WO1999034828A1 - A transdermally administered pharmaceutical composition containing astringents - Google Patents

A transdermally administered pharmaceutical composition containing astringents Download PDF

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Publication number
WO1999034828A1
WO1999034828A1 PCT/KR1999/000016 KR9900016W WO9934828A1 WO 1999034828 A1 WO1999034828 A1 WO 1999034828A1 KR 9900016 W KR9900016 W KR 9900016W WO 9934828 A1 WO9934828 A1 WO 9934828A1
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Prior art keywords
drug
pharmaceutical composition
aluminum
zinc
ionic
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PCT/KR1999/000016
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French (fr)
Inventor
Byung Chul Shin
Sung Soo Kim
Jae Hong Kim
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Korea Research Institute Of Chemical Technology
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Publication of WO1999034828A1 publication Critical patent/WO1999034828A1/en

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones

Definitions

  • the present invention relates to a transdermally administered pharmaceutical composition and more particularly, to the transdermally administered pharmaceutical composition, formulated in such a manner that a certain astringent is added to the water-soluble composition containing ionic, weak ionic or non-ionic molecules of drug and then an electric driving force such as iontophoresis is applied to the composition, whereby ensuring better absorption rate of drug in skin.
  • the iontophoresis refers to a method designed to rapidly deliver a larger amount of drug via skin or mucosa for therapeutic use, in a manner that ionic molecule or ion moves from anode to cathode or inversely in accordance with flow of electrical current.
  • iontophoresis for drug delivery into the skin in 1970s, the skin delivery system of ionic drug such as protein and peptide drug using the iontophoresis was reported.
  • the iontophoresis serves to provide a driving force to ionic drugs for their permeation into the skin with electrical current.
  • electrolyte solution as well as ionic drug is required.
  • the iontophoresis-based patch was firstly introduced by ALZA Co. and ELAN Co. so as to deliver protein and peptide drug.
  • ALZA Co. has prepared iontophoresis-based patch containing fentanyl, an analgesic agent for the relief of pain in cancer patient.
  • ELAN Co. developed a power patch, which delivers insulin for therapeutics of diabetes and LHRH, hormone-stimulating factor, using electroosmosis.
  • an object of this invention is to provide a transdermally administered pharmaceutical composition for better enhancement of drug delivery via skin, formulated in such a manner that an organic astringent such as some salt compound, tannic acid and phenol is added to a water-soluble pharmaceutical composition containing an ionic, weak ionic or non-ionic drug substance for denaturing and precipitating protein present in the micro- permeation path in skin.
  • an organic astringent such as some salt compound, tannic acid and phenol
  • Figure 1 is a graph showing the results of skin permeation test using the pharmaceutical composition of EXAMPLE 2 and other composition in the absence of astringent;
  • Figure 2 is a graph showing the results of skin permeation test using the pharmaceutical composition of EXAMPLE 2 and IOMED of USA.
  • This invention is characterized by a transdermally administered pharmaceutical composition
  • ionic drug ionic drug, weak ionic drug or non- ionic drug with its molecular weight of 100-100,000 including one or more astringents selected from the group consisting of salt compound such as aluminum, zinc, iron and bismuth, tannic acid and phenol.
  • This invention pertains to a pharmaceutical composition containing an astringent for better permeation of ionic, weak ionic or non-ionic drug via skin.
  • an astringent refers to a precipitating agent of protein acting on skin or mucosa. Use of the astringent prevents movement of plasma protein, which leads to inhibition of local edema and inflammation, while reducing a permeability of cell membrane accompanied bv cell shrinkage and micro-folding. In addition, the astringent causes some mucosa and secretion ion tube to dry and shrink.
  • the astringent used is salt form which is ionized in aqueous solution.
  • the salts with positive charge move toward cathode in competition with drug molecules.
  • the ionized salts with a larger electric density and smaller molecular size more rapidly move to surface of skin, binds to micro- permeation path of sweat glands or pillar pore and constraints protein molecules of the path, followed by destroying uniform arrangement of lipid components bound to the protein.
  • the astringent includes a salt compound containing nietal such as aluminum, zinc, manganese, iron and bismuth.
  • the salt compound as astringent is also employed as substitute of electrolyte since the compound is ionized in aqueous solution, and thus the amount of unnecessary ions is reduced in the process of iontophoresis.
  • the salt compound as astringent of this invention is one or more compounds selected from the group consisting of alum, aluminum acetate, aluminum chloride, aluminum chlorohydrate, aluminum subacetate, aluminum sulfate, aluminum zirconium chlorohydrate, bismuth subcarbonate, bismuth subnitrate, calamine, ferric chloride tincture, glutaral, potassium permanganate, resorcinol, silver nitrate, zinc sulfate, zinc chloride, zinc oxide, zinc phenolsulfonate, zinc pyrithione and zinc undecylenate.
  • the alum is selected from the group consisting of A1K(S0 4 ) 2 • 12H 2 0, A1 2 (NH 4 ) (S0 4 ) ⁇ 12LLO and alumen.
  • the astringent also includes some organic compounds such as tannic acid and phenol in addition to the foregoing salt compounds. Since these organic compounds have no free ion compared with the salt compound mentioned above, it cannot be used as electrolyte but such organic compounds serves to form the penetration path by precipitating the proteins present in skin tissues, which results in further enhancing the skin permeation of drug.
  • the amount of astringent is in the range of 0J-50wt% to the total pharmaceutical composition; if the amount is less than 0Jwt%, the permeation effect is not effectively obtained; in the case of exceeding 50wt%, the excess amount may be responsible for skin rash, etc.
  • the drug of this invention includes ionic, weak ionic or non-ionic drug.
  • astringent is added to the drug dissolved in alcohol, phenol or some acid as a solvent so as to improve the skin permeation of drug via skin.
  • the molecular weight of drug is in the range of 100-100,000.
  • the drug is one or more drugs selected from the group consisting of peptide drug, protein drug, steroid drug, l o hormone drug, anti-inflammatory drug, analgesia, anticancer drug, antiviral ' drug, antibacterial drug and vitamins. If the molecular weight of drug is less than 100, the astringent of this invention becomes meaningless and unnecessary; in the case of exceeding 100,000, the drug may not penetrate via skin in the presence of astringent.
  • the method providing electric driving force which is applied to the above pharmaceutical composition so as to improve the permeation via skin, is one or more methods selected from the group consisting of iontophoresis, electroosmosis, electroporation and sonophoresis , which are well known to those skilled in the art.
  • iontophoresis electroosmosis
  • electroporation electroporation and sonophoresis
  • Lidocaine as drug was added to 20% aqueous solution of ethanol and thus prepared 50 m ft of alcoholic aqueous solution of lidocaine(2wt%). Then, 2wt% of aluminum acetate were added to the solution with stirring and dissolved by saturation point. If the non-dissolved precipitate of aluminum acetate might be generated in the above step, the solubility of the solution was increased with the slight heating. Hence, 2wt% of the aluminum acetate is sufficient due to its extremely low solubility in aqueous solution.
  • the skin permeation test for the pharmaceutical composition prepared in EXAMPLE 1 was performed using iontophoresis as follows:
  • the pharmacuetical composition was placed in diffusion cell of 4 in ft in volume.
  • the skin of hairless mouse having the diameter of 15 uini was placed at the middle of the diffusion cell.
  • 4 ml' ot phosphate buffer solution(pH 7.2) was added to the opposite cell to the diffusion cell, and platinum electrode was immersed in both cell, followed by fixing at sampling port.
  • the platinum electrode in aqueous solution of the lidocaine was connected to cathode, while the platinum electrode in phosphate buffer solution to anode.
  • An electrical power supplier was connected both electrodes to send a constant current of 2 in ⁇ until the test was completed.
  • the permeation amount of lidocaine via skin of hairless mouse was measured with ⁇ o HPLC at 254 nn ⁇ .
  • the skin permeation test of the pharmaceutical composition prepared in EXAMPLE 2 was performed in the same manner as TEST 1 and the 15 permeation amount of lidocaine via skin was measured. The results were presented in Figure 1.
  • EXAMPLE 2 showed much higher permeation rate 5 of the drug in proportion to treatment time of electric current and a large amount of penetrated drugs. However, the control without astringent showed less effective manner in terms of permeation rate and amount. COMPARATIVE TEST 2
  • EXAMPLE 2 showed much higher permeation rate and larger amount of penetrated drugs at 30 minutes of treatinent time of electric current. However, the IOMED showed much less effective manner in terms of permeation rate and amount.
  • composition containing astringent according to this invention may be effectively improved in terms of permeation extent of drug, when applied to skin or mucosa.

Abstract

The present invention relates to a transdermally administered pharmaceutical composition and more particularly, to the transdermally administered pharmaceutical composition, formulated in such a manner that a certain astringent is added to the water-soluble composition containing ionic, weak ionic or non-ionic molecules of drug and then an electric driving force such as iontophoresis is applied to the composition, whereby ensuring better absorption rate of drug in skin.

Description

A TRANSDERMALLY ADMINISTERED PHARMACEUTICAL COMPOSITION CONTAINING ASTRINGENTS
BACKGROUND OF THE INVENTION Field of the Invention
The present invention relates to a transdermally administered pharmaceutical composition and more particularly, to the transdermally administered pharmaceutical composition, formulated in such a manner that a certain astringent is added to the water-soluble composition containing ionic, weak ionic or non-ionic molecules of drug and then an electric driving force such as iontophoresis is applied to the composition, whereby ensuring better absorption rate of drug in skin.
Description of the Related .Art In general, when an ionic, weak ionic or non-ionic drug in larger amount is transdermally administrated via the skin or mucosa of human body for its rapid absorption, a method of utilizing the electric movement of drug or solvent molecules in ions by electric driving force is widely applied.
To this end, the following methods for utilizing the electric driving force have been used: a) iontophoresis, b) electroosmosis, c) electroporation, d) sonophoresis using a sonic wave and e) laserporation using light beam.
Among them, the iontophoresis is well known. The iontophoresis refers to a method designed to rapidly deliver a larger amount of drug via skin or mucosa for therapeutic use, in a manner that ionic molecule or ion moves from anode to cathode or inversely in accordance with flow of electrical current.
With the introduction of iontophoresis for drug delivery into the skin in 1970s, the skin delivery system of ionic drug such as protein and peptide drug using the iontophoresis was reported. The iontophoresis serves to provide a driving force to ionic drugs for their permeation into the skin with electrical current. Generally, in an effort to improve the efficiency ot iontophoresis, electrolyte solution as well as ionic drug is required.
? Hitherto, results of many studies and patents on a method of delivering drug by iontophoresis has been provided as follows: a) a delivery of insulin through pig skin (R. L. Stephev et al., Biomed. Biochem. Actn, 43(5), 553(1984)) was performed; b) it was presented through experiment with mouse-rabbit model that the extent of delivering cirug is larger in pulse current l o than direct current (Y. W. Chien, Int. ]. Pharni., 44, 197(1988)); and c) electroosmosis-applied delivering method was disclosed with presentation ot solvent composition of iontophoresis and delivery system (Korean Patent Appln. No. 88-989 and 88-1245). In addition, the Patents relating to this invention are US Patent Nos. 4,842,577; 4,878,892; 4,927,408; 4,940,456;
15 5,003,987 and 5,084,006.
The conventional methods have centered on the conditions of electric current and selection of electrolyte solution in iontophoresis. Accordingly, much progress has been made in the drug delivery system using iontophoresis. In the meantime, many pharmaceutical companies began research on 0 iontophoresis since the early of 1980s. IOMED of Motion Control Co. (Salt Lake City, UT) has developed local anesthetic system, which comprises iontophoresis apparatus for delivering lidocaine and pharmaceutical composition and obtained the patent based on the invention, and commercialized a patch preparation manufactured in such a manner that 5 dexamethasone is ionized by using sodium phosphate, which is subjected to iontophoresis.
Currently, an antibiotic patch by iontophoresis has been under development for the treatment of skin wounds or tumor. In addition, it has been a major object of research that iontophoresis is applied to protein and peptide drug, which has no suitable route of administration except injection.
The iontophoresis-based patch was firstly introduced by ALZA Co. and ELAN Co. so as to deliver protein and peptide drug. ALZA Co. has prepared iontophoresis-based patch containing fentanyl, an analgesic agent for the relief of pain in cancer patient. ELAN Co. developed a power patch, which delivers insulin for therapeutics of diabetes and LHRH, hormone-stimulating factor, using electroosmosis.
Although many products were successfully commercialized in parallel with the growing number of patients in the world, restricted permeation ot drug into skin can be explained as follows: a) many drugs tend to be hvdrophobic and cannot be readily ionized so that they are not easily applied in iontophoresis, and if the drug is ionized, it is not preferred since the ionized solution may be toxic to skin; and b) the drug with high molecular weight mav not readily permeate to skin or mucosa, though it is hydrophilic and ionized, since the skin and mucosa is a minute structure in human body.
SUMMARY OF THE INVENTION
Therefore, an object of this invention is to provide a transdermally administered pharmaceutical composition for better enhancement of drug delivery via skin, formulated in such a manner that an organic astringent such as some salt compound, tannic acid and phenol is added to a water-soluble pharmaceutical composition containing an ionic, weak ionic or non-ionic drug substance for denaturing and precipitating protein present in the micro- permeation path in skin.
Description of the Drawings
Figure 1 is a graph showing the results of skin permeation test using the pharmaceutical composition of EXAMPLE 2 and other composition in the absence of astringent;
Figure 2 is a graph showing the results of skin permeation test using the pharmaceutical composition of EXAMPLE 2 and IOMED of USA.
Detailed Description of the Invention
This invention is characterized by a transdermally administered pharmaceutical composition comprising ionic drug, weak ionic drug or non- ionic drug with its molecular weight of 100-100,000 including one or more astringents selected from the group consisting of salt compound such as aluminum, zinc, iron and bismuth, tannic acid and phenol.
This invention is explained in more detail as set forth hereunder: This invention pertains to a pharmaceutical composition containing an astringent for better permeation of ionic, weak ionic or non-ionic drug via skin. In general, an astringent refers to a precipitating agent of protein acting on skin or mucosa. Use of the astringent prevents movement of plasma protein, which leads to inhibition of local edema and inflammation, while reducing a permeability of cell membrane accompanied bv cell shrinkage and micro-folding. In addition, the astringent causes some mucosa and secretion ion tube to dry and shrink.
In accordance with this invention, the astringent used is salt form which is ionized in aqueous solution. When an electric current is applied to pharmaceutical composition of this invention in the process of iontophoresis, the salts with positive charge move toward cathode in competition with drug molecules. The ionized salts with a larger electric density and smaller molecular size more rapidly move to surface of skin, binds to micro- permeation path of sweat glands or pillar pore and constraints protein molecules of the path, followed by destroying uniform arrangement of lipid components bound to the protein.
In addition, since some protein present in the micro-penetration path of sweat glands or pillar pore is generally weak anionic in physiological pH condition and thus the posit 'ely charged salts bind to it. Then, the protein is neutralized and finally the resistant of permeation is reduced.
In this invention, the astringent includes a salt compound containing nietal such as aluminum, zinc, manganese, iron and bismuth. The salt compound as astringent is also employed as substitute of electrolyte since the compound is ionized in aqueous solution, and thus the amount of unnecessary ions is reduced in the process of iontophoresis.
The salt compound as astringent of this invention is one or more compounds selected from the group consisting of alum, aluminum acetate, aluminum chloride, aluminum chlorohydrate, aluminum subacetate, aluminum sulfate, aluminum zirconium chlorohydrate, bismuth subcarbonate, bismuth subnitrate, calamine, ferric chloride tincture, glutaral, potassium permanganate, resorcinol, silver nitrate, zinc sulfate, zinc chloride, zinc oxide, zinc phenolsulfonate, zinc pyrithione and zinc undecylenate. The alum is selected from the group consisting of A1K(S04)2 • 12H20, A12(NH4) (S04) ■ 12LLO and alumen. According to this invention, the astringent also includes some organic compounds such as tannic acid and phenol in addition to the foregoing salt compounds. Since these organic compounds have no free ion compared with the salt compound mentioned above, it cannot be used as electrolyte but such organic compounds serves to form the penetration path by precipitating the proteins present in skin tissues, which results in further enhancing the skin permeation of drug.
According to this invention, it is preferred that the amount of astringent is in the range of 0J-50wt% to the total pharmaceutical composition; if the amount is less than 0Jwt%, the permeation effect is not effectively obtained; in the case of exceeding 50wt%, the excess amount may be responsible for skin rash, etc.
The drug of this invention includes ionic, weak ionic or non-ionic drug.
5 The above mentioned astringent is added to the drug dissolved in alcohol, phenol or some acid as a solvent so as to improve the skin permeation of drug via skin. According to this invention, it is preferred that the molecular weight of drug is in the range of 100-100,000. The drug is one or more drugs selected from the group consisting of peptide drug, protein drug, steroid drug, l o hormone drug, anti-inflammatory drug, analgesia, anticancer drug, antiviral ' drug, antibacterial drug and vitamins. If the molecular weight of drug is less than 100, the astringent of this invention becomes meaningless and unnecessary; in the case of exceeding 100,000, the drug may not penetrate via skin in the presence of astringent.
15 In this invention, the method providing electric driving force, which is applied to the above pharmaceutical composition so as to improve the permeation via skin, is one or more methods selected from the group consisting of iontophoresis, electroosmosis, electroporation and sonophoresis , which are well known to those skilled in the art. 0 The following specific examples are intended to be illustrative of the invention and should not be construed as limiting the scope of the invention as defined by appended claims.
EXAMPLE 1
Lidocaine as drug was added to 20% aqueous solution of ethanol and thus prepared 50 m ft of alcoholic aqueous solution of lidocaine(2wt%). Then, 2wt% of aluminum acetate were added to the solution with stirring and dissolved by saturation point. If the non-dissolved precipitate of aluminum acetate might be generated in the above step, the solubility of the solution was increased with the slight heating. Hence, 2wt% of the aluminum acetate is sufficient due to its extremely low solubility in aqueous solution.
EXAMPLE 2-5
The pharmaceutical compositions were prepared in the same manner as EXAMPLE 1 according to the composition as shown in the following Table 1. Table. 1
Figure imgf000009_0001
TEST 1
The skin permeation test for the pharmaceutical composition prepared in EXAMPLE 1 was performed using iontophoresis as follows:
First, the pharmacuetical composition was placed in diffusion cell of 4 in ft in volume. The skin of hairless mouse having the diameter of 15 uini was placed at the middle of the diffusion cell. Then, 4 ml' ot phosphate buffer solution(pH 7.2) was added to the opposite cell to the diffusion cell, and platinum electrode was immersed in both cell, followed by fixing at sampling port. Thereafter, the platinum electrode in aqueous solution of the lidocaine was connected to cathode, while the platinum electrode in phosphate buffer solution to anode. An electrical power supplier was connected both electrodes to send a constant current of 2 inΛ until the test was completed. And the permeation amount of lidocaine via skin of hairless mouse was measured with ι o HPLC at 254 nnι.
TEST 2
The skin permeation test of the pharmaceutical composition prepared in EXAMPLE 2 was performed in the same manner as TEST 1 and the 15 permeation amount of lidocaine via skin was measured. The results were presented in Figure 1.
COMPARATIVE TEST 1
The skin permeation test of the pharmaceutical composition prepared 0 in EXAMPLE 2 without alum was performed in the same manner .as TEST 1 and the permeation amount of lidocaine via skin was measured. The results were presented as control in Figure 1.
As revealed in Figure 1, the pharmaceutical composition prepared in
EXAMPLE 2 according to this invention showed much higher permeation rate 5 of the drug in proportion to treatment time of electric current and a large amount of penetrated drugs. However, the control without astringent showed less effective manner in terms of permeation rate and amount. COMPARATIVE TEST 2
The skin permeation test of the IOMED on the market of USA, the aqueous solution of lidocaine for the use of iontophoresis, was performed in the same manner as TEST 1 and the permeation amount of lidocaine via skin was measured. The results were presented in Figure 2.
As revealed in Figure 2, the pharmaceutical composition prepared in
EXAMPLE 2 according to this invention showed much higher permeation rate and larger amount of penetrated drugs at 30 minutes of treatinent time of electric current. However, the IOMED showed much less effective manner in terms of permeation rate and amount.
As mentioned above, it is well known that the pharmaceutical composition containing astringent according to this invention may be effectively improved in terms of permeation extent of drug, when applied to skin or mucosa.

Claims

What is claimed is:
Λ . A transdermally administered pharmaceutical composition, which comprises: (a) an drug, wherein the cirug is selected from the group consisting of ionic drug, weak ionic drug and non-ionic drug, and has molecular weight of 100-100,000; and (b) an astringent, wherein the astringent is one or more compounds selected from the group consisting of salt compound including aluminum, zinc, iron and bismuth, tannic acid and phenol.
2. The transdermally administered pharmaceutical composition according to claim 1, wherein the salt compound is one or more compounds selected from the group consisting of alum, aluminum acetate, aluminum chloride, aluminum chlorohydrate, aluminum subacetate, aluminum sulfate, aluminum zirconium chlorohydrate, bismuth subcarbonate, bismuth subnitrate, calamine, ferric chloride tincture, glutaral, potassium permanganate, resorcinol, silver nitrate, zinc sulfate, zinc chloride, zinc oxide, zinc phenolsulfonate, zinc pyrithione, zinc undecylenate; in which the alum is selected from the group consisting of A1K(S04)2 ΓÇó 12H20, A12(NH4)
(SO,) - 12H,O and alumen.
3. The transdermally administered pharmaceutical composition according to claim 1, wherein the drug is one or more drugs selected from the group consisting of peptide drug, protein drug, steroid drug, hormone drug, anti- inflammatorv drug, analgesia, anticancer drug, antiviral drug, antibacterial drug and vitamins. The transdermalh' administered pharmaceutical composition according to claim 3, wherein the drug is dissolved in alcohol solvent or acid solvent.
PCT/KR1999/000016 1998-01-09 1999-01-08 A transdermally administered pharmaceutical composition containing astringents WO1999034828A1 (en)

Applications Claiming Priority (2)

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KR1019980000412A KR100315160B1 (en) 1998-01-09 1998-01-09 Drug composition added with skin astringent for transdermal administration
KR1998/412 1998-01-09

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US7018661B2 (en) * 2003-05-20 2006-03-28 Montes Joseph G Aluminum-zirconium compound-based treatment for herpes simplex virus lesions

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Publication number Priority date Publication date Assignee Title
JP4546228B2 (en) 2004-12-02 2010-09-15 株式会社資生堂 Oily skin external composition for promoting percutaneous absorption

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