JP6430871B2 - Method for producing transdermal administration tape containing basic drug salt - Google Patents

Description

  The present invention relates to a method for producing a stable transdermal administration tape containing a basic drug salt.

  There are many basic drug salts (basic drug salts) in pharmaceuticals, and various means for promoting transdermal absorbability of the basic drug salts have been developed. For example, a technique in which sodium acetate is contained in a transdermal preparation containing ketotifen fumarate (Patent Document 1), and a technique in which an adhesive and sodium acetate are mixed in a transdermal tape containing fentanyl or a salt thereof (Patent Document) 2) A technique (Patent Document 3) in which an organic acid salt such as sodium acetate is pulverized and blended with a basic drug salt so as to have a powder average particle diameter of 0.1 to 100 μm has been reported.

JP-A-8-157365 Japanese Patent Laid-Open No. 10-45570 Japanese Patent Laid-Open No. 11-302161

However, as described in Patent Document 2, the solubility of sodium acetate that promotes the absorption of basic drug salts in the adhesive is low. There is a problem that decreases. Patent Document 3 describes that in order to uniformly disperse such sodium acetate in the pressure-sensitive adhesive, it is necessary to grind in order to reduce the particle diameter.
Accordingly, an object of the present invention is to provide a transdermal administration tape containing a basic drug salt which does not require any special pulverization step, has excellent transdermal absorbability and has no problems such as crystal precipitation.

  Therefore, the present inventor performed sodium acetate pulverization and particle size control by adding a small amount of water when the basic drug salt is dissolved in an organic solvent and sodium acetate-containing liquid or made into an oily state. The inventors have found that a transdermal administration tape having good transdermal absorbability can be obtained without precipitation of sodium acetate or leaving large crystals even without it, and the present invention has been completed.

That is, the present invention provides the following [1] to [7].
[1] A method for producing a basic drug salt-containing transdermal administration tape comprising a step of dissolving a basic drug salt in a liquid containing water, sodium acetate and an organic solvent or converting it into an oily state. .
[2] The production method according to [1], wherein the compounding amount of sodium acetate is 2.5 to 3.5 mol per 1 mol of the basic drug salt.
[3] The production method according to [1] or [2], wherein the amount of water added is 4.5 to 18.2 mol with respect to 1 mol of sodium acetate.
[4] The production method according to any one of [1] to [3], wherein the basic drug salt is selected from fentanyl citrate, oxybutynin hydrochloride and bisoprolol fumarate.
[5] The production method according to any one of [1] to [4], wherein the adhesive base of the transdermal administration tape is a rubber adhesive or an acrylic adhesive.
[6] Any one of [1] to [5] including a step of dehydrating the basic drug salt in a solution containing water, sodium acetate and an organic solvent, or after dehydrating the solution. The manufacturing method of crab.
[7] The production method according to any one of [1] to [5], wherein the organic solvent is one or more selected from liquid paraffin, crotamiton, ethyl acetate, and toluene.

  According to the method of the present invention, the transdermal absorbability of the basic drug salt is good without requiring operations such as pulverizing sodium acetate using a pulverizer and controlling the particle diameter of the pulverized sodium acetate. In addition, a stable transdermal administration tape without precipitation of sodium acetate can be obtained.

The digital microscope image of the sodium acetate (anhydrate) used for the Example and the comparative example is shown. The state (digital microscope image) of the active ingredient solution of Example 1 is shown. The state (digital microscope image) of the active ingredient solution of Example 2 is shown. The state (digital microscope image) of the active ingredient solution of the comparative example 2 is shown. The state (digital microscope image) of the coating solution of the comparative example 4 is shown. The skin permeability test result (cumulative permeation amount) is shown.

  The method for producing a basic drug salt-containing transdermal administration tape of the present invention comprises the steps of (a) dissolving a basic drug salt in a liquid containing water, sodium acetate and an organic solvent or converting it into an oily state (process) (A)) is included.

  The basic drug salt is an active ingredient of a transdermal tape, and is not limited as long as it is a basic drug salt. Ergotamine mesylate, methamphetamine hydrochloride, methylphenidate hydrochloride, chlorpromazine hydrochloride, imipramine hydrochloride, lidocaine hydrochloride, procaine hydrochloride, oxybutynin hydrochloride, tizanidine hydrochloride, eperisone hydrochloride, pridinol mesylate, pergolide mesylate, bromocriptine mesylate, trihexyphenidyl hydrochloride , Amantadine hydrochloride, clemastine fumarate, diphenhydramine tannate, tulobuterol hydrochloride, procaterol hydrochloride, isoprenaline hydrochloride, dopamine hydrochloride, diltiazem hydrochloride Verapamil hydrochloride, nicamethate citrate, trazoline hydrochloride, flunarizine hydrochloride, nicardipine hydrochloride, benidipine hydrochloride, efonidipine hydrochloride, bisoprolol fumarate, timolol maleate, diltiazem hydrochloride, metoprolol tartrate, propranolol hydrochloride, alprenolol hydrochloride, ketotifen fumarate, azelastine hydrochloride , Betahistine mesylate, diphenidol hydrochloride, ondansetron hydrochloride, granisetron hydrochloride, ropinirole hydrochloride, chromadinone acetate, buprenorphine hydrochloride, donepezil hydrochloride, and the like. Of these, fentanyl citrate, oxybutynin hydrochloride and bisoprolol fumarate are preferred, and fentanyl citrate is particularly preferred.

  The amount of the basic drug salt used is preferably 0.5 to 8% by mass with respect to the total mass of the pressure-sensitive adhesive layer of the transdermal administration tape preparation of the present invention from the viewpoint of stable compoundability and transdermal absorbability. 8 mass% is more preferable, and 1-6 mass% is further more preferable.

  Sodium acetate promotes the percutaneous absorption of basic drug salts. As sodium acetate, anhydrous and trihydrate are generally known, but any of them may be used. In the present invention, sodium acetate is not particularly required to be pulverized or adjusted in particle size, and ordinary sodium acetate, that is, particles having a particle size exceeding 100 μm can be used.

  The amount of sodium acetate used is preferably 0.5 to 5 moles per mole of the basic drug salt from the viewpoint of enhancing the transdermal absorption of the basic drug salt and preventing skin irritation and the like. Mole is more preferable, and 2.5 to 3.5 mol is more preferable.

  The organic solvent is not particularly limited as long as the adhesive base of the tape agent and the basic drug salt are dissolved or made into an oily state. For example, hydrocarbon solvents such as liquid paraffin, toluene, hexane, and cyclohexane; Ester solvents such as ethyl acetate, butyl acetate, higher fatty acid esters, polyhydric alcohol fatty acid esters; amide solvents such as crotamiton and dimethylacetamide; cyclic ether solvents such as tetrahydrofuran; ketone solvents such as acetone and methyl ethyl ketone It is done. Of these, hydrocarbon solvents, ester solvents, amide solvents are preferred, and one or more selected from liquid paraffin, ethyl acetate, toluene, crotamiton, higher fatty acid esters and polyhydric alcohol fatty acid esters are more preferred, One or more solvents selected from liquid paraffin, crotamiton, ethyl acetate and toluene are more preferred.

  The amount of the organic solvent used in the step (a) is not particularly limited as long as the basic drug salt can be dissolved or converted into an oily state, but from the viewpoint of workability, with respect to 1 part by mass of the basic drug salt, 0.5 parts by mass or more is preferable.

The present invention is characterized in that water is used in addition to an organic solvent and ethyl acetate in a medium for dissolving a basic drug salt into an oily state. When water is not added, it is necessary to use sodium acetate that has been pulverized to adjust the particle size. On the other hand, by adding a small amount of water in step (a), it is possible to suppress the precipitation of sodium acetate and the remaining of large crystals, and it is possible to use sodium acetate that is not pulverized.
The amount of water added is not particularly limited as long as sodium acetate can be dissolved to such an extent that no trouble occurs in the coating and drying process. However, 1 mol of sodium acetate from the viewpoint of the preparation efficiency of the basic drug salt solution. The water is preferably 4.5 to 18.2 mol, more preferably 8.7 to 9.5 mol. When there is little water with respect to sodium acetate, the efficiency which melt | dissolves sodium acetate will worsen. On the other hand, if it is more, it takes a long time to dehydrate the basic drug salt solution.

  Moreover, in addition to the said component, lower alcohols, such as ethanol, can be mix | blended with the solution of a process (a) so that it may be easy to spin-dry | dehydrate by an azeotropic action in a spin-drying | dehydration process.

  In the step (a), the basic drug salt may be dissolved or oiled in a liquid composed of water, sodium acetate and an organic solvent, and the order of addition of these components is not particularly limited. In dissolution, it may be heated if necessary, and the heating temperature is preferably 60 to 100 ° C, more preferably 70 to 90 ° C. It is only necessary to confirm that all the components are dissolved or in an oily state, and the stirring time and heating time are not limited.

Next, the solution may be dehydrated as necessary (dehydration step). However, when a solution containing an organic solvent, sodium acetate and water is dehydrated without adding a basic drug salt, crystals of sodium acetate are precipitated. That is, once a solution or oily solution containing a basic drug salt, water, sodium acetate and an organic solvent is formed (via step (a)), sodium acetate is precipitated even after dehydration. Absent.
The dehydration step only needs to remove water to such an extent that a uniform coating solution can be obtained. Specifically, the water content is 0.25 parts by mass with respect to 100 parts by mass of the solid content in the coating solution. In the following, more preferably, it may be a method that can be removed to 0.2 parts by mass or less, for example, a method of heating and stirring the solution in an open state, a method of stirring while heating under reduced pressure, a warm air while stirring. Or a method of blowing a dry airflow (air, nitrogen, etc.).

  The solution obtained in the step (a) or the solution subjected to the dehydration step as necessary is mixed with the base solution to form a coating solution, and the obtained coating solution is coated and dried for transdermal administration. A tape is obtained.

  The base solution contains an adhesive base, and a tackifier, a plasticizer, an absorption accelerator, a solubilizer, an antioxidant and the like can be blended as necessary.

As the adhesive base, a rubber adhesive or an acrylic adhesive is preferable. Examples of rubber adhesives include styrene / isoprene / styrene copolymer (SIS), polyisobutylene rubber (PIB), isoprene rubber, styrene / butadiene / styrene copolymer (SBS), styrene butadiene rubber, and silicone rubber. It is done. Examples of the acrylic pressure-sensitive adhesive include alkyl acrylate esters.
0.1-98 mass% is preferable with respect to the whole adhesive layer, as for content of an adhesive base, 0.1-70 mass% is more preferable, and 0.1-50 mass% is further more preferable.

  Examples of the tackifier include rosin resins, alicyclic saturated hydrocarbon resins, aliphatic hydrocarbon resins, terpene resins, maleic resins, and the like. Plasticizers include liquid paraffin, polybutene, higher fatty acid esters (isopropyl myristate, isopropyl palmitate, diisopropyl adipate, diethyl sebacate, etc.), triacetin, triethyl citrate, squalane, squalene, vegetable oil (castor oil, jojoba oil, Olive oil, etc.). Absorption accelerators include higher alcohols (oleyl alcohol, myristyl alcohol, stearyl alcohol, etc.), higher fatty acid esters (isopropyl myristate, isopropyl palmitate, diisopropyl adipate, diethyl sebacate, etc.), polyhydric alcohol fatty acid esters, polyoxy An ethylene alkyl ether etc. are mentioned. Examples of the solubilizer include N-methylpyrrolidone, polyhydric alcohol (propylene glycol, glycerin, polyethylene glycol, butanediol, etc.), crotamiton and the like. Examples of the antioxidant include dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), sodium bisulfite, sodium sulfite, ascorbic acids and the like.

  The transdermal administration tape of the present invention preferably has a form in which a pressure-sensitive adhesive layer containing the above components has a support and a liner. The support is preferably a polyester film laminated with a nonwoven fabric such as polyester, polypropylene, polyethylene or the like. As the liner, a polyester film having a silicone-based or fluorine-based release coating is preferable.

  One or a plurality of the transdermal administration tapes of the present invention can be stored in a sealed bag.

  EXAMPLES Next, an Example is given and this invention is demonstrated further.

(I) Preparation of preparation sample Preparations of formulation A and formulation B shown in Table 1 were prepared. Formulation A was prepared by the methods of Examples 1-3 and Comparative Examples 1-3. Formulation B was prepared by the methods of Example 4 and Comparative Example 4.
However, in Comparative Examples 2 and 4, purified water was not added. Further, in Comparative Example 4, sodium acetate (anhydrous) was pulverized using a mortar.

(Ii) Base solution SIS, alicyclic saturated hydrocarbon resin, liquid paraffin, BHT and lauryl alcohol were added to ethyl acetate and dissolved by stirring to obtain base solution A.
SIS, PIB, alicyclic saturated hydrocarbon resin, liquid paraffin and BHT were added to toluene and dissolved by stirring to obtain a base solution B.

Example 1
Sodium acetate (anhydrous) (Nippon Synthetic Chemical, average particle size of 1400 μm or more) and purified water were added to liquid paraffin and stirred to dissolve sodium acetate. Next, fentanyl citrate was added and stirred at 80 ° C. for 30 minutes. Furthermore, what was stirred and dehydrated at 70 ° C. under reduced pressure was used as an active ingredient solution.
The active ingredient solution was added to the base solution A and stirred to obtain a coating solution.
Next, the coating solution was coated and dried on the silicone-treated surface of the polyester film subjected to silicone treatment, and then the support was laminated and cut into a predetermined size to obtain a preparation sample.
The coating amount of the coating solution was adjusted so that the amount of fentanyl citrate per preparation sample (40 cm ² ) was 8 mg.

Example 2
Fentanyl citrate and sodium acetate (anhydrous) were added to the liquid paraffin and stirred at 80 ° C. for 2 hours. Next, purified water was added and stirred at 80 ° C. to dissolve sodium acetate. Furthermore, what was stirred and dehydrated at 70 ° C. under reduced pressure was used as an active ingredient solution.
The obtained active ingredient solution was operated in the same manner as in Example 1 to obtain a preparation sample.

Example 3
Sodium acetate (anhydrous) and purified water were added to liquid paraffin and stirred to dissolve the sodium acetate. Next, fentanyl citrate was added and stirred at 80 ° C. for 30 minutes. Further, the mixture was stirred while blowing warm air of 80 ° C. and dehydrated to obtain an active ingredient solution.
The obtained active ingredient solution was operated in the same manner as in Example 1 to obtain a preparation sample.

Example 4
Sodium acetate (anhydrous) and purified water were added to crotamiton and stirred to dissolve sodium acetate. Next, fentanyl citrate was added and stirred at 80 ° C. for 30 minutes. Furthermore, what was stirred and dehydrated while heating on a hot plate (set temperature 110 ° C.) was used as an active ingredient solution.
The active ingredient solution was added to the base solution B and stirred to obtain a coating solution.
The obtained coating solution was operated in the same manner as in Example 1 to obtain a preparation sample.

Comparative Example 1
Sodium acetate (anhydrous) and purified water were added to liquid paraffin and stirred to dissolve sodium acetate. Next, after dehydrating by stirring at 70 ° C. under reduced pressure, fentanyl citrate was added, and the mixture stirred at 80 ° C. for 2 hours was used as an active ingredient solution.
The obtained active ingredient solution was operated in the same manner as in Example 1 to obtain a preparation sample.
In Comparative Example 1, sodium acetate was precipitated by dehydration. This precipitate did not disappear even when fentanyl citrate was added and stirred.

Comparative Example 2
Fentanyl citrate and sodium acetate (anhydrous) were added to liquid paraffin and stirred at 80 ° C. for 2 hours to obtain an active ingredient solution.
The obtained active ingredient solution was operated in the same manner as in Example 1.
In Comparative Example 2, large crystals of sodium acetate were dispersed in the coating solution, so that the coating and drying could not be performed well, and a preparation sample could not be obtained.

Comparative Example 3
Sodium acetate (anhydrous) and purified water were added to liquid paraffin and stirred to dissolve the sodium acetate. Next, fentanyl citrate was added and stirred for 30 minutes at 80 ° C. to obtain an active ingredient solution.
The obtained active ingredient solution was operated in the same manner as in Example 1.
In Comparative Example 3, when the active ingredient solution was added to the base solution and stirred, the base component was aggregated and a preparation sample could not be obtained.

Comparative Example 4
Fentanyl citrate and crushed sodium acetate (anhydrate) were added to crotamiton and stirred at 80 ° C. for 2 hours to obtain an active ingredient solution.
The obtained active ingredient solution was operated in the same manner as in Example 4 to obtain a preparation sample.

A. Evaluation of active ingredient solution The state of the active ingredient solution was visually evaluated according to the following score.

  Moreover, the states of the active ingredient solution and the coating solution were observed using a digital microscope (HIROX KH-8700 type) as necessary.

B. Skin permeability test Male hairless mice 7 weeks old abdominal excised skin is attached to a horizontal diffusion cell (Chem. Pharm. Bull. 37 (5) 1404-1406 1989), and a prescribed preparation sample is applied to the stratum corneum side. did.
On the other hand, 2.5 mL of isotonic phosphate buffer (pH 7.4) was applied as a receiving solution to the receiver side (dermis layer side).
During the test, the receiving solution was kept at 32 ° C. and stirred using a magnetic stirrer.
1 mL of the receiving solution was collected at a predetermined time and used as a sample solution. Immediately after collecting the sample solution, 1 mL of a new isotonic phosphate buffer was replenished.
Fentanyl citrate in the sample solution was quantified by high performance liquid chromatography, and the cumulative amount of fentanyl citrate permeated was determined (μg / cm ² ).

C. Evaluation of active ingredient solutions

D. Results of skin permeability test are shown in FIG.

The digital microscope image of the crystal | crystallization of the sodium acetate (anhydrate) used for the Example and the comparative example is shown in FIG. It can be seen that the crystals of sodium acetate have a particle diameter exceeding 100 μm.
In Example 1 in which water was added to dissolve sodium acetate and then fentanyl citrate was added to prepare an active ingredient solution, an active ingredient solution having almost no sodium acetate crystals was obtained (FIG. 2). The skin permeability of the preparation using this active ingredient solution was good. Similar results were obtained in Example 4.
When fentanyl citrate and sodium acetate were added to liquid paraffin according to Example 5 described in Patent Document 2, large crystals of sodium acetate in the active ingredient solution did not disappear (FIG. 4). In this state, as a result of adding to the base solution, a coating solution in which large crystals of sodium acetate were dispersed was obtained, and a preparation sample could not be successfully obtained (Comparative Example 2).
On the other hand, when purified water was added to the active ingredient solution of Comparative Example 2, large crystals of sodium acetate disappeared (FIG. 3), and a good preparation similar to Example 1 could be obtained (Example 2).
After adding water to dissolve sodium acetate and dehydrating before adding fentanyl citrate, sodium acetate precipitated. The crystals of sodium acetate did not disappear even when fentanyl citrate was added and stirred (Comparative Example 1). The skin permeability of this preparation was low.
In Comparative Example 4, although sodium acetate was pulverized, fine crystals of sodium acetate remained in the active ingredient solution. These crystals did not disappear even when the base solution was added (FIG. 5).
In Example 4 where the same formulation (solid content) as Comparative Example 4 was prepared by the method of the present invention, no crystals were observed in the active ingredient solution even when sodium crushed sodium acetate was used, and the coating solution It was the same among them.
The production method of the present invention, in which water is added to dissolve the crystals of sodium acetate, can provide a coating solution having no crystals compared to the prior art. This technique is particularly useful in the production of a patch having a small coating amount per unit area of the coating solution, that is, having a small coating clearance.

Claims (5)

A step of dissolving a basic drug salt in a liquid containing water, sodium acetate and an organic solvent or making it into an oily substance , and then dehydrating the liquid, wherein the amount of water added is 1 mol of sodium acetate. The method for producing a tape for transdermal administration containing a basic drug salt, wherein the amount is 4.5 to 18.2 mol .   The production method according to claim 1, wherein the blending amount of sodium acetate is 2.5 to 3.5 mol per 1 mol of the basic drug salt. The production method according to claim 1 or 2 , wherein the basic drug salt is selected from fentanyl citrate, oxybutynin hydrochloride and bisoprolol fumarate. The production method according to any one of claims 1 to 3 , wherein the adhesive base of the transdermal administration tape is a rubber adhesive or an acrylic adhesive. The organic solvent is, liquid paraffin, crotamiton, one or two or more at which claim 1 method of any one of claims 4 selected from ethyl acetate and toluene.