CA2060048C - Skin cream preparation for external use - Google Patents
Skin cream preparation for external useInfo
- Publication number
- CA2060048C CA2060048C CA002060048A CA2060048A CA2060048C CA 2060048 C CA2060048 C CA 2060048C CA 002060048 A CA002060048 A CA 002060048A CA 2060048 A CA2060048 A CA 2060048A CA 2060048 C CA2060048 C CA 2060048C
- Authority
- CA
- Canada
- Prior art keywords
- weight
- group
- diglycerol
- cream preparation
- fatty acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
Abstract
A W/O skin cream preparation for external use useful as a remedy for skin diseases which consists of a cream base comprising a diglycerol fatty acid ester and/or a sorbitan fatty acid ester having an HLB value of from 3 to 7, a polyvalent metal salt of a saturated or unsaturated fatty acid having 10 to 22 carbon atoms, an inorganic or organic acid salt, an oily phase component, and water together with an active ingredient.
Description
DESCRIPTION
SKIN CREAM PREPARATION FOR EXTERNAL USE
Technical lield:
'rhis invention re]ates to a cream preparation for external use which contains a remedy for ski.n diseases as an active ingredient. More particularly, it relates to a W/O ski.n cream preparation for external use wliich contains a remedy for skin diseases, such as an antiinflammatory agent, an antibacterial agent or an antiallergic agent, as an active ingredient and is useful in treating, for example, eczema, dermatitis, prurigo, atopic dermatitis, psoriasis, candidiasis or tri.chophytia.
lS
Background Art:
A W/O cream base which comprises an oily external phase and thus exerts an effect of protecting the skin is superior to an O/W one as a base for a remedy for skin diseases. However, O/W cream base preparati.ons containing remedies for skin diseases have been often used hitherto, while W/O crearn preparations have been scarcely employed. This is because the conventional W/O cream bases contain a ]arge amount of oily phase components and thus are inferior to the O/W cream bases in the comfortableness in the use and the stabili.ty of preparation. When ar) acti.ve ingredient :i~ blende(i witll a W/O cream base of a high moistllre content, in particular, the comfortableness in the use is improved but the heat stability of the preparation is deteriorated. Thus no satisfactory cream preparation has been obtained so far.
Examples of the prior art cream preparation containing ketotifen or its fumarate include Japanese Patent Appliaction Laid-Open Gazette Nos. Sho. 51-32724, Sho. ~1-142543, Sho. 62-164624, Tlei. 1-102024 and Hei. 1-121218. However none of these cream preparations containing ketotifen or its rumarate disclosed in the above references is satisfactory from the viewpoints of the stabilities of the preparation and drug and the percutaneous absorption of the drug.
The conventional W/O cream base contains a very large amount of an oily phase, i.e., the external phase. When applied to the skin, therefore, it poorly dries and has a persistent stickiness, thus being uncomfortable. Furthermore, it is apt to cause liquid separation due to the high content of the oily phase, which means that it has a poor stability. In addition, it shows on]y a poor release of the active ingredient from the preparation. Therefore, it has been urgent]y required to develop a W/O cream preparation capable of effectively releasing a drug from the viewpoint of pharmaco]ogica] ef~rccts too. ~ccording:ly, it is an ob~ect of the present invention to provide a W/O cream preparation which is comfortable in the use, has a high stability and efrecl,ively releases the drug.
For instance, when ketotifen having a high chemical activity is added to the conventional crearn S base, the active ingredient, i.e., ketotifen or its fumarate, reacts with the components of the cream base or impurities contained therein and thus causes a decrease in the content of the active ingredient or a color change with the lapse of time. ~urthermore, it is sometimes observed that the cream is degraded into an emulsion or causes liquid separation. In the case of a W/0 cream preparation which is inherently inferior to an 0/W one in stability, in particular, it is highly difficult to maintain a preparation containing ketotifen or its fumarate in a stable state.
Accor(3inFly, it is another object of the present invention to provide: (1) a stable W/0 cream preparation containing ketotifen or its fumarate; and
SKIN CREAM PREPARATION FOR EXTERNAL USE
Technical lield:
'rhis invention re]ates to a cream preparation for external use which contains a remedy for ski.n diseases as an active ingredient. More particularly, it relates to a W/O ski.n cream preparation for external use wliich contains a remedy for skin diseases, such as an antiinflammatory agent, an antibacterial agent or an antiallergic agent, as an active ingredient and is useful in treating, for example, eczema, dermatitis, prurigo, atopic dermatitis, psoriasis, candidiasis or tri.chophytia.
lS
Background Art:
A W/O cream base which comprises an oily external phase and thus exerts an effect of protecting the skin is superior to an O/W one as a base for a remedy for skin diseases. However, O/W cream base preparati.ons containing remedies for skin diseases have been often used hitherto, while W/O crearn preparations have been scarcely employed. This is because the conventional W/O cream bases contain a ]arge amount of oily phase components and thus are inferior to the O/W cream bases in the comfortableness in the use and the stabili.ty of preparation. When ar) acti.ve ingredient :i~ blende(i witll a W/O cream base of a high moistllre content, in particular, the comfortableness in the use is improved but the heat stability of the preparation is deteriorated. Thus no satisfactory cream preparation has been obtained so far.
Examples of the prior art cream preparation containing ketotifen or its fumarate include Japanese Patent Appliaction Laid-Open Gazette Nos. Sho. 51-32724, Sho. ~1-142543, Sho. 62-164624, Tlei. 1-102024 and Hei. 1-121218. However none of these cream preparations containing ketotifen or its rumarate disclosed in the above references is satisfactory from the viewpoints of the stabilities of the preparation and drug and the percutaneous absorption of the drug.
The conventional W/O cream base contains a very large amount of an oily phase, i.e., the external phase. When applied to the skin, therefore, it poorly dries and has a persistent stickiness, thus being uncomfortable. Furthermore, it is apt to cause liquid separation due to the high content of the oily phase, which means that it has a poor stability. In addition, it shows on]y a poor release of the active ingredient from the preparation. Therefore, it has been urgent]y required to develop a W/O cream preparation capable of effectively releasing a drug from the viewpoint of pharmaco]ogica] ef~rccts too. ~ccording:ly, it is an ob~ect of the present invention to provide a W/O cream preparation which is comfortable in the use, has a high stability and efrecl,ively releases the drug.
For instance, when ketotifen having a high chemical activity is added to the conventional crearn S base, the active ingredient, i.e., ketotifen or its fumarate, reacts with the components of the cream base or impurities contained therein and thus causes a decrease in the content of the active ingredient or a color change with the lapse of time. ~urthermore, it is sometimes observed that the cream is degraded into an emulsion or causes liquid separation. In the case of a W/0 cream preparation which is inherently inferior to an 0/W one in stability, in particular, it is highly difficult to maintain a preparation containing ketotifen or its fumarate in a stable state.
Accor(3inFly, it is another object of the present invention to provide: (1) a stable W/0 cream preparation containing ketotifen or its fumarate; and
(2) a cream preparation excellent in the percutaneous absorption of ketotifen or its fumarate.
Disclosure of Invention:
Under these circumstances, the present i,nvent,ors have conc3ucte(3 extensi,ve Stl~(3i es and consequent]y succeeded in achieving the aforesaid objects by provi,ding a W/0 cre~m whicll contains a much ]arger ~lnlo~ t, ~ ll<)i.~t;llrc t,ll~lll t,~lc <~<~r~v<~rlt,i<)o~ /o ~r~
bases. Name]y, they have found out that the aforesaid problems can be solved at once by providing a W/0 crearn prep.lratiorl consisting of a cream base comprising a diglycerol fatty acid ester and/or a sorbitan fatty acid ester and a polyvalent metal salt -of a saturated or unsaturated fatty acid having 10 to 22 carbon atorns, which are used as emulsifiers, an inorganic or organic acid salt, an oily phase component and water together with an active ingredient, th~ls completing the present invention.
Accordingly, the skin cream preparation for external use o-f the present invention consists of a cream base compri.sing from 1 to 10% by weight of a diglycerol. fatty acid ester-and/or a sorbitan fatty acid ester having an IILB value of from 3 to 7 employed as a surfactant, from 0.01 to 1.0% by wei.ght of a polyvalent metal salt of a saturated or unsaturated fatty acid having 10 to 22 carbon atoms, from 0.1 to 5% by weight of an inorganic or organic acid salt, from 1 to 20% by weight Or an oi]y phase component, and from 70 to 90% by we:igh1 of water together with an active ingredient.
Now the presen1 invention wi]]. be described in greater detai]
Preferab]e examples of the active ingredient to be used in the skin crearn preparati.on for external use of`
the present invent:iorl i.ncl.ude reme(lies i`or ski.n _ 5 _ 20600~8 diseases, such as antiinflammatory agents, antibacteri.a] agerlts and antiallerg:ic agents.
Examples of avai]able anliinflammatory agents include nonsteroidal ones such as ketoprofen, indomethacin, flurbiprofen, re]binac, ibuprofen piconol, benzadac, butyl fulfenamate, bu~examac, piroxicam, loxoprofen, felbinac ethyl, alurni.noprofen and oxaprodine and steroidal ones sucl-l as clobetaso] 17-propionate, dexamethasone 17-valerate, difurazon di.acetate, betamethasone 17, 2]-dipropionate, diflucortolone 21-valerate, r]uocinonide, halcinonide, amcinonide and hydrocortisone 17-butyrate 21-propionate. Examp]es of the antibacterial agents include tolnaftate, exa]amide, tolciclate, siccanin, ciclopirox olamine, clotrimazole, lS bifonazole, miconazole nitrate, econazole nitrate, omoconcazole ni.trate, isoconazole nitrate, oxiconazole nitrate, ketoconazole nitrate, itraconazole, fluconazole, butenafine, hydrochloride and meticonaso]e. Examr)]es of the antial]ergic agents include ketotifen and its salts, azelastine and its salts, oxatomide, tranilast, sodium chromoglycolate, mequitazine, amlexanox, repirinast, oxatomide, ibudilast and glycyrrhetin. Among these compounds, ketotifen and i.ts fumarate are particularly important.
These active i.ngredients may be used i.n the effective content of e.lch ingredi.ent, name]y, from ~.~l to 3% by wc.igh~ t})e erc.~ )rer)al-at~iorl. Eor exarllr)]e, 2rJ60~$~
ketotifen or its fumarate may be preferably employed in an amount of frolll 0.0] to 1% by weight.
In order to produce the W/0 cream preparation of the present invention, a diglycerol fatty acid es1er and/or a sorl)itan fat;ty acid ester having an IILB
(hydrophile/lipophile balance) value of from 3 to 7 are used as a surfactant. Examples of the diglycerol fatty acid ester inc]ude diglycerol monooleate, diglycerol monostearate, diglycerol monoisostearate and diglycerol dioleate. Example of the sorbitan fatty acid ester include sorbitan sesquioleate, sorbitan monoisostearate, sorbitan monooleate and sorbitan monostearate. These surfactants may be used in an amount of from 1 to 10% by weight, preferably from 2 to 5% by weight. In addition to these surfactants, other surfactants common1y used for producing a W/0 cream may be further used.
Further, a polyvalent metal salt of a saturated or unsaturated fatty acid having lO to 22 carbon atoms is used in the present invention. Preferable examples of the polyvalent metal salt of a fatty acid include metal salts of fatty acids having 12 to 18 carbon atoms, e.g., alumin13rn stearate, a]um3num palmitate, magnesium stearate, aluminum laurate and aluminum oleate. Among these componds, al1lminllm stearate and magnesium stearate ar~ particllLar]y pre-ferable. Altho13gh the l~olyv.l]~ t ~ t~ lt lll~ Illor~o~ ol- t;l-i-lll~t<
salt, it is most pre-ferable to select a monometal salt.
These polyva]ent metal sa]ts of f`atty acids may be used in an amolJnt of from 0.0] to 10% by weight, preferably from 0.05 to ().5% by weight.
S Examples of the inorganic or organic acid salt to be used in the present invention include potassium sulfate, magnesium sulfate, sodium sulfate, aluminum fulfate, aluminum nitrate, potassium carbonate, magnesium acetate and potassium acetate. Among these compounds, ~otassium sulfate and magnesium sulfate are particular]y ~referal)le. These inorganic or organic acid salts may be used in an amount of from 0.1 to 5%
by weight, preferably from 0.3 to 2% by weight.
Examples of the oily phase component to be used in the present invention include hydrocarbons such as squa]ane, liquid paraffin and ceresin oil, fatty acid esters such as isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl sebacate, diisopropyl adipate, glycerol caprate and glycerol caprylate, liquid higher alcohols such as 2-octyldodecanol and 2-hexyldecanol, crotamiton, 1-menthol, mentlla oil, benxyl alcohol and silicone oil.
These oily phase components may be used in an amount of from 1 to 20% by weight, preferably from 5 to 15% by weight.
20~0048 The cream preparation of the present invention further contains form 70 to 90% by weight, preferably from 75 to 85% by weight, of water.
In addition to the essential components as cited above, the skin cream preparation for external use of the present invention may further contain appropriate amounts of viscosity modifiers such as carboxyvinyl polymer, hydroxypropylcellulose or polyvinyl alcohol, moistening agents (such as 1,3-buty]ene glycol, propylene glycol, glycerol or methylbuteanediol, preservatives such as methylparaben, propylparaben or isopropylmethylphenol, or powders such as silicon powder, talc or po]ystyrene powder (fine pearl), i-f required.
Now a process ror producing the W/0 cream preparation of the present invention wil] be described.
The cream preparation of the present invention may be produced in the following manner. First, a surfactant, a polyvalent metal salt of a fatty acid, an inorganic or organic aci(l sal~ and an oily phase comporlent arc melted together by heating to 80 to 80C to thereby give an oily ~hase. Next, water heated to 60 to 80C
is added to t;lle oi]y phase and the obtained mixture is emulsified by st,irring. Then the mixture is cooled to room temperature under stirring. The active ingredient, may be a(lde(l cithcr to tl~e oily l)hase or in the e~ i r ~ 0" ~t~l~, r~ ,y stirrillg.
2~60048 The production process as mentioned above is merely an examp]e and thus some part thereof may be modified.
Best ~lode for C<lrrying Out the Invention:
To further illl~strate the present invention in greater detai], the following Examples will be given.
Example l Component % by weight (1) c]otrimazole 1.0 (2) diglycery] monooleate 4.0
Disclosure of Invention:
Under these circumstances, the present i,nvent,ors have conc3ucte(3 extensi,ve Stl~(3i es and consequent]y succeeded in achieving the aforesaid objects by provi,ding a W/0 cre~m whicll contains a much ]arger ~lnlo~ t, ~ ll<)i.~t;llrc t,ll~lll t,~lc <~<~r~v<~rlt,i<)o~ /o ~r~
bases. Name]y, they have found out that the aforesaid problems can be solved at once by providing a W/0 crearn prep.lratiorl consisting of a cream base comprising a diglycerol fatty acid ester and/or a sorbitan fatty acid ester and a polyvalent metal salt -of a saturated or unsaturated fatty acid having 10 to 22 carbon atorns, which are used as emulsifiers, an inorganic or organic acid salt, an oily phase component and water together with an active ingredient, th~ls completing the present invention.
Accordingly, the skin cream preparation for external use o-f the present invention consists of a cream base compri.sing from 1 to 10% by weight of a diglycerol. fatty acid ester-and/or a sorbitan fatty acid ester having an IILB value of from 3 to 7 employed as a surfactant, from 0.01 to 1.0% by wei.ght of a polyvalent metal salt of a saturated or unsaturated fatty acid having 10 to 22 carbon atoms, from 0.1 to 5% by weight of an inorganic or organic acid salt, from 1 to 20% by weight Or an oi]y phase component, and from 70 to 90% by we:igh1 of water together with an active ingredient.
Now the presen1 invention wi]]. be described in greater detai]
Preferab]e examples of the active ingredient to be used in the skin crearn preparati.on for external use of`
the present invent:iorl i.ncl.ude reme(lies i`or ski.n _ 5 _ 20600~8 diseases, such as antiinflammatory agents, antibacteri.a] agerlts and antiallerg:ic agents.
Examples of avai]able anliinflammatory agents include nonsteroidal ones such as ketoprofen, indomethacin, flurbiprofen, re]binac, ibuprofen piconol, benzadac, butyl fulfenamate, bu~examac, piroxicam, loxoprofen, felbinac ethyl, alurni.noprofen and oxaprodine and steroidal ones sucl-l as clobetaso] 17-propionate, dexamethasone 17-valerate, difurazon di.acetate, betamethasone 17, 2]-dipropionate, diflucortolone 21-valerate, r]uocinonide, halcinonide, amcinonide and hydrocortisone 17-butyrate 21-propionate. Examp]es of the antibacterial agents include tolnaftate, exa]amide, tolciclate, siccanin, ciclopirox olamine, clotrimazole, lS bifonazole, miconazole nitrate, econazole nitrate, omoconcazole ni.trate, isoconazole nitrate, oxiconazole nitrate, ketoconazole nitrate, itraconazole, fluconazole, butenafine, hydrochloride and meticonaso]e. Examr)]es of the antial]ergic agents include ketotifen and its salts, azelastine and its salts, oxatomide, tranilast, sodium chromoglycolate, mequitazine, amlexanox, repirinast, oxatomide, ibudilast and glycyrrhetin. Among these compounds, ketotifen and i.ts fumarate are particularly important.
These active i.ngredients may be used i.n the effective content of e.lch ingredi.ent, name]y, from ~.~l to 3% by wc.igh~ t})e erc.~ )rer)al-at~iorl. Eor exarllr)]e, 2rJ60~$~
ketotifen or its fumarate may be preferably employed in an amount of frolll 0.0] to 1% by weight.
In order to produce the W/0 cream preparation of the present invention, a diglycerol fatty acid es1er and/or a sorl)itan fat;ty acid ester having an IILB
(hydrophile/lipophile balance) value of from 3 to 7 are used as a surfactant. Examples of the diglycerol fatty acid ester inc]ude diglycerol monooleate, diglycerol monostearate, diglycerol monoisostearate and diglycerol dioleate. Example of the sorbitan fatty acid ester include sorbitan sesquioleate, sorbitan monoisostearate, sorbitan monooleate and sorbitan monostearate. These surfactants may be used in an amount of from 1 to 10% by weight, preferably from 2 to 5% by weight. In addition to these surfactants, other surfactants common1y used for producing a W/0 cream may be further used.
Further, a polyvalent metal salt of a saturated or unsaturated fatty acid having lO to 22 carbon atoms is used in the present invention. Preferable examples of the polyvalent metal salt of a fatty acid include metal salts of fatty acids having 12 to 18 carbon atoms, e.g., alumin13rn stearate, a]um3num palmitate, magnesium stearate, aluminum laurate and aluminum oleate. Among these componds, al1lminllm stearate and magnesium stearate ar~ particllLar]y pre-ferable. Altho13gh the l~olyv.l]~ t ~ t~ lt lll~ Illor~o~ ol- t;l-i-lll~t<
salt, it is most pre-ferable to select a monometal salt.
These polyva]ent metal sa]ts of f`atty acids may be used in an amolJnt of from 0.0] to 10% by weight, preferably from 0.05 to ().5% by weight.
S Examples of the inorganic or organic acid salt to be used in the present invention include potassium sulfate, magnesium sulfate, sodium sulfate, aluminum fulfate, aluminum nitrate, potassium carbonate, magnesium acetate and potassium acetate. Among these compounds, ~otassium sulfate and magnesium sulfate are particular]y ~referal)le. These inorganic or organic acid salts may be used in an amount of from 0.1 to 5%
by weight, preferably from 0.3 to 2% by weight.
Examples of the oily phase component to be used in the present invention include hydrocarbons such as squa]ane, liquid paraffin and ceresin oil, fatty acid esters such as isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl sebacate, diisopropyl adipate, glycerol caprate and glycerol caprylate, liquid higher alcohols such as 2-octyldodecanol and 2-hexyldecanol, crotamiton, 1-menthol, mentlla oil, benxyl alcohol and silicone oil.
These oily phase components may be used in an amount of from 1 to 20% by weight, preferably from 5 to 15% by weight.
20~0048 The cream preparation of the present invention further contains form 70 to 90% by weight, preferably from 75 to 85% by weight, of water.
In addition to the essential components as cited above, the skin cream preparation for external use of the present invention may further contain appropriate amounts of viscosity modifiers such as carboxyvinyl polymer, hydroxypropylcellulose or polyvinyl alcohol, moistening agents (such as 1,3-buty]ene glycol, propylene glycol, glycerol or methylbuteanediol, preservatives such as methylparaben, propylparaben or isopropylmethylphenol, or powders such as silicon powder, talc or po]ystyrene powder (fine pearl), i-f required.
Now a process ror producing the W/0 cream preparation of the present invention wil] be described.
The cream preparation of the present invention may be produced in the following manner. First, a surfactant, a polyvalent metal salt of a fatty acid, an inorganic or organic aci(l sal~ and an oily phase comporlent arc melted together by heating to 80 to 80C to thereby give an oily ~hase. Next, water heated to 60 to 80C
is added to t;lle oi]y phase and the obtained mixture is emulsified by st,irring. Then the mixture is cooled to room temperature under stirring. The active ingredient, may be a(lde(l cithcr to tl~e oily l)hase or in the e~ i r ~ 0" ~t~l~, r~ ,y stirrillg.
2~60048 The production process as mentioned above is merely an examp]e and thus some part thereof may be modified.
Best ~lode for C<lrrying Out the Invention:
To further illl~strate the present invention in greater detai], the following Examples will be given.
Example l Component % by weight (1) c]otrimazole 1.0 (2) diglycery] monooleate 4.0
(3) alumiriurn tristearate 0.08
(4) ]iquid paraffin 8.0
(5) isopropyl myristate 2.0
(6) potassium sulfate 1.0
(7) methy]paraben 0.2
(8) 1,3-butylene glycol 2.0
(9) purified water the balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately, the components (~,) to (9) were dissolved by heating to 70C
to thereby g3ve an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emll]sified by stirring. Next, the
to thereby g3ve an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emll]sified by stirring. Next, the
- 10 -20 6~ 0 48 component (]) was added thereto and dispersed therein by stirring. The mixture was cooled to room temperature under further stirring. Thus a cream preparation containing an antibacterial agent was obtained.
Example 2 Component % by weight (1) clotrimazo]e 1.0 (2) dig]yceryl monoisostearate 5.0 (3) aluminum tristearate 0.08 (4) liquid paraffin 6.0 (5) isopropyl myristate 2.0 (6) magnesillm sulfate 1.0 (7) methy],paraben 0.2 (8) propylene glycol 3.0 (9) pur,i,fied water the balance in total 100.00 The components (2) to (5) were melted by heati,ng to 70C to thereby give an oily phase. Separately, the components (6) to (9) were di,ssolved by heating to 70C
to thereby give an aqueous phase. Then the aqueolls phase was ad(ie(i to the oily phase and the obtained mixtnlre was emlllsirie(l hy s1,irring. Next, the COIIIpOnellt, ( 1. ) was added thereto and disperse(l therei,n by stirring. 'I'he mixture was cooled to room temperature under further stirring. Thus a cream preparation containing an antibacterial agent was obtained.
Example 3 Component % by weight (1) hi-rona7,0]e 1.0 (2) diglyceryl monooleate 5.0 (3) aluminum tristearate 0.08 t4) squalane 8.0 (5) diisopropyl sebacate 2.0 (6) magnesium sulfate 1.0 (7) methylpolysiloxane 0.2 (8) propylene glycol 3.0 (9) purified ~ater the balance in total 100.00 The cornponents (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately, the -components (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily p}-~ase and the obtained mixture was emulsi~ied by stirring. Next, the component (1) was added thereto and dispersed therein by stirring. T}le mixture was coo]ed to room temperature under further stirring. Thus a cream preparation containing an antibacteria] agent was obtained.
Example 4 Component % by weight (1) clohetasol 17-propionate 0.05 (2) diglyceryl monooleate 5.0 (3) alumi~ m monostearate 0.08 (4) squalane 8.0 (5) isopropyl myristate 2.0 (6) magnesium sulfate 1.0 (7) methylparaben 0.2 (8) propylene glycol 3.0 (9) puri~ied water the balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (9) were dissolved by heating to 70C
to thereby give an agueous phase. Then the aqueolls phase was added to the oily phase and the obtained mixture was emulsi~ied by stirring. Next, the component (1) was added thereto and dispersed therein by stirring. 'I'l~e mixture W-lS coo]ed to room temperature under further stirring. 'I`llus a cream ]3 preparation containlng a steroida] antiinflammatory agent was obtained.
Example 5 Component % by weight (1) fulllocinonide 0.05 (2) diglyceryl monooleate 5.0 (3) a]urrlinurn monostearate 0.08 (4) sotualane 8.0 (5) ta]c 2.0 (6) magnesium sulfate 1.0 (7) methy]paraben 0.2 (8) propylene glycol 3.0 (9) purified water the balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (9) were disso]ved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oi]y phase and the ot)tained mixture was emu]siried by stirring. Next, the component (1) was added thereto and dispersed therein by stirring. The mixture was cooled to room temperature llnder fllrt;ller stirring. 'I`hlJs a crealr preparation contairllng a steroidal antiinf]ammatory agent was obtained.
Examp]e 6 Component % by weight (1) fluocinoni,(le 0.05 (2) diglyceryl monooleate 5.0 (3) alumi,nurn tristearate 0.08 (4) liquid parafin 8.0 (5) fine pearl 2.0 (6) potassium sulfate 1.0 (7) methylparaben 0.3 (8) gl,ycerol 3.0 (9) purifi,ed water the balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby gi,ve an oily phase. Separately, the components (6) to (9) were di,ssolved by heati,ng to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsified by stirring. Next, the component (1) was added thereto and dispersed therein by stirring. rl'he mixtllre was cooled to room tem~erature under fllrther stirring. Thus a crearn 206~ 048 preparation containing a steroidal antiinflammatory agent was obtained.
Example 7 Cornponent % by weight (]) clol)etasol 17-propionate 0.0'~
(2) sorbitan monoisostearate 5.0 (3) a]uminum tristearate 0.08 (4) sqllalarle 8.0 (5) diethyl ceb~cate 2.0 (6) potassium sulfate 1.0 (7) methylparaben 0.2 (8) propy]ene glycol 3.0 (9) purifie(l water the balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was adde(l to tl~e oily phase and the obtained mixture was emulsified by stirring. Next, the component (I) was added thereto and dispersed therein by stirring. 'I'he mixture was coo:Led to room telnperatllrc ul)(lc~ lrlhcr st-irrin~. 'I'l~us a creum preparation containing a steroi(~al antiinflarnmatory agent was obt;aille(3.
Example 8 Cornponent % by weight (]) l~tor)roren 0.5 (2) Aig]yceryl monooleate 5.() (3) aluminllm tristearate 0.08 (4) liquid paraffine 8.0 (5) i'ine pear] 2.0 (6) potassium sulfate 1.0 (7) methyiparaben 0.3 (8) glycero:l 3.0 (9) puri~'icd wat;er the ba]ance in total 100.00 The components (2) to (5) were me]ted by heating to 70C to thereby give an oily phase. Separate]y the components (6) to (9) were dissolved by heating to 70C
to thereby give an aqlleolls phase. Then the aqueous phase was adde(l to the oily phase and the obtained mixture was elllll I S.ii'i cd by stirring. Next the component (I) was a(lded thereto and dispersed therein by stirring. 'l'he mixture ~as cooled to room temperatllre under ~'llrther stirring. Thlls a cream 20~0048 preparation containing a nonsteroida]. antiinflammatory agent was obtained.
Example 9 Comr)onent % by weight (1) indomethacin 0.5 (2) diglycery] monooleate 5.0 (3) magneci.llm monostearate 0.1 (4) squalane 8.0 (5) met;lly]r~o]ys:i]oxane 0.~
(6) octyldodecy] myristate 2.0 (7) potassium sulfate 1.0 (8) methylparabene 0.2 (9) glycerol 3.0 (]0) purified water the balance in total 100.00 The components (2) to (6) were melted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (10) were dissolved by heating to 70C to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture W.lS emulsified by stirring. Next, the component (1) was added thereto and dispersed therein by sti.rrin~. 'I`lle rnixture was cooled ~o room t~?lllr)~?r~lt~ll l^(? Illl(i(?l' ~ 11 1' I,IIC 1' ~; t, i 1'1- i llg . I IlllS ~1 ('1'~?-1111 preparation containing a nonsteroidal antiinflammatory agent was obtained.
Examp]e 10 Component % by weight (1) :I.oxor)roren ].O
(2) diglyceryl monoisostearate 5.0 (3) magnesium monostearate 0.1 (4) liquid paraffine 8.0 (5) isopropyl myristate 0.2 (6) magnesium sulfate 1.0 (7) methylparaben 0.2 (8) glyccrol 4.0 (9) purified water the balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (9) were dissolved by heating to 70C
to thereby give an agueous phase. Then the aqueous phase was ad(led to the oily phase and the obtained mixture was emulsified by stirring, Next, the component (1) was added thereto and dispersed therein by stirring. The mixture was cooled to room temperature under further stirring. Thus a cream 206004~
preparation containing a nonsteroida] antiinflalllmatory agent was obtaille(1.
Example 11 Component % by weight (1) ketotifen fumarate 0.5 (2) diglyceryl monooleate 5.0 (3) aluminium tristearate 0.08 (4) liquid paraffine 8.0 (5) fine pear] 2.0 (6) potassium sul-~ate 1.0 (7) methyiparaben 0.3 (8) glycerol 3.0 lS (9) pllri-ried watcr the balance in total 100.00 The com~onents (2) to (4) were melted by heating to 70C to thereby give an oily phase. Separately, the component (1) and components (5) to (9) were dissolved by heating to 70C to thereby give an aqueous phase.
Then the aqueous phase was added to the oily phase and the obtained mixture was emulsified by stirring. Next, the mixture was cooled to room temperature under furtller s1irrirl~. 'I`}-nls ~ cream prepara1ion cont.lining an antial]ergic agerlt was obtained.
20~0048 Example 12 Component % by weight (1) ketoti~en 0.1 (2) diglyceryl monoi,sostearate 4.0 (3) a]uminium monostearate 0.08 (4) liguid paraf`~ine 8.0 (5) isopropy] myristate 2.0 (6) potassium sulfate 1.0 (7) methy]paraben` 0.2 (8) propylene g]ycol 2.0 (9) puri~ied water the balance in total 100.00 ~ The components (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsified by stirring. Next, the component (1) was added thereto and dispersed therein by stirring. T}~e rnixture was cooled to room temperature under ~urther stirring. Thus a cream preparation containing an antiallergic agent was obtai,ned.
20~0048 Examp]e ]3 Component % by weight (]) ketotiphen O.1 (2) sorbitan monoisostearate 5.0 (3) aluminium monostearate 0.08 (4) liquid paraffine 6.0 (5) isopropy] myristate 2.0 (6) magnesium sulrate ].0 (7) metllylparaben 0.2 (8) 1,3-butylene glycol 3.0 (9) pllrified wa~er lhe balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsified by stirring. Next, the component (1) was added thereto and dispersed therein by stirring. The mixture was coo]ed to roorn t;emperal;ure llnder ~llrther stirri.ng. 'I'hlls .1 cream preparation containing an antiallergic agent was obtaine(l.
20~0048 Examp]e 14 Component % by weight (1) ketoti~en 0.3 (2) diglyceryl monooleate 5.0 (3) aluminium monostearate 0.]2 (4) squalane 8.0 (5) isopropyl sebacate 2.0 (6) magnesium sulfate 1.0 (7) methylpolysi],oxane 0.2 (8) propylene glycol 3.0 (9) puri~ied water the balance in tota] 100.00 The com~onents (2) to (5) were melted by heating to 70C to thereby give an oi]y phase. Separate]y, the components (6) to (9) were disso]ved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsi~ied by stirring. Next, the component (1) was added thereto and dispersed therein by stirring. The mixture was coo]ed to room temperature un(3er rurther stirring. 'I'hus a cream preparation containing an antia]]er~ic agent W-lS
obtained.
20 600 ~
Example 15 Component % by weight (1) ketotifen 0.05 (2) diglycery] monoisostearate 5.0 (3) aluminium tristearate 0.08 (4) squalane 8.0 (5) i.sopropyl myrista1,e 2.0 (6) magnesium sulfate ].0 (7) methylparaben 0.2 (8) propylene g.l.yco] 3.0 (9) puri.fied water the balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby give an oi.ly phase. ~eparate]y, the component,s (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsifi.ed by sti.rring. Next, the component (1) was added thereto and dispersed therei.n by stirring. The mixture was cooled to room temperature under iurther sti.rring. Ihus a cream preparation containing an antiallergic agent was obtained.
2060~48 Exam~le 16 (omporlerlt % by weight (1) ketotiren fumarlte 0.1 (2) diglyceryl monooleate 5.0 (3) alurninium tristearate 0.08 (4) s(~ua]aTle 8.0 (5) talc 2.0 (6) magrlesium su]fate 1.0 (7) methylparaben 0.2 (8) glycerol 3.0 (9) pllrified water the balance in tota] 100.00 The corn~onenls (2) to (5) uere melted by heating to 70C to thereby give an oily phase. Separately the components (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsified by stirring. Next the component (1) was added thereto and dispersed therein by stirring. I`hc mixtlTre was cooled to room temperature un(ler rllrt}ler stirring. Ihus a cream preparation containing an antiallergic agent was obtained.
2 ~ & 0 0 48 Exarnp]e ]7 Component % l~y weight (]) ketotifen 0.2 (2) diglyceryl monoo]eate 5.0 (3) aluminium monostearate 0.08 (4) liqllid paraffin 8.0 (5) i`ine pear] 2.0 (6) potassium suli`ate 1.0 (7) me~hy]paraben 0.3 (8) g]ycero] 3.0 (9) purii`~ed water the balance in total 100.00 Tl~e coml)onents (2) to (5) were rnelted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsii'ied by stirring. Next, the component (1) was added thereto and dispersed therein l)y ~tirring. 'I'l~e Illixtllre W<lS (~oo]ed to room temperature llnder i`~lrther stirring. Thus a cream preparation containing an antiallergic agent was obtained.
- 2~ - 2U60048 Examp]e 18 Cornponent % by weight (1) ketotifen o.]
(2) dig]yceryl monoisostearate 5.0 (3) aluminium monostearate 0.08 (4) sq~lalane 8.0 (.~) isopror)yl m,Yri.state 2.0 (6) pot.lssium su]fate 1.0 (7) methylparaben 0.2 (8) propylene glycol 3.0 (9) carboxyv,iny],polymer 0.05 (10) puri~ie(l water the balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby give an oi]y phase. Separately, the components (6) to (8) and a part of the components (10) were dissolved by heating to 70C to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsified by stirring. Next, the component (9), which was swelled by the residue of the components (10), was added to the thlls obtained cr~ ]sioll and rllrt,her the coml~ollent; (~) was added thereto and dis~ersed therein by stirring.
The mixtllre was cooled to room temperature under further stirring. Thus a cream preparation containing an antia:llcrgi( agellt was obtained.
- 27 - 20600~8 Example ]9 Component % by weight (]) ketotiren fl~marate 0.188 (2) dlglyceryl rnonoisostearate 4.() (3) magnesillm monostearate 0.]
( 4 ) S(~lla] ane 8.0 (5) isopropyl myristate 1.5 (6) potassium sulfate 1.0 (7) methylparaben 0.15 (8) Iine pearl 1.0 (9) propylene glycol 3.0 (10) purified water the balance in total l00.00 The components (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately the components (6) to (~0) were dissolved by heating to 70C to thereby give an aqueous phase. Then the aqueous phase was ad(1ed to the oily phase and the obtained mixture was emulsified by stirring. Next the component (1) was added thereto and dispersed therein by stirring. The mixture was cooled to room temperature under further stirring. Thus a cream preparation containing an anliallergic agent was obtained.
20~0048 Reference Exampl,e l Compollent, % by weigl~t, (1) clotri ma7~01e 1.o (2) hexag]yceryl, polyricinol,ate 5.0 (3) alumi,nium tristearate 0.08 (4) li~ui(l paraffin 8.0 (5) fine pearl 2.0 (6) potassium sulfate 1.0 (7) methylparaben 0.3 (8) glycerol 3.0 (9) puri~ied water the balance in total 100.00 The components (2) to (5) were me]ted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to tlle oily phase and the obtained mixture was emulsi,fied by stirring. Next, the component (1) was added thereto and dispersed therein by stirring. The mixture was cooled to room temperature under rurther stirring. Thus a cream preparation containing an antibacterial agent was obtained.
2~"048 Reference rxample 2 Component % by weight (1) clotrimazole 1.0 (2) decaglyceryl pentaoleate 5.0 (3) aluminium tristearate 0.08 (4) liquid paraffin 8.0 (5) octyldodecy] myristate 2.0 (6) potassillm sulfate 1.0 (7) methylparaben 0.3 (8) glycerol 3.0 (9) purified water the ba]ance in total 100.00 The components (2) to (5) were melted by heating to 70C to 1hereby give an oi]y phase. Separately the components (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture wa~ cmulsirie(l ~y stirring. Next the component (1) was added thereto and dispersed therein by stirring. lhe mixture was cooled to room temperature un(3er furtl~er stirring. Thlls a crearn preparation containing an antibacterial agent was 2S obtained.
~e~erence ~xarnr)le 3 Component % by weight (1) ketotifen 0.1 (2) white petrolatum 40.0 (3) cetanol 10.0 (4) white beeswax 5.0 (~) sorbitan sesqllioleate 5.0 (6) lauromacrogol 0.5 (7) methy]paraben 0.1 (8) propyl parabene 0.1 (9) puri~ied water the balance in total 100.00 The components (2) to (6) were melted by heating to 70C to thereby give an oily phase. Separately, the components (7) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsi-fied by stirring. Next, after cooling the thus obtained emulsion to 40C, the component (1) was added thereto and dispersed therein by stirring.
The mixture was cooled to room temperature under rurther stirring. Thus a crearn preparation containing an 25 anti.-l].lCr~.iC .l~ellt was ol)taine(3.
- 31 ~ 20 6004 Test Example 1 [Heat stability test A]
The cream preparation of the Example 1 and the one of the Reference Example 1 were each packed in a tube and stored at 40C and 50C. Thus the heat stability of each product was evaluated. Table 1 shows the results.
20~0048 .
C ~ ._ o C' I
O A
c~ C c~ _ m C. o O o C
~ O
t~ A
C bO
~< O C ~ ~ C
O ~ ~--~ O O A
_1 C' ~ C' O
C~
C~
O ~
A ~ ~1) 0~ b4 C C C
~ O ~ I ~
a~ E~ O A O A
C" C C.) C ~
.~
ta .,t A ~
~d r~ C C C
o~ O
tn o e o . ~ o A
~ C O C
C~
C
o . . .~
C~ A ~
C ~ t~ C
C ~ ~ ~ ~
,r ~ ~L) O A
e c ~, ~ tn c o o o ~3 _ e _ e . ~ .
X ~ ~ X ~ ~ X
20~0~48 As is ar~parent from rah]e 1 the cream preparation of the Example 1 rernained l-lig}lly stable after being stored at 40C and 50C compared with those of the Reference Examp].es l and 2 containing different surfactants.
[l~eat stability test B]
The cream preparation of the Examples 12 and 13 and the one of` the Re~erence Examr)le 3 were each packed in a tul)e and store(i at 5() C. Il~ s the heat stahility of each product was eva]uated. Table 2 shows the results.
Table 2: lleat stability test for cream preparation .50C 50C
(change in appearance) (residue %) 1 week 2 weeks 1 month 15 days 30 days Cream o-f no no no Ex. 12 change change change98.8 9~.7 Cream of no no no Ex. 13 cllange change change97.7 95.9 Cream of liquid - - - -Re~. Ex.3 scparal;i.on As ia apparent from Table 2 the properties o~ the active ingredi.cnts and 1;he cream r~rePclral;ions o~ the Examples 12 and 13 remained highly stab]e a-rter being stored at .')0C comr)ared with that of the Reference Exampl.e 3 pro(lllce(l l)y lls-i.ng l;he converlt;iona] W/0 t;yr~e (~ r c ~ <1 .~
206004~
Test Exarnp]e 2 [Re]else test]
The cream preparation of the Example 1 and a commercially avai]able cream preparation containing clotrima%ole were suhjected to a release test by the following test method. Table 3 (polycarbonate film) and Table 4 (silicone film) show tlle resu]ts.
[Test method]
~ S.llll~ I C was introdllced into a glass disk (diameter: 20 mlll tllickness: 2 mm) and the surface was covered with a film followed by fixing with an 0 ring.
This disk was introduced into a mesh bag and immersed in a re]casing sollltioll. Ihen the amollrlt Or`
clotrimazole liberated from the sample under stirring was determined by liquid chromatography 20~0048 Table 3: Release tes~ (po]ycarbonate ri]l"
expresse(l i,n rel,ease ratio Time (hr) Preparation *A 0 4.638.],], ],],.3 14.63 **B 0 ].25 l.R1 2.05 2.37 *A: the crealll preparation oi` the Example ].
**B: the markete(~ crellm prepar.ltion.
[Elution conditions]
Film: polycarbonate (pore size = 10 ~m).
Temperature: 37C
Solvent: 30% methanol, 200 ml.
Amount of sample: 1 ml.
Table 4: Release test (si]icone fi,],m):
expressed in release ratio 'I'ime (llr) 5Preparation () 2 4 8 *A 0 5.63 ]0.],5 14.05 **B 0 0.87 1.03 1.63 *A: the cream preparation Or the Example 1.
**B: the marketed cream preparation.
[Elution conditions]
Ei]m: si..1i cone (po],ydimethylsi],oxane, a product of Dow Corning Co.) Temperature: 37C
Solvent: 30% methanol, 200 ml.
Amount of sample: 1 ml.
As the above Tables 3 and 4 clearly show, the cream preparati.on (A) of the present invention of the Example 1 was sl]perior in the drug-releasing propert,ies to the commerci.ally available 0/W cream preparation (B).
Test Example 3 Skin permeation test on.hairless mouse:
[Test method]
The ski.n of a hairl,ess mouse was peeled off and intro(luce(l into a Eranz-type dirfusion cell (application area: 0.785 cm2, capacity of receptor phase: 5 ml) in sucll a marlrler tllat the corneal. Iayer side served IS tlle dol~or ~ ase. 5 m]. Or a 50 m~l phosphate buffer soluti.on (pll: 7.4)/physiological sa]i.ne (P13~) corlt.~ g 1.0% o-f ethanol ~as fed into l}-~e receptor p}lase as a receptor solution. Next, the receptor solution was sampled in 0.5-ml portions at given time int;erva]s and the same amount of the receptor so]ut.i.on was supplied after eacll sampling procedure. To the receptor solution, 0.025% of sodium azide was added as a preservative.
The dose of a sample was determined in the fol]owing manner. Narnely, t}-le cell containing the lS hairless mouse skin was first weighed. After administering the sample to the donor phase, the cell was weighe(3 agai.n. T}llls the di.fference was defi.ned as the dose of the samr)le. The dose of the sample was 30 mg + 5%. Then the ketotifen contained in the receptor solution was ~ietermi.rled by IIPIC after 4 hours and 8 hours.
The ketotifen pooled in the skin was determined by the fo~lowing method. After the completion of the sarnpling in the aforesaid skin permeation test, the skin was taken out of the cell and the sample on the surface thereof was wiped away wi.th methallo].. I`llcll tllc ski.rl was put into a entrifugll.
tube coIltaining methanol and cut into sma]] pieces witll scissors. Then it was homogenized in a homogenizer and shaken in a shaker for 30 minutes to thereby extract the ketotifen from the skin into the methanol. After filtering and filling up to 50 ml, a sample for determining the ketotifen pooled in the skin was obtained. Then the ketotifen pooled in the skin was determined by IIPLC at an UV wavelength of 297 nm.
Table 5 and 6 show the results.
[IIPLC conditions]
Wavelength: 297 nm (UV).
Device: LC-6A (Shimadzu Seisakusho).
Mobile phase: MeOlT/(0.05 M) borax (0.1 M) KH2 P4 buffer solution (pll: 9.0) = 6.5/3.5.
Column temperature: 40C.
Column: Capsule Pack C-18 SG-120 (Shiseido).
The skin permeation ratio was calculated in accordance with the following equation:
drug permeated into receptor skin permeation ratio (%) = x 100 drug dose [Test result]
1. Skin permeation ratio (%) 2~)~0048 'I'abl e 5: Permeation rat;io o-I` ket,otifen into hairl.ess mouse skin 4 hours 8 hours Cream preparat:i.on of Ex. 12 6.48** 28.52**
Cream preparation of Ex. 13 3.81* 18.16*
Cream preparation of Ref. Ex. 3 1.92 7.08 *: P < 0.05.
**: P < 0.0] .
Thus it was found out that the cream preparatiorls Or t,he ~xamples 12 and 13 showed signi-~icant d.Lfrcrellces respect,ively at significant levels (P) of ]ess than 1% and less than 5%, from the cream preparation of the Reference Example 3 (according to the t-t,est).
2. Pool ratio i.n skin Table 6: Pool ratio of ketotifen in hairless mouse skin Pool ratio in skin (%) Cream preparation Or Ex. 12 24.83**
Cream ~rc~)aratiorl or Ex. ].3, 1.6.80**
Cream preparation of Ref. Ex. 32.63 **: P < 0.0]
20~0048 ~ llus it was found out that the cream preparations of the Examples 12 and 13 showed each a significant difrerence at a significant level (P) of less than 1% fl-olll t;lle cream preparation of the Reference Exarnp~e 3 (according to the t-test).
As is apparent from Tables 5 and 6 the cream preparations of tlle present invention obtained in tlle Examples 12 and 13 were significantly sllperior in the permeability into the hairless mouse skin and the pool properties of ketoti-ren in the skin to the cream preparation of the ~eference Example 1 produced by using the conventional cream base.
Industrial ~pplicability:
Tlle W/0 cream preparation of the present invention llas a l~igll lleat stability and sufrers from neither liquid separation nor any change in appearance even when stored ~or a long time. Further it contains less oily phase components and a larger amount of water and thus is less sticky and nongreasy so that it is excellent in the comfortableness in the use.
~urthermore this cream preparation has a good adhesiveness to the skin and efficiently re~eases the active ingredient which makes it preferable from the pharmacological viewpoint too.
~ or ex<~mp]e ~l cream prepar~t;ion or the present .i nVCllt; i <)n l)~lrt, i Cll~.ar L y c<)nt;aining kctotif(n IIS
4]_ a higl-l heat stabi]ity and suffers from neither liqui(l separation nor any change in the appearance or the active ingredient even after prolonged storage.
~urther, it contains less oily phase components and a larger amount of water and thus is less sticky and nongreasy, so that it is excellent in the comfortableness in the use. ~urthermore, this cream preparation is excel]ent in the adhesiveness to the skin and the percutaneous absorption of the active ingredient, which makes it preferab]e from the pharmaco]ogical vie~point too.
Accordingly, the cream preparation of the present invention containing, for example, an antiinflammatory agent, an antiallergic agent or an antibacterial agent is highly useful as a remedy for skin diseases such as dermatitis, eczema, trichophytia, candidiasis, chromophytosis and atopic eczema.
Example 2 Component % by weight (1) clotrimazo]e 1.0 (2) dig]yceryl monoisostearate 5.0 (3) aluminum tristearate 0.08 (4) liquid paraffin 6.0 (5) isopropyl myristate 2.0 (6) magnesillm sulfate 1.0 (7) methy],paraben 0.2 (8) propylene glycol 3.0 (9) pur,i,fied water the balance in total 100.00 The components (2) to (5) were melted by heati,ng to 70C to thereby give an oily phase. Separately, the components (6) to (9) were di,ssolved by heating to 70C
to thereby give an aqueous phase. Then the aqueolls phase was ad(ie(i to the oily phase and the obtained mixtnlre was emlllsirie(l hy s1,irring. Next, the COIIIpOnellt, ( 1. ) was added thereto and disperse(l therei,n by stirring. 'I'he mixture was cooled to room temperature under further stirring. Thus a cream preparation containing an antibacterial agent was obtained.
Example 3 Component % by weight (1) hi-rona7,0]e 1.0 (2) diglyceryl monooleate 5.0 (3) aluminum tristearate 0.08 t4) squalane 8.0 (5) diisopropyl sebacate 2.0 (6) magnesium sulfate 1.0 (7) methylpolysiloxane 0.2 (8) propylene glycol 3.0 (9) purified ~ater the balance in total 100.00 The cornponents (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately, the -components (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily p}-~ase and the obtained mixture was emulsi~ied by stirring. Next, the component (1) was added thereto and dispersed therein by stirring. T}le mixture was coo]ed to room temperature under further stirring. Thus a cream preparation containing an antibacteria] agent was obtained.
Example 4 Component % by weight (1) clohetasol 17-propionate 0.05 (2) diglyceryl monooleate 5.0 (3) alumi~ m monostearate 0.08 (4) squalane 8.0 (5) isopropyl myristate 2.0 (6) magnesium sulfate 1.0 (7) methylparaben 0.2 (8) propylene glycol 3.0 (9) puri~ied water the balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (9) were dissolved by heating to 70C
to thereby give an agueous phase. Then the aqueolls phase was added to the oily phase and the obtained mixture was emulsi~ied by stirring. Next, the component (1) was added thereto and dispersed therein by stirring. 'I'l~e mixture W-lS coo]ed to room temperature under further stirring. 'I`llus a cream ]3 preparation containlng a steroida] antiinflammatory agent was obtained.
Example 5 Component % by weight (1) fulllocinonide 0.05 (2) diglyceryl monooleate 5.0 (3) a]urrlinurn monostearate 0.08 (4) sotualane 8.0 (5) ta]c 2.0 (6) magnesium sulfate 1.0 (7) methy]paraben 0.2 (8) propylene glycol 3.0 (9) purified water the balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (9) were disso]ved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oi]y phase and the ot)tained mixture was emu]siried by stirring. Next, the component (1) was added thereto and dispersed therein by stirring. The mixture was cooled to room temperature llnder fllrt;ller stirring. 'I`hlJs a crealr preparation contairllng a steroidal antiinf]ammatory agent was obtained.
Examp]e 6 Component % by weight (1) fluocinoni,(le 0.05 (2) diglyceryl monooleate 5.0 (3) alumi,nurn tristearate 0.08 (4) liquid parafin 8.0 (5) fine pearl 2.0 (6) potassium sulfate 1.0 (7) methylparaben 0.3 (8) gl,ycerol 3.0 (9) purifi,ed water the balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby gi,ve an oily phase. Separately, the components (6) to (9) were di,ssolved by heati,ng to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsified by stirring. Next, the component (1) was added thereto and dispersed therein by stirring. rl'he mixtllre was cooled to room tem~erature under fllrther stirring. Thus a crearn 206~ 048 preparation containing a steroidal antiinflammatory agent was obtained.
Example 7 Cornponent % by weight (]) clol)etasol 17-propionate 0.0'~
(2) sorbitan monoisostearate 5.0 (3) a]uminum tristearate 0.08 (4) sqllalarle 8.0 (5) diethyl ceb~cate 2.0 (6) potassium sulfate 1.0 (7) methylparaben 0.2 (8) propy]ene glycol 3.0 (9) purifie(l water the balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was adde(l to tl~e oily phase and the obtained mixture was emulsified by stirring. Next, the component (I) was added thereto and dispersed therein by stirring. 'I'he mixture was coo:Led to room telnperatllrc ul)(lc~ lrlhcr st-irrin~. 'I'l~us a creum preparation containing a steroi(~al antiinflarnmatory agent was obt;aille(3.
Example 8 Cornponent % by weight (]) l~tor)roren 0.5 (2) Aig]yceryl monooleate 5.() (3) aluminllm tristearate 0.08 (4) liquid paraffine 8.0 (5) i'ine pear] 2.0 (6) potassium sulfate 1.0 (7) methyiparaben 0.3 (8) glycero:l 3.0 (9) puri~'icd wat;er the ba]ance in total 100.00 The components (2) to (5) were me]ted by heating to 70C to thereby give an oily phase. Separate]y the components (6) to (9) were dissolved by heating to 70C
to thereby give an aqlleolls phase. Then the aqueous phase was adde(l to the oily phase and the obtained mixture was elllll I S.ii'i cd by stirring. Next the component (I) was a(lded thereto and dispersed therein by stirring. 'l'he mixture ~as cooled to room temperatllre under ~'llrther stirring. Thlls a cream 20~0048 preparation containing a nonsteroida]. antiinflammatory agent was obtained.
Example 9 Comr)onent % by weight (1) indomethacin 0.5 (2) diglycery] monooleate 5.0 (3) magneci.llm monostearate 0.1 (4) squalane 8.0 (5) met;lly]r~o]ys:i]oxane 0.~
(6) octyldodecy] myristate 2.0 (7) potassium sulfate 1.0 (8) methylparabene 0.2 (9) glycerol 3.0 (]0) purified water the balance in total 100.00 The components (2) to (6) were melted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (10) were dissolved by heating to 70C to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture W.lS emulsified by stirring. Next, the component (1) was added thereto and dispersed therein by sti.rrin~. 'I`lle rnixture was cooled ~o room t~?lllr)~?r~lt~ll l^(? Illl(i(?l' ~ 11 1' I,IIC 1' ~; t, i 1'1- i llg . I IlllS ~1 ('1'~?-1111 preparation containing a nonsteroidal antiinflammatory agent was obtained.
Examp]e 10 Component % by weight (1) :I.oxor)roren ].O
(2) diglyceryl monoisostearate 5.0 (3) magnesium monostearate 0.1 (4) liquid paraffine 8.0 (5) isopropyl myristate 0.2 (6) magnesium sulfate 1.0 (7) methylparaben 0.2 (8) glyccrol 4.0 (9) purified water the balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (9) were dissolved by heating to 70C
to thereby give an agueous phase. Then the aqueous phase was ad(led to the oily phase and the obtained mixture was emulsified by stirring, Next, the component (1) was added thereto and dispersed therein by stirring. The mixture was cooled to room temperature under further stirring. Thus a cream 206004~
preparation containing a nonsteroida] antiinflalllmatory agent was obtaille(1.
Example 11 Component % by weight (1) ketotifen fumarate 0.5 (2) diglyceryl monooleate 5.0 (3) aluminium tristearate 0.08 (4) liquid paraffine 8.0 (5) fine pear] 2.0 (6) potassium sul-~ate 1.0 (7) methyiparaben 0.3 (8) glycerol 3.0 lS (9) pllri-ried watcr the balance in total 100.00 The com~onents (2) to (4) were melted by heating to 70C to thereby give an oily phase. Separately, the component (1) and components (5) to (9) were dissolved by heating to 70C to thereby give an aqueous phase.
Then the aqueous phase was added to the oily phase and the obtained mixture was emulsified by stirring. Next, the mixture was cooled to room temperature under furtller s1irrirl~. 'I`}-nls ~ cream prepara1ion cont.lining an antial]ergic agerlt was obtained.
20~0048 Example 12 Component % by weight (1) ketoti~en 0.1 (2) diglyceryl monoi,sostearate 4.0 (3) a]uminium monostearate 0.08 (4) liguid paraf`~ine 8.0 (5) isopropy] myristate 2.0 (6) potassium sulfate 1.0 (7) methy]paraben` 0.2 (8) propylene g]ycol 2.0 (9) puri~ied water the balance in total 100.00 ~ The components (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsified by stirring. Next, the component (1) was added thereto and dispersed therein by stirring. T}~e rnixture was cooled to room temperature under ~urther stirring. Thus a cream preparation containing an antiallergic agent was obtai,ned.
20~0048 Examp]e ]3 Component % by weight (]) ketotiphen O.1 (2) sorbitan monoisostearate 5.0 (3) aluminium monostearate 0.08 (4) liquid paraffine 6.0 (5) isopropy] myristate 2.0 (6) magnesium sulrate ].0 (7) metllylparaben 0.2 (8) 1,3-butylene glycol 3.0 (9) pllrified wa~er lhe balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsified by stirring. Next, the component (1) was added thereto and dispersed therein by stirring. The mixture was coo]ed to roorn t;emperal;ure llnder ~llrther stirri.ng. 'I'hlls .1 cream preparation containing an antiallergic agent was obtaine(l.
20~0048 Examp]e 14 Component % by weight (1) ketoti~en 0.3 (2) diglyceryl monooleate 5.0 (3) aluminium monostearate 0.]2 (4) squalane 8.0 (5) isopropyl sebacate 2.0 (6) magnesium sulfate 1.0 (7) methylpolysi],oxane 0.2 (8) propylene glycol 3.0 (9) puri~ied water the balance in tota] 100.00 The com~onents (2) to (5) were melted by heating to 70C to thereby give an oi]y phase. Separate]y, the components (6) to (9) were disso]ved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsi~ied by stirring. Next, the component (1) was added thereto and dispersed therein by stirring. The mixture was coo]ed to room temperature un(3er rurther stirring. 'I'hus a cream preparation containing an antia]]er~ic agent W-lS
obtained.
20 600 ~
Example 15 Component % by weight (1) ketotifen 0.05 (2) diglycery] monoisostearate 5.0 (3) aluminium tristearate 0.08 (4) squalane 8.0 (5) i.sopropyl myrista1,e 2.0 (6) magnesium sulfate ].0 (7) methylparaben 0.2 (8) propylene g.l.yco] 3.0 (9) puri.fied water the balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby give an oi.ly phase. ~eparate]y, the component,s (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsifi.ed by sti.rring. Next, the component (1) was added thereto and dispersed therei.n by stirring. The mixture was cooled to room temperature under iurther sti.rring. Ihus a cream preparation containing an antiallergic agent was obtained.
2060~48 Exam~le 16 (omporlerlt % by weight (1) ketotiren fumarlte 0.1 (2) diglyceryl monooleate 5.0 (3) alurninium tristearate 0.08 (4) s(~ua]aTle 8.0 (5) talc 2.0 (6) magrlesium su]fate 1.0 (7) methylparaben 0.2 (8) glycerol 3.0 (9) pllrified water the balance in tota] 100.00 The corn~onenls (2) to (5) uere melted by heating to 70C to thereby give an oily phase. Separately the components (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsified by stirring. Next the component (1) was added thereto and dispersed therein by stirring. I`hc mixtlTre was cooled to room temperature un(ler rllrt}ler stirring. Ihus a cream preparation containing an antiallergic agent was obtained.
2 ~ & 0 0 48 Exarnp]e ]7 Component % l~y weight (]) ketotifen 0.2 (2) diglyceryl monoo]eate 5.0 (3) aluminium monostearate 0.08 (4) liqllid paraffin 8.0 (5) i`ine pear] 2.0 (6) potassium suli`ate 1.0 (7) me~hy]paraben 0.3 (8) g]ycero] 3.0 (9) purii`~ed water the balance in total 100.00 Tl~e coml)onents (2) to (5) were rnelted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsii'ied by stirring. Next, the component (1) was added thereto and dispersed therein l)y ~tirring. 'I'l~e Illixtllre W<lS (~oo]ed to room temperature llnder i`~lrther stirring. Thus a cream preparation containing an antiallergic agent was obtained.
- 2~ - 2U60048 Examp]e 18 Cornponent % by weight (1) ketotifen o.]
(2) dig]yceryl monoisostearate 5.0 (3) aluminium monostearate 0.08 (4) sq~lalane 8.0 (.~) isopror)yl m,Yri.state 2.0 (6) pot.lssium su]fate 1.0 (7) methylparaben 0.2 (8) propylene glycol 3.0 (9) carboxyv,iny],polymer 0.05 (10) puri~ie(l water the balance in total 100.00 The components (2) to (5) were melted by heating to 70C to thereby give an oi]y phase. Separately, the components (6) to (8) and a part of the components (10) were dissolved by heating to 70C to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsified by stirring. Next, the component (9), which was swelled by the residue of the components (10), was added to the thlls obtained cr~ ]sioll and rllrt,her the coml~ollent; (~) was added thereto and dis~ersed therein by stirring.
The mixtllre was cooled to room temperature under further stirring. Thus a cream preparation containing an antia:llcrgi( agellt was obtained.
- 27 - 20600~8 Example ]9 Component % by weight (]) ketotiren fl~marate 0.188 (2) dlglyceryl rnonoisostearate 4.() (3) magnesillm monostearate 0.]
( 4 ) S(~lla] ane 8.0 (5) isopropyl myristate 1.5 (6) potassium sulfate 1.0 (7) methylparaben 0.15 (8) Iine pearl 1.0 (9) propylene glycol 3.0 (10) purified water the balance in total l00.00 The components (2) to (5) were melted by heating to 70C to thereby give an oily phase. Separately the components (6) to (~0) were dissolved by heating to 70C to thereby give an aqueous phase. Then the aqueous phase was ad(1ed to the oily phase and the obtained mixture was emulsified by stirring. Next the component (1) was added thereto and dispersed therein by stirring. The mixture was cooled to room temperature under further stirring. Thus a cream preparation containing an anliallergic agent was obtained.
20~0048 Reference Exampl,e l Compollent, % by weigl~t, (1) clotri ma7~01e 1.o (2) hexag]yceryl, polyricinol,ate 5.0 (3) alumi,nium tristearate 0.08 (4) li~ui(l paraffin 8.0 (5) fine pearl 2.0 (6) potassium sulfate 1.0 (7) methylparaben 0.3 (8) glycerol 3.0 (9) puri~ied water the balance in total 100.00 The components (2) to (5) were me]ted by heating to 70C to thereby give an oily phase. Separately, the components (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to tlle oily phase and the obtained mixture was emulsi,fied by stirring. Next, the component (1) was added thereto and dispersed therein by stirring. The mixture was cooled to room temperature under rurther stirring. Thus a cream preparation containing an antibacterial agent was obtained.
2~"048 Reference rxample 2 Component % by weight (1) clotrimazole 1.0 (2) decaglyceryl pentaoleate 5.0 (3) aluminium tristearate 0.08 (4) liquid paraffin 8.0 (5) octyldodecy] myristate 2.0 (6) potassillm sulfate 1.0 (7) methylparaben 0.3 (8) glycerol 3.0 (9) purified water the ba]ance in total 100.00 The components (2) to (5) were melted by heating to 70C to 1hereby give an oi]y phase. Separately the components (6) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture wa~ cmulsirie(l ~y stirring. Next the component (1) was added thereto and dispersed therein by stirring. lhe mixture was cooled to room temperature un(3er furtl~er stirring. Thlls a crearn preparation containing an antibacterial agent was 2S obtained.
~e~erence ~xarnr)le 3 Component % by weight (1) ketotifen 0.1 (2) white petrolatum 40.0 (3) cetanol 10.0 (4) white beeswax 5.0 (~) sorbitan sesqllioleate 5.0 (6) lauromacrogol 0.5 (7) methy]paraben 0.1 (8) propyl parabene 0.1 (9) puri~ied water the balance in total 100.00 The components (2) to (6) were melted by heating to 70C to thereby give an oily phase. Separately, the components (7) to (9) were dissolved by heating to 70C
to thereby give an aqueous phase. Then the aqueous phase was added to the oily phase and the obtained mixture was emulsi-fied by stirring. Next, after cooling the thus obtained emulsion to 40C, the component (1) was added thereto and dispersed therein by stirring.
The mixture was cooled to room temperature under rurther stirring. Thus a crearn preparation containing an 25 anti.-l].lCr~.iC .l~ellt was ol)taine(3.
- 31 ~ 20 6004 Test Example 1 [Heat stability test A]
The cream preparation of the Example 1 and the one of the Reference Example 1 were each packed in a tube and stored at 40C and 50C. Thus the heat stability of each product was evaluated. Table 1 shows the results.
20~0048 .
C ~ ._ o C' I
O A
c~ C c~ _ m C. o O o C
~ O
t~ A
C bO
~< O C ~ ~ C
O ~ ~--~ O O A
_1 C' ~ C' O
C~
C~
O ~
A ~ ~1) 0~ b4 C C C
~ O ~ I ~
a~ E~ O A O A
C" C C.) C ~
.~
ta .,t A ~
~d r~ C C C
o~ O
tn o e o . ~ o A
~ C O C
C~
C
o . . .~
C~ A ~
C ~ t~ C
C ~ ~ ~ ~
,r ~ ~L) O A
e c ~, ~ tn c o o o ~3 _ e _ e . ~ .
X ~ ~ X ~ ~ X
20~0~48 As is ar~parent from rah]e 1 the cream preparation of the Example 1 rernained l-lig}lly stable after being stored at 40C and 50C compared with those of the Reference Examp].es l and 2 containing different surfactants.
[l~eat stability test B]
The cream preparation of the Examples 12 and 13 and the one of` the Re~erence Examr)le 3 were each packed in a tul)e and store(i at 5() C. Il~ s the heat stahility of each product was eva]uated. Table 2 shows the results.
Table 2: lleat stability test for cream preparation .50C 50C
(change in appearance) (residue %) 1 week 2 weeks 1 month 15 days 30 days Cream o-f no no no Ex. 12 change change change98.8 9~.7 Cream of no no no Ex. 13 cllange change change97.7 95.9 Cream of liquid - - - -Re~. Ex.3 scparal;i.on As ia apparent from Table 2 the properties o~ the active ingredi.cnts and 1;he cream r~rePclral;ions o~ the Examples 12 and 13 remained highly stab]e a-rter being stored at .')0C comr)ared with that of the Reference Exampl.e 3 pro(lllce(l l)y lls-i.ng l;he converlt;iona] W/0 t;yr~e (~ r c ~ <1 .~
206004~
Test Exarnp]e 2 [Re]else test]
The cream preparation of the Example 1 and a commercially avai]able cream preparation containing clotrima%ole were suhjected to a release test by the following test method. Table 3 (polycarbonate film) and Table 4 (silicone film) show tlle resu]ts.
[Test method]
~ S.llll~ I C was introdllced into a glass disk (diameter: 20 mlll tllickness: 2 mm) and the surface was covered with a film followed by fixing with an 0 ring.
This disk was introduced into a mesh bag and immersed in a re]casing sollltioll. Ihen the amollrlt Or`
clotrimazole liberated from the sample under stirring was determined by liquid chromatography 20~0048 Table 3: Release tes~ (po]ycarbonate ri]l"
expresse(l i,n rel,ease ratio Time (hr) Preparation *A 0 4.638.],], ],],.3 14.63 **B 0 ].25 l.R1 2.05 2.37 *A: the crealll preparation oi` the Example ].
**B: the markete(~ crellm prepar.ltion.
[Elution conditions]
Film: polycarbonate (pore size = 10 ~m).
Temperature: 37C
Solvent: 30% methanol, 200 ml.
Amount of sample: 1 ml.
Table 4: Release test (si]icone fi,],m):
expressed in release ratio 'I'ime (llr) 5Preparation () 2 4 8 *A 0 5.63 ]0.],5 14.05 **B 0 0.87 1.03 1.63 *A: the cream preparation Or the Example 1.
**B: the marketed cream preparation.
[Elution conditions]
Ei]m: si..1i cone (po],ydimethylsi],oxane, a product of Dow Corning Co.) Temperature: 37C
Solvent: 30% methanol, 200 ml.
Amount of sample: 1 ml.
As the above Tables 3 and 4 clearly show, the cream preparati.on (A) of the present invention of the Example 1 was sl]perior in the drug-releasing propert,ies to the commerci.ally available 0/W cream preparation (B).
Test Example 3 Skin permeation test on.hairless mouse:
[Test method]
The ski.n of a hairl,ess mouse was peeled off and intro(luce(l into a Eranz-type dirfusion cell (application area: 0.785 cm2, capacity of receptor phase: 5 ml) in sucll a marlrler tllat the corneal. Iayer side served IS tlle dol~or ~ ase. 5 m]. Or a 50 m~l phosphate buffer soluti.on (pll: 7.4)/physiological sa]i.ne (P13~) corlt.~ g 1.0% o-f ethanol ~as fed into l}-~e receptor p}lase as a receptor solution. Next, the receptor solution was sampled in 0.5-ml portions at given time int;erva]s and the same amount of the receptor so]ut.i.on was supplied after eacll sampling procedure. To the receptor solution, 0.025% of sodium azide was added as a preservative.
The dose of a sample was determined in the fol]owing manner. Narnely, t}-le cell containing the lS hairless mouse skin was first weighed. After administering the sample to the donor phase, the cell was weighe(3 agai.n. T}llls the di.fference was defi.ned as the dose of the samr)le. The dose of the sample was 30 mg + 5%. Then the ketotifen contained in the receptor solution was ~ietermi.rled by IIPIC after 4 hours and 8 hours.
The ketotifen pooled in the skin was determined by the fo~lowing method. After the completion of the sarnpling in the aforesaid skin permeation test, the skin was taken out of the cell and the sample on the surface thereof was wiped away wi.th methallo].. I`llcll tllc ski.rl was put into a entrifugll.
tube coIltaining methanol and cut into sma]] pieces witll scissors. Then it was homogenized in a homogenizer and shaken in a shaker for 30 minutes to thereby extract the ketotifen from the skin into the methanol. After filtering and filling up to 50 ml, a sample for determining the ketotifen pooled in the skin was obtained. Then the ketotifen pooled in the skin was determined by IIPLC at an UV wavelength of 297 nm.
Table 5 and 6 show the results.
[IIPLC conditions]
Wavelength: 297 nm (UV).
Device: LC-6A (Shimadzu Seisakusho).
Mobile phase: MeOlT/(0.05 M) borax (0.1 M) KH2 P4 buffer solution (pll: 9.0) = 6.5/3.5.
Column temperature: 40C.
Column: Capsule Pack C-18 SG-120 (Shiseido).
The skin permeation ratio was calculated in accordance with the following equation:
drug permeated into receptor skin permeation ratio (%) = x 100 drug dose [Test result]
1. Skin permeation ratio (%) 2~)~0048 'I'abl e 5: Permeation rat;io o-I` ket,otifen into hairl.ess mouse skin 4 hours 8 hours Cream preparat:i.on of Ex. 12 6.48** 28.52**
Cream preparation of Ex. 13 3.81* 18.16*
Cream preparation of Ref. Ex. 3 1.92 7.08 *: P < 0.05.
**: P < 0.0] .
Thus it was found out that the cream preparatiorls Or t,he ~xamples 12 and 13 showed signi-~icant d.Lfrcrellces respect,ively at significant levels (P) of ]ess than 1% and less than 5%, from the cream preparation of the Reference Example 3 (according to the t-t,est).
2. Pool ratio i.n skin Table 6: Pool ratio of ketotifen in hairless mouse skin Pool ratio in skin (%) Cream preparation Or Ex. 12 24.83**
Cream ~rc~)aratiorl or Ex. ].3, 1.6.80**
Cream preparation of Ref. Ex. 32.63 **: P < 0.0]
20~0048 ~ llus it was found out that the cream preparations of the Examples 12 and 13 showed each a significant difrerence at a significant level (P) of less than 1% fl-olll t;lle cream preparation of the Reference Exarnp~e 3 (according to the t-test).
As is apparent from Tables 5 and 6 the cream preparations of tlle present invention obtained in tlle Examples 12 and 13 were significantly sllperior in the permeability into the hairless mouse skin and the pool properties of ketoti-ren in the skin to the cream preparation of the ~eference Example 1 produced by using the conventional cream base.
Industrial ~pplicability:
Tlle W/0 cream preparation of the present invention llas a l~igll lleat stability and sufrers from neither liquid separation nor any change in appearance even when stored ~or a long time. Further it contains less oily phase components and a larger amount of water and thus is less sticky and nongreasy so that it is excellent in the comfortableness in the use.
~urthermore this cream preparation has a good adhesiveness to the skin and efficiently re~eases the active ingredient which makes it preferable from the pharmacological viewpoint too.
~ or ex<~mp]e ~l cream prepar~t;ion or the present .i nVCllt; i <)n l)~lrt, i Cll~.ar L y c<)nt;aining kctotif(n IIS
4]_ a higl-l heat stabi]ity and suffers from neither liqui(l separation nor any change in the appearance or the active ingredient even after prolonged storage.
~urther, it contains less oily phase components and a larger amount of water and thus is less sticky and nongreasy, so that it is excellent in the comfortableness in the use. ~urthermore, this cream preparation is excel]ent in the adhesiveness to the skin and the percutaneous absorption of the active ingredient, which makes it preferab]e from the pharmaco]ogical vie~point too.
Accordingly, the cream preparation of the present invention containing, for example, an antiinflammatory agent, an antiallergic agent or an antibacterial agent is highly useful as a remedy for skin diseases such as dermatitis, eczema, trichophytia, candidiasis, chromophytosis and atopic eczema.
Claims (8)
1. A W/O skin cream preparation for external use consisting of (A) a cream base comprising a) from 1 to 10% by weight of at least one diglycerol fatty acid ester selected from the group consisting of diglycerol monoisostearate and diglycerol monooleate having an HLB value of from 3 to 7, b) from 0.01 to 1.0% by weight of a polyvalent metal salt of a saturated or unsaturated fatty acid having 10 to 22 carbon atoms, c) from 0.1 to 5% by weight of an inorganic or organic acid salt, d) from 1 to 20% by weight of an oily phase component, e) from 2 to 3% by weight of a moistening agent selected from the group consisting of glycerol, propylene glycol and 1,3-butylene glycol, f) from 0.15 to 0.3% by weight of methyl paraben as a preservative, and g) from 70 to 90% by weight of water; and (B) a pharmaceutically active agent selected from the group consisting of omoconazole nitrate, ketotifen and ketotifen fumarate.
2. A W/O skin cream preparation for external use consisting of (A) a cream base comprising a) from 1 to 10% by weight of at least one diglycerol fatty acid ester selected from the group consisting of diglycerol monoisostearate and diglycerol monooleate having an HLB value of from 3 to 7, b) from 0.01 to 1.0% by weight of a polyvalent metal salt of a saturated or unsaturated fatty acid having 10 to 22 carbon atoms, c) from 0.1 to 5% by weight of an inorganic or organic acid salt, d) from 1 to 20% by weight of an oily phase component, e) from 2 to 3% by weight of a moistening agent selected from the group consisting of glycerol, propylene glycol and 1,3-butylene glycol, f) from 0.15 to 0.3% by weight of methyl paraben as a preservative, g) from 70 to 90% by weight of water, and h) 0.05% by weight of a viscosity modifier selected from the group consisting of a carboxyvinyl polymer, hydroxypropyl cellulose and polyvinyl alcohol, and (B) a pharmaceutically active agent selected from the group consisting of omoconazole nitrate, ketotifen and ketotifen fumarate.
3. A W/O skin cream preparation for external use consisting of (A) a cream base comprising a) from 1 to 10% by weight of at least one diglycerol fatty acid ester selected from the group consisting of diglycerol monoisostearate and diglycerol monooleate having an HLB value of from 3 to 7, b) from 0.01 to 1.0% by weight of a polyvalent metal salt of a saturated or unsaturated fatty acid having 10 to 22 carbon atoms, c) from 0.1 to 5% by weight of an inorganic or organic acid salt, d) from l to 20% by weight of an oily phase component, e) from 2 to 3% by weight of a moistening agent selected from the group consisting of glycerol, propylene glycol and 1,3-butylene glycol, f) from 0.15 to 0.3% by weight of methyl paraben as a preservative, g) from 70 to 90% by weight of water, and h) 1% by weight of a powder selected from the group consisting of silicon powder, talc and polystyrene powder; and (B) a pharmaceutically active agent selected from the group consisting of omoconazole nitrate, ketotifen and ketotifen fumarate.
4. A W/O skin cream preparation according to claim 1, 2 or 3, wherein said pharmaceutically active agent is present in an amount of 0.01 to 3%
by weight.
by weight.
5. A W/O skin cream preparation according to claim 1, 2 or 3, wherein said polyvalent metal salt of said saturated or unsaturated fatty acid is at least one member selected from the group consisting of aluminum mono-, di- or tri-stearate and magnesium mono-, di- or tri-stearate.
6. A W/O skin cream preparation according to claim 1, 2 or 3, wherein said inorganic or organic acid salt is at least one member selected from the group consisting of potassium sulfate, magnesium sulfate, sodium sulfate, aluminum sulfate, aluminum nitrate, potassium carbonate, magnesium acetate and potassium acetate.
7. A W/O skin cream preparation according to claim 1, 2 or 3, wherein said oily phase component is at least one member selected from the group consisting of squalane, liquid paraffin, ceresin oil, isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl sebacate, diisopropyl adipate, glycerol caprate, glycerol caprylate, 2-octyldodecanol, 2-hexyldecanol, crotamiton, 1-menthol, mentha oil, benzyl alcohol and silicone oil.
8. The composition according to claim 1, 2 or 3, wherein said diglycerol monoisostearate and said diglycerol monooleate exhibit an HLB value of 5.5.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JPHEI.1-202338 | 1989-08-03 | ||
| JP20233889 | 1989-08-03 | ||
| JP3118990 | 1990-02-09 | ||
| JPHEI.2-31189 | 1990-02-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2060048A1 CA2060048A1 (en) | 1991-02-04 |
| CA2060048C true CA2060048C (en) | 1995-11-07 |
Family
ID=26369637
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002060048A Expired - Fee Related CA2060048C (en) | 1989-08-03 | 1990-07-27 | Skin cream preparation for external use |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5322685A (en) |
| EP (1) | EP0484529B1 (en) |
| JP (1) | JP2835985B2 (en) |
| KR (1) | KR950002878B1 (en) |
| AT (1) | ATE104862T1 (en) |
| AU (1) | AU629671B2 (en) |
| CA (1) | CA2060048C (en) |
| DE (1) | DE69008534T2 (en) |
| DK (1) | DK0484529T3 (en) |
| ES (1) | ES2063369T3 (en) |
| WO (1) | WO1991001716A1 (en) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994013257A1 (en) * | 1992-12-16 | 1994-06-23 | Creative Products Resource Associates, Ltd. | Occlusive/semi-occlusive lotion for treatment of a skin disease or disorder |
| DE4309390C2 (en) * | 1993-03-23 | 2003-06-18 | Goldschmidt Ag Th | Method for regulating the viscosity of emulsions |
| FR2723312A1 (en) * | 1994-08-02 | 1996-02-09 | Cird Galderma | Fungicidal shampoo for hair and body |
| ES2304783T3 (en) * | 1994-09-16 | 2008-10-16 | Hisamitsu Pharmaceutical Co., Inc. | EXTERNAL USE PATCH. |
| US20020048596A1 (en) * | 1994-12-30 | 2002-04-25 | Gregor Cevc | Preparation for the transport of an active substance across barriers |
| JPH09194372A (en) * | 1996-01-22 | 1997-07-29 | Yougo Takaoka | Medicine for external use for athlete's foot |
| JPH10120560A (en) * | 1996-08-26 | 1998-05-12 | Sankyo Co Ltd | Loxoprofen-containing preparation for external use |
| DE19645319A1 (en) * | 1996-11-04 | 1998-05-07 | Beiersdorf Ag | Foaming composition, useful as skin care medium e.g. as shaving foam |
| US6190680B1 (en) * | 1998-04-01 | 2001-02-20 | The Nisshin Oil Mills, Ltd. | Oily composition and process for producing the same |
| CA2325553A1 (en) * | 1998-04-17 | 1999-10-28 | Penederm Inc. | Topical formulations for the treatment of nail fungal diseases |
| JP2002533379A (en) * | 1998-12-23 | 2002-10-08 | イデア アクチェンゲゼルシャフト | Improved formulation for locally non-invasive use in vivo |
| DK1031346T3 (en) | 1999-01-27 | 2002-08-12 | Idea Ag | Non-invasive skin vaccination |
| SI1031347T1 (en) | 1999-01-27 | 2002-10-31 | Idea Ag | Transnasal transport/immunisation with highly adaptable carriers |
| US6261603B1 (en) | 1999-05-11 | 2001-07-17 | Mcelwain Elizena A. | Skin cream |
| MXPA02000053A (en) * | 1999-07-05 | 2003-07-21 | Idea Ag | A method for the improvement of transport across adaptable semi-permeable barriers. |
| EP1151745A1 (en) * | 2000-05-05 | 2001-11-07 | L'oreal | Water-in-oil emulsion and its use in cosmetics |
| KR100423666B1 (en) * | 2001-02-07 | 2004-03-18 | 보령제약 주식회사 | Composition of Antifungal Topical preparations |
| AU766539B2 (en) * | 2001-04-20 | 2003-10-16 | Evonik Goldschmidt Gmbh | Compositions for controlling microorganisms, comprising an effective content of enzymatically prepared esters of polyglycerol |
| JP2003212773A (en) | 2002-01-04 | 2003-07-30 | Oramon Arzneimittel Gmbh | Topical medicine composition of cetirizine and loratadine |
| US20040105881A1 (en) * | 2002-10-11 | 2004-06-03 | Gregor Cevc | Aggregates with increased deformability, comprising at least three amphipats, for improved transport through semi-permeable barriers and for the non-invasive drug application in vivo, especially through the skin |
| US7306810B1 (en) | 2002-11-25 | 2007-12-11 | Piedmont Cosmeceuticals, Inc. | Skin cream |
| JP4628649B2 (en) * | 2003-02-10 | 2011-02-09 | 理研ビタミン株式会社 | Antistatic method of biodegradable polyester resin composition and film, sheet and molded article |
| WO2006050926A2 (en) * | 2004-11-12 | 2006-05-18 | Idea Ag | Extended surface aggregates in the treatment of skin conditions |
| GB0517043D0 (en) * | 2005-08-19 | 2005-09-28 | York Pharma Plc | Improvements in pharmaceutical compositions |
| WO2007134219A2 (en) * | 2006-05-11 | 2007-11-22 | Living Proof, Inc. | In situ polymerization for skin treatment |
| WO2012006107A2 (en) | 2010-06-28 | 2012-01-12 | Stemtide, Inc. | Skin care compositions |
| US20140328952A1 (en) | 2011-12-21 | 2014-11-06 | Dana FLAVIN | Topical compositions |
| US11612560B2 (en) * | 2015-09-08 | 2023-03-28 | The University Of Toledo | Treatment of Raynaud's phenomenon by inhibition of transient receptor potential melastatin-8 (TRPM-8) |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2241016C3 (en) * | 1972-08-21 | 1980-12-04 | Henkel Kgaa, 4000 Duesseldorf | Emulsifier combination for creams of the water in oil type and their use |
| US4216201A (en) * | 1978-05-22 | 1980-08-05 | Germaine Monteil Cosmetiques Corp. | Cosmetic emulsion compositions having skin moisturizing properties |
| JPS5531037A (en) * | 1978-08-26 | 1980-03-05 | Kanebo Ltd | W/o-type creamy or milky lotion composition |
| JPS6026366B2 (en) * | 1979-09-07 | 1985-06-24 | 花王株式会社 | water-in-oil cosmetics |
| JPS6027646B2 (en) * | 1979-10-31 | 1985-06-29 | 花王株式会社 | cosmetics |
| ATE16684T1 (en) * | 1980-09-15 | 1985-12-15 | Unilever Nv | WATER-IN-OIL EMULSIONS. |
| DE3224619A1 (en) * | 1981-07-14 | 1983-05-19 | Freund Industrial Co., Ltd., Tokyo | Oral pharmaceutical composition |
| JPS61194007A (en) * | 1985-02-22 | 1986-08-28 | Shiseido Co Ltd | External preparation for skin |
| DE3534742A1 (en) * | 1985-09-28 | 1987-04-09 | Beiersdorf Ag | HYDROCORTISON'S MOST CONTAINING W / O CREAM |
| JPH0643390B2 (en) * | 1986-04-08 | 1994-06-08 | 久光製薬株式会社 | Azacycloalkane derivative |
| JPS6379825A (en) * | 1986-09-22 | 1988-04-09 | Nippon Oil & Fats Co Ltd | Fat emulsion for intravenous injection |
| US4829092A (en) * | 1987-07-27 | 1989-05-09 | Chesebrough-Pond's Inc. | Glycerol and diglycerol mixtures for skin moisturizing |
| JPH01121218A (en) * | 1987-11-04 | 1989-05-12 | Ikeda Mohandou:Kk | Cream for external use for remedy of dermatic disease |
| DE3818293C2 (en) * | 1988-05-30 | 1997-05-07 | Solvay Werke Gmbh | Process for the preparation of nonionic surfactants, their use and preparations using the same |
-
1990
- 1990-07-27 CA CA002060048A patent/CA2060048C/en not_active Expired - Fee Related
- 1990-07-27 AT AT9090910892T patent/ATE104862T1/en not_active IP Right Cessation
- 1990-07-27 DE DE69008534T patent/DE69008534T2/en not_active Expired - Fee Related
- 1990-07-27 US US07/820,638 patent/US5322685A/en not_active Expired - Lifetime
- 1990-07-27 KR KR1019920700239A patent/KR950002878B1/en not_active IP Right Cessation
- 1990-07-27 DK DK90910892.0T patent/DK0484529T3/en active
- 1990-07-27 EP EP90910892A patent/EP0484529B1/en not_active Expired - Lifetime
- 1990-07-27 WO PCT/JP1990/000965 patent/WO1991001716A1/en active IP Right Grant
- 1990-07-27 AU AU60547/90A patent/AU629671B2/en not_active Ceased
- 1990-07-27 JP JP2510433A patent/JP2835985B2/en not_active Expired - Fee Related
- 1990-07-27 ES ES90910892T patent/ES2063369T3/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| ES2063369T3 (en) | 1995-01-01 |
| CA2060048A1 (en) | 1991-02-04 |
| EP0484529B1 (en) | 1994-04-27 |
| AU629671B2 (en) | 1992-10-08 |
| JP2835985B2 (en) | 1998-12-14 |
| EP0484529A4 (en) | 1992-07-22 |
| DE69008534D1 (en) | 1994-06-01 |
| DE69008534T2 (en) | 1994-08-18 |
| AU6054790A (en) | 1991-03-11 |
| KR950002878B1 (en) | 1995-03-28 |
| KR920703009A (en) | 1992-12-17 |
| ATE104862T1 (en) | 1994-05-15 |
| US5322685A (en) | 1994-06-21 |
| DK0484529T3 (en) | 1994-05-30 |
| WO1991001716A1 (en) | 1991-02-21 |
| EP0484529A1 (en) | 1992-05-13 |
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| EEER | Examination request | ||
| MKLA | Lapsed |