JPH07213627A - Matrix for ionto-phoresis - Google Patents

Abstract

PURPOSE:To provide a matrix for practicable ionto-phoresis which is extremely enhanced in utilization efficiency of a medicine. CONSTITUTION:This matrix contains the ionized medicine in a cathode side and a water-soluble acidic material or its salt in an anode side. The medicine is dosed with good utilization efficiency into a living body by executing the ionto-phoresis by using this matrix for the ionto-phoresis.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel matrix for iontophoresis.

[0002]

2. Description of the Related Art Iontophoresis
Is a percutaneous absorption promotion system that uses electricity as an external stimulus, and its principle is that molecules charged positively in the electric field generated between the cathode and the anode due to energization exit from the anode and are negatively charged to the cathode. Molecules facilitate the skin barrier penetration of drug molecules based on their ability to exit the cathode and move to the anode [Journal of C
ontorolled Release) Volume 18, 1992, 213-2
20; Advanced Drug Delivery Review, Vol. 9, 1992
Year, p. 119; Pharmacological Research (Pharma
ceutical Research) Volume 3, 1986, 318-32.
See page 6]. Due to recent advances in synthetic technology and genetic engineering, naturally occurring peptides or proteins, or those with altered amino acid composition or chemically modified derivatives have been produced in pure and large amounts, and have been used as pharmaceuticals. Is expected to be applied. On the other hand, however, strict drug control is required in order to maximize the efficacy of these peptides and proteins having a variety of physiological activities in a minute amount in a limited disease and to minimize the side effects. For example, parathyroid hormone and its active fragments have contradictory effects on bone, namely osteoblast and osteoclast. However, intermittent administration causes strong osteoblast action, and thus treatment of osteoporosis. It is used for medicine. However, it is generally known that such physiologically active peptides or proteins are degraded in the gastrointestinal tract by digestive fluid or hydrolyzed by a degrading enzyme in the digestive wall, resulting in poor absorption. Therefore, in order to expect a sufficient drug effect, the administration method of these physiologically active peptides or proteins is usually
Although it is administered by injection instead of oral administration, the patient suffers from a great deal of pain and the inability to self-administer is a heavy burden on the patient. Especially when intermittent continuous administration such as the above-mentioned active fragment of parathyroid hormone is required.

In the pharmaceutical field, iontophoresis has been vigorously studied as a new drug delivery system (drug delivery system) capable of coping with such physiologically active peptides and proteins. Japanese Patent Laid-Open No. 4-224770 discloses a device for iontophoresis, which comprises a voltage adjusting means for blending a drug into a pair of electrodes and alternately switching between positive and negative voltages applied between the electrodes. Is listed. Canadian Published Patent Application No. 2042994 describes an iontophoresis device characterized in that both the positive and negative electrodes contain a drug and the cathode is kept at a high pH and the anode is kept at a low pH. US Pat. No. 5,042,975 describes the influence of the isoelectric point of the drug and the pH of the electrode on the absorbability of the drug in iontophoresis.

[0004]

However, the conventional iontophoresis methods have the drawbacks that the absorption of the drug is not sufficient or the absorption decreases with time, and there is a problem in putting it to practical use as it is. there were. In view of the current situation, there is a demand for the development of a practical matrix for iontophoresis, which has significantly improved drug utilization efficiency.

[0005]

Means for Solving the Problems The inventors of the present invention have made intensive studies in order to solve such problems. As a result, a cationized drug is formed on the anode side and a water-soluble acidic substance or a salt thereof is formed on the cathode side. When iontophoresis was carried out with the inclusion of the drug, it was found that the transdermal absorbability of the drug was remarkably increased.
As a result of further intensive studies, the present invention has been completed. That is, the present invention relates to (1) a cationized drug on the anode side, an iontophoresis matrix containing a water-soluble acidic substance on the cathode side, and (2) the above-mentioned drug cationized with a water-soluble carboxylic acid. (1) The matrix, (3) the carboxylic acid is an aliphatic carboxylic acid, the matrix described in (2) above, (4) the acidic substance is a water-soluble organic acid, the matrix described in (1) above, (5) The matrix according to (1) above, wherein the acidic substance is a water-soluble inorganic acid, (6) the matrix according to (1) above, wherein the acidic substance is an aliphatic carboxylic acid, and (7) the aliphatic carboxylic acid has 2 to 6 carbon atoms. (3) or (6) which is an aliphatic carboxylic acid, the matrix according to (7) above, wherein (8) the aliphatic carboxylic acid is citric acid, and (9) the pH of the anode side is 1 to 5. Demon Matrix according to (1) is,
(10) The matrix according to (1) above, wherein the drug is a physiologically active peptide having at least one basic functional group in the molecule, (11) the matrix according to (10) above, wherein the peptide has a molecular weight of 7,000 or less, (12) The matrix according to (10) above, wherein the peptide has an isoelectric point of 5.5 or more, (13) the matrix according to (1) above, wherein the drug is a calcium-regulating hormone, and (14) the calcium-regulating hormone is a parathyroid gland. The matrix according to (13) above, which is a hormone, a derivative thereof, or a salt thereof, (1
5) The matrix according to (13) above, wherein the calcium-regulating hormone is calcitonin, a derivative thereof, or a salt thereof, and (16) the iontophoresis matrix according to (1), wherein a cycle of energization / de-energization is repeated. Iontophoresis, (17) Pulsed direct current is applied, (16) Iontophoresis is described, (18) Continuous direct current is applied, (16) Iontophoresis and (19) DC current of about 0.01 to 4 mA / cm
^The iontophoresis according to the above (17) or (18) is characterized in that the current is applied at a current value of ² .

The drug in the present invention is a cationizable drug, and if it is water-soluble in the cationized state,
Any drug can be used. Preferable examples of the drug include peptides having physiological activity and having at least one basic functional group in the molecule.
The molecular weight of the peptide is preferably about 7,000 or less, more preferably about 6000 or less.
Particularly, about 5000 or less is preferable. The isoelectric point of the water-soluble peptide is preferably about 5.5 or higher, more preferably about 6 or higher.

The water solubility of a drug is defined by the oil-water partition ratio between water and n-octanol. It is preferably applied to a drug having an n-octanol / water solubility ratio of 1 or less, and preferably 0.1 or less. The application is more preferable. The oil-water distribution rate is measured by
"Physical Chemistry Experimental Method" written by Saburo Samejima, published by Shokabo, Showa 36
The method described in the year may be followed. That is, first, in a test tube, n-octanol and a buffer solution of pH 5.5 (1
1: 1 mixture). Examples of the buffer include Sφerenzen buffer [Ergeb. Physiol.] 12 , 393 (19)
12)], Clark-Lubs buffer [J. Bact. 2 (1), 109,
191 (1917)], MacIlvaine buffer [Journal of Biological Chemistry (J. Bi
ol. Chem.) 49 , 183 (1921)], Michaelis
s) buffer solution (Die Wasser-stoffionenkonzentratio
n.) p. 186 (1914)], Kolthoff buffer (Biochem. Z.) 179 ,
410 (1926)] and the like. An appropriate amount of these drugs is added, and the container is further stoppered, immersed in a constant temperature bath (25 ° C.), and often shaken vigorously. Then, when the drug dissolves between both liquid layers and it seems that equilibrium has been reached, the liquid is left standing or centrifuged,
A fixed amount of liquid was removed from each of the upper and lower layers with a pipette and analyzed to determine the concentration of the drug in each layer. The concentration of the drug in the n-octanol layer / the concentration of the drug in the aqueous layer was determined. If the ratio is taken, it becomes the oil-water distribution rate.

In this specification, amino acids, peptides and the like are represented by abbreviations such as IUPAC-IUB.
Commission on Biochemical Nomenclature
Or an abbreviation conventionally used in the art, and when an amino acid may have optical isomers, the L form is shown unless otherwise specified.

Preferred specific examples of the above peptides include, for example, luteinizing hormone-releasing hormone (LH-RH) and LH-RH.
A derivative having the same action as that of, for example, the formula (I): (Pyr) G
lu-R ¹ -Trp-Ser-R ² -R ³ -R ⁴ -Arg-Pro-R ⁵ (I) (wherein R ¹
Is His, Tyr, Trp or p-NH ₂ -Phe, R ² is Tyr or
Phe, R ³ are Gly or D type amino acid residues, R ⁴ is Le
u, Ile or Nle, R ⁵ is Gly-NH-R ⁶ (R ⁶ is H or a lower alkyl group optionally having a hydroxyl group) or NH-
R ⁶ (R ⁶ is as defined above) or a salt thereof [US Pat. No. 3,583,837,
No. 4008209, No. 3972859, British Patent No. 1423083, Proceedings of the National Academy of Science (Procee).
dings of the National Academy of Science) 78th
Vol., 6509-6512 (1981)]; LH
-RH antagonist, for example formula (II): N-α-t-butoxycarbonyl-O-benzyl-Ser-Trp-Ser-Tyr-X ₁ -Leu-Arg-P
ro-GlyNH ₂ (II) [wherein, X ₁ represents D-Ser or D-Trp] or a salt thereof (US Pat. Nos. 4,086,219, 4,124,577, and 4,253,997). No. 4,317,815); insulin; somatostatin, somatostatin derivatives such as formula (III):

[Chemical 1] [In the formula, Y is D-Ala, D-Ser or D-Val, and Z is Asn.
Or a salt thereof (US Pat. Nos. 4,087,390 and 4,093).
No. 574, No. 4100117, No. 4253998.
No.); adrenocorticotropic hormone (ACTH); melanocyte-stimulating hormone (MSH); thyroid-stimulating hormone-releasing hormone (TRH), a derivative thereof, such as formula (IV):

[Chemical 2] [In the formula, X ′ represents a 4-, 5- or 6-membered heterocyclic group, Y ′ represents imidazol-4-yl or 4-hydroxyphenyl,
Z ′ is CH ₂ or S, R ^{1 ′} and R ^{2 ′} are the same or different and each represents hydrogen or a lower alkyl group, and R ^{3 ′} is hydrogen or an aralkyl group which may have a substituent. Compound or salt thereof (Japanese Patent Application Laid-Open No. 50-12173)
Japanese Patent Application Laid-Open No. 52-116465); Parathyroid hormone (PTH) and its derivatives, for example, formula (V): R ^{1 ″} -V
al-Ser-Glu-Leu-R ^{2 ''} -His-Asn-R ^{3 ''} -R ^{4 ''} -R ^{5 ''} -His-Leu
-Asn-Ser-R ^{6 ''} -R ^{7 ''} -Arg-R ^{8 ''} -Glu-R ^{9 ''} -Leu-R ^{10 ''} -R
^{11 ''} -R ^{12 ''} -Leu-Gln-Asp-Val-His-Asn-R ^{13 ''} (V) 〔R〕
^{1 ''} is Ser or Aib, R ^{2 ''} is Met or natural fat-soluble amino acid, R ^{3 ''} is Leu, Ser, Lys or aromatic amino acid, R ^{4 ''} is Gly or D-amino acid, R ^{5 ''} Is Lys
Or Leu, R ^{6 ''} is Met or natural fat-soluble amino acid, R ^{7 ''} is Glu or basic amino acid, R ^{8 ''} is Val
Or basic amino acid, R ^{9 ''} is Trp or 2- (1,3-dithiolan-2-yl) Trp, R ^{10 ''} is Arg or His, R
^{11 ''} for Lys or His, R ^{12 ''} for Lys, Gln or L
eu, R ^{13 ″} represents Phe or Phe-NH ₂ ] or a salt thereof (JP-A-5-32696,
No. 4-247034, European Patent Publication No. 510.
No. 662, No. 477,885, No. 5,39,491), a peptide fragment (abbreviated as hPTH (1 → 34)) at the N-terminus (1 → 34 position) of human PTH [GWTre
gear et al., Endocrinology, 9
3 , 1349-1353 (1973)]; vasopressin, vasopressin derivative {desmopressin [Journal of the Endocrine Society of Japan, Vol. 54, No. 5, pp. 676-691 (19)
78)]}}; Oxytocin; Calcitonin, a derivative having a similar action to that of calcitonin, for example, formula (VI):

[Chemical 3] [Wherein, X ″ is 2-aminosuberic acid] or a salt thereof [Endocrinolo
gy) 1992, 131/6 (2885-2890)];
Glucagon; Gastrin; Secretin; Cholecystokinin; Angiotensin; Enkephalin, an enkephalin derivative such as formula (VII):

[Chemical 4] [Wherein R ^{1 ″ ′} and R ^{3 ′ ″} are hydrogen or an alkyl group having 1 to 6 carbon atoms, R ^{2 ′ ″} is hydrogen or a D-α-amino acid, R
^{4 ′ ″} represents hydrogen or an optionally substituted aliphatic acyl group having 1 to 8 carbon atoms] or a salt thereof (US Pat. No. 4,277,394, European Patent Publication No. 31567). And other peptides; endorphins; kyotorphins; interleukins (I to XI); tuftsin; thymopoietin; thymic humoral factor (THF); blood thymic factor (FTS)
And derivatives thereof, such as formula (VIII): PGlu-X '''-Lys-
Ser-Gln-Y '''-Z'''-Ser-Asn-OH (VIII) [wherein X '''
Is L- or D-Ala, Y '"and Z'" are each Gly or a D-amino acid having 3 to 9 carbon atoms] or a salt thereof (see US Pat. No. 4,229,438). And other thymus hormones [thymosin α ₁
And β ₄ , Symic Factor X, etc., History of Medicine, Vol. 125, No. 10, pp. 835-843 (198).
3 years)]; Motilin; Deynorphin; Bombesin; Neurotensin; Cerulein; Bradykinin; Urokinase; Substance P; Polymyxin B; Colistin; Gramicidin; Bacitracin; Protein synthesis stimulating peptide (UK Patent No. 8232082); Peptide (GIP); vasoactive intestinal poly
peptide (VIP)]; Platelet-derived growth fa
ctor (PDGF)]; growth hormone secretory factor (GRF,
Somatoclinin) and the like.

These physiologically active peptides may be derived from humans or other animals such as cattle, pigs, chickens, salmon and eels, and may be chimeric bodies derived from humans and those animals. Further, it may be an active derivative whose structure is partially changed. For example, porcine-derived insulin, or calcitonin, which is a pig-, chicken-, salmon-, or eel-derived chimera or a chimera of human and salmon, has the formula (IX): Cys-Gly-Asn-Leu-Ser-Thr-Cys- Met-Leu-Gly-Ly
s-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-
Peptide represented by Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro (IX) [Endocrinology 19
92, 131/6 (2885-2890)] and the like.

Among the above drugs, parathyroid hormone (PT
H), its derivatives or salts thereof; calcitonin, its derivatives or salts thereof; luteinizing hormone-releasing hormone (LH-RH), derivatives having a similar action to LH-RH or salts thereof; thyrotropin-releasing hormone. (TR
H), its derivatives or their salts; vasopressin,
Derivatives thereof; insulin is preferred. Further, parathyroid hormone, a derivative thereof or a salt thereof; calcitonin, a derivative thereof or a salt thereof are particularly preferable.

The amount of the drug compounded into the anode depends on the type of drug used, the animal to be administered (eg, mouse, rat, cow, horse, monkey, warm-blooded mammal such as human), the site of administration (eg, arm,
It depends on the abdomen, back, etc.), but an effective amount of the drug may be used. For example, a matrix for administration of human parathyroid hormone, a derivative thereof or a salt thereof to an adult (body weight: 50 kg) is preferably about 0.01 to 10% by weight of the drug per 1 g of the matrix, more preferably about 0.1. 03 to 8% by weight, particularly preferably about 0.05 to 5
It is contained by weight%.

As a method for cationizing a drug, any method may be used as long as the drug is water-soluble in the cationized state. A preferred method is, for example, a method of bringing a drug into contact with a water-soluble carboxylic acid. In particular,
For example, it is carried out by adding a water-soluble carboxylic acid to a solution obtained by dissolving or suspending a drug in water to form a uniform solution.
In this case, the water-soluble carboxylic acid is added so that the pH of the anode is in the range of about 1 to 5, preferably about 3 to 4. Specifically, the ratio of the number of moles of the drug to the number of moles of the carboxylic acid (number of moles of carboxylic acid × number of charges of carboxylic acid) is about 1:20 to 1: 400, preferably about 1:40 to 1: It is preferable to mix them so as to be 400.

Preferred examples of the water-soluble carboxylic acid include water-soluble aliphatic carboxylic acid. More preferred is a water-soluble aliphatic carboxylic acid having 2 to 6 carbon atoms. Particularly preferred are aliphatic mono-, di- and tricarboxylic acids having 2 to 6 carbon atoms which may have 1 to 5 hydroxyl groups. Specific examples of the water-soluble carboxylic acid include, for example, monocarboxylic acids such as acetic acid, propionic acid, ascorbic acid, lactic acid, gluconic acid and glucuronic acid, oxalic acid, malonic acid, succinic acid, malic acid, tartaric acid, phthalic acid, Examples include dicarboxylic acids such as maleic acid and tricarboxylic acids such as citric acid. Among these, acetic acid, propionic acid, ascorbic acid, lactic acid, gluconic acid, glucuronic acid, malonic acid, succinic acid, maleic acid,
Malic acid, tartaric acid and citric acid are preferable, and citric acid, tartaric acid and succinic acid are more preferable. Citric acid is particularly preferred.

Examples of the water-soluble acidic substance used on the cathode side include water-soluble organic acids and water-soluble inorganic acids. These water-soluble acidic substances are preferably water-soluble acidic substances that do not show pharmacological effects. As the water-soluble organic acid, for example, a water-soluble carboxylic acid is preferable. A preferable example of the water-soluble carboxylic acid is, for example, a water-soluble aliphatic carboxylic acid. More preferred is a water-soluble aliphatic carboxylic acid having 2 to 6 carbon atoms. Particularly preferred are aliphatic mono-, di- and tricarboxylic acids having 2 to 6 carbon atoms which may have 1 to 5 hydroxyl groups. Specific examples of the water-soluble carboxylic acid include acetic acid, propionic acid,
Examples thereof include monocarboxylic acids such as ascorbic acid, lactic acid, gluconic acid and glucuronic acid, dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, malic acid, tartaric acid, phthalic acid and maleic acid, and tricarboxylic acids such as citric acid. Among these, acetic acid, propionic acid, ascorbic acid, lactic acid,
Gluconic acid, glucuronic acid, malonic acid, succinic acid, maleic acid, malic acid, tartaric acid and citric acid are preferable, and citric acid, tartaric acid and succinic acid are more preferable. Citric acid is particularly preferred. Examples of the water-soluble inorganic acid include phosphoric acid,
Polyphosphoric acid, phosphonic acid (phosphorous acid), hydrochloric acid and the like are preferable. Phosphoric acid can also be used as an ester with an alcohol (eg, methyl phosphate, ethyl phosphate, etc.).

The above-mentioned water-soluble acidic substance may be used as its salt as long as it shows acidity, and examples thereof include alkali metals (eg, sodium, potassium, etc.), ammonia, organic amines [eg, alkylamines (eg, Diethylamine,
Examples thereof include salts of triethylamine and the like), aromatic amines (eg, pyridine, lutidine and the like) and the above di- or tricarboxylic acid. Specific examples thereof include monosodium citrate, monosodium tartrate, and monopotassium succinate. Water solubility in a water-soluble carboxylic acid or water-soluble acidic substance is indicated by the amount of water required to dissolve 1 g or 1 ml of the carboxylic acid or acidic substance at 20 ± 5 ° C. In the present invention, the amount of water is preferably about 1
Less than 0 ml, more preferably less than 5 ml, particularly preferably less than about 1 ml of carboxylic acid or acidic substance is used. The amount of the water-soluble acidic substance or its salt to be added to the cathode side may be any amount as long as it does not adversely affect the skin (irritation, corrosion, etc.). Specifically, for example, about 0.1 to 15% by weight is blended with respect to the entire matrix. Preferably about 0.1 to 12% by weight, especially about 0.3.
To 10% by weight.

As the base material of the matrix containing the drug, any base material can be used as long as it does not adversely affect the skin (irritation, corrosion, etc.), has excellent skin adhesion, and shows conductivity. . As a preferable example of the base, for example, a hydrophilic resin or a polymer compound is used. Examples of the hydrophilic resin include acrylic resins such as polyacrylamide, polyacrylic acid or alkali metal salts or esters thereof, vinyl resins such as polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl ethyl ether and copolymers thereof, tragacanth gum, karaya gum and the like. Natural polysaccharides, and high molecular compounds include methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose,
Examples thereof include hyaluronic acid or its alkali metal salt. As the matrix, it is also possible to use a material such as cotton, filter paper, or membrane filter impregnated with a drug-containing liquid having conductivity. The matrix is prepared to such an extent that it can maintain its self-holding property, and is spread into a film or sheet. The thickness is preferably about 0.05 to 3.0 mm, particularly preferably about 0.1 to 2.0 mm. If it is too thick, good transdermal absorption may not be obtained.

The iontophoresis matrix of the present invention is produced, for example, as follows. That is, the matrix of the matrix containing the drug is dissolved in water, the drug, a compound for cationizing the drug is added to this solution, and the mixture is kneaded and then molded to produce a matrix for the anode side. The matrix for iontophoresis can be produced by dissolving the base of (1) in water, adding a water-soluble acidic substance or its salt to this solution, kneading and molding the mixture to produce a matrix for the cathode side. At that time, as a softening plasticizer, water, polyethylene glycol,
Propylene glycol, glycerin, etc. are appropriately blended, and sodium chloride, sodium carbonate, phosphoric acid, sodium citrate, etc. are appropriately blended as an electrolyte for imparting dielectric properties.

The amount of the base used varies depending on the type of the base, the shape of the matrix (eg, film shape, sheet shape, etc.), but it is used to such an extent that the self-shape retention of the matrix can be maintained. For example, the amount used as an aqueous solution is preferably about 0.1 to 30% by weight, more preferably about 0.5 to 20% by weight, and particularly preferably about 1 to 15% by weight. The blending amount of each raw material is appropriately selected so that the amount of each raw material in the final product satisfies the above range.
In the above production method, if desired, a protease inhibitor, an isotonicity agent, a preservative, an antioxidant, a pH adjuster, a plasticizer, a surfactant, an osmotic pressure enhancer and the like may be appropriately added.

Examples of proteolytic enzyme inhibitors include gabexate mesylate, α-1-antitrypsin, aprotinin, pepstatin and the like. Examples of the tonicity agent include mannitol, sorbitol and the like. Examples of preservatives include benzalkonium chloride, cetrimide (cetyltrimethylammonium bromide), benzoic acid, benzyl alcohol, paraben (methyl p-hydroxybenzoic acid,
Trademarks for ethyl-, propyl- and bryl-esters), chlorhexidine, chlorobutanol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate,
Examples thereof include potassium sorbate, sodium benzoate, sorbic acid, thiomersal (mercurythiosalicylate), and a mixture thereof.

Examples of the antioxidant include sodium metabisulfite and butylated anisole.
droxyanisole) and butylhydroxytoluene (buty
lated hydroxytoluene) or a mixture thereof. Examples of pH adjusters include citric acid and sodium citrate. As a plasticizer,
Examples thereof include diethyl phthalate, dibutyl phthalate and tributyl citrate. As a surfactant,
Examples thereof include sodium lauryl sulfate, diethylene glycol monostearate, propylene glycol monostearate, polyethylene glycol, polysorbate and polyvinyl alcohol, which are commercially available under the trademark MACROGOL. Examples of the osmotic pressure enhancer include dimethyl sulfoxide, N, N-dimethylacetamide, N, N-dimethylformamide, 2-pyrrolidone, N-methyl-2-pyrrolidone and 1-dodecylazacyclo-heptan-2-one. Can be mentioned.

Iontophoresis is carried out by combining the iontophoresis matrix of the present invention with an appropriate power source to give drugs such as warm-blooded mammals (eg, mouse, rat, cow, horse, monkey, human etc.). Can be safely administered transdermally. The power source may be any power source as long as it can efficiently transfer the drug into the living body from the iontophoresis matrix of the present invention.
As a preferable example of the power source, for example, a power source capable of applying a continuous direct current or a pulse direct current to the iontophoresis matrix of the present invention can be mentioned. Further, a power source capable of applying a pulsed direct current is preferable. Particularly, a power source capable of applying a rectangular pulse direct current is preferable. The current value of the continuous DC current is preferably about 0.01 to 4 mA / cm ² . More preferably, it is about 0.1 to 4 mA / cm ² . The frequency of the pulsed direct current is preferably about 0.1 to 200 kH
z, more preferably about 1 to 100 kHz, particularly preferably about 5 to 80 kHz. The on / off ratio of the pulsed direct current is preferably about 1/100 to 20/1, more preferably about 1/5.
0 to 15/1, particularly preferably about 1/30 to 10 /
It is appropriately selected from the range of 1. Current value of the pulse direct current, more preferably from about 0.1 4mA / cm ^2, more preferably about 0.3 to 3.5mA / cm ^2, particularly preferably in the range from about 0.5 to 3mA / cm ² It is selected appropriately. The energization time is preferably about 24 hours or less, more preferably about 12 hours or less, and particularly preferably about 6 hours or less in continuous energization.

A preferred energizing method is, for example, about 1 minute to 6 minutes.
Time, more preferably about 1 minute to 2 hours, particularly preferably about 10 minutes to 1.5 hours, followed by about 1 minute to 6 hours, more preferably about 10 minutes to 4 hours, particularly preferably about 30 minutes to 2 hours. When the total non-energization period of time is one cycle, it is preferable to repeat the cycle at least twice. It is particularly preferable to repeat the energized / non-energized cycle three times or more. When the cycle of energization / de-energization is repeated, the total energization period is preferably about 10 minutes to 24 hours. More preferably, it is about 30 minutes to 2 hours. For the iontophoresis that repeats the above-mentioned energization / de-energization cycle, for example, pulsed direct current, continuous direct current, preferably pulsed direct current is used. The frequency of this pulsed direct current is
About 1 to 100 kHz is preferred, more preferably about 20
To 60 kHz. The ON / OFF ratio of this pulsed DC current is preferably about 10/1 to 1/10. More preferably, it is about 3/1 to 1/3. Current value of the pulse direct current is preferably 1.0 mA / cm ² to about 0.01, and more preferably 3.0 mA / cm ² to about 0.5. Particularly preferably, it is about 0.8 to 1.8 mA / cm ² . The current value of the continuous direct current is preferably 1.0 mA / cm ² to about 0.01, more preferably from 1 mA / cm ² to about 0.01. Particularly preferably, it is about 0.05 to 0.3 mA / cm ² . The iontophoresis matrix of the present invention can be used in the form as shown in FIG. 1 or 2, for example.

[0024]

EXAMPLES The present invention will be specifically illustrated below with reference to Reference Examples, Examples and Experimental Examples, but the present invention is not limited to these. Unless otherwise specified,% in the reference examples is% by volume, and% in the examples and experimental examples is% by weight. Reference Example 1 Acetate of an active fragment of human parathyroid hormone (hereinafter abbreviated as hPTH) consisting of amino acids from the amino group terminal to the 34th amino acid [hPTH (1 → 3)
Abbreviated as 4)] and purification of the peptide. This peptide was synthesized by the solid phase synthesis method of peptide developed by Merrifield et al.
(RB Merrifield) Advances in Enzymology (Adv. Enzymol.) Volume 32, 221-296.
1969), using an automatic peptide synthesizer 430A (Applied Biosystems, USA). The protected peptide-resin was synthesized using the protocol specified by Applied Biosystems. A tertiary butyloxycarbonyl (BOC) group was used to protect the α-amino group of each amino acid during condensation. The side functional group protection was performed as follows. The hydroxyl groups of serine and threonine are o-benzyl ethers, the carboxyl groups of glutamic acid and aspartic acid are benzyl esters, the imidazole nitrogen of histidine is benzyloxymethyl, and the side chain amino group of lysine is 2-chlorobenzyloxycarboxyl, The guanidine functional group of arginine was protected with a p-toluenesulfonyl group, and the indoleimine of tryptophan was protected with a formyl group. All amino acids were obtained from Applied Biosystems Japan or Bachem Chemicals.

Boc-L-phenylalanine-p-oxymethylphenylacetamidomethyl resin (polystyrene-
1% divinylbenzene) was used as a starting material, and successively protected amino acids were condensed thereto. After condensation of all amino acids on the resin, the protected peptide resin was removed from the synthesizer and dried. Peptide resin (1 g) was added to p-cresol (1 m
l), 1,2-ethanedithiol (1 ml) and anhydrous hydrogen fluoride (8 mg) containing 2-mercaptopyridine (100 mg).
ml) at 0 ° C. for 2 hours. After completion of the reaction, hydrogen fluoride was distilled off, the residue was washed with diethyl ether, and most of the mixed reagents were removed. Peptide was converted to
ml) and the resin was removed by filtration. The filtrate was purified by gel filtration using Sephadex G-25. The conditions for gel filtration are column size 2.8 × 60 cm, detection wavelength 230 or 280 nm; solvent, 3% acetic acid; flow rate 40.
ml / hour. Fractions containing the peptide were collected and lyophilized and the resulting powder preparation was further purified by reverse phase high performance liquid chromatography. Column YMC-Pack, A-324 ODS (10 × 250 mm) Elution solvent A, 0.1% trifluoroacetic acid-99.9% water; Elution solvent B, 0.1% trifluoroacetic acid-99.9% acetonitrile; Elution gradient program, 0 min (90% A + 1
0% B), 30 minutes (60% A + 40% B) Elution rate 1.
6 ml / min, detection wavelength 230 or 280 nm. Biorad AGI x 8 by collecting peak fractions containing pure target
After passing through a column of (acetic acid type, 1.8 × 5 cm), a washing solution was collected and acetonitrile was distilled off, followed by freeze-drying. Yield 10
5 mg. Amino acid analysis values after hydrolysis with 6N hydrochloric acid in the presence of 4% thioglycolic acid in a vacuum sealed tube at 110 ° C. for 24 hours were as follows. Theoretical values are in parentheses. Asp 4.0
0 (4); Ser 2.54 (3); Glu 4.92 (5); Gly 0.91 (1); V
al 2.61 (3); Met 1.97 (2); Ile 0.83 (1); Len 4.90
(5); Phe 0.91 (1); Lys 2.82 (3); His 2.48 (3); Tr
p 0.76 (1); Arg 1.74 (2).

Example 1 hPTH (1 → 34) (10 mg) produced in Reference Example 1 and citric acid hydrate (7 mg) were dissolved in an 8% aqueous polyvinyl alcohol solution (1 g) (pH 3.8) to give a gel. Cylinder having a cross-sectional area of 8 cm ² and a thickness of 1 mm was used as a matrix for the anode side, and citric acid hydrate (7 mg) was dissolved in 1 g of an 8% polyvinyl alcohol aqueous solution to form a gel. An iontophoresis matrix was produced by using a cylindrical material having a cross-sectional area of 8 cm ² and a thickness of 1 mm as the cathode-side matrix. Example 2 hPTH (1 → 34) (10 mg) and citric acid monohydrate (70 mg) were added to 8% polyvinyl alcohol aqueous solution (1 g).
Dissolved in (pH 2.8), gelled / molded, cross-sectional area 8c
A cylinder with m ² and a thickness of 1 mm was used as the matrix for the anode side, and citric acid hydrate (70 mg) was dissolved in 8% polyvinyl alcohol aqueous solution (1 g), gelled and molded to form a cross-sectional area of 8 cm. ^{2. A} 1 mm-thick cylinder was used as a matrix for the cathode side to produce a matrix for iontophoresis. Example 3 hPTH (1 → 34) (10 mg) and citric acid monohydrate (7 mg) were combined with 8% aqueous polyvinyl alcohol solution (0.4 mg).
g) was dissolved (pH 3.8), gelled and molded to form a cylinder with a cross-sectional area of 3.2 cm ² and a thickness of 1 mm as the matrix for the anode side, and citric acid hydrate (7 mg). 8%
An iontophoresis matrix was produced by dissolving in a polyvinyl alcohol aqueous solution (0.4 g), gelling and molding it into a cylindrical shape having a cross-sectional area of 3.2 cm ² and a thickness of 1 mm as a cathode side matrix.

Example 4 Human insulin (Shimizu Pharmaceutical, 10 mg) and tartaric acid (1
(0 mg) was dissolved in 8% polyvinyl alcohol aqueous solution (1 g) (pH 3.4), gelled and molded to form a cylinder with a cross-sectional area of 8 cm ² and a thickness of 1 mm as the matrix for the anode side, and tartaric acid (10 mg). ) Is dissolved in 8% polyvinyl alcohol aqueous solution (1 g), gelled and molded to obtain a cross-sectional area of 8 c
An iontophoresis matrix was manufactured by using a cylindrical column having m ² and a thickness of 1 mm as the cathode side matrix. Example 5 Salmon calcitonin (Seikagaku Corporation, 2 mg) and citric acid-
The hydrate (5 mg) was used as an 8% aqueous solution of polyvinyl alcohol (0.1%).
Dissolved in 4 g (pH 3.4), gelled and molded, cross-sectional area 8c
A cylindrical column with m ² and a thickness of 1 mm was used as a matrix for the anode side, and citric acid hydrate (5 mg) was dissolved in an 8% polyvinyl alcohol aqueous solution (0.4 g) to form a gel.
An iontophoresis matrix was produced by using a molded cylindrical product having a cross-sectional area of 3.2 cm ² and a thickness of 1 mm as a cathode side matrix.

Example 6 6.25% of hydroxypropyl cellulose [HPC-L (Nippon Soda)] was added to 1 ml of 50 mM citric acid aqueous solution containing 1% of hPTH (1 → 34) produced in Reference Example 1.
4 ml of ethyl alcohol solution was added to make a uniform solution. 0.5 g of this solution was added to a silicone rubber bottom area of 8 cm ² ,
It is poured into a cylindrical recess with a thickness of about 1 mm,
5 ° C) Evaporate the alcohol under normal pressure (1 atm) to remove hP
A cylindrical iontophoresis matrix having a cross-sectional area of 8 cm ² , a weight of 27 mg, and a thickness of 0.024 mm containing 1 mg of TH (1 → 34) was produced. Example 7 1.0 g of a solution of hPTH (1 → 34) and HPC-L produced in the same manner as in Example 6 was poured into a cylindrical recess having a silicon rubber bottom area of 16 cm ² and a thickness of about 1 mm, Alcohol was evaporated at room temperature (25 ° C.) and normal pressure (1 atm), and a cylindrical iontophoresis matrix having a cross-sectional area of 16 cm ² , a weight of 54 mg and a thickness of 0.024 mm containing 2 mg of hPTH (1 → 34) was obtained. Manufactured.

Example 8 0.2 g of a solution of hPTH (1 → 34) and HPC-L produced in the same manner as in Example 6 was added to a cylindrical depression made of silicone rubber and having a bottom area of 3.2 cm ² and a thickness of about 1 mm. Alcohol is evaporated at room temperature (25 ° C) and atmospheric pressure (1 atm), and 0.4 mg of hPTH (1 → 34) is poured into
Cross-sectional area contained 3.2 cm ² Weight 10 mg Thickness 0.02
A 2 mm cylindrical iontophoretic matrix was prepared. Example 9 In the same manner as in Example 6 except that the 3.25% ethyl alcohol solution of HPC-L was used instead of the 6.25% ethyl alcohol solution of HPC-L, hPTH (1 →
34) containing 1 mg of cross-sectional area 8 cm ² , weight 14.5
A cylindrical iontophoretic matrix of mg and thickness of 0.013 mm was produced. Example 10 In the same manner as in Example 6 except that the 6.25% ethyl alcohol solution of HPC-L was replaced with a 12.5% ethyl alcohol solution of HPC-L, hPTH (1 → 3) was used.
4) cross-sectional area 8 cm ² containing 1 mg, weight 52 mg,
A cylindrical iontophoresis matrix having a thickness of 0.046 mm was produced.

Example 11 Example 10 except that a 50 mM aqueous citric acid solution containing 0.2% hPTH (1 → 34) was used in place of the 50 mM aqueous citric acid solution containing 1% hPTH (1 → 34). In the same manner as 6, hPTH (1 → 34) 0.2m
A cylindrical iontophoretic matrix having a cross-sectional area of 8 cm ² , a weight of 26.2 mg, and a thickness of 0.023 mm containing g was produced. Example 12 In the same manner as in Example 6 except that a 50 mM citric acid aqueous solution containing 2% hPTH (1 → 34) was used in place of the 50 mM citric acid aqueous solution containing 1% hPTH (1 → 34). , HPTH (1 → 34) 2mg in cross section 8cm ² , weight 28mg, thickness 0.025mm
A cylindrical iontophoretic matrix was manufactured. Example 13 In the same manner as in Example 6 except that a 50 mM aqueous citric acid solution containing 4% hPTH (1 → 34) was used in place of the 50 mM aqueous citric acid solution containing 1% hPTH (1 → 34). , HPTH (1 → 34) 4mg containing cross-sectional area 8cm ² , weight 30mg, thickness 0.027mm
A cylindrical iontophoretic matrix was manufactured.

Example 14 Example except that a 6.25% ethyl alcohol dispersion of hydroxypropylmethyl cellulose [TC-5 (manufactured by Shin-Etsu Chemical Co.)] was used in place of the 6.25% ethyl alcohol solution of HPC-L. Similar to 6, hPTH (1
→ cross-sectional area containing 1 mg of 34) 8 cm ² , weight 27 m
A cylindrical iontophoretic matrix having a thickness of 0.024 mm was prepared. Although TC-5 exists as a colloidal dispersion in 100% ethyl alcohol, h
After mixing a 50 mM citric acid solution containing 1% of PTH (1 → 34), the TC-5 colloid was dissolved. Example 15 In place of the 6.25% ethyl alcohol solution of HPC-L, HPC-L containing 3.125% HPC-L and 3.125% methylcellulose [Metrose SM (manufactured by Shin-Etsu Chemical Co.)] was prepared. In the same manner as in Example 6 except that an ethyl alcohol solution was used,
Cross-sectional area 8c containing 1 mg of hPTH (1 → 34)
A cylindrical iontophoretic matrix with m ² , weight 27 mg and thickness 0.024 mm was prepared. Example 16 Salmon calcitonin (hereinafter, abbreviated as sCT; manufactured by Sigma, USA) in an amount of 0.2% was used in place of a 50 mM citric acid aqueous solution containing 1% of hPTH (1 → 34).
A cross-sectional area of 8 cm ² containing 0.2 mg of sCT was carried out in the same manner as in Example 6 except that an aqueous solution of mM citric acid was used.
A cylindrical iontophoretic matrix having a weight of 26.2 mg and a thickness of 0.023 mm was produced.

Example 17 50 m containing 0.02% sCT instead of 50 mM citric acid aqueous solution containing 1% hPTH (1 → 34)
A cross-sectional area of 8 cm ² containing 0.02 mg of sCT was obtained in the same manner as in Example 6 except that an aqueous solution of M citric acid was used.
A cylindrical iontophoresis matrix having a weight of 26 mg and a thickness of 0.023 mm was produced. Example 18 Except that a 50 mM citric acid aqueous solution containing 1% bovine pancreatic insulin (Wako Pure Chemical Industries, Ltd.) was used in place of the 50 mM citric acid aqueous solution containing 1% hPTH (1 → 34),
In the same manner as in Example 6, the cross-sectional area containing 1 mg of bovine pancreatic insulin was 8 cm ² , the weight was 27 mg, and the thickness was 0.023 m.
m cylindrical iontophoresis matrix was prepared. Example 19 Instead of a 50 mM citric acid aqueous solution containing 1% of hPTH (1 → 34), TRH [International Journal of Pharmacy (International Jou
rnal of Pharmaceutics) Vol. 69, pp. 69-75 (1
991) was used according to the method described above], and a cross-sectional area of 8 cm ² containing 1 mg of TRH and a weight of 27 mg was obtained in the same manner as in Example 6 except that a 50 mM citric acid aqueous solution containing 1% was used. A cylindrical iontophoresis matrix having a thickness of 0.023 mm was produced. Example 20 Except that a 50 mM citric acid aqueous solution containing 0.2% of leuprolide (manufactured by Takeda Pharmaceutical Co., Ltd.) was used in place of the 50 mM citric acid aqueous solution containing 1% of hPTH (1 → 34). 6, in the same manner as in 6, but containing 0.2 mg of leuprolide, a cross sectional area of 8 cm ² , and a weight of 26.2.
A cylindrical iontophoresis matrix of mg, thickness 0.023 mm was prepared.

Experimental Example 1 hPTH (1 → 34) (10 mg) was dissolved in an 8% polyvinyl alcohol aqueous solution (1 g) (about pH 6.5), gelled and molded, and a cross-sectional area of 8 cm ² and a cylindrical shape with a thickness of 1 mm were used. Was used as the matrix for the anode side, and 8% polyvinyl alcohol aqueous solution (1 g) was gelled and molded to obtain a cross-sectional area of 8c.
An iontophoresis matrix was manufactured by using a cylindrical column having m ² and a thickness of 1 mm as the cathode side matrix (referred to as Comparative Matrix 1). A carbon-coated titanium electrode (hereinafter abbreviated as an electrode) was attached to the matrix of Example 1 and the comparative matrix 1, and these were attached to the abdomen of the SD male rat (7 weeks old) that had been hair-removed in advance. Rats equipped with the matrix of Example 1 were divided into two groups, and one group was subjected to time-course blood collection from the tail vein without being energized in the state of being mounted (a non-energized administration group), and the remaining group. The group equipped with Comparative Matrix 1 was energized. ADIS4030 [ADVANCE, Japan] was used as the electricity supply device. The energization condition was a constant current condition of 1 mA / cm ² (40 kHz, on / off = 3/7), and energization was continued for 4 hours. HPTH at this time (1 → 3
The results of the time course of serum concentration in 4) are shown in FIG.
The non-energized administration group remained at the same level as before the administration even when the matrix was attached, and in the comparative matrix 1 administration group, it remained 3 after administration.
At 0 minutes, the serum concentration increased to 3 times the pre-administration value, but then rapidly decreased, and the pre-administration level was maintained during and after energization. In the matrix-administered group of Example 1, the level increased to about 5 times the level before the administration by 1 hour after the administration, and the level reached to about 30 times after 4 hours.
Such delayed phenomenon of increase in serum concentration is considered to be due to the formation of depot in the skin. This result indicates that the incorporation of carboxylic acid significantly promotes the absorption effect of iontophoresis. In addition, serum hPTH (1 → 34)
Concentration is radioimmunoassay [rat rat
Rat PTH Kit, Immunotropic
Co., Ltd. (Immutopics Inc., USA)] (hereinafter, serum hPTH (1 → 34) concentration was measured in the same manner).

Experimental Example 2 hPTH (1 → 34) (10 mg) and citric acid hydrate (2.1 mg) were added to an 8% aqueous polyvinyl alcohol solution (0.4 mg).
g) was dissolved (about pH 5.3), gelled and molded to form a cylinder with a cross-sectional area of 3.2 cm ² and a thickness of 1 mm as the matrix for the anode side, and citric acid hydrate (7 mg) 8%
An iontophoresis matrix was prepared by dissolving in a polyvinyl alcohol aqueous solution (0.4 g), gelling and molding it into a cylindrical shape having a cross-sectional area of 3.2 cm ² and a thickness of 1 mm as a cathode side matrix (comparison). Matrix 2). Electrodes were attached to the matrix of Example 3 and the comparative matrix 2 respectively, and these were mounted on SD male rats (7
Aged (weeks old). ADIS4030 (Advance, Japan) was used as the electricity supply device. Energization condition is ² mA / cm ² (40 kHz, on / off = 3
The current was continuously applied for 4 hours under the constant current condition of / 7). At this time
The results of the time course of the serum concentration of hPTH (1 → 34) are shown in FIG. Serum concentrations in both groups remained at almost the same level for 4 hours after the start of energization.
After the lapse of time, the serum concentration of the matrix-administered group of Example 1 having a low pH markedly increased, and at the 6th hour, 10
Serum concentration is more than doubled. From this result, it is clear that there is an important relationship between the increase in absorbability and the pH of the preparation.

Experimental Example 3 hPTH (1 → 34) (10 mg) and citric acid hydrate (7 mg) were dissolved in 8% polyvinyl alcohol aqueous solution (1 g) (pH 3.8), gelled and molded, and cross-sectional area was obtained. 8 cm ² ,
A 1 mm-thick cylindrical material was used as the matrix for the anode side, and citric acid hydrate (7 mg) was dissolved in 8% polyvinyl alcohol aqueous solution (1 g), gelled and molded to form a cross-sectional area of 8
An iontophoresis matrix was manufactured by using a cathode-side matrix having a cylindrical shape of cm ² and a thickness of 1 mm. A carbon-coated titanium electrode was attached to each matrix, and they were attached to the pre-hair-removed abdomen of the rat. ADIS4030 for electricity supply
(Advance, Japan) was used. Energization condition is 1.5
Under constant current condition of mA / cm ² (40kHz, on / off = 3/7), first turn on the power for 2 hours continuously, then turn off the power for the next 2 hours. 0.5 mA / cm ² ,
The energization was repeated at 40 kHz, on / off = 3/7, constant current condition). During this time, the matrix remains attached.
Blood was collected from the tail vein over time, and the serum concentration of hPTH (1 → 34) was measured. The results of the time course of serum concentration of hPTH (1 → 34) at this time are shown in FIG. The serum hPTH (1 → 34) concentration also increases / decreases in conjunction with the two repetitions of energization, although there is a slight delay.
Moreover, the maximum serum concentration at each energization has reached the concentration required for manifesting a drug effect related to the bone-forming effect obtained from subcutaneous injection.

Experimental Example 4 A solution of hPTH (1 → 34) (1 mg) in a 33 mM citric acid aqueous solution containing 8% of polyvinyl alcohol 0.8
dissolved in ml. This solution was poured into a silicon mold having a surface area of 8 cm ² and a thickness of 1 mm, frozen and stored, and then thawed to prepare a matrix for the anode side. Further, a matrix for the cathode side having the same composition containing no drug was prepared in the same manner to produce a matrix for iontophoresis. Carbon-coated titanium electrodes were connected to both matrices, and those matrices were used for rat abdomen (male SD weight approximately 250
g; the abdomen is shaved the day before), and current is applied under the following conditions to measure hPTH (1 → 34) concentration in serum over time to accelerate absorption of hPTH (1 → 34) Was evaluated. Energization condition: A pulse direct current (40 kHz; ON / OFF = 3/7; current value, 1.5 mA / cm ² ) was used, and a cycle of energization period of 2 hours / non-energization period of 2 hours was performed twice. Measured hPTH
The time course of serum concentration of (1 → 34) is shown in FIG. A high serum hPTH (1 → 34) concentration in response to the electrification was shown.

Experimental Example 5 In the same manner as in Experimental Example 4, except that electricity was applied under the following conditions,
The absorption promoting property of hPTH (1 → 34) was evaluated. Energization condition: A pulse direct current (40 kHz; ON / OFF = 3/7; current value, 1.5 mA / cm ² ) was used, and a cycle of energization period 1 hour / non-energization period 1 hour was repeated 4 times. Measured hP
The time course of the serum concentration of TH (1 → 34) is shown in [FIG. 7]. High serum h with 3 peaks in response to energization
A PTH (1 → 34) concentration pattern was shown.

Experimental Example 6 In the same manner as in Experimental Example 4, except that electricity was applied under the following conditions:
The absorption promoting property of hPTH (1 → 34) was evaluated. Energization condition: Pulse DC current (40kHz; ON / OFF = 3/7; current value, 1.5mA / cm ² ) is used, and a cycle of 0.5 hours of energization period / 1.5 hours of non-conduction period is repeated 4 times. It was The time course of the measured serum concentration of hPTH (1 → 34) is shown in FIG. A high serum hPTH (1 → 34) concentration pattern with two peaks in response to electric current was shown.

Experimental Example 7 In the same manner as in Experimental Example 4, except that electricity was applied under the following conditions:
The absorption promoting property of hPTH (1 → 34) was evaluated. Energization condition: Pulse DC current (40kHz; ON / OFF = 3/7; current value, 1.5mA / cm ² ) is used, and the cycle of energization period 0.5 hours / de-energization period 0.5 hours is repeated twice. Then, the cycle of 0.5 hour of energization period / 1.5 hours of non-energization period was repeated 4 times. The time course of the measured serum concentration of hPTH (1 → 34) is shown in FIG. 9. A high serum hPTH (1 → 34) concentration pattern with four peaks in response to electric current was shown.

Experimental Example 8 In the same manner as in Experimental Example 4, except that electricity was applied under the following conditions,
The absorption promoting property of hPTH (1 → 34) was evaluated. Energization condition: A pulse direct current (40 kHz; ON / OFF = 3/7; current value, ² mA / cm ² ) was used, and a cycle of energization period 0.25 hours / non-energization period 1.75 hours was repeated 4 times. The time course of the measured serum concentration of hPTH (1 → 34) is shown in FIG. 10. A high serum hPTH (1 → 34) concentration pattern with two peaks in response to electric current was shown.

Experimental Example 9 The iontophoresis matrix prepared in Examples 6 to 20 was attached to a cylindrical gel having a cross-sectional area of 8 cm ² and a thickness of 1 mm obtained by gelling and molding an 8% polyvinyl alcohol aqueous solution. The matrix dissolved within 1 minute after application. Further, in the same manner as in Example 6, hPTH (1 → 3
A matrix not containing 4) was prepared and contacted with the skin of the upper arm that had been previously moistened with water. The matrix dissolved within 1 minute after application. Experimental Example 10 A 33 mM citric acid aqueous solution (0.8 ml) containing 8% polyvinyl alcohol was gelated and molded to obtain a cross-sectional area 8c.
The iontophoresis matrix of Example 6 was peeled off from the silicon mold using tweezers and attached to a cylindrical column having a square meter of m ² and a thickness of 1 mm to form an anode-side matrix. In addition, gelling 33 mM citric acid aqueous solution (0.8 ml) containing 8% polyvinyl alcohol
A cylindrical matrix having a cross-sectional area of 8 cm ² and a thickness of 1 mm was used as a cathode side matrix. Carbon-coated titanium electrodes were attached to these matrices, and they were brought into contact with the pre-hair-removed abdomen of male SD rats (body weight: about 250 g). Especially the anode side matrix is
The surface to which the drug-containing layer of Example 6 was attached was brought into contact with the abdomen. In contacting the rats with the anode and cathode matrices, the rats were anesthetized with ether, and immediately before the contact, the anode matrix and the cathode matrix with the iontophoresis matrix of Example 6 attached were contacted with the rat abdomen. After fixing with an elastic bandage, the rat was further retained in a Bormann cage. The electricity supply device includes an ADIS4030 [Advance (ADVANC
E), Japan] was used. Energization is direct current pulse current (40 kHz; ON / OFF = 3/7; current value, 1.5
mA / cm ² ) was energized for 1 hour. HPTH in serum (1
→ 34) Concentration is radioimmunoassay method [Rat PTH Kit (Imutopics, Inc)]
It was measured by. HPTH in serum after administration (1 → 34)
The maximum concentration in blood (about 840 pg /
ml). This result indicates that rapid absorption and high bioavailability can be obtained by using the iontophoresis matrix obtained by attaching the iontophoresis matrix of Example 6 to the electrode matrix.

Experimental Example 11 The transdermal absorbability of sCT was evaluated in the same manner as in Experimental Example 10 except that the iontophoresis matrix of Example 16 was used in place of the iontophoresis matrix of Example 6. The transdermal absorbability of sCT was evaluated by measuring the serum calcium concentration over time. The serum calcium concentration was measured by a blood calcium measurement kit (calcium E-Test Wako, manufactured by Wako Pure Chemical Industries, Ltd.). The time course of serum calcium concentration is shown in FIG. After 1 hour and 2 hours, the calcium concentration was significantly lower than the normal level before administration of sCT, indicating rapid absorption of sCT. Experimental Example 12 Except that iontophoresis was performed under the following energization conditions,
In the same manner as in Experimental Example 10, the percutaneous absorption promotion of hPTH (1 → 34) was evaluated. Energization condition: Pulse DC current (40 kHz; ON / OFF)
= 3/7; current value, 1.5 A / cm ² ) was used, and a cycle of energization period 1 hour / non-energization period 1 hour was repeated 4 times. The time course of serum hPTH (1 → 34) concentration is shown in [FIG. 12]. A high blood PTH (3-34) concentration pattern with three peaks in response to electric current was shown.

Experimental Example 13 Except that iontophoresis was carried out under the following energization conditions,
The transdermal absorbability of sCT was evaluated in the same manner as in Experimental Example 11. Energization condition: Pulse DC current (40 kHz; ON / OFF)
= 3/7; current value, 1.5 A / cm ² ) was used, and a cycle of energization period 1 hour / non-energization period 1 hour was repeated 4 times. The time course of serum calcium is shown in FIG. It was shown that a significant decrease in serum calcium concentration (about 60 to 65% of the normal value before administration) was maintained for a long period of time. Experimental Example 14 The drug-containing layer of Example 6 was attached to a release paper (manufactured by Takara) on which a paste (manufactured by KOKUYO) was thinly applied in advance, and the adhesive was loosely adhered. The drug-containing layer has a cross-sectional area of 8 cm ² and a thickness of 1 obtained by gelling and molding an aqueous 8% polyvinyl alcohol solution.
After contacting the matrix for cylindrical electrodes of mm with appropriate pressure and then peeling off the release paper, the drug-containing layer remained and adhered to the cylindrical gel cross section. Experimental Example 15 The drug-containing layer containing sCT of Example 16 was cooled to room temperature (25
After storage for 1 week at (° C.), the decrease in sCT content in the drug-containing layer was evaluated by high performance liquid chromatography (HPLC) method. HPLC conditions: column: GL-PACK manufactured by GL Sciences Ltd .; elution method: gradient method [solution A: 0.1% (v / v) trifluoroacetic acid aqueous solution, solution B: 0] Acetonitrile containing 1% (v / v) trifluoroacetic acid, A liquid / B liquid ratio of 80
Linear gradient from / 20 (v / v) to 50/50 (v / v)]; Detection, UV280 nm As a result, the decrease in the sCT content is 0%, and the sCT in the drug-containing layer of Example 16 is stable. It was shown to exist in.

[0044]

INDUSTRIAL APPLICABILITY In the iontophoresis using the matrix of the present invention, the drug is efficiently percutaneously absorbed, and there are almost no side effects such as skin sores.

[Brief description of drawings]

FIG. 1 is a schematic illustration of an apparatus using the iontophoresis matrix of the present invention. In the figure, 1 is a cathode side matrix, 2 is an anode side matrix, 3 is a power source, 4 is a stratum corneum, and 5 is an epidermis.

FIG. 2 is a schematic illustration of an apparatus using the iontophoresis matrix of the present invention. In the figure, 1 is a cathode side matrix, 2 is an anode side matrix, 3 is a power source, 4 is a stratum corneum, 5 is a skin, and 6 is an insulating layer.

FIG. 3 shows time course of serum concentration of hPTH (1 → 34) in Experimental Example 1.

FIG. 4 shows the time course of serum concentration of hPTH (1 → 34) in Experimental Example 2.

FIG. 5: Time course of serum concentration of hPTH (1 → 34) in Experimental Example 3

FIG. 6 shows the time course of serum concentration of hPTH (1 → 34) in Experimental Example 4.

FIG. 7: Time course of serum concentration of hPTH (1 → 34) in Experimental Example 5

FIG. 8: Time course of serum concentration of hPTH (1 → 34) in Experimental Example 6

FIG. 9: Time course of serum concentration of hPTH (1 → 34) in Experimental Example 7

FIG. 10: Time course of serum concentration of hPTH (1 → 34) in Experimental Example 8

FIG. 11: Time course of serum concentration of calcium in Experimental Example 11

FIG. 12: Time course of serum concentration of hPTH (1 → 34) in Experimental Example 12

FIG. 13: Time course of serum concentration of calcium in Experimental Example 13

[Explanation of symbols]

 In FIG. 3, − ◯ − represents a non-energized administration group. In FIG. 3, −Δ− indicates the comparison matrix 1. In FIG. 3,-●-indicates the matrix of Example 1.

[Chemical 5] In FIG. 4, − ◯ − indicates the comparison matrix 2. In FIG. 4,-●-shows the matrix of Example 3.

[Chemical 6]

[Chemical 7]

[Chemical 8]

[Chemical 9]

[Chemical 10]

[Chemical 11]

[Chemical 12]

[Chemical 13]

[Chemical 14]

Claims (19)

[Claims] 1. An iontophoresis matrix comprising a cationized drug on the anode side and a water-soluble acidic substance on the cathode side. 2. The matrix according to claim 1, wherein the drug is cationized with a water-soluble carboxylic acid. 3. The matrix according to claim 2, wherein the carboxylic acid is an aliphatic carboxylic acid. 4. The matrix according to claim 1, wherein the acidic substance is a water-soluble organic acid. 5. The matrix according to claim 1, wherein the acidic substance is a water-soluble inorganic acid. 6. The matrix according to claim 1, wherein the acidic substance is an aliphatic carboxylic acid. 7. The matrix according to claim 3, wherein the aliphatic carboxylic acid is an aliphatic carboxylic acid having 2 to 6 carbon atoms. 8. The matrix according to claim 7, wherein the aliphatic carboxylic acid is citric acid. 9. The matrix according to claim 1, wherein the pH on the anode side is in the range of 1 to 5. 10. The matrix according to claim 1, wherein the drug is a physiologically active peptide having at least one basic functional group in the molecule. 11. The matrix according to claim 10, wherein the molecular weight of the peptide is 7,000 or less. 12. The matrix according to claim 10, wherein the peptide has an isoelectric point of 5.5 or more. 13. The matrix according to claim 1, wherein the drug is a calcium-regulating hormone. 14. The matrix according to claim 13, wherein the calcium regulating hormone is parathyroid hormone, a derivative thereof or a salt thereof. 15. The matrix according to claim 13, wherein the calcium regulating hormone is calcitonin, a derivative thereof or a salt thereof. 16. An iontophoresis, characterized in that the iontophoresis matrix according to claim 1 is repeatedly energized / deenergized. 17. The iontophoresis according to claim 16, wherein a pulsed direct current is applied. 18. The iontophoresis according to claim 16, wherein a continuous direct current is applied. 19. A direct current of about 0.01 to 4 mA / cm
^The iontophoresis according to claim 17 or 18, wherein the current is applied at a current value of ² .