JP2521091B2 - Topical preparation of catecholamines - Google Patents

Description

TECHNICAL FIELD OF THE INVENTION The present invention relates to an external preparation of catecholamines, and more specifically, to a buffer solution containing a stabilizer, which contains catecholamines, a medium-chain fatty acid glyceride and a surfactant. The present invention relates to an external preparation of catecholamines characterized by comprising:

BACKGROUND ART Catecholamine is a generic term for amines having a catechol nucleus in a part of the molecular structure, and as medicines, for example, sympathomimetic drugs such as adrenaline, noradrenaline, isoproterenol, dopamine, and dobutamine, or Parkinson's. Levodopa, which is a drug for treating diseases, is known.

These catecholamines are mainly used as oral agents and injectable agents, but most of the oral agents are monoamine oxidase (monoamineooxidase) in the small intestine and liver.
xidase) and catechol-O-methyltransferase are inactivated by the enzyme and cause a decrease in pharmacological activity.
It is necessary to use it in combination with enzyme inhibitors or to devise pharmaceuticals. In addition, although the effect of injection is rapid,
Since it has a strong cardiac stimulating action, it is necessary to set the dosage and administration according to the patient's symptoms and hemodynamics, which is troublesome to use.

Further, as another dosage form, an inhalant of isoproterenol is used when treating bronchial asthma, but in such a case, the dose of the drug is unclear and it is difficult to predict the effect.

Thus, in consideration of the complexity of using the existing preparations of catecholamines, it is useful to apply the preparations by transdermal administration, which is easy to handle and highly safe.

However, in general, when administered through the skin, the stratum corneum in the epidermis fulfills the physiological function as a barrier against permeation of substances into the body, and the drug absorption amount is remarkably small as compared with the absorption from the digestive tract. Therefore, by forming a drug into a prodrug or forming an ion pair with another drug, it enhances the lipophilicity of the drug and increases its absorption amount, or in combination with a compound having a transdermal absorption promoting action such as dimethyl sulfoxide or urea. Although various studies have been studied to increase the absorption of drugs by using these methods, although absorption has been improved, these methods have problems such as restrictions on use as pharmaceuticals and toxicity. The current situation is that it has hardly been put to practical use.

Recently, regarding the external preparation of isoproterenol, JP-A-61
-204117 and 61-286323 have been reported, but they have not been sufficiently improved in terms of stability of the main drug in the preparation and safety of the transdermal absorption enhancer used. It is hard to say that

Problems to be Solved by the Invention Since the above-mentioned catecholamines have poor transdermal absorbability, they cannot absorb a sufficient amount necessary for the human body by themselves, and the method applied to existing external preparations cannot be used. Even if an external preparation is prepared by using it as it is, it is impossible to obtain an effective external preparation in terms of affinity to skin, absorbability and the like.

Therefore, it is necessary to find a suitable percutaneous absorption enhancer for external preparation of catecholamines, but a percutaneous absorption enhancer useful as an external preparation component of catecholamines is not yet known.

Under these circumstances, the present inventors have started the development of external preparations of catecholamines, and have conducted diligent research to search for a desirable transdermal absorption enhancer. It was found that the combined use promotes transdermal absorption of catecholamines,
The present invention has been completed.

Means for Solving the Problems According to the present invention, there is provided an external preparation of atecholamines, which comprises a buffer containing a stabilizer and atecholamines, a medium-chain fatty acid glyceride and a surfactant. To be done.

Further, the external preparation of the catecholamines is prepared by, for example, dissolving (suspending) the catecholamines in a buffer solution containing a stabilizer, and then adding and dispersing a medium chain fatty acid glyceride and a surfactant to prepare an emulsion. It can be obtained by blending with a desired base material for external use.

The catecholamines used in the present invention have a pH of
It is used by dissolving (suspending) it in a buffer solution such as lactic acid, acetic acid, and citric acid adjusted to 3.5 to 6.5, but since catecholamines are unstable in an aqueous solution, sodium bisulfite and metabisulfite are previously used. It is convenient to prepare a solution (suspension) of catecholamines using a buffer containing 0.01 to 1.0% by weight of a stabilizer such as sodium or cysteine hydrochloride.

Catecholamines are usually contained in an external preparation in an amount of 0.05 to 70.0
%, Preferably 0.1 to 50.0% by weight, and if less than 0.05% by weight, the drug effect is poorly expressed. On the other hand, the drug may be contained at a high concentration in a supersaturated state. However, 70.0% by weight or less is desirable for formulation preparation.

As the medium chain fatty acid glyceride, a monoglyceride of a fatty acid having 6 to 18 carbon atoms or a diglyceride or a mixture of two or more kinds of monoglyceride and / or diglyceride is used. Suitable examples include caproic acid monoglyceride and diglyceride, caprylic acid monoglyceride and iglyceride, capric acid monoglyceride and iglyceride, and for example, commercially available "Nikkor MGK"
(Product name: Nikko Chemicals Co., Ltd. product) can be used as it is. These are usually added to the topical formulation at 0.1
〜40.0 wt%, preferably 1.0 to 30.0 wt% is desirable to be blended, less than 0.1% wt% is poor absorption promoting effect, on the other hand, if it exceeds 40.0 wt%, preparation preparation becomes difficult, and It is economically disadvantageous.

Further, a surfactant is added for the purpose of facilitating emulsification and stabilizing the emulsion when preparing an emulsion, and sorbitan fatty acid ester, sorbitol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester. , Polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil derivative, polyoxyethylene polyoxypropylene alkyl ether, and the like. For example, commercially available "Tween 20" (trade name: product of Junsei Chemical Co., Ltd.), "HCO-60""(Product name: Nikko Chemicals Co., Ltd. product) etc. can be used as they are. These are usually 0.01 to 10.0% by weight in the external preparation, preferably 0.1.
It is desirable to mix it in a proportion of 05 to 1.0% by weight.

The external preparation of catecholamines according to the present invention can be made into various external preparations expected to exhibit a pharmacological effect by percutaneous absorption, for example, gels, ointments, patches, liquids, etc. A desired external preparation can be produced by appropriately selecting an external base suitable for the above dosage form and formulating it according to a conventional method.

As the external base used at this time, a substance which does not exhibit a medicinal effect per se is desirable, for example, hydrophilic petrolatum, purified lanolin, water-absorbing ointment, a water-absorbing base such as hydrolanolin,
Hydrophilic bases such as hydrophilic ointment, water-soluble bases such as macrogol ointment, starch, pullulan, gum arabic, tragalant gum, gelatin, dextran, methyl cellulose,
Examples thereof include natural water-soluble polymers such as carboxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose, synthetic water-soluble polymers such as carboxyvinyl polymer, polyacrylic acid (sodium) and polyvinyl alcohol.

Further, if necessary, an emulsifier such as gum arabic, lecithin, glycerin, propylene glycol, a suspending agent, a moisturizing agent and other conventional additives may be added.

Examples The present invention will be described in more detail below with reference to Examples, but the technical scope of the present invention is not limited to these Examples.

Example 1 100 mg of isoproterenol hydrochloride was dissolved in 7.45 g of a lactic acid buffer solution of pH 4.06 containing 50 mg of sodium bisulfite, and "Tween 20" (product name: product of Junsei Kagaku Co., Ltd.) 5
After the addition of 0 mg, 2 g of "Nikkor MGK" (product name: Nikko Chemicals Co., Ltd. product) was added with stirring, and 300 mg of hydroxypropyl cellulose as a gel base was further added and kneaded to obtain a gel preparation.

Example 2 According to the same procedure as in Example 1, 20 mg of levodopa instead of 100 mg of isoproterenol hydrochloride and 7.53 g of lactate buffer solution were used.
Was used to obtain a gel formulation.

Example 3 According to the same procedure as in Example 1, a gel preparation was obtained by using 100 mg of dopamine hydrochloride instead of 100 mg of isoproterenol hydrochloride.

Example 4 White petrolatum 10 g, cetanol 28 g, "Nikkor MGK"
Take 20 g, butyl paraoxybenzoate 0.1 g, lauromacrogol 0.5 g and sorbitan sesquioleate 5 g and keep at 75 ° C. on a water bath. Separately, 0.1 g of ethyl paraoxybenzoate,
Isoproterenol hydrochloride 1 g, sodium bisulfite 0.1 g
Along with 35.2 g of pH 4.06 lactate buffer, the mixture was heated to 80 ° C. and gradually added to the above solution with stirring. After the addition was completed, heating was stopped, and the mixture was thoroughly mixed and stirred until it solidified to obtain an ointment preparation.

Example 5 According to the same procedure as in Example 4, an ointment preparation was obtained by using levodopa 0.2 g and lactate buffer 36 g instead of isoproterenol hydrochloride 1 g and lactate buffer 35.2 g, respectively.

Example 6 Isoproterenol hydrochloride 5 g was added to sodium bisulfite 10
Suspended in 9.25 g of pH 4.0 lactate buffer containing 0 mg,
After adding "Tween 20" 50mg, stir it with stirring "Nikkor MG
K ″ (500 mg) was added, and further hydroxypropyl cellulose (100 mg) was added as a gel base to form a gel preparation.

Example 7 A gel preparation was obtained according to the same procedure as in Example 6 except that 5 g of isoproterenol hydrochloride and 9.25 g of lactate buffer were replaced with 100 mg of levodopa and 9.45 g of lactate buffer, respectively.

Example 8 According to the same procedure as in Example 6, a gel preparation was obtained by using 5 g of dopamine hydrochloride instead of 5 g of isoproterenol hydrochloride.

Example 9 100 mg of isoproterenol hydrochloride was dissolved in 7.45 g of a lactic acid buffer having a pH of 4.06 and containing 50 mg of sodium hydrogen sulfite, and 0.1 g of 100 μCi ³ H-labeled isoproterenol hydrochloride solution was added thereto. Continue to "Tween 20" 50mg
After adding, 2 g of "Nikkor MGK" was added with stirring, 300 mg of hydroxypropyl cellulose was further added as a gel base, and the mixture was kneaded to obtain a gel preparation.

Example 10 According to the same procedure as in Example 9, a gel preparation was obtained by using dopamine hydrochloride instead of isoproterenol hydrochloride.

Example 11 20 mg levodopa contained 50 mg sodium bisulfite
It was dissolved in 6.73 g of pH 4.0 lactate buffer, and 0.8 g of ¹⁴ C-labeled 40 μCi levodopa solution was added thereto. Continue to add 100 mg of "Tween 20", and then stir under stirring "Nikkor MG
K "2 g was added, and further hydroxypropyl cellulose-H 300 mg was added as a gel base and kneaded to obtain a gel preparation.

Test Example Below, a transdermal absorption test and an organ distribution test were conducted on the external preparation of the present invention, and the methods and results are shown.

Test Example 1 (in vitro skin permeation test) (Method) Hairless rats weighing 250 to 290 g were anesthetized with pentobarbital sodium, and the abdominal skin was excised.
The experiment was carried out by mounting the cell on a Franz type skin permeation test cell (effective area 2 cm ² , volume 5 ml).

As a sample, the gel preparation of isoproterenol hydrochloride prepared in Example 1 was used, and the transmittance was measured by measuring isoproterenol hydrochloride by a high performance liquid chromatography method.

As a control, a gel preparation prepared according to the procedure of Example 1 except for "Nikkor MGK" was used.

 (Results) The results are shown in Table 1.

Test Example 2 (in vitro skin permeation test) (Method) Two Chamber Diffusio was used as a skin permeation test cell.
Example 2 using n Cell (effective area 1.54 cm ² , volume 5 ml)
The same procedure as in Test Example 1 was performed using the levodopa gel preparation prepared in.

 (Results) The results are shown in Table 2.

Test Example 3 (In vitro skin permeation test) (Method) Two Chamber Diffusio was used as a cell for skin permeation experiment.
Example 3 using n Cell (effective area 1.54 cm ² , volume 5 ml)
The same procedure as in Test Example 1 was performed using the dopamine hydrochloride gel preparation prepared in.

 (Results) The results are shown in Table 3.

Test Example 4 (in vitro skin permeation test) (Method) Two Chamber Diffusio was used as a skin permeation test cell.
Example 6 using n Cell (effective area 1.54 cm ² , volume 5 ml)
The same procedure as in Test Example 1 was carried out using the suspension of isoproterenol hydrochloride before the addition of the gel base obtained according to.

 (Results) The results are shown in Table 4.

Test Example 5 (In vitro skin permeation test) (Method) Two Chamber Diffusio was used as a cell for skin permeation test.
Example 7 using n Cell (effective area 1.54 cm ² , volume 5 ml)
The same procedure as in Test Example 1 was carried out using the suspension of levodopa before the addition of the gel base obtained according to.

 (Results) The results are shown in Table 5.

Test Example 6 (In vitro skin permeation test) (Method) Two Chamber Diffusio was used as a cell for skin permeation test.
Example 8 using n Cell (effective area 1.54 cm ² , volume 5 ml)
The same procedure as in Test Example 1 was performed using the suspension of dopamine hydrochloride before the addition of the gel base obtained according to the above.

Test Example 7 (Blood Concentration in Vivo and Distribution in Organs) (Method) 2 g of the gel preparation of isoproterenol hydrochloride prepared in Example 9 is soaked in "Catery Pad" (trade name: Nichiban Co., Ltd. product). It was applied to the abdomen of a rat, further covered with a vinyl sheet and fixed with "Elastopore" (product name: Nichiban Co., Ltd. product). Applicable area is 22
The radioactivity administered was 10 μCi / head in cm ² (5.5 × 4 cm).

Rats should be placed in a Ballman gauge, after drug application, 2.
About 200 μl of blood was collected from the jugular vein at 4, 6, 8, 10, and 24 hours, and 100 μl of the blood was used as a sample for measuring radioactivity.

Also, after 32 hours, the rat was sacrificed, and each organ was removed and used as a radioactivity measurement sample.

Radioactivity in blood and organs is measured by an automatic combustion device (Pacher
d Oxidizer 360) and a liquid scintillation counter (Aloka LSC-700).

 (Results) Table 7 shows the time-dependent changes in blood concentration.

Table 8 shows the concentration of isoproterenol hydrochloride in each organ.
It was shown to.

The preparation of the present invention has about the same amount in kidney and liver as the control preparation.
The value was 10 times or more.

Test Example 8 (blood concentration in vivo) (Method) Gel preparation of dopamine hydrochloride prepared in Example 10
2 g was soaked in "Cately pad" and applied to the abdomen of the rat, which was then placed on a vinyl sheet and fixed with "Elastopore". The application area is 2.5 cm ² , and the radioactivity administered is
It was 10 μCi / head.

Rats should be placed in a Ballman gauge, after drug application, 2.
About 200 μl of blood was collected from the jugular vein at 4, 6, 8 and 10 hours, and 100 μl of the blood was used as a radioactivity measurement sample.

 (Results) The results are shown in Table 9.

Test Example 9 (Blood Concentration in Vivo and Distribution in Organs) (Method) 2 g of the levodopa gel preparation prepared in Example 11 was soaked in a “catery pad” and applied to the rat abdomen,
Furthermore, cover it with a vinyl sheet, and "Elastopore"
Fixed in. The applied area was 22 cm ² (5.5 × 4 cm), and the administered radioactivity was 8 μCi / head.

Rats were placed in a Ballman gauge, and after drug application, 2.
At 4, 6, 8, 10, and 24 hours, 100 μl of blood was collected from the tail vein and used as a radioactivity measurement sample.

In addition, after 24 hours, the rat was sacrificed, each organ was removed and used as a radioactivity measurement sample.

Radioactivity in blood and organs is measured by an automatic combustion device (Pacher
d Oxidizer 306) and a liquid scintillation counter (Aloka LSC-700).

 (Results) Table 10 shows the time-dependent changes in blood concentration.

Table 11 shows the concentration of levodopa in each organ.

The formulation of the present invention showed higher values than the control formulation in each organ except the spleen.

EFFECTS OF THE INVENTION According to the present invention, an external preparation prepared by adding a medium-chain fatty acid glyceride and a surfactant to catecholamines, which has been conventionally considered to be difficult to apply as an external preparation, has extremely excellent skin permeation. The sex was recognized. Further, higher skin permeability was observed by increasing the concentration of catecholamines contained in the external preparation, but such a preparation can reduce the application area to the skin, and the drug Controlled release allows continuous administration.

Furthermore, since the dose can be easily adjusted, side effects due to overdose can be avoided, and the formulation is excellent in terms of usefulness and safety.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 47/14 A61K 47/14 EN

Claims (3)

(57) [Claims] 1. An external preparation for catecholamines, which comprises a catecholamine, a medium-chain fatty acid glyceride and a surfactant mixed in a buffer solution containing a stabilizer. 2. The medium-chain fatty acid glyceride is a monoglyceride or diglyceride of a fatty acid having 6 to 18 carbon atoms or a mixture of two or more kinds of monoglyceride and / or diglyceride. External preparation of the catecholamines described. 3. The catecholamines according to claim 1, wherein the catecholamines are adrenaline, noradrenaline, isoproterenol, dopamine, dobutamine, levodopa and / or their hydrochlorides. Topical formulation.