CA1192496A - Topical pharmaceutical compositions - Google Patents
Topical pharmaceutical compositionsInfo
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- CA1192496A CA1192496A CA000400470A CA400470A CA1192496A CA 1192496 A CA1192496 A CA 1192496A CA 000400470 A CA000400470 A CA 000400470A CA 400470 A CA400470 A CA 400470A CA 1192496 A CA1192496 A CA 1192496A
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- active agent
- ester
- emulsifier
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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
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- Biophysics (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Abstract of the Disclosure A skin penetration pharmaceutical composition incor-porating a difficultly skin-penetrable pharmacologically active agent, wherein the composition is in the form of a microemulsion formed from skin compatible excipients.
Description
~9~
TOPTCAL PHA~MACEUTIOAl. COMPOSITIONS
This invention relates to topical pharmaceutical composi-tions, particularly ~hose conta-ining pharmacologically active agents ~hich only difficultly penetrate the skin horny layer.
The therapeutic ef~iciency of a topical pharmaceutical com-position depends upon inter alia the availab;lity of the pharmacologically active agent for absorption and the skin-penetrabil-ity of the active agent. Before any topically 10 applied pharmacologically active agent can act at its site of action ~hether in the deeper dermal layers belnw-th~
horny layer or else~lhere in the body it must penetrate the barrier Of the horny layer of the skin (stratum corneum).
The penetration of the stratum corneum is the rate-limiting 15 step of the total percutaneous process and is accompanied by the creation of a reservoir of pharmacologically active agent, i.e. the deposition of pharmacologically active agent on and in the layer. In the rare case the pharmacolo-gically active agent is normally li~uid and penetrates the 20 skin layer efficiently, e.g. isosorbide dinitrate or gly-ceryl trinitrate~otherwise various methods must be employed to obtain sufficient penetration of the pharmacologically active agent through the horny layer, especially for active agents ~Ihich are generally adrninistered in solid form.
25 Often the pharmacologically active agent is capable of pe-netrating the skin horny layer when applied to the skin in a conventional system such as a triglyceride or paraffin ointment, but has a penetration flux of less than about 10 9 Mol cm 2 hour 1~ e.g. lC 10 Mol cm 2 hour 1. Such 30 pharmacologically active agents are hereinafter referred to as difficultly skin-penetrable pharmacologically active agents.
~, 4~3~
TOPTCAL PHA~MACEUTIOAl. COMPOSITIONS
This invention relates to topical pharmaceutical composi-tions, particularly ~hose conta-ining pharmacologically active agents ~hich only difficultly penetrate the skin horny layer.
The therapeutic ef~iciency of a topical pharmaceutical com-position depends upon inter alia the availab;lity of the pharmacologically active agent for absorption and the skin-penetrabil-ity of the active agent. Before any topically 10 applied pharmacologically active agent can act at its site of action ~hether in the deeper dermal layers belnw-th~
horny layer or else~lhere in the body it must penetrate the barrier Of the horny layer of the skin (stratum corneum).
The penetration of the stratum corneum is the rate-limiting 15 step of the total percutaneous process and is accompanied by the creation of a reservoir of pharmacologically active agent, i.e. the deposition of pharmacologically active agent on and in the layer. In the rare case the pharmacolo-gically active agent is normally li~uid and penetrates the 20 skin layer efficiently, e.g. isosorbide dinitrate or gly-ceryl trinitrate~otherwise various methods must be employed to obtain sufficient penetration of the pharmacologically active agent through the horny layer, especially for active agents ~Ihich are generally adrninistered in solid form.
25 Often the pharmacologically active agent is capable of pe-netrating the skin horny layer when applied to the skin in a conventional system such as a triglyceride or paraffin ointment, but has a penetration flux of less than about 10 9 Mol cm 2 hour 1~ e.g. lC 10 Mol cm 2 hour 1. Such 30 pharmacologically active agents are hereinafter referred to as difficultly skin-penetrable pharmacologically active agents.
~, 4~3~
-2- 100-5~32 One method to increase the penetration rate ïs to dissolve the skin-penetrable pharmacologically active agent in a non-~.oxic sol Yen t whi ch i s skin compat;ble e.gO
that does not cause skin irritation over an extended period of time:as indicated in s~andard -tests usin~ l~uman skin or - more sensitive guineapig skin. The solutions may be applied in the form of macroemulsions i.e. opaque oil-in-water or water-in-oil systems formed from water and water in~liscibleorgan;c solvents in the presence of an 10 emulsifier.
Such systems suffer from disadvantages especially in the case of difficultly skin-penetra-table pharmacologically actiYe agents- -15 We have now found that skin penetration pharmaceuticalcompositions wherein the composition is in the form oF
a microemulsion have particularly advantageous properties in respect of difficultly skin-penetrable pharmacologi-cally active agents
that does not cause skin irritation over an extended period of time:as indicated in s~andard -tests usin~ l~uman skin or - more sensitive guineapig skin. The solutions may be applied in the form of macroemulsions i.e. opaque oil-in-water or water-in-oil systems formed from water and water in~liscibleorgan;c solvents in the presence of an 10 emulsifier.
Such systems suffer from disadvantages especially in the case of difficultly skin-penetra-table pharmacologically actiYe agents- -15 We have now found that skin penetration pharmaceuticalcompositions wherein the composition is in the form oF
a microemulsion have particularly advantageous properties in respect of difficultly skin-penetrable pharmacologi-cally active agents
3~
-3- 100-553~
A recellt review on microemul:sions is by M.Rosoff p.405 in Pro-~ress in Surface and Mem~rane Science 12, 1~78 Academic Press A microemulsion is generally recoallised to be a coloured or colourless (oil-in-water or water-in-oil) emulsion wherein the diameter of the ~articles or droplets are less than about 1500 Angstrom units (150 nm) which is less than 1~4 of the wavelength of l;ght. They do therefore no-t scatter visible light, the diameter of the particles or droplets arising from e.g. any micellar aggregate struc-10 ture present being suf^ficiently small. The emulsion thusappears transparent when viewed by optical microscopic means. It may be isotropic or anisotropic. An anisotropic structure may ho~Yever:be ohseruable using x-ray techniques.
The particles in a microemulsion may be spherical but other 15 structures are feasib7e, e.g. liquid crystals with lamellar, hexagonal or isotropic symmetries.
Usually microemulsions are prodllced from an emulsifier (a surfactant) and a co-emulsifier (i.e. a co-surfactant, polar additive, co-solubili7er) which lowers the interfacial 2Q tension between the oil-in-water phases to a very small amount (typically less than 1 dyne/cm). The microemulsions ~ften form practically spontaneously and represent a single thermodynamically stable phase. In contrast, macroemulsions are thermodynamically unstable two phase systems, and in 25 their formation energy supply in the form of heating or rapid agitation is required.
Microemulsions are well known in other fiëlds,e.g.cosmetic preparat;ons,floor polishes,pain~s and foods.However,the formulation of microemulsions is to a certain extent largely 30 empirical (cee for example p.34-56 in Microemulsions Theory ~nd Practice,Ed.L.Prince~1977) and up to now no skin pene-tration pharmaceutical compos;tion for the systemic admini-stration of a difficultly skin-penetrable pharmacologically active agent has been produced from skin compatible excipienis.
a~
on-ss32 J. Ziegenmeyer and C.Fuhrer in Acta Pharm~ceutica Techno-logica 1980 26 (4) p.273-275 have disclosed a microemul-sion pharmaceutical composition containing 1~ tetracycline.
hydrochloride and decanol.Ho~lever the composition is not capable nf producing a systemic therapeutic effect anlount of tetracycline as the tetracycline con-centratioll in the pharmaceutical composi~ion is too low.
More importantly decanol is not skin compatible. For example in sensitiYe animal skin irritation tests moderate 10 irritation of yuinea pi~ skin and severe ;rritation o-f the rabbit skin has been found see for example lndustrial Hygiene and Toxicology Second Revised Edition Editor F.Patty Vol.II (1962) p 1467f Interscience Publishers John Wileyj New York and London In less sensitive tests 15 using human skin exposed to decanol over a 24 hour period significant irritation has been observed see - for example p.753 W.Kastner J.Soc. Cosmet.Chemists (1974) 28 741-754. Additionally the specific hydrocarbon solvents suggested are not applicable for man.
20 We have found that microemulsions may be made containing pharmacologically active agents and skin compatible exci-pients which sho~l particularly advantageous penetra-- tion properties producing a penetration flux sufficient to produce a therapeutic effect in the deeper dermal 25 layers or through -the system;c circwlation as indicated in trials mentioned hereinafter.
-5- 100~5532 In one aspect the present invelltion provide~ a skin pene-tration phanmaceutical composition incorporating a - -_ skin-penet~able pharmacolo~ically activè agent, wherein the con1position is in the form of an microemul-sion formed from s~in compatible excipients.
In another aspect the present inven~ion provides a methodof enhancing the penetration o-F a skin-pene-trable pharmacologically active agent through the skin ~hich compr;ses applying the active agent to the skin in the form of a microemulsion consistin~ of s~in cnmpatible excipients.
In a further aspect the present invention provides the use of a microemulsion consisting of skin compa~ible exci-pients to administer percutaneous~y - ~ askirl-15 ~penetrab1e pharmacologically active agent.
In yet a further aspect the present invention provides a process for the production of a skin-penetrable pharmaceutical composition which comprises forming a microemuls;on from water and a skin-penetrable pharmacologically active agent and skin compatible excipients capable of f~nction-ing as a water-imm;scible organic solvent, an emulsifier, and a co-emulsifier.
The microemulsions may be produced in convent;onal manner for the preparation of topical pharmaceutical compositions.
The skin compatible pharmacologically active agent, water-immiscible organic solvent~ water,emulsif;er and co-emulsi-fier may ~e mixed,conveniently at a max-imum of 100C,e.g.
from about 60; to abou~ 95C and the mixture is cooled.
It is not importànt that a microemulsion be formed above I~ a microemulsion is formed above 32C
then the phase inversions should preferably be reversible.
Indeed it is quite comlllon that a r,lilky macloelllulsion may be forllled at high temperatures whicll on cooling passes throll~h one or more cloudy transitional phases alternately with microemulsion phases.
Desirably a microenllllsion is produced throughout ~he ~em-perature range of from about 20C to about 32C~ prefe:rably from about 15C to about 35C.
The water-immiscible orgallic solvent may be for example a hydrocarbon or lipid.
An emulsifier is present to form an oil-in-water or wa~er in-oil emulsion wherein the oil is the water-immiscible organic solvent. The co-emulsifier contributes to the for-mation and the stability of the microemulsion.
The chemical structure or chainlength of the co-emulsifier is a governing factor in controlling the size of the drop-lets or particles in the emulsions and should match the structure or chainlength of the hydrocarbon part of the emulsifier. The co-emulsifier should be compatible with the water^immiscjble organic solvent forming the lipophilic phase.
The organic solvent emulsifier and co-emulsifier should also be compatible with the pharmacologically active 2~ agent.
Naturally it is possible that the same excipient acts as a water-immiscible organic solvent and simultaneously as a co-emulsi~ier. Conveniently different excipients are used as organic solvent and co-emulsifier~ however.
The microemulsions may be colourless or coloured~ e.g.
yellow.
A suitable combination of an emulsifier wi-th a co-emul-sifier may be, for example, a IYater-soluble non-ionic eMulsifier and a fatty alcohol OT a suitable chain length.
Another suitable combination may be a mixtllre of water-solub1e and water-insoluble non-ionic tensides.
Conveniently a-t least two of the water-immiscible oganic solvent, co-emulsifier and emulsifier has a chain length moiety of 12 to 20 carbon atoms.
For any particular skin compatible pharmacologically active agent, water-immiscible organic solvent~ater,emulsifier, and co-emulsifier system the relative amount of excipienr.s can be varied and full phase equilibria diagrams may be drawn. It is sometimes more convenient merely to obtain a microemulsion at any temperature, even above room tempera-ture~from one set of excipients in order to show they arecompatible and then vary the amounts slightly to produce a suitable microemulsion at room temperature. As a very rough guide the microen1ulsion may contain:-a) 0.01 ~o 15% of skin compatible skin-pene--trable pharmacologically active agent,b) 5 to 30%,e.s. 10 to 30~, of skin compatible water-imrniscible or~anic solvent, c) 10 to 30% of skin compatible emulsifier, d) 4 to 30~ of skin compatible co-emulsifier, and e) 15 to 55% ~Ja`ter.
Where the same compound may act as,e.g.both water~immis-cible organic solvent and co-emulsifier,and in particular when another co-emulsifier or organic solvent is omitted then a part of the concentration of the compound (together with any other water-imm.scible solvent present) may be reckoned as ~ater-immiscible solvent and a part (together with any other co-emulsifier present) as co-ernulsifier.
~ 100-553 Wh~re the san~. excipient acts ~s both IYaten~ nliscible or~anic solvent and co-emulsifier and ~liere is no co-emuls;fier or orgariic solvent present thell this excipient Inay be presellt from 9 to ~0~
o f the compos i ti on .
The microemulsions of the inventioll may be in the forr,l of liquids or preferably in the Form of gels "~hich are semi~viscous, con-taining less \Yater. Some microgels may have appropriate viscoelastic proper-ties to form swinging gels.
100-~5~2 In respeet ~ any o~ the excipients mentioned hereinafter any aliphatic carboxylic acid may be straight-chain or branched ancl saturated or unsaturated, preferably l~ith one or t~o clouble bonds. Any alipha-tic alcohol is a uni~alent Al cohol unless otherw;~elllentioned, and is preferably a secondary or especially a primary alcohol. They are branched or preferably straight-chain and are unsaturated with preferably one or t~o double bonds or especially saturated~ Any glyceryl ether or ester is primarily .etheri-fied or esteri~ied at one or both of the termin~l glycerYl hydroxy groupS
lQ Suitable - - skin compatible excipiènts may be the following:-1) an ester bf an aliphatic (C3 18) alcohol ~it'n an ali-phatic (C1O 2~ carboxylic acid, or 2~ a hydrocarbon having a straight carbon (C12 32) chain substituted by from 6 to 16 methyl groups and having up to 6 double bonds, may be suitable ~later-immiscible organic solvents.
Examples of class 1) include i sopropyl 1 aurate, hexyl laurate and decyl laurate~ isopropyl myristate and lauryl myristate.
Particularly suitable examples are isopropyl laurate, hexyl laurate and -isopropyl myristate, especially hexyl laurate.
Examples of class 2) includeterpenes such as poly-methylbutanes and polymethylbutenes~ e.g. 2,6,10,15,l9, 23-hexamethyl-2,6,10,14,18,22 tetracosahexaene3 also known as squalene (C30H50) and the perhydro analogue, Sqllalane A particularly suitable example is squalane.
-10- 100-5~32 Skin compatible excipients chosen from 3) a mono-ester of ethylene glycol or propylene glycol with an aliphat;c (C~ 22) carboxylic ac;d,
-3- 100-553~
A recellt review on microemul:sions is by M.Rosoff p.405 in Pro-~ress in Surface and Mem~rane Science 12, 1~78 Academic Press A microemulsion is generally recoallised to be a coloured or colourless (oil-in-water or water-in-oil) emulsion wherein the diameter of the ~articles or droplets are less than about 1500 Angstrom units (150 nm) which is less than 1~4 of the wavelength of l;ght. They do therefore no-t scatter visible light, the diameter of the particles or droplets arising from e.g. any micellar aggregate struc-10 ture present being suf^ficiently small. The emulsion thusappears transparent when viewed by optical microscopic means. It may be isotropic or anisotropic. An anisotropic structure may ho~Yever:be ohseruable using x-ray techniques.
The particles in a microemulsion may be spherical but other 15 structures are feasib7e, e.g. liquid crystals with lamellar, hexagonal or isotropic symmetries.
Usually microemulsions are prodllced from an emulsifier (a surfactant) and a co-emulsifier (i.e. a co-surfactant, polar additive, co-solubili7er) which lowers the interfacial 2Q tension between the oil-in-water phases to a very small amount (typically less than 1 dyne/cm). The microemulsions ~ften form practically spontaneously and represent a single thermodynamically stable phase. In contrast, macroemulsions are thermodynamically unstable two phase systems, and in 25 their formation energy supply in the form of heating or rapid agitation is required.
Microemulsions are well known in other fiëlds,e.g.cosmetic preparat;ons,floor polishes,pain~s and foods.However,the formulation of microemulsions is to a certain extent largely 30 empirical (cee for example p.34-56 in Microemulsions Theory ~nd Practice,Ed.L.Prince~1977) and up to now no skin pene-tration pharmaceutical compos;tion for the systemic admini-stration of a difficultly skin-penetrable pharmacologically active agent has been produced from skin compatible excipienis.
a~
on-ss32 J. Ziegenmeyer and C.Fuhrer in Acta Pharm~ceutica Techno-logica 1980 26 (4) p.273-275 have disclosed a microemul-sion pharmaceutical composition containing 1~ tetracycline.
hydrochloride and decanol.Ho~lever the composition is not capable nf producing a systemic therapeutic effect anlount of tetracycline as the tetracycline con-centratioll in the pharmaceutical composi~ion is too low.
More importantly decanol is not skin compatible. For example in sensitiYe animal skin irritation tests moderate 10 irritation of yuinea pi~ skin and severe ;rritation o-f the rabbit skin has been found see for example lndustrial Hygiene and Toxicology Second Revised Edition Editor F.Patty Vol.II (1962) p 1467f Interscience Publishers John Wileyj New York and London In less sensitive tests 15 using human skin exposed to decanol over a 24 hour period significant irritation has been observed see - for example p.753 W.Kastner J.Soc. Cosmet.Chemists (1974) 28 741-754. Additionally the specific hydrocarbon solvents suggested are not applicable for man.
20 We have found that microemulsions may be made containing pharmacologically active agents and skin compatible exci-pients which sho~l particularly advantageous penetra-- tion properties producing a penetration flux sufficient to produce a therapeutic effect in the deeper dermal 25 layers or through -the system;c circwlation as indicated in trials mentioned hereinafter.
-5- 100~5532 In one aspect the present invelltion provide~ a skin pene-tration phanmaceutical composition incorporating a - -_ skin-penet~able pharmacolo~ically activè agent, wherein the con1position is in the form of an microemul-sion formed from s~in compatible excipients.
In another aspect the present inven~ion provides a methodof enhancing the penetration o-F a skin-pene-trable pharmacologically active agent through the skin ~hich compr;ses applying the active agent to the skin in the form of a microemulsion consistin~ of s~in cnmpatible excipients.
In a further aspect the present invention provides the use of a microemulsion consisting of skin compa~ible exci-pients to administer percutaneous~y - ~ askirl-15 ~penetrab1e pharmacologically active agent.
In yet a further aspect the present invention provides a process for the production of a skin-penetrable pharmaceutical composition which comprises forming a microemuls;on from water and a skin-penetrable pharmacologically active agent and skin compatible excipients capable of f~nction-ing as a water-imm;scible organic solvent, an emulsifier, and a co-emulsifier.
The microemulsions may be produced in convent;onal manner for the preparation of topical pharmaceutical compositions.
The skin compatible pharmacologically active agent, water-immiscible organic solvent~ water,emulsif;er and co-emulsi-fier may ~e mixed,conveniently at a max-imum of 100C,e.g.
from about 60; to abou~ 95C and the mixture is cooled.
It is not importànt that a microemulsion be formed above I~ a microemulsion is formed above 32C
then the phase inversions should preferably be reversible.
Indeed it is quite comlllon that a r,lilky macloelllulsion may be forllled at high temperatures whicll on cooling passes throll~h one or more cloudy transitional phases alternately with microemulsion phases.
Desirably a microenllllsion is produced throughout ~he ~em-perature range of from about 20C to about 32C~ prefe:rably from about 15C to about 35C.
The water-immiscible orgallic solvent may be for example a hydrocarbon or lipid.
An emulsifier is present to form an oil-in-water or wa~er in-oil emulsion wherein the oil is the water-immiscible organic solvent. The co-emulsifier contributes to the for-mation and the stability of the microemulsion.
The chemical structure or chainlength of the co-emulsifier is a governing factor in controlling the size of the drop-lets or particles in the emulsions and should match the structure or chainlength of the hydrocarbon part of the emulsifier. The co-emulsifier should be compatible with the water^immiscjble organic solvent forming the lipophilic phase.
The organic solvent emulsifier and co-emulsifier should also be compatible with the pharmacologically active 2~ agent.
Naturally it is possible that the same excipient acts as a water-immiscible organic solvent and simultaneously as a co-emulsi~ier. Conveniently different excipients are used as organic solvent and co-emulsifier~ however.
The microemulsions may be colourless or coloured~ e.g.
yellow.
A suitable combination of an emulsifier wi-th a co-emul-sifier may be, for example, a IYater-soluble non-ionic eMulsifier and a fatty alcohol OT a suitable chain length.
Another suitable combination may be a mixtllre of water-solub1e and water-insoluble non-ionic tensides.
Conveniently a-t least two of the water-immiscible oganic solvent, co-emulsifier and emulsifier has a chain length moiety of 12 to 20 carbon atoms.
For any particular skin compatible pharmacologically active agent, water-immiscible organic solvent~ater,emulsifier, and co-emulsifier system the relative amount of excipienr.s can be varied and full phase equilibria diagrams may be drawn. It is sometimes more convenient merely to obtain a microemulsion at any temperature, even above room tempera-ture~from one set of excipients in order to show they arecompatible and then vary the amounts slightly to produce a suitable microemulsion at room temperature. As a very rough guide the microen1ulsion may contain:-a) 0.01 ~o 15% of skin compatible skin-pene--trable pharmacologically active agent,b) 5 to 30%,e.s. 10 to 30~, of skin compatible water-imrniscible or~anic solvent, c) 10 to 30% of skin compatible emulsifier, d) 4 to 30~ of skin compatible co-emulsifier, and e) 15 to 55% ~Ja`ter.
Where the same compound may act as,e.g.both water~immis-cible organic solvent and co-emulsifier,and in particular when another co-emulsifier or organic solvent is omitted then a part of the concentration of the compound (together with any other water-imm.scible solvent present) may be reckoned as ~ater-immiscible solvent and a part (together with any other co-emulsifier present) as co-ernulsifier.
~ 100-553 Wh~re the san~. excipient acts ~s both IYaten~ nliscible or~anic solvent and co-emulsifier and ~liere is no co-emuls;fier or orgariic solvent present thell this excipient Inay be presellt from 9 to ~0~
o f the compos i ti on .
The microemulsions of the inventioll may be in the forr,l of liquids or preferably in the Form of gels "~hich are semi~viscous, con-taining less \Yater. Some microgels may have appropriate viscoelastic proper-ties to form swinging gels.
100-~5~2 In respeet ~ any o~ the excipients mentioned hereinafter any aliphatic carboxylic acid may be straight-chain or branched ancl saturated or unsaturated, preferably l~ith one or t~o clouble bonds. Any alipha-tic alcohol is a uni~alent Al cohol unless otherw;~elllentioned, and is preferably a secondary or especially a primary alcohol. They are branched or preferably straight-chain and are unsaturated with preferably one or t~o double bonds or especially saturated~ Any glyceryl ether or ester is primarily .etheri-fied or esteri~ied at one or both of the termin~l glycerYl hydroxy groupS
lQ Suitable - - skin compatible excipiènts may be the following:-1) an ester bf an aliphatic (C3 18) alcohol ~it'n an ali-phatic (C1O 2~ carboxylic acid, or 2~ a hydrocarbon having a straight carbon (C12 32) chain substituted by from 6 to 16 methyl groups and having up to 6 double bonds, may be suitable ~later-immiscible organic solvents.
Examples of class 1) include i sopropyl 1 aurate, hexyl laurate and decyl laurate~ isopropyl myristate and lauryl myristate.
Particularly suitable examples are isopropyl laurate, hexyl laurate and -isopropyl myristate, especially hexyl laurate.
Examples of class 2) includeterpenes such as poly-methylbutanes and polymethylbutenes~ e.g. 2,6,10,15,l9, 23-hexamethyl-2,6,10,14,18,22 tetracosahexaene3 also known as squalene (C30H50) and the perhydro analogue, Sqllalane A particularly suitable example is squalane.
-10- 100-5~32 Skin compatible excipients chosen from 3) a mono-ester of ethylene glycol or propylene glycol with an aliphat;c (C~ 22) carboxylic ac;d,
4) an ester of an aliphatic (C12~22) al~ohol with lactic acid, or
5) a mono-or diester of glycerol with an aliphatic tC6 22) sarboxylic acid, may be suitable for use as water~immiscible organic sol-vents and/br co-emulsi~iers.
1~ When a exc;p;ent of any of classes 3),4) or 5) is present as an organic solvent, then the same or different excip;ent may be present as a co-emulsifier.
Examples of class 3) include propylene glycol mono-laurate and propylene glycol monomyristate and preferably propylene 15 glycol monolaurate. An example of class 4) is myristyl or preferably lauryl lactate.An example of class 5) is glyceryl caprolate .
Any skin compatible excipients chosen from
1~ When a exc;p;ent of any of classes 3),4) or 5) is present as an organic solvent, then the same or different excip;ent may be present as a co-emulsifier.
Examples of class 3) include propylene glycol mono-laurate and propylene glycol monomyristate and preferably propylene 15 glycol monolaurate. An example of class 4) is myristyl or preferably lauryl lactate.An example of class 5) is glyceryl caprolate .
Any skin compatible excipients chosen from
6) an ester of a poly~27)ethylene glycol glvcerol ether 20 having at least one free hydroxyl group and an aliphatic (C6_22) carboxylic acid, may be suitable for use as water-immiscible solvents or co-emulsifiers.
Some of this class may be water-miscible ~hen for example the polyethylene glycol moiety has a low molecular weight, 25 and so will not be suitable as organic solvents,but they may be suitable co-emulsifiers.An example is poly(7)ethyl-ene glycol glyceryl cocoate.
If the excipient is a transesterification prodllct of a vege-table oil triglyceride and a polyethylene glycol of molecu-30 lar height 200 to 400,e.g. as described in USP 3,288,8243 i ~ 100-5532 then the produc~s may he water-imllliscible ancl suitable for use as an ~ate~^-illlnliscible orgallic solvent.
Skin compatible excipients chosen from
Some of this class may be water-miscible ~hen for example the polyethylene glycol moiety has a low molecular weight, 25 and so will not be suitable as organic solvents,but they may be suitable co-emulsifiers.An example is poly(7)ethyl-ene glycol glyceryl cocoate.
If the excipient is a transesterification prodllct of a vege-table oil triglyceride and a polyethylene glycol of molecu-30 lar height 200 to 400,e.g. as described in USP 3,288,8243 i ~ 100-5532 then the produc~s may he water-imllliscible ancl suitable for use as an ~ate~^-illlnliscible orgallic solvent.
Skin compatible excipients chosen from
7) alipllatic (C12 22) alcohol, or
8~ an ester of having at least one hydroxy sioup of a poly-(2-10)-glycerol with an aliphatic (C6~22) carboxy lic acid~
may be also suitable co-emulsifie~s.
Examples oF class 7) include dodecanol tetradecanol oleylalcohol~ 2-hexyldecanol and 2-octyl-decanol.
Particularly suitable examples include tetradecanol and especially dodecanol.
Pre~erably the alcohol is liquid at 32C.
f~
Skin compatible excipi~nts chosen from
may be also suitable co-emulsifie~s.
Examples oF class 7) include dodecanol tetradecanol oleylalcohol~ 2-hexyldecanol and 2-octyl-decanol.
Particularly suitable examples include tetradecanol and especially dodecanol.
Pre~erably the alcohol is liquid at 32C.
f~
Skin compatible excipi~nts chosen from
9) a mono-ether of a poly-etIlylene-glycol with an alipha~
tic (C12 1~) alcoholS haYing an HLB value of from 10 to 18~ or
tic (C12 1~) alcoholS haYing an HLB value of from 10 to 18~ or
10) an ester of an aliphatic ~C6 22) carboxylic acid with a) a !-olyethvlene ql~Ycol b) a saccharose c) a sorbitan or - d) a poly-et~ylene glycol sorbitan ether, the ester haYing an HLB value of from 10 to 18s may be suitable emulsifiers.
Preferably the emulsifiers haYe an HLB value of from 12 to 15 (HLB values are an indication o-f the hydrophilic lipophilic balance in an emulsifier and have been dis-cussed extensively in the literature, see for example Pharm.Act.Helv. (19~9) 44,~ and H.P.Fiedler, Lexicon der Hilfs`stoffe fiir Pharmazie, Kosmetic und angrenzende Ge biete, 2nd Edi~ion, 1981 ~ Editio Cantor AG, BP~n).
A preferred example of class 9) is commercially available polyoxyethylene-(10)-ol.eyl ether.
Prefer2bly tile microemulsions are made up from excipients from class 1) ancl 2) as water-immiscible or~anic solvents;
especially class l); class 7) as co-emulsifier and class 9) as emulsifier.
The exact choice of organic solvent, emulsifier and co-emulsifier ~/ill depend 011 inter alia the pharmacolQgically active agent used.
The pharnlacologically active agent may be any compound ~hic~n . penetrate the skin horny layer, 10 e.g. of molecular weight up to about 3,000, although higher molecular ~leight compounds may possibly be used.
In general the molecular weight of the pharmacologically active agent is cor,veniently below 1000. Conveniently the active agent has a good hydrophilic/lipophilic balance.
15 The molecule of the active agent for example may be cor,-veniently structurally compact, may contain aromatic groups and conveniently does not con-tain-many reactive groups such as hydroxyl groups The microe~ulsions of the invention are capable of con~-2Q taining ~ery high amounts of active agents,e~g. from 5%up to 15% or even up to 20% of the total we;ght.When a systemic ~ction ;s desired, the pharmacologically active agent should be sufficiently active to be able co produce a systemic therapeutic ef-fect when penetration the skin at 25 rates of the order of 10 8 Mole cm ~ hour 1. When a local action in the deeper dermal layer is required, then a skin penetration flux of 10 9 Mole cm 2 hour 1 may be suf-ficient.
Suitable a~ents may be for example those li-th an,e.g.oral~
daily dose of about 0.1 to about 20 mg, preferably up to 30 1 mg.
~ 100-5532 The microemulsion~ of tlle inv2lltion may be indicated fon the sy~e-n~ic administration of any acti~e agellt.Theylllay be conveniently used for propllylactic agents and nmyotonolytics.The microen1~l1sions of the invention may be indicated for the adminis-tration of pharma-cologica~ly ac-~ive agents which act under the honny 1ayer~e.g.anti~
acne agents and anti-funsal agents.
Examples of active agents include (Ej-N-methyl-5,6-dimethyl-N-(naphthylmethyl)hept-2-en 4-inyl-l-amine, proquazone, (E)~N-meth~l-N-~l-nap)lthylnletilyl)-3-phenyl-propen-2-yl-amine (hereinafter naftifin), 4-(1-methyl-4-piperidylidene~-4H-benzo[4,5]cyclollepta-[1,2-b]thiophen-lQ(9H)-one (hereinafter ketotifen), 4~(1-methyl-4-piperidylidene)-9,10-dihydro-4H-benzo-(4,5)-cyclohep-ta(1,2-b) thiophelle (hereinafter pizoti-fen),-griseofulvin, fluocinolone acetonide, Tr-iam-cinolone acetonide, and 14-0-[5-(2-amino-1,3~4-triazol-yl)thioacetyl]-dihydro-mutiline, and preferably (~)-l-methyl-2-[2-(c~-methyl-p-chlorodiphenyl-methoxy)-ethyl]-pyrrolidine (hereinafter clemastine) and especially 5-chloro-4-(2-imidazolin-2-ylamino~-2,1,3-benzothiadiazole (hereinafter tizanidine) In respect of clemastine a microern~llsion preferably con-tains any of the following concentrations:-5 to 15% of clemastine.5 to 30% of an ~ater-immiscibleorganic solvent~
15 to 25% of an emulsifier.
5 to 25% of a co-emulsifier..
10 to 45% of water.
More pre,erably a microemulsion contain~ any of the following concentrations:-7.5 to 12.5% of clemastine~
7.5 to 28.5% of water~imnliscible organic solvent~
i9.5 to 22% of an emulsifier~
7.5 to 22.5C/~ of a co-emulsifier~
13 to 42~ of water . .
~ore especially a clemastine microen1ulsion contains any of the follo\~ing concentratinns:-8 to 12~ of clemastine.
8 to 27'~ of ~ater-immiscible organic solvent.
5 20 to 21% of an emlllsifier.
8 to 21%:of a co-emulsifier.
15 to 40~ of ~Yater.
The excipients are preferably chosen from class (1) as defined above, as organic solvent.
The excipients o~ class (3) as defined ahove may be pre-sent as or~anic solvent or co-emulsiFierfespeciall~ pro-pylene glycol mono-laulate~Ti!e co-emulsifier alternatively is an excipien~ of class (5) as defined aboYe espec;ally poly(7)ethylene gliycolylyceryl cocoate~or propylene glycol myristate. The preferl-ed emulsifier -is chosen from class (9) as defined above, especially polyoxyethylene (10) oleyl ether e.g. having an HLB value of about 12 to 13.
With clemastine microgels containing hiyh concentrations of clemastine can be produced whereas it is very diffi-cult to produce stable macroemulsions con-taining such high clemastine concentrations.
In the respect of tizanidine a microemulsion preferably contains any of the following concentrations:-6 to 10% of tizanidine.
15 to 25% of ~Yater-immiscible orgar,ic solvent.
15 to 25% of an emulsifier.
5 to 10% of a co-emulsifier.
30 to 35% of water.
Pr2ferably the microenlulsion contains any of the follo~ing concentrations:-7.5 to 8.5% o~ tizani di ne~
19.5 to 21.5% of water-i~miscible organic sblventO
19 to 22% of an emlllsifier~
5.5 to 21 5% of a co-emulsifier 3~ to 42~ Of water.
More particularly the microemuls;on contains any of the following concentratiorls:
lC 8 to 8.4% of tizallidine~
20 to 21% of water-immiscible organic solventO
20 to 21% of an ~muls-ifier~
6.2 to 8.4~% of a co-emulsifier~
33 to 42% Of water Naturally the choice of ~Yater-in~misci6le organic solvent 7 emulsifier and co-emulsifier for a microemulsion system will vary from pharmacologically active agent to pharmacologically active agent and in some cases a particular excipient may be suitable in one system as e.g. an wa~er~imlniscible organic solvent and in another system as an e.g. co-emulsifier.
The pH of the pharmaceutical composition may be adjusted to a skin compa-tible pH with appropriate acids or bases preferably weak acids or bases e.g. lactic or acetic acid.
It is preferred that the pharmacologically active agent is at least partially present in free form e.g. free base form/as the skin penetration may be increased. Con-veniently the pH of the micrGemulsions are weakly acidic.
Other skin compatible agents may be present e.g. water~
imiscible solvents such as propylene glycol~and ethanol -17- 1()0~553 and isopropanol or ~ater so'luble film-formillg a~ents used in cocnl2tic preparations e.g. par-tially hydro-lysed colla~enyieldill~ medlum-weight polypeptides to diminish solvellt evapora~ioll after ru~bing on the skin.
S Naturally the microelllulsion should be compc~sed of com-ponents that are skin compatible. The components should be non~toxic non-allergic and well--tolerated by the skin tissue. Such components can be chosen by stalldard acute and chronic tests.
The tests may be effècted on hulnan skin or ~ ch mol^e sen-sitive animal skin~e.~. ~uinea-pig skin.
The microernulsions of the invention are indicated for use in the percutareous admin1stration c~pharnnacologicall~Y active agents becallse of the skin penetrat;on - -' enhancing e-Ffects~and the capacity of the skin microemu'lsions to contain large amounts OT pharmacologi-cally acti~/e agents.
The skin~p~netration enhancing effect may be observed in standard in vitro and in vivo tests for example using 2Q human skin.
One in vitro test is the wel'l~known diffusion test which may be effected according to the principles described by H.Schaeffer et al in Adv.Pharmacol.Ther.CProc.7th Int.
Congr .Phalmacol.~ 9 223-235 (1978) ed by Y.Cohen Pergamon 0x-ford (1979); H.Schaeffer et al pp.80-94 in Current Problems in Dermatolo~y 7 Ed. G.A.Simon et al.
Karger Basel (1978) and J.M.Franz et al Arch. Dermatol.
Res.(1981) 27'l:275-282 using isolated human sk-in.
L~
- 1 ~3 ~ 1 00 '~i5J2 ~icroemuision~ ~Yit.h the ph~rlnacolocJically ac-ti~e ayent in rcldio-active labelled form are applied to isolatetl pieces o~ unbrol~en human al?dominal slcin of about 2 square centimetres in area ~ at; an amol~nt of about 5 to S about 10 mg of microelllulsion per square centimetres.rile s~in is maintained at 32C as a barrier bet~een an upper chamber and physiological saline placed in a lower chamber.
After 100 3nO and 1000 minlltes at 32C the skin is -fixed on a stopper.The residue is removed from the skin surface lO by a COttOil swab and the radioac-tivity measured.The horny layer is removecl by stripping and the radioactivity is de-termined in each individual stripping.Th~ remainin~ skin is congealed and sliced into sections of about 20 4n~u with a mic,-otome.. The radioactivity in the various slices 15 is determined.l~he radioactivity in a~uous saline in contact with the underside o the skin is also measured.
Since the penetration of the pharmacologically active agent through the horny layer represents in general the rate limiting step the amount of pharmacologically active agent -20 that has passed the horny layer is relevant to the syste mic activity.This fraction of pharlnacologically active agent contained in the different dermal layersti.e. epi-dermis,upper corium (ca ~00 microns tllic~) lo~er corium - (ca 1000 micron~ thick) and sub-cutis (ca 1500 microns 25 thick)~ould in vivo be removed by the capillary system into the blood stream and hence into the general circula-tion.
For convenience the fraction of the pharmacologically active agent that has penetrated t~e horny layer after 16 30 hours and is presen-t in the deeper dermal layers is measured to give a mean percutaneolls penetration flux (F) on the basis of a number of trials (n) as well as a per cutaneous resorption quota in % o~ the applied dose (RQ).
3~
I 00-55~2 Res~llts obtained .re as ~ollo\lls:^
Exampl e No F (0-16 hours ) X 1 OS
M 1 ~ 2 1 -1 n R Q ( % ) - 1 2.~ + 0.5 8 24 3 1.4 + 0.3 20 14~
4 ca 1 . G 4 1 3~io ca 2,6 . ~ 2`1%
13 1.3 l~0.01 12 12,' 1~ 1.7 +l).7 8 12%
1 0 1 7 c a 1 . 2 4 1 5 G,,/
18 ca 1.~ 4 25%
cc~ 1,3 4 12 1.6 + 0.6 8 13~
* The examples are 1 isted hereinafter. .
-20- 1~0-5532 In vi~o trials may be efrec.ed e.g. incllldin~ a conlparativt? oral and ~ercutaneo~ls a~lmin;st~ation of the pharnlacolo~ical`ly acti~e a~ent in a cross-over stu~y~in a healthy sublect.
In on~ study ~180 In~ of a micro~lnulsion in th~ form of a gel as clescribed in Exalllple 1 containing 40 mg of active agent tizanidine was applied behind the ear or a tablet containing 4 m3 tizanidille was ad,~ istered orally The urine ~as collected over 72 hours alld tlle anlount of unchansed acti~e agent and correspo~id ng -~wo metabolites were measured separately.
The results obtain2(l were as follo~1s:
Period al^~er unchanged drug after unchall~ed drug af~er administration oral administration percu~aneous admini-[Jug/hr~ -.stration [Jlg/hr]
0-2 3.08 0.03 2-4 1.61 1.01 4-6 0.53 1.~'1 20 6-8 0.24 1.33 8-12 0.04 3.36 12-24 --- 4.16 24-36 --- 2.54 36-48 --- 1.57 25 48-60 --- 1.10 ~0-72 --- 1.07 Cumulative % absorption oral percutaneous of tizanidine 0.28% 0.37 %
of lletabolite A 2. 5 ~ 0.4 %
of l~ietabolite R 1.1 ~ 0.16 ~
-21- 100-~553~
The abo~e reslllts confirm the signi~icani; percutdneous absnrpiicll ob~ailleci in tl~e -in vicro tests~ and indicate a - ~ sustain~d- release effec'c.
Additionally the relatively lo~er amQullt oF metabol-ite S found indicates a si~nificantly lower first pass effect.
100 m~ of the clemastine composition of Example 3 (con-taining 10 mg clemas-tille) is applied behind the ear oF
2 or 3 sub~iects (age 1~. to 38 yeans) corresponding to an amount of active agen~ of 10 my of clemastine.
The amount of acrive agen~ in the urine is delermined accordin~ to t.he principles of R~Tham.Arzrleim.F'orsch.
(1978) 2~ 1017.
Period after active a~ent in' administratioil urine~ly/hr~ Subjects hours 0-6 -~ 3 5-8 0.~86 + 0.164 3 `3-12 0.890 + 0.3g4 3 12-24 1.042 + 0.621 3 24-36 1.101 + 0.422 3 36-48 1.469 + 0.455 3 48-i~0 0.504 + 0.211 2 : 60-72 0.231 + 0.05 2 c~ Cumular.ive elinlination of unchany'ed'drug ~.664 ~ O.lS3 In comparison 2 m~ of' clemastine gi~en oral'ly over 72 hours yield 7.10% 1. a.~6o,0 of the ullcllcinyed drug in the urine.
The results show an excellent effect ~lith -the m~ximum concertration in the urine occunrin~ 3~ hours after admirli-stration and a resorp'cion quota of al~o!!t 10~ of the clemastine topically a~ministered.
-22- 1 00-55~2 As indicated. by ~he above resul~:s the mi-roelnulsions of the present inventiorl may produce systernic action O'f the pharmacolo~Jically active agellt.In particular ~Ye have surprisingl~\~ foulld that topical admin;stration of tiza-nidine is -feasible.
The present invent;on accordingly provi(les a top-ical pharmaceutical composition containil-g tizanidine as active agent.In another aspect the present invention provides a nlethod of topically adlnin;steriny tizanidine Q to a subject in need of such treatment.
The penetration rate observed may thus be at least in the order of 1 to 3 x 10 S Mole cm 2 hour 1 to produce a systemic action and in the orcler of about i x 10 9 r~lole cm~2 hour 1 to produce local action in ti~e deeper dermal layers and the concentration of pharmacologically active agent in the microemulsion:may be chosen accor~
dingly.
The amount of pharmacologically active agent to be admini-stered in the microemulsions of the present invention ~
depend inter alia on the penetra-tion rate o-F the pharma-cologically active agent observed in the in vitro or in vivo tests the potency of the active agent the size uf the skin area treated with the microemulsion~ the part of the body treated and the duration of action -- required.
In ger,eral a suitable daily ciose is about from 5 to 20 `times the dose ef-fective in oral or topical administration~
and the dose rnay be increaâed i-f longer duration than 1 day is required.
In general a suit:able application area is from about 1 to about 4 square centimeters.fhe microemulsions of ~he in vention may be applied in conventional manner.
-23- lQO-~532 In the case of li~uid preplratiolls ~he microemlllsion cal be applied for eXdm~le fr~ plexi~lass col)t~ er in cor~tact ~litll e.g. the uppen arm or f~om a plaster soa~ed ~ h the n~icroelllulsion placed e.g.behind the ear.In the case of semi solid microgels these may be rubbed in the skin.
For exall~ple in the case of tizanidille and clemastine a suitable sin~le dose is froln lQ to 50 mg~and this may last for Ilp -;:o 3 d3ys.
The microemuls-ions of the inventicll may b2 used for the same indica-tion that other forms of the pharlnacelltical'lY active agents are used for e.s. cle~a~tine as an anti-histalllille agen-t and ~izanicline as myotonolytic anti-depressant nr minor tranquilli~er.
The microelnulsiorls o-f the invention may en!lance the penetration of the pharmacologically active agent which is accumulated in the horny layer of the epidermis. A depot ef-ect may then result wher~upon lS the pharmacolo3ically active agent slo~lly passes into the systemic circulation ~/ithout inactivation by the liver resulting in a long-lasting concentration of ac-tive agent in the blood (retard effect).
The blood cor.centration ach;eved by percutarJeous delivery may be characteri7.ed by the absence of an initial dr~lg concentration blood 2Q peak in contras' to oral administration.Side effects may be minimiJeci.
Additionally t:he accumulated pharmacologically active a~ent ir the horny layer may p~ovide a local effect if the pharmacologically active agent is locally active.
The microemulsions of the invention may in general possess -signifi-cant other advanlages over macroernulsions.For example they may in general be thermodynamically stable~and sho~ litt'le or no coalescerle.
In general the microelrulsions of the invention have good spreading properties on the skin surface.They don'-t in general stick to the - surface of the skin but may be easily rllb~ed in.They may lea~Je little greas~ '`feeling behind and may be l~lashed off with water if desired. The skin may not be significantly dehydrated as the s;ngle ~ater con~aining phase may be easily available to the skin.
~ 3~
~2~- 100-5532 I
The following Examples illustr~te the invention:-Poly~xye~hylene-(10)-oleyl ether is for example either BRIJ 97 having an HLB value of 12.~ available from Atlas~ Essen, W.Germany, or YOLPO~10 having an HLB va1ue of 12.4 available from Croda, Humberside,~UK~
Polyeth~ylene glycol glycero~ -fatty acid ester ;s for example brand Labrafi ~ M 19445a~ailable from Gatte-fosse, Boulogne, France. ~
Hexyllaurate is for example brand CETIOL A, available from Henkel, D-usseldorf..
Polyethylene~lycol-~7)-glyceryl cocoate is for example brand CETIOL HE available from Henkel, Lactic acid is a 90g pure aqueous solution Colladerm~350 is a zinc salt of highly purified collagen-derivedcosmetic medium molecular weight polypeptide available from Stepan Chemical Company, Northfield, Ill, USA~ ~
Lauryl lactate is for example brand Ceraphyl 31, and 20 myristyl lactate is for example brand Ceraphyl~50 from Van Dyk, Belleville, N~J.,USA.
~1 Further details on these products can be obtained from Fiedler H.P.Lexikon der Hilfsstoffe Fur Pharmazie~ Kos-metik und angrenzende Chemie, 2nd Edition, Editor Cantor~
-2~- 10~-5532 EXA~lPLE ONE: Ti ~:An i di ne microgel 500 9 oF a n~ tllre having the following composition :-Per cent Ti2anidine 8.2 5 Isopropyl laurate 20.5 Polyoxyetllylene (10~
oleyl ether 20.5 (BriJ 97) nodecanol 6.5 Water 41.0 10 Lactic acid 3,3 are made and ~I!armerl by a water bath at. about 90C. Themixture is allo\~ed to cool to rOO`TI telTlperatUre ~y cooling the water 1C per minute.
As the mixture is coolecl various dil`ferent phases are ob served as follows:-P_ase TemDeratu~e Milky macro-emulsion 92-72GC
Transitional light cloudy 72-70GC
phase Microemulsion transpa-rent phase 70-66C
Transitional light cloudy 66-63C
phase Microemulsion transparent phase 63-51C
Transitional light cloudy phase 51-46~C
Microemulsion transparent phase 46G--room temperature The cooled gel is filled into metal tubes.
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~ ~0 ~9~r96 * Table or pharmacologically active a(Jents 1 . ( E ) -N-m~? th~yl N- ( 1 -naphl:hyl metllyl ) -3-phenyl -propen-2-yl ami ne .
2 . (~ methyl -2~ [2- (c~ -me l;hyl p-chl orodi phenyl -methGxy) -ethyl ]-pyrrol i d i ne .
3. 5-chloro-4-~2-imidazol ;n-2-ylal11ino)-2~1 ,3-benzoth ia-di azol e.
4. 4-(l-methyl-4-piperidylidene)-41t-ben7o[4,5:1cycloneD-ta[l ,2-b]thiophen-10(9H~-one.
5. 4-(1-methyl-4-piperidylidene)-9,10-dihydro-4H-benzo-(4,5)-cyclohep-ta~(l ,2-b)-thiophene.
~ . Gri seo ~ul vi n .
7 . Fl uoci nol one acetoni de .
8 . Tri amci nol one ace-toni de .
9 14-0-[5-(2-amino-1 ,3,4-triaznlyl )thioacetyl~-dihydrn-mu t i 1 i r, e t al so kno~n a s 14- [5-am i no 4H-1, 2 ,4-tri azol -3-y i ) -thi o-acetoxy]-l 4 -deoxy-l 9, 20-di hydromuti 1 i n .
**Table of con1mercidl products A GRIJ 97 HL13 value 12.4 (ATLAS) B VOLPn 10 HLB `vallle 12.4 (C~ODA) 20 C CETIOL HE (HENKEL) D LAFABRIL l9~Y-S(GATTEFOSSE) Colladerrn 350: A solution of a ~n salt of a highly puri-fi ed cosmeti c pol ypepti de of col 1 a gen (STEPHAN CHEMICAL COMPANY).
Preferably the emulsifiers haYe an HLB value of from 12 to 15 (HLB values are an indication o-f the hydrophilic lipophilic balance in an emulsifier and have been dis-cussed extensively in the literature, see for example Pharm.Act.Helv. (19~9) 44,~ and H.P.Fiedler, Lexicon der Hilfs`stoffe fiir Pharmazie, Kosmetic und angrenzende Ge biete, 2nd Edi~ion, 1981 ~ Editio Cantor AG, BP~n).
A preferred example of class 9) is commercially available polyoxyethylene-(10)-ol.eyl ether.
Prefer2bly tile microemulsions are made up from excipients from class 1) ancl 2) as water-immiscible or~anic solvents;
especially class l); class 7) as co-emulsifier and class 9) as emulsifier.
The exact choice of organic solvent, emulsifier and co-emulsifier ~/ill depend 011 inter alia the pharmacolQgically active agent used.
The pharnlacologically active agent may be any compound ~hic~n . penetrate the skin horny layer, 10 e.g. of molecular weight up to about 3,000, although higher molecular ~leight compounds may possibly be used.
In general the molecular weight of the pharmacologically active agent is cor,veniently below 1000. Conveniently the active agent has a good hydrophilic/lipophilic balance.
15 The molecule of the active agent for example may be cor,-veniently structurally compact, may contain aromatic groups and conveniently does not con-tain-many reactive groups such as hydroxyl groups The microe~ulsions of the invention are capable of con~-2Q taining ~ery high amounts of active agents,e~g. from 5%up to 15% or even up to 20% of the total we;ght.When a systemic ~ction ;s desired, the pharmacologically active agent should be sufficiently active to be able co produce a systemic therapeutic ef-fect when penetration the skin at 25 rates of the order of 10 8 Mole cm ~ hour 1. When a local action in the deeper dermal layer is required, then a skin penetration flux of 10 9 Mole cm 2 hour 1 may be suf-ficient.
Suitable a~ents may be for example those li-th an,e.g.oral~
daily dose of about 0.1 to about 20 mg, preferably up to 30 1 mg.
~ 100-5532 The microemulsion~ of tlle inv2lltion may be indicated fon the sy~e-n~ic administration of any acti~e agellt.Theylllay be conveniently used for propllylactic agents and nmyotonolytics.The microen1~l1sions of the invention may be indicated for the adminis-tration of pharma-cologica~ly ac-~ive agents which act under the honny 1ayer~e.g.anti~
acne agents and anti-funsal agents.
Examples of active agents include (Ej-N-methyl-5,6-dimethyl-N-(naphthylmethyl)hept-2-en 4-inyl-l-amine, proquazone, (E)~N-meth~l-N-~l-nap)lthylnletilyl)-3-phenyl-propen-2-yl-amine (hereinafter naftifin), 4-(1-methyl-4-piperidylidene~-4H-benzo[4,5]cyclollepta-[1,2-b]thiophen-lQ(9H)-one (hereinafter ketotifen), 4~(1-methyl-4-piperidylidene)-9,10-dihydro-4H-benzo-(4,5)-cyclohep-ta(1,2-b) thiophelle (hereinafter pizoti-fen),-griseofulvin, fluocinolone acetonide, Tr-iam-cinolone acetonide, and 14-0-[5-(2-amino-1,3~4-triazol-yl)thioacetyl]-dihydro-mutiline, and preferably (~)-l-methyl-2-[2-(c~-methyl-p-chlorodiphenyl-methoxy)-ethyl]-pyrrolidine (hereinafter clemastine) and especially 5-chloro-4-(2-imidazolin-2-ylamino~-2,1,3-benzothiadiazole (hereinafter tizanidine) In respect of clemastine a microern~llsion preferably con-tains any of the following concentrations:-5 to 15% of clemastine.5 to 30% of an ~ater-immiscibleorganic solvent~
15 to 25% of an emulsifier.
5 to 25% of a co-emulsifier..
10 to 45% of water.
More pre,erably a microemulsion contain~ any of the following concentrations:-7.5 to 12.5% of clemastine~
7.5 to 28.5% of water~imnliscible organic solvent~
i9.5 to 22% of an emulsifier~
7.5 to 22.5C/~ of a co-emulsifier~
13 to 42~ of water . .
~ore especially a clemastine microen1ulsion contains any of the follo\~ing concentratinns:-8 to 12~ of clemastine.
8 to 27'~ of ~ater-immiscible organic solvent.
5 20 to 21% of an emlllsifier.
8 to 21%:of a co-emulsifier.
15 to 40~ of ~Yater.
The excipients are preferably chosen from class (1) as defined above, as organic solvent.
The excipients o~ class (3) as defined ahove may be pre-sent as or~anic solvent or co-emulsiFierfespeciall~ pro-pylene glycol mono-laulate~Ti!e co-emulsifier alternatively is an excipien~ of class (5) as defined aboYe espec;ally poly(7)ethylene gliycolylyceryl cocoate~or propylene glycol myristate. The preferl-ed emulsifier -is chosen from class (9) as defined above, especially polyoxyethylene (10) oleyl ether e.g. having an HLB value of about 12 to 13.
With clemastine microgels containing hiyh concentrations of clemastine can be produced whereas it is very diffi-cult to produce stable macroemulsions con-taining such high clemastine concentrations.
In the respect of tizanidine a microemulsion preferably contains any of the following concentrations:-6 to 10% of tizanidine.
15 to 25% of ~Yater-immiscible orgar,ic solvent.
15 to 25% of an emulsifier.
5 to 10% of a co-emulsifier.
30 to 35% of water.
Pr2ferably the microenlulsion contains any of the follo~ing concentrations:-7.5 to 8.5% o~ tizani di ne~
19.5 to 21.5% of water-i~miscible organic sblventO
19 to 22% of an emlllsifier~
5.5 to 21 5% of a co-emulsifier 3~ to 42~ Of water.
More particularly the microemuls;on contains any of the following concentratiorls:
lC 8 to 8.4% of tizallidine~
20 to 21% of water-immiscible organic solventO
20 to 21% of an ~muls-ifier~
6.2 to 8.4~% of a co-emulsifier~
33 to 42% Of water Naturally the choice of ~Yater-in~misci6le organic solvent 7 emulsifier and co-emulsifier for a microemulsion system will vary from pharmacologically active agent to pharmacologically active agent and in some cases a particular excipient may be suitable in one system as e.g. an wa~er~imlniscible organic solvent and in another system as an e.g. co-emulsifier.
The pH of the pharmaceutical composition may be adjusted to a skin compa-tible pH with appropriate acids or bases preferably weak acids or bases e.g. lactic or acetic acid.
It is preferred that the pharmacologically active agent is at least partially present in free form e.g. free base form/as the skin penetration may be increased. Con-veniently the pH of the micrGemulsions are weakly acidic.
Other skin compatible agents may be present e.g. water~
imiscible solvents such as propylene glycol~and ethanol -17- 1()0~553 and isopropanol or ~ater so'luble film-formillg a~ents used in cocnl2tic preparations e.g. par-tially hydro-lysed colla~enyieldill~ medlum-weight polypeptides to diminish solvellt evapora~ioll after ru~bing on the skin.
S Naturally the microelllulsion should be compc~sed of com-ponents that are skin compatible. The components should be non~toxic non-allergic and well--tolerated by the skin tissue. Such components can be chosen by stalldard acute and chronic tests.
The tests may be effècted on hulnan skin or ~ ch mol^e sen-sitive animal skin~e.~. ~uinea-pig skin.
The microernulsions of the invention are indicated for use in the percutareous admin1stration c~pharnnacologicall~Y active agents becallse of the skin penetrat;on - -' enhancing e-Ffects~and the capacity of the skin microemu'lsions to contain large amounts OT pharmacologi-cally acti~/e agents.
The skin~p~netration enhancing effect may be observed in standard in vitro and in vivo tests for example using 2Q human skin.
One in vitro test is the wel'l~known diffusion test which may be effected according to the principles described by H.Schaeffer et al in Adv.Pharmacol.Ther.CProc.7th Int.
Congr .Phalmacol.~ 9 223-235 (1978) ed by Y.Cohen Pergamon 0x-ford (1979); H.Schaeffer et al pp.80-94 in Current Problems in Dermatolo~y 7 Ed. G.A.Simon et al.
Karger Basel (1978) and J.M.Franz et al Arch. Dermatol.
Res.(1981) 27'l:275-282 using isolated human sk-in.
L~
- 1 ~3 ~ 1 00 '~i5J2 ~icroemuision~ ~Yit.h the ph~rlnacolocJically ac-ti~e ayent in rcldio-active labelled form are applied to isolatetl pieces o~ unbrol~en human al?dominal slcin of about 2 square centimetres in area ~ at; an amol~nt of about 5 to S about 10 mg of microelllulsion per square centimetres.rile s~in is maintained at 32C as a barrier bet~een an upper chamber and physiological saline placed in a lower chamber.
After 100 3nO and 1000 minlltes at 32C the skin is -fixed on a stopper.The residue is removed from the skin surface lO by a COttOil swab and the radioac-tivity measured.The horny layer is removecl by stripping and the radioactivity is de-termined in each individual stripping.Th~ remainin~ skin is congealed and sliced into sections of about 20 4n~u with a mic,-otome.. The radioactivity in the various slices 15 is determined.l~he radioactivity in a~uous saline in contact with the underside o the skin is also measured.
Since the penetration of the pharmacologically active agent through the horny layer represents in general the rate limiting step the amount of pharmacologically active agent -20 that has passed the horny layer is relevant to the syste mic activity.This fraction of pharlnacologically active agent contained in the different dermal layersti.e. epi-dermis,upper corium (ca ~00 microns tllic~) lo~er corium - (ca 1000 micron~ thick) and sub-cutis (ca 1500 microns 25 thick)~ould in vivo be removed by the capillary system into the blood stream and hence into the general circula-tion.
For convenience the fraction of the pharmacologically active agent that has penetrated t~e horny layer after 16 30 hours and is presen-t in the deeper dermal layers is measured to give a mean percutaneolls penetration flux (F) on the basis of a number of trials (n) as well as a per cutaneous resorption quota in % o~ the applied dose (RQ).
3~
I 00-55~2 Res~llts obtained .re as ~ollo\lls:^
Exampl e No F (0-16 hours ) X 1 OS
M 1 ~ 2 1 -1 n R Q ( % ) - 1 2.~ + 0.5 8 24 3 1.4 + 0.3 20 14~
4 ca 1 . G 4 1 3~io ca 2,6 . ~ 2`1%
13 1.3 l~0.01 12 12,' 1~ 1.7 +l).7 8 12%
1 0 1 7 c a 1 . 2 4 1 5 G,,/
18 ca 1.~ 4 25%
cc~ 1,3 4 12 1.6 + 0.6 8 13~
* The examples are 1 isted hereinafter. .
-20- 1~0-5532 In vi~o trials may be efrec.ed e.g. incllldin~ a conlparativt? oral and ~ercutaneo~ls a~lmin;st~ation of the pharnlacolo~ical`ly acti~e a~ent in a cross-over stu~y~in a healthy sublect.
In on~ study ~180 In~ of a micro~lnulsion in th~ form of a gel as clescribed in Exalllple 1 containing 40 mg of active agent tizanidine was applied behind the ear or a tablet containing 4 m3 tizanidille was ad,~ istered orally The urine ~as collected over 72 hours alld tlle anlount of unchansed acti~e agent and correspo~id ng -~wo metabolites were measured separately.
The results obtain2(l were as follo~1s:
Period al^~er unchanged drug after unchall~ed drug af~er administration oral administration percu~aneous admini-[Jug/hr~ -.stration [Jlg/hr]
0-2 3.08 0.03 2-4 1.61 1.01 4-6 0.53 1.~'1 20 6-8 0.24 1.33 8-12 0.04 3.36 12-24 --- 4.16 24-36 --- 2.54 36-48 --- 1.57 25 48-60 --- 1.10 ~0-72 --- 1.07 Cumulative % absorption oral percutaneous of tizanidine 0.28% 0.37 %
of lletabolite A 2. 5 ~ 0.4 %
of l~ietabolite R 1.1 ~ 0.16 ~
-21- 100-~553~
The abo~e reslllts confirm the signi~icani; percutdneous absnrpiicll ob~ailleci in tl~e -in vicro tests~ and indicate a - ~ sustain~d- release effec'c.
Additionally the relatively lo~er amQullt oF metabol-ite S found indicates a si~nificantly lower first pass effect.
100 m~ of the clemastine composition of Example 3 (con-taining 10 mg clemas-tille) is applied behind the ear oF
2 or 3 sub~iects (age 1~. to 38 yeans) corresponding to an amount of active agen~ of 10 my of clemastine.
The amount of acrive agen~ in the urine is delermined accordin~ to t.he principles of R~Tham.Arzrleim.F'orsch.
(1978) 2~ 1017.
Period after active a~ent in' administratioil urine~ly/hr~ Subjects hours 0-6 -~ 3 5-8 0.~86 + 0.164 3 `3-12 0.890 + 0.3g4 3 12-24 1.042 + 0.621 3 24-36 1.101 + 0.422 3 36-48 1.469 + 0.455 3 48-i~0 0.504 + 0.211 2 : 60-72 0.231 + 0.05 2 c~ Cumular.ive elinlination of unchany'ed'drug ~.664 ~ O.lS3 In comparison 2 m~ of' clemastine gi~en oral'ly over 72 hours yield 7.10% 1. a.~6o,0 of the ullcllcinyed drug in the urine.
The results show an excellent effect ~lith -the m~ximum concertration in the urine occunrin~ 3~ hours after admirli-stration and a resorp'cion quota of al~o!!t 10~ of the clemastine topically a~ministered.
-22- 1 00-55~2 As indicated. by ~he above resul~:s the mi-roelnulsions of the present inventiorl may produce systernic action O'f the pharmacolo~Jically active agellt.In particular ~Ye have surprisingl~\~ foulld that topical admin;stration of tiza-nidine is -feasible.
The present invent;on accordingly provi(les a top-ical pharmaceutical composition containil-g tizanidine as active agent.In another aspect the present invention provides a nlethod of topically adlnin;steriny tizanidine Q to a subject in need of such treatment.
The penetration rate observed may thus be at least in the order of 1 to 3 x 10 S Mole cm 2 hour 1 to produce a systemic action and in the orcler of about i x 10 9 r~lole cm~2 hour 1 to produce local action in ti~e deeper dermal layers and the concentration of pharmacologically active agent in the microemulsion:may be chosen accor~
dingly.
The amount of pharmacologically active agent to be admini-stered in the microemulsions of the present invention ~
depend inter alia on the penetra-tion rate o-F the pharma-cologically active agent observed in the in vitro or in vivo tests the potency of the active agent the size uf the skin area treated with the microemulsion~ the part of the body treated and the duration of action -- required.
In ger,eral a suitable daily ciose is about from 5 to 20 `times the dose ef-fective in oral or topical administration~
and the dose rnay be increaâed i-f longer duration than 1 day is required.
In general a suit:able application area is from about 1 to about 4 square centimeters.fhe microemulsions of ~he in vention may be applied in conventional manner.
-23- lQO-~532 In the case of li~uid preplratiolls ~he microemlllsion cal be applied for eXdm~le fr~ plexi~lass col)t~ er in cor~tact ~litll e.g. the uppen arm or f~om a plaster soa~ed ~ h the n~icroelllulsion placed e.g.behind the ear.In the case of semi solid microgels these may be rubbed in the skin.
For exall~ple in the case of tizanidille and clemastine a suitable sin~le dose is froln lQ to 50 mg~and this may last for Ilp -;:o 3 d3ys.
The microemuls-ions of the inventicll may b2 used for the same indica-tion that other forms of the pharlnacelltical'lY active agents are used for e.s. cle~a~tine as an anti-histalllille agen-t and ~izanicline as myotonolytic anti-depressant nr minor tranquilli~er.
The microelnulsiorls o-f the invention may en!lance the penetration of the pharmacologically active agent which is accumulated in the horny layer of the epidermis. A depot ef-ect may then result wher~upon lS the pharmacolo3ically active agent slo~lly passes into the systemic circulation ~/ithout inactivation by the liver resulting in a long-lasting concentration of ac-tive agent in the blood (retard effect).
The blood cor.centration ach;eved by percutarJeous delivery may be characteri7.ed by the absence of an initial dr~lg concentration blood 2Q peak in contras' to oral administration.Side effects may be minimiJeci.
Additionally t:he accumulated pharmacologically active a~ent ir the horny layer may p~ovide a local effect if the pharmacologically active agent is locally active.
The microemulsions of the invention may in general possess -signifi-cant other advanlages over macroernulsions.For example they may in general be thermodynamically stable~and sho~ litt'le or no coalescerle.
In general the microelrulsions of the invention have good spreading properties on the skin surface.They don'-t in general stick to the - surface of the skin but may be easily rllb~ed in.They may lea~Je little greas~ '`feeling behind and may be l~lashed off with water if desired. The skin may not be significantly dehydrated as the s;ngle ~ater con~aining phase may be easily available to the skin.
~ 3~
~2~- 100-5532 I
The following Examples illustr~te the invention:-Poly~xye~hylene-(10)-oleyl ether is for example either BRIJ 97 having an HLB value of 12.~ available from Atlas~ Essen, W.Germany, or YOLPO~10 having an HLB va1ue of 12.4 available from Croda, Humberside,~UK~
Polyeth~ylene glycol glycero~ -fatty acid ester ;s for example brand Labrafi ~ M 19445a~ailable from Gatte-fosse, Boulogne, France. ~
Hexyllaurate is for example brand CETIOL A, available from Henkel, D-usseldorf..
Polyethylene~lycol-~7)-glyceryl cocoate is for example brand CETIOL HE available from Henkel, Lactic acid is a 90g pure aqueous solution Colladerm~350 is a zinc salt of highly purified collagen-derivedcosmetic medium molecular weight polypeptide available from Stepan Chemical Company, Northfield, Ill, USA~ ~
Lauryl lactate is for example brand Ceraphyl 31, and 20 myristyl lactate is for example brand Ceraphyl~50 from Van Dyk, Belleville, N~J.,USA.
~1 Further details on these products can be obtained from Fiedler H.P.Lexikon der Hilfsstoffe Fur Pharmazie~ Kos-metik und angrenzende Chemie, 2nd Edition, Editor Cantor~
-2~- 10~-5532 EXA~lPLE ONE: Ti ~:An i di ne microgel 500 9 oF a n~ tllre having the following composition :-Per cent Ti2anidine 8.2 5 Isopropyl laurate 20.5 Polyoxyetllylene (10~
oleyl ether 20.5 (BriJ 97) nodecanol 6.5 Water 41.0 10 Lactic acid 3,3 are made and ~I!armerl by a water bath at. about 90C. Themixture is allo\~ed to cool to rOO`TI telTlperatUre ~y cooling the water 1C per minute.
As the mixture is coolecl various dil`ferent phases are ob served as follows:-P_ase TemDeratu~e Milky macro-emulsion 92-72GC
Transitional light cloudy 72-70GC
phase Microemulsion transpa-rent phase 70-66C
Transitional light cloudy 66-63C
phase Microemulsion transparent phase 63-51C
Transitional light cloudy phase 51-46~C
Microemulsion transparent phase 46G--room temperature The cooled gel is filled into metal tubes.
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%L-Z pL~e ~L~3eL %Z Lb%9 oz-3uaL~'~f3~xo~iod ~ 9 9 loue~3poa'q9 OZ L~do~dosI %~-8 S 8L
. _ . .. _ ' 3 ~
~-r ~
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V.~*
%06,l3~3~a LA3L0-Ol _ ~ pLoe ~L~ %S 5~ %s oz-au~!~u~a~xot;lod %0-8 Loue~3pel~a~ S CZ a~ elL~c~sL~w %Z 8 ~ . 9;.
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,~ ~ PL~ ~L'~eL %0 Lb %s-oz-~uaLt~lfa~sxo~lod %S 9 Loue~pe~.a~ 5-oz afe~eL!~Ine^i %Z 8 ~ S!
C~ % 3 % q ~ % ~' N
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-~n- loo 5~;32 r rv r~rv r~ X
~~ ~ rv ru rD
r~
r~ ~j~ ~ t r~
--' O ~ 5 r,~
r~ rv a~ ~ ~t--r~Dt C~ r~ g -; g -5 c-t I c~ -s G ~ ~
_; ~ J. ~
'-) X O C-t '' O -- O --? r ct C~ O ~ O ::5 0 r,~ ;nD -- I r,~ ~ rD ---t ~ _ J c Q r~
~ l ~ l c_ c--t rv rv C~ ~.n ., . ... . , _ , ~
1~ r=~ ~ 3 o X' 0 3 o r ~ ~C r? ~ ~ C r, O O n ~D rD v~
r I ~C r~ C
~ rv l ~ r~a c~
:~ o o ~ o o ~ O o . ~ c> o r-l D I -- D I ~ D I ~ j D ~ ~ -O ~C O ~ O ~ O '~
r~ D rD ~ ~ r~
~C ~ ~ C ~ ~ ~ -~
--r~ --~ --r --~ c-- ~ -D ~-- c~ r t r~ cV ~ r~> n r" r~
S ~ S S S ::~ ! S ~S - .
~D rD rD ~ r.~
rV r~ r~: rv O O o ' O
ul u ~ ~ ~ .
-- '~D C -- :~ Q_ ~ r D C-t O ~ ~D r.~ X
O O o r3~ n ~ , c~ ~
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n r~ ; ' r.~
~ 'T P~
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--- ~
C, (~ ~ I
ci~
~ ~0 ~9~r96 * Table or pharmacologically active a(Jents 1 . ( E ) -N-m~? th~yl N- ( 1 -naphl:hyl metllyl ) -3-phenyl -propen-2-yl ami ne .
2 . (~ methyl -2~ [2- (c~ -me l;hyl p-chl orodi phenyl -methGxy) -ethyl ]-pyrrol i d i ne .
3. 5-chloro-4-~2-imidazol ;n-2-ylal11ino)-2~1 ,3-benzoth ia-di azol e.
4. 4-(l-methyl-4-piperidylidene)-41t-ben7o[4,5:1cycloneD-ta[l ,2-b]thiophen-10(9H~-one.
5. 4-(1-methyl-4-piperidylidene)-9,10-dihydro-4H-benzo-(4,5)-cyclohep-ta~(l ,2-b)-thiophene.
~ . Gri seo ~ul vi n .
7 . Fl uoci nol one acetoni de .
8 . Tri amci nol one ace-toni de .
9 14-0-[5-(2-amino-1 ,3,4-triaznlyl )thioacetyl~-dihydrn-mu t i 1 i r, e t al so kno~n a s 14- [5-am i no 4H-1, 2 ,4-tri azol -3-y i ) -thi o-acetoxy]-l 4 -deoxy-l 9, 20-di hydromuti 1 i n .
**Table of con1mercidl products A GRIJ 97 HL13 value 12.4 (ATLAS) B VOLPn 10 HLB `vallle 12.4 (C~ODA) 20 C CETIOL HE (HENKEL) D LAFABRIL l9~Y-S(GATTEFOSSE) Colladerrn 350: A solution of a ~n salt of a highly puri-fi ed cosmeti c pol ypepti de of col 1 a gen (STEPHAN CHEMICAL COMPANY).
Claims (43)
1. A skin penetration pharmaceutical composition incorp-orating a skin-penetrable pharmacologically active agent, wherein the composition is in the form of a microemulsion formed from skin compatible excipients.
?. A composition as claimed in claim 1 wherein the composition is in the form of a microgel.
3. A composition as claimed in claim 1 wherein the active agent is a difficultly skin-penetrable active agent.
4. A composition as claimed in claim 3 comprising from 5 to 30% by weight of a water-immiscible skin compatible solvent.
5. A composition as claimed in claim 1, 2 or 3 containing from 4 to 30% by weight of a skin compatible emulsifier.
6. A composition as claimed in claim 1, 2 or 3 comprising 10 to 30% by weight of a skin compatible coemulsifier.
7. A composition as claimed in claim 1, 2 or 3 comprising 15 to 55% by weight of water.
8. A composition as claimed in claim 1 containing 0.01 to 15% by weight of skin-penetrable pharmacologically active agent.
9. A composition as claimed in claim 8 containing from 5 to 15% by weight of skin-penetrable pharmacologically active agent.
10. A composition as claimed in claim 1 containing a skin compatible ester of an aliphatic (C3-18) alcohol with an aliphatic (C10-22) carboxylic acid.
11. A composition as claimed in claim 10 wherein the ester is chosen from isopropyl laurate, hexyl laurate, decyl laurate, isopropyl myristate and lauryl myristate.
12. A composition as claimed in claim 10 wherein the ester is isopropyl laurate, hexyl laurate or isopropyl myristate.
13. A composition as claimed in claim 10 wherein the ester is hexyl laurate.
14. A composition as claimed in claim 1 containing a skin compatible hydrocarbon having a straight carbon (C12-32) chain substituted by from 6 to 16 methyl groups and having up to 6 double bonds.
15. A composition as claimed in claim 14 containing squalane.
16. A composition as claimed in claim 1 containing a skin compatible mono-ester of ethylene glycol or propylene glycol with an aliphatic (C6-22) carboxylic acid.
17. A composition as claimed in claim 16 wherein the ester is propylene glycol monolaurate or propylene glycol monomyristate.
18. A composition as claimed in claim 1 wherein the ester is a skin compatible ester of an aliphatic (C12-22) alcohol with lactic acid.
19. A composition as claimed in claim 18 wherein the ester is myristyl lactate or lauryl lactate.
20. A composition as claimed in claim 1 containing a skin compatible aliphatic (C12-22) alcohol.
21. A composition as claimed in claim 20 wherein the alcohol is dodecanol, tetradecanol, oleyl alcohol, 2-hexyl-decanol or 2-octyldecanol.
22. A composition as claimed in claim 20 wherein the alcohol is dodecanol.
23. A composition as claimed in claim 1, 2 or 3 contain-ing a skin compatible ester of a poly(2-7)ethylene glycol glycerol ether having at least one free hydroxyl group and an aliphatic (C6-22) carboxylic acid.
24. A composition as claimed in claim 23 wherein the ester is poly(7)ethylene glycol glyceryl cocoate.
25. A composition as claimed in claim 1, 2 or 3 containing a skin compatible mono or diester of glycerol with an aliphatic (C6-22) carboxylic acid.
26. A composition as claimed in claim 1, 2 or 3 containing a skin compatible ester having at least one hydroxyl group of a poly(2-10)glycerol with an aliphatic (C6-22)carboxylic acid.
27. A composition as claimed in claim 1 containing a skin compatible mono-ether of a polyethyleneglycol with an aliphatic (C12-18) alcohol having an HLB value of from 10 to 18.
28. A composition as claimed in claim 27 wherein the mono ether is polyoxyethylenet(10)oleyl ether.
29. A composition as claimed in claim 1, 2 or 3 containing a skin compatible ester of an aliphatic (C6-22) carboxylic acid with a) a polyethylene glycol b) a saccharose c) a sorbitan or d) a polyethylene glycol sorbitan ether, the ester having an HLB value of from 10 to 18.
30. A composition according to claim 1, containing as active agent (E)-N-methyl-6,6-dimethyl-N-(naphthyl-methyl)hept-2-en-4-inyl-1-amine, naftifin, ketotifen, pizotifen, griseofulvin, fluocinolone acetonide, triamcinolone acetonide, 14-0-[5-(2-amino-1,3,4-triazolyl) thioacetyl]-dihydro-mutiline, or proquazone.
31. A composition according to claim 1, containing as active agent clemastine.
32. A composition according to claim 1, containing as active agent tizanidine.
33. A composition according to claim 30 containing 14-0-[5-(2-amino-1,3,4-triazolyl)thioacetyl]-dihydro-mutiline.
34. A composition according to claim 31 or 33 containing hexyl laurate, poly(7)ethylene glycol glyceryl cocoate and polyoxyethylene(10)oleylether.
35. A composition according to claim 32 containing 6 to 10% of tizanidine, 15 to 25% of water-immiscible organic solvent, 15 to 25% of emulsifier, 5 to 10% of co-emulsifier, and 30 to 35% of water.
36. A composition according to claim 35 containing isopropyl laurate, polyoxyethylene(lo)oleyl ether and dodecanol.
37. A process for the production of a skin-penetrable pharmaceutical composition which comprises forming a microemulsion from water and a skin-penetrable pharma-cologically active agent and skin compatible excipients capable of functioning as a water-immiscible organic solvent, an emulsifier and a co-emulsifier.
38. A process according to claim 37 wherein the skin-penetrable pharmacologically active agent, water-immiscible organic solvent and emulsifier are heated to a maximum of 100°C to form an emulsion and then cooled to form a microemulsion.
39. A skin penetration pharmaceutical composition incorporating a skin-penetrable pharmaceutically active agent selected from (E)-N-methyl-6,6-dimethyl-N-(naphthyl-methyl)hept-2-en-4-inyl-1-amine, naftifin, ketotifen, pizotifen, griseofulvin, fluocinolane acetonide, triam-cinolone acetonide, 14-0-[5-(2-amino-1,3,4-triazolyl) thioacetyl]-dihydro-mutiline, or proquazone, wherein the composition is in the form of a microemulsion formed from skin compatible excipients.
40. A skin penetration pharmaceutical composition incorporating a skin-penetrable pharmaceutically active agent selected from clemastine and tizanidine, wherein the composition is in the form of a microemulsion formed from skin compatible excipients.
41. A topical skin penetration pharmaceutical composition incorporating tizanidine, wherein the composition is in the form of a microemulsion formed from skin compatible excipients.
42. A semi-solid skin penetration pharmaceutical compos-ition incorporating tizanidine, wherein the composition is in the form of a microemulsion formed from skin compatible excipients.
43. A topical skin penetration pharmaceutical composition comprising tizanidine together with a skin compatible diluent or carrier.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH2327/81 | 1981-04-06 | ||
| CH2327/81A CH653256A5 (en) | 1981-04-06 | 1981-04-06 | Microemulsion for cutaneous use |
| CH2631/81 | 1981-04-22 | ||
| CH2631/81A CH647149A5 (en) | 1981-04-22 | 1981-04-22 | Composition with 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3-benzothiadiazole for cutaneous use |
| CH327881 | 1981-05-20 | ||
| CH3278/81 | 1981-05-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1192496A true CA1192496A (en) | 1985-08-27 |
Family
ID=27173625
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000400470A Expired CA1192496A (en) | 1981-04-06 | 1982-04-05 | Topical pharmaceutical compositions |
Country Status (16)
| Country | Link |
|---|---|
| AU (1) | AU564570B2 (en) |
| CA (1) | CA1192496A (en) |
| DE (1) | DE3212053A1 (en) |
| DK (1) | DK155882A (en) |
| ES (1) | ES511169A0 (en) |
| FI (1) | FI821123L (en) |
| FR (1) | FR2502951B1 (en) |
| GB (2) | GB2098865B (en) |
| GR (1) | GR75462B (en) |
| IL (1) | IL65424A0 (en) |
| IT (1) | IT8220611A0 (en) |
| MY (1) | MY8600571A (en) |
| NL (1) | NL8201413A (en) |
| NZ (1) | NZ200232A (en) |
| PT (1) | PT74703B (en) |
| SE (1) | SE8202172L (en) |
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| USRE39128E1 (en) | 1997-10-29 | 2006-06-13 | Smithkline Beecham P.L.C. | Pleuromutilin derivatives as antimicrobials |
| US20100081669A1 (en) * | 2008-10-01 | 2010-04-01 | Taiwan Biotech Co., Ltd. | Pressure sensitive adhesive matrix device or system for the treatment or prevention of onychomycosis or tinea pedis |
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| US4767625A (en) * | 1985-09-02 | 1988-08-30 | Kao Corporation | Lamella type single phase liquid crystal composition and oil-base cosmetic compositions using the same |
| US4690774A (en) | 1985-09-11 | 1987-09-01 | Chesebrough Pond's Inc. | Novel translucent water in oil emulsions |
| US4797272A (en) * | 1985-11-15 | 1989-01-10 | Eli Lilly And Company | Water-in-oil microemulsions for cosmetic uses |
| DE3805744C2 (en) * | 1987-03-04 | 1999-09-23 | Novartis Ag | Phenylcarbamate for the inhibition of acetylcholinesterase |
| IL88076A (en) * | 1987-10-28 | 1993-01-14 | Nippon Shinyaku Co Ltd | Fat emulsions as drug carriers |
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| US6007840A (en) * | 1988-09-16 | 1999-12-28 | Novartis Ag | Pharmaceutical compositions comprising cyclosporins |
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| JPH06507172A (en) * | 1991-04-19 | 1994-08-11 | アフィニティー バイオテック，インコーポレイテッド | Convertible microemulsion formulation |
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| DE4442999A1 (en) * | 1994-12-02 | 1996-06-05 | Hexal Pharma Gmbh | Pharmaceutical composition containing an active loratidine metabolite |
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| US6008191A (en) * | 1997-09-08 | 1999-12-28 | Panacea Biotec Limited | Pharmaceutical compositions containing cyclosporin |
| US6187747B1 (en) | 1997-09-08 | 2001-02-13 | Panacea Biotech Limited | Pharmaceutical composition comprising cyclosporin |
| US6346511B1 (en) | 1997-09-08 | 2002-02-12 | Panacea Biotec Limited | Pharmaceutical composition comprising cyclosporin |
| US6391282B1 (en) * | 1997-11-10 | 2002-05-21 | Flemington Pharmaceutical Corp. | Antihistamine sprays and ointments for relief of delayed contact dermatitis |
| DE19825856A1 (en) * | 1998-06-10 | 1999-12-16 | Labtec Gmbh | New topical formulation which includes active agent as liquid lipid nanoparticles in an oil-in-water emulsion |
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| US9034858B2 (en) | 2010-11-30 | 2015-05-19 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
| US20180153904A1 (en) | 2010-11-30 | 2018-06-07 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
| US20120148675A1 (en) | 2010-12-10 | 2012-06-14 | Basawaraj Chickmath | Testosterone undecanoate compositions |
| US20170246187A1 (en) | 2014-08-28 | 2017-08-31 | Lipocine Inc. | (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE |
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| CH570401A5 (en) * | 1972-05-09 | 1975-12-15 | Wander Ag Dr A | |
| GB1559811A (en) * | 1975-07-28 | 1980-01-30 | Sandoz Ltd | Pharmaceutically active benzothiadiazole derivatives |
| CH632268A5 (en) * | 1977-01-14 | 1982-09-30 | Sandoz Ag | Method for producing new heterocyclylaminoderivaten. |
-
1982
- 1982-03-30 FR FR8205611A patent/FR2502951B1/en not_active Expired
- 1982-03-31 FI FI821123A patent/FI821123L/en not_active Application Discontinuation
- 1982-04-01 DE DE19823212053 patent/DE3212053A1/en not_active Withdrawn
- 1982-04-02 GB GB8209940A patent/GB2098865B/en not_active Expired
- 1982-04-02 NL NL8201413A patent/NL8201413A/en not_active Application Discontinuation
- 1982-04-05 ES ES511169A patent/ES511169A0/en active Granted
- 1982-04-05 NZ NZ200232A patent/NZ200232A/en unknown
- 1982-04-05 AU AU82334/82A patent/AU564570B2/en not_active Ceased
- 1982-04-05 IL IL65424A patent/IL65424A0/en unknown
- 1982-04-05 GR GR67821A patent/GR75462B/el unknown
- 1982-04-05 CA CA000400470A patent/CA1192496A/en not_active Expired
- 1982-04-05 PT PT74703A patent/PT74703B/en unknown
- 1982-04-05 DK DK155882A patent/DK155882A/en not_active IP Right Cessation
- 1982-04-06 IT IT8220611A patent/IT8220611A0/en unknown
- 1982-09-10 SE SE8202172A patent/SE8202172L/en not_active Application Discontinuation
-
1984
- 1984-04-04 GB GB08408654A patent/GB2148711B/en not_active Expired
-
1986
- 1986-12-30 MY MY571/86A patent/MY8600571A/en unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| USRE39128E1 (en) | 1997-10-29 | 2006-06-13 | Smithkline Beecham P.L.C. | Pleuromutilin derivatives as antimicrobials |
| USRE43390E1 (en) | 1997-10-29 | 2012-05-15 | Glaxosmithkline Llc | Pleuromutilin derivatives as antimicrobials |
| US20100081669A1 (en) * | 2008-10-01 | 2010-04-01 | Taiwan Biotech Co., Ltd. | Pressure sensitive adhesive matrix device or system for the treatment or prevention of onychomycosis or tinea pedis |
| US9308203B2 (en) * | 2008-10-01 | 2016-04-12 | Taiwan Biotech Co., Ltd. | Pressure sensitive adhesive matrix device or system for the treatment or prevention of onychomycosis or tinea pedis |
Also Published As
| Publication number | Publication date |
|---|---|
| NZ200232A (en) | 1985-08-16 |
| FR2502951B1 (en) | 1985-12-06 |
| FR2502951A1 (en) | 1982-10-08 |
| FI821123A0 (en) | 1982-03-31 |
| GB2148711A (en) | 1985-06-05 |
| SE8202172L (en) | 1982-10-07 |
| DK155882A (en) | 1982-12-10 |
| GB2148711B (en) | 1985-12-18 |
| ES8308698A1 (en) | 1983-10-01 |
| PT74703A (en) | 1982-05-01 |
| PT74703B (en) | 1984-05-30 |
| NL8201413A (en) | 1982-11-01 |
| MY8600571A (en) | 1986-12-31 |
| IT8220611A0 (en) | 1982-04-06 |
| DE3212053A1 (en) | 1982-10-21 |
| FI821123L (en) | 1982-10-07 |
| IL65424A0 (en) | 1982-07-30 |
| GB2098865B (en) | 1985-12-18 |
| AU8233482A (en) | 1982-10-14 |
| GB8408654D0 (en) | 1984-05-16 |
| AU564570B2 (en) | 1987-08-20 |
| ES511169A0 (en) | 1983-10-01 |
| GB2098865A (en) | 1982-12-01 |
| GR75462B (en) | 1984-07-20 |
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