With regard to methods for administration of drugs, oral administration, rectal administration, percutaneous administration and intravenous administration have known. Among them, oral administration is widely used. In case of oral administration, however, administered drug has disadvantages to receive the first-pass effect after absorption and to show a temporally excessive over blood concentration after administration. Further, in oral administration, many adverse effects such as gastrointestinal trouble, vomiting sensation and anorexia have reported. In addition, in the recent aging society, numbers of patients with dysphagia are increased, and easily ingestible preparations are required from the clinical standpoint.
As a result, development of preparations for percutaneous administration has positively promoted for the purpose of solving such disadvantages of oral administration and obtaining easily ingestible preparations for patients with safety and repeatedly, and such the improved preparations are launched in the market.
However, percutaneous absorbability of drug in such preparations for percutaneous absorption is still insufficient. In addition, since many drugs have low percutaneous absorbability, development of the preparations for percutaneous absorption is difficult and the objectives for absorption have not successful. Namely, since the normal skin has barrier function for protecting infiltration of foreign matters into the body, base ingredients used in the conventional preparations for percutaneous absorption can not reveal sufficient percutaneous absorption of the combined active ingredient.
For that solution, a contrivance for increasing percutaneous absorption of drug through the stratum corneum of skin is required, and in general so called a promoter for percutaneous absorption is combined with the base ingredient. For example, a combination of absorption promoter of lower alkylamide such as dimethyl acetamide and ethyl alcohol, isopropyl alcohol or isopropyl palmitate (U.S. Pat. No. 3,472,931); a combination of 2-pyrrolidone and proper oil or that of straight chain fatty acid and alcohol ester (U.S. Pat. No. 4,017,641); and a combination of lower alcohol and C7-20 alcohol, C5-30 aliphatic cyclic hydrocarbon, C19-26 aliphatic carboxylic acid alcohol ester, C10-24 mono- or di-ether or C11-15 ketone and water (JP-A-61-249934) have proposed. However, these conventional absorption promoters and the composition of absorption promoter are not sufficiently safe on the skin. Further, in case of the preparations for percutaneous absorption containing salt of basic drug, its effect can not be expected.
Examples of preparations for percutaneous administration such as a combination of drug and organic acid have reported. For example, tapes combining betamethasone valerate and organic acid in natural rubber adhesives (JP-B-63-45368), tapes combining steroid antiinflammatory agent and organic acid in acrylic adhesives (JP-B-7-47535), and cataplasms combining methyl salicylate as an active ingredient, emulsifier, organic acid, plasticizer, adhesive resin and water in polymer of styrene-isoprene-styrene block copolymer (JP-B-3-31685) have proposed. Objectives of these organic acids are, however, improvement of stability, improvement of solubility and pH adjuster. Further, since these drugs are acidic or neutral, objectives of these preparations are not to improve skin permeability of bioactive substance through formation of ion pair, which is an object to use organic acids in the present invention.
Means for improving skin permeability of basic bioactive substances are known. For example, tapes combining citric acid and isoproterenol hydrochloride in acrylic adhesives (JP-A-63-79820), and tapes combining organic acid and vinpocetine in acrylic adhesives (JP-A-5-25039) have reported. These preparations have problems such as irritation in detaching and no sufficient effect for treatment in release of drugs.
Means for combining drug and organic acid have reported as preparations for percutaneous administration. For example, a preparation containing organic acid and glycol in nonsteroidal antiinflammatory agent (JP-A-62-181226), and a patch containing alkaline metal salt of nonsteroidal antiinflammatory agent and free nonsteroidal antiinflammatory agent as well as stronger organic acid (JP-B-7-47535) have reported. These inventions relate to acidic drugs and not to basic drugs. Examples of combination of basic drug or its salt, C2-5 alcohol, C2-5 organic acid and C16-20 carboxylic acid ester have known, but no use of organic acid salt is described. In WO 96/16642, patch preparation with a salt of basic drug containing organic acid salt is disclosed, but the fact that organic acid salt increases solubility of basic drug salt in the liquid component having specific solubility parameter ranging from 7 to 13 (cal/cm3)1/2 is not disclosed. In the prior known inventions, preparations for percutaneous absorption, in which basic drug in the form of salt is dissolved in a liquid component to achieve percutaneous absorption of drug, have not known.