WO2011111384A1 - Transdermal composition containing therapeutic agent for parkinson's disease - Google Patents

Abstract

Disclosed is a transdermal pharmaceutical which uses non-ergot antidopaminergic D₂ receptor agonists such as ropinirole hydrochlorides or pramipexole hydrochlorides. The disclosed pharmaceutical takes into account skin safety and drug stability, exhibits excellent skin permeability, and uses the non-ergot antidopaminergic D₂ receptor agonists such as ropinirole that are currently used as oral preparations in a new manner as transdermal agents. The disclosed transdermal pharmaceutical is formed by combining a non-ergot antidopaminergic D₂ receptor agonist with a hydrophobic solvent and surfactant to form a minute micelle in a water-polyhydric alcohol solvent, and then preparing a colloidal solution containing the non-ergot antidopaminergic D₂ receptor agonist. By selecting and adjusting the pH of the colloidal solution, the non-ergot antidopaminergic D₂ receptor agonists project from the exterior of the micelle, increasing the transdermal absorbability and the initial permeability of the non-ergot antidopaminergic D₂ receptor agonists.

Description

Transdermal composition containing a therapeutic agent for Parkinson's disease

The present invention relates to a transdermal composition containing a therapeutic agent for Parkinson's disease. More particularly, the present invention relates to a transdermal composition containing ropinirole hydrochloride or pramipexole hydrochloride which is a dopamine D ₂ receptor agonist.

As motor function diseases, intractable neurological diseases such as Parkinson's disease, restless leg syndrome (RLS), and essential tremor are known, and several therapeutic agents including L-Dopa are used. Recently, ropinirole and pramipexole to selectively stimulate dopamine D ₂ receptor system of striatal postsynaptic is promising.
Parkinson's disease is characterized by deformation and loss of neurons in the midbrain substantia nigra, which produces dopamine, a neurotransmitter that is important for the realization of motor function. As a result, the smooth performance of exercise is impaired, and symptoms such as “muscles become stiff”, “hands and feet shake”, “motion becomes sluggish” gradually appear and go to bed after several years It is an intractable disease that will eventually lead to death.
Restless Legs Syndrome (RLS) is generally associated with discomfort such as pruritus, itching, twitching, twitching, muscle spasms, or tingling pain that occurs when a patient lies down. It is a movement disorder characterized by the urge to move the foot to relieve the pain. In addition, essential tremor is the most frequent involuntary tremor in the hand and head, and is said to be due to an abnormality in the motor control area of the brain.

It is known that ropinirole and pramipexole, which are promising therapeutic agents for Parkinson's disease, have the following characteristics. The hydrochloride salt of ropinirole (ie 4- [2- (dipropylamino) ethyl] -1,3-dihydro-2H-indol-2-one) and pramipexole (ie (S) -2-amino-4,5,6) , 7-tetrahydro-6-propylaminobenzothiazole) is a selective anti-dopamine D ₂ receptor agonist with a non-ergot structure and is associated with Parkinson's disease, restless leg syndrome (RLS), It is useful for treatment such as war (Patent Document 1).
For example, ropinirole hydrochloride is usually determined to be a starting dose of 0.75 mg / day and a maintenance dose of 3-9 mg / day for adults, and can be administered orally in three divided doses per day. (Non-Patent Document 1). The half-life in blood of healthy adults when administered orally is as short as about 5 hours, suggesting a large first-pass effect in the liver. Pramipexole hydrochloride can be treated at a dose lower than that of ropinirole, but the half-life in blood of healthy adults when administered orally is short, about 6 hours.

Thus, since ropinirole and pramipexole are easily affected on the living body side by oral administration, a transdermal administration method is suitable as an administration method with less influence on the living body side. That is, transdermal administration was considered useful as an administration method in order to maintain a constant blood concentration for a long time and to reduce side effects.
However, as a problem of transdermal administration, in the case of transdermal administration, the transfer rate of the drug into the blood is slower than oral administration. On the other hand, as a therapeutic agent for Parkinson's disease, a faster effect is desired as well as drug persistence. Therefore, a transdermal preparation of ropinirole and pramipexole needs to have a high initial permeation rate as well as drug durability. Furthermore, in view of the characteristics of the above Parkinson's disease, since it is a long-term continuous transdermal administration, it is indispensable to reduce the safety and burden on the skin.

In the field of patches for transdermal administration, a salt of a drug formed by a combination of an acid and a base such as hydrochloride is usually highly water-soluble in protonated form, and has a skin permeability. It is known not to show. Therefore, in many cases, a technique is used in which the composition is free base and has skin permeability.
Jamyson et al. Also confirmed the permeability after ropinirole was made the free base by bringing the composition to pH 7-8.5 because ropinirole hydrochloride did not find skin permeability in the experiment. (Patent Document 3).
However, ropinirole and pramipexole are basic compounds and are unstable and easily discolored at pH 7 or higher. Further, considering the safety to the skin, the pH range (pH 7 to 8.5) in which the above preparation has good absorbability was not desirable.

Special table flat 11-506462 Special table 2001-518058 Special table 2009-542657

In the present invention, in consideration of the safety to the skin and the stability of the drug, not the free bases of nonergot anti-dopamine D ₂ receptor agonists (ropinirole or pramipexole), but their hydrochlorides are used, and excellent skin It aims at providing the liquid agent which shows permeability | transmittance.

The present inventor conducted a search for a liquid agent that enhances the skin permeability of non-ergot anti-dopamine D ₂ receptor agonists (ropinirole and pramipexole) using the in vitro rat skin permeability test as an index. First, the study proceeded with a focus on ropinirole. As a result of intensive studies, it was found that percutaneous absorbability can be improved by preparing a microdispersed solution of ropinirole. That is, ropinirole hydrochloride is partially neutralized in an aqueous solution to form a free base (free form), a hydrophobic solvent and a surfactant are added, mixed and stirred, and micelles partially containing ropinirole are mixed. Formed. The micelle aqueous solution was diluted and stirred with a polyhydric alcohol to prepare a colloidal solution in which the micelles were small and uniformly dispersed. The colloidal solution was shown to have excellent ropinirole transdermal absorbability. Further investigation revealed that the transdermal absorbability was better when the pH of the colloidal solution was 4-6. The above-described colloidal solution, which is a composition for transdermal use of the present invention, has been shown to exhibit a clear Tyndall phenomenon and excellent transdermal absorbability as the average particle size decreases.

As described above, the transdermal composition of the present invention is uniformly dispersed by forming micelles (ropinirole, hydrophobic solvent and surfactant) having an average particle diameter of 1 μm or less in a water-polyhydric alcohol solvent. It is what. In order to exhibit excellent transdermal absorbability, it is further desirable that the average particle diameter of the micelle is as small as 100 nm or less.
In the transdermal composition of the present invention, since the liquidity of the solution is weakly acidic, the tertiary amine residue of the ropinirole side chain in the micelle partially protrudes into the water-polyhydric alcohol solvent. It is thought that it is protonated. When minute micelles with such a structure come into contact with the skin, they are protonated, so they are likely to adhere to the skin surface, and the micelle's hydrophobic solvent acts as a transdermal absorption enhancer, resulting in intercellular lipids in the epidermis. It has been considered to promote percutaneous absorption of ropinirole by softening. The same is thought to have occurred with pramipexole.
The present inventor completed the present invention based on the above findings.

That is, the gist of the present invention is as follows.
(1) Non-ergot anti-dopamine D ₂ receptor agonist, micelle composed of hydrophobic solvent and surfactant is uniformly dispersed in water-polyhydric alcohol solvent, pH 4-6 A transdermal composition characterized by being slightly acidic.
(2) The transdermal composition according to (1), wherein the transdermal composition is a liquid agent exhibiting a Tyndall phenomenon.
(3) The transdermal composition according to (2), wherein the solution is a colloid solution preparation.
(4) The transdermal composition according to any one of (1) to (3) above, wherein the non-ergot anti-dopamine D ₂ receptor agonist is ropinirole or pramipexole.
(5) The transdermal composition according to any one of (1) to (4) above, wherein the surfactant is a nonionic surfactant or lecithin.
(6) The transdermal composition according to (5), wherein the nonionic surfactant is a polyoxyethylene sorbitan fatty acid ester.
(7) The transdermal composition according to (6), wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, polysorbate 60, polysorbate 65, or polysorbate 80.
(8) The transdermal composition according to (6), wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 80.
(9) The hydrophobic solvent according to any one of (1) to (8) above, wherein the hydrophobic solvent is at least one selected from crotamiton, diethyl sebacate, medium chain fatty acid triglyceride, and liquid paraffin. Transdermal composition.
(10) The transdermal composition according to (9), wherein the hydrophobic solvent is crotamiton or liquid paraffin.
(11) The transdermal composition according to any one of (1) to (10) above, wherein the polyhydric alcohol is at least one of propylene glycol and butylene bricol.
(12) The process according to any one of (1) to (11) above, wherein the pH regulator used for setting the liquidity to pH 4 to 6 is at least one of citric acid, tartaric acid, and higher fatty acids. Skin composition.
(13) The transdermal composition according to (12), wherein the higher fatty acid is a saturated or unsaturated fatty acid having 4 to 18 carbon atoms.
(14) The transdermal composition according to (12), wherein the higher fatty acid is an unsaturated fatty acid having 4 to 18 carbon atoms.
(15) The transdermal composition according to (14), wherein the unsaturated fatty acid having 4 to 18 carbon atoms is oleic acid.
(16) non-ergot anti dopamine _{D 2} receptor agonist is contained 0.1 to 10 percent as the hydrochloride salt, transdermal composition according to the above (1).
(17) A non-ergot anti-dopamine D ₂ receptor agonist hydrochloride is defined as 1, with a molar ratio of hydrophobic solvent of 0.4 to 2 times mol and surfactant of 0.1 to 0.4 times mol. The transdermal composition according to (16) above.
(18) The transdermal composition according to any one of (1) to (17), wherein the liquid property is pH 5 ± 0.5.
(19) The transdermal composition according to any one of (1) to (18) above, wherein the micelle has an average particle diameter of 20 nm to 1 μm and exhibits a clear Tyndall phenomenon.
(20) The transdermal composition according to any one of (1) to (18) above, wherein the micelle has an average particle diameter of 30 to 500 nm.
(21) The transdermal composition according to any one of (1) to (18) above, wherein the micelle has an average particle diameter of 50 to 150 nm.

(22) In the method of the following comprises the step non-ergot anti dopamine D ₂ receptor agonist transdermal composition containing,
a) After adding water to the non-ergot anti-dopamine D ₂ receptor agonist hydrochloride to dissolve it, the pH is adjusted to about 6.5 with a diluted aqueous alkali metal hydroxide solution,
b) Stir vigorously after adding a hydrophobic solvent to the aqueous solution.
c) A surfactant is added to the above solution and stirred further to obtain a uniform milky suspension.
d) adjusting the liquidity to about pH 4-6 using a pH adjusting agent in the suspension;
e) The above d) solution is added to a polyhydric alcohol solvent and uniformly dispersed,
f) The average particle size of the micelle is 20 nm to 1 μm,
g) the production method of the uniform dispersion of the micelles, characterized in that it presents a Tyndall effect, non-ergot anti dopamine D ₂ receptor agonist transdermal composition containing.
(23) non-ergot anti dopamine D ₂ receptor agonist is ropinirole or pramipexole, method of manufacturing transdermal composition according to the above (22).
(24) The production method of the above (22) or (23), wherein the alkali metal hydroxide is at least one of sodium hydroxide and potassium hydroxide.
(25) The hydrophobic solvent according to any one of the above (22) to (24), wherein the hydrophobic solvent is at least one selected from crotamiton, diethyl sebacate, medium chain fatty acid triglyceride, and liquid paraffin. Production method.
(26) The production method according to any one of (22) to (25) above, wherein the surfactant is a nonionic surfactant or lecithin.
(27) The production method according to any one of (22) to (26) above, wherein the nonionic surfactant is a polyoxyethylene sorbitan fatty acid ester.
(28) The production method according to (27), wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, polysorbate 60, polysorbate 65, or polysorbate 80.
(29) The production method according to (27), wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 80.
(30) The production method according to any one of the above (22) to (29), wherein the polyhydric alcohol is at least one of propylene glycol and butylene bricol.
(31) The production method according to any one of (22) to (30), wherein the liquid pH is adjusted to about 5.
(32) The production method according to any one of (22) to (31) above, wherein the pH regulator is at least one of citric acid, tartaric acid, and oleic acid.
(33) non-ergot anti dopamine _{D 2} receptor agonist is contained 0.1 to 10 percent as the hydrochloride salt, the production method according to (22).

The transdermal compositions of the present invention, emulsion solution prepared with non-ergot anti dopamine D ₂ receptor agonist and a hydrophobic solvent and a surfactant is uniformly dispersed in a solvent of water and a polyhydric alcohol It is a colloidal solution having a pH of 4-6. The transdermal composition of the present invention was able to achieve the desired excellent skin permeability and high initial permeability. As a result, an excellent therapeutic effect can be achieved by administering the transdermal composition of the present invention against Parkinson's disease, restless leg syndrome (RLS), essential tremor and other neurological movement disorders.

It is a figure showing the result of the in-vitro percutaneous absorption test to the Ropinirole composition example and comparative example for 8 hours. It is a figure showing the result of the 24-hour in-vitro transdermal absorbability test of a ropinirole composition example and a comparative example. It is a figure showing the measurement result (particle size distribution) of the average particle diameter of the micelle of a ropinirole composition (Experiment No. A).

The “non-ergot anti-dopamine D ₂ receptor agonist” of the present invention is a drug that stimulates dopamine D ₂ receptor, produces acetylcholine, and treats Parkinson's disease. This is one of the two types of non-ergot alkaloids. For example, ergot anti-dopamine D ₂ receptor agonists are cabergoline, pergolide, bromocriptine, and non-ergot anti-dopamine D ₂ receptor agonists refer to ropinirole, pramipexole, and talipexol. Currently, ropinirole hydrochloride is marketed as Requip, pramipexole hydrochloride is marketed as biciflor, and talipexol hydrochloride is marketed as domine, both as therapeutic agents for Parkinson's disease.
The “hydrophobic solvent” of the present invention is, for example, isopropyl isostearate, methyl stearate, butyl stearate, butyl myristate, ethyl linoleate, isopropyl linoleate, ethyl olive oleate, myristyl myristate, cetyl isoctanate, myristine Non-octyldodecyl acid, diisopropyl adipate, cetyl palmitate, retinol palmitate, methyl laurate, methyl myristate, methyl caproate, methyl palmitate, isopropyl myristate, isopropyl palmitate, diethyl sebacate, diethyl adipate, etc. Lower fatty acid monohydric alcohol esters such as oleic acid triglyceride, Panacet 800, Panacet 810 and other medium chain fatty acid triglycerides such as olive oil and palm oil Vegetable oils, N- methyl-2-pyrrolidone derivative of pyrrolidone, liquid paraffin, can be mentioned crotamiton. Preferred examples include crotamiton, diethyl sebacate, and medium chain fatty acid triglycerides.

The “surfactant” of the present invention refers to a substance having a hydrophilic group and a hydrophobic group, which has a function of forming micelles and uniformly mixing a polar substance and a nonpolar substance. Surfactants are classified into anionic surfactants, nonionic surfactants, zwitterionic surfactants, and cationic surfactants because of their chemical structure. Furthermore, there are types of synthetic surfactants and natural surfactants depending on the production method. Preferred surfactants are nonionic surfactants for synthetic surfactants and lecithin for natural surfactants.
The “nonionic surfactant” of the present invention is, for example, monooleyl polyoxyethylene sorbitan (for example, polysorbate 20, polysorbate 60, polysorbate 65, polysorbate 80, etc.), sorbitan monolaurate, sorbitan monopalmitate, sorbitan sesquioxide. Polyoxyethylene sorbitan fatty acid esters such as oleate, polyoxyethylene castor oil derivatives, polyoxyethylene hydrogenated castor oil, glycerin fatty acid esters such as glycerin monostearate and sorbitan monooleate, sorbitan fatty acids such as sorbitan monostearate and sorbitan sesquioleate Esters, polyoxyethylene higher alcohol ethers such as polyoxyethylene ether ether, polyoxyethylene alkylphenol, polyoxyethylene Oxypropylene copolymer (e.g., Pluronic, etc.) and the like. A preferable example is polysorbate 80.
The “lecithin” of the present invention refers to a lipid product containing a phospholipid such as phosphatidylcholine. Lecithin is further classified according to what is used as a raw material. Those using egg yolk as a raw material are called “yolk lecithin”, and those using soybean as a raw material are called “soy lecithin”. In addition, including purification methods, it is also classified into plant lecithin, fractionated lecithin, egg yolk lecithin, enzyme-treated lecithin, enzyme-decomposed lecithin, hydrogenated lecithin and the like. Preferable examples include egg yolk lecithin.
Examples of the “polyhydric alcohol solvent” of the present invention include dihydric alcohols such as ethylene glycol, propylene glycol and 1,3-butylene glycol, and trihydric alcohols such as glycerin. Preferable examples include dihydric alcohols such as ethylene glycol, propylene glycol, and 1,3-butylene glycol. More preferred are propylene glycol and 1,3-butylene glycol.

The “micelle” of the present invention is an aggregate of a hydrophobic solvent, ropinirole, and a nonionic surfactant, which is spherical in a water-polyhydric alcohol solvent with the hydrophobic portion facing inward and the hydrophilic portion facing outward. Say what you gathered. In the micelle of the present invention, the side chain tertiary amine residue of ropinirole can be protonated and transferred to the hydrophilic portion by appropriately adjusting the liquidity (pH) of the water-polyhydric alcohol solvent.
The “particle diameter” in the present invention means the average particle diameter of the above micelles, and can be measured, for example, with a photon correlation measuring device (manufactured by Sysmex, Zeta Sizer Nano ZS). The preferred particle size is preferably 20 nm to 1 μm in order to obtain good transdermal absorbability. More preferable examples include 30 to 500 nm. More preferable examples include those having a thickness of 50 to 150 nm. Such minute micelles are referred to as micellized nanoparticles.
The “Tyndall phenomenon” of the present invention means that when a red laser beam is applied to a solution in which the micelles of the present invention are uniformly dispersed (colloidal solution), particles in the solution scatter light (Mie scattering), and a single laser beam is emitted. A phenomenon that can be seen. When the laser beam is irradiated and the optical path of the laser can be clearly seen in the solution, it can be said to be a clear Tyndall phenomenon. In addition, when the average particle diameter of the micelle increases and exceeds 1 μm, the Tyndall phenomenon does not occur, and the whole solution is irregularly reflected. That is, when the average particle diameter of the micelle exceeds 1 μm, the solution is not transparent and becomes turbid.

“Liquid” in the present invention refers to the pH of a transdermal composition (mixed solvent system of water and polyhydric alcohol). The pH is desirably in the range of about 4 to 6, and a pH of about 5 is preferred.
The “alkali metal hydroxide” in the present invention refers to lithium hydroxide, sodium hydroxide, and potassium hydroxide, preferably sodium hydroxide and potassium hydroxide.
The transdermal composition of the present invention is a liquid, and a suspending agent or thickener, a stabilizer, a buffer, a pH adjuster, a colorant, a fragrance and the like can be added depending on the purpose.
Suspensions or thickeners that can be added include gum arabic, ragant, pullulan, locust bin gum, tamarind gum, pectin, xanthan gum, guar gum, carrageenan and other polysaccharides, methylcellulose, carmellose, carmellose sodium, polyvinyl alcohol, polyvinyl Examples include pyrrolidone, acrylic acid copolymer, carboxyvinyl polymer, and the like.
Examples of stabilizers that can be added include preservatives and antioxidants. Examples of the preservative include parahydroxybenzoates such as methylparaben and propylparapen, alcohols such as chlorobutanol, pendyl alcohol, and phenylethyl alcohol, thimerosal, acetic anhydride, sorbic acid, and EDTA. Examples of the antioxidant include sodium bisulfite, L-ascorbic acid, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate, tocopherol acetate, dl-α-tocopherol and the like.

Examples of the pH adjuster include lower fatty acids such as acetic acid, lactic acid, citric acid, and oxalic acid, for example, saturated or unsaturated higher fatty acids having 4 to 18 carbon atoms such as butanoic acid, decanoic acid, palmitic acid, oleic acid, and stearic acid. Mention may be made of organic acids such as fatty acids. Preferable examples include higher fatty acids such as decanoic acid, palmitic acid, and oleic acid.
Examples of the wetting agent that can be added include polyhydric alcohols such as glycerin, propylene glycol, butylene glycol (1,3-butylene glycol), and sorbitol.
Furthermore, for example, mint oil, l-menthol, camphor, thymol, tocopherol acetate, glycyrrhetinic acid, nonyl acid vanillylamide, pepper extract and the like can be added.
In addition to these additives, pharmaceuticals having other drugs can be added as long as they do not interfere with the effects of the external preparation of the present invention.
The additives exemplified above are appropriately selected according to the dosage form of the external preparation of the present invention,
These addition amounts are also appropriately selected within the range usually used according to each dosage form.

The dosage form of the transdermal composition of the present invention is not particularly limited as long as it can be applied on the basis of a liquid and can be locally administered to the skin. For example, the present invention may be any preparation that can be mixed and impregnated with the liquid preparation of the present invention in a base or matrix such as an ointment, cream, gel, poultice, lotion, aerosol, etc. It can be used as a dosage form of
The transdermal compositions of the present invention, depending on the content and dosage form of a non-ergot anti dopamine D ₂ receptor agonist, may be administered topically. The amount of the transdermal composition may be selected depending on the content of the non-ergot anti dopamine D ₂ receptor agonist, for example, once a day or more than once or continuously used for more than a few days The number of uses can be set according to the pathology of Parkinson's disease.

The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to the following examples, and can be appropriately modified and implemented. It is included in the technical scope of the invention.

(Example 1) Colloid solution composition containing ropinirole hydrochloride as a non-ergot anti-dopamine D ₂ receptor agonist. 34 g of water was added to 4 g (13.5 mM) of ropinirole hydrochloride to dissolve it. Next, the pH was adjusted to about 6.5 with 0.01 N sodium hydroxide solution, and 3 g (14.8 mM) of crotamiton was added and stirred. Further, 3 g (about 2.3 mM) of polysorbate 80 was added and stirred again, and then oleic acid was added to adjust the pH to 5. Thereafter, 55 g of propylene glycol was added as a polyhydric alcohol to obtain a uniform dispersion solution. When this uniform solution was irradiated with a red laser, a Tyndall phenomenon occurred and a red light path was observed in the solution. The average particle size of the colloidal solution was about 79 nm as measured by Zetasizer Nano ZS manufactured by Sysmex.
Further, the polyhydric alcohol was similarly replaced with butylene glycol as shown in Table 1 to prepare a colloidal solution. The obtained colloidal solution was evaluated for transdermal absorbability by the method of Test Example 1 and listed in Table 1 together with the average particle size result. In addition, the average particle diameter of the colloid solution composition was calculated from the particle size distribution of the micelles of FIG. 3 (Experiment No. A) (the average particle diameter of Experiment No. A was 79 nm). Other compositions were measured in the same manner, and the average particle size was calculated.

According to the results in Table 1 above, it was found that crotamiton is superior among crotamiton, diethyl sebacate, and medium-chain fatty acid triglycerides as hydrophobic solvents. And it turned out that propylene glycol is better than butylene glycol as a hydrophilic polyhydric alcohol solvent for forming a colloidal solution.

Example 2 Confirmation of Effect of Hydrophobic Solvent In order to confirm the contribution of the hydrophobic solvent (crotamiton or the like), a preparation (Comparative Example 1) free from the hydrophobic solvent crotamiton was prepared. That is, as shown in Comparative Example 1 of Table 2, 34 g of water was dissolved in 4 g of ropinirole hydrochloride, and then the pH was adjusted to about 6.5 with 0.01 N sodium hydroxide solution. Thereafter, 3 g of polysorbate 80 was added and stirred, and oleic acid was added to adjust the pH to 5. Next, 55 g of propylene glycol was added to prepare a uniform solution. The particle diameter of the obtained Comparative Example 1 was measured in the same manner as in Example 1. About the comparative example 1, transdermal absorbability was evaluated by the method of the test example 1, and it described in Table 2 with the result of the average particle diameter.

As shown in Table 2 above, the transdermal absorbability of ropinirole was reduced without the hydrophobic solvent. In addition, the sample of Comparative Example 1 is an experiment No. Unlike the sample of A, the Tyndall phenomenon was not shown and diffuse reflection was shown.
Therefore, a hydrophobic solvent is required to show excellent transdermal absorbability, and it is necessary to form micelles in an aqueous solution. That is, it was found that when a colloidal solution in which micelles containing ropinirole were uniformly dispersed was prepared, the transdermal absorbability of ropinirole was greatly improved.

(Example 3) Confirmation of effect of pH The pKa of ropinirole is 10.2 in the tertiary amine of the side chain and 12.8 in the indole ring. Thus, for ropinirole, as the pH of the solution changes, the partition coefficient between the aqueous phase and the oil phase varies. In order to increase the free mass of ropinirole, it is necessary to increase the pH of the solution. However, when the pH was set to 7 or higher, it was observed that the solution containing ropinirole was oxidized and gradually turned brown.
Therefore, in order to examine the effect of the pH of the solution, a preparation (Comparative Example 2) in which the pH adjuster shown in Table 3 below was not added was prepared. For Comparative Example 2, the transdermal absorbability was evaluated by the method of Test Example 1, and the results are shown in Table 3 together with the average particle size results.

As shown in Table 3 above, unless the final pH of the solution is adjusted to about 5, the average particle size of micelles is 1 μm or more, and the transdermal absorbability of ropinirole is about 1/10. It was shown to decrease. Further, the sample of Comparative Example 2 did not show the Tyndall phenomenon and caused irregular reflection.
That is, it was shown that the liquid property adjustment of pH with a pH adjusting agent (oleic acid) has a great influence on the formation of micelles. Moreover, when the average particle diameter of the micelle was 1 μm or more, the transdermal absorbability was greatly reduced, and the transdermal absorbability was lower than that of the solution not forming the micelle (Comparative Example 1).

(Example 4) Confirmation of effect of water The composition of the present invention is a colloidal solution in which ropinirole and a hydrophobic solvent are uniformly dispersed in a hydrophilic solvent of water and a polyhydric alcohol. Therefore, the presence of water is considered indispensable for forming micelles. Therefore, as shown in Table 4 below, a formulation with no water (Comparative Example 3) was prepared, and the effect of water was evaluated in comparison with the above-described formulation (Experiment No. A, B). For Comparative Example 3, the transdermal absorbability was evaluated by the method of Test Example 1, and the results are shown in Table 4 together with the average particle size results.

As shown in Table 4 above, in the absence of water, ropinirole was dispersed in a polyhydric alcohol solvent, but the particle diameter was as large as 1000 nm and the transdermal absorbability was greatly reduced. Further, the sample of Comparative Example 3 did not show the Tyndall phenomenon and caused irregular reflection.
From the above, it was shown that when there is no water and the micelles containing ropinirole cannot form a colloidal solution dispersed in an aqueous solvent, the transdermal absorbability is greatly reduced. Therefore, it turns out that a chemical | medical agent, a hydrophobic solvent, water, and surfactant are essential in the formulation of this invention.

Example 5 Effect of Surfactant and Hydrophobic Solvent In order to examine the influence of the surfactant and the hydrophobic solvent, lecithin was used as the surfactant and the effect of the nonionic surfactant was compared. It was. In addition, liquid paraffin was used as the hydrophobic solvent, which also served as a comparison with the medium chain fatty acid triglyceride. According to the method of Example 1, preparations (Experiment No. E) shown in Table 5 below were prepared and compared with preparations (Experiment No. C) using a nonionic surfactant. The skin permeation amount of ropinirole was evaluated by the method of Test Example 1 and listed in Table 5. When the preparation of Table 5 (Experiment No. E) was irradiated with a red laser, a Tyndall phenomenon occurred and a red light path was seen in the solution.

As shown in Table 5 above, it was shown that the percutaneous absorbability of ropinirole did not change much even when the surfactant was changed to lecithin or the hydrophobic solvent was changed to liquid paraffin. .

(Example 6) Nonergot-type anti-dopamine D ₂ receptor agonist and effect on transdermal absorbability Ropinirole and pramipexole are taken as non-ergot-type anti-dopamine D ₂ receptor agonists according to the method of Example 1. The preparations shown in Table 6 below (Experiment No. E, No. F) were prepared and compared. The skin permeation amounts of ropinirole and pramipexole were evaluated by the method of Test Example 1 and listed in Table 6. Moreover, when a red laser was irradiated to the preparation (Experiment No. F) in Table 6, a Tyndall phenomenon occurred, and a red light path was seen in the solution.

As shown in Table 6 above, it was revealed that the colloid solution preparation of the present invention showed excellent transdermal absorbability with respect to ropinirole and pramipexole.

(Test Example 1) Evaluation test of transdermal absorbability by Franz cell In order to compare percutaneous absorbability with respect to the samples of Examples A to D and Comparative Examples 1 to 3, 0.7 mL was collected from each sample. Then, a transdermal absorbability evaluation test was performed as follows using a Franz diffusion cell (permeation area: 1 cm ² , receptor liquid volume: 8 mL) at a test temperature of 32 ° C.
(1) Rat skin: 6-week-old Wistar rat (male) abdominal skin (2) Receptor solution: physiological saline: ethanol (10: 1)
(3) Permeabilized drug concentration measurement: HPLC method The rat abdominal skin (6-week-old Wistar rat) is sandwiched between vertical diffusion cells (effective diffusion area: 1 cm ² ) and described in Tables 1 to 4 on the stratum corneum side. 0.7 mL of each sample was added, and a physiological saline / ethanol (10: 1) solution was applied to the dermis layer side. At the 4th, 6th, 8th, and 24th hours after the start of the experiment, 100 μL of physiological saline was sampled, the drug concentration permeated through the skin was measured by HPLC, and the cumulative permeation of the drug at each time was measured. The amount was measured. As a result, the percutaneous absorbability of ropinirole as shown in FIGS. 1 and 2 could be evaluated.
As shown in the results of FIGS. 1 and 2, the ropinirole-containing colloidal solution of the present invention was found to have excellent skin permeability and high initial permeability.

Using non-ergot anti dopamine D ₂ transdermal preparation containing the receptor agonist and a manufacturing method thereof of the present invention, it is possible to produce superior formulations of transdermal absorbability containing ropinirole and pramipexole It was. That is, it is an invention of a colloidal solution formulation in which fine micelles are formed in a water-polyhydric alcohol solvent by a combination of a hydrophobic solvent and a surfactant together with ropinirole or pramipexole. That is, by selecting and adjusting the pH of the colloidal solution, it can be prepared so that the side chain of ropinirole or pramipexole can easily come out on the surface of the micelle. Ropinirole in such micelles has a high transdermal absorbability.
In the ropinirole-containing transdermal composition of the present invention, it is not necessary to use a free ropinirole base (free form), the hydrochloride can be used as it is, and the preparation of the preparation is easy. Moreover, the composition for transdermal use of the present invention is stable, has high safety to the skin and high skin permeability.

Claims (13)

1. Non-ergot anti dopamine D ₂ receptor agonist, micelles composed of hydrophobic solvent and surfactant, water - polyhydric alcohol homogeneously dispersed liquid and is weakly acidic pH 4 ~ 6 in a solvent A transdermal composition.
2. The transdermal composition according to claim 1, wherein the transdermal composition is a liquid agent exhibiting a Tyndall phenomenon.
3. Non-ergot anti dopamine D ₂ receptor agonist is ropinirole or pramipexole, transdermal composition according to claim 1 or 2.
4. The transdermal composition according to any one of claims 1 to 3, wherein the surfactant is a nonionic surfactant or lecithin.
5. The transdermal composition according to claim 4, wherein the nonionic surfactant is polysorbate 80.
6. The transdermal composition according to any one of claims 1 to 5, wherein the hydrophobic solvent is at least one of crotamiton, diethyl sebacate, medium chain fatty acid triglyceride, and liquid paraffin.
7. The transdermal composition according to any one of claims 1 to 6, wherein the polyhydric alcohol is at least one of propylene glycol and butylene bricol.
8. The transdermal composition according to any one of claims 1 to 7, wherein the pH adjuster used for setting the liquidity to pH 4 to 6 is at least one of citric acid, tartaric acid and higher fatty acids.
9. The transdermal composition according to claim 8, wherein the higher fatty acid is oleic acid.
10. Non-ergot anti dopamine D ₂ receptor agonist is contained 0.1 to 10 percent as the hydrochloride salt, transdermal composition according to claim 1.
11. The non-ergot anti-dopamine D ₂ receptor agonist hydrochloride is 1, and the molar ratio of the hydrophobic solvent is 0.4 to 2 times mol and the surfactant is 0.1 to 0.4 times mol. Item 2. The transdermal composition according to Item 1.
12. The transdermal composition according to any one of claims 1 to 11, wherein the liquid property is pH 5 ± 0.5.
13. 12. The transdermal composition according to claim 1, wherein the micelle has an average particle diameter of 20 nm to 1 μm.

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