JPH1072374A - Medicinal administration composition for iontophoresis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare the subject composition capable of promoting the percutaneous absorbability of a medicine in an energizing responsive manner without damaging a horny substance of skin and imparting a high biological utilization efficiency of the medicine by including an ionizable medicine and a humectant therein. SOLUTION: This composition comprises (A) an ionizable medicine and (B) a humectant. Preferably amides, especially preferably urea, N-methyl-2- pyrrolidone or mixtures thereof are cited as the ingredient B. Various ionizable and percutaneously absorbable medicines, e.g. physiologically active peptides, proteins, etc., are used as the ingredient A. A cationizable medicine is preferably used as the ingredient A. Thereby, the evaporation of water from a solution containing the medicine dissolved therein can be suppressed to maintain energizing properties for a long period and the percutaneous absorbability of the medicine is promoted. As a result, the medicine can safely be administered at a high absorption ratio.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a drug administration composition used in iontophoresis applied to deliver a drug or a physiologically active substance into a living body in the medical field.

[0002]

2. Description of the Related Art Iontophoresis
Oresis) is a percutaneous or transmucosal absorption promotion system that uses electricity for external stimulation, and mainly charged molecules in an electric field generated between an anode and a cathode by energization move out of the anode and move to the cathode. Is a system that promotes the penetration of drug molecules through the skin barrier based on the force that negatively charged molecules exit the cathode and travel to the anode [Journal
Of controlled release (Journal o
f Controlled Release) 18 volumes,
1992, pp. 213-220; Advanced Drug Delivery Review
g Delivery Review) Volume 9, 1992
Year, p. 119; Pharmaceutical Research (P
(harmaceutical Research) 3
Vol. 1986, pp. 318-326, etc.].

[0003] In recent years, due to advances in synthetic techniques and genetic engineering, naturally occurring peptides and proteins, or those having altered amino acid compositions or chemically modified derivatives, have been produced in pure and large quantities. It is expected to be applied as a medicine. However, on the other hand, as research on these peptides and proteins has progressed, it has come to be understood that the diverse physiological activities of these peptides and proteins are physiologically controlled by subtle and complex pharmacokinetics. In order to maximize the efficacy of peptides and proteins in limited diseases and to minimize side effects, a system that can respond to strict dosing control has been required. For example, calcitonin has the effect of suppressing bone loss by suppressing bone resorption, and is used in the treatment of osteoporosis and Paget's disease, but excessive administration causes side effects such as anorexia, In addition, it is necessary to administer the drug repeatedly and frequently in order to achieve a therapeutic effect.

[0004] Further, some peptides exhibit different effects depending on the administration method. For example, parathyroid hormone has a contradictory effect between bone resorption-promoting action and bone formation-promoting action. It is known that the action is strongly expressed. In order to use parathyroid hormone as a therapeutic agent for osteoporosis or the like with the expectation of an osteogenic effect, it must be a pulsatile release type preparation instead of a sustained release type preparation. However, it is generally known that such a physiologically active peptide or protein is degraded by digestive juice in the gastrointestinal tract or hydrolyzed by a digestive enzyme on the digestive tract wall, resulting in poor absorption. Therefore, the administration method of these physiologically active peptides or proteins cannot be expected to have a sufficient drug effect by oral administration, and therefore, administration by injection is usually performed. However, injections cause a great deal of pain to patients and cannot be self-administered. This is especially true when repeated and continuous administration is required, such as the aforementioned calcitonin and parathyroid hormone.

[0005] In the pharmaceutical field, iontophoresis has attracted attention as a new drug delivery system (drug delivery system) that can cope with the administration of such physiologically active peptides and proteins, and has been vigorously studied. As a formulation applicable by this iontophoresis, if a formulation capable of self-administration by a patient himself can be used for a drug which could be administered only as an injection so far, a path to home treatment will be opened. In addition, it is considered that an arbitrary absorption pattern can be created by precise control of the energization time, and particularly in the replacement therapy of an endogenous compound, more effective drug treatment can be realized in consideration of the circadian rhythm of the living body.

[0006] In addition, with respect to the applicator used for iontophoresis (here, the applicator is used to refer to a device in a broad sense consisting of an interface, an electrode, a container, and the like). The interface for iontophoresis (contact with the skin and mucous membrane) for percutaneous absorption of drugs has also been energetically studied. For example, there has been reported an interface for iontophoresis including a drug holding film designed so that a drug is efficiently brought into contact with the skin surface and a drug solution contained in a spacer (JP-A-6-16535).
issue). However, even when this interface is used, there is a limit to efficiently absorbing a water-soluble drug having a relatively large molecular weight by iontophoresis.

[0007] In order to solve this problem, there has been reported a method of improving absorption by blending, for example, an absorption promoter (monoterpene or aliphatic monoglyceride) having a surfactant activity inside the interface (Japanese Patent Application Laid-Open No. HEI 9-301). 6-16538
issue). However, it is pointed out that absorption enhancers generally act on the skin to cause skin irritation, and safe use is not guaranteed. In addition, the interface for iontophoresis including the drug solution contained in the drug holding film and the spacer is small and has relatively high absorbency, but the drug solution is evaporated and the skin surface and drug retention due to evaporation of the drug solution during energization. Insufficient moisture in the body, resulting in reduced electrical conductivity. Therefore, in iontophoresis using this type of interface, sufficient transdermal absorption could not be obtained with long-term application.

In view of the above problems in the prior art, the present inventor has prevented the evaporation of water inside the interface for iontophoresis and acts without causing irritation to the skin to promote absorption. Focusing on humectants as an indicator of the effect, we conducted intensive experiments, research, and studies.As a result, when a humectant was added to the drug solution or drug holding film included in the interface for iontophoresis, the conductivity Have been found to be able to be administered transdermally with remarkably high bioavailability and reproducibility, and have reached the present invention.

[0009]

That is, an object of the present invention is to provide a humectant which suppresses evaporation of water from a drug solution during administration of a drug by iontophoresis, maintains electrical conductivity for a long period of time, Acts on the stratum corneum, which acts as a barrier to the penetration of the drug through the skin, and responds to the current without damaging the stratum corneum (ie, the drug is not absorbed when the power is turned off, but is absorbed when the current is turned on). An object of the present invention is to provide a drug administration composition for iontophoresis, which promotes skin absorption and provides high bioavailability of a drug.

[0010]

That is, the present invention relates to a drug administration composition for iontophoresis, comprising a drug to be ionized and a humectant. It provides a composition. The composition of the present invention is usually applied to the skin,
Of course, it can be applied to mucous membranes.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION As the humectant in the present invention, amides are preferably used, and one or more amides are used. Particularly preferred examples of the amides include urea, N-methyl-2-pyrrolidone or a mixture thereof. Further, the humectant of the present invention contains at least one kind of amides, and may be used in combination with a humectant other than amides. Amino acids or derivatives thereof are preferably used as combined humectants other than amides, but the combined humectants are not limited to one type, and two or more types can be used in combination.

[0012] In the drug administration composition for iontophoresis of the present invention, the drug to be ionized includes various drugs which can be transdermally absorbed and have a molecular weight of about 8 for example.
A bioactive peptide or protein having a molecular weight of 000 or less, a low molecular weight drug, or the like is used. Among them, the physiologically active peptide includes, for example, a calcium-regulating hormone, and a typical example thereof includes a calcium-regulating hormone selected from parathyroid hormone, a derivative thereof, or a salt thereof. The drug to be ionized can be an anionized drug or a cationized drug, but preferably a cationized drug is used. When a cationized drug is used, the drug can be preferably applied as a cationized drug with a buffer having a pH of 3 to 7.
As the buffer, a buffer containing a water-soluble aliphatic carboxylic acid is preferably used. As the water-soluble aliphatic carboxylic acid, preferably, a carbon number which may have 1 to 5 hydroxyl groups is used. There may be mentioned 2 to 6 aliphatic monocarboxylic acids, dicarboxylic acids or tricarboxylic acids, and these may be used as salts thereof. Examples of the aliphatic carboxylic acid include acetic acid, propionic acid, oxalic acid, ascorbic acid, lactic acid, succinic acid, citric acid, malic acid, tartaric acid, maleic acid, salts thereof and / or hydrates thereof. And citric acid, succinic acid, tartaric acid, salts thereof and / or
Alternatively, their hydrates are used. As the salt, an inorganic salt such as a sodium salt, a calcium salt, and a potassium salt is used, and more preferably, a sodium salt is used.

Hereinafter, the present invention will be described in more detail. In addition, in this specification, a drug and a physiologically active substance are also referred to as "drug" as appropriate. In the present specification, when abbreviations are used for amino acids, peptides, and the like,
PAC-IUB Commission on Biochemical
No Men Creature (Commission onB)
This is described based on the abbreviation by Iochemical Nomenclature or an abbreviation commonly used in the art, and when an amino acid may have an optical isomer, it means the L-form unless otherwise specified.

The humectant of the present invention contained in the drug solution suppresses the evaporation of water from the drug solution, retains water on the skin surface and mucous membrane surface and the drug carrier, and protects the skin and mucous membrane. The substance is not particularly limited as long as it is a substance that acts on the stratum corneum and mucous membrane of the skin without adversely affecting the skin. Preferred examples thereof include amides. Examples of amides include urea, dimethylacetamide, diethyltoluamide, diethylformamide, dimethyloctamide, dimethyldecamide, biodegradable urea (1-alkyl-4-imidazolin-2-one), N-methyl -2-pyrrolidone, 2-pyrrolidone, 1-lauryl-2-pyrrolidone, 1-methyl-4-carboxy-2-pyrrolidone, 1-hexyl-4
-Carboxy-2-pyrrolidone, 1-lauryl-4-carboxy-2-pyrrolidone, 1-methyl-4-methoxycarbonyl-2-pyrrolidone, 1-hexyl-4-methoxycarbonyl-2-pyrrolidone, 1 -Lauryl-
4-methoxycarbonyl-2-pyrrolidone, N-cyclohexylpyrrolidone, N-dimethylaminopropylpyrrolidone, N-cocoalkylpyrrolidone, N-talloalkylpyrrolidone, N- (2-hydroxyethyl) -2-pyrrolidone, 1-dodecyl Azacycloheptane-2-one, 1-geranylazaazaheptane-2-one, 1
-Farnesyl azacycl heptane-2-one, 1-
(3,7-dimethyloctyl) azacycloheptane-2
-One, 1- (3,7,11-trimethyldodecyl) azacycloheptan-2-one, 1-geranylazacyclohexane-2-one, 1-geranylazacyclopentane-2,5-dione, 1-farnesylaza Cyclopentan-2-one and 1- [2- (decylthio) ethyl] azacyclopentan-2-one. Of these, urea and N-methyl-2-pyrrolidone are particularly preferably used. In the case of urea and N-methyl-2-pyrrolidone, it is more effective to use both in combination.

[0015] In the present invention, preferably, at least one kind of the above-mentioned humectants is contained, and a humectant other than the above-mentioned humectants is used in combination. As a humectant to be used in combination, "Natural Moisturizing Fac
tor [Fragrance Journal Vol.
1 p. 71-80 (1995)] ", examples of which are polyhydric alcohols,
Examples include sugar alcohols, acidic mucopolysaccharides, and amino acids (in this case, amino acid derivatives and cyclic amino acids). Among them, amino acids, amino acid derivatives and cyclic amino acids are not particularly limited, but glycine, alanine, valine, leucine, Isoleucine, serine, threonine, glutamic acid, aspartic acid, phenylalanine, tyrosine, tryptophan, proline, hydroxyproline, arginine, lysine, histidine, L-α-aminobutyric acid, L-methylglutamic acid, α-methyl-D-serine, pyrrolidone carboxylic acid, piperidyl carbonyl , Piperidylmethylcarbonyl, pyrrolidinylcarbonyl (prolyl), pyrrolidinylmethylcarbonyl and the like are preferably used. In particular, L-proline is very useful for reducing skin irritation upon administration of iontophoresis, and is therefore more effective when used in combination with urea, N-methyl-2-pyrrolidone or a mixture thereof. .

The content of the humectant of the present invention in the drug solution can be appropriately selected within a range that suppresses evaporation of water from the drug solution and retains water on the skin or mucous membrane surface and in the drug carrier. . Specifically, it is in the range of about 0.1 to 90% (w / w), preferably in the range of 0.5 to 80% (w / w), and more preferably 1 to 90% (w / w) in the drug administration composition for iontophoresis. Used in the range of 30% (w / w). This amount is the same when the amide and the combined humectant are used in combination, and the ratio of both can be appropriately selected within a range that can achieve such an object. For example, urea as a humectant,
When N-methyl-2-pyrrolidone or a mixture thereof is used, the concentration of urea, N-methyl-2-pyrrolidone or a mixture thereof is about 1 to 30% (w / w) in the composition.
When urea and N-methyl-2-pyrrolidone are used as a mixture, their mixing ratio (weight) is about 1:30 to 30: 1, preferably about 1:10 to about 1
0: 1, more preferably about 1: 1. When L-proline is used as the combined humectant, the concentration of L-proline can be used in a range of about 1 to 30% (w / w) in the composition.

Of the above, particularly preferred embodiments are described as follows: (i) a drug to be ionized and (ii) a humectant as described in (a), (b), (c), (d) or (e) below.
And a drug administration composition for iontophoresis characterized by containing any one of the above.
(A) urea, (b) urea and N-methyl-2-pyrrolidone, (c) N-methyl-2-pyrrolidone and L-proline, (d) urea, N-methyl-2-pyrrolidone and L-proline, (E) Urea and L-proline. These compositions may further contain a water-soluble aliphatic carboxylic acid having 2 to 6 carbon atoms, and preferred examples thereof include citric acid, salts thereof and / or hydrates thereof.
In this case, the ratio of the number of moles of the drug to be ionized and the number of moles of the aliphatic carboxylic acid (the number of moles of the carboxylic acid × the number of charges of the carboxylic acid) is from about 1:20 to about 1: 100,000,
Preferably, it can be blended in the range of about 1:40 to about 1: 50,000. When the humectant is (e) urea and L-proline, urea and L-proline are used.
Proline compounding ratio (weight) is about 30: 1 to about 1:30
And preferably from about 5: 1 to about 1: 5,
More preferably, it can be used in a ratio of about 1: 2.

Next, as the drug holding member constituting the interface for iontophoresis, various members having a porous or capillary structure capable of holding a drug and allowing the drug to pass therethrough (hereinafter simply referred to as a porous body) Is used). As such a porous body, an organic porous body is preferably used. Examples of this include natural fibers such as cellulose, semi-synthetic fibers such as cellulose acetate, polyethylene, polypropylene, nylon, fiber aggregates formed of synthetic fibers such as polyester, sheets such as paper, woven and non-woven fabrics and the like. Cloth, porous polypropylene, porous polystyrene, porous polymethyl methacrylate, porous nylon, porous polysulfone, porous fluororesin, and porous synthetic resins such as polyvinylidene fluoride with a hydrophilic group introduced. Can be mentioned. Particularly, polyvinylidene fluoride having a hydrophilic group introduced is more preferably used because it has a low adsorptivity to a drug such as a peptide and has a property of easily releasing the drug when brought into contact with water.

The shape of the porous body is not particularly limited, and may be formed in a sheet shape or any other appropriate shape. When it is a sheet-like porous body, its thickness can be appropriately selected depending on the amount of drug held and the like, for example, about 1 to about 500 μm.
m, preferably in the range of about 10 to about 200 μm. The porous body may have flexibility or plasticity, and may be non-deformable. Amount holding area of the porous sheet is a drug, it can be appropriately selected depending on the area of skin or mucous membrane that contacts, for example in a range from about 1 to 20 cm ^2, preferably in the range of about 2 to 10 cm ² is there. Further, the pore size of the sheet-like porous body can be appropriately selected within a range that does not impair the drug holding amount, release property, and the like. For example, the average pore size is about 0.01 to 50 μm, preferably about 0.2 to 20 μm.
It can be in the range of μm.

In the present invention, examples of the drug retained in the porous material include various drugs which can be ionized and transdermally absorbed, such as a bioactive peptide or protein having a molecular weight of about 8000 or less, or a drug having a low molecular weight. Used. The drug to be ionized may be such that at least a part of the retained drug is ionized. The drug to be ionized may be an anionized drug or a cationized drug, but preferably a cationized drug is used. As the physiologically active peptide, for example, the following peptides (1) to (9) are used, and among them, those having a molecular weight of 5,000 or less are preferably used.

(1) Luteinizing hormone-releasing hormone (LH-RH), a derivative having the same action as LH-RH, for example, a polypeptide represented by the following formula (I) or a salt thereof [US Pat. No. 3,853,837; The fourth
008209 and 3972859, British Patent No. 1
No. 423083, Proceedings of the National Academy of Sciences (Procee
dings of the National Aca
demy of Science), vol. 78, 6509
６５6512 (1981)].

(Pyr) Glu-R1-Trp-Ser-R2-R3-R4-Arg-Pro-R5 (I) [In the formula (I), R1 is His, Tyr, Trp or p -
NH ₂ -Phe, R 2 is Tyr or Phe, R 3 is Gl
R4 is Leu, Ile or Nle, R5 is Gly-NH-R6 (R6 is H or a lower alkyl group optionally having a hydroxyl group) or NH-R6 (R
6 is as defined above)]

(2) LH-RH antagonists, for example, a polypeptide represented by the following formula (II) or a salt thereof (US Pat. Nos. 4,086,219 and 4,124,577)
No. 4,253,997 and No. 4,317,815).

Embedded image N-α-t-butoxycarbonyl-O-benzyl-Ser-Trp-Ser-Tyr-X 1 -Leu-Arg-Pro-GlyNH ₂ (II) [in the formula (II) , X1 represents D-Ser or D-Trp]

(3) insulin, somatostatin,
Somatostatin derivatives, for example, a polypeptide represented by the following formula (III) or a salt thereof (US Pat.
Nos. 087390, 4093574 and 4100
No. 117 and No. 4253998).

[Formula 3] [In the formula (III), Y is D-Ala, D-Ser or D-
Val and Z represent Asn or Ala]

(4) Cortical stimulating hormone (ACT)
H), melanocyte stimulating hormone (MSH), thyroid stimulating hormone releasing hormone (TRH) and derivatives thereof, for example, a compound represented by the following formula (IV) or a salt thereof (Japanese Patent Application Laid-Open Nos. 50-121273 and 52)
-116465).

[Formula 4] [In the formula (IV), Xa represents a 4-, 5- or 6-membered heterocyclic group;
a is imidazol-4-yl or 4-hydroxyphenyl, Za is CH ₂ or S, R 1a and R 2a are the same or different and are hydrogen or a lower alkyl group, and R 3a is hydrogen or may have a substituent. Represents an aralkyl group)

(5) Parathyroid hormone (PTH) and its derivatives, for example, a peptide represented by the following formula (V) or a salt thereof (JP-A-5-32696, JP-A-5-32696)
No. 247034, EP-A-510662.
Nos. 478885 and 539491), a peptide fragment at the N-terminal (position 1 → 34) of human PTH (hereinafter abbreviated as hPTH (1 → 34)) and the like [G. W. Tregear et al., Endocrinology, 93, 1349.
1353 (1973)], vasopressin, a vasopressin derivative ｛desmopressin [Journal of the Endocrine Society of Japan, Vol. 54, No. 5, pp. 676-691 (197)
8)] See｝. In particular, examples of indications for the administration of iontophoresis using the above-mentioned PTH and its derivatives, its peptides or their salts, and hPTH (1 → 34) include osteoporosis, fractures, and myocardial infarction.

Embedded image R1′-Val-Ser-Glu-Leu-R2′-His-Asn-R3′-R4′-R5′-His-Leu-Asn-Ser-R6′-R7′-Arg-R8′- Glu-R9'-Leu-R10'-R11'-R12'-Leu-Gln-Asp-Val-His-Asn-R13 '(V) [In the formula (V), R1' is Ser. Or Aib, R2 'is Me
t or a natural fat-soluble amino acid, R3 'is Leu, Se
r, Lys or an aromatic amino acid, R4 'is Gly or D
An amino acid, R5 'is Lys or Leu, R6' is Met
Or a natural fat-soluble amino acid, R7 'is Glu or a basic amino acid, R8' is Val or a basic amino acid, R9 '
Is Trp or 2- (1,3-dithiolan-2-yl) T
rp, R10 'is Arg or His, R11' is Lys or His, R12 'is Lys, Gln or Leu, R13' shows the the Phe or Phe-NH _2]

(6) oxytocin, calcitonin,
A derivative having the same action as calcitonin, for example, a compound represented by the following formula (VI) or a salt thereof [Endocrinology 19]
92, 131/6 (2885-2890)], glucagon, gastrin, secretin, cholecystokinin, angiotensin.

[Formula 6] [In formula (VI), X ^b is 2-aminosuberic acid]

(7) Enkephalins and enkephalin derivatives, for example, oligopeptides and endorphins such as peptides represented by the following formula (VII) or salts thereof (see US Pat. No. 4,277,394 and EP-A-31567).

[Formula 7] [In the formula (VII), R ^1C and R ^3C are hydrogen or a group having 1 to 6 carbon atoms.
R ^2C is hydrogen or a D-α-amino acid; R ^4C
Represents hydrogen or an optionally substituted aliphatic acyl group having 1 to 8 carbon atoms.]

(8) Kyotorphin, interleukin (I to XI), tuftsin, thymopoietin, thymic factor (THF), blood thymic factor (F
TS) and its derivatives, for example, a peptide represented by the following formula (VIII) or a salt thereof (US Pat. No. 4,294,294)
No. 38) and other thymic hormones [Thymosin α1 and β4, Simic Factor X, etc., The History of Medicine, Vol. 125, No. 10, 835-843 (1.
983)].

Embedded image PGlu-Xd-Lys-Ser-Gln-Yd-Zd-Ser-Asn-OH (VIII) [In the formula (VIII), Xd is L-Ala or D-Ala, Yd
And Zd each represent Gly or a D-amino acid having 3 to 9 carbon atoms]

(9) (a) Motilin, (b) Deinorphin, (c) Bombesin, (d) Neurotensin, (e) Cerulein, (f) Bradykinin, (g) Urokinase, (h)
Substance P, (i) polymyxin B, (j) colistin, (k) gramicidin, (l) bacitracin, (m) protein synthesis stimulating peptide, (n) gastric acid secretion inhibiting polypeptide (GIP), (o) bathoactive Intentinal polypeptide [vasoactive intest
internal polypeptide (VIP)], (p) platelet-derived growth factor [platelet-derived growth factor]
factor (PDGF)], (q) growth hormone secreting factor (GRF, somatocrinin).

These physiologically active peptides may be of human type or derived from other animals such as bovine, porcine, chicken, salmon and eel, and may be chimeras of human and those derived from such animals. Further, an active derivative having a partially changed structure may be used. For example, insulin derived from pig, calcitonin is derived from pig, chicken, salmon, eel, or a chimera of human and salmon, and has the following formula (I)
X) [Endclinology (En
docrinology) 1992, 131/6 (28
85-2890)].

[Image Omitted] Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro -Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro (IX)

The low molecular weight drug applied in the present invention includes compounds having a molecular weight of about 1,000 or less and having pharmacological activity. The type of low molecular weight drug is not particularly limited, and examples thereof include antibiotics, antifungal agents, antihyperlipidemic agents, cardiovascular agents, antiplatelet agents, antitumor agents, antipyretic, analgesic,
Anti-inflammatory, antitussive, antiseptic, sedative, muscle relaxant, antiepileptic, antiulcer, antidepressant, antiallergic, cardiotonic, vasodilator, antihypertensive, antiarrhythmic, antidiabetic,
Anticoagulants, hemostatic agents, antituberculous agents, hormonal agents, narcotic antagonists, bone resorption inhibitors, angiogenesis inhibitors, local anesthetics and the like are used.

As the above antibiotics, for example, gentanmycin, lipidomycin, sisomicin, tetracycline hydrochloride, ampicillin, cephalothin, cefotiam, cefazolin, thienacine, sulfazecin and the like are used. Examples of antifungal agents include 2-[(1R,
2R) -2- (2,4-difluorophenyl-2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2 ,
3,3-tetrafluoropropoxy) phenyl] -3
(2H, 4H) -1,2,4-triazolone or the like is used. Examples of the antihyperlipidemic agent include pravastatin and simvastatin, and examples of the circulatory agent include delapril hydrochloride and the like.

As the above-mentioned antiplatelet agent, for example, ticlopidine, cilostazol, limaprostat, aspirin and the like are used. As the antitumor agent, for example, bleomycin hydrochloride, actinomachine D, mitomachine C, adriamycin, fluorouracil and the like are used. . Antipyretics, analgesics and anti-inflammatory agents include, for example, sodium salicylate, sulpyrine, indomethacin sodium, diclofenac sodium, loxoprofen sodium, buprenorphine hydrochloride, pentazocine, eptazosin hydrobromide, budolphanol tartrate, tramazol hydrochloride, ketorolac, meperidine hydrochloride, morphine hydrochloride, sulphate sulfate Morphine, hydromorphone (hydromorphine), fentanyl citrate, fentanyl, safentanil, alfentanil and the like are used. As an antitussive and expectorant, for example, ephedrine hydrochloride, codin phosphate, picoperidamine hydrochloride and the like are used. For example, lidocaine or the like is used as a local anesthetic. Examples of sedatives include chlorpromazine hydrochloride and atropine sulfate, examples of the muscle relaxants include pridinol methanesulfonate and tubocurarine chloride, and examples of antiepileptic agents include phenytoin sodium and ethosuximide.

As the above-mentioned antiulcer agent, for example, metoclopromide is used, and as the antidepressant, for example, imiplan, phenelzine sulfate and the like are used. As the antiallergic agent, for example, diphenylhydramine hydrochloride, tripelenamine hydrochloride, clemizole hydrochloride and the like are used,
As the cardiotonic agent, for example, trans-bioxo camphor, theophyllol and the like are used. As the arrhythmia treatment agent, for example, propranol hydrochloride, oxyprenol hydrochloride and the like are used. As the vasodilator, for example, oxyfedrine hydrochloride, trazoline hydrochloride, pamethane sulfate and the like are used. As the antihypertensive diuretic, for example, pentolinium, hexamethonium bromide or the like is used.
Examples of antidiabetic agents include glymidine sodium,
Glipizide, metformin and the like are used, and as an anti-thrombotic agent, for example, sodium citrate and the like are used.

Further, as the hemostatic agent, for example, sodium menadione bisulfite, acetomenaphthone, tranexamic acid and the like are used. As the antituberculous agent, for example, isoniazid, ethambutol and the like are used. Hormonal agents include, for example, β-estradiol, testosterone, prednisolone succinate, dexamethasone sodium sulfate, methimazole and the like. As the narcotic antagonist, for example, levallorphan tartrate, nalorphine hydrochloride and the like are used. As the bone resorption inhibitor, for example, (sulfur-containing alkyl) aminomethylenebisphosphonic acid is used. Examples of angiogenesis inhibitors include, for example, angiogenesis-inhibiting steroids [Science
e) Vol.221, p.719 (1983)], fumagillol derivatives [for example, O-monochloroacetylcarbamoylfumagillol, O-dichloroacetylcarbamoylfumagillol and the like (European Patent Application Publication No. 357)
Nos. 061, 359036 and 386667
No. 4,115,294)]).

The above-mentioned drug is made to be a solution with, for example, distilled water for injection, physiological saline for injection, or the like, and then retained on the drug carrier by a commonly used method, for example, impregnation, spraying, dropping, and drying. Can be. When the drug is a physiologically active peptide, for example, a disaccharide (eg, trehalose, maltose, mannitol, inositol, etc.) may be added to the drug solution at a ratio of, for example, about 1 to 100 mg / ml. Increases the stability of the drug in the dry state. By storing the drug holding the drug in a dry state, the drug holding body can be stored for a long period of time while maintaining the activity of the drug. Specifically, for example, after a drug support holding a drug is dried well, a film having low moisture permeability (for example, an aluminum film or the like)
A method such as vacuum-sealing packaging is used. Further, a desiccant (for example, a desiccant made of zeolite such as Serum (registered trademark, manufactured by Tokai Chemical Co., Ltd.) or a desiccant made of silica gel) may be enclosed in vacuum-sealing packaging to ensure a dry state. When the drug is oxidatively decomposed by oxygen, an oxygen absorbent [for example, Ageless (registered trademark, manufactured by Mitsubishi Gas Chemical Company) or the like] may be enclosed in addition to the desiccant.

The amount of the drug retained in the drug carrier may be an effective amount according to the type of the drug, the type of the drug carrier, the site of administration, etc., for example, about 0.1 per cm ^{2 of the} drug carrier.
５０50000 μg, preferably about 0.5-100
Used in the range of 0 μg. Further, it is not always necessary to hold the drug in the thin film, and the drug solution may be injected near the thin film at the time of use. Furthermore, a solution for dissolving the drug may contain a suitable adsorption inhibitor [eg, bovine serum albumin (BSA), human serum albumin, benzalkonium chloride, benzethonium chloride, Tween 80, etc.] to prevent the loss of adsorption of bioactive peptides and proteins. ] May be contained.

Next, an applicator provided with an interface described below is useful for transdermally administering a drug by iontophoresis. 1 and 2
FIG. 1 is a cross-sectional view showing one embodiment of an applicator provided with the interface. FIG. 1 shows an ion exchange membrane type, and FIG. 2 shows an ion exchange resin type. In addition,
The materials, dimensions, and the like described in the following description are merely examples.

First, in FIG. 1, the basic part of the applicator for iontophoresis is that an electrode 2 is provided on the bottom of a cup-shaped container 1 (for example, made of polyester: 30 mm in inner diameter) having a cylindrical hollow (cylindrical concave portion). (For example, a foil type silver electrode punched in a circular shape, diameter 23 mm, thickness 0.04 m
m), ring 3 (for example, O-ring, made of polyethylene:
Inner diameter 23 mm, outer diameter 28 mm), conductive layer 4 (for example, nonwoven fabric, WP-2085, product number, manufactured by Japan Vilene Co., Ltd.):
(Diameter 23 mm, thickness 0.63 mm), ion exchange membrane 5
(For example, AC201 membrane, manufactured by Asahi Kasei, trade name: diameter 28
mm, thickness 0.23 mm), ring 6 (for example, O-ring, made of polyethylene: inner diameter 23 mm, outer diameter 28 mm),
Conductive layer 7 (for example, nonwoven fabric, LMW-9007, product number, manufactured by Japan Vilene Co., Ltd .: diameter 23 mm, thickness 0.63
mm).

The thickness of the cup-shaped container 1 is designed so that the lower surface of the cup-shaped container 1 is at the same level as the surface of the conductive layer 7 such as a nonwoven fabric. In addition, a small hole is formed in the center of the cup-shaped container 1 so that the electrode portion can be connected to a power supply, and a connection terminal 8 (connector to the power supply unit) is formed in the small hole.
Is attached. An adhesive layer 9 (for example, an adhesive sheet having a hole having a diameter of 23 mm, a blender, a registered trademark, 3
A drug holding film 10 (a thin film holding a drug, for example, a hydrophilic Durapore membrane, registered trademark, manufactured by Millipore, Inc .: diameter 28 mm, thickness 0.125 mm) attached to
It is used so that the surface of the drug holding film 10 contacts the skin. The moisturizing agent and the buffer component of the present invention include the conductive layer 4, the ion exchange membrane 5, and / or the drug holding layer 10 made of a nonwoven fabric or the like.
To be blended.

Next, in FIG. 2, reference numeral 11 denotes a cup-shaped container (for example, made of polypropylene: 30 mm in inner diameter) having a cylindrical hollow (cylindrical concave portion), and 12 denotes an electrode (for example,
Foil-shaped silver electrode punched in a circle at the bottom, diameter 23m
m, thickness 0.04 mm) and 14 are dispersed and dispersed, for example, in an ion exchange resin 13 containing 8 wt% of cholestyramine (strongly basic anion exchange resin, quaternary ammonium salt type containing chloride ion, manufactured by Sigma). And / or a mixed gel layer (eg, agar gel layer, UP-16, product number, manufactured by Ina Foods Co., Ltd.). The thickness of the cup-shaped container 11 is such that the lower surface of the cup-shaped container 11 has the same level as the surface of the gel layer 14 (level).
It is designed to be.

As the gel used for the gel layer, a material capable of dispersing an ion exchange resin and dissolving an active ingredient in a drug layer when used as a device is used, and a hydrophilic polymer gel is preferably used. . Such hydrophilic polymer gels include, for example, agar, gelatin, xanthan gum, locust bean gum, carrageenan, gellan gum, tamarind gum, curdlan, pectin, furceleran, guar gum, alginic acid, sodium alginate, cod gum, karaya gum, cellulose and the like. Derivatives and the like are used, and these are used alone or in combination of two or more. Further, an electrolyte, a pH adjuster, a stabilizer, a thickener, a wetting agent, a surfactant, a solubilizer, an absorption promoter, a preservative, and the like may be added to the gel layer as needed.

A connection terminal 15 (connector to the power supply) is attached to a small hole opened in the center of the cup so that the electrode can be connected to a power supply. A drug holding film 17 previously attached to an adhesive layer 16 (for example, an adhesive sheet, blender, registered trademark, manufactured by 3M Company) having a hole having a diameter of 23 mm, for example, on the interface thus configured.
(Thin film holding drug, for example hydrophilic Durapore membrane:
(Diameter: 28 mm, thickness: 0.125 mm) is used so that the surface of the drug holding film 17 contacts the skin.
The humectant and the buffer component of the present invention are blended in the gel layer 14 and / or the drug holding film 17.

Transdermal administration of a drug by iontophoresis can be carried out by applying a DC voltage to the electrodes of the interface and the reference electrode and applying a current.
As a power source, a device capable of applying a continuous DC voltage or a pulse DC voltage is preferable, and a device capable of applying a pulse DC voltage is more preferably used, and a rectangular pulse DC voltage can be applied as a power source of the pulse DC voltage. Power supplies are particularly preferred. The frequency of the pulse DC voltage is appropriately selected from the range of preferably 0.1 to 200 kHz, more preferably 1 to 100 kHz, and particularly preferably 5 to 80 kHz. The on / off ratio of the pulse DC voltage is 1/100 to 20/1, preferably 1/5.
0 to 15/1, more preferably 1/30 to 10/1
Is appropriately selected from the range. Energization time is 24 with continuous energization
Hours or less, preferably 12 hours or less, particularly preferably 6 hours or less.
Less than an hour. On the other hand, in the case of intermittent energization, the total energization time is 24 hours or less, preferably 12 hours or less, particularly preferably 6 hours or less.

[0045]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but it goes without saying that the present invention is not limited to these Examples. << Experimental Example 1 >> This Experimental Example 1 was carried out by using an applicator having the interface shown in FIG. The constituent materials and dimensions are those made of the materials and dimensions described as an example in the above description of FIG. Under anesthesia with pentobarbital, the abdominal skin of an SD rat male (7 weeks old) was shaved with a clipper and treated with a shaver.
It was rubbed gently with absorbent cotton containing a 0% ethanol aqueous solution for degreasing. A drug application applicator was applied to the skin on the left flank of the rat across the midline, and 12% PVA (polyvinyl alcohol) gel (containing 0.9% sodium chloride, 2 mm thick) was applied to the skin on the right flank of the rat. ) Was affixed. A silver electrode was used as the applicator, and a silver chloride electrode (2.5 c) was used as a control electrode (negative electrode).
m ² ) was fixed.

In iontophoresis, pulse depolarization by a short-circuit switch (frequency: 30 kHz, o
n / off: 3/7, voltage value: 10 V) and “1
Repeating the pattern of "energizing for 5 minutes and stopping for 5 minutes sequentially three times (total time of energizing time and energizing stop time = 60 minutes, substantial energizing time = 45 minutes), and then 60 minutes of non-energizing time" are repeated three times During this time, the rats were kept on a fixed plate under anesthesia with pentobarbital.
Then, the peptide concentration in the serum is determined by Rat PTH Kit
(Registered trademark, manufactured by Nichols Corporation) using a radioimmunoassay method. In the interface shown in FIG. 1, the nonwoven fabric 7 was impregnated with the composition liquid of each of the following Examples and Comparative Examples as an electric conductive layer liquid, and used for the experiment.
As for the drug, 40 μg of hPTH (1 → 34) was applied to the drug holding membrane 10.
The experiment was carried out. In addition, the content of each component is all described by weight%.

<Example 1> Component content (%) Urine 5 Citrate buffer (33 mM, pH = 5) 95% ─────────── Total 100

Example 2 Component content (%) N-methyl-2-pyrrolidone 5 citrate buffer (33 mM, pH = 5) 95% ──────────────── Total 100

Example 3 Component Content (%) Urine 5 N-methyl-2-pyrrolidone 5 Citrate buffer (33 mM, pH = 5) 90 ° ─────────────────── Total 100

Comparative Example 1 Component content (%) Citrate buffer (33 mM, pH = 5) 100 ─────────────────────── ──────── Total 100

Comparative Example 2 Ingredient Content (%) Propylene Glycol 30 Citrate Buffer (10 mM, pH = 5) 70% ─────────── Total 100

The results obtained in Examples 1 to 3 and Comparative Examples 1 and 2 are shown in FIG. As is clear from FIG. 3, in the cases of Examples 1 to 3, it was found that a higher serum peptide concentration was obtained with higher reproducibility than in Comparative Examples 1 and 2. Among them, the case of Example 3 (indicated by □ in FIG. 3) is a case in which urea and N-methyl-2-pyrrolidone are used in combination as a humectant, and Example 1 in which they are used alone.
(Urea: circle in FIG. 3) and Example 2 (N-methyl-2-
Pyrrolidone: mark ｐ in FIG. 3), and in Example 3, 6000 pg / ml and 3
It shows serum parathyroid hormone hPTH (1 → 34) concentration which reaches 4000 pg / ml at the first time. Also,
Table 1 shows the bioavailability (B.C.) calculated from the area under the peptide concentration-time curve (AUC) in serum obtained by intravenous administration of hPTH (1 → 34) at 2 μg / kg.
A. ), As shown in Table 1, Examples 1 to
In each of Examples 3, extremely high utilization rates were obtained as compared with Comparative Examples 1 and 2, and particularly in Example 3, a bioavailability rate (BA) as high as 48.89% was shown.

[0053]

[Table 1]

<Experimental Example 2> In Experimental Example 2, the experiment was performed in the same manner as in Example 1, and the applicator shown in FIG. 2 was used. The constituent materials and dimensions of each of the pieces were the same as those described as an example in the above description of FIG. In the interface shown in FIG. 2, the agar gel layer 14 was impregnated with the composition liquid of each of the following Examples and Comparative Examples as an electric conductive layer liquid. As the drug, 40 μg of hPTH (1 → 34) was impregnated in the drug holding film 17. The contents of the following components are all expressed in terms of% by weight.

Example 4 Ingredient Content (%) Urine 5 Agar 1 Cholestyramine 8 Citric acid monohydrate 0.25 Trisodium citrate dihydrate 0.7 Distilled water for injection 85. 05 ─────────────────────────────── Total 100

Example 5 Ingredient Content (%) N-methyl-2-pyrrolidone 5 Agar 1 Cholestyramine 8 Citric acid monohydrate 0.25 Trisodium citrate dihydrate 0.7 Injection For distilled water 85.05 ─────────────────────────────── total amount 100

Example 6 Ingredient Content (%) Urine 5 N-methyl-2-pyrrolidone 5 Agar 1 Cholestyramine 8 Citric acid monohydrate 0.25 Trisodium citrate dihydrate 0 .7 Distilled water for injection 80.05 ─────────────────────────────── Total volume 100

Comparative Example 3 Ingredient Content (%) Agar 1 Cholestyramine 8 Citric acid monohydrate 0.25 Trisodium citrate dihydrate 0.7 Distilled water for injection 90.05 注射───────────────────────────── Total 100

The results obtained in Examples 4 to 6 and Comparative Example 3 are shown in FIG. As is clear from FIG.
In the case of Examples 4 to 6, it can be seen that a higher serum peptide concentration was obtained with higher reproducibility than in Comparative Example 3. Among them, Example 6 (indicated by □ in FIG. 4) is a case where urea and N-methyl-2-pyrrolidone are used in combination as humectants, and Example 4 (urea: in FIG. It is even better than that of the mark (○) and Example 5 (N-methyl-2-pyrrolidone: mark in FIG. 4), and in the case of Example 6, it is about 5900 pg / ml for the second time and about 5800 pg for the third time. 1 shows serum parathyroid hormone hPTH (1 → 34) concentrations as high as 1 / ml. Table 2 shows that
The area under the peptide concentration-time curve in serum obtained by intravenous administration of hPTH (1 → 34) at 2 μg / kg (A
2 shows the bioavailability (BA) calculated from UC). As shown in Table 2, in Examples 4 to 6, extremely high utilization rates were obtained as compared with Comparative Example 3, and particularly in Example 6, the bioavailability rate as high as 54.85% (B.A. .).

[0060]

[Table 2]

<< Experimental Example 3 >> In Experimental Example 3, an applicator having an embodiment shown in FIG. 1 was used. The constituent materials and dimensions of each piece were configured by the materials and dimensions described as an example in the above description of FIG. In the applicator shown in FIG. 1, nonwoven fabrics 4 and 7 were used, and iontophoresis was administered to non-anesthetized rats every day using an applicator in which the ion exchange membrane 5 was impregnated with an electroconductive layer solution. The maintenance of absorbency over time was investigated. The administration conditions for the rats were the same as in Experiment 1, except for the continuous administration method described below. That is, the left half of the abdomen (including the adjacent back) is shaved under ether anesthesia with the rat's midline separated, the drug application applicator is attached to the abdomen, and the control electrode (negative electrode) is placed on the back. Attach and perform continuous administration for 5 days, then leave a 2-day rest period, repeat 5 consecutive doses on the left half abdomen, leave a 2-day rest period, and continue for another 2 days Administration was performed. At the time of administration, the abdomen was wrapped around with an elastic bandage so that the applied patch did not come off the abdomen, and the rats were kept in a Bolman cage.

Prior to this experiment, the skin at the administration site after the iontophoresis administration was repeated for 3 days was preliminarily tested using the same applicator as in Experimental Example 1; However, skin irritation due to energization was observed. Therefore, the composition of Example 1 is further reduced by L
When the following composition containing 10% proline was used, it was found that skin irritation was avoided. Accordingly, in this experiment, an electric conductive layer solution having the composition shown in Example 7 was used, and 200 μg of hPTH (1 → 34) was contained in the drug holding film 10. In the following, the contents of the respective components are all shown in% by weight.

Example 7 Ingredient Content (%) Urine 5 L-Proline 10 Citrate buffer (33 mM, pH = 5) 85% ─────────────── Total 100

FIGS. 5 and 6 show the results obtained in the seventh embodiment. First, as shown in FIGS. 5 (a) to (l), hPTH
Regarding the change in serum concentration of (1 → 34), a high serum peptide concentration in response to energization was maintained for each administration, and even after 16 days, the evaporation of water was suppressed and the electrical conductivity was maintained. It can be seen that the maintained energization response is maintained. Thus, it can be said that the concentration pattern in serum of these pulse waveform types was sufficient to induce the bone-increasing action of hPTH (1 → 34). Also, hPTH (1 →
The bioavailability (BA%) calculated from the area under the peptide concentration-time curve (AUC) in serum obtained by intravenous administration of 34) at 2 μg / kg was as shown in FIG. is there. As shown in FIG. 6, it can be seen that hPTH (1 → 34) is maintained at a high utilization rate for each administration.

<Experimental Example 4> An electric conductive composition was prepared from the electric conductive composition shown in Example 7 without L-proline (5% by weight of urea, citrate buffer (33 m
M, pH = 5) 95% by weight), this composition and Example 7
Using the same applicator as in Experimental Example 1, iontophoresis was administered to rats under the same energization and administration conditions as in Experimental Example 1, and after one day and two days later, the rats were subjected to iontophoresis. After the administration, the presence or absence of local irritation at the administration site was observed. Table 3 shows the results. In Table 3, 0 = no stimulation, 1 = slight stimulation, 2 = medium stimulation, 3 = severe stimulation. As shown in Table 3, mild or moderate local irritation was observed in the electrically conductive composition not containing L-proline. On the other hand, the composition of Example 7 did not show any local irritation.

[0066]

[Table 3]

<Experimental Example 5> In Experimental Example 5, xanthan gum and locust bean gum, which are thickeners, were used in the composition shown in FIG. A preservative, benzoic acid and methyl parahydroxybenzoate were added to prepare an electrically conductive composition. In the experiment of iontophoresis administration in rats, a drug-impregnated membrane 17 impregnated with 200 μg of hPTH (1 → 34) was used at 0.1 mA / c.
m ² of the constant transmission current of a pulse direct current (50 kHz, 5
(0% duty) for 60 minutes.

Example 8 Ingredient Content (%) Urine 5 L-Proline 10 Agar 1 Xanthan Gum 0.25 Locust Bean Gum 0.25 Cholestyramine 5 Benzoic Acid 0.2 Methyl Parahydroxybenzoate 0 .2 Citric acid monohydrate 0.25 Trisodium citrate dihydrate 0.7 Distilled water for injection 77.15───────────────────── ────────── Total 100

Example 9 Ingredient Content (%) Urine 5 L-Proline 10 Agar 1 Xanthan Gum 0.25 Locust Bean Gum 0.25 Cholestyramine 5 Benzoic Acid 0.1 Methyl Parahydroxybenzoate 0 .2 Trisodium citrate dihydrate 0.2 Distilled water for injection 78.00 ─ Total 100

Example 10 Ingredient Content (%) Urine 5 L-Proline 10 Agar 1 Xanthan Gum 0.25 Locust Bean Gum 0.25 Cholestylamine 5 Benzoic Acid 0.2 Methyl parahydroxybenzoate 0.2 Trisodium citrate dihydrate 0.25 Distilled water for injection 77.85 ───────────────────────────── ── Total 100

FIG. 7 shows serum hPT in the electroconductive compositions of Examples 8, 9 and 10 when iontophoresis was administered.
The time transition of the H (1 → 34) concentration is shown. In each of the compositions of the examples, good absorptivity in response to electricity was shown. In addition, regarding the compositions of Examples 8 and 10, bacteria and fungi were ingested, and the change in the number of bacteria was examined.
The result satisfies Category II, which is the criterion of No. 3 (both bacteria and fungi are at the same level or lower than the number of ingested bacteria).

[0072]

According to the drug administration composition for iontophoresis containing the humectant according to the present invention, evaporation of water from the drug solution is suppressed to maintain the electrical conductivity for a long time, By promoting transdermal absorption, the drug can be safely and transdermally administered at a high absorption rate. As a humectant, urea or N-methyl-2-pyrrolidone is particularly preferably used, but it is more effective if both are used in combination, and more effective if L-proline is used as a humectant used in combination with these humectants. is there.

[Brief description of the drawings]

FIG. 1 is a sectional view showing an example of an applicator.

FIG. 2 is a sectional view showing another example of the applicator.

FIG. 3 shows hPT in Examples 1 to 3 and Comparative Examples 1 and 2.
The graph which shows the time transition of the serum concentration of H (1 → 34).

FIG. 4 shows hPTH in Examples 4 to 6 and Comparative Example 3.
The graph which shows the time transition of the serum concentration of (1 → 34).

FIG. 5 is a graph showing the time course of serum concentration of hPTH (1 → 34) during daily iontophoresis administration in Example 7.

FIG. 6 is a graph showing the bioavailability of hPTH (1 → 34) during daily iontophoresis administration in Example 7.

FIG. 7 shows serum hPTH (1 → 3) in the electroconductive compositions of Examples 8, 9, and 10 upon administration of iontophoresis.
4) A graph showing the time transition of the concentration.

[Explanation of symbols]

DESCRIPTION OF SYMBOLS 1 Cup-shaped container which has a cylindrical hollow (cylindrical recessed part) 2 Electrode (a foil type electrode punched out circularly at the bottom) 3, 6 Ring (O-ring etc.) 4 Conductive layer (nonwoven fabric etc.) 5 Ion exchange membrane 7 8 Conductive layer (nonwoven fabric, etc.) 8 Connection terminal (connector to power supply) 9 Adhesive layer (adhesive sheet, etc.) 10 Drug holding film 11 Cup-shaped container having cylindrical hollow (cylindrical concave part) 12 Electrode (circular at bottom) 13 Ion exchange resin 14 Gel layer (agar gel layer etc.) 15 Connection terminal (connector to power supply) 16 Adhesive layer (adhesive sheet etc.) 17 Drug holding film

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical display location // A61N 1/30 A61K 37/30 AED (72) Inventor Kenji Mori 1 Kannondai, Tsukuba, Ibaraki No. 25-11, Hisamitsu Pharmaceutical Co., Ltd., Tsukuba Research Laboratories (72) Inventor Katsumi Iga 1st A-808, Mayigaoka Nishi, Saita City, Osaka

Claims (19)

[Claims] 1. A drug administration composition for iontophoresis, comprising a drug to be ionized and a humectant. 2. The composition for drug administration for iontophoresis according to claim 1, wherein the concentration of the humectant is 0.1 to 90% by weight. 3. The composition according to claim 1, wherein the humectant is an amide. 4. The drug administration composition for iontophoresis according to claim 1, wherein the humectant is a humectant comprising a mixture of an amide and an amino acid or a derivative thereof. 5. An amide comprising urea or urea and N-methyl-2.
Amides comprising a mixture of -pyrrolidone.
Or the drug administration composition for iontophoresis according to 4. 6. The composition for drug administration for iontophoresis according to claim 4, wherein the amino acid or a derivative thereof is a cyclic amino acid or a derivative thereof. 7. The drug administration composition for iontophoresis according to claim 6, wherein the amino acid is L-proline. 8. The drug administration composition for iontophoresis according to claim 5, wherein the concentration of urea or a mixture of urea and N-methyl-2-pyrrolidone is in the range of 1 to 30% (w / w) in the composition. Stuff. 9. The composition according to claim 1, wherein the concentration of L-proline is 1 to 30% in the composition.
The drug administration composition for iontophoresis according to claim 7, which is in the range of (w / w). 10. The drug administration composition for iontophoresis according to claim 1, wherein the drug to be ionized is a drug cationized with a buffer having a pH of 3 to 7. 11. The drug administration composition for iontophoresis according to claim 10, wherein the buffer is a buffer containing a water-soluble aliphatic carboxylic acid having 2 to 6 carbon atoms. 12. The drug administration composition for iontophoresis according to claim 11, wherein the water-soluble aliphatic carboxylic acid is citric acid, a salt thereof and / or a hydrate thereof. 13. A pharmaceutical composition comprising: (i) a drug to be ionized; and (ii)
A drug administration composition for iontophoresis, comprising any one of the following (a), (b), (c), (d) or (e) as a humectant. (A) Urea (b) Urea and N-methyl-2-pyrrolidone (c) N-methyl-2-pyrrolidone and L-proline (d) Urea, N-methyl-2-pyrrolidone and L-proline (e) Urea And L-proline 14. A humectant having a concentration of 1 to 60% (w / w).
The drug administration composition for iontophoresis according to claim 13, which is in the range of: 15. A drug administration composition for iontophoresis, further comprising a water-soluble aliphatic carboxylic acid having 2 to 6 carbon atoms,
The drug administration composition for iontophoresis according to claim 13, which is a composition containing a salt thereof and / or a hydrate thereof. 16. The composition for administration of a drug for iontophoresis according to claim 13, wherein the mixing ratio of (e) urea and L-proline is from about 30: 1 to about 1:30 by weight. A drug administration composition for iontophoresis. 17. The drug administration composition for iontophoresis according to claim 1, wherein the drug to be ionized is a physiologically active peptide. 18. The composition for drug administration for iontophoresis according to claim 17, wherein the physiologically active peptide is a calcium-regulating hormone. 19. The drug administration composition for iontophoresis according to claim 18, wherein the calcium-regulating hormone is parathyroid hormone, a derivative thereof, or a salt thereof.