JP3136413B2 - Percutaneous absorption type pollakiuria / urinary incontinence treatment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a transdermally absorbable therapeutic agent for pollakiuria and urinary incontinence, and more particularly to an externally administered therapeutic agent for transdermally absorbable pollakiuria and incontinence.

[0002]

2. Description of the Related Art In Japan, the population is aging rapidly. The proportion of elderly people aged 65 and over in the total population is currently about 11%, but this is increasing year by year, and is expected to well exceed 20% 30 years from now.

[0003] The aging of the population has various effects on society, and one of them is an increase in the number of elderly people who need nursing care such as bedridden elderly people and demented elderly people. However, if about half of demented elderly who are bedridden or asleep or awake will have incontinence, it is estimated that the number of incontinent patients in this field is now well over two million and is increasing in the future.

Many attempts have been made to treat urinary abnormalities such as pollakiuria and urinary incontinence. For example, many kinds of medicines have already been used as orally administered urinary abnormalities improvers for treating urinary abnormalities as described above. It is commercially available.

[0005]

However, among the causative diseases that cause frequent urination, for example, cerebrospinal trauma, cerebrovascular disorder,
Patients after tumor surgery in various places require a bedridden period. In the case of these patients, in the case of oral administration, it is often difficult to administer the medicine because the medicine must be taken at regular intervals.

On the other hand, in recent years, transdermal administration routes have attracted attention from the viewpoint of effective drug administration routes, that is, the concept of drug delivery systems. With conventional oral administration, the drug absorbed from the intestinal tract is necessarily sent to the liver via the portal vein for metabolism, so-called a first-pass effect, and the bioavailability is greatly reduced. Therefore, in order to maintain the effective blood concentration, it is necessary to administer a relatively large amount of the drug, which naturally increases the incidence of side effects. In this regard, according to transdermal administration, the drug immediately enters the subcutaneous capillaries and reaches the target site via the vein and heart without undergoing any substantial degradation. That is,
The bioavailability of the drug is close to maximal and the drug is needed in relatively small amounts. Therefore, a drug having a strong side effect, a drug which has been mainly used for oral or injection administration, and a drug which has a short effective blood concentration holding time and needs to be administered several times a day can reduce side effects without causing pain. It can be gradually and continuously absorbed from the skin. For this reason, transdermal administration is effective as a method for sustained release of a drug, and a transdermal administration type is expected as the drug for improving urinary abnormalities.

[0007] However, since skin originally has the property of preventing foreign substances from entering the body, drugs that can be administered from the skin have been very limited. In addition, a method of increasing the transdermal absorption of a drug using a keratolytic agent such as Aison has been attempted.However, these keratolytic agents are highly irritating to the skin and may cause rash due to side effects. difficult.

The present invention is to solve the above-mentioned problems of the prior art. It is an object of the present invention to provide a transdermal absorption type urinary frequency / urinary incontinence therapeutic agent which is easy to administer, has few side effects, is safe, and can gradually and efficiently absorb the active ingredient from the skin. Is to provide.

[0009]

Means for Solving the Problems The therapeutic agent for transcutaneous absorption of pollakiuria / urinary incontinence of the present invention comprises propiverine [1-methyl-4-piperidyl α, α-diphenyl-α-n-propoxyacetate] or a pharmaceutical agent. And a base for external preparations. In the transdermal absorption type pollakiuria / urinary incontinence therapeutic agent, telodiline [(±) -N-tert-butyl-1-methyl-3,3-diphenylpropyl] is used as an active ingredient related to the active ingredient of the present invention. Amine), oxybutynin [4-diethylamino-2-butynyl (±) -α-cyclohexyl-α-phenylglycolate], flavoxate [2-
Piperidinoethyl 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate]
Or those selected from the group consisting of pharmaceutically acceptable salts thereof.

As the active ingredient, propiverine or a pharmaceutically acceptable salt thereof such as a hydrochloride, commercially available ones can be used.

The base for external preparations is selected from the group consisting of water-soluble polymer compounds, fat-soluble polymer compounds, fatty acids and derivatives thereof, animal and vegetable oils and fats, alcohols, terpene compounds, surfactants and water. Those composed of at least one kind are preferred.

Water-soluble polymer compounds which can be used as a base for external preparations include polyacrylic acid and its derivatives, cellulose derivatives, polyvinyl alcohol, gelatin, casein, polyethylene glycol, gum arabic, methyl vinyl ether / maleic anhydride copolymer. It is preferable to use at least one selected from the group consisting of coalesced and natural polysaccharides.

Fat-soluble polymer compounds that can be used as a base for external preparations include natural rubber, isoprene rubber, butyl rubber,
It is preferable to use at least one selected from the group consisting of styrene isoprene block copolymer, styrene butadiene copolymer, silicone, lanolin, petrolatum, plastic base, beeswax, gay wax, and solid paraffin.

The fatty acids and derivatives thereof which can be used as a base for external preparations are preferably monocarboxylic acids having 3 to 30 carbon atoms, esters thereof or alkali metal salts thereof. Examples of fatty acids are hexanoic, heptanoic, octanoic, nonanoic, decanoic, dodecanoic, tetradecanoic, hexadecanoic, octadecanoic, oleic, linoleic. Octadecanoic acid, oleic acid,
Linoleic acid is most preferred. The fatty acid ester is preferably one in which the alkyl portion of the alcohol residue is hexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, or oleyl. Most preferred are tetradecyl tetradecanoate, hexadecyl hexadecanoate, and oleyl oleate. The fatty acid alkali metal salt is most preferably a fatty acid sodium salt.

Animal and vegetable oils and fats which can be used as a base for external preparations include almond oil, olive oil, camellia oil, persic oil, peppermint oil, sesame oil, soybean oil, mink oil, cottonseed oil, corn oil, safflower oil and coconut oil. And at least one selected from the group consisting of eucalyptus oil and castor oil. Olive oil, peppermint oil and eucalyptus oil are most preferred.

The fatty acids and their derivatives and animal and vegetable fats and oils may be used alone or in combination of two or more. The amount used is preferably about 1.0% to about 30% by weight based on the total weight of the aqueous base.

The alcohol which can be used as a base for external preparations preferably has 1 to 30 carbon atoms and 1 to 10 hydroxyl groups in the molecule. Examples of polyhydric alcohols are glycerin, propylene glycol,
Octanediol, butanediol, polyethylene glycol and D-sorbit. These can be used in combination of two or more. The amount of the alcohol used is about 10% by weight to about 5% by weight based on the total weight of the base.
It is preferably 0% by weight.

Terpene compounds which can be used as a base for external preparations include menthol, mentone, limonene, pinene,
At least one selected from the group consisting of piperiton, terpinene, terpinolene, terpinol, and carveol
Those consisting of seeds are preferred.

The surfactant which can be used as a base for external preparations is preferably one comprising at least one selected from the group consisting of nonionic surfactants, anionic surfactants and cationic surfactants.

The base for external preparation may contain, if desired, other additives other than the above components, such as cellulose derivatives, alkali metal salts of polyacrylic acid, gelatin, kaolin, bentonite, titanium white, etc., and pH adjusters such as citric acid, tartaric acid. May be included in a predetermined amount.

As an example of the method for producing the preparation of the present invention, propiverine or a pharmaceutically acceptable salt thereof can be prepared by adding a water-soluble polymer compound, a fat-soluble polymer compound, a fatty acid and its derivative, animal and vegetable oils and fats, alcohols, terpene. Compound,
At least one selected from the group consisting of a surfactant and water
A method of dissolving in a seed and uniformly kneading the same with other components of the base for external preparation.

If the concentration of the active ingredient consisting of propiverine or a pharmaceutically acceptable salt thereof is too low, the action as a medicament will be insufficient, and if it is too high, the cost will be disadvantageous. Occurs. Therefore, the concentration of the active ingredient is from 0.02% by weight to 1% by weight based on the total weight of the external preparation.
The content is preferably 0% by weight.

The therapeutic agent for transcutaneous absorption of urinary frequency and urinary incontinence of the present invention thus obtained is spread, for example, on a suitable base cloth, such as flannel or non-woven fabric, and then the polyethylene or polypropylene is exposed on the exposed surface of the drug. And a peeling film of polyester or the like can be adhered to provide a commercially available external preparation.

[0024]

The percutaneous absorption type urinary frequency / urinary incontinence therapeutic agent of the present invention does not contain a component having high skin irritation, so that it has few side effects and the base is well adapted to the skin. Furthermore, by appropriately blending various components with the base, the active ingredient and the base can be easily and homogeneously mixed.

The transdermally absorbable therapeutic agent for pollakiuria / urinary incontinence of the present invention can effectively and gradually absorb the active ingredient from the skin.

[0026]

The present invention will be described in more detail with reference to the following examples.

Example 1 1 part of "terodiline hydrochloride" was dissolved in 43.1 parts of water, and 5 parts of peppermint oil, 15 parts of glycerin and 1 part of butanediol were dissolved.
5 parts, sodium carboxymethyl cellulose 9 parts, sodium polyacrylate 7 parts, gelatin 4 parts, sorbitan monooleate 0.1 part, polyoxyethylene sorbitan monooleate 0.3 part and citric acid 0.5 part The formulation of Example 1 was obtained by uniformly kneading the ingredients.

Example 2 1 part of "oxybutynin hydrochloride" was dissolved in 43.1 parts of water.
5 parts of mint oil, 15 parts of glycerin, 15 parts of butanediol, 9 parts of sodium carboxymethylcellulose
Parts, sodium polyacrylate 7 parts, gelatin 4 parts, sorbitan monooleate 0.1 part, polyoxyethylene sorbitan monooleate 0.3 part and citric acid 0.5
And kneaded uniformly with each of the components of Example 2 to obtain the preparation of Example 2.

Example 3 1 part of "propiverine hydrochloride" was dissolved in 43.1 parts of water, and 5 parts of mint oil, 15 parts of glycerin, 15 parts of butanediol, 9 parts of sodium carboxymethylcellulose were dissolved in 4 parts of water.
Performed by uniformly kneading with 7 parts of sodium polyacrylate, 4 parts of gelatin, 0.1 part of sorbitan monooleate, 0.3 part of polyoxyethylene sorbitan monooleate and 0.5 part of citric acid. The formulation of Example 3 was obtained.

Example 4 1 part of "flaboxate hydrochloride" is dissolved in 43.1 parts of water,
5 parts of mint oil, 15 parts of glycerin, 15 parts of butanediol, 9 parts of sodium carboxymethylcellulose
Parts, sodium polyacrylate 7 parts, gelatin 4 parts, sorbitan monooleate 0.1 part, polyoxyethylene sorbitan monooleate 0.3 part and citric acid 0.5
To obtain a preparation of Example 4.

Example 5 1 part of "terodiline hydrochloride" was dissolved in 53.6 parts of water and 10 parts of propylene glycol, and 5 parts of eucalyptus oil, 5 parts of stearic acid, 5 parts of cetyl alcohol and 5 parts of beeswax were dissolved.
Parts, 5 parts of solid paraffin, 10 parts of liquid paraffin, 0.1 part of sorbitan monooleate and 0.3 part of polyoxyethylene sorbitan monooleate were uniformly kneaded to obtain the preparation of Example 5. .

Example 6 One part of "terodiline hydrochloride" was dissolved in 10 parts of propylene glycol, and this was uniformly kneaded with each of the components consisting of 5 parts of oleic acid, 74 parts of natural rubber and 10 parts of polybutene. I got

Example 7 One part of "terodiline hydrochloride" was dissolved in 10 parts of propylene glycol, and this was dissolved in 5 parts of d-limonene and purified lanolin 40.
Parts, 40 parts of gay wax and 4 parts of white petrolatum were uniformly kneaded to obtain the preparation of Example 7.

Comparative Example 1 1 part of "terodiline hydrochloride" was dissolved in 48.1 parts of water, and 15 parts of glycerin, 15 parts of butanediol, 9 parts of sodium carboxymethylcellulose, 7 parts of sodium polyacrylate, 4 parts of gelatin, Each component consisting of 0.1 part of sorbitan monooleate, 0.3 part of polyoxyethylene sorbitan monooleate and 0.5 part of citric acid was uniformly kneaded to obtain a preparation of Comparative Example 1.

Comparative Example 2 One part of "terodiline hydrochloride" was dissolved in 47.1 parts of water, and this was dissolved in one part of peppermint oil, 15 parts of glycerin and one part of butanediol.
5 parts, sodium carboxymethyl cellulose 9 parts, sodium polyacrylate 7 parts, gelatin 4 parts, sorbitan monooleate 0.1 part, polyoxyethylene sorbitan monooleate 0.3 part and citric acid 0.5 part The components were uniformly kneaded to obtain a preparation of Comparative Example 2.

Comparative Example 3 One part of "terodiline hydrochloride" was dissolved in 38.1 parts of water, and 10 parts of peppermint oil, 15 parts of glycerin, 15 parts of butanediol, 9 parts of sodium carboxymethylcellulose,
Knead uniformly with each component consisting of 7 parts of sodium polyacrylate, 4 parts of gelatin, 0.1 part of sorbitan monooleate, 0.3 part of polyoxyethylene sorbitan monooleate and 0.5 part of citric acid, and compare The formulation of Example 3 was obtained.

Comparative Example 4 One part of "terodiline hydrochloride" was dissolved in 42.1 parts of water, and this was dissolved in peppermint oil 5 parts, glycerin 15 parts, butanediol 1
5 parts, 9 parts of sodium carboxymethylcellulose, 7 parts of sodium polyacrylate, 4 parts of gelatin, 0.1 part of sorbitan monooleate, 0.3 part of polyoxyethylene sorbitan monooleate and 1.5 parts of citric acid The ingredients were uniformly kneaded to obtain a preparation of Comparative Example 4.

Comparative Example 5 1 part of "terodiline hydrochloride" was dissolved in 42.6 parts of water, and this was mixed with 5 parts of peppermint oil, 15 parts of glycerin and 1 part of butanediol.
5 parts, 9 parts of sodium carboxymethyl cellulose, 7 parts of sodium polyacrylate, 4 parts of gelatin, 0.1 part of sorbitan monooleate, 0.3 part of polyoxyethylene sorbitan monooleate and 1.0 part of citric acid The components were uniformly kneaded to obtain a preparation of Comparative Example 5.

Comparative Example 6 One part of "terodiline hydrochloride" was dissolved in 43.6 parts of water, and this was dissolved in 5 parts of eucalyptus oil, 15 parts of glycerin, 15 parts of butanediol, 9 parts of sodium carboxymethylcellulose,
The components of Comparative Example 6 were uniformly kneaded with each component consisting of 7 parts of sodium polyacrylate, 4 parts of gelatin, 0.1 part of sorbitan monooleate and 0.3 part of polyoxyethylene sorbitan monooleate. .

Comparative Example 7 One part of "terodiline hydrochloride" was dissolved in 43.1 parts of water, and this was dissolved in peppermint oil 5 parts, glycerin 15 parts, butanediol 1
5 parts, 9 parts of sodium carboxymethyl cellulose, 7 parts of sodium polyacrylate, 4 parts of gelatin, 0.1 part of sorbitan monooleate, 0.3 part of polyoxyethylene sorbitan monooleate and 0.5 part of triethanolamine The ingredients were uniformly kneaded to obtain a preparation of Comparative Example 7.

<Performance Evaluation Test>

Test Example 1 (Drug Permeation Rate of Drug) Using the preparation of Example 1-7, the skin permeability of the drug was evaluated by an in vitro test. In this test, the absorption cell shown in FIG. 1 was used.

The rat abdominal skin was sandwiched between the fixtures 1, the preparation to be tested was attached to the fixture 2, and the external patch was brought into contact with the rat abdominal skin of the fixture 1. The container 3 was filled with 5,18 ml of Tyrode's solution so that air did not enter.
Place the absorption cell in a 37 ° C. incubator and stirrer 4
While the Tyrode's solution 5 is being stirred, 0.5 ml of the Tyrode's solution 5 is collected at each time of 1 to 7 hours, and the drug concentration in the external patch to be tested is determined by measuring the drug concentration therein. The permeation rate to rat abdominal skin was determined. Table 1 shows the results.

[0044]

[0045]Test Example 2 (Mentha oil concentration and skin permeation rate
Every time) Relationship between Concentration of Mint Oil as an Additive and Skin Permeability
investigated. Table 2 shows the results.

[0046]

As is clear from Table 2, the skin permeability was improved when the concentration of mint oil was 1-10% by weight, and the skin permeability was maximized when the concentration of mint oil was 5% by weight.

Test Example 3 (Terodiline uptake in rats )
Yield test) An external patch using the preparations of Example 1 and Comparative Example 4-7 was cut into a 2 cm x 2 cm size and applied to the abdominal skin of a hairless rat. Blood was collected at 2, 4, 8, 24 and 48 hours after application, and the telodiline concentration in the serum was measured. The results are shown in FIG.

FIG. 2 shows that the skin permeability of terodiline is pH
It turns out that it is good when the preparation is adjusted to 6.0-8.0. The terodiline absorption lasted for pH 7.0-9.
It can be seen that it is good when the preparation is adjusted to 0. Therefore,
It can be seen that it is best to adjust the formulation to pH 7.0-8.0 in order to combine excellent skin permeability and sustained absorption of telodiline.

[0050]

As described above, the transdermal absorption-type pollakiuria of the present invention
Since the therapeutic agent for urinary incontinence is composed of an active ingredient composed of propiverine or a pharmaceutically acceptable salt thereof and a base for external preparation, it can be used as an external preparation, for example, an external patch, and the drug can be applied simply to the skin. It can be simply applied or affixed to the skin, and is easier to administer than conventional oral percutaneous absorption type pollakiuria / urinary incontinence treatment.

The therapeutic agent for transcutaneous absorption of pollakiuria / urinary incontinence according to the present invention is useful for sustained release of a drug, has little side effects, is safe, and allows the drug to be gradually and efficiently absorbed from the skin. it can.

[Brief description of the drawings]

FIG. 1 is a schematic configuration diagram of an absorption cell used for evaluating skin permeability of an active ingredient blended in an external patch.

FIG. 2 shows the results of terodiline absorption test in rats.

[Explanation of Signs] 1, 2 Fixture 3 Container 4 Stirrer 5 Tyrode Liquid

Claims (9)

(57) [Claims] 1. An active ingredient comprising propiverine [1-methyl-4-piperidyl α, α-diphenyl-α-n-propoxyacetate] or a pharmaceutically acceptable salt thereof, and a base for external preparation. A transdermal absorption-type therapeutic agent for pollakiuria and urinary incontinence. 2. The external preparation base is a water-soluble polymer compound,
2. The process according to claim 1, comprising at least one selected from the group consisting of fat-soluble polymer compounds, fatty acids and their derivatives, animal and vegetable fats and oils, alcohols, terpene compounds, surfactants and water. Skin absorption type pollakiuria / urinary incontinence treatment. 3. The water-soluble polymer compound is polyacrylic acid and a derivative thereof, a cellulose derivative, polyvinyl alcohol, gelatin, casein, polyethylene glycol,
3. The therapeutic agent for transcutaneous absorption of pollakiuria / urinary incontinence according to claim 2, comprising at least one member selected from the group consisting of gum arabic, methyl vinyl ether / maleic anhydride copolymer and natural polysaccharide. 4. The fat-soluble polymer compound is a natural rubber, isoprene rubber, butyl rubber, styrene isoprene block copolymer, styrene butadiene copolymer, silicone,
3. The transdermal absorption-type therapeutic agent for pollakiuria and urinary incontinence according to claim 2, comprising at least one selected from the group consisting of lanolin, vaseline, plastic base, beeswax, gay wax, and solid paraffin. 5. The fatty acid and its derivative have 3 carbon atoms.
3. The transdermal absorption-type therapeutic agent for pollakiuria and urinary incontinence according to claim 2, which is a monocarboxylic acid or an ester thereof or an alkali metal salt thereof. 6. The animal or vegetable oil or fat from almond oil, olive oil, camellia oil, persic oil, peppermint oil, sesame oil, soybean oil, mink oil, cottonseed oil, corn oil, safflower oil, coconut oil, eucalyptus oil and castor oil. 3. The transdermal absorption-type therapeutic agent for pollakiuria / urinary incontinence according to claim 2, wherein the therapeutic agent comprises at least one member selected from the group consisting of: 7. The method according to claim 1, wherein the alcohol has 1 to 3 carbon atoms.
3. The therapeutic agent for transcutaneous absorption of pollakiuria / urinary incontinence according to claim 2, wherein the agent has 0 and 1 to 10 hydroxyl groups in the molecule. 8. The process according to claim 2, wherein the terpene compound is at least one selected from the group consisting of menthol, menthol, limonene, pinene, piperiton, terpinene, terpinolene, terpinol, and carveol. Skin absorption type pollakiuria / urinary incontinence treatment. 9. The transdermal absorption method according to claim 2, wherein the surfactant comprises at least one selected from the group consisting of a nonionic surfactant, an anionic surfactant, and a cationic surfactant. Type urinary frequency / urinary incontinence treatment.