CA1227753A - Method for percutaneously administering physiologically active agents using an adjuvant, a solvent and a diol moderator - Google Patents
Method for percutaneously administering physiologically active agents using an adjuvant, a solvent and a diol moderatorInfo
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- CA1227753A CA1227753A CA000455978A CA455978A CA1227753A CA 1227753 A CA1227753 A CA 1227753A CA 000455978 A CA000455978 A CA 000455978A CA 455978 A CA455978 A CA 455978A CA 1227753 A CA1227753 A CA 1227753A
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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Abstract
METHOD FOR PERCUTANEOUSLY ADMINISTERING PHYSIOLOGICALLY ACTIVE
AGENTS USING AN ADJUVANT, A SOLVENT AND A DIOL MODERATOR
ABSTRACT OF THE DISCLOSURE
A method of percutaneously administering a physiologi-cally active agent which comprises applying to the skin of a mammal a physiologically active agent in a carrier system which comprises at least one adjuvant, at least one solvent and at least one diol moderator. The adjuvant can be selected from aliphatic hydrocarbons, halogen substituted aliphatic hydrocarbons, alcohol esters of aliphatic carboxylic acids, mono- or di-ethers, ketones, higher monoalcohols or mixtures thereof. The solvent can be selected from thioglycerols, lactic acid and esters thereof, cyclic ureas, compounds represented by the general formula R1R2NCONR3R4, pyrrolidone-type compounds, amides, lactones or mixtures thereof.
AGENTS USING AN ADJUVANT, A SOLVENT AND A DIOL MODERATOR
ABSTRACT OF THE DISCLOSURE
A method of percutaneously administering a physiologi-cally active agent which comprises applying to the skin of a mammal a physiologically active agent in a carrier system which comprises at least one adjuvant, at least one solvent and at least one diol moderator. The adjuvant can be selected from aliphatic hydrocarbons, halogen substituted aliphatic hydrocarbons, alcohol esters of aliphatic carboxylic acids, mono- or di-ethers, ketones, higher monoalcohols or mixtures thereof. The solvent can be selected from thioglycerols, lactic acid and esters thereof, cyclic ureas, compounds represented by the general formula R1R2NCONR3R4, pyrrolidone-type compounds, amides, lactones or mixtures thereof.
Description
METHOD FOR PERCUTANEOUSLY ADMINISTERING P~-~SIOLOGICALLY ACTIVE
AGENTS USING AN AGENT, A SOLVENT AND A DILL MODERATOR
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The present invention relates to a method for acceder-cling the percutaneous absorption of a physiologically act 5tive agent (hereafter often merely an "active agent" for brevity).
. DESCRIPTION OF THE PRIOR ART
Active agents are commonly administered to the skin or mucosal tissues to treat local problems and systemic ad-ministration of active agents is commonly accomplished by ingesting pills or by injections. However, recently at-tempts have been made to achieve systemic administration of active agents by topical applications to the skin or mucosal tissues. Such topical means of achieving systemic ad minis-15tration has the advantage that desired blood levels can be readily achieved and maintained so that duration of therapy can be readily controlled. Thus, side effects due to an overdose of the active agent can be prevented. Also, metal-holism due to a first pass through the liver and gastric disk 20turbances, which are characteristic of certain drugs such as indomethacin when administered orally, can also be elm-noted.
However, normal skin is relatively impermeable to most therapeutic agents in that desired blood levels of the 25~ therapeutic agent cannot be achieved by means of percutane-out absorption. The percutaneous absorption of therapeutic --- ` ' ~227753 -I 1 agents can, however, be enhanced by means of adjutants or penetration enhancers.
One of the best known of such penetrating adjutants is dim ethyl sulfoxide, the use of which is described in detail in US. Patent 3,551,554 Herschler et at, which patent broadly suggests the use of dim ethyl sulfoxide as a penes treating adjutant for psychopharmacological drugs such as benzodiazepine derivatives.
British Patent 1,504,302 Brooked et at deals with soda-live methods and compositions and discloses the administer-lion of sedatives by applying to the skin of a non-human an-imal a sedating amount of one or more sedative compounds in various penetrating adjutants such as hydrocarbons such as - aromatic hydrocarbons or paraffins, halogenated aliphatic hydrocarbons, kittens, esters, ethers, alcohols, asides or sulfones. Brooked et at broadly indicates that one or more of the above liquids can be used in combination, but exempt iffy the halogenated aliphatic hydrocarbons only with carbon tetrachloride and exemplify the asides only with dim ethyl-formamide.
Japanese Patent Application 52-148,614 (unexamined) Yonemushi discloses, without supporting data or explanation of substance, the use of sulfones by-produced in the resin--in of petroleum "as solvents to enhance the efficacy of drugs for skin disease" and assay drug penetration enhancers".
US. Patent 4,202,888 Eckert et at discloses absorbable pharmaceutical compositions comprising at least one cardiac glycoside distributed in a vehicle comprising an absorption-enhancing amount of at least a partial glyceride of a fatty acid of medium chain length.
~ZZ7753 1 US. Patent 3,472,931 Stoughton relates to percutaneous absorption using lower alkyd asides, and exemplifies binary systems which comprise dimethylacetamide and ethanol, dip methylacetamide and isopropyl alcohol and dimethylacetamide and isopropyl palpitate. Stoughton does not exemplify or disclose the combination of dimethylacetamide with higher molecular weight alcohols or lower molecular weight esters.
US, Patent 4,017,641 DiGiulio deals with skin moisture icing compositions comprising 2-pyrrolidones which can be used with suitable oils and waxes including aliphatic straight chain fatty acids and alcohols of from about 10 to about 20 carbon atoms. This patent does not, however, deal with percutaneous administration of physiologically active agents.
Canadian Patent 1,165,240 discloses binary percutaneous administration systems which comprise a monoglyceride, a doll or a dill ether in combination with a second component such as an alcohol, ester, aside or the like.
The present invention involves multi component carrier systems for the percutaneous administration of physiologic gaily active agents which differ from the systems disclosed in the above prior art.
SUMMARY OF THE INVENTION
Per the present invention, it has been discovered that a certain multi component carrier systems provide enhanced and controlled percutaneous administration of physiologically active agents.
B
I` ~L2Z7753 1 The carrier systems of the present invention comprise at least one adjutant (Component A), at least one solvent (Component B) and at least one dill moderator.
The adjutants of the present invention are selected from aliphatic hydrocarbons or halogen substituted aliphatic hydrocarbons, alcohol esters of aliphatic carboxylic acids, moo- or dithers, kittens, higher aliphatic monoalcohols or mixtures thereof. It is necessary that the adjutant of the present invention have a melting point below 38C.
The solvents of the present invention are selected from thioglycerols, lactic acid or esters thereof, cyclic ureas, compounds represented by the general formula RlR2NCONR3R4, pyrrolidone-type compounds, Andes, lactones or mixtures thereof.
Per the present invention, a physiologically alive agent can be percutaneously administered by blending the same with a combination of Component A.
Component B and a dill moderator and applying the same to I the skin.
The above-described compositions can be used as bases for medical preparations comprising active agents applicable to the outer skin.
One object of the present invention is to provide base compositions or percutaneous absorption 1 enhancing combinations of Component A, Component B and a dill moderator (often abbreviated as PACE or Paces hereafter) for medical preparations for external use which enhance the permeability of active agents through the skin and the percutaneous absorption of active agents.
- pa -second object of the present invention is to provide pharmaceutical compositions comprising a Pace for external use itch provides good permeability of active agents through the skin and percutaneous absorption of active s agents.
A third object of the present invention is to provide a method for enhancing the permeability of active agents through the skin and percutaneous absorption of active agents using a PACE per the present invention.
In a preferred embodiment, the combination of the present invention which enhances percutaneous absorption comprises one or more members selected from the group con-sitting of certain pyrrolidone-type compounds and asides and mixtures thereof, one or more members selected from the group consisting of certain alkyd halides, fatty acid esters, higher aliphatic monoalcohols, hydrocarbons and mixtures thereof and one or more dill moderators.
A fourth object of the present invention is to provide Paces which ensure rapid and controlled transepidermal delivery of physiologically active agents in man or other - animals.
A fifth object of the present invention is to provide such rapid and controlled transepidermal delivery which provides drug blood levels in the therapeutic range fourth treatment of humans and other animals.
A sixth object of the present invention-is to provide, through transepidermal delivery, at appropriately adjusted rates, relatively constant therapeutic blood levels so as to avoid the side effects and reduced therapeutic effects that may result from wide fluctuations in blood levels over time.
lZ277S3 ,, BRIEF DESCRIPTION OF THE DRAWING
The Figure is a plot of diazepam flux versus time in hours for various compositions per the present invention and a comparison composition.
DESCRIPTION OF PREFERRED EMBODIMENTS
Examples of Component A include the following compounds.
(1) Straight, branched or cyclic aliphatic hydrocar-buns having 5 to 24 carbon atoms which may be substituted with one or more halogens.
As halogen substituents, bromide and chlorine are preferred. -Straight or branched hydrocarbons having 5 to 24 (preferably 6 to 18) carbon atoms can be used which may be saturated or unsaturated with preferably 1 to 2 unsaturated bonds. In the case of cyclic hydrocarbons, 6 to 10 member Ed moo- or 10 to 12 member Ed di-cyclic hydrocarbons are pro-furred and such may be substituted with saturated or unsaturated alkyd groups having 1 to 4 carbon atoms such as methyl, bottle, isopropenyl, etc.
Specific examples include n-pentane, Nixon, nope-lane, n-octane, n-nonane, n-decane, n-undecane, n-dodecane, n-tetradecane, n-hexadecane, n-octadecane, 2-methylpentane,
AGENTS USING AN AGENT, A SOLVENT AND A DILL MODERATOR
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The present invention relates to a method for acceder-cling the percutaneous absorption of a physiologically act 5tive agent (hereafter often merely an "active agent" for brevity).
. DESCRIPTION OF THE PRIOR ART
Active agents are commonly administered to the skin or mucosal tissues to treat local problems and systemic ad-ministration of active agents is commonly accomplished by ingesting pills or by injections. However, recently at-tempts have been made to achieve systemic administration of active agents by topical applications to the skin or mucosal tissues. Such topical means of achieving systemic ad minis-15tration has the advantage that desired blood levels can be readily achieved and maintained so that duration of therapy can be readily controlled. Thus, side effects due to an overdose of the active agent can be prevented. Also, metal-holism due to a first pass through the liver and gastric disk 20turbances, which are characteristic of certain drugs such as indomethacin when administered orally, can also be elm-noted.
However, normal skin is relatively impermeable to most therapeutic agents in that desired blood levels of the 25~ therapeutic agent cannot be achieved by means of percutane-out absorption. The percutaneous absorption of therapeutic --- ` ' ~227753 -I 1 agents can, however, be enhanced by means of adjutants or penetration enhancers.
One of the best known of such penetrating adjutants is dim ethyl sulfoxide, the use of which is described in detail in US. Patent 3,551,554 Herschler et at, which patent broadly suggests the use of dim ethyl sulfoxide as a penes treating adjutant for psychopharmacological drugs such as benzodiazepine derivatives.
British Patent 1,504,302 Brooked et at deals with soda-live methods and compositions and discloses the administer-lion of sedatives by applying to the skin of a non-human an-imal a sedating amount of one or more sedative compounds in various penetrating adjutants such as hydrocarbons such as - aromatic hydrocarbons or paraffins, halogenated aliphatic hydrocarbons, kittens, esters, ethers, alcohols, asides or sulfones. Brooked et at broadly indicates that one or more of the above liquids can be used in combination, but exempt iffy the halogenated aliphatic hydrocarbons only with carbon tetrachloride and exemplify the asides only with dim ethyl-formamide.
Japanese Patent Application 52-148,614 (unexamined) Yonemushi discloses, without supporting data or explanation of substance, the use of sulfones by-produced in the resin--in of petroleum "as solvents to enhance the efficacy of drugs for skin disease" and assay drug penetration enhancers".
US. Patent 4,202,888 Eckert et at discloses absorbable pharmaceutical compositions comprising at least one cardiac glycoside distributed in a vehicle comprising an absorption-enhancing amount of at least a partial glyceride of a fatty acid of medium chain length.
~ZZ7753 1 US. Patent 3,472,931 Stoughton relates to percutaneous absorption using lower alkyd asides, and exemplifies binary systems which comprise dimethylacetamide and ethanol, dip methylacetamide and isopropyl alcohol and dimethylacetamide and isopropyl palpitate. Stoughton does not exemplify or disclose the combination of dimethylacetamide with higher molecular weight alcohols or lower molecular weight esters.
US, Patent 4,017,641 DiGiulio deals with skin moisture icing compositions comprising 2-pyrrolidones which can be used with suitable oils and waxes including aliphatic straight chain fatty acids and alcohols of from about 10 to about 20 carbon atoms. This patent does not, however, deal with percutaneous administration of physiologically active agents.
Canadian Patent 1,165,240 discloses binary percutaneous administration systems which comprise a monoglyceride, a doll or a dill ether in combination with a second component such as an alcohol, ester, aside or the like.
The present invention involves multi component carrier systems for the percutaneous administration of physiologic gaily active agents which differ from the systems disclosed in the above prior art.
SUMMARY OF THE INVENTION
Per the present invention, it has been discovered that a certain multi component carrier systems provide enhanced and controlled percutaneous administration of physiologically active agents.
B
I` ~L2Z7753 1 The carrier systems of the present invention comprise at least one adjutant (Component A), at least one solvent (Component B) and at least one dill moderator.
The adjutants of the present invention are selected from aliphatic hydrocarbons or halogen substituted aliphatic hydrocarbons, alcohol esters of aliphatic carboxylic acids, moo- or dithers, kittens, higher aliphatic monoalcohols or mixtures thereof. It is necessary that the adjutant of the present invention have a melting point below 38C.
The solvents of the present invention are selected from thioglycerols, lactic acid or esters thereof, cyclic ureas, compounds represented by the general formula RlR2NCONR3R4, pyrrolidone-type compounds, Andes, lactones or mixtures thereof.
Per the present invention, a physiologically alive agent can be percutaneously administered by blending the same with a combination of Component A.
Component B and a dill moderator and applying the same to I the skin.
The above-described compositions can be used as bases for medical preparations comprising active agents applicable to the outer skin.
One object of the present invention is to provide base compositions or percutaneous absorption 1 enhancing combinations of Component A, Component B and a dill moderator (often abbreviated as PACE or Paces hereafter) for medical preparations for external use which enhance the permeability of active agents through the skin and the percutaneous absorption of active agents.
- pa -second object of the present invention is to provide pharmaceutical compositions comprising a Pace for external use itch provides good permeability of active agents through the skin and percutaneous absorption of active s agents.
A third object of the present invention is to provide a method for enhancing the permeability of active agents through the skin and percutaneous absorption of active agents using a PACE per the present invention.
In a preferred embodiment, the combination of the present invention which enhances percutaneous absorption comprises one or more members selected from the group con-sitting of certain pyrrolidone-type compounds and asides and mixtures thereof, one or more members selected from the group consisting of certain alkyd halides, fatty acid esters, higher aliphatic monoalcohols, hydrocarbons and mixtures thereof and one or more dill moderators.
A fourth object of the present invention is to provide Paces which ensure rapid and controlled transepidermal delivery of physiologically active agents in man or other - animals.
A fifth object of the present invention is to provide such rapid and controlled transepidermal delivery which provides drug blood levels in the therapeutic range fourth treatment of humans and other animals.
A sixth object of the present invention-is to provide, through transepidermal delivery, at appropriately adjusted rates, relatively constant therapeutic blood levels so as to avoid the side effects and reduced therapeutic effects that may result from wide fluctuations in blood levels over time.
lZ277S3 ,, BRIEF DESCRIPTION OF THE DRAWING
The Figure is a plot of diazepam flux versus time in hours for various compositions per the present invention and a comparison composition.
DESCRIPTION OF PREFERRED EMBODIMENTS
Examples of Component A include the following compounds.
(1) Straight, branched or cyclic aliphatic hydrocar-buns having 5 to 24 carbon atoms which may be substituted with one or more halogens.
As halogen substituents, bromide and chlorine are preferred. -Straight or branched hydrocarbons having 5 to 24 (preferably 6 to 18) carbon atoms can be used which may be saturated or unsaturated with preferably 1 to 2 unsaturated bonds. In the case of cyclic hydrocarbons, 6 to 10 member Ed moo- or 10 to 12 member Ed di-cyclic hydrocarbons are pro-furred and such may be substituted with saturated or unsaturated alkyd groups having 1 to 4 carbon atoms such as methyl, bottle, isopropenyl, etc.
Specific examples include n-pentane, Nixon, nope-lane, n-octane, n-nonane, n-decane, n-undecane, n-dodecane, n-tetradecane, n-hexadecane, n-octadecane, 2-methylpentane,
2-methylhexane, 2,3-dimethylhexane, 2-methylnonane, 2,6-25dimethyloctane, 2,2,4,4,6,8,8-heptamethylnonane, pristine, limonene, hydrogenated limonene diver, cyclohexane, 1,3-dimethylcyclohexane, cyclooctane, isobutyl-cyclohexane, cyclododecane, methyldecaline, decline, octal chloride, t decal chloride, dodecyl chloride, hexadecyl chloride, dodecyl bromide, dichlorododecane, etc.
` 6 ~Z27753 , .
1 (2) Alcohol esters of aliphatic carboxylic acid having a total number of carbon atoms of from 7 to 18, preferably 7 to 17:
As the alcohol moiety, monovalent alcohols having 1 to 6 carbon atoms such as methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, iso-butyl alcohol, sec-butyl alcohol, t-butyl alcohol, namely alcohol, iso-amyl alcohol, n-hexyl alcohol, etc., are preferred. Further, as the carboxylic acid moiety, fatty acids having 6 to 16 carbon atoms are preferred and saturated fatty acids having 8 to 14 carbon atoms are most preferred. Specific examples of such esters include methyl laureate, ethyl laureate, bottle laureate, isopropyl myristate, etc.
` 6 ~Z27753 , .
1 (2) Alcohol esters of aliphatic carboxylic acid having a total number of carbon atoms of from 7 to 18, preferably 7 to 17:
As the alcohol moiety, monovalent alcohols having 1 to 6 carbon atoms such as methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, iso-butyl alcohol, sec-butyl alcohol, t-butyl alcohol, namely alcohol, iso-amyl alcohol, n-hexyl alcohol, etc., are preferred. Further, as the carboxylic acid moiety, fatty acids having 6 to 16 carbon atoms are preferred and saturated fatty acids having 8 to 14 carbon atoms are most preferred. Specific examples of such esters include methyl laureate, ethyl laureate, bottle laureate, isopropyl myristate, etc.
(3) Moo- or dithers having 10 to 18 carbon atoms:
Specifically, there are alkyd monoethers such as dihexyl ether, ductile ether, methoxydodecane, ethoxydodecane, etc., ethers having an alicyclic group such as sunnily, etc., alkyd dithers such as ethylene glycol dibutyl ether, ethylene glycol ductile ether, etc.
I Kittens having 10 to 18 carbon atoms:
Aliphatic kittens are preferred, examples of which include 2-undecanone, 3-undecanone, 4-undecanone, 5-undecanone, 6-undecanone, 2-dodecanone, 4-dodecanone~ 5-dodecanone, 7-tridecanone, etc.
lZZ7~7S3 1 (5) Higher aliphatic monoalcohols having from 10 to 26 carbon atoms which may be branched, straight chain, saturated, unsaturated or cyclic and which may be primary, secondary or tertiary.
Examples of Component include the following compounds:
(1) Thioglycerols:
Any Mooney, dip and trithioglycerols can be used, an example of which includes ~-monothioglycerol.
(2) Lactic acid and esters thereof:
As the alcohol moiety in the esters, monovalent caliph-attic alcohols having l to 4 carbon atoms are preferred, specific examples of which include lactic acid, methyl lactate, ethyl lactate, bottle lactate, etc.
(3) Cyclic ureas:
lo 5-Membered or 6-membered rings are preferred, specific examples of which include ethylene urea, N,N-dimethyl-ethylene urea and the corresponding propylene ureas, etc.
Specifically, there are alkyd monoethers such as dihexyl ether, ductile ether, methoxydodecane, ethoxydodecane, etc., ethers having an alicyclic group such as sunnily, etc., alkyd dithers such as ethylene glycol dibutyl ether, ethylene glycol ductile ether, etc.
I Kittens having 10 to 18 carbon atoms:
Aliphatic kittens are preferred, examples of which include 2-undecanone, 3-undecanone, 4-undecanone, 5-undecanone, 6-undecanone, 2-dodecanone, 4-dodecanone~ 5-dodecanone, 7-tridecanone, etc.
lZZ7~7S3 1 (5) Higher aliphatic monoalcohols having from 10 to 26 carbon atoms which may be branched, straight chain, saturated, unsaturated or cyclic and which may be primary, secondary or tertiary.
Examples of Component include the following compounds:
(1) Thioglycerols:
Any Mooney, dip and trithioglycerols can be used, an example of which includes ~-monothioglycerol.
(2) Lactic acid and esters thereof:
As the alcohol moiety in the esters, monovalent caliph-attic alcohols having l to 4 carbon atoms are preferred, specific examples of which include lactic acid, methyl lactate, ethyl lactate, bottle lactate, etc.
(3) Cyclic ureas:
lo 5-Membered or 6-membered rings are preferred, specific examples of which include ethylene urea, N,N-dimethyl-ethylene urea and the corresponding propylene ureas, etc.
(4) Compounds represented by the general formula:
N - C - N
R2 / \ R4 wherein R1, R2, R3 and R4 each represents a hydrogen atom, a lower alkyd group having 1 to 4 carbon atoms (methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.) or an azalea group having 1 or 2 carbon atoms:
Specific examples thereof include urea, N-methylurea, N-ethylurea, N-butylurea, l,l-dimethylurea, 1,3-dimethyl-urea, 1,1,3,3-tetramethylurea, N-acetyl-N'-methylurea, etc.
N - C - N
R2 / \ R4 wherein R1, R2, R3 and R4 each represents a hydrogen atom, a lower alkyd group having 1 to 4 carbon atoms (methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.) or an azalea group having 1 or 2 carbon atoms:
Specific examples thereof include urea, N-methylurea, N-ethylurea, N-butylurea, l,l-dimethylurea, 1,3-dimethyl-urea, 1,1,3,3-tetramethylurea, N-acetyl-N'-methylurea, etc.
(5) Compounds represented by the general formula:
C
(SHEA) n .
27~7$3 wherein R5 represents a hydrogen atom or a lower alkyd group having 1 to 4 carbon atoms (methyl, ethyl, n-propyl, isopropyl, etc.) and n represents an integer of 3 to 5:
s Specific examples thereof include 2-pyrrolidone, N-methyl-pyrrolidone, N-methylpiperidone, caprolactam, N-methylcaprolactam, etc.
C
(SHEA) n .
27~7$3 wherein R5 represents a hydrogen atom or a lower alkyd group having 1 to 4 carbon atoms (methyl, ethyl, n-propyl, isopropyl, etc.) and n represents an integer of 3 to 5:
s Specific examples thereof include 2-pyrrolidone, N-methyl-pyrrolidone, N-methylpiperidone, caprolactam, N-methylcaprolactam, etc.
(6) Compounds represented by the general formula:
R
RON
wherein R6 represents a hydrogen atom or an alkyd group having 1 to 3 carbon atoms (methyl, ethyl, n-propyl, etc.) and I and R8 each represents an alkyd group having 1 to 3 carbon atoms, with the proviso that R6, R7 and R8 have in total at least 3 carbon atoms:
- Specific examples thereof include N,N-diethyl formamide, N,N-dimethylacetamide, N,N-diethylacetamide, N,N-dimethylpropionamide, N,N-diethylpropionamide, etc.
R
RON
wherein R6 represents a hydrogen atom or an alkyd group having 1 to 3 carbon atoms (methyl, ethyl, n-propyl, etc.) and I and R8 each represents an alkyd group having 1 to 3 carbon atoms, with the proviso that R6, R7 and R8 have in total at least 3 carbon atoms:
- Specific examples thereof include N,N-diethyl formamide, N,N-dimethylacetamide, N,N-diethylacetamide, N,N-dimethylpropionamide, N,N-diethylpropionamide, etc.
(7) Lactones having 4 to 6 carbon atoms:
Specific examples thereof include y-butyrolactone, ~-valerolactone, etc.
As earlier indicated, a dill moderator is used in combination with the active agent and Components A and B of the prevent invention. The dill can be straight or branched chain and the dill selected is -preferably a dill comprising 3 to 8 carbon atoms, most preferably 3 to 6 carbon atoms, , .
~L2277S3 e.g., an aliphatic dill such as 1,2-propane dill, 1,3-butane dill, 2,3-butane dill, pontoon dill or 1,6-hexane dill.
However, other dills can be used. --The amount of dill moderator used is not unduly limp tied, but is typically on the order of about 10 to about 400 weight percent, more preferably about 25 to about 200 weight percent, based on the weight of solvent Component s. The resulting combination of materials must, of course, be liquid.
The dill moderator reduces the activity of Components A
and B of the present invention which provides a means of further controlling the rate of active agent absorption.
Greater amounts of dill moderator decrease the rate of active agent flux while lesser amounts of dill moderator increase the rate of active agent flux as compared to greater amounts.
It is to understood that the dill moderator does not enhance percutaneous absorption per the present invention, rather, in all amounts it reduces the rate of percutaneous absorption, which effect has not been suspected in the art.
In addition to the above, there are certain most pro-furred Paces per the present invention, and these are discussed below.
We are unsure why the most preferred combination of Paces of the present invention offers enhanced percutaneous absorption; however, the data we have generated indicate that there is a synergistic effect between Components A and B which can be appropriately moderated, as desired, by varying the amount of dill moderator.
We consider the materials such us the pyrrolidone-type compounds and asides to basically serve a solvent function Jo ` 10 lZ~7753 and materials such as the alkyd halides, fatty acid esters, higher aliphatic monoalcohols and aliphatic hydrocarbons to serve as adjutants which enhance the salivating function of the solvent. We further believe that the solvents carry the active agent whereas the adjutants open up the stratum corneum. We do not wish to be bound by these theories, and we merely use the terminology "solvent" and "adjutant" to maintain a line of distinction between the two classes of materials which are mandatorily used in combination.
The most preferred adjutants as Component A of the present invention include one or more members selected from the group consisting of alkyd halides, fatty acid esters, higher aliphatic monoalcohols, aliphatic hydrocarbons and mixtures thereof.
Of the alkyd halides, those having from 8 to 16 carbon atoms are most preferred, with chloride being the preferred halogen. Both alkyd bromides and iodizes are potentially useful, but alkyd bromides and alkyd iodizes tend to be unstable. Alkyd fluorides are also useful.
The alkyd moiety may be straight or branched chain, may be cycloaliphatic or unsaturated, e.g., alikeness and alikeness are useful.
Most preferred alkyd halides are later exemplified.
The aliphatic hydrocarbons most preferably have 10 to 18 carbon atoms. They may be straight or branched chain and may be cycloaliphatic or unsaturated, erg,, alikeness and alikeness are useful.
The fatty acid esters are conveniently represented by the formula RlCOOR2, Al representing the acid moiety and R2 t representing the alcohol moiety. It is most preferred that 1227~7S3 the total number of carbon atoms ill Al and R2 be from 10 to 17.
Al and R2 may be linear, branched, saturated, unsaturated.
Preferred higher monoalcohols are the aliphatic moo-alcohols with from 12 to 24 carbon atoms. The aliphatic monoalcohols may be branched chain, straight chain, Saturn axed, unsaturated or cyclic.
The most preferred solvents as Component B include the pyrrolidone-type compounds and the asides.
The pyrrolidones are most preferably alkyd pyrrolidones of the formula:
R
N
C = O
(c~2 no where Al is an alkyd group containing up to 4 carbon atoms and n is 3 to 5.
The asides are most preferably represented by the formula:
where R2 can be hydrogen or an alkyd group with up two 3 carbon atoms and R3 and R4 can be an aliphatic group with up to 3 carbon atoms.
The base compositions of the present invention can be prepared by dissolving Component A in Component B and then :~ZZ7753 mixing the dill moderator therein. The order of Mooney is not important. The amount of Component A to be used is generally from 0.1 to 80% by weight based on the total weight of Components A and B, preferably 0.5 to 50% by - 5 weight. Preferred properties of dill moderator have earlier been given. Of course, pharmaceutically acceptable add-lives such as water, etc., can also be added to the base compositions.
The pharmaceutical compositions for topical application per the present invention can be prepared by blending active agents with the above-described composition. There is no particular limit on the active agents used so long as the active agents are systemically active and percutaneously applicable.
Specific examples of active agents include benzodiaze-pines (e.g., Diazepam, Nitrazepam, Flunitrazepam, Lorazepam, Fludiazepam, Clonazepam), diuretic agents [e.g., thiazides (e.g., Bendroflumethiazide, Polythiazide, Methyclothiazide, Trichlorométhiazide, Cyclopenthiazide, ~entylhydrochloro-thiazide, Hydrochlorothiazide, Bumetanide)], antihyperten-size agents (e.g., Clonidine), antihistamic agents [e.g., amino ethers (e.g., diphenhydramine, Carbinoxamine, Diphenyl-praline), ethylenediamines (e.g., Fenbenzamine), monoamine (e.g., Chlorophenylamines)]; non-steroid antiinflammatory agents (e.g., Indomethacine, Ibuprofen, Ibufenac, Alkali-fence, Diclofenac, Mefenamic acid, Flurbiprofen, Flufenamic acid, Ketoprofen), anti-tumor agents (e.g., 5-fluorouracil, 1-(2-tetrahydrofuryl)-5-fluorouracil, Cytarabine, Flexor-dine). Steroid antiinflammatory agents (e.g., Cortisone, Hydrocortisone, Prednisolone, Predonisone, Triamcinolone, Dexamethasone, Betamethasone), anti epileptic agents (e.g., - ~lZZ77S3 Ethosuximide), antiarrytl~ic agents (e.g., Ajmalin, Purajmalin. Pindolol, Propranolol, Quinidine), psychotropic agents [e.g., Clofluperol, Trifluperidol, Haloperidol, Moper one), scopolamine (e.g., methyl scopolamine, bottle scopolamine), metoclopramide, chlorpromazine, atropines (e.g., methyl atropine bromide, methylanisotropine bromide), vascular dilating agents (e.g., isosorbide dinitrate, vitro-glycerine, pentaerythritol tetranitrate, propanyl nitrate, dipyridamole), antibiotics, e.g., te~racyclines (e.g., Tetracycline, Oxytetracycline, metacycline, doxycycline, Minocycline), chloramphenicols, erythromycines], etc. The method of the present invention can also be utilized to percutaneously administer peptizes such as LH-RH, insulin and the like. Of course, pharmaceutically acceptable salts such as the hydrochloride, sodium, potassium, hydrobromide, etc., salts can be used.
Since the present invention is of particular applique-lion with respect to the benzodiazepine materials, these are discussed in more detail below. Particularly preferred bent zodiazepine materials are those which illustrate the buoyancy-diazepine skeleton as schematically illustrated as follows:
Roy, Jo .
~2277S3 wherein is Of, Bra or NO
and Y is with varying degrees of unsaturation and substitution-at positions 1, 2, 3, 4, and 5 as follows:
a) 1, 2 and 4, 5 are unsaturated: Al and R3 are H; R2 is NOR (R is H or SHEA) and N-Z is N O.
b) 1, 2 are saturated and 4, 5 are unsaturated; R3 is H
or OH; -R2 is -H or JO or ON*; R1 is NOR (R is H, SHEA
or SHEA Jo SHEA CHINOOK or Al is CON*
(R is H or SHEA) and is joined to R2 via "*" (a single bond) as follows:
R N
I \ . .
:~1`2D
I 1 2 and 4, 5 are saturated: Al is H; -R2 is JO; R3 is H and positions 4 and 5 constitute a second ring system as follows:
Y 4 R ._ .; o, <
where R and Al are H and SHEA.
Specific examples of benzodiazepines which can be percutaneously administered using the active ingredient/
12;~7753 penetration adjutant combinations of the present invention-include:
a) Chlordiazepoxide; 7-Chloro-2-methylamino-5-phenyl-3H-l, 4-benzodiazèpine-4-oxide b) Diazepam; 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one c) Oxazepam; 7-Chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepine-2-one d) Temazepam; 7-Chloro-1,3-dihydro-3-hydroxy-1-methyl-5-2H-1,4-benzodiazepine-2-one e) Lorazepam; 7-Chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepine-2-one f) Prazepam; 7-Chloro-1-cyclopropylmethyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one g) Fludiazepam; 7-Chloro-1,3-dihydrG-5-(2-fluorophenyl)-1-methyl-2H-1,4-be~zodiazepine-2-one 0 h) Flurazepam; 7-Chloro-1-(2-(dimethylamino)ethyl)-5-(o-fluorophenyl)-1~,3-dihydro-2H-1,4-benzodiazepine-2-one i) Medazepam; 7-Chloro-2,3-dihydro-1-methyl-5-phenyl-lH-5,4-benzodiazepine j) Bromazepam;. 7-Bromo-5-(2-pyridyl)-3H-1,4-benzodiaze-pine-2(lH)-one k) Nitrazepam; 1,3-Dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one 1) Nimetazepam; 1-Methyl-7-nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one m) Clonazepam; 5-(o-Chloro~henyl)-7-nitro-lH-1,4-benzodiazeplrle-2(3H)-one n) Flunitrazepam; 5-(o-Fluorophenyl)-1~3-dihydro-l-meth ,7-nitro-2H-1,4-benzodiazeplne-2-one o) Estazolam; 8-Chloro-1~6-phenyl-4H-s-triazolo(4l3 -A) (1,4)-benzodiazeplne p) Triazolam; 8-Chloro-6-(o-chlorophenyl)-l-methyl-aH
s-triazolo(4,3-A)(1,4)-benzodiazeplne 0 q) Alprazolam; 8-Chloro-l-methyl-6-phenyl-4H-s-triazolo (4,3-A)(1,4~-benzodiazeplne r) Oxazolam; 10-Chloro-2,3,5,6,7,11b-hexahydro-2-methyl-llb-phenylbenzo(6,7)-1,4-diazepino(5,4-b-oxazol-6-one , ~L2Z7753 1 s) Cloxazolam; 10-Chloro-llb-(o-chlorophenyl)-2,3,5,6,7, llb-hexahydrobenzo(6,7)-1,4-diazepino-(S,4-b)oxazol-6-one t) Haloxazolam; 10-Bromo-llb-(o-fluorophenyl)-2,3,7,11b-tetrahydro-oxazolo(3,2,~d)(1,4)benzo-diazepine-6(5H)-one Especially preferred are benzodiazepines b), e), i), k), 1), n) and o).
The amount of active agent(s) blended is sufficient if it is effective for achieving the desired pharmaceutical effect, which varies depending upon the kind of active agents, body weight of the patient, symptoms, etc. The amount may thus be suitably chosen depending upon these conditions. In general, it is preferred that active agents be employed in an amount of 0.01 to 50% by weight, more preferably 0.05 to 10% by weight, based on the total amount of Component A and Component B.
The dose of the active agents administered can be controlled by increasing or decreasing the area of skin to which the pharmaceutical compositions are applied. Accord-tingly, the amount of the active agent is not necessarily limited to the above-described ones.
As will be apparent to one skilled in the art, with increasing concentrations of active agent increasing amounts of active agent will be absorbed by the subject. The lot-lowing discussion is given in texts of flood levels of drug (ng/ml of plasma), this being dependent upon the total area ; of dermal application, as there is a substantially linear increase in amount of active agent absorbed with area.
For a constant area of application and a constant absolute amount of adjutant, the blood level of active agent at any given time is a function of the concentration of I 27'753 i active agility in the composition. That is, increased concern-tractions of active agent in the formulation result in more rapid active agent penetration and higher blood levels.
A further factor which must be considered is that the amount of active agent absorbed will depend on the site of application, for example, scalp, ventral forearm, behind the ear, chest, etc. Typically an area rich in blood vessels is selected.
For most applications, the concentration of active agent in the PACE will generally be on the order of 0.01 to 50% based on Components A and B, the amount of PACE
applied will be about 0.1 my to 100 my per cm and the total . area of application will be on the order of about 0.5 cm2 to about 100 cm2, which will provide therapeutic blood levels of the desired active agent.
These ranges are not, however, to be considered as limitative.
In general, the rate of transepidermal active agent absorption will approach the rate of oral absorption depend-in upon the factors previously discussed (nature and amount of PACE, concentration of active agent in the formulation, and surface area of skin application). Thus, peak blood levels of the active agent may be reached more slowly or at about the same rate and wilt reach about the same level as those obtained by oral administration. Alternatively, the blood level of active agent attained by single dose oral administration may be maintained for an extended period by subsequent percutaneous administration of the active agent.
In the latter case, the initial oral dose may be smaller than the normal therapeutic oral dose so that side effects associated with higher-than-minimal therapeutic blood levels ~l2Z7753 - Tandy by a reduced oral dose may be maintained by the subsequent transepideraml administration at a proper rate.
Therapeutic oral doses of diazepam in man produce blood levels ox approximately 100 ng/ml plasma SUE. Kaplan, MEL. Jack, K. Alexander, and RYE. We infield, J. Harm. sat., 62, 1789-1796 (1973)]. Such a blood level is easily attain-able by percutaneous administration by way of the present invention and produces pharmacological (behavioral) signs of therapeutic effectiveness in appropriate animal models for man, e.g., the rhesus monkey.
The method of the present invention finds application with mammals in general, most particularly man and domestic animals such as Cassiopeia horses, dogs, cats and the like. -The pharmaceutical composition of the present invention is administered to the outer skin as a simple mixture or as a medical preparation by adding known pharmaceutically acceptable third components in the form of solutions, joint-mints (paste-including creams and gels) lotions, adhesive tapes, a plaster, etc.
For example, solutions may simply comprise the active agent dissolved in the PACE with optional components, e.g., glycerin, and the solutions may be incorporated into absorb bunts, e.g., a gauze, porous membrane, etc.
Ointments, gels or creams may contain conventional ingredients (e.g., polyethylene glycol and hydroxy propel-cellulose, etc.) to form the same, and the same may be spread onto backing materials, e.g., a plastic film.
Similarly, plasters or adhesives tapes may contain the active agent and PACE in an adhesive base, e.g., acrylic copolymers or other synthetic gums.
.
The above listed components should essentially be inert in the system and not increase or decrease the effect of the PACE.
The PACE may be added to such a composition in varying amounts as desired, generally from 10 to 99~ by weight.
In developing the present invention, we used both diffusion cells and an animal model. The diffusion cell methods provided a qualitative assessment of the active agent/PAEC effect on percutaneous absorption. The animal model rhesus monkey test also provides an acceptable pharmacokinetic model for man as indicated in J. Sock Comet. Chum., 30, 297-307. Sept./Oct. 1979 and Toxically.
Apply Pharmacol., 32, 394-398, 1975.
EXPERIMENTAL
In Vitro Skin Penetration Studies with Diffusion Cell Technique -Rat full thickness skins were used in the diffusion cell method of Michael, Ache Journal, 21 [5], 985-996, 1975. The rat skin was mounted in the diffusion cell in a vertical position between the upstream and the downstream compartments; the exposed area of the skin approximated 4.15 cm .
The skin was excised from the shaved abdominal site of male albino rats weighing 250 300 g, and washed with normal saline solution after the subcutaneous fat was carefully removed with scissors. .
The active agent/PAEC solution of known concentration was added to the upper compartment of the cell, which was exposed to the epithelial side of the skin and a normal saline solution was placed in the lower compartment.
12;~7753 , The penetration rate s sty Ed in a thermostat Ed bath at 30C. At appropriate intervals samples were withdrawn from the lower compartment and subsequently analyzed for active agent concentration by standard analytical methods.
As an alternative, the finite dose technique of Franz, Cuff. Prowl. Dermatol., Vol. 7, p. 58 68 (Larger, Beset, 1978) can also be followed where the rat skin is mounted horizontally in a diffusion cell apparatus and the exposed area of the skin approximates 0.7 cm2.
The active agent/PAEC solution of known concentration was added to the upstream compartment to which the epithet-tat side of the skin was exposed, and a normal saline solution was added to the downstream compartment.
In Viva Rhesus Monkey Test If desired, an in viva rhesus monkey test as described below can also be used to determine the effect of the PAEC/diol moderator combinations of the present invention.
Male rhesus monkeys weighing 10-14 Kg can be used as the subject. An appropriate area of the monkey's chest is shaved 24 hours before drug application.
Drug formulations comprising the PACE are applied to a certain area of the chest. The monkey is restrained in a chair to prevent it from touching its chest.
Blood samples are taken at appropriate intervals after the application. The heparinized blood is centrifuged, and the plasma removed and stored at -20C until analyzed.
Diazepam in plasma can be analyzed following the GLC
method of Angles, J. Chromatog., 75, 55-78, 1973.
.
1;~27~753 .
1 Hereafter the present invention will be illustrated with reference to an example in more detail but it is not to be deemed to be limited thereto, Examples of certain combinations of Components A and B
per the present invention are given in Canadian Patent Apply-cation No. 453,790 filed April 25~ 1984 in the names of S.
Swept et at and entitled METHOD FOR PERCUTANEOUSLY
ADMINISTERING PHYSIOLOGICALLY ACTIVE AGENTS wherein no dill moderator is used, and in Canadian Patent Application No, 455,975 filed June, I 84 in renames of K, Swept et at and entitled METHOD FOR PERCUTANEOUSLY ADMINISTERING PHYSIC-LOGICALLY ACTIVE AGENTS USING ON ALCOHOL ADJUTANT AND A
SOLVENT, Compositions were prepared by firstly dissolving Component A with Component By then mixing the active agent in the mixture and then mixing the dill therein. The order of mixing is not important, In the case that Component B is a solid at ambient temperature or will not homogeneously mix with Component A 20 wt.% of ethylene glycol monobutyl ether based on the weight of Components A and B was used as an agent for assisting dissolution.
Further in the following example, the abbreviations below are used:
C12H dodecanol C12Cl - dodecyl chloride DMAc - dim ethyl acetamide MY - l-methyl-2-pyrrolidone I
1 Unless otherwise indicated in the following examples the active agent was diazepam or metoclopramide hydrochlor-ides The flux of the active agent is given in the terms of ~g/cm2/8 hours. 25 Volume percent component A with respect to component A and component B volume with or without dills aye I
~2Z77S3 was used in the composition along with 2.5 ~7eigllt percent of the active agent. For purposes of comparison, in one instance the result for an adjutant alone with a dill is given.
Example 1 The Figure is a plot of a diazepam flux versus time (in hours) illustrating the moderating effect of dills for the systems 25% C12Cl in DMAc, 25% C12Cl in a 1:1 weight mixture of DMAc/2,3-butane dill and 25% C12Cl in a 1:2 weight mixture of DMAc/2,3-butane dill. 25% C12Cl in 2,3-butane dill is also shown for comparison.
Example 2 This example shows the moderating effect of dills for the systems 25% C120H in MY and 25% C120H in a 1:1 volume mixture of MY / 1,2-propane dill. Table 2 shows the met-clopramide HO flux for 8 hours with these systems.
Table 2 Flux (~q/cm2/8 his) 25% C120H in MY 4382 25% KIWI in a 1:1 volume mixture 1369 - of MP/1,2-propane dill While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
` 23
Specific examples thereof include y-butyrolactone, ~-valerolactone, etc.
As earlier indicated, a dill moderator is used in combination with the active agent and Components A and B of the prevent invention. The dill can be straight or branched chain and the dill selected is -preferably a dill comprising 3 to 8 carbon atoms, most preferably 3 to 6 carbon atoms, , .
~L2277S3 e.g., an aliphatic dill such as 1,2-propane dill, 1,3-butane dill, 2,3-butane dill, pontoon dill or 1,6-hexane dill.
However, other dills can be used. --The amount of dill moderator used is not unduly limp tied, but is typically on the order of about 10 to about 400 weight percent, more preferably about 25 to about 200 weight percent, based on the weight of solvent Component s. The resulting combination of materials must, of course, be liquid.
The dill moderator reduces the activity of Components A
and B of the present invention which provides a means of further controlling the rate of active agent absorption.
Greater amounts of dill moderator decrease the rate of active agent flux while lesser amounts of dill moderator increase the rate of active agent flux as compared to greater amounts.
It is to understood that the dill moderator does not enhance percutaneous absorption per the present invention, rather, in all amounts it reduces the rate of percutaneous absorption, which effect has not been suspected in the art.
In addition to the above, there are certain most pro-furred Paces per the present invention, and these are discussed below.
We are unsure why the most preferred combination of Paces of the present invention offers enhanced percutaneous absorption; however, the data we have generated indicate that there is a synergistic effect between Components A and B which can be appropriately moderated, as desired, by varying the amount of dill moderator.
We consider the materials such us the pyrrolidone-type compounds and asides to basically serve a solvent function Jo ` 10 lZ~7753 and materials such as the alkyd halides, fatty acid esters, higher aliphatic monoalcohols and aliphatic hydrocarbons to serve as adjutants which enhance the salivating function of the solvent. We further believe that the solvents carry the active agent whereas the adjutants open up the stratum corneum. We do not wish to be bound by these theories, and we merely use the terminology "solvent" and "adjutant" to maintain a line of distinction between the two classes of materials which are mandatorily used in combination.
The most preferred adjutants as Component A of the present invention include one or more members selected from the group consisting of alkyd halides, fatty acid esters, higher aliphatic monoalcohols, aliphatic hydrocarbons and mixtures thereof.
Of the alkyd halides, those having from 8 to 16 carbon atoms are most preferred, with chloride being the preferred halogen. Both alkyd bromides and iodizes are potentially useful, but alkyd bromides and alkyd iodizes tend to be unstable. Alkyd fluorides are also useful.
The alkyd moiety may be straight or branched chain, may be cycloaliphatic or unsaturated, e.g., alikeness and alikeness are useful.
Most preferred alkyd halides are later exemplified.
The aliphatic hydrocarbons most preferably have 10 to 18 carbon atoms. They may be straight or branched chain and may be cycloaliphatic or unsaturated, erg,, alikeness and alikeness are useful.
The fatty acid esters are conveniently represented by the formula RlCOOR2, Al representing the acid moiety and R2 t representing the alcohol moiety. It is most preferred that 1227~7S3 the total number of carbon atoms ill Al and R2 be from 10 to 17.
Al and R2 may be linear, branched, saturated, unsaturated.
Preferred higher monoalcohols are the aliphatic moo-alcohols with from 12 to 24 carbon atoms. The aliphatic monoalcohols may be branched chain, straight chain, Saturn axed, unsaturated or cyclic.
The most preferred solvents as Component B include the pyrrolidone-type compounds and the asides.
The pyrrolidones are most preferably alkyd pyrrolidones of the formula:
R
N
C = O
(c~2 no where Al is an alkyd group containing up to 4 carbon atoms and n is 3 to 5.
The asides are most preferably represented by the formula:
where R2 can be hydrogen or an alkyd group with up two 3 carbon atoms and R3 and R4 can be an aliphatic group with up to 3 carbon atoms.
The base compositions of the present invention can be prepared by dissolving Component A in Component B and then :~ZZ7753 mixing the dill moderator therein. The order of Mooney is not important. The amount of Component A to be used is generally from 0.1 to 80% by weight based on the total weight of Components A and B, preferably 0.5 to 50% by - 5 weight. Preferred properties of dill moderator have earlier been given. Of course, pharmaceutically acceptable add-lives such as water, etc., can also be added to the base compositions.
The pharmaceutical compositions for topical application per the present invention can be prepared by blending active agents with the above-described composition. There is no particular limit on the active agents used so long as the active agents are systemically active and percutaneously applicable.
Specific examples of active agents include benzodiaze-pines (e.g., Diazepam, Nitrazepam, Flunitrazepam, Lorazepam, Fludiazepam, Clonazepam), diuretic agents [e.g., thiazides (e.g., Bendroflumethiazide, Polythiazide, Methyclothiazide, Trichlorométhiazide, Cyclopenthiazide, ~entylhydrochloro-thiazide, Hydrochlorothiazide, Bumetanide)], antihyperten-size agents (e.g., Clonidine), antihistamic agents [e.g., amino ethers (e.g., diphenhydramine, Carbinoxamine, Diphenyl-praline), ethylenediamines (e.g., Fenbenzamine), monoamine (e.g., Chlorophenylamines)]; non-steroid antiinflammatory agents (e.g., Indomethacine, Ibuprofen, Ibufenac, Alkali-fence, Diclofenac, Mefenamic acid, Flurbiprofen, Flufenamic acid, Ketoprofen), anti-tumor agents (e.g., 5-fluorouracil, 1-(2-tetrahydrofuryl)-5-fluorouracil, Cytarabine, Flexor-dine). Steroid antiinflammatory agents (e.g., Cortisone, Hydrocortisone, Prednisolone, Predonisone, Triamcinolone, Dexamethasone, Betamethasone), anti epileptic agents (e.g., - ~lZZ77S3 Ethosuximide), antiarrytl~ic agents (e.g., Ajmalin, Purajmalin. Pindolol, Propranolol, Quinidine), psychotropic agents [e.g., Clofluperol, Trifluperidol, Haloperidol, Moper one), scopolamine (e.g., methyl scopolamine, bottle scopolamine), metoclopramide, chlorpromazine, atropines (e.g., methyl atropine bromide, methylanisotropine bromide), vascular dilating agents (e.g., isosorbide dinitrate, vitro-glycerine, pentaerythritol tetranitrate, propanyl nitrate, dipyridamole), antibiotics, e.g., te~racyclines (e.g., Tetracycline, Oxytetracycline, metacycline, doxycycline, Minocycline), chloramphenicols, erythromycines], etc. The method of the present invention can also be utilized to percutaneously administer peptizes such as LH-RH, insulin and the like. Of course, pharmaceutically acceptable salts such as the hydrochloride, sodium, potassium, hydrobromide, etc., salts can be used.
Since the present invention is of particular applique-lion with respect to the benzodiazepine materials, these are discussed in more detail below. Particularly preferred bent zodiazepine materials are those which illustrate the buoyancy-diazepine skeleton as schematically illustrated as follows:
Roy, Jo .
~2277S3 wherein is Of, Bra or NO
and Y is with varying degrees of unsaturation and substitution-at positions 1, 2, 3, 4, and 5 as follows:
a) 1, 2 and 4, 5 are unsaturated: Al and R3 are H; R2 is NOR (R is H or SHEA) and N-Z is N O.
b) 1, 2 are saturated and 4, 5 are unsaturated; R3 is H
or OH; -R2 is -H or JO or ON*; R1 is NOR (R is H, SHEA
or SHEA Jo SHEA CHINOOK or Al is CON*
(R is H or SHEA) and is joined to R2 via "*" (a single bond) as follows:
R N
I \ . .
:~1`2D
I 1 2 and 4, 5 are saturated: Al is H; -R2 is JO; R3 is H and positions 4 and 5 constitute a second ring system as follows:
Y 4 R ._ .; o, <
where R and Al are H and SHEA.
Specific examples of benzodiazepines which can be percutaneously administered using the active ingredient/
12;~7753 penetration adjutant combinations of the present invention-include:
a) Chlordiazepoxide; 7-Chloro-2-methylamino-5-phenyl-3H-l, 4-benzodiazèpine-4-oxide b) Diazepam; 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one c) Oxazepam; 7-Chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepine-2-one d) Temazepam; 7-Chloro-1,3-dihydro-3-hydroxy-1-methyl-5-2H-1,4-benzodiazepine-2-one e) Lorazepam; 7-Chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepine-2-one f) Prazepam; 7-Chloro-1-cyclopropylmethyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one g) Fludiazepam; 7-Chloro-1,3-dihydrG-5-(2-fluorophenyl)-1-methyl-2H-1,4-be~zodiazepine-2-one 0 h) Flurazepam; 7-Chloro-1-(2-(dimethylamino)ethyl)-5-(o-fluorophenyl)-1~,3-dihydro-2H-1,4-benzodiazepine-2-one i) Medazepam; 7-Chloro-2,3-dihydro-1-methyl-5-phenyl-lH-5,4-benzodiazepine j) Bromazepam;. 7-Bromo-5-(2-pyridyl)-3H-1,4-benzodiaze-pine-2(lH)-one k) Nitrazepam; 1,3-Dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one 1) Nimetazepam; 1-Methyl-7-nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one m) Clonazepam; 5-(o-Chloro~henyl)-7-nitro-lH-1,4-benzodiazeplrle-2(3H)-one n) Flunitrazepam; 5-(o-Fluorophenyl)-1~3-dihydro-l-meth ,7-nitro-2H-1,4-benzodiazeplne-2-one o) Estazolam; 8-Chloro-1~6-phenyl-4H-s-triazolo(4l3 -A) (1,4)-benzodiazeplne p) Triazolam; 8-Chloro-6-(o-chlorophenyl)-l-methyl-aH
s-triazolo(4,3-A)(1,4)-benzodiazeplne 0 q) Alprazolam; 8-Chloro-l-methyl-6-phenyl-4H-s-triazolo (4,3-A)(1,4~-benzodiazeplne r) Oxazolam; 10-Chloro-2,3,5,6,7,11b-hexahydro-2-methyl-llb-phenylbenzo(6,7)-1,4-diazepino(5,4-b-oxazol-6-one , ~L2Z7753 1 s) Cloxazolam; 10-Chloro-llb-(o-chlorophenyl)-2,3,5,6,7, llb-hexahydrobenzo(6,7)-1,4-diazepino-(S,4-b)oxazol-6-one t) Haloxazolam; 10-Bromo-llb-(o-fluorophenyl)-2,3,7,11b-tetrahydro-oxazolo(3,2,~d)(1,4)benzo-diazepine-6(5H)-one Especially preferred are benzodiazepines b), e), i), k), 1), n) and o).
The amount of active agent(s) blended is sufficient if it is effective for achieving the desired pharmaceutical effect, which varies depending upon the kind of active agents, body weight of the patient, symptoms, etc. The amount may thus be suitably chosen depending upon these conditions. In general, it is preferred that active agents be employed in an amount of 0.01 to 50% by weight, more preferably 0.05 to 10% by weight, based on the total amount of Component A and Component B.
The dose of the active agents administered can be controlled by increasing or decreasing the area of skin to which the pharmaceutical compositions are applied. Accord-tingly, the amount of the active agent is not necessarily limited to the above-described ones.
As will be apparent to one skilled in the art, with increasing concentrations of active agent increasing amounts of active agent will be absorbed by the subject. The lot-lowing discussion is given in texts of flood levels of drug (ng/ml of plasma), this being dependent upon the total area ; of dermal application, as there is a substantially linear increase in amount of active agent absorbed with area.
For a constant area of application and a constant absolute amount of adjutant, the blood level of active agent at any given time is a function of the concentration of I 27'753 i active agility in the composition. That is, increased concern-tractions of active agent in the formulation result in more rapid active agent penetration and higher blood levels.
A further factor which must be considered is that the amount of active agent absorbed will depend on the site of application, for example, scalp, ventral forearm, behind the ear, chest, etc. Typically an area rich in blood vessels is selected.
For most applications, the concentration of active agent in the PACE will generally be on the order of 0.01 to 50% based on Components A and B, the amount of PACE
applied will be about 0.1 my to 100 my per cm and the total . area of application will be on the order of about 0.5 cm2 to about 100 cm2, which will provide therapeutic blood levels of the desired active agent.
These ranges are not, however, to be considered as limitative.
In general, the rate of transepidermal active agent absorption will approach the rate of oral absorption depend-in upon the factors previously discussed (nature and amount of PACE, concentration of active agent in the formulation, and surface area of skin application). Thus, peak blood levels of the active agent may be reached more slowly or at about the same rate and wilt reach about the same level as those obtained by oral administration. Alternatively, the blood level of active agent attained by single dose oral administration may be maintained for an extended period by subsequent percutaneous administration of the active agent.
In the latter case, the initial oral dose may be smaller than the normal therapeutic oral dose so that side effects associated with higher-than-minimal therapeutic blood levels ~l2Z7753 - Tandy by a reduced oral dose may be maintained by the subsequent transepideraml administration at a proper rate.
Therapeutic oral doses of diazepam in man produce blood levels ox approximately 100 ng/ml plasma SUE. Kaplan, MEL. Jack, K. Alexander, and RYE. We infield, J. Harm. sat., 62, 1789-1796 (1973)]. Such a blood level is easily attain-able by percutaneous administration by way of the present invention and produces pharmacological (behavioral) signs of therapeutic effectiveness in appropriate animal models for man, e.g., the rhesus monkey.
The method of the present invention finds application with mammals in general, most particularly man and domestic animals such as Cassiopeia horses, dogs, cats and the like. -The pharmaceutical composition of the present invention is administered to the outer skin as a simple mixture or as a medical preparation by adding known pharmaceutically acceptable third components in the form of solutions, joint-mints (paste-including creams and gels) lotions, adhesive tapes, a plaster, etc.
For example, solutions may simply comprise the active agent dissolved in the PACE with optional components, e.g., glycerin, and the solutions may be incorporated into absorb bunts, e.g., a gauze, porous membrane, etc.
Ointments, gels or creams may contain conventional ingredients (e.g., polyethylene glycol and hydroxy propel-cellulose, etc.) to form the same, and the same may be spread onto backing materials, e.g., a plastic film.
Similarly, plasters or adhesives tapes may contain the active agent and PACE in an adhesive base, e.g., acrylic copolymers or other synthetic gums.
.
The above listed components should essentially be inert in the system and not increase or decrease the effect of the PACE.
The PACE may be added to such a composition in varying amounts as desired, generally from 10 to 99~ by weight.
In developing the present invention, we used both diffusion cells and an animal model. The diffusion cell methods provided a qualitative assessment of the active agent/PAEC effect on percutaneous absorption. The animal model rhesus monkey test also provides an acceptable pharmacokinetic model for man as indicated in J. Sock Comet. Chum., 30, 297-307. Sept./Oct. 1979 and Toxically.
Apply Pharmacol., 32, 394-398, 1975.
EXPERIMENTAL
In Vitro Skin Penetration Studies with Diffusion Cell Technique -Rat full thickness skins were used in the diffusion cell method of Michael, Ache Journal, 21 [5], 985-996, 1975. The rat skin was mounted in the diffusion cell in a vertical position between the upstream and the downstream compartments; the exposed area of the skin approximated 4.15 cm .
The skin was excised from the shaved abdominal site of male albino rats weighing 250 300 g, and washed with normal saline solution after the subcutaneous fat was carefully removed with scissors. .
The active agent/PAEC solution of known concentration was added to the upper compartment of the cell, which was exposed to the epithelial side of the skin and a normal saline solution was placed in the lower compartment.
12;~7753 , The penetration rate s sty Ed in a thermostat Ed bath at 30C. At appropriate intervals samples were withdrawn from the lower compartment and subsequently analyzed for active agent concentration by standard analytical methods.
As an alternative, the finite dose technique of Franz, Cuff. Prowl. Dermatol., Vol. 7, p. 58 68 (Larger, Beset, 1978) can also be followed where the rat skin is mounted horizontally in a diffusion cell apparatus and the exposed area of the skin approximates 0.7 cm2.
The active agent/PAEC solution of known concentration was added to the upstream compartment to which the epithet-tat side of the skin was exposed, and a normal saline solution was added to the downstream compartment.
In Viva Rhesus Monkey Test If desired, an in viva rhesus monkey test as described below can also be used to determine the effect of the PAEC/diol moderator combinations of the present invention.
Male rhesus monkeys weighing 10-14 Kg can be used as the subject. An appropriate area of the monkey's chest is shaved 24 hours before drug application.
Drug formulations comprising the PACE are applied to a certain area of the chest. The monkey is restrained in a chair to prevent it from touching its chest.
Blood samples are taken at appropriate intervals after the application. The heparinized blood is centrifuged, and the plasma removed and stored at -20C until analyzed.
Diazepam in plasma can be analyzed following the GLC
method of Angles, J. Chromatog., 75, 55-78, 1973.
.
1;~27~753 .
1 Hereafter the present invention will be illustrated with reference to an example in more detail but it is not to be deemed to be limited thereto, Examples of certain combinations of Components A and B
per the present invention are given in Canadian Patent Apply-cation No. 453,790 filed April 25~ 1984 in the names of S.
Swept et at and entitled METHOD FOR PERCUTANEOUSLY
ADMINISTERING PHYSIOLOGICALLY ACTIVE AGENTS wherein no dill moderator is used, and in Canadian Patent Application No, 455,975 filed June, I 84 in renames of K, Swept et at and entitled METHOD FOR PERCUTANEOUSLY ADMINISTERING PHYSIC-LOGICALLY ACTIVE AGENTS USING ON ALCOHOL ADJUTANT AND A
SOLVENT, Compositions were prepared by firstly dissolving Component A with Component By then mixing the active agent in the mixture and then mixing the dill therein. The order of mixing is not important, In the case that Component B is a solid at ambient temperature or will not homogeneously mix with Component A 20 wt.% of ethylene glycol monobutyl ether based on the weight of Components A and B was used as an agent for assisting dissolution.
Further in the following example, the abbreviations below are used:
C12H dodecanol C12Cl - dodecyl chloride DMAc - dim ethyl acetamide MY - l-methyl-2-pyrrolidone I
1 Unless otherwise indicated in the following examples the active agent was diazepam or metoclopramide hydrochlor-ides The flux of the active agent is given in the terms of ~g/cm2/8 hours. 25 Volume percent component A with respect to component A and component B volume with or without dills aye I
~2Z77S3 was used in the composition along with 2.5 ~7eigllt percent of the active agent. For purposes of comparison, in one instance the result for an adjutant alone with a dill is given.
Example 1 The Figure is a plot of a diazepam flux versus time (in hours) illustrating the moderating effect of dills for the systems 25% C12Cl in DMAc, 25% C12Cl in a 1:1 weight mixture of DMAc/2,3-butane dill and 25% C12Cl in a 1:2 weight mixture of DMAc/2,3-butane dill. 25% C12Cl in 2,3-butane dill is also shown for comparison.
Example 2 This example shows the moderating effect of dills for the systems 25% C120H in MY and 25% C120H in a 1:1 volume mixture of MY / 1,2-propane dill. Table 2 shows the met-clopramide HO flux for 8 hours with these systems.
Table 2 Flux (~q/cm2/8 his) 25% C120H in MY 4382 25% KIWI in a 1:1 volume mixture 1369 - of MP/1,2-propane dill While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
` 23
Claims (8)
- Claim 1 continued the proviso that R6 , R7 and R8 have in total at least 3 carbon atoms, and lactones having 4 to 6 carbon atoms, wherein Components A and B are present in an amount effective to enhance percutaneous administration of the active agent and the diol moderator is present in an amount effective to moderate the rate of percutaneous absorption of the active agent within the range of therapeutically effective rates.
2. The composition of claim 1 wherein Component A is selected from the group consisting of a halogen substituted alkyl halide having from 8 to 18 carbon atoms, an aliphatic hydrocarbon group having from 10 to 18 carbon atoms, a fatty acid ester represented by the formula R1COOR2 wherein the total number of carbon atoms in R1 and R2 is from 10 to 17, an aliphatic mono-alcohol having from 12 to 24 carbon atoms and mixtures thereof, and wherein Component B is selected from the group consisting of pyrrolidone-type compounds repre-sented by the formula: - Claim 2 continued where n is an integer of 3 to 5, and R1 is an alkyl group containing from 1 to 4 carbon atoms or an amide represented by the general formula:
where R2 can be hydrogen or an alkyl group with up to 3 carbon atoms and R3 and R4 can be an alkyl group with up to 3 carbon atoms, with the proviso that the total number of carbon atoms in R2 to R4 is at least 3. - 3. The composition of claim 1 or 2 wherein said diol has 3 to 8 carbon atoms.
- 4. The composition of claim 1 or 2 wherein said diol is an alipatic diol having 3 to 6 carbon atoms.
5. A carrier system for percutaneous administration of a physiologically active agent comprising at least one of the following Components A, at least one of the following Components B and at least one diol moderator:
Component A: straight, branched or cyclic aliphatic hydrocarbons having 5 to 24 carbon atoms, straight, branched or cyclic aliphatic hydrocarbons having 5 to 24 carbon atoms substituted with one or more halogen atoms, an alcohol ester of an aliphatic carboxylic acid having a total number of carbon atoms of from 7 to 18, a mono or diether having 10 to 18 carbon atoms, a ketone having 11 to 15 carbon atoms, an aliphatic monoalcohol having from 10 to 26 carbon atoms and mixtures thereof;
Component B: a thioglycerol, a lactic acid or an ester thereof, a cyclic urea, a compound represented by the general formula:
- Claim 5 continued...
where R1 to R4 each represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, or an acyl group having 1 or 2 carbon atoms, a compound represented by the formula:
wherein R5 represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms and n represents an integer of 3 to 5, a compound represented by the general formula:
wherein R6 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and R7 and R8 each represents an alkyl group having 1 to 3 carbon atoms, with the proviso that R6, R7 and R8 have in total at least 3 carbon atoms, and lactones having 4 to 6 carbon atoms.
6. The carrier system of claim 5 wherein Component A
is selected from the group consisting of a halogen substituted alkyl halide having from 8 to 18 carbon atoms, an aliphatic hydrocarbon group having from 10 to 18 carbon atoms, a fatty acid ester represented by the formula R1COOR2 wherein the total number of carbon atoms in R1 and R2 is - Claim 6 continued....
from 10 to 17, an aliphatic monoalcohol having from 12 to 24 carbon atoms and mixtures thereof, and wherein Component B
is selected from the group consisting of pyrrolidone-type compounds represented by the formula:
where n is an integer of 3 to 5, and R1 is an alkyl group containing from 1 to 4 carbon atoms or an amide represented by the general formula:
where R2 can be hydrogen or an alkyl group with up to 3 carbon atoms and R3 and R4 can be alkyl group with up to 3 carbon atoms, with the proviso that the total number of carbon atoms in R2 to R4 is at least 3. - 7. The carrier system of claim 5 or 6 wherein said diol has 3 to 8 carbon atoms.
- 8. The carrier system of claim 5 or 6 wherein said diol is an aliphatic diol having 3 to 6 carbon atoms.
1. A pharmaceutical composition for percutaneous administration comprising a mixture of a physiologi-cally active agent and a carrier system enhancing per-cutaneous absorption of said active agent, said carrier system comprising at least one of the following Compon-ents A, at least one of the following Components B and at least one diol moderator;
Component A: straight, branched or cyclic aliphatic hydrocarbons having 5 to 24 carbon atoms, straight, branched or cyclic aliphatic hydrocarbons having 5 to 24 carbon atoms substituted with one or more halogen atoms, an alcohol ester of an aliphatic carboxylic acid having a total number of carbon atoms of from 7 to 18, a mono or diether having 10 to 18 carbon atoms, a ketone having 11 to 15 carbon atoms, an aliphatic monoalcohol having from 10 to 26 carbon atoms and mixtures thereof;
Component B: a thioglycerol, a lactic acid or an ester thereof, a cyclic urea, a compound represented by the general formula:
Claim 1 continued where R1 to R4 each represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, or an acyl group having 1 or 2 carbon atoms, a compound repre-sented by the formula:
wherein R5 represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms and n represents an integer of 3 to 5, a compound represented by the gen-eral formula:
wherein R6 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and R7 and R8 each repre-sents an alkyl group having 1 to 3 carbon atoms, with
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US51010083A | 1983-07-01 | 1983-07-01 | |
US510,100 | 1983-07-01 |
Publications (1)
Publication Number | Publication Date |
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CA1227753A true CA1227753A (en) | 1987-10-06 |
Family
ID=24029385
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000455978A Expired CA1227753A (en) | 1983-07-01 | 1984-06-06 | Method for percutaneously administering physiologically active agents using an adjuvant, a solvent and a diol moderator |
Country Status (9)
Country | Link |
---|---|
JP (1) | JPS6013720A (en) |
CA (1) | CA1227753A (en) |
CH (1) | CH658993A5 (en) |
DE (1) | DE3424058C3 (en) |
DK (1) | DK315984A (en) |
FR (1) | FR2548024B1 (en) |
GB (1) | GB2142238B (en) |
NL (1) | NL8402045A (en) |
SE (1) | SE8403488L (en) |
Families Citing this family (4)
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JPS60199822A (en) * | 1984-03-23 | 1985-10-09 | Takeda Chem Ind Ltd | External pharmaceutical for percutaneous absorption |
DE4209862A1 (en) * | 1992-03-26 | 1993-09-30 | Linde Ag | Pallet truck |
US5693335A (en) * | 1995-06-07 | 1997-12-02 | Cygnus, Inc. | Skin permeation enhancer composition for use with sex steroids |
GB9826656D0 (en) | 1998-12-03 | 1999-01-27 | Novartis Ag | Organic compounds |
Family Cites Families (19)
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NL281225A (en) * | 1961-07-20 | |||
FR2001768A1 (en) * | 1968-02-12 | 1969-10-03 | Gillette Co | N-Alkyl-2-pyrrolidone to improve cutaneous absorption - methyl, ethyl and n-butyl pyrrolidone(s), opt. with water and/or ethanol give improved skin penetration |
SE325667B (en) * | 1968-03-06 | 1970-07-06 | Medisan Ab | |
US3551554A (en) * | 1968-08-16 | 1970-12-29 | Crown Zellerbach Corp | Enhancing tissue penetration of physiologically active agents with dmso |
US3472931A (en) * | 1969-01-17 | 1969-10-14 | Foster Milburn Co | Percutaneous absorption with lower alkyl amides |
GB1404583A (en) * | 1971-10-08 | 1975-09-03 | Vymatt Sa | Urea compositions and methods of preparation thereof |
DE2528516A1 (en) * | 1974-07-05 | 1976-01-22 | Sandoz Ag | NEW GALENIC PREPARATION |
GB1504302A (en) * | 1974-08-23 | 1978-03-15 | Fisons Ltd | Sedative method and composition |
US3969516A (en) * | 1974-12-19 | 1976-07-13 | Nelson Research & Development Company | Composition and method for treatment of acne |
US4017641A (en) * | 1975-01-31 | 1977-04-12 | The Procter & Gamble Company | Skin moisturizing compositions containing 2-pyrrolidinone |
GB1538903A (en) * | 1975-04-11 | 1979-01-24 | Nelson Res & Dev | Carrier for a topically applied physiologically active agent or cosmetic agent |
GB1553310A (en) * | 1975-06-19 | 1979-09-26 | Nelson Res & Dev | Vehicle composition containing 1-substituted azacycloalkan-2-ones |
DE2608221B1 (en) * | 1976-02-28 | 1977-07-21 | Beiersdorf Ag | COSMETIC AGENT FOR SMOOTHING THE SKIN |
JPS52148614A (en) * | 1976-06-04 | 1977-12-10 | Masao Yonemushi | Production of additive for skin medicine |
US4202888A (en) * | 1976-07-12 | 1980-05-13 | Kali-Chemie Pharma Gmbh. | Readily enterally absorbable pharmaceutical compositions of cardiac glycosides and preparation thereof |
US4291062A (en) * | 1978-06-16 | 1981-09-22 | Phares Pharmaceutical Research N.V. | Pharmaceutical compositions containing urea |
DE2847975A1 (en) * | 1978-11-04 | 1980-05-14 | Merck Patent Gmbh | Free formaldehyde removal from pharmaceuticals and cosmetics - by adding urea to bind the formaldehyde |
CA1165240A (en) * | 1980-07-09 | 1984-04-10 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions |
JPS58164520A (en) * | 1982-03-24 | 1983-09-29 | Nitto Electric Ind Co Ltd | Base composition and drug composition for external use |
-
1984
- 1984-02-20 JP JP2867084A patent/JPS6013720A/en active Granted
- 1984-06-06 CA CA000455978A patent/CA1227753A/en not_active Expired
- 1984-06-26 CH CH308384A patent/CH658993A5/en not_active IP Right Cessation
- 1984-06-27 GB GB08416358A patent/GB2142238B/en not_active Expired
- 1984-06-28 FR FR8410276A patent/FR2548024B1/en not_active Expired
- 1984-06-28 NL NL8402045A patent/NL8402045A/en not_active Application Discontinuation
- 1984-06-28 DK DK315984A patent/DK315984A/en not_active Application Discontinuation
- 1984-06-29 DE DE19843424058 patent/DE3424058C3/en not_active Expired - Lifetime
- 1984-06-29 SE SE8403488A patent/SE8403488L/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
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SE8403488L (en) | 1985-01-02 |
GB2142238A (en) | 1985-01-16 |
DK315984D0 (en) | 1984-06-28 |
JPS6013720A (en) | 1985-01-24 |
CH658993A5 (en) | 1986-12-31 |
DK315984A (en) | 1985-01-02 |
DE3424058C2 (en) | 1986-05-22 |
DE3424058C3 (en) | 1992-05-07 |
GB8416358D0 (en) | 1984-08-01 |
NL8402045A (en) | 1985-02-01 |
SE8403488D0 (en) | 1984-06-29 |
FR2548024A1 (en) | 1985-01-04 |
JPH0119365B2 (en) | 1989-04-11 |
GB2142238B (en) | 1987-04-15 |
FR2548024B1 (en) | 1988-04-29 |
DE3424058A1 (en) | 1985-01-10 |
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