CN107865825A - A kind of luliconazole external spraying agent pharmaceutical composition and preparation method thereof - Google Patents
A kind of luliconazole external spraying agent pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN107865825A CN107865825A CN201610856077.8A CN201610856077A CN107865825A CN 107865825 A CN107865825 A CN 107865825A CN 201610856077 A CN201610856077 A CN 201610856077A CN 107865825 A CN107865825 A CN 107865825A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/4164—1,3-Diazoles
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
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- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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Abstract
The invention provides a kind of luliconazole external spraying agent pharmaceutical composition and preparation method thereof.The composition includes luliconazole, medium-chain fatty glyceride, polyethylene glycol, stabilizer, phosphoric acid, absolute ethyl alcohol.Present composition auxiliary material composition is simple, and preparation technology is simple and easy to do, and without inflammable and explosive MEK used as stabilizers, obtained composition stability is good, and luliconazole amide impurities are can be controlled in very low scope, significantly improve product quality.
Description
Technical field
The present invention relates to a kind of luliconazole external spraying agent pharmaceutical composition and preparation method thereof, belongs to medical science neck
Domain.
Background technology
Fungal dermatopathy is the result of skin histology position fungal infection.Fungal infection position can be distributed in whole body skin
Skin, morbidity highest are cuticula, and its Typical Representative illness is tinea disease, monilial infection and leucoderma.Investigation display, skin are true
Bacterium infected patient accounts for 13% or so of Dermatology Outpatient Department patient, the tinea patient including 88.0%, 8.5% candida albicans sense
Patient and 3.4% patients with vitiligo are contaminated, it is tinea pedis to have 64.0% again in tinea disease.
Tinea disease is a kind of intractable disease of skin, including tinea pedis, ringworm of the body, jock itch etc., and the course of disease is slow, recurrence rate after healing compared with
Height, inflammation is more obvious during morbidity, and has the skin lesion phenomenon such as blister, the scales of skin that peel off and incrustation, is often accompanied by different degrees of itch, seriously
Influence the quality of life of people.Main Pathogenic Bacteria has Trichophyton rubrum, alpha fungus, acrothesium floccosum etc..Tinea pedis is commonly called as
" tinea pedis ", it is that incidence of disease highest is a kind of in dermatophytosis, Trichophyton rubrum is its most common pathogenic bacteria.Ringworm of the body, jock itch
Tinea pedis and manus is collectively referred to as, the incidence of disease is only below tinea pedis, mainly caused by Trichophyton rubrum, alpha fungus and acrothesium floccosum.Foot
Tinea also has infectiousness, is the tinea manuum, ringworm of the body, jock itch and onychomycosis illness important root.
At present, tinea disease medicine mainly has two major classes：First kind Allylamines medicine, such as Terbinafine, Butenafine
With Naftifine etc., they are by suppressing squalene cyclase, causing the shortage of ergosterol and the accumulation of squalene, so as to rise
To the antifungal drug of bactericidal action.Second class imidazoles (imidazoles) medicine, such as Miconazole, econazole, clotrimazole, ketone
Health azoles and bifonazole.They are the antifungal drugs of a kind of synthesis, can the α of selective depression fungal cell lanosterol 14-go
Methyl enzymatic activity, the synthesis of cell membrane ergosterol is prevented, sexually revises cell membrane penetration, causes intracellular important substance to lose and make
Fungi is dead.Imidazoles antifungal drug is that clinically the most frequently used a kind for the treatment of tinea disease medicine, clinical practice are very wide at present
It is general.
Luliconazole (structural formula is as shown in following formula I) is a kind of new imidazoles antimycotic medicine for external application, is La Nuokang
Azoles analog, developed by Nihon Nihyaku Co., Ltd (Nihon Nohyaku Co., Ltd.s).In April, 2005 luliconazole emulsifiable paste
And lotion is in the granted listing of Japan, trade name2010,2012 respectively in India and Discussion on Chinese Listed；2013
Listed in the U.S., trade nameIn addition to for treating tinea pedis, jock itch and ringworm of the body, luliconazole is also exploited for onychomycosis
(onychomycosis) is treated.Compared with common antimycotic externally applied drug, luliconazole has good storing property of skin, has a broad antifungal spectrum, antibacterial
The advantages that activity is strong, therefore its medication cycle short (for the half of general medicine), good effect and uneasy to recur, therefore with very strong
Competitiveness.
But because the cyano group in luliconazole molecular structure is more unstable, acid amides is easily hydrolyzed under certain condition
Group, the impurity (as shown in following formula II) of luliconazole amide form thereof is formed, have impact on the quality of luliconazole preparation.Listing production
Product are not controlled to the impurity.
CN104619320A, which is provided, controls the acid amides shape that is formed related to the pharmaceutical composition containing luliconazole
The method of the forming amount of formula, said composition contain luliconazole and selected from following one or more components：Carboxylic acid and its derivative
Thing, ketone (being mainly selected from MEK and acetone), phosphoric acid and its derivative, local anesthetic, antihistaminic and based on POE it is non-from
Subtype surfactant；Wherein stored 3 weeks at 60 DEG C or after 40 DEG C store 6 months, the amide derivatives of luliconazole contain
Amount is no more than 0.2% by mass relative to the addition of luliconazole.But MEK wherein used, acetone belong to inflammable and explosive
Chemical substance, it is unfavorable for industrialized production；And MEK belongs to malicious -3 class chemicals of easily system, by control；Meanwhile MEK pair
Skin has excitant, should not be used in the preparation of external preparation.And WO2003105841A1, CN101820877A,
CN102395274A, CN102387785A, CN102481286A, CN103957907A etc. employ MEK (or acetone)
Prepare luliconazole external preparation.
Referred in CN104662017A, its luliconazole preparation provided can be in acceleration environment or tightened up condition
Under, such as store 3 weeks at 60 DEG C, amide form thereof is suppressed to by mass no more than 1%, it is more excellent to be no more than 0.5%, Yi Jigeng
Add preferably more than 0.1%.But it, which is not provided, has any different in other special technology letters of luliconazole preparation prior art
Breath.
Therefore, exploitation is a kind of controls outside the luliconazole of luliconazole amide impurities well without MEK while and can
With preparation, the problem of being this area urgent need to resolve.
The content of the invention
In order to overcome the above-mentioned deficiencies of the prior art, the present invention provide a kind of auxiliary material composition it is simple and without MEK, into
The luliconazole external spraying agent pharmaceutical composition and its preparation side that this is cheap, preparation technology is easy, amide impurities content is extremely low
Method.
The present invention is achieved through the following technical solutions：
The luliconazole external spraying agent pharmaceutical composition, includes luliconazole, medium-chain fatty glyceride, poly- second two
Alcohol, stabilizer, absolute ethyl alcohol and phosphoric acid.
Further, the medium-chain fatty glyceride is in the monoglyceride, diester or three esters of C8~C12 aliphatic acid
One or more mixtures.
Further, the polyethylene glycol is selected from polyethylene glycol 200, Liquid Macrogol, polyethylene glycol 400, polyethylene glycol
600th, polyethylene glycol-800, cetomacrogol 1000, polyethylene glycol 1500, polyethylene glycol 2000, Macrogol 4000, polyethylene glycol
One or more mixtures in 6000.
Further, the stabilizer is selected from butylated hydroxy anisole, dibutyl hydroxy toluene, propylgallate, disappeared
Revolve one or more mixtures in alpha-tocopherol.
Further, the composition includes per 100mL：
Wherein described medium-chain fatty glyceride is one kind in the monoglyceride, diester or three esters of C8~C12 aliphatic acid
Or a variety of mixtures, the polyethylene glycol are selected from polyethylene glycol 200, Liquid Macrogol, polyethylene glycol 400, polyethylene glycol
600th, polyethylene glycol-800, cetomacrogol 1000, polyethylene glycol 1500, polyethylene glycol 2000, Macrogol 4000, polyethylene glycol
One or more mixtures in 6000, the stabilizer are butylated hydroxy anisole, dibutyl hydroxy toluene, gallic acid
One or more mixtures in propyl ester, racemization alpha-tocopherol.
In one embodiment, the composition includes per 100mL：
In one embodiment, the composition includes per 100mL：
In one embodiment, the composition includes per 100mL：
In one embodiment, the composition includes per 100mL：
Further, luliconazole external spraying agent pharmaceutical composition of the present invention also includes 2~5g of preservative per 100mL,
Wherein described preservative is selected from Kathon CG, phenmethylol or the mixture of the two.
The present invention also provides the preparation method of the luliconazole external spraying agent pharmaceutical composition, comprises the following steps：
(1) each supplementary material is weighed by recipe quantity；
(2) first add about 80% absolute ethyl alcohol into Agitation Tank, turn on agitator, sequentially add stabilizer, phosphoric acid, in
Chain fatty acid triglyceride and polyethylene glycol, then the absolute ethyl alcohol into residue about 20% is added to prescribed volume, stir；
(3) luliconazole, stirring and dissolving are added；
(4) by decoction with 3 μm of polypropylene filter element filterings；
(5) finished product is obtained by the filling mouth that rolls of 10mL/ bottles.
If composition further includes preservative, its preparation process is：
(1) each supplementary material is weighed by recipe quantity；
(2) about 80% absolute ethyl alcohol is first added into Agitation Tank, turn on agitator, stabilizer, phosphoric acid is sequentially added, prevents
Rotten agent, medium-chain fatty glyceride and polyethylene glycol, then the absolute ethyl alcohol into residue about 20% is added to prescribed volume, stirring is
It is even；
(3) luliconazole, stirring and dissolving are added；
(4) by decoction with 3 μm of polypropylene filter element filterings；
(5) finished product is obtained by the filling mouth that rolls of 10mL/ bottles.
Luliconazole external spraying agent of the present invention and preparation method thereof has advantages below：
(1) medicine stability is good, and in accelerated test, luliconazole amide impurities content is extremely low, is significantly less than 0.1%
(0.002%~0.008%), Z isomer impurities content is less than 0.1%, SE isomer impurities contents below 1%.
(2) preferably go out the used as stabilizers such as racemization alpha-tocopherol, inhibit the generation of luliconazole amide impurities well, no
But substitution is unfavorable for keeping the safety in production and has the chemicals of skin irritation using MEK this one kind in the prior art, and it is made
Luliconazole amide impurities content is greatly reduced in agent product, improves product quality.
(3) compared with prior art, the auxiliary material composition that pharmaceutical composition of the present invention uses is simpler, and preparation technology is easier
It is easy.
(4) luliconazole spray this new exterior-applied formulation is added, clinical demand is further met, improves trouble
Compliance of the person to medicine.
Embodiment
Below will by embodiment, the invention will be further described, these description be not present invention is made into
The restriction of one step.It should be understood by those skilled in the art that the equivalent substitution made to present invention, or be correspondingly improved, still
Belong within protection scope of the present invention.
The preparation of the luliconazole external spraying agent of embodiment 1
Prescription：
Preparation method：
(1) each supplementary material is weighed by recipe quantity；
(2) first add about 80% absolute ethyl alcohol into Agitation Tank, turn on agitator, sequentially add propylgallate,
Phosphoric acid, MCT Oil and Liquid Macrogol, then the absolute ethyl alcohol into residue about 20% is added to 1000mL, stir
Mix uniformly；
(3) luliconazole, stirring and dissolving are added；
(4) by decoction with 3 μm of polypropylene filter element filterings；
(5) filling 100 bottles of 10mL/ bottles are pressed, mouth is rolled and obtains finished product.
The preparation of the luliconazole external spraying agent of embodiment 2
Prescription：
Preparation method：
(1) each supplementary material is weighed by recipe quantity；
(2) about 80% absolute ethyl alcohol is first added into Agitation Tank, turn on agitator, sequentially adds butylated hydroxy-a
Benzene, phosphoric acid, MCT Oil and polyethylene glycol 400, then the absolute ethyl alcohol into residue about 20% is added to 1000mL,
Stir；
(3) luliconazole, stirring and dissolving are added；
(4) by decoction with 3 μm of polypropylene filter element filterings；
(5) filling 100 bottles of 10mL/ bottles are pressed, mouth is rolled and obtains finished product.
The preparation of the luliconazole external spraying agent of embodiment 3
Prescription：
Preparation method：
(1) each supplementary material is weighed by recipe quantity；
(2) first add about 80% absolute ethyl alcohol into Agitation Tank, turn on agitator, sequentially add racemization alpha-tocopherol,
Phosphoric acid, MCT Oil and polyethylene glycol 400, then the absolute ethyl alcohol into residue about 20% is added to 1000mL, stir
Mix uniformly；
(3) luliconazole, stirring and dissolving are added；
(4) by decoction with 3 μm of polypropylene filter element filterings；
(5) filling 100 bottles of 10mL/ bottles are pressed, mouth is rolled and obtains finished product.
The preparation of the luliconazole external spraying agent of embodiment 4
Prescription：
Preparation method：
(1) each supplementary material is weighed by recipe quantity；
(2) first add about 80% absolute ethyl alcohol into Agitation Tank, turn on agitator, sequentially add racemization alpha-tocopherol,
Phosphoric acid, phenmethylol, MCT Oil and polyethylene glycol 400, then add into residue about 20% absolute ethyl alcohol extremely
1000mL, stir；
(3) luliconazole, stirring and dissolving are added；
(4) by decoction with 3 μm of polypropylene filter element filterings；
(5) filling 100 bottles of 10mL/ bottles are pressed, mouth is rolled and obtains finished product.
The preparation of the luliconazole external spraying agent of embodiment 5
Prescription：
Preparation method：
(1) each supplementary material is weighed by recipe quantity；
(2) about 80% absolute ethyl alcohol is first added into Agitation Tank, turn on agitator, sequentially adds butylhydroxy fennel
Ether, phosphoric acid, Kathon CG, MCT Oil and polyethylene glycol 200, then add into residue about 20% absolute ethyl alcohol extremely
1000mL, stir；
(3) luliconazole, stirring and dissolving are added；
(4) by decoction with 3 μm of polypropylene filter element filterings；
(5) filling 100 bottles of 10mL/ bottles are pressed, mouth is rolled and obtains finished product.
The preparation of the luliconazole external spraying agent of embodiment 6
Prescription：
Preparation method：
(1) each supplementary material is weighed by recipe quantity；
(2) about 80% absolute ethyl alcohol is first added into Agitation Tank, turn on agitator, sequentially adds butylated hydroxy-a
Benzene, phosphoric acid, MCT Oil and Macrogol 6000, then add into residue about 20% absolute ethyl alcohol extremely
1000mL, stir；
(3) luliconazole, stirring and dissolving are added；
(4) by decoction with 3 μm of polypropylene filter element filterings；
(5) filling 100 bottles of 10mL/ bottles are pressed, mouth is rolled and obtains finished product.
The study on the stability of embodiment 7 (accelerated test)
(1) sample made from embodiment 1,3,5 is placed under temperature 60 C by simulation commercially available back places 3 weeks, and detection respectively has
Material is closed, as a result see the table below 1：
3 weeks relevant materials are investigated at 1 60 DEG C of table
(2) sample made from embodiment 1,3,5 is placed at 40 DEG C of temperature by simulation commercially available back places 6 months, and detection is each
Relevant material, as a result see the table below 2：
6 months relevant materials are investigated at 2 40 DEG C of table
From table 1, table 2, in accelerated test, 6 monthly do not detect luliconazole at three 40 DEG C of embodiment samples
Amide impurities, detect within 3 weeks that the amide impurities content is up to 0.008% at three 60 DEG C of samples, minimum 0.002%, significantly
Less than 0.2% in CN104619320A under equal conditions and 0.1% in CN104662017A；Its Z isomer impurities content
Less than 0.1%, SE isomer impurities contents below 1%, conform to quality requirements；Other maximum single miscellaneous contents, in addition to isomers
Total miscellaneous content meets the requirements in prescribed limit.
Claims (12)
1. a kind of luliconazole external spraying agent pharmaceutical composition, it is characterised in that include luliconazole, medium chain fatty acid
Ester, polyethylene glycol, stabilizer, absolute ethyl alcohol and phosphoric acid.
2. pharmaceutical composition as claimed in claim 1, it is characterised in that the medium-chain fatty glyceride is C8 ~ C12 fat
One or more mixtures in the monoglyceride of acid, diester or three esters.
3. pharmaceutical composition as claimed in claim 1, it is characterised in that the polyethylene glycol is selected from polyethylene glycol 200, poly- second
Glycol 300, polyethylene glycol 400, Macrogol 600, polyethylene glycol-800, cetomacrogol 1000, polyethylene glycol 1500, poly- second two
One or more mixtures in alcohol 2000, Macrogol 4000, Macrogol 6000.
4. pharmaceutical composition as claimed in claim 1, it is characterised in that the stabilizer is selected from butylated hydroxy anisole, two
One or more mixtures in butylated hydroxytoluene, propylgallate, racemization a- tocopherols.
5. pharmaceutical composition as claimed in claim 1, it is characterised in that the composition includes per 100mL：
0.2 ~ 5g of luliconazole,
5 ~ 40g of medium-chain fatty glyceride,
5 ~ 60g of polyethylene glycol,
0.005 ~ 0.2g of stabilizer,
0.001 ~ 0.02g of phosphoric acid,
Absolute ethyl alcohol complements to 100mL,
Wherein described medium-chain fatty glyceride is the one or more in the monoglyceride, diester or three esters of C8 ~ C12 aliphatic acid
Mixture, the polyethylene glycol be selected from polyethylene glycol 200, Liquid Macrogol, polyethylene glycol 400, Macrogol 600, poly- second
In glycol 800, cetomacrogol 1000, polyethylene glycol 1500, polyethylene glycol 2000, Macrogol 4000, Macrogol 6000
One or more mixtures, the stabilizer are butylated hydroxy anisole, dibutyl hydroxy toluene, propylgallate, disappeared
Revolve one or more mixtures in a- tocopherols.
6. pharmaceutical composition as claimed in claim 5, it is characterised in that the composition includes per 100mL：
0.5 ~ 2g of luliconazole,
12 ~ 26g of MCT Oil,
20 ~ 50g of Macrogol 600,
0.01 ~ 0.15g of butylated hydroxy anisole,
0.003 ~ 0.015g of phosphoric acid,
Absolute ethyl alcohol complements to 100mL.
7. pharmaceutical composition as claimed in claim 5, it is characterised in that the composition includes per 100mL：
Luliconazole 1g,
10 ~ 20g of MCT Oil,
20 ~ 50g of Liquid Macrogol,
0.005 ~ 0.1g of propylgallate,
0.003 ~ 0.015g of phosphoric acid,
Absolute ethyl alcohol complements to 100mL.
8. pharmaceutical composition as claimed in claim 5, it is characterised in that the composition includes per 100mL：
Luliconazole 1g,
10 ~ 20g of MCT Oil,
10 ~ 40g of polyethylene glycol 400,
0.0075 ~ 0.1g of dibutyl hydroxy toluene,
0.003 ~ 0.015g of phosphoric acid,
Absolute ethyl alcohol complements to 100mL.
9. pharmaceutical composition as claimed in claim 5, it is characterised in that the composition includes per 100mL：
Luliconazole 1g,
10 ~ 20g of MCT Oil,
10 ~ 40g of polyethylene glycol 400,
Racemization a- 0.001 ~ 0.05g of tocopherol,
0.003 ~ 0.015g of phosphoric acid,
Absolute ethyl alcohol complements to 100mL.
10. the pharmaceutical composition as described in any one of claim 1 ~ 9, it is characterised in that the composition also includes per 100mL
2 ~ 5g of preservative, the preservative are selected from Kathon CG, phenmethylol or the mixture of the two.
11. the preparation method of any one of claim 1 ~ 9 described pharmaceutical composition, it is characterised in that comprise the following steps：
（1）Each supplementary material is weighed by recipe quantity；
（2）About 80% absolute ethyl alcohol is first added into Agitation Tank, turn on agitator, sequentially adds stabilizer, phosphoric acid, middle chain fat
Fatty acid glyceride and polyethylene glycol, then the absolute ethyl alcohol into residue about 20% is added to prescribed volume, stir；
（3）Add luliconazole, stirring and dissolving；
（4）By decoction 3mm polypropylene filter element filterings；
（5）Finished product is obtained by the filling mouth that rolls of 10mL/ bottles.
12. the preparation method of claim 10 described pharmaceutical composition, it is characterised in that comprise the following steps：
（1）Each supplementary material is weighed by recipe quantity；
（2）First add about 80% absolute ethyl alcohol into Agitation Tank, turn on agitator, sequentially add stabilizer, phosphoric acid, preservative,
Medium-chain fatty glyceride and polyethylene glycol, then the absolute ethyl alcohol into residue about 20% is added to prescribed volume, stir；
（3）Add luliconazole, stirring and dissolving；
（4）By decoction 3mm polypropylene filter element filterings；
（5）Finished product is obtained by the filling mouth that rolls of 10mL/ bottles.
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| CN201610856077.8A CN107865825B (en) | 2016-09-28 | 2016-09-28 | Luliconazole external spray pharmaceutical composition and preparation method thereof |
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| CN201610856077.8A CN107865825B (en) | 2016-09-28 | 2016-09-28 | Luliconazole external spray pharmaceutical composition and preparation method thereof |
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| CN107865825B CN107865825B (en) | 2022-05-20 |
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| WO2011155640A1 (en) * | 2010-06-11 | 2011-12-15 | Pola Pharma Inc. | Antimycotic pharmaceutical composition |
| JP2012144449A (en) * | 2011-01-07 | 2012-08-02 | Nippon Nohyaku Co Ltd | Formulation for improving skin permeability of luliconazole |
| CN103957907A (en) * | 2011-09-26 | 2014-07-30 | 日本农药株式会社 | Anti-fungal agent |
| CN104105472A (en) * | 2011-12-20 | 2014-10-15 | 维奥姆生物科学有限公司 | Topical oil composition for treating fungal infections |
| JP2014208618A (en) * | 2013-03-28 | 2014-11-06 | 大正製薬株式会社 | Pharmaceutical liquid composition |
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2016
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