WO2004054552A1 - Composition transdermique renfermant un agent antivomitif - Google Patents

Composition transdermique renfermant un agent antivomitif Download PDF

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Publication number
WO2004054552A1
WO2004054552A1 PCT/KR2003/002428 KR0302428W WO2004054552A1 WO 2004054552 A1 WO2004054552 A1 WO 2004054552A1 KR 0302428 W KR0302428 W KR 0302428W WO 2004054552 A1 WO2004054552 A1 WO 2004054552A1
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Prior art keywords
transdermal
buffer solution
glycerol
transdermal composition
skin
Prior art date
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PCT/KR2003/002428
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English (en)
Inventor
Joong Woong Cho
Jin Deog Song
Chaul Min Pai
Original Assignee
Samyang Corporation
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Filing date
Publication date
Application filed by Samyang Corporation filed Critical Samyang Corporation
Priority to AU2003279578A priority Critical patent/AU2003279578A1/en
Publication of WO2004054552A1 publication Critical patent/WO2004054552A1/fr

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    • 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
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms

Definitions

  • the present invention relates to a transdermal composition of an antivomiting agent, and more particularly to a transdermal composition of the antivomiting agent tropisetron.
  • 'serotonin' 5-hydroxytryptamine subtype 3
  • tropisetron, ondansetron, granisetron and dolasetron known as serotonin receptor antagonists
  • the dosage needed for transdermal administration would be higher than in other formulations due to limitations in the amount and rate of the antivomiting agent absorbed.
  • ondansetron is not suitable for a transdermal formulation since the dose for transdermal administrationis is much higher than the dose needed for efficacious oral or parenteral administration(24 to 32 mg per day).
  • tropisetron when administered orally or parenterally, can exhibit efficacy even at a dose of 5 mg/day, thus requiring only 30 mg/day for efficacious transdermal administration. Therefore, tropisetron appears more suitable for a transdermal formulation.
  • U. S. Pat. No. 6,019,997 which relates to a composition useful for the transdermal delivery of a drug, discloses a transdermal system comprising a drug dissolved in a lower alcohol and water and at least two emulsifiers, with a viscosity of more than 4,000 centipoises at room temperature, which can allow a drug to penetrate through the skin in the absence of an auxiliary thickener.
  • a transdermal system comprising a drug dissolved in a lower alcohol and water and at least two emulsifiers, with a viscosity of more than 4,000 centipoises at room temperature, which can allow a drug to penetrate through the skin in the absence of an auxiliary thickener.
  • the emulsifier system uses an emulsifier having such a special structure as to be sufficiently viscous in the absence of an auxiliary thickener, (ii) because a solid emulsifier must be used as at least one of the emulsifiers, the composition forms a suspension, in which a solid is dispersed in liquid solution, having too high a viscosity and reduced safety, and (iii) no method of minimizing skin irritation is taught.
  • European Pat. No. 0682942 relates to a composition for external use for delivery through the skin of a physiologically active substance comprising antivomiting agents such as ondansetron and granisetron.
  • the above patent provides a system which can enhance the absorption of the physiologically active substance through skin and also decrease skin irritation by way of dissolving a physiologically active substance in a mixed solution consisting of an alcohol and a buffer solution as well as using a monoterpene as a skin penetration enhancer along with a nonionic surfactant.
  • the above European patent has the following drawbacks: (i) the monoterpene used therein as a skin penetration enhancer is highly irritating to the skin and the skin penetration rate thereof was relatively low as well, (ii) the patent does not disclose any method for increasing the viscosity of the composition into a suitable range, which is an important property for transdermal drug delivery compositions.
  • WO 00/47208 relates to a transdermal composition of an antivomiting agent, and more particularly to a transdermal composition of an antivomiting agent comprising: (i) a lower alcohol and water as a solvent, (ii) fatty acid derivatives and amide compounds as skin penetration enhancers, (ii) tropisetron, ondansetron, granisetron or a mixture thereof as the antivomiting agent.
  • the above-mentioned invention also has problems in that there was no disclosure relating to enhancing the skin penetration rate by adjusting the pH of the transdermal composition containing an antivomiting agent.
  • the present invention provides a composition which can enhance the rate of skin penetration of a drug as well as minimize skin irritation by way of (i) using, as an antivomiting agent, tropisetron, which is efficacious in acute vomiting induced by chemotherapic agents such as cisplatin, and is suitable for a transdermal formulation as well, even at a low concentration, and (ii) adjusting the pH of the composition thereby improving the skin penetration rate of tropisetron thereby requiring use of minimal amounts of tropisetron hydrochloride salt and glycerol monolaurate, which are the main causes of skin irritation.
  • the transdermal composition of an antivomiting agent comprises:(a) a vehicle for transdermal delivery comprising (i) 25 to 45 wt% of a mixed solution comprising ethanol and propylene glycol, (ii) a skin penetration enhancer containing 0.5 to 1.5 wt% of a fatty acid ester, 2 to 5 wt% of an amide compound; (iii) 50 to 70 wt% of a buffer solution; and (b) 2 to 4 wt% of tropisetron, based on the weight of the tropisetron vehicle, wherein the pH of said composition is within the range of 8 to 9.
  • the present invention also provides a method of transdermally delivering an antivomiting agent to a warm blooded animal comprising administering a transdermal delivery device containing the composition of the present invention.
  • the present invention relates to a transdermal composition of an antivomiting agent for treatment as well as prevention of nausea or vomiting induced during anticancer treatment which comprises (a) a vehicle for transdermal delivery and (b) an antivomiting agent.
  • Tropisetron which is used in the present invention as the antivomiting agent, is a selective serotonin (i.e. 5-hydroxytriptamine subtype 3) receptor antagonist and is very effective in preventing acute vomiting induced by administration of a chemotherapeutic agent, such as cisplatin. It is preferable to use tropisetron in the form of a pharmaceutically acceptable salt thereof, more preferably as the tropisetron hy drochloride salt.
  • Tropisetron is used as an antivomiting agent in an amount of 2 to 4 wt%, more preferably 2.5 to 3.5 wt% based on the weight of the vehicle, so as to exhibit the desired skin penetration rate with minimal skin irritation. If the amount of antivomiting agent is less than 2 wt%, the transdermal composition does not show substantial efficacy. In contrast, if the amount exceeds 4 wt% the skin penetration rate increases, and in turn, skin irritation increases as well.
  • the vehicle of the present invention comprises a solvent for enhancing the solubility of the drug and the intercellular fluidity, a fatty acid ester which acts on the lipids of the keratotic skin layer thus enhancing lipid solubility and intercellular fluidity thereby promoting distribution of the drug into the lipids, and skin penetration enhancers such as amide compounds, and a buffer solution as a base vehicle.
  • the mixed solvent which is used in the present invention comprises ethanol as the main solvent and propylene glycol as an auxiliary solvent.
  • Ethanol reversibly changes the structure of the keratin layer of the skin by extracting polar lipids therefrom, thereby promoting skin penetration of the antivomiting agent, and it also plays a role in dissolving the antivomiting agent and the penetration enhancers which have low solubility in the water-soluble vehicle.
  • propylene glycol when used in combination with a fatty acid ester, synergistically promotes the skin penetration of the antivomiting agent.
  • Tropisetron is used as the antivomiting agent in an amount of 2 to 4 wt%, more preferably 2.5 to 3.5 wt% based on the weight of the vehicle.
  • Ethanol is used in the amount of 15 to 25 wt%, more preferably 18 to 22 wt%, with reference to 100 wt% of the vehicle.
  • the solution comprise propylene glycol in an amount of 10 to 20 wt%, more preferably 14 to 16 wt%, with reference to 100 wt% of the vehicle.
  • the fatty acid ester which is used in the present invention is selected from the group consisting of glycerol monolaurate, glycerol monooleate, glycerol monolinoleate, glycerol trilaurate, glycerol trioleate, glycerol tricaprylate, propylene glycol monolaurate, propylene glycol dilaurate, caprylic/capric triglyceride, methyl laurate, methyl caprate, isopropyl myristate, isopropyl palmitate, ethyl oleate and oleyl oleate.
  • glycerol monolaurate is most preferred.
  • the fatty acid ester of the present invention is used in the amount of 0.5 to 1.5 wt%, preferably 1 to 1.5 wt%. If the amount of the fatty acid ester is less than 0.5 wt%, the desired skin penetration rate cannot be achieved. In contrast, if the amount exceeds 1.5 wt%, there is a problem with increased skin irritation.
  • the amide compound which is used in the present invention is selected from the group consisting of N, N-diethyl-m-tplua- ⁇ de, lauric acid diethanolamide, urea, dimethylformamide and dimethylacetamide, and among these, N, N-diethyl-m- toluamide is most preferred. It is preferable that the vehicle contains the amide compound in the amount of 2 to 5 wt%, preferably 2 to 4 wt%. If the amount of the fatty acid amide is less than 2 wt%, the desired skin penetration rate cannot be achieved. In contrast, if the amount exceeds 5 wt%, there is a problem with increased skin irritation.
  • the buffer solution which is used in the present invention is selected from the group consisting of a borate buffer solution, a phosphate buffer solution, a sodium bicarbonate buffer solution, a glycine buffer solution.
  • the pH of the buffer solution used in the present invention is not specifically limited but is acceptable as long as the pH of the transdermal composition falls within the range of 8 to 9.
  • the buffer solution is used in such an amount as to bring the final composition to 100 wt% and is preferably in the amount of 50 to 70 wt% with reference to 100 wt% of the vehicle. It is preferable that the pH of the transdermal composition herein ranges from
  • the antivomiting agent tropisetron
  • the hydrochloride salt which has a high solubility in the transdermal composition and an increased pH provides a stronger driving force for skin penetration.
  • the pH is less than 8
  • the pH is greater than 9
  • the transdermal composition of the present invention may further comprise a thickener for preventing the composition from running down and out of the patch. It may be necessary to use a thickener when the transdermal composition is formulated into a reservoir patch.
  • Hydroxypropyl cellulose can be used, as a thickener herein, which is a cellulose with a weight average molecular weight ranging from 50,000 to 1,250,000 and having a partially substituted poly(hydroxypropyl) ether and in addition may further comprise more than 0.6 % of silica or other suitable anticaking agents.
  • a hydroxypropyl cellulose with a weight average molecular weight of 800,000 to 1,000,000 in an amount of 4 to 5 wt% with reference to 100 wt% of the vehicle.
  • the preferred dose of the composition of the present invention to be administered depends on the physical condition and body weight of the test subject, the form of the inventive composition, and the route and term of administration. In general, the preferred daily dose for an adult is 0.05 to 0.1 mg/kg.
  • the less skin-irritating transdermal composition of an antivomiting agent as described herein may be prepared in a formulation for transdermal administration, such as a patch.
  • a monolith vehicle patch preferably a reservoir patch, may be employed in the present invention.
  • the present invention adjusts the pH of the composition to be within the range of 8 to 9 thus enhancing the skin penetration rate of tropisetron and lowering the dose of skin irritating skin penetration agents or drug needed.
  • the skin penetration rate of the transdermal composition of an antivomiting agent herein was measured as follows: A piece of cadaver skin was placed in a compartment between a donor and a receptor side such that the keratin layer of the skin faced the donor-side compartment. The effective area of skin exposed to the receptor solution was 0.636 cm 2 . The receptor was filled with 5 ml of distilled water (receptor solution) and stirred at 600 rpm using a magnetic bar while the temperature was maintained at 32+0.5 °C using a thermostat with a circulatory pump. The donor compartment was filled with a degassed transdermal composition and a formulation to be tested and then sealed.
  • the skin penetration rate was determined by the amount of antivomiting agent which penetrated per unit area of the skin per unit time, according to formula
  • J s represents the penetration rate of the drug at a steady state
  • A represents the skin area
  • (dQ/dt) ss means an amount ( ⁇ g/h) of the drug penetrated per unit time at a steady state.
  • the degree of skin irritation of the transdermal composition herein was determined as follows: Patch samples with and without the transdermal compositions were prepared.
  • the skin surface of the test animal's backbone were carefully shaved 24 hours before testing. Each animal was prepared with two parts of abraded skin and two parts of intact skin. Then, two patch samples with the transdermal compositions were applied, one to an abraded area and one to intact skin parts, respectively. Two patch samples without the transdermal compositions were applied, one to an abraded area and one to intact skin.
  • the skin irritation was evaluated by the Toxicity Test Method and is numerically presented according to the widely employed Draiz method.
  • the patches were categorized into three groups according to the degree of skin irritation (P. 1. 1.), and only the transdermal compositions with a P. I. I. range below 2 were suitable for transdermal administration.
  • a transdermal composition of an antivomiting agent comprising such ingredients as shown in TABLE 2, was formed by dissolving the tropisetron hydrochloride salt in a mixed solution consisting of anhydrous ethanol, propylene glycol, a borate buffer solution, glycerol monolaurate, diethyl toluamide followed by further addition of hydroxypropyl cellulose (M w 1,000,000) and then totally dissolving it in the mixture solution.
  • the borate buffer solution was prepared by ⁇ adding 0.2 M of sodium hydroxide to a solution " admixed " with 0.2 M of borate and 0.2 M of potassium chloride.
  • TABLE 2 are shown the skin penetration rates of the prepared transdermal compositions determined using cadaver skin as mentioned above and the Primary Irritation Indices (P.I.I) determined by the degree of skin irritation caused by the transdermal compositions.
  • P.I.I Primary Irritation Indices
  • the transdermal compositions of the present invention employing borate -buffer, solutions with pH .values ranging -from.8 ⁇ to- 9 showed superior skin penetration rates and a low degree of skin irritation. Moreover, the skin penetration rate increased with an increase in the pH of the borate buffer solution. However, when the pH was higher than 11, the skin -enfin .. , , c_ y 4
  • a transdermal composition of an antivomiting agent comprising such ingredients as shown in TABLE 3 was made by dissolving the tropisetron hydrochloride salt in a mixed solution consisting of anhydrous ethanol for pharmacopoeia, propylene glycol, a glycine buffer solution, glycerol monolaurate, diethyl toluamide followed by further addition of hydroxypropyl cellulose (M w 1,000,000) and then dissolving it in the mixture solution.
  • the glycine buffer solution was prepared by using 0.2 M of glycine and 0.2 M of sodium hydroxide.
  • TABLE 3 are shown the skin penetration rates of the prepared transdermal compositions determined using cadaver skin as mentioned above and the Primary Irritation Indices (P.I.I.) determined by the degree of skin irritation caused by the transdermal compositions.
  • P.I.I. Primary Irritation Indices
  • the transdermal compositions of the present invention employing a glycine buffer solution with a pH ranging from 8 to 9 showed superior skin penetration rates and a low degree of skin irritation. Moreover, the skin penetration rate increased with increases in the pH of the glycine buffer solution.
  • a transdermal composition of an antivomiting agent comprising such ingredients as shown in TABLE 4 was made by dissolving the tropisetron hydrochloride salt in a mixed solution consisting of anhydrous ethanol, propylene glycol, a sodium bicarbonate buffer solution, glycerol monolaurate, diethyl toluamide followed by further addition of hydroxypropyl cellulose (M w 1,000,000) and then dissolving it in the mixture solution.
  • the sodium bicarbonate buffer solution was prepared by using 0.05 M of sodium bicarbonate and 0.1 M of sodium hydroxide.
  • TABLE 4 are shown the skin penetration rates of the prepared transdermal compositions determined using cadaver skin as mentioned above and the Primary Irritation Indices (P.I.I.) determined by the degree of skin irritation caused by the transdermal compositions.
  • P.I.I. Primary Irritation Indices
  • the transdermal compositions of the present invention employing a sodium bicarbonate buffer solution with a pH ranging from 8 to 9 showed superior skin penetration rates and a low degree of skin irritation. Moreover, the skin penetration rate increased with increases in the pH of the sodium bicarbonate buffer solution.
  • a transdermal composition of an antivomiting agent comprising such ingredients as shown in TABLE 5 was made by dissolving the tropisetron hydrochloride salt in a mixed solution consisting of anhydrous ethanol, propylene glycol, a borate buffer solution, glycerol monolaurate, diethyl toluamide followed by further addition of hydroxypropyl cellulose (M w 1,000,000) and then dissolving it in the mixture solution.
  • the degree of skin irritation as well as the skin penetration rate increased with an increase in the content of the glycerol monolaurate. Therefore, in order to maintain a low degree of skin irritation, i.e. to keep the P.I.I below 2, the content of glycerol monolaurate could not be higher than 1.5 wt%.
  • a transdermal composition of an an antivomiting agent comprising such ingredients as shown in TABLE 6 was made by dissolving the tropisetron hydrochloride salt in a mixed solution consisting of anhydrous ethanol, propylene glycol, a borate buffer solution, glycerol monolaurate, diethyl toluamide followed by further addition of hydroxypropyl cellulose (M w 1,000,000) and then dissolving it in the mixture solution.
  • the degree of skin irritation as well as the skin penetration rate increased with an increase in content of the tropisetron hydrochloride salt. Therefore, in order to maintain a low degree of skin irritation, i.e. to keep the P.I.I, below 2, the content of the tropisetron hydrochloride salt could not be higher than 4 wt%.
  • a transdermal composition of antivomiting agent comprising such ingredients as shown in TABLE 7 was made by dissolving a tropisetron hydrochloride salt in a mixed solution consisting of anhydrous ethanol, propylene glycol, a borate buffer solution, glycerol monolaurate, and diethyl toluamide followed by further addition of hydroxypropyl cellulose (M w 1,000,000), polyvinyl pyrrolidone or a carbomer and then totally dissolving them in the mixture solution.
  • M w 1,000,000 hydroxypropyl cellulose
  • P.I.I. Primary Irritation Indices
  • a transdermal composition of an antivomiting agent comprising such ingredients as shown in TABLE 8 was made by dissolving the tropisetron hydrochloride salt in a mixed solution consisting of anhydrous ethanol, propylene glycol, a water or buffer solution, glycerol monolaurate, and diethyl toluamide followed by further addition of hydroxypropyl cellulose (M w 1,000,000) and then dissolving it in the mixture solution.
  • M w 1,000,000 hydroxypropyl cellulose
  • a transdermal composition of an antivomiting agent comprising such ingredients as shown in TABLE 9 was formed by dissolving the tropisetron hydrochloride salt in a mixed solution consisting of anhydrous ethanol, propylene glycol, a TRIS buffer solution,, glycerol monolaurate, diethyl toluamide followed by further addition of hydroxypropyl cellulose (Mw 1,000,000) and then totally dissolving it in the mixture solution.
  • the TRIS buffer solution was prepared by using 0.1 M of tris(hydroxymethyl)aminomethane and 0.1 M of hydrochloric acid.
  • the transdermal compositions employing a TRIS buffer solution with a pH ranging from 8 to 9 showed a high degree of skin irritation.
  • a transdermal composition of an antivomiting agent comprising such ingredients as shown in TABLE 10 was made by dissolving the tropisetron hydrochloride salt in a mixed solution consisting of anhydrous ethanol, propylene glycol, an ammonia buffer solution, glycerol monolaurate, diethyl toluamide followed by further addition of hydroxypropyl cellulose (M w 1,000,000) and then dissolving it in the mixture solution.
  • the ammonia buffer solution was prepared by using 2 M of ammonia and 2 M of ammonium chloride.
  • the transdermal compositions employing an ammonia buffer solution of with a pH ranging from 8 to 9 showed a high degree of skin irritation.
  • the transdermal composition of the present invention has the effect of enhancing the skin penetration rate as well as lowering the degree of skin irritation caused. Moreover, the transdermal composition of the present invention is adequately viscous and has a superior skin penetration rate and therefore is particularly suitable to be used in the form of a patch.

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Abstract

La présente invention concerne une composition transdermique renfermant un agent antivomitif, et plus particulièrement une composition transdermique renfermant un agent antivomitif qui réduit les irritations cutanées. Cette composition transdermique renferme du tropisétron comme agent antivomitif et a un pH compris entre 8 et 9, ce qui augmente son taux de pénétration dans la peau et réduit la dose d'activateur de pénétration nécessaire.
PCT/KR2003/002428 2002-12-13 2003-11-12 Composition transdermique renfermant un agent antivomitif WO2004054552A1 (fr)

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AU2003279578A AU2003279578A1 (en) 2002-12-13 2003-11-12 Transdermal composition of an antivomiting agent

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KR10-2002-0079659 2002-12-13

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11872199B2 (en) 2019-11-06 2024-01-16 Smartech Topical, Inc. Topical formulations of cyclooxygenase inhibitors and their use

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000047208A1 (fr) * 1999-02-09 2000-08-17 Samyang Corporation Composition transdermique d'un agent antiemetique et preparation contenant cette composition

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000047208A1 (fr) * 1999-02-09 2000-08-17 Samyang Corporation Composition transdermique d'un agent antiemetique et preparation contenant cette composition

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11872199B2 (en) 2019-11-06 2024-01-16 Smartech Topical, Inc. Topical formulations of cyclooxygenase inhibitors and their use

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KR20040053777A (ko) 2004-06-24
KR100569858B1 (ko) 2006-04-11

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