc oxide, if black, can utilize the iron oxide black, if red, can utilize Indian red, toluidine red, quinacridone red, if blue, can utilize ultramarine, dark purple, phthalocyanine blue, if green, can utilize phthalocyanine green, chrome green, cadmium green, if yellow, can utilize yellow iron oxide, azophosphine etc.
At this, the munsell color coordinate is the coloring system by use lightness (V), chroma (C) and these 3 axle apparent colors of tone (H) of Munsell (H.A.Munsell) design, thinks that it utilizes the expression excellence of the human perception color identification of coordinate figure.Generally speaking, known color can by 3 independently stimulus value make up to express, there are RGB coloring system, XYZ coloring system etc., it is generally acknowledged the easiest by the color coordinates sensualness what imagine color is Munsell coloring system (Japanese chromatology can be compiled " newly organized color science handbook " juridical person Tokyo University and publish, clear and 60 on JIUYUE 10).
In addition, this plastic holding device also with shading as element.In this utility model, so-called shading refers to that plastic holding device does not show transmittance in the mensuration of UV, visible light absorbance spectrum.More specifically, refer to the resin sheet of plastic holding device is arranged in UV, visible light absorbance meter, measure uv absorption, visible absorbance, transmission is below 5%, and preferred 0%.
The mensuration of UV, visible light absorbance spectrum for example can be with UV, visible light absorbance meter (V-660: Japanese light splitting Co., Ltd. make), carry out under wavelength 200～750nm.
That is, in medicine of the present utility model, plastic holding device is with specific color, at least a portion of resin face, the face that preferably will contact with content to be carried out paintedly, can say to have shaded effect as essential important document.At present, have various functions in order to make container, adopt multiple structure.In this utility model, in described color gamut, be 1 layer even consist of the resin bed of plastic holding device, also can stably keep containing the compound shown in above-mentioned general formula (I) and/or the pharmaceutical composition of its salt.Therefore, also can configure for the outside of described painted is carried out additive color the layer etc., such mode also belongs to technical scope of the present utility model.In the situation that even shading fully and not belongs to described color gamut, existence can't stably keep the situation of pharmaceutical composition.Thus, infer that the stability of the pharmaceutical composition of filling in plastic holding device of the present utility model is not the direct effect that depends on light, but depend on via the secondary of container etc. or indirectly effect.Do not depend on that the reduction of direct acting stability of light is normally unknown.Therefore, under this situation, can by with specific color, container being carried out the painted effect of keeping the stability of pharmaceutical composition, can be described as special effect.Container of the present utility model has this effect.
In addition, as long as the shape of container satisfies described condition, can adopt the shape of using in common medicine.Such as preferably illustration bottle (bottle) shape, tubulose, tank shape etc., if consider to fill pharmaceutical composition of the present utility model, illustration doleiform shape particularly preferably.
And then, at vpg connection, if the preferred example of illustration is as shown in Figure 1 the doleiform shape of realizing hatch frame by the extruding to affected part that has.Namely, the bottle of Fig. 1 is shaped as the doleiform shape, at leading section, concubine is set, the structure (utilizing elastomeric pushing structure and movable bolt) of switching is set at the linking part of this concubine and container body medicine containing section by elastomer, this structure can be closed by elastomer usually, becomes hatch frame by the bar-shaped section of being pressed into of pushing the affected part contact portion.This bar-shaped section of being pressed into is provided with a plurality of otch longitudinally, thereby in the situation that push this part to this affected part, linking part is opened, become following structure: the medicament of taking in the medicine containing section of container body flows into concubine, further flow through groove, supply with a certain amount of medicament to affected part continuously.
In addition, as material, preferably illustration polyethylene, polypropylene, polyethylene terephthalate, acrylic resin, polyester, polyamide etc. are if consider to fill pharmaceutical composition of the present utility model, more preferably polyethylene or polypropylene, further preferably polyethylene.In this resin, for the purpose of shading, can contain the metal-oxides such as titanium dioxide, zinc oxide.From cost aspect consideration, from manufacturing cost aspect and manufacture method aspect consideration, preferably make dyed layer only be one deck.
As long as container satisfies above-mentioned condition, can adopt the manufacture method of the container that common medicine uses.For example, the painted resin face of plastic holding device can carry out resin self paintedly, also can carry out at the inner coloring agent with not affecting pharmaceutical composition of resin etc. painted.
As coloring agent, can use above-mentioned coloring agent etc.
＜2〉pharmaceutical composition
In plastic holding device of the present utility model, the preferred pharmaceutical composition of filling contains the compound shown in above-mentioned general formula (I) and/or its salt.As the compound shown in this general formula (I), preferably illustration R
1Be chlorine atom, R
2Be the lanoconazole of hydrogen atom, R
1, R
2Be the luliconazole of chlorine atom etc.This pharmaceutical composition can contain any in these compounds.The known manufacture method (for example, Japanese kokai publication hei 09-100279 communique etc.) that this composition is arranged.In this pharmaceutical composition, the preferred content of the compound shown in above-mentioned general formula (I) and salt thereof, preferred 0.1～20 quality %, more preferably 0.2～10 quality %.This is because can keep stability in this content range.Particularly in the situation that pharmaceutical composition is used with preparation as fingernail, be preferably the solution of transparent and homogeneous, the high solution of concentration of compound shown in general formula (I), particularly, particularly preferably illustration with N-alkyl-2-Pyrrolidone as solvent, the content of compound shown in general formula (I) is 3～8 quality %, the more preferably pharmaceutical composition of 4～6 quality % with respect to the total amount of pharmaceutical composition.
In aforementioned pharmaceutical compositions, its dosage form also is suitable for the common dosage form of using of medicine except the fingernail preparation.As dosage form in this case, preferably the lotion dosage form of illustration oil-in-water type or solvable type, emulsion agent dosage form, unguentum dosage form, ointment dosage form etc.In these dosage forms, lotion dosage form particularly preferably.This is because the lotion dosage form easily becomes key subjects to the stability of light etc.
Pharmaceutical composition of the present utility model contains the N-alkyl pyrrolidone, it utilizes the luliconazole of the N-alkyl-2-Pyrrolidone class such as METHYLPYRROLIDONE to excellent effects such as the premium properties of the impregnability of fingernail, three-dimensional stability raising effects, in this implication, contain N-alkyl-2-Pyrrolidone as essential element.As N-alkyl-2-Pyrrolidone, the carbon number 1～4 of preferred alkyl, such as preferably illustration METHYLPYRROLIDONE, N-ethyl-2-pyrrolidone, N-propyl group-2-Pyrrolidone, N-butyl-2-Pyrrolidone etc., more preferably the carbochain of alkyl is short, particularly, press the order of METHYLPYRROLIDONE, N-ethyl-2-pyrrolidone, N-propyl group-2-Pyrrolidone, N-butyl-2-Pyrrolidone preferred.This composition can only contain a kind of, also can make up contain two or more.With respect to the pharmaceutical composition total amount, the preferred content of N-alkyl-2-Pyrrolidone in pharmaceutical composition of the present utility model is counted 6～15 quality % with total amount, more preferably 7～12 quality %.When this is very few because of content, sometimes can't show the preferred characteristic of N-alkyl-2-Pyrrolidone, in the time of too much, sometimes produce the preferred phenomenons such as crystallization.
In pharmaceutical composition of the present utility model, except N-alkyl-2-Pyrrolidone, to contain 1～3 quality %, more preferably the hydroxyalkyl benzene such as benzyl alcohol of 1～2 quality % are as essential element.The hydroxyalkyl benzene such as benzyl alcohol have the liquefiable effect of the luliconazole of making, but opposite with it, are to have the characteristic that easily causes crystallization under the cryopreservation condition in the situation that be processed into preparation.By it being controlled in described content range, can solve the problem of such crystallization, make high concentrate formulation.That is, the use level of the hydroxyalkyl benzene such as benzyl alcohol is compared very few or too much all can be obtained luliconazole and surpasses 3 quality % and the good preparation of stability of solution under the actual degree of using of tolerance with above-mentioned use level.
In above-mentioned hydroxyalkyl benzene, as alkyl, preferred carbon number 1～4, particularly, preferably illustration benzyl alcohol, phenethanol, phenylpropanol, benzene butanols etc.This composition can only contain a kind of, also can make up contain two or more.Be particularly preferably benzyl alcohol or phenethanol, more preferably benzyl alcohol.By containing hydroxyalkyl benzene with content as mentioned above, can bring into play following effect: at the low-temperature region of compound shown in above-mentioned general formula (I) and/or its salt, for example near the preservation 5 ℃, make molten attitude stable, performance prevents the effect of crystallization.
For pharmaceutical composition of the present utility model, as preferred mode, contain dibasic acid diester.As dibasic acid diester, do not comprise carbonic diester in this utility model.As dibasic acid diester, illustration particularly preferably: for example, diethylene adipate, diisopropyl adipate, ethyl sebacate, dipropyl sebacate etc.Wherein, diisopropyl adipate particularly preferably.This composition has the effect that prevents crystallization at low temperatures in containing the luliconazole solution of benzyl alcohol.This effect replenishes N-alkyl-2-Pyrrolidone for the solubility of luliconazole.In order to show such effect, in total amount, preferably contain 10～16 quality % with respect to the pharmaceutical composition total amount, more preferably contain the dibasic acid diester of 12～14 quality %.
In the preferred implementation of pharmaceutical composition of the present utility model, contain organic acid 3～6 quality %, more preferably contain 4～5 quality %.As organic acid, preferred 'alpha '-hydroxy acids, wherein, more preferably lactic acid, glycolic.When described composition suppresses pharmaceutical composition is attached to fingernail surperficial, the effect of the such phenomenon of moment crystallization is excellent.In addition, show too: the inhibition of the crystallization when cryopreservation, the inhibitory action that crystallization is easily separated out when coating by cryopreservation.Therefore, pharmaceutical composition of the present utility model can not hinder it idiocratically to realize the excellent impregnability of organizing.
Pharmaceutical composition of the present utility model is except mentioned component, can contain the alcohols such as ethanol, the tunicle such as polyvinylpyrrolidone, methylcellulose forming agent, the wetting agent such as propylene glycol, Polyethylene Glycol, the stabilizing agents such as phosphoric acid, the composition that methyl ethyl ketone, medium-chain fatty acid triglyceride equal solvent etc. use in pharmaceutical composition usually.Pharmaceutical composition of the present utility model can by must composition with these, become packet combining to process according to conventional methods to make arbitrarily.
Pharmaceutical composition of the present utility model can preferably be made by following manufacture method.
With the luliconazole moistening, after adding wherein benzyl alcohol and organic acid that it is disperseed, add wherein remaining composition to make with the part (being for example 1～5 quality % with respect to the pharmaceutical composition total amount) of METHYLPYRROLIDONE.
In addition, can bring into play the above-mentioned character that especially easily is engaged to nail tissue, the pharmaceutical composition of using as fungal infection of nail is used.
That is, medicine of the present utility model or pharmaceutical composition preferably utilize the compound shown in general formula (I) and/or the characteristic of its salt, and the treatment or the prevention that are used for fungus-caused disease worsen.As fungus-caused disease, can illustration such as the foot tinea alba disease of tinea pedis and so on, body tinea alba disease as candidiasis, tinea versicolor and so on, hard keratin tinea alba disease partly as fingernail tinea alba and so on, its effect is remarkable, therefore, be particularly preferred for processing as the hard keratin of fingernail tinea alba and so on part.The effect of pharmaceutical composition of the present utility model also relates to common dermatophytes disease particularly preferably in showing on fingernail, therefore, also belongs to technical scope of the present utility model for the pharmaceutical composition that this utility model consists of that satisfies of dermatophytes disease.As such dermatophytes disease, can illustration appear at cutin proliferous type tinea alba disease that heel etc. locates etc. in foot tinea alba disease, sufficient tinea alba disease.In above-mentioned dermatophytes disease, show the significant effect of the present invention when being applicable to cutin proliferous type tinea alba disease that conventional dose is difficult to prove effective, therefore preferred.
Its occupation mode can be considered the suitable selections such as patient's body weight, age, sex, symptom, usually in the situation that the adult, and compound and/or its salt shown in the general formula (I) of preferred every 1 day administration 0.01～1g.In addition, can be with reference to the compound shown in the general formula that is generally used for fungus-caused disease (I) and/or the use amount of its salt.
For example, if external preparation can be enumerated every day 1 time or repeatedly be coated with in right amount at the disease place, carried out this processing in preferred continuous several days.Particularly for the fingernail tinea alba, can be that luliconazole moves in fingernail with the effective ingredient of the amount that can't realize in common preparation.Thus, can be only by being used for treating the fingernail tinea alba outward and without the long-term drink antifungal.In addition, recurrence reaches to infect again becomes problem larger in the fingernail tinea alba, but can prevent such recurrence and infection again by all pharmaceutical compositions of the present utility model of administration 1～2 after symptom is stable.Under such mode, pharmaceutical composition of the present utility model plays preventive effect.
Pharmaceutical composition of the present utility model can stably be kept compound and/or its salt shown in the above-mentioned general formula (I) of high concentration, in one embodiment, have following (1)～(6) physical property any or all.
(1) crystallization not under room temperature, the preservation condition of 3 years.
(2) with respect to the use level of luliconazole, the content of the SE configuration of luliconazole is below 0.5 quality %.
(3) with respect to the use level of luliconazole, the content of the Z configuration of luliconazole is below 0.5 quality %.
(4) under the preservation condition of 40 ℃, 6 months, the growing amount of SE configuration is below 0.2 quality % with respect to the use level of luliconazole.
(5) under the preservation condition of 40 ℃, 6 months, the growing amount of Z configuration is below 0.2 quality % with respect to the use level of luliconazole.
(6) can be on fingernail after just being coated on fingernail crystallization.
Need to prove, separating out of crystallization can be measured by perusal.
The content of the isomer of luliconazole can be measured by following: for example using can be with the optical activity immobile phase of luliconazole and optical isomer separation thereof, by liquid chromatography, it is carried out optical fractionation, utilize the peak area of the optical isomer in the chart that obtains to obtain.
＜3〉medicine
Medicine of the present utility model is medicine as described below: fill in plastic holding device of the present utility model and contain the compound shown in above-mentioned general formula (I) and/or the pharmaceutical composition of its salt forms.
Plastic holding device of the present utility model can stably be kept compound and/or its salt shown in the above-mentioned general formula (I) of high concentration.Therefore, medicine of the present utility model is following medicine: pharmaceutical composition of the present utility model is filled in plastic holding device of the present utility model forms, described pharmaceutical composition contains compound and/or its salt shown in the above-mentioned general formula (I) of high concentration by above-mentioned specific composition.
Embodiment
Below, enumerate embodiment this utility model is described in more detail, but this utility model is not limited to these embodiment.
＜embodiment 1 〉
Make pharmaceutical composition of the present utility model according to the prescription shown in table 2.That is, make the luliconazole moistening with methyl ethyl ketone, add therein Polyethylene Glycol, make it homogeneous and disperse, next add remainder and heating to make its dissolving, cooling, obtain pharmaceutical composition of the present utility model.With high performance liquid chromatography (condition: post: Inertsil ODS-24.6 * 150mm, column temperature: 40 ℃, mobile phase: 0.13%1-hendecane sodium sulfonate mixed liquor (water/acetonitrile/acetic acid (54:45:1, v/v/v) solution), flow velocity: 1.0mL/ minute, detect: 295nm) mensuration is as the SE configuration of the impurity of luliconazole and the growing amount of Z configuration.
Below prepare the container of character as shown in table 1.Namely, use titanium dioxide as Chinese white, use yellow iron oxide as yellow uitramarine, use dark purple and phthalocyanine blue as blue pigment, use phthalocyanine green, chrome green as green pigment, use Indian red, toluidine red as red pigments, use Black Rouge as black pigment, take with respect to the resin total amount as the mode of 2 quality % adds pigment, change pigment ratio and carry out suitable adjustment, access color of object.Above-mentioned pigment is added to the resin of melting, make container by blowing out hollow forming.
To the wall of the painted resin face that comprises container material measure the UV, visible light absorbance spectrum (V-660: Japanese light splitting Co., Ltd. makes, 200～750nm).
Pharmaceutical composition shown in ST Stuffing Table 2, carry out the rayed test under 2 following conditions therein.Take out pharmaceutical composition after exposure experiment finishes, use high effective liquid chromatography for measuring as the SE configuration of the impurity of luliconazole and the growing amount of Z configuration, the character of the liquid that detects by an unaided eye simultaneously.Show the result in table 3.
Distinguish the shading that is filled in the drug utilization container of the present utility model in Lycoperdon polymorphum Vitt, dark brown, green container of sample 1～3 and have excellent photostability by the result of table 3.In addition, all in sample, the transmission of ultraviolet, visible light is 0%, therefore, only also distinguishes and can't play such effect by shading.
＜rayed experimental condition 1 〉
White fluorescent lamp: white fluorescent lamp National FLR-20S W/M
Total illumination: 1,200,000 1x/h
Set illumination: 5klx
Irradiation natural law: 10 days
＜rayed experimental condition 2 〉
Nearultraviolet rays fluorescent lamp: fluorescence chemical lamp FLR-20S BL/M-(A)
Total nearultraviolet rays radiant: 200W/h/m
2
Set uitraviolet intensity: 15W/m
2
Irradiation time: 13.5 hours
[table 1]
| Sample number into spectrum | Color (tone, lightness/chroma) | Material (thickness) | The transmission of ultraviolet, visible light |
| Sample 1 | Lycoperdon polymorphum Vitt (7.56Y, 5.0/0.7) | PE(1.2mm) | 0% |
| Sample 2 | Green (9.46Y, 2.1/7.2) | PE(1.2mm) | 0% |
| Sample 3 | Dark brown (8.4YR, 1.7/4.2) | PE(1.2mm) | 0% |
| Sample 4 | White (2.16Y, 9.8/3.8) | PE(1.2mm) | 0% |
| Sample 5 | Blue (3.6PB, 2.0/8.0) | PE(1.2mm) | 0% |
In table, PE represents polyethylene.
[table 2]
| The preparation composition | Quality % |
| Luliconazole | 1.0 |
| Polyethylene Glycol | 20 |
| The medium-chain fatty acid triglyceride | 25 |
| Methyl ethyl ketone | 5 |
| Phosphoric acid | (add take pH as 5.5 mode) in right amount |
| Ethanol | Residue |
[table 3]
Table 3-1
Table 3-2
| Sample number into spectrum | ? |
| Sample 1 | Clear, colorless |
| Sample 2 | Clear, colorless |
| Sample 3 | Clear, colorless |
| Sample 4 | Transparent, little yellow |
| Sample 5 | Clear, colorless |
In table, represented by following structural formula as SE configuration and the Z configuration of impurity.
[chemical formula 4]
＜embodiment 2 〉
Make pharmaceutical composition 1 of the present utility model according to the prescription shown in table 4.Namely, with the part of METHYLPYRROLIDONE with whole luliconazole moistenings, add therein whole benzyl alcohol, add again lactic acid, add remaining METHYLPYRROLIDONE and whole diisopropyl adipate, add ethanol, polyvinylpyrrolidone after fully mixing, heating mixes makes its solubilization, stirring is cooled to room temperature, obtains pharmaceutical composition 1 of the present utility model.The content of the SE configuration after just having made is 0.27 quality %, and the content of the SE configuration of the sample at 40 ℃ after preserving 6 months is 0.27 quality %, does not almost generate new SE configuration.In addition, about the Z configuration, just made rear Z and be configured as 0.03 quality %, the content of the Z configuration of the sample at 40 ℃ after preserving 6 months is 0.05 quality %, and preserving the growing amount that causes is 0.02 quality %.In addition, do not observe crystallization after room temperature, the long preservation test of 9 months yet.Generally speaking, with approximate in the room temperature preservation result of 3 years, can regard the result of at room temperature preserving 3 years in the long preservation result of the tests of 40 ℃, 6 months and room temperature, the long preservation result of the test of 9 months as.In addition, do not find crystallization during use on fingernail.Thus, distinguish that said preparation satisfies the condition of following (1)～(6).
(1) can crystallization under room temperature, the preservation condition of 3 years.
(2) with respect to the use level of luliconazole, the content of the SE configuration of luliconazole is below 0.5 quality %.
(3) with respect to the use level of luliconazole, the content of the Z configuration of luliconazole is below 0.5 quality %.
(4) under the preservation condition of 40 ℃, 6 months, the growing amount of the SE configuration of luliconazole is below 0.2 quality % with respect to the use level of luliconazole.
(5) under the preservation condition of 40 ℃, 6 months, the growing amount of the Z configuration of luliconazole is below 0.2 quality % with respect to the use level of luliconazole.
(6) can crystallization on fingernail after just being coated on fingernail.
Thus, the characteristics such as premium properties, three-dimensional stability raising effect that keep as can be known the impregnability of METHYLPYRROLIDONE in fingernail in said preparation.
In addition, also as below with reference to as shown in example 1,2, also can distinguish: although be difficult to stably dissolve the luliconazole of 3 quality % in the compositions of the METHYLPYRROLIDONE that usually contains 8 quality %, can stably dissolve the luliconazole of 5 quality % in pharmaceutical composition of the present utility model.
[table 4]
| The preparation composition | Quality % |
| Luliconazole | 5 |
| Benzyl alcohol | 2 |
| Diisopropyl adipate | 10 |
| METHYLPYRROLIDONE | 8 |
| Lactic acid | 4 |
| Polyvinylpyrrolidone | 0.5 |
| Ethanol | Residue |
＜embodiment 3 〉
According to the prescription shown in table 5, make similarly to Example 2 pharmaceutical composition 2～4 of the present utility model.These pharmaceutical compositions present the character of clear solution after just making.In addition, carry out room temperature, the long preservation test of 9 months, the degree of the crystallization that detects by an unaided eye.Result similarly is shown in table 5.Thus, the preferred content of distinguishing benzyl alcohol is 1～3 quality %, more preferably 1～2 quality %.
[table 5]
＜embodiment 4 〉
According to prescription shown in table 6, make similarly to Example 2 pharmaceutical composition 5 of the present utility model and 6.These pharmaceutical compositions present the character of clear solution after manufacturing.In addition, carry out room temperature, the long preservation test of 9 months, with the naked eye investigate the degree of crystallization.Result similarly is shown in table 6.The preferred content of distinguishing diisopropyl adipate is 11～16 quality %, more preferably 11～14 quality %.
[table 6]
＜embodiment 5 〉
The pharmaceutical composition 1 of embodiment 2 is filled in the container of sample 1 of embodiment 1 as medicine of the present utility model.Although this medicine contains the luliconazole of high concentration, stable in the preservation test of 40 ℃, 6 months.
＜reference example 1 〉
Make the preparation of luliconazole according to the prescription shown in table 7.That is, add benzyl alcohol in luliconazole, after dissolving, be sequentially added into ethanol, diisopropyl adipate, METHYLPYRROLIDONE, lactic acid, be cooled to room temperature after the heating solubilization, obtain the preparation of transparent solution character.It is preserved 2 weeks, crystallization as a result at 5 ℃.The amount of distinguishing benzyl alcohol in this system is more than this utility model scope, and the cooperation limit of luliconazole is lower than 3 quality %.
[table 7]
| The preparation composition | Quality % |
| Luliconazole | 3 |
| Benzyl alcohol | 4 |
| Diisopropyl adipate | 10 |
| METHYLPYRROLIDONE | 8 |
| Lactic acid | 4 |
| Polyvinylpyrrolidone | 0.5 |
| Ethanol | Residue |
＜reference example 2 〉
According to the prescription shown in table 8, similarly operate with reference example 1, obtain the pharmaceutical composition of transparent solution character.This pharmaceutical composition is observed crystallization under 5 ℃, the preservation in 12 weeks.The amount of distinguishing benzyl alcohol is more than this utility model scope, and in containing the luliconazole pharmaceutical solutions of N-alkyl-2-Pyrrolidone, the cooperation limit of luliconazole is 3 quality %.
[table 8]
| The preparation composition | Quality % |
| Luliconazole | 3 |
| Benzyl alcohol | 4 |
| Isopropyl myristate | 10 |
| METHYLPYRROLIDONE | 8 |
| Lactic acid | 4 |
| Polyvinylpyrrolidone | 0.5 |
| Ethanol | Residue |
＜embodiment 6 〉
With pharmaceutical composition 1 similarly according to table 9 pharmaceutical compositions 7.It is filled in the container of sample 1 of embodiment 1,60 ℃ and 40 ℃ of preservations, studies its stability.Show the result in table 10.Thus, distinguish under the state of pharmaceutical composition 7 in the container of the sample 1 that is filled in embodiment 1 to have excellent stability.
[table 9]
| The composition name | Use level (quality %) |
| Luliconazole | 5.0 |
| METHYLPYRROLIDONE | 8.0 |
| Benzyl alcohol | 2.0 |
| Diisopropyl adipate | 12.0 |
| Lactic acid | 4.0 |
| Polyvidone | 0.5 |
| Dehydrated alcohol | 68.5 |
[table 10]
| Assessment item | During beginning | 60 ℃, 3 weeks | 40 ℃, 1 month |
| S-E configuration (quality %) | 0.02 | 0.04 | 0.03 |
| Z configuration (quality %) | 0.00 | 0.05 | 0.01 |
| Other similar substance total amount (quality %) | 0.00 | 0.06 | 0.00 |
| Content (%) | 100.13 | 102.79 | 101.95 |
Industrial applicibility
This utility model can be applicable to medicine.
Claims (7)
1. plastic holding device, it is for filling the plastic holding device of content, wherein, this plastic holding device have in the munsell color coordinate tone (H) as 7.0Y～9.99Y or 7.0YR～9.99YR, lightness (V) as 1.0～6.0, chroma (C) carried out painted resin face as the color in 0.5～7.5 scope.
2. plastic holding device according to claim 1, wherein, described plastic holding device does not show transmittance in the mensuration of UV, visible light absorbance spectrum.
3. plastic holding device according to claim 1, wherein, the material of described plastic holding device is polypropylene or polyethylene.
4. plastic holding device according to claim 2, wherein, the material of described plastic holding device is polypropylene or polyethylene.
5. the described plastic holding device of any one according to claim 1～4, it is bottle container.
6. the described plastic holding device of any one according to claim 1～4, it is used for holding containing the compound shown in following general formula (I) and/or the pharmaceutical composition of its salt,
General formula (I)
In general formula (I), R
1, R
2Represent independently respectively hydrogen atom or halogen atom.
7. plastic holding device according to claim 5, it is used for holding containing the compound shown in following general formula (I) and/or the pharmaceutical composition of its salt,
General formula (I)
In general formula (I), R
1, R
2Represent independently respectively hydrogen atom or halogen atom.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2012-061536 | 2012-03-19 | ||
| JP2012061536 | 2012-03-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN203263805U true CN203263805U (en) | 2013-11-06 |
Family
ID=49185150
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310087430.7A Active CN103315907B (en) | 2012-03-19 | 2013-03-19 | Plastic holding device filled with antifungal medicine composition |
| CN2013201238978U Withdrawn - After Issue CN203263805U (en) | 2012-03-19 | 2013-03-19 | Resin container filled with antifungal drug composition |
| CN201710513125.8A Active CN107198686B (en) | 2012-03-19 | 2013-03-19 | Antifungal medicine composition |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310087430.7A Active CN103315907B (en) | 2012-03-19 | 2013-03-19 | Plastic holding device filled with antifungal medicine composition |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201710513125.8A Active CN107198686B (en) | 2012-03-19 | 2013-03-19 | Antifungal medicine composition |
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| JP (3) | JP5980700B2 (en) |
| CN (3) | CN103315907B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103315907A (en) * | 2012-03-19 | 2013-09-25 | 宝丽制药股份有限公司 | Resin container filled with antifungal pharmaceutical composition |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9480746B2 (en) | 2014-04-21 | 2016-11-01 | Pola Pharma Inc. | Resin container filled with antifungal pharmaceutical composition |
| 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 |
| CN109071283B (en) * | 2016-04-26 | 2022-03-04 | 奥加诺株式会社 | Water treatment agent composition and water treatment method |
| CN114262476B (en) * | 2021-12-30 | 2023-09-05 | 沈阳兴齐眼药股份有限公司 | Packaging container for improving stability of tobramycin eye drops |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0651399B2 (en) * | 1986-02-01 | 1994-07-06 | 三菱化成株式会社 | High-purity chemical container |
| JPH0788438B2 (en) * | 1986-09-03 | 1995-09-27 | 株式会社資生堂 | Resin composition |
| JPH0651112U (en) * | 1992-07-08 | 1994-07-12 | 株式会社資生堂 | Resin bottle container |
| JP3219958B2 (en) * | 1995-01-13 | 2001-10-15 | 大日精化工業株式会社 | Colored resin composition for infusion bags |
| JP2001048182A (en) * | 1999-08-05 | 2001-02-20 | Showa Denko Kk | Plastic bottle for beer |
| JP2003267872A (en) * | 2002-03-12 | 2003-09-25 | Taiyo Yakuhin Kogyo Kk | Medicinal preparation for injection |
| JP4156398B2 (en) * | 2003-02-20 | 2008-09-24 | 大日本印刷株式会社 | Bottle with shrink label |
| CN100515381C (en) * | 2003-04-23 | 2009-07-22 | 株式会社大塚制药工厂 | Drug solution filling plastic ampoule and production method therefor |
| GB0318242D0 (en) * | 2003-08-04 | 2003-09-03 | Glaxosmithkline Biolog Sa | Novel device |
| JP2005261598A (en) * | 2004-03-17 | 2005-09-29 | Rohto Pharmaceut Co Ltd | Packaged azulene derivative-including composition |
| JP4322740B2 (en) * | 2004-06-15 | 2009-09-02 | 株式会社リコー | Resin production method, resin fine particle production method, resin fine particle |
| JP4742674B2 (en) * | 2005-05-20 | 2011-08-10 | 東洋製罐株式会社 | Light-shielding container and manufacturing method thereof |
| JP2007015747A (en) * | 2005-07-08 | 2007-01-25 | Koopakku International Kk | Shrinkable label, and pet bottle for beer |
| RU2415669C2 (en) * | 2006-03-08 | 2011-04-10 | Нихон Нохияку Ко., Лтд. | Pharmaceutic composition for external application |
| WO2007102241A1 (en) * | 2006-03-08 | 2007-09-13 | Nihon Nohyaku Co., Ltd. | External pharmaceutical composition |
| CA2645070C (en) * | 2006-03-08 | 2014-02-04 | Nihon Nohyaku Co., Ltd. | Pharmaceutical composition for external use |
| PT2266521E (en) * | 2008-03-14 | 2013-09-06 | Otsuka Pharma Co Ltd | Plastic ampule |
| JP5654497B2 (en) * | 2009-02-13 | 2015-01-14 | トピカ ファーマシューティカルズ，インコーポレイテッド | Antifungal preparation |
| CN201912439U (en) * | 2010-11-02 | 2011-08-03 | 浙江金石包装有限公司 | Blister package |
| JP5980700B2 (en) * | 2012-03-19 | 2016-08-31 | 株式会社ポーラファルマ | Resin container filled with antifungal pharmaceutical composition |
-
2013
- 2013-02-22 JP JP2013033100A patent/JP5980700B2/en active Active
- 2013-03-19 CN CN201310087430.7A patent/CN103315907B/en active Active
- 2013-03-19 CN CN2013201238978U patent/CN203263805U/en not_active Withdrawn - After Issue
- 2013-03-19 CN CN201710513125.8A patent/CN107198686B/en active Active
-
2015
- 2015-08-17 JP JP2015160473A patent/JP6110908B2/en active Active
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- 2016-04-04 JP JP2016075226A patent/JP2016174907A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103315907A (en) * | 2012-03-19 | 2013-09-25 | 宝丽制药股份有限公司 | Resin container filled with antifungal pharmaceutical composition |
| CN103315907B (en) * | 2012-03-19 | 2017-10-13 | 宝丽制药股份有限公司 | Plastic holding device filled with antifungal medicine composition |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107198686B (en) | 2019-07-30 |
| CN107198686A (en) | 2017-09-26 |
| CN103315907B (en) | 2017-10-13 |
| JP6110908B2 (en) | 2017-04-05 |
| CN103315907A (en) | 2013-09-25 |
| JP5980700B2 (en) | 2016-08-31 |
| JP2016026570A (en) | 2016-02-18 |
| JP2013223715A (en) | 2013-10-31 |
| JP2016174907A (en) | 2016-10-06 |
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Granted publication date: 20131106 Effective date of abandoning: 20171013 |