CA2188566A1 - Topical polymeric drug delivery system - Google Patents
Topical polymeric drug delivery systemInfo
- Publication number
- CA2188566A1 CA2188566A1 CA 2188566 CA2188566A CA2188566A1 CA 2188566 A1 CA2188566 A1 CA 2188566A1 CA 2188566 CA2188566 CA 2188566 CA 2188566 A CA2188566 A CA 2188566A CA 2188566 A1 CA2188566 A1 CA 2188566A1
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- drug
- topical
- beta
- cyclodextrin
- progesterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Dispersion Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A topical polymeric drug delivery system for the delivery of drugs to the skin for either topical or systemic effect is described. The system involves the use of a propellant-free airless pump for the delivery.
Description
TITLF, OF THF, INVENTION
TOPICAL POLYMERIC DRUG DELIVERY SYSTEM
This ar~ tirn is a c~ ;...,-in-part of crr~n~1in~
application Serial No. 08/238,409 filed May 5, 1994.
BACKGROUND OF THE INVENTION
The present invention is directed to a topical polymeric delivery system for the ?~I...;";~I"";I~n of certain drugs over an extended period of time via a non-propellant aerosol pump device.
Sustained release devices for controlled topical delivery of drugs is a highly useful method of supplying m~ tinn when it is beneficial to ~.1",;";~1~. m~.tlic~tic~n cnntiml~ ly. The idea of aerosol delivery of a thin film for direct spraying on a woumd has been 5 described in an article by Fujita et aL, "Ph~rm9~-eutir~1 Research" 9, (1992). However, the method described involves a CFC c~.lll;~;ll;
aerosol propellant.
Some of the advantages of this system over known tr~ncd~rm~l delivery systems include:
1 ) Ease of application;
2) Ease of removal since the film is water soluble;
TOPICAL POLYMERIC DRUG DELIVERY SYSTEM
This ar~ tirn is a c~ ;...,-in-part of crr~n~1in~
application Serial No. 08/238,409 filed May 5, 1994.
BACKGROUND OF THE INVENTION
The present invention is directed to a topical polymeric delivery system for the ?~I...;";~I"";I~n of certain drugs over an extended period of time via a non-propellant aerosol pump device.
Sustained release devices for controlled topical delivery of drugs is a highly useful method of supplying m~ tinn when it is beneficial to ~.1",;";~1~. m~.tlic~tic~n cnntiml~ ly. The idea of aerosol delivery of a thin film for direct spraying on a woumd has been 5 described in an article by Fujita et aL, "Ph~rm9~-eutir~1 Research" 9, (1992). However, the method described involves a CFC c~.lll;~;ll;
aerosol propellant.
Some of the advantages of this system over known tr~ncd~rm~l delivery systems include:
1 ) Ease of application;
2) Ease of removal since the film is water soluble;
3) Freedom from adhesives;
4) Freedom from the use of a rate controlling Illc;l.ll,l~llle;
S) High patient s~rc-pf?~-ility as the film is practically invisible;
and 6) The use of a propellant-free aerosol which is ~ IVil...l,l....l~lly friendly.
SUMMARY OF THE INVENTION
According to the present invention it has been discovered that certain drugs can be delivered via a propellant-free aerosol as a ~ulllluc~ lll of a polymeric system for prolonged adlllilli~ ion compared to conventional formlll~ n~ In particular, the compound inrlom.oth~lin and certain cyclou~y~llase II inhibitors such as 3-[3,4-WO9~/30409 ~i 8856~ PCT/CA95/00260 diri UUIUIU~ ly]]-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone can be topically applied usmg the delivery system of the invention resulting in prolonged ~,l.";";~",~ir)n compared to conventional dosage forms.
FUILII~1I1IUI~ the system is capable of providing systemic delivery of 5 the ",r.l;. ~~1~ without causing the gastric irritation a~CoCiAf. d ~vith indc,lll~,Llld~,ul, in particular, and NSAIDs, in general.
DESCRIPTION OF T}~F INVENTIQN
There has been discovered a novel polymeric drug delivery system for prolonged topical delivery of a mf riir~mf nt via a propellant-free aerosol pump. The system is adaptable to arly drug which is soluble and stable in hydroalcoholic solutions and comprises a film forming po]ymer, a pl~ctir.i7in~ agent, a crystAlli7Atil~n hlllibilul/~ilizer, a ~nf tr~tjon enhancer, an alcoholic or hydro~lcnhnlir solution and a suitable drug .
Suitable drugs for use in therdpy with the device of the invention include without limit~ti~n 1. Protein drugs such as insulin;
2. Anti-infectives, such as antibiotics, including penicillin, t~,.la~ycliule, chlorotetracycline bacitracin, nystatin, ~LIUI ~OIIIY~;UI~ neomycin, polymyxin, gramicidin, oxytetracycline, chlul- "l)i.- ,;rol, and ~ LIll~llly-;iul;
sulfnn~mi~ifg, including slllfArft~midP, glllrAlll~ ;ll;~n Sulr~ull~,lll~iulC~ glllf?~fi~7inf, Svlr~ .f~ and s~lfi~oS- 1~, cefoxitin; anti-virals includir~g irfnsllri~iin and other arlti-infectives including ~ lurul~C~ and sodium propionate;
3. Steroidal anti-;~ri- ~ ly agents such as hydrocortisone, cortisone, l~ydluculLi~ullc acetdte, dex~llcLlldsûl~, dex~ll.,Lll~sull~, 21-~ , fluocinolone, triamcinolone, medrysone, prednisolone, prednisolone 21-phosphate and prednisolone acetate;
4. Estrogens such as estrone, 17 ~-estrddiol, ethinyl estradiol and diethyl stilbesterol;
21 ~8~66 5. P.u~ AI agents such as pro~,~,at~,lvllc, megestrûl, mf lf n~f. strûl, chlnrmq~linonf, clllialelulle, nul~illy.lodl~
19-nor-~,1u~,_at-,lulle, norethindrone, medroAy~lu~,.,si~lu-le and 17 ,~-hydroxy-pro~ a~-,lulle;
5 6. Humoral agents such as the prosta~lqn~in~) for example, PGE1, PGE2 and PFG2;
7. Allli~,.y.~,lics anolgf~irS such as aspirin, sodium salicylate, salicylamide and ~lifllmi~al;
8. Al.~ ,.. ,n-lins such as atropine, .. ~ inf, papaverine and ~ c.,~,olamine bromide;
9. A..l;l.i~ ...i..f-~, such as lil h~,lllly~ f, dllll~llllydlil~t~, II;~-~f-1~,""A"~;"f.~ F...~ f' and chlolu~ ;llf;
10. Non steroidal anti-i.,llA~ u,y agents such as i".~ llal ... and sulindac; and 1 1. Cyclooxygenase Il inhibitors such as those disclosed in U.S.
Patent No. 5,409,944 issued April 25, 1995 and those disclosed in copending applications 08/147,804 filed November 4, 1993; 08/179,467 filed January 10, 1994;
08/330,172 filed October 27, 1994; 08/361,268 filed December 21, 1994 and 08/371,179 filed January 11, 1995.
Other drugs having the same or different physiological activity as those recited above can be employed in drug-delivery devices within the scope of the present invention.
This system is particularly useful with drugs such as 2s in~nmftllarin which can cause severe upper gAs~ l irritation and nausea when ,a"llllilli~lrlud by conventional means.
The system involves the use of film forming polymers which are soluble and rapidly form a thin film upon application via a Ilydlu-,~bùll propellant-free system. The film fonned allows vapor 30 penetration and can be considered l,lti_lllal~lc. The choice of a chloro-fluoro-carbon (CFC) free preparation was essential due to the potentially cllvi ulllll~ lly damagimg ~ t~,lialh,s of CFC
propellants. With the use of a llydlu~,~bull propellant-free system, it was also essential that the solvent employed be volatile enough to allow 2 1 ~ g 5 6 6 ` ` :
rapid film formation on A.l,..;..;~, Al;on Alcohols or hydroalcoholic solutiorls using lower alkanol solvents such as ethanol and isv,u~v~ol have been found useful with ethanol being the preferred solvent. Other potential solvent systems may include ethyl acetate.
The film forlning polymer selected was ~ ~ " ,;. ,~ in view of the solvent employed. It is necessary that the polymer be soluble in the solvent chosen. Polymers which have been foumd to be useful in the invention include J~ yla~s, celluloses, siloxanes amd copoly2ners of methac~ylates, celluloses and silox~mes. PrefeIred polymers are meth-0 acrylates with poly(2-hydroxy ethyl ~~ iLa.,~ylaL~) (PHEMA) the most prefeIred choice. PED~A was the most preferred because of the quality of the film formed in the system.
Plasticizing agerlts are also necessary for the delivery system.
The rlAchr.i7~rc are used to impart the desired IIIF. IIAII;I .A1 proper~ies to the fi]m such as fiexibility. Suitable r1A~ agents include Tween 20 (TradeMarkforpolyoxyethylene(20)sorbitan~.. r.1A ~AIr)andTween (Trade Mark) products of higher molecular weight, low molecular weight po~yethylene glycola, glycerine or Labrasol (Trade Mark for PEG-8-capryiic-capritriglyceride). Preferred rlAch~i7~rc are the Tween (Trade 2 o Mark) products with Tween 20 the most prefelred. The rlA chr;7in~ agent is generally present in an amount from about 10%-50% as a IJ~ of the total solid contents of the film An additional ~ for the delively system is a cr~st^Alli7Ah~-n ir~hibitor/stabilizer andlor a penetration erlhancer. These are2 5 used to modulate drug delivery. Suitable c~lmr~ ' include, 1 ~
~y~ 1.~1. . 11 .1.~ such as ~dlu~.yl~uyyl beta-cyclodextrm (HPBCD), Ly~Lu~.,lLyl beta-~iy~,lod~"~L...~ diethyl beta-~y-,lod.,~L~ and hy~Lu~,Lilyl and Ly~Lu~y~lu~yl ga~ma cyclodextrin and transcutol, urea and ;s..t 1~ ~ ~ The choice of cyclodextrm iâ governed by the si_e of the drug 3 o . molecule used in the particular ff~rmlll~hr~n Hydroxypropyl beta-cyclodextnn (HPBCD) was the preferred cry~-c~lli7Ahon m~ubitor.
The following example illustrates the invention but is not construed to be limiting.
AMENDE~ SHEE`T
`21 ~856~
E~AMPLE 1 Fihn Formation PHEMA was dissolved in a Tween (Trade Mark)/ethanol solution w_ich hadbeen warmed to 50C. TnrTr)m.-fhArin free acid was 5 added to the solution and when fully dissolved the resultant solution was poured imto a glass petri dish. The petri dish was covered with an inverted funnel and the solution was left to evaporate to dryness at room C~ . The films were placed in a vacuum oven for 16 hours at 37C
to ensure that the moisture level in all fihns was cnmr~r-hl~ Moisture 0 levels were d~ .. ;"~.d to be less than 3/O, in all fihns, by theremogravi-metric analysis As a p~ of the total solid contents of the fihn, ;".1,).,.. ~ was present in quantities ranging from 9 to 14%, and Tween 20 (Trade Mark) from 14 to 45%. In films containing HPBCD, ~uanthies were used which gave molar ratios of 1:1, 1:2 and 1 3, inrlrlm~t~A-5 cin:HPBCD.
EXAMPL~ II .
In Yitr~ Dissolution Testin~ of Fihns ~ th T...TI~..,, :1. . .;..
Films were cut to the ~ U~Iial~ size to fit an Enhancer (Trade 2 o Mark) cell (Varlkel Industries, USA) and were weighted before testing. The film was covered with a Durapore (Trade Mark) .. I~ filter (Millipore, USA) to provide additional -.f.~ I support. Dissolution testing, using the USP paddle method (100 r.p.m ), waS carried out irl phosphate buffer (pH 7.2) at 37C. Sarnples were taken over an eighthour 2 5 period and inrTr m~.th~rin c~" ,~...., l, A; ~r~n was qTl~n1;tAtPd by HPLC.
HPLC Conditions A Beclc~nan Ultrasphere 511 C-18 (Trade Mark) (4.6 x 250 mm) colurnn was used at 40C with a mobile phase of 35% aqueous (3% acetic 3 o acid in distilled water) and 65% organic (15% aAetr ni~ and 85%
methanol) phases. F1QW rate was 1 ml/min When arl~lyzing T.,~ .;"
AMENDED SHET
2 1 ~ 8 5 6~ . . ` `
samples and standards, 4-androsten-17,~-ol-3-one (t~,DLUb~lUllC) was used as _n int~m_l standard. Detechon was by W Dy~.LI..D~,u~y measuring at 260 nm. An inflf~rnf th~^in standard curve was cl .,.~I. . . t~ ~ by prepa7ing st~7ndards in met7aanol which ramged from 0.5 to 10 ~/ml each with 10 5 ~g/ml ot ~eD~uDt~ u l . c. The limit of detection for inflf mf th -f in ~
by 1 IPL'~ with W detection at 260 nm was d~ .. rd as 0.05 ~lg/ml.
D~ , was linear over the range O. l to 100 ~/rnl. The ~ irul ~ y of detection was ~ . ".;,.. 3 by injecting the same st~mdard ten times and ~,7~tf.nnjnin~ the relative standard deviation for the peak areaD obtained. The relative standard deviation was less than two.
EXAMPLE m Fil7n Fomlation PH~MA was dissolved in a Tween (Trade Mark)/HPBCD/-eth~nol solution which had been warmed to 50C. 3-[3,4-Difluorophenyl]-4-E4-(methylsulforlyl)phenyl]-2(5H)-furanone was added to the solution and stir~ed umtil fully dissolved. The resulting solution was filled into a Valois (Trade Mark) airless pump and made up to volume with ethanol.
The pump was sealed with a metered valve (200ml, VP36, 20m7n CS gasket 2 o 3/~æ, spring 1674). As a ~ L.~ of the total solid content of the f~m 3-r3,4-difluoro-phenyl}-4-[4-~ LhylDulru,.yl)phenyl]-2(5H)-furanone was present in quantities ranging from 1.15% to 4.45/0, HPBCD at 10% amd Tween 20 (Trade Mark) from 14 to 4~%.
2~ Rat Paw Edenna Assav-Protocol Five Fuzzy rats (250-300g) (Harlan Sprague Dawley, In~ f lic ~. USA) were used. The dorsal mid-lumbar area was spayed topica7.1y with the r.. ~ .T~ .. covering an area of about 4 x 4 cm.
This 5l.1.. ~l.rl.. was given once a day for tbree days. On the 3 o th7rd day, one hour at^ter the topica7. ~.l, .., ., . ~l ". l ;f n a line was d7 awn using a p~.. . ,~L marker at the level above the a7~1e 7n one hind paw .
AMENDED SHEEr to define the area of the paw to be monitored. The paw volume was measured using a pL,ll~ llu~ ,t~,l (Ugo-Basile, Italy) based on ~e principle of water ~ "~ , l The animals were then injected Z~"~ ly with 50 ~11 of a 1% call~g~ll~l solution in saline (FMC
5 Corp., Maine) into the paw using an insulin syringe with a 25-gauge needle (i.e., S00 llg C~ lldll per paw). Three hours later, the paw volume was measured and the increases in the paw volume were r~ ,d A five hour plasma sample was also taken to correlate the plasma levels with % paw edema inhi1~i*nn The animals were ;,f d by C02 d~ iàli-J.I. Paw edema data were compared with the vehicle control group and percent inhibition r~ taking the values in the control group as 100%. The topical fnrrmlls'fi~n was given at different doses to the animals and was also compared to an orally ,d dose of j"~ ;., and a ~ ... f l~ lly available topical gel fnrrnllls~if~)n of illf~l.lllr~ ;ll Re~ ive results are shown in Table 1.
21 8856~
F~rm~ tio3ls Dose (m~ ) % Inhibition Plasma Conc (3hr) (U~lml~
(5hr) 5 Tnt-lm~th~in spray 1 31 + l 3.6 i 1,2 3 54:~2 7,6~2.1 ', 10 70 i: 2 8.5 i l.2 0 Amuno~) Gel 5 41 i 2 4,5 i 1.5 Oral Tntl~m~th~.in (0,5 % Methocel - Trade Mark) 3 55 i 3 7,2 i 3.1 3-[3,4-Diiluoro-phenyl]4-[4-(methyl-sulfonyl)phenyl 1]-2-(5H)-f~ranone spray 7 56 i 5 1.2 ~ 0 2
S) High patient s~rc-pf?~-ility as the film is practically invisible;
and 6) The use of a propellant-free aerosol which is ~ IVil...l,l....l~lly friendly.
SUMMARY OF THE INVENTION
According to the present invention it has been discovered that certain drugs can be delivered via a propellant-free aerosol as a ~ulllluc~ lll of a polymeric system for prolonged adlllilli~ ion compared to conventional formlll~ n~ In particular, the compound inrlom.oth~lin and certain cyclou~y~llase II inhibitors such as 3-[3,4-WO9~/30409 ~i 8856~ PCT/CA95/00260 diri UUIUIU~ ly]]-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone can be topically applied usmg the delivery system of the invention resulting in prolonged ~,l.";";~",~ir)n compared to conventional dosage forms.
FUILII~1I1IUI~ the system is capable of providing systemic delivery of 5 the ",r.l;. ~~1~ without causing the gastric irritation a~CoCiAf. d ~vith indc,lll~,Llld~,ul, in particular, and NSAIDs, in general.
DESCRIPTION OF T}~F INVENTIQN
There has been discovered a novel polymeric drug delivery system for prolonged topical delivery of a mf riir~mf nt via a propellant-free aerosol pump. The system is adaptable to arly drug which is soluble and stable in hydroalcoholic solutions and comprises a film forming po]ymer, a pl~ctir.i7in~ agent, a crystAlli7Atil~n hlllibilul/~ilizer, a ~nf tr~tjon enhancer, an alcoholic or hydro~lcnhnlir solution and a suitable drug .
Suitable drugs for use in therdpy with the device of the invention include without limit~ti~n 1. Protein drugs such as insulin;
2. Anti-infectives, such as antibiotics, including penicillin, t~,.la~ycliule, chlorotetracycline bacitracin, nystatin, ~LIUI ~OIIIY~;UI~ neomycin, polymyxin, gramicidin, oxytetracycline, chlul- "l)i.- ,;rol, and ~ LIll~llly-;iul;
sulfnn~mi~ifg, including slllfArft~midP, glllrAlll~ ;ll;~n Sulr~ull~,lll~iulC~ glllf?~fi~7inf, Svlr~ .f~ and s~lfi~oS- 1~, cefoxitin; anti-virals includir~g irfnsllri~iin and other arlti-infectives including ~ lurul~C~ and sodium propionate;
3. Steroidal anti-;~ri- ~ ly agents such as hydrocortisone, cortisone, l~ydluculLi~ullc acetdte, dex~llcLlldsûl~, dex~ll.,Lll~sull~, 21-~ , fluocinolone, triamcinolone, medrysone, prednisolone, prednisolone 21-phosphate and prednisolone acetate;
4. Estrogens such as estrone, 17 ~-estrddiol, ethinyl estradiol and diethyl stilbesterol;
21 ~8~66 5. P.u~ AI agents such as pro~,~,at~,lvllc, megestrûl, mf lf n~f. strûl, chlnrmq~linonf, clllialelulle, nul~illy.lodl~
19-nor-~,1u~,_at-,lulle, norethindrone, medroAy~lu~,.,si~lu-le and 17 ,~-hydroxy-pro~ a~-,lulle;
5 6. Humoral agents such as the prosta~lqn~in~) for example, PGE1, PGE2 and PFG2;
7. Allli~,.y.~,lics anolgf~irS such as aspirin, sodium salicylate, salicylamide and ~lifllmi~al;
8. Al.~ ,.. ,n-lins such as atropine, .. ~ inf, papaverine and ~ c.,~,olamine bromide;
9. A..l;l.i~ ...i..f-~, such as lil h~,lllly~ f, dllll~llllydlil~t~, II;~-~f-1~,""A"~;"f.~ F...~ f' and chlolu~ ;llf;
10. Non steroidal anti-i.,llA~ u,y agents such as i".~ llal ... and sulindac; and 1 1. Cyclooxygenase Il inhibitors such as those disclosed in U.S.
Patent No. 5,409,944 issued April 25, 1995 and those disclosed in copending applications 08/147,804 filed November 4, 1993; 08/179,467 filed January 10, 1994;
08/330,172 filed October 27, 1994; 08/361,268 filed December 21, 1994 and 08/371,179 filed January 11, 1995.
Other drugs having the same or different physiological activity as those recited above can be employed in drug-delivery devices within the scope of the present invention.
This system is particularly useful with drugs such as 2s in~nmftllarin which can cause severe upper gAs~ l irritation and nausea when ,a"llllilli~lrlud by conventional means.
The system involves the use of film forming polymers which are soluble and rapidly form a thin film upon application via a Ilydlu-,~bùll propellant-free system. The film fonned allows vapor 30 penetration and can be considered l,lti_lllal~lc. The choice of a chloro-fluoro-carbon (CFC) free preparation was essential due to the potentially cllvi ulllll~ lly damagimg ~ t~,lialh,s of CFC
propellants. With the use of a llydlu~,~bull propellant-free system, it was also essential that the solvent employed be volatile enough to allow 2 1 ~ g 5 6 6 ` ` :
rapid film formation on A.l,..;..;~, Al;on Alcohols or hydroalcoholic solutiorls using lower alkanol solvents such as ethanol and isv,u~v~ol have been found useful with ethanol being the preferred solvent. Other potential solvent systems may include ethyl acetate.
The film forlning polymer selected was ~ ~ " ,;. ,~ in view of the solvent employed. It is necessary that the polymer be soluble in the solvent chosen. Polymers which have been foumd to be useful in the invention include J~ yla~s, celluloses, siloxanes amd copoly2ners of methac~ylates, celluloses and silox~mes. PrefeIred polymers are meth-0 acrylates with poly(2-hydroxy ethyl ~~ iLa.,~ylaL~) (PHEMA) the most prefeIred choice. PED~A was the most preferred because of the quality of the film formed in the system.
Plasticizing agerlts are also necessary for the delivery system.
The rlAchr.i7~rc are used to impart the desired IIIF. IIAII;I .A1 proper~ies to the fi]m such as fiexibility. Suitable r1A~ agents include Tween 20 (TradeMarkforpolyoxyethylene(20)sorbitan~.. r.1A ~AIr)andTween (Trade Mark) products of higher molecular weight, low molecular weight po~yethylene glycola, glycerine or Labrasol (Trade Mark for PEG-8-capryiic-capritriglyceride). Preferred rlAch~i7~rc are the Tween (Trade 2 o Mark) products with Tween 20 the most prefelred. The rlA chr;7in~ agent is generally present in an amount from about 10%-50% as a IJ~ of the total solid contents of the film An additional ~ for the delively system is a cr~st^Alli7Ah~-n ir~hibitor/stabilizer andlor a penetration erlhancer. These are2 5 used to modulate drug delivery. Suitable c~lmr~ ' include, 1 ~
~y~ 1.~1. . 11 .1.~ such as ~dlu~.yl~uyyl beta-cyclodextrm (HPBCD), Ly~Lu~.,lLyl beta-~iy~,lod~"~L...~ diethyl beta-~y-,lod.,~L~ and hy~Lu~,Lilyl and Ly~Lu~y~lu~yl ga~ma cyclodextrin and transcutol, urea and ;s..t 1~ ~ ~ The choice of cyclodextrm iâ governed by the si_e of the drug 3 o . molecule used in the particular ff~rmlll~hr~n Hydroxypropyl beta-cyclodextnn (HPBCD) was the preferred cry~-c~lli7Ahon m~ubitor.
The following example illustrates the invention but is not construed to be limiting.
AMENDE~ SHEE`T
`21 ~856~
E~AMPLE 1 Fihn Formation PHEMA was dissolved in a Tween (Trade Mark)/ethanol solution w_ich hadbeen warmed to 50C. TnrTr)m.-fhArin free acid was 5 added to the solution and when fully dissolved the resultant solution was poured imto a glass petri dish. The petri dish was covered with an inverted funnel and the solution was left to evaporate to dryness at room C~ . The films were placed in a vacuum oven for 16 hours at 37C
to ensure that the moisture level in all fihns was cnmr~r-hl~ Moisture 0 levels were d~ .. ;"~.d to be less than 3/O, in all fihns, by theremogravi-metric analysis As a p~ of the total solid contents of the fihn, ;".1,).,.. ~ was present in quantities ranging from 9 to 14%, and Tween 20 (Trade Mark) from 14 to 45%. In films containing HPBCD, ~uanthies were used which gave molar ratios of 1:1, 1:2 and 1 3, inrlrlm~t~A-5 cin:HPBCD.
EXAMPL~ II .
In Yitr~ Dissolution Testin~ of Fihns ~ th T...TI~..,, :1. . .;..
Films were cut to the ~ U~Iial~ size to fit an Enhancer (Trade 2 o Mark) cell (Varlkel Industries, USA) and were weighted before testing. The film was covered with a Durapore (Trade Mark) .. I~ filter (Millipore, USA) to provide additional -.f.~ I support. Dissolution testing, using the USP paddle method (100 r.p.m ), waS carried out irl phosphate buffer (pH 7.2) at 37C. Sarnples were taken over an eighthour 2 5 period and inrTr m~.th~rin c~" ,~...., l, A; ~r~n was qTl~n1;tAtPd by HPLC.
HPLC Conditions A Beclc~nan Ultrasphere 511 C-18 (Trade Mark) (4.6 x 250 mm) colurnn was used at 40C with a mobile phase of 35% aqueous (3% acetic 3 o acid in distilled water) and 65% organic (15% aAetr ni~ and 85%
methanol) phases. F1QW rate was 1 ml/min When arl~lyzing T.,~ .;"
AMENDED SHET
2 1 ~ 8 5 6~ . . ` `
samples and standards, 4-androsten-17,~-ol-3-one (t~,DLUb~lUllC) was used as _n int~m_l standard. Detechon was by W Dy~.LI..D~,u~y measuring at 260 nm. An inflf~rnf th~^in standard curve was cl .,.~I. . . t~ ~ by prepa7ing st~7ndards in met7aanol which ramged from 0.5 to 10 ~/ml each with 10 5 ~g/ml ot ~eD~uDt~ u l . c. The limit of detection for inflf mf th -f in ~
by 1 IPL'~ with W detection at 260 nm was d~ .. rd as 0.05 ~lg/ml.
D~ , was linear over the range O. l to 100 ~/rnl. The ~ irul ~ y of detection was ~ . ".;,.. 3 by injecting the same st~mdard ten times and ~,7~tf.nnjnin~ the relative standard deviation for the peak areaD obtained. The relative standard deviation was less than two.
EXAMPLE m Fil7n Fomlation PH~MA was dissolved in a Tween (Trade Mark)/HPBCD/-eth~nol solution which had been warmed to 50C. 3-[3,4-Difluorophenyl]-4-E4-(methylsulforlyl)phenyl]-2(5H)-furanone was added to the solution and stir~ed umtil fully dissolved. The resulting solution was filled into a Valois (Trade Mark) airless pump and made up to volume with ethanol.
The pump was sealed with a metered valve (200ml, VP36, 20m7n CS gasket 2 o 3/~æ, spring 1674). As a ~ L.~ of the total solid content of the f~m 3-r3,4-difluoro-phenyl}-4-[4-~ LhylDulru,.yl)phenyl]-2(5H)-furanone was present in quantities ranging from 1.15% to 4.45/0, HPBCD at 10% amd Tween 20 (Trade Mark) from 14 to 4~%.
2~ Rat Paw Edenna Assav-Protocol Five Fuzzy rats (250-300g) (Harlan Sprague Dawley, In~ f lic ~. USA) were used. The dorsal mid-lumbar area was spayed topica7.1y with the r.. ~ .T~ .. covering an area of about 4 x 4 cm.
This 5l.1.. ~l.rl.. was given once a day for tbree days. On the 3 o th7rd day, one hour at^ter the topica7. ~.l, .., ., . ~l ". l ;f n a line was d7 awn using a p~.. . ,~L marker at the level above the a7~1e 7n one hind paw .
AMENDED SHEEr to define the area of the paw to be monitored. The paw volume was measured using a pL,ll~ llu~ ,t~,l (Ugo-Basile, Italy) based on ~e principle of water ~ "~ , l The animals were then injected Z~"~ ly with 50 ~11 of a 1% call~g~ll~l solution in saline (FMC
5 Corp., Maine) into the paw using an insulin syringe with a 25-gauge needle (i.e., S00 llg C~ lldll per paw). Three hours later, the paw volume was measured and the increases in the paw volume were r~ ,d A five hour plasma sample was also taken to correlate the plasma levels with % paw edema inhi1~i*nn The animals were ;,f d by C02 d~ iàli-J.I. Paw edema data were compared with the vehicle control group and percent inhibition r~ taking the values in the control group as 100%. The topical fnrrmlls'fi~n was given at different doses to the animals and was also compared to an orally ,d dose of j"~ ;., and a ~ ... f l~ lly available topical gel fnrrnllls~if~)n of illf~l.lllr~ ;ll Re~ ive results are shown in Table 1.
21 8856~
F~rm~ tio3ls Dose (m~ ) % Inhibition Plasma Conc (3hr) (U~lml~
(5hr) 5 Tnt-lm~th~in spray 1 31 + l 3.6 i 1,2 3 54:~2 7,6~2.1 ', 10 70 i: 2 8.5 i l.2 0 Amuno~) Gel 5 41 i 2 4,5 i 1.5 Oral Tntl~m~th~.in (0,5 % Methocel - Trade Mark) 3 55 i 3 7,2 i 3.1 3-[3,4-Diiluoro-phenyl]4-[4-(methyl-sulfonyl)phenyl 1]-2-(5H)-f~ranone spray 7 56 i 5 1.2 ~ 0 2
Claims (18)
1. A topical polymeric delivery system suitable for administering a drug soluble in hydroalcoholic solutions which comprises:
(a) a film forming polymer;
(b) a plasticizing agent;
(c) a crystallization inhibitor/stabilizer;
(d) a penetration enhancer;
(e) an alcoholic or hydroalcoholic solution; and (f) a suitable drug.
(a) a film forming polymer;
(b) a plasticizing agent;
(c) a crystallization inhibitor/stabilizer;
(d) a penetration enhancer;
(e) an alcoholic or hydroalcoholic solution; and (f) a suitable drug.
2. The system according to Claim 1 wherein the drug is adapted to be administered via a propellant-free aerosol pump.
3. The system according to Claim 1 wherein the film forming polymer is selected from the group consisting of methacrylates, celluloses and siloxanes and co-polymers of methacrylates, celluloses and siloxanes.
4. The system according to Claim 3 wherein the film forming polymer is a methacrylate.
5. The system according to Claim 4 wherein the methacrylate is poly(2-hydroxy ethyl methacrylate).
6. The system according to Claim 1 wherein the plasticizing agent is selected from Tween (Trade Mark), low molecular weight polyglycols, glycerin and Labrasol (Trade Mark).
7. The system according to Claim 6 wherein the plasticizing agent is Tween 20 (Trade Mark).
8. The system according to Claim 1 wherein the crystallization inhibitor is selected from the group consisting of hydroxypropyl beta-cyclodextrin, hydroxyethyl beta-cyclodextrin, diethyl beta-cyclodextrin, hydroxyethyl gamma-cyclodextrin or hydroxypropyl gamma-cyclodextrin.
9. The system according to Claim 1 wherein the suitable drug is selected from the group consisting of a) Protein drugs such as insulin;
b) Anti-infectives, such as antibiotics, including penicillin, tetracycline, chlorotetracycline bacitracin, nystatin, streptomycin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, and erythromycin;
sulfonamides, including sulfacetamide, sulfamethizole, sulfamethazine, sulfadiazine, sulfamerazine, and sulfisoxazole, cefoxitin; anti-virals including idoxuridine;
and other anti-infectives including nitrofurazone and sodium propionate;
c) Steroidal anti-inflammatory agents such as hydrocortisone, cortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, triamcinolone, medrysone, prednisolone, prednisolone 21-phosphate, and prednisolone acetate;
d) Estrogens such as estrone, 17 .beta.-estradiol, ethinyl estradiol, and diethyl stilbesterol;
e) Progestational agents such as progesterone, megestrol, melengestrol, chlormadinone, ethisterone, norethynodrel, 19-nor-progesterone, norethindrone, medroxyprogesterone and 17 .beta.-hydroxy-progesterone;
f) Humoral agents such as the prostaglandins, for example, PGE1, PGE2 and PFG2;
g) Antipyretics analgesics such as aspirin, sodium salicylate, salicylamide, and diflunisal;
h) Antispasmodics such as atropine, methantheline, papaverine, and methscopolamine bromide;
i) Antihistamines such as diphenhydramine, dimenhydrinate, tripelennamine, perphenazine, and clorophenazine;
j) Non steroidal anti-inflammatory agents such as indomethacin, and sulindac; and k) Cyclooxygenase II inhibitors such as 3-[3,4-difluorophenyl]-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone.
b) Anti-infectives, such as antibiotics, including penicillin, tetracycline, chlorotetracycline bacitracin, nystatin, streptomycin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, and erythromycin;
sulfonamides, including sulfacetamide, sulfamethizole, sulfamethazine, sulfadiazine, sulfamerazine, and sulfisoxazole, cefoxitin; anti-virals including idoxuridine;
and other anti-infectives including nitrofurazone and sodium propionate;
c) Steroidal anti-inflammatory agents such as hydrocortisone, cortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, triamcinolone, medrysone, prednisolone, prednisolone 21-phosphate, and prednisolone acetate;
d) Estrogens such as estrone, 17 .beta.-estradiol, ethinyl estradiol, and diethyl stilbesterol;
e) Progestational agents such as progesterone, megestrol, melengestrol, chlormadinone, ethisterone, norethynodrel, 19-nor-progesterone, norethindrone, medroxyprogesterone and 17 .beta.-hydroxy-progesterone;
f) Humoral agents such as the prostaglandins, for example, PGE1, PGE2 and PFG2;
g) Antipyretics analgesics such as aspirin, sodium salicylate, salicylamide, and diflunisal;
h) Antispasmodics such as atropine, methantheline, papaverine, and methscopolamine bromide;
i) Antihistamines such as diphenhydramine, dimenhydrinate, tripelennamine, perphenazine, and clorophenazine;
j) Non steroidal anti-inflammatory agents such as indomethacin, and sulindac; and k) Cyclooxygenase II inhibitors such as 3-[3,4-difluorophenyl]-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone.
10. The system according to Claim 9 wherein the drug is selected from the group consisting of non-steroidal and steroidal anti-inflammatory agents, antihistamines and cyclooxygenase II inhibitors.
11. A method for the topical or systemic delivery of a therapeutic dose of a drug selected from the group consisting of a) Protein drugs such as insulin;
b) Anti-infectives, such as antibiotics, including penicillin, tetracycline, chlorotetracycline bacitracin, nystatin, streptomycin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, and erythromycin;
sulfonamides, including sulfacetamide, sulfamethizole, sulfamethazine, sulfadiazine, sulfamerazine, and sulfisoxazole, cefoxitin; anti-virals including idoxuridine;
and other anti-infectives including nitrofurazone and sodium propionate;
c) Steroidal anti-inflammatory agents such as hydrocortisone, cortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, triamcinolone, medrysone, prednisolone, prednisolone 21-phosphate, and prednisolone acetate;
d) Estrogens such as estrone, 17 .beta.-estradiol, ethinyl estradiol, and diethyl stilbesterol;
e) Progestational agents such as progesterone, megestrol, melengestrol, chromadinone, ethisterone, norethynodrel, 19-nor-progesterone, norethindrone, medroxyprogesterone and 17.beta.-hydroxy-progesterone;
f) Humoral agents such as the prostaglandins, for example, PGE1, PGE2 and PFG2;
g) Antipyretics analgesics such as aspirin, sodium salicylate, salicylamide and diflunisal;
h) Antispasmodics such as atropine, methantheline, papaverine and methscopolamine bromide;
i) Antihistamines such as diphenhydramine, dimenhydrinate, tripelennamine, perphenazine and chlorophenazine;
j) Non steroidal anti-inflammatory agents such as indo-methacin and sulindac k) Cyclooxygenase II inhibitors such as 3-[3,4-difluorophenyl]-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone, which comprises employing the system of Claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
b) Anti-infectives, such as antibiotics, including penicillin, tetracycline, chlorotetracycline bacitracin, nystatin, streptomycin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, and erythromycin;
sulfonamides, including sulfacetamide, sulfamethizole, sulfamethazine, sulfadiazine, sulfamerazine, and sulfisoxazole, cefoxitin; anti-virals including idoxuridine;
and other anti-infectives including nitrofurazone and sodium propionate;
c) Steroidal anti-inflammatory agents such as hydrocortisone, cortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, triamcinolone, medrysone, prednisolone, prednisolone 21-phosphate, and prednisolone acetate;
d) Estrogens such as estrone, 17 .beta.-estradiol, ethinyl estradiol, and diethyl stilbesterol;
e) Progestational agents such as progesterone, megestrol, melengestrol, chromadinone, ethisterone, norethynodrel, 19-nor-progesterone, norethindrone, medroxyprogesterone and 17.beta.-hydroxy-progesterone;
f) Humoral agents such as the prostaglandins, for example, PGE1, PGE2 and PFG2;
g) Antipyretics analgesics such as aspirin, sodium salicylate, salicylamide and diflunisal;
h) Antispasmodics such as atropine, methantheline, papaverine and methscopolamine bromide;
i) Antihistamines such as diphenhydramine, dimenhydrinate, tripelennamine, perphenazine and chlorophenazine;
j) Non steroidal anti-inflammatory agents such as indo-methacin and sulindac k) Cyclooxygenase II inhibitors such as 3-[3,4-difluorophenyl]-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone, which comprises employing the system of Claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
12. A method for the topical or systemic delivery of a therapeutic dose of a drug selected from the group consisting of non-steroidal and steroidal anti-inflammatory agents, antihistamines and cyclooxygenase II inhibitors which comprises employing the system of Claim 1,2,3,4,5,6,7,8,9,10 or 11.
13. A method for the topical or systemic delivery of a therapeutic dose of indomethacin which comprises employing the system of Claim 1,2,3,4,5,6,7,8,9,10 or 11.
14. A topical polymeric delivery system according to Claim 1 wherein the polymer is poly(2-hydroxy ethyl methacrylate), the plasticizing agent is Tween 20 (Trade Mark), the crystallization inhibitor is hydroxypropyl beta-cyclodextrin, the alcoholic solution is absolute ethanol and the drug is indomethacin.
15. A method for the topical or systemic delivery of a therapeutic dose of 3-[3,4-difluorophenyl]-4-(methylsulfonyl)phenyl]-2-(5H)-furanone which comprises employing the system of Claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
16. A topical polymeric delivery system according to Claim 1 wherein the polymer is poly(2-hydroxy ethyl methacrylate), the plasticizing agent is Tween 20 (Trade Mark), the crystallization inhibitor is hydroxypropyl beta-cyclodextrin, the alcoholic solution is absolute ethanol and the drug is 3-[3,4-difluorophenyl]-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone.
17. A topical polymeric delivery system for administering a drug which comprises:
(a) a film forming polymer;
(b) a plasticizing agent;
(c) a solvent effective for film formation of said polymer, and (d) at least one of:
(i) a crystallization inhibitor/stabilizer; and (ii) a penetration enhancer.
(a) a film forming polymer;
(b) a plasticizing agent;
(c) a solvent effective for film formation of said polymer, and (d) at least one of:
(i) a crystallization inhibitor/stabilizer; and (ii) a penetration enhancer.
18. A system of Claim 17 for use in topical or systemic delivery of a drug soluble in said solvent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23840994A | 1994-05-05 | 1994-05-05 | |
| US238,409 | 1994-05-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2188566A1 true CA2188566A1 (en) | 1995-11-16 |
Family
ID=22897769
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2188566 Abandoned CA2188566A1 (en) | 1994-05-05 | 1995-05-02 | Topical polymeric drug delivery system |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0758229A1 (en) |
| JP (1) | JPH09512562A (en) |
| AU (1) | AU2402495A (en) |
| CA (1) | CA2188566A1 (en) |
| WO (1) | WO1995030409A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019149681A1 (en) * | 2018-02-01 | 2019-08-08 | Beiersdorf Ag | Cosmetic product comrpising a dispenser and an anhydrous cosmetic preparation |
| CN114404664A (en) * | 2022-02-17 | 2022-04-29 | 浙江瑞谷生物科技有限公司 | Bone repair scaffold material with long-acting slow release function and preparation method and application thereof |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2740038B1 (en) * | 1995-10-20 | 1998-01-02 | Lafon Labor | COMPOSITION FOR TRANSDERMAL ADMINISTRATION |
| AUPO379596A0 (en) | 1996-11-22 | 1996-12-19 | Soltec Research Pty Ltd | Percutaneous delivery system |
| DE19828273B4 (en) | 1998-06-25 | 2005-02-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing hormones and crystallization inhibitors |
| DE59913181D1 (en) * | 1998-10-23 | 2006-04-27 | Aventis Pharma Sa | PREPARATIONS FOR THE TOPICAL APPLICATION OF ANTI-ACID EFFECTIVE SUBSTANCES |
| AUPQ419099A0 (en) * | 1999-11-23 | 1999-12-16 | Ko, Thomas Sai Ying | Novel compositions and methods |
| AUPQ681200A0 (en) * | 2000-04-10 | 2000-05-11 | Unisearch Limited | Antimicrobial coatings |
| WO2008045461A2 (en) * | 2006-10-11 | 2008-04-17 | Oregon Health & Science University | Transdermal diethylstilbestrol for treating prostate cancer |
| CA2719512A1 (en) | 2010-11-01 | 2012-05-01 | Stiefel Research Australia Pty Ltd | Polymeric topical compositions |
| US9301920B2 (en) | 2012-06-18 | 2016-04-05 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| HUE055562T2 (en) | 2011-11-23 | 2021-11-29 | Therapeuticsmd Inc | Natural combination hormone replacement formulations and therapies |
| US20150196640A1 (en) | 2012-06-18 | 2015-07-16 | Therapeuticsmd, Inc. | Progesterone formulations having a desirable pk profile |
| US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US20130338122A1 (en) | 2012-06-18 | 2013-12-19 | Therapeuticsmd, Inc. | Transdermal hormone replacement therapies |
| US11246875B2 (en) | 2012-12-21 | 2022-02-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US10537581B2 (en) | 2012-12-21 | 2020-01-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US10568891B2 (en) | 2012-12-21 | 2020-02-25 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US10471072B2 (en) | 2012-12-21 | 2019-11-12 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US9180091B2 (en) | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
| RU2016143081A (en) | 2014-05-22 | 2018-06-26 | Терапьютиксмд, Инк. | NATURAL COMBINED HORMONE SUBSTITUTION COMPOSITIONS AND THERAPIES |
| US10328087B2 (en) | 2015-07-23 | 2019-06-25 | Therapeuticsmd, Inc. | Formulations for solubilizing hormones |
| US10286077B2 (en) | 2016-04-01 | 2019-05-14 | Therapeuticsmd, Inc. | Steroid hormone compositions in medium chain oils |
| KR20180126582A (en) | 2016-04-01 | 2018-11-27 | 쎄러퓨틱스엠디, 인코퍼레이티드 | Steroid hormone pharmaceutical composition |
| CN117695225B (en) * | 2023-12-26 | 2024-07-26 | 石家庄石牧药业有限公司 | Aureomycin spray and preparation method thereof |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE7702990L (en) * | 1976-03-19 | 1977-09-20 | Minnesota Mining & Mfg | TROPICAL ADMINISTRATIVE SYSTEM FOR MEDICINAL PRODUCTS WITH INCREASED PEUTRATION |
| JPH07116035B2 (en) * | 1987-12-08 | 1995-12-13 | 塩野義製薬株式会社 | Film-forming antifungal composition |
| US5158766A (en) * | 1989-04-13 | 1992-10-27 | Ecolab, Inc. | Storage stable aqueous soluble germicidal film forming composition |
| AU5885690A (en) * | 1989-07-11 | 1991-01-17 | Union Carbide Chemicals And Plastics Company Inc. | Emulsions comprising aminopolysaccharides |
| US4997643A (en) * | 1989-07-12 | 1991-03-05 | Union Carbide Chemicals And Plastics Company Inc. | Polymeric salt delivery systems |
| US5262087A (en) * | 1991-05-01 | 1993-11-16 | Kose Corporation | Water-in-oil type emulsified composition |
| TW247878B (en) * | 1991-07-02 | 1995-05-21 | Takeda Pharm Industry Co Ltd | |
| US5254541A (en) * | 1991-11-15 | 1993-10-19 | Merck Frosst Canada, Inc. | (Quinolin-2-ylmethoxy)indole/cyclodextrin complex |
-
1995
- 1995-05-02 JP JP7528565A patent/JPH09512562A/en active Pending
- 1995-05-02 CA CA 2188566 patent/CA2188566A1/en not_active Abandoned
- 1995-05-02 WO PCT/CA1995/000260 patent/WO1995030409A1/en not_active Application Discontinuation
- 1995-05-02 EP EP95917847A patent/EP0758229A1/en not_active Withdrawn
- 1995-05-02 AU AU24024/95A patent/AU2402495A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019149681A1 (en) * | 2018-02-01 | 2019-08-08 | Beiersdorf Ag | Cosmetic product comrpising a dispenser and an anhydrous cosmetic preparation |
| CN114404664A (en) * | 2022-02-17 | 2022-04-29 | 浙江瑞谷生物科技有限公司 | Bone repair scaffold material with long-acting slow release function and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995030409A1 (en) | 1995-11-16 |
| JPH09512562A (en) | 1997-12-16 |
| EP0758229A1 (en) | 1997-02-19 |
| AU2402495A (en) | 1995-11-29 |
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